Pharmaceutical compositions of anti-TRBV9 antibodies and uses thereof

Abstract

The present invention relates to the field of pharmaceuticals and medicines, specifically to a pharmaceutical composition of anti-TRBV9 antibody.The present invention further relates to the use of said composition for treating a disease or disorder mediated by T lymphocytes carrying a TRBV9 segment in their T cell receptor in a subject in need of said disease or disorder treatment.

Description

[Technical field]

[0001] The present invention relates to the field of pharmaceuticals and medicine, specifically to pharmaceutical compositions of anti-TRBV9 antibodies that can be used to treat diseases or disorders mediated by T lymphocytes that have a TRBV9 segment in their T cell receptor. [Background technology]

[0002] Autoimmune diseases are caused by autoreactive T lymphocytes (Haroon N et al., Arthritis Rheum. 2013 Oct; 65(10):2645-54; Duarte J. et al., PloS One 2010 May 10;5(5):e10558; Konig M. et al., Front Immunol 2016 Jan 25;7:11). The main role in the emergence of autoreactive T lymphocyte clones is played by the interaction of the antigen-recognizing T cell receptor (TCR) with proteins of the major histocompatibility complex (MHC, HLA), which presents on its surface processed peptides of intracellular proteins or proteins of pathogenic organisms. Many autoimmune diseases are associated with the presence of certain variants of the HLA genes in humans. Thus, the HLA-B27 allele is associated with ankylosing spondylitis, reactive arthritis, and Crohn's disease. The risk of developing autoimmune diseases in carriers of certain HLA allele variants can be explained by the fact that these alleles preferentially present certain peptides, which are self-antigens, against which the immune reaction leads to the development of autoimmune diseases. One of the possible mechanisms underlying autoimmune reactions is the presentation by histocompatibility complex molecules of peptides from proteins of bacterial or viral origin that are homologous to the organism's own peptides, a fact that can lead to an immune reaction against self-antigens as a result of cross-reactivity.

[0003] In the prior art, T cell receptor (TCR) sequences are considered to be markers that can distinguish T lymphocyte clones involved in the pathogenesis of autoimmune diseases. T cell receptor subunits structurally belong to the immunoglobulin superfamily and are formed from several gene segments. The variable region of the TCR forms the antigen-binding center of the TCR. This means that the variable region of the TCR is clone-specific, i.e., it is different in T lymphocytes that react to different antigens.

[0004] T lymphocytes (T cells) are stimulated when an antigen binds to their T cell receptor (TCR). The TCR, the structure that defines a T cell, is a transmembrane heterodimer consisting of either alpha and beta or delta and gamma chains linked by disulfide bonds. These chains have complementarity determining regions (CDRs) that determine the antigen to which the TCR binds. TCR development occurs by a lymphocyte-specific genetic recombination process that assembles the final sequence from a number of potential segments. This genetic recombination of TCR gene segments in somatic T cells occurs during early developmental stages in the thymus. The TCRα locus contains variable (V) and joining (J) gene segments (Vβ and Jβ), while the TCRβ locus contains a D gene segment in addition to the Vα and Jα segments. Thus, the α chain is generated from VJ recombination, and the β chain is involved in VDJ recombination.

[0005] The TCR α chain locus consists of 46 variable segments (TRAV), 8 joining segments (TRAJ), and a constant region. The TCR β chain locus consists of 48 variable segments (TRBV), followed by 2 diversity segments (TRBD), 12 joining segments (TRBJ), and 2 constant regions. (Bio-Rad. Mini-review | An overview of T cell receptors [electronic resource] / / Bio-Rad. URL: https: / / www.bio-rad-antibodies.com / t-cell-receptor-minireview.html (Accessed: April 24, 2020)).

[0006] To date, a large amount of data has accumulated indicating that the development of HLA-B27-associated diseases is due to the expansion of antigen-specific T lymphocyte clones. A consensus variant of an autoimmune TCR has been reported in ankylosing spondylitis (radiographic axial spondyloarthritis); it has been shown to be present in synovial fluid and peripheral blood of patients with ankylosing spondylitis and not present at the same analytical depth in healthy donors, regardless of the status of the HLA*B27 allele (Faham M. et al., Arthritis Rheumatol. 2017;69(4):774-784; Komech E et al., 12th EJI-EFIS Tatra Immunology Conference; 3-7 September 2016; Strbske Pleso, Slovakia. Abstract book 39). The TCR belongs to the TRBV9 family (according to the IMGT nomenclature).

[0007] T cell receptors with beta chains of the TRBV9 family have also been shown to be involved in the development of autoimmune diseases such as celiac disease (Petersen J et al., J Immunol. 2015; 194(12): 6112-22). This T cell receptor is also found on the surface of T cells undergoing malignant transformation in T cell lymphomas and T cell leukemias, including those caused by Epstein-Barr virus (EBV) (Toyabe S et al., Clin Exp Immunol. 2003; 134(1): 92-97).

[0008] In view of the above, the TRBV9 protein may serve as a target for cytotoxic monoclonal antibodies to induce depletion of TRBV9+ T lymphocytes (TRBV9-positive T lymphocytes), including pathogenic autoreactive T lymphocyte clones.

[0009] Monoclonal anti-TRBV9 antibodies are known from the prior art: WO2019 / 132738, WO2020 / 139171, WO2020 / 091635, WO2020 / 139175. The prior art also provides pharmaceutical compositions of anti-TRBV9 antibodies with citrate buffer (WO2020 / 139171). However, the authors of the present invention found that compositions of anti-TRBV9 antibodies with citrate buffer are not stable, since anti-TRBV9 antibodies in citrate buffer tend to aggregate. Summary of the Invention [Means for solving the problem]

[0010] In relation to the above, there is a need to develop stable pharmaceutical compositions of anti-TRBV9 antibodies that can be used as medicaments for treating diseases or disorders mediated by human T cell receptors bearing TRBV9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Definition Unless otherwise defined herein, all technical and scientific terms used in connection with the present invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0012] Further, unless otherwise required by context, singular terms shall include plural terms and plural terms shall include the singular term. As used in this specification and the claims that follow, the words "have," "include," and "comprise," or variations thereof such as "has," "having," "includes," "including," "comprises," or "comprising," are understood to mean the inclusion of a specified integer or group of integers but not the exclusion of any other integer or group of integers, unless the context otherwise dictates.

[0013] The term "antibody" or "immunoglobulin" (Ig) includes full length antibodies or any antigen binding fragment (i.e., "antigen-binding portion") or individual chains thereof. The term "antibody" within the scope of the present invention is used in the broadest sense and may include, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, humanized, fully human antibodies, and chimeric antibodies.

[0014] A full-length antibody refers to a glycoprotein that contains at least two heavy chains (H) and two light chains (L) interconnected by disulfide bonds. Each heavy chain contains a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The constant region is identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α, and δ have a constant region consisting of three constant domains CH1, СН2, CH3 (in line) and a hinge region for increased flexibility (Woof J., Burton D., Nat Rev Immunol 4, 2004, pp. 89-99). In mammals, only two types of light chains are known, designated lambda (λ) and kappa (κ). Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The approximate length of a light chain is 211-217 amino acids. Preferably, the light chain is a lambda (λ) light chain, and the constant domain CL is preferably Clamda (λ).

[0015] The VL and VH regions may be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), located between more conserved regions, called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (C1q).

[0016] As used herein, the term "antigen-binding portion" or "antigen-binding fragment" of an antibody refers to one or more antibody fragments that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. As used herein, the term "antigen-binding fragment" refers to a Fab fragment, i.e., a monovalent fragment consisting of the VL, VH, CL, and CH1 domains and associated with an Fc fragment monomer.

[0017] The term "variable" refers to the fact that certain portions of the variable domains vary widely in sequence among antibodies. The V domains mediate antigen binding and determine the specificity of each particular antibody for a particular antigen. However, variability is not evenly distributed across the 110 amino acid span of the variable domains. Instead, the V regions consist of invariant segments of 15-30 amino acids called framework regions (FRs), which are separated by shorter regions of high variableity called "hypervariable regions" or CDRs. Native heavy and light chain variable domains each consist of four FRs, adopting a primarily beta-sheet structure, connected by three hypervariable regions that form loops connecting the beta-sheet structure and, in some cases, forming part of the beta-sheet structure. The hypervariable regions of each chain are held together in close proximity by the FRs and, together with the hypervariable regions of the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest. 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). The constant domains are not directly involved in binding the antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity (ADCC).

[0018] The term "hypervariable region" according to the present specification refers to the amino acid residues of an antibody which are responsible for antigen binding. The hypervariable region typically comprises amino acid residues from the "complementarity determining regions" or "CDRs" and / or residues from the "hypervariable loops".

[0019] "Kabat numbering scheme" or "Kabat numbering" as used herein refers to a system of numbering amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues within the variable regions of antibody heavy and light chains (Kabat et al., Ann. NY Acad. Sci., 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242 (1991)).

[0020] The antibody of the present invention that "binds" to a target antigen refers to an antibody that binds to the antigen with such affinity that it can be used as a diagnostic and / or therapeutic agent targeting proteins or cells or tissues expressing the antigen, and that cross-reacts only slightly with other proteins. In such embodiments, the degree of binding of the antibody to non-target proteins is less than 10% of the binding of the antibody to the specific target protein, according to analytical methods: fluorescence activated cell sorting (FACS), radioimmunoassay (RIA), or ELISA. With respect to the binding of an antibody to a target molecule, the term "specific binding" or the phrase "specifically binds" or "is specific for" a particular polypeptide or epitope on a particular target polypeptide means binding that is significantly (measurably) different from non-specific interactions.

[0021] Specific binding can be measured, for example, by determining the binding of a molecule compared to the binding of a control molecule. For example, specific binding can be determined by competition with another molecule similar to the target, for example, excess unlabeled target. In this case, specific binding is indicated if the binding of the labeled target to the probe is competitively inhibited by excess unlabeled target. As used herein, the term "specific binding" or the phrase "specifically binds" or "is specific" to a particular polypeptide or epitope on a particular target polypeptide can be illustrated by the example of a molecule with a KD (affinity constant) for the target of at least about 200nM, or at least about 150nM, or at least about 100nM, or at least about 60nM, or at least about 50nM, or at least about 40nM, or at least about 30nM, or at least about 20nM, or at least about 10nM, or at least about 8nM, or at least about 6nM, or at least about 4nM, or at least about 2nM, or at least about 1nM, or more. In one aspect, the term "specific binding" refers to binding by a molecule to a particular polypeptide or an epitope on a particular polypeptide, and not to substantially bind to any other polypeptides or epitopes on polypeptides.

[0022] The term "monoclonal antibody" or "mAb" refers to an antibody synthesized and isolated as a discrete clonal cell population. The term "recombinant antibody" refers to an antibody expressed in a cell or cell line that contains a nucleotide sequence encoding the antibody, where said nucleotide sequence is not naturally associated with the cell.

[0023] The term "isolated" as applied to describe various antibodies according to the invention refers to an antibody that has been identified, isolated and / or recovered from the cell or cell culture in which it is expressed. Impurities (contaminating components) from the natural environment are typically substances that would interfere with the diagnostic or therapeutic use of the polypeptide and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. An isolated polypeptide is typically prepared by at least one purification step.

[0024] The terms "anti-TRBV9 antibody," "antibody against TRBV9," "antibody that specifically binds to the TRBV9 family beta chain," and "antibody against the TRBV9 family beta chain" are interchangeable within the scope of the present invention and relate to an antibody that specifically binds to an epitope of the TRBV9 family beta chain of the human T-cell receptor.

[0025] The term "pharmaceutical composition" refers to a composition and / or formulation comprising a therapeutically effective amount of an anti-TRBV9 antibody and excipients or auxiliary substances (carriers, diluents, fillers, solvents, etc.), the selection and proportions of which depend on the type and route of administration, as well as the dosage.

[0026] The term "excipient" or "auxiliary substance" is used herein to describe any ingredient other than the compound of the invention. These are substances of inorganic or organic nature used in the production / manufacturing of pharmaceutical products to impart the necessary physicochemical properties to the pharmaceutical product.

[0027] As used herein, the term "aqueous composition" refers to a water-based composition, and the water in the composition may be water, water for injection, or saline (aqueous solution of 0.9% to 1.0% sodium chloride).

[0028] As used herein, the term "lyophilized" refers to a formulation that has been subjected to a process known in the art as freeze-drying, which involves freezing the formulation and then removing the ice from the frozen contents.

[0029] A pharmaceutical composition is "stable" if the active agent maintains physical stability and / or chemical stability and / or biological activity during a specified storage period, for example at a storage temperature of 2-8°C. Furthermore, the active agent can maintain both physical and chemical stability, as well as biological activity. The storage period is adjusted based on the results of stability testing under accelerated or natural aging conditions.

[0030] The term "long-term storage" or "long-term stability" should be understood to mean that the pharmaceutical composition can be stored for 3 months or more, 6 months or more, 1 year or more, and the minimum stable shelf life of the composition may be at least 2 years.

[0031] The term "buffer" refers to an acid or base component (typically a weak acid or weak base) of a buffer or buffer solution. A buffer helps to maintain the pH value of a given solution at or near a predetermined value, and the buffer is generally selected to complement the predetermined value. A buffer may be a single compound that produces the desired buffering effect, particularly when said buffer is mixed with an appropriate amount (according to the desired predetermined value) of a corresponding "acid / base conjugate" (suitably capable of proton exchange).

[0032] The term "buffer" or "buffer solution" or "buffer system" refers to an aqueous solution containing a mixture of an acid (typically a weak acid such as acetic acid, citric acid, etc.) and its conjugate base (e.g., acetate or citrate, e.g., sodium acetate, sodium citrate, and hydrates of said salts, e.g., sodium acetate trihydrate), or alternatively, a mixture of a base (typically a weak base such as histidine) and its conjugate acid (e.g., histidine hydrochloride or histidine hydrochloride monohydrate or L-histidine hydrochloride (h / c) monohydrate (m / h) or L-histidine h / cm / h or histidine h / cm / h). The pH value of a "buffer solution" changes only slightly when small amounts of a strong base or strong acid are added, as well as when diluted or concentrated, due to the "buffering effect" imparted by the "buffering agent".

[0033] The buffer solution may be, for example, acetate, phosphate, citrate, histidine, succinate, and other buffer solutions. In general, the pharmaceutical composition preferably has a pH in the range of 4.0 to 8.0.

[0034] "Stabilizer" refers to an excipient or a mixture of two or more excipients that provides physical and / or chemical stability of an active agent. The terms "osmotic agent" or "tonicity modifier", as well as "osmolyte", as used herein refer to an excipient capable of providing the required osmotic pressure of a liquid antibody solution. In some embodiments, the tonicity modifier can increase the osmotic pressure of the liquid antibody formulation to isotonicity, so that the liquid antibody formulation is physiologically compatible with the cells of the tissue of the subject organism. In another embodiment, the tonicity modifier can contribute to improving the stability of the antibody. An "isotonic" formulation is a formulation that has an osmotic pressure equivalent to that of human blood. The osmotic pressure of an isotonic formulation is typically about 239-376 mOsm / kg.

[0035] As used herein, the term "solubilizer" refers to a pharma- ceutically acceptable non-ionic surfactant. Both one solubilizer and a combination of solubilizers can be used. Exemplary solubilizers include, but are not limited to, polysorbate 20 or polysorbate 80, poloxamer 184 or poloxamer 188, or PLURONIC®.

