Stable liquid formulation of Anti-CD20 antibody

Abstract

The present invention relates to: a liquid formulation comprising an anti-CD20 antibody and a buffer and having a pH of about 4.0-8.5 or a liquid formulation comprising an anti-CD20 antibody and not comprising a buffer; a device comprising the liquid formulation; and uses thereof for treating a condition associated with B cells expressing CD20. The liquid formulations have excellent stability, and thus can be effectively used as pharmaceutical products.

Description

Stable liquid formulation of anti-CD20 antibody

[0001] A stable liquid formulation of an anti-CD20 antibody, a device comprising the same, and their use for treating conditions involving B cells expressing CD20.

[0002] Antibody drugs have larger molecular weights and complex secondary and higher-order structures compared to typical protein drugs, which can lead to physicochemical instability. For this reason, the development of optimal formulations that ensure quality and stability throughout the entire process of antibody drugs, from manufacturing and storage to patient administration, is essential. Protein instability can be caused by various external factors, such as temperature, light, and chemical factors, and can lead to decreased activity, reduced efficacy, or immunogenicity when administered to the human body. Therefore, improving the instability of antibody drugs and maintaining optimal quality until administration to patients is crucial. To achieve optimal quality, methods such as changing buffer solutions, assessing optimal pH, and adding stabilizers are used. Because the material properties of each antibody protein vary, and the optimal combination of buffer solution, pH, and stabilizer can vary, developing a formulation appropriate for the target substance is essential to address these issues.

[0003] For example, ocrelizumab, which binds to CD20 and eliminates B cells, is a liquid formulation consisting of 30 mg / mL anti-CD20 expressing B-cell IgG, 2.14 mg / mL sodium acetate trihydrate, 0.25 mg / mL acetic acid, 40 mg / mL trehalose, and 0.2 mg / mL polysorbate 20, which is sold as Ocrevus. ®) is manufactured and sold under the trade name of Ocrelizumab. In order to stabilize liquid preparations containing various antibody proteins such as Ocrelizumab, various conditions such as the type and concentration of each component, such as adding amino acids, buffers, and surfactants, or applying a specific pH, as in the composition of Ocrevus products, are being reviewed and applied.

[0004] However, to confirm protein stability before administration to patients, critical qualities must be assessed under storage temperature conditions and up to the expiration date. Therefore, validation of developed formulations requires a long period of time. To effectively assess protein stability and optimal formulations in a short period of time, exposure to heat (temperature) and chemicals, factors that cause structural and physicochemical denaturation of proteins, can be analyzed for new quality indicators to select the optimal formulation combination.

[0005] Additionally, with the trend toward developing subcutaneous formulations alongside intravenous formulations for patient convenience and reduced medical costs, the development of high-concentration formulations for subcutaneous injection is becoming increasingly necessary. When developing high-concentration formulations, if the inherent buffering capacity of the protein can replace the function of a buffer solution, the buffer solution can be selectively omitted, resulting in a buffer-free formulation. To confirm this, the buffering capacity of each formulation can be assessed to determine the optimal concentration.

[0006] Accordingly, the present disclosure relates to a stable liquid formulation of an anti-CD20 antibody, such as ocrelizumab. Specifically, the present disclosure provides a formulation having increased stability compared to commercially available formulations of an anti-CD20 antibody, such as ocrelizumab (e.g., Ocrevus), by applying a formulation method that minimizes physicochemical changes in the anti-CD20 antibody, such as ocrelizumab.

[0007] The present disclosure also relates to a self-buffering liquid formulation of an anti-CD20 antibody, such as ocrelizumab. Specifically, the present disclosure provides a liquid formulation of an anti-CD20 antibody, such as ocrelizumab, that has buffering capacity without including a buffer. More specifically, the present disclosure provides a liquid formulation of an anti-CD20 antibody for subcutaneous injection that does not include a buffer.

[0008] One aspect is to provide a liquid formulation comprising an anti-CD20 antibody; and a buffer, wherein the pH is from about 4.0 to about 8.0.

[0009] Another aspect is to provide a liquid formulation comprising an anti-CD20 antibody and no buffer.

[0010] Another aspect is to provide a device comprising the above liquid formulation.

[0011] Another aspect provides a method of treating a condition involving B cells expressing CD20, comprising administering the liquid formulation to a subject in need thereof.

[0012] Another aspect provides the use of the liquid formulation in the manufacture of a medicament for treating a condition involving B cells expressing CD20.

[0013] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art in the relevant field of the present invention. Furthermore, while preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. Furthermore, numerical values ​​described herein are considered to include the meaning of "about," even if not explicitly stated. The contents of all publications cited as references herein are incorporated herein by reference in their entirety.

[0014] The terms "about" or "approximately" in this specification can generally be interpreted to mean a value or range that is within 10%, 5%, 4%, 3%, 2%, or 1% above or below a given value or range.

[0015] One aspect provides a stable liquid formulation of anti-CD20 antibody, specifically,

[0016] anti-CD20 antibodies; and

[0017] Contains a buffer,

[0018] The pH is about 4.0 to about 8.0,

[0019] Provides liquid formulation.

[0020] In this specification, a liquid formulation according to the above aspect may be expressed as a “buffer-containing formulation.”

[0021] Another aspect provides a self-buffering liquid formulation of anti-CD20 antibodies, specifically:

[0022] Contains anti-CD20 antibodies,

[0023] Does not contain buffer,

[0024] Provides liquid formulation.

[0025] In this specification, a liquid formulation according to the above aspect may be expressed as a “buffer-free formulation.”

[0026] (1) Antibodies

[0027] The term "antibody" as used herein may be interpreted to mean a full-length antibody or an antigen-binding fragment thereof. The antibody includes a monoclonal antibody, a polyclonal antibody, a humanized antibody, a human antibody, and a chimeric antibody.

[0028] The term "antigen-binding fragment" refers to a fragment comprising the antigen-binding site of an antibody. For example, an antigen-binding fragment includes, but is not limited to, a Fab fragment, an F(ab')2 fragment, an Fc fragment, or an scFv fragment.

[0029] In this specification, the antibody may be an anti-CD20 antibody. The anti-CD20 antibody may refer to any antibody that specifically binds to CD20. The anti-CD20 antibody may be an antibody that targets B cells that express CD20.

[0030] The above anti-CD20 antibody may be ocrelizumab (CAS No. 637334-45-3). Therefore, the liquid formulation may be a stable liquid formulation of ocrelizumab. Ocrelizumab is a humanized monoclonal antibody that binds to CD20 expressed on the surface of B cells. Ocrelizumab is Ocrevus. ® ) is sold under the trade name Ocrevus. Ocrevus has been approved by the U.S. Food and Drug Administration (FDA) as a treatment for multiple sclerosis (MS) and is used to treat various types of MS. The sequence of ocrelizumab is known and can be produced by general methods known in the art. More detailed information on ocrelizumab is readily available to those skilled in the art from publicly available databases.

[0031] The term “ocrelizumab” herein may also be interpreted to mean ocrelizumab having a modified amino acid sequence (deletion, insertion, and / or substitution) and / or a modified glycosylation characteristic, as long as it does not affect the polypeptide function.

[0032] The above anti-CD20 antibody may be included in a therapeutically effective amount in a liquid formulation.

[0033] In a buffer-free formulation according to one aspect, the anti-CD20 antibody has a pH buffering function in the liquid formulation. The concentration of the anti-CD20 antibody may be a concentration suitable for providing a buffering function to the liquid formulation.

[0034] The concentration of the anti-CD20 antibody is about 1 mg / ml to about 400 mg / ml, about 1 mg / ml to about 350 mg / ml, about 1 mg / ml to about 300 mg / ml, about 1 mg / ml to about 250 mg / ml, about 1 mg / ml to about 200 mg / ml, about 1 mg / ml to about 175 mg / ml, about 1 mg / ml to about 150 mg / ml, about 1 mg / ml to about 125 mg / ml, about 1 mg / ml to about 100 mg / ml, about 1 mg / ml to about 75 mg / ml, about 1 mg / ml to about 50 mg / ml, about 5 mg / ml to about 400 mg / ml, about 5 mg / ml to about 350 mg / ml, about 5 mg / ml to about 300 mg / ml, about 5 mg / ml to about 250 mg / ml, about 5 mg / ml to about 200 mg / ml, about 5 mg / ml to about 175 mg / ml, about 5 mg / ml to about 150 mg / ml, about 5 mg / ml to about 125 mg / ml, about 5 mg / ml to about 100 mg / ml, about 5 mg / ml to about 75 mg / ml, about 5 mg / ml to about 50 mg / ml, about 10 mg / ml to about 400 mg / ml, about 10 mg / ml to about 350 mg / ml, about 10 mg / ml to about 300 mg / ml, about 10 mg / ml to about 250 mg / ml, about 10 mg / ml to about 200 mg / ml, about 10 mg / ml to about 175 mg / ml, about 10 mg / ml to about 150 mg / ml, about 10 mg / ml to about 125 mg / ml, about 10 mg / ml to about 100 mg / ml, about 10 mg / ml to about 75 mg / ml, about 10 mg / ml to about 50 mg / ml, about 25 mg / ml to about 400 mg / ml, about 25 mg / ml to about 350 mg / ml, about 25 mg / ml to about 300 mg / ml, about 25 mg / ml to about 250 mg / ml,About 25 mg / ml to about 200 mg / ml, about 25 mg / ml to about 175 mg / ml, about 25 mg / ml to about 150 mg / ml, about 25 mg / ml to about 125 mg / ml, about 25 mg / ml to about 100 mg / ml, about 25 mg / ml to about 75 mg / ml, about 25 mg / ml to about 50 mg / ml, about 30 mg / ml to about 400 mg / ml, about 30 mg / ml to about 350 mg / ml, about 30 mg / ml to about 300 mg / ml, about 30 mg / ml to about 250 mg / ml, about 30 mg / ml to about 200 mg / ml, about 30 mg / ml to about 175 mg / ml, about 30 mg / ml to about 150 mg / ml, about 30 mg / ml About 125 mg / ml, About 30 mg / ml to about 100 mg / ml, About 30 mg / ml to about 75 mg / ml, About 30 mg / ml to about 50 mg / ml, About 30 mg / ml to about 45 mg / ml, About 50 mg / ml to about 400 mg / ml, About 50 mg / ml to about 350 mg / ml, About 50 mg / ml to about 300 mg / ml, About 50 mg / ml to about 250 mg / ml, About 50 mg / ml to about 200 mg / ml, About 50 mg / ml to about 175 mg / ml, About 50 mg / ml to about 150 mg / ml, About 50 mg / ml to about 125 mg / ml, About 50 mg / ml to about 100 mg / ml, About 50 mg / ml to about 75 mg / ml, About 75 mg / ml to about 400 mg / ml, about 75 mg / ml to about 350 mg / ml, about 75 mg / ml to about 300 mg / ml, about 75 mg / ml to about 250 mg / ml, about 75 mg / ml to about 200 mg / ml, about 75 mg / ml to about 175 mg / ml, about 75 mg / ml to about 150 mg / ml, about 75 mg / ml to about 125 mg / ml,About 75 mg / ml to about 100 mg / ml, about 90 mg / ml to about 400 mg / ml, about 90 mg / ml to about 350 mg / ml, about 90 mg / ml to about 300 mg / ml, about 90 mg / ml to about 250 mg / ml, about 90 mg / ml to about 200 mg / ml, about 90 mg / ml to about 175 mg / ml, about 90 mg / ml to about 150 mg / ml, about 90 mg / ml to about 125 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 400 mg / ml, about 100 mg / ml to about 350 mg / ml, about 100 mg / ml to about 300 mg / ml, about 100 mg / ml to about 250 mg / ml, about 100 mg / ml to about 200 mg / ml, about 100 mg / ml to about 175 mg / ml, about 100 mg / ml to about 150 mg / ml, about 100 mg / ml to about 125 mg / ml, about 120 mg / ml to about 400 mg / ml, about 120 mg / ml to about 350 mg / ml, about 120 mg / ml to about 300 mg / ml, about 120 mg / ml to about 250 mg / ml, about 120 mg / ml to about 200 mg / ml, about 120 mg / ml to about 175 mg / ml, or about 120 mg / ml to about 150 mg / ml.

[0035] In one embodiment, the concentration of the anti-CD20 antibody can be about 2 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 8 mg / ml, about 10 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 40 mg / ml, about 45 mg / ml, about 50 mg / ml, about 75 mg / ml, about 100 mg / ml, about 120 mg / ml, about 125 mg / ml, about 130 mg / ml, about 150 mg / ml, about 175 mg / ml, about 200 mg / ml, about 250 mg / ml, or about 300 mg / ml.

[0036] In certain embodiments, the concentration of the anti-CD20 antibody may be about 30 mg / ml.

[0037] In certain embodiments, the concentration of the anti-CD20 antibody may be about 40 mg / ml.

[0038] In certain embodiments, the concentration of the anti-CD20 antibody may be about 45 mg / ml.

[0039] In one specific embodiment, the concentration of the anti-CD20 antibody may be a high concentration. The high concentration may mean a concentration higher than that of the antibody of Ocrevus. Specifically, the concentration of the anti-CD20 antibody may be greater than about 30 mg / ml, greater than about 35 mg / ml, greater than about 40 mg / ml, greater than about 45 mg / ml, greater than about 75 mg / ml, greater than about 100 mg / ml, greater than about 120 mg / ml, or greater than about 130 mg / ml. More specifically, the concentration of the anti-CD20 antibody is from about 30 mg / ml to about 400 mg / ml, from about 30 mg / ml to about 350 mg / ml, from about 30 mg / ml to about 300 mg / ml, from about 30 mg / ml to about 250 mg / ml, from about 30 mg / ml to about 200 mg / ml, from about 30 mg / ml to about 150 mg / ml, from about 30 mg / ml to about 100 mg / ml, from about 30 mg / ml to about 75 mg / ml, from about 30 mg / ml to about 50 mg / ml, from about 30 mg / ml to about 45 mg / ml, from about 35 mg / ml to about 400 mg / ml, from about 35 mg / ml to about 350 mg / ml, from about 35 mg / ml to about 300 mg / ml, from about 35 mg / ml to about 250 mg / ml, about 35 mg / ml to about 200 mg / ml, about 35 mg / ml to about 150 mg / ml, about 35 mg / ml to about 100 mg / ml, about 35 mg / ml to about 75 mg / ml, about 35 mg / ml to about 50 mg / ml, about 35 mg / ml to about 45 mg / ml, about 40 mg / ml to about 400 mg / ml, about 40 mg / ml to about 350 mg / ml, about 40 mg / ml to about 300 mg / ml, about 40 mg / ml to about 250 mg / ml, about 40 mg / ml to about 200 mg / ml, about 40 mg / ml to about 150 mg / ml,About 40 mg / ml to about 100 mg / ml, about 40 mg / ml to about 75 mg / ml, about 40 mg / ml to about 50 mg / ml, about 40 mg / ml to about 45 mg / ml, about 75 mg / ml to about 400 mg / ml, about 75 mg / ml to about 350 mg / ml, about 75 mg / ml to about 300 mg / ml, about 75 mg / ml to about 250 mg / ml, about 75 mg / ml to about 200 mg / ml, about 75 mg / ml to about 175 mg / ml, about 75 mg / ml to about 150 mg / ml, about 100 mg / ml to about 400 mg / ml, about 100 mg / ml to about 350 mg / ml, about 100 mg / ml to about 300 mg / ml, about 100 mg / ml to about 250 mg / ml, about 100 mg / ml to about 200 mg / ml, about 100 mg / ml to about 175 mg / ml, about 100 mg / ml to about 150 mg / ml, about 120 mg / ml to about 400 mg / ml, about 120 mg / ml to about 350 mg / ml, about 120 mg / ml to about 300 mg / ml, about 120 mg / ml to about 250 mg / ml, about 120 mg / ml to about 200 mg / ml, about 120 mg / ml to about 175 mg / ml, about 120 mg / ml to about 150 mg / ml, about 130 mg / ml to about 400 mg / ml, about 130 mg / ml to about 350 mg / ml, about 130 mg / ml to about 300 mg / ml, about 130 mg / ml to about 250 mg / ml, about 130 mg / ml to about 200 mg / ml, about 130 mg / ml to about 175 mg / ml, about 130 mg / ml to about 150 mg / ml, about 150 mg / ml to about 400 mg / ml, about 150 mg / ml to about 350 mg / ml, about 150 mg / ml to about 300 mg / ml, about 150 mg / ml to about 250 mg / ml,It may be about 150 mg / ml to about 200 mg / ml, or about 150 mg / ml to about 175 mg / ml.

