Use of Anti-trop2 antibody-drug conjugate and VEGF-a inhibitor in combination for treating tumor

Abstract

The present invention relates to a method for treating a tumor using a TROP2-targeting antibody-drug conjugate and a VEGF-A inhibitor in combination or use of the TROP2-targeting antibody-drug conjugate and the VEGF-A inhibitor in combination for treating the tumor.

Description

Use of anti-TROP2 antibody-drug conjugates and VEGF-A inhibitors in combination for the treatment of tumors Technical Field

[0001] This invention relates to the use of anti-TROP2 antibody-drug conjugates and VEGF-A inhibitors, such as bevacizumab, in the preparation of medicaments for the treatment of tumors. Background Technology

[0002] Cancer is a common and fatal disease. Chemotherapy, as one of the standard treatments for advanced tumors, still plays an important role in clinical treatment. However, its poor selectivity and strong toxic side effects lead some patients to refuse it or be unable to tolerate it. TROP2 (trophoblast cell surface glycoprotein antigen 2) is overexpressed in various cancer cells, such as gastric cancer, colon cancer, papillary thyroid carcinoma, urothelial carcinoma, prostate cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, oral squamous cell carcinoma, ovarian epithelial carcinoma, and cervical cancer. Currently, there is a huge unmet clinical need for cancer treatment and prognosis. Exploring drug therapies or combination therapies targeting various mechanisms of action to benefit more patients is a pressing clinical issue that needs to be addressed. Summary of the Invention

[0003] TROP2 (trophoblast cell surface glycoprotein antigen 2) is overexpressed in various cancer cells. This invention provides a method or use of an anti-TROP2 antibody-drug conjugate and a VEGF-A inhibitor for treating tumors, comprising administering an effective amount of the anti-TROP2 antibody-drug conjugate and the VEGF-A inhibitor to a patient with a tumor. In one aspect, this invention provides the use of the anti-TROP2 antibody-drug conjugate and the VEGF-A inhibitor in the preparation of a medicament for treating tumors. In another aspect, this invention provides the use of the anti-TROP2 antibody-drug conjugate and the VEGF-A inhibitor in combination for treating tumors. In another aspect, this invention provides a pharmaceutical composition of the anti-TROP2 antibody-drug conjugate and the VEGF-A inhibitor, and its use in treating tumors. In another aspect, this invention provides the use of the anti-TROP2 antibody-drug conjugate in the preparation of a medicament for treating tumors in combination with a VEGF-A inhibitor. In yet another aspect, this invention provides the use of the VEGF-A inhibitor in the preparation of a medicament for treating tumors in combination with the anti-TROP2 antibody-drug conjugate. On one hand, this invention provides the use of an anti-TROP2 antibody-drug conjugate in combination with a VEGF-A inhibitor for the treatment of tumors. On the other hand, this invention provides the use of a VEGF-A inhibitor in combination with an anti-TROP2 antibody-drug conjugate for the treatment of tumors.

[0004] In some embodiments, the antibody-drug conjugate has a structure as shown in Formula I-1 or Formula I-2, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

[0005] in

[0006] Abu is an anti-TROP2 antibody or its antigen-binding unit;

[0007] D is a DNA topoisomerase I inhibitor or a salt thereof. For example, the DNA topoisomerase I inhibitor is selected from irinotecan, irinotecan hydrochloride, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, 9-chloro-10-hydroxycamptothecin, camptothecin derivative SN-38, 22-hydroxyeclipticine, topotecan, letopotecan, belotecone, homosilatecan, 6,8-dibromo-2-methyl-3-[2-(D-pyranoxylamino)phenyl]-4(3H)-quinazolinone, 2-cyano-3-(3,4-dihydroxyphenyl)-N- (phenylmethyl)-(2E)-2-acrylamide, 2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-hydroxyphenylpropyl)-(E)-2-acrylamide, 12-β-D-glucopyranosyl-12,13-dihydro-2,10-dihydroxy-6-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione, N-[2-(dimethylamino)ethyl]-4-acrylamide, N-[2-(dimethylamino)ethyl]-4-acrylamide, eczetidine or eczetidine derivatives;

[0008] n is an integer from 1 to 24, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24;

[0009] p is approximately 1-10, for example approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, or approximately 10.

[0010] In some implementations, D is ixotecan or an ixotecan derivative.

[0011] In some implementations, D is

[0012] Where X 1 and X 2 Each is independently a C1-C6 alkyl, halogen, or -OH; ** represents a connection point.

[0013] In some embodiments, the C1-C6 alkyl group is -CH3.

[0014] In some implementations, the halogen is F.

[0015] In some implementation schemes, X 1 and X 2 Each can be independently -CH3, F, or -OH.

[0016] In some implementation schemes, X 1 and X 2 Each is -CH3.

[0017] In some implementation schemes, X 1 and X 2 Each can be F, Cl, Br, or I independently.

[0018] In some implementation schemes, X 1 and X 2 Each is F.

[0019] In some implementation schemes, X 1 and X 2 Each can be either F or -CH3.

[0020] In some implementation schemes, X 1 For -CH3 and X 2 It is F.

[0021] In some implementations, n is an integer from 4 to 12. In some implementations, n is an integer from 4 to 8. In some implementations, n is 4. In some implementations, n is 8.

[0022] In some embodiments, p is about 2-8. In some embodiments, p is about 4-8. In some embodiments, p is about 4-5. In some embodiments, p is about 6-8. In some embodiments, p is about 7-8. In some embodiments, p is about 4-6. In some embodiments, p is about 5-7. In some embodiments, p is about 5.5-6.5. In some embodiments, p is about 4. In some embodiments, p is about 6.

[0023] In some embodiments, the antibody-drug conjugate has the structure shown in formula I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, or I-16, or I-17, I-18, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

[0024] in,

[0025] Abu is an anti-TROP2 antibody or its antigen-binding unit;

[0026] n is an integer from 1 to 24, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24;

[0027] p is approximately 1-10, for example approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, or approximately 10.

[0028] In some implementations, n is an integer from 4 to 12. In some implementations, n is an integer from 4 to 8. In some implementations, n is 4. In some implementations, n is 8.

[0029] In some embodiments, p is about 2-8. In some embodiments, p is about 4-8. In some embodiments, p is about 4-5. In some embodiments, p is about 6-8. In some embodiments, p is about 7-8. In some embodiments, p is about 4-6. In some embodiments, p is about 5-7. In some embodiments, p is about 5.5-6.5. In some embodiments, p is about 4. In some embodiments, p is about 6.

[0030] In some implementations, Abu is an anti-TROP2 antibody.

[0031] In some implementations, the anti-TROP2 antibody can specifically target the Trop2 protein.

[0032] In some implementations, the anti-TROP2 antibody is a fully human monoclonal antibody.

[0033] In some implementations, the anti-TROP2 antibody is a humanized monoclonal antibody.

