Combined use of antibody-drug conjugate and Anti-VEGF antibody

Abstract

The present invention relates to use of an antibody-drug conjugate alone or in combination in the preparation of a drug for preventing and / or treating cancer. Specifically, the present invention provides use of an antibody-drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof in combination with an anti-VEGF antibody, or in combination with an anti-VEGF antibody and one or more chemotherapeutic agents, in the preparation of a drug for preventing and / or treating cancer.

Description

Combined use of antibody-drug conjugates and anti-VEGF antibodies Technical Field

[0001] This application belongs to the pharmaceutical field and relates to the use of an antibody-drug conjugate, either alone or in combination, in the preparation of medicaments for the prevention and / or treatment of cancer. Specifically, this invention provides the use of an antibody-drug conjugate or a pharmaceutically acceptable salt, metabolite, or solvent compound thereof, in combination with a VEGF antibody, in the preparation of medicaments for the prevention and / or treatment of cancer. Background Technology

[0002] Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. In 2020, there were 1.932 million new cases of colorectal cancer globally, with 935,000 deaths. The 2020 China Cancer Statistics Report shows that there were 555,000 new cases of colorectal cancer and 286,000 deaths in my country, ranking second and fifth respectively among all malignant tumors. The incidence and mortality rates are increasing year by year, showing a trend of earlier onset. The 5-year survival rates for colon and rectal cancer patients in China are 57.6% and 56.9% respectively, both lower than the global median. The occurrence of colorectal cancer is closely related to physiological, genetic, behavioral, lifestyle, and disease factors. At the time of initial diagnosis, 83% of colorectal cancer patients are in the middle or late stages, and 44% have already developed metastases to sites such as the liver and lungs. Early-stage colorectal cancer can be treated with surgical resection. Advanced or metastatic colorectal cancer is treated as a first- or second-line regimen using fluorouracil-based chemotherapy combined with targeted therapies. Third-line treatment primarily involves monotherapy. Immunotherapy can be used for patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). However, severe toxic side effects and drug resistance limit the clinical efficacy of current standard treatments. Less than one-third of patients benefit from targeted therapy and immunotherapy. There is a significant unmet need in clinical practice, requiring new drugs or treatment modalities.

[0003] B7-H3 is a member of the B7 family of immune checkpoint proteins. It plays an immunosuppressive role, helping cancer cells evade immune surveillance by negatively regulating immune cells, thus promoting tumor progression. B7-H3 is not expressed or is expressed at low levels in normal tissues, but is highly expressed in various solid tumors, including colorectal cancer. Furthermore, the expression level of B7-H3 is negatively correlated with the prognosis of various tumors.

[0004] It has been reported that approximately 50% of colorectal cancers express VEGF-A (70% in advanced stages), while it is expressed at low levels or not at all in normal colonic mucosa and adenomas. VEGF-A expression levels are closely related to the prognosis of CRC patients. Currently, the anti-VEGF-A antibody bevacizumab combined with chemotherapy has become the standard first- and second-line treatment for colorectal cancer. Meanwhile, with the introduction of the FOLFOX regimen, a 5-FU-based combination chemotherapy regimen using irinotecan and oxaliplatin, the response rate has significantly improved. However, these newer combination chemotherapy regimens unfortunately have increased toxicity; irinotecan-containing regimens are associated with severe diarrhea and other gastrointestinal toxicities, while oxaliplatin-containing regimens are associated with neurotoxicity.

[0005] In view of this, it is both necessary and urgent to find and develop a safer and more effective combination therapy for anti-tumor drugs. Summary of the Invention

[0006] This application provides the use of an antibody-drug conjugate and an anti-VEGF antibody in the preparation of a drug for treating cancer.

[0007] This application also discloses the use of the antibody-drug conjugate and the anti-VEGF antibody, in combination with one or more chemotherapeutic agents, in the preparation of a medicament for treating cancer.

[0008] This application also provides the use of an antibody-drug conjugate, an anti-VEGF antibody, and optionally a combination of one or more chemotherapeutic agents in the preparation of a medicament for treating colorectal cancer.

[0009] In some embodiments, the structure of the antibody-drug conjugate is shown in formula (I):

[0010] in:

[0011] n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, and n is a decimal or an integer;

[0012] Pc is an anti-B7H3 antibody or its antigen-binding fragment.

[0013] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises: heavy chains HCDR1, HCDR2, and HCDR3 as shown in the amino acid sequences of SEQ ID NO: 01, 02, and 03, respectively, and light chains LCDR1, LCDR2, and LCDR3 as shown in the amino acid sequences of SEQ ID NO: 04, 05, and 06, respectively.

[0014] In this application, the amino acid sequences of the CDRs listed above are all as shown in the Kabat definition rules. However, it is well known to those skilled in the art that antibody CDRs can be defined in various ways. Although the scope of protection claimed in this invention is based on the sequences shown in the Kabat definition rules, amino acid sequences corresponding to other CDR definition rules should also fall within the scope of protection of this invention.

[0015] The CDR sequences mentioned above are shown in Table A below:

[0016] Table A. CDR sequences of each heavy chain and light chain Note: The CDR sequence is derived from the rules defined by Kabat.

[0017] Preferably, the anti-B7H3 antibody or its antigen-binding fragment is selected from chimeric antibodies or their fragments, humanized antibodies or their fragments, and fully human antibodies or their fragments.

[0018] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment described in this application is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

[0019] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment described in this application comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotypes, preferably comprising a heavy chain constant region of human IgG1 or IgG4 isotypes.

[0020] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment described in this application comprises a light chain constant region of human κ or λ.

[0021] Furthermore, the heavy chain variable region of the anti-B7H3 antibody or its antigen-binding fragment described in this application contains the sequence shown in SEQ ID NO:07 or a variant thereof, and the light chain variable region contains the sequence shown in SEQ ID NO:08 or a variant thereof.

[0022] Furthermore, the heavy chain variable region sequence of the anti-B7H3 antibody or its antigen-binding fragment described in this application 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.

[0023] Furthermore, the heavy chain variable region sequence of the anti-B7H3 antibody or its antigen-binding fragment described in this application is shown in SEQ ID NO:07, and the light chain variable region sequence is shown in SEQ ID NO:08.

[0024] The sequences of the aforementioned anti-B7H3 antibody or its antigen-binding fragment heavy chain variable region and light chain variable region are shown below:

[0025] Heavy chain variable region sequence

[0026] Light chain variable region sequence

[0027] Note: The sequence is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The italics in the sequence represent the FR sequence, and the underlined sequences represent the CDR sequence. The CDR sequence is derived from the Kabat definition rules.

[0028] Furthermore, the heavy chain of the anti-B7H3 antibody or its antigen-binding fragment described in this application contains the sequence shown in SEQ ID NO:09 or a variant thereof, and the light chain contains the sequence shown in SEQ ID NO:10 or a variant thereof.

[0029] Furthermore, the heavy chain sequence of the anti-B7H3 antibody or its antigen-binding fragment described in this application 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.

[0030] Furthermore, the heavy chain sequence of the anti-B7H3 antibody or its antigen-binding fragment described in this application is shown in SEQ ID NO:09, and the light chain sequence is shown in SEQ ID NO:10.

[0031] The heavy and light chain sequences of the aforementioned anti-B7H3 antibody or its antigen-binding fragment are shown below:

[0032] Heavy chain (IgG1) amino acid sequence: (SEQ ID NO: 09)

[0033] Light chain (λ) amino acid sequence: (SEQ ID NO: 10)

[0034] In some embodiments, the anti-VEGF antibody is selected from bevacizumab, ranibizumab, sevacizumab, suvemcitug, varisacumab, CMAB-801, and LYN-00101.

[0035] In some preferred embodiments, the anti-VEGF antibody is selected from bevacizumab.

[0036] Furthermore, the heavy and light chain sequences of the aforementioned bevacizumab are shown below:

[0037] Heavy chain amino acid sequence: (SEQ ID NO: 11)

[0038] Light chain amino acid sequence: (SEQ ID NO: 12)

[0039] In some implementations, the aforementioned antibody-drug conjugates and anti-VEGF antibodies are contained as active ingredients in different formulations and are administered simultaneously, in parallel, sequentially, continuously, alternately, or separately.

[0040] On the other hand, this application discloses the use of the antibody-drug conjugate and the anti-VEGF antibody, in combination with one or more chemotherapeutic agents, in the preparation of a drug for treating cancer.

[0041] On the other hand, this application discloses the use of an antibody-drug conjugate, an anti-VEGF antibody, and one or more chemotherapeutic agents in combination in the preparation of a drug for treating cancer.

[0042] In an optional implementation, one or more chemotherapeutic agents are platinum compounds or fluoropyrimidines.

[0043] In an optional implementation, one or more chemotherapeutic agents are oxaliplatin, cisplatin, carboplatin, fluorouracil, capecitabine, tegafur, gimeracil, or oteracil.

[0044] In a preferred embodiment, one or more chemotherapeutic agents are fluorouracil, oxaliplatin and fluorouracil, capecitabine.

[0045] In an optional embodiment, the chemotherapeutic agent further comprises a chemoprotective agent; preferably, the chemoprotective agent is calcium leucovorin or levoleucovorin; more preferably, the chemoprotective agent is calcium leucovorin.

[0046] In an optional implementation, the one or more chemotherapeutic agents are selected from the group consisting of: leucovorin / fluorouracil (FU-LV), oxaliplatin / leucovorin / fluorouracil (FOLFOX), and capecitabine.

