Aqueous pharmaceutical composition of lebilimab

Abstract

The present disclosure relates to the fields of pharmacy and medicine, and in particular to an aqueous composition of the anti-IL-6R antibody revilimab, which can be used as a medicament for treating IL-6R-related diseases.

Description

[Technical Field]

[0001] The present invention relates to the fields of pharmacy and medicine, and more particularly to an aqueous composition of the anti-IL-6R antibody levilimab, which can be used as a pharmaceutical for treating IL-6R-related diseases. [Background technology]

[0002] Interleukin-6 (IL-6, IL6) is one of the major pro-inflammatory cytokines. IL-6 is produced by activated monocytes, macrophages, T cells, and several other cells. Along with other cytokines, IL-6 is involved in processes related to immune responses, inflammation, angiogenesis, and bone metabolism. The primary effect of IL-6 is related to its involvement in the differentiation, maturation, and conversion of B lymphocytes into immunoglobulin-secreting plasma cells. IL-6 also induces the expression of IL-6 receptors in activated cells of the immune system, further inducing IL-2 production by T lymphocytes. IL-6 stimulates T lymphocyte proliferation and hematopoietic responses. From the perspective of various producing cells and targets regarding its biological effects, interleukin-6 is one of the most active cytokines involved in the manifestation of immune and inflammatory responses. An imbalance between the pro-inflammatory and anti-inflammatory effects of IL-6 can cause various autoimmune diseases; chronic inflammation and osteoporosis, psoriasis, while its excessive production has been shown to be associated with various forms of cancer.

[0003] Therefore, suppression of IL-6 is an attractive therapeutic target (Peter C. Heinrich Biochem. J. (2003) 374:1). The IL-6 receptor (IL-6R, IL6R), when activated, triggers a series of reactions within cells that lead to the active synthesis of proteins involved in inflammatory responses. The receptor is activated during the binding of IL-6 to the IL-6 (CD126) receptor subunit alpha and two gp130 molecules that transmit signals within the cell (Simon A. Jones The FASE B Journal 15(1):43-58). Two forms of the α-receptor exist: membrane (mIL-6R) and soluble (sIL-6R). The soluble form is produced as a result of proteolysis of the transmembrane portion mIL-6R or alternative splicing of mIL-6R mRNA. The soluble form sIL-6R provides a response to IL-6 cells in the absence of surface mIL-6R.

[0004] Thus, IL-6 signaling is transmitted to cells via two pathways. In the first pathway (classical signaling), IL-6 binds to immune system cells that express mRNA, associated with the gp130 molecule, on their surface. In the second pathway (transsignaling), IL-6 binds to circulating sIL-6R, forming a complex that binds to cells with only the gp130 molecule on its membrane, i.e., potentially any cell in the human body. In this case, a complete IL-6 receptor complex is assembled on the cell membrane, followed by induction of an intracellular signaling cascade.

[0005] The action of IL-6, and therefore the blocking of the inflammatory response, can be achieved by inhibiting the complete assembly of the IL-6 receptor complex, which consists of the alpha-subunit, the gp130 molecule, and IL-6. Upon binding to IL-6R, the polypeptide can interfere with the assembly of the complete complex; thus, it blocks intracellular signaling.

[0006] A polypeptide that specifically binds to IL-6 (patent RU2550262), IL-6R, or gp130 showed significant inhibitory effects on IL-6 function. As an antibody that binds to IL-6R, IgG1 was constructed by grafting the complementarity-determining region (CDR) of a mouse anti-IL-6R antibody onto human IgG1. kTocilizumab, a recombinant humanized monoclonal antibody of the (gamma-1, kappa) immunoglobulin subclass, is currently known.

[0007] Drugs based on antibodies (tocilizumab) that bind to IL-6R and block its interaction with IL-6 are used to treat rheumatoid arthritis and systemic juvenile idiopathic arthritis, both as monotherapy and in combination with methotrexate and / or other basic anti-inflammatory drugs.

[0008] Furthermore, rebilimab (also known as BCD-089), an IgG1 isotype monoclonal antibody in which a mutation has been introduced into the constant region, is known as a novel antibody against IL-6R. Rebilimab is currently undergoing clinical trials in patients with various diseases, including adult rheumatoid arthritis and (acute) respiratory distress syndrome.

[0009] It is well known that the use of monoclonal antibodies against the interleukin-6 receptor (IL6R, IL-6R) can effectively reverse cytokine storm syndrome that develops when CAR T therapy is used in cancer treatment. The efficacy of the therapy (reversal of syndrome within 14 days of the first and only administration) reaches 69%.

[0010] Regarding the COVID-19 pandemic, the successful use of anti-IL-6R therapy in patients with severe or critical symptoms of COVID-19 pneumonia has been demonstrated. A meta-analysis of published data on the efficacy of IL-6R inhibitors in COVID-19 patients has preliminaryly confirmed their efficacy (Xu, X.; Han, M.; et al., Effective treatment of severe COVID-19 patients with tocilizumab. Proc. Natl. Acad. Sci. USA 2020; Coomes, EA; Haghbayan, H., Interleukin-6 in COVID-19: A Systematic Review and Meta-analysis. medRxiv 2020, 2020.03.30.20048058).

[0011] In the clinical course of COVID-19 pneumonia, there is a gap of approximately 5 to 7 days between diagnosis and the onset of multiple organ failure syndrome. After this, most patients show improvement, but about 20% of patients show an increase in the severity of pneumonia (CRS, ARDS). To improve prognosis and reduce mortality, proactive anti-inflammatory therapy starting from the time of diagnosis of COVID-19 pneumonia is recommended (Sun, X.; Wang, T.; et al., Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev 2020).

[0012] IL-6R inhibitors are included in the Russian COVID-19 treatment guidelines as drugs for proactive anti-inflammatory treatment of COVID-19 in adults (patients with a moderate to severe course: acute respiratory distress syndrome, cytokine storm syndrome). [Overview of the project] [Problems that the invention aims to solve]

[0013] From the above, it is clear that there is currently a need for the creation of novel, improved, and stable aqueous pharmaceutical compositions for the anti-IL-6R antibody rebilimab. [Brief explanation of the drawing]

[0014] [Figure 1] Figure 1 is a graph showing the dependence of the optical density of the solution at 400 nm on the PEG concentration for the monoclonal antibody against the IL-6 receptor rebilimab in the test formulation. [Figure 2] Figure 2 is a graph showing the temperature trend of pharmaceutical composition 5 Acet.Buf+300Glu (selection of penetrating substance). [Figure 3] Figure 3 is a graph showing the temperature trend of pharmaceutical composition 5 Acet Buf. + Mann (selection of penetrating substance). [Figure 4]Figure 4 is a graph showing the temperature trend of the pharmaceutical composition 5 Acet.Buf+100Arg+Mann (selection of osmotic substance). [Figure 5] Figure 5 is a graph showing the temperature trend of the pharmaceutical composition 5 Acet Buf.+200Arg (selection of osmotic substance). [Figure 6] Figure 6 is a graph showing the change in quality indicators as a function of time under accelerated storage conditions at a concentration of 220 mg / ml of rebrilimab. [Figure 7] Figure 7 is a graph showing the change in quality indicators as a function of time under accelerated storage conditions at a concentration of 180 mg / ml of rebrilimab. [Figure 8] Figure 8 is a graph showing the change in quality indicators as a function of time under accelerated storage conditions at a concentration of 20 mg / ml of rebrilimab. [Figure 9] Figure 9 is a graph showing the percentage of patients who achieved improvement equivalent to ACR20 up to weeks 4, 8, 12, 16, 24, 36, 48, and 52 during the course of the disease. [Figure 10] Figure 10 is a graph showing the percentage of patients who achieved improvement equivalent to ACR50 up to weeks 4, 8, 12, 16, 24, 36, 48, and 52 during the course of the disease. [Figure 11] Figure 11 is a graph showing the percentage of patients who achieved improvement equivalent to ACR70 up to weeks 4, 8, 12, 16, 24, 36, 48, and 52 during the course of the disease. [Figure 12] Figure 12 is a graph showing the change in the DAS-28-CRP index compared to the baseline during 52 weeks of treatment. [Figure 13] Figure 13 is a graph showing the percentage of patients who achieved remission of the disease at weeks 24, 36, 48, and 52 of treatment. [Figure 14] Figure 14 is a graph showing the change in ESR due to treatment. [[ID=三十二]] [Figure 15] [[ID=三十三]]Figure 15 is a graph showing the kinetics of the concentration of soluble interleukin-6 receptor in patients during 12 weeks of treatment. [[ID=三十四]] [[ID=三十五]] [Figure 16]Figure 16 is a graph showing the changes in serum C-reactive protein concentration in patients during 12 weeks of treatment. [Modes for carrying out the invention]

[0015] definition Unless otherwise specified herein, all technical and scientific terms used in connection with the present invention shall have the same meaning as those generally understood by those skilled in the art.

[0016] Furthermore, unless otherwise required by context, singular terms encompass plurals, and plural terms encompass singular terms. Typically, the current classifications and methods of cell culture, molecular biology, immunology, microbiology, genetics, analytical chemistry, organic synthesis chemistry, medical and pharmaceutical chemistry, and protein and nucleic acid hybridization and chemistry described herein are well known to those skilled in the art and are widely used in the art. Enzymatic reactions and purification methods are carried out as is common in the art or in accordance with the manufacturer's guidelines as described herein.

[0017] As used in this specification, the terms “antibody” or “immunoglobulin” (Ig) include a full-size antibody and any antigen-binding fragments thereof (i.e., “antigen-binding moieties”) or separate chains.

[0018] The terms “antigen-binding moiety” or “antigen-binding fragment” (or simply “antibody moiety” or “antibody fragment”) of an antibody, as used in this specification, mean one or more fragments that possess the ability of an antibody to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by a full-size antibody fragment. Examples of binding fragments included in the term “antigen-binding moiety” of an antibody include (i) a monovalent fragment consisting of VL, VH, CL, and CH1 domains, the Fab-fragment; (ii) a bivalent fragment containing two Fab-fragments linked at a hinge region by disulfide crosslinking, the F(ab')2 fragment; (iii) an Fd-fragment consisting of VH and CH1 domains; (iv) an Fv-fragment consisting of VL and VH domains within a single arm of the antibody; (v) a dAb-fragment consisting of a VH / VHH domain (Ward et al., (1989) Nature 341:544-546); and (vi) an isolated complementarity-determining region (CDR). Furthermore, the two regions of the Fv-fragment, VL and VH, are encoded by different genes and can be conjugated using recombination methods with synthetic linkers that allow them to be received as a single protein chain when the VL and VH regions are paired to form a monovalent molecule (known as single-chain Fv (scFv); see, for example, Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc.Natl.Acad.Sci.USA 85:5879-5883). Such single-chain molecules are also assumed to be included in the "antigen-binding portion" of the antibody. Such antibody fragments are produced using conventional techniques known to those skilled in the art, and these fragments are screened in the same way as intact antibodies.

[0019] Preferably, the CDR of the antigen-binding portion, or the entire antigen-binding portion of the antibody of the present invention, is derived from a mouse, llama, or human donor library or is substantially of human origin, and several amino acid residues are modified, for example, by substitution with different amino acid residues to optimize certain properties of the antibody, such as KD, koff, IC50, EC50, and ED50. Preferably, the framework region of the antibody of the present invention is of human origin or substantially of human origin (at least 80, 85, 90, 95, 96, 97, 98, or 99% of human origin).

[0020] The term “monoclonal antibody” or “mAb” refers to an antibody synthesized and isolated from cells of a distinct clonal population. The clonal population may be a clonal population of immortalized cells. In some aspects of the present invention, the immortalized cells within the clonal population are typically hybrid cells, or hybridomas, produced by the fusion of individual B lymphocytes from an immunized animal with individual cells from a lymphocytic tumor. Hybridomas are a type of constructed cell and do not exist in nature.

[0021] As used herein, the term "monoclonal antibody" refers to a homogeneous or substantially homogeneous antibody population (i.e., at least about 96%, more preferably at least about 97 or 98%, or even more preferably at least 99% of the antibodies in the population compete for the same antigen or epitope in an enzyme-linked immunosorbent assay (ELISA), or more preferably the antibodies are identical in amino acid sequence).

[0022] Naturally occurring full-size antibodies are immunoglobulin molecules consisting of four polypeptide chains linked by disulfide bonds: two heavy (H) chains (approximately 50 to 70 kDa in total length) and two light (L) chains (approximately 25 kDa in total length). The amino-terminus of each chain contains a variable domain of approximately 100 to 110 or more amino acids responsible for binding to the antigen. The carboxyl-terminus of each chain determines the constant region, which is primarily responsible for effector function. The light chains are classified as kappa and lambda and are characterized by specific constant regions. Each light chain consists of a variable N-terminal light chain region (referred to in this application as VL or VK) and a constant light chain region consisting of a single domain (CL or CK). The heavy chains are classified as γ, δ, α, μ, and ε, defining antibody isotypes such as IgG, IgM, IgA, IgD, and IgE, respectively; some of these further IgA can be divided into subclasses (isotypes) such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. Each heavy chain type is characterized by a specific constant region Fc. Each heavy chain consists of a variable N-terminal heavy chain region (referred to as VH in this application) and a constant (heavy chain) region CH. The constant heavy chain region consists of three domains (CH1, CH2, and CH3) in IgG, IgD, and IgA, and four domains (CH1, CH2, CH3, and CH4) in IgM and IgE. The VH and VL variable domains can be further divided into hypervariable regions (hypervariable regions CDR) interspersed among more conservative framework regions (FRs). Each variable domain consists of three CDRs and four FRs arranged in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from the N-terminus to the C-terminus.

[0023] Each variable region of the light / heavy chain pair forms the antigen-binding site of the antibody. Therefore, an intact IgG antibody has two binding sites. Except for bifunctional or bispecific antibodies, the two binding sites are identical. As used in this application, “antigen-binding moiety,” “antigen-binding region,” or “antigen-binding domain” are synonymous with an antibody molecular portion that contains amino acid residues that interact with an antigen and confer its specificity and affinity to the antibody in relation to that antigen. Such an antibody moiety contains framework amino acid residues necessary to maintain the proper conformation of the antigen-binding residues.

[0024] An "antibody fragment" may be represented by an antibody fragment or an antibody fragment having the activity of a full-size antibody. The antibody fragment may be F(ab')2, F(ab)2, Fab', Fab Fv, and scFv.

[0025] With respect to the functional activity of the antibodies of the present invention, the terms “inhibit” or “neutralize,” when used in this application, mean the ability to significantly block, prevent, limit, slow down, stop, reduce or reverse the onset or severity of the target of inhibition, including, but not limited to, biological activity (e.g., IL-6R activity) or properties, disease or condition. The binding of the antibodies of the present invention to IL-6R results in inhibition or neutralization of IL-6R activity, preferably at least 20, 30, 40, 50, 60, 70, 80, 90, 95% or more.

[0026] When used in relation to nucleic acid or protein products (e.g., antibodies), the terms “isolated” or “removed” mean a nucleic acid or protein molecule that has been identified and separated from at least one contaminant that typically coexists with it in its natural source. Preferably, “isolated antibody” is an antibody that substantially does not contain other antibodies having specific antigen specificity (for example, the pharmaceutical composition according to the present invention contains an isolated antibody that specifically binds to IL-6R and substantially does not contain antibodies that specifically bind to antigens other than IL-6R).

[0027] When used in this application, the term "specifically binding" means a situation in which one member of a specific binding pair does not significantly bind to any molecule other than its specific binding partner. This term also applies, for example, when the antigen-binding domain of the antibody of the present invention is specific to a particular epitope supported by several antigens; in this case, the specific antibody having the antigen-binding domain can specifically bind to a variety of epitope-supporting antigens.