[0034] In some embodiments, the anti-TROP2 antibody is an antibody disclosed in the following patent documents: WO2021147993A1 (e.g., PD3), CN101264325B (e.g., RS7, hRS7), CN105849126B (e.g., hTINA1-H1L1, hTINA1-H2L1, hTINA1-H2L2, hTINA1-H3L3), CN110903395A (e.g., M1, M2, M3), CN1 13896796A (e.g., 4D3, 7F11), US20130089872 (e.g., K5-70, K5-107, K5-116-2-1, T6-16, T5-86), US5840854A (e.g., BR110), US20130122020 (e.g., 3E9, 6G11, 7E6, 15E2, 18B1), US20120237518 (e.g., 77220, KM4097, KM4590).

[0035] In some embodiments, the anti-TROP2 antibody is commercially available, including LS-C126418, LS-C178765, LS-C126416, LS-C126417 (LifeSpan BioSciences, Inc., Seattle, WA); 10428-MM01, 10428-MM02, 10428-R001, 10428-R030 (Sino Biological Inc., Beijing, China); MR54 (eBioscience, San Diego, CA); sc-376181, sc-376746 (Santa Cruz Biotechnology, Santa Cruz, CA); MM0588-49D6 (Novus Biologicals, Littleton, CO); ab79976 and ab89928 (Cambridge, MA).

[0036] In some embodiments, the anti-TROP2 antibody is anti-TROP2 antibodies 162-25.3 and 162-46.2 disclosed by Lipinski et al. (1981, Proc. Natl. Acad. Sci. USA, 78: 5147-50) or Pr1E11 anti-TROP2 antibody disclosed by Ikeda et al. (2015, Biochem Biophys Res Comm 458: 877-82), which recognize a unique epitope on TROP2.

[0037] In some embodiments, the anti-TROP2 antibody comprises a heavy chain as shown in SEQ ID NO:1 and a light chain as shown in SEQ ID NO:2.

[0038] In some implementations, the anti-TROP2 antibody is an hRS9 antibody.

[0039] In some embodiments, the anti-TROP2 antibody-drug conjugate is ADC1 or its stereoisomer or a pharmaceutically acceptable salt or solvate thereof, wherein ADC1 has the structure shown in Formula II:

[0040] Where p is approximately 4-8.

[0041] In some embodiments, p is about 4-6. In some embodiments, p is about 5-7. In some embodiments, p is about 5.5-6.5. In some embodiments, p is about 4, about 5, about 6, about 7, or about 8. In some embodiments, p is about 6.

[0042] In some embodiments, the anti-TROP2 antibody-drug conjugate is ADC2 or its stereoisomer or a pharmaceutically acceptable salt or solvate thereof, wherein ADC2 has the structure shown in Formula III:

[0043] Where p is approximately 4-8.

[0044] In some embodiments, p is about 4-6. In some embodiments, p is about 5-7. In some embodiments, p is about 5.5-6.5. In some embodiments, p is about 4, about 5, about 6, about 7, or about 8. In some embodiments, p is about 6.

[0045] In some embodiments, the anti-TROP2 antibody-drug conjugate is the anti-TROP2 antibody-drug conjugate disclosed in WO2022 / 253284.

[0046] In some embodiments, the dose of the anti-TROP2 antibody-drug conjugate is about 0.1-10 mg / kg per administration. In some embodiments, the dose of the anti-TROP2 antibody-drug conjugate is about 1-5 mg / kg per administration. In some embodiments, the dose of the anti-TROP2 antibody-drug conjugate is about 2-3 mg / kg per administration. In some embodiments, the dose of the anti-TROP2 antibody-drug conjugate is about 0.1 mg / kg, about 0.8 mg / kg, about 1.2 mg / kg, about 2.1 mg / kg, about 2.4 mg / kg, about 2.7 mg / kg, about 3.0 mg / kg, about 3.3 mg / kg, about 3.6 mg / kg, about 4.0 mg / kg, about 4.8 mg / kg, about 6.0 mg / kg, about 7.2 mg / kg, about 8.4 mg / kg, or about 10 mg / kg, or a range (including endpoints) of any two of these values, or any value therein.

[0047] In some embodiments, the dose of the anti-TROP2 antibody-drug conjugate is about 5-3000 mg per administration. In some embodiments, the dose of the anti-TROP2 antibody-drug conjugate is about 5-2000 mg, 5-1500 mg, 5-1000 mg, 5-800 mg, 5-600 mg, 48-432 mg, 48-216 mg, 72-504 mg, 100-2000 mg, 200-1000 mg, 300-800 mg, or 400-700 mg per administration. In some embodiments, the dose of the anti-TROP2 antibody-drug conjugate administered per dose is about 5 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg, or a range (including endpoints) between any two of these values, or any value therein.

[0048] In some embodiments, a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks, or a range (including endpoints) between any two of these values, or any value therein. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately once weekly, or approximately every 2 weeks, approximately every 3 weeks, approximately every 4 weeks, approximately every 5 weeks, approximately every 6 weeks, or approximately every 7 weeks. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 3 weeks. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 2 weeks. In some embodiments, the first dosing cycle of the anti-TROP2 antibody-drug conjugate is 3 weeks, followed by dosing approximately every 2 weeks.

[0049] In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 1, 2, 3, 4, 5, 6, or 7 weeks, with each dose being approximately 0.1-10 mg / kg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 1, 2, 3, 4, 5, 6, or 7 weeks, with each dose being approximately 1-5 mg / kg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 1, 2, 3, 4, 5, 6, or 7 weeks, with each dose being approximately 2-3 mg / kg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 1, 2, 3, 4, 5, 6, or 7 weeks, with each administration dose of the anti-TROP2 antibody-drug conjugate being approximately 0.1 mg / kg, approximately 0.8 mg / kg, approximately 1.2 mg / kg, approximately 2.1 mg / kg, approximately 2.4 mg / kg, approximately 2.7 mg / kg, approximately 3.0 mg / kg, approximately 3.3 mg / kg, approximately 3.6 mg / kg, approximately 4.0 mg / kg, approximately 4.8 mg / kg, approximately 6.0 mg / kg, approximately 7.2 mg / kg, approximately 8.4 mg / kg, or approximately 10 mg / kg, or a range (including endpoints) of any two of these values, or any value thereof.

[0050] In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 3 weeks at a dose of approximately 0.1-30 mg / kg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 3 weeks at a dose of approximately 0.1-10 mg / kg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 3 weeks at a dose of approximately 1-5 mg / kg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 3 weeks at a dose of approximately 2-3 mg / kg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 3 weeks at a dose of approximately 0.1 mg / kg, approximately 0.5 mg / kg, approximately 0.8 mg / kg, approximately 1 mg / kg, approximately 1.2 mg / kg, approximately 2.1 mg / kg, approximately 2.4 mg / kg, approximately 2.7 mg / kg, approximately 3.0 mg / kg, approximately 3.3 mg / kg, approximately 3.6 mg / kg, approximately 4.0 mg / kg, approximately 4.8 mg / kg, approximately 6.0 mg / kg, approximately 7.2 mg / kg, approximately 8.4 mg / kg, or approximately 10 mg / kg, or a range between any two of these values ​​(including the endpoints) or any value thereof.