[0036] Typically, amino acid is L-amino acid.For example, when histidine and histidine hydrochloride monohydrate are used, typically L-histidine and L-histidine hydrochloride monohydrate are used.For example, when proline is used, typically L-proline is used.Amino acid equivalents, such as pharma- ceutically acceptable proline salts (e.g., proline hydrochloride) can also be used.

[0037] The term "medicament" or "preparation" refers to a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, solutions, ointments and other ready-made forms intended for the restoration, improvement or modification of physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetics, etc.

[0038] The term "use" refers to the possible use of a pharmaceutical composition of an anti-TRBV9 antibody according to the present invention for treating a disease or disorder, ameliorating the course of, promoting remission, or reducing the recurrence rate of a disease or disorder.

[0039] The term "disease or disorder mediated by T lymphocytes having a TRBV9 segment in their T cell receptor" refers to any disease or disorder directly or indirectly associated with T lymphocytes carrying a TRBV9 segment in their T cell receptor, including the etiology, onset, progression, persistence or pathology of the disease or disorder.

[0040] "Treat", "treatment" and "therapy" refer to a method of alleviating or eliminating at least one of a biological disorder and / or its associated symptoms. As used herein, "alleviating" a disease, disorder or condition means reducing the severity and / or frequency of occurrence of the symptoms of the disease, disorder or condition. Additionally, references herein to "treatment" include references to curative, palliative, and prophylactic treatment.

[0041] The term "parenteral administration" refers to administration regimens that are typically performed by injection (infusion) and includes intravenous, intramuscular, intraarterial, intratracheal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection or infusion, among others.

[0042] Abbreviation Anti-TRBV9 (Anti-TRBV9) - Monoclonal antibody against TRBV9 IC- Incoming Inspection FT - Freeze-thaw k D- Diffusion interaction parameters SH- Shake Tag- Agglomeration temperature Tonset - melting start temperature Tm- Melting point T-Temperature TS-Heat Stress C- Protein concentration Osm-osmolarity TS50 96H- Heat stress at 50℃ for 96 hours ΔTS50 96H- Change in quality parameters after 120 hours of heat stress at 50℃ TS50 120H- Heat stress at 50℃ for 96 hours ΔTS50 120H - Change in quality parameters after 120 hours of heat stress at 50℃ Acid 3.0 24H Adjust the pH to 3.0, perform acid hydrolysis, and mature for 1 hour or 24 hours. ΔAcid 3.0 24H- Changes in quality parameters after stress by acid hydrolysis at pH 3.0 and aging for 1 or 24 hours Basic 9.0 1H - pH 9.0, base hydrolysis, aging for 1 hour ΔBasic 9.0 1H- Changes in quality parameters after stress by alkaline hydrolysis at pH 9.0 and aging for 1 h SH800 96H- Shake at 800 rpm for 96 hours ΔSH800 96H- Change in quality parameters after 96 hours of shaking at 800 rpm SH800 120H - Shake at 800 rpm for 120 hours ΔSH800 120H- Change in quality parameters after shaking at 800 rpm for 120 hours fr-th3 cycle - 3 freeze-thaw cycles Δfr-th3 cycle - Changes in quality parameters after three freeze-thaw cycles FT 5C- 5 freeze-thaw cycles ΔFT 5C - Change in quality parameters after 5 freeze-thaw cycles IE HPLC - Ion Exchange High Performance Liquid Chromatography SW - Software SE HPLC - Size Exclusion High Performance Liquid Chromatography n / a- undecided abs- absolute change in quality parameter C con - concentration after concentration DSF - Differential Scanning Fluorescence DLS - Dynamic Light Scattering ABP- Acid-Base Profile Oxid 0.1% - Oxidation with 0.1% hydrogen peroxide solution ΔOxid 0.1% - Change in quality parameters after oxidation with 0.1% hydrogen peroxide solution Surfactant AS37- Accelerated storage at 37℃ 2W- 2 weeks 4W- 4 weeks ΔAS37- Change in quality parameters after accelerated storage at 37°C Max - Maximum value Min - Minimum value pH- Hydrogen exponent Cfin. / Cin. - Ratio of concentration before and after concentration N- viscosity CE - Capillary Electrophoresis Red.- Reduction Conditions Non-red.- Non-reducing conditions The present invention discloses a stable pharmaceutical composition of an anti-TRBV9 antibody, which can be used as a medicament for treating a disease or disorder mediated by T lymphocytes carrying a TRBV9 segment in their T cell receptor.

[0043] In one aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one anti-TRBV9 antibody in combination with one or more pharma- ceutically acceptable excipients. In one aspect, the present invention relates to a pharmaceutical composition comprising an anti-TRBV9 antibody in combination with one or more pharma- ceutically acceptable excipients.

[0044] During the selection of the formulation, the purpose of the drug, the route of administration, and tolerability (e.g., reduced discomfort during administration), as well as maintenance of stability and activity of the protein molecule within the formulation were taken into consideration. In one aspect, the present invention relates to a pharmaceutical composition comprising: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) Water for injection.

[0045] The anti-TRBV9 antibody may be an antibody that specifically binds to the TRBV9 family beta chain. The anti-TRBV9 antibody may be a full-length antibody or an antigen-binding fragment thereof that specifically binds to the TRBV9 family beta chain. The anti-TRBV9 antibody may be of different specificity (e.g., monospecific, bispecific antibody), different valency (e.g., monovalent, bivalent, trivalent antibody), different format (e.g., classical antibody, scFv, scFv-Fc, minibody), different origin (e.g., mouse, human, camel, chimeric antibody).

[0046] In some embodiments of the present invention, the anti-TRBV9 antibodies relate to isolated monoclonal antibodies. In some embodiments of the present invention, the anti-TRBV9 antibodies relate to monospecific antibodies.

[0047] In some embodiments of the invention, the anti-TRBV9 antibody is a recombinant antibody. In some embodiments of the invention, the anti-TRBV9 antibody comprises: 1) a heavy chain variable domain comprising: (a) HCDR1 having the amino acid sequence of SEQ ID NO:1; (b) an HCDR2 having the amino acid sequence of SEQ ID NO:2, and (c) an HCDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6; 2) a light chain variable domain comprising: (a) LCDR1 having the amino acid sequence of SEQ ID NO: 7; (b) an LCDR2 having the amino acid sequence of SEQ ID NO:8, and (c) an LCDR3 having the amino acid sequence of SEQ ID NO:9.

[0048] Antibodies according to the invention can be of any class (e.g., IgA, IgD, IgE, IgG, and IgM) or subclass (isotype) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2).

[0049] In some embodiments of the invention, the anti-TRBV9 antibody is a full-length IgG antibody. In some embodiments of the invention, the anti-TRBV9 antibody is of the human IgG1, IgG2, IgG3, or IgG4 isotype.

[0050] In some embodiments of the present invention, the anti-TRBV9 antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO:14 and a light chain variable domain having the amino acid sequence of SEQ ID NO:17.

[0051] In some embodiments of the present invention, the anti-TRBV9 antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 22 and a light chain having the amino acid sequence of SEQ ID NO: 25 (Candidate 42 or Antibody 42).

[0052] In some embodiments of the present invention, the anti-TRBV9 antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO:15 and a light chain variable domain having the amino acid sequence of SEQ ID NO:17.

[0053] In some embodiments of the present invention, the anti-TRBV9 antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 23 and a light chain having the amino acid sequence of SEQ ID NO: 25 (Candidate 43 or Antibody 43).

[0054] The concentration of the anti-TRBV9 antibody contained in the pharmaceutical composition of the present invention can vary depending on the desired properties of the composition and the particular conditions, methods and intended uses of the pharmaceutical composition. In some embodiments of the present invention, the anti-TRBV9 antibody is present at a concentration of 0.5 to 300.0 mg / ml. In some embodiments of the present invention, the anti-TRBV9 antibody is present at a concentration of 0.5 to 280.0 mg / ml. In some embodiments of the present invention, the anti-TRBV9 antibody is present at a concentration of 0.5 to 250.0 mg / ml.

[0055] In some embodiments of the invention, the anti-TRBV9 antibody is present at a concentration of 0.5 to 225.0 mg / ml. In some embodiments of the invention, the anti-TRBV9 antibody is at a concentration of 1.5 to 190.0 mg / ml, or 200.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml; or 1.5 to 125.0 mg / ml, or 150.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml; or 1.5 to 125.0 mg / ml, or 180.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml; or 1.5 to 95 mg / ml, or 100 to 125.0 mg / ml, or 150.0 to 2 25.0mg / ml, or 240.0-300.0mg / ml; or 1.5-95mg / ml, or 100-125.0mg / ml, or 180.0-225.0mg / ml, or 240.0-300.0mg / ml; or 1.5-85mg / ml, or 90.0-125.0mg / ml, or 150.0-225.0mg / ml, or 240.0-300.0mg / ml; or 1.5-95mg / ml, or 100-125.0mg / ml, or 180.0-225.0mg / ml, or 240 .0-300.0mg / ml; or 1.5-75mg / ml, or 80.0-125.0mg / ml, or 150.0-225.0mg / ml, or 240.0-300.0mg / ml; or 1.5-75mg / ml, or 80.0-125.0mg / ml, or 180.0-225.0mg / ml, or 240.0-300.0mg / ml; or 1.5-50.0mg / ml, or 60.0-125.0mg / ml, or 150.0-225.0mg / ml, or 240.0-300.0mg / ml or present in a concentration of 1.5 to 50.0 mg / ml, or 60.0 to 125.0 mg / ml, or 180.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml; or 1.5 to 30.0 mg / ml, or 40.0 to 125.0 mg / ml, or 150.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml; or 1.5 to 30.0 mg / ml, or 40.0 to 125.0 mg / ml, or 180.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml.

[0056] In some embodiments of the invention, the anti-TRBV9 antibody is present at a concentration of 1.5 to 50.0 mg / ml, or 60.0 to 150.0 mg / ml, or 180.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml.

[0057] In some embodiments of the invention, the anti-TRBV9 antibody is present at a concentration of 1.5 to 35.0 mg / ml, or 40.0 to 60.0 mg / ml, or 70.0 to 125.0 mg / ml, or 180.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml.

[0058] In some embodiments of the invention, the anti-TRBV9 antibody is present at a concentration of 4.0 to 6.0 mg / ml, or 8.0 to 12.0 mg / ml, or 23.0 to 32.0 mg / ml, or 40.0 to 60.0 mg / ml, or 70.0 to 105.0 mg / ml, or 180.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml.

[0059] In some embodiments of the invention, the anti-TRBV9 antibody is present at a concentration of 4.0 to 6.0 mg / ml, or 8.0 to 12.0 mg / ml, or 23.0 to 32.0 mg / ml, or 50.0 to 105.0 mg / ml, or 180.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml.

[0060] In some embodiments of the invention, the anti-TRBV9 antibody is present at a concentration of 4.0 to 6.0 mg / ml, or 8.0 to 12.0 mg / ml, or 23.0 to 32.0 mg / ml, or 70.0 to 105.0 mg / ml, or 180.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml.

[0061] In some embodiments of the invention, the anti-TRBV9 antibody is present at a concentration of 1.5 mg / ml, or 5.0 mg / ml, or 10.0 mg / ml, or 25.0 mg / ml, or 30.0 mg / ml, or 40.0 mg / ml, or 50.0 mg / ml, or 60.0 mg / ml, or 70.0 mg / ml, or 73.0 mg / ml, or 80.0 mg / ml, or 85.0 mg / ml, or 90.0 mg / ml, or 91.4 mg / ml, or 91.8 mg / ml, or 100.0 mg / ml, or 103.0 mg / ml, or 125.0 mg / ml, or 186.0 mg / ml, or 212.0 mg / ml.

[0062] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine buffer; (iii) Water for injection.

[0063] In some embodiments of the invention, the histidine buffer is a mixture of histidine and histidine hydrochloride monohydrate. In some embodiments of the invention, histidine is present in a concentration of 0.4 to 14.11 mg / ml.

[0064] In some embodiments of the invention, histidine is present at a concentration of 0.4 to 11.0 mg / ml. In some embodiments of the invention, histidine is present at a concentration of 0.4 to 10.0 mg / ml.

[0065] In some embodiments of the invention, histidine is present at a concentration of 0.4 to 8.0 mg / ml. In some embodiments of the invention, histidine is present at a concentration of 0.4-5.0 mg / ml.

[0066] In some embodiments of the invention, histidine is present at a concentration of 0.4 to 3.0 mg / ml. In some embodiments of the invention, histidine is present at a concentration of 0.4 to 1.5 mg / ml.

[0067] In some embodiments of the invention, histidine is present at a concentration of 0.4-1.0 mg / ml. In some embodiments of the invention, histidine is present at a concentration of 0.4 to 0.8 mg / ml.

[0068] In some embodiments of the invention, histidine is present at a concentration of 0.45 to 0.8 mg / ml. In some embodiments of the invention, histidine is present at a concentration of 0.5-0.8 mg / ml.

[0069] In some embodiments of the invention, histidine is present at a concentration of 0.45-0.6 mg / ml, or 0.65-0.8 mg / ml. In some embodiments of the invention, histidine is present at a concentration of 0.5-0.6 mg / ml, or 0.65-0.8 mg / ml.

[0070] In some embodiments of the invention, histidine is present at a concentration of 0.517 mg / ml, or 0.580 mg / ml, or 0.689 mg / ml, or 0.746 mg / ml.

[0071] In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.05 to 19.06 mg / ml. In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.05 to 15.0 mg / ml.

[0072] In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.05 to 12.0 mg / ml. In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.05 to 10.0 mg / ml.

[0073] In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.05 to 8.0 mg / ml. In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.05 to 6.0 mg / ml.

[0074] In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.05 to 5.0 mg / ml. In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.05 to 4.5 mg / ml.

[0075] In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.08 to 4.2 mg / ml. In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.08 to 4.0 mg / ml.

[0076] In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.1-4.2 mg / ml. In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.1-4.0 mg / ml.

[0077] In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.1-3.5 mg / ml. In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.08-1.0 mg / ml or 2.0-4.2 mg / ml.

[0078] In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.08-0.15 mg / ml, or 0.2-0.4 mg / ml, or 2.2-4.2 mg / ml.

[0079] In some embodiments of the invention, histidine hydrochloride monohydrate is present in a concentration of 0.117 mg / ml, or 0.270 mg / ml, or 0.350 mg / ml, or 3.185 mg / ml.

[0080] In some embodiments of the invention, the histidine buffer is a mixture of the following: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml.

[0081] In some embodiments of the invention, the histidine buffer is a mixture of the following: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml.

[0082] In some embodiments of the invention, the histidine buffer is a mixture of the following: Histidine 0.746mg / ml and Histidine hydrochloride monohydrate 3.185mg / ml.

[0083] In some embodiments of the invention, the histidine buffer is a mixture of the following: Histidine 0.580mg / ml and Histidine hydrochloride monohydrate 0.270mg / ml.

[0084] In some embodiments of the invention, the histidine buffer is a mixture of the following: Histidine 0.689mg / ml and Histidine hydrochloride monohydrate 0.117mg / ml.

[0085] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) Water for injection: Make up to 1 ml.

[0086] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.746mg / ml and Histidine hydrochloride monohydrate 3.185mg / ml; (iii) Water for injection: Make up to 1 ml.

[0087] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.580mg / ml and Histidine hydrochloride monohydrate 0.270mg / ml; (iii) Water for injection: Make up to 1 ml.

[0088] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.689mg / ml and Histidine hydrochloride monohydrate 0.117mg / ml; (iii) Water for injection: Make up to 1 ml.

