TW201221141A - Stabilized formulations containing anti-interleukin-4 receptor (IL-4R) antibodies - Google Patents

Abstract

The present invention provides pharmaceutical formulations comprising a human antibody that specifically binds to human interleukin-4 receptor (hIL-4R). The formulations may contain, in addition to an anti-hIL-4R antibody, at least one amino acid, at least one sugar, or at least one non-ionic surfactant. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability after storage for several months.

Description

201221141 VI. Description of the Invention: [Technical Field to Which the Invention Is Applicable] [_1] The present invention relates to the field of therapeutic antibody formulations, and the present invention relates to a human comprising a conjugated human-4 receptor The field of antibody pharmaceutical formulations. Sequence Listing [0002] This patent specification also contains the phased-character floor. The content of the text is quoted by the person (4). The people's gold ST.25 is in line with the heart of the shop. _ County Finance as part of the specification. [Prior Art] _3] The therapeutic macromolecule (e.g., antibody) must be formulated in a manner that not only enables the molecule to be administered to a patient but also maintains stability in the presence and subsequent use. For example, 'therapeutic antibodies in liquid solutions are prone to degradation, aggregation or poor chemical modification unless the solution is formulated. The stability of the antibodies in the liquid formulation depends not only on the type of excipients used in the formulation, but also on the relative amounts and proportions between the agents. In addition, other factors must be considered in addition to the preparation of the liquid anti-fine product. Examples of such additional considerations include the adaptation of the viscosity of the solution - the visual quality or appeal of the known formulation. Therefore, / ni „ 匕, when formulating a therapeutic antibody requires: Master: to maintain a stable formulation, contain appropriate antibodies, and to have the appropriate viscosity and other properties of this compound to be administered to the patient. [00041] Human interleukin-4 receptor a (an antibody to hIL-4Rc〇 is an example of a therapeutically relevant macromolecule that needs to be properly formulated. Anti-hIL-4R alpha antibody is clinically used to treat or prevent, for example, atopic Dermatitis and allergic asthma, as well as diseases of other conditions. Examples of anti-hIL-4R alpha antibodies have been described in particular in U.S. Patent Nos. 7,605,237, 7,608,693, 7,465,450 and 7,186,809; and U.S. Patent Application Nos. 2010-0047254 and 2010- 0021476 [0005] Although anti-hIL-4Ra antibodies are well known in the art, there is still a need in the art for a novel pharmaceutical formulation containing an anti-hIL-4Ra antibody that is sufficiently stable and suitable for administration to a patient. SUMMARY [0006] The present invention provides a pharmaceutical formulation comprising a human antibody that specifically binds to human interleukin-4 receptor a (hIL-4Rα) to meet the above needs. [0007] In one aspect Provided is a liquid pharmaceutical formulation comprising: (i) a human antibody capable of specifically binding human interleukin-4 receptor a (hIL-4R α ); (ii) a buffer; (iii) an organic help Solvent; (iv) - thermal stabilizer; and (v) - detackifier. [0008] In a particular embodiment, the concentration of the antibody is about 150 mg / ml ± 50 mg / ml. In another embodiment In one embodiment, the concentration of the antibody is about 150 mg/ml ± 15 mg/ml. In a particular embodiment, the concentration of the antibody is about 150 mg/ml. 201221141 [0009] In a particular embodiment, The antibody comprises any one or more amino acid sequences of sequence identification number: 1 to 8. In one embodiment, the antibody comprises (a) a sequence identification number: 2, a sequence identification number: 3, and a sequence identification number: The heavy chain complementation of 4 determines one heavy chain variable region (HCVR) of regions 1, 2 and 3 (HCDR1 - HCDR2-HCDR3); and (b) contains sequence identification number: 6, sequence identification number: 7 and sequence identification number, respectively. The light chain complement of 8 determines a light chain variable region (LCVR) of zones 1, 2 and 3 (LCDR1-LCDR2-LCDR3). In an embodiment, the antibody comprises an HCVR and an LCVR comprising an amino acid sequence of sequence identification number: 1 and sequence identification number: 5, respectively. [0010] In a specific embodiment, the antibody comprises a sequence identification number: 9 Any one or more amino acid sequences of ~16. In a specific embodiment, the antibody comprises (4) a heavy sequence comprising the sequence identification number: 10, sequence identification number: 11 and sequence identification number: 12, heavy chain complementarity determining regions 1, 2 and 3 (HCDR1-HCDR2-HCDR3) Chain variable region (HCVR); and (b) respectively containing sequence identification number: 14, sequence identification number: 15 and sequence identification number: 16 light chain complementarity determining regions 1, 2 and 3 (LCDR1-LCDR2-LCDR3) A light chain variable region (LCVR). In a specific embodiment, the antibody comprises an HCVR and an LCVR comprising an amino acid sequence of sequence identification number: 9 and sequence identification number: 13, respectively. [0011] In a specific embodiment, the antibody comprises any one or more of the amino acid sequences of the sequence identification number: 17-24. In a specific embodiment, the antibody comprises (a) a heavy chain complementarity determining region 1, 2 and 3 (SEQ ID NO: 18, Sequence 6 201221141 Identification Number: 19 and Sequence Identification Number: 20, respectively) (HCDR1-HCDR2- One heavy chain variable region (HCVR) of HCDR3); and (8) contains sequence identification number: 22, sequence identification number: 23, and sequence identification number: 24 light chain complementarity determining regions 1, 2, and 3 (LCDR1-LCDR2-LCDR3, respectively) A light chain variable region (LCVR). In a specific embodiment, the antibody comprises an HCVR and an LCVR comprising an amino acid sequence of sequence identification number: 17 and sequence identification number: 21, respectively. [0012] In a specific embodiment, the pH of the liquid formulation is about 5·9±〇·5. In a particular embodiment, the liquid formulation has a enthalpy of about 5. 9 ± 0.1. In one embodiment, the liquid medical buffer comprises one or more buffers that buffer from about pH 5.6 to about 6.2 6.2. [0013] In a specific embodiment, the liquid pharmaceutical formulation comprises a buffer system comprising at least two buffers. In a specific embodiment, the buffer system comprises a first buffer having an effective pH range of 3.6 to 5.6 and a second buffer having an effective pH range of 5.5 to 7.4. In a specific embodiment, the first buffer has a pKa of about 4.8 ± 0.3 and the second buffer has a pKa of about 6.0 ± 0.3. In a specific embodiment, the first buffer is an acetate buffer and the second buffer is a histidine buffer. In a specific embodiment, the concentration of the vinegar salt is 12.5 ± 1.9 mM and the concentration of histidine is 2 Torr 3 mM. In one embodiment, the organic cosolvent is a nonionic europium molecule containing a polyoxyethylene group. In some embodiments 201221141 the organic cosolvent is any one or more of polysorbate 20, poloxamer 181 and polyethylene glycol 3350. In a particular embodiment, the organic co-solvent is polysorbate 20. [0015] In a specific embodiment, the concentration of the organic cosolvent is from about 0.2% ± 〇. 〇 3% to about 1% ± 〇. 15% "weight by volume, or "w/v", wherein For example, 0.1 g/ml = 1 〇〇 / 0 and 〇 Oi g / ml = 1 〇 / 〇). In a specific embodiment, the concentration of the organic co-solvent is about 0.2% ± 〇 〇 3% w / v of polysorbate 20. [0016] In a specific embodiment, the thermal stabilizer is a sugar. In a particular embodiment, the sugar system is selected from the group consisting of sucrose, mannose, and trehalose. In a particular embodiment, the thermal stabilizer is sucrose.

[0017] In a specific embodiment, the concentration of the heat stabilizer is from about 9.9_.135% to about 〇% ±1 5% w/v. In a specific embodiment, the concentration of the stabilizer is about 5% ± G. In the second embodiment, the de-adherent is selected from the group consisting of secretory, thiocyanate, ammonium silicate, thiolin, and chlorination. In the embodiment of the group consisting of gasification calcium, Wei zinc and B., the detackifying agent b arginine hydrochloride is about 1 〇 [〇〇〇1 2] in the body: 'The concentration of the debonding agent is lower than

=: = 1 - In the example, the concentration of this _ is mM ± 7.5 mM. In each of the counties, the L degree is 25 b + 3 75 _. In the case of = ^, the concentrated detackifying agent of the detacking agent is a concentration of _ + 3 ? ^ a = frequency in the embodiment of the ~. / 5 mM L-spermine hydrochloride. 8 201221141 [0020] In a specific embodiment, the viscosity of the liquid pharmaceutical formulation is less than or specific to about 35 ± 3.5 cpoise. In one embodiment, the delta viscosity is about 21.5 ± 13.5 centipoise, about 11 ± 1.1 apo, or about 8.5 ± 0.85 centipoise. In a particular embodiment, the liquid pharmaceutical formulation has a viscosity of about 8.5 ± 0.85 poise. [0021] In one embodiment, the liquid pharmaceutical formulation has an osmolality of less than about 450 mOsm/kg. In one embodiment, the liquid pharmaceutical formulation has an osmolality of about 290 ± 20 mOsm/kg. [0022] In a specific embodiment, the liquid pharmaceutical formulation can be harvested from the liquid pharmaceutical formulation at least 90% or at least 95% after storage for six months at 5 ° C as determined by size exclusion chromatography. Natural anti-hIL-4Ra antibody. In a specific embodiment, at least 98% of the native antibody can be recovered from the liquid pharmaceutical formulation after storage for six months at 5 °C as determined by size exclusion chromatography. In one embodiment, at least 90% of the native antibody can be recovered from the liquid pharmaceutical formulation after storage for eight weeks at 45 ° C as determined by size exclusion chromatography. [0024] In one embodiment, less than 45% of the acid form of the antibody can be recovered from the liquid pharmaceutical formulation after storage for eight weeks at 45 ° C as determined by cation exchange chromatography. [0025] In one embodiment, less than about 4% of the antibody can be recovered from the liquid pharmaceutical formulation after storage for six months at 25 ° C as determined by size exclusion exchange stratification. In one aspect, a liquid pharmaceutical formulation is provided, comprising: 201221141

