The present invention relates generally to antibody formulations. Specifically, the present invention relates to monoclonal antibody formulations with improved stability and low viscosity.

BACKGROUND

Antibody formulations can lose their efficacy over time due, for example, to the effects of denaturation, oxidation, aggregation, or other degradation reactions.

Degradation and aggregation of antibodies in an antibody formulation can also pose risks such as toxicity or immunogenicity. High solution viscosity can negatively impact the manufacturability and performance of protein therapeutic agents, especially those formulated at high protein concentrations.

The low level of stability exhibited by currently available pharmaceutical antibody formulations is disadvantageous due to, for example, loss of efficacy of the antibody formulation before administration and possible toxicity and immunogenicity due to the degradation/aggregation. Traditional excipients used to stabilize proteins in solution can often increase the viscosity of the solution. Therefore, there is a need in the art for an antibody formulation that will allow for improved stability of antibodies. Additionally, there is a need in the art of antibody formulation that will allow for the development of stable and low-viscosity antibody solutions.

SUMMARY

The present invention is based on the discovery that antibodies can be stabilized in solution by including a salt selected from the group of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate. The resulting stabilized antibody solutions are also less viscous compared to formulations which do not include one of these salts or that contain traditional excipients, for example sugars like sucrose, used to stabilize proteins. The osmolality of stabilized antibody solutions with one of these salts is also less than that with sugars and polyols such as sucrose, trehalose, sorbitol, mannitol etc. when formulated at equipotent concentrations.

In view of this discovery, provided herein are aqueous antibody formulations that include about 0.1 mg/mL to about 500 mg/mL of 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); about 1 mM to about 100 mM of a buffer (e.g., any of the exemplary buffers described herein or known in the art); and about 1 mM to 750 mM of a salt selected from the group consisting of: magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, where the formulations have a pH of about 4 to about 8.

Also provided are an aqueous antibody formulations that include about 0.1 mg/mL to about 500 mg/mL of 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); and about 1 mM to 750 mM of a salt selected from the group of: magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, where the formulations have a pH of about 4 to about 8. In some embodiments of the aqueous antibody formulations, the aqueous antibody formulation is a buffer-free aqueous antibody formulation.

Some embodiments of any of the aqueous antibody formulations described herein can 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). Also provided are injection devices that include any of these formulations, and kits including one or more vials containing any of these formulations.

Also provided are methods of making an aqueous antibody formulation that include 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 (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, where (i) to (vi) are mixed or combined in amounts sufficient to generate any of the formulations described herein.

Also provided herein are methods of making an aqueous antibody formulation that include 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); and (ii) a salt selected from the group of: magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, (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) to (v) are mixed or combined in amounts sufficient to generate any of the formulations described herein. In some embodiments of these methods, the method does not include mixing or combining a buffer with (i) and (ii), and the method results in a buffer-free aqueous antibody formulation.

Also provided are methods of treating a subject in need thereof that include administering to the subject a therapeutically effective amount of any of the formulations described herein.

Provided herein are aqueous antibody formulations that include: 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; 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, 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 formulation has a pH of about 4 to about 8 and optionally, an osmolality of about 250 mOsm/kg to about 1500 mOsm/kg.

Also provided herein are aqueous antibody formulations that include: about 0.1 mg/mL to about 500 mg/mL of an antibody or an antigen-binding fragment thereof; and about 1 mM to about 750 mM of a salt selected from the group of: magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, where the formulation has 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.

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 includes about 10 mM to about 750 mM of the salt. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 20 mM to about 750 mM of the salt.

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 includes about 10 mM to about 750 mM of the salt. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 20 mM to about 750 mM of the salt.

In some embodiments of any of the aqueous antibody formulations described herein, the salt is lithium acetate, lithium aspartate, lithium glutamate, or lithium sulfate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is lithium acetate. In some embodiments of any of the aqueous antibody

formulations described herein, the salt is lithium aspartate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is lithium glutamate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is lithium sulfate. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 10 mM to about 750 mM of the salt. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 20 mM to about 750 mM of the salt.

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 includes

about 1 mM to about 100 mM of the buffer. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 1 mM to about 75 mM of the buffer. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 1 mM to about 50 mM of the buffer. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 1 mM to about 20 mM of the buffer.

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.

In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes 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 has an Fc amino acid substitution that decreases its conformational stability as compared to a similar antibody not including the Fc amino acid substitution. In some embodiments of any of the aqueous antibody formulations described herein, the mAb is an IgGl or an IgG4 antibody.

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 includes a heavy chain including SEQ ID NO: 1 and a light chain including SEQ ID NO: 2.

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

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.

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)-Fc engineered monoclonal antibody. In some embodiments of any of the aqueous antibody formulations described herein, the anti-CEACAM5-Fc engineered 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 anti-CEACAM5-Fc engineered 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 anti-CEACAM5-Fc engineered monoclonal antibody comprises a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO: 14.

In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 0.1 mg/mL to 400 mg/mL of the antibody or the antigen-binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 0.1 mg/mL to 250 mg/mL of the antibody or the antigen-binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 0.1 mg/mL to about 200 mg/mL of the antibody or the antigen-binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 0.1 mg/mL to about 150 mg/mL of the antibody or the antigen-binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 0.1 mg/mL to about 100 mg/mL of the antibody or the antigen-binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the

formulation includes about 0.1 mg/mL to about 50 mg/mL of the antibody or the antigen binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the formulation includes about 0.1 mg/mL to about 25 mg/mL of the antibody or the antigen-binding antibody fragment.

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.

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

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

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.

Some embodiments of any of the aqueous antibody formulations described herein further includes one or more of a stabilizer, an anti-oxidant, 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, a maltodextrin, a dextran, starch, mannitol, xylitol, maltitol, lactitol, glucitol, sucrose, trehalose, raffinose, maltose, sorbitol, mannitol, an amino sugar, sodium chloride, and glycerol.

In some embodiments of any of the aqueous antibody formulations described herein, the antioxidant is methionine, ascorbic acid, or N-acetyl cysteine. In some embodiments of any of the aqueous antibody formulations described herein, the metal chelator is sodium ethylenediaminetetraacetic acid (EDTA), calcium EDTA, or diethylenetriamine pentaacetate (DTP A). In some embodiments of any of the aqueous antibody formulations described herein, the viscosity modifier is arginine, histidine, lysine, proline, glycine, or sodium chloride.

In some embodiments of any of the aqueous antibody formulations described herein, the surfactant is selected from the group of: sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan trioleate, glycerine monocaprylate, glycerine monomyristate, glycerine monostearate, decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate, polyoxyethylene sorbitan monolaurate, polyoxythylene sorbitan monocleate, polyoxyethylene sorbitan

monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethyene 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, polyoxythylene 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, a glycerophosopholipid, a sphingophospholipid, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer 188, triton-X, sodium lauryl sulfate, polyethylene glycol, and propylene glycol.

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

Also provided herein are injection devices including any of the aqueous antibody formulations described herein.

