Use of Anti-frα antibody-drug conjugate and PD-1 antagonist in treatment of tumors

Abstract

The present invention relates to a use of an anti-FRα antibody-drug conjugate and a PD-1 antagonist in treatment of tumors. A treatment method comprises administering to a patient in need thereof an effective amount of an anti-FRα antibody-drug conjugate and an effective amount of a PD-1 antagonist.

Description

Application of anti-FRα antibody-drug conjugates and PD-1 antagonists in the treatment of tumors Technical Field

[0001] This invention relates to the field of drug therapy, specifically to the application of anti-FRα antibody-drug conjugates and PD-1 antagonists in the treatment of tumors. Background Technology

[0002] Cancer is a common and fatal disease. Chemotherapy, as one of the standard treatments for advanced cancer, 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.

[0003] Folic acid, an essential vitamin required for DNA synthesis and repair, and cell division, is transported via endocytosis through the binding of folic acid receptors on the cell surface. The folic acid receptors are internalized and then recycled back to the cell membrane. The folic acid receptor is a transmembrane single-chain glycoprotein linked to glycosylated phosphatidylinositol and has a high affinity for folic acid. There are three subtypes of folic acid receptors: folic acid receptor α (FOLR1, FRα), folic acid receptor β (FOLR2), and folic acid receptor γ (FOLR3). Folic acid receptor expression is highly restricted in normal cells but significantly overexpressed in tumor cells. Folic acid receptor α has been overexpressed in various malignant tumors, making it a popular target for anticancer drugs.

[0004] There is currently a huge unmet clinical need for cancer treatment and prognosis. Seeking drug therapies or combination therapies targeting various targets or mechanisms of action so that more patients can benefit from them is an urgent clinical problem to be solved. Summary of the Invention

[0005] This invention provides a method or use of an anti-FRα antibody-drug conjugate and a PD-1 antagonist for treating tumors, comprising administering an effective amount of the anti-FRα antibody-drug conjugate and the PD-1 antagonist to a patient in need. In one aspect, this invention provides the use of the anti-FRα antibody-drug conjugate and the PD-1 antagonist in the preparation of a medicament for treating tumors. In another aspect, this invention provides the use of the anti-FRα antibody-drug conjugate and the PD-1 antagonist in combination for treating tumors. In another aspect, this invention provides a pharmaceutical composition of the anti-FRα antibody-drug conjugate and the PD-1 antagonist, and its use in treating tumors. In another aspect, this invention provides the use of the anti-FRα antibody-drug conjugate in the preparation of a medicament for treating tumors in combination with a PD-1 antagonist. In yet another aspect, this invention provides the use of the anti-FRα antibody-drug conjugate in the treatment of tumors in combination with a PD-1 antagonist. In yet another aspect, this invention provides the use of the anti-FRα antibody-drug conjugate in the treatment of tumors in combination with a PD-1 antagonist. On the one hand, the present invention provides the use of PD-1 antagonists in combination with anti-FRα antibody drug conjugates for the treatment of tumors.

[0006] In one or more embodiments, the anti-FRα 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:

[0007] in

[0008] Abu is an FRα binding unit.

[0009] 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,

[0010] n is an integer from 1 to 24;

[0011] p is 1-10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0012] In one or more embodiments, D is eczetidine or an eczetidine derivative.

[0013] In one or more embodiments, D is...

[0014] Where X 1 and X 2 Each is independently a C1-C6 alkyl, halogen, or -OH; ** represents a connection point.

[0015] In one or more embodiments, the C1-C6 alkyl group is -CH3.

[0016] In one or more embodiments, the halogen is F.

[0017] In one or more embodiments, X 1 and X 2 Each can be independently -CH3, F, or -OH.

[0018] In one or more embodiments, X 1 and X 2 Each is -CH3.

[0019] In one or more embodiments, X 1 and X 2 Each can be F, Cl, Br, or I independently.

[0020] In one or more embodiments, X 1 and X 2 Each is F.

[0021] In one or more embodiments, X 1 and X 2 Each can be either F or -CH3.

[0022] In one or more embodiments, X 1 For -CH3 and X 2 It is F.

[0023] In one or more embodiments, n is an integer from 4 to 12. In one or more embodiments, n is an integer from 4 to 8. In one or more embodiments, n is 8.

[0024] In one or more embodiments, p is 2-10. In one or more embodiments, p is 2-8. In one or more embodiments, p is 4-8. In one or more embodiments, p is 6-8. In one or more embodiments, p is 7-8.

[0025] In one or more embodiments, the anti-FRα antibody-drug conjugate has a structure as 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, I-17, or I-18, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

[0026] in,

[0027] Abu is an FRα binding unit.

[0028] n is an integer from 1 to 24.

[0029] p is 1-10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0030] In one or more embodiments, n is an integer from 4 to 12. In one or more embodiments, n is an integer from 4 to 8. In one or more embodiments, n is 8.

[0031] In one or more embodiments, p is 2-10. In one or more embodiments, p is 2-8. In one or more embodiments, p is 4-8. In one or more embodiments, p is 6-8. In one or more embodiments, p is 7-8.

[0032] In one or more embodiments, Abu is an anti-FRα antibody or its antigen-binding fragment.

[0033] In one or more embodiments, the anti-FRα antibody or its antigen-binding fragment comprises one or more of (a)-(f):

[0034] (a) VH CDR1 contains the amino acid sequence shown in SEQ ID NO:1, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:1, or is composed of the amino acid sequence shown in SEQ ID NO:1;

[0035] (b) VH CDR2 contains the amino acid sequence shown in SEQ ID NO:2, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:2, or is composed of the amino acid sequence shown in SEQ ID NO:2;

[0036] (c) VH CDR3 contains the amino acid sequence shown in SEQ ID NO:3, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:3, or is composed of such amino acid sequences;

[0037] (d) VL CDR1 contains the amino acid sequence shown in SEQ ID NO:4, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:4, or is composed of the amino acid sequence shown in SEQ ID NO:4;

[0038] (e)VL CDR2 contains the amino acid sequence shown in SEQ ID NO:5, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:5, or is composed of such amino acid sequences.

[0039] (f) VL CDR3 contains the amino acid sequence shown in SEQ ID NO:6, or has one or more sites of substitution, deletion or insertion of amino acid sequences compared to the amino acid sequence shown in SEQ ID NO:6, or is composed of such amino acid sequences.

[0040] In one or more embodiments, the anti-FRα antibody or its antigen-binding fragment comprises VH CDR1 as shown in SEQ ID NO:1, VH CDR2 as shown in SEQ ID NO:2, VH CDR3 as shown in SEQ ID NO:3, VL CDR1 as shown in SEQ ID NO:4, VL CDR2 as shown in SEQ ID NO:5, and VL CDR3 as shown in SEQ ID NO:6.

[0041] In one or more embodiments, the anti-FRα antibody or its antigen-binding fragment further comprises one or more of (g)-(n):

[0042] (g)VH FR1 contains an amino acid sequence as shown in SEQ ID NO:11, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:11, or an amino acid sequence that has one or more substitutions, deletions or insertions compared with the amino acid sequence shown in SEQ ID NO:11.

[0043] (h)VH FR2 contains an amino acid sequence as shown in SEQ ID NO:12, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:12, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:12.

[0044] (i) VH FR3 contains an amino acid sequence as shown in SEQ ID NO:13, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:13, or an amino acid sequence that has one or more substitutions, deletions or insertions compared with the amino acid sequence shown in SEQ ID NO:13.

[0045] (j)VH FR4 contains an amino acid sequence as shown in SEQ ID NO:14, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:14, or an amino acid sequence that has one or more substitutions, deletions or insertions compared with the amino acid sequence shown in SEQ ID NO:14.

[0046] (k)VL FR1 contains an amino acid sequence as shown in SEQ ID NO:15, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:15, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:15.

[0047] (l)VL FR2 contains an amino acid sequence as shown in SEQ ID NO:16, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:16, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:16.

[0048] (m)VLFR3 contains an amino acid sequence as shown in SEQ ID NO:17, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:17, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:17.

[0049] (n)VL FR4 contains an amino acid sequence as shown in SEQ ID NO:18, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:18, or an amino acid sequence that has one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:18.

[0050] In one or more embodiments, the anti-FRα antibody or its antigen-binding fragment comprises VH FR1 as shown in SEQ ID NO:11, VH FR2 as shown in SEQ ID NO:12, VH FR3 as shown in SEQ ID NO:13, and VH FR4 as shown in SEQ ID NO:14.