[0028] When used in this application, “Kabat numbering scheme” or “Kabat-compliant numbering” refers to a system for numbering amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the variable regions of the heavy and light chains of antibodies (Kabat et al., Ann. NYAcad. Sci., 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242 (1991)).

[0029] The term "pharmaceutical composition" means a composition and / or formulation containing a therapeutically effective amount of the antibody according to the present invention, in addition to excipients or auxiliary substances (carriers, diluents, vehicles, solvents and other excipients).

[0030] The term "buffer" or "buffer solution" refers to an aqueous solution containing a mixture of an acid (typically a weak acid such as acetic acid or citric acid) and its conjugate base (for example, an acetate or citrate, such as sodium acetate, sodium citrate, and hydrates of the salts, such as sodium acetate trihydrate), or instead a mixture of a base (typically a weak base, such as histidine) and its conjugate acid (for example, histidine hydrochloride). Due to the "buffering effect" provided by the "buffering agent," the pH value of a "buffer solution" changes slightly when a small amount of strong base or strong acid is added, and when it is diluted or concentrated.

[0031] In this application, “buffer system” comprises one or more buffering agents and / or their acid / base conjugates, more preferably one or more buffering agents and / or their acid / base conjugates, and most preferably only one buffering agent and / or its acid / base conjugate. Unless otherwise specified, any concentration (buffer concentration) used in relation to “buffer system” in this invention may mean the combined concentration of the buffering agent and / or its acid / base conjugate. In other words, the concentration used in relation to “buffer system” in this application may mean the combined concentration of the relevant buffering species (i.e., species in dynamic equilibrium with each other, e.g., citrate / citric acid). The overall pH value of a composition containing the relevant buffer system is a reflection of the equilibrium concentrations of each of the relevant buffering species (i.e., the balance between the buffering agent and its acid / base conjugate).

[0032] The term "buffer" refers to the acidic or basic component (usually a weak acid or weak base) of a buffering agent or buffer solution. Buffers help maintain the pH value of a given solution at or near a predetermined value, and are generally selected to complement that predetermined value. A buffer can be a single compound that produces the desired buffering action, especially when mixed with an appropriate amount of its corresponding "acid / base conjugate" (and appropriately, when proton exchange is possible), depending on the predetermined desired value.

[0033] As used herein, the term “solubilizer” means a pharmaceutically acceptable nonionic surfactant. Both a single solubilizer or a combination of multiple solubilizers may be used. Typical solubilizers include, but are not limited to, polysorbate 20 or polysorbate 80, poloxamer 184 or poloxamer 188, or PLURONIC®.

[0034] The terms “osmotic agent” or “tonicity modifier,” as well as “osmolyte,” as used herein, refer to excipients that can bring a required osmotic pressure to a liquid antibody solution. In some embodiments, a tonicity modifier can increase the osmotic pressure of a liquid antibody product to an isotonic pressure so that the liquid antibody product is physiologically compatible with the cells of the tissue of the organism under study. In other embodiments, a tonicity modifier can contribute to the increased stability of the antibody. An “isotonic” pharmaceutical is a pharmaceutical that has an osmotic pressure equivalent to that of human blood. Isotonic preparations typically have an osmotic pressure of about 239–376 mOsm / kg. The term “hypotonic” describes a preparation with an osmotic pressure lower than that of human blood. Correspondingly, the term “hypertonic” is used to describe a preparation with an osmotic pressure higher than that of human blood. Isotonicity can be measured, for example, using a vapor pressure or freezing point depression osmometer. Tonicity adjusters may exist as enantiomers (e.g., L- or D-enantiomers) or racemates; in the form of isomers such as alpha, alpha; or beta, beta; or alpha, beta; or beta, alpha; as free acids or free bases; as salts; as hydrates (e.g., monohydrates); or as anhydrous substances. Typical osmotic substances are, but are not limited to, sugars (trehalose dihydrate, sucrose, glucose), polyols (mannitol, sorbitol), amino acids (proline, arginine, glycine), or salts (sodium chloride, potassium chloride, magnesium chloride).

[0035] The terms “long-term storage” or “long-term stability” are understood to mean that the pharmaceutical composition can be stored for three months or more, six months or more, preferably one year or more, with a minimum stable storage period of at least two years. Generally, the terms “long-term storage” and “long-term stability” further include a stable storage period that is at least equivalent to or longer than the stable storage period typically required for currently available commercial formulations of the anti-IL-6R antibody revilimab, without loss of stability that would render the formulation unsuitable for its intended pharmaceutical use.

[0036] The term "parenteral administration" typically refers to administration regimens carried out by injection (infusion), and in particular includes intravenous, intramuscular, intra-arterial, intratracheal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intra-articular, subcapsular, subarachnoid, intrathecal, epidural, and upper abdominal injections or infusions.

[0037] The term “drug” or “preparation” refers to a substance (or mixture of substances as a pharmaceutical composition) in the form of tablets, capsules, liquids, ointments, or other ready-to-use forms intended to restore, improve, or modify physiological function in humans and animals, and intended for the treatment and prevention of disease, diagnosis, anesthesia, contraception, cosmetic use, etc.

[0038] The term “IL-6R-related disease or disorder” or “IL-6R-mediated disease or disorder” means all diseases or disorders that are directly or indirectly related to activation of the IL-6 signaling pathway, including the etiology, onset, progression, persistence, or pathology of the disease or disorder.

[0039] The term “use” applies to the possibility of using the antibodies of the present invention or pharmaceutical compositions containing them to treat, eliminate disease progression, promote remission, and reduce relapse rates for diseases or disorders mediated by receptors to which the antibodies of the present invention can bind. Representative diseases, but not limited to, include rheumatoid arthritis, juvenile chronic arthritis, scleroderma, graft-versus-host disease, transplant organ rejection, acute or chronic immune disorders associated with organ transplantation, cachexia, adult (acute) respiratory distress syndrome, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's arteritis / arteritis, cytokine therapy-associated disorders, cytokine release syndrome, iridocyclitis, uveitis, optic neuritis, neuromyelitis optica, juvenile rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis; cancer, particularly multiple myeloma and malignant solid tumors, colorectal cancer, prostate cancer, and ovarian cancer.

[0040] The term “treatment method” means the possibility of using the antibodies of the present invention or pharmaceutical compositions containing them to treat diseases or disorders associated with IL-6R activity, to eliminate disease progression, to promote remission, and to reduce subsequent relapse rates. “Treatment” or “treatment” or “prevention” of a disease, disorder, or condition may include preventing or delaying the onset of clinical symptoms of a disease, disorder, or condition that manifest in humans, suppressing the disease, disorder, or condition, i.e., stopping, reducing, or delaying the onset of the disease or its relapse (in the case of maintenance therapy) or at least one clinical or subclinical symptom, or alleviating or easing the disease, i.e., causing regression of the disease, disorder, or condition. Representative diseases include, but are not limited to, rheumatoid arthritis, juvenile chronic arthritis, scleroderma, graft-versus-host disease, organ rejection, acute or chronic immune disorders associated with organ transplantation, cachexia, adult (acute) respiratory distress syndrome, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's arteritis / arteritis, cytokine therapy-related disorders, cytokine release syndrome, iridocyclitis, uveitis, optic neuritis, neuromyelitis optica, juvenile rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis; cancer, particularly multiple myeloma and malignant solid tumors, colorectal cancer, prostate cancer, and ovarian cancer.

[0041] As used herein, the term "aqueous composition" means a composition based on water, and the water in the composition may be water, water for injection, or physiological saline (a 0.9% to 1.0% aqueous solution of sodium chloride).

[0042] In one embodiment of the present invention, the subject of treatment, or patient, is a mammal, preferably a human subject. The subject may be male or female of any age. When used herein and in the subsequent claims, unless otherwise indicated by context, the words “have,” “include,” “comprise,” or their variations such as “has,” “having,” “includes,” or “including,” “comprises,” “comprising,” should be understood to indicate that they include the integer or group of things mentioned, but do not exclude any other things or groups of things. The present invention includes, but is not limited to, the following embodiments. [Aspect 1] (i) Lebilimab at a dose of 5 to 220 mg / ml; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) Polyols in a concentration of 20 to 50 mg / ml; (iv) Glycine 5 to 10 mg / ml; and (v) Acetic acid to adjust pH to 4.5-6.5 An aqueous pharmaceutical composition containing lebilimab. [Aspect 2] The aqueous pharmaceutical composition according to Embodiment 1, wherein lebilimab is present at a concentration of 5 to 40 mg / ml. [Aspect 3] The aqueous pharmaceutical composition according to Embodiment 1, wherein lebilimab is present at a concentration of 20 mg / ml. [Aspect 4] The aqueous pharmaceutical composition according to Embodiment 1, wherein lebilimab is present at a concentration of 180 to 220 mg / ml. [Aspect 5] The aqueous pharmaceutical composition according to Embodiment 1, wherein lebilimab is present at a concentration of 180 mg / ml. [Aspect 6] The aqueous pharmaceutical composition according to any one of embodiments 1 to 5, wherein the sodium acetate trihydrate is present at a concentration of 0.4 to 1.0 mg / ml. [Aspect 7] The aqueous pharmaceutical composition according to any one of embodiments 1 to 5, wherein the sodium acetate trihydrate is present at a concentration of 0.4 to 0.5 mg / ml. [Aspect 8] The aqueous pharmaceutical composition according to any one of embodiments 1 to 5, wherein the sodium acetate trihydrate is present at a concentration of 0.436 mg / ml. [Aspect 9] The aqueous pharmaceutical composition according to any one of embodiments 1 to 8, wherein the polyol is present at a concentration of 20 to 26 mg / ml. [Aspect 10] The aqueous pharmaceutical composition according to any one of embodiments 1 to 8, wherein the polyol is present at a concentration of 23 mg / ml. [Aspect 11] The aqueous pharmaceutical composition according to any one of embodiments 1 to 8, wherein the polyol is selected from mannitol, sorbitol, or a combination thereof. [Aspect 12] The aqueous pharmaceutical composition according to any one of embodiments 1 to 11, wherein the glycine is present at a concentration of 7 to 8 mg / ml. [Aspect 13] The aqueous pharmaceutical composition according to any one of embodiments 1 to 11, wherein the glycine is present at a concentration of 7.5 mg / ml. [Aspect 14] The aqueous pharmaceutical composition according to any one of embodiments 1 to 13, wherein the acetic acid is added up to a pH of 5.0. [Aspect 15] (i) 20 mg / ml lebirimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 The aqueous pharmaceutical composition according to embodiment 1, comprising: [Aspect 16] (i) 180 mg / ml of lebilimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 The aqueous pharmaceutical composition according to embodiment 1, comprising: [Aspect 17] (i) Lebilimab at a dose of 5 to 220 mg / ml; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) Arginine hydrochloride 10 to 32 mg / ml; and (iv) Acetic acid to adjust pH to 4.5-6.5 An aqueous pharmaceutical composition containing lebilimab. [Aspect 18] The aqueous pharmaceutical composition according to embodiment 17, wherein lebilimab is present at a concentration of 5 to 40 mg / ml. [Aspect 19] The aqueous pharmaceutical composition according to embodiment 17, wherein lebilimab is present at a concentration of 20 mg / ml. [Aspect 20] The aqueous pharmaceutical composition according to embodiment 17, wherein lebilimab is present at a concentration of 180 to 220 mg / ml. [Aspect 21] The aqueous pharmaceutical composition according to embodiment 17, wherein the lebilimab is present at a concentration of 180 mg / ml. [Aspect 22] The aqueous pharmaceutical composition according to any one of embodiments 17 to 21, wherein the sodium acetate trihydrate is present at a concentration of 1.7 to 1.8 mg / ml. [Aspect 23] The aqueous pharmaceutical composition according to any one of embodiments 17 to 21, wherein the sodium acetate trihydrate is present at a concentration of 1.744 mg / ml. [Aspect 24] The aqueous pharmaceutical composition according to any one of embodiments 17 to 23, wherein the arginine hydrochloride is present at a concentration of 18 to 24 mg / ml. [Pattern 25] The aqueous pharmaceutical composition according to any one of embodiments 17 to 23, wherein the arginine hydrochloride is present at a concentration of 21.1 mg / ml. [Aspect 26] The aqueous pharmaceutical composition according to any one of embodiments 17 to 25, wherein the acetic acid is added up to a pH of 5.0. [Aspect 27] (i) 20 mg / ml lebirimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 The aqueous pharmaceutical composition according to embodiment 17, comprising: [Aspect 28] (i) 180 mg / ml of lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 The aqueous pharmaceutical composition according to embodiment 17, comprising: [Aspect 29] (i) 162 mg of lebilimab; (ii) 0.392 mg of sodium acetate trihydrate; (iii) 20.7 mg of a polyol selected from mannitol or sorbitol; (iv) 6.75 mg of glycine; (v) Acetic acid to set the pH to 5.0; and (vi) Up to 0.9 ml of sterile water for injection An aqueous pharmaceutical composition containing lebilimab. [Aspect 30] (i) 162 mg of lebilimab; (ii) 1.57 mg of sodium acetate trihydrate; (iii) 18.99 mg of arginine hydrochloride; (iv) Acetic acid to set the pH to 5.0; and (v) Up to 0.9 ml of sterile water for injection An aqueous pharmaceutical composition containing lebilimab. [Aspect 31] The aqueous pharmaceutical composition according to any one of embodiments 1 to 30, wherein the acetic acid is glacial acetic acid. [Aspect 32] The aqueous pharmaceutical composition according to any one of embodiments 1 to 31, wherein the composition is intended for parenteral administration. [Aspect 33] The aqueous pharmaceutical composition according to any one of embodiments 1 to 31, wherein the composition is intended for intramuscular, intravenous, or subcutaneous administration. [Aspect 34] The aqueous pharmaceutical composition according to any one of embodiments 1 to 31, wherein the composition is present in a vial. [Aspect 35] The aqueous pharmaceutical composition according to embodiment 34, wherein the vial is a glass vial or a plastic vial. [Aspect 36] The aqueous pharmaceutical composition according to embodiments 34 to 35, wherein the vial has a volume of 4 to 20 ml. [Aspect 37] The aqueous pharmaceutical composition according to embodiment 31, wherein the vial has a volume of 4 ml, 10 ml, or 20 ml. [Aspect 38] The aqueous pharmaceutical composition according to any one of embodiments 1 to 31, wherein the composition is present in a syringe or an automatic injection device. [Aspect 39] The aqueous pharmaceutical composition according to embodiment 38, wherein the syringe or automatic injection device is a glass syringe or automatic injection device, or a plastic syringe or automatic injection device. [Aspect 40] The aqueous pharmaceutical composition according to embodiments 38 to 39, wherein the syringe or automatic injection device has a maximum volume of 1 ml. [Aspect 41] The aqueous pharmaceutical composition according to any one of embodiments 1 to 31, wherein the composition is present in a pre-filled syringe or a pre-filled automatic injection device. [Aspect 42] The aqueous pharmaceutical composition according to embodiment 41, wherein the pre-filled syringe or pre-filled automatic injection device is a glass pre-filled syringe or automatic injection device or a plastic pre-filled syringe or automatic injection device. [Aspect 43] The aqueous pharmaceutical composition according to embodiments 41 to 42, wherein the pre-filled syringe or pre-filled automatic injection device has a maximum volume of 1 ml. [Aspect 44] Use of an aqueous pharmaceutical composition of lebilimab according to any one of embodiments 1, 17, 29, or 30 for the treatment or prevention of IL-6R-related disease or disorder. [Aspect 45] IL-6R-related disease or disorder: Use according to aspect 44, selected from rheumatoid arthritis, juvenile chronic arthritis, scleroderma, graft-versus-host disease, organ rejection, acute or chronic immune disorders associated with organ transplantation, cachexia, adult (acute) respiratory distress syndrome, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's arteritis / arteritis, cytokine therapy-related disorders, cytokine release syndrome, iridocyclitis, uveitis, optic neuritis, neuromyelitis optica, juvenile rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis; cancer, particularly multiple myeloma and malignant solid tumors, colorectal cancer, prostate cancer, and ovarian cancer. [Aspect 46] The use according to embodiment 44, wherein the aqueous pharmaceutical composition is administered parenterally. [Aspect 47] The use according to embodiment 46, wherein the aqueous pharmaceutical composition is administered intramuscularly, intravenously, or subcutaneously. [Aspect 48] Use of an aqueous pharmaceutical composition of lebilimab according to any one of embodiments 1, 17, 29, or 30 for the treatment of rheumatoid arthritis. [Aspect 49] The use according to embodiment 48, wherein the aqueous pharmaceutical composition is administered in a dose of 162 mg of rebilimab. [Aspect 50] The use according to embodiment 48, wherein the aqueous pharmaceutical composition is administered once a week or once every two weeks. [Aspect 51] The use according to embodiment 48, wherein the aqueous pharmaceutical composition is administered parenterally. [Aspect 52] The use according to embodiment 51, wherein the aqueous pharmaceutical composition is administered intramuscularly, intravenously, or subcutaneously. [Aspect 53] The use according to embodiment 48, further comprising the use of methotrexate. [Aspect 54] Use of an aqueous pharmaceutical composition of lebilimab according to any one of embodiments 1, 17, 29, or 30 for the treatment of active rheumatoid arthritis. [Aspect 55] The use according to embodiment 54, wherein the aqueous pharmaceutical composition is administered in a dose of 324 mg or 648 mg of rebilimab. [Aspect 56] The aqueous pharmaceutical composition is administered once every two weeks, once every four weeks, or once every six weeks. Use as described in aspect 54. [Aspect 57] The use according to embodiment 54, wherein the aqueous pharmaceutical composition is administered parenterally. [Aspect 58] The use according to embodiment 57, wherein the aqueous pharmaceutical composition is administered intramuscularly, intravenously, or subcutaneously. [Aspect 59] The use according to embodiment 54, further comprising the use of methotrexate. [Aspect 60] Use of an aqueous pharmaceutical composition of lebilimab according to any one of embodiments 1, 17, 29, or 30 for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome. [Aspect 61] The use according to embodiment 60, wherein the aqueous pharmaceutical composition is administered in a dose of 324 mg or 648 mg of rebilimab. [Aspect 62] The use according to embodiment 60, wherein the aqueous pharmaceutical composition is administered once, twice, three times, or four times at intervals of at least eight hours. [Aspect 63] The use according to embodiment 60, wherein the aqueous pharmaceutical composition is administered parenterally. [Aspect 64] The use according to embodiment 63, wherein the aqueous pharmaceutical composition is administered intramuscularly, intravenously, or subcutaneously. [Aspect 65] Lebilimab at doses of 5 to 220 mg / ml, Sodium acetate trihydrate at a concentration of 0.4 to 1.8 mg / ml; Polyols in a concentration of 20 to 50 mg / ml; 5 to 10 mg / ml of glycine; and Acetic acid to adjust the pH to 4.5-6.5 A method for producing the aqueous pharmaceutical composition according to embodiment 1, comprising the step of mixing with the other. [Aspect 66] Lebilimab at doses of 5 to 220 mg / ml, Sodium acetate trihydrate at a concentration of 0.4 to 1.8 mg / ml; Arginine hydrochloride at 10 to 32 mg / ml; and Acetic acid to adjust the pH to 4.5-6.5 A method for producing the aqueous pharmaceutical composition according to embodiment 17, comprising the step of mixing with the other. [Aspect 67] The method according to embodiments 65 to 66, wherein the acetic acid is glacial acetic acid.

