Use of Anti-trop2 antibody-drug conjugate and PD-1 antagonist in combined treatment of solid tumor

Abstract

The present invention relates to a method or use for treating a solid tumor with the combined administration of a TROP2-targeting antibody-drug conjugate and a PD-1 antagonist.

Description

Use of anti-TROP2 antibody drug conjugates and PD-1 antagonists in the combined treatment of solid tumors Technical Field

[0001] The present invention relates to use of an anti-TROP2 antibody-drug conjugate and a PD-1 antagonist in preparing a medicament for treating solid tumors. Background Art

[0002] Cancer is a common fatal disease. Chemotherapy, as one of the standard treatments for advanced tumors, still plays an important role in clinical treatment. However, its shortcomings such as poor selectivity and strong toxic side effects lead some patients to directly refuse or be unable to tolerate it. TROP2 (trophoblast surface glycoprotein antigen 2) is overexpressed in many 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, cervical cancer, etc. At present, there is a huge unmet clinical need for the treatment and prognosis of cancer. Seeking drug therapies or drug combination therapies with various targets or mechanisms of action so that more patients can benefit from them is an urgent problem to be solved in the clinic. Summary of the Invention

[0003] The present invention provides a method or use of an anti-TROP2 antibody drug conjugate and a PD-1 antagonist for treating solid tumors, comprising administering an effective amount of an anti-TROP2 antibody drug conjugate and a PD-1 antagonist to a patient suffering from a solid tumor. In one aspect, the present invention provides the use of an anti-TROP2 antibody drug conjugate and a PD-1 antagonist in the preparation of a pharmaceutical composition for treating solid tumors. In one aspect, the present invention provides the use of an anti-TROP2 antibody drug conjugate and a PD-1 antagonist in combination for treating solid tumors. In one aspect, the present invention provides a pharmaceutical composition of an anti-TROP2 antibody drug conjugate and a PD-1 antagonist and its use in treating solid tumors. In one aspect, the present invention provides the use of an anti-TROP2 antibody drug conjugate in the preparation of a medicament for use in combination with a PD-1 antagonist for treating solid tumors. In one aspect, the present invention provides the use of a PD-1 antagonist in the preparation of a medicament for use in combination with an anti-TROP2 antibody drug conjugate for treating solid tumors. In one aspect, the present invention provides the use of an anti-TROP2 antibody-drug conjugate in combination with a PD-1 antagonist for the treatment of solid tumors. In one aspect, the present invention provides the use of a PD-1 antagonist in combination with an anti-TROP2 antibody-drug conjugate for the treatment of solid 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 derivatives SN-38, 22-hydroxyecliprine, topotecan, lertotecan, belotecan, homosilatecan, 6,8-dibromo-2-methyl-3-[2-(D-xylopyranosylamino)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-acridinecarboxamide, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide, exitecan or an exitecan derivative,

[0008] n is an integer from 1 to 24; or n is an integer from 4 to 12,

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

[0010] In some embodiments, D is exitecan or an exitecan derivative.

[0011] In some embodiments, D is

[0012] where X 1 and X 2 Each is independently C1-C6 alkyl, halogen or -OH; ** is the point of attachment.

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

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

[0015] In some embodiments, X 1 and X 2 Each is independently -CH3, F or -OH.

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

[0017] In some embodiments, X 1 and X 2 are each independently F, Cl, Br or I.

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

[0019] In some embodiments, X 1 and X 2 Each is independently F or -CH3.

[0020] In some embodiments, X 1 -CH3 and X 2 For F.

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

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

[0023] In some embodiments, the antibody drug conjugate has a structure shown in Formula I-17, Formula I-18, 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 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; 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 6; or n is 8,

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

[0028] In some embodiments, p is 2-8. In some embodiments, p is 4-8. In some embodiments, p is 4-5. In some embodiments, p is 6-8. In some embodiments, p is 7-8. In some embodiments, p is 4-6. In some embodiments, p is 5-7. In some embodiments, p is about 4.2. In some embodiments, p is about 6.

[0029] In some embodiments, the Abu is an anti-TROP2 antibody.

[0030] In some embodiments, the anti-TROP2 antibody can specifically act on the Trop2 protein.

[0031] In some embodiments, the anti-TROP2 antibody is a fully human monoclonal antibody.

[0032] In some embodiments, the anti-TROP2 antibody is a humanized monoclonal antibody.

[0033] In some embodiments, the anti-TROP2 antibody is an antibody disclosed in the following patent documents: WO2021147993A1 (such as PD3), CN101264325B (such as RS7, hRS7), CN105849126B (such as hTINA1-H1L1, hTINA1-H2L1, hTINA1-H2L2, hTINA1-H3L3), CN110903395A (such as M1, M2, M3), CN1 13896796A (such as 4D3, 7F11), US20130089872 (such as K5-70, K5-107, K5-116-2-1, T6-16, T5-86), US5840854A (such as BR110), US20130122020 (such as 3E9, 6G11, 7E6, 15E2, 18B1), US20120237518 (such as 77220, KM4097, KM4590).

[0034] In some embodiments, the anti-TROP2 antibodies are 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).

[0035] In some embodiments, the anti-TROP2 antibody is the 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 the Pr1E11 anti-TROP2 antibody disclosed by Ikeda et al. (2015, Biochem Biophys Res Comm 458: 877-82), which recognize a unique epitope on TROP2.

[0036] In some embodiments, the anti-TROP2 antibody is an hRS9 antibody, which comprises a heavy chain and a light chain having sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively.

[0037] SEQ ID NO: 1

[0038] SEQ ID NO:2

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

[0040] wherein p is about 4-8.

[0041] In some embodiments, p is about 4-6.

[0042] In some embodiments, p is about 5-7.

[0043] In some embodiments, p is about 4, about 5, about 6, about 7, or about 8.

[0044] In some embodiments, p is about 6.

[0045] In some embodiments, the anti-TROP2 antibody drug conjugate is ADC2 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof, and ADC2 has the structure shown in Formula III:

[0046] wherein p is about 4-8.

[0047] In some embodiments, p is about 4-6.

[0048] In some embodiments, p is about 5-7.

[0049] In some embodiments, p is about 4, about 5, about 6, about 7, or about 8.

[0050] In some embodiments, p is about 6.

