Anti-il-17 antibody formulation, and preparation method and use therefor

Abstract

The present application belongs to the field of biological formulations, and provides a formulation comprising an anti-IL-17 antibody. The antibody formulation has good stability under high temperature and illumination, can be stored in liquid form, and is convenient to use.

Description

Anti-il-17 antibody formulations, methods of making and using the same TECHNICAL FIELD

[0001] The present application belongs to the field of biological preparations, and particularly relates to anti-IL-17 antibody formulations, methods of making and using the same. BACKGROUND

[0002] Anti-IL-17 antibodies have significant efficacy in treating various autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, diabetes, asthma, chronic plaque psoriasis, multiple sclerosis, etc. As a protein product, anti-IL-17 antibodies are prone to degradation, and need to be prepared into stable formulations to ensure their effects. Currently, there are various anti-IL-17 antibody formulations, but there is still a need for stable formulations of anti-IL-17 antibodies in the art. SUMMARY

[0003] The present application provides anti-IL-17 antibody formulations, methods of making and using the same.

[0004] In one aspect, the present application provides an antibody formulation comprising an anti-IL-17 antibody and a buffer.

[0005] In one aspect, the present application provides an antibody formulation comprising an anti-IL-17 antibody, a buffer, a stabilizer, and a surfactant.

[0006] In some embodiments, the anti-IL-17 antibody comprises a heavy chain variable region and a light chain variable region;

[0007] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 1, or an amino acid sequence that is at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 1, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the amino acid sequence as set forth in SEQ ID NO: 1; and / or

[0008] the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 2, or an amino acid sequence that is at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 2, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the amino acid sequence as set forth in SEQ ID NO: 2.

[0009] In some embodiments, the anti-IL-17 antibody comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 1, or an amino acid sequence that is at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 1, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the amino acid sequence as set forth in SEQ ID NO: 1; the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 2, or an amino acid sequence that is at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 2, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the amino acid sequence as set forth in SEQ ID NO: 2.

[0010] In some embodiments, the anti-IL-17 antibody comprises a heavy chain variable region as set forth in SEQ ID NO: 1 and a light chain variable region as set forth in SEQ ID NO: 2.

[0011] In some embodiments, the anti-IL-17 antibody comprises a heavy chain and a light chain;

[0012] the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 3, or an amino acid sequence that is at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 3, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the amino acid sequence as set forth in SEQ ID NO: 3; and / or

[0013] the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 4, or an amino acid sequence that is at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 4, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the amino acid sequence as set forth in SEQ ID NO: 4.

[0014] In some embodiments, the anti-IL-17 antibody comprises a heavy chain and a light chain; the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 3, or an amino acid sequence that is at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 3, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the amino acid sequence as set forth in SEQ ID NO: 3; the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 4, or an amino acid sequence that is at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 4, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the amino acid sequence as set forth in SEQ ID NO: 4.

[0015] In some embodiments, the anti-IL-17 antibody comprises a heavy chain set forth in SEQ ID NO: 3 and a light chain set forth in SEQ ID NO: 4.

[0016] Table 1 Anti-IL-17 antibodies

[0017] In some embodiments, the anti-IL-17 antibody is secukinumab (also known as sukinumab).

[0018] In some embodiments, the anti-IL-17 antibody has a concentration of 5-200 mg / mL. In some embodiments, the anti-IL-17 antibody has a concentration of 5-150 mg / mL. In some embodiments, the anti-IL-17 antibody has a concentration of 5-100 mg / mL. In some embodiments, the anti-IL-17 antibody has a concentration of 10-50 mg / mL. In some embodiments, the anti-IL-17 antibody has a concentration of 15-35 mg / mL. In some embodiments, the anti-IL-17 antibody has a concentration of about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 50 mg / mL, about 100 mg / mL, about 150 mg / mL, about 200 mg / mL, or a range between any two of these values, inclusive of the endpoints, or any value therein. In some embodiments, the anti-IL-17 antibody has a concentration of about 25 mg / mL.

[0019] In some embodiments, the antibody formulation has a pH of 5.0-7.0. In some embodiments, the antibody formulation has a pH of 5.0-6.7. In some embodiments, the antibody formulation has a pH of 5.5-6.4. In some embodiments, the antibody formulation has a pH of 5.8 ± 0.3. In some embodiments, the antibody formulation has a pH of 6.1 ± 0.3. In some embodiments, the antibody formulation has a pH of about 5.0, about 5.5, about 5.8, about 6.1, about 6.4, about 6.7, about 7.0, or a range between any two of these values, inclusive of the endpoints, or any value therein. In some embodiments, the antibody formulation has a pH of about 5.8. In some embodiments, the antibody formulation has a pH of about 6.1.

[0020] In some embodiments, the buffer comprises a phosphate buffer, a citrate buffer, and / or a histidine salt buffer. In some embodiments, the buffer comprises a phosphate and citrate buffer. In some embodiments, the buffer comprises a citrate buffer. In some embodiments, the buffer is a phosphate buffer. In some embodiments, the buffer is a histidine salt buffer. In some embodiments, the histidine salt buffer is a combination of histidine and histidine hydrochloride.

