Combination of antibody-drug conjugate and ATM inhibitor

Abstract

Provided is a drug for combination therapy for tumors, comprising an antibody-drug conjugate and an ATM inhibitor. Also provided is a method for treating tumors, comprising administering a therapeutically effective amount of the antibody-drug conjugate and the ATM inhibitor to a patient or subject in need of treatment. Also provided is use of the antibody-drug conjugate in the preparation of a drug for use in combination with the ATM inhibitor to treat tumors.

Description

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

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

[0002] Cancer is a group of diseases caused by the malignant proliferation, migration, and invasion of cells. Lung cancer is the malignant tumor with the highest incidence and mortality rate in my country and worldwide. Most patients are diagnosed at an advanced stage, resulting in a low 5-year survival rate, a heavy disease burden, and a serious threat to the health of the Chinese population. Colorectal cancer (CRC) is the third most common cancer worldwide, accounting for approximately 10% of all cancer cases, and is also the second leading cause of cancer-related deaths globally. The prognosis for patients with advanced metastatic colorectal cancer (mCRC) is extremely poor, with a 5-year survival rate of only 14%. Stomach cancer is one of the most common malignant tumors. Its incidence and mortality rates rank fifth among all malignant tumors globally. Breast cancer is one of the most common malignant tumors in women, ranking first in incidence among female malignant tumors, seriously endangering women's physical and mental health. According to data released by the World Cancer Research Center in 2024, the global incidence of breast cancer was 2.3 million, ranking second among all cancers. Therefore, the above-mentioned cancers have high incidence rates, a large number of patients, short survival times, and low cure rates, creating an urgent need for effective treatments.

[0003] Epidermal growth factor receptor (EGFR) is a member of the HER family. EGFR is a constitutive expressed component of many normal epithelial tissues, such as skin and hair follicles. Furthermore, EGFR is highly expressed in a variety of human malignant tumors: 40%–80% in lung cancer, 33%–74% in gastric cancer, 25%–77% in colorectal cancer, 14%–91% in breast cancer, and 36%–100% in head and neck cancer. EGFR overexpression and / or mutation in most tumors are associated with poor prognosis.

[0004] Antibody-drug conjugates (ADCs) targeting EGFR have become a hot topic in drug development. 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, the most advanced is MRG003 from Meyac, which has entered Phase II clinical trials. CN202211461614.0 discloses an EGFR-targeting antibody-drug conjugate.

[0005] 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.

[0006] ATM is a member of the phosphatidylinositol 3-kinase-related kinases (PIKKs) family and participates in DNA damage responses. ATM is a typical signaling pathway in DNA damage repair, cell cycle arrest, and apoptosis. The kinase activity of ATM is typically specific to serine or threonine residues, followed by glutamine (SQ-TQ motif), and hundreds of ATM substrates have been identified. Double-strand DNA breaks activate ATM, initiating a complex phosphorylation cascade that participates in DNA repair, cell cycle checkpointing, and apoptosis. CN202180066150.0 discloses a selective inhibitor of ataxia-telangiectasia mutated (ATM) protein kinases.

[0007] However, there are no publicly available reports on the combined use of antibody-drug conjugates and ATM inhibitors for cancer treatment. Whether the combination of these antibody-drug conjugates and ATM inhibitors can provide more effective treatment for tumors requires further research.

[0008] Invention Overview

[0009] This invention provides a drug combination or a combined therapy for tumors, comprising or consisting of an antibody-drug conjugate (ADC) and an ATM inhibitor, wherein the ADC is an EGFR-targeting ADC. It also provides a method for treating tumors, comprising administering a therapeutically effective amount of the ADC and the ATM inhibitor to a patient or subject requiring treatment, wherein the ADC is an EGFR-targeting ADC. Furthermore, it provides the use of the ADC in the preparation of a drug for treating tumors in combination with an ATM inhibitor, wherein the ADC is an EGFR-targeting ADC. Compared to monotherapy, the combined administration of the ADC and the ATM inhibitor of this invention 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.

[0010] This invention provides a pharmaceutical combination or a combined medicament for treating tumors, comprising or consisting of: an antibody-drug conjugate of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, and an ATM inhibitor of formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof. A method of treating tumors is also provided, the method comprising administering to a patient or subject requiring treatment a therapeutically effective amount of the antibody-drug conjugate of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof and the ATM inhibitor of formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof. The use of the antibody-drug conjugate of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors in combination with the ATM inhibitor of formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof is also provided. Compared to monotherapy, the present invention combines the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt with the ATM inhibitor of Formula (II) or its stereoisomer or pharmaceutically acceptable salt to further enhance the efficacy of drug therapy for tumors, exhibiting a synergistic effect, and is safe and tolerable, providing a new approach for more effective tumor treatment.

[0011] The antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by formula (I) of the present invention has the following structure:

[0012] 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.

[0013] When n is a decimal, it refers to the average number of linker-drug molecules conjugated to each antibody unit.

[0014] Furthermore, the EGFR-targeting antibody or its antigen-binding fragment includes a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region sequence 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.

[0015] More preferably, the antibody targeting EGFR or its antigen-binding tablet includes a heavy chain variable region (VH) and a light chain variable region (VL), wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7 and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8.

[0016] More preferably, the antibody targeting EGFR or its antigen-binding fragment comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO:9 and the amino acid sequence of the light chain is shown in SEQ ID NO:10.

[0017] Furthermore, the antibody-drug conjugate shown in formula (I) is ADC-1 or its stereoisomer or a pharmaceutically acceptable salt:

[0018] 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.

[0019] In this invention, the amino acid sequence of the antibody CDR is determined using the Kabat numbering rule.

[0020] The ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) of the present invention has the following structure:

[0021] in,

[0022] R1 is independently selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -N(R)1a (R) 1b -C(O)N(R) 1a (R) 1b ), -N(R 1a )C(O)(R 1b ), -S(O)N(R 1a (R) 1b ), -N(R 1a )S(O)(R 1b -SO2N(R) 1a (R) 1b ), -N(R 1a SO2(R) 1b );

[0023] R 1a R 1b Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl;

[0024] m1 and m2 are each independently selected from 0, 1, and 2;

[0025] R2 and R3 are each independently selected from the arbitrarily substituted C. 1-6 Alkyl group; or R2 and R3 together with the nitrogen atom to which they are attached to form an optionally substituted 3-12 membered heterocyclic group; wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently replaced by R. 3a Replaced;

[0026] R 3a Independently selected from deuterium, halogen, hydroxyl, amino, cyano, -R 3b -C(O)R 3b -C(O)OR 3b -N(R) 3b )2、-C(O)NH(R 3b -NHC(O)R 3b ;

[0027] R 3b Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl groups are optionally separated by one or more elements, each independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, C3-6 Substituents include cycloalkyl, 3-6 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups;

[0028] R4 is independently selected from deuterium, halogen, nitro, amino, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally replaced by one or more substituents, each independently selected from deuterium, halogen, hydroxyl, and amino groups;

[0029] R5 is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups;

[0030] L represents CH or N;

[0031] A is

[0032] in, Indicates a single or double bond; Q1 is connected to W;

[0033] t1, t2, t3, t4, t5, and t6 are each independently 0 or 1;

[0034] n1 and n2 are each independently 0 or 1, and n1 and n2 are not both 0 at the same time;

[0035] W is selected from C, O, N, or S;

[0036] Q1 is C; Q2 is C; Q3 is C; when the key connecting one side of Q3 is a double key, R 10 Or R 11 It does not exist;

[0037] R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, -R. 6a -NH(R) 6a ), -N(R 6a (R) 6b ); or R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Any two substituents attached to the same atom can form =O or =NR. 6a =CH-R 6a; or any two adjacent atoms from W, Q1, Q2, and Q3 and their attached substituents together form an atom optionally controlled by one or more R 6c The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 aryl, 5-12 heteroaryl; or any one atom from W, Q1, Q2, and Q3 and its attached substituents together form an aryl group optionally bonded to one or more R groups. 6c The following groups are substituted: C 3-10 cycloalkyl groups, 3-10 membered heterocyclic groups;

[0038] R 6a R 6b Each is independently selected from hydrogen, deuterium, or optionally by one or more R 6c The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 aryl, 5-12 heteroaryl; or R 6a and R 6b Together with the nitrogen atom to which it is attached, they form an optional structure with one or more R atoms. 6c The following groups are substituted: 3-10 membered heterocyclic groups, 5-12 membered heteroaryl groups;

[0039] R 6c Independently selected from deuterium, halogen, hydroxyl, amino, -R 6d -OR 6d -N(R) 6d )2、-C(O)R 6d -C(O)N(R) 6d )2、-N(R 6d )C(O)R 6d -C(O)OR 6d ;

[0040] R 6d Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl;

[0041] The heteroatoms in the heteroaryl and heterocyclic groups are independently selected from O, N, and S, and the number of heteroatoms is 1, 2, 3, or 4.

[0042] In some implementation schemes, R 1a R 1b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 3-4Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl.

[0043] In some implementation schemes, R 1a R 1b Each is independently selected from hydrogen, methyl, ethyl, cyclopropyl, and phenyl.

[0044] In some implementations, R1 is independently selected from halogens, amino groups, and C. 1-3 Alkyl, -NH(R) 1b ), -NHC(O)(R 1b ),-NHSO2(R 1b ).

[0045] In some implementations, R1 is independently selected from -F, -Cl, -Br, -NH2, -CH3, -CH2CH3, -NHC(O)CH3, -C(O)NHCH3,

[0046] In some implementations, m1 is selected from 0 or 1; preferably 0.

[0047] In some implementations, m2 is selected from 0 or 1; preferably 0.

[0048] In some implementations, R2 and R3 are each independently selected from optional alternatives of C. 1-6 Alkyl group; or R2 and R3 together with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered heterocyclic group; the optional substitution means that it is optionally substituted by one or more R groups. 3a What it replaced.

[0049] In some implementations, R2 and R3 are each independently selected from optional alternatives of C. 1-4 Alkyl group; or R2 and R3 together with the nitrogen atom to which they are attached to form an optionally substituted 5-6 membered heterocyclic group; the optional substitution means that it is optionally substituted by one or more R groups. 3a What it replaced.

[0050] In some implementations, R2 and R3 are each independently selected from optional alternatives of C. 1-3 Alkyl group (e.g., methyl); or R2 and R3 together with the nitrogen atom to which they are attached to form an optionally substituted 5-6 membered heterocyclic group; wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1, 2 or 3; the optional substitution means optionally being substituted by one or more R... 3a What it replaced.