[0089] In some embodiments of the invention, the anti-TRBV9 antibody is present at a concentration of 0.5 to 300.0 mg / ml, or 1.5 to 225.0 mg / ml, or 5.0 to 125.0 mg / ml, or 5.0 to 100.0 mg / ml, 5.0 to 50.0 mg / ml, or 5.0 to 30.0 mg / ml.

[0090] In some embodiments of the invention, the anti-TRBV9 antibody is present at a concentration of 1.5 mg / ml, or 5.0 mg / ml, or 10.0 mg / ml, or 25.0 mg / ml, or 30.0 mg / ml, or 40.0 mg / ml, or 50.0 mg / ml, or 60.0 mg / ml, or 70.0 mg / ml, or 73.0 mg / ml, or 80.0 mg / ml, or 85.0 mg / ml, or 90.0 mg / ml, or 91.4 mg / ml, or 91.8 mg / ml, or 100.0 mg / ml, or 103.0 mg / ml, or 125.0 mg / ml, or 186.0 mg / ml, or 212.0 mg / ml, 225.0 mg / ml, or 300.0 mg / ml.

[0091] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) Water for injection: Make up to 1 ml.

[0092] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5~125.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) Water for injection: Make up to 1 ml.

[0093] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5~100.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) Water for injection: Make up to 1 ml.

[0094] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) Water for injection: Make up to 1 ml.

[0095] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) Water for injection: Make up to 1 ml.

[0096] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) Water for injection: Make up to 1 ml.

[0097] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 5~125.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) Water for injection: Make up to 1 ml.

[0098] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 5~100.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) Water for injection: Make up to 1 ml.

[0099] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) acetate buffer; (iii) Water for injection.

[0100] In some aspects of the invention, the acetate buffer is a mixture of sodium acetate and acetic acid. In some embodiments of the invention, sodium acetate is present in a concentration of 0.014 to 12.88 mg / ml.

[0101] In some embodiments of the invention, sodium acetate is present in a concentration of 0.014 to 8.0 mg / ml. In some embodiments of the invention, sodium acetate is present in a concentration of 0.5-3.0 mg / ml.

[0102] In some embodiments of the invention, sodium acetate is present in a concentration of 0.5-2.5 mg / ml. In some embodiments of the invention, sodium acetate is present in a concentration of 0.5-0.8 mg / ml, or 1.6-3.0 mg / ml.

[0103] In some embodiments of the invention, sodium acetate is present at a concentration of 0.644 mg / ml, or 2.311 mg / ml. In some aspects of the invention, the sodium acetate is sodium acetate trihydrate.

[0104] In some embodiments of the present invention, acetic acid is added to adjust the pH to 3.5 to 6.1. In some embodiments of the present invention, acetic acid is added to adjust the pH to 5.4 to 6.1. In some embodiments of the present invention, acetic acid is added to adjust the pH to 5.4 to 5.6, or to 5.9 to 6.1.

[0105] In some embodiments of the invention, acetic acid is added to bring the pH to 5.5 or to 6.0. In some aspects of the invention, the acetic acid is glacial acetic acid.

[0106] In some embodiments of the invention, the acetate buffer is a mixture of the following: Sodium acetate 0.5-3.0mg / ml and Acetic acid: Adjust pH to 5.4-6.1.

[0107] In some embodiments of the invention, the acetate buffer is a mixture of the following: Sodium acetate 0.5-2.5mg / ml and Acetic acid: Adjust pH to 5.4-6.1.

[0108] In some embodiments of the invention, the acetate buffer is a mixture of the following: Sodium acetate 0.644mg / ml and Acetic acid pH 6.0.

[0109] In some embodiments of the invention, the acetate buffer is a mixture of the following: Sodium acetate 2.311mg / ml and Acetic acid pH 5.5.

[0110] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) an acetate buffer which is a mixture of: Sodium acetate 0.644mg / ml and Acetic acid pH 6.0.

[0111] (iii) Water for injection: Make up to 1 ml. In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) an acetate buffer which is a mixture of: Sodium acetate 2.311mg / ml and Acetic acid pH 5.5.

[0112] (iii) Water for injection: Make up to 1 ml. In some embodiments of the invention, the anti-TRBV9 antibody is present at a concentration of 0.5 to 300.0 mg / ml, or 1.5 to 225.0 mg / ml, or 5.0 to 125.0 mg / ml, or 5.0 to 100.0 mg / ml, 5.0 to 50.0 mg / ml, or 5.0 to 30.0 mg / ml.

[0113] In some embodiments of the invention, the anti-TRBV9 antibody is present at a concentration of 1.5 mg / ml, or 5.0 mg / ml, or 10.0 mg / ml, or 25.0 mg / ml, or 30.0 mg / ml, or 40.0 mg / ml, or 50.0 mg / ml, or 60.0 mg / ml, or 70.0 mg / ml, or 73.0 mg / ml, or 80.0 mg / ml, or 85.0 mg / ml, or 90.0 mg / ml, or 91.4 mg / ml, or 91.8 mg / ml, or 100.0 mg / ml, or 103.0 mg / ml, or 125.0 mg / ml, or 186.0 mg / ml, or 212.0 mg / ml, 225.0 mg / ml, or 300.0 mg / ml.

[0114] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) an acetate buffer which is a mixture of: Sodium acetate 0.5-3.0mg / ml and Acetic acid to pH 5.4-6.1; (iii) Water for injection: Make up to 1 ml.

[0115] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~125.0mg / ml; (ii) an acetate buffer which is a mixture of: Sodium acetate 0.5-3.0mg / ml and Acetic acid to pH 5.4-6.1; (iii) Water for injection: Make up to 1 ml.

[0116] In some embodiments of the invention, the pharmaceutical composition comprises: (iv) Anti-TRBV9 antibody 0.5~100.0mg / ml; (v) An acetate buffer solution which is a mixture of: Sodium acetate 0.5-3.0mg / ml and Acetic acid to pH 5.4-6.1; (vi) Water for injection: Make up to 1 ml.

[0117] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) an acetate buffer which is a mixture of: Sodium acetate 0.5-3.0mg / ml and Acetic acid to pH 5.4-6.1; (iii) Water for injection: Make up to 1 ml.

[0118] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) an acetate buffer which is a mixture of: Sodium acetate 0.644mg / ml and Acetic acid to pH 6.0; (iii) Water for injection: Make up to 1 ml.

[0119] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) an acetate buffer which is a mixture of: Sodium acetate 2.311mg / ml and Acetic acid to pH 5.5; (iii) Water for injection: Make up to 1 ml.

[0120] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5~125.0mg / ml; (ii) an acetate buffer which is a mixture of: Sodium acetate 0.644mg / ml and Acetic acid to pH 6.0; (iii) Water for injection: Make up to 1 ml.

[0121] In some embodiments of the invention, the pharmaceutical composition comprises: (iv) Anti-TRBV9 antibody 5~100.0mg / ml; (v) An acetate buffer solution which is a mixture of: Sodium acetate 0.644mg / ml and Acetic acid to pH 6.0; (vi) Water for injection: Make up to 1 ml.

[0122] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5~125.0mg / ml; (ii) an acetate buffer which is a mixture of: Sodium acetate 2.311mg / ml and Acetic acid to pH 5.5; (iii) Water for injection: Make up to 1 ml.

[0123] In some embodiments of the invention, the pharmaceutical composition comprises: (iv) Anti-TRBV9 antibody 5~100.0mg / ml; (v) An acetate buffer solution which is a mixture of: Sodium acetate 2.311mg / ml and Acetic acid to pH 5.5; (vi) Water for injection: Make up to 1 ml.

[0124] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) an acetate buffer which is a mixture of: Sodium acetate 0.644mg / ml and Acetic acid to pH 6.0; (iii) Water for injection: Make up to 1 ml.

[0125] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) an acetate buffer which is a mixture of: Sodium acetate 2.311mg / ml and Acetic acid to pH 5.5; (iii) Water for injection: Make up to 1 ml.

[0126] In some embodiments of the present invention, the pharmaceutical composition further comprises one or more osmotic agents. In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) osmotic agents; (iv) Water for injection.

[0127] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) osmotic agents; (iv) Water for injection: Make up to 1 ml.

[0128] The osmotic agent may be present in enantiomer (e.g., L- or D-enantiomer) or racemic form; in isomeric form such as alpha or beta, for example, alpha, alpha, or beta, beta, or alpha, beta, or beta, alpha; in free acid or free base form; in salt form; in hydrated form (e.g., monohydrate or dihydrate) or anhydrous form. Exemplary osmotic agents are, but are not limited to, sugars (trehalose, trehalose dihydrate, sucrose, glucose), polyols (mannitol, sorbitol), amino acids (proline or L-proline, arginine or L-arginine, glycine or L-glycine), or salts (sodium chloride, potassium chloride, magnesium chloride).

[0129] In some embodiments of the invention, the osmotic agent is present in a concentration of 0.001 to 200.0 mg / ml. In some embodiments of the invention, the osmotic agent is present in a concentration of 0.001 to 180.0 mg / ml.

[0130] In some embodiments of the invention, the osmotic agent is present in a concentration of 0.001 to 150.0 mg / ml. In some embodiments of the invention, the osmotic agent is present in a concentration of 0.001 to 130.0 mg / ml.

[0131] In some embodiments of the invention, the osmotic agent is present in a concentration of 6.0 to 130.0 mg / ml. In some aspects of the invention, the osmotic agent is proline, sorbitol, trehalose, or sodium chloride.

[0132] In some embodiments of the invention, proline is present in a concentration of 0.001 to 60.0 mg / ml. In some embodiments of the invention, proline is present at a concentration of 14.0 to 32.0 mg / ml.

[0133] In some embodiments of the invention, proline is present at a concentration of 17.0 to 32.0 mg / ml. In some embodiments of the invention, proline is present at a concentration of 17.0-23.0 mg / ml or 25.0-29.0 mg / ml.

[0134] In some embodiments of the invention, proline is present at a concentration of 19.0 mg / ml, 21.0 mg / ml or 27.0 mg / ml. In some embodiments of the invention, sorbitol is present in a concentration of 0.001 to 100.0 mg / ml.

[0135] In some embodiments of the invention, sorbitol is present in a concentration of 20.0 to 80.0 mg / ml. In some embodiments of the invention, sorbitol is present in a concentration of 35.0 to 65.0 mg / ml.

[0136] In some embodiments of the invention, sorbitol is present in a concentration of 40.0 to 60.0 mg / ml. In some embodiments of the invention, sorbitol is present in a concentration of 45.0 to 55.0 mg / ml.

[0137] In some embodiments of the invention, sorbitol is present at a concentration of 50.0 mg / ml. In some embodiments of the invention, trehalose is present in a concentration of 0.001 to 200.0 mg / ml.

[0138] In some embodiments of the invention, trehalose is present in a concentration of 0.001 to 180.0 mg / ml. In some embodiments of the invention, trehalose is present in a concentration of 40.0 to 160.0 mg / ml.

[0139] In some embodiments of the invention, trehalose is present in a concentration of 60.0 to 140.0 mg / ml. In some embodiments of the invention, trehalose is present in a concentration of 70.0 to 130.0 mg / ml.

[0140] In some embodiments of the invention, trehalose is present at a concentration of 80.0 to 120.0 mg / ml. In some embodiments of the invention, trehalose is present at a concentration of 90.0 to 110.0 mg / ml.

[0141] In some embodiments of the invention, trehalose is present at a concentration of 100.0 mg / ml. In some embodiments of the invention, sodium chloride is present in a concentration of 0.001 to 18.0 mg / ml.

[0142] In some embodiments of the invention, sodium chloride is present in a concentration of 3.0 to 16.0 mg / ml. In some embodiments of the invention, sodium chloride is present in a concentration of 5.0 to 14.0 mg / ml.

[0143] In some embodiments of the invention, sodium chloride is present in a concentration of 7.0 to 12.0 mg / ml. In some embodiments of the invention, sodium chloride is present in a concentration of 7.0 to 11.0 mg / ml.

[0144] In some embodiments of the invention, sodium chloride is present in a concentration of 7.5 to 11.5 mg / ml. In some embodiments of the invention, sodium chloride is present in a concentration of 7.5 to 10.5 mg / ml.

[0145] In some embodiments of the invention, sodium chloride is present in a concentration of 8.0 to 10.0 mg / ml. In some embodiments of the invention, sodium chloride is present in a concentration of 8.5-9.5 mg / ml.

[0146] In some embodiments of the invention, sodium chloride is present at a concentration of 9.0 mg / ml. In some embodiments of the present invention, the pharmaceutical composition further comprises one or more stabilizers.

[0147] Stabilizers can be, for example, but are not limited to, amino acids such as arginine, histidine, glycine, lysine, glutamine, and proline; surfactants can be, for example, but are not limited to, polysorbate 20 (trade name: Tween 20), polysorbate 80 (trade name: Tween 80), polyethylene polypropylene glycol and its copolymers (trade names: Poloxamer, Pluronic (registered trademark), sodium dodecyl sulfate (SDS)); antioxidants can be, for example, but are not limited to, methionine, acetylcysteine, ascorbic acid, monothioglycerol, sulfites, and the like; chelating agents can be, for example, but are not limited to, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), sodium citrate, and the like.

[0148] In some embodiments of the invention, the stabilizer is present in a concentration of 0.001 to 100.0 mg / ml. In some embodiments of the invention, the stabilizer is present in a concentration of 0.001 to 50.0 mg / ml.

[0149] In some embodiments of the invention, the stabilizer is present in a concentration of 0.001 to 30.0 mg / ml. In some embodiments of the invention, the stabilizer is present in a concentration of 0.35 to 9.5 mg / ml.

[0150] In some aspects of the invention, the stabilizer is an amino acid or a surfactant. In some embodiments of the invention, the amino acid is present at a concentration of 0.001 to 100.0 mg / ml.

[0151] In some embodiments of the invention, the amino acid is present at a concentration of 0.001 to 50.0 mg / ml. In some embodiments of the invention, the amino acid is present at a concentration of 0.001 to 30.0 mg / ml.

[0152] In some embodiments of the invention, the amino acid is present at a concentration of 0.35 to 9.5 mg / ml. In some embodiments of the invention, the amino acid is present in a concentration of 1.1 to 9.5 mg / ml.

[0153] In some aspects of the invention, the amino acid is glycine or methionine. In some embodiments of the invention, glycine is present in a concentration of 0.001 to 100.0 mg / ml.

[0154] In some embodiments of the invention, glycine is present in a concentration of 0.001 to 80.0 mg / ml. In some embodiments of the invention, glycine is present in a concentration of 0.001 to 60.0 mg / ml.

[0155] In some embodiments of the invention, glycine is present in a concentration of 0.001 to 40.0 mg / ml. In some embodiments of the invention, glycine is present in a concentration of 0.001 to 20.0 mg / ml.

[0156] In some embodiments of the invention, glycine is present in a concentration of 0.001 to 15.0 mg / ml. In some embodiments of the invention, glycine is present in a concentration of 3.0 to 12.0 mg / ml.

[0157] In some embodiments of the invention, glycine is present in a concentration of 5.5 to 9.5 mg / ml. In some embodiments of the invention, glycine is present at a concentration of 6.0-9.0 mg / ml.

[0158] In some embodiments of the invention, glycine is present in a concentration of 6.5-8.5 mg / ml. In some embodiments of the invention, glycine is present at a concentration of 7.0-8.0 mg / ml.