Also provided herein are kits including one or more vials containing any of the aqueous antibody formulations described herein. In some embodiments of any of the kits described herein, the kit further includes an injection device for administration of the aqueous antibody formulation to a subject in need thereof.

Provided herein are methods of making an aqueous antibody formulation that include mixing or combining: (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) to (vi) are mixed or combined in amounts sufficient to generate any of the aqueous antibody formulations described herein.

Also provided herein are methods of making an aqueous antibody formulation that include mixing or combining: (i) an antibody or an antigen-binding fragment thereof; and (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) to (v) are mixed or combined in amounts sufficient to generate any of the aqueous antibody formulations described herein. In some embodiments of any of the aqueous antibody formulations described herein, the method does not include mixing a buffer with (i) to (v) and the method results in the generation of a buffer-free aqueous antibody formulation.

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

Also provided herein are methods of treating a subject in need thereof, the method includes administering to the subject a therapeutically effective amount of any of the aqueous antibody formulations described herein.

The term“stabilizer” refers to an additional agent (e.g., not including any of the salts of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate) that improves or otherwise enhances 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. Additional examples of stabilizers are known in the art. The term“surfactant” generally includes an agent that protects a protein (e.g., an antibody or an antigen-binding antibody fragment) from air/solution interface-induced stress and/or solution/surface induced-stress. In some embodiments, a surfactant may protect a protein (e.g., an antibody or an antigen-binding antibody

fragment) from aggregation. Non-limiting examples of surfactants are described herein. Additional examples of surfactants are known in the art.

The term“subject” refers to any mammal. In some embodiments, the subject or “subject in need of treatment” can be a canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), ovine, bovine, porcine, caprine, primate, e.g., a simian (e.g., a monkey (e.g., a marmoset, baboon), or an ape (e.g., a gorilla, chimpanzee, orangutan, or gibbon), a human; or a rodent (e.g., a mouse, a guinea pig, a hamster, or a rat). In some embodiments, the subject or“subject suitable for treatment” may be a non-human mammal, especially mammals that are conventionally used as models for demonstrating therapeutic efficacy in humans (e.g., murine, lapine, porcine, canine or primate animals) may be employed.

As used herein,“treating” means a reduction in the number, severity, or frequency of one or more symptoms of a medical disease or condition in a subject (e.g., any of the exemplary subjects described herein).

As used herein,“buffer-free” means no or trace amount of a buffer (e.g., any of the buffers described herein).

Unless otherwise defined, 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; other, suitable methods and materials known in the art can 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 by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

DESCRIPTION OF DRAWINGS

Figure 1 is a graph showing the lowest unfolding temperature (Tmi) for antibody A (1 mg/mL) in histidine-buffered solutions (pH 5.5) containing labeled excipients at 200 mM concentration.

Figure 2 is a graph showing kagg for 150 mg/mL antibody A following storage at 40 °C vs. increase in Tmi (ATmi) in histidine-buffered solutions (pH 5.5) containing labeled excipients at 200 mM concentration. Solution with no added excipient is labeled Control.

Figure 3 is a graph showing ATmi for antibody B (1 mg/mL) in histidine-buffered solutions (pH 6.2) containing labeled excipients at 200 mM concentration.

Figure 4 is a graph showing rates of aggregation (kagg) for 50 mg/mL antibody B following storage at 40 °C vs. ATmi in histidine-buffered solutions (pH 6.2) containing labeled excipients at 200 mM concentration. Solution with no added excipient is labeled Control.

Figure 5 is a graph showing the effect of excipient concentration on Tmi for antibody A in solution (1 mg/mL) in histidine-buffered solutions (pH 5.5) containing labeled excipients.

Figure 6 is a graph showing the percent aggregate for 150 mg/mL antibody A following storage at 40 °C for 4 weeks in histidine-buffered solutions (pH 5.5) containing labeled excipients.

Figure 7 is a graph showing the effect of excipient concentration on Tmi for antibody C (1 mg/mL) in histidine-buffered solutions (pH 6.2) containing labeled excipients.

Figure 8 is a graph showing increase in Tmi for wild-type anti-CEACAM5 antibody and its antibody D, antibody E, and antibody DE mutants (1 mg/mL) in histidine-buffered (pH 5.5) solutions with labeled salts at 200 mM compared to the respective salt-free solutions.

Figure 9 is a graph showing the viscosity of -150 mg/mL antibody C solutions at 20 °C in histidine-buffered solutions (pH 6.2) containing labeled excipients at 200 mM concentration. Solution with no added excipient is labeled Control.

Figure 10 is a graph showing the viscosity of -150 mg/mL antibody A solutions at 20 °C vs. ATmi in histidine-buffered solutions (pH 5.5) containing labeled excipients at 200 mM concentration or sucrose between 2% and 30% (2% sucrose, 5% sucrose, 10% sucrose, 15% sucrose and 30% sucrose). Solution with no added excipient is labeled Control.

Figure 11 is a graph showing the osmolality of -150 mg/mL antibody A solutions at 20 °C vs. DTmI in histidine-buffered solutions (pH 5.5) containing labeled excipients at 200 mM concentration or sucrose between 2% and 30% (2% sucrose, 5% sucrose, 10% sucrose, 15% sucrose and 30% sucrose).

DETAILED DESCRIPTION

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. There is an ever-increasing reliance on these complex molecules in various therapeutic areas including but not limited to oncology, immunology, immuno-oncology, cardiology with nearly 100 molecules approved for therapeutic use to date and more than 500 at various stages of development or clinical trials.

A fundamental aspect for ensuring the transition of these therapeutic entities from the lab into manufacturable and marketable products of high and consistent quality is their stability in the dosage form. Owing to their complex chemistry and structure, proteins are susceptible to various forms of physical and chemical degradation that can compromise the biological efficacy and safety of the final drug product. Protein aggregation for example is a key quality attribute that is routinely monitored for protein-based products and is critical to the determination of product shelf life. At a fundamental level, protein aggregation is linked to the stability of the native form of the protein, with a growth in non-native cell (e.g., a non-native mammalian cell) generally linked to an increased rate and extent of aggregation. Thus, it is no surprise that attempts to control and minimize aggregation during product shelf life (kinetic stability) are often mediated through the use of excipients or formulation conditions intended to increase

conformational stability of the protein. Essentially, the intent is to stabilize the protein in its native conformation in order to minimize the population of aggregation-competent “non-native” species. Sugars and polyols, such as sucrose, trehalose, mannitol, sorbitol etc. are often used to stabilize proteins in their native state and reduce rates of aggregation. However an unwanted effect of using these stabilizers is the concentration-dependent increase in solution viscosity.

