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

Abstract

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

Description

Application of anti-FRα antibody-drug conjugates and VEGF 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 VEGF antagonists in the treatment of tumors. Background Technology

[0002] Chemotherapy remains an important treatment for advanced cancers, but 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 VEGF antagonist for treating tumors, comprising administering an effective amount of the anti-FRα antibody-drug conjugate and the VEGF antagonist to a patient in need. In one aspect, this invention provides the use of the anti-FRα antibody-drug conjugate and the VEGF 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 VEGF antagonist in combination for treating tumors. In another aspect, this invention provides a pharmaceutical composition of the anti-FRα antibody-drug conjugate and the VEGF 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 VEGF antagonist. In yet another aspect, this invention provides the use of the VEGF antagonist in the preparation of a medicament for treating tumors in combination with an anti-FRα antibody-drug conjugate. In yet another aspect, this invention provides the use of the anti-FRα antibody-drug conjugate in combination with a VEGF antagonist for treating tumors. On the one hand, the present invention provides the use of VEGF 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 anti-FRα antibody or its antigen-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, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24.

[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 independently F, Cl, Br, or I.

[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 4. 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 6-9. 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 anti-FRα antibody or its antigen-binding unit.

[0028] n is an integer from 1 to 24, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24.

[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 4. 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 6-9. In one or more embodiments, p is 7-8.

[0032] In one or more embodiments, the anti-FRα antibody or its antigen-binding unit comprises one or more of (a)-(f):

[0033] (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;

[0034] (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;

[0035] (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;

[0036] (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;

[0037] (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.

[0038] (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.

[0039] In one or more embodiments, the anti-FRα antibody or its antigen-binding unit 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.

[0040] In one or more embodiments, the anti-FRα antibody or its antigen-binding unit 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.

[0041] In one or more embodiments, the anti-FRα antibody or its antigen-binding unit 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.

[0042] In one or more embodiments, the anti-FRα antibody or its antigen-binding unit 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, 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.

[0043] In one or more embodiments, the anti-FRα antibody or its antigen-binding unit comprises a heavy chain variable region (VH) and / or a light chain variable region (VL), wherein:

[0044] 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

[0045] 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.

[0046] In one or more embodiments, the anti-FRα antibody or its antigen-binding unit 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.

[0047] In one or more embodiments, the anti-FRα antibody comprises a heavy chain (H) and a light chain (L).

[0048] 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

[0049] 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.

[0050] 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.

[0051] In one or more embodiments, the anti-FRα antibody is antibody 1.

[0052] Table 1. Amino acid sequence of anti-FRα antibody

[0053] In one or more embodiments, the anti-FRα antibody has two identical heavy chains and two identical light chains.

[0054] In one or more embodiments, the site substitution, deletion, or insertion is independent of one, two, or three.

[0055] In one or more embodiments, the substitution is a conserved amino acid substitution.

[0056] In one or more embodiments, the antibody or its antigen-binding unit is chimeric, humanized, or fully human.

[0057] 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).

[0058] 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:

[0059] in

[0060] Abu is antibody 1.

[0061] p is 7-8.

[0062] In one or more embodiments, the VEGF antagonist is an anti-VEGF antibody.

[0063] In one or more embodiments, the anti-VEGF antibody is bevacizumab. In one or more embodiments, the bevacizumab may be Avastin, Prevotol, Pyruvate, Betaine, Henbeta, Eritrexate, Brono, Dysiocin, Avzivi, Alymsys, Zirabev, Mvasi, Vegzelma, Onbevzi, Oyavas, Aybintio, or Abevmy.

[0064] 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 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 75 mg / m2 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 The values ​​may be, or a range (including endpoints) between any two of these values, or any value therein. In one or more embodiments, the anti-FRα antibody-drug conjugate is a single-dose administration. In one or more embodiments, it is administered once every 1-8 weeks. In one or more embodiments, it is administered once every 2-4 weeks. In one or more embodiments, it is administered once 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 once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, or once every 7 weeks. In one or more embodiments, it is administered once every 3 weeks. The dosing window may be ±3 days from the second dose.

[0065] 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 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 75 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 2Or, 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. 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 .

[0066] 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 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 75 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, the anti-FRα antibody-drug conjugate (e.g., ADC1) described herein is administered at approximately 84 mg / m² every 3 weeks. 2In 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 .

[0067] 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 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 .

[0068] In one or more embodiments, the VEGF antagonist (e.g., bevacizumab) is administered at a dose of about 1 mg / kg to about 15 mg / kg per administration. In one or more embodiments, the VEGF antagonist (e.g., bevacizumab) is administered at a dose of about 10 mg / kg to about 20 mg / kg per administration. In one or more embodiments, the VEGF antagonist (e.g., bevacizumab) is administered at a dose of about 5 mg / kg to about 10 mg / kg per administration. In one or more embodiments, the VEGF antagonist (e.g., bevacizumab) is administered at a dose of about 1 mg / kg, about 5 mg / kg, about 7.5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg per administration, or a range (including endpoints) of any two of these values, or any value therein. In one or more embodiments, the VEGF antagonist 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, the drug is administered once 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, the drug is administered once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, or once every 7 weeks. In one or more embodiments, the drug is administered once every 3 weeks. In one or more embodiments, starting from the second dose, the dosing window may be within ±3 days of the prescribed dosing date.

[0069] In one or more embodiments, the VEGF antagonist described herein (e.g., bevacizumab) is administered once every 2-4 weeks at approximately 1 mg / kg to approximately 15 mg / kg, or approximately 10 mg / kg to approximately 20 mg / kg, or approximately 5 mg / kg to approximately 10 mg / kg, or a formulation containing this dose of the VEGF antagonist (e.g., bevacizumab). In one or more embodiments, the VEGF antagonist described herein (e.g., bevacizumab) is administered once every 2-4 weeks at approximately 1 mg / kg, approximately 5 mg / kg, approximately 7.5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, approximately 20 mg / kg, or a range (including endpoints) of any two of these values, or any value thereof, or a formulation containing this dose of the VEGF antagonist (e.g., bevacizumab). In one or more embodiments, the VEGF antagonist described herein (e.g., bevacizumab) is administered once every 2-4 weeks at approximately 7.5 mg / kg. In one or more embodiments, the VEGF antagonist described herein (e.g., bevacizumab) is administered at approximately 15 mg / kg every 2-4 weeks.

[0070] In one or more embodiments, a VEGF antagonist (e.g., bevacizumab) of about 1 mg / kg to about 15 mg / kg, or about 10 mg / kg to about 20 mg / kg, or about 5 mg / kg to about 10 mg / kg, or a formulation containing this dose of VEGF antagonist (e.g., bevacizumab), is administered every 3 weeks. In one or more embodiments, a VEGF antagonist (e.g., bevacizumab) of about 1 mg / kg, about 5 mg / kg, about 7.5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or a range (including endpoints) of any two of these values, or any value thereof, or a formulation containing this dose of VEGF antagonist (e.g., bevacizumab), is administered every 3 weeks. In one or more embodiments, a VEGF antagonist (e.g., bevacizumab) of about 7.5 mg / kg is administered every 3 weeks. In one or more embodiments, the VEGF antagonist described herein (e.g., bevacizumab) is administered at approximately 15 mg / kg every 3 weeks.