[0051] In some embodiments, the dosage of each administration of the anti-TROP2 antibody drug conjugate is about 0.1-10 mg / kg. In some embodiments, the dosage of each administration of the anti-TROP2 antibody drug conjugate is about 1-5 mg / kg. In some embodiments, the dosage of each administration of the anti-TROP2 antibody drug conjugate is about 2-3 mg / kg. In some embodiments, the dosage of each administration 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 4.8 mg / kg, about 6.0 mg / kg, about 7.2 mg / kg, about 8.4 mg / kg, or about 10 mg / kg, or the range between any two values ​​of these values ​​(including the endpoints) or any value therein.

[0052] 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 between any two of these values ​​(including the endpoints) or any value therein.

[0053] In some embodiments, a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks, or the range (including endpoints) between any two values ​​of these numerical values ​​or any value therein. In some embodiments, 1 administration is performed in each treatment cycle.

[0054] In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks. In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately every 2 weeks. In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately every 2 weeks, with administration on day 1 of each cycle.

[0055] In some embodiments, the anti-TROP2 antibody drug conjugate is administered about once a week, or about every 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, or about every 7 weeks. In some embodiments, the anti-TROP2 antibody drug conjugate is administered about once every 2 weeks.

[0056] In some embodiments, the anti-TROP2 antibody drug conjugate is administered once every 1, 2, 3, 4, 5, 6 or 7 weeks, and the dose of each administration of the anti-TROP2 antibody drug conjugate is about 0.1-30 mg / kg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered once every 1, 2, 3, 4, 5, 6 or 7 weeks, and the dose of each administration of the anti-TROP2 antibody drug conjugate is about 0.1-10 mg / kg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered once every 1, 2, 3, 4, 5, 6 or 7 weeks, and the dose of each administration of the anti-TROP2 antibody drug conjugate is about 1-5 mg / kg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered once every 1, 2, 3, 4, 5, 6 or 7 weeks, and the dose of each administration of the anti-TROP2 antibody drug conjugate is about 2-3 mg / kg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately once every 1, 2, 3, 4, 5, 6, or 7 weeks, and the dose of each administration 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 4.8 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 between any two of these values ​​(including the endpoints), or any value therein.

[0057] In some embodiments, the anti-TROP2 antibody drug conjugate is administered in a dosing cycle of about 1, 2, 3, 4, 5, 6, or 7 weeks, and the dose of each administration of the anti-TROP2 antibody drug conjugate is about 0.1-30 mg / kg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered in a dosing cycle of about 1, 2, 3, 4, 5, 6, or 7 weeks, and the dose of each administration of the anti-TROP2 antibody drug conjugate is about 0.1-10 mg / kg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered in a dosing cycle of about 1, 2, 3, 4, 5, 6, or 7 weeks, and the dose of each administration of the anti-TROP2 antibody drug conjugate is about 1-5 mg / kg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered in a dosing cycle of about 1, 2, 3, 4, 5, 6, or 7 weeks, and the dose of each administration of the anti-TROP2 antibody drug conjugate is about 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 for a dosing cycle, and the dose of each administration 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 4.8 mg / kg, about 6.0 mg / kg, about 7.2 mg / kg, about 8.4 mg / kg, or about 10 mg / kg, or the range (including endpoints) between any two of these values ​​or any value therein. In some embodiments, the drug is administered once in each treatment cycle.

[0058] In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately once every 2 weeks at a dose of about 0.1-30 mg / kg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately once every 2 weeks at a dose of about 0.1-10 mg / kg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately once every 2 weeks at a dose of about 1-5 mg / kg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately once every 2 weeks at a dose of about 2-3 mg / kg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately once every 2 weeks, with each dose being about 0.1 mg / kg, about 0.5 mg / kg, about 0.8 mg / kg, about 1 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 4.8 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 between any two of these values ​​(including the endpoints), or any value therein.

[0059] In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately once every 2 weeks at a dose of about 5-3000 mg. In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately once every 2 weeks at a dose of 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. In some embodiments, the anti-TROP2 antibody drug conjugate is administered approximately once every 2 weeks, with each dose being 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 between any two of these values ​​(including the endpoints), or any value therein.

[0060] In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0061] In some embodiments, the anti-PD-1 antibody is pembrolizumab, nivolumab, tislelizumab, carrelizumab, sintilimab, toripalimab, putelimab, slulizumab, sepalizumab, penampalizumab, dotalizumab, seplizumab, rivulimab, batilizumab, ipalolizumab, enlangsubiamab, genoluzumab, fenolizumab, lonelizumab, bruglimab, cetrelimab, prolgolimab, nofazinlimab, sasanlimab, spartalizumab, ezabenlimab, peramprizumab, pidilizumab, or pimivalimab.

[0062] In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1 shown in SEQ ID NO: 3, HCDR2 shown in SEQ ID NO: 4, and HCDR3 shown in SEQ ID NO: 5, and the light chain variable region comprising LCDR1 shown in SEQ ID NO: 6, LCDR2 shown in SEQ ID NO: 7, and LCDR3 shown in SEQ ID NO: 8.

[0063] In some embodiments, the heavy chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:9, and the light chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:10.

[0064] In some embodiments, the anti-PD-1 antibody comprises the heavy chain sequence shown in SEQ ID NO:11 and the light chain sequence shown in SEQ ID NO:12.

[0065] In some embodiments, the anti-PD-1 antibody is antibody A, comprising a heavy chain sequence as shown in SEQ ID NO: 11 and a light chain sequence as shown in SEQ ID NO: 12, containing two heavy chains with identical sequences and two light chains with identical sequences.

[0066] Table 1

[0067] In some embodiments, the dose of the anti-PD-1 antibody administered per dose is about 50-600 mg, or a formulation containing such a dose of the anti-PD-1 antibody. In some embodiments, the dose of the anti-PD-1 antibody administered per dose is about 50 mg, about 60 mg, about 80 mg, about 120 mg, about 200 mg, about 210 mg, about 220 mg, about 250 mg, about 290 mg, about 300 mg, about 330 mg, about 380 mg, about 390 mg, about 400 mg, about 434 mg, about 480 mg, about 500 mg, about 567 mg, about 580 mg, about 600 mg, or a range (including endpoints) between any two of these values ​​or any value therein, or a formulation containing such a dose of the anti-PD-1 antibody. In some embodiments, the dose of the anti-PD-1 antibody administered per dose is about 100-600 mg, or a formulation containing such a dose of the anti-PD-1 antibody. In some embodiments, the dose of the anti-PD-1 antibody administered per time is about 200-400 mg, or a formulation containing such a dose of the anti-PD-1 antibody.

