Antibody formulations

Abstract

Problem of the present invention is to provide a novel preparation for preventing autoimmune disease or graft versus host disease (GVHD) or hematological cancer, inhibiting progression of autoimmune disease or graft versus host disease (GVHD) or symptom of hematological cancer, inhibiting autoimmune disease or graft versus host disease (GVHD) or relapse of hematological cancer or treatment of autoimmune diseases or graft versus host disease (GVHD) or hematological cancer, comprising an anti-PD-1 / CD3 bispecific antibody as an active ingredient. The present invention provides aqueous pharmaceutical compositions and formulations thereof useful for both subcutaneous and intravenous administration in a single additive composition, containing an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further containing, for example, an acetate buffer, trehalose, L-methionine, polysorbate 80, and sodium chloride.

Description

Technical Field

[0001] The present disclosure relates to pharmaceutical compositions (hereinafter referred to as "pharmaceutical compositions of the present invention") comprising antibodies, in particular bispecific antibodies that can specifically bind to PD-1 and CD3, respectively (hereinafter referred to as "anti-PD-1 / CD3 bispecific antibodies") as active ingredients, and preparations thereof (hereinafter referred to as "preparations of the present invention"). Background Art

[0002] PD-1 is an immunosuppressive receptor belonging to the immunoglobulin family and is a molecule that functions to inhibit T cell immune activation signals activated by stimulation through antigen receptors. Analysis of PD-1 knockout mice and other studies has shown that PD-1 signaling plays an important role in suppressing autoimmune diseases such as autoimmune dilated cardiomyopathy, lupus-like syndrome, autoimmune encephalomyelitis, systemic lupus erythematosus, graft-versus-host disease, type 1 diabetes, and rheumatoid arthritis. Therefore, it is suggested that substances that enhance PD-1 signaling may be preventive or therapeutic agents for autoimmune diseases.

[0003] Until now, bispecific antibodies that recognize PD-1 have been known as substances that enhance PD-1 signals (Patent References 1 to 5). Bispecific antibodies are composed of an antigen recognition site of an antibody that recognizes CD3 (a member of the T cell receptor complex) and an antigen recognition site of an antibody that recognizes PD-1, these two recognition sites being linked to each other using genetic engineering. These bispecific antibodies have the effect of enhancing PD-1's inhibitory signal against the T cell receptor complex by increasing the frequency of PD-1 localization near the T cell receptor complex.

[0004] The pharmaceutical composition of the present invention is characterized by comprising an anti-PD-1 / CD3 bispecific antibody in a concentration range of about 0.01 mg / mL to about 200 mg / mL as an active ingredient, and contains acetate buffer, trehalose, L-methionine, polysorbate 80, and sodium chloride as one embodiment of its formulation additives, and the formulations listed in Patent Documents 6 to 14 have been reported as antibody formulations.

[0005] Patent Document 6 relates to a formulation in which the immunosuppressive effect in the target tissue can be minimized by non-systemic administration (e.g., intravenous administration) to achieve tissue-specific immunomodulation by an anti-CD3 antibody. As such a formulation, it discloses an oral formulation containing 0.1 to 10 mg of an anti-CD3 antibody as an active ingredient per dose and sodium acetate trihydrate, sodium chloride, polysorbate 80, trehalose, and methionine as its formulation additives, and a subcutaneous injection formulation containing 2 mg / mL of an anti-CD3 antibody as an active ingredient and sodium acetate trihydrate, sodium chloride, and polysorbate 80 as its formulation additives. However, it does not disclose that any formulation containing those additives can be used as an intravenous formulation in which it is difficult to minimize the immunosuppressive effect in the target tissue, and further, there is no indication that trehalose and L-methionine can be further added to the above-mentioned subcutaneous injection formulation. Furthermore, although the concentration of polysorbate 80 in both formulations of this document is equal to 0.02% (w / v), this does not at all suggest that approximately 0.1% (w / v) is optimal or necessary for the pharmaceutical composition of the present invention in terms of inhibiting aggregation.

[0006] Patent Document 7 discloses a formulation containing 150 mg / mL of an anti-OX40L antibody as an active ingredient and acetate buffer, trehalose, polysorbate 20, and methionine as additives. Trehalose and methionine are used as tonicity agents or stabilizers in the additives of the formulation disclosed in this document, but there is no indication that sodium chloride, which also functions as a tonicity agent or stabilizer, is added to the formulation in the presence of trehalose and methionine. Furthermore, there is no indication that polysorbate 20, contained in the formulation examples exhibiting superior performance, is used as a substitute for sorbitan 80.

[0007] Patent Document 8 discloses a formulation containing 150 mg / mL of an anti-GM-CSF-Rα antibody as an active ingredient and acetate buffer, sodium chloride, polysorbate 80, and trehalose as formulation additives, but does not disclose the addition of L-methionine.

[0008] Furthermore, although formulations applicable to antibodies with low or neutral pI values ​​are generally set to a pH that deviates by 1 pH from the pI value of the antibody, Patent Document 8 is designed to be applicable to formulations whose pH is set within a range of 5.5 to 7.5, close to the pI value of the antibody, taking into account the colloidal stability of the antibody. Therefore, the composition in the formulation is not applicable to any pharmaceutical composition having a pH other than this (e.g., the pharmaceutical composition of the present invention having a pH of 4.7 to 5.3).

[0009] Patent Document 9 discloses a formulation containing about 45 to 55 mg / mL of adalimumab as an active ingredient and acetate buffer, sodium chloride, polysorbate 80, and trehalose as its formulation additives, but indicates that it does not substantially contain or does not contain any free amino acids, or even if present, it is 0.1 mM or lower. In addition, it discloses that the presence of free amino acids (including L-methionine) significantly worsens the stability of the antibody (fragmentation of antibodies at pH 5.0 or lower). In addition, although it is desired to adopt a simple formulation with fewer ingredients, it is shown that since trehalose is very promising with respect to antioxidant properties, it is not necessary to further add an antioxidant.

[0010] Although Patent Documents 10 and 11 disclose formulations containing 20 mg / mL of an anti-EGFR antibody as an active ingredient and acetate buffer, sodium chloride, polysorbate 80, and trehalose as additives, the sodium chloride concentration in these formulations is equivalent to 100 mM. On the other hand, the sodium chloride concentration in the pharmaceutical composition of the present invention is set to approximately 34.2 mM or less, and therefore, aggregate formation is significant at a concentration equivalent to 100 mM, which is not applicable to this formulation. Furthermore, there is no mention of the addition of L-methionine.

[0011] Although Patent Documents 12 and 13 disclose formulations containing acetate buffer, polysorbate 80, trehalose, methionine, and DTPA for treating visible particles that are prominent in IgG4 isotype antibodies, they do not indicate whether these formulations are applicable to the anti-PD-1 / CD3 bispecific antibody of the present invention, which is an IgG1 isotype antibody with different physical properties (DOI(JaLC): 10.15083 / 00006491). Furthermore, although the concentration of polysorbate 80 in the formulations of these documents is set at 0.02% (w / v), there is no indication that approximately 0.1% (w / v) is optimal or necessary for the pharmaceutical composition of the present invention in terms of aggregation inhibition.

[0012] Patent Document 14 discloses a formulation containing an anti-TIGIT antibody as an active ingredient, and as an embodiment of the formulation, contains acetate buffer, trehalose, sodium chloride, and polysorbate 80 as additives. However, in reality, it discloses that since the addition of sodium chloride shows a sharp decrease in the monomer purity of the antibody, it is preferable not to include sodium chloride, and as a result of comparing the concentration of polysorbate 80 at 0.02% and 0.04%, a low concentration of 0.02% is preferred in terms of a sharp decrease in monomer purity. On the other hand, sodium chloride is added to the pharmaceutical composition of the present invention, and the concentration of polysorbate 80 is more preferably about 0.1% (w / v).

[0013] To date, there has been no discovery of a pharmaceutical composition of the present invention containing an anti-PD-1 / CD3 bispecific antibody as an active ingredient and present in a composition comprising the above-mentioned additives, wherein a single composition can be applied to both subcutaneous and intravenous administration of the antibody over a wide concentration range, and this is not suggested at all from any of the formulations disclosed in the above-mentioned patent documents.

[0014] [Citation List]

[0015] [Patent Document]

[0016] Patent Document 1: International Publication No. 2003 / 011911

[0017] Patent Document 2: International Publication No. 2004 / 072286

[0018] Patent Document 3: International Publication No. 2013 / 022091

[0019] Patent Document 4: International Publication No. 2019 / 156199

[0020] Patent Document 5: International Publication No. 2021 / 020416

[0021] Patent Document 6: Japanese Translation of PCT International Application Publication No. 2019-526627

[0022] Patent Document 7: International Publication No. 2011 / 161226

[0023] Patent Document 8: Japanese Translation of PCT International Application Publication No. 2020-509025

[0024] Patent Document 9: Japanese Translation of PCT International Application Publication No. 2017-516846

[0025] Patent Document 10: Chinese Patent Application Publication No. 107987161

[0026] Patent Document 11: Chinese Patent Application Publication No. 115869395

[0027] Patent Document 12: International Publication No. 2023 / 031969

[0028] Patent Document 13: International Publication No. 2023 / 031970

[0029] Patent Document 14: International Publication No. 2022 / 152245 SUMMARY OF THE INVENTION

[0031] [Technical Issues]

[0032] The problem underlying the present invention was to provide a single pharmaceutical composition and its formulation which is suitable for both subcutaneous and intravenous administration of antibodies, in particular anti-PD-1 / CD3 bispecific antibodies, which can be used in a wide concentration range.

[0033] [Solution to the problem]

[0034] The present inventors have diligently studied and discovered a pharmaceutical composition and a preparation thereof that can solve the above-mentioned problems, and have subsequently completed the present invention.

[0035] In other words, the present invention mainly provides the following embodiments.

[0036] <1> An aqueous pharmaceutical composition or a formulation thereof for subcutaneous or intravenous administration, comprising an antibody (preferably an anti-PD-1 / CD3 bispecific antibody) as an active ingredient and further comprising a buffer (preferably acetate buffer), trehalose, an antioxidant (preferably L-methionine), polysorbate 80, and sodium chloride.

[0037] <2> An aqueous pharmaceutical composition or a formulation thereof for subcutaneous or intravenous administration, which is the same as the aforementioned <1> The aqueous pharmaceutical composition or formulation thereof described in is bioequivalent, and

[0038] <3> The aforementioned items <1> or <2> Use of the aqueous pharmaceutical composition described in or its formulation in preventing autoimmune diseases or graft-versus-host disease (GVHD) or blood cancers, inhibiting symptom progression of autoimmune diseases or graft-versus-host disease (GVHD) or blood cancers, inhibiting recurrence of autoimmune diseases or graft-versus-host disease (GVHD) or blood cancers and / or treating autoimmune diseases or graft-versus-host disease (GVHD) or blood cancers.

[0039] [Advantageous Effects of the Invention]

[0040] The pharmaceutical composition of the present invention for anti-PD-1 / CD3 bispecific antibodies or their formulations can be new drugs for preventing autoimmune diseases or graft-versus-host disease (GVHD) or blood cancers, inhibiting the progression of symptoms of autoimmune diseases or graft-versus-host disease (GVHD) or blood cancers, inhibiting the recurrence of autoimmune diseases or graft-versus-host disease (GVHD) or blood cancers, and / or treating autoimmune diseases or graft-versus-host disease (GVHD) or blood cancers. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] [ Figure 1] It shows the respective amino acid sequences of the heavy chain and light chain that constitute the antigen binding site that specifically binds to PD-1 and the heavy chain and light chain that constitute the antigen binding site that specifically binds to CD3, constituting the anti-PD-1 / CD3 bispecific antibody A (details are described below).

[0042] [ Figure 2 ] It shows the respective amino acid sequences of the heavy chain constant regions in the heavy chain and light chain that constitute the antigen binding site that specifically binds to PD-1 in the heavy chain constant region that constitutes the anti-PD-1 / CD3 bispecific antibody B (details are described below).

[0043] [ Figure 3 ] It shows the respective amino acid sequences of the heavy chain constant regions in the heavy chain and light chain that constitute the antigen binding site that specifically binds to CD3 in the heavy chain constant region that constitutes the anti-PD-1 / CD3 bispecific antibody B (details are described below).

[0044] [ Figure 4 ] It shows the relationship between the binding activity (%) of antibody α (details are described below) to PD-1 (relative activity when the activity of antibody α as a standard is 100%) and the oxidation degree (%) of the 101st methionine residue (hereinafter, may be simply referred to as "Met101") located in the complementarity determining region of PD-1 on the antibody (the ratio of antibody α in which the 101st methionine residue is oxidized).

[0045] [Description of embodiment]

[0046] The present invention relates to antibodies, in particular antibodies that have binding specificity for two different antigen molecules or epitopes in one molecule, i.e., bispecific antibodies. The anti-PD-1 / CD3 bispecific antibody of the present invention is,

[0047] (i) heavy and light chains that constitute the antigen-binding site that specifically binds to PD-1, and

[0048] (ii) heavy and light chains that constitute the antigen binding site that specifically binds to CD3.

[0049] (a) the heavy chain of the aforementioned item (i) comprises any one of the amino acid sequences selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5,

[0050] (b) the heavy chain of the aforementioned item (ii) comprises the amino acid sequence of SEQ ID NO: 6, and

[0051] (c) The light chains of the aforementioned items (i) and (ii) both comprise the amino acid sequence of SEQ ID NO: 7.

[0052] Herein, the term "heavy and light chains comprising an antigen-binding site that specifically binds to PD-1" refers to a heavy chain / light chain complex in which the heavy chain and light chain associate via disulfide bonds to form an antigen-binding site that specifically binds to PD-1. The term "antigen-binding site" is the minimum unit of an antibody that has binding activity to its antigen, and the term "specifically binds to PD-1" is used to refer to a heavy chain / light chain complex with a binding activity of more than 1 x 10 -5 M, preferably 1 × 10 -7 M, more preferably 1 × 10 -9 The binding activity with an affinity (dissociation constant (Kd value)) of M is characteristic of binding directly to PD-1 and substantially not binding to any other receptor members belonging to the so-called CD28 family of receptors, such as at least CD28, CTLA-4 and ICOS.

[0053] As used herein, the term "heavy and light chains comprising an antigen binding site that specifically binds to CD3" refers to a heavy chain / light chain complex in which the heavy chain and light chain associate via disulfide bonds to form an antigen binding site that specifically binds to CD3. -5 M, preferably 1 × 10 -7 M, more preferably 1× 10 -9 The binding activity with M affinity (dissociation constant (Kd value)) is a characteristic of direct binding to CD3 and substantially no binding to any other protein.

[0054] In the above-mentioned anti-PD-1 / CD3 bispecific antibody (hereinafter collectively referred to as "anti-PD-1 / CD3 bispecific antibody A"), the antibody used in the pharmaceutical composition or preparation thereof of the present invention is preferably an anti-PD-1 / CD3 bispecific antibody (hereinafter referred to as "antibody α"), the heavy chain of which comprises an antigen-binding site that specifically binds to PD-1 and comprises the amino acid sequence shown in SEQ ID NO: 5.

[0055] The anti-PD-1 / CD3 bispecific antibody A can be produced according to the method disclosed in WO2019 / 156199 and corresponds to the anti-PD-1 / CD3 bispecific antibody clones PD1-1 (Bi) to PD1-5 (Bi), respectively, wherein antibody α corresponds to clone PD1-5 (Bi).

[0056] In addition, an anti-PD-1 / CD3 bispecific antibody (hereinafter collectively referred to as "anti-PD-1 / CD3 bispecific antibody B") in which the heavy chain constant region of the heavy chain constituting the antigen-binding site that specifically binds to PD-1 of antibody α is replaced by a heavy chain constant region comprising any one of the amino acid sequences selected from SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, and in which the heavy chain constant region of the heavy chain constituting the antigen-binding site that specifically binds to CD3 is replaced by a heavy chain constant region comprising any one of the amino acid sequences selected from SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19 can also be used in the pharmaceutical composition or formulation thereof of the present invention. Note that anti-PD-1 / CD3 bispecific antibody B can be produced according to the method disclosed in WO2021 / 020416.

[0057] Note that both anti-PD-1 / CD3 bispecific antibody A and anti-PD-1 / CD3 bispecific antibody B are of IgG1 isotype.

[0058] The pharmaceutical composition of the present invention contains the anti-PD-1 / CD3 bispecific antibody at any concentration of about 0.01 to about 200 mg / mL (e.g., about 0.01 mg / mL, about 0.02 mg / mL, about 0.03 mg / mL, about 0.04 mg / mL, about 0.05 mg / mL, about 0.06 mg / mL, about 0.07 mg / mL, about 0.08 mg / mL, about 0.09 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 5 The present invention relates to an agonist or anti-inflammatory drug that is administered at a concentration of about 1 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, or about 200 mg / mL, preferably any concentration from about 0.1 to about 150 mg / mL, more preferably any concentration from about 0.1 to 1.2 mg / mL (e.g., about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6

[0014] The present invention relates to a pharmaceutical composition comprising a pharmaceutical composition comprising at least one pharmaceutically acceptable salt and a concentration of at least one pharmaceutically acceptable salt. The pharmaceutical composition comprises at least one pharmaceutically acceptable salt and a concentration of at least one pharmaceutically acceptable salt. The pharmaceutical composition comprises at least one pharmaceutically acceptable salt and a concentration of at least one pharmaceutically acceptable salt. More preferably, the pharmaceutical composition comprises at least one pharmaceutically acceptable salt and a concentration of at least one pharmaceutically acceptable salt.

[0059] The anti-PD-1 / CD3 bispecific antibody suitable for use in the aqueous pharmaceutical composition of the present invention (preferably for intravenous administration) having a volume of, for example, 5 mL per formulation is any amount from about 0.05 to about 1000 mg (preferably about 0.5 to about 750 mg, more preferably about 0.5 to about 6 mg, about 25 to about 125 mg, or about 400 to about 750 mg, even more preferably about 2.5 mg, about 5 mg, about 50 mg, or about 500 mg). On the other hand, the anti-PD-1 / CD3 bispecific antibody suitable for use in the aqueous pharmaceutical composition (preferably for subcutaneous administration) having a volume of, for example, 1 mL is 1 / 5 of the above amount of the antibody suitable for use in the above aqueous pharmaceutical composition having a volume of 5 mL. If the volumes are, for example, about 2 mL, about 0.8 mL, about 0.6 mL, about 0.5 mL, about 0.4 mL, and about 0.2 mL, respectively, they are suitable for use in 5 mL. About 2 / 5, about 4 / 25, about 3 / 25, about 1 / 10, about 2 / 25 and about 1 / 25 of the above amount of the antibody in the above aqueous pharmaceutical composition in mL volume.

[0060] Note that as used in this specification, the term "pharmaceutical composition" refers to a mixture of an active ingredient and one or more other additives, and the term "aqueous pharmaceutical composition" refers to a pharmaceutical composition in which the pharmaceutical composition is substantially dissolved in an aqueous solvent. A preferred form of the pharmaceutical composition of the present invention is an aqueous pharmaceutical composition.

[0061] As used in this specification, the term "preparation" refers to a drug in a form suitable for a route or method of administration appropriately selected for the pharmaceutical composition. As used in this specification, the term "about" means that the indicated numerical value may vary within a range of 10% or less below or above, and the term "to" indicating a range means including each of its lower and upper limits.