[0043] Summary of the Invention This invention discloses a stable aqueous pharmaceutical composition for the anti-IL-6R antibody rebilimab, which can be used as a pharmaceutical for the treatment of IL-6R-related diseases.

[0044] The antibody revilimab against IL-6R, which is an IgG1 isotype monoclonal antibody, comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 5, in which the heavy chain variable domain (SEQ ID NO: 4) contains HCDR1 (SEQ ID NO: 1), HCDR2 (SEQ ID NO: 2), and HCDR3 (SEQ ID NO: 3); and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10, in which the light chain variable domain (SEQ ID NO: 9) contains LCDR1 (SEQ ID NO: 6), LCDR2 (SEQ ID NO: 7), and LCDR3 (SEQ ID NO: 8).

[0045] Rebilimab is a recombinant monoclonal antibody against the interleukin-6 receptor. Rebilimab binds to and blocks both soluble (sIL-6R) and membrane (mIL-6R) IL-6 receptors. Blocking both receptor forms prevents the development of IL-6-related pro-inflammatory cascades, such as activation of antigen-presenting cells, B and T cells, monocytes and macrophages, endothelial cells and fibroblasts, and overproduction of other pro-inflammatory cytokines. IL-6 is involved in the activation and maintenance of local inflammatory responses (pannus formation in synovial fluid, stimulation of osteoclast formation (cartilage erosion), osteoporosis); in addition, IL-6 directly induces the synthesis of acute-phase proteins in hepatocytes: CRP, fibrinogen, and serum amyloid A proteins (SAA, hepcidin, leptin).

[0046] In one aspect, the present invention: (a) Lebilimab at a dose of 5 to 220 mg / ml; (b) Sodium acetate trihydrate in a concentration of 0.4 to 1.8 mg / ml; (c) 20 to 50 mg / ml of polyol and 5 to 10 mg / ml of glycine or Arginine hydrochloride at 10 to 32 mg / ml; and (d) Acetic acid to adjust the pH to 4.5-6.5 This relates to an aqueous pharmaceutical composition of lebilimab containing the above.

[0047] In some embodiments of the present invention, the polyol is selected from mannitol or sorbitol. In one aspect, the present invention (i) Lebilimab at a dose of 5 to 220 mg / ml; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) Polyols in a concentration of 20 to 50 mg / ml; (iv) Glycine 5 to 10 mg / ml; and (v) Acetic acid to adjust pH to 4.5-6.5 This relates to an aqueous pharmaceutical composition of lebilimab containing the above.

[0048] The concentration of lebilimab contained in the pharmaceutical composition of the present invention may vary depending on the desired properties of the composition, as well as the individual conditions, methods, and purposes of use of the pharmaceutical composition. In some embodiments of the present invention, the lebilimab is present at a concentration of 5 to 40 mg / ml.

[0049] In some embodiments of the present invention, the lebilimab is present at a concentration of 5 mg / ml. In some embodiments of the present invention, the lebilimab is present at a concentration of 5 to 15 mg / ml.

[0050] In some embodiments of the present invention, the lebilimab is present at a concentration of 10 mg / ml. In some embodiments of the present invention, the lebilimab is present at a concentration of 15 to 25 mg / ml.

[0051] In some embodiments of the present invention, the lebilimab is present at a concentration of 20 mg / ml. In some embodiments of the present invention, the lebilimab is present at a concentration of 100 to 180 mg / ml.

[0052] In some embodiments of the present invention, the lebilimab is present at a concentration of 140 to 220 mg / ml. In some embodiments of the present invention, the lebilimab is present at a concentration of 180 to 220 mg / ml.

[0053] In some embodiments of the present invention, the lebilimab is present at a concentration of 160 to 200 mg / ml. In some embodiments of the present invention, the lebilimab is present at a concentration of 180 mg / ml.

[0054] In some embodiments of the present invention, the lebilimab is present at a concentration of 200 mg / ml. In some embodiments of the present invention, the sodium acetate trihydrate is present at a concentration of 0.4 to 1.0 mg / ml.

[0055] In some embodiments of the present invention, the sodium acetate trihydrate is present at a concentration of 0.4 to 0.5 mg / ml. In some embodiments of the present invention, the sodium acetate trihydrate is present at a concentration of 0.436 mg / ml.

[0056] In some embodiments of the present invention, the polyol is present at a concentration of 20 to 26 mg / ml. In some embodiments of the present invention, the polyol is present at a concentration of 22 to 24 mg / ml.

[0057] In some embodiments of the present invention, the polyol is present at a concentration of 23 mg / ml. In some embodiments of the present invention, the polyol may be selected from sugar alcohols such as mannitol, sorbitol, glycerin, or xylitol, or combinations thereof.

[0058] In some embodiments of the present invention, the mannitol is present at a concentration of 20 to 26 mg / ml. In some embodiments of the present invention, the mannitol is present at a concentration of 22 to 24 mg / ml.

[0059] In some embodiments of the present invention, the mannitol is present at a concentration of 23 mg / ml. In some embodiments of the present invention, the sorbitol is present at a concentration of 20 to 26 mg / ml.

[0060] In some embodiments of the present invention, the sorbitol is present at a concentration of 22 to 24 mg / ml. In some embodiments of the present invention, the sorbitol is present at a concentration of 23 mg / ml.

[0061] In some embodiments of the present invention, the combination of mannitol and sorbitol is present at a concentration of 20 to 26 mg / ml. In some embodiments of the present invention, the combination of mannitol and sorbitol is present at a concentration of 22 to 24 mg / ml.

[0062] In some embodiments of the present invention, the combination of mannitol and sorbitol is present at a concentration of 23 mg / ml. In some embodiments of the present invention, the glycine is present at a concentration of 7 to 8 mg / ml.

[0063] In some embodiments of the present invention, the glycine is present at a concentration of 7.5 mg / ml. The desired pH value of the pharmaceutical composition of the present invention can be obtained by adding acetic acid.

[0064] In some aspects of the present invention, the acetic acid is added so that the pH is between 4.5 and 5.5. In some aspects of the present invention, the acetic acid is added so that the pH is 4.5, 5.0, 5.5, 6.0, or 6.5.

[0065] In some embodiments of the present invention, (i) 20 mg / ml lebirimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0066] In some embodiments of the present invention, (i) 5 mg / ml lebirimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0067] In some embodiments of the present invention, (i) 10 mg / ml lebilimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0068] In some embodiments of the present invention, (i) 100 mg / ml of lebilimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0069] In some embodiments of the present invention, (i) 180 mg / ml of lebilimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) 23 mg / ml of mannitol or sorbitol; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0070] In some embodiments of the present invention, (i) 200 mg / ml of lebilimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0071] In some embodiments of the present invention, (i) 220 mg / ml of lebilimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0072] In one aspect, the present invention (i) Lebilimab at a dose of 5 to 220 mg / ml; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) Arginine hydrochloride 10 to 32 mg / ml; and (iv) Acetic acid to adjust pH to 4.5-6.5 This relates to an aqueous pharmaceutical composition of lebilimab, including the above.

[0073] In some embodiments of the present invention, the lebilimab is present at a concentration of 5 to 40 mg / ml. In some embodiments of the present invention, the lebilimab is present at a concentration of 5 mg / ml.

[0074] In some embodiments of the present invention, the lebilimab is present at a concentration of 5 to 15 mg / ml. In some embodiments of the present invention, the lebilimab is present at a concentration of 10 mg / ml.

[0075] In some embodiments of the present invention, the lebilimab is present at a concentration of 15 to 25 mg / ml. In some embodiments of the present invention, the lebilimab is present at a concentration of 20 mg / ml.

[0076] In some embodiments of the present invention, the lebilimab is present at a concentration of 100 to 180 mg / ml. In some embodiments of the present invention, the lebilimab is present at a concentration of 140 to 220 mg / ml.

[0077] In some embodiments of the present invention, the lebilimab is present at a concentration of 180 to 220 mg / ml. In some embodiments of the present invention, the lebilimab is present at a concentration of 160 to 200 mg / ml.

[0078] In some embodiments of the present invention, the lebilimab is present at a concentration of 200 mg / ml. In some embodiments of the present invention, the lebilimab is present at a concentration of 180 mg / ml.

[0079] In some embodiments of the present invention, the sodium acetate trihydrate is present at a concentration of 1.7 to 1.8 mg / ml. In some embodiments of the present invention, the sodium acetate trihydrate is present at a concentration of 1.744 mg / ml.

[0080] In some embodiments of the present invention, the arginine hydrochloride is present at a concentration of 18 to 24 mg / ml. In some embodiments of the present invention, the arginine hydrochloride is present at a concentration of 20 to 22 mg / ml.

[0081] In some embodiments of the present invention, the arginine hydrochloride is present at a concentration of 21.1 mg / ml. In some aspects of the present invention, the acetic acid is added so that the pH is between 4.5 and 5.5.

[0082] In some aspects of the present invention, the acetic acid is added so that the pH is 4.5, 5.0, 5.5, 6.0, or 6.5. In some embodiments of the present invention, (i) 20 mg / ml lebirimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0083] In some embodiments of the present invention, (i) 5 mg / ml lebirimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0084] In some embodiments of the present invention, (i) 10 mg / ml lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0085] In some embodiments of the present invention, (i) 100 mg / ml of lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0086] In some embodiments of the present invention, (i) 180 mg / ml of lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0087] In some embodiments of the present invention, (i) 200 mg / ml of lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0088] In some embodiments of the present invention, (i) 220 mg / ml of lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 An aqueous pharmaceutical composition containing [a specific substance] is provided.

[0089] In one aspect, the present invention (i) 162 mg of lebilimab; (ii) 0.392 mg of sodium acetate trihydrate; (iii) 20.7 mg of mannitol or sorbitol; (iv) 6.75 mg of glycine; (v) Acetic acid to set the pH to 5.0; and (vi) Dilute sterile water for injection to 0.9 ml This relates to an aqueous pharmaceutical composition of lebilimab, including the above.

[0090] In one aspect, the present invention (i) 162 mg of lebilimab; (ii) 1.57 mg of sodium acetate trihydrate; (iii) 18.99 mg of arginine hydrochloride; (iv) Acetic acid to set the pH to 5.0; and (v) Dilute with 0.9 ml of sterile water for injection This relates to an aqueous pharmaceutical composition of lebilimab, including the above.

[0091] In one aspect, the present invention relates to the composition per 0.9 mL: (i) 162 mg of lebilimab; (ii) 0.392 mg of sodium acetate trihydrate; (iii) 20.7 mg of mannitol or sorbitol; (iv) 6.75 mg of glycine; (v) Acetic acid to set the pH to 5.0; and (vi) Dilute sterile water for injection to 0.9 ml This relates to an aqueous pharmaceutical composition of lebilimab, including the above.

[0092] In one aspect, the present invention relates to the composition per 0.9 mL: (i) 162 mg of lebilimab; (ii) 1.57 mg of sodium acetate trihydrate; (iii) 18.99 mg of arginine hydrochloride; (iv) Acetic acid to set the pH to 5.0; and (v) Dilute with 0.9 ml of sterile water for injection This relates to an aqueous pharmaceutical composition of lebilimab, including the above.

[0093] In some embodiments of the present invention, the acetic acid is glacial acetic acid. In some embodiments of the present invention, the aqueous pharmaceutical composition of lebilimab of the present invention is intended for parenteral administration.

[0094] In some aspects of the present invention, the aqueous pharmaceutical composition of levilimab of the present invention is intended for intramuscular, intravenous, or subcutaneous administration. In some embodiments of the present invention, the aqueous pharmaceutical composition of lebilimab of the present invention may be administered intravenously as an infusion.

[0095] The pharmaceutical composition of the present invention can be stored in any suitable container, such as a glass or plastic container, vial, ampoule, syringe, cartridge, auto-injector, or bottle of the desired volume.

[0096] In some embodiments of the present invention, the aqueous pharmaceutical composition is provided in a vial. In some embodiments of the present invention, the vial is a glass or plastic vial.