[0068] In some embodiments, the anti-PD-1 antibody is administered about once a week, or about every 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, or about every 7 weeks. In some embodiments, the anti-PD-1 antibody is administered about every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-PD-1 antibody is administered about every 4 weeks. In some embodiments, the anti-PD-1 antibody is administered about every 3 weeks. In some embodiments, the anti-PD-1 antibody is administered about every 2 weeks.

[0069] In some embodiments, the anti-PD-1 antibody is administered at a dose of about 200-220 mg per administration, administered once every 2 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose of about 200 mg, about 210 mg, or about 220 mg per administration, administered once every 2 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose of about 200 mg per administration, administered once every 2 weeks.

[0070] In some embodiments, the anti-PD-1 antibody is administered at a dose of about 280-320 mg per administration, administered once every 3 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose of about 300 mg per administration, administered once every 3 weeks.

[0071] In some embodiments, the anti-PD-1 antibody is administered at a dose of about 380-400 mg per administration, administered once every 4 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose of about 380 mg, about 390 mg, or about 400 mg per administration, administered once every 4 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose of about 400 mg per administration, administered once every 4 weeks.

[0072] In some embodiments, the dosage of antibody A is about 200-220 mg per administration, administered once every 2 weeks. In some embodiments, the dosage of antibody A is about 200 mg, about 210 mg, or about 220 mg per administration, administered once every 2 weeks. In some embodiments, the dosage of antibody A is about 200 mg per administration, administered once every 2 weeks.

[0073] In some embodiments, the anti-TROP2 antibody drug conjugate is ADC1, which is administered approximately once every 2 weeks at a dose of approximately 2-3 mg / kg each time; and the antibody A is administered at a dose of approximately 200-220 mg each time, which is administered once every 2 weeks.

[0074] In some embodiments, the anti-TROP2 antibody drug conjugate is ADC1, which is administered approximately once every 2 weeks at a dose of approximately 2.1 or 2.4 mg / kg each time; and the antibody A is administered at a dose of approximately 200 mg each time, which is administered once every 2 weeks.

[0075] The "combination" described herein is a mode of administration, which includes various situations in which two or more drugs are administered sequentially or simultaneously. In some embodiments, the anti-TROP2 antibody drug conjugate and PD-1 antagonist are prepared as a single pharmaceutical composition, and the anti-TROP2 antibody drug conjugate and PD-1 antagonist are administered to patients in need at the same time. In some embodiments, the anti-TROP2 antibody drug conjugate and PD-1 antagonist are prepared as separate pharmaceutical compositions, and the anti-TROP2 antibody drug conjugate and PD-1 antagonist are administered to patients in need at the same time, or the anti-TROP2 antibody drug conjugate and PD-1 antagonist are administered to patients in need at different times during the treatment regimen. For example, the anti-TROP2 antibody drug conjugate is administered before the PD-1 antagonist is administered, or the anti-TROP2 antibody drug conjugate is administered after the PD-1 antagonist is administered, or the anti-TROP2 antibody drug conjugate and PD-1 antagonist are administered in an alternating regimen. In some embodiments, the anti-TROP2 antibody drug conjugate is administered after the PD-1 antagonist is administered. Herein, the anti-TROP2 antibody drug conjugate and the PD-1 antagonist are administered to a patient in need thereof in a single dose or multiple doses.

[0076] In some embodiments, the ADC1 is administered after the antibody A is administered to the patient.

[0077] In some embodiments, the patient receives one treatment cycle. In some embodiments, the patient receives multiple (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, or a range (including endpoints) between any two of these values ​​or any value therein) treatment cycles. In some embodiments, the patient receives treatment until the condition is alleviated and no longer requires treatment.

[0078] In some embodiments, the treatment cycle is ±5 days or ±3 days of the above treatment cycle.

[0079] In some embodiments, in the methods for treating solid tumors provided by the present invention, the anti-TROP2 antibody drug conjugate and the PD-1 antagonist can be administered by any convenient route, such as by infusion or push injection, absorbed through the epithelium or skin mucosa (such as oral mucosa, rectal and intestinal mucosa, etc.), and can be co-administered with other bioactive agents. Therefore, the pharmaceutical composition of the anti-TROP2 antibody drug conjugate and the PD-1 antagonist can be administered intravenously, subcutaneously, orally, rectally, parenterally, intracerebrally, intravaginally, intraperitoneally, topically (such as by powder, ointment, drops or transdermal patch), orally or by oral or nasal spray. In some embodiments, the route of administration is intravenous (iv) infusion (i.e., intravenous infusion). In some embodiments, the medicament used for the anti-TROP2 antibody drug conjugate and / or PD-1 antagonist can be formulated into a pharmaceutical composition and administered to the patient in a form suitable for the selected route of administration, such as parenteral, intravenous (iv), intramuscular, topical or subcutaneous (sc). In some embodiments, the route of administration is intravenous infusion.

[0080] In some embodiments, the anti-TROP2 antibody drug conjugate, the PD-1 antagonist is administered by intravenous infusion. In some embodiments, the intravenous infusion duration of the anti-TROP2 antibody drug conjugate, the pharmaceutical composition comprising the anti-TROP2 antibody drug conjugate 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 the range (including endpoints) between any two values ​​in these numerical values ​​or any value therein. In some embodiments, the duration of intravenous infusion of the anti-TROP2 antibody drug conjugate or the pharmaceutical composition comprising the anti-TROP2 antibody drug conjugate is 30 minutes or more.

[0081] Examples of solid 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, esophageal cancer, thymic cancer, head and neck tumors, urothelial cancer, 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, 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 cancer.

[0082] In some embodiments, the solid tumor is triple-negative breast cancer, small cell lung cancer, non-small cell lung cancer, gastric adenocarcinoma, esophageal cancer, cervical cancer, head and neck squamous cell carcinoma, or thymic carcinoma.

[0083] In some embodiments, the solid tumor is a solid tumor of epithelial origin.

