Search

EP-4740958-A1 - PHARMACEUTICAL PREPARATION OF ANTI-HUMAN CCR8 MONOCLONAL ANTIBODY AND USE THEREOF

EP4740958A1EP 4740958 A1EP4740958 A1EP 4740958A1EP-4740958-A1

Abstract

Provided are a stable pharmaceutical preparation of an anti-human CCR8 monoclonal antibody and the use thereof. The pharmaceutical preparation of the anti-human CCR8 antibody is very stable, can still meet the requirements for pharmaceutical use after enduring long-term storage, high temperatures or low temperatures, freeze-thaw cycles and oscillation, and has wide application prospects.

Inventors

  • LI, HUIHUI
  • ZHANG, Le
  • AN, Zhenming
  • LIU, JUN
  • SUN, Lixia
  • LI, NA
  • SHEN, Qinyong
  • YANG, YONG
  • CAO, Yawen

Assignees

  • QILU PHARMACEUTICAL CO., LTD.
  • Shanghai Qilu Pharmaceutical Research and Development Centre Ltd.

Dates

Publication Date
20260513
Application Date
20240705

Claims (17)

  1. A pharmaceutical preparation of an anti-human CCR8 monoclonal antibody, comprising an anti-human CCR8 monoclonal antibody or an antigen-binding fragment thereof and a buffer, wherein the sequences of the three CDRs in the heavy chain variable region of the anti-human CCR8 monoclonal antibody or antigen-binding fragment thereof are SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the sequences of the three CDRs in the light chain variable region of the anti-human CCR8 monoclonal antibody or antigen-binding fragment thereof 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.
  2. The pharmaceutical preparation according to claim 1, wherein the sequence of the heavy chain variable region of the anti-human CCR8 monoclonal antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 7, and the sequence of the light chain variable region of the anti-human CCR8 monoclonal antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 8.
  3. The pharmaceutical preparation according to claim 2, wherein the sequence of the heavy chain of the anti-human CCR8 monoclonal antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 9, and the sequence of the light chain of the anti-human CCR8 monoclonal antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 10.
  4. The pharmaceutical preparation according to claim 1, wherein the preparation further comprises a stabilizer selected from sucrose, trehalose or sorbitol.
  5. The pharmaceutical preparation according to claim 1, wherein the preparation further comprises a solubilizer selected from polysorbate 20, polysorbate 80 or poloxamer 188.
  6. The pharmaceutical preparation according to claim 1, wherein the pH value of the preparation is 4.5-6.0.
  7. The pharmaceutical preparation according to claim 1, wherein the content of the anti-human CCR8 monoclonal antibody or antigen-binding fragment thereof in the preparation is 20-160 mg/ml, and preferably 20 mg/ml, 50 mg/ml, 80 mg/ml, 100 mg/ml, 120 mg/ml or 160 mg/ml.
  8. The pharmaceutical preparation according to claim 1, wherein the content of sodium acetate in the preparation is 5-20 mmol/L, and preferably, 5 mmol/L, 10 mmol/L, 15 mmol/L or 20 mmol/L.
  9. The pharmaceutical preparation according to claim 4, wherein the content of sucrose in the preparation is 50-90 mg/ml, and preferably, 50 mg/ml, 70 mg/ml, 80 mg/ml or 90 mg/ml.
  10. The pharmaceutical preparation according to claim 5, wherein the content of polysorbate 80 in the preparation is 0.04-2 mg/ml, and preferably, 0.04 mg/ml, 0.2 mg/ml, 0.5 mg/ml, 0.7 mg/ml or 2 mg/ml.
  11. The pharmaceutical preparation according to claim 5, wherein the content of polysorbate 20 in the preparation is 0.5-2 mg/ml, and preferably, 0.5 mg/ml, 0.7 mg/ml or 2 mg/ml.
  12. The pharmaceutical preparation according to any one of claims 1-11, wherein the preparation comprises 20-160 mg/ml of the anti-human CCR8 monoclonal antibody or antigen-binding fragment thereof, 5-20 mmol/L of sodium acetate, 50-90 mg/ml of sucrose, and 0.5-2 mg/ml of polysorbate 20, and the pH value of the preparation is 4.5-6.0.
  13. The pharmaceutical preparation according to any one of claims 1-11, wherein the preparation comprises 20-160 mg/ml of the anti-human CCR8 monoclonal antibody or antigen-binding fragment thereof, 5-20 mmol/L of sodium acetate, 50-90 mg/ml of sucrose, and 0.04-2 mg/ml of polysorbate 80, and the pH value of the preparation is 4.5-6.0.
  14. The pharmaceutical preparation according to claim 12, wherein the preparation comprises 20-30 mg/ml of the anti-human CCR8 monoclonal antibody or antigen-binding fragment thereof, 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 preparation is 4.5-6.0.
  15. The pharmaceutical preparation according to claim 13, wherein the preparation comprises 20-30 mg/ml of the anti-human CCR8 monoclonal antibody or antigen-binding fragment thereof, 10 mmol/L of sodium acetate, 90 mg/ml of sucrose, and 0.5 mg/ml of polysorbate 80, and the pH value of the preparation is 4.5-6.0.
  16. A lyophilized preparation, which is obtained by freeze-drying the pharmaceutical preparation according to any one of claims 1-15.
  17. Use of the pharmaceutical preparation according to any one of claims 1-15 or the lyophilized preparation according to claim 16 in the manufacture of a medicament for treating advanced solid tumors.

Description

TECHNICAL FIELD The present disclosure belongs to the field of antibody preparations, and specifically relates to a pharmaceutical preparation of an anti-human CCR8 monoclonal antibody and use thereof. BACKGROUND Immune checkpoint inhibitors, such as PD-1/PD-L1 drugs, have achieved good therapeutic effects in the treatment of various tumors, and however, their efficacy rates are still relatively low, ranging from about 15% to 40%, depending on different cancer types. In addition, some patients who initially showed clinical responses develop drug resistance over time, possibly due to compensatory mechanisms in tumor microenvironment (TME) to escape the anti-tumor effects of immune checkpoint inhibitors. Tregs are one of CD4+ T cell lineages, and specifically express Forkhead box P3 (Foxp3). They can be divided into naive, effector and non-Treg cells according to their different sources. Naive Treg cells have a weak immunosuppressive function, and can proliferate and differentiate into effector Treg cells after stimulation by T cell receptors (TCRs). Effector Treg cells are in a terminally differentiated state of immune and have strong immunosuppressive effects, and mainly exert immunosuppression by releasing inhibitory cytokines, directly killing antigen-presenting cells, inhibiting immune function through immune checkpoints, and regulating metabolism such as adenosine pathways. Non-Treg cells have no immunosuppressive activity, but produce inflammatory cytokines. Generally speaking, the number of effector Treg cells is 1%-5% in human peripheral blood, and is about 10%-50% in the TME. Existing studies have shown that a high proportion of Treg infiltration in the TME is negatively correlated with the survival rate of different types of tumors, and therefore, activation of tumor immune responses by targeted clearance of Tregs is expected to be used to enhance tumor immunity. Currently, classic Treg-related targets such as CD25, CTLA4, and CCR4 have been proven to inhibit tumor growth by eliminating Tregs, but these targets are also highly expressed on T effector cells, which can easily lead to adverse reactions. Therefore, there is an unmet clinical need to find targets that are specifically expressed on tumor Tregs and have low or no expression on T effector cells for further development. C-C chemokine receptor 8 (CCR8) protein is one member of the chemokine receptor subfamily and belongs to the G protein-coupled receptor, and its ligands include CCL1 and so on. The main role of CCR8 is to participate in the recruitment of Tregs and Th2 cells to inflammatory and tumor sites. The expression of CCR8 target is highly specific. Studies have shown that CCR8 is expressed at low levels on Treg cells, CD4+T cells, and CD8+T cells in the peripheral blood of tumor patients, while its expression is highly upregulated on Treg cells in the corresponding tumor tissues of the patients, and its expression is low on CD4+ and CD8+T cells in tumor tissues. The expression of CCR8 in different tissues of normal mice and tumor model mice was compared in other literature. The results showed that CCR8 was very low or almost not expressed in normal mouse tissues, whereas was highly expressed in the tumor tissues of tumor-bearing mice, with low expression in spleen and lymph nodes, and almost no expression in other tissues. In summary, an antibody targeting CCR8 can specifically eliminate Tregs in tumor tissues and alleviate the immunosuppression of tumor tissues. It is expected that an antibody targeting CCR8 in combination with PD-1/PD-L1 drugs has a synergistic effect, and will not affect tumor-infiltrating T effector cells, resulting in a lower risk of systemic autoimmunity and better safety. SUMMARY OF THE INVENTION In order to pursue a better clinical effect, an anti-human CCR8 monoclonal antibody, named J06 is firstly obtained in the present disclosure. Based on the J06 antibody, further exploration and research had been conducted on the formulation of J06 preparation, and ultimately, a solution preparation that was most suitable for monoclonal antibody J06 and can stably preserve the monoclonal antibody was obtained. This preparation can fully prevent the aggregation, degradation, oxidation or denaturation or the like of the monoclonal antibody J06 protein, thereby maintaining the biological activity of its effective components, and is suitable for clinical use. Further, based on the monoclonal antibody J06 preparation, the pharmacological function of the preparation was deeply studied, and it was found that the preparation had a good anti-tumor activity. DETAILED DESCRIPTION OF DISCLOSURE 1. Terminology All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Before the present disclosure is described in d