(i) about 150 mg/ml ± 50 mg/ml of a human antibody that specifically binds hiL-4R α, wherein the antibody comprises a heavy amino acid sequence containing sequence identification number: 1 and sequence identification number: 5, respectively. Chain variable region (HCVR) and light chain variable region (LCVR); (ii) about 12.5 mg/ml ± 2 mM acetate; (iii) about 20 mM ± 3 mM histidine; (iv) about 5 % ± 0.75% (w / v) of sucrose; (v) about 2% ± 0 · 〇 3% (w / v) of polysorbate 20; and (vi) at about 5.9 ± 0.5 pH Approximately 25 mM ± 3.75 mM arginine. [0027] In a specific embodiment, the liquid pharmaceutical formulation has a viscosity of from about 8.5 ± 0.85 poise to about ΐ ΐ ΐ ΐ ΐ 。. In a specific embodiment, the liquid pharmaceutical formulation has a viscosity of about 8.5 ± 0.85 poise. [0028] In a specific embodiment, the liquid pharmaceutical formulation is physiologically isotonic. In one embodiment, the liquid pharmaceutical formulation has an osmolality of about 290 ± 20 mOsm/kg. In one embodiment, at least 98% of the native anti-hIL-4Ra antibody can be recovered from the liquid pharmaceutical formulation after storage for six months at 5 ° C as determined by size exclusion chromatography. In one embodiment, at least 90% of the native anti-hIL-4Ra antibody can be recovered from the liquid pharmaceutical formulation after storage for eight weeks at 45 ° C as determined by size exclusion chromatography. In one embodiment, less than 45% of the acid form of the antibody can be recovered from the liquid pharmaceutical formulation after storage for 8 weeks at 4 5 Torr as determined by cation exchange chromatography. [0032] In one embodiment, the antibody recoverable from the liquid pharmaceutical formulation is less than about 4% aggregated after storage for six months at 25 ° C as determined by the size exclusion exchange layer 201221141 assay. In one aspect, a stable low viscosity isotonic liquid pharmaceutical formulation comprising at least 1 mg/ml of a stable anti-hIL-4R alpha antibody is provided. In a specific embodiment, the concentration of the antibody is about 150 mg/ml soil 50 mg/m. In a particular embodiment, the concentration of the antibody is about 150 mg/ml ± 15 mg/ml. In a specific embodiment, the antibody comprises any one or more amino acid sequences of sequence identification numbers: 1-8. In a specific embodiment, the antibody comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR/LCVR combination comprises a separate 'J containing sequence 歹 ij identification number: 2_3_4 and sequence Identification number: heavy and light chain complementarity determining regions of the amino acid sequence of 6-7-8 (HCDR1-HCDR2-HCDR3/LCDR1-LCDR2-LCDR3). In a specific embodiment, an HCVR and an LCVR of the anti-hIL-4Ra antibody. [0035] In some embodiments, the viscosity of the formulation is less than 35 ± 3.5 centipoise, less than 20 ± 2 drops, less than 15 ± 1.5 centipoise, or less than 1 ± 1 centipoise . In a particular embodiment, the liquid formulation has a viscosity of about 8.5 ± 2.5 centipoise. [0036] In one embodiment, the formulation has a physiologically compatible molar osmolality. In a particular embodiment, the formulation comprises an osmolality of 290 ± 20 mOsm/kg. In one embodiment, the antibody has a stability of at least about six months at about 5 °C. In a specific embodiment, at least about 98% of the antibody is stored for about six months at 5 ° C as determined by the 201221141 size exclusion chromatography to retain its natural configuration. In one embodiment, the antibody has a storage stability of at least about eight weeks at about 45 °C. In a specific embodiment, at least about 90% of the antibody retains its natural configuration when stored for about eight weeks at 45 ° C as determined by size exclusion chromatography. In a specific embodiment, storage for about eight weeks at 45 ° C is less than about 45 °/ when measured by cation exchange chromatography. It is an antibody in acid form. In one embodiment, the antibody has a storage stability of at least about six months at about 25 °C. In a specific embodiment, about six months of antibody storage at 25 ° C is less than about 4% aggregation when measured by size exclusion chromatography. [0040] In a specific embodiment, the formulation comprises a buffer having a pH of about 5.9 ± 0.5. In one embodiment, the buffer comprises an acetate buffer and a set of amine acid buffers. In a specific embodiment, the acetate concentration is 12.5 mM ± 1.9 mM and the histamine concentration is 20 mM ± 3 mM. In one embodiment, the formulation comprises an organic co-solvent having a concentration of from about 0.2% ± 0.03% to about 1% ± 0.15% w/v. In a specific embodiment, the organic cosolvent is a nonionic polymer containing a polyoxyethylene group. In some embodiments, the organic co-solvent is any one or more of polysorbate 20, poloxamer 181, and polyethylene glycol 3350. In a specific embodiment, the organic co-solvent is a polysorbate 20 having a concentration of about 0.2% ± 0.03% w/v. In one embodiment, the formulation comprises a thermal stabilizer at a concentration of from about 12 201221141 0.9% ± 0.135 ° / 〇 w / v to about 10% ± 1.5% w / v. In a specific embodiment, the thermal stabilizer is sucrose. In a specific embodiment the sugar is selected from the group consisting of sucrose, mannose and trehalose. In a particular embodiment, the thermal stabilizer is sucrose at a concentration of about 5% ± 0.75% w/v. [0043] In one embodiment, the formulation comprises a detackifying agent at a concentration of no more than about 100 mM. In a specific embodiment, the detackifying agent is arginine. In a specific embodiment, the detackifying agent is a concentration of 25 mM ± 3.75 mM L-spermine hydrochloride. [0044] In a particular embodiment, the stabilized low viscosity isotonic liquid pharmaceutical formulation has a viscosity of about 8.5 ± 2.5 centipoise and an osmolality of about 290 ± 20 mOsm/kg, and comprises: (1) 15 〇 An anti-hIL-4Ra antibody of mg/ml ± 15 mg/ml, wherein the antibody comprises an HCVR and an LCVR comprising the sequence identification number: 1 and the amino acid sequence of sequence identification number: 5; (ii) 12.5 mM ± 1.9 mM acetate; (iii) 20 mg/ml ± 3 mM histidine; (iv) 0.2% soil 0.03% w/v polysorbate 20; (v) 5 〇 / 〇 ± 0.75% W/v sucrose; and (vi) 25 mM ± 3.75 mM L-spermine hydrochloride. According to this embodiment, (i) at least about 98% of the antibody retained at 5 ° C for at least about six months when retained by volume exclusion chromatography retains its natural configuration; (η) when by volume At least about 90% of the antibody retained at 45 〇c for at least about 8 weeks when retained by blocking chromatography, retaining its natural configuration; (out) when stored by cation exchange chromatography, stored in a shirt for less than about 45 weeks % is an acid form of the antibody; and (iv) less than about 4% aggregation of the antibody is stored at 25 ° C for about six months when measured by size exclusion chromatography. 13 201221141 [0045] In a - aspect, a liquid pharmaceutical formulation of any of the above aspects of the container is provided. In a particular embodiment, the container is a glass bottle. In another embodiment, the container is a micro-syringe. In another embodiment, the H-series is injected. In a specific embodiment of the mosquito, the syringe comprises a fluorocarbon coated piston. In a specific embodiment, the syringe is a low tungsten syringe. [0046] A specific embodiment of the present invention will be more apparent from the detailed description of the sun and the moon. DETAILED DESCRIPTION OF THE INVENTION [0047] Before the present invention is described, it is to be understood that the invention is not intended to be limited * [0 (M8] Unless otherwise stated, otherwise all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Or a range of values means that the value does not exceed 1% of the stated value. Example &, the expression "about 100" described here includes 99 and ιοί u and all values therebetween (eg 99.1, 99·) 2, 99·3, 99.4, etc.) [0049] Although any similar or identical methods and materials described herein can also be applied to the practice or experiment of the present invention, it is still described below. The present invention is fully described herein by reference to all publications referred to herein. Pharmaceutical Formulations [0050] The statement herein "medical formulation" means at least one active ingredient 201221141 (eg, small molecules, macromolecules, compounds, etc., which exhibit biological effects in humans or non-human animals) and at least one inactive component, and σ, when mixed with the active ingredient and one or more additional inactive It can be therapeutically administered to humans when it is formed into a knife Non-human animal. The term "formulation" herein means a "medical formulation" unless otherwise stated. The invention provides a pharmaceutical formulation comprising at least one therapeutic polypeptide. According to certain embodiments of the invention The therapeutic polypeptide specifically binds to human interleukin-4 antibody a (an antibody or antigen-binding fragment thereof of hIL-4R〇〇. More specifically, the present invention includes (1) specifically binding hIL_4R α human antibody; (ii) monoacetate/histidine buffer system; (out) a nonionic surfactant organic cosolvent; (iv) a carbohydrate thermal stabilizer; and (v) - go Pharmaceutical Formulations for Adhesives. Specific exemplary ingredients and formulations contained in the present invention are described in detail below. Antibodies that specifically bind to hIL-4R [0051] The pharmaceutical formulations of the present invention comprise a specific binding to hIL- Human antibody or antigen-binding fragment thereof of 4R α. The term "hIL-4R α " - as used herein, refers to a human cytokine receptor that specifically binds to interleukin-4 (IL-4). In the specific embodiment, the medicine contained in the invention The antibody in the preparation specifically binds to the extracellular region of hIL-4Ra. An exemplary human IL-4 receptor a (hIL_4R α ) amino acid sequence is described in Sequence Identification No.: 25. hIL-4R<3: antibody The extracellular region described in U.S. Patent Nos. 7,6〇5 237 and 7,608,693 °h IL-4Ra is represented by the amino acid sequence of SEQ ID NO: 26. [0052] The term "antibody" as used herein generally means Containing four polypeptides 15 201221141 bond, two heavy chains (Η) and two light chains (L)# immunoglobulin molecules interconnected by disulfide bonds and their multimers (eg IgM); however, only by weight Immunoglobulin molecules consisting of a chain (ie, no light chain) are also within the definition of "antibody". Each heavy chain comprises a heavy chain variable region (herein referred to as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CHI, CH2 and CH3. Each light chain comprises a light chain variable region (referred to herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises a domain (CL1). The vH and the hypervariable regions, which may be further subdivided into more conserved regions called framework regions (FR), are referred to as complementary decision regions (CDRs). Each VH and VL consists of three CDRs and four FRs from the amino terminus to the slow terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. [0053] Unless otherwise stated, the term "antibody" as used herein shall be taken to include the complete antibody molecule as well as the antigen-binding fragment thereof. The "antigen-binding region" or "antigen-binding fragment" (or simply "antibody region" or "antibody fragment") of an antibody as used herein means retention specificity, binding to WL-4Ra or its epitope (epitope) one or more fragments of an antibody. [0054] As used herein, "isolated antibody" means an antibody that is substantially free of other antibodies having different antigenic specificities (eg, an isolated antibody capable of specifically binding to hIL-4Ra, which is substantially non-specifically bound except for hIL -4Ra antigen antibody). The term "specifically binds" and the like means that an antibody or antigen-binding fragment thereof forms a complex with an antigen which is relatively stable under physiological conditions. Specific binding is characterized by having a dissociation constant of at least about M or higher. Whether the two molecules are specifically and bound to each other has been determined by 201221141 t and includes, for example, dialysis balance method, surface plasmon other γ, etc. However, an isolated antibody that specifically binds hiL-4Ra has π Cross-reactivity, such as _ (homologous genes) from other lines. In the context of the present invention, a hIL 4R =multispecific (bispecific) antibody and one or more additional antigens are considered:, ', specifically bound" hIL_4Ra. In addition, an isolated antibody may be substantially free of other cells. Substances or Chemicals [0056] Examples of anti-Minjiang _4 ft « antibodies incorporated into the pharmaceutical formulations of the present invention are described in us 7, 6 〇 5, 237 and us 7 608, 693, which are incorporated herein by reference.

According to some embodiments of the invention, the anti-hIL_4R a anti-system comprises a heavy chain variable region of one of the igHV 3-9 subtypes and a human IgG1 of the light chain variable region of one of the IGKV 2-28 subtypes (See Barbie and Lefranc, Human Immunoglobulin/c Variable Region (IGKV) Gene and Linker (IGKJ) Fragments, Five X/?· CVz·”. 1998, 15:

