Pharmaceutical formulations of anti-human CCR8 monoclonal antibodies and their use

Abstract

This disclosure relates to a stable pharmaceutical formulation of an anti-human CCR8 monoclonal antibody and its use. The pharmaceutical formulation of the anti-human CCR8 antibody described herein is highly stable and can meet pharmaceutical use requirements even after long-term storage, high or low temperatures, freeze-thaw cycles, and shaking, and is expected to have a wide range of applications.

Description

Technical Field

[0001] The present disclosure relates to the field of antibody formulations, and specifically to pharmaceutical formulations of anti-human CCR8 monoclonal antibodies and their use.

Background Art

[0002] Immune checkpoint inhibitors (e.g., PD-1 / PD-L1 agents) have achieved good therapeutic effects in the treatment of various tumors, but the efficacy is still low for some types of cancer, about 15% - 40%. Furthermore, some patients who initially showed a clinical response may develop resistance over time, which may be due to a compensatory mechanism that appears in the tumor microenvironment (TME) to avoid the anti-tumor effect of immune checkpoint inhibitors.

[0003] Treg is a lineage of CD4 + T cells, and specifically expresses Forkhead box P3 (Foxp3). Depending on its origin, it is classified into immature, effector, and non-Treg cells. Immature Treg cells have a weak immunosuppressive function and proliferate and differentiate into effector Treg cells upon stimulation of the T cell receptor (TCR). Effector Treg cells are in the terminal differentiation state of immunity and have a strong immunosuppressive effect, mainly performing immunosuppression through the release of inhibitory cytokines, direct killing of antigen-presenting cells, suppression of immune functions via immune checkpoints, and metabolic regulation such as the adenosine pathway. Non-Treg cells do not have immunosuppressive activity but produce inflammatory cytokines. Generally, the number of effector Treg cells in human peripheral blood is 1% - 5%, but in the tumor microenvironment (TME) it is about 10% - 50%. Existing studies have shown that a high proportion of Treg infiltration in the TME has a negative correlation with the survival rate of various tumors. Therefore, activation of the tumor immune response by targeted removal of Treg is expected to be effective in enhancing tumor immunity.

[0004] Currently, classical Treg-related targets such as CD25, CTLA4, and CCR4 have been demonstrated to potentially suppress tumor growth by eliminating Tregs; however, these targets are also highly expressed in T-effect cells and readily cause adverse reactions. Therefore, the search for and further development of targets that are specifically expressed in tumor Tregs and are low-expression or absent in T-effect cells remains a clinically unmet need.

[0005] CC chemokine receptor 8 protein (CCR8) is a member of the chemokine receptor subfamily, belonging to the G protein-coupled receptor class, and its ligands include CCL1. The main role of CCR8 is to be involved in the recruitment of Treg and Th2 cells to inflammatory and tumor sites. Expression of CCR8 targets is highly specific, and studies have shown that it is particularly effective in the peripheral blood of tumor patients with Treg cells and CD4 + T cells, CD8 + CCR8 expression levels in T cells are relatively low, but its expression is highly elevated in Treg cells in the tumor tissue of the corresponding patients, and CD4 in tumor tissue + and CD8 + Expression in T cells is relatively low. Other studies comparing CCR8 expression in different tissues of normal mice and tumor model mice have shown that CCR8 is expressed very little or almost never in normal mouse tissues, but highly in tumor tissues of tumor mice, low in the spleen and lymph nodes, and almost never in other tissues. Overall, antibodies targeting CCR8 can specifically remove Tregs in tumor tissue, alleviate immunosuppression in tumor tissue, and are expected to have a synergistic effect when used in combination with PD-1 / PD-L1 drugs, without affecting tumor-infiltrating T-effect cells, with a low risk of systemic autoimmunity and excellent safety.

[0006] [Contents of the invention] In pursuit of superior clinical efficacy, this disclosure first describes the acquisition of an anti-human CCR8 monoclonal antibody named J06. Based on the acquisition of the J06 antibody, further exploration and research were conducted on the formulation of the J06 preparation. Ultimately, a solution formulation was obtained that is most suitable for the J06 monoclonal antibody and allows for the stable storage of the monoclonal antibody. This formulation effectively prevents aggregation, degradation, oxidation, or denaturation of the monoclonal antibody J06 protein, maintaining the biological activity of its active ingredient, and is suitable for clinical use. Furthermore, based on the acquisition of the monoclonal antibody J06 formulation, its pharmacological function was thoroughly studied, and it was discovered that the formulation possesses good antitumor activity.