[0021] In some embodiments, the buffer is a citrate buffer and / or a histidine salt buffer. In some embodiments, the buffer is a histidine salt buffer. In some embodiments, the histidine salt buffer is a combination of histidine and histidine hydrochloride.

[0022] In some embodiments, the concentration of the buffer is 5-50 mM. In some embodiments, the concentration of the buffer is 10-30 mM. In some embodiments, the concentration of the buffer is 15-25 mM. In some embodiments, the concentration of the buffer is 18-22 mM. In some embodiments, the concentration of the buffer is about 5 mM, about 10 mM, about 15 mM, about 18 mM, about 20 mM, about 22 mM, about 25 mM, about 30 mM, about 40 mM, about 50 mM, or a range between any two of these values, inclusive of the endpoints, or any value therein.

[0023] In some embodiments, the buffer is a histidine salt buffer at about 20 mM. In some embodiments, the buffer comprises about 7.3 mM histidine and about 12.7 mM histidine hydrochloride.

[0024] In some embodiments, the stabilizer is selected from one or more of sorbitol, sucrose, trehalose, and methionine. In some embodiments, the stabilizer comprises sucrose or methionine or a combination thereof. In some embodiments, the stabilizer comprises sucrose and methionine. In some embodiments, the stabilizer is a combination of sucrose and methionine.

[0025] In some embodiments, the concentration of the stabilizer is 50-350 mM. In some embodiments, the concentration of the stabilizer is 100-320 mM. In some embodiments, the concentration of the stabilizer is 150-300 mM. In some embodiments, the concentration of the stabilizer is 200-280 mM. In some embodiments, the concentration of the stabilizer is about 50 mM, about 70 mM, about 90 mM, about 100 mM, about 120 mM, about 150 mM, about 170 mM, about 180 mM, about 191 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, about 250 mM, about 267 mM, about 280 mM, about 300 mM, about 320 mM, about 350 mM, or a range between any two of these values, inclusive of the endpoints, or any value therein.

[0026] In some embodiments, the stabilizer comprises 50-350 mM sucrose. In some embodiments, the stabilizer comprises 100-320 mM sucrose. In some embodiments, the stabilizer comprises 150-300 mM sucrose. In some embodiments, the stabilizer comprises 200-280 mM sucrose. In some embodiments, the stabilizer comprises about 240 mM sucrose. In some embodiments, the stabilizer comprises 10-50 mM methionine. In some embodiments, the stabilizer comprises 15-35 mM methionine. In some embodiments, the stabilizer comprises 20-30 mM methionine. In some embodiments, the stabilizer comprises about 27 mM methionine. In some embodiments, the stabilizer comprises 150-300 mM sucrose and 10-50 mM methionine. In some embodiments, the stabilizer comprises 200-280 mM sucrose and 15-35 mM methionine. In some embodiments, the stabilizer comprises 220-260 mM sucrose and 20-30 mM methionine. In some embodiments, the stabilizer comprises about 240 mM sucrose (i.e., about 82 mg / mL sucrose) and about 27 mM methionine (i.e., about 4 mg / mL methionine). In some embodiments, the stabilizer is a combination of about 240 mM sucrose and about 27 mM methionine.

[0027] In some embodiments, the surfactant is a polysorbate or a poloxamer. In some embodiments, the surfactant is polysorbate 80, polysorbate 20, or poloxamer 188. In some embodiments, the surfactant is polysorbate 80.

[0028] In some embodiments, the concentration of the surfactant is 0.01-0.2%. In some embodiments, the concentration of the surfactant is 0.01-0.1%. In some embodiments, the concentration of the surfactant is 0.02-0.08%. In some embodiments, the concentration of the surfactant is about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.07%, about 0.08%, about 0.1%, about 0.2%, or a range between any two of these values, inclusive of the endpoints, or any value therein. In some embodiments, the concentration of the surfactant is about 0.05%.

[0029] In some embodiments, the surfactant is about 0.05% polysorbate 80 (i.e., about 0.5 mg / mL polysorbate 80).

[0030] In some embodiments, the pH of the antibody formulation is 5.0-7.0. In some embodiments, the pH of the antibody formulation is 5.0-6.7. In some embodiments, the pH of the antibody formulation is 5.5-6.4. In some embodiments, the pH of the antibody formulation is 5.8 ± 0.3. In some embodiments, the pH of the antibody formulation is about 5.0, about 5.5, about 5.8, about 6.1, about 6.4, about 6.7, about 7.0, or a range between any two of these values, inclusive of the endpoints, or any value therein. In some embodiments, the pH of the antibody formulation is about 5.8.

[0031] In some embodiments, the antibody formulation comprises an anti-IL-17 antibody, a histidine salt buffer, a stabilizer, and a surfactant; the stabilizer comprises sucrose and methionine; the pH of the antibody formulation is 5.0-7.0.

