Anti-il-36r antibody formulations

Abstract

This invention relates to the administration of an anti-IL-36R formulation to an individual.

Description

Technical Field

[0001] This invention relates to a pharmaceutical formulation for use with therapeutic antibodies. More specifically, this invention relates to a pharmaceutical formulation for use with the anti-IL-36R antibody disclosed herein. Prior Technology

[0002] The anti-IL-36R antibody described herein reduces or blocks IL36 ligand-mediated signaling and is suitable for the treatment of diseases or conditions associated with such signaling. A stable liquid or lyophilized antibody formulation for anti-IL-36R antibody is needed, suitable for non-enteral administration to humans, including intravenous, intramuscular, or subcutaneous injection.

[0003] Therapeutic antibodies are large complex molecules and therefore undergo degradation processes, especially in liquid form. While antibody production and purification are well-controlled processes, developing stable formulations suitable for delivery to patients is challenging. Antibody instability is a major obstacle to the commercial development of antibody drugs. For example, antibody formulations may have short shelf lives, and antibodies may lose their biological activity due to chemical and physical degradation during storage. Chemical degradation processes include deamination, racemization, hydrolysis, oxidation, β-elimination, and disulfide exchange. Physical degradation processes include aggregation, precipitation, and adsorption (Cleland et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1993, 10(4): 307-377). Despite some structural similarities shared by antibodies, the development of commercially viable antibody drugs is not straightforward due to their unique and somewhat unpredictable solution properties. Due to significant differences in the primary sequence among different antibodies, the intensity of degradation pathways (such as denaturation, aggregation, surface adsorption, deamination, oxidation, isomerization, fragmentation, etc.) can vary significantly. (Wang et al., J Pharm Sci., Antibody Structure, Instability, and Formulation, 2007, 96(1):1-26).

[0004] The following lists various reference materials for formulations.

[0005] U.S. Patent No. 10,166,993 describes a concentrated protein formulation with reduced viscosity, comprising: a protein in an amount of at least about 80 mg / mL and a buffer in an amount of at least about 50 mM, so as to have a pH of about 4.2 to about 4.9 or about 7.1 to about 12.0 and a kinematic viscosity of about 50 cs or less at 25°C, thereby making the formulation suitable for subcutaneous administration.

[0006] WO 2011 / 109365 describes a formulation comprising a concentrated protein in an amount greater than 100 mg / mL or less than about 200 mg / mL, a salt-based tonic, a buffer present in a combined amount of about 110 mM to about 120 mM, and a surfactant, wherein the formulation is low osmotic pressure (having a weight molar osmotic concentration of less than 290 mOsm).

[0007] U.S. Patent No. 9,517,226 describes a formulation for an anti-c-Met antibody. It discloses a liquid formulation of an anti-c-Met antibody containing a surfactant, a buffer, and a liquid medium, wherein the buffer includes succinic acid, citric acid, or a combination thereof.

[0008] WO 2016 / 128564 describes a pharmaceutical composition comprising an antibody, at least one buffer selected from the group consisting of acetate and histidine, at least one amino acid selected from the group consisting of glycine, aspartic acid and glutamine, and / or at least one excipient selected from the group consisting of trehalose and mannitol, and a surfactant, wherein the pH of the composition is from 5.0 to 6.5.

[0009] Despite the information provided in this or similar references, it is conventionally understood that the performance of antibodies with different sequences is unpredictable under various conditions, including shaking, long-term storage, exposure to light, freeze-thaw processes, and lyophilization. It is also unpredictable how an antibody will behave in a formulation specifically prepared with or for another antibody or protein. For example, slight changes in a formulation can destabilize a protein and lead to aggregation. Protein aggregates generally have reduced activity and, more importantly, greater immunogenic potential due to the multiplicity of antigenic determinants and / or conformational changes. Immunoglobulin aggregates have been shown to cause severe renal failure and anaphylactic reactions such as headache, fever, and chills (Wang et al., see above).

[0010] Therefore, there is a need for stable formulations of the anti-IL-36R antibody described herein that exhibit, for example, increased stability, low to undetectable levels of physical or chemical degradation, and minimal or even lost antibody biological activity, even during long storage periods. Summary of the Invention

[0011] This invention addresses the above needs by providing stable liquid or lyophilized pharmaceutical formulations of anti-IL-36R antibodies, as further described below. Specifically, this invention provides stable liquid or powdered pharmaceutical formulations of the anti-IL-36R antibodies disclosed herein. These anti-IL-36R antibody formulations of the present invention are suitable for administration to mammals, particularly humans, or patients suffering from autoimmune diseases or other malignant diseases. The formulations according to the present invention possess improved characteristics compared to other formulations existing in this art, as described below.

[0012] In a first embodiment, the present invention provides a pharmaceutical formulation of an anti-IL-36R antibody, wherein the formulation comprises: a therapeutic amount of an anti-IL-36R antibody or an antigen-binding fragment thereof (disclosed herein); and i) a pharmaceutically acceptable buffer; or ii) a pharmaceutically acceptable tension modulator; or iii) a pharmaceutically acceptable stabilizer; or iv) a pharmaceutically acceptable salt; or v) a pharmaceutically acceptable surfactant; or vi) a pharmaceutically acceptable buffer and a pharmaceutically acceptable tension modulator; or vii) Pharmaceutically acceptable buffers, pharmaceutically acceptable tension modifiers, and pharmaceutically acceptable stabilizers; or viii) pharmaceutically acceptable buffers, pharmaceutically acceptable tension modifiers, pharmaceutically acceptable stabilizers, and pharmaceutically acceptable salts; or ix) pharmaceutically acceptable buffers, pharmaceutically acceptable tension modifiers, pharmaceutically acceptable stabilizers, pharmaceutically acceptable salts, and pharmaceutically acceptable surfactants; each in a pharmaceutically acceptable amount and at a pharmaceutically acceptable pH.

[0013] In the second embodiment, the present invention relates to a pharmaceutical formulation of a therapeutic anti-IL-36R antibody or antibody fragment (disclosed herein), wherein the formulation comprises: (a) the anti-IL-36R antibody or its antigen-binding fragment, present at a concentration in the range of about 0.5 mg / mL to about 220 mg / mL; and (b) a pharmaceutically acceptable buffer; wherein the formulation is characterized by a pH in the range of about 5 to about 8. In one embodiment associated with this embodiment, the buffer is present at a concentration in the range of about 20 mM to about 80 mM. In another embodiment associated with this embodiment, the formulation further comprises a pharmaceutically acceptable tonic modulator. In a related embodiment, the tonic modulator is present at a concentration in the range of about 100 mM to about 250 mM.

[0014] In the third embodiment, the present invention provides a pharmaceutical product comprising a vial or syringe and a dispensing device (e.g., an auto-injector, a needle safety device), the pharmaceutical product comprising the pharmaceutical preparation according to either the first or second embodiment of the present invention. []

[0015] In the fourth state, the present invention relates to a method for preparing the pharmaceutical formulation of the present invention, the method comprising: a) culturing mammalian cells encoding one or more of the light and heavy chains of an anti-IL-36R antibody (as disclosed herein) whose nucleic acids have been stably incorporated into their genome, such that the cells secrete the antibody into a cell culture medium and purify the antibody from the cell culture medium; and b) preparing the formulation according to either the first or second state.

[0016] In the fifth state sample, the present invention relates to a method for reducing the aggregation and / or fragmentation of the anti-IL-36R antibody disclosed herein, comprising formulating the antibody in a buffer system and a surfactant, and evaluating data (e.g., any antibody aggregation) before and after formulating the antibody. In one embodiment associated with the fifth state sample, the antibody system is formulated according to any of the embodiments of the first or second state sample.

[0017] In the sixth state sample, the present invention relates to a kit of dispensing portions comprising: at least one container comprising a pharmaceutical preparation according to either the first or second state sample; and an injection device according to the third state sample. In one embodiment related to the sixth state sample, the injection device is a pre-assembled injection device comprising an auto-injector or a needle safety device. In a related embodiment, the auto-injector or needle safety device each comprises: (a) about 300 mg of the antibody in a total volume of about 2 mL; (b) about 225 mg of the antibody in a total volume of about 1.5 mL; (c) about 150 mg of the antibody in a total volume of about 1 mL; (d) about 75 mg of the antibody in a total volume of about 0.5 mL; or (e) about 60 mg of the antibody in a total volume of about 0.4 mL.

[0018] According to another aspect of the invention, the use of the formulation according to the invention, the pre-assembled injection device according to the invention, or the kit of the dispensing portion according to the invention is provided for infusion, intravenous and / or subcutaneous administration.

[0019] According to another aspect of the invention, the use of a formulation according to the invention, a pre-assembled injection device according to the invention, or a kit of dispensing portions according to the invention is provided for treating at least one disease selected from a group consisting of autoimmune diseases and / or malignant diseases. Non-limiting examples of autoimmune disorders covered by this definition include psoriasis, rheumatoid arthritis, inflammatory bowel disease or psoriatic arthritis, chronic obstructive pulmonary disease (COPD), asthma, scleroderma, palmoplantar pustulosis, generalized pustular psoriasis, atopic dermatitis, diabetic nephropathy, lupus nephritis, scleroderma, ankylosing spondylitis, IL-36 receptor antagonist autoimmune disease (DITRA), IL-1 receptor antagonist autoimmune disease (DIRA) or cryptothermal protein-related periodic syndrome (CAPS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, and Sjogren's syndrome. Syndrome), multiple sclerosis, psoriasis, psoriatic arthritis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), lung inflammation, asthma, idiopathic thrombocytopenic purpura (ITP), epithelial inflammatory diseases, fibrosis, and ankylosing spondylitis. In another preferred embodiment, the kit includes instructions for administering the formulation subcutaneously or intramuscularly to an individual.

[0020] Additional features and advantages of the present invention will be set forth in the description below, and will be apparent to some extent from the description, or may be learned by practice of the present invention. The advantages of the present invention will be realized and obtained by means of the structures particularly pointed out in the written description and claims herein and in the accompanying drawings.

[0021] It should be understood that both the foregoing general description and the following detailed description are merely illustrative and explanatory, and are intended to provide further explanation of the claimed inventive techniques. Simple Explanation of the Diagram

[0022] [picture] [1] Colloidal stability was demonstrated by diffusion coefficients measured using DLS. Protein concentrations in individual buffers varied between 5 and 20 mg / mL, as shown on the X-axis. Diffusion coefficients are shown on the Y-axis of the buffers tested. [] [picture] [2] High molecular weight (HMW) results measured by HP-SEC are shown (Y-axis). Results after one (black column) and three (shaded column) freeze-thaw cycles (FT) are provided for polysorbate 20 (PS20) with dosages of 0, 0.02, 0.04 and 0.06% (w / v). [] [picture] [3] High molecular weight (HMW) results measured by HP-SEC are shown (Y-axis). Solutions containing 0, 0.02, 0.04 and 0.06% (w / v) polysorbate 20 (PS20) were shaken. Results are shown after shaking at room temperature (RT) for 3, 6, 24 and 48 hours. [picture] [4] High molecular weight (HMW) results measured by HP-SEC are shown (Y-axis). Six formulations (F1 to F6) containing anti-IL-36R antibody at a target protein concentration of 150 mg / mL were stored at 40°C. Data after 0, 2, 4, 6 and 8 weeks (8w) of storage are plotted on the X-axis. [] [picture] [5] Viscosity data of different proteins (anti-IL-36R antibody, protein C, protein D) and different formulations (formulation I, formulation V, formulation VIII, formulation IX, formulation VI, formulation VII) at 20°C are presented with protein concentrations ranging from 145 to 189 mg / mL. Viscosity data of anti-IL-36R antibody at a protein concentration of 60 mg / mL are also provided. Viscosity values ​​are displayed on the Y-axis. Protein formulations with increasing protein concentrations are shown on the X-axis. [picture] [6] High molecular weight (HMW) results measured by HP-SEC are shown (Y-axis). The two formulations (F1 and F2) were stored at 2 to 8°C. Data for F1 after storage for up to 36 months and data for F2 after storage for up to 30 months are depicted. [picture] [7] Turbidity results (Y-axis) are shown by 90° light scattering analysis at 400 to 600 nm. Data for F1 and F2 (reference formulations) after storage at 40°C for up to 3 months under stress conditions are shown on the X-axis. [picture] [8] High molecular weight (HMW) results measured by HP-SEC are presented. Data for F1 and F2 (reference formulations) after storage at 40°C for up to 3 months under stress conditions are depicted. [picture] [9] Turbidity results (Y-axis) are shown by 90° light scattering analysis at 400 to 600 nm. Data are given on the X-axis before lyophilization, after lyophilization, and after the lyophilized powder formulations were stored under stress at 40°C for up to 6 months. [picture]

[10] High molecular weight (HMW) results measured by HP-SEC are shown (Y-axis). Data are depicted before freeze-drying, after freeze-drying, and after the freeze-dried powder formulations were stored under stress at 40°C for up to 6 months. Implementation

[0023] [Sequence List] []

[0024] This application contains a sequence list, which has been submitted via EFS-Web in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on March 2, 2020, and is named 09-0694-TW-SL.txt, with a size of 146,026 bytes.

[0025] Without wishing to be bound by any theory or mechanism, this invention is based in part on the unexpected finding that the anti-IL-36R formulation of this invention, exhibiting the lowest dissolution temperature (Tm), is associated with the most promising properties (i.e., minimized protein-protein interactions, maximum diffusion, and increased long-term stability). See examples. This contrasts with the conventional view that increased Tm is associated with increased long-term stability of the protein under study (see, for example, He et al., J Pharm Sci 2011; 100:1330-40).

[0026] As previously discussed, the physical and chemical instability of antibodies is a combination of solubility conditions, temperature, and their primary structure. Antibodies are susceptible to deamination, isomerization, oxidation, proteolysis, aggregation, and other modifications. These phenomena are suspected of leading to reduced efficacy or even potential clinical side effects or toxicity, as aggregates can decrease efficacy and enhance the immunogenicity of protein drugs. Antibody aggregation is also a source of batch-to-batch variability in the antibody production chain, and its control results in a regulatory and quality control burden with extremely high costs. Furthermore, once removed from optimal storage conditions, antibody aggregation affects its storage stability, including shelf life and time to market.

[0027] Aqueous antibody formulations typically require at least one buffer to maintain a given pH range and a tonic modulator to ensure that the formulation has a weight mole osmotic concentration similar to that of physiological fluids.

[0028] There is a need to provide therapeutic antibodies for the treatment of chronic diseases in a form that can be administered by the patient themselves (“home”, “self-administered”, or “self-injected”), because in many cases, medications will have to be administered frequently over a long period. The suitability of formulations for self-administration will therefore increase patient compliance and reduce costs, as patients will not have to see a healthcare professional every time they need an injection.

[0029] Undesirable degradation occurs in solutions not stored under optimal conditions, such as at elevated temperatures above the recommended range of 2 to 8°C, including the formation of insoluble and / or soluble aggregates. These insoluble and soluble aggregates may form in a liquid state through association with antibody molecules. When liquid formulations are stored for extended periods, the bioactivity of antibody molecules can be reduced, for example, by aggregation or oxidation. Cyclic freezing and thawing can also induce the formation of degraded and aggregated antibody molecules.

[0030] Therefore, solutions can exhibit reduced activity, increased toxicity, and / or increased immunogenicity. In fact, peptide precipitation can cause embolism, dosage form heterogeneity, and immune responses. Therefore, the safety and efficacy of any pharmaceutical formulation of a peptide are directly related to its stability.

[0031] However, self-administration and its suitability present new challenges regarding storage. Patients will have to store large quantities of medication at home, where storage conditions are often less suitable than in medical practice. Formulas containing therapeutic antibodies suitable for self-administration will therefore need to outperform existing formulas in terms of storage stability, even under suboptimal conditions (e.g., cold chain disruptions or conditions that would otherwise allow for the storage of the formula or medication).

[0032] For home and / or self-administered medications, patients require subcutaneous or intramuscular administration. To deliver the required dose, home-use medications typically require higher protein concentrations than those needed for intravenous administration due to injection volume limitations. However, higher protein concentrations increase the viscosity of the solution. This increased viscosity makes drug delivery via syringe needles challenging. Additionally, some buffered solutions are known to cause pain when present in products administered subcutaneously or intramuscularly.

[0033] Therefore, there is a need for stable antibody formulations that offer advantages in administration and dosing, especially regarding improved storage stability, including shelf life and dosing availability.

[0034] The problems mentioned above are solved by the embodiments characterized in the claims and further described below. [definition] []

[0035] Phrases such as "a single example" do not imply that this example is essential to the present invention or that this example is applicable to all configurations of the present invention. The disclosure relating to an example may apply to all configurations or one or more configurations. A single example can provide one or more instances of the present invention. Phrases such as "a single example" may refer to one or more examples, and vice versa. Phrases such as "an embodiment" do not imply that this embodiment is essential to the present invention or that this embodiment is applicable to all configurations of the present invention. The disclosure relating to an embodiment may apply to all embodiments or one or more embodiments. An embodiment can provide one or more instances of the present invention.

[0036] The term "about" generally refers to the acceptable degree of error or deviation of a measured quantity given the nature or precision of the measurement. Typically, an illustrative degree of error or deviation is within 5%, 3%, or 1% of a given value or range of values. For example, the expression "about 100" includes 105 and 95, or 103 and 97, or 101 and 99, and all values ​​in between (e.g., for the range of 95 to 105, 95.1, 95.2, etc.; or for the range of 97 to 103, 97.1, 97.2, etc.; for the range of 99 to 101, 99.1, 99.2, etc.). Unless otherwise stated, the numerical quantities given herein are approximate values, meaning that the term "about" can be inferred when not explicitly stated.

[0037] As used herein, the general embodiment “comprising” or “comprise” encompasses the more specific embodiment “consisting of”. Furthermore, the singular and plural forms are not used in a limiting manner. As used herein, unless expressly stated otherwise, the singular forms “a” and “the” represent both the singular and plural.

[0038] "Pharmaceutical formulation" or "formulation" refers to the process and process products in which an active pharmaceutical ingredient or agent is combined with a chemical substance to produce a final pharmaceutical product or drug. Therefore, a final formulation refers to a pharmaceutical product such as a liquid, powder, or composition. Thus, in one embodiment, the pharmaceutical formulation is a pharmaceutical composition.

[0039] In this context, "pharmaceutical composition" refers to a liquid or powder formulation that is in such a form as to allow for the proven bioactivity of the active ingredient and that it does not contain any additional components that would be significantly toxic to the individual to whom the composition will be administered. Such compositions are sterile. "Powder" refers to a lyophilized, freeze-dried, or spray-dried pharmaceutical composition intended for non-enteral use. Powders are typically reconstituted or dissolved in water. Lyophilization is a low-temperature dehydration process that involves freezing the product, reducing pressure, and subsequently removing the ice by sublimation. Lyophilization produces high-quality products because of the low temperatures used in the processing. For well-developed lyophilized formulations, the shape and appearance of the product remain unchanged over time, and the quality of the rehydrated product is excellent. Spray drying is a method of producing a dry powder from a liquid or slurry by rapidly drying it with hot air with the aim of achieving a constant particle size distribution.

[0040] As used in this article, the term "water" refers to water for injection.

[0041] "Medically acceptable" excipients (mediators, additives) are reagents that are suitable for administration to an individual outside the intestine.

[0042] In one embodiment, the pharmaceutical formulation of the present invention is stable.

[0043] "Stability" refers to chemical and physical stability that can be assessed qualitatively and / or quantitatively using various analytical techniques described in this technique and, for example, reviewed in the following literature: Peptide and Protein Drug Delivery, 247-301, Vincent Lee (ed.), Marcel Dekker, Inc., New York, NY, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10: 29-90 (1993). These methods include assessing aggregate and particle formation (e.g., using size exclusion chromatography, by measuring turbidity, microscopically visible particles by light shielding or microfluidic imaging and / or by visual inspection); assessing charge heterogeneity using cation exchange chromatography or capillary isoelectric focusing; mass spectrometry; capillary gel electrophoresis (CGE) analysis to compare reducing and intact antibodies; peptide mapping (e.g., trypsin or Lys-C digest analysis); assessing antibody bioactivity or antigen-binding function; and so on. Instability can involve any or more of the following: aggregation, deacetylation (e.g., Asn deacetylation), oxidation (e.g., Met oxidation), isomerization (e.g., Asp isomerization), pruning / hydrolysis / fragmentation (e.g., hinge region fragmentation), succinimide formation, unpaired cysteine, etc. The term "deacetylated" monoclonal antibody in this document refers to a monoclonal antibody in which one or more aspartic acid residues have been modified post-translationally to, for example, aspartic acid or isofaradine. To measure stability, samples of the formulations of this invention can be tested in stability studies, wherein the samples are exposed to stress conditions for a selected time period, followed by quantitative and qualitative analysis of chemical and physical stability using appropriate analytical techniques.

[0044] Therefore, stability can be measured at selected temperatures for selected time periods, for example, by storing samples at different temperatures such as -40°C, 5°C, 25°C and 40°C for up to 2 months and by performing qualitative and quantitative analyses using methods such as HP-SEC, CEX, light-masking, CGE or binding activity.

[0045] As stated above, a "stabilizing formulation" is a formulation that stabilizes and / or maintains the biological activity of an antibody physically and chemically after storage.

[0046] Chemical stability can be assessed by detecting and quantifying the forms of chemical alterations to the antibody. Chemical alterations may involve size modifications (e.g., trimming), which can be assessed using, for example, size exclusion chromatography, CGE, and / or matrix-assisted laser desorption / ionization / time-of-flight mass spectrometry (MALDI / TOF MS). Other types of chemical alterations include charge changes (e.g., due to deacetylation), which can be assessed, for example, by ion exchange chromatography. In the context of this invention, chemical stability is measured, for example, by cation exchange chromatography (CEX), where a change of, for example, 5% is considered significant.

[0047] In the context of this invention, "physical stability" essentially refers to antibodies exhibiting very little or no signs of aggregation, precipitation, and / or denaturation. Methods for assessing physical stability include, for example, size exclusion chromatography (SEC), light obscuration (LO), and color and clarity. For size exclusion chromatography (SEC), in the context of this invention, under the test conditions depending on the column used, operating pressure, and buffer flow rate, a difference of ≥0.1% in concentration can be considered significant.

[0048] If an antibody in a pharmaceutical formulation has the biological activity intended for its intended use, then the antibody "retains its biological activity" in the pharmaceutical formulation. For example, if the biological activity of an antibody in a pharmaceutical composition is within about 30%, about 20%, or about 10% of a reference standard (within analytical error) (e.g., as determined in an antigen binding assay), then the biological activity is retained. As those skilled in the art know, the percentage of monomeric antibody maintained in solution is of utmost importance for a suitable pharmaceutically active composition. Because aggregates can cause several and serious side effects, the amount of monomer indicates the actual pharmaceutically active amount of the drug or antibody or its antibody fragment.

[0049] In the context of this invention, the term "stress" or "stress condition" refers to, for example, mechanical stress, thermal stress, optical stress, or stress caused by freezing and thawing. Various methods and conditions are available for simulating mechanical stress, thermal stress, optical stress, or stress caused by freezing and thawing, and are known to those skilled in the art. Mechanical stress can be, for example, oscillation at 300 rpm for up to 48 hours at room temperature. For example, thermal stress refers to storage at a decreasing or increasing temperature for a certain period of time; in one instance, the sample may be stored at 5°C, 25°C, and 40°C, where, for example, 25°C and 40°C refer to stress conditions. Optical stress can be, for example, storing the sample at room temperature for 5 days under a light intensity of approximately 1100 lux. The sample can be exposed to stress from freezing and thawing by exposing it to several freezing cycles, for example, 24 hours at -40°C and 2 hours at room temperature, wherein the cycles are repeated three times.

[0050] As used herein, "buffer" refers to a buffer solution that resists pH changes by the action of its acid-base combination components. "pH" herein refers to the acidity or alkalinity of the composition at room temperature. Standard methods for measuring the pH of a composition are known to those skilled in the art. Typically, pH measurement involves calibrating the instrument, placing the electrode in a well-mixed sample, and then reading the pH directly from a pH meter. Exemplary buffers of this invention include acetates, citrates, histidines, succinates, phosphates, and Tris.

[0051] As used herein, the terms "tonomodulator," "tonochemical," or "tonochemical agent" refer to substances that provide an osmotic pressure equivalent to that of serum in vivo, including salts (e.g., sodium chloride, potassium chloride, magnesium chloride, magnesium sulfate (MgSO4)) or sugars / polyols (e.g., sucrose, trehalose, sorbitol, glycerol, mannitol, or dextrose). Additionally, sugars / polyols present in solution act as cryoprotectants for proteins, allowing the active pharmaceutical ingredient to be frozen without damage. This allows for shipment in frozen form and long-term storage of the active pharmaceutical ingredient prior to injection.

[0052] Exemplary tension modifiers of the present invention include sodium chloride, potassium chloride, magnesium chloride, magnesium sulfate (MgSO4) (salts) and / or sucrose, trehalose, sorbitol, glycerol, mannitol, or dextrose (sugar / polyol). In some embodiments, the tension modifier is a sugar or polyol selected from the group consisting of sucrose, trehalose, sorbitol, glycerol, mannitol, and dextrose. []

[0053] As used herein, the terms "stabilizer" or "stabilizing agent" refer to substances that promote the stability of an active ingredient in a pharmaceutical formulation. Exemplary stabilizers of the present invention include arginine, histidine, glycine, cysteine, proline, methionine, lysine, or pharmaceutically acceptable salts thereof.

[0054] As used herein, the term "surfactant" refers to a substance that tends to reduce the surface tension of the liquid to which it is dissolved. Exemplary surfactants of the present invention include poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. []

[0055] This invention relates to a formulation of an anti-IL-36R antibody for administration to mammals, particularly humans. The formulation of this invention comprises a humanized antibody disclosed herein that binds to the IL-36 receptor (IL-36R). In specific embodiments herein, the sequences of these humanized antibodies have been identified.

[0056] The formulations of this invention minimize antibody aggregate formation and turbidity, while ensuring that the antibodies retain their biological activity over time. Specifically, the inventors of this invention have made the remarkable discovery demonstrated in the examples: the monomer content of the formulated antibodies is more stable, and at 40°C, after storage for up to 3 months, aggregate formation is far less pronounced in some formulations of this invention than in other formulations tested. See Example 7.