[0040] In certain embodiments, the concentration of the anti-CD20 antibody may be about 40 mg / ml, about 45 mg / ml, about 75 mg / ml, about 120 mg / ml, or about 150 mg / ml.

[0041] In a buffer-free formulation according to one aspect, the concentration of the anti-CD20 antibody may be a high concentration of greater than about 30 mg / ml.

[0042] (2) Buffer and pH

[0043] (2-1) Buffer-containing formulation

[0044] A buffer can regulate the pH of a formulation. A buffer can maintain the pH of a liquid formulation at a certain value or within a certain range. Therefore, a buffer can provide a pH of a liquid formulation at a certain value or within a certain range.

[0045] A buffer-containing formulation according to one aspect comprises a buffer.

[0046] The above buffer is not limited to a specific type as long as it is applicable to biopharmaceuticals.

[0047] The buffer may include at least one selected from acetate, histidine, phosphate, citrate, succinate, malate, tartarate, carbonate, salts thereof, and hydrates thereof.

[0048] The term "salt" may be a pharmaceutically acceptable salt. The salt may include an inorganic acid salt, an organic acid salt, a metal salt, etc. of the compound. The inorganic acid salt may be a hydrochloride, a bromate, a phosphate, a sulfate, or a disulfate. The organic acid salt may be a formate, an acetate, a propionate, a lactate, an oxalate, a tartrate, a malate, a maleate, a citrate, a fumarate, a besylate, a camsylate, an edisyl salt, a trichloroacetic acid, a trifluoroacetate, a benzoate, a gluconate, a methanesulfonate, a glycolate, a succinate, a 4-toluenesulfonate, a galacturonate, an embonate, a glutamate, an ethanesulfonate, a benzenesulfonate, a p-toluenesulfonate, or an aspartate. The metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.

[0049] The term "hydrate" refers to a substance containing water molecules within its molecule. The hydrate may be a monohydrate, dihydrate, or trihydrate. For example, a hydrate of acetate may include sodium acetate trihydrate. Additionally, a hydrate of histidine may include histidine monohydrochloride monohydrate.

[0050] The pH of the liquid formulation according to the aspect may be from about 4.0 to about 8.0. The pH of the liquid formulation may be provided by a buffer.

[0051] Specifically, the pH of the formulation can be any range or any value selected from about 4.0 to about 8.0. For example, the pH may be from about 4.0 to about 8.0, from about 4.0 to about 7.5, from about 4.0 to about 7.0, from about 4.0 to about 6.8, from about 4.0 to about 6.5, from about 6.2, from about 4.0 to about 6.0, from about 4.0 to about 5.8, from about 4.0 to about 5.5, from about 4.0 to about 5.2, from about 4.0 to about 5.0, from about 4.0 to about 4.8, from about 4.0 to about 4.5, from about 4.5 to about 8.0, from about 4.5 to about 7.5, from about 4.5 to about 7.0, from about 4.5 to about 6.8, from about 4.5 to about 6.5, from about 4.5 to about 6.3, from about 4.5 to about 6.2, from about 4.5 to about 6.0, about 4.5 to about 5.8, about 4.5 to about 5.5, about 4.5 to about 5.2, about 4.5 to about 5.0, about 4.5 to about 4.8, about 4.8 to about 8.0, about 4.8 to about 7.5, about 4.8 to about 7.0, about 4.8 to about 6.8, about 4.8 to about 6.5, about 4.8 to about 6.3, about 4.8 to about 6.2, about 4.8 to about 6.0, about 4.8 to about 5.8, about 4.8 to about 5.5, about 4.8 to about 5.2, about 4.8 to about 5.0, about 5.0 to about 8.0, about 5.0 to about 7.5, about 5.0 to about 7.0, about 5.0 to about 6.8, about 5.0 to about 6.5, about 5.0 to about 6.4, about 5.0 to about 6.3, about 5.0 to about 6.2, about 5.0 to about 6.1, about 5.0 to about 6.0, about 5.0 to about 5.9, about 5.0 to about 5.8, about 5.0 to about 5.7, about 5.0 to about 5.6, about 5.0 to about 5.5, about 5.0 to about 5.4, about 5.0 to about 5.3, about 5.0 to about 5.2, about 5.2 to about 8.0, about 5.2 to about 7.5, about 5.2 to about 7.0, about 5.2 to about 6.8, about 5.2 to about 6.5, about 5.2 to about 6.4, about 5.2 to about 6.3, about 5.2 to about 6.2, about 5.2 to about 6.1, about 5.2 to about 6.0, about 5.2 to about 5.9, about 5.2 to about 5.8, about 5.2 to about 5.7, about 5.2 to about 5.6, about 5.2 to about 5.5, about 5.2 to about 5.4, about 5.2 to about 5.3, about 5.5 to about 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 5.5 to about 6.8, about 5.5 to about 6.5, about 5.5 to About 6.4, about 5.5 to about 6.3, about 5.5 to about 6.2, about 5.5 to about 6.1, about 5.5 to about 6.0, about 5.5 to about 5.9, about 5.5 to about 5.8, about 5.5 to about 5.7, about 5.5 to about 5.6, about 5.8 to about 8.0, about 5.8 to about 7.5, about 5.8 to about 7.0, about 5.8 to about 6.8, about 5.8 to about 6.5, about 5.8 to about 6.4, about 5.8 to about 6.3, about 5.8 to about 6.2, about 5.8 to about 6.1, about 5.8 to about 6.0, about 5.8 to about 5.9, about 6.0 to about 8.0, About 6.0 to about 7.5, about 6.0 to about 7.0, about 6.0 to about 6.9, about 6.0 to about 6.8, about 6.0 to about 6.7, about 6.0 to about 6.6, about 6.0 to about 6.5, about 6.0 to about 6.4, about 6.0 to about 6.3, about 6.0 to about 6.2, about 6.0 to about 6.1, about 6.1 to about 8.0, about 6.1 to about 7.5, about 6.1 to about 7.0, about 6.1 to about 6.9, about 6.1 to about 6.8, about 6.1 to about 6.7, about 6.1 to about 6.6, about 6.1 to about 6.5, about 6.1 to about 6.4, about 6.1 to About 6.3, or about 6.It can be from 1 to about 6.2.

[0052] In one embodiment, the pH of the liquid formulation can be about 4.0, about 4.5, about 5.0, about 5.3, about 5.5, about 6.0, about 6.5, or about 7.0.

[0053] In one embodiment, the pH of the liquid formulation can be any range or any value selected from the range of about 4.0 to about 7.0, about 4.0 to about 6.5, about 4.0 to about 6.0, greater than or equal to 4.0 and less than or equal to 6.0, about 4.0 to about 5.2, about 4.0 to about 5.0, about 5.0 to about 7.0, about 5.0 to about 6.5, about 5.0 to about 6.0, or about 5.0 to about 5.5.

[0054] In one embodiment, the buffer may include one or more selected from acetate, histidine, phosphate, citrate, succinate, salts thereof, and hydrates thereof.

[0055] In certain embodiments, the buffer may comprise one or more selected from acetate, histidine, salts thereof, and hydrates thereof. In such embodiments, the pH of the liquid formulation may be from about 4.0 to about 7.0, from about 4.0 to about 6.5, from about 4.0 to about 6.0, from greater than or equal to 4.0 to less than 6.0, from about 4.0 to about 5.2, from about 4.0 to about 5.0, from about 5.0 to about 7.0, from about 5.0 to about 6.5, from about 5.0 to about 6.0, or from about 5.0 to about 5.5.

[0056] In certain embodiments, the buffer may comprise one or more selected from acetate, a salt thereof, and a hydrate thereof. In such embodiments, the pH of the liquid formulation may be any range or any value selected from the range of from about 4.0 to about 6.0, from about 4.0 to about 5.5, from about 4.0 to about 5.2, from about 4.0 to about 5.0, from about 5.0 to less than 6.0, or from about 5.0 to about 5.5, for example, the pH may be 4.0, 4.5, 5.0, 5.3, or 5.5.

[0057] In certain embodiments, the buffer may comprise one or more selected from histidine, a salt thereof, and a hydrate thereof. In such embodiments, the pH of the liquid formulation can be any range or any value selected from the range of about 4.0 to about 7.0, about 4.0 to about 6.5, about 4.0 to about 6.0, about 4.0 to about 5.5, about 4.0 to about 5.0, about 4.5 to about 7.0, about 4.5 to about 6.5, about 4.5 to about 6.0, about 4.5 to about 5.5, about 4.5 to about 5.0, about 5.0 to about 7.0, about 5.0 to about 6.5, about 5.0 to about 6.0, or about 5.0 to about 5.5, for example, the pH can be 5.0, 5.3, 5.5, 6.0, 6.5, or 7.0.

[0058] In certain embodiments, the combination of buffer and pH may be selected from the following, and specifically, the liquid formulation has a diffusion interaction parameter (K) greater than about 19.4 mL / g D ) may have: the liquid formulation comprises acetate or histidine as a buffer, and the pH of the liquid formulation is from about 4.0 to about 7.0.

[0059] In certain embodiments, the combination of buffer and pH may be selected from the following, and specifically, the liquid formulation has a diffusion interaction parameter (K) greater than about 19.4 mL / g D ) may have:

[0060] A) the buffer contains acetate and has a pH of 4.0 or more and less than 6.0; or

[0061] B) The buffer contains histidine and has a pH of about 5.0 to about 7.0.

[0062] The concentration of the buffer may be any range or any value selected from about 0.1 mM to about 100 mM. For example, the concentration of the buffer may be from about 0.1 mM to about 100 mM, from about 0.1 mM to about 70 mM, from about 0.1 mM to about 50 mM, from about 0.1 mM to about 40 mM, from about 0.1 mM to about 30 mM, from about 0.1 mM to about 20 mM, from about 0.1 mM to about 15 mM, from about 0.1 mM to about 12 mM, from about 0.1 mM to about 10 mM, from about 0.1 mM to about 9 mM, from about 0.1 mM to about 8 mM, from about 0.1 mM to about 7 mM, from about 0.1 mM to about 6 mM, from about 0.1 mM to about 5 mM, from about 0.1 mM to about 4 mM, from about 0.1 mM to about 3 mM, from about 0.1 mM to about 2 mM, from about 0.5 mM to about 100 mM, from about 0.5 mM to About 70 mM, about 0.5 mM to about 50 mM, about 0.5 mM to about 40 mM, about 0.5 mM to about 30 mM, about 0.5 mM to about 20 mM, about 0.5 mM to about 15 mM, about 0.5 mM to about 12 mM, about 0.5 mM to about 10 mM, about 0.5 mM to about 9 mM, about 0.5 mM to about 8 mM, about 0.5 mM to about 7 mM, about 0.5 mM to about 6 mM, about 0.5 mM to about 5 mM, about 0.5 mM to about 4 mM, about 0.5 mM to about 3 mM, about 0.5 mM to about 2 mM, about 1 mM to about 100 mM, about 1 mM to about 70 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 1 mM to about 20 mM, about 1 to about 15 mM, about 1 mM to about 12 mM, about 1 mM to about 10 mM, about 1 mM to about 9 mM, about 1 mM to about 8 mM,About 1 mM to about 7 mM, about 1 mM to about 6 mM, about 1 mM to about 5 mM, about 1 mM to about 4 mM, about 1 mM to about 3 mM, about 1 mM to about 2 mM, about 5 mM to about 100 mM, about 5 mM to about 70 mM, about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30 mM, about 5 mM to about 20 mM, about 5 mM to about 19 mM, about 5 mM to about 18 mM, about 5 mM to about 17 mM, about 5 mM to about 16 mM, about 5 mM to about 15 mM, about 5 mM to about 14 mM, about 5 mM to about 13 mM, about 5 mM to about 12 mM, about 5 mM to about 11 mM, about 5 mM to about 10 mM, about 5 mM to about 9 mM, about 5 mM About 8 mM, About 5 mM to about 7 mM, About 5 mM to about 6 mM, About 10 mM to about 100 mM, About 10 mM to about 70 mM, About 10 mM to about 50 mM, About 10 mM to about 40 mM, About 10 mM to about 30 mM, About 10 mM to about 20 mM, About 15 mM to about 100 mM, About 15 mM to about 70 mM, About 15 mM to about 50 mM, About 15 mM to about 40 mM, About 15 mM to about 30 mM, About 15 mM to about 25 mM, About 15 mM to about 22 mM, About 18 mM to about 100 mM, About 18 mM to about 50 mM, About 18 mM to about 40 mM, About 18 mM to about 30 mM, About 18 mM to about 25 mM, About 18 mM to about 22 mM, or about 19 mM to about 21 mM.

[0063] In one specific embodiment, the concentration of the acetate can be any range or any value selected within the range of about 0.5 mM to about 50 mM. Specifically, the concentration of the acetate is about 0.5 mM to about 50 mM, about 0.5 mM to about 40 mM, about 0.5 mM to about 30 mM, about 0.5 mM to about 25 mM, about 0.5 mM to about 22 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 1 mM to about 25 mM, about 1 mM to about 22 mM, about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30 mM, about 5 mM to about 25 mM, about 5 mM to about 22 mM, about 10 mM to about 50 mM, about 10 mM to about 40 mM, about 10 mM to about 30 mM, about 10 mM to about 25 mM, about 10 mM to about 22 mM, about 15 mM to about 50 mM, about 15 mM to about 40 mM, about 15 mM to about 30 mM, about 15 mM to about 25 mM, about 15 mM to about 22 mM, about 18 mM to about 50 mM, about 18 mM to about 40 mM, about 18 mM to about 30 mM, about 18 mM to about 25 mM, or about 18 mM to about 22 mM.

[0064] In certain embodiments, the concentration of the acetate may be about 20 mM.

[0065] In one specific embodiment, the concentration of histidine can be any range or any value selected from the range of about 0.5 mM to about 70 mM. Specifically, the concentration of histidine is about 0.5 mM to about 70 mM, about 0.5 mM to about 60 mM, about 0.5 mM to about 50 mM, about 0.5 mM to about 40 mM, about 0.5 mM to about 30 mM, about 0.5 mM to about 25 mM, about 0.5 mM to about 22 mM, about 1 mM to about 70 mM, about 1 mM to about 60 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 1 mM to about 25 mM, about 1 mM to about 22 mM, about 5 mM to about 70 mM, about 5 mM to about 60 mM, about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30 mM, about 5 mM to about 25 mM, About 5 mM to about 22 mM, about 10 mM to about 70 mM, about 10 mM to about 60 mM, about 10 mM to about 50 mM, about 10 mM to about 40 mM, about 10 mM to about 30 mM, about 10 mM to about 25 mM, about 10 mM to about 22 mM, about 15 mM to about 70 mM, about 15 mM to about 60 mM, about 15 mM to about 50 mM, about 15 mM to about 40 mM, about 15 mM to about 30 mM, about 15 mM to about 25 mM, about 15 mM to about 22 mM, about 18 mM to about 70 mM, about 18 mM to about 60 mM, about 18 mM to about 50 mM, about 18 mM to about 40 mM, about 18 mM to about 30 mM, about 18 mM to about 25 mM, or about 18 mM to about 22 mM.

[0066] In certain embodiments, the concentration of histidine may be about 20 mM.

