CN120437318A

CN120437318A - Combination therapy of antibody-drug conjugates and immune checkpoint inhibitors

Info

Publication number: CN120437318A
Application number: CN202510130591.2A
Authority: CN
Inventors: 孙丹妮; 周远锋; 徐敏; 刘军豪; 邱鹏超
Original assignee: Changzhou Hengbang Pharmaceutical Co ltd; Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Current assignee: Changzhou Hengbang Pharmaceutical Co ltd; Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Priority date: 2024-02-07
Filing date: 2025-02-05
Publication date: 2025-08-08

Abstract

The present invention relates to the combined use of an antibody-drug conjugate and an immune checkpoint inhibitor, specifically, the use of an antibody-drug conjugate alone or in combination in the preparation of a drug for the prevention and/or treatment of cancer. Specifically, the present invention provides the use of an antibody-drug conjugate or a pharmaceutically acceptable salt, metabolite, or solvate thereof alone or in combination with an immune checkpoint inhibitor in the preparation of a drug for the prevention and/or treatment of cancer.

Description

Combined use of antibody drug conjugates and immune checkpoint inhibitors

Technical Field

The application belongs to the field of medicines, and relates to application of antibody drug conjugate in preparation of a drug for preventing and/or treating cancers. In particular, the application provides an antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof, and application of single drug or combined immune checkpoint inhibitor in preparing a drug for preventing and/or treating cancer.

Background

Antibody-drug conjugates (ADCs) are a class of targeted biological agents that link cytotoxic drugs to monoclonal antibodies via linkers, which serve as carriers to efficiently transport small molecule cytotoxic drugs into target tumor cells in a targeted manner. The tumor specific antibody enables the ADC drug to selectively deliver the small molecular cytotoxicity drug, so that the off-target effect of the small molecular cytotoxicity drug is reduced, the anti-tumor characteristic of the small molecular cytotoxicity drug is maintained, and the benefit risk ratio of anti-tumor treatment is effectively improved. The B7 homology 3 protein (B7-H3, also referred to herein as CD276, "B7-H3" or "B7H 3") is a type I transmembrane glycoprotein of the immunoglobulin superfamily, which is a B7 immune co-stimulatory and co-inhibitory family member, over-expressed in a variety of solid tumors such as lung cancer, prostate cancer, esophageal cancer, head and neck squamous carcinoma, osteosarcoma, bladder cancer, and melanoma, but limited expression in normal tissues, and thus B7-H3 is an ideal target for ADC drugs.

Immune checkpoint inhibitors (immune checkpoint inhibitors, ICIs) release immune function inhibition caused by immune checkpoints by blocking the binding of immune checkpoints to their ligands, thereby reactivating immune cells to exert antitumor effects. At present, a plurality of ICIs have remarkable effects in the clinical application of anti-tumor, and are breakthrough progress in the field of tumor treatment. Inhibitors targeting cytotoxic T lymphocyte-associated antigen 4 (cytotoxic Tlymphocyte-associated antigen-4, CTLA-4), programmed death receptor 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have been successfully used in clinical treatment of various malignant tumors, wherein PD-1/PD-L1 antibody drugs have a broad anticancer spectrum and show durable and powerful therapeutic effects in some tumor patients, and 10 PD-1 monoclonal antibodies and 3 PD-L1 monoclonal antibodies have been approved for clinical treatment of 11 cancer species such as non-small cell lung cancer, melanoma, head and neck cancer, colorectal cancer and gastric cancer. Although ICIs has significant antitumor activity in many types of malignant tumors, its response rate is low in most tumors, and development of new schemes for improving ICIs therapeutic response rate is needed.

Classical osteosarcoma (hereinafter abbreviated as osteosarcoma) is a common malignant bone tumor, accounting for 35% of all malignant bone tumors. Classical osteosarcoma is a major malignancy in adolescents, with a median age of 20 years, and is the most common primary malignancy in children and adolescents. About 10% -15% of newly diagnosed osteosarcoma patients develop distant metastasis, the 5-year survival rate of limited osteosarcoma patients is about 60%, while the 5-year survival rate of advanced (recurrent or metastatic) osteosarcoma patients is only about 20%. The first line standard chemotherapy regimen for osteosarcoma is a regimen containing methotrexate, doxorubicin, cisplatin and ifosfamide. Patients with osteosarcoma who cannot undergo radical surgical treatment, after failure of standard chemotherapy, lack of effective treatment, and no drugs or other treatment can show significant survival benefits for such patients. At present, no two-line treatment scheme is adopted, and the existing treatment method has larger hematology toxicity and more adverse reactions. Therefore, improving the curative effect of the two-line osteosarcoma treatment and prolonging the life span of the patient are one of the purposes of the current clinical study, and new treatment methods are needed to meet the treatment demands of the patient.

The preferred combination therapy of the invention exhibits a higher effect than the individual therapies, while enhancing efficacy, with lower side effects of the combination, promoting maximal survival benefit in patients receiving immunotherapy.

Disclosure of Invention

The present disclosure provides a use of an antibody drug conjugate and an immune checkpoint inhibitor in combination for the preparation of a medicament for treating cancer, the structure of the antibody drug conjugate is shown as formula (I):

Where n is a non-zero integer or fraction of 1 to 10, preferably a fraction or integer of between 1 and 8, preferably a fraction or integer of between 2 and 8, more preferably 3 to 8, and may be an integer or fraction, more preferably 4.1.

Pc is an anti-B7H 3 antibody or antigen-binding fragment thereof.

In some embodiments, the anti-B7H 3 antibody or antigen-binding fragment thereof comprises heavy chains HCDR1, HCDR2, HCDR3 as shown in amino acid sequences SEQ ID NO. 01, 02, and 03, respectively, and light chains LCDR1, LCDR2, and LCDR3 as shown in amino acid sequences SEQ ID NO. 04, 05, and 06, respectively.

In the present invention, the amino acid sequences of the CDRs listed above are all shown according to the Kabat definition rules. However, it is well known to those skilled in the art that the CDRs of an antibody can be defined by a variety of methods in the art. Although the scope of the claimed invention is based on the sequences shown by the Kabat definition rules, amino acid sequences corresponding to the definition rules according to other CDRs should also fall within the scope of the claimed invention.

Wherein, each CDR sequence described above is shown in the following table:

TABLE 1 CDR sequences for each heavy and light chain

Note that the CDR sequences are derived from those shown by the Kabat definition rules.

Preferably, the anti-B7H 3 antibody or antigen-binding fragment thereof is selected from humanized antibodies or fragments thereof.

In some alternative embodiments, the anti-B7H 3 antibody or antigen-binding fragment thereof of the application is an antibody fragment selected from the group consisting of Fab, fab '-SH, fv, scFv, and (Fab') ₂ fragments.

In some alternative embodiments, the anti-B7H 3 antibodies or antigen-binding fragments thereof of the application comprise a heavy chain constant region of a human IgG1, igG2, igG3 or IgG4 isotype, preferably a heavy chain constant region of an IgG1 or IgG4 isotype.

In other alternative embodiments, the anti-B7H 3 antibody or antigen-binding fragment thereof comprises a light chain constant region of kappa or lambda.

Further, it is preferable that the heavy chain variable region sequence of the anti-B7H 3 antibody or antigen-binding fragment thereof is a sequence shown as SEQ ID NO:07 or a variant thereof, and the light chain variable region sequence is a sequence shown as SEQ ID NO:08 or a variant thereof.

The sequence of the heavy and light chain variable region of the anti-B7H 3 antibody or antigen binding fragment is shown below

SSAMHVISYDGSNKYYVDSVKGSARLYASFDY

SEQ ID NO. 07 light chain variable region sequence

GLSSGSVSTSHYPSNTNTRSS AIHVDRDIWV

SEQ ID NO:08

Note that the sequence is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, italics in the sequence is FR sequence and underlines the CDR sequence, wherein the CDR sequence is derived from the Kabat definition rules.

Further, it is preferable that the heavy chain sequence of the anti-B7H 3 antibody or antigen-binding fragment thereof is a sequence shown as SEQ ID NO:09 or a variant thereof, and the light chain sequence is a sequence shown as SEQ ID NO:10 or a variant thereof.

