Drug composition, its use in the preparation of a drug for treating lymphopenia, and an anti-tumor drug

Abstract

The present invention belongs to the field of biomedicine, and discloses a pharmaceutical composition, its application in the preparation of a drug for treating lymphopenia, and an anti-tumor drug. The pharmaceutical composition provided by the present invention comprises thymosin α1 and recombinant human interleukin-2. Through the synergistic cooperation of thymosin α1 and recombinant human interleukin-2, it can act well on the immune system of tumor patients damaged by treatment means such as cancer cell attack, chemotherapy, cell transplantation or targeted therapy, regulate the expression balance of immune factors related to the immune system reconstruction, improve the activity of normal lymphocytes, achieve immune system reconstruction to a certain extent, promote the proliferation of lymphocytes, especially T cell subsets, relieve or treat lymphopenia caused by chemotherapy in tumor patients, and the pharmaceutical composition can also synergistically enhance the therapeutic effect of existing chemotherapy drugs, promote the clearance of cancer cells, and achieve a better anti-tumor therapeutic effect.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to a pharmaceutical composition, its application in the preparation of a drug for treating lymphopenia, and an anti-tumor drug. Background Art

[0002] Chemotherapy refers to a treatment method that uses chemical drugs to inhibit or kill tumor cells to achieve an anti-cancer effect, and is widely used in tumor treatment. However, existing chemotherapy drugs have poor targeting. While killing cancer cells and reducing the tumor burden, they also non-selectively attack the body's immune system, resulting in the occurrence of lymphopenia. Research shows that lymphopenia significantly increases the risk of patients being infected with pathogens such as viruses and bacteria, and the reduction of immune cells leads to low or incompetent immune function, affecting the tumor treatment effect, increasing the escape of tumor cells, making the growth of tumor cells out of control, and promoting the recurrence and metastasis of tumors. Treating or alleviating lymphopenia that occurs during the chemotherapy of tumor patients and increasing the number of lymphocytes is beneficial to improving or reconstructing the immune function of patients, thereby achieving a better tumor treatment effect, which has important clinical significance. However, there is still a lack of effective intervention measures for lymphopenia caused by chemotherapy in clinical practice, which has great limitations. Summary of the Invention

[0003] The first object of the present invention is to provide a new pharmaceutical composition. The pharmaceutical composition includes thymosin α1 and recombinant human interleukin-2. Through the synergistic cooperation of thymosin α1 and recombinant human interleukin-2, it can act well on the immune system of tumor patients that has been damaged by treatment means such as cancer cell attack, chemotherapy, cell transplantation, or targeted therapy, regulate the expression balance of immune factors related to the immune system, improve the activity of normal lymphocytes, achieve immune system reconstruction to a certain extent, promote the proliferation of lymphocytes, especially T cell subsets, and can well alleviate or treat lymphopenia caused by chemotherapy in tumor patients. Moreover, this pharmaceutical composition can also synergistically enhance the therapeutic effect of existing chemotherapy drugs, promote the clearance of cancer cells, and achieve a better therapeutic effect.

[0004] It should be noted that the pharmaceutical composition provided by the present invention, especially for hematological tumor patients with severely damaged immune systems (the absolute number of lymphocytes is as low as 0.03×10 9 / L), has a very excellent therapeutic effect. After 7 days of short-term drug administration treatment for hematological tumor patients, the number of lymphocytes and their T cell subsets increased significantly, effectively treating or alleviating lymphopenia caused by factors such as cancer cell attack, chemotherapy, cell transplantation, or targeted therapy in tumor patients.

[0005] The second object of the present invention is to provide the use of the above-mentioned pharmaceutical composition in the preparation of a medicament for treating lymphopenia.

[0006] The third object of the present invention is to provide an anti-tumor drug.

[0007] Specifically, the pharmaceutical composition provided by the present invention comprises thymosin α1 and recombinant human interleukin-2.