[0047] In optional embodiments, the above-mentioned antibody-drug conjugate, anti-VEGF antibody, one or more chemotherapeutic agents are contained as active ingredients in different formulations and are administered simultaneously, in parallel, sequentially, continuously, alternately, or separately.

[0048] This disclosure also provides the use of an antibody-drug conjugate, an anti-VEGF antibody, and a combination of leucovorin calcium and fluorouracil in the preparation of a medicament for treating cancer.

[0049] In optional embodiments, the above-mentioned antibody-drug conjugate, anti-VEGF antibody, leucovorin calcium and fluorouracil are contained as active ingredients in different formulations and are administered simultaneously, in parallel, sequentially, continuously, alternately or separately.

[0050] This disclosure also provides the use of an antibody-drug conjugate, an anti-VEGF antibody, and a combination of oxaliplatin, leucovorin, and fluorouracil in the preparation of a medicament for treating cancer.

[0051] In optional embodiments, the above-mentioned antibody-drug conjugates, anti-VEGF antibody, oxaliplatin, leucovorin calcium, and fluorouracil are contained as active ingredients in different formulations and are administered simultaneously, in parallel, sequentially, continuously, alternately, or separately.

[0052] This disclosure also provides the use of an antibody-drug conjugate, an anti-VEGF antibody, and capecitabine in the preparation of a medicament for treating cancer.

[0053] In optional embodiments, the above-mentioned antibody-drug conjugates, anti-VEGF antibody, and capecitabine are contained as active ingredients in different formulations and are administered simultaneously, in parallel, sequentially, continuously, alternately, or separately.

[0054] This disclosure also provides the use of an antibody-drug conjugate, bevacizumab, and the combination of leucovorin and fluorouracil in the preparation of a medicament for treating cancer.

[0055] In optional implementations, the aforementioned antibody-drug conjugates, bevacizumab, leucovorin calcium, and fluorouracil are contained as active ingredients in different formulations and are administered simultaneously, in parallel, sequentially, continuously, alternately, or separately.

[0056] This disclosure also provides the use of an antibody-drug conjugate, bevacizumab, and oxaliplatin, leucovorin, and fluorouracil in the preparation of a medicament for treating cancer.

[0057] In optional implementations, the aforementioned antibody-drug conjugates, bevacizumab, oxaliplatin, leucovorin calcium, and fluorouracil are contained as active ingredients in different formulations and are administered simultaneously, in parallel, sequentially, continuously, alternately, or separately.

[0058] This disclosure also provides the use of an antibody-drug conjugate, bevacizumab, and capecitabine in combination in the preparation of a medicament for treating cancer.

[0059] In an optional implementation, the aforementioned antibody-drug conjugates, bevacizumab, and capecitabine are contained as active ingredients in different formulations and are administered simultaneously, in parallel, sequentially, continuously, alternately, or separately.

[0060] In an optional implementation, the effective dosage of leucovorin calcium is 200-600 mg / m². 2 Preferably 200 mg / m 2 250mg / m 2 300mg / m 2 350mg / m 2 400mg / m 2 450mg / m 2 500mg / m 2 550mg / m 2 Or 600mg / m 2 More preferably 400 mg / m 2 The administration frequency is once a week, once every two weeks, once every three weeks, or once every four weeks, preferably once every two weeks or once every four weeks, and more preferably once every two weeks.

[0061] In a preferred embodiment, the effective dosage of leucovorin calcium is 400 mg / m². 2 The administration frequency is once every two weeks.

[0062] In an optional embodiment, the effective dosage of fluorouracil is 1200–4800 mg / m². 2 The preferred concentration is 1800–3200 mg / m³. 2 More preferably, 1800–2400 mg / m³ 2 The administration frequency is once a week, once every two weeks, once every three weeks, or once every four weeks, preferably once every two weeks or once every four weeks, and more preferably once every two weeks.

[0063] In a preferred embodiment, the effective dosage of fluorouracil is 1800–3200 mg / m². 2 The administration frequency is once every two weeks.

[0064] In a preferred embodiment, the effective dosage of fluorouracil is 1800 mg / m². 2 The dosing frequency is once every two weeks. In a preferred embodiment, the effective dosage of fluorouracil is 2100 mg / m². 2 The dosing frequency is once every two weeks. In a preferred embodiment, the effective dosage of fluorouracil is 2400 mg / m². 2 The dosing frequency is once every two weeks. In a preferred embodiment, the effective dosage of fluorouracil is 2800 mg / m². 2The administration frequency is once every two weeks.

[0065] In an optional embodiment, the fluorouracil is administered at a dose of 400 mg / m² on day 1. 2 A single intravenous dose was administered, followed by doses of 1200 mg / (m²) on days 2 and 3. 2 *d) The fluorouracil was administered intravenously at a dose of once a week, once every two weeks, once every three weeks, or once every four weeks, preferably once every two weeks or once every four weeks, and more preferably once every two weeks.

[0066] In an optional embodiment, the fluorouracil is administered at a dose of 300 mg / m² on day 1. 2 A single intravenous dose was administered, followed by doses of 900 mg / (m²) on days 2 and 3. 2 *d) The fluorouracil was administered intravenously at a dose of once a week, once every two weeks, once every three weeks, or once every four weeks, preferably once every two weeks or once every four weeks, and more preferably once every two weeks.

[0067] In a preferred embodiment, the fluorouracil is administered at a dose of 400 mg / m² on day 1. 2 A single intravenous dose was administered, followed by doses of 1200 mg / (m²) on days 2 and 3. 2 *d) dose administered intravenously; dosing frequency is once every two weeks.

[0068] In a preferred embodiment, the fluorouracil is administered at a dose of 300 mg / m² on day 1. 2 A single intravenous dose was administered, followed by doses of 900 mg / (m²) on days 2 and 3. 2 *d) dose administered intravenously; dosing frequency is once every two weeks.

[0069] In an optional implementation, the effective dosage of oxaliplatin, calculated based on body surface area, is preferably 20-200 mg / m². 2 More preferably 45 mg / m 2 50mg / m 2 55mg / m 2 60mg / m 2 65mg / m 2 70mg / m 2 75mg / m 2 80mg / m 2 85mg / m 2 90mg / m 2 100mg / m 2 110mg / m 2 120mg / m 2 130mg / m2 140mg / m 2 Or 150mg / m 2 More preferably 50 mg / m 2 65mg / m 2 130mg / m 2 The administration frequency is once a week, once every two weeks, once every three weeks, or once every four weeks, preferably once every two weeks or once every three weeks.

[0070] In a preferred embodiment, the effective dosage of oxaliplatin is 50 mg / m². 2 65mg / m 2 130mg / m 2 The administration frequency is once every two weeks and once every three weeks.

[0071] In a preferred embodiment, the effective dosage of oxaliplatin is 50 mg / m². 2 The administration frequency is once every two weeks.

[0072] In a preferred embodiment, the effective dosage of oxaliplatin is 65 mg / m². 2 The administration frequency is once every two weeks.

[0073] In a preferred embodiment, the effective dosage of oxaliplatin is 130 mg / m². 2 The dosage is once every three weeks.

[0074] In an optional implementation, the effective dose of capecitabine, calculated based on body surface area, is preferably 500-2000 mg / m². 2 More preferably 600 mg / m 2 700mg / m 2 800mg / m 2 850mg / m 2 900mg / m 2 950mg / m 2 1000mg / m 2 1050mg / m 2 1100mg / m 2 1150mg / m 2 1200mg / m 2 1250mg / m 2 1300mg / m 2 1350mg / m 2 1400mg / m 2 1450mg / m 2 1500mg / m 2 1600mg / m 21700mg / m 2 1800mg / m 2 1900mg / m 2 Or 2000mg / m 2 More preferably 600 mg / m 2 800mg / m 2 The medication is administered twice daily for 14 consecutive days, followed by a 7-day break. Each course of treatment lasts three weeks.

[0075] In a preferred embodiment, the effective dose of capecitabine, calculated based on body surface area, is 800 mg / m². 2 The medication is administered twice daily for 14 consecutive days, followed by a 7-day break. Each course of treatment lasts three weeks.

[0076] In a preferred embodiment, the effective dose of capecitabine, calculated based on body surface area, is 600 mg / m². 2 The medication is administered twice daily for 14 consecutive days, followed by a 7-day break. Each course of treatment lasts three weeks.

[0077] In optional embodiments, the dosage of the antibody-drug conjugate is from 1.0 mg / kg to 16.0 mg / kg, preferably from 4.0 mg / kg to 12.0 mg / kg, and more preferably 1.0 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 3.2 mg / kg, etc. kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.8mg / kg, 4.0mg / kg, 4.2mg / kg, 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.8mg / kg, 5.0mg / kg, 5.2mg / kg, 5.4mg / kg, 5.5mg / kg, 5.6mg / kg, 5.8mg / kg, 6.0mg / kg, 6.2mg / kg, 6.4mg / kg, 6.5mg / kg, 6.6m g / kg, 6.8mg / kg, 7.0mg / kg, 7.2mg / kg, 7.4mg / kg, 7.5mg / kg, 7.6mg / kg, 7.8mg / kg, 8.0mg / kg, 8.2mg / kg, 8.4mg / k g, 8.5mg / kg, 8.6mg / kg, 8.8mg / kg, 9.0mg / kg, 9.2mg / kg, 9.4mg / kg, 9.5mg / kg, 9.6mg / kg, 9.8mg / kg, 10.0mg / kg, 1 0.2 mg / kg, 10.4 mg / kg, 10.6 mg / kg, 10.8 mg / kg, 11.0 mg / kg, 11.2 mg / kg, 11.4 mg / kg, 11.6 mg / kg, 11.8 mg / kg or 12.0 mg / kg; more preferably 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.5 mg / kg, 8.0 mg / kg or 10.0 mg / kg.