[0032] In some embodiments, the antibody formulation comprises 5-200 mg / mL anti-IL-17 antibody, 10-30 mM histidine salt buffer, 50-350 mM stabilizer, and 0.01-0.2% polysorbate 80; the pH of the antibody formulation is 5.0-7.0. In some embodiments, the stabilizer comprises sucrose and methionine.

[0033] In some embodiments, the antibody formulation comprises 5-100 mg / mL anti-IL-17 antibody, 10-30 mM histidine salt buffer, 150-300 mM sucrose, 10-50 mM methionine, and 0.01-0.2% polysorbate 80; the pH of the antibody formulation is 5.0-7.0.

[0034] In some embodiments, the antibody formulation comprises 10-50 mg / mL anti-IL-17 antibody, 10-30 mM histidine salt buffer, 150-300 mM sucrose, 10-50 mM methionine, and 0.02-0.08% polysorbate 80; the antibody formulation has a pH of 5.0-7.0.

[0035] In some embodiments, the antibody formulation comprises 15-35 mg / mL anti-IL-17 antibody, 10-30 mM histidine salt buffer, 200-280 mM sucrose, 15-35 mM methionine, and 0.02-0.08% polysorbate 80; the antibody formulation has a pH of 5.8 ± 0.3.

[0036] In some embodiments, the antibody formulation comprises about 25 mg / mL anti-IL-17 antibody, about 20 mM histidine salt buffer, about 240 mM sucrose (equivalent to about 82.15 mg / mL sucrose), about 27 mM methionine (equivalent to about 4 mg / mL methionine), and about 0.05% polysorbate 80; the antibody formulation has a pH of 5.8 ± 0.3.

[0037] In some embodiments, the antibody formulation comprises 5-200 mg / mL secukinumab, 10-30 mM histidine salt buffer, 50-350 mM stabilizer, and 0.01-0.2% polysorbate 80; the antibody formulation has a pH of 5.0-7.0. In some embodiments, the stabilizer comprises sucrose and methionine.

[0038] In some embodiments, the antibody formulation comprises 5-100 mg / mL secukinumab, 10-30 mM histidine salt buffer, 150-300 mM sucrose, 10-50 mM methionine, and 0.01-0.2% polysorbate 80; the antibody formulation has a pH of 5.0-7.0.

[0039] In some embodiments, the antibody formulation comprises 10-50 mg / mL secukinumab, 10-30 mM histidine salt buffer, 150-300 mM sucrose, 10-50 mM methionine, and 0.02-0.08% polysorbate 80; the antibody formulation has a pH of 5.0-7.0.

[0040] In some embodiments, the antibody formulation comprises 15-35 mg / mL secukinumab, 10-30 mM histidine salt buffer, 200-280 mM sucrose, 15-35 mM methionine, and 0.02-0.08% polysorbate 80; the antibody formulation has a pH of 5.8 ± 0.3.

[0041] In some embodiments, the antibody formulation comprises about 25 mg / mL secukinumab, about 20 mM histidine salt buffer, about 240 mM sucrose, about 27 mM methionine, and about 0.05% polysorbate 80; the pH of the antibody formulation is 5.8 ± 0.3.

[0042] In some embodiments, the antibody formulation comprises about 25 mg / mL secukinumab, about 20 mM histidine salt buffer, about 240 mM sucrose, about 27 mM methionine, and about 0.05% polysorbate 80; the pH of the antibody formulation is 5.8 ± 0.3.

[0043] In some embodiments, the antibody formulation is a liquid formulation. In some embodiments, the solvent of the antibody formulation is water. In some embodiments, the solvent of the antibody formulation is water for injection.

[0044] In some embodiments, the antibody formulation is for injection, such as intravenous injection or subcutaneous injection.

[0045] In another aspect, the present application provides a method for preparing the antibody formulation, comprising: taking each component in a formulation amount, dissolving in water and mixing uniformly, adjusting the pH to obtain the antibody formulation.

[0046] In another aspect, the present application provides a method for preparing the antibody formulation, comprising: preparing a buffer, ultrafiltrating the antibody into the buffer, and optionally diluting the antibody to a specified concentration to obtain the antibody formulation.

[0047] In another aspect, the present application provides a method for preparing the antibody formulation, comprising: preparing a buffer, ultrafiltrating the antibody into the buffer, adding excipients, and diluting the antibody to a specified concentration to obtain the antibody formulation.

[0048] In another aspect, the present application provides use of the antibody formulation in the preparation of a medicament for treating an IL-17 related disease.

[0049] In another aspect, the present application provides an antibody drug product for treating an IL-17 related disease, comprising the antibody formulation described herein and a container for storing the antibody formulation. The antibody drug product can further comprise instructions for use. The container can be any container conventionally used in the art for storing a pharmaceutical product, such as a pre-filled container, a pre-filled syringe, a vial, an ampoule, a pouch, etc.

[0050] In some embodiments, the IL-17 related disease is an autoimmune disease.

[0051] In some embodiments, the autoimmune disease includes, but is not limited to, rheumatoid arthritis, psoriatic arthritis, diabetes, asthma, chronic plaque psoriasis, and multiple sclerosis. In some embodiments, the autoimmune disease is autoimmune diabetes.