[0051] In one or more embodiments, the anti-FRα antibody or its antigen-binding fragment comprises VLFR1 as shown in SEQ ID NO:15, VLFR2 as shown in SEQ ID NO:16, VLFR3 as shown in SEQ ID NO:17, and VLFR4 as shown in SEQ ID NO:18.

[0052] In one or more embodiments, the anti-FRα antibody or its antigen-binding fragment comprises VH FR1 as shown in SEQ ID NO:11, VH FR2 as shown in SEQ ID NO:12, VH FR3 as shown in SEQ ID NO:13, VH FR4 as shown in SEQ ID NO:14, VL FR1 as shown in SEQ ID NO:15, VL FR2 as shown in SEQ ID NO:16, VLFR3 as shown in SEQ ID NO:17, and VLFR4 as shown in SEQ ID NO:18.

[0053] In one or more embodiments, the anti-FRα antibody or its antigen-binding fragment comprises a heavy chain variable region (VH) and / or a light chain variable region (VL), wherein:

[0054] The heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:7, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:7, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:7; and / or

[0055] The light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:8, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:8, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:8.

[0056] In one or more embodiments, the anti-FRα antibody or its antigen-binding fragment comprises a heavy chain variable region as shown in SEQ ID NO:7 and a light chain variable region as shown in SEQ ID NO:8.

[0057] In one or more embodiments, the anti-FRα antibody comprises a heavy chain (H) and a light chain (L).

[0058] In one or more embodiments, the heavy chain of the anti-FRα antibody comprises an amino acid sequence as shown in SEQ ID NO:9, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:9, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:9; and / or

[0059] The light chain of the anti-FRα antibody comprises an amino acid sequence as shown in SEQ ID NO:10, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:10, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:10.

[0060] In one or more embodiments, the anti-FRα antibody comprises a heavy chain as shown in SEQ ID NO:9 and a light chain as shown in SEQ ID NO:10.

[0061] In one or more embodiments, the anti-FRα antibody is antibody 1.

[0062] Table 1. Amino acid sequence of anti-FRα antibody

[0063] VH FR1:QVQLVQSGVEVKKPGASVKVSCKASGYSFT(SEQ ID NO:11)

[0064] VH FR2:WVRQAPGQGLEWIG(SEQ ID NO:12)

[0065] VH FR3:KATLTVDKSTTTAYMELKSLQFDDTAVYYCTR(SEQ ID NO:13)

[0066] VH FR4:WGQGTTVTVSS(SEQ ID NO:14)

[0067] VL FR1:EIVLTQSPATLSLSPGERATLSC(SEQ ID NO:15)

[0068] VL FR2:WYQQKPGQAPRLLIY(SEQ ID NO:16)

[0069] VL FR3:GVPARFSGSGSKTDFTLTISSLEPEDFAVYYC(SEQ ID NO:17)

[0070] VL FR4: FGGGTKVEIK(SEQ ID NO:18)

[0071] In one or more embodiments, the anti-FRα antibody has two identical heavy chains and two identical light chains.

[0072] In one or more embodiments, the anti-FRα antibody-drug conjugate is ADC1 or its stereoisomer or a pharmaceutically acceptable salt or solvate thereof, wherein ADC1 has a structure as shown in Formulas I-6:

[0073] in

[0074] Abu is antibody 1.

[0075] p is 7-8.

[0076] In one or more embodiments, the PD-1 antagonist is an anti-PD-1 antibody or its antigen-binding fragment.

[0077] In one or more embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises one or more of (o)-(t):

[0078] (o)VH CDR1 contains the amino acid sequence shown in SEQ ID NO:19, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:19, or is composed of the amino acid sequence shown in SEQ ID NO:19;

[0079] (p)VH CDR2 contains the amino acid sequence shown in SEQ ID NO:20, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:20, or is composed of such amino acid sequences.

[0080] (q)VH CDR3 contains the amino acid sequence shown in SEQ ID NO:21, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:21, or is composed of the amino acid sequence shown in SEQ ID NO:21;

[0081] (r)VL CDR1 contains the amino acid sequence shown in SEQ ID NO:22, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:22, or is composed of the amino acid sequence shown in SEQ ID NO:22;

[0082] (s)VL CDR2 contains the amino acid sequence shown in SEQ ID NO:23, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:23, or is composed of the amino acid sequence shown in SEQ ID NO:23;

[0083] (t)VL CDR3 contains the amino acid sequence shown in SEQ ID NO:24, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:24, or is composed of the amino acid sequence shown in SEQ ID NO:24.

[0084] In one or more embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises VH CDR1 as shown in SEQ ID NO:19, VH CDR2 as shown in SEQ ID NO:20, VH CDR3 as shown in SEQ ID NO:21, VL CDR1 as shown in SEQ ID NO:22, VL CDR2 as shown in SEQ ID NO:23, and VL CDR3 as shown in SEQ ID NO:24.

[0085] In one or more embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region (VH) and / or a light chain variable region (VL), wherein:

[0086] The heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:25, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:25, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:25; and / or

[0087] The light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:26, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:26, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:26.

[0088] In one or more embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region as shown in SEQ ID NO:25 and a light chain variable region as shown in SEQ ID NO:26.

[0089] In one or more embodiments, the anti-PD-1 antibody comprises a heavy chain (H) and a light chain (L).

[0090] In one or more embodiments, the heavy chain of the anti-PD-1 antibody comprises an amino acid sequence as shown in SEQ ID NO:27, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:27, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:27; and / or

[0091] The light chain of the anti-PD-1 antibody comprises an amino acid sequence as shown in SEQ ID NO:28, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:28, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:28.

[0092] In one or more embodiments, the anti-PD-1 antibody comprises a heavy chain as shown in SEQ ID NO:27 and a light chain as shown in SEQ ID NO:28.

[0093] In one or more embodiments, the anti-PD-1 antibody is antibody A.

[0094] Table 2. Amino acid sequences of anti-PD-1 antibodies

[0095] In one or more embodiments, the anti-PD-1 antibody has two identical heavy chains and two identical light chains.

[0096] In one or more embodiments, the site substitution, deletion, or insertion is independent of one, two, or three.

[0097] In one or more embodiments, the substitution is a conserved amino acid substitution.

[0098] In one or more embodiments, the antibody or its antigen-binding fragment is chimeric, humanized, or fully human.

[0099] In one or more embodiments, the antibody is a monoclonal antibody, a multispecific antibody, or an antigen-binding fragment thereof (e.g., a bispecific antibody or an antigen-binding fragment thereof).

[0100] In one or more embodiments, the anti-FRα antibody-drug conjugate (e.g., ADC1) is administered at a dose of approximately 5 mg / m² body surface area. 2 (approximately 150 mg / m²) 2 or about 30mg / m 2 Approximately 120 mg / m 2 or about 50mg / m 2 Approximately 120 mg / m 2 or about 70mg / m 2 Approximately 100 mg / m 2 or approximately 75 mg / m 2 Approximately 93 mg / m 2 or approximately 76 mg / m³ 2 Approximately 93 mg / m 2 In one or more embodiments, the dose of the anti-FRα antibody-drug conjugate (e.g., ADC1) is approximately 5 mg / m² per administration. 2 Approximately 30 mg / m 2 Approximately 50 mg / m 2 Approximately 70 mg / m 2 Approximately 75mg / m 2 Approximately 76 mg / m 2 Approximately 84 mg / m 2 Approximately 93 mg / m 2 Approximately 100 mg / m 2 Approximately 120 mg / m 2 Approximately 150 mg / m 2This refers to a range (including endpoints) between any two of these values, or any value within that range. In one or more embodiments, the anti-FRα antibody-drug conjugate is administered as a single dose. In one or more embodiments, it is administered every 1-8 weeks. In one or more embodiments, it is administered every 2-4 weeks. In one or more embodiments, it is administered every approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, or approximately 8 weeks. In one or more embodiments, it is administered weekly, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, or every 7 weeks. In one or more embodiments, it is administered every 3 weeks.