[0057] Therefore, in the first embodiment, the present invention provides a pharmaceutical formulation of an anti-IL-36R antibody, wherein the formulation comprises: a therapeutic amount of an anti-IL-36R antibody or an antigen-binding fragment thereof (disclosed herein); and i) a pharmaceutically acceptable buffer; or ii) a pharmaceutically acceptable tension modulator; or iii) a pharmaceutically acceptable stabilizer; or iv) a pharmaceutically acceptable salt; or v) a pharmaceutically acceptable surfactant; or vi) a pharmaceutically acceptable buffer and a pharmaceutically acceptable tension modulator; or vii (viii) pharmaceutically acceptable buffers, pharmaceutically acceptable tension modifiers, and pharmaceutically acceptable stabilizers; or (ix) pharmaceutically acceptable buffers, pharmaceutically acceptable tension modifiers, pharmaceutically acceptable stabilizers, and pharmaceutically acceptable salts; each in a pharmaceutically acceptable amount and at a pharmaceutically acceptable pH. Formulations according to the invention have the improved properties described below.

[0058] The table below provides typical concentration ranges for the components of the formulations of this invention: [surface] [I] Typical concentration range of components in the formulation [] [Components] [Concentration Range] Anti-IL-36R antibody 0.5 to 220 mg / mL Buffers: Acetate, Citrate, Histidine, Succinate, Phosphate, TRIS 20 to 80 mM Tenosynovitis inhibitors: such as sucrose, trehalose, sorbitol, glycerol, mannitol, dextrose, and combinations thereof. 100 to 250 mM Stabilizers: Arginine, histidine, glycine, proline, methionine, lysine, cysteine, or their pharmaceutically acceptable salts. 0 to 80 mM Salts: NaCl, MgCl2, MgSO4, KCl 0 to 150 mM Surfactants: Polysorbate (20, 40, 60, 80), Poloxamer (188) 0.1 to 1.5 g / L (equivalent to 0.01 to 0.15 % (w / v))

[0059] The following table provides exemplary formulations of the present invention and reference formulations XI and XIb: [surface] [Ia] [Example formulation] [] [Mode] [Anti-IL-36R] [Antibody] [Buffer] [Tension agent] [Stabilizer] [Salt] [Surfactants] [pH] I 20 mg / ml 40 mM histidine 120 mM sucrose 50 mM L-arginine 5 mM NaCl 1.0 g / L Polysorbate 20 6.0 II 60 mg / mL 45 mM Acetate 150 mM sucrose 25 mM L-arginine - 0.4 g / L Polysorbate 20 5.5 III 20 mg / mL 45 mM Acetate 180 mM sucrose 25 mM glycine - 0.4 g / L Polysorbate 80 5.5 IV 150 mg / mL 25 mM citrate 150 mM Trehalose 25 mM methionine - 0.2 g / L Polysorbate 20 6.0 V 60 mg / mL 25 mM histidine 160 mM sucrose 20 mM mannitol - - 0.2 g / L Polysorbate 20 6.0 VI 20 mg / mL 25 mM citrate 200 mM sucrose - - 0.4 g / L Polysorbate 80 6.5 VII 150 mg / mL 45 mM acetate 150 mM sucrose 25 mM L-arginine - 0.4 g / L Polysorbate 20 5.5 VIII 15 mg / mL 35 mM histidine 180 mM Trehalose 25 mM L-arginine 3 mM NaCl 0.4 g / L Polysorbate 80 6.0 IX 80 mg / mL 25 mM acetate 100 mM mannitol - 50 mM NaCl 0.2 g / L Polysorbate 20 5.5 X 100 mg / mL 20 mM succinate 220 mM sucrose - - 0.1 g / L Polysorbate 80 6.0 XI 60 mg / mL 25 mM citrate - - - 0.4 g / L Polysorbate 20 6.5 [surface] [Ib] [Example formulation] [] [Mode] [Anti-IL-36R] [Antibody] [Buffer] [Tension agent] [Stabilizer] [Salt] [Surfactants] [pH] Ib 20 mg / mL to 150 mg / mL 40 mM histidine 120 mM sucrose 50 mM L-arginine 5 mM NaCl 1.0 g / L Polysorbate 20 6.0 IIb 20 mg / mL to 150 mg / mL 45 mM Acetate 150 mM sucrose 25 mM L-arginine - 0.4 g / L Polysorbate 20 5.5 IIIb 20 mg / mL to 150 mg / mL 45 mM Acetate 180 mM sucrose 25 mM glycine - 0.4 g / L Polysorbate 80 5.5 IVb 20 mg / mL to 150 mg / mL 25 mM citrate 150 mM Trehalose 25 mM methionine - 0.2 g / L Polysorbate 20 6.0 Vb 20 mg / mL to 150 mg / mL 25 mM histidine 160 mM sucrose 20 mM mannitol - - 0.2 g / L Polysorbate 20 6.0 VIb 20 mg / mL 25 mM citrate 200 mM sucrose - - 0.4 g / L Polysorbate 80 6.5 VIIb 20 mg / mL to 150 mg / mL 45 mM acetate 150 mM sucrose 25 mM L-arginine - 0.4 g / L Polysorbate 20 5.5 VIIIb 20 mg / mL to 150 mg / mL 35 mM histidine 180 mM Trehalose 25 mM L-arginine 3 mM NaCl 0.4 g / L Polysorbate 80 6.0 IXb 20 mg / mL to 150 mg / mL 25 mM acetate 100 mM mannitol - 50 mM NaCl 0.2 g / L Polysorbate 20 5.5 Xb 20 mg / mL to 150 mg / mL 20 mM succinate 220 mM sucrose - - 0.1 g / L Polysorbate 80 6.0 XIb 20 mg / mL to 150 mg / mL 25 mM citrate - - - 0.4 g / L Polysorbate 20 6.5

[0060] Based on the above, in one embodiment, the pharmaceutical composition of the present invention has at least one feature selected from the group consisting of: (a) The percentage of aggregates that was significantly reduced, as measured by high-performance size exclusion chromatography (HP-SEC). (b) As measured by HP-SEC, a significantly higher percentage of monomers after storage at approximately 40°C. (c) The percentage of higher main peaks associated with less chemical degradation, as measured by CEX. (d) Lower turbidity as assessed visually and / or lower turbidity values ​​measured in Formazine Nephelometry Units (FNU), and (e) Lower values ​​of microscopically visible particles (≥10 µm and ≥25 µm), For comparison with a reference formulation.

[0061] According to the present invention, terms such as "decreased", "higher", "less", "smaller", "increased", "lower" or "less" that indicate a quantitative difference between two states include significant differences between the two states.

[0062] According to the present invention, the term "reference formulation" refers to formulation XI in Table Ia and / or formulation XIb in Table Ib. In one embodiment, the reference formulation comprises an anti-IL-36R antibody or its antigen-binding fragment as disclosed herein, present, for example, at the same concentration as the formulation being compared, but in a different amount and / or type of buffer system, and / or in a different amount and / or type of tension modifier (and / or in a different amount and / or type of surfactant), such as in formulation XI in Table Ia and / or formulation XIb in Table Ib; wherein the formulation is characterized in that, when in aqueous solution form, the pH is in the range of about 5 to about 7.

[0063] In one embodiment, the aggregate amount of the formulation of the present invention, after storage at approximately 40°C, is reduced by at least approximately 10%, 25%, or 50% compared to the aggregate amount of a reference formulation, as measured by high-performance size exclusion chromatography (HP-SEC). For example, if the experimental value decreases from 1.0% to 0.9%, then according to the preceding sentence, the relative reduction is 10%. []

[0064] In one embodiment, the amount of monomers in the formulation of the present invention after storage at about 40°C is increased by at least about 10%, 25% or 50% compared to the reference formulation after storage at about 40°C, as measured by HP-SEC. []

[0065] In one embodiment, the amount of the main peak of the formulation of the present invention after storage at about 40°C increases by at least about 10%, 25% or 50% compared to the reference formulation (due to chemical degradation reduction), as measured by CEX. []

[0066] In one embodiment, the turbidity value of the formulation of the present invention is at least about 10%, 25% or 50% lower than that of a reference formulation, in turbidity unit (FNU). []

[0067] In one embodiment, the increase in microscopic visible particles (such as ≥10 µm and ≥25 µm) in the formulations of the present invention is at least about 10%, 25%, 50%, 75% or 100% less than that in the reference formulations. []

[0068] In one embodiment related to the first state sample, the anti-IL-36R antibody or its antigen-binding fragment is present in the formulation at concentrations ranging from about 0.5 mg / mL to about 220 mg / mL, or from about 10 to about 175 mg / mL, or from about 10 to about 30 mg / mL, or from about 45 to about 75 mg / mL, or from about 125 to about 175 mg / mL, or at concentrations of about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 60 mg / mL, about 75 mg / mL, about 80 mg / mL, about 100 mg / mL, or about 150 mg / mL. In one embodiment, the anti-IL-36R antibody or its antigen-binding fragment is present in the formulation at a concentration of about 20 mg / mL. In another embodiment, the anti-IL-36R antibody or its antigen-binding fragment is present in the formulation at a concentration of about 60 mg / mL. In yet another embodiment, the anti-IL-36R antibody or its antigen-binding fragment is present in the formulation at a concentration of approximately 150 mg / mL.

[0069] In another related embodiment, a pharmaceutically acceptable buffer is present in the formulation at concentrations ranging from about 20 mM to about 80 mM, or from about 20 to about 70 mM, or from about 20 to about 60 mM, or from about 20 mM to about 50 mM, or at concentrations of about 20 mM, about 25 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, or about 60 mM. The buffer may comprise histidine, phosphate, succinate, citrate, acetate, or TRIS. In some embodiments, the buffer is selected from the group consisting of histidine, phosphate, succinate, citrate, acetate, and TRIS, specifically acetate and citrate. In one embodiment, the buffer is citrate. In another embodiment, the buffer is histidine. In yet another embodiment, the buffer is acetate.

[0070] In another related embodiment, a pharmaceutically acceptable tonic modifier is present in the formulation at concentrations ranging from about 100 mM to about 250 mM, or from about 120 mM to about 220 mM, or from about 130 mM to about 190 mM, or from about 140 mM to about 190 mM, or at concentrations of about 100 mM, about 120 mM, about 150 mM, about 180 mM, about 200 mM, or about 220 mM. The tonic modifier may be a salt, sugar, or polyol. In one embodiment, the tonic modifier is one or more sugars and / or polyols. The tonic modifier may be one or more sugars and / or polyols, including sucrose, trehalose, sorbitol, glycerol, mannitol, or dextran, specifically sucrose or trehalose. In one embodiment, the tension modifier is one or more sugars and / or polyols selected from the group consisting of: sucrose, trehalose, sorbitol, glycerol, mannitol or dextrose, specifically sucrose and trehalose, specifically sucrose or trehalose.

[0071] In another related embodiment, the pharmaceutically acceptable stabilizer is present in the formulation at concentrations ranging from about 0 mM to about 80 mM, or from about 0 to about 70 mM, or from about 0 to about 60 mM, or from about 0 to about 50 mM. In the presence of the stabilizer, it may be present at concentrations ranging from about 5 mM to about 80 mM, or from about 10 mM to 70 mM, or from about 20 mM to 50 mM, or at concentrations of about 25 mM or about 50 mM. In one embodiment, the stabilizer is present in the formulation at concentrations of about 20 mM, or about 25 mM, or about 30 mM, or about 35 mM, or about 40 mM, or about 45 mM. The stabilizer may comprise an amino acid, such as arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartic acid, glutamic acid, or a pharmaceutically acceptable salt thereof, more specifically arginine. In one embodiment, the stabilizer is selected from the group consisting of arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartic acid, glutamic acid, and a pharmaceutically acceptable salt thereof. In yet another embodiment, the stabilizer is L-arginine or a pharmaceutically acceptable salt thereof.

[0072] In another related embodiment, the pharmaceutically acceptable salt is present in the formulation at concentrations ranging from about 0 to about 150 mM, or from about 0 to about 120 mM, or from about 0 to about 90 mM, or from about 0 to about 10 mM, or at concentrations of about 3 mM, 5 mM, 10 mM, 25 mM, or 50 mM. In another related embodiment, the pharmaceutically acceptable formulation comprises one or more sugars and / or polyols as tonic modulators and another pharmaceutically acceptable salt at a concentration ranging from about 3 to about 150 mM, or from about 3 to about 120 mM, or from about 3 to about 90 mM, or from about 3 to about 10 mM, or at concentrations of about 3 mM, 5 mM, 10 mM, 25 mM, or 50 mM. The salt may comprise sodium chloride (NaCl), magnesium chloride (MgCl2), magnesium sulfate (MgSO4), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl2), borate, or zinc chloride (ZnCl2). In one embodiment, the salt system is selected from the group consisting of: sodium chloride (NaCl), magnesium chloride (MgCl2), magnesium sulfate (MgSO4), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl2), borate, and zinc chloride (ZnCl2). In a particular embodiment, the salt is sodium chloride.

[0073] In another related embodiment, a pharmaceutically acceptable surfactant is present in the formulation at concentrations ranging from about 0 g / L to about 1.5 g / L, or from about 0.1 g / L to about 1.5 g / L, or from about 0.1 g / L to about 1.0 g / L, or from about 0.1 g / L to about 0.6 g / L, or from about 0.15 g / L to about 0.5 g / L, or at concentrations of about 0.1 g / L, 0.2 g / L, 0.4 g / L, 0.5 g / L, or 1 g / L. The surfactant may comprise polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. In one embodiment, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, specifically from the group consisting of polysorbate 20 and polysorbate 80.

[0074] In one embodiment related to the first state sample, the formulation is characterized by a pH in the range of about 5 to about 8, or in the range of about 5 to about 7, or in the range of about 5 to about 6.5. In another related embodiment, the pH is about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, or about 8. Those skilled in the art will understand that the pH of the formulation refers to the pH of the formulation when it is in aqueous solution form.

[0075] In one embodiment associated with the first state sample, the anti-IL-36R antibody or its antigen-binding fragment comprises: a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody comprises: a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127. In a particular embodiment, the anti-IL-36R antibody comprises: a light chain variable region comprising an amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising an amino acid sequence SEQ ID NO: 89. In another specific embodiment, the anti-IL-36R antibody consists of a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127.

[0076] In one embodiment related to the first state sample, the anti-IL-36R antibody comprises a light chain variable region comprising the amino acid sequence SEQ ID NO: 80 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87. In another related embodiment, the anti-IL-36R antibody comprises a light chain variable region comprising the amino acid sequence SEQ ID NO: 80 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88. In another related embodiment, the anti-IL-36R antibody comprises a light chain variable region comprising the amino acid sequence SEQ ID NO: 80 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89. In yet another related embodiment, the anti-IL-36R antibody comprises a light chain comprising the amino acid sequence listed as SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence listed as SEQ ID NO: 125. In another related embodiment, the anti-IL-36R antibody comprises a light chain containing the amino acid sequence listed in SEQ ID NO: 118 and a heavy chain containing the amino acid sequence listed in SEQ ID NO: 126. In another related embodiment, the anti-IL-36R antibody comprises a light chain containing the amino acid sequence listed in SEQ ID NO: 118 and a heavy chain containing the amino acid sequence listed in SEQ ID NO: 127.

[0077] In the second embodiment, the present invention relates to a pharmaceutical formulation of a therapeutic anti-IL-36R antibody or antibody fragment (disclosed herein), wherein the formulation comprises: (a) an anti-IL-36R antibody or an antigen-binding fragment thereof, present at a concentration in the range of about 0.5 mg / mL to about 220 mg / mL; and (b) a pharmaceutically acceptable buffer; wherein the formulation is characterized by a pH in the range of about 5 to about 8. In one embodiment associated with this embodiment, the buffer is present at a concentration in the range of about 20 mM to about 80 mM. In another embodiment associated with this embodiment, the formulation further comprises a pharmaceutically acceptable tonic modulator. In a related embodiment, the tonic modulator is present at a concentration in the range of about 100 mM to about 250 mM. Therefore, in one embodiment, the pharmaceutical formulation comprises: (a) an anti-IL-36R antibody or an antigen-binding fragment thereof, present at a concentration in the range of about 0.5 mg / mL to about 220 mg / mL; (b) a buffer present at a concentration in the range of about 20 mM to about 80 mM; and (c) a tonic modulator present at a concentration in the range of about 100 mM to about 250 mM; wherein the formulation is characterized in that, when in aqueous solution form, the pH is in the range of about 5 to about 8.

[0078] In one embodiment related to the second state, the pharmaceutical formulation of the present invention comprises: a) an anti-IL-36R antibody or an antigen-binding fragment thereof as disclosed herein, wherein the antibody or the antigen-binding fragment thereof is present at a concentration of about 20 mg / mL, 60 mg / mL or 150 mg / mL; b) an acetate buffer, present at a concentration of about 25 to 50 mM; c) sucrose or trehalose, present at a concentration of about 150 mM to 200 mM; and, if applicable, d) L-arginine or a pharmaceutically acceptable salt thereof, present at a concentration of about 25 mM; and / or e) polysorbate 20 or polysorbate 80, present at a concentration of about 0.4 g / L; wherein the formulation is characterized in that, when in aqueous solution, the pH is in the range of about 5 to about 7.

[0079] In another embodiment related to the second state, the anti-IL-36R antibody or its antigen-binding fragment is present in the formulation at concentrations ranging from about 0.5 mg / mL to about 220 mg / mL, or from about 10 to about 175 mg / mL, or from about 10 to about 30 mg / mL, or from about 45 to about 75 mg / mL, or from about 125 to about 175 mg / mL, or at concentrations of about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 60 mg / mL, about 75 mg / mL, about 80 mg / mL, about 100 mg / mL, or about 150 mg / mL. In one embodiment, the anti-IL-36R antibody or its antigen-binding fragment is present in the formulation at a concentration of about 20 mg / mL. In another embodiment, the concentration is about 60 mg / mL. In yet another embodiment, the concentration is about 150 mg / mL.

[0080] In another related embodiment, a pharmaceutically acceptable buffer is present in the formulation at concentrations ranging from about 20 mM to about 80 mM, or from about 20 to about 70 mM, or from about 20 to about 60 mM, or from about 20 mM to about 50 mM, or at concentrations of about 20 mM, about 25 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, or about 60 mM. The buffer may comprise histidine, phosphate, succinate, citrate, acetate, or TRIS. In some embodiments, the buffer is selected from the group consisting of histidine, phosphate, succinate, citrate, acetate, and TRIS, specifically acetate and citrate. In one embodiment, the buffer is citrate. In another embodiment, the buffer is histidine. In yet another embodiment, the buffer is acetate.

[0081] In another related embodiment, a pharmaceutically acceptable tonic modifier is present in the formulation at concentrations ranging from about 100 mM to about 250 mM, or from about 120 mM to about 220 mM, or from about 130 mM to about 190 mM, or from about 140 mM to about 190 mM, or at concentrations of about 100 mM, about 120 mM, about 150 mM, about 180 mM, about 200 mM, or about 220 mM. The tonic modifier may be a salt, sugar, or polyol. In one embodiment, the tonic modifier is one or more sugars and / or polyols. The tonic modifier may be one or more sugars and / or polyols, including sucrose, trehalose, sorbitol, glycerol, mannitol, or dextran, specifically sucrose or trehalose. In one embodiment, the tension modifier is one or more sugars and / or polyols selected from the group consisting of: sucrose, trehalose, sorbitol, glycerol, mannitol or dextrose, specifically sucrose and trehalose, specifically sucrose or trehalose.

[0082] In another related embodiment, a pharmaceutically acceptable stabilizer is present in the formulation at concentrations ranging from about 0 mM to about 80 mM, or from about 0 to about 70 mM, or from about 0 to about 60 mM, or from about 0 to about 50 mM. In the presence of a stabilizer, it may be present at concentrations ranging from about 5 mM to about 80 mM, or from about 10 mM to 70 mM, or from about 20 mM to 50 mM, or at concentrations of about 25 mM or about 50 mM. The stabilizer may comprise amino acids such as arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartic acid, glutamic acid, or pharmaceutically acceptable salts thereof, more specifically arginine. In one embodiment, the stabilizer is selected from the group consisting of arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartic acid, glutamic acid, and pharmaceutically acceptable salts thereof. In a particular embodiment, the stabilizer is L-arginine or a pharmaceutically acceptable salt thereof.

[0083] In another related embodiment, the pharmaceutically acceptable salt is present in the formulation at concentrations ranging from about 0 to about 150 mM, or from about 0 to about 120 mM, or from about 0 to about 90 mM, or from about 0 to about 10 mM, or at concentrations of about 3 mM, 5 mM, 10 mM, 25 mM, or 50 mM. In another related embodiment, the pharmaceutically acceptable formulation comprises one or more sugars and / or polyols as tonic modulators and another pharmaceutically acceptable salt at a concentration ranging from about 3 to about 150 mM, or from about 3 to about 120 mM, or from about 3 to about 90 mM, or from about 3 to about 10 mM, or at concentrations of about 3 mM, 5 mM, 10 mM, 25 mM, or 50 mM. The salt may comprise sodium chloride (NaCl), magnesium chloride (MgCl2), magnesium sulfate (MgSO4), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl2), borate, or zinc chloride (ZnCl2). In one embodiment, the salt system is selected from the group consisting of: sodium chloride (NaCl), magnesium chloride (MgCl2), magnesium sulfate (MgSO4), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl2), borate, and zinc chloride (ZnCl2). In a particular embodiment, the salt is sodium chloride.

[0084] In another related embodiment, a pharmaceutically acceptable surfactant is present in the formulation at concentrations ranging from about 0 g / L to about 1.5 g / L, from about 0.1 g / L to about 1.5 g / L, from about 0.1 g / L to about 1.0 g / L, from about 0.1 g / L to about 0.6 g / L, from about 0.15 g / L to about 0.5 g / L, or at concentrations of about 0.1 g / L, 0.2 g / L, 0.4 g / L, 0.5 g / L, or 1 g / L. The surfactant may comprise polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. In one embodiment, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, specifically from the group consisting of polysorbate 20 and polysorbate 80.

[0085] In one embodiment related to the first state sample, the formulation is characterized by a pH in the range of about 5 to about 8, or in the range of about 5 to about 7, or in the range of about 5 to about 6.5. In another related embodiment, the pH is about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, or about 8.

[0086] In one embodiment related to the second state sample, the anti-IL-36R antibody or its antigen-binding fragment comprises: a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody comprises: a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127. In a particular embodiment, the anti-IL-36R antibody comprises: a light chain variable region comprising an amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising an amino acid sequence SEQ ID NO: 89. In another specific embodiment, the anti-IL-36R antibody consists of a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127.

[0087] In one embodiment related to the second state, the anti-IL-36R antibody comprises a light chain variable region comprising the amino acid sequence SEQ ID NO: 80 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87. In another related embodiment, the anti-IL-36R antibody comprises a light chain variable region comprising the amino acid sequence SEQ ID NO: 80 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88. In yet another related embodiment, the anti-IL-36R antibody comprises a light chain variable region comprising the amino acid sequence SEQ ID NO: 80 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89. In yet another related embodiment, the anti-IL-36R antibody comprises a light chain comprising the amino acid sequence listed as SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence listed as SEQ ID NO: 125. In another related embodiment, the anti-IL-36R antibody comprises a light chain containing the amino acid sequence listed in SEQ ID NO: 118 and a heavy chain containing the amino acid sequence listed in SEQ ID NO: 126. In another related embodiment, the anti-IL-36R antibody comprises a light chain containing the amino acid sequence listed in SEQ ID NO: 118 and a heavy chain containing the amino acid sequence listed in SEQ ID NO: 127.