[0159] In some embodiments of the invention, glycine is present at a concentration of 7.51 mg / ml. In some embodiments of the invention, methionine is present in a concentration of 0.001 to 5.8 mg / ml.

[0160] In some embodiments of the invention, methionine is present in a concentration of 1.1 to 5.8 mg / ml. In some embodiments of the invention, methionine is present at a concentration of 1.1-1.9 mg / ml or 3.2-5.8 mg / ml.

[0161] In some embodiments of the invention, methionine is present at a concentration of 1.49 mg / ml or 4.48 mg / ml. In some embodiments of the invention, the surfactant is present in a concentration of 0.001 to 6.0 mg / ml.

[0162] In some embodiments of the invention, the surfactant is present in a concentration of 0.001 to 4.0 mg / ml. In some embodiments of the invention, the surfactant is present in a concentration of 0.001 to 3.0 mg / ml.

[0163] In some embodiments of the invention, the surfactant is present in a concentration of 0.1 to 2.0 mg / ml. In some embodiments of the invention, the surfactant is present in a concentration of 0.35 to 1.3 mg / ml.

[0164] In some embodiments of the invention, the surfactant is poloxamer 188 or polysorbate 80 or polypropylene glycol. In some embodiments of the invention, poloxamer 188 is present in a concentration of 0.001 to 6.0 mg / ml.

[0165] In some embodiments of the invention, poloxamer 188 is present in a concentration of 0.001 to 4.0 mg / ml. In some embodiments of the invention, poloxamer 188 is present in a concentration of 0.001 to 2.5 mg / ml.

[0166] In some embodiments of the invention, poloxamer 188 is present in a concentration of 0.35 to 1.3 mg / ml. In some embodiments of the invention, poloxamer 188 is present in a concentration of 0.35-0.65 mg / ml or 0.7-1.3 mg / ml.

[0167] In some embodiments of the invention, poloxamer 188 is present in a concentration of 0.35-0.65 mg / ml or 0.8-1.2 mg / ml. In some embodiments of the invention, poloxamer 188 is present at a concentration of 0.5 mg / ml or 1.0 mg / ml.

[0168] In some embodiments of the invention, polysorbate 80 is present in a concentration of 0.001 to 5.0 mg / ml. In some embodiments of the invention, polysorbate 80 is present in a concentration of 0.001 to 3.5 mg / ml.

[0169] In some embodiments of the invention, polysorbate 80 is present in a concentration of 0.001 to 2.5 mg / ml. In some embodiments of the invention, polysorbate 80 is present in a concentration of 0.7-1.3 mg / ml.

[0170] In some embodiments of the invention, polysorbate 80 is present in a concentration of 0.8-1.2 mg / ml. In some embodiments of the invention, polysorbate 80 is present at a concentration of 1.0 mg / ml.

[0171] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) osmotic agent 0.001-200.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0172] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) osmotic agent 0.001-130.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0173] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) osmotic agent 0.001-200.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0174] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) osmotic agent 0.001-130.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0175] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) osmotic agents; (iv) stabilizers; (v) Water for injection.

[0176] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) osmotic agents; (iv) stabilizers; (v) Water for injection: Make up to 1 ml.

[0177] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) osmotic agents; (iv) stabilizer; 0.001 to 100.0 mg / ml; (v) Water for injection: Make up to 1 ml.

[0178] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) osmotic agents; (iv) stabilizer; 0.35-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0179] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) Osmotic agent; 0.001-130.0 mg / ml; (iv) stabilizer; 0.35-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0180] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) osmotic agent 0.001-200.0 mg / ml; (iv) stabilizer; 0.35-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0181] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) osmotic agent 0.001-130.0 mg / ml; (iv) stabilizer; 0.35-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0182] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) Histidine or acetate buffer (iii) an osmotic agent which is proline; (iv) Water for injection: Make up to 1 ml.

[0183] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) Histidine or acetate buffer (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0184] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) Histidine or acetate buffer (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0185] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0186] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0187] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5~125.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0188] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5~100.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0189] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) Histidine or acetate buffer (iii) an osmotic agent which is proline, 27 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0190] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) Histidine or acetate buffer (iii) an osmotic agent which is proline, 27 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0191] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is proline, 27 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0192] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is proline, 27 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0193] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25mg / ml; (ii) Histidine or acetate buffer (iii) an osmotic agent which is proline, 27 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0194] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is proline, 27 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0195] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) Histidine or acetate buffer (iii) an osmotic agent which is proline, 19 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0196] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) Histidine or acetate buffer (iii) an osmotic agent which is proline, 19 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0197] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 25.0mg / ml; (ii) Histidine or acetate buffer (iii) an osmotic agent which is proline, 19 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0198] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.689mg / ml and Histidine hydrochloride monohydrate 0.117mg / ml.

[0199] (iii) an osmotic agent which is proline, 19 mg / ml; (iv) Water for injection: Make up to 1 ml. In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.689mg / ml and Histidine hydrochloride monohydrate 0.117mg / ml.

[0200] (iii) an osmotic agent which is proline, 19 mg / ml; (iv) Water for injection: Make up to 1 ml. In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.689mg / ml and Histidine hydrochloride monohydrate 0.117mg / ml.

[0201] (iii) an osmotic agent which is proline, 19 mg / ml; (iv) Water for injection: Make up to 1 ml. In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline; (iv) a stabilizer which is glycine; (v) Water for injection.

[0202] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent that is proline (iv) a stabilizer which is glycine; 0.001 to 100.0 mg / ml; (v) Water for injection: Make up to 1 ml.

[0203] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent that is proline (iv) a stabilizer which is glycine; 5.5-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0204] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is glycine; 5.5-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0205] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is glycine, 5.5-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0206] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~125.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is glycine, 5.5-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0207] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~100.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is glycine, 5.5-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0208] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is glycine, 5.5-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0209] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is glycine, 5.5-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0210] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5~125.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is glycine, 5.5-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0211] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5~100.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is glycine, 5.5-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0212] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is glycine, 5.5-9.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0213] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline, 21 mg / ml; (iv) a stabilizer which is glycine, 7.51 mg / ml; (v) Water for injection: Make up to 1 ml.

[0214] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline, 21 mg / ml; (iv) a stabilizer which is glycine, 7.51 mg / ml; (v) Water for injection: Make up to 1 ml.

[0215] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is proline, 21 mg / ml; (iv) a stabilizer which is glycine, 7.51 mg / ml; (v) Water for injection: Make up to 1 ml.

[0216] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is proline, 21 mg / ml; (iv) a stabilizer which is glycine, 7.51 mg / ml; (v) Water for injection: Make up to 1 ml.

[0217] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is proline, 21 mg / ml; (iv) a stabilizer which is glycine, 7.51 mg / ml; (v) Water for injection: Make up to 1 ml.

[0218] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline; (iv) a stabilizer which is poloxamer 188; (v) Water for injection.

[0219] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent that is proline (iv) a stabilizer which is poloxamer 188, 0.35-1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0220] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 0.35-1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0221] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 0.35-1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0222] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 0.35-1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0223] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 0.35-1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0224] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5.0~125.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 0.35-1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0225] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5.0~100.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is proline, 14.0-32.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 0.35-1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0226] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline, 9.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 0.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0227] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is proline, 9.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 0.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0228] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is proline, 9.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 0.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0229] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is proline, 9.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 0.5 mg / ml; (v) Water for injection: Make up to 1 ml.

[0230] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is proline, 9.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 1.0 mg / ml; (v) Water for injection: Make up to 1 ml.

[0231] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is proline, 9.0 mg / ml; (iv) a stabilizer which is poloxamer 188, 1.0 mg / ml; (v) Water for injection: Make up to 1 ml.

[0232] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sorbitol (iv) Water for injection.

[0233] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sorbitol, 35.0-65.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0234] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sorbitol, 35.0-65.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0235] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is sorbitol, 35.0-65.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0236] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sorbitol, 50.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0237] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sorbitol, 50.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0238] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) sorbitol, osmolality 50.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0239] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sorbitol, 50.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0240] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sorbitol (iv) a stabilizer which is methionine; 1.1-5.8 mg / ml; (v) Water for injection: Make up to 1 ml.

[0241] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sorbitol; 35.0-65.0 mg / ml; (iv) a stabilizer which is methionine; 1.1-5.8 mg / ml; (v) Water for injection: Make up to 1 ml.

[0242] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sorbitol, 35.0-65.0 mg / ml; (iv) a stabilizer which is methionine; 1.1-5.8 mg / ml; (v) Water for injection: Make up to 1 ml.

[0243] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is sorbitol, 35.0-65.0 mg / ml; (iv) a stabilizer which is methionine; 1.1-5.8 mg / ml; (v) Water for injection: Make up to 1 ml.

[0244] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sorbitol, 50.0 mg / ml; (iv) a stabilizer which is methionine; 1.49 mg / ml; (v) Water for injection: Make up to 1 ml.

[0245] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.05~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sorbitol, 50.0 mg / ml; (iv) a stabilizer which is methionine; 1.49 mg / ml; (v) Water for injection: Make up to 1 ml.

[0246] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sorbitol, 50.0 mg / ml; (iv) a stabilizer which is methionine; 1.49 mg / ml; (v) Water for injection: Make up to 1 ml.

[0247] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sorbitol, 50.0 mg / ml; (iv) a stabilizer which is methionine; 4.48 mg / ml; (v) Water for injection: Make up to 1 ml.

[0248] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sorbitol, 50.0 mg / ml; (iv) a stabilizer which is methionine; 4.48 mg / ml; (v) Water for injection: Make up to 1 ml.

[0249] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sorbitol, 50.0 mg / ml; (iv) a stabilizer which is methionine; 4.48 mg / ml; (v) Water for injection: Make up to 1 ml.

[0250] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is trehalose; (iv) Water for injection.

[0251] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent, which is trehalose, 0.001-200.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0252] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is trehalose, 70-130.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0253] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is trehalose, 70-130.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0254] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is trehalose, 70-130.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0255] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is trehalose, 70-130.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0256] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5.0~125.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is trehalose, 70-130.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0257] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5.0~100.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is trehalose, 70-130.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0258] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is trehalose, 100.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0259] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is trehalose, 100.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0260] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is trehalose, 100.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0261] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sodium chloride; (iv) Water for injection.

[0262] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sodium chloride, 6.0-11.5 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0263] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sodium chloride, 6.0-11.5 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0264] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is sodium chloride, 6.0-11.5 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0265] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is sodium chloride, 6.0-11.5 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0266] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5~125.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is sodium chloride, 6.0-11.5 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0267] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5~100.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is sodium chloride, 6.0-11.5 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0268] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sodium chloride, 9.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0269] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5.0~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sodium chloride, 9.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0270] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sodium chloride, 9.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

[0271] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sodium chloride; (iv) a stabilizer which is poloxamer 188 or polysorbate 80; (v) Water for injection.

[0272] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sodium chloride, 6.0-11.5 mg / ml; (iv) a stabilizer which is poloxamer 188 or polysorbate 80, 0.35 to 1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0273] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; 0.5~300.0mg / ml; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sodium chloride, 6.0-11.5 mg / ml; (iv) a stabilizer which is poloxamer 188 or polysorbate 80, 0.35 to 1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0274] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is sodium chloride, 6.0-11.5 mg / ml; (iv) a stabilizer which is poloxamer 188 or polysorbate 80, 0.35 to 1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0275] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is sodium chloride, 6.0-11.5 mg / ml; (iv) a stabilizer which is poloxamer 188 or polysorbate 80, 0.35 to 1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0276] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 5.0~100.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0mg / ml and Histidine hydrochloride monohydrate 0.08-4.2mg / ml; (iii) an osmotic agent which is sodium chloride, 6.0-11.5 mg / ml; (iv) a stabilizer which is poloxamer 188 or polysorbate 80, 0.35 to 1.3 mg / ml; (v) Water for injection: Make up to 1 ml.

[0277] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sodium chloride, 9.0 mg / ml; (iv) 1.0 mg / ml of a stabilizer which is poloxamer 188 or polysorbate 80; (v) Water for injection: Make up to 1 ml.

[0278] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 0.5~300.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sodium chloride, 9.0 mg / ml; (iv) a stabilizer which is poloxamer 188 or polysorbate 80, 1.0 mg / ml; (v) Water for injection: Make up to 1 ml.

[0279] In some embodiments of the invention, the pharmaceutical composition comprises: (i) Anti-TRBV9 antibody 25.0mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml and Histidine hydrochloride monohydrate 0.350mg / ml; (iii) an osmotic agent which is sodium chloride, 9.0 mg / ml; (iv) a stabilizer which is poloxamer 188 or polysorbate 80, 1.0 mg / ml; (v) Water for injection: Make up to 1 ml.

[0280] In one aspect, the present invention relates to a pharmaceutical composition comprising an anti-TRBV9 antibody and at least one other therapeutically active compound for treating a disease or disorder mediated by T lymphocytes carrying a TRBV9 segment in their T cell receptor in a subject in need of treatment for the disease or disorder.

[0281] In some embodiments, the therapeutically active compound is an antibody, a chemotherapeutic agent, or an anti-hormonal agent. In one aspect, the present invention relates to pharmaceutical compositions of anti-TRBV9 antibodies provided in dry (i.e., powder or granule) form for reconstitution with a suitable solvent (e.g., water) prior to administration. Such formulations can be prepared, for example, by lyophilization, a process known in the art as freeze-drying, which involves freezing the product and then removing the solvent from the frozen material.

[0282] In one aspect, the present invention relates to a pharmaceutical composition of an anti-TRBV9 antibody prepared by lyophilizing any of the above pharmaceutical compositions of an anti-TRBV9 antibody. Thus, the pharmaceutical composition of the present invention can be either an aqueous pharmaceutical composition or a lyophilized pharmaceutical composition (lyophilisate).

[0283] Lyophilisates are used to prepare other dosage forms, such as lyophilisates for preparing solutions for injection, lyophilisates for preparing concentrates for preparing solutions for injection. Lyophilisates are reconstituted by dissolving in a suitable solvent, most typically water for injection. Lyophilisates are also reconstituted first with the required amount of solvent, most typically water, and then further diluted with a suitable solvent, such as 5% glucose solution, 0.9% sodium chloride solution.

[0284] The pharmaceutical composition according to the present invention is suitable for parenteral administration, typically as a sterile preparation intended for administration to the human body by injection, infusion and implantation, bypassing the gastrointestinal tract and through a breach in the skin or mucous membrane barrier.In particular, parenteral administration is intended to include, among others, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, ​​intracranial, intrasynovial, transdermal injection or infusion, and kidney dialysis infusion techniques.Preferred embodiments include intravenous and subcutaneous routes.Any method for administering peptides or proteins that is accepted in the art can be suitably used for the composition of anti-TRBV9 antibodies according to the present invention.

[0285] In some embodiments of the invention, the pharmaceutical composition of the anti-TRBV9 antibody according to the invention is intended for parenteral administration. In some embodiments of the invention, the pharmaceutical composition of the anti-TRBV9 antibody according to the invention is intended for intramuscular, intravenous or subcutaneous administration.

[0286] In some embodiments of the present invention, the pharmaceutical composition of the anti-TRBV9 antibody according to the present invention can be administered intravenously as an infusion. The pharmaceutical composition of the anti-TRBV9 antibody of the present invention can be used after dilution. For this purpose, the required amount of the composition is transferred from the vial into an injection container containing a sterile 0.9% sodium chloride solution or a sterile 5% dextrose solution. The resulting solution is stirred by gently inverting the injection container.