[0071] In one or more embodiments, bevacizumab described herein is administered at a dose of about 10 mg / kg to about 20 mg / kg every 2-4 weeks. In one or more embodiments, bevacizumab described herein is administered at a dose of about 5 mg / kg to about 10 mg / kg every 2-4 weeks. In one or more embodiments, bevacizumab described herein is administered at a dose of about 7.5 mg / kg every 3 weeks. In one or more embodiments, bevacizumab described herein is administered at a dose of about 15 mg / kg every 3 weeks.

[0072] 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 ; administer bevacizumab described in this article at a dose of approximately 5 mg / kg to approximately 10 mg / kg every 2-4 weeks.

[0073] 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 ; administer bevacizumab described in this article at a dose of approximately 10 mg / kg to approximately 20 mg / kg every 2-4 weeks.

[0074] In one or more embodiments, the ADC1 described herein is administered at approximately 84 mg / m² every 3 weeks. 2 The bevacizumab described in this article is administered once every 3 weeks at a dose of approximately 7.5 mg / kg.

[0075] In one or more embodiments, the ADC1 described herein is administered at approximately 93 mg / m² every 3 weeks. 2 The bevacizumab described in this article is administered once every 3 weeks at a dose of approximately 7.5 mg / kg.

[0076] In one or more embodiments, the ADC1 described herein is administered at approximately 84 mg / m² every 3 weeks. 2 The bevacizumab described in this article is administered once every 3 weeks at a dose of approximately 15 mg / kg.

[0077] In one or more embodiments, the ADC1 described herein is administered at approximately 93 mg / m² every 3 weeks. 2 The bevacizumab described in this article is administered once every 3 weeks at a dose of approximately 15 mg / kg.

[0078] 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 VEGF antagonist are prepared as a single pharmaceutical composition (e.g., a combination formulation) and administered simultaneously to a patient in need of the anti-FRα antibody-drug conjugate and VEGF antagonist. In one or more embodiments, the anti-FRα antibody-drug conjugate and VEGF antagonist are prepared as separate pharmaceutical compositions and administered simultaneously to a patient in need of the anti-FRα antibody-drug conjugate and VEGF antagonist, or administered at different times during a treatment regimen. For example, the anti-FRα antibody-drug conjugate may be administered before, after, or in an alternating manner with the VEGF antagonist. In this document, the anti-FRα antibody-drug conjugate and VEGF antagonist may be administered to a patient in need of the anti-FRα antibody-drug conjugate in a single dose or in multiple doses.

[0079] 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.

[0080] In one or more embodiments, in the method and use for treating tumors provided by the present invention, the anti-FRα antibody-drug conjugate and VEGF antagonist can be administered via any convenient route, such as by infusion or bolus injection, absorption through epithelial or skin mucosa (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 VEGF 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 pharmaceutical preparations used for the anti-FRα antibody-drug conjugate and / or VEGF 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.

[0081] In one or more embodiments, the anti-FRα antibody-drug conjugate and VEGF 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, about 90 minutes, about 100 minutes, about 110 minutes, or about 120 minutes, or a range (including endpoints) between any two of these values, or any value thereof. In one or more embodiments, the duration of the intravenous infusion is 90 ± 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 90 ± 10 minutes, and subsequent intravenous infusions last 30 to 60 minutes.

[0082] In one or more embodiments, the tumor is a solid tumor. In one or more embodiments, the tumor is cancer. In one or more embodiments, the tumor is ovarian cancer. In one or more embodiments, the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In one or more embodiments, the ovarian cancer is advanced ovarian cancer. In one or more embodiments, the ovarian cancer is recurrent and / or refractory ovarian cancer. In one or more embodiments, the ovarian cancer is platinum-sensitive or platinum-resistant ovarian cancer. In one or more embodiments, the ovarian cancer is platinum-sensitive ovarian cancer. In one or more embodiments, the ovarian cancer is platinum-sensitive recurrent ovarian cancer. In one or more embodiments, the ovarian cancer is selected from high-grade serous epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In one or more embodiments, the patient has serous ovarian cancer or ovarian cancer that is predominantly serous. In one or more embodiments, the patient has high-grade serous ovarian cancer or ovarian cancer that is predominantly high-grade serous. In one or more embodiments, the patient has high-grade serous epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In one or more embodiments, the patient has previously received at least two lines of platinum-based chemotherapy. In one or more embodiments, the patient has previously received at least two lines of platinum-based chemotherapy, and for the penultimate line of platinum-based chemotherapy, the patient achieved a CR, PR, or SD response at the end of chemotherapy; or the patient has platinum-sensitive recurrent ovarian cancer when ovarian cancer recurs after the completion of that course of chemotherapy. Platinum-sensitive recurrence is defined as disease progression occurring at least 6 months after the completion of platinum-based chemotherapy. In one or more embodiments, the patient has previously received at least two lines of platinum-based chemotherapy. In one or more embodiments, for last-line platinum-based chemotherapy, the patient has received 4–8 cycles of a platinum-based, bevacizumab-containing three-drug chemotherapy regimen (e.g., at least 3 cycles containing bevacizumab) or, if receiving less than 6 cycles of chemotherapy, has no intolerance to bevacizumab; or the patient's response to this first-line chemotherapy is CR, PR, or SD; or CA-125 is within the normal range after chemotherapy or CA-125 decreases by >90% during the chemotherapy cycle and lasts for at least 7 days, and the increase in CA-125 before treatment with this method is no more than 15% relative to CA-125 after chemotherapy; or the patient is within 8 weeks after the completion of last-line platinum-based chemotherapy. In one or more embodiments, the patient is BRCA-negative. In one or more embodiments, the patient is BRCA-positive. In one or more embodiments, the BRCA-positive patient received maintenance therapy with poly(ADP-ribose) polymerase inhibitors (PARPi) after / during first-line treatment.In one or more embodiments, the patient has previously received first-line platinum-based chemotherapy and is in a platinum-sensitive population, and is currently receiving second-line platinum-based therapy. In one or more embodiments, for second-line platinum-based therapy, the patient has received 4 to 8 cycles of treatment, with at least 3 cycles containing bevacizumab; or the patient is within 9 weeks of the completion of their last chemotherapy session. In one or more embodiments, the patient's treatment outcome is assessed as CR, PR, or SD within 3 to 9 weeks after completion of chemotherapy. In one or more embodiments, the platinum-based therapy includes platinum-based drugs and one or more of paclitaxel, liposomal doxorubicin (PLD), gemcitabine, and bevacizumab. In one or more embodiments, the platinum-based therapy is a three-drug regimen including platinum-based drugs, bevacizumab and paclitaxel, liposomal doxorubicin (PLD), and gemcitabine. In one or more embodiments, the patient has received surgical treatment and chemotherapy containing at least 2 cycles of bevacizumab.