[0052] The antibody preparation of the present application has good stability under high temperature and light, and can be stored in liquid form, which is convenient to use. DETAILED DESCRIPTION

[0053] The present application will be illustrated by specific embodiments, but the content of the present application is not limited thereto.

[0054] It should be noted that in the present application, "%" referring to the components of liquid preparation means weight volume (w / v) percentage, wherein the weight unit can be g and the volume unit can be mL. For example, 1% surfactant in solution means 1 g surfactant in 100 mL solution, or the content of surfactant is 0.01 g / mL.

[0055] "About" means the conventional error range for the corresponding numerical value known to those skilled in the relevant art. In some embodiments, "about" as referred to herein means the numerical value described and a range of ±10%, ±5% or ±1% thereof.

[0056] "Comprise" or "comprising" means that the composition and method, etc. include the listed elements (such as components in the composition, steps in the method, etc.), but do not exclude other elements. When "consisting essentially of" is used to define the composition and method, it means excluding other elements that have a fundamental influence on the combination for the intended use, but not excluding elements that do not essentially affect the characteristics of the composition or method. "Consisting of" means excluding elements not specifically listed. Embodiments defined by each of these transitional terms are within the scope of the present application. For example, when the composition is described as comprising ingredients A, B and C, the composition consisting essentially of A, B and C and the composition consisting of A, B and C are independently within the scope of the present application.

[0057] "Antibody," "antigen binding fragment" refers to a polypeptide or polypeptide complex that specifically recognizes and binds an antigen. An antibody can be an intact antibody and any antigen binding fragment thereof or a single chain thereof. Thus, the term "antibody" includes any protein or peptide that comprises at least a portion of an immunoglobulin molecule that has the biological activity of binding to an antigen. Antibodies and antigen binding fragments include, but are not limited to, a complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a variable region of a heavy chain (VH), a variable region of a light chain (VL), a constant region of a heavy chain (CH), a constant region of a light chain (CL), a framework region (FR), or any portion thereof, or at least a portion of a binding protein. CDR regions include CDR regions of a light chain (LCDR1-3) and CDR regions of a heavy chain (HCDR1-3). An antibody and antigen binding fragment can be a polypeptide or polypeptide complex that specifically recognizes and binds one or more (e.g., two) antigens. An antibody or antigen binding fragment that specifically recognizes and binds multiple (e.g., two) antigens can be referred to as a multispecific (e.g., bispecific) antibody or antigen binding fragment. The term "antigen binding fragment" refers to a portion of an antibody, and antigen binding fragments of the present application can be composed of similar structural motifs as F(ab')2, F(ab)2, Fab', Fab, Fv, scFv, etc., in single specific antibody fragments. Regardless of structure, an antigen binding fragment binds to the same antigen recognized by the intact antibody. The term "antigen binding fragment" includes aptamers, mirror images, and diabodies. The term "antigen binding fragment" also includes any synthetic or genetically engineered protein that functions as an antibody by forming a complex with a particular antigen.

[0058] Antibodies, antigen binding fragments disclosed herein include, but are not limited to, polyclonal, monoclonal, multispecific, fully human, humanized, primatized, chimeric antibodies, single chain antibodies, epitope binding fragments (e.g., Fab, Fab', and F(ab')2, single chain Fv (scFv)).

[0059] Antibodies disclosed herein can be derived from any animal, including birds and mammals. Preferably, the antibodies are human, murine, equine, rabbit, goat, camelid, llama, condricthoid (e.g., from a shark), horse, or chicken antibodies.

[0060] A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a side chain (R group) of similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. Examples of groups of amino acids that have chemical properties similar include: 1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine and methionine.

[0061] "Homology" or "identity" refers to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing positions in each sequence that can be aligned. When a position in the compared sequences is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences. "At least 90% identical" is about 90% identical, about 91% identical, about 92% identical, about 94% identical, about 95% identical, about 98% identical, about 99% identical, or a range between any of these values, inclusive of the endpoints, or any value therein.

[0062] The term "buffer" also referred to as a buffer system or a buffer system, includes, but is not limited to, organic acids and their salts, such as succinic acid, acetic acid, citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, or phthalic acid and their salts; Tris, or inorganic acids and their salts, such as phosphate buffers. In addition, amino acids and their salts can also be used as buffers. Such amino acid components include, but are not limited to, glycine, histidine, arginine, lysine, ornithine, isoleucine, leucine, alanine, glutamic acid, or aspartic acid and their salts. In some embodiments, the buffer is a histidine salt buffer, which comprises histidine and / or a histidine salt (such as histidine hydrochloride).

[0063] The amount of buffer in the present application refers to the total amount of the buffer pair in the buffer system that constitutes the buffer. In some embodiments, molarity is used as the unit of the amount of the buffer, the value of which refers to the molarity of the buffer pair in the buffer system of the buffer. For example, when a histidine salt buffer, which is composed of histidine and histidine hydrochloride, is used as the buffer, a given concentration of the histidine salt buffer (e.g., 20 mM) is the combined concentration of histidine and histidine hydrochloride (e.g., 7.3 mM of histidine and 12.7 mM of histidine hydrochloride).