Solution viscosity is a key attribute of protein products especially those that are formulated at high protein concentrations (for example ³100 mg/mL for an antibody or Fc-derived proteins of similar molecular weight) and it can critically impact the utility and success of the product. The manufacturability of a product and the end use by the patient or healthcare practitioner is intimately linked to the ability of a solution to flow seamlessly. High viscosity, for example, can necessitate the use of specialized administration devices or protocols which may not always be suitable for the desired population thereby limiting the use of the product. In other instances, high solution viscosity may require the application of manufacturing technologies which may negatively impact the stability of the protein (for example high-temperature processing). It is thus not unusual to employ viscosity-reducing excipients, such as salts and amino acids, in high protein concentration solutions. However, these excipients can negatively impact the stability of the protein thereby resulting in solutions with an increased aggregation rate compared to high- viscosity control solutions lacking the viscosity-reducing agent. In essence, commonly employed stabilizers and the viscosity-reducing excipients can have an opposite effect on product performance thereby complicating its development.

Another critical attribute for injectable products (most protein-based products) that needs to be considered is its osmolality. While intravenous solutions generally need to be isotonic, it is not unusual for subcutaneous solutions to be hypertonic. In fact, there is evidence in literature of hypertonic formulations resulting in enhanced protein bioavailability following subcutaneous administration (Fathallah, A.M. et al, Biopharm Drug Dispos. 2015 Mar; 36(2): 115-25). Thus, the impact of solution osmolality (and thus tonicity) on injection site discomfort and/or reaction as well as bioavailability in the patient population needs to be carefully monitored and characterized during clinical development phases.

Thus, there is a need in the art of formulating antibody and other Fc-derived products for developing stable, low-viscosity solution formulations with well characterized osmotic properties.

Provided herein are aqueous antibody formulations that include about 0.1 mg/mL to about 500 mg/mL of 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); about 1 mM to about 100 mM of a buffer (e.g., any of the exemplary buffers described herein or known in the art); and about 1 mM to 750 mM of a salt selected from the group consisting of: magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, where the formulations have a pH of about 4 to about 8.

Also provided herein are aqueous antibody formulations include about 0.1 mg/mL to about 500 mg/mL (e.g., any of the subranges of this range described herein) of an antibody or an antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding fragments described herein or known in the art); and about 1 mM to 750 mM (e.g., any of the subranges of this range described herein) of a salt selected from the group of: magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, where the formulations have a pH of about 4 to about 8.

In some embodiments, the aqueous antibody formulation is a buffer-free aqueous antibody formulation.

Also provided are injection devices that include any of these formulations, and kits including one or more vials containing any of these formulations.

Also provided are methods of making an aqueous antibody formulation that include 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, where (i) to (vi) are mixed or combined in amounts sufficient to generate any of the formulations described herein.

Also provided herein are methods of making an aqueous antibody formulations that include mixing or combining: (i) an antibody or an antigen-binding fragment thereof; and (ii) a salt selected from the group of: magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate; (iii) a stabilizer); (iv) a surfactant); and (v) sterile water, wherein (i) to (v) are mixed or combined in amounts sufficient to generate 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) to (v) and the method results in a buffer- free aqueous antibody formulation.

Also provided are methods of treating a subject in need thereof that include administering to the subject a therapeutically effective amount of any of the formulations described herein.

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

Antibodies and Antigen-Binding Antibody Fragments

The aqueous antibody formulations provided herein can include, e.g., about 0.1 mg/mL to about 500 mg/mL, about 0.1 mg/mL to about 480 mg/mL, about 0.1 mg/mL to about 460 mg/mL, about 0.1 mg/mL to about 440 mg/mL, about 0.1 mg/mL to about 420 mg/mL, about 0.1 mg/mL to about 400 mg/mL, about 0.1 mg/mL to about 380 mg/mL, about 0.1 mg/mL to about 360 mg/mL, about 0.1 mg/mL to about 340 mg/mL, about 0.1 mg/mL to about 320 mg/mL, about 0.1 mg/mL to about 300 mg/mL, about 0.1 mg/mL to about 280 mg/mL, about 0.1 mg/mL to about 260 mg/mL, about 0.1 mg/mL to about 240

