CN117883565A - Application of salmeterol and PD-1 antibody combination in preparation of medicine for treating melanoma - Google Patents
Application of salmeterol and PD-1 antibody combination in preparation of medicine for treating melanoma Download PDFInfo
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Abstract
The invention discloses an application of salmeterol and PD-1 antibody combination in preparing a medicine for treating melanoma. According to the invention, the drug resistance of melanoma to the PD-1 antibody is reversed by combining salmeterol and the PD-1 antibody, and the therapeutic effect of the PD-1 antibody on the melanoma is promoted by salmeterol, so that the progress of the melanoma is obviously inhibited.
Description
Technical Field
The invention belongs to the technical field of medical application, and in particular relates to application of salmeterol and PD-1 antibody combination in preparation of a medicine for treating melanoma.
Background
Cutaneous melanoma is a malignant tumor formed by pigment-producing cells (called melanocytes). It is one of the most severe and deadly cutaneous malignant tumors. In the last few decades, the incidence of melanoma has increased gradually, and melanocytes are present in the basal epidermis layer, responsible for the production of dark pigments, called melanin, responsible for imparting color to the skin. Melanoma is the third most common cutaneous malignancy next to basal cell carcinoma and squamous cell carcinoma, accounting for less than 5% of cases. Nevertheless, it is still the most aggressive skin cancer and is associated with death of most skin cancers, with a total mortality rate of over 10%. The natural history of cutaneous melanoma describes an invasive disease that increases metastatic potential based on primary cancer Breslow thickness, tumor ulceration and regional lymph node basin metastasis. Patients often develop new pigmentation or abnormal appearance growth on the skin, ulcers, itching, desquamation, bleeding, weeping, swelling or pain around the mole, and in severe cases pigment continues to diffuse from the spot to the surrounding skin, causing a greater extent of ulcers.
The treatment method of melanoma mainly comprises surgical excision, chemotherapy, radiotherapy, targeted therapy and immunotherapy, wherein the targeted therapy and the immunotherapy are significant progress in recent years, and the survival rate and the quality of life of patients are remarkably improved. Targeted therapies are directed to specific genetic mutations in melanoma, such as BRAF, MEK, etc., using small molecule drugs to inhibit proliferation and survival of tumor cells. Various targeted drugs such as vemurafenib, dabrafenib, terrafenib, bimatinib and the like have been approved. Immunotherapy is a mechanism that uses the immune system of the human body to recognize and destroy tumor cells, and uses antibody drugs to block tumor cells from escaping immune surveillance. Various immune checkpoint inhibitors have been approved such as ipilimumab, na Wu Liyou mab, palbociclizumab, pritizumab and the like. The targeted therapy and the immunotherapy can be used singly or in combination, and the optimal scheme is selected according to the mutation condition, the immune state and the toxic and side effects of the patient. Some novel therapeutic approaches, such as T Cell Receptor (TCR) therapy, mRNA tumor vaccines, TIL cell therapy, etc., also exhibit good effects in clinical trials.
The discovery of immune checkpoints is critical for the development of cancer immunotherapy, and melanoma-targeted immune checkpoint inhibitors of programmed cell death protein 1 (PD-1) completely alter the treatment of metastatic melanoma patients, with stage III clinical trials (e.g., checkMate-067, KEYNOTE-006) reporting objective remissions of 42-45% and overall survival of 5% for 5 years.
Although anti-PD-1 antibodies have made breakthroughs in the treatment of patients with advanced melanoma, the major problems with current treatment of melanoma with PD-1 single agents include: (1) the therapeutic response rate is limited: while PD-1 inhibitors exhibit significant efficacy in certain cancer types, not all patients respond positively to this treatment. Clinical trials have shown that only about 25% of melanoma patients have a durable therapeutic effect on PD-1 inhibitors. (2) Drug resistance: the low response rate and therapeutic resistance of a substantial proportion of patients after receiving anti-PD-1 immunotherapy significantly hampers the efficacy of PD-1, with approximately 55% of melanoma patients exhibiting innate resistance to single-drug PD-1 inhibitors (approximately 1% of the innate resistance to CTLA40+ PD4 inhibitor combination). (3) Immune toxic side effects: PD-1 inhibitors may cause immune toxic side effects such as immune-related pneumonia, immune-related hypothyroidism, immune-related hepatotoxicity, etc.