[0287] The pharmaceutical compositions of the present invention can be stored in any suitable container, such as a glass or plastic container, a vial, an ampoule, a syringe, a cartridge, or a bottle of the desired volume. The container may be equipped with additional administration means, such as a dropper, an auto-injector, etc.

[0288] The pharmaceutical composition according to the present invention can be manufactured, packaged or widely sold in the form of a ready-to-use preparation in the form of a single unit dose or a plurality of single unit doses.The term "single unit dose" as used herein refers to a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient.The amount of active ingredient is typically equal to the dose of active ingredient that will be administered to a subject, or a convenient fraction of such dose, for example, half or one third of such dose.

[0289] In one aspect, the present invention relates to the use of the above-mentioned pharmaceutical composition of an anti-TRBV9 antibody for treating a disease or disorder mediated by T lymphocytes having a TRBV9 segment in their T cell receptor in a subject in need of treatment for the disease or disorder.

[0290] The therapeutically effective amount of the pharmaceutical composition of the anti-TRBV9 antibody according to the present invention depends on the subject's condition, the severity of the condition, previous treatment, and the patient's medical history and response to the therapeutic agent. The appropriate dose can be adjusted according to the judgment of the attending physician and can be administered to the patient in one or several injections.

[0291] In some aspects of the invention, the subject or patient to be treated is a mammal, preferably a human subject, said subject being of any age, either male or female. In some embodiments of the present invention, the disease or disorder mediated by T lymphocytes having a TRBV9 segment in their T cell receptor is selected from the group including arthropathy, inflammatory bowel disease, eye disease, vasculitis, cardiovascular disease, kidney disease, digestive disease, and lymphoproliferative disorders.

[0292] In some embodiments of the present invention, the disease or disorder mediated by T lymphocytes having a TRBV9 segment in their T cell receptor is Arthropathy, especially spondyloarthritis (radiographic axial spondyloarthritis (ankylosing spondylitis), axial spondyloarthritis, peripheral spondyloarthritis, psoriatic arthritis, spondyloarthritis associated with inflammatory bowel disease, reactive arthritis, peripheral spondyloarthritis unclassifiable), sacroiliitis associated with psoriasis, sacroiliitis associated with inflammatory bowel disease, oligoarthropathy unclassifiable, juvenile spondylitis / enthesitis-associated arthritis, juvenile ankylosing spondylitis (enthesitis-associated arthritis), juvenile arthritis, juvenile arthritis unclassifiable; Inflammatory bowel disease, especially ulcerative colitis and Crohn's disease; Eye diseases, especially non-infectious uveitis and anterior uveitis; Vasculitis, especially Behçet's disease; Cardiovascular diseases, in particular aortitis, fibrosis of the aortic and / or mitral valves with regurgitation, rhythm disorders, conduction disorders, left ventricular dysfunction, pericarditis, myocarditis; Kidney disease, especially IgA nephropathy; Digestive disorders, especially celiac disease; Lymphoproliferative disorders, especially T-cell lymphoma and T-cell leukemia The compound is selected from the group consisting of:

[0293] In some embodiments of the invention, the disease or disorder mediated by T lymphocytes having a TRBV9 segment in the T cell receptor is selected from the group comprising spondyloarthritis, sacroiliitis associated with psoriasis, sacroiliitis associated with inflammatory bowel disease, unclassified oligoarthropathy, juvenile spondylitis / enthesitis-associated arthritis, juvenile ankylosing spondylitis (enthesitis-associated arthritis), juvenile arthritis, unclassified juvenile arthritis, ulcerative colitis, Crohn's disease, non-infectious uveitis, anterior uveitis, Behcet's disease, aortitis, fibrosis of the aortic and / or mitral valve with regurgitation, rhythm disorders, conduction disorders, left ventricular dysfunction, pericarditis, myocarditis, IgA nephropathy, celiac disease, T cell lymphoma, T cell leukemia.

[0294] In some embodiments of the invention, the spondyloarthritis is radiographic axial spondyloarthritis (ankylosing spondylitis), axial spondyloarthritis, peripheral spondyloarthritis, psoriatic arthritis, spondyloarthritis associated with inflammatory bowel disease, reactive arthritis, unclassified peripheral spondyloarthritis.

[0295] The pharmaceutical composition can be administered as a single therapeutic agent or in combination with additional therapeutic agents as required.Thus, in one embodiment, the present method for treatment and / or prevention is used in combination with the administration of a therapeutically effective amount of another active agent.The other active agent can be administered before, during, or after the administration of the pharmaceutical composition according to the present invention.The other active agent can be administered as part of the composition of the present invention or as a separate formulation. Implementation of the Invention The following examples are provided for a better understanding of the present invention. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any manner.

[0296] All publications, patents, and patent applications cited herein are incorporated herein by reference. Although the foregoing invention has been described in detail by way of illustration and example for clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of the invention that certain changes and modifications can be made thereto without departing from the spirit or scope of the accompanying embodiments.

[0297] Method : 1. Preparation of monoclonal antibody samples against TRBV9. Antibody samples with concentrations between 5 and 50 mg / ml were prepared in stirred cells (Millipore) under pressure. For this purpose, the initial antibody formulation was placed in the cell and concentrated to the desired protein concentration under a compressed air stream with continuous stirring, after which at least 10-fold volumes of an aqueous solution containing the target formulation, including buffers, osmotic agents, and, if necessary, additional water-soluble stabilizers, were added stepwise to the cell. After diafiltration, the concentration was continued to a concentration above the target concentration, which was removed from the cell and the exact protein concentration was measured by UV spectroscopy. The corresponding concentrates of excipient solutions and concentrates of surfactants were then added to the sample to generate a solution with the target protein concentration.

[0298] Protein samples with concentrations of 20 mg / ml or higher were prepared in a Pellicon cassette (Millipore) in tangential flow mode. For this purpose, the initial antibody formulation was placed in a diafiltration tank and the protein was concentrated to the desired concentration, i.e. at least 10 times the volume of the solution containing the target formulation with buffer, and additional water-soluble stabilizers were fed into the system if necessary. After diafiltration, the concentration was continued to a concentration above the target concentration, which was removed from the system and the exact protein concentration was measured.

[0299] When obtaining a formulation containing a solubilizing agent such as Poloxamer 188, a detergent concentrate was added to the antibody after diafiltration and concentration, and the antibody was finally diluted to the target concentration with excipient solution. During aseptic filling into the final container (eg, sterile glass / plastic container, vial, or syringe), the antibody solution was filtered using a 0.22 μm sterile membrane. 2. Determining Protein Concentration in Test Samples Protein concentrations were measured by UV spectrophotometry at a wavelength of 280 nm on a UV spectrophotometer plate. Each sample was diluted with the appropriate excipient solution to a concentration of approximately 0.5 mg / ml. 150 μl of the diluted sample was placed in a well of a UV spectrophotometer plate. The optical density of the solution in the plate well was measured at a wavelength of 280 nm using a plate spectrophotometer. The appropriate excipient solution was used as a reference solution.

[0300] The protein (C) concentration (mg / ml) was calculated using the following formula:

[0301]

number

[0302] where A280 is the value of the optical density at a wavelength of 280 nm; ε is the extinction coefficient of the test protein; b is the total dilution factor of the sample; 1 is the layer thickness in the plate well (cm), which is 0.56 cm for a standard 200 μl 96-well plate. For a 175 μl half-area plate, the layer thickness in the plate well is 1 cm. For a 150 μl full-size plate, the layer thickness in the plate well is 0.42 cm. 3. Determination of protein aggregation temperature by dynamic light scattering.

[0303] The aggregation points of the test proteins (concentrations 1-5 mg / ml) were determined using a DynaPro plate reader II. For this purpose, 35 μl of the solution was placed in the wells of a black polymer plate with an optically transparent bottom, which was gradually heated in the instrument while the scattered light intensity was continuously measured.

[0304] Measurement Settings: ·Initial measurement temperature - 25℃. · Scattered light intensity at θ = 158°. Number of measurements per replicate – 3. Time per measurement – ​​5 seconds. ·Heating rate - 0.15℃ / min. ·Final temperature - 80℃.

[0305] Temperature trends and aggregation points were determined using Dynamics V7 software. 4. Determination of protein melting temperature by differential scanning fluorimetry. Sypro Orange fluorescent stain was added to the protein samples. Samples were analyzed in real-time mode on a CFX96 C1000 Touch thermal cycler amplifier. Heating was from 25 to 85 °C and the detection channel was ROX. The CFX Manager (Bio-Rad) software was used to process the results. 5. Determining the Hydrodynamic Radius of Particles in Solution by Dynamic Light Scattering For analysis, 35 μl of each concentration sample was placed into wells of a black polymer plate with an optically clear bottom. The analysis was performed using a DynaPro plate reader II instrument. Each well was analyzed 10 times. The resulting data was processed with Dynamics V7 software. 6. Diffusion interaction parameter (k D ) Determination Protein solutions were generated by serial dilution ranging from 30 mg / ml down to 0.94 mg / ml. Appropriate excipient solutions were used as solvents. For the analysis, 35 μl of each concentration sample was placed in the wells of a black polymer plate with an optically transparent bottom. The analysis was carried out using a DynaPro plate reader II instrument. Each well was analyzed 10 times. The data obtained were processed with Dynamics V7 software to plot the dependence of the diffusion coefficient on the protein concentration in solution and to determine the linear slope of the resulting dependence. 7. Determination of thermal stability under 50°C heat stress (TS50).

[0306] The test samples were divided into two aliquots of 150 μl each and placed in separate glass vials: one vial per composition was stored in the refrigerator at 5±3° C., and the remaining vial was placed in a thermostat and incubated for 96 or 120 hours at 50° C. At the time of selecting the control points or after heating, the vials were removed from the thermostat and kept at room temperature for approximately 15 minutes before being transferred for analysis. 8. Determination of colloidal stability under shaking (SH800).

[0307] The test samples were divided into two aliquots of 150 μl each and placed in glass vials, one vial per formulation was stored in a refrigerator at 5±3° C. and the remaining vial was placed in a thermal shaker and shaken at 800 rpm for 96 or 120 hours at 5±3° C. During control point selection or after stress, the vials were removed from the thermal shaker and transferred for analysis. 9. Determination of colloidal stability under freeze-thaw (FT(-20)).

[0308] The test samples were divided into two aliquots and placed in plastic vials: one vial per formulation was stored in the refrigerator at 5±3°C and the remaining vial was stored in the freezer at minus (20±2)°C until completely frozen. The vials were then removed from the freezer and kept at room temperature until the contents were completely thawed; the solution was mixed using a vortex and placed back in the freezer. This was repeated as many times as necessary. After stress, the vials were removed from the freezer and kept at room temperature until the contents were completely thawed; the solution was mixed using a vortex and transferred for analysis. 10. Determination of stability under acid hydrolysis (Acid).

[0309] The test samples were divided into two aliquots and placed in polymeric vials: one vial per formulation was stored in a refrigerator at 5 ± 3 °C (the input control could be transferred for analysis once for all studies at the beginning of storage). The pH of the remaining vial was adjusted to 4.0 ± 0.1 or 3.0 ± 0.1 with hydrochloric acid solution under stirring and then transferred to a refrigerator at 5 ± 3 °C for storage. After 1 h or 24 h, sodium hydroxide solution was added to the initial pH value with stirring to stop the hydrolysis. The solutions were then transferred for analysis. 11. Determination of stability under base hydrolysis (Basic).

[0310] The test samples were divided into two aliquots and placed in polymeric vials: one vial per formulation was stored in a refrigerator at 5±3° C. (the input control could be transferred for analysis once for all studies at the beginning of storage), and the pH of the remaining vial was adjusted to 9.0±0.1 with sodium hydroxide solution under stirring, then transferred to the refrigerator and stored at 5±3° C. After 1 or 24 hours, hydrolysis was stopped by adding hydrochloric acid solution to the initial pH value under stirring. The solutions were then transferred for analysis. 12. Accelerated storage.

[0311] The test samples were divided into separate aliquots (one aliquot for input control - possible to transfer for analysis once for all studies at the beginning of storage) and placed in separate sterile glass vials: one part of the vial of each formulation was placed in the refrigerator and stored at 5±3°C (input control); the remaining vials were placed in a thermostat and incubated at 25±2°C for 6 months, with control points being selected periodically according to the plan. At the time of selection of the control points and after storage, the vials were removed from the thermostat and transferred for analysis. 13. Determination of sample purity by size exclusion high performance liquid chromatography (SE HPLC).

[0312] Column: Tosoh TSK-Gel G3000SWXL 7.8mm ID x 30cm, 5μm. Precolumn: TSK-Gel Guard SW XL , 6.0mm ID×4.0cm, 7μm, 300Å. Column temperature: 25°C. Mobile phase flow rate: 0.5ml / min Injection volume: 25 μl. Sample concentration: 0.5mg / ml. Detector wavelengths 214 and 360 nm. Elution time: 30 min. Mobile phase: anhydrous disodium hydrogen phosphate 14.196 mg / ml. Sodium chloride 11.688 mg / ml. The mobile phase pH was adjusted to 6.9 with orthophosphoric acid. 14. Evaluation of Charge Variant Profiles in Capillaries on the Caliper LabChip GX II Instrument The analysis was carried out according to the instructions of the HT Protein Charge Variant Kit. Test samples were adjusted to a protein concentration of 1 mg / ml by dilution or concentration (depending on the initial concentration of the sample) with a 0.5 ml Amicon Ultra 10 kDa centrifugal filter (Millipore). Protein content was then measured by UV spectrophotometry at a wavelength of 280 nm.

[0313] To each of the resulting samples, 2 μl of carboxypeptidase solution was added and the samples were incubated for 2 hours at a temperature of 37±2° C. After the indicated time, the samples were dialyzed against water in Amicon Ultra centrifuge tubes and concentrated to 2 mg / ml.

[0314] A 96-well plate was filled with the labeling buffer solution, the dye mixture solution, and 25 μl of the test sample in the amounts specified in the instructions, the plate was placed in the dark for 10 minutes, and then each well was filled with 60 μl of water and mixed.

[0315] The plate containing the solutions was centrifuged using a plate centrifuge rotor and placed in the Caliper LabChip GX II instrument. Special chips filled with running buffer solutions at pH according to the manufacturer's instructions were used for analysis. Results were processed using the LabChip GX software. 15. Determination of charge variant profile by ion exchange high performance liquid chromatography (IE HPLC).

[0316] Column: ProPac WCX-10, 4 x 250 mm, particle size: 10 μm Precolumn: ProPac WCX-10G, 4 x 50mm, particle size: 10μm Eluent A: 28.8 mM sodium dihydrogen phosphate solution, pH = 6.5 Eluent B: 28.8 mM sodium dihydrogen phosphate solution, 250 mM sodium chloride solution, pH = 6.5 Flow rate: 0.7ml / min. Column temperature: 30°C Autosampler temperature: 4℃ Detector: UV, 280 nm, Bandwidth: 16 nm Reference wavelength: 360nm, bandwidth 100nm Sample volume: 40 μl, needle wash mode Chromatography time: 60 min.