mg/mL, about 0.1 mg/mL to about 220 mg/mL, about 0.1 mg/mL to about 200 mg/mL, about 0.1 mg/mL to about 190 mg/mL, about 0.1 mg/mL to about 180 mg/mL, about 0.1 mg/mL to about 170 mg/mL, about 0.1 mg/mL to about 160 mg/mL, about 0.1 mg/mL to about 140 mg/mL, about 0.1 mg/mL to about 130 mg/mL, about 0.1 mg/mL to about 120 mg/mL, about 0.1 mg/mL to about 110 mg/mL, about 0.1 mg/mL to about 100 mg/mL, about 0.1 mg/mL to about 90 mg/mL, about 0.1 mg/mL to about 80 mg/mL, about 0.1 mg/mL to about 70 mg/mL, about 0.1 mg/mL to about 60 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 25 mg/mL, about 0.1 mg/mL to about 20 mg/mL, about 0.1 mg/mL to about 15 mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.1 mg/mL to about 5 mg/mL, about 0.1 mg/mL to about 2.5 mg/mL, about 0.1 mg/mL to about 1.0 mg/mL, 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 about 320 mg/mL, about 1.0 mg/mL to about 300 mg/mL, about 1.0 mg/mL to about 280 mg/mL, about 1.0 mg/mL to about 260 mg/mL, about 1.0 mg/mL to about 240 mg/mL, about 1.0 mg/mL to about 220 mg/mL, about 1.0 mg/mL to about 200 mg/mL, about 1.0 mg/mL to about 190 mg/mL, about 1.0 mg/mL to about 180 mg/mL, about 1.0 mg/mL to about 170 mg/mL, about 1.0 mg/mL to about 160 mg/mL, about 1.0 mg/mL to about 140 mg/mL, about 1.0 mg/mL to about 130 mg/mL, about 1.0 mg/mL to about 120 mg/mL, about 1.0 mg/mL to about 110 mg/mL, about 1.0 mg/mL to about 100 mg/mL, about 1.0 mg/mL to about 90 mg/mL, about 1.0 mg/mL to about 80 mg/mL, about 1.0 mg/mL to about 70 mg/mL, about 1.0 mg/mL to about 60 mg/mL, about 1.0 mg/mL to about 50 mg/mL, about 1.0 mg/mL to about 45 mg/mL, about 1.0 mg/mL to about 40 mg/mL, about 1.0 mg/mL to about 35 mg/mL, about 1.0 mg/mL to about 30 mg/mL, about 1.0 mg/mL to about 25 mg/mL, about 1.0 mg/mL to about 20 mg/mL, about 1.0 mg/mL to about 15 mg/mL, about 1.0 mg/mL to about 10 mg/mL, about 1.0 mg/mL to about 5 mg/mL, about 1.0 mg/mL to about 2.5 mg/mL, about 2.5 mg/mL to about 500 mg/mL, about 2.5 mg/mL to about 480 mg/mL, about 2.5 mg/mL to about 460 mg/mL, about 2.5 mg/mL to about 440 mg/mL, about 2.5 mg/mL to about 420 mg/mL, about 2.5 mg/mL to about 400 mg/mL, about 2.5 mg/mL to about 380 mg/mL, about 2.5 mg/mL to about 360 mg/mL, about 2.5 mg/mL to about 340 mg/mL, about 2.5 mg/mL to about 320 mg/mL, about 2.5 mg/mL to about 300 mg/mL, about 2.5 mg/mL to about 280 mg/mL, about 2.5 mg/mL to about 260 mg/mL, about 2.5 mg/mL to about 240 mg/mL, about 2.5 mg/mL to about 220 mg/mL, about 2.5 mg/mL to about 200 mg/mL, about 2.5 mg/mL to about 190 mg/mL, about 2.5 mg/mL to about 180 mg/mL, about 2.5 mg/mL to about 170 mg/mL, about 2.5 mg/mL to about 160 mg/mL, about 2.5 mg/mL to about 140 mg/mL, about 2.5 mg/mL to about 130 mg/mL, about 2.5 mg/mL to about 120 mg/mL, about 2.5 mg/mL to about 110 mg/mL, about 2.5 mg/mL to about 100 mg/mL, about 2.5 mg/mL to about 90 mg/mL, about 2.5 mg/mL to about 80 mg/mL, about 2.5 mg/mL to about 70 mg/mL, about 2.5 mg/mL to about 60 mg/mL, about 2.5 mg/mL to about 50 mg/mL, about 2.5 mg/mL to about 45 mg/mL, about 2.5 mg/mL to about 40 mg/mL, about 2.5 mg/mL to about 35 mg/mL, about 2.5 mg/mL to about 30 mg/mL, about 2.5 mg/mL to about 25 mg/mL, about 2.5 mg/mL to about 20 mg/mL, about 2.5 mg/mL to about 15 mg/mL, about 2.5 mg/mL to about 10 mg/mL, about 2.5 mg/mL to about 5 mg/mL, about 5 mg/mL to about 500 mg/mL, about 5 mg/mL to about 480 mg/mL, about 5 mg/mL to about 460 mg/mL, about 5 mg/mL to about 440 mg/mL, about 5 mg/mL to about 420 mg/mL, about 5 mg/mL to about 400 mg/mL, about 5 mg/mL to about 380 mg/mL, about 5 mg/mL to about 360 mg/mL, about 5 mg/mL to about 340 mg/mL, about 5 mg/mL to about 320 mg/mL, about 5 mg/mL to about 300 mg/mL, about 5 mg/mL to about 280 mg/mL, about 5 mg/mL to about 260 mg/mL, about 5 mg/mL to about 240 mg/mL, about 5 mg/mL to about 220 mg/mL, about 5 mg/mL to about 200 mg/mL, about 5 mg/mL to about 190 mg/mL, about 5 mg/mL to about 180 mg/mL, about 5 mg/mL to about 170 mg/mL, about 5 mg/mL to about 160 mg/mL, about 5 mg/mL to about 140 mg/mL, about 5 mg/mL to about 130 mg/mL, about 5 mg/mL to about 120 mg/mL, about 5 mg/mL to about 110 mg/mL, about 5 mg/mL to about 100 mg/mL, about 5 mg/mL to about 90 mg/mL, about 5 mg/mL to about 80 mg/mL, about 5 mg/mL to about 70 mg/mL, about 5 mg/mL to about 60 mg/mL, about 5 mg/mL to about 50 mg/mL, about 5 mg/mL to about 45 mg/mL, about 5 mg/mL to about 40 mg/mL, about 5 mg/mL to about 35 mg/mL, about 5 mg/mL to about 30 mg/mL, about 5 mg/mL to about 25 mg/mL, about 5 mg/mL to about 20 mg/mL, about 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 mg/mL, about 15 mg/mL to about 240 mg/mL, about 15 mg/mL to about 220 mg/mL, about 15 mg/mL to about 200 mg/mL, about 15 mg/mL to about 190 mg/mL, about 15 mg/mL to about 180 mg/mL, about 15 mg/mL to about 170 mg/mL, about 15 mg/mL to about 160 mg/mL, about 15 mg/mL to about 140 mg/mL, about 15 mg/mL to about 130 mg/mL, about 15 mg/mL to about 120 mg/mL, about 15 mg/mL to about 110 mg/mL, about 15 mg/mL to about 100 mg/mL, about 15 mg/mL to about 90 mg/mL, about 15 mg/mL to about 80 mg/mL, about 15 mg/mL to about 70 mg/mL, about 15 mg/mL to about 60 mg/mL, about 15 mg/mL to about 50 mg/mL, about 15 mg/mL to about 45 mg/mL, about 15 mg/mL to about 40 mg/mL, about 15 mg/mL to about 35 mg/mL, about 15 mg/mL to about 30 mg/mL, about 15 mg/mL to about 25 mg/mL, about 15 mg/mL to about 20 mg/mL, about 20 mg/mL to about 500 mg/mL, about 20 mg/mL to about 480 mg/mL, about 20 mg/mL to about 460 mg/mL, about 20 mg/mL to about 440 mg/mL, about 20 mg/mL to about 420 mg/mL, about 20 mg/mL to about 400 mg/mL, 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 220 mg/mL, about 30 mg/mL to about 200 mg/mL, about 30 mg/mL to about 190 mg/mL, about 30 mg/mL to about 180 mg/mL, about 30 mg/mL to about 170 mg/mL, about 30 mg/mL to about 160 mg/mL, about 30 mg/mL to about 140 mg/mL, about 30 mg/mL to about 130 mg/mL, about 30 mg/mL to about 120 mg/mL, about 30 mg/mL to about 110 mg/mL, about 30 