[0078] In optional implementations, the antibody-drug conjugate is administered once a week, once every two weeks, once every three weeks, or once every four weeks, preferably once every two weeks or once every three weeks.

[0079] In an optional implementation, the dosage of the antibody-drug conjugate is 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.5 mg / kg, 8.0 mg / kg, or 10.0 mg / kg, and the dosing frequency is once every two weeks or once every three weeks.

[0080] In an optional implementation, the antibody-drug conjugate is administered at doses of 5.5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.5 mg / kg, 8.0 mg / kg, and 10.0 mg / kg, with a dosing frequency of once every three weeks.

[0081] In an optional implementation, the antibody-drug conjugate is administered at doses of 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, and 6.0 mg / kg, with a dosing frequency of once every two weeks.

[0082] In a preferred embodiment, the antibody-drug conjugate is administered at a dose of 3.0 mg / kg, once every two weeks. In a preferred embodiment, the antibody-drug conjugate is administered at a dose of 4.0 mg / kg, once every two weeks. In a preferred embodiment, the antibody-drug conjugate is administered at a dose of 5.0 mg / kg, once every two weeks. In a preferred embodiment, the antibody-drug conjugate is administered at a dose of 6.0 mg / kg, once every two weeks.

[0083] In a preferred embodiment, the antibody-drug conjugate is administered at a dose of 5.5 mg / kg, once every three weeks. In a preferred embodiment, the antibody-drug conjugate is administered at a dose of 6.0 mg / kg, once every three weeks. In a preferred embodiment, the antibody-drug conjugate is administered at a dose of 6.5 mg / kg, once every three weeks. In a preferred embodiment, the antibody-drug conjugate is administered at a dose of 7.5 mg / kg, once every three weeks. In a preferred embodiment, the antibody-drug conjugate is administered at a dose of 8.0 mg / kg, once every three weeks. In a preferred embodiment, the antibody-drug conjugate is administered at a dose of 10.0 mg / kg, once every three weeks.

[0084] In optional embodiments, the dose of the anti-VEGF antibody is from 1.0 mg / kg to 16.0 mg / kg, preferably 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, 9.0 mg / kg, 9.5 mg / kg, or 10.0 mg / kg, more preferably 5.0 mg / kg or 7.5 mg / kg; the dosing frequency is once a week, once every two weeks, or once every three weeks, preferably once every two weeks or once every three weeks.

[0085] In an optional implementation, the anti-VEGF antibody dose is 5.0 mg / kg or 7.5 mg / kg, administered once every three weeks. In another optional implementation, the anti-VEGF antibody dose is 5.0 mg / kg or 7.5 mg / kg, administered once every two weeks.

[0086] In a preferred embodiment, the anti-VEGF antibody dose is 5.0 mg / kg, administered once every two weeks. In another preferred embodiment, the anti-VEGF antibody dose is 7.5 mg / kg, administered once every three weeks.

[0087] In an optional embodiment, this disclosure provides the use of an antibody-drug conjugate and bevacizumab in combination in the preparation of a drug for treating cancer, wherein the antibody-drug conjugate is administered at a dose of 8.0 mg / kg, 6.0 mg / kg or 10.0 mg / kg once every three weeks, and the bevacizumab is administered at a dose of 7.5 mg / kg once every three weeks.

[0088] In an optional embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating cancer. The antibody-drug conjugate is administered at doses of 4.0 mg / kg, 3.0 mg / kg, or 5.0 mg / kg, every two weeks; the bevacizumab dose is 5.0 mg / kg, administered every two weeks; and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, with fluorouracil administered at a dose of 300 mg / m² on day 1. 2 Or 400mg / m 2 A single intravenous dose was administered, followed by doses of 900 mg / (m²) on days 2 and 3. 2 *d) or 1200mg / (m 2 *d) dose administered intravenously; dosing frequency is once every two weeks.

[0089] In an optional embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating cancer, wherein the antibody-drug conjugate is administered at a dose of 5.0 mg / kg, 4.0 mg / kg, or 6.0 mg / kg every two weeks; the bevacizumab dose is 5.0 mg / kg every two weeks; and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 1800 mg / m². 2 Or 2400mg / m 2 The administration frequency is once every two weeks.

[0090] In an optional embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and capecitabine in combination in the preparation of a medicament for treating cancer. The antibody-drug conjugate is administered at doses of 6.5 mg / kg, 5.5 mg / kg, or 7.5 mg / kg every three weeks; the bevacizumab dose is 7.5 mg / kg every three weeks; and the effective dose of capecitabine, calculated based on body surface area, is 600 mg / m². 2 Or 800mg / m 2 The medication is administered twice daily for 14 consecutive days, followed by a 7-day break. Each course of treatment lasts three weeks.

[0091] In an optional embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, oxaliplatin, leucovorin, and fluorouracil in the preparation of a medicament for treating cancer, wherein the antibody-drug conjugate is administered at a dose of 4.0 mg / kg, 3.0 mg / kg, or 5.0 mg / kg every two weeks, the bevacizumab dose is 5.0 mg / kg every two weeks, and the effective dose of oxaliplatin is 50 mg / kg. 2 65mg / m 2 The dosage is once every two weeks, and the effective dose of leucovorin calcium is 400 mg / m². 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 1800 mg / m². 2 Or 2400mg / m 2 The administration frequency is once every two weeks.

[0092] In an optional implementation, the cancer is selected from colorectal cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, uterine cancer, head and neck cancer, lung cancer, stomach cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, bladder cancer, esophageal cancer, salivary gland cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, vulvar cancer, penile cancer, testicular cancer, urothelial carcinoma, urethral cancer, colon cancer, and rectal cancer.

[0093] In a preferred embodiment, the cancer is selected from colorectal cancer.

[0094] In a preferred embodiment, the colorectal cancer is colorectal adenocarcinoma, colorectal adenosquamous carcinoma, colorectal squamous cell carcinoma, or colorectal small cell carcinoma, more preferably metastatic colorectal adenocarcinoma, and even more preferably advanced metastatic colorectal adenocarcinoma.

[0095] In a preferred embodiment, the cancer is colorectal cancer, more preferably metastatic colorectal cancer, more preferably advanced metastatic colorectal cancer, and even more preferably advanced metastatic colorectal adenocarcinoma.

[0096] In an optional embodiment, the colorectal cancer is selected from colorectal cancer with a non-MSI-H / dMMR phenotype; preferably, it is advanced metastatic colorectal cancer with a non-MSI-H / dMMR phenotype; more preferably, it is advanced metastatic colorectal cancer with a non-MSI-H / dMMR phenotype that has previously received standard treatment and failed, advanced metastatic colorectal cancer with a non-MSI-H / dMMR phenotype that has not received any systemic antitumor therapy in the advanced metastatic stage, or advanced metastatic colorectal cancer with a non-MSI-H / dMMR phenotype that has not previously received any anti-angiogenic drug therapy.

[0097] In an optional embodiment, the colorectal cancer is selected from colorectal cancer with the MSI-H / dMMR phenotype; preferably, it is advanced metastatic colorectal cancer with the MSI-H / dMMR phenotype; more preferably, it is advanced metastatic colorectal cancer with the MSI-H / dMMR phenotype that has previously received immune checkpoint inhibitor therapy and has progressed or is intolerant to it.

[0098] In a preferred embodiment, the cancer is advanced metastatic colorectal adenocarcinoma of the non-MSI-H / dMMR phenotype that has failed a previous standard treatment regimen based on fluorouracil, oxaliplatin, and / or irinotecan.

[0099] In a preferred embodiment, the cancer is advanced metastatic colorectal adenocarcinoma of the non-MSI-H / dMMR phenotype that has not received any systemic antitumor therapy at an advanced metastatic stage.

[0100] In a preferred embodiment, the cancer is advanced metastatic colorectal adenocarcinoma of the MSI-H / dMMR phenotype that has progressed or is intolerant to immune checkpoint inhibitor therapy.

[0101] In an optional embodiment, the colorectal cancer is selected from RAS / BRAF mutant colorectal cancer and RAS / BRAF wild-type colorectal cancer, preferably RAS / BRAF wild-type colorectal cancer with the primary lesion located in the right colorectal region.

[0102] This disclosure also provides a pharmaceutical composition comprising the above-described antibody-drug conjugate, an anti-VEGF antibody, and one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0103] This disclosure also provides a pharmaceutical composition comprising the above-described antibody-drug conjugate, an anti-VEGF antibody, and one or more chemotherapeutic agents, as well as one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0104] This disclosure also provides the use of an antibody-drug conjugate, an anti-VEGF antibody, and one or more chemotherapeutic agents in the preparation of a medicament for treating cancer.

[0105] This disclosure also provides a method for treating cancer, the method comprising administering, to a subject in need, in combination the above-described antibody-drug conjugate, anti-VEGF antibody, and one or more chemotherapeutic agents; the combination administration may be simultaneous, parallel, sequential, continuous, alternating, or separate.