[0062] The aqueous pharmaceutical composition of the present invention contains a buffer to stabilize its pH. Any buffer is acceptable as long as it sufficiently stabilizes the potential pH of the aqueous pharmaceutical composition of the present invention and does not affect the stabilization of the anti-PD-1 / CD3 bispecific antibody, but acetate buffer is preferred. The concentration of acetate buffer in the aqueous pharmaceutical composition of the present invention is from about 7.3 to about 73.0 mM (e.g., about 7.3 mM, about 10 mM, about 14.6 mM, about 15 mM, about 18 mM, about 20 mM, about 20.07 mM, about 21 mM, about 22 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 43.8 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 70 mM, and about 73.0 mM), preferably any concentration from about 14.6 to about 43.8 mM, more preferably any concentration from about 18 to about 22 mM, even more preferably about 20 mM, and more specifically about 20.07 mM. Note that, in this specification, for example, if the term "10 mM acetate buffer" or "10 mM acetate buffer solution" is used, it means that the aqueous pharmaceutical composition of the present invention contains acetate buffer at a concentration equivalent to 10 mM.

[0063] Herein, such acetate buffer can be prepared by a known method of adding acetic acid to a sodium acetate solution (e.g., an aqueous solution of anhydrous sodium acetate, sodium acetate dihydrate, or sodium acetate trihydrate) to achieve an arbitrary pH. For example, an acetate buffer suitable for an aqueous pharmaceutical composition having a volume of 5 mL per dosage form (preferably for intravenous administration) is composed of: (i) any amount of sodium acetate trihydrate equivalent to about 3.4 to about 34 mg (preferably about 6.8 to about 20.4 mg, more preferably about 8.4 to about 10.2 mg), and (ii) any amount of glacial acetic acid, for example, equivalent to achieving a pH of the acetate buffer solution of about 4.9 to 5.1, corresponding to the above amount of sodium acetate trihydrate, and further in this case, a preferred embodiment of the acetate buffer is composed of about 9.4 mg (specifically, about 9.35 mg) of sodium acetate trihydrate and about 1.9 mg of glacial acetic acid.

[0064] On the other hand, the acetate buffer suitable for an aqueous pharmaceutical composition with a volume of, for example, about 1 mL (preferably for subcutaneous administration) consists of about 1 / 5 of the above-mentioned corresponding amounts of sodium acetate trihydrate and glacial acetic acid suitable for a volume of 5 mL of the above-mentioned aqueous pharmaceutical composition, and if the volumes are, for example, about 2 mL, about 0.8 mL, about 0.6 mL, about 0.5 mL, about 0.4 mL and about 0.2 mL, respectively, the acetate buffer consists of about 2 / 5, about 4 / 25, about 3 / 25, about 1 / 10, about 2 / 25 and about 1 / 25 of the above-mentioned corresponding amounts of sodium acetate trihydrate and glacial acetic acid suitable for a volume of 5 mL of the above-mentioned aqueous pharmaceutical composition, respectively.

[0065] Buffers suitable for use in the aqueous pharmaceutical composition of the present invention also include buffers having pH buffering properties equivalent to those of the acetate buffer described above.

[0066] The aqueous pharmaceutical compositions of the present invention have any pH of about 4.7 to about 5.3 (i.e., in the range of about 5.0±0.3) (e.g., about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, or about 5.3), preferably any pH of about 4.9 to about 5.1 (i.e., in the range of about 5.0±0.1), more preferably a pH of about 5.0.

[0067] The aqueous pharmaceutical composition of the present invention contains a sugar primarily for regulating its osmotic pressure. Any sugar is acceptable as long as it can adequately regulate the osmotic pressure of the aqueous pharmaceutical composition of the present invention and does not affect the stabilization of the anti-PD-1 / CD3 bispecific antibody. Trehalose is preferred, and can be added in the form of a hydrate (e.g., a monohydrate, preferably a dihydrate) or an anhydrate. The concentration of trehalose in the aqueous pharmaceutical composition of the present invention is any concentration from about 5 to about 286.1 mM (e.g., about 5 mM, about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 172 mM, about 180 mM, about 182 mM, about 182.3 mM, about 182.38 mM, about 182.4 mM, about 190 mM, about 193 mM, about 200 mM, about 207.9 mM, about 210 mM, about 220 mM, about 225 182.4 mM, and more specifically about 182.38 mM).

[0068] The sugar in the aqueous pharmaceutical composition of the present invention is trehalose, and the trehalose suitable for an aqueous pharmaceutical composition with a volume of, for example, 5 mL per preparation (preferably for intravenous administration) is any amount of about 9.46 to about 541.2 mg of its dihydrate (preferably about 18.9 to about 393.3 mg, more preferably about 325 to about 365.1 mg, even more preferably about 345 mg), and on the other hand, the trehalose suitable for an aqueous pharmaceutical composition with a volume of, for example, 1 mL (preferably for subcutaneous administration) is 1 / 5 of the above amount of trehalose dihydrate suitable for a volume of 5 mL, and if the volumes are, for example, about 2 mL, about 0.8 mL, about 0.6 mL, about 0.5 mL, about 0.4 mL and about 0.2 mL, respectively, the trehalose suitable for 5 mL is 1 / 5 of the above amount of trehalose dihydrate. Trehalose dihydrate in an amount of about 2 / 5, about 4 / 25, about 3 / 25, about 1 / 10, about 2 / 25 and about 1 / 25 of the above amount of the above aqueous pharmaceutical composition in mL volume.

[0069] Sugars suitable for use in the aqueous pharmaceutical composition of the present invention also include sugars having an osmotic pressure regulating ability equivalent to that of the above-mentioned trehalose.

[0070] The aqueous pharmaceutical composition of the present invention contains an antioxidant to inhibit oxidation of the anti-PD-1 / CD3 bispecific antibody or the resulting reduction in pharmacological activity. Any antioxidant is acceptable as long as it can inhibit oxidation of the anti-PD-1 / CD3 bispecific antibody or the resulting reduction in pharmacological activity to the desired extent. However, L-methionine or DTPA (diethylenetriaminepentaacetic acid) are preferred, with L-methionine being more preferred. If the antioxidant in the aqueous pharmaceutical composition of the present invention is L-methionine, the L-methionine is at any concentration from about 5 to about 30.2 mM (e.g., about 5 mM, about 8 mM, about 10 mM, about 10.05 mM, about 12 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, or about 30.2 mM), preferably at any concentration from about 5 to about 20 mM, more preferably at any concentration from about 5 to about 15 mM, even more preferably at any concentration from about 8 to about 12 mM, most preferably at about 10 mM, and more specifically at about 10.05 mM.

[0071] The antioxidant in the aqueous pharmaceutical composition of the present invention is L-methionine, and the L-methionine suitable for each preparation volume of, for example, 5 mL of the aqueous pharmaceutical composition (preferably for intravenous administration) is any amount of about 3.75 to about 22.5 mg (preferably about 3.75 to about 15.0 mg, more preferably about 3.75 to about 11.25 mg, even more preferably about 6 to about 9 mg, most preferably about 7.5 mg), and on the other hand, the L-methionine suitable for an aqueous pharmaceutical composition with a volume of, for example, about 1 mL (preferably for subcutaneous administration) is 1 / 5 of the above amount suitable for the above aqueous pharmaceutical composition with a volume of 5 mL, and if the volumes are, for example, about 2 mL, about 0.8 mL, about 0.6 mL, about 0.5 mL, about 0.4 mL and about 0.2 mL, respectively, the L-methionine suitable for 5 mL is 1 / 5 of the above amount. About 2 / 5, about 4 / 25, about 3 / 25, about 1 / 10, about 2 / 25 and about 1 / 25 of the above amount of L-methionine in mL volume of the above aqueous pharmaceutical composition.

[0072] The antioxidant in the aqueous pharmaceutical composition of the present invention further includes an antioxidant having an antioxidant capacity equivalent to that of the above-mentioned L-methionine against the anti-PD-1 / CD3 bispecific antibody.

[0073] The aqueous pharmaceutical composition of the present invention contains a surfactant to mainly inhibit the aggregation of the anti-PD-1 / CD3 bispecific antibody. Any surfactant is acceptable as long as it can inhibit the aggregation of the anti-PD-1 / CD3 bispecific antibody, but polysorbate 80 is preferred, and its concentration is any one of about 0.01 to about 0.5% (w / v) (e.g., about 0.01% (w / v), about 0.02% (w / v), about 0.04% (w / v), about 0.05% (w / v), about 0.06% (w / v), about 0.08% (w / v), about 0.1% (w / v) ), about 0.12% (w / v), about 0.15% (w / v), about 0.2% (w / v), about 0.25% (w / v), about 0.3% (w / v), about 0.35% (w / v), about 0.4% (w / v), about 0.45% (w / v) or about 0.5% (w / v)), preferably any concentration from about 0.05 to about 0.3% (w / v), more preferably any concentration from about 0.8 to about 1.2% (w / v), even more preferably about 0.1% (w / v).

[0074] The surfactant in the aqueous pharmaceutical composition of the present invention is polysorbate 80, and the polysorbate 80 suitable for an aqueous pharmaceutical composition with a volume of, for example, 5 mL (preferably for intravenous administration) per preparation is any amount of about 0.5 to about 25 mg (preferably about 2.5 to about 15 mg, more preferably about 4 to about 6 mg, even more preferably about 5 mg), and on the other hand, the polysorbate 80 suitable for an aqueous pharmaceutical composition with a volume of, for example, 1 mL (preferably for subcutaneous administration) is 1 / 5 of the amount of polysorbate 80 suitable for the above-mentioned aqueous pharmaceutical composition with a volume of 5 mL, and if the volumes are, for example, about 2 mL, about 0.8 mL, about 0.6 mL, about 0.5 mL, about 0.4 mL and about 0.2 mL, respectively, the polysorbate 80 is about 2 / 5, about 4 / 25, about 3 / 25, about 1 / 10, about 2 / 25 and about 1 / 25 of the above-mentioned corresponding amounts of polysorbate 80 suitable for the above-mentioned aqueous pharmaceutical composition with a volume of 5 mL, respectively.

[0075] Surfactants suitable for the aqueous pharmaceutical composition of the present invention also include surfactants having aggregation inhibition properties of the anti-PD-1 / CD3 bispecific antibody equivalent to those of the above-mentioned polysorbate 80.

[0076] The aqueous pharmaceutical composition of the present invention contains a salt for stabilization (inhibition of aggregation). Such salt, any salt is acceptable as long as it can achieve such stabilization, but sodium chloride is preferred, and its concentration is any one of about 0.5 to about 34.2 mM (e.g., about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 19.6 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 23.27 mM, about 24.0 mM, about 25 mM, about 25.7 mM, about 30 mM or about 34.2 mM), preferably about 1.0 to about 25.7 mM. Any concentration from about 19.6 to about 25.7 mM, more preferably about 23 mM, and more specifically about 23.27 mM.

[0077] Note that the aqueous pharmaceutical composition of the present invention preferably has a conductivity of about 2.6 to about 3.1 mS / cm (e.g., about 2.6 mS / cm, about 2.7 mS / cm, about 2.8 mS / cm, about 2.9 mS / cm, about 3.0 mS / cm, or about 3.1 mS / cm), and more preferably about 2.8 mS / cm.

[0078] The salt in the aqueous pharmaceutical composition of the present invention is sodium chloride, and the sodium chloride suitable for each preparation volume of, for example, 5 mL of the aqueous pharmaceutical composition (preferably for intravenous administration) is any amount of about 0.15 to about 10.0 mg (preferably about 0.29 to about 7.5 mg, more preferably about 5.8 to about 7.5 mg, even more preferably about 6.8 mg), and on the other hand, the sodium chloride suitable for a volume of, for example, 1 mL of the aqueous pharmaceutical composition (preferably for subcutaneous administration) is 1 / 5 of the above amount of sodium chloride suitable for a volume of 5 mL of the above aqueous pharmaceutical composition, and when the volumes are, for example, about 2 mL, about 0.8 mL, about 0.6 mL, about 0.5 mL, about 0.4 mL and about 0.2 mL, respectively, the sodium chloride is about 2 / 5, about 4 / 25, about 3 / 25, about 1 / 10, about 2 / 25 and about 1 / 25 of the above amount of sodium chloride suitable for a volume of 5 mL of the above aqueous pharmaceutical composition, respectively.

[0079] Salts suitable for use in the aqueous pharmaceutical compositions of the present invention also include those having equivalent stabilizing abilities to the aforementioned sodium chloride.

[0080] Note that in this specification, the amount of each additive contained in the aqueous pharmaceutical composition of the present invention may be the amount of each additive per unit volume (e.g., 1 mL), and one example of an embodiment thereof contains 1.87 mg / mL of sodium acetate trihydrate, 0.38 mg / mL of acetic acid, 69 mg / mL of trehalose dihydrate, 1.5 mg / mL of L-methionine, 1.0 mg / mL of polysorbate 80, and 1.36 mg / mL of sodium chloride.

[0081] Examples of embodiments of the aqueous pharmaceutical compositions of the present invention include:

[0082] (A) A pharmaceutical composition comprising:

[0083] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 1 mg / mL or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0084] (b) a buffer (preferably an acetate buffer of about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20 mM, more specifically about 20.07 mM) or a buffer having pH buffering properties equivalent to those of the acetate buffer),

[0085] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182 mM, more specifically about 182.38 mM) of trehalose,

[0086] (d) about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10 mM, more specifically about 10.05 mM) of L-methionine,

[0087] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0088] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23 mM, more specifically about 23.27 mM) of sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0),

[0089] (B) A pharmaceutical composition comprising:

[0090] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 1 mg / mL or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0091] (b) about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20 mM, more specifically about 20.07 mM) acetate buffer,

[0092] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182 mM, more specifically about 182.38 mM) of trehalose,

[0093] (d) an antioxidant of L-methionine (preferably about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10 mM, more specifically about 10.05 mM) or an antioxidant having an antioxidant capacity equivalent to that of the above-mentioned L-methionine),

[0094] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0095] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23 mM, more specifically about 23.27 mM) of sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0), and

[0096] (C) A pharmaceutical composition comprising:

[0097] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 1 mg / mL or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0098] (b) a buffer (preferably an acetate buffer of about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20 mM, more specifically about 20.07 mM) or a buffer having pH buffering properties equivalent to those of the acetate buffer),

[0099] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182 mM, more specifically about 182.38 mM) of trehalose,

[0100] (d) an antioxidant of L-methionine (preferably about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10 mM, more specifically about 10.05 mM) or an antioxidant having an antioxidant capacity equivalent to that of the above-mentioned L-methionine),

[0101] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0102] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23 mM, more specifically about 23.27 mM) of sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0). Note that these aqueous pharmaceutical compositions in (A) to (C) can be used for both intravenous and subcutaneous administration.

[0103] On the other hand, in the aqueous pharmaceutical composition of the present invention, examples of embodiments for subcutaneous administration include:

[0104] (D) A pharmaceutical composition comprising:

[0105] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody (preferably Antibody α) as an active ingredient, and further containing:

[0106] (b) a buffer (preferably an acetate buffer of about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20 mM, more specifically about 20.07 mM) or a buffer having pH buffering properties equivalent to those of the acetate buffer),

[0107] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182 mM, more specifically about 182.38 mM) of trehalose,

[0108] (d) about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10 mM, more specifically about 10.05 mM) of L-methionine,

[0109] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0110] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23 mM, more specifically about 23.27 mM) of sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0),

[0111] (E) A pharmaceutical composition comprising:

[0112] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody (preferably Antibody α) as an active ingredient, and further containing:

[0113] (b) about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20 mM, more specifically about 20.07 mM) acetate buffer,

[0114] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182 mM, more specifically about 182.38 mM) of trehalose,

[0115] (d) an antioxidant of L-methionine (preferably about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10 mM, more specifically about 10.05 mM) or an antioxidant having an antioxidant capacity equivalent to that of the above-mentioned L-methionine),

[0116] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0117] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23 mM, more specifically about 23.27 mM) of sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0), and

[0118] (F) A pharmaceutical composition comprising:

[0119] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody (preferably Antibody α) as an active ingredient, and further containing:

[0120] (b) a buffer (preferably an acetate buffer of about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20 mM, more specifically about 20.07 mM) or a buffer having pH buffering properties equivalent to those of the acetate buffer),

[0121] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182 mM, more specifically about 182.38 mM) of trehalose,

[0122] (d) an antioxidant of L-methionine (preferably about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10 mM, more specifically about 10.05 mM) or an antioxidant having an antioxidant capacity equivalent to that of the above-mentioned L-methionine),

[0123] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0124] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23 mM, more specifically about 23.27 mM) of sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more specifically about 5.0).

[0125] Additionally, examples of alternative embodiments of the aqueous pharmaceutical compositions of the present invention include:

[0126] (A1) A pharmaceutical composition comprising:

[0127] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0128] (b) about 7.3 to about 73.0 mM acetate buffer,

[0129] (c) from about 5 to about 286.1 mM trehalose,

[0130] (d) about 5 to about 30.2 mM L-methionine,

[0131] (e) about 0.01 to about 0.5% (w / v) polysorbate 80, and

[0132] (f) about 0.5 to about 34.2 mM sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3, preferably,

[0133] (B1) A pharmaceutical composition comprising:

[0134] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0135] (b) about 14.6 to about 43.8 mM (preferably about 18 to about 22 mM) acetate buffer,

[0136] (c) about 10 to about 207.9 mM (preferably about 172 to about 193 mM) trehalose,

[0137] (d) about 5 to about 20 mM (preferably about 5 to about 15 mM) of L-methionine,

[0138] (e) about 0.05 to about 0.3% (w / v) (preferably about 0.08 to 0.12% (w / v)) polysorbate 80, and

[0139] (f) about 1.0 to about 25.7 mM (preferably about 19.6 to about 25.7 mM) of sodium chloride, and the pH of the pharmaceutical composition is about 4.9 to about 5.1, and more preferably,

[0140] (C1) A pharmaceutical composition comprising:

[0141] (a) about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient (preferably antibody α), and further comprising:

[0142] (b) about 20.1 mM (specifically about 20.07 mM) acetate buffer,

[0143] (c) about 182.4 mM (specifically about 182.38 mM) trehalose,

[0144] (d) about 10.1 mM (specifically about 10.05 mM) of L-methionine,

[0145] (e) about 0.1% (w / v) polysorbate 80, and

[0146] (f) about 23.3 mM (specifically about 23.27 mM) sodium chloride, and the pH of the pharmaceutical composition is about 5.0. Note that the aqueous pharmaceutical compositions in (A1) to (C1) can be used for intravenous and subcutaneous administration.

[0147] On the other hand, among the aqueous pharmaceutical compositions of the present invention, examples of alternative embodiments of the aqueous pharmaceutical composition for subcutaneous administration include:

[0148] (D1) A pharmaceutical composition comprising:

[0149] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody (preferably Antibody α) as an active ingredient, and further containing:

[0150] (b) about 7.3 to about 73.0 mM acetate buffer,

[0151] (c) from about 5 to about 286.1 mM trehalose,

[0152] (d) about 5 to about 30.2 mM L-methionine,

[0153] (e) about 0.01 to about 0.5% (w / v) polysorbate 80, and

[0154] (f) about 0.5 to about 34.2 mM sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3, preferably,

[0155] (E1) A pharmaceutical composition comprising:

[0156] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody (preferably Antibody α) as an active ingredient, and further containing:

[0157] (b) about 14.6 to about 43.8 mM (preferably about 18 to about 22 mM) acetate buffer,

[0158] (c) about 10 to about 207.9 mM (preferably about 172 to about 193 mM) trehalose,

[0159] (d) about 5 to about 20 mM (preferably about 5 to about 15 mM) of L-methionine,

[0160] (e) about 0.05 to about 0.3% (w / v) (preferably about 0.08 to about 0.12% (w / v)) polysorbate 80, and

[0161] (f) about 1.0 to about 25.7 mM (preferably about 19.6 to about 25.7 mM) of sodium chloride, and the pH of the pharmaceutical composition is about 4.9 to about 5.1, and more preferably,

[0162] (F1) A pharmaceutical composition comprising:

[0163] (a) about 100 mg / mL of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further comprising:

[0164] (b) about 20.1 mM (specifically about 20.07 mM) acetate buffer,

[0165] (c) about 182.4 mM (specifically about 182.38 mM) trehalose

[0166] (d) about 10.1 mM (specifically about 10.05 mM) of L-methionine,

[0167] (e) about 0.1% (w / v) polysorbate 80, and

[0168] (f) about 23.3 mM (specifically, about 23.27 mM) sodium chloride, and the pH of the pharmaceutical composition is about 5.0.