[0064] The formulations described herein can be prepared with the excipients or hydrates thereof. For example, histidine hydrochloride, also known as hydrochloric acid histidine, can be anhydrous histidine hydrochloride or a hydrate of histidine hydrochloride, such as histidine hydrochloride monohydrate. For example, "12.7 mM histidine hydrochloride" means 12.7 mmol of histidine hydrochloride or histidine hydrochloride monohydrate is dissolved in a solvent to form a 1 L solution.

[0065] The term "stabilizer" refers to a pharmaceutically acceptable excipient that protects the active pharmaceutical ingredient and / or the formulation from chemical and / or physical degradation during manufacture, storage, and use. Stabilizers include, but are not limited to, sugars, amino acids, polyols (e.g., mannitol, sorbitol, xylitol, dextran, glycerol, arabitol, propylene glycol, polyethylene glycol), cyclodextrins (e.g., hydroxypropyl-beta-cyclodextrin, sulfobutyl ethyl-beta- cyclodextrin, beta-cyclodextrin), polyethylene glycols (e.g., PEG 3000, PEG 3350, PEG 4000, PEG 6000), albumin (e.g., human serum albumin (HSA), bovine serum albumin (BSA)), salts (e.g., sodium chloride, magnesium chloride, calcium chloride), chelators (e.g., EDTA). A stabilizer can be present in the formulation in an amount of about 1 mM to about 500 mM, for example, in an amount of about 50 mM to about 350 mM, or in an amount of about 100 mM to about 320 mM. More than one stabilizer can be present in the formulation.

[0066] The term "sugar" includes monosaccharides and oligosaccharides. A monosaccharide is a monomeric carbohydrate that cannot be hydrolyzed by acid, including monosaccharides and derivatives thereof, such as amino sugars. Sugars are typically in the D configuration. Examples of monosaccharides include glucose, fructose, galactose, mannose, sorbose, ribose, deoxyribose, neuraminic acid. Oligosaccharides are carbohydrates composed of more than one monomeric sugar unit, which are linked by one or more glycosidic bonds, which can be branched or linear. The monomeric sugar units in an oligosaccharide can be the same or different. Depending on the number of monomeric sugar units, oligosaccharides are disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, and so on. Unlike polysaccharides, monosaccharides and oligosaccharides are water soluble. Examples of oligosaccharides include sucrose, trehalose, lactose, maltose, and raffinose. In some embodiments, a sugar can be present in the formulation in an amount of about 50 mM to about 350 mM. In some embodiments, a sugar can be present in the formulation in an amount of about 100 mM to about 320 mM. In some embodiments, a sugar can be present in the formulation in an amount of about 240 mM. Examples of amino acids include, but are not limited to, arginine, glycine, ornithine, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, tyrosine, tryptophan, methionine, serine, proline. In some embodiments, a basic amino acid, such as arginine, histidine, or lysine, is employed in its inorganic salt form (e.g., hydrochloric acid salt form, i.e., as the hydrochloric acid amino acid). In some embodiments, the amino acid is methionine. In some embodiments, methionine is used at a concentration of about 10 mM to about 50 mM, for example, about 27 mM.

[0067] The term "surfactant" includes, but is not limited to, polysorbates (e.g., polysorbate 20 and polysorbate 80); poloxamers (e.g., poloxamer 188); Triton; sodium dodecyl sulfate (SDS); sodium lauryl sulfate; octyl glucoside sodium salt; lauryl sulfobetaine, myristyl sulfobetaine, linoleyl sulfobetaine, or stearyl sulfobetaine; lauryl sarcosine, myristyl sarcosine, linoleyl sarcosine, or stearyl sarcosine; linoleyl betaine, myristyl betaine, or cetyl betaine; lauryl amidopropyl betaine, cocamidopropyl betaine, linoleamidopropyl betaine, myristamidopropyl betaine, palmitamidopropyl betaine, or isostearamidopropyl betaine (e.g., lauryl amidopropyl); myristamidopropyl dimethylamine, palmitamidopropyl dimethylamine, or isostearamidopropyl dimethylamine; sodium methyl cocoyl taurate or disodium methyl oleyl taurate; polyethylene glycol, polypropylene glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics, PF68, etc.); and the like. In some embodiments, the surfactant is a polysorbate, e.g., polysorbate 80.

[0068] "Stable", "stability" herein refer to the state of an antibody (including antigen-binding fragments thereof) in a liquid formulation comprising the antibody that does not, or only very little, aggregate, degrade or fragmentize under given production, preparation, transportation and / or storage conditions. A "stable" formulation retains its biological activity under given production, preparation, transportation and / or storage conditions. The stability of the antibody can be assessed by measuring the extent of aggregation, degradation or fragmentization of the formulation, for example, by SEC-HPLC, IEC-HPLC, CE-SDS (NR), visual inspection and turbidity, insoluble microparticles, DLS detection of particle size and the like techniques.