[0106] In an optional implementation, the one or more chemotherapeutic agents are selected from: calcium leucovorin, fluorouracil, capecitabine, and oxaliplatin.

[0107] In a preferred embodiment, the one or more chemotherapeutic agents are leucovorin calcium and fluorouracil (FU-LV).

[0108] In a preferred embodiment, the one or more chemotherapeutic agents are leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX).

[0109] In a preferred embodiment, the one or more chemotherapeutic agents are capecitabine.

[0110] In an optional implementation, the cancer is selected from colorectal cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, uterine cancer, head and neck cancer, lung cancer, stomach cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, bladder cancer, esophageal cancer, salivary gland cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, vulvar cancer, penile cancer, testicular cancer, urothelial carcinoma, urethral cancer, colon cancer, and rectal cancer.

[0111] In a preferred embodiment, the cancer is selected from colorectal cancer.

[0112] In a preferred embodiment, the cancer is colorectal cancer, more preferably colorectal adenocarcinoma, more preferably metastatic colorectal adenocarcinoma, and even more preferably advanced metastatic colorectal adenocarcinoma.

[0113] In a preferred embodiment, the cancer is colorectal cancer, more preferably metastatic colorectal cancer, more preferably advanced metastatic colorectal cancer, and even more preferably advanced metastatic colorectal adenocarcinoma.

[0114] In an optional embodiment, the colorectal cancer is selected from colorectal cancer with a non-MSI-H / dMMR phenotype; preferably, it is advanced metastatic colorectal cancer with a non-MSI-H / dMMR phenotype; more preferably, it is advanced metastatic colorectal cancer with a non-MSI-H / dMMR phenotype that has previously received standard treatment and failed, advanced metastatic colorectal cancer with a non-MSI-H / dMMR phenotype that has not received any systemic antitumor therapy in the advanced metastatic stage, or advanced metastatic colorectal cancer with a non-MSI-H / dMMR phenotype that has not previously received any anti-angiogenic drug therapy.

[0115] In an optional embodiment, the colorectal cancer is selected from colorectal cancer with the MSI-H / dMMR phenotype; preferably, it is advanced metastatic colorectal cancer with the MSI-H / dMMR phenotype; more preferably, it is advanced metastatic colorectal cancer with the MSI-H / dMMR phenotype that has previously received immune checkpoint inhibitor therapy and has progressed or is intolerant to it.

[0116] In a preferred embodiment, the cancer is advanced metastatic colorectal adenocarcinoma of the non-MSI-H / dMMR phenotype that has failed a previous standard treatment regimen based on fluorouracil, oxaliplatin, and / or irinotecan.

[0117] In a preferred embodiment, the cancer is advanced metastatic colorectal adenocarcinoma of the non-MSI-H / dMMR phenotype that has not received any systemic antitumor therapy at an advanced metastatic stage.

[0118] In a preferred embodiment, the cancer is advanced metastatic colorectal adenocarcinoma of the MSI-H / dMMR phenotype that has progressed or is intolerant to immune checkpoint inhibitor therapy.

[0119] In an optional embodiment, the colorectal cancer is selected from RAS / BRAF mutant colorectal cancer and RAS / BRAF wild-type colorectal cancer, preferably RAS / BRAF wild-type colorectal cancer with the primary lesion located in the right colorectal region.

[0120] On the other hand, this disclosure provides the use of an antibody-drug conjugate and bevacizumab in combination in the preparation of a medicament for treating metastatic colorectal cancer.

[0121] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate and bevacizumab in combination in the preparation of a drug for treating metastatic colorectal cancer, wherein the antibody-drug conjugate is administered at a dose of 8.0 mg / kg every three weeks, and the bevacizumab is administered at a dose of 7.5 mg / kg every three weeks.

[0122] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate and bevacizumab in combination in the preparation of a drug for treating metastatic colorectal cancer, wherein the antibody-drug conjugate is administered at a dose of 6.0 mg / kg every three weeks, and the bevacizumab is administered at a dose of 7.5 mg / kg every three weeks.

[0123] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate and bevacizumab in combination in the preparation of a drug for treating metastatic colorectal cancer, wherein the antibody-drug conjugate is administered at a dose of 10.0 mg / kg every three weeks, and the bevacizumab is administered at a dose of 7.5 mg / kg every three weeks.

[0124] On the other hand, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating metastatic colorectal cancer.

[0125] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 4.0 mg / kg every two weeks, the bevacizumab dose is 5.0 mg / kg every two weeks, and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, with fluorouracil administered at a dose of 400 mg / m² on day 1. 2 A single intravenous dose was administered, followed by doses of 1200 mg / (m²) on days 2 and 3. 2 *d) dose administered intravenously; dosing frequency is once every two weeks.

[0126] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 5.0 mg / kg every two weeks, the bevacizumab dose is 5.0 mg / kg every two weeks, and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, with fluorouracil administered at a dose of 400 mg / m² on day 1. 2 A single intravenous dose was administered, followed by doses of 1200 mg / (m²) on days 2 and 3. 2 *d) dose administered intravenously; dosing frequency is once every two weeks.

[0127] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 3.0 mg / kg every two weeks, the bevacizumab dose is 5.0 mg / kg every two weeks, and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, with fluorouracil administered at a dose of 400 mg / m² on day 1. 2 A single intravenous dose was administered, followed by doses of 1200 mg / (m²) on days 2 and 3. 2 *d) dose administered intravenously; dosing frequency is once every two weeks.

[0128] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 4.0 mg / kg every two weeks, the bevacizumab dose is 5.0 mg / kg every two weeks, and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, with fluorouracil administered at a dose of 300 mg / m² on day 1. 2 A single intravenous dose was administered, followed by doses of 900 mg / (m²) on days 2 and 3. 2 *d) dose administered intravenously; dosing frequency is once every two weeks.

[0129] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 3.0 mg / kg every two weeks, the bevacizumab dose is 5.0 mg / kg every two weeks, and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, with fluorouracil administered at a dose of 300 mg / m² on day 1. 2 A single intravenous dose was administered, followed by doses of 900 mg / (m²) on days 2 and 3. 2 *d) dose administered intravenously; dosing frequency is once every two weeks.

[0130] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 5.0 mg / kg every two weeks, the bevacizumab dose is 5.0 mg / kg every two weeks, and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 2400 mg / m². 2 The administration frequency is once every two weeks.

[0131] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 6.0 mg / kg every two weeks, bevacizumab at a dose of 5.0 mg / kg every two weeks, and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 2400 mg / m².2 The administration frequency is once every two weeks.

[0132] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 4.0 mg / kg every two weeks, the bevacizumab dose is 5.0 mg / kg every two weeks, and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 2400 mg / m². 2 The administration frequency is once every two weeks.

[0133] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 5.0 mg / kg every two weeks, the bevacizumab dose is 5.0 mg / kg every two weeks, and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 1800 mg / m². 2 The administration frequency is once every two weeks.

[0134] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and a combination of leucovorin and fluorouracil in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 4.0 mg / kg every two weeks, the bevacizumab dose is 5.0 mg / kg every two weeks, and the effective dosage of leucovorin is 400 mg / kg. 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 1800 mg / m². 2 The administration frequency is once every two weeks.

[0135] On the other hand, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and capecitabine in combination in the preparation of a medicament for treating metastatic colorectal cancer.

[0136] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and capecitabine in combination in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 6.5 mg / kg every three weeks, bevacizumab at a dose of 7.5 mg / kg every three weeks, and the effective dose of capecitabine, calculated based on body surface area, is 800 mg / m². 2The medication is administered twice daily for 14 consecutive days, followed by a 7-day break. Each course of treatment lasts three weeks.

[0137] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and capecitabine in combination in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 7.5 mg / kg every three weeks; the bevacizumab dose is 7.5 mg / kg every three weeks; and the effective dose of capecitabine, calculated based on body surface area, is 800 mg / m². 2 The medication is administered twice daily for 14 consecutive days, followed by a 7-day break. Each course of treatment lasts three weeks.

[0138] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and capecitabine in combination in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 5.5 mg / kg every three weeks, bevacizumab at a dose of 7.5 mg / kg every three weeks, and the effective dose of capecitabine, calculated based on body surface area, is 800 mg / m². 2 The medication is administered twice daily for 14 consecutive days, followed by a 7-day break. Each course of treatment lasts three weeks.

[0139] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and capecitabine in combination in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 6.5 mg / kg every three weeks, bevacizumab at a dose of 7.5 mg / kg every three weeks, and the effective dose of capecitabine, calculated based on body surface area, is 600 mg / m². 2 The medication is administered twice daily for 14 consecutive days, followed by a 7-day break. Each course of treatment lasts three weeks.

[0140] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and capecitabine in combination in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 5.5 mg / kg every three weeks, bevacizumab at a dose of 7.5 mg / kg every three weeks, and the effective dose of capecitabine, calculated based on body surface area, is 600 mg / m². 2 The medication is administered twice daily for 14 consecutive days, followed by a 7-day break. Each course of treatment lasts three weeks.

[0141] On the other hand, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, and oxaliplatin, leucovorin, and fluorouracil in combination in the preparation of a medicament for the treatment of metastatic colorectal cancer.

[0142] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, oxaliplatin, leucovorin, and fluorouracil in combination in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 4.0 mg / kg every two weeks, bevacizumab at a dose of 5.0 mg / kg every two weeks, and the effective dose of oxaliplatin is 65 mg / kg. 2 The dosage is once every two weeks, and the effective dose of leucovorin calcium is 400 mg / m². 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 2400 mg / m². 2 The administration frequency is once every two weeks.