[0317] The test samples were diluted to a concentration of 1.0 mg / ml and treated with carboxypeptidase B in a ratio of 100:2.8; the resulting solution was stirred and incubated at a temperature of 37±2° C. for 2 hours. Elution Mode:

[0318] [Table 1]

[0319] 16. Determination of purity and related impurities by capillary gel electrophoresis in the presence of sodium dodecyl sulfate (CE reducing and non-reducing conditions). Test samples were diluted to a concentration of 4.0 mg / ml. 25 μl of the resulting solution was placed in a 1.5 ml microtube; to this was added 70 μl of SDS-MW sample buffer, 2 μl of internal standard with a molecular weight of 10 kDa, 5 μl of 0.5 M iodoacetamide solution (for CE non-reducing conditions), or 5 μl of 2-mercaptoethanol (for CE reducing conditions). The resulting solution was vortexed for 15 seconds, centrifuged at 2800 rpm for 5 seconds, and placed in a solid-state thermostat at 65° C. for 4 minutes (CE non-reducing conditions) or 70° C. for 10 minutes (CE reducing conditions). The solution was cooled to room temperature.

[0320] The SDS MW Separation-PA 800 plus.met analytical method was used in the 32Karat software. Capillary gel electrophoresis conditions: Capillary: 50μm×30.2cm Effective length of capillary: 20.0 cm Polarity: Reverse, inlet on the left (-), outlet on the right (+) Capillary temperature: 25℃ Analysis time and separation voltage: 35 min, 15 kV Detection wavelength: 220nm. 17. Determination of sample purity on Caliper Labchip GXII instrument under non-reducing conditions. Preparation of samples for analysis.

[0321] The reconstitution solution was prepared using 700 μl of HT Protein Express sample buffer. The alkylating agent (24.5 μl of 1 M iodoacetamide (IAM)) was added to the buffer.

[0322] 35 μl of reconstitution buffer was added to the microtube. Samples were diluted to a concentration of 2 mg / ml. 5 μl of sample was added to the tube. Samples were denatured at 100° C. for 5 minutes. The tube was mixed using a vortex, then 70 μl of water was added and the tube was mixed using a vortex. 44 μl of each sample was transferred to a well of a 96-well plate.

[0323] Preparation of working solutions and chips was done according to the manufacturer's protocol using the HT Protein Express Reagent kit. Initiation of analysis was done according to standard procedures. Analysis method: HT Protein Express 200. 18. Determining the acid-base profile of a sample by capillary zone electrophoresis 50-100 μl of the test sample was placed in an Amicon Ultra type centrifugal ultrafilter (0.5 ml, 10 kDa, UFC501096, Millipore Ltd.), 400 μl of purified water was added, and ultrafiltration was performed for 10 minutes using a centrifuge at 10000 rpm and a temperature of 10°C. The ultrafiltration procedure was carried out three times, each time adding 400-450 μl of water to each retentate of the centrifugal ultrafilter. After ultrafiltration, the retentate was transferred to a 0.5 ml microtube.

[0324] The protein content of the resulting solution was determined spectrophotometrically. The 32Karat software was started and the instrument with the UV or PDA detector was selected. For the UV detector, a filter with a wavelength of 214 nm was selected. Analysis conditions: Isolation voltage: 30kV Polarity: Positive (inlet on the left (+), outlet on the right (-)) Capillary temperature in cartridge: 25℃ Temperature inside the sample tray: 10℃ Detection wavelength: 214nm Data transfer rate: 4Hz Analysis time: 15 minutes A quartz capillary with an inner diameter of 50 μm and a length of 30.2 cm (effective length of 20 cm) was prepared. The capillary was attached to a cartridge with an opening of 200 × 100 μm. The following solutions were introduced into a plastic vial with a volume of 1.5 ml: - 1.5ml of 0.1M HCl solution; - 1.5ml of separation buffer; - 1.5ml of purified water; - Purified wastewater 1.0ml.

[0325] The “CZE conditioning-PA800 plus ABP.met” analysis method was selected in the 32Karat software. 19. Measurement of sample viscosity by viscometry Test samples of 350-400 μl volume were collected with a microVISC pipette, a viscosity measurement pipette. The pipette was attached to a RheoSence microVISC viscometer. Viscosity was measured at 25.0°C in automatic mode (AUTO) using the viscometer thermostat. 20.Measure pH.

[0326] Test samples with a volume of 200–300 μl were transferred to microtubes and pH was measured on a Mettler Toledo SevenEasy instrument using a Mettler Toledo InLabUltraMicro electrode. 21. Determination of stability under oxidation.

[0327] Test samples were divided into two aliquots of 150 μl each and placed in separate glass vials: one vial per formulation was stored in a refrigerator at 5 ± 3 °С, to the remaining samples hydrogen peroxide was added to a final hydrogen peroxide concentration in the samples of 0.1% and the samples were aged for 4 h at (5 ± 3) °C. Oxidation was stopped by adding an equal volume of L-methionine. 22. Processing of results.

[0328] The absolute change in quality index when stressed was calculated using the following formula: Δ = (value after stress - value before stress) The absolute change in the charge variant profile was calculated by the following formula: = |Acid fraction content before stress - Acid fraction content after stress| +|Basic fraction content before stress -Basic fraction content after stress| +|Predominant fraction content before stress -Dominant fraction content after stress | 23. Preparation of infusion solutions.

[0329] Solutions were prepared by diluting the test formulation with 0.9% NaCl solution to a protein concentration of 0.5 mg / ml. EXAMPLES

[0330] The following example is provided for an anti-TRBV9 antibody that comprises the following heavy chain variable domains: (a) HCDR1 having the amino acid sequence of SEQ ID NO:1; (b) an HCDR2 having the amino acid sequence of SEQ ID NO:2, and (c) an HCDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6; 1) a light chain variable domain comprising: (a) LCDR1 having the amino acid sequence of SEQ ID NO: 7; (b) an LCDR2 having the amino acid sequence of SEQ ID NO:8, and (c) an LCDR3 having the amino acid sequence of SEQ ID NO:9.

[0331] In particular, the following examples are provided for an anti-TRBV9 antibody comprising a heavy chain variable domain having the amino acid sequence of SEQ ID NO:14 and a light chain variable domain having the amino acid sequence of SEQ ID NO:17.

[0332] In particular, the following examples are shown for an anti-TRBV9 antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 22 and a light chain having the amino acid sequence of SEQ ID NO: 25 (Candidate 42 or Antibody 42).

[0333] Example 1. Selection of the nature of the buffer system. The buffers selected for use in this study are suitable for pharmaceutical use and are excipients used in therapeutic protein-based formulations. Four typical buffer systems suitable for parenteral administration were selected as the basis for the pharmaceutical composition: acetate, citrate, histidine, and phosphate buffer systems. To facilitate the comparison of the stabilizing properties of buffer solutions of different nature, the pH and concentration of the solutions were reduced to 5.5 and 20 mM, respectively.

[0334] To evaluate the suitability of the buffer system, the influence of the buffer properties on the colloidal and conformational stability of the protein was studied. To assess the influence, the aggregation temperature, melting point, diffusion interaction parameters, concentrating ability, purity after thermal stress and changes in acid-base profile were determined.

[0335] Table 1 shows the formulation of the test buffer solution.

[0336] [Table 2]

[0337] Research into stability prediction indicators. The diffusion interaction parameter (k D ) reflects the diffusion coefficient of a sample as a function of the concentration of the molecule. If the diffusion coefficient decreases as the concentration increases (k D<0), the polydispersity of a given solution increases and larger particles are formed. Such samples have low solubility and tend to aggregate, so the use of the formulation is not recommended.

[0338] The aggregation temperature and melting point allow the aggregation tendency of a protein to be assessed. The most stable samples are those where particle aggregation begins at higher temperatures and smaller particles are formed under heating.

[0339] The results of the studies of aggregation temperature by method 3, melting point by method 4, diffusion interaction parameter by method 6, and viscosity by method 19 are shown in Table 2.

[0340] [Table 3]

[0341] Determination of thermal stability. Thermal stability was assessed by method 7. Before and after heat stress, purity was determined by SE HPLC by method 13, purity was determined by electrophoresis under non-reducing conditions by method 17, charge variant profile was determined by Labchip by method 14, and hydrodynamic radius was determined by method 5. Absolute changes in charge variant profile were calculated by method 22. Results are shown in Table 3.

[0342] [Table 4]

[0343] Acetate buffer-based formulations have been shown to provide conformational stability (high melting point), colloidal stability (high aggregation temperature by DLS, k D >0, high protein concentration after direct concentration, low viscosity of the solution at a protein concentration of 160 mg / ml, low aggregate content after heat stress followed by SE HPLC), and showed good stabilization properties in terms of chemical stability (satisfactory changes in isoform profile after heat stress).

[0344] The histidine buffer-based formulations showed superior colloidal stability: D >0, high concentration value upon direct concentration, low solution viscosity at a protein concentration of 160 mg / ml. Example 2. Selection of pH / concentration of buffer solution In this study, two typical buffer systems suitable for parenteral administration, namely acetate buffer system and histidine buffer system, were selected as the basis for the pharmaceutical composition. The study was carried out in a complete two-factorial experimental design with two levels and a center point. The pH level (5.0-6.0 for acetate buffer solution and 5.5-6.5 for histidine buffer solution) and the concentration of the buffer (5-50 mM) were studied as quantitative factors.

[0345] To evaluate the suitability of the buffer system, the effect of the buffer solution properties on the colloidal and conformational stability of the protein was studied. The aggregation temperature, melting point, diffusion interaction parameters, changes in purity and acid-base profile after thermal stress, as well as the concentration capacity were determined as responses. The tested formulations are shown in Table 4.

[0346] [Table 5-1]

[0347] [Table 5-2]

[0348] Research into stability prediction indicators. The determinations of the aggregation temperature by method 3, the melting point by method 4, the diffusion interaction parameter by method 6, and the concentration capacity by method 1 are shown in Table 5.

[0349] [Table 6]

[0350] Determination of thermal stability. Thermal stability was assessed by Method 7. Before and after heat stress, purity was determined by SE HPLC by Method 13, purity was determined by electrophoresis under non-reducing conditions by Method 17, charge variant profile was determined in a capillary by Method 14, hydrodynamic radius was determined by Method 5, and absolute change in charge variant profile was determined by Method 22. The results are shown in Table 6.

[0351] [Table 7]

[0352] Acetate buffer-based pharmaceutical compositions showed excellent conformational stability, high melting points. Furthermore, these formulations showed low aggregation temperatures and k D These formulations were characterized by high charge variant values, a slight increase in impurities (tracked by SE HPLC and LabChip), and no change in hydrodynamic radius under thermal stress. Moreover, these formulations showed the ability to stabilize the charge variant profile.

[0353] The histidine buffer system formulations showed excellent conformational stability: the test proteins in the given buffers had high melting points, colloidal stability, aggregation temperatures and k D Higher values ​​indicate improved stability under concentration and diafiltration and a lower tendency to aggregate. These formulations show high concentration values ​​under direct concentration and control results show only minor changes in protein quality under heat stress (followed by SE HPLC and Labchip under non-reducing conditions). These formulations also demonstrate excellent stabilization of the acid-base profile.

[0354] Example 3. Selection of osmotic agents. In this study, a histidine buffer system is employed as the basis for the pharmaceutical composition. Excipients suitable for parenteral administration were investigated for use as osmotic agents. The amount of osmotic agent that provides an osmotic pressure close to that of the physiological medium of an organism was calculated by the following formula:

[0355]

number

[0356] In the formula, C osm is the osmolality of the solution, in milliosmoles per liter (mOsm / l); m is the content of the substance in the solution, g / l; M is the molar mass of the substance, g; n is the total number of ions produced from one solute molecule as a result of dissociation (n=1 for substances that do not dissociate, n=2, 3 for substances that produce the respective number of ions upon dissolution).

[0357] To evaluate the suitability of the buffer system, the effect of the buffer solution properties on the colloidal and conformational stability of the protein was studied. The responses were determined as aggregation temperature, melting point, diffusion interaction parameters, purity and acid-base profile changes after thermal stress, acid hydrolysis, and shaking; and the concentrating ability was evaluated. The formulations tested are shown in Table 7.

[0358] [Table 8]

[0359] Research into stability prediction indicators. The determinations of the aggregation temperature by method 3, the melting point by method 4, the diffusion interaction parameter by method 6, and the concentration capacity by method 1 are shown in Table 8.

[0360] [Table 9]

[0361] Determination of thermal stability. Thermal stability was assessed by Method 7. Before and after heat stress, purity was determined by SE HPLC by Method 13, purity by electrophoresis under non-reducing conditions by Method 17, charge variant profile in capillary by Method 14, and hydrodynamic radius by Method 5; absolute change in charge variant profile was calculated by Method 22. Results are shown in Table 9.

[0362] [Table 10]

[0363] Determination of stability under acid hydrolysis. Stability under acid hydrolysis was evaluated by Method 10. Before and after hydrolysis, purity was determined by SE HPLC by Method 13, purity by electrophoresis under non-reducing conditions by Method 17, charge variant profile in capillary by Method 14, hydrodynamic radius by Method 5, and absolute change in charge variant profile was calculated by Method 22. The results are shown in Table 10.

[0364] [Table 11]

[0365] Determination of stability under shaking. Stability under shaking was assessed by Method 8. Before and after shaking, purity was determined by SE HPLC by Method 13, purity by electrophoresis under non-reducing conditions by Method 17, charge variant profile in capillary by Method 14, hydrodynamic radius by Method 5, and absolute change in charge variant profile was calculated by Method 22. The results are shown in Table 11.

[0366] [Table 12]

[0367] A given formulation may have a high melting point, a high aggregation temperature, and an acceptable k D values ​​were shown. The given formulation shows high concentration values ​​when directly concentrated and according to the control results there is a slight change in the protein quality under heat stress and shaking (control by SE HPLC). Furthermore, the given formulation shows insignificant values ​​of absolute change in acid-base profile under shaking and acid hydrolysis.

[0368] Example 4. Selection of osmotic agents with added stabilizers This study employs a histidine buffer system as the basis for the pharmaceutical composition. Excipients suitable for parenteral administration listed in Table 12 were investigated for use as stabilizers.

[0369] To ensure the physiological osmolality of the composition, the content of the osmotic agent was reduced, taking into account the contribution of the stabilizer to the osmolality of the solution. As part of the study, the effect of the resulting formulations on the colloidal and conformational stability of the protein was evaluated: the aggregation temperature, melting point, diffusion interaction parameters, changes in purity and acid-base profile after thermal stress, shaking, acid hydrolysis, several freeze-thaw cycles were determined as responses.

[0370] [Table 13-1]

[0371] [Table 13-2]

[0372] Research into stability prediction indicators. Melting points were determined by Method 4 and aggregation points were determined by Method 3. Diffusion interaction parameters were determined by Method 6. Samples were concentrated according to Method 1. Viscosity was measured according to Method 19. Results are shown in Table 13.

[0373] [Table 14]

[0374] Determination of thermal stability. Thermal stability was assessed by Method 7. Before and after thermal stress, purity was determined by SE HPLC by Method 13, charge variant profile in capillary by Method 14, and hydrodynamic radius by Method 5; absolute change in charge variant profile was calculated by Method 22. Results are shown in Table 14.

[0375] [Table 15-1]

[0376] [Table 15-2]

[0377] Determination of stability under acid hydrolysis. Stability under acid hydrolysis was evaluated by Method 10. Before and after hydrolysis, purity was determined by SE HPLC by Method 13, charge variant profile in capillary by Method 14, and hydrodynamic radius by Method 5; absolute change in charge variant profile was calculated by Method 22. Results are shown in Table 15.

[0378] [Table 16-1]

[0379] [Table 16-2]

[0380] Determination of stability under shaking Stability under shaking was assessed by Method 8. Before and after shaking, purity was determined by SE HPLC by Method 13, charge variant profile in capillary by Method 14, and hydrodynamic radius by Method 5; absolute change in charge variant profile was calculated by Method 22. Results are shown in Table 16.