171~183; and Scaviner, D. et al., Human immunoglobulin heavy chain, /C and lambda variable regions and protein expression of the junction region, five C7M 1999, 16: 234~240). In some embodiments, the anti-hIL-4Ra comprises at least one amino acid substitution which results in a charge change of the antibody relative to the exposed surface of the germline IGHV 3-9 sequence or the germline IGKV 2-28 sequence. The germline IGHV3~9 and germline IGKV2~28 sequences shown here, as well as the amino acid position designation number and the International Immunogenetics (IMGT) information system, have been described in Lefranc, M.-P. et al., IMGT. ®, International Immunogenomics Information System®, 1 Secret & 37, 17 201221141 D1006~D1012 (2009). In some embodiments, the exposed surface comprises a complementarity determining region (CDR). In some embodiments, the one or more substitutions of the amino acid are selected from the group consisting of (a) a basic amino acid substituted for a native amino acid of CDR2 of IGHV 3 to 9 (eg, at position 58); b) - a native amino acid substituted for the amino acid of IGHV 3 to 9 (as in position 107); and (c) a native amino acid substituted for CDR1 of IGKV 2 to 28 (as in position 33) A combination of a test amino acids. The particular arrangement of an antibody, particularly within the charge distribution of the environmental interface (e.g., CDRs), will result in an unpredictable condition for the stability of the antibody within the solution. In some embodiments, the anti-hIL-4Ra antibody comprises at least one amino acid substitution in the framework of an antibody variable region relative to the germline IGHV 3~9 sequence or the germline IGKV 2-28 sequence A change in torsional strain occurs in the zone. In some embodiments, the one or more substitutions of the amino acid are selected from the group consisting of (a)-proline to the framework region 3 (FR3) of IGHV 3 to 9 (eg, at position 96). Amine acid; and (b) a combination of a non-proline amino acid substituted for a proline in the framework region 2 (FR2) of IGKV 2-28 (as in position 46). Altering the peptide chain specifically refers to the ability of the backbone to affect the CDR and solvent interface to cause an unpredictable condition in the stability of the antibody in solution. [0060] According to some embodiments of the invention, the anti-hIL-4Ra antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) of sequence identification number: 2, an HCDR2 of sequence identification number: 3, and a sequence Identification number: 4 HCDR3. In certain embodiments, the anti-hIL-4Ra antibody or antigen-binding fragment thereof comprises an HCVD sequence number: 2121. [0061] According to some embodiments of the invention, the anti-hIL-4Ra antibody or antigen-binding fragment thereof comprises a light chain (kappa) complementarity determining region (LCDR) of sequence identification number: 6 and a sequence identification number: 7 An LCDR2, and an LCDR3 of sequence identification number: 8 In some embodiments, the anti-hIL-4Ra antibody or antigen-binding fragment thereof comprises an LCVD of sequence number: 5. According to some other specific embodiments of the present invention, the anti-hIL-4Ra antibody or antigen-binding fragment thereof comprises a sequence identification number: a HCDIU of 1〇, an HCDR of sequence identification number: 11, and a sequence identification number: 12. An HCDR3, an LCDiU of sequence identification number: 14, an LCDR2 of sequence identification number: 15, and an LCDR3 of sequence identification number: 16. In certain embodiments, the anti-hIL-4Ra antibody or antigen-binding fragment thereof comprises an HCVD of sequence number: 9 and an LCVD of sequence number: 13. According to some other specific embodiments of the invention, the anti-hIL-4Rα antibody or antigen-binding fragment thereof comprises an HCDR1 of sequence identification number: 18, an HCDR2 of sequence identification number: 19, and a sequence identification number: 20. An HCDR3, an LCD number of sequence identification number: 22, an LCDR2 of sequence identification number: 23, and an LCDR3 of sequence identification number: 24. In certain embodiments, the anti-hIL-4R alpha antibody or antigen-binding fragment thereof comprises an HCVD of sequence number: 17 and an LCVD of sequence number: 21. [0064] Non-limiting exemplary antibodies in the examples herein are referred to as "mAbl". This antibody is also known as H4H098p in US 7,608,693. 201221141 mAbl(H4H098 P) contains a HCVR/LCVR amino acid sequence pair with sequence identification number: i/5, and stands for sequence identification number: 2-3-4/ sequence identification number: 6-7-8 of HCDR1- HCDR2-HCDR3/LCDR1-LCDR2-LCDR3 domain. [0 0 6 5] Another non-limiting exemplary antibody for use in the practice of the invention is referred to as "mAb2." This antibody is also known as H4H083P in US 7,608,693. mAb2 (H4H083P) comprises a HCVR/LCVR amino acid sequence pair with sequence identification number: 9/13, and HCDR1-HCDR2- representing sequence identification number: 10-11-12/SEQ ID NO: 14-15-16 HCDR3/LCDR1-LCDR2-LCDR3 Domain 0 [0066] Yet another non-limiting example antibody for use in the practice of the invention is referred to as nmAb3". This antibody is also referred to as H4H095P in US 7,608,693. mAb3 (H4H095P) comprises An HCVR/LCVR amino acid sequence pair with sequence identification number: 17/21, and HCDR1-HCDR2-HCDR3/LCDR1-LCDR2 with sequence identification number: 18-19-20/SEQ ID NO: 22-23-24 - LCDR3 domain 0 [0067] The amount of antibody or antigen-binding fragment thereof in a pharmaceutical formulation of the invention depends on the particular nature of the formulation and the particular circumstances and uses in which the formulation is intended to be employed. In one embodiment, the pharmaceutical formulation comprises from about 100 ± 10 to about 200 ± 20 mg/ml, from about 110 soil 11 to about 190 ± 19 mg/m, from about 120 ± 12 to about 180 ± 18 mg/m, about 130 ± 13 to An antibody of about 170 ± 17 mg/ml, about 140 ± 14 to about 160 ± 16 20 201221141 mg/ml, or about 150 ± 15 mg/ml Liquid formulation. For example, the formulation of the present invention contains about 90 mg/m, about 95 mg/m, about 100 mg/ml, about 105 mg/ml, about 110 mg/ml, about 115 mg/ml, about 120. Mg/ml, about 125 mg/ml, about 130 mg/ml, about 131 mg/ml, about 132 mg/ml, about 133 mg/ml, about 134 mg/ml, about 135 mg/ml, about 140 mg/ Ml, about 145 mg/ml, about 150 mg/ml, about 155 mg/ml, about 160 mg/ml, about 165 mg/ml, about 170 mg/ml, about 175 mg/ml, about 180 mg/ml, An antibody or antigen-binding fragment thereof that specifically binds hIL-4Ra at about 185 mg/ml, about 190 mg/m, about 195 mg/ml, or about 200 mg/ml.

Excipients and pH

[0068] The pharmaceutical formulations of the invention comprise one or more excipients. The term "excipient" as used herein refers to any non-therapeutic substance that is added to a formulation to provide the desired consistency, viscosity or stabilizing effect. In certain embodiments, the pharmaceutical formulations of the present invention comprise at least one type of organic co-solvent capable of stabilizing the type and amount of the hIL-4R a antibody in a vigorous manner, such as in an oscillating state. In some embodiments, "sting"", 1 means that the aggregated antibody on the total f (on a molar basis) of the antibody is prevented from forming more than 2% during the lag. In some specific examples, the vigorous operation was to oscillate a solution containing the antibody and the organic co-solvent for about 120 minutes. [0070] In some embodiments, the organic co-solvent is a non-ionic watch, such as a silk (oxyethylene). Can be incorporated into the formulation of the invention - mosquitoes - subsurfaces, including, for example, Jushan 21 201221141

Pearitol esters such as polysorbate 20, p〇lyS〇rbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81 ' and polysorbate 85; poloxamers such as poloxamer 181, poloxamer 188, p〇l 〇-xamer407; or polyethylene glycol (PEG). Polysorbate 20 is also known as Tween 20 (TWEEN 20), sorbitol monolaurate and polyoxyethylene sorbitan monolaurate. The poloxamer 181 is also known as the PLURONIC F68. The organic co-solvent content of the pharmaceutical formulations of the present invention will depend on the particular nature of the formulation and the particular circumstances and uses in which the formulation is intended to be employed. In certain embodiments, the surfactant has a surfactant content of from about 0.1% to about 2% to about 2%. For example, a formulation of the invention may contain about 0-09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, about 0.20%, about 0.21%, about 0.22%, about 0.23%, about 0.24%, about 0.25%, about 0.26%, about 0.27%, about 0.28%, about 0.29%' or about 0.30% Polysorbate 20 or poloxamer 181. For example, a formulation of the invention may contain about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0% PEG 3350. An exemplary organic cosolvent that stabilizes the hIL-4R alpha antibody comprises 0.2% ± 0.02% polysorbate 20, 0.2% ± 0.02% polyxamer 18 b or 1% ± 0.1% PEG 3350. The pharmaceutical formulation of the present invention also comprises one or more heat-amplifiers that are capable of stabilizing the type and amount of the hIL-4Ra antibody under heat-stress conditions. 201221141 contains the order d, which means "stable" means = antibody and heat-stable solution are stored in a natural conformational antibody that is greater than about 92% from about hunger to about 28 days. In some embodiments, the stabilization-word means when the antibody and the thermal stabilizer are contained. = less than about 5% of aggregated antibody can be maintained at about 45 Ctfl to about 28 days. _74] In some implementations, the thermal stabilizer is selected from the group consisting of strict sugar, seaweed fresh gansin or its oily - or a sugar alcohol, its content in the formulation will depend on the particular circumstances and the purpose for which the formulation is intended to be used. In certain embodiments, the formulation contains from about 2.5% to about 10%, about 3 % to about 9.5%, about 3.5% to about 9%, about 4% to about 8.5%, about 4.5% to about 8%, about 5% to about 7.5%, about 5.5% to about 7%, or about 6.0% Up to about 6.5% sugar or sugar alcohol. For example, the pharmaceutical formulation of the present invention may contain about 2.5% ± 〇. 375%, about 3 〇 /. + 〇 · 45%, about 3.5% ± 0.825%, about 4 〇. %±〇6%, about 4 0 · 675 〇 / 〇, about 5.0% ± 0.75 〇 / 〇, about 5.5% ± 0.825 〇 / 〇, about 6. 〇〇 / 0 + 0.9%, about 6.5% ± 0.975%, about 7.0 〇 / 〇 ± 1. 〇5%, about 7 1.125%, about 8.0%±1.2%, about 8.5%±1.47%, about 9.0〇/^1.35%, or about ίο.〇%±ι.5% of sugar or sugar alcohol ( Such as botanical, sucrose or mannose. '[0075] The pharmaceutical formulation of the present invention may also contain a buffer or buffer system as a means of maintaining pH and helping to stabilize the hIL-4Ra antibody. In the examples, the term 'stable' means that the solution of the antibody and the buffer is stored at about 45 ° C for up to about 14 days. 8 ^ is maintained below 3. 0% ± 0. 5%. Aggregated antibody. In some embodiments 23 201221141, the term "stable" means that when the solution containing the antibody and buffer is stored at about 25 C for about 6 months, it can be maintained below 3 7%. An aggregated antibody of ±0 5 〇/〇. In some specific embodiments, the term "stable" means that when the solution containing the antibody and buffer is stored for about 45 to as high as about 14 days Determination of at least 95% ± 〇.5% of natural structure by size exclusion chromatography In some embodiments, the term "stable" means that when the solution containing the antibody and buffer is stored at about 25 ° C for up to about 6 months, it can be determined by size exclusion chromatography. Maintain a natural configuration of at least 96 〇 / alumina 0.5% of the carcass. In some embodiments, the term "stabilized" is intended to mean that a solution containing the antibody and buffer is stored at about ((: up to about 14 days, cation exchange chromatography can be maintained at least 62). 〇/〇±0.5% of a neutral conformation antibody. In some embodiments, the term "stable" means cation exchange chromatography when the antibody is contained and buffered at about hunger to about 6 materials. The method maintains a neutral conformational antibody of at least 54% ± 0.5 〇 / 。., Neutral configuration" phono ion exchange touches the antibody portion of the dialysis from the scale, one side of which is more "alkaline" spike and the other The side is more "acidic," a spike. [0076] The pharmaceutical formulation of the invention has a pH of from about 5.2 to about 64. For example, a pharmaceutical formulation of the invention can have a W' about 5.3, about 5.4' A pH of about 5.5, about 5 6 , about 5 7 , about 5 8 , about $ 9 , about 6. 〇 , about 6. about 6.2 , about 6.3 , or about 6.4. In some embodiments , the pH is about 5 3 ± 〇 2, about 5 about 6.0 ± 0 · 2. ♦ %, at least one of the buffer or buffer system partial range [0077] in some embodiments Containing completely overlapping or granules at ρΗ 52~64 24 201221141. In one embodiment, the buffer or buffer system comprises two buffers, the first of which is in the effective pH range of 3.6 to 5.6 and the second In an effective pH range of 5.5 to 7.4. In a particular embodiment, the first buffer has a pKa of about 4.8 ± 0.3 and the second buffer has a pKa of about 6.0 ± 0.3. In some embodiments, The buffer system comprises an acetate buffer and a histidine buffer. In some embodiments, about 1.3 to 1.9 parts of histamine is contained per part of the molar ratio acetate. In some embodiments, each One part of the molar ratio acetate contains about 1.6 ± 0.25 parts of histidine. In certain embodiments, the concentration of the acetate is from about 2.5 mM to about 22.5 mM, from about 3.0 mM to about 22 mM, about 3.5. mM to about 21.5 mM, about 4.0 mM to about 21.0 mM, about 4.5 mM to about 20.5 mM, about 5.0 mM to about 20 mM, about 5.5 mM to about 19.5 mM, about 6.0 mM to about 19.0 mM, about 6.5 mM to About 18.5 mM, about 7.0 mM to about 18.0 mM, about 7.5 mM to about 17.5 mM, about 8.0 mM to about 1 7.0 mM, from about 8.5 mM to about 16.5 mM, from about 9.0 mM to about 16.0 mM, from about 9.5 mM to about 15.5 mM, from about 10.0 mM to about 15.0 mM, from about 10.5 mM to about 14.5 mM, from about 12.5 mM to about 1.875 mM From about 11.0 mM to about 14.0 mM, from about 11.5 mM to about 13.5 Mm, or from about 12.0 mM to about 13.0 mM. In certain embodiments, the concentration of the histamine is from about 10 mM to about 30 mM, from about 11 mM to about 29 mM, from about 12 mM to about 28 mM, from about 13 mM to about 27 mM, about 14 mM. To about 26 mM, from about 15 mM to about 25 mM, from about 16 mM to about 24 mM, from about 17 mM to about 23 mM, from about 18 mM to about 22 mM, or from about 19 mM to about 21 mM. In certain embodiments, the buffer system comprises about 12.5 mM acetate at about pH 5.9 and about 20 mM histidine. The pharmaceutical formulations of the present invention also comprise one or more excipients for maintaining a low viscosity or reducing the viscosity of a formulation containing a high concentration of protein (e.g., > 100 mg/ml protein). In some embodiments, the formulation has a arginine acid content sufficient to maintain the viscosity of the liquid formulation below about 35 cPoise, less than about 30 cPoise, less than about 25 cPise, less than about 20 cPoise, low. At about 15 cPoise, less than about 14 cP 〇ise, less than about 13 cPoise, less than about 12 cPoise, less than about 10 cP 〇ise, or less than about 9 cPoise.