[0083] In one or more embodiments, the cancer is cancer with FRα expression ≥1%. In one or more embodiments, the cancer is cancer with FRαTPS (tumor cell positivity fraction) ≥1%. In one or more embodiments, the cancer is cancer with FRα expression >25%. In one or more embodiments, the cancer is cancer with FRαTPS (tumor cell positivity fraction) >25%. In one or more embodiments, the cancer is detected (e.g., by immunohistochemistry (IHC), flow cytometry, or nucleic acid hybridization) having FRαTPS >25%. In one or more embodiments, the cancer is cancer with FRα expression <50%. In one or more embodiments, the cancer is cancer with FRαTPS <50%. In one or more embodiments, the cancer is cancer with FRα expression ≥50%. In one or more embodiments, the cancer is cancer with FRαTPS ≥50%. In one or more embodiments, the cancer is cancer with FRα expression ≥50% and <75%. In one or more embodiments, the cancer is cancer with FRα expression ≥75%. In one or more embodiments, the cancer is cancer with FRαTPS ≥75%.

[0084] In one or more embodiments, the cancer is ovarian cancer with FRαTPS > 25%. In one or more embodiments, the ovarian cancer is detected (e.g., by immunohistochemistry) having FRαTPS > 25%. In one or more embodiments, the cancer is FRαTPS > 50%. In one or more embodiments, the ovarian cancer is detected (e.g., by immunohistochemistry) having FRαTPS > 50%. In one or more embodiments, the cancer is ovarian cancer with FRα expression < 50%. In one or more embodiments, the cancer is ovarian cancer with FRαTPS < 50%. In one or more embodiments, the cancer is ovarian cancer with FRα expression ≥ 50%. In one or more embodiments, the cancer is ovarian cancer with FRαTPS ≥ 50%. In one or more embodiments, the cancer is ovarian cancer with FRα expression ≥ 50% and < 75%. In one or more embodiments, the cancer is ovarian cancer with FRα expression ≥ 75%. In one or more embodiments, the cancer is ovarian cancer with FRαTPS ≥ 75%.

[0085] In one or more embodiments, the patient has FRα expression ≥1%. In one or more embodiments, the patient has FRα TPS ≥1%. In one or more embodiments, the patient has FRα expression >25%. In one or more embodiments, the patient has FRα TPS >25%. In one or more embodiments, the patient is detected (e.g., by immunohistochemistry, flow cytometry, or nucleic acid hybridization) to have FRα TPS >25%. In one or more embodiments, the patient is detected to have FRα TPS >50%. In one or more embodiments, the patient has FRα expression <50%. In one or more embodiments, the patient has FRα TPS <50%. In one or more embodiments, the patient has FRα expression ≥50%. In one or more embodiments, the patient has FRα TPS ≥50%. In one or more embodiments, the patient has FRα TPS ≥50% and <75%. In one or more embodiments, the patient has FRα expression ≥75%. In one or more embodiments, the patient has FRα TPS ≥75%.

[0086] In one or more embodiments, the anti-FRα antibody-drug conjugate and VEGF antagonist treatment is maintenance therapy. In one or more embodiments, the anti-FRα antibody-drug conjugate and VEGF antagonist treatment is maintenance therapy following chemotherapy (e.g., platinum-based chemotherapy). In one or more embodiments, the patient's CA-125 is within the normal range at the time of initial treatment with the anti-FRα antibody-drug conjugate and VEGF antagonist. In one or more embodiments, the patient's CA-125 decreases by >90% during the chemotherapy cycle. In one or more embodiments, the patient's CA-125 at the time of initial treatment with the anti-FRα antibody-drug conjugate and VEGF antagonist is no more than 15% higher than the CA-125 at the end of chemotherapy. In one or more embodiments, the patient has at least one measurable lesion as defined by RECIST v1.1 and achieves PR or SD. In one or more embodiments, the patient has no measurable lesions (may have / may not have unmeasurable lesions) and achieves PR or SD, but CA-125 remains elevated. In one or more embodiments, the patient achieves CR, has no lesions, and CA-125 is normal.

[0087] In one or more embodiments, the combination of the anti-FRα antibody-drug conjugate and the VEGF antagonist of the present invention exhibits good safety and tolerability. In some embodiments, the combination of the anti-FRα antibody-drug conjugate and the VEGF 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 VEGF 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), overall survival (OS), and health-related quality of life (HRQoL).

[0088] 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 VEGF antagonist. The percentage can vary, for example, from about 2% to 90% by weight of a given dosage form. Attached Figure Description

[0089] Figure 1 shows the tumor growth curves of tumor-bearing mice with human ovarian cancer OV90 subcutaneous xenograft tumor model after treatment with the test drug; the data points represent the mean tumor volume within the group, and the error bars represent the standard error (SEM); the tumor volume of all mice after euthanasia was calculated based on the tumor volume on the day of euthanasia; mpk in the figure represents mg / kg.

[0090] Figure 2 shows the survival rate curves of tumor-bearing mice in the OV90 subcutaneous xenograft model of human ovarian cancer after treatment with the test drug. Detailed Implementation

[0091] 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.

[0092] definition

[0093] 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.

[0094] 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.

[0095] "Approximately" refers to a typical error range for a given 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%.

[0096] "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.

[0097] 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 can inhibit tumor growth (e.g., inhibit an increase in tumor volume); reduce tumor growth (e.g., reduce tumor volume); reduce the number of cancer cells; and / or alleviate one or more symptoms associated with cancer to some extent. For example, an effective amount can improve progression-free survival (PFS), improve overall survival (OS), or reduce the likelihood of recurrence.

[0098] 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.

[0099] A “VEGF antagonist” is any agent that binds to or interacts with VEGF, inhibiting the binding of VEGF to its receptors (VEGFR1 and VEGFR2) and / or inhibiting the biological signaling and activity of VEGF. VEGF antagonists comprise molecules that interfere with the interaction between VEGF and its native VEGF receptor, for example, molecules that bind to VEGF or its receptor and block or otherwise impede the interaction between VEGF and its receptor. Specific exemplary VEGF antagonists include anti-VEGF antibodies (e.g., bevacizumab), anti-VEGF receptor antibodies (e.g., anti-VEGFR1 antibodies, anti-VEGFR2 antibodies, etc.), small molecule inhibitors of VEGF (e.g., sunitinib), and VEGF receptor-based chimeric molecules or VEGF-inhibiting fusion proteins, such as aflibercept. Other examples of VEGF antagonists can be found in U.S. Patents US7,070,959, US7,306,799, US7,374,757, US7,374,758, US7,531,173, US7,608,261, US5,952,199, US6,100,071, US6,383,486, US6,897,294, and US7,771,721, which are incorporated herein by reference.

