Application of Anti-frα antibody-drug conjugate in treatment of diseases

Abstract

An application of an anti-FRα antibody-drug conjugate in the treatment of diseases. A treatment method comprises: administering an effective amount of the anti-FRα antibody-drug conjugate to a patient in need thereof.

Description

Application of anti-FRα antibody-drug conjugates in the treatment of diseases Technical Field

[0001] The present invention relates to the field of drug therapy, and in particular to the application of anti-FRα antibody-drug conjugates in treating diseases. Background Art

[0002] Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies targeting specific antigens and small molecule cytotoxic drugs connected by linkers. They combine the powerful killing effect of traditional small molecule chemotherapy with the tumor targeting of antibody drugs. They can efficiently transport small molecule cytotoxic drugs to target tumor cells in a targeted manner, thereby overcoming the cytotoxic effect on normal cells. They have become one of the hot research directions in the field of precision tumor treatment.

[0003] Folic acid is an essential vitamin required for DNA synthesis and repair, and cell division. It is transported by endocytosis by binding to folate receptors on the cell surface, where the folate receptor is internalized and then recycled back to the cell membrane. The folate receptor is a transmembrane single-chain glycoprotein linked to glycosylated phosphatidylinositol and has a high affinity for folic acid. The folate receptor includes three subtypes: folate receptor α (Folate Receptorα, FOLR1, FRα), folate receptor β (Folate Receptorβ, FOLR2), and folate receptor γ (Folate Receptorγ, FOLR3). The expression of folate receptors is highly restricted in normal cells, but significantly overexpressed on tumor cells. Among them, folate receptor α has been found to be overexpressed in many malignant tumors, making it one of the popular targets for anticancer drugs.

[0004] Summary of the Invention

[0005] The present invention provides use of an anti-folate receptor alpha (FRα) antibody-drug conjugate in treating diseases (eg, cancer).

[0006] In one or more embodiments, the present invention provides a method for treating and / or preventing a disease (e.g., cancer), comprising administering an effective amount of an antibody drug conjugate to a patient in need thereof (e.g., a human patient). In one or more embodiments, the administration is by injection.

[0007] In one or more embodiments, the present invention provides a method for treating and / or preventing cancer, comprising administering an effective amount of an antibody drug conjugate to a human patient in need thereof by injection.

[0008] In one or more embodiments, the present invention provides use of an effective amount of the antibody-drug conjugate or pharmaceutical composition in the preparation of a drug for treating and / or preventing a disease (eg, cancer).

[0009] In one or more embodiments, the present invention provides use of an effective amount of the antibody-drug conjugate or pharmaceutical composition in treating and / or preventing a disease (eg, cancer).

[0010] In one or more embodiments, the dosage of the antibody drug conjugate is 0.5 mg / kg to 5 mg / kg, administered once a day to once every 7 weeks. In one or more embodiments, the dosage of the antibody drug conjugate is 1.7 mg / kg to 2.5 mg / kg, administered once every 2-4 weeks.

[0011] In one or more embodiments, the dosage of the antibody drug conjugate is 10 mg to 300 mg, administered once a day to once every 7 weeks. In one or more embodiments, the dosage of the antibody drug conjugate is 100 mg to 250 mg, administered once every 2-4 weeks.

[0012] In one or more embodiments, the dosage of the antibody drug conjugate is 5 mg / m 2 Up to 150 mg / m 2 , administered once a day to once every 7 weeks. In one or more embodiments, the dosage of the antibody drug conjugate is 70 mg / m 2 Up to 100 mg / m 2 , administered once every 2-4 weeks. In one or more embodiments, the dosage of the antibody drug conjugate is 75 mg / m 2 Up to 100 mg / m 2 , administered once every 2-4 weeks.

[0013] In one or more embodiments, the antibody-drug conjugate comprises an anti-FRα antibody or an antigen-binding unit thereof coupled to a drug via a linker.

[0014] In one or more embodiments, the linker is a cleavable linker.

[0015] In one or more embodiments, the antibody drug conjugate has a structure as shown in Formula I or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof:

[0016] in

[0017] Abu is an anti-FRα antibody or its antigen-binding unit;

[0018] D is the drug;

[0019] M is Wherein * connects to Abu, ** connects to B, and R is selected from: -(CH2) r -、-(CHR m ) r -, C3-C8 carbocyclic group, -O-(CH2) r -, arylene, -(CH2) r -Arylene-, -Arylene-(CH2) r -、-(CH2) r -(C3-C8 carbocyclyl)-, -(C3-C8 carbocyclyl)-(CH2) r -, C3-C8 heterocyclic group, -(CH2) r -(C3-C8 heterocyclyl)-, -(C3-C8 heterocyclyl)-(CH2) r -、-(CH2) r C(O)NR m (CH2) r -、-(CH2CH2O) r -、-(CH2CH2O) r -CH2-, -(CH2) r C(O)NR m (CH2CH2O) r -、-(CH2) r C(O)NR m (CH2CH2O) r -CH2-, -(CH2CH2O) r C(O)NR m (CH2CH2O) r -、-(CH2CH2O) r C(O)NR m (CH2CH2O) r -CH2- and -(CH2CH2O) r C(O)NR m (CH2) r -; each R m R is independently H, C1-C6 alkyl, C3-C8 carbocyclyl, phenyl or benzyl; and each r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0020] B is For example, Where * connects to M, ** connects to L, and *** connects to G;

[0021] L is -(AA) i -(FF) f-, wherein AA is an amino acid or a polypeptide, i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; each FF is independently Among them, each R F are independently C1-C6 alkyl, C1-C6 alkoxy, -NO2 or halogen, z is 0, 1, 2, 3 or 4, wherein * is connected to AA and ** is connected to D; f is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0022] G is wherein n is an integer from 1 to 24, for example, 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;

[0023] p is 1-10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0024] In one or more embodiments, R is -(CH2) r -.

[0025] In one or more embodiments, R is -(CH2) r -, r is 1 or 5.

[0026] In one or more embodiments, each AA is independently selected from the following amino acid or peptide sequences: Val-Cit, Val-Lys, Phe-Lys, Lys-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Trp, Cit, Phe-Ala, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val, Ala-Leu-Ala-Leu, β-Ala-Leu-Ala-Leu, and Gly-Phe-Leu-Gly.

[0027] In one or more embodiments, AA is Val-Cit.

[0028] In one or more embodiments, i is 1.

[0029] In one or more embodiments, AA is Val-Cit, and i is 1.

[0030] In one or more embodiments, the halogen is F.

[0031] In one or more embodiments, R FIt is -CH3, F, -NO2 or -OCH3.

[0032] In one or more embodiments, z is 0.

[0033] In one or more embodiments, z is 1 or 2.

[0034] In one or more embodiments, each FF is independently Where * connects AA and ** connects D.

[0035] In one or more embodiments, f is 1.

[0036] In one or more embodiments, FF is Where * connects AA and ** connects D.

[0037] In one or more embodiments, FF is f is 1, where * connects AA and ** connects D.

[0038] In one or more embodiments, L is Where * connects to B and ** connects to D.

[0039] In one or more embodiments, L is Where * connects to B and ** connects to D.

[0040] In one or more embodiments, n is an integer from 4 to 12.

[0041] In one or more embodiments, n is an integer from 4 to 8.

[0042] In one or more embodiments, n is 4.

[0043] In one or more embodiments, n is 8.

[0044] In one or more embodiments, p is 2-8.

[0045] In one or more embodiments, p is 4-8.

[0046] In one or more embodiments, p is 6-8.

[0047] In one or more embodiments, p is 7-8.

[0048] In one or more embodiments, p is 7.4.

[0049] In one or more embodiments, p is 7.

[0050] In one or more embodiments, p is 8.

[0051] In one or more embodiments, the antibody drug conjugate has a structure as shown in Formula I-1 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof:

[0052] in

[0053] Abu is an anti-FRα antibody or its antigen-binding unit;

[0054] R is selected from: -(CH2) r -、-(CHR m )r-, C3-C8 carbocyclic group, -O-(CH2) r -, arylene, -(CH2) r -Arylene-, -Arylene-(CH2) r -、-(CH2) r -(C3-C8 carbocyclyl)-, -(C3-C8 carbocyclyl)-(CH2) r -, C3-C8 heterocyclic group, -(CH2) r -(C3-C8 heterocyclyl)-, -(C3-C8 heterocyclyl)-(CH2) r -、-(CH2) r C(O)NR m (CH2) r -、-(CH2CH2O) r -、-(CH2CH2O) r -CH2-, -(CH2) r C(O)NR m (CH2CH2O) r -、-(CH2) r C(O)NR m (CH2CH2O) r -CH2-, -(CH2CH2O) r C(O)NR m (CH2CH2O) r -、-(CH2CH2O) r C(O)NR m (CH2CH2O) r -CH2- and -(CH2CH2O) r C(O)NR m (CH2) r -; each R mR is independently H, C1-C6 alkyl, C3-C8 carbocyclyl, phenyl or benzyl; and each r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0055] D is the drug;

[0056] n is an integer from 1 to 24, for example, 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;

[0057] p is 1-10, for example 1, 2, 3, 4, 5, 6, 7, 7.4, 8, 9 or 10.

[0058] In one or more embodiments, R is -(CH2) r -.

[0059] In one or more embodiments, R is -(CH2) r -, r is 1 or 5.

[0060] In one or more embodiments, n is an integer from 4 to 12.

[0061] In one or more embodiments, n is an integer from 4 to 8.

[0062] In one or more embodiments, n is 4.

[0063] In one or more embodiments, n is 8.

[0064] In one or more embodiments, p is 2-8.

[0065] In one or more embodiments, p is 4-8.

[0066] In one or more embodiments, p is 6-8.

[0067] In one or more embodiments, p is 7-8.

[0068] In one or more embodiments, p is 7.4.

[0069] In one or more embodiments, p is 7.

[0070] In one or more embodiments, p is 8.

[0071] In one or more embodiments, the antibody drug conjugate has a structure as shown in Formula I-2 or I-2-1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

[0072] in

[0073] Abu is an anti-FRα antibody or its antigen-binding unit;

[0074] R is selected from: -(CH2) r -、-(CHR m )r-, C3-C8 carbocyclic group, -O-(CH2) r -, arylene, -(CH2) r -Arylene-, -Arylene-(CH2) r -、-(CH2) r -(C3-C8 carbocyclyl)-, -(C3-C8 carbocyclyl)-(CH2) r -, C3-C8 heterocyclic group, -(CH2) r -(C3-C8 heterocyclyl)-, -(C3-C8 heterocyclyl)-(CH2) r -、-(CH2) r C(O)NR m (CH2) r -、-(CH2CH2O) r -、-(CH2CH2O) r -CH2-, -(CH2) r C(O)NR m (CH2CH2O) r -、-(CH2) r C(O)NR m (CH2CH2O) r -CH2-, -(CH2CH2O) r C(O)NR m (CH2CH2O) r -、-(CH2CH2O) r C(O)NR m (CH2CH2O) r -CH2- and -(CH2CH2O) r C(O)NR m (CH2) r -; each R m R is independently H, C1-C6 alkyl, C3-C8 carbocyclyl, phenyl or benzyl; and each r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0075] D is the drug;

[0076] n is an integer from 1 to 24, for example, 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;

[0077] p is 1-10, for example 1, 2, 3, 4, 5, 6, 7, 7.4, 8, 9 or 10.

[0078] In one or more embodiments, R is -(CH2) r -.

[0079] In one or more embodiments, R is -(CH2) r -, r is 1 or 5.

[0080] In one or more embodiments, n is an integer from 4 to 12.

[0081] In one or more embodiments, n is an integer from 4 to 8.

[0082] In one or more embodiments, n is 4.

[0083] In one or more embodiments, n is 8.

[0084] In one or more embodiments, p is 2-8.

[0085] In one or more embodiments, p is 4-8.

[0086] In one or more embodiments, p is 6-8.

[0087] In one or more embodiments, p is 7-8.

[0088] In one or more embodiments, p is 7.4.

[0089] In one or more embodiments, p is 7.

[0090] In one or more embodiments, p is 8.

[0091] In one or more embodiments, the antibody drug conjugate has a structure as shown in Formula I-3 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof:

[0092] in

[0093] Abu is an anti-FRα antibody or its antigen-binding unit;

[0094] D is the drug;

[0095] n is an integer from 1 to 24, for example, 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;

[0096] p is 1-10, for example 1, 2, 3, 4, 5, 6, 7, 7.4, 8, 9 or 10.

[0097] In one or more embodiments, n is an integer from 4 to 12.

[0098] In one or more embodiments, n is an integer from 4 to 8.

[0099] In one or more embodiments, n is 4.

[0100] In one or more embodiments, n is 8.

[0101] In one or more embodiments, p is 2-8.

[0102] In one or more embodiments, p is 4-8.

[0103] In one or more embodiments, p is 6-8.

[0104] In one or more embodiments, p is 7-8.

[0105] In one or more embodiments, p is 7.4.

[0106] In one or more embodiments, p is 7.

[0107] In one or more embodiments, p is 8.

[0108] In one or more embodiments, the antibody drug conjugate has a structure as shown in Formula I-4 or I-4-1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

[0109] in

[0110] Abu is an anti-FRα antibody or its antigen-binding unit;

[0111] D is the drug;

[0112] n is an integer from 1 to 24, for example, 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;

[0113] p is 1-10, for example 1, 2, 3, 4, 5, 6, 7, 7.4, 8, 9 or 10.

[0114] In one or more embodiments, n is an integer from 4 to 12.

[0115] In one or more embodiments, n is an integer from 4 to 8.

[0116] In one or more embodiments, n is 4.

[0117] In one or more embodiments, n is 8.

[0118] In one or more embodiments, p is 2-8.

[0119] In one or more embodiments, p is 4-8.

[0120] In one or more embodiments, p is 6-8.

[0121] In one or more embodiments, p is 7-8.

[0122] In one or more embodiments, p is 7.4.

[0123] In one or more embodiments, p is 7.

[0124] In one or more embodiments, p is 8.

[0125] In one or more embodiments, the antibody drug conjugate has a structure as shown in Formula I-5, I-5-1, I-6, I-6-1, I-7, I-7-1, I-8, I-8-1, I-9, I-9-1, I-10, I-10-1, I-11, or I-11-1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

[0126] in

[0127] Abu is an anti-FRα antibody or its antigen-binding unit;

[0128] D is the drug;

[0129] p is 1-10, for example 1, 2, 3, 4, 5, 6, 7, 7.4, 8, 9 or 10.

[0130] In one or more embodiments, p is 2-8.

[0131] In one or more embodiments, p is 4-8.

[0132] In one or more embodiments, p is 6-8.

[0133] In one or more embodiments, p is 7-8.

[0134] In one or more embodiments, p is 7.4.

[0135] In one or more embodiments, p is 7.

[0136] In one or more embodiments, p is 8.

[0137] In one or more embodiments, the drug is an anticancer drug, a cytotoxic drug, a cell differentiation factor, a stem cell trophic factor, a steroid drug, a drug for treating an autoimmune disease, an anti-inflammatory drug, or a drug for treating an infectious disease.

[0138] In one or more embodiments, the drug is a tubulin inhibitor, a DNA damaging agent, or a DNA topoisomerase inhibitor.

[0139] In one or more embodiments, the tubulin inhibitor is selected from dolastatin, auristatins, and maytansines.

[0140] In one or more embodiments, the drug is an auristatin, such as monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), or auristatin (AF).

[0141] In one or more embodiments, the drug is a DNA damaging agent, such as calicheamicins, duocarmycins, and anthramycin derivatives such as PBD (pyrrolobenzodiazepine).

[0142] In one or more embodiments, the drug is a DNA topoisomerase inhibitor or a salt thereof, such as irinotecan, irinotecan hydrochloride, a derivative of isotecan, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, 9-chloro-10-hydroxycamptothecin, camptothecin derivatives SN-38, 22-hydroxyecliptin, topotecan, lertotecan, belotecan, isotecan, homosilatecan, 6,8-dibromo-2-methyl-3-[2-(D-xylopyranosylamino)phenyl]-4(3H)-quinazolinone, 2-cyano-3-(3,4 -dihydroxyphenyl)-N-(phenylmethyl)-(2E)-2-acrylamide, 2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-hydroxyphenylpropyl)-(E)-2-acrylamide, 12-β-D-glucopyranosyl-12,13-dihydro-2,10-dihydroxy-6-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide dihydrochloride, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide.

[0143] In one or more embodiments, the DNA topoisomerase inhibitor is camptothecin, 10-hydroxycamptothecin, topotecan, belotecan, irinotecan, 22-hydroxyelicholine or exitecan, or a salt thereof.

[0144] In one or more embodiments, the drug is a Tubulysin, a taxane derivative, a leptomycine derivative, CC-1065 and its analogs, an Amatoxin, a spliceosome inhibitor, a benzodiazepine (PBD) dimer, doxorubicin, methotrexate, vincristine, vinblastine, daunorubicin, mitomycin C, melphalan, or a chlorambucil derivative.

[0145] In one or more embodiments, the drug is in

[0146] X 1 and X 2 Each independently is:

[0147] H,

[0148] hydroxyl groups,

[0149] C1-C6 alkyl,

[0150] C1-C6 alkyl substituted by one or more hydroxyl, halogen, nitro or cyano groups,

[0151] C2-C6 alkenyl,

[0152] C2-C6 alkynyl,

[0153] C1-C6 alkoxy,

[0154] C1-C6 aminoalkoxy,

[0155] halogen,

[0156] Nitro,

[0157] cyano group,

[0158] sulfhydryl,

[0159] Alkylthio,

[0160] amino, amino substituted by an amino protecting group, C1-C6 aminoalkyl optionally substituted by an amino protecting group or a C1-C6 alkyl group at the amino moiety,

[0161] C1-C6 aminoalkylamino optionally substituted with an amino protecting group or a C1-C6 alkyl group at the amino moiety,

[0162] C1-C6 alkyl group connected to a heterocyclic ring, said heterocyclic ring being optionally substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, amino groups, halogen groups, nitro groups or cyano groups,

[0163] C1-C6 alkylamino group connected to a heterocyclic ring, the heterocyclic ring is optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, the amino group is optionally substituted by an amino protecting group, halogen, nitro, cyano or a protecting group,

[0164] An amino-substituted heterocyclic group, which is optionally substituted by a protecting group or one or more C1-C6 alkyl groups at the nitrogen atom of the heterocyclic ring or the amino group,

[0165] Heterocyclic amino group, which is optionally substituted by a protecting group or a C1-C6 alkyl group at the nitrogen atom of the heterocyclic ring portion or the amino portion,

[0166] a carbamoyl group optionally substituted with a carbamoyl protecting group or a C1-C6 alkyl group,

[0167] Morpholin-1-yl, or

[0168] Piperidin-1-yl;

[0169] X 3 is a C1-C6 alkyl group;

[0170] X 4 H, -(CH2) q -CH3、-(CHR n ) q -CH3, C3-C8 carbocyclyl, -O-(CH2)q -CH3, arylene-CH 3, -(CH2) q -Arylene-CH3, -Arylene-(CH2) q -CH3, -(CH2) q -(C3-C8 carbocyclyl)-CH3, -(C3-C8 carbocyclyl)-(CH2) q -CH3, C3-C8 heterocyclic group, -(CH2) q -(C3-C8 heterocyclyl)-CH3, -(C3-C8 heterocyclyl)-(CH2) q -CH3, -(CH2) q C(O)NR n (CH2) q -CH3, -(CH2CH2O) q -CH3, -(CH2CH2O) q -CH2-CH3, -(CH2) q C(O)NR n (CH2CH2O) q -CH3, -(CH2) q C(O)NR n (CH2CH2O) q -CH2-CH3, -(CH2CH2O) q C(O)NR n (CH2CH2O) q -CH3, -(CH2CH2O) q C(O)NR n (CH2CH2O) q -CH2-CH3, or -(CH2CH2O) q C(O)NR n (CH2) q -CH3; each R n is independently H, C1-C6 alkyl, C3-C8 carbocyclyl, phenyl or benzyl; and each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0171] ** is the connection point;

[0172] y is 0, 1, or 2;

[0173] Y is O, S or CR 1 R 2 , where R 1 and R 2 Each independently is H or C1-C6 alkyl;

[0174] s and t are each independently 0, 1 or 2, but not both 0.