[0088] For convenience, various other examples or embodiments related to the first and second aspects of the present invention are described in the numbered clauses (1, 2, 3, etc.) below. These clauses are provided as examples and do not limit the technology of the present invention. It should be noted that any of the appended clauses may be combined in any combination and placed in separate independent clauses (e.g., clause 1). Other clauses may be presented in a similar manner. 1. A pharmaceutical preparation comprising: a. An anti-IL-36R antibody or its antigen-binding fragment as disclosed herein, present at a concentration ranging from about 0.5 mg / mL to about 220 mg / mL; and b. A pharmaceutically acceptable buffer present at a concentration in the range of about 20 mM to about 80 mM; The formulation is characterized in that, when in aqueous solution form, the pH ranges from about 5 to about 8. 2. The formulation as described in clause 1, wherein the formulation is in liquid or powder form. 3. The formulation as described in clause 1 or 2, wherein the anti-IL-36R anti-system is present at a concentration in the range of about 10 mg / mL to about 200 mg / mL. 4. The formulation as described in clause 1, wherein the anti-IL-36R anti-system is present at a concentration of approximately 20 mg / mL. 5. The formulation as described in clause 1, wherein the anti-IL-36R anti-system is present at a concentration of approximately 60 mg / mL. 6. The formulation as described in clause 1, wherein the anti-IL-36R anti-system is present at a concentration of approximately 150 mg / mL. 7. A formulation of any one of clauses 1 to 6, wherein the buffer comprises histidine, phosphate, succinate, citrate, acetate or TRIS. 8. The formulation as described in clause 7, wherein the buffer contains citrate or acetate. 9. The formulation as described in clause 7, wherein the buffer contains histidine. 10. The formulation as described in clause 8, wherein the buffer contains acetate. 11. A formulation of any one of clauses 1 to 10, wherein the formulation further comprises a pharmaceutically acceptable tension modifier present at a concentration in the range of about 100 mM to about 250 mM. 12. The formulation as described in clause 11, wherein the tension modifier is one or more sugars and / or polyols. 13. The formulation of clause 12, wherein the tension modifier is one or more sugars and / or polyols selected from the group consisting of: sucrose, trehalose, sorbitol, glycerol, mannitol or dextrose. 14. The formulation as described in clause 13, wherein the tension modifier is sucrose or trehalose. 15. The formulation as described in clause 14, wherein the tension modifier is sucrose. 16. The formulation as described in clause 14, wherein the tension modifier is trehalose. 17. A formulation of any one of clauses 1 to 16, wherein the formulation further comprises a pharmaceutically acceptable stabilizer present at a concentration in the range of about 0 mM to about 80 mM or about 5 mM to about 80 mM. 18. A formulation as described in Clause 17, wherein the stabilizer comprises an amino acid selected from the group consisting of: arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartic acid, glutamic acid, or a pharmaceutically acceptable salt thereof. 19. The formulation of paragraph 17, wherein the stabilizer is L-arginine or a pharmaceutically acceptable salt thereof. 20. A formulation of any one of clauses 11 to 16, wherein the formulation further comprises a pharmaceutically acceptable salt present at a concentration in the range of about 0 to about 150 mM. 21. The formulation of paragraph 20, wherein the salt comprises sodium chloride (NaCl), magnesium chloride (MgCl2), magnesium sulfate (MgSO4), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl2), borate or zinc chloride (ZnCl2). 22. The formulation as described in section 20, wherein the salt is sodium chloride (NaCl). 23. A formulation of any one of clauses 1 to 22, wherein the formulation further comprises a pharmaceutically acceptable surfactant present at a concentration in the range of about 0.1 g / L to about 1.5 g / L. 24. The formulation of clause 23, wherein the surfactant comprises poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80. 25. The formulation of paragraph 23, wherein the surfactant is selected from the group consisting of: polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80. 26. The formulation as described in clause 23, wherein the surfactant is polysorbate 20. 27. The formulation as described in clause 23, wherein the surfactant is polysorbate 80. 28. A pharmaceutical preparation comprising: a. Anti-IL-36R antibodies or their antigen-binding fragments as disclosed herein are present at concentrations ranging from about 10 mg / mL to about 200 mg / mL; b. Acetate and / or histidine buffers, present at concentrations ranging from about 20 mM to about 80 mM; c. Sucrose and / or trehalose, present at a concentration in the range of about 100 mM to about 250 mM; d. L-arginine and / or its pharmaceutically acceptable salts, present at concentrations ranging from about 0 mM to about 80 mM; e. Sodium chloride (NaCl), present at a concentration ranging from about 0 to about 150 mM; and f. Polysorbate 20 and / or polysorbate 80, present at a concentration in the range of about 0 g / L to about 1.5 g / L or about 0.1 g / L to about 1.5 g / L; The formulation is characterized in that, when in aqueous solution form, the pH ranges from about 5 to about 7. 29. A pharmaceutical preparation comprising: a. The anti-IL-36R antibody or its antigen-binding fragment, as disclosed in this article, exists at a concentration of approximately 20 mg / mL; b. Citrate buffer, present at a concentration of approximately 25 mM; c. Sucrose and / or trehalose, present at a concentration of approximately 200 mM; d. Polysorbate 80, present at a concentration of approximately 0.4 g / L; The formulation is characterized in that, when in aqueous solution form, the pH is in the range of about 6 to about 7. 30. A pharmaceutical preparation comprising: a. The anti-IL-36R antibody or its antigen-binding fragment, as disclosed in this article, exists at a concentration of approximately 60 mg / mL; b. Acetate buffer, present at a concentration of approximately 45 mM; c. Sucrose and / or trehalose, present at a concentration of approximately 150 mM; d. L-arginine or a pharmaceutically acceptable salt thereof, present at a concentration of about 25 mM; and e. Polysorbate 20, present at a concentration of approximately 0.4 g / L; The formulation is characterized in that, when in aqueous solution form, the pH is in the range of about 5 to about 6. 31. A pharmaceutical preparation comprising: a. The anti-IL-36R antibody or its antigen-binding fragment, as disclosed herein, exists at a concentration of approximately 150 mg / mL; b. Acetate buffer, present at a concentration of approximately 45 mM; c. Sucrose or trehalose, present at a concentration of approximately 150 mM; d. L-arginine or a pharmaceutically acceptable salt thereof, present at a concentration of about 25 mM; and e. Polysorbate 20, present at a concentration of approximately 0.4 g / L; The formulation is characterized in that, when in aqueous solution form, the pH is in the range of about 5 to about 6. 32. A pharmaceutical compound as described in any of clauses 1 to 31, wherein the compound is characterized by a weight molar osmotic concentration in the range of about 210 mOsmol / kg to about 390 mOsm / kg. 33. A pharmaceutical compound of any one of items 1 to 32, wherein less than about 5% of the antibody is present in the compound in the form of aggregates. 34. Any of the pharmaceutical preparations listed in items 1 to 33, wherein the preparation is sterile. 35. A pharmaceutical compound as described in any of clauses 1 to 34, wherein the compound is stable upon freezing and thawing. 36. A pharmaceutical compound as described in any of clauses 1 to 35, wherein the compound contains water or is reconstituted with water. 37. A pharmaceutical compound as described in any of clauses 1 to 36, wherein the compound is in liquid form or has a pH between about 5 and about 6 when reconstituted with water. 38. A pharmaceutical compound as described in any of clauses 1 to 37, wherein the compound is in liquid form or has a pH of about 6 when reconstituted with water. 39. A pharmaceutical compound as described in any of clauses 1 to 37, wherein the compound has at least one characteristic selected from the group consisting of: (i) Increased storage period, (ii) Better temperature stability, (iii) Reduced aggregate formation, (iv) Better chemical stability, (v) Reduced viscosity, and For comparison with a reference formulation. 40. A pharmaceutical compound as described in any of clauses 1 to 37, wherein the compound has at least one characteristic selected from the group consisting of: (a) The percentage of reduced aggregates, as measured by high-performance size exclusion chromatography (HP-SEC). (b) If measured by HP-SEC, a higher percentage of monomers, (c) A higher percentage of the main peak, as measured by CEX (less degradation of charge variants), (d) The lower percentage of microscopically visible particles, such as ≥ 10 µm and ≥ 25 µm, and (e) Lower turbidity values, measured in formalin turbidity units (FNU), after storage at approximately 40°C, as compared with the reference formulation. 41. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation is selected from the following groups of components: I. Contains the following formulation: approximately 20 mg / mL anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-arginine, approximately 5 mM NaCl, and approximately 1.0 g / L polysorbate 20, pH approximately 6.0; II. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; III. Contains the following formulation: approximately 20 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM glycine, approximately 0.4 g / L polysorbate 80, pH approximately 5.5; IV. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; V. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 25 mM histidine, approximately 160 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; VI. Contains the following formulations: approximately 20 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g / L polysorbate 80, pH approximately 6.5; VII. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; VIII. Contains the following formulation: approximately 15 mg / mL anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-arginine, approximately 3 mM NaCl, approximately 0.4 g / L polysorbate 80, pH approximately 6.0; IX. Contains the following formulations: approximately 80 mg / mL anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g / L polysorbate 20, pH approximately 5.5; and X. Contains the following formulation: approximately 100 mg / mL anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g / L polysorbate 80, pH approximately 6.0. 42. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation contains approximately 20 mg / mL of anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-arginine, approximately 5 mM NaCl, and approximately 1.0 g / L polysorbate 20, with a pH of approximately 6.0. 43. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation contains approximately 60 mg / mL of anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, and a pH of approximately 5.5. 44. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation contains approximately 20 mg / mL of anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM glycine, approximately 0.4 g / L polysorbate 80, and a pH of approximately 5.5. 45. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation includes approximately 150 mg / mL of anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g / L polysorbate 20, and a pH of approximately 6.0. 46. ​​A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation contains approximately 60 mg / mL of anti-IL-36R antibody, approximately 25 mM histidine, approximately 160 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g / L polysorbate 20, and a pH of approximately 6.0. 47. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation includes approximately 20 mg / mL of anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g / L polysorbate 80, and a pH of approximately 6.5. 48. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation contains approximately 150 mg / mL of anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, and a pH of approximately 5.5. 49. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation contains approximately 15 mg / mL of anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-arginine, approximately 3 mM NaCl, approximately 0.4 g / L polysorbate 80, and a pH of approximately 6.0. 50. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation includes approximately 80 mg / mL of anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g / L polysorbate 20, and a pH of approximately 5.5. 51. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation includes approximately 100 mg / mL of anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g / L polysorbate 80, and a pH of approximately 6.0. 52. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation includes approximately 60 mg / mL of anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, and a pH of approximately 5.5. 53. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 89; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation includes approximately 20 mg / mL of anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-arginine, approximately 5 mM NaCl, and approximately 1.0 g / L polysorbate 20, with a pH of approximately 6.0. 54. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 89; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation includes approximately 60 mg / mL of anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, and a pH of approximately 5.5. 55. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 89; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation includes approximately 20 mg / mL of anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM glycine, approximately 0.4 g / L polysorbate 80, and a pH of approximately 5.5. 56. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 89; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation includes approximately 150 mg / mL of anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g / L polysorbate 20, and a pH of approximately 6.0. 57. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 89; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation includes approximately 60 mg / mL of anti-IL-36R antibody, approximately 25 mM histidine, approximately 160 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g / L polysorbate 20, and a pH of approximately 6.0. 58. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 89; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation includes approximately 20 mg / mL of anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g / L polysorbate 80, and a pH of approximately 6.5. 59. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 89; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation includes approximately 150 mg / mL of anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, and a pH of approximately 5.5. 60. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 89; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation includes approximately 15 mg / mL of anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-arginine, approximately 3 mM NaCl, approximately 0.4 g / L polysorbate 80, and a pH of approximately 6.0. 61. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 89; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation includes approximately 80 mg / mL of anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g / L polysorbate 20, and a pH of approximately 5.5. 62. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 89; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation includes approximately 100 mg / mL of anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g / L polysorbate 80, and a pH of approximately 6.0. 63. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation includes approximately 60 mg / mL of anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, and a pH of approximately 5.5. 64. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation is selected from the following groups of components: I. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-arginine, approximately 5 mM NaCl, and approximately 1.0 g / L polysorbate 20, with a pH of approximately 6.0; II. Contains the following formulation: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; III. Contains the following formulation: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM glycine, approximately 0.4 g / L polysorbate 80, pH approximately 5.5; IV. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; V. Contains the following formulation: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM histidine, approximately 160 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; VI. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g / L polysorbate 80, pH approximately 6.5; VII. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; VIII. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-arginine, approximately 3 mM NaCl, approximately 0.4 g / L polysorbate 80, pH approximately 6.0; IX. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g / L polysorbate 20, pH approximately 5.5; and X. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g / L polysorbate 80, pH approximately 6.0. 65. A pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: The variable region comprising the light chain of amino acid sequence SEQ ID NO: 77; and the variable region comprising the heavy chain of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 77; and the heavy chain variable region of amino acid sequence SEQ ID NO: 89; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 87; or Contains the light chain variable region of amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of amino acid sequence SEQ ID NO: 88; or It contains the light chain variable region of the amino acid sequence SEQ ID NO: 80; and the heavy chain variable region of the amino acid sequence SEQ ID NO: 89; The formulation is selected from the following groups of components: I. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-arginine, approximately 5 mM NaCl, and approximately 1.0 g / L polysorbate 20, with a pH of approximately 6.0; II. Contains the following formulation: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; III. Contains the following formulation: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM glycine, approximately 0.4 g / L polysorbate 80, pH approximately 5.5; IV. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; V. Contains the following formulation: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM histidine, approximately 160 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; VI. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g / L polysorbate 80, pH approximately 6.5; VII. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; VIII. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-arginine, approximately 3 mM NaCl, approximately 0.4 g / L polysorbate 80, pH approximately 6.0; IX. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g / L polysorbate 20, pH approximately 5.5; and X. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g / L polysorbate 80, pH approximately 6.0.

[0089] In one embodiment associated with either the first or second state sample, the formulation comprises about 20 mg / mL to about 150 mg / mL of anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-arginine, about 5 mM NaCl, and about 1.0 g / L polysorbate 20, with a pH of about 6.0; wherein the anti-IL-36R antibody comprises a light chain variable region comprising the amino acid sequence SEQ ID NO: 80 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87. In one related embodiment, the formulation comprises 20 mg / mL of antibody. In one related embodiment, the formulation comprises 150 mg / mL of antibody. In another embodiment, the formulation comprises about 20 mg / mL to about 150 mg / mL of anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, about 0.4 g / L polysorbate 20, and a pH of about 5.5; wherein the anti-IL-36R antibody comprises a light chain variable region comprising the amino acid sequence SEQ ID NO: 80 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87. In a related embodiment, the formulation comprises 20 mg / mL of antibody. In a related embodiment, the formulation comprises 150 mg / mL of antibody.

[0090] In one embodiment associated with either the first or second state sample, the formulation comprises about 20 mg / mL to about 150 mg / mL of anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-arginine, about 5 mM NaCl, and about 1.0 g / L polysorbate 20, with a pH of about 6.0; wherein the anti-IL-36R antibody comprises a light chain variable region comprising the amino acid sequence SEQ ID NO: 80 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89. In one related embodiment, the formulation comprises 20 mg / mL of antibody. In one related embodiment, the formulation comprises 150 mg / mL of antibody. In another embodiment, the formulation comprises about 20 mg / mL to about 150 mg / mL of anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, about 0.4 g / L polysorbate 20, and a pH of about 5.5; wherein the anti-IL-36R antibody comprises a light chain variable region comprising the amino acid sequence SEQ ID NO: 80 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89. In a related embodiment, the formulation comprises 20 mg / mL of antibody. In a related embodiment, the formulation comprises 150 mg / mL of antibody.

[0091] In one embodiment associated with either the first or second state sample, the formulation comprises about 20 mg / mL to about 150 mg / mL of anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-arginine, about 5 mM NaCl, and about 1.0 g / L polysorbate 20, with a pH of about 6.0; wherein the anti-IL-36R antibody consists of a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125. In one related embodiment, the formulation comprises 20 mg / mL of antibody. In one related embodiment, the formulation comprises 150 mg / mL of antibody. In another embodiment, the formulation comprises about 20 mg / mL to about 150 mg / mL of anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, about 0.4 g / L polysorbate 20, and a pH of about 5.5; wherein the anti-IL-36R antibody consists of a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125. In a related embodiment, the formulation comprises 20 mg / mL of antibody. In a related embodiment, the formulation comprises 150 mg / mL of antibody.

[0092] In one embodiment associated with either the first or second state sample, the formulation comprises about 20 mg / mL to about 150 mg / mL of anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-arginine, about 5 mM NaCl, and about 1.0 g / L polysorbate 20, with a pH of about 6.0; wherein the anti-IL-36R antibody consists of a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127. In one related embodiment, the formulation comprises 20 mg / mL of antibody. In one related embodiment, the formulation comprises 150 mg / mL of antibody. In another embodiment, the formulation comprises about 20 mg / mL to about 150 mg / mL of anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, about 0.4 g / L polysorbate 20, and a pH of about 5.5; wherein the anti-IL-36R antibody consists of a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127. In a related embodiment, the formulation comprises 20 mg / mL of antibody. In a related embodiment, the formulation comprises 150 mg / mL of antibody.

[0093] In one embodiment associated with either the first or second state sample, the formulation comprises about 20 mg / mL to about 150 mg / mL of anti-IL-36R antibody, about 25 mM citrate, and about 0.4 g / L polysorbate 20, at a pH of about 6.5; wherein the anti-IL-36R antibody comprises a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127. In another embodiment, the formulation comprises about 20 mg / mL to about 150 mg / mL of anti-IL-36R antibody, about 25 mM citrate, and about 0.4 g / L polysorbate 20, at a pH of about 6.5; wherein the anti-IL-36R antibody comprises a light chain variable region comprising an amino acid sequence SEQ ID NO: 80 and a heavy chain variable region comprising an amino acid sequence SEQ ID NO: 89.

[0094] In a third embodiment, the present invention provides a pharmaceutical product comprising a vial, syringe, or device (e.g., an autoinjector or needle safety device) containing a pharmaceutical preparation according to a first or second embodiment of the present invention. In one related embodiment, the pharmaceutical product comprises a pre-assembled injection device comprising a syringe (a syringe containing a pharmaceutical preparation) according to a first or second embodiment of the present invention. In a related embodiment, the pre-assembled injection device is an autoinjector or needle safety device.

[0095] In one embodiment related to the third state, the "pre-assembled injection device" is a syringe, needle safety device, or autoinjector with a plunger rod and finger flange. The needle safety device provides a needle protection mechanism that retracts the needle from the injection site upon initiation or injection. For example, the needle safety device may be spring-driven. An autoinjector is a medical device designed to deliver a single dose of medication, specifically an injectable drug. Syringes, needle safety devices, and autoinjectors eliminate the need for transferring medication from a vial to the injection device, a laborious, often difficult, and risky process (e.g., contamination or misadministration). Autoinjectors and needle safety devices are easy to use and designed for patient self-administration or administration by untrained personnel. Autoinjectors have a retractable needle or a needle protected by a specific shield. Compared to syringes, they offer easier disposal and thus reduce the risk of injury or contamination, contributing to their suitability for home use.

[0096] Autoinjectors further help overcome the self-dispensing and associated hesitations typically associated with needle-based drug delivery devices, thus providing enhanced patient compliance. This, in turn, ensures regular medication intake according to the prescribed dosage regimen, thereby increasing the likelihood of treatment success. This is particularly important in treatment regimens requiring repeated treatment, such as in many chronic diseases, including autoimmune diseases, or in many types of cancer that have become chronic or near-chronic due to targeted therapies.

[0097] Furthermore, in such indications, it is particularly beneficial if the patient can treat themselves at home, such as using an autoinjector and needle safety device. Home treatment further reduces treatment costs and increases patient compliance because the patient does not have to see a healthcare professional for medication delivery at each dosing regimen. In one embodiment of the invention, the autoinjector is a spring-loaded injector type. This type includes a spring-loaded needle connected to the injector. In another embodiment, the autoinjector is a gas jet autoinjector type. The latter includes a pressurizing cylinder and propels a fine jet of liquid through the skin without the use of a needle. This has the advantages that the autoinjector can be reloaded and that various different doses or different drugs can be used. In another embodiment of the invention, the pre-assembled injection device is selected from the group consisting of conventional autoinjectors and / or wet / dry autoinjectors.

[0098] Conventional autoinjectors include syringes (syringes filled with pharmaceutical formulations) as described above and can be used for direct dispensing. Wet / dry autoinjectors (also known as "liquid-drying autoinjectors" or "dual-chamber autoinjectors") are two-chamber autoinjectors that place pharmaceutical formulations or their active components in a dry, stable form (e.g., lyophilized) in a dry chamber until use. Before dispensing, the pharmaceutical formulation or its active component is reconstituted by transferring it to a second chamber containing solvent (the "wet" chamber), or by transferring the solvent from the second chamber to the first chamber. For this application, the dry chamber containing solid drug powder may, for example, also contain a large amount of air or other gases, which are replaced by solvent during the reconstitution of the pharmaceutical formulation or its active component.

[0099] Preferably, the autoinjector is a disposable autoinjector for single use. Suitable autoinjectors for use in the context of this invention include those manufactured by Ypsomed. These autoinjectors include single-dose devices, such as products sold under the trademarks "LyoTwist," "YpsoMate," "YpsoJect," and "VarioJect." In one embodiment, the casing of the autoinjector is customized to improve ease of use and safety for the user.

[0100] Other suitable autoinjectors for use in this invention include autocoinjectors manufactured by SHL. These injectors include products sold under the trademarks "Molly™", "DAI™", "DAI™-RNS", "DAI™-R", "SDI MIX+NIT™", "VSDI™", "PSDI™", "Naisa™", and "DCP™ (OEM)".

[0101] Another preferred type of autoinjector is the Physioject™ disposable autoinjector manufactured by Becton Dickinson. This conventional type of autoinjector features a 1-2 mL pre-filled syringe with a hypodermic needle, is easy to assemble (two assembly components), is robust, has a large visual inspection window, and is packaged in a tamper-evident transparent package.

[0102] Another preferred type of autoinjector is the BD™ Liquid-Dry Injector™ manufactured by Becton Dickinson™. This wet / dry autoinjector allows patients to recover and inject lyophilized pharmaceutical preparations according to the invention, eliminating the need for handling vials and syringes.

[0103] Other suitable autoinjectors include the ASI™ auto™ injector and OTS™ disposable autoinjector from BespakInjectables™, the SafeClick™ autoinjector from Aqueo Future Injection Technologies™, and the SafeClick™-Lyo and SafeClick™-Visco from Future Injection Technology™. However, this list is not restrictive.

[0104] Preferably, the needle safety device is a disposable needle safety device for single use. Suitable needle safety devices applicable to the present invention include needle safety devices manufactured by Nemera. These needle safety devices include single-dose devices, such as the passive safety device Safe'n'Sound®.

[0105] In one embodiment of the invention related to Nemeras Safe'n'Sound®, the customizability of the plunger rod and finger flange increases ease of handling for the user.

[0106] Other suitable passive needle safety devices that can be used in the context of this invention include BD Preventis™ or BD Ultrasafe™ manufactured by BD.

[0107] Other passive needle safety devices include, for example, Biocorp Newguard™ or Owen Mumford Unisafe™.

[0108] Preferably, the needle safety device is a disposable needle safety device for single use. Suitable needle safety devices applicable to the present invention include those manufactured by Nemera. These needle safety devices include single-dose devices, such as the passive safety device Safe'n'Sound®. In one embodiment, the Nemera Safe'n'Sound® needle safety device has a modified plunger rod and finger flange to increase ease of use and disposal for the user.

[0109] Other suitable passive needle safety devices that can be used in the context of this invention include BD Preventis™ or BD Ultrasafe™ manufactured by BD.

[0110] Other passive needle safety devices include, for example, Biocorp Newguard™ or Owen Mumford Unisafe™.

[0111] In another embodiment of the invention related to the third state, the injection device is a pre-filled syringe or in the form of a syrette. A syrette is a device for injecting liquids via a needle. It is similar to a syringe, except that it has a closed, flexible tube instead of a rigid tube and plunger. The term "pre-filled syringe" is self-explanatory. Pre-filled syringes share many advantages with autoinjectors. Like autoinjectors, pre-filled syringes can be used as conventional syringes and wet / dry syringes (also known as dual-chamber syringes). The syringes are provided, for example, by Becton Dickinson™, Nuova Ompi™, AG, and other companies. The plunger stop is provided, for example, by Becton Dickinson™, West Pharmaceuticals™, and other companies. The pre-filled syringe can be manufactured, for example, by Boehringer Ingelheim™, Vetter Pharma International, and other companies.

[0112] In one embodiment related to the third state sample, the present invention relates to formulations of anti-IL-36R antibodies as disclosed herein, provided in various dosage forms and strengths, including: (i) An autoinjector (AI), such as a custom model provided by YpsoMate®, comprising: a. Approximately 300 mg of antibody is prepared in approximately 2 mL of solution in a single AI dose; b. Approximately 225 mg of antibody is prepared in a single AI dose of approximately 1.5 mL. c. Approximately 150 mg of antibody is prepared in approximately 1 mL of the AI ​​in a single dose; d. Approximately 75 mg of antibody in a single AI dose, prepared in approximately 0.5 mL volume; or e. Approximately 60 mg of antibody is prepared in a single AI dose of approximately 0.4 mL. (ii) A pre-filled syringe equipped with a needle safety device and, for example, custom EFF and PR, comprising: a. Approximately 300 mg of antibody is prepared in a single-dose pre-filled glass syringe in a volume of approximately 2 mL; b. Approximately 225 mg of antibody is prepared in a single-dose pre-filled glass syringe in a volume of approximately 1.5 mL; c. Approximately 150 mg of antibody is prepared in a single-dose pre-filled glass syringe in a volume of approximately 1 mL; d. Approximately 75 mg of antibody is prepared in a single-dose pre-filled glass syringe at a volume of approximately 0.5 mL; or e. Approximately 60 mg of antibody, prepared in a single-dose prefilled glass syringe at a volume of approximately 0.4 mL; or (iii) A pre-filled syringe without a needle-free safety component, comprising: a. Approximately 300 mg of antibody is prepared in a single-dose pre-filled glass syringe in a volume of approximately 2 mL; b. Approximately 225 mg of antibody is prepared in a single-dose pre-filled glass syringe in a volume of approximately 1.5 mL; c. Approximately 150 mg of antibody is prepared in a single-dose pre-filled glass syringe in a volume of approximately 1 mL; d. Approximately 75 mg of antibody is prepared in a single-dose pre-filled glass syringe at a volume of approximately 0.5 mL; or e. Approximately 60 mg of antibody, prepared in a single-dose prefilled glass syringe at a volume of approximately 0.4 mL; or (iv) A vial containing: a. Approximately 1200 mg of antibody is prepared in a single-dose glass vial in a volume of approximately 20 mL; b. Approximately 900 mg of antibody is prepared in a single-dose glass vial in a volume of approximately 15 mL; c. Approximately 600 mg of antibody is prepared in a single-dose glass vial in a volume of approximately 10 mL; d. Approximately 450 mg of antibody is prepared in a single-dose glass vial in a volume of approximately 7.5 mL; e. Approximately 300 mg of antibody is prepared in a single-dose glass vial in a volume of approximately 5 mL; f. Approximately 150 mg of antibody is prepared in a single-dose glass vial in a volume of approximately 2.5 mL; or g. Approximately 75 mg of antibody prepared in a single-dose glass vial in a volume of approximately 1.25 mL; or h. Approximately 60 mg of antibody is prepared in a single-dose glass vial with a volume of approximately 1 mL. i. Approximately 30 mg of antibody is prepared in a single-dose glass vial in a volume of approximately 0.5 mL; or (v) An infusion bag, which contains: a. 30 mg to 1200 mg of antibody in approximately 100 mL to 500 mL of 0.9% NaCl solution.