[0100] Chemotherapy, or chemotherapy, is a method of treating cancer by using potent chemicals to kill rapidly growing cells in the body or to stop their growth and spread. Chemotherapy includes, but is not limited to, chemotherapeutic alkylating agents that interfere with the DNA and / or RNA of cancer cells to prevent their replication, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, and mitomycin inhibitors that prevent cancer cells from dividing and forming new cells.

[0101] Platinum-based chemotherapy refers to chemotherapy regimens that use chemotherapy drugs containing platinum, such as cisplatin or carboplatin. Platinum-based drugs are commonly used in chemotherapy; they work by binding to DNA within cells, inhibiting DNA replication and transcription, thereby preventing the growth and division of cancer cells.

[0102] 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), i.e., ORR = CR + PR.

[0103] 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.

[0104] Disease control rate (DCR): The percentage of cases that achieve remission (PR+CR) and stable disease (SD) after treatment out of the evaluable cases, i.e., DCR = CR + PR + SD.

[0105] Progression-free survival (PFS): The time from the first dose to the first recorded time of disease progression or death from any cause that meets the RECIST 1.1 disease progression criteria (whichever occurs first).

[0106] 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.

[0107] The Eastern Cooperative Oncology Group (ECOG) has developed a simplified activity status scoring system that classifies patients' activity status into 6 levels, from 0 to 5. The ECOG activity status scoring system uses scores of 0, 1, 2, 3, 4, and 5.

[0108] Single-dose pharmacokinetic parameters: C max T max T 1 / 2 CL, Vd, Ke, MRT, AUC (0-τ) AUC (0-∞) ;

[0109] Multiple-dose pharmacokinetic parameters: C max,ss C avg,ss C min,ss AUC (0-τ)ss AUC (0-∞)ss T max,ss T 1 / 2,ss CL, V ss Ke, MRT, accumulation index (R) ac ), Volatility Index (DF).

[0110] 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.

[0111] The term "drug-antibody conjugation ratio" or "DAR" refers to the amount of drug (e.g., eczemab) 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 amount of drug 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 9, or about 7 to about 8. DAR values ​​may be expressed as p herein. The DAR value of ADC can be determined using methods such as 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).

[0112] "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.

[0113] Various substituents are defined as follows.

[0114] "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).

[0115] "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.

[0116] 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.

[0117] 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)).

[0118] All publications and patents cited in this document are incorporated herein by reference for all purposes.

[0119] Example

[0120] Unless otherwise specified, the materials and reagents used in the following examples can be obtained commercially or by known methods.

[0121] According to the preparation method of ADC1 described in patent WO2023 / 116911, an anti-FRα antibody-drug conjugate (hereinafter referred to as ADC1) is prepared. The structure of ADC1 is shown in Formula I-6, where Abu is antibody 1, which contains 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.

[0122] Example 1: In vivo efficacy study of bevacizumab and ADC1 in a female Balb / c nude mouse model of subcutaneous xenograft human ovarian cancer OV90 tumor.

[0123] Subcutaneous injection of 5×10⁵ cells into the right nape of the neck of female Balb / c nude mice (6-8 weeks old) 6 The average tumor volume of the individual ovarian cancer cell line OV90 (ATCC-CRL-11732) reached 144 mm² on day 14 post-cell seeding. 3 When the animals were divided into groups, drug administration began (see Table 2). The day of grouping was recorded as D0, and drug administration started on D1. The health status and mortality of the animals were monitored daily. Routine checks included observing tumor growth and the effects of drug treatment on the animals' daily behavior, such as activity levels, food and water intake, weight changes (measured twice weekly), physical appearance, or other abnormalities. The number of deaths and side effects within each group was recorded based on the number of animals in each group. Mice with tumor volumes exceeding 3000 mm² were considered at risk. 3 He was euthanized.

[0124] The formula for calculating tumor volume is: Tumor volume (mm²) 3 )=0.5a×b 2 , where a and b represent the long and short diameters of the tumor, respectively.

[0125] Relative tumor volume (RTV): The formula is RTV = V t / V0, where V0 is the tumor volume of the animal at the time of group administration (i.e., D0), V t This represents the tumor volume of the animal at a particular measurement.

[0126] Relative tumor proliferation rate T / C (%): The calculation formula is T / C% = T RTV / C RTV ×100%, T RTV C represents the average RTV of the treatment group at a given measurement. RTV T represents the average RTV of the negative control group during a specific measurement. RTV With C RTV Take data from the same day.

[0127] Tumor growth inhibition rate (TGI%): The calculation formula is TGI% = (1 - T / C) × 100%.

[0128] Table 2. Animal grouping and administration regimen for in vivo efficacy studies of bevacizumab and ADC1. Note: Vehicle is physiological saline.

[0129] Figure 1 shows the tumor growth curves in tumor-bearing mice with a human ovarian cancer OV90 subcutaneous xenograft tumor model after treatment with the test product. Table 3 shows the in vivo efficacy evaluation of the test product in the human ovarian cancer OV90 subcutaneous xenograft tumor model.

[0130] Table 3. In vivo efficacy evaluation of bevacizumab and ADC1 in a human ovarian cancer OV90 subcutaneous xenograft tumor model (calculated based on D46 tumor volume).

[0131] a. Average value ± SEM;

[0132] The bp value was calculated based on the tumor volume. The difference in efficacy between the test drug group and the solvent control group (group 1) was analyzed using one-way ANOVA. ** represents p<0.01, *** represents p<0.001, and **** represents p<0.0001.

[0133] On day 46 after grouping, the tumor volume of tumor-bearing mice in the solvent control group reached 2307 mm3, while the ADC in the single-drug administration group was 11.8 mg / kg (tumor volume = 608 mm3). 3 TGI = 73.69%, T / C = 26.31%, p < 0.0001; ADC in the single-drug group was 13.6 mg / kg (tumor volume = 338 mmHg). 3 TGI = 85.42%, T / C = 14.58%, p < 0.0001; in the combination therapy group, ADC1 + bevacizumab 1.8 mg / kg + 5 mg / kg (tumor volume = 474 mmHg) was administered. 3 TGI = 79.38%, T / C = 20.62%, p < 0.0001) and the combination therapy group ADC1 + bevacizumab 3.6 mg / kg + 5 mg / kg (tumor volume = 79 mm) 3 (TGI = 96.45%, T / C = 3.55%, p < 0.0001), both showed significant tumor-suppressing effects compared with the solvent control group.

[0134] Figure 2 shows the survival curves of bevacizumab and ADC1 in different groups of tumor-bearing mice with subcutaneous xenograft tumors of human ovarian cancer OV90. 3As the endpoint of the mouse experiment, except for groups 1 and 2, all tumor-bearing mice in the other groups survived on day 56.