[0067] (2-2) Buffer-free formulation

[0068] According to one aspect, the liquid formulation does not contain a buffer. Therefore, the liquid formulation may be a buffer-free formulation, a bufferless formulation, or a self-buffering formulation. Although the liquid formulation is a buffer-free formulation, it has a buffering capacity and thus may have stability equivalent to or greater than that of the Ocrevus formulation containing a buffer. In addition, by not containing a buffer, the liquid formulation may avoid problems that may arise due to the inclusion of a buffer. For example, problems that may arise due to the inclusion of a buffer may include the self-decomposition of some buffers under stress conditions and the failure of some buffers to maintain pH in a frozen environment.

[0069] The term "buffering" refers to the resistance of a composition to changes in pH due to the addition of an acid or base. Therefore, "buffering capacity" can be defined as the ability of a composition to resist changes in pH. Furthermore, "buffering capacity (β)" is generally expressed as the amount of strong acid or strong base required to change the pH of a composition by a given amount. Buffering capacity (β) is a unitless number, with a higher value indicating greater buffering capacity. Methods for assessing or measuring buffering capacity are well known in the art.

[0070] The term 'free of component A' or 'substantially free of A' may be interpreted to include cases where component A is not present at all, or where component A is present in trace amounts that do not substantially affect the properties of the formulation, or where it is present in undetectable amounts.

[0071] In this specification, the phrase "does not contain a buffer" may be interpreted to mean that the formulation does not contain a buffer component, or that the formulation contains such a component that it cannot function as the intended buffer within the formulation.

[0072] The term "self-buffering" may be understood to mean that the buffering capacity of the antibody formulation is substantially or completely provided by the antibody itself.

[0073] The above liquid formulation may be a self-buffering formulation. Accordingly, the liquid formulation may substantially contain no buffering agent other than the anti-CD20 antibody (e.g., ocrelizumab).

[0074] The liquid formulation may have a buffering capacity of at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 100%, at least about 110%, at least about 115%, at least about 120%, at least about 150%, or at least about 180% of the buffering capacity of a liquid formulation comprising an acetate buffer.

[0075] The acetate buffer may comprise at least one selected from acetic acid and acetate. The acetate buffer may comprise a combination of acetic acid and acetate. The concentration of the acetate buffer may be about 20 mM.

[0076] The above liquid formulation may have a superior buffering capacity compared to a liquid formulation comprising a 20 mM acetate buffer without including a buffer. For example, the liquid formulation may comprise more than 30 mg / ml of an anti-CD20 antibody, such as ocrelizumab, thereby having a buffering capacity that is at least as high as a liquid formulation that does not comprise the antibody and comprises an acetate buffer.

[0077] Additionally, the liquid formulation may have a buffering capacity of at least about 90%, at least about 100%, or at least about 110% of the buffering capacity of an Ocrevus formulation containing 20 mM acetate buffer (e.g., 2.14 mg / mL sodium acetate trihydrate + 0.25 mg / mL acetic acid) without including a buffer. Therefore, the liquid formulation may have a buffering capacity without including a buffer, and thus may have superior stability compared to a formulation containing a buffer, such as Ocrevus.

[0078] The above liquid formulation does not contain, or substantially does not contain, a buffering agent.

[0079] The buffer may include at least one selected from acetate, histidine, phosphate, citrate, succinate, malate, tartarate, carbonate, salts thereof, and hydrates thereof.

[0080] In one specific embodiment, the buffer may include one or more selected from acetate, its salt, and its hydrate. Accordingly, the liquid formulation may not include any of acetate, its salt, and its hydrate as the buffer.

[0081] In one specific embodiment, the buffer may comprise acetic acid, acetate, or a combination thereof. Accordingly, the liquid formulation may comprise neither acetic acid nor acetate as a buffer.

[0082] The pH of the liquid formulation, depending on the aspect, may be from about 4.0 to about 8.0.

[0083] Specifically, the pH of the formulation can be any range or any value selected from about 4.0 to about 8.0. For example, the pH may be from about 4.0 to about 8.0, from about 4.0 to about 7.5, from about 4.0 to about 7.0, from about 4.0 to about 6.8, from about 4.0 to about 6.5, from about 6.2, from about 4.0 to about 6.0, from about 4.0 to about 5.8, from about 4.0 to about 5.5, from about 4.0 to about 5.2, from about 4.0 to about 5.0, from about 4.0 to about 4.8, from about 4.0 to about 4.5, from about 4.5 to about 8.0, from about 4.5 to about 7.5, from about 4.5 to about 7.0, from about 4.5 to about 6.8, from about 4.5 to about 6.5, from about 4.5 to about 6.3, from about 4.5 to about 6.2, from about 4.5 to about 6.0, about 4.5 to about 5.8, about 4.5 to about 5.5, about 4.5 to about 5.2, about 4.5 to about 5.0, about 4.5 to about 4.8, about 4.8 to about 8.0, about 4.8 to about 7.5, about 4.8 to about 7.0, about 4.8 to about 6.8, about 4.8 to about 6.5, about 4.8 to about 6.3, about 4.8 to about 6.2, about 4.8 to about 6.0, about 4.8 to about 5.8, about 4.8 to about 5.5, about 4.8 to about 5.2, about 4.8 to about 5.0, about 5.0 to about 8.0, about 5.0 to about 7.5, about 5.0 to about 7.0, about 5.0 to about 6.8, about 5.0 to about 6.5, about 5.0 to about 6.4, about 5.0 to about 6.3, about 5.0 to about 6.2, about 5.0 to about 6.1, about 5.0 to about 6.0, about 5.0 to about 5.9, about 5.0 to about 5.8, about 5.0 to about 5.7, about 5.0 to about 5.6, about 5.0 to about 5.5, about 5.0 to about 5.4, about 5.0 to about 5.3, about 5.0 to about 5.2, about 5.2 to about 8.0, about 5.2 to about 7.5, about 5.2 to about 7.0, about 5.2 to about 6.8, about 5.2 to about 6.5, about 5.2 to about 6.4, about 5.2 to about 6.3, about 5.2 to about 6.2, about 5.2 to about 6.1, about 5.2 to about 6.0, about 5.2 to about 5.9, about 5.2 to about 5.8, about 5.2 to about 5.7, about 5.2 to about 5.6, about 5.2 to about 5.5, about 5.2 to about 5.4, about 5.2 to about 5.3, about 5.5 to about 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 5.5 to about 6.8, about 5.5 to about 6.5, about 5.5 to About 6.4, about 5.5 to about 6.3, about 5.5 to about 6.2, about 5.5 to about 6.1, about 5.5 to about 6.0, about 5.5 to about 5.9, about 5.5 to about 5.8, about 5.5 to about 5.7, about 5.5 to about 5.6, about 5.8 to about 8.0, about 5.8 to about 7.5, about 5.8 to about 7.0, about 5.8 to about 6.8, about 5.8 to about 6.5, about 5.8 to about 6.4, about 5.8 to about 6.3, about 5.8 to about 6.2, about 5.8 to about 6.1, about 5.8 to about 6.0, about 5.8 to about 5.9, about 6.0 to about 8.0, About 6.0 to about 7.5, about 6.0 to about 7.0, about 6.0 to about 6.9, about 6.0 to about 6.8, about 6.0 to about 6.7, about 6.0 to about 6.6, about 6.0 to about 6.5, about 6.0 to about 6.4, about 6.0 to about 6.3, about 6.0 to about 6.2, about 6.0 to about 6.1, about 6.1 to about 8.0, about 6.1 to about 7.5, about 6.1 to about 7.0, about 6.1 to about 6.9, about 6.1 to about 6.8, about 6.1 to about 6.7, about 6.1 to about 6.6, about 6.1 to about 6.5, about 6.1 to about 6.4, about 6.1 to About 6.3, or about 6.It can be from 1 to about 6.2.

[0084] In one embodiment, the pH of the liquid formulation can be any range or any value selected from the range of about 5.0 to about 6.0 or from about 5.0 to about 5.5.

[0085] (3) Stabilizer

[0086] The term "stabilizer" refers to a substance added to prevent changes in state or chemical changes when preserving a substance.

[0087] Liquid formulations according to the aspect may additionally contain a stabilizer.

[0088] In one specific embodiment, the liquid formulation may be a liquid formulation comprising an anti-CD20 antibody; a buffer; and a stabilizer, and having a pH of about 4.0 to about 8.0.

[0089] In one specific embodiment, the liquid formulation may be a liquid formulation comprising an anti-CD20 antibody and a stabilizer, and not comprising a buffer.

[0090] The above stabilizer is not limited to a specific type as long as it is applicable to biopharmaceuticals.

[0091] The above stabilizer may include at least one selected from sugar, sugar alcohol, amino acid, metal salt, salts thereof, and hydrates thereof.

[0092] The sugar may be a monosaccharide, a disaccharide, an oligosaccharide, or a polysaccharide. The sugar may include one or more selected from sucrose, trehalose, galactose, mannose, maltose, lactose, fructose, and glucose.

[0093] The sugar alcohol described above is a general term for polyols having two or more hydroxyl groups, which are formed by reducing an aldehyde group or a ketone group of a sugar to an alcohol group. The sugar alcohol may include at least one selected from mannitol, sorbitol, xylitol, arabitol, erythritol, lactitol, maltitol, and inositol. The sugar alcohol includes an anhydride or hydrate of the sugar alcohol. For example, trehalose may include not only trehalose but also trehalose dihydrate.

[0094] The above amino acids may include one or more selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, and glutamic acid.

[0095] The above metal salt may include one or more selected from NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, CaCl2, MgCl2, and K2SO4.

[0096] The concentration of the sugar can be freely adjusted within a range that maintains the stability of the antibody, and can vary individually depending on each specific sugar type. The concentration of the sugar can be any range or value selected from about 0.1% (w / v) to about 20.0% (w / v). For example, the concentration of the sugar may be from about 0.1% (w / v) to about 20.0% (w / v), from about 0.1% (w / v) to about 15.0% (w / v), from about 0.1% (w / v) to about 12.0% (w / v), from about 0.1% (w / v) to about 10.0% (w / v), from about 0.1% (w / v) to about 8.0% (w / v), from about 0.1% (w / v) to about 5.0% (w / v), from about 1.0% (w / v) to about 20.0% (w / v), from about 1.0% (w / v) to about 15.0% (w / v), from about 1.0% (w / v) to about 12.0% (w / v), from about 1.0% (w / v) to about 10.0% (w / v), about 1.0% (w / v) to about 8.0% (w / v), about 1.0% (w / v) to about 5.0% (w / v), about 2.0% (w / v) to about 20.0% (w / v), about 2.0% (w / v) to about 15.0% (w / v), about 2.0% (w / v) to about 12.0% (w / v), about 2.0% (w / v) to about 10.0% (w / v), about 2.0% (w / v) to about 8.0% (w / v), about 2.0% (w / v) to about 5.0% (w / v), about 4.0% (w / v) to about 20.0% (w / v), about 4.0% (w / v) to about 15.0% (w / v), about 4.0% (w / v) to about 12.0% (w / v), about 4.0% (w / v) to about 10.0% (w / v), about 4.0% (w / v) to about 9.0% (w / v), about 4.0% (w / v) to about 8.0% (w / v), about 4.0% (w / v) to about 5.0% (w / v), about 5.0% (w / v) to about 20.0% (w / v), about 5.0% (w / v) to about 15.0% (w / v), about 5.0% (w / v) to about 12.0% (w / v), about 5.0% (w / v) to about 10.0% (w / v), about 5.0% (w / v) to about 9.0% (w / v), about 5.0% (w / v) to about 8.0% (w / v), about 6.0% (w / v) to about 20.0% (w / v), about 6.0% (w / v) to about 15.0% (w / v), about 6.0% (w / v) to about 12.0% (w / v), about 6.0% (w / v) to about 10.0% (w / v), about 6.0% (w / v) to about 9.0% (w / v), about 6.0% (w / v) to about 8.0% (w / v), about 7.0% (w / v) to about 20.0% (w / v), about 7.0% (w / v) to about 15.0% (w / v), about 7.0% (w / v) to about 12.0% (w / v), about 7.0% (w / v) to about 10.0% (w / v), about 7.0% (w / v) to about 9.0% (w / v), about 7.0% (w / v) to about 8.0% (w / v), about 7.5% (w / v) to about 20.0% (w / v), about 7.5% (w / v) to about 15.0% (w / v), about 7.5% (w / v) to about 12.0% (w / v), about 7.5% (w / v) to about 10.0% (w / v), about 7.5% (w / v) to about 9.0% (w / v), about 7.5% (w / v) to about 8.5% (w / v), about 7.5% (w / v) to about 8.0% (w / v), about 8.0% (w / v) to about 20.0% (w / v), about 8.0% (w / v) to about 15.0% (w / v), about 8.0% (w / v) to about 14.0% (w / v), about 8.0% (w / v) to about 13.0% (w / v), about 8.0% (w / v) to about 12.0% (w / v), about 8.0% (w / v) to about 11.0% (w / v), about 8.0% (w / v) to about 10.0% (w / v), about 8.0% (w / v) to about 9.5% (w / v), or about 8.0% (w / v) to about 9.0% (w / v).

[0097] The concentration of the sugar alcohol can be freely adjusted within a range that maintains the stability of the antibody, and may vary individually depending on the type of each specific sugar alcohol. The concentration of the sugar alcohol can be any range or any value selected from about 0.1% (w / v) to about 20.0% (w / v). For example, the concentration of the sugar alcohol is about 0.1% (w / v) to about 20.0% (w / v), about 0.1% (w / v) to about 15.0% (w / v), about 0.1% (w / v) to about 12.0% (w / v), about 0.1% (w / v) to about 10.0% (w / v), about 0.1% (w / v) to about 8.0% (w / v), about 0.1% (w / v) to about 5.0% (w / v), about 1.0% (w / v) to about 20.0% (w / v), about 1.0% (w / v) to about 15.0% (w / v), about 1.0% (w / v) to about 12.0% (w / v), about 1.0% (w / v) to about 10.0% (w / v), about 1.0% (w / v) to about 8.0% (w / v), about 1.0% (w / v) to about 5.0% (w / v), about 2.0% (w / v) to about 20.0% (w / v), about 2.0% (w / v) to about 15.0% (w / v), about 2.0% (w / v) to about 12.0% (w / v), about 2.0% (w / v) to about 10.0% (w / v), about 2.0% (w / v) to about 8.0% (w / v), about 2.0% (w / v) to about 5.0% (w / v), about 3.0% (w / v) to about 20.0% (w / v), about 3.0% (w / v) to about 15.0% (w / v), about 3.0% (w / v) to about 12.0% (w / v), about 3.0% (w / v) to about 10.0% (w / v), about 3.0% (w / v) to about 9.0% (w / v), about 3.0% (w / v) to about 8.0% (w / v), about 3.0% (w / v) to about 7.0% (w / v), about 3.0% (w / v) to about 6.0% (w / v), about 3.0% (w / v) to about 5.0% (w / v), about 3.0% (w / v) to about 4.5% (w / v), about 3.0% (w / v) to about 4.0% (w / v), about 3.0% (w / v) to about 3.5% (w / v), about 4.0% (w / v) to about 20.0% (w / v), about 4.0% (w / v) to about 15.0% (w / v), about 4.0% (w / v) to about 12.0% (w / v), about 4.0% (w / v) to about 10.0% (w / v), about 4.0% (w / v) to about 9.0% (w / v), about 4.0% (w / v) to about 8.0% (w / v), about 4.0% (w / v) to about 7.0% (w / v), about 4.0% (w / v) to about 6.0% (w / v), about 4.0% (w / v) to about 5.0% (w / v), about 4.5% (w / v) to about 20.0% (w / v), about 4.5% (w / v) to about 15.0% (w / v), about 4.5% (w / v) to about 12.0% (w / v), about 4.5% (w / v) to about 10.0% (w / v), about 4.5% (w / v) to about 9.0% (w / v), about 4.5% (w / v) to about 8.0% (w / v), about 4.5% (w / v) to about 7.0% (w / v), about 4.5% (w / v) to about 6.0% (w / v), or about 4.5% (w / v) to It can be about 5.0% (w / v).

