A pharmaceutical formulation of an FcRn inhibitor suitable for subcutaneous administration.

Abstract

This invention provides an improved formulation and administration method of an FcRn inhibitor for use in the treatment of autoimmune diseases. [Solution] An aqueous formulation containing approximately 100-300 mg / mL of an FcRn antagonist, 20-60 mM histidine / histidine HCl, 0-70 mM sucrose, 0-150 mM NaCl, 0-250 mM arginine HCl, 0%-0.05% (w / v) polysorbate 20 or polysorbate 80, and 0-15 mM L-methionine. The aqueous formulation has a pH of 6.0-6.5, and the FcRn antagonist consists of a variant Fc region, which consists of two Fc domains that form a homodimer.

Description

Background Art

[0001] (Background) Immunoglobulin gamma (IgG) antibodies play an important role in the pathology of many disorders, such as autoimmune diseases, inflammatory diseases, and disorders characterized by overexpression of IgG antibodies (e.g., hypergammaglobulinemia) (see, e.g., Junghans, Immunol Res. 16(1):29 (1997)). The half-life of IgG in serum is long compared to the serum half-lives of other plasma proteins (Roop enian et al., J Immunol. 170:3528 (2003); Junghans and Anderson, Proc. Natl . Acad. Sci. USA 93:5512 (1996)). This long half-life is due, in part, to the binding of the Fc region of IgG to the neonatal Fc receptor (FcRn). FcRn was originally characterized as the receptor for neonatal transport of maternal IgG, but in adults, it also functions to protect IgG from degradation. FcRn binds to IgG that has undergone pinocytosis and protects IgG from transport to degradative lysosomes by recycling IgG back to the extracellular compartment. This recycling is facilitated by the pH-dependent binding of IgG to FcRn, where the IgG / FcRn interaction is stronger at the acidic pH of the endosome than at the physiological pH outside the cell. Reference)

[0002] When the serum concentration of IgG reaches a level that exceeds the available FcRn molecules, unbound IgG is not protected from the degradation mechanism and will consequently have a reduced serum half-life. Thus enian et al., J Immunol. 170:3528 (2003); Junghans and Anderson, Proc. Natl . Acad. Sci. USA 93:5512 (1996)) to the binding of the Fc region of IgG to the neonatal Fc receptor (FcRn). FcRn was originally characterized as the receptor for neonatal transport of maternal IgG, but in adults, it also functions to protect IgG from degradation. FcRn binds to IgG that has undergone pinocytosis and protects IgG from transport to degradative lysosomes by recycling IgG back to the extracellular compartment. This recycling is facilitated by the pH-dependent binding of IgG to FcRn, where the IgG / FcRn interaction is stronger at the acidic pH of the endosome than at the physiological pH outside the cell. to the binding of the Fc region of IgG to the neonatal Fc receptor (FcRn). FcRn was originally characterized as the receptor for neonatal transport of maternal IgG, but in adults, it also functions to protect IgG from degradation. FcRn binds to IgG that has undergone pinocytosis and protects IgG from transport to degradative lysosomes by recycling IgG back to the extracellular compartment. This recycling is facilitated by the pH-dependent binding of IgG to FcRn, where the IgG / FcRn interaction is stronger at the acidic pH of the endosome than at the physiological pH outside the cell. to the binding of the Fc region of IgG to the neonatal Fc receptor (FcRn). FcRn was originally characterized as the receptor for neonatal transport of maternal IgG, but in adults, it also functions to protect IgG from degradation. FcRn binds to IgG that has undergone pinocytosis and protects IgG from transport to degradative lysosomes by recycling IgG back to the extracellular compartment. This recycling is facilitated by the pH-dependent binding of IgG to FcRn, where the IgG / FcRn interaction is stronger at the acidic pH of the endosome than at the physiological pH outside the cell. to the binding of the Fc region of IgG to the neonatal Fc receptor (FcRn). FcRn was originally characterized as the receptor for neonatal transport of maternal IgG, but in adults, it also functions to protect IgG from degradation. FcRn binds to IgG that has undergone pinocytosis and protects IgG from transport to degradative lysosomes by recycling IgG back to the extracellular compartment. This recycling is facilitated by the pH-dependent binding of IgG to FcRn, where the IgG / FcRn interaction is stronger at the acidic pH of the endosome than at the physiological pH outside the cell. to the binding of the Fc region of IgG to the neonatal Fc receptor (FcRn). FcRn was originally characterized as the receptor for neonatal transport of maternal IgG, but in adults, it also functions to protect IgG from degradation. FcRn binds to IgG that has undergone pinocytosis and protects IgG from transport to degradative lysosomes by recycling IgG back to the extracellular compartment. This recycling is facilitated by the pH-dependent binding of IgG to FcRn, where the IgG / FcRn interaction is stronger at the acidic pH of the endosome than at the physiological pH outside the cell. to the binding of the Fc region of IgG to the neonatal Fc receptor (FcRn). FcRn was originally characterized as the receptor for neonatal transport of maternal IgG, but in adults, it also functions to protect IgG from degradation. FcRn binds to IgG that has undergone pinocytosis and protects IgG from transport to degradative lysosomes by recycling IgG back to the extracellular compartment. This recycling is facilitated by the pH-dependent binding of IgG to FcRn, where the IgG / FcRn interaction is stronger at the acidic pH of the endosome than at the physiological pH outside the cell.

[0003] When the serum concentration of IgG reaches a level that exceeds the available FcRn molecules, unbound IgG is not protected from the degradation mechanism and will consequently have a reduced serum half-life. Thus When the serum concentration of IgG reaches a level that exceeds the available FcRn molecules, unbound IgG is not protected from the degradation mechanism and will consequently have a reduced serum half-life. Thus Therefore, inhibition of IgG binding to FcRn prevents IgG endosome repurposing, It reduces the serum half-life of IgG. Therefore, drugs that antagonize the binding of IgG to FcRn, for example If so, it may be useful in regulating, treating, or preventing antibody-mediated disorders such as autoimmune diseases and inflammatory diseases. It may be useful. Some of these diseases are at least to some extent derived from human donors. Currently, these autoimmune diseases are being treated with intravenous infusion of IgG (IVIg). Since it is a chronic condition, affected individuals may need IVIg and / or other medications to manage the disease. Repeated administration of the appropriate therapy may be necessary.

[0004] In another approach, an antiblocking antibody against FcRn was developed to inhibit IgG Fc binding to FcRn. (See, for example, WO 2002 / 043658). It binds to FcRn and antagonizes its function. Peptides have also been identified (see, for example, US 6,212,022 and US 8,101,186). Varian has enhanced FcRn binding that antagonizes FcRn binding to IgG and reduced pH dependence. Full-length IgG antibodies containing the Fc receptor have also been identified (e.g., US No. 8,163,881 and Vaccaro et al.) See the reference, Nat Biotechnol. 23(10): 1283-1288(2005).

[0005] Recently, another F1 fragment, called fgarchigimodo, is a modified version of the human IgG1 Fc fragment. The cRn inhibitor (also known as ARGX-113) was developed. Its entirety is cited herein by reference. See WO 2015 / 100299 for details on its incorporation. ARGX-113 is currently used for myasthenia gravis (M G) and several autoimmune diseases, including immunothrombocytopenia (ITP), have undergone clinical trials. That is the situation.

[0006] Improved formulations of FcRn inhibitors for use in the treatment of autoimmune diseases and The need for a specific method still exists. [Overview of the project]

[0007] (overview) Disclosed herein are various formulations of ARGX-113, including formulations useful as pharmaceutical compositions. This includes the preparation method, the apparatus containing various formulations, and the use thereof. In one embodiment, Therefore, the formulation is suitable and useful for administering ARGX-113 to human subjects. In one embodiment The formulation is suitable and useful for subcutaneous administration of ARGX-113 to human subjects. The formulation is FcRn-mediated It can be used in the treatment of any disease that would benefit from the inhibition of antibody reuse. Diseases such as those mentioned above include, but are not limited to, myasthenia gravis (MG) and immunothrombocytopenia. You must list one or more of the various antibody-mediated autoimmune diseases, including ITP (intracranial pulmonary palsy). It is possible.

[0008] One aspect of the present invention relates to an isolated neonatal Fc receptor (FcRn) antagonist at approximately 100-300 mg / mL. To, 20-60 mM histidine / histidine HCl, 0-70 mM sucrose, 0-150 mM NaCl, 0-250 mM arginine HCl, 0%~0.05% (w / v) polysorbate 20 or polysorbate 80, 0~15 mM L - An aqueous preparation containing methionine in a pH of 6.0-6.5, wherein the isolated FcRn antagonist is present. The NIST consists of a variant Fc region, where the variant Fc region consists of two Fc domains forming a homodimer, and where the amino acid sequence of each of the Fc domains consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. In one embodiment, the aqueous formulation comprises from about 100 to 300 mg / mL of an isolated neonatal Fc receptor (FcRn) antagonist in 20 - 60 mM histidine / histidine HCl, 0 - 70 mM sucrose, about 100 mM

[0009] NaCl, 0% - 0.05% (w / v) polysorbate 20 or polysorbate 80, 0 - 15 mM L-methionine , at pH 6.0 - 6.5, where the isolated FcRn antagonist consists of a variant Fc region, where the variant Fc region consists of two Fc domains forming a homodimer, and where the amino acid sequence of each of the Fc domains consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. In one embodiment, the aqueous formulation comprises from about 100 to 300 mg / mL of an isolated neonatal Fc receptor (FcRn) antagonist in 20 - 60 mM histidine / histidine HCl, 0 - 70 mM sucrose, 100 - 250 mM arginine HCl, 0% - 0.05% (w / v) polysorbate 20 or polysorbate 80, 0 - 15 mM L- methionine, at pH 6.0 - 6.5, where the isolated FcRn antagonist consists of a variant Fc region, where the variant Fc region consists of two Fc domains forming a homodimer, and where the amino acid sequence of each of the Fc domains consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0010] ]> In one embodiment, the aqueous formulation comprises from about 100 to 300 mg / mL of an isolated neonatal Fc receptor (FcRn) antagonist in 20 - 60 mM histidine / histidine HCl, 0 - 70 mM sucrose, 100 - 250 mM arginine HCl, 0% - 0.05% (w / v) polysorbate 20 or polysorbate 80, 0 - 15 mM L- methionine, at pH 6.0 - 6.5, where the isolated FcRn antagonist consists of a variant Fc region, where the variant Fc region consists of two Fc domains forming a homodimer, and where the amino acid sequence of each of the Fc domains consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0011] In one embodiment, the aqueous formulation contains approximately 100-300 mg / mL of isolated neonatal Fc receptor (FcRn ) Antagonist, 20-60 mM histidine / histidine HCl, 100-250 mM arginine HCl, 0 0.05% (w / v) polysorbate 20 or polysorbate 80, 0-15 mM L-methionine, pH 6. Included in 0-6.5, where the isolated FcRn antagonist is derived from the variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer. Here, each amino acid sequence of the Fc domain is SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 It consists of.

[0012] In each of the aforementioned embodiments and models, in one embodiment, the aqueous formulation is 20 or Contains 50 mM histidine.

[0013] In each of the aforementioned embodiments and models, in one embodiment, the aqueous formulation is 0.02% Contains ~0.04% (w / v) polysorbate 20 or polysorbate 80.

[0014] In each of the aforementioned embodiments and models, in one embodiment, the aqueous formulation is 0 or 1 Contains 0 mM L-methionine.

[0015] In each of the aforementioned embodiments and models, in one embodiment, the pH is 6.0 or 6.5. be.

[0016] In each of the aforementioned embodiments and models, in one embodiment, each of the Fc domains The amino acid sequence is as shown in SEQ ID NO: 1.

[0017] One aspect of the present invention relates to an isolated neonatal Fc receptor (FcRn) antagonist at approximately 100-200 mg / mL. The solution consists of 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.02%~0.04 This is an aqueous formulation containing %(w / v) polysorbate 20 or polysorbate 80, pH 6.0, and here The isolated FcRn antagonist consists of a variant Fc region, where the barrier The Fc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0018] In one embodiment, the aqueous formulation contains approximately 100-200 mg / mL of ARGX-113 and 20 mM histidine / Stidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.02%~0.04% (w / v) polysorbate 20 Alternatively, it may be contained in polysorbate 80, pH 6.0, where ARGX-113 is derived from the variant Fc region. This is an isolated FcRn antagonist, where the variant Fc region is a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is It consists of column number 1.

[0019] One aspect of the present invention involves 150 mg / mL of ARGX-113 mixed with 20 mM histidine / histidine HCl and 60 mM sulfate. This is an aqueous formulation containing rose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0. Here, ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0020] One aspect of the present invention involves 165 mg / mL of ARGX-113 mixed with 20 mM histidine / histidine HCl and 60 mM sulfate. A water-based formulation containing rose, 100 mM NaCl, and approximately 0.04% (w / v) polysorbate 20, pH 6.0. Here, ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region. Yes, and here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0021] One aspect of the present invention involves 175 mg / mL of ARGX-113 mixed with 20 mM histidine / histidine HCl and 60 mM chlorine. This is an aqueous formulation containing rose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0. Here, ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0022] One aspect of the present invention involves 180 mg / mL of ARGX-113 mixed with 20 mM histidine / histidine HCl and 60 mM chlorine. This is an aqueous formulation containing rose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0. Here, ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0023] One aspect of the present invention involves water, 200 mg / mL of ARGX-113, 20 mM histidine / histidine HCl, and 60 mM Aqueous formulation containing sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0. Here, ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0024] One aspect of the present invention relates to an isolated neonatal Fc receptor (FcRn) antagonist at approximately 100-200 mg / mL. To prepare the solution, use 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 10 mM L-methionine. This is contained in 0.02%~0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0. This is an aqueous formulation in which the isolated FcRn antagonist is derived from the variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer. Here, each amino acid sequence of the Fc domain is SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 It consists of.

[0025] In one embodiment, the aqueous formulation contains approximately 100-200 mg / mL of ARGX-113 and 20 mM histidine / Stidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.02%~0.04% (w / v) An aqueous formulation containing polysorbate 20 or polysorbate 80, pH 6.0, where A RGX-113 is an isolated FcRn antagonist consisting of a variant Fc region, where, The variant Fc region consists of two Fc domains that form a homodimer, where the Fc Each amino acid sequence in the domain is represented by sequence number 1.

[0026] One aspect of the present invention involves using 165 mg / mL of an isolated neonatal Fc receptor (FcRn) antagonist, and 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0 This is an aqueous formulation containing 0.04% (w / v) polysorbate 20, pH 6.0, where the isolated Fc The Rn antagonist consists of a variant Fc region, where the variant Fc region is homo It consists of two Fc domains that form a dimer, and here, the amino acid composition of each Fc domain Each column consists of sequence number 1, sequence number 2, or sequence number 3.

[0027] In one embodiment, the aqueous formulation contains 165 mg / mL of ARGX-113 and 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.04% (w / v) polysorbate It contains 20, pH 6.0, where ARGX-113 is an isolated Fc region consisting of the variant Fc region. It is an Rn antagonist, where the variant Fc region consists of two Fs that form a homodimer. It consists of a c domain, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1. .

[0028] One aspect of the present invention involves 175 mg / mL of ARGX-113 mixed with 20 mM histidine / histidine HCl and 60 mM chlorine. Rose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20, pH 6.0 This is an aqueous formulation containing ARGX-113, in which ARGX-113 is an isolated FcRn consisting of a variant Fc region. It is an antagonist, and here the variant Fc region is two Fc that form a homodimer. It consists of a domain, where the amino acid sequence of each Fc domain is as follows: .

[0029] One aspect of the present invention involves 180 mg / mL of ARGX-113 mixed with 20 mM histidine / histidine HCl and 60 mM chlorine. Rose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20, pH 6.0 This is an aqueous formulation containing ARGX-113, in which ARGX-113 is an isolated FcRn consisting of a variant Fc region. It is an antagonist, and here the variant Fc region is two Fc that form a homodimer. It consists of a domain, where the amino acid sequence of each Fc domain is as follows: .

[0030] One aspect of the present invention involves using 200 mg / mL of ARGX-113 in a solution of 20 mM histidine / histidine HCl and 60 mM sulfate. Rose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20, pH 6.0 This is an aqueous formulation containing ARGX-113, in which ARGX-113 is an isolated FcRn consisting of a variant Fc region. It is an antagonist, and here the variant Fc region is two Fc that form a homodimer. It consists of a domain, where the amino acid sequence of each Fc domain is as follows: .

[0031] One aspect of the present invention relates to an isolated neonatal Fc receptor (FcRn) antagonist at approximately 100-200 mg / mL. The solution consists of 50 mM histidine / histidine HCl, 60 mM sucrose, 150 mM arginine HCl, and 0.02 A water-based formulation containing 0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0. Here, the isolated FcRn antagonist consists of a variant Fc region, where The variant Fc region consists of two Fc domains that form a homodimer, where the Fc Each amino acid sequence in the domain consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0032] In one embodiment, the aqueous formulation contains approximately 100-200 mg / mL of ARGX-113 and 50 mM histidine / Stidine HCl, 60 mM sucrose, 100 mM arginine HCl, and 0.02%~0.04% (w / v) polysol It is contained in Bate 20 or Polysorbate 80, pH 6.0, where ARGX-113 is variant Fc region. An isolated FcRn antagonist consisting of a region, where the variant Fc region is Fc- It consists of a main homodimer, where the amino acid sequence of each Fc domain is as follows: Ranaru.

