The combined use of mobocertinib and anti-PD-1 antibody for cancer treatment

Abstract

This invention discloses a method for the combined use of mobocertinib and anti-PD-1 antibody to treat cancer. The study investigates the effects of mobocertinib on non-EGFR exon 20 insertion mutation diseases and its synergistic effect with anti-PD-1 antibody, revealing that its mechanism of action is related to the regulation of abnormal SET expression. This invention provides a novel application of mobocertinib and a technical solution for its combined use, offering a new research direction for the treatment of cancers related to abnormal SET expression.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a method for treating cancer by combining Mobocertinib with an anti-PD-1 antibody. Background Technology

[0002] The SET gene, short for SET nuclear proto-oncogene, is located on human chromosome 9q34.11. The protein encoded by this gene plays a crucial role in the cell nucleus, belonging to both the INHAT complex and the SET complex, and is also a member of the nucleosome assembly protein superfamily. SET is highly expressed in rapidly dividing cells and is a highly expressed oncoprotein in various tumor types. It can interact with multiple key factors, promoting tumor-related behaviors in cells. Studies have shown that aberrant SET expression can promote tumorigenesis and development.

[0003] Mobocertinib is a novel, highly selective small-molecule tyrosine kinase inhibitor (TKI) that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) exon 20 insertion mutations (ex20ins). In clinical trials, mobocertinib has shown significant therapeutic efficacy in adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease progressed during or after platinum-based chemotherapy. Because mobocertinib is a targeted drug against EGFR exon 20 insertion mutations, there are no studies on its potential therapeutic effects in other non-EGFR exon 20 insertion mutation diseases, nor is its molecular mechanism of action clear. Therefore, this invention investigates the efficacy of mobocertinib in non-EGFR exon 20 insertion mutation diseases and provides new applications and combination therapies for mobocertinib. Summary of the Invention

[0004] In view of the shortcomings of the prior art, the present invention provides a new application of Mobocertinib in non-EGFR exon 20 insertion mutation diseases, and its combined application with anti-PD-1 antibodies.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] A first aspect of the present invention provides a pharmaceutical composition for treating cancer, the pharmaceutical composition comprising a first component and a second component.

[0007] The first component is Mobocertinib or a pharmaceutically acceptable salt thereof.

[0008] Mobocertinib is a kinase inhibitor that targets the human epidermal growth factor receptor (EGFR). It is specifically used to treat non-small cell lung cancer (NSCLC) caused by exon 20 insertion mutations in the EGFR gene, which are generally associated with a poorer prognosis (compared to the "classic" EGFR mutations that cause NSCLC).

[0009] In this invention, the pharmaceutically acceptable salt refers to a salt of an active compound (such as Mobocertinib) and is prepared by reacting the active compound with a suitable organic or inorganic acid or acid derivative. Pharmaceutically acceptable salts include, but are not limited to, hydrochlorides, sulfates, phosphates, citrates, hydrobromides, acetates, benzoates, benzenesulfonates, tartrates, carbonates, citrates, gluconates, lactates, malates, methanesulfonates, stearates, valerates, nitrates, sodium salts, calcium salts, potassium salts, zinc salts, and meglumine salts.

[0010] The second component is an anti-PD-1 antibody.

[0011] PD-1 (also known as CD279) is a type I transmembrane protein with a relative molecular weight of 55,000-60,000. It is mainly expressed on activated immune cells such as CD4+ T cells, CD8+ T cells, B cells, NK cells, monocytes, and dendritic cells, promoting T cell maturation. Monoclonal antibodies against PD-1 can block the binding of PD-1 to its ligands, thereby restoring the tumor-killing function of T cells.

[0012] Furthermore, the antibody is a chimeric antibody, a humanized antibody, or a human antibody. Monoclonal antibodies derived from mammals are particularly preferred. Monoclonal antibodies derived from mammals include those produced by hybridomas and those produced by hosts transformed using genetic engineering methods with expression vectors containing antibody genes.

[0013] Furthermore, the anti-PD-1 antibody is selected from anti-mouse PD-1 antibody, anti-human PD-1 antibody, and anti-cynomolgus monkey PD-1 antibody.

[0014] Furthermore, the anti-PD-1 antibody is an anti-mouse PD-1 antibody.