[0079] In certain embodiments, the pharmaceutical formulation of the present invention preferably comprises L-spermine hydrochloride having a arginine concentration of about 25.5% mM, about 50 mM ± 7.5 mM, Or about 1 〇〇 mM ± 15

mM. In certain embodiments, the concentration of the arginine is from about 2 mM to about 30 mM, from about 21 mM to about 29 mM, from about 21.25 mM to about 28.75 mM, from about 22 mM to about 28 mM, about 23 mM to about 27 mM, or about 24 mM to about 26 mM. Representative Formulations [0080] According to one aspect of the invention, the pharmaceutical formulation is a low viscosity, generally physiologically isotonic liquid formulation comprising: (i) specifically binding to hIL-4R[alpha] (eg mAb 1, mAb2 or mAb3 [as above]) human antibodies at a concentration of about 100 mg/ml or higher; (1) a buffer system sufficient to buffer at about pH 5.9 ± 0.6; (iii) especially for use as a thermal stabilizer (iv) an organic solubilizing agent that protects the structural integrity of the antibody; and (V) an amino acid that maintains the viscosity of the subcutaneous injection. [0081] According to a specific embodiment, the pharmaceutical formulation comprises: (1) specifically binding to hIL-4R〇: and comprising a substituted IGhv type 3-9 heavy chain variable region and a substituted IGLV 2-28 light chain. A variable region (eg, mAbl) having a concentration of from about 1 mg/mi to about 2 mg/ml of human IgG1 antibody; (ii) sufficient to buffer acetate and histidine comprising about pH 5.9 ± 0.6. a buffer system; (iii) sucrose as a thermal stabilizer; (iv) a polysorbate as an organic cosolvent; and (v) arginine as a detackifier. [0082] According to a specific embodiment, the pharmaceutical formulation comprises: (1) specifically binding hIL-4R〇: and an HCDR comprising sequence identification number: 2, an HCDR of sequence identification number: 3, and a sequence identification number: 4 An HCDR3, sequence identification number: an LCDR1 of 6, an LCDR2 of sequence identification number: 7, and a human IgG1 antibody of sequence identification number: 8 with an LCDR3 concentration of about 15 mg/ml of soil 25 mg/ml; Ii) an acetate sufficient to buffer about 12.5 mM ± 1.9 mM and a histidine of about 2 mM ± 3 mM at about pH 5.9 ± 0.3; (iii) sucrose at about 5% ± 0.75% w/v; a polysorbate 20 at about 2% ± 〇 〇 w w w/v; and (v) arginine as L-spermine hydrochloride at about 25 mM ± 3.75 mM. Other non-limiting examples of pharmaceutical formulations of the present invention are described elsewhere herein, including the examples described below. Stability and Viscosity of Pharmaceutical Formulations [0084] The pharmaceutical formulations of the present invention generally exhibit a high degree of stability 27 201221141. The term "safety" as used herein with respect to the pharmaceutical formulation means that the antibody within the pharmaceutical formulation maintains an acceptable degree of chemical structure or biological function under defined storage conditions. The antibody contained in a formulation is Storage—After a period of time, the chemical structure or biological function cannot be maintained at 100%, but it is still stable. In some cases, the structure or function of the antibody is maintained at about 90%, about 95% after a period of storage. Approximately 96%, about 97%, about 98%, or about 99°/. can be considered "stable". [0085] The stability can be determined by storing the percentage of natural antibody retained in the formulation, particularly after storage for a period of time. The percentage of native antibodies can be determined, inter alia, by size exclusion chromatography (e.g., size exclusion high performance liquid chromatography [SE-HPLC]). A phrase "an acceptable level of stability" as used herein means a natural antibody that is detectable in the formulation after storage for a given period of time, at least 9 Å. In some embodiments, At least about 90%, 91%, 92%, 93%, 94% '95%, 96%, 97%, 98%, 99%, or 100 can be detected in the formulation after a defined temperature storage period. % of the natural antibody. The defined period of stability is at least 2 weeks, at least 1 month 'at least 2 months, at least 3 months, at least 'solid month, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 1 month, at least p months at least p months, at least 18 months 'at least 24 months, or longer. The defined temperature at which the pharmaceutically acceptable medicinal formulation is determined to be stable can be any temperature - m: to about hunger, for example, stored at about -30 t, about. c, = ^ about generation ~ ^ about ^ about hunger" (four) ^ For example, if - pharmaceutical preparations in η: after storage for 3 months by se_hplc 28 201221141 can be measured greater than about 90%, 95%, 96%, 97% or 98% of the natural antibodies can be considered as stable. If a pharmaceutical formulation is stored at 5 ° C for 6 months, greater than about 90%, 95%, 96%, 97 can be determined by SE-HPLC. % or 98% of the natural antibody can also be considered as stable. If a pharmaceutical formulation is stored at 5 ° C for 9 months, it can be determined by SE-HPLC to be greater than about 90%, 95%, 96%, 97. % or 98% of the natural antibody can also be considered as stable. If a pharmaceutical formulation is stored at 25 ° C for 3 months, it can be greater than about 90%, 95%, 96% or 97 by SE-HPLC. % of the natural antibody can also be considered as stable. If a pharmaceutical formulation is stored at 25 ° C for 6 months, greater than about 90%, 95%, 96% or 97% of the native antibody can be detected by SE-HPLC. It can also be considered as stable. If a pharmaceutical preparation is stored at 25 ° C for 9 months, more than about 90%, 95%, 96% or 97% of the natural antibodies can be detected by se-HPLC. Considered to be stable. [0086] can be borrowed after defining the temperature storage period In particular, the stability of the assay is determined by the method of measuring the percentage of aggregated antibody in the assay, wherein the stability is inversely proportional to the percentage of aggregated antibody formed, in particular by size exclusion chromatography (eg, size exclusion high performance liquid chromatography). Method [SE-HPLC]) Determination of the percentage of aggregated antibodies. As described herein, an acceptable degree of stability, the phrase means that - at a given temperature for a period of time after preparation, up to 5% of the formulation can be made. Poly # antibody. In some specific smears, the degree of acceptable stability means that up to about 5%, 4%, 3%, 2% can be detected in the formulation after a given temperature storage period. , 1%, 〇.5%, or 〇1% of aggregated antibodies. The defined period of time to be stable is at least 2 weeks, at least u months, at least 29 201221141 2 months, at least 3 months, at least 4 Months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 Months, or longer. The defined temperature for a stable susceptable medicinal formulation can be any temperature The degree is from about -80 ° C to about 45 ° C, for example, stored at about -30 ° C, about -20 ° C, about 〇 ° C, about 4 ° C ~ 8 ° C, about 5 ° C, about 25 ° C, or about 45 ° C. For example, if a pharmaceutical formulation is stored at 5 ° C for 3 months, if less than about 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% is measured Aggregation of antibodies can be considered as stability. A pharmaceutical formulation is less than about 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% after storage for 6 months at 5 °C. Aggregation of antibodies can also be considered as stability. A pharmaceutical formulation that is less than about 5%, 4°/〇, 3%, 2%, 1%, 0.5%, or 0.1% of aggregated antibody after 9 months of storage at 5 ° C can also be considered stable. A pharmaceutical formulation that is less than about 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of aggregated antibody after 3 months of storage at 25 °C can also be considered stable. A pharmaceutical formulation that is less than about 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of aggregated antibody after 6 months storage at 25 °C can also be considered stable. A pharmaceutical formulation that is less than about 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of aggregated antibody after storage for 9 months at 25 °C can also be considered as stable. [00 8 7] The stability can be determined, in particular, by measuring the ratio of antibody migration to a more acidic moiety ("acid form") during ion exchange to the major portion of the antibody ("neutral configuration") The sex is inversely proportional to the antibody in the acid form. Without being immersed in theory, deamidation of antibodies can cause the 201221141 antibody to carry more negative charges and therefore be more acidic than non-deaminamide antibodies (see, for example, Robinson, N., Protein Deamination) , corpse see, April 16, 2002, 99 (8): 5283 ~ 5288). In particular, "acidification" or "deamination" antibodies can be determined by ion exchange chromatography (eg, cation exchange high performance liquid chromatography [CEX-HPLC]) as described herein. The phrase "stability" means that up to 45% of the acid form of the antibody can be detected in the formulation after a defined temperature storage period. In some embodiments, an acceptable level of stability means After the temperature has been stored for a period of time, up to about 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2% can be detected in the formulation. , 1%, 0.5% or 0.1% of the acid form of the antibody. The defined period of stability is at least 2 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 Months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or The defined temperature at which the stable susceptable medicinal formulation is determined can be any temperature from about _8 (TC to about 45 ° C, for example stored at about -30. (: Approximately -20. (:, about 0 ° C, about 4 ° C ~ 8 ° C, about 5 ° C, about 25 ° C, or about 45 ° C. For example, a pharmaceutical preparation stored at 5 ° C 3 If measured after month, it is less than about 15%, 14%, 13%, 12%, 1〇〇/0, 9〇/〇, 8%, 7%, 6%, 5%, 4%, 3%, 2 %, 1%, 0.5% or 0.1% of the acid form of the antibody can be considered as stable. A pharmaceutical formulation at 25. (: less than about 18%, 17%, 16% after 3 months of storage) , 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% 31 201221141 The acid form of the antibody can also be considered as stable. A pharmaceutical formulation is less than about 45%, 40%, 35%, 30%, 25%, 20%, 15 after storage for 8 weeks at 45 °C. %, 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% of the acid form of the antibody may also be considered as stable. A pharmaceutical formulation is stored at 40 ° C for 2 weeks. Measured below about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% of the acid form of the antibody may also be considered to be stable. [0088] Other methods may be used to determine the hair It was formulation stability, such as for example in differential scanning calorimetry (DSC) determination of thermal stability, to control the mechanical stability assay agitation method, and turbidity was measured at an absorbance of about 350, or about at 405 nm. For example, a pharmaceutical formulation of the invention may have a change from zero time point OD405 of less than about 405D405 of about 0.05 (eg, 0.04, 0.03, 0.02 after storage for 6 or more months at about 5 ° C to about 25 ° C). When it is 0.01 or lower, it is considered to be stable. The stability of the antibody can also be assessed by determining the biological activity of the antibody or binding to its target affinity. For example, a formulation of the present invention contains an anti-IL-4Rα antibody contained in the formulation after storage for a period of time (for example, 1 to 12 months) at 5 ° C, 25 ° C, 45 ° C, etc. When binding affinity is at least 90%, 95% or higher binding to IL-4Ra, it can be considered as stability. The binding affinity is determined by, for example, ELISA or plasma resonance. The biological activity is measured by the IL-4Ra activity assay, for example, by directing IL-4Ra cells to a formulation containing the anti-ILWRa antibody. The binding of such cells to the antibody can be directly determined, for example, via FACS analysis. Alternatively, the downstream activity of the IL-4Ra system is determined in the presence of the antibody and an il_4r 32 201221141 alpha agonist, and the IL-4R〇 without antibody is compared to the activity of the system. In some embodiments, the IL-4Ra can be endogenous to the cell. In other embodiments, the IL-4Ra can be ectopically expressed within the cell. Other methods for determining antibody stability in a formulation are illustrated in the Examples below. [0091] In certain embodiments, the pharmaceutical formulations of the present invention exhibit low to moderate viscosity. As described herein, "stickiness, can be, dynamic viscosity, or “absolute viscosity”. "Dynamic viscosity" is the flow resistance measured by a liquid under the influence of gravity. When two equal volumes of liquid are placed in the same capillary viscometer and flow under gravity, a viscous liquid requires a lower viscosity liquid to flow through the capillary for a longer period of time. For example, if one liquid takes 2 〇 〇 seconds and the other liquid takes 400 seconds to complete its flow, the second liquid is the first two-fold viscosity on a dynamic viscosity scale. "Absolute viscosity" is a product of dynamic viscosity and liquid density (absolute viscosity = dynamic viscosity χ density), sometimes referred to as power or simple viscosity. The dynamic viscosity dimension is L2/T, and the L-system length and T-system time "normal" dynamic viscosity are expressed as PCT (cSt). The SI unit of dynamic viscosity is mm2/s, which refers to 1 cSt. The absolute viscosity is in centipoise (cP). The absolute viscosity of the SI unit is centiples per second (mPa-s), which is 1 cP = l mPa-s. As described herein, a low viscosity liquid formulation of the present invention will exhibit an absolute viscosity of less than about 15 centipoise (ep). For example, the present invention - when the liquid formulation is considered to have, under low viscosity, as measured by standard viscosity measurements, the formulation will exhibit about 15 cP, about 14 cp, about 13 cp _, about 12 cP, about 11 CP, about 1 〇 cP, about 9 cP, about 8 cp, dragging 33 201221141 low absolute viscosity. As described herein, a medium viscosity liquid formulation of the present invention will exhibit an absolute viscosity of from about 35 cp to about 15 CP. For example, a liquid formulation of the present invention, if considered to have "medium viscosity", will exhibit about 34 cP, about 33 cP, about 32 cP, about 31 cP, about 30 cP, about 29 cP, About 28 cP, about 27 cP, about 26 cP, about 25 cP, about 24 cP, about 23 cP, about 22 cP, about 21 cP, about 20 cP, about 19 cP, about is cp, about 17 cP, about 16 cP, or an absolute viscosity of about 15.1 cP. [0093] As described in the examples below, the inventors have unexpectedly discovered that by formulating the antibody from about 25 mM to about 100 mM of arginine, it is possible to obtain a drug containing a south concentration. Low to medium viscosity liquid formulations of hIL-4Ra antibodies (eg, from about 100 mg/ml up to at least 200 mg/ml). 'It has further been found that the viscosity of the formulation can be reduced even more by adjusting the sucrose content to less than about 1%. Containers for administration of the pharmaceutical formulation and method of administration [0094] The pharmaceutical formulation of the present invention can be Implanting any container suitable for storing the drug and his therapeutic composition. For example, the pharmaceutical formulation can be placed into a sealed and sterilized plastic having a defined volume such as a vial, ampoule, syringe, vial or vial or Within the glass container, the formulations of the present invention can be placed into different types of vials such as clear and opaque (e.g., amber) glass or plastic bottles. Likewise, any type of syringe can be used to accommodate or otherwise administer the pharmaceutical formulation of the present invention. [0095] The pharmaceutical formulation of the present invention can be placed into a "n-tungstate" syringe or a "low tungsten" syringe. As is familiar to those skilled in the art, 34 201221141 solution, manufacture The process of the glass cylinder typically involves the use of a hot tungsten strip as a penetrating glass to create a small hole through which the liquid can be drawn from the barrel. This process results in a trace amount of tungsten deposited on the inner surface of the barrel. Use washing and other processing steps to reduce the amount of cranes in the syringe. As described here, "Nandurate " A 5 Sisixin syringe contains more than 500 billion fractions (ppb) of cranes. , low tungsten ingenuity means that the syringe contains less than 500 ppb of tungsten. For example, a low tungsten syringe according to the present invention may contain less than about 49 〇, 480, 470, 460, 450, 440, 430, 420. Cranes of 410, 390, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 1 or less ppb. [0096] A rubber plunger for the syringe and a rubber stopper for closing the opening of the vial can be coated to avoid contamination of the syringe or the drug in the bottle, or to preserve its stability. Thus, the pharmaceutical formulation of the present invention according to certain embodiments can be placed in a syringe containing a coated plunger or in a glass bottle sealed with a rubber stopper. For example, the plunger or rubber stopper can be coated with a fluorocarbon film. Examples of coated plungers or rubber stoppers for use in glass bottles and syringes containing the pharmaceutical formulations of the present invention are described in U.S. Patent Nos. 4,997,423, 5,908,686, 6,286,699, 6,645,635 and 7,226,554, the entire contents of each of this. Special coated rubber plungers and rubber stoppers used in the present invention are available from West