[0113] For convenience, various other examples or embodiments related to the third aspect of the present invention are described in the numbered clauses (66 to 77) below. These clauses are provided as examples and do not limit the technology of the present invention. It should be noted that any of the appended clauses may be combined in any combination and placed in separate independent clauses (e.g., clause 64). Other clauses may be presented in a similar manner. 66. A pharmaceutical product comprising a vial or syringe containing a pharmaceutical preparation as described in any of the first or second states. 67. The pharmaceutical product of paragraph 66 further includes a pre-assembled injection device. 68. The pharmaceutical product of paragraph 67, wherein the pre-assembled injection device is an auto-injector or a syringe with or without a needle safety device. 69. A pre-assembled injection device comprising a pharmaceutical preparation according to any one of the terms of a first or second state sample. 70. A pre-assembled injection device as described in clause 69, wherein the device is an auto-injector or an injector with or without a needle safety device. 71. The pre-assembled injection device of paragraph 69, wherein the preparation is suitable for intravenous, subcutaneous or intramuscular administration. 72. The pre-assembled injection device of clause 70, wherein the autoinjector or the injector having or not having a needle safety device includes a pharmaceutical preparation comprising: Anti-IL-36R antibody or its antigen-binding fragment, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or The formulation comprises a light chain containing an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain containing an amino acid sequence as listed in SEQ ID NO: 127; wherein the formulation is selected from the group consisting of: I. Contains the following formulation: approximately 20 mg / ml anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-arginine, approximately 5 mM NaCl, and approximately 1.0 g / L polysorbate 20, with a pH of approximately 6.0; II. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; III. Contains the following formulation: approximately 20 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM glycine, approximately 0.4 g / L polysorbate 80, pH approximately 5.5; IV. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; V. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 25 mM histidine, approximately 160 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; VI. Contains the following formulations: approximately 20 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g / L polysorbate 80, pH approximately 6.5; VII. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; VIII. Contains the following formulation: approximately 15 mg / mL anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-arginine, approximately 3 mM NaCl, approximately 0.4 g / L polysorbate 80, pH approximately 6.0; IX. Contains the following formulations: approximately 80 mg / mL anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g / L polysorbate 20, pH approximately 5.5; and X. Contains the following formulation: approximately 100 mg / mL anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g / L polysorbate 80, pH approximately 6.0. 73. The pre-assembled injection device of clause 70, wherein the autoinjector or the injector having a needle safety device comprises: a. Approximately 300 mg of antibody in a 2 mL reconstitution volume; or b. Approximately 225 mg of antibody in a reconstituted volume of approximately 1.5 mL; or c. Approximately 150 mg of antibody in a 1 mL reconstitution volume; or d. Approximately 0.5 mL of antibody, prepared as approximately 75 mg; or e. Approximately 60 mg of antibody in a volume of approximately 0.4 mL. 74. The vial as described in item 66, wherein the vial comprises: a. Approximately 1200 mg of antibody in a reconstituted volume of approximately 20 mL; or b. Approximately 900 mg of antibody in a reconstituted volume of approximately 15 mL; or c. Approximately 600 mg of antibody in a reconstituted volume of approximately 10 mL; or d. Approximately 300 mg of antibody, prepared in approximately 150 mL of solution; or e. Approximately 1500 mg of antibody in a 2.5 mL reconstitution volume. 75. A pharmaceutical product comprising: a vial containing about 100 mg to 1500 mg of anti-IL-36R antibody in powder form; instructions for reconstitution of the anti-IL-36R antibody; and instructions for preparing the reconstitution antibody for infusion, wherein the anti-IL-36R antibody comprises: a light chain containing an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain containing an amino acid sequence as listed in any one of SEQ ID NO: 125, 126 or 127; and the reconstitution instructions require reconstitution with water for injection to a drawable volume of 1 to 50 mL. [] 76. A pharmaceutical product as described in any one of clauses 66 to 68, or a pre-assembled injection device as described in any one of clauses 69 to 73, wherein the pharmaceutical formulation comprises: a. An anti-IL-36R antibody or its antigen-binding fragment, present at a concentration ranging from about 0.5 mg / mL to about 220 mg / mL; b. A buffer, present at a concentration in the range of about 20 mM to about 80 mM; c. A tension modifier present at a concentration ranging from about 100 mM to about 400 mM; The formulation is characterized in that, when in aqueous solution form, the pH ranges from about 5 to about 8. 77. A pharmaceutical compound as described in any of items 1 to 10, wherein the pharmaceutical compound comprises: d. Anti-IL-36R antibody or its antigen-binding fragment, present at a concentration ranging from about 0.5 mg / mL to about 220 mg / mL; e. A buffer, present at a concentration in the range of about 20 mM to about 80 mM; f. A tension modifier present at a concentration ranging from about 100 mM to about 400 mM; The formulation is characterized in that, when in aqueous solution form, the pH ranges from about 5 to about 8.

[0114] In one embodiment relating to the third state and / or clauses 66 to 77, the anti-IL-36R antibody or its antigen-binding fragment comprises: a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody comprises: a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127. In a particular embodiment, the anti-IL-36R antibody comprises: a light chain variable region comprising an amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising an amino acid sequence SEQ ID NO: 89. In another specific embodiment, the anti-IL-36R antibody consists of a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127.

[0115] In the fourth embodiment, the present invention relates to a method for preparing the pharmaceutical formulation of the present invention, the method comprising: a) culturing mammalian cells encoding one or more nucleic acids of the light and heavy chains of the anti-IL-36R antibody as disclosed herein, which have been stably incorporated into their genome, such that the cells secrete the antibody into a cell culture medium, and purifying the antibody from the cell culture medium; and b) preparing the formulation according to the first or second embodiment. In one related embodiment, the nucleic acid encoding the light chain of the anti-IL-36R antibody comprises the nucleotide sequence encoding SEQ ID NO: 118, and wherein the nucleic acid encoding the heavy chain of the anti-IL-36R antibody comprises the nucleotide sequence encoding SEQ ID NO: 125. In another related embodiment, the nucleic acid encoding the light chain of the anti-IL-36R antibody comprises the nucleotide sequence encoding SEQ ID NO: 118, and wherein the nucleic acid encoding the heavy chain of the anti-IL-36R antibody comprises the nucleotide sequence encoding SEQ ID NO: 126. In another related embodiment, the nucleic acid encoding the light chain of the anti-IL-36R antibody comprises the nucleotide sequence encoding SEQ ID NO: 118, and wherein the nucleic acid encoding the heavy chain of the anti-IL-36R antibody comprises the nucleotide sequence encoding SEQ ID NO: 127.

[0116] In another embodiment related to the fourth state sample, the formulation comprises: an anti-IL-36R antibody or an antigen-binding fragment thereof, which comprises: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation is selected from the following groups of components: I. Contains the following formulation: approximately 20 mg / mL anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-arginine, approximately 5 mM NaCl, and approximately 1.0 g / L polysorbate 20, pH approximately 6.0; II. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; III. Contains the following formulation: approximately 20 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM glycine, approximately 0.4 g / L polysorbate 80, pH approximately 5.5; IV. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; V. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 25 mM histidine, approximately 160 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; VI. Contains the following formulations: approximately 20 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g / L polysorbate 80, pH approximately 6.5; VII. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; VIII. Contains the following formulation: approximately 15 mg / mL anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-arginine, approximately 3 mM NaCl, approximately 0.4 g / L polysorbate 80, pH approximately 6.0; IX. Contains the following formulations: approximately 80 mg / mL anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g / L polysorbate 20, pH approximately 5.5; and X. Contains the following formulation: approximately 100 mg / mL anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g / L polysorbate 80, pH approximately 6.0.

[0117] In one embodiment related to the fourth state, the anti-IL-36R antibody or its antigen-binding fragment comprises: a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody comprises: a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127. In a particular embodiment, the anti-IL-36R antibody comprises: a light chain variable region comprising an amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising an amino acid sequence SEQ ID NO: 89. In another specific embodiment, the anti-IL-36R antibody consists of a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127.

[0118] In the fifth state sample, the present invention relates to a method for reducing the aggregation and / or fragmentation of the anti-IL-36R antibody disclosed herein, comprising formulating the antibody in a buffer system and a surfactant, and evaluating data (e.g., any antibody aggregation) before and after formulating the antibody. In one embodiment associated with the fifth state sample, the antibody system is formulated according to any of the embodiments of the first or second state sample.

[0119] In one embodiment related to the fifth state sample, the formulation includes: an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation is selected from the following groups of components: I. Contains the following formulation: approximately 20 mg / ml anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-arginine, approximately 5 mM NaCl, and approximately 1.0 g / L polysorbate 20, with a pH of approximately 6.0; II. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; III. Contains the following formulation: approximately 20 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM glycine, approximately 0.4 g / L polysorbate 80, pH approximately 5.5; IV. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; V. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 25 mM histidine, approximately 160 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; VI. Contains the following formulations: approximately 20 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g / L polysorbate 80, pH approximately 6.5; VII. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; VIII. Contains the following formulation: approximately 15 mg / mL anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-arginine, approximately 3 mM NaCl, approximately 0.4 g / L polysorbate 80, pH approximately 6.0; IX. Contains the following formulations: approximately 80 mg / mL anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g / L polysorbate 20, pH approximately 5.5; and X. Contains the following formulation: approximately 100 mg / mL anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g / L polysorbate 80, pH approximately 6.0.

[0120] In one embodiment related to the fifth state, the anti-IL-36R antibody or its antigen-binding fragment comprises: a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody comprises: a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127. In a particular embodiment, the anti-IL-36R antibody comprises: a light chain variable region comprising an amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising an amino acid sequence SEQ ID NO: 89. In another specific embodiment, the anti-IL-36R antibody consists of a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127.

[0121] In the sixth embodiment, the invention relates to a kit for dispensing portions, comprising: at least one container containing a pharmaceutical preparation according to either the first or second embodiment; and an injection device according to the third embodiment. In one embodiment, the kit for dispensing portions comprises at least one container containing a pharmaceutical preparation according to the first or second embodiment. In a related embodiment, the kit for dispensing portions comprises one or more vials containing a preparation according to the first or second embodiment and instructions for administering the preparation subcutaneously or intramuscularly to an individual. The kit for dispensing portions or the injection device according to the invention are suitable, for example, for subcutaneous administration. In this case, the injection needle preferably has a length of ≥10 mm to ≤100 mm and a specification between 0.2 mm and 1 mm (specifications 33 to 19).

[0122] In one embodiment related to the sixth state sample, the formulation includes an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: i. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or ii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or iii. A light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; The formulation is selected from the following groups of components: I. Contains the following formulation: approximately 20 mg / ml anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-arginine, approximately 5 mM NaCl, and approximately 1.0 g / L polysorbate 20, with a pH of approximately 6.0; II. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; III. Contains the following formulation: approximately 20 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM glycine, approximately 0.4 g / L polysorbate 80, pH approximately 5.5; IV. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; V. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 25 mM histidine, approximately 160 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; VI. Contains the following formulations: approximately 20 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g / L polysorbate 80, pH approximately 6.5; VII. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; VIII. Contains the following formulation: approximately 15 mg / mL anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-arginine, approximately 3 mM NaCl, approximately 0.4 g / L polysorbate 80, pH approximately 6.0; IX. Contains the following formulations: approximately 80 mg / mL anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g / L polysorbate 20, pH approximately 5.5; and X. Contains the following formulation: approximately 100 mg / mL anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g / L polysorbate 80, pH approximately 6.0.

[0123] In one embodiment related to the sixth state, the injection device is a pre-assembled injection device comprising an autoinjector or a needle safety device. In one related embodiment, the autoinjector or needle safety device each comprises: (a) approximately 300 mg of the antibody in a total volume of approximately 2 mL; (b) approximately 225 mg of the antibody in a total volume of approximately 1.5 mL; (c) approximately 150 mg of the antibody in a total volume of approximately 1 mL; (d) approximately 75 mg of the antibody in a total volume of approximately 0.5 mL; or (e) approximately 60 mg of the antibody in a total volume of approximately 0.4 mL.

[0124] According to another aspect of the invention, the use of the formulation according to the invention, the pre-assembled injection device according to the invention, or the kit of the dispensing portion according to the invention is provided for intravenous and / or subcutaneous administration.

[0125] In one embodiment related to the sixth state, the anti-IL-36R antibody or its antigen-binding fragment comprises: a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody comprises: a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127. In a particular embodiment, the anti-IL-36R antibody comprises: a light chain variable region comprising an amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising an amino acid sequence SEQ ID NO: 89. In another specific embodiment, the anti-IL-36R antibody consists of a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127.

[0126] According to another aspect of the invention, the use of a formulation according to the invention, a pre-assembled injection device according to the invention, or a kit of dispensing portions according to the invention is provided for treating at least one disease selected from a group consisting of autoimmune diseases and / or malignant diseases. Non-limiting examples of autoimmune diseases covered by this definition include psoriasis, rheumatoid arthritis, inflammatory bowel disease or psoriatic arthritis, chronic obstructive pulmonary disease (COPD), asthma, scleroderma, palmoplantar pustulosis, generalized pustular psoriasis, atopic dermatitis, diabetic nephropathy, lupus nephritis, scleroderma, ankylosing spondylitis, IL-36 receptor antagonist deficiency autoimmune disease (DITRA), IL-1 receptor antagonist deficiency autoimmune disease (DIRA) or cryptothermal protein-associated periodic syndrome (CAPS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, Scheregler's syndrome, multiple sclerosis, psoriasis, psoriatic arthritis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), lung inflammation, asthma, idiopathic thrombocytopenic purpura (ITP), epithelial inflammatory diseases, fibrosis, and ankylosing spondylitis. In another preferred embodiment, the kit includes instructions for administering the formulation subcutaneously or intramuscularly to an individual. [Antibody] []

[0127] The anti-IL-36R antibody of the present invention is disclosed in U.S. Patent No. 9,023,995 or WO 2013 / 074569, the entire contents of each of which are incorporated herein by reference.

[0128] The messenger RNAs of IL-36α, IL-36β and IL-36γ are highly expressed in several tissues, specifically, in internal epithelial tissues exposed to pathogens and in the skin. Interestingly, the expression of IL-36Ra and IL-36α is significantly upregulated in human keratinocytes stimulated with IL-1β / TNF-α, and IL-36Ra and IL-36γ mRNAs are highly increased in lesional psoriatic skin. In addition, the production of IL-36γ protein in human keratinocytes is enhanced after stimulation with TNF-α and IFN-γ. Elevated IL-36α mRNA and protein expression have also been reported in chronic kidney disease. Taken together, these data indicate that IL-36 ligands, including IL-36α, IL-36β, IL-36γ and IL-36Ra, exert pro-inflammatory effects in vitro and in vivo, and IL-36Ra acts as a natural antagonist, thus mimicking the IL-1 / IL-1Ra system. Evidence suggests that IL-36R ligands are involved in multiple disease conditions including inflammatory diseases. The anti-IL-36R antibodies described herein reduce or block IL-36 ligand-mediated signal transduction and are applicable for treating such conditions or diseases. The variable regions and CDRs of representative antibodies of the present invention are disclosed as follows: [anti-] [IL-36R] [murine antibody sequence] , ]

[0129] The variable regions and CDRs of a representative murine lead antibody (murine lead) of the present invention are shown as follows: [light chain variable region] [(VK)] [amino acid sequence] >33D10B12vK protein (antibody 33D10) QIVLTQSPAIMSASLGERVTMTCTASSSVSSSYLHWYQKKPGSSPKLWVYSTSNLASGVPVRFSGSGSGTSYSLTISSMEAEDAATYYCHQHHRSPVTFGSGTKLEMK (SEQ ID NO: 1) >172C8B12 vK protein (antibody 172C8) ​​DIQMTQSPASQSASLGESVTFTCLASQTIGTWLAWYQQRPGKSPQLLIYAATSLADGVPSRFSGSGSGTQFSFNIRSLQAEDFASYYCQQVYTTPLTFGGGTKLEIK (SEQ ID NO: 2) >67E7E8 vK protein (Antibody 67E7) DIQMTQSPASQSASLGESVTFTCLASQTIGTWLGWYQQKPGKSPQLLIYRSTTLADGVPSRFSGSGSGTKFSFKISSLQAADFASYYCQQLYSAPYTFGGGTKLEIR (SEQ ID NO: 3) >78C8D1 vK protein (Antibody 78C8) DVLLTQTPLSLPVSLGDQASISCRSSQNIVHSNGNTYLQWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPFTFGAGTKLELK (SEQ ID NO: 4) >81A1D1 vK protein (Antibody 81A1) DIQMTQTTSSLSASLGDRVTISCRASQDIYKYLNWYQQKPDGTLKLLIYYTSGLHSGVPSRFSGSGSGTDFSLTISNLEPEDIATYFCQQDSKFPWTFGGDTKLEIK (SEQ ID NO: 5) >81B4E11 vK protein (Antibody 81B4) QIVLTQSPAIMSASLGERVTMTCTASSSVSSSYFHWYQQKPGSSPKLWIYRTSNLASGVPGRFSGSGSGTSYSLTISSMEAEDAATYYCHQFHRSPLTFGAGTKLELK (SEQ ID NO: 6) >73C5C10 vK protein (Antibody 73C5) DIVMTQSQKFLSTSVGVRVSVTCKASQDVGTNVLWYQQKIGQSPKPLIYSASYRHSGVPDRFTGSGSGTDFTLIISNVQSEDLAEYFCQQYSRYPLTFGPGTKLELK (SEQ ID NO: 7) >73F6F8 vK protein (antibody 73F6) DIVMTQSQKFLSTSVGVRVSVTCKASQDVGTNVLWYQQKIGQSPKALIYSASYRHSGVPDRFTGSGSGTDFTLIITNVQSEDLAEYFCQQYSRYPLTFGPGTKLELK (SEQ ID NO: 8) >76E10E8 vK protein (antibody 76E10) DIVMTQSQKFMSATVGGRVNITCKASQNVGRAVAWYQQKPGQSPKLLTHSASNRYTGVPDRFTGSGSGTDFTLTITNMQSEDLADYFCQQYSSYPLTFGAGTKLDLK (SEQ ID NO: 9) >89A12B8 vK protein (antibody 89A12) DIQMTQSPASQSASLGESVTFSCLASQTIGTWLGWYQQKPGKSPQLLIYRATSLADGVPSRFSGSGSGTNFSFKISSLQAEDLASYYCQQLYSGPYTFGGGTKLEIR (SEQ ID NO: 10) [Heavy chain variable region] [(VH)] [Amino acid sequence] [] >33D10B12vH protein (antibody 33D10) QVQLQQSGTELLKPGASVKLSCKASGNTVTSYWMHWVKQRPGQGLEWIGEILPSTGRTNYNENFKGKAMLTVDKSSSTAYMQLSSLASEDSAVYYCTIVYFGNPWFAYWGQGTLVTVSA (SEQ ID NO: 11) >172C8B12 vH protein (antibody 172C8) EVQLQQSGPELVKPGASVKLSCKASGYTFTDNYMNWVRQSHGKSLEWIGRVNPSNGDTKYNQNFKGKATLTVDKSLSTAYMQLNGLTSEDSAVYYCGRTKNFYSSYSYDDAMDYWGQGTSVTVSS (SEQ ID NO: 12) >67E7E8 vH protein (antibody 67E7) EVQLQQSGAEFVRPGASVKFSCTASGFNIKDDYIHWVRQRPEQGLEWVGRIDPANGNTKYAPKFQDKATITADTSSNTAYLQLSSLTSEDTAVYYCAKSFPNNYYSYDDAFAYWGQGTLVTVSA (SEQ ID NO: 13) >78C8D1 vH protein (antibody 78C8) QVQLKESGPVLVAPSQSLSITCTVSGFSLTKFGVHWIRQTPGKGLEWLGVIWAGGPTNYNSALMSRLTISKDISQSQVFLRIDSLQTDDTAMYYCAKQIYYSTLVDYWGQGTSVTVSS (SEQ ID NO: 14) >8IAID1 vH protein (antibody 81A1) QVQLKESGPGLVAPSQSLFITCTVSGFSLSSYEINWVRQVPGKGLEWLGVIWTGITTNYNSALISRLSISKDNSKSLVFLKMNSLQTDDTAIYYCARGTGTGFYYAMDYWGQGTSVTVSS (SEQ ID NO: 15) >81B4E11 vH protein (antibody 81B4) QVQLQQPGADFVRPGASMRLSCKASGYSFTSSWIHWVKQRPGQGLEWIGEINPGNVRTNYNENFRNKATLTVDKSSTTAYMQLRSLTSADSAVYYCTVVFYGEPYFPYWGQGTLVTVSA (SEQ ID NO: 16) >73C5C10 vH protein (antibody 73C5) QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYAVHWVRQFPGKGLEWLGVIWSDGSTDFNAPFKSRLSINKDNSKSQVFFKMNSLQIDDTAIYYCARKGGYSGSWFAYWGQGTLVTVSA (SEQ ID NO: 17) >73F6F8 vH protein (antibody 73F6) QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYAVHWVRQFPGKGLEWLGVIWSDGSTDYNAPFKSRLSINKDNSKSQVFFKMNSLQTDDTAIYYCARKGGYSGSWFAYWGQGTLVTVSA (SEQ ID NO: 18) >76E10E8 vH protein (antibody 76E10) QVQLKESGPVLVAPSQSLSITCTVSGFSLTNYGVHWVRQPPGKGLEWLGVIWPVGSTNYNSALMSRLSIHKDNSKSQVFLRMNSLQTDDTAIYYCAKMDWDDFFDYWGQGTTLTVSS(SEQ ID NO: 19) >89A12B8 vH protein (antibody 89A12) EVQLQQSGAELVRPGASVRLSCTASGFNIKDDYIHWVRQRPKQGLEWLGRIDPANGNTKYDPRFQDKATITADTSSNTAYLHLSSLTSEDTAVYYCAKSFPDNYYSYDDAFAYWGQGTLVTVSA (SEQ ID NO: 20) [Light Chain] [CDR-1 (L-CDR1)] [Amino acid sequence] [] >33D10G1 L-CDR1 TASSSVSSSYLH (SEQ ID NO: 21) >172C8B12 L-CDR1 LASQTIGTWLA (SEQ ID NO: 22) >67E7E8 L-CDR1 LASQTIGTWLG (SEQ ID NO: 23) >78C8D1 L-CDR1 RSSQNIVHSNGNTYLQ (SEQ ID NO: 24) >81A1D1 L-CDR1 RASQDIYKYLN (SEQ ID NO: 25) >81B4E11 L-CDR1 TASSSVSSSYFH (SEQ ID NO: 26) >73C5C10 L-CDR1 KASQDVGTNVL (SEQ ID NO: 27) >73F6F8 L-CDR1 KASQDVGTNVL (SEQ ID NO: 27) >76E10E8 L-CDR1 KASQNVGRAVA (SEQ ID NO: 28) >89A12B8 L-CDR1 LASQTIGTWLG (SEQ ID NO: 29) [Light Chain] [CDR-2 (L-CDR2)] [Amino acid sequence] [] >33D10B12 L-CDR2 STSNLAS (SEQ ID NO: 30) >172C8B12 L-CDR2 AATSLAD (SEQ ID NO: 31) >67E7E8 L-CDR2 RSTTLAD (SEQ ID NO: 32) >78C8D1 L-CDR2 KVSNRFS (SEQ ID NO: 33) >81A1D1 L-CDR2 YTSGLHS (SEQ ID NO: 34) >81B4E11 L-CDR2 RTSNLAS (SEQ ID NO: 35) >73C5C10 L-CDR2 SASYRHS (SEQ ID NO: 36) >73F6F8 L-CDR2 SASYRHS (SEQ ID NO: 36) >76E10E8 L-CDR2 SASNRYT (SEQ ID NO: 37) >89A12B8 L-CDR2 RATSLAD (SEQ ID NO: 38) [ , ] [] [Light Chain] [CDR-3 (L-CDR3)] [Amino acid sequence] [] >33D10B12 L-CDR3 HQHHRSPVT (SEQ ID NO: 39) >172C8B12 L-CDR3 QQVYTTPLT (SEQ ID NO: 40) >67E7E8 L-CDR3 QQLYSAPYT (SEQ ID NO: 41) >78C8D1 L-CDR3 FQGSHVPFT (SEQ ID NO: 42) >81A1D1 L-CDR3 QQDSKFPWT (SEQ ID NO: 43) >81B4E11 L-CDR3 HQFHRSPLT (SEQ ID NO: 44) >73C5C10 L-CDR3 QQYSRYPLT (SEQ ID NO: 45) >73F6F8 L-CDR3 QQYSRYPLT (SEQ ID NO: 45) >76E10E8 L-CDR3 QQYSSYPLT (SEQ ID NO: 46) >89A12B8 L-CDR3 QQLYSGPYT (SEQ ID NO: 47) [Rechain] [CDR-1 (H-CDR1)] [Amino acid sequence] [] >33D10B12 H-CDR1 GNTVTSYWMH (SEQ ID NO: 48) >172C8B12 H-CDR1 GYTFTDNYMN (SEQ ID NO: 49) >67E7E8 H-CDR1 GFNIKDDYIH (SEQ ID NO: 50) >78C8D1 H-CDR1 GFSLTKFGVH (SEQ ID NO: 51) >81A1D1 H-CDR1 GFSLSSYEIN (SEQ ID NO: 52) >81B4E11 H-CDR1 GYSFTSSWIH (SEQ ID NO: 53) >73C5C10 H-CDR1 GFSLTNYAVH (SEQ ID NO: 54) >73F6F8 H-CDR1 GFSLTNYAVH (SEQ ID NO: 54) >76E10E8 H-CDR1 GFSLTNYGVH (SEQ ID NO: 55) >89A12B8 H-CDR1 GFNIKDDYIH (SEQ ID NO: 56) [Heavy chain] [CDR-2 (H-CDR2)] [[ID=1�]][Amino acid sequence] [] >33D10B12 H-CDR2 EILPSTGRTNYNENFKG (SEQ ID NO: 57) >172C8B12 H-CDR2 RVNPSNGDTKYNQNFKG (SEQ ID NO: 58) >67E7E8 H-CDR2 RIDPANGNTKYAPKFQD (SEQ ID NO: 59) >78C8D1 H-CDR2 VIWAGGPTNYNSALMS (SEQ ID NO: 60) >81A1D1 H-CDR2 VIWTGITTNYNSALIS (SEQ ID NO: 61) >81B4E11 H-CDR2 EINPGNVRTNYNENF (SEQ ID NO: 62) >73C5C10 H-CDR2 VIWSDGSTDFNAPFKS (SEQ ID NO: 63) >73F6F8 H-CDR2 VIWSDGSTDYNAPFKS (SEQ ID NO: 64) >76E10E8 H-CDR2 VIWPVGSTNYNSALMS (SEQ ID NO: 65) >89A12B8 H-CDR2 RIDPANGNTKYDPRFQD (SEQ ID NO: 66) [Heavy chain] [CDR-3 (H-CDR3)] [Amino acid sequence] [] >33D10B12 H-CDR3 VYFGNPWFAY (SEQ ID NO: 67) >172C8B12 H-CDR3 TKNFYSSYSYDDAMDY (SEQ ID NO: 68) >67E7E8 H-CDR3 SFPNNYYSYDDAFAY (SEQ ID NO: 69) >78C8D1 H-CDR3 QIYYSTLVDY (SEQ ID NO: 70) >81A1D1 H-CDR3 GTGTGFYYAMDY (SEQ ID NO: 71) >81B4E11 H-CDR3 VFYGEPYFPY (SEQ ID NO: 72) >73C5C10 H-CDR3 KGGYSGSWFAY (SEQ ID NO: 73) [[ID=�]] >73F6F8 H-CDR3 KGGYSGSWFAY (SEQ ID NO: 73) >76E10E8 H-CDR3 MDWDDFFDY (SEQ ID NO: 74) >89A12B8 H-CDR3 SFPDNYYSYDDAFAY (SEQ ID NO: 75) [] [Anti-] [IL-36R] [Mouse] [CDR] [sequence] []