[0169] Furthermore, if the volume per formulation thereof is about 5 mL, examples of other alternative embodiments of the aqueous pharmaceutical composition of the present invention include,

[0170] (A2) A pharmaceutical composition comprising:

[0171] (a) about 0.5 to about 6 mg or about 25 to about 125 mg (preferably about 2.5 mg, about 5 mg or about 50 mg, respectively) of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0172] (b) an acetate buffer consisting of: (b1) about 3.4 to about 34.0 mg of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.7 to about 5.3, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0173] (c) about 9.46 to about 541.2 mg of trehalose dihydrate,

[0174] (d) about 3.75 to about 22.5 mg of L-methionine,

[0175] (e) from about 0.5 to about 25.0 mg of polysorbate 80, and

[0176] (f) about 0.15 to about 10.0 mg of sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3, preferably,

[0177] (B2) A pharmaceutical composition comprising:

[0178] (a) about 0.5 to about 6 mg or about 25 to about 125 mg (preferably about 2.5 mg, about 5 mg or about 50 mg, respectively) of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0179] (b) an acetate buffer consisting of: (b1) about 6.8 to about 20.4 mg (preferably about 8.4 to about 10.2 mg) of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0180] (c) about 18.9 to about 393.3 mg (preferably about 325 to about 365.1 mg) of trehalose dihydrate,

[0181] (d) about 3.75 to about 15.0 mg (preferably about 3.75 to about 11.25 mg) of L-methionine,

[0182] (e) about 2.5 to about 15.0 mg (preferably about 4 to about 6 mg) of polysorbate 80, and

[0183] (f) about 0.29 to about 7.5 mg (preferably about 5.8 to about 7.5 mg) of sodium chloride, and the pH of the pharmaceutical composition is about 4.9 to about 5.1, and more preferably,

[0184] (C2) A pharmaceutical composition comprising:

[0185] (a) about 2.5 mg, about 5 mg, or about 50 mg of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further comprising:

[0186] (b) acetate buffer consisting of about 9.4 mg (specifically about 9.35 mg) of sodium acetate trihydrate and about 1.9 mg of glacial acetic acid,

[0187] (c) about 345 mg of trehalose dihydrate,

[0188] (d) about 7.5 mg of L-methionine,

[0189] (e) approximately 5.0 mg of polysorbate 80, and

[0190] (f) about 6.8 mg of sodium chloride, and the pH of the pharmaceutical composition is about 5.0. Note that the aqueous pharmaceutical compositions in (A2) to (C2) can be used for both intravenous and subcutaneous administration.

[0191] Note that in the formulation of the aqueous pharmaceutical composition of the present invention, the volume per formulation can be selected according to the dose per administration. For example, in the case of the pharmaceutical compositions described in items (A2) to (C2) above, the volume per formulation can also be selected from any one of about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 6 mL, about 8 mL, about 10 mL, and about 20 mL. In this case, the amount of the anti-PD-1 / CD3 bispecific antibody and each additive is about 1 / 5, about 2 / 5, about 3 / 5, about 4 / 5, about 6 / 5, about 8 / 5, about twice, and about four times the corresponding amount when the volume per formulation described in items (A2) to (C2) above is about 5 mL.

[0192] Additionally, examples of other alternative embodiments of the aqueous pharmaceutical compositions of the present invention include:

[0193] (D2) A pharmaceutical composition comprising:

[0194] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0195] (b) an acetate buffer consisting of: (b1) about 0.68 to about 6.8 mg / mL of sodium acetate trihydrate and (b2) an amount of acetic acid to achieve a pH of about 4.7 to about 5.3, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0196] (c) about 1.9 to about 108.3 mg / mL of trehalose dihydrate,

[0197] (d) about 0.75 to about 4.5 mg / mL of L-methionine,

[0198] (e) about 0.1 to about 5.0 mg / mL of polysorbate 80, and

[0199] (f) about 0.03 to about 2.0 mg / mL of sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3, preferably,

[0200] (E2) A pharmaceutical composition comprising:

[0201] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0202] (b) an acetate buffer consisting of: (b1) about 1.36 to about 4.08 mg / mL (preferably about 1.68 to about 2.05 mg / mL) of sodium acetate trihydrate and (b2) an amount of acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0203] (c) about 3.8 to about 78.7 mg / mL (preferably about 65.1 to about 72.6 mg / mL) of trehalose dihydrate,

[0204] (d) about 0.75 to about 3.0 mg / mL (preferably about 0.75 to about 2.25 mg / mL) of L-methionine,

[0205] (e) about 0.5 to about 3.0 mg / mL (preferably about 0.8 to about 1.2 mg / mL) of polysorbate 80, and

[0206] (f) about 0.06 to about 1.5 mg / mL (preferably about 1.15 to about 1.5 mg / mL) of sodium chloride, and the pH of the pharmaceutical composition is about 4.9 to about 5.1, and more preferably,

[0207] (F2) A pharmaceutical composition comprising:

[0208] (a) about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0209] (b) an acetate buffer consisting of about 1.9 mg / mL (specifically about 1.87 mg / mL) of sodium acetate trihydrate and about 0.4 mg / mL (specifically about 0.38 mg / mL) of acetic acid,

[0210] (c) about 69 mg / mL of trehalose dihydrate,

[0211] (d) about 1.5 mg / mL of L-methionine,

[0212] (e) about 1.0 mg / mL of polysorbate 80, and

[0213] (f) about 1.4 mg / mL (specifically about 1.36 mg / mL) of sodium chloride, and the pH of the pharmaceutical composition is about 5.0. Note that the aqueous pharmaceutical compositions in (D2) to (F2) can be used for both intravenous and subcutaneous administration.

[0214] On the other hand, in the aqueous pharmaceutical composition of the present invention, if the volume per preparation thereof is about 1 mL, examples of other alternative embodiments of the aqueous pharmaceutical composition for subcutaneous administration include:

[0215] (A3) A pharmaceutical composition comprising:

[0216] (a) about 80 to about 150 mg (preferably about 100 mg) of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0217] (b) an acetate buffer consisting of: (b1) about 0.68 to about 6.8 mg of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.7 to about 5.3, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0218] (c) from about 1.9 to about 108.3 mg of trehalose dihydrate,

[0219] (d) about 0.75 to about 4.5 mg of L-methionine,

[0220] (e) from about 0.1 to about 5.0 mg of polysorbate 80, and

[0221] (f) about 0.03 to about 2.0 mg of sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3, preferably,

[0222] (B3) A pharmaceutical composition comprising:

[0223] (a) about 80 to about 150 mg (preferably about 100 mg) of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further containing:

[0224] (b) an acetate buffer consisting of: (b1) about 1.36 to about 4.08 mg (preferably about 1.68 to about 2.05 mg) of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0225] (c) about 3.8 to about 78.7 mg (preferably about 65.1 to about 72.6 mg) of trehalose dihydrate,

[0226] (d) about 0.75 to about 3.0 mg (preferably about 0.75 to about 2.25 mg) of L-methionine,

[0227] (e) from about 0.5 to about 3.0 mg of polysorbate 80, and

[0228] (f) about 0.06 to about 1.5 mg (preferably about 1.15 to about 1.5 mg) of sodium chloride, and the pH of the pharmaceutical composition is about 4.9 to about 5.1, and more preferably,

[0229] (C3) A pharmaceutical composition comprising:

[0230] (a) about 100 mg of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further comprising:

[0231] (b) acetate buffer consisting of about 1.9 mg (specifically about 1.87 mg) of sodium acetate trihydrate and about 0.4 mg (specifically about 0.38 mg) of glacial acetic acid,

[0232] (c) about 69 mg of trehalose dihydrate,

[0233] (d) about 1.5 mg of L-methionine,

[0234] (e) approximately 1.0 mg of polysorbate 80, and

[0235] (f) about 1.4 mg (specifically about 1.36 mg) of sodium chloride, and the pH of the pharmaceutical composition is about 5.0.

[0236] If the aqueous pharmaceutical composition of the present invention comprises the pharmaceutical composition of any of the aforementioned items (A3) to (C3), the volume of each preparation can be selected from, for example, about 0.1 mL, about 0.2 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.8 mL, and about 1.2 mL. In this case, the amount of the anti-PD-1 / CD3 bispecific antibody and each additive is about 1 / 10, about 1 / 5, about 2 / 5, about 3 / 5, about 4 / 5, and about 6 / 5 of the corresponding amount when the volume of each preparation described in the aforementioned items (A3) to (C3) is about 1 mL.

[0237] Furthermore, among the aqueous pharmaceutical compositions of the present invention, examples of other alternative embodiments of the aqueous pharmaceutical composition for subcutaneous administration include,

[0238] (D3) A pharmaceutical composition comprising:

[0239] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody (preferably Antibody α) as an active ingredient, and further containing:

[0240] (b) an acetate buffer consisting of: (b1) about 0.68 to about 6.8 mg / mL of sodium acetate trihydrate and (b2) an amount of acetic acid to achieve a pH of about 4.7 to about 5.3, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0241] (c) about 1.9 to about 108.3 mg / mL of trehalose dihydrate,

[0242] (d) about 0.75 to about 4.5 mg / mL of L-methionine,

[0243] (e) about 0.1 to about 5.0 mg / mL of polysorbate 80, and

[0244] (f) about 0.03 to about 2.0 mg / mL of sodium chloride, and the pH of the pharmaceutical composition is about 4.7 to about 5.3, preferably,

[0245] (E3) A pharmaceutical composition comprising:

[0246] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody (preferably Antibody α) as an active ingredient, and further containing:

[0247] (b) an acetate buffer consisting of: (b1) about 1.36 to about 4.08 mg / mL (preferably about 1.68 to about 2.05 mg / mL) of sodium acetate trihydrate and (b2) an amount of acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0248] (c) about 3.8 to about 78.7 mg / mL (preferably about 65.1 to about 72.6 mg / mL) of trehalose dihydrate,

[0249] (d) about 0.75 to about 3.0 mg / mL (preferably about 0.75 to about 2.25 mg / mL) of L-methionine,

[0250] (e) about 0.5 to about 3.0 mg / mL (preferably about 0.8 to about 1.2 mg / mL) of polysorbate 80, and

[0251] (f) about 0.06 to about 1.5 mg / mL (preferably about 1.15 to about 1.5 mg / mL) of sodium chloride, and the pH of the pharmaceutical composition is about 4.9 to about 5.1, and more preferably,

[0252] (F3) A pharmaceutical composition comprising:

[0253] (a) about 100 mg / mL of an anti-PD-1 / CD3 bispecific antibody (preferably antibody α) as an active ingredient, and further comprising:

[0254] (b) an acetate buffer consisting of about 1.9 mg / mL (specifically about 1.87 mg / mL) of sodium acetate trihydrate and about 0.4 mg / mL (specifically about 0.38 mg / mL) of acetic acid,

[0255] (c) about 69 mg / mL of trehalose dihydrate,

[0256] (d) about 1.5 mg / mL of L-methionine,

[0257] (e) about 1.0 mg / mL of polysorbate 80, and

[0258] (f) about 1.4 mg / mL (specifically about 1.36 mg / mL) of sodium chloride, and the pH of the pharmaceutical composition is about 5.0.

[0259] The aqueous pharmaceutical compositions of the present invention also include aqueous pharmaceutical compositions for intravenous or subcutaneous administration, whose bioavailability in a bioequivalence study is equivalent to that of any of the pharmaceutical compositions listed in (A) to (F), (A1) to (F1), (A2) to (F2), and (A3) to (F3) above, and which contain the anti-PD-1 / CD3 bispecific antibody of the present invention (preferably antibody α) as an active ingredient. Pharmaceutical compositions include those containing the same additives as those in any of the pharmaceutical compositions listed in (A) to (F), (A1) to (F1), (A2) to (F2), and (A3) to (F3) above, but also include those having different composition ratios and those in which any one or more additives are different. Examples include (i) a pharmaceutical composition containing at least trehalose, L-methionine, polysorbate 80, and sodium chloride, (ii) a pharmaceutical composition containing at least acetate buffer, trehalose, polysorbate 80, and sodium chloride, and (iii) a pharmaceutical composition containing at least trehalose, polysorbate 80, and sodium chloride.

[0260] In this context, bioequivalence can be determined, for example, by a bioequivalence study as described in the "Guidelines for Bioequivalence Studies of Generic Drugs" prescribed by the Ministry of Health, Labour and Welfare in Notice No. 1124005 of the Pharmaceutical and Food Safety Bureau on November 24, 2006, or its subsequent revisions. Specifically, in the guidelines, a crossover method is used in principle, but when blood is used as a sample, AUCt (AUC (area under the blood drug concentration-time curve) up to the final sampling time t) and Cmax (maximum blood concentration) in a single-dose study are used as bioequivalence measurement parameters.

[0261] According to the guidelines, after selecting appropriate research methods and then statistically analyzing the bioequivalence parameters of the test preparation and the standard preparation for bioequivalence, the test preparation and the standard preparation can be determined to be bioequivalent when they are within predetermined ranges. For example, according to the guidelines, when AUC and Cmax are log-normally distributed, when bioequivalence is expressed as the ratio of the population means of the parameters of the test preparation and the standard preparation, the acceptable range is 0.80 to 1.25, and when the 90% confidence interval of the difference between the logarithmic means of the parameters for the bioequivalence determination of the test preparation and the standard preparation is within the range of log(0.80) to log(1.25), the test preparation and the standard preparation are judged to be bioequivalent. Even if the above criteria are not met, the test formulation and the standard formulation are judged to be bioequivalent when the difference between the logarithmic means of the bioequivalence determination parameters of the test formulation and the standard formulation is within the range of log(0.90) to log(1.11), and when the dissolution behavior is judged to be similar in a dissolution study conducted in accordance with Section 3, A, V. of the Guidelines. However, this provision applies only when a total of 20 or more subjects (10 subjects per group) are used. Note that in the present invention, a formulation comprising the pharmaceutical composition listed in (A) to (F), (A1) to (F1), (A2) to (F2), and (A3) to (F3) above, respectively, is equivalent to the "standard formulation."

[0262] The aqueous pharmaceutical composition of the present invention is preferably sterilized before production. When an aseptic operation method is used as the aseptic treatment, for example, it can be prepared by diluting or dissolving the weighed antibody and each additive related to the present invention in water for injection (e.g., sterile purified water and distilled water for injection), and then filtering and sterilizing the resulting solution. Pharmaceutical compositions also include those prepared by reconstituting a lyophilized product containing the antibody and each additive related to the present invention with water for injection.

[0263] The formulations of the present invention can be in forms suitable for intravenous and subcutaneous administration. For example, for intravenous administration, the formulation can be sealed in a vial or ampoule, the size of which can be selected based on the total volume of the aqueous pharmaceutical composition. Note that even when sealed in a vial or ampoule, it can be collected in a syringe at the medical site and then administered subcutaneously.

[0264] If the preparation of the present invention is in the form of a preparation for subcutaneous administration, it can be provided as a pre-filled syringe preparation, wherein the pharmaceutical composition is pre-filled into a clean and sterile syringe. In addition, the pharmaceutical composition of the present invention can also be provided in the form of being filled and sealed in a clean and sterile cartridge, and further filled in a syringe pen, an automatic injector or a needle-free device (e.g., MediJector and BioJector (registered trademarks)).

[0265] [Pharmaceutical Uses of the Preparation of the Present Invention]

[0266] The aqueous pharmaceutical composition or formulation thereof related to the anti-PD-1 / CD3 bispecific antibody of the present invention can be used to prevent autoimmune diseases, graft-versus-host disease (GVHD), or blood cancers, inhibit the progression of symptoms of autoimmune diseases, graft-versus-host disease (GVHD), or blood cancers, inhibit the recurrence of autoimmune diseases, graft-versus-host disease (GVHD), or blood cancers, and / or treat autoimmune diseases, graft-versus-host disease (GVHD), or blood cancers.

[0267] Examples of autoimmune diseases that can be prevented, whose symptom progression or recurrence can be suppressed, and / or that can be treated by the aqueous pharmaceutical composition of the present invention or its formulation include Behçet's disease, systemic lupus erythematosus, chronic discoid lupus erythematosus, multiple sclerosis (systemic scleroderma and progressive systemic sclerosis), scleroderma, polymyositis, dermatomyositis, periarteritis nodosa (polyarteritis nodosa and microscopic polyangiitis), aortitis syndrome (Takayasu's arteritis), malignant rheumatoid arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthritis, mixed connective tissue disease, Sjögren's syndrome, adult-onset Still's disease , vasculitis, allergic granulomatosis with polyangiitis, allergic vasculitis, rheumatoid vasculitis, large vessel vasculitis, ANCA-associated vasculitis (such as granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis), Cogan's syndrome, RS3PE syndrome, temporal arteritis, polymyalgia rheumatica, fibromyalgia, antiphospholipid antibody syndrome, eosinophilic fasciitis, IgG4-related diseases (such as primary sclerosing cholangitis and autoimmune insulitis, etc.), Guillain-Barré syndrome, myasthenia gravis, chronic atrophic gastritis, autoimmune hepatitis, nonalcoholic steatohepatitis, primary biliary cirrhosis, Goodpasture's syndrome, Rapidly progressive glomerulonephritis, megaloblastic anemia, autoimmune hemolytic anemia, pernicious anemia, autoimmune neutropenia, idiopathic thrombocytopenic purpura, Basedow disease (Graves' disease (hyperthyroidism)), Hashimoto's thyroiditis, autoimmune adrenal insufficiency, primary hypothyroidism, Addison's disease (chronic adrenocortical insufficiency), idiopathic Addison's disease, type 1 diabetes, slowly progressive type 1 diabetes (latent autoimmune diabetes in adults), limited scleroderma, psoriasis, psoriatic arthritis, bullous pemphigoid, pemphigus, pemphigoid, pregnancy Herpes, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, alopecia areata, vitiligo, vitiligo vulgaris, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, sarcoidosis, giant cell arteritis, amyotrophic lateral sclerosis, Harada disease, autoimmune optic neuropathy, idiopathic azoospermia, habitual miscarriage, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), celiac disease, ankylosing spondylitis, severe asthma, chronic urticaria, transplant immunity, familial Mediterranean fever, eosinophilic chronic sinusitis, dilated cardiomyopathy, systemic mastocytosis and inclusion body myositis, etc.

[0268] In particular, preferred autoimmune diseases that can be prevented, symptom progression or recurrence inhibited, and / or treated by the aqueous pharmaceutical composition or formulation thereof of the present invention include psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, and myasthenia gravis.

[0269] In addition, examples of blood cancers that can be prevented, whose symptom progression or recurrence can be suppressed, and / or treated by the aqueous pharmaceutical composition of the present invention or its formulation include multiple myeloma, malignant lymphoma (e.g., non-Hodgkin's lymphoma (e.g., B-cell non-Hodgkin's lymphoma and T / NK-cell non-Hodgkin's lymphoma (e.g., precursor T-cell lymphoblastic lymphoma, chronic T-cell lymphocytic leukemia, T-cell large granular lymphocytic lymphoma, NK-cell large granular leukemia, aggressive NK-cell leukemia, peripheral T-cell lymphoma, unspecified peripheral T-cell lymphoma, unclassified peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, (CD30-positive) anaplastic large cell lymphoma, Tumor, angiocentric lymphoma, intestinal T-cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic gamma delta T-cell lymphoma, cutaneous T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, Sézary syndrome, Hodgkin-like / Hodgkin-related anaplastic large cell lymphoma, extranodal NK / T-cell lymphoma, adult T-cell leukemia, T-cell prolymphocytic leukemia, NK-cell chronic lymphoproliferative disease, systemic EBV-positive childhood T-cell lymphoma, hydropic vaccinia-like lymphoproliferative disorder, extranodal NK / T-cell lymphoma (nasal type), enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, indolent gastrointestinal T-cell lymphoproliferative disorder, hepatosplenic T-cell lymphoma, primary cutaneous CD30-positive T-cell lymphoproliferative disorder, lymphomatoid papulosis, primary cutaneous anaplastic large cell lymphoma, primary cutaneous gamma delta T-cell lymphoma, primary cutaneous C D8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, primary cutaneous acral CD8-positive T-cell lymphoma, primary cutaneous CD4-positive small / medium T-cell lymphoproliferative disorder, follicular T-cell lymphoma, nodal peripheral T-cell lymphoma with TFH phenotype, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, and breast implant-associated anaplastic large cell lymphoma (and Hodgkin lymphoma), leukemia (e.g., acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, and chronic myeloid leukemia), primary central nervous system lymphoma, and myeloproliferative syndrome.