[0101] In one or more embodiments, the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered at approximately 5 mg / m² every 2-4 weeks. 2 Approximately 150 mg / m 2 or about 30mg / m 2 Approximately 120 mg / m 2 or about 50mg / m 2 Approximately 120 mg / m 2 or about 70mg / m 2 Approximately 100 mg / m 2 or approximately 75 mg / m 2 Approximately 93 mg / m 2 or approximately 76 mg / m³ 2 Approximately 93 mg / m 2 Or a formulation containing this dose of an anti-FRα antibody-drug conjugate (e.g., ADC1). In one or more embodiments, the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered at approximately 5 mg / m² every 2-4 weeks. 2 Approximately 30 mg / m 2 Approximately 50 mg / m 2 Approximately 70 mg / m 2 Approximately 75mg / m 2 Approximately 76 mg / m 2 Approximately 84 mg / m 2 Approximately 93 mg / m 2 Approximately 100 mg / m 2 Approximately 120 mg / m 2 Approximately 150 mg / m 2 Or, a range between any two of these values ​​(including endpoints) or any value therein, or a formulation containing this dose of an anti-FRα antibody-drug conjugate (e.g., ADC1). In one or more embodiments, approximately 75 mg / m² of the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered every 2-4 weeks. 2In one or more embodiments, the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered at approximately 76 mg / m² every 2-4 weeks. 2 In one or more embodiments, the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered at approximately 84 mg / m² every 2-4 weeks. 2 In one or more embodiments, the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered at approximately 93 mg / m² every 2-4 weeks. 2 .

[0102] In one or more embodiments, the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered at approximately 5 mg / m² every 3 weeks. 2 Approximately 150 mg / m 2 or about 30mg / m 2 Approximately 120 mg / m 2 or about 50mg / m 2 Approximately 120 mg / m 2 or about 70mg / m 2 Approximately 100 mg / m 2 or approximately 75 mg / m 2 Approximately 93 mg / m 2 or approximately 76 mg / m³ 2 Approximately 93 mg / m 2 Or a formulation containing this dose of an anti-FRα antibody-drug conjugate (e.g., ADC1). In one or more embodiments, the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered at approximately 5 mg / m² every 3 weeks. 2 Approximately 30 mg / m 2 Approximately 50 mg / m 2 Approximately 70 mg / m 2 Approximately 75mg / m 2 Approximately 76 mg / m 2 Approximately 84 mg / m 2 Approximately 93 mg / m 2 Approximately 100 mg / m 2 Approximately 120 mg / m 2 Approximately 150 mg / m 2 Or, a range between any two of these values ​​(including endpoints) or any value therein, or a formulation containing this dose of an anti-FRα antibody-drug conjugate (e.g., ADC1). In one or more embodiments, approximately 75 mg / m² of the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered every 3 weeks. 2 In one or more embodiments, approximately 76 mg / m² of the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered every 3 weeks.2 In one or more embodiments, the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered at approximately 84 mg / m² every 3 weeks. 2 In one or more embodiments, the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered at approximately 93 mg / m² every 3 weeks. 2 .

[0103] In one or more embodiments, the ADC1 described herein is administered at approximately 70 mg / m² every 2-4 weeks. 2 Approximately 100 mg / m 2 In one or more embodiments, the ADC1 described herein is administered at a dose of approximately 75 mg / m² every 3 weeks. 2 In one or more embodiments, the ADC1 described herein is administered at a dose of approximately 76 mg / m² every 3 weeks. 2 In one or more embodiments, the ADC1 described herein is administered at approximately 84 mg / m² every 3 weeks. 2 In one or more embodiments, the ADC1 described herein is administered at a dose of approximately 93 mg / m² every 3 weeks. 2 .

[0104] In one or more embodiments, the PD-1 antagonist (e.g., antibody A) is administered at a dose of about 50 mg to about 600 mg, or about 100 mg to about 500 mg, or about 200 mg to about 400 mg per administration. In one or more embodiments, the PD-1 antagonist (e.g., antibody A) is administered at a dose of about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or a range (including endpoints) of any two of these values, or any value therein. In one or more embodiments, the PD-1 antagonist is administered as a single dose. In one or more embodiments, it is administered every 1 to 8 weeks. In one or more embodiments, it is administered every 2 to 4 weeks. In one or more embodiments, it is administered every about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks. In one or more embodiments, the drug is administered once weekly, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every seven weeks. In one or more embodiments, the drug is administered once every three weeks.

[0105] In one or more embodiments, about 50 mg to about 600 mg, or about 100 mg to about 500 mg, or about 200 mg to about 400 mg, or a formulation containing this dose of the PD-1 antagonist (e.g., antibody A), is administered every 2-4 weeks. In one or more embodiments, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or a range (including endpoints) or any of these values, or a formulation containing this dose of the PD-1 antagonist (e.g., antibody A), is administered every 2-4 weeks. In one or more embodiments, about 300 mg of the PD-1 antagonist (e.g., antibody A), is administered every 2-4 weeks.

[0106] In one or more embodiments, about 50 mg to about 600 mg, or about 100 mg to about 500 mg, or about 200 mg to about 400 mg, or a formulation containing this dose of the PD-1 antagonist (e.g., antibody A), is administered every 3 weeks. In one or more embodiments, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or a range (including endpoints) or any of these values, or a formulation containing this dose of the PD-1 antagonist (e.g., antibody A), is administered every 3 weeks. In one or more embodiments, about 300 mg of the PD-1 antagonist (e.g., antibody A), is administered every 3 weeks.

[0107] In one or more embodiments, about 200 mg to about 400 mg of the antibody A described herein is administered every 2-4 weeks. In one or more embodiments, about 300 mg of the antibody A described herein is administered every 3 weeks.

[0108] In one or more embodiments, the ADC1 described herein is administered at approximately 70 mg / m² every 2-4 weeks. 2 Approximately 100 mg / m 2 The antibody A described herein is administered at a dose of approximately 200 mg to approximately 400 mg every 2-4 weeks. In one or more embodiments, the ADC1 described herein is administered at a dose of approximately 70 mg / m² every 3 weeks. 2 Approximately 100 mg / m 2 ; administer approximately 200 mg to approximately 400 mg of the antibody A described herein every 3 weeks.

[0109] In one or more embodiments, the ADC1 described herein is administered at approximately 75 mg / m² every 2-4 weeks. 2Approximately 76 mg / m 2 Approximately 84 mg / m 2 or approximately 93 mg / m 2 Administer approximately 300 mg of antibody A described herein every 2-4 weeks. In one or more embodiments, administer approximately 75 mg / m² of ADC1 described herein every 3 weeks. 2 Approximately 76 mg / m 2 Approximately 84 mg / m 2 or approximately 93 mg / m 2 ; administer approximately 300 mg of antibody A described in this article once every 3 weeks.

[0110] 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 one or more embodiments, the anti-FRα antibody-drug conjugate and the PD-1 antagonist are prepared as a single pharmaceutical composition and administered simultaneously to a patient in need of the anti-FRα antibody-drug conjugate and the PD-1 antagonist. In one or more embodiments, the anti-FRα antibody-drug conjugate and the PD-1 antagonist are each prepared as an independent pharmaceutical composition and administered simultaneously to a patient in need of the anti-FRα antibody-drug conjugate and the PD-1 antagonist, or administered to a patient in need of the anti-FRα antibody-drug conjugate and the PD-1 antagonist at different times during a treatment regimen. For example, the anti-FRα antibody-drug conjugate may be administered before, after, or alternately with the PD-1 antagonist. In one or more embodiments, the anti-FRα antibody-drug conjugate may be administered after the PD-1 antagonist. In this article, the anti-FRα antibody-drug conjugate and PD-1 antagonist were administered to patients in need in single or multiple doses.

[0111] In one or more embodiments, the ADC1 is administered after the antibody A is administered.

[0112] In one or more embodiments, the patient receives one treatment cycle. In one or more embodiments, 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 one or more embodiments, the patient receives treatment until the symptoms are relieved and treatment is no longer required. In one or more embodiments, a treatment cycle is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, or at least 7 weeks. In one or more embodiments, a treatment cycle is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or about 7 weeks, or a range (including endpoints) or any of these values.

[0113] In one or more embodiments, in the methods and uses for treating tumors provided by the present invention, the anti-FRα antibody-drug conjugate and PD-1 antagonist 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-FRα antibody-drug conjugate and PD-1 antagonist 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 one or more embodiments, the route of administration is intravenous (iv) infusion (i.e., intravenous infusion). In one or more embodiments, the agents used for the anti-FRα 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 parenterally, intravenously (iv), intramuscularly, locally, or subcutaneously (sc). In one or more embodiments, the route of administration is intravenous infusion.

[0114] In one or more embodiments, the anti-FRα antibody-drug conjugate and PD-1 antagonist are administered via intravenous infusion. In one or more embodiments, the duration of the intravenous infusion 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, or about 90 minutes, or a range (including endpoints) between any two of these values, or any value therein. In one or more embodiments, the duration of the intravenous infusion is 60 ± 10 minutes. In one or more embodiments, the duration of the intravenous infusion is 30 to 60 minutes. In one or more embodiments, the initial intravenous infusion lasts 60 ± 10 minutes, and subsequent intravenous infusions last 30 to 60 minutes.