[0051] In some embodiments, R2, R3, and the nitrogen atom to which they are attached together form the following groups: Preferred

[0052] In some implementation schemes, R 3a Independently selected from deuterium, halogens (e.g., fluorine, chlorine, bromine), hydroxyl, amino, cyano, -R 3b -C(O)R 3b -C(O)OR 3b -N(R) 3b )2、-C(O)NH(R 3b -NHC(O)R 3b ;

[0053] R 3b Independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally replaced by one or more substituents, each independently selected from deuterium, halogens (e.g., fluorine, chlorine, bromine), hydroxyl, and amino groups.

[0054] In some implementation schemes, R 3a It is independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, -NH(CH3), -N(CH3)(CH3), -C(O)NH2, -CH3, -CH2CH3, -CH2CH2CH3.

[0055] In some implementations, R4 is independently selected from halogens, amino groups, and C. 1-6 Alkyl groups; preferably fluorine, chlorine, or methoxy groups.

[0056] In some implementations, R5 is independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl; preferably methyl.

[0057] In some implementation schemes, R 6a R 6b Each is independently selected from hydrogen, deuterium, or optionally by one or more R 6c The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; or R 6a and R 6b Together with the nitrogen atom to which it is attached, they form an optional R 6c The following groups are substituted: 3-6 membered heterocyclic groups and 5-6 membered heteroaryl groups.

[0058] In some implementation schemes, R 6a R 6b Each is independently selected from hydrogen or optionally by one or more R 6c The following groups are substituted: C1-3 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl), C 1-3 Alkyl groups (e.g., methoxy, ethoxy, n-propoxy, isopropoxy).

[0059] In some implementation schemes, R 6c Independently selected from deuterium, fluorine, chlorine, hydroxyl, amino, -NH(C 1-6 Alkyl), -N(CH3)(C 1-6 Alkyl), -C(O)(C 1-6 Alkyl), -C(O)NH(C 1-6 Alkyl), -NHC(O)(C 1-6 Alkyl), -C(O)O(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl.

[0060] In some implementation schemes, R 6c Independently selected from deuterium, deuterium, halogen, hydroxyl, amino, C 1-3 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl), C 1-3 Alkyl groups (e.g., methoxy, ethoxy, n-propoxy, isopropoxy).

[0061] In some implementation schemes, R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally by one or more R. 6c The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; R 6c Independently selected from deuterium, halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)(C 1-6 Alkyl), -C(O)NH(C 1-6 Alkyl), -NHC(O)(C 1-6 Alkyl), -C(O)O(C 1-6 Alkyl), C 3-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl.

[0062] In some implementation schemes, R6, R7, R8, R9, R 10 R 11R 12 and R 13 Each time it appears, it is independently selected from hydrogen or arbitrarily selected by one or more R. 6c The following groups are substituted: C 1-3 Alkyl, C 1-3 Alkoxy; R 6c Independently selected from halogens, hydroxyl groups, amino groups, and C 1-3 Alkyl, C 1-3 Alkyl group.

[0063] In some implementations, the sum of n1 and n2 is 1 (i.e., n1 is 1 and n2 is 0; or n1 is 0 and n2 is 1).

[0064] In some implementations, W is selected from O and S; O is preferred.

[0065] In some embodiments, any two adjacent atoms of W, Q1, Q2, and Q3 and their attached substituents together form an array optionally bounded by one or more R atoms. 6c The following groups are substituted: C 5-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl.

[0066] In some implementations, any two adjacent atoms of W, Q1, Q2, and Q3, together with their attached substituents, form the following group:

[0067] In some embodiments, any one of W, Q1, Q2, and Q3 and its attached substituents together form an atom optionally bonded to one or more R atoms. 6c The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic group; preferably, any one atom of W, Q1, Q2 and Q3 and the substituents attached thereto form an optional R group. 6c The following groups are substituted: C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups; further, any one atom of W, Q1, Q2, and Q3 and its attached substituents together form an optional R group. 6c The following groups are substituted: C 3-4 Cycloalkyl groups, 3-6 membered heterocyclic groups, wherein the heteroatom in the heterocyclic group is selected from O, N, S, and the number of heteroatoms is 1 or 2.

[0068] In some implementations, any one of W, Q1, Q2, and Q3 and its attached substituents together form the following group:

[0069] In some embodiments, the ATM inhibitor represented by formula (II) is a compound or its stereoisomer or a pharmaceutically acceptable salt having the following structure:

[0070] In some embodiments, the ATM inhibitor represented by formula (II) is compound 1 or its stereoisomer or a pharmaceutically acceptable salt:

[0071] On one hand, the present invention provides a drug combination or a drug for the combined treatment of tumors, comprising or consisting of: an antibody-drug conjugate of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and an ATM inhibitor of formula (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0072] On the other hand, the present invention provides the use of the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof and the ATM inhibitor of Formula (II) or its stereoisomer or pharmaceutically acceptable salt thereof in combination in the preparation of a medicament for treating tumors.

[0073] Thirdly, the present invention 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) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and an ATM inhibitor of formula (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0074] Fourthly, the present invention provides the use of the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors in combination with the ATM inhibitor of Formula (II) or its stereoisomer or pharmaceutically acceptable salt thereof.

[0075] Fifthly, the present invention provides a combination or combination of the above-mentioned drugs for treating tumors.

[0076] In some embodiments, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) 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, or they can be separately prepared into clinically acceptable dosage forms and packaged into the drug. That is, the drug of the present invention not only includes a compound pharmaceutical formulation (single formulation), but also includes a combination drug package or kit product (packaged together), and also includes separately prepared into clinically acceptable dosage forms (including kits), separately packaged into the drug, for combined use. The compound pharmaceutical formulation contains, in one dosage unit, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II), and is formulated into a clinically acceptable dosage form. In the aforementioned combination drug package or kit product, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) are respectively prepared into clinically acceptable pharmaceutical formulations. That is, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) are respectively contained in different formulation units and presented in the form of a combination package, optionally including instructions for use according to any of the uses or methods described in this disclosure. In the combined use of the two products or kit products (including cases where at least one of the two products is a kit product), the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt and the ATM inhibitor of Formula (II) or its stereoisomer or pharmaceutically acceptable salt are respectively prepared into clinically acceptable pharmaceutical formulations, i.e., the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt and the ATM inhibitor of Formula (II) or its stereoisomer or pharmaceutically acceptable salt are respectively contained in different formulation units and presented in separate packages, optionally including instructions for use according to any of the uses or methods described in this disclosure. The kit may also include instructions for selecting individuals suitable for treatment (e.g., how to combine the compound of Formula (I) and / or the compound of Formula (II) and its stereoisomer or pharmaceutically acceptable salt form and at least one other anticancer agent into a single dose form, the cancer types to which the kit is applicable, the frequency of administration of the compound of Formula (I) or Formula (II) or its pharmaceutically acceptable form as a single or combined dose form, and other information related to co-administration). The kit may optionally include other components, such as buffer solutions and instructions.The instructions provided with the kits disclosed herein are generally written instructions on a label or packaging insert (e.g., a single sheet of paper included in the kit), but machine-readable instructions (e.g., instructions carried on a disk or optical disc) are also acceptable. The antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II) may be in the same or different formulations.

[0077] In some embodiments, the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt and the ATM inhibitor of Formula (II) or its stereoisomer or pharmaceutically acceptable salt are respectively formulated into clinically acceptable dosage forms and packaged together or separately as said drugs. Preferably, the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt is a lyophilized powder for injection or an injection solution, and the ATM inhibitor of Formula (II) or its stereoisomer or pharmaceutically acceptable salt is a solid oral dosage form (such as tablets or capsules), a lyophilized powder for injection, or an injection solution. More preferably, the ATM inhibitor of Formula (II) is a tablet.

[0078] In some embodiments, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II) can be administered simultaneously or separately. That is, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II) can be contained in the same compound formulation unit and administered simultaneously. Alternatively, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II) can 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 at clinically acceptable time intervals according to the respective dosing frequencies and cycles of the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II). The antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II) are not particularly restricted in their order of administration and can be used as a first or second treatment as needed clinically. Simultaneous or concurrent administration means that the first and second treatments are started simultaneously, or that the first treatment is still being delivered when the second treatment is started.

[0079] In some embodiments, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt as shown in Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt as shown in Formula (II) are administered at their respective frequencies and cycles.

[0080] In some embodiments, the mass ratio of the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by formula (I) to the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) is selected from (1-100):(1-100), such as (1-50):(1-50), (1-30):(1-30), (1-10):(1-100). ), (1-10):(1-50), 1:(1-50), 1:(1-40), 1:(1-35), 1:(1-30), 1:(1-25), 1:(1-20), 1:(1-15), 1:(1-10), 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 3:1, 5:1, 6:1, 7:1, 9:1, 10:1. Preferred 1:(1-30), 1:(1-20), 1:(1-10), further preferred 1:30, 1:20, 1:6, 1:2.

[0081] In some embodiments, when the drug of the present invention is a drug combination composition (i.e., a compound drug formulation (single formulation)), a combination drug pack, or a kit product, the mass ratio of the therapeutically effective amount (or per-cycle dose) of the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) is selected from (1-100):(1-100), such as (1-5). 0):(1-50), (1-30):(1-30), (1-10):(1-10), (1-10):(1-50), 1:(1-50), 1:(1-40), 1:(1-35), 1:(1-30), 1:(1-25), 1:(1-20), 1:(1-15), 1:(1-10), 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1. Preferably 1:(1-30), 1:(1-20), 1:(1-10), further preferably 1:30, 1:20, 1:6, 1:2, 3:1, 5:1, 6:1, 7:1, 9:1, 10:1.

[0082] In this invention, unless otherwise stated, the mass of the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by formula (I) is based on the antibody-drug conjugate represented by formula (I); the mass of the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) is based on the ATM inhibitor represented by formula (II).

[0083] The mass ratio range of the above form (AB):(CD) includes any ratio m:n within this range, where m is any value in the range AB and n is any value in the range CD. m and n can be coprime or non-coprime. For example, (1-100):(1-100) includes 3:97, 30:50, or 70:20, etc.

[0084] In some embodiments, the therapeutically effective amount (based on the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof, in mg and kg, 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, and about 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, approximately 14 mg / kg; preferably 2 mg / kg-10 mg / kg; more preferably 2.8 mg / kg-4.8 mg / kg, such as approximately 2.8 mg / kg, approximately 3 mg / kg, approximately 3.2 mg / kg, approximately 3.6 mg / kg, approximately 4.0 mg / kg, approximately 4.8 mg / kg.

[0085] In some embodiments, the therapeutically effective amount of the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) is the conventional amount of the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II).