The sequences of the heavy and light chains of the aforementioned anti-B7H 3 antibodies or antigen binding fragments thereof are shown below:

Heavy chain (IgG 1) amino acid sequence (SEQ ID NO: 09)

QVQLVQSGGGVVQPGTSLRLSCAASGFIFSSSAMHWVRQAPGKGLEWVAVISYDGSNKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSARLYASFDYWGQGALVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light chain (lambda) amino acid sequence (SEQ ID NO: 10)

DTVVTQEPSFSVSPGGTVTLTCGLSSGSVSTSHYPSWYQQTPGQAPRMLIYNTNTRSSGVPDRFSGSILGNKAALTITGAQADDESDYYCAIHVDRDIWVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTEC

In some embodiments, the immune checkpoint inhibitor is selected from an antibody or antigen binding fragment thereof that targets PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA, A aR, B7-H3, B7-H4. Antibodies or antigen binding fragments thereof that target PD-1, PD-L1 are preferred.

In some embodiments, the immune checkpoint inhibitor is selected from terlipressin Li Shan antibody (Toripalimab), bedi Li Shan antibody (Sintilimab), karilizumab (Camrelizumab), dorsalizumab (Dostarlimab), tirelimumab (Tislelizumab), sirolimumab (Zimberelimab), pie An Puli mab (Penpulimab), s Lu Lishan antibody (Serplulimab), pralidmumab (Pucotenlimab), pamilimumab (Pembrolizumab), na Wu Liyou mab (Nivolumab), shu Geli mab (Sugemalimab), en Wo Lishan antibody (Envafolimab), albelimab (Adebrelimab), atilizumab (Atezolizumab), dulcis You Shan antibody (Durvalumab), ipilimumab (Ipilimumab), californica Li Kangti (Candonilimab), preferably, karilimumab (Camrelizumab), albelimumab (Adebrelimab), dorrelimumab (Dostarlimab), palivimumab (Pembrolizumab), dulcis You Shan antibody (Durvalumab).

The sequences of the heavy and light chains of the above-mentioned karellizumab are as follows:

Heavy chain amino acid sequence (SEQ ID NO: 11)

EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Light chain amino acid sequence (SEQ ID NO: 12)

DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

The sequences of the heavy and light chains of the aforementioned aldebrilmumab are shown below:

heavy chain amino acid sequence (SEQ ID NO: 13)

QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVRQAPGQGLEWMGRIGPNSGFTSYNEKFKNRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGSSYDYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLGK

Light chain amino acid sequence (SEQ ID NO: 14)

DIVLTQSPASLAVSPGQRATITCRASESVSIHGTHLMHWYQQKPGQPPKLLIYAASNLESGVPARFSGSGSGTDFTLTINPVEAEDTANYYCQQSFEDPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVT KSFNRGEC

The main structure and function of rituximab, a PD-1 blocked IgG4 humanized monoclonal antibody, commercially available under the name JEMPERLI, has been described in WO 2014/179664, WO 2018/085468 and WO 2018/129559.

The heavy and light chain sequences of the rituximab are as follows:

Heavy chain amino acid sequence (SEQ ID NO: 15)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGG

GSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGT

TVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF

PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAP

EFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT

KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ

VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF

LYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Light chain amino acid sequence (SEQ ID NO: 16)

DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLH

TGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSV

FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST

YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

In some embodiments, the rituximab, or a biological analog thereof, is administered to a patient in need thereof at a dose of 500mg once every three weeks (Q3W).

In some embodiments, the rituximab or a biological analog thereof is administered to a patient in need thereof at a dose of 500mg once every three weeks (Q3W) for 4-6 cycles, followed by 1000mg of the rituximab or a biological analog thereof once every 6 weeks (Q6W).

Palbociclib is a PD-1 blocked IgG4 humanized monoclonal antibody, commercially available as KEYTRUDA.

The heavy and light chain sequences of palbociclib were as follows:

Heavy chain amino acid sequence (SEQ ID NO: 17)

QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGI

NPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFD

YWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGAL

TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP

PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGV

EVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA

KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV

LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Light chain amino acid sequence (SEQ ID NO: 18)

EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLAS

YLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

In some embodiments, palbociclib or a biological analog thereof is administered to a patient in need thereof at a dose of 200mg once every three weeks (Q3W), or at a dose of 400mg once every six weeks (Q6W).

The divaline You Shan was an IgG1 monoclonal antibody against PD-L1 blocking under the trade name IMFINZI.

The heavy and light chain sequences of the rivarotid You Shan antibody are as follows:

heavy chain amino acid sequence (SEQ ID NO: 19)

EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQ

DGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFD

YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA

LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD

KTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTI

SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Light chain amino acid sequence (SEQ ID NO: 20)

EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRA

TGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

In some embodiments, the degree of administration Li Youshan antibody, or a biological analogue thereof, is administered to a patient in need of ≡30kg, at a dose of 1500mg once every three weeks (Q3W).

In some embodiments, the degree of administration Li Youshan antibody, or a biological analogue thereof, is administered to <30kg of the desired patient at a dose of 20mg/kg, once every three weeks (Q3W).

In some embodiments, the degree of administration Li Youshan antibody, or a biological analogue thereof, is administered to a patient in need of ≡30kg, at a dose of 1120mg, once every three weeks (Q3W).

In some embodiments, the dose of 15mg/kg once every three weeks (Q3W) of the anti-ceriva Li Youshan, or a biological analog thereof, is administered to <30kg of the patient in need thereof.

In another aspect, the disclosure discloses the use of the antibody drug conjugate and the immune checkpoint inhibitor in further combination with a platinum-based drug for the preparation of a medicament for treating cancer.

In alternative embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedaplatin (NEDAPLATIN), lobaplatin, satraplatin (satraplatin), cycloplatin (cycloplatin), midaplatin (Miboplatin), enloplatin, iproplatin, dicycloplatin, preferably carboplatin and/or cisplatin.

In alternative embodiments, the antibody drug conjugate and the immune checkpoint inhibitor are contained as active ingredients in separate formulations and administered simultaneously or not simultaneously.

In alternative embodiments, the antibody drug conjugate, the immune checkpoint inhibitor, and the platinum-based drug are contained as active ingredients in separate formulations and administered simultaneously or not simultaneously, respectively.

In another aspect, the antibody drug conjugate and the immune checkpoint inhibitor are contained as active ingredients in a single formulation and administered.

In another aspect, the antibody drug conjugate, the immune checkpoint inhibitor, and the platinum-based drug are contained in a single formulation as active ingredients and administered.

In alternative embodiments, the dosage of the antibody drug conjugate is from 0.1mg/kg to 12.0mg/kg, preferably from 1.0mg/kg to 12.0mg/kg, more preferably from 4.0mg/kg to 12.0mg/kg, more preferably 1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg、10.2mg/kg、10.4mg/kg、10.6mg/kg、10.8mg/kg、11.0mg/kg、11.2mg/kg、11.4mg/kg、11.6mg/kg、11.8mg/kg or 12.0mg/kg.

In alternative embodiments, the antibody drug conjugate is administered once a week, once every two weeks, once every three weeks, or once every four weeks.

In a preferred embodiment, the antibody drug conjugate is administered at an initial dose of 6.0mg/kg or 8.0mg/kg, at a frequency of once every three weeks.

In alternative embodiments, the dose of immune checkpoint inhibitor is from 10mg to 2000mg, preferably 10mg、15mg、20mg、25mg、30mg、40mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、310mg、320mg、325mg、330mg、340mg、350mg、360mg、370mg、375mg、380mg、390mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1120mg、1150mg、1200mg、1250mg、1300mg、1350mg、1400mg、1450mg、1500mg.

In alternative embodiments, the dose of immune checkpoint inhibitor is from 1.0mg/kg to 100mg/kg, preferably from 1.0mg/kg to 40mg/kg, more preferably from 1.0mg/kg to 30mg/kg, more preferably 1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg、10.2mg/kg、10.4mg/kg、10.6mg/kg、10.8mg/kg、11.0mg/kg、11.2mg/kg、11.4mg/kg、11.6mg/kg、11.8mg/kg、12.0mg/kg、12.2mg/kg、12.4mg/kg、12.6mg/kg、12.8mg/kg、13.0mg/kg、13.2mg/kg、13.4mg/kg、13.6mg/kg、13.8mg/kg、14.0mg/kg、14.2mg/kg、14.4mg/kg、14.6mg/kg、14.8mg/kg、15.0mg/kg、15.2mg/kg、15.4mg/kg、15.6mg/kg、15.8mg/kg、16.0mg/kg、16.2mg/kg、16.4mg/kg、16.6mg/kg、16.8mg/kg、17.0mg/kg、17.2mg/kg、17.4mg/kg、17.6mg/kg、17.8mg/kg、18.0mg/kg、18.2mg/kg、18.4mg/kg、18.6mg/kg、18.8mg/kg、19.0mg/kg、19.2mg/kg、19.4mg/kg、19.6mg/kg、19.8mg/kg、20.0mg/kg、20.2mg/kg、20.4mg/kg、20.6mg/kg、20.8mg/kg、30.0mg/kg.