[0098] The concentration of the amino acid can be freely adjusted within a range that maintains the stability of the antibody, and may vary individually depending on each specific amino acid type. The concentration of the amino acid can be any range or value selected from about 1 mM to about 400 mM. For example, the concentration of the amino acid may be about 1 mM to about 400 mM, about 1 mM to about 300 mM, about 1 mM to about 200 mM, about 1 mM to about 100 mM, about 10 mM to about 400 mM, about 10 mM to about 300 mM, about 10 mM to about 200 mM, about 10 mM to about 100 mM, about 20 mM to about 400 mM, about 20 mM to about 300 mM, about 20 mM to about 200 mM, about 20 mM to about 150 mM, about 20 mM to about 100 mM, about 20 mM to about 50 mM, about 20 mM to about 40 mM, about 20 mM to about 30 mM, about 30 mM to about 400 mM, about 30 mM to about 300 mM, about 30 mM to about 200 mM, about 30 mM to about 150 mM, about 30 mM to about 100 mM, about 30 mM to about 80 mM, about 30 mM to about 50 mM, about 30 mM to about 40 mM, about 40 mM to about 400 mM, about 40 mM to about 300 mM, about 40 mM to about 200 mM, about 40 mM to about 150 mM, about 40 mM to about 100 mM, about 40 mM to about 80 mM, about 40 mM to about 50 mM, about 50 mM to about 400 mM, about 50 mM to about 300 mM, about 50 mM to about 250 mM, about 50 mM to about 200 mM, about 50 mM to about 150 mM, about 50 mM to about 100 mM, about 50 mM to about 80 mM, about 60 mM to about 400 mM, about 60 mM to about 300 mM,About 60 mM to about 250 mM, about 60 mM to about 200 mM, about 60 mM to about 150 mM, about 60 mM to about 100 mM, about 60 mM to about 80 mM, about 70 mM to about 400 mM, about 70 mM to about 300 mM, about 70 mM to about 250 mM, about 70 mM to about 200 mM, about 70 mM to about 150 mM, about 70 mM to about 100 mM, about 70 mM to about 90 mM, about 70 mM to about 80 mM, about 80 mM to about 400 mM, about 80 mM to about 300 mM, about 80 mM to about 250 mM, about 80 mM to about 200 mM, about 80 mM to about 150 mM, about 80 mM to about 120 mM, about 80 mM to about 100 mM, about 90 mM to about 400 mM, about 90 mM to about 300 mM, about 90 mM to about 250 mM, about 90 mM to about 200 mM, about 90 mM to about 150 mM, about 90 mM to about 100 mM, about 100 mM to about 400 mM, about 100 mM to about 300 mM, about 100 mM to about 280 mM, about 100 mM to about 250 mM, about 100 mM to about 220 mM, about 100 mM to about 200 mM, about 100 mM to about 180 mM, about 100 mM to about 150 mM, about 110 mM to about 400 mM, about 110 mM to about 300 mM, about 110 mM to about 280 mM, about 110 mM to about 250 mM, about 110 mM to about 220 mM, about 110 mM to about 200 mM, about 110 mM to about 180 mM, about 110 mM to about 150 mM, about 120 mM to about 400 mM, about 120 mM to about 300 mM, about 120 mM to about 280 mM, about 120 mM to about 250 mM,About 120 mM to about 220 mM, about 120 mM to about 200 mM, about 120 mM to about 180 mM, about 120 mM to about 150 mM, about 130 mM to about 400 mM, about 130 mM to about 300 mM, about 130 mM to about 280 mM, about 130 mM to about 250 mM, about 130 mM to about 220 mM, about 130 mM to about 200 mM, about 130 mM to about 180 mM, about 130 mM to about 150 mM, about 130 mM to about 140 mM, about 140 mM to about 400 mM, about 140 mM to about 300 mM, about 140 mM to about 280 mM, about 140 mM to about 250 mM, about 140 mM to about 220 mM, about 140 mM to about 200 mM, about 140 mM to about 180 mM, about 140 mM to about 150 mM, about 150 mM to about 400 mM, about 150 mM to about 300 mM, about 150 mM to about 250 mM, about 150 mM to about 200 mM, about 200 mM to about 400 mM, about 200 mM to about 350 mM, about 200 mM to about 300 mM, about 200 mM to about 250 mM, about 220 mM to about 400 mM, about 220 mM to about 350 mM, about 220 mM to about 300 mM, or about 220 mM to about 280 mM.

[0099] The concentration of the metal salt can be freely adjusted within a range that maintains the stability of the antibody, and may vary individually depending on the type of each specific metal salt. The concentration of the metal salt can be any range or value selected from about 1 mM to about 400 mM.For example, the concentration of the metal salt may be from about 1 mM to about 400 mM, from about 1 mM to about 300 mM, from about 1 mM to about 200 mM, from about 1 mM to about 100 mM, from about 1 mM to about 50 mM, from about 10 mM to about 400 mM, from about 10 mM to about 300 mM, from about 10 mM to about 200 mM, from about 10 mM to about 100 mM, from about 20 mM to about 400 mM, from about 20 mM to about 300 mM, from about 20 mM to about 200 mM, from about 20 mM to about 150 mM, from about 20 mM to about 100 mM, from about 50 mM to about 400 mM, from about 50 mM to about 300 mM, from about 50 mM to about 200 mM, from about 50 mM to about 150 mM, from about 50 mM to About 100 mM, about 80 mM to about 400 mM, about 80 mM to about 300 mM, about 80 mM to about 200 mM, about 80 mM to about 150 mM, about 100 mM to about 400 mM, about 100 mM to about 300 mM, about 100 mM to about 200 mM, about 100 mM to about 150 mM, about 100 mM to about 140 mM, about 120 mM to about 400 mM, about 120 mM to about 300 mM, about 120 mM to about 200 mM, about 120 mM to about 180 mM, about 120 mM to about 150 mM, about 120 mM to about 140 mM, about 130 mM to about 400 mM, about 130 mM to about 300 mM, about 130 It may be about 1 mM to about 200 mM, about 130 mM to about 180 mM, about 130 mM to about 150 mM, or about 130 mM to about 140 mM.

[0100] In one embodiment, the stabilizer may include one or more selected from sucrose, trehalose, sorbitol, mannitol, arginine, lysine, histidine, methionine, glycine, and NaCl.

[0101] In one embodiment, the stabilizer may include one or more selected from sucrose, sugar alcohols, and non-polar amino acids.

[0102] The sugar alcohol may include at least one selected from sorbitol and mannitol. The sugar alcohol may include mannitol.

[0103] The non-polar amino acid may include one or more selected from methionine, glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, and tryptophan. The non-polar amino acid may include one or more selected from methionine and glycine.

[0104] In certain embodiments, the stabilizer may include two or more selected from sucrose, sugar alcohols, and non-polar amino acids.

[0105] In certain embodiments, the stabilizer may include one or more or two or more selected from sucrose, mannitol, methionine, and glycine.

[0106] In certain embodiments, the stabilizer may include one or more or two or more selected from sucrose, methionine, and glycine.

[0107] In certain embodiments, the stabilizer may include methionine and glycine.

[0108] In certain embodiments, the stabilizer may include sucrose and methionine.

[0109] In certain embodiments, the stabilizer may include all of sucrose, methionine, and glycine.

[0110] In these specific examples, 'two or more kinds' may be, for example, two or more kinds including one kind of non-polar amino acid and sucrose; or two or more kinds including one kind of sugar alcohol and one kind of non-polar amino acid; or it may also be possible to select two or more kinds only from non-polar amino acids.

[0111] In these specific examples, the liquid formulation has a coagulation temperature (T) greater than 76.1°C. agg ) or have a diffusion interaction parameter (K) greater than 19.4 mL / g D ) may have.

[0112] Additionally, in these specific examples, the liquid formulation may have a Gibbs free energy change value (ΔG) greater than 3.43 kcal / mol in guanidine-HCl.

[0113] In one specific embodiment, the stabilizer may be selected from:

[0114] A) Sucrose;

[0115] B) Methionine;

[0116] C) Glycine;

[0117] D) Sucrose and methionine;

[0118] E) Sucrose and glycine;

[0119] F) Methionine and Glycine; or

[0120] G) Sucrose, methionine and glycine.

[0121] In certain embodiments, the stabilizer may comprise sucrose. The concentration of the sucrose is about 0.1% (w / v) to about 20.0% (w / v), about 0.1% (w / v) to about 15.0% (w / v), about 0.1% (w / v) to about 12.0% (w / v), about 0.1% (w / v) to about 10.0% (w / v), about 0.1% (w / v) to about 8.0% (w / v), about 0.1% (w / v) to about 5.0% (w / v), about 1.0% (w / v) to about 20.0% (w / v), about 1.0% (w / v) to about 15.0% (w / v), about 1.0% (w / v) to about 12.0% (w / v), about 1.0% (w / v) to about 10.0% (w / v), about 1.0% (w / v) to about 8.0% (w / v), about 1.0% (w / v) to about 5.0% (w / v), about 2.0% (w / v) to about 20.0% (w / v), about 2.0% (w / v) to about 15.0% (w / v), about 2.0% (w / v) to about 12.0% (w / v), about 2.0% (w / v) to about 10.0% (w / v), about 2.0% (w / v) to about 8.0% (w / v), about 2.0% (w / v) to about 5.0% (w / v), about 4.0% (w / v) to about 20.0% (w / v), about 4.0% (w / v) to about 15.0% (w / v), about It can be from about 4.0% (w / v) to about 12.0% (w / v), from about 4.0% (w / v) to about 10.0% (w / v), from about 4.0% (w / v) to about 9.0% (w / v), from about 4.0% (w / v) to about 8.0% (w / v), or from about 4.0% (w / v) to about 7.0% (w / v).

[0122] In certain embodiments, the stabilizer may comprise sorbitol. The concentration of the sorbitol is about 0.1% (w / v) to about 20.0% (w / v), about 0.1% (w / v) to about 15.0% (w / v), about 1.0% (w / v) to about 20.0% (w / v), about 1.0% (w / v) to about 15.0% (w / v), about 1.0% (w / v) to about 12.0% (w / v), about 1.0% (w / v) to about 10.0% (w / v), about 1.0% (w / v) to about 8.0% (w / v), about 1.0% (w / v) to about 5.0% (w / v), about 2.0% (w / v) to about 20.0% (w / v), about 2.0% (w / v) to about 15.0% (w / v), about 2.0% (w / v) to about 12.0% (w / v), about 2.0% (w / v) to about 10.0% (w / v), about 2.0% (w / v) to about 8.0% (w / v), about 2.0% (w / v) to about 5.0% (w / v), about 3.0% (w / v) to about 20.0% (w / v), about 3.0% (w / v) to about 15.0% (w / v), about 3.0% (w / v) to about 12.0% (w / v), about 3.0% (w / v) to about 10.0% (w / v), about 3.0% (w / v) to about 9.0% (w / v), about 3.0% (w / v) to about 8.0% (w / v), about 3.0% (w / v) to about 7.0% (w / v), about 3.0% (w / v) to about 6.0% (w / v), about 3.0% (w / v) to about 5.0% (w / v), about 4.0% (w / v) to about 20.0% (w / v), about 4.0% (w / v) to about 15.0% (w / v), about 4.0% (w / v) to about 12.0% (w / v), about 4.0% (w / v) to about 10.0% (w / v), about 4.0% (w / v) to about 9.0% (w / v), about 4.0% (w / v) to about 8.0% (w / v), about 4.0% (w / v) to about 7.0% (w / v), about 4.0% (w / v) to about 6.0% (w / v), approx. 4.It may be from 0% (w / v) to about 5.0% (w / v), or about 4.7% (w / v).

[0123] In certain embodiments, the stabilizer may comprise mannitol. The concentration of the mannitol is about 0.1% (w / v) to about 20.0% (w / v), about 0.1% (w / v) to about 15.0% (w / v), about 1.0% (w / v) to about 20.0% (w / v), about 1.0% (w / v) to about 15.0% (w / v), about 1.0% (w / v) to about 12.0% (w / v), about 1.0% (w / v) to about 10.0% (w / v), about 1.0% (w / v) to about 8.0% (w / v), about 1.0% (w / v) to about 5.0% (w / v), about 2.0% (w / v) to about 20.0% (w / v), about 2.0% (w / v) to about 15.0% (w / v), about 2.0% (w / v) to about 12.0% (w / v), about 2.0% (w / v) to about 10.0% (w / v), about 2.0% (w / v) to about 8.0% (w / v), or about 2.0% (w / v) to about 5.0% (w / v).

[0124] In certain embodiments, the stabilizer may comprise a nonpolar amino acid. The concentration of the nonpolar amino acid is about 1 mM to about 400 mM, about 1 mM to about 300 mM, about 1 mM to about 200 mM, about 1 mM to about 150 mM, about 1 mM to about 100 mM, about 10 mM to about 400 mM, about 10 mM to about 300 mM, about 10 mM to about 200 mM, about 10 mM to about 150 mM, about 10 mM to about 100 mM, about 20 mM to about 400 mM, about 20 mM to about 300 mM, about 20 mM to about 200 mM, about 20 mM to about 150 mM, about 20 mM to about 100 mM, about 50 mM to 400 mM, about 50 mM to about 300 mM, about 50 mM to about 250 mM, about 50 mM to about 200 mM, about 50 mM to about 150 mM, about 50 mM to about 100 mM, about 60 mM to about 400 mM, about 60 mM to about 300 mM, about 60 mM to about 250 mM, about 60 mM to about 200 mM, about 60 mM to about 150 mM, about 60 mM to about 100 mM, about 70 mM to about 400 mM, about 70 mM to about 300 mM, about 70 mM to about 250 mM, about 70 mM to about 200 mM, about 70 mM to about 150 mM, about 70 mM to about 100 mM, about 80 mM to about 400 mM, about 80 mM to about 300 mM, about 80 mM to about 250 mM, about 80 mM to about 200 mM, about 80 mM to It may be about 150 mM, about 80 mM to about 120 mM, or about 80 mM to about 100 mM.

[0125] In certain embodiments, the stabilizer may comprise methionine. The concentration of the methionine is about 1 mM to about 400 mM, about 1 mM to about 300 mM, about 1 mM to about 200 mM, about 1 mM to about 150 mM, about 1 mM to about 100 mM, about 10 mM to about 400 mM, about 10 mM to about 300 mM, about 10 mM to about 200 mM, about 10 mM to about 150 mM, about 10 mM to about 100 mM, about 20 mM to about 400 mM, about 20 mM to about 300 mM, about 20 mM to about 200 mM, about 20 mM to about 150 mM, about 20 mM to about 100 mM, about 50 mM to 400 mM, about 50 mM to about 300 mM, about 50 mM to about 250 mM, about 50 mM to about 200 mM, about 50 mM to about 150 mM, about 50 mM to about 100 mM, about 60 mM to about 400 mM, about 60 mM to about 300 mM, about 60 mM to about 250 mM, about 60 mM to about 200 mM, about 60 mM to about 150 mM, about 60 mM to about 100 mM, about 70 mM to about 400 mM, about 70 mM to about 300 mM, about 70 mM to about 250 mM, about 70 mM to about 200 mM, about 70 mM to about 150 mM, about 70 mM to about 100 mM, about 80 mM to about 400 mM, about 80 mM to about 300 mM, about 80 mM to about 250 mM, about 80 mM to about 200 mM, about 80 mM to It may be about 150 mM, about 80 mM to about 120 mM, about 80 mM to about 100 mM, or about 90 mM.

[0126] In certain embodiments, the stabilizer may comprise glycine. The concentration of the glycine is about 1 mM to about 400 mM, about 10 mM to about 400 mM, about 10 mM to about 300 mM, about 10 mM to about 250 mM, about 50 mM to about 400 mM, about 50 mM to about 300 mM, about 50 mM to about 250 mM, about 50 mM to about 200 mM, about 50 mM to about 150 mM, about 100 mM to about 400 mM, about 100 mM to about 300 mM, about 100 mM to about 280 mM, about 100 mM to about 250 mM, about 150 mM to about 400 mM, about 150 mM to about 300 mM, about 150 mM to about 250 mM, about 200 mM to about 400 mM, about 200 mM to about 350 mM, about 200 mM to about 300 mM, about 200 mM to about 250 mM, about 220 mM to about 400 mM, about 220 mM to about 350 mM, about 220 mM to about 300 mM, or about 220 mM to about 280 mM.