[0086] In some embodiments, the therapeutically effective amount of the ATM inhibitor represented by formula (II) or its stereoisomer or pharmaceutically acceptable salt is 1 mg-1000 mg / day, 10 mg-400 mg / day, such as about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 1 30 mg / day, approximately 140 mg / day, approximately 150 mg / day, approximately 160 mg / day, approximately 170 mg / day, approximately 180 mg / day, approximately 190 mg / day, approximately 200 mg / day, approximately 300 mg / day, approximately 400 mg / day; preferably 10 mg-400 mg / day; more preferably 20 mg-200 mg / day; even more preferably 20 mg-80 mg / day, such as 20 mg / day, approximately 40 mg / day, approximately 60 mg / day, approximately 80 mg / day.

[0087] In some embodiments, the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt and / or the ATM inhibitor of Formula (II) or its stereoisomer or pharmaceutically acceptable salt may be administered once daily (QD), or the therapeutically effective dose may be divided into multiple doses throughout the day, such as twice daily (BID) or three times daily (TID). It may be administered once weekly (QW), or the therapeutically effective dose may be divided into multiple doses throughout the week, such as twice weekly (BIW) or three times weekly (TIW). It may be administered once every two weeks (Q2W), or the therapeutically effective dose may be divided into multiple doses throughout the two weeks, such as twice every two weeks (BI2W) or three times every two weeks (TI2W). It may be administered once every three weeks (Q3W), or the therapeutically effective dose may be divided into multiple doses throughout the three weeks, such as twice every three weeks (BI3W, such as administration on D1 and D8, every three-week cycle) 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 (BIM) or three times a month (TIM). It can also be administered at intervals, such as once every 2-7 days, or once every 2, 3, 4, 5, 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. Exemplary administration methods include: administering once on day 1 of each 3-week cycle; or administering once on day 1 and day 8 of each 3-week cycle; or administering once on day 1 of each 2-week cycle.

[0088] In some embodiments, the antibody-drug conjugate of formula (I) or its stereoisomer or pharmaceutically acceptable salt may be administered once every 3 weeks (Q3W), with a 3-week cycle; once on days 1 and 8 of each cycle, with a 3-week cycle (D1D8 Q3W); or once every 2 weeks (Q2W), with a 2-week cycle.

[0089] In some embodiments, the ATM inhibitor represented by formula (II), or its stereoisomer or a pharmaceutically acceptable salt thereof, may be administered orally for 5 consecutive days, followed by a 2-day rest period, repeated weekly; or orally for 4 consecutive days, followed by a 3-day rest period, repeated weekly; or orally for 3 consecutive days, followed by a 4-day rest period, repeated weekly; or orally for 5 consecutive days, repeated per cycle; or orally for 4 consecutive days, repeated per cycle; or orally for 3 consecutive days, repeated per cycle; or orally for 5 consecutive days, starting in the second week of each cycle; further preferably, once daily (QD). In this document, unless otherwise stated, the term "cycle" in "repeated per cycle" refers to the entire cycle of combined administration.

[0090] In some embodiments, the ATM inhibitor represented by formula (II), or its stereoisomer or a pharmaceutically acceptable salt thereof, may be administered once daily (QD) for 5 consecutive days, followed by a 2-day rest period, repeated weekly; or once daily for 4 consecutive days, followed by a 3-day rest period, repeated weekly; or once daily for 3 consecutive days, followed by a 4-day rest period, repeated weekly; or once daily for 5 consecutive days, repeated every 2 weeks (i.e., a 2-week cycle); or once daily for 5 consecutive days, repeated every 3 weeks (i.e., a 3-week cycle). The dosage can be taken once daily for 5 consecutive days, repeated every 4 weeks (i.e., one cycle of 4 weeks); or once daily for 4 consecutive days, repeated every 2 weeks; or once daily for 4 consecutive days, repeated every 3 weeks; or once daily for 4 consecutive days, repeated every 4 weeks; or once daily for 3 consecutive days, repeated every 2 weeks; or once daily for 3 consecutive days, repeated every 3 weeks; or once daily for 3 consecutive days, repeated every 4 weeks; or once daily for 5 consecutive days, followed by a 2-day break, starting in the second week of each cycle. Alternatively, the above-mentioned therapeutically effective dose can be divided into multiple administrations throughout the day, such as twice daily (BID) or three times daily (TID).

[0091] In some embodiments, the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt may be administered once every three weeks (Q3W), and the ATM inhibitor of Formula (II) or its stereoisomer or pharmaceutically acceptable salt may be administered once daily (QD).

[0092] In some embodiments, the preferred dosing regimen is the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt as shown in Formula (I): 2.8-4.8 mg / kg (e.g., about 2.8 mg / kg, about 3.0 mg / kg, about 3.2 mg / kg, about 3.6 mg / kg, about 4.0 mg / kg, or about 4.5 mg / kg); once every 3 weeks (Q3W), for a 3-week cycle; or once on days 1 and 8 of each cycle, for a 3-week cycle (D1, D8, Q3W); or Once every 2 weeks (Q2W), one cycle is 2 weeks; combined with ATM inhibitors as shown in formula (II): 20-80 mg / day (e.g., about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day); once daily for 5 consecutive days, followed by a 2-day rest, repeated weekly; or once daily for 5 consecutive days, repeated per cycle; or once daily for 4 consecutive days, repeated per cycle; or once daily for 3 consecutive days, repeated per cycle; or once daily for 5 consecutive days, repeated per cycle.

[0093] In some embodiments, the antibody-drug conjugate of formula (I) or its stereoisomer or pharmaceutically acceptable salt may be a lyophilized powder for injection or an injection solution, and the ATM inhibitor of formula (II) or its stereoisomer or pharmaceutically acceptable salt may be a solid oral dosage form (such as a tablet or capsule) or an injection solution. More preferably, the ATM inhibitor of formula (II) or its stereoisomer or pharmaceutically acceptable salt may be a tablet.

[0094] In some embodiments, the administration may be oral or injectable. Preferably, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by formula (I) is administered by injection, and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) is administered orally.

[0095] In some embodiments, the tumor is a solid tumor, adenocarcinoma, or squamous cell carcinoma, such as lung cancer, breast cancer, gastrointestinal tumors, and head and neck cancer; preferably, the lung cancer is selected from non-small cell lung cancer (NSCLC) and small cell lung cancer, the gastrointestinal tumor is selected from esophageal cancer (including cancers of the gastroesophageal junction), gastric cancer (including cancers of the gastrointestinal junction), and colorectal cancer (such as advanced metastatic colorectal cancer), and the head and neck cancer is selected from nasopharyngeal carcinoma.

[0096] In some implementations, the solid tumor is an advanced solid tumor, such as stage IIIB, IIIC, or IV, or is unsuitable for surgical resection or radical chemoradiotherapy, or has failed previous standard treatment, or is locally advanced or metastatic, or expresses or abnormally expresses EGFR (e.g., EGFR positive, overexpressed, high-expressed, intermediate-expressed, low-expressed, non-expressed, deleted, amplified, or mutated), or has previously received adjuvant / neo-effective adjuvant chemotherapy and the disease progressed 6 months after the end of treatment, or is a cancer carrying at least one EGFR-sensitive mutation (ex19del or L858R, which may be combined with other EGFR mutations).

[0097] In some implementations, the tumor is an EGFR target-related tumor, such as one that expresses or aberrantly expresses EGFR, such as an EGFR-positive, overexpressing, high-expressing, moderately-expressing, low-expressing, non-expressing, deleted, amplified, or mutated tumor.

[0098] In some implementations, the tumor is adenocarcinoma.

[0099] In some implementations, the tumor is squamous cell carcinoma.

[0100] The present invention combines the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt with the ATM inhibitor of Formula (II), which can produce a synergistic effect through complementary mechanisms, thereby enhancing the activity of the effective payload. The antibody-drug conjugate of Formula (I), its stereoisomer or pharmaceutically acceptable salt, binds to the EGFR receptor on the surface of tumor cells, internalizes and releases small toxic molecules, induces DNA damage, and thus induces apoptosis. The ATM inhibitor of Formula (II) can inhibit the repair of DNA damage, leading to persistent DNA double-strand breaks. It is expected to enhance the sensitivity of the antibody-drug conjugate of Formula (I), such as ADC-1, to DNA damage, overcome drug resistance, and improve its efficacy. Combined administration can significantly inhibit tumor growth (especially lung cancer, gastric cancer, colorectal cancer, and breast cancer), showing a significantly greater tumor-suppressive effect compared to single-agent therapy, achieving a synergistic effect. Furthermore, clinical studies have verified that the antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt, in combination with the ATM inhibitor of Formula (II) or its stereoisomer or pharmaceutically acceptable salt, can effectively treat advanced malignant tumors, bringing clinical benefits superior to existing treatments to patients with metastatic, previously treated, multi-drug chemotherapy, or immunotherapy-failed advanced solid tumors, and their condition can be controlled or alleviated.

[0101] It should be understood that the aspects and embodiments of the invention described herein include those described as "comprising," "forming," and "consisting substantially of." Preferred embodiments of the invention have been described in detail above; however, the invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as part of the disclosure of this invention and are all within the protection scope of this invention.

[0102] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0103] Invention Details

[0104] the term

[0105] The terms “optional,” “arbitrary,” “optionally,” or “arbitrarily” mean that the event or condition described below may, but is not required, occur, and the description includes both the occurrence of said event or condition and the non-occurrence of said event or condition.

[0106] "Optionally substituted by one or more substituents selected independently from..." or "Optionally substituted by one or more..." means 2, 3, 4, 5, 6, 7, 8, 9 or 10; preferably 2, 3 or 4; more preferably 2.

[0107] Unless otherwise specified, the term "alkyl" refers to a straight-chain or branched, saturated aliphatic hydrocarbon group that may contain 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl group). For example, "C 1-6 "Alkyl" means that the group is alkyl and the number of carbon atoms on the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5, or 6). Exemplary examples of alkyl groups include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0108] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, wherein the alkyl group as defined above may contain 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl groups). For example, "C 1-6"Alkoxy" refers to a group that is an alkoxy group and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Exemplary examples of alkoxy groups include (but are not limited to) methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0109] Unless otherwise specified, the terms “halogen” or “halogenated” refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0110] Unless otherwise specified, the term "haloalkyl" refers to a group formed by substituting one, two, more, or all of the hydrogen atoms of an alkyl group as defined above with a halogen. Exemplary examples of haloalkyl groups include (but are not limited to) -CCl3, -CF3, -CHCl2, -CH2Cl, -CH2Br, -CH2I, -CH2CF3, -CF2CF3, etc.