[0135] Example 2: A randomized, open-label, multicenter phase II / III clinical trial evaluating the efficacy and safety of ADC1 combined with bevacizumab versus bevacizumab monotherapy as maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.

[0136] The study is divided into two parts:

[0137] Part 1 is a Phase II study to determine the safety of ADC1 in combination with bevacizumab. ADC1 plus bevacizumab group (combination group): ADC1: 84 mg / m² 2 And bevacizumab: 7.5 mg / kg.

[0138] Part II is a Phase III study comparing the efficacy and safety of either the ADC1 plus bevacizumab group (combination group) or the bevacizumab monotherapy group (monotherapy group). Combination group: ADC1: 84 mg / m² 2 Bevacizumab: 7.5 mg / kg; Monotherapy group: bevacizumab 7.5 mg / kg.

[0139] Dosage regimen:

[0140] Both ADC1 and bevacizumab are administered via intravenous infusion. The initial infusion time is 90±10 minutes for each. If there are no safety issues, it is recommended that subsequent infusions be administered over 30 to 60 minutes every 3 weeks (Q3W).

[0141] Inclusion criteria

[0142] 1. Females aged 18 years or older;

[0143] 2. Having histologically confirmed high-grade serous or predominantly high-grade serous ovarian cancer (including primary peritoneal cancer and fallopian tube cancer);

[0144] 3. The patient must be willing to provide archived or fresh tumor tissue specimens to confirm the FRα expression level;

[0145] 4. Patients who have previously undergone somatic or germline testing for BRCA and are BRCA-positive must have received PARPi maintenance therapy after / during first-line treatment;

[0146] 5. Has previously received at least two lines of platinum-based chemotherapy, and meets the following requirements for each:

[0147] 5-1. For penultimate line platinum-based chemotherapy, patients need to meet the following requirements: ① At the end of chemotherapy, the patient's treatment effect of this line of chemotherapy is CR, PR or SD; ② When the patient has ovarian cancer recurrence after the end of this course of chemotherapy, it must be platinum-sensitive recurrent ovarian cancer, that is, the patient's disease progression occurs 6 months after the end of this course of chemotherapy (medical records show 6-12 months or ≥12 months).

[0148] 5-2. For the last-line platinum-based chemotherapy for platinum-sensitive recurrent ovarian cancer mentioned above, the following conditions must be met: ① The patient has received 4–8 cycles of a three-drug chemotherapy regimen consisting of platinum-based and bevacizumab-based drugs (at least 3 cycles of bevacizumab). If the patient has received less than 6 cycles of chemotherapy, bevacizumab intolerance must be ruled out (this must be recorded in the medical record). ② The patient's response to this first-line chemotherapy is CR, PR, or SD. ③ After chemotherapy, CA-125 is within the normal range or CA-125 decreases by >90% during the chemotherapy cycle and lasts for at least 7 days, and the increase in CA-125 before enrollment is no more than 15% relative to the CA-125 after chemotherapy. ④ The patient must complete (randomization) enrollment within 8 weeks after the completion of the last-line platinum-based chemotherapy.

[0149] 6. ECOG performance status score is 0 or 1;

[0150] 7. Possesses sufficient organ and bone marrow reserves;

[0151] 8. Women of reproductive age who have a negative pregnancy test result at enrollment and commit to using adequate and effective contraception or abstaining from sexual intercourse during the study period and for 3 months after the last administration of study medication are eligible to enroll in this study. Alternatively, women without potential fertility may be enrolled, defined as any of the following: ① women who have undergone surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy); or ② women ≥60 years of age; ③ women ≥40 and <60 years of age, who have been menopausal for more than 12 months, and whose follicle-stimulating hormone (FSH) test results are within the postmenopausal reference range of the study institution.

[0152] Exclusion criteria

[0153] 1. Individuals who have undergone major organ surgery (level 3-4 surgery) or have not yet recovered from surgery within 4 weeks prior to enrollment;

[0154] 2. Complete / incomplete intestinal obstruction with clinical symptoms within 4 weeks prior to enrollment;

[0155] 3. Within 3 weeks prior to enrollment (or within 5 half-lives, whichever is shorter, if applicable), the patient has received chemotherapy, radiotherapy, biotherapy, immunotherapy, investigational drugs, or traditional Chinese medicine or herbal medicine with proven anti-cancer effects (bisphosphonates and denosumab may continue to be used if they have been used at a stable dose before enrollment).

[0156] 4. Any infectious disease requiring intravenous antibiotic treatment within 4 weeks prior to enrollment, or any signs of active infection within 2 weeks prior to enrollment;

[0157] 5. Patients who underwent ascites drainage during the last two chemotherapy cycles before enrollment or who currently have other serous cavity effusions requiring drainage;

[0158] 6. Individuals with a known history of severe allergies, or those who have previously experienced a grade ≥3 allergic reaction to macromolecular protein preparations / monoclonal antibodies, or those who are known to be allergic to bevacizumab;

[0159] 7. There are still acute adverse events of grade ≥2 caused by previous treatment, unless the investigator judges that the AE has reached a stable state (such as alopecia, neurological disease and specific laboratory abnormalities);

[0160] 8. Patients who need to take folic acid supplements (such as those with folic acid deficiency);

[0161] 9. Those with a history of intestinal fistula or gastrointestinal perforation;

[0162] 10. Individuals with a history of tissue or organ transplantation surgery;

[0163] 11. Other active malignant tumors within 5 years prior to enrollment (locally cured and stable tumors may be included, such as basal cell carcinoma of the skin, low-risk non-muscle-invasive bladder cancer, or breast carcinoma in situ, etc.);

[0164] 12. Patients with meningeal metastases or symptomatic brain metastases (asymptomatic brain metastases that have reached clinical control can be included, but must meet the following conditions at the same time: ① clinical symptoms have been stable for ≥4 weeks before enrollment; ② no progression of central nervous system disease was found on enhanced cranial MRI within 4 weeks before enrollment; ③ antiepileptic drugs have been discontinued for ≥2 weeks before the first dose of medication, and the dose of prednisone is ≤10mg / day or equivalent dose of hormones).

[0165] 13. 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: New York Heart Association (NYHA) class II or higher heart failure, 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 arrhythmias requiring drug control (atrial fibrillation or supraventricular tachycardia may be considered for inclusion), cerebral hemorrhage or ischemic stroke, aortic aneurysm or dissecting aneurysm, severe aortic stenosis, etc.; or a history of Gilbert's syndrome.

[0166] 14. Untreated active hepatitis B. Subjects with hepatitis B meeting the following criteria may also be considered: HBV viral load <200 IU / ml or <10 mmol / L before enrollment. 3 The number of copies / ml is 1, but researchers should consider administering anti-HBV treatment during the study.