[0084] In some embodiments, the solid tumor is an advanced solid tumor. In some embodiments, the solid tumor is an advanced solid tumor of epithelial origin.

[0085] In some embodiments, the advanced solid tumor is an advanced or metastatic epithelial solid tumor confirmed by histopathology or cytology, for which standard treatment has failed or is unavailable, or for which standard treatment is intolerant or rejected.

[0086] In some embodiments, the standard treatment refers to the standard treatment regimen for the solid tumor recommended by the NCCN guidelines and the CSCO diagnosis and treatment guidelines.

[0087] In some embodiments, the advanced solid tumor is locally advanced or metastatic triple-negative breast cancer confirmed by histological or cytological examination. In some embodiments, the advanced solid tumor is locally advanced or metastatic triple-negative breast cancer confirmed by histological or cytological examination, which is incurable by radical resection or radiation therapy and has received at least one systemic chemotherapy regimen for advanced or metastatic disease.

[0088] In some embodiments, the advanced solid tumor is an advanced or metastatic epithelial solid tumor that is intolerant to or refuses standard treatment, and the solid tumor includes but is not limited to: small cell lung cancer, non-small cell lung cancer (e.g., non-squamous non-small cell lung cancer), gastric cancer (e.g., gastric adenocarcinoma), esophageal cancer, cervical cancer, head and neck squamous cell carcinoma, and thymic carcinoma.

[0089] In some embodiments, the solid tumor is a TROP2-expressing solid tumor.

[0090] In some embodiments, the combination of the anti-TROP2 antibody drug conjugate of the present invention and the PD-1 antagonist has good safety and tolerability. In some embodiments, the combination of the anti-TROP2 antibody drug conjugate of the present invention and the PD-1 antagonist has good anti-tumor efficacy. In some embodiments, the combination of the anti-TROP2 antibody drug conjugate of the present invention and the PD-1 antagonist results in at least one improvement selected from the following: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS). DETAILED DESCRIPTION

[0091] "About" refers to the normal error range of the corresponding numerical value that is easily known to those skilled in the relevant art. In some embodiments, "about" mentioned herein refers to the described numerical value and its ±10%, ±5% or ±1% range.

[0092] "Treatment" refers to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent, slow, ameliorate or halt an undesirable physiological change or disorder, such as the progression of a disease, including but not limited to the following results, whether detectable or undetectable, relief of symptoms, reduction in the severity of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement, palliation, alleviation or elimination of the disease state (whether partial or complete), prolongation of life expectancy compared to that expected in the absence of treatment, etc. Patients in need of treatment include those already suffering from the disease or disorder, those susceptible to the disease or disorder, or those in need of prevention of the disease or disorder, and those who can or are expected to benefit from the administration of the antibodies or pharmaceutical compositions disclosed herein for detection, diagnostic procedures and / or treatment.

[0093] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a drug, such as an antibody or ADC, that is sufficient to reduce or improve the severity and / or duration of a condition (e.g., cancer) or one or more symptoms thereof; prevent the progression of the condition; cause the condition to regress; prevent the 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 amount of an antibody can 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 amount can improve progression-free survival (PFS), improve overall survival (OS), or reduce the likelihood of recurrence.

[0094] The terms "patient" and "subject" are used interchangeably and refer to any mammal in need of diagnosis, prognosis or treatment, including but not limited to humans, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, etc., especially animals with one or more conditions of solid tumors. In some embodiments, the patient is a human.

[0095] Anti-tumor efficacy indicators include objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) defined according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) (Eisenhauer, EA et al., Eur J Cancer. 2009; 45(2): 228-247).

[0096] Objective response rate (ORR) refers to the proportion of patients whose tumors shrink to a certain extent and for a certain period of time, including both complete response (CR) and partial response (PR). Objective response is assessed using the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Patients must have measurable tumor lesions at baseline. Response assessment is based on RECIST, version 1.1, with complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).

[0097] Duration of response (DOR): DOR is defined as the time from the first objective response of the tumor to the first PD assessment or death from any cause before PD, reflecting the duration of ORR.

[0098] Disease control rate (DCR) refers to 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).

[0099] Progression-free survival (PFS): The time from the first dose to the occurrence of objective tumor progression or all-cause death (whichever occurs first).

[0100] Overall survival (OS) was calculated from the date of first dose until death from any cause. Patients who were still alive at the time of analysis were considered to have the last contact date as the cutoff date.

[0101] Maximum tolerated dose (MTD) definition: The MTD is defined as the highest dose level in a dose group at which dose-limiting toxicity (DLT) is observed in ≤1 / 6 subjects during the DLT evaluation period.

[0102] The Eastern Cooperative Oncology Group (ECOG) has developed a simpler activity status scoring table, which divides the patient's activity status into 6 levels from 0 to 5. The ECOG physical condition scoring standard is 0, 1, 2, 3, 4, and 5 points.

[0103] Single-dose PK parameter: C max 、T max 、T 1 / 2 , CL, Vd, Ke, MRT, AUC (0-τ) , AUC (0-∞) .

[0104] Multiple-dose PK 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.

[0105] 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) connected to one or more drugs, which may optionally be a therapeutic agent or a cytotoxic agent. In some embodiments, the ADC comprises an antibody, a drug (such as a cytotoxic drug), and a linker that enables the drug to be attached or coupled to the antibody. Non-limiting examples of drugs that may be included in an ADC are mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, anti-angiogenic agents, antimetabolites, boron-containing agents, chemoprotectants, hormones, antihormonal agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclide agents, topoisomerase inhibitors, kinase inhibitors (e.g., TEC-family kinase inhibitors and serine / threonine kinase inhibitors), and radiosensitizers.

[0106] The term "drug-antibody coupling ratio" or "DAR" refers to the number of drugs (e.g., exotecan) attached to one antibody of 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 attachment sites on the antibody. The term DAR can 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, the 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 a composition, that is, the average number of drug bindings of the antibody, or the average drug-antibody coupling ratio, the value is selected from about 0 to about 10, or about 2 to about 8. In some embodiments, the average drug-antibody coupling ratio is about 3 to about 6. In some embodiments, the average drug-antibody coupling ratio is about 4 to about 5. In other embodiments, the average drug-antibody coupling ratio is about 6 to about 8, or about 7 to about 8. In some embodiments, the average drug-antibody coupling ratio is about 6. The DAR value is represented herein by p. The DAR value of an ADC can be determined using ultraviolet-visible absorption spectroscopy (UV-Vis), high-performance liquid chromatography-hydrophobic chromatography (HPLC-HIC), high-performance liquid chromatography-reverse phase chromatography (RP-HPLC), liquid chromatography-mass spectrometry (LC-MS), and the like. These techniques are described in Ouyang, J. Methods Mol Biol, 2013, 1045: p. 275-83.

