System for treating cancer

Abstract

A system for treating cancer is disclosed. According to an embodiment of the present invention, the system comprises: an electric field applying device for applying an electric field for tumor treatment; and a delivery system for delivering an antibody-conjugated drug; the antibody coupling drug is selected from one of a group consisting of a group consisting of Wei Dicetuzumab, a group consisting of detrastuzumab, a group consisting of enmetrastuzumab, DP-303c, a group consisting of SHR-A1811, SYD985, a group consisting of LCB14-0110, a group consisting of BDC-1001, a group consisting of BB-1701, a group consisting of TAA013 and a group consisting of A166. According to the system provided by the embodiment of the invention, non-small cell lung cancer cell proliferation can be inhibited.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of combination drug therapy, in particular to a system for treating cancer, further to the use of an electric field application device in the preparation of a cancer treatment system, the use of an antibody-drug conjugate in the preparation of a medicament, a method of treating cancer cells, a method of drug screening, and a method of inhibiting the proliferation of cancer cells. BACKGROUND

[0002] Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors in the world, accounting for more than 80% of lung cancer patients. In the treatment of non-small cell lung cancer, currently, multiple means such as surgery, chemotherapy, radiotherapy, targeted therapy and immunotherapy are mainly used. For early stage patients, surgical resection is still the preferred treatment method, and postoperative adjuvant chemotherapy and radiotherapy can help reduce the risk of recurrence. However, most patients have lost the opportunity for surgical resection when diagnosed. Although targeted therapy and immunotherapy have achieved significant efficacy in some patients, not all patients can benefit from them. In addition, the long-term efficacy and side effects of these two treatment methods also need further study. Tumor treating electric field (TTFields) is a new non-invasive treatment method, which can interfere with mitosis of tumor cells by applying a specific alternating electric field in the tumor area, leading to cell death.

[0003] Due to the complexity of non-small cell lung cancer, single treatment method often has limited effect. Therefore, it is urgent to combine tumor treating electric field with chemotherapy, targeted therapy and other treatment methods to achieve better therapeutic effect. SUMMARY

[0004] The present application aims to at least partially solve at least one of the technical problems existing in the prior art. To this end, the present application provides a system for treating cancer.

[0005] The present application is based on the following findings of the inventors:

[0006] Non-small cell lung cancer patients have lost the opportunity for surgery when they seek medical treatment. Chemotherapy and radiotherapy have limited effect on non-small cell lung cancer tumors, and have large side effects. In order to overcome this problem, the inventors use tumor treating electric field (TTFields) combined with antibody-drug conjugate (ADC) to treat non-small cell lung cancer, thereby achieving the purpose of inhibiting the proliferation of non-small cell lung cancer cells.

[0007] In a first aspect, the present invention provides a system for treating cancer. According to an embodiment of the invention, the system includes: an electric field application device for applying an electric field for tumor treatment; and a delivery system for delivering an antibody-drug conjugate selected from one of vedilactumab, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166. The system according to an embodiment of the invention is capable of inhibiting at least one of non-small cell lung cancer, breast cancer, urothelial carcinoma, ovarian cancer, gastric cancer, and colorectal cancer.

[0008] In a second aspect, the invention proposes the use of an electric field application device in the preparation of a cancer treatment system in which cancer patients are treated with antibody-drug conjugates (ADCs) before, after, or concurrently with cancer treatment, said ADC being selected from one of the following: vediclofenac, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166.

[0009] In a third aspect, the present invention provides the use of an antibody-drug conjugate in the preparation of a medicament for treating cancer in a patient who is treated with an electric field applied by an electric field application device before, after, or simultaneously with the treatment of a patient. The antibody-drug conjugate is selected from one of the following: vediclofenac, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166.

[0010] In a fourth aspect, the present invention provides a method for treating cancer cells. According to an embodiment of the invention, the method includes: treating cancer cells under conditions where an electric field is applied by an electric field application device; pre-treatment, post-treatment, or simultaneous administration of an antibody-drug conjugate to the cancer cells; wherein the antibody-drug conjugate is selected from one of vediclofenac, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166. The method according to an embodiment of the invention can inhibit the proliferation of at least one of non-small cell lung cancer cells, breast cancer cells, urothelial carcinoma cells, ovarian cancer cells, gastric cancer cells, and colorectal cancer cells.