[0127] (4) Surfactant

[0128] Liquid formulations according to the aspect may additionally contain a surfactant.

[0129] In one specific embodiment, the liquid formulation may be a liquid formulation comprising an anti-CD20 antibody; a buffer; and a surfactant, and having a pH of about 4.0 to about 8.0.

[0130] In one specific embodiment, the liquid formulation may be a liquid formulation comprising an anti-CD20 antibody; a buffer; a stabilizer; and a surfactant, and having a pH of about 4.0 to about 8.0.

[0131] In one specific embodiment, the liquid formulation may be a liquid formulation comprising an anti-CD20 antibody and a surfactant, and not comprising a buffer.

[0132] In one specific embodiment, the liquid formulation may be a liquid formulation comprising an anti-CD20 antibody; a stabilizer; and a surfactant, and not comprising a buffer.

[0133] The surfactant may be selected from any pharmaceutically acceptable surfactants capable of evenly dispersing a protein (e.g., antibody) in a liquid formulation medium.

[0134] The above surfactant may be a nonionic surfactant.

[0135] Specifically, the surfactant may be at least one selected from the group consisting of polysorbate, poloxamer, sorbitan ester of other fatty acids, polyethylene-polypropylene glycol, polyoxyethylene compound, and sodium dodecyl sulfate (SDS).

[0136] The above polysorbate may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85.

[0137] The above poloxamer may include a PEO-PPO-PEO copolymer (PEO is poly(ethylene oxide) and PPO is poly(propylene oxide)). For example, the above poloxamer may include poloxamer 188, poloxamer 407, etc.

[0138] The above sorbitan esters of other fatty acids may mean sorbitan esters of other fatty acids than polysorbates, and may include, for example, sorbitan polyethoxylates.

[0139] The above polyoxyethylene compound may include polyoxyethylene-stearate, polyoxyethylene alkyl ether (alkyl: C1-C30), polyoxyethylene monolyl ether, alkylphenyl polyoxyethylene copolymer (alkyl: C1-C30), etc.

[0140] In one embodiment, the surfactant may include one or more selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, poloxamer 188, and poloxamer 407.

[0141] In one embodiment, the surfactant may include polysorbate 20, polysorbate 80, poloxamer 188, or a combination of two or more thereof.

[0142] In certain embodiments, the surfactant may comprise polysorbate 20.

[0143] In certain embodiments, the surfactant may comprise polysorbate 80.

[0144] In certain embodiments, the surfactant may comprise poloxamer 188.

[0145] The concentration of the surfactant may be any range or any value selected from about 0.01% (w / v) to about 0.9% (w / v). For example, the concentration of the surfactant can be from about 0.01% (w / v) to about 0.9% (w / v), from about 0.01% (w / v) to about 0.5% (w / v), from about 0.01% (w / v) to about 0.1% (w / v), from about 0.01% (w / v) to about 0.09% (w / v), from about 0.01% (w / v) to about 0.05% (w / v), from about 0.02% (w / v) to about 0.1% (w / v), from about 0.02% (w / v) to about 0.08% (w / v), or from about 0.02% (w / v) to about 0.06% (w / v).

[0146] In certain embodiments, the concentration of the surfactant may be about 0.02% (w / v).

[0147] In certain embodiments, the concentration of the surfactant may be about 0.06% (w / v).

[0148] (5) Diluent

[0149] Liquid formulations according to the aspect may additionally contain a diluent.

[0150] The diluent may be an aqueous carrier. The aqueous carrier may be a pharmaceutically acceptable carrier that is safe and non-toxic when administered to humans, such as water, saline solution, Ringer's solution, dextrose, or a mixture thereof.

[0151] In one specific embodiment, the diluent may be water. The water may be water in its standard state. Accordingly, the liquid formulation may be an aqueous liquid formulation.

[0152] The term "standard state" is a reference to the temperature and pressure used to describe a solution having a specific composition, and may mean, for example, a temperature of 25°C±2°C and a pressure of 1 atmosphere. Those skilled in the art will recognize that liquid formulations equivalent to those disclosed herein can be produced at other temperatures and pressures. Whether such liquid formulations are equivalent to those disclosed herein can be determined under standard state conditions.

[0153] (6) Stability

[0154] Liquid formulations according to the daily pattern are Ocrevus ® ) may be a biosimilar. Therefore, the liquid formulation according to the aspect has improved stability compared to Ocrevus.

[0155] The term "biosimilar," also known as "biogeneric," refers to a copy of an original biopharmaceutical. Because biopharmaceuticals are produced through cells rather than synthetic chemicals, they cannot be perfectly identical to the original drug. Therefore, a biopharmaceutical copy is called a biosimilar, meaning it is similar, though not identical, to the original drug.

[0156] The term "stability" means that the antibody (e.g., ocrelizumab) contained in the formulation substantially retains its physical stability, chemical stability, and / or biological activity before, during, and after administration, further manufacturing processes, storage, or preservation. Physical stability, chemical stability, and / or biological activity can be assessed by conventionally known methods.

[0157] A method for evaluating the stability of antibodies contained in a formulation over a short period of time is to expose the formulation to heat (temperature) or chemicals, which are factors that cause structural and physicochemical denaturation of proteins, and then measure the diffusion interaction parameter (K D ), coagulation temperature (T agg ), there are methods to measure the change in Gibbs free energy (ΔG), etc. For example, "improved stability" means the measured K for the formulation D, T agg , or ΔG value may mean an increase of 0.01% or more, 0.1% or more, 0.5% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, or 20% or more compared to the existing formulation. K D , T agg , or an increase in the ΔG value may indicate improved stability due to a decrease in the degree to which antibodies within the formulation aggregation due to external factors (e.g., heat, temperature, chemicals).

[0158] The term "aggregate" may refer to high molecular weight (HMW) species formed by aggregation of antibody proteins. The term "protein aggregation rate" may be expressed as the percentage of high molecular weight species content (%HMW) of the antibody in the formulation at a given point in time. %HMW may be measured by, but is not limited to, size exclusion chromatography (SEC). For example, "improved stability" may mean that the %HMW of the antibody measured for the formulation is reduced by at least 0.01%, at least 0.1%, at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, or at least 20% compared to the original formulation. A decrease in %HMW may mean that the degree to which the antibody in the formulation undergoes aggregation is reduced, thereby improving stability.

[0159] The stability assessment may be performed immediately after manufacturing the formulation; or after a certain period of storage under accelerated stability conditions or stress stability conditions. The accelerated stability conditions may include conditions used in accelerated tests for pharmaceuticals, such as a temperature of 25±2°C and a relative humidity (RH) of 60±5%. The stress stability conditions may include conditions used in stress tests for pharmaceuticals, such as a temperature of 40±2°C and a relative humidity (RH) of 75+5%.

[0160] The above liquid formulation has an increased diffusion interaction parameter (K D ) may have.

[0161] The above liquid formulation contains acetic acid and acetate as buffers and has an increased K compared to the liquid formulation having a pH of 5.3. D The liquid formulation may have an increased K compared to the liquid formulation containing 20 mM acetate buffer and having a pH of 5.3.D It may have .

[0162] The above liquid formulation has increased K compared to the liquid formulation containing trehalose as a stabilizer. D The liquid formulation may have increased K compared to the liquid formulation containing 4% (w / v) trehalose stabilizer. D It may have .

[0163] The above liquid formulation has increased K compared to Ocrevus. D It may have .

[0164] The liquid formulation has a diffusion interaction parameter (K) of greater than 19.4 mL / g, greater than or equal to about 19.5 mL / g, greater than or equal to about 20.00 mL / g, greater than or equal to about 30.00 mL / g, greater than or equal to about 50.00 mL / g, or greater than or equal to about 100.00 mL / g. D ) may have.

[0165] In one embodiment, the liquid formulation has a diffusion interaction parameter (K) greater than 19.4 mL / g D ) and contains acetate or histidine as a buffer, and the pH of the liquid formulation may be about 4.0 to about 7.0.

[0166] In one embodiment, the liquid formulation has a diffusion interaction parameter (K) greater than 19.4 mL / g D ) and can be selected from the following:

[0167] A) the buffer contains acetate and has a pH of 4.0 or more and less than 6.0; or

[0168] B) The buffer contains histidine and has a pH of about 5.0 to about 7.0.

[0169] In one embodiment, the liquid formulation has a diffusion interaction parameter (K) greater than 19.4 mL / g D ) and can be selected from the following:

[0170] A) The stabilizer contains sucrose;

[0171] B) the stabilizer contains a sugar alcohol; or

[0172] C) The stabilizer contains nonpolar amino acids.

[0173] In one embodiment, the liquid formulation has a diffusion interaction parameter (K) greater than 19.4 mL / g D ) and can be selected from the following:

[0174] A) The stabilizer contains sucrose;

[0175] B) The stabilizer contains sorbitol;

[0176] C) the stabilizer contains methionine; or

[0177] D) The stabilizer contains glycine.

[0178] The above liquid formulation may inhibit aggregation of antibodies.

[0179] The above liquid formulation has an increased coagulation temperature (T agg ) may have.

[0180] The above liquid formulation has increased T compared to the liquid formulation containing trehalose as a stabilizer. agg The liquid formulation may have an increased T compared to the liquid formulation containing 4% (w / v) trehalose stabilizer. agg The liquid formulation may have increased T compared to Ocrevus. agg It may have .

[0181] The above liquid formulation has a coagulation temperature (T) of greater than 76.1°C or about 76.11°C or higher. agg ) may have.

[0182] In one specific embodiment, the liquid formulation has a coagulation temperature (T) greater than 76.1°C. agg) and may contain sugar alcohols or non-polar amino acids as stabilizers.

[0183] In one specific embodiment, the liquid formulation has a coagulation temperature (T) greater than 76.1°C. agg ), and the liquid formulation may contain mannitol or glycine as a stabilizer.

[0184] The above liquid formulation may inhibit denaturation of antibodies.

[0185] The above liquid formulation may have an increased Gibbs free energy change value (ΔG) upon treatment with a denaturant.

[0186] The liquid formulation may have an increased ΔG compared to a liquid formulation comprising trehalose as a stabilizer. The liquid formulation may have an increased ΔG compared to a liquid formulation comprising 4% (w / v) trehalose stabilizer. The liquid formulation may have an increased ΔG compared to Ocrevus.

[0187] The liquid formulation may have a Gibbs free energy change value (ΔG) of greater than about 3.43 kcal / mol, greater than or equal to about 3.44 kcal / mol, greater than or equal to about 3.5 kcal / mol, or greater than or equal to about 4.0 kcal / mol in guanidine-HCl.

[0188] In one embodiment, the liquid formulation has a Gibbs free energy change value (ΔG) of greater than about 3.43 kcal / mol in guanidine-HCl, and may include sucrose, a sugar alcohol, or a non-polar amino acid as a stabilizer.

[0189] The above liquid formulation may have a reduced high molecular weight species content (%HMW).

[0190] The above liquid formulation may have a %HMW of antibody of 0.73% or less or less than 0.73% measured after storage at 40°C for 4 weeks.

[0191] The above liquid formulation may have a %HMW of antibody of less than 0.64% or less than 0.63% measured after storage at 40°C for 2 weeks.

[0192] The above liquid formulation may have a %HMW of antibody of 0.53% or less, less than 0.53%, or 0.52% or less measured after storage at 25°C for 2 weeks.

[0193] In one specific embodiment, the liquid formulation has a %HMW of antibody of 0.73% or less after 4 weeks of storage at 40°C; a %HMW of antibody of 0.64% or less after 2 weeks of storage at 40°C; and / or a %HMW of antibody of 0.53% or less after 2 weeks of storage at 25°C, and may be selected from the following:

[0194] A) the buffer comprises acetate, the pH is 4.0 or more and less than 6.0, and the stabilizer is at least one selected from sucrose, sugar alcohol, and non-polar amino acid; and

[0195] B) The buffer comprises histidine, the pH is about 5.0 to about 7.0, and the stabilizer is at least one selected from sucrose, sugar alcohol, and non-polar amino acid.

[0196] Buffer-free formulations, according to one aspect, can exhibit self-buffering capabilities without the inclusion of a buffer. Therefore, they may exhibit superior stability compared to commercially available formulations, such as Ocrevus, which contain buffers.

[0197] (7) Formulation

[0198] The term "liquid formulation" means a formulation in liquid form.

[0199] The liquid formulation according to one aspect is a stable liquid formulation of an anti-CD20 antibody. The liquid formulation may have improved stability compared to Ocrevus.

[0200] Liquid formulations containing buffers according to the aspect of the invention may be selected from the following items:

[0201] 1) A liquid formulation comprising an anti-CD20 antibody (e.g., ocrelizumab) and a buffer, and having a pH of about 4.0 to about 8.0;

[0202] 2) A liquid formulation comprising an anti-CD20 antibody (e.g., ocrelizumab); and at least one selected from acetate, a salt thereof, and a hydrate thereof as a buffer, and having a pH of 4.0 or more and less than 6.0;

[0203] 3) A liquid formulation comprising an anti-CD20 antibody (e.g., ocrelizumab); and at least one selected from acetate, a salt thereof, and a hydrate thereof as a buffer, and having a pH of 4.0 to 5.5;

[0204] 4) A liquid formulation comprising an anti-CD20 antibody (e.g., ocrelizumab); and at least one selected from acetate, a salt thereof, and a hydrate thereof as a buffer, and having a pH of 4.0 to 5.0;

[0205] 5) A liquid formulation comprising an anti-CD20 antibody (e.g., ocrelizumab); and at least one selected from histidine, a salt thereof, and a hydrate thereof as a buffer, and having a pH of 5.0 to 7.0;

[0206] 6) A liquid formulation comprising an anti-CD20 antibody (e.g., ocrelizumab); a buffer; and a stabilizer, and having a pH of 4.0 to 8.0;

[0207] 7) A liquid formulation comprising an anti-CD20 antibody (e.g., ocrelizumab); a buffer; and at least one selected from sucrose, a sugar alcohol, and a non-polar amino acid as a stabilizer, and having a pH of 4.0 to 8.0;

[0208] 8) A liquid formulation comprising an anti-CD20 antibody (e.g., ocrelizumab); a buffer; and at least one selected from sucrose, mannitol, methionine, and glycine as a stabilizer, and having a pH of 4.0 to 8.0;

[0209] 9) A liquid formulation comprising an anti-CD20 antibody (e.g., ocrelizumab); a buffer; and at least one selected from sucrose, methionine, and glycine as a stabilizer, and having a pH of 4.0 to 8.0;

[0210] 10) A liquid formulation comprising an anti-CD20 antibody (e.g., ocrelizumab); a buffer; and two or more selected from sucrose, methionine, and glycine as a stabilizer, and having a pH of 4.0 to 8.0;

[0211] 11) A liquid formulation having a combination of the buffer and pH of any one of items 6 to 10;

[0212] 12) A liquid formulation further comprising a surfactant according to any one of items 1 to 11;

[0213] 13) In item 12, a liquid formulation comprising the surfactant polysorbate 20, polysorbate 80, poloxamer 188, or a combination of two or more thereof;

[0214] 14) A liquid formulation according to any one of items 12 to 13, wherein the concentration of the surfactant is from about 0.01% (w / v) to about 0.9% (w / v);

[0215] 15) A liquid formulation comprising ocrelizumab; histidine as a buffer; one or more selected from sucrose, sugar alcohol, and non-polar amino acid as a stabilizer; and a non-ionic surfactant, and having a pH of about 5.0 to about 6.5;

[0216] 16) A liquid formulation comprising about 5 mg / ml to about 300 mg / ml of ocrelizumab; histidine as a buffer; one or more selected from sucrose, mannitol, methionine, and glycine as a stabilizer; and polysorbate 20, polysorbate 80, poloxamer 188, or a combination of two or more thereof as a nonionic surfactant, and having a pH of about 5.0 to about 6.0.