[0381] [Table 17-1]

[0382] [Table 17-2]

[0383] Determination of freeze-thaw stability Stability under freeze-thaw was determined only for formulations containing proline. Stability under freeze-thaw was assessed by Method 9. Purity was determined before and after freeze-thaw by SE HPLC by Method 13, charge variant profile in capillary by Method 14, and hydrodynamic radius by Method 5; absolute change in charge variant profile was calculated by Method 22. Results are shown in Table 17.

[0384] [Table 18]

[0385] The given formulation showed excellent results in terms of colloidal and chemical stability: under thermal stress, slight changes in monomer content and charge variant profile were evident (SE HPLC, Labchip). Furthermore, the given composition exhibited high melting and aggregation temperatures, which indicates high protein stability under thermal stress. The given formulation also has a high concentration capacity.

[0386] Example 5. Determination of important quantitative factors of formulation and formulation optimization This study employs a histidine buffer system as the basis for the pharmaceutical composition. The study was carried out with a fractional 3-factor experiment design containing two levels. Protein concentration (10-50), pH (5.7-6.9), and osmotic agent concentration (19-35) were studied as quantitative factors.

[0387] As part of the study, the effect of test factors on the colloidal and conformational stability of the protein was evaluated. The responses determined were aggregation temperature, melting point, diffusion interaction parameters, changes in purity and acid-base profile after heat stress, shaking, acid and alkaline hydrolysis, several freeze-thaw cycles, oxidation.

[0388] The test formulations are shown in Table 18. Table 19 shows the formulations of 5 mM histidine buffers at various pHs involved in the experiment.

[0389] [Table 19]

[0390] [Table 20]

[0391] Research into stability prediction indicators. The melting point and onset of denaturation were determined by Method 4, and the aggregation point was determined by Method 3. The diffusion interaction parameters were determined by Method 6, and the pH was determined by Method 20. The results are shown in Table 20.

[0392] [Table 21]

[0393] Determination of thermal stability. Thermal stability was assessed by Method 7. Purity was determined before and after heat stress by SE HPLC by Method 13, purity by CE under non-reducing conditions by Method 16, charge variant profile by Method 18, and hydrodynamic radius by Method 5; absolute change in charge variant profile was calculated by Method 22. Results are shown in Table 21.

[0394] [Table 22]

[0395] Determination of stability under shaking. Stability under shaking was assessed by Method 8. Before and after shaking, purity was determined by SE HPLC by Method 13, purity by electrophoresis under non-reducing conditions by Method 16, charge variant profile in capillary by Method 18, hydrodynamic radius by Method 5, and absolute change in charge variant profile was calculated by Method 22. The results are shown in Table 22.

[0396] [Table 23]

[0397] Determination of stability under base hydrolysis. Stability under base hydrolysis was assessed by Method 11. Before and after hydrolysis, purity was determined by SE HPLC by Method 13, purity by electrophoresis under non-reducing conditions by Method 18, charge variant profile in capillary by Method 14, hydrodynamic radius by Method 5, and absolute change in charge variant profile was calculated by Method 22. The results are shown in Table 23.

[0398] [Table 24]

[0399] Determination of stability under acid hydrolysis. Stability under acid hydrolysis was assessed by Method 10. Before and after hydrolysis, purity was determined by SE HPLC by Method 13, purity by electrophoresis under non-reducing conditions by Method 16, charge variant profile in capillary by Method 18, hydrodynamic radius by Method 5, and absolute change in charge variant profile was calculated by Method 22. The results are shown in Table 24.

[0400] [Table 25]

[0401] Determination of stability under freeze-thaw conditions. Stability under freeze-thaw was assessed by Method 9. Purity was determined by SE HPLC by Method 13, charge variant profile in capillary by Method 18, and hydrodynamic radius by Method 5, before and after five freeze-thaw cycles; absolute change in charge variant profile was calculated by Method 22. Results are shown in Table 25.

[0402] [Table 26]

[0403] Determination of stability under oxidation. Stability under oxidation was assessed by Method 21. Before and after oxidation, purity was determined by SE HPLC by Method 13, purity by electrophoresis under non-reducing conditions by Method 16, charge variant profile in capillary by Method 18, hydrodynamic radius by Method 5, and absolute change in charge variant profile was calculated by Method 22. Results are shown in Table 26.

[0404] [Table 27]

[0405] The given formulations showed excellent values ​​of melting point, aggregation temperature, hydrodynamic radius and diffusion interaction parameter values, which indicates high stability under thermal and other types of stress. The given formulations also showed a positive effect on colloidal and chemical stability: oxidation, base and acid hydrolysis, as well as little change in monomer content under freeze-thaw (SE HPLC, CE non-reduced).

[0406] Example 6. Selection of additional osmotic agents and stabilizers In this study, a histidine buffer system (5 mM histidine buffer, pH 6.3) is employed as the basis for the pharmaceutical composition. Excipients suitable for parenteral administration were investigated for use as stabilizers and surfactants.

[0407] As part of the study, the effect of each of the tested osmotic agents, stabilizers, and surfactants on the colloidal and conformational stability of the protein was evaluated. The responses determined were the aggregation temperature, melting point, diffusion interaction parameters, changes in purity and acid-base profile after thermal stress, shaking, several freeze-thaw cycles. Additionally, the hydrodynamic radius and purity (SE HPLC) were evaluated in the infusion solution of a given formulation before and after storage at 2-8°C for 24 hours.

[0408] The test formulations are shown in Table 27.

[0409] [Table 28-1]

[0410] [Table 28-2]

[0411] Research into stability prediction indicators. Formulations containing surfactants were not subjected to heat-related tests such as determination of onset temperature of denaturation and melting point, aggregation temperature due to the decomposition of the surfactant under heat and the resulting uninterpretable results. Also, these formulations were not subjected to direct concentration because micelle formation by the surfactant may affect the concentration process.

[0412] The determinations of aggregation temperature by method 3, denaturation onset temperature and melting point by method 4, diffusion interaction parameters by method 6, and direct concentration by method 1 are shown in Table 28.

[0413] [Table 29]

[0414] Determination of thermal stability. Thermal stability was also not studied for surfactant formulations due to their degradation under heat. Thermal stability was assessed by Method 7. Purity was determined before and after thermal stress by SE HPLC by Method 13, charge variant profile by Method 15, and hydrodynamic radius by Method 5; absolute change in charge variant profile was calculated by Method 22. Results are shown in Table 29.

[0415] [Table 30]

[0416] Determination of stability under shaking. Stability under shaking was assessed by Method 8. Before and after shaking, purity was determined by SE HPLC by Method 13, charge variant profile by Method 15, and hydrodynamic radius by Method 5; absolute change in charge variant profile was calculated by Method 22. Results are shown in Table 30.

[0417] [Table 31]

[0418] Determination of stability under freeze-thaw conditions. Stability under freeze-thaw was assessed by Method 9. Purity was determined by SE HPLC by Method 13, charge variant profile by Method 15, and hydrodynamic radius by Method 5 before and after five freeze-thaw cycles; absolute change in charge variant profile was calculated by Method 22. Results are shown in Table 31.

[0419] [Table 32]

[0420] Determination of the stability of the infusion solution of the obtained formulation. Injection solutions were prepared according to Method 23. Before and after storage of the injection solutions, purity was determined by SE HPLC by Method 13, and hydrodynamic radius was determined by Method 5. The results are shown in Table 32.

[0421] [Table 33]

[0422] The given formulations showed high denaturation onset temperature and melting point, as well as aggregation temperature and diffusion interaction parameters, indicating enhanced thermal stability. The given formulations showed excellent colloidal stability under shaking, freeze-thawing, and dilution with injection solutions; the given formulations also showed little change in monomer content by SE HPLC and excellent stability of charge variant profile by IE HPLC under all types of stress.

[0423] Example 7. Confirmation of stability under accelerated aging In this study, a histidine buffer system (5 mM histidine buffer, pH 6.3) was employed as the basis for the pharmaceutical composition, and proline was used as the osmotic agent. As part of the study, the effect of adding a surfactant at two different concentrations, 0.5 and 1.0 mg / ml, was studied, and a sample without surfactant was used as the reference sample. Changes in concentration, pH, purity, and acid-base profile were determined before and after stress. The test formulations are shown in Table 33.

[0424] [Table 34]

[0425] Determination of stability during accelerated storage. Accelerated stability was assessed by Method 12. Before and after stress, protein content was determined by Method 2, pH by Method 20, purity by SE HPLC by Method 13, and charge variant profile in a capillary by Method 14. The results of the study are shown in Tables 34-36.

[0426] [Table 35]

[0427] [Table 36]

[0428] [Table 37]

[0429] The given formulation showed excellent colloidal stability in accelerated storage stability studies (T=37° C.), high monomer content by SE HPLC and stable charge variant profile by IE HPLC.

Claims

1. A pharmaceutical composition of an anti-TRBV9 antibody, comprising: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) Water for injection 23. A pharmaceutical composition comprising:

2. The anti-TRBV9 antibody, 1) a heavy chain variable domain comprising: (a) HCDR1 having the amino acid sequence of SEQ ID NO:1; (b) an HCDR2 having the amino acid sequence of SEQ ID NO:2; and (c) an HCDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6; 2) a light chain variable domain comprising: (a) an LCDR1 having the amino acid sequence of SEQ ID NO:7; (b) an LCDR2 having the amino acid sequence of SEQ ID NO:8; and (c) an LCDR3 having the amino acid sequence of SEQ ID NO:

9. The pharmaceutical composition of claim 1 , comprising:

3. The pharmaceutical composition of claim 1 , wherein the anti-TRBV9 antibody is a full-length IgG antibody.

4. 2. The pharmaceutical composition of claim 1, wherein the anti-TRBV9 antibody is of the human IgG1, IgG2, IgG3, or IgG4 isotype.

5. the anti-TRBV9 antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 14 and a light chain variable domain having the amino acid sequence of SEQ ID NO: 17; or A heavy chain variable domain having the amino acid sequence of SEQ ID NO: 15 and a light chain variable domain having the amino acid sequence of SEQ ID NO:

17. The pharmaceutical composition of claim 1.

6. the anti-TRBV9 antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:22 and a light chain having the amino acid sequence of SEQ ID NO:25; or A heavy chain having the amino acid sequence of SEQ ID NO:23 and a light chain having the amino acid sequence of SEQ ID NO:

25. The pharmaceutical composition of claim 1.

7. 2. The pharmaceutical composition of claim 1, wherein the anti-TRBV9 antibody is present at a concentration of 0.5 to 300.0 mg / ml.

8. 2. The pharmaceutical composition of claim 1, wherein the anti-TRBV9 antibody is present at a concentration of 0.5 to 225.0 mg / ml.

9. 2. The pharmaceutical composition of claim 1, wherein the anti-TRBV9 antibody is present at a concentration of 1.5 to 50.0 mg / ml, or 60.0 to 150.0 mg / ml, or 180.0 to 225.0 mg / ml, or 240.0 to 300.0 mg / ml.

10. 2. The pharmaceutical composition of claim 1, wherein the anti-TRBV9 antibody is present at a concentration of 1.5-35.0 mg / ml, or 70.0-125.0 mg / ml, or 180.0-225.0 mg / ml, or 240.0-300.0 mg / ml.

11. 2. The pharmaceutical composition of claim 1, wherein the anti-TRBV9 antibody is present at a concentration of 4.0-6.0 mg / ml, or 8.0-12.0 mg / ml, or 23.0-32.0 mg / ml, or 50.0-105.0 mg / ml, or 180.0-225.0 mg / ml, or 240.0-300.0 mg / ml.

12. 2. The pharmaceutical composition of claim 1, wherein the anti-TRBV9 antibody is present at a concentration of 1.5 mg / ml, or 5.0 mg / ml, or 10.0 mg / ml, or 25.0 mg / ml, or 30.0 mg / ml, or 50.0 mg / ml, or 60.0 mg / ml, or 70.0 mg / ml, or 73.0 mg / ml, or 80.0 mg / ml, or 85.0 mg / ml, or 90.0 mg / ml, or 91.4 mg / ml, or 91.8 mg / ml, or 100.0 mg / ml, or 103.0 mg / ml, or 125.0 mg / ml, or 186.0 mg / ml, or 212.0 mg / ml.

13. 2. The pharmaceutical composition of claim 1, wherein the histidine buffer is a mixture of histidine and histidine hydrochloride monohydrate.

14. 14. The pharmaceutical composition of claim 13, wherein histidine is present in a concentration of 0.4 to 14.11 mg / ml.

15. histidine is present at a concentration of 0.4 to 11.0 mg / ml; or histidine is present at a concentration of 0.4 to 10.0 mg / ml; or histidine is present at a concentration of 0.4 to 8.0 mg / ml; or histidine is present at a concentration of 0.4 to 5.0 mg / ml; or histidine is present at a concentration of 0.4 to 3.0 mg / ml; or histidine is present at a concentration of 0.4 to 1.5 mg / ml; or histidine is present at a concentration of 0.4 to 1.0 mg / ml; or Histidine is present at a concentration of 0.4-0.8 mg / ml; The pharmaceutical composition of claim 13.

16. 14. The pharmaceutical composition of claim 13, wherein histidine is present in a concentration of 0.45 to 0.6 mg / ml, or 0.65 to 0.8 mg / ml.

17. 14. The pharmaceutical composition of claim 13, wherein histidine is present in a concentration of 0.517 mg / ml, or 0.580 mg / ml, or 0.689 mg / ml, or 0.746 mg / ml.

18. 14. The pharmaceutical composition of claim 13, wherein the histidine hydrochloride monohydrate is present in a concentration of 0.05 to 19.06 mg / ml.

19. histidine hydrochloride monohydrate is present in a concentration of 0.05 to 15.0 mg / ml; or histidine hydrochloride monohydrate is present in a concentration of 0.05 to 12.0 mg / ml; or histidine hydrochloride monohydrate is present in a concentration of 0.05 to 10.0 mg / ml; or histidine hydrochloride monohydrate is present in a concentration of 0.05 to 8.0 mg / ml; or histidine hydrochloride monohydrate is present in a concentration of 0.05 to 6.0 mg / ml; or histidine hydrochloride monohydrate is present in a concentration of 0.05 to 5.0 mg / ml; or histidine hydrochloride monohydrate is present in a concentration of 0.05 to 4.5 mg / ml; or Histidine hydrochloride monohydrate is present in a concentration of 0.08 to 4.2 mg / ml; The pharmaceutical composition of claim 13.

20. 14. The pharmaceutical composition of claim 13, wherein histidine hydrochloride monohydrate is present in a concentration of 0.08 to 1.0 mg / ml or 2.0 to 4.2 mg / ml.

21. 14. The pharmaceutical composition of claim 13, wherein histidine hydrochloride monohydrate is present in a concentration of 0.08 to 0.15 mg / ml, or 0.2 to 0.4 mg / ml, or 2.2 to 4.2 mg / ml.

22. 14. The pharmaceutical composition of claim 13, wherein histidine hydrochloride monohydrate is present in a concentration of 0.117 mg / ml, or 0.270 mg / ml, or 0.350 mg / ml, or 3.185 mg / ml.

23. 2. The pharmaceutical composition of claim 1, wherein the acetate buffer is a mixture of sodium acetate and acetic acid.

24. 24. The pharmaceutical composition of claim 23, wherein sodium acetate is present in a concentration of 0.014 to 12.88 mg / ml.