[0051] In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 2 weeks at a dose of approximately 0.1-30 mg / kg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 2 weeks at a dose of approximately 0.1-10 mg / kg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 2 weeks at a dose of approximately 1-5 mg / kg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 2 weeks at a dose of approximately 2-3 mg / kg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 2 weeks at a dose of approximately 0.1 mg / kg, approximately 0.5 mg / kg, approximately 0.8 mg / kg, approximately 1 mg / kg, approximately 1.2 mg / kg, approximately 2.1 mg / kg, approximately 2.4 mg / kg, approximately 2.7 mg / kg, approximately 3.0 mg / kg, approximately 3.3 mg / kg, approximately 3.6 mg / kg, approximately 4.0 mg / kg, approximately 4.8 mg / kg, approximately 6.0 mg / kg, approximately 7.2 mg / kg, approximately 8.4 mg / kg, or approximately 10 mg / kg, or a range between any two of these values ​​(including the endpoints) or any value therein.

[0052] In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 3 weeks at a dose of approximately 5-3000 mg. In other embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 3 weeks at doses of approximately 5-2000 mg, 5-1500 mg, 5-1000 mg, 5-800 mg, 5-600 mg, 48-432 mg, 48-216 mg, 72-504 mg, 100-2000 mg, 200-1000 mg, 300-800 mg, or 400-700 mg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 3 weeks at a dose of approximately 5 mg, approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 500 mg, approximately 600 mg, approximately 700 mg, approximately 1000 mg, approximately 1500 mg, approximately 2000 mg, approximately 2500 mg, or approximately 3000 mg, or a range (including endpoints) of any two of these values, or any value thereof.

[0053] In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every two weeks at a dose of approximately 5-3000 mg. In other embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every two weeks at doses of approximately 5-2000 mg, 5-1500 mg, 5-1000 mg, 5-800 mg, 5-600 mg, 48-432 mg, 48-216 mg, 72-504 mg, 100-2000 mg, 200-1000 mg, 300-800 mg, or 400-700 mg. In some embodiments, the anti-TROP2 antibody-drug conjugate is administered approximately every 2 weeks at a dose of approximately 5 mg, approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, approximately 500 mg, approximately 600 mg, approximately 700 mg, approximately 1000 mg, approximately 1500 mg, approximately 2000 mg, approximately 2500 mg, or approximately 3000 mg, or a range between any two of these values ​​(including the endpoints) or any value therein.

[0054] In some embodiments, the VEGF-A inhibitor is an anti-VEGF-A antibody.

[0055] In some embodiments, the VEGF-A inhibitor is bevacizumab. In some embodiments, the bevacizumab may be Avastin or its biosimilar, such as Prucidia, Alymsys, Avasi, Avenizumab, Aybintio, Alymsys, Alymsys, Zirabev, Mvasi, Vegzelma, Onbevzi, Oyavas, Aybintio, or Abevmy.

[0056] In some embodiments, the bevacizumab is administered at a dose of about 3-15 mg / kg per administration. In some embodiments, the bevacizumab is administered at a dose of about 5-15 mg / kg per administration. In some embodiments, the bevacizumab is administered at a dose of about 5 mg / kg per administration.

[0057] In some embodiments, the bevacizumab is administered every 1, 2, 3, 4, 5, 6, or 7 weeks. In some embodiments, the bevacizumab is administered every 2, 3, or 4 weeks. In some embodiments, the bevacizumab is administered every 2 weeks. In some embodiments, the bevacizumab is administered every 3 weeks. In some embodiments, the first dosing cycle of the bevacizumab is 3 weeks, followed by dosing approximately every 2 weeks.

[0058] In some embodiments, the bevacizumab is administered once every 3 weeks at a dose of approximately 5 mg / kg. In some embodiments, the bevacizumab is administered once every 2 weeks at a dose of approximately 5 mg / kg. In some embodiments, the first dosing cycle of the bevacizumab is 3 weeks, followed by dosing once every 2 weeks at a dose of approximately 5 mg / kg.

[0059] In some embodiments, the anti-TROP2 antibody-drug conjugate is ADC1, administered at a dose of 2-3 mg / kg every 2 or 3 weeks; and the bevacizumab is administered at a dose of about 5 mg / kg every 2 or 3 weeks. In some embodiments, the anti-TROP2 antibody-drug conjugate is ADC1, administered at a dose of about 2.1 or about 2.4 mg / kg every 2 or 3 weeks; and the bevacizumab is administered at a dose of about 5 mg / kg every 2 or 3 weeks.

[0060] In some embodiments, the anti-TROP2 antibody-drug conjugate is ADC1, administered at a dose of about 2.1 or about 2.4 mg / kg every 2 weeks; the bevacizumab is administered at a dose of about 5 mg / kg every 2 weeks.

[0061] In some embodiments, the anti-TROP2 antibody-drug conjugate is ADC1, administered at a dose of about 2.1 or about 2.4 mg / kg every 3 weeks; the bevacizumab is administered at a dose of about 5 mg / kg every 3 weeks.

[0062] In some embodiments, the anti-TROP2 antibody-drug conjugate is ADC1, administered at a dose of about 2.1 or about 2.4 mg / kg per administration, with an initial dosing cycle of 3 weeks, followed by administration every 2 weeks; the bevacizumab is administered at a dose of about 5 mg / kg per administration, with an initial dosing cycle of 3 weeks, followed by administration every 2 weeks.

[0063] The term "combination" as used herein refers to a route of administration that includes various situations in which two or more drugs are administered sequentially or simultaneously. In some embodiments, the anti-TROP2 antibody-drug conjugate and VEGF-A inhibitor are prepared as a single pharmaceutical composition (e.g., a combination formulation) and administered simultaneously to a patient in need of both the anti-TROP2 antibody-drug conjugate and the VEGF-A inhibitor. In some embodiments, the anti-TROP2 antibody-drug conjugate and VEGF-A inhibitor are prepared as separate pharmaceutical compositions and administered simultaneously to a patient in need of both the anti-TROP2 antibody-drug conjugate and the VEGF-A inhibitor, or administered to a patient in need of both the anti-TROP2 antibody-drug conjugate and the VEGF-A inhibitor at different times during a treatment regimen. For example, the anti-TROP2 antibody-drug conjugate may be administered before, after, or in an alternating manner with the VEGF-A inhibitor. In some embodiments, the anti-TROP2 antibody-drug conjugate may be administered after the VEGF-A inhibitor. In this article, the anti-TROP2 antibody-drug conjugate and VEGF-A inhibitor were administered to patients in need in single or multiple doses.

[0064] In some implementations, the bevacizumab is administered after the ADC1 is administered.

[0065] In some implementations, the patient receives one treatment cycle. In some implementations, the patient receives multiple treatment cycles (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 cycles, or a range (including endpoints) or any of these values). In some implementations, the patient receives treatment until the symptoms are relieved and treatment is no longer necessary.