[0217] 17) A liquid formulation for intravenous injection in any one of items 1 to 16.

[0218] The liquid formulation according to one aspect is a self-buffering liquid formulation of an anti-CD20 antibody. Since the liquid formulation can have a buffering capacity without including a buffer, it can have excellent stability.

[0219] Buffer-free liquid formulations according to the aspect may be selected from the following items:

[0220] 1) A liquid formulation containing an anti-CD20 antibody (e.g., ocrelizumab) and not containing a buffer;

[0221] 2) A liquid formulation containing an anti-CD20 antibody (e.g., ocrelizumab) and not containing an acetate buffer;

[0222] 3) A liquid formulation comprising an anti-CD20 antibody (e.g., ocrelizumab) and not containing acetic acid, acetate, or a combination thereof as a buffer;

[0223] 4) A liquid formulation in any one of items 1 to 3, wherein the concentration of the anti-IL-23 antibody is greater than about 30 mg / ml;

[0224] 5) A liquid formulation, which is a self-buffering formulation in any one of items 1 to 4;

[0225] 6) A liquid formulation substantially free of a buffer other than the anti-CD20 antibody in any one of items 1 to 5;

[0226] 7) A liquid formulation further comprising a stabilizer in any one of items 1 to 6;

[0227] 8) In item 7, the stabilizer is a liquid formulation comprising at least one selected from sugar, sugar alcohol, amino acid, metal salt, salt thereof and hydrate thereof;

[0228] 9) In item 7, a liquid formulation comprising at least one selected from sucrose, trehalose, sorbitol, mannitol, arginine, lysine, histidine, methionine, glycine, and NaCl;

[0229] 10) In item 7, a liquid formulation comprising at least one stabilizer selected from sucrose, sugar alcohol, and non-polar amino acid;

[0230] 11) In item 10, a liquid formulation wherein the stabilizer is at least one selected from sucrose, methionine, and glycine;

[0231] 12) A liquid formulation further comprising a surfactant according to any one of items 1 to 11;

[0232] 13) In item 12, a liquid formulation comprising the surfactant polysorbate 20, polysorbate 80, poloxamer 188, or a combination of two or more thereof;

[0233] 14) A liquid formulation according to any one of items 12 to 13, wherein the concentration of the surfactant is from about 0.01% (w / v) to about 0.9% (w / v), from about 0.01% (w / v) to about 0.1% (w / v), or from about 0.02% (w / v);

[0234] 15) A liquid formulation comprising ocrelizumab in excess of 30 mg / ml; one or more selected from sucrose, sugar alcohol, and non-polar amino acid as a stabilizer; and a non-ionic surfactant, and not including a buffer; or

[0235] 16) A liquid formulation for subcutaneous injection in any one of items 1 to 15.

[0236] (8) Device

[0237] Another aspect provides a device comprising a liquid formulation according to the above aspect.

[0238] The device is primarily intended for parenteral administration (e.g., subcutaneous, intramuscular, intravenous, intraperitoneal, intracerebrospinal, intraarticular, intrasynovial, and / or intrathecal administration). The device may be accompanied by instructions for administration.

[0239] The device may contain the liquid formulation in a container selected from among a syringe, a pre-filled syringe, an autoinjector, a bottle, a vial, and a tube.

[0240] In one specific embodiment, the liquid formulation may be contained in a vial. The vial may be a single-dose vial.

[0241] In one specific example, the liquid formulation may be contained in a prefilled syringe. The prefilled syringe may be a single-dose prefilled syringe.

[0242] (9) Treatment of diseases

[0243] Another aspect provides a method for treating a condition involving B cells expressing CD20, comprising administering to a subject in need thereof a liquid formulation according to the above aspect. The liquid formulation may be contained in a device.

[0244] Another aspect provides the use of a liquid formulation according to the above aspect in the manufacture of a medicament for treating a condition involving B cells expressing CD20.

[0245] The method for treating a condition involving B cells expressing CD20 may further comprise, prior to the administering step, a step of identifying a subject in need of administration of an anti-CD20 antibody (e.g., ocrelizumab).

[0246] The subject may be a subject requiring administration of a liquid formulation containing the anti-CD20 antibody (e.g., ocrelizumab). The subject requiring administration of the liquid formulation containing the anti-CD20 antibody (e.g., ocrelizumab) may be a subject having a disease or disorder that can be significantly treated (e.g., symptoms eliminated, alleviated, relieved, or improved, etc.) by administration of the anti-CD20 antibody. The subject may be selected from mammals, including humans.

[0247] The above liquid formulation can be administered in a pharmaceutically effective amount.

[0248] The condition associated with B cells expressing CD20 may include any condition or disease that can be treated by administration of an anti-CD20 antibody. The condition or disease that can be treated by administration of an anti-CD20 antibody (e.g., ocrelizumab) may include any indication currently approved or that may be approved in the future for an anti-CD20 antibody (e.g., ocrelizumab).

[0249] The above condition may be any one selected from lymphoma, leukemia, tissue transplant rejection, autoimmune disease, and multiple sclerosis (MS).

[0250] The condition may be multiple sclerosis (MS). The multiple sclerosis may be relapsing forms of multiple sclerosis (RMS), primary pregressive multiple sclerosis (PPMS), clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), or active secondary progressive multiple sclerosis (active SPMS).

[0251] (10) Route of administration and dosage

[0252] Liquid formulations, depending on the dosage form, may be administered parenterally. Such parenteral routes may include subcutaneous administration, intravenous administration, etc. Parenteral administration may be by bolus injection or continuous infusion.

[0253] In one embodiment, the liquid formulation may be for intravenous injection. In a specific embodiment, the buffer-containing formulation may be for intravenous injection.

[0254] In one embodiment, the liquid formulation may be for subcutaneous injection. In a specific embodiment, the buffer-free formulation may be for subcutaneous injection.

[0255] The above liquid formulation may be formulated into a formulation suitable for the above administration route. For example, the above liquid formulation may be formulated into an injection, a ready-to-use injectable, etc., but is not limited thereto.

[0256] The liquid formulation may be formulated to contain the entire amount or a pharmaceutically effective amount of the anti-CD20 antibody (e.g., ocrelizumab) in one formulation, or may be formulated to contain two or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) formulations. The liquid formulation may be included in a single-dose form of the device.

[0257] The above liquid formulation may be administered into the body at once (e.g., within 1 minute, within 30 seconds, within 20 seconds, or within 10 seconds) for the entire amount of the anti-CD20 antibody (e.g., ocrelizumab) contained in one formulation; or may be administered into the body slowly over a period of, but not limited to, 5 minutes or more, 10 minutes or more, 30 minutes or more, 60 minutes or more, 90 minutes or more, 120 minutes or more, 150 minutes or more, 180 minutes or more, 210 minutes or more, or 240 minutes or more.

[0258] The target of administration of the above liquid formulation may be selected from mammals including primates (e.g., humans, etc.), rodents (e.g., mice, rats, guinea pigs, hamsters, rabbits, etc.), cats, dogs, pigs, cows, horses, etc.

[0259] The pharmaceutically effective amount of the above liquid formulation or the anti-CD20 antibody (e.g., ocrelizumab) contained therein may refer to an amount or dosage that can exhibit a desired pharmacological effect, such as elimination, reduction, alleviation, or improvement of symptoms. The pharmaceutically effective amount may be determined in various ways depending on factors such as the formulation method, administration method, patient's age, weight, sex, pathological condition (severity of condition), food, administration time, administration interval, administration route, excretion rate, response sensitivity, previous therapy, clinical history, etc. The dosage may be adjusted according to the judgment of the physician in charge. The pharmaceutically effective amount may be administered at once or administered in two or more divided doses.

[0260] For example, the liquid formulation can be administered once every two weeks to six months over a period of two weeks or more at a dose such that the anti-CD20 antibody (e.g., ocrelizumab) is about 600 mg, about 500 mg, about 400 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 50 mg, about 25 mg, or about 10 mg.

[0261] The above liquid formulation can be prepared as a general bulk formulation, and the components of the liquid formulation can be adjusted to a higher concentration than that required for administration and used after being suitably diluted before administration.

[0262] Liquid formulations of anti-CD20 antibodies according to one aspect may have improved stability compared to existing commercial formulations.

[0263] Liquid formulations of anti-CD20 antibodies according to one aspect can have excellent stability because they have self-buffering ability even without containing a buffer.

[0264] Therefore, the above liquid formulation can be usefully used as a pharmaceutical agent for treating conditions related to B cells expressing CD20.

[0265] Figure 1 shows the diffusion interaction parameters (K) for 24 formulations with different buffer types and pH combinations and one formulation with the same buffer and pH conditions as Ocrevus. D ) is a graph showing the results of measurement.

[0266] Figure 2 shows the coagulation temperature (T) for 11 formulations with different stabilizer types and 1 formulation with the same stabilizer conditions as Ocrevus. agg ) is a graph showing the results of measurement.

[0267] Figure 3 shows the diffusion interaction parameter (K) for 11 formulations with different stabilizer types and 1 formulation with the same stabilizer conditions as Ocrevus. D) is a graph showing the results of measurement.

[0268] Figure 4 shows the Gibbs free energy change (ΔG) values ​​for 11 formulations with different stabilizer types and 1 formulation with the same stabilizer conditions as Ocrevus. 1600 ug / mL ) is a graph showing the results of measurement.

[0269] Figure 5 is a graph showing the results of measuring the percentage of high molecular weight species (%HMW) for 12 formulations of Table 3 with various buffer / pH and stabilizer combinations and 1 formulation with the same composition as Ocrevus.

[0270] Figure 6 is a graph showing the results of measuring the high molecular weight species content (%HMW) for 11 formulations of Table 4 with various buffer / pH and stabilizer combinations and 1 formulation with the same composition as Ocrevus.

[0271] Figure 7 is a titration curve measuring the pH according to the concentration (μmol / mL) of HCl or NaOH added for seven formulations with different buffering agents and antibody concentrations.

[0272] Figure 8 is a graph showing the results of evaluating the buffer capacity (β) for seven formulations with different buffering agents and antibody concentrations.

[0273] Figure 9 is a graph showing the results of measuring the percentage of high molecular weight species content (%HMW) for seven buffer-free formulations with various stabilizer types and one formulation with the same buffer and stabilizer conditions as Ocrevus.

[0274] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0275] [Experimental Method]

[0276] 1. Analysis of the diffusion interaction parameter Kd

[0277] To evaluate whether the binding force in the fluid phase is attractive or repulsive as the protein concentration increases when the sample is exposed at room temperature, the diffusion interaction parameter, K D was analyzed. This is a parameter that enables evaluation or ranking of excellent formulations according to aggregation tendency by evaluating the binding force between substances that causes irreversible aggregation. Specifically, each sample was diluted using a buffer (protein concentration: 2, 4, 6, 8, 10 mg / mL) and loaded into a 96-well plate. The plate was loaded into a DynaPro® Plate ReaderTM II (Wayatt Technology). The diffusion coefficient value according to the protein concentration of the prepared sample was measured, and then the slope and y-intercept of the graph were used to calculate K D If the value is positive, the repulsion between substances is dominant, so the cohesion tendency is weak, and if it is negative, the attraction is dominant, so the cohesion tendency is strong. K D The larger the positive number, the more stable the formulation.

[0278] 2. Measurement of coagulation temperature (Tagg)

[0279] The aggregation temperature was measured using dynamic light scattering (DLS) measurement. Specifically, each sample was diluted with each buffer and loaded into a 96-well plate. The plate was loaded into a DynoPro® Plate ReaderTM II (Wyatt Technology). The sample was heated at a rate of 0.25°C / min in the range of 25 to 80°C, and the size of the aggregates in the formulation was measured using DLS. The stability was evaluated by measuring the temperature at which the size of the aggregates changed, and the aggregation temperature (T agg ) The higher the value, the more stable the formulation.

[0280] 3. Analysis of high molecular weight species content (%HMW)

[0281] The percentage of high molecular weight species (%HMW) was determined using Waters size exclusion chromatography (SEC). The protein was separated into three peaks based on its molecular weight. These three peaks correspond to the HMW peak (protein aggregation), the Monomer peak, and the LMW peak (protein degradation), in descending order of retention time (i.e., increasing protein molecular weight).

[0282] [Calculation Formula 1]

[0283] %HMW = {area of ​​HMW / area of ​​(HMW + monomer + LMW)}*100

[0284] Each formulation sample for stability testing was stored in a chamber maintaining accelerated stability conditions of 25±2℃ and 60±5% relative humidity (RH), or in a chamber maintaining harsh stability conditions of 40±2℃ and 75±5% RH.

[0285] 4. Measurement of Gibbs free energy change value (ΔG)

[0286] The HUNKY device (HUNKY, Unchained Labs) is a device that can assess protein stability through chemical denaturation. This device uses a denaturant and a sample to measure the change in Gibbs free energy (ΔG). Specifically, 6M guanidine-HCl, used as a denaturant, was gradually added to a 1600 µg / ml ocrelizumab sample formulation, and the degree of denaturation was measured. A higher ΔG indicates a more stable formulation.

[0287] 5. Buffer capacity (β) evaluation

[0288] Buffer capacity (β) is measured by gradually adding a titrant solution (e.g. HCl or NaOH) of a specific concentration to the manufactured formulation, and the resulting value is used to calculate the amount of acid (H) required for a pH change of 1. + ion) or base (OH - The number of moles (mole) of ions was calculated and evaluated. The buffering capacity (β) is calculated according to the following calculation formula 2, and the higher the β value, the higher the buffering capacity and the more stable the formulation.

[0289] [Calculation Formula 2]

[0290] β = (moles of H + or OH - ) / (ΔpH)(volume of buffer in mL)

[0291] [Example]

[0292] Example 1. Screening for the optimal combination of buffer and pH through Kd measurement.

[0293] Ocrevus ®) is a liquid formulation containing 30 mg / mL ocrelizumab, 20 mM acetate (2.14 mg / mL sodium acetate trihydrate + 0.25 mg / mL acetic acid), 40 mg / mL (4% (w / v)) trehalose, 0.2 mg / mL (0.02% (w / v)) polysorbate 20, pH 5.3.

[0294] The Ocrevus formulation was manufactured by varying the combination of buffer types and pH within the range applicable to approved biopharmaceuticals. Specifically, using ocrelizumab (CAS No. 637334-45-3), an anti-CD20 antibody, a liquid formulation having the composition shown in Table 1 below was manufactured.

[0295] K of each manufactured formulation D was measured. Attractive interaction between proteins is the main cause of protein aggregation. K D An increase in K indicates a decrease in the inter-protein attraction. Therefore, increased K D means improved stability.

[0296] Table 1 shows the K of the formulation according to various combinations of buffer types and pH. D These are the measurement results.

[0297] No. a buffer pHK D(mL / g)1-120 mM acetate 4.0168.71-220 mM acetate 4.577.91-320 mM acetate 5.036.11-420 mM acetate 5.522.61-520 mM acetate 6.014.31-620 mM histidine 5.021.51-720 mM histidine 5.520.01-820 mM histidine 6.027.91-920 mM histidine 6.550.41-1020 mM histidine 7.082.81-1120 mM phosphate 6.0-3.01-1220 mM phosphate 6.5-13.71-1320 mM phosphate 7.0-22.11-1420 mM Phosphate 7.5-28.31-1520 mM Phosphate 8.0-29.21-1620 mM Citrate 4.5 1.41-1720 mM Citrate 5.0-7.41-1820 mM Citrate 5.5-14.61-1920 mM Citrate 6.0-18.11-2020 mM Citrate 6.5-22.11-2120 mM Succinate 4.5 2.3 2.11-2220 mM Succinate 5.0 9.31-2320 mM Succinate 5.5-0.81-2420 mM Succinate 6.0-8.11-25 b 20 mM acetate 5.319.4

[0298] a Formulations 1-1 to 1-25 do not contain polysorbate 20. Additionally, formulations 1-1 to 1-24 do not contain a trehalose stabilizer.

[0299] b Formulation 1-25 (Originator) has the same buffer, pH and stabilizer conditions as Ocrevus.