[0130] The CDR sequences of mouse leader antibodies are summarized below: Antibody H-CDR sequence L-CDR sequence 33D10 GNTVTSYWMH (H-CDR1) SEQ ID No: 48 EILPSTGRTNYNENFKG (H-CDR2) SEQ ID No: 57 VYFGNPWFAY (H-CDR3) SEQ ID No: 67 TASSSVSSSYLH (L-CDR1) SEQ ID No: 21 STSNLAS (L-CDR2) SEQ ID No: 30 HQHHRSPVT (L-CDR3) SEQ ID No: 39 172C8 GYTFTDNYMN (H-CDR1) SEQ ID No: 49 RVNPSNGDTKYNQNFKG (H-CDR2) SEQ ID No: 58 TKNFYSSYSYDDAMDY (H-CDR3) SEQ ID No: 68 LASQTIGTWLA (L-CDR1) SEQ ID No: 22 AATSLAD (L-CDR2) SEQ ID No: 31 QQVYTTPLT (L-CDR3) SEQ ID No: 40 67E7 GFNIKDDYIH (H-CDR1) SEQ ID No: 50 RIDPANGNTKYAPKFQD (H-CDR2) SEQ ID No: 59 SFPNNYYSYDDAFAY (H-CDR3) SEQ ID No: 69 LASQTIGTWLG (L-CDR1) SEQ ID No: 23 RSTTLAD (L-CDR2) SEQ ID No: 32 QQLYSAPYT (L-CDR3) SEQ ID No: 41 78C8 GFSLTKFGVH (H-CDR1) SEQ ID No: 51 VIWAGGPTNYNSALMS (H-CDR2) SEQ ID No: 60 QIYYSTLVDY (H-CDR3) SEQ ID No: 70 RSSQNIVHSNGNTYLQ (L-CDR1) SEQ ID No: 24 KVSNRFS (L-CDR2) SEQ ID No: 33 FQGSHVPFT (L-CDR3) SEQ ID No: 42 81A1 GFSLSSYEIN (H-CDR1) SEQ ID No: 52 VIWTGITTNYNSALIS (H-CDR2) SEQ ID No: 61 GTGTGFYYAMDY (H-CDR3) SEQ ID No: 71 RASQDIYKYLN (L-CDR1) SEQ ID No: 25 YTSGLHS (L-CDR2) SEQ ID No: 34 QQDSKFPWT (L-CDR3) SEQ ID No: 43 [] 81B4 GYSFTSSWIH (H-CDR1) SEQ ID No: 53 EINPGNVRTNYNENF (H-CDR2) SEQ ID No: 62 VFYGEPYFPY (H-CDR3) SEQ ID No: 72 TASSSVSSSYFH (L-CDR1) SEQ ID No: 26 RTSNLAS (L-CDR2) SEQ ID No: 35 HQFHRSPLT (L-CDR3) SEQ ID No: 44 [] 73C5 GFSLTNYAVH (H-CDR1) SEQ ID No: 54 VIWSDGSTDFNAPFKS (H-CDR2) SEQ ID No: 63 KGGYSGSWFAY (H-CDR3) SEQ ID No: 73 KASQDVGTNVL (L-CDR1) SEQ ID No: 27 SASYRHS (L-CDR2) SEQ ID No: 36 QQYSRYPLT (L-CDR3) SEQ ID No: 45 73F6 GFSLTNYAVH (H-CDR1) SEQ ID No: 54 VIWSDGSTDYNAPFKS (H-CDR2) SEQ ID No: 64 KGGYSGSWFAY (H-CDR3) SEQ ID No: 73 KASQDVGTNVL (L-CDR1) SEQ ID No:27 SASYRHS (L-CDR2) SEQ ID No: 36 QQYSRYPLT (L-CDR3) SEQ ID No: 45 76E10 GFSLTNYGVH (H-CDR1) SEQ ID No: 55 VIWPVGSTNYNSALMS (H-CDR2) SEQ ID No: 65 MDWDDFFDY (H-CDR3) SEQ ID No: 74 KASQNVGRAVA (L-CDR1) SEQ ID No: 28 SASNRYT (L-CDR2) SEQ ID No: 37 QQYSSYPLT (L-CDR3) SEQ ID No: 46 89A12 GFNIKDDYIH (H-CDR1) SEQ ID No: 56 RIDPANGNTKYDPRFQD (H-CDR2) SEQ ID No: 66 SFPDNYYSYDDAFAY (H-CDR3) SEQ ID No: 75 LASQTIGTWLG (L-CDR1) SEQ ID No: 29 RATSLAD (L-CDR2) SEQ ID No: 38 QQLYSGPYT (L-CDR3) SEQ ID No: 47 [] [Anti-] [IL-36R] [Humanized antibody sequence] [ , ]

[0131] Based on structural homology, CDR structure, conserved canonical residues, conserved interface-filling residues, and other parameters, human structural sequences are selected for mouse leader to generate humanized variable regions.

[0132] Representative humanized variable regions derived from antibodies 81B4 and 73C5 are shown below. [Light Chain Variable Region] [(VK)] [Amino acid sequence] [] >81B4vK32_3 vK protein EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSTLASGIPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 76) >81B4vK32_105 vK protein EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 77) >81B4vK32_116 vK protein EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 78) >81B4vK32_127 vK protein EIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 79) >81B4vK32_138 vK protein QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIK (SEQ ID NO: 80) >81B4vK32_140 vK protein QIVLTQSPGTLSLSPGERVTMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSQLASGIPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 81) >81B4vK32_141 vK protein QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSKLASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 82) >81B4vK32_147 vK protein EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSHLASGIPGRFSGSGSGTDFTLTISRLEPEDAAVYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 83) [] >73C5vK39_2 vK protein EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPDRFSGSGSGTEFTLTISSLQSEDFAEYFCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 84) >73C5vK39_7 vK protein EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPDRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 85) >73C5vK39_15 vK protein EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPARFSGSGSGTEFTLTISSLQSEDFAEYYCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 86) [] [Heavy chain variable region] [(VH)] [Amino acid sequence] [] >81B4vH33_49 vH protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGNVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSS (SEQ ID NO: 87) >81B4vH33_85T vH protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGNVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSS (SEQ ID NO: 88) >81B4vH33_90 vH protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEINPGNVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSS (SEQ ID NO: 89) >81B4vH33_93 vH protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEINPGNVRTNYNENFRNRATLTRDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSS (SEQ ID NO: 90) >81B4vH50_22 vH protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEILPGVVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSS (SEQ ID NO: 91) >81B4vH50_30 vH protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGAVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSS (SEQ ID NO: 92) >81B4vH51_13 vH protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGLVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSS (SEQ ID NO: 93) >81B4vH51_15 vH protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGAVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSS (SEQ ID NO: 94) >81B4vH52_83 vH protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGSVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSS (SEQ ID NO: 95) [] >73C5vH46_4 vH protein QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTINKDTSKSQVSFKMSSVQAADTAVYYCARKGGYSGSWFAYWGQGTLVTVSS (SEQ ID NO: 96) >�3C5vH46_19 vH protein QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDTSKNQVSLKMNSLTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSS (SEQ ID NO: 97) >73C5vH46_40 vH protein QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDNSKSQVSLKMNSVTVADTAVYYCARKGGYSGSWFAYWGQGTLVTVSS (SEQ ID NO: 98) >73C5vH47_65 vH protein It should be noted that in the translation of line 15, there is a character "�" in the original text which may be an incorrect character. If it is a misprint, it should be corrected before translation for a more accurate result.QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWVRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDTSKNQVSFKLSSVTVDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSS (SEQ ID NO: 99) >73C5vH47_77 vH protein QVQLQESGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSDGSTDFNAPFKSRVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSS (SEQ ID NO: 100) >73C5vH58_91 vH protein QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDNSKSQVSFKMSSVTADDTAVYYCARKGGYSGSWFAYWGQGTLVTVSS (SEQ ID NO: 101) The CDR sequence from the humanized variable regions of antibodies 81B4 and 73C5, as shown above, is depicted below. [L-CDR1] [Amino acid sequence] [] >81B4vK32_3 L-CDR1 TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_105 L-CDR1 TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_116 L-CDR1 TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_127 L-CDR1 TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_138 L-CDR1 TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_140 L-CDR1 TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_141 L-CDR1 TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_147 L-CDR1 TASSSVSSSYFH (SEQ ID NO: 26) >73C5vK39_2 L-CDR1 KASQDVGTNVL (SEQ ID NO: 27) >73C5vK39_7 L-CDR1 KASQDVGTNVL (SEQ ID NO: 27) >73C5vK39_15 L-CDR1 KASQDVGTNVL (SEQ ID NO: 27) [L-CDR2] [Amino acid sequence] [] >81B4vK32_3 L-CDR2 (SEQ ID 102) RTSTLAS >81B4vK32_105 L-CDR2 (SEQ ID 103) RTSILAS >81B4vK32_116 L-CDR2 (SEQ ID 104) RTSRLAS >81B4vK32_127 L-CDR2 (SEQ ID 104) RTSRLAS >81B4vK32_138 L-CDR2 (SEQ ID 104) RTSRLAS >81B4vK32_140 L-CDR2 (SEQ ID 105) RTSQLAS >81B4vK32_141 L-CDR2 (SEQ ID 106) RTSKLAS >81B4vK32_147 L-CDR2 (SEQ ID 140) RTSHLAS >73C5vK39_2 L-CDR2 SASYRHS (SEQ ID NO: 36) >73C5vK39_7 L-CDR2 SASYRHS (SEQ ID NO: 36) >73C5vK39_15 L-CDR2 SASYRHS (SEQ ID NO: 36) [L-CDR3] [Amino acid sequence] [] >81B4vK32_3 L-CDR3 [[ID=,29]] HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_105 L-CDR3 HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_116 L-CDR3 HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_127 L-CDR3 HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_138 L-CDR3 HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_140 L-CDR3 HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_141 L-CDR3 HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_147 L-CDR3 HQFHRSPLT (SEQ ID NO: 44) >73C5vK39_2 L-CDR3 QQYSRYPLT (SEQ ID NO: 45) >73C5vK39_7 L-CDR3 QQYSRYPLT (SEQ ID NO: 45) >73C5vK39_15 L-CDR3 QQYSRYPLT (SEQ ID NO: 45) [H-CDR1] [Amino acid sequence] [] >81B4vH33_49 H-CDR1 GYSFTSSWIH (SEQ ID NO: 53) >81B4vH33_85T H-CDR1 GYSFTSSWIH (SEQ ID NO: 53) >81B4vH33_90 H-CDR1 GYSFTSSWIH (SEQ ID NO: 53) >81B4vH33_93 H-CDR1 GYSFTSSWIH (SEQ ID NO: 53) >81B4vH50_22 H-CDR1 GYSFTSSWIH (SEQ ID NO: 53) >81B4vH50_30 H-CDR1 GYSFTSSWIH (SEQ ID NO: 53) >81B4vH51_13 H-CDR1 GYSFTSSWIH (SEQ ID NO: 53) >81B4vH51_15 H-CDR1 GYSFTSSWIH (SEQ ID NO: 53) >81B4vH52_83 H-CDR1 GYSFTSSWIH (SEQ ID NO: 53) >73C5vH46_4 H-CDR1 GFSLTDYAVH (SEQ ID NO: 107) >73C5vH46_19 H-CDR1 GFSLTDYAVH (SEQ ID NO: 107) >73C5vH46_40 H-CDR1 GFSLTDYAVH (SEQ ID NO: 107) >73C5vH47_65 H-CDR1 GFSLTDYAVH (SEQ ID NO: 107) >73C5vH47_77 H-CDR1 GFSLTDYAVH (SEQ ID NO: 107) >73C5vH58_91 H-CDR1 GFSLTDYAVH (SEQ ID NO: 107) [] [H-CDR2] [Amino acid sequence] [] >81B4vH33_49 H-CDR2 EINPGNVRTNYNENF (SEQ ID NO: 62) >81B4vH33_85T H-CDR2 EINPGNVRTNYNENF (SEQ ID NO: 62) >81B4vH33_90 H-CDR2 EINPGNVRTNYNENF (SEQ ID NO: 62) >81B4vH33_93 H-CDR2 EINPGNVRTNYNENF (SEQ ID NO: 62) >81B4vH50_22 H-CDR2 EILPGVVRTNYNENF (SEQ ID NO: 108) >81B4vH50_30 H-CDR2 EINPGAVRTNYNENF (SEQ ID NO: 109) >81B4vH51_13 H-CDR2 EINPGLVRTNYNENF (SEQ ID NO: 110) >81B4vH51_15 H-CDR2 EINPGAVRTNYNENF (SEQ ID NO: 109) >81B4vH52_83 H-CDR2 EINPGSVRTNYNENF (SEQ ID NO: 111) >73C5vH46_4 H-CDR2 VIWSDGSTDYNAPFKS (SEQ ID NO: 64) >73C5vH46_19 H-CDR2 VIWSDGSTDYNAPFKS (SEQ ID NO: 64) >73C5vH46_40 H-CDR2 VIWSDGSTDYNAPFKS (SEQ ID NO: 64) >73C5vH47_65 H-CDR2 VIWSDGSTDYNAPFKS (SEQ ID NO: 64) >73C5vH47_77 H-CDR2 VIWSDGSTDFNAPFKS (SEQ ID NO: 63) >73C5vH58_91 H-CDR2 VIWSDGSTDYNAPFKS (SEQ ID NO: 64) [] [H-CDR3] [Amino acid sequence] [] >81B4vH33_49 H-CDR3 VFYGEPYFPY (SEQ ID NO: 72) >81B4vH33_85T H-CDR3 VFYGEPYFPY (SEQ ID NO: 72) >81B4vH33_90 H-CDR3 VFYGEPYFPY (SEQ ID NO: 72) >81B4vH33_93 H-CDR3 VFYGEPYFPY (SEQ ID NO: 72) >81B4vH50_22 H-CDR3 VFYGEPYFPY (SEQ ID NO: 72) >81B4vH50_30 H-CDR3 VFYGEPYFPY (SEQ ID NO: 72) >81B4vH51_13 H-CDR3 VFYGEPYFPY (SEQ ID NO: 72) >81B4vH51_15 H-CDR3 VFYGEPYFPY (SEQ ID NO: 72) >81B4vH52_83 H-CDR3 VFYGEPYFPY (SEQ ID NO: 72) >73C5vH46_4 H-CDR3 KGGYSGSWFAY (SEQ ID NO: 73) >73C5vH46_19 H-CDR3 KGGYSGSWFAY (SEQ ID NO: 73) >73C5vH46_40 H-CDR3 KGGYSGSWFAY (SEQ ID NO: 73) >73C5vH47_65 H-CDR3 KGGYSGSWFAY (SEQ ID NO: 73) >73C5vH47_77 H-CDR3 KGGYSGSWFAY (SEQ ID NO: 73) >73C5vH58_91 H-CDR3 KGGYSGSWFAY (SEQ ID NO: 73)

[0133] In one state, the variable region of the present invention is connected to a constant region. For example, the variable region of the present invention is connected to a constant region as shown below to form the heavy or light chain of the antibody. [The heavy chain constant region downstream of the humanized variable heavy chain region] [:] [ , ] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 112) [Light chain constant region connected downstream of the humanized variable light chain region] [:] [ , ] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:113)

[0134] The representative light and heavy chain sequences of this invention are shown below (humanized variable regions derived from antibodies 81B4 and 73C5 are linked to constant regions). [Light chain amino acid sequence] [ , ] >81B4vK32_3 Light Chain EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSTLASGIPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 114) >81B4vK32_105 light chain EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 115) >81B4vK32_116 light chain EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 116) >81B4vK32_127 light chain EIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 117) >81B4vK32_138 light chain QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 118) >81B4vK32_140 light chain QIVLTQSPGTLSLSPGERVTMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSQLASGIPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 119) >81B4vK32_141 light chain QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSKLASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 120) >81B4vK32_147 light chain EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSHLASGIPGRFSGSGSGTDFTLTISRLEPEDAAVYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 121) [] >73C5vK39_2 light chain EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPDRFSGSGSGTEFTLTISSLQSEDFAEYFCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 122) >73C5vK39_7 light chain EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPDRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 123) >73C5vK39_15 light chain EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPARFSGSGSGTEFTLTISSLQSEDFAEYYCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 124) [] [Heavy chain amino acid sequence] [] >81B4vH33_49 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGNVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 125) >81B4vH33_*85T Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGNVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 126) >81B4vH33_90 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEINPGNVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 127) >81B4vH33_93 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEINPGNVRTNYNENFRNRATLTRDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 128) >81B4vH50_22 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEILPGVVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 129) >81B4vH50_30 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGAVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 130) >81B4vH51_13 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGLVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 131) >81B4vH51_15 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGAVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 132) >81B4vH52_83 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGSVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 133) [] >73C5vH46_4 heavy chain QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTINKDTSKSQVSFKMSSVQAADTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 134) >73C5vH46_19 Heavy Chain QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDTSKNQVSLKMNSLTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 135) >73C5vH46_40 heavy chain QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDNSKSQVSLKMNSVTVADTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 136) >73C5vH47_65 heavy chain QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWVRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDTSKNQVSFKLSSVTVDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 137) >73C5vH47_77 heavy chain QVQLQESGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSDGSTDFNAPFKSRVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 138) >73C5vH58_91 heavy chain QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDNSKSQVSFKMSSVTADDTAVYYCARKGGYSGSWFAYWGQG TLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 139)

[0135] The CDRs listed above are defined using the Chothia numbering system (Al-Lazikani et al. (1997) JMB 273, 927-948).

[0136] In one state, the antibody of the present invention comprises 3 light chain CDRs and 3 heavy chain CDRs, as described above.

[0137] In one state, the antibody of the present invention comprises the light chain and heavy chain variable regions as described above. In one state, the light chain variable region of the present invention is fused with a light chain constant region, such as a κ or λ constant region. In one state, the heavy chain variable region of the present invention is fused with a heavy chain constant region, such as IgA, IgD, IgE, IgG, or IgM, particularly IgG1, IgG2, IgG3, or IgG4.

[0138] The present invention provides an anti-IL-36R antibody comprising: a light chain containing the amino acid sequence SEQ ID NO: 115; and a heavy chain (antibody B1) containing the amino acid sequence SEQ ID NO: 125.

[0139] The present invention provides an anti-IL-36R antibody comprising: a light chain containing the amino acid sequence SEQ ID NO: 115; and a heavy chain (antibody B2) containing the amino acid sequence SEQ ID NO: 126.

[0140] The present invention provides an anti-IL-36R antibody comprising: a light chain containing the amino acid sequence SEQ ID NO: 115; and a heavy chain (antibody B3) containing the amino acid sequence SEQ ID NO: 127. []

[0141] The present invention provides an anti-IL-36R antibody comprising: a light chain containing the amino acid sequence SEQ ID NO: 118; and a heavy chain (antibody B4) containing the amino acid sequence SEQ ID NO: 125.

[0142] The present invention provides an anti-IL-36R antibody comprising: a light chain containing the amino acid sequence SEQ ID NO: 118; and a heavy chain (antibody B5) containing the amino acid sequence SEQ ID NO: 126.

[0143] The present invention provides an anti-IL-36R antibody comprising: a light chain containing the amino acid sequence SEQ ID NO: 118; and a heavy chain (antibody B6) containing the amino acid sequence SEQ ID NO: 127.

[0144] The present invention provides an anti-IL-36R antibody comprising: a light chain containing the amino acid sequence SEQ ID NO: 123; and a heavy chain (antibody C3) containing the amino acid sequence SEQ ID NO: 138.

[0145] The present invention provides an anti-IL-36R antibody comprising: a light chain containing the amino acid sequence SEQ ID NO: 123; and a heavy chain (antibody C2) containing the amino acid sequence SEQ ID NO: 139.

[0146] The present invention provides an anti-IL-36R antibody comprising: a light chain containing the amino acid sequence SEQ ID NO: 124; and a heavy chain (antibody C1) containing the amino acid sequence SEQ ID NO: 138.

[0147] The representative antibodies of this invention are shown below. Table A [Antibody] [Light chain sequence, , ] [Heavy chain sequence, , ] B1 EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 115) [] QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGNVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 125) [] B2 EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 115) [] QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGNVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 126) [] B3 EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 115) QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEINPGNVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEKPKSCDK THTCPPCPAPEAAGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLPGS (SEQ ID NO: 127) B4 QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 118) [] QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGNVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 125) [] B5 QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 118) QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGNVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 126) B6 QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 118) QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEINPGNVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 127) Table B [Antibody] [Light chain sequence] [[ID=**********]] [Heavy chain sequence] [C1] EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPARFSGSGSGTEFTLTISSLQSEDFAEYYCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 124) [] QVQLQESGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSDGSTDFNAPFKSRVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 138) [] [C2] EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPDRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 123) [] QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDNSKSQVSFKMSSVTADDTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEKSCDK THTCPPCPAPEAAGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLPGS (SEQ ID NO: 139) [] [C3] EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPDRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 123) [] QVQLQESGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSDGSTDFNAPFKSRVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 138) []

[0148] The antibodies of this invention are applicable to methods for treating various human diseases or conditions, such as immune diseases, inflammatory diseases, autoimmune diseases, and respiratory diseases. For example, the antibodies of this invention are applicable to methods for treating psoriasis, rheumatoid arthritis, inflammatory bowel disease, or psoriatic arthritis. For example, the antibodies of this invention are applicable to methods for treating chronic obstructive pulmonary disease (COPD) or asthma. For example, the antibodies of this invention are applicable to methods for treating scleroderma, palmoplantar pustulosis, generalized pustular psoriasis, diabetic nephropathy, lupus nephritis, scleroderma, ankylosing spondylitis, IL-36 receptor antagonist deficiency autoimmune disease (DITRA), IL-1 receptor antagonist deficiency autoimmune disease (DIRA), or cryptothermal protein-associated periodic syndrome (CAPS).

[0149] In some samples, the humanized antibody exhibits blocking activity, thereby reducing the binding of IL-36 ligand to IL-36 receptor by at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. The ability of the antibody to block the binding of IL-36 ligand to IL-36 receptor can be measured using competitive binding assays known in this art. Alternatively, the blocking activity of the antibody can be measured by assessing the biological effects of IL-36, such as the production of IL-8, IL-6, and GM-CSF, to determine whether IL-36 receptor-mediated signaling is inhibited.

[0150] In another embodiment, the present invention provides a humanized anti-IL-36R antibody with advantageous physiological properties. In one embodiment, the humanized anti-IL-36R antibody of the present invention is present in a buffer at a monomeric form of at least 90%, at least 92%, or at least 95%. In another embodiment, the humanized anti-IL-36R antibody of the present invention remains in a buffer at a monomeric form of at least 90%, at least 92%, or at least 95% for one month or four months. [ , ]

[0151] In one embodiment, the humanized antibody of the present invention is antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2, or antibody C3. Therefore, in one embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 125 (antibody B1). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 126 (antibody B2). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 127 (antibody B3). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 125 (antibody B4). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 126 (antibody B5). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 127 (antibody B6). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 124 and the heavy chain sequence of SEQ ID NO: 138 (antibody C1). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 123 and the heavy chain sequence of SEQ ID NO: 139 (antibody C2). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 123 and the heavy chain sequence of SEQ ID NO: 138 (antibody C3).

[0152] In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 125 (antibody B1). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 126 (antibody B2). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 127 (antibody B3). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 125 (antibody B4). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 126 (antibody B5). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 127 (antibody B6). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 124 and the heavy chain sequence of SEQ ID NO: 138 (antibody C1). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 123 and the heavy chain sequence of SEQ ID NO: 139 (antibody C2). In another embodiment, the humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO: 123 and the heavy chain sequence of SEQ ID NO: 138 (antibody C3).

[0153] In some embodiments, the humanized anti-IL-36R antibody, including its antigen-binding fragments such as heavy and light chain variable regions, comprises an amino acid sequence of residues derived from antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2, or antibody C3.

[0154] In another embodiment, the present invention provides an anti-IL-36R antibody or its antigen-binding fragment that competitively binds to human IL-36R, such as antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2, or antibody C3 as described herein. The ability of the antibody or antigen-binding fragment to competitively bind to IL-36R can be measured using competitive binding assays known in this art. [ , ]

[0155] Humanized anti-IL-36R antibodies may include specific amino acid substitutions in common or germline framework regions, depending on the specificity of the substitutions. Compared to the efficacy exhibited by humanized antibodies formed by “directly exchanging” CDR or HVL into human germline framework regions, specific substitutions of amino acid residues at these framework sites can improve various aspects of antibody efficacy, including binding affinity and / or stability.

[0156] In some embodiments, the present invention describes other monoclonal antibodies containing a light chain variable region having the amino acid sequences listed in any of SEQ ID NO: 1 to 10. In some embodiments, the present invention describes other monoclonal antibodies containing a heavy chain variable region having the amino acid sequences listed in any of SEQ ID NO: 11 to 20. Placing these CDRs within the FRs of the human common heavy chain and light chain variable regions will produce suitable humanized antibodies of the present invention.

[0157] In detail, the present invention provides monoclonal antibodies having combinations of the following light chain variable and heavy chain variable regions: SEQ ID NO: 1 / 11, 2 / 12, 3 / 13, 4 / 14, 5 / 15, 6 / 16, 7 / 17, 8 / 18, 9 / 19, 10 / 20. These variable regions can be combined with human constant regions.

[0158] In some embodiments, the present invention describes other humanized antibodies containing a light chain variable region having an amino acid sequence listed in any one of SEQ ID NO: 76 to 86. In some embodiments, the present invention describes other humanized antibodies containing a heavy chain variable region having an amino acid sequence listed in any one of SEQ ID NO: 87 to 101. Specifically, the present invention provides monoclonal antibodies having combinations of the following light chain variable and heavy chain variable regions: SEQ ID NO: 77 / 89, 80 / 88, 80 / 89, 77 / 87, 77 / 88, 80 / 87, 86 / 100, 85 / 101, 85 / 100. Such variable regions can be combined with human constant regions.