[0097] In some embodiments of the present invention, the vial has a volume of 4 to 20 ml. In some embodiments of the present invention, the vial has a volume of 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml, or 20 ml.

[0098] In some embodiments of the present invention, the aqueous pharmaceutical composition is contained within a syringe or an automatic injection device. In some embodiments of the present invention, the syringe or automatic injection device is a glass or plastic syringe or automatic injection device.

[0099] In some embodiments of the present invention, the syringe or automatic injection device has a maximum volume of 0.9 ml. In some embodiments of the present invention, the syringe or automatic injection device has a maximum volume of 1 ml.

[0100] In some embodiments of the present invention, the syringe or automatic injector has a maximum volume of 2 ml. In some embodiments of the present invention, the syringe or automatic injection device may have a volume of 1 ml and a filling volume of 0.9 ml.

[0101] In some embodiments of the present invention, the aqueous pharmaceutical composition is contained within a pre-filled syringe or a pre-filled automatic injector. In some embodiments of the present invention, the pre-filled syringe or pre-filled automatic injector is a pre-filled syringe or pre-filled automatic injector made of glass or plastic.

[0102] In some embodiments of the present invention, the pre-filled syringe or pre-filled automatic injector has a maximum volume of 0.9 ml. In some embodiments of the present invention, the pre-filled syringe or pre-filled automatic injector has a maximum volume of 1 ml.

[0103] In some embodiments of the present invention, the pre-filled syringe or pre-filled automatic injector has a maximum volume of 2 ml. In some embodiments of the present invention, the pre-filled syringe or pre-filled automatic injector may have a volume of 1 ml and a filling volume of 0.9 ml.

[0104] In one embodiment, the present invention relates to the use of an aqueous pharmaceutical composition of rebilimab of the present invention for the treatment or prevention of IL-6R-related diseases or disorders. In one embodiment, the present invention is (i) Lebilimab at a dose of 5 to 220 mg / ml; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) Polyols in a concentration of 20 to 50 mg / ml; (iv) Glycine 5 to 10 mg / ml; and (v) Acetic acid to adjust pH to 4.5-6.5 The use of an aqueous pharmaceutical composition of rebilimab containing [the specified compound] for the treatment or prevention of IL-6R-related diseases or disorders.

[0105] In one embodiment, the present invention is (i) 20 mg / ml lebirimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 The use of an aqueous pharmaceutical composition of rebilimab containing [the specified compound] for the treatment or prevention of IL-6R-related diseases or disorders.

[0106] In one embodiment, the present invention is (i) 180 mg / ml of lebilimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 The use of an aqueous pharmaceutical composition of rebilimab containing [the specified compound] for the treatment or prevention of IL-6R-related diseases or disorders.

[0107] In one embodiment, the present invention is (i) Lebilimab at a dose of 5 to 220 mg / ml; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) Arginine hydrochloride 10 to 32 mg / ml; and (iv) Acetic acid to adjust pH to 4.5-6.5 The use of an aqueous pharmaceutical composition of rebilimab containing [the specified compound] for the treatment or prevention of IL-6R-related diseases or disorders.

[0108] In one embodiment, the present invention is (i) 20 mg / ml lebirimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 The use of an aqueous pharmaceutical composition of rebilimab containing [the specified compound] for the treatment or prevention of IL-6R-related diseases or disorders.

[0109] In one embodiment, the present invention is (i) 180 mg / ml of lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 The use of an aqueous pharmaceutical composition of rebilimab containing [the specified compound] for the treatment or prevention of IL-6R-related diseases or disorders.

[0110] In one embodiment, the present invention is (i) 162 mg of lebilimab; (ii) 0.392 mg of sodium acetate trihydrate; (iii) 20.7 mg of a polyol selected from mannitol or sorbitol; (iv) 6.75 mg of glycine; (v) Acetic acid to set the pH to 5.0; and (vi) Up to 0.9 ml of sterile water for injection The use of an aqueous pharmaceutical composition of rebilimab containing [the specified compound] for the treatment or prevention of IL-6R-related diseases or disorders.

[0111] In one embodiment, the present invention is (i) 162 mg of lebilimab; (ii) 1.57 mg of sodium acetate trihydrate; (iii) 18.99 mg of arginine hydrochloride; (iv) Acetic acid to set the pH to 5.0; and (v) Up to 0.9 ml of sterile water for injection The use of an aqueous pharmaceutical composition of rebilimab containing [the specified compound] for the treatment or prevention of IL-6R-related diseases or disorders.

[0112] In some aspects of the present invention, the IL-6R-related disease or disorder is selected from rheumatoid arthritis, juvenile chronic arthritis, scleroderma, graft-versus-host disease, organ rejection, acute or chronic immune disorders associated with organ transplantation, cachexia, adult (acute) respiratory distress syndrome, cytokine release syndrome, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's arteritis / arteritis, cytokine therapy-related disorders, iridocyclitis, uveitis, optic neuritis, neuromyelitis optica, juvenile rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis; cancer, particularly multiple myeloma and malignant solid tumors, colorectal cancer, prostate cancer, and ovarian cancer.

[0113] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of rebilimab of the present invention may include administering the composition parenterally. In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of rebilimab of the present invention may include administering the composition intramuscularly, intravenously, or subcutaneously.

[0114] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of levilimab of the present invention may include administering the composition intravenously as an infusion. In one embodiment, the present invention relates to the use of an aqueous pharmaceutical composition of levilimab for the treatment of rheumatoid arthritis.

[0115] In one embodiment, the present invention is (i) Lebilimab at a dose of 5 to 220 mg / ml; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) Polyols in a concentration of 20 to 50 mg / ml; (iv) Glycine 5 to 10 mg / ml; and (v) Acetic acid to adjust pH to 4.5-6.5 The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of rheumatoid arthritis.

[0116] In one embodiment, the present invention is (i) 20 mg / ml lebirimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of rheumatoid arthritis.

[0117] In one embodiment, the present invention is (i) 180 mg / ml of lebilimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of rheumatoid arthritis.

[0118] In one embodiment, the present invention is (i) Lebilimab at a dose of 5 to 220 mg / ml; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) Arginine hydrochloride 10 to 32 mg / ml; and (iv) Acetic acid to adjust pH to 4.5-6.5 The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of rheumatoid arthritis.

[0119] In one embodiment, the present invention is (i) 20 mg / ml lebirimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of rheumatoid arthritis.

[0120] In one embodiment, the present invention is (i) 180 mg / ml of lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of rheumatoid arthritis.

[0121] In one embodiment, the present invention is (i) 162 mg of lebilimab; (ii) 0.392 mg of sodium acetate trihydrate; (iii) 20.7 mg of a polyol selected from mannitol or sorbitol; (iv) 6.75 mg of glycine; (v) Acetic acid to set the pH to 5.0; and (vi) Up to 0.9 ml of sterile water for injection The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of rheumatoid arthritis.

[0122] In one embodiment, the present invention is (i) 162 mg of lebilimab; (ii) 1.57 mg of sodium acetate trihydrate; (iii) 18.99 mg of arginine hydrochloride; (iv) Acetic acid to set the pH to 5.0; and (v) Up to 0.9 ml of sterile water for injection The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of rheumatoid arthritis.

[0123] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of levilimab of the present invention for the treatment of rheumatoid arthritis may include administering the composition at a dose of 162 mg of levilimab.

[0124] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of levilimab of the present invention for the treatment of rheumatoid arthritis may include administering the composition once a week or once every two weeks.

[0125] In some aspects of the present invention, the use of the aqueous pharmaceutical composition of levilimab of the present invention for the treatment of rheumatoid arthritis may include administering the composition in a monthly dose of 4 mg of levilimab per kg of body weight.

[0126] In some aspects of the present invention, the use of the aqueous pharmaceutical composition of levilimab of the present invention for the treatment of rheumatoid arthritis may include administering the composition in a monthly dose of 8 mg of levilimab per kg of body weight.

[0127] In some aspects of the present invention, the use of the aqueous pharmaceutical composition of levilimab of the present invention for the treatment of rheumatoid arthritis may include administering the composition parenterally. In some aspects of the present invention, the use of the aqueous pharmaceutical composition of levilimab of the present invention for the treatment of rheumatoid arthritis may include administering the composition intramuscularly, intravenously, or subcutaneously.

[0128] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of levilimab of the present invention for the treatment of rheumatoid arthritis may include administering the composition intravenously as an infusion.

[0129] In some aspects of the present invention, the use of the aqueous pharmaceutical composition of lebilimab of the present invention for the treatment of rheumatoid arthritis may further include the use of methotrexate. In one embodiment, the present invention relates to the use of an aqueous pharmaceutical composition of lebilimab for the treatment of active rheumatoid arthritis.

[0130] In one embodiment, the present invention (i) Lebilimab at a dose of 5 to 220 mg / ml; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) A polyol at 20 to 50 mg / ml; (iv) Glycine at 5 to 10 mg / ml; and (v) Acetic acid to adjust the pH to 4.5 - 6.5 Regarding the use of an aqueous pharmaceutical composition of revirimab containing the above for treating active rheumatoid arthritis.

[0131] In one aspect, the present invention relates to (i) Revirimab at 20 mg / ml; (ii) Sodium acetate trihydrate at 0.436 mg / ml; (iii) A polyol selected from mannitol or sorbitol at 23 mg / ml; (iv) Glycine at 7.5 mg / ml; and (v) Acetic acid to adjust the pH to 5.0 Regarding the use of an aqueous pharmaceutical composition of revirimab containing the above for treating active rheumatoid arthritis.

[0132] In one aspect, the present invention relates to (i) Revirimab at 180 mg / ml; (ii) Sodium acetate trihydrate at 0.436 mg / ml; (iii) A polyol selected from mannitol or sorbitol at 23 mg / ml; (iv) Glycine at 7.5 mg / ml; and (v) Acetic acid to adjust the pH to 5.0 Regarding the use of an aqueous pharmaceutical composition of revirimab containing the above for treating active rheumatoid arthritis.

[0133] <00​​​​​​​​The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of active rheumatoid arthritis.

[0134] In one embodiment, the present invention is (i) 20 mg / ml lebirimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of active rheumatoid arthritis.

[0135] In one embodiment, the present invention is (i) 180 mg / ml of lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of active rheumatoid arthritis.

[0136] In one embodiment, the present invention is (i) 162 mg of lebilimab; (ii) 0.392 mg of sodium acetate trihydrate; (iii) 20.7 mg of a polyol selected from mannitol or sorbitol; (iv) 6.75 mg of glycine; (v) Acetic acid to set the pH to 5.0; and (vi) Up to 0.9 ml of sterile water for injection The present invention relates to the use of an aqueous pharmaceutical composition of lebilimab, which contains [a specific compound], for the treatment of active rheumatoid arthritis.

[0137] In one embodiment, the present invention is (i) 162 mg of lebilimab; (ii) 1.57 mg of sodium acetate trihydrate; (iii) 18.99 mg of arginine hydrochloride; (iv) acetic acid to adjust the pH to 5.0; and (v) water for injection up to 0.9 ml It relates to the use of an aqueous pharmaceutical composition of revlimid for treating active rheumatoid arthritis.

[0138] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of revlimid of the present invention for treating active rheumatoid arthritis may include administering the composition at a dose of 324 mg or 648 mg of revlimid.

[0139] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of revlimid of the present invention for treating active rheumatoid arthritis may include administering the composition at a dose of 4 mg of revlimid per kg of body weight.

[0140] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of revlimid of the present invention for treating active rheumatoid arthritis may include administering the composition at a dose of 8 mg of revlimid per kg of body weight.

[0141] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of revlimid of the present invention for treating active rheumatoid arthritis may include administering the composition once every two weeks, or once every four weeks, or once every six weeks.

[0142] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of revlimid of the present invention for treating active rheumatoid arthritis may include administering the composition parenterally. In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of revlimid of the present invention for treating active rheumatoid arthritis may include administering the composition intramuscularly, intravenously or subcutaneously.

[0143] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of levilimab of the present invention for the treatment of active rheumatoid arthritis may include administering the composition intravenously as an infusion.

[0144] In some aspects of the present invention, the use of the aqueous pharmaceutical composition of lebilimab of the present invention for the treatment of active rheumatoid arthritis may further include the use of methotrexate. In one embodiment, the present invention relates to the use of an aqueous pharmaceutical composition of rebilimab of the present invention for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome.

[0145] In one embodiment, the present invention is (i) Lebilimab at a dose of 5 to 220 mg / ml; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) Polyols in a concentration of 20 to 50 mg / ml; (iv) Glycine 5 to 10 mg / ml; and (v) Acetic acid to adjust pH to 4.5-6.5 The present invention relates to the use of an aqueous pharmaceutical composition of rebilimab, which contains [a specific compound], for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome.

[0146] In one embodiment, the present invention is (i) 20 mg / ml lebirimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 The present invention relates to the use of an aqueous pharmaceutical composition of rebilimab, which contains [a specific compound], for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome.

[0147] In one embodiment, the present invention (i) 180 mg / ml of lebilimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at a concentration of 23 mg / ml; (iv) 7.5 mg / ml of glycine; and (v) Acetic acid to adjust pH to 5.0 The present invention relates to the use of an aqueous pharmaceutical composition of rebilimab, which contains [a specific compound], for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome.

[0148] In one embodiment, the present invention is (i) Lebilimab at a dose of 5 to 220 mg / ml; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) Arginine hydrochloride 10 to 32 mg / ml; and (iv) Acetic acid to adjust pH to 4.5-6.5 The present invention relates to the use of an aqueous pharmaceutical composition of rebilimab, which contains [a specific compound], for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome.

[0149] In one embodiment, the present invention is (i) 20 mg / ml lebirimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 The present invention relates to the use of an aqueous pharmaceutical composition of rebilimab, which contains [a specific compound], for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome.

[0150] In one embodiment, the present invention (i) 180 mg / ml of lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml of arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 The present invention relates to the use of an aqueous pharmaceutical composition of rebilimab, which contains [a specific compound], for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome.

[0151] In one embodiment, the present invention is (i) 162 mg of lebilimab; (ii) 0.392 mg of sodium acetate trihydrate; (iii) 20.7 mg of a polyol selected from mannitol or sorbitol; (iv) 6.75 mg of glycine; (v) Acetic acid to set the pH to 5.0; and (vi) Up to 0.9 ml of sterile water for injection The present invention relates to the use of an aqueous pharmaceutical composition of rebilimab, which contains [a specific compound], for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome.

[0152] In one embodiment, the present invention is (i) 162 mg of lebilimab; (ii) 1.57 mg of sodium acetate trihydrate; (iii) 18.99 mg of arginine hydrochloride; (iv) Acetic acid to set the pH to 5.0; and (v) Up to 0.9 ml of sterile water for injection The present invention relates to the use of an aqueous pharmaceutical composition of rebilimab, which contains [a specific compound], for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome.

[0153] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of rebilimab of the present invention for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome may include administering the composition in doses of 324 mg or 648 mg of rebilimab.

[0154] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of rebilimab of the present invention for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome may include administering the composition at a dose of 4 mg of rebilimab per kg of body weight.

[0155] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of rebilimab of the present invention for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome may include administering the composition at a dose of 8 mg of rebilimab per kg of body weight.

[0156] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of rebilimab of the present invention for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome may include administering the composition once, twice, three times, or four times at intervals of at least eight hours.

[0157] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of rebilimab of the present invention for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome may include administering the composition parenterally.

[0158] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of rebilimab of the present invention for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome may include administering the composition intramuscularly, intravenously, or subcutaneously.