[0066] In some embodiments, in the method of treating tumors provided by the present invention, the anti-TROP2 antibody-drug conjugate and VEGF-A inhibitor can be administered via any convenient route, such as by infusion or bolus injection, absorption through epithelial or mucosal membranes (e.g., oral mucosa, rectal and intestinal mucosa), and can be co-administered with other bioactive agents. Therefore, the pharmaceutical composition of the anti-TROP2 antibody-drug conjugate and VEGF-A inhibitor can be administered intravenously, subcutaneously, orally, rectally, parenterally, intracerebrally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, drops, or transdermal patch), orally, orally or via nasal spray. In some embodiments, the route of administration is intravenous (iv) infusion (i.e., intravenous infusion). In some embodiments, the agents used for the anti-TROP2 antibody-drug conjugate and / or VEGF-A inhibitor can be formulated into a pharmaceutical composition and administered to the patient in a form suitable for the selected route of administration, such as parenterally, intravenously (iv), intramuscularly, locally, or subcutaneously (sc). In some implementations, the route of administration is intravenous infusion.

[0067] In some implementations, the anti-TROP2 antibody-drug conjugate or VEGF-A inhibitor is administered via intravenous infusion. In some embodiments, the duration of intravenous infusion of the anti-TROP2 antibody-drug conjugate, VEGF-A inhibitor, or pharmaceutical composition comprising the anti-TROP2 antibody-drug conjugate and / or VEGF-A inhibitor is about 15 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 105 minutes, about 120 minutes, about 135 minutes, about 150 minutes, about 165 minutes, about 180 minutes, about 195 minutes, about 210 minutes, about 225 minutes, or about 240 minutes, or a range (including endpoints) between any two of these values, or any value therein. In some embodiments, the intravenous infusion of the anti-TROP2 antibody-drug conjugate or the pharmaceutical composition comprising the anti-TROP2 antibody-drug conjugate is administered for a duration of 30 minutes or more. In some embodiments, the intravenous infusion of the VEGF-A inhibitor is administered for a duration of about 90 minutes, about 60 minutes, or about 30 minutes.

[0068] Examples of tumors include, but are not limited to, triple-negative breast cancer, hormone receptor-positive and HER2-negative (HR+ / HER2-) breast cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), gastric cancer (including gastric adenocarcinoma), esophageal cancer, thymic carcinoma, head and neck tumors (including head and neck squamous cell carcinoma), urothelial carcinoma, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, fallopian tube cancer, breast cancer, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), peritoneal cancer, pancreatic cancer, glioblastoma, liver cancer, bladder cancer, urethral cancer, hepatoma, colon cancer, rectal cancer, colorectal cancer, colorectal cancer, large intestine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, glioblastoma, medulloblastoma, T-cell lymphoma, melanoma, Kaposi's sarcoma, and hepatobiliary carcinoma.

[0069] In some implementations, the tumor is a solid tumor.

[0070] In some implementations, the tumor is an advanced solid tumor.

[0071] In some implementations, the tumor is a locally advanced or metastatic solid tumor.

[0072] In some implementations, the tumor is an advanced solid tumor of epithelial origin.

[0073] In some implementations, the tumor is a pathologically or cytologically confirmed advanced or metastatic epithelial-derived solid tumor that has failed or is not treated with standard therapy, or is intolerant to or refuses standard therapy.

[0074] In some implementations, the tumor is non-squamous non-small cell lung cancer, small cell lung cancer, gastric adenocarcinoma, esophageal cancer, cervical cancer, or head and neck squamous cell carcinoma.

[0075] In some embodiments, the tumor is locally advanced or metastatic non-squamous non-small cell lung cancer diagnosed by histological or cytological examination, or a solid tumor that is incurable by radical resection or radiation therapy. In some embodiments, the tumor is locally advanced or metastatic non-squamous non-small cell lung cancer diagnosed by histological or cytological examination and incurable by radical resection or radiation therapy. In some embodiments, the tumor is a driver gene-negative solid tumor that has previously received at least one line of systemic chemotherapy. In some embodiments, the tumor is a driver gene-positive solid tumor that has previously received EGFR-TKI treatment for locally advanced or metastatic disease and has failed treatment.

[0076] In some implementations, the tumor is an advanced or metastatic epithelial-derived solid tumor that is intolerant to or refuses other standard treatments.

[0077] In some implementations, the non-limiting tumors are gastric adenocarcinoma, esophageal cancer, small cell lung cancer, cervical cancer, and head and neck squamous cell carcinoma.

[0078] In some implementations, the tumor is a solid tumor expressing TROP2.

[0079] In some implementations, the standard treatment refers to the standard treatment regimen for the tumor recommended by the NCCN guidelines and CSCO guidelines.

[0080] In some implementation schemes, the RECIST v1.1 evaluation criteria are primarily used to assess the antitumor efficacy of ADC1 with or without bevacizumab.

[0081] In some embodiments, the combination of the anti-TROP2 antibody-drug conjugate and the VEGF-A inhibitor of the present invention exhibits good safety and tolerability. In some embodiments, the combination of the anti-TROP2 antibody-drug conjugate and the VEGF-A inhibitor of the present invention results in improvements selected from at least one of the following: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

[0082] In some embodiments, the pharmaceutical composition further includes pharmaceutically acceptable excipients. In some embodiments, pharmaceutically acceptable excipients may comprise antibacterial and / or antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In some embodiments, pharmaceutically acceptable excipients may comprise isotonic agents, such as sugars, polyols (such as mannitol, sorbitol), sodium chloride. In some embodiments, the pharmaceutical composition comprises at least 0.1% of an anti-TROP2 antibody-drug conjugate and / or a VEGF-A inhibitor. The percentage can vary, for example, from about 2% to 90% by weight of a given dosage form. Detailed Implementation

[0083] the term

[0084] "About" or "approximately" refers to a typical error range for a given value that is readily known to those skilled in the art. In some embodiments, "about" or "approximately" as used herein refers to the described value and its range of ±10%, ±5%, ±1%, or ±0.1%.

[0085] "Treatment" refers to therapeutic treatments and preventative or preventative measures aimed at preventing, mitigating, improving, or stopping adverse physiological changes or disorders, such as disease progression, including but not limited to the following, whether detectable or undetectable: symptom relief, reduction of disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement, mitigation, reduction, or disappearance of the disease state (whether partial or complete), and prolongation of expected survival without treatment. Patients requiring treatment include those already suffering from the condition or disorder, those susceptible to the condition or disorder, or those needing prevention of the condition or disorder, as well as those who can or are expected to benefit from the application of the antibody or pharmaceutical composition disclosed in this invention for detection, diagnostic procedures, and / or treatment.

[0086] As used herein, the term "effective dose" or "therapeutic effective dose" refers to a dose of a drug, such as an antibody or ADC, sufficient to reduce or improve the severity and / or duration of a condition (e.g., cancer) or one or more of its symptoms; prevent disease progression; induce disease remission; prevent recurrence, development, onset, or progression of one or more symptoms associated with the condition; detect the condition; or enhance or improve the preventive or therapeutic effect of another therapy (e.g., a prophylactic or therapeutic agent). For example, an effective dose of an antibody may inhibit tumor growth (e.g., inhibit an increase in tumor volume); reduce tumor growth (e.g., reduce tumor volume); reduce the number of cancer cells; and / or alleviate one or more symptoms associated with cancer to some extent. For example, an effective dose may improve progression-free survival (PFS), improve overall survival (OS), or reduce the likelihood of recurrence.