[0115] Examples of tumors include, but are not limited to, colorectal cancer, lung cancer (e.g., non-small cell lung cancer), ovarian cancer, endometrial cancer, peritoneal cancer, fallopian tube cancer, pancreatic cancer, nasopharyngeal cancer, laryngeal cancer, liver cancer, breast cancer, brain cancer, kidney cancer (e.g., renal cell carcinoma), colon cancer, testicular cancer, cervical cancer, tongue cancer, bladder cancer, retinoblastoma, glioblastoma, mesothelioma, oral epithelioid carcinoma, choriocarcinoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), melanoma (e.g., malignant metastatic melanoma), prostate cancer (e.g., hormone-resistant prostate adenocarcinoma), esophageal cancer, thyroid cancer, glioblastoma, or glioma.

[0116] In one or more embodiments, the tumor is an advanced solid tumor.

[0117] In one or more embodiments, the tumor is selected from non-small cell lung cancer, ovarian cancer, endometrial cancer, and breast cancer.

[0118] In one or more embodiments, the tumor is ovarian epithelial carcinoma.

[0119] In one or more embodiments, the tumor is serous ovarian epithelial carcinoma.

[0120] In one or more embodiments, the tumor is high-grade serous epithelial ovarian carcinoma.

[0121] In one or more embodiments, the tumor is PD-L1 overexpressing. The expression level and overexpression of PD-L1 can be detected by known methods, such as immunohistochemical (IHC) staining, quantitative immunofluorescence (IF) and flow cytometry (FC), enzyme-linked immunosorbent assay (ELISA), etc.

[0122] In one or more embodiments, the tumor is FRα-positive (e.g., FRα ≥ 1%, FRα ≥ 10%, FRα ≥ 20%, FRα ≥ 30%, FRα ≥ 40%, FRα ≥ 50%). The expression level and overexpression of the folate receptor can be detected using known methods, such as immunohistochemical (IHC) staining, fluorescence in situ hybridization (FISH), radiolabeled ligand binding detection, etc.

[0123] In one or more embodiments, the tumor is FRα-positive (e.g., FRα ≥ 1%) ovarian cancer.

[0124] In one or more embodiments, the tumor is FRα-positive (e.g., FRα ≥ 1%) endometrial cancer.

[0125] In one or more embodiments, the patient has a metastatic or locally advanced unresectable tumor that is unsuitable for local treatment. In one or more embodiments, the patient has a histologically or cytologically diagnosed metastatic or locally advanced unresectable tumor that is unsuitable for local treatment, and the patient no longer benefits from or is unsuitable for standard treatment. In one or more embodiments, the patient has a histologically or cytologically diagnosed metastatic or locally advanced unresectable solid tumor (e.g., ovarian cancer, endometrial cancer, breast cancer, or non-small cell lung cancer) that is unsuitable for local treatment. In one or more embodiments, the patient has a histologically or cytologically diagnosed metastatic or locally advanced unresectable solid tumor (e.g., ovarian cancer, endometrial cancer, breast cancer, or non-small cell lung cancer) that is unsuitable for local treatment, and the patient no longer benefits from or is unsuitable for standard treatment.

[0126] In one or more embodiments, the patient has ovarian cancer, endometrial cancer, breast cancer, non-small cell lung cancer, ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer (e.g., high-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, mucinous carcinoma, or low-grade serous carcinoma).

[0127] In one or more embodiments, the patient is platinum-resistant. In one or more embodiments, the patient has previously received no more than three lines of treatment. In one or more embodiments, the patient is platinum-sensitive. In one or more embodiments, the patient's disease progressed after receiving two lines of platinum-based therapy.

[0128] In one or more embodiments, the patient has received at least one line of anti-tumor therapy. In one or more embodiments, the patient has received at least two lines of anti-tumor therapy. In one or more embodiments, the patient has received at least three lines of anti-tumor therapy.

[0129] In one or more embodiments, the patient has a pathologically diagnosed endometrial cancer (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, dedifferentiated / undifferentiated carcinoma, mixed carcinoma, carcinosarcoma, or other nonspecific carcinoma) and has experienced disease recurrence or progression after receiving at least one line of platinum-based chemotherapy or one line of immunotherapy. In one or more embodiments, the patient has received no more than three lines of prior treatment (hormonal therapy is not counted as a line and does not require washout; hormone therapy combined with CDK4 / 6 inhibitors or mTOR or other PI3K pathway inhibitors is not counted as a line).

[0130] In one or more embodiments, the patient is a patient with a histologically or cytologically confirmed advanced or metastatic solid tumor who has failed or is intolerant of standard treatment. In one or more embodiments, the patient is a patient with a histologically or cytologically confirmed advanced or metastatic breast cancer who has failed or is intolerant of standard treatment. In one or more embodiments, the patient is a patient with a histologically or cytologically confirmed advanced or metastatic non-small cell lung cancer who has failed or is intolerant of standard treatment. In one or more embodiments, the patient is a patient with a histologically or cytologically confirmed advanced or metastatic endometrial cancer who has failed or is intolerant of standard treatment. In one or more embodiments, the patient is a patient with a histologically or cytologically confirmed advanced or metastatic ovarian cancer who has failed or is intolerant of standard treatment.

[0131] In one or more embodiments, the combination of the anti-FRα antibody-drug conjugate and the PD-1 antagonist of the present invention exhibits good safety and tolerability. In some embodiments, the combination of the anti-FRα antibody-drug conjugate and the PD-1 antagonist of the present invention exhibits good antitumor efficacy. In one or more embodiments, the combination of the anti-FRα antibody-drug conjugate and the PD-1 antagonist of the present invention provides 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).

[0132] In one or more embodiments, the pharmaceutical composition further includes pharmaceutically acceptable excipients. In one or more embodiments, the pharmaceutically acceptable excipients may comprise antibacterial and / or antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In one or more embodiments, the pharmaceutically acceptable excipients may comprise isotonic agents, such as sugars, polyols (such as mannitol, sorbitol), sodium chloride. In one or more embodiments, the pharmaceutical composition comprises at least 0.1% of an anti-FRα antibody-drug conjugate and / or a PD-1 antagonist. The percentage can vary, for example, from about 2% to 90% by weight of a given dosage form. Detailed Implementation

[0133] Unless otherwise defined, the scientific and technical terms used in this invention have the meanings that are commonly understood by those skilled in the art.

[0134] definition

[0135] It should be noted that the term “a” refers to one or more of the same entity. For example, “a method” should be understood as one or more methods. Therefore, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably in this document.

[0136] As used herein, the terms “comprising” or “including” mean that antibodies, compositions, or methods include the listed elements, such as components or steps, but do not exclude others. “Substantially composed of” means that antibodies, compositions, or methods exclude other elements that fundamentally affect the characterization of the composition, but do not exclude elements that do not substantially affect the antibody, composition, or method. “Composed of” means excluding elements not specifically listed.

[0137] "Approximately" refers to a typical error range for the corresponding value that is readily known to those skilled in the art. In some embodiments, "approximately" as used herein refers to the described value and its range of ±10%, ±5%, or ±1%.

[0138] "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.

[0139] As used herein, the term "effective amount" refers to an amount 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 amount 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 amount may improve progression-free survival (PFS), improve overall survival (OS), or reduce the likelihood of recurrence.

[0140] 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.

[0141] "PD-1 antagonist" refers to any chemical compound or biomolecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or NKT cells), and preferably also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or synonyms for PD-1 and its ligands include: for PD-1, PDCD1, PD1, CD279, and SLEB2; for PD-L1, PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H; and for PD-L2, PDCD1L2, PDL2, B7-DC, Btdc, and CD273. In any treatment method, medicine, and use of this invention for treating a human individual, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and preferably blocks the binding of both human PD-L1 and PD-L2 to human PD1. The amino acid sequence of human PD-1 can be found at NCBI locus number: NP_005009. The amino acid sequences of human PD-L1 and PD-L2 can be found at NCBI loci numbers: NP_054862 and NP_079515, respectively.

[0142] PD-1 antagonists that can be used in any of the treatment methods, pharmaceuticals, and uses of the present invention include monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1, and preferably specifically bind to human PD-1 or human PD-L1. mAbs can be human antibodies, humanized antibodies, or chimeric antibodies, and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in a preferred embodiment, the human constant region is the IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0143] "Overexpression" refers to a gene that is typically transcribed or translated at a detectably higher level in certain cells, such as cancer cells, compared to normal cells. Overexpression can be the overexpression of a protein or RNA (due to increased transcription, post-transcriptional processing, translation, post-translational processing, altered stability, and altered protein degradation), as well as localized overexpression (increased nuclear localization) and enhanced functional activity resulting from altered protein transport patterns, such as increased enzymatic hydrolysis of substrates. Overexpression can be 1%, 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or more compared to normal or control cells.