[0011] In a fifth aspect, the present invention provides a method for screening antibody-drug conjugates (ADCs). According to an embodiment of the invention, the method includes: subjecting cancer cells to an electric field applied by an electric field application device; contacting the cancer cells treated with the electric field with a candidate drug; and determining, based on the state of the cancer cells before and after the contact, whether the candidate drug is a drug suitable for treating cancer; wherein the ADC is selected from one of vediclofenac, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166. The method according to an embodiment of the invention is capable of screening ADCs for treating cancer.

[0012] In a sixth aspect, the present invention provides a method for inhibiting the proliferation of cancer cells. According to an embodiment of the invention, the method includes: treating cancer cells under conditions where an electric field is applied by an electric field applying device; wherein the frequency of the electric field applied by the electric field applying device is 100–700 kHz, preferably 100–250 kHz, more preferably 140–160 kHz; and the field strength of the electric field applied by the electric field applying device is 1–3 V / cm, preferably 1.6–2.0 V / cm, more preferably 1.7–1.9 V / cm. The method according to an embodiment of the invention can inhibit the proliferation of at least one of non-small cell lung cancer cells, breast cancer cells, urothelial carcinoma cells, ovarian cancer cells, gastric cancer cells, and colorectal cancer cells.

[0013] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0014] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0015] Figure 1 This is a three-dimensional assembly diagram of a TTF cell experimental apparatus according to one embodiment of this application.

[0016] Figure 2 for Figure 1 A partial three-dimensional exploded view of the TTF cell experimental setup shown.

[0017] Figure 3 In Example 1 of this application, TTFields+ is used in combination. Using TTFields alone, using alone A graph showing the cytotoxicity of NCI-H1781 cells obtained by cell counting 96 hours after treatment.

[0018] Figure 4 In Example 1 of this application, TTFields and different concentrations of [unclear text - possibly a reference to a specific ingredient or ingredient] were applied to NCI-H1781 cells. Image of the processed cell clone.

[0019] Figure 5 In Example 1 of this application, TTFields and different concentrations of [unclear text - possibly a reference to a specific ingredient or ingredient] were applied to NCI-H1781 cells. A graph showing the cell clone count analysis after processing.

[0020] Figure label:

[0021] Electric field application device 100; body 1; circuit board 2; petri dish 3; electrode sheet 4; bottom plate 11; top plate 12; support plate 13. Detailed Implementation

[0022] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0023] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this invention, unless otherwise stated, "a plurality of" means two or more.

[0024] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0025] To facilitate understanding of this invention, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined elsewhere in this invention, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0026] In this invention, the terms "comprising" or "including" are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0027] In this invention, the terms “optionally,” “optionally,” or “optionally” generally refer to events or conditions described subsequently that may but may not occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0028] In this invention, the term "treatment" refers to the use of drugs to achieve desired pharmacological and / or physiological effects. These effects may be preventative in terms of complete or partial prevention of disease or its symptoms, and / or therapeutic in terms of partial or complete cure of disease and / or adverse effects caused by disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of disease in susceptible individuals who have not yet been diagnosed with the disease; (b) suppression of disease, such as inhibiting disease progression; or (c) alleviating disease, such as reducing disease-related symptoms. As used herein, "treatment" encompasses any administration of drugs or transgenic immune cells to an individual to treat, cure, alleviate, improve, reduce, or suppress the individual's disease, including but not limited to administration of drugs containing cells with chimeric antigen receptors as described herein to an individual in need.

[0029] In this invention, the term "antibody-drug conjugate" refers to a complex typically formed by the conjugation of an antibody to a drug molecule via a linker. This drug molecule can be a chemotherapeutic agent, a radioactive isotope, or a toxin, which targets specific antigens on the surface of cells to achieve a therapeutic purpose. Antibody-drug conjugates, as a targeted therapy, possess high selectivity and specificity, enabling the treatment of various diseases, including tumors and autoimmune diseases.

[0030] In this invention, the term "antibody" broadly refers to an immunoglobulin (Ig) molecule, typically composed of four polypeptide chains, two heavy (H) chains, and two light (L) chains. Antibodies contain complementarity-determining regions (CDRs), also known as hypervariable regions, within the variable domains of both the light and heavy chains. The more conserved portions of the variable domains are referred to as frames (FRs). As is known in the art, the amino acid positions / boundaries that delineate the hypervariable regions of an antibody can vary depending on the context and various definitions known in the art. Some positions within the variable domains can be considered mixed hypervariable positions because they may be considered within the hypervariable region under one set of criteria and outside the hypervariable region under another set of criteria. One or more of these positions may also be found within extended hypervariable regions. The variable domains of the native heavy and light chains each contain four FR regions, primarily through a β-sheet configuration, linked by three CDRs, forming loops and, in some cases, forming part of a β-sheet structure. The CDRs in each chain are tightly held together by the FR regions and, together with CDRs from the other chain, contribute to the formation of the antigen-binding site of the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, MD, 1987). As used herein, immunoglobulin amino acid residues are numbered according to the immunoglobulin amino acid residue numbering system of Kabat et al., unless otherwise stated.