[0167] 15. Subjects with active HCV infection (HCV antibody positive and HCV-RNA level above the detection limit);

[0168] 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;

[0169] 17. Known history of human immunodeficiency virus (HIV) infection;

[0170] 18. The subject is pregnant or breastfeeding, or is expected to become pregnant or give birth during the planned study period;

[0171] Research objectives and endpoints

[0172] Main purpose

[0173] To evaluate the efficacy of ADC1 in combination with bevacizumab as maintenance therapy in patients with recurrent ovarian cancer who have achieved complete remission (CR), partial remission (PR), or stable disease (SD) after platinum-based chemotherapy.

[0174] Secondary objective

[0175] To evaluate the safety of ADC1 combined with bevacizumab;

[0176] Further evaluate the efficacy of ADC1 combined with bevacizumab as maintenance therapy for patients with recurrent ovarian cancer who have achieved CR, PR, or SD after platinum-based chemotherapy;

[0177] To evaluate the pharmacokinetic (PK) characteristics and immunogenicity of ADC1 in combination with bevacizumab;

[0178] To evaluate the correlation between FRα expression level and antitumor activity;

[0179] Assess patient-reported health-related quality of life (HRQoL).

[0180] Primary endpoint

[0181] Progression-free survival (PFS) in phase III studies assessed by blinded independent central review (BICR).

[0182] Secondary endpoint

[0183] The incidence, timing, and severity of treatment-related adverse events (TEAEs) are classified according to Common Terminology for Adverse Events (CTCAE) 5.0 or later.

[0184] PFS as assessed by researchers according to RECIST v1.1 criteria, objective response rate (ORR) as assessed by BICR, duration of response (DOR), disease control rate (DCR), time to remission (TTR), overall survival (OS), disease-free survival (DFS), CA-125 response rate based on Gynecologic Cancer International (GCIG) criteria, and time to second disease progression (PFS2).

[0185] Single and multiple administrations of ADC1 C max T max T 1 / 2 AUC (0-∞) PK parameters and ADA / Nab;

[0186] Correlation between FRα expression levels in tumor tissue before treatment and efficacy indicators;

[0187] The European Quality of Life 5-Dimensional 5-Level Health Questionnaire (EQ-5D-5L) and the Functional Assessment of Cancer Treatment - Ovarian Symptom Index (FOSI).

[0188] The combination therapy of the ADC and bevacizumab of the present invention is expected to have good safety and tolerability, and may lead to at least one improvement in ORR, DOR, DCR, PFS, DFS, OS and health-related quality of life.

[0189] Example 3: A randomized, open-label, multicenter phase II / III clinical trial evaluating the efficacy and safety of ADC1 combined with bevacizumab versus bevacizumab monotherapy as maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.

[0190] The study is divided into two parts:

[0191] The first part is a phase II study, in which subjects are randomly assigned in a 1:1 ratio to receive ADC 184 mg / m². 2 Combined with bevacizumab (combination group 1), ADC 193 mg / m 2 The combination group (combination group 2) was used to evaluate the safety and preliminary efficacy of different doses of ADC1 combined with bevacizumab. Combination group 1: ADC1: 84 mg / m² 2 Combination group 2: bevacizumab: 15 mg / kg; Combination group 3: ADC1: 93 mg / kg 2 And bevacizumab: 15mg / kg.

[0192] Part II is a Phase III study, which will determine the Phase III recommended dose (RP3D) of ADC1 based on the safety and efficacy data from Part I. Subsequently, subjects will be randomly assigned in a 1:1 ratio to either the combination group (ADC1 RP3D plus bevacizumab) or the monotherapy group (bevacizumab alone) to compare their efficacy and safety. Combination group: ADC1: RP3D and bevacizumab: 15 mg / kg; Monotherapy group: bevacizumab 15 mg / kg.

[0193] Dosage regimen:

[0194] Both ADC1 and bevacizumab are administered via intravenous infusion. The initial infusion time is 90±10 minutes for each. If there are no safety issues, it is recommended that subsequent infusions be administered over 30 to 60 minutes every 3 weeks (Q3W).

[0195] Inclusion criteria

[0196] 1. Females aged 18 years or older;

[0197] 2. Has histologically confirmed high-grade serous epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer;

[0198] 3. Subjects must be willing to provide archived or fresh tumor tissue specimens for testing and be able to confirm FRα expression levels;

[0199] 4. Subjects who have previously undergone BRCA testing (through blood / tumor tissue) and are BRCA (germline or somatic) positive must have received PARP inhibitor maintenance therapy in first-line treatment (subjects who have previously received PARP inhibitor maintenance therapy and / or bevacizumab therapy may be considered for inclusion);

[0200] 5. Subjects must have received first-line platinum-based chemotherapy and be in the platinum-sensitive population (defined as disease relapse occurring more than 6 months after the last platinum-based first-line chemotherapy) and are currently receiving second-line platinum-based therapy (platinum + paclitaxel / pegylated liposomal doxorubicin (PLD) / gemcitabine + bevacizumab). For second-line therapy, the following requirements must be met:

[0201] ① The subject has received 4–8 cycles of treatment, with at least 3 cycles containing bevacizumab. Note: Platinum-based chemotherapy requires at least ≥4 treatment cycles;

[0202] ②Subjects must complete enrollment within 9 weeks after the end of the last chemotherapy cycle (the last dose of the last chemotherapy cycle);

[0203] Note: Subjects who underwent intermediate debulking surgery during second-line chemotherapy must receive at least two cycles of bevacizumab during chemotherapy; subjects who underwent initial debulking surgery before second-line chemotherapy must receive at least two cycles of bevacizumab during chemotherapy after surgery and before randomization.

[0204] 6. Subjects must be assessed by investigators as CR, PR, or SD within 3 to 9 weeks after completing chemotherapy.

[0205] Note: Subjects must meet any of the following criteria: ① They have at least one measurable lesion as defined by RECIST v1.1 and the investigator judges it to have achieved PR or SD; ② Although there are no more measurable lesions, CA-125 is still elevated (there may be / may not be any unmeasurable lesions), and the investigator judges it to be PR or SD; ③ There are no lesions and CA-125 is normal, and the investigator judges it to be CR.

[0206] 7. ECOG performance status score is 0 or 1;

[0207] 8. Possess sufficient organ and bone marrow reserves;

[0208] 9. Subjects must:

[0209] • Infertility, i.e., surgical sterilization or postmenopause;

[0210] • If of childbearing age, a pregnancy test must be negative before the first dose of the study drug and within 7 days before each cycle of administration. Participants must agree not to attempt pregnancy, not to donate eggs, and to use two highly effective methods of contraception after signing the informed consent form, during the study, and for at least 90 days after the last dose of the study drug, or to use one highly effective method of contraception plus one barrier method of contraception, after signing the informed consent form, during the study, and for at least 90 days after the last dose of the study drug.