[0159] In another embodiment, the present invention relates to an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: a humanized light chain variable domain comprising the CDR of SEQ ID NO: 77 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the light chain variable domain of SEQ ID NO: 77; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO: 89 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the heavy chain variable domain of SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0160] In another embodiment, the present invention relates to an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: a humanized light chain variable domain comprising the CDR of SEQ ID NO: 80 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the light chain variable domain of SEQ ID NO: 80; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO: 88 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the heavy chain variable domain of SEQ ID NO: 88. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0161] In another embodiment, the present invention relates to an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: a humanized light chain variable domain comprising the CDR of SEQ ID NO: 80 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the light chain variable domain of SEQ ID NO: 80; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO: 89 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the heavy chain variable domain of SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0162] In another embodiment, the present invention relates to an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: a humanized light chain variable domain comprising the CDR of SEQ ID NO: 77 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the light chain variable domain of SEQ ID NO: 77; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO: 87 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the heavy chain variable domain of SEQ ID NO: 87. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0163] In another embodiment, the present invention relates to an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: a humanized light chain variable domain comprising the CDR of SEQ ID NO: 77 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the light chain variable domain of SEQ ID NO: 77; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO: 88 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the heavy chain variable domain of SEQ ID NO: 88. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0164] In another embodiment, the present invention relates to an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: a humanized light chain variable domain comprising the CDR of SEQ ID NO: 80 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the light chain variable domain of SEQ ID NO: 80; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO: 87 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the heavy chain variable domain of SEQ ID NO: 87. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0165] In another embodiment, the present invention relates to an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: a humanized light chain variable domain comprising the CDR of SEQ ID NO: 86 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the light chain variable domain of SEQ ID NO: 86; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO: 100 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the heavy chain variable domain of SEQ ID NO: 100. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0166] In another embodiment, the present invention relates to an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: a humanized light chain variable domain comprising the CDR of SEQ ID NO: 85 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the light chain variable domain of SEQ ID NO: 85; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO: 101 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the heavy chain variable domain of SEQ ID NO: 101. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0167] In another embodiment, the present invention relates to an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: a humanized light chain variable domain comprising the CDR of SEQ ID NO: 85 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the light chain variable domain of SEQ ID NO: 85; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO: 100 and an amino acid sequence having at least 90%, at least 93%, or at least 95% homology with the amino acid sequence of the heavy chain variable domain of SEQ ID NO: 100. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0168] In some specific embodiments, the humanized anti-IL-36R antibody disclosed herein comprises at least one heavy or light chain variable domain, which includes the CDR or HVL of the murine monoclonal antibody or humanized antibody as disclosed herein and the FR of the human germline heavy and light chain variable domains.

[0169] In another embodiment, the present invention provides an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising: a light chain CDR1 (L-CDR1) sequence of any one of SEQ ID NO: 21 to 29; a light chain CDR2 (L-CDR2) sequence of any one of SEQ ID NO: 30 to 38; a light chain CDR3 (L-CDR3) sequence of any one of SEQ ID NO: 39 to 47; a heavy chain CDR1 (H-CDR1) sequence of any one of SEQ ID NO: 48 to 56; a heavy chain CDR2 (H-CDR2) sequence of any one of SEQ ID NO: 57 to 66; and a heavy chain CDR3 (H-CDR3) sequence of any one of SEQ ID NO: 67 to 75. In one state, the anti-IL-36R antibody or its antigen-binding fragment comprises: a light chain variable region comprising L-CDR1, L-CDR2 and L-CDR3 listed above; and a heavy chain variable region comprising H-CDR1, H-CDR2 and H-CDR3 listed above.

[0170] In another embodiment, the present invention provides an anti-IL-36R antibody or its antigen-binding fragment, comprising: a) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 21, 30, 39, 48, 57, and 67, respectively; or b) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 22, 31, 40, 49, 58, and 68, respectively; or c) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 23, 32, 41, 50, 59, and 69, respectively; or d) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 24, 33, 42, 51, 60, and 70, respectively; or e) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 25, 34, 43, 52, 61, and 71, respectively; or f) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 26, 35, 44, 53, 62, and 72, respectively; or g) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 27, 36, 45, 54, 63, and 73, respectively; or h) are the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 27, 36, 45, 54, 64, and 74, respectively; or i) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 27, 36, 45, 54, 64, and 73, respectively; or j) are the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 28, 37, 46, 55, 65, and 74, respectively; or k) are the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO: 29, 38, 47, 56, 66 and 75 respectively.

[0171] In another embodiment, the present invention provides an anti-IL-36R antibody or its antigen-binding fragment, comprising: a) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 26, 103, 44, 53, 62, and 72, respectively; or b) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 26, 104, 44, 53, 62, and 72, respectively; or c) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NO: 27, 36, 45, 107, 63, and 73, respectively; or d) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO: 27, 36, 45, 107, 64 or 73 respectively.

[0172] In one state, the anti-IL-36R antibody or its antigen-binding fragment comprises: a light chain variable region comprising the combination of L-CDR1, L-CDR2 and L-CDR3 listed above; and a heavy chain variable region comprising the combination of H-CDR1, H-CDR2 and H-CDR3 listed above.

[0173] In certain embodiments, it is anticipated that chimeric antibodies having exchanged CDR regions (i.e., exchanging one or both CDRs of a mouse antibody or a humanized antibody derived therefrom with a similar CDR from another mouse antibody or a humanized antibody derived therefrom) between these exemplary immunoglobulins can produce suitable antibodies.

[0174] In some embodiments, the humanized anti-IL-36R antibody is an antibody fragment. Various antibody fragments have been generally discussed above, and techniques for generating antibody fragments have been developed. Fragments can be obtained by proteolytic digestion of intact antibodies (see, for example, Morimoto et al., 1992, Journal of Biochemical and Biophysical Methods 24:107-117; and Brennan et al., 1985, Science 229:81). Alternatively, fragments can be generated directly in recombinant host cells. For example, the Fab'-SH fragment can be directly recovered from *E. coli* and chemically coupled to form the F(ab')2 fragment (see, for example, Carter et al., 1992, Bio / Technology 10:163-167). Alternatively, the F(ab')2 fragment can be directly isolated from recombinant host cell cultures. Other techniques for generating antibody fragments will be apparent to those skilled in the art. Therefore, in one embodiment, the present invention provides an antibody fragment comprising one of the CDRs described herein, specifically the combinations of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 described herein. In another embodiment, the present invention provides an antibody fragment comprising a variable region described herein, such as one of the combinations of light chain variable regions and heavy chain variable regions described herein.

[0175] Some embodiments include the F(ab')2 fragment of a humanized anti-IL-36R antibody, comprising a combination of the light chain sequence of any one of SEQ ID NO: 115 or 118 and the heavy chain sequence of SEQ ID NO: 125, 126 or 127. Such embodiments may include a complete antibody comprising this F(ab')2.

[0176] Some embodiments include the F(ab')2 fragment of a humanized anti-IL-36R antibody, comprising a combination of the light chain sequence of either SEQ ID NO: 123 or 124 and the heavy chain sequence of either SEQ ID NO: 138 or 139. Such embodiments may include a complete antibody comprising this F(ab')2.

[0177] In some embodiments, the antibody or antibody fragment includes a constant region that mediates effector function. The constant region can provide antibody-dependent cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), and / or complement-dependent cytotoxicity (CDC) responses against target cells expressing IL-36R. The effector domain can be, for example, the Fc region of an Ig molecule.

[0178] The effector domain of an antibody can originate from any suitable vertebrate species and isotype. The difference between isotypes from different animal species lies in their ability to mediate effector functions. For example, the ability of human immunoglobulins to mediate CDC and ADCC / ADCP generally follows the order IgM≈IgG1≈IgG3 >IgG2 >IgG4 and IgG1≈IgG3 >IgG2 / IgM / IgG4, respectively. Mouse immunoglobulins generally mediate CDC and ADCC / ADCP in the order mouse IgM≈IgG3 >>IgG2b >IgG2a >>IgG1 and IgG2b >IgG2a >IgG1 >>IgG3, respectively. In another example, mouse IgG2a mediates ADCC, while mouse IgG2a and IgM mediate CDC. [Humanization and amino acid sequence variants] []

[0179] Amino acid sequence variants of anti-IL-36R antibodies can be prepared by introducing appropriate nucleotide changes into the anti-IL-36R antibody DNA or by peptide synthesis. Such variants include, for example, deletions and / or insertions and / or substitutions of residues within the amino acid sequence of the anti-IL-36R antibodies exemplified herein. Any combination of deletions, insertions, and substitutions can be performed to obtain the final construct, provided that the final construct possesses the desired characteristics. Amino acid changes can also alter the post-translational processes of humanized or mutated anti-IL-36R antibodies, such as changing the number or location of glycosylation sites.

[0180] A method for identifying preferred sites for mutation induction of anti-IL-36R antibodies is called "alanine scan mutation induction," as described by Cunningham and Wells (Science, 244:1081-1085 (1989)). Here, a group of residues or target residues is identified (e.g., charged residues such as arg, asp, his, lys, and glu) and substituted with a neutral or negatively charged amino acid (usually alanine) to influence the interaction of the amino acid with the IL-36R antigen. Subsequently, the amino acid position exhibiting functional sensitivity to the substitution is optimized by introducing additional or other variants at or for the substitution site. Therefore, while the site for introducing amino acid sequence variations is predetermined, the nature of the mutation itself does not need to be predetermined. For example, to analyze the efficacy of a mutation at a given site, alanine scan or random mutation induction can be performed on the target codon or target region, and anti-IL-36R antibody variants exhibiting the desired activity can be screened.

[0181] Amino acid sequence insertions include amino-terminal and / or carboxyl-terminal fusions of peptides ranging in length from one residue to one hundred or more residues, as well as intra-sequence insertions of single or multiple amino acid residues. Examples of terminal insertions include anti-IL-36R antibodies fused to antigenic determinant tags. Other insertion variants of anti-IL-36R antibody molecules include fusions of the N-terminus or C-terminus of the anti-IL-36R antibody with an enzyme or a peptide that extends the serum half-life of an antibody.

[0182] Another type of variant is the amino acid substitution variant. These variants remove at least one amino acid residue from the anti-IL-36R antibody molecule and insert a different residue at that position. The substitution mutation sites of greatest concern include hypervariable regions, but also cover FR changes. Conserved substitutions are shown in Table C under the heading "Preferred Substitutions". If such substitutions result in changes in biological activity, further substantial changes, designated "Exemplary Substitutions" or as described below regarding amino acid categories, can be introduced, and products can be screened. Table C: Exemplary substitution of original residues vs. better substitution Ala (A) val; leu; ile [val] Arg (R) lys; gln; asn [lys] Asn (N) gln; his; asp, lys; arg [gln] Asp (D) glu; asn [glu] Cys (C) ser; ala [ser] Gln (Q) asn; glu [asn] Glu (E) asp; gln [asp] Gly (G) ala [ala] His (H) arg; asn; gln; lys; [arg] Ile (I) leu; val; met; ala; phe; leucine [leu] Leu (L) ile; leucine; val; met; ala; phe [ile] Lys (K) arg; gln; asn [arg] Met (M) leu; phe; ile [leu] Phe (F) tyr; leu; val; ile; ala; [tyr] Pro (P) ala [ala] Ser (S) thr [thr] Thr (T) ser [ser] Trp (W) tyr; phe [tyr] Tyr (Y) phe;trp; thr; ser [phe] Val (V) leu; ile; met; phe ala; leucine; [leu]

[0183] In protein chemistry, the biological properties of antibodies are generally recognized as being achieved by selecting substitutions that significantly differ in maintaining the following effects: (a) the structure of the polypeptide backbone in the substituted region, for example, a sheet or helical conformation; (b) the charge or hydrophobicity of the molecule at the target site; or (c) the volume of the side chain. Based on common side chain characteristics, naturally occurring residues are classified into the following groups: (1) Hydrophobicity: Leucine, Met, Ala, Val, Leu, Il; (2) Neutral hydrophilicity: cys, ser, thr; (3) Acidic: asp, glu; (4) Alkaline: asn, gin, his, lys, arg; (5) Residues affecting chain orientation: gly, pro; and (6) Fang ethnic group: trp, tyr, phe. Non-conservative substitution will necessarily involve replacing members of one of these categories with members of another category.

[0184] Any cysteine ​​residues that do not participate in maintaining the proper conformation of humanized or modified anti-IL-36R antibodies can generally be substituted with serine to improve the oxidative stability of the molecule, prevent aberrant cross-linking, or provide established binding sites for cytotoxic or cell growth-inhibiting compounds. Conversely, cysteine ​​bonds can be added to antibodies to improve their stability (especially when the antibody is an antibody fragment such as the Fv fragment).

[0185] One type of substitution variant involves replacing one or more hypervariable residues of a parent antibody (e.g., a humanized or human antibody). Generally, variants selected for further development should possess modified biological characteristics relative to the parent antibody that produced them. A suitable method for generating such substitution variants is phage-presented affinity maturation. In short, several hypervariable sites (e.g., 6 to 7 sites) are mutated to produce all possible amino acid substitutions at each site. The resulting antibody variant is presented monovalently from filamentous phage particles as a fusion with the M13 gene III product packaged within each particle. Subsequently, the phage-presented variant is screened for biological activity (e.g., binding affinity). To identify candidate hypervariable sites for modification, alanine scanning mutation induction can be performed to identify hypervariable residues that significantly contribute to antigen binding. Alternatively, it may be beneficial to analyze the crystal structure of the antigen-antibody complex to identify the contact points between the antibody and human IL-36R. These contact residues and adjacent residues are candidates for substitution according to the techniques detailed herein. After generating these variants, the variant set is screened as described herein, and antibodies with superior properties can be selected for further development in one or more relevant analyses.

[0186] Another type of antibody amino acid variant alters the original glycosylation pattern of the antibody. "Altered" means that one or more carbohydrate moieties found in the antibody are missing, and / or one or more glycosylation sites not present in the antibody are added.

[0187] In some embodiments, the antibodies of the present invention may need to be modified to add glycosylation sites. Antibody glycosylation is typically N-linked or O-linked. N-linked glycosylation refers to the linking of a carbohydrate moiety to a side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine (where X is any amino acid other than proline) are recognition sequences for the enzymatic linking of the carbohydrate moiety to the asparagine side chain. Therefore, the presence of any of these tripeptide sequences in the polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the linking of one of the sugars N-acetylglucosamine, galactose, or xylose to a hydroxylamine, most commonly serine or threonine, but 5-hydroxyproline or 5-hydroxylysine may also be used. Therefore, to glycosylate a given protein (e.g., an antibody), the amino acid sequence of the protein is engineered to contain one or more of the tripeptide sequences described above (for N-linked glycosylation sites). Alterations can also be made by adding one or more serine or threonine residues to the original antibody sequence or by replacing the original antibody sequence with such residues (targeting O-linked glycosylation sites).

[0188] Nucleic acid molecules encoding amino acid sequence variants of anti-IL-36R antibodies are prepared using a variety of methods known in this technology. These methods include (but are not limited to) isolation from natural sources (in the case of naturally occurring amino acid sequence variants) or preparation by oligonucleotide-mediated (or site-directed) mutation induction, PCR mutation induction, and cartridge mutation induction of early-prepared variants or non-variant forms of anti-IL-36R antibodies. [Polynucleotides, vectors, host cells, and recombination methods] []

[0189] Other embodiments encompass isolated polynucleotides containing sequences encoding humanized anti-IL-36R antibodies, vectors and host cells containing the polynucleotides, and recombinant technologies for generating such humanized antibodies. Isolated polynucleotides can encode any desired form of anti-IL-36R antibody, including, for example, full-length monoclonal antibodies, Fab, Fab', F(ab')2 and Fv fragments, bifunctional antibodies, linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0190] Some embodiments include isolated polynucleotides comprising sequences encoding an antibody or antibody fragment having a light chain variable region having any of the amino acid sequences SEQ ID NO: 1 to 10. Some embodiments include isolated polynucleotides comprising sequences encoding an antibody or antibody fragment having a heavy chain variable region having amino acid sequences SEQ ID NO: 11 to 20.

[0191] Some embodiments include isolated polynucleotides comprising sequences encoding an antibody or antibody fragment having an amino acid sequence of any one of SEQ ID NO: 76 to 86. Some embodiments include isolated polynucleotides comprising sequences encoding an antibody or antibody fragment having an amino acid sequence of SEQ ID NO: 87 to 101.

[0192] Some embodiments include a separated polynucleotide comprising a light chain of an antibody having any of the amino acid sequences SEQ ID NO: 114 to 124. Some embodiments include a separated polynucleotide comprising a heavy chain of an antibody having the amino acid sequences SEQ ID NO: 125 to 139.

[0193] In one state, an antibody or antibody fragment encoded by a separated polynucleotide sequence having a light chain and a heavy chain variable region, wherein the light chain and heavy chain variable regions respectively contain amino acid sequences SEQ ID NO: 115 and SEQ ID NO: 127; respectively contain SEQ ID NO: 118 and SEQ ID NO: 126; respectively contain SEQ ID NO: 118 and SEQ ID NO: 127; respectively contain SEQ ID NO: 115 and SEQ ID NO: 125; respectively contain SEQ ID NO: 115 and SEQ ID NO: 126; respectively contain SEQ ID NO: 118 and SEQ ID NO: 125; respectively contain SEQ ID NO: 124 and SEQ ID NO: 138; respectively contain SEQ ID NO: 123 and SEQ ID NO: 139; respectively contain SEQ ID NO: 123 and SEQ ID NO: 138.

[0194] Polynucleotides containing sequences encoding humanized anti-IL-36R antibodies or fragments or chains thereof may be fused with one or more regulatory or control sequences known in this art and may be contained in suitable expression vectors or host cells known in this art. Each of the polynucleotide molecules encoding heavy or light chain variable domains may be independently fused with a polynucleotide sequence encoding a constant domain, such as a human constant domain, thereby enabling the generation of a complete antibody. Alternatively, polynucleotides or portions thereof may be fused together to provide a template for the generation of single-chain antibodies.

[0195] For recombinant production, a polynucleotide encoding an antibody is inserted into a reproducible vector for selection (DNA amplification) or expression. Many vectors suitable for expressing recombinant antibodies are available. Vector components generally include (but are not limited to) one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence.

[0196] Humanized anti-IL-36R antibodies can also be produced in fusion peptide form, where the antibody is fused with a heterologous peptide, such as a signal sequence or another peptide having a specific cleavage site at the amino terminus of a mature protein or peptide. The selected heterologous signal sequence is typically a signal sequence that is recognized and processed by the host cell (i.e., cleaved by a signal peptidase). For prokaryotic host cells that do not recognize and process the humanized anti-IL-36R antibody signal sequence, the signal sequence can be replaced by a prokaryotic signal sequence. The signal sequence can be, for example, alkaline phosphatase, penicillinase, lipoprotein, heat-stable enterotoxin II leader sequence, and similar signal sequences. For yeast secretion, the native signal sequence can be replaced by, for example, a leader sequence derived from yeast invertase α-factor (including yeast (Saccharomyces) and Kluyveromyces) α-factor leader, acid phosphatase, Candida albicans amylase leader sequence, or a signal described in WO90 / 13646. In mammalian cells, mammalian signal sequences and viral secretory leaders, such as the herpes simplex gD signal, can be used. The DNA in this precursor region binds to the DNA encoding the humanized anti-IL-36R antibody within the reading frame.

[0197] Expression vectors and selection vectors contain nucleic acid sequences that enable the vector to replicate in one or more selected host cells. Generally, in selection vectors, this sequence is the one that enables the vector to replicate independently of the host chromosomal DNA and includes an origin of replication or an autonomous replication sequence. Such sequences are well known for use in various bacteria, yeasts, and viruses. The origin of replication of plasmid pBR322 is suitable for most Gram-negative bacteria. Plasmid origins are suitable for yeast, and various viral origins (SV40, polyomaviruses, adenoviruses, VSVs, and BPVs) are suitable for selection vectors in mammalian cells. Generally, mammalian expression vectors do not require an origin of replication component (usually only the SV40 origin can be used because it contains an early promoter).

[0198] Expression vectors and selection vectors may contain genes encoding optional markers to aid in phenotype identification. Typical optional marker genes encode proteins that confer resistance to antibiotics or other toxins, such as ampicillin, neomycin, methotrexate, or tetracycline, or supplement auxotrophic deficiencies, or in other alternatives, provide specific nutrients not present in compound media, such as genes encoding D-alanine racemic enzymes for bacilli.

[0199] One example of selection is the use of drugs to inhibit host cell growth. Cells successfully transformed with a heterologous gene produce drugs-resistant proteins and thus survive the selected therapy. Examples of this dominant selection include the use of drugs such as neomycin, mycophenolate mofetil, and hygromycin. Common selectable markers for mammalian cells are those that allow the identification of cells capable of taking up nucleic acids encoding humanized anti-IL-36R antibodies, such as DHFR (dihydrofolate reductase), thymidine kinase, metallothionein-I and metallothionein-II (such as the primate metallothionein gene), adenosine deaminase, ornithine decarboxylase, and their analogues. Cells transformed with the DHFR selection gene are first identified by culturing all transformants in a medium containing methotrexate (Mtx) (a competitive antagonist of DHFR). When using wild-type DHFR, a suitable host cell line is the Chinese hamster ovary (CHO) cell line (e.g., DG44) lacking DHFR activity.

[0200] Alternatively, host cells (especially wild-type hosts containing endogenous DHFR) transformed or co-transformed with a DNA sequence encoding an anti-IL-36R antibody, wild-type DHFR protein, and another optional marker (such as aminoglycoside 3'-phosphotransferase (APH)) can be selected by growing the cells in a medium containing a selector targeting the optional marker (such as an aminoglycoside antibiotic, for example, conomycin, neomycin, or G418). See, for example, U.S. Patent No. 4,965,199.

[0201] In cases where yeast cells are used as host cells for recombinant production, the TRP1 gene, present in yeast plastid YRp7 (Stinchcomb et al., 1979, Nature 282: 39), can be used as an optional marker. The TRP1 gene provides a selection marker for yeast mutants lacking tryptophan (e.g., ATCC number 44076 or PEP4-1) (Jones, 1977, Genetics 85:12). Damage to trp1 in the yeast host cell genome provides an effective environment for detecting transformation by growth in the absence of tryptophan. Similarly, Leu2p-deficient yeast strains such as ATCC 20,622 and 38,626 are supplemented by known plastids carrying the LEU2 gene.

[0202] Additionally, vectors derived from the 1.6 μm circular plasmid pKD1 can be used for the transformation of Kluyveromyces. Alternatively, an expression system for the large-scale production of recombinant calf rennet has been reported for Kluyveromyces lactis (Van den Berg, 1990, Bio / Technology 8:135). Stable multiple-copy expression vectors for the secretion of mature recombinant human serum albumin by industrial Kluyveromyces strains have also been revealed (Fleer et al., 1991, Bio / Technology 9:968-975).

[0203] Expression vectors and selection vectors typically contain a promoter that is recognized by the host organism and operatively linked to a nucleic acid molecule encoding an anti-IL-36R antibody or its polypeptide chain. Suitable promoters for use with prokaryotic hosts include the phoA promoter, β-endoramiase and lactose promoter systems, alkaline phosphatase, tryptophan (trp) promoter systems, and hybrid promoters such as the tac promoter. Other known bacterial promoters are also suitable. Promoters used in bacterial systems will also contain a Shine-Dalgarno (SD) sequence operatively linked to DNA encoding a humanized anti-IL-36R antibody.

[0204] Many eukaryotic promoter sequences are known. Almost all eukaryotic genes possess an AT-rich region, located approximately 25 to 30 bases upstream of the transcription start site. Another sequence found 70 to 80 bases upstream of the transcription start site in many genes is the CNCAAT region, where N can be any nucleotide. At the 3' end of most eukaryotic genes is the AATAAA sequence, which can be a signal for poly-A tail addition to the 3' end of the coding sequence. All such sequences are suitable for insertion into eukaryotic expression vectors.

[0205] Examples of suitable promoter sequences for use with a yeast host include promoters of 3-phosphoglycerate kinase or other sugar-degrading enzymes such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triose phosphate isomerase, phosphoglucose isomerase, and glucoskinase.

[0206] Inducible promoters offer additional transcriptional advantages controlled by growth conditions. These promoters include yeast promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, nitrogen metabolism-related derivatives, metallothioneins, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Vectors and promoters suitable for yeast expression are further described in EP 73,657. Yeast enhancers are also suitable for use with yeast promoters.

[0207] Humanized anti-IL-36R antibody transcription systems derived from vectors in mammalian host cells can be controlled, for example, by the genomes of viruses such as polyomavirus, fowlpox virus, adenovirus (such as adenovirus 2), bovine papillomavirus, avian sarcoma virus, cytomegalovirus, retrovirus, hepatitis B virus, and simian virus 40 (SV40), by heterologous mammalian promoters such as actin promoters or immunoglobulin promoters, or by promoters derived from heat shock promoters (provided such promoters are compatible with the host cell system).

[0208] Early and late promoters of SV40 virus are preferably obtained in the form of SV40 restriction fragments that also contain the SV40 virus replication origin. Immediate early promoters of human cytomegalovirus are preferably obtained in the form of HindIII E restriction fragments. A system for expressing DNA using bovine papillomavirus as a vector in mammalian hosts is disclosed in U.S. Patent No. 4,419,446. Modifications to this system are described in U.S. Patent No. 4,601,978. See also Reyes et al., 1982, Nature 297:598-601, which discloses the expression of human p-interferon cDNA in mouse cells under the control of a thymidine kinase promoter derived from herpes simplex virus. Alternatively, long terminal repeat sequences of Rous sarcoma virus can be used as promoters.

[0209] Another suitable element for use in recombinant expression vectors is the enhancer sequence, which is used to amplify the DNA encoding the humanized anti-IL-36R antibody via transcription by higher eukaryotes. Many enhancer sequences from mammalian genes (e.g., hemoglobin, elastase, albumin, alpha-fetoprotein, and insulin) are known. However, enhancers from eukaryotic viruses are commonly used. Examples include the SV40 enhancer following the origin of replication (bp 100-270), the cytomegalovirus early promoter enhancer, the polyomavirus enhancer following the origin of replication, and the adenovirus enhancer. For a description of elements enhancing eukaryotic promoter activation, see Yaniv, 1982, Nature 297:17-18. The enhancer can be spliced ​​into the vector at position 5' or 3' of the humanized anti-IL-36R antibody coding sequence, but is preferably located at the 5' site of the promoter.

[0210] Expression vectors used in eukaryotic host cells (yeast cells, fungal cells, insect cells, plant cells, animal cells, human cells, or nucleated cells from other multicellular organisms) may also contain sequences required to terminate transcription and stabilize mRNA. Such sequences are typically derived from the 5' and occasionally 3' untranslated regions of eukaryotic or viral DNA or cDNA. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding anti-IL-36R antibodies. A suitable transcription termination component is the bovine growth hormone polyadenylated region. See WO94 / 11026 and the expression vectors disclosed therein. In some embodiments, humanized anti-IL-36R antibodies may be expressed using the CHEF system. (See, for example, U.S. Patent No. 5,888,809; the disclosure of which is incorporated herein by reference.)