[0015] The compositions of the present invention may further comprise a pharmaceutically acceptable carrier or excipient, wherein a "pharmaceutically acceptable carrier or excipient" refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulation material, or formulation aid of any type. The carrier should be biologically acceptable, meaning it is compatible with other components in the formulation and harmless to the patient, and will not elicit an adverse reaction (e.g., an immune response) when administered to the host.

[0016] Furthermore, the pharmaceutical composition further includes pharmaceutically acceptable excipients selected from one or more of the following: diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH adjusters, antioxidants, or antibacterial agents.

[0017] Furthermore, the dosage forms of the first component and the second component in the pharmaceutical composition may be the same or different.

[0018] Furthermore, the dosage forms include drops, tablets, capsules, granules, films, gels, powders, emulsions, pellets, suppositories, aerosols, sprays, powder sprays, patches, solutions, sterile powders for injection, ointments, or creams.

[0019] Furthermore, the first component and the second component are applied simultaneously or sequentially. Specifically, the interval between sequential applications can be 0, 1, 2, 3, 4, 5, 6, 7 or more days.

[0020] Furthermore, the first component is administered daily, and the second component is administered every three days.

[0021] Furthermore, the dosage ratio of the first component and the second component is 2-2.5:1.

[0022] Furthermore, the dosage of the first component is 3 mg / kg, and the dosage of the second component is 30 μg.

[0023] In this invention, regarding the dosage ratio of the first component and the second component, those skilled in the art can appropriately adjust and convert the dosage ratio according to the species of the target organism, based on differences in body surface area, pharmacological, physiological and anatomical factors, pharmacokinetic parameters, metabolic function, receptors and lifespan, for example, by using allometric scaling to reasonably adjust and convert the dosage ratio.

[0024] Furthermore, the cancer in question is a cancer with abnormal SET expression.

[0025] In this invention, SET includes wild-type, mutant, or fragments thereof. The term encompasses full-length, unprocessed SET, as well as any form of SET derived from cells and processed. The term encompasses naturally occurring variants of SET (e.g., splice variants or allelic variants). The term encompasses, for example, the SET gene, human SET, and SET from any other vertebrate source, including mammals such as primates and rodents (e.g., mice and rats). In a specific embodiment of the invention, SET is a human gene with gene ID 6418.

[0026] Furthermore, the cancers with abnormal SET expression include solid tumors with abnormal SET expression and hematologic malignancies with abnormal SET expression.

[0027] Furthermore, the solid tumors in which SET is abnormally expressed include colorectal cancer, melanoma, breast cancer, ovarian cancer, liver cancer, non-small cell lung cancer, and kidney cancer.

[0028] Furthermore, the hematologic malignancies in which SET is abnormally expressed include leukemia and Hodgkin's lymphoma.

[0029] Furthermore, the cancers in which SET is abnormally expressed are colorectal cancer or melanoma.

[0030] In this invention, the term "treatment" refers to the process of intervening in or altering a specific health condition, including eliminating the cause, symptomatic treatment, or supportive treatment, and does not necessarily mean curing or completely eliminating a disease, symptom, or the symptoms of a disease or symptom. Treatment may refer to a reduction or improvement in the severity of symptoms / effects of an identified disease by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0031] The second aspect of the present invention provides the use of the pharmaceutical composition described in the first aspect of the present invention in the preparation of a cancer treatment drug, wherein the cancer is a cancer with abnormal SET expression.

[0032] Furthermore, the cancers with abnormal SET expression include solid tumors with abnormal SET expression and hematologic malignancies with abnormal SET expression.

[0033] Furthermore, the solid tumors in which SET is abnormally expressed include colorectal cancer, melanoma, breast cancer, ovarian cancer, liver cancer, non-small cell lung cancer, and kidney cancer.

[0034] Furthermore, the hematologic malignancies in which SET is abnormally expressed include leukemia and Hodgkin's lymphoma.

[0035] Furthermore, the cancers in which SET is abnormally expressed are colorectal cancer or melanoma.

[0036] A third aspect of the invention provides the use of Mobocertinib or a pharmaceutically acceptable salt thereof, said use comprising any one of the following:

[0037] 1) Application in the preparation of drugs that enhance patients' sensitivity to anti-PD-1 antibodies;

[0038] 2) Application in the preparation of cancer therapeutic drugs with non-EGFR exon 20 insertion mutations.