[0175] In one or more embodiments, X 4 is H or C1-C6 alkyl.

[0176] In one or more embodiments, the heterocycle is azetidine, acetaldehyde, morpholine, pyrrolidine, piperidine, imidazole, thiazole, oxazole, or pyridine.

[0177] In one or more embodiments, the amino protecting group is formyl, acetyl, trityl, tert-butoxycarbonyl, benzyl or p-methoxybenzyloxycarbonyl.

[0178] In one or more embodiments, the drug is where X 1 and X 2 Each is independently C1-C6 alkyl, halogen or -OH; ** is the point of attachment.

[0179] In one or more embodiments, the drug is where X 1 and X 2 Each is independently C1-C6 alkyl, halogen or -OH; ** is the point of attachment.

[0180] In one or more embodiments, the C1-C6 alkyl group is -CH3.

[0181] In one or more embodiments, the halogen is F.

[0182] In one or more embodiments, X 1 and X 2 Each is independently -CH3, F or -OH.

[0183] In one or more embodiments, X 1 and X 2 Each is -CH3.

[0184] In one or more embodiments, X 1 and X 2 are each independently F, Cl, Br or I.

[0185] In one or more embodiments, X 1 and X 2 Each is F.

[0186] In one or more embodiments, X 1 and X 2 Each is independently F or -CH3.

[0187] In one or more embodiments, X1 -CH3 and X 2 For F.

[0188] In one or more embodiments, the antibody drug conjugate has a structure as shown in Formula I-26, I-27, I-12, I-12-1, I-13, I-13-1, I-14, I-14-1, I-15, I-15-1, I-16, I-16-1, I-17, I-17-1, I-18, I-18-1, I-19, I-19-1, I-20, I-20-1, I-21, I-21-1, I-22, I-22-1, I-23, I-23-1, I-24, I-24-1, I-25, or I-25-1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

[0189] in

[0190] Abu is an anti-FRα antibody or its antigen-binding unit;

[0191] n is an integer from 1 to 24, for example, 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;

[0192] p is 1-10, for example 1, 2, 3, 4, 5, 6, 7, 7.4, 8, 9 or 10.

[0193] In one or more embodiments, n is an integer from 4 to 12.

[0194] In one or more embodiments, n is an integer from 4 to 8.

[0195] In one or more embodiments, n is 4.

[0196] In one or more embodiments, n is 8.

[0197] In one or more embodiments, p is 2-8.

[0198] In one or more embodiments, p is 4-8.

[0199] In one or more embodiments, p is 6-8.

[0200] In one or more embodiments, p is 7-8.

[0201] In one or more embodiments, p is 7.4.

[0202] In one or more embodiments, p is 7.

[0203] In one or more embodiments, p is 8.

[0204] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises one or more of (a)-(f):

[0205] (a) VH CDR1 comprises 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 consists of the same;

[0206] (b) VH CDR2 comprises 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 consists of the same;

[0207] (c) VH CDR3 comprises 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 consists of the same;

[0208] (d) VL CDR1 comprises 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 consists of the same;

[0209] (e) VL CDR2 comprises 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 consists of the same;

[0210] (f) VL CDR3 comprises the amino acid sequence shown in SEQ ID NO: 6, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO: 6, or consists of the same.

[0211] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises:

[0212] (a) VH CDR1 comprises 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 consists of the same; and

[0213] (b) VH CDR2 comprises 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 consists of the same; and

[0214] (c) VH CDR3 comprises 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 consists of the same.

[0215] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises a VH CDR1 as shown in SEQ ID NO: 1, a VH CDR2 as shown in SEQ ID NO: 2, and a VH CDR3 as shown in SEQ ID NO: 3.

[0216] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises:

[0217] (d) VL CDR1 comprises 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 consists of the same; and

[0218] (e) VL CDR2 comprises 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 consists of the same; and

[0219] (f) VL CDR3 comprises the amino acid sequence shown in SEQ ID NO: 6, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO: 6, or consists of the same.

[0220] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises a VL CDR1 as shown in SEQ ID NO:4, a VL CDR2 as shown in SEQ ID NO:5, and a VL CDR3 as shown in SEQ ID NO:6.

[0221] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises:

[0222] (a) VH CDR1 comprises 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 consists of the same; and

[0223] (b) VH CDR2 comprises 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 consists of the same; and

[0224] (c) VH CDR3 comprises 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 consists of the same; and

[0225] (d) VL CDR1 comprises 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 consists of the same; and

[0226] (e) VL CDR2 comprises 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 consists of the same; and

[0227] (f) VL CDR3 comprises the amino acid sequence shown in SEQ ID NO: 6, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO: 6, or consists of the same.

[0228] In one or more embodiments, the substitution, deletion or insertion of the sites is independently one, two or three.

[0229] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises a VH CDR1 as shown in SEQ ID NO: 1, a VH CDR2 as shown in SEQ ID NO: 2, a VH CDR3 as shown in SEQ ID NO: 3, a VL CDR1 as shown in SEQ ID NO: 4, a VL CDR2 as shown in SEQ ID NO: 5, and a VL CDR3 as shown in SEQ ID NO: 6.

[0230] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof further comprises one or more of (g)-(n):

[0231] (g) VH FR1 comprises the amino acid sequence as set forth in SEQ ID NO: 15, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence as set forth in SEQ ID NO: 15, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence as set forth in SEQ ID NO: 15;

[0232] (h) VH FR2 comprises the amino acid sequence of SEQ ID NO: 16, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 16, or an amino acid sequence having one or more substitutions, deletions or insertions with respect to the amino acid sequence of SEQ ID NO: 16;

[0233] (i) VH FR3 comprises the amino acid sequence set forth in SEQ ID NO: 17, or an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence set forth in SEQ ID NO: 17;

[0234] (j) VH FR4 comprises the amino acid sequence of SEQ ID NO: 18, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 18, or an amino acid sequence having one or more substitutions, deletions or insertions with respect to the amino acid sequence of SEQ ID NO: 18;

[0235] (k) VL FR1 comprises the amino acid sequence set forth in SEQ ID NO: 19, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO: 19, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence set forth in SEQ ID NO: 19;

[0236] (1) VL FR2 comprises the amino acid sequence set forth in SEQ ID NO: 20, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO: 20, or an amino acid sequence having one or more substitutions, deletions, or insertions with respect to the amino acid sequence set forth in SEQ ID NO: 20;

[0237] (m) VL FR3 comprises the amino acid sequence set forth in SEQ ID NO: 21, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO: 21, or an amino acid sequence having one or more substitutions, deletions, or insertions compared to the amino acid sequence set forth in SEQ ID NO: 21;

[0238] (n) VL FR4 comprises the amino acid sequence shown in SEQ ID NO: 22, or an amino acid sequence having at least 90% sequence identity with 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.

[0239] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises:

[0240] (g) VH FR1 comprises the amino acid sequence shown in SEQ ID NO: 15, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 15, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO: 15; and

[0241] (h) VH FR2 comprises the amino acid sequence shown in SEQ ID NO: 16, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 16, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO: 16; and

[0242] (i) VH FR3 comprises the amino acid sequence shown in SEQ ID NO: 17, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 17, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO: 17; and

[0243] (j) VH FR4 comprises the amino acid sequence shown in SEQ ID NO: 18, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 18, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO: 18; and / or

[0244] (k) VL FR1 comprises the amino acid sequence shown in SEQ ID NO: 19, or an amino acid sequence having at least 90% sequence identity with 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; and

[0245] (1) VL FR2 comprises the amino acid sequence shown in SEQ ID NO: 20, or an amino acid sequence having at least 90% sequence identity with 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; and

[0246] (m) VL FR3 comprises the amino acid sequence shown in SEQ ID NO: 21, or an amino acid sequence having at least 90% sequence identity with 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; and

[0247] (n) VL FR4 comprises the amino acid sequence shown in SEQ ID NO: 22, or an amino acid sequence having at least 90% sequence identity with 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.

[0248] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises VH FR1 as shown in SEQ ID NO:15, VH FR2 as shown in SEQ ID NO:16, VH FR3 as shown in SEQ ID NO:17, and VH FR4 as shown in SEQ ID NO:18.

[0249] In one or more embodiments, the anti-FRα antibody or its antigen-binding unit comprises VL FR1 as shown in SEQ ID NO: 19, VL FR2 as shown in SEQ ID NO: 20, VL FR3 as shown in SEQ ID NO: 21, and VL FR4 as shown in SEQ ID NO: 22.

[0250] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises VH FR1 as shown in SEQ ID NO: 15, VH FR2 as shown in SEQ ID NO: 16, VH FR3 as shown in SEQ ID NO: 17, VH FR4 as shown in SEQ ID NO: 18, VL FR1 as shown in SEQ ID NO: 19, VL FR2 as shown in SEQ ID NO: 20, VL FR3 as shown in SEQ ID NO: 21, and VL FR4 as shown in SEQ ID NO: 22.

[0251] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises a heavy chain variable region (VH) and / or a light chain variable region (VL), wherein:

[0252] The heavy chain variable region comprises the amino acid sequence 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

[0253] The light chain variable region comprises the amino acid sequence 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 site substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:8.

[0254] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof 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.

[0255] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises a heavy chain constant region (CH) and / or a light chain constant region (CL), wherein:

[0256] The heavy chain constant region comprises the amino acid sequence 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

[0257] The light chain constant region comprises the amino acid sequence 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 site substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO: 10.

[0258] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof comprises a heavy chain constant region as shown in SEQ ID NO:9 and a light chain constant region as shown in SEQ ID NO:10.

[0259] In one or more embodiments, the anti-FRα antibody comprises a heavy chain (H) and a light chain (L).

[0260] In one or more embodiments, the heavy chain of the anti-FRα antibody comprises a heavy chain variable region as shown in SEQ ID NO: 7 and a heavy chain constant region as shown in SEQ ID NO: 9; the light chain of the anti-FRα antibody comprises a light chain variable region as shown in SEQ ID NO: 8 and a light chain constant region as shown in SEQ ID NO: 10.

[0261] In one or more embodiments, the heavy chain comprises the amino acid sequence shown in SEQ ID NO: 11, or an amino acid sequence having at least 90% sequence identity to the amino acid sequence shown in SEQ ID NO: 11, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO: 11; and / or

[0262] The light chain comprises the amino acid sequence shown in SEQ ID NO: 13, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 13, or an amino acid sequence having one or more site substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO: 13.

[0263] In one or more embodiments, the anti-FRα antibody comprises a heavy chain as shown in SEQ ID NO:11 and a light chain as shown in SEQ ID NO:13.

[0264] In one or more embodiments, the anti-FRα antibody is Antibody 1.

[0265] In one or more embodiments, the substitutions are conservative amino acid substitutions.

[0266] In one or more embodiments, the antibody or antigen binding unit thereof is chimeric, humanized, or fully human.

[0267] In one or more embodiments, the anti-FRα antibody is a monoclonal antibody, a multispecific antibody or an antigen-binding unit thereof (eg, a bispecific antibody or an antigen-binding unit thereof).

[0268] In one or more embodiments, the anti-FRα antibody has two heavy chains with identical sequences and two light chains with identical sequences. In one or more embodiments, the Fc regions are paired to form disulfide bonds.

[0269] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof is an isolated antibody or antigen-binding unit thereof.

[0270] In one or more embodiments, the anti-FRα antibody or antigen-binding unit thereof is a monoclonal antibody or a fragment thereof.

[0271] 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 (such as by an assay such as 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 expression≥75%. In one or more embodiments, the patient has FRα TPS≥75%.

[0272] In one or more embodiments, the present invention provides a method for treating cancer, comprising administering to a patient with FRαTPS>25% an effective amount of an antibody drug conjugate, wherein the antibody drug conjugate has a structure as shown in Formula I-13-1 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof:

[0273] in,

[0274] Abu is an anti-FRα antibody, the heavy chain of which comprises the amino acid sequence set forth in SEQ ID NO: 11, and the light chain of which comprises the amino acid sequence set forth in SEQ ID NO: 13;

[0275] p is 7-8.

[0276] In one or more embodiments, the dosage of the antibody drug conjugate is 0.5 mg / kg to 5 mg / kg, administered once a day to once every 7 weeks.

[0277] In one or more embodiments, the dosage of the antibody drug conjugate is 10 mg to 300 mg, administered once a day to once every 7 weeks.

[0278] In one or more embodiments, the dosage of the antibody drug conjugate is 5 mg / m 2 Up to 150 mg / m 2 , administered once a day to once every 7 weeks.

[0279] In one or more embodiments, p is 7.4.

[0280] In one or more embodiments, p is 7.

[0281] In one or more embodiments, p is 8.

[0282] In one or more embodiments, the present invention provides a method for treating cancer, comprising administering an effective amount of an antibody drug conjugate to a patient with FRαTPS>25%, wherein the antibody drug conjugate is administered at a dose of 0.5 mg / kg to 5 mg / kg, administered once a day to once every 7 weeks.

[0283] In one or more embodiments, the present invention provides a method for treating cancer, comprising administering an effective amount of an antibody drug conjugate to a patient with FRαTPS>25%, wherein the dosage of the antibody drug conjugate is 10 mg to 300 mg, administered once a day to once every 7 weeks.

[0284] In one or more embodiments, the present invention provides a method for treating cancer, comprising administering an effective amount of an antibody drug conjugate to a patient with FRα TPS>25%, wherein the dosage of the antibody drug conjugate is 5 mg / m 2 Up to 150 mg / m 2 , administered once a day to once every 7 weeks.

[0285] In one or more embodiments, the patient has a FRα TPS > 50%. In one or more embodiments, the patient has a FRα TPS < 50%. In one or more embodiments, the patient has a FRα TPS ≥ 50%. In one or more embodiments, the patient has a FRα TPS ≥ 75%.

[0286] In one or more embodiments, the antibody drug conjugate has a structure as shown in Formula I-13-1 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof:

[0287] in,

[0288] Abu is an anti-FRα antibody, the heavy chain of which comprises the amino acid sequence set forth in SEQ ID NO: 11, and the light chain of which comprises the amino acid sequence set forth in SEQ ID NO: 13;

[0289] p is 1-10.

[0290] In one or more embodiments, p is 2-8.

[0291] In one or more embodiments, p is 4-8.

[0292] In one or more embodiments, p is 6-8.

[0293] In one or more embodiments, p is 7-8.

[0294] In one or more embodiments, p is 7.4.

[0295] In one or more embodiments, p is 7.

[0296] In one or more embodiments, p is 8.

[0297] In one or more embodiments, the present invention provides a method for treating cancer, comprising administering an effective amount of an antibody drug conjugate to a patient with FRαTPS>25%; wherein the dosage of the antibody drug conjugate is 0.5 mg / kg to 5 mg / kg, or 10 mg to 300 mg, or 5 mg / m 2 Up to 150 mg / m 2 , administered once a day to once every 7 weeks; the antibody drug conjugate has a structure as shown in Formula I-13-1 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof:

[0298] in,

[0299] Abu is an anti-FRα antibody, the heavy chain of which comprises the amino acid sequence set forth in SEQ ID NO: 11, and the light chain of which comprises the amino acid sequence set forth in SEQ ID NO: 13;

[0300] p is 1-10.

[0301] In one or more embodiments, p is 2-8.

[0302] In one or more embodiments, p is 4-8.

[0303] In one or more embodiments, p is 6-8.

[0304] In one or more embodiments, p is 7-8.

[0305] In one or more embodiments, p is 7.4.

[0306] In one or more embodiments, p is 7.

[0307] In one or more embodiments, p is 8.

[0308] In one or more embodiments, the antibody drug conjugate is ADC1 or a pharmaceutically acceptable salt or solvate thereof, wherein ADC1 is

[0309] in,

[0310] Abu is an anti-FRα antibody, the heavy chain of which comprises the amino acid sequence set forth in SEQ ID NO: 11, and the light chain of which comprises the amino acid sequence set forth in SEQ ID NO: 13;

[0311] p is 7-8.

[0312] In one or more embodiments, the antibody drug conjugate is ADC2 or a pharmaceutically acceptable salt or solvate thereof, wherein ADC2 is

[0313] in,

[0314] Abu is an anti-FRα antibody, the heavy chain of which comprises the amino acid sequence set forth in SEQ ID NO: 11, and the light chain of which comprises the amino acid sequence set forth in SEQ ID NO: 13;

[0315] p is 3.5-4.5.

[0316] In one or more embodiments, a pharmaceutical composition comprising an antibody drug conjugate as described herein and a pharmaceutically acceptable carrier, excipient, and / or adjuvant is administered to a patient.

[0317] In one or more embodiments, the disease is a disease associated with FRα expression. In one or more embodiments, the disease is a disease associated with FRα overexpression. In one or more embodiments, the disease is a tumor. In one or more embodiments, the disease is a tumor that expresses FRα. In one or more embodiments, the disease is a tumor that overexpresses FRα. In one or more embodiments, the disease is cancer. In one or more embodiments, the disease is a cancer that expresses FRα. In one or more embodiments, the disease is a cancer that overexpresses FRα. In one or more embodiments, the cancer is a cancer with FRα expression ≥1%. In one or more embodiments, the cancer is a cancer with FRα TPS (tumor cell positive score) ≥1%. In one or more embodiments, the cancer is a cancer with FRα expression >25%. In one or more embodiments, the cancer is a cancer with FRα TPS (tumor cell positive score) >25%. In one or more embodiments, the cancer is detected (such as by immunohistochemistry (IHC), flow cytometry, or nucleic acid hybridization) as having FRα TPS >25%. In one or more embodiments, the cancer is a cancer with FRα expression <50%. In one or more embodiments, the cancer is a cancer with FRα TPS < 50%. In one or more embodiments, the cancer is a cancer with FRα expression ≥ 50%. In one or more embodiments, the cancer is a cancer with FRα TPS ≥ 50%. In one or more embodiments, the cancer is a cancer with FRα expression ≥ 75%. In one or more embodiments, the cancer is a cancer with FRα TPS ≥ 75%.