[0159] In some embodiments of the present invention, the use of the aqueous pharmaceutical composition of rebilimab of the present invention for the treatment or prevention of adult (acute) respiratory distress syndrome or cytokine release syndrome may include administering the composition intravenously as an infusion.

[0160] In one embodiment, the present invention relates to a method for treating or preventing an IL-6R-related disease or disorder, comprising administering a therapeutically effective amount of an aqueous pharmaceutical composition of revilimab of the present invention to a subject in need of such prevention or treatment.

[0161] In some aspects of the present invention, the IL-6R-related disease or disorder is selected from: rheumatoid arthritis, juvenile chronic arthritis, scleroderma, graft-versus-host disease, transplant organ rejection, acute or chronic immune disorders associated with organ transplantation, cachexia, adult (acute) respiratory distress syndrome, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's arteritis / arteritis, cytokine therapy-related disorders, cytokine release syndrome, iridocyclitis, uveitis, optic neuritis, neuromyelitis optica, juvenile rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis; cancer, particularly multiple myeloma and malignant solid tumors, colorectal cancer, prostate cancer, and ovarian cancer.

[0162] In some embodiments of the present invention, a method for treating or preventing IL6R-related disease or disorder in a target population may include administering a therapeutically effective amount of the aqueous pharmaceutical composition of revilimab of the present invention parenterally.

[0163] In some embodiments of the present invention, a method for treating or preventing IL6R-related disease or disorder in a target population may include administering a therapeutically effective amount of the aqueous pharmaceutical composition of revilimab of the present invention intramuscularly, intravenously, or subcutaneously.

[0164] In some embodiments of the present invention, a method for treating or preventing IL6R-related disease or disorder in a target population may include administering a therapeutically effective amount of the aqueous pharmaceutical composition of revilimab of the present invention intravenously as an infusion.

[0165] In one embodiment, the present invention relates to a method for treating rheumatoid arthritis, comprising administering a therapeutically effective amount of an aqueous pharmaceutical composition of revilimab of the present invention to a subject in need of prevention or treatment of such rheumatoid arthritis.

[0166] In some embodiments of the present invention, a method for treating rheumatoid arthritis in a subject requiring attention may include administering an aqueous pharmaceutical composition of levilimab according to the present invention at a dose of 162 mg of levilimab.

[0167] In some embodiments of the present invention, a method for treating rheumatoid arthritis in a subject requiring attention may include administering an aqueous pharmaceutical composition of levilimab according to the present invention once a week or once every two weeks.

[0168] In some embodiments of the present invention, a method for treating rheumatoid arthritis in a subject of interest may include administering an aqueous pharmaceutical composition of levilimab according to the present invention at a monthly dose of 4 mg of levilimab per kg of body weight.

[0169] In some embodiments of the present invention, a method for treating rheumatoid arthritis in a subject requiring attention may include administering an aqueous pharmaceutical composition of levilimab according to the present invention at a monthly dose of 8 mg of levilimab per kg of body weight.

[0170] In some embodiments of the present invention, a method for treating rheumatoid arthritis in a subject requiring attention may include administering an aqueous pharmaceutical composition of levilimab according to the present invention parenterally. In some embodiments of the present invention, a method for treating rheumatoid arthritis in a subject requiring attention may include administering an aqueous pharmaceutical composition of levilimab according to the present invention intramuscularly, intravenously, or subcutaneously.

[0171] In some embodiments of the present invention, a method for treating rheumatoid arthritis in a subject requiring attention may include administering an aqueous pharmaceutical composition of levilimab according to the present invention intravenously as an infusion.

[0172] In some embodiments of the present invention, a method for treating rheumatoid arthritis in a subject requiring it may further include administering methotrexate. In one embodiment, the present invention relates to a method for treating active rheumatoid arthritis, comprising administering a therapeutically effective amount of an aqueous pharmaceutical composition of revilimab of the present invention to a subject in need of prevention or treatment of such condition.

[0173] In some embodiments of the present invention, a method for treating active rheumatoid arthritis in a subject of interest may include administering an aqueous pharmaceutical composition of lebilimab according to the present invention at a dose of 324 mg or 648 mg of lebilimab.

[0174] In some embodiments of the present invention, a method for treating active rheumatoid arthritis in a subject of interest may include administering an aqueous pharmaceutical composition of levilimab according to the present invention at a dose of 4 mg of levilimab per kg of body weight.

[0175] In some embodiments of the present invention, a method for treating active rheumatoid arthritis in a subject of interest may include administering an aqueous pharmaceutical composition of levilimab according to the present invention at a dose of 8 mg of levilimab per kg of body weight.

[0176] In some embodiments of the present invention, a method for treating active rheumatoid arthritis in a subject requiring attention may include administering an aqueous pharmaceutical composition of levilimab according to the present invention once every two weeks, once every four weeks, or once every six weeks.

[0177] In some embodiments of the present invention, a method for treating active rheumatoid arthritis in a subject of interest may include parenterally administering an aqueous pharmaceutical composition of levilimab according to the present invention.

[0178] In some embodiments of the present invention, a method for treating active rheumatoid arthritis in a subject requiring attention may include administering an aqueous pharmaceutical composition of levilimab according to the present invention intramuscularly, intravenously, or subcutaneously.

[0179] In some embodiments of the present invention, a method for treating active rheumatoid arthritis in a subject requiring attention may include administering an aqueous pharmaceutical composition of lebilimab according to the present invention intravenously as an infusion.

[0180] In some embodiments of the present invention, a method for treating active rheumatoid arthritis in a subject requiring it may further include administering methotrexate. In one embodiment, the present invention relates to a method for treating or preventing adult (acute) respiratory distress syndrome or cytokine release syndrome, comprising administering a therapeutically effective amount of an aqueous pharmaceutical composition of revilimab of the present invention to a subject in need of such prevention or treatment.

[0181] In some embodiments of the present invention, a method for treating or preventing adult (acute) respiratory distress syndrome or cytokine release syndrome in a subject requiring it may include administering an aqueous pharmaceutical composition of rebilimab according to the present invention at a dose of 324 mg or 648 mg of rebilimab.

[0182] In some embodiments of the present invention, a method for treating or preventing adult (acute) respiratory distress syndrome or cytokine release syndrome in a subject requiring it may include administering an aqueous pharmaceutical composition of rebilimab according to the present invention at a dose of 4 mg of rebilimab per kg of body weight.

[0183] In some embodiments of the present invention, a method for treating or preventing adult (acute) respiratory distress syndrome or cytokine release syndrome in a subject requiring it may include administering an aqueous pharmaceutical composition of rebilimab according to the present invention at a dose of 8 mg of rebilimab per kg of body weight.

[0184] In some embodiments of the present invention, a method for treating or preventing adult (acute) respiratory distress syndrome or cytokine release syndrome in a subject requiring treatment may include administering one, two, three, or four aqueous pharmaceutical compositions of rebilimab according to the present invention at intervals of at least eight hours.

[0185] In some embodiments of the present invention, a method for treating or preventing adult (acute) respiratory distress syndrome or cytokine release syndrome in a subject requiring it may include parenterally administering an aqueous pharmaceutical composition of rebilimab according to the present invention.

[0186] In some embodiments of the present invention, a method for treating or preventing adult (acute) respiratory distress syndrome or cytokine release syndrome in a subject requiring it may include administering an aqueous pharmaceutical composition of rebilimab according to the present invention intramuscularly, intravenously, or subcutaneously.

[0187] In some embodiments of the present invention, a method for treating or preventing adult (acute) respiratory distress syndrome or cytokine release syndrome in a subject requiring it may include administering an aqueous pharmaceutical composition of rebilimab according to the present invention intravenously as an infusion.

[0188] In one embodiment, the present invention relates to an aqueous pharmaceutical composition of rebilimab according to the present invention used to treat or prevent IL6R-related diseases or disorders. In some aspects of the present invention, the IL6R-related disease or disorder is selected from: rheumatoid arthritis, juvenile chronic arthritis, scleroderma, graft-versus-host disease, organ rejection, acute or chronic immune disorders associated with organ transplantation, cachexia, adult (acute) respiratory distress syndrome, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's arteritis / arteritis, cytokine therapy-related disorders, cytokine release syndrome, iridocyclitis, uveitis, optic neuritis, neuromyelitis optica, juvenile rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis; cancer, particularly multiple myeloma and malignant solid tumors, colorectal cancer, prostate cancer, and ovarian cancer.

[0189] In some embodiments of the present invention, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent IL6R-related diseases or disorders, may be administered parenterally. In some embodiments of the present invention, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent IL6R-related diseases or disorders, may be administered intramuscularly, intravenously, or subcutaneously.

[0190] In some embodiments of the present invention, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent IL6R-related diseases or disorders, may be administered intravenously as an infusion.

[0191] In one embodiment, the present invention relates to an aqueous pharmaceutical composition of levilimab according to the present invention used for the treatment of rheumatoid arthritis. In some embodiments of the present invention, the aqueous pharmaceutical composition of lebirimab used to treat rheumatoid arthritis may be administered in a dose of 162 mg of lebirimab.

[0192] In some embodiments of the present invention, an aqueous pharmaceutical composition containing levilimab used to treat rheumatoid arthritis may be administered once a week or once every two weeks. In some embodiments of the present invention, an aqueous pharmaceutical composition containing levilimab used to treat rheumatoid arthritis may be administered at a dose of 4 mg of levilimab per kg of body weight.

[0193] In some embodiments of the present invention, an aqueous pharmaceutical composition containing levilimab used to treat rheumatoid arthritis may be administered at a dose of 8 mg of levilimab per kg of body weight.

[0194] In some embodiments of the present invention, an aqueous pharmaceutical composition containing levilimab used to treat rheumatoid arthritis may be administered parenterally. In some aspects of the present invention, an aqueous pharmaceutical composition containing levilimab used to treat rheumatoid arthritis may be administered intramuscularly, intravenously, or subcutaneously.

[0195] In some embodiments of the present invention, an aqueous pharmaceutical composition of levilimab used to treat rheumatoid arthritis may be administered intravenously as an infusion. In some aspects of the present invention, an aqueous pharmaceutical composition of levilimab used for the treatment of rheumatoid arthritis may be used in combination with methotrexate.

[0196] In one embodiment, the present invention relates to an aqueous pharmaceutical composition comprising levilimab used for the treatment of active rheumatoid arthritis. In some embodiments of the present invention, an aqueous pharmaceutical composition of lebilimab according to the present invention, used for the treatment of active rheumatoid arthritis, may be administered in doses of 324 mg or 648 mg of lebilimab.

[0197] In some embodiments of the present invention, an aqueous pharmaceutical composition of lebilimab according to the present invention, used for the treatment of active rheumatoid arthritis, may be administered at a dose of 4 mg of lebilimab per kg of body weight.

[0198] In some embodiments of the present invention, an aqueous pharmaceutical composition of lebilimab according to the present invention, used for the treatment of active rheumatoid arthritis, may be administered at a dose of 8 mg of lebilimab per kg of body weight.

[0199] In some embodiments of the present invention, an aqueous pharmaceutical composition of levilimab according to the present invention, used for the treatment of active rheumatoid arthritis, may be administered once every two weeks, once every four weeks, or once every six weeks.

[0200] In some embodiments of the present invention, an aqueous pharmaceutical composition of lebilimab according to the present invention, used for the treatment of active rheumatoid arthritis, may be administered parenterally. In some aspects of the present invention, an aqueous pharmaceutical composition of lebilimab according to the present invention, used for the treatment of active rheumatoid arthritis, may be administered intramuscularly, intravenously, or subcutaneously.

[0201] In some embodiments of the present invention, an aqueous pharmaceutical composition of lebilimab according to the present invention, used for the treatment of active rheumatoid arthritis, may be administered intravenously as an infusion. In some embodiments of the present invention, an aqueous pharmaceutical composition of lebilimab according to the present invention, used for the treatment of active rheumatoid arthritis, may be used in combination with methotrexate.

[0202] In one embodiment, the present invention relates to an aqueous pharmaceutical composition of rebilimab according to the present invention used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome.

[0203] In some embodiments of the present invention, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered in doses of 324 mg or 648 mg of rebilimab.

[0204] In some embodiments of the present invention, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered at a dose of 4 mg of rebilimab per kg of body weight.

[0205] In some embodiments of the present invention, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered at a dose of 8 mg of rebilimab per kg of body weight.

[0206] In some embodiments of the present invention, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered once, twice, three times, or four times at intervals of at least eight hours.

[0207] In some embodiments of the present invention, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered parenterally.

[0208] In some embodiments of the present invention, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered intramuscularly, intravenously, or subcutaneously.

[0209] In some embodiments of the present invention, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered intravenously as an infusion.

[0210] In one aspect, the present invention relates to lebilimab in a dose of 5 to 220 mg / ml, Sodium acetate trihydrate at a concentration of 0.4 to 1.8 mg / ml; Polyols in a concentration of 20 to 50 mg / ml; 5 to 10 mg / ml of glycine; and Acetic acid to adjust the pH to 4.5-6.5 The present invention relates to a method for producing an aqueous pharmaceutical composition of lebilimab, which includes mixing together [a certain substance].

[0211] In one aspect, the present invention relates to lebilimab in a dose of 5 to 220 mg / ml, Sodium acetate trihydrate at a concentration of 0.4 to 1.8 mg / ml; Arginine hydrochloride at 10 to 32 mg / ml; and Acetic acid to adjust the pH to 4.5-6.5 The present invention relates to a method for producing an aqueous pharmaceutical composition of lebilimab, which includes mixing together [a certain substance].

[0212] In one aspect, the present invention relates to a method for producing an aqueous pharmaceutical composition of levilimab, wherein the acetic acid is glacial acetic acid. The present invention relates to suitable aqueous pharmaceutical compositions of the anti-IL-6R antibody revilimab. One aqueous pharmaceutical composition may contain revilimab, an acetate-based buffer, a polyol, glycine, and acetic acid. Another aqueous pharmaceutical composition may contain revilimab, an acetate-based buffer, arginine hydrochloride, and acetic acid.

[0213] Acetate-based buffers may be the result of mixing acetic acid with sodium acetate trihydrate. While sodium acetate trihydrate may be used as a salt for acetate-based buffers, it is understood that any other acetate, such as potassium acetate, may also be used in acetate-based buffers without departing from the teachings of the present invention.

[0214] In the aqueous pharmaceutical composition of lebilimab according to the present invention, arginine, particularly L-arginine, or arginine hydrochloride may be used. The present invention relates to the use of an aqueous pharmaceutical composition of levilimab according to the present invention for the treatment or prevention of IL6R-related diseases or disorders.

[0215] Diseases or disorders that can be treated with the compositions provided herein include, but are not limited to, rheumatoid arthritis, juvenile chronic arthritis, scleroderma, graft-versus-host disease, transplant organ rejection, acute or chronic immune disorders associated with organ transplantation, cachexia, adult (acute) respiratory distress syndrome, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's arteritis / arteritis, cytokine therapy-related disorders, cytokine release syndrome, iridocyclitis, uveitis, optic neuritis, neuromyelitis optica, juvenile rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis; cancer, particularly multiple myeloma and malignant solid tumors, colorectal cancer, prostate cancer, and ovarian cancer.

[0216] The provided pharmaceutical composition may be administered to a subject in need of treatment by systemic injection, for example, by intravenous or subcutaneous injection, or by intramuscular injection; or by direct injection. The aqueous pharmaceutical composition of rebilimab according to the present invention may be used after dilution. For this purpose, the required volume of the composition is transferred from the vial to an injector containing a sterile 0.9% sodium chloride solution or a sterile 5% dextrose solution. The resulting solution is stirred by gently inverting the injector to avoid foaming.

[0217] In one embodiment of the present invention, the dose may be delivered as one or more infusions. The dose may be delivered as one, two, or three infusions. In some embodiments of the present invention, the duration of treatment may be one or more infusions.