[0211] Exclusion criteria

[0212] 1. Subjects with mixed tumors containing endometrioid carcinoma, clear cell carcinoma, mucinous carcinoma or sarcoma tissue, or low-grade / borderline tumors, and subjects resistant to platinum;

[0213] 2. The current line of treatment must have been preceded by more than one line of anti-tumor therapy. The definition of previous lines of treatment includes: adjuvant therapy ± neoadjuvant therapy is considered as one line of treatment; maintenance therapy is considered part of the previous first-line treatment; changes in treatment regimen due to drug toxicity without disease progression are considered the same line of treatment (i.e., not counted independently, such as when the changed drugs are platinum-based, taxane-based, anthracyclines, or PARP inhibitors); hormone therapy, if part of maintenance therapy, is not counted separately as a line of treatment.

[0214] 3. Subjects whose disease progresses (PD) during second-line platinum-based therapy;

[0215] 4. Subjects who, in the investigator's judgment, are not suitable for administration of bevacizumab 15 mg / kg at the start of maintenance therapy;

[0216] 5. Individuals who have undergone major organ surgery within 4 weeks prior to enrollment or who have not yet recovered post-surgery;

[0217] 6. Complete intestinal obstruction within 3 months prior to enrollment; for subjects who have experienced incomplete intestinal obstruction, researchers must determine their suitability for enrollment based on imaging examinations during the screening period.

[0218] 7. Subjects who received bevacizumab maintenance therapy or other anti-tumor therapies after second-line platinum-based therapy prior to enrollment;

[0219] 8. Patients who have previously received ADC therapy with other toxic molecules that are topoisomerase I inhibitors;

[0220] 9. Any infectious disease requiring systemic anti-infective treatment within 2 weeks prior to enrollment;

[0221] 10. Patients who have undergone ascites drainage within 4 weeks prior to enrollment or who currently have other serous cavity effusions requiring drainage;

[0222] 11. Individuals with a known history of severe allergies, or those who have previously experienced a grade ≥3 allergic reaction to macromolecular protein preparations / monoclonal antibodies, or those who are known to be allergic to bevacizumab;

[0223] 12. There are still grade ≥2 adverse events caused by previous anti-tumor treatment, unless the investigator judges that the adverse events have reached long-term stability / cannot be further relieved (such as alopecia, peripheral neuropathy and specific laboratory abnormalities);

[0224] 13. Subjects who need to take folic acid supplements (e.g., those with folic acid deficiency);

[0225] 14. Subjects with a history of enterocutaneous fistula or gastrointestinal perforation, tracheal or digestive tract stent implantation, etc.; subjects with unhealed or poorly healed wounds, portal hypertension or tumor thrombus formation, or tumor invasion of vital organs (such as major blood vessels, trachea, esophagus, spinal cord, etc.); and subjects with serous cavity effusions (including abdominal, pelvic, pleural, pericardial, etc.) requiring drainage.

[0226] 15. Other malignant tumors within the 3 years prior to enrollment. Note: Subjects with a history of other natural disease courses or whose treatments do not interfere with the evaluation of the safety and efficacy of the investigational drug may be included (e.g., controlled basal cell carcinoma or squamous cell carcinoma of the skin, cervical carcinoma in situ, or breast carcinoma in situ).

[0227] 16. Patients with meningeal metastases or symptomatic brain metastases (asymptomatic brain metastases that have reached clinical control can be included, but must meet the following conditions at the same time: ① clinical symptoms have been stable for ≥4 weeks before enrollment; ② no new metastases / progression of the central nervous system were found on enhanced cranial MRI before enrollment; ③ antiepileptic drugs and glucocorticoids have been discontinued for ≥2 weeks before the first dose of medication);

[0228] 17. Patients with poorly controlled cardiovascular disease within 6 months prior to the first administration of the investigational drug, including but not limited to the following: heart failure of NYHA class II 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, or serious arrhythmias requiring drug control (atrial fibrillation or supraventricular tachycardia may be considered for inclusion); a history of cerebral hemorrhage or ischemic stroke, transient ischemic attack, subarachnoid hemorrhage, aortic aneurysm or dissecting aneurysm, severe aortic stenosis, active gastrointestinal bleeding, or other bleeding disorders within 6 months prior to the first administration of the investigational drug; or a history of deep vein thrombosis, pulmonary embolism, or other coagulation disorders within 3 months prior to the first administration.

[0229] 18. Subjects known to have Gilbert's syndrome (defined as UGT1A1 positive);

[0230] 19. Individuals with a history of human immunodeficiency virus (HIV) infection, active tuberculosis, or currently receiving anti-tuberculosis treatment. Individuals with active hepatitis B or hepatitis C are also eligible. For inactive hepatitis B (HBsAg positive and / or anti-HBc positive subjects, HBV DNA testing is required, with titers below the research center's detection limit) and who are not currently receiving continuous antiviral therapy, inclusion is permitted. Individuals with cured hepatitis C (negative HCV RNA test) are also eligible. Note: For HBsAg-positive individuals meeting the inclusion criteria, researchers must consider initiating antiviral therapy at least one week prior to starting study treatment.

[0231] 20. The subject is pregnant or breastfeeding, or is expected to become pregnant or give birth during the planned study period;

[0232] 21. Subjects with a known history of any mental illness, substance abuse, immunosuppressant use, alcoholism, or drug addiction that would affect the conduct of the study;

[0233] 22. Other circumstances where the researcher deems the individual unsuitable to participate in this study.

[0234] Research objectives and endpoints

[0235] Main purpose

[0236] To evaluate the efficacy of ADC1 in combination with bevacizumab as maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer (PSROC) who have achieved complete remission (CR), partial remission (PR), or stable disease (SD) after platinum-based chemotherapy.

[0237] Secondary objective

[0238] To evaluate the safety of ADC1 combined with bevacizumab;

[0239] Further evaluate the efficacy of ADC1 combined with bevacizumab as maintenance therapy in PSROC subjects with different FRα expression levels who achieved CR, PR, or SD after platinum-based chemotherapy;

[0240] To evaluate the pharmacokinetic (PK) characteristics and immunogenicity of ADC1 in combination with bevacizumab;

[0241] Assess participants' reported health-related quality of life (HRQoL).

[0242] Primary endpoint

[0243] Blinded Independent Center Review (BICR) of progression-free survival (PFS) in the population with FRαTPS ≥ 50% as assessed by the Recognition of Efficacy in Solid Tumors (RECIST) v1.1; PFS in the population with FRαTPS ≥ 1% as assessed by BICR of BICR of RECIST v1.1; and PFS in the entire population as assessed by BICR of BICR of RECIST v1.1.

[0244] Secondary endpoint

[0245] The incidence, timing, and severity of treatment-related adverse events (TEAEs) are classified according to Common Terminology for Adverse Events (CTCAE) 5.0 or later.