[0069] The water for injection used in the present application is water obtained by distillation of purified water. The purified water used in the present application is pharmaceutical water prepared by distillation, ion exchange, reverse osmosis or other suitable methods from drinking water, and does not contain any additives.

[0070] "Treatment" refers to therapeutic treatment and prophylactic or preventative measures, and aims to prevent, slow down, ameliorate or stop adverse physiological changes or disorders, such as the progression of a disease, including but not limited to alleviation of symptoms, reduction in extent of disease, stabilization (i.e. not worsening) of state of disease, delay or slowing of disease progression, amelioration of disease state, remission, whether partial or total, prolonging of survival, and the like, whether detectable or undetectable. Patients in need of treatment include those already with a condition or disorder, those prone to have a condition or disorder, or those in which a condition or disorder is to be prevented, and those who can or are expected to benefit from administration of the antibody or pharmaceutical composition disclosed herein for detection, diagnostic procedures and / or treatment.

[0071] In the following examples, unless otherwise specified, the reagents and instruments used are conventional reagents and instruments in the art, which can be obtained by commercial means; the methods used are conventional technical methods in the art, and those skilled in the art can implement the methods without any doubt and obtain the corresponding results according to the content of the examples.

[0072] The anti-IL-17 antibody used in the following examples is secukinumab (also known as sukinumab).

[0073] The anti-IL-17 antibody used in the examples is expressed by CHO cells, and is prepared after cell culture, separation and purification. The CHO cells, antibody expression method, plasmid construction and purification method and the like are purchased and operated according to conventional methods.

[0074] Example 1: Buffer screening

[0075] The effects of different buffers on the stability of the anti-IL-17 antibody were investigated.

[0076] 1 Experimental Methods

[0077] Each of Formulations 1-1, 1-2, 1-3 and 1-4 contained the buffers described in Table 2 and the anti-IL-17 antibody at 8 mg / mL. The stability experimental conditions and test items are shown in Table 3.

[0078] Table 2 Formulation Components

[0079] Table 3 Experimental Conditions and Test Items

[0080] 2 Experimental Results

[0081] 2.1 High Temperature Experiment

[0082] Table 4 SEC-HPLC and IEC-HPLC Test Results for Samples Under High Temperature Conditions

[0083] From the data in Table 4, it can be seen that after 4 weeks of high temperature experiment, the SEC-HPLC monomer purity of Formulation 1-4 was better than that of the other groups. From the SEC-HPLC polymer data, it can be seen that the SEC-HPLC polymer of Formulation 1-4 increased most slowly. From the IEC-HPLC acid peak data, it can be seen that the IEC-HPLC acid peak of Formulation 1-4 increased most slowly.

[0084] Table 5 CE-SDS(NR) Test Results for Samples Under High Temperature Conditions

[0085] From the CE-SDS(NR) monomer purity data, it can be seen that the change trends of the four groups of antibody formulations were basically the same.

[0086] 2.2 Light Experiment

[0087] Table 6 SEC-HPLC and IEC-HPLC Test Results for Samples Under Light Conditions

[0088] From the data in Table 6, it can be seen that after 14 days under light conditions, the SEC-HPLC monomer content of Formulation 1-4 was the highest. The SEC-HPLC polymer of Formulation 1-4 increased most slowly.

[0089] Table 7 CE-SDS(NR) Test Results for Samples Under Light Conditions

[0090] From the data in Table 7, it can be seen that the CE-SDS(NR) main peak content of Formulation 1-4 decreased most slowly.

[0091] The results of SEC-HPLC, IEC-HPLC and CE-SDS(NR) show that the stability of the preparations 1-4 is the best under the high temperature of 40°C and light environment.

[0092] Example 2: pH range optimization screening experiment

[0093] 1. Experimental method

[0094] Six antibody preparations containing 20 mM His buffer, with an antibody concentration of 20 mg / mL and pH values of 5.5, 5.8, 6.1, 6.4, 6.7 and 7.0, respectively, were prepared, and the preparation numbers were 2-1, 2-2, 2-3, 2-4, 2-5 and 2-6, respectively. The experimental conditions and detection items are shown in Table 8.

[0095] Table 8 Experimental conditions and detection items

[0096] 2. Experimental results

[0097] 2.1 High temperature experiment

[0098] Table 9 SEC-HPLC detection results of samples under high temperature conditions

[0099] From the SEC-HPLC monomer purity data, it can be known that the monomer content of the antibody preparations with pH 5.5 to pH 6.4 is higher from the second week of high temperature.

[0100] Table 10 CE-SDS(NR) detection results of samples under high temperature conditions

[0101] From the CE-SDS(NR) main peak content data, it can be known that the high temperature condition has little effect on the CE stability of the preparations.

[0102] 2.2 Light experiment

[0103] Table 11 SEC-HPLC detection results of samples under light conditions

[0104] From the SEC-HPLC monomer purity data, it can be known that the monomer content of the antibody preparations with pH 5.5 to pH 6.4 is higher at the same time point.

[0105] Table 12 CE-SDS(NR) detection results of samples under light conditions

[0106] From the CE-SDS(NR) main peak content data, it can be known that the change trends of the six groups of antibody preparations are basically the same.