[0111] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic or polycyclic, saturated or partially unsaturated, aliphatic hydrocarbon group that may contain 3 to 12 carbon atoms (i.e., C64-C64). 3-12 cycloalkyl groups, preferably containing 3-10 carbon atoms (i.e., C64-C ... 3-10 Cycloalkyl groups, more preferably containing 3-7 carbon atoms (i.e., C64-C75-C ... 3-7 cycloalkyl groups), 4-6 carbon atoms (i.e., C64) 4-6 cycloalkyl groups or 5-6 carbon atoms (i.e., C64) 5-6 cycloalkyl). For example, "C 3-10 "Cycloalkyl" means that the group is cycloalkyl and the number of carbon atoms on the carbon ring is between 3 and 10 (specifically 3, 4, 5, 6, 7, 8, 9, or 10). Exemplary examples of cycloalkyl include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethylcyclopentyl, dimethylcyclobutyl, etc.

[0112] Unless otherwise specified, the term "heterocyclic" or "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure containing 3-20 ring atoms, wherein one, two, three, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0113] Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a monocyclic or polycyclic aromatic carbocyclic hydrocarbon group that may contain 6-16 ring carbon atoms (i.e., C16-C16). 6-16 aryl), 6-14 ring carbon atoms (i.e., C 6-14 aryl), 6-12 ring carbon atoms (i.e., C 6-12 aryl group or 6-10 ring carbon atoms (i.e., C46) 6-10 Aryl). In some embodiments, the term "aryl" may be used interchangeably with the term "aromatic ring". Exemplary examples of aryl include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, pyrene, etc.

[0114] Unless otherwise specified, the term "heteroaryl" or "heterocyclic aromatic group" refers to a monocyclic or polycyclic aromatic group that may contain 5-14 ring atoms (i.e., 5-14-membered heteroaryl), 5-10 ring atoms (i.e., 5-10-membered heteroaryl), 5-8 ring atoms (i.e., 5-8-membered heteroaryl), or 5-6 ring atoms (i.e., 5-6-membered heteroaryl), wherein one, two, three, or more ring atoms are heteroatoms, independently selected from O, N, or S, and the remaining ring atoms are C. In some embodiments, the term "heteroaryl" may be used interchangeably with the term "heterocyclic aromatic group." Exemplary examples of heteroaryl groups include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzeneyl. Pyrazinyl, benzimidazolyl, benziphthalazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0115] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within reasonable medical judgment, is suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0116] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and blocked isomers. Any mixture of stereoisomers obtained may be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization. The compounds and pharmaceutically acceptable salts described in this specification may include one or more chiral (i.e., asymmetric) centers. If a structure or chemical name in this specification does not indicate chirality, the structure or name is intended to include any single stereoisomer (i.e., any single chiral isomer) corresponding to that structure or name, as well as any mixture of stereoisomers (e.g., racemic mixtures). In some embodiments, a single stereoisomer is obtained by separating it from a mixture of isomers (e.g., racemates) using, for example, chiral chromatography. In other embodiments, the single stereoisomer is obtained, for example, by direct synthesis from chiral starting materials.

[0117] Unless otherwise specified, the compounds of this invention and pharmaceutically acceptable salts also include their "isotope derivatives". The term "isotope derivative" refers to compounds of this invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotope derivatives may, for example, be selected from deuterated derivatives. Isotopes can be radioactive or non-radioactive isotopes. Commonly used isotopes for isotope labeling are: hydrogen isotopes: 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O、 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0118] Unless otherwise specified, the antibody-drug conjugates targeting EGFR described in this invention also include Akalux (cetuximab sarotalocan) from Lotte Medical, Depatuxizumab Mafodotin (ABT-414, Depatux-M) and ABBV-221 from AbbVie, AVID100 from Forbius, MRG003 from Mead Johnson, BB-1705 from Bausch & Lomb, HLX4 from Henlius Biotech, LR-DM1 from the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, RC68 (MC-VC) and RC68 (PY-VC) from Rongchang Biotech, and SHR-A1307 from Hengrui Medicine. Baili Tianheng's BL-B01D1, AstraZeneca's AZD9592, Merck's M1231, Innovent Biologics' IBI3001, Aikeruisi's ADC2313, Biocytogen / Doma Pharma's BCG011, Biocytogen's BCG019 and YH013, Promis / Hansen Pharmaceutical's PM1080-ADC, Pufang Bio's PRO-1286, Simcere Pharmaceutical's SIM0618, and Chengfan Pharma's VBC101-F11.

[0119] Unless otherwise specified, the ATM inhibitors described in this invention also include AstraZeneca's AZD1390, AZD0156, AZ31, and AZ32; Merck's M4076 (Lartesertib) and M3541; Xrad Therapeutics Inc.'s XRD-0394; ZN-B-2262 from Zanrong Pharmaceuticals; WSD0628 from Weishang Biotechnology; atipeksen from the Korea Advanced Institute of Science and Technology; CGK733 from the Korea Advanced Institute of Science and Technology; A011 from Sichuan University; CP466722 from Pfizer; IMP08 from Yingpai Pharmaceuticals; and KU-55933, KU-59403, and KU-60019 from KuDos Pharmaceuticals.

[0120] The drugs and their combinations described in this invention include any two of the aforementioned antibody-drug conjugates targeting EGFR and ATM inhibitors.

[0121] Unless otherwise specified, the compounds of this invention and pharmaceutically acceptable salts also include their "solvates" or "solvents". The terms "solvate" or "solvent" refer to the physical association of the compounds of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. Solvent molecules in a solvate may be present in a regular and / or disordered arrangement. Solvates may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art. The term "hydrate" refers to a substance in which water molecules are bonded to cations or anions in a compound by coordinate or covalent bonds, or to a substance in which water ions do not directly bond to cations or anions but exist in a certain proportion at defined positions in a solid crystal lattice.

[0122] Unless otherwise specified, the compounds of this invention and pharmaceutically acceptable salts also include their "prodrugs". The term "prodrug" refers to a drug that is converted into a parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are generally related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include metabolism that is too rapid or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable orally, whereas the parent drug cannot. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited thereto, can be any compound of this invention administered as an ester ("prodrug") to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and which is subsequently metabolized and hydrolyzed into a carboxylic acid, i.e., the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.

[0123] 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 the patient or subject after the condition has been diagnosed and before the condition has been cured or eliminated or treatment has been 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, so there is 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 of these situations, 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 relief of symptoms, or a similar effect is observed with the first treatment. In some embodiments, the delivery results in greater relief of symptoms or other parameters related to the condition 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.

[0124] 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.

[0125] 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.

[0126] The terms "subject" or "patient" are intended to include animals that are capable of having or suffering from malignant neoplastic diseases. Examples of subjects or patients include mammals such as humans, monkeys, dogs, cattle, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the subject is a human, such as a human with a malignant neoplastic disease, at risk of having a malignant neoplastic disease, or potentially capable of having a malignant neoplastic disease.

[0127] The term "therapeutic effect" refers to a beneficial local or systemic effect in animals, such as mammals (e.g., humans), resulting from the application of the compounds or compositions of this disclosure. The phrase "therapeutic effective amount" refers to the amount of the compounds or compositions 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.

[0128] The terms "combination therapy" or "combination therapy" refer to a dosing regimen that requires the administration of at least two different compounds to a patient or subject. These at least two different compounds may be administered simultaneously or concurrently, or sequentially at different times within a day at clinically acceptable intervals, or administered at clinically acceptable intervals according to the respective dosing frequencies and cycles of the antibody-drug conjugate of Formula (I) and the ATM inhibitor of Formula (II). The dosing regimens of the at least two compounds may, but are not required to, overlap.

[0129] The terms "co-administration" or "combined use" refer to the simultaneous exposure of 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 (in completely non-overlapping dosing regimens); in some embodiments, two or more compounds may be administered in 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. In some embodiments, the compounds to be co-administered are individual dosage forms, packaged separately as said medicines, and used in combination.

[0130] 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.

[0131] 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.

[0132] The antibody-drug conjugate (including specific ADC drugs) of formula (I) of the present invention, or its stereoisomers or pharmaceutically acceptable salts, and the preparation methods thereof are disclosed in patent applications CN116135232A and WO2023088382A1, the entire contents of which are incorporated herein by reference.

[0133] The ATM inhibitors (including specific compounds) of formula (II) of the present invention, or their stereoisomers or pharmaceutically acceptable salts, and methods for their preparation are disclosed in patent applications CN116322699A and WO2022063303A1, the entire contents of which are incorporated herein by reference.

[0134] It should be understood that this invention 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 the invention. Other aspects, improvements, and modifications within the scope of this invention will be apparent to those skilled in the art. Therefore, those skilled in the art should recognize that the scope of the invention also includes the improvements and modifications to the said aspects and embodiments. Example

[0135] The ADC-1 used in the following examples was prepared according to the method disclosed in WO2023088382A1:

[0136] ADC-1:

[0137] 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.

[0138] Compound 1 used in the following examples was prepared according to the method disclosed in WO2022063303A1:

[0139] Compound 1:

[0140] Example 1: Efficacy study of ADC-1 combined with compound 1 in a human non-small cell lung cancer NCI-H1975 xenograft model

[0141] 1. Laboratory animals

[0142] NU / NU female mice, 6-7 weeks old, 48 mice.

[0143] 2. Experimental Objective

[0144] In this experiment, a xenograft tumor model was constructed by subcutaneously inoculating the right forelimb axilla of NU / NU female mice with human lung adenocarcinoma cell line NCI-H1975, and the inhibitory effect of ADC-1 combined with ATM inhibitor compound 1 on tumor was investigated.

[0145] 3. Drug dosage and grouping

[0146] Table 1: Animal Grouping and Dosage Table Note: iv: intravenous injection; ig: gavage administration.

[0147] 4. Test Methods

[0148] NCI-H1975 cell suspension was subcutaneously inoculated into the axilla of the right forelimb of mice at a volume of 0.1 mL per mouse, containing approximately 1 × 10⁻⁶ tumor cells. 7 A NU / NU mouse NCI-H1975 xenograft model was established. When the mouse tumor volume reached 130 mm², the xenograft was successfully developed. 3 At approximately 10:00 AM, animals were evenly divided into the following groups according to tumor size: a solvent control (Vehicle) group, an ADC-1 0.3 mg / kg (qw×3, once a week for 3 weeks) group, an ADC-1 1 mg / kg (single, single dose) group, a compound 1 6 mg / kg (qd×21, once a day for 21 days) group, a combination of compound 1 0.3 mg / kg (qw×3) and compound 1 6 mg / kg (qd×21) group, and a combination of ADC-1 1 mg / kg (single) and compound 1 6 mg / kg (qd×21) group. Compound 1 was administered by gavage, and ADC-1 was administered via tail vein. The animals were observed for 21 days after grouping.