[0007] [Detailed description of the invention] 1. Terminology All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same degree as any individual publication, patent, or patent application is specifically and individually incorporated herein by reference.

[0008] Before describing this disclosure in detail below, it should be understood that this disclosure is not limited to the specific methodologies, protocols, and reagents described herein, as they are subject to change. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments and is not intended to limit the scope of this disclosure. Unless otherwise noted, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to whom this disclosure relates.

[0009] Certain embodiments disclosed herein include numerical ranges, and certain aspects of this disclosure may be described in the form of ranges. Unless otherwise specified, numerical ranges or descriptions in the form of ranges are for the purpose of brevity and convenience only and should be understood as not to strictly limit the scope of the invention. Accordingly, descriptions in the form of ranges should be interpreted as specifically disclosing all possible subranges and all possible specific numerical points within those ranges, as these subranges and associated numerical points are clearly stated herein. The above principle applies equally regardless of the width of the numerical values. In the case of descriptions in the form of ranges, the range includes the endpoints of the range.

[0010] When referring to measurable values ​​(e.g., quantity, temporary duration, etc.), the term “approximately” means that the change may be within ±20%, or in some cases ±10%, or in some cases ±5%, or in some cases ±1%, or in some cases ±0.1% of the specified value.

[0011] As used herein, the term “antibody” typically refers to a Y-type tetrameric protein consisting of two heavy (H) polypeptide chains and two light (L) polypeptide chains held together by covalent disulfide and non-covalent interactions. Natural IgG antibodies have such a structure. Each light chain contains one light chain variable domain (VL) and one light chain constant domain (CL). Each heavy chain contains one heavy chain variable domain (VH) and one heavy chain constant domain (CH) (also called the heavy chain constant region (CH)).

[0012] The term "monoclonal antibody" (also known as "monoclonal antibody" or "mAb") refers to a substantially homogeneous antibody produced by a single cell clone that targets only a specific antigen epitope. Monoclonal antibodies can be prepared using a variety of techniques known in the art, such as hybridoma technology, recombinant technology, phage display technology, transgenic animal technology, synthetic technology, or a combination of these technologies.

[0013] 2. Disclosure details The purpose of this disclosure is to provide a stable formulation suitable for anti-human CCR8 monoclonal antibodies and its use. This disclosure provides, in one embodiment, a pharmaceutical formulation of an anti-human CCR8 monoclonal antibody comprising an anti-human CCR8 monoclonal antibody or its antigen-binding fragment and a buffer, wherein three CDR sequences in the heavy chain variable region of the anti-human CCR8 monoclonal antibody or its antigen-binding fragment are SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and three CDR sequences in the light chain variable region are SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively, and the buffer is a sodium acetate buffer, a histidine buffer, or a sodium citrate buffer.

[0014] Preferably, the sequence of the heavy chain variable region of the anti-human CCR8 monoclonal antibody or its antigen-binding fragment is shown in SEQ ID NO:7, and the sequence of the light chain variable region is shown in SEQ ID NO:8. Preferably, the heavy chain sequence of the anti-human CCR8 monoclonal antibody or its antigen-binding fragment is shown in SEQ ID NO:9, and the light chain sequence is shown in SEQ ID NO:10. Preferably, the formulation further comprises a stabilizer selected from sucrose, trehalose, or sorbitol. Preferably, the formulation further comprises a solubilizer selected from polysorbate 20, polysorbate 80, or poloxamer 188.

[0015] Preferably, the pH value of the formulation is 4.5 to 6.0. Preferably, the content of the anti-human CCR8 monoclonal antibody or its antigen-binding fragment in the formulation is 20 to 160 mg / mL, and preferably 20 mg / mL, 50 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, or 160 mg / mL. Preferably, the sodium acetate content in the formulation is 5 to 20 mmol / L, and more preferably 5 mmol / L, 10 mmol / L, 15 mmol / L, or 20 mmol / L.

[0016] Preferably, the sucrose content in the formulation is 50 to 90 mg / mL, and more preferably 50 mg / mL, 70 mg / mL, 80 mg / mL, or 90 mg / mL. Preferably, the polysorbate 80 content in the formulation is 0.04 to 2 mg / mL, and more preferably 0.04 mg / mL, 0.2 mg / mL, 0.5 mg / mL, 0.7 mg / mL, or 2 mg / mL. Preferably, the polysorbate 20 content in the formulation is 0.5 to 2 mg / mL, and more preferably 0.5 mg / mL, 0.7 mg / mL, or 2 mg / mL.