[0270] In particular, preferred blood cancers that can be prevented, symptom progression or recurrence suppressed, and / or treated by the aqueous pharmaceutical composition or formulation of the present invention include peripheral T-cell lymphoma and cutaneous T-cell lymphoma.

[0271] As used herein, in the present invention, the term "treating" refers to curing or ameliorating a disease or its symptoms, the term "preventing" refers to preventing or delaying the onset of a disease or its symptoms over a certain period of time, and the term "inhibiting symptom progression" refers to inhibiting the progression or worsening of symptoms to prevent the progression of the disease condition. Note that "preventing" also includes inhibiting recurrence. The term "inhibiting recurrence" refers to preventing the recurrence of a disease or its syndrome or reducing the likelihood of recurrence.

[0272] The present invention provides examples of the embodiments listed in the following [1] to

[95] , [1-1] to [1-3], and [2-1] to [2-3], respectively.

[0273] [1] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising an antibody (preferably an anti-PD-1 / CD3 bispecific antibody) as an active ingredient, and further comprising a buffer (preferably acetate buffer), trehalose, an antioxidant (preferably L-methionine), polysorbate 80, and sodium chloride;

[0274] [2] The aqueous pharmaceutical composition or formulation according to the aforementioned item [1], wherein the anti-PD-1 / CD3 bispecific antibody is present at about 0.01 to about 200 mg / mL (preferably about 0.1 to about 150 mg / mL (preferably about 0.1 to about 1.2 mg / mL, about 5 to about 25 mg / mL, or about 80 to about 150 mg / mL));

[0275] [3] The aqueous pharmaceutical composition or formulation thereof according to the aforementioned item [1], wherein the anti-PD-1 / CD3 bispecific antibody is about 0.01 mg / mL, about 0.02 mg / mL, about 0.03 mg / mL, about 0.04 mg / mL, about 0.05 mg / mL, about 0.06 mg / mL, about 0.07 mg / mL, about 0.08 mg / mL, about 0.09 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 5 mg / mL, about 10 about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, or about 200 mg / mL;

[0276] [4] The aqueous pharmaceutical composition or formulation according to item [1], wherein the anti-PD-1 / CD3 bispecific antibody is at a concentration of about 0.5 mg / mL, about 1 mg / mL, about 10 mg / mL, or about 100 mg / mL;

[0277] [5] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [1] to [4], wherein the acetate buffer is about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM);

[0278] [6] The aqueous pharmaceutical composition or formulation thereof according to any one of the preceding items [1] to [4], wherein the acetate buffer is about 7.3 mM, about 10 mM, about 14.6 mM, about 15 mM, about 18 mM, about 20 mM, about 20.07 mM, about 21 mM, about 22 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 43.8 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 70 mM or about 73.0 mM;

[0279] [7] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [1] to [4], wherein the acetate buffer is about 20.07 mM;

[0280] [8] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [5] to [7], wherein the acetate buffer consists of a combination of sodium acetate trihydrate and acetic acid;

[0281] [9] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [1] to [8], wherein the amount of trehalose is from about 5 to about 286.1 mM (preferably from about 10 to about 207.9 mM, more preferably from about 172 to about 193 mM);

[0282]

[10] The aqueous pharmaceutical composition or formulation thereof according to any one of the aforementioned items [1] to [8], wherein the trehalose is about 5 mM, about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 172 mM, about 180 mM, about 182 mM, about 182.3 mM, about 182.38 mM, about 182.4 mM, about 190 mM, about 193 mM, about 200 mM, about 207.9 mM, about 210 mM, about 220 mM, about 225 mM, about 230 mM, about 240 mM, about 250 mM, about 260 mM, about 270 mM, about 280 mM, about 285 mM, about 286 mM, or about 286.1 mM;

[0283]

[11] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [1] to [8], wherein the trehalose content is about 182.38 mM;

[0284]

[12] The aqueous pharmaceutical composition or formulation according to any one of the aforementioned items [1] to [8], wherein the trehalose is trehalose dihydrate;

[0285]

[13] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [1] to

[12] , wherein the amount of L-methionine is about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM);

[0286]

[14] The aqueous pharmaceutical composition or formulation according to any one of items [1] to

[12] , wherein the amount of L-methionine is about 5 mM, about 10 mM, about 10.05 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM or about 30.2 mM;

[0287]

[15] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [1] to

[12] , wherein the amount of L-methionine is about 10.05 mM;

[0288]

[16] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [1] to

[15] , wherein the content of polysorbate 80 is about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to about 0.12% (w / v);

[0289]

[17] The aqueous pharmaceutical composition or formulation according to any one of items [1] to

[15] , wherein the content of polysorbate 80 is about 0.01% (w / v), about 0.02% (w / v), about 0.04% (w / v), about 0.05% (w / v), about 0.06% (w / v), about 0.08% (w / v), about 0.1% (w / v), about 0.12% (w / v), about 0.15% (w / v), about 0.2% (w / v), about 0.25% (w / v), about 0.3% (w / v), about 0.35% (w / v), about 0.4% (w / v), about 0.45% (w / v) or about 0.5% (w / v);

[0290]

[18] The aqueous pharmaceutical composition or formulation according to any one of items [1] to

[15] , wherein the content of polysorbate 80 is about 0.1% (w / v);

[0291]

[19] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [1] to

[18] , wherein the sodium chloride content is about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM);

[0292]

[20] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [1] to

[18] , wherein the sodium chloride is about 0.5 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 19.6 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 23.27 mM, about 24.0 mM, about 25 mM, about 25.7 mM, about 30 mM or about 34.2 mM;

[0293]

[21] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [1] to

[18] , wherein the sodium chloride content is about 23.27 mM;

[0294]

[22] The aqueous pharmaceutical composition or formulation according to any one of items [1] to

[21] , wherein the volume per formulation of the aqueous pharmaceutical composition (preferably for intravenous administration) is about 5 mL;

[0295]

[23] The aqueous pharmaceutical composition or formulation according to the aforementioned item

[22] , wherein the acetate buffer suitable for use in the aqueous pharmaceutical composition of the aforementioned item

[22] is composed of: (i) about 3.4 to about 34 mg of sodium acetate trihydrate and (ii) an amount of glacial acetic acid to achieve a pH of about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0), corresponding to the amount of sodium acetate trihydrate in the aforementioned item (i);

[0296]

[24] The aqueous pharmaceutical composition or formulation according to the aforementioned item

[22] , wherein the acetate buffer suitable for use in the aqueous pharmaceutical composition of the aforementioned item

[22] is composed of: (i) about 6.8 to about 20.4 mg (preferably about 8.4 to about 10.2 mg) of sodium acetate trihydrate and (ii) an amount of glacial acetic acid to achieve a pH of about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0), corresponding to the amount of sodium acetate trihydrate in the aforementioned item (i);

[0297]

[25] The aqueous pharmaceutical composition or formulation according to item

[22] , wherein the acetate buffer suitable for the aqueous pharmaceutical composition of item

[22] is composed of about 9.4 mg (specifically about 9.35 mg) of sodium acetate trihydrate and about 1.9 mg of glacial acetic acid;

[0298]

[26] The aqueous pharmaceutical composition or formulation according to any one of items

[22] to

[25] , wherein the trehalose is trehalose dihydrate;

[0299]

[27] The aqueous pharmaceutical composition or formulation according to the aforementioned item

[26] , wherein the amount of trehalose dihydrate is about 9.46 to about 541.2 mg (preferably about 18.9 to about 393.3 mg, more preferably about 325 to about 365.1 mg, even more preferably about 345 mg);

[0300]

[28] The aqueous pharmaceutical composition or formulation thereof according to any one of the aforementioned items

[22] to

[27] , wherein the antioxidant is L-methionine.

[0301]

[29] The aqueous pharmaceutical composition or formulation according to the aforementioned item

[28] , wherein the amount of L-methionine is about 3.75 to about 22.5 mg (preferably about 3.75 to about 15.0 mg, more preferably about 3.75 to about 11.25 mg, even more preferably about 7.5 mg);

[0302]

[30] The aqueous pharmaceutical composition or formulation according to any one of items

[22] to

[29] , wherein the amount of polysorbate 80 is about 0.5 to about 25 mg (preferably about 2.5 to about 15 mg, more preferably about 5 mg);

[0303]

[31] The aqueous pharmaceutical composition or formulation according to any one of items

[22] to

[30] , wherein the amount of sodium chloride is about 0.15 to about 10.0 mg (preferably about 0.29 to about 7.5 mg, more preferably about 5.8 to about 7.5 mg, even more preferably about 6.8 mg);

[0304]

[32] The aqueous pharmaceutical composition or formulation thereof according to any one of items [1] to

[21] , wherein the volume of each formulation of the aqueous pharmaceutical composition is about 2 mL, and the amount of the corresponding additive is about 2 / 5 of the amount of the corresponding additive according to any one or more of items

[23] to

[31] ;

[0305]

[33] The aqueous pharmaceutical composition or formulation according to any one of items [1] to

[21] , wherein the volume of each formulation of the aqueous pharmaceutical composition (preferably for subcutaneous administration) is about 1 mL;

[0306]

[34] The aqueous pharmaceutical composition or formulation according to the aforementioned item

[33] , wherein the acetate buffer suitable for use in the aqueous pharmaceutical composition of the aforementioned item

[33] is composed of: (i) about 0.68 to about 6.8 mg of sodium acetate trihydrate and (ii) an amount of glacial acetic acid to achieve a pH of about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0), corresponding to the amount of sodium acetate trihydrate in the aforementioned item (i);

[0307]

[35] The aqueous pharmaceutical composition or formulation according to the aforementioned item

[33] , wherein the acetate buffer suitable for the aqueous pharmaceutical composition of the aforementioned item

[33] is composed of: (i) about 1.36 to about 4.08 mg (preferably about 1.68 to about 2.05 mg) of sodium acetate trihydrate and (ii) an amount of glacial acetic acid to achieve a pH of about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0), corresponding to the amount of sodium acetate trihydrate in the aforementioned item (i);

[0308]

[36] The aqueous pharmaceutical composition or formulation according to item

[33] , wherein the acetate buffer suitable for the aqueous pharmaceutical composition of item

[33] is composed of about 1.9 mg (specifically about 1.87 mg) of sodium acetate trihydrate and about 0.4 mg (specifically about 0.38 mg) of glacial acetic acid;

[0309]

[37] The aqueous pharmaceutical composition or formulation according to any one of items

[33] to

[36] , wherein the trehalose is trehalose dihydrate;

[0310]

[38] The aqueous pharmaceutical composition or formulation according to the aforementioned item

[37] , wherein the amount of trehalose dihydrate is about 1.9 to about 108.3 mg (preferably about 3.8 to about 78.7 mg, more preferably about 65.1 to about 72.6 mg, even more preferably about 69 mg);

[0311]

[39] The aqueous pharmaceutical composition or formulation according to any one of items

[33] to

[38] , wherein the antioxidant is L-methionine;

[0312]

[40] The aqueous pharmaceutical composition or formulation according to the aforementioned item

[39] , wherein the amount of L-methionine is about 0.75 to about 4.5 mg (preferably about 0.75 to about 3.0 mg, more preferably about 0.75 to about 2.25 mg, even more preferably about 1.5 mg);

[0313]

[41] The aqueous pharmaceutical composition or formulation according to any one of items

[33] to

[40] , wherein the amount of polysorbate 80 is about 0.1 to about 5.0 mg (preferably about 0.5 to about 3.0 mg, more preferably about 1.0 mg);

[0314]

[42] The aqueous pharmaceutical composition or formulation according to any one of items

[33] to

[41] , wherein the amount of sodium chloride is about 0.03 to about 2.0 mg (preferably about 0.06 to about 1.5 mg, more preferably about 1.15 to about 1.5 mg, even more preferably about 1.4 mg (specifically about 1.36 mg));

[0315]

[43] The aqueous pharmaceutical composition or formulation according to any one of items [1] to

[42] , wherein the pH of the aqueous pharmaceutical composition is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0);

[0316]

[44] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0317] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 0.5 mg / mL, about 1 mg / mL or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further containing:

[0318] (b) about 7.3 to 73.0 mM acetate buffer,

[0319] (c) from about 5 to about 286.1 mM trehalose,

[0320] (d) about 5 to about 30.2 mM L-methionine,

[0321] (e) about 0.01 to about 0.5% (w / v) polysorbate 80, and

[0322] (f) from about 0.5 to about 34.2 mM sodium chloride, and

[0323] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.7 to about 5.3;

[0324]

[45] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0325] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 0.5 mg / mL, about 1 mg / mL or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further containing:

[0326] (b) about 14.6 to about 43.8 mM (preferably about 18 to about 22 mM) acetate buffer,

[0327] (c) about 10 to about 207.9 mM (preferably about 172 to about 193 mM) trehalose,

[0328] (d) about 5 to about 20 mM (preferably about 5 to about 15 mM) of L-methionine,

[0329] (e) about 0.05 to about 0.3% (w / v) (preferably about 0.08 to about 0.12% (w / v)) polysorbate 80, and

[0330] (f) about 1.0 to about 25.7 mM (preferably about 19.6 to about 25.7 mM) sodium chloride, and

[0331] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.9 to about 5.1;

[0332]

[46] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0333] (a) about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0334] (b) about 20.07 mM acetate buffer,

[0335] (c) about 182.38 mM trehalose,

[0336] (d) about 10.05 mM L-methionine,

[0337] (e) about 0.1% (w / v) polysorbate 80, and

[0338] (f) approximately 23.27 mM sodium chloride, and

[0339] The pH of the aqueous pharmaceutical composition or formulation thereof is about 5.0;

[0340]

[47] An aqueous pharmaceutical composition for subcutaneous administration or a formulation thereof, comprising:

[0341] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0342] (b) about 7.3 to about 73.0 mM acetate buffer,

[0343] (c) from about 5 to about 286.1 mM trehalose,

[0344] (d) about 5 to about 30.2 mM L-methionine,

[0345] (e) about 0.01 to about 0.5% (w / v) polysorbate 80, and

[0346] (f) from about 0.5 to about 34.2 mM sodium chloride, and

[0347] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.7 to about 5.3;

[0348]

[48] ​​An aqueous pharmaceutical composition for subcutaneous administration or a formulation thereof, comprising:

[0349] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0350] (b) about 14.6 to about 43.8 mM (preferably about 18 to about 22 mM) acetate buffer,

[0351] (c) about 10 to about 207.9 mM (preferably about 172 to about 193 mM) trehalose,

[0352] (d) about 5 to about 20 mM (preferably about 5 to about 15 mM) of L-methionine,

[0353] (e) about 0.05 to about 0.3% (w / v) (preferably about 0.08 to about 0.12% (w / v)) polysorbate 80, and

[0354] (f) about 1.0 to about 25.7 mM (preferably about 19.6 to about 25.7 mM) sodium chloride, and

[0355] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.9 to about 5.1;

[0356]

[49] An aqueous pharmaceutical composition or a formulation thereof for subcutaneous administration, comprising:

[0357] (a) about 100 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0358] (b) about 20.07 mM acetate buffer,

[0359] (c) about 182.38 mM trehalose,

[0360] (d) about 10.05 mM L-methionine,

[0361] (e) about 0.1% (w / v) polysorbate 80, and

[0362] (f) approximately 23.27 mM sodium chloride, and

[0363] The pH of the aqueous pharmaceutical composition or formulation thereof is about 5.0;

[0364]

[50] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0365] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 0.5 mg / mL, about 1 mg / mL or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further containing:

[0366] (b) an acetate buffer consisting of: (b1) about 0.68 to about 6.8 mg / mL of sodium acetate trihydrate and (b2) an amount of acetic acid to bring the pH to about 4.7 to about 5.3, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0367] (c) about 1.9 to about 108.3 mg / mL of trehalose dihydrate,

[0368] (d) about 0.75 to about 4.5 mg / mL of L-methionine

[0369] (e) about 0.1 to about 5.0 mg / mL of polysorbate 80, and

[0370] (f) about 0.03 to about 2.0 mg / mL of sodium chloride, and

[0371] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.7 to about 5.3;

[0372]

[51] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0373] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 0.5 mg / mL, about 1 mg / mL or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further containing:

[0374] (b) an acetate buffer consisting of: (b1) about 1.36 to about 4.08 mg / mL (preferably about 1.68 to about 2.05 mg / mL) of sodium acetate trihydrate and (b2) an amount of acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0375] (c) about 3.8 to about 78.7 mg / mL (preferably about 65.1 to about 72.6 mg / mL) of trehalose dihydrate,

[0376] (d) about 0.75 to about 3.0 mg / mL (preferably about 0.75 to about 2.25 mg / mL) of L-methionine,

[0377] (e) about 0.5 to about 3.0 mg / mL (preferably about 0.8 to about 1.2 mg / mL) of polysorbate 80, and

[0378] (f) about 0.06 to about 1.5 mg / mL (preferably about 1.15 to about 1.5 mg / mL) of sodium chloride, and

[0379] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.9 to about 5.1;

[0380]

[52] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0381] (a) about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0382] (b) an acetate buffer consisting of about 1.9 mg / mL (specifically about 1.87 mg / mL) of sodium acetate trihydrate and about 0.4 mg / mL (specifically about 0.38 mg / mL) of acetic acid,

[0383] (c) about 69 mg / mL of trehalose dihydrate,

[0384] (d) about 1.5 mg / mL of L-methionine,

[0385] (e) about 1.0 mg / mL of polysorbate 80, and

[0386] (f) about 1.4 mg / mL (specifically about 1.36 mg / mL) of sodium chloride, and

[0387] The pH of the aqueous pharmaceutical composition or formulation thereof is about 5.0;

[0388]

[53] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0389] (a) about 0.5 to about 6 mg or about 25 to about 125 mg (preferably about 2.5 mg, about 5 mg or about 50 mg, respectively) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0390] (b) an acetate buffer consisting of: (b1) about 3.4 to about 34.0 mg of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.7 to about 5.3, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0391] (c) from about 9.46 to about 541.2 mg of trehalose dihydrate,

[0392] (d) about 3.75 to about 22.5 mg of L-methionine,

[0393] (e) from about 0.5 to about 25.0 mg of polysorbate 80, and

[0394] (f) from about 0.15 to about 10.0 mg of sodium chloride, and

[0395] The pH of the aqueous pharmaceutical composition or formulation thereof is about 4.7 to about 5.3, and the volume of each formulation is about 5 mL;

[0396]

[54] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0397] (a) about 0.5 to about 6 mg or about 25 to about 125 mg (preferably about 2.5 mg, about 5 mg or about 50 mg, respectively) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0398] (b) an acetate buffer consisting of: (b1) about 6.8 to about 20.4 mg (preferably about 8.4 to about 10.2 mg) of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0399] (c) about 18.9 to about 393.3 mg (preferably about 325 to about 365.1 mg) of trehalose dihydrate,

[0400] (d) about 3.75 to about 15.0 mg (preferably about 3.75 to about 11.25 mg) of L-methionine,