The market for Pharmaceutical Services (Lionville, PA) "FluroTec®". [0097] According to some embodiments of the invention, the pharmaceutical formulation can be placed into a low crane syringe containing a fluorocarbon coated piston. The pharmaceutical formulation can be administered to a patient via an enteral route such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) or transdermal, mucosal, nasal, pulmonary or buccal administration. Many portable injection pens or automatic injection infusion devices can be used for subcutaneous infusion of the pharmaceutical formulations of the present invention. Examples include, but are not limited to, AUTOTINTM (Owen Mumford, Woodstock, UK), DISETRONICTlv^ (Disetronic Medical, Bergdorf, Switzerland), HUMALOG MIX 75/25TM pen, HUMALOGTM pen, HUMALIN 70/30 pen (Indianapolis, Indiana) City Eli Lilly), NOVOPENTM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIORTM (Novo Nordisk, Copenhagen, Denmark), BDTM pen (Becton Dickinson, Franklin, New Jersey), OPTIPENTM , OPTIPEN PROTM > OPTIPEN STARLETTM, and OPTICLIKTM (Sanofi-Aventis, Frankfurt, Germany). Examples of portable injection pens or automatic injection infusion devices that have been used for subcutaneous infusion of the pharmaceutical compositions of the present invention include, but are not limited to, SOLOSTARTM (Sanofi-Aventis), FLEXPENTM (Novo Nordisk), and KWIKPENTM (Eli Lilly); SURECLICKTM autoinjectors (Amgen, Thousand Oaks, Likou), PENLETTM (Haselmeier, Stuttgart, Germany), EPIPENTM (Dey, LP), and HUMIRATM (Abbott Laboratories, Abbott Park, Ill.). [0099] The pharmaceutical formulations of the present invention are also infused herein using a microsyringe. As used herein, "microinjector" means slow administration of large amounts (e.g., up to about 2.5 ml or more) for long periods of time (e.g., about 10, 15, 20, 25, 30 minutes or longer). A subcutaneous infusion set of the formulation. See, for example, 36 201221141 US 6,629,949, US 6,659,982; and Meehan et al., J. 匸〇«卜〇//^/^/ deduct this 46:107~116 (1996). Microinfusions are best suited for infusion of large doses of therapeutic proteins, or viscous solutions, at high concentrations (eg, about 100, 125, 150, 175, 200 mg/ml, or higher). [0100] In one embodiment, the liquid pharmaceutical formulation containing about 150 ± 15 mg/ml of anti-IL-4Ra antibody is administered subcutaneously from a prefilled syringe in an autoinjector at a volume of about 1 ± 0.15 ml. In another specific embodiment, the formulation is administered from a microsyringe in a volume of between about 1 ml and 2.5 ml. The formulation can be prefilled into a pouch or cartridge of a microsyringe. Therapeutic Uses of Emirates Formulations [0101] The pharmaceutical formulations of the present invention are particularly useful for treating, preventing or ameliorating any disease or disorder associated with IL-4 activity, including a disease or disorder that is activated. Non-limiting exemplary diseases and disorders that can be treated or prevented by administration of the pharmaceutical formulations of the invention include various allergic diseases such as atopic dermatitis, allergic conjunctival, allergic rhinitis, asthma, and other IgE/ Th2-mediated disease. Therefore, the present invention includes a method for treating, preventing or ameliorating the tongue with the IL_4 disease, including any of the above-mentioned exemplary diseases, disorders, and diseases t/(4). The treatment method of the present invention The body: == Ra antibody formulation is administered to the organism, the organism of the organism can be, for example, such a treatment is required:: either a heterozygous or a heterozygous or an eight-cheek or non-human animal. For example, the organism 37 201221141 The subject may be an individual diagnosed or considered to be at risk of developing the above mentioned diseases or disorders. The present invention further comprises any of the pharmaceutical formulations disclosed herein for use in the manufacture, prevention or amelioration of IL-4 Use of any disease or disorder associated with activation or IL_4Ra activation, including any of the above-described exemplary diseases, disorders, and conditions. [Embodiment] [0103] The following examples provide a method of how to make and use the present invention and those skilled in the art. A complete disclosure and illustration of the composition, and not intended to limit the scope of the invention to the inventor. Although efforts have been made to ensure the accuracy of the numbers used (eg, quantity, temperature, etc.), some experiments are still possible. b Some errors and deviations occur ◎ Unless otherwise stated, the fractions are molar purity, the molecular weight is the average molecular weight, the temperature is in degrees Celsius, and the force is at or near atmospheric pressure. [0104] Activities to form preliminary formulations It relates to screening organic solvating agents, thermal ampoules and buffers in liquid formulations of mAbl (anti-IL-4R α antibody of the invention) to confirm that the excipients are compatible with proteins and contribute to their stability, The osmolality and the viscosity for subcutaneous injection can be maintained. The buffer conditions are also checked to determine the optimum pH for the highest protein stability. Example 1. Organic cosolvent [0105] mAbl has been found to be unstable at oscillating tracking The loss of protein and the increase of agglutinating protein when mAbl was shaken at room temperature were confirmed by reversed-phase liquid chromatography (RP_HPLC) and size exclusion high performance liquid chromatography (SE-HPLC). Table 1, see, no cosolvent " number 38 201221141 and RP-HPLC measured protein degradation (Table 1). However, it has been found that the addition of some organic cosolvents will reduce the thermal stability of mAbl (Table 2). Found to contain PEG 3350 (3%) Formulations of PEG 300 (10% and 20%) will lose the recovered protein as measured by rP_HPLC after heat compression (Table 2). In addition, PLURONIC F68 (poloxamer 181) (0.2%), PEG 300 (10% and Formulations of 20%) and propylene glycol (20%) formed more aggregates measured by SE-HPLC than formulations without solvent. 卩〇1>^〇1^316 20(0.2%) and 卩〇1&gt ;^〇1^&16 80 (0.2%) is quite stable to oscillation and heat stress. [0106] According to Table 1, 0.3 ml of mAbl in a 2 ml glass vial at 15 mg/ml in 10 mM acid salt pH 6.0 and various organic co-solvents were shaken for about 120 minutes. The optical density (OD) at 405 nm was measured for turbidity and the relative change in OD of the starting material at 405 nm was compared. The percentage of native and aggregated mAbl was determined by size exclusion HPLC (SE-HPLC). The SE-HPLC results shown in the "Starting Materials" table are the average of the various formulations that were not shaken. Table 1 Organic cosolvent appearance Turbidity pH Total mAbl% (RP-HPLC) Natural mAbl% (SE-HPLC) Aggregation mAbl% (SE-HPLC) Starting material 2 (not oscillated) Qualified 0.00 6.0 100 96.8 1.8 No solvent Failure 0.87 6.0 86 95.6 3.5 0.2% Polysorbate 20 Qualified 0.01 5.9 98 97.0 1.7 0.2% Polysorbate 80 Qualified 0.00 5.9 100 96.6 2.0 0.2% Pluronic F68 Qualified 0.00 5.9 99 96.9 1.7 3% PEG 3350 Qualified 0.00 6.0 102 96.7 2.0 1% PEG 3350 Qualified 0.01 6.0 99 96.8 1.8 20% PEG 300 Qualified 0.01 5.9 101 96.1 2.6 10% PEG 300 Qualified 0.01 6.0 100 96.7 2.0 20% propylene glycol qualified 0.00 6.0 101 96.7 2.0 39 201221141 [0107] According to Table 2, 2 ml glass bottle 0.3 ml of mAbl in mg/ml of l〇mM hydrate pH 6.0 and various organic co-solvents were stored at about 45 ° C for about 28 days. The optical density (0D) at 405 nm was measured for turbidity and the relative change in OD of the starting material at 405 nm was compared. The percentage of total recovered mAbl was determined by reverse phase HPLC (RP-HPLC). The percentage of native and aggregated mAbl was determined by size exclusion HPLC (SE-HPLC). The SE-HPLC results shown in the "Starting Materials" table are the average of the formulations that were not subjected to heat stress. Table 2 Organic cosolvent appearance turbidity PH total mAbl% (RP-HPLC) Natural mAbl% (SE-HPLC) Aggregation mAbl% (SE-HPLC) Starting material (not accelerated) Qualified 0.00 6.0 100 96.8 1.8 Non-solvent qualified 0.00 6.2 98 94.9 3.5 0.2% Polysorbate 20 Qualified 0.00 6.3 98 94.6 3.6 0.2% Polysorbate 80 Qualified 0.00 6.2 97 94.3 3.8 0.2% Pluronic F68 Qualified 0.00 6.2 96 93.0 5.1 3% PEG 3350 Qualified 0.00 6.2 73 96.5 1.4 1% PEG 3350 Qualified 0.01 6.0 ___ 97 94.6 3.8 20% PEG 300 Qualified 0.04 — 4.5 74 8.5 87.5 10% PEG 300 Qualified 0.02 4.8 93 57.7 38.1 20% propylene glycol qualified 0.00 6.3 97 93.6 4.7 Example 2. Thermal stabilizer [0108] Check various thermal stabilizers For example, the ability of sugars, amino acids, and inorganic salts to degrade in one of the hungers. A summary of the research on thermal stabilizers is shown in Table 3. Formulations containing sugar or sea sugar are more stable (as determined by SE-muscle C) when cultured in a high temperature solution. Because - has been used for long-term preparation of monoclonal antibodies 201221141 The safety history of the substance was chosen as a stabilizer. [0109] According to Table 3, 3 ml of a 2 ml glass vial was stored at 25 mg/ml of mAbl in 1 mM NaOH salt pH 5.3 and various heat stabilizers were stored at about 45 ° C for about 28 days. The optical density (OD) at 405 nm was measured for turbidity and the relative change in OD of the starting material at 4〇5 mn was compared. The turbidity difference can be ignored for all samples. The percentage of total recovered mAbl was determined by reverse phase HPLC (RP-HPLC). The percentage of native and aggregated mAbl was determined by volume exclusion HPLC (SE-HPLC). An acidic or basic substance is defined as the total amount of mAbl peaks that are diafiltered from the cation exchange (CEX-HPLC) column earlier than the main peak or at a later residence time. The SE-HPLC results shown in the "Starting Materials," table are the average of the formulations that are not subjected to heat stress. Buffer and pH Total mAbl% Natural mAbl% Aggregation mAbl% % mAbl (CEX-HPLO ρη rRP-HPLC (SE-HPL. (SE-HPLC) Acid peak main peak basic peak starting material (not cultured at 45 ° C) 5.3 100 97.8 1.2 17.6 68.2 13.2 No heat stabilizer 5.4 106 91.9 5.8 28.1 56.5 15.4 " 8.5% sucrose 5.4 105 93.3 4.6 29.5 54.7 15.8 4.5% sorbitol 5.3 105 91.2 6.6 34.4 51.5 14.1 4.5% mannitol 5.3 104 92.6 5.2 28.4 56.0 15.6 9.4% dihydrate trehalose 5.4 103 93.4 4.5 29.1 55.6 15.3 2.2% glycine 5.4 104 86.6 10.6 33.5 50.7 15.8 0.9% sodium chloride 5.4 98 85.0 8.7 25.2 56.0 18.7 2.5% glycerol 5.4 104 91.9 6.0 29.7 56.1 ~ Ϊ 4.3 5% arginine 5.4 97 83.2 11.4 25.3 57.1 17.6