[0300] Figure 1 shows the diffusion interaction parameters (K) for 24 formulations with different buffer types and pH combinations and one formulation with the same buffer and pH conditions as Ocrevus. D ) is a graph showing the results of measurement.

[0301] As a result, as shown in Table 1 and Figure 1, K of Formulation 1-25 having the same acetate buffer and pH 5.3 conditions as Ocrevus D (19.4 mL / g) vs. K D Ten formulations (Formulations 1-1 to 1-4, 1-6 to 1-10, and 1-21) with improved colloidal stability were identified.

[0302] Therefore, it was confirmed that (i) the combination of acetate and pH 4.0 or higher to pH 6.0 or (ii) the combination of histidine and pH 5.0 to pH 7.0 showed a superior effect on protein stabilization compared to the combination of acetate and pH 5.3 contained in Ocrevus.

[0303] Example 2. Screening for optimal stabilizers through Tagg, Kd, ​​and ΔG measurements.

[0304] The type of stabilizer in the Ocrevus formulation was varied to match the type used in approved biopharmaceuticals. Specifically, a liquid formulation was prepared using ocrelizumab, an anti-CD20 antibody, with the composition shown in Table 2 below.

[0305] T of each manufactured formulation agg , K D , and ΔG were measured.

[0306] T agg An increase in T means that the temperature at which aggregation is formed has increased. Therefore, the increased T agg means improved thermal stability.

[0307] An increase in ΔG indicates that the protein retains its specific secondary and higher-order structures despite the addition of denaturants. Therefore, an increased ΔG indicates improved chemical stability.

[0308] Table 2 shows the T of the formulation according to the type of stabilizer. agg , K D , and ΔG These are the measurement results.

[0309] No. a Stabilizer T agg (℃)K D (mL / g)ΔG 1600 ug / mL 2-18% (w / v) sucrose 73.92 1.3 3.6 32-29% (w / v) trehalose 72.91 5.75 0.72-34.7% (w / v) sorbitol 75.82 0.5 3.73 2-44.7% (w / v) mannitol 76.51 9.24 0.02-5140 mM arginine 71.3-14.64 2.92-6135 mM lysine 72.0-20.03 942-7170 mM histidine 66.5-12.13 762-8160 mM methionine 73.82 4.24 2.92-9160 mM glycine 74.92 6.23 522-10250 mM Glycine 76.226.03.812-11137 mM NaCl 71.1-17.53.692-12 b 4% (w / v) trehalose 76.119.43.43

[0310] a All formulations contain 20 mM acetate, 0.02% (w / v) polysorbate 20, pH 5.3.

[0311] b Formulation 2-12 (Originator) has the same stabilizer conditions as Ocrevus.

[0312] Figure 2 shows the coagulation temperature (T) for 11 formulations with different stabilizer types and 1 formulation with the same stabilizer conditions as Ocrevus. agg ) is a graph showing the results of measurement.

[0313] Figure 3 shows the diffusion interaction parameter (K) for 11 formulations with different stabilizer types and 1 formulation with the same stabilizer conditions as Ocrevus. D ) is a graph showing the results of measurement.

[0314] Figure 4 shows the Gibbs free energy change (ΔG) values ​​for 11 formulations with different stabilizer types and 1 formulation with the same stabilizer conditions as Ocrevus. 1600 ug / mL ) is a graph showing the results of measurement.

[0315] As a result, as shown in Table 2 and Figures 2 to 4, T of Formulation 2-12 having the same trehalose stabilizer as Ocrevus agg (76.1°C) or K D (19.4 mL / g) vs. T agg Increased thermal stability or K D Six formulations (Formulations 2-1, 2-3, 2-4, 2-8, 2-9, and 2-10) with improved colloidal stability were identified. In addition, Formulations 2-1 to 2-11 all had higher ΔG values ​​than Formulation 2-12, which has the same trehalose stabilizer as Ocrevus, confirming superior stability.

[0316] Therefore, it was confirmed that sucrose, sugar alcohols (e.g., sorbitol, mannitol), or non-polar amino acids (e.g., methionine, glycine) showed superior effects on protein stabilization compared to trehalose contained in Ocrevus.

[0317] Example 3. Evaluation of the optimal combination of buffer, pH, and stabilizer through %HMW measurement.

[0318] By combining the respective upper formulation components selected through the buffer / pH combination screening of Example 1 and the stabilizer screening of Example 2, 13 liquid formulations (Formulations 3-1 to 3-13) having the compositions shown in Table 3 below and 12 liquid formulations (Formulations 4-1 to 4-12) having the compositions shown in Table 4 were prepared.

[0319] For the formulations in Table 3, %HMW was measured under harsh stability conditions (40°C, 4 weeks).

[0320] For the formulations in Table 4, %HMW was measured under harsh stability conditions (40°C, 2 weeks) or accelerated stability conditions (25°C, 2 weeks).

[0321] No. a pH buffer stabilizer 1 stabilizer 2% HMW initial (%)%HMW 40℃ / 4주 (%)Δ%HMW 40℃ / 4주 (%p)3-16.520 mMHistidine70 mMMethionine1.5% (w / v)Sucrose0.460.610.153-25.320 mMHistidine70 mMMethionine1.5% (w / v)Sucrose0.440.540.093-35.320 mMAcetate70 mMMethionine1.5% (w / v)Sucrose0.440.560.133-46.520 mMHistidine70 mMMethionineN / A0.460.600.143-55.320 mMHistidine70 mMMethionineN / A0.450.550.113-65.320 mMAcetate70 mMMethionineN / A0.440.590.153-76.520 mMHistidine 110 mMGlycine N / A 0.46 0.90 0.443-85.320 mMHistidine 110 mMGlycine N / A 0.45 0.65 0.203-95.320 mMAcetate 110 mMGlycine N / A 0.45 0.72 0.273-106.520 mMHistidine 2.1% (w / v)Mannitol N / A 0.48 0.73 0.253-115.320 mMHistidine 2.1% (w / v)Mannitol N / A 0.45 0.61 0.163-125.320 mMAcetate 2.1% (w / v)Mannitol N / A 0.46 0.69 0.23 3-13 b 5.320 mM acetate N / A 4% (w / v) trehalose 0.46 0.73 0.28

[0322] a All formulations contained 30 mg / mL ocrelizumab and 0.02% (w / v) polysorbate 20.

[0323] b Formulation 3-13 (Originator) has the same buffer, pH, and stabilizer conditions as Ocrevus.

[0324] No. a Buffer stabilizer 1 stabilizer 2 surfactant c %HMW (%)Δ%HMW (%p)Initial40℃ / 2 weeks25℃ / 2 weeks40℃ / 2 weeks25℃ / 2 weeks4-120 mMHistidine110 mMGlycine10 mMMethionine0.02% (w / v) PS200.530.510.51-0.02-0.034-220 mMHistidine90 mMGlycine30 mMMethionine0.02% (w / v) PS200.530.510.50-0.02-0.034-320 mMHistidine60 mMGlycine60 mMMethionine0.02% (w / v) PS200.520.520.49-0.01-0.034-420 mMHistidine3.6% (w / v)Sucrose10 mMMethionine0.02% (w / v) PS200.540.520.51-0.02-0.044-520 mMHistidine2.9% (w / v)Sucrose30 mMMethionine0.02% (w / v) PS200.540.510.51-0.03-0.044-620 mMHistidine2.0% (w / v)Sucrose60 mMMethionine0.02% (w / v) PS200.530.500.50-0.04-0.044-720 mMHistidine110 mMGlycine60 mMMethionine0.02% (w / v) PS200.530.500.49-0.04-0.044-820 mMHistidine3.6% (w / v)Sucrose60 mMMethionine0.02% (w / v) PS200.540.480.49-0.05-0.044-920 mMHistidine110 mMGlycine10 mMMethionine0.06% (w / v) PS200.520.520.500.00-0.024-1020 mMHistidine110 mMGlycine10 mMMethionine0.02% (w / v) PS800.530.520.51-0.01-0.024-1120 mMHistidine110 mMGlycine10 mMMethionine0.02% (w / v) P1880.540.510.51-0.03-0.024-12 b 20 mM acetate N / A 4% (w / v) trehalose 0.02% (w / v) PS 20 0.46 0.64 0.53 0.18 0.07

[0325] a All formulations contain 30 mg / mL ocrelizumab and have a pH of 5.3.

[0326] b Formulation 4-12 (Originator) has the same buffer, pH, and stabilizer conditions as Ocrevus.

[0327] C PS20: Polysorbate 20, PS80: Polysorbate 80, P188: Poloxamer 188.

[0328] Figure 5 is a graph showing the results of measuring the percentage of high molecular weight species (%HMW) for 12 formulations of Table 3 with various buffer / pH and stabilizer combinations and 1 formulation with the same composition as Ocrevus.

[0329] Figure 6 is a graph showing the results of measuring the high molecular weight species content (%HMW) for 11 formulations of Table 4 with various buffer / pH and stabilizer combinations and 1 formulation with the same composition as Ocrevus.

[0330] As a result, as shown in Table 3 and Figure 5, the %HMW of the Ocrevus formulation having the acetate / pH 5.3 and trehalose combination 40℃ / 4주 (0.73%) or Δ%HMW 40℃ / 4주 Eleven formulations (Formulations 3-1 to 3-6 and 3-8 to 3-12) were identified with improved stability due to a decrease in %HMW or Δ%HMW compared to (0.28%p).

[0331] Also, as shown in Table 4 and Figure 6, the %HMW of Ocrevus formulations with acetate / pH 5.3 and trehalose combinations 40℃ / 2주 (0.64%) and %HMW 25℃ / 2주 Compared to (0.53%), the %HMW of all tested formulations (Formulations 4-1 to 4-11) was reduced, confirming improved stability.

[0332] Therefore, it was confirmed that a formulation having a combination of buffer / pH conditions and stabilizer conditions, in which the buffer / pH conditions are histidine / pH 5.0 to pH 7.0 or acetate / pH 4.0 or higher to less than pH 6.0, and the stabilizer conditions are at least one excipient selected from nonpolar amino acids (e.g., methionine, glycine), sucrose, and sugar alcohols (e.g., mannitol), exhibits a superior effect on protein stabilization compared to Ocrevus.

[0333] Example 4. Buffering capacity evaluation

[0334] Various formulations were prepared by varying the presence or absence of buffer and antibody concentration in the Ocrevus formulation. Specifically, liquid formulations having the compositions shown in Table 5 below were prepared using ocrelizumab (CAS No. 637334-45-3), an anti-CD20 antibody.

[0335] Buffering capacity was analyzed for each manufactured formulation.

[0336] Table 5 shows the results of the buffering capacity evaluation of the formulation according to the presence or absence of buffer and various antibody concentrations.

[0337] No. a Buffer antibody concentration (mg / mL)Buffer capacity (μmol / mL)5-1Buffer-free00.035-2Buffer-free302.045-3Buffer-free754.035-4Buffer-free1205.365-5Buffer-free1506.255-620 mM acetate03.375-7 b 20 mM acetate 305.51

[0338] a All formulations contain 4% (w / v) trehalose and 0.02% (w / v) polysorbate 20.

[0339] b Formulations 5-7 (Originator) have exactly the same composition as Ocrevus.

[0340] Figure 7 is a titration curve measuring the pH according to the concentration (μmol / mL) of HCl or NaOH added for seven formulations with different buffering agents and antibody concentrations.

[0341] Figure 8 is a graph showing the results of evaluating the buffer capacity (β) for seven formulations with different buffering agents and antibody concentrations.

[0342] As a result, as shown in Table 5, Figure 7, and Figure 8, in the case of formulation 5-1 without acetate buffer and without ocrelizumab (antibody concentration: 0 mg / mL), the pH changed rapidly depending on the addition of acid (HCl) or base (NaOH). On the other hand, the buffer-free formulation containing more than 30 mg / mL of ocrelizumab had a buffering capacity equivalent to or higher than that of formulation 5-6 containing acetate buffer without ocrelizumab, confirming that it had self-buffering capacity.

[0343] Example 5. Stability Evaluation of Buffer-Free Formulations by %HMW Measurement

[0344] As shown in the compositions in Table 6 below, seven buffer-free liquid formulations (Formulations 6-1 to 6-7) with various types of stabilizers and a buffer-containing liquid formulation (Formulation 6-8) having the same buffer and stabilizer conditions as Ocrevus were prepared.

[0345] For each formulation manufactured, %HMW was measured under accelerated stability conditions (25°C, 2 weeks).

[0346] Table 6 shows the %HMW measurement results of formulations according to the presence or absence of buffer and type of stabilizer.

[0347] No. aBuffer Stabilizer 1 Stabilizer 2 %HMW (%) Δ %HMW (%p) Initial 25℃ / 2 weeks 25℃ / 2 weeks 6-1 Buffer-free 165 mM Glycine 10 mM Methionine 0.53 0.50-0.036-2 Buffer-free 135 mM Glycine 10 mM Methionine 0.53 0.49-0.046-3 Buffer-free 90 mM Glycine 10 mM Methionine 0.54 0.48-0.066-4 Buffer-free 5.4% (w / v) Sucrose 10 mM Methionine 0.53 0.51-0.026-5 Buffer-free 4.4% (w / v) Sucrose 10 mM Methionine 0.54 0.51-0.036-6 Buffer-free 3.0% (w / v) Sucrose 10 mM Methionine 0.54 0.53 0.00 6-7 Buffer-free 110 mM Glycine + 3.6% (w / v) Sucrose 10 mM Methionine 0.55 0.50-0.04 6-8 b 20 mM acetate N / A 4% (w / v) trehalose 0.49 0.63 0.15

[0348] a All formulations contained 45 mg / mL ocrelizumab, pH 5.3, and 0.02% (w / v) polysorbate 20.

[0349] b Formulations 6-8 (Originator) have the same pH, buffer, and stabilizer conditions as Ocrevus.

[0350] Figure 9 is a graph showing the results of measuring the percentage of high molecular weight species content (%HMW) for seven buffer-free formulations with various stabilizer types and one formulation with the same buffer and stabilizer conditions as Ocrevus.

[0351] As a result, as shown in Table 6 and Fig. 9, it was confirmed that the stability was improved by reducing %HMW in all seven tested formulations (Formulations 6-1 to 6-7) compared to Formulations 6-8, which had the same acetate buffer and trehalose stabilizer as Ocrevus.

[0352] Therefore, it was confirmed that buffer-free formulations having one or more stabilizer conditions selected from excipients including nonpolar amino acids (e.g., methionine, glycine) and sucrose had superior stability compared to Ocrevus.

[0353] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. Anti-CD20 antibody; and Contains a buffer, The pH is about 4.0 to about 8.0, Liquid formulation.

2. A liquid formulation according to claim 1, wherein the anti-CD20 antibody is an antibody that targets B cells expressing CD20.

3. A liquid formulation according to claim 1, wherein the anti-CD20 antibody is ocrelizumab.

4. A liquid formulation according to claim 1, wherein the concentration of the anti-CD20 antibody is from about 1 mg / ml to about 400 mg / ml.

5. A liquid formulation according to claim 1, wherein the concentration of the anti-CD20 antibody is from about 5 mg / ml to about 100 mg / ml.

6. A liquid formulation according to claim 1, wherein the concentration of the anti-CD20 antibody is about 30 mg / ml.

7. A liquid formulation according to claim 1, wherein the buffer comprises at least one selected from acetate, histidine, phosphate, citrate, succinate, malate, tartrate, carbonate, salts thereof, and hydrates thereof.

8. A liquid formulation according to claim 1, wherein the buffer comprises at least one selected from acetate, histidine, phosphate, citrate, succinate, salts thereof, and hydrates thereof.

9. A liquid formulation according to claim 1, wherein the buffer comprises at least one selected from acetate, histidine, salts thereof, and hydrates thereof.

10. A liquid formulation according to claim 1, wherein the pH of the liquid formulation is from about 4.0 to about 7.

0.

11. A liquid formulation according to claim 1, wherein the buffer comprises at least one selected from acetate, a salt thereof, and a hydrate thereof.