[0149] 5. Evaluation Indicators

[0150] 5.1 Tumor volume assessment

[0151] (1) Tumor volume: V = 1 / 2 × A × B 2

[0152] (2) Tumor suppression rate:

[0153] Note: V: Tumor volume

[0154] A: Tumor growth

[0155] B: Tumor width

[0156] TV Xn Mean tumor volume on day n in the treatment group

[0157] TV X0 Mean tumor volume on day 0 in the treatment group

[0158] TV Mn Mean tumor volume on day n in the solvent group

[0159] TV M0 Average tumor volume on day 0 in the solvent group

[0160] 5.2 Evaluation of tumor weight and drug synergistic effect

[0161] At the end of the experiment, the animals were euthanized by dislocation, and the tumors were removed and weighed.

[0162] (1) Tumor weight inhibition rate % = (1 - tumor weight in the drug treatment group / tumor weight in the solvent group) × 100%

[0163] (2) Evaluation of drug synergy: Burgi modified formula [1]: Q=E(a+b) / [E(a)+E(b)-E(a)*E(b)]

[0164] Q<0.85 antagonism

[0165] Adding 0.85 ≤ Q ≤ 1.15

[0166] Q>1.15 Collaboration

[0167] E(a+b): Tumor weight inhibition rate after combined administration of drugs a and b

[0168] E(a): Tumor weight inhibition rate when a is administered alone.

[0169] E(b): Tumor weight inhibition rate when b is administered alone.

[0170] 6 Results

[0171] Based on tumor volume data, both ADC-1 monotherapy groups significantly inhibited tumor growth compared to the Vehicle group (P<0.001). Compared to ADC-1 monotherapy, both ADC-1 combination therapy groups significantly enhanced the inhibitory effect of ADC-1 on tumor growth (P<0.001). Based on tumor weight data, both ADC-1 monotherapy groups also significantly inhibited tumor growth compared to the Vehicle group (P<0.001). The combination therapy groups of both ADC-1 and ATM inhibitor (compound 1) significantly increased the tumor inhibition rate compared to the individual ADC-1 and compound 1 monotherapy groups, respectively, and all showed synergistic effects (Q>1.15).

[0172] Table 2: Tumor parameters of each group on day 21 after drug administration Note: ***P<0.001 compared with the vehicle group; ▲▲▲ P < 0.001 compared with the ADC-1 0.3 mg / kg (qw*3) group;◆◆◆ P < 0.001 compared with the ADC-1 1 mg / kg (singledose) group; ###P < 0.001 compared with compound 1 group.

[0173] Example 2: Efficacy study of ADC-1 combined with compound 1 in a human non-small cell lung cancer NCI-H1975 xenograft model

[0174] 1. Laboratory animals

[0175] NU / NU female mice, 6–7 weeks old, 24 mice.

[0176] 2. Experimental Objective

[0177] In this experiment, a xenograft tumor model was constructed by subcutaneously inoculating the right forelimb axilla of NU / NU female mice with human lung adenocarcinoma cell line NCI-H1975, and the inhibitory effect of ADC-1 combined with ATM inhibitor compound 1 on tumor was investigated.

[0178] 3. Drug dosage and grouping

[0179] Table 3: Animal Grouping and Dosage Table Note: iv: intravenous injection; ig: gavage administration.

[0180] 4. Test Methods

[0181] Twenty-four female NU / NU mice were subcutaneously inoculated with NCI-H1975 cell suspension in the axilla of their right forelimb. The inoculation volume was 0.1 mL per mouse, containing approximately 1 × 10⁻⁶ tumor cells. 7 A NU / NU mouse NCI-H1975 xenograft model was established. When the mouse tumor volume reached 118.3 mm... 3 At approximately 10:00 AM, animals were evenly divided into the following groups according to tumor size: a solvent control (Vehicle) group, an ADC-1 0.3 mg / kg (qw×2) group, a compound 1 6 mg / kg (qd(5d on, 2d off)) group, and an ADC-1 + compound 1 group (ADC-1 + compound 1) group (ADC-1 + compound 1). Compound 1 was administered by gavage, and ADC-1 was administered via tail vein. The animals were observed for 21 days after grouping.

[0182] 5. Evaluation indicators (same as in Example 1)

[0183] 6 Results

[0184] Based on tumor volume data, compared with the Vehicle group, ADC-1 monotherapy significantly inhibited tumor growth (P<0.001); compared with ADC-1 monotherapy, the combination of ADC-1 and the ATM inhibitor (compound 1) significantly enhanced the inhibitory effect of ADC-1 on tumor growth (P<0.001); based on tumor weight data, compared with the Vehicle group, ADC-1 also significantly inhibited tumor growth (P<0.05), and the combination of ADC-1 and the ATM inhibitor (compound 1) synergistically inhibited tumor growth (Q>1.15).

[0185] Table 4: Tumor parameters of each group on day 21 after drug administration Note: *P<0.05, **P<0.01, ***P<0.001 are compared with the vehicle group; #P<0.05, ##P<0.01 are compared with the ADC-1 group; △△△P<0.001 are compared with the compound 1 group.

[0186] Example 3: Typical Clinical Case

[0187] Clinical trials have been conducted or are being prepared for the treatment of patients with solid tumors using ADC-1 in combination with compound 1, and preliminary efficacy evaluations have been performed in patients with colorectal cancer, gastric cancer, esophageal cancer, lung cancer, breast cancer, and head and neck cancer (including nasopharyngeal carcinoma).

[0188] Drugs: ADC-1, lyophilized powder for injection; Compound 1, tablets.

[0189] Investigator-initiated study dosing regimens for subjects: ADC-1, intravenous infusion, 2.8-4.8 mg / kg, every 3 weeks (Q3W), one cycle every 3 weeks; or once on days 1 and 8 of each cycle, one cycle every 3 weeks (D1D8 Q3W); or once every 2 weeks (Q2W), one cycle every 2 weeks. Compound 1, oral administration, 20-80 mg, once daily for 5 consecutive days, followed by a 2-day rest period, repeated weekly; or once daily for 5 consecutive days, repeated per cycle for combination therapy. Combination therapy continued until disease progression or intolerance to toxicity occurred.

[0190] Dosing regimen for subjects in the registration study: ADC-1, intravenous infusion, 3.2 or 3.6 mg / kg, every 2 weeks (Q2W), for a 2-week cycle. Compound 1, oral administration, 20-80 mg once daily for 5 consecutive days, repeated per cycle for combination therapy. Combination therapy continued until disease progression or intolerance to toxicity occurred.

[0191] Tumor assessment criteria:

[0192] In this study, lesion size in participants was assessed every 6 weeks ± 7 days (9 weeks ± 7 days or 8 weeks ± 7 days after 24 weeks) using imaging techniques (including CT and MRI) according to RECIST V1.1 criteria. The imaging methods used should be consistent with those used for baseline detection. The same imaging equipment should be preferred for subsequent tumor evaluation visits, and the same investigator or radiologist should be involved in the evaluation whenever possible. If the response evaluation was PR or CR, imaging was repeated 4 weeks later to confirm the efficacy.

[0193] Validity endpoints include:

[0194] Objective response rate (ORR): The proportion of participants in a study who achieved the best overall response of complete remission (CR) or partial remission (PR) (i.e., CR+PR) as assessed by RECIST V1.1;

[0195] Progression-free survival (PFS): defined as the time from the start of treatment with the investigational drug to the date of first recorded PD or death, whichever comes first.

[0196] Duration of Response (DOR): The time from the first assessment of CR or PR of the tumor to the first assessment of disease progression (PD) or death from any cause;

[0197] Disease control rate (DCR): Assessed according to RECIST V1.1 criteria, the optimal time point response is CR, PR, and the proportion of disease-stable (SD) (i.e., CR+PR+SD);

[0198] Overall survival (OS): defined as the time between the start of treatment with the investigational drug and the date of death.

[0199] In this investigator-initiated study, patients with solid tumors who had failed at least one first-line standard therapy were included, and RECIST V1.1 was used to assess efficacy. Most patients experienced stable or remission of clinical symptoms. A total of 24 subjects received treatment in this study, including 17 patients with colorectal cancer and 7 patients with gastric cancer. Of the treated patients, 22 were evaluable for efficacy, with 4 achieving partial remission (PR), 10 achieving stable disease (SD), and 11 experiencing tumor shrinkage after treatment. The overall objective response rate (ORR) was 16.7%, and the disease control rate (DCR) was 58.3%. Among the colorectal cancer patients, 15 were evaluable for efficacy, with 1 achieving PR and 7 achieving SD; among the gastric cancer patients, 7 were evaluable for efficacy, with 3 achieving PR and 3 achieving SD, resulting in a disease control rate of 85.7%, and all 6 patients experienced reduction in target lesions. Common drug-related adverse events (TRAEs) are mainly gastrointestinal reactions and hematological toxicities. TRAEs with an incidence ≥30% include decreased white blood cell count, decreased neutrophil count, decreased platelet count, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased bilirubin, decreased appetite, hypoalbuminemia, hypokalemia, nausea, constipation, vomiting, weakness, anemia, and hair loss. Common grade ≥3 TRAEs are mainly hematological toxicities. TRAEs with an incidence ≥10% include decreased white blood cell count, decreased neutrophil count, decreased platelet count, vomiting, and anemia. These usually improve with symptomatic treatment.

[0200] The registration study included patients with gastrointestinal cancers who had failed at least one first-line standard therapy, and efficacy was assessed using RECIST V1.1. Most patients experienced stable or remission of clinical symptoms. As of the data collection date, a total of 108 subjects received treatment, including 39 patients with colorectal cancer, 64 patients with gastric cancer, and 5 patients with esophageal cancer. Of the treated patients, 89 were evaluable for response, including 10 partial remissions (PR), 42 stable disease (SD), and 29 patients whose tumors shrank after treatment. The overall objective response rate (ORR) was 11.2%, and the disease control rate (DCR) was 58.4%. Among the colorectal cancer patients, 37 were evaluable for response, with 2 achieving PR and 15 achieving SD; among the gastric cancer patients, 47 were evaluable for response, with 7 achieving PR and 24 achieving SD, resulting in a DCR of 66.0%. At a dose of ADC-1 3.2 mg / kg Q2W combined with compound 1 40 mg / day (5 days per cycle), efficacy was evaluable in 31 patients with gastric cancer, with 7 achieving partial response (PR), an objective response rate (ORR) of 22.5%, and a disease control rate (DCR) of 74.2%. 38 patients are still under treatment. Common drug-related adverse events (TRAEs) were mainly gastrointestinal reactions and hematological toxicities. TRAEs with an incidence ≥30% included anemia, decreased neutrophil count, decreased white blood cell count, nausea, fatigue, hypoalbuminemia, decreased appetite, and decreased platelet count. Common grade ≥3 TRAEs were mainly hematological toxicities, with TRAEs with an incidence ≥10% including anemia and decreased neutrophil count.