Example 3. Buffer and PH

[0110] The effect of pH and buffer type on the stability of mAbl was also examined. The mAbl of 15 mg/ml was incubated with different buffers at different pH values ranging from pH 4.5 to 7.0. Protein stability was monitored by SE-HPLC and cation exchange HPLC (CEX-HPLC). The maximum protein stability as determined by SE-HPLC and CEX-HPLC was obtained when ^Abl was equilibrated with pH 6_0 histidine buffer or pH 5_3 acetate buffer (Table 4 and Table 5). The acetate buffer system has a broader pH stability range and a lower rate of variation charge formation relative to formulations containing histidine buffer (Table 5). Therefore, a pH 5.3 acetate buffer was selected for the formulation of the m Ab 1 drug. [0111] According to Table 4', 10 mM of each buffer was mixed with 3 ml of a 15 ml/ml mAbl, 0.2% polysorbate 20 2 ml glass vial at about 45 ° C for about 14 days. The optical density (〇d) at 405 nm was measured for turbidity and the relative change in the 0D of the starting material at 405 nm was compared. The turbidity difference can be ignored for all samples. The percentage of total recovered mAbl was determined by reverse phase HPLC (RP-HPLC). The percentage of native and aggregated mAbl was determined by size exclusion HPLC (SE-HPLC). An acidic or basic substance is defined as the total amount of mAbl peaks that are dialyzed from the cation exchange (CEX-HPLC) column earlier than the main peak or at a later residence time. The SE-HPLC results shown in the "Starting Materials" table are the average of the formulations that are not subjected to heat stress. Table 4 Buffer and pH Total recovery mAbl% (RP-HPLC) Recovery of natural mAbl% (SE-HPLC) Recovery of aggregated mAbl% (SE-HPLC) Recovery of %111 in!) 12 ~ (CEX-HPLC) Acid peak main peak base Starting material of the peak ^ (not cultured at 45 ° C) 100 96.8 1.7 19.1 66.4 14.5 Phosphate, pH 7.0 97 93.9 4.5 39.1 50.1 10.8 Phosphate, pH 6.5 96 94.4 4.0 31.7 55.9 12.5 Phosphate, pH 6.0 99 95.2 3.1 23.8 62.2 14.〇~ 42 201221141

According to Table 5, various buffers of i mM were mixed with 3 ml of 15 mg/ml mAbl, 〇·2〇/. The 2 ml glass vial of p〇iyS〇rbate 2〇 was stored at approximately 45 ° C for approximately 14 days. The optical density (OD) at 405 nm was measured for turbidity and the relative change in starting material at 405 nm 〇D was compared. The turbidity difference can be ignored for all samples. The percentage of total recovered mAb oxime was determined by reverse phase HPLC (RP-HPLC). The percentage of native and aggregated mAbl was determined by volume exclusion HPLC (SE-HPLC). An acidic or a test substance is defined as the total amount of mAbl peaks that are diafiltered from the cation exchange (CEX-HPLC) column earlier than the main peak or at a later residence time. The SE_HPLC results shown in the "starting materials" table are the average of the formulations that are not subjected to heat stress. The formulation formation test showed that the mAbl in the solution could be deamidamine under the conditions of the assay (pH > 6.5). Conversely, below pH 5 已, a rate of mAbl that increases the molecular weight of the variant has been found to increase. Based on these data, the pH of the mAbl formulation was maintained between about pH 5.6 and pH 6.2. It has been found that mAbl can be stably present in this pH range. Table 5 Buffer and pH Total recovery mAbl% iRP-ΤΤΡϊ C\ Recycled natural mAbl% (SE-HPLC) Recovered aggregated mAbl% (SE-HPLC) Recovered natural mAbl% .. (CEX-HPLC1 Acid peak main peak starting material 3 (Not cultured at 45 ° C) 100 96.5 2.1 18.7 66.7 14.6 Histamine, pH 5.5 94 87.5 9.1 ~ 22.7 58 7 1}Γ2 ι 〇.〇---- 43 201221141 Histamine, pH 6.0 100 96.6 2.4 22.7 63.0 14.2 Histamine, pH 6.5 97 89.8 7.7 32.1 43.8 24.0 Acetate, pH 4.7 90 90.1 6.4 18.4 66.1 15.5 Acetate, pH 5.0 100 93.7 4.3 18.0 67.0 15.0 Acetate, pH 5.3 99 95.2 3.0 18.1 67.5 14.5 Acetate, pH 5.6 100 93.6 5.3 22.1 61.7 14.3 [0114] Further evaluation of the formulation containing 20 mM histidine pH 6, 12.5 111] acetate acetate 115.3 or mixed 2〇111]^ histidine and 12.5 acetate pH 5.9 pH And the effect of the buffer type on the stability of mAbl (Table 6). Comparing the individual buffer systems, the formulation contains histidine and the mAbl of about pH 5.9 acetate is most stable. When mAbl is formulated in this mixing buffer system (SE- HPLC has the slowest rate of aggregation (Table 6). Table 6 Buffer and pH total Recovery mAbl% (RP-HPLC) Recovery of natural mAbl% (SE-HPLC) Recovery of aggregated mAbl% (SE-HPLC) Recovery of natural mAbl%2 (CEX-HPLC) Acid peak main peak Basic peak Starting material 3 (not 45° C culture) 100 97.0 2.6 27.4 62.1 10.5 20 mM histidine » pH 5.5 100 95.2 4.3 34.8 53.9 11.4 12.5 mM acetate » pH 5.3 103 94.8 4.8 30.9 56.0 13.1 Mix 20 mM histidine and 12.5 mM acetate, pH 5.9 104 95.9 3.7 33.7 54.1 12.1 [0115] According to Table 6, a 2 ml glass bottle was mixed with 0.4 ml of 150 mg/mi mAbl, 1% sucrose, 〇2% P〇lyS〇rbate 2 in various buffers at about 45°. C is kept for about 14 days. The optical density (OD) at 405 nm was measured for turbidity and relative change in specific OD. The turbidity difference can be ignored for all sample starting materials at 405'. The percentage of total recovered mAM was determined by the reverse phase of the 201221141 phase HPLC (RP-HPLC) method. The percentage of pure accumulation by the size exclusion HPLC (SE_Mine C) method. An acidic or basic substance is defined as the total mAbl peak value that is diafiltered from the cation exchange (CEX_HPLC) column to the earlier or later residence time. The se_hplc results shown in the "Starting Materials" table are the average of the formulations that are not subjected to heat stress. Example 4. Control of Viscosity and Tension [0116] Evaluate the viscosity and tension of various excipients mixed with high concentrations of mAbl (ie 15 〇 mg/ml, 175 mg/ml and 200 mg/ml) (expressed as Mohr infiltration) Pressure concentration). The contents of vegetable sugar, sodium carbonate and L-arginine hydrochloride were adjusted to form a low viscosity and physiological isotonic formulation containing a high concentration of mAbl which was easily and comfortably and rapidly infused with a high amount of subcutaneous infusion of mAbl (Table 7). a liquid formulation containing 25 mM arginine, 20 mM histidine, 12.5 mM acetate, 5% (w/v) sucrose, 0.2% (w/v) polysorbate 20 and 150 mg/ml mAbl pH 5.9 ( Formulation A) is the best formulation with low viscosity (about 8.5 cPoise) and physiological isotonic (about 293 mOsm/kg) while still maintaining mAbl stability. Table 7 mAbl (mg/ml) Histamine (mM) Acetate (mM) Arginine (mM) Sodium Chloride (mM) Sucrose (% w/v) pH Viscosity (cPois) Permeation Μ (mOsm/kg) A 150 20 12.5 25 0 5 5.9 8.5 293 B 150 20 12.5 0 0 10 5.9 11 448 C 175 20 12.5 100 0 1 5.9 ~ 8.0 ~ 290 D 175 20 12.5 50 0 5 5.9 ~ 9.5 ~ 370 E 175 20 12.5 0 0 10 5.9 ~ 20 - 440 F 200 20 12.5 100 0 1 5.9 ~ 15 - 290 G 200 20 12.5 0 100 5 5.9 ~ 19.2 - 430 Η 200 20 12.5 100 0 5 5.9 ~ 17 ~ 430 I 200 20 12.5 50 0 5 5.9 ~18 -330 J 200 20 12.5 25 0 5 5.9 ~23 ~290 45 201221141 K 200 20 ] ~440 -1~~~~^ 1 10 | 5.9 I ~35 Example 5·Characteristics of Formulation A [0117] The main degradation pathways in the formation of the mabl liquid formulation are the generation of aggregates, fracture products and charge variants. These degradation products can be reduced by formulating mAbl in a formulation containing pH 5.9 of 20 mM histidine, 12 5 mM acetate, 〇2〇/〇polysorbate 20, 5% sucrose, and 25 mM hydrochloric acid L-arginine. form. These clear, slightly milky white liquid solutions of 150 mg/ml mAbl formulated to be substantially free of macroscopic particles have been found. The formulated mAb I had physical and chemical stability under various pressing conditions (25 ° C and 45 ° C culture) and immediate storage conditions (5 ° C) (Table 8). The mAbl is at 25 ° C (3 months) or 5. (: The appearance was not affected when stored for 6 months. In addition, it was found that the recovery of the pH, turbidity or mAbl of the solution was not affected. After the preparation of mAbl was stored at 25eC for 3 months, the antibody determined by SE-HPLC was not obvious. The degradation of the ground and the degradation by CEX-HPLC was only 3.3% higher. It was found at 45. (: After 8 weeks of storage, the amount of degradation measured by SE-HPLC and CEX-HPLC was increased to show the formation of aggregation and charge variation. The main degradation pathway of mAbl antibody molecule. No degradation was found when the prepared mAbl antibody was stored at 5 ° C for 6 months. Table 8 Tight test" 25 °C storage time • 2 months 3 months 6 months 1 Appropriate appearance of qualified visually qualified turbidity (OD405nm) 0.00 0.00 0.00 0.00 0.01 0.01 pH 6.0 6.0 5.9 19 6.0 6.0 % mAbl (RP-HPLC) 100 97 104 97 102 46 % Natural mAbl (SE-H) PLC) 98ΓΊ 98.2 98.2 98.1 97.8 %mAbl (CEX-HPLC spike) Acidity 14.6 14.7 14.7 16.0 17.6 Main peak testability - 70.7 -----. 14.7 70.5 70.4 69.8 67.4 14.8 14.9 H 14.3 15.0 Tight test 45〇C Storage time 2 4 weeks, 8 weeks, 4 weeks outside Qualified qualified turbidity (01) 405 nmj wide 0.00 0.02 0.03 0.05 pH — L 6.0 6.0 6.0 6.0 % mAbl (RP-HPLO 102 98 100 % natural mAbl (SE-H PLC) 98.1 95.9 94.2 90.5 % mAbl Acid 14.6 20.8 29.9 44.0 (CEX-HPLC spike) Main peak 70.7 64.5 Ί 56.7 45.1 Qualitative 14.7 14.7 13.4 10.9 201221141 [0119] According to Table 8, 〇d = optical density; RP-HPLC = reversed-phase high performance liquid chromatography 'SE -HPLC = = size exclusion high performance liquid chromatography; and CEX-HPLC = cation exchange high performance liquid chromatography. Acidic or test substances are defined as cation exchange (CEX_HPLC) columns are earlier than the main peak or The total amount of mAbi peaks that were dialyzed at a later residence time. Example 6. Vessels [0120] Filter-sterilized mAbl containing formulations have been tested to demonstrate stability. The manufacturing system on the clinical supply uses a microporous MILLIPAK filter device' while the same composition of the filter (micro-Luxex DURAPORE) is used in the laboratory. At least 2.5 ml of 150 mg/ml mAbl, 5% (w/v) sucrose, 25 mM L-arginine, 0.2% (w/v) polysorbate 20, 12.5 mM acetate at pH 5.9 20 mM histidine was filled into a 5 ml glass vial. A 0.5 ml excess formulation was used in a 5 ml vial to ensure that 2.0 ml of the formulation could be withdrawn. This excess and 201221141 are not used to compensate for the degradation during the manufacturing of mAbl or mAbl-containing formulations during the manufacturing period, and the degradation period of the storage lie (shelf life). Length [0122] compared to storage in a glass bottle, when prepared in a polypropylene glycol official, polystyrene, polycarbonate tube, or in a glass bottle containing a stainless steel block, the formulated mAbl (formulation A) Stability is not affected 9)° Table 9 Storage temperature storage ϋ Unstored glass 40°C Storage polystyrene 14 days Polycarbonate Brewed Appearance Approved Qualified Qualified Qualified turbidity (OD at 405 nm) 0.00 0.01 0.01 0.02 0.02 0.01 pH 5.9 5.9 5.7 5.8 5.8 5 9 % mAbl (RP-HPLC) 100 102 103 107 106 102 % natural mAbl (SE-HPLC) 98.4 97.6 I 97.4 97.5 97.5 96.1 % mAbl spike (CEX-HPLC) Acidity 14.8 18.4 19.1 18.4 18.4 20.3 Main peak 70.7 65.8 65.5 66.0 66.5 65.0 Alkaline 14.5 15.8 15.3 15.6 15.1 14.7 [0123] According to Table 9 '150 mg/ml mAbl, pH 5.9, 5% sucrose, 25 mM arginine hydrochloride, 0.2% PS -20, 20 mM histidine, 12.5 mM acetate was stored in various materials at 40 ° C for 14 days. 〇D = optical density; RP-HPLC = reversed-phase high performance liquid chromatography; SE-HPLC = size exclusion high performance liquid chromatography; and CEX-HPLC = cation exchange high performance liquid chromatography. Turbidity was recorded as the difference in turbidity at 405 nm OD compared to the starting material. The acidic or basic substance is defined as the total amount of mAb 1 peak that is dialyzed from the CEX-HPLC column earlier than the main peak or at a later residence time. 48 201221141 Sequence Listing <110> Regeneron Pharmaceuticals, Inc. <120> Stabilization Formulation Containing Anti-Interleukin-4 Receptor (IL-4R) Antibody <130> 6032 <160> 26 <170> Patentln version 3.5 <210> 1 <211> 124 <212> PRT <213> Homo sapiens <400>