[0033] One aspect of the present invention relates to an isolated neonatal Fc receptor (FcRn) antagonist at approximately 100-200 mg / mL. The solution consists of 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, and 10 mM L- Methionine, and 0.02%~0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0 The aqueous formulation contained herein is the isolated FcRn antagonist, which is the variant Fc region It consists of a region, where the variant Fc region is composed of two Fc domains that form a homodimer. Therefore, here, each amino acid sequence of the Fc domain is sequence number 1, sequence number 2, or It consists of column number 3.

[0034] In one embodiment, the aqueous formulation contains approximately 100-200 mg / mL of ARGX-113 and 20 mM histidine / Stidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.02%~ Contains 0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0, where ARGX-11 3 is an isolated FcRn antagonist consisting of a variant Fc region, where the variant The antFc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence of n is represented by sequence number 1.

[0035] One aspect of the present invention involves 175 mg / mL of ARGX-113 mixed with 20 mM histidine / histidine HCl and 60 mM chlorine. Rose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20, This is an aqueous formulation contained in pH 6.0, where ARGX-113 is an isolated variant consisting of the Fc region. It is a modified FcRn antagonist, where the variant Fc region forms a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is as follows: SEQ ID NO: 1 Ranaru.

[0036] One aspect of the present invention involves 180 mg / mL of ARGX-113 mixed with 20 mM histidine / histidine HCl and 60 mM chlorine. Rose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20, This is an aqueous formulation contained in pH 6.0, where ARGX-113 is an isolated variant consisting of the Fc region. It is a modified FcRn antagonist, where the variant Fc region forms a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is as follows: SEQ ID NO: 1 Ranaru.

[0037] One aspect of the present invention involves using 200 mg / mL of ARGX-113 in a solution of 20 mM histidine / histidine HCl and 60 mM sulfate. Rose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20, This is an aqueous formulation contained in pH 6.0, where ARGX-113 is an isolated variant consisting of the Fc region. It is a modified FcRn antagonist, where the variant Fc region forms a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is as follows: SEQ ID NO: 1 Ranaru.

[0038] One aspect of the present invention involves providing ARGX-113 in a concentration of 250 mg / mL, 300 mg / mL, or more than 300 mg / mL, at a pH of approximately 6.0. Contains 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, and 10 mM L - An aqueous formulation containing methionine and 0.03% (w / v) polysorbate 20, where ARGX -113 is an isolated FcRn antagonist consisting of a variant Fc region, where the The riant Fc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence of 'in' corresponds to sequence number 1.

[0039] One aspect of the present invention relates to an isolated neonatal Fc receptor (FcRn) antagonist at approximately 100-300 mg / mL. The solution contains approximately 50 mM histidine / histidine HCl and approximately 200 mM arginine HCl in a solution with a pH of 6.5. The aqueous formulation contains the isolated FcRn antagonist in the variant Fc region. Therefore, here, the variant Fc region consists of two Fc domains that form a homodimer. Here, each amino acid sequence of the Fc domain is represented by Sequence ID No. 1, Sequence ID No. 2, or Sequence No. It consists of three parts.

[0040] In one embodiment, the aqueous formulation contains approximately 200-300 mg / mL of isolated neonatal Fc receptor (FcRn ) Antagonist, 50 mM histidine / histidine HCl, 200 mM arginine, with a pH of 6.5 It is contained in HCl, and here the isolated FcRn antagonist is from the variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0041] In one embodiment, the aqueous formulation contains approximately 250-300 mg / mL of isolated neonatal Fc receptor (FcRn ) Antagonist, 50 mM histidine / histidine HCl, 200 mM arginine, with a pH of 6.5 It is contained in HCl, and here the isolated FcRn antagonist is from the variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0042] In some embodiment of each of the above-described aspects of the present invention, the aqueous formulation substantially contains dissolved oxygen. Not included.

[0043] In one embodiment of each of the above-described aspects of the present invention, the aqueous formulation is for in vivo use. It is suitable.

[0044] In one embodiment of each of the aforementioned aspects of the present invention, the aqueous formulation is used subcutaneously in vivo. It is suitable for use.

[0045] One aspect of the present invention relates to the therapeutically effective amount of any one of the above-described aspects and embodiments of an aqueous formulation. It is a packaged pharmaceutical product that includes a sterile container.

[0046] One aspect of the present invention relates to the therapeutically effective amount of any one of the above-described aspects and embodiments of an aqueous formulation. It is a device that includes [something].

[0047] In one embodiment, the apparatus includes or includes a syringe containing an aqueous formulation. Yes.

[0048] In one embodiment, the syringe is a pre-filled syringe. [Brief explanation of the drawing]

[0049] (Brief explanation of the drawing) [Figure 1] Figure 1 shows the shear fluidization / viscosification behavior of ARGX-113 at maximum concentration, tested with shear rates ranging from 0 to 4000 s⁻¹. [Figure 2] Figure 2 shows the concentration (mg / mL) versus viscosity (mPa·s) of ARGX-113 in HisHCl+ salt at the indicated concentrations and temperatures (°C). [Figure 3] Figure 3 shows the protein concentrations of the ARGX-113 formulation described in Example 2, measured by UV / Vis. sh5, shaking at 5°C; sh25, shaking at 25°C; 4w5, 4 weeks at 5°C; 4w25, 4 weeks at 25°C; 4w40, 4 weeks at 40°C; 8w5, 8 weeks at 5°C; 8w25, 8 weeks at 25°C; 4w40, 8 weeks at 40°C. [Figure 4]Figures 4A and 4B show the main peak and high molecular weight (HMW) species size exclusion chromatography (SEC) results for the ARGX-113 formulation described in Example 2, respectively. sh5, shaken at 5°C; sh25, shaken at 25°C; 4w5, 4 weeks at 5°C; 4w25, 4 weeks at 25°C; 4w40, 4 weeks at 40°C; 8w5, 8 weeks at 5°C; 8w25, 8 weeks at 25°C; 4w40, 8 weeks at 40°C. [Figure 5] Figures 5A to 5C show the chemical decomposition of the ARGX-113 formulation described in Example 2, as determined by iCE, including the main peak, acidic variant, and basic variant. sh5, shaken at 5°C; sh25, shaken at 25°C; 4w5, 4 weeks at 5°C; 4w25, 4 weeks at 25°C; 4w40, 4 weeks at 40°C; 8w5, 8 weeks at 5°C; 8w25, 8 weeks at 25°C; 4w40, 8 weeks at 40°C. [Figure 6] Figures 6A to 6D show invisible particles of the ARGX-113 formulation described in Example 2 with diameters of ≥2 μm, ≥5 μm, ≥10 μm, and ≥25 μm, respectively. sh5, shaken at 5°C; sh25, shaken at 25°C; 4w5, 4 weeks at 5°C; 4w25, 4 weeks at 25°C; 4w40, 4 weeks at 40°C; 8w5, 8 weeks at 5°C; 8w25, 8 weeks at 25°C; 4w40, 8 weeks at 40°C. [Figure 7] Figure 7 shows the turbidity of the ARGX-113 formulation described in Example 2. [Figure 8] Figure 8 shows the protein concentrations of the ARGX-113 formulation described in Example 3, measured by UV / Vis. sh 5, shaken at 5°C; sh 25, shaken at 25°C; 2w5, 2 weeks at 5°C; 2w25, 2 weeks at 25°C; 2w40, 1 week at 40°C. [Figure 9] Figure 9 shows the osmolality of the ARGX-113 formulation described in Example 3, as measured by freezing point depression. [Figure 10]Figure 10 shows the turbidity of the ARGX-113 formulation described in Example 3. sh 5, shaken at 5°C; sh 25, shaken at 25°C; 2w5, 2 weeks at 5°C; 2w25, 2 weeks at 25°C; 2w40, 1 week at 40°C. [Figure 11] Figures 11A and 11B show the main peak and high molecular weight (HMW) species size exclusion chromatography (SEC) results for the ARGX-113 formulation described in Example 3, respectively. sh 5, shaken at 5°C; sh 25, shaken at 25°C; 2w5, 2 weeks at 5°C; 2w25, 2 weeks at 25°C; 2w40, 1 week at 40°C. [Figure 12] Figures 12A-12C show the chemical decomposition of the ARGX-113 formulation described in Example 3, as determined by iCE, including the main peak, acidic variant, and basic variant. sh 5, shaken at 5°C; sh 25, shaken at 25°C; 2w5, 2 weeks at 5°C; 2w25, 2 weeks at 25°C; 2w40, 1 week at 40°C. [Figure 13] Figures 13A to 13D show invisible particles of the ARGX-113 formulation described in Example 3 with diameters of ≥2 μm, ≥5 μm, ≥10 μm, and ≥25 μm, respectively. sh 5, shaken at 5°C; sh 25, shaken at 25°C; 2w5, 2 weeks at 5°C; 2w25, 2 weeks at 25°C; 2w40, 1 week at 40°C. [Figure 14] Figure 14 shows the turbidity of the ARGX-113 formulation described in Example 4. sh 5, shaken at 5°C; sh 25, shaken at 25°C; 3 weeks at 5°C for 3 weeks; 3 weeks at 25°C for 3 weeks; 3 weeks at 40°C for 3 weeks; 6 weeks at 5°C for 6 weeks; 6 weeks at 25°C for 6 weeks; 6 weeks at 40°C for 6 weeks; 9 weeks at 5°C for 9 weeks; 9 weeks at 25°C for 9 weeks; 9 weeks at 40°C for 9 weeks. [Figure 15]Figures 15A and 15B show the main peak and high molecular weight (HMW) species size exclusion chromatography (SEC) results for the ARGX-113 formulation described in Example 4, respectively. sh 5, shaken at 5°C; sh 25, shaken at 25°C; 3w5, 3 weeks at 5°C; 3w2, 3 weeks at 25°C; 3w40, 3 weeks at 40°C; 6w5, 6 weeks at 5°C; 6w2, 6 weeks at 25°C; 6w40, 6 weeks at 40°C; 9w5, 9 weeks at 5°C; 9w2, 9 weeks at 25°C; 9w40, 9 weeks at 40°C. [Figure 16] Figures 16A-16C show the chemical decomposition of the ARGX-113 formulation described in Example 4, as determined by iCE, including the main peak, acidic variant, and basic variant. sh 5, shaken at 5°C; sh 25, shaken at 25°C; 3w5, 3 weeks at 5°C; 3w2, 3 weeks at 25°C; 3w40, 3 weeks at 40°C; 6w5, 6 weeks at 5°C; 6w2, 6 weeks at 25°C; 6w40, 6 weeks at 40°C; 9w5, 9 weeks at 5°C; 9w2, 9 weeks at 25°C; 9w40, 9 weeks at 40°C. [Figure 17] Figures 17A to 17D show invisible particles of the ARGX-113 formulation described in Example 4 with diameters of ≥2 μm, ≥5 μm, ≥10 μm, and ≥25 μm, respectively. sh 5, shaken at 5°C; sh 25, shaken at 25°C; 3w5, 3 weeks at 5°C; 3w25, 3 weeks at 25°C; 3w40, 3 weeks at 40°C; 6w5, 6 weeks at 5°C; 6w25, ​​6 weeks at 25°C; 6w40, 6 weeks at 40°C; 9w5, 9 weeks at 5°C; 9w25, 9 weeks at 25°C; 9w40, 9 weeks at 40°C. [Modes for carrying out the invention]

[0050] (Detailed explanation) (ARGX-113) In one embodiment, the isolated FcRn antagonist consists of a variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer, Thus, each amino acid sequence of the Fc domain is such that of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 ARGX-113 is a variant Fc region of human IgG1, where the Fc region is These contain amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively. nothing.

[0051] In particular, ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region. Here, the variant Fc region consists of an Fc domain homodimer, and here the Fc domain Each amino acid sequence corresponds to sequence number 1. [ka]

[0052] The N-terminal aspartic acid residue (D) of SEQ ID NO: 1 corresponds to EU position 221, and the C-terminal residue of SEQ ID NO: 2 Lysine (K) corresponds to EU position 447.

[0053] In one embodiment, the aqueous formulation and pharmaceutical composition of the present invention are polypeptide of SEQ ID NO: 1 It is substantially uniform in terms of D. In one embodiment, the aqueous formulation and pharmaceutical composition of the present invention The substance comprises a group of polypeptides, wherein at least 90% of the polypeptides (for example, At least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more. Most of the Fc domains consist of homodimers, where each of the Fc domains of the homodimer The amino acid sequence is as shown in SEQ ID NO: 1.

[0054] In one embodiment, the aqueous formulation and pharmaceutical composition of the present invention are polypeptide of SEQ ID NO: 2 The thiosulfate is substantially homogeneous. In certain preferred embodiments, the aqueous formulation of the present invention and pharmaceutical compositions comprise a group of polypeptides, wherein at least 90 of the polypeptides % (For example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%) , or more) consists of an Fc domain homodimer, where the Fc domain of the homodimer The main amino acid sequence of each is as shown in SEQ ID NO: 2. In one embodiment, the polyp Over 90% of plutidos lack a C-terminal lysine residue (K) at EU position 448.

[0055] In one embodiment, each Fc domain of ARGX-113 has an N-linked glycan at EU position 297. It further contains, where the N-linked glycan is bisecting N-acetylglucosa It has a mine (GlcNAc) structure.

[0056] In one embodiment, the aqueous formulation and pharmaceutical composition of the present invention are polypeptide of SEQ ID NO: 3 It is substantially uniform in terms of D. In one embodiment, the aqueous formulation and pharmaceutical composition of the present invention The substance comprises a group of polypeptides, wherein at least 90% of the polypeptides (for example, At least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more. Most of the Fc domains consist of homodimers, where each of the Fc domains of the homodimer The amino acid sequence is as shown in SEQ ID NO: 3.

[0057] (Antibody-mediated autoimmune disease) The formulations and compositions of the present invention are used in the treatment of antibody-mediated and / or antibody-related autoimmune diseases. They will find a use for it.

[0058] Antibody-mediated and / or antibody-related autoimmune diseases are well known. Non-exclusive examples of related autoimmune diseases include allogeneic islet transplant rejection, alopecia areata, and ankylosing pancreatic leukemia. Spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, Alzheimer's disease, antineutrophil cytoplasmic Autoimmune diseases of the body (ANCA), adrenal glands, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune muscle inflammation, autoimmune neutropenia, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, Autoimmune urticaria, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman syndrome, Celiac plue dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating polyneuropathy CIDP (Cholesterol-Inflammatory Disease), Churg-Strauss syndrome, pemphigoid scarring, CREST (calcification, Raynaud's phenomenon) Esophageal motility disorders, finger sclerosis, and telangiectasia syndrome, cold agglutinin disease, Crohn's disease Dermatomyositis, lupus discoid, mixed essential cryoglobulinemia, factor VIII deficiency, fibrosis Myalgia - Fibromyalgia, Glomerulonephritis, Graves' disease, Guillain-Barré syndrome, Goodpasture Syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, type A hemophilia, idiopathic pulmonary fibrosis, idiopathic hematology Thylem-pneumonic purpura (immunothrombocytopenia; ITP), IgA neuropathy, IgM polyneuropathy - Immune-mediated thrombocytopenia, juvenile arthritis, Kawasaki disease, lichen planus, lupus erythematosus, Nyelle's disease, mixed connective tissue disease, multiple sclerosis, type 1 diabetes, multifocal motor neuropathy - (MMN), Myasthenia Gravis (MG), Paraneoplastic Bullous Pemphigoid, Pemphigus Vulgaris, Pemphigus Foliaceus, Pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyalgia Myositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic Arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, cy Egren's syndrome, parenchymal organ graft rejection, Stiffman syndrome, systemic lupus erythematosus SLE (Systemic Lupus Erythema Infectiosum), Takayasu's arteritis, Toxic Epidermal Necrolysis (TEN), Stevens-Johnson Syndrome (S) JS), temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura, ulcerative colitis, uvea Inflammation, herpetiform dermatitis, vasculitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, vitiligo, and Wegener's disease. Granulomatous disease is one example.

[0059] In one embodiment, antibody-mediated autoimmune diseases include immunothrombocytopenia (ITP) and severe illness. The group will be selected from those with myasthenia gravis (MG).

[0060] (formulation) The formulations and compositions of the present invention are intended to reduce the serum levels of Fc-containing drugs in the target population. It will find uses in any disease or illness that is particularly problematic. Fc-containing drugs are limited to... Examples of antibodies, though not all, include autoantibodies, therapeutic antibodies, diagnostic antibodies, and immune complexes. Further non-limiting examples of Fc-containing drugs include imaging agents (e.g., labeled antibodies) and antibodies. - Drug conjugates (ADCs), Fc fusion proteins (e.g., immunoadhesins), and immunogens Examples include non-human antibodies.

[0061] Furthermore, in diseases or conditions requiring the administration of therapeutic agents, the target is an antibody to the therapeutic agent. This often causes the body to produce antibodies (for example, anti-drug antibodies), and as a result, the therapeutic agent then... It may be prevented from being used for the therapeutic purposes shown, or it may cause adverse reactions in the subject. Therefore, the formulations and compositions disclosed herein are intended to treat the therapeutic effects that occur in the subject. It can also be used to remove antibodies against therapeutic agents (e.g., anti-drug antibodies).