[0201] Case 1: A 67-year-old male patient with gastric cancer, clinically stage IV, had multiple metastases in the lungs and lymph nodes (baseline target lesion diameter sum 70.8 mm). His disease had previously progressed after multidrug chemotherapy combined with immunotherapy. He received ADC-1 combined with compound 1 therapy (Cycle 1: ADC-1: intravenous infusion, 4.8 mg / kg Q3W; Compound 1: oral, 80 mg / day, 5 days administration, 2 days rest, repeated weekly; Cycle 2 and subsequent cycles: ADC-1: intravenous infusion, 3.2 mg / kg Q2W; Compound 1: oral, 40 mg / day, 5 days administration, 2 days rest, repeated weekly). The first efficacy assessment at week 6 showed a partial response (PR), with the target lesion shrinking by 40%. Follow-up assessments at weeks 12 and 18 also showed PR, with disease remission lasting >18 weeks.

[0202] Typical Case 2: A 49-year-old male patient was diagnosed with gastric adenocarcinoma, clinically stage IV, with peritoneal, retroperitoneal lymph node, and liver metastases (cTxNxM1, stage IV). He had previously received multiple chemotherapy drugs combined with immunotherapy, which had progressed the disease. The patient was in poor nutritional status and could not tolerate the combined chemotherapy and immunotherapy. Participants in a clinical trial of ADC-1 combined with compound 1 were screened for multiple metastases, including multiple liver, bone, peritoneal, and ascites. The largest lesion was in the right lobe of the liver, with a maximum diameter of 126.31 mm. The patients received combination therapy (cycles 1-2: ADC-1: intravenous infusion, 4.8 mg / kg Q3W; compound 1: oral, 40 mg / day, 5 days on, 2 days off, repeated weekly; cycles 3 and subsequent: ADC-1: intravenous infusion, 3.2 mg / kg Q2W; compound 1: oral, 40 mg / day, 5 days on, 2 days off, repeated weekly). After week 6, the lesion shrank to 86.7 mm (a 31.4% reduction), and the overall efficacy assessment was PR.

[0203] Typical Case 3: A 71-year-old male patient with colorectal cancer, RAS / BRAF wild-type, clinical stage IV, with multiple metastases in the lungs, lymph nodes, etc. He had failed second-line treatment (received targeted combined with multi-drug chemotherapy and immunotherapy), and had a large baseline tumor burden (target lesion 124.4 mm). The patient received ADC-1 combined with compound 1 therapy (cycle 1: ADC-1: intravenous infusion, 2.8 mg / kg, D1D8, Q3W; compound 1: oral, 80 mg / day, 5 days on, 2 days off, repeated weekly; cycle 2: ADC-1: intravenous infusion, 2.8 mg / kg, D1D8, Q3W; compound 1: oral, 40 mg / day, 5 days on, 2 days off, repeated weekly; cycle 3 and subsequent: ADC-1: intravenous infusion, 3.6 mg / kg, Q2W; compound 1: oral, 80 mg / day, 5 consecutive days, repeated per cycle). The first efficacy assessment at week 6 was PR, and the second assessment at week 12 was still PR. The patient is currently still undergoing treatment.

[0204] Case 4: A 71-year-old male patient was diagnosed with stage IV colorectal cancer. Upon admission, he was diagnosed with rectal adenocarcinoma with local tumor progression. He had previously received multidrug chemotherapy combined with immunotherapy, which had led to disease progression. He participated in a clinical trial of ADC-1 combined with compound 1. During the screening period, he had multiple metastases in the lungs, kidneys, adrenal glands, peritoneum, inguinal lymph nodes, and mediastinal lymph nodes, with a large tumor burden (target lesion 124.4 mm). The patient received combination therapy (cycle 1: ADC-1: intravenous infusion, 3.2 mg / kg Q2W, compound 1: oral, 80 mg / day, 5 days on, 2 days off, repeated weekly; cycles 2-3: ADC-1: intravenous infusion, 3.2 mg / kg Q2W, compound 1: oral, 40 mg / day, 5 days on, 2 days off, repeated weekly; cycles 4 and subsequent: ADC-1: intravenous infusion, 3.2 mg / kg Q2W, compound 1: oral, 40 mg / day, 5 consecutive days, repeated per cycle). The first efficacy assessment at week 6 showed a partial response (lesion shrank to 86.6 mm), and the second assessment at week 12 also showed a partial response (target lesion 84.2 mm). The patient is currently still undergoing treatment (PFS > 4.5 months).

[0205] Case 5: A 60-year-old male patient was diagnosed with stage IV colorectal cancer and admitted to the hospital with a diagnosis of colonic adenocarcinoma with liver metastasis. He had previously received multidrug chemotherapy combined with immunotherapy, which had led to disease progression. Participants in a clinical trial of ADC-1 combined with compound 1 were screened for multiple liver metastases, retroperitoneal, peritoneal, and periintestinal lymph node metastases, with a total target lesion diameter of 83 mm. They received combination therapy (cycle 1: ADC-1: intravenous infusion, 2.8 mg / kg, D1D8, Q3W; compound 1: oral, 80 mg / day, 5 days on, 2 days off, repeated weekly; cycle 2: ADC-1: intravenous infusion, 2.8 mg / kg, D1D8, Q3W; compound 1: oral, 40 mg / day, 5 days on, 2 days off, repeated weekly; cycles 3-5: ADC-1: intravenous infusion, 2.8 mg / kg, D1D8, Q3W; compound 1: oral, 40 mg / day, 5 consecutive days, repeated per cycle; cycle 6 and subsequent: ADC-1: intravenous infusion, 2.8 mg / kg...). D1D8, Q3W, Compound 1: Oral administration, 60 mg / day, for 5 consecutive days, repeated per cycle), after week 18, the size decreased to 70 mm (16% reduction), and the disease remained stable for >4 months.

[0206] Case 6: A 58-year-old female patient was diagnosed with stage IV colon cancer and admitted to the hospital with a diagnosis of sigmoid colon cancer with liver metastasis. She had previously received multidrug chemotherapy combined with immunotherapy, which had led to disease progression. The patient participated in a clinical trial of ADC-1 combined with compound 1. During the screening period, the patient had multiple metastases in the liver, lungs, and retroperitoneal lymph nodes, with a total target lesion diameter of 95.5 mm. The patient received combination therapy (cycle 1: ADC-1: intravenous infusion, 2.8 mg / kg D1D8Q3W; compound 1: oral, 80 mg / day, 5 days on, 2 days off, repeated weekly; cycle 2: ADC-1: intravenous infusion, 2.8 mg / kg D1D8Q3W; compound 1: oral, 40 mg / day, 5 days on, 2 days off, repeated weekly; cycle 3 and subsequent: ADC-1: intravenous infusion, 2.8 mg / kg D1D8Q3W; compound 1: oral, 80 mg / day, 5 consecutive days, repeated per cycle). The lesions continued to shrink, and the disease remained stable for more than 4 months. The patient is currently still undergoing treatment.

[0207] Case 7: A 58-year-old male patient was diagnosed with colon cancer, clinically stage IVB, and had previously experienced disease progression after combination chemotherapy. He participated in a clinical trial of ADC-1 combined with compound 1. During the screening phase, he had multiple lymph node metastases, with a total target lesion diameter of 57 mm. He received combination therapy (ADC-1, intravenous infusion, 3.2 mg / kg, Q2W, every 2 weeks; compound 1, oral, 60 mg once daily for 5 consecutive days, repeated per cycle). At week 6, the first efficacy assessment showed a partial response (30.2% reduction in target lesions). At week 32, the tumor assessment still showed a partial response (38.07% reduction in target lesions). The patient is currently still undergoing treatment (PFS > 7.5 months).

[0208] Case 8: A 53-year-old female patient was diagnosed with gastric cancer, clinically stage IVB. Her disease had progressed after previous combination chemotherapy and immunotherapy. She participated in a clinical trial of ADC-1 combined with compound 1. During the screening phase, she had lymph node metastasis, and the total diameter of the target lesions was 28.6 mm. She received combination therapy (ADC-1, intravenous infusion, 3.6 mg / kg, Q2W, every 2 weeks; compound 1, oral, 20 mg once daily for 5 consecutive days, repeated per cycle). At week 6, the first efficacy assessment showed SD (target lesion reduction of 15%). At week 12, the tumor assessment achieved PR (target lesion reduction of 35.7%). At week 24, the tumor assessment remained PR (target lesion reduction of 43.7%). The patient is currently still undergoing treatment (PFS > 5.6 months).

[0209] Case 9: A 57-year-old male patient was diagnosed with colon cancer, clinically stage IVC, and had previously experienced disease progression after combination chemotherapy. He participated in a clinical trial of ADC-1 combined with compound 1. During the screening phase, he had multiple metastases in the liver, adrenal glands, and lymph nodes, with large target lesions totaling 145.4 mm in diameter. He received combination therapy (ADC-1, intravenous infusion, 3.6 mg / kg, Q2W, every 2 weeks; compound 1, oral, 20 mg once daily for 5 consecutive days, repeated per cycle). At week 6, the first efficacy assessment showed SD (target lesion reduction of 20.4%). At week 12, the tumor assessment achieved PR (target lesion reduction of 34.9%). At week 32, the tumor assessment remained PR (target lesion reduction of 37.6%). The patient is currently still undergoing treatment (PFS > 7.5 months).

[0210] Case 10: A 58-year-old male patient was diagnosed with gastric cancer, clinically stage IV, and had previously experienced disease progression after combination chemotherapy. He participated in a clinical trial of ADC-1 combined with compound 1. During the screening period, he had multiple liver and lymph node metastases, with a total target lesion diameter of 76.5 mm. He received combination therapy (ADC-1, intravenous infusion, 3.6 mg / kg, Q2W, every 2 weeks; compound 1, oral, 40 mg once daily for 5 consecutive days, repeated every cycle). At week 6, the first efficacy assessment showed a partial response (53.07% reduction in target lesions). At week 18, the tumor assessment still showed a partial response (49.54% reduction in target lesions). Currently, the patient has completed treatment due to disease progression, with a progression-free survival (PFS) of 5.6 months.

[0211] Case 11: A 62-year-old male patient was diagnosed with gastric cancer, clinically stage IV. His disease had progressed after multiple lines of combination chemotherapy and immunotherapy. He participated in a clinical trial of ADC-1 combined with compound 1. During the screening phase, he had multiple lymph node metastases, with a total target lesion diameter of 42.96 mm. He received combination therapy (ADC-1, intravenous infusion, 3.6 mg / kg, Q2W, every 2 weeks; compound 1, oral, 40 mg once daily for 5 consecutive days, repeated per cycle). At week 6, the first efficacy assessment showed SD (target lesion reduction of 25.12%). At week 12, the tumor assessment achieved PR (target lesion reduction of 30.98%). At week 24, the tumor assessment remained PR (target lesion reduction of 45.07%). The patient is currently still undergoing treatment (PFS > 5.6 months).