[0246] BICR is based on objective response rate (ORR), duration of response (DOR), disease control rate (DCR), overall survival (OS) in the RECISTv1.1-assessed population, FRαTPS≥50%, FRαTPS≥1%, and the general population, CA-125 response rate based on GCIG criteria, and investigator-assessed time to second disease progression (PFS2).

[0247] Single and multiple administrations of ADC1 C max T max T 1 / 2 AUC (0-∞) PK parameters and ADA / Nab;

[0248] Functional Assessment of Cancer Treatment - Trial Outcome Index for Ovarian Cancer (FACT-O-TOI).

[0249] The combination therapy of the ADC and bevacizumab of the present invention is expected to have good safety and tolerability, and may lead to at least one improvement in ORR, DOR, DCR, PFS, DFS, OS and health-related quality of life.

Claims

1. A method of treating a tumor, comprising administering to a patient in need an effective amount of an anti-FRα antibody-drug conjugate and a VEGF antagonist; said 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: in Abu is an anti-FRα antibody or its antigen-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, wherein D is ixotecan or an ixotecan derivative.

3. The method as described in claim 1, wherein 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 of treating a tumor, comprising administering to a patient in need an effective amount of an anti-FRα antibody-drug conjugate and a VEGF antagonist; 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: in Abu is an anti-FRα antibody or its antigen-binding unit. n is an integer from 1 to 24. p is 1-10.

5. The method as described in any one of claims 1-4, wherein n is an integer from 4 to 12, or an integer from 4 to 8, or n is 4, or n is 8.

6. The method according to any one of claims 1-5, wherein p is 2-10, or p is 6-9, or p is 7-8.

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

8. The method according to any one of claims 1-7, wherein the anti-FRα antibody or its antigen-binding unit 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.

9. The method according to any one of claims 1-8, wherein the anti-FRα antibody or its antigen-binding unit further 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; and / or The anti-FRα antibody or its antigen-binding unit further comprises VL FR1 as shown in SEQ ID NO:15, VL FR2 as shown in SEQ ID NO:16, VL FR3 as shown in SEQ ID NO:17, and VL FR4 as shown in SEQ ID NO:

18.

10. The method according to any one of claims 1-9, wherein the anti-FRα antibody or its antigen-binding unit 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.

11. The method according to any one of claims 1-10, wherein 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.

12. The method according to any one of claims 1-11, wherein the VEGF antagonist is bevacizumab.

13. The method according to any one of claims 1-12, wherein the dose of the anti-FRα antibody-drug conjugate is about 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 84 mg / m 2 or approximately 93 mg / m³ 2 .

14. The method according to any one of claims 1-13, wherein the VEGF antagonist is administered at a dose of about 1 mg / kg to about 15 mg / kg, or about 10 mg / kg to about 20 mg / kg, or about 5 mg / kg to about 10 mg / kg, or about 7.5 mg / kg, or about 15 mg / kg.

15. The method according to any one of claims 1-14, wherein the anti-FRα antibody-drug conjugate and / or VEGF antagonist are administered once every 1-8 weeks, and the dosing window may be within ±3 days of the prescribed dosing date starting from the second dosing.

16. The method according to any one of claims 1-14, wherein the anti-FRα antibody-drug conjugate and / or VEGF antagonist are administered once every 2-4 weeks, and the dosing window is within ±3 days of the prescribed dosing date, starting from the second dosing.

17. The method according to any one of claims 1-14, wherein the dose of the anti-FRα antibody-drug conjugate is approximately 70 mg / m² per administration. 2 Approximately 100 mg / m 2 The VEGF antagonist is administered once every 2-4 weeks; the dose of the VEGF antagonist is approximately 5 mg / kg to approximately 10 mg / kg, administered once every 2-4 weeks. Alternatively, the dose of the anti-FRα antibody-drug conjugate is approximately 70 mg / m² per administration. 2 Approximately 100 mg / m 2 The VEGF antagonist is administered once every 2-4 weeks; the dose of the VEGF antagonist is approximately 10 mg / kg to approximately 20 mg / kg, administered once every 2-4 weeks. Starting from the second dose, the dosing window can be within ±3 days of the scheduled dosing date.

18. The method according to any one of claims 1-14, wherein the dose of the anti-FRα antibody-drug conjugate is approximately 84 mg / m² per administration. 2 The VEGF antagonist is administered once every 2-4 weeks at a dose of approximately 7.5 mg / kg every 2-4 weeks. Alternatively, the dose of the anti-FRα antibody-drug conjugate is approximately 93 mg / m² per administration. 2 The VEGF antagonist is administered once every 2-4 weeks at a dose of approximately 7.5 mg / kg every 2-4 weeks. Alternatively, the dose of the anti-FRα antibody-drug conjugate is approximately 84 mg / m² per administration. 2 The VEGF antagonist is administered once every 2-4 weeks at a dose of approximately 15 mg / kg every 2-4 weeks. Alternatively, the dose of the anti-FRα antibody-drug conjugate is approximately 93 mg / m² per administration. 2 The VEGF antagonist is administered once every 2-4 weeks at a dose of approximately 15 mg / kg every 2-4 weeks. Starting from the second dose, the dosing window can be within ±3 days of the scheduled dosing date.

19. The method according to any one of claims 1-18, wherein the anti-FRα antibody-drug conjugate is administered once every 3 weeks, and the administration window is within ±3 days of the prescribed administration date, starting from the second administration.

20. The method according to any one of claims 1-19, wherein the VEGF antagonist is administered once every 3 weeks, and the administration window is within ±3 days of the prescribed administration date, starting from the second administration.

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

22. The method according to any one of claims 1-21, wherein the tumor is ovarian cancer.

23. The method according to any one of claims 1-22, wherein the tumor is selected from epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; or, the ovarian cancer is advanced ovarian cancer; or, the ovarian cancer is recurrent and / or refractory ovarian cancer; or, the ovarian cancer is platinum-sensitive or platinum-resistant ovarian cancer; or, the ovarian cancer is platinum-sensitive ovarian cancer; or, the ovarian cancer is platinum-sensitive recurrent ovarian cancer; or, the ovarian cancer is selected from high-grade serous epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

24. The method according to any one of claims 1-23, wherein the patient has serous ovarian cancer or ovarian cancer predominantly serous; or, the patient has high-grade serous ovarian cancer or ovarian cancer predominantly high-grade serous; or, the patient has high-grade serous epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

25. The method of any one of claims 1-24, wherein the patient has previously received at least two lines of platinum-based chemotherapy.

26. The method according to any one of claims 1-25, wherein the patient has FRα expression ≥1%; or, the patient has FRα TPS ≥1%; or, the patient has FRα expression >25%; or, the patient has FRα TPS >25%; or, the patient has FRα expression <50%; or, the patient has FRα TPS <50%; or, the patient has FRα expression ≥50%; or, the patient has FRα TPS ≥50%; or, the patient has FRα expression ≥75%; or, the patient has FRα TPS ≥75%.

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