[0401] (e) about 2.5 to about 15.0 mg (preferably about 4 to about 6 mg) of polysorbate 80, and

[0402] (f) from about 0.29 to about 7.5 mg (preferably from about 5.8 to about 7.5 mg) of sodium chloride, and

[0403] The pH of the aqueous pharmaceutical composition or formulation thereof is about 4.9 to about 5.1, and the volume of each formulation is about 5 mL;

[0404]

[55] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0405] (a) about 2.5 mg, about 5 mg, or about 50 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0406] (b) acetate buffer consisting of about 9.4 mg (specifically about 9.35 mg) of sodium acetate trihydrate and about 1.9 mg of glacial acetic acid,

[0407] (c) about 345 mg of trehalose dihydrate,

[0408] (d) about 7.5 mg of L-methionine,

[0409] (e) approximately 5.0 mg of polysorbate 80, and

[0410] (f) approximately 6.8 mg of sodium chloride, and

[0411] The pH of the aqueous pharmaceutical composition or its formulation is about 5.0, and the volume of each formulation is about 5 mL;

[0412]

[56] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0413] (a) about 0.2 to about 2.4 mg or about 10 to about 50 mg (preferably about 1 mg, about 2 mg or about 20 mg, respectively) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further containing:

[0414] (b) an acetate buffer consisting of: (b1) about 1.36 to about 13.6 mg of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.7 to about 5.3, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0415] (c) from about 3.8 to about 216.6 mg of trehalose dihydrate,

[0416] (d) about 1.5 to about 9.0 mg of L-methionine,

[0417] (e) from about 0.2 to about 10.0 mg of polysorbate 80, and

[0418] (f) from about 0.06 to about 4.0 mg of sodium chloride, and

[0419] The pH of the aqueous pharmaceutical composition or formulation thereof is about 4.7 to about 5.3, and the volume of each formulation is about 2 mL;

[0420]

[57] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0421] (a) about 0.2 to about 2.4 mg or about 10 to about 50 mg (preferably about 1 mg, about 2 mg or about 20 mg, respectively) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further containing:

[0422] (b) an acetate buffer consisting of: (b1) about 2.72 to about 8.16 mg (preferably about 3.36 to about 4.1 mg) of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0423] (c) about 7.6 to about 157.4 mg (preferably about 130.2 to about 145.2 mg) of trehalose dihydrate,

[0424] (d) about 1.5 to about 6.0 mg (preferably about 1.5 to about 4.5 mg) of L-methionine,

[0425] (e) from about 1.0 to about 6.0 mg of polysorbate 80, and

[0426] (f) about 0.12 to about 3.0 mg (preferably about 2.3 to about 3.0 mg) of sodium chloride, and

[0427] The pH of the aqueous pharmaceutical composition or formulation thereof is about 4.9 to about 5.1, and the volume of each formulation is about 2 mL;

[0428]

[58] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0429] (a) about 1 mg, about 2 mg, or about 20 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0430] (b) an acetate buffer consisting of about 3.7 mg (specifically about 3.74 mg) of sodium acetate trihydrate and about 0.8 mg (specifically about 0.76 mg) of glacial acetic acid,

[0431] (c) about 138 mg of trehalose dihydrate,

[0432] (d) about 3.0 mg of L-methionine,

[0433] (e) approximately 2.0 mg of polysorbate 80, and

[0434] (f) about 2.7 mg (specifically about 2.72 mg) of sodium chloride, and

[0435] The pH of the aqueous pharmaceutical composition or its formulation is about 5.0, and the volume of each formulation is about 2 mL;

[0436]

[59] An aqueous pharmaceutical composition for subcutaneous administration or a formulation thereof, comprising:

[0437] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0438] (b) an acetate buffer consisting of (b1) about 0.68 to about 6.8 mg / mL of sodium acetate trihydrate and (b2) an amount of acetic acid to achieve a pH of about 4.7 to about 5.3, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0439] (c) about 1.9 to about 108.3 mg / mL of trehalose dihydrate,

[0440] (d) about 0.75 to about 4.5 mg / mL of L-methionine,

[0441] (e) about 0.1 to about 5.0 mg / mL of polysorbate 80, and

[0442] (f) about 0.03 to about 2.0 mg / mL of sodium chloride, and

[0443] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.7 to about 5.3;

[0444]

[60] An aqueous pharmaceutical composition for subcutaneous administration or a formulation thereof, comprising:

[0445] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0446] (b) an acetate buffer consisting of: (b1) about 1.36 to about 4.08 mg / mL (preferably about 1.68 to about 2.05 mg / mL) of sodium acetate trihydrate and (b2) an amount of acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0447] (c) about 3.8 to about 78.7 mg / mL (preferably about 65.1 to about 72.6 mg / mL) of trehalose dihydrate,

[0448] (d) about 0.75 to about 3.0 mg / mL (preferably about 0.75 to about 2.25 mg / mL) of L-methionine,

[0449] (e) about 0.5 to about 3.0 mg / mL (preferably about 0.8 to about 1.2 mg / mL) of polysorbate 80, and

[0450] (f) about 0.06 to about 1.5 mg / mL (preferably about 1.15 to about 1.5 mg / mL) of sodium chloride, and

[0451] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.9 to about 5.1;

[0452]

[61] An aqueous pharmaceutical composition or a formulation thereof for subcutaneous administration, comprising:

[0453] (a) about 100 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0454] (b) an acetate buffer consisting of about 1.9 mg / mL (specifically about 1.87 mg / mL) of sodium acetate trihydrate and about 0.4 mg / mL (specifically about 0.38 mg / mL) of acetic acid,

[0455] (c) about 69 mg / mL of trehalose dihydrate,

[0456] (d) about 1.5 mg / mL of L-methionine,

[0457] (e) about 1.0 mg / mL of polysorbate 80, and

[0458] (f) about 1.4 mg / mL (specifically about 1.36 mg / mL) of sodium chloride, and

[0459] The pH of the aqueous pharmaceutical composition or formulation thereof is about 5.0;

[0460]

[62] An aqueous pharmaceutical composition or a formulation thereof for subcutaneous administration, comprising:

[0461] (a) about 80 to about 150 mg (preferably about 100 mg) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0462] (b) an acetate buffer consisting of (b1) about 0.68 to about 6.8 mg of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to achieve a pH of about 4.7 to about 5.3, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0463] (c) from about 1.9 to about 108.3 mg of trehalose dihydrate,

[0464] (d) about 0.75 to about 4.5 mg of L-methionine,

[0465] (e) from about 0.1 to about 5.0 mg of polysorbate 80, and

[0466] (f) from about 0.03 to about 2.0 mg of sodium chloride, and

[0467] The pH of the aqueous pharmaceutical composition or formulation thereof is about 4.7 to about 5.3, and the volume of each formulation is about 1 mL;

[0468]

[63] An aqueous pharmaceutical composition or a formulation thereof for subcutaneous administration, comprising:

[0469] (a) about 80 to about 150 mg (preferably about 100 mg) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0470] (b) an acetate buffer consisting of: (b1) about 1.36 to about 4.08 mg (preferably about 1.68 to about 2.05 mg) of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0471] (c) about 3.8 to about 78.7 mg (preferably about 65.1 to about 72.6 mg) of trehalose dihydrate,

[0472] (d) about 0.75 to about 3.0 mg (preferably about 0.75 to about 2.25 mg) of L-methionine,

[0473] (e) from about 0.5 to about 3.0 mg of polysorbate 80, and

[0474] (f) from about 0.06 to about 1.5 mg (preferably from about 1.15 to about 1.5 mg) of sodium chloride, and

[0475] The pH of the aqueous pharmaceutical composition or formulation thereof is about 4.9 to about 5.1, and the volume of each formulation is about 1 mL;

[0476]

[64] An aqueous pharmaceutical composition or a formulation thereof for subcutaneous administration, comprising:

[0477] (a) about 100 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0478] (b) acetate buffer consisting of about 1.9 mg (specifically about 1.87 mg) of sodium acetate trihydrate and about 0.4 mg (specifically about 0.38 mg) of glacial acetic acid,

[0479] (c) about 69 mg of trehalose dihydrate,

[0480] (d) about 1.5 mg of L-methionine,

[0481] (e) approximately 1.0 mg of polysorbate 80, and

[0482] (f) about 1.4 mg (specifically about 1.36 mg) of sodium chloride, and

[0483] The pH of the aqueous pharmaceutical composition or its formulation is about 5.0, and the volume of each formulation is about 1 mL;

[0484]

[65] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0485] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 0.5 mg / mL, about 1 mg / mL or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further containing:

[0486] (b) a buffer (preferably an acetate buffer of about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20.07 mM) or a buffer having pH buffering properties equivalent to those of the acetate buffer),

[0487] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182.38 mM) of trehalose,

[0488] (d) about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10.05 mM) of L-methionine,

[0489] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to about 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0490] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23.27 mM) of sodium chloride, and

[0491] The pH of the aqueous pharmaceutical composition or its formulation is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0);

[0492]

[66] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0493] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 0.5 mg / mL, about 1 mg / mL or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further containing:

[0494] (b) about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20.07 mM) acetate buffer,

[0495] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182.38 mM) of trehalose,

[0496] (d) an antioxidant of L-methionine (preferably about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10.05 mM) or an antioxidant having an antioxidant capacity equivalent to that of the above-mentioned L-methionine),

[0497] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to about 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0498] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23.27 mM) of sodium chloride, and

[0499] The pH of the aqueous pharmaceutical composition or its formulation is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0);

[0500]

[67] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0501] (a) about 0.1 to about 1.2 mg / mL or about 5 to about 25 mg / mL (preferably about 0.5 mg / mL, about 1 mg / mL or about 10 mg / mL, respectively) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further containing:

[0502] (b) a buffer (preferably an acetate buffer of about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20.07 mM) or a buffer having pH buffering properties equivalent to those of the acetate buffer),

[0503] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182.38 mM) of trehalose,

[0504] (d) an antioxidant of L-methionine (preferably about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10.05 mM) or an antioxidant having an antioxidant capacity equivalent to that of the above-mentioned L-methionine),

[0505] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to about 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0506] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23.27 mM) of sodium chloride, and

[0507] The pH of the aqueous pharmaceutical composition or its formulation is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0);

[0508]

[68] An aqueous pharmaceutical composition for subcutaneous administration or a formulation thereof, comprising:

[0509] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0510] (b) a buffer (preferably an acetate buffer of about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20.07 mM) or a buffer having pH buffering properties equivalent to those of the acetate buffer),

[0511] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182.38 mM) of trehalose,

[0512] (d) about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10.05 mM) of L-methionine,

[0513] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to about 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0514] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23.27 mM) of sodium chloride, and

[0515] The pH of the aqueous pharmaceutical composition or its formulation is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0);

[0516]

[69] An aqueous pharmaceutical composition for subcutaneous administration or a formulation thereof, comprising:

[0517] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0518] (b) about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20.07 mM) acetate buffer,

[0519] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182.38 mM) of trehalose,

[0520] (d) an antioxidant of L-methionine (preferably about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10.05 mM) or an antioxidant having an antioxidant capacity equivalent to that of the above-mentioned L-methionine),

[0521] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to about 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0522] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23.27 mM) of trehalose, and

[0523] The pH of the aqueous pharmaceutical composition or its formulation is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0);

[0524]

[70] An aqueous pharmaceutical composition or a formulation thereof for subcutaneous administration, comprising:

[0525] (a) about 80 to about 150 mg / mL (preferably about 100 mg / mL) of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0526] (b) a buffer (preferably an acetate buffer of about 7.3 to about 73.0 mM (preferably about 14.6 to about 43.8 mM, more preferably about 18 to about 22 mM, even more preferably about 20.07 mM) or a buffer having pH buffering properties equivalent to those of the acetate buffer),

[0527] (c) about 5 to about 286.1 mM (preferably about 10 to about 207.9 mM, more preferably about 172 to about 193 mM, even more preferably about 182.38 mM) of trehalose,

[0528] (d) an antioxidant of L-methionine (preferably about 5 to about 30.2 mM (preferably about 5 to about 20 mM, more preferably about 5 to about 15 mM, even more preferably about 10.05 mM) or an antioxidant having an antioxidant capacity equivalent to that of the above-mentioned L-methionine),

[0529] (e) about 0.01 to about 0.5% (w / v) (preferably about 0.05 to about 0.3% (w / v), more preferably about 0.08 to about 0.12% (w / v), even more preferably about 0.1% (w / v)) of polysorbate 80, and

[0530] (f) about 0.5 to about 34.2 mM (preferably about 1.0 to about 25.7 mM, more preferably about 19.6 to about 25.7 mM, even more preferably about 23.27 mM) of trehalose, and

[0531] The pH of the aqueous pharmaceutical composition or its formulation is about 4.7 to about 5.3 (preferably about 4.9 to about 5.1, more preferably about 5.0);

[0532]

[71] The aqueous pharmaceutical composition or formulation thereof according to any one of the preceding items [1] to

[70] , wherein the anti-PD-1 / CD3 bispecific antibody is the anti-PD-1 / CD3 bispecific antibody disclosed in the specification of the patent application designated by WO2019 / 156199;

[0533]

[72] The aqueous pharmaceutical composition or formulation thereof according to any one of items [1] to

[70] , wherein the anti-PD-1 / CD3 bispecific antibody comprises:

[0534] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0535] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0536] (a) wherein the heavy chain described in item (i) above comprises any one of the amino acid sequences selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5,

[0537] (b) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0538] (c) The light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0539]

[73] The aqueous pharmaceutical composition or formulation according to item

[72] , wherein the heavy chain constituting the antigen binding site that specifically binds to PD-1 comprises the amino acid sequence shown in SEQ ID NO: 5;

[0540]

[74] The aqueous pharmaceutical composition or formulation thereof according to any one of items

[71] to

[73] , wherein the heavy chain constant region of the heavy chain constituting the antigen-binding site that specifically binds to PD-1 as described in item

[72] or

[73] is replaced by a heavy chain constant region comprising any one of the amino acid sequences selected from SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, and the heavy chain constant region of the heavy chain constituting the antigen-binding site that specifically binds to CD3 as described in item

[72] is replaced by a heavy chain constant region comprising any one of the amino acid sequences selected from SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19;

[0541]

[75] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0542] (a) about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0543] (b) about 14.6 to about 43.8 mM (preferably about 18 to about 22 mM) acetate buffer,

[0544] (c) about 10 to about 207.9 mM (preferably about 172 to about 193 mM) trehalose,

[0545] (d) about 5 to about 20 mM (preferably about 5 to about 15 mM) of L-methionine,

[0546] (e) about 0.05 to about 0.3% (w / v) (preferably about 0.08 to about 0.12% (w / v)) polysorbate 80, and

[0547] (f) about 1.0 to about 25.7 mM (preferably about 19.6 to about 25.7 mM) sodium chloride, and

[0548] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.9 to about 5.1, and

[0549] The anti-PD-1 / CD3 bispecific antibody comprises:

[0550] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0551] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0552] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0553] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0554] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0555]

[76] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0556] (a) about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0557] (b) about 20.07 mM acetate buffer,

[0558] (c) about 182.38 mM trehalose,

[0559] (d) about 10.05 mM L-methionine,

[0560] (e) about 0.1% (w / v) polysorbate 80, and

[0561] (f) approximately 23.27 mM sodium chloride, and

[0562] The pH of the aqueous pharmaceutical composition or formulation thereof is about 5.0, and

[0563] The anti-PD-1 / CD3 bispecific antibody comprises:

[0564] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0565] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0566] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0567] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0568] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0569]

[77] An aqueous pharmaceutical composition or a formulation thereof for subcutaneous administration, comprising:

[0570] (a) about 100 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0571] (b) about 14.6 to about 43.8 mM (preferably about 18 to about 22 mM) acetate buffer,

[0572] (c) about 10 to about 207.9 mM (preferably about 172 to about 193 mM) trehalose,

[0573] (d) about 5 to about 20 mM (preferably about 5 to about 15 mM) of L-methionine,

[0574] (e) about 0.05 to about 0.3% (w / v) (preferably about 0.08 to about 0.12% (w / v)) polysorbate 80, and

[0575] (f) about 1.0 to about 25.7 mM (preferably about 19.6 to about 25.7 mM) sodium chloride, and

[0576] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.9 to about 5.1, and

[0577] The anti-PD-1 / CD3 bispecific antibody comprises:

[0578] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0579] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0580] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0581] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0582] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0583]

[78] An aqueous pharmaceutical composition or a formulation thereof for subcutaneous administration, comprising:

[0584] (a) about 100 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0585] (b) about 20.07 mM acetate buffer,

[0586] (c) about 182.38 mM trehalose,

[0587] (d) about 10.05 mM L-methionine,

[0588] (e) about 0.1% (w / v) polysorbate 80, and

[0589] (f) approximately 23.27 mM sodium chloride, and

[0590] The pH of the aqueous pharmaceutical composition or formulation thereof is about 5.0, and

[0591] The anti-PD-1 / CD3 bispecific antibody comprises:

[0592] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0593] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0594] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0595] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0596] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0597]

[79] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0598] (a) about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0599] (b) an acetate buffer consisting of: (b1) about 1.36 to about 4.08 mg / mL (preferably about 1.68 to about 2.05 mg / mL) of sodium acetate trihydrate and (b2) an amount of acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0600] (c) about 3.8 to about 78.7 mg / mL (preferably about 65.1 to about 72.6 mg / mL) of trehalose dihydrate,

[0601] (d) about 0.75 to about 3.0 mg / mL (preferably about 0.75 to about 2.25 mg / mL) of L-methionine,

[0602] (e) about 0.5 to about 3.0 mg / mL (preferably about 0.8 to about 1.2 mg / mL) of polysorbate 80, and

[0603] (f) about 0.06 to about 1.5 mg / mL (preferably about 1.15 to about 1.5 mg / mL) of sodium chloride, and

[0604] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.9 to about 5.1, and

[0605] The anti-PD-1 / CD3 bispecific antibody comprises:

[0606] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0607] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0608] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0609] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0610] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0611]

[80] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0612] (a) about 0.5 mg / mL, about 1 mg / mL, or about 10 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0613] (b) an acetate buffer consisting of about 1.9 mg / mL (specifically about 1.87 mg / mL) of sodium acetate trihydrate and about 0.4 mg / mL (specifically about 0.38 mg / mL) of acetic acid,

[0614] (c) about 69 mg / mL of trehalose dihydrate,

[0615] (d) about 1.5 mg / mL of L-methionine,

[0616] (e) about 1.0 mg / mL of polysorbate 80, and

[0617] (f) about 1.4 mg / mL (specifically about 1.36 mg / mL) of sodium chloride, and

[0618] The pH of the aqueous pharmaceutical composition or formulation thereof is about 5.0, and

[0619] The anti-PD-1 / CD3 bispecific antibody comprises:

[0620] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0621] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0622] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0623] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0624] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0625]

[81] An aqueous pharmaceutical composition for subcutaneous administration or a formulation thereof, comprising:

[0626] (a) about 100 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0627] (b) an acetate buffer consisting of (b1) about 1.36 to about 4.08 mg / mL (preferably about 1.68 to about 2.05 mg / mL) of sodium acetate trihydrate and (b2) an amount of acetic acid to achieve a pH of about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0628] (c) about 3.8 to about 78.7 mg / mL (preferably about 65.1 to about 72.6 mg / mL) of trehalose dihydrate,

[0629] (d) about 0.75 to about 3.0 mg / mL (preferably about 0.75 to about 2.25 mg / mL) of L-methionine,

[0630] (e) about 0.5 to about 3.0 mg / mL (preferably about 0.8 to about 1.2 mg / mL) of polysorbate 80, and

[0631] (f) about 0.06 to about 1.5 mg / mL (preferably about 1.15 to about 1.5 mg / mL) of sodium chloride, and