[0318] Examples of cancer include, but are not limited to, solid tumors, hematological cancers, and metastatic lesions. Specific examples of such cancers include, but are not limited to, colorectal cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), ovarian cancer, uterine cancer, endometrial cancer, peritoneal cancer, fallopian tube cancer, pancreatic cancer, head and neck squamous cell carcinoma, nasopharyngeal cancer, laryngeal cancer, lung adenocarcinoma, liver cancer, breast cancer, brain cancer, kidney cancer, renal cell carcinoma, colon cancer, testicular cancer, cervical cancer, cervical cancer, tongue cancer, bladder cancer, retinoblastoma, glioblastoma, mesothelioma, oral epithelioid carcinoma, choriocarcinoma, head and neck cancer. In one or more embodiments, the cancer is advanced or metastatic cancer. In one or more embodiments, the cancer is platinum-refractory cancer. In one or more embodiments, the cancer is platinum-refractory ovarian cancer. In one or more embodiments, the patient suffers from platinum-refractory advanced or metastatic ovarian cancer. In one or more embodiments, the cancer is selected from platinum-refractory epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In one or more embodiments, the patient has platinum-refractory advanced or metastatic epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In one or more embodiments, the cancer is a platinum-resistant cancer. In one or more embodiments, the cancer is platinum-resistant ovarian cancer. In one or more embodiments, the patient has platinum-resistant advanced or metastatic ovarian cancer. In one or more embodiments, the cancer is selected from platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In one or more embodiments, the patient has platinum-resistant advanced or metastatic epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

[0319] In one or more embodiments, the patient has been treated with bevacizumab. In one or more embodiments, the patient has been treated with a poly(ADP-ribose) polymerase inhibitor (PARPi).

[0320] In one or more embodiments, the patient has platinum-resistant advanced or metastatic epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer and has received no more than 3 lines of prior treatment.

[0321] In one or more embodiments, the patient has an advanced or metastatic solid tumor that has failed or is intolerant to standard therapy.

[0322] In one or more embodiments, the patient has advanced or metastatic endometrial cancer, breast cancer, or non-small cell lung cancer that has failed or is intolerant to standard treatment.

[0323] In one or more embodiments, the cancer is an ovarian cancer with a FRαTPS>25%. In one or more embodiments, the ovarian cancer is detected (e.g., by immunohistochemistry) as having a FRαTPS>25%. In one or more embodiments, the cancer is an ovarian cancer with a FRαTPS>50%. In one or more embodiments, the ovarian cancer is detected (e.g., by immunohistochemistry) as having a FRαTPS>50%. In one or more embodiments, the cancer is an ovarian cancer with a FRα expression<50%. In one or more embodiments, the cancer is an ovarian cancer with a FRαTPS<50%. In one or more embodiments, the cancer is an ovarian cancer with a FRα expression≥50%. In one or more embodiments, the cancer is an ovarian cancer with a FRαTPS≥50%. In one or more embodiments, the cancer is an ovarian cancer with a FRα expression≥75%. In one or more embodiments, the cancer is an ovarian cancer with a FRαTPS≥75%.

[0324] In one or more embodiments, the present invention provides a method for treating cancer (such as ovarian cancer), comprising administering an effective amount of ADC1 to a patient with cancer (such as ovarian cancer) having FRαTPS>25%. In one or more embodiments, the effective amount refers to the amount of active compound or agent that results in a biological or medicinal response of a tissue, system, animal, individual, or human being that is being sought by a researcher, veterinarian, physician, or other clinician, which includes treating a disease. In one or more embodiments, the cancer has been treated with radiotherapy, chemotherapy, targeted therapy (such as PARPi therapy), and / or surgery.

[0325] In one or more embodiments, the antibody drug conjugate can be formulated into a pharmaceutical composition and administered to a patient in a form suitable for a selected route of administration, such as parenteral, intravenous (iv), intramuscular, topical, or subcutaneous.

[0326] In one or more embodiments, the dosage of the antibody drug conjugate (eg, ADC1 or ADC2) is 0.5 mg / kg-5 mg / kg; or, 0.5 mg / kg-3 mg / kg; or, 1.3 mg / kg-3 mg / kg; or, 1.7 mg / kg-2.5 mg / kg. In one or more embodiments, the dosage of the antibody drug conjugate (eg, ADC1 or ADC2) is about 0.5 mg / kg, about 1 mg / kg, about 1.2 mg / kg, about 1.5 mg / kg, about 1.8 mg / kg, about 2.1 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.0 mg / kg, about 4.5 mg / kg, about 5.0 mg / kg, or a range (including endpoints) between any two of these values ​​or any value therein.

[0327] In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) administered each time is 0.5 mg / kg-5 mg / kg; or, 0.5 mg / kg-3 mg / kg; or, 1.3 mg / kg-3 mg / kg; or, 1.7 mg / kg-2.5 mg / kg, or a formulation containing such a dose of an antibody drug conjugate (e.g., ADC1 or ADC2). In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) administered each time is about 0.5 mg / kg, about 1 mg / kg, about 1.2 mg / kg, about 1.5 mg / kg, about 1.8 mg / kg, about 2.1 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.0 mg / kg, about 4.5 mg / kg, about 5.0 mg / kg, or a range (including endpoints) between any two of these values ​​or any value therein, or a formulation containing this dose of antibody drug conjugate (e.g., ADC1 or ADC2). In one or more embodiments, the antibody drug conjugate is administered in a single dose. In one or more embodiments, the drug is administered once a day to once every 7 weeks. In one or more embodiments, the drug is administered once every 2 days to once every 6 weeks. In one or more embodiments, the drug is administered once every 2-4 weeks. In one or more embodiments, the drug is administered twice a week, or once every 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or about 7 weeks. In one or more embodiments, the drug is administered once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, twice a week, once a week, 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.

[0328] In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every three weeks at 0.5 mg / kg-5 mg / kg; or, 0.5 mg / kg-3 mg / kg; or, 1.3 mg / kg-3 mg / kg; or, 1.7 mg / kg-2.5 mg / kg, or a formulation containing such a dose of an antibody drug conjugate (e.g., ADC1 or ADC2). In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks at about 0.5 mg / kg, about 1 mg / kg, about 1.2 mg / kg, about 1.5 mg / kg, about 1.8 mg / kg, about 2.1 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.0 mg / kg, about 4.5 mg / kg, about 5.0 mg / kg, or a range (including endpoints) between any two of these values ​​or any value therein, or a formulation containing such a dose of an antibody drug conjugate (e.g., ADC1 or ADC2). In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks at about 1.2 mg / kg. In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks at about 1.5 mg / kg. In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks at approximately 1.8 mg / kg. In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks at approximately 2.1 mg / kg. In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks at approximately 2.4 mg / kg. In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks at approximately 3.0 mg / kg. In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks at approximately 3.6 mg / kg.

[0329] In one or more embodiments, the dosage of the antibody drug conjugate (eg, ADC1 or ADC2) is 5 mg / m 2 -150mg / m 2 Alternatively, 5 mg / m 2 -120mg / m 2 Alternatively, 10 mg / m 2 -120mg / m 2 Alternatively, 30 mg / m 2 -120mg / m 2 Alternatively, 50 mg / m2 -120mg / m 2 or 60 mg / m 2 -120mg / m 2 or 70 mg / m 2 -100mg / m 2 or 75 mg / m 2 -100mg / m 2 or 80 mg / m 2 -95mg / m 2 or 76 mg / m 2 -93mg / m 2 or 76 mg / m 2 -84 mg / m 2 or 84 mg / m 2 -93mg / m 2 or 87 mg / m 2 -93mg / m 2 In one or more embodiments, the antibody drug conjugate (eg, ADC1 or ADC2) is administered at a dose of about 5 mg / m 2 , about 10mg / m 2 , about 30mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 76mg / m 2 , about 80mg / m 2 , about 84mg / m 2 , about 87mg / m 2 , about 90mg / m 2 , about 93mg / m 2 , about 95mg / m 2 , about 100mg / m 2 , about 120mg / m 2 , about 150mg / m 2 , or a range between any two of these values ​​(including the endpoints) or any value therein.

[0330] In one or more embodiments, each administration of an antibody drug conjugate described herein (eg, ADC1 or ADC2) is 5 mg / m 2 -150mg / m 2 Alternatively, 5 mg / m 2 -120mg / m 2 Alternatively, 10 mg / m 2 -120mg / m 2 Alternatively, 30 mg / m 2 -120mg / m2 Alternatively, 50 mg / m 2 -120mg / m 2 or 60 mg / m 2 -120mg / m 2 or 70 mg / m 2 -100mg / m 2 or 75 mg / m 2 -100mg / m 2 or 80 mg / m 2 -95mg / m 2 or 76 mg / m 2 -93mg / m 2 or 76 mg / m 2 -84 mg / m 2 or 84 mg / m 2 -93mg / m 2 or 87 mg / m 2 -93mg / m 2 In one or more embodiments, each administration of an antibody drug conjugate described herein (eg, ADC1 or ADC2) is about 5 mg / m 2 , about 10mg / m 2 , about 30mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 76mg / m 2 , about 80mg / m 2 , about 84mg / m 2 , about 87mg / m 2 , about 90mg / m 2 , about 93mg / m 2 , about 95mg / m 2 , about 100mg / m 2 , about 120mg / m 2 , about 150mg / m 2, or the range (including endpoints) between any two values ​​in these numerical values ​​or any value therein. In one or more embodiments, the antibody drug conjugate is a single dose. In one or more embodiments, the administration is from once a day to once every 7 weeks. In one or more embodiments, the administration is from once every 2 days to once every 6 weeks. In one or more embodiments, the administration is once every 2-4 weeks. In one or more embodiments, the administration is twice in about 1 week, or once in about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or about 7 weeks. In one or more embodiments, the administration is once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, twice a week, once a week, 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.

[0331] In one or more embodiments, an antibody drug conjugate described herein (eg, ADC1 or ADC2) is administered once every three weeks at 5 mg / m 2 -150mg / m 2 Alternatively, 5 mg / m 2 -120mg / m 2 Alternatively, 10 mg / m 2 -120mg / m 2 Alternatively, 30 mg / m 2 -120mg / m 2 Alternatively, 50 mg / m 2 -120mg / m 2 or 60 mg / m 2 -120mg / m 2 or 70 mg / m 2 -100mg / m 2 or 75 mg / m 2 -100mg / m 2 or 80 mg / m 2 -95mg / m 2 or 76 mg / m 2 -93mg / m 2 or 76 mg / m 2 -84 mg / m 2 or 84 mg / m 2 -93mg / m 2 or 87 mg / m 2 -93mg / m 2, or a formulation containing such a dose of an antibody drug conjugate (e.g., ADC1 or ADC2). In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every three weeks at a dose of about 5 mg / m 2 , about 10mg / m 2 , about 30mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 76mg / m 2 , about 80mg / m 2 , about 84mg / m 2 , about 87mg / m 2 , about 90mg / m 2 , about 93mg / m 2 , about 95mg / m 2 , about 100mg / m 2 , about 120mg / m 2 , about 150mg / 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 antibody drug conjugate (e.g., ADC1 or ADC2). In one or more embodiments, the antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every three weeks at a dose of about 76 mg / m 2 In one or more embodiments, the antibody drug conjugate described herein (eg, ADC1 or ADC2) is administered once every three weeks at a dose of approximately 84 mg / m 2 In one or more embodiments, an antibody drug conjugate described herein (eg, ADC1 or ADC2) is administered once every three weeks at a dose of approximately 93 mg / m 2 .

[0332] In one or more embodiments, the dosage of the antibody drug conjugate is 10 mg to 300 mg; or, 30 mg to 300 mg; or, 50 mg to 280 mg; or, 100 mg to 250 mg. In one or more embodiments, the dosage of the antibody drug conjugate is about 10 mg, about 30 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 84 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg, about 120 mg, about 126 mg, about 130 mg, about 140 mg, about 144 mg, about 145 mg, about 150 mg, about 160 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 180 mg, about 186 mg, about 187 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg or about 150 mg, about 160 mg, about 165 mg, about 168 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 245 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, or a range between any two of these values ​​(including the endpoints) or any value therein.

[0333] In one or more embodiments, the amount of an antibody drug conjugate described herein (e.g., ADC1 or ADC2) administered each time is 10 mg-300 mg; or, 30 mg-300 mg; or, 50 mg-280 mg; or, 100 mg-250 mg, or a formulation containing such a dose of an antibody drug conjugate (e.g., ADC1 or ADC2). In one or more embodiments, the amount of an antibody drug conjugate described herein (e.g., ADC1 or ADC2) administered each time is about 10 mg, about 30 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 84 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg, about 120 mg, about 126 mg, about 130 mg, about 140 mg, about 144 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg In one or more embodiments, the antibody drug conjugate is administered at a dose of 1 mg, about 160 mg, about 165 mg, about 168 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 245 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, or a range (including endpoints) between any two of these values ​​or any value therein, or a formulation containing this dose of an antibody drug conjugate (e.g., ADC1 or ADC2). In one or more embodiments, the antibody drug conjugate is administered once a day. In one or more embodiments, the administration is from once every 7 weeks to once every 1 day. In one or more embodiments, the administration is from once every 2 days to once every 6 weeks. In one or more embodiments, the administration is once every 2-4 weeks. In one or more embodiments, the drug is administered twice a week, or once every 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or about 7 weeks. In one or more embodiments, the drug is administered once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, twice a week, once a week, 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.

[0334] In one or more embodiments, the amount of the antibody drug conjugate described herein (e.g., ADC1 or ADC2) administered per treatment cycle is 10 mg-300 mg; or, 30 mg-300 mg; or, 50 mg-280 mg; or, 100 mg-250 mg. In one or more embodiments, the amount of the antibody drug conjugate described herein (e.g., ADC1 or ADC2) administered per treatment cycle is about 10 mg, about 30 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 84 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg, about 120 mg, about 126 mg, about 130 mg, about 140 mg, about 144 mg, about about 280 mg, about 290 mg, about 300 mg, or a range (including endpoints) between any two of these values ​​or any value therein.

[0335] In one or more embodiments, 10 mg-300 mg of the antibody drug conjugate described herein (e.g., ADC1 or ADC2); or, 30 mg-300 mg; or, 50 mg-280 mg; or, 100 mg-250 mg, or a formulation containing such a dose of the antibody drug conjugate (e.g., ADC1 or ADC2) is administered once every three weeks. In one or more embodiments, about 10 mg, about 30 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 84 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg, about 120 mg, about 126 mg, about 130 mg, about 140 mg, about 144 mg, about 145 mg, about 150 mg, about 156 mg, about 158 ​​mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg 5mg, about 160mg, about 165mg, about 168mg, about 170mg, about 175mg, about 180mg, about 190mg, about 200mg, about 210mg, about 216mg, about 220mg, about 230mg, about 240mg, about 245mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, or a range (including endpoints) between any two of these values ​​or any value therein, or a formulation containing this dose of an antibody drug conjugate (e.g., ADC1 or ADC2). In one or more embodiments, about 72mg of an antibody drug conjugate (e.g., ADC1 or ADC2) described herein is administered once every 3 weeks. In one or more embodiments, about 90mg of an antibody drug conjugate (e.g., ADC1 or ADC2) described herein is administered once every 3 weeks. In one or more embodiments, about 108 mg of an antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks. In one or more embodiments, about 126 mg of an antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks. In one or more embodiments, about 144 mg of an antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks. In one or more embodiments, about 180 mg of an antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks. In one or more embodiments, about 216 mg of an antibody drug conjugate described herein (e.g., ADC1 or ADC2) is administered once every 3 weeks.

[0336] In one or more embodiments, the method includes at least 1, at least 2, at least 3, at least 4, at least 5 or at least 6 treatment cycles. In one or more embodiments, a treatment cycle is at least 1 day, at least 2 days, at least 3 days, at least 5 days, 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 1 month, about 5 weeks, about 6 weeks, about 2 months, about 6 months or about 1 year, or the range (including endpoints) between any two values ​​of these numerical values ​​or any value therein. In one or more embodiments, a treatment cycle is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 2 months or about 6 months. In one or more embodiments, a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or the range (including endpoints) between any two values ​​of these numerical values ​​or any value therein.

[0337] In one or more embodiments, the patient is administered once per treatment cycle. In one or more embodiments, the patient is administered multiple times per treatment cycle, for example 2, 3, 4, or 5 times. In one or more embodiments, the patient receives treatment for one treatment cycle. In one or more embodiments, the patient receives treatment for multiple (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) treatment cycles. In one or more embodiments, the patient receives treatment until the condition is alleviated and no longer requires treatment.

[0338] In one or more embodiments, the antibody drug conjugate or a pharmaceutical composition comprising the same is administered by injection. In one or more embodiments, the antibody drug conjugate or a pharmaceutical composition comprising the same is administered by subcutaneous (sc) injection, intraperitoneal (ip) injection, parenteral injection, intraarterial injection or intravenous (iv) injection. In one or more embodiments, the antibody drug conjugate or a pharmaceutical composition comprising the same is administered by infusion. In one or more embodiments, the antibody drug conjugate or a pharmaceutical composition comprising the same is administered by bolus injection. In one or more embodiments, the antibody drug conjugate or a pharmaceutical composition comprising the same is administered by intravenous injection. In one or more embodiments, the antibody drug conjugate or a pharmaceutical composition comprising the same is administered by subcutaneous injection. In one or more embodiments, the antibody drug conjugate or a pharmaceutical composition comprising the same is administered by intraperitoneal injection. In one or more embodiments, the antibody drug conjugate or a pharmaceutical composition comprising the same is administered by intravenous infusion.

[0339] In one or more embodiments, the present invention provides a method for treating cancer, comprising administering an effective amount of an antibody drug conjugate to a patient in need thereof by injection; wherein the dosage of the antibody drug conjugate is 1.8 mg / kg, 2.1 mg / kg, 2.4 mg / kg, 76-93 mg / m 2 or 84-93 mg / m 2 , administered once every 3 weeks; the antibody drug conjugate has the structure shown in Formula I-13-1 or its stereoisomers or pharmaceutically acceptable salts or solvates:

[0340] in,

[0341] Abu is an anti-FRα antibody, the heavy chain of which comprises the amino acid sequence set forth in SEQ ID NO: 11, and the light chain of which comprises the amino acid sequence set forth in SEQ ID NO: 13;

[0342] p is 3.5-4.5, or 7-8.

[0343] In one or more embodiments, the present invention provides a method for treating cancer, comprising administering an effective amount of an antibody drug conjugate to a patient in need thereof by injection; wherein the dosage of the antibody drug conjugate is 1.8 mg / kg, 2.1 mg / kg, 2.4 mg / kg, 76-93 mg / m 2 or 84-93 mg / m 2 , administered once every 3 weeks; the antibody drug conjugate has a structure as shown in Formula I-13-1 or a pharmaceutically acceptable salt or solvate thereof:

[0344] in,

[0345] Abu is an anti-FRα antibody, the heavy chain of which comprises the amino acid sequence set forth in SEQ ID NO: 11, and the light chain of which comprises the amino acid sequence set forth in SEQ ID NO: 13;

[0346] p is 3.5-4.5.