[0017] Preferably, the formulation contains 20 to 160 mg / mL of an anti-human CCR8 monoclonal antibody or its antigen-binding fragment, 5 to 20 mmol / L of sodium acetate, 50 to 90 mg / mL of sucrose, and 0.5 to 2 mg / mL of polysorbate 20, and the pH value of the formulation is 4.5 to 6.0. Preferably, the formulation contains 20 to 160 mg / mL of an anti-human CCR8 monoclonal antibody or its antigen-binding fragment, 5 to 20 mmol / L of sodium acetate, 50 to 90 mg / mL of sucrose, and 0.04 to 2 mg / mL of polysorbate 80, and the pH value of the formulation is 4.5 to 6.0. Preferably, the formulation contains 20-30 mg / mL of an anti-human CCR8 monoclonal antibody or its antigen-binding fragment, 10 mmol / L of sodium acetate, 90 mg / mL of sucrose, and 0.5 mg / mL of polysorbate 20, and the pH value of the formulation is 4.5-6.0.

[0018] Preferably, the preparation contains an anti-human CCR8 monoclonal antibody or an antigen-binding fragment thereof at 20-30 mg / mL, sodium acetate at 10 mmol / L, sucrose at 90 mg / mL, and polysorbate 80 at 0.5 mg / mL, and the pH value of the preparation is 4.5-6.0. In another embodiment, the present disclosure further provides a lyophilized preparation obtained by lyophilizing the pharmaceutical preparation.

[0019] In another embodiment, the present disclosure further provides the use of the pharmaceutical preparation or the lyophilized preparation in the manufacture of a medicament for treating progressive solid tumors. The preparation of the present disclosure has the following beneficial effects. The preparation according to the present disclosure is very stable and can meet the pharmaceutical use requirements even after long-term storage, exposure to high or low temperatures, freeze-thaw cycles, or shaking, and broad applications are expected.

Brief Description of Drawings

[0020] [Figure 1] It is a diagram showing the monomer purity by SE-HPLC in the pH range screening test. [Figure 2] It is a diagram showing the main peak purity by nrCE-SDS in the pH range screening test. [Figure 3] It is a diagram showing the monomer purity by SE-HPLC in the excipient (auxiliary material) screening test. [Figure 4] It is a diagram showing the main peak purity by nrCE-SDS in the excipient screening test.

Modes for Carrying Out the Invention

[0021] The present disclosure will be further described in detail by the following examples. Based on the present disclosure, as long as changes in the component concentrations in the preparation or addition of other substances do not significantly affect the stability of the anti-human CCR8 antibody, these changes are also regarded as part of the present disclosure.

[0022] Size exclusion chromatography (SE-HPLC) The content of high molecular weight substances (HMWS), monomers, and low molecular weight substances (LMWS) in this product was measured using size exclusion chromatography. This method was performed on a Waters e2695-2489 HPLC system using an X Bridge BEH 200Å SEC column (Waters). The detection wavelength was 215 nm, the mobile phase was 100 mM sodium phosphate and 250 mM sodium chloride buffer (pH 7.3), the flow rate was 0.5 mL / min, and the execution time was 30 min. The sample was diluted with the mobile phase to a protein content of 1 mg / mL, and 20 μg was injected. Integration was performed using Empower 3 software (Waters).

[0023] Capillary electrophoresis (CE-SDS) The main peak and (LC+HC) purity were measured using non-reducing CE-SDS (nrCE) and reduced CE-SDS (rCE), respectively. This test was performed using a SCIEX PA800 plus capillary electrophoresis system with an uncoated quartz capillary (effective separation length 20 cm, total length 30.2 cm) with an inner diameter (ID) of 50 μm, at a PDA of 220 nm and a bandwidth of 10 nm.

[0024] Surface Plasmon Resonance technology (SPR) The affinity of this product for recombinant human CCR8 was measured using surface plasmon resonance (SPR) technology. In this method, recombinant human CCR8 protein was immobilized on the experimental channel of a CM5 chip by amino coupling using a direct fixation method, with a coupling amount of approximately 15 RU. 1 nM of this product was serially diluted with running buffer to 31.25 pM. A series of concentrations of the product from 1 nM to 31.25 pM were sequentially passed through the reference channel and experimental channel, respectively, with 3 minutes of binding and 10 minutes of dissociation. After each cycle, the samples were regenerated twice for 30 seconds each with 50 mM HCl. The obtained data were analyzed using Biacore 8K Evaluation software and fitted with a 1:1 binding model.