[0107] Example 3: Formulation stability study

[0108] Stability of different anti-IL-17 antibody formulations was investigated.

[0109] 1. Experimental method

[0110] The formulation components and contents are shown in Table 13. The experimental conditions and detection items are shown in Table 14.

[0111] Table 13 Formulation design

[0112] Table 14 Experimental conditions and detection items

[0113] 2. Experimental results

[0114] 2.1 SEC-HPLC detection

[0115] Table 15 SEC-HPLC detection results of samples under light and high temperature conditions

[0116] According to the SEC-HPLC detection results in Table 15, under high temperature and light conditions, the SEC-HPLC monomer relative reduction of formulation 3-2 was the slowest, and the stability was the best.

[0117] Table 16 SEC-HPLC detection results of samples under long-term and accelerated investigation conditions

[0118] According to the SEC-HPLC detection results in Table 16, with the extension of long-term and accelerated investigation time, the change trends of the three formulations were similar.

[0119] 2.2 IEC-HPLC detection

[0120] Table 17 IEC-HPLC detection results of samples under high temperature conditions

[0121] According to the IEC-HPLC detection results in Table 17, the results of formulations 3-2 and 3-3 were better than that of formulation CB.

[0122] 2.3 CE-SDS(NR) detection

[0123] Table 18 CE-SDS(NR) detection results of samples under light and high temperature conditions

[0124] According to the CE-SDS(NR) detection results in Table 18, with the extension of light time, the difference between formulations 3-2 and 3-3 was not large; with the extension of high temperature time, the change trends of the three formulations were similar.

[0125] 2.6 Insoluble Particles Test

[0126] Table 19 Results of Insoluble Particles Test (particles / mL) of Samples under Light, High Temperature, Accelerated Investigation and Long-term Investigation Conditions

[0127] From the results of Table 19, it can be seen that as the time length increases, the number of particles of Formulation 3-2 is less in terms of the number of particles of ≥ 2 μm and ≥ 5 μm.

Claims

1. An antibody formulation comprising an anti-IL-17 antibody and a buffer; the anti-IL-17 antibody comprises a heavy chain variable region set forth in SEQ ID NO: 1 and a light chain variable region set forth in SEQ ID NO: 2; the antibody formulation has a pH of 5.0-7.

0.

2. The antibody formulation of claim 1, wherein the buffer comprises a phosphate buffer, a citrate buffer, and / or a histidine salt buffer.

3. The antibody formulation of claim 1, the buffer comprises a phosphate and a citrate buffer.

4. The antibody formulation of claim 1, the buffer comprises a citrate buffer.

5. The antibody formulation of claim 1, the buffer comprises a phosphate buffer.

6. The antibody formulation of claim 1, the buffer comprises a histidine salt buffer.

7. The antibody formulation of claim 1, further comprising a stabilizer and a surfactant.

8. The antibody formulation of any one of claims 1-7, wherein the concentration of the anti-IL-17 antibody is 5-200 mg / mL.

9. The antibody formulation of any one of claims 1-7, wherein the concentration of the anti-IL-17 antibody is 5-150 mg / mL.

10. The antibody formulation of any one of claims 1-7, wherein the concentration of the anti-IL-17 antibody is 5-100 mg / mL.

11. The antibody formulation of any one of claims 1-7, wherein the concentration of the anti-IL-17 antibody is 10-50 mg / mL.

12. The antibody formulation of any one of claims 1-7, wherein the concentration of the anti-IL-17 antibody is 15-35 mg / mL.

13. The antibody formulation of any one of claims 1-7, wherein the concentration of the anti-IL-17 antibody is about 25 mg / mL.

14. The antibody formulation of any one of claims 1-13, wherein the concentration of the buffer is 5-50 mM.

15. The antibody formulation of any one of claims 1-13, wherein the concentration of the buffer is 10-30 mM.

16. The antibody formulation of any one of claims 1-13, wherein the concentration of the buffer is 15-25 mM.

17. The antibody formulation of any one of claims 1-13, wherein the concentration of the buffer is 18-22 mM.

18. The antibody formulation of any one of claims 1-13, wherein the concentration of the buffer is about 20 mM.

19. The antibody formulation of any one of claims 7-18, wherein the stabilizer is selected from one or more of sorbitol, sucrose, trehalose, and methionine.

20. The antibody formulation of any one of claims 7-18, wherein the stabilizer comprises sucrose or methionine or a combination thereof.

21. The antibody formulation of any one of claims 7-18, wherein the stabilizer comprises sucrose and methionine.

22. The antibody formulation of any one of claims 7-18, wherein the stabilizer is a combination of sucrose and methionine.