[0347] In one or more embodiments, the present invention provides a method for treating cancer, comprising administering an effective amount of an antibody drug conjugate to a patient in need thereof by injection; wherein the dosage of the antibody drug conjugate is 1.8 mg / kg, 2.1 mg / kg, 2.4 mg / kg, 76-93 mg / m 2 or 84-93 mg / m 2, administered once every 3 weeks; the antibody drug conjugate has a structure as shown in Formula I-13-1 or a pharmaceutically acceptable salt or solvate thereof:

[0348] in,

[0349] Abu is an anti-FRα antibody, the heavy chain of which comprises the amino acid sequence set forth in SEQ ID NO: 11, and the light chain of which comprises the amino acid sequence set forth in SEQ ID NO: 13;

[0350] p is 7-8.

[0351] In one or more embodiments, the present invention provides a method for treating cancer comprising injecting a human patient in need thereof with an amount of about 1.8 mg / kg of ADC1 once every 3 weeks. In one or more embodiments, the present invention provides a method for treating cancer comprising injecting a human patient in need thereof with an amount of about 2.1 mg / kg of ADC1 once every 3 weeks. In one or more embodiments, the present invention provides a method for treating cancer comprising injecting a human patient in need thereof with an amount of about 2.4 mg / kg of ADC1 once every 3 weeks. In one or more embodiments, the present invention provides a method for treating cancer comprising injecting a human patient in need thereof with an amount of 76-93 mg / m 2 In one or more embodiments, the present invention provides a method for treating cancer, comprising injecting 84-93 mg / m2 of ADC1 into a human patient in need thereof once every 3 weeks. 2 In one or more embodiments, the present invention provides a method of treating cancer comprising injecting about 76 mg / m2 of ADC1 into a human patient in need thereof once every 3 weeks. 2 In one or more embodiments, the present invention provides a method of treating cancer comprising injecting about 84 mg / m2 of ADC1 into a human patient in need thereof once every 3 weeks. 2 In one or more embodiments, the present invention provides a method of treating cancer comprising injecting about 93 mg / m2 of ADC1 into a human patient in need thereof once every 3 weeks. 2 ADC1 of the quantity.

[0352] In one or more embodiments, the antibody drug conjugate or the pharmaceutical composition comprising the same is administered by intravenous (iv) infusion mode (i.e., intravenous infusion). In one or more embodiments, the intravenous infusion duration is about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 81 minutes, about 87 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 150 minutes, or the range (including endpoints) between any two values ​​in these numerical values ​​or any value therein. In one or more embodiments, the intravenous infusion time is ≥30 minutes. In one or more embodiments, the intravenous infusion time is ≥60 minutes. In one or more embodiments, the intravenous infusion time is ≥90 minutes.

[0353] In one or more embodiments, the uses and methods of the present invention utilize pharmaceutical compositions suitable for injection, such as bolus-type pharmaceutical compositions or infusion (drip)-type pharmaceutical compositions, comprising the antibody drug conjugate. Pharmaceutical compositions suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injection solutions or dispersions.

[0354] For intravenous administration, suitable carriers include solvents or dispersion media of physiological saline, antibacterial water or phosphate buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.), and suitable mixtures thereof. In one or more embodiments, the pharmaceutical composition also includes a pharmaceutically acceptable carrier. In one or more embodiments, the pharmaceutically acceptable carrier can include antibacterial and / or antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. to achieve. In one or more embodiments, the pharmaceutically acceptable carrier can include isotonic agents, such as sugars, polyols (such as mannitol, sorbitol), sodium chloride. In one or more embodiments, the pharmaceutical composition includes at least 0.1% antibody drug conjugate. The amount of the antibody drug conjugate in this pharmaceutical composition can be an effective amount for administration.

[0355] The methods and uses of the present invention provide substantial single-agent clinical efficacy while maintaining a favorable safety profile. In one or more embodiments, the methods and uses of the present invention can achieve an ORR greater than or equal to 40%, and / or a DCR greater than or equal to 80%. In one or more embodiments, the methods and uses of the present invention can also reduce toxicity, such as hematologic or gastrointestinal toxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0356] Figure 1 shows the overall efficacy data for subjects in all dose groups; in the figure, from left to right, columns 1, 2, 4, 5, 7, 8, 11, 17, 18, 21, 24, 27-29 are 2.4 mg / kg, columns 3, 9, 10, 14, 16, 19, 22, 23, 26 are 2.1 mg / kg, columns 6, 12, 13, 20, 25 are 1.8 mg / kg, and column 15 is 1.2 mg / kg.

[0357] Figure 2 is a diagram of subjects swimming; in the figure, only the 18th row from top to bottom received 1.2 mg / kg treatment.

[0358] Figure 3 shows the efficacy data for subjects with ovarian cancer and fallopian tube cancer.

[0359] FIG. 4 is a spider diagram of subjects with ovarian and fallopian tube cancer (N=17).

[0360] Figure 5 is a waterfall plot of the maximum target lesion reduction in PROC patients (N=54); in the figure, from left to right, columns 2, 8, 11, 20, 23, 26, 32, 36, 37, 43, 46-49 are 2.1 mg / kg, columns 29 and 40 are 1.8 mg / kg, and columns 4, 9, 14, 25, 27, 28, 39, 41, and 45 are 93 mg / m 2 .

[0361] FIG6 is a spider diagram of PROC patients (N=54).

[0362] Figure 7 shows the Kaplan-Meier curve of PFS.

[0363] Figure 8 shows the Kaplan-Meier curve of OS. DETAILED DESCRIPTION

[0364] Unless otherwise defined, the meanings of scientific and technical terms used in the present invention are those commonly understood by those skilled in the art.

[0365] definition

[0366] It should be noted that the term "a" entity refers to one or more of that entity, e.g., "an antibody" should be understood as one or more antibodies, and thus, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein.

[0367] As used herein, the terms "comprising" or "including" mean that the antibody, composition, or method, etc. includes the listed elements, such as components or steps, but does not exclude others. "Essentially consisting of" means that the antibody, composition, or method, etc. excludes other elements that have a fundamental effect on the characteristics of the combination, but does not exclude elements that do not substantially affect the antibody, composition, or method, etc. "Consisting of" means excluding elements not specifically listed.

[0368] "About" refers to the conventional error range of the corresponding numerical value that is easily known to those skilled in the relevant art. In some embodiments, "about" mentioned herein refers to the described numerical value and its ±10%, ±5% or ±1% range.

[0369] "Treatment" refers to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent, slow, ameliorate or halt an undesirable physiological change or disorder, such as the progression of a disease, including but not limited to the following results, whether detectable or undetectable, relief of symptoms, reduction in the severity of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement, alleviation, reduction or elimination of the disease state (whether partial or complete), prolongation of life expectancy compared to that expected in the absence of treatment, etc. Patients in need of treatment include those already suffering from the disease or disorder, those susceptible to the disease or disorder, or those in need of prevention of the disease or disorder, and those who can or are expected to benefit from the administration of the antibodies or pharmaceutical compositions disclosed herein for detection, diagnostic procedures and / or treatment.

[0370] The term "cancer" refers to or is intended to describe a physiological state in mammals that is typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, or leukemia. More specific examples of such cancers include, but are not limited to, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, endometrial cancer, salivary gland cancer, peritoneal cancer, fallopian tube cancer, pancreatic cancer, thyroid cancer, head and neck squamous cell carcinoma, nasopharyngeal cancer, laryngeal cancer, lung adenocarcinoma, lung squamous cell carcinoma, liver cancer, hepatocellular carcinoma, gastrointestinal cancer, glioblastoma, breast cancer, brain cancer, kidney cancer, renal cell carcinoma, colon cancer, rectal cancer, prostate cancer, vulvar cancer, testicular cancer, squamous cell carcinoma, small cell lung cancer, cervical cancer, cervical cancer, tongue cancer, bladder cancer, retinoblastoma, glioblastoma, mesothelioma, oral epithelioid carcinoma, choriocarcinoma, and head and neck cancer.

[0371] The terms "overexpression" or "overexpressed" interchangeably refer 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 overexpression of protein or RNA (due to increased transcription, post-transcriptional processing, translation, post-translational processing, altered stability and altered protein degradation), as well as local overexpression (increased nuclear localization) and enhanced functional activity due to altered protein trafficking patterns, such as, for example, increased enzymatic hydrolysis of a substrate. Overexpression can be 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90% or more compared to normal cells or control cells. In certain embodiments, the anti-FRα antibodies and antibody drug conjugates of the present invention are used to treat solid tumors that may overexpress folate receptor alpha.

[0372] In some embodiments, folate receptor alpha expression in a tumor sample is higher than background levels of immune tissue (e.g., as determined by immunohistochemical staining) indicating that the tumor is a folate receptor alpha-overexpressing tumor. Methods for detecting folate receptor alpha expression in tumors are known in the art, such as immunohistochemical assays.

[0373] The term "in need thereof" refers to a patient who has been identified as being in need of a particular method or treatment. In some embodiments, identification can be performed by any diagnostic means. In any of the methods and treatments described herein, a patient may be in need.

[0374] The term "patient" refers to any mammal in need of diagnosis, prognosis or treatment, including but not limited to humans, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, etc. In some embodiments, the patient is a human.

[0375] As used herein, the term "administration" or "application" refers to the administration of a substance to achieve a therapeutic purpose (e.g., to treat a tumor). The administration route can be parenteral, enteral, and topical. Parenteral administration is typically by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0376] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a drug, such as an antibody or ADC, that is sufficient to reduce or improve the severity and / or duration of a condition (e.g., cancer) or one or more symptoms thereof; prevent the progression of the condition; cause the condition to regress; prevent the recurrence, development, onset, or progression of one or more symptoms associated with the condition; detect the condition; or enhance or improve the preventive or therapeutic effect of another therapy (e.g., a prophylactic or therapeutic agent). For example, an effective amount of an antibody can inhibit tumor growth (e.g., inhibit an increase in tumor volume); reduce tumor growth (e.g., reduce tumor volume); reduce the number of cancer cells; and / or alleviate one or more symptoms associated with cancer to some extent. For example, an effective amount can improve disease-free survival (DFS), improve overall survival (OS), or reduce the likelihood of recurrence.

[0377] The term "antibody drug conjugate" or "ADC" refers to a binding protein (such as an antibody or its antigen binding unit) connected to one or more chemical drugs, which may optionally be a therapeutic agent or a cytotoxic agent. In a preferred embodiment, the ADC comprises an antibody, a drug (such as a cytotoxic drug) and a linker that enables the drug to be attached or coupled to the antibody. Non-limiting examples of drugs that may be included in an ADC are mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, anti-angiogenic agents, antimetabolites, boron-containing agents, chemoprotectants, hormones, anti-hormonal agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclide agents, topoisomerase inhibitors, kinase inhibitors (e.g., TEC-family kinase inhibitors and serine / threonine kinase inhibitors) and radiosensitizers.

[0378] The terms "antibody drug conjugate" and "ADC" are used interchangeably. The terms "anti-folate receptor alpha antibody drug conjugate," "anti-FRα antibody drug conjugate," "anti-FRα ADC," and "anti-folate receptor alpha ADC" are used interchangeably and refer to an ADC comprising an antibody that specifically binds to folate receptor alpha, wherein the antibody is conjugated to one or more drugs. In one or more embodiments, the anti-FRα ADC comprises an antibody conjugated to exitecan. In one or more embodiments, the anti-FRα antibody or ADC binds to folate receptor alpha (e.g., human folate receptor alpha).

[0379] The term "drug-antibody coupling ratio" or "DAR" refers to the number of drugs (e.g., exotecan) attached to an antibody of an ADC. The DAR of an ADC can range from 1 to 10, but higher loadings (e.g., 20) are possible depending on the number of attachment sites on the antibody. The term DAR can be used when referring to the number of drugs loaded onto a single antibody, or alternatively, when referring to the average or mean DAR of a group of ADCs. In some embodiments, the value is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. When considering the average number of small molecule drugs bound, that is, the average number of drugs bound to the antibody, or the average drug-antibody coupling ratio, the value is selected from about 0 to about 10, or about 2 to about 8. In some embodiments, the drug-antibody coupling ratio is about 3 to about 6. In other embodiments, the drug-antibody coupling ratio is about 6 to about 8, or about 7 to about 8. DAR values ​​can be represented herein by p. Those skilled in the art understand that the average DAR value (p) of different batches of the same ADC can vary slightly. The DAR value of an ADC can be measured using ultraviolet-visible absorption spectroscopy (UV-Vis), high-performance liquid chromatography-hydrophobic chromatography (HPLC-HIC), high-performance liquid chromatography-reverse phase chromatography (RP-HPLC), liquid chromatography-mass spectrometry (LC-MS), etc. These techniques are described in Ouyang, J. Methods Mol Biol, 2013, 1045: p. 275-83.

[0380] Various substituents are defined as follows. In some cases, the number of carbon atoms in a substituent (for example, alkyl, alkenyl, alkynyl, alkoxy, aminoalkoxy, aminoalkyl, aminoalkylamino, alkylamino, heterocyclic radical, heterocyclic amino and aryl) is indicated by prefix "Cx-Cy" or "Cx-y", where x is the minimum value of carbon atoms and y is the maximum value of carbon atoms. Therefore, for example, "C1-C6 alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms. If a substituent is described as "substituted by ... ", the hydrogen atoms on carbon or nitrogen are replaced by non-hydrogen groups. For example, a substituted alkyl substituent is an alkyl substituent in which at least one hydrogen atom on the alkyl group is replaced by a non-hydrogen group. For illustration, monofluoroalkyl is an alkyl group substituted by a fluoro group, and difluoroalkyl is an alkyl group substituted by two fluoro groups. It should be appreciated that if there is more than one substitution on a substituent, each substitution can be identical or different (unless otherwise indicated). If a substituent is described as being "optionally substituted with...", the substituent may be (1) unsubstituted or (2) substituted. Possible substituents include, but are not limited to, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 aminoalkoxy, halogen, nitro, cyano, mercapto, alkylthio, amino, C1-C6 aminoalkyl, C1-C6 aminoalkylamino, C1-C6 alkyl attached to a heterocycle, C1-C6 alkylamino attached to a heterocycle, heterocyclyl, amino-substituted heterocyclyl, heterocyclamino, carbamoyl, morpholin-1-yl, piperidin-1-yl, -(CH2) q -CH3、-(CHR n ) q -CH3, C3-C8 carbocyclyl, -O-(CH2) q -CH3, arylene-CH3, -(CH2) q -Arylene-CH3, -Arylene-(CH2) q -CH3, -(CH2) q -(C3-C8 carbocyclyl)-CH3, -(C3-C8 carbocyclyl)-(CH2) q -CH3, C3-C8 heterocyclic group, -(CH2) q -(C3-C8 heterocyclyl)-CH3, -(C3-C8 heterocyclyl)-(CH2) q -CH3, -(CH2) q C(O)NR n (CH2) q -CH3, -(CH2CH2O) q -CH3, -(CH2CH2O) q -CH2-CH3, -(CH2) q C(O)NR n(CH2CH2O) q -CH3, -(CH2) q C(O)NR n (CH2CH2O) q -CH2-CH3, -(CH2CH2O) q C(O)NR n (CH2CH2O) q -CH3, -(CH2CH2O) q C(O)NR n (CH2CH2O) q -CH2-CH3, or -(CH2CH2O) q C(O)NR n (CH2) q -CH3; each R n is independently H, C1-C6 alkyl, C3-C8 carbocyclyl, phenyl or benzyl; and each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0381] "Alkyl" refers to a saturated aliphatic hydrocarbon group, and the term includes straight and branched hydrocarbon groups. For example, C1-C20 alkyl, such as C1-C6 alkyl. C1-C20 alkyl refers to an alkyl group with 1 to 20 carbon atoms, for example, an alkyl group with 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms or 20 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl etc. The alkyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxyl, aryl, heteroaryl, amine, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.

[0382] The term "alkenyl" by itself or as part of another substituent refers to an unsaturated branched, straight chain or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of a hydrogen atom from a single carbon atom of a parent alkene. Typical alkenyl groups include, but are not limited to, vinyl; propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl); cycloprop-2-en-1-yl; butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, but-1,3-dien-1-yl, but-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1,3-dien-1-yl, etc.), and the like.

[0383] The term "alkynyl" by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl group having at least one carbon-carbon triple bond, the triple bond being derived by removing a hydrogen atom from a single carbon atom of the parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl, etc.); butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.); and the like.

[0384] "Carbocyclyl" refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from 3 to 15 carbon atoms, for example, from 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms, and which is saturated or unsaturated and attached to the remainder of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decahydronaphthyl, etc. When specified, a carbocyclyl may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, cyano, nitro, oxo, aryl, aralkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl.

[0385] "Aryl" refers to an all-carbon monocyclic or all-carbon fused ring having a completely conjugated π electron system, typically having 5-14 carbon atoms, for example, 6, 10, 12, or 14 carbon atoms. An aryl group can be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carboxyl, aryl, aralkyl, amine, halogen, sulfonyl, sulfinyl, and phosphonyl. Examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

[0386] "Heterocyclyl" refers to a stable 3- to 18-membered aromatic or non-aromatic ring substituent consisting of 2 to 8 (e.g., 2, 3, 4, 5, 6, 7, or 8) carbon atoms and 1 to 6 (1, 2, 3, 4, 5, or 6) heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, dioxinyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, piperrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, 1,2,4-thiadiazol-5(4H)-yl, tetrahydrofuranyl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. When specifically stated in the specification, heterocyclyl can be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halogen, haloalkyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl.

[0387] "Alkoxy" refers to the formula -O-(alkyl), where alkyl is an alkyl group as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Alkoxy groups may be substituted or unsubstituted.

[0388] "Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0389] "Amino" refers to -NH2.

[0390] "Cyano" refers to -CN.

[0391] "Nitro" refers to -NO2.

[0392] "Hydroxyl" refers to -OH.

[0393] "Carboxyl" refers to -COOH.

[0394] "Mercapto" refers to -SH.

[0395] "Carbonyl" refers to C=O.

[0396] "Stereoisomers" refer to isomeric compounds that have the same order of attachment of atoms but different arrangements of atoms in space. Stereoisomers can have one or more stereocenters and each center can exist as R or S. Stereoisomers can also be cis-trans isomers. Stereoisomers of the compounds provided herein include any one of all diastereomeric, enantiomeric, and cis-trans isomeric forms thereof or suitable mixtures thereof.

[0397] Pharmaceutically acceptable salts include pharmaceutically acceptable salts of the compounds with a wide variety of organic and inorganic counterions well known in the art. Exemplary salts include, when the molecule contains an acidic functional group, organic or inorganic salts such as lithium, sodium, potassium, calcium, magnesium, ammonium, isopropylamine, trimethylamine, diethylamino, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethyl, piperidine, polyamine resins, and tetraalkylammonium salts; and when the molecule contains a basic functional group, organic or inorganic acid salts such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, and oxalate. Other non-limiting examples of acids include sulfuric acid, nitric acid, phosphoric acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid salicylic acid, etc. These salts can generally be prepared by conventional methods by reacting, for example, an appropriate acid or base with the compound. Solvates include hydrates.

[0398] All publications and patents cited herein are incorporated by reference in their entirety for all purposes.

[0399] Antibody Drug Conjugates

[0400] In one or more embodiments, the ADC is a structure as shown in Formula I or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof.