In alternative embodiments, the immune checkpoint inhibitor is administered once a week, once every two weeks, once every three weeks or once every four weeks.

In a preferred embodiment, the dose of immune checkpoint inhibitor is 20mg/kg and the dosing frequency is once every three weeks.

In alternative embodiments, the platinum drug is administered at a dose of 1 to 20mg/ml/min, preferably 1 to 10mg/ml/min, more preferably 2mg/ml/min, 3mg/ml/min, 4mg/ml/min, 5mg/ml/min, 6mg/ml/min, 7mg/ml/min, 8mg/ml/min, 9mg/ml/min, as calculated by area under the curve (AUC), at a frequency of once a week, once a three week or once a four week period.

In alternative embodiments, the platinum group drug is administered at a dose of 10mg/m ² to 500mg/m ², preferably 10mg/m ² to 200mg/m ², more preferably 25mg/m²、50mg/m²、75mg/m²、100mg/m²、125mg/m²、150mg/m²、175mg/m² or 200mg/m ², at a frequency of once per week, once per two weeks, once every three weeks or once every four weeks.

In an alternative embodiment, the platinum-based drugs are co-administered for 4-6 cycles.

In a preferred embodiment, the platinum-based agent is administered as cisplatin 75mg/m ² or carboplatin AUC 5mg/ml/min by intravenous drip, at a frequency of once every three weeks.

In alternative embodiments, the cancer is selected from at least one of lung cancer, esophageal cancer, nasopharyngeal cancer, sarcoma, gastric cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, bladder cancer, salivary gland cancer, head and neck cancer, skin cancer, pharynx cancer, larynx cancer, gall bladder cancer, bile duct cancer, thyroid cancer, uterine cancer, vulval cancer, penile cancer, testicular cancer, urothelial cancer, urethral cancer, colon cancer, rectal cancer, colorectal cancer, esophageal and gastric junction adenocarcinoma, gastrointestinal stromal tumor, squamous cell carcinoma, peritoneal cancer, leukemia, malignant lymphoma, plasma cell tumor, myeloma, neuroepithelial tissue tumor, nerve sheath tumor, mesothelioma, paget's disease.

Further, the lung cancer is selected from non-small cell lung cancer, esophageal squamous carcinoma of esophagus, sarcoma is osteosarcoma, chondrosarcoma, and osteofibrosarcoma.

In an alternative embodiment, the small cell lung cancer is a broad phase small cell lung cancer, a limited phase small cell lung cancer. The non-small cell lung cancer is non-small cell lung squamous carcinoma and non-small cell lung adenocarcinoma.

In alternative embodiments, the cancer is advanced solid cancer that has failed or is intolerant or is not treated with effective criteria by first line therapy.

In alternative embodiments, the cancer is a relapsed, metastatic and/or drug resistant cancer.

In alternative embodiments, the cancer is advanced solid tumors such as small cell lung cancer, non-small cell lung squamous carcinoma, non-small cell lung adenocarcinoma, esophageal squamous carcinoma, and nasopharyngeal carcinoma.

In an alternative embodiment, the small cell lung cancer is a broad phase small cell lung cancer, a limited phase small cell lung cancer.

In alternative embodiments, the cancer is a patient with extensive stage Small Cell Lung Cancer (SCLC) that fails or is intolerant upon at least one line of treatment, locally advanced or metastatic non-small cell lung squamous carcinoma (NSCLC) that progresses or is intolerant upon at least one line of treatment, unresectable locally advanced, recurrent or metastatic esophageal squamous carcinoma (ESCC) that progresses or is intolerant upon at least one line of treatment, locally advanced recurrent or metastatic nasopharyngeal carcinoma (NPC) that progresses or is intolerant upon at least one line of treatment, or other advanced solid tumor that fails or is not treated with an effective standard.

In an alternative embodiment, the osteosarcoma is an advanced osteosarcoma.

In an alternative embodiment, advanced osteosarcoma is advanced osteosarcoma that progresses after standard treatment, with no more than 2 treatment lines going to the total treatment line.

The disclosure also provides a pharmaceutical composition comprising the antibody drug conjugate and an immune checkpoint inhibitor, and one or more pharmaceutically acceptable carriers, excipients and diluents.

In some embodiments, the pharmaceutical composition further comprises the platinum-group drug, and one or more pharmaceutically acceptable carriers, excipients, diluents.

The present disclosure also provides a method of treating cancer comprising administering to a subject in need thereof the antibody drug conjugate described above in combination with an immune checkpoint inhibitor, which may be administered simultaneously or at different time points.

The present disclosure also provides a method of treating cancer comprising administering to a subject in need thereof the above antibody drug conjugate, immune checkpoint inhibitor and platinum-based drug in combination, which may be administered simultaneously or at different time points.

In an alternative embodiment, the lung cancer is selected from the group consisting of non-small cell lung cancer, esophageal squamous carcinoma, sarcoma osteosarcoma, chondrosarcoma, and osteofibrosarcoma.

In alternative embodiments, the cancer is an advanced solid cancer that has failed or is intolerant or is not treated with effective criteria by first line therapy.

In an alternative embodiment, the osteosarcoma is an advanced osteosarcoma.

Another aspect of the present disclosure provides an anti-B7H 3 antibody drug conjugate as described above for use in the treatment of cancer, the anti-B7H 3 antibody drug conjugate being used in combination with the anti-PD-1 antibody or antigen-binding fragment thereof as described above.

Another aspect of the present disclosure provides an anti-B7H 3 antibody drug conjugate as described above for use in the treatment of cancer, the anti-B7H 3 antibody drug conjugate being used in combination with the anti-PD-L1 antibody or antigen-binding fragment thereof as described above.

Another aspect of the present disclosure provides an anti-B7H 3 antibody drug conjugate as described above for use in the treatment of cancer, the anti-B7H 3 antibody drug conjugate being used in combination with the anti-PD-1 antibody or antigen-binding fragment thereof, the platinum-based drug as described above.

Another aspect of the present disclosure provides an anti-B7H 3 antibody drug conjugate as described above for use in the treatment of cancer, the anti-B7H 3 antibody drug conjugate being used in combination with the anti-PD-L1 antibody or antigen-binding fragment thereof, the platinum-based drug as described above.

In the present disclosure, the term "combination" is intended to include a mode of administration which includes the various instances of two or more drugs administered sequentially, or simultaneously.

The mode of administration of simultaneous, separately formulated and co-administered or separately formulated and sequentially administered is a combination as described in the present disclosure. By "simultaneously" is meant herein that at least one dose of an anti-PD-1/PD-L1 antibody or antigen-binding fragment thereof, and an anti-B7H 3 antibody drug conjugate are administered over a period of time, optionally within 3 days, within 2 days, or within 1 day of administration of two or more drugs, wherein both or more substances exhibit pharmacological effects. By "sequential" administration is meant to include the case where the anti-PD-1/PD-L1 antibody or antigen-binding fragment thereof, and the anti-B7H 3 antibody drug conjugate are administered separately during different administration periods. The period of time may be within one administration cycle, alternatively within 4 weeks, within 3 weeks, within 2 weeks, within 1 week. Such a period includes treatment in which the anti-PD-1/PD-L1 antibody or antigen-binding fragment thereof, and the anti-B7H 3 antibody drug conjugate are administered by the same administration route or by different administration routes.

Terminology

For easier understanding of the present disclosure, certain technical and scientific terms are specifically defined below. Unless defined otherwise herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

The present disclosure incorporates the entire contents of application WO2020063673 into the present application.

The term "antibody drug conjugate" refers to an antibody linked to a biologically active drug through a stable linking unit. In the present disclosure, an "antibody drug conjugate" refers to a monoclonal antibody or antibody fragment linked to a biologically active toxic drug through a stable linking unit.

The term "antibody" refers to an immunoglobulin that is a tetrapeptide chain structure formed by joining two identical heavy chains and two identical light chains via interchain disulfide bonds. The immunoglobulin heavy chain constant region differs in amino acid composition and sequence, and thus, in antigenicity. Accordingly, immunoglobulins can be categorized into five classes, or isotypes, igM, igD, igG, igA and IgE, with their respective heavy chains being the μ, δ, γ, α, and epsilon chains, respectively. The same class of Ig can be further classified into different subclasses according to the amino acid composition of the hinge region and the number and position of disulfide bonds of the heavy chain, e.g., igG can be classified into IgG1, igG2, igG3, and IgG4. Light chains are classified by the difference in constant regions as either kappa chains or lambda chains. Each of the five classes of Ig may have either a kappa chain or a lambda chain.