[0211] In this article, the host cells suitable for selecting or expressing DNA in a vector are the prokaryotic, yeast, or higher eukaryotic cells described above. Prokaryotes suitable for this purpose include eubacteria, such as Gram-negative or Gram-positive organisms, such as Enterobacteriaceae, such as Escherichia (e.g., Escherichia coli), Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella (e.g., Salmonella typhimurium), Serratia (e.g., Serratia marcescans), and Shigella; and Bacilli (such as B. subtilis and B. licheniformis) (e.g., B. licheniformis disclosed in DD 266,710, published April 12, 1989). Pseudomonas (such as P. aeruginosa) and Streptomyces. A preferred host for *Escherichia coli* is *Escherichia coli* 294 (ATCC 31,446), but other strains such as *Escherichia coli* B, *Escherichia coli* X1776 (ATCC 31,537), and *Escherichia coli* W3110 (ATCC 27,325) are suitable. These examples are illustrative and not limiting.

[0212] Besides prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeasts are suitable colonization or expression hosts for humanized anti-IL-36R antibody encoding vectors. Among lower eukaryotic host microorganisms, Saccharomyces cerevisiae or common baker's yeast are most commonly used. However, many other genera, species, and strains are generally available and applicable to this study, such as *Schizosaccharomyces pombe*; hosts of the genus *Kluyveromyce*, such as *Kluyveromyce* lactic acid yeast, *Kluyveromyce* fragilis (ATCC 12,424), *Kluyveromyce* bulgaricus (ATCC 16,045), *Kluyveromyce* wickeramii (ATCC 24,178), *Kluyveromyce* waltii (ATCC 56,500), *Kluyveromyce* drosophilarum (ATCC 36,906), *Kluyveromyce* thermotolerans, and *Kluyveromyce* marxianus; *Yarrowia* (EP 402,226); and *Pichia pastors* (EP 402,226). 183,070); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa; Schwanniomyce, such as Schwanniomyces occidentalis; and filamentous fungi, such as Neurospora, Penicillium, Tolypocladium and Aspergillus hosts, such as Aspergillus nidulans and Aspergillus niger.

[0213] The host cell lines suitable for expressing glycosylated humanized anti-IL-36R antibodies are derived from multicellular organisms. Examples of invertebrate cells include plant and insect cells, including, for example, many baculovirus strains and variants, and corresponding permissible insect host cells from hosts such as: armyworm (Spodoptera frugiperda) (caterpillar), Aedes aegypti (mosquito), Aedes albopictus (mosquito), Drosophila melanogaster (fruit fly), and Bombyx mori (silkworm). Various viral strains used for transfection are publicly available, such as the L-1 variant of Autographa californica NPV and the Bm-5 strain of Bombyx mori NPV, and these viruses are particularly useful for transfecting armyworm cells.

[0214] Plant cell cultures of cotton, corn, potatoes, soybeans, petunias, tomatoes, and tobacco can also be used as hosts.

[0215] In another variant, the expression of humanized anti-IL-36R occurred in vertebrate cells. The propagation of vertebrate cells in cultures (tissue cultures) has become a routine procedure and a widely available technique. Examples of suitable mammalian host cell lines include SV40-transformed monkey kidney CV1 cell line (COS-7, ATCC CRL 1651), human embryonic kidney cell line (293 or 293 cells selected for growth in suspension culture, Graham et al., 1977, J. Gen Virol. 36: 59), juvenile hamster kidney cells (BHK, ATCC CCL 10), Chinese hamster ovary cells / -DHFR1 (CHO, Urlaub et al., 1980, Proc. Natl. Acad. Sci. USA 77: 4216; e.g., DG44), mouse sertoli cells (TM4, Mather, 1980, Biol. Reprod. 23:243-251), monkey kidney cells (CV1 ATCC CCL 70), and African green monkey kidney cells (VERO-76, ATCC). CRL-1587, human cervical cancer cells (HELA, ATCC CCL 2), canine kidney cells (MDCK, ATCC CCL 34), buffalo rat liver cells (BRL 3A, ATCC CRL 1442), human lung cells (W138, ATCC CCL 75), human hepatocytes (Hep G2, HB 8065), mouse mammary tumors (MMT 060562, ATCC CCL51), TR1 cells (Mather et al., 1982, Annals NY Acad. Sci. 383: 44-68), MRC 5 cells, FS4 cells, and human liver tumor cell line (Hep G2).

[0216] The host cells are transformed with the expression or selection vector described above for the production of humanized anti-IL-36R antibodies and cultured in a familiar nutrient medium regulated as appropriate in order to induce promoters, select transformants, or amplify genes encoding the desired sequences.

[0217] The host cells used to generate the humanized anti-IL-36R antibody described herein can be cultured in a variety of culture media. Commercially available culture media such as Ham's F10 (Sigma-Aldrich Co., St. Louis, Mo.), Minimal Essential Medium (MEM, Sigma-Aldrich Co.), RPMI-1640 (Sigma-Aldrich Co.), and Dulbecco's Modified Eagle's Medium (DMEM, Sigma-Aldrich Co.) are suitable for culturing host cells. Additionally, Ham et al., 1979, Meth. Enz. 58: 44; Barnes et al., 1980, Anal. Biochem. 102: 255; U.S. Patent Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655, 5,122,469, WO 90 / 103430, and WO Any of the culture media described in one or more of 87 / 00195 may be used as a culture medium for host cells. Any of these culture media may be supplemented as needed with hormones and / or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (e.g., sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics (such as gentamicin), trace elements (defined as inorganic compounds typically present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Other supplements may also be included at appropriate concentrations known to those skilled in the art. The culture conditions (such as temperature, pH, and similar conditions) are those previously used for the selected host cells for expression and will be readily apparent to those generally skilled in the art.

[0218] When using recombinant technology, antibodies can be produced intracellularly, in the periplasmic space, or secreted directly into the culture medium. If antibodies are produced intracellularly, the first step is to disrupt the cells to release the proteins. Microparticle debris, i.e., host cells or lysed fragments, can be removed, for example, by centrifugation or ultrafiltration. Carter et al., 1992, Bio / Technology 10:163-167, describe a procedure for isolating antibodies secreted into the periplasmic space of *E. coli*. Briefly, the cell slurry is thawed for approximately 30 minutes in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonylurea fluoride (PMSF). Cell debris can be removed by centrifugation. In cases where antibodies are secreted into the culture medium, the supernatant of such performance systems is typically concentrated first using a commercially available protein concentrater (e.g., an Amicon or Millipore Pellicon ultrafiltration unit). Protease inhibitors such as PMSF can be included in any prior step to inhibit protein degradation, and antibiotics can be included to prevent the growth of foreign contaminants. Various methods can be used to isolate antibodies from host cells.

[0219] Cell-derived antibody compositions can be purified using techniques such as hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a typical purification technique. The suitability of protein A as an affinity ligand depends on the type and isotype of any immunoglobulin Fc domain present in the antibody. Protein A can be used to purify antibodies based on human γ1, γ2, or γ4 heavy chains (see, for example, Lindmark et al., 1983 J. Immunol. Meth. 62:1-13). For all mouse isotypes and human γ3, protein G is recommended (see, for example, Guss et al., 1986 EMBO J. 5:1567-1575). Agarose is the most common matrix for linking affinity ligands, but other matrix systems are available. Mechanically stable matrices (such as controlled-pore glass or poly(divinyl)styrene) achieve faster flow rates and shorter processing times compared to those achievable with agarose. When the antibody contains a CH3 domain, Bakerbond ABX™ resin (JT Baker, Phillipsburg, NJ) is suitable for purification. Depending on the antibody to be recovered, other protein purification techniques may also be used, such as fractionation on ion exchange columns, ethanol precipitation, reverse-phase HPLC, silica chromatography, heparin SEPHAROSE™ chromatography, anion or cation exchange resin (such as polyaspartic acid columns) chromatography, chromatography focusing, SDS-PAGE, and ammonium sulfate precipitation.

[0220] Following any initial purification step, the mixture containing the antibody of interest and contaminants can undergo low-pH hydrophobic interaction chromatography, typically performed at low salt concentrations (e.g., about 0–0.25 M salt) using a dissociation buffer at a pH between about 2.5 and 4.5.

[0221] This also includes nucleic acids that hybridize with all or part (e.g., a portion encoding a variable region) of a separated polynucleotide sequence encoding an antibody or antibody fragment of the present invention under low, medium, and high stringency conditions as defined herein. The hybridization portion of the nucleic acid is typically at least 15 (e.g., 20, 25, 30, or 50) nucleotides in length. The hybridization portion of the nucleic acid is at least 80%, for example, at least 90%, at least 95%, or at least 98%, identical to a portion or all of the nucleic acid encoding an anti-IL-36R polypeptide (e.g., a variable region of the heavy or light chain) or its complementary sequence. Hybrid nucleic acids of the types described herein can be used, for example, as selection probes, primers, such as PCR primers or diagnostic probes. [Therapeutic Use] []

[0222] In another embodiment, the humanized anti-IL-36R antibody disclosed herein is suitable for treating various conditions associated with the manifestations of IL-36R as described herein. A method of treating IL-36R-related conditions comprises administering a therapeutically effective amount of the humanized anti-IL-36R antibody to an individual in need.

[0223] Humanized anti-IL-36R antibodies or agents are administered by any suitable method, including non-enteral, subcutaneous, intrapulmonary, and intranasal administration, and, as needed, intralesional administration (including perfusion or other methods of contacting the graft with the antibody prior to transplantation) for local immunosuppressive therapy. Humanized anti-IL-36R antibodies or agents can be administered, for example, by infusion or bolus. Non-enteral infusion includes intramuscular, intravenous, intra-arterial, or subcutaneous administration. Additionally, humanized anti-IL-36R antibodies are preferably administered by pulsed infusion, specifically, with decreasing antibody dose. In one administration method, depending on whether the administration is short-term or long-term, it can be administered by injection, preferably intravenous or subcutaneous injection.

[0224] For the prevention or treatment of disease, the appropriate dosage of antibodies will depend on various factors, such as the type of disease to be treated as defined above, the severity and duration of the disease, whether the antibody is administered for prevention or treatment purposes, prior therapy, the patient's clinical history and response to the antibody, and the judgment of the attending physician. Antibodies may be administered to the patient in a single dose or as part of a series of treatments.

[0225] Depending on the type and severity of the disease, an antibody dose of approximately 1 µg / kg to 20 mg / kg (e.g., 0.1 to 15 mg / kg) is the initial candidate dose for administration to the patient, whether administered as a single or multiple separate dose or as a continuous infusion. Typical daily doses can range from approximately 1 μg / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, treatment continues until the required suppression of disease symptoms is achieved, depending on the condition. However, other dosing regimens may be applicable. Progression of this therapy can be easily monitored using known techniques and analysis. An illustrative dosing regimen is the one disclosed in WO 94 / 04188.

[0226] The term "suppression" is used in this article in the same context as "improvement" and "relief," meaning the reduction of one or more features of the disease.

[0227] The antibody composition will be formulated, administered, and delivered in accordance with good medical practice. Factors considered in this context include the specific disease being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disease, the drug delivery site, the method of administration, the timing of administration, and other factors known to the medical practitioner. The "therapeutic effective dose" of the antibody to be administered will be controlled by these considerations and will be the minimum amount required to prevent, improve, or treat the condition associated with IL-36R expression.

[0228] Antibodies are not mandatory, but are used in combination with one or more currently used agents for the prevention or treatment of the condition in question, depending on the circumstances. The effective amount of such other agents depends on the amount of humanized anti-IL-36R23p19 antibody present in the formulation, the type of condition or treatment, and other factors discussed above. These agents are generally used at the same dosage and route of administration as described above, or at approximately 1% to 99% of the dosage used to date. [Treatment using antibody-modified formulations] []

[0229] In one embodiment, the present invention provides a method for treating an individual’s disease or symptom, comprising administering to the individual a formulation described herein in an amount effective in treating the disease or symptom.

[0230] The antibody formulations of this invention are suitable for use in methods of treating various human diseases or conditions, such as immune diseases, inflammatory diseases, autoimmune diseases, and respiratory diseases. For example, the antibody formulations of this invention are suitable for use in methods of treating psoriasis, rheumatoid arthritis, inflammatory bowel disease, or psoriatic arthritis. For example, the antibody formulations of this invention are suitable for use in methods of treating chronic obstructive pulmonary disease (COPD) or asthma. For example, the antibody formulations of this invention are suitable for use in treating scleroderma, palmoplantar pustulosis, generalized pustular psoriasis, diabetic nephropathy, lupus nephritis, scleroderma, ankylosing spondylitis, IL-36 receptor antagonist deficiency autoimmune disease (DITRA), IL-1 receptor antagonist deficiency autoimmune disease (DIRA), or cryptothermal protein-associated periodic syndrome (CAPS).

[0231] Formulations containing an IL-36R binder (e.g., an anti-IL-36R antibody) can be administered to individuals suffering from or at risk of immune disorders, respiratory conditions, or cancer. The invention further provides the use of the IL-36R binder (e.g., an anti-IL-36R antibody) in the manufacture of medicaments for the prevention or treatment of cancer, respiratory conditions, or immune disorders. As used herein, the term "individual" means any mammalian patient to whom an IL-36R binder may be administered, including, for example, humans and non-human mammals such as primates, rodents, and dogs. Individuals particularly desiring treatment using the methods described herein include humans. Antibodies or medicaments can be administered alone or in combination with other compositions to prevent or treat immune disorders, respiratory conditions, or cancer. Such compositions that can be administered in combination with antibodies or medicaments include methotrexate (MTX) and immunomodulators, such as antibodies or small molecules. []

[0232] In one embodiment, the present invention relates to a method of treating an individual's disease or condition (such as those listed above), the method comprising administering to the individual a therapeutic amount of a stable pharmaceutical formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 20 mM to about 80 mM of a pharmaceutically acceptable buffer (e.g., acetate buffer), about 100 mM to about 250 mM of a pharmaceutically acceptable tonic modulator (e.g., sucrose), about 0 mM to about 80 mM of a pharmaceutically acceptable stabilizer (e.g., arginine) or a pharmaceutically acceptable salt thereof, about 0 to about 150 mM of a pharmaceutically acceptable salt (e.g., sodium chloride), and an amount of about 0.1 g / L to about 1.5 g / L of a pharmaceutically acceptable surfactant (e.g., polysorbate 20), wherein the disease or condition is treated. In a related embodiment, the stable pharmaceutical formulation is an aqueous solution of a pharmaceutical formulation. In one related embodiment, the pH of the aqueous solution of the pharmaceutical preparation is about 5 to about 7. In one related embodiment, the pharmaceutical preparation is used for intravenous administration to an individual. In one related embodiment, the pharmaceutical preparation is used for subcutaneous administration to an individual. In one related embodiment, the pharmaceutical preparation used for intravenous administration contains about 60 mg / mL of anti-IL-36R antibody. In one related embodiment, the pharmaceutical preparation used for subcutaneous administration contains about 150 mg / mL of anti-IL-36R antibody. In one related embodiment, the anti-IL-36R antibody comprises: (i) a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or (ii) a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or (iii) a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127.In one related embodiment, the anti-IL-36R antibody comprises: a light chain variable region comprising the amino acid sequence SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or comprising the light chain variable region comprising the amino acid sequence SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or comprising the light chain variable region comprising the amino acid sequence SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89; or comprising the light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or comprising the light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or comprising the light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89.

[0233] In one embodiment, the treatment method according to any of the foregoing states comprises administering to an individual a therapeutic dose of a stable pharmaceutical preparation selected from the group consisting of: I. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-arginine, approximately 5 mM NaCl, and approximately 1.0 g / L polysorbate 20, with a pH of approximately 6.0; II. Contains the following formulation: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; III. Contains the following formulation: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM glycine, approximately 0.4 g / L polysorbate 80, pH approximately 5.5; IV. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; V. Contains the following formulation: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM histidine, approximately 160 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; VI. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g / L polysorbate 80, pH approximately 6.5; VII. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; VIII. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-arginine, approximately 3 mM NaCl, approximately 0.4 g / L polysorbate 80, pH approximately 6.0; IX. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g / L polysorbate 20, pH approximately 5.5; and X. Contains the following formulations: approximately 20 mg / mL to approximately 150 mg / mL anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g / L polysorbate 80, pH approximately 6.0. The disease or condition is treated. In one related embodiment, the stable pharmaceutical preparation is an aqueous solution of the pharmaceutical preparation. In one related embodiment, the pharmaceutical preparation is used for intravenous administration to an individual. In one related embodiment, the pharmaceutical preparation is used for subcutaneous administration to an individual. In one related embodiment, the pharmaceutical preparation used for intravenous administration contains approximately 60 mg / mL of anti-IL-36R antibody. In one related embodiment, the pharmaceutical preparation used for subcutaneous administration contains approximately 150 mg / mL of anti-IL-36R antibody. In one related embodiment, the anti-IL-36R antibody comprises: (i) a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or (ii) a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or (iii) a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127. In one related embodiment, the anti-IL-36R antibody comprises: a light chain variable region comprising the amino acid sequence SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89.

[0234] In one embodiment, the treatment method according to any of the foregoing states comprises administering to an individual a therapeutic dose of a stable pharmaceutical preparation selected from the group consisting of: I. Contains the following formulation: approximately 20 mg / ml anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-arginine, approximately 5 mM NaCl, and approximately 1.0 g / L polysorbate 20, with a pH of approximately 6.0; II. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; III. Contains the following formulation: approximately 20 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM glycine, approximately 0.4 g / L polysorbate 80, pH approximately 5.5; IV. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; V. Contains the following formulation: approximately 60 mg / mL anti-IL-36R antibody, approximately 25 mM histidine, approximately 160 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g / L polysorbate 20, pH approximately 6.0; VI. Contains the following formulations: approximately 20 mg / mL anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g / L polysorbate 80, pH approximately 6.5; VII. Contains the following formulation: approximately 150 mg / mL anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-arginine, approximately 0.4 g / L polysorbate 20, pH approximately 5.5; VIII. Contains the following formulation: approximately 15 mg / mL anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-arginine, approximately 3 mM NaCl, approximately 0.4 g / L polysorbate 80, pH approximately 6.0; IX. Contains the following formulations: approximately 80 mg / mL anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g / L polysorbate 20, pH approximately 5.5; and X. Contains the following formulation: approximately 100 mg / mL anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g / L polysorbate 80, pH approximately 6.0. The disease or condition is treated. In one related embodiment, the stable pharmaceutical preparation is an aqueous solution of the pharmaceutical preparation. In one related embodiment, the pharmaceutical preparation is used for intravenous administration to an individual. In one related embodiment, the pharmaceutical preparation is used for subcutaneous administration to an individual. In one related embodiment, the pharmaceutical preparation used for intravenous administration contains approximately 60 mg / mL of anti-IL-36R antibody. In one related embodiment, the pharmaceutical preparation used for subcutaneous administration contains approximately 150 mg / mL of anti-IL-36R antibody. In one related embodiment, the anti-IL-36R antibody comprises: (i) a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 125; or (ii) a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 126; or (iii) a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127. In one related embodiment, the anti-IL-36R antibody comprises: a light chain variable region comprising the amino acid sequence SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 89.

[0235] Examples of antibodies used in such pharmaceutical formulations are antibodies comprising an antibody or antibody fragment having a light chain variable region amino acid sequence having any of SEQ ID NO: 1 to 10. Examples of antibodies used in such pharmaceutical compositions are also antibodies comprising a humanized antibody or antibody fragment having a heavy chain variable region amino acid sequence having any of SEQ ID NO: 11 to 20.

[0236] Other examples of antibodies used in such pharmaceutical formulations are antibodies comprising humanized antibodies or antibody fragments having the light chain variable region amino acid sequence of any one of SEQ ID NO: 76 to 86. Preferred antibodies for use in such pharmaceutical compositions are also antibodies comprising humanized antibodies or antibody fragments having the heavy chain variable region amino acid sequence of any one of SEQ ID NO: 87 to 101.

[0237] Other examples of antibodies used in such pharmaceutical formulations are antibodies comprising humanized antibodies or antibody fragments having a light chain variable region and a heavy chain variable region having any of the following: SEQ ID NO: 77 and 89, SEQ ID NO: 80 and 88, SEQ ID NO: 80 and 89, SEQ ID NO: 77 and 87, SEQ ID NO: 77 and 88, SEQ ID NO: 80 and 87, SEQ ID NO: 86 and 100, SEQ ID NO: 85 and 101 or SEQ ID NO: 85 and 10.

[0238] Other examples of antibodies used in such pharmaceutical formulations include those comprising humanized antibodies having the light chain amino acid sequence of any one of SEQ ID NO: 115, 118, 123, or 124. Preferred antibodies for use in such pharmaceutical compositions are also those comprising humanized antibodies having the heavy chain variable region amino acid sequence of any one of SEQ ID NO: 125, 126, 127, 138, or 139.

[0239] Other examples of antibodies used in such pharmaceutical formulations include antibodies such as antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2, or antibody C3.

[0240] Various delivery systems are known and can be used to administer the IL-36R binder. Methods of administration include (but are not limited to) intradermal, intramuscular, intravenous, subcutaneous, intranasal, epidural, and oral routes. The IL-36R binder can be administered, for example, by infusion, bolus, or injection, and can be administered together with other bioactive agents such as chemotherapeutic agents. Administration can be systemic or local. In a preferred embodiment, administration is performed by subcutaneous injection. Formulations for such injections can be prepared in pre-filled syringes, for example, for administration once weekly.

[0241] In certain embodiments, the IL-36R binder formulation is administered by injection, via a catheter, via suppository, or via an implant, which is a porous, non-porous, or gel-like material comprising a membrane, such as a silicone rubber membrane or fiber. Typically, when administering the formulation, a material that is not absorbed by the anti-IL-36R antibody or the drug is used.

[0242] In other embodiments, the anti-IL-36R antibody or agent is delivered using a controlled release system. In one embodiment, a pump may be used (see, for example, Langer, 1990, Science 249:1527-1533; Sefton, 1989, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). In another embodiment, a polymeric material may be used. (See, for example, Medical Applications of Controlled Release (Langer and Wise, eds., CRC Press, Boca Raton, Fla., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball, eds., Wiley, New York, 1984); Ranger and Peppas, 1983, Macromol. Sci. Rev. Macromol. Chem. 23:61. See also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105.) Other controlled release systems are discussed, for example, by Ranger, see above.

[0243] IL-36R binders (such as anti-IL-36R antibodies) may be administered in the form of a pharmaceutical formulation comprising a therapeutically effective amount of the binder and one or more pharmaceutically compatible components.

[0244] When administering medications by infusion, an infusion bottle containing sterile pharmaceutical-grade water or physiological saline can be used to prepare the medication. When administering medications by injection, ampoules containing sterile water or physiological saline for injection can be provided so that the components can be mixed before administration.

[0245] In addition, pharmaceutical formulations may be provided in the form of pharmaceutical kits comprising (a) a container containing an IL-36R conjugate (e.g., an anti-IL-36R antibody) in lyophilized form and (b) a second container containing a pharmaceutically acceptable injectable diluent (e.g., sterile water). The pharmaceutically acceptable diluent may be used to reconstitute or dilute the lyophilized anti-IL-36R antibody or pharmaceutical preparation. Where applicable, such containers may be associated with precautions in the form prescribed by the governmental agency regulating the manufacture, use, or sale of pharmaceutical or biological products, reflecting approval by the entity to which they are manufactured, used, or sold in human presence.

[0246] The dosage of an IL-36R conjugate (e.g., an anti-IL-36R antibody) effective in treating or preventing immune disorders or cancer can be determined using standard clinical techniques. In addition, in vitro analysis may be used, as appropriate, to help identify the optimal dosage range. The precise dosage to be used in the formulation will also depend on the route of administration and the stage of the immune disorder or cancer, and should be determined based on the physician's judgment and the individual patient's condition.

[0247] In some embodiments, a pharmaceutical formulation comprising an IL-36R binder may further comprise a therapeutic agent, whether or not bound to the binder. An anti-IL-36R antibody or IL-36R binder may be co-administered in combination with one or more therapeutic agents used to treat or prevent immune disorders or cancer.

[0248] Such combination therapies can have additive or synergistic effects on disease parameters (such as the severity of symptoms, the number of symptoms, or the frequency of recurrence).

[0249] Regarding the combination therapy regimen, in one specific embodiment, the anti-IL-36R antibody or IL-36R binder is administered concurrently with the therapeutic agent. In another specific embodiment, the therapeutic agent is administered at least one hour to several months before or after administration of the anti-IL-36R antibody or IL-36R binder, for example, at least one hour, five hours, 12 hours, one day, one week, one month, or three months before or after administration of the anti-IL-36R antibody or IL-36R binder. [Products] []

[0250] In another embodiment, the product includes an article containing materials suitable for treating the conditions described above. The article includes a container and label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container can be formed from various materials, such as glass or plastic. The container holds the preparation for the effective treatment of the condition and may have a sterile access port. For example, the container may be an intravenous solution bag or vial with a stopper that can be punctured by a hypodermic needle. The active agent in the preparation is a humanized anti-IL-36R antibody. A label on or associated with the container indicates that the preparation is for the treatment of the selected condition. The article may further include a second container containing a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer's solution, and dextran solution. It may further include other materials deemed necessary from a commercial and user's point of view, including other buffers, diluents, filters, needles, syringes, and a product information leaflet with instructions for use.

[0251] The present invention is further described in the following examples, which are not intended to limit the scope of the invention. [Example] [ , ] [Example] [1] [Configuration and Colloidal Stability] [(pH)] [And buffer screening] [)]

[0252] Thermal stability in the pH range of 5.5 to 6.5 was assessed using DSF (Differential Scanning Fluorescence) by monitoring the development temperature (T(h)). T(h) is the temperature at which hydrophobic exposure occurs, which is similar to Tm and is reported here as Tm, thus representing the temperature at which the protein develops. Samples were diluted with individual buffers to a target concentration of 0.5 mg / mL for thermal stability screening by DSF.

[0253] The colloidal stability of the formulation was assessed using DLS (dynamic light scattering). The diffusion coefficient of the antibody of this invention was measured in different buffers at several different protein concentrations.