[0401] wherein Abu, M, B, G, L, D, and p are as defined herein.

[0402] In one or more embodiments, Abu is Antibody 1.

[0403] In one or more embodiments, the ADC is ADC1 or ADC2 or a pharmaceutically acceptable salt or solvate thereof.

[0404] Synthesis method

[0405] The intermediates and antibody-drug conjugates of the present invention can be prepared by known preparations and methods.

[0406] In one or more embodiments, the method for preparing intermediate compound 1-7 is as follows.

[0407] Step 1: reacting a compound of formula 1-1 with a compound of formula 1-1' under alkaline conditions to obtain a compound of formula 1-2;

[0408] Step 2: Compounds of formula 1-2 and formula (AA) i -(FF 1 ) f In the presence of a condensing agent, react under alkaline conditions to obtain a compound of formula 1-3;

[0409] Step 3: removing the amino protecting group W1 of the compound of formula 1-3 to obtain the compound of formula 1-4;

[0410] Step 4: reacting the compound of formula 1-4 with the compound of formula 1-5 under alkaline conditions to obtain the compound of formula 1-6;

[0411] Step 5: The compound of formula 1-6 reacts with di(p-nitrobenzene) carbonate under alkaline conditions to obtain the compound of formula 1-7.

[0412] in

[0413] W1 is an amino protecting group, such as 9-fluorenylmethoxycarbonyl; W2 is a carboxylic acid active ester, such as succinimide ester.

[0414] Wherein, n, AA, R, i, and f are as described herein, and each FF 1 Independent Among them, each R F are independently C1-C6 alkyl, C1-C6 alkoxy, -NO2 or halogen; z is 0, 1, 2, 3 or 4; wherein * connects AA; each FF 2 Independent Among them, each R F is independently C1-C6 alkyl, C1-C6 alkoxy, -NO2 or halogen; z is 0, 1, 2, 3 or 4; wherein * connects AA.

[0415] In one or more embodiments, R F For F.

[0416] In one or more embodiments, z is 0.

[0417] In one or more embodiments, z is 1 or 2.

[0418] The above-mentioned alkaline conditions can be provided by reagents, which include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and lithium hydroxide.

[0419] The above condensing agent can be selected from N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole- N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.

[0420] In one or more embodiments, the method for preparing intermediate compound 1-8 is as follows.

[0421] The compound of formula 1-7 reacts with D in the presence of a condensing agent under alkaline conditions to obtain the compound of formula 1-8.

[0422] Among them, n, AA, R, i, f, FF 2 , FF, and D are as described in this article.

[0423] The above-mentioned alkaline conditions can be provided by reagents, which include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and lithium hydroxide.

[0424] The above condensing agent can be selected from N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole- N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.

[0425] In one or more embodiments, the method for preparing antibody drug conjugate compounds 1-9 is as follows.

[0426] The compound of formula 1-8 is coupled with Abu under weakly acidic conditions to obtain the compound of formula 1-9.

[0427] wherein n, AA, R, i, f, FF, D, Abu, and p are as described herein.

[0428] Specifically, the interchain disulfide bonds on the anti-FRα antibodies provided by the present invention are reduced and opened by a thiol reducing agent to generate free sulfhydryl groups, which then undergo a coupling reaction with the compound of formula 1-8 to obtain the antibody-drug conjugate of formula 1-9.

[0429] The above-mentioned weakly acidic conditions can be provided by reagents, which include organic acids and inorganic acids. The organic acids include but are not limited to acetic acid, benzoic acid, tartaric acid, oxalic acid, malic acid, citric acid, ascorbic acid, citric acid, citric acid, salicylic acid, caffeic acid, sorbic acid, quinic acid, oleanolic acid, succinic acid, chlorogenic acid, formic acid, and propionic acid. The inorganic acids include but are not limited to carbonic acid, nitrous acid, acetic acid, hypochlorous acid, hydrofluoric acid, sulfurous acid, hydrosulfuric acid, silicic acid, metasilicic acid, phosphoric acid, metaphosphoric acid, sodium bicarbonate, and sodium bisulfite.

[0430] The drug conjugate can be purified by conventional methods, such as preparative high performance liquid chromatography (prep-HPLC).

[0431] Treatment methods and uses

[0432] The antibodies or antigen binding units thereof or ADCs provided by the present invention or pharmaceutical compositions comprising the same can be used for diagnosis, prognosis, monitoring, treatment, alleviation and / or prevention of diseases and conditions associated with abnormal expression of FRα in patients. When the presence of diseases and conditions associated with abnormal expression of FRα in patients is identified by conventional methods, the antibodies or antigen binding units thereof or ADCs described in the present invention or pharmaceutical compositions comprising the same can be administered. In one or more embodiments, the degree of FRα expression is detected by immunohistochemistry (IHC), flow cytometry or nucleic acid hybridization. WO 2014 / 036495 and WO 2015 / 031815 provide exemplary antibodies, detection methods and kits for detecting FRα, all of which are incorporated herein by reference.

[0433] In one or more embodiments, the present invention relates to a method for treating related diseases with FRα as a therapeutic target, thereby improving, slowing down, inhibiting, treating or preventing any disease or condition associated with abnormal FRα expression (e.g., FRα overexpression); and relates to providing a method for treating patient tumors (including benign tumors and cancers), a method for alleviating symptoms of patient tumors (including benign tumors and cancers), and a method for avoiding recurrence of patient tumors (including benign tumors and cancers), the method comprising administering to the patient an effective amount of any antibody or antigen-binding unit thereof or ADC described herein.

[0434] In one or more embodiments, the present invention provides a method for preventing, treating or ameliorating a disease, comprising administering an effective amount of an anti-FRα antibody or its antigen binding unit or ADC or a pharmaceutical composition comprising the same to a patient in need thereof. In one or more embodiments, the present invention provides the use of the antibody or its antigen binding unit or ADC in the preparation of a medicament for preventing, treating or ameliorating a disease. In one or more embodiments, the present invention provides the use of the antibody or its antigen binding unit or ADC in preventing, treating or ameliorating a disease. In one or more embodiments, the disease is a disease associated with abnormal expression of FRα. In one or more embodiments, the disease is a disease associated with overexpression of FRα. In one or more embodiments, the disease is a tumor. In one or more embodiments, the disease is a tumor expressing FRα. In one or more embodiments, the disease is a tumor overexpressing FRα. In one or more embodiments, the disease is cancer. In one or more embodiments, the disease is a cancer overexpressing FRα. In one or more embodiments, the disease is a cancer overexpressing human FRα.

[0435] In one or more embodiments, the present invention provides a method for treating tumors (including benign tumors and cancers), comprising administering an effective amount of an anti-FRα antibody or its antigen-binding unit or ADC or a pharmaceutical composition comprising the same to a patient in need thereof. In one or more embodiments, the present invention provides the use of the antibody or its antigen-binding unit or ADC in the preparation of a medicament for treating tumors (including benign tumors and cancers). In one or more embodiments, the present invention provides the use of the antibody or its antigen-binding unit or ADC in the treatment of tumors (including benign tumors and cancers).

[0436] Examples of cancer include, but are not limited to, solid tumors, hematological cancers, and metastatic lesions. Specific examples of such cancers include, but are not limited to, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, endometrial cancer, peritoneal cancer, fallopian tube cancer, pancreatic cancer, head and neck squamous cell carcinoma, nasopharyngeal cancer, laryngeal cancer, lung adenocarcinoma, liver cancer, breast cancer, brain cancer, kidney cancer, renal cell carcinoma, colon cancer, testicular cancer, cervical cancer, cervical cancer, tongue cancer, bladder cancer, retinoblastoma, glioblastoma, mesothelioma, oral epithelioid carcinoma, choriocarcinoma, and head and neck cancer. More specific examples of such cancers include ovarian cancer, epithelial ovarian cancer, primary ovarian peritoneal cancer, or fallopian tube cancer. In one or more embodiments, the cancer is metastatic or advanced cancer. In one or more embodiments, the patient is a patient with increased FRα expression levels.

[0437] Combination therapy

[0438] In one or more embodiments, the antibodies or antigen-binding units thereof or ADCs of the present invention can be used in conjunction with other treatment or prevention regimens, including one or more antibodies or antigen-binding units thereof or ADCs of the present invention and one or more other therapeutic agents or methods. For combination therapy, the antibodies or antigen-binding units thereof or ADCs can be administered simultaneously or separately with the other therapeutic agents. When administered separately, the antibodies or antigen-binding units thereof or ADCs of the present invention can be administered before or after administration of the other therapeutic agent.

[0439] In one or more embodiments, when administering an antibody or antigen-binding unit thereof or ADC of the present invention to a patient, the patient may also be administered an antibody or antigen-binding unit thereof or ADC or pharmaceutical composition or immunoconjugate disclosed herein in combination with one or more other therapies, such as treatment modalities and / or other agents (e.g., therapeutic agents).

[0440] In one or more embodiments, the antibodies of the present invention or their antigen binding units or ADCs can be used together with immune checkpoint inhibitors. In one or more embodiments, the antibodies of the present invention or their antigen binding units or ADCs are administered in combination with other treatments or prevention regimens, such as radiotherapy.

[0441] Such combination therapies encompass simultaneous administration (wherein two or more formulations are contained in the same formulation or in separate formulations), and separate administration, in which case administration of the antibody, or its antigen binding unit, or ADC of the invention can occur before, simultaneously with, and / or after administration of another therapy, such as a treatment modality and / or therapeutic agent. The antibody, or its antigen binding unit, or ADC and / or other therapies, such as a therapeutic agent or treatment modality can be administered during active disease or during remission or less active disease. The antibody, or its antigen binding unit, or ADC can be administered before, simultaneously with, after, or during remission of the disease.

[0442] The citation of publications and patents herein does not constitute an admission that any of the foregoing is prior art, nor does it constitute an admission of their content or date. While the present invention has been described in the form of a written specification, those skilled in the art will recognize that the invention may be practiced in a variety of embodiments, and the foregoing description and the following examples are intended to illustrate, not to limit, the present invention as claimed. All publications, patents, and patent applications cited herein are incorporated by reference in their entirety for all purposes.

[0443] Example

[0444] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources or known methods.

[0445] Example 1: Antibody Preparation

[0446] The amino acid and nucleic acid sequences of Antibody 1 are shown in Table 1. The nucleic acid sequences encoding the heavy and light chains of Antibody 1 were cloned into expression vectors, transiently transfected into HEK293F cells, cultured, and purified to obtain the antibody. Sequencing confirmed the expected sequence.

[0447] Table 1 Amino acid sequence and nucleic acid sequence of Antibody 1

[0448] Example 2: Synthesis of Compound (1S,9S)-1-amino-9-ethyl-4,5-difluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione hydrochloride (D-1)

[0449] 1. Synthesis of N,N'-(3,4-difluoro-8-oxo-5,6,7,8-tetrahydronaphthalene-1,7-diyl)diethylamide

[0450] Under nitrogen, add potassium tert-butoxide solution (42 mL, 1 M) in tetrahydrofuran to a dry reaction flask with stirring and cool to 0-5°C. Slowly add N-(3,4-difluoro-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (CAS No. 143655-49-6, 5 g, 21 mmol) dissolved in tetrahydrofuran (25 mL) dropwise to the reaction flask, followed by tert-butyl nitrite (4.32 g, 2 eq) dropwise (temperature controlled at 0-5°C). Heat to 15-20°C and stir for 2 h. After the reaction is complete, cool to 0-5°C, add acetic acid (25 mL) and acetic anhydride (25 mL) dropwise (temperature controlled at no more than 10°C), and stir for 20 min. Maintain 5-10°C and add zinc powder (8 eq) according to the amount of N-(3,4-difluoro-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, and stir at 20-25°C for 1 hour. Filter, rinse the solid with ethyl acetate (50 mL), cool to 0-5°C, add 15% NaCO3 aqueous solution (50 mL) dropwise and wash three times, extract with ethyl acetate (25 mL), combine the organic phases, and wash with saturated NaCl aqueous solution. Add ethyl acetate (10 mL), stir at 40°C for 30 minutes, slowly reduce to 0-5°C and stir for 2 hours. Filter, wash the solid with ethyl acetate / petroleum ether (1 / 2, 10 mL). Dry in vacuo to obtain a gray powder (2.1 g, 33.7%). LC-MS: [M+H] + =297.

[0451] 2. Synthesis of N-(8-amino-5,6-difluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide

[0452] Add N,N'-(3,4-difluoro-8-oxo-5,6,7,8-tetrahydronaphthalene-1,7-diyl)diethylamide (500 mg, 1.68 mmol) to a 2M hydrochloric acid-ethanol solution (5 mL) and stir at 50°C for 4 h. After the reaction is complete, add water (7.5 mL), cool to 0-5°C, and add triethylamine (1.03 g) dropwise, stirring for 3 h. Filter and wash with 40% cold ethanol (3 mL) and water (3 mL), respectively. Dry in vacuo to obtain a gray powder (320 mg, 74.6%). LC-MS: [M+H] + =255.

[0453] 3. Synthesis of N-((9S)-9-ethyl-4,5-difluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3';4':6,7]indolizino[1,2-b]quinolin-1-yl)acetamide

[0454] Under nitrogen atmosphere, N-(8-amino-5,6-difluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (1.1 g, 1 eq), (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (1.15 g, 1 eq), and toluene (50 mL) were added to a reaction flask. The temperature was raised to reflux, stirred for 1 h, and then 4-methylbenzenesulfonic acid pyridine (100 mg) was added. Stirring and reflux were continued for 20 h. The temperature was lowered to room temperature and stirred for 1 h. The mixture was filtered and the solid was washed with acetone (10 mL) and cold ethanol (5 mL). The mixture was dried under vacuum to obtain a gray-brown powder (1.1 g, 53%). LC-MS: [M+H] + =482.

[0455] 4. Synthesis of (1S,9S)-1-amino-9-ethyl-4,5-difluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione hydrochloride (D-1)

[0456] N-((9S)-9-ethyl-4,5-difluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)acetamide (1.1 g, 2.28 mmol) and 6M aqueous hydrochloric acid (44 mL) were added to a reaction flask and refluxed under nitrogen for 4 h. The solvent was removed by concentration and the product was purified by HPLC to obtain a white powder (200 mg, 18%). LC-MS: [M+H] + =440.

[0457] Example 3: Synthesis of 4-((30S,33S,36S)-30-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamido)-33-isopropyl-26,31,34-trioxo-36-(3-ureidopropyl)-2,5,8,11,14,17,20,23-octaoxo-27,32,35-triazaheptatriacontane-37-amino)benzyl(4-nitrophenyl)carbonate (CB07)

[0458] 1) Synthesis of (S)-30-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-26-oxo-2,5,8,11,14,17,20,23-octaoxa-27-aza-triacontane-31-oic acid (CB01).

[0459] Under nitrogen protection at 0-5°C, 8.14g of N2-fluorenylmethoxycarbonyl-L-2,4-diaminobutyric acid (CB00-2) was dissolved in 40mL of dimethylformamide (DMF), and 10g of 4,7,10,13,16,19,22,25-octaoxacohexacanoic acid-N-succinimide ester (CB00-3) and 10mL of DMF were added. 6.5mL of DIPEA was added dropwise while maintaining the temperature at 0-5°C. After 1h of addition, the mixture was stirred and reacted at room temperature for 4h. After completion of the reaction, DMF was removed under reduced pressure, and 14.2g of CB01 was obtained as a light yellow oily liquid by silica gel column chromatography (dichloromethane and methanol in a volume ratio of 20:1 as the elution solvent).

[0460] 2) Synthesis of (9H-fluoren-9-yl)methyl [(S)-1-[[(S)-1-[[4-(hydroxymethyl)phenyl]amino]-1-oxo-5-ureidopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate (CB02).

[0461] Under nitrogen protection at room temperature, 11g (S) -2- ((S) -2- ((((9H-fluorene-9-yl) methoxy) carbonyl) amino) -3-methylbutyrylamino) -5-ureidopentanic acid (CB00-4) and 5.5g p-aminobenzyl alcohol (CB00-5) were dissolved in 400mL of dichloromethane and 200mL of methanol. Under mechanical stirring, 17g of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) was added in batches and reacted for 15h in the dark. After the reaction was completed, the solvent was removed under reduced pressure to obtain a pasty solid, and silica gel column chromatography (dichloromethane and methanol volume ratio of 20: 1 as elution solvent) gave 11.9g CB02 as an off-white solid.

[0462] 3) Synthesis of (S)-2-((S)-2-amino-3-methylbutyramido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CB03).

[0463] Under nitrogen protection at room temperature, 300 mL of acetonitrile was added to 11.9 g of [(S)-1-[[(S)-1-[[4-(hydroxymethyl)phenyl]amino]-1-oxo-5-ureidopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamic acid (9H-fluorene-9-yl)methyl ester (CB02), and 18 mL of piperidine was added dropwise with stirring. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 h. After completion of the reaction, the solvent and piperidine were removed by distillation under reduced pressure, and 7.5 g of CB03 was obtained as a white solid by silica gel column chromatography (dichloromethane and methanol volume ratio 20:1 as elution solvent).

[0464] 4) Synthesis of (9H-fluoren-9-yl)methyl ((30S,33S,36S)-41-amino-36-((4-(hydroxymethyl)phenyl)carbamoyl)-33-isopropyl-26,31,34,41-tetraoxo-2,5,8,11,14,17,20,23-octaoxa-27,32,35,40-tetraaza-30-yl)carbamate (CB04).

[0465] Under a nitrogen atmosphere at 0°C, 14.2 g of (S)-30-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-26-oxo-2,5,8,11,14,17,20,23-octaoxa-27-aza-triacontane-31-oic acid (CB01) was dissolved in 100 mL of DMF, and 11 g of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (HATU) was added portionwise. After stirring for 30 min, 7.5 g of (S)-2-((S)-2-amino-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (CB03) was added, and the reaction was maintained at 0°C for 2.5 h. After the reaction was completed, the solvent was distilled off under reduced pressure, and 9.66 g of solid CB04 was obtained by silica gel column chromatography (dichloromethane and methanol in a volume ratio of 10:1 as elution solvent).

[0466] 5) Synthesis of N-((S)-3-amino-4(((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-oxyl)-2,5,8,11,14,17,20,23-octaoxahexacosa-26-amide (CB05).

[0467] Under nitrogen protection at room temperature, 9.66g of (9H-fluoren-9-yl)methyl ((30S,33S,36S)-41-amino-36-((4-(hydroxymethyl)phenyl)carbamoyl)-33-isopropyl-26,31,34,41-tetrahydro-2,5,8,11,14,17,20,23-octaoxa-27,32,35,40-tetraaza-30-yl)carbamate (CB04) was dissolved in 50mL DMF, 12mL diethylamine was added, and the reaction was stirred for 1.5h. After the reaction was completed, the solvent was distilled off under reduced pressure, and 7.7g CB05 was obtained as a light yellow solid by silica gel column chromatography (dichloromethane and methanol volume ratio 7.5:1 as elution solvent).

[0468] 6) Synthesis of N-((S)-3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamido)-4-(((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-butanone-2-yl)amino)-4-oxo)-2,5,8,11,14,17,20,23-octaoxahexacosa-26-amide (CB06).

