Bioactive matter conjugate as well as preparation method and application thereof

Abstract

The invention relates to a bioactive substance conjugate as well as a preparation method and application thereof, and particularly discloses a ligand drug conjugate as shown in a formula XV, a preparation method thereof and application of the ligand drug conjugate in prevention and / or treatment of diseases related to abnormal cell activity, including but not limited to prevention and / or treatment of tumor diseases. # imgabs0 #

Description

[0001] The applicant submitted PCT application PCT / CN2022 / 073822 on January 25, 2022, entitled “Bioactive Conjugates, Preparation Methods, and Uses Thereof.” The PCT application entered the Chinese national phase on September 7, 2022, with application number 202280003045.7. This application is a divisional application of that Chinese application.

[0002] This application claims priority to Chinese patent application No. 2021101781361, filed on February 9, 2021; claims priority to Chinese patent application No. 2021103408065, filed on March 30, 2021; claims priority to Chinese patent application No. 202110825932X, filed on July 21, 2021; claims priority to Chinese patent application No. 2021108259226, filed on July 21, 2021, and a sequence listing (txt) was filed concurrently with Chinese patent application No. 2021108259226 on July 21, 2021; and claims priority to Chinese patent application No. 2021108259067, filed on July 21, 2021, and a sequence listing (txt) was filed concurrently with Chinese patent application No. 2021108259067 on July 21, 2021. This application incorporates the entire text of the aforementioned Chinese patent applications. The sequence listing contained in this application is part of the specification and is herein incorporated by reference in its entirety. Technical Field

[0003] The present disclosure belongs to the field of medical technology and relates to bioactive substance conjugates (ligand-drug conjugates), compounds, drug-linker conjugates and preparation methods thereof, as well as their use in preventing and / or treating diseases associated with abnormal cell activity, including but not limited to preventing and / or treating tumor diseases. Background Art

[0004] Cytotoxic chemotherapy was once the standard treatment for cancer, but highly potent cytotoxic molecules can kill normal cells and cause severe side effects. Targeted anti-tumor drugs, due to their combined targeting and anti-tumor activity, have become a hot topic in oncology research. However, these drugs often produce significant side effects due to their target selectivity, limiting their therapeutic efficacy. Biological macromolecule drugs, such as antibodies or antibody fragments, while highly targeted, have limited or no therapeutic effect against solid tumors. ADCs, conjugates of antibodies and small molecule drugs, combine the targeting properties of antibodies with the activity of bioactive molecules, creating a biological missile with highly promising efficacy and safety advantages. Antibodies guide ADCs to target cells, where they are then internalized. The small molecule drug is then released through enzymatic degradation by specific enzymes to treat the disease.

[0005] ADC drugs have developed very rapidly in recent years, and there are 14 ADCs on the market: (1) Mylotarg (Gemtuzumab Ozogamicin, Gemtuzumab (CD33)-Cazitamycin), CD33-positive acute myeloid leukemia (AML), approved by the FDA in 2000, withdrawn from the market in 2010, and re-launched in 2017; (2) Adcetris (Brentuximab Vedotin, CD30 monoclonal antibody-MMAE), classical Hodgkin lymphoma and anaplastic large cell lymphoma, approved by the FDA in 2011; (3) Kadcyla (Trastuzumab Emtansine, Trastuzumab (Her2)-Maytansine alkaloid TM1), HER2-positive breast cancer, approved by the FDA in 2013; (4) Besponsa (Inotuzumab Vedotin, CD30 monoclonal antibody-MMAE), HER2-positive breast cancer, approved by the FDA in 2013; (5) (5) Lumoxiti (Moxetumomab pasudotox-tdfk, CD22-Pseudomonas exotoxin), relapsed or refractory hairy cell leukemia (HCL), launched in 2018; (6) Polivy (Polatuzumab vedotin-piiq, CD79b-MMAE), relapsed or refractory diffuse large B-cell lymphoma (R / R DLBCL), launched in 2019; (7) Padcev (Enfortumab vedotin-ejfv, Nectin4-MMAE), locally advanced or metastatic urothelial carcinoma (UC), launched in 2019; (8) Enhertu (Famtrastuzumab vedotin-ejfv), locally advanced or metastatic urothelial carcinoma (UC), launched in 2019; (1) deruxtecan-nxki (Her2-topoisomerase I inhibitor), breast cancer, launched in 2019; (2) Trodelvy (Trop2-topoisomerase I inhibitor ADC), triple-negative breast cancer, approved by the FDA in April 2020; (3) BCMA ADC Belantamab mafodotin (GSK2857916); (4) CD19 ADC Zynlonta (loncastuximab tesirine); (5) EGFR ADC Akalux; (6) Her2 ADC Vedicizumab RC48; (7) Tissue Factor ADC Tivadak (tisotumab vedotin).