[0107] "Antibody" and "antigen-binding fragment" refer to polypeptides or polypeptide complexes that specifically recognize and bind to an antigen. An antibody can be a complete antibody, any antigen-binding fragment thereof, or a single chain thereof. Therefore, the term "antibody" includes any protein or peptide that contains at least a portion of an immunoglobulin molecule that has the biological activity of binding to an antigen. Antibodies and antigen-binding fragments include, but are not limited to, the complementarity determining regions (CDRs) of a heavy chain or light chain or its ligand-binding portion, a heavy chain variable region (VH), a light chain variable region (VL), a heavy chain constant region (CH), a light chain constant region (CL), a framework region (FR), or any portion thereof, or at least a portion of a 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.

[0108] The various substituents are defined below.

[0109] " alkyl " refers to a saturated aliphatic hydrocarbon group, and the term includes straight and branched hydrocarbon groups. For example, C1-C20 alkyl, such as C1-C6 alkyl. C1-C20 alkyl refers to an alkyl with 1 to 20 carbon atoms, for example, an alkyl with 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms or 20 carbon atoms. The limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl, sec-butyl, the tert-butyl, n-pentyl, neopentyl, n-hexyl etc. " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0110] "Stereoisomers" refer to isomeric compounds that have the same order of attachment of atoms but different arrangements of atoms in space. Stereoisomers can have one or more stereocenters and each center can exist as R or S. Stereoisomers can also be cis-trans isomers. Stereoisomers of the compounds provided herein include any one of all diastereomeric, enantiomeric, and cis-trans isomeric forms thereof or suitable mixtures thereof.

[0111] Pharmaceutically acceptable salts include pharmaceutically acceptable salts of the compounds with a wide variety of organic and inorganic counterions well known in the art. Exemplary salts include, when the molecule contains an acidic functional group, 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, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethyl, polyamine resins, and tetraalkylammonium salts; and when the molecule contains a basic functional group, 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 salicylic acid, etc. These salts can generally be prepared by conventional methods by reacting, for example, an appropriate acid or base with the compound. Solvates include hydrates.

[0112] Other chemical terms are used herein according to conventional usage in the art, as described in The McGraw-Hill Dictionary of Chemical Terms (Parker, S. ed., McGraw-Hill, San Francisco (1985)).

[0113] All publications and patents cited herein are incorporated by reference in their entirety for all purposes.

[0114] Example

[0115] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources or known methods.

[0116] An anti-Trop2 antibody-drug conjugate (hereinafter referred to as ADC1) was prepared according to the preparation method described in patent document WO2022 / 253284. The structure of ADC1 is shown in Formula II, where p is the average drug-antibody ratio (DAR) of approximately 6. The preparation method of Antibody A can be referred to patent application WO2020207432A1, and its amino acid sequence is shown in Table 1.

[0117] Example 1: A multicenter, open-label clinical study of the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of ADC1 combined with Antibody A in patients with advanced solid tumors

[0118] 1. Overall research design:

[0119] This research project is a multicenter, open-label, exploratory, first-in-human clinical trial. It primarily explores the safety, tolerability, and PK characteristics of ADC1 combined with Antibody A in patients with advanced solid tumors, explores the maximum tolerated dose (MTD), provides recommended doses and reasonable dosing regimens for subsequent clinical studies, and preliminarily evaluates anti-tumor efficacy. The study is generally divided into two phases. The first phase plans to use accelerated titration and a "3+3" dose escalation rule to explore the safety and tolerability of the study drug. The second phase, based on the preliminary safety and efficacy results of the previous phase, will select appropriate doses and tumor types within the safe dose range for expansion studies to further explore the safety and clinical efficacy of ADC1 combined with Antibody A and determine the optimal dosing dose for subsequent clinical studies.

[0120] The first phase is a dose-escalation tolerance study, which uses accelerated titration and a "3+3" dose-escalation rule to explore the safety and tolerability of ADC1 combined with antibody A.

[0121] ADC1 was divided into two dose groups, Group A (2.1 mg / kg) and Group B (2.4 mg / kg); the dose of antibody A was fixed at 200 mg; the drug was administered once every 2 weeks, on the first day of each cycle.

[0122] The dose escalation pattern of the standard "3+3" rule is shown in the following table:

[0123] The second phase is an expanded cohort study, which selects triple-negative breast cancer and other advanced epithelial tumors to further study the safety and clinical efficacy of ADC1 injection combined with antibody A injection.

[0124] Dosage regimen:

[0125] The order of administration is to administer ADC1 after the administration of antibody A.

[0126] Antibody A is administered by intravenous infusion once every 2 weeks (Q2W) over 30 minutes.

[0127] ADC1 is administered by intravenous infusion every two weeks (Q2W), on the first day of each cycle. The infusion should be over 30 minutes. The baseline weight is the body weight before dosing on the first day of the first cycle (C1D1). If the body weight changes by more than 10% from baseline within the three days prior to each dose, the dose should be recalculated. Starting from the second cycle, the dosing window can be ±3 days.

[0128] 2. Definition of Dose-Limiting Toxicity (DLT)

[0129] AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. DLT was defined as any AE of grade 3 or higher related to the trial drug occurring within 21 days of the first dose of the subject and meeting the following definitions:

[0130] Grade 5 toxicity:

[0131] ■ Definition of hepatotoxicity (DLT): Grade 4 AST or ALT elevation; in subjects with hepatocellular carcinoma or liver metastases, if AST or ALT is ≤ 3 times ULN at baseline, and AST or ALT is elevated > 5 times ULN and persists for > 5 days during the DLT evaluation period; in subjects with hepatocellular carcinoma or liver metastases, if AST or ALT is elevated > 8 times ULN and persists for 5 days during the DLT evaluation period, if AST or ALT is elevated > 3 times ULN at baseline, and AST or ALT is elevated > 5 times ULN and persists for > 5 days during the DLT evaluation period; in subjects without liver metastases, if AST or ALT is elevated > 5 times ULN and persists for > 5 days;

[0132] AST or ALT > 5 times the upper limit of normal range (ULN), accompanied by ≥ Grade 2 total bilirubin elevation.