[0144] Objective Response Rate (ORR): The proportion of patients whose tumor volume shrinks to a predetermined value and can be maintained for the minimum required period of time. It is the sum of the proportions of patients with complete response (CR) and partial response (PR). ORR = CR + PR.

[0145] 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 objective response.

[0146] Disease control rate (DCR): The percentage of cases that achieve remission (PR+CR) and stable disease (SD) after treatment out of the evaluable cases. DCR = CR+PR+SD.

[0147] Progression-free survival (PFS): the time from the first dose of medication to the occurrence of objective tumor progression or all-cause death (whichever comes first).

[0148] Overall Survival (OS): The time from the date of first administration to death from any cause. For patients still alive at the time of analysis, the cutoff date is the date of their last contact.

[0149] Maximum tolerated dose (MTD): MTD is defined as the highest dose level at which DLT is observed in ≤1 / 6 of subjects during the DLT assessment period.

[0150] The terms "antibody-drug conjugate" or "ADC" are used interchangeably and refer to a binding protein (such as an antibody or its antigen-binding fragment) 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, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormones, antihormonal agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclides, topoisomerase inhibitors, kinase inhibitors (e.g., TEC-family kinase inhibitors and serine / threonine kinase inhibitors), and radiosensitizers.

[0151] 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 other embodiments, the average drug-antibody conjugation ratio is about 6 to about 8, or about 7 to about 8. DAR values ​​may be expressed as p herein. The DAR value of 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.

[0152] "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 thereof, or a single chain thereof. Therefore, the term "antibody" includes any protein or peptide containing at least a portion of an immunoglobulin molecule having 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 fragment can specifically recognize and bind to a polypeptide or polypeptide complex containing one or more (e.g., two) antigens.

[0153] Various substituents are defined as follows.

[0154] "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).

[0155] "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.

[0156] 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.

[0157] 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)).

[0158] All publications and patents cited in this document are incorporated herein by reference for all purposes.

[0159] Example

[0160] Unless otherwise specified, the materials and reagents used in the following examples can be obtained commercially or by known methods.

[0161] Anti-FRα antibody-drug conjugates (hereinafter referred to as ADC1) are prepared according to the preparation method of ADC1 described in patent WO2023 / 116911. The structure of ADC1 is shown in Formula I-6, wherein Abu is antibody 1, containing a heavy chain as shown in SEQ ID NO:9 and a light chain as shown in SEQ ID NO:10, and p (i.e., average drug-antibody conjugate ratio (DAR)) is 7-8. Antibody A is an anti-PD-1 antibody, containing a heavy chain as shown in SEQ ID NO:27 and a light chain as shown in SEQ ID NO:28, and its preparation method is described in WO2020 / 207432.

[0162] Example 1: A multicenter, open-label phase Ib / II clinical study of the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of ADC1 combined with antibody A in patients with advanced solid tumors.

[0163] This study is designed as a multicenter, open-label phase Ib / II clinical trial to evaluate the safety, tolerability, PK characteristics, and efficacy of ADC1 combined with antibody A in patients with advanced solid tumors, the maximum tolerated dose (MTD) of the combination therapy, and to provide recommended doses and reasonable dosing regimens for subsequent clinical studies.

[0164] The study is broadly divided into two phases. The first phase will use a "3+3" dose escalation rule to evaluate the safety and tolerability of the investigational drug. The second phase will expand the study by selecting appropriate doses and tumor types within the safe dose range based on the preliminary safety and efficacy results of the previous phase, in order to further evaluate the safety and clinical efficacy of ADC1 combined with antibody A.

[0165] Phase Ib dose escalation study

[0166] The safety and tolerability of ADC1 combined with antibody A in advanced solid tumors were evaluated using a "3+3" dose escalation rule. ADC1 was divided into three dose groups: escalation group A1 (75 mg / m²) and 2 dose groups. 2 B (84mg / m 2 C (93mg / m 2 ), or, respectively, climbing group A2 (76mg / m 2 B (84mg / m 2 C (93mg / m 2 Antibody A was administered at a fixed dose of 300 mg. The dose escalation regimen is shown in Tables 3 and 4.

[0167] Table 3 Dosage escalation scheme 1

[0168] Table 4 Dosage escalation scheme 2

[0169] The “3+3” dose escalation regimen is as follows:

[0170] Phase II Dosage Extension Study

[0171] In the Phase II study, based on the preliminary safety and efficacy results from the Phase Ib study, ADC1 will be used in combination with 300 mg of antibody A at a dosing frequency of Q3W in advanced ovarian cancer, advanced endometrial cancer, or other advanced solid tumors to further evaluate the safety and efficacy of ADC1 in combination with antibody A.

[0172] Dosage regimen:

[0173] Infuse antibody A first, then ADC1. Both drugs are administered intravenously. The initial infusion time is 60 ± 10 minutes for each drug. If there are no safety concerns, subsequent infusions are recommended to be 30–60 minutes, administered once every 3 weeks (Q3W).

[0174] DLT definition:

[0175] Adverse events (AEs) will be assessed based on CTCAE v5.0. Dose-limiting toxicities (DLTs) are defined as AEs that occur during the DLT observation period (within 21 days after the first dose) and are considered at least potentially related to the study drug, as follows:

[0176] Any Level 5 After Effects;

[0177] Hematologic toxicity: Grade 4 anemia; Grade 4 neutropenia >7 days; Grade 4 thrombocytopenia lasting >7 days or Grade 3 thrombocytopenia associated with bleeding; Grade 3-4 febrile neutropenia;

[0178] Non-hematologic AEs: Grade 3-4 non-hematologic AEs (AEs not discovered solely by laboratory tests); Grade 3-4 non-hematologic laboratory abnormalities requiring clinical intervention, which are classified as SAEs; any AE that causes a delay of >3 weeks in the second cycle of treatment.

[0179] The following AEs are not defined as DLTs:

[0180] Grade 3 cancer pain;

[0181] Grade 3 endocrine toxicity can be controlled with hormone replacement therapy;

[0182] Grade 3 infusion reactions can be relieved to ≤ Grade 2 within 6 hours with clinical intervention;

[0183] Grade 3 rashes decreased to grade ≤2 within 7 days after treatment;

[0184] Grade 3 nausea, vomiting, or diarrhea that decreases to ≤ Grade 2 within 72 hours after treatment or supportive care;

[0185] Level 3 fatigue lasting ≤7 days;

[0186] Electrolyte disturbances of grade 3 or above resolve spontaneously or after treatment.

[0187] Selection criteria:

[0188] 1. Age 18-75 years old, gender not limited;

[0189] 2. Depending on the stage of the research, participants must meet the following requirements:

[0190] 2.1. Dose escalation phase: Metastatic or locally advanced unresectable solid tumors (including ovarian cancer, endometrial cancer, breast cancer, and non-small cell lung cancer) diagnosed histologically or cytologically as unsuitable for local treatment, where the subject no longer benefits from or is unsuitable for standard treatment. For ovarian cancer subjects, FRα expression must be positive (FRα ≥ 1% based on archived specimens or fresh tumor tissue analysis results).

[0191] 2.2. Extension Phase:

[0192] Cohort A (Ovarian Cancer): ①Pathologically diagnosed ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer (high-grade serous carcinoma; endometrioid carcinoma; clear cell carcinoma; mucinous carcinoma; low-grade serous carcinoma), and previous treatment meeting the following criteria: platinum-based drug resistance (duration of response to platinum-based chemotherapy is 3-6 months after the last dose), and no more than 3 lines of treatment have been received in total; or platinum-based drug sensitivity (duration of response to platinum-based chemotherapy is 6 months or longer after the last dose), disease progression after 2 lines of platinum-based drug treatment, and no more than 3 lines of treatment have been received in total; ② Positive FRα expression (based on archived specimens or fresh tumor tissue test results, FRα ≥ 1%).