[0031] In this invention, the term "monoclonal antibody" or "monoclonal antibody" is not limited to antibodies produced by hybridoma technology. Monoclonal antibodies are derived from a single clone by any means available in the art or known to the public, including any eukaryotic, prokaryotic, or phage clone. Monoclonal antibodies that can be used in this disclosure can be prepared using a variety of techniques known in the art, including hybridoma, recombinant, and phage display technologies, or combinations thereof. Among the many uses of this disclosure are in vivo use in humans of chimeric antibodies, primate-derived antibodies, humanized antibodies, or human antibodies.

[0032] The terms "non-EGFR-expressing tumor" or "non-EGFR-expressing cancer" refer to tumors or cancers that do not express EGFR. For example, the "non-EGFR-expressing tumor" or "non-EGFR-expressing cancer" as used in this invention refers to non-small cell lung cancer, breast cancer, urothelial carcinoma, ovarian cancer, gastric cancer, and colorectal cancer, especially non-small cell lung cancer.

[0033] The term "administration" refers to the delivery of a substance (such as an ADC) for therapeutic purposes. Administration can be parenteral, enteral, or local. Parenteral administration is typically performed by injection and includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0034] The term "tumor therapeutic electric field" generally refers to the use of alternating electric fields to treat cancer. U.S. Patent Nos. 6,868,289 and 7,016,725 (each of which is incorporated herein by reference in its entirety) disclose methods and apparatus for treating tumors using alternating electric fields in the range of 1-10 V / cm with frequencies between 50 kHz and 500 kHz, and the efficiency of those electric fields increases when more than one field direction is used (e.g., when the field is switched between two or three directions oriented about 90° apart from each other).

[0035] This invention proposes a system for treating cancer, the use of an electric field application device in the preparation of a cancer treatment system, the use of antibody-drug conjugates in the preparation of drugs, a method for treating cancer cells, a method for screening antibody-drug conjugates, and a method for inhibiting cancer cell proliferation, which will be described in detail below.

[0036] Systems for treating cancer

[0037] In a first aspect, the present invention provides a system for treating cancer. According to an embodiment of the invention, the system includes: an electric field application device for applying an electric field for tumor treatment; and a delivery system for delivering an antibody-drug conjugate selected from one of vedilactumab, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166. The system according to an embodiment of the invention is capable of inhibiting at least one of non-small cell lung cancer, breast cancer, urothelial carcinoma, ovarian cancer, gastric cancer, and colorectal cancer.

[0038] According to an embodiment of the present invention, trastuzumab (DS-8201), (Trastuzumabderuxtecan(T-DXd)) was jointly developed by AstraZeneca and Daiichi Sankyo. A humanized monoclonal antibody targeting HER2, trastuzumab, is linked to a novel small-molecule toxic drug, a topoisomerase 1 inhibitor, exatecan derivative (DX-8951 derivative, DXd), via a tetrapeptide linker. Upon binding to HER2 on tumor cells, T-DXd undergoes internalization and cleavage by intracellular linkers of lysosomal enzymes. Released, the membrane-permeable DXd enters the cell nucleus, leading to DNA damage and cell death. It has been approved for multiple oncology indications worldwide, including HER2-positive breast cancer, gastric cancer, gastroesophageal junction cancer, and HER2-mutant metastatic or unresectable non-small cell lung cancer (NSCLC).

[0039] In some respects, ADC drugs for treating tumors expressing HER2 can be used in combination with alternating electric fields. ADC drugs for treating tumors expressing HER2 include, but are not limited to, vedicituzumab (RC-48), trastuzumab (Enhertu), trastuzumab emtansine (Kadcyla), DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166.

[0040] According to embodiments of the present invention, the method includes applying an alternating electric field of a certain frequency and field strength to a target site in the lungs of a subject for a period of time via an electric field application device; and administering a recommended dose of trastuzumab to the target site in the lungs of a subject in need. Specifically, the alternating electric field can be applied before, after, or simultaneously with the administration of trastuzumab. Applying the alternating electric field before the administration of trastuzumab can include several seconds, minutes, hours, or days prior to the administration. Applying the alternating electric field after the administration of trastuzumab can include several seconds, minutes, hours, or days after the administration. Applying an alternating electric field while administering trastuzumab can occur several seconds or minutes before or after administration of trastuzumab. Simultaneous application of an alternating electric field and trastuzumab can also include administering trastuzumab while the alternating electric field is being applied.

[0041] Preferably, during the treatment phase, one cycle is 3 weeks (21 days). Trastuzumab 5.4 mg / kg is administered intravenously on day 1 of each cycle, Q3W (once every 3 weeks) until disease progression or unacceptable toxicity occurs.

[0042] The alternating electric field will be used for continuous treatment starting from day 1 of cycle 1 (C1D1) of the entire treatment course, with a daily treatment time of ≥18 hours, continuing throughout the entire treatment phase until disease progression (PD) is confirmed or intolerable toxicity occurs. The frequency of the alternating electric field is 100–700 kHz, and the field strength is 1–3 V / cm.

[0043] According to an embodiment of the present invention, the electric field application device is adapted to perform electrotherapy on cancer cells.

[0044] According to a specific embodiment of the present invention, see Figure 1 and Figure 2 The electric field applying device 100 includes a body 1, a circuit board 2, multiple petri dishes 3, and multiple pairs of electrode plates 4. The body 1 includes a base plate 11, a top plate 12, and multiple support plates 13 supported between the base plate 11 and the top plate 12. The circuit board 2 is laid flat and fixed to the top surface of the top plate 12. The petri dishes 3 are placed horizontally on the base plate 11, located between the base plate 11 and the top plate 12. The electrode plates 4 are disposed between the petri dishes 3 and the top plate 12, with the bottom of the electrode plates 4 inserted into the petri dishes 3 and the top of the electrode plates 4 extending upwards through the top plate 12 and connecting to the circuit board 2. The petri dishes 3 contain culture media, which can be the same or different types, selected according to experimental needs. An electric field generator (not shown) of a tumor electric field therapy device (not shown) is connected to a circuit board 2. The alternating electrical signal generated by the electric field generator (not shown) is applied to tumor cells in the culture medium through the circuit board 2 and electrode plates 4 to create a tumor therapeutic electric field. The effects of the frequency, field strength, direction, and exposure time of the tumor therapeutic electric field on tumor cell growth are studied. The electric field application device can refer to the TTF cell experimental device in CN218561476U, which is incorporated herein by reference in its entirety.

[0045] According to an embodiment of the present invention, in order to ensure cell survival, the electrode 4 is equipped with a thermistor (not shown) that can record the temperature data of the culture medium in real time. During the experiment, the specific incubator ambient temperature is set to 33-34°C according to the voltage of the electric field therapy device (not shown), thereby controlling the temperature in the culture medium within the range of 36.5-37.5°C.

[0046] According to embodiments of the present invention, the cancer includes, but is not limited to, at least one of non-small cell lung cancer, breast cancer, urothelial carcinoma, ovarian cancer, gastric cancer, and colorectal cancer.

[0047] According to embodiments of the present invention, antibody-drug conjugates (ADCs) are novel anticancer drugs that deliver cytotoxic drugs directly to tumor cells via monoclonal antibodies. For tumor cells that do not express EGFR, ADC drugs can be programmed to target other specific antigens on the surface of tumor cells, thereby inhibiting tumor cell growth. In non-small cell lung cancer (NSCLC), EGFR is one of the important therapeutic targets. However, many NSCLC patients may not express EGFR or may be resistant to EGFR inhibitors. In such cases, for tumor cells that do not express EGFR, ADC drugs can target other antigens overexpressed on the surface of tumor cells, such as one of CD33, CD30, CD22, CD79b, Nectin-4, Trop-2, BCMA, CD19, TF, FRα, HER2, Trop-2, and CLDN18.2.

[0048] According to an embodiment of the present invention, the frequency of the electric field applied by the electric field applying device is in the mid-frequency range, specifically 100–700 kHz, preferably 100–250 kHz, and more preferably 140–160 kHz. According to an embodiment of the present invention, the frequency of the electric field applied by the electric field applying device can be 100 kHz, 150 kHz, 200 kHz, 300 kHz, 400 kHz, 500 kHz, 600 kHz, 650 kHz, 700 kHz, or a range between these values ​​(100–650 kHz, 100–600 kHz, and 100–500 kHz). A suitable frequency can effectively inhibit the proliferation of non-small cell lung cancer cells.

[0049] According to embodiments of the present invention, the electric field strength applied by the electric field applying device is 1-3 V / cm, preferably 1.6-2.0 V / cm, and more preferably 1.7-1.9 V / cm. According to embodiments of the present invention, the electric field strength applied by the electric field applying device can be 1 V / cm, 1.1 V / cm, 1.2 V / cm, 1.3 V / cm, 1.4 V / cm, 1.5 V / cm, 1.6 V / cm, 1.7 V / cm, 1.8 V / cm, 1.9 V / cm, 2.0 V / cm, 2.1 V / cm, 2.2 V / cm, 2.3 V / cm, 2.4 V / cm, 2.5 V / cm, 2.6 V / cm, 2.7 V / cm, 2.8 V / cm, 2.9 V / cm, 3 V / cm, or a range between these values, specifically 1-2.9 V / cm, 1-2.8 V / cm, and 1-2.7 V / cm. A moderate field strength can effectively inhibit the proliferation of non-small cell lung cancer cells.

[0050] According to an embodiment of the present invention, the electric field applying device applies an electric field for a period of not less than 24 hours, preferably not less than 48 hours, more preferably 48 to 120 hours, for example, 48 hours, 50 hours, 55 hours, 60 hours, 65 hours, 70 hours, 75 hours, 80 hours, 85 hours, 90 hours, 95 hours, 100 hours, 105 hours, 110 hours, 115 hours, or 120 hours.

[0051] According to embodiments of the present invention, TTFields exhibit field-strength-dependent cytotoxicity against NCI-H1781 non-small cell lung cancer cells. Treatment with an alternating electric field at a frequency of 150 kHz and a field strength of 1.8 V / cm inhibits the proliferation of NCI-H1781 non-small cell lung cancer cells.

[0052] Application of electric field application devices in the preparation of cancer treatment systems

[0053] In a second aspect, the invention proposes the use of an electric field application device in the preparation of a cancer treatment system in which cancer patients are treated with antibody-drug conjugates (ADCs) before, after, or concurrently with cancer treatment, said ADC being selected from one of the following: vediclofenac, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166.

[0054] According to embodiments of the present invention, the cancer is selected from at least one of non-small cell lung cancer, breast cancer, urothelial carcinoma, ovarian cancer, gastric cancer, and colorectal cancer.

[0055] Uses of antibody-drug conjugates in drug preparation

[0056] In a third aspect, the present invention provides the use of an antibody-drug conjugate in the preparation of a medicament for treating cancer in a patient who is treated with an electric field applied by an electric field application device before, after, or simultaneously with the treatment of the patient, wherein the antibody-drug conjugate is selected from one of the following: vediclofenac, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166.

[0057] According to embodiments of the present invention, the cancer is selected from at least one of non-small cell lung cancer, breast cancer, urothelial carcinoma, ovarian cancer, gastric cancer, and colorectal cancer.

[0058] According to an embodiment of the present invention, the frequency of the electric field applied by the electric field applying device is 100-700 kHz, preferably 100-250 kHz, and more preferably 140-160 kHz.

[0059] According to an embodiment of the present invention, the electric field strength applied by the electric field applying device is 1-3V / cm, preferably 1.6-2.0V / cm, and more preferably 1.7-1.9V / cm.

[0060] According to an embodiment of the present invention, the electric field treatment time applied by the electric field application device is not less than 24 hours, preferably not less than 48 hours, and more preferably 48 to 120 hours.

[0061] Methods for treating cancer cells

[0062] In a fourth aspect, the present invention provides a method for treating cancer cells. According to an embodiment of the invention, the method includes: treating cancer cells under an electric field applied by an electric field application device; pre-treatment, post-treatment, or simultaneous administration of an antibody-drug conjugate to the cancer cells; wherein the antibody-drug conjugate is selected from one of vediclofenac, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166. The method according to an embodiment of the invention can inhibit the proliferation of at least one of non-small cell lung cancer cells, breast cancer cells, urothelial carcinoma cells, ovarian cancer cells, gastric cancer cells, and colorectal cancer cells.

[0063] According to an embodiment of the present invention, the frequency of the electric field applied by the electric field applying device is 100-700 kHz, preferably 100-250 kHz, and more preferably 140-160 kHz.

[0064] According to an embodiment of the present invention, the electric field strength applied by the electric field applying device is 1-3V / cm, preferably 1.6-2.0V / cm, and more preferably 1.7-1.9V / cm.

[0065] According to an embodiment of the present invention, the electric field treatment time applied by the electric field application device is not less than 24 hours, preferably not less than 48 hours, and more preferably 48 to 120 hours.

[0066] According to embodiments of the present invention, the cancer cells are selected from at least one of non-small cell lung cancer cells, breast cancer cells, urothelial carcinoma cells, ovarian cancer cells, gastric cancer cells, and colorectal cancer cells.

[0067] Methods for screening antibody-drug conjugates

[0068] In a fifth aspect, the present invention provides a method for screening antibody-drug conjugates (ADCs). According to an embodiment of the invention, the method includes: subjecting cancer cells to an electric field applied by an electric field application device; contacting the cancer cells treated with the electric field with a candidate drug; and determining, based on the state of the cancer cells before and after the contact, whether the candidate drug is a drug suitable for treating cancer; wherein the ADC is selected from one of vediclofenac, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166. The method according to an embodiment of the invention is capable of screening ADCs for treating cancer.

[0069] According to an embodiment of the present invention, the frequency of the electric field treatment is 100-700 kHz, preferably 100-250 kHz, and more preferably 140-160 kHz.

[0070] According to an embodiment of the present invention, the electric field strength of the electric field treatment is 1-3V / cm, preferably 1.6-2.0V / cm, and more preferably 1.7-1.9V / cm.

[0071] According to an embodiment of the present invention, the electric field treatment is applied for a period of not less than 24 hours, preferably not less than 48 hours, and more preferably 48 to 120 hours.

[0072] According to embodiments of the present invention, the cancer cells are selected from at least one of non-small cell lung cancer cells, breast cancer cells, urothelial carcinoma cells, ovarian cancer cells, gastric cancer cells, and colorectal cancer cells.

[0073] Methods to inhibit cancer cell proliferation

[0074] In a sixth aspect, the present invention provides a method for inhibiting the proliferation of cancer cells. According to an embodiment of the invention, the method includes: treating cancer cells under an electric field applied by an electric field applying device; wherein the frequency of the electric field applied by the electric field applying device is 100–700 kHz, preferably 100–250 kHz, more preferably 140–160 kHz; and the field strength of the electric field applied by the electric field applying device is 1–3 V / cm, preferably 1.6–2.0 V / cm, more preferably 1.7–1.9 V / cm. The method according to an embodiment of the invention can inhibit the proliferation of at least one of non-small cell lung cancer cells, breast cancer cells, urothelial carcinoma cells, ovarian cancer cells, gastric cancer cells, and colorectal cancer cells.

[0075] According to an embodiment of the present invention, the electric field applying device applies the electric field for a period of not less than 24 hours, preferably not less than 48 hours, and more preferably 48 to 120 hours.

[0076] According to an embodiment of the present invention, the method further includes pre-treatment, post-treatment, or simultaneous administration of the antibody-drug conjugate to the cancer cells; wherein the antibody-drug conjugate is selected from one of vidicitrazumab, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166.

[0077] According to embodiments of the present invention, the cancer cells are selected from at least one of non-small cell lung cancer cells, breast cancer cells, urothelial carcinoma cells, ovarian cancer cells, gastric cancer cells, and colorectal cancer cells.

[0078] Treatment methods for non-small cell lung cancer

[0079] In a seventh aspect, the present invention provides a method for treating non-small cell lung cancer. According to an embodiment of the invention, the method includes: treating non-small cell lung cancer cells under an electric field applied by an electric field applying device; wherein the frequency of the electric field applied by the electric field applying device is 100–700 kHz, preferably 100–250 kHz, more preferably 140–160 kHz; and the field strength of the electric field applied by the electric field applying device is 1–3 V / cm, preferably 1.6–2.0 V / cm, more preferably 1.7–1.9 V / cm. The method according to the embodiment of the invention can inhibit the proliferation of non-small cell lung cancer.

[0080] According to an embodiment of the present invention, the electric field applying device applies the electric field for a period of not less than 24 hours, preferably not less than 48 hours, and more preferably 48 to 120 hours.

[0081] According to an embodiment of the present invention, the method further includes pre-treatment, post-treatment, or simultaneous administration of the antibody-drug conjugate to the cancer cells; wherein the antibody-drug conjugate is selected from one of trastuzumab, SHR-A1811, LCB14-0110, BB-1701, and A166.

[0082] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0083] Example 1: Combined with TTF to inhibit the proliferation of NCI-H1781 non-small cell lung cancer cells

[0084] This embodiment uses the ADC drug trastuzumab. The efficacy of the combination therapy of ADC drugs and TTFields was tested in the HER2-mutant NSCLC cell line NCI-H1781 using cytotoxicity and clonal effect assays. In the following examples, the antibody-drug conjugate... Purchased from Selleck, catalog number: E0200, batch number: E020001.

[0085] 1. The experimental procedure in this embodiment is as follows:

[0086] (1) Cell Culture

[0087] The NCI-H1781 cell growth medium consisted of 10% fetal bovine serum, 1% penicillin-streptomycin solution, and 90% RPMI-1640 (Roswell Park Memorial Institute-1640) medium. All cells were incubated in a cell culture incubator at 37°C with 95% air, 5% CO2, and saturated humidity. The NCI-H1781 cells were then transferred to culture dishes, and trypsin containing 0.25% EDTA was added to digest the cells. The cells were then seeded onto 20mm circular spreaders in 12-well plates and incubated for another 96 hours at 37°C with 5% CO2.

[0088] (2) Optimal frequency selection of electric field for TTF tumor therapy

[0089] Twelve NCI-H1781 cell slides in excellent condition were selected. Three slides were grouped together and placed in four culture dishes. 15 mL of culture medium was added to each culture dish. Three of the culture dishes were placed in three TTF cell culture apparatuses. An alternating electric field of different frequencies (100 kHz, 150 kHz, 200 kHz) with an intensity of 1.8 V / cm was applied to the cell samples in the three culture dishes using a TTF in vitro cell culture system. The three TTF cell culture apparatuses, each with one culture dish, were then placed in a 5% CO2 constant temperature cell culture incubator at a temperature of 33-34℃ (the temperature in the culture medium was adjusted according to the electric field strength to control the temperature within the range of 36.5-37.5℃). The culture dish without TTF was placed in a 5% CO2 constant temperature cell culture incubator at a temperature of 36.5-37.5℃. All were incubated at saturated humidity for 96 h.

[0090] (3) Cytotoxicity test and conclusion

[0091] Ninety-six hours after NCI-H1781 cell therapy, cell slides from each group were removed. The NCI-H1781 cells were digested with trypsin containing 0.25% EDTA to prepare a single-cell suspension. The number of NCI-H1781 cells in each group was detected using a handheld cell counter Scepter 3.0, and the cytotoxic effect was determined by cell counting.

[0092] Cell counting experiments showed that the number of cells decreased in all TTFields groups at different frequencies compared to those without TTFields, with the most significant decrease observed in the 150kHz TTFields group. Therefore, 150kHz TTFields exhibited the best inhibitory effect on the growth of NCI-H1781 cells, and the 150kHz TTFields combined with [other treatments] was ultimately selected. Further experiments will be conducted on NCI-H1781 cells to inhibit their proliferation.

[0093] (4) Combined TTF treatment

[0094] Thirty-six NCI-H1781 cell slides in excellent condition were selected. Three slides were placed in each of twelve culture dishes. The twelve culture dishes were then divided into two groups, with one group receiving treatment alone. This group contains 6 petri dishes with different concentrations of... The culture was carried out in media containing (0 ng / mL, 2.5 ng / mL, 5 ng / mL, 10 ng / mL, 20 ng / mL, 40 ng / mL); another group was treated with... Simultaneously, TTF was applied to six culture dishes in this group containing different concentrations. Six culture dishes were cultured in media containing (0 ng / mL, 2.5 ng / mL, 5 ng / mL, 10 ng / mL, 20 ng / mL, 40 ng / mL) of medium. These dishes were placed in a TTF cell culture apparatus, and an alternating electric field with a frequency of 150 kHz and an intensity of 1.8 V / cm was applied to the cell samples using the TTF in vitro cell culture system. The TTF cell culture apparatus was then placed in a 5% CO2 incubator at a temperature of 33-34℃ (adjusted according to the electric field strength to maintain the temperature within the range of 36.5-37.5℃). Six culture dishes without TTF were placed in a 5% CO2 constant temperature cell culture incubator at a temperature of 36.5-37.5℃ and incubated at saturated humidity for 96 hours.

[0095] (5) Cytotoxicity detection

[0096] Ninety-six hours after NCI-H1781 cell therapy, cell slides from each group were removed. The NCI-H1781 cells were digested with trypsin containing 0.25% EDTA to prepare a single-cell suspension. The number of NCI-H1781 cells in each group was detected using a handheld cell counter Scepter 3.0, and the cytotoxic effect was determined by cell counting.

[0097] Cell counting experiment results as follows Figure 3 As shown, compared to application alone Compared to applying TTF alone, TTFields+ The cytotoxic effect was significantly higher in NCI-H1781 cells (two-way ANOVA followed by multiple comparisons, *P<0.05; **P<0.01).

[0098] (6) Cell clone formation

[0099] After cell counting is completed, select three... Small numbers of NCI-H178 cells from treatment groups (10 ng / mL, 20 ng / mL, 40 ng / mL) were seeded into 6-well plates, with 10,000 NCI-H178 cells seeded per well. Culture was continued until the majority of individual clones contained more than 50 cells, with medium changes and cell status observed every 3 days. After cloning, cells were washed once with PBS, fixed with 4% paraformaldehyde for 30 min, washed once with PBS, and stained with 1% crystal violet solution for 10 min per well. Cells were washed several times with PBS, air-dried, photographed, and counted. Clonal formation rate was calculated as (number of clones / number of seeded cells) × 100%, and the clonal effect was determined by the clonal formation rate.

[0100] The results of the clonal effect are as follows Figure 4 and Figure 5 As shown, compared to application alone Compared to cells treated with or treated with TTF alone, TTFields+ The number of cell colonies was significantly reduced in the treated cells (two-way ANOVA followed by multiple comparisons, *P<0.05; **P<0.01).

[0101] The results of this embodiment show that when an antibody-drug conjugate containing trastuzumab is administered in combination with TTFields to non-small cell lung cancer cells NCI-H1781 (corresponding to non-small cell lung cancer and drug target HER2), the combination of TTFields and the antibody-drug conjugate containing trastuzumab is more effective than either TTFields or the antibody-drug conjugate containing trastuzumab alone, as determined by the detection of cytotoxic and clonal effects.

[0102] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0103] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A system for treating cancer, characterized in that, include: An electric field application device for applying an electric field for tumor treatment; and a delivery system for delivering antibody-drug conjugates; The antibody-drug conjugate is selected from one of the following: vedictitumab, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166.

2. The system according to claim 1, characterized in that, The cancer is selected from at least one of non-small cell lung cancer, breast cancer, urothelial carcinoma, ovarian cancer, gastric cancer, and colorectal cancer.

3. The system according to claim 1, characterized in that, The target of the antibody-drug conjugate is selected from HER2.

4. The system according to claim 1, characterized in that, The frequency of the electric field applied by the electric field applying device is 100-700 kHz, preferably 100-250 kHz, and more preferably 140-160 kHz; Optionally, the electric field strength applied by the electric field applying device is 1 to 3 V / cm, preferably 1.6 to 2.0 V / cm, and more preferably 1.7 to 1.9 V / cm; Optionally, the electric field applying device applies the electric field for a period of not less than 24 hours, preferably not less than 48 hours, and more preferably 48 to 120 hours.

5. The use of an electric field application device in the preparation of a cancer treatment system, characterized in that, Cancer patients receive antibody-drug conjugate therapy before, during, or concurrently with treatment, wherein the antibody-drug conjugate is selected from one of the following: vedictitumab, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166.

6. The use according to claim 5, characterized in that, The cancer is selected from at least one of non-small cell lung cancer, breast cancer, urothelial carcinoma, ovarian cancer, gastric cancer, and colorectal cancer.

7. The use of antibody-drug conjugates in the preparation of drugs, characterized in that, The drug is used to treat a patient's cancer, the patient receiving pre-treatment, post-treatment, or concurrent treatment with an electric field applied by an electric field application device, and the antibody-drug conjugate is selected from one of the following: vedictitumab, trastuzumab, trastuzumab emtansine, DP-303c, SHR-A1811, SYD985, LCB14-0110, BDC-1001, BB-1701, TAA013, and A166.

8. The use according to claim 7, characterized in that, The cancer is selected from at least one of non-small cell lung cancer, breast cancer, urothelial carcinoma, ovarian cancer, gastric cancer, and colorectal cancer.

9. The use according to claim 7, characterized in that, The frequency of the electric field applied by the electric field applying device is 100-700 kHz, preferably 100-250 kHz, and more preferably 140-160 kHz.

10. The use according to claim 7, characterized in that, The electric field strength applied by the electric field applying device is 1 to 3 V / cm, preferably 1.6 to 2.0 V / cm, and more preferably 1.7 to 1.9 V / cm.

11. The use according to claim 7, characterized in that, The electric field treatment time applied by the electric field application device is not less than 24 hours, preferably not less than 48 hours, and more preferably 48 to 120 hours.

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