[0133] ■Definition of hematologic toxicity (DLT): asymptomatic grade 4 hematologic toxicity lasting ≥14 days; grade 4 thrombocytopenia; grade ≥3 febrile neutropenia; grade ≥3 thrombocytopenia with bleeding.

[0134] ■Definition of non-hepatotoxicity and non-hematologic toxicity (DLT): Other grade ≥ 3 non-hepatotoxicity and non-hematologic toxicity that persists for > 3 days after optimal treatment.

[0135] ■The following TEAEs are not considered DLTs: laboratory abnormalities without clinically relevant symptoms or signs, including increased ALP, increased uric acid, increased blood amylase, increased lipase, or decreased lymphocytes to Grade 3 or 4; Grade 3 infusion reactions that can be resolved within 24 hours after treatment.

[0136] 3. Study population:

[0137] Inclusion criteria:

[0138] 1. Age ≥ 18 years old, regardless of gender;

[0139] 2. Patients must have advanced or metastatic epithelial solid tumors confirmed by histopathology or cytology, who have failed standard treatment or have no standard treatment, are intolerant to standard treatment, or refuse standard treatment.

[0140] Expansion study phase (tumor types in the expansion cohort can be added or deleted based on real-time study results):

[0141] Cohort A: Patients with histologically or cytologically confirmed locally advanced or metastatic triple-negative breast cancer who were incurable by radical resection or radiotherapy and who had received at least one prior systemic chemotherapy regimen for advanced or metastatic disease.

[0142] Cohort B: Patients with advanced or metastatic epithelial solid tumors who are intolerant to or refuse other standard treatments, with priority given to the following types: non-squamous non-small cell lung cancer, gastric adenocarcinoma, esophageal cancer, small cell lung cancer, cervical cancer, head and neck squamous cell carcinoma, thymic carcinoma, etc.

[0143] 3. According to RECIST 1.1 criteria, there must be evaluable tumor lesions in the dose escalation phase, and at least one measurable tumor lesion in the dose expansion phase;

[0144] 4. The Eastern Cooperative Oncology Group (ECOG) performance status score must be 0 or 1;

[0145] 5. The estimated survival period is ≥12 weeks after evaluation;

[0146] 6. Have sufficient organ and bone marrow reserve functions.

[0147] Exclusion criteria:

[0148] 1. Patients who have received experimental drug treatment or participated in clinical research of medical devices within 4 weeks before the first administration of study drug;

[0149] 2. 1) Patients who have received chemotherapy, radical radiotherapy (palliative radiotherapy must be completed within 2 weeks before the first dose), biological therapy, endocrine therapy, immunotherapy, or other anti-tumor treatment within 4 weeks before the first dose; 2) Fluorouracil and small molecule targeted drugs within 2 weeks before the first use of the study drug or 5 half-lives of the drug (whichever is longer); 3) Nitrosoureas or mitomycin C within 42 days before the first use of the study drug;

[0150] 3. Within one week before administration, patients have received Chinese patent medicine or treatment that has anti-tumor related functions clearly stated in the NMPA-approved drug instructions, or have received Chinese herbal medicine treatment with anti-tumor purposes clearly recorded in the medical records;

[0151] 4. Before the first administration of the study drug, the AEs (CTCAE 5.0) caused by previous anti-tumor treatment were still greater than grade 1, except for toxicities that the researchers judged to have no safety risks, such as alopecia and grade 2 peripheral neuropathy.

[0152] 5. Major surgery (excluding diagnostic procedures) was required within 4 weeks before the first administration of study drug or major surgery is expected to be required during the study;

[0153] 6. Patients who have previously received ADCs (such as Trop2-ADC) and whose small molecule toxins are topoisomerase I inhibitors will be excluded from the study;

[0154] 7. Patients who have experienced grade ≥3 irAEs in the past or have stopped immunotherapy due to irAEs of any grade in the past.

[0155] 8. Those with a history of allogeneic cell or solid organ transplantation;

[0156] 9. Patients with primary central nervous system tumors or symptomatic central nervous system metastases, past or current meningeal metastases, or a history of epilepsy. Patients are allowed if the brain metastases are stable after treatment and the lesions have been stable for at least 4 weeks before the medication, with no new lesions, or if asymptomatic lesions are first discovered within 4 weeks and the researcher determines that the condition is stable, or if corticosteroid treatment has been discontinued 7 days before the first dose of the study drug;

[0157] 10. Patients with other active malignant tumors within 5 years before the first administration of the drug, except for locally cured tumors (such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or breast carcinoma in situ, etc.);

[0158] 11. The following cardiovascular diseases occurred within 6 months before the first use of the drug: symptomatic heart failure of New York Heart Association (NYHA) grade 2 or above, left ventricular ejection fraction (LVEF) <50%, unstable arrhythmia or unstable angina, myocardial infarction requiring treatment, pulmonary embolism, uncontrolled hypertension (defined in this protocol as systolic blood pressure >160 mmHg and / or diastolic blood pressure >100 mmHg after treatment despite optimal antihypertensive treatment, and assessed by the investigator to be clinically significant), QTcF >480 ms obtained by 12-lead electrocardiogram (QTcF using the Fridericia correction formula);

[0159] 12. Patients with any other serious underlying diseases (e.g., Gilbert syndrome, uncontrolled diabetes, active gastric ulcer, uncontrolled seizures, cerebrovascular events / gastrointestinal bleeding within 3 months before the first dose, coagulation disorders with severe symptoms or signs) that may affect the patient's participation in the study, treatment and follow-up, affect the patient's compliance, or may cause complications related to the study drug;

[0160] 13. Patients who have had non-infectious pneumonia / lung inflammation requiring glucocorticoid treatment, or interstitial lung disease (ILD) in the past, or currently have interstitial lung disease (ILD), or whose imaging examinations during the screening period failed to rule out the possibility of ILD / lung inflammation;

[0161] 14. Patients with a history of autoimmune diseases (excluding autoimmune thyroid disease and type 1 diabetes that can be treated with hormone replacement therapy);