[0469] 7.7 g of N-((S)-3-amino-4(((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-oxyl)-2,5,8,11,14,17,20,23-octaoxahexacosa-26-amide (CB05) was dissolved in 40 mL of DMF. Maleimidoacetic acid succinimidyl ester (CB00-1) was added portionwise under a nitrogen atmosphere at 0-5° C., and the reaction was maintained at 0-5° C. for 4 h. After completion of the reaction, the solvent was distilled off under reduced pressure, and 9.5 g of CB06 was obtained as a light yellow solid by silica gel column chromatography (dichloromethane and methanol in a volume ratio of 10:1 as the elution solvent).

[0470] 7) Synthesis of 4-((30S,33S,36S)-30-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamido)-33-isopropyl-26,31,34-trioxo-36-(3-ureidopropyl)-2,5,8,11,14,17,20,23-octaoxo-27,32,35-triazaheptatriacontane-37-amino)benzyl(4-nitrophenyl)carbonate (CB07).

[0471] 9.5 g of N-((S)-3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamido)-4-(((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-butanone-2-yl)amino)-4-oxo)-2,5,8,11,14,17,20,23-octaoxahexacosanetan-26-carboxamide (CB06) was dissolved in 50 mL of DMF. Under a nitrogen atmosphere at 0°C, 14.0 g of di(p-nitrobenzene) carbonate ((PNP)2CO) was added. After dissolution, 8.2 mL of N,N-diisopropylethylamine (DIPEA) was added, and the reaction was maintained at 0°C for 4 h. After the reaction was completed, the solvent was distilled off under reduced pressure, and 2.6 g of CB07 was obtained as a white solid by silica gel column chromatography (dichloromethane and methanol in a volume ratio of 8:1 as the elution solvent).

[0472] Example 4: Synthesis of 4-((18S,21S,24S)-18-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamido)-21-isopropyl-14,19,22-trioxo-24-(3-ureidopropyl)-2,5,8,11-tetraoxo-15,20,23-triazapentacosane-25-amino)benzyl(4-nitrophenyl)carbonate (CB14)

[0473] CB14 was prepared by referring to the synthesis of CB07 in Example 3, except that 4,7,10,13,16,19,22,25-octaoxahexacosadecanoic acid-N-succinimidyl ester was replaced with 4,7,10,13-tetraoxatetradecanoic acid-N-succinimidyl ester to obtain CB14 as a white solid.

[0474] Example 5: Synthesis of Intermediate (CB07-Exatecan)

[0475] Synthesis of 4-(30S,33S,36S)-30-(2-(2,5-dioxa-2,5-dihydro-1H-pyrrol-1-yl)acetamido)-33-isopropyl-26,31,34-trioxa-36-(3-ureidopropyl)-2,5,8,11,14,17,20,23-octaoxa-27,32,35-triazaheptatriaminoaconit-37-yl)benzoyl(1s,9s)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-1-carbamate (CB07-Exatecan).

[0476] 4-((30S,33S,36S)-30-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamido)-33-isopropyl-26,31,34-trioxo-36-(3-ureidopropyl)-2,5,8,11,14,17,20,23-octaoxo-27,32,35-triazatriacontane-37-amino)benzyl(4-nitrophenyl)carbonate (CB07) (2.6 g, 2.21 mmol) and N,N-dimethylformamide (23 mL) were added to reaction flask R1, stirred under nitrogen protection and cooled to 0-5°C. Meanwhile, (1S,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione mesylate (Ixitecan mesylate, 0.98 g, 1.84 mmol, Advanced ChemBlocks) and N,N-dimethylformamide (5 mL) were added to another reaction flask R2. Triethylamine (230 mg, 2.27 mmol) was added dropwise at 0-5°C and stirred until completely dissolved. The solution in reaction flask R2 was added dropwise to reaction flask R1. After washing reaction flask R2 with N,N-dimethylformamide (2 mL), the washing solution was added to reaction flask R1. 1-Hydroxybenzotriazole (497 mg, 3.68 mmol) and pyridine (1.45 g, 18.4 mmol) were weighed and added to reaction flask R1. Stirring was continued at 0-5°C for 10 min, then at room temperature for 5.5 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure at 35°C. Purification by preparative high-performance liquid chromatography (prep-HPLC) and lyophilization afforded a white powder (CB07-Exatecan, 1.6 g, 59%). LC-MS: [1 / 2 M+H] + =737.

[0477] Example 6: Synthesis of intermediate (CB07-D-1)

[0478] Synthesis of 4-(30S,33S,36S)-30-(2-(2,5-dioxa-2,5-dihydro-1H-pyrrol-1-yl)acetamido)-33-isopropyl-26,31,34-trioxa-36-(3-ureidopropyl)-2,5,8,11,14,17,20,23-octaoxa-27,32,35-triazaheptatriaminoaconit-37-yl)benzoyl (1S,9S)-9-ethyl-4,5-difluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-1-carbamate (CB07-D-1).

[0479] 4-((30S,33S,36S)-30-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamido)-33-isopropyl-26,31,34-trioxo-36-(3-ureidopropyl)-2,5,8,11,14,17,20,23-octaoxo-27,32,35-triazaheptatriacontane-37-amino)benzyl(4-nitrophenyl)carbonate (CB07) (220 mg, 0.189 mmol) and N,N-dimethylformamide (5 ml) were added to reaction flask R1, stirred under nitrogen protection and cooled to 0-5°C. Meanwhile, (1S,9S)-1-amino-9-ethyl-4,5-difluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13Hbenzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione hydrochloride (D-1) (90 mg, 0.189 mmol) and N,N-dimethylformamide (5 mL) were added to another reaction flask R2. Three drops of triethylamine were added dropwise at 0-5°C and stirred until completely dissolved. The solution in reaction flask R2 was added dropwise to reaction flask R1. 1-Hydroxybenzotriazole (60 mg, 0.44 mmol) and pyridine (0.5 mL) were then weighed and added to reaction flask R1. Stirring was continued at 0-5°C for 10 minutes. After the mixture was heated to room temperature and stirred for 3 hours, the solvent was removed under reduced pressure. Purify by preparative high performance liquid chromatography (prep-HPLC) and freeze-dry to obtain a white powder (CB07-D-1, 55 mg, 20%). LC-MS: [1 / 2M+H] + =739.

[0480] Example 7: Synthesis of Intermediate (CB14-Exatecan)

[0481] Synthesis of 4-(18S,21S,24S)-18-(2-(2,5-dioxane-2,5-dihydro-1H-pyrrol-1-yl)acetamido)-21-isopropyl-14,19,22-trioxo-24-(3-ureidopropyl)-2,5,8,11-tetraoxo-15,20,23-triazapentacosan-25-amino)-(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-1-carbamate (CB14-Exatecan).

[0482] Similarly, 4-((18S,21S,24S)-18-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamido)-21-isopropyl-14,19,22-trioxo-24-(3-ureidopropyl)-2,5,8,11-tetraoxo-15,20,23-triazapentacosan-25-amino)benzyl(4-nitrophenyl)carbonate (190 mg, 0.19 mmol) and N,N-dimethylformamide (23 mL) were added to reaction flask R1, and the mixture was stirred under nitrogen and cooled to 0-5°C. Meanwhile, (1S,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione mesylate (101 mg, 0.19 mmol; Advanced ChemBlocks) and N,N-dimethylformamide (5 mL) were added to another reaction flask R2. Three drops of triethylamine were added dropwise at 0-5°C and stirred until completely dissolved. The solution in reaction flask R2 was added dropwise to reaction flask R1. After washing reaction flask R2 with N,N-dimethylformamide (1 mL), the washing solution was added to reaction flask R1. 1-Hydroxybenzotriazole (60 mg, 0.44 mmol) and pyridine (0.5 mL) were weighed and added to reaction flask R1. Stirring was performed at 0-5°C for 10 min, then at room temperature for 5.5 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure at 35°C. Purification by preparative high-performance liquid chromatography (prep-HPLC) and lyophilization afforded CB14-Exatecan as a white powder.

[0483] Example 8: Synthesis of ADC

[0484] ADC1 conjugation process:

[0485] Reduction reaction: Use coupling buffer (10 mM succinic acid aqueous solution) to adjust the concentration of antibody 1 to 18 g / L. Add 0.1 M EDTA aqueous solution to a final EDTA concentration of 2 mM. Based on the amount of antibody substance, add 5.4 molar equivalents of 0.2 M TCEP aqueous solution. Adjust the pH to 7. Stir the reaction at 25°C and 180 rpm for 2 h to reduce the interchain disulfide bonds of the antibody to free sulfhydryl groups.

[0486] Use a 30KD ultrafiltration membrane to replace 10 volumes of liquid to remove the reducing agent TCEP in the system.

[0487] Coupling reaction: Based on the amount of antibody, 15-fold molar equivalents of a 100 mM solution of CB07-Exatecan in dimethylacetamide (DMA) were added, and the reaction was stirred at 180 rpm at 25°C for 2 h. Finally, 0.2 M aqueous N-acetylcysteine ​​was added to a final concentration of 2 mM and the reaction was continued for 15 min to terminate the coupling reaction. The reaction mixture was purified and ultrafiltered to obtain ADC1 at a concentration of 23.56 mg / mL. The DAR (p) was 8 (Batch 1) as determined by reverse-phase chromatography.

[0488] ADC2 conjugation process:

[0489] Reduction reaction: Use coupling buffer (10 mM succinic acid aqueous solution) to adjust the concentration of Antibody 1 to approximately 18 g / L. Add 0.1 M EDTA aqueous solution to a final EDTA concentration of 2 mM. Based on the amount of antibody, add 2.5 molar equivalents of 10 mM TCEP aqueous solution. Adjust the pH to 7. Incubate on a shaker at 25°C for 2 h to reduce the interchain disulfide bonds of the antibody to free sulfhydryl groups.

[0490] The ultrafiltration solution was changed by 10 volumes to remove the reducing agent TCEP in the system.

[0491] Coupling reaction: Based on the amount of antibody, 6 molar equivalents of a 100 mM solution of CB07-Exatecan in dimethylacetamide (DMA) were added and the reaction was shaken at 25°C for 1 hour. Finally, 0.1 M aqueous N-acetylcysteine ​​was added to a final concentration of 1.5 mM and the reaction was continued for 15 minutes to terminate the coupling reaction. The reaction mixture was purified to obtain ADC2 at a concentration of 1.34 mg / mL. The DAR (p) was 4 as determined by reverse-phase chromatography.

[0492] Example 9: Clinical study of ADC1

[0493] This study is a multicenter, open-label, dose-escalation, dose-expansion Phase I clinical study that uses a rapid titration and "3+3" dose-escalation design to explore the safety, tolerability, and PK characteristics of injectable ADC1 in patients with advanced solid tumors.

[0494] Study Objectives

[0495] Main Purpose:

[0496] Evaluate the safety and tolerability of ADC1 in patients with advanced solid tumors, explore the maximum tolerated dose (MTD), and provide recommended doses for subsequent clinical trials.

[0497] Secondary objectives:

[0498] To evaluate the pharmacokinetic (PK) and metabolite profiles of ADC1 after single and repeated doses in patients with advanced solid tumors;

[0499] Evaluate the immunogenicity of ADC1;

[0500] Preliminary evaluation of the anti-tumor efficacy of ADC1;

[0501] To evaluate the relationship between the anti-tumor efficacy of ADC1 and the expression of folate receptor in tumor tissue and the level of FRα in serum.

[0502] Study endpoints

[0503] Primary endpoint:

[0504] Tolerability and safety endpoints: vital signs, physical examination, laboratory tests, electrocardiogram, cardiac ultrasound, adverse events, dose-limiting toxicity (DLT) events and their incidence, etc.

[0505] Secondary endpoints:

[0506] Pharmacokinetic characteristics and metabolite analysis under single and multiple doses;

[0507] Immunogenicity;

[0508] Clinical efficacy: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS);

[0509] Tumor marker testing;

[0510] Biomarkers: folate receptor expression in tumor tissue and FRα level in serum.

[0511] Inclusion criteria

[0512] 1. Applicants must be between 18 and 75 years old (inclusive), regardless of gender;

[0513] 2. For different cohorts, subjects must meet the following requirements:

[0514] 2-1) Dose-escalation studies: Patients must have histologically or cytologically confirmed advanced or metastatic solid tumors who have failed or have no effective standard treatment, are intolerant to or refuse standard treatment. The dose-escalation study is based on the clinician's judgment, taking into account the different tumor types.

[0515] 2-2) Dose Expansion Study: Cohort 1) Ovarian Cancer: ① Patients with histologically or cytologically confirmed platinum-resistant advanced or metastatic epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who have received no more than three lines of prior therapy; ② Platinum resistance is defined as platinum-resistant recurrent ovarian cancer according to the Gynecologic Oncology Group (GOG) criteria (radiologically confirmed disease progression or recurrence within 6 months of receiving platinum-containing chemotherapy); ③ Tumor tissue is positive for FRα expression; Cohort 2) Other Advanced Solid Tumors: ① Patients with histologically or cytologically confirmed advanced or metastatic solid tumors who have failed or are intolerant to standard therapy (limited to endometrial cancer, breast cancer, and non-small cell lung cancer). ② Tumor tissue with FRα expression assay available.

[0516] 3. According to RECIST 1.1 criteria, there is at least one measurable tumor lesion;

[0517] 4. The Eastern Cooperative Oncology Group (ECOG) performance status score must be 0 or 1;

[0518] 5. The expected survival time as assessed by the investigator is ≥12 weeks;

[0519] 6. Have sufficient organ and bone marrow reserve function;

[0520] 7. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose and be willing to take effective birth control / contraception methods to prevent pregnancy during the study period and until 6 months after the last dose of the study. Male patients must agree to take effective contraception methods during the study period and until 6 months after the last dose of the study; postmenopausal women must have been amenorrheic for at least 12 months to be considered infertile;

[0521] 8. Dose-escalation studies: Patients must be willing to provide previously archived or fresh tumor tissue samples (patients without previously archived tumor tissue may be exempted if the investigator assesses that there is a high risk of re-sampling primary or metastatic tumor tissue); Dose-expansion studies: Patients must be willing to provide previously archived or fresh tumor tissue samples that can be used to detect FRα expression levels;

[0522] 9. Be able to understand the trial requirements, and be willing and able to comply with the trial and follow-up procedures.

[0523] Exclusion criteria

[0524] 1. Patients who have received experimental drug treatment or participated in clinical research of medical devices within 4 weeks before the first administration of study drug;

[0525] 2. Patients who have received chemotherapy, radiotherapy, small molecule targeted therapy, biological therapy, endocrine therapy, immunotherapy or other anti-tumor treatment within 4 weeks before the first use of study drugs (if the 5-fold half-life of the drug is less than 28 days, the inclusion can be decided based on its pharmacological characteristics after discussion), excluding the following: ① Nitrosourea or mitomycin C within 6 weeks before the first use of study drugs; ② Oral fluorouracil within 2 weeks before the first use of study drugs or 5 half-lives of the drug (whichever is longer); ③ Systemic treatment with traditional Chinese medicine / Chinese patent medicine with clear anti-tumor effects, immunomodulatory drugs (including but not limited to thymosin, interferon, interleukin, etc.) within 2 weeks before the first use of study drugs; ④ Palliative radiotherapy within 2 weeks before the first use of study drugs;

[0526] 3. Patients who have previously received any topoisomerase I inhibitor (such as irinotecan) and experienced a drug-related or unclear-related AE of grade 3 or higher (graded using CTCAE v5.0);

[0527] 4. Patients with AEs (CTCAE 5.0) caused by previous anti-tumor treatment still > Grade 1 before the first administration of the study drug, except for the following: a. Alopecia; b. Pigmentation; c. A distant toxicity caused by chemotherapy or radiotherapy that is judged to be irreversible; d. Hypothyroidism that has been stabilized by hormone replacement therapy;

[0528] 5. Patients who have undergone major surgery within 4 weeks before the first administration of study drug or have not yet recovered from the surgery, or have suffered significant trauma, or need to undergo elective surgery during the trial;

[0529] 6. Those with a history of allogeneic cell or solid organ transplantation;

[0530] 7. Patients with primary central nervous system tumors or symptomatic central nervous system metastases, meningeal metastases, or a history of epilepsy. Patients with asymptomatic central nervous system metastases that have achieved clinical control, or those with symptoms but are judged by the investigator to be stable, may be included, but must meet the following conditions at the same time: a. Clinical symptoms have been stable for ≥4 weeks before the first dose; b. No evidence of central nervous system disease progression 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 prednisone dosage is ≤10 mg / day or equivalent dose of hormones;

[0531] 8. Other active malignant tumors within 5 years before the first dose, excluding locally cured tumors (such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or breast carcinoma in situ, etc.);

[0532] 9. The following cardiovascular diseases occurred within 6 months before the first medication: symptomatic heart failure of New York Heart Association (NYHA) grade 2 or above, left ventricular ejection fraction (LVEF) <50%, unstable arrhythmia or unstable angina, myocardial infarction requiring treatment, pulmonary embolism, uncontrolled hypertension (defined in this protocol as systolic blood pressure >160 mmHg and / or diastolic blood pressure >100 mmHg after treatment despite optimal antihypertensive treatment, and assessed by the investigator to be clinically significant);

[0533] 10. Suffering from any other disease, or physical examination or laboratory test results that make the researcher unsuitable for the use of study drugs;

[0534] 11. Patients who have had non-infectious pneumonia / lung inflammation requiring glucocorticoid treatment in the past, or currently have interstitial lung disease (ILD), or whose imaging during the screening period cannot rule out the possibility of interstitial lung disease / lung inflammation;

[0535] 12. Subjects with tuberculosis who need treatment or are currently being treated, including but not limited to pulmonary tuberculosis; those who have received standard anti-tuberculosis treatment and have been confirmed to be cured by the researchers may be included;

[0536] 13. Severe infection occurred within 4 weeks or active infection occurred within 2 weeks before the first use of the drug;

[0537] 14. Patients with the following diseases: Human immunodeficiency virus (HIV) infection; Active hepatitis B virus infection [Hepatitis B surface antigen (HBsAg) positive, and hepatitis B virus deoxyribonucleic acid (HBV-DNA) test > 200 IU / ml or 10 3 copies / ml]; patients infected with hepatitis C virus [positive results of HCV antibody and viral RNA (HCV-RNA) test]; patients with positive Treponema pallidum antibody and RPR;

[0538] 15. Known hypersensitivity or delayed allergic reaction to any component of the study drug;

[0539] 16. Patients who are known to have had a grade 3 or higher allergic reaction to large molecular protein preparations / monoclonal antibodies;

[0540] 17. Patients with uncontrolled pleural effusion, pericardial effusion or ascites effusion or those requiring drainage;

[0541] 18. Those with the following risks of thrombosis or bleeding:

[0542] a. Cerebrovascular accident or transient ischemic attack occurred within 6 months before the first dose;

[0543] b. A history of deep vein thrombosis, pulmonary embolism, or any other serious thromboembolism within 3 months before the first dose of the drug (implanted venous port or catheter-derived thrombosis, or superficial vein thrombosis is not considered "serious" thromboembolism);

[0544] c. Any life-threatening bleeding event or grade 3 or 4 gastrointestinal / variceal bleeding event requiring blood transfusion, endoscopic or surgical treatment within 3 months before the first dose;

[0545] d. Other diseases that the researcher believes will increase the risk of bleeding or thrombosis in the future;

[0546] 19. The presence of any other serious underlying disease (e.g., uncontrolled diabetes, active gastric ulcer, uncontrolled seizures, coagulation disorders with severe symptoms or signs);

[0547] 20. Known history of mental illness, substance abuse, alcoholism or drug abuse, which may affect the test results;

[0548] 21. Pregnant or breastfeeding women or women or men who are planning to have children;

[0549] 22. It is estimated that the patient's compliance in participating in this clinical study is insufficient or the researcher believes that there are other factors that make the patient unsuitable for participation in this study.