[0212] Case 12: A 60-year-old male patient was diagnosed with esophageal cancer, clinically stage IVB. His disease had progressed after previous combination chemotherapy and immunotherapy. He participated in a clinical trial of ADC-1 combined with compound 1. During the screening phase, he had multiple metastases in the lungs, lymph nodes, and peritoneum, with a total target lesion diameter of 47 mm. He received combination therapy (ADC-1, intravenous infusion, 3.6 mg / kg, Q2W, every 2 weeks; compound 1, oral, 40 mg once daily for 5 consecutive days, repeated per cycle). At week 6, the first efficacy assessment showed a partial response (53.2% reduction in target lesions). At week 18, the tumor assessment remained at a partial response (76.6% reduction in target lesions). The patient is currently still undergoing treatment (PFS > 4.2 months).

[0213] Case 13: A 50-year-old female patient was diagnosed with gastric cancer, clinically stage IV, and had experienced disease progression after multiple lines of chemotherapy. She participated in a clinical trial of ADC-1 combined with compound 1. During the screening period, she had liver and lymph node metastases, with a total target lesion diameter of 59.8 mm. She received combination therapy (ADC-1, intravenous infusion, 3.2 mg / kg, Q2W, every 2 weeks; compound 1, oral, 40 mg once daily for 5 consecutive days, repeated every cycle). At week 6, the first efficacy assessment showed SD (target lesion reduction of 18.1%). At week 40, the tumor assessment still showed SD (target lesion reduction of 17.9%). The patient is currently still undergoing treatment (PFS > 9.3 months).

[0214] The study results indicate that the combined administration of ADC-1 and compound 1 is effective in treating advanced malignant tumors. It remains effective in patients who have failed standard treatment, allowing for disease control or remission, thus providing a new treatment option for patients with advanced solid tumors.

[0215] The sequences used in the above embodiments of the present invention are shown in the following sequence list. It should be understood that the following sequences are merely exemplary sequences for embodiments of the present invention and are not intended to limit the scope of the present invention in any way.

[0216] Sequence List:

[0217] EGFR antibody SWY2110

[0218] Light chain (SEQ ID NO:10):

[0219] Heavy chain (SEQ ID NO:9):

[0220] SWY2110 HCDR1:NYDVH SEQ ID NO:1

[0221] SWY2110 HCDR2:VIWSGGNTDYNTPFTS SEQ ID NO:2

[0222] SWY2110 HCDR3:ALDYYDYEFAY SEQ ID NO:3

[0223] SWY2110 LCDR1:RASQSIGTNIH SEQ ID NO:4

[0224] SWY2110 LCDR2:YASESIS SEQ ID NO:5

[0225] SWY2110 LCDR3:QQNNEWPTS SEQ ID NO:6

[0226] SWY2110 VH:SEQ ID NO:7

[0227] SWY2110 VL:SEQ ID NO:8

Claims

1. A pharmaceutical combination comprising or consisting of: Antibody-drug conjugate, wherein the antibody-drug conjugate is an antibody-drug conjugate targeting EGFR, and ATM inhibitors; Preferably, the antibody-drug conjugate is the antibody-drug conjugate of formula (I) or its stereoisomer or a pharmaceutically acceptable salt. in, Ab is an antibody targeting EGFR or its antigen-binding fragment; 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, more preferably 1, 2, 3, 4, 5, 6, 7, 8, and more preferably 8; and / or Preferably, the ATM inhibitor is a compound of formula (II) or its stereoisomer or a pharmaceutically acceptable salt. in, R1 is independently selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -N(R) 1a (R) 1b -C(O)N(R) 1a (R) 1b ), -N(R 1a )C(O)(R 1b ), -S(O)N(R 1a (R) 1b ), -N(R 1a )S(O)(R 1b -SO2N(R) 1a (R) 1b ), -N(R 1a SO2(R) 1b ); R 1a R 1b Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; m1 and m2 are each independently selected from 0, 1, and 2; R2 and R3 are each independently selected from the arbitrarily substituted C. 1-6 Alkyl group; or R2 and R3 together with the nitrogen atom to which they are attached to form an optionally substituted 3-12 membered heterocyclic group; wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently replaced by R. 3a Replaced; R 3a Independently selected from deuterium, halogen, hydroxyl, amino, cyano, -R 3b -C(O)R 3b -C(O)OR 3b -N(R) 3b )2、-C(O)NH(R 3b -NHC(O)R 3b ; R 3b Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl groups are optionally separated by one or more elements, each independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, C 3-6 Substituents include cycloalkyl, 3-6 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups; R4 is independently selected from deuterium, halogen, nitro, amino, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally replaced by one or more substituents, each independently selected from deuterium, halogen, hydroxyl, and amino groups; R5 is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups; L represents CH or N; A is in, Indicates a single or double bond; Q1 is connected to W; t1, t2, t3, t4, t5, and t6 are each independently 0 or 1; n1 and n2 are each independently 0 or 1, and n1 and n2 are not both 0 at the same time; W is selected from C, O, N, or S; Q1 is C; Q2 is C; Q3 is C; when the key connecting one side of Q3 is a double key, R 10 Or R 11 It does not exist; R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, -R. 6a -NH(R) 6a ), -N(R 6a (R) 6b ); or R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Any two substituents attached to the same atom can form =O or =NR. 6a =CH-R 6a ; or any two adjacent atoms from W, Q1, Q2, and Q3 and their attached substituents together form an atom optionally controlled by one or more R 6c The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 aryl, 5-12 heteroaryl; or any one atom from W, Q1, Q2, and Q3 and its attached substituents together form an aryl group optionally bonded to one or more R groups. 6c The following groups are substituted: C 3-10 cycloalkyl groups, 3-10 membered heterocyclic groups; R 6a R 6b Each is independently selected from hydrogen, deuterium, or optionally by one or more R 6c The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 aryl, 5-12 heteroaryl; or R 6a and R 6b Together with the nitrogen atom to which it is attached, they form an optional structure with one or more R atoms. 6c The following groups are substituted: 3-10 membered heterocyclic groups, 5-12 membered heteroaryl groups; R 6c Independently selected from deuterium, halogen, hydroxyl, amino, -R 6d -OR 6d -N(R) 6d )2、-C(O)R 6d -C(O)N(R) 6d )2、-N(R 6d )C(O)R 6d -C(O)OR 6d ; R 6d Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-12 heteroaryl; The heteroatoms in the heteroaryl and heterocyclic groups are independently selected from O, N, and S, and the number of heteroatoms is 1, 2, 3, or 4. More preferably, the antibody targeting EGFR or its antigen-binding fragment includes a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region sequence 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 as shown in SEQ ID NO:1, the amino acid sequence of HCDR2 is as shown in SEQ ID NO:2, the amino acid sequence of HCDR3 is as shown in SEQ ID NO:3, and / or the amino acid sequence of LCDR1 is as shown in SEQ ID NO:4, the amino acid sequence of LCDR2 is as shown in SEQ ID NO:5, and the amino acid sequence of LCDR3 is as shown in SEQ ID NO:6; or The antibody targeting EGFR or its antigen-binding fragment includes a heavy chain variable region (VH) and a light chain variable region (VL), wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8; or The antibody targeting EGFR or its antigen-binding fragment includes a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO:9 and the amino acid sequence of the light chain is shown in SEQ ID NO:

10. and / or More preferably, R 1a R 1b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 3-4 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; or R 1a R 1b Each is independently selected from hydrogen, methyl, ethyl, cyclopropyl, and phenyl; and / or More preferably, R1 is independently selected from halogens, amino groups, and C. 1-3 Alkyl, -NH(R) 1b ), -NHC(O)(R 1b ),-NHSO2(R 1b );or R1 is independently selected from -F, -Cl, -Br, -NH2, -CH3, -CH2CH3, -NHC(O)CH3, -C(O)NHCH3, and / or More preferably, m1 is selected from 0, 1; or is 0; and / or More preferably, m2 is selected from 0, 1; or is 0; and / or More preferably, R2 and R3 are each independently selected from the optionally substituted C. 1-6 Alkyl group; or R2 and R3 together with the nitrogen atom to which they are attached to form an optionally substituted 5-10 membered heterocyclic group; the optional substitution means that it is optionally substituted by one or more R groups. 3a Replaced; or R2 and R3 are each independently selected from the arbitrarily substituted C. 1-4 Alkyl group; or R2 and R3 together with the nitrogen atom to which they are attached to form an optionally substituted 5-6 membered heterocyclic group; the optional substitution means that it is optionally substituted by one or more R groups. 3a Replaced; or R2 and R3 are each independently selected from the arbitrarily substituted C. 1-3 Alkyl group (e.g., methyl); or R2 and R3 together with the nitrogen atom to which they are attached to form an optionally substituted 5-6 membered heterocyclic group; wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1, 2, or 3; the optional substitution means that it is optionally substituted by one or more R... 3a Replaced; or R2, R3, and the nitrogen atom they are attached to together form the following groups: Or for and / or More preferably, R 3a Independently selected from deuterium, halogens (e.g., fluorine, chlorine, bromine), hydroxyl, amino, cyano, -R 3b -C(O)R 3b -C(O)OR 3b -N(R) 3b )2、-C(O)NH(R 3b -NHC(O)R 3b ; R 3b Independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted by one or more substituents, each independently selected from deuterium, halogens (e.g., fluorine, chlorine, bromine), hydroxyl, and amino groups; or R 3a Independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, -NH(CH3), -N(CH3)(CH3), -C(O)NH2, -CH3, -CH2CH3, -CH2CH2CH3; and / or More preferably, R4 is independently selected from halogens, amino groups, and C. 1-6 Alkyl groups; or fluorine, chlorine, or methoxy groups; and / or More preferably, R5 is independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl; or methyl; and / or More preferably, R 6a R 6b Each is independently selected from hydrogen, deuterium, or optionally by one or more R 6c The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; or R 6a and R 6b Together with the nitrogen atom to which it is attached, they form an optional R 6c The following groups are substituted: 3-6 membered heterocyclic groups, 5-6 membered heteroaryl groups; or R 6a R 6b Each is independently selected from hydrogen or optionally by one or more R 6c The following groups are substituted: C 1-3 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl), C 1-3 Alkyl groups (e.g., methoxy, ethoxy, n-propoxy, isopropoxy); and / or More preferably, R 6c Independently selected from deuterium, fluorine, chlorine, hydroxyl, amino, -NH(C 1-6 Alkyl), -N(CH3)(C 1-6 Alkyl), -C(O)(C 1-6 Alkyl), -C(O)NH(C 1-6 Alkyl), -NHC(O)(C 1-6 Alkyl), -C(O)O(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; or R 6c Independently selected from deuterium, deuterium, halogen, hydroxyl, amino, C 1-3 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl), C 1-3 Alkyl groups (e.g., methoxy, ethoxy, n-propoxy, isopropoxy); and / or More preferably, R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally by one or more R. 6c The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; R 6c Independently selected from deuterium, halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)(C 1-6 Alkyl), -C(O)NH(C 1-6 Alkyl), -NHC(O)(C 1-6 Alkyl), -C(O)O(C 1-6 Alkyl), C 3-6 cycloalkyl, 5-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; or R6, R7, R8, R9, R 10 R 11 R 12 and R 13 Each time it appears, it is independently selected from hydrogen or arbitrarily selected by one or more R. 6c The following groups are substituted: C 1-3 Alkyl, C 1-3 Alkoxy; R 6c Independently selected from halogens, hydroxyl groups, amino groups, and C 1-3 Alkyl, C 1-3 Alkoxy; and / or More preferably, the sum of n1 and n2 is 1 (i.e., n1 is 1 and n2 is 0; or n1 is 0 and n2 is 1); and / or More preferably, W is selected from O or S; or is O; and / or More preferably, any two adjacent atoms in W, Q1, Q2, and Q3 and their attached substituents together form an atom optionally bonded by one or more R. 6c The following groups are substituted: C 5-6 cycloalkyl, 5-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; or Any two adjacent atoms in W, Q1, Q2, and Q3, together with their attached substituents, form the following groups: and / or More preferably, any one of W, Q1, Q2, and Q3 and its attached substituents together form an atom optionally bonded by one or more R atoms. 6c The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups; or, any one atom from W, Q1, Q2, and Q3 and its attached substituents together form an optional compound with one or more R groups. 6c The following groups are substituted: C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups; or, any one atom from W, Q1, Q2, and Q3 and its attached substituents together form an optional compound with one or more R groups. 6c The following groups are substituted: C 3-4 Cycloalkyl groups, 3-6 membered heterocyclic groups, wherein the heteroatom in the heterocyclic group is selected from O, N, S, and the number of heteroatoms is 1 or 2; and / or More preferably, any one of W, Q1, Q2, and Q3 and the substituents attached to it together form the following group: Most preferably, the antibody-drug conjugate 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. Or its stereoisomers or pharmaceutically acceptable salts; and / or Most preferably, the ATM inhibitor is: Or its stereoisomers or pharmaceutically acceptable salts.