[0632] The pH of the aqueous pharmaceutical composition or formulation thereof is from about 4.9 to about 5.1, and

[0633] The anti-PD-1 / CD3 bispecific antibody comprises:

[0634] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0635] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0636] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0637] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0638] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0639]

[82] An aqueous pharmaceutical composition or a formulation thereof for subcutaneous administration, comprising:

[0640] (a) about 100 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0641] (b) an acetate buffer consisting of about 1.9 mg / mL (specifically about 1.87 mg / mL) of sodium acetate trihydrate and about 0.4 mg / mL (specifically about 0.38 mg / mL) of acetic acid,

[0642] (c) about 69 mg / mL of trehalose dihydrate,

[0643] (d) about 1.5 mg / mL of L-methionine,

[0644] (e) about 1.0 mg / mL of polysorbate 80, and

[0645] (f) about 1.4 mg / mL (specifically about 1.36 mg / mL) of sodium chloride, and

[0646] The pH of the aqueous pharmaceutical composition or formulation thereof is about 5.0, and

[0647] The anti-PD-1 / CD3 bispecific antibody comprises:

[0648] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0649] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0650] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0651] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0652] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0653]

[83] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0654] (a) about 2.5 mg, about 5 mg, or about 50 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0655] (b) an acetate buffer consisting of: (b1) about 6.8 to about 20.4 mg (preferably about 8.4 to about 10.2 mg) of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0656] (c) about 18.9 to about 393.3 mg (preferably about 325 to about 365.1 mg) of trehalose dihydrate,

[0657] (d) about 3.75 to about 15.0 mg (preferably about 3.75 to about 11.25 mg) of L-methionine,

[0658] (e) about 2.5 to about 15.0 mg (preferably about 4 to about 6 mg) of polysorbate 80, and

[0659] (f) from about 0.29 to about 7.5 mg (preferably from about 5.8 to about 7.5 mg) of sodium chloride, and

[0660] The pH of the aqueous pharmaceutical composition or formulation thereof is about 4.9 to about 5.1, and the volume of each formulation is about 5 mL, and

[0661] The anti-PD-1 / CD3 bispecific antibody comprises:

[0662] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0663] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0664] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0665] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0666] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0667]

[84] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0668] (a) about 2.5 mg, about 5 mg, or about 50 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0669] (b) acetate buffer consisting of about 9.4 mg (specifically about 9.35 mg) of sodium acetate trihydrate and about 1.9 mg of glacial acetic acid,

[0670] (c) about 345 mg of trehalose dihydrate,

[0671] (d) about 7.5 mg of L-methionine,

[0672] (e) approximately 5.0 mg of polysorbate 80, and

[0673] (f) approximately 6.8 mg of sodium chloride, and

[0674] The pH of the aqueous pharmaceutical composition or its formulation is about 5.0, and the volume of each formulation is about 5 mL, and

[0675] The anti-PD-1 / CD3 bispecific antibody comprises:

[0676] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0677] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0678] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0679] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0680] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0681]

[85] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0682] (a) about 1 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0683] (b) an acetate buffer consisting of: (b1) about 2.72 to about 8.16 mg (preferably about 3.36 to about 4.1 mg) of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0684] (c) about 7.6 to about 157.4 mg (preferably about 130.2 to about 145.2 mg) of trehalose dihydrate,

[0685] (d) about 1.5 to about 6.0 mg (preferably about 1.5 to about 4.5 mg) of L-methionine,

[0686] (e) from about 1.0 to about 6.0 mg of polysorbate 80, and

[0687] (f) about 0.12 to about 3.0 mg (preferably about 2.3 to about 3.0 mg) of sodium chloride, and

[0688] The pH of the aqueous pharmaceutical composition or formulation thereof is about 4.9 to about 5.1, and the volume of each formulation is about 2 mL, and

[0689] The anti-PD-1 / CD3 bispecific antibody comprises:

[0690] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0691] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0692] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0693] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0694] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0695]

[86] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising:

[0696] (a) about 1 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0697] (b) acetate buffer consisting of about 3.7 mg (specifically about 3.74 mg) of sodium acetate trihydrate and about 0.8 mg (specifically about 0.76 mg) of glacial acetic acid,

[0698] (c) about 138 mg of trehalose dihydrate,

[0699] (d) about 3.0 mg of L-methionine,

[0700] (e) approximately 2.0 mg of polysorbate 80, and

[0701] (f) about 2.7 mg (specifically about 2.72 mg) of sodium chloride, and

[0702] The pH of the aqueous pharmaceutical composition or its formulation is about 5.0, and the volume of each formulation is about 2 mL, and

[0703] The anti-PD-1 / CD3 bispecific antibody comprises:

[0704] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0705] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0706] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0707] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0708] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0709]

[87] An aqueous pharmaceutical composition for subcutaneous administration or a formulation thereof, comprising:

[0710] (a) about 100 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0711] (b) an acetate buffer consisting of: (b1) about 1.36 to about 4.08 mg (preferably about 1.68 to about 2.05 mg) of sodium acetate trihydrate and (b2) an amount of glacial acetic acid to bring the pH to about 4.9 to about 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1),

[0712] (c) about 3.8 to about 78.7 mg (preferably about 65.1 to about 72.6 mg) of trehalose dihydrate,

[0713] (d) about 0.75 to about 3.0 mg (preferably about 0.75 to about 2.25 mg) of L-methionine,

[0714] (e) from about 0.5 to about 3.0 mg of polysorbate 80, and

[0715] (f) from about 0.06 to about 1.5 mg (preferably from about 1.15 to about 1.5 mg) of sodium chloride, and

[0716] The pH of the aqueous pharmaceutical composition or its formulation is about 4.9 to about 5.1, and the volume of each formulation is about 1 mL, and

[0717] The anti-PD-1 / CD3 bispecific antibody comprises:

[0718] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0719] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0720] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0721] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0722] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0723]

[88] An aqueous pharmaceutical composition for subcutaneous administration or a formulation thereof, comprising:

[0724] (a) about 100 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient, and further comprising:

[0725] (b) acetate buffer consisting of about 1.9 mg (specifically about 1.87 mg) of sodium acetate trihydrate and about 0.4 mg (specifically about 0.38 mg) of glacial acetic acid,

[0726] (c) about 69 mg of trehalose dihydrate,

[0727] (d) about 1.5 mg of L-methionine,

[0728] (e) approximately 1.0 mg of polysorbate 80, and

[0729] (f) about 1.4 mg (specifically about 1.36 mg) of sodium chloride, and

[0730] The pH of the aqueous pharmaceutical composition or its formulation is about 5.0, and the volume of each formulation is about 1 mL, and

[0731] The anti-PD-1 / CD3 bispecific antibody comprises:

[0732] (i) heavy chains and light chains that constitute the antigen binding site that specifically binds to PD-1; and

[0733] (ii) heavy and light chains that constitute the antigen-binding site that specifically binds to CD3, and

[0734] wherein (α) the heavy chain described in item (i) above comprises the amino acid sequence shown in SEQ ID NO: 5,

[0735] (β) the heavy chain described in the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and

[0736] (γ) the light chains described in items (i) and (ii) above both comprise the amino acid sequence shown in SEQ ID NO: 7;

[0737]

[89] The aqueous pharmaceutical composition or formulation according to any one of the preceding items [1] to

[88] , wherein the conductivity is about 2.6 to about 3.1 mS / cm;

[0738]

[90] An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising an antibody (preferably an anti-PD-1 / CD3 bispecific antibody) as an active ingredient, and further comprising a buffer (preferably acetate buffer), trehalose, an antioxidant (preferably L-methionine), polysorbate 80, and having a conductivity of about 2.6 to about 3.1 mS / cm;

[0739]

[91] The aqueous pharmaceutical composition or formulation according to any one of items [1] to

[90] , wherein the electrical conductivity is about 2.8 mS / cm;

[0740]

[92] An aqueous pharmaceutical composition or formulation for intravenous administration, which is bioequivalent to the aqueous pharmaceutical composition or formulation described in any one of items

[75] ,

[76] ,

[79] ,

[80] ,

[83] to

[86] , and

[89] to

[91] , and contains the anti-PD-1 / CD3 bispecific antibody described in the same item as an active ingredient;

[0741]

[93] An aqueous pharmaceutical composition or formulation thereof for subcutaneous administration, which is bioequivalent to the aqueous pharmaceutical composition or formulation thereof described in any one of items

[75] to

[91] above and contains the anti-PD-1 / CD3 bispecific antibody described in said item as an active ingredient;

[0742]

[94] The aqueous pharmaceutical composition or formulation thereof according to the aforementioned item

[92] , wherein the bioequivalence is defined as a relationship in which the 90% confidence interval of the difference between the following (i) and (ii) is within the range of log(0.80) to log(1.25):

[0743] (i) the mean of the logarithmic values ​​of the parameters determining bioequivalence under the conditions of administration thereof, and

[0744] (ii) the mean value of the logarithmic value of the bioequivalence determination parameter under the conditions of administration of the aqueous pharmaceutical composition or formulation described in any one of items

[75] ,

[76] ,

[79] ,

[80] ,

[83] to

[86] , and

[89] to

[91] ;

[0745]

[95] The aqueous pharmaceutical composition or formulation thereof according to the aforementioned item

[93] , wherein the bioequivalence is defined as a relationship in which the 90% confidence interval of the difference between the following (i) and (ii) is within the range of log(0.80) to log(1.25):

[0746] (i) the mean of the logarithmic values ​​of the parameters determining bioequivalence under the conditions of administration thereof, and

[0747] (ii) the average value of the logarithmic values ​​of the bioequivalence determination parameters under the conditions of administration of the aqueous pharmaceutical composition or formulation described in any one of items

[75] to

[91] above;

[0748] [1-1] A prefilled syringe or cartridge prefilled with the aqueous pharmaceutical composition for subcutaneous administration according to any one of items [1] to

[91] ,

[93] , and

[95] above;

[0749] [1-2] A syringe pen, an autoinjector, or a needle-free device, wherein the syringe pen, the autoinjector, or the needle-free device is filled with the cartridge of the above item [1-1];

[0750] [1-3] A vial or ampoule container comprising the aqueous pharmaceutical composition of any one of the above items [1] to

[95] (preferably for intravenous administration);

[0751] [2-1] Use of (i) the aqueous pharmaceutical composition or formulation described in any one of items [1] to

[95] above, (ii) the prefilled syringe or cartridge described in item [1-1] above, (iii) the syringe pen, autoinjector or needle-free device described in item [1-2] above, or (iv) the vial or ampoule container described in item [1-3] above for preventing autoimmune diseases, graft-versus-host disease (GVHD) or blood cancers, inhibiting symptom progression of autoimmune diseases, graft-versus-host disease (GVHD) or blood cancers, inhibiting recurrence of autoimmune diseases, graft-versus-host disease (GVHD) or blood cancers, and / or treating autoimmune diseases, graft-versus-host disease (GVHD) or blood cancers;

[0752] [2-2] The use according to the aforementioned item [2-1], wherein the autoimmune disease is psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, or myasthenia gravis; and

[0753] [2-3] The use according to the aforementioned Item [2-1], wherein the hematological cancer is peripheral T-cell lymphoma or cutaneous T-cell lymphoma.

[0754] In this specification, the contents of all patent and non-patent documents or references explicitly cited herein may be incorporated as part of this specification.

[0755] The present invention is further described in detail by the following examples, but the scope of the present invention is not limited thereto. Various changes or modifications based on the description of the present invention are possible for those skilled in the art, and these changes or modifications are also included in the present invention. Example

[0756] Example 1: Formulation Screening

[0757] The optimal basic conditions for the formulation of the anti-PD-1 / CD3 bispecific antibody (Antibody α) of the present invention were searched for. 30 samples (B1 to B30) were prepared under the conditions shown in Tables 1 and 2, respectively, to achieve an antibody concentration of 20 mg / mL.

[0758] [Table 1]

[0759]

[0760] [Table 2]

[0761]

[0762] The diffusion interaction parameter (KD), aggregation onset temperature (Tag), and solubility of 30 samples were measured. In addition, accelerated and storage tests were performed, and concentration and turbidity were measured, as well as the residual monomer content measured by SEC-HPLC.

[0763] The diffusion interaction parameters for each sample were measured and analyzed at 25°C for each antibody concentration (1.25, 2.5, 5.0, 10, and 15 mg / mL) and the diffusion coefficients (μm 2 / s) to calculate.

[0764] Aggregation onset temperature was measured and analyzed by increasing the temperature from 25°C to 80°C at an antibody concentration of 1 mg / mL for each sample. By plotting the particle size (nm) for each formulation, the aggregation onset temperature was defined as the value at which the average particle size increased by 10% from the average particle size at 25°C.

[0765] Note that diffusion interaction parameters and aggregation onset temperature were measured using a microplate reader (DynaPro PlateReader II (WYATT Technology)) and analysis software (Dynamics V7).

[0766] For solubility measurements, 2 mg / mL samples were reacted with 10 solvent concentrations of ammonium sulfate ranging from 1.1 M to 2.0 M at 0.1 M intervals, followed by centrifugation at 15,000 g for 30 minutes. After centrifugation, the absorbance of the supernatant at 280 nm was measured. The solubility (%) of the sample was plotted against the concentration of ammonium sulfate, and the concentration of ammonium sulfate at 50% solubility was compared. Note that absorbance was measured using a microplate reader (INFINITE 200 PRO M PLEX (TECAN)).

[0767] For storage and accelerated testing, samples (1 mg / mL) were sterilized using a 0.22 μm filter and dispensed into vials.

[0768] The storage test was carried out at 4°C and 20°C for 0 and 4 weeks respectively. The concentration, turbidity and SEC-HPLC analysis of the storage samples were evaluated. All supernatants obtained by centrifugation for 30 minutes at 15,000 g were used as measurement samples. The concentration was calculated based on the absorbance at 280 nm (optical path length 2 mm). The turbidity was calculated based on the absorbance at 500 nm (optical path length 1 cm). Under the conditions shown in Table 3, SEC-HPLC was carried out on an Alliance HPLC system (Waters).

[0769] The accelerated test was performed by shaking at 500 rpm for 3 days at 20° C. This evaluation was performed in the same manner as the storage test.

[0770] [Table 3]

[0771]

[0772] The calculated and measured results of the diffusion interaction parameter (KD), the aggregation onset temperature (Tagg), and the solubility are shown in descending order in Table 4. In addition, the results of the storage test (4°C for 4 weeks) are shown in Table 5, the results of the storage test (20°C for 4 weeks) are shown in Table 6, and the results of the accelerated test (20°C for 3 days with shaking) are shown in Table 7. In each table, sample numbers 1 to 30 correspond to samples B1 to B30 shown in Tables 1 and 2.

[0773] [Table 4]

[0774]

[0775] [Table 5]

[0776]

[0777] [Table 6]

[0778]

[0779] [Table 7]

[0780]

[0781] Based on comprehensive evaluations of colloidal stability, thermal stability, and monomer reduction rate during shaking and storage, Sample 4 (20 mM acetate buffer (pH 5.0)), Sample 5 (20 mM acetate buffer (pH 5.0), 20 mM sodium chloride), and Sample 22 (20 mM histidine buffer (pH 6.0)) were selected as the formulations for the next evaluation. Note that the notation "20 mM" indicating the concentration of the acetate buffer in the samples listed in Tables 1 and 2 is a simplified notation and is precisely 20.07 mM. The same applies to the notation "20 mM acetate buffer" in Tables 8 to 11, Table 27, Table 33, Table 38, Table 45, and Table 51, as well as corresponding Examples 1 to 10.

[0782] Example 2: Additive Evaluation (1)

[0783] As shown in Table 8, 24 formulations S1 to S24 were prepared by adding sugars (sucrose, trehalose, D-mannitol, and sorbitol) to the formulations of samples 4, 5, and 22 selected in the evaluation of Example 1, respectively.

[0784] [Table 8]

[0785]

[0786] The diffusion interaction parameter (KD) and aggregation onset temperature (Tagg) of 24 samples were measured.

[0787] Diffusion interaction parameters were measured and analyzed at 25°C for samples with varying antibody concentrations (1, 2, 4, 8, and 10 mg / mL) and calculated by plotting the diffusion coefficients (μm2 / s) of the formulations.

[0788] The aggregation onset temperature was measured and analyzed by increasing the temperature of a sample having an antibody concentration of 1 mg / mL from 25°C to 80°C. By plotting the particle size (nm) in the formulation, the aggregation onset temperature was defined as the value at which the average particle size increased by 10% from the average particle size at 25°C.

[0789] The KD values ​​calculated for the samples are listed in Table 9 in descending order.

[0790] [Table 9]

[0791]

[0792] The coagulation onset temperature (Tagg) measured for each sample is listed in Table 10 in descending order.

[0793] [Table 10]

[0794]

[0795] Based on a comprehensive evaluation of the diffusion interaction parameter (KD) and the aggregation onset temperature (Tg), samples S3 (20 mM acetate buffer (pH 5.0), 285 mM trehalose), S5 (20 mM acetate buffer (pH 5.0), 285 mM D-mannitol), and S23 (20 mM histidine buffer (pH 6.0), 285 mM sorbitol) were selected. Note that the formulation without sodium chloride was selected because all acetate buffers containing sodium chloride had low scores.

[0796] Example 3: Additive Evaluation (2)

[0797] As shown in Table 11, 15 samples E1 to E15 were prepared by adding polysorbates (polysorbate 80 (PS80) and polysorbate 20 (PS20)) to the corresponding formulations of samples S3, S5, and S23 selected in the evaluation of Example 2.

[0798] [Table 11]

[0799]

[0800] Fifteen samples (1 mg / mL) were sterilized using a 0.22 μm filter, dispensed into vials, and subjected to storage test, accelerated test, and freeze-thaw test.

[0801] The storage test was carried out at 20°C and 40°C for 4 weeks. The storage samples were evaluated by visual assessment, concentration, turbidity and SEC-HPLC analysis. All supernatants obtained by centrifugation at 15,000 g for 30 minutes were used as evaluation samples. The concentration was calculated based on the absorbance at 280 nm (optical path length 2 mm). The turbidity was calculated based on the absorbance at 500 nm (optical path length 1 cm). SEC-HPLC analysis was carried out under the conditions shown in Table 2.

[0802] The accelerated test was performed by shaking at 500 times / min at 20°C for 3 days.

[0803] Freeze-thaw experiments were performed by repeated freezing three times (-80°C for 10 min and 25°C for 10 min).

[0804] All samples were clear immediately after preparation and no visible particles were observed.

[0805] The results of the storage test (20°C for 4 weeks) are shown in Table 12, the results of the storage test (40°C for 4 weeks) are shown in Table 13, the results of the accelerated test (20°C with shaking for 3 days) are shown in Table 14, and the results of the freeze-thaw test (-80°C for 10 minutes and 25°C for 10 minutes) are shown in Table 15.

[0806] [Table 12]

[0807]

[0808] [Table 13]

[0809]

[0810] [Table 14]

[0811]

[0812] [Table 15]

[0813]

[0814] As shown in Table 14, the results of the accelerated test showed that the aggregation stability of samples E1, E6, and E11 was significantly low. These samples are formulations that do not contain polysorbate, confirming that polysorbate is essential. In addition, as a result of the comprehensive evaluation of this example, samples E3 (20 mM acetate buffer (pH 5.0), 285 mM trehalose, 0.1% PS80), E4 (20 mM acetate buffer (pH 5.0), 285 mM trehalose, 0.01% PS20), E10 (20 mM acetate buffer (pH 5.0), 285 mM D-mannitol, 0.1% PS20), and E13 (20 mM histidine buffer (pH 6.0), 285 mM sorbitol, 0.1% PS80) were selected as the formulations for the next evaluation.

[0815] Example 4: Stability evaluation test (1)

[0816] For the acetate formulation (20 mM acetate buffer (pH 5.0), 285 mM trehalose, 0.1% PS80) and histidine formulation (20 mM histidine buffer (pH 6.0), 0.1% PS80) selected for evaluation in Example 3, samples containing 100 mg / mL antibody α were prepared.