[0143] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, oxaliplatin, leucovorin, and fluorouracil in combination in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 5.0 mg / kg every two weeks, the bevacizumab dose is 5.0 mg / kg every two weeks, and the effective dose of oxaliplatin is 65 mg / kg. 2 The dosage is once every two weeks, and the effective dose of leucovorin calcium is 400 mg / m². 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 2400 mg / m². 2 The administration frequency is once every two weeks.

[0144] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, oxaliplatin, leucovorin, and fluorouracil in combination in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 3.0 mg / kg every two weeks, bevacizumab at a dose of 5.0 mg / kg every two weeks, and the effective dose of oxaliplatin is 65 mg / kg. 2 The dosage is once every two weeks, and the effective dose of leucovorin calcium is 400 mg / m². 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 2400 mg / m². 2 The administration frequency is once every two weeks.

[0145] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, oxaliplatin, leucovorin, and fluorouracil in combination in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 4.0 mg / kg every two weeks, bevacizumab at a dose of 5.0 mg / kg every two weeks, and the effective dose of oxaliplatin is 50 mg / kg. 2 The dosage is once every two weeks, and the effective dose of leucovorin calcium is 400 mg / m². 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 1800 mg / m². 2 The administration frequency is once every two weeks.

[0146] In a preferred embodiment, this disclosure provides the use of an antibody-drug conjugate, bevacizumab, oxaliplatin, leucovorin, and fluorouracil in combination in the preparation of a medicament for treating metastatic colorectal cancer. The antibody-drug conjugate is administered at a dose of 3.0 mg / kg every two weeks, bevacizumab at a dose of 5.0 mg / kg every two weeks, and the effective dose of oxaliplatin is 50 mg / kg. 2 The dosage is once every two weeks, and the effective dose of leucovorin calcium is 400 mg / m². 2 The dosing frequency is once every two weeks, and the effective dose of fluorouracil is 1800 mg / m². 2 The administration frequency is once every two weeks.

[0147] In a preferred embodiment, the metastatic colorectal cancer is advanced metastatic colorectal adenocarcinoma of the non-MSI-H / dMMR phenotype that has failed a previous standard treatment regimen based on fluorouracil, oxaliplatin, and / or irinotecan.

[0148] In a preferred embodiment, the metastatic colorectal cancer is advanced metastatic colorectal adenocarcinoma of the non-MSI-H / dMMR phenotype that has not received any systemic antitumor therapy at the advanced metastatic stage.

[0149] In a preferred embodiment, the metastatic colorectal cancer is advanced metastatic colorectal adenocarcinoma of the MSI-H / dMMR phenotype that has progressed or is intolerant to immune checkpoint inhibitor therapy.

[0150] In this disclosure, the terms “comprise” and “include” are used herein in an open-ended and unrestricted sense unless otherwise stated.

[0151] In this disclosure, "combination" is a method of administration that includes various situations in which two or more drugs are administered sequentially or simultaneously.

[0152] Simultaneous administration, administration of independently prepared and co-prepared formulations, or administration of independently prepared and sequential formulations all fall under the category of combined administration as described in this disclosure. "Simultaneous" here refers to administering at least one dose of bevacizumab and an anti-B7H3 antibody-drug conjugate, along with one or more optional chemotherapeutic agents, within a specified time period. This administration may be carried out over 3 days, 2 days, or 1 day, where both or more substances exhibit pharmacological effects. "Sequential" administration includes administering bevacizumab and the anti-B7H3 antibody-drug conjugate, along with one or more optional chemotherapeutic agents, separately within different dosing cycles. The time period can be within a single dosing cycle, optionally within 4 weeks, 3 weeks, 2 weeks, or 1 week. This time period includes treatments in which bevacizumab and the anti-B7H3 antibody-drug conjugate, along with one or more optional chemotherapeutic agents, are administered via the same or different routes of administration. Attached Figure Description

[0153] Figure 1. Effect of combined treatment with drugs A and B on HCT-116 tumor volume.

[0154] Figure 2. Effects of combined treatment with drugs A and B on body weight changes in HCT-116 tumor-bearing mice. Detailed Implementation

[0155] the term

[0156] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0157] This disclosure incorporates the entire contents of application WO2020063673.

[0158] "Optional" or "optionally" means that the event or circumstances described below may, but do not have to, occur, including the circumstances in which the event or circumstances may or may not occur.

[0159] The term "antibody-drug conjugate" refers to an antibody linked to a biologically active drug via a stable linker. In this disclosure, "antibody-drug conjugate" refers to a monoclonal antibody or antibody fragment linked to a biologically active toxic drug via a stable linker.

[0160] The term "antibody" refers to immunoglobulin, a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The amino acid composition and sequence of the constant region of the heavy chain of immunoglobulins differ, thus their antigenicity also differs. Based on this, immunoglobulins can be divided into five classes, or isotypes of immunoglobulins: IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being μ, δ, γ, α, and ε chains, respectively. Within the same class of Ig, differences in the amino acid composition of the hinge region and the number and position of disulfide bonds in the heavy chain can further divide them into different subclasses; for example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. The light chains are classified as κ or λ chains based on differences in the constant region. Each of the five classes of Ig can have either a κ chain or a λ chain.

[0161] The approximately 110 amino acids near the N-terminus of both the antibody heavy and light chains exhibit significant sequence variation and are termed the variable region (Fv region); the remaining amino acid sequences near the C-terminus are relatively stable and constitute the constant region. The variable region includes three hypervariable regions (HVRs) and four relatively conserved backbone regions (FRs). The three hypervariable regions determine the antibody's specificity and are also known as complementarity-determining regions (CDRs). Each light chain variable region (LCVR) and heavy chain variable region (HCVR) consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDRs of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDRs of the heavy chain refer to HCDR1, HCDR2, and HCDR3.

[0162] In this disclosure, the amino acid sequences of the aforementioned CDRs are all derived according to the Kabat definition rules. However, it is well known to those skilled in the art that antibody CDRs can be defined in various ways, such as 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 antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, USDepartment of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), the international ImMunoGeneTics database (IMGT) (imgt.cines.fr / ), and the North CDR definition based on affinity propagation clustering using a large number of crystal structures. Those skilled in the art will understand that, unless otherwise specified, the terms "CDR" and "complementarity-determining region" for a given antibody or its region (e.g., variable region) should be understood to encompass complementarity-determining regions defined as described above by any of the known schemes described in this invention. While the scope of protection claimed by this invention is based on the sequence shown in the Kabat definition rules, amino acid sequences corresponding to other CDR definition rules should also fall within the scope of protection of this invention.

[0163] The term “antigen-binding fragment” refers to one or more fragments of an antibody that maintain the ability to specifically bind to an antigen. It has been shown that fragments of full-length antibodies can be used for antigen-binding function. Examples of binding fragments included in “antigen-binding fragments” include (i) Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, bivalent fragments comprising two Fab fragments linked by disulfide bridges on hinge regions; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of VH and VL domains of a single arm of the antibody; (v) single-domain or dAb fragments (Ward et al., (1989) Nature 341: 544-546) consisting of a VH domain; and (vi) separate complementarity-determining regions (CDRs) or (vii) combinations of two or more separate CDRs optionally linked by synthetic linkers.

[0164] The term "drug loading" refers to the average number of cytotoxic drugs loaded onto each ligand in a molecule of formula (I), and can also be expressed as the ratio of drug amount to antibody amount. The drug loading range can be 0-12, preferably 1-10, cytotoxic drugs (D) linked to each antibody (Pc). In embodiments of this disclosure, the drug loading is expressed as n, also known as the DAR value, exemplarily the average of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 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.

[0165] The term "combination" or "drug combination" defines a fixed combination of dosage units or a kit of drugs for combined administration, wherein the therapeutic agents can be administered simultaneously or separately at time intervals, so that the therapeutic agents can exhibit a synergistic effect, such as a synergistic effect.

[0166] The term “pharmaceutically acceptable” is defined herein as those compounds, materials, biological agents, compositions and / or dosage forms that are suitable for contact with the tissues of a subject (such as mammals or humans) within the limits of reasonable medical judgment, without excessive toxicity, irritation, allergic reactions and other problematic complications, and with a reasonable benefit / risk ratio.

[0167] The term "pharmaceutical composition" refers to a product that optionally contains one or more active ingredients (e.g., antibodies, ADCs) in a specific amount, and any product directly or indirectly produced by combining one or more active ingredients in optional specific amounts. The different active ingredients in a pharmaceutical composition may be administered independently as separate formulations, including synergistically, either simultaneously or at different times. In this disclosure, "pharmaceutical composition" and "formulation" are not mutually exclusive.

[0168] The term "treatment" means administering an oral or topical therapeutic agent, such as a composition comprising any of the compounds disclosed herein, to a patient who has symptoms of one or more diseases, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, a therapeutic agent is administered in a treated patient or population in an amount that effectively relieves symptoms of one or more diseases to induce the regression of such symptoms or inhibit their progression to any clinically measurable extent. The amount of a therapeutic agent that effectively relieves any specific disease symptom (also referred to as a "therapeuticly effective amount") can vary depending on a variety of factors, such as the patient's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the patient. Whether the disease symptoms have been relieved can be evaluated using any clinical testing method commonly used by a physician or other healthcare professional to assess the severity or progression of the symptoms. Although the embodiments of this disclosure (e.g., treatment methods or products) may be ineffective in alleviating symptoms of each target disease, they should reduce symptoms of the target disease in a statistically significant number of patients, as determined by any statistical test known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test.