[0218] The therapeutically effective amount in the provided formulation of the aqueous composition containing rebilimab according to the present invention depends on the condition to be treated, the severity of that condition, previous therapies, and the patient's medical history and response to the drug. The appropriate dose can be adjusted at the discretion of the attending physician so that it can be administered to the patient by one or several injections.

[0219] In one embodiment, the effective dose of lebilimab per patient is approximately 4 mg per kg of body weight or 8 mg per kilogram of body weight. The dose may be delivered as one or more injections. The dose may be delivered as one, two, or three injections. A single injection may contain 0.9 ml, 1 ml, 1.8 ml, or 2 ml of the composition disclosed herein.

[0220] In one embodiment, the aqueous pharmaceutical composition of levilimab of the present invention, used to treat rheumatoid arthritis, can be administered by a single injection at a dose of 162 mg of levilimab. In one embodiment, the aqueous pharmaceutical composition of levilimab of the present invention, used to treat active rheumatoid arthritis, may be administered by a single injection at a dose of 324 mg.

[0221] In one embodiment, the aqueous pharmaceutical composition of levilimab of the present invention, used to treat active rheumatoid arthritis, may be administered in a dose of 324 mg by injecting 162 mg twice.

[0222] In one embodiment, the aqueous pharmaceutical composition of levilimab of the present invention, used to treat active rheumatoid arthritis, may be administered by a single injection at a dose of 648 mg. In one embodiment, the aqueous pharmaceutical composition of levilimab of the present invention, used to treat active rheumatoid arthritis, may be administered in a dose of 648 mg by injecting 324 mg twice.

[0223] In one embodiment, the aqueous pharmaceutical composition of levilimab of the present invention, used to treat active rheumatoid arthritis, may be administered in a dose of 648 mg by four injections of 162 mg each.

[0224] In one embodiment, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered by a single injection at a dose of 324 mg.

[0225] In one embodiment, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered in a dose of 324 mg by injecting 162 mg twice.

[0226] In one embodiment, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered by a single injection at a dose of 648 mg.

[0227] In one embodiment, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered in a dose of 648 mg by injecting 324 mg twice.

[0228] In one embodiment, an aqueous pharmaceutical composition of rebilimab according to the present invention, used to treat or prevent adult (acute) respiratory distress syndrome or cytokine release syndrome, may be administered in a dose of 648 mg by four injections of 162 mg each.

[0229] In another embodiment, the pharmaceutical composition of the present invention may be prepared as a bulk formulation, in which the components of the pharmaceutical composition are essentially present in a larger amount than may be required for administration and are therefore diluted before administration.

[0230] Alternatively, the pharmaceutical composition may be freeze-dried, spray-dried, or lyophilized and reconstituted with a suitable sterile carrier before application. Lyophilization can be carried out using techniques known in the art, which include various steps such as freezing, annealing, initial drying, and re-drying.

[0231] The pharmaceutical composition may be administered as a single therapeutic agent or, as necessary, in combination with additional therapeutic agents. Thus, in one embodiment, the method provided for treatment and / or prevention is used in combination with the administration of another therapeutically effective amount of active agent. The other active agent may be administered before, together with, or after the administration of the pharmaceutical composition of the present invention. The other active agent may be administered as part of the provided composition or, instead, as a separate formulation.

[0232] The pharmaceutical composition may be provided in a vial, package, or dispenser device that may contain one or more unit dose forms containing the active ingredient, if desired. In one embodiment, the dispenser device may include a syringe containing a ready-to-use single-dose liquid formulation for injection. The syringe may be accompanied by instructions for administration.

[0233] In yet another embodiment, the present invention relates to a kit or container containing an aqueous pharmaceutical composition according to the present invention. The kit may also be accompanied by instructions for use. method 1. Preparation of lebilimab sample Antibody samples at concentrations of 5 to 20 mg / ml were prepared under pressure in a millpore cell. For this purpose, the initial antibody preparation was placed in the cell, and the protein was concentrated to a concentration of 10 mg / ml while continuously stirring under a stream of compressed air. Then, at least 10 times the volume of aqueous solution containing the target preparation, including buffer, permeable, and additional water-soluble stabilizers if necessary, was added to the cell. After dialysfiltration, the antibody was concentrated to a concentration of approximately 30 mg / ml, removed from the cell, and the precise protein concentration was measured by UV spectroscopy. Then, a suitable solution of excipients was added to the sample to prepare a solution containing the target concentration of protein.

[0234] Protein samples with concentrations of 20 mg / ml or higher were prepared using a tangential flow Pellicon cassette (Millipore). For this purpose, the initial antibody preparation was placed in a dialysis filtration tank, and the protein was concentrated to a concentration of approximately 45 to 50 mg / ml. Then, at least 10 times the volume of the solution containing the target preparation, along with buffers and, if necessary, additional water-soluble stabilizers, was supplied to the system. After dialysis filtration, the antibody was concentrated to a concentration of 100 mg / ml, removed from the system, and the osmoticon and stabilizers were added. Concentration was continued to a concentration exceeding the target concentration, and the sample was removed from the system to determine the exact protein concentration. Then, a suitable solution of excipients was added to the sample to prepare a solution containing the target concentration of protein.

[0235] When obtaining a formulation containing a solubilizer, the antibody was concentrated to the target concentration by diafiltration and final dilution of the antibody, including the excipient solution, and then a surfactant concentrate was added to the antibody. During sterile filling into the final container (e.g., sterile glass / plastic container, vial, or syringe), the antibody solution was filtered using a 0.22 μm germicidal membrane.

[0236] 2. Determination of protein concentration in test samples Protein concentration was measured by UV spectroscopy at a wavelength of 280 nm on a UV transparent plate.

[0237] Each sample was diluted to a concentration of approximately 0.5 mg / ml with a suitable excipient solution. 150 μl of the diluted sample was placed in a UV spectroscopy plate well. The optical density of the solution in the plate well was measured at a wavelength of 280 nm using a plate spectrophotometer. A suitable excipient solution was used as a standard solution.

[0238] The protein concentration (mg / ml) (C) was calculated using the following formula:

[0239]

number

[0240] During the ceremony, A 280 This is the optical density value at a wavelength of 280 nm; ε is the absorbance count of the test protein; b is the total dilution factor of the sample; l is the layer thickness within the plate well; for 150 μl, l = 0.42 cm.

[0241] 3. Determination of protein aggregation temperature by dynamic light scattering The aggregation points of the test protein (concentration 1 mg / ml) were determined using the Zetasizer Nano ZSP instrument. For this purpose, 0.5 ml of the solution was placed in a dust-free quartz cuvette and gradually heated in the instrument while continuously measuring the scattered light intensity.

[0242] • Analytical model: Protein analysis. Mode: Temperature trend, mod: Protein aggregation point 50-83°C, heating increment 1.5°C. • Maintain the temperature at the same level as before measurement for 30 seconds.

[0243] • Scattered light intensity was detected at an angle of θ = 173°. • For each point, the average value of 13 measurements per instance. Temperature trends and condensation points were determined using instrument software.

[0244] 4. Determination of colloidal stability by PEG aggregation A solution of PEG 6000 at a mass concentration of 20 to 25% was prepared in the test excipient composition. The resulting solution was filtered through a 0.45 μm Durapore filter.

[0245] Estimated amounts of sample, excipient solution, and 20–25% PEG 6000 solution were transferred to a 96-well UV plate so that the PEG 6000 concentration in some wells ranged from 0–18%, and the protein concentration in each well was 1 mg / ml. All solutions prepared in the wells were thoroughly mixed by pipetting.

[0246] Next, the turbidity of the solution was visually evaluated, and the optical density of the solution at a wavelength of 400 nm was measured. Protein precipitation in the presence of PEG is associated with volume displacement, meaning the protein is sterically excluded from the solvent region by the polymer (L. Li, A. Kantor, N. Warne. Application of a PEG precipitation method for solubility screening: A tool for developing high protein concentration formulations, Protein Sci. 2013 Aug;22(8):1118-1123). As a result, the protein is concentrated beyond its solubility until it precipitates. The lower the stability of the sample, the lower the PEG 6000 concentration at which the sample forms visible aggregates (protein luminescence).

[0247] Determination of thermal stability under thermal stress at 5.50°C Each test sample was divided into two 150 μl portions and placed in separate glass vials: one vial per composition was stored in a refrigerator at 2 to 8°C, and the remaining vial was placed in a thermostat and incubated at the required temperature for the specified time. When selecting a control point or after heating, the vials were removed from the thermostat and allowed to stand at room temperature for approximately 15 minutes before being analyzed.

[0248] 6. Determination of colloidal stability during shaking Each test sample was divided into two 150 μl portions and placed in glass vials. One vial per formulation was stored in a refrigerator at 5±3°C, while the remaining vial was placed in a thermal shaker and shaken at 800 rpm at 5±3°C for the specified period. During control point selection or after stress, the vials were removed from the thermal shaker and proceeded to analysis.

[0249] 7. Determination of colloidal stability during freezing and thawing. The test sample was divided into two portions and placed in plastic vials: one vial per formulation was stored in a refrigerator at 5±3°C, and the remaining vial was stored in a freezer at -16 to -20°C for the specified time. After stressing, the vials were removed from the freezer and kept at room temperature until the contents were completely thawed; the solutions were mixed using a vortex mixer and then proceeded to analysis.

[0250] 8. Accelerated storage Test samples with protein concentrations of 20, 180, and 220 mg / ml were divided into separate fractions (one for ingestion control, which was transferred to analysis once at the start of storage for all studies) and placed in separate sterile glass vials and syringes: a portion of each vial and syringe for each composition was stored in a refrigerator at 5±3°C (ingestion control), and the remainder was placed in a thermostat and incubated at 25°C for 6 months, with control points selected periodically according to the plan. When selecting control points and after storage, the vials and syringes were removed from the thermostat and transferred to analysis.

[0251] 9. Determination of sample purity by size exclusion high-performance liquid chromatography (SE HPLC). Tosoh TSK-GelG3000SWXL column, 7.8mm ID x 30cm, catalog number 08541.

[0252] Column temperature: 25°C. Mobile phase flow rate: 0.7ml / min. Injection volume: 10μl.

[0253] Sample concentration: 5 mg / ml. Detector wavelengths: 220 and 280 nm. Dissolution time: 23 minutes.

[0254] Mobile phase: Disodium hydrogen phosphate anhydrous 7.1 mg / ml. Sodium chloride 17.54 mg / ml. The mobile phase pH was adjusted to 7.0 with orthophosphate.

[0255] 10. Determination of charge morphology profile by ion exchange high-performance liquid chromatography (IE HPLC) Column: TSKgel CM-STAT, 4.6mm x 100mm, 7 micron particle size (Tosoh Bioscience LLC, Japan, 21966) Eluent A: 10 mM disodium hydrogen phosphate anhydrous solution, pH=6.8 Eluent B: 10 mM disodium hydrogen phosphate anhydrous solution, 200 mM NaCl, pH=6.8 Flow rate: 0.7ml / min.

[0256] Column temperature: 35℃ Autosampler temperature: 5℃ Detector: UV, 280nm Reference wavelength: 360nm, bandwidth: 100nm Sample volume: 40 μl Elution mode: Eluent A 100 → 0 → 100% Eluent B 0→100→0% Chromatography time: 60 minutes.

[0257] The test sample was diluted to a concentration of 1.0 mg / ml and treated with carboxypeptidase B (1% of the sample volume) at a temperature of (37±1)°C for 2 hours. 11. Determination of homogeneity by vertical polyacrylamide gel electrophoresis (reducing VPAGE and non-reducing VPAGE) under reducing and non-reducing conditions. PAAG was prepared on a glass plate in the presence of sodium dodecyl sulfate. The plate consisted of a concentration layer of 4% PAAG and a separation layer of 12.5% ​​PAAG (under reducing conditions) / 8% PAAG (under non-reducing conditions).

[0258] The electrophoresis tank was assembled and set up according to the vertical electrophoresis apparatus user manual. Probes were prepared by diluting the sample with purified water to a final concentration of 1 mg / ml. An equivalent volume of 40 μg was taken, and the prepared probe of the test sample was mixed with a 4× sample buffer solution containing 2-mercaptoethanol (reducing conditions) and a 4× sample buffer solution without 2-mercaptoethanol (non-reducing conditions) in a ratio of 3:1 (volume / volume), and stirred. The resulting solutions were incubated at (99±1) °C for 3 minutes (sample containing 2-mercaptoethanol) and at (99±1) °C for 1 minute (sample without 2-mercaptoethanol). The solutions were cooled to room temperature, mixed, and transferred to the PAAG well below the electrode buffer solution layer.

[0259] Electrophoresis was performed in constant current mode using a water-cooling system. The power supply parameters were set as follows: voltage was 110V while the die front passed through the concentration gel. After the die front moved to the lower separation gel at a level of 5 to 7 mm, the voltage was increased to 180V. The power supply was stopped when the die front reached the bottom line of the gel.

[0260] After electrophoresis, the gel was removed from the glass and the proteins were fixed with a fixative solution at room temperature for 16 to 18 hours. The gel was then stained (with Acid Blue 83 solution) and washed to obtain clear visualization of the bands. The gel was scanned. Purity and impurities in the test samples were evaluated using GelPro software.

[0261] 12. Determination of relative specific activity Specific activity was determined using an antiproliferative assay against DS-1 cell cultures. Samples were processed using a TecanEvo 200 robotic platform; RPMI1640 containing 2 mM Gln, 10% FBS, 1 mM sodium pyruvate, and 50 μg / ml gentamicin was used as the assay medium (quantification medium).

[0262] The test antibody sample was diluted to a concentration of 5 mg / ml using assay medium and placed in a robotic platform. Using TecanEvo 200, three independent dilutions of the standard and test sample were prepared using assay medium at concentrations of 1,000,000, 250,000, 1,000,000, 25,000, 5,000, 2,500, 1,000, 250, 50, 5, and 0 ng / ml. The dilutions and assay medium were transferred to culture plates and (1.5 ± 0.1) × 10⁻⁶. 5 A DS-1 cell suspension at a concentration of cells / ml and IL-6 standard solution at 7.5 ng / ml were added to the dilutions of the test and standard samples. The culture plates were placed in a CO2 incubator and incubated in humidified air with a carbon dioxide content of 5% at a temperature of (37±1)°C for 70 to 72 hours.

[0263] After the incubation period, Alamar blue dye was added to the wells of the culture plate, and the plate was incubated under the same conditions until a gradient color appeared. Fluorescence intensity was measured at excitation / emission wavelengths of 544 / 590 nm. Using Magellan 7.2 software, we plotted a graph of the dependence of fluorescence intensity on protein concentration. The relative specific activity of the test sample was determined as the ratio of the ED50 of the standard sample to the ED50 of the test sample and expressed as a percentage.

[0264] 13. Processing the results The absolute difference in quality indicators under stress was calculated using the following formula: △ = (Value after stress - Value before stress) The absolute difference in charge type profiles was calculated using the following formula: △ = |Acid fraction content before stress - Acid fraction content after stress| + |Alkaline fraction content before stress - Alkaline fraction content after stress| + |Major fraction content before stress - Major fraction content after stress| [Examples]

[0265] Example 1. Selection of a buffer system In this study, two typical buffering systems suitable for parenteral administration, namely acetate and histidine buffering systems, were selected as the basis for the pharmaceutical compositions.

[0266] To evaluate the suitability of buffer systems in relation to the processing characteristics of pharmaceutical compositions, the effect of buffer solutions on the colloidal stability of proteins during concentration was studied. As a reaction, the filtration time of the sample through a 0.22-micron sterile filter was measured. The test pharmaceutical compositions are shown in Table 1.