[0087] The terms "patient" and "subject" are used interchangeably and refer to any mammal requiring diagnosis, prognosis, or treatment, including but not limited to humans, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, and especially animals with one or more conditions involving solid tumors. In some implementations, the patient is a human.

[0088] The efficacy indicators for antitumor therapy include objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) as defined by the Remission Assessment Criteria for Solid Tumors (RECIST 1.1) (Eisenhauer, EA et al., Eur J Cancer. 2009; 45(2):228-247).

[0089] Objective response rate (ORR): This refers to the proportion of patients whose tumors shrink to a certain extent and remain so for a certain period of time, including CR and PR cases. RECIST version 1.1 criteria are used to assess objective response. Patients must have measurable tumor lesions at baseline. The efficacy assessment criteria, according to RECIST version 1.1, are divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).

[0090] Duration of Response (DOR): DOR is defined as the time from the first assessment of objective response to the first assessment of disease progression (PD) or death from any cause prior to PD, reflecting the duration of ORR.

[0091] Disease control rate (DCR): The proportion of patients whose tumors shrink or stabilize for a certain period of time, including cases of CR, PR and SD, also known as clinical benefit rate (CBR).

[0092] Progression-free survival (PFS): the time from the first dose to the occurrence of objective tumor progression or all-cause death (whichever comes first).

[0093] Overall survival (OS): The time from the date of first administration to death from any cause. For subjects still alive at the time of analysis, the cutoff date is the date of their last contact.

[0094] The Eastern Cooperative Oncology Group (ECOG) has developed a simplified activity status scoring system that classifies patients' activity status into 6 levels, from 0 to 5. The ECOG activity status scoring system uses scores of 0, 1, 2, 3, 4, and 5.

[0095] Single-dose pharmacokinetic parameters: C max T max T 1 / 2 CL, Vd, Ke, MRT, AUC (0-τ) AUC (0-∞)。

[0096] Multiple-dose pharmacokinetic parameters: C max,ss C avg,ss C min,ss AUC (0-τ)ss AUC (0-∞)ss T max,ss T 1 / 2,ss CL, V ss Ke, MRT, Accumulation Index (R) ac ), Volatility Index (DF).

[0097] The terms "antibody-drug conjugate" or "ADC" are used interchangeably and refer to a binding protein (such as an antibody or its antigen-binding unit) linked to one or more drugs, which may optionally be a therapeutic agent or a cytotoxic agent. In some embodiments, an ADC includes an antibody, a drug (e.g., a cytotoxic drug), and a connector capable of attaching or conjugating the drug to the antibody. Non-limiting examples of drugs that may be included in an ADC include mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, anti-angiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormones, anti-hormonal agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclides, topoisomerase inhibitors, kinase inhibitors (e.g., TEC-family kinase inhibitors and serine / threonine kinase inhibitors), and radiosensitizers.

[0098] The term "drug-antibody conjugation ratio" or "DAR" refers to the number of drugs (e.g., eczemac) attached to one antibody in an ADC. The DAR of an ADC can range from 1 to 10, but higher loadings (e.g., 20) are possible depending on the number of binding sites on the antibody. The term DAR may be used when referring to the number of drugs loaded onto a single antibody, or alternatively, when referring to the average or mean DAR of a group of ADCs. In some embodiments, its value is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. When considering the average number of drug-antibody bindings in the composition, i.e., the average number of drug bindings to the antibody, or the average drug-antibody conjugation ratio, its value is selected from about 0 to about 10, or about 2 to about 8. In some embodiments, the average drug-antibody conjugation ratio is about 4 to about 7. In some embodiments, the average drug-antibody conjugation ratio is about 4 to about 5. In other embodiments, the average drug-antibody conjugation ratio is about 6 to about 8, or about 7 to about 8. In some embodiments, the average drug-antibody conjugation ratio is about 5.5 to about 6.5. In some implementations, the average drug-antibody conjugate ratio (DAR) is approximately 6. The DAR value is expressed as p in this document. The DAR value of the ADC can be determined using ultraviolet-visible absorption spectroscopy (UV-Vis), high-performance liquid chromatography-hydrophobic chromatography (HPLC-HIC), high-performance liquid chromatography-reversed-phase chromatography (RP-HPLC), and liquid chromatography-mass spectrometry (LC-MS). These techniques are described in Ouyang, J. Methods Mol Biol, 2013, 1045: pp. 275-83.

[0099] "Antibody" or "antigen-binding fragment" refers to a polypeptide or polypeptide complex that specifically recognizes and binds to an antigen. An antibody can be a complete antibody, any antigen-binding fragment, or a single chain thereof. Therefore, the term "antibody" includes any protein or peptide containing at least a portion of an immunoglobulin molecule that has biological activity of binding to an antigen. Antibody and antigen-binding fragments include, but are not limited to, the complementarity-determining region (CDR), heavy chain variable region (VH), light chain variable region (VL), heavy chain constant region (CH), light chain constant region (CL), framework region (FR), or any portion thereof of the heavy chain or light chain or its ligand-binding moiety, or at least a portion of the binding protein. CDR regions include the CDR regions of the light chain variable region (VL CDR1-3) and the CDR regions of the heavy chain variable region (VH CDR1-3). An antibody or its antigen-binding unit can specifically recognize and bind to a polypeptide or polypeptide complex of one or more (e.g., two) antigens.

[0100] Various substituents are defined as follows.

[0101] "Alkyl" refers to a saturated aliphatic hydrocarbon group; this term includes both straight-chain and branched hydrocarbon groups. C1-C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, such as alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. "Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0102] "Stereoisomers" refer to isomers of compounds that have the same atomic bond sequence but different spatial arrangements of atoms. Stereoisomers may have one or more stereocenters, and each center may be present as R or S. Stereoisomers may also be cis-trans isomers. The stereoisomers of compounds provided herein include any one or suitable mixtures of all their diastereomeric, enantiomeric, and cis-trans isomeric forms.

[0103] Pharmaceutically acceptable salts include those produced by compounds with a wide variety of organic and inorganic counterions well known in the art. Exemplary salts include, when the molecule contains acidic functional groups, organic or inorganic salts such as lithium, sodium, potassium, calcium, magnesium, ammonium, isopropylamine, trimethylamine, diethylamino, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethyl, polyamine resins, and tetraalkylammonium salts; and when the molecule contains basic functional groups, organic or inorganic acid salts such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, and oxalate. Other non-limiting examples of acids include sulfuric acid, nitric acid, phosphoric acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. These salts can usually be prepared by conventional methods by reacting the compound with, for example, a suitable acid or base. Solvates include hydrates.

[0104] Other chemical terms used in this article are used in accordance with the usual usage in the field, such as in The McGraw-Hill Dictionary of Chemical Terms (edited by Parker, S., McGraw-Hill, San Francisco (1985)).

[0105] All publications and patents cited in this document are incorporated herein by reference for all purposes.