[0169] The term "effective dose" or "therapeutic effective dose" for a combination of therapeutic agents is the amount that is sufficient to provide a significant improvement in clinically observable signs and symptoms compared to baseline for the cancer treated by the combination.

[0170] Example

[0171] The present application will be explained in more detail below with reference to the embodiments. The embodiments of the present application are only used to illustrate the technical solutions of the present application and are not intended to limit the substance and scope of the present application.

[0172] Example 1. Preparation of anti-B7H3 antibody-drug conjugate

[0173] According to the production method described in WO2020063673, an anti-B7H3 antibody-drug conjugate with the structure shown below was prepared using h1702DS (anti-B7H3 antibody) and an eczema analog. The average value calculated by the HIC method was n = 4.1, i.e., FADC-2. The heavy chain sequence of h1702DS is shown in SEQ ID NO:09, and the light chain sequence is shown in SEQ ID NO:10.

[0174] Example 2. Evaluation of the in vivo inhibitory effect of anti-B7H3 antibody-drug conjugate combined with anti-VEGF antibody on human colorectal cancer cell HCT-116 mouse xenografts.

[0175] 1. Experimental Materials

[0176] The human colorectal cancer cell line HCT-116 was purchased from Guangzhou Genio Biotechnology Co., Ltd.

[0177] Drug A: The anti-B7H3 antibody-drug conjugate prepared as in Example 1, which is dissolved in water for injection.

[0178] Drug B: Bevacizumab, provided by Suzhou Shengdiya Biopharmaceutical Co., Ltd.

[0179] Drug C: Irinotecan, purchased from Jiangsu Hengrui Medicine Co., Ltd.;

[0180] Drug D: Fluorouracil, purchased from Shanghai Xudong Haipu Pharmaceutical Co., Ltd.;

[0181] Drug E: Leucovorin calcium, purchased from Jiangsu Hengrui Medicine Co., Ltd.

[0182] HCT-116 cells were cultured in vitro as a monolayer under RPMI 1640 medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin in a 37°C, 5% CO2 cell culture incubator. Cells were passaged twice weekly using trypsin-EDTA digestion. When cell saturation reached 80%-90% and the desired number was achieved, cells were harvested, counted, and seeded.

[0183] BALB / c nude mice, female, 8-10 weeks old, weighing 17-25g, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0184] 2. Experimental Methods

[0185] HCT-116 cells were resuspended in PBS and the density was adjusted to 4 × 10⁶ cells / mL. 7 Cells / mL, subcutaneously injected into the right back of each mouse, with an injection volume of 0.1 mL (4 × 10⁻⁶ cells / mL). 6 (cells / mouse), until the average tumor volume grows to 100-200 mm 3 Mice were divided into groups and administered drugs on Day 0. Mice were administered a single intravenous injection (iv, drug A); or an intraperitoneal injection (ip), once weekly (QW, drugs C, D, and E) or twice weekly (BIW, drug B); the administration volume was 10 mL / kg; the solvent group received the same volume of "solvent" (PBS or Saline); specific dosages and administration regimens are shown in Table 1. Tumor volume was measured, mouse weight was recorded, and data were recorded.

[0186] The experimental indicator was to examine the effect of the drug on tumor growth, specifically the tumor inhibition rate (TGI%). The tumor diameter was measured using calipers, and the tumor volume (V) was calculated using the following formula:

[0187] V = 1 / 2 × a × b 2 Where a and b represent the long and short diameters of the tumor, respectively.

[0188] TGI (%) = 100 - (T i -T0) / (C i -C0)′100

[0189] Note: T i and C i Let Ti be the tumor volume on day i of the experiment, and T0 and C0 be the tumor volumes at the start of the experiment. When tumor regression occurs, TGI(%) = 100 - (Ti - C0)2. i -T0) / T0′100

[0190] The experiment ends, the experimental endpoint is reached, or the average tumor volume reaches 2,000 mmHg. 3 The mice were euthanized, and then dissected to remove the tumor and take pictures.

[0191] Experimental data were analyzed and plotted using GraphPad Prism 9. Based on the tumor volume and weight change rates at different time points for each group, two-way ANOVA was used to assess differences between groups; one-way ANOVA was used to analyze differences in tumor volume between groups on the endpoint; and t-tests were used to analyze differences in tumor volume between the two groups. A p-value < 0.05 was defined as statistically significant.

[0192] Table 1. Dosing regimens of drug A in combination with drug B in a human colorectal cancer cell model HCT-116.

[0193] 3. Experimental Results

[0194] The growth-inhibiting effects of drug A combined with drug B on the HCT-116 model are shown in Table 2 and Figure 1. The changes in body weight of mice in each group are shown in Table 3 and Figure 2.

[0195] After the administration period ended (Day 21), the average tumor volume in the drug A, drug B, and drug C monotherapy groups was 379 mm. 3 542mm 3 and 832mm 3 The tumor inhibition rates were 80.95%, 67.00%, and 42.40%, respectively, compared with the solvent group (1,329 mm). 3 Compared to the previous treatment, all single-drug therapy groups showed significant tumor suppression (P<0.01); the average tumor volume in the drug A + drug B combination group (G5), drug B + drug C combination group (G6), and drug B + drug C + drug D + drug E combination group (G7) was 198 mm.3 498mm 3 and 211mm 3 The tumor inhibition rates were 96.26%, 70.78%, and 95.25%, respectively. Compared with the solvent group, all combination therapy groups showed significant tumor inhibition (P<0.0001). Compared with the individual drug groups (G2, G3) and the combination therapy group (G6), the tumor volume at the endpoint of the drug A + drug B combination group (G5) was statistically significantly different (P<0.01), and the tumor inhibition effect was comparable to that of the standard therapy group (G7).

[0196] Table 2. Growth inhibitory effects of drug A combined with drug B on the HCT-116 model Note: P-value (Day 21): Based on the tumor volume of each animal in different groups, the value obtained by Dunnett analysis using one-way ANOVA with the solvent group as the control; # Compared with the group treated with a combination of drug A and drug B, the results were obtained using t-test analysis. ## P<0.01, ### P<0.001;

[0197] Throughout the experiment, HCT-116 tumor-bearing mice showed good tolerance to drugs A, B, and the combination of drug A and drug B, with no significant decrease in body weight. Mice in the drug C, drug B + drug C, and drug B + drug C + drug D + drug E groups experienced significant weight loss after administration, with slight recovery after administration of nutritional gel. Statistical results showed that the weight change in the drug A + drug B group (G5) was significantly different from that in the drug B + drug C + drug D + drug E group (G7) (P<0.01), indicating better animal tolerance.

[0198] Table 3. Effects of drug A combined with drug B on body weight in HCT-116 tumor-bearing mice. Note: P-value: Based on the weight change rate data at different time points of each group, with the solvent group as the control, the value obtained by Dunnett analysis using two-way ANOVA; & Compared with the combination therapy group of drug A and drug B, the results obtained using two-way ANOVA analysis... && P<0.01;

[0199] In summary, the combination of drug A and drug B showed better tumor-suppressing effects than their respective single-drug groups, and was comparable to the standard therapy group (drug B + drug C + drug D + drug E), demonstrating good in vivo synergistic effects. Regarding safety, HCT-116 tumor-bearing mice showed better tolerance to the combination of drug A and drug B compared to the standard therapy.

[0200] Example 3. Clinical trial of anti-B7H3 antibody-drug conjugate combined with anti-VEGF antibody and optional chemotherapy agent for the treatment of advanced metastatic colorectal cancer.

[0201] 1. Name of the test drug:

[0202] (1) Anti-B7H3 antibody-drug conjugate

[0203] Dosage form: Injection (lyophilized powder), specification: 100mg / vial, packaged in 20mL borosilicate glass vials, manufacturer: Shanghai Hansen Biomedical Technology Co., Ltd.

[0204] (2) Anti-VEGF antibody

[0205] Bevacizumab, dosage form: injection, specification: 100mg (4ml), borosilicate glass vial, 1 vial / box, manufacturer: Suzhou Shengdiya Biomedical Co., Ltd.

[0206] (3) Chemotherapy agents

[0207] Leucovorin Calcium Injection, Dosage Form: Injection, Specification: 10ml: 0.1g, vial. 10 vials / box and 1 vial / box, Manufacturer: Jiangsu Hengrui Medicine Co., Ltd.

[0208] Fluorouracil Injection, Dosage Form: Injection, Specification: 10ml: 0.25g, 5 vials / box, Manufacturer: Tianjin Jinyao Pharmaceutical Co., Ltd.

[0209] Oxaliplatin Injection, Dosage Form: Injection, Specification: 10ml: 50mg, Borosilicate Glass Controlled Injection Bottle, 1 bottle / box, Manufacturer: Jiangsu Hengrui Medicine Co., Ltd.

[0210] Capecitabine, dosage form: tablets, specifications: 0.5g / 0.15g, manufacturer: Jiangsu Hengrui Medicine Co., Ltd.

[0211] 2. Target audience:

[0212] The target population for this study is shown in Table 4.