[0817] The samples were sterilized using a 0.22 μm filter and 1 mL was dispensed into sterile vials. The conditions shown in Table 16 were then followed by a stability evaluation test for each sample.

[0818] [Table 16]

[0819]

[0820] The samples subjected to the conditions shown in the table above were evaluated by the following: (a) pH measurement, (b) antibody concentration measurement, (c) turbidity measurement, (d) SEC-HPLC (size exclusion chromatography) analysis, (e) SDS-PAGE analysis, (f) IE-HPLC (ion exchange chromatography) analysis, (g) viscosity measurement, (h) FIA (flow imaging analysis) and (i) sliding resistance measurement.

[0821] (a) A pH meter (LAQUA F-74 (HORIBA)) and a micro-sample measuring electrode (Micro Tou pH electrode (HORIBA)) were used for pH measurement.

[0822] (b) For the supernatant obtained by centrifuging the sample at 15,000 g for 30 minutes, the antibody concentration was measured based on the absorbance at 280 nm with an optical path length of 1 cm or 2 mm. Note that the sample was diluted so that its absorbance was 0.1 to 1.0, and the concentration was determined by the antibody's absorbance coefficient ε280 = 1.51 (mg / mL). -1 cm -1 Note that a spectrophotometer (BioSpectrometer (Eppendorf)) was used for these measurements.

[0823] (c) In the turbidity measurement, the absorbance at 500 nm is measured at a 1 cm optical path length. Note that a spectrophotometer is used for this measurement.

[0824] (d) SEC-HPLC analysis was performed under the conditions shown in Table 3.

[0825] (e) SDS-PAGE analysis was performed using the supernatant obtained by centrifuging the sample at 15,000 g for 30 minutes under reducing (100 mM DTT) and non-reducing (-DTT) conditions and electrophoresing 2 μg of the sample on a 4% to 12% Bis-Tris gel at 100 V for approximately 30 minutes.

[0826] (f) IE-HPLC analysis was performed under the conditions shown in Table 17.

[0827] [Table 17]

[0828]

[0829] (g) In the viscosity measurement, the viscosity of the supernatant obtained by centrifuging the sample at 15,000 g for 30 minutes was measured at 20°C. Note that the density was set to 1.0 g / cm 3 And measure the relative viscosity.

[0830] (h) Sliding resistance measurement: The supernatant obtained by centrifugation at 15,000 g for 30 minutes was used as the measurement sample. 400 μL of the sample was filled into a 29G staked 1 mL COP syringe and allowed to stand for approximately 5 hours. Using an autograph, the syringe was pushed out at 6 mL / min and the sliding resistance was measured. Note that the sliding resistance measurement was performed only on the sample in its initial state.

[0831] (i) In FIA, 150 μL of sample was measured at a flow rate of 0.05 mL / min using a flow imaging device, and aggregates larger than 1 μm in size were evaluated.

[0832] (Results of stability assessment)

[0833] Visual inspection of samples before and after the stability evaluation test was performed. Initially, samples of both the acetate and histidine formulations were yellow in color. However, after 4 and 12 weeks of storage, and after 3 days of shaking, under the respective conditions, no significant color change was observed. In samples of the histidine formulation, microparticles were observed after 4 weeks of storage at 5°C and after 12 weeks of storage at both 5°C and 25°C. Furthermore, after 4 weeks of storage at 40°C, both the acetate and histidine formulations exhibited no microparticles, but were completely turbid white.

[0834] (a) No significant pH changes were observed in all samples after the stability evaluation test.

[0835] (b) No significant concentration changes were observed in all samples after the stability test.

[0836] (c) The results of turbidity measurement before and after the stability test are shown in Table 18.

[0837] [Table 18]

[0838]

[0839] After 4 weeks of storage, storage of the acetate formulation samples at 40°C and storage of the histidine formulation samples at 25°C and 40°C increased turbidity by more than 20% compared to the initial state ("Initial" in the table). Storage of the acetate formulation samples at 40°C for 12 weeks increased turbidity by approximately 50% compared to the initial state. Storage of the histidine formulation samples at 5°C, 25°C, and 40°C increased turbidity by more than 90% compared to the initial state.

[0840] (d) The measurement results of SEC-HPLC analysis before and after the stability test are shown in Table 19.

[0841] [Table 19]

[0842]

[0843] SEC-HPLC analysis showed that the monomer (monomeric area) in all samples of the acetate formulation decreased by 3% to 5% after 4 and 12 weeks of storage at 40°C. In histidine formulation samples, storage at 25°C and 40°C for 12 weeks reduced the monomer derived from the same antibody by 2% to 5% and 4%, respectively. It is hypothesized that these reduced monomers were converted to high molecular weight (HMW) species due to antibody aggregation. Almost no effects of shaking or freeze-thaw were observed.

[0844] (e) SDS-PAGE analysis before and after the stability test showed that bands similar to those of the standard were observed in each sample in the initial state and under reducing and non-reducing conditions, confirming that no degradation occurred during sample preparation, such as purification and concentration.

[0845] (f) The results of IE-HPLC analysis before and after the stability test are shown in Table 20.

[0846] [Table 20]

[0847]

[0848] The samples of the acetate formulation and the histidine formulation showed little effect under any of the conditions of storage at 5°C for 4 weeks and 12 weeks, shaking, and freeze-thaw.

[0849] After storage at 25°C for 4 weeks, histidine formulation samples showed a 3% increase in acidic molecular species and a 3% decrease in neutral molecular species.

[0850] After 4 weeks of storage at 40°C, the acetate formulation showed a 15% increase in acidic species, a 19% decrease in neutral species, and a 5% increase in basic species. The histidine formulation also showed a 15% increase in acidic species and a 15% decrease in neutral species.

[0851] After 12 weeks of storage at 25°C, samples of the acetate formulation showed a 9% increase in acidic species and a 9% decrease in neutral species. Samples of the histidine formulation also showed an 8% increase in acidic species and an 8% decrease in neutral species.

[0852] After 12 weeks of storage at 40°C, samples of the acetate formulation showed a 33% increase in acidic species, a 37% decrease in neutral species, and a 4% increase in basic species. Samples of the histidine formulation also showed a 32% increase in acidic species and a 32% decrease in neutral species.

[0853] The reduction of neutral molecular species is believed to be due to oxidation to mainly acidic molecular species.

[0854] The results of storage at 25°C for 4 weeks showed that the acetate formulation was more stable.

[0855] (g) The results of viscosity measurement before and after the stability evaluation test showed that in all the preparations, there was no significant change in viscosity before and after the stability evaluation test.

[0856] Note that the viscosity of the samples in the initial state was 4.41 mPa s for the acetate formulation sample and 4.2 mPa s for the histidine formulation sample, which were very low values ​​even at a concentration of 100 mg / mL.

[0857] (h) The results of the sliding resistance measurement of the samples in the initial state showed that the sliding resistance values ​​of both the acetate formulation and the histidine formulation samples were very low (7.66 N and 7.46 N).

[0858] (i) The particle concentrations before and after the stability evaluation test obtained by subtracting the particle concentration in the formulation solution from the particle concentration in each formulation containing the antibody are shown in Table 21.

[0859] [Table 21]

[0860]

[0861] The acetate formulation sample stored at 40°C for 12 weeks and the histidine formulation sample stored at 25°C for 12 weeks had the highest particle concentrations.

[0862] Under all conditions evaluated, particle concentrations of histidine formulations were tens to thousands of times higher than those of acetate formulations.

[0863] The results of the stability evaluation presented in this example indicate that the acetate formulation (20 mM acetate buffer (pH 5.0), 285 mM trehalose, 0.1% PS80) is considered more suitable as a formulation for the antibody α related to the present invention.

[0864] Example 5: Additive Evaluation (3)

[0865] The acetate formulation selected based on the evaluation in Example 4 (20 mM acetate buffer (pH 5.0), 285 mM trehalose, 0.1% PS80) was subjected to further optimization studies.

[0866] Check the salt concentration to ensure conductivity stability.

[0867] As shown in Table 22, 8 types of samples N1 to N8 were prepared by adding sodium chloride to selected acetate formulations (20 mM acetate buffer (pH 5.0), 285 mM trehalose, 0.1% PS80).

[0868] [Table 22]

[0869]

[0870] The eight types of samples were sterilized using a 0.22 μm filter, dispensed into sterile vials of 1 or 5 mL each, and the stability was evaluated under the corresponding conditions listed in Table 23.

[0871] [Table 23]

[0872]

[0873] Samples subjected to the conditions listed in the table above were evaluated by: (a) SEC-HPLC analysis, (b) IE-HPLC analysis, (c) RP-HPLC (reverse phase chromatography) analysis, (d) binding activity, (e) FIA, and (f) peptide mapping (denaturation site analysis by liquid chromatography mass spectrometry (LC-MS)).

[0874] Note that (a) SEC-HPLC analysis was performed under the conditions listed in Table 24.

[0875] [Table 24]

[0876]

[0877] (b) IE-HPLC analysis was performed under the conditions listed in Table 25.

[0878] [Table 25]

[0879]

[0880] (c) RP-HPLC analysis was performed under the conditions listed in Table 26.

[0881] Note that the coloration index is calculated as (fluorescence intensity value) / (UV 280 nm absorption area value) × 100. The ratio of the coloration index to the coloration index of the standard ((coloration index of the sample) / (coloration index of the standard)) is used as an index value representing the amount of the colored substance in the sample.

[0882] [Table 26]

[0883]

[0884] (d) Binding activity to PD-1 and CD3 was measured by surface plasmon resonance (SPR).

[0885] (e) In FIA, aggregates larger than 2 μm in size were evaluated by measuring 500 μL of sample at a flow rate of 0.1 mL / min using a flow imaging system.

[0886] (f) Peptide mapping analysis using LC-MS.

[0887] (Storage test)

[0888] (a) The percentage of high molecular weight substances (HMW) before and after the storage test (assessed by SEC-HPLC analysis) is shown in Table 27. At all concentrations, no significant increase in HMWS was observed at 5°C for 12 weeks. At 25°C, no increase in HMWS was observed in the formulation at 20 mg / mL antibody concentration, but a linear increase trend in HMWS was observed in the formulation at 100 mg / mL. On the other hand, no difference in behavior with conductivity was observed. At 40°C, HMWS increased at all concentrations, but the formulation at 20 mg / mL showed a trend of HMWS increasing as conductivity increased. At 5°C and 25°C, the formulation was found to be stable.

[0889] [Table 27]

[0890]

[0891] (b) The percentages of acidic molecular species before and after the storage test (assessed by IE-HPLC analysis) are shown in Table 28.

[0892] [Table 28]

[0893]

[0894] At 40°C, acidic molecular species tended to increase, but at 5°C and 25°C, no increase in acidic molecular species was observed, confirming that the formulation was stable. In addition, no effect on conductivity was observed.

[0895] (c) The percentage of colored entities before and after the storage test (assessed by RP-HPLC analysis) is shown in Table 29.

[0896] [Table 29]

[0897]

[0898] While there was no change at 5° C., an increase in the percentage of colored entities was observed at 25° C. and 40° C. No difference in conductivity was observed.

[0899] (d) The results of the SPR evaluation of the binding activity to PD-1 before and after the storage test are shown in Table 30, and the results of the binding activity to CD3 are shown in Table 31. The values ​​in each table represent the specific activity (%) of antibody α against the standard. No decrease in binding activity to either PD-1 or CD3 was observed at 5°C and 25°C. On the other hand, a decrease in binding activity to PD-1 was observed at 40°C, and the decrease in binding activity was more significant at an antibody concentration of 20 mg / mL.

[0900] [Table 30]

[0901]

[0902] [Table 31]

[0903]

[0904] (e) The amount of particles in samples N5 and N8 after the storage test was respectively evaluated by FIA, but no significant difference in the amount of particles or the maximum amount of particles was observed among the samples.

[0905] (Oscillation test)

[0906] (a) The percentage of HMWS before and after the shaking test was assessed by SEC-HPLC, but no significant increase in HMWS was observed in all samples and conditions.

[0907] (b) The percentage of acidic molecular species before and after the shaking test was evaluated by IE-HPLC, but no significant increase in acidic molecular species was observed in all samples and conditions.

[0908] (c) The percentage of colored entities before and after the shaking test was assessed by RP-HPLC, but no significant increase in colored entities was observed in all samples and conditions.

[0909] (d) The binding activities to PD-1 and CD3 were evaluated by SPR before and after the oscillation test, but no significant difference in the decrease of binding activity was observed among the samples.

[0910] (e) The amount of particles in samples N5 and N8 after the oscillation test was evaluated by FIA, but no increase in the amount of particles or the maximum particle size due to the oscillation pressure was observed in any of the samples.

[0911] (Freeze-Thaw)

[0912] (a) The percentage of HMWS before and after freeze-thaw experiments was evaluated by SEC-HPLC, but all samples did not show significant changes in the percentage of HMWS and were found to be stable to freeze-thaw stress.

[0913] (b) The percentage of acidic molecular species before and after the freeze-thaw test was evaluated by IE-HPLC, but all samples did not show significant changes in the percentage of acidic molecular species and were similarly found to be stable to freeze-thaw stress.

[0914] (c) The percentage of colored entities before and after the shaking test was evaluated by RP-HPLC, but no significant changes in the percentage of colored entities were observed in all samples.

[0915] (d) The binding activities of PD-1 and CD3 were evaluated by SPR before and after freeze-thaw assay, but no significant changes in binding activities were observed in all samples.

[0916] (e) The amount of particles in samples N5 and N8 after freeze-thaw tests was evaluated by FIA, but no increase in the amount of particles or the maximum particle size due to freeze-thaw stress was observed in any sample. There were no significant differences between the evaluated samples.

[0917] (Syringe flow test)

[0918] The percentage (%) of HMWS in sample N8 before and after the syringe flow test was evaluated by SEC-HPLC, and no generation of HMWS was observed.

[0919] (Peptide Mapping Analysis)

[0920] As shown in Table 30, the factor analysis of the reduction in binding activity to PD-1 caused by long-term storage at 40°C was performed by peptide mapping. As a representative example, the degree of oxidation (%) of the 101st methionine residue in the PD-1 complementary determining region (hereinafter referred to as "Met101") is shown in Table 32. At 5°C and 25°C, the degree of oxidation of Met101 was low, and no difference was observed between the samples. In addition, compared with the case of 100 mg / mL antibody concentration, significant oxidation was observed at 20 mg / mL. Figure 4 As shown, there is a correlation between oxidation of Met101 and reduced binding activity to PD-1, suggesting that this oxidation may be the cause of reduced binding activity.

[0921] [Table 32]

[0922]

[0923] Example 6: Stability Assessment (2)

[0924] Since it was shown in Example 5 that the stability of the antibody α related to the present invention may decrease at low concentrations, its stability at low concentrations was evaluated.

[0925] As shown in Table 33, samples L1 and L2 containing 1 and 50 mg / mL of Antibody α, respectively, were prepared in acetate formulation (20 mM acetate buffer (pH 5.0), 285 mM trehalose, 0.1% PS80, 1.25 mg / mL sodium chloride).

[0926] [Table 33]

[0927]

[0928] These two samples were sterilized using a 0.22 μm filter and 1 or 5 mL of each was dispensed into sterile vials and subjected to stability evaluation under the conditions listed in Table 34.

[0929] [Table 34]

[0930]

[0931] For the samples stored under each condition, (a) SEC-HPLC analysis, (b) IE-HPLC analysis, and (c) measurement of binding activity to PD-1 and CD3 were performed. Note that SEC-HPLC analysis was performed under the conditions shown in Table 24, and IE-HPLC analysis was performed under the conditions shown in Table 25. Binding activity to PD-1 and CD3 was measured by SPR.

[0932] (a) The percentage of HMWS before and after storage (assessed by SEC-HPLC) is shown in Table 35. In all formulations, HMWS increased significantly during long-term storage at 40°C, but the accumulation of HMWS was more pronounced at low antibody concentration L1. This suggests an increased likelihood of aggregation under low concentration conditions.

[0933] [Table 35]

[0934]

[0935] (b) The percentage of acidic molecular species before and after storage (assessed by IE-HPLC) is shown in Table 36. Acidic molecular species tended to increase at 40°C at all concentrations, and oxidation tended to proceed faster at 1 mg / mL.

[0936] [Table 36]

[0937]

[0938] (c) The results of PD-1 binding activity before and after storage (assessed by SPR) are shown in Table 37. At 5°C and 25°C, the binding activity to PD-1 and CD3 did not decrease, but at 40°C, the binding activity to PD-1 decreased significantly in both samples. This suggests that oxidation of the complementarity determining region on PD-1 may promote oxidation of the antibody.

[0939] [Table 37]

[0940]

[0941] Example 7: Additive Evaluation (4)

[0942] Example 6 shows that the effect of long-term storage leads to the progressive oxidation of the antibody α related to the present invention, resulting in a decrease in the binding activity to PD-1 and CD3, in particular, a significant decrease in the binding activity to PD-1.

[0943] The addition of antioxidants (L-methionine or DTPA) to acetate formulations (20 mM acetate buffer (pH 5.0), 193 mM trehalose, 0.1% PS80, 1.15 mg / mL sodium chloride) was studied. As shown in Table 38, samples A1 to A8 containing 1 mg / mL and 20 mg / mL of antibody α, respectively, were prepared.

[0944] [Table 38]

[0945]

[0946] The eight samples were sterilized with a 0.22 μm filter and 1 mL each was dispensed into sterile vials, and the stability was evaluated as shown in Table 34. In the same evaluation, the stored samples were subjected to (a) SEC-HPLC analysis, (b) IE-HPLC analysis, (c) RP-HPLC analysis, (d) measurement of binding activity to PD-1 and CD3, and (e) peptide mapping analysis under the conditions listed in Table 34. Note that the SEC-HPLC analysis was performed under the conditions shown in Table 24, the IE-HPLC analysis was performed under the conditions shown in Table 25, and the RP-HPLC analysis was performed under the conditions shown in Table 26. In addition, the binding activity to PD-1 and CD3 was measured by SPR, and peptide mapping analysis was performed using LC-MS.

[0947] (a) The percentage (%) of HMWS before and after storage (assessed by SEC-HPLC analysis) is shown in Table 39. Even without the addition of an antioxidant, there was no change at 5°C and 25°C. On the other hand, for samples with 10 mM L-methionine or 20 μM DTPA, the production of HMWS was significantly inhibited when stored at 40°C for 12 weeks. The inhibitory effect of L-methionine or DTPA on the production of HMWS was also observed at antibody concentrations of 1 and 20 mg / mL.

[0948] [Table 39]

[0949]

[0950] (b) The percentages (%) of acidic molecular species before and after storage (assessed by IE-HPLC analysis) are shown in Table 40. At both antibody concentrations of 1 and 20 mg / mL, acidic molecular species tended to increase at 40°C. In particular, at an antibody concentration of 1 mg / mL, the addition of 10 mM L-methionine or 20 μM DTPA was found to effectively inhibit the generation of acidic molecular species.

[0951] [Table 40]

[0952]

[0953] (c) Coloration index before and after storage (assessed by IE-HPLC analysis) is shown in Table 41. At both antibody concentrations of 1 and 20 mg / mL, significant inhibition of the formation of colored entities at 40°C was observed. In particular, at an antibody concentration of 1 mg / mL, the addition of 10 mM L-methionine or 20 μM DTPA was found to effectively inhibit the formation of colored entities.

[0954] [Table 41]

[0955]

[0956] (d) As assessed by SPR, the results for PD-1 binding activity (%) before and after storage are shown in Table 42, and the results for CD3 binding activity (%) are shown in Table 43. When stored at 25°C or higher without an antioxidant, both PD-1 and CD3 binding activity decreased at both antibody concentrations of 1 and 20 mg / mL. On the other hand, at 40°C, the addition of an antioxidant significantly suppressed the decrease in binding activity at antibody concentrations of 1 and 20 mg / mL. This suggests that the addition of an antioxidant inhibits the generation of HMWS and acidic molecules, leading to the suppression of the decrease in binding activity.