[0106] Example

[0107] The following specific embodiments further illustrate the technical solution of the present invention. These specific embodiments do not represent a limitation on the scope of protection of the present invention. Non-essential modifications and adjustments made by others based on the concept of the present invention still fall within the scope of protection of the present invention.

[0108] Unless otherwise specified, the materials and reagents used in the following examples can be obtained commercially or by known methods.

[0109] The antibody hRS9 and intermediate CB07-Exatecan were prepared according to the preparation method described in patent document WO2022 / 253284. Antibody hRS9 is an anti-TROP2 antibody, comprising the heavy chain shown in SEQ ID NO:1 and the light chain shown in SEQ ID NO:2. The structure of intermediate CB07-Exatecan is shown in Formula IV:

[0110] The anti-Trop2 antibody-drug conjugate (hereinafter referred to as ADC1) has the structure shown in Formula II, where p is the drug-antibody ratio (DAR), approximately 6. Based on the amount of antibody, 3.1 molar equivalents of TCEP were added to the hRS9 antibody, and the pH of the system was adjusted to 7.5 with 1M Tris base. The system was incubated at 25°C for 1 hour for reduction. TCEP (tricarboxyethylphosphine) was removed by ultrafiltration with 10 mM succinic acid. The thiol antibody value was determined by absorbance measurement. The equivalent amount of free thiol groups was determined by measuring the absorbance at 412 nm of the reaction product of the thio group and DTNB (5,5'-dithiobis(2-nitrobenzoic acid), Aldrich).

[0111] During the coupling reaction, 7 molar equivalents of CB07-Exatecan were added based on the amount of antibody and the content of free sulfhydryl groups. After stirring at 25°C for 1 hour, 0.1M acetylcysteine ​​was added to a final concentration of 2mM, and the reaction was terminated by stirring for another 15 minutes. The mixture was then purified using Capto S ImpAct (cation exchange packing material).

[0112] The DAR value (p) of ADC1 was determined to be approximately 6.

[0113] bevacizumab is

[0114] Example 1: A multicenter, open-label phase IB-II clinical study of the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of ADC1 combined with bevacizumab in patients with advanced solid tumors.

[0115] 1. Overall research objective:

[0116] The study was broadly divided into two phases. The first phase was a dose escalation tolerance study, which included two dose groups: ADC1 doses in group A (2.1 mg / kg) and group B (2.4 mg / kg), and bevacizumab doses in both groups of 5 mg / kg.

[0117] The second phase is extended research.

[0118] Dosage regimen:

[0119] The order of administration was: 1) ADC1, 2) bevacizumab.

[0120] ADC1 is administered via intravenous infusion every 2 weeks (Q2W) (the first dosing cycle is 21 days (i.e., 3 weeks)), with administration on the first day of each cycle. The infusion should take at least 30 minutes.

[0121] Bevacizumab is administered via intravenous infusion every two weeks (Q2W) (the first dosing cycle is 21 days (i.e., 3 weeks)). The initial intravenous infusion should last 90 minutes. If the first infusion is well tolerated, the second infusion can be completed in 60 minutes. If the patient also tolerates the 60-minute infusion well, all subsequent infusions can be completed in 30 minutes.

[0122] The baseline weight is the body weight before administration on the first day of the first cycle (C1D1). If the body weight changes by more than 10% from the baseline within 3 days before each administration, the dose is recalculated.

[0123] 2. Study population

[0124] 3.1 Selection Criteria:

[0125] 1. Age ≥ 18 years old, gender not limited;

[0126] 2. Voluntarily sign the informed consent form;

[0127] 3. Patients with advanced or metastatic epithelial-derived solid tumors who have been pathologically or cytologically diagnosed, have failed standard treatment or have no standard treatment available, are intolerant to standard treatment, or refuse standard treatment.

[0128] Extended research phase (tumor types in the extended cohort can be added or removed based on real-time research results):

[0129] 1) Patients with locally advanced or metastatic non-squamous non-small cell lung cancer diagnosed by histological or cytological examination, and who are not curable by radical resection or radiotherapy. They must also meet the following criteria: a. Driver gene-negative patients have previously received at least one line of systemic chemotherapy; b. Driver gene-positive patients have previously received EGFR-TKI treatment for locally advanced or metastatic disease and have failed the treatment.

[0130] 2) For patients with advanced or metastatic epithelial-derived solid tumors who are intolerant to or refuse standard treatment, the following types are preferred: gastric adenocarcinoma, esophageal cancer, small cell lung cancer, cervical cancer, and head and neck squamous cell carcinoma.

[0131] 4. According to RECIST 1.1 criteria, there must be an evaluable tumor lesion during the dose escalation phase and at least one measurable tumor lesion during the dose expansion phase.

[0132] 5. The Eastern Cooperative Oncology Group (ECOG) performance status score requirement is 0 or 1.

[0133] 6. Assess expected survival of ≥12 weeks;

[0134] 7. Possess sufficient organ and bone marrow reserves;

[0135] 8. Meets the standards for the use of bevacizumab.

[0136] 3.2 Exclusion Criteria

[0137] 1. Within 4 weeks prior to the first administration of the investigational drug, the individual had received treatment with an experimental drug or participated in a clinical trial of a medical device;

[0138] 2. 1) Patients who have received chemotherapy, radical radiotherapy (palliative radiotherapy must be completed within 2 weeks before the first dose), biotherapy, endocrine therapy, immunotherapy, or other anti-tumor treatments within 4 weeks prior to the first dose; 2) For fluorouracil and small molecule targeted drugs, the first dose must be within 5 half-lives of the investigational drug; 3) For nitrosoureas or mitomycin C, the first dose must be within 42 days prior to the first dose of the investigational drug.

[0139] 3. Patients who have received traditional Chinese medicine, proprietary Chinese medicine, or immunomodulatory drugs (including thymopeptides, interferon, interleukin, etc.) with antitumor indications within 2 weeks prior to the first administration of the study drug;

[0140] 4. Prior to the first administration of the study drug, patients with adverse events (CTCAE 5.0) of grade >1 caused by previous antitumor therapy, excluding toxicities that are deemed to pose no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, etc.

[0141] 5. If a major surgery (excluding diagnostic procedures) is required within 4 weeks prior to the first administration of the investigational drug, or if a major surgery is expected to be required during the study period;

[0142] 6. Individuals who have previously received Trop2-ADC and whose small molecule toxin is a topoisomerase I inhibitor;

[0143] 7. Individuals with a history of allogeneic cell or solid organ transplantation surgery;

[0144] 8. Patients with primary central nervous system tumors or symptomatic central nervous system metastases, those with past or present meningeal metastases, or those with a history of epilepsy. If the brain metastases are stable after treatment, and the lesions have been stable for at least 4 weeks prior to medication with no new lesions, or if an asymptomatic lesion is first discovered within 4 weeks and the patient's condition is assessed as stable, or if corticosteroid treatment has been discontinued 7 days before the first administration of the investigational drug, then this is permitted.

[0145] 9. Having other active malignant tumors within 5 years prior to the first dose. This excludes locally cured tumors (e.g., basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or breast carcinoma in situ, etc.).