[0213] Table 4. Study Enrollment Population

[0214] Queue 1 (The following four conditions must be met simultaneously)

[0215] a. Subjects with advanced metastatic colorectal adenocarcinoma who have previously received standard treatment and have completed at least one line of treatment in the metastatic stage;

[0216] b. Non-MSI-H / dMMR subjects must have previously received standard treatment for advanced mCRC based on fluorouracil, oxaliplatin, and / or irinotecan (in combination with bevacizumab / cetuximab if appropriate) and failed. MSI-H / dMMR subjects must have previously received immune checkpoint inhibitor therapy and progressed or become intolerant;

[0217] c. If a subject has only received one line of treatment during the metastatic phase, they must not have received any treatment regimens containing irinotecan;

[0218] d. If non-MSI-H / dMMR subjects received adjuvant therapy based on fluorouracil, oxaliplatin, and / or irinotecan (and bevacizumab if appropriate) after radical surgery, or if MSI-H / dMMR subjects received adjuvant therapy based on immune checkpoint inhibitors after surgery, disease progression in the above populations occurring within 6 months after the end of the corresponding adjuvant therapy can be considered as having received first-line treatment for metastatic stage.

[0219] Queues 2 / 3 / 4 (all four conditions must be met simultaneously)

[0220] a. Subjects with advanced metastatic colorectal adenocarcinoma who have previously received standard treatment and have completed 1 line of treatment in the metastatic stage;

[0221] b. Patients in the metastatic stage who have not received irinotecan-containing treatment regimens must have previously received standard treatment for advanced mCRC based on fluorouracil and oxaliplatin (and, if appropriate, bevacizumab / cetuximab) and failed. MSI-H / dMMR patients must have previously received immune checkpoint inhibitor therapy and experienced progression or intolerance.

[0222] c. For subjects who have received neoadjuvant / adjuvant therapy before or after radical surgery, disease progression occurring within 6 months after the end of the last neoadjuvant / adjuvant therapy can be considered as having received first-line treatment for metastatic stage.

[0223] Queue 5 (The following three conditions must be met simultaneously)

[0224] a. Subjects with known advanced metastatic colorectal adenocarcinoma who are not MSI-H / dMMR;

[0225] b. No systemic anti-tumor treatment was received during the advanced metastatic stage;

[0226] c. For subjects who have received neoadjuvant / adjuvant therapy before or after radical surgery, the condition must be that more than 6 months have passed since the end of the last neoadjuvant / adjuvant therapy.

[0227] 3. Dosing regimen:

[0228] This study uses a treatment cycle (C) of either 2 weeks (14 days) or 3 weeks (21 days). For investigational drugs already marketed in the combination therapy, administration will be guided by guidelines and marketing authorization labels. Dosage escalation will be determined by the SRC meeting based on the safety and tolerability characteristics of the starting dose, and the dosage for the next group will be decided accordingly.

[0229] Cohort 1: Anti-B7H3 antibody-drug conjugate + bevacizumab

[0230] Recommended dosing priority: Administer bevacizumab first, followed by anti-B7H3 antibody-drug conjugate therapy at least 30 minutes after the initial administration. The entire dosing regimen (bevacizumab + anti-B7H3 antibody-drug conjugate) should be completed on the same day, starting from the first dose of this combination therapy and ending with the last dose.

[0231] Bevacizumab, 7.5 mg / kg, the total dose was calculated based on the subject's weight before administration, administered intravenously, every 3 weeks.

[0232] The anti-B7H3 antibody-drug conjugate was administered intravenously at a pre-set dose of 8.0 mg / kg, every 3 weeks. Based on the safety and tolerability of the initial dose, the dosage for the next group was determined by the SRC meeting, with an increment of 10.0 mg / kg and a decrement of 6.0 mg / kg.

[0233] Cohort 2: Anti-B7H3 antibody-drug conjugate + bevacizumab + leucovorin and fluorouracil

[0234] Recommended dosing priority: Administer bevacizumab first, followed by anti-B7H3 antibody-drug conjugate (ADD) at least 30 minutes after the initial administration; then, administer leucovorin and fluorouracil at least 60 minutes after the ADD administration. The entire dosing regimen (bevacizumab + ADD + leucovorin and fluorouracil) should be completed within 72 hours, calculated from the first dose of this combination therapy until the last dose.

[0235] The bevacizumab dose was fixed at 5.0 mg / kg. The total dose was calculated based on the subject's weight before administration. The bevacizumab was administered intravenously every two weeks.

[0236] The anti-B7H3 antibody-drug conjugate was administered intravenously at a pre-set dose of 4.0 mg / kg, every two weeks (Q2W). Based on the safety and tolerability of the initial dose, the dosage for the next group was determined by the SRC meeting, with an increment of 5.0 mg / kg and a decrement of 3.0 mg / kg.

[0237] Leucovorin calcium and fluorouracil were administered at doses calculated based on body surface area, using the subject's pre-administration body surface area. Leucovorin calcium was administered first, followed by fluorouracil, as detailed below:

[0238] Calcium leucovorin, 400 mg / m 2 Intravenous infusion over 120 minutes, day 1, every 2 weeks.

[0239] Fluorouracil, 400 mg / m² 2 Intravenous bolus injection, day 1; then 1200 mg / (m 2 ·d) Continuous intravenous infusion for 2 days (total dose 2400 mg / m²) 2 Infusion over 46–48 hours, Q2W. Based on the safety and tolerability of the initial dose, the dosage for the next group is determined by the SRC meeting, with a reduction dose of 300 mg / m². 2 Administered intravenously as a bolus injection on day 1; then 900 mg / (m²) 2 ·d) Continuous intravenous infusion for 2 days (total dose 2400 mg / m²) 2 (Infusion over 46-48 hours), Q2W.

[0240] Cohort 3: Anti-B7H3 antibody-drug conjugate + bevacizumab + leucovorin and fluorouracil

[0241] Recommended dosing priority: Administer bevacizumab first, followed by anti-B7H3 antibody-drug conjugate (ADD) at least 30 minutes after the initial administration; then, administer leucovorin and fluorouracil at least 60 minutes after the ADD administration. The entire dosing regimen (bevacizumab + ADD + leucovorin and fluorouracil) should be completed within 72 hours, calculated from the first dose of this combination therapy until the last dose.

[0242] The bevacizumab dose was fixed at 5.0 mg / kg. The total dose was calculated based on the subject's weight before administration. The bevacizumab was administered intravenously every two weeks.

[0243] The anti-B7H3 antibody-drug conjugate was administered intravenously at a pre-set dose of 5.0 mg / kg, every two weeks (Q2W). Based on the safety and tolerability of the initial dose, the dosage for the next group was determined by the SRC meeting, with an increment of 6.0 mg / kg and a decrement of 4.0 mg / kg.

[0244] Leucovorin calcium and fluorouracil were administered at doses calculated based on body surface area, using the subject's pre-administration body surface area. Leucovorin calcium was administered first, followed by fluorouracil, as detailed below:

[0245] Calcium leucovorin, 400 mg / m 2 Intravenous infusion over 120 minutes, day 1, every 2 weeks.

[0246] Fluorouracil, 1200 mg / (m 2 ·d) Continuous intravenous infusion for 2 days (total dose 2400 mg / m²) 2 The infusion time is 46–48 hours, Q2W. Based on the safety and tolerability of the initial dose, the dosage for the next group is determined by the SRC meeting, with the decreasing dose being 900 mg / (m2·d) × 2 days of continuous intravenous infusion (total dose 2400 mg / m2, infusion time 46–48 hours), Q2W.

[0247] Cohort 4: Anti-B7H3 antibody-drug conjugate + bevacizumab + capecitabine

[0248] Recommended dosing priority: Administer bevacizumab first, followed by anti-B7H3 antibody-drug conjugate therapy at least 30 minutes after the completion of bevacizumab administration; capecitabine treatment can be started on the same day after the completion of anti-B7H3 antibody-drug conjugate administration.

[0249] The bevacizumab dose was fixed at 7.5 mg / kg. The total dose was calculated based on the subject's weight before administration. The bevacizumab was administered intravenously every 3 weeks.

[0250] The anti-B7H3 antibody-drug conjugate was administered intravenously at a pre-set dose of 6.5 mg / kg, every 3 weeks. Based on the safety and tolerability of the initial dose, the dosage for the next group was determined by the SRC meeting, with an increment of 7.5 mg / kg and a decrement of 5.5 mg / kg.

[0251] Capecitabine: 800 mg / m 2 The total dosage was calculated based on the subjects' pre-dose weight. The medication was administered orally twice daily for days 1-14, every 3 weeks. Based on the safety and tolerability of the initial dose, the dosage for the next group was determined at the SRC meeting, with a reduction dose of 600 mg / m². 2 .

[0252] Cohort 5: Anti-B7H3 antibody-drug conjugate + bevacizumab + oxaliplatin + leucovorin and fluorouracil

[0253] Recommended dosing priority: Administer bevacizumab first, followed by anti-B7H3 antibody-drug conjugate (ADD) at least 30 minutes after completion of the ADD; then, administer oxaliplatin at least 60 minutes after the ADD, followed by leucovorin and fluorouracil (Note: Investigators may administer oxaliplatin and leucovorin concurrently based on clinical practice; refer to the oxaliplatin package insert for details). The entire dosing regimen (bevacizumab + ADD + oxaliplatin + leucovorin and fluorouracil) must be completed within 72 hours, calculated from the first dose of this combination therapy until the last dose.

[0254] The bevacizumab dose was fixed at 5.0 mg / kg. The total dose was calculated based on the subject's weight before administration. The bevacizumab was administered intravenously every two weeks.