The sequences of the heavy and light chains of antibodies vary greatly from about 110 amino acids near the N-terminus to the variable region (Fv region) and the remaining amino acid sequences near the C-terminus are relatively stable as constant regions. The variable region includes 3 hypervariable regions (HVRs) and 4 Framework Regions (FR) that are relatively conserved in sequence. The 3 hypervariable regions determine the specificity of the antibody, also known as Complementarity Determining Regions (CDRs). Each of the Light Chain Variable Region (LCVR) and Heavy Chain Variable Region (HCVR) consists of 3 CDR regions and 4 FR regions, arranged in the order of FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 from amino terminus to carboxy terminus. The 3 CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3, and the 3 CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.

In the present disclosure, the amino acid sequences of the CDRs are all shown according to the Kabat definition rules. However, it is well known to those skilled in the art that CDRs of an antibody can be defined in a variety of ways, such as Chothia (Chothia et al (1989) Nature 342:877-883; al-Lazikani et al ,"Standard conformations for the canonical structures of immunoglobulins",Journal of Molecular Biology,273,927-948(1997)),) based on Kabat (Kabat et al Sequences of Proteins of Immunological Interest, 4 th edition ,U.S.Department of Health and Human Services,National Institutes of Health(1987)),AbM(University of Bath),Contact(University College London), International ImMunoGeneTics database (IMGT) (world Wide Web IMGT. Cines. Fr /), and North CDR definitions based on neighbor-transmitted clusters (affinity propagation clustering) using a large number of crystal structures, unless otherwise specified, it should be understood by those skilled in the art that the terms "CDR" and "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any of the above known schemes as described by the present invention.

The term "antigen binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind an antigen. Fragments of full length antibodies have been shown to be useful for performing the antigen binding function of antibodies. Examples of binding fragments included in "antigen binding fragments" include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains, (ii) a F (ab') ₂ fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fd fragment consisting of the VH and CH1 domains, (iv) a Fv fragment consisting of the VH and VL domains of a single arm of an antibody, (v) a single domain or dAb fragment (Ward et al, (1989) Nature 341:544-546) consisting of the VH domain, and (vi) an isolated Complementarity Determining Region (CDR) or (vii) a combination of two or more isolated CDRs, optionally linked by a synthetic linker.

The term "drug loading" refers to the average amount of cytotoxic drug loaded per ligand in the molecule of formula (I), which may also be expressed as a ratio of the amount of drug to the amount of antibody, and the drug loading may range from 0 to 12, preferably 1 to 10, cytotoxic drugs (D) per antibody (Pc). In embodiments of the present disclosure, the drug loading is expressed as n, which may also be referred to as the DAR value, with an exemplary average of 1,2,3, 4, 5, 6, 7,8, 9, 10. The average number of drugs per ADC molecule after the coupling reaction can be identified using conventional methods such as UV/visible spectroscopy, mass spectrometry, ELISA assays and HPLC characterization.

The term "immune checkpoint inhibitor" refers to an agent that inhibits the immune suppression system to activate tumor immunity.

The term "anti-PD-1 antibody or antigen-binding fragment thereof" refers to an antibody that specifically binds to PD-1 (programmed cell death-1; CD279; PDCD1) and has activity in reducing, inhibiting and/or interfering with signal transduction caused by the interaction between PD-1 and PD-L1 or PD-L2 as a binding partner. The anti-PD-1 antibodies used in the present disclosure are not particularly limited as long as their clinical efficacy and safety have been demonstrated.

The term "anti-PD-L1 antibody or antigen-binding fragment thereof" refers to an antibody that specifically binds to PD-L1 (programmed cell death ligand 1; CD274; B7-H1) and has activity in reducing, inhibiting and/or interfering with signal transduction caused by the interaction between PD-L1 and PD-1 or B7.1 (CD 80) as a binding partner. The anti-PD-L1 antibody used in the present disclosure is not particularly limited as long as its clinical efficacy and safety have been confirmed.

The term "pharmaceutical composition" is a product comprising one or more active ingredients (e.g., antibodies, ADCs) in optionally specified amounts, as well as any product produced directly or indirectly by combining one or more active ingredients in optionally specified amounts. The different active ingredients in the pharmaceutical composition may be administered separately in separate formulations, including simultaneous or combined potentiation at different time points. In the present disclosure, "pharmaceutical composition" and "formulation" are not mutually exclusive.

The term "treatment" means administration of an internally or externally used therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient having one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the patient or population being treated to induce regression of such symptoms or to inhibit the development of such symptoms to any clinically measurable extent. The amount of therapeutic agent (also referred to as a "therapeutically effective amount") effective to alleviate any particular disease symptom can vary depending on a variety of factors, such as the disease state, age, and weight of the patient, and the ability of the drug to produce a desired therapeutic effect in the patient. Whether a disease symptom has been reduced can be assessed by any clinical test method that a physician or other healthcare professional typically uses to assess the severity or progression of the symptom. While embodiments of the present disclosure (e.g., therapeutic methods or articles of manufacture) may be ineffective in alleviating each target disease symptom, it should be determined according to any statistical test method known in the art, such as Student t-test, chi-square test, U-test according to Mann and Whitney, kruskal-Wallis test (H test), jonckheere-Terpstra test, and Wilcoxon test, that the target disease symptom should be alleviated in a statistically significant number of patients.

Drawings

FIG. 1 therapeutic effect of drug A in combination with drug B on Calu-6 subcutaneous xenograft tumor model.

FIG. 2 therapeutic effect of drug A in combination with drug C on Calu-6 subcutaneous xenograft tumor model.

FIG. 3 therapeutic effect of drug A in combination with drug B on SJSA-1 subcutaneous xenograft tumor model.

FIG. 4 therapeutic effect of drug A in combination with drug C on SJSA-1 subcutaneous xenograft tumor model.

Figure 5 weight change in mice of each group in example 4.

FIG. 6 therapeutic effect of drug A in combination with drug D, drug B or drug C on SJSA-1 subcutaneous xenograft tumor model.

Detailed Description

The present application will be explained in more detail with reference to the following examples, which are only for illustrating the technical aspects of the present application and do not limit the spirit and scope of the present application.

EXAMPLE 1 preparation of anti-B7H 3 antibody drug conjugates

According to the production method described in WO2020063673, an anti-B7H 3 antibody-drug conjugate shown in the following structure was prepared using H1702DS (anti-B7H 3 antibody) and an irinotecan analog, and the HIC method calculated the average value: n=4.1, i.e., FADC-2. Wherein the h1702DS heavy chain sequence is shown as SEQ ID NO:09, and the light chain sequence is shown as SEQ ID NO: 10.

Example 2. Single/combination drug efficacy on PBMC humanized NCG mice allograft model of human lung cancer cell line Calu-6.

1. Experimental materials

1.1 Human lung cancer cell Calu-6 CDX model information

Calu-6 cells were cultured in a 37℃incubator with 5% CO2 in DMEM medium containing 10% fetal bovine serum and 1% green streptomycin diabody. After the cells grow fully, the cells are passaged in bottles, calu-6 cells in the logarithmic growth phase are collected, counted and inoculated.

1.2PBMC information

PBMC were purchased from Massa biosciences Inc., the area of self-trade, zhejiang, batch P121090306C.

1.3 Laboratory animals

NCG mice, females, weighing 17-19g, were purchased from Jiangsu Jiuyaokang Biotech Co.

1.4 Test drug

1) The medicine A is prepared by adopting the method in WO2020063673 and is prepared by physiological saline.

2) The sequences of heavy and light chains of the carlizumab for injection are respectively shown as SEQ ID NO. 11 and SEQ ID NO. 12. Saline for pharmaceutical formulation, supplied by the company of biological medicine, inc., of Cheng Diya, suzhou, lot number 202201004F.

3) The sequence of the heavy chain and the light chain of the medicine C, the Alde Bei Lishan anti-injection, is shown as SEQ ID NO 13 and SEQ ID NO 14 respectively. Saline for pharmaceutical formulation, supplied by the company of biological medicine, inc., of Cheng Diya, suzhou, lot number 202304004C.