[0146] 10. The following cardiovascular diseases occurred within 6 months prior to the first use of medication: symptomatic heart failure of NYHA class 2 or higher, unstable arrhythmia or unstable angina, myocardial infarction requiring treatment, pulmonary embolism, uncontrolled hypertension (defined in this regimen as systolic blood pressure >160 mmHg and / or diastolic blood pressure >100 mmHg after treatment, even with optimal antihypertensive therapy, and clinically significant as assessed); QTcF >480 ms as obtained from a 12-lead electrocardiogram (QTcF is calculated using the Fridricia correction formula);

[0147] 11. Patients with any other serious underlying diseases (e.g., Gilbert's syndrome, uncontrolled diabetes, uncontrolled hypertension, active gastric ulcer, uncontrolled seizures, cerebrovascular event within 3 months prior to first administration, gastrointestinal bleeding, coagulation disorders with severe symptoms or signs) that are deemed to affect their participation in the study, treatment and follow-up, affect patient compliance or may lead to complications related to the study drug;

[0148] 12. Received systemic glucocorticoid (prednisone >10 mg / day or equivalent dose of the same drug) or other immunosuppressants within 14 days prior to the first use of the study drug; excluding the following: use of topical, ocular, intra-articular, intranasal, and inhaled glucocorticoids, or short-term use of glucocorticoids for prophylactic treatment (e.g., prevention of contrast agent allergy).

[0149] 13. Patients with tuberculosis who are either untreated or currently undergoing treatment, including but not limited to pulmonary tuberculosis; those who have undergone standardized anti-tuberculosis treatment and have been confirmed to be cured may be included;

[0150] 14. A serious infection occurred within 4 weeks prior to the first use of medication, or an active infection occurred within 2 weeks prior to the first use of medication;

[0151] 15. Individuals infected with the following diseases: Human immunodeficiency virus (HIV) infection; active hepatitis B virus infection [HBsAg positive, and HBV-DNA >200 IU / ml or 103 copies / ml]; hepatitis C virus infection [HCV antibody and HCV-RNA positive]; Treponema pallidum antibody positive and RPR / TRUST positive.

[0152] 16. Newly diagnosed thromboembolic events requiring treatment within 6 months (patients with stable lower extremity deep vein thrombosis and patients with port-of-care thrombosis are allowed to be included);

[0153] 17. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures (once a month or more);

[0154] 18. It is known that there is a hypersensitivity reaction or delayed-type hypersensitivity reaction to any component of the research drug;

[0155] 19. Individuals who have a known history of grade ≥3 allergic reactions to macromolecular protein preparations / monoclonal antibodies;

[0156] 20. Known history of mental illness, drug abuse, alcoholism, or drug use that may affect the test results;

[0157] 21. Pregnant or breastfeeding women or women or men who are planning to have children.

[0158] 3. Study endpoint

[0159] The purpose of the dose escalation study and the extended cohort study is to evaluate the safety and tolerability of ADC1 combined with bevacizumab in patients with advanced solid tumors, explore the maximum tolerated dose, preliminarily evaluate the antitumor efficacy of ADC1 combined with bevacizumab, and provide recommended doses for subsequent clinical trials; to explore the relationship between the antitumor efficacy of ADC1 combined with bevacizumab and the expression levels of PD-L1 and Trop2 in tumor tissues, and to evaluate the pharmacokinetic (PK) characteristics and immunogenicity of ADC1 combined with bevacizumab in patients with advanced solid tumors under single and multiple dosing.

[0160] Dose escalation studies:

[0161] Primary endpoint:

[0162] Tolerability and safety endpoints: vital signs, physical examination, laboratory tests, electrocardiogram, echocardiography, adverse events, dose-limiting toxicity (DLT) events and their incidence, etc.

[0163] Secondary endpoint:

[0164] Pharmacokinetic parameters for single and multiple administrations (mainly including: C60 for a single administration) max T max T 1 / 2 CL, Vd, Ke, MRT, AUC (0-τ) AUC (0-∞) ; Multiple doses of C max,ss C avg,ss C min,ss AUC (0-τ)ss AUC (0-∞)ss T max,ss T 1 / 2,ss CL, V ss Ke, MRT, Accumulation Index (R) ac (Volatility Index DF).

[0165] Immunogenicity assessment indicators: Anti-drug antibody (ADA) / neutralizing antibody (NAb).

[0166] Clinical efficacy indicators: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

[0167] Biomarkers: expression levels of PDL1 and Trop2 in tumor tissue.

[0168] Extended Cohort Research:

[0169] Primary endpoint:

[0170] Tolerability and safety endpoints: vital signs, physical examination, laboratory tests, electrocardiogram, echocardiography, adverse events, dose-limiting toxicity (DLT) events and their incidence, etc.

[0171] Clinical efficacy indicators: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

[0172] Secondary endpoint:

[0173] Pharmacokinetic parameters for single and multiple administrations (mainly including: C60 for a single administration) max T max T 1 / 2 CL, Vd, Ke, MRT, AUC (0-τ) AUC(0-∞); C for multiple doses max,ss C avg,ss C min,ss AUC (0-τ)ss AUC (0-∞)ss T max,ss T 1 / 2,ss CL, V ss Ke, MRT, Accumulation Index (R) ac ), Volatility Index (DF).

[0174] Immunogenicity evaluation indicators: anti-drug antibody (ADA) / neutralizing antibody (NAb).

[0175] Biomarkers: expression levels of PDL1 and Trop2 in tumor tissue.

[0176] The combination administration of ADC1 and bevacizumab of the present invention is expected to have good safety and tolerability, or result in improvements in at least one of the following: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Claims

1. Use of an anti-TROP2 antibody-drug conjugate and a VEGF-A inhibitor in the preparation of a pharmaceutical composition for treating tumors, comprising administering to a patient with a tumor an effective amount of an anti-TROP2 antibody-drug conjugate and a VEGF-A inhibitor, said anti-TROP2 antibody-drug conjugate having a structure as shown in Formula I-1 or Formula I-2, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof: Equation I-1 is: Equation I-2 is: in Abu is an anti-TROP2 antibody or its antigen-binding unit; D is a DNA topoisomerase I inhibitor or a salt thereof. For example, the DNA topoisomerase I inhibitor is selected from irinotecan, irinotecan hydrochloride, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, 9-chloro-10-hydroxycamptothecin, camptothecin derivative SN-38, 22-hydroxyeclipticine, topotecan, letopotecan, belotecone, homosilatecan, 6,8-dibromo-2-methyl-3-[2-(D-pyranoxylamino)phenyl]-4(3H)-quinazolinone, 2-cyano-3-(3,4-dihydroxyphenyl)-N- (phenylmethyl)-(2E)-2-acrylamide, 2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-hydroxyphenylpropyl)-(E)-2-acrylamide, 12-β-D-glucopyranosyl-12,13-dihydro-2,10-dihydroxy-6-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione, N-[2-(dimethylamino)ethyl]-4-acrylamide, N-[2-(dimethylamino)ethyl]-4-acrylamide, eczetidine or eczetidine derivatives; n is an integer from 1 to 24; p is approximately 1-10.