[0550] The study was divided into two parts:

[0551] Part I: Dose escalation study: Rapid titration and a "3+3" dose escalation rule were used to explore the safety, tolerability, and pharmacokinetic characteristics of injectable ADC1 (Batch 2, DAR of 7.4).

[0552] The 1.2 mg / kg, 1.8 mg / kg, 2.1 mg / kg, and 2.4 mg / kg groups were set up. The 1.2 mg / kg group used a rapid titration method for dose escalation, while the 1.8 mg / kg, 2.1 mg / kg, and 2.4 mg / kg groups were dose-escalated according to the standard "3+3" rule.

[0553] Dosage regimen:

[0554] The drug is administered by intravenous infusion once every 3 weeks (Q3W). The recommended infusion time for the first cycle is ≥90 minutes. If no infusion reaction occurs, subsequent cycles can be completed within 30 to 120 minutes.

[0555] Definition of Dose-Limiting Toxicity (DLT):

[0556] AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. DLT was defined as any grade 3 or higher toxicity related to the trial drug occurring within 21 days of the first dose of the subject and meeting the following definitions:

[0557] ■Level 5 toxicity

[0558] ■ Definition of hepatotoxicity DLT:

[0559] Grade 4 AST or ALT elevation

[0560] AST or ALT > 5 times the upper limit of normal range (ULN) with ≥ grade 2 elevated blood bilirubin

[0561] Subjects with hepatocellular carcinoma or liver metastasis, if AST or ALT is ≤ 3 times ULN at baseline, and AST or ALT increases to > 5 times ULN and persists for > 5 days during the DLT evaluation period

[0562] Subjects with hepatocellular carcinoma or liver metastasis, if AST or ALT is >3 times ULN at baseline, and AST or ALT increases to >8 times ULN and persists for >5 days during the DLT evaluation period

[0563] In subjects without hepatocellular carcinoma or liver metastasis, AST or ALT elevation > 5 times ULN persisting for > 5 days

[0564] ■ Definition of hematologic toxicity DLT:

[0565] Grade 4 neutropenia lasting >7 days

[0566] Grade 3 or higher neutropenia with fever (single temperature > 38.3°C or continuous temperature ≥ 38°C for more than 1 hour)

[0567] Grade 4 anemia

[0568] Grade 4 thrombocytopenia

[0569] Grade 3 or higher thrombocytopenia lasting for more than 7 days

[0570] ≥Grade 3 thrombocytopenia with bleeding

[0571] ■ Definition of non-hepatotoxicity and non-hematologic toxicity DLTs:

[0572] Other grade ≥3 non-hepatotoxicity, non-hematologic toxicity

[0573] ■The following treatment-emergent adverse events (TEAEs) were not considered DLTs:

[0574] Grade 3 nausea, vomiting, diarrhea, anorexia, fatigue, or rash that is controlled with standard supportive care and resolves to ≤ Grade 2 within 3 days

[0575] Laboratory abnormalities without clinically relevant symptoms or signs, including elevated ALP, elevated uric acid, elevated blood amylase, elevated lipase, or lymphocytopenia to Grade 3 or 4, or Grade 1 hyponatremia at baseline upgraded to Grade 3 but lasting <72 hours

[0576] Patients with grade 3 infusion reactions that can be relieved within 6 hours after treatment

[0577] Tolerability and safety evaluation:

[0578] Tolerability evaluation indicators: dose-limiting toxicity (DLT) events and their incidence.

[0579] Safety evaluation indicators: vital signs, physical examination, laboratory tests (blood routine, blood biochemistry, cardiac function, thyroid function, coagulation routine, urine routine, stool routine, pregnancy test), ECOG score, electrocardiogram, adverse events, etc.

[0580] Pharmacokinetic evaluation:

[0581] All subjects in all dose groups were required to collect blood samples at the prescribed time points during treatment (the first 6 treatment cycles) and monitor plasma concentrations (C trough The concentrations of ADC1, Exatecan, and FRα total antibodies in serum were detected to study the pharmacokinetic (PK) characteristics of ADC1.

[0582] The following PK parameters were calculated using the actual administered dose, actual sampling time, and non-compartmental model:

[0583] Single dose: C max T max 、T 1 / 2 , CL, Vd, Ke, MRT, AUC (0-τ) , AUC (0-∞) ;

[0584] Multiple doses: 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.

[0585] Immunogenicity evaluation:

[0586] Subjects in all dose groups need to collect blood samples at specific time points during treatment to detect anti-drug antibodies and neutralizing antibodies in the serum.

[0587] The immunogenicity evaluation indicators are as follows:

[0588] The sample and individual positive rates of anti-ADC1 antibodies (ADA);

[0589] ADA-positive samples will continue to be tested for neutralizing antibodies (Nab);

[0590] The number and percentage of subjects with positive ADA antibodies and Nab.

[0591] Pharmacodynamic evaluation:

[0592] 1. Detect the level of FRα in serum before administration;

[0593] 2. Folate receptor expression levels in archived tumor tissue samples or freshly collected tumor tissue samples during the screening period;

[0594] 3. Changes in tumor markers.

[0595] Clinical effectiveness evaluation:

[0596] Throughout the trial, the RECIST v1.1 evaluation criteria were mainly used to evaluate the anti-tumor efficacy of injected ADC1.

[0597] Anti-tumor efficacy indicators include:

[0598] Objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were defined according to RECIST 1.1.

[0599] Dose escalation study results

[0600] I. Enrollment in the Dose-Escalation Phase

[0601] In a Phase I dose-escalation study of ADC1, 29 subjects with advanced solid tumors received at least one dose of ADC1. Subjects were enrolled in the 1.2 mg / kg (N=1), 1.8 mg / kg (N=5), 2.1 mg / kg (N=9), and 2.4 mg / kg (N=14) dose cohorts. Enrolled tumors included 16 patients with ovarian cancer, 6 with breast cancer, 2 with lung cancer, 2 with cervical cancer, and 1 patient each with fallopian tube cancer, tongue cancer, and endometrial cancer. Baseline characteristics are shown in Table 2.

[0602] Table 2 Baseline characteristics

[0603] 2. Preliminary efficacy data in the dose escalation phase

[0604] A total of 29 subjects underwent at least one efficacy assessment, of which 9 achieved partial remission (PR) (7 cases with FRα expression ≥50%), including 6 cases of ovarian cancer, 1 case of fallopian tube cancer, 1 case of breast cancer and 1 case of endometrial cancer, and 16 cases achieved stable disease (SD). The current objective response rate (ORR) is 31%, and the disease control rate (DCR) is 86.2% (Figure 1). Most of the ovarian cancer subjects had received more than 3 lines of anti-tumor treatment including bevacizumab, PARPi and other drugs. All PR cases achieved partial remission in the first or second tumor assessment; no subject ended the study treatment due to safety issues; some subjects have been treated for more than 1 year (Figure 2).

[0605] In subjects with ovarian and fallopian tube cancer, the ORR was 7 / 17 (41%), with a DCR of 88.2%. Among 14 subjects with ovarian and fallopian tube cancer whose FRα TPS (tumor cell proportion score) was greater than 25%, the ORR was 7 / 14 (50%), with a DCR of 92.8%. In the 15 subjects with ovarian cancer (including fallopian tube cancer) in the 2.1 and 2.4 mg / kg dose groups, regardless of FRα expression level, the ORR was 46.7%, with a DCR of 86.7%. Among the 12 subjects with FRα TPS greater than 25%, the ORR was 7 / 12 (58.3%), 4 / 6 (66.7%) in the 2.4 mg / kg group, and 3 / 6 (50%) in the 2.1 mg / kg group, with a DCR of 91.7% (Figures 3 and 4). Responses were also observed in subjects with breast and endometrial cancer (see Table 3).

[0606] Table 3 Effects of ADC1 on breast cancer and endometrial cancer

[0607] The most common adverse events were decreased platelet count, decreased neutrophil count, anemia, leukopenia, nausea, vomiting, and constipation.

[0608] Treatment-related adverse events (TRAEs) of grade ≥3 were mainly hematologic toxicities.

[0609] 3. Preliminary Pharmacokinetic Data in the Dose-Escalation Phase

[0610] Twenty subjects treated with ADC1 were included in the PK analysis. After the first dose, systemic exposure of ADC1 increased with increasing doses. PK parameters for the 1.2, 2.1, and 2.4 mg / kg dose groups are shown in Tables 4-6.

[0611] Table 4 PK parameters of ADC1

[0612] Table 5 PK parameters of total anti-FRα antibodies

[0613] Table 6 PK parameters of Exatecan

[0614] Part II: Dose expansion study. The dose of the subjects currently enrolled was analyzed using the dose corrected for body surface area, safety, and efficacy. The dose was found to be approximately 87-93 mg / m 2 The safety is relatively good and the possibility of therapeutic benefit is high. 2 and 84 mg / m 2 The two doses will be expanded in cohorts 1 and 2 respectively. Subjects with ovarian cancer or other tumor types will be randomly assigned in a 1:1 manner to receive ADC193mg / m 2 Q3W or 84 mg / m 2 Treatment was given Q3W (see Table 7).

[0615] Table 7 Grouping and drug administration

[0616] Baseline characteristics of ovarian cancer patients:

[0617] As of May 8, 2024, 96 subjects with platinum-refractory or platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (PROC) were enrolled and received ADC 11.8 mg / kg (N=2), 2.1 mg / kg (N=16), 2.4 mg / kg (N=15), 84 mg / m 2 (N=32) or 93 mg / m 2 (N=31). Most subjects (89.6%, 86 / 96) had not received pelvic radiotherapy before. All subjects had received bevacizumab treatment, and 53.1% (51 / 96) of them had received PARPi treatment before.

[0618] Table 8 Baseline characteristics of ovarian cancer subjects (N=96)

[0619] Efficacy in patients with ovarian cancer:

[0620] As of May 8, 2024, 54 PROC subjects underwent at least one tumor assessment after ADC1 treatment, of whom 38.9% (21 / 54) had previously received >3 lines of systemic therapy. Regardless of FRα expression level, the ORR (including unconfirmed PR) was 37.0% (20 / 54) and the DCR was 77.8% (42 / 54) in all subjects; in subjects with FRα TPS <50%, the ORR was 33.3% (7 / 21) and the DCR was 71.4% (15 / 21); in subjects with FRα TPS ≥50%, the ORR was 39.4% (13 / 33) and the DCR was 81.8% (27 / 33) (see Table 9).

[0621] Table 9 ORR of ovarian cancer patients (N=54)

[0622] Note: * includes 3 unconfirmed PRs, # includes 2 unconfirmed PRs

[0623] Figures 5 and 6 show that the majority of subjects treated with ADC1 experienced tumor shrinkage, and the study treatment resulted in sustained shrinkage of target tumor lesions in the majority of subjects.

[0624] At a median follow-up of 6.5 months (range, 1.3, 18.0), the median duration of response (mDOR) was 6.3 months (range, 1.8-16.5 months). The majority of subjects with a PR remain on treatment.

[0625] The Kaplan-Meier curve showed that the mPFS was 7.47 months (4.27-NA), and the 6-month and 1-year OS rates were both 83.0% (see Figures 7-8).

[0626] ADC1 had a favorable safety profile. No ILD or significant ocular toxicity was reported. ADC1 demonstrated superior preliminary efficacy in all PROC patients, regardless of FRα expression level.

[0627] Example 10: A multicenter, open-label, phase 2 clinical study of ADC1 (DAR 7-8) in the treatment of patients with platinum-resistant ovarian cancer

[0628] The trial patients were subjects with histologically or cytologically confirmed platinum-resistant advanced or metastatic epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who had received no more than three lines of previous treatment.

[0629] Definition of platinum-resistant ovarian cancer:

[0630] a. Patients who have received only one line of platinum-based therapy must have received at least four cycles of platinum-based therapy and achieved remission (CR or PR), with disease progression occurring between >1 month and ≤6 months after the last platinum-based chemotherapy;

[0631] b. Patients who have received 2 or 3 prior platinum-based therapies must have disease progression within 6 months of the last platinum-based therapy.

[0632] Note: 1) Progression should be calculated from the date of administration of the last platinum-containing treatment to the date of disease progression shown by imaging; 2) Patients who are platinum-refractory during first-line treatment are not included.

[0633] Study Design:

[0634] Part I: Dose-finding study. Three dose groups were set up, with dose A: 76 mg / m 2 Dose B: 84 mg / m 2 and dose C: 93 mg / m 2 Patients will be stratified according to FRα expression level (TPS < 50%, 50% ≤ TPS < 75%, TPS ≥ 75% [FRα unevaluable subjects will be included in the TPS < 50% group]).

[0635] Part II: Dose Expansion Study. The dose used will be determined based on the data generated in Part I.

[0636] Dosage: Intravenous infusion, administered once every 3 weeks (Q3W). The recommended infusion time for the first dosing cycle is ≥ 90 minutes. If no infusion reaction occurs, the infusion time for subsequent cycles can be completed within 30 to 60 minutes.

Claims

1. A method for treating and / or preventing cancer, comprising injecting an effective amount of an antibody drug conjugate into a human patient in need thereof; wherein: The dosage of the antibody drug conjugate is 1.7 mg / kg to 2.5 mg / kg, or 100 mg to 250 mg, or 70 mg / kg. 2 -100mg / m 2 , or 75 mg / m 2 Up to 100 mg / m 2 , administered once every 2-4 weeks; the antibody-drug conjugate comprises an anti-FRα antibody or an antigen-binding unit thereof coupled to a drug via a linker.

2. A method for treating and / or preventing cancer, comprising injecting an effective amount of an antibody drug conjugate into a human patient in need; wherein: The dosage of the antibody drug conjugate is 1.7 mg / kg to 2.5 mg / kg, or 100 mg to 250 mg, or 70 mg / kg. 2 -100mg / m 2 , or 75 mg / m 2 Up to 100 mg / m 2 , administered once every 2-4 weeks; the antibody drug conjugate has a structure as shown in Formula I or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof: in, Abu is an anti-FRα antibody or an antigen-binding unit thereof; D is the drug; M is Wherein * connects to Abu, ** connects to B, and R is selected from: -(CH2) r -、-(CHR m ) r -, C3-C8 carbocyclic group, -O-(CH2) r -, arylene, -(CH2) r -Arylene-, -Arylene-(CH2) r -、-(CH2) r -(C3-C8 carbocyclyl)-, -(C3-C8 carbocyclyl)-(CH2) r -, C3-C8 heterocyclic group, -(CH2) r -(C3-C8 heterocyclic group)-, -(C3-C8 heterocyclic group)-(CH2) r -、-(CH2) r C(O)NR m (CH2) r -、-(CH2CH2O) r -、-(CH2CH2O) r -CH2-, -(CH2) r C(O)NR m (CH2CH2O) r -、-(CH2) r C(O)NR m (CH2CH2O) r -CH2-, -(CH2CH2O) r C(O)NR m (CH2CH2O) r -、-(CH2CH2O) r C(O)NR m (CH2CH2O) r -CH2- and -(CH2CH2O) r C(O)NR m (CH2) r -; each R m is independently H, C1-C6 alkyl, C3-C8 carbocyclyl, phenyl or benzyl; and each r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; B is or Where * connects to M, ** connects to L, and *** connects to G; L is -(AA) i -(FF) f -, wherein AA is an amino acid or a polypeptide, i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; each FF is independently Among them, each R F are independently C1-C6 alkyl, C1-C6 alkoxy, -NO2 or halogen, z is 0, 1, 2, 3 or 4, wherein * is connected to AA, ** is connected to D; f is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; G is Where n is an integer from 1 to 24; p is 1-10.

3. The method of claim 2, wherein each AA is independently selected from the following amino acid or peptide sequences: Val-Cit, Val-Lys, Phe-Lys, Lys-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Trp, Cit, Phe-Ala, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val, Ala-Leu-Ala-Leu, β-Ala-Leu-Ala-Leu and Gly-Phe-Leu-Gly.

4. The method of claim 2 or 3, wherein AA is Val-Cit.

5. The method according to any one of claims 2 to 4, wherein i is 1.

6. The method according to any one of claims 2 to 5, wherein each FF is independently Where * connects AA, ** connects D; or FF is Among them, * connects AA and ** connects D.

7. The method according to any one of claims 2 to 6, wherein L is Where * connects to B and ** connects to D.

8. A method for treating and / or preventing cancer, comprising injecting an effective amount of an antibody drug conjugate into a human patient in need thereof; wherein: The dosage of the antibody drug conjugate is 1.7 mg / kg to 2.5 mg / kg, or 100 mg to 250 mg, or 70 mg / kg. 2 -100mg / m 2 , or 75 mg / m 2 Up to 100 mg / m 2 , administered once every 2-4 weeks; the antibody drug conjugate has a structure as shown in Formula I-1, I-2 or I-2-1 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof, wherein The formula I-1 is: The formulas I-2 and I-2-1 are: in Abu is an anti-FRα antibody or an antigen-binding unit thereof; R is selected from: -(CH2) r -、-(CHR m ) r -, C3-C8 carbocyclic group, -O-(CH2) r -, arylene, -(CH2) r -Arylene-, -Arylene-(CH2) r -、-(CH2) r -(C3-C8 carbocyclyl)-, -(C3-C8 carbocyclyl)-(CH2) r -, C3-C8 heterocyclic group, -(CH2) r -(C3-C8 heterocyclic group)-, -(C3-C8 heterocyclic group)-(CH2) r -、-(CH2) r C(O)NR m (CH2) r -、-(CH2CH2O) r -、-(CH2CH2O) r -CH2-, -(CH2) r C(O)NR m (CH2CH2O) r -、-(CH2) r C(O)NR m (CH2CH2O) r -CH2-, -(CH2CH2O) r C(O)NR m (CH2CH2O) r -、-(CH2CH2O) r C(O)NR m (CH2CH2O) r -CH2- and -(CH2CH2O) r C(O)NR m (CH2) r -; each R m is independently H, C1-C6 alkyl, C3-C8 carbocyclyl, phenyl or benzyl; and each r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; D is the drug; n is an integer from 1 to 24; p is 1-10.

9. The method of any one of claims 2 to 8, wherein R is -(CH2) r -.

10. The method according to any one of claims 2 to 9, wherein r is 1 or 5.

11. The method according to any one of claims 1 to 10, wherein the antibody drug conjugate has a structure as shown in Formula I-3, I-4 or I-4-1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof: The formulas I-4 and I-4-1 are: in Abu is an anti-FRα antibody or an antigen-binding unit thereof; D is the drug; n is an integer from 1 to 24; p is 1-10.