1.5 Laboratory apparatus

TABLE 1 Instrument for experiments

1.6 Experimental reagent and consumables

TABLE 2 reagents and consumables for experiments

2. Experimental method

PBMC cells were removed from liquid nitrogen, slowly shaken in a 37 ℃ water bath to thaw, centrifuged, resuspended in PBS and inoculated. After 8 days of PBMC cell seeding, 0.1mL of Calu-6 cell suspension (containing 5X 10 ⁶ cells) was inoculated subcutaneously on the right back of NCG mice. Tumor growth was observed and random groupings were made according to tumor volume and animal body weight, with an average tumor volume of 145mm ³. The day of grouping is defined as day 0, PG-D0. All animals were dosed on the day of grouping and the remaining animals were euthanized at the end of the experiment. The specific dosages and schedules are shown in Table 3. Tumor volume, mouse body weight, was measured and data recorded.

TABLE 3 administration and grouping

A. the administration volume was 10. Mu.l/g based on the body weight of the mice. Stopping administration when weight loss exceeds 15%, and recovering

And recovery of administration is achieved within 10%.

The experimental index is used for examining the influence of the drug on the tumor growth, and the specific index is the relative tumor proliferation rate T/C (%) or tumor inhibition rate TGI (%). Tumor volume measurement, two measurements per week using vernier calipers, tumor volume calculation formula v=0.5a×b ², a and b representing the long and wide diameters of the tumor, respectively.

Calculation of TGI (%) = [1- (mean tumor volume at the end of treatment group administration-mean tumor volume at the end of treatment group)/(mean tumor volume at the end of vehicle control group treatment-mean tumor volume at vehicle control group) ]100% when tumor does not regress. When there was regression of the tumor, TGI (%) = [1- (mean tumor volume at the end of administration of a treatment group-mean tumor volume at the treatment group)/mean tumor volume at the treatment group ] ×100%.

Calculation of T/C (%) = average tumor volume at the end of dosing of a treatment group/average tumor volume at the end of treatment of vehicle control group x 100%.

At the end of the experiment (PG-D21), all animals were euthanized in the group order, in turn, by CO ₂ asphyxiation. After euthanasia, the animals were stripped of the tumor mass and the tumor mass was weighed and photographed.

All data are expressed in mean±sem. Based on tumor volume data at different time points for each group, statistical analysis was performed to assess the differences between groups using Dunnett's multiple comparisons test in Two-way ANOVA. Group-to-group differential analysis of tumor volumes was performed using Dunnett's multiple comparisons test in One-way ANOVA. The t-test was used to conduct a differential analysis of tumor volume between the two groups. All data analysis was performed with GRAPHPAD PRISM, p <0.05 was considered significant differences.

3. Experimental results

The growth inhibition effect of single drug or combined therapy of drug A, drug B and drug C on human lung cancer cell Calu-6 subcutaneous xenograft tumor is shown in Table 4, figure 1 and figure 2, wherein the data of the Vehicle group, drug A_1mg/kg group and drug A_2mg/kg group are the same experimental data.

TABLE 4 evaluation of tumor-inhibiting efficacy of drug A, drug B and drug C on Calu-6 xenograft tumor model by monotherapy or combination therapy

a.Mean±SEM;

B. Statistical analysis was performed using Dunnett's multiple comparisons test in One-way ANOVA, as compared to the Vehicle group. In addition, statistical analysis was performed using t-test, with the p-value being 0.0364 and <0.0001 for the drug A_2mg/kg combined drug B_3mg/kg compared to the drug A_2mg/kg and drug B_3mg/kg, respectively, and the p-value being <0.0001 for the drug A_2mg/kg combined drug C_20mg/kg compared to the drug C_20mg/kg.

In the PBMC humanized human lung cancer cell strain Calu-6 xenograft tumor model, the tumor inhibition rates of drug A_1mg/kg and drug A_2mg/kg for single drug treatment are 51.25% and 74.82% respectively, and the significant and dose-dependent tumor inhibition effects are shown. The tumor inhibition rates of the single drug treatment of drug B_3mg/kg and drug C_20mg/kg are respectively 0.97% and-4.55%, and no obvious tumor inhibition effect is shown. The tumor inhibition rates of the combination treatment of the medicine A_1mg/kg and the medicine A_2mg/kg and the medicine B_3mg/kg are 58.63% and 89.93%, respectively, wherein the combination treatment group of the medicine A_2mg/kg and the medicine B_3mg/kg has obviously improved tumor inhibition effect compared with the single medicine treatment group of the medicine A_2mg/kg and the single medicine treatment group of the medicine B_3mg/kg. The tumor inhibition rate of the combined treatment of the medicine A_2mg/kg and the medicine C_20mg/kg is 80.34%, and the tumor inhibition effect of the combined treatment group is obviously superior to that of the single medicine treatment group of the medicine C_20mg/kg and is superior to that of the single medicine treatment group of the medicine A_2mg/kg. In addition, mice did not develop treatment-related mortality and other abnormal symptoms, indicating that tumor-bearing mice were well tolerated for drug a single treatment, as well as for drug B, drug C in combination.

During the experiment, the average body weight of the Vehicle group animals was relatively stable, and at the end of the experiment (day 21), the average body weight change rate of the group animals was 8.97%. The average body weight change rates of the tumor-bearing mice in the drug A_1mg/kg single drug group and the drug A_2mg/kg single drug group were 8.27% and 6.22%, respectively. The average weight change rates of tumor-bearing mice in the single drug group of drug B_3mg/kg and the combination treatment group of drug A_1mg/kg and drug A_2mg/kg are-3.79%, 1.73% and-1.53%, respectively. The average body weight change rate of the tumor-bearing mice in the single drug group of drug C_20mg/kg and the treatment group of drug A_2mg/kg is 6.58% and 1.84%, respectively. The tumor-bearing mice can well tolerate the single drug treatment of the drug A of the tested drugs and the combined treatment of the drug B and the drug C.

In conclusion, the tumor-bearing mice are resistant to single drug treatment of drug A or combined drug B and drug C, the anti-tumor efficacy of the combined drug treatment group of drug A_2mg/kg and drug B_3mg/kg is obviously superior to that of each single drug treatment group, and the anti-tumor efficacy of the combined drug treatment group of drug A_2mg/kg and drug C_20mg/kg is obviously superior to that of the single drug treatment group of drug C_20mg/kg, and is superior to that of the single drug treatment group of drug A_2mg/kg.

Example 3 clinical trials of anti-B7H 3 antibody drug conjugate in combination with immune checkpoint inhibitor+ -platinum drugs for the treatment of advanced solid tumors

1. Purpose of test

The experiment was used to evaluate the safety, tolerability, efficacy of each combination treatment regimen in patients with advanced solid tumors, study endpoints including, but not limited to, MTD or Maximum Applicable Dose (MAD) of intravenous infusion of anti-B7H 3 antibody drug conjugate in the combination treatment regimen, objective Remission Rate (ORR), disease Control Rate (DCR), duration of remission (DoR) and Progression Free Survival (PFS), total survival (OS) assessed by the study personnel according to RECIST 1.1 criteria, pharmacokinetic profile of intravenous infusion of anti-B7H 3 antibody drug conjugate in the combination treatment regimen, immunogenicity of anti-B7H 3 antibody drug conjugate in the combination treatment regimen.

2. Test drug:

(1) anti-B7H 3 antibody drug conjugates

The preparation is injection (freeze-dried powder) with the specification of 100 mg/bottle, and is packaged by adopting a 20mL medium borosilicate glass tube injection bottle, and the manufacturer is Shanghai Hansen biological medicine technology Co., ltd.

(2) Immune checkpoint inhibitors

The Aldebelimumab is in the form of injection with the specification of 600mg (12 ml)/bottle, and is bottled by medium borosilicate glass tube injection, and the manufacturer is Suzhou Cheng Diya biological medicine Co.

(3) Platinum medicine

Carboplatin, in the form of injection, 50mg (10 mL)/100 mg (10 mL), ampoule package, manufacturer, qilu pharmaceutical Co.

Cisplatin, injection, 6ml, 30mg, bottled antibiotic, and manufactured by Jiangsu Haoshen pharmaceutical Co., ltd.