2. The method of claim 1, wherein D is Wherein X1 and X2 are each independently C1-C6 alkyl, halogen or -OH; Or the C1-C6 alkyl group is -CH3; Or the halogen is F; ** is the connection point.

3. Use of the anti-TROP2 antibody-drug conjugate and VEGF-A inhibitor in the preparation of pharmaceutical compositions for the treatment of tumors, including administering an effective amount of the anti-TROP2 antibody-drug conjugate and VEGF-A inhibitor to a patient with tumors, wherein, The antibody-drug conjugate has the structure shown in formula I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16 or I-17, I-18, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof: in, Abu is an anti-TROP2 antibody or its antigen-binding unit; n is an integer from 1 to 24, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, or n is an integer from 4 to 12, or n is an integer from 4 to 8, or n is 4, or n is 8; p is approximately 1-10, for example approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, or approximately 10.

4. The use as described in any one of claims 1-3, characterized in that, n is an integer between 4 and 12, or an integer between 4 and 8, or n is 4, or n is 8.

5. The use as described in any one of claims 1-4, characterized in that, p is approximately 2-8, or p is approximately 4-8, or p is approximately 4-5, or p is approximately 6-8, or p is approximately 7-8, or p is approximately 4-6, or p is approximately 5-7, or p is approximately 5.5-6.5, or p is approximately 4, or p is approximately 6.

6. The use according to any one of claims 1-5, wherein the Abu is an anti-TROP2 antibody, and the anti-TROP2 antibody comprises the heavy chain shown in SEQ ID NO:1 and the light chain shown in SEQ ID NO:

2.

7. The use according to any one of claims 1-6, wherein the anti-TROP2 antibody-drug conjugate has the structure shown in Formula II or Formula III, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof: in, p is approximately 4-8, or p is approximately 5-7; or p is approximately 5.5-6.5; or p is approximately 6.

8. The use according to any one of claims 1-7, wherein the antibody-drug conjugate is administered at a dose of 0.1-10 mg / kg; or, the antibody-drug conjugate is administered at a dose of about 1-5 mg / kg; or, the antibody-drug conjugate is administered at a dose of about 2-3 mg / kg; or, the antibody-drug conjugate is administered at a dose of about 0.1 mg / kg, about 0.8 mg / kg, about 1.2 mg / kg, about 2.1 mg / kg, about 2.4 mg / kg, about 2.7 mg / kg, about 3.0 mg / kg, about 3.3 mg / kg, about 3.6 mg / kg, about 4.0 mg / kg, about 4.8 mg / kg, about 6.0 mg / kg, about 7.2 mg / kg, about 8.4 mg / kg, or about 10 mg / kg.

9. The use according to any one of claims 1-7, wherein the dose of the antibody-drug conjugate is about 5-3000 mg per administration; or, the dose of the antibody-drug conjugate is about 5-2000 mg, 5-1500 mg, 5-1000 mg, 5-800 mg, 5-600 mg, 48-432 mg, 48-216 mg, 72-504 mg, 100-2000 mg, 200-1000 mg, 300-800 mg, or 400-700 mg per administration.

10. The use according to any one of claims 1-9, wherein the antibody-drug conjugate is administered once every 1, 2, 3, 4, 5, 6 or 7 weeks; or, the antibody-drug conjugate is administered once every 2, 3 or 4 weeks; or, the antibody-drug conjugate is administered once every 2 weeks; or, the antibody-drug conjugate is administered once every 3 weeks; or, the first dosing cycle of the antibody-drug conjugate is 3 weeks, followed by approximately once every 2 weeks.

11. The use according to any one of claims 1-10, wherein the antibody-drug conjugate is administered once every 2, 3 or 4 weeks, at a dose of about 2-3 mg / kg each time.

12. The use according to any one of claims 1-10, wherein the first dosing cycle of the antibody-drug conjugate is 3 weeks, followed by dosing every 2 weeks, with each dosing dose being about 2-3 mg / kg.

13. The use according to any one of claims 1-10, wherein the antibody-drug conjugate is first administered for 3 weeks, and then administered every 2 weeks, with each administration dose being about 2.1 or about 2.4 mg / kg.

14. The use according to any one of claims 1-13, wherein the VEGF-A inhibitor is bevacizumab.

15. The use as described in claim 14, wherein the bevacizumab is administered at a dose of about 5-15 mg / kg per administration.

16. The use as described in claim 14 or 15, wherein the bevacizumab is administered once every 1, 2, 3, 4, 5, 6 or 7 weeks; or, the bevacizumab is administered once every 2, 3 or 4 weeks; or, the bevacizumab is administered once every 2 weeks; or, the bevacizumab is administered once every 3 weeks.

17. The use as described in claim 14 or 15, wherein the first dosing cycle of the bevacizumab is 3 weeks, followed by dosing approximately every 2 weeks.

18. The use as described in claim 14 or 15, wherein the first dosing cycle of the bevacizumab is 3 weeks, followed by dosing approximately every 2 weeks at a dose of approximately 5 mg / kg.

19. The use according to any one of claims 1-18, wherein the tumor is a solid tumor.

20. The use according to any one of claims 1-19, wherein the tumor is an advanced solid tumor.

21. The use according to any one of claims 1-20, wherein the tumor is a solid tumor of epithelial origin.

22. The use according to any one of claims 1-21, wherein the tumor is an advanced or metastatic epithelial-derived solid tumor that has been pathologically or cytologically diagnosed, has failed or is not treated with standard treatment, or is intolerant to or refuses standard treatment.

23. The use according to any one of claims 1-22, wherein the tumor includes, but is not limited to, triple-negative breast cancer, hormone receptor-positive and HER2-negative (HR+ / HER2-) breast cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), gastric cancer (including gastric adenocarcinoma), esophageal cancer, thymic carcinoma, head and neck tumors (including head and neck squamous cell carcinoma), urothelial carcinoma, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, fallopian tube cancer, breast cancer, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), peritoneal cancer, pancreatic cancer, glioblastoma, liver cancer, bladder cancer, urethral cancer, hepatoma, colon cancer, rectal cancer, colorectal cancer, colorectal cancer, large intestine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, glioblastoma, medulloblastoma, T-cell lymphoma, melanoma, Kaposi's sarcoma, and hepatobiliary carcinoma.

24. The use according to any one of claims 1-23, wherein the tumor is non-squamous non-small cell lung cancer, small cell lung cancer, gastric adenocarcinoma, esophageal cancer, cervical cancer, or head and neck squamous cell carcinoma.

25. The use according to any one of claims 1-24, wherein the tumor is locally advanced or metastatic non-squamous non-small cell lung cancer diagnosed by histological or cytological examination.

26. The use according to any one of claims 1-23, wherein the tumor is an advanced or metastatic epithelial-derived solid tumor that is intolerant to or refuses other standard treatments, including but not limited to gastric adenocarcinoma, esophageal cancer, small cell lung cancer, cervical cancer, and head and neck squamous cell carcinoma.

27. The use according to any one of claims 1-26, wherein the tumor is an advanced solid tumor expressing TROP2.

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