[0193] Cohort B (Endometrial Cancer): ① Pathologically diagnosed endometrial cancer (endometrioid carcinoma; serous carcinoma; clear cell carcinoma; dedifferentiated / undifferentiated carcinoma; mixed carcinoma; carcinosarcoma; other non-specific carcinomas), and disease recurrence or progression after at least one line of platinum-based chemotherapy or one line of immunotherapy, and with no more than three lines of prior treatment (hormonal therapy is not counted as a line and does not require washout; hormone therapy combined with CDK4 / 6 inhibitors or mTOR or other PI3K pathway inhibitors is not counted as a line), ② Tumor tissue available for detecting FRα expression levels;

[0194] Cohort C (Other Advanced Solid Tumors): ① Patients with histologically or cytologically confirmed advanced or metastatic solid tumors who have failed or are intolerant of standard treatment, such as breast cancer or non-small cell lung cancer. ② Tumor tissue available for detecting FRα expression levels;

[0195] 3. According to RECIST 1.1 criteria, there must be at least one measurable lesion (lesions previously treated with radiotherapy cannot be considered measurable lesions unless the lesion has clearly progressed after radiotherapy);

[0196] 4. ECOG performance status score is 0 or 1;

[0197] 5. Life expectancy greater than 12 weeks;

[0198] 6. Possessing sufficient organ and bone marrow reserves, defined as follows:

[0199] 7. Agree to provide archived pathological tissue or fresh biopsy tumor tissue for FRα and PD-L1 level testing (FRα expression level must be obtained before enrollment, PD-L1 expression level is not a necessary inclusion criterion);

[0200] 8. Female subjects of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose and agree to use effective contraception to prevent pregnancy from the start of the first dose of study treatment until 180 days after the last dose of study treatment; male subjects must agree to use adequate contraception from the start of the first dose of study treatment until 180 days after the last dose of study treatment.

[0201] Exclusion criteria:

[0202] 1. Within 4 weeks prior to the first administration of the investigational drug, the patient had received any other drug clinical trial treatment or participated in a medical device clinical study;

[0203] 2. Patients who have received other anti-tumor treatments within 4 weeks prior to the first administration of the study drug, such as chemotherapy, radiotherapy, targeted therapy / immunotherapy, or hormone therapy (if the drug's 5-fold half-life is less than 4 weeks, the investigator and sponsor may decide whether to include the patient based on its pharmacological characteristics after medical discussion; palliative radiotherapy must be completed within 2 weeks prior to the first administration; hormone replacement therapy is permitted); or who have received lung radiotherapy >30 Gy within 6 months prior to enrollment.

[0204] 3. Underwent major organ surgery (excluding biopsy) within 4 weeks prior to the first use of the investigational drug or have not yet recovered from the surgery, or have experienced significant trauma, or are scheduled to undergo elective surgery during the trial;

[0205] 4. AEs caused by previous anti-tumor treatment have not recovered to CTCAE grade 5.0 ≤ 1, except for the following: a. hair loss; b. pigmentation; c. distal toxicity caused by chemotherapy and radiotherapy that is determined to be irreversible; d. hypothyroidism that has been stabilized by hormone replacement therapy;

[0206] 5. Patients who must take folic acid supplements (e.g., those with folic acid deficiency);

[0207] 6. Subjects with a known history of severe allergies, or subjects who have previously experienced a grade ≥3 allergic reaction to macromolecular protein preparations / monoclonal antibodies;

[0208] 7. Patients who have a history of non-infectious pneumonia requiring glucocorticoid treatment within 2 years prior to enrollment, or who currently have or have not ruled out interstitial pneumonia;

[0209] 8. Individuals who have previously experienced grade ≥3 irAEs or who have previously discontinued immunotherapy due to irAEs;

[0210] 9. A history of drug-related or unspecified grade ≥3 adverse events (graded using CTCAE v5.0) following treatment with any topoisomerase I inhibitor (such as irinotecan);

[0211] 10. Patients with dural metastases or symptomatic brain metastases (asymptomatic brain metastases that have reached clinical control may be included, but must meet the following conditions simultaneously: a. Clinical symptoms have been stable for ≥4 weeks before the first dose; b. No progression of central nervous system disease was found on enhanced cranial MRI within 4 weeks before the first dose; c. Antiepileptic drugs have been discontinued for ≥2 weeks before the first dose, and the prednisone dose is ≤10mg / day or equivalent dose of hormones);

[0212] 11. Patients with poorly controlled cardiovascular disease within 6 months prior to the first administration of the study drug, including but not limited to the following: heart failure of New York Heart Association (NYHA) class III or higher, left ventricular ejection fraction (LVEF) <50%, unstable angina, uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg after optimal antihypertensive therapy), hypertensive crisis or hypertensive encephalopathy, myocardial infarction, severe arrhythmia requiring drug control (patients with atrial fibrillation or supraventricular tachycardia may be considered for inclusion), thrombotic or ischemic stroke, aortic aneurysm or dissecting aneurysm, severe aortic stenosis, etc.

[0213] 12. Patients with uncontrolled pleural effusion, pericardial effusion, or ascites, or those requiring continued drainage;

[0214] 13. Known history of human immunodeficiency virus (HIV) infection;

[0215] 14. Untreated active hepatitis B;

[0216] Note: Hepatitis B subjects who meet the following criteria may also be considered:

[0217] a. The HBV viral load must be <200 IU / ml or <103 copies / ml before the first dose. Researchers should consider administering anti-HBV treatment during the study.

[0218] b. Subjects with anti-HBc(+), HBsAg(-), anti-HBs(-) and HBV viral load(-) do not need to receive prophylactic anti-HBV treatment, but need to be closely monitored for viral reactivation;

[0219] 15. Subjects with active HCV infection (HCV antibody positive and HCV-RNA level above the detection limit);

[0220] 16. Subjects with tuberculosis who are untreated or under treatment, including but not limited to pulmonary tuberculosis; those who have been cured by standard anti-tuberculosis treatment and confirmed by the investigator may be included;

[0221] 17. Any other concurrent infectious disease requiring intravenous antibiotics within 2 weeks prior to the first administration of the study drug;

[0222] 18. Individuals with a history of tissue or organ transplantation surgery;

[0223] 19. History of autoimmune diseases (excluding vitiligo and autoimmune thyroid diseases and type I diabetes that can be treated with hormone replacement therapy);

[0224] 20. Received systemic glucocorticoids (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, short-term use of glucocorticoids for prophylactic treatment (e.g., prevention of contrast agent allergy);

[0225] 21. Those who have received or plan to receive a live / attenuated vaccine within 4 weeks prior to screening during the study period;

[0226] 22. Other active malignancies within 5 years prior to the first dose (this may include locally cured and stable tumors, such as basal cell carcinoma of the skin, low-risk non-muscle-invasive bladder cancer, or breast carcinoma in situ, etc.);

[0227] 23. The subject is pregnant or lactating, or is expected to become pregnant or give birth during the planned study period;

[0228] 24. Subjects with Gilbert's syndrome or any other serious underlying disease (e.g., uncontrolled diabetes, uncontrolled hypertension, active gastric ulcer, uncontrolled seizures, gastrointestinal bleeding, coagulation disorders with severe symptoms or signs, and uncontrolled or requiring continued drainage of pleural effusion, pericardial effusion, or peritoneal effusion), whose mental, psychological, family, or geographical factors, as determined by the investigator or designated personnel, may affect the subject's participation in the study, treatment, and follow-up, affect subject compliance, or may lead to complications related to the study drug;

[0229] 25. Other circumstances where the researcher deems the individual unsuitable to participate in this study.

[0230] Research objectives and endpoints

[0231] Dosage escalation phase

[0232] Main purpose

[0233] To evaluate the safety and tolerability of ADC1 combined with antibody A in patients with advanced solid tumors; to determine the maximum tolerated dose (MTD) of the combination therapy and to provide recommended doses and reasonable dosing regimens for phase II or subsequent clinical studies;

[0234] Secondary objective

[0235] Evaluate the pharmacokinetic (PK) characteristics of ADC1 combined with antibody A;

[0236] Preliminary evaluation of the antitumor activity of ADC1 combined with antibody A;

[0237] Evaluation of the immunogenicity of ADC1 combined with antibody A;

[0238] To evaluate the correlation between programmed death-ligand 1 (PD-L1) expression level, FRα expression level and antitumor activity.

[0239] Primary endpoint

[0240] Tolerability and safety endpoints: vital signs, physical examination, laboratory tests, electrocardiogram, echocardiography, adverse events, dose-limiting toxicity (DLT) events and their incidence, etc.

[0241] Secondary endpoint

[0242] C for single-dose and multiple-dose administration max T max T 1 / 2 AUC (0-∞) wait;

[0243] Objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS);

[0244] Immunogenicity assessment indicators: Anti-drug antibody (ADA) / neutralizing antibody (NAb);

[0245] Correlation between PD-L1 and FRα expression levels in tumor tissues before treatment and efficacy indicators.