3. Target population:

patients with advanced solid tumors that failed or were intolerant or not treated with effective criteria by first-line therapy are specified by (1) wide-phase small-cell lung cancer (SCLC) that failed or were intolerant with at least one first-line therapy, (2) wide-phase small-cell lung cancer (SCLC) that was not treated with wide-phase, (3) locally advanced or intolerant non-small-cell squamous lung cancer (NSCLC) that progressed or was intolerant after at least one first-line therapy, (4) locally advanced or metastatic non-small-cell squamous lung cancer (NSCLC) that was not treated with an advanced stage, (5) unresectable locally advanced recurrent or metastatic squamous esophageal cancer (ESCC) that progressed or was intolerant after at least one first-line therapy, (6) unresectable locally advanced recurrent or metastatic squamous esophageal cancer (ESCC) that was untreated with an advanced or intolerant locally advanced stage recurrent or metastatic squamous esophageal cancer (NPC) that was developed or was intolerant after at least one first-line therapy, (8) that was not treated with a post-stage recurrent or metastatic squamous esophageal cancer (NPC) that was treated with an advanced stage, and (9) that were not treated with an advanced stage of non-grade recurrent or metastatic squamous esophageal cancer (ESCC) that were not treated with an effective criteria by at least one first-line therapy, (6) that were not resistant to be able to be sufficient to be treated with sufficient criteria by one second-line therapy, and no clinical cancer

4. Dosing regimen:

The study was one treatment cycle (C) every 3 weeks (21 days).

Queue 1a:

The recommended administration priority is to administer the adobevacizumab first and to administer the anti-B7H 3 antibody drug conjugate treatment at intervals of at least 30min after completion of administration. The entire dosing regimen (adobevacizumab + anti-B7H 3 antibody drug conjugate) was required to be completed within 72 hours, starting from the first drug administration to the last drug administration of the combination therapy.

The total dose, i.e., intravenous drip, Q3W, was calculated from the pre-subject weight measurements of 20mg/kg of Aldebizumab until objective disease progression (excluding the gift) or other criteria for termination of study treatment were met as prescribed by the regimen. anti-B7H 3 antibody drug conjugates were administered at an initial dose of 8.0mg/kg, intravenously instilled, Q3W, until objective disease progression (except for the gift) or other criteria for termination of study treatment as prescribed by the regimen were met.

Queue 1b:

The recommended administration priority is to administer the adobevacizumab first, the anti-B7H 3 antibody drug conjugate treatment at intervals of at least 30min after the administration is completed, and the anti-B7H 3 antibody drug conjugate treatment at intervals of at least 60min after the administration is completed. The entire dosing regimen (adobevacizumab + anti-B7H 3 antibody drug conjugate + cisplatin/carboplatin) was required to be completed within 72 hours, starting from the first drug administration to the last drug administration of the combination therapy.

The total dose, i.e., intravenous drip, Q3W, was calculated from the pre-subject weight measurements of 20mg/kg of Aldebizumab until objective disease progression (excluding the gift) or other criteria for termination of study treatment were met as prescribed by the regimen. anti-B7H 3 antibody drug conjugates were administered at an initial dose of 6.0mg/kg, intravenously instilled, Q3W, until objective disease progression (except for the gift) or other criteria for termination of study treatment as prescribed by the regimen were met.

Cisplatin/carboplatin cisplatin 75mg/m2 or carboplatin AUC 5mg/ml/min intravenous drip, Q3W, co-administration for 4-6 cycles. The researcher may choose cisplatin or carboplatin according to the specific circumstances of the subject. Cisplatin is allowed to be used interchangeably with carboplatin during treatment due to tolerability issues, but the subject should be adequately informed of the risk of cross-allergy. If the subject is intolerant for safety, the treatment with the drug is terminated.

5. Test results:

At 2025, month 01 and 15, 111 subjects were enrolled, each of which was first administered with adobelizumab, and after completion of administration, an anti-B7H 3 antibody drug conjugate treatment was administered, with a total of 50 subjects completing at least 1 tumor assessment.

In all 50 populations, 22 PR (44%), 27 SD (54%), 1 PD (2%), ORR 44.0% and DCR 98.0% were counted. In terms of safety, 50 subjects did not see an unacceptable severe adverse reaction.

The analysis of the curative effect results of specific cancer groups is shown in table 5, wherein the objective relief rate ORR of extensive stage small cell lung cancer is 55.6%, the objective relief rate ORR of nasopharyngeal carcinoma is 50.0%, the objective relief rate ORR of non-small cell lung adenocarcinoma is 36.4%, the objective relief rate ORR of esophageal cancer is 33.3%, and the objective relief rate ORR of non-small cell lung squamous cell carcinoma is 23.1%.

TABLE 5 summary of objective remission rate and disease control rate for cohort 1a

In conclusion, the anti-B7H 3 antibody drug conjugate and the Alde Bei Lishan antibody are treated in a combined way, and the exact anti-tumor effect is observed in patients with extensive stage small cell lung cancer, non-small cell lung squamous cell carcinoma, non-small cell lung adenocarcinoma, esophagus cancer and nasopharyngeal carcinoma. The security event is predictable and manageable.

EXAMPLE 4 in vivo inhibition of human osteosarcoma cell mouse transplantation tumor by drug A in combination with drug B or drug C

1. Experimental materials

Human osteosarcoma cell line SJSA-1 was purchased from Ji Ni European biotechnology Co., ltd. In vitro monolayer culture under the conditions of DMEM medium plus 10% fetal bovine serum and 37℃in a 5% CO ₂ cell incubator. Passaging was performed twice a week with conventional digestion treatments with pancreatin-EDTA. When the saturation of the cells is 80% -90% and the number reaches the requirement, the cells are collected, counted and inoculated.

NOG-dKO mice, females, weighing 16-22g, purchased from Zhejiang Violet laboratory animal technologies Co., ltd

2. Experimental method

PBMC cells (human peripheral blood mononuclear cells) were resuspended in PBS to a density of 5.0×10 ⁷ cells/mL, injected tail vein, and each mouse was vaccinated with 0.1mL (5.0×10 ⁶ cells/mouse);

After one week of seeding of PBMC cells, SJSA-1 cells were resuspended in PBS, the density was adjusted to 1.0 x 10 ⁸ cells/mL, the resuspended cells were mixed with an equal volume of Matrigel, seeded subcutaneously on the right back of each mouse, and each seeded 0.1mL (5.0 x 10 ⁶ cells/mouse);

When the average tumor volume is 50-100mm ³, the preparation is divided into groups (D0) and is administrated (D0). Intravenous administration (i.v., drug a) or intraperitoneal administration (i.p., drug B or drug C) to the mice at single (Singledose, drug a) or twice weekly (BIW, drug B or drug C), at 10mL/kg of volume, at the same volume of "solvent" (Saline) given in the solvent group, and the specific dosages and regimens are shown in table 6. Tumor volume was measured, mice were weighed, and data were recorded.

The experimental index is to examine the influence of the drug on the tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).

The tumor diameter is measured by a vernier caliper, and the calculation formula of the tumor volume (V) is as follows:

V=1/2×a×b ² where a, b represent the long and short diameters of the tumor, respectively.

T/C (%) = (T-T _i)/(C-C_i) ×100 where T and C are tumor volumes of the administration group and the control group at the end of the experiment, and T _i and C _i are tumor volumes of the administration group and the control group at the beginning of the experiment.

Tumor inhibition ratio (TGI) (%) =100-T/C (%).

Tumor inhibition ratio (TGI) (%) =100- (T-Ti)/ti×100 when tumor regression occurs.

If the tumor is reduced from the initial volume, i.e., T < T _i or C < C _i, it is defined as partial tumor regression (PR), and if the tumor is completely disappeared, it is defined as complete tumor regression (CR).

At the end of the experiment, at the end of the experiment or at an average tumor volume of 2,000mm ³, mice were euthanized, then dissected for tumor removal and photographed.

Experimental data were analyzed and plotted with GRAPHPAD PRISM. Based on tumor volume data at different time points for each group, statistical analysis was performed to assess inter-group differences using Two-way ANOVA. P <0.05 was defined as statistically significant.

TABLE 6 dosing regimen of drug A in combination with B or drug C in human osteosarcoma SJSA-1 model

3. Experimental results

The growth inhibition effect of drug A in combination with drug B on SJSA-1 model is shown in Table 7 and figure 3. The growth inhibitory effect of drug A in combination with drug C on SJSA-1 model is shown in Table 8 and FIG. 4. The body weight changes of each group of mice are shown in figure 5.

TABLE 7 growth inhibition of SJSA-1 model by drug A combination drug B

Note that:

p value Day 22, which is a value obtained by analyzing the tumor volume of each animal in different groups by taking the solvent group as a control;

^# Analysis was performed using Two-way ANOVA with ^##P<0.01、^### P <0.001 compared to drug A+drug B combination.