[0267] [Table 1]

[0268] Measurement of filtration time The samples were concentrated according to Method 1. The sterile filtration time of the pharmaceutical compositions was measured when concentrations of 100 mg / ml, 130 mg / ml, and 180 mg / ml were reached. The results of the sterile filtration time study are shown in Table 2.

[0269] [Table 2]

[0270] The use of an acetate buffer system reduces the filtration time of a pharmaceutical composition containing 180 mg / ml of protein by approximately 1.7 times compared to a histidine buffer system, demonstrating its superior solubility and colloidal stability.

[0271] Example 2. Initial selection of permeating substances Test formulation We studied excipients suitable for parenteral administration, which should be used as permeable substances. The test formulations are shown in Table 3.

[0272] [Table 3]

[0273] Determination of colloidal stability by PEG aggregation The PEG agglutination assay, similarly replaced with the inert polymer PEG 6000, simulates the direct enrichment of rebilimab and allows for comparative evaluation of the theoretical solubility of the antibody against various formulations. The study was conducted according to Method 4. The average optical density data of the solutions are shown in Table 4. The results are also shown in Figure 1.

[0274] [Table 4]

[0275] Determination of thermal stability Thermal stability was measured using methods 3 and 5. The total impurity content was measured before and after thermal stress by SE HPLC using method 9.

[0276] The results are shown in Table 5 and Figures 2, 3, 4, and 5.

[0277] [Table 5]

[0278] A pharmaceutical composition based on an acetate buffer system containing mannitol, trehalose dihydrate, and glycine as permeating agents showed better colloidal stability during PEG aggregation. High thermal stability was demonstrated by a composition based on an acetate buffer solution containing glycine and mannitol as permeating agents.

[0279] Example 3. Screening of penetrating substances and stabilizers Penetrants and stabilizers were screened using excipients suitable for parenteral administration. The test formulations are shown in Table 6. Pharmaceutical compositions containing rebilimab at a concentration of 10 mg / ml in the test formulations were prepared according to Technique 2.

[0280] [Table 6-1]

[0281] [Table 6-2]

[0282] [Table 6-3]

[0283] Determination of thermal stability Thermal stability was studied for 96 hours according to Technique 5. The analysis was performed according to Techniques 9-10. The results are shown in Table 7. The results were analyzed using the heatmap tool in Microsoft Excel software. The best results have brighter colors.

[0284] [Table 7]

[0285] Determination of colloidal stability during shaking Colloidal stability was studied for 96 hours according to Method 6. The results are shown in Table 8. The results were analyzed using the heatmap tool in Microsoft Excel software. The best results have brighter colors.

[0286] [Table 8]

[0287] Determination of colloidal stability during freezing and thawing Colloidal stability was studied for 96 hours according to Method 7. The results are shown in Table 9. The results were analyzed using the heatmap tool in Microsoft Excel software. The best results have brighter colors.

[0288] [Table 9]

[0289] Among the test samples, the following formulations can be distinguished by their stability: Lebilimab 10 mg / ml Sodium acetate trihydrate 1.742 mg / ml Glacial acetic acid up to pH 5.0 Sorbitol 45 mg / ml Glycine 100mM This pharmaceutical composition exhibited sufficient stabilization properties among all test samples: low levels of absolute difference in the acid-base profile under heat stress, as well as low decreases in monomer content during heat stress and freezing.

[0290] A formulation containing mannitol as a permeable agent and glycine as a stabilizer showed the smallest monomer reduction under heat stress. The study did not reveal any significant advantages of using solubilizers for the thermal or colloidal stability of proteins compared to using amino acids as stabilizers.

[0291] Example 4. Determination of accelerated storage stability The following formulations were studied for stability: two formulations containing glycine as a stabilizer and sorbitol and mannitol as permeabilis, as well as a formulation based on an arginine-acetate buffer system. The formulations containing arginine showed relatively low levels of change in the acid-base profile during thermal stress and shaking. Furthermore, according to the literature (Hong, T. et al., Current Protein and Peptide Science, 2018.19, 748-758), the use of arginine significantly reduces the viscosity of the pharmaceutical composition. The test formulations are shown in Table 10.

[0292] [Table 10]

[0293] Accelerated preservation Pharmaceutical compositions containing protein at concentrations of 20, 180, and 220 mg / ml were prepared by diafiltration according to Technique 1 and subjected to accelerated storage at a temperature of 25 ± 2°C according to Technique 8. The results of the study are shown in Table 11 and Figures 6, 7, and 8.

[0294] [Table 11-1]

[0295] [Table 11-2]

[0296] All pharmaceutical compositions showed acceptable levels of change during accelerated storage. Pharmaceutical compositions containing an acetate-arginine buffer system showed acceptable levels of aggregation and low changes in the acid-base profile during accelerated storage, both at a monoclonal antibody concentration against the IL-6 receptor of 20 mg / ml and at increased concentrations from 180 to 220 mg / ml.

[0297] The pharmaceutical composition containing arginine showed a reduced viscosity value. Pharmaceutical compositions containing sorbitol as a penetrating agent showed accelerated reduction in monomer content during storage at both a monoclonal antibody concentration of 20 mg / ml against the IL-6 receptor and increased concentrations of 180 to 220 mg / ml.

[0298] Examples of studies using aqueous pharmaceutical compositions of rebilimab to treat IL-6-related diseases are provided. The aqueous pharmaceutical compositions used in these studies are listed in Table 11.1:

[0299] [Table 12]

[0300] The pharmaceutical compositions of rebilimab according to the present invention in different doses, as described in Table 11.1, and / or the aqueous pharmaceutical compositions of rebilimab according to the present invention, have been shown to be suitable for treating the corresponding IL-6-related diseases.

[0301] Example 5. International, multicenter, comparative, randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of rebilimab in different dosing regimens in patients with active rheumatoid arthritis. The study included a screening period, a primary period (the period during which subjects received treatment blinded), an open-label period (the period during which subjects received treatment without being blinded), and a follow-up period: • Screening period (28 to 42 days) • Main examination period: Weeks 0 to 12 • Open label period (12 to 52 weeks) • Observation period (4 calendar weeks up to 56 weeks).

[0302] The study included men and women aged 18 to 80 years who were definitively diagnosed with rheumatoid arthritis meeting the 2010 ACR criteria, diagnosed at least six months prior to the date of informed consent signing, and received a constant dose of methotrexate for at least three months and at least four weeks immediately preceding the diagnosis, but maintained disease activity at the time of informed consent signing, maintained rheumatoid arthritis activity without significant concomitant pathology despite methotrexate treatment during the screening period (four to six weeks), and met the selection and exclusion criteria for the study.

[0303] The final group for this trial consisted of 105 participants: • 35 subjects were randomly assigned to receive a 162 mg dose of levilimab subcutaneously once a week (LVL QW group); • 35 subjects were randomly assigned to receive a 162 mg dose of levilimab subcutaneously every two weeks (LVL Q2W group); • 35 participants were randomly assigned to receive a placebo for the first 12 weeks of treatment (placebo / LVL Q2W treatment group). Participants in this group began receiving 162 mg of levilimab subcutaneously every two weeks from week 12 until week 52 of the study.

[0304] Investigational drug: INN: Rebilimab, a monoclonal antibody against the interleukin-6 receptor, injectable solution, 180 mg / ml. Dosage: 162 mg / 0.9 ml Route of administration: Subcutaneous.

[0305] Duration of treatment with lebilimab: • LVL QW treatment group: 53 weeks (weeks 0 to 52). Participants in this treatment group were able to receive up to 53 injections of levilimab. • LVL Q2W treatment group: 53 weeks (weeks 0 to 52). Participants in this treatment group were able to receive up to 27 injections of the drug revilimab. • Placebo / LVL Q2W treatment group: 41 weeks (weeks 12 to 52). Participants in this treatment group were able to receive up to 21 injections of the drug levilimab over the period in question.

[0306] Endpoints for evaluating the effectiveness during the primary trial period: Primary endpoints: • The proportion of rheumatoid arthritis patients in each treatment group who achieved an improvement equivalent to ACR20 during the course of the disease by 12 weeks after the first dose of BCD-089 / placebo.

[0307] Additional endpoints for the primary trial period: • The proportion of rheumatoid arthritis patients in each treatment group who achieved an improvement equivalent to ACR20 during the course of the disease at 4 and 8 weeks from the first dose of BCD-089 / placebo. • In each treatment group, the proportion of rheumatoid arthritis patients who achieved improvement equivalent to ACR50 / 70 during the course of the disease at 4, 8, and 12 weeks after the initial administration of BCD-089 / placebo (DAS28-CRP(4)). • In each treatment group, the proportion of subjects with low RA activity as measured by DAS28-CRP(4) index (DAS28-CRP(4) < 3.2), CDAI (CDAI ≤ 10), and SDAI (SDAI ≤ 11) at weeks 4, 8, and 12 after the initial administration of BCD-089 / placebo. Changes in DAS28-CRP(4), CDAI, and SDAI indices compared to baseline values ​​at 12 weeks. • Changes in erythrocyte sedimentation rate (ESR) compared to baseline values ​​at 12 weeks of treatment.

[0308] Additional endpoints for the open-label trial period • Percentage of rheumatoid arthritis patients who achieved improvement equivalent to ACR20 / 50 / 70 during the course of the disease at 16, 24, 36, 48, and 52 weeks after the first administration of BCD-089. • Percentage of subjects with low RA activity at weeks 16, 24, 36, 48, and 52 after the first administration of BCD-089, as measured by DAS28-CRP(4) index (DAS28-CRP(4) < 3.2), CDAI (CDAI ≤ 10), and SDAI (SDAI ≤ 11). • Changes in DAS28-CRP(4), CDAI, and SDAI indices compared to baseline values. • Percentage of patients who achieved remission according to the ACR / EULAR 2011 criteria at weeks 24, 36, 48, and 52 of BCD-089 treatment. • Patient-reported assessments of quality of life using the SF36 questionnaire before treatment and at 24 and 52 weeks after the first dose of BCD-089. • Change in erythrocyte sedimentation rate compared to baseline values. • X-ray characteristics of the affected joint 52 weeks after the first dose of BCD-089. - Average change in total score using the Sharp-van der Heijde (1989) modified assessment method. - Percentage of patients with rheumatoid arthritis showing increased X-ray stage (assessed using the Steinbrocker method).

[0309] Pharmacodynamic evaluation endpoints Secondary endpoint Pharmacodynamics were analyzed by determining the serum concentrations of the following samples using solid-phase ELISA: • Soluble interleukin-6 receptor • C-reactive protein IL-6 ·TNFα Secondary endpoint ·E min (Minimum serum concentration of CRP). ·ET min (Time to reach the minimum concentration of CRP). ·AUEC 0-last (AUC - area under the curve from product administration to the final concentration measurement, "Concentration-Time for CRP, sIL-6R, TNFα, and IL-6") ·E max (Maximum serum concentration of SIL-6R). ·ET max (Time to reach the maximum concentration of sIL-6R).

[0310] Endpoints for safety evaluation • The percentage of patients in each treatment group who experienced adverse events, including serious adverse events. • The percentage of patients experiencing serious adverse events in each treatment group. • The percentage of patients in each treatment group experiencing grade 3 to 4 adverse events. • The proportion of patients with grade 3 to 4 neutropenia in each treatment group. • The proportion of subjects in each treatment group experiencing adverse events characteristic of IL-6 receptor inhibitors. - Increased ALT / AST activity; - leukopenia / neutropenia; - Thrombocytopenia; - Upper respiratory tract infections; cellulitis; pneumonia; herpes simplex virus type 1 and herpes zoster infections; diverticulitis; - Increased total cholesterol / HDL / LDL / triglycerides. • The percentage of subjects who discontinued the trial early due to AE / SAE in each treatment group.

[0311] Endpoints for immunogenicity assessment Main examination period • Percentage of subjects in whom binding and / or neutralizing antibodies to the BCD-089 product were detected at 12 weeks.

[0312] Open-label trial period • Percentage of subjects in whom binding and / or neutralizing antibodies to the BCD-089 product were detected at weeks 24 and 52.

[0313] Results of efficacy evaluation: During the year-long use of rebilimab, we observed a continuous increase in the number of subjects who improved throughout the course of the disease. Simultaneously, the smallest apparent response corresponding to ACR20 was achieved in the majority of subjects during the first 24 weeks of treatment, and thereafter, the increasing number of responders was attributed to subjects achieving ACR50 and, more often, ACR70 (Figures 9, 10, 11).

[0314] Starting at 4 weeks of treatment, the proportion of subjects with low RA activity was numerically higher in the LVL QW treatment group compared to the LVL Q2W treatment group with respect to CDAI and SDAI indices, but the difference in DAS28-CRP(4) reached statistical significance at 12 weeks. The DAS-28-CRP(4), CDAI, and SDAI indices showed different favorable trends throughout 52 weeks of treatment, reflecting a decrease in the severity of clinical symptoms of RA. During the first 12 weeks of treatment, the changes in indices were numerically more pronounced in the LVL QW treatment group compared to the LVL Q2W treatment group, but the difference in the DAS28-CRP index(4) also reached statistical significance by 12 weeks (Figure 12). In general, the dynamics of RA activity, reflected in both the proportion of subjects with low activity and the changes in indices, show a higher proportion of clinical response in the LVL QW treatment group.

[0315] (According to ACR / EULAR 2011) The frequency of achieving remission during the course of RA was similar in the LVL QW and LVL Q2W treatment groups at 52 weeks of treatment. However, despite the lack of statistical significance of the difference, the LVL QW treatment group had numerically higher values ​​on the indicator compared to the LVL Q2W treatment group at 24, 36, and 48 weeks. This also supports the higher proportion of clinical response in the treatment group for subjects using the drug once a week (Figure 13).

[0316] Analysis of changes in ESR compared to baseline against the background of rebilimab therapy revealed that the LVL QW and LVL Q2W treatment groups showed a significant decrease in erythrocyte sedimentation rate after the first dose of the study drug. This decrease reached its minimum value during the first 2 to 4 weeks of treatment and remained at the minimum until the end of the study without significant change (Figure 14).

[0317] The results of the SF-36 questionnaire assessment of the physical (PH) and mental health (MH) components of quality of life showed that revilimab therapy was accompanied by improvements in patient-reported assessments of both the physical and mental health components of quality of life.

[0318] Evaluation of radiographic changes in the joints (using the Sharp-van der Heijde modified method) showed that the absolute values ​​of the indicators did not differ statistically significantly between screening and 52 weeks with respect to the background of revilimab therapy. However, analysis of changes in the indicators revealed a statistically significant difference (p=0.0494) between the LVL QW and LVL Q2W treatment groups at 52 weeks. The LVL QW treatment group showed no change in total score throughout the year, while the LVL Q2W treatment group showed increased radiographic changes in three subjects. An increase in the radiographic stage of RA by the Steinbrocker method was observed in only one subject in the placebo / LVL Q2W treatment group.

[0319] The assessment of the proportion of patients with increasing radiographic stage in rheumatoid arthritis did not reveal any patients with progression of radiographic stage by the Steinbrocker method in the LVL QW and LVL Q2W treatment groups.

[0320] The data on primary endpoint efficacy allow us to accept the hypothesis of superior efficacy of revilimab compared to placebo in all study populations (PP and ITT) when using both once-weekly and once-biweekly regimens. Therefore, we can conclude that both study dosing regimens of revilimab are effective in subjects with active rheumatoid arthritis and that the study achieved its objectives. Furthermore, the more frequent administration of the study drug (once a week for one year) showed slightly better efficacy compared to the once-biweekly regimen in terms of both time to achieve the objective and magnitude of response to therapy.