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Glu Gin Pro Gly Gly 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr 20 25 30

Ala Met Thr Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ser lie Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 201221141

Ala Lys Asp Arg Leu Ser lie Thr lie Arg Pro Arg Tyr Tyr Gly Leu 100 105 110

Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser 115 120 <210> 2 <211> 8 <212> PRT <213> Homo sapiens <400> 2

Gly Phe Thr Phe Arg Asp Tyr Ala 1 5 <210> 3 <211> 8 <212> PRT <213> Homo sapiens <400> 3 lie Ser Gly Ser Gly Gly Asn Thr 1 5 <210> 4 <211> 16 <212> PRT <213> Homo sapiens <400> 4

Ala Lys Asp Arg Leu Ser lie Thr lie Arg Pro Arg Tyr Tyr Gly Leu 15 10 15 2 201221141 <210> 5 <211> 112 <212> PRT <213> Homo sapiens <400>

Asp lie Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 15 10 15

Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu Tyr Ser 20 25 30 lie Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gin Lys Ser Gly Gin Ser 35 40 45

Pro Gin Leu Leu He Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys He 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gin Ala 85 90 95

Leu Gin Thr Pro Tyr Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys 100 105 110 <210> 6 <211> 11 <212> PRT <213> Homo sapiens 3 <400> 201221141

Gin Ser Leu Leu Tyr Ser lie Gly Tyr Asn Tyr 15 10 <210> 7 <211> 3 <212> PRT <213> Homo sapiens <400>

Leu Gly Ser 1 <210> 8 <211> 9 <212> PRT <213> Homo sapiens <400> 8

Met Gin Ala Leu Gin Thr Pro Tyr Thr 1 5 <210> 9 <211> 118 <212> PRT <213> Homo sapiens <400>

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30

Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 4 201221141 35 40 45

Ser Gly Leu Ser Arg Thr Ser Val Ser lie Gly Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80

Leu Glu Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95

Ala Lys Trp Gly Thr Arg Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser 115 <210> 10 <211> 8 <212> PRT <213> Homo sapiens <400>

Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 11 <211〉 8 <212> PRT <213> Homo sapiens <400>

Leu Ser Arg Thr Ser Val Ser lie 5 5 201221141 <210> 12 <211> 11 <212> PRT <213> Homo sapiens <400> 12

Ala Lys Trp Gly Thr Arg Gly Tyr Phe Asp Tyr 15 10 <210> 13 <211> 107 <212> PRT <213> Homo sapiens <400>

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp lie Ser lie Trp 20 25 30

Leu Ala Trp Tyr Gin Gin Ser Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Asn Val Ala Ser Arg Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Asn Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Val Thr Tyr Tyr Cys Gin Gin Ala Asn Ser Phe Pro lie 6 201221141 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 <210> 14 <211> 6 <212> PRT <213> Homo sapiens <400>

Gin Asp lie Ser lie Trp 1 5 <210> 15 <211> 3 <212> PRT <213> Homo sapiens <400>

Val Ala Ser 1 <210> 16 <211> 9 <212> PRT <213> Homo sapiens <400> 16

Gin Gin Ala Asn Ser Phe Pro lie Thr 1 5 <210> 17 <211> 117 201221141 <212> PRT <213> Homo sapiens <400>

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr lie Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Asn 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Leu Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Glu Gly Arg Gly Gly Phe Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110

Val Thr Val Ser Ser 115 <210> 18 <211> 8 <212> PRT <213> Homo sapiens 201221141 <400> 18

Gly Phe Thr Phe Arg Ser Tyr Gly 1 5 <210> 19 <211> 8 <212> PRT <213> Homo sapiens <400> 19 lie Ser Tyr Asp Gly Ser Asn Lys 1 5 <210> 20 <211> 10 <212> PRT <213> Homo sapiens <400> 20

Ala Lys Glu Gly Arg Gly Gly Phe Asp Tyr 15 10 <210>21 <211> 107 <212> PRT <213> Homo sapiens <400> 21

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Asn Asn Tyr 20 25 30 201221141

Leu Ala Trp Phe Gin Gin Lys Pro Gly Lys Val Pro Lys Ser Leu lie 35 40 45

His Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Ser His Pro Trp 85 90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 100 105 <210> 22 <211> 6 <212> PRT <213> Homo sapiens <400>22

Gin Val lie Asn Asn Tyr 1 5 <210> 23 <211> 3 <212> PRT <213> Homo sapiens <400> 23

Ala Ala Ser 1 10 201221141 <210> 24 <211> 9 <212> PRT <213> Homo sapiens <400> 24

Gin Gin Tyr Asn Ser His Pro Trp Thr 1 5 <210> 25 <211> 825 <212> PRT <213> Homo sapiens <400> 25

Met Gly Trp Leu Cys Ser Gly Leu Leu Phe Pro Val Ser Cys Leu Val 15 10 15

Leu Leu Gin Val Ala Ser Ser Gly Asn Met Lys Val Leu Gin Glu Pro 20 25 30

Thr Cys Val Ser Asp Tyr Met Ser lie Ser Thr Cys Glu Trp Lys Met 35 40 45

Asn Gly Pro Thr Asn Cys Ser Thr Glu Leu Arg Leu Leu Tyr Gin Leu 50 55 60

Val Phe Leu Leu Ser Glu Ala His Thr Cys He Pro Glu Asn Asn Gly 65 70 75 80

Gly Ala Gly Cys Val Cys His Leu Leu Met Asp Asp Val Val Ser Ala 85 90 95 11 201221141

Asp Asn Tyr Thr Leu Asp Leu Trp Ala Gly Gin Gin Leu Leu Trp Lys 100 105 110

Gly Ser Phe Lys Pro Ser Glu His Val Lys Pro Arg Ala Pro Gly Asn 115 120 125

Leu Thr Val His Thr Asn Val Ser Asp Thr Leu Leu Leu Thr Trp Ser 130 135 140

Asn Pro Tyr Pro Pro Asp Asn Tyr Leu Tyr Asn His Leu Thr Tyr Ala 145 150 155 160

Val Asn lie Trp Ser Glu Asn Asp Pro Ala Asp Phe Arg lie Tyr Asn 165 170 175

Val Thr Tyr Leu Glu Pro Ser Leu Arg lie Ala Ala Ser Thr Leu Lys 180 185 190

Ser Gly lie Ser Tyr Arg Ala Arg Val Arg Ala Trp Ala Gin Cys Tyr 195 200 205

Asn Thr Thr Trp Ser Glu Trp Ser Pro Ser Thr Lys Trp His Asn Ser 210 215 220

Tyr Arg Glu Pro Phe Glu Gin His Leu Leu Leu Gly Val Ser Val Ser 225 230 235 240

Cys lie Val lie Leu Ala Val Cys Leu Leu Cys Tyr Val Ser lie Thr 245 250 255

Lys lie Lys Lys Glu Trp Trp Asp Gin lie Pro Asn Pro Ala Arg Ser 12 201221141 260 265 270

Arg Leu Val Ala lie lie Gin Asp Ala Gin Gly Ser Gin Trp Glu 275 280 285

Lys Arg Ser Arg Gly Gin Glu Pro Ala Lys Cys Pro His Trp Lys Asn 290 295 300

Cys Leu Thr Lys Leu Leu Pro Cys Phe Leu Glu His As Met Lys Arg 305 310 315 320

Asp Glu Asp Pro His Lys Ala Ala Lys Glu Met Pro Phe Gin Gly Ser 325 330 335

Gly Lys Ser Ala Trp Cys Pro Val Glu lie Ser Lys Thr Val Leu Trp 340 345 350

Pro Glu Ser lie Ser Val Val Arg Cys Val Glu Leu Phe Glu Ala Pro 355 360 365

Val Glu Cys Glu Glu Glu Glu Glu Val Glu Glu Glu Lys Gly Ser Phe 370 375 380

Cys Ala Ser Pro Glu Ser Ser Arg Asp Asp Phe Gin Glu Gly Arg Ala 385 390 395 400

Gly lie Val Ala Arg Leu Thr Glu Ser Leu Phe Leu Asp Leu Leu Gly 405 410 415

Glu Glu Asn Gly Gly Phe Cys Gin Gin Asp Met Gly Glu Ser Arg Leu 420 425 430 13 201221141