Therefore, the current treatment of melanoma is still limited greatly, most patients adopt palliative treatment, and survival prognosis is poor. Therefore, the specific mechanism of melanoma drug resistance is deeply known, so that finding new therapeutic targets or therapeutic means is still an urgent problem to be solved in melanoma research.
Disclosure of Invention
In view of the above-mentioned prior art problems, a primary object of the present invention is to provide the use of salmeterol and PD-1 antibodies in combination for the preparation of a medicament for the treatment of melanoma. The combined use of salmeterol and the PD-1 antibody reverses the drug resistance of melanoma to the PD-1 antibody, and promotes the treatment effect of the PD-1 antibody on the melanoma, thereby obviously inhibiting the progress of the melanoma.
A second object of the present invention is to provide an application of salmeterol in the preparation of a medicament for improving the therapeutic effect of a PD-1 antibody on melanoma or for reducing the resistance of melanoma to the PD-1 antibody.
A third object of the present invention is to provide a pharmaceutical composition.
The fourth object of the invention is to provide an application of the pharmaceutical composition in preparing medicines for treating melanoma.
In order to achieve the above object, the present invention is realized by the following technical scheme:
the invention claims the use of salmeterol and a PD-1 antibody in combination for the manufacture of a medicament for the treatment of melanoma.
The structural formula of Salmeterol (Salmeterol) is shown as the following formula (I):
PD-1 antibodies have made great breakthroughs in the treatment of a variety of tumors, but some patients have poor response to PD-1 antibody therapy and most responding patients develop resistance after a period of time following treatment with PD-1 antibodies. The low response rate and therapeutic resistance of patients significantly hamper the efficacy of PD-1 antibodies. The invention aims to restore the sensitivity of tumor cells to PD-1 antibodies, thereby achieving the purpose of treating tumors.
Salmeterol is a novel selective long-acting beta 2 receptor agonist, has strong effect of inhibiting lung mast cells from releasing allergic reaction medium, can inhibit early and late phase reactions induced by inhaled antigen, and reduces airway hyperresponsiveness. It is mainly used for asthma (including nocturnal asthma and athletic asthma), asthmatic bronchitis and reversible airway obstruction. At present, the medicine can not be used for improving the curative effect of the PD-1 antibody, so that the tumor progress or other similar effects are inhibited.
According to the invention, through a mouse model, salmeterol is injected into a mouse inoculated with melanoma cells, so that the treatment effect of the PD-1 antibody can be effectively improved, and the progress of melanoma is obviously inhibited, so that the combination of salmeterol and the PD-1 antibody can reverse the drug resistance of the melanoma to the PD-1 antibody, promote the treatment effect of the PD-1 antibody to the melanoma, and obviously inhibit the progress of the melanoma.
The advantages of the present invention using a PD-1 antibody for salmeterol Luo Lian over a single PD-1 antibody are manifold. Salmeterol Luo Lian can improve the treatment effect of PD-1 antibodies on melanoma, reduce the drug resistance of melanoma cells and increase the survival time of patients by using the PD-1 antibodies. The PD-1 antibody used by salmeterol Luo Lian can also reduce the side effect of the PD-1 antibody, and the salmeterol Luo Ba is more specific to melanoma cells, so that non-specific damage can be avoided, and the life quality of patients can be improved. In addition, the PD-1 used in salmeterol Luo Lian can also reduce the treatment cost, shorten the treatment time and lighten the economic burden of patients.
Preferably, the PD-1 antibody is selected from one or more of palbociclizumab (Pembrolizumab), nal Wu Liyou mab (Nivolumab), karilizumab (Camrelizumab), terlipp Li Shan antibody (JS-001), sindilimab Li Shan antibody (sintillimab), tirelizumab (tishellizumab) or neutralizing antibodies targeting PD-1 protein.
Preferably, the PD-1 antibody is a neutralizing antibody targeting PD-1 protein.
Preferably, the melanoma comprises melanoma B16F10 cells.
Further, the invention claims the application of salmeterol in preparing drugs for improving the treatment effect of PD-1 antibodies on melanoma or reducing the drug resistance of melanoma on PD-1 antibodies.
Preferably, the PD-1 antibody is selected from one or more of palbociclizumab (Pembrolizumab), nal Wu Liyou mab (Nivolumab), karilizumab (Camrelizumab), terlipp Li Shan antibody (JS-001), sindilimab Li Shan antibody (sintillimab), tirelizumab (tishellizumab) or neutralizing antibodies targeting PD-1 protein.
Preferably, the PD-1 antibody is a neutralizing antibody targeting PD-1 protein.
Preferably, the melanoma comprises melanoma B16F10 cells.
Further, the invention claims a pharmaceutical composition comprising a therapeutically effective amount of salmeterol, a PD-1 antibody, and an adjuvant.
Further, the invention claims the application of a pharmaceutical composition in preparing a medicine for treating melanoma.
In the present invention, the drug may be administered in the following form: orally, for example in the form of capsules, tablets, pills, powders, in the form of sustained release injections (such as sterile solutions, suspensions or emulsions); by topical treatment forms such as pastes, creams or ointments; or by suppositories such as suppository forms; or by inhalation or insufflation.
In the present invention, a "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, subject, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
Compared with the prior art, the invention has the following beneficial effects:
the advantages of the present invention using a PD-1 antibody for salmeterol Luo Lian over a single PD-1 antibody are manifold. Salmeterol Luo Lian can improve the treatment effect of PD-1 antibodies on melanoma, reduce the drug resistance of melanoma cells and increase the survival time of patients by using the PD-1 antibodies. The PD-1 antibody used by salmeterol Luo Lian can also reduce the side effect of the PD-1 antibody, and the salmeterol Luo Ba is more specific to melanoma cells, so that non-specific damage can be avoided, and the life quality of patients can be improved. In addition, the PD-1 used in salmeterol Luo Lian can also reduce the treatment cost, shorten the treatment time and lighten the economic burden of patients.
Drawings
FIG. 1 shows subcutaneous tumors in the PD-1 antibody-treated group after treatment of melanoma with salmeterol, the PD-1 antibody-combined group.
FIG. 2 is a graph showing tumor volume growth after treatment of the PD-1 antibody-treated group, salmeterol, and the PD-1 antibody-combined group.
FIG. 3 is a statistical plot of tumor volumes after treatment of the PD-1 antibody-treated group, salmeterol, and the PD-1 antibody-combined group.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Example 1 combination of salmeterol with PD-1 antibody to inhibit melanoma experiments
(1) Experimental animal and medicine used by same
20 female C57BL/6J mice were purchased from Beijing vitamin Toril LiHua Co. All mice were housed under specific pathogen-free conditions and used according to protocols approved by the institutional care and use committee of animal welfare at the university of Zhongshan. Mice were initially randomized by age and weight and 6-8 weeks of age at injection.
Salmeterol Luo is prepared from Aladin (S346847-50), powder is dissolved in DMSO and the mother liquor is split per 200 ml. The dissolved mother liquor was diluted to 50mg/ml before subcutaneous injection and mice were treated by intratumoral injection in a volume of 0.1 ml.
PD-1 antibodies were purchased from Biocell company (BE 0146) and stored at 4 ℃. Mice were treated by intraperitoneal injection at the time of subcutaneous injection in a volume of 100 ug.
(2) Salmeterol and PD-1 antibody combination therapy experiment
For the following salmeterol and PD-1 combination mouse model established in C57BL/6J, melanoma B16F10 cells were first resuspended in sterile PBS at a density of 1X 10 7 The melanoma B16F10 cells were then subcutaneously injected into the groin of mice on one side in a volume of 0.1 ml per ml of cells. The 20 mice were randomly divided into four groups of five each, grouped into: (1) control group; (2) PD-1 antibody-treated group; (3) salmeterol treatment group; (4) salmeterol, PD-1 antibody combination.
The growth of tumor cells was measured every 3 days starting on day 1 of tumor cell inoculation.
On day 7, the tumor volume was found to reach 100mm subcutaneously 3 In this case, each mouse in the PD-1 antibody-treated group and salmeterol, PD-1 antibody-combined group received PD-1 antibody treatment (100 ug PD-1 antibody per 3 days by intraperitoneal injection) for three total treatments。
Starting on day 7, each mouse in the salmeterol treatment group and salmeterol, PD-1 antibody combination group received salmeterol treatment (salmeterol Luo Xishi to 50mg/ml, then mice were given intratumoral injection treatment at a volume of 0.1 ml, twice a week) for two weeks.
The experiment was terminated immediately when the subcutaneous tumor volume was near the ethical endpoint, and after 21 days post-implantation, the mice were sacrificed, the tumors excised, weighed and pictures taken. The tumor volume of the mice was measured continuously every three days throughout the experimental period until the end of the experiment.
(3) Experimental results
FIG. 1 shows subcutaneous tumors in the PD-1 antibody-treated group after treatment of melanoma with salmeterol, the PD-1 antibody-combined group. FIG. 2 is a graph showing tumor volume growth after treatment of the PD-1 antibody-treated group, salmeterol, and the PD-1 antibody-combined group. FIG. 3 is a statistical plot of tumor volumes after treatment of the PD-1 antibody-treated group, salmeterol, and the PD-1 antibody-combined group.
As shown in fig. 1-3, when PD-1 antibody was combined with salmeterol, the subcutaneous tumor volume significantly decreased (fig. 1), tumor growth was slow (fig. 2), and the subcutaneous tumor volume significantly decreased (fig. 3). The salmeterol can promote the treatment effect of PD-1 antibody on tumors and obviously inhibit the progress of melanoma.
According to the invention, through a mouse model, salmeterol is injected into a mouse inoculated with melanoma cells, so that the treatment effect of the PD-1 antibody can be effectively improved, and the progress of melanoma is obviously inhibited, so that the combination of salmeterol and the PD-1 antibody can reverse the drug resistance of the melanoma to the PD-1 antibody, promote the treatment effect of the PD-1 antibody to the melanoma, and obviously inhibit the progress of the melanoma.
The advantages of the present invention using a PD-1 antibody for salmeterol Luo Lian over a single PD-1 antibody are manifold. Salmeterol Luo Lian can improve the treatment effect of PD-1 antibodies on melanoma, reduce the drug resistance of melanoma cells and increase the survival time of patients by using the PD-1 antibodies. The PD-1 antibody used by salmeterol Luo Lian can also reduce the side effect of the PD-1 antibody, and the salmeterol Luo Ba is more specific to melanoma cells, so that non-specific damage can be avoided, and the life quality of patients can be improved. In addition, the PD-1 used in salmeterol Luo Lian can also reduce the treatment cost, shorten the treatment time and lighten the economic burden of patients.
The foregoing examples are illustrative only and serve to explain some features of the method of the invention. The claims that follow are intended to claim the broadest possible scope as conceivable and the embodiments presented herein are demonstrated for the applicant's true test results. It is, therefore, not the intention of the applicant that the appended claims be limited by the choice of examples illustrating the features of the invention. Some numerical ranges used in the claims also include sub-ranges within which variations in these ranges should also be construed as being covered by the appended claims where possible.
Claims (10)
1. Use of salmeterol and a PD-1 antibody in combination for the manufacture of a medicament for the treatment of melanoma.
2. The use according to claim 1, wherein the PD-1 antibody is selected from one or more of palbociclib, nal Wu Liyou mab, carlizumab, terlipressin Li Shan, singdi Li Shan, tirelib mab or neutralizing antibodies targeting PD-1 protein.
3. The use according to claim 1, wherein the PD-1 antibody is a neutralizing antibody targeting PD-1 protein.
4. The use according to claim 1, wherein the melanoma comprises melanoma B16F10 cells.
5. Use of salmeterol in the manufacture of a medicament for increasing the therapeutic effect of a PD-1 antibody on melanoma or for reducing the resistance of melanoma to a PD-1 antibody.
6. The use according to claim 5, wherein the PD-1 antibody is selected from one or more of palbociclib, na Wu Liyou mab, carlizumab, terlipressin Li Shan, singdi Li Shan antibody, tirelib mab or neutralizing antibody targeting PD-1 protein.
7. The use according to claim 5, wherein the PD-1 antibody is a neutralizing antibody targeting PD-1 protein.
8. The use according to claim 5, wherein the melanoma comprises melanoma B16F10 cells.
9. A pharmaceutical composition comprising a therapeutically effective amount of salmeterol, a PD-1 antibody, and an adjuvant.
10. Use of the pharmaceutical composition of claim 9 for the preparation of a medicament for the treatment of melanoma.
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| CN202311799237.6A CN117883565A (en) | 2023-12-25 | 2023-12-25 | Application of salmeterol and PD-1 antibody combination in preparation of medicine for treating melanoma |
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