At the end of the experiment (Day 22), the average tumor volumes of the drug A, the drug B and the drug A+drug B are respectively 1,763mm ³、1,900mm³ and 907mm ³, the tumor inhibition rates are respectively 31.26%, 25.67% and 66.08%, compared with the solvent group, each administration group has obvious tumor inhibition effect, and the drug A+drug B combined treatment group (G5) has statistically significant difference compared with the single drug groups (G2 and G3), and shows stronger tumor inhibition effect.

TABLE 8 growth inhibition of SJSA-1 model by drug A combination drug C

Note that:

^# Analysis was performed using Two-way ANOVA with ^### P <0.001 compared to drug A+drug C combination.

At the end of the experiment (Day 22), the average tumor volumes of the drug A, the drug C and the drug A+drug C are respectively 1,763mm ³、1,911mm³ and 558mm ³, the tumor inhibition rates are respectively 31.26%, 25.25% and 80.26%, compared with the solvent group, each administration group has obvious tumor inhibition effect, and the drug A+drug C combined treatment group (G6) has statistically significant difference compared with the single drug groups (G2 and G4), and has stronger tumor inhibition effect.

In the whole experimental process, the SJSA-1 tumor-bearing mice have better tolerance to the drug A, the drug B, the drug C, the drug A combined drug B and the drug A combined drug C.

In general, in a human osteosarcoma cell SJSA-1 mouse model, the drug A+drug B combined treatment and the drug A+drug C combined treatment have better tumor inhibition effect than the single drugs.

Example 5. Single/combination drug efficacy on PBMC humanized NCG dKO mice xenograft model of human osteosarcoma cell line SJSA-1.

1. Experimental materials

1.1 Human osteosarcoma cell SJSA-1CDX model information

SJSA-1 cells were cultured in an incubator at 37℃with RPMI 1640 medium containing 10% fetal bovine serum and 1% green streptomycin diabody. After the cells grow fully, the cells are passaged in bottles, SJSA-1 cells in the logarithmic growth phase are collected, counted and inoculated.

1.2PBMC information

PBMCs were purchased from shanghai hundred biotechnology limited, batch 2304120048.

1.3 Laboratory animals

NCG dKO mice, females, weighing 18-26g, were purchased from Jiangsu Jiuyaokang biotechnology Co.

1.4 Test drug

2) The sequences of heavy and light chains of the carlizumab for injection are respectively shown as SEQ ID NO. 11 and SEQ ID NO. 12. Saline for pharmaceutical formulation, supplied by the company of biological medicine, inc., of Cheng Diya, suzhou, lot number 202210055F.

4) Cisplatin as medicine D. Purchased from MedChemExpress, lot 421942, stock solution was prepared with water for injection, and stock solution was diluted with normal saline for drug preparation.

1.5 Laboratory apparatus

TABLE 9 Instrument for experiments

1.6 Experimental reagent and consumables

TABLE 10 reagents and consumables for experiments

2. Experimental method

PBMC cells were removed from liquid nitrogen, slowly shaken in a 37 ℃ water bath to thaw, centrifuged, resuspended in PBS and inoculated. After 8 days of PBMC cell seeding, 0.1mL of SJSA-1 cell suspension (containing 5X 10 ⁶ cells) was inoculated subcutaneously on the right back of NCG dKO mice. Tumor growth was observed and random groupings were made according to tumor volume and animal body weight, with an average tumor volume of 84mm ³. The day of grouping is defined as day 0, PG-D0. All animals were dosed on the day of grouping and the remaining animals were euthanized at the end of the experiment. The specific dosages and schedules are shown in Table 11. Tumor volume, mouse body weight, was measured and data recorded.

TABLE 11 administration and grouping

B. The administration volume was 10. Mu.L/g based on the body weight of the mice. The administration was stopped when the body weight was reduced by more than 15%, and was resumed when the body weight was restored to within 10%.

At the end of the experiment (PG-D18), all animals were euthanized by CO ₂ asphyxiation in sequence in the group order. After euthanasia, the animals were stripped of the tumor mass and the tumor mass was weighed and photographed.

All data are expressed in mean±sem. Based on tumor volume data at different time points for each group, statistical analysis was performed to assess the differences between groups using Dunnett's multiple comparisons test in Two-way ANOVA. Group-to-group differential analysis of tumor volumes was performed using Dunnett's multiple comparisons test in One-way ANOVA. The t-test was used to conduct a differential analysis of tumor volume between the two groups. All data analysis was performed with GRAPHPAD PRISM a, p <0.05 was considered significant differences.

3. Experimental results

The growth inhibition effect of drug A, drug B, drug C and drug D on human osteosarcoma cell SJSA-1 subcutaneous xenograft tumor by single or combined treatment is shown in Table 12 and figure 6.

TABLE 12 evaluation of tumor inhibiting efficacy of drug A, drug B, drug C and drug D on SJSA-1 xenograft tumor model by single or combination therapy

a.Mean±SEM;

B. Statistical analysis was performed using Dunnett's multiple comparisons test in One-way ANOVA, as compared to the Vehicle group. In addition, statistical analysis was performed using t-test, with drug A_12mg/kg in combination with drug B_10mg/kg and drug D_2.5mg/kg in combination with drug A_12mg/kg, drug B_10mg/kg and drug, respectively

The group D_2.5mg/kg was compared with p values of 0.0238, <0.0001 and 0.0092, respectively, the group A_12mg/kg of the combination drug C_30mg/kg and the group D_2.5mg/kg were compared with the group A_12mg/kg, the group C_30mg/kg and the group D_2.5mg/kg, respectively, p values of 0.0179, <0.0001 and 0.0097, respectively.

In the PBMC humanized human osteosarcoma cell strain SJSA-1 allograft tumor model, the tumor inhibition rate of drug A_12mg/kg single drug treatment is 60.76%, and the tumor inhibition effect is obvious. The tumor inhibition rates of the single drug treatment of the drug B_10mg/kg and the drug C_30mg/kg are 25.93 percent and 26.74 percent respectively, and the drug does not show obvious tumor inhibition effect, and the tumor inhibition rate of the single drug treatment of the drug D_2.5mg/kg is 46.18 percent, so that the drug has obvious tumor inhibition effect.

The tumor inhibition rate of the combination drug B_10mg/kg of the drug A_12mg/kg and the combination drug D_2.5mg/kg is 76.50%, the tumor inhibition effect is obvious, the three-drug combination drug has the advantages that the tumor inhibition effect is obviously improved compared with the single drug groups, the three-drug combination drug has statistical differences, the tumor inhibition rate of the combination drug C_30mg/kg of the drug A_12mg/kg and the combination drug D_2.5mg/kg is 78.95%, the tumor inhibition effect is obvious, the three-drug combination drug has the obvious tumor inhibition effect which is obviously improved compared with the single drug groups, and the three-drug combination drug has the statistical differences.

In conclusion, the triple drug effect of the drug A combined drug D and the drug B or the drug C is obvious and is obviously superior to the single drug treatment.

Example 6 clinical trials of anti-B7H 3 antibody drug conjugate in combination with immune checkpoint inhibitor for the treatment of advanced osteosarcoma

1. Test purpose:

Safety, tolerability, pharmacokinetics (PK) and efficacy of the injectable anti-B7H 3 antibody drug conjugate combination treatment regimen were evaluated in advanced osteosarcoma subjects.

An extended study of the target population will be conducted in determining safe and potentially effective doses to obtain further safety, PK and efficacy of the combination treatment regimen, and to determine the target dose of the combination treatment regimen.

2. Test drug name:

(1) anti-B7H 3 antibody drug conjugates

(2) Immune checkpoint inhibitors

3. Target population:

Queue 2

Dose escalation/expansion of the population advanced osteosarcoma following standard treatment requires simultaneous satisfaction of the following conditions:

① Advanced osteosarcoma is defined as a. Primary or locally recurrent tumor cannot be radically treated by surgery or other local treatment means (e.g., stereotactic radiosurgery, argon helium knife, ultrasonic focusing knife, etc.), or the patient refuses surgery or other local treatment. b. Distant metastasis has occurred and the metastasis cannot be radically cured by surgery or other local treatment means (e.g., stereotactic radiosurgery, argon helium knife, ultrasonic focusing knife, etc.), or the patient refuses surgery or other local treatment.