[0025] The following describes the disclosure with specific examples, but it should be understood that these examples are for illustrative purposes only and do not limit the scope of the disclosure.

[0026] [Example 1] Acquisition of anti-human CCR8 monoclonal antibody J06 and sequence information Based on the information described in PCT / US2023 / 060686, an anti-human CCR8 monoclonal antibody J06 (corresponding to anti-CCR8 Mab1187 in the above patent) was obtained. The three CDR sequences in the heavy chain variable region of anti-human CCR8 monoclonal antibody J06 were SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and the three CDR sequences in the light chain variable region were SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively. The sequence of the heavy chain variable region of anti-human CCR8 monoclonal antibody J06 is shown in SEQ ID NO:7, and the sequence of the light chain variable region is shown in SEQ ID NO:8. The heavy chain sequence of anti-human CCR8 monoclonal antibody J06 is shown in SEQ ID NO:9, and the light chain sequence is shown in SEQ ID NO:10.

[0027] [Example 2] Preparation of anti-human CCR8 monoclonal antibody J06 Anti-human CCR8 monoclonal antibody J06 is a monoclonal antibody expressed in CHO cells. The complete molecule of this monoclonal antibody consists of two heavy chains (HC) and two light chains (LC), with each heavy chain consisting of 453 amino acid residues and each light chain consisting of 219 amino acid residues. The above anti-human CCR8 monoclonal antibody J06 was expressed in CHO cells, purified to obtain the stock solution, and then used in further experiments.

[0028] [Example 3] Solubilizer screening test The protein used in the following experiments was the anti-human CCR8 monoclonal antibody J06 prepared in Example 2. Based on a formulation of a protein concentration of 30 mg / mL, sucrose (90 mg / mL), and a 10 mmol / L sodium acetate buffer system, the type of solubilizer (polysorbate 20, polysorbate 80) and the amount used were screened. The formulation designs are shown in Table 1.

[0029] JPEG2026522034000002.jpg36167

[0030] Samples prepared according to the above prescription were subjected to influence factor testing. The study was conducted under high temperature conditions (40°C ± 2°C), with samples taken and tested on day 0, week 1, week 2, and week 3. The study was conducted under shaking conditions, with samples taken and tested at 24 hours and 48 hours. The study was conducted under freeze-thaw conditions (one cycle consisted of freezing at -80°C for 16 hours and thawing at 25°C for 8 hours), with samples taken and tested after 6 and 10 cycles.

[0031] Inspection items: Appearance, presence or absence of visible foreign matter, protein content, size exclusion chromatography (SE-HPLC) purity, non-reducing capillary electrophoresis (nrCE-SDS) purity. The test results are shown in Table 2.

[0032] JPEG2026522034000003.jpg208170

[0033] The test results showed that after being left for 3 weeks under high temperature conditions (40°C ± 2°C), visible foreign matter in the form of protein flocs (cotton-like precipitates) was observed in the sample without solubilizer (R0) and the sample with polysorbate 20 (0.2 mg / mL) added (R1). The main peak purity of samples (R1-R4) containing different types of solubilizers (polysorbate 20, polysorbate 80) and concentrations (0.2 mg / mL, 0.5 mg / mL) all showed a decreasing trend, but the decreasing trend was basically the same. No significant changes were observed in the individual test indicators of R1-R4 during 48-hour observation under shaking conditions and 10 observations under freeze-thaw conditions. Based on these test results, 0.5 mg / mL of polysorbate 20 and 0.2 mg / mL or 0.5 mg / mL of polysorbate 80 can be used as solubilizers for J06.

[0034] [Example 4] pH value range screening test Based on formulations containing protein concentration (20 mg / mL), sucrose (90 mg / mL), polysorbate 80 (0.5 mg / mL), and a sodium acetate (10 mmol / L) buffer system, the pH range was screened. The pH range was set to 4.0 to 6.0, and the formulations are shown in Table 3.

[0035] JPEG2026522034000004.jpg43126

[0036] The liquid prepared according to the above prescription was sterilized, filtered, and dispensed (packaged). An influence factor test (high temperature 40°C ± 2°C) was performed on the prepared samples, and samples were taken and tested on day 0, week 1, and week 2.

[0037] Test items: Appearance, protein content, presence or absence of visible foreign matter, size exclusion chromatography (SE-HPLC) purity, and non-reducing capillary electrophoresis (nrCE-SDS) purity. The test results are shown in Table 4.

[0038] JPEG2026522034000005.jpg100126

[0039] After examining the samples under high temperature conditions (40°C ± 2°C) for two weeks, no significant changes were observed in the appearance, presence of visible foreign matter, or protein content of each formulation. As shown in Figures 1 and 2, the SE-HPLC and nrCE-SDS purity of the sample with a pH of 4.0 (R1) decreased by 4.3% and 2.7% respectively compared to 0 hours, indicating a significant decrease. On the other hand, while the purity indicators of the samples from formulations R6 to R11 (pH 4.5 to 6.0) decreased slightly, the decreasing trend was basically the same, and no differences were observed between the formulations. Based on the combined test results of each formulation, the candidate pH range was determined to be 4.5 to 6.0.

[0040] [Example 5] Excipient screening test The protein used in the following experiments is the anti-human CCR8 monoclonal antibody J06 prepared in Example 2. Formulations were screened using various excipients, and the formulation designs are shown in Table 5.

[0041] JPEG2026522034000006.jpg32119

[0042] Samples prepared according to the above prescription were subjected to an influence factor test (high temperature 40°C ± 2°C), and samples were collected and tested on day 0, day 7, day 14, and day 30.

[0043] Test items: Appearance, presence or absence of visible foreign matter, protein content, size exclusion chromatography (SE-HPLC) purity, and non-reducing capillary electrophoresis (nrCE-SDS) purity. The test results are shown in Table 6.

[0044] JPEG2026522034000007.jpg68125

[0045] The test results showed no significant changes in the appearance, presence of visible foreign matter, or protein content of each formulation after 30 days of observation under high temperature (40°C ± 2°C) conditions. While each purity index showed a slight downward trend, the downward trend was essentially the same, and no significant differences were observed between the test indicators of each formulation during the 30 days under high temperature (40°C ± 2°C) conditions. In summary, these test results indicate that protein concentrations can be selected from 20 to 160 mg / mL, sodium acetate, histidine, or sodium citrate can all be used as buffers, sucrose, trehalose, or sorbitol can all be used as stabilizers, and polysorbate 80 or poloxamer 188 can all be used as solubilizers.

[0046] Conclusion: Through the above formulation screening tests, the buffer system can be selected from sodium acetate, histidine, or sodium citrate; the stabilizer can be selected from sucrose, trehalose, or sorbitol; and the solubilizer can be selected from polysorbate 20, polysorbate 80, or poloxamer 188.

[0047] [Example 6] Stability test of the formulation Based on the above test results, the following priority formulation was adopted for stability studies: protein concentration (20 mg / mL), sucrose as a stabilizer (concentration 90 mg / mL), polysorbate 80 as a solubilizer (concentration 0.5 mg / mL), sodium acetate as a buffer system (concentration 10 mmol / L), and pH value 4.5-6.0. This included forced condition tests (high temperature tests), accelerated tests, and long-term tests. In the stability studies, samples were placed vertically, and all samples for the long-term, accelerated, and high-temperature tests used the same packaging as the marketed product. The test conditions for each test are shown in Table 7.

[0048] JPEG2026522034000008.jpg2584

[0049] The stability results under each of the above consideration conditions are shown in Tables 8 to 10.

[0050] JPEG2026522034000009.jpg57111

[0051] JPEG2026522034000010.jpg63116

[0052] JPEG2026522034000011.jpg64108

[0053] The results above demonstrate that this antibody preparation has good stability and can meet quality standards even when examined in high-temperature tests (40°C ± 2°C) and accelerated tests (25°C ± 2°C).

[0054] [Example 7] Affinity analysis of anti-human CCR8 monoclonal antibody J06 formulation and human CCR8 recombinant protein Based on the above results, affinity analysis was performed on the preferred formulation of Example 6. Using SPR technology, the affinity between the anti-human CCR8 monoclonal antibody J06 formulation and recombinant human CCR8 protein was measured. As shown in Table 11, the K that was fitted by affinity analysis of the J06 formulation to recombinant human CCR8 was D The value was 7.77 pM, indicating that the J06 formulation has a higher affinity for recombinant human CCR8.

[0055] JPEG2026522034000012.jpg20124

Claims

1. A pharmaceutical formulation of an anti-human CCR8 monoclonal antibody comprising an anti-human CCR8 monoclonal antibody or its antigen-binding fragment and a buffer, The three CDR sequences in the heavy chain variable region of the anti-human CCR8 monoclonal antibody or its antigen-binding fragment are, respectively, SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:

3. The three CDR sequences in the light chain variable region of the anti-human CCR8 monoclonal antibody or its antigen-binding fragment are SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively. A pharmaceutical formulation characterized in that the buffering agent is a sodium acetate buffering agent, a histidine buffering agent, or a sodium citrate buffering agent.

2. The sequence of the heavy chain variable region of the anti-human CCR8 monoclonal antibody or its antigen-binding fragment is shown in SEQ ID NO:

7. The sequence of the light chain variable region of the anti-human CCR8 monoclonal antibody or its antigen-binding fragment is shown as SEQ ID NO:

8. The pharmaceutical preparation according to claim 1.

3. The sequence of the heavy chain of the anti-human CCR8 monoclonal antibody or its antigen-binding fragment is shown in SEQ ID NO:

9. The sequence of the light chain of the anti-human CCR8 monoclonal antibody or its antigen-binding fragment is shown in SEQ ID NO:

10. The pharmaceutical preparation according to claim 2.

4. The pharmaceutical formulation according to claim 1, characterized in that the formulation further comprises a stabilizer selected from sucrose, trehalose, or sorbitol.

5. The pharmaceutical formulation according to claim 1, characterized in that the formulation further comprises a solubilizing agent selected from polysorbate 20, polysorbate 80, or poloxamer 188.

6. The pharmaceutical preparation according to claim 1, characterized in that the pH value of the preparation is 4.5 to 6.

0.

7. The pharmaceutical formulation according to claim 1, characterized in that the content of the anti-human CCR8 monoclonal antibody or its antigen-binding fragment in the formulation is 20 to 160 mg / mL, preferably 20 mg / mL, 50 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, or 160 mg / mL.

8. The pharmaceutical formulation according to claim 1, characterized in that the sodium acetate content in the formulation is 5 to 20 mmol / L, preferably 5 mmol / L, 10 mmol / L, 15 mmol / L, or 20 mmol / L.

9. The pharmaceutical formulation according to claim 4, characterized in that the sucrose content in the formulation is 50 to 90 mg / mL, preferably 50 mg / mL, 70 mg / mL, 80 mg / mL, or 90 mg / mL.

10. The pharmaceutical formulation according to claim 5, characterized in that the polysorbate 80 content in the formulation is 0.04 to 2 mg / mL, preferably 0.04 mg / mL, 0.2 mg / mL, 0.5 mg / mL, 0.7 mg / mL, or 2 mg / mL.

11. The pharmaceutical formulation according to claim 5, characterized in that the polysorbate 20 content in the formulation is 0.5 to 2 mg / mL, preferably 0.5 mg / mL, 0.7 mg / mL, or 2 mg / mL.

12. The aforementioned preparation contains 20 to 160 mg / mL of anti-human CCR8 monoclonal antibody or its antigen-binding fragment, 5 to 20 mmol / L of sodium acetate, 50 to 90 mg / mL of sucrose, and 0.5 to 2 mg / mL of polysorbate 20. A pharmaceutical preparation according to any one of claims 1 to 11, characterized in that the pH value of the preparation is 4.5 to 6.

0.

13. The aforementioned preparation contains 20 to 160 mg / mL of anti-human CCR8 monoclonal antibody or its antigen-binding fragment, 5 to 20 mmol / L of sodium acetate, 50 to 90 mg / mL of sucrose, and 0.04 to 2 mg / mL of polysorbate 80. A pharmaceutical preparation according to any one of claims 1 to 11, characterized in that the pH value of the preparation is 4.5 to 6.

0.

14. The aforementioned preparation contains 20-30 mg / mL of an anti-human CCR8 monoclonal antibody or its antigen-binding fragment, 10 mmol / L of sodium acetate, 90 mg / mL of sucrose, and 0.5 mg / mL of polysorbate 20. The pharmaceutical formulation according to claim 12, characterized in that the pH value of the formulation is 4.5 to 6.

0.

15. The aforementioned preparation contains 20-30 mg / mL of anti-human CCR8 monoclonal antibody or its antigen-binding fragment, 10 mmol / L of sodium acetate, 90 mg / mL of sucrose, and 0.5 mg / mL of polysorbate 80. The pharmaceutical preparation according to claim 13, characterized in that the pH value of the preparation is 4.5 to 6.

0.

16. A lyophilized preparation obtained by lyophilizing a pharmaceutical preparation according to any one of claims 1 to 15.

17. Use of a pharmaceutical formulation according to any one of claims 1 to 15 or a lyophilized formulation according to claim 16 in the manufacture of a pharmaceutical for treating progressive solid tumors.

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