[0162] 15. Patients who require long-term use or have received systemic glucocorticoids (prednisone > 10 mg / day or equivalent doses of similar drugs) or other immunosuppressive treatments (such as cyclophosphamide, thalidomide, and anti-tumor necrosis factor) within 14 days before the first use of the study drug; excluding the following situations: treatment with topical, ocular, intra-articular, intranasal, and inhaled glucocorticoids, and short-term use of glucocorticoids such as dexamethasone for prevention / treatment (lasting no more than 2 weeks, such as dexamethasone to prevent contrast agent allergy, infusion reaction, etc.);

[0163] 16. Tuberculosis patients who have not been treated or are currently being treated, including but not limited to pulmonary tuberculosis; those who have received standard anti-tuberculosis treatment and have been confirmed to have been cured by the patient can be included;

[0164] 17. Severe infection occurred within 4 weeks or active infection occurred within 2 weeks before the first use of the drug;

[0165] 18. Patients with the following diseases: Human immunodeficiency virus (HIV) infection; Active hepatitis B virus infection [Hepatitis B surface antigen (HBsAg) positive, and hepatitis B virus deoxyribonucleic acid (HBV-DNA) test > 200 IU / ml or 10 3 copies / ml]; patients infected with hepatitis C virus [positive results of HCV antibody and viral RNA (HCV-RNA) test]; patients with positive Treponema pallidum antibody and RPR;

[0166] 19. Newly diagnosed thromboembolic events requiring treatment within 6 months (patients with stable lower limb deep vein thrombosis and infusion port thrombosis are allowed to be included);

[0167] 20. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring repeated drainage surgery (once a month or more frequently);

[0168] 21. Known hypersensitivity or delayed allergic reaction to any component of the study drug;

[0169] 22. Those who are known to have had a grade 3 or higher allergic reaction to large molecular protein preparations / monoclonal antibodies;

[0170] 23. A history of psychiatric disorders, substance abuse, alcoholism, or drug abuse that may affect the test results;

[0171] 24. Pregnant or lactating women or women or men who are preparing to have children.

[0172] 4. Study endpoints:

[0173] The purpose of the dose-escalation study and expansion cohort study is to evaluate the safety and tolerability of ADC1 combined with Antibody A in patients with advanced solid tumors, explore the maximum tolerated dose (MTD), preliminarily evaluate the anti-tumor efficacy of ADC1 combined with Antibody A, provide recommended doses for subsequent clinical trials, explore the relationship between anti-tumor efficacy and the expression levels of PDL1 and Trop2 in tumor tissues, and evaluate the pharmacokinetic (PK) characteristics and immunogenicity of ADC1 combined with Antibody A after single and multiple doses in patients with advanced solid tumors.

[0174] Dose escalation study:

[0175] Primary endpoint:

[0176] Tolerability and safety endpoints: vital signs, physical examination, laboratory tests, electrocardiogram, cardiac ultrasound, adverse events, dose-limiting toxicity (DLT) events and their incidence, etc.

[0177] Secondary endpoints:

[0178] Pharmacokinetic parameters under single and multiple administration (mainly including: C 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, Vss, Ke, MRT, accumulation index (Rac), fluctuation index (DF).

[0179] Immunogenicity evaluation indicators: anti-drug antibodies (ADA) / neutralizing antibodies (NAb).

[0180] Clinical efficacy indicators: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

[0181] Biomarkers: PDL1 and Trop2 expression levels in tumor tissue.

[0182] Extension cohort study:

[0183] Primary endpoint:

[0184] Tolerability and safety endpoints: vital signs, physical examination, laboratory tests, electrocardiogram, cardiac ultrasound, adverse events, dose-limiting toxicity (DLT) events and their incidence, etc.

[0185] Clinical efficacy indicators: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

[0186] Secondary endpoints:

[0187] Pharmacokinetic parameters under single and multiple administration (mainly including: single administration C 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.

[0188] Immunogenicity evaluation indicators: anti-drug antibodies (ADA) / neutralizing antibodies (NAb).

[0189] Biomarkers: PDL1 and Trop2 expression levels in tumor tissue.

[0190] 5. Research Results

[0191] As of February 14, 2025, a total of 32 patients had undergone at least one anti-tumor efficacy evaluation, including 1 case of cervical cancer (achieved partial remission) and 1 case of lung cancer (stable disease) in Group A, and 12 cases of triple-negative breast cancer, 16 cases of lung cancer, 1 case of thymic cancer (stable disease) and 1 case of gastric cancer (progressive disease) in Group B. For the triple-negative breast cancer patient group, 3 patients achieved partial remission (PR), 6 patients had stable disease (SD), ORR was 25% (3 / 12), and DCR was 75% (9 / 12). For group B lung cancer patients, 3 patients achieved partial remission (PR), 12 patients had stable disease (SD), ORR was 18.8% (3 / 16), and DCR was 93.8% (15 / 16). The combined administration mode of the present invention has good anti-tumor efficacy.

[0192] The combined administration of ADC1 and antibody A of the present invention has good safety and tolerability, good anti-tumor efficacy, or leads to at least one improvement selected from 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 PD-1 antagonist in the preparation of a pharmaceutical composition for treating solid tumors, comprising administering an effective amount of an anti-TROP2 antibody-drug conjugate and a PD-1 antagonist to a patient with a solid tumor, wherein the anti-TROP2 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: The formula I-1 is: The formula 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 derivatives SN-38, 22-hydroxyecliprine, topotecan, lertotecan, belotecan, homosilatecan, 6,8-dibromo-2-methyl-3-[2-(D-xylopyranosylamino)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-acridinecarboxamide, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide, exitecan or an exitecan derivative, n is an integer from 1 to 24, p is 1-10.

2. The method according to claim 1, wherein D is where X 1 and X 2 Each is 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 an anti-TROP2 antibody drug conjugate and a PD-1 antagonist in the preparation of a pharmaceutical composition for treating solid tumors, comprising administering an effective amount of the anti-TROP2 antibody drug conjugate to a patient suffering from a solid tumor; wherein, The anti-TROP2 antibody drug conjugate has a structure as shown in Formula I-17, Formula I-18, 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 a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein Formula I-17, Formula I-18, 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 is: in Abu is an anti-TROP2 antibody or its antigen-binding unit, n is an integer from 1 to 24; p is 1-10, or p is 2-8; or p is 4-8; or p is 4-6; or p is 5-7; or p is about 4.2; or p is about 6.