12. The method according to any one of claims 2 to 11, wherein n is an integer from 4 to 12.

13. The method according to any one of claims 2 to 12, wherein n is an integer from 4 to 8.

14. The method of any one of claims 2 to 13, wherein n is 4 or 8.

15. The method according to any one of claims 1 to 14, wherein the antibody drug conjugate has a structure as shown in Formula I-5, I-5-1, I-6, I-6-1, I-7, I-7-1, I-8, I-8-1, I-9, I-9-1, I-10, I-10-1, I-11 or I-11-1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein The formulas I-5 and I-5-1 are: The formulas I-6 and I-6-1 are: The formulas I-7 and I-7-1 are: The formulas I-8 and I-8-1 are: The formulas I-9 and I-9-1 are: The formulas I-10 and I-10-1 are: The formulas I-11 and I-11-1 are: in Abu is an anti-FRα antibody or an antigen-binding unit thereof; D is the drug; p is 1-10.

16. The method according to any one of claims 1 to 15, wherein the drug is an anticancer drug, a cytotoxic drug, a cell differentiation factor, a stem cell trophic factor, a steroid drug, a drug for treating an autoimmune disease, an anti-inflammatory drug, or a drug for treating an infectious disease; or the drug is an anticancer drug; or the drug is a microtubule inhibitor, a DNA damaging agent, or a DNA topoisomerase inhibitor; or the microtubule inhibitor is selected from the group consisting of dolastatin, auristatins, and maytansines; or the drug is an auristatin selected from the group consisting of M MAE, MMAF or AF; or the drug is a DNA damaging agent selected from calicheamicins, duocarmycins, anthramycin derivatives PBD; or the drug is a DNA topoisomerase inhibitor or a salt thereof selected from irinotecan, irinotecan hydrochloride, isotecan derivatives, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, 9-chloro-10-hydroxycamptothecin, camptothecin derivatives SN-38, 22-hydroxycamptothecin, topotecan, lortotecan, belotecan, isotecan Tecan, silyl homocamptothecin, 6,8-dibromo-2-methyl-3-[2-(D-pyranosylamino)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-pyranosyl-12,13-dihydro-2,10-dihydroxy-6-[[2-hydroxy- [1-(hydroxymethyl)ethyl]amino]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide dihydrochloride, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide; or the DNA topoisomerase inhibitor is camptothecin, 10-hydroxycamptothecin, topotecan, belotecan, irinotecan, 22-hydroxyelixirine or exitecan; or a pharmaceutically acceptable salt or solvate thereof.

17. The method according to any one of claims 1 to 15, wherein the drug is in X 1 and X 2 Each independently is: H， Hydroxyl, C1-C6 alkyl, C1-C6 alkyl substituted by one or more hydroxyl, halogen, nitro or cyano groups, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 aminoalkoxy, halogen, Nitro, Cyano, Thiol, Alkylthio, amino, amino substituted by an amino protecting group, C1-C6 aminoalkyl optionally substituted by an amino protecting group or a C1-C6 alkyl at the amino moiety, C1-C6 aminoalkylamino optionally substituted by an amino protecting group or a C1-C6 alkyl group at the amino moiety, C1-C6 alkyl linked to a heterocyclic ring, the heterocyclic ring being optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, amino, halogen, nitro or cyano groups, C1-C6 alkylamino group connected to a heterocyclic ring, the heterocyclic ring is optionally substituted by C1-C6 alkyl group, C1-C6 alkoxy group, the amino group is optionally substituted by an amino protecting group, a halogen, a nitro, a cyano group or a protecting group, An amino-substituted heterocyclic group, which is optionally substituted by a protecting group or one or more C1-C6 alkyl groups at the nitrogen atom of the heterocyclic ring or the amino moiety, A heterocyclic amino group, wherein the nitrogen atom of the heterocyclic ring part or the amino part is optionally substituted by a protecting group or a C1-C6 alkyl group, a carbamoyl group optionally substituted with a carbamoyl protecting group or a C1-C6 alkyl group, Morpholin-1-yl, or Piperidin-1-yl; X 3 is a C1-C6 alkyl group; X 4 H, -(CH2) q -CH3、-(CHR n ) q -CH3, C3-C8 carbocyclic group, -O-(CH2) q -CH3, arylene-CH3, -(CH2) q -Arylene-CH3, -Arylene-(CH2) q -CH3, -(CH2) q -(C3-C8 carbocyclyl)-CH3, -(C3-C8 carbocyclyl)-(CH2) q -CH3, C3-C8 heterocyclic group, -(CH2) q -(C3-C8 heterocyclic group)-CH3, -(C3-C8 heterocyclic group)-(CH2) q -CH3, -(CH2) q C(O)NR n (CH2) q -CH3, -(CH2CH2O) q -CH3, -(CH2CH2O) q -CH2-CH3, -(CH2) q C(O)NR n (CH2CH2O) q -CH3, -(CH2) q C(O)NR n (CH2CH2O) q -CH2-CH3, -(CH2CH2O) q C(O)NR n (CH2CH2O) q -CH3, -(CH2CH2O) q C(O)NR n (CH2CH2O) q -CH2-CH3, or -(CH2CH2O) q C(O)NR n (CH2) q -CH3; each R n is independently H, C1-C6 alkyl, C3-C8 carbocyclyl, phenyl or benzyl; and each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; or, X 4 is H or C1-C6 alkyl; ** is the connection point; y is 0, 1, or 2; Y is O, S or CR 1 R 2 , where R 1 and R 2 Each independently is H or C1-C6 alkyl; s and t are each independently 0, 1 or 2, but not both 0.

18. The method according to any one of claims 1 to 15 and 17, wherein the drug is Where X 1 and X 2 Each is independently C1-C6 alkyl, halogen or -OH; or the C1-C6 alkyl is -CH3; or the halogen is F; ** is the connection point.

19. The method according to any one of claims 1-15, 17-18, wherein the drug is Where X 1 and X 2 Each is independently C1-C6 alkyl, halogen or -OH; or the C1-C6 alkyl is -CH3; or the halogen is F; ** is the connection point.

20. A method for treating and / or preventing cancer, comprising administering an effective amount of an antibody drug conjugate by injection to a human patient in need thereof; wherein: The dosage of the antibody drug conjugate is 1.7 mg / kg to 2.5 mg / kg, or 100 mg to 250 mg, or 70 mg / kg. 2 -100mg / m 2 , or 75 mg / m 2 Up to 100 mg / m 2 , administered once every 2-4 weeks; the antibody drug conjugate has a structure as shown in Formula I-26 or I-27 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof: in Abu is an anti-FRα antibody or an antigen-binding unit thereof; n is an integer from 1 to 24; p is 1-10.

21. The method of claim 20, wherein n is an integer from 4 to 12.

22. The method of claim 20 or 21, wherein n is an integer from 4 to 8.

23. The method of any one of claims 20-22, wherein n is 4 or 8.

24. A method for treating and / or preventing cancer, comprising injecting an effective amount of an antibody drug conjugate into a human patient in need thereof; wherein: The dosage of the antibody drug conjugate is 1.7 mg / kg to 2.5 mg / kg, or 100 mg to 250 mg, or 70 mg / kg. 2 -100mg / m 2 , or 75 mg / m 2 Up to 100 mg / m 2 , administered once every 2-4 weeks; the antibody drug conjugate has the formula I-12, I-12-1, I-13, I-13-1, I-14, I-14-1, I-15, I-15-1, I-16, I-16-1, I-17, I-17-1, I- 18. The structure shown in I-18-1, I-19, I-19-1, I-20, I-20-1, I-21, I-21-1, I-22, I-22-1, I-23, I-23-1, I-24, I-24-1, I-25 or I-25-1 Or its stereoisomer or its pharmaceutically acceptable salt or solvate, wherein the formula I-12, I-12-1, I-13, I-13-1, I-14, I-14-1, I-15, I-15-1, I-16, I-16-1, I-17, I-17-1, I-18, I-18-1, I-19, I-19-1, I-20, I-20-1, I-21, I-21-1, I-22, I-22-1, I-23, I-23-1, I-24, I-24-1, I-25 or I-25-1 are respectively: in Abu is an anti-FRα antibody or an antigen-binding unit thereof; p is 1-10.

25. The method of any one of claims 2-24, wherein p is 2-8.

26. The method of any one of claims 2-25, wherein p is 4-8.

27. The method of any one of claims 2-26, wherein p is 6-8.

28. The method of any one of claims 2-27, wherein p is 7-8.

29. The method of any one of claims 2-28, wherein p is about 7.

30. The method of any one of claims 2-28, wherein p is about 7.

4.

31. The method of any one of claims 2-28, wherein p is about 8.

32. The method of any one of claims 1 to 31, wherein the anti-FRα antibody or antigen-binding unit thereof comprises a VH CDR1 as shown in SEQ ID NO: 1, a VH CDR2 as shown in SEQ ID NO: 2, a VH CDR3 as shown in SEQ ID NO: 3, a VL CDR1 as shown in SEQ ID NO: 4, a VL CDR2 as shown in SEQ ID NO: 5, and a VL CDR3 as shown in SEQ ID NO: 6; and optionally comprises one or more of (g) to (n): (g) VH FR1 comprises the amino acid sequence as shown in SEQ ID NO: 15, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence as shown in SEQ ID NO: 15, or an amino acid sequence having one or more positions substituted, deleted or inserted compared to the amino acid sequence as shown in SEQ ID NO: 15; (h) VH FR2 comprises the amino acid sequence as shown in SEQ ID NO: 16, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence as shown in SEQ ID NO: 16, or an amino acid sequence having one or more positions substituted, deleted or inserted compared to the amino acid sequence as shown in SEQ ID NO: 16; (i) VH FR3 comprises the amino acid sequence as shown in SEQ ID NO: 17, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence as shown in SEQ ID NO: 17, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence as shown in SEQ ID NO:

17. An amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence shown in ID NO: 17; (j) VH FR4 comprises the amino acid sequence as shown in SEQ ID NO: 18, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence as shown in SEQ ID NO: 18, or an amino acid sequence having one or more substitutions, deletions or insertions compared to the amino acid sequence as shown in SEQ ID NO: 18; (k) VL FR1 comprises the amino acid sequence as shown in SEQ ID NO: 19, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence as shown in SEQ ID NO: 19, or an amino acid sequence having one or more positions substituted, deleted or inserted compared to the amino acid sequence as shown in SEQ ID NO: 19; (l) VL FR2 comprises the amino acid sequence as shown in SEQ ID NO:20, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence as shown in SEQ ID NO:20, or an amino acid sequence having one or more positions substituted, deleted or inserted compared to the amino acid sequence as shown in SEQ ID NO:20; (m) VL FR3 comprises the amino acid sequence as shown in SEQ ID NO:21, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence as shown in SEQ ID NO:21, or an amino acid sequence having one or more positions substituted, deleted or inserted compared to the amino acid sequence as shown in SEQ ID NO:21; (n) VL FR4 comprises the amino acid sequence shown in SEQ ID NO:22, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:22, or an amino acid sequence having one or more site substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:

22.

33. The method of any one of claims 1 to 32, wherein the anti-FRα antibody or antigen binding unit thereof comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region comprises the 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 as shown in SEQ ID NO:7, or an amino acid sequence having one or more site substitutions, deletions or insertions compared to the amino acid sequence as shown in SEQ ID NO:7; and / or The light chain variable region comprises the amino acid sequence 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 site substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:

8.

34. The method of any one of claims 1 to 33, wherein the anti-FRα antibody or antigen binding unit thereof comprises a heavy chain and a light chain, wherein: The heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 11, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence as shown in SEQ ID NO: 11, or an amino acid sequence having one or more site substitutions, deletions or insertions compared to the amino acid sequence as shown in SEQ ID NO: 11; and / or The light chain comprises an amino acid sequence as shown in SEQ ID NO:13, or an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:13, or an amino acid sequence having one or more site substitutions, deletions or insertions compared to the amino acid sequence shown in SEQ ID NO:

13.

35. The method of any one of claims 1-34, wherein the patient has FRα expression ≥1%; or, the patient has FRαTPS ≥1%; or, the patient has FRα expression >25%; or, the patient has FRαTPS >25%; or, the patient has FRα expression <50%; or, the patient has FRαTPS <50%; or, the patient has FRα expression ≥50%; or, the patient has FRαTPS ≥50%; or, the patient has FRα expression ≥75%; or, the patient has FRαTPS ≥75%.

36. The method of any one of claims 1-35, wherein the antibody drug conjugate is administered at a dose of 1.7 mg / kg to 2.5 mg / kg.

37. The method of any one of claims 1-35, wherein the antibody drug conjugate is administered at a dose of 100 mg to 250 mg.

38. The method of any one of claims 1 to 35, wherein the dosage of the antibody drug conjugate is 70 mg / m 2 -100mg / m 2 .

39. The method of any one of claims 1 to 35, wherein the dosage of the antibody drug conjugate is 75 mg / m 2 Up to 100 mg / m 2 .

40. The method of any one of claims 1-39, wherein the antibody drug conjugate is administered once every 2 weeks.

41. The method of any one of claims 1-39, wherein the antibody drug conjugate is administered once every 3 weeks.

42. The method of any one of claims 1-39, wherein the antibody drug conjugate is administered once every 4 weeks.

43. A method for treating cancer, the method comprising administering an effective amount of an antibody drug conjugate to a patient with FRαTPS>25%, wherein the antibody drug conjugate has a structure as shown in Formula I-13-1 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof: in, Abu is an anti-FRα antibody, the heavy chain of which comprises the amino acid sequence shown in SEQ ID NO: 11, and the light chain of which comprises the amino acid sequence shown in SEQ ID NO: 13; p is 7-8; or p is 7.4; or p is 7; or p is 8.

44. The method of claim 43, wherein the dosage of the antibody drug conjugate is 0.5 mg / kg to 5 mg / kg, or 10 mg to 300 mg, or 5 mg / kg. 2 Up to 150 mg / m 2 , administered once a day to once every 7 weeks.

45. A method for treating cancer, the method comprising administering an effective amount of an antibody drug conjugate to a patient with FRαTPS>25%, wherein the dosage of the antibody drug conjugate is 0.5 mg / kg to 5 mg / kg, or 10 mg to 300 mg, or 5 mg / m 2 Up to 150 mg / m 2 , administered once a day to once every 7 weeks.

46. ​​The method of claim 45, wherein the antibody drug conjugate has a structure as shown in Formula I-13-1 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof: in, Abu is an anti-FRα antibody, the heavy chain of which comprises the amino acid sequence shown in SEQ ID NO: 11, and the light chain of which comprises the amino acid sequence shown in SEQ ID NO: 13; p is 1-10; or p is 2-8; or p is 4-8; or p is 6-8; or p is 7-8; or p is 7.4; or p is 7; or p is 8.

47. The method of any one of claims 1-46, wherein the patient has a FRαTPS < 50%; or, the patient has a FRαTPS ≥ 50%; or, the patient has a FRαTPS ≥ 75%.

48. The method of any one of claims 1-47, wherein the cancer is selected from the group consisting of colorectal cancer, lung cancer (such as non-small cell lung cancer), ovarian cancer, uterine cancer, endometrial cancer, peritoneal cancer, fallopian tube cancer, pancreatic cancer, head and neck squamous cell carcinoma, nasopharyngeal cancer, laryngeal cancer, liver cancer, breast cancer, brain cancer, kidney cancer, renal cell carcinoma, colon cancer, testicular cancer, cervical cancer, tongue cancer, bladder cancer, retinoblastoma, glioblastoma, mesothelioma, oral epithelioid carcinoma, choriocarcinoma, and head and neck cancer; or the cancer is a platinum-refractory cancer; or the cancer is platinum-refractory ovarian cancer; or the patient suffers from platinum-refractory advanced or metastatic ovarian cancer; or the cancer is selected from platinum-refractory epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; or the patient suffers from platinum-refractory advanced or metastatic epithelial Ovarian cancer, primary peritoneal cancer or fallopian tube cancer; or the cancer is platinum-resistant cancer; or the cancer is platinum-resistant ovarian cancer; or the patient suffers from platinum-resistant advanced or metastatic ovarian cancer; or the cancer is selected from platinum-resistant epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer; or the patient suffers from platinum-resistant advanced or metastatic epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer; or the patient suffers from platinum-resistant advanced or metastatic epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer and has not received more than 3 lines of previous treatment; or the patient suffers from advanced or metastatic solid tumors that have failed standard treatment or are intolerant to standard treatment; or the patient suffers from advanced or metastatic endometrial cancer, breast cancer, non-small cell lung cancer that have failed standard treatment or are intolerant to standard treatment.

49. The method of any one of claims 43-48, wherein the antibody drug conjugate is administered at a dose of 0.5 mg / kg to 3 mg / kg, or 1.3 mg / kg to 3 mg / kg, or 1.7 mg / kg to 2.5 mg / kg.

50. The method of any one of claims 43-48, wherein the antibody drug conjugate is administered at a dose of 30 mg to 300 mg, 50 mg to 280 mg, or 100 mg to 250 mg.

51. The method according to any one of claims 43 to 48, wherein the dosage of the antibody drug conjugate is 30 mg / m 2 Up to 120 mg / m 2 , or 50 mg / m 2 Up to 120 mg / m 2 , or 70 mg / m 2 -100mg / m 2 , or 75 mg / m 2 Up to 100 mg / m 2 .

52. The method of any one of claims 1-51, wherein the antibody drug conjugate is administered once every 2 weeks, once every 3 weeks, or once every 4 weeks.

53. The method of any one of claims 1 to 51, wherein the antibody drug conjugate is administered at a dosage of about 2.4 mg / kg, administered once every 2-4 weeks, such as once every 3 weeks; the antibody drug conjugate is administered at a dosage of about 2.1 mg / kg, administered once every 2-4 weeks, such as once every 3 weeks; or, the antibody drug conjugate is administered at a dosage of about 1.8 mg / kg, administered once every 2-4 weeks, such as once every 3 weeks; or, the antibody drug conjugate is administered at a dosage of about 1.5 mg / kg, administered once every 2-4 weeks, such as once every 3 weeks; or, the antibody drug conjugate is administered at a dosage of about 93 mg / kg. 2 , administered once every 2-4 weeks, for example, once every 3 weeks; or, the dosage of the antibody drug conjugate is about 84 mg / m 2 , administered once every 2-4 weeks, for example, once every 3 weeks; or, the dosage of the antibody drug conjugate is about 76 mg / m 2 , administered once every 2-4 weeks, for example, once every 3 weeks.

54. The method of any one of claims 1 to 53, wherein the antibody drug conjugate is administered at a dose of about 84 mg / m 2 , administered once every 2-4 weeks, for example, once every 3 weeks.

55. The method of any one of claims 1-53, wherein the antibody drug conjugate is administered at a dose of about 93 mg / m 2 , administered once every 2-4 weeks, for example, once every 3 weeks.

56. The method according to any one of claims 1 to 55, wherein the antibody-drug conjugate is administered by injection; or, the antibody-drug conjugate is administered by intravenous injection, subcutaneous injection or intraperitoneal injection; or, the administration is by intravenous infusion.

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