[0062] One aspect of the present invention relates to an isolated neonatal Fc receptor (FcRn) antagonist at approximately 100-300 mg / mL. To, 20-60 mM histidine / histidine HCl, 0-70 mM sucrose, 0-150 mM NaCl, 0-250 mM arginine HCl, 0%~0.05% (w / v) polysorbate 20 or polysorbate 80, 0~15 mM L - An aqueous preparation containing methionine in a pH of 6.0-6.5, wherein the isolated FcRn antagonist is present. The st consists of a variant Fc region, where the variant Fc region forms a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is: It consists of number 1, sequence number 2, or sequence number 3.

[0063] In one embodiment, the aqueous formulation contains approximately 100-300 mg / mL of isolated neonatal Fc receptor (Fc Rn) Antagonist, 20-60 mM histidine / histidine HCl, 0-70 mM sucrose, 100 mM NaCl, 0%~0.05% (w / v) polysorbate 20 or polysorbate 80, 0~15 mM L-methionine , contained in pH 6.0~6.5, where the isolated FcRn antagonist is variant Fc region It consists of a region, where the variant Fc region is composed of two Fc domains that form a homodimer. Therefore, here, each amino acid sequence of the Fc domain is sequence number 1, sequence number 2, or It consists of column number 3.

[0064] In one embodiment, the aqueous formulation contains approximately 100-300 mg / mL of isolated neonatal Fc receptor (Fc Rn) Antagonist, 20-60 mM histidine / histidine HCl, 0-70 mM sucrose, 100-2 50 mM arginine HCl, 0%~0.05% (w / v) polysorbate 20 or polysorbate 80, 0~15 mM L-methionine is contained in pH 6.0-6.5, and here the isolated FcRn antagonist is... It consists of a variant Fc region, where the variant Fc region has two Fs that form a homodimer. It consists of a c domain, where the amino acid sequence of each Fc domain is given by Sequence ID No. 1, Sequence No. It consists of code number 2 or sequence number 3.

[0065] In one embodiment, the aqueous formulation contains approximately 100-300 mg / mL of isolated neonatal Fc receptor (Fc Rn) Antagonist, 20-60 mM histidine / histidine HCl, 100-250 mM arginine HCl, 0%~0.05% (w / v) polysorbate 20 or polysorbate 80, 0~15 mM L-methionine, pH 6 It is contained in 0~6.5, where the isolated FcRn antagonist is from the variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer. Here, each amino acid sequence of the Fc domain is SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: It consists of 3.

[0066] In each of the aforementioned embodiments and models, in one embodiment, the aqueous formulation is 20 or Contains 50 mM histidine.

[0067] In each of the aforementioned embodiments and models, in one embodiment, the aqueous formulation is 0.02% Contains approximately 0.04% polysorbate 20 or polysorbate 80.

[0068] In each of the aforementioned embodiments and models, in one embodiment, the aqueous formulation is 0 or 1 Contains 0 mM L-methionine.

[0069] In each of the aforementioned embodiments and models, in one embodiment, the pH is 6.0 or 6.5. be.

[0070] In each of the aforementioned embodiments and models, in one embodiment, each of the Fc domains The amino acid sequence is as shown in SEQ ID NO: 1.

[0071] One aspect of the present invention involves using an isolated FcRn antagonist in a concentration of about 100 to about 300 mg / mL, and 20 mM histamine. Thidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.02%~0.04% (w / v) polysorbate This is an aqueous formulation containing Rubate 20 or Polysorbate 80, pH 6.0, wherein the isolated The FcRn antagonist consists of a variant Fc region, where the variant Fc region is, It consists of two Fc domains that form a homodimer, where each of the amino acids of the Fc domain The acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0072] One aspect of the present invention involves using an isolated FcRn antagonist at a concentration of approximately 100 to 200 mg / mL in 20 mM histamine. Thidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.02%~0.04% (w / v) polysorbate This is an aqueous formulation containing Rubate 20 or Polysorbate 80, pH 6.0, wherein the isolated The FcRn antagonist consists of a variant Fc region, where the variant Fc region is, It consists of two Fc domains that form a homodimer, where each of the amino acids of the Fc domain The acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0073] One aspect of the present invention relates to an isolated neonatal Fc receptor (FcRn) antagonist at approximately 100-300 mg / mL. The solution consists of 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0%~0.04% ( This is an aqueous formulation containing w / v) polysorbate 20 or polysorbate 80, pH 6.0, where, The isolated FcRn antagonist consists of a variant Fc region, where the variant The Fc region consists of two Fc domains that form a homodimer, where each of the Fc domains Each amino acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0074] In one embodiment, the present invention provides ARGX-113 in a concentration of about 100 to about 300 mg / mL, along with 20 mM histidine / Histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.02%~0.04% (w / v) polysorbate This is an aqueous formulation containing 20 or polysorbate 80, pH 6.0, where ARGX-113 is a barrier. An isolated FcRn antagonist consisting of the variant Fc region, where the variant Fc region It consists of two Fc domains that form a homodimer, where each of the Fc domains The amino acid sequence consists of sequence number 1.

[0075] One aspect of the present invention relates to an isolated neonatal Fc receptor (FcRn) antagonist at approximately 100-200 mg / mL. The solution consists of 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.02%~0.04 This is an aqueous formulation containing %(w / v) polysorbate 20 or polysorbate 80, pH 6.0, and here The isolated FcRn antagonist consists of a variant Fc region, where the barrier The Fc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0076] In one embodiment, the present invention provides ARGX-113 in a concentration of about 100 to about 200 mg / mL, along with 20 mM histidine / Histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.02%~0.04% (w / v) polysorbate This is an aqueous formulation containing 20 or polysorbate 80, pH 6.0, where ARGX-113 is a barrier. An isolated FcRn antagonist consisting of the variant Fc region, where the variant Fc region It consists of two Fc domains that form a homodimer, where each of the Fc domains The amino acid sequence consists of sequence number 1.

[0077] As used herein, the term “about” means ±10% of any given specified amount. This refers to an amount within a certain range. For example, approximately 200 mg / mL is 90% to 110% of 200 mg / mL, i.e., 180 to 220 mg / mL. Includes g / mL

[0078] In one embodiment, the aqueous formulation contains 100-300 mg / mL of ARGX-113.

[0079] In one embodiment, the aqueous formulation contains 100-200 mg / mL of ARGX-113.

[0080] In one embodiment, the aqueous formulation contains approximately 150 to approximately 200 mg / mL of ARGX-113. In this embodiment, the aqueous formulation contains 150-200 mg / mL of ARGX-113.

[0081] In one embodiment, the aqueous formulation contains approximately 150 to approximately 180 mg / mL of ARGX-113. In this embodiment, the aqueous formulation contains 150-180 mg / mL of ARGX-113.

[0082] In one embodiment, the aqueous formulation contains approximately 165 mg / mL of ARGX-113.

[0083] In one embodiment, the aqueous formulation contains approximately 175 mg / mL of ARGX-113.

[0084] In one embodiment, the aqueous formulation contains approximately 180 mg / mL of ARGX-113.

[0085] In one embodiment, the aqueous formulation contains approximately 250 mg / mL of ARGX-113.

[0086] In one embodiment, the aqueous formulation contains approximately 300 mg / mL of ARGX-113.

[0087] According to each of the embodiments described above, in one embodiment, the aqueous formulation is 0.02% to 0.04% Contains (w / v) polysorbate 20. In one embodiment, the aqueous formulation contains 0.02% (w / v) polysorbate 20. Contains Rubate 20. In one embodiment, the aqueous formulation contains 0.03% (w / v) polysorbate 20 It includes. In one embodiment, the aqueous formulation contains 0.04% (w / v) polysorbate 20.

[0088] Alternatively, according to each of the embodiments described above, in one embodiment, the aqueous formulation is 0.02% Contains ~0.04% (w / v) polysorbate 80. In one embodiment, the aqueous formulation contains 0.02% (w / v) Contains polysorbate 80. In one embodiment, the aqueous formulation contains 0.03% (w / v) polysorbate 80. Contains 80 polysorbate. In one embodiment, the aqueous formulation contains 0.04% (w / v) polysorbate 80. include.

[0089] In one embodiment, the aqueous formulation contains 165 mg / mL of ARGX-113 and 20 mM histidine / histidine Contains HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0. Here, ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0090] One aspect of the present invention involves using approximately 150 mg / mL of isolated FcRn antagonist in a solution of 20 mM histidine / Histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6 An aqueous formulation containing 0, wherein the isolated FcRn antagonist is variant Fc It consists of a region, where the variant Fc region is composed of two Fc domains that form a homodimer. It consists of, where each amino acid sequence of the Fc domain is, SEQ ID NO: 1, SEQ ID NO: 2, or It consists of sequence number 3.

[0091] In one embodiment, the present invention provides 150 mg / mL of ARGX-113, and 20 mM histidine / histidine H Contains Cl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0. It is an aqueous formulation in which ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region. It is a gonist, and here the variant Fc region is two Fc domains that form a homodimer. It consists of, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0092] One aspect of the present invention involves using approximately 175 mg / mL of an isolated FcRn antagonist, along with 20 mM histidine / Histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6 An aqueous formulation containing 0, wherein the isolated FcRn antagonist is variant Fc It consists of a region, where the variant Fc region is composed of two Fc domains that form a homodimer. It consists of, where each amino acid sequence of the Fc domain is, SEQ ID NO: 1, SEQ ID NO: 2, or It consists of sequence number 3.

[0093] In one embodiment, the present invention provides 175 mg / mL of ARGX-113, and 20 mM histidine / histidine H Contains Cl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0. It is an aqueous formulation in which ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region. It is a gonist, and here the variant Fc region is two Fc domains that form a homodimer. It consists of, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0094] One aspect of the present invention involves using approximately 200 mg / mL of isolated FcRn antagonist in a solution of 20 mM histidine / Histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6 An aqueous formulation containing 0, wherein the isolated FcRn antagonist is variant Fc It consists of a region, where the variant Fc region is composed of two Fc domains that form a homodimer. It consists of, where each amino acid sequence of the Fc domain is, SEQ ID NO: 1, SEQ ID NO: 2, or It consists of sequence number 3.

[0095] In one embodiment, the present invention provides 200 mg / mL of ARGX-113, and 20 mM histidine / histidine H Contains Cl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0. It is an aqueous formulation in which ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region. It is a gonist, and here the variant Fc region is two Fc domains that form a homodimer. It consists of, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0096] One aspect of the present invention involves using an isolated FcRn antagonist at approximately 100-300 mg / mL, mixed with 20 mM histamine. Zin / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0%~0.04 This is an aqueous formulation containing %(w / v) polysorbate 20 or polysorbate 80, pH 6.0, and here The isolated FcRn antagonist consists of a variant Fc region, where the barrier The Fc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0097] In one embodiment, the present invention provides ARGX-113 at approximately 100-300 mg / mL, and 20 mM histidine / histidine Tidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0%~0.04% (w / v) phosphate. This is an aqueous formulation containing Resorbate 20 or Polysorbate 80, pH 6.0, where ARGX-1 13 is an isolated FcRn antagonist consisting of a variant Fc region, where the variant The antFc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence of n is represented by sequence number 1.

[0098] One aspect of the present invention involves using an isolated FcRn antagonist at approximately 100-200 mg / mL, and 20 mM histamine. Zin / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.02%~0 This is an aqueous formulation containing 0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0. Thus, the isolated FcRn antagonist consists of a variant Fc region, where the variant The antFc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence of n consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0099] In one embodiment, the present invention provides ARGX-113 at approximately 100-200 mg / mL, and 20 mM histidine / histidine Tidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.02%~0.04% (w / v ) An aqueous formulation containing polysorbate 20 or polysorbate 80, pH 6.0, where ARG X-113 is an isolated FcRn antagonist consisting of a variant Fc region, where the The variant Fc region consists of two Fc domains that form a homodimer, where the Fc domain The main amino acid sequence for each component starts with Sequence ID No. 1.

[0100] One aspect of the present invention involves using an isolated neonatal Fc receptor (FcRn) antagonist at approximately 165 mg / mL. 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and This is an aqueous formulation containing 0.04% (w / v) polysorbate 20, pH 6.0, wherein the isolated The FcRn antagonist consists of a variant Fc region, where the variant Fc region is, It consists of two Fc domains that form a homodimer, where each of the amino acids of the Fc domain The acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0101] In one embodiment, the present invention provides 165 mg / mL of ARGX-113, and 20 mM histidine / histidine H Cl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.04% (w / v) polysorbate 20. An aqueous formulation contained in pH 6.0, where ARGX-113 is a single variant consisting of the Fc region. It is a separated FcRn antagonist, where the variant Fc region forms a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is, It consists of item 1.

[0102] One aspect of the present invention involves using approximately 175 mg / mL of an isolated FcRn antagonist, along with 20 mM histidine / Histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) phosphate. This is an aqueous formulation contained in Resorbate 20, pH 6.0, in which the isolated FcRn antagonist is present. The strium consists of a variant Fc region, where the variant Fc region forms a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is, It consists of code 1, sequence number 2, or sequence number 3.

[0103] In one embodiment, the present invention provides 175 mg / mL of ARGX-113, and 20 mM histidine / histidine H Cl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20. An aqueous formulation contained in pH 6.0, where ARGX-113 is a single variant consisting of the Fc region. It is a separated FcRn antagonist, where the variant Fc region forms a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is, It consists of item 1.

[0104] One aspect of the present invention involves using approximately 200 mg / mL of isolated FcRn antagonist in a solution of 20 mM histidine / Histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) phosphate. This is an aqueous formulation contained in Resorbate 20, pH 6.0, in which the isolated FcRn antagonist is present. The strium consists of a variant Fc region, where the variant Fc region forms a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is, It consists of code 1, sequence number 2, or sequence number 3.

[0105] In one embodiment, the present invention provides 200 mg / mL of ARGX-113, and 20 mM histidine / histidine H Cl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20. An aqueous formulation contained in pH 6.0, where ARGX-113 is a single variant consisting of the Fc region. It is a separated FcRn antagonist, where the variant Fc region is homozygous for the Fc domain. It consists of a mer, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0106] One aspect of the present invention involves using an isolated FcRn antagonist in a concentration of about 100 to about 300 mg / mL, and 50 mM histamine. Thidine / histidine HCl, 60 mM sucrose, 150 mM arginine HCl, and 0.02%~0.04% (w / v ) an aqueous formulation containing polysorbate 20 or polysorbate 80, pH 6.0, wherein the The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each of the Fc domains The amino acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0107] In one embodiment, the present invention provides ARGX-113 at approximately 100 to approximately 300 mg / mL, and 50 mM histidine / Stidine HCl, 60 mM sucrose, 150 mM arginine HCl, and 0.02%~0.04% (w / v) polysol This is an aqueous formulation contained in β20 or polysorbate 80, pH 6.0, where ARGX-113 is An isolated FcRn antagonist consisting of a variant Fc region, where the variant The Fc region consists of two Fc domains that form a homodimer, where each of the Fc domains Each amino acid sequence is derived from Sequence ID No. 1.

[0108] In one embodiment according to this aspect of the present invention, the aqueous formulation contains 100-300 mg / mL of ARGX-11 Includes 3.

[0109] In one embodiment according to this aspect of the present invention, the aqueous formulation contains approximately 150 to approximately 200 mg / mL of ARG. Contains X-113. In one embodiment, according to this aspect of the present invention, the aqueous formulation is 150-20 Contains 0 mg / mL of ARGX-113.

[0110] In one embodiment according to this aspect of the present invention, the aqueous formulation contains approximately 150 to approximately 180 mg / mL of ARG. Contains X-113. In one embodiment, according to this aspect of the present invention, the aqueous formulation is 150-180 Contains mg / mL of ARGX-113.

[0111] According to each of the embodiments described above, in one embodiment, the aqueous formulation is 0.02% to 0.04% Contains (w / v) polysorbate 20. In one embodiment, the aqueous formulation contains 0.02% (w / v) polysorbate 20. Contains Rubate 20. In one embodiment, the aqueous formulation contains 0.03% (w / v) polysorbate 20 It includes. In one embodiment, the aqueous formulation contains 0.04% (w / v) polysorbate 20.

[0112] One aspect of the present invention involves using an isolated FcRn antagonist in a concentration of approximately 100 to 200 mg / mL, and 50 mM histamine. Thidine / histidine HCl, 60 mM sucrose, 150 mM arginine HCl, and 0.02%~0.04% (w / v ) an aqueous formulation containing polysorbate 20 or polysorbate 80, pH 6.0, wherein the The isolated FcRn antagonist consists of a variant Fc region, where the variant Fc The region consists of two Fc domains that form a homodimer, where each of the Fc domains The amino acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0113] In one embodiment, the present invention provides ARGX-113 at approximately 100 to approximately 200 mg / mL, and 50 mM histidine / Stidine HCl, 60 mM sucrose, 150 mM arginine HCl, and 0.02%~0.04% (w / v) polysol This is an aqueous formulation contained in β20 or polysorbate 80, pH 6.0, where ARGX-113 is An isolated FcRn antagonist consisting of a variant Fc region, where the variant The Fc region consists of two Fc domains that form a homodimer, where each of the Fc domains Each amino acid sequence is derived from Sequence ID No. 1.

[0114] In one embodiment according to this aspect of the present invention, the aqueous formulation contains 100-300 mg / mL of ARGX-11 Includes 3.

[0115] In one embodiment according to this aspect of the present invention, the aqueous formulation contains approximately 150 to approximately 200 mg / mL of ARG. Contains X-113. In one embodiment, according to this aspect of the present invention, the aqueous formulation is 150-20 Contains 0 mg / mL of ARGX-113.

[0116] In one embodiment according to this aspect of the present invention, the aqueous formulation contains approximately 150 to approximately 180 mg / mL of ARG. Contains X-113. In one embodiment, according to this aspect of the present invention, the aqueous formulation is 150-18 Contains 0 mg / mL of ARGX-113.

[0117] According to each of the embodiments described above, in one embodiment, the aqueous formulation is 0.02% to 0.04% Contains (w / v) polysorbate 20. In one embodiment, the aqueous formulation contains 0.02% (w / v) polysorbate 20. Contains Rubate 20. In one embodiment, the aqueous formulation contains 0.03% (w / v) polysorbate 20 It includes. In one embodiment, the aqueous formulation contains 0.04% (w / v) polysorbate 20.

[0118] Alternatively, according to each of the embodiments described above, in one embodiment, the aqueous formulation is 0.02% Contains ~0.04% (w / v) polysorbate 80. In one embodiment, the aqueous formulation contains 0.02% (w / v) Contains polysorbate 80. In one embodiment, the aqueous formulation contains 0.03% (w / v) polysorbate 80. Contains 80 polysorbate. In one embodiment, the aqueous formulation contains 0.04% (w / v) polysorbate 80. include.

[0119] In one embodiment, the aqueous formulation contains approximately 150 mg / mL of ARGX-113 and 50 mM histidine / histidine. Zin HCl, 60 mM sucrose, 150 mM arginine HCl, and 0.04% (w / v) polysorbate 80, pH Included in 6.0.

[0120] In one embodiment, the aqueous formulation contains 150 mg / mL of ARGX-113 and 50 mM histidine / histidine Arginine HCl, 60 mM sucrose, 150 mM arginine HCl, 10 mM L-methionine, and 0.04% (w / v) phosphate. Contains Resorbate 80, pH 6.0.

[0121] One aspect of the present invention involves using an isolated FcRn antagonist at approximately 100-200 mg / mL, and 20 mM histamine. Zin / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0 A water-based formulation containing 0.02%~0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0. Here, the isolated FcRn antagonist consists of a variant Fc region, The variant Fc region consists of two Fc domains that form a homodimer, where the F Each amino acid sequence in the c domain consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0122] In one embodiment, the present invention provides ARGX-113 at approximately 100-200 mg / mL, and 20 mM histidine / histidine Thidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.02%~0. This is an aqueous formulation containing 0.4% (w / v) polysorbate 20 or polysorbate 80, pH 6.0. Thus, ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region, Thus, the variant Fc region consists of two Fc domains that form a homodimer, and here The amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0123] One aspect of the present invention involves using approximately 175 mg / mL of an isolated FcRn antagonist, along with 20 mM histidine / Histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v) Polysorbate 20, pH 6.0 aqueous formulation containing the isolated FcRn The antagonist consists of a variant Fc region, where the variant Fc region is homodimeric It consists of two Fc domains that form the body, and the amino acid sequence of each of these Fc domains is It consists of sequence number 1, sequence number 2, or sequence number 3.

[0124] In one embodiment, the present invention provides 175 mg / mL of ARGX-113, and 20 mM histidine / histidine H Cl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate Rubate 20 is an aqueous formulation contained in pH 6.0, where ARGX-113 is a variant in the Fc region. It is an isolated FcRn antagonist, wherein the variant Fc region consists of an Fc domain homodimer, wherein each amino acid sequence of the Fc domain consists of SEQ ID NO: 1 .

[0125] One aspect of the present invention is an aqueous formulation containing an isolated FcRn antagonist at about 200 mg / mL in 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20, pH 6.0, wherein the isolated FcRn a ntagonist consists of a variant Fc region, wherein the variant Fc region consists of an Fc domain homodimer, wherein each amino acid sequence of the Fc domain consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0126] In one embodiment, the present invention provides an aqueous formulation containing 200 mg / mL of ARGX-113 in 20 mM histidine / histidine H Cl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v) polysorb ate 20, pH 6.0, wherein ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region, wherein the variant Fc region consists of an Fc domain homodimer, wherein each amino acid sequence of the Fc domain consists of SEQ ID NO: 1 .

[0127] One aspect of the present invention is an aqueous formulation containing an isolated neonatal Fc receptor (FcRn) antagonist at about 100 - 300 mg / mL in 50 mM histidine / histidine HCl, 200 mM arginine HCl, pH 6.5 . ​Here, the isolated FcRn antagonist consists of a variant Fc region, The variant Fc region consists of two Fc domains that form a homodimer, where the F Each amino acid sequence in the c domain consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0128] In one embodiment, the aqueous formulation contains approximately 200-300 mg / mL of isolated neonatal Fc receptor (FcRn ) The antagonist is placed in 50 mM histidine / histidine HCl, 200 mM arginine HCl, pH 6.5. The aqueous formulation contains the isolated FcRn antagonist in the variant Fc region. Therefore, here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0129] In one embodiment, the aqueous formulation contains approximately 250-300 mg / mL of isolated neonatal Fc receptor (FcRn ) The antagonist is placed in 50 mM histidine / histidine HCl, 200 mM arginine HCl, pH 6.5. The aqueous formulation contains the isolated FcRn antagonist in the variant Fc region. Therefore, here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0130] According to each of the embodiments described above, in one embodiment, the aqueous formulation is dissolved acid Substantially contains no elements. Where used herein, “substantially contains” is a term that is not substantially derived from the original. This means that it does not contain at least 95% of the substance. For example, in one embodiment, the aqueous formulation is dissolved It contains at least 95% dissolved oxygen. In various embodiments, the aqueous formulation contains dissolved oxygen Contains at least 96%, at least 97%, at least 98%, at least 99%, or 100% No. Assuming that water is equilibrium in an atmosphere that is normally 20% oxygen, in one embodiment In this context, an aqueous formulation that substantially contains no dissolved oxygen contains 1% or less dissolved oxygen. In the application method, the aqueous formulation does not contain 100% dissolved oxygen.

[0131] According to each of the aforementioned embodiments and models, in one embodiment, the aqueous formulation is an inv Suitable for use in blotting. For example, in such an embodiment, the aqueous formulation is sterilized. Furthermore, it does not contain toxic substances in amounts unacceptable for pharmaceutical use, such as endotoxins. Such aqueous formulations are subject to regulations published by, for example, the U.S. Food and Drug Administration (FDA). It can comply with excellent manufacturing process (GMP) quality standards.

[0132] (Method for preparing the formulation) The formulation according to the present invention can be prepared using any suitable method. Typically, ARGX-1 13 is prepared from eukaryotic cells containing an expression vector or nucleic acid sequence encoding the Fc domain. For example, eukaryotic cells include Chinese hamster ovary (CHO) cells, DG44 and DUXB11 (Chinese hamster ovary (CHO) cells). Needs hamster ovary strain (DHFR negative), HELA (human cervical cancer), CVI (monkey kidney strain), COS ( (Derivative of CVI possessing SV40 T antigen), R1610 (Chinese hamster fibroblast), BALBC / 3 T3 (mouse fibroblasts), HAK (hamster kidney cell line), SP2 / 0 (mouse myeloma), BFA-1c1BPT (U It can be a SHEN endothelial cell), RAJI (human lymphocyte), 293 (human kidney), or NS0 cell. In one embodiment, the eukaryotic cell used to express ARGX-113 is a CHO cell. For example, see WO 2015 / 100299, the entire content of which is incorporated herein by reference. ARGX-113 is typically expressed as a secreted protein that can be isolated from cells using techniques known in the art. Normally, the isolated and unconcentrated protein product is then placed in a sterile aqueous solution such as Tris / glycine, pH 7.2 or 20 mM L-histidine / L-histidine HCl·H2O, pH 6.0.

[0133] Subsequently, the initial product is concentrated as needed to reach a concentrated protein solution containing ARGX-113 at a concentration equal to or exceeding the target final concentration and subjected to buffer exchange. For example, concentration increase and buffer exchange can result in an intermediate product containing about 200 mg / mL of ARGX-113 in 20 mM L-histidine / L-histidine HCl·H2O, 100 mM NaCl, pH 6.0.

[0134] The concentration increase can be carried out using any suitable method known in the art. Such methods include, but are not limited to, tangential flow filtration (TFF), dialysis, ultrafiltration, and lyophilization. For commercial production, TFF can usually be used.

[0135] Subsequently, additional components can be added to reach the desired final formulation. For example, NaCl , additional components such as arginine HCl, sucrose, and / or polysorbate, Each concentrated stock solution can be added, and if desired, water can be added. The final formulation can be reached. In a particular embodiment, polysorbate (PS20) It is added as the very last excipient in the formulation to ensure that the correct pH value is achieved (polyso Since the molecular weight of Rubate is the same as that of ARGX-113, polysorbate is added last. This helps to avoid an increase in concentration.

[0136] In one embodiment, the intermediate solution and additional components are degassed or otherwise treated. Reduce or eliminate dissolved oxygen. For example, the intermediate solution and additional components are oxidized with argon or nitrogen. It can be balanced.

[0137] In one embodiment, the final aqueous formulation is degassed or otherwise treated to remove dissolved oxygen. To reduce or eliminate dissolved oxygen. For example, the final aqueous formulation reduces or eliminates dissolved oxygen from the formulation. By bubbling argon or nitrogen in the final aqueous formulation for a sufficient period of time, , equilibration can be achieved with the gas. In one embodiment, the final aqueous formulation is then, It is stored under a nitrogen atmosphere.

[0138] The aqueous formulations prepared in this manner are usually sterile filtered and then used as described herein. It is dispensed into sterile containers or devices and stored.

[0139] (Route of administration) The aqueous formulation of the present invention is suitable for parenteral administration. In one embodiment, the aqueous formulation of the present invention The formulation is suitable for subcutaneous administration. In one embodiment, the aqueous formulation of the present invention is administered intravenously. It is suitable for administration. In one embodiment, the aqueous formulation of the present invention is suitable for intraperitoneal administration. .

[0140] (Effective dose) The preparations and compositions are usually administered in an effective dose. The "effective dose" is the desired dose. This refers to the amount sufficient to achieve the desired effect. In one embodiment, the effective dose is the therapeutic effective dose. In other words, it refers to a quantity sufficient to achieve the desired therapeutic effect in the subject. Examples, though not limited to them, include a decrease in total serum IgG, as well as myasthenia gravis (MG) and This includes the treatment of various antibody-mediated autoimmune diseases such as immunothrombocytopenia (ITP).

[0141] (subject) As used herein, “subject” usually refers to mammals. In some embodiments, The subject is a mammal other than a human or a non-human primate. In one embodiment, the subject is a human or a non-human primate. In one embodiment, the subject is a human. In one embodiment, the subject is an adult, i.e., a human being at least 18 years of age. In this study, the subjects are individuals under the age of 18.

[0142] (Pharmaceutical products) One aspect of the present invention is a packaged medical device comprising a sterile container containing a therapeutically effective amount of the aqueous formulation of the present invention. It is a pharmaceutical product. In various embodiments, the packaged pharmaceutical product is a single-use vial, multiple It can be presented as a vial for multiple uses or as a pre-filled syringe.

[0143] (Device) One aspect of the present invention is an apparatus containing a therapeutically effective amount of the aqueous formulation of the present invention.

[0144] In one embodiment, the aqueous formulation contains approximately 100-200 mg / mL of isolated FcRn antagonists. The solution consists of 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.02%~0.04 This is an aqueous formulation containing %(w / v) polysorbate 20 or polysorbate 80, pH 6.0, and here The isolated FcRn antagonist consists of a variant Fc region, where the barrier The Fc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0145] In one embodiment, the aqueous formulation contains 150 mg / mL of isolated FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysol This is an aqueous formulation contained in Bate 20, pH 6.0, in which the isolated FcRn antagonist is , consisting of a variant Fc region, where the variant Fc region forms a homodimer 2 It consists of two Fc domains, where the amino acid sequence of each Fc domain is as follows: It consists of either Sequence ID 2 or Sequence ID 3.

[0146] In one embodiment, the aqueous formulation contains 175 mg / mL of isolated FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysol This is an aqueous formulation contained in Bate 20, pH 6.0, in which the isolated FcRn antagonist is , consisting of a variant Fc region, where the variant Fc region forms a homodimer 2 It consists of two Fc domains, where the amino acid sequence of each Fc domain is as follows: It consists of either Sequence ID 2 or Sequence ID 3.

[0147] In one embodiment, the aqueous formulation contains 200 mg / mL of isolated FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysol This is an aqueous formulation contained in Bate 20, pH 6.0, in which the isolated FcRn antagonist is , consisting of a variant Fc region, where the variant Fc region forms a homodimer 2 It consists of two Fc domains, where the amino acid sequence of each Fc domain is as follows: It consists of either Sequence ID 2 or Sequence ID 3.

[0148] In one embodiment, the aqueous formulation contains approximately 100-300 mg / mL of ARGX-113, along with 20 mM histidine / Histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0%~0.04% (w / v) polysorbate 20 Alternatively, it is an aqueous formulation contained in polysorbate 80, pH 6.0, where ARGX-113 is Varian An isolated FcRn antagonist consisting of an Fc region, where the variant Fc region is It consists of two Fc domains that form a homodimer, and here, each of the Fc domains The no-acid sequence consists of sequence number 1.

[0149] In one embodiment, the aqueous formulation contains approximately 100-200 mg / mL of ARGX-113 and 20 mM histidine / Histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.02%~0.04% (w / v) polysorbate This is an aqueous formulation containing 20 or polysorbate 80, pH 6.0, where ARGX-113 is a barrier. An isolated FcRn antagonist consisting of the variant Fc region, where the variant Fc region It consists of two Fc domains that form a homodimer, where each of the Fc domains The amino acid sequence consists of sequence number 1.

[0150] In one embodiment, the aqueous formulation contains 150 mg / mL of ARGX-113 and 20 mM histidine / histidine. Zin HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0 It is an aqueous formulation in which ARGX-113 is an isolated FcRn variant consisting of the Fc region. It is an antagonist, and here the variant Fc region is two Fc units that form a homodimer. It consists of a main component, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0151] In one embodiment, the aqueous formulation contains 175 mg / mL of ARGX-113 and 20 mM histidine / histidine Zin HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0 It is an aqueous formulation in which ARGX-113 is an isolated FcRn variant consisting of the Fc region. It is an antagonist, and here the variant Fc region is two Fc units that form a homodimer. It consists of a main component, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0152] In one embodiment, the aqueous formulation contains 200 mg / mL of ARGX-113 and 20 mM histidine / histidine. Zin HCl, 60 mM sucrose, 100 mM NaCl, and 0.04% (w / v) polysorbate 20, pH 6.0 It is an aqueous formulation in which ARGX-113 is an isolated FcRn variant consisting of the Fc region. It is an antagonist, and here the variant Fc region is two Fc units that form a homodimer. It consists of a main component, where the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0153] In one embodiment, the aqueous formulation contains approximately 100-300 mg / mL of isolated FcRn antagonists. To prepare the solution, use 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 10 mM L-methionine. N, and aqueous solutions contained in 0%~0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0. The formulation is such that the isolated FcRn antagonist consists of a variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer, The amino acid sequence of each Fc domain is derived from SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. Yes.

[0154] In one embodiment, the aqueous formulation contains 150 mg / mL of isolated FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0 This is an aqueous formulation containing 0.04% (w / v) polysorbate 20, pH 6.0, wherein the isolated The FcRn antagonist consists of a variant Fc region, where the variant Fc region is H It consists of two Fc domains that form a monimer, where each amino acid of the Fc domain The sequence consists of sequence number 1, sequence number 2, or sequence number 3.

[0155] In one embodiment, the aqueous formulation contains 165 mg / mL of isolated FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0 This is an aqueous formulation containing 0.04% (w / v) polysorbate 20, pH 6.0, where the isolated Fc The Rn antagonist consists of a variant Fc region, where the variant Fc region is homo It consists of two Fc domains that form a dimer, and here, the amino acid composition of each Fc domain Each column consists of sequence number 1, sequence number 2, or sequence number 3.

[0156] In one embodiment, the aqueous formulation contains 175 mg / mL of isolated FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0 This is an aqueous formulation containing 0.04% (w / v) polysorbate 20, pH 6.0, where the isolated Fc The Rn antagonist consists of a variant Fc region, where the variant Fc region is homo It consists of two Fc domains that form a dimer, and here, the amino acid composition of each Fc domain Each column consists of sequence number 1, sequence number 2, or sequence number 3.

[0157] In one embodiment, the aqueous formulation contains 180 mg / mL of isolated antagonist, 20 mM hydroxyl Stidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.04 This is an aqueous formulation containing %(w / v) polysorbate 20, pH 6.0, wherein the isolated FcRn The antagonist consists of a variant Fc region, where the variant Fc region is homozygous It consists of two Fc domains that form a mer, where the amino acid sequence of each Fc domain is This consists of sequence number 1, sequence number 2, or sequence number 3.

[0158] In one embodiment, the aqueous formulation contains 200 mg / mL of isolated FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0 This is an aqueous formulation containing 0.04% (w / v) polysorbate 20, pH 6.0, where the isolated Fc The Rn antagonist consists of a variant Fc region, where the variant Fc region is homo It consists of two Fc domains that form a dimer, and here, the amino acid composition of each Fc domain Each column consists of sequence number 1, sequence number 2, or sequence number 3.

[0159] In one embodiment, the aqueous formulation contains 300 mg / mL of isolated FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0 This is an aqueous formulation containing 0.04% (w / v) polysorbate 20, pH 6.0, where the isolated Fc The Rn antagonist consists of a variant Fc region, where the variant Fc region is homo It consists of two Fc domains that form a dimer, and here, the amino acid composition of each Fc domain Each column consists of sequence number 1, sequence number 2, or sequence number 3.

[0160] In one embodiment, the aqueous formulation contains approximately 100-300 mg / mL of ARGX-113, along with 20 mM histidine / Histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0%~0.04% (w / v) An aqueous formulation containing polysorbate 20 or polysorbate 80, pH 6.0, where AR GX-113 is an isolated FcRn antagonist consisting of a variant Fc region, where the The variant Fc region consists of two Fc domains that form a homodimer, where the Fc domain The main amino acid sequence for each component starts with Sequence ID No. 1.

[0161] In one embodiment, the aqueous formulation contains 150 mg / mL of ARGX-113 and 20 mM histidine / histidine. Zin HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysol This is an aqueous formulation contained in β20, pH 6.0, where ARGX-113 is derived from the variant Fc region. This is an isolated FcRn antagonist, where the variant Fc region is a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is: It consists of sequence number 1.

[0162] In one embodiment, the aqueous formulation contains approximately 165 mg / mL of ARGX-113, and 20 mM histidine / histidine Tidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.04% (w / v) polysorbate Rubate 20 is an aqueous formulation contained in pH 6.0, where ARGX-113 is a variant in the Fc region. These are isolated FcRn antagonists, where the variant Fc region is homodimeric. It consists of two Fc domains that form the body, and the amino acid sequence of each of these Fc domains is It consists of sequence number 1.

[0163] In one embodiment, the aqueous formulation contains approximately 165 mg / mL of isolated FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and This is an aqueous formulation containing 0.04% (w / v) polysorbate 20, pH 6.0, in which isolated F is present. The cRn antagonist consists of a variant Fc region, where the variant Fc region is H It consists of two Fc domains that form a monimer, where each amino acid of the Fc domain The sequence consists of sequence number 1, sequence number 2, or sequence number 3.

[0164] In one embodiment, the aqueous formulation contains 165 mg / mL of ARGX-113 and 20 mM histidine / histidine Zin HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.04% (w / v) polysol This is an aqueous formulation contained in β20, pH 6.0, where ARGX-113 is derived from the variant Fc region. This is an isolated FcRn antagonist, where the variant Fc region is a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is: It consists of sequence number 1.

[0165] In one embodiment, the aqueous formulation contains 175 mg / mL of ARGX-113 and 20 mM histidine / histidine Zin HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysol This is an aqueous formulation contained in β20, pH 6.0, where ARGX-113 is derived from the variant Fc region. This is an isolated FcRn antagonist, where the variant Fc region is a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is: It consists of sequence number 1.

[0166] In one embodiment, the aqueous formulation contains 200 mg / mL of ARGX-113 and 20 mM histidine / histidine. Zin HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysol This is an aqueous formulation contained in β20, pH 6.0, where ARGX-113 is derived from the variant Fc region. This is an isolated FcRn antagonist, where the variant Fc region is a homodimer. It consists of two Fc domains, where the amino acid sequence of each Fc domain is: It consists of sequence number 1.

[0167] In one embodiment, the aqueous formulation contains approximately 100 to 200 mg / mL of isolated FcRn antagonist The solution consists of 50 mM histidine / histidine HCl, 60 mM sucrose, 150 mM arginine HCl, and 0. A water-based formulation containing 0.2%~0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0. Here, the isolated FcRn antagonist consists of a variant Fc region, The variant Fc region consists of two Fc domains that form a homodimer, where the F Each amino acid sequence in the c domain consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0168] In one embodiment, the aqueous formulation contains approximately 100 to 200 mg / mL of ARGX-113 and 50 mM histidine. Histidine HCl, 60 mM sucrose, 150 mM arginine HCl, and 0.02%~0.04% (w / v) phosphate. This is an aqueous formulation containing Resorbate 20 or Polysorbate 80, pH 6.0, where ARGX-1 13 is an isolated FcRn antagonist consisting of a variant Fc region, where the variant The antFc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence of n is represented by sequence number 1.

[0169] In one embodiment, the aqueous formulation contains approximately 100 to 200 mg / mL of isolated FcRn antagonist The solution is 50 mM histidine / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L - Methionine, and 0.02%~0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0 The aqueous formulation contained herein is the isolated FcRn antagonist, which is the variant Fc region It consists of a region, where the variant Fc region is composed of two Fc domains that form a homodimer. Therefore, here, each amino acid sequence of the Fc domain is sequence number 1, sequence number 2, or It consists of column number 3.

[0170] In one embodiment, the aqueous formulation contains approximately 150 mg / mL of isolated FcRn antagonist, 50 mM histidine / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine This is an aqueous formulation containing nin and 0.02%~0.04% (w / v) polysorbate 20, pH 6.0. Thus, the isolated FcRn antagonist consists of a variant Fc region, where the variant The antFc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence of n consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0171] In one embodiment, the aqueous formulation contains approximately 175 mg / mL of isolated FcRn antagonist, 50 mM histidine / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine This is an aqueous formulation containing nin and 0.02%~0.04% (w / v) polysorbate 20, pH 6.0. Thus, the isolated FcRn antagonist consists of a variant Fc region, where the variant The antFc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence of n consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0172] In one embodiment, the aqueous formulation contains approximately 200 mg / mL of isolated FcRn antagonist, 50 mM histidine / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine This is an aqueous formulation containing nin and 0.02%~0.04% (w / v) polysorbate 20, pH 6.0. Thus, the isolated FcRn antagonist consists of a variant Fc region, where the variant The antFc region consists of two Fc domains that form a homodimer, and here, the Fc domain Each amino acid sequence of n consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0173] In one embodiment, the aqueous formulation contains approximately 100 to 200 mg / mL of ARGX-113 and 50 mM histidine. 0.0 / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.0 This is an aqueous formulation containing 2% to 0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0. Here, ARGX-113 is an isolated FcRn antagonist consisting of a variant Fc region. Here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0174] In one embodiment, the aqueous formulation contains approximately 150 mg / mL of ARGX-113, and 50 mM histidine / histidine Tidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v ) An aqueous formulation contained in polysorbate 20, pH 6.0, where ARGX-113 is variant F An isolated FcRn antagonist consisting of a c region, where the variant Fc region is It consists of two Fc domains that form a homodimer, where each of the amino acids of the Fc domain The acid sequence consists of sequence number 1.

[0175] In one embodiment, the aqueous formulation contains approximately 175 mg / mL of ARGX-113, and 50 mM histidine / histidine Tidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v ) An aqueous formulation contained in polysorbate 20, pH 6.0, where ARGX-113 is variant F An isolated FcRn antagonist consisting of a c region, where the variant Fc region is It consists of two Fc domains that form a homodimer, where each of the amino acids of the Fc domain The acid sequence consists of sequence number 1.

[0176] In one embodiment, the aqueous formulation contains approximately 200 mg / mL of ARGX-113, and 50 mM histidine / histidine Tidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and 0.03% (w / v ) An aqueous formulation contained in polysorbate 20, pH 6.0, where ARGX-113 is variant F An isolated FcRn antagonist consisting of a c region, where the variant Fc region is It consists of two Fc domains that form a homodimer, where each of the amino acids of the Fc domain The acid sequence consists of sequence number 1.

[0177] In one embodiment, the aqueous formulation contains approximately 100-300 mg / mL of isolated neonatal Fc receptor (Fc Rn) Antagonist in 50 mM histidine / histidine HCl, 200 mM arginine HCl, pH 6.5 This is an aqueous formulation containing the isolated FcRn antagonist, wherein the variant Fc region It consists of, where the variant Fc region is composed of two Fc domains that form a homodimer. Here, each amino acid sequence of the Fc domain is sequence number 1, sequence number 2, or sequence number It consists of the number 3.

[0178] In one embodiment, the aqueous formulation contains approximately 200-300 mg / mL of isolated neonatal Fc receptor (FcRn ) The antagonist is placed in 50 mM histidine / histidine HCl, 200 mM arginine HCl, pH 6.5. The aqueous formulation contains the isolated FcRn antagonist in the variant Fc region. Therefore, here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0179] In one embodiment, the aqueous formulation contains approximately 250-300 mg / mL of isolated neonatal Fc receptor (FcRn ) The antagonist is placed in 50 mM histidine / histidine HCl, 200 mM arginine HCl, pH 6.5. The aqueous formulation contains the isolated FcRn antagonist in the variant Fc region. Therefore, here, the variant Fc region consists of two Fc domains that form a homodimer. Here, the amino acid sequence of each Fc domain is as shown in SEQ ID NO: 1.

[0180] According to each of the aforementioned embodiments of this aspect, in one embodiment, the apparatus is about 1 to about 2 It contains 0.5 mL of aqueous formulation. According to each of the above embodiments of this aspect, in one embodiment The device contains 1 to 2.5 mL of aqueous formulation.

[0181] In one embodiment, the apparatus includes a syringe containing an aqueous formulation. For this purpose, it is preferable to administer at least a portion of the aqueous solution contained in the syringe to the target. A suitable needle can be attached. A fine gauge needle (small diameter) causes less pain to the patient. However, a low-viscosity agent is required. The needle gauge is preferably 27 gauge or larger (i.e., (Smaller diameter). The outer diameter of the needle may be 0.413 mm, 0.41 mm, or smaller.

[0182] In one embodiment, the syringe is provided as a pre-filled syringe. The filled syringe should be suitable for single use, or, instead, for multiple (two or more) uses. This is possible. In such pre-filled syringes, optionally, a small amount of the aqueous solution contained in the syringe can be added. A needle suitable for administering to a portion of the target can be attached. In one embodiment, In this case, the pre-filled syringe is provided in a single-unit package.

[0183] In one embodiment, the pre-filled syringe is substantially free of air. In such embodiments, the aqueous formulation contained in the pre-filled syringe substantially reduces the dissolved oxygen. Not included. For example, an aqueous formulation contained in a pre-filled syringe is not included in the description herein. Prepare it with nitrogen, then put it in a syringe, and remove the atmosphere with a nitrogen atmosphere. It can be sealed under air pressure. In one such embodiment, the pre-filled syringe is It can be supplied in a gas-impermeable package.

[0184] In certain embodiments, the present invention provides, for example, 360 mg / 2 mL (= 180 mg / mL) or 330 mg / 2 mL (= 1 Isolated neonatal Fc receptor (FcRn) antagonists (65 mg / mL), including, for example, ARGX-113, A pre-filled syringe filled with 2 mL or 2.1 mL of the aqueous formulation described herein. The present invention provides, for example, a solution containing isolated neonatal Fc receptor (FcRn) at a concentration of 360 mg / 2.2 mL (= 165 mg / mL). A 2.2 mL aqueous formulation as described herein, containing a tagonist, for example, ARGX-113, is filled. These are vials. Such vials are included in the kit, containing aqueous solutions. It can be combined with a needle suitable for administering at least a portion of the liquid to a target.

[0185] The present invention further includes additional aqueous formulations comprising 2 mL, 2.1 mL, 2.2 mL, or more than approximately 2.5 mL of the present invention. The invention envisions an additional device. Such a device may include, for example, but is not limited to, the present invention. Approximately 1.8 mL, 2 mL, 2.1 mL, 2.2 mL, 2.4 mL, 2.6 mL, 2.8 mL, 3 mL, 5 mL, approximately 10 mL, approximately 20 mL This can contain approximately 50 mL and approximately 100 mL of aqueous formulations according to the present invention. By using a pre-filled syringe containing L, 2.2 mL, or 5 mL of aqueous formulation, the formulation can be administered subcutaneously. It has the advantage of being administered by the patient themselves in a single injection (one shot). Yes. Such a "push" subcutaneous administration takes approximately 12-20 seconds or up to 1 minute. For comparison: Infusion by a nurse or caregiver may take several minutes to several hours; manufactured by ARGX-113. The intravenous (IV) infusion of the drug takes approximately 60 minutes. The pre-filled syringe is administered subcutaneously by self-administration. It can be used as a maintenance dose, thus benefiting the patient.

[0186] The present invention has been further illustrated by the following embodiments, which are to be interpreted as further limitations. It should not be done. The sequence listing, drawings, and all referenced throughout this application The contents of the references, patents, and published patent applications are expressly incorporated herein by reference. It can be done. [Examples]

[0187] (Examples) (Example 1. Rheological feature analysis) This example describes experiments conducted to develop and characterize high-concentration formulations of ARGX-113. In particular, the purpose of this series of experiments was to confirm the concentration-viscosity relationship. The experiment was conducted at two temperatures, 5°C and 25°C. Five concentrations of ARGX-113 were tested at the optimal shear rate. Screening and rheological profiling of ARGX-113 in platform buffer I checked the code.

[0188] Start with 4-5 mg / mL of ARGX-113 in Tris / glycine buffer, pH 7.2, then add ARGX-113. Replace the fur and add sodium phosphate + salt at pH 6.7 until the maximum possible concentration (target 250 mg / mL), and Separately, the concentration was increased in histidine HCl (HisHCl) + salt at pH 6.0. During the treatment, the concentration... Temperature and pH were monitored. Viscoelastic behavior was observed from 0 to 4000 s. -1 Depending on the shear rate with an incline The maximum concentration in HisHCl+ salt at pH 6.0 was then investigated. Serial dilutions were performed (6 concentrations), and UV-absorbance was observed. Degree measurement (A 280 This was confirmed using ). Viscosity vs. concentration measurement was performed for 2000 seconds. -1 The procedure was performed at the following shear rate.

[0189] ARGX-113 precipitated in solution at a concentration of ~130 mg / mL in sodium phosphate, pH 6.7+ salt.

[0190] The treatment to increase the concentration of ARGX-113 in sodium phosphate + salt at pH 6.7 was very slow. High concentrations (~130 mg / mL) of ARGX-113 in sodium phosphate + salt under storage conditions (5°C vs 25°C) Therefore, it showed a reversible solid / liquid phase transition. High concentration in sodium phosphate + salt at pH 6.7 ( ARGX-113 at ~130 mg / mL showed very large visible particles in terms of both number and size at 5°C.

[0191] In contrast, ARGX-113 in HisHCl+ salt at pH 6.0 remains in the solution at a concentration of at least ~260 mg / mL. It existed.

[0192] The treatment to increase the concentration of ARGX-113 in HisHCl+ salt at pH 6.0 was rapid.

[0193] In contrast to sodium phosphate buffer + salt, both precipitation and phase separation are significantly observed as the concentration increases. It was not seen.

[0194] Concentration-dependent sol-gel transition was observed after storage at 5°C. The HisHCl formulation was administered at ~260 mg / At mL concentrations (260>200>>120 mg / mL), it appears very jelly-like, and this can be warmed to room temperature or pip It quickly turned into a liquid when I petted it.

[0195] ARGX-113, at very high concentrations and low temperatures (>180 mg / mL, 5°C), in HisHCl+ salt at pH 6.0, It appears to exhibit some thixotropic behavior.

[0196] Shear fluidization / viscosification of ARGX-113 at maximum concentration (pH 6.0, in HisHCl+ salt at 25°C, 267 mg / mL) , 0~4000s -1 The test was conducted using shear rates with an inclination. Typical results are shown in Figure 1. As shown in the figure, ARGX-113 operates at 1000-4000s. -1 Significant shear viscosity in the range It did not show any signs of transformation or fluidization. (2000s) -1 This was selected as the shear rate for the additional tests.

[0197] Representative results of the concentration-to-viscosity test of ARGX-113 in HisHCl+ salt at pH 6.0 are shown in Figure 2. As shown in the figure, the viscosity at 5°C and 25°C, and at approximately 180 mg / mL, is 6 and 6, respectively. The viscosity was 17 mPa·s, and the viscosity at 5°C and 25°C, and at approximately 200 mg / mL, was 9 and 33 mPa·s, respectively. .

[0198] Additional tests were conducted to evaluate the various excipients and pH values ​​of the ARGX-113 solution with increased concentration. Started with 4-5 mg / mL of ARGX-113 in Tris / glycine buffer, pH 7.2, and continued with ARGX-113 Replace the buffer and add sodium phosphate + salt at pH 6.7 until the target concentration of 175 mg / mL is reached. Separately, the concentration was increased in HisHCl+ salt at pH 6.0. During the treatment, the concentration and pH were monitored. We prepared stock solutions of different excipients to obtain various target formulation compositions. The formulation conditions of 11(11) using excipients and pH were evaluated for viscosity reduction at a high concentration of 175 mg / mL. The various formulations considered are shown in Table 1. Table 1. [Table 1] ArgHCl: Arginine HCl SodPhos: Sodium phosphate

[0199] Due to significant precipitation, the phosphate formulation could not be formulated in concentrations exceeding 100 mg / mL. All formulations were stored at 5°C for approximately 48 hours, and any phase transitions were observed. (All 11 formulations) Viscosity measurement at 5°C for 2000 seconds -1 The procedure was performed at the specified shear rate, and the viscosity of the selective formulation was measured at 25°C. .

[0200] All formulations, excluding stock, remain liquid and clear even after two days when stored at 5°C. The result was that F11 (SodPhos + NaCl) became turbid and precipitated when the concentration increased to ~129 mg / mL. The results were shown. The phosphate preparation formed a clear solution after being mixed and stored at 5°C. F9 (pH 6.5) The formulation was slightly opaque, and this became slightly clearer at 5°C.

[0201] Viscosity was low at 5°C for all formulations F1-F11 (<25 mPa·s). Viscosity was low for F2 and F5. It showed an effective reduction. Sucrose was present in 20 mM His / HisHCl, pH 6.0 (F6 and F8), at a concentration of 175 mg. The viscosity was increased by / mL.

[0202] (Example 2. Further rheological feature analysis) This example was conducted to develop and characterize candidate formulations of ARGX-113 at higher concentrations. This document describes the experiments conducted. In particular, the purpose of this series of experiments was to test specific characteristics and short-term stability. Identifying candidate high-concentration liquid formulations of ARGX-113 for preclinical toxicity testing and early clinical trials based on [the following criteria]. That was the task.

[0203] The compositions of the four aqueous formulations of ARGX-113 examined in this example are shown in Table 2. Table 2. [Table 2]

[0204] Starting with ARGX-113 at ~136 mg / mL in 20 mM L-histidine / L-histidine HCl·H2O, ARGX -113 Buffer was replaced to achieve the target buffer concentration and pH, and then as shown in Table 2. The concentration was increased beyond the target concentration. Because the material solidifies when the concentration increases, F14 was increased to 100 mg / mL. It was prepared to the following concentration. As a result, after compounding with the stock solution, the formulation concentration was 100 ml. The concentration was restricted to g / mL.

[0205] Initial characterization of these formulations involves pH, osmolality due to freezing point depression, and actual The determination of protein concentrations was included. Representative results are shown in Table 3. Table 3. [Table 3]

[0206] Each aliquot of the formulation was shaken in an orbital shaker at a target speed of 115 rpm at room temperature and The samples were subjected to shaking stress in a horizontal position for approximately 7 days under cold temperature conditions.

[0207] Each aliquot of the formulation was frozen and thawed five times in a vertical position, from below -65°C to room temperature. It was offered to Ikuru.

[0208] As shown in Figure 3, the ARGX-113 concentration remained stable under all test conditions. The bars shown in Figure 3 from left to right are: F1=F12; F2=F13; F3=F14; F4=F15. The following applies: F1 Initial; F1 Shaking at 5°C (shaking sh 5); F1 Shaking at 25°C (shaking sh 2 5); F1 5 cycles of freeze / thaw stress (freeze / thaw F / T); F1 4 weeks at 5°C (4W5); F1 25 4 weeks at ℃ (4W25); F1 4 weeks at 40℃ (4W40); F1 8 weeks at 5℃ (8w5); F1 8 weeks at 25℃ (8w2 5); F1 8 weeks at 40℃ (8w40); F2 Initial stage; F2 Shaking at 5℃ (shaking sh 5); F2 Shaking at 25℃ ( Shaking sh 25); F2 5 cycles of freeze / thaw stress (freeze / thaw F / T); F2 4 weeks at 5℃ (4W5 ); F2 25℃ for 4 weeks (4W25); F2 40℃ for 4 weeks (4W40); F2 5℃ for 8 weeks (8w5); F2 25℃ 8 weeks (8w25); F2 8 weeks at 40℃ (8w40); F3 initial; F3 shaking at 5℃ (shaking sh 5); F3 25 Shaking at °C (shaking sh 25); F3 5 cycles of freeze / thaw stress (freeze / thaw F / T); F3 5°C 4 weeks (4W5); 4 weeks at F3 25℃ (4W25); 4 weeks at F3 40℃ (4W40); 8 weeks at F3 5℃ (8W5); F 3. 8 weeks at 25°C (8w25); F3. 8 weeks at 40°C (8w40); F4. Initial stage; F4. Shaking at 5°C (shaking sh 5) ; F4 Shaking at 25℃ (Shaking sh 25); F4 5 cycles of freeze / thaw stress (Freeze / thaw F / T); F 4 weeks at 45°C (4W5); 4 weeks at 25°C (4W25); 4 weeks at 40°C (4W40); 8 weeks at 5°C (4W4) (8w5); 8 weeks at F4 25℃ (8w25); 8 weeks at F4 40℃ (8w40).

[0209] As shown in Figures 4A-4B, size exclusion chromatography was performed on all test liquid formulations. No significant differences in aggregation and fragmentation were observed using Raffy (SEC). (See Figure 5A) As shown in ~5C, by integrated chip-based capillary electrophoresis (iCE), No significant chemical degradation was observed. As shown in Figures 6A–6D, the overall visible grains were present. The number of subatomic and invisible particles was lower during shaking and freeze / thaw stress. This data shows that There is no significant difference between the polysorbate 20 formulation and the polysorbate 80 formulation, and polysorbate Both Rubate 20 and Polysorbate 80 are rated at 0.04% w / v and are subjected to stirring and freeze / thaw stress. This suggests that ARGX-113 is protected equally well. In Figures 4A-4B, 5A-5C, and 6A-6D: F1=F12; F2=F13; F3=F14; F4=F15. In Figures 4A-4B, 5A-5C, and 6A-6D, the order is from left to right. The bars shown are as follows: F1 Initial; F1 Shaking at 5°C (shaking sh 5); F1 25 Shaking at °C (shaking sh 25); F1 5 cycles of freeze / thaw stress (freeze / thaw F / T); F1 at 5°C 4 weeks (4W5); F1 4 weeks at 25℃ (4W25); F1 4 weeks at 40℃ (4W40); F1 8 weeks at 5℃ (8W5); F 1. 8 weeks at 25°C (8w25); F1 8 weeks at 40°C (8w40); F2 Initial stage; F2 Shaking at 5°C (Shaking sh 5) ; F2 Shaking at 25℃ (Shaking sh 25); F2 5 cycles of freeze / thaw stress (Freeze / thaw F / T); F 2. 4 weeks at 5°C (4W5); 4 weeks at 25°C (4W25); 4 weeks at 40°C (4W40); 8 weeks at 5°C (4W40) (8w5); F2 8 weeks at 25℃ (8w25); F2 8 weeks at 40℃ (8w40); F3 initial; F3 5℃ with shaking (shaking) (Shake sh 5); Shake at F3 25℃ (Shake sh 25); Freeze / thaw stress for 5 cycles at F3 (Freeze / thaw) Frozen F / T); F3 5°C for 4 weeks (4W5); F3 25°C for 4 weeks (4W25); F3 40°C for 4 weeks (4W40); F3 5 8 weeks at ℃ (8w5); 8 weeks at F3 25℃ (8w25); 8 weeks at F3 40℃ (8w40); F4 initial; F4 5℃ Shake (shake sh 5); Shake at F4 25℃ (shake sh 25); F4 5 cycle freeze / thaw storage Freeze / Thaw F / T); F4 5℃ for 4 weeks (4W5); F4 25℃ for 4 weeks (4W25); F4 40℃ for 4 weeks (4W 40); 8 weeks at F4 5℃ (8w5); 8 weeks at F4 25℃ (8w25); 8 weeks at F4 40℃ (8w40).

[0210] Short-term stability data for up to 2 months (8 weeks) shows that ARGX-113 maintained a stable pH of 0.8-1.7% after 8 weeks at 40°C in SEC. This suggests that it has a moderate tendency to aggregate, accompanied by an increase in aggregation area. The aggregation rate of ARGX-113 is The effect was dependent on the concentration, pH, and composition under specific storage conditions. F13 formulations containing NaCl were At 40°C, it showed greater aggregation compared to F12 containing arginine. The F14 formulation at pH 6.5 Compared to F15 at 40°C with a concentration of 100 mg / mL and pH 6.0, this data showed greater aggregation. This suggests that ARGX-113 exhibits better stability at pH 6.0 compared to pH 6.5. Fragmentation was below the limit of quantification (LOQ) in the SEC.

[0211] In iCE, ARGX-113 exhibits highly basic and highly acidic species with low primary peaks in the early stages. Furthermore, this decreased rapidly in terms of stability, particularly at high temperatures, depending on the pH and composition. The iCE profile shows that the main peak of ARGX-113 in the liquid formulation is at 40°C for 8 weeks of stability. This suggests that it is mainly converted to acidic variants (~24%). (100 mg / mL and 150 mg / mL) Regarding the 2-month stability of ARGX-113, the rate and degree of chemical degradation in liquid formulations are as follows: No significant differences were observed. Basic peaks were not detected for all tested formulations and stability time points. No significant changes were observed.

[0212] Furthermore, CE-SDS (Caliper, PerkinElmer) showed no significant changes over an 8-week stability test. They did not show it (the results were not shown).

[0213] All formulations, except for formulation F12 which showed a large number of particles (particle cloud) after 8 weeks at 40°C, were initially in a similar state. The solution was free of visible particles after 8 weeks at 5, 25, and 40°C. The color of the solution was determined during storage and formulation. Depending on the conditions, the color varies from slightly brown to brown, and all formulations are initially and then 5, 2 5. After 8 weeks at 40°C, a stable target pH (±0.2) was observed.

[0214] As shown in Figure 7, the overall turbidity of the 150 mg / mL formulation is 15 FNU (formazin turbidimetric). It was higher than (units). Furthermore, sodium chloride preparations were compared to arginine-containing preparations. It showed higher turbidity. F13 showed a significant increase in turbidity after 4 and 8 weeks at 40°C. In Figure 7: F1=F12; F2=F13; F3=F14; F4=F15. In Figure 7, the following are shown in order from left to right. - is as follows: F1 Initial; F1 Shaking at 5℃ (shaking sh 5); F1 Shaking at 25℃ (shaking sh 25); F1 5 cycles of freeze / thaw stress (freeze / thaw F / T); F1 4 weeks at 5℃ (4W5); F 1. 4 weeks at 25°C (4W25); F1 4 weeks at 40°C (4W40); F1 8 weeks at 5°C (8W5); F1 8 weeks at 25°C Interval (8w25); F2 Initial; F2 Shake at 5℃ (shake sh 5); F2 Shake at 25℃ (shake sh 25); F2 5 cycles of freeze / thaw stress (freeze / thaw F / T); 4 weeks at F2 5°C (4W5); 4 weeks at F2 25°C (4W25); F2 40℃ for 4 weeks (4W40); F2 5℃ for 8 weeks (8w5); F2 25℃ for 8 weeks (8w25); F3 Initial; Shake at F3 5℃ (shake sh 5); Shake at F3 25℃ (shake sh 25); F3 5 cycles of freezing Freezing / Thawing Stress (Freezing / Thawing F / T); F3 5℃ for 4 weeks (4W5); F3 25℃ for 4 weeks (4W25); F3 4 4 weeks at 0°C (4W40); 8 weeks at 5°C (8w5); 8 weeks at 25°C (8w25); F4 initial; F4 5°C Shake (shake sh 5); Shake at F4 25℃ (shake sh 25); F4 5 cycle freeze / thaw storage Freeze / Thaw F / T); F4 5℃ for 4 weeks (4W5); F4 25℃ for 4 weeks (4W25); F4 40℃ for 4 weeks (4W 40); 8 weeks at F4 5℃ (8w5); 8 weeks at F4 25℃ (8w25).

[0215] From the results obtained in this example, (i) the formulation containing NaCl is the formulation containing arginine It showed higher turbidity, and the increase in turbidity was higher with the NaCl preparation at a concentration of 150 mg / mL at 40°C; (ii ) Except for F12 showing an increase in visible and invisible particles at 40°C, the overall number of invisible particles (iii) Although the initial level of aggregation is high, the aggregation is The rate of increase is moderate after 8 weeks at 40°C; (iv) Arginine preparations are compared to NaCl preparations (v)ARGX-113 shows lower aggregation in terms of 8-week stability; (v)ARGX-113 at concentrations of 150 and 100 mg / mL It shows good physical stability, but the physical stability at a concentration of 100 mg / mL is lower than that at 150 mg / mL at pH 6.0. Compared to the formulation, it is slightly higher; (vi) The initial level of the charged variant is high, and the main peak is, It was concluded that all liquid formulations primarily become acidic variants. (Formulation with pH 6.5) It showed the formation of slightly higher acidic variants compared to the pH 6.0 formulation; and (vii) Polysorbate 20 and polysorbate 80 at a concentration of 0.04% w / v are subjected to stirring and freeze-thaw stress. It was equally effective in protecting ARGX-113 from [the virus].

[0216] (Example 3. pH and surfactant optimization) This example was conducted to develop and characterize candidate formulations of ARGX-113 at higher concentrations. The document describes additional experiments. In particular, the purpose of this series of experiments was to identify specific characteristics and short-term stability. A high-concentration liquid formulation candidate of ARGX-113 for preclinical toxicity testing and early clinical trials based on sex studies. The objective was to identify it.

[0217] The compositions of the seven aqueous formulations of ARGX-113 examined in this example are shown in Table 4. Table 4. [Table 4]

[0218] Experiments were conducted on each formulation to determine its stability for 2 weeks at 5°C, 25°C, and 40°C, and its stability for 1 week at 5°C. The samples were subjected to shaking stress, shaking stress at 25°C for one week, and freeze / thaw stress for five cycles. did.

[0219] In 20 mM HisHCl and 100 mM NaCl, buffer exchange and concentration increase were performed at the selected pH. Immediately afterward, an appropriate amount of sucrose and surfactant stock was added to achieve the target concentration. The formulation was stored overnight at 5°C, and the phase transition was observed. Phase separation was observed at F17 (200 mg / mL), After equilibration at room temperature, it returned to the liquid phase. Then, the various formulations were filtered and separated into individual vials. I put it in the 'ru' section.

[0220] After storage at 5°C for one week, and similarly after stirring at 5°C for five days, a reversible solid-liquid phase transition occurs. Transfer was observed in samples F17, F18, and F19. When heated / equilibriumized to room temperature, the formulation was clear. It returned to a liquid solution. Other formulations (F12, F16, F20, and F21) were visible under these same conditions. It did not exhibit any visible solidification / phase transition.

[0221] After storage at 5°C for two weeks, a reversible solid-liquid phase transition was observed in samples F17, F18, and F19. When heated / equilibriumized to room temperature, the formulation returned to a clear liquid solution. Other formulations (F12, F 16, F20, and F21) did not show any visible solidification / phase transition under these same conditions.

[0222] After storage at 25°C for two weeks, all samples remained in the liquid phase, but many particles were visible in F21. .

[0223] After storage at 40°C for two weeks, an increase in opaque light was observed in F13, F18, F19, and F20. Considering the results of Example 2, the increase in milky white light observed at F13 was unexpected.

[0224] Figure 8 shows that there was no significant change in ARGX-113 protein concentration during these stability tests. This indicates.

[0225] Figure 9 shows the osmolality of the formulation after storage at 5°C for two weeks.

[0226] Figure 10 shows that after storage at 40°C for two weeks, F13 and F18 showed a significant increase in turbidity. It is present. After storage at 40°C for two weeks, the turbidity doubled for F19 and F20.

[0227] Figures 11A and 11B show the results of aggregation.

[0228] Figures 12A to 12C show the results of iCE.

[0229] Figures 13A to 13D show the results for invisible particles.

[0230] In Figures 8, 9, 10, 11A-11B, 12A-12C, and 13A-13D: F1=F13; F2=F16; F3=F17; F4=F 18; F5=F19; F6=F20; F7=F21. In Figures 8, 10, 11A-11B, 12A-12C, and 13A-13D, from left to right The bars shown in order from right to left are as follows (Note: Some of the bars in Figures 13A to 13D are very Even if the bar is low and hardly visible in the graph, the order of the bars remains the same: F 1. Initial; F1 shake at 5°C (shake sh 5); F1 shake at 25°C (shake sh 25); F1 5 cycles of freezing Freezing / Thawing Stress (Freezing / Thawing F / T); F1 2 weeks at 5°C (2W5); F1 2 weeks at 25°C (2W25); F1 4 2 weeks at 0°C (2W40); F2 initial stage; F2 shaking at 5°C (shaking sh 5); F2 shaking at 25°C (shaking sh 25); F2 5 cycle freeze / thaw stress (freeze / thaw F / T); F2 2 weeks at 5℃ (2W5); F2 2 5°C for 2 weeks (2W25); F2 40°C for 2 weeks (2W40); F3 Initial; F3 Shaking at 5°C (shaking sh 5); F3 Shaking at 25°C (Shaking sh 25); Freeze / thaw stress for 5 cycles at F3 (Freeze / thaw F / T); F3 5°C F3 at 25°C for 2 weeks (2W5); F3 at 40°C for 2 weeks (2W40); F4 initial; F4 at 5°C Shaking (shaking sh 5); Shaking at F4 25℃ (shaking sh 25); Freezing / thawing stress for 5 cycles at F4 (freezing F4 5°C for 2 weeks (2W5); F4 25°C for 2 weeks (2W25); F4 40°C for 2 weeks (2W40); F5 Initial; F5 Shake at 5°C (shake sh 5); F5 Shake at 25°C (shake sh 25); F5 5 cycles Freeze / thaw stress (freeze / thaw F / T); F5 2 weeks at 5°C (2W5); F5 2 weeks at 25°C (2W25); F5 40°C for 2 weeks (2W40); F6 Initial; F6 Shaking at 5°C (Shaking sh 5); F6 Shaking at 25°C (Shaking sh 25); F6 5 cycles of freeze / thaw stress (freeze / thaw F / T); F6 2 weeks at 5°C (2W5); F6 25 2 weeks at ℃ (2W25); F6 2 weeks at 40℃ (2W40); F7 Initial; F7 Shaking at 5℃ (shakingsh 5); F7 2 Shaking at 5°C (shaking sh 25); F7 5 cycles of freeze / thaw stress (freeze / thaw F / T); F7 5°C Two weeks at F7 25℃ (2W5); two weeks at F7 25℃ (2W25); two weeks at F7 40℃ (2W40).

[0231] From the results obtained in this example, (i) 0.02% polysorbate 20 and 0.04% polysorbate 2 0 refers to shaking and freezing ARGX-113 regardless of protein concentration (e.g., 150 or 175 mg / mL). / Equally effective in protecting against thawing stress; (ii) Polysorbate 20 and Polysorbate 80 protects ARGX-113 from shaking and freeze / thaw stress. (iii) Polysorbate 20 and poloxamer 188 are equally effective when shaking ARGX-113. (iv) Aggregation is concentration-dependent. These are still available, and F16 and F17 (175 mg / mL and 200 mg / mL, respectively) were stored at 40°C for 2 weeks. Compared to F13 (150 mg / mL), it has greater aggregation; (v) ARGX-113 concentrations > 175 mg / mL , exhibits a reversible temperature-dependent solid-liquid phase transition; and (vi) below pH (5.0 and 5.3), reversible It shows a higher risk of temperature-dependent solid-liquid phase transitions, and pH 5.0 is associated with the formation of basic species. It was concluded that this indicates a potential risk of chemical degradation and fragmentation.

[0232] (Example 4. Further characteristic analysis of the excipient) This example was conducted to develop and characterize candidate formulations of ARGX-113 at higher concentrations. Furthermore, additional experiments are described. In particular, the purpose of this series of experiments is to identify specific characteristics and short High-concentration liquid preparation of ARGX-113 for preclinical toxicity testing and initial clinical trials based on long-term stability testing. The objective was to identify potential drug candidates.

[0233] The compositions of the seven aqueous formulations of ARGX-113 examined in this example are shown in Table 5. Table 5. [Table 5]

[0234] F22 and F23 were prepared as 2.0 mL aliquots in vials.

[0235] F24 and F25 were prepared as 2.0 mL aliquots in Nuovo Ompi glass syringes.

[0236] F26 and F27 were prepared as 2.0 mL aliquots in BD SCF Neopak glass syringes.

[0237] F22, F24, and F26 contain or do not contain 10 mM L-methionine, and 20 mM HisHCl. Then, in 100 mM ArgCl, the buffer was changed and the concentration increased at the selected pH, and then the bulk... After filtration, an appropriate amount of sucrose and surfactant stock is added to the formulation sample. The target concentration was achieved. The combined and uncombined formulations were stored overnight at 5°C, and the phase transition was observed. Phase separation was not observed in either the combined or uncombined formulations. The compounded formulation was then filtered, filled, and completed.

[0238] F23, F25, and F27 contain or do not contain 10 mM L-methionine, and 20 mM HisHCl. Then, in 100 mM NaCl, the buffer was exchanged and the concentration increased at the selected pH, and then bulk filtration was performed. For the formulation sample, an appropriate amount of sucrose and surfactant stock was added to achieve the target. The concentration was achieved. The combined and uncombined formulations were stored overnight at 5°C, and the phase transition was observed. Phase separation was not observed in either the combined or uncombined formulations, however, phase separation This was observed in the unmixed bulk formulation. The mixed formulation was then filtered, filled, and completed.

[0239] Afterward, all preparations are subjected to specific storage conditions for a specified period, and their appearance, color, and clarity are evaluated. pH, invisible particles, purity by SE-HPLC, purity by iCE, purity by CE-SDS, viscosity, and fracture We analyzed the measured values ​​of shearing force and sliding force.

[0240] Under the conditions of storage at 5°C for 3 weeks, storage at 25°C for 3 weeks, and storage at 40°C for 3 weeks, all The formulation remained in the liquid phase.

[0241] Under the conditions of storage at 5°C for 6 weeks, storage at 25°C for 6 weeks, and storage at 40°C for 6 weeks, all Although some of the formulation remained in the liquid phase, after storage at 40°C for 6 weeks, some of the formulation remained in F22 and F26. The formation of haze was observed.

[0242] Under the conditions of storage at 5°C for 9 weeks, storage at 25°C for 9 weeks, and storage at 40°C for 9 weeks, all Although some of the formulation remained in the liquid phase, some precipitate was found in all formulations stored at 40°C for 9 weeks. The lord observed.

[0243] Protein concentration was measured for each of F22-F27 by shaking at 5°C, shaking at 25°C, freeze / thaw, and 5 Store at ℃ for 3 weeks, store at 25℃ for 3 weeks, store at 40℃ for 3 weeks, store at 5℃ for 6 weeks, store at 25℃ for 6 weeks Storage for 1 week, storage for 6 weeks at 40°C, storage for 9 weeks at 5°C, storage for 9 weeks at 25°C, and storage for 9 weeks at 40°C. It was found to be basically stable under the condition of being stored for a week (at an initial concentration of 10 percent). (Within)

[0244] pH levels F22-F27 were determined by shaking at 5°C, shaking at 25°C, freezing / thawing, and storage at 5°C for 3 weeks. Storage: Store at 25°C for 3 weeks, store at 40°C for 3 weeks, store at 5°C for 6 weeks, store at 25°C for 6 weeks, 4 It can be stored at 0°C for 6 weeks, at 5°C for 9 weeks, at 25°C for 9 weeks, and at 40°C for 9 weeks. Under these conditions, it was found to be stable.

[0245] Excluding F22 and F24 after being stored at 40°C for 6 weeks, and all formulations after being stored at 40°C for 9 weeks. Furthermore, all formulations tested throughout the entire testing period contained virtually no visible particles.

[0246] Osmolality, viscosity, breaking force, and sliding force of various syringe formulations stored at 5°C for 9 weeks. This is shown in Table 6. Table 6. [Table 6]

[0247] As shown in Figure 14, the increase in turbidity was observed in all formulations stored at 40°C for 9 weeks. It was observed that NaCl preparations and preparations without L-methionine were slightly higher than ArgCl preparations. It showed turbidity.

[0248] Aggregation was evaluated using SE-HPLC. Figures 15A-15B show the aggregation results. After storage for a week, a loss of approximately 1.5–1.9% of the main peak was observed depending on the formulation. F23 and F 25 (NaCl preparation) showed a slightly higher main peak at 40°C compared to F22 and F24 (ArgCl preparations). The following losses were observed. F26 and F27 (without L-methionine) were compared to formulations containing L-methionine. In comparison, it showed a slightly higher loss of the main peak at 40°C. Monomer loss was mainly due to high This was due to molecular weight (HMW) and aggregation formation. F23 and F25 (NaCl preparations) were due to F22 and F24 (Ar Compared to gCl preparations, F26 and F27 (L-methionine) showed slightly higher aggregation at 40°C. (Without L-methionine) showed a slightly higher HMW at 40°C compared to formulations containing L-methionine. Ta.

[0249] Figures 16A-16C show the results of iCE. After storage at 40°C for 9 weeks, all formulations were similar. The main peak (29-32%) showed loss. Similar increases were observed for both basic and acidic species. .

[0250] Figures 17A-17D show the results for invisible particles. These are for samples stored at 40°C for 9 weeks. The data presented may be unreliable due to precipitation in these samples.

[0251] From the results obtained in this example, (i) the ArgCl-free formulation, after storage at 5°C, yielded approximately 200 mg (ii) Even at concentrations of / mL, it remains in a liquid state; (ii) In contrast, the NaCl-containing non-containing formulation is approximately 200 mg / mL (iii) ArgCl-containing formulations, when stored at 5°C, do not remain in a liquid state; (iii) ArgCl-containing formulations, when stored at 40°C (iv) In contrast, the NaCl-containing formulation was stored at 40°C for 6 weeks. (v) NaCl-containing formulations show a higher aggregation rate than ArgCl formulations; and (vi) It was concluded that precipitation of the NaCl-containing formulation was observed after storage at 40°C for 9 weeks. .

[0252] Figure 14, 15A~15B, 16A~16C, 17A~17D: F1V=F22; F2V=F23; F1S=F24; F2S=F25; F3S=F2 6; F4S=F27. The bars shown in left to right in Figures 14, 15A-15B, 16A-16C, and 17A-17D. The following are the results (Note: Some bars in Figures 17A-17D are very low, but the bars are in the graph) Even if they are hardly visible inside, the order of the bars is the same): F1V Initial; F1V at 5℃ Shaking (shaking sh 5); Shaking at F1V 25℃ (shaking sh 25); Freeze / thaw stress for 5 cycles at F1V ( Freeze / Thaw F / T); F1V 5℃ for 3 weeks (3W5); F1V 25℃ for 3 weeks (3W25); F1V 40℃ for 3 weeks (3W 40); F1V 5℃ for 6 weeks (6W5); F1V 25℃ for 6 weeks (6W25); F1V 40℃ for 6 weeks (6W40); F1V 9 weeks at 5°C (9W5); F1V 9 weeks at 25°C (9W25); F1V 9 weeks at 40°C (9W40); F2V Initial; F2 V 5℃ with shaking (shake sh 5); F2V 25℃ with shaking (shake sh 25); F2V 5 cycles of freeze / thaw Stress (freezing / thawing F / T); 3 weeks at F2V 5℃ (3W5); 3 weeks at F2V 25℃ (3W25); F2V 40℃ 3 weeks at F2V 5℃ (3W40); 6 weeks at F2V 25℃ (6W25); 6 weeks at F2V 40℃ (6W 40); F2V 5℃ for 9 weeks (9W5); F2V 25℃ for 9 weeks (9W25); F2V 40℃ for 9 weeks (9W40); F1S Initial; F1S 5℃ with shaking (shake sh 5); F1S 25℃ with shaking (shake sh 25); F1S 5 cycles of freezing Freezing / Thawing Stress (Freezing / Thawing F / T); F1S 3 weeks at 5°C (3W5); F1S 3 weeks at 25°C (3W25); F1S 3 weeks at 40°C (3W40); F1S 6 weeks at 5°C (6W5); F1S 6 weeks at 25°C (6W25); F1S 6 weeks at 40°C Weekly (6W40); 9 weeks at F1S 5℃ (9W5); 9 weeks at F1S 25℃ (9W25); 9 weeks at F1S 40℃ (9W40) ; F2S Initial; F2S Shake at 5℃ (shake sh 5); F2S Shake at 25℃ (shake sh 25); F2S 5℃ Freezing / thawing stress on Kuru (freezing / thawing F / T); F2S 3 weeks at 5°C (3W5); F2S 3 weeks at 25°C (3W 25); F2S 40°C for 3 weeks (3W40); F2S 5°C for 6 weeks (6W5); F2S 25°C for 6 weeks (6W25); F2S 6 weeks at 40°C (6W40); F2S 9 weeks at 5°C (9W5); F2S 9 weeks at 25°C (9W25); F2S 9 weeks at 40°C Interval (9W40); F3S Initial; F3S Shake at 5℃ (shake sh 5); F3S Shake at 25℃ (shake sh 25); F3S 5 cycles of freeze / thaw stress (freeze / thaw F / T); F3S at 5°C for 3 weeks (3W5); F3S at 25°C for 3 weeks Weekly (3W25); 3 weeks at F3S 40℃ (3W40); 6 weeks at F3S 5℃ (6W5); 6 weeks at F3S 25℃ (6W25) ; F3S 40℃ for 6 weeks (6W40); F3S 5℃ for 9 weeks (9W5); F3S 25℃ for 9 weeks (9W25); F3S 40 9 weeks at ℃ (9W40); F4S initial stage; F4S shaking at 5℃ (shaking sh 5); F4S shaking at 25℃ (shaking sh 2 5); F4S 5 cycles of freeze / thaw stress (freeze / thaw F / T); F4S 3 weeks at 5°C (3W5); F4S 3 weeks at 25°C (3W25); F4S 3 weeks at 40°C (3W40); F4S 6 weeks at 5°C (6W5); F4S 6 weeks at 25°C Interval (6W25); F4S 40°C for 6 weeks (6W40); F4S 5°C for 9 weeks (9W5); F4S 25°C for 9 weeks (9W25); F4S at 40℃ for 9 weeks (9W40).

[0253] (Example 5. Further pH optimization test) This example compares two preparation methods: Method 1 (Pilot) is compared with Method 2 (GMP). As described, Method 2 yielded a more accurate pH compared to Preparation 1.

[0254] Several excipients were added to WFI (Water for Injection), dissolved, and then mixed with different excipients. The formulation buffer was brought to its volume. The excipients were added in a random order.

[0255] The obtained formulation buffer is then subjected to the UF / DF (ultrafiltration / diafiltration) formulation process for the protein (ARGX-113). It was used in this way. Polysorbate 20 had not yet been added at this stage. Table 7. [Table 7]

[0256] Next, polysorbate was added via a 10% solution at a dilution of 996:4 (e.g., 1000 kg of preparation). (4008 ml of excipient buffer was added to the product formulation buffer.) This was then used in the excipient addition process. This is called [a specific term]. In this way, polysorbate 20 (PS20) is added after the dialysis filtration / ultrafiltration process. .

[0257] As a result, the following final ARGX-113 formulation was obtained: 20 mM L-histidine / L-histidine hydrochloride, 100 mM salt containing 0.04% (w / v) polysorbate 20 ARGX-113 contains 165 mg / mL of sodium hydroxide, 60 mM sucrose, and 10 mM L-methionine in a solution at pH 6.0.

[0258] Using the method of this embodiment, a protein (ARGX-113) concentration higher than 165 mg / mL can be obtained, for example, 18 It is possible to produce formulations with concentrations of 0 mg / mL, 200 mg / mL, or even 300 mg / mL, as is known to those skilled in the art. Therefore, it is understood.

[0259] (Example 6. Ultra-high concentration formulation) In this example, additional experiments were conducted to test even higher concentrations, for example, 250-300 mg / mL of ARG. The potential of X-113 as a viscosity-reducing formulation was evaluated. For this purpose, different pH values ​​and ions were used. Three formulations of varying strengths were prepared. The three target formulations are shown in Table 8. Table 8. Target Formulation [Table 8]

[0260] (Materials and Methods) The stock solution of ARGX-113 was subjected to buffer exchange, and then the concentration was increased, and the protein The concentration of (ARGX-113) was measured, diluted to approximately 250 mg / mL, and excipients were added. Each of the resulting formulations The lots were further classified into those stored at 5°C and those stored at 25°C, and then their viscosity, osmolality, and appearance were evaluated. The inspection and filtration test using a 0.22 μm filter were performed regularly over a 14-day period. The analysis was performed on day 0 (D0; preparation day), day 3 (D3), day 7 (D7), and day 14 (D14). .

[0261] (result) The observed pH, osmolality, protein concentration, viscosity, and appearance are shown in Table 9. ru. Table 9. [Table 9] nd: Not implemented

[0262] In summary: Three formulations of ARGX-113 with concentrations of ≥250 mg / mL were prepared using 200 mM arginine. The viscosity of the three formulations decreased with increasing pH. Formulation F103 was tested at 5 and 25°C over a two-week period. It was the formulation with the lowest viscosity (measured at pH=6.5, 24 mPa·s, and 5°C). The F101 formulation could not be prepared uniformly on a small scale in order to form gel particles. • The F102 formulation showed unexpected variability in viscosity, which decreased over time. That's what it seemed like. The F103 formulation exhibited consistently low viscosity within two weeks. • The appearance of preservative formulations F102 and F103 remains unchanged for two weeks, regardless of whether they are stored at 5°C or 25°C. The situation remained the same for a considerable period. A whitish, highly viscous solution was observed after 7 days in a stock solution containing 100 mM arginine. (270-280 mg / mL protein). After 14 days, a solid gel was observed (data not shown). • Filtration test was performed: After filtration at 5°C, the viscosity of F102 and F103 remained low (<26 mP). a·s). This application provides the invention in the following embodiments. (Aspect 1) Approximately 100-300 mg / mL of isolated neonatal Fc receptor (FcRn) antagonist is administered in 20-60 mM histamine. Thidine / histidine HCl, 0-70 mM sucrose, 0-150 mM NaCl, 0-250 mM arginine HCl, 0 0.05% (w / v) polysorbate 20 or polysorbate 80, 0-15 mM L-methionine, pH 6. Aqueous formulation containing 0-6.5, wherein the isolated FcRn antagonist is in the variant Fc region. It consists of, where the variant Fc region consists of two Fc domains that form a homodimer. Here, each amino acid sequence of the Fc domain is sequence number 1, sequence number 2, or sequence number 1. The aqueous formulation comprising No. 3. (Aspect 2) Approximately 100-200 mg / mL of the isolated neonatal Fc receptor (FcRn) antagonist is mixed with 20 mM histamine. Thidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, and 0.02%~0.04% (w / v) polysorbate It is contained in Rubate 20 or Polysorbate 80, pH 6.0, where each of the Fc domains The aqueous formulation according to embodiment 1, wherein the mino acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. (Aspect 3) 150 mg / mL of ARGX-113 is mixed with 20 mM histidine / histidine HCl, 60 mM sucrose, and 100 mM NaCl. , and contained in 0.04% (w / v) polysorbate 20, pH 6.0, where ARGX-113 is isolated It is a modified FcRn antagonist, where the amino acid sequence of each of the Fc domains is sequence number An aqueous formulation according to embodiment 1, comprising part 1. (Aspect 4) 175 mg / mL of ARGX-113 is mixed with 20 mM histidine / histidine HCl, 60 mM sucrose, and 100 mM NaCl. , and contained in 0.04% (w / v) polysorbate 20, pH 6.0, where ARGX-113 is isolated It is a modified FcRn antagonist, where the amino acid sequence of each of the Fc domains is sequence number An aqueous formulation according to embodiment 1, comprising part 1. (Appendix 5) 200 mg / mL of ARGX-113 is mixed with 20 mM histidine / histidine HCl, 60 mM sucrose, and 100 mM NaCl. , and contained in 0.04% (w / v) polysorbate 20, pH 6.0, where ARGX-113 is isolated It is a modified FcRn antagonist, where the amino acid sequence of each of the Fc domains is sequence number An aqueous formulation according to embodiment 1, comprising part 1. (Aspect 6) Approximately 100-200 mg / mL of the isolated neonatal Fc receptor (FcRn) antagonist is mixed with 20 mM histamine. Thidine / histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.02% ~0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0, where F Each amino acid sequence of the c domain consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. Aqueous formulation as described in Item 1. (Aspect 7) Approximately 165 mg / mL of the isolated neonatal Fc receptor (FcRn) antagonist is mixed with 20 mM histidine. / Histidine HCl, 60 mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.04% (w / v) phosphate Resorbate 20, pH 6.0, contains, where, each amino acid sequence of the Fc domain is distributed An aqueous formulation according to embodiment 1, comprising sequence number 1, sequence number 2, or sequence number 3. (Pattern 8) 175 mg / mL of ARGX-113 is mixed with 20 mM histidine / histidine HCl, 60 mM sucrose, and 100 mM NaCl. , 10 mM L-methionine, and 0.03% (w / v) polysorbate 20, pH 6.0 are contained, where, AR GX-113 is the isolated FcRn antagonist, where each of the Fc domains The aqueous formulation according to embodiment 1, wherein the mino acid sequence consists of sequence number 1. (Aspect 9) 200 mg / mL of ARGX-113 is mixed with 20 mM histidine / histidine HCl, 60 mM sucrose, and 100 mM NaCl. , 10 mM L-methionine, and 0.03% (w / v) polysorbate 20, pH 6.0 are contained, where, AR GX-113 is the isolated FcRn antagonist, where each of the Fc domains The aqueous formulation according to embodiment 1, wherein the mino acid sequence consists of sequence number 1. (Aspect 10) Approximately 100-200 mg / mL of the isolated neonatal Fc receptor (FcRn) antagonist is mixed with 50 mM histamine. Thidine / histidine HCl, 60 mM sucrose, 150 mM arginine HCl, and 0.02%~0.04% (w / v ) contained in polysorbate 20 or polysorbate 80, pH 6.0, where the Fc domain Each amino acid sequence consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, according to Embodiment 1. Sexual preparations. (Aspect 11) Approximately 100-200 mg / mL of the isolated neonatal Fc receptor (FcRn) antagonist is mixed with 20 mM histamine. Thidine / histidine HCl, 60 mM sucrose, 100 mM arginine HCl, 10 mM L-methionine, and It contains 0.02%~0.04% (w / v) polysorbate 20 or polysorbate 80, pH 6.0, and here And each amino acid sequence of the Fc domain is either SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 The aqueous formulation described in Embodiment 1. (Aspect 12) ARGX-113 at 175 mg / mL is mixed with 20 mM histidine / histidine HCl, 60 mM sucrose, and 100 mM alcohol. It contains ginine HCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20, pH 6.0. Here, ARGX-113 is the isolated FcRn antagonist, and here the Fc domain An aqueous formulation in which each amino acid sequence corresponds to Sequence ID No. 1. (Aspect 13) 200 mg / mL of ARGX-113 is mixed with 20 mM histidine / histidine HCl, 60 mM sucrose, and 100 mM alcohol. It contains ginine HCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20, pH 6.0. Here, ARGX-113 is the isolated FcRn antagonist, and here the Fc domain The aqueous formulation according to embodiment 1, wherein each amino acid sequence corresponds to sequence number 1. (Aspect 14) Approximately 100-300 mg / mL of the isolated neonatal Fc receptor (FcRn) antagonist is mixed with 50 mM histamine. The Fc domain is contained in thidine / histidine HCl, 200 mM arginine HCl, pH 6.5. Each of the amino acid sequences is the same as in the embodiment of 1, consisting of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. Aqueous formulation. (Aspect 15) A package containing a sterile container containing a therapeutically effective amount of the aqueous preparation described in any one of the embodiments 1 to 14. A pharmaceutical product. (Aspect 16) A device containing a therapeutically effective amount of the aqueous preparation described in any one of the embodiments 1 to 14. (Aspect 17) The apparatus according to embodiment 16, wherein the apparatus includes a syringe containing the aqueous formulation.

Claims

1. Approximately 100 for use in methods of treating subjects with antibody-mediated autoimmune diseases FcRn antagonist up to 300 mg / mL, 20–60 mM histidine / histidine HCl, 0–70 mM sucrose -, 0-150 mM NaCl, 0-250 mM arginine HCl, 0%-0.05% (w / v) polysorbate 20 or An aqueous formulation containing polysorbate 80 and 0-15 mM L-methionine, The method includes administering the FcRn antagonist to the subject, The aqueous formulation has a pH of 6.0 to 6.5, and the FcRn antagonist consists of the variant Fc region. The variant Fc region consists of two Fc domains that form a homodimer, and the Fc domain Each of the amino acid sequences consists of the amino acid sequence described in Sequence ID No. 1 or Sequence ID No.

2. Aqueous formulation.

2. The aforementioned antibody-mediated autoimmune diseases include allogeneic islet transplant rejection, alopecia areata, ankylosing spondylitis, Antiphospholipid syndrome, autoimmune Addison's disease, Alzheimer's disease, anti-neutrophil cytoplasmic antibodies (ANCA) Adrenal autoimmune diseases, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myositis, auto Immune neutropenia, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, autoimmune Urticaria, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman syndrome, celiac disease Kuspru's dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP) Churg-Strauss syndrome, pemphigoid scarring, CREST (calcification, Raynaud's phenomenon, esophageal movement) Arteriosclerosis, finger sclerosis, and telangiectasia syndrome, cold agglutinin disease, Crohn's disease, dermatomuscular dystrophy Inflammation, lupus discoid, mixed essential cryoglobulinemia, factor VIII deficiency, fibromyalgia Physiomyositis, glomerulonephritis, Graves' disease, Guillain-Barré syndrome, Goodpasture syndrome, Graft-versus-host disease (GVHD), Hashimoto's thyroiditis, Hemophilia A, Idiopathic pulmonary fibrosis, Idiopathic thrombocytopenia Ill-mediated purpura, immunothrombocytopenia (ITP), IgA neuropathy, IgM polyneuropathy, immuno Thrombocytopenia-mediated, juvenile arthritis, Kawasaki disease, lichen planus, lupus erythematosus, Meniere's disease Diseases, mixed connective tissue disease, multiple sclerosis, type 1 diabetes, multifocal motor neuropathy (MMN), Myasthenia gravis (MG), paraneoplastic bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, pernicious anemia, Polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis and skin Dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Innault's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome Syndrome, parenchymal organ graft rejection, Stiffman syndrome, systemic lupus erythematosus (SLE) Takayasu's arteritis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), temporal bone Arteritis / Giant cell arteritis, thrombotic thrombocytopenic purpura, ulcerative colitis, uveitis, herpes zoster Dermatitis vasculitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, vitiligo, or Wegener's granulomatosis An aqueous formulation according to claim 1, selected from the group consisting of the following.

3. The aqueous formulation according to claim 2, wherein the antibody-mediated autoimmune disease is ITP.

4. The aqueous formulation according to claim 2, wherein the antibody-mediated autoimmune disease is MG.

5. The variant Fc region consists of two Fc domains that form a homodimer, and the Fc domain Each amino acid sequence of n consists of the amino acid sequence described in SEQ ID NO: 1, according to claims 1 to 4. Any aqueous preparation as described in item 1.

6. The variant Fc region consists of two Fc domains that form a homodimer, and the Fc domain Each amino acid sequence of n consists of the amino acid sequence described in SEQ ID NO: 2, according to claims 1 to 4. Any aqueous preparation as described in item 1.

7. Approximately 100-200 mg / mL of the aforementioned FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM s Cloth, 100 mM NaCl, and 0.02%–0.04% (w / v) polysorbate 20 or polysorbate 8 The water according to any one of claims 1 to 6, comprising 0, wherein the aqueous formulation has a pH of 6.

0. Sexual preparations.

8. Approximately 150 mg / mL of the aforementioned FcRn antagonist, 20 mM histidine / histidine HCl, and 60 mM sucrose. The aqueous formulation comprises 6.0 mM NaCl and 0.04% (w / v) polysorbate 20, where the aqueous formulation is 6.0 An aqueous formulation according to any one of claims 1 to 6, having a pH of [value].

9. Approximately 175 mg / mL of the aforementioned FcRn antagonist, 20 mM histidine / histidine HCl, and 60 mM sucrose. The aqueous formulation comprises 6.0 mM NaCl and 0.04% (w / v) polysorbate 20, where the aqueous formulation is 6.0 An aqueous formulation according to any one of claims 1 to 6, having a pH of [value].

10. Approximately 200 mg / mL of the aforementioned FcRn antagonist, 20 mM histidine / histidine HCl, and 60 mM sucrose. The aqueous formulation comprises 6.0 mM NaCl and 0.04% (w / v) polysorbate 20, where the aqueous formulation is 6.0 An aqueous formulation according to any one of claims 1 to 6, having a pH of [value].

11. Approximately 100-200 mg / mL of the aforementioned FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM s Cloth, 100 mM NaCl, 10 mM L-methionine, and 0.02%–0.04% (w / v) polysorbate 20 Alternatively, the aqueous formulation comprises polysorbate 80, wherein the aqueous formulation has a pH of 6.0, according to claims 1 to 6. An aqueous preparation as described in any one of the items.

12. Approximately 165 mg / mL of the aforementioned FcRn antagonist, 20 mM histidine / histidine HCl, and 60 mM sucrose. It contains 100 mM NaCl, 10 mM L-methionine, and 0.04% (w / v) polysorbate 20, and here The aqueous formulation according to any one of claims 1 to 6, wherein the aqueous formulation has a pH of 6.

0.

13. Approximately 175 mg / mL of the aforementioned FcRn antagonist, 20 mM histidine / histidine HCl, and 60 mM sucrose. A claim comprising 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20. An aqueous preparation as described in any one of items 1 to 6.

14. Approximately 200 mg / mL of the aforementioned FcRn antagonist, 20 mM histidine / histidine HCl, and 60 mM sucrose. A claim comprising 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20. An aqueous preparation as described in any one of items 1 to 6.

15. Approximately 100-200 mg / mL of the aforementioned FcRn antagonist, 50 mM histidine / histidine HCl, 60 mM s Cloth, 150 mM arginine HCl, and 0.02%–0.04% (w / v) polysorbate 20 or polysorbate A formulation comprising Rubate 80, wherein the aqueous formulation has a pH of 6.0, any one of claims 1 to 6 The aqueous formulation described in item [number].

16. Approximately 100-200 mg / mL of the aforementioned FcRn antagonist, 20 mM histidine / histidine HCl, 60 mM s Cloth, 100 mM arginine HCl, 10 mM L-methionine, and 0.02%–0.04% (w / v) polysol A claim comprising β-20 or polysorbate 80, wherein the aqueous formulation has a pH of 6.

0. An aqueous preparation as described in any one of items 1 to 6.

17. Approximately 100–300 mg / mL of the aforementioned FcRn antagonist, 50 mM histidine / histidine HCl and 200 mM The aqueous formulation comprises arginine HCl, wherein the aqueous formulation has a pH of 6.5, any one of claims 1 to 6. Aqueous preparation as described in item 1.

18. Polypeptide population of approximately 100–300 mg / mL, 20–60 mM histidine / histidine HCl, 0–70 mM Sucrose, 0–150 mM NaCl, 0–250 mM arginine HCl, 0%–0.05% (w / v) polysorbate An aqueous formulation comprising 20 or polysorbate 80 and 0-15 mM L-methionine, The aqueous formulation has a pH of 6.0 to 6.5 and contains at least 90% of the polypeptide population. The plutido consists of an Fc domain homodimer, where each of the Fc domains of the homodimer The aqueous formulation wherein the amino acid sequence consists of SEQ ID NO: 1 or SEQ ID NO:

2.

19. The amino acid sequence of each Fc domain of the homodimer is as follows, according to claim 18. A water-based formulation.

20. The amino acid sequence of each Fc domain of the homodimer is as follows, according to claim 18. A water-based formulation.

21. A group of polypeptides at approximately 100–200 mg / mL, 20 mM histidine / histidine HCl, 60 mM s Cloth, 100 mM NaCl, and 0.02%–0.04% (w / v) polysorbate 20 or polysorbate 8 The present invention relates to any one of claims 18 to 20, wherein the aqueous formulation has a pH of 6.

0. Aqueous formulation.

22. Approximately 150 mg / mL of the aforementioned polypeptide, 20 mM histidine / histidine HCl, 60 mM sucrose The aqueous formulation comprises 6.0 mM NaCl and 0.04% (w / v) polysorbate 20, where the aqueous formulation is 6.0 An aqueous formulation according to any one of claims 18 to 20, having a pH of [value missing].

23. Approximately 175 mg / mL of the aforementioned polypeptide population, 20 mM histidine / histidine HCl, 60 mM sucrose. The aqueous formulation comprises 6.0 mM NaCl and 0.04% (w / v) polysorbate 20, where the aqueous formulation is 6.0 An aqueous formulation according to any one of claims 18 to 20, having a pH of [value missing].

24. Approximately 200 mg / mL of the aforementioned polypeptide, 20 mM histidine / histidine HCl, 60 mM sucrose The aqueous formulation comprises 6.0 mM NaCl and 0.04% (w / v) polysorbate 20, where the aqueous formulation is 6.0 An aqueous formulation according to any one of claims 18 to 20, having a pH of [value missing].

25. A group of polypeptides at approximately 100–200 mg / mL, 20 mM histidine / histidine HCl, 60 mM s Cloth, 100 mM NaCl, 10 mM L-methionine, and 0.02%–0.04% (w / v) polysorbate 20 Alternatively, the aqueous formulation comprises polysorbate 80, wherein the aqueous formulation has a pH of 6.0, claims 18-20 An aqueous preparation as described in any one of the items.

26. Approximately 165 mg / mL of the aforementioned polypeptide population, 20 mM histidine / histidine HCl, 60 mM sucrose. It contains 100 mM NaCl, 10 mM L-methionine, and 0.04% (w / v) polysorbate 20, and here The aqueous formulation according to any one of claims 18 to 20, wherein the aqueous formulation has a pH of 6.

0.

27. A group of polypeptides at approximately 100–200 mg / mL, 20 mM L-histidine / L-histidine HCl, 60 Contains mM sucrose, 100 mM NaCl, 10 mM L-methionine, and 0.04% (w / v) polysorbate 20. The aqueous formulation according to any one of claims 18 to 20.

28. A 180 mg / mL dose of the aforementioned polypeptide, 20 mM L-histidine / L-histidine HCl, and 60 mM saturates. Contains rose, 100 mM NaCl, 10 mM L-methionine, and 0.04% (w / v) polysorbate 20. An aqueous formulation as described in any one of the requests 18 to 20.

29. Approximately 175 mg / mL of the aforementioned polypeptide population, 20 mM histidine / histidine HCl, 60 mM sucrose. A claim comprising 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20. An aqueous preparation as described in any one of items 18 to 20.

30. Approximately 200 mg / mL of the aforementioned polypeptide, 20 mM histidine / histidine HCl, 60 mM sucrose A claim comprising 100 mM NaCl, 10 mM L-methionine, and 0.03% (w / v) polysorbate 20. An aqueous preparation as described in any one of items 18 to 20.

31. A packaged pharmaceutical product comprising a sterile container containing an aqueous formulation according to any one of claims 1 to 30. Item.

32. The packaging according to claim 31, wherein the sterile container includes a single-use vial or a multi-use vial. A packaged pharmaceutical product.

33. The packaged pharmaceutical product according to claim 31, wherein the sterile container includes a single-use vial.

34. Apparatus comprising an aqueous formulation according to any one of claims 1 to 30.

35. The apparatus according to claim 34, wherein the apparatus includes a syringe containing the aqueous formulation.

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