4. The use according to any one of claims 1 to 3, wherein n is an integer of 4 to 12; or n is an integer of 4 to 8; or n is 4 or 6 or 8; or n is 6; or n is 8.

5. The use according to any one of claims 1 to 4, wherein the Abu is an anti-TROP2 antibody, Alternatively, the Abu is the hRS9 antibody, comprising the heavy chain shown in SEQ ID NO: 1 and the light chain shown in SEQ ID NO:

2.

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

7. The use according to any one of claims 1 to 6, wherein the dose of the anti-TROP2 antibody drug conjugate is 0.1-10 mg / kg per administration; or, the dose of the anti-TROP2 antibody drug conjugate is about 1-5 mg / kg per administration; or, the dose of the anti-TROP2 antibody drug conjugate is about 2-3 mg / kg per administration; or, the dose per administration is 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 4.8 mg / kg, about 6.0 mg / kg, about 7.2 mg / kg, about 8.4 mg / kg, or about 10 mg / kg.

8. The use according to any one of claims 1 to 7, wherein the dosage of the anti-TROP2 antibody-drug conjugate is 5-3000 mg per administration; or, the dosage of the anti-TROP2 antibody-drug conjugate is 5-2000 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.

9. The use according to any one of claims 1 to 8, wherein the anti-TROP2 antibody-drug conjugate is administered once every 1, 2, 3, 4, 5, 6 or 7 weeks; or, the anti-TROP2 antibody-drug conjugate is administered once every 2 weeks, every 3 weeks or every 4 weeks; or, the anti-TROP2 antibody-drug conjugate is administered once every 2 weeks.

10. The use according to any one of claims 1 to 9, wherein the anti-TROP2 antibody drug conjugate is administered once every 2, 3 or 4 weeks, with each dose being about 2 mg / kg to about 3 mg / kg.

11. The use according to any one of claims 1 to 10, wherein the anti-TROP2 antibody drug conjugate is administered once every 2 weeks, with each administration dose being about 2 mg / kg to about 3 mg / kg.

12. The use according to any one of claims 1 to 11, wherein the anti-TROP2 antibody drug conjugate is administered once every 2 weeks, with each dose being about 2.1 mg / kg.

13. The use according to any one of claims 1 to 11, wherein the anti-TROP2 antibody drug conjugate is administered once every 2 weeks, with each dose being about 2.4 mg / kg.

14. The use according to any one of claims 1 to 13, wherein the PD-1 antagonist is an anti-PD-1 antibody or an antigen-binding fragment thereof, such as pembrolizumab, nivolumab, tislelizumab, camrelizumab, sintilimab, toripalimab, putelimab, slulizumab, sepalizumab, penampalizumab, dotalizumab, seplizumab, rivulimab, batilizumab, ipalolizumab, enlangsubiamab, genoluzumab, fenolizumab, lonelizumab, bruglimab, cetrelimab, prolgolimab, nofazinlimab, sasanlimab, spartalizumab, ezabenlimab, peramprizumab, pidilizumab, or pimivalimab.

15. The use according to any one of claims 1 to 14, wherein the anti-PD-1 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1 shown in SEQ ID NO: 3, HCDR2 shown in SEQ ID NO: 4, and HCDR3 shown in SEQ ID NO: 5, and the light chain variable region comprising LCDR1 shown in SEQ ID NO: 6, LCDR2 shown in SEQ ID NO: 7, and LCDR3 shown in SEQ ID NO:

8.

16. The use according to any one of claims 1 to 15, wherein the heavy chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO: 9, and the light chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:

10.

17. The use according to any one of claims 1 to 15, wherein the anti-PD-1 antibody comprises the heavy chain sequence shown in SEQ ID NO: 11 and the light chain sequence shown in SEQ ID NO:

12.

18. The use according to any one of claims 14 to 17, wherein the dose of the anti-PD-1 antibody administered per administration is about 50-600 mg; or, the dose of the anti-PD-1 antibody administered per administration is about 100-600 mg; or, the dose of the anti-PD-1 antibody administered per administration is about 200-400 mg; or, the dose of the anti-PD-1 antibody administered per administration is about 50 mg, about 60 mg, about 80 mg, about 120 mg, about 200 mg, about 210 mg, about 220 mg, about 250 mg, about 290 mg, about 300 mg, about 330 mg, about 380 mg, about 390 mg, about 400 mg, about 434 mg, about 480 mg, about 500 mg, about 567 mg, about 580 mg, or about 600 mg.

19. The use according to any one of claims 14 to 18, wherein the anti-PD-1 antibody is administered about once a week, or about every 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, or about every 7 weeks; or, the anti-PD-1 antibody is administered about every 2 weeks, every 3 weeks, or every 4 weeks.

20. The use according to any one of claims 14 to 19, wherein the anti-PD-1 antibody is administered at a dose of about 200-220 mg per administration, and is administered once every 2 weeks.

21. The use according to any one of claims 14 to 20, wherein the anti-PD-1 antibody is administered at a dose of about 300 mg per administration, once every three weeks.

22. The use according to any one of claims 14 to 21, wherein the anti-PD-1 antibody is administered at a dose of about 380-400 mg per administration, once every 4 weeks.

23. The use according to any one of claims 1 to 22, wherein the solid tumor is an advanced solid tumor.

24. The use according to any one of claims 1 to 23, wherein the solid tumor is an advanced or metastatic epithelial solid tumor confirmed by histopathology or cytology, for which standard treatment has failed or is unavailable, or for which standard treatment is intolerant or rejected.

25. The method of any one of claims 1 to 24, wherein the solid 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, esophageal cancer, thymic cancer, head and neck tumors, 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, 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 cancer.

26. The use according to any one of claims 1 to 25, wherein the solid tumor is triple-negative breast cancer, small cell lung cancer, non-small cell lung cancer, gastric adenocarcinoma, esophageal cancer, cervical cancer, head and neck squamous cell carcinoma, or thymic carcinoma.

27. The use according to any one of claims 1 to 26, wherein the solid tumor is locally advanced or metastatic triple-negative breast cancer confirmed by histological or cytological examination.

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

29. The use according to any one of claims 1 to 28, wherein the solid tumor is an advanced solid tumor expressing TROP2.

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