12. A liquid formulation according to claim 11, wherein the pH of the liquid formulation is about 4.0 to about 6.

0.

13. A liquid formulation according to claim 11, wherein the pH of the liquid formulation is about 4.0 to about 5.

5.

14. A liquid formulation according to claim 1, wherein the buffer comprises at least one selected from histidine, a salt thereof, and a hydrate thereof.

15. A liquid formulation according to claim 14, wherein the pH of the liquid formulation is about 5.0 to about 7.

0.

16. A liquid formulation according to claim 14, wherein the pH of the liquid formulation is about 5.0 to about 6.

5.

17. A liquid formulation according to claim 14, wherein the pH of the liquid formulation is about 5.0 to about 5.

5.

18. A liquid formulation according to any one of claims 1 to 17, wherein the concentration of the buffer is from about 0.1 mM to about 100 mM.

19. A liquid formulation according to any one of claims 1 to 18, further comprising a stabilizer.

20. A liquid formulation according to claim 19, wherein the stabilizer comprises at least one selected from sugar, sugar alcohol, amino acid, metal salt, salt thereof, and hydrate thereof.

21. A liquid formulation according to claim 20, wherein the sugar comprises at least one selected from sucrose, trehalose, galactose, mannose, maltose, lactose, fructose, and glucose.

22. A liquid formulation according to claim 20, wherein the sugar alcohol comprises at least one selected from sorbitol, mannitol, xylitol, arabitol, erythritol, lactitol, maltitol, and inositol.

23. A liquid formulation according to claim 20, wherein the amino acid comprises at least one selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, and glutamic acid.

24. A liquid formulation according to claim 20, wherein the metal salt comprises at least one selected from among NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, CaCl2, MgCl2, and K2SO4.

25. A liquid formulation according to claim 20, wherein the concentration of the sugar is from about 0.1% (w / v) to about 20.0% (w / v).

26. A liquid formulation according to claim 20, wherein the concentration of the sugar alcohol is from about 0.1% (w / v) to about 20.0% (w / v).

27. A liquid formulation according to claim 20, wherein the concentration of the amino acid is from about 1 mM to about 400 mM.

28. A liquid formulation according to claim 20, wherein the concentration of the metal salt is from about 1 mM to about 400 mM.

29. A liquid formulation according to claim 19, wherein the stabilizer comprises at least one selected from sucrose, trehalose, sorbitol, mannitol, arginine, lysine, histidine, methionine, glycine, and NaCl.

30. A liquid formulation according to claim 19, wherein the stabilizer comprises at least one selected from sucrose, sugar alcohol, and non-polar amino acid.

31. A liquid formulation according to claim 30, wherein the sugar alcohol comprises at least one selected from sorbitol and mannitol.

32. A liquid formulation according to claim 30, wherein the non-polar amino acid comprises at least one selected from methionine, glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, and tryptophan.

33. A liquid formulation according to claim 30, wherein the non-polar amino acid comprises at least one selected from methionine and glycine.

34. A liquid formulation according to claim 19, wherein the stabilizer comprises two or more selected from sucrose, sugar alcohol, and non-polar amino acid.

35. A liquid formulation according to claim 19, wherein the stabilizer comprises at least one selected from sucrose, mannitol, methionine, and glycine.

36. A liquid formulation according to claim 19, wherein the stabilizer comprises two or more selected from sucrose, mannitol, methionine, and glycine.

37. A liquid formulation according to any one of claims 30 to 36, wherein the concentration of sucrose is from about 0.1% (w / v) to about 20.0% (w / v).

38. A liquid formulation according to any one of claims 30 to 34, wherein the concentration of the sugar alcohol is from about 0.1% (w / v) to about 15.0% (w / v).

39. A liquid formulation according to claim 35 or 36, wherein the concentration of mannitol is from about 1.0% (w / v) to about 10.0% (w / v).

40. A liquid formulation according to claim 30 or 34, wherein the concentration of the nonpolar amino acid is from about 1 mM to about 400 mM.

41. A liquid formulation according to any one of claims 32, 33, 35 and 36, wherein the concentration of methionine is from about 1 mM to about 400 mM.

42. A liquid formulation according to claim 41, wherein the concentration of methionine is from about 1 mM to about 150 mM.

43. A liquid formulation according to any one of claims 32, 33, 35 and 36, wherein the concentration of glycine is from about 1 mM to about 400 mM.

44. A liquid formulation according to claim 42, wherein the concentration of glycine is from about 10 mM to about 300 mM.

45. In claim 1, the liquid formulation is selected from the following: A) the buffer comprises acetate, the pH is 4.0 or more and less than 6.0, and the stabilizer is at least one selected from nonpolar amino acids, sucrose, and sugar alcohols; and B) The buffer comprises histidine, the pH is about 5.0 to about 7.0, and the stabilizer is at least one selected from a nonpolar amino acid, sucrose, and a sugar alcohol.

46. ​​In claim 1, the liquid formulation is selected from the following: A) the buffer comprises acetate, the pH is about 5.0 to about 5.5, and the stabilizer is at least one selected from methionine, glycine, sucrose, and mannitol; and B) The buffer comprises histidine, the pH is about 5.0 to about 6.5, and the stabilizer is at least one selected from methionine, glycine, sucrose, and mannitol.

47. In claim 1, The above buffer comprises histidine, The pH is about 5.0 to about 6.5, A liquid formulation wherein the stabilizer is one or two selected from methionine, glycine, and sucrose.

48. A liquid formulation according to any one of claims 1 to 47, further comprising a surfactant.

49. A liquid formulation according to claim 48, wherein the surfactant is a nonionic surfactant.

50. A liquid formulation according to claim 48, wherein the surfactant comprises at least one selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, poloxamer 188, and poloxamer 407.

51. A liquid formulation according to claim 48, wherein the surfactant comprises polysorbate 20, polysorbate 80, poloxamer 188, or a combination of two or more thereof.

52. A liquid formulation according to any one of claims 48 to 51, wherein the concentration of the surfactant is from about 0.01% (w / v) to about 0.9% (w / v).

53. A liquid formulation according to claim 52, wherein the concentration of the surfactant is from about 0.01% (w / v) to about 0.1% (w / v).

54. A liquid formulation according to claim 52, wherein the concentration of the surfactant is from about 0.02% (w / v) to about 0.06% (w / v).

55. In any one of claims 1 to 54, the liquid formulation has a diffusion interaction parameter (K) greater than 19.4 mL / g D ) having a liquid formulation.

56. A liquid formulation according to claim 55, wherein the liquid formulation comprises acetate or histidine as a buffer, and the pH of the liquid formulation is about 4.0 to about 7.

0.

57. In claim 55, the liquid formulation is selected from the following: A) the buffer contains acetate and has a pH of 4.0 or more and less than 6.0; or B) The buffer contains histidine and has a pH of about 5.0 to about 7.

0.

58. In claim 55, the liquid formulation is selected from the following: A) The stabilizer contains sucrose; B) the stabilizer contains a sugar alcohol; or C) The stabilizer contains nonpolar amino acids.

59. In claim 55, the liquid formulation is selected from the following: A) The stabilizer contains sucrose; B) The stabilizer contains sorbitol; C) the stabilizer contains methionine; or D) The stabilizer contains glycine.

60. A liquid formulation according to any one of claims 1 to 54, wherein the liquid formulation inhibits aggregation of antibodies.

61. In any one of claims 1 to 54, the liquid formulation has a coagulation temperature (T) greater than 76.1° C. agg ) having a liquid formulation.

62. A liquid formulation according to claim 61, wherein the liquid formulation comprises a sugar alcohol or a non-polar amino acid as a stabilizer.

63. A liquid formulation according to claim 61, wherein the liquid formulation comprises mannitol or glycine as a stabilizer.

64. A liquid formulation according to any one of claims 1 to 54, wherein the liquid formulation has a Gibbs free energy change value (ΔG) of greater than 3.43 kcal / mol in guanidine-HCl.

65. In any one of claims 1 to 54, The high molecular weight species content ratio (%HMW) of the antibody measured after 4 weeks of storage at 40°C is 0.73% or less; The high molecular weight species content (%HMW) of the antibody measured after 2 weeks of storage at 40°C is less than 0.64%; or A liquid formulation, wherein the high molecular weight species content ratio (%HMW) of the antibody measured after storage for two weeks at 25°C is 0.53% or less.

66. In claim 65, the liquid formulation is selected from the following: A) the buffer comprises acetate, the pH is 4.0 or more and less than 6.0, and the stabilizer is at least one selected from sucrose, sugar alcohol, and non-polar amino acid; and B) The buffer comprises histidine, the pH is about 5.0 to about 7.0, and the stabilizer is at least one selected from sucrose, sugar alcohol, and non-polar amino acid.

67. In claim 1, Ocrelizumab; Histidine as a buffer; At least one selected from sucrose, sugar alcohol, and non-polar amino acid as a stabilizer; and Contains nonionic surfactants, The pH is about 5.0 to about 6.5, Liquid formulation.

68. In claim 1, Ocrelizumab at about 5 mg / ml to about 300 mg / ml; Histidine as a buffer; At least one selected from sucrose, mannitol, methionine, and glycine as a stabilizer; and A nonionic surfactant comprising polysorbate 20, polysorbate 80, poloxamer 188, or a combination of two or more thereof, The pH is about 5.0 to about 6.0, Liquid formulation.

69. A liquid formulation for intravenous injection according to any one of claims 1 to 68.

70. Contains anti-CD20 antibodies, Does not contain buffer, Liquid formulation.

71. A liquid formulation according to claim 70, wherein the anti-CD20 antibody is an antibody that targets B cells expressing CD20.

72. A liquid formulation according to claim 70, wherein the anti-CD20 antibody is ocrelizumab.

73. A liquid formulation according to claim 70, wherein the concentration of the anti-CD20 antibody is from about 5 mg / ml to about 300 mg / ml.

74. A liquid formulation according to claim 70, wherein the concentration of the anti-CD20 antibody is greater than 30 mg / ml.

75. A liquid formulation according to claim 70, wherein the concentration of the anti-CD20 antibody is from about 35 mg / ml to about 300 mg / ml.

76. A liquid formulation according to claim 70, wherein the concentration of the anti-CD20 antibody is from about 35 mg / ml to about 150 mg / ml.

77. A liquid formulation according to claim 70, wherein the concentration of the anti-CD20 antibody is about 40 mg / ml.

78. A liquid formulation according to claim 70, wherein the concentration of the anti-CD20 antibody is about 45 mg / ml.

79. A liquid formulation according to any one of claims 70 to 78, which is a self-buffering formulation.

80. A liquid formulation according to any one of claims 70 to 78, wherein the liquid formulation substantially does not contain a buffer other than an anti-CD20 antibody.

81. A liquid formulation according to any one of claims 70 to 80, wherein the pH of the liquid formulation is about 4.0 to about 8.

0.

82. A liquid formulation according to any one of claims 70 to 80, wherein the pH of the liquid formulation is about 5.0 to about 6.

5.

83. A liquid formulation according to any one of claims 70 to 80, wherein the pH of the liquid formulation is about 5.0 to about 5.

5.

84. A liquid formulation according to any one of claims 70 to 83, further comprising a stabilizer.

85. A liquid formulation according to claim 84, wherein the stabilizer comprises at least one selected from sugar, sugar alcohol, amino acid, metal salt, salt thereof, and hydrate thereof.

86. A liquid formulation according to claim 85, wherein the sugar comprises at least one selected from sucrose, trehalose, galactose, mannose, maltose, lactose, fructose, and glucose.

87. A liquid formulation according to claim 85, wherein the sugar alcohol comprises at least one selected from sorbitol, mannitol, xylitol, arabitol, erythritol, lactitol, maltitol, and inositol.

88. A liquid formulation according to claim 85, wherein the amino acid comprises at least one selected from glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, and glutamic acid.

89. A liquid formulation according to claim 85, wherein the metal salt comprises at least one selected from among NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, CaCl2, MgCl2, and K2SO4.

90. A liquid formulation according to claim 85, wherein the concentration of the sugar is from about 0.1% (w / v) to about 20.0% (w / v).

91. A liquid formulation according to claim 85, wherein the concentration of the sugar alcohol is from about 0.1% (w / v) to about 20.0% (w / v).

92. A liquid formulation according to claim 85, wherein the concentration of the amino acid is from about 1 mM to about 400 mM.

93. A liquid formulation according to claim 85, wherein the concentration of the metal salt is from about 1 mM to about 400 mM.

94. A liquid formulation according to claim 84, wherein the stabilizer comprises at least one selected from sucrose, sugar alcohol, and non-polar amino acid.

95. A liquid formulation according to claim 94, wherein the stabilizer comprises at least one selected from sucrose and non-polar amino acids.

96. A liquid formulation according to claim 95, wherein the non-polar amino acid comprises at least one selected from methionine, glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, and tryptophan.

97. A liquid formulation according to claim 95, wherein the non-polar amino acid comprises at least one selected from methionine and glycine.

98. A liquid formulation according to claim 95, wherein the concentration of sucrose is from about 0.1% (w / v) to about 20.0% (w / v).

99. A liquid formulation according to claim 97, wherein the concentration of methionine is from about 1 mM to about 400 mM.

100. A liquid formulation according to claim 97, wherein the concentration of glycine is from about 1 mM to about 400 mM.

101. A liquid formulation according to any one of claims 70 to 100, further comprising a surfactant.

102. A liquid formulation according to claim 101, wherein the surfactant comprises a nonionic surfactant.

103. A liquid formulation according to claim 101, wherein the surfactant comprises at least one selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, poloxamer 188, and poloxamer 407.

104. A liquid formulation according to claim 101, wherein the surfactant comprises polysorbate 20, polysorbate 80, poloxamer 188, or a combination of two or more thereof.

105. A liquid formulation according to any one of claims 101 to 104, wherein the concentration of the surfactant is from about 0.01% (w / v) to about 0.9% (w / v).

106. A liquid formulation according to claim 105, wherein the concentration of the surfactant is from about 0.01% (w / v) to about 0.1% (w / v).

107. A liquid formulation according to claim 105, wherein the concentration of the surfactant is from about 0.02% (w / v) to about 0.06% (w / v).

108. In claim 70, Ocrelizumab greater than 30 mg / ml; At least one selected from sucrose, sugar alcohol, and non-polar amino acid as a stabilizer; and Contains nonionic surfactants, Does not contain a buffer, Liquid formulation.

109. A liquid formulation according to claim 108, wherein the liquid formulation substantially does not contain a buffer other than ocrelizumab.

110. A liquid formulation for subcutaneous injection according to any one of claims 70 to 109.

111. A device comprising the liquid formulation of any one of claims 1 to 110.

112. A device according to claim 111, comprising the liquid formulation in a container selected from a syringe, a pre-filled syringe, an autoinjector, a bottle, a vial, and a tube.

113. A device according to claim 111, comprising the liquid formulation in a vial.

114. A device according to claim 113, wherein the vial is a single-dose vial.

115. A device according to claim 111, comprising the liquid formulation in a prefilled syringe.

116. A device according to claim 115, wherein the prefilled syringe is a single-dose prefilled syringe.

117. A method for treating a condition involving B cells expressing CD20, comprising administering to a subject in need thereof a liquid formulation of any one of claims 1 to 110.

118. A method for treating a condition associated with B cells expressing CD20, wherein the condition is any one selected from the group consisting of lymphoma, leukemia, tissue transplant rejection, autoimmune disease, and multiple sclerosis (MS), according to claim 117.

119. A method for treating a condition involving B cells expressing CD20, wherein the condition is multiple sclerosis (MS), according to claim 117.

120. A method for treating a condition associated with B cells expressing CD20, according to claim 119, wherein the multiple sclerosis is relapsing forms of multiple sclerosis (RMS), primary pregressive multiple sclerosis (PPMS), clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), or active secondary progressive multiple sclerosis (active SPMS).

121. Use of a liquid formulation of any one of claims 1 to 110 in the manufacture of a medicament for treating a condition involving B cells expressing CD20.

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