[0255] The anti-B7H3 antibody-drug conjugate was administered intravenously at a pre-set dose of 4.0 mg / kg, every two weeks (Q2W). Based on the safety and tolerability of the initial dose, the dosage for the next group was determined by the SRC meeting, with an increment of 5.0 mg / kg and a decrement of 3.0 mg / kg.

[0256] Oxaliplatin dosage is calculated based on body surface area, using the subject's pre-administration body surface area. 65 mg / m² 2 Administer intravenously over at least 120 minutes, every 2 weeks. The dosage for the next group will be determined by the SRC meeting based on the safety and tolerability of the initial dose, with a decreasing dose of 50 mg / m². 2 .

[0257] Leucovorin calcium and fluorouracil were administered at doses calculated based on body surface area, using the subject's pre-administration body surface area. Leucovorin calcium was administered first, followed by fluorouracil, as detailed below:

[0258] Leucovorin calcium, 400 mg / m2, intravenous infusion over 120 minutes, every 2 weeks.

[0259] Fluorouracil, total dose 2400 mg / m² 2 Continuous intravenous infusion for 48 hours, Q2W. Based on the safety and tolerability of the initial dose, the dosage for the next group will be determined by the SRC meeting, with a decreasing dose of 1800 mg / m². 2 .

[0260] After 4–6 cycles of oxaliplatin treatment, medication was discontinued. If the investigator assessed the patient's overall condition and tolerance, the dose of the anti-B7H3 antibody-drug conjugate could be increased by one dose level (1 mg / kg). 4. Trial Results:

[0261] Based on current follow-up of patients, the treatment regimens in each cohort have shown clinical benefits, good clinical efficacy, and good clinical safety and tolerability.

Claims

1. Use of an antibody drug conjugate, an anti-VEGF antibody, and optionally one or more chemotherapeutic agents in the manufacture of a medicament for treating colorectal cancer, wherein The structure of the antibody drug conjugate is shown as formula (I): wherein: n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, 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 an antigen binding fragment thereof comprises heavy chain HCDR1, HCDR2, HCDR3 as shown in the amino acid sequences of SEQ ID NO: 01, 02 and 03, respectively, and light chain LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO: 04, 05 and 06, respectively; Preferably, the heavy chain variable region sequence of the anti-B7H3 antibody or an antigen binding fragment thereof is a sequence as shown in SEQ ID NO: 07 or a variant thereof, and the light chain variable region sequence is a sequence as shown in SEQ ID NO: 08 or a variant thereof; More preferably, the heavy chain sequence of the anti-B7H3 antibody or an antigen binding fragment thereof is a sequence as shown in SEQ ID NO: 09 or a variant thereof, and the light chain sequence is a sequence as shown in SEQ ID NO: 10 or a variant thereof.

3. The use according to claim 1 or 2, wherein the anti-VEGF antibody is selected from Bevacizumab, Ranibizumab, Sevacizumab, Suvemcitug, Varisacumab, CMAB-801, LYN-00101; Preferably, the anti-VEGF antibody is selected from Bevacizumab.

4. The use according to any one of claims 1 to 3, wherein the antibody drug conjugate, anti-VEGF antibody are contained as active ingredients in different formulations, respectively, and are administered simultaneously, concurrently, sequentially, continuously, alternately or separately.

5. The use according to any one of claims 1 to 4, wherein the one or more chemotherapeutic agents are platinum compounds and / or fluoropyrimidines; Preferably, the one or more chemotherapeutic agents are oxaliplatin, cisplatin, carboplatin, fluorouracil, capecitabine, tegafur, gimeracil, or oteracil; More preferably, the one or more chemotherapeutic agents are fluorouracil, oxaliplatin and fluorouracil, or capecitabine.

6. The use according to any one of claims 1 to 5, wherein the chemotherapeutic agent further comprises a chemoprotective agent; Preferably, the chemoprotective agent is calcium folinate or levofolinate; More preferably, the chemoprotective agent is calcium folinate.

7. The use of any one of claims 1 to 6, wherein the one or more chemotherapeutic agents are selected from the group consisting of calcium folinate / fluorouracil (FU-LV), oxaliplatin / calcium folinate / fluorouracil (FOLFOX), capecitabine.

8. The use of any one of claims 1 to 7, wherein the antibody drug conjugate, the anti-VEGF antibody, and the one or more chemotherapeutic agents are comprised as active ingredients in different formulations, respectively, and are administered simultaneously, concurrently, sequentially, continuously, alternately or separately.

9. Use according to any one of claims 6 to 8, wherein the effective amount of administration of the calcium folinate is 200-600 mg / m 2 , preferably 200 mg / m 2 , 250 mg / m 2 , 300 mg / m 2 , 350 mg / m 2 , 400 mg / m 2 , 450 mg / m 2 , 500 mg / m 2 , 550 mg / m 2 or 600 mg / m 2 , more preferably 400 mg / m 2 ; The dosing frequency is once a week, once every two weeks, once every three weeks or once every four weeks, preferably once every two weeks or once every four weeks, more preferably once every two weeks.

10. Use according to any one of claims 5 to 9, wherein the effective fluorouracil administration amount is 1800 to 2400 mg / m 2 , preferably 1800 mg / m 2 , 2100 mg / m 2 , 2400 mg / m 2 , 2800 mg / m 2 . The dosing frequency is once every two weeks or once every four weeks, preferably once every two weeks.

11. The use according to any one of claims 5 to 9, wherein the fluorouracil is administered intravenously in a single dose of 400 mg / m 2 2 on day 1, followed by the fluorouracil intravenously in a dose of 1200 mg / (m 2 *d) on day 2, and day 3; with a dosing frequency of every two weeks or every four weeks, preferably every two weeks. or, the fluorouracil is administered intravenously at a single dose of 300 mg / m 2 2 and day 3 at a dose of 900 mg / (m 2 *d); the dosing frequency is biweekly or quarterly, preferably biweekly.

12. The use according to any one of claims 5 to 11, wherein the effective oxaliplatin administration amount is 45 mg / m2, 50 mg / m2, 55 mg / m2, 60 mg / m2, 65 mg / m2, 70 mg / m2, 75 mg / m2, 80 mg / m2, 85 mg / m2, 90 mg / m2, 100 mg / m2, 110 mg / m2, 120 mg / m2, 130 mg / m2, 140 mg / m2, or 150 mg / m2, preferably 50 mg / m2, 65 mg / m2, 130 mg / m2. 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 ;​​​​​​​​​​​​​​​​​​ The dosing frequency is once every two weeks, once every three weeks, preferably once every two weeks.

13. The use according to any one of claims 5 to 12, wherein the effective amount of capecitabine is 600 mg / m 2 800 mg / m 2 2 per day, with 7 days off after 14 days of continuous administration, for a three-week cycle.

14. The use of any one of claims 1 to 13, wherein the dose of the antibody drug conjugate is 5.5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 10.0 mg / kg, with a dosing frequency of once every three weeks; or, the dose of the antibody drug conjugate is 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0 mg / kg, with a dosing frequency of once every two weeks.

15. The use of any one of claims 1 to 14, wherein the dose of the anti-VEGF antibody is 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, 9.0 mg / kg, 9.5 mg / kg, 10.0 mg / kg, with a dosing frequency of once every two weeks, once every three weeks; preferably, the dose of the anti-VEGF antibody is 5.0 mg / kg, with a dosing frequency of once every two weeks; or, the dose of the anti-VEGF antibody is 7.5 mg / kg, with a dosing frequency of once every three weeks.

16. The use of any one of claims 1 to 15, wherein the colorectal cancer is colorectal adenocarcinoma, colorectal adenosquamous carcinoma, colorectal squamous cell carcinoma, colorectal small cell carcinoma; preferably, metastatic colorectal adenocarcinoma; more preferably, advanced metastatic colorectal adenocarcinoma.

17. The use of claim 16, wherein the colorectal cancer is selected from colorectal cancer of non-MSI-H / dMMR phenotype; preferably, advanced metastatic colorectal adenocarcinoma of non-MSI-H / dMMR phenotype, or, advanced metastatic colorectal adenocarcinoma of MSI-H / dMMR phenotype; more preferably, advanced metastatic colorectal adenocarcinoma of non-MSI-H / dMMR phenotype that has previously received and failed standard treatment regimen based on fluorouracil, oxaliplatin and / or irinotecan, or, advanced metastatic colorectal adenocarcinoma of non-MSI-H / dMMR phenotype that has not received any systemic anti-tumor treatment at the advanced metastatic stage, or, advanced metastatic colorectal cancer of MSI-H / dMMR phenotype who have previously received immune checkpoint inhibitor therapy and progressed or were intolerant.

18. A method of treating or preventing colorectal cancer, the method comprising administering to a subject in need thereof: the antibody drug conjugate of claim 2 or 14, the anti-VEGF antibody of claim 3 or 15, and optionally, one or more chemotherapeutic agents of any one of claims 5 to 13, in combination, wherein the combination administration can be simultaneous, concurrent, sequential, continuous, alternating, or separate administration.

19. The method of claim 18, wherein the colorectal cancer is colorectal adenocarcinoma, colorectal adenosquamous carcinoma, colorectal squamous cell carcinoma, colorectal small cell carcinoma; preferably, advanced metastatic colorectal adenocarcinoma; more preferably, advanced metastatic colorectal adenocarcinoma of non-MSI-H / dMMR phenotype, advanced metastatic colorectal adenocarcinoma of MSI-H / dMMR phenotype.

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