mg/mL to about 100 mg/mL, about 30 mg/mL to about 90 mg/mL, about 30 mg/mL to about 80 mg/mL, about 30 mg/mL to about 70 mg/mL, about 30 mg/mL to about 60 mg/mL, about 30 mg/mL to about 50 mg/mL, about 30 mg/mL to about 45 mg/mL, about 30 mg/mL to about 40 mg/mL, about 30 mg/mL to about 35 mg/mL, about 35 mg/mL to about 500 mg/mL, about 35 mg/mL to about 480 mg/mL, about 35 mg/mL to about 460 mg/mL, about 35 mg/mL to about 440 mg/mL, about 35 mg/mL to about 420 mg/mL, about 35 mg/mL to about 400 mg/mL, about 35 mg/mL to about 380 mg/mL, about 35 mg/mL to about 360 mg/mL, about 35 mg/mL to about 340 mg/mL, about 35 mg/mL to about 320 mg/mL, 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, about 40 mg/mL to about 440 mg/mL, about 40 mg/mL to about 420 mg/mL, about 40 mg/mL to about 400 mg/mL, about 40 mg/mL to about 380 mg/mL, about 40 mg/mL to about 360 mg/mL, about 40 mg/mL to about 340 mg/mL, about 40 mg/mL to about 320 mg/mL, about 40 mg/mL to about 300 mg/mL, about 40 mg/mL to about 280 mg/mL, about 40 mg/mL to about 260 mg/mL, about 40 mg/mL to about 240 mg/mL, about 40 mg/mL to about 220 mg/mL, about 40 mg/mL to about 200 mg/mL, about 40 mg/mL to about 190 mg/mL, about 40 mg/mL to about 180 mg/mL, about 40 mg/mL to about 170 mg/mL, about 40 mg/mL to about 160 mg/mL, about 40 mg/mL to about 140 mg/mL, about 40 mg/mL to about 130 mg/mL, about 40 mg/mL to about 120 mg/mL, about 40 mg/mL to about 110 mg/mL, about 40 mg/mL to about 100 mg/mL, about 40 mg/mL to about 90 mg/mL, about 40 mg/mL to about 80 mg/mL, about 40 mg/mL to about 70 mg/mL, about 40 mg/mL to about 60 mg/mL, about 40 mg/mL to about 50 mg/mL, about 40 mg/mL to about 45 mg/mL, about 45 mg/mL to about 500 mg/mL, about 45 mg/mL to about 480 mg/mL, about 45 mg/mL to about 460 mg/mL, about 45 mg/mL to about 440 mg/mL, about 45 mg/mL to about 420 mg/mL, about 45 mg/mL to about 400 mg/mL, about 45 mg/mL to about 380 mg/mL, about 45 mg/mL to about 360 mg/mL, about 45 mg/mL to about 340 mg/mL, about 45 mg/mL to about 320 mg/mL, about 45 mg/mL to about 300 mg/mL, about 45 mg/mL to about 280 mg/mL, about 45 mg/mL to about 260 mg/mL, about 45 mg/mL to about 240 mg/mL, about 45 mg/mL to about 220 mg/mL, about 45 mg/mL to about 200 mg/mL, about 45 mg/mL to about 190 mg/mL, about 45 mg/mL to about 180 mg/mL, about 45 mg/mL to about 170 mg/mL, about 45 mg/mL to about 160 mg/mL, about 45 mg/mL to about 140 mg/mL, about 45 mg/mL to about 130 mg/mL, about 45 mg/mL to about 120 mg/mL, about 45 mg/mL to about 110 mg/mL, about 45 mg/mL to about 100 mg/mL, about 45 mg/mL to about 90 mg/mL, about 45 mg/mL to about 80 mg/mL, about 45 mg/mL to about 70 mg/mL, about 45 mg/mL to about 60 mg/mL, about 45 mg/mL to about 50 mg/mL, about 50 mg/mL to about 500 mg/mL, about 50 mg/mL to about 480 mg/mL, about 50 mg/mL to about 460 mg/mL, about 50 mg/mL to about 440 mg/mL, about 50 mg/mL to about 420 mg/mL, about 50 mg/mL to about 400 mg/mL, about 50 mg/mL to about 380 mg/mL, about 50 mg/mL to about 360 mg/mL, about 50 mg/mL to about 340 mg/mL, about 50 mg/mL to about 320 mg/mL, about 50 mg/mL to about 300 mg/mL, about 50 mg/mL to about 280 mg/mL, about 50 mg/mL to about 260 mg/mL, about 50 mg/mL to about 240 mg/mL, about 50 mg/mL to about 220 mg/mL, about 50 mg/mL to about 200 mg/mL, about 50 mg/mL to about 190 mg/mL, about 50 mg/mL to about 180 mg/mL, about 50 mg/mL to about 170 mg/mL, about 50 mg/mL to about 160 mg/mL, about 50 mg/mL to about 140 mg/mL, about 50 mg/mL to about 130 mg/mL, about 50 mg/mL to about 120 mg/mL, about 50 mg/mL to about 110 mg/mL, about 50 mg/mL to about 100 mg/mL, about 50 mg/mL to about 90 mg/mL, about 50 mg/mL to about 80 mg/mL, about 50 mg/mL to about 70 mg/mL, about 50 mg/mL to about 60 mg/mL, about 60 mg/mL to about 500 mg/mL, about 60 mg/mL to about 480 mg/mL, about 60 mg/mL to about 460 mg/mL, about 60 mg/mL to about 440 mg/mL, about 60 mg/mL to about 420 mg/mL, about 60 mg/mL to about 400 mg/mL, about 60 mg/mL to about 380 mg/mL, about 60 mg/mL to about 360 mg/mL, about 60 mg/mL to about 340 mg/mL, about 60 mg/mL to about 320 mg/mL, about 60 mg/mL to about 300 mg/mL, about 60 mg/mL to about 280 mg/mL, about 60 mg/mL to about 260 mg/mL, about 60 mg/mL to about 240 mg/mL, about 60 mg/mL to about 220 mg/mL, about 60 mg/mL to about 200 mg/mL, about 60 mg/mL to about 190 mg/mL, about 60 mg/mL to about 180 mg/mL, about 60 mg/mL to about 170 mg/mL, about 60 mg/mL to about 160 mg/mL, about 60 mg/mL to about 140 mg/mL, about 60 mg/mL to about 130 mg/mL, about 60 mg/mL to about 120 mg/mL, about 60 mg/mL to about 110 mg/mL, about 60 mg/mL to about 100 mg/mL, about 60 mg/mL to about 90 mg/mL, about 60 mg/mL to about 80 mg/mL, about 60 mg/mL to about 70 mg/mL, about 70 mg/mL to about 500 mg/mL, about 70 mg/mL to about 480 mg/mL, about 70 mg/mL to about 460 mg/mL, about 70 mg/mL to about 440 mg/mL, about 70 mg/mL to about 420 mg/mL, about 70 mg/mL to about 400 mg/mL, about 70 mg/mL to about 380 mg/mL, about 70 mg/mL to about 360 mg/mL, about 70 mg/mL to about 340 mg/mL, about 70 mg/mL to about 320 mg/mL, about 70 mg/mL to about 300 mg/mL, about 70 mg/mL to about 280 mg/mL, about 70 mg/mL to about 260 mg/mL, about 70 mg/mL to about 240 mg/mL, about 70 mg/mL to about 220 mg/mL, about 70 mg/mL to about 200 mg/mL, about 70 mg/mL to about 190 mg/mL, about 70 mg/mL to about 180 mg/mL, about 70 mg/mL to about 170 mg/mL, about 70 mg/mL to about 160 mg/mL, about 70 mg/mL to about 140 mg/mL, about 70 mg/mL to about 130 mg/mL, about 70 mg/mL to about 120 mg/mL, about 70 mg/mL to about 110 mg/mL, about 70 mg/mL to about 100 mg/mL, about 70 mg/mL to about 90 mg/mL, about 70 mg/mL to about 80 mg/mL, about 80 mg/mL to about 500 mg/mL, about 80 mg/mL to about 480 mg/mL, about 80 mg/mL to about 460 mg/mL, about 80 mg/mL to about 440 mg/mL, about 80 mg/mL to about 420 mg/mL, about 80 mg/mL to about 400 mg/mL, about 80 mg/mL to about 380 mg/mL, about 80 mg/mL to about 360 mg/mL, about 80 mg/mL to about 340 mg/mL, about 80 mg/mL to about 320 mg/mL, about 80 mg/mL to