2. The pharmaceutical combination of claim 1, used for treating tumors.

3. A combination therapy for treating tumors, comprising the antibody-drug conjugate of claim 1 and the ATM inhibitor of claim 1.

4. A method for treating a tumor, the method comprising administering a therapeutically effective amount of an antibody-drug conjugate and an ATM inhibitor to a patient or subject requiring treatment. The antibody-drug conjugate described herein is the antibody-drug conjugate of claim 1. The ATM inhibitor is the ATM inhibitor according to claim 1.

5. The use of an antibody-drug conjugate in the preparation of a medicament for the treatment of tumors in combination with an ATM inhibitor, or the use of an antibody-drug conjugate in combination with an ATM inhibitor in the preparation of a medicament for the treatment of tumors. The antibody-drug conjugate described herein is the antibody-drug conjugate of claim 1. The ATM inhibitor is the ATM inhibitor according to claim 1.

6. The pharmaceutical combination of claim 1 or 2, or the pharmaceutical product of claim 3, or the method of claim 4, or the use of claim 5, wherein, The antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II) 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, or they can be separately prepared into clinically acceptable dosage forms and packaged into the drug; preferably, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II) are contained in different formulation units and presented in separate packaging; more preferably, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) is a lyophilized powder for injection or an injection solution, and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II) is a solid oral formulation (such as tablets or capsules, preferably tablets), a lyophilized powder for injection, or an injection solution.

7. The pharmaceutical combination of claim 1, 2, or 6, or the pharmaceutical product of claim 3 or 6, or the method of claim 4 or 6, or the use of claim 5 or 6, wherein, The antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II) can be administered simultaneously or separately; preferably, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II) are contained in different formulation units and administered simultaneously or in parallel, or sequentially at different times within a clinically acceptable time interval, or administered at clinically acceptable time intervals according to the respective dosing frequencies and cycles of the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by Formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by Formula (II).

8. A pharmaceutical combination of any one of claims 1, 2, and 6-7, or a pharmaceutical product of any one of claims 3 and 6-7, or a method of any one of claims 4 and 6-7, or the use of any one of claims 5 and 6-7, wherein, The therapeutically effective mass ratio of the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by formula (I) and the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) is selected from (1-100):(1-100); preferably 1:(1-30), 1:(1-20), 1:(1-10); more preferably 1:30, 1:20, 1:6, 1:

2.

9. A pharmaceutical combination of any one of claims 1, 2, and 6-8, or a pharmaceutical product of any one of claims 3 and 6-8, or a method of any one of claims 4 and 6-8, or the use of any one of claims 5 and 6-8, wherein, The therapeutically effective amount (based on the antibody-drug conjugate of Formula I and the patient's weight, mg being the dosage of the antibody-drug conjugate of Formula I and kg being the patient's weight) of the antibody-drug conjugate of Formula I is 1 mg / kg to 15 mg / kg; preferably 2 mg / kg to 10 mg / kg; more preferably 2.8 mg / kg to 4.8 mg / kg; such as about 2.8 mg / kg, about 3 mg / kg, about 3.2 mg / kg, about 3.6 mg / kg, about 4.0 mg / kg, and about 4.8 mg / kg.

10. A pharmaceutical combination of any one of claims 1, 2, and 6-9, or a pharmaceutical product of any one of claims 3 and 6-9, or a method of any one of claims 4 and 6-9, or the use of any one of claims 5 and 6-9, wherein, The therapeutically effective amount of the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) is 1 mg to 1000 mg; preferably 10 mg to 400 mg / day; more preferably 20 mg to 200 mg / day; even more preferably 20 mg to 80 mg / day, such as about 20 mg / day, about 40 mg / day, about 60 mg / day, or about 80 mg / day.

11. A pharmaceutical combination of any one of claims 1, 2, and 6-10, or a pharmaceutical product of any one of claims 3 and 6-10, or a method of any one of claims 4 and 6-10, or use of any one of claims 5 and 6-10, wherein, The antibody-drug conjugate of Formula (I) or its stereoisomer or pharmaceutically acceptable salt and / or the ATM inhibitor of Formula (II) or its stereoisomer or pharmaceutically acceptable salt may be administered once daily (QD), or the 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 the 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 the above-mentioned therapeutically effective dose may be divided into multiple doses throughout the two weeks. It can be administered, for example, 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 used as the total dose and administered on multiple days within three weeks, for example, twice every three weeks (BI3W, such as administration on D1 and 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 used as the total dose and administered on multiple days within one month, for example, twice a month (BIM) or three times a month (TIM); it can also be administered at intervals, such as once every 2-7 days, or once every 2, 3, 4, 5, or 6 days, or once every 2-4 weeks. The drug may be administered once, 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 cycle or in a 4-week cycle), and 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, in a 4-week cycle, or continuously for 2 weeks, stop for 1 week, in a 3-week cycle, or continuously for 2 weeks, stop for 2 weeks, in a 4-week cycle, or once every 2 weeks (once every 4 weeks), in a 4-week cycle; preferably, the antibody-drug conjugate of formula (I) or its stereoisomer or pharmaceutically acceptable form is used. The salt can be administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W); the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) can be administered once a day (QD), or the above therapeutically effective amount can be divided into multiple doses throughout the day as the total daily dose, for example, divided into two doses per day (BID) or three doses per day (TID). More preferably, the antibody-drug conjugate or its stereoisomer or pharmaceutically acceptable salt represented by formula (I) can be administered once every three weeks (Q3W); the ATM inhibitor or its stereoisomer or pharmaceutically acceptable salt represented by formula (II) can be administered once a day (QD).

12. A combination of pharmaceutical ingredients according to any one of claims 1, 2, and 6-11, or a pharmaceutical ingredient according to any one of claims 3 and 6-11, or a method according to any one of claims 4 and 6-11, or an use according to any one of claims 5 and 6-11, wherein, The dosing regimen is as shown in Formula (I): 2.8–4.8 mg / kg (e.g., about 2.8 mg / kg, about 3.0 mg / kg, about 3.2 mg / kg, about 3.6 mg / kg, about 4.0 mg / kg, or about 4.5 mg / kg); once every 3 weeks (Q3W), for a 3-week cycle; or once on days 1 and 8 of each cycle, for a 3-week cycle (D1, D8, Q3W); or once every 2 weeks (Q2W), for a 2-week cycle. Period; combined with the ATM inhibitor shown in formula (II) or its stereoisomer or pharmaceutically acceptable salt: 20-80 mg / day (e.g., about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day); once daily for 5 consecutive days, followed by a 2-day rest period, repeated weekly; or once daily for 5 consecutive days, repeated per cycle; or once daily for 4 consecutive days, repeated per cycle; or once daily for 3 consecutive days, repeated per cycle; or once daily for 5 consecutive days, starting in the second week of each cycle.

13. A combination of medicines according to any one of claims 1, 2, and 6-12, or a medicine according to any one of claims 3 and 6-12, or a method according to any one of claims 4 and 6-12, or the use according to any one of claims 5 and 6-12, wherein the tumor is a solid tumor, adenocarcinoma, or squamous cell carcinoma; preferably, the tumor is selected from head and neck cancer (such as nasopharyngeal carcinoma), lung cancer, breast cancer, and gastrointestinal tumors; preferably, the lung cancer is selected from non-small cell lung cancer (NSCLC) and small cell lung cancer, and the gastrointestinal tumor is selected from esophageal cancer, gastroesophageal junction cancer, gastric cancer, and colorectal cancer (such as advanced metastatic colorectal cancer).

14. A combination of medicines of any one of claims 1, 2 and 6-13, or a medicine of any one of claims 3 and 6-13, or a method of any one of claims 4 and 6-13, or the use of any one of claims 5 and 6-13, wherein the tumor is a solid tumor, the solid tumor is an advanced solid tumor; or the tumor is adenocarcinoma, or the tumor is squamous cell carcinoma.

15. A combination of drugs according to any one of claims 1, 2, and 6-14, or a drug according to any one of claims 3 and 6-14, or a method according to any one of claims 4 and 6-14, or a use according to any one of claims 5 and 6-14, wherein the tumor is an EGFR-expressing or abnormally expressing tumor, such as an EGFR-overexpressing, high-expressing, moderate-expressing, low-expressing, non-expressing, deleted, amplified, or mutant tumor.

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