23. The antibody formulation of any one of claims 19-22, wherein the concentration of sucrose is 50-350 mM.

24. The antibody formulation of any one of claims 19-22, wherein the concentration of sucrose is 100-320 mM.

25. The antibody formulation of any one of claims 19-22, wherein the concentration of sucrose is 150-300 mM.

26. The antibody formulation of any one of claims 19-22, wherein the concentration of sucrose is 200-280 mM.

27. The antibody formulation of any one of claims 19-22, wherein the concentration of sucrose is about 240 mM.

28. The antibody formulation of any one of claims 19-27, wherein the concentration of methionine is 10-50 mM.

29. The antibody formulation of any one of claims 19-27, wherein the concentration of methionine is 15-35 mM.

30. The antibody formulation of any one of claims 19-27, wherein the concentration of methionine is 20-30 mM.

31. The antibody formulation of any one of claims 19-27, wherein the concentration of methionine is about 27 mM.

32. The antibody formulation of any one of claims 7-31, wherein the surfactant is a polysorbate or a poloxamer.

33. The antibody formulation of any one of claims 7-31, wherein the surfactant is polysorbate 80, polysorbate 20, or poloxamer 188.

34. The antibody formulation of any one of claims 7-33, wherein the concentration of the surfactant is 0.01%-0.2%.

35. The antibody formulation of any one of claims 7-33, wherein the concentration of the surfactant is 0.01%-0.1%.

36. The antibody formulation of any one of claims 7-33, wherein the concentration of the surfactant is 0.02%-0.08%.

37. The antibody formulation of any one of claims 7-33, wherein the concentration of the surfactant is about 0.05%.

38. An antibody formulation comprising 5-200 mg / mL of an anti-IL-17 antibody, 10-30 mM of a histidine salt buffer, 50-350 mM of a stabilizer, and 0.01%-0.2% of polysorbate 80; the stabilizer comprises sucrose and methionine; the antibody formulation has a pH of 5.0-7.0; or 5-100 mg / mL of an anti-IL-17 antibody, 10-30 mM of a histidine salt buffer, 150-300 mM of sucrose, 10-50 mM of methionine, and 0.01%-0.2% of polysorbate 80; the antibody formulation has a pH of 5.0-7.0; or 10-50 mg / mL of an anti-IL-17 antibody, 10-30 mM of a histidine salt buffer, 150-300 mM of sucrose, 10-50 mM of methionine, and 0.02%-0.08% of polysorbate 80; the antibody formulation has a pH of 5.0-7.0; or about 20 mM histidine salt buffer, about 240 mM sucrose, about 27 mM methionine, and about 0.05% polysorbate 80; the antibody formulation has a pH of 5.8 ± 0.

3. about 20 mM histidine salt buffer, about 240 mM sucrose, about 27 mM methionine, and about 0.05% polysorbate 80; the antibody formulation has a pH of 5.8 ± 0.

3. wherein the anti-IL-17 antibody comprises a heavy chain variable region of SEQ ID NO: 1 and a light chain variable region of SEQ ID NO:

2.

39. The antibody formulation of any one of claims 1-38, wherein the anti-IL-17 antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 3, or an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 3, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the amino acid sequence of SEQ ID NO: 3; and a light chain comprising an amino acid sequence of SEQ ID NO: 4, or an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 4, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the amino acid sequence of SEQ ID NO:

4.

40. The antibody formulation of any one of claims 1-38, wherein the anti-IL-17 antibody comprises a heavy chain of SEQ ID NO: 3 and a light chain of SEQ ID NO:

4.

41. The antibody formulation of any one of claims 1-38, wherein the anti-IL-17 antibody is secukinumab.

42. An antibody formulation comprising about 25 mg / mL secukinumab, about 15-25 mM histidine salt buffer, about 220-260 mM sucrose, about 25-30 mM methionine, and about 0.04-0.06% polysorbate 80; or comprising about 25 mg / mL secukinumab, about 20 mM histidine salt buffer, about 240 mM sucrose, about 27 mM methionine, and about 0.05% polysorbate 80; the antibody formulation has a pH of 5.8 ± 0.

3.

43. A method of preparing an antibody preparation of any one of claims 1-42, comprising: Prepare the formulation by dissolving each ingredient in water, mixing well, and adjusting the pH to obtain the antibody formulation.

44. A method of preparing an antibody preparation of any one of claims 1-42, comprising: Prepare the buffer, ultrafilter the antibody into the buffer, add the excipients, and dilute the antibody to the specified concentration to obtain the antibody formulation.

45. Use of the antibody formulation of any one of claims 1-42 in the manufacture of a medicament for treating an IL-17 associated disease.

46. The use of claim 45, wherein the IL-17 associated disease is an autoimmune disease.

47. The use of claim 46, wherein the autoimmune disease is rheumatoid arthritis, psoriatic arthritis, diabetes (e.g., autoimmune diabetes), asthma, chronic plaque psoriasis, or multiple sclerosis.

48. An antibody drug product for treating an IL-17 associated disease, comprising the antibody formulation of any one of claims 1-42 and a container for holding the antibody formulation.

49. The product of claim 48, wherein the IL-17 associated disease is an autoimmune disease.

50. The product of claim 49, wherein the autoimmune disease is rheumatoid arthritis, psoriatic arthritis, diabetes (e.g., autoimmune diabetes), asthma, chronic plaque psoriasis, or multiple sclerosis.

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