[0254] DSF analysis results for pH / buffer screening showed that pH significantly affects the thermal expansion temperature (Tm). Thermal stability data indicated that configurational stability increased slightly with increasing pH. Table 1 shows the buffers evaluated and their corresponding Tm values ​​for each buffer. [surface] [1] [:] [pH / ] [Buffer Screening] [:] [By] [DSF] [Research Measurement] [Tm] [value] [] buffer Tm (°C) Histidine pH 6.5 71 Phosphate pH 6.5 71 Succinate pH 6.4 71 Citrate pH 6.5 70 Succinate pH 6.0 70 Citrate pH 6.0 70 Histidine pH 6.0 69 Acetate pH 5.5 69

[0255] Colloidal stability screening studies (Figure 1) revealed the following unexpected results: formulations of anti-IL-36R antibodies (as presented in this paper) exhibited the most promising properties (minimal protein-protein interactions and highest diffusion) at pH 5.5 (25 mM acetate) and pH 6.0 (25 mM histidine). Colloidal screening analysis predicted minimal protein-protein interactions at acetate (pH 5.5) and histidine (pH 6.0). Colloidal stability screening studies of anti-IL-36R antibodies were conducted at concentrations ranging from 5 to 20 mg / mL. [Example] [2] [:] [] [Chemical Stability Study] [(] [exist]

[40] [℃] [Down] [2] [week] [)]

[0256] The chemical stability of the anti-IL-36R antibody of the present invention was evaluated as a function of pH / buffer level. Samples were prepared at a concentration of 80 mg / mL within a pH range of 5.5 to 6.5. 1 mL of sample was filled into 2 mL glass vials. Samples were incubated at 40°C for 14 days. The samples were evaluated, in particular, by visual assessment, protein concentration (A280), HP-SEC (high performance size exclusion chromatography) for determining monomer content and aggregate formation, and CEX (cation exchange chromatography) for measuring charge variants exhibiting APG (acidic peak group), BPG (basic peak group), and main peak forms.

[0257] Visual assessment of the samples showed that most samples became turbid by the end of 14 days. Surprisingly, after 14 days at 40°C, only the sample at 25 mM acetate pH 5.5 remained clear.

[0258] HP-SEC indicates that the most favorable buffers for the percentage of peak remaining after 14 days are 25 mM acetate at pH 5.5 (98.5%), followed by 25 mM citrate at pH 6.5 (97.5%) and 25 mM citrate at pH 6.0 (97.1%). Other buffers, such as histidine at pH 6.0, phosphate at 6.5, and succinate at pH 6.4, show peak data between 88.9% and 91.9% after 14 days at 40°C.

[0259] CEX data after 14 days at 40°C indicate that the 25 mM acetate buffer at pH 5.5 has the highest percentage of the main peak (54.0%) compared to other tested buffers (33.3% to 44.5%).

[0260] CEX data after 14 days at 40°C indicate that the acid peak percentage at pH 5.5 with 25 mM acetate is the lowest (38.1%) compared to other tested buffers (up to 58.1%). This buffer also demonstrates comparable effectiveness to other buffers in minimizing the presence of basic species.

[0261] Based on visual assessments and results obtained from HP-SEC and CEX, 25 mM acetate at pH 5.5 was found to be the most favorable formulation buffer after a 14-day accelerated stability study.

[0262] Although the Tm was lowest at pH 5.5 in the heat screening study, it was concluded that conformational stability would be improved by adding an excluded solute stabilizer (e.g., sucrose). Therefore, 25 mM acetate at pH 5.5 was selected as the buffer for the anti-IL-36R antibody used in this invention. [Example] [3] [:] [] [Surfactant Research] []

[0263] This example was conducted to optimize the concentration of polysorbate 20 in four different formulations containing 25 mM acetate at pH 5.5 (Table 2). Samples were filled into 2 mL glass vials (1 mL / vial). [surface] [2] [Formulations evaluated in surfactant optimization studies] [] [Formulation Matrix] [Ingredient 1] [Ingredient 2] [Ingredient 3] [Ingredient 4] Anti-IL-36R antibody (as revealed in this article) 150 mg / mL 150 mg / mL 150 mg / mL 150 mg / mL Acetate 25 mM 25 mM 25 mM 25 mM sucrose 200 mM 200 mM 200 mM 200 mM Polysorbate 20 0% (w / v) 0.02% (w / v) 0.04% (w / v) 0.06% (w / v)

[0264] The following experiments were conducted for surfactant research: freeze-thaw stability and stirring stability. The following analyses were performed on samples from different experiments: especially HP-SEC and microscopically visible particles. [freezing] [-] [Thawing stability study] []

[0265] The solution of the anti-IL-36R antibody of this invention was frozen in a glass vial at -40°C for 24 hours, and then thawed at room temperature for 2 hours. This procedure was repeated up to 3 times. The samples were then analyzed by HP-SEC.

[0266] Surprisingly, the HP-SEC results showed that the formulation with 0.06% polysorbate 20 had a higher content of high molecular weight species after three freeze-thaw cycles (Figure 2) compared to other formulations with lower concentrations of polysorbate 20. Other formulations with polysorbate 20 concentrations between 0 and 0.04% performed similarly well to, and slightly better than, the formulation with 0.06% polysorbate 20. [Stirring stability] []

[0267] The mixture was stirred at room temperature for 48 hours. The microscopically visible particle (SVP) content was measured, particularly using HP-SEC and flow imaging microscopy.

[0268] HP-SEC results indicated a slight increase in aggregation when polysorbate 20 was absent (Figure 3). All other formulations showed similar levels of aggregation at each sampling point.

[0269] Surprisingly, the SVP results showed that the formulation with 0.04% PS20 had the lowest number of microscopically visible particles after stirring for 48 hours (Table 3). [surface] [3] [:] [Stirring stability] [(] [Surfactant Optimization] [)] [Of] [SVP] [result] [] [Sample Name] [particles / mL] [Diameter 10-25 µm] [Diameter 25 µm] [and larger] Stir 0% polysorbate 20 for 48 hours. 3854 277 Stir 0.02% polysorbate 20 for 48 hours. 1178 149 Stir 0.04% polysorbate 20 for 48 hours. 139 15 Stir 0.06% polysorbate 20 for 48 hours. 273 36

[0270] Increasing the concentration of polysorbate 20 to above 0.04% (w / v) unexpectedly resulted in a slight increase in aggregates in frozen-thawed samples. Conversely, stirring studies showed that removing polysorbate 20 slightly increased aggregates. Furthermore, after stirring, the SVP (Surplus Value Per Second) was higher at both above and below 0.04% (w / v) polysorbate 20 concentrations, which was unexpected. Based on these results, a final concentration of polysorbate 20 of 0.04% (w / v) was selected. Additionally, studies showed that 0.04% (w / v) polysorbate 20 was also feasible for solutions containing 60 mg / mL of protein. [Example] [4] [] [Final formulation screening study] []

[0271] Based on the initial screening data, six candidate formulations (Table 4) were selected for testing in the final formulation screening using 150 mg / mL of the anti-IL-36R antibody of this invention. Arginine (HCl) and NaCl were added to evaluate their potential to reduce protein-protein interactions. Reducing protein-protein interactions can decrease aggregation and viscosity. [surface] [4] [:Composition of the formulation used for final formulation screening] [] [Ingredients] [sugar] [Polysorbide 20] [Buffer] [pH] [Other excipients] F1 200 mM sucrose 0.04% 45 mM acetate 5.5 - F2 150 mM sucrose 0.04% 45 mM acetate 5.5 25 mM arginine HCl F3 150 mM sucrose 0.04% 45 mM acetate 5.5 25 mM NaCl F4 200 mM Trehalose 0.04% 45 mM acetate 5.5 - F5 150 mM Trehalose 0.04% 45 mM acetate 5.5 25 mM arginine HCl F6 150 mM Trehalose 0.04% 45 mM acetate 5.5 25 mM NaCl

[0272] The following experiments were conducted to screen the final formulations of the six candidate formulations: eight-week accelerated stability study, freeze-thaw stability, stirring stability, and light stability. [Eight-Week Accelerated Stability Study] []

[0273] All formulations had a protein concentration of 150 mg / mL, with measured concentrations ranging from 155 to 166 mg / mL. Samples were filled into 2 mL vials (1 mL / vial). The acetate concentration was 45 mM. Samples were stored at three different temperatures (5°C, 25°C, and 40°C). Samples were analyzed using the following methods: microscopically visible particles, HP-SEC, IL-36R binding (potency), non-reducing CGE (capillary gel electrophoresis for detecting fragments), and icIEF (imaging capillary isoelectric focusing for measuring charge variants). [] [Microscopically visible particles] [(SVP)] []

[0274] Monitoring of microscopically visible particles in the candidate formulations was performed using flow imaging microscopy. Surprisingly, no significant trend was observed in the counting of particles with diameters of 10 to 25 µm or 25 µm and larger for samples stored at 5°C, 25°C, and 40°C. Similar results were observed for all six formulations in both categories, exhibiting low microscopically visible particle counts at the end of the eight-week study. [icIEF]

[0275] The general charge characteristic curve of the anti-IL-36R antibody of this invention exhibits acidic, basic, and main peak groups. After 8 weeks at 40°C, the charge variants of the anti-IL-36R antibody of this invention show a remarkably similar trend among the formulations. [Non-reducible] [CGE] []

[0276] To assess the fragmentation and disulfide bond reduction of the anti-IL-36R antibody formulations of this invention during storage, the results of non-reducing capillary gel electrophoresis were evaluated. At three storage temperatures, all formulations showed similar levels of fragmentation and disulfide bond reduction (LMW%). [HP-SEC]

[0277] The stability of the formulations relative to aggregation (HMW%) was assessed using HP-SEC. After 8 weeks at 25°C and 40°C, F2 and F5 exhibited lower HMW% (Figure 4). [Effectiveness] []

[0278] The potency of the candidate formulations of this invention against IL-36R antibodies was evaluated using conjugation analysis. Notably, even after storage at 40°C for eight weeks, the potency of all six formulations remained stable. [Frozen candidate ingredients] [-] [Thawing stability] []

[0279] The anti-IL-36R antibody solution (1 mL) of the present invention was filled into 2 mL glass vials (1 mL / vial) and frozen at -40°C, followed by thawing at room temperature. This procedure was repeated for a total of 3 cycles. Analysis was performed using the following methods: visual assessment, pH, protein concentration, HP-SEC, non-reducing CGE, and microscopically visible particles.

[0280] It is worth noting that all the results of the analytical method showed that all six formulations performed well. [Stirring stability of candidate formulations] []

[0281] The solution of the anti-IL-36R antibody of this invention was filled into 2 mL glass vials (1 mL / vial). The sample was shaken at room temperature for 48 h. The sample was analyzed by the following methods: pH, protein concentration, visual assessment, HP-SEC, non-reducing CGE, and icIEF.

[0282] Surprisingly, stirring had no effect on the performance of the six formulations in the evaluated analytical results. [Photostability of candidate formulations] []

[0283] Six formulations were filled into 2 mL glass vials (1 mL / vial), sealed, and capped. The vials were placed at room temperature under light intensity of approximately 1100 lux for 5 days. The samples were analyzed using the following parameters: visual assessment, protein concentration, pH, HP-SEC, icIEF, and non-reducing CGE.

[0284] Visual assessments, pH, protein concentration, icIEF, and non-reducing CGE results showed that exposure had no effect on any of the tested formulations.

[0285] A slight effect on the main peak content was observed in HP-SEC, but the decrease in F5 was minimal after 5 days at room temperature and exposure (Table 5). In principle, all formulations were unexpectedly stable to exposure. [surface] [5] [:] [By] [HP-SEC] [Of] [The Pinnacle of Optical Stability Research] [%] [] [Ingredients] [F1] [F2] [F3] [F4] [F5] [F6] 5 days, with light 99.0 99.0 98.8 99.0 99.4 98.9 [Overview of the final formulation screening study] []

[0286] Surprisingly, evaluation of data from the eight-week accelerated stability study showed that all formulations performed equally well in various analyses. The only exception was that, for high molecular weight species, formulations F2 and F5 showed slightly greater stability than the other formulation after eight weeks of storage, particularly at 25°C and 40°C. This indicates that arginine has a positive effect by reducing protein-protein interactions of the anti-IL-36R antibody of this invention, thereby reducing aggregation tendency. Furthermore, F5 showed slightly less loss of the main peak in the exposure study. [Example] [5] [] [Viscosity of different proteins and formulations] []

[0287] The lower viscosity of protein formulations is particularly advantageous for home use and self-administration by patients. Protein solutions with lower viscosity can be injected comfortably. Furthermore, due to the low viscosity, finer syringe needles can be used while still maintaining acceptable injection force. The finer needle also reduces injection pain.

[0288] However, high-concentration protein solutions typically exhibit high viscosity.

[0289] Viscosity data for different proteins and formulations at 20°C are shown in Figure 5. Data were generated using a Thermo Scientific Haake rheometer (Mars III) and plate-cone measurement geometry. Examples of different proteins with concentrations ranging from 145 to 189 mg / mL are included. Data are shown on the X-axis as protein concentration increases. Additionally, viscosity data for anti-IL-36R antibody at 60 mg / mL is presented illustratively to demonstrate the effect of protein concentration on viscosity (lower protein concentrations result in lower viscosity). Compared to typical high-concentration protein solutions, the anti-IL-36R antibody solution exhibits a surprisingly low viscosity value. [Example] [6] [] [Long-term stability study of the final formulation] []

[0290] Two formulations (Table 6) were selected for testing in a long-term stability study. The two formulations containing the anti-IL-36R antibody of this invention were stored at 5°C for at least 30 months. [surface] [6] [Composition of formulations used in long-term stability studies] [] [Ingredients] [Anti-IL-36R] [Antibody Concentration] [sugar] [Surfactants] [Buffer] [pH] [Other excipients] F1 20 mg / mL 200 mM sucrose 0.04% Polysorbate 80 25 mM citrate 6.5 NA F2 150 mg / mL 150 mM sucrose 0.04% Polysorbate 20 45 mM Acetate 5.5 25 mM arginine HCl

[30] [Monthly Stability Study] []

[0291] The stability of each formulation was monitored at 0, 1, 3, 6, 9, 12, 18, 24, and 30 or 36 months. Samples were analyzed by the following assays: microscopic visible particles, HP-SEC, IL-36R binding (potency), non-reducing CGE (capillary gel electrophoresis for detecting fragments), and icIEF (imaging capillary isoelectric focusing for measuring charge variants). [] [Microscopically visible particles] [(SVP)]

[0292] Monitoring of microscopically visible particles in candidate formulations was performed using flowing light shielding. Surprisingly, low numbers of particles with diameters of 10 to 25 µm or larger were observed in both F1 and F2 samples stored at 5°C for 30 months or at least 30 months (data not shown). [icIEF]

[0293] The general charge characteristic curves of the anti-IL-36R antibody of this invention exhibit acidic, basic, and main peak groups. After storage at 5°C for at least 30 months, the charge characteristic curves of both F1 and F2 showed minimal changes (data not shown). [Non-reducible] [CGE] []

[0294] To assess the fragmentation and disulfide bond reduction of the anti-IL-36R antibody formulation of the present invention during storage, the results of non-reducing capillary gel electrophoresis were evaluated. For both F1 and F2, very low levels of fragmentation and disulfide bond reduction (LMW%) were observed after storage at 5°C for at least 30 months (data not shown). [HP-SEC]

[0295] The stability of the formulations relative to aggregation (HMW%) was assessed using HP-SEC. Surprisingly, F1 and F2 exhibited extremely low HMW% after being stored at 5°C for at least 30 months (Figure 6). [Effectiveness] []

[0296] The potency of the anti-IL-36R antibodies of the candidate formulations of this invention was evaluated using conjugation analysis. Notably, the potency of F1 and F2 remained stable even after storage at 5°C for at least 30 months (data not shown). [Overview of Long-Term Stability Studies] []

[0297] Evaluation of data from a 30-month stability study showed that both F1 and F2 performed equally well in various analyses. Notably, the formulations exhibited extremely low HMW content after storage for at least 30 months. [Example] [7] [] [Accelerated Stability Study] []

[0298] Two formulations (Table 7) were selected for stability studies under stress conditions. The two formulations containing the anti-IL-36R antibody of this invention were kept in 10 mL glass vials (8 mL / vial) at 40°C for up to three months. Formulation F2 indicates that it can be used for non-enteral administration with the reference formulation. [surface] [7] [Composition of formulations used to accelerate stability studies] [] [Formulation Matrix] [Ingredient F1] [Ingredient F2] Anti-L-36R antibody concentration 60 mg / mL 60 mg / mL Acetate 45 mM 0 mM citrate 0 mM 25 mM sucrose 150 mM 0 mM L-arginine HCl 25 mM 0 mM PS20 0.04% (w / v) 0.04% (w / v) pH 5.5 6.5 [Turbidity] []

[0299] The stability of the two formulations was monitored at 0, 1, and 3 months. Samples were analyzed by measuring turbidity. Turbidity was analyzed using a Hach Lange TL2350 turbidimeter at 400 to 600 nm using 90° light scattering. The data are shown in Figure 7. Formulation F2 showed at least twice the turbidity of formulation F1. Formulation F1 unexpectedly exhibited extremely low turbidity over a period of up to three months from the initial sampling point. [] [HP-SEC]

[0300] The stability of the formulations relative to aggregation (HMW%) was assessed using HP-SEC. Data are depicted in Figure 8. Surprisingly, formulation F1 exhibited a very low HMW% compared to the reference formulation F2, over a study period of up to three months from the initial sampling point. The reference formulation F2 had an HMW% at least 45% higher than formulation F1. [Overview of Accelerated Stability Studies] []

[0301] Evaluation of data from a three-month stability study under stress conditions at 40°C showed that the turbidity of reference formulation F2 was at least twice that of formulation F1. Furthermore, compared to reference formulation F2, formulation F1 exhibited extremely low HMW over a study period of up to three months from the initial sampling point. [Example] [8] [] [Stability of freeze-dried formulations] []

[0302] The stability of the lyophilized formulations was assessed using a standard lyophilization process in 6 mL glass vials containing 2.5 mL of anti-IL-36R antibody formulations (Table 8). Samples were stored at 40°C for up to 6 months. [surface] [8] [Composition of ingredients] [] [Anti-IL-36R] [Antibody Concentration] [sugar] [Surfactants] [Buffer] [pH] [Other excipients] 60 mg / mL 160 mM sucrose Polysorbate 20, 0.02% (w / v) 25 mM histidine 6.0 20 mM mannitol

[0303] The stability of the formulation was monitored before freeze-drying, immediately after freeze-drying and reconstitution, and after storage at 40°C for 1, 3, and 6 months. Samples were analyzed using the following methods: turbidity, microscopic particle count, and aggregate content as measured by HP-SEC. [] [Turbidity] []

[0304] Turbidity was measured using a Hach Lange TL2350 turbidimeter by 90° light scattering (ʎ=400 to 600 nm). The tested formulations exhibited low turbidity unaffected by the lyophilization process. Surprisingly, the turbidity value did not increase after 6 months of storage at 40°C (Figure 9). [HP-SEC]

[0305] Furthermore, the stability of the powder formulation relative to aggregation (HMW%) was assessed using HP-SEC. Surprisingly, the freezing concentration and stress at the ice-water interface generated during freeze-drying did not induce protein aggregate formation. Moreover, the powder formulation exhibited extremely low HMW% after storage at 40°C for at least 6 months (Figure 10). [Overview of the stability of freeze-dried formulations] []

[0306] The assessment of data from this study unexpectedly demonstrated the feasibility of lyophilizing the anti-IL36R antibody formulation without any impact on protein quality. Furthermore, subsequent stability studies under stress at 40°C confirmed the exceptional stability of the anti-IL-36R antibody in the aforementioned powder formulation.

[0307] The foregoing description is provided to enable those skilled in the art to practice the various configurations described herein. Although the techniques of the invention have been specifically described with reference to various fi...

Claims

1. A pharmaceutical formulation comprising: a. an anti-IL-36R antibody present at a concentration ranging from 10 mg / mL to 200 mg / mL, wherein the anti-IL-36R antibody comprises a light chain variable region containing an amino acid sequence of SEQ ID NO: 80 and a heavy chain variable region containing an amino acid sequence of SEQ ID NO: 89; b. a buffer present at a concentration ranging from 20 mM to 80 mM, wherein the buffer is an acetate; c. a tonic modulator present at a concentration ranging from 100 mM to 250 mM, wherein the tonic modulator is one or more sugars and / or a polyol containing sucrose or trehalose; d. L-arginine and / or a pharmaceutically acceptable salt thereof present at a concentration of up to 80 mM; and e. polysorbate 20 and / or polysorbate 80 present at a concentration ranging from 0.1 g / L to 1.5 g / L. It exists at concentrations in the range of g / L; wherein the formulation is characterized in that, when in aqueous solution, the pH is in the range of 5 to 7.

2. The pharmaceutical compound of claim 1, wherein the anti-IL-36R antibody comprises a light chain variable region containing the amino acid sequence of SEQ ID NO: 118 and a heavy chain variable region containing the amino acid sequence of SEQ ID NO:

127.

3. The pharmaceutical preparations as requested in item 1 or 2, wherein the preparations are in liquid or powder form.

4. The pharmaceutical formulation of claim 1 or 2, wherein the anti-IL-36R anti-system is present at a concentration of 20 mg / mL, 60 mg / mL, or 150 mg / mL.

5. A pharmaceutical formulation comprising: a. an anti-IL-36R antibody present at a concentration of 60 mg / mL, wherein the anti-IL-36R antibody comprises a light chain variable region containing an amino acid sequence of SEQ ID NO: 80 and a heavy chain variable region containing an amino acid sequence of SEQ ID NO: 89; b. an acetate buffer present at a concentration of 45 mM; c. sucrose and / or trehalose present at a concentration of 150 mM; d. L-arginine or a pharmaceutically acceptable salt thereof present at a concentration of 25 mM; and e. polysorbate 20 present at a concentration of 0.4 g / L; wherein the formulation is characterized in that, when in aqueous solution, the pH is in the range of 5 to 6.

6. A pharmaceutical formulation comprising: a. an anti-IL-36R antibody present at a concentration of 150 mg / mL, wherein the anti-IL-36R antibody comprises a light chain variable region containing an amino acid sequence of SEQ ID NO: 80 and a heavy chain variable region containing an amino acid sequence of SEQ ID NO: 89; b. an acetate buffer present at a concentration of 45 mM; c. sucrose or trehalose present at a concentration of 150 mM; d. L-arginine or a pharmaceutically acceptable salt thereof present at a concentration of 25 mM; and e. polysorbate 20 present at a concentration of 0.4 g / L; wherein the formulation is characterized in that, when in aqueous solution, the pH is in the range of 5 to 6.

7. A pharmaceutical compound as described in any of the claims 1, 2, 5 and 6, wherein the weight molar osmotic concentration of the compound is in the range of 210 mOsmol / kg to 390 mOsm / kg.

8. For any of the pharmaceutical formulations described in claims 1, 2, 5 and 6, less than 5% of the antibody system is present in the formulation in the form of aggregates.

9. Any of the pharmaceutical preparations requested in items 1, 2, 5 and 6, wherein the preparation is sterile.

10. A pharmaceutical compound as described in any of the claims 1, 2, 5 and 6, wherein the compound is stable after freezing and thawing.

11. A pharmaceutical preparation as described in any of claims 1, 2, 5 and 6, wherein the preparation contains water or is reconstituted with water.

12. A pharmaceutical compound as described in any of claims 1, 2, 5 and 6, wherein the compound is in liquid form or has a pH between 5 and 6 when reconstituted with water.

13. A pharmaceutical preparation as described in any of claims 1, 2, 5 and 6, wherein the preparation is a liquid or has a pH of 6 when reconstituted with water.

14. A pharmaceutical compound as claimed in any one of claims 1, 2, 5 and 6, wherein the compound has at least one characteristic selected from the group consisting of: (i) increased shelf life, (ii) better temperature stability, (iii) reduced aggregate formation, (iv) better chemical stability, (v) reduced viscosity, and as compared with a reference compound.

15. A pharmaceutical formulation as claimed in any of items 1, 2, 5 and 6, wherein the formulation has at least one characteristic selected from the group consisting of: (a) a reduced percentage of aggregates as measured by high performance size exclusion chromatography (HP-SEC), (b) a higher percentage of monomers as measured by HP-SEC, (c) a higher percentage of the main peak (less degradation of charge variants) as measured by CEX, (d) a lower percentage of microscopically visible particles such as ≥ 10 µm and ≥ 25 µm, and (e) a lower turbidity value in Formazine Nephelometry Units (FNU) after storage at 40°C, as compared with the reference formulation.

16. A pharmaceutical product comprising a vial or syringe containing a pharmaceutical preparation as claimed in any one of claims 1 to 15.

17. The pharmaceutical product of claim 16 further includes a pre-assembled injection device.

18. The pharmaceutical product of claim 17, wherein the pre-assembled injection device is an auto-injector or a needle safety device.

19. A pre-assembled injection device comprising a pharmaceutical preparation as claimed in any one of claims 1 to 15.

20. The pre-assembled injection device as claimed in claim 19, wherein the device is an auto-injector or needle safety device, or a syringe.

21. The pre-assembled injection device of claim 20, wherein the preparation is suitable for subcutaneous or intramuscular administration.

22. A kit of dispensing components comprising at least one container, the at least one container containing a pharmaceutical preparation and an injection device as claimed in any one of claims 1 to 15.

23. The kit of claim 22, which includes instructions for administering the compound subcutaneously or intramuscularly to an individual or instructions for self-administration subcutaneously or intramuscularly.

24. A pharmaceutical formulation comprising: a. an anti-IL-36R antibody comprising: a light chain comprising an amino acid sequence as listed in SEQ ID NO: 118, and a heavy chain comprising an amino acid sequence as listed in SEQ ID NO: 127; wherein the antibody is present at a concentration of 20 mg / mL, 60 mg / mL, or 150 mg / mL; and b. an acetate buffer present at a concentration of 45 mM; c. sucrose present at a concentration of 150 mM; d. L-arginine HCl present at a concentration of 25 mM; e. polysorbate 20 present at a concentration of 0.4 g / L; and wherein the formulation is characterized by a pH in the range of 5 to 6.

25. A method for preparing a pharmaceutical formulation, comprising: a. culturing mammalian cells encoding one or more nucleic acids of the light and heavy chains of an anti-IL-36R antibody that have been stably incorporated into their genome, such that the cells secrete the antibody into a cell culture medium, and purifying the antibody from the cell culture medium; and b. preparing a formulation as claimed in any one of claims 1 to 15, wherein the anti-IL-36R antibody comprises a light chain variable region containing the amino acid sequence of SEQ ID NO: 80, and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89.

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