[0246] Expansion phase

[0247] Main purpose

[0248] Further evaluation of the safety and tolerability of ADC1 combined with antibody A in advanced ovarian cancer, advanced endometrial cancer, and other advanced solid tumors, to determine the optimal RP2D and dosing regimen for subsequent studies;

[0249] To evaluate the preliminary efficacy of ADC1 combined with antibody A in advanced ovarian cancer, advanced endometrial cancer, or other advanced solid tumors;

[0250] Secondary objective

[0251] Further evaluation of the other clinical benefits of ADC1 combined with antibody A in the treatment of advanced ovarian cancer, advanced endometrial cancer or other advanced solid tumors;

[0252] Evaluate the pharmacokinetic (PK) characteristics of ADC1 combined with antibody A;

[0253] Evaluation of the immunogenicity of ADC1 combined with antibody A;

[0254] To evaluate the correlation between programmed death-ligand 1 (PD-L1) expression level, FRα expression level and antitumor activity.

[0255] Primary endpoint

[0256] Tolerability and safety endpoints: vital signs, physical examination, laboratory tests, electrocardiogram, echocardiography, adverse events and their incidence, etc.

[0257] Clinical efficacy indicator: Objective response rate (ORR);

[0258] Secondary endpoint

[0259] Other clinical efficacy indicators: duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS);

[0260] C for single-dose and multiple-dose administration max T max T 1 / 2 AUC (0-∞) wait;

[0261] Immunogenicity assessment indicators: Anti-drug antibody (ADA) / neutralizing antibody (NAb);

[0262] Correlation between PD-L1 and FRα expression levels in tumor tissues before treatment and efficacy indicators.

[0263] The combined administration of ADC1 and antibody A is expected to have good safety and tolerability, with 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).

[0264] Research findings:

[0265] The study was conducted using dose escalation scheme 2, and the results showed that at an ADC concentration of 184 mg / m²... 2 One case of DLT was observed in the dose group, which was a grade 4 decrease in platelet count; at ADC 193 mg / m² 2Two cases of DLT (disease-related neutropenia) were observed in the dosage group, classified as grade 3 and 4 febrile neutropenia, respectively. The main drug-related adverse reactions (DLTs) associated with the combination therapy included decreased neutrophil count, decreased platelet count, anemia, decreased white blood cell count, nausea, vomiting, constipation, and fatigue; among these, grade ≥3 DLTs were primarily hematological toxicities, including decreased neutrophil count, decreased platelet count, anemia, and decreased white blood cell count. Currently, the safety profile of the combination therapy is similar to that of ADC1 monotherapy, with no new safety signals identified; no investigational drug-related deaths have been reported; and no interstitial lung disease or ocular toxicity has been reported.

[0266] Based on clinical data from dose-escalation studies, ADC1 was selected at 76 mg / m². 2 84mg / m 2 Two doses combined with 300 mg of antibody A were used in dose expansion studies in ovarian cancer, endometrial cancer, and other advanced solid tumors.

[0267] The following is a summary table of patients for whom best treatment outcomes were evaluable as of April 14, 2025:

[0268] The combined administration of ADC1 and antibody A has good safety and tolerability, and has shown promising preliminary efficacy in advanced solid tumors that have previously undergone multiple lines of therapy.

Claims

1. A method for treating tumors, characterized in that, The method includes administering an effective amount of an anti-FRα antibody-drug conjugate and a PD-1 antagonist to a patient in need; the anti-FRα 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: Wherein, Abu is an FRα binding unit. D is a DNA topoisomerase I inhibitor or a salt thereof. n is an integer from 1 to 24. p is 1-10.

2. The method as described in claim 1, characterized in that, 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.

3. The method as described in claim 1, characterized in that, The D is Where X 1 and X 2 Each is independently a C1-C6 alkyl, halogen, or -OH; or the C1-C6 alkyl is -CH3; or the halogen is F; ** is a connection point.

4. A method for treating tumors, characterized in that, The method includes administering an effective amount of an anti-FRα antibody-drug conjugate and a PD-1 antagonist to a patient in need; said anti-FRα antibody-drug conjugate having a structure or stereoisomer of 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, I-17 or I-18, wherein said formulas 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, I-17 and I-18 are: Wherein, Abu is an FRα binding unit. n is an integer from 1 to 24. p is 1-10.

5. The method according to any one of claims 1-4, characterized in that, n is an integer between 4 and 12; or an integer between 4 and 8; or n is 8.

6. The method according to any one of claims 1-5, characterized in that, p is 2-10; or p is 7-8.

7. The method according to any one of claims 1-6, characterized in that, The anti-FRα antibody-drug conjugate has a structure as shown in Formula I-6, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof: Where p is 7-8.

8. The method according to any one of claims 1-7, characterized in that, The Abu is an anti-FRα antibody or its antigen-binding fragment.

9. The method according to any one of claims 1-8, characterized in that, The anti-FRα antibody or its antigen-binding fragment includes VH CDR1 as shown in SEQ ID NO:1, VH CDR2 as shown in SEQ ID NO:2, VH CDR3 as shown in SEQ ID NO:3, VL CDR1 as shown in SEQ ID NO:4, VL CDR2 as shown in SEQ ID NO:5, and VL CDR3 as shown in SEQ ID NO:

6.

10. The method as described in claim 9, characterized in that, The anti-FRα antibody or its antigen-binding fragment further comprises one or more of (g)-(n): (g)VH FR1 contains an amino acid sequence as shown in SEQ ID NO:11, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:11, or an amino acid sequence that has one or more substitutions, deletions or insertions compared with the amino acid sequence shown in SEQ ID NO:

11. (h)VH FR2 contains an amino acid sequence as shown in SEQ ID NO:12, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:12, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:

12. (i) VH FR3 contains an amino acid sequence as shown in SEQ ID NO:13, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:13, or an amino acid sequence that has one or more substitutions, deletions or insertions compared with the amino acid sequence shown in SEQ ID NO:

13. (j)VH FR4 contains an amino acid sequence as shown in SEQ ID NO:14, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:14, or an amino acid sequence that has one or more substitutions, deletions or insertions compared with the amino acid sequence shown in SEQ ID NO:

14. (k)VL FR1 contains an amino acid sequence as shown in SEQ ID NO:15, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:15, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:

15. (l)VL FR2 contains an amino acid sequence as shown in SEQ ID NO:16, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:16, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:

16. (m)VLFR3 contains an amino acid sequence as shown in SEQ ID NO:17, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:17, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:

17. (n)VL FR4 contains an amino acid sequence as shown in SEQ ID NO:18, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:18, or an amino acid sequence that has one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:

18.

11. The method according to any one of claims 1-8, characterized in that, The anti-FRα antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:7, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:7, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:7; and / or The light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:8, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:8, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:

8.

12. The method according to any one of claims 1-8, characterized in that, The anti-FRα antibody comprises a heavy chain and a light chain, wherein: The heavy chain comprises an amino acid sequence as shown in SEQ ID NO:9, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:9, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:9; and / or The light chain comprises an amino acid sequence as shown in SEQ ID NO:10, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:10, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:

10.

13. The method according to any one of claims 1-12, characterized in that, The PD-1 antagonist is an anti-PD-1 antibody or its antigen-binding fragment.

14. The method according to any one of claims 1-13, characterized in that, The anti-PD-1 antibody or its antigen-binding fragment includes VH CDR1 as shown in SEQ ID NO:19, VH CDR2 as shown in SEQ ID NO:20, VH CDR3 as shown in SEQ ID NO:21, VL CDR1 as shown in SEQ ID NO:22, VL CDR2 as shown in SEQ ID NO:23, and VL CDR3 as shown in SEQ ID NO:

24.

15. The method according to any one of claims 1-13, characterized in that, The anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:25, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:25, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:25; and / or The light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:26, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:26, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:

26.

16. The method according to any one of claims 1-13, characterized in that, The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein: The heavy chain comprises an amino acid sequence as shown in SEQ ID NO:27, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:27, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:27; and / or The light chain comprises an amino acid sequence as shown in SEQ ID NO:28, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:28, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:

28.

17. A method for treating tumors, characterized in that, The method includes administering an effective amount of an anti-FRα antibody-drug conjugate and a PD-1 antagonist to a patient in need; the PD-1 antagonist being an anti-PD-1 antibody or its antigen-binding fragment. The anti-PD-1 antibody or its antigen-binding fragment includes VH CDR1 as shown in SEQ ID NO:19, VH CDR2 as shown in SEQ ID NO:20, VH CDR3 as shown in SEQ ID NO:21, VL CDR1 as shown in SEQ ID NO:22, VL CDR2 as shown in SEQ ID NO:23, and VL CDR3 as shown in SEQ ID NO:

24.

18. The method as described in claim 17, characterized in that, The anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:25, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:25, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:25; and / or The light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:26, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:26, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:

26.