about 300 mg/mL, about 80 mg/mL to about 280 mg/mL, about 80 mg/mL to about 260 mg/mL, about 80 mg/mL to about 240 mg/mL, about 80 mg/mL to about 220 mg/mL, about 80 mg/mL to about 200 mg/mL, about 80 mg/mL to about 190 mg/mL, about 80 mg/mL to about 180 mg/mL, about 80 mg/mL to about 170 mg/mL, about 80 mg/mL to about 160 mg/mL, about 80 mg/mL to about 140 mg/mL, about 80 mg/mL to about 130 mg/mL, about 80 mg/mL to about 120 mg/mL, about 80 mg/mL to about 110 mg/mL, about 80 mg/mL to about 100 mg/mL, about 80 mg/mL to about 90 mg/mL about 90 mg/mL to about 500 mg/mL, about 90 mg/mL to about 480 mg/mL, about 90 mg/mL to about 460 mg/mL, about 90 mg/mL to about 440 mg/mL, about 90 mg/mL to about 420 mg/mL, about 90 mg/mL to about 400 mg/mL, about 90 mg/mL to about 380 mg/mL, about 90 mg/mL to about 360 mg/mL, about 90 mg/mL to about 340 mg/mL, about 90 mg/mL to about 320 mg/mL, about 90 mg/mL to about 300 mg/mL, about 90 mg/mL to about 280 mg/mL, about 90 mg/mL to about 260 mg/mL, about 90 mg/mL to about 240 mg/mL, about 90 mg/mL to about 220 mg/mL, about 90 mg/mL to about 200 mg/mL, about 90 mg/mL to about 190 mg/mL, about 90 mg/mL to about 180 mg/mL, about 90 mg/mL to about 170 mg/mL, about 90 mg/mL to about 160 mg/mL, about 90 mg/mL to about 140 mg/mL, about 90 mg/mL to about 130 mg/mL, about 90 mg/mL to about 120 mg/mL, about 90 mg/mL to about 110 mg/mL, about 90 mg/mL to about 100 mg/mL, about 100 mg/mL to about 500 mg/mL, about 100 mg/mL to about 480 mg/mL, about 100 mg/mL to about 460 mg/mL, about 100 mg/mL to about 440 mg/mL, about 100 mg/mL to about 420 mg/mL, about 100 mg/mL to about 400 mg/mL, about 100 mg/mL to about 380 mg/mL, about 100 mg/mL to about 360 mg/mL, about 100 mg/mL to about 340 mg/mL, about 100 mg/mL to about 320 mg/mL, about 100 mg/mL to about 300 mg/mL, about 100 mg/mL to about 280 mg/mL, about 100 mg/mL to about 260 mg/mL, about 100 mg/mL to about 240 mg/mL, about 100 mg/mL to about 220 mg/mL, about 100 mg/mL to about 200 mg/mL, about 100 mg/mL to about 190 mg/mL, about 100 mg/mL to about 180 mg/mL, about 100 mg/mL to about 170 mg/mL, about 100 mg/mL to about 160 mg/mL, about 100 mg/mL to about 140 mg/mL, about 100 mg/mL to about 130 mg/mL, about 100 mg/mL to about 120 mg/mL, about 100 mg/mL to about 110 mg/mL, about 110 mg/mL to about 500 mg/mL, about 110 mg/mL to about 480 mg/mL, about 110 mg/mL to about 460 mg/mL, about 110 mg/mL to about 440 mg/mL, about 110 mg/mL to about 420 mg/mL, about 110 mg/mL to about 400 mg/mL, about 110 mg/mL to about 380 mg/mL, about 110 mg/mL to about 360 mg/mL, about 110 mg/mL to about 340 mg/mL, about 110 mg/mL to about 320 mg/mL, about 110 mg/mL to about 300 mg/mL, about 110 mg/mL to about 280 mg/mL, about 110 mg/mL to about 260 mg/mL, about 110 mg/mL to about 240 mg/mL, about 110 mg/mL to about 220 mg/mL, about 110 mg/mL to about 200 mg/mL, about 110 mg/mL to about 190 mg/mL, about 110 mg/mL to about 180 mg/mL, about 110 mg/mL to about 170 mg/mL, about 110 mg/mL to about 160 mg/mL, about 110 mg/mL to about 140 mg/mL, about 110 mg/mL to about 130 mg/mL, about 110 mg/mL to about 120 mg/mL, about 120 mg/mL to about 500 mg/mL, about 120 mg/mL to about 480 mg/mL, about 120 mg/mL to about 460 mg/mL, about 120 mg/mL to about 440 mg/mL, about 120 mg/mL to about 420 mg/mL, about 120 mg/mL to about 400 mg/mL, about 120 mg/mL to about 380 mg/mL, about 120 mg/mL to about 360 mg/mL, about 120 mg/mL to about 340 mg/mL, about 120 mg/mL to about 320 mg/mL, about 120 mg/mL to about 300 mg/mL, about 120 mg/mL to about 280 mg/mL, about 120 mg/mL to about 260 mg/mL, about 120 mg/mL to about 240 mg/mL, about 120 mg/mL to about 220 mg/mL, about 120 mg/mL to about 200 mg/mL, about 120 mg/mL to about 190 mg/mL, about 120 mg/mL to about 180 mg/mL, about 120 mg/mL to about 170 mg/mL, about 120 mg/mL to about 160 mg/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/mL, about 300 mg/mL to about 500 mg/mL, about 300 mg/mL to about 480 mg/mL, about 300 mg/mL to about 460 mg/mL, about 300 mg/mL to about 440 mg/mL, about 300 mg/mL to about 420 mg/mL, about 300 mg/mL to about 400 mg/mL, about 300 mg/mL to about 380 mg/mL, about 300 mg/mL to about 360 mg/mL, about 300 mg/mL to about 340 mg/mL, about 300 mg/mL to about 320 mg/mL, about 320 mg/mL to about 500 mg/mL, about 320 mg/mL to about 480 mg/mL, about 320 mg/mL to about 460 mg/mL, about 320 mg/mL to about 440 mg/mL, about 320 mg/mL to about 420 mg/mL, about 320 mg/mL to about 400 mg/mL, about 320 mg/mL to about 380 mg/mL, about 320 mg/mL to about 360 mg/mL, about 320 mg/mL to about 340 mg/mL, about 340 mg/mL to about 500 mg/mL, about 340 mg/mL to about 480 mg/mL, about 340 mg/mL to about 460 mg/mL, about 340 mg/mL to about 440 mg/mL, about 340 mg/mL to about 420 mg/mL, about 340 mg/mL to about 400 mg/mL, about 340 mg/mL to about 380 mg/mL, about 340 mg/mL to about 360 mg/mL, about 360 mg/mL to about 500 mg/mL, about 360 mg/mL to about 480 mg/mL, about 360 mg/mL to about 460 mg/mL, about 360 mg/mL to about 440 mg/mL, about 360 mg/mL to about 420 mg/mL, about 360 mg/mL to about 400 mg/mL, about 360 mg/mL to about 380 mg/mL, about 380 mg/mL to about 500 mg/mL, about 380 mg/mL to about 480 mg/mL, about 380 mg/mL to about 460 mg/mL, about 380 mg/mL to about 440 mg/mL, about 380 mg/mL to about 420 mg/mL, about 380 mg/mL to about 400 mg/mL, about 400 mg/mL to about 500 mg/mL, about 400 mg/mL to about 480 mg/mL, about 400 mg/mL to about 460 mg/mL, about 400 mg/mL to about 440 mg/mL, about 400 mg/mL to about 420 mg/mL, about 420 mg/mL to about 500 mg/mL, about 420 mg/mL to about 480 mg/mL, about 420 mg/mL to about 460 mg/mL, about 420 mg/mL to about 440 mg/mL, about 440 mg/mL to about 500 mg/mL, about 440 mg/mL to about 480 mg/mL, about 440 mg/mL to about 460 mg/mL, about 460 mg/mL to about 500 mg/mL, about 460 mg/mL to about 480 mg/mL, or about 480 mg/mL to about 500 mg/mL, of an antibody or an antigen-binding antibody fragment (e.g., any of the exemplary antibodies or antigen binding antibody fragments described herein).