[0321] A one-year safety analysis of rebilimab data in patients with active rheumatoid arthritis demonstrated that the 162 mg dose of rebilimab product had a favorable safety profile and low immunogenicity, regardless of the mode of administration.

[0322] During treatment with the investigational drug, we observed significant changes in pharmacodynamic markers, namely increased serum concentrations of sIL-6R and IL-6, and decreased serum concentrations of CRP. The once-weekly regimen resulted in a significantly more pronounced increase in sIL-6R concentration (characteristic of the sIL-6R inhibitor group) and was characterized by a faster and more pronounced trend in CRP concentration. In general, the dynamics of the pharmacodynamic markers indicate highly effective neutralization of soluble IL-6 receptors by the revilimab product, which then manifests as a rapid and pronounced decrease in serum CRP concentration, reflecting effective suppression of the inflammatory process in subjects with active rheumatoid arthritis. Furthermore, administration of revilimab in the once-weekly regimen showed greater efficacy with respect to pharmacodynamic markers compared to the once-every-two-weeks regimen.

[0323] Example 6. Evaluation of pharmacodynamics Serum concentrations of soluble interleukin-6 receptor (sIL-6R) and C-reactive protein (CRP) were used as pharmacodynamic markers in this study.

[0324] The pharmacodynamic parameter analysis included data from 104 subjects: 35 subjects received weekly s / c doses of revilimab (BCD-089 QW treatment group), 34 subjects received bi-weekly s / c doses of revilimab (BCD-089 Q2W treatment group), and 35 subjects received placebo.

[0325] One patient in the BCD-089 Q2W treatment group who withdrew informed consent to participate in the study during the first visit prior to the first dose of the investigational drug was excluded from the pharmacodynamic analysis. Evaluation of soluble IL-6 receptor (sIL-6R) concentration The concentration of sIL-6R in serum (reflecting the blockade of the receptor by the test drug, which is a characteristic of the drug in the sIL6R inhibitor group) increased in the sera of subjects in both test drug treatment groups, and the BCD-089 QW treatment group reached the highest value (E max ) at 3240960 [1937060 to 4108080] pg / ml after 2016 [1344 to 2016] hours. The BCD-089 Q2W treatment group showed an E max of 1835030 [1536920 to 3020400] pg / ml after 2016 [1344; 2016] hours. The placebo treatment group did not show an increase in sIL-6R concentration, and the E max was 228440 [168822 to 367380] pg / ml after 96 [48 to 504] hours. Statistically significant differences were evident between the test drug treatment groups and the placebo treatment group (p < 0.0001; Kruskal-Wallis test), and between the test drug treatment groups (p = 0.0112; Kruskal-Wallis test).

[0326] The detailed results of the statistical analysis of SIL-6R concentration are shown in the following table. The administered dose of BCD-089 determined the value of the area under the concentration / time curve (AUEC 0-last ), which reached significantly higher values in the BCD-089 QW treatment group and BCD-089 Q2W and placebo (p < 0.0001; Kruskal-Wallis test). Furthermore, the difference between the test treatment groups also showed a significant difference (p = 0.0066; Kruskal-Wallis test) (Figure 15).

[0327]

Table 13

[0328] Evaluation of C-reactive protein concentration The C-reactive protein concentration in the sera of subjects in the treatment groups showed different decreases during the course of treatment. The greatest reduction was detected in the BCD-089 QW treatment group, and the E minThe value was 0[0;404]ng / ml, achieved after 672[336;1344] hours. The corresponding value in the BCD-089 Q2W treatment group was 72[0;421]ng / ml, reached after 1344[504;2016] hours, but no significant difference was observed between the treatment groups (p>0.05).

[0329] The lowest CRP concentration in the placebo group was 1421 [1087;2266] ng / ml, observed after 336 [96;672] hours. min and ET min The indicators differed significantly from the corresponding indicators in both treatment groups of the study drugs (Figure 16).

[0330] [Table 14]

[0331] During treatment with the investigational drug, we observed significant changes in serum concentrations of pharmacodynamic markers, namely increased sIL-6R concentration and decreased CRP concentration. The pharmacodynamic indices obtained showed statistically significant differences compared to those obtained in the placebo group. Furthermore, parameters characterizing sIL-6R enrichment (the increased concentration reflects receptor blockade by the test drug and is characteristic of the sIL6R inhibitor group) also showed significant differences between the test drug treatment groups. Additionally, the BCD-089 qw treatment group showed a more rapid and pronounced decrease in CRP concentration compared to the BCD-089 Q2W treatment group, although these differences were not statistically significant.

[0332] In general, the dynamics of pharmacodynamic markers show highly effective neutralization of soluble IL-6 receptors by the BCD-089 product, which then manifests as a rapid and clear decrease in serum CRP concentration, indicating effective suppression of the inflammatory response in subjects with active rheumatoid arthritis. Administration of the BCD-089 product in a once-weekly regimen showed better efficacy in terms of pharmacodynamic markers compared to a once-two-weeks regimen.

[0333] The use of anti-IL-6R therapy is known to be effective in cytokine release syndrome and adult (acute) respiratory distress syndrome. Considering the data obtained regarding the pharmacodynamics of rebilimab, which demonstrates its ability to efficiently block IL-6 signaling, it can be concluded that rebilimab would be effective in the treatment of cytokine release syndrome (CRS) and adult (acute) respiratory distress syndrome (ARDS).

[0334] CRS has been identified as a major cause of mortality in subjects with SARS-CoV, MERS-CoV, and COVID-19, where elevated interleukin-6 (IL-6) levels are observed and associated with C-reactive protein (CRP) levels, respiratory failure, ARDS, and unfavorable clinical outcomes.

Claims

1. (a) (i) 5 to 220 mg / ml of lebilimab; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol or a combination thereof in a concentration of 20 to 50 mg / ml; (iv) 5 to 10 mg / ml of glycine; and (v) Acetic acid to adjust the pH to 4.5-6.5; or, (b) (i) 5 to 220 mg / ml of lebilimab; (ii) 0.4 to 1.8 mg / ml of sodium acetate trihydrate; (iii) Arginine hydrochloride in doses of 10 to 32 mg / ml; and (iv) Acetic acid to adjust pH to 4.5-6.5 An aqueous pharmaceutical composition containing lebilimab.

2. The aqueous pharmaceutical composition according to claim 1, wherein lebilimab is present at a concentration of 5 to 40 mg / ml.

3. The aqueous pharmaceutical composition according to claim 1, wherein lebilimab is present at a concentration of 20 mg / ml.

4. The aqueous pharmaceutical composition according to claim 1, wherein lebilimab is present at a concentration of 180 to 220 mg / ml.

5. The aqueous pharmaceutical composition according to claim 1, wherein lebilimab is present at a concentration of 180 mg / ml.

6. The aqueous pharmaceutical composition according to any one of claims 1 to 5, wherein the sodium acetate trihydrate is present at a concentration of 0.4 to 1.0 mg / ml.

7. The aqueous pharmaceutical composition according to any one of claims 1 to 5, wherein the sodium acetate trihydrate is present at a concentration of 0.4 to 0.5 mg / ml.

8. The aqueous pharmaceutical composition according to any one of claims 1 to 5, wherein the sodium acetate trihydrate is present at a concentration of 0.436 mg / ml.

9. The aqueous pharmaceutical composition according to any one of claims 1 to 8, wherein the polyol is present at a concentration of 20 to 26 mg / ml.

10. The aqueous pharmaceutical composition according to any one of claims 1 to 8, wherein the polyol is present at a concentration of 23 mg / ml.

11. The aqueous pharmaceutical composition according to any one of claims 1 to 10, wherein the glycine is present at a concentration of 7 to 8 mg / ml.

12. The aqueous pharmaceutical composition according to any one of claims 1 to 10, wherein the glycine is present at a concentration of 7.5 mg / ml.

13. The aqueous pharmaceutical composition according to any one of claims 1 to 12, wherein the acetic acid is added up to a pH of 5.

0.

14. The aqueous pharmaceutical composition according to claim 1, wherein the sodium acetate trihydrate is present at a concentration of 1.744 mg / ml.

15. The aqueous pharmaceutical composition according to claim 1, wherein the arginine hydrochloride is present at a concentration of 18 to 24 mg / ml.

16. The aqueous pharmaceutical composition according to claim 1, wherein the arginine hydrochloride is present at a concentration of 21.1 mg / ml.

17. (a) (i) 20 mg / ml lebilimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at 23 mg / ml; (iv) 7.5 mg / ml glycine; and (v) Acetic acid to reduce pH to 5.0; or, (b) (i) 180 mg / ml of lebilimab; (ii) 0.436 mg / ml sodium acetate trihydrate; (iii) A polyol selected from mannitol or sorbitol at 23 mg / ml; (iv) 7.5 mg / ml glycine; and (v) Acetic acid to reduce pH to 5.0; or, (c) (i) 20 mg / ml lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml arginine hydrochloride; and (iv) Acetic acid to reduce pH to 5.0; or, (d) (i) 180 mg / ml of lebilimab; (ii) 1.744 mg / ml sodium acetate trihydrate; (iii) 21.1 mg / ml arginine hydrochloride; and (iv) Acetic acid to adjust pH to 5.0 The aqueous pharmaceutical composition according to claim 1, comprising:

18. (a) (i) 162 mg of lebilimab; (ii) 0.392 mg of sodium acetate trihydrate; (iii) 20.7 mg of a polyol selected from mannitol or sorbitol; (iv) 6.75 mg of glycine; (v) Acetic acid to reduce pH to 5.0; and (vi) Up to 0.9 ml of sterile water for injection; or, (b) (i) 162 mg of lebilimab; (ii) 1.57 mg of sodium acetate trihydrate; (iii) 18.99 mg of arginine hydrochloride; (iv) Acetic acid to reduce pH to 5.0; and (v) Up to 0.9 ml of sterile water for injection An aqueous pharmaceutical composition of lebilimab according to claim 1, comprising:

19. The aqueous pharmaceutical composition according to any one of claims 1 to 18, wherein the acetic acid is glacial acetic acid.

20. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the aqueous pharmaceutical composition is intended for parenteral administration.

21. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the aqueous pharmaceutical composition is intended for intramuscular, intravenous, or subcutaneous administration.

22. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the aqueous pharmaceutical composition is present in a vial.

23. The aqueous pharmaceutical composition according to claim 22, wherein the vial is a glass vial or a plastic vial.

24. The aqueous pharmaceutical composition according to claim 22 or 23, wherein the vial has a volume of 4 to 20 ml.

25. The aqueous pharmaceutical composition according to claim 22 or 23, wherein the vial has a volume of 4 ml, 10 ml, or 20 ml.

26. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the aqueous pharmaceutical composition is contained in a syringe or an automatic injection device.

27. The aqueous pharmaceutical composition according to claim 26, wherein the syringe or automatic injection device is a glass syringe or automatic injection device, or a plastic syringe or automatic injection device.

28. The aqueous pharmaceutical composition according to claim 26 or 27, wherein the syringe or automatic injection device has a maximum volume of 1 ml.

29. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the aqueous pharmaceutical composition is present in a pre-filled syringe or a pre-filled automatic injection device.

30. The aqueous pharmaceutical composition according to claim 29, wherein the pre-filled syringe or pre-filled automatic injection device is a glass pre-filled syringe or automatic injection device or a plastic pre-filled syringe or automatic injection device.

31. The aqueous pharmaceutical composition according to claim 29 or 30, wherein the pre-filled syringe or pre-filled automatic injection device has a maximum volume of 1 ml.

32. An aqueous pharmaceutical composition of levilimab according to claim 1 or 18 for treating or preventing IL-6R-related disease or disorder.

33. IL-6R-related disease or disorder: Aqueous pharmaceutical composition of levilimab according to claim 32, selected from rheumatoid arthritis, juvenile chronic arthritis, scleroderma, graft-versus-host disease, organ rejection, acute or chronic immune disorders associated with organ transplantation, cachexia, adult (acute) respiratory distress syndrome, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's arteritis / arteritis, cytokine therapy-associated disorders, cytokine release syndrome, iridocyclitis, uveitis, optic neuritis, neuromyelitis optica, juvenile rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis; cancer, particularly multiple myeloma and malignant solid tumors, colorectal cancer, prostate cancer, and ovarian cancer.

34. The aqueous pharmaceutical composition of rebilimab according to claim 32, wherein the aqueous pharmaceutical composition is administered parenterally.

35. The aqueous pharmaceutical composition of rebilimab according to claim 34, wherein the aqueous pharmaceutical composition is administered intramuscularly, intravenously, or subcutaneously.

36. An aqueous pharmaceutical composition of lebilimab according to claim 1 or 18 for the treatment of rheumatoid arthritis.

37. The aqueous pharmaceutical composition of rebilimab according to claim 36, wherein the aqueous pharmaceutical composition is administered in a dose of 162 mg of rebilimab.

38. The aqueous pharmaceutical composition of levilimab according to claim 36, wherein the aqueous pharmaceutical composition is administered once a week or once every two weeks.

39. The aqueous pharmaceutical composition of rebilimab according to claim 36, wherein the aqueous pharmaceutical composition is administered parenterally.

40. The aqueous pharmaceutical composition of levilimab according to claim 39, wherein the aqueous pharmaceutical composition is administered intramuscularly, intravenously, or subcutaneously.

41. Aqueous pharmaceutical composition of lebilimab according to claim 36, further comprising the use of methotrexate thing.

42. An aqueous pharmaceutical composition of lebilimab according to claim 1 or 18 for the treatment of active rheumatoid arthritis.

43. The aqueous pharmaceutical composition of rebilimab according to claim 42, wherein the aqueous pharmaceutical composition is administered in a dose of 324 mg or 648 mg of rebilimab.

44. The aqueous pharmaceutical composition of rebilimab according to claim 42, wherein the aqueous pharmaceutical composition is administered once every two weeks, once every four weeks, or once every six weeks.

45. The aqueous pharmaceutical composition of rebilimab according to claim 42, wherein the aqueous pharmaceutical composition is administered parenterally.

46. The aqueous pharmaceutical composition of rebilimab according to claim 45, wherein the aqueous pharmaceutical composition is administered intramuscularly, intravenously, or subcutaneously.

47. An aqueous pharmaceutical composition of rebilimab according to claim 42, further comprising the use of methotrexate.

48. An aqueous pharmaceutical composition of rebilimab according to claim 1 or 18 for treating or preventing adult (acute) respiratory distress syndrome or cytokine release syndrome.

49. The aqueous pharmaceutical composition of rebilimab according to claim 48, wherein the aqueous pharmaceutical composition is administered in a dose of 324 mg or 648 mg of rebilimab.

50. The aqueous pharmaceutical composition of levilimab according to claim 48, wherein the aqueous pharmaceutical composition is administered once, twice, three times, or four times at intervals of at least eight hours.

51. The aqueous pharmaceutical composition of rebilimab according to claim 48, wherein the aqueous pharmaceutical composition is administered parenterally.

52. The aqueous pharmaceutical composition of rebilimab according to claim 51, wherein the aqueous pharmaceutical composition is administered intramuscularly, intravenously, or subcutaneously.

53. Lebilimab at doses of 5 to 220 mg / ml, (a) Sodium acetate trihydrate at a concentration of 0.4 to 1.8 mg / ml; Polyols at 20 to 50 mg / ml; 5 to 10 mg / ml of glycine; and Acetic acid to adjust the pH to 4.5-6.5; or, (b) Sodium acetate trihydrate at a concentration of 0.4 to 1.8 mg / ml; Arginine hydrochloride at 10 to 32 mg / ml; and Acetic acid to adjust the pH to 4.5-6.5 A method for producing the aqueous pharmaceutical composition according to claim 1, comprising the step of mixing with the other.

54. The method according to claim 53, wherein the acetic acid is glacial acetic acid.

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