[0039] The pharmaceutical compositions of the present invention, or Mobocertinib or a pharmaceutically acceptable salt thereof, are administered to mammals or tumor cells of said mammals. The mammals are preferably rodents, even-toed ungulates, perissodactyls, lagomorphs, primates, etc. The primates are preferably monkeys, apes, or Homo sapiens. The subject may be a patient with a tumor, or ex vivo tumor cells from a patient with a tumor.

[0040] In this invention, the terms "medicine," "pharmaceutical composition," "cancer drug," "cancer treatment drug," and "tumor drug" have the same meaning, representing substances or combinations of substances that can treat cancer. The pharmaceutical compositions provided by this invention have a cancer-treating effect. "Treatment" includes preventing or delaying the onset of symptoms and complications of a disease (such as cancer), as well as prolonging the survival of cancer patients, improving quality of life, alleviating symptoms, shrinking or even eliminating tumors, inhibiting tumor metastasis, and preventing tumor recurrence. In this invention, "cancer treatment" and "inhibition of cell proliferation" have the same meaning.

[0041] Furthermore, the patient in question is a cancer patient.

[0042] Furthermore, the cancer in question is a cancer with abnormal SET expression.

[0043] Furthermore, the cancers with abnormal SET expression include solid tumors with abnormal SET expression and hematologic malignancies with abnormal SET expression.

[0044] Furthermore, the solid tumors in which SET is abnormally expressed include colorectal cancer, melanoma, breast cancer, ovarian cancer, liver cancer, non-small cell lung cancer, and kidney cancer.

[0045] Furthermore, the hematologic malignancies in which SET is abnormally expressed include leukemia and Hodgkin's lymphoma.

[0046] Furthermore, the cancers in which SET is abnormally expressed are colorectal cancer or melanoma.

[0047] Furthermore, the antibody is a chimeric antibody, a humanized antibody, or a human antibody.

[0048] Furthermore, the anti-PD-1 antibody is selected from anti-mouse PD-1 antibody, anti-human PD-1 antibody, and anti-cynomolgus monkey PD-1 antibody.

[0049] Furthermore, the anti-PD-1 antibody is an anti-mouse PD-1 antibody.

[0050] Furthermore, the cancers with non-EGFR exon 20 insertion mutations are cancers with abnormal SET expression.

[0051] Advantages and benefits of the present invention: The present invention provides a new application of Mobocertinib in the treatment of cancers with non-EGFR exon 20 insertion mutations, and the application of Mobocertinib in combination with anti-PD-1 antibodies to treat cancer or in drugs that enhance patients' sensitivity to anti-PD-1 antibodies. Furthermore, through the study of its mechanism of action, it provides a new research direction for the treatment of cancers related to abnormal SET expression. Attached Figure Description

[0052] Figure 1 The images show the Western blot results of the inhibitory effect of Mobocertinib on SET expression. In the images, A represents the SET expression level of colorectal cancer MC38 cells after treatment with gradient concentrations of Mobocertinib; B represents the SET expression level of colorectal cancer MC38 cells after treatment with MG132, CHQ, and Mobocertinib; C represents the SET expression level of melanoma B16 cells after treatment with gradient concentrations of Mobocertinib; and D represents the SET expression level of melanoma B16 cells after treatment with MG132, CHQ, and Mobocertinib.

[0053] Figure 2 A statistical chart showing the tumor inhibition rate of the combined application of Mobocertinib and anti-PD-1 antibody in a mouse subcutaneous tumorigenesis model of colorectal cancer MC38 cells.

[0054] Figure 3 This is a statistical chart showing the tumor inhibition rate of the combined application of Mobocertinib and anti-PD-1 antibody in a mouse subcutaneous tumorigenesis model of melanoma B16 cells.

[0055] Figure 4 This is a statistical graph showing the tumor weight on day 19 of a mouse subcutaneous tumor model of melanoma B16 cells after the combined application of Mobocertinib and anti-PD-1 antibody. Detailed Implementation

[0056] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0057] Example

[0058] I. Experimental Materials

[0059] 1. Mouse strain: C57 BL / 6, 6-week-old male and female mice weighing between 20 and 25g.

[0060] 2. Reagent catalog numbers: Mobocertinib (MedChemExpress, AP32788); anti-mouse PD-1 (BioXCell, BE0146).

[0061] II. Experimental Methods and Results

[0062] 1. Inhibitory effect of Mobocertinib on SET

[0063] Previous studies have shown that the small molecule compound Mobocertinib can regulate SET protein expression. Further verification of the inhibitory effect of Mobocertinib on SET expression was conducted using cells with non-EGFR exon 20 insertion mutations and high SET expression. For example, using colorectal cancer MC38 tumor cells and melanoma B16 tumor cells as cell models, Western blotting experiments were performed to examine SET protein expression in cell models treated with Mobocertinib. The results showed that Mobocertinib could gradually reduce SET expression in tumor cells (see results below). Figure 1 (As shown in A and C in the figure). Furthermore, by treating with the protein synthesis inhibitors MG132 and CHQ, we found that MG132 treatment could partially reverse the Mobocertinib-induced decrease in SET expression (results are shown in the figure). Figure 1 As shown in B and D in the diagram, this further illustrates that Mobocertinib may degrade SET protein expression through the proteasome pathway. Therefore, the following study will investigate whether Mobocertinib has a therapeutic effect on cancers with abnormal SET expression, using colorectal cancer and melanoma, which have been reported in the literature as examples.

[0064] 2. Subcutaneous tumor formation model of colorectal cancer in mice

[0065] 1) Methods: Subcutaneous tumorigenic mice inoculated with mouse colorectal cancer tumor cells MC38 were divided into four groups for treatment: (1) control group; (2) Mobocertinib monotherapy at a dose of 3 mg / kg (intraperitoneal injection daily); (3) Anti-PD-1 antibody monotherapy at a dose of 30 µg (intraperitoneal injection once every three days); (4) Mobocertinib monotherapy at a dose of 3 mg / kg and anti-PD-1 antibody monotherapy at a dose of 30 µg (Mobocertinib: intraperitoneal injection daily; anti-PD-1 antibody: intraperitoneal injection once every three days).

[0066] 2) Results: After approximately 25 days, we found that Mobocertinib alone could inhibit the growth of colorectal cancer cells with non-EGFR exon 20 insertion mutations, with a tumor inhibition rate of approximately 41%; anti-PD-1 antibody alone could also inhibit tumor cell growth, with a tumor inhibition rate of approximately 49%; when Mobocertinib and anti-PD-1 antibody were combined, tumor growth was significantly inhibited, with a tumor inhibition rate of approximately 80%. Figure 2 As shown.

[0067] The q-value for the combined use of Mobocertinib and anti-PD-1 antibody was calculated using the King's formula, which is commonly used in this field. A q-value greater than 1 indicates a synergistic effect between the two.

[0068] The inhibition rate of 3 mg / kg Mobocertinib was 41% (n=8) (EA).

[0069] The inhibition rate of 30 µg anti-PD-1 antibody was 49% (n=8) (EB).

[0070] The combined inhibition rate of the two was 80% (n=8) (E(A+B)).

[0071] Substituting into King's formula: q=E(A+B) / (EA+EB-EA*EB)=80% / (41%+49%-41%*49%)=1.144>1.

[0072] Based on the above calculations, a q value > 1 indicates that Mobocertinib and anti-PD-1 antibody produce a synergistic effect when used in combination. Mobocertinib and anti-PD-1 have a synergistic effect in the combined treatment of colorectal cancer.

[0073] 3. Subcutaneous tumor formation model of melanoma in mice

[0074] 1) Methods: Subcutaneous tumor-forming mice inoculated with mouse melanoma tumor cells B16 were divided into four groups for treatment: (1) control group; (2) Mobocertinib at a dose of 3 mg / kg alone (intraperitoneal injection daily); (3) Anti-PD-1 antibody at a dose of 30 µg alone (intraperitoneal injection once every three days); (4) Mobocertinib at a dose of 3 mg / kg and anti-PD-1 antibody in combination (Mobocertinib: intraperitoneal injection daily; anti-PD-1 antibody: intraperitoneal injection once every three days).

[0075] 2) Results: After approximately 19 days, we found that Mobocertinib alone could inhibit the growth of melanoma tumor cells with non-EGFR exon 20 insertion mutations, with a tumor inhibition rate of approximately 38%; anti-PD-1 antibody alone could also inhibit tumor cell growth, with a tumor inhibition rate of approximately 46%; when Mobocertinib and anti-PD-1 antibody were combined, tumor growth was significantly inhibited, with a tumor inhibition rate of approximately 80%. Figure 3 As shown in the figure. Tumor weight in mice on day 19 was compared, and the trend was consistent with the mouse growth curve, as shown in the figure. Figure 4 As shown.

[0076] The q-value for the combined use of Mobocertinib and anti-PD-1 antibody was calculated using the King's formula, which is commonly used in this field. A q-value greater than 1 indicates a synergistic effect between the two.

[0077] The inhibition rate of 3 mg / kg Mobocertinib was 38% (n=8) (EA).

[0078] The inhibition rate of 30 µg anti-PD-1 antibody was 46% (n=8) (EB).

[0079] The combined inhibition rate of the two was 80% (n=8) (E(A+B)).

[0080] Substituting into King's formula: q=E(A+B) / (EA+EB-EA*EB)=80% / (38%+46%-38%*46%)=1.203>1.

[0081] Based on the above calculations, a q value > 1 indicates that Mobocertinib and anti-PD-1 antibody produce a synergistic effect when used in combination. Mobocertinib and anti-PD-1 have a synergistic effect in the combined treatment of melanoma.

[0082] The above description of the embodiments is only for understanding the method and core ideas of the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principles of the invention, and these improvements and modifications will also fall within the protection scope of the claims of the present invention.

Claims

1. A pharmaceutical composition for treating cancer, characterized in that, The pharmaceutical composition comprises a first component and a second component; The cancer is either colorectal cancer or melanoma; The first component is Mobocertinib or a pharmaceutically acceptable salt thereof; The second component is an anti-mouse PD-1 antibody.

2. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition further includes pharmaceutically acceptable excipients selected from one or more of the following: fillers, binders, wetting agents, disintegrants, emulsifiers, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH adjusters, antioxidants, or antibacterial agents.

3. The pharmaceutical composition according to claim 1, characterized in that, The dosage forms of the first and second components in the pharmaceutical composition may be the same or different.

4. The pharmaceutical composition according to claim 3, characterized in that, The dosage forms include drops, tablets, capsules, granules, films, gels, powders, emulsions, pellets, suppositories, aerosols, sprays, powder sprays, patches, solutions, sterile powders for injection, ointments, or creams.

5. The pharmaceutical composition according to claim 1, characterized in that, The first and second components are applied simultaneously or sequentially. Specifically, the interval between sequential applications can be 1, 2, 3, 4, 5, 6, 7 or more days.

6. The pharmaceutical composition according to claim 5, characterized in that, The first component is administered daily, and the second component is administered every three days.

7. The pharmaceutical composition according to claim 5, characterized in that, The dosage ratio of the first component and the second component is 2-2.5:

1.

8. The pharmaceutical composition according to claim 5, characterized in that, The dosage of the first component is 3 mg / kg, and the dosage of the second component is 30 μg.

9. The pharmaceutical composition according to claim 1, characterized in that, The colorectal cancer or melanoma mentioned is a cancer that is not EGFR / HER2 exon 20 insertion mutation and has abnormal SET expression.

10. Use of the pharmaceutical composition according to any one of claims 1-9 in the preparation of a medicament for treating colorectal cancer or melanoma.

11. The application according to claim 10, characterized in that, The colorectal cancer or melanoma mentioned is a cancer that is not EGFR / HER2 exon 20 insertion mutation and has abnormal SET expression.

12. The use of Mobocertinib or a pharmaceutically acceptable salt thereof, characterized in that the use comprises any one of the following: 1) Application in the preparation of drugs that enhance the sensitivity of patients to anti-PD-1 antibodies, wherein the patients are colorectal cancer patients or melanoma patients; and the PD-1 antibody is an anti-mouse PD-1 antibody; 2) Application in the preparation of drugs for treating colorectal cancer or melanoma.

13. The application according to claim 12, characterized in that, The colorectal cancer or melanoma mentioned is a cancer that is not EGFR / HER2 exon 20 insertion mutation and has abnormal SET expression.

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