② After standard treatment, standard treatment is defined as receiving 2 or more of the following standard therapeutic drugs, methotrexate, anthracyclines, cisplatin or ifosfamide. If the subject has been previously only subjected to first-line treatment (2 standard therapeutic drugs) and disease progression occurs within 6 months after treatment, then patients over 6 months will need to be assessed by the researcher to determine whether the subject is in the treatment study by risk benefit assessment.

③ The total number of treatment lines in the past is not more than 2.

4. Dosing regimen

All two drug combination cohorts (cohort 2 a) were pre-set with an initial dose of 10.0mg/kg Q3W for anti-B7H 3 antibody drug conjugate, and in cohort 2a the combined drug dose was fixed and only the dose of anti-B7H 3 antibody drug conjugate was adjusted.

Aldebarlimab, 20mg/kg, intravenous drip, Q3W, until objective disease progression (except continued treatment after disease progression) or other criteria prescribed by the protocol for termination of study treatment are met.

Anti-B7H 3 antibody drug conjugates were administered at a preset dose of 10mg/kg, intravenously instilled, Q3W, until objective disease progression (except for continued treatment after disease progression) or other criteria for termination of study treatment prescribed by the protocol were met.

While specific embodiments of the invention have been described in detail, it will be appreciated by those skilled in the art that various modifications and alternatives to those details could be developed in light of the overall teachings of the disclosure and that such modifications would be within the scope of the invention. The full scope of the invention is given by the appended claims together with any equivalents thereof.

Claims

1. Use of an antibody-drug conjugate and an immune checkpoint inhibitor in combination for the preparation of a drug for treating cancer, wherein the structure of the antibody-drug conjugate is shown in formula (I):

in:

n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, and n is a decimal or an integer;

Pc is an anti-B7H3 antibody or an antigen-binding fragment thereof.

2. The use according to claim 1, wherein the anti-B7H3 antibody or antigen-binding fragment thereof comprises: heavy chain HCDR1, HCDR2, HCDR3 as shown in the amino acid sequences of SEQ ID NOs: 01, 02 and 03, respectively, and light chain LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NOs: 04, 05 and 06, respectively.

3. The use according to claim 1 or 2, wherein the anti-B7H3 antibody or antigen-binding fragment thereof is selected from a humanized antibody or a fragment thereof.

4. The use according to claim 3, wherein the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, and a light chain constant region comprising κ or λ; preferably, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain constant region of IgG1 or IgG4 isotype.

5. The use according to claim 3, wherein the heavy chain variable region sequence of the anti-B7H3 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 07 or a variant thereof, and the light chain variable region sequence is as shown in SEQ ID NO: 08 or a variant thereof.

6. The use according to any one of claims 1 to 5, wherein the heavy chain sequence of the anti-B7H3 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 09 or a variant thereof, and the light chain sequence is as shown in SEQ ID NO: 10 or a variant thereof.

7. The use according to any one of claims 1 to 6, wherein the immune checkpoint inhibitor is selected from antibodies or antigen-binding fragments thereof targeting PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA, A2aR, B7-H3, B7-H4, preferably antibodies or antigen-binding fragments thereof targeting PD-1 or PD-L1.

8. The use according to any one of claims 1 to 7, wherein the immune checkpoint inhibitor is selected from Toripalimab, Sintilimab, Camrelizumab, Dostarlimab, Tislelizumab, Zimberelimab, Penpulimab, Serplulimab, Pucotenlimab, Pembrolizumab, Nivolumab, umab), Sugemalimab, Envafolimab, Adebrelimab, Atezolizumab, Durvalumab, Ipilimumab, Candonilimab; preferably Camrelizumab, Adebrelimab, Dostarlimab, Pembrolizumab, Durvalumab.

9. The use according to any one of claims 1 to 8, further combined with a platinum drug.

10. The use according to claim 9, wherein the platinum drug is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, nedaplatin, lobaplatin, satraplatin, cycloplatin, miboplatin, enloplatin, iproplatin, and dicycloplatin, preferably carboplatin and/or cisplatin.

11. The use according to any one of claims 1 to 10, wherein the antibody drug conjugate and the immune checkpoint inhibitor are contained in different preparations as active ingredients, respectively, and are administered simultaneously or at different times.

12 . The use according to claim 1 , wherein the antibody drug conjugate and the immune checkpoint inhibitor are contained in a single formulation as active ingredients and administered.

13. The use according to claim 9 or 10, wherein the dosage of the platinum drug is calculated as the area under the curve (AUC) and is 1 to 10 mg/ml/min, preferably 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/min, 8 mg/ml/min, and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks.

14. The use according to claim 9 or 10, wherein the dosage of the platinum drug is 10 mg/ ^m2 to 500 mg/ ^m2 , preferably 10 mg/ ^m2 to 200 mg/ ^m2 , more preferably 25 mg/ ^m2 , 50 mg/ ^m2 , 75 mg/m2, 100 mg/ ^m2 , 125 mg/ ^m2 , 150 mg/ ^m2 , 175 mg/ ^m2 or 200 ^mg / ^m2 , and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks.

15. The use according to any one of claims 1 to 14, wherein the dosage of the antibody drug conjugate is 0.1 mg/kg to 12.0 mg/kg, preferably 1.0 mg/kg to 12.0 mg/kg, and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks.

16. The use according to any one of claims 1 to 15, wherein the dosage of the immune checkpoint inhibitor is 10 mg to 2000 mg, preferably 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1120 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks.

17. The use according to any one of claims 1 to 16, wherein the dosage of the immune checkpoint inhibitor is 1.0 mg/kg to 100 mg/kg, preferably 1.0 mg/kg to 40 mg/kg, more preferably 1.0 mg/kg to 30 mg/kg, and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks.

18. The method of claim 1 , wherein the cancer is selected from at least one of the following: lung cancer, esophageal cancer, nasopharyngeal cancer, sarcoma, gastric cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, bladder cancer, salivary gland cancer, head and neck cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, uterine cancer, vulvar cancer, penile cancer, testicular cancer, urothelial cancer, urethral cancer, colon cancer, rectal cancer, colorectal cancer, esophageal and gastric junction cancer, gastrointestinal stromal tumor, squamous cell carcinoma, peritoneal cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, neuroepithelial tumor, nerve sheath tumor, mesothelioma, and Paget's disease.

19. The use according to claim 18, wherein the lung cancer is selected from non-small cell lung cancer and small cell lung cancer, the esophageal cancer is esophageal squamous cell carcinoma, and the sarcoma is osteosarcoma, chondrosarcoma, or fibrosarcoma of bone.

20. The use according to any one of claims 1 to 17, wherein the cancer is an advanced solid tumor that has failed first-line treatment or is intolerant to or has no effective standard treatment.

21. The use according to claim 19, wherein the osteosarcoma is advanced osteosarcoma, preferably advanced osteosarcoma that has progressed after standard treatment, and the total number of previous treatment lines does not exceed 2 lines of treatment.

22. A pharmaceutical composition comprising an antibody drug conjugate as defined in any one of claims 1 to 21 and an immune checkpoint inhibitor, and one or more pharmaceutically acceptable carriers, excipients, and diluents.

23. A method for treating cancer, comprising administering to a subject in need thereof a combination of an antibody drug conjugate as defined in any one of claims 1 to 21, an immune checkpoint inhibitor as defined in any one of claims 1 to 21, and optionally a platinum drug as defined in any one of claims 9-20, wherein the combined administration may be simultaneous or at different time points.

24. The method of claim 23, wherein the cancer is selected from at least one of the following: lung cancer, esophageal cancer, nasopharyngeal cancer, sarcoma, gastric cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, bladder cancer, salivary gland cancer, head and neck cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, uterine cancer, vulvar cancer, penile cancer, testicular cancer, urothelial cancer, urethral cancer, colon cancer, rectal cancer, colorectal cancer, esophageal gastric junction cancer, gastrointestinal stromal tumor, squamous cell carcinoma, peritoneal cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, neuroepithelial tissue tumor, nerve sheath tumor, mesothelioma, Paget's disease.

25. The method according to claim 24, wherein the lung cancer is selected from non-small cell lung cancer and small cell lung cancer, the esophageal cancer is esophageal squamous cell carcinoma, and the sarcoma is osteosarcoma, chondrosarcoma, or fibrosarcoma of bone.

26. The method of claim 23, wherein the cancer is an advanced solid tumor that has failed or is intolerant to first-line treatment or has no effective standard treatment.

27. The method according to claim 25, wherein the osteosarcoma is advanced osteosarcoma, preferably advanced osteosarcoma that has progressed after standard treatment, and the total number of previous treatment lines does not exceed 2 lines of treatment.