[0006] ADC drugs are composed of three parts: antibodies, bioactive molecules (drug molecules) and linkers. The bioactive molecules are covalently coupled to the antibodies through the linker. In addition to targeting and bioactivity, the coupling method of the bioactive molecules and antibodies is also one of the core features of ADC drugs. It determines the uniformity and stability of the drug and greatly affects the pharmacokinetic properties and toxicity of the ADC. Improving the stability of the linker between the bioactive molecules and the antibody will increase the stability of the ADC systemic circulation and reduce the shedding of the drug in non-target tissues, thereby relatively increasing the amount of drugs brought into the target cells and around the target cells, increasing the release of the bioactive molecules in and around the target cells, and further enhancing efficacy and reducing toxicity. Therefore, increasing the stability of the connection between the bioactive molecules and the antibody is one of the extremely important technical fields in ADC drug research.

[0007] There are two main ways to couple the 10 ADC antibodies and linkers currently on the market: (1) Lysine is the most common linking site in antibodies, and its ε-amino group can react with the activated carboxyl group of the linker to form an amide bond. Currently, there is a technology that can achieve site-specific coupling, that is, using an activating group to activate the carboxyl group of the linker, and then forming an amide bond with the specific lysine ε-amino group in the antibody to complete the coupling. On the one hand, the site-specific quantitative coupling achieved through this type of amide bond does not have broad practicality and can only be used in certain specific situations; on the other hand, it is easy to hydrolyze under the action of enzymes in the body, causing the bioactive molecules and antibodies to fall off before reaching the target cells, increasing toxicity. (2) The sulfhydryl group (SH) of the cysteine ​​of the antibody exists in the form of a disulfide bond. Opening the disulfide bond in the antibody can provide multiple free sulfhydryl groups as coupling sites. One method of coupling with the antibody sulfhydryl group is to react the free sulfhydryl group on the antibody with maleimide through Michael addition reaction, or a specific substrate can react with the free sulfhydryl group on the antibody through two Michael addition reactions to form a unique structural sulfur bridge bond. However, many literature reports show that 30% or more of the ADCs obtained by the thiol Michael addition method will undergo reverse Michael addition in the systemic circulation, resulting in premature toxin shedding and toxic reactions.

[0008] Antibody-drug conjugates can be divided into four generations based on their development history:

[0009] The first generation of antibody-drug conjugates are based on mouse antibodies, which can produce complex immunogenicity and thus have strong toxic side effects;

[0010] Second-generation antibody-drug conjugates (ADCs) utilize humanized or fully human antibodies based on the first generation, resulting in significantly improved drug properties. The first and second generation ADCs are relatively random in the connection between the antibody and the drug, resulting in a multi-component mixture. These drugs are not only highly toxic but also difficult to control in terms of quality.

[0011] The third generation of antibody-drug conjugates uses humanized or fully human antibodies to simultaneously achieve site-specific and quantitative conjugation of toxins, linkers, and antibodies, thereby generating uniform single-molecule antibody-drug conjugates. The toxicity and quality control of this type of antibody-drug conjugate are significantly improved compared to the second generation.

[0012] The fourth generation of antibody-drug conjugates is based on the third generation and has innovated the toxin-linker. The fourth generation of antibody-drug conjugates changed the previous antibody-drug conjugate strