Immunoglobulin preparations for the treatment of systemic sclerosis

Abstract

This disclosure relates to the use of immunoglobulin preparations, such as liquid polyclonal immunoglobulin preparations, for the treatment of systemic sclerosis (SSc), including diffuse systemic sclerosis (dcSSc) and limited systemic sclerosis (lcSSc). In some embodiments, the preparation is administered subcutaneously (SCIG preparation). In some embodiments, the preparation has a high concentration of immunoglobulin, such as 15-30% or 16-22% by mass / volume.

Description

[Technical Field]

[0001] field This disclosure relates to the use of immunoglobulin preparations, such as liquid polyclonal immunoglobulin preparations, for the treatment of systemic sclerosis (SSc), such as diffuse cutaneous systemic sclerosis (dcSSc) and limited cutaneous systemic sclerosis (lcSSc). In some embodiments, the preparation is administered subcutaneously (SCIG preparation). In some embodiments, the preparation has a high concentration of immunoglobulin, such as 15-30% or 16-22% by mass / volume. [Background technology]

[0002] background Systemic scleroderma (SSc), also known as scleroderma, is an autoimmune connective tissue disease. SSc is characterized by vascular damage (vascular dysfunction) followed by poor neovascularization and impaired vascular remodeling, as well as fibrosis of the skin and various organ systems (e.g., lungs, kidneys, heart, gastrointestinal tract, and musculoskeletal system). The disease has a poor prognosis and limited treatment options. Dermatofibrosis is a major diagnostic feature of SSc, and the degree of cutaneous complications is used to stratify patients into two main subsets: localized systemic scleroderma (lcSSc) and diffuse systemic scleroderma (dcSSc). In contrast to scSSc and dcSSc, scleroderma-free SSc is a rare manifestation of classic visceral but skin-thickened SSc, occurring in less than 5% of individuals with SSc. Generally, patients with lcSSc exhibit dermatofibrosis distal to the elbows and knees, whereas in dcSSc, complications occur proximal to the elbows and knees and can encompass a large portion of the limbs. Patients with dcSSc are at increased risk of complications such as scleroderma renal crisis and interstitial lung disease (ILD), which can be life-threatening, although some patients with lcSSc may also develop these complications. SSc-ILD is the most frequent direct cause of death in SSc, surpassing renal crisis and SSc-associated pulmonary arterial hypertension (SSc-PAH).

[0003] The pathogenesis of SSc is mediated by immune and inflammatory cells. Vascular injury promotes the infiltration of mast cells, T lymphocytes, and macrophages into the injured tissue early in the disease. This leads to persistent pro-inflammatory and pro-fibrotic responses mediated by myofibroblast differentiation, as well as the production of cytokines such as interleukin-6 (IL-6) and transforming growth factor (TGF-β). [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] Treatment strategies for SSc may include immunosuppressive therapy, vasomodulation, and / or symptomatic management. However, since the skin in SSc patients thickens and hardens over time (i.e., dermatofibrosis), it is unclear whether treatments can be applied subcutaneously; therefore, it is necessary to determine whether subcutaneous treatments can be safely administered and whether such treatments have sufficient bioavailability in SSc patients. [Means for solving the problem]

[0005] Abstract Among the methods disclosed herein is a method for treating systemic sclerosis (SSc) in human subjects, comprising subcutaneous administration of a liquid human polyclonal immunoglobulin preparation containing 16-22% mass / volume immunoglobulin, wherein the preparation is administered once, twice, or three times per week to achieve a weekly dose of 0.1 g / kg to 1 g / kg (Embodiment 1). Another method encompassed in this disclosure is a method for treating systemic sclerosis (SSc) in human subjects, comprising subcutaneous administration of a liquid human polyclonal immunoglobulin preparation containing 16-22% mass / volume immunoglobulin, wherein the preparation is administered twice per week to achieve a weekly dose of 0.1 g / kg to 1 g / kg (Embodiment 2).

[0006] Embodiment 3 comprises the method of Embodiment 1 or 2, wherein the liquid human polyclonal immunoglobulin preparation may contain 20-22% immunoglobulin. Embodiment 4 comprises the method of any one of Embodiments 1-3, wherein the immunoglobulin is derived from pooled plasma from more than 1000 human donors. Embodiment 5 comprises the method of any one of Embodiments 1-4, wherein the preparation contains a stabilizer, such as proline, glycine, or an amino acid such as arginine. Embodiment 6 comprises Embodiment 5, wherein the stabilizer contains proline. The proline in Embodiment 6 may optionally be at concentrations such as 100-500 mM, e.g., 200-300 mM, 250 mM, etc. Embodiment 7 comprises Embodiment 5 or 6, wherein the stabilizer further contains a surfactant, such as polysorbate 80 or polysorbate 20, at concentrations such as 5-50 mg / L, 8-30 mg / L, etc. Embodiment 8 comprises the method of any one of Embodiments 1-7, wherein the preparation has a pH of 4.6-5.2. Embodiment 9 comprises the method according to any one of Embodiments 1 to 8, wherein the preparation does not contain carbohydrate stabilizers, does not contain more than 50 μg / mL of IgA, and / or does not contain preservatives.

[0007] In any one of Embodiments 1 to 9, SSc may be diffuse systemic sclerosis (dcSSc) or localized SSc (lcSSc) (Embodiment 10). In Embodiment 11, the method of any one of Embodiments 1 to 9 is performed, wherein SSc is dcSSc. Embodiment 12 includes the method of Embodiment 10 or 11, wherein the subject does not have dcSSc at the subcutaneous injection site. Embodiment 13 includes the method of any one of Embodiments 1 to 12, further comprising the administration of at least one further therapeutic agent. Embodiment 14 includes the method of Embodiment 13, wherein at least one further therapeutic agent does not include an antibody therapeutic agent. Embodiment 14 includes the method of Embodiment 13, wherein at least one further therapeutic agent does not include an anti-CD20 antibody and / or does not include anti-IL6 and / or does not include an anti-IL6 receptor antibody. Embodiment 16 includes the method of any one of Embodiments 1 to 15, wherein the subject has not previously received treatment with an anti-CD20 antibody and / or has not previously received treatment with an anti-IL6 antibody and / or has not previously received treatment with an anti-IL6 receptor antibody. Accordingly, in some embodiments herein, the method of any one of Embodiments 1 to 14 is performed, wherein the subject is not treated with an anti-CD20 antibody and / or has not previously been treated with an anti-CD20 antibody. In some embodiments herein, the method of any one of Embodiments 1 to 14 is performed, wherein the subject is not treated with an anti-IL6 antibody or an anti-IL6 receptor antibody and / or has not previously been treated with an anti-IL6 antibody or an anti-IL6 receptor antibody. Embodiment 17 includes the method of any one of Embodiments 1 to 16, wherein the subject has not been diagnosed with a rheumatic autoimmune disease other than SSc.

[0008] Embodiment 18 includes the method according to any one of Embodiments 1 to 17, wherein the preparation is administered twice a week to achieve a weekly dose of 0.5 g / kg. Embodiment 19 includes the method according to any one of Embodiments 1 to 18, wherein the preparation is administered for a period of at least one month, at least three months, at least four months, at least six months, or at least one year. Embodiment 20 includes the method according to any one of Embodiments 1 to 19, wherein the subject has no history of dermatitis, eczema, or psoriasis prior to the initiation of treatment. Embodiment 21 includes the method according to any one of Embodiments 1 to 20, wherein the subject has a modified Rodnan skin thickness score of 15 to 45 prior to treatment with the preparation. Embodiment 22 includes the method according to any one of Embodiments 1 to 21, wherein the subject does not experience a mild or moderate to severe injection site skin reaction after administration of the preparation. Embodiment 23 includes the method according to any one of Embodiments 1 to 22, wherein the subject does not experience an injection site reaction, such as injection site pain or injection site swelling, within the first month or within the first three months of the procedure. Embodiment 24 includes the method according to any one of Embodiments 1 to 23, wherein the preparation is administered subcutaneously using an infusion pump device. Embodiment 25 includes the method according to any one of Embodiments 1 to 24, wherein a volume of 10 mL to 100 mL is administered subcutaneously in each dose.

[0009] Embodiment 26 involves administering the preparation for a period of at least one month, where the subject receives treatment after one month, three months, or four months: • Having a trough serum IgG concentration of at least 18 g / L, at least 19 g / L, or at least 20 g / L; • Having an mRSS value that has decreased by at least 3, at least 4, or at least 5 compared to baseline, or decreased by at least 15%, at least 20%, or at least 25%; • Having a SHAQ VAS score that is at least 5%, at least 10%, or at least 15% lower than baseline; • Having a PGA that has decreased by at least 5%, at least 10%, or at least 15% compared to baseline; • Having MDGA reduced by at least 5%, at least 10%, or at least 15% compared to baseline; • Pain, swelling, and / or friction have decreased in at least one joint compared to baseline; and / or The method described in any one of Embodiments 1 to 25 includes a method in which the UCLA SCTC GI 2.0 score has not increased compared to baseline.

[0010] Furthermore, in some cases, in the method according to any one of Embodiments 1 to 26, the subject is treated after 1 month, 3 months, or 4 months: Swelling or pain is reduced in or in more joints; The number of joint swellings has not increased, or the number of joint swellings has decreased (e.g., a decrease in one joint or at least one joint); The number of tender joints has not increased, or the number of tender joints has decreased (e.g., a decrease of one joint or at least one joint); The total manual muscle testing (MMT) score does not decrease by more than 5% or more than 10% (i.e., the total MMT score increases, remains the same, or decreases by 5% or less or 10% or less); and / or Forced vital capacity (FVC) does not decrease by more than 5%, more than 2%, or more than 1% in percentage (i.e., FVC% increases, remains the same, or decreases by 5%, 2%, or 1% or less).

[0011] The present disclosure further includes Embodiment 27, which includes a liquid human polyclonal immunoglobulin preparation according to any one of Embodiments 1-9 for use in the method according to any one of Embodiments 1, 2, or 10-26. The disclosure herein also encompasses Embodiment 28, which includes the use of a liquid human polyclonal immunoglobulin preparation according to any one of Embodiments 1-9 in the manufacture of a medicament for treating SSc according to any one of Embodiments 1, 2, or 10-26.

[0012] Of course, both the foregoing general description and the following more detailed description are exemplary and for illustrative purposes only, and do not limit the claims. References cited herein are incorporated by reference in their entirety.

Brief Description of the Drawings

[0013] [Figure 1] Figure 1 shows a diagram of a clinical trial in subjects with dcSSc described in the examples herein. Some PK samples were collected to evaluate the steady-state and carry-over effects from treatment period 1 during treatment period 2 of IgPro20 or IgPro10 for measuring IgG trough concentration. Further, PK samples were collected frequently during the last dosing period to fully characterize the PK of IgPro20 and IgPro10. dcSSc, diffuse cutaneous systemic sclerosis; EOT, end of treatment; IgG, immunoglobulin G; IgPro10, 10% intravenous human immunoglobulin, Privigen(R), CSL Behring; IgPro20, 20% subcutaneous human immunoglobulin, Hizentra(R), CSL Behring; PK, pharmacokinetics. [Figure 2A]Figure 2A shows the mean (SD) serum IgG concentration-time profiles of dcSSc patients after the first infusion of the last cycle of IgPro20 (0.5 g / kg / week) or IgPro10 (2 g / kg / 4 weeks divided over 2 - 5 days). More specifically, the serum IgG concentrations (g / L) after treatment with IgPro10 (intravenous 10% immunoglobulin preparation; solid line) or IgPro20 (subcutaneous 20% immunoglobulin preparation; dashed line) are shown on a linear scale against the number of days after the start of infusion as shown on the x-axis. Since not all subjects provided PK samples at all time points, the numbers on the x-axis reflect subjects without missing values; raw data for IgPro10 above and for IgPro20 below. Bars represent the standard deviation; IgG, immunoglobulin G; IgPro10, 10% intravenous human immunoglobulin, Privigen(R), CSL Behring; IgPro20, 20% subcutaneous human immunoglobulin, Hizentra(R), CSL Behring; SD, standard deviation. [Figure 2B] Figure 2B shows the mean (SD) serum IgG concentration-time profiles of dcSSc patients after the first infusion of the last cycle of IgPro20 (0.5 g / kg / week) or IgPro10 (2 g / kg / 4 weeks divided over 2 - 5 days). More specifically, the serum IgG concentrations (g / L) after treatment with IgPro10 (intravenous 10% immunoglobulin preparation; solid line) or IgPro20 (subcutaneous 20% immunoglobulin preparation; dashed line) are shown on a log-linear scale against the number of days after the start of infusion as shown on the x-axis. Bars represent the standard deviation. Since not all subjects provided PK samples at all time points, the numbers on the x-axis reflect subjects without missing values as shown in Figure 2A.

Mode for Carrying Out the Invention

[0014] Description of Exemplary Embodiments Definitions Naturally, methodologies, protocols, cell lines, animal species or genera, and reagents can change, so this disclosure is not limited to the specific methodologies, protocols, cell lines, animal species or genera, and reagents described herein. Also, naturally, the terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of this disclosure, which is limited only by the appended claims.

[0015] As used herein, the term "about" refers to numerical values, whether expressly indicated or not, such as integers, fractions, and percentages. Generally, the term "about" refers to a range of numerical values ​​(e.g., + / - 5 to 10% of the stated range) that a person skilled in the art would consider equivalent to (e.g., having the same function or result as) the stated value. Where terms such as "at least" and "about" precede a list of numerical values ​​or ranges, these terms qualify all values ​​or ranges provided in that list. In some cases, the term "about" may include numerical values ​​rounded to the nearest significant figure.

[0016] As used herein, the singular nouns “a,” “and,” and “the” include multiple references unless otherwise explicitly indicated by the context. For example, a reference to “a cell” includes multiple such cells, and a reference to “the protein” includes one or more proteins and their equivalents known to those skilled in the art. All technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs, unless otherwise explicitly indicated.

[0017] In this disclosure, “comprises,” “comprising,” “contains,” “have,” “includes,” “including,” and their linguistic variations have the meanings given to them under U.S. patent law and permit the presence of further components beyond those expressly described.

[0018] In this application, the use of “or” means “and / or” unless otherwise specified. In the context of multiple dependent claims, the use of “or” refers only to one or more preceding independent or dependent claims. Also, terms such as “element” or “component” encompass both elements and components containing one unit and elements and components containing one or more subunits, unless otherwise specifically specified.

[0019] As used herein, terms such as “to treat,” “to treat,” and “treatment” include reducing, managing, or relieving a disorder such as SSc and / or at least one sign or symptom associated therewith, or slowing or halting the progression of the disorder or one or more of its signs or symptoms. Naturally, though not excluded, treating a disorder such as SSc does not require the complete elimination of the disorder or its associated symptoms. Furthermore, naturally, treatment is often initiated after the onset of symptoms such as dermatofibrosis, particularly after the diagnosis of the disorder.

[0020] "Therapeutic effective dose" refers to the amount of drug sufficient to produce a therapeutic effect in a human subject, such as reducing, reducing or slowing the progression of, or preventing the onset of, at least one symptom of a disorder like SSc.

[0021] In this specification, the terms "subject," "patient," or "individual" to be treated refer to a human being unless otherwise specifically indicated.

[0022] Systemic sclerosis (SSc) is a progressive connective tissue disorder generally characterized by vascular damage, immunodysregulation or autoimmunity, and fibrosis. Vascular damage symptoms include Raynaud's phenomenon, finger ulcers, hypertensive renal failure, cardiomyopathy, and pulmonary hypertension. Fibrosis generally manifests as skin thickening, gastrointestinal dysmotility, myocardial fibrosis, or pulmonary fibrosis. Often, patients first present with Raynaud's phenomenon, followed by non-Raynaud's symptoms such as skin thickening within one to several years. Patients may be classified into subtypes of SSc based on the distribution of skin thickening. Subtypes include diffuse systemic sclerosis, localized systemic sclerosis, and, in certain rare cases, systemic sclerosis without skin complications.

[0023] Diffuse systemic sclerosis (dcSSc) refers to SSc patients who have skin thickening in areas including the proximal elbows and knees, and therefore frequently extending to the entire limbs. These are generally considered a more severe form of SSc and account for approximately 20–40% of SSc cases. Early visceral complications and a high mortality rate may also be characteristic. "Limited systemic sclerosis" (lcSSc) refers to SSc patients who have skin thickening limited to distal areas of the elbows and knees, face, and neck. This accounts for the majority of the remaining SSc cases.

[0024] Raynaud's phenomenon refers to a localized reduction in blood flow to peripheral arteries, such as those in the fingers or toes. The affected body parts, such as the fingers or toes, become pale or white, and in some cases may then turn blue. In some cases, there is numbness, coldness, or pain. Blood flow may return after a few minutes or hours, resulting in redness and a burning sensation in the affected body parts.

[0025] As used herein, the terms “polyclonal immunoglobulin preparation” and “immunoglobulin preparation” refer to a composition comprising polyclonal antibodies. In some embodiments, such preparations can be obtained from plasma from multiple donors, i.e., “pooled plasma.” Unless otherwise explicitly stated herein, donors are human, and preparations are for use in humans. The immunoglobulins in these preparations are predominantly in IgG form and are referred to herein as either “IgG” or “immunoglobulin G.” Therefore, “immunoglobulin preparation” as used herein may, in some examples, be interchangeably referred to as “IgG preparation,” “immunoglobulin G preparation,” or “Ig preparation.” In some embodiments, low levels of IgM and / or IgA are also present. The term “immunoglobulin” alone refers to an antibody molecule.

[0026] In this specification, the term “subcutaneous,” i.e., “subcutaneous immunoglobulin preparation” or “subcutaneous IgG preparation,” and similar terms, when modifying immunoglobulin preparations, means that the preparation is administered subcutaneously to the subject. Such preparations are also known by the abbreviation “SCIG.” In some embodiments, such subcutaneous immunoglobulin preparations have a higher polyclonal IgG concentration than alternative “intravenous” immunoglobulin preparations (abbreviated as IVIG), which are preparations administered intravenously. Examples of subcutaneous and intravenous IgG preparations in this specification include, in particular, the subcutaneous IgG preparation IgPro20 and the intravenous IgG preparation IgPro10, which are mentioned in the following examples.

[0027] As used herein when referring to "subcutaneous immunoglobulin preparations," "relative bioavailability" means the relative amount (provided as a ratio or percentage) of immunoglobulin reaching systemic circulation compared to the administration of an intravenous immunoglobulin preparation (which is administered directly into the bloodstream and therefore has a bioavailability of 100%).

[0028] In this specification, when referring to scores or index values ​​such as mRSS, HAQ DI, MDGA, PGA, or similar, the term “baseline” means the point in time before the commencement of treatment with the subcutaneous immunoglobulin preparation according to the methods herein. Therefore, if a score changes after a particular time of treatment compared to the baseline, the baseline value of a particular index refers to the value of that index taken before the commencement of treatment.

[0029] As used herein, “stabilizer” refers to molecules such as amino acids, carbohydrates, surfactants, sugar alcohols, or proteins that may be added to polyclonal immunoglobulin preparations to improve their shelf life during storage, for example, by reducing aggregation, oxidation, discoloration, or the like.

[0030] A "surfactant" refers to a molecule that has an amphiphilic structure, being hydrophilic at one end due to, for example, a polar or charged chemical group, and hydrophobic at the other end due to, for example, a carbohydrate group. Examples include polysorbates, poloxamers, and various fatty acids and lipids.

[0031] A "preservative" is a substance that prevents the growth of bacteria or other microorganisms in a solution.

[0032] Further definitions can be found in the following sections.

[0033] A. Immunoglobulin preparations Examples of immunoglobulin preparations as used herein include preparations primarily of immunoglobulin G (abbreviated as IVIG and SCIG, respectively) administered intravenously or subcutaneously. In some cases, the immunoglobulin preparation is in liquid form, i.e., has not been previously lyophilized or has been previously lyophilized and then reconstituted into a liquid form. In some cases, the preparation has not been previously lyophilized. In some embodiments, the preparation is in a “ready-to-use” form, meaning that it can be injected or administered directly to a subject without dilution, reconstitution, or similar processes.

[0034] In some cases, the immunoglobulin preparation is a relatively high-concentration IgG preparation administered subcutaneously. In some embodiments, the preparation contains at least 15% by mass / volume, at least 20% by mass / volume, at least 25% by mass / volume, or at least 30% by mass / volume immunoglobulin. In some cases, the concentration of immunoglobulin (i.e., IgG and other immunoglobulin forms, e.g., IgA and IgM) in the preparation is 15–30% by mass / volume. In some cases, the preparation contains 16–25% by mass / volume immunoglobulin. In some cases, the preparation contains 16–22% by mass / volume immunoglobulin. In some cases, the preparation contains 18–22% by mass / volume immunoglobulin. In some cases, the preparation contains 20–22% by mass / volume immunoglobulin. In some such cases, the preparation is a ready-to-use liquid preparation administered subcutaneously to a subject.

[0035] In some cases, the preparation is administered subcutaneously once, twice, or three times a week. In some cases, the weekly dose of the preparation is 0.1 g / kg to 1 g / kg. In some cases, the weekly dose of the preparation is 0.1 g / kg to 0.6 g / kg. In some cases, the weekly dose of the preparation is 0.1 g / kg to 0.5 g / kg. In some cases, the weekly dose of the preparation is 0.2 g / kg to 0.5 g / kg. In some cases, the weekly dose of the preparation is 0.1 g / kg to 0.4 g / kg. In some cases, the weekly dose of the preparation is 0.4 g / kg to 0.6 g / kg. In some cases, the weekly dose is 0.1 g / kg, 0.15 g / kg, 0.2 g / kg, 0.25 g / kg, 0.3 g / kg, 0.4 g / kg, 0.5 g / kg, 0.6 g / kg, 0.75 g / kg, or 1 g / kg. In some cases, the weekly dose of the preparation is 0.5 g / kg. In some cases, if the subject's body weight is greater than 100 kg, a fixed weekly dose of 50 g of the preparation is administered. In some cases, according to the above medication regimen, the subcutaneous dose is administered twice a week, for example, on the 1st and 3rd or 4th day of each week.

[0036] In some embodiments, the immunoglobulins in the preparation are derived from pooled plasma from hundreds or thousands of individual human donors. For example, in some cases, the preparation is derived from pooled plasma from more than 1,000 human donors.

[0037] The immunoglobulin preparations described herein can be stabilized in a variety of ways. For example, in some embodiments, the preparation includes a stabilizer containing an amino acid such as proline, glycine, or arginine. In some cases, the amino acid is glycine. In other cases, the amino acid is proline. In some cases, the stabilizer consists essentially of an amino acid. In some cases, the stabilizer contains or consists essentially of proline at concentrations such as 100–500 mM, e.g., 200–300 mM, 250 mM, etc. In some cases, the stabilizer further includes a surfactant such as polysorbate 80 or polysorbate 20. In some embodiments, the polysorbate surfactant is provided at concentrations of 100 mg / L or less, or 70 mg / L or less, e.g., 5–50 mg / L, 8–30 mg / L, etc. In some embodiments, the stabilizer contains both an amino acid and a surfactant. In some embodiments, the stabilizer consists essentially of both an amino acid and a surfactant. In some cases, the stabilizer contains proline and a surfactant, or consists essentially of proline and a surfactant. In some such cases, the proline concentration is 100–500 mM, e.g., 200–300 mM, 250 mM, etc., and the surfactant is polysorbate 80 or polysorbate 20 at a concentration of 5–50 mg / L, e.g., 8–30 mg / L. In some embodiments, the preparation has a pH of 4.6–5.2, e.g., 4.8–5.2. In some cases, the preparation does not contain carbohydrate stabilizers. In some cases, the preparation does not contain carbohydrates, sugar alcohols, or protein stabilizers (e.g., albumin). In some cases, where the stabilizer consists essentially of amino acids, or essentially of amino acids and a surfactant, the preparation may further contain trace amounts of salts such as sodium or potassium, peptides, or other components found in trace amounts in either the immunoglobulin or the stabilizer. In some cases, the preparation does not contain any preservatives. In some cases, the liquid polyclonal immunoglobulin preparation has never been lyophilized.

[0038] In some cases, the immunoglobulin content of the preparation is at least 98% IgG. In some cases, the immunoglobulin subclass distribution is 60-75% IgG1, 20-35% IgG2, 2-5% IgG3, and 1-3% IgG4. In some cases, the subclass distribution is 62-74% IgG1, 22-34% IgG2, 2-5% IgG3, and 1-3% IgG4. In some cases, the preparation does not contain more than 100 μg / mL of IgA, or more than 50 μg / mL of IgA. In some cases, the IgA content is 100 μg or less per 100 mg of immunoglobulin, or 50 μg or less per 100 mg of immunoglobulin, or 25 μg or less per 100 mg of immunoglobulin. In some cases, the preparation does not contain carbohydrate stabilizers, does not contain more than 50 μg / mL of IgA, and / or contains preservatives. In some cases, the preparations do not contain carbohydrate stabilizers, IgA more than 50 μg / mL, and preservatives. In some cases, the preparations contain at least 98% IgG, 200-300 mM (or 250 mM) proline, 8-30 mg / L polysorbate 80, trace amounts of sodium, and IgA less than or equal to 50 μg / mL, and do not contain preservatives.

[0039] Examples of immunoglobulin preparations suitable for the subcutaneous administration method of the present invention include, for example, the subcutaneous immunoglobulin preparation Hizentra(R) (subcutaneous immunoglobulin), which is a ready-to-use 20% liquid immunoglobulin preparation for subcutaneous administration, containing at least 98% IgG, 200-300 mM (or 250 mM) proline, 8-30 mg / L polysorbate 80, trace amounts of sodium, and ≤ 50 μg / mL of IgA, with a pH of 4.6-5.2 (Hizentra(R) FDA insert, 2021). Other examples of subcutaneous immunoglobulin preparations include, for example, Cuvitru(R) and Vivaglobin(R). For example, Vivaglobin(R) contains 16% mass / volume immunoglobulin, glycine as a stabilizer, and sodium chloride, with a pH of 6.4-7.2 (Vivaglobin(R) FDA insert). For example, Cuvitru(R) contains 20% immunoglobulin, and the immunoglobulin in this preparation is at least 98% IgG. It contains 250 mM glycine as a stabilizer and has a pH of 4.6–5.2 (e.g., 4.6–5.1). It contains an IgA content of ≤100 μg / mL (Cuvitru(R) 2021 FDA Prescription).

[0040] On the other hand, examples of immunoglobulin preparations administered intravenously include Privigen(R), Sandoglobulin(R) / Carimune(R), and also Gamunex-C(R), Gammagard(R), and Octagam(R). For example, Privigen(R) contains 10% mass / volume immunoglobulin along with IgG monomer of at least 98% purity, and further contains 250 mM L-proline (in the range of 210-290 mM), trace amounts of sodium, is free of carbohydrate stabilizers and preservatives, has a pH of 4.8 (in the range of 4.6-5.0), and contains IgA at less than 25 μg / mL or equal to 25 μg / mL (Privigen(R) FDA Prescription 2017, 56th edition).

[0041] In some embodiments, the preparation is provided in single-dose containers such as pre-filled syringes, for example in 5 mL, 10 mL, 20 mL, and 50 mL; or in single-dose tamper-evident vials, for example in 5 mL, 10 mL, 20 mL, and 50 mL. In some cases, the preparation is administered using an infusion pump device. In some cases, the total volume of fluid administered to the subject in each dose is between 10 mL and 100 mL, for example between 50 mL and 100 mL, or between 25 mL and 75 mL.

[0042] B. Treatment of systemic sclerosis and administration of subcutaneous immunoglobulin preparations SSc includes two main subsets: localized systemic sclerosis (lcSSc) and diffuse systemic sclerosis (dcSSc). Both conditions are characterized by dermatofibrosis—thickening and hardening of the skin. Patients with lcSSc may exhibit dermatofibrosis distal to the elbows and knees, e.g., hands, face, feet, and / or forearms, and may experience symptoms such as abnormal skin pigmentation and skin texture, as well as Raynaud's phenomenon. Patients with dcSSc exhibit dermatofibrosis proximal to the elbows and knees, and thus can spread over a large portion of the limbs. Patients with dcSSc may also experience symptoms such as Raynaud's phenomenon, gastroesophageal reflux, and difficulty eating (dysphagia), and in some cases, complications involve the lungs and / or kidneys, including pulmonary fibrosis and renal failure.

[0043] The mechanisms of action of polyclonal immunoglobulin preparations, such as those described herein, are complex and not fully understood, but an increase in the overall concentration of IgG antibodies may be involved, which may in part block the interaction between disease-associated autoantibodies and the Fc gamma receptor or other targets. In general, autoantibodies that interact with the Fc gamma receptor are frequently found in patients with autoimmune diseases, including SSc patients. The Fc gamma receptor is a surface glycoprotein that modulates the coordination between activating and inhibitory signals in immune cells. While not constrained by theory, one possible treatment strategy that may be applicable to SSc patients is to target the Fc gamma receptor. Thus, targeting the Fc gamma receptor may help attenuate inflammation and autoimmunity in SSc.

[0044] The methods described herein involve subcutaneous administration of polyclonal immunoglobulin preparations, as described in the preceding section, to subjects having SSc, such as dcSSC or lcSSc. In some cases, SSc is diffuse systemic sclerosis (dcSSc) or localized SSc (lcSSc). In some cases, SSc is dcSSc.

[0045] Because dermatofibrosis causes thickening and hardening of the skin over time, it was unclear whether polyclonal immunoglobulin preparations, such as those described herein, could be safely administered subcutaneously to SSc patients without causing either a reaction at the subcutaneous injection site or low bioavailability due to difficulties in penetrating the affected skin. For example, when immunoglobulin preparations are administered subcutaneously to treat other conditions, adverse effects may include, among other things, local injection site reactions, rash, local fever, local pain, and itching. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 injection sites are used simultaneously for subcutaneous administration of the treatment. In some embodiments, these injection sites are positioned such that each site is at least 2 inches away from another site. In some cases, the injection sites are located on the abdomen, thigh, and / or lateral buttocks of the subject. In some cases, subjects with SSc do not have skin thickening at the subcutaneous injection site(s). For example, the subject may show evidence of skin thickening in other areas of the body. However, this may not always be possible when multiple sites are required. Therefore, in some cases, the site chosen for subcutaneous administration may not show evidence of skin thickening, while other areas of the body may. Thus, in other cases, the subject will have skin thickening at at least one subcutaneous injection site. For example, in some cases, the subject will not have mild or moderate to severe skin thickening at one or more injection sites with an mRSS score of 2 or lower. In some cases, prior to the initiation of the procedure, the subject will not have a history of dermatitis, eczema, or psoriasis, or a history of dermatitis, eczema, or psoriasis at one or more subcutaneous injection sites.

[0046] When the preparation is administered subcutaneously, it may be self-administered by the subject, for example, using an infusion pump or similar device. For example, for a weekly dose of 0.1–1 g / kg, the volume of subcutaneous infusion may be approximately 10–100 mL per week, for example, 10–50 mL or 10–20 mL or 20–50 mL. In some cases, the preparation is administered for a period of at least 2 weeks, at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year.

[0047] In some cases, the above method further includes the administration of at least one additional therapeutic agent. In some cases, at least one additional therapeutic agent does not include an antibody therapeutic agent. In some such cases, at least one additional therapeutic agent does not include an anti-CD20 antibody and / or does not include either an anti-IL6 antibody or an anti-IL6 receptor antibody. In some cases, the subject has never previously received treatment with an anti-CD20 antibody and / or has never previously received treatment with an anti-IL6 antibody and / or has never previously received treatment with an anti-IL6 receptor antibody. In other cases, the subject has previously been administered an antibody therapeutic agent. Examples of antibody therapeutic agents include nintedanib, tocilizumab, crazakizumab, and rituximab. Therefore, in some cases, the subject does not receive therapeutic treatment with any of nintedanib, tocilizumab, crazakizumab, and rituximab in conjunction with an immunoglobulin preparation. In other cases, the subject has been previously treated with one or more of nintedanib, tocilizumab, and rituximab, or with an anti-CD20, anti-IL6, or anti-IL6 receptor antibody.

[0048] In some embodiments, the subject is treated with at least one further therapeutic agent, including an immunosuppressant. In some embodiments, the subject is treated with at least one further therapeutic agent, including a small molecule immunosuppressant. In some embodiments, the subject is also treated with cyclophosphamide, methotrexate, mycophenolate mofetil (MMF), and / or autologous hematopoietic stem cell transplantation (aSCT). For example, agents such as cyclophosphamide, methotrexate, and mycophenolate mofetil may be administered as further therapeutic agents for the treatment of fibrotic symptoms such as cutaneous sclerosis and SSc-ILD. In some embodiments, at least one further therapeutic agent includes an angiotensin-converting enzyme inhibitor and / or an endothelin receptor antagonist. In some embodiments, at least one further therapeutic agent includes ambrisentan. In some embodiments, at least one further therapeutic agent may treat symptoms associated with interstitial lung disease (SSc-ILD) in SSc. In some embodiments, at least one further therapeutic agent includes a phosphodiesterase type 5 inhibitor. In some embodiments, at least one further therapeutic agent is tadalafil.

[0049] In some cases, the subjects have never been diagnosed with a rheumatic autoimmune disease other than SSc. For example, in some cases, the subjects have never been diagnosed with one or more of the following: rheumatoid arthritis, lupus, mixed connective tissue disease, polymyositis, dermatomyositis, Sjögren's syndrome, myositis, or primary biliary cholangitis. In some cases, the subjects have never been diagnosed with one or more of the following: rheumatoid arthritis, lupus, mixed connective tissue disease, polymyositis, or dermatomyositis. In other cases, the subjects have been diagnosed with at least one other rheumatic autoimmune disease. In some cases, systemic sclerosis autoantibodies have been detected in the subjects. In some cases, the subjects have no history of dermatitis, eczema, or psoriasis at the subcutaneous injection site(s) prior to the initiation of the procedure.

[0050] Potential adverse events associated with subcutaneous administration of immunoglobulin preparations include injection site pain, swelling, or inflammation. In some cases, subjects described herein experience injection site skin reactions that are mild to moderate after administration of the preparation. In some cases, subjects do not experience injection site reactions such as injection site pain or swelling within the first month or first three months of treatment.

[0051] C. Efficacy, bioavailability, and pharmacokinetics of treatments using subcutaneous immunoglobulin preparations. As described in the following examples, a clinical trial was conducted comparing the administration of an intravenous IgG preparation, IgPro10 (containing 10% mass / volume immunoglobulin), with that of a subcutaneous IgG preparation, IgPro20 (20% mass / volume immunoglobulin), in 27 human subjects with SSc. As described in the following examples, subjects were treated either intravenously with IgPro10 followed by subcutaneously with IgPro20 for 17 weeks each, or subcutaneously with IgPro20 followed by intravenously with IgPro10 for 17 weeks each. On average, in the 27 subjects, the population-relative bioavailability of subcutaneous IgG was 76% compared to intravenous IgG (set to 100%) (standard deviation approximately 8%; dose-normalized, baseline-adjusted AUC). 0-tau (Based on...). In detail, when IgPro20 was administered first in the sequence, its relative bioavailability compared to IgPro10 was 83% on average, whereas when IgPro20 was administered second in the sequence, its relative bioavailability compared to IgPro10 was 70% on average. Term "AUC" 0-tau" refers to the area under the curve (AUC) measured from the beginning to the end of the drug administration period, i.e., over the entire drug administration period. Accordingly, in some embodiments herein, the relative bioavailability of the subcutaneous IgG preparation may be at least 65%, at least 70%, at least 75%, or at least 80% compared to an intravenous IgG preparation (set as 100%) administered intravenously in the same total dose in the subject. In some embodiments, this relative bioavailability is (AUC 0-tau (SC / SC dose) / (IV AUC) 0-tau The calculation is based on the dose of IV, where SC is the subcutaneous immunoglobulin preparation and IV is the comparative intravenous immunoglobulin preparation.

[0052] In the following examples, the IgPro10 and IgPro20 comparative studies also compared various parameters related to the pharmacokinetics and efficacy of subcutaneous and intravenous preparations in the treated subjects.

[0053] For example, for all subjects in each group in the study, serum IgG concentrations were determined in the subjects throughout the entire treatment period in order to calculate the mean trough serum IgG concentration, among other parameters. It was found that subcutaneous administration of immunoglobulin preparations resulted in higher trough serum IgG concentrations. Therefore, in the method herein, for example, a subject may have a trough serum IgG concentration of at least 18 g / L, at least 19 g / L, or at least 20 g / L after subcutaneous administration of an immunoglobulin preparation. In some cases, a subject may have a trough serum IgG concentration in the range of 18–25 g / L, 19–25 g / L, 20–25 g / L, 20–24 g / L, or 21–24 g / L after subcutaneous administration of an immunoglobulin preparation. In some subjects, the trough serum IgG concentration ranges from 22–24 g / L or 21–23 g / L or 21–22 g / L. In contrast, the mean trough serum IgG concentration after intravenous administration of immunoglobulin preparations in the subjects assayed in the study was 17–18 g / L. The baseline serum IgG concentration in the subjects was 12–13 g / L.

[0054] Subjects treated according to the methods described herein may also show improvement in several efficacy criteria, as shown in Tables 3 and 4 below, for example. For example, in some cases, the subject's skin thickness is assessed before administration, and a modified Rodnan skin thickness score (mRSS) is calculated for that subject (PJ Clements et al., J. Rheumatol. 20(11):1892~6(1993); D. Khanna et al., JSRD 2(1):11~18(2017)). The modified Rodnan skin thickness score (mRSS) is a physician-administered assessment criterion often used to examine the progression of dermatofibrosis (i.e., skin thickening) over time. The mRSS is a semi-quantitative score. The mRSS assesses skin thickness at 17 different skin sites, with scores ranging from 0 (normal) to 1 (mild skin thickness), 2 (moderate skin thickness), or 3 (severe or thick) for each site. The total score ranges from 0 to 51, with higher scores indicating thicker skin. Since changes in mRSS scores correlate with histological skin thickness, they are often used as a primary or secondary outcome in clinical trials. The mRSS can not only provide a means of monitoring the potential effects of treatment on skin thickness, but also a way to assess whether skin thickness may interfere with the subcutaneous administration of a procedure.

[0055] In some cases, subjects have a modified Rodnan skin thickness score (mRSS) of at least 15 prior to administration and treatment with the preparation, and in some cases, an mRSS score of 15–45 prior to treatment with the preparation. In some cases, the injection site is selected from sites with an mRSS score of 2 or less. In some cases, treatment with the preparation described herein reduces the patient's mRSS compared to the score before administration. In some subjects tested, the mRSS decreased from a value of 3–8 points after at least 17 weeks of treatment with the subcutaneous IgG preparation, where the starting mRSS was between 20–25. Thus, for example, in some embodiments, the starting mRSS value of a subject decreases by at least 3, at least 4, at least 5, at least 6, at least 8, or at least 10 after at least 1, 2, 3, or 4 months of treatment. In some embodiments, the starting mRSS value decreases by 2-10, 2-8, 3-8, 2-5, 3-10, 4-10, 5-10, 4-8, or 5-8 after treatment for at least 1, 2, 3, or 4 months according to the method herein. In some embodiments, the subject has a reduction of at least 15%, at least 20%, or at least 25% of the mRSS after treatment for at least 1, 2, 3, or 4 months according to the method herein.

[0056] For example, as described in the following examples, of 27 subjects, 11 (40.7%) showed a reduction of at least 5 points or at least 25% in mRSS after 1 to 17 weeks of treatment, and 18 (66.7%) showed a reduction of at least 5 points or at least 25% in mRSS over 1 to 32 weeks. Of the 27 subjects, 13 (48.1%) showed a reduction of at least 4 points or at least 20% in mRSS over 1 to 17 weeks, and 20 (74.1%) showed a reduction of at least 4 points or at least 20% in mRSS over 1 to 32 weeks.

[0057] In the following examples, patients also showed a decrease (improvement) in their mean Scleroderma Health Assessment Questionnaire (SHAQ) overall disease score, measured using the Visual Analog Scale (SHAQ VAS) and the HAQ Disability Index (HAQ DI) score. The SHAQ consists of both the HAQ-DI and scleroderma-specific VAS items. The SHAQ VAS is a self-report questionnaire focused on quality of life for SSc subjects and focuses on the following items: pain, bowel disease, respiratory problems, Raynaud's syndrome, finger ulcers, and overall disease. Each VAS item is assessed separately, with higher scores indicating more severe disease. (See, for example, J. Pope, Arthritis Care & Research, 63(S11), pp. S98-S110 (2011)). In some cases, the SHAQ VAS after 17 weeks of treatment decreased by at least 5%, at least 10%, at least 15%, or at least 20% compared to baseline before treatment. For example, the SHAQ VAS, which has a scale of 0 to 3 (where higher numbers indicate a worse patient condition), had a mean score of 1.2 before treatment in the study, and a mean score of 1.0 to 1.1 after 17 or 32 weeks of treatment. Thus, in some cases, the SHAQ VAS score of patients after at least 1, 2, 3, or 4 months of treatment following the methods herein may decrease by at least 5%, at least 10%, at least 15%, or at least 20%. In some cases, subjects may also have an improvement (i.e., a decrease) in the HAQ DI score. The HAQ-DI is a self-report questionnaire of 20 questions referring to 8 domains: dressing / grooming, getting up, eating, walking, hygiene, extension, grip strength, and activity, in which case the total score indicates the self-assessed level of impairment. Each question is graded on a scale of 0 (no difficulty), 1 (somewhat difficult), 2 (quite difficult), or 3 (unable). The total score is calculated by dividing the sum of the domain scores by the number of domains that have a score. Based on this range of 0 to 3, a higher total score indicates a more severe impairment.(JFFries et al., Arthritis Rheum., 23(2):137~45 (1980); V. Steen & T.A. Medsger, Jr., Arthritis Rheum. 44:2828~35 (2001); J. Pope, ibid.; C. Almeida et al., Autoimmun. Rev. 14:1087~96 (2015)). In some cases, the HAQ DI score of patients after treatment for at least 1, 2, 3, or 4 months following the methods herein may also decrease by at least 5%, at least 10%, at least 15%, or at least 20%.

[0058] In some cases, the UCLA (University of California at Los Angeles) Scleroderma Clinical Trial Consortium Gastrointestinal Tract score is used to assess the subject (UCLA SCTC GIT 2.0 score). This is a self-reported score based on gastrointestinal symptoms in SSc patients. (See, for example, D. Khanna et al., Arthritis Rheum., 61(9):1257~63 (2009); D. Khanna et al., J. Rheumatol., 38(9):1920~24 (2011); G. Abignano et al., J. Rheumatol. 48(9):1422~26 (2021)). The study consisted of 34 questions covering the following items: reflux (1-8), bloating / distention (9-12), fecal ingestion (13), diarrhea (14-15), social functioning (16-21), mental well-being (22-30), and constipation (31-34). These items were scored on a scale of 0, 1, 2, or 3, where 0 indicated better health and a higher number indicated worse health. Scores from each subset, excluding constipation, combined to form the total GIT score, capturing the overall burden of SSc-related GIT severity. In the subjects tested, GIT scores did not increase on average during treatment. In some cases, the UCLA SCTC GIT 2.0 score did not increase by more than 15%, or increase by more than 10%, or decrease after at least 1, 2, 3, or 4 months of treatment according to the methods herein.

[0059] In some cases, after at least one, two, three, or four months of treatment according to the methods herein, subjects have a reduction (improvement) in the Physician Global Assessment (MDGA) test. The MDGA is assessed by a physician, and MDGA values ​​range from 0 to 10, with higher scores indicating a worse patient condition. In some cases, the MDGA value decreases by at least 5%, at least 10%, at least 15%, or at least 20% compared to baseline before treatment with the immunoglobulin preparation after at least one, two, three, or four months of treatment according to the methods herein.

[0060] In some cases, after at least one, two, three, or four months of treatment according to the methods herein, subjects have a reduction (improvement) in a Patient General Assessment Test (PGA), which is a patient self-report test. The PGA is also scored on a scale from 0 (good) to 10 (very bad), with higher scores indicating a worse disease. In some cases, the PGA value decreases by at least 5%, at least 10%, at least 15%, or at least 20% over this period compared to baseline.

[0061] In some cases, subjects treated according to the methods herein will show improvement in at least one of the mRSS, SHAQ-DI and / or VAS scores, UCLA SCTX GIT 2.0 score, PGA, or MDGA compared to the pre-treatment score (baseline), for example, by at least 5%, at least 10%, at least 15%, or at least 20%, after at least 1, 2, 3, or 4 months of treatment. In some cases, the methods herein will produce improvement in at least 5%, at least 10%, at least 15%, or at least 20%, compared to the pre-treatment score (baseline), in one or more of the mRS total score, SHAQ-DI and VAS scores, PGA, and MDGA, after at least 4 weeks, at least 8 weeks, at least 12 weeks, or at least 16 weeks of treatment.

[0062] In some cases, swelling or pain in one or more joints is evaluated in the subject. For example, swelling in joints such as the proximal interphalangeal joints of the fingers, metacarpophalangeal joints, wrist, elbow, shoulder, and / or knee may be evaluated by a physician as either swollen or absent. These same joints may also be evaluated for tenderness as either tender or absent. In some cases, or in more joints, swelling or tenderness decreases after at least one, two, three, or four months of treatment following the methods herein. For example, in some cases, the number of joint swellings does not increase after at least one, two, three, or four months of treatment following the methods herein. In some cases, the number of joint swellings decreases after at least one, two, three, or four months of treatment following the methods herein, for example, by one joint. For example, in some cases, the number of tender joints does not increase after at least one, two, three, or four months of treatment following the methods herein. In some cases, the number of tender joints decreases after at least one, two, three, or four months of treatment following the methods herein, for example, by one joint. In some patients, a qualified individual may perform manual muscle testing (MMT), for example, testing the axial flexors of the neck and the following bilateral proximal muscles (middle deltoid, biceps brachii, gluteus maximus, gluteus medius, quadriceps), and the following distal muscles: wrist extensors and ankle dorsiflexors. In some cases, these assessments may be used to guide the overall MMT total score. In some cases, the MMT total score does not increase after at least one, two, three, or four months of treatment following the methods herein, and in some cases, it does not decrease by more than 5% or more than 10% after at least one, two, three, or four months of treatment following the methods herein (i.e., it increases, remains the same, or decreases by 5% or less or 10% or less).

[0063] In some cases, predicted forced vital capacity (FVC) is determined as a percentage for the subject. "Predicted FVC%" measures the adjusted volume of air that can be forcibly exhaled from the lungs after taking the deepest possible breath (adjusted as a percentage of the expected normal value based on the patient's age, height, sex, and ethnicity). In some such cases, the subject does not show a decrease in FVC% of more than 5%, more than 2%, or more than 1% after treatment for at least 1, 2, 3, or 4 months according to the method herein.

[0064] The following examples are presented to provide a complete disclosure and description of methods for manufacturing and using the subject matter disclosures, and are not intended to limit the scope of what is considered the present disclosure. While efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantities, temperatures, concentrations, etc.), some experimental error and deviation should be taken into account. The entire disclosure of each cited document (including patents, patent applications, academic papers, abstracts, instructions, books, or other disclosures) is incorporated herein by reference as a whole. [Examples]

[0065] Example 1. Safety and pharmacokinetics of IGPRO20 (subcutaneous immunoglobulin) and IGPRO10 (intravenous immunoglobulin) in adults with systemic sclerosis. This example relates to the evaluation of the local injection safety, bioavailability, and pharmacokinetics (PK) of subcutaneous IgG (SCIG) (IgPro20) in adults with diffuse SSc (dcSSc).

[0066] A. Exam summary and results A randomized, open-label, crossover trial was designed (NCT04138485). Adult subjects with (1) a diagnosis of dcSSc within 5 years of the first non-Raynaud's phenomenon and (2) a modified Rodnan skin thickness score of 15–45 at screening were randomly selected in a 1:1 ratio to receive one of two treatment sequences: (1) Sequence A (IgPro20, 20% normal human subcutaneous immunoglobulin, followed by IgPro10, 10% normal human intravenous immunoglobulin), or (2) Sequence B (IgPro10, followed by IgPro20). A total of 27 subjects were randomly selected, with 13 subjects assigned to Sequence A and 14 subjects assigned to Sequence B. Figure 1 provides the overall trial design.

[0067] Each subject completed two 16-week treatment periods over a study period of up to 40 weeks (including screening). The administered doses were 0.5 g / kg / week for IgPro20, divided into two sessions, and 2 g / kg / 4 weeks for IgPro10, divided over 2–5 days. The primary endpoint was the safety of IgPro20, described as treatment-induced adverse events (TEAEs) and changes in clinical findings. Secondary endpoints included the proportion of subjects meeting the cardiopulmonary or renal failure criteria on the ACR CRISS, the proportion of responders (ACR CRISS > 0.6), and the mean change in the modified Rodnan skin thickness score over, for example, 48 weeks.

[0068] Exclusion criteria for subjects also included diagnoses of primary rheumatic diseases other than dcSSc, such as rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, polymyositis, and dermatomyositis. Subjects with fibromyalgia, secondary Sjögren's syndrome, and scleroderma-associated myopathy or myositis were not excluded. Further exclusion criteria included positive anti-centromere antibodies; evidence of severe chronic kidney disease or being on dialysis; a history of thrombotic episodes such as myocardial infarction or stroke, documented thrombophilic abnormalities; three or more of the following: presence of atrial fibrillation, coronary disease, diabetes mellitus, dyslipidemia, hypertension, or obesity; presence of bacterial or viral infection; malignancy; known hypoalbuminemia; and known IgA deficiency.

[0069] The study results, described in more detail in the following section, demonstrate that subcutaneous administration of IgPro20 has an acceptable safety, bioavailability, and PK profile in dcSSc patients.

[0070] Of the 27 treated subjects, 25 completed the study. During the 36-week study period, 107 treatment-induced adverse events (TEAEs) occurred in 22 subjects (81.5%), the majority of which were mild or moderate. Based on basic vocabulary (PT), the most common TEAEs (>10% of subjects) were headache (12 events in 6 subjects [22.2%]), COVID-19 (3 ​​events in 3 subjects [11.1%]), diarrhea (3 events in 3 subjects [11.1%]), and vomiting (3 events in 3 subjects [11.1%]). A total of 10 serious adverse events (SAEs) were reported in 6 subjects (viral infection, chronic gastritis, vomiting, dehydration, upper gastrointestinal bleeding, chest pain, myocardial infarction, myocardial ischemia, breast cancer, and interstitial lung disease). Among these subjects, one experienced two SAEs (myocardial ischemia and myocardial infarction), and the study procedure was discontinued. The principal investigator determined that neither SAE was related to the study procedure, and no deaths were reported.

[0071] For IgPro20, 14 injection site reactions (ISRs) occurred in 5 subjects (19.2%); all were mild to moderate in severity. The most common ISRs were injection site pain and injection site swelling (3 events each in 2 subjects, 7.7%). A total of 686 IgPro20 injections were performed, resulting in an overall ISR rate of 0.02 per injection, or 2 ISRs per 100 injections. No ISRs were reported for IgPro10.

[0072] No clinically relevant trends were observed in vital signs, body weight, laboratory tests, electrocardiogram, or pulmonary function tests. The PK profile and bioavailability in dcSSc subjects were similar to those observed in other approved indications such as primary immunodeficiency. Dose-normalized baseline adjusted AUC 0-tau The population-relative bioavailability of IgPro20 based on this was 0.761 (90% CI: 0.7033, 0.8232), which was 76.1% compared to IgPro10 (intravenous IgG).

[0073] The overall safety profiles of IgPro20 and IgPro10 in subjects with dcSSc were consistent with those in approved indications such as chronic inflammatory demyelinating polyneuropathy (CIDP), including a relatively low ISR rate for IgPro20. The PK profiles and bioavailability were also similar to those in other indications, as will be discussed further below.

[0074] B. Overall test design and plan: Description Subjects diagnosed with dcSSc with a disease duration of ≤5 years and a skin thickness score ≥15 to ≤45 as measured by mRSS were eligible to enroll in the study. During the screening period, the principal investigators assessed the suitability of potential subjects by using the 2013 European League Against Rheumatism / ACR criteria for SSc (van den Hoogen et al., Ann. Rherm. Dis. 72(11):1747-55 (2013)) and diffuse characteristics to accurately confirm their classification as dcSSc (LeRoy et al., J. Rheumatology 15(2):202-5 (1988); LeRoy et al., J. Rheumatology 28(7):1573-6 (2001)). All eligible subjects were randomly selected (1:1) to either Sequence A (IgPro20-IgPro10 treatment sequence) or Sequence B (IgPro10-IgPro20 treatment sequence). Each subject was to complete two treatment periods (Treatment Period 1 and Treatment Period 2; 16 weeks each) over a trial period of up to 40 weeks (including screening).

[0075] Subjects in Sequence A received a total dose of 0.5 g / kg IgPro20 weekly over two sessions per week during Treatment Period 1, and a total dose of 2 g / kg IgPro10 every four weeks over two to five sessions on consecutive days during Treatment Period 2. Subjects in Sequence B received a total dose of 2 g / kg IgPro10 every four weeks over two to five sessions during Treatment Period 1, and a total dose of 0.5 g / kg IgPro20 weekly over two sessions per week during Treatment Period 2. A weekly dose of 0.5 g of IgPro20 per kg of body weight is equivalent to a four-week dose of IgPro10 (2 g per kg of body weight) when using a 1:1 conversion. This was the highest possible IgPro20 SC dose due to volume limitations and uncharacterized safety in SSc subjects with skin dysfunction.

[0076] 1. Test Design Since the differences between IgPro20 and IgPro10 treatments are measured within a single subject rather than between subjects with SSc, a crossover design of two sequences was chosen to provide reliable predictions for IgPro20; both inter- and intra-individual variability was characterized. This study design also allowed for the investigation of potential differences in the relative bioavailability of IgPro20 (SCIG) when administered before or after IgPro10 (IVIG) in SSc subjects. Several PK samples were collected to measure IgG trough concentrations during both treatment periods 1 and 2 in each sequence to evaluate the steady-state and carry-over effects of IgPro20 or IgPro10 from treatment period 1 to treatment period 2. Furthermore, PK samples were frequently collected during the last treatment period to adequately characterize the PKs of IgPro20 and IgPro10, respectively, for each treatment period in this patient population.

[0077] Sixteen weeks of treatment for both IgPro20 and IgPro10 allowed for the evaluation of safety and preliminary efficacy signals, as well as the assessment of steady-state IgPro20 and IgPro10 PK profiles. The duration of PK evaluation was based on IgG trough concentrations measured in a pivotal phase 3 trial (IgPro20_3003 trial) in subjects with CIDP, indicating that IgPro20 and IgPro10 would reach steady state within approximately eight weeks. Importantly, several trough concentrations were determined for IgPro20 and IgPro10 in this trial, and it was confirmed that the complete PK profiles of IgPro20 or IgPro10 reached steady state before being evaluated in subjects with SSc.

[0078] Since the complete PK profile of IgPro10 during each treatment period of each sequence was obtained at the end of the treatment period and it was considered that steady state would have been reached, the study did not have a washout period. The relative bioavailability of IgPro20 was evaluated based on dose-normalized AUC 0-tau of IgPro20 and IgPro10 without the need for a washout period. Furthermore, the absence of a washout period between the two treatments shortened the study period and potentially reduced the burden on SSc subjects.

[0079] 2. Pharmacokinetic evaluation Serum samples for IgG trough level determination were collected at several study visits. Additional blood samples for rich PK sampling of IgG levels were collected at the end of each treatment period to calculate PK parameters (AUC 0-tau ), AUC 0-last , C max , C trough , and time to reach maximum plasma concentration [Tmax]). IgG concentrations from PK sampling were tabulated for each individual subject and summarized for nominal (planned) time points. Individual concentration-time profiles and mean (±SD) profiles after the first injection of the last infusion cycle in each treatment period and treatment sequence were plotted using actual time points for individual plots and nominal (planned) time points for mean profiles.

[0080] Non-compartmental PK analysis was performed by ICON Early Clinical & Bioanalytical using Phoenix WinNonLin (Build 8.0.0.3176). PK parameters were calculated using only the concentration-time profiles after the first injection of the last infusion cycle in each treatment period and treatment sequence. PK parameters (AUC 0-tau ), AUC 0-last , C max , C trough , and T maxThe results were derived using actual sampling time and a non-compartmental analysis approach from serum IgG levels. Serum PK parameters were listed and summarized for each treatment period in each treatment sequence, along with the mean (±SD) and geometric mean (geometric %CV and 95%CI) for all PK parameters except Tmax based on the PK set. trough This was organized by treatment within each treatment sequence at each point in time. max It was only listed on the list.

[0081] Relative bioavailability, baseline-adjusted C trough and dose-normalized baseline corrected C trough The analysis was based on the following: Population bioavailability was defined as the area under the logarithmically transformed, dose-normalized, baseline-corrected curve (C) from the beginning to the end of the treatment period after the administration of the first dose of IgPro20. trough Relative bioavailability was assessed using mixed model repeated measures (AUC) for tau concentration-time (AUC) after administration of the initial dose of IgPro20 or IgPro10 in the final week of IgPro20 administration. 0-tau The geometric mean ratio of ]) was calculated. This model included treatment, treatment period, and treatment-by-treatment-period interactions as fixed effects using an unstructured covariance matrix. The dose-normalized baseline-adjusted AUC was calculated using the geometric mean ratio and the corresponding 90% CI derived from the statistical model. 0-tau The relative bioavailability of IgPro20 was evaluated based on the following: In detail, the relative bioavailability was: (AUC 0-tau The calculation was performed using the formula: (IgPro20(SC) / (dose of IgPro20(SC)) / (AUC0-tau of IgPro10(IV) / dose of IgPro10(IV)).

[0082] After reviewing the serum IgG concentration data, two outlier observations were identified, one for each treatment (IgPro10 outlier, sample AP21; IgPro20 outlier, sample BH22). In each case, the IgG concentration in the sample was considerably higher than in the previous sample, and consequently, these sample points had an unbalanced influence on the estimated parameters. Both samples were excluded from the PK parameter calculation as per CSL guidelines. Other data were not excluded from the PK analysis. The mean (+ / - standard deviation) of the serum IgG concentration-time profile after the first infusion of the last infusion cycle is shown for each treatment in Figure 2A (linear scale) and Figure 2B (logarithmic-linear scale), where solid lines represent data for the IgPro10 treatment and dashed lines represent data for the IgPro20 treatment.

[0083] Table 1 summarizes the serum PK parameters of IgPro10 and IgPro20 for each treatment and overall, and Table 2 shows their relative bioavailability.

[0084] [Table 1]

[0085] [Table 2]

[0086] At week 1 (baseline), mean (SD) serum IgG concentrations were 13.271 g / L (4.3011) and 12.349 g / L (4.2912) for sequence A (IgPro20 / IgPro10) and sequence B (IgPro10 / IgPro20), respectively. In both Sequence A and B, the mean trough serum IgG concentration during the IgPro20 period was higher than the mean trough serum IgG concentration during the IgPro10 period, ranging from 22.175 to 23.821 g / L (for IgPro20 in Sequence A, when IgPro20 was administered first) and 20.590 to 22.042 g / L (for IgPro20 in Sequence B, when IgPro20 was administered second), compared to 17.322 to 17.945 g / L (for IgPro10 in Sequence B, when IgPro10 was administered first) and 17.080 to 19.559 g / L (for IgPro10 in Sequence A, when IgPro10 was administered second). max The AUC was higher after IgPro10 administration compared to IgPro20 administration. Dose-normalized baseline-adjusted AUC 0-tau The population relative bioavailability based on this was 0.761 (i.e., 76.1%). The relative bioavailability of IgPro20 was higher in sequence A (IgPro20 / IgPro10) than in sequence B (IgPro10 / IgPro20), with geometric mean ratios (90% CI) of 0.831 and 0.698, respectively.

[0087] The geometric mean (geometric SD) AUC0-tau and Cmax were 3711.73 h*g / L (1.172) and 23.714 g / L (1.1570) for IgPro20, and 17,303.50 h*g / L (1.163) and 46.099 g / L (1.2405) for IgPro10, respectively. Dose-normalized baseline-adjusted AUC 0-tau The relative bioavailability of IgPro20 based on this was 0.761 (90% CI: 0.7033, 0.8232).

[0088] 3. Effectiveness Evaluation In diffuse systemic scleroderma, various efficacy measures were used, including the American College of Rheumatology (ACR) Composite Response Index (ACR CRISS) Step 1 and Step 2, the Modified Rodnan Skin Thickness Score (mRSS), the Scleroderma Health Assessment Questionnaire (SHAQ) Visual Analog Scale (VAS), and the Health Assessment Questionnaire Digital Impairment (HAQ DI), the UCLA Scleroderma Clinical Trials Collaborative Gastrointestinal (UCLA SCTC GIT) version 2.0, the Physician Global Assessment (MDGA), and the Patient Global Assessment (PGA) trials, as well as assessments of muscle strength, tenderness or swelling of joints, and levels of friction in the joints.

[0089] ACR-CRISS incorporates multiple systems of complications in dcSSc and is calculated as a two-step process. The first step assesses a clinically significant reduction in renal or cardiopulmonary complications associated with SSc and requiring treatment. Patients are considered not to have improved in Step 1 (i.e., meet Step 1 criteria) if they develop any of the following four outcomes after treatment: a) a new scleroderma renal crisis; b) a relative decrease in FVC of 15% or more of the predicted FVC, confirmed by another FVC% within one month, high-resolution computed tomography confirming interstitial lung disease and FVC% less than 80% of the predicted FVC due to SSc; c) a new decrease to 45% or less of the left ventricular ejection fraction due to SSc and requiring treatment; or d) a new onset of pulmonary arterial hypertension (defined as mean resting pulmonary artery pressure ≥ 25 mmHg, end-expiratory pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance > 3 Wood units) due to SSc and requiring treatment.

[0090] No subjects met the ACR-CRISS Step 1 criteria. A serious adverse event (SAE) of chest pain was reported in one subject, which was recorded in the database as meeting the ACR-CRISS Step 1 criterion of "new onset of left ventricular failure requiring intervention (left ventricular ejection fraction ≤ 45%)." This event was recorded in the database as meeting the ACR-CRISS Step 1 criteria. This subject was ultimately diagnosed with possible microvascular coronary disease based on clinical presentation and exclusion of coronary artery disease. The contribution of SSc-related microvascular disease could not be ruled out or confirmed; however, this subject had other risk factors such as dyslipidemia and obesity.

[0091] The second step of the ACR CRISS was performed based on changes in mRSS, predicted FVC%, PGA, MDGA, and HAQ-DI. The mean (SD) Step 2 components at baseline, as well as the mean changes from baseline at 17 weeks prior to infusion and at 32 weeks / final infusion, are summarized in Table 3.

[0092] Overall, four subjects (14.8%) were ACR-CRISS responders (defined as meeting ACR-CRISS > 0.6) from week 1 to week 17, including three subjects in sequence A (IgPro20 / IgPro10) and one subject in sequence B (IgPro10 / IgPro20); between weeks 1 and 32, 12 subjects (44.4%) were responders (meeting ACR-CRISS > 0.6).

[0093] An improvement in the mean total mRSS score was observed after each treatment at weeks 17 and 32. The mean predicted forced vital capacity (FVC, %) at weeks 17 and 32 were similar to those observed at baseline. An improvement from baseline in the mean MDGA outcome was observed at weeks 17 and 32 during the IgPro20 period. The mean PGA outcome at weeks 17 and 32 was similar to those observed at baseline. The mean HAQ-DI value at week 32 was similar to those observed at baseline. Of the 27 subjects, 11 (40.7%) were responders based on mRSS at weeks 1–17, and 18 (66.7%) were responders over weeks 1–32, applying the mRSS response definition of change from reference (baseline) visit ≤ -5 and percentage change from reference (baseline) visit ≤ -25%. Of the 27 subjects, 13 (48.1%) were responders from weeks 1 to 17, and 20 (74.1%) were responders from weeks 1 to 32, applying the mRSS response definition of change from reference (baseline) visit ≤ -4 and percentage change from reference (baseline) visit ≤ -20%. Overall, the total mRSS score at baseline before treatment ranged from 20 to 25, and decreased by only 3 to 8 after the 17-week IgPro20 treatment.

[0094] [Table 3]

[0095] [Table 4]

[0096] A decrease (improvement) in the mean SHAQ overall disease score was observed at weeks 17 and 32 (Table 4). A slight improvement from baseline was generally observed for each SHAQ VAS item (pain, bowel disease, respiratory problems, Raynaud's syndrome, finger ulcers, and overall disease). The mean total score and the mean scores for each item (reflux, bloating, fecal adhesion, diarrhea, social functioning, mental stability, and constipation) were generally similar before and after the evaluation period.

[0097] MDGA scores decreased by approximately 0.3–1.3 from an initial score of 3.4–3.8 in the two patient groups, or by an average of 0.8 from an initial mean score of 0.8. PGA scores decreased by 0–0.7 after 17 weeks of treatment, with an average decrease of 0.4–0.7 from an initial mean score of 3.9 over the treatment period. UCLA SCTC GIT 2.0 scores did not increase on average in the study subjects (see Tables 3–4).

[0098] The mean total scleroderma cutaneous patient-reported outcomes (SSPRO) scores before the 17-week infusion and at the 32-week / final infusion decreased from baseline (indicating symptom exacerbation) after both treatment sequences (Table 4). This decrease from baseline (indicating symptom exacerbation) was observed in each of the SSPRO components: physical functioning, social impact, psychological impact, and physical functioning. SSPRO assesses skin-specific health-related quality of life in SSc patients (A. Man et al., Ann. Rheum. Dis. 76:1374~80 (2017)). This test consists of 18 items representing four health-related quality of life scales: physical symptoms, social impact, psychological impact, and physical functioning. Each is scored on a 7-point Likert scale, and the total score is normalized to a 0-100 scale.

[0099] The principal investigator also evaluated swelling in 28 joints: 10 proximal interphalangeal joints of the fingers, 10 metacarpophalangeal joints, wrist, elbow, shoulder, and knee. The number of subjects with ≥4 joint swelling was small, observed in 1 subject (3.7%) at baseline and 1 subject (3.7%) at week 32 / final dose (Table 14.2.5.5). The number of joint swellings was small, with a total mean (SD) of 0.2 (0.85) at baseline. The mean total number of joint swellings was similar throughout the study; 0.0 (0.20) at week 17, before infusion, and 0.3 (0.94) at week 32 / final dose.

[0100] The principal investigator also evaluated 28 joints for tenderness: 10 proximal interphalangeal joints of the fingers, 10 metacarpophalangeal joints, wrist, elbow, shoulder, and knee. A total of 6 subjects (22.2%) had ≥4 tender joints at baseline. The number of subjects with ≥4 tender joints decreased from 6 (22.2%) at week 17 to 1 (3.7%) at week 32 / final dose. The number of tender joints was low, with a total mean (SD) of 2.1 (3.23) at baseline. The mean number of tender joints decreased during the study; from 1.8 (2.48) before the week 17 infusion to 0.6 (1.86) at week 32 / final dose, changes from baseline of -0.4 (3.03) and -1.4 (2.36), respectively.

[0101] Simple bilateral palpation of the extensor and flexor tendons of the fingers and wrists, as well as the tendons of the elbows, knees, ankles, shoulders, and scapulae, to assess tendon friction sounds. At baseline, one subject (3.7%) had tendon friction sounds; this increased to four subjects (14.8%) at week 17, before infusion, and to three subjects (11.1%) at week 32 / final infusion.

[0102] The total MMT score was also obtained. The mean (SD) total score for the Manual Muscle Testing (MMT) was 141.5 (24.19). This decreased slightly during the study (indicating symptom exacerbation), and was 139.5 (21.88) before the 17-week infusion, a change of -1.0 (13.63) from baseline, and 137.5 (23.43) at 32 weeks / final dose, a change of -4.0 (18.48) from baseline. When aggregated by sequence, a mean decrease (exacerbation) was observed for sequence A, and a slight increase (improvement) was observed for sequence B.

[0103] For the ACR-CRISS components (mRSS, predicted FVC%, PGA, MDGA, and HAQ-DI), a trend of improvement with IgPro20 was observed in mRSS and MDGA (clinician-reported scale). Improvement was observed during the initial treatment period and persisted in mRSS and MDGA after crossover to IgPro10, regardless of sequence, throughout each treatment period with IgPro20. The trend of improvement with IgPro20 and IgPro10 was also observed in SHAQ VAS for the overall disease, regardless of sequence. For example, the SHAQ VAS overall disease score decreased on average from 1.2 at baseline to 1.0 after treatment.

[0104] The UCLA SCTC GIT 2.0 survey was also conducted. The average total score and average score for each item in the UCLA SCTC GIT were generally similar before and after the evaluation period.

Claims

1. A method for treating systemic sclerosis (SSc) in a human subject, comprising subcutaneous administration of a liquid human polyclonal immunoglobulin preparation containing 16-22% by mass / volume immunoglobulin, wherein the preparation is administered once, twice, or three times per week to achieve a weekly dose of 0.1 g / kg to 1 g / kg.

2. A method for treating systemic sclerosis (SSc) in a human subject, comprising subcutaneous administration of a liquid human polyclonal immunoglobulin preparation containing 16-22% by mass / volume immunoglobulin, wherein the preparation is administered twice a week to achieve a weekly dose of 0.1 g / kg to 1 g / kg.

3. The method according to claim 1 or 2, wherein the liquid human polyclonal immunoglobulin preparation contains 20-22% immunoglobulin.

4. The method according to any one of claims 1 to 3, wherein the immunoglobulin is derived from pooled plasma of more than 1,000 human donors.

5. The method according to any one of claims 1 to 4, wherein the preparation comprises a stabilizer containing an amino acid such as proline, glycine, or arginine.

6. The method according to claim 5, wherein the stabilizer may contain proline at a concentration of 100 to 500 mM, for example, 200 to 300 mM or 250 mM.

7. The method according to claim 5 or 6, wherein the stabilizer further comprises a surfactant such as polysorbate 80 or polysorbate 20 in a concentration of 5 to 50 mg / L, 8 to 30 mg / L, etc.

8. The method according to any one of claims 1 to 7, wherein the preparation has a pH of 4.6 to 5.

2.

9. The preparation according to any one of claims 1 to 8, wherein the preparation does not contain carbohydrate stabilizers, does not contain more than 50 μg / mL of IgA, and / or does not contain preservatives.

10. The method according to any one of claims 1 to 9, wherein SSc is diffuse systemic sclerosis (dcSSc) or localized SSc (lcSSc).

11. The method according to any one of claims 1 to 9, wherein SSc is dcSSc.

12. The method according to claim 10 or 11, wherein the subcutaneous injection site does not have dcSSc.

13. The method according to any one of claims 1 to 12, further comprising the administration of at least one further therapeutic agent.

14. The method according to claim 13, wherein at least one further therapeutic agent does not include an antibody therapeutic agent.

15. The method according to claim 13, wherein at least one further therapeutic agent does not contain an anti-CD20 antibody and / or an anti-IL6 and / or an anti-IL6 receptor antibody.

16. The method according to any one of claims 1 to 15, wherein the subject has not previously received treatment with an anti-CD20 antibody, and / or the subject has not previously received treatment with an anti-IL6 antibody, and / or the subject has not previously received treatment with an anti-IL6 receptor antibody.

17. The method according to any one of claims 1 to 16, applicable to individuals who have never been diagnosed with a rheumatic autoimmune disease other than SSc.

18. The method according to any one of claims 1 to 17, wherein the preparation is administered twice a week to achieve a weekly dose of 0.5 g / kg.

19. The method according to any one of claims 1 to 18, wherein the preparation is administered for a period of at least one month, at least three months, at least four months, at least six months, or at least one year.

20. The method according to any one of claims 1 to 19, wherein the subject does not have a history of dermatitis, eczema, or psoriasis prior to the commencement of treatment.

21. The subject is the method according to any one of claims 1 to 20, wherein the subject has a modified Rodnan skin thickness score of 15 to 45 prior to treatment with the preparation.

22. The subject is the method according to any one of claims 1 to 21, wherein the patient does not experience a mild or moderate to severe injection site skin reaction after administration of the preparation.

23. The method according to any one of claims 1 to 22, wherein the subject does not experience an injection site reaction such as injection site pain or injection site swelling within the first month of the procedure or within the first three months of the procedure.

24. The method according to any one of claims 1 to 23, wherein the preparation is administered subcutaneously using an infusion pump device.

25. The method according to any one of claims 1 to 24, wherein a volume of 10 mL to 100 mL is administered subcutaneously in each dose.

26. The preparation is administered for a period of at least one month, with subjects being treated after one month, three months, or four months: a. Having a trough serum IgG concentration of at least 18 g / L, at least 19 g / L, or at least 20 g / L; b. Having an mRSS value that is at least 3, at least 4, or at least 5 compared to baseline, or at least 15%, at least 20%, or at least 25% lower; c. Having a SHAQ VAS that is reduced by at least 5%, at least 10%, or at least 15% compared to baseline; d. Having a PGA that is at least 5%, at least 10%, or at least 15% lower than baseline; e. Having MDGA reduced by at least 5%, at least 10%, or at least 15% compared to baseline; f. Pain, swelling, and / or friction have decreased in at least one joint compared to baseline; and / or g. The method according to any one of claims 1 to 25, wherein the UCLA SCTC GI 2.0 score has not increased compared to baseline.

27. A liquid human polyclonal immunoglobulin preparation according to any one of claims 1 to 9, for use in the method according to any one of claims 1, 2, or 10 to 26.

28. Use of a liquid human polyclonal immunoglobulin preparation according to any one of claims 1 to 9 in the manufacture of a pharmaceutical for treating SSc according to any one of claims 1, 2, or 10 to 26.

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