Leu Pro Pro Ser Gly Ser Thr Ser Ala His Met Pro Trp Asp Glu Phe 435 440 445

Pro Ser Ala Gly Pro Lys Glu Ala Pro Pro Trp Gly Lys Glu Gin Pro 450 455 460

Leu His Leu Glu Pro Ser Pro Pro Ala Ser Pro Thr Gin Ser Pro Asp 465 470 475 480

Asn Leu Thr Cys Thr Glu Thr Pro Leu Val lie Ala Gly Asn Pro Ala 485 490 495

Tyr Arg Ser Phe Ser Asn Pro Leu Ser Gin Ser Pro Cys Pro Arg Glu 500 505 510

Leu Gly Pro Asp Pro Leu Leu Ala Arg His Leu Glu Glu Val Glu Pro 515 520 525

Glu Met Pro Cys Val Pro Gin Leu Ser Glu Pro Thr Thr Val Pro Gin 530 535 540

Pro Glu Pro Glu Thr Trp Glu Gin lie Leu Arg Arg Asn Val Leu Gin 545 550 555 560

His Gly Ala Ala Ala Ala Pro Val Ser Ala Pro Thr Ser Gly Tyr Arg 565 570 575

Glu Phe Val His Ala Val Glu Gin Gly Gly Thr Gin Ala Ser Ala Val 580 585 590

Val Gly Leu Gly Pro Pro Gly Glu Ala Gly Tyr Lys Ala Phe Ser Ser 14 201221141 595 600 605

Leu Leu Ala Ser Ser Ala Val Ser Pro Glu Lys Cys Gly Phe Gly Ala 610 615 620

Ser Ser Gly Glu Glu Gly Tyr Lys Pro Phe Gin Asp Leu lie Pro Gly 625 630 635 640

Cys Pro Gly Asp Pro Ala Pro Val Pro Val Pro Leu Phe Thr Phe Gly 645 650 655

Leu Asp Arg Glu Pro Pro Arg Ser Pro Gin Ser Ser His Leu Pro Ser 660 665 670

Ser Ser Pro Glu His Leu Gly Leu Glu Pro Gly Glu Lys Val Glu Asp 675 680 685

Met Pro Lys Pro Pro Leu Pro Gin , Glu Gin Ala Thr Asp Pro Leu Val 690 695 700

Asp Ser Leu Gly Ser Gly lie Val Tyr Ser Ala Leu Thr Cys His Leu 705 710 715 720

Cys Gly His Leu Lys Gin Cys His Gly Gin Glu Asp Gly Gly Gin Thr 725 730 735

Pro Val Met Ala Ser Pro Cys Cys Gly Cys Cys Cys Gly Asp Arg Ser 740 745 750

Ser Pro Pro Thr Thr Pro Leu Arg Ala Pro Asp Pro Ser Pro Gly Gly 755 760 765 15 201221141

Val Pro Leu Glu Ala Ser Leu Cys Pro Ala Ser Leu Ala Pro Ser Gly 770 775 780 lie Ser Glu Lys Ser Lys Ser Ser Ser Ser Phe His Pro Ala Pro Gly 785 790 795 800

Asn Ala Gin Ser Ser Ser Gin Thr Pro Lys lie Val Asn Phe Val Ser 805 810 815

Val Gly Pro Thr Tyr Met Arg Val Ser 820 825 <210> 26 <211> 207 <212> PRT <213> Homo sapiens <400>

Met Lys Val Leu Gin Glu Pro Thr Cys Val Ser Asp Tyr Met Ser lie 15 10 15

Ser Thr Cys Glu Trp Lys Met Asn Gly Pro Thr Asn Cys Ser Thr Glu 20 25 30

Leu Arg Leu Leu Tyr Gin Leu Val Phe Leu Leu Ser Glu Ala His Thr 35 40 45

Cys lie Pro Glu Asn Asn Gly Gly Ala Gly Cys Val Cys His Leu Leu 50 55 60

Met Asp Asp Val Val Ser Ala Asp Asn Tyr Thr Leu Asp Leu Trp Ala 65 70 75 80 16 201221141

Gly Gin Gin Leu Leu Trp Lys Gly Ser Phe Lys Pro Ser Glu His Val 85 90 95

Lys Pro Arg Ala Pro Gly Asn Leu Thr Val His Thr Asn Val Ser Asp 100 105 110

Thr Leu Leu Leu Thr Trp Ser Asn Pro Tyr Pro Pro Asp Asn Tyr Leu 115 120 125

Tyr Asn His Leu Thr Tyr Ala Val Asn lie Trp Ser Glu Asn Asp Pro 130 135 140

Ala Asp Phe Arg lie Tyr Asn Val Thr Tyr Leu Glu Pro Ser Leu Arg 145 150 155 160 lie Ala Ala Ser Thr Leu Lys Ser Gly lie Ser Tyr Arg Ala Arg Val 165 170 175

Arg Ala Trp Ala Gin Cys Tyr Asn Thr Thr Trp Ser Glu Trp Ser Pro 180 185 190

Ser Thr Lys Trp His Asn Ser Tyr Arg Glu Pro Phe Glu Gin His 195 200 205 17

Claims (1)

201221141 VII. Patent application scope: L A liquid pharmaceutical preparation containing (i) a human antibody that specifically binds to human &quot;albumin-4 receptor a (hIL-4Ra); (ii) a buffer of ρΗ5·9 ±0.5; (iii) an organic cosolvent; (iv) a thermal stabilizer; and (v) a detackifier. 2. A liquid pharmaceutical formulation as claimed in claim 1, wherein the antibody has a farmer's degree of about 150 ± 50 mg/ml. 3. The liquid pharmaceutical formulation of claim 1 or 2, wherein the concentration of the antibody is about 150 ± 15 mg/m. 4. The liquid pharmaceutical formulation according to any one of claims 1 to 3. 'The buffer system comprises a first buffer having an effective pH range of 3.6 to 5.6 and a second buffer having an effective pH range of 5.5 to 7.4. 5. The liquid pharmaceutical formulation of claim 4, wherein the first buffer has a pKa of about 4.8 ± 0.3 and the second buffer has a pKa of about 6.0 ± 0.3. 6* = Liquid pharmaceutical formulation of claim 5, wherein the first buffer is acetate and the second buffer is histidine. 7. The liquid pharmaceutical preparation according to any one of the preceding claims, wherein the concentration of the acetate is 12 5 mM ± 丄 85 and the concentration of the female acid is 20 mM ± 〇 3 mM. The liquid pharmaceutical formulation of the liquid medicine formulation of any of the above-mentioned patents 1-1 to 7 is selected from the group consisting of polysorbate 2, poloxamer 181 and polyethylene glycol 335. The group that makes up. For example, the formulation of liquid medicine for any of the eight items of the patent stipulations is included in the liquid medicine 201221141 w/v. The concentration of the organic solvent in the range of about G.G85% to about l15% ίο. 11. 12. 13. 14. 15. 16. 17. 18. The liquid medicine preparation of the item is second. The organic co-solvent is a polysorbate 20 having a concentration of about 0.2% ± 0.03% W/v. Version application: Patent (4) Liquid pharmaceutical preparations in items 1 to 1Q, ', + occupational stabilizers are selected from the group consisting of auditory, mannitol and trehalose. Liquid pharmaceutical preparation of any of the above-mentioned patents (4) - (wherein the concentration of the heat stabilizer is from about 3.5% to about 11% w/v. The liquid pharmaceutical formulation of any one of the above-mentioned items of the invention, wherein the heat stabilizer is sucrose having a concentration of 5% ± 〇 75% w/v. The liquid pharmaceutical formulation of any one of the inventions of the present invention, wherein the concentration of the detackifying agent is less than about 10 mM. A liquid pharmaceutical formulation according to any one of the preceding claims, wherein the detackifying agent is arginine having a concentration of 25 mM ± 3.75 mM or 50 mM of soil 7.5 mM. The liquid pharmaceutical formulation of any one of claims 1 to 15 wherein the viscosity of the liquid is less than or equal to 35 ± 3.5 centipoise. The liquid pharmaceutical preparation of any one of claims 1 to 16 wherein the viscosity of the liquid is 21.5 ± 13.5 centipoise. The liquid pharmaceutical formulation of any one of claims 1 to 16 wherein the viscosity of the liquid is 11 ± 1.1 centipoise or 8.5 ± 0.85 centipoise. The liquid pharmaceutical formulation of any one of the above claims, wherein the liquid has an osmolality of 290 ± 20 mOsm / kg. The liquid pharmaceutical formulation of any one of claims 1 to 19, wherein at least about 6 months after storage at about 5 ° C when measured by size exclusion chromatography, at least six months can be harvested. About 90% of natural antibodies. The pharmaceutical formulation of any one of claims 1 to 20, wherein at least about 95% is harvested after storage for about six months at about 5 ° C when measured by size exclusion chromatography. Natural antibody. 22. The pharmaceutical formulation of any one of claims 1 to 21, wherein at least about 98% is harvested after storage for about six months at about 5 ° C when measured by size exclusion chromatography. Natural antibody. 23. The liquid pharmaceutical formulation of any one of claims 1 to 22, wherein at least about 90% of the liquid pharmaceutical formulation is harvested after storage for about eight weeks at about 45 ° C as determined by size exclusion chromatography. Natural antibody. 24. The liquid pharmaceutical formulation of any one of claims 1 to 23, wherein less than about 45% can be harvested after storage for about eight weeks at about 45 ° C when measured by cation exchange chromatography. antibody. 25. The liquid pharmaceutical formulation of any one of claims 1 to 24, wherein less than about 4% can be harvested after storage at 25 ° C for six months as determined by size exclusion exchange chromatography. Aggregated antibodies. 26. The liquid pharmaceutical formulation of claim 1, wherein the human antibody that specifically binds hIL-4R comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein (8) The HCVR comprises (1) sequence identification number: 2. sequence identification number: 3 and sequence identification number: 4; (ii) sequence identification number: 10, sequence identification number: 11 and sequence identification number:; or (iii) sequence identification No.: 18, sequence identification number: 19 and sequence identification number: the weight of the amino acid sequence of 20; 201221141 strand complementarity determining region HCDIU, HCDR2 and HCDR3; and (b) the LCVR contains (1) sequence identification number: 6, Sequence identification number: 7 and sequence identification number: 8; (ii) sequence identification number: 14, sequence identification number: 15 and sequence identification number: 16; or (iii) sequence identification number: 22, sequence identification number: 23 and sequence Identification Number: The light chain complementarity of the amino acid sequence of 24 determines the regions LCDR 1, LCDR 2 and LCDR 3. 27. The liquid pharmaceutical formulation of claim 26, wherein the HCVR and LCVR comprise a sequence identification number: 1 and an amino acid sequence of sequence identification number: 5, respectively. 28. The liquid pharmaceutical formulation as claimed in any one of claims 1 to 27, which is placed in a glass bottle. 29. The liquid pharmaceutical formulation as claimed in any one of claims 1 to 27, which is placed in a syringe. 30. A liquid pharmaceutical formulation according to any one of claims 1 to 27, which is placed in a microinjector. 31. The liquid pharmaceutical formulation of claim 29, wherein the syringe comprises a fluorocarbon coated piston. 32. The liquid pharmaceutical formulation of claim 29 or 31, wherein the syringe is a low tungsten syringe. 33. A liquid pharmaceutical formulation comprising: (1) a 150 mg/ml ± 50 mg/ml human antibody that specifically binds hlL_4Rα, wherein the antibody comprises a sequence identification number of 1/5 amino acid sequence pair Heavy and light chain variable regions (X1 / 〇 ^ 11); (called 12.5 1 ^ ± 2 111) ^ sulphate; (out) 20 mM ± 3 mM histidine; (iv) 5% ± 0.75% sucrose; (v) 〇2% 201221141 ±0.03% p〇lysorbate2〇; and (vi) 25 mM ± 3.75 mM arginine at ρΗ5·9±0·5. 34. A liquid pharmaceutical formulation wherein the viscosity of the liquid is 11 ± 1.1 centipoise or 8.5 ± 0.85 centipoise. 35. The liquid pharmaceutical formulation of claim 33 or 34, wherein the osmolality of the liquid 290±20 mOsm/kg. 36. A liquid pharmaceutical formulation as claimed in any one of claims 33 to 35 wherein it is determined by size exclusion chromatography at 5. (: stored for six months) At least about 98% of the natural antibody can be recovered. 37. The liquid pharmaceutical formulation of any one of claims 33 to 36, wherein when measured by size exclusion chromatography At a time of 45. (: at least about 90% of the natural antibody can be recovered after eight weeks of storage. 38. The liquid pharmaceutical formulation of any one of claims 33 to 37, wherein by cation exchange chromatography </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Residual exchange chromatography can recover less than about 4% of aggregation after storage for 6 months at 25 ° C. 5 201221141 IV. Designated representative map: (1) The representative representative of the case is: (No) map. The symbol of the symbol of this representative figure is simple: No. 5. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: