Combination of antibody-drug conjugate and immune checkpoint inhibitor

Abstract

Provided in the present application is a drug for combined treatment of tumors, which comprises an antibody-drug conjugate and a PD-1 antibody or an antigen-binding fragment thereof. Also provided is a method for treating a tumor, and the method comprises administering to a patient or subject in need of treatment a therapeutically effective amount of the antibody-drug conjugate and the PD-1 antibody or the antigen-binding fragment thereof. Also provided is use of the antibody-drug conjugate in the preparation of a drug for treating tumors in combination with the PD-1 antibody or the antigen-binding fragment thereof.

Description

A combination of an antibody-drug conjugate and an immune checkpoint inhibitor Technical Field

[0001] This application belongs to the field of biomedicine, specifically relating to a combination of an antibody-drug conjugate and an immune checkpoint inhibitor. Background Technology

[0002] Primary bronchogenic carcinoma, or lung cancer for short, is one of the malignant tumors with high incidence and mortality rates worldwide and in my country. According to WHO statistics, in 2020, there were over 2.2067 million new cases of lung cancer globally, with an incidence rate of 22.4 per 100,000, ranking second among malignant tumors. In 2020, there were over 1.7961 million deaths from lung cancer globally, with a mortality rate of 18.0 per 100,000, ranking first among malignant tumors. According to statistics from my country's National Cancer Center, in 2016, there were over 828,100 new cases of lung cancer, with an incidence rate of 36.5 per 100,000, ranking first among malignant tumors. In 2016, there were over 657,000 deaths from lung cancer, with a mortality rate of 28.1 per 100,000, ranking first among malignant tumors.

[0003] Early-stage lung cancer often presents with no obvious symptoms, and most patients are already in advanced stages when they seek medical attention. The overall 5-year survival rate for patients with advanced lung cancer is not high. According to a meta-analysis of 94,703 non-small cell lung cancer (NSCLC) patients reported in the 8th edition of the American Joint Committee on Cancer Staging Manual in 2017, the 5-year survival rate for NSCLC stage IA patients is approximately 80%; for stage IB patients, it is 68%; for stage II patients, it is approximately 55%; for stage III patients, the 5-year survival rate drops to around 20%; and for stage IV patients, the 5-year survival rate is less than 5%, with a median survival of only 7 months (National Health Commission of the People's Republic of China, 2022).

[0004] Several immunotherapies, either as monotherapy or in combination with platinum-based doublet chemotherapy, have been approved both domestically and internationally for first-line treatment of advanced NSCLC without driver gene mutations. While immunotherapy has made significant strides in advanced NSCLC and other advanced solid tumors, the efficacy of immunotherapy monotherapy remains limited, and patients with advanced cancer still inevitably require traditional platinum-based doublet chemotherapy. The nephrotoxicity and gastrointestinal toxicity associated with cisplatin restrict its clinical use.

[0005] Colorectal cancer (CRC) is the third most common cancer worldwide, accounting for about 10% of all cancer cases; nasopharyngeal carcinoma, esophageal cancer, and other cancers are also common malignant tumors globally, with a high incidence rate in China.

[0006] Currently, various gene mutations and abnormal expression mechanisms have been confirmed to be associated with the pathogenesis of NSCLC, CRC, nasopharyngeal carcinoma, esophageal cancer, etc., among which the epidermal growth factor receptor (EGFR) is one of the main driver genes. EGFR is a 170-kDa transmembrane glycoprotein composed of 1186 amino acids. It consists of three parts: an extracellular receptor region, a transmembrane region, and an intracellular tyrosine kinase region. Ligands that have been identified as binding to EGFR include epidermal growth factor (EGF), transforming growth factor a (TGFa), bidirectional regulatory factors, heparin-bound EGF, and cytokines. In human tissues, EGF and TGFa are considered to be the two most important EGFR ligands.

[0007] EGFR is a constitutively expressed component of many normal epithelial tissues, such as skin and hair follicles. Furthermore, EGFR is highly expressed in various human malignant tumor tissues, including 40%–80% in lung cancer, 14%–91% in breast cancer, 33%–74% in gastric cancer, 25%–77% in colon cancer, 30%–50% in pancreatic cancer, 40%–80% in prostate cancer, 50%–90% in renal cell carcinoma, 35%–70% in ovarian cancer, and 36%–100% in head and neck cancer. EGFR overexpression and / or mutation in most tumors are associated with poor prognosis. In vitro studies and experimental animal models have shown that EGFR activation is involved in regulating several important cellular functions in cell transformation and tumor cell progression: proliferation / differentiation, survival, angiogenesis induction, metastatic potential, and resistance to chemotherapy and radiotherapy.

[0008] Currently, antibody-drug conjugates (ADCs) targeting EGFR are a hot research topic. ADCs consist of a specific monoclonal antibody targeting tumor molecules conjugated to a cytotoxic payload. After the monoclonal antibody binds to its target, the drug is internalized, the linker degenerates, and the cytotoxic payload is released, thereby producing an anti-tumor effect. Currently marketed EGFR-ADC products include Rakuten Medical's Akalux (cetuximab sarotalocan), which received accelerated approval in Japan on September 25, 2020, for the treatment of unresectable locally advanced or recurrent head and neck cancer, becoming the world's first approved photoimmunotherapy drug. In China, MRG003 from Meyac is progressing rapidly and has entered Phase II clinical trials.

[0009] CN202211461614.0 discloses an antibody-drug conjugate targeting EGFR:

[0010] Ab is an antibody targeting EGFR. In vitro studies have shown that this ADC has a good inhibitory effect on a variety of tumor cells.

[0011] Immune checkpoints are inhibitory signaling pathways in the immune system that regulate the persistence and intensity of immune responses in peripheral tissues to prevent tissue damage and participate in maintaining tolerance to self-antigens. Studies have found that tumor cells utilize these inhibitory signaling pathways of immune checkpoints to suppress T lymphocyte activity, thereby evading the killing effects of the body's immune system, particularly T lymphocytes. Important immune checkpoint molecules include CTLA-4, PD-1, VISTA, LAG-3, and TIM-3. Among these, PD-1 / PD-L1 pathway antibodies have become a focus of research. PD-1 antibodies, upon binding to PD-1, inhibit its binding to ligands PD-L1 and PD-L2, promoting T lymphocyte proliferation and cytokine production, and relieving the PD-1 system's suppression of tumor-active T lymphocyte immune surveillance. Continuously emerging data indicate that immune checkpoint inhibitors have the potential to become first-line drugs for the treatment of NSCLC. However, for NSCLC patients, the expression rate of immune-related targets in NSCLC tissues is too low, resulting in poor response rates to related drugs. In addition, when patients have low immunity, the efficacy of tumor immunotherapy drugs will also decrease significantly. These shortcomings will undoubtedly hinder the application of tumor immunotherapy drugs in NSCLC.

[0012] Currently, there are no references describing the combination of this antibody-drug conjugate and immune checkpoint inhibitor. Whether this combination can provide more effective treatment for tumors requires further investigation.

[0013] Invention Overview

[0014] This application provides a combination therapy for tumors comprising an antibody-drug conjugate of formula (I) and a PD-1 antibody or its antigen-binding fragment. It also provides a method for treating tumors, comprising administering a therapeutically effective amount of the antibody-drug conjugate of formula (I) and the PD-1 antibody or its antigen-binding fragment to a patient or subject requiring treatment. The use of the antibody-drug conjugate of formula (I) in the preparation of a drug for treating tumors in combination with a PD-1 antibody or its antigen-binding fragment is also provided. Compared to monotherapy, the combined administration of the antibody-drug conjugate of formula (I) and the PD-1 antibody or its antigen-binding fragment in this application further enhances the therapeutic effect on tumors, exhibiting a synergistic effect, and is safe and tolerable, providing a new approach for more effective tumor treatment.

[0015] The antibody-drug conjugate structure represented by formula (I) in this application is as follows:

[0016] Wherein Ab is an antibody targeting EGFR or its antigen-binding fragment, and n is selected from an integer from 1 to 8 or a decimal from 1 to 8, preferably an integer from 4 to 8 or a decimal from 4 to 8, further preferably 1, 2, 3, 4, 5, 6, 7, 8, and more preferably 8.

[0017] In some embodiments, when the Ab is an antibody targeting EGFR or its antigen-binding fragment, it includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes heavy chain complementarity-determining region 1 (HCDR1), heavy chain complementarity-determining region 2 (HCDR2), and heavy chain complementarity-determining region 3 (HCDR3), and the light chain variable region includes light chain complementarity-determining region 1 (LCDR1), light chain complementarity-determining region 2 (LCDR2), and light chain complementarity-determining region 3 (LCDR3), wherein the amino acid sequence of HCDR1 is shown in SEQ ID NO:1, the amino acid sequence of HCDR2 is shown in SEQ ID NO:2, the amino acid sequence of HCDR3 is shown in SEQ ID NO:3, and / or the amino acid sequence of LCDR1 is shown in SEQ ID NO:4, the amino acid sequence of LCDR2 is shown in SEQ ID NO:5, and the amino acid sequence of LCDR3 is shown in SEQ ID NO:6.

[0018] In some embodiments, the EGFR-targeting antibody or its antigen-binding fragment includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:7, or is the amino acid sequence shown in SEQ ID NO:7, and the light chain variable region comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:8, or is the amino acid sequence shown in SEQ ID NO:8.

[0019] In some embodiments, the EGFR-targeting antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 9, or is the amino acid sequence shown in SEQ ID NO. 9; the light chain comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 10, or is the amino acid sequence shown in SEQ ID NO. 10.

[0020] In some implementations, the antibody-drug conjugate represented by formula (I) is ADC-1.

[0021] ADC-1

[0022] Among them, SWY2110 is an antibody having two heavy chains with amino acid sequences as shown in SEQ ID NO:9 and two light chains with amino acid sequences as shown in SEQ ID NO:10.

[0023] In some embodiments, the PD-1 antibody or its antigen-binding fragment described in this application includes a heavy chain variable region and a light chain variable region. The heavy chain variable region includes heavy chain complementarity-determining region 1 (HCDR1), heavy chain complementarity-determining region 2 (HCDR2), and heavy chain complementarity-determining region 3 (HCDR3). The light chain variable region includes light chain complementarity-determining region 1 (LCDR1), light chain complementarity-determining region 2 (LCDR2), and light chain complementarity-determining region 3 (LCDR3). The amino acid sequence of HCDR1 is shown in SEQ ID NO:11, the amino acid sequence of HCDR2 is shown in SEQ ID NO:12, the amino acid sequence of HCDR3 is shown in SEQ ID NO:13, and / or the amino acid sequence of LCDR1 is shown in SEQ ID NO:14, the amino acid sequence of LCDR2 is shown in SEQ ID NO:15, and the amino acid sequence of LCDR3 is shown in SEQ ID NO:16.

[0024] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 17, or is the amino acid sequence shown in SEQ ID NO. 17; the light chain variable region comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 18, or is the amino acid sequence shown in SEQ ID NO. 18.

[0025] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 19, or is the amino acid sequence shown in SEQ ID NO. 19, and the light chain comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 20, or is the amino acid sequence shown in SEQ ID NO. 20.

[0026] In some embodiments, the anti-PD-1 antibody is an antibody having two heavy chains having an amino acid sequence as shown in SEQ ID NO:19 and two light chains having an amino acid sequence as shown in SEQ ID NO:20.

[0027] In a first aspect, this application provides a medicament for the combined treatment of tumors, comprising an antibody-drug conjugate as shown in formula (I) and the aforementioned PD-1 antibody or its antigen-binding fragment. In some embodiments, the medicament further comprises a chemotherapeutic agent. The chemotherapeutic agent is preferably a platinum-based drug, such as carboplatin and / or cisplatin.

[0028] Secondly, this application provides the use of the antibody-drug conjugate shown in Formula (I) and the above-mentioned PD-1 antibody or its antigen-binding fragment in the preparation of a medicament for treating tumors.

[0029] Thirdly, this application provides a method for treating tumors, the method comprising administering to a patient or subject requiring treatment a therapeutically effective amount of an antibody-drug conjugate of formula (I) and the aforementioned PD-1 antibody or its antigen-binding fragment. In some embodiments, the method further comprises administering a chemotherapeutic agent. The chemotherapeutic agent is preferably a platinum-based drug, such as carboplatin and / or cisplatin.

[0030] Fourthly, this application provides the use of the antibody-drug conjugate shown in Formula (I) in the preparation of a medicament for treating tumors in combination with the above-mentioned PD-1 antibody or its antigen-binding fragment.

[0031] Fifthly, this application provides the aforementioned combined treatment of tumors for the treatment of tumors.

[0032] In some embodiments, the antibody-drug conjugate shown in formula (I) and the PD-1 antibody or its antigen-binding fragment described above can be simultaneously contained in a clinically acceptable pharmaceutical formulation (single formulation), or they can be separately prepared into clinically acceptable dosage forms and combined and packaged into the drug. That is, the drug described in this application not only includes a combination pharmaceutical formulation (single formulation), but also a combination pharmaceutical package or kit product. The combination pharmaceutical formulation contains both the antibody-drug conjugate shown in formula (I) and the PD-1 antibody or its antigen-binding fragment described above in a single formulation unit, prepared into a clinically acceptable dosage form. In the combination pharmaceutical package or kit product, the antibody-drug conjugate shown in formula (I) and the PD-1 antibody or its antigen-binding fragment described above are separately prepared into clinically acceptable pharmaceutical formulations, that is, the antibody-drug conjugate shown in formula (I) and the PD-1 antibody or its antigen-binding fragment described above are contained in different formulation units and presented in a combined package form; the formulation forms of the antibody-drug conjugate shown in formula (I) and the PD-1 antibody or its antigen-binding fragment described above can be the same or different.

[0033] In some embodiments, the antibody-drug conjugate of formula (I) and the PD-1 antibody or its antigen-binding fragment are respectively prepared into clinically acceptable dosage forms and packaged together to form the drug. Preferably, the antibody-drug conjugate of formula (I) is a lyophilized powder for injection or an injection solution, and the PD-1 antibody or its antigen-binding fragment is a lyophilized powder for injection or an injection solution.

[0034] In some embodiments, the antibody-drug conjugate (ADC) of formula (I) and the PD-1 antibody or its antigen-binding fragment can be administered simultaneously or separately. That is, the ADC of formula (I) and the PD-1 antibody or its antigen-binding fragment can be contained in the same combination formulation unit and administered simultaneously. Alternatively, the ADC of formula (I) and the PD-1 antibody or its antigen-binding fragment can be contained in different formulation units and administered simultaneously or in parallel, or sequentially at different times within a clinically acceptable time interval on a given day, or administered separately at clinically acceptable time intervals according to their respective dosing frequencies and cycles. There are no particular restrictions on the order of administration of the ADC of formula (I) and the PD-1 antibody or its antigen-binding fragment; both can be used as a first or second treatment as needed clinically. Simultaneous or parallel administration means that the first and second treatments begin simultaneously, or that the first treatment is still being delivered when the second treatment begins.

[0035] In some embodiments, the antibody-drug conjugate shown in Formula (I) and the PD-1 antibody or its antigen-binding fragment are administered at their respective dosing frequencies and cycles. If administered on the same day, preferably, the antibody-drug conjugate shown in Formula (I) is injected first, followed by the PD-1 antibody or its antigen-binding fragment.

[0036] In some embodiments, the ratio of the antibody-drug conjugate shown in Formula (I) to the above-mentioned PD-1 antibody or its antigen-binding fragment per cycle is selected from (1-100):(1-100), such as (1-50):(1-50), (1-30):(1-30), (1-10):(1-10), (5-15):(1-5), (1-5):(1-10), 2:1, 1:30, 1:15, 1:10, 1:5, 1:4 and 1:2.

[0037] In some embodiments, when the drug described in this application is a combination drug package or kit product, the mass ratio of the antibody-drug conjugate represented by formula (I) and the above-mentioned PD-1 antibody or its antigen-binding fragment is selected from (1-100):(1-100), such as (1-50):(1-50), (1-30):(1-30), (1-10):(1-10), (5-15):(1-5), (1-5):(1-10), 2:1, 1:30, 1:15, 1:10, 1:5, 1:4 and 1:2.

[0038] In some embodiments, the therapeutically effective amount of the antibody-drug conjugate represented by formula (I) (based on the antibody-drug conjugate represented by formula (I) and the patient's weight, where mg is the mass of the antibody-drug conjugate represented by formula (I) and kg is the patient's weight) is 1 mg / kg to 15 mg / kg, such as about 1.5 mg / kg, about 1.8 mg / kg, about 2.0 mg / kg, about 2.2 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.8 mg / kg, about 3 mg / kg, about 3.2 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.8 mg / kg, about 4.0 mg / kg, about 4.2 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.8 mg / kg, and about 5.0 mg / kg. Approximately 5.2 mg / kg, approximately 5.4 mg / kg, approximately 5.5 mg / kg, approximately 5.6 mg / kg, approximately 5.8 mg / kg, approximately 6.0 mg / kg, approximately 6.2 mg / kg, approximately 6.4 mg / kg, approximately 6.6 mg / kg, approximately 6.8 mg / kg, approximately 7.0 mg / kg, approximately 7.2 mg / kg, approximately 7.5 mg / kg, approximately 7.8 mg / kg, approximately 8.0 mg / kg, approximately 8.2 mg / kg, approximately 8.5 mg / kg, approximately 8.6 mg / kg, approximately 8.8 mg / kg, approximately 9.0 mg / kg, approximately 9.5 mg / kg, approximately 10.0 mg / kg, approximately 10.5 mg / kg, approximately 11 mg / kg, approximately 11.5 mg / kg, approximately 12.0 mg / kg, approximately 13 mg / kg, approximately 14 mg / kg.

[0039] In some embodiments, the therapeutically effective amount of the PD-1 antibody or its antigen-binding fragment is the conventional amount of the PD-1 antibody or its antigen-binding fragment.

[0040] In some embodiments, the therapeutically effective dose of the aforementioned PD-1 antibody or its antigen-binding fragment is 100 mg to 500 mg per dose, such as about 120 mg per dose, about 150 mg per dose, about 180 mg per dose, about 210 mg per dose, about 240 mg per dose, about 270 mg per dose, about 300 mg per dose, about 330 mg per dose, about 360 mg per dose, about 390 mg per dose, about 420 mg per dose, about 450 mg per dose, or about 480 mg per dose. Preferably, it is about 360 mg per dose.

[0041] In some embodiments, the antibody-drug conjugate and / or PD-1 antibody or its antigen-binding fragment represented by formula (I) can be administered once daily (QD), or the therapeutically effective dose can be divided into multiple doses throughout the day, such as twice daily (BID) or three times daily (TID). It can be administered once weekly (QW), or the therapeutically effective dose can be divided into multiple doses throughout the week, such as twice weekly (BIW) or three times weekly (TIW). It can be administered once every two weeks (Q2W), or the therapeutically effective dose can be divided into multiple doses throughout the two weeks, such as twice every two weeks (BI2W) or three times every two weeks (TI2W). It can be administered once every three weeks (Q3W), or the therapeutically effective dose can be divided into multiple doses throughout the three weeks, such as twice every three weeks (BI3W, e.g., D1, D8 every three weeks) or three times every three weeks (TI3W). It can be administered once a month (QM), or the above-mentioned therapeutically effective dose can be divided into multiple doses over several days within a month, such as twice a month (BI2M) or three times a month (TIM). It can also be administered at intervals, such as once every 2-7 days, or once every 3 days, 4 days, 5 days, or 6 days, or once every 2-4 weeks, such as once every 2 weeks (once every 3 weeks, every 3-week cycle), once every 1 week (once every 2 weeks, every 2-week cycle or every 4-week cycle), and once every 3 weeks (once every 4 weeks, every 4-week cycle), or once every 1-3 months, such as once every 1 month (every 2 months); or continuously for 3 weeks, stop for 1 week, every 4-week cycle, or continuously for 2 weeks, stop for 1 week, every 3-week cycle, or continuously for 2 weeks, stop for 2 weeks, every 4-week cycle, or once every 1 week (once every 2 weeks), every 4-week cycle. An exemplary administration method includes administering the drug once on the first day of each cycle, which consists of 3-week cycles.

[0042] In some implementations, the antibody-drug conjugate represented by formula (I) can be administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W).

[0043] In some implementations, the PD-1 antibody or its antigen-binding fragment may be administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W).

[0044] In some embodiments, the antibody-drug conjugate represented by formula (I) can be administered once every three weeks (Q3W), and the PD-1 antibody or its antigen-binding fragment can be administered once every three weeks (Q3W).

[0045] In some implementations, the preferred dosing regimen is a therapeutically effective dose of the antibody-drug conjugate shown in Formula (I) of 1.8-4.5 mg / kg (e.g., about 1.8 mg / kg, about 3.2 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, or about 4.5 mg / kg); once every 3 weeks (Q3W), for a 3-week cycle, or once every 2 weeks (Q2W), for a 2-week cycle; or a therapeutically effective dose in combination with the above-mentioned PD-1 antibody or its antigen-binding fragment of 240-360 mg / dose (e.g., about 240 mg / dose, about 270 mg / dose, about 300 mg / dose, about 330 mg / dose, about 360 mg / dose); once every 3 weeks (Q3W), for a 3-week cycle, or once every 2 weeks (Q2W), for a 2-week cycle.

[0046] In some embodiments, the antibody-drug conjugate represented by formula (I) can be a lyophilized powder for injection or an injection solution, and the PD-1 antibody or its antigen-binding fragment can be a lyophilized powder for injection or an injection solution.

[0047] In some embodiments, the administration may be oral or injectable. Preferably, the antibody-drug conjugate and the PD-1 antibody or its antigen-binding fragment shown in formula (I) are administered by injection, such as intravenous infusion.

[0048] In some embodiments, the tumor is a solid tumor, including advanced solid tumors such as EGFR and ALK wild-type advanced solid tumors, preferably EGFR and ALK wild-type non-small cell lung cancer (NSCLC), and more preferably EGFR and ALK wild-type advanced non-small cell lung cancer (NSCLC).

[0049] In some implementations, the tumor proportion score (TPS) PD-L1 expression of the tumor is ≥1% or <1%.

[0050] In some implementations, the tumor is head and neck squamous cell carcinoma (including recurrent or metastatic head and neck squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer, such as non-squamous non-small cell lung cancer, squamous cell lung cancer, and squamous cell lung cancer that has achieved remission after first-line immunotherapy / chemotherapy), nasopharyngeal carcinoma (including advanced nasopharyngeal carcinoma), digestive system cancer (including (recurrent or metastatic) esophageal cancer, bile duct cancer, gastric cancer, colorectal cancer), or cervical cancer.

[0051] In some embodiments, the combination therapy for tumors described in this application further comprises a platinum-based drug. The platinum-based drug, the antibody-drug conjugate of formula (I), and the PD-1 antibody or its antigen-binding fragment may be contained in the same combination formulation unit and administered simultaneously; or, they may be contained in different formulation units and administered simultaneously or in parallel, or sequentially at different times within a clinically acceptable time interval, or administered separately at clinically acceptable time intervals according to their respective dosing frequencies and cycles.

[0052] In some embodiments, the antibody-drug conjugate, the PD-1 antibody or its antigen-binding fragment, and the platinum-based drug are administered at their respective frequencies and cycles according to Formula (I). If administered on the same day, preferably, the antibody-drug conjugate of Formula (I) is injected first, followed by the platinum-based drug, and finally the PD-1 antibody or its antigen-binding fragment.

[0053] In some implementations, the platinum-based drugs can be administered once every three weeks (Q3W).

[0054] In some embodiments, the dosage of the platinum-based drug, such as carboplatin, is AUC = 3-7, preferably 5; the dosage of cisplatin is 50-100 mg / m². 2 Preferred concentration: 60-75 mg / m³ 2 More preferably 75mg / m 2 .

[0055] This application demonstrates that the combined administration of the antibody-drug conjugate of Formula (I) and the PD-1 antibody or its antigen-binding fragment significantly inhibits tumor growth (especially lung cancer), exhibiting a significantly greater tumor-suppressing effect compared to monotherapy, achieving a synergistic effect. Clinical studies show that the antibody-drug conjugate of Formula (I) combined with the PD-1 antibody or its antigen-binding fragment can effectively treat advanced malignant tumors, particularly EGFR and ALK wild-type non-small cell lung cancer, providing patients with advanced solid tumors, including non-small cell lung cancer, with clinical benefits superior to existing treatments, and achieving disease control or remission.

[0056] It should be understood that the aspects and embodiments of this application described herein include those described as "comprising," "forming," and "essentially consisting of." The preferred embodiments of this application have been described in detail above; however, this application is not limited thereto. Within the scope of the technical concept of this application, various simple modifications can be made to the technical solutions of this application, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in this application and are all within the protection scope of this application.

[0057] Invention Details

[0058] the term

[0059] As used herein, “combined” or “aggregated” administration refers to the administration of two (or more) different treatments to a patient or subject during the course of suffering from a condition. For example, administering two or more medications to a patient or subject after diagnosis and before the condition is cured, eliminated, or treatment is discontinued for other reasons. In some embodiments, the delivery of the first treatment is still in progress when the delivery of the second treatment begins, thus creating overlap in terms of administration. This situation is sometimes referred to herein as “simultaneous” or “parallel delivery.” In other embodiments, the delivery of one treatment has ended before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective due to combined administration. For example, the second treatment is more effective, for instance, an equivalent effect is observed with less second treatment compared to the results observed when the second treatment is administered in the absence of the first treatment, or the second treatment provides greater symptom relief, or a similar effect is observed with the first treatment. In some embodiments, the delivery results in greater symptom or other condition-related parameters relief compared to the results observed when the other treatment is delivered in the absence of one treatment. The effects of two (or more) treatments can be additive, additive, or greater than additive. This delivery allows the effect of the first treatment to remain detectable even when the second treatment is delivered.

[0060] The term "treatment" means to reduce, decrease, or alleviate at least one symptom of a subject's disease. For example, in the context of malignant neoplasms, the term "treatment" may mean preventing or delaying the onset of the disease (i.e., the period preceding the clinical manifestation of the disease or its symptoms) and / or reducing the risk of the occurrence or worsening of disease symptoms. When used in conjunction with a disease such as cancer, the term includes, but is not limited to, one or more of the following: stopping cancer growth; causing cancer to shrink in weight or volume; prolonging the expected survival time of a patient or subject; inhibiting tumor growth; reducing tumor size; reducing the size or number of metastatic lesions; inhibiting the development of new metastatic lesions; prolonging survival; prolonging progression-free survival; prolonging time to progression; and / or improving quality of life.

[0061] The terms “treatment,” “relief,” and “improvement” are used interchangeably herein. These terms refer to methods used to achieve beneficial or desired outcomes, including but not limited to therapeutic and / or preventative benefits. A therapeutic benefit refers to the eradication or improvement of the underlying disorder being treated. The eradication or improvement of one or more physical symptoms associated with the underlying disorder also achieves a therapeutic benefit, such that improvement is observed in a patient or subject, even though the patient or subject may still be troubled by the underlying disorder. Regarding preventative benefits, the pharmaceutical composition may be administered to a patient or subject at risk of developing a specific disease, or to a patient or subject who has reported one or more physical symptoms of a disease, even if the disease may not yet be diagnosed. In one embodiment, these terms also refer to the partial or complete suppression or relief of a condition suffered by an individual. In one embodiment, these terms refer to actions taken to reduce the severity of the condition or to delay or slow the progression of the condition when a patient or subject is suffering from or diagnosed with the condition. Treatment does not need to result in a complete cure of the condition; this term includes partial suppression or relief of the condition. Treatment is intended to include prevention or avoidance.

[0062] The terms "subject" or "patient" are intended to include animals that have or suffer from a malignant neoplastic disease. Examples of subjects or patients include mammals such as humans, dogs, cattle, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the subject or patient is a human, such as a human with a malignant neoplastic disease, at risk of developing a malignant neoplastic disease, or potentially capable of developing a malignant neoplastic disease.

[0063] The term "therapeutic effective amount" refers to the amount of a compound or composition of this disclosure that is effective in treating a disease or condition with a reasonable benefit / risk ratio. The therapeutic effective amount of the compound or composition will vary depending on the subject being treated and the disease or condition, the subject's weight and age, the severity of the disease or condition, the method of administration, etc., and this therapeutic effective amount can be readily determined by those skilled in the art.

[0064] The term "co-administration" means exposing a subject to two or more treatment regimens (e.g., two or more compounds). In some embodiments, two or more compounds may be administered simultaneously; in some embodiments, two or more compounds may be administered sequentially (according to completely non-overlapping dosing regimens); in some embodiments, two or more compounds may be administered according to partially overlapping dosing regimens. In some embodiments, "administration" of combination therapy may involve administering one or more compounds to a subject who has already received other compounds (one or more). For clarity, combination therapy does not require the individual compounds to be administered together in a single composition (or even simultaneously), but in some embodiments, two or more compounds may be administered together in a single composition. In some embodiments, the compounds to be co-administered are individual dosage forms, but packaged together to facilitate their co-administration.

[0065] In this article, when referring to "A combined with B for the treatment of tumors," "A and B in combination for the treatment of tumors," or "A combined with B for the preparation of drugs for the treatment of tumors," it generally means that A and B can produce a synergistic effect in the treatment of tumors. That is, the combined therapeutic effect of A and B is better than the therapeutic effect of A or B alone, or the combined side effects / adverse reactions of A and B are lower than the individual side effects / adverse reactions of A or B. This includes, but is not limited to, A enhancing the therapeutic effect of an equivalent dose of B, so that the combined therapeutic effect of A and B can be better than the sum of the individual therapeutic effects of A and B; A reducing the dose of B while producing equivalent therapeutic effect, thereby reducing the side effects / adverse reactions that may occur from using high doses of B; A directly reducing or avoiding the side effects / adverse reactions that B may produce, etc.

[0066] Some quantitative data in this document do not use the term "about". It should be understood that, whether the term "about" is explicitly used or not, each numerical value given herein includes not only the actual given value (the given value), but also approximations of such a given value based on reasonable deduction by one of ordinary skill in the art, including equivalents and approximations of such a given value due to experimental and / or measurement conditions. These approximations are preferably ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±3%, 2%, or ±1% of the given value.

[0067] It should be understood that this application includes the various aspects, embodiments, and combinations of said aspects and / or embodiments described herein. The above description and the following examples are intended to illustrate, not limit, the scope of this application. Other aspects, improvements, and modifications within the scope of this application will be apparent to those skilled in the art to which this application pertains. Therefore, those skilled in the art should recognize that the scope of this application also includes the improvements and modifications to the said aspects and embodiments. Example

[0068] Example 1: Efficacy study of the combined use of ADC-1 and PD-1-001 antibodies against EGFR V769_D770insASV-BAF3 xenografts in Balb / c nude mice

[0069] 1. Laboratory animals

[0070] 28 NCG mice, aged 6-7 weeks, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0071] 2. Experimental Objective

[0072] An immune reconstitution model of human PBMCs (peripheral blood mononuclear cells) was established using NCG mice to investigate the antitumor effect of the combination of ADC-1 and PD-1-001 antibody.

[0073] 3. Test drug

[0074] 1) ADC-1:

[0075] Drug source: Provided by CSPC Jushi Biopharmaceutical Co., Ltd., prepared in accordance with PCT / CN2024 / 093528.

[0076] 2) PD-1-001 antibody (PD-1-001 antibody is an antibody having two heavy chains with amino acid sequences as shown in SEQ ID NO:19 and two light chains with amino acid sequences as shown in SEQ ID NO:20.)

[0077] Drug source: Provided by CSPC Jushi Biopharmaceutical Co., Ltd.

[0078] 4. Drug dosage and grouping

[0079] Table 1 Animal grouping and dosage table Note: iv: intravenous injection; ip: intraperitoneal injection; biw: twice a week; single: single dose.

[0080] 5. Test Methods

[0081] Twenty-eight female NCG mice were subcutaneously inoculated in the axilla of their right forelimb with a suspension of SK-MES-1 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) and Human PBMCs (purchased from Shanghai Aoneng Co., Ltd.). The inoculation volume was 0.2 mL per mouse, containing 8 × 10⁶ SK-MES-1 cells. 6 Human PBMC 8×10 5 This study validated the antitumor efficacy of the combination of ADC-1 and PD-1-001 antibody. When the tumor volume in mice reached 119 mm... 3 At approximately 10:00 AM, animals were evenly divided into four groups based on tumor size: a solvent group (5% glucose injection), an ADC-1 1 mg / kg group, a PD-1-001 antibody 5 mg / kg group, and a combination group of ADC-1 (1 mg / kg) and PD-1-001 antibody (5 mg / kg). ADC-1 was administered via a single tail vein injection (D0); PD-1-001 antibody was administered via intraperitoneal injection twice weekly for a total of 5 weeks (biw×5, D0, D4, D7, D11, D14), with the trial ending on D18. In the combination groups, the administration methods and frequencies of both drugs remained consistent with the corresponding single-drug administrations. Body weight, tumor volume, and other indicators were evaluated.

[0082] 5. Evaluation Indicators

[0083] (1) Tumor volume: V = 1 / 2 × A × B 2

[0084] (2) Tumor suppression rate:

[0085] Note: V: Tumor volume

[0086] A: Tumor growth

[0087] B: Tumor width

[0088] RTV xnd Average relative tumor volume on day n

[0089] TV Xn Mean tumor volume on day n in the treatment group

[0090] TV X0 Mean tumor volume on day 0 in the treatment group

[0091] TV Mn Mean tumor volume on day n in the solvent group

[0092] TV M0 Average tumor volume on day 0 in the solvent group

[0093] 6. Results

[0094] Compared with the Vehicle, both the ADC-1 group and the ADC-1+PD-1-001 antibody group significantly inhibited tumor volume and relative tumor volume growth in mice (P<0.01); compared with the ADC-1 or PD-1-001 antibody monotherapy groups, the combined administration group was significantly more effective than the monotherapy group (P<0.05). In the ADC-1+PD-1-001 antibody group, 6 out of 7 mice achieved complete response (CR) on day 18. See Table 2 for details.

[0095] Table 2. Tumor parameters of each group on day 18 after drug administration. Note: *** P<0.001 compared with the vehicle group; ### P<0.001, compared with the ADC-1 group; △Δ△ P<0.001 compared with the PD-1-001 antibody group.

[0096] Example 2: An open-label, multicenter phase I / II clinical trial of the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of ADC-1 combined with PD-1 antibody in patients with EGFR and ALK wild-type advanced non-small cell lung cancer and other advanced solid tumors.

[0097] 1. Investigational drug

[0098] 1) ADC-1:

[0099] Drug dosage form: Lyophilized powder for injection;

[0100] Specification: 100mg / bottle;

[0101] Administration method: Intravenous drip

[0102] Storage conditions: Store at 2-8℃, away from light.

[0103] Drug source: Provided by CSPC Jushi Biopharmaceutical Co., Ltd., prepared in accordance with PCT / CN2024 / 093528.

[0104] 2) PD-1-001 antibody (PD-1-001 antibody is an antibody having two heavy chains with amino acid sequences as shown in SEQ ID NO:19 and two light chains with amino acid sequences as shown in SEQ ID NO:20.)

[0105] Specification: 10ml:100mg

[0106] Dosage form: Injection

[0107] Storage conditions: Store at 2-8℃, away from light, and avoid freezing.

[0108] Drug source: Provided by CSPC Jushi Biopharmaceutical Co., Ltd.

[0109] 3) Carboplatin for injection

[0110] Drug dosage form: lyophilized powder;

[0111] Specification: 0.1g;

[0112] Storage conditions: Store in a dark, airtight container.

[0113] Drug source: Commercially available

[0114] 4) Cisplatin for injection

[0115] Drug dosage form: lyophilized powder;

[0116] Specifications: 10mg, 20mg

[0117] Storage conditions: Store in a dark, airtight container.

[0118] Drug source: Commercially available

[0119] 2. Research Design

[0120] This study is a multicenter phase I / II clinical trial. The phase I phase includes a dose escalation study and a pharmacokinetic (PK) expansion study, while the phase II phase includes a randomized controlled trial in Part 1 and a cohort expansion study in Part 2.

[0121] Phase I

[0122] Dose escalation studies

[0123] A conventional 3+3 design was used to conduct a dose-escalation study simultaneously in three cohorts of patients with EGFR and ALK wild-type advanced NSCLC or other advanced solid tumors.

[0124] Cohort A1: ADC-1 combined with PD-1-001 antibody injection;

[0125] Cohort A2: ADC-1 combined with PD-1-001 antibody injection and carboplatin;

[0126] Cohort A3: ADC-1 combined with PD-1-001 antibody injection and cisplatin.

[0127] This study investigated the dose escalation phase of ADC-1 combined with PD-1-001 antibody ± chemotherapy. PD-1-001 antibody and chemotherapy were administered at fixed doses, with dose escalation focused solely on ADC-1. The PD-1-001 antibody injection dose was 360 mg, carboplatin dose had an AUC of 5, and cisplatin dose was 75 mg / m². 2All treatments were administered intravenously, every 3 weeks (Q3W), with a treatment cycle of 21 days. ADC-1 was pre-set at three doses: 1.8 mg / kg, 3.6 mg / kg, and 4.8 mg / kg, administered intravenously every 3 weeks (Q3W), with a treatment cycle of 21 days.

[0128] If necessary, the dosage adjustment of ADC-1 combined with PD-1-001 antibody injection ± chemotherapy should be determined based on the obtained information on safety, tolerability, PK, and efficacy.

[0129] PK Extended Research

[0130] Once the dose escalation group has completed safety assessments and proven to be tolerable, PK expansion enrollment can begin in that dose group. Each dose group can be expanded to a maximum of 20 participants (including those enrolled in the dose escalation phase).

[0131] Phase II

[0132] Part 1 Randomized Controlled Studies

[0133] Following the completion of the dose escalation study in cohort A1 and the PK expansion study, and based on the safety, tolerability, and pharmacokinetic characteristics of ADC-1 combined with PD-1-001 antibody injection ± chemotherapy, the phase II recommended dose (RP2D) for ADC-1 combined with PD-1-001 antibody injection ± chemotherapy was determined. A randomized controlled trial was then initiated in patients with EGFR and ALK wild-type advanced NSCLC, with a planned enrollment of 120 participants, randomly assigned 1:1 to the following two groups:

[0134] Group 1: ADC-1 combined with PD-1-001 antibody injection;

[0135] Group 2: ADC-1 combined with PD-1-001 antibody injection and carboplatin or cisplatin.

[0136] The randomization stratification factors were PD-L1 expression status (PD-L1 tumor proportion score (TPS) ≥1%, PD-L1 TPS <1%) and pathological type (adenocarcinoma, squamous cell carcinoma).

[0137] Part 2: Research on Queue Expansion

[0138] Based on the safety, tolerability, and pharmacokinetic data of the Phase I study of ADC-1 combined with PD-1-001 antibody ± chemotherapy, and after obtaining the RP2D of ADC-1 combined with PD-1-001 antibody ± chemotherapy, the study will be expanded to a cohort. If necessary, two dosing regimens will be selected for the cohort study, which will include no more than 300 patients with advanced non-small cell lung cancer and other advanced solid tumors. The cohort expansion will be divided into the following 5 cohorts according to tumor type:

[0139] Cohort B1: Recurrent or metastatic squamous cell carcinoma of the head and neck;

[0140] Cohort B2: Advanced nasopharyngeal carcinoma;

[0141] Cohort B3: Recurrent or metastatic esophageal cancer;

[0142] Cohort B4: Other advanced solid tumors, such as cholangiocarcinoma, gastric cancer, cervical cancer, etc.

[0143] Cohort B5: Maintenance therapy for squamous cell lung cancer that has achieved remission after first-line immunotherapy / chemotherapy.

[0144] Dosing regimen: Cohorts B1-B4 used RP2D, which combines ADC-1 with PD-1-001 antibody ± chemotherapy as determined in the Phase I study, while Cohort B5 used RP2D, which combines ADC-1 with PD-1-001 antibody as determined in Cohort A1 of the Phase I study and the PK extension study.

[0145] All participants in this study underwent safety assessments after their first treatment with the investigational drug, and blood samples for pharmacokinetic (PK) and immunogenicity were collected after a single dose and during continuous treatment. Additionally, participants underwent tumor imaging assessments every 6 weeks for the first 24 weeks of treatment, every 9 weeks thereafter, and at the end of treatment (if no tumor imaging assessment was performed within the previous 4 weeks). All participants received continuous treatment with the investigational drug until the end of treatment, after which they entered a follow-up period.

[0146] 2. Selection Criteria:

[0147] Participants must meet all of the following inclusion criteria to be eligible for this study:

[0148] 1. Age 18 to 75 (inclusive), gender not limited.

[0149] 2. Patients with pathologically confirmed EGFR and ALK wild-type advanced non-small cell lung cancer and other advanced solid tumors:

[0150] 1) Dose escalation studies and PK expansion studies included patients who had failed or were intolerant of standard treatment, had no standard treatment, or refused standard treatment;

[0151] 2) Cohort expansion studies (excluding cohort B5) include patients who have not previously received systemic therapy. Patients who have previously received adjuvant / neoadjuvant therapy and whose disease progressed 6 months after the end of treatment are eligible for inclusion.

[0152] 3) Cohort expansion study Cohort B5 included patients with squamous cell lung cancer who achieved remission after first-line immunotherapy combined with platinum-based doublet chemotherapy.

[0153] 3. Safety evaluation

[0154] From the time participants sign the ICF until 90 days after the last dose, all adverse events (AEs) of all participants are observed and recorded, including abnormal clinical symptoms and vital signs, abnormal laboratory test results, and their correlation with the investigational drug is determined.

[0155] For participants in dose escalation studies, DLT events were observed during the dose-limiting toxicity (DLT) observation period.

[0156] Participants need to undergo safety evaluations during the screening period, at baseline, and after administration, including physical examination, ECOG score, laboratory tests, and electrocardiogram.

[0157] In addition to home visits, unplanned home visits may be conducted as needed based on the occurrence of adverse events (AEs) in participants.

[0158] 4. Evaluation of therapeutic effect

[0159] Efficacy evaluation was performed using the RECIST v1.1 criteria. CT / MRI imaging assessments were conducted every 6 weeks for the first 24 weeks after initial drug administration, every 9 weeks thereafter, and at the end-of-treatment visit (if no tumor imaging assessment had been performed within the previous 4 weeks). The permissible time window for imaging examinations was ±7 days. Efficacy evaluations were performed at the prescribed time points and were not delayed by drug administration delays.

[0160] 5. Therapeutic effect analysis

[0161] Stage I will descriptively summarize the efficacy by dose group. Stage II will perform a pooled analysis of best overall response (BOR), objective response rate (ORR), and disease control rate (DCR). If data support this, progression-free survival (PFS), duration of response (DOR), and overall survival (OS) will also be analyzed. Analysis methods overview:

[0162] According to the tumor efficacy assessment criteria specified in the protocol, BOR was aggregated by cohort, and ORR and DCR were calculated, with the 95% CI calculated using the Clopper-Pearson exact method. Where data are applicable, PFS, DoR, and OS will be analyzed using the Kaplan-Meier method, including estimating median time and its 95% CI, and plotting Kaplan-Meier curves. Considering the purpose of efficacy exploration, efficacy analyses will be performed in the Safety Analysis Set (SAS) and the Efficacy Evaluable Analysis Set (EES).

[0163] Interim Results 1

[0164] Fifty-two patients (42 with non-small cell lung cancer (NSCLC), 3 with nasopharyngeal carcinoma, 2 with cholangiocarcinoma, 3 with esophageal cancer, 1 with colorectal cancer, and 1 with small cell lung cancer) were enrolled in a phase I / II study and received ADC-1 therapy, covering six dose levels: 1.8 mg / kg (n=3), 3.6 mg / kg (n=4), 4.2 mg / kg (n=16), and 4.5 mg / kg (n=6), administered every 3 weeks (Q3W); 3.2 mg / kg (n=10) and 3.6 mg / kg (n=13), administered every 2 weeks (Q2W). Twenty-three patients (40.4%) had received more than three lines of prior therapy, with 63.5% and 80.8% having previously received immunotherapy and platinum-based chemotherapy, respectively. The median duration of treatment was 3 weeks (range: 3.0–9.0 weeks), and 34 patients (63.0%) were still receiving treatment. Treatment-related adverse events (TRAEs) occurred in 44 patients (84.6%), of which only 13 patients (25%) experienced ≥ grade 3 TRAEs. Two dose-limiting toxicities (DILTs) occurred, namely grade 4 thrombocytopenia and grade 3 creatinine elevation, but no TRAEs led to treatment discontinuation.

[0165] In 44 evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 25% and 68.2%, respectively. The ORRs for non-squamous non-small cell lung cancer (mutant), non-squamous non-small cell lung cancer (driver gene negative), and squamous cell lung cancer were 47.6%, 37.5%, and 25%, respectively.

[0166] Typical Case 1, AGA-negative lung adenocarcinoma:

[0167] A 71-year-old male patient was diagnosed with wild-type lung adenocarcinoma, clinically stage IV. He had previously received first-line therapy (tislelizumab combined with pemetrexed, best response, stable disease), but the disease progressed. He participated in a combined immunotherapy clinical trial and, during the screening phase, developed multiple metastases in the right upper lobe, pulmonary lymph nodes, peritoneal lymph nodes, cervical lymph nodes, and bilateral pulmonary nodules, indicating a large tumor burden (baseline target lesion size 115.4 mm). He received combination therapy (ADC-1: 3.6 mg / kg IV Q3W, PD-1-001 antibody: 360 mg IV Q3W). At week 6, the first efficacy assessment showed partial response (target lesion shrank to 53.3 mm), and the partial response was maintained at weeks 12, 18, and 24. The patient is currently still undergoing treatment (progression-free survival > 7 months).

[0168] Typical Case 2, Nasopharyngeal Carcinoma:

[0169] A 54-year-old female patient was diagnosed with non-keratinizing nasopharyngeal carcinoma, clinically stage IV. Her disease had progressed after multiple lines of immunotherapy combined with chemotherapy. She participated in a combined immunotherapy clinical trial. During the screening period, she had multiple metastases in the right and left submastoid soft tissues of the head and neck, cervical lymph nodes, both lungs, nasopharynx, oropharynx, and laryngopharynx, with a large tumor burden (baseline target lesion 105.1 mm). She received combination therapy (ADC-1: 4.5 mg / kg IV Q3W, PD-1-001 antibody: 360 mg IV Q3W). At week 6, the initial efficacy assessment showed a 17% reduction in SD (target lesion reduced to 87.2 mm). At week 12, the SD reduction was maintained at 17%. At week 18, the tumor PD assessment resulted in disqualification (PFS = 4.2 months).

[0170] Typical Case 3, Bile Duct Cancer:

[0171] A 47-year-old female patient was diagnosed with intrahepatic cholangiocarcinoma, clinically stage IV. She had previously received multiple lines of immunotherapy combined with chemotherapy and fluorouracil-based drugs, which led to disease progression. She participated in a combined immunotherapy clinical trial, during which she developed multiple metastases in the liver, lungs, peritoneum, and pelvis. At baseline, the target lesion was 44.1 mm. She received combination therapy (ADC-1: 1.8 mg / kg IV Q3W, PD-1-001 antibody: 360 mg IV Q3W, carboplatin AUC=5 for one cycle). At week 6, the first efficacy assessment showed a partial response (target lesion reduced to 15.2 mm), and the partial response was maintained at weeks 12, 18, and 24. The patient is currently still undergoing treatment (PFS > 7 months).

[0172] Typical Case 4, Squamous Cell Carcinoma of the Lung:

[0173] A 48-year-old female patient was diagnosed with squamous cell carcinoma of the lung, clinically stage IV. She had previously received first-line therapy (pembrolizumab + liposome paclitaxel + carboplatin, followed by pembrolizumab monotherapy maintenance), but her disease progressed. She participated in an ADC-1 combined immunotherapy clinical trial. During the screening period, she had multiple metastases in both lungs, mediastinal lymph nodes, and pleura, with a baseline target lesion size of 54 mm. She received combination therapy (ADC-1: 4.2 mg / kg IV Q3W, PD-1-001 antibody: 360 mg IV Q3W). At week 6, the first efficacy assessment showed a partial response (PR) (target lesion reduced to 34.7 mm), and at week 12, continued shrinkage maintained the PR (target lesion reduced to 26.1 mm). The patient is currently still undergoing treatment (PFS > 3 months).

[0174] Typical Case 5, Esophageal squamous cell carcinoma:

[0175] A 62-year-old male patient was diagnosed with stage IV esophageal squamous cell carcinoma. He had previously received first-line therapy (atezolizumab + cisplatin + paclitaxel) and second-line anti-angiogenic therapy, but his disease progressed. He participated in a combined immunotherapy clinical trial. During the screening period, in addition to the primary lesion, he had multiple metastases in the left upper cervical lymph nodes and mediastinal lymph nodes. The target lesion size at baseline was 15.61 mm. He received combination therapy (ADC-1: 3.6 mg / kg IV Q2W, PD-1-001 antibody: 240 mg IV Q2W). At week 6, the first efficacy assessment showed a partial response (target lesion shrank to 10.37 mm). The patient is currently still undergoing treatment (progression-free survival > 3 months).

[0176] Conclusion: ADC-1 was well tolerated at intravenous doses ranging from 1.8 to 4.5 mg / kg, administered once every 21 days / every 14 days, without reaching the maximum tolerated dose (MTD). The safety profile was manageable, with no interstitial pneumonia (ILD) reported. Encouraging antitumor activity was observed in heavily treated, previously treated patients during dose escalation, dose selection, and pharmacokinetic expansion phases, even before reaching the MTD: the objective response rate (ORR) was 25% in all evaluable patients (including non-squamous non-small cell lung cancer and squamous cell lung cancer), and 47.6% in non-squamous non-small cell lung cancer (mutant type); the ORR was 37.5% in non-squamous non-small cell lung cancer (driver gene negative) and 25% in squamous cell lung cancer, ensuring long-term treatment and prolonging progression-free survival (PFS) in later-line patients.

[0177] The study results indicate that the combined administration of ADC-1 and PD-1-001 antibodies can effectively treat advanced malignant tumors, particularly EGFR-positive advanced solid tumors, such as EGFR and ALK wild-type advanced non-small cell lung cancer. This combination can provide patients with advanced solid tumors, including non-small cell lung cancer, with clinical benefits superior to existing treatments, enabling disease control or remission.

[0178] The sequences used in the above embodiments of this application are shown in the following sequence list. It should be understood that the following sequences are merely exemplary sequences for the embodiments of this application, and not any limitation thereof.

[0179] Sequence List:

[0180] EGFR antibody SWY2110

Claims

1. A combination therapy for tumors, comprising an antibody-drug conjugate of formula (I) and a PD-1 antibody or an antigen-binding fragment thereof, Wherein Ab is an antibody targeting EGFR or its antigen-binding fragment, and n is selected from an integer from 1 to 8 or a decimal from 1 to 8, preferably an integer from 4 to 8 or a decimal from 4 to 8, further preferably 1, 2, 3, 4, 5, 6, 7, 8, and more preferably 8.

2. A method for treating a tumor, the method comprising administering to a patient or subject requiring treatment a therapeutically effective amount of an antibody-drug conjugate of formula (I) and a PD-1 antibody or its antigen-binding fragment, Wherein Ab is an antibody targeting EGFR or its antigen-binding fragment, and n is selected from an integer from 1 to 8 or a decimal from 1 to 8, preferably an integer from 4 to 8 or a decimal from 4 to 8, further preferably 1, 2, 3, 4, 5, 6, 7, 8, and more preferably 8.

3. The use of the antibody-drug conjugate shown in formula (I) in the preparation of a drug for the treatment of tumors in combination with a PD-1 antibody or its antigen-binding fragment. Wherein Ab is an antibody targeting EGFR or its antigen-binding fragment, and n is selected from an integer from 1 to 8 or a decimal from 1 to 8, preferably an integer from 4 to 8 or a decimal from 4 to 8, further preferably 1, 2, 3, 4, 5, 6, 7, 8, and more preferably 8.

4. The medicament of claim 1, or the method of claim 2, or the use of claim 3, wherein the antibody targeting EGFR or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein, The heavy chain variable region includes heavy chain complementarity-determining region 1 (HCDR1), heavy chain complementarity-determining region 2 (HCDR2), and heavy chain complementarity-determining region 3 (HCDR3), and the light chain variable region includes light chain complementarity-determining region 1 (LCDR1), light chain complementarity-determining region 2 (LCDR2), and light chain complementarity-determining region 3 (LCDR3), wherein the amino acid sequence of HCDR1 is shown in SEQ ID NO:1, the amino acid sequence of HCDR2 is shown in SEQ ID NO:2, the amino acid sequence of HCDR3 is shown in SEQ ID NO:3, and / or the amino acid sequence of LCDR1 is shown in SEQ ID NO:4, the amino acid sequence of LCDR2 is shown in SEQ ID NO:5, and the amino acid sequence of LCDR3 is shown in SEQ ID NO:6; Preferably, the EGFR-targeting antibody or its antigen-binding fragment includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:7, or is the amino acid sequence shown in SEQ ID NO:7; and the light chain variable region comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:8, or is the amino acid sequence shown in SEQ ID NO:

8. More preferably, the EGFR-targeting antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 9, or is the amino acid sequence shown in SEQ ID NO. 9; the light chain comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 10, or is the amino acid sequence shown in SEQ ID NO.

10.

5. The drug according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein, The antibody-drug conjugate shown in formula (I) is: Among them, SWY2110 is an antibody having two heavy chains with amino acid sequences as shown in SEQ ID NO:9 and two light chains with amino acid sequences as shown in SEQ ID NO:

10.

6. The medicament according to any one of claims 1 and 4-5, or the method according to any one of claims 2 and 4-5, or the use according to any one of claims 3-5, wherein the PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein, The heavy chain variable region includes heavy chain complementarity-determining region 1 (HCDR1), heavy chain complementarity-determining region 2 (HCDR2), and heavy chain complementarity-determining region 3 (HCDR3), and the light chain variable region includes light chain complementarity-determining region 1 (LCDR1), light chain complementarity-determining region 2 (LCDR2), and light chain complementarity-determining region 3 (LCDR3), wherein the amino acid sequence of HCDR1 is shown in SEQ ID NO:11, the amino acid sequence of HCDR2 is shown in SEQ ID NO:12, the amino acid sequence of HCDR3 is shown in SEQ ID NO:13, and / or the amino acid sequence of LCDR1 is shown in SEQ ID NO:14, the amino acid sequence of LCDR2 is shown in SEQ ID NO:15, and the amino acid sequence of LCDR3 is shown in SEQ ID NO:16; Preferably, the anti-PD-1 antibody or its antigen-binding fragment includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 17, or is the amino acid sequence shown in SEQ ID NO. 17; the light chain variable region comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 18, or is the amino acid sequence shown in SEQ ID NO. 18; More preferably, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 19, or is the amino acid sequence shown in SEQ ID NO. 19, and the light chain comprises an amino acid sequence having at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO. 20, or is the amino acid sequence shown in SEQ ID NO.

20.

7. The medicament according to any one of claims 1 and 4-6, or the method according to any one of claims 2 and 4-6, or the use according to any one of claims 3-6, wherein, The antibody-drug conjugate and the anti-PD-1 antibody or its antigen-binding fragment shown in Formula (I) are simultaneously contained in a clinically acceptable pharmaceutical formulation (single formulation), or are prepared separately into clinically acceptable dosage forms and packaged together to form the drug; preferably, the antibody-drug conjugate and the anti-PD-1 antibody shown in Formula (I) are contained in different formulation units and presented in a combined packaging form; more preferably, the antibody-drug conjugate shown in Formula (I) is a lyophilized powder for injection or an injection solution, and the anti-PD-1 antibody or its antigen-binding fragment is an injection solution.

8. The medicament according to any one of claims 1 and 4-7, or the method according to any one of claims 2 and 4-7, or the use according to any one of claims 3-7, wherein, The antibody-drug conjugate and the anti-PD-1 antibody or its antigen-binding fragment represented by Formula (I) may be administered simultaneously or separately; preferably, the antibody-drug conjugate and the anti-PD-1 antibody or its antigen-binding fragment represented by Formula (I) are contained in different formulation units and administered simultaneously or in parallel, or administered sequentially at different times within a day at clinically acceptable time intervals, or administered separately at clinically acceptable time intervals according to the respective dosing frequencies and cycles of the antibody-drug conjugate and the anti-PD-1 antibody or its antigen-binding fragment represented by Formula (I); more preferably, the antibody-drug conjugate represented by Formula (I) is injected first, followed by the anti-PD-1 antibody or its antigen-binding fragment.

9. The medicament according to any one of claims 1 and 4-8, wherein, The mass ratio of the antibody-drug conjugate and the anti-PD-1 antibody or its antigen-binding fragment shown in Formula (I) is selected from (1-100):(1-100), such as (1-50):(1-50), (1-30):(1-30), (1-10):(1-10), (5-15):(1-5), (1-5):(1-10), 2:1, 1:30, 1:15, 1:10, 1:5, 1:4 and 1:

2.

10. The method according to any one of claims 2 and 4-8, or the use according to any one of claims 3-8, wherein the ratio of the antibody-drug conjugate and the anti-PD-1 antibody or its antigen-binding fragment shown in formula (I) is selected from (1-100):(1-100), such as (1-50):(1-50), (1-30):(1-30), (1-10):(1-10), (5-15):(1-5), (1-5):(1-10), 2:1, 1:30, 1:15, 1:10, 1:5, 1:4 and 1:

2.

11. The medicament according to any one of claims 1 and 4-9, or the method according to any one of claims 2, 4-8 and 10, or the use according to any one of claims 3-8 and 10, wherein, The therapeutically effective dose of the antibody-drug conjugate shown in formula (I) is 1 mg / kg-15 mg / kg, such as approximately 1.5 mg / kg, approximately 1.8 mg / kg, approximately 2.0 mg / kg, approximately 2.2 mg / kg, approximately 2.4 mg / kg, approximately 2.5 mg / kg, approximately 2.8 mg / kg, approximately 3 mg / kg, approximately 3.2 mg / kg, approximately 3.5 mg / kg, approximately 3.6 mg / kg, approximately 3.8 mg / kg, approximately 4.0 mg / kg, approximately 4.2 mg / kg, approximately 4.4 mg / kg, approximately 4.5 mg / kg, approximately 4.6 mg / kg, approximately 4.8 mg / kg, approximately 5.0 mg / kg, approximately 5.2 mg / kg, approximately 5.4 mg / kg, approximately 5.5 mg / kg, approximately 5.6 mg / kg, approximately... 5.8 mg / kg, approximately 6.0 mg / kg, approximately 6.2 mg / kg, approximately 6.4 mg / kg, approximately 6.6 mg / kg, approximately 6.8 mg / kg, approximately 7.0 mg / kg, approximately 7.2 mg / kg, approximately 7.5 mg / kg, approximately 7.8 mg / kg, approximately 8.0 mg / kg, approximately 8.2 mg / kg, approximately 8.5 mg / kg, approximately 8.6 mg / kg, approximately 8.8 mg / kg, approximately 9.0 mg / kg, approximately 9.5 mg / kg, approximately 10.0 mg / kg, approximately 10.5 mg / kg, approximately 11 mg / kg, approximately 11.5 mg / kg, approximately 12.0 mg / kg, approximately 13 mg / kg, or approximately 14 mg / kg, where mg is the mass of the antibody-drug conjugate shown in Formula I, and kg is the patient's body weight.

12. The medicament according to any one of claims 1, 4-9, and 11, or the method according to any one of claims 2, 4-8, and 10-11, or the use according to any one of claims 3-8 and 10-11, wherein, The therapeutically effective dose of the anti-PD-1 antibody or its antigen-binding fragment is 100mg-500mg / dose, such as about 120mg / dose, about 150mg / dose, about 180mg / dose, about 210mg / dose, about 240mg / dose, about 270mg / dose, about 300mg / dose, about 330mg / dose, about 360mg / dose, about 390mg / dose, about 420mg / dose, about 450mg / dose, or about 480mg / dose, preferably about 360mg / dose.

13. The medicament according to any one of claims 1, 4-9, and 11-12, or the method according to any one of claims 2, 4-8, and 10-12, or the use according to any one of claims 3-8 and 10-12, wherein, The antibody-drug conjugate and / or anti-PD-1 antibody or its antigen-binding fragment represented by formula (I) may be administered once daily (QD), or its therapeutically effective dose may be divided into multiple doses throughout the day, such as twice daily (BID) or three times daily (TID); or once weekly (QW), or its therapeutically effective dose may be divided into multiple doses throughout the week, such as twice weekly (BIW) or three times weekly (TIW); or once every two weeks (Q2W), or its therapeutically effective dose may be divided into multiple doses throughout the two weeks. Administered in various ways, such as twice every two weeks (BI2W) or three times every two weeks (TI2W); or once every three weeks (Q3W), or the therapeutically effective dose is divided into multiple doses over three weeks, such as twice every three weeks (BI3W, e.g., D1, D8 every three weeks) or three times every three weeks (TI3W); or once a month (QM), or the therapeutically effective dose is divided into multiple doses over one month, such as twice a month (BI2M) or three times a month (TIM); or administered at intervals, such as once every 2-7 days, or once every 3 days. The medication may be administered once every 4, 5, or 6 days, or once every 2-4 weeks, such as once every 2 weeks (once every 3 weeks, in a 3-week cycle), once every 1 week (once every 2 weeks, in a 2-week or 4-week cycle), or once every 3 weeks (once every 4 weeks, in a 4-week cycle), or once every 1-3 months, such as once every 1 month (every 2 months); or continuously for 3 weeks, stop for 1 week, and repeat every 4 weeks, or continuously for 2 weeks, stop for 1 week, and repeat every 3 weeks, or continuously for 2 weeks, stop for 2 weeks, and repeat every 4 weeks. One cycle, or administration at 1-week intervals (once every 2 weeks), or every 4 weeks; preferably, the antibody-drug conjugate of formula (I) is administered once a week (QW), or once every two weeks (Q2W), or once every three weeks (Q3W); the anti-PD-1 antibody or its antigen-binding fragment is administered once a week (QW), or once every two weeks (Q2W), or once every three weeks (Q3W), more preferably, the antibody-drug conjugate of formula (I) is administered once every three weeks (Q3W); the anti-PD-1 antibody or its antigen-binding fragment is administered once every three weeks (Q3W).

14. The medicament according to any one of claims 1, 4-9 and 11-13, further comprising a chemotherapeutic agent, wherein the chemotherapeutic agent is preferably a platinum-based agent, and the platinum-based agent is preferably carboplatin and / or cisplatin.

15. The method of any one of claims 2, 4-8 and 10-13, further comprising administering a chemotherapy drug, wherein the chemotherapy drug is preferably a platinum-based drug, and the platinum-based drug is preferably carboplatin and / or cisplatin.

16. The method of claim 15, wherein the platinum-based drug is administered once every three weeks (Q3W).

17. The method of claim 15 or 16, wherein the dosage of carboplatin is AUC = 3-7, preferably AUC = 5; and the dosage of cisplatin is 50-100 mg / m². 2 Preferred concentration: 60-75 mg / m³ 2 More preferably 75mg / m 2 .

18. Use of the medicament according to any one of claims 1, 4-9 and 11-14 for the treatment of tumors.

19. The method according to any one of claims 2, 4-8, 10-13 and 15-17, or the use according to any one of claims 3-8 and 10-13, wherein the tumor is a solid tumor, preferably lung cancer, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, digestive system cancer (including esophageal cancer, bile duct cancer, gastric cancer, colorectal cancer), cervical cancer, more preferably non-small cell lung cancer (NSCLC); more preferably EGFR and ALK wild-type non-small cell lung cancer, and more preferably the tumor has TPS PD-L1 expression ≥1% or <1%.

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