[0957] [Table 42]

[0958]

[0959] [Table 43]

[0960]

[0961] (e) As shown in Table 42, the decrease in binding activity to PD-1 during long-term storage at 40°C was factored by peptide mapping. As a representative example, the degree of oxidation (%) of the methionine residue (Met101) in the complementary determining region of PD-1 is shown in Table 44. It was observed that Met101 was highly oxidized at an antibody concentration of 1 mg / mL and when stored at 40°C. On the other hand, the addition of an antioxidant significantly inhibited the oxidation of Met101 and also significantly inhibited the decrease in binding activity to PD-1. Therefore, it was confirmed that the addition of an antioxidant is very useful for improving the stability of antibody α.

[0962] [Table 44]

[0963]

[0964] Example 8: Stability test (3)

[0965] Conditions enabling stable storage of the antibody α according to the present invention were found in the studies of Examples 1 to 7. It was decided to determine a range of sugar concentrations in order to establish even more stable conditions.

[0966] As shown in Table 45, samples T1 to T3 containing 1 mg / mL of antibody α were prepared in acetate formulations (20 mM acetate buffer (pH 5.0), 172 mM, 182.38 mM, or 193 mM trehalose, 0.1% PS80, 1.36 mg / mL sodium chloride, 10 mM L-methionine). Note that each concentration of trehalose "182 mM" in Tables 45 and 47 to 59 is an abbreviation of "182.38 mM."

[0967] [Table 45]

[0968]

[0969] These two samples were sterilized using a 0.22 μm filter and dispensed into sterile vials at 1 mL each, and then subjected to stability evaluation under the conditions listed in Table 46.

[0970] [Table 46]

[0971]

[0972] For samples stored under each condition, (a) IE-HPLC analysis, (b) RP-HPLC, and (c) measurement of binding activity to PD-1 and CD3 were performed. IE-HPLC analysis was performed under the conditions listed in Table 25. RP-HPLC was performed under the conditions listed in Table 26. Binding activity to PD-1 and CD3 was measured by SPR.

[0973] (a) The percentages (%) of acidic molecular species before and after storage (assessed by IE-HPLC) are shown in Table 47. In all formulations, acidic molecular species increased during long-term storage at 25°C and 40°C. They were stable at 5°C (normal storage temperature). No differences were observed between formulations.

[0974] [Table 47]

[0975]

[0976] (b) The percentage of colored entities before and after storage (assessed by RP-HPLC) is shown in Table 48. In all formulations, colored entities increased during long-term storage at 40° C. No differences were observed between formulations.

[0977] [Table 48]

[0978]

[0979] (c) As evaluated by SPR, the results of the binding activity to PD-1 before and after storage are shown in Table 49, and the results of the binding activity to CD3 are shown in Table 50. The values ​​in each table represent the specific activity (%) of antibody α against the standard. No significant decrease in the binding activity to PD-1 and CD-3 was observed under any conditions. In addition, no differences were observed between the preparations.

[0980] [Table 49]

[0981]

[0982] [Table 50]

[0983]

[0984] Example 9: Stability test (4)

[0985] The conditions for stable storage of the antibody α of the present invention were found in the studies of Examples 1 to 8. After comprehensive consideration of these conditions, stability tests were conducted under conditions considered to be optimal.

[0986] As shown in Table 51, samples F1 and F2 containing 1 mg / mL or 100 mg / mL of antibody α, respectively, were prepared in acetate formulation (20 mM acetate buffer (pH 5.0), 182.38 mM trehalose, 0.1% PS80, 1.36 mg / mL sodium chloride, 10 mM L-methionine).

[0987] [Table 51]

[0988]

[0989] These two samples were sterilized using a 0.22 μm filter and dispensed into sterile vials at 1 mL each, and then subjected to stability evaluation under the conditions listed in Table 52.

[0990] [Table 52]

[0991]

[0992] For the samples stored under each condition, (a) SEC-HPLC, (b) IE-HPLC analysis, (c) isoelectric point electrophoresis (iCIEF), (d) RP-HPLC, and (e) measurement of binding activity to PD-1 and CD3 were performed. SEC-HPLC analysis was performed under the conditions shown in Table 24. IE-HPLC analysis was performed under the conditions shown in Table 25. iCIEF was performed by capillary isoelectrophoresis. RP-HPLC was performed under the conditions shown in Table 26. Binding activity to PD-1 and CD3 was measured by SPR.

[0993] (a) The percentage of HMWS before and after storage (assessed by SEC-HPLC) is shown in Table 53. HMWS increased at 100 mg / mL concentration at 25°C and 40°C, but did not increase significantly at 5°C, and was considered stable at 5°C.

[0994] [Table 53]

[0995]

[0996] (b) The percentages of acidic molecular species before and after storage (assessed by IE-HPLC) are shown in Table 54. Acidic molecular species increased under long-term storage conditions at 25°C and 40°C, but did not increase significantly at 5°C. It is considered stable at 5°C.

[0997] [Table 54]

[0998]

[0999] (c) The percentages (%) of acidic molecular species before and after storage (assessed by iCIEF) are shown in Table 55. Acidic molecular species increased under long-term storage conditions at 25°C and 40°C, but did not increase significantly at 5°C. It is considered stable at 5°C.

[1000] [Table 55]

[1001]

[1002] (d) The percentage of colored entities before and after storage (assessed by RP-HPLC) is shown in Table 56. The colored entities increased under long-term storage conditions at 25°C and 40°C, but did not increase significantly at 5°C. It is considered stable at 5°C.

[1003] [Table 56]

[1004]

[1005] (e) As evaluated by SPR, the results of the binding activity to PD-1 before and after storage are shown in Table 57, and the results of the binding activity to CD3 are shown in Table 58. The values ​​in each table represent the specific activity (%) against the standard. At 40°C, a decrease in the binding activity to PD-1 was observed. On the other hand, at 5°C and 25°C, the binding activity to PD-1 and CD3 did not decrease, indicating that they were sufficiently stable.

[1006] [Table 57]

[1007]

[1008] [Table 58]

[1009]

[1010] As shown in Table 59, samples L1 to L4 containing 0.01 mg / mL to 1.0 mg / mL of antibody α, respectively, were prepared in acetate formulations (20 mM acetate buffer (pH 5.0), 182.38 mM trehalose, 0.1% PS80, 1.36 mg / mL sodium chloride, 10 mM L-methionine) to evaluate the stability of low-concentration formulations.

[1011] [Table 59]

[1012]

[1013] Both samples were sterilized using a 0.22 μm filter and dispensed into sterile vials before stability evaluation under the conditions listed in Table 60.

[1014] [Table 60]

[1015]

[1016] Samples stored under each condition were subjected to analytical evaluation as evaluated above in this example.

[1017] (a) The percentage of HMWS before and after storage (assessed by SEC-HPLC) is shown in Table 61. At concentrations of 0.5 mg / mL and 1.0 mg / mL, no increase in the percentage of HMWS was observed under the conditions of 5°C, 25°C, and 40°C.

[1018] [Table 61]

[1019]

[1020] (b) The ratio of acidic molecular species before and after storage (assessed by IE-HPLC) is shown in Table 62. An increase in acidic molecular species was observed under long-term storage conditions at 25°C and 40°C, but no significant increase was observed at 5°C. It is considered stable at 5°C.

[1021] [Table 62]

[1022]

[1023] (c) The ratio (%) of acidic molecular species before and after storage (assessed by iCIEF) is shown in Table 63. An increase in acidic molecular species was observed under long-term storage conditions at 25°C and 40°C, but no significant increase was observed at 5°C. It is considered stable at 5°C.

[1024] [Table 63]

[1025]

[1026] (d) As evaluated by SPR, the results of the binding activity to PD-1 before and after storage are shown in Table 64, and the results of the binding activity to CD3 are shown in Table 65. The values ​​in each table represent the specific activity (%) against the standard. No decrease in the binding activity of PD-1 or CD3 was observed over all temperature and concentration ranges, indicating that they are sufficiently stable.

[1027] [Table 64]

[1028]

[1029] [Table 65]

[1030]

[1031] Example 10: Preparation method

[1032] The following describes a method for preparing an aqueous pharmaceutical composition of the present invention using sample F2 in Example 9 as an example. Note that aqueous pharmaceutical compositions of the present invention having antibody concentrations different from those of sample F2 can also be prepared in the same manner.

[1033] (a) Formulation solution 1 was prepared to contain 20 mM acetate buffer (pH 5.0), 182.38 mM trehalose, 1.36 mg / mL sodium chloride, and 10 mM L-methionine.

[1034] (b) Formulation solution 2 was prepared to contain 20 mM acetate buffer (pH 5.0), 182.38 mM trehalose, 2% PS80, 1.36 mg / mL sodium chloride, and 10 mM L-methionine.

[1035] (c) Formulation solution 3 was prepared to contain 20 mM acetate buffer (pH 5.0), 182.38 mM trehalose, 0.1% PS80, 1.36 mg / mL sodium chloride, and 10 mM L-methionine.

[1036] (d) During the preparation of Antibody α, the solution composition of the treated solution obtained in the virus filtration process was replaced with Preparation Solution 1 using an ultrafiltration / diafiltration membrane.

[1037] (e) In the above item (d), the treated solution containing antibody α (the solution composition of the treated solution was replaced with the formulation solution 1) was concentrated to about 140 mg / mL using an ultrafiltration / diafiltration membrane.

[1038] (f) Preparation solution 2 containing a high concentration of PS80 was added to the treatment solution containing antibody α concentrated in the above item (e) to adjust the PS80 concentration to 0.1%.

[1039] (g) Preparation solution 3 is added to the treatment solution containing antibody α adjusted to the desired PS80 concentration in the above item (f), and diluted so that the antibody concentration becomes the desired 100 mg / mL.

[1040] [Industrial Availability]

[1041] The pharmaceutical composition or preparation thereof of the present invention contains an anti-PD-1 / CD3 bispecific antibody as an active ingredient and can be used to prevent autoimmune diseases, graft-versus-host disease (GVHD), or blood cancers, inhibit the progression of symptoms of autoimmune diseases, graft-versus-host disease (GVHD), or blood cancers, inhibit the recurrence of autoimmune diseases, graft-versus-host disease (GVHD), or blood cancers, or treat autoimmune diseases, graft-versus-host disease (GVHD), or blood cancers.

Claims

1. An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising: (a) 0.1 to 1.2 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient; and further comprising: (b) 18 to 22 mM acetate buffer; (c) 172 to 193 mM trehalose; (d) 5 to 15 mM L-methionine; (e) 0.05 to 0.3% (w / v) polysorbate 80; and (f) 19.6 to 25.7 mM sodium chloride, and The pH of the aqueous pharmaceutical composition or its formulation is 4.9 to 5.1, and The anti-PD-1 / CD3 bispecific antibody comprises: (i) heavy and light chains that constitute the antigen-binding site that specifically binds to PD-1; and (ii) heavy and light chains that form an antigen-binding site that specifically binds to CD3, and in (α) the heavy chain of the aforementioned item (i) comprises the amino acid sequence shown in SEQ ID NO: 5, (β) the heavy chain of the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and (γ) The light chains of the aforementioned items (i) and (ii) both comprise the amino acid sequence shown in SEQ ID NO:

7.

2. The aqueous pharmaceutical composition or formulation thereof according to claim 1, wherein the anti-PD-1 / CD3 bispecific antibody is at a concentration of 0.5 mg / mL or 1 mg / mL.

3. An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising: (a) 0.5 mg / mL or 1 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient; and further comprising: (b) 20.07 mM acetate buffer; (c) 182.38 mM trehalose; (d) 10.05 mM L-methionine; (e) 0.1% (w / v) polysorbate 80; and (f) 23.27 mM sodium chloride, and The pH of the aqueous pharmaceutical composition or its formulation is 5.0, and The anti-PD-1 / CD3 bispecific antibody comprises: (i) heavy and light chains that constitute the antigen-binding site that specifically binds to PD-1; and (ii) heavy and light chains that form an antigen-binding site that specifically binds to CD3, and in (α) the heavy chain of the aforementioned item (i) comprises the amino acid sequence shown in SEQ ID NO: 5, (β) the heavy chain of the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and (γ) The light chains of the aforementioned items (i) and (ii) both comprise the amino acid sequence shown in SEQ ID NO:

7.

4. An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising: (a) 0.1 to 1.2 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient; and further comprising: (b) Acetate buffer consisting of: (b1) 1.68 to 2.05 mg / mL of sodium acetate trihydrate; and (b2) an amount of acetic acid to adjust the pH to 4.9 to 5.1, corresponding to the amount of sodium acetate trihydrate in the aforementioned item (b1), (c) 65.1 to 72.6 mg / mL of trehalose dihydrate; (d) 0.75 to 2.25 mg / mL of L-methionine; (e) 0.5 to 0.3 mg / mL polysorbate 80; and (f) 1.15 to 1.5 mg / mL of sodium chloride, and The pH of the aqueous pharmaceutical composition or its formulation is 4.9 to 5.1, and The anti-PD-1 / CD3 bispecific antibody comprises: (i) heavy and light chains that constitute the antigen-binding site that specifically binds to PD-1; and (ii) heavy and light chains that form an antigen-binding site that specifically binds to CD3, and in (α) the heavy chain of the aforementioned item (i) comprises the amino acid sequence shown in SEQ ID NO: 5, (β) the heavy chain of the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and (γ) The light chains of the aforementioned items (i) and (ii) both comprise the amino acid sequence shown in SEQ ID NO:

7. The aqueous pharmaceutical composition or formulation thereof according to claim 4 , wherein the anti-PD-1 / CD3 bispecific antibody is at a concentration of 0.5 mg / mL or 1 mg / mL.

6. An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising: (a) 0.5 mg / mL or 1 mg / mL of an anti-PD-1 / CD3 bispecific antibody as an active ingredient; and further comprising: (b) acetate buffer consisting of 1.87 mg / mL sodium acetate trihydrate and 0.38 mg / mL acetic acid; (c) 69 mg / mL trehalose dihydrate; (d) 1.5 mg / mL L-methionine; (e) 1.0 mg / mL of polysorbate 80; and (f) 1.36 mg / mL of sodium chloride, and The pH of the aqueous pharmaceutical composition or its formulation is 5.0, and The anti-PD-1 / CD3 bispecific antibody comprises: (i) heavy and light chains that constitute the antigen-binding site that specifically binds to PD-1; and (ii) heavy and light chains that form an antigen-binding site that specifically binds to CD3, and in (α) the heavy chain of the aforementioned item (i) comprises the amino acid sequence shown in SEQ ID NO: 5, (β) the heavy chain of the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and (γ) The light chains of the aforementioned items (i) and (ii) both comprise the amino acid sequence shown in SEQ ID NO:

7.

7. An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising: (a) 0.5 to 6 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient; and further containing: (b) Acetate buffer consisting of: (b1) 8.4 to 10.2 mg of sodium acetate trihydrate; and (b2) an amount of glacial acetic acid to adjust the pH to 4.9 to 5.1, corresponding to the amount of sodium acetate trihydrate in the above item (b1); (c) 325 to 365.1 mg of trehalose dihydrate; (d) 3.75 to 11.25 mg of L-methionine; (e) 2.5 to 15.0 mg of polysorbate 80; and (f) 5.8 to 7.5 mg of sodium chloride, and The pH of the aqueous pharmaceutical composition or its formulation is 4.9 to 5.1, and the volume of each formulation is 5 mL, and The anti-PD-1 / CD3 bispecific antibody comprises: (i) heavy and light chains that constitute the antigen-binding site that specifically binds to PD-1; and (ii) heavy and light chains that form an antigen-binding site that specifically binds to CD3, and in (α) the heavy chain of the aforementioned item (i) comprises the amino acid sequence shown in SEQ ID NO: 5, (β) the heavy chain of the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and (γ) The light chains of the aforementioned items (i) and (ii) both comprise the amino acid sequence shown in SEQ ID NO:

7.

8. The aqueous pharmaceutical composition or formulation thereof according to claim 7, wherein the anti-PD-1 / CD3 bispecific antibody is 2.5 mg or 5 mg.

9. An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising: (a) 2.5 mg or 5 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient; and further containing: (b) acetate buffer consisting of 9.35 mg of sodium acetate trihydrate and 1.9 mg of glacial acetic acid; (c) 345 mg of trehalose dihydrate; (d) 7.5 mg of L-methionine; (e) 5.0 mg of polysorbate 80; and (f) 6.8 mg of sodium chloride, and The pH of the aqueous pharmaceutical composition or its formulation is 5.0, and the volume of each formulation is 5 mL, and The anti-PD-1 / CD3 bispecific antibody comprises: (i) heavy and light chains that constitute the antigen-binding site that specifically binds to PD-1; and (ii) heavy and light chains that form an antigen-binding site that specifically binds to CD3, and in (α) the heavy chain of the aforementioned item (i) comprises the amino acid sequence shown in SEQ ID NO: 5, (β) the heavy chain of the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and (γ) The light chains of the aforementioned items (i) and (ii) both comprise the amino acid sequence shown in SEQ ID NO:

7.

10. An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising: (a) 0.2 to 2.4 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient; and further comprising: (b) Acetate buffer consisting of: (b1) 3.36 to 4.1 mg of sodium acetate trihydrate; and (b2) an amount of glacial acetic acid to adjust the pH to 4.9 to 5.1, corresponding to the amount of sodium acetate trihydrate in the above item (b1); (c) 130.2 to 145.2 mg of trehalose dihydrate; (d) 1.5 to 4.5 mg of L-methionine; (e) 1.0 to 6.0 mg of polysorbate 80; and (f) 2.3 to 3.0 mg of sodium chloride, and The pH of the aqueous pharmaceutical composition or its formulation is 4.9 to 5.1, and the volume of each formulation is 2 mL, and The anti-PD-1 / CD3 bispecific antibody comprises: (i) heavy and light chains that constitute the antigen-binding site that specifically binds to PD-1; and (ii) heavy and light chains that form an antigen-binding site that specifically binds to CD3, and in (α) the heavy chain of the aforementioned item (i) comprises the amino acid sequence shown in SEQ ID NO: 5, (β) the heavy chain of the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and (γ) The light chains of the aforementioned items (i) and (ii) both comprise the amino acid sequence shown in SEQ ID NO:

7. The aqueous pharmaceutical composition or formulation thereof according to claim 10 , wherein the anti-PD-1 / CD3 bispecific antibody is 1 mg.

12. An aqueous pharmaceutical composition or formulation thereof for subcutaneous or intravenous administration, comprising: (a) 1 mg of an anti-PD-1 / CD3 bispecific antibody as an active ingredient; and further comprising: (b) acetate buffer consisting of 3.74 mg of sodium acetate trihydrate and 0.76 mg of glacial acetic acid; (c) 138 mg of trehalose dihydrate; (d) 3.0 mg of L-methionine; (e) 2.0 mg of polysorbate 80; and (f) 2.72 mg of sodium chloride, and The pH of the aqueous pharmaceutical composition or its formulation is 5.0, and the volume of each formulation is 2 mL, and The anti-PD-1 / CD3 bispecific antibody comprises: (i) heavy and light chains that constitute the antigen-binding site that specifically binds to PD-1; and (ii) heavy and light chains that form an antigen-binding site that specifically binds to CD3, and in (α) the heavy chain of the aforementioned item (i) comprises the amino acid sequence shown in SEQ ID NO: 5, (β) the heavy chain of the aforementioned item (ii) comprises the amino acid sequence shown in SEQ ID NO: 6, and (γ) The light chains of the aforementioned items (i) and (ii) both comprise the amino acid sequence shown in SEQ ID NO: 7.

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