[0008] Further, the amino acid sequence of the thymosin α1 is as shown in SEQ ID NO:1.

[0009] Further, the amino acid sequence of the recombinant human interleukin-2 is as shown in SEQ ID NO:2 and / or SEQ ID NO:3.

[0010] Further, the amino acid sequence of the recombinant human interleukin-2 is as shown in SEQ ID NO:2.

[0011] Further, the addition ratio of the thymosin α1 and the recombinant human interleukin-2 is (1.5-1.8) mg:(80-120)×10^4 units.

[0012] The present invention also provides the use of the above-mentioned pharmaceutical composition in the preparation of a medicament for treating and / or alleviating lymphopenia.

[0013] Further, the lymphopenia is a side effect caused by chemotherapy in patients with hematological malignancies.

[0014] The anti-tumor drug provided by the present invention comprises a chemotherapeutic drug and the above-mentioned pharmaceutical composition.

[0015] Further, the anti-tumor drug is used for treating one or more of leukemia, lymphoma and myeloma. Description of the Drawings

[0016] Figure 1 It is a graph showing the experimental results of the lymphocyte amplification multiple before and after the combined drug treatment of Delsheng and Zadaxin in group A clinical patients provided in the examples of the present invention. Detailed Embodiments

[0017] In long-term clinical work, the inventors of the present invention found that while tumor treatment methods such as chemotherapy can kill tumor cells, they also non-selectively attack the body's immune system, leading to the occurrence of immune deficiency diseases such as lymphopenia. Especially for hematological tumors originating from the immune system, tumor treatment methods such as chemotherapy cause more profound and extensive damage to the immune system. Although known immunomodulators such as CYT107, TJ107, and KGF can, to a certain extent, improve lymphopenia caused by pathogen infection, non-immune system primary tumors, and their treatments, they have no improvement effect on hematological tumor patients with severely damaged immune systems and may even cause chemotherapy delay, affecting the treatment effect.

[0018] Based on the above problems, through extensive research and clinical practice, the inventors creatively discovered that the combined treatment of hematological tumor patients with thymosin alpha-1 and recombinant human interleukin-2 can significantly increase the number of lymphocytes and their T cell subsets in hematological tumor patients, effectively improve lymphopenia, and at the same time can, to a certain extent, synergistically enhance the anti-tumor effect of chemotherapy drugs, achieving a better treatment effect. Based on this, the technical solution of the present invention was obtained.

[0019] The present invention provides a pharmaceutical composition, which specifically comprises thymosin alpha-1 and recombinant human interleukin-2.

[0020] In the prior art, when thymosin alpha-1 or recombinant human interleukin-2 is administered alone to hematological tumor patients according to the standard dosage, it cannot effectively improve the lymphopenia of the patients and may even cause chemotherapy delay.

[0021] In the present invention, in the pharmaceutical composition, through the synergistic cooperation of thymosin alpha-1 and recombinant human interleukin-2, it can significantly improve the lymphopenia of the patients, and at the same time synergistically with chemotherapy drugs to inhibit and kill tumor cells, and to a certain extent, rebuild the severely damaged immune system to ultimately achieve a better anti-tumor treatment effect.

[0022] In the present invention, the thymosin alpha-1 (Tα1) is a small molecule bioactive peptide derived from thymosin fraction 5 (TF5), and the specific amino acid sequence is preferably as shown in SEQ ID NO:1; the present invention does not particularly limit its specific source, and it can be specifically prepared by genetic engineering technology by itself or obtained by purchase.

[0023] In the present invention, the recombinant human interleukin-2 (rIL-2) is a recombinant protein with lymphocyte factor activity, and the specific amino acid sequence is preferably as shown in SEQ ID NO:2 and / or SEQ ID NO:3; the present invention does not particularly limit its specific source, and it can be specifically prepared by genetic engineering technology by itself or obtained by purchase.

[0024] In some specific embodiments, the amino acid sequence of the recombinant human interleukin-2 is preferably as shown in SEQ ID NO:2. At this time, the recombinant human interleukin-2 can better cooperate with thymosin α1 to play a role, so as to achieve a better improvement effect on lymphopenia in tumor patients.

[0025] In the present invention, the addition ratio of the thymosin α1 and the recombinant human interleukin-2 is preferably (1.5-1.8):(80-120) (mg: ten thousand units), such as 1.5:80 (mg: ten thousand units), 1.6:100 (mg: ten thousand units), 1.7:80 (mg: ten thousand units), 1.8:120 (mg: ten thousand units) or any value therebetween.

[0026] In the present invention, the pharmaceutical composition may further include pharmaceutically acceptable excipients, and those skilled in the art can select from the existing known excipients according to actual needs. The present invention does not particularly limit its specific components and their ratios.

[0027] Based on the effect of the above-mentioned pharmaceutical composition in treating and / or alleviating lymphopenia in patients, the present invention further provides the application of the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or alleviating lymphopenia.

[0028] In the present invention, for patients with hematological malignancies whose immune systems are severely damaged, the above-mentioned pharmaceutical composition has the effect of treating and / or alleviating lymphopenia that existing known immunomodulators do not have. That is, the above-mentioned pharmaceutical composition has a significant effect of treating and / or alleviating lymphopenia in hematological malignancy patients caused by chemotherapy.

[0029] Based on the effect of the above-mentioned pharmaceutical composition in treating and / or alleviating lymphocytosis in hematological malignancy patients and enhancing the efficacy in combination with chemotherapy drugs, the present invention further provides an anti-tumor drug.

[0030] In the present invention, the anti-tumor drug includes a chemotherapy drug and the above-mentioned pharmaceutical composition.

[0031] In the present invention, the chemotherapeutic drug is a type of drug used to kill or inhibit the growth of tumor cells. Those skilled in the art can select it according to the actual situation of the patient and based on the "Guidelines for Clinical Application of Antineoplastic Drugs", and the present invention does not specifically limit it.

[0032] In some specific embodiments, specific examples of the chemotherapeutic drug include but are not limited to: one or more of imatinib, bortezomib, blinatumomab, chidamide, and zanubrutinib. At this time, the pharmaceutical composition cooperates synergistically with the above chemotherapeutic drugs for treating hematological malignancies such as leukemia, lymphoma, and myeloma, and can synergistically enhance the therapeutic effect of the chemotherapeutic drug well.

[0033] The embodiments of the present invention are described in detail below. The examples of the embodiments are intended to explain the present invention and should not be construed as a limitation of the present invention. For those not specifying specific techniques or conditions in the embodiments, the techniques or conditions described in the literature in the art or according to the product specifications are followed. For reagents or instruments without indicating the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0034] Example

[0035] This example is used to illustrate a pharmaceutical composition and its effect of treating and / or alleviating lymphopenia drugs, specifically including:

[0036] 1. Case selection

[0037] The cases in the clinical trial are from hematological malignancy patients in the Department of Hematology, The First Affiliated Hospital of Xiamen University. The inclusion criteria include: (1) diagnosed as leukemia by bone marrow puncture, lymphoma by lymph node pathological biopsy, or multiple myeloma according to the "Chinese Guidelines for the Diagnosis and Treatment of Multiple Myeloma (2022 Edition)"; (2) aged 35 - 80 years old; (3) having completed at least 1 round or more of basic treatment such as chemotherapy, hematopoietic stem cell transplantation, or targeted therapy; (4) presenting with lymphopenia, with an absolute lymphocyte count < 0.8×10 9 / L.

[0038] 2. Administration method

[0039] There are 107 patients in the experiment. While the patients were undergoing basic chemotherapy treatment under the guidance of the "Guidelines for Clinical Application of Antineoplastic Drugs" in combination with their own conditions, they were divided into Group A, Group B, Group C, Group D, and Group E for grouped treatment. The treatment cycle was 7 days, specifically:

[0040] Group A: Combined drug treatment was administered by subcutaneous injection at a dosage of 1 million units / d of recombinant human interleukin - 2 (Deruxtecan) and 1.6 mg / d of thymosin α1 (Zadaxin). The number of cases was 27.

[0041] Group B: Therapeutic treatment with Deruxtecan alone was administered subcutaneously at a dosage of 1 million units / d, with 24 cases.

[0042] Group C: Therapeutic treatment with Zadaxin alone was administered subcutaneously at a dosage of 1.6 mg / d, with 26 cases.

[0043] Group D: Observation group without any treatment, with 30 cases.

[0044] 3. Observation indicators

[0045] Before treatment and on the 7th day after treatment, fasting venous blood was taken from the patients in the early morning. Flow cytometry was used to detect the number of lymphocytes, and the lymphocyte amplification multiple was calculated. The results are shown in Table 1 and Figure 1 as follows.

[0046] Table 1.

[0047]

[0048] From Table 1 and Figure 1 the test results shown, in the observation group and the treatment groups given Deruxtecan or Zadaxin alone, there was no significant difference in the number of lymphocytes in the patients before and after treatment. Compared with the observation group and the treatment groups given Deruxtecan or Zadaxin alone, after 7 days of combined drug treatment with Deruxtecan and Zadaxin, the lymphocyte amplification multiple in the patients was 9.95 ± 11.06, and the patients with a lymphocyte amplification multiple of more than 5 times accounted for more than 47% of the total number of cases. It could well improve or relieve lymphocytopenia in hematological tumor patients whose immune systems were severely damaged by chemotherapy treatment; and during the combined drug treatment process, only 2 patients had transient fever, and no obvious toxic and side effects were seen, showing high safety.

[0049] The inventor further analyzed the lymphocytes of the clinical cases in Group A and found that: the main lymphocyte subsets with amplification were T cells, among which the median amplification multiple of CD3 + T cells was 2.75 times (1.45 - 60), the median amplification multiple of CD4 + T cell subsets was 2.36 times (1 - 18.7), the median amplification multiple of CD8 + T cells was 3.92 times (1.18 - 60), and the median amplification multiple of NK cells was 1.90 times (0.37 - 61).

[0050] It is worth noting that the inventor also found that clinically, Deruxtecan and Zadaxin also had a certain improvement and remission effect on lymphocytopenia in patients who had undergone hematopoietic stem cell transplantation or targeted therapy.

[0051] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention without departing from the principles and spirit of the present invention.

[0052] The amino acid sequences related to the present invention are shown in Table 3.

[0053] Table 3.

[0054]

[0055]

Claims

1. Use of a pharmaceutical composition in the preparation of a drug for treating and / or alleviating lymphocytopenia, characterized in that: The pharmaceutical composition comprises thymosin α1 and recombinant human interleukin-2, and the lymphocytopenia is a side effect caused by chemotherapy in patients with blood tumors.

2. Use of the pharmaceutical composition according to claim 1 in the preparation of a drug for treating and / or alleviating lymphocytopenia, characterized in that: The amino acid sequence of the thymosin α1 is shown in SEQ ID NO:

1.

3. Use of the pharmaceutical composition according to claim 1 in the preparation of a drug for treating and / or alleviating lymphocytopenia, characterized in that: The amino acid sequence of the recombinant human interleukin-2 is shown in SEQ ID NO: 2 and / or SEQ ID NO:

3.

4. Use of the pharmaceutical composition according to claim 1 in the preparation of a drug for treating and / or alleviating lymphocytopenia, characterized in that: The amino acid sequence of the recombinant human interleukin-2 is shown in SEQ ID NO:

2.

5. Use of the pharmaceutical composition according to claim 1 in preparing a drug for treating and / or alleviating lymphocytopenia, characterized in that: The addition ratio of the thymosin α1 and recombinant human interleukin-2 is (1.5-1.8) mg: (800,000-1.20) million units.

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