25. Sodium acetate is present in a concentration of 0.014 to 8.0 mg / ml; or 24. The pharmaceutical composition of claim 23, wherein the sodium acetate is present in a concentration of 0.5 to 3.0 mg / ml.

26. 24. The pharmaceutical composition of claim 23, wherein sodium acetate is present in a concentration of 0.5 to 0.8 mg / ml, or 1.6 to 3.0 mg / ml.

27. 24. The pharmaceutical composition of claim 23, wherein sodium acetate is present in a concentration of 0.644 mg / ml or 2.311 mg / ml.

28. 24. The pharmaceutical composition of claim 23, wherein the sodium acetate is sodium acetate trihydrate.

29. The pharmaceutical composition according to claim 23, wherein the pH is adjusted to 3.5 to 6.1 by adding acetic acid.

30. The pharmaceutical composition according to claim 23, wherein the pH is adjusted to 5.4 to 5.6, or to 5.9 to 6.1 by adding acetic acid.

31. 24. The pharmaceutical composition of claim 23, wherein the pH is adjusted to 5.5 or to 6.0 by adding acetic acid.

32. 24. The pharmaceutical composition of claim 23, wherein the acetic acid is glacial acetic acid.

33. 10. The pharmaceutical composition of claim 1, further comprising one or more osmotic agents.

34. the osmotic agent is present in a concentration of 0.001 to 200.0 mg / ml; or The osmotic agent is present in a concentration of 0.001 to 130.0 mg / ml.

34. The pharmaceutical composition of claim 33.

35. 34. The pharmaceutical composition of claim 33, wherein the osmotic agent is proline, sorbitol, trehalose or sodium chloride.

36. 36. The pharmaceutical composition of claim 35, wherein proline is present in a concentration of 0.001 to 60.0 mg / ml.

37. 36. The pharmaceutical composition of claim 35, wherein proline is present in a concentration of 14.0 to 32.0 mg / ml.

38. 36. The pharmaceutical composition of claim 35, wherein proline is present in a concentration of 17.0 to 23.0 mg / ml or 25.0 to 29.0 mg / ml.

39. 36. The pharmaceutical composition of claim 35, wherein proline is present at a concentration of 19.0 mg / ml, 21.0 mg / ml or 27.0 mg / ml.

40. 36. The pharmaceutical composition of claim 35, wherein sorbitol is present in a concentration of 0.001 to 100.0 mg / ml.

41. Sorbitol is present in a concentration of 20.0 to 80.0 mg / ml; or Sorbitol is present in a concentration of 35.0 to 65.0 mg / ml; 36. The pharmaceutical composition of claim 35.

42. 36. The pharmaceutical composition of claim 35, wherein sorbitol is present in a concentration of 50.0 mg / ml.

43. 36. The pharmaceutical composition of claim 35, wherein trehalose is present in a concentration of 0.001 to 200.0 mg / ml.

44. trehalose is present in a concentration of 0.001 to 180.0 mg / ml; or trehalose is present in a concentration of 40.0 to 160.0 mg / ml; or trehalose is present in a concentration of 60.0 to 140.0 mg / ml; or trehalose is present at a concentration of 70.0 to 130.0 mg / ml; 36. The pharmaceutical composition of claim 35.

45. 36. The pharmaceutical composition of claim 35, wherein trehalose is present at a concentration of 100.0 mg / ml.

46. 36. The pharmaceutical composition of claim 35, wherein sodium chloride is present in a concentration of 0.001 to 18.0 mg / ml.

47. Sodium chloride is present in a concentration of 3.0 to 16.0 mg / ml; or Sodium chloride is present in a concentration of 5.0 to 14.0 mg / ml; or Sodium chloride is present in a concentration of 7.0 to 12.0 mg / ml; or Sodium chloride is present in a concentration of 7.5 to 11.5 mg / ml; 36. The pharmaceutical composition of claim 35.

48. 36. The pharmaceutical composition of claim 35, wherein sodium chloride is present in a concentration of 9.0 mg / ml.

49. 34. The pharmaceutical composition of any one of claims 1 or 33, further comprising one or more stabilizers.

50. 50. The pharmaceutical composition of claim 49, wherein the stabilizer is present in a concentration of 0.001 to 100.0 mg / ml.

51. 50. The pharmaceutical composition of claim 49, wherein the stabilizer is present in a concentration of 0.35 to 9.5 mg / ml.

52. 50. The pharmaceutical composition of claim 49, wherein the stabilizer is an amino acid or a surfactant.

53. 53. The pharmaceutical composition of claim 52, wherein the amino acid is present in a concentration of 0.001 to 100.0 mg / ml.

54. 53. The pharmaceutical composition of claim 52, wherein the amino acid is present in a concentration of 1.1 to 9.5 mg / ml.

55. 53. The pharmaceutical composition of claim 52, wherein the amino acid is glycine or methionine.

56. 56. The pharmaceutical composition of claim 55, wherein glycine is present in a concentration of 0.001 to 100.0 mg / ml.

57. Glycine is present in a concentration of 0.001 to 80.0 mg / ml; or Glycine is present in a concentration of 0.001 to 60.0 mg / ml; or Glycine is present in a concentration of 0.001 to 40.0 mg / ml; or Glycine is present in a concentration of 0.001 to 20.0 mg / ml; or Glycine is present at a concentration of 0.001 to 15.0 mg / ml; 56. The pharmaceutical composition of claim 55.

58. Glycine is present at a concentration of 3.0 to 12.0 mg / ml; or Glycine is present at a concentration of 5.5 to 9.5 mg / ml; 56. The pharmaceutical composition of claim 55.

59. 56. The pharmaceutical composition of claim 55, wherein glycine is present at a concentration of 7.51 mg / ml.

60. 56. The pharmaceutical composition of claim 55, wherein methionine is present in a concentration of 0.001 to 5.8 mg / ml.

61. 56. The pharmaceutical composition of claim 55, wherein methionine is present in a concentration of 1.1 to 5.8 mg / ml.

62. 56. The pharmaceutical composition of claim 55, wherein methionine is present in a concentration of 1.1 to 1.9 mg / ml or 3.2 to 5.8 mg / ml.

63. 56. The pharmaceutical composition of claim 55, wherein methionine is present at a concentration of 1.49 mg / ml or 4.48 mg / ml.

64. 53. The pharmaceutical composition of claim 52, wherein the surfactant is present in a concentration of 0.001 to 6.0 mg / ml.

65. 53. The pharmaceutical composition of claim 52, wherein the surfactant is present in a concentration of 0.35 to 1.3 mg / ml.

66. 53. The pharmaceutical composition of claim 52, wherein the surfactant is poloxamer 188 or polysorbate 80 or polypropylene glycol.

67. 67. The pharmaceutical composition of claim 66, wherein the poloxamer 188 is present in a concentration of 0.001 to 6.0 mg / ml.

68. Poloxamer 188 is present in a concentration of 0.001 to 4.0 mg / ml; or Poloxamer 188 is present in a concentration of 0.001 to 2.5 mg / ml; or Poloxamer 188 is present in a concentration of 0.35 to 1.3 mg / ml; or Poloxamer 188 is present in a concentration of 0.35 to 0.65 mg / ml or 0.7 to 1.3 mg / ml; 67. The pharmaceutical composition of claim 66.

69. 67. The pharmaceutical composition of claim 66, wherein poloxamer 188 is present in a concentration of 0.5 mg / ml or 1.0 mg / ml.

70. Polysorbate 80 is present in a concentration of 0.001 to 5.0 mg / ml; or Polysorbate 80 is present in a concentration of 0.001 to 3.5 mg / ml; or Polysorbate 80 is present in a concentration of 0.001 to 2.5 mg / ml; or Polysorbate 80 is present at a concentration of 0.7-1.3 mg / ml; 67. The pharmaceutical composition of claim 66.

71. 67. The pharmaceutical composition of claim 66, wherein polysorbate 80 is present at a concentration of 1.0 mg / ml.

72. 34. The pharmaceutical composition of claim 33, comprising: (i) Anti-TRBV9 antibody; (ii) Histidine buffer or acetate buffer (iii) an osmotic agent which is proline, 14.0 to 32.0 mg / ml; (iv) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) Histidine buffer or acetate buffer (iii) an osmotic agent which is sorbitol 35.0 to 65.0 mg / ml; (iv) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is trehalose, 70 to 130.0 mg / ml; (iv) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sodium chloride, 6.0 to 11.5 mg / ml; (iv) Water for injection: Make up to 1 ml.

73. 34. The pharmaceutical composition of claim 33, comprising: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0 mg / ml histidine hydrochloride monohydrate 0.08-4.2 mg / ml; (iii) an osmotic agent which is proline, 14.0 to 32.0 mg / ml; (iv) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0 mg / ml histidine hydrochloride monohydrate 0.08-4.2 mg / ml; (iii) an osmotic agent which is sorbitol 35.0 to 65.0 mg / ml; (iv) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0 mg / ml histidine hydrochloride monohydrate 0.08-4.2 mg / ml; (iii) an osmotic agent which is trehalose, 70 to 130.0 mg / ml; (iv) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0 mg / ml histidine hydrochloride monohydrate 0.08-4.2 mg / ml; (iii) an osmotic agent which is sodium chloride, 6.0 to 11.5 mg / ml; (iv) Water for injection: Make up to 1 ml.

74. 34. The pharmaceutical composition of claim 33, comprising: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml Histidine hydrochloride monohydrate 0.350 mg / ml; (iii) an osmotic agent which is proline 27 mg / ml; (iv) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.689mg / ml Histidine hydrochloride monohydrate 0.117 mg / ml; (iii) an osmotic agent which is proline 19 mg / ml; (iv) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml Histidine hydrochloride monohydrate 0.350 mg / ml; (iii) an osmotic agent which is sorbitol 50.0 mg / ml; (iv) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml Histidine hydrochloride monohydrate 0.350 mg / ml; (iii) an osmotic agent which is trehalose 100.0 mg / ml; (iv) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml Histidine hydrochloride monohydrate 0.350 mg / ml; (iii) an osmotic agent which is sodium chloride 9.0 mg / ml; (iv) Water for injection: Make up to 1 ml.

75. 34. The pharmaceutical composition of claim 33, comprising: (i) Anti-TRBV9 antibody 25mg / ml; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml Histidine hydrochloride monohydrate 0.350 mg / ml; (iii) an osmotic agent which is proline 27 mg / ml; (iv) Water for injection: Make up to 1 ml.

76. 50. The pharmaceutical composition of claim 49, comprising: (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline, 14.0 to 32.0 mg / ml; (iv) a stabilizer which is glycine, 5.5-9.5 mg / ml; (v) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is proline, 14.0 to 32.0 mg / ml; (iv) a stabilizer which is Poloxamer 188, 0.35-1.3 mg / ml; (v) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sorbitol 35.0 to 65.0 mg / ml; (iv) a stabilizer which is methionine; 1.1-5.8 mg / ml; (v) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) histidine or acetate buffer; (iii) an osmotic agent which is sodium chloride, 6.0 to 11.5 mg / ml; (iv) a stabilizer which is poloxamer 188 or polysorbate 80, 0.35 to 1.3 mg / ml; (v) Water for injection: make up to 1 ml.

77. 50. The pharmaceutical composition of claim 49, comprising: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0 mg / ml histidine hydrochloride monohydrate 0.08-4.2 mg / ml; (iii) an osmotic agent which is proline, 14.0 to 32.0 mg / ml; (iv) a stabilizer which is glycine, 5.5-9.5 mg / ml; (v) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0 mg / ml histidine hydrochloride monohydrate 0.08-4.2 mg / ml; (iii) an osmotic agent which is proline, 14.0 to 32.0 mg / ml; (iv) a stabilizer which is Poloxamer 188, 0.35-1.3 mg / ml; (v) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0 mg / ml histidine hydrochloride monohydrate 0.08-4.2 mg / ml; (iii) an osmotic agent which is sorbitol 35.0 to 65.0 mg / ml; (iv) a stabilizer which is methionine; 1.1-5.8 mg / ml; (v) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.4-1.0 mg / ml histidine hydrochloride monohydrate 0.08-4.2 mg / ml; (iii) an osmotic agent which is sodium chloride, 6.0 to 11.5 mg / ml; (iv) a stabilizer which is poloxamer 188 or polysorbate 80, 0.35 to 1.3 mg / ml; (v) Water for injection: make up to 1 ml.

78. 50. The pharmaceutical composition of claim 49, comprising: (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml Histidine hydrochloride monohydrate 0.350 mg / ml; (iii) an osmotic agent which is proline 21 mg / ml; (iv) glycine stabilizer 7.51 mg / ml; (v) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml Histidine hydrochloride monohydrate 0.350 mg / ml; (iii) an osmotic agent which is proline 9.0 mg / ml; (iv) a stabilizer which is Poloxamer 188, 0.5 mg / ml; (v) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml Histidine hydrochloride monohydrate 0.350 mg / ml; (iii) an osmotic agent which is proline 9.0 mg / ml; (iv) a stabilizer which is Poloxamer 188 1.0 mg / ml; (v) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml Histidine hydrochloride monohydrate 0.350 mg / ml; (iii) an osmotic agent which is sorbitol 50.0 mg / ml; (iv) a stabilizer which is methionine; 1.49 mg / ml; (v) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml Histidine hydrochloride monohydrate 0.350 mg / ml; (iii) an osmotic agent which is sorbitol 50.0 mg / ml; (iv) a stabilizer which is methionine; 4.48 mg / ml; (v) Water for injections to 1 ml; or (i) Anti-TRBV9 antibody; (ii) a histidine buffer which is a mixture of: Histidine 0.517mg / ml Histidine hydrochloride monohydrate 0.350 mg / ml; (iii) an osmotic agent which is sodium chloride 9.0 mg / ml; (iv) a stabilizer which is poloxamer 188 or polysorbate 80 1.0 mg / ml; (v) Water for injection: make up to 1 ml.

79. Use of a pharmaceutical composition of an anti-TRBV9 antibody described in any one of claims 1 to 78 for treating a disease or disorder mediated by a T lymphocyte having a TRBV9 segment in its T cell receptor in a subject in need of treatment for the disease or disorder.

80. 80. The use of claim 79, wherein the disease or disorder mediated by T lymphocytes having a TRBV9 segment in their T cell receptor is selected from the group comprising arthropathy, inflammatory bowel disease, eye disease, vasculitis, cardiovascular disease, kidney disease, gastrointestinal disease, lymphoproliferative disease.

81. 80. The use of claim 79, wherein the disease or disorder mediated by T lymphocytes carrying a TRBV9 segment in the T cell receptor is selected from the group comprising spondyloarthritis, sacroiliitis associated with psoriasis, sacroiliitis associated with inflammatory bowel disease, unclassified oligoarthropathy, juvenile spondylitis / enthesitis associated arthritis, juvenile ankylosing spondylitis (enthesitis associated arthritis), juvenile arthritis, unclassified juvenile arthritis, ulcerative colitis, Crohn's disease, non-infectious uveitis, anterior uveitis, Behcet's disease, aortitis, fibrosis of the aortic and / or mitral valve with regurgitation, rhythm disorders, conduction disorders, left ventricular dysfunction, pericarditis, myocarditis, IgA nephropathy, celiac disease, T cell lymphoma, T cell leukemia.

82. 82. The use according to claim 81, wherein the spondyloarthritis is radiographic axial spondyloarthritis (ankylosing spondylitis), axial spondyloarthritis, peripheral spondyloarthritis, psoriatic arthritis, spondyloarthritis associated with inflammatory bowel disease, reactive arthritis, unclassified peripheral spondyloarthritis.

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