The term“antibody” as used herein is used broadly to mean any polypeptide that includes an antigen-binding domain. Non-limiting examples of types of antibodies are described herein. Additional examples of antibodies are known in the art.

The term“antigen-binding antibody fragment” refers to a fragment of a mammalian (e.g., human) IgGl, IgG2, IgG3, IgG4, IgM, IgE, or IgA that retains its ability to bind specifically to an antigen. Non-limiting examples of antigen-binding antibody fragments are described herein. Additional examples of antigen-binding antibody fragments are known in the art.

In some embodiments, an antibody can be a VHH domain, a VNAR domain, a scFv, a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CF-scFv, a HSAbody, scDiabody-HAS, or a tandem-scFv.

A VHH domain is a single monomeric variable antibody domain that can be found in camelids. A VNAR domain is a single monomeric variable antibody domain that can be found in cartilaginous fish. Non-limiting aspects of VHH domains and VNAR domains are described in, e.g., 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.

In some embodiments, an antibody can be a VHH-scAb, a VHH-Fab, a Dual scFab, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-IgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a kl-body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a 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, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab’)2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc, an Intrabody, a dock and lock, a ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl-PEG-scFv2.

Non-limiting examples of an antigen-binding antibody fragments include an Fv fragment, a Fab fragment, a F(ab')2 fragment, and a Fab' fragment. Additional examples of antigen-binding antibody fragments include any antigen-binding fragment of an IgG (e.g., an antigen-binding fragment of IgGl, IgG2, IgG3, or IgG4) (e.g., an antigen binding fragment of a human or humanized IgQ e.g., human or humanized IgGl, IgG2, IgG3, or IgG4); an antigen-binding fragment of an IgA (e.g., an antigen-binding fragment of IgAl or IgA2) (e.g., an antigen-binding fragment of a human or humanized IgA, e.g., a human or humanized IgAl or IgA2); an antigen-binding fragment of an IgD (e.g., an antigen-binding fragment of a human or humanized IgD); an antigen-binding fragment of an IgE (e.g., an antigen-binding fragment of a human or humanized IgE); or an antigen binding fragment of an IgM (e.g., an antigen-binding fragment of a human or humanized IgM).

A“Fv” fragment includes a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

A“Fab” fragment includes, the constant domain of the light chain and the first constant domain (CHI) of the heavy chain, in addition to the heavy and light chain variable domains of the Fv fragment.

A“F(ab')2” fragment includes two Fab fragments joined, near the hinge region, by disulfide bonds.

A“dual variable domain immunoglobulin” or“DVD-Ig” refers to multivalent and multispecific binding proteins as described, e.g., 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.

DARTs are described in, e.g., Garber, Nature Reviews Drug Discovery 13:799- 801, 2014.

An antibody or an antigen-binding antibody fragment can bind to its epitope or antigen with a dissociation equilibrium constant (KD) of less than 1 x 10-7 M, less than 1 x 10-8 M, less than 1 x 10-9 M, less than 1 x 10-10M, less than 1 x 10-11 M, less than 1 x 10-12 M, or less than 1 x 10-13 M. In some embodiments, the antibody or the antigen-binding antibody fragment can bind to its antigen or epitope with a KD of about 1 x 10-3 M to about 1 x 10-5 M, about 1 x 10-4 M to about 1 x 10-6 M, about 1 x 10-5 M to about 1 x 10-7 M, about 1 x 10-6 M to about 1 x 10-8 M, about 1 x 10-7 M to about 1 x 10-9M, about 1 x 10-8 M to about 1 x 10-10 M, or about 1 x 10-9 M to about 1 x 10-11M (inclusive).

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

In some embodiments, the mAb can have an Fc region comprising one or more amino acid substitutions that result in low CH2 domain unfolding temperature compared to an antibody having a wildtype Fc region. In some embodiments, the mAb can have an Fc region comprising one or more amino acid substitutions that decrease the stability of the antibody, e.g., as compared to the stability of a similar antibody lacking the one or more amino acid substitutions.

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

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 heavy chain comprising or consisting of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO: 1 and a light chain comprising or consisting of a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 99% identical, or 100% identical SEQ ID NO: 2. In some

embodiments, the anti-CXCR3 antibody includes the three CDRs present in SEQ ID NO:

1 and the three CDRs present in SEQ ID NO: 2.

In some embodiments, the mAb is an anti-cluster of differentiation 38 (CD38) mAb (e.g., a human or humanized anti-CD38 antibody). In some embodiments, the anti-CD38 mAb comprises a heavy chain comprising or consisting of a sequence that is at

least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO: 3 and a light chain comprising or consisting 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 SEQ ID NO: 4. In some

embodiments, the anti-CD38 antibody includes the three CDRs present in SEQ ID NO: 3 and the three CDRs present in SEQ ID NO: 4.

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

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

10. In some embodiments, the anti-CEACAM5 antibody includes the three CDRs present in SEQ ID NO: 9 and the three CDRs present in SEQ ID NO: 10.

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

In some embodiments, the mAb is an anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-Fc engineered mAb (e.g., a human or humanized antibody). In some embodiments, the anti-CEACAM5-Fc engineered mAb comprises a heavy chain comprising or consisting of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO: 11 and a light chain comprising or consisting 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 SEQ ID NO: 12. In some embodiments, the anti-CEACAM5-Fc engineered mAb includes the three CDRs present in SEQ ID NO: 11 and the three CDRs present in SEQ ID NO: 12.

In some embodiments, the mAb is an anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-Fc engineered mAb (e.g., a human or humanized antibody). In some embodiments, the anti-CEACAM5-Fc engineered mAb comprises a heavy chain comprising or consisting of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO: 13 and a light chain comprising or consisting 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 SEQ ID NO: 14. In some embodiments, the anti-CEACAM5-Fc engineered mAb includes the three CDRs present in SEQ ID NO: 13 and the three CDRs present in SEQ ID NO: 14.

In some embodiments, an antibody can be conjugated to a drug (e.g., a chemotherapeutic drug, a small molecule), a toxin, or a radioisotope. In some embodiments, an antibody can be conjugated to a drug through a linker. Non-limiting examples of linkers include: hydrazone linkers, peptide linkers, disulfide linkers, thioether linker. See, e.g., Carter et al. (2008) Cancer J. 14(3): 154-69; Sanderson et al. (2005) Clin. Cancer Res. 11(2 Ptl): 843-852; Chan et al (2008) Ace 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.