19. The method as described in claim 17, characterized in that, The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein: The heavy chain comprises an amino acid sequence as shown in SEQ ID NO:27, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:27, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:27; and / or The light chain comprises an amino acid sequence as shown in SEQ ID NO:28, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:28, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:

28.

20. The method according to any one of claims 17-19, characterized in that, The anti-FRα 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: Equation I-1 is: Equation I-2 is: in Abu is an FRα binding unit. D is a DNA topoisomerase I inhibitor or a salt thereof. n is an integer from 1 to 24. p is 1-10.

21. The method as described in claim 20, characterized in that, 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.

22. The method as described in claim 20, characterized in that, The D is Where X 1 and X 2 Each is independently a C1-C6 alkyl, halogen, or -OH; or the C1-C6 alkyl is -CH3; or the halogen is F; ** is a connection point.

23. The method according to any one of claims 17-22, characterized in that, The anti-FRα antibody-drug conjugate has a structure, stereoisomer, or pharmaceutically acceptable salt or solvate of 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, I-17, or I-18, wherein formulas 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, I-17, and I-18 are: Wherein, Abu is an FRα binding unit. n is an integer from 1 to 24. p is 1-10.

24. The method according to any one of claims 20-23, characterized in that, n is an integer between 4 and 12; or an integer between 4 and 8; or n is 8.

25. The method according to any one of claims 20-24, characterized in that, p is 2-10; or p is 7-8.

26. The method according to any one of claims 17-25, characterized in that, The anti-FRα antibody-drug conjugate has a structure as shown in Formula I-6, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof: Where p is 7-8.

27. The method according to any one of claims 20-26, characterized in that, The Abu is an anti-FRα antibody or its antigen-binding fragment.

28. The method according to any one of claims 20-27, characterized in that, The anti-FRα antibody or its antigen-binding fragment includes VH CDR1 as shown in SEQ ID NO:1, VH CDR2 as shown in SEQ ID NO:2, VH CDR3 as shown in SEQ ID NO:3, VL CDR1 as shown in SEQ ID NO:4, VL CDR2 as shown in SEQ ID NO:5, and VL CDR3 as shown in SEQ ID NO:

6.

29. The method as described in claim 28, characterized in that, The anti-FRα antibody or its antigen-binding fragment further comprises one or more of (g)-(n): (g)VH FR1 contains an amino acid sequence as shown in SEQ ID NO:11, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:11, or an amino acid sequence that has one or more substitutions, deletions or insertions compared with the amino acid sequence shown in SEQ ID NO:

11. (h)VH FR2 contains an amino acid sequence as shown in SEQ ID NO:12, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:12, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:

12. (i) VH FR3 contains an amino acid sequence as shown in SEQ ID NO:13, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:13, or an amino acid sequence that has one or more substitutions, deletions or insertions compared with the amino acid sequence shown in SEQ ID NO:

13. (j)VH FR4 contains an amino acid sequence as shown in SEQ ID NO:14, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:14, or an amino acid sequence that has one or more substitutions, deletions or insertions compared with the amino acid sequence shown in SEQ ID NO:

14. (k)VL FR1 contains an amino acid sequence as shown in SEQ ID NO:15, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:15, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:

15. (l)VL FR2 contains an amino acid sequence as shown in SEQ ID NO:16, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:16, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:

16. (m)VLFR3 contains an amino acid sequence as shown in SEQ ID NO:17, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:17, or an amino acid sequence that has one or more sites of substitution, deletion or insertion compared with the amino acid sequence shown in SEQ ID NO:

17. (n)VL FR4 contains an amino acid sequence as shown in SEQ ID NO:18, or an amino acid sequence that has at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:18, or an amino acid sequence that has one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:

18.

30. The method according to any one of claims 20-27, characterized in that, The anti-FRα antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:7, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:7, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:7; and / or The light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:8, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:8, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:

8.

31. The method according to any one of claims 20-27, characterized in that, The anti-FRα antibody comprises a heavy chain and a light chain, wherein: The heavy chain comprises an amino acid sequence as shown in SEQ ID NO:9, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:9, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:9; and / or The light chain comprises an amino acid sequence as shown in SEQ ID NO:10, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:10, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence shown in SEQ ID NO:

10.

32. The method according to any one of claims 1-31, characterized in that, The anti-FRα antibody-drug conjugate is administered at a dose of approximately 5 mg / m² per administration. 2 Approximately 150 mg / m 2 or about 30mg / m 2 Approximately 120 mg / m 2 or about 50mg / m 2 Approximately 120 mg / m 2 or about 70mg / m 2 Approximately 100 mg / m 2 or approximately 75 mg / m 2 Approximately 93 mg / m 2 Or approximately 76 mg / m³ 2 Approximately 93 mg / m 2 .

33. The method according to any one of claims 1-32, characterized in that, The anti-FRα antibody-drug conjugate is administered at a dose of approximately 75 mg / m² per administration. 2 Approximately 76 mg / m 2 Approximately 84 mg / m 2 or approximately 93 mg / m 2 .

34. The method according to any one of claims 1-33, characterized in that, The PD-1 antagonist is administered in doses of about 50 to about 600 mg, or about 100 to about 500 mg, or about 200 to about 400 mg; for example, about 300 mg.

35. The method according to any one of claims 1-34, characterized in that, The anti-FRα antibody-drug conjugate and / or PD-1 antagonist are administered once every 1-8 weeks, or once every 2-4 weeks; for example, once every 3 weeks.

36. The method according to any one of claims 1-35, characterized in that, The anti-FRα antibody-drug conjugate is administered at a dose of approximately 70 mg / m² per administration. 2 Approximately 100 mg / m 2 The PD-1 antagonist is administered once every 2-4 weeks, for example, once every 3 weeks; the dose of the PD-1 antagonist is about 200 mg to about 400 mg each time, administered once every 2-4 weeks, for example, once every 3 weeks.

37. The method according to any one of claims 1-36, characterized in that, The anti-FRα antibody-drug conjugate is administered at a dose of approximately 75 mg / m² per administration. 2 The PD-1 antagonist is administered once every 2-4 weeks, for example once every 3 weeks, at a dose of approximately 300 mg per administration.

38. The method according to any one of claims 1-36, characterized in that, The anti-FRα antibody-drug conjugate is administered at a dose of approximately 76 mg / m² per administration. 2 The PD-1 antagonist is administered once every 2-4 weeks, for example once every 3 weeks, at a dose of approximately 300 mg per administration.

39. The method according to any one of claims 1-36, characterized in that, The anti-FRα antibody-drug conjugate is administered at a dose of approximately 84 mg / m² per administration. 2 The PD-1 antagonist is administered once every 2-4 weeks, for example once every 3 weeks, at a dose of approximately 300 mg per administration.

40. The method according to any one of claims 1-36, characterized in that, The anti-FRα antibody-drug conjugate is administered at a dose of approximately 93 mg / m² per administration. 2 The PD-1 antagonist is administered once every 2-4 weeks, for example once every 3 weeks, at a dose of approximately 300 mg per administration.

41. The method according to any one of claims 1-40, characterized in that, The tumor was an advanced solid tumor.

42. The method according to any one of claims 1-41, characterized in that, The tumors are selected from colorectal cancer, lung cancer (e.g., non-small cell lung cancer), ovarian cancer, endometrial cancer, peritoneal cancer, fallopian tube cancer, pancreatic cancer, nasopharyngeal cancer, laryngeal cancer, liver cancer, breast cancer, brain cancer, kidney cancer (e.g., renal cell carcinoma), colon cancer, testicular cancer, cervical cancer, tongue cancer, bladder cancer, retinoblastoma, glioblastoma, mesothelioma, oral epithelioid carcinoma, choriocarcinoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), melanoma (e.g., malignant metastatic melanoma), prostate cancer (e.g., hormone-resistant prostate adenocarcinoma), esophageal cancer, thyroid cancer, glioblastoma, and glioma.

43. The method according to any one of claims 1-42, characterized in that, The tumors were selected from non-small cell lung cancer, ovarian cancer, endometrial cancer, and breast cancer.

44. The method according to any one of claims 1-43, characterized in that, The tumor is a FRα-positive tumor.

45. The method according to any one of claims 1-44, characterized in that, The tumor was an ovarian cancer that expressed FRα.

46. ​​The method according to any one of claims 1-45, characterized in that, The patient had a metastatic or locally advanced unresectable tumor that was diagnosed histologically or cytologically as unsuitable for local treatment.

47. The method according to any one of claims 1-46, characterized in that, The patient no longer benefits from or is unsuitable for standard treatment.

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