An antibody can be produced by introducing into a cell a nucleic acid sequence encoding the antibody to produce a recombinant cell; and culturing the recombinant cell under conditions sufficient for the expression of the antibody. In some embodiments, the introducing step includes introducing into a cell an expression vector including a sequence encoding the antibody to produce a recombinant cell.

An antigen 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 may include, for example, mammalian (e.g., rodent, non human primate, or human), insect, fungal, 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 eukaryote, such as mammalian, avian, plant, or insect cells.

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

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

Provided herein are methods that further include isolation of the antibody from a cell (e.g., a eukaryotic cell) using techniques well-known in the art (e.g., ammonium sulfate precipitation, polyethylene glycol precipitation, ion-exchange chromatography (anion or cation), chromatography based on hydrophobic interaction, metal-affinity chromatography, ligand-affinity chromatography, size exclusion chromatography).

Buffers

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

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

WHAT IS CLAIMED IS:

1. An aqueous antibody formulation comprising:

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; 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, 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 formulation has a pH of about 4 to about 8.

2. An aqueous antibody formulation comprising:

about 0.1 mg/mL to about 500 mg/mL of an antibody or an antigen-binding fragment thereof; 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, 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 formulation has a pH of about 4 to about 8.

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

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

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

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

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

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

9. The formulation of any one of claims 1-8, wherein the formulation comprises about 10 mM to about 750 mM of the salt.

10. The formulation of claim 9, wherein the formulation comprises about 20 mM to about 750 mM of the salt.

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

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

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

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

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

16. The formulation of any one of claim 11-15, wherein the formulation comprises about 10 mM to about 750 mM of the salt.

17. The formulation of claim 16, wherein the formulation comprises about 20 mM to about 750 mM of the salt.

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

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

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

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

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

23. The formulation of any one of claim 18-22, wherein the formulation comprises about 10 mM to about 750 mM of the salt.

24. The formulation of claim 23, wherein the formulation comprises about 20 mM to about 750 mM of the salt.

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

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

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

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

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

30. The formulation of any one of claims 1 and 4-29, wherein the formulation comprises about 1 mM to about 100 mM of the buffer.

31. The formulation of claim 30, wherein the formulation comprises about 1 mM to about 75 mM of the buffer.

32. The formulation of claim 31, wherein the formulation comprises about 1 mM to about 50 mM of the buffer.

33. The formulation of claim 32, wherein the formulation comprises about 1 mM to about 20 mM of the buffer.

34. The formulation of any one of claims 1-33, wherein the formulation has a pH of about 5 to about 6.

35. The formulation of claim 34, wherein the formulation has a pH of about 5.5.

36. The formulation of any one of claims 1-35, wherein the formulation comprises an antibody.

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

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

39. The formulation of claim 37, wherein the monoclonal antibody has an Fc amino acid substitution that decreases its conformational stability as compared to a similar antibody not including the Fc amino acid substitution.

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

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

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

46. The formulation of claim 45, wherein the anti-CEACAM5-Fc engineered monoclonal antibody comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.

47. The formulation of claim 45, wherein the anti-CEACAM5-Fc engineered monoclonal antibody comprises a heavy chain comprising SEQ ID NO: 11 and a light chain comprising SEQ ID NO: 12.

48. The formulation of claim 45, wherein the anti-CEACAM5-Fc engineered monoclonal antibody comprises a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO: 14.

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

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

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

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

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

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

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

56. The formulation of any one of claims 1-55, wherein the formulation has a viscosity of about 1 cP to about 50 cP.

57. The formulation of claim 56, wherein the formulation has a viscosity of about 1 cP to about 40 cP.

58. The formulation of claim 57, wherein the formulation has a viscosity of about 1 cP to about 30 cP.

59. The formulation of claim 58, wherein the formulation has a viscosity of about 1 cP to about 20 cP.

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

61. The formulation of claim 60, wherein the formulation has an osmolality of about 250 mOsm/kg to about 750 mOsm/kg.

62. The formulation of claim 61, wherein the formulation has an osmolality of about 250 mOsm/kg to about 500 mOsm/kg.

63. The formulation of claim 62, wherein the formulation has an osmolality of about 250 mOsm/kg to about 400 mOsm/kg.

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

65. The formulation of claim 1-63, wherein the formulation is stable at 40 °C about 1 hour to about 8 weeks.

66. The formulation of any one of claims 1-65, wherein the formulation is suitable for intravenous, intramuscular, or subcutaneous administration.

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

68. The formulation of claim 66, wherein the formulation is suitable for subcutaneous administration.

69. The formulation of any one of claims 1-68, wherein the formulation further comprises one or more of a stabilizer, an anti-oxidant, a metal chelator, a viscosity modifier, an amino acid, and a surfactant.

70. The formulation of claim 69, wherein the stabilizer is fructose, maltose, galactose, glucose, O-mannose, sorbose, lactose, sucrose, trehalose, cellobiose, raffinose, melezitose, a maltodextrin, a dextran, starch, mannitol, xylitol, maltitol, lactitol, glucitol, sucrose, trehalose, raffinose, maltose, sorbitol, mannitol, an amino sugar, sodium chloride, and glycerol.

71. The formulation of claim 69, wherein the antioxidant is methionine, ascorbic acid, or N-acetyl cysteine.

72. The formulation of claim 69, wherein the metal chelator is sodium

ethylenediaminetetraacetic acid (EDTA), calcium EDTA, or diethylenetriamine pentaacetate (DTPA).

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

74. The formulation of claim 69, wherein the surfactant is selected from the group consisting of: sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan trioleate, glycerine monocaprylate, glycerine monomyristate, glycerine monostearate, decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate, polyoxyethylene sorbitan monolaurate, polyoxythylene sorbitan monocleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethyene 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, polyoxythylene 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, a glycerophosopholipid, a sphingophospholipid, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer 188, triton-X, sodium lauryl sulfate, polyethylene glycol, and propylene glycol.

75. 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. An injection device comprising a formulation of any one of claims 1-75.

77. A kit comprising one or more vials containing a formulation of any one of claims 1-75.

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

79. A method of making an aqueous antibody formulation, the method comprising mixing or combining:

(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, and

(iv) a stabilizer;

(v) a surfactant; and

(vi) sterile water,

wherein (i) to (vi) are mixed or combined in amounts sufficient to generate the formulation of any one of claims 1-75.

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

81. A method of making an aqueous antibody formulation, the method comprising 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, and

(iv) a stabilizer;

(v) a surfactant; and

(vi) sterile water,

wherein (i) to (v) are mixed or combined in amounts sufficient to generate the formulation of any one of claims 1-75.

82. The method of claim 81 , wherein the method does not comprise mixing or combining a buffer with (i) to (v).

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 to (i) to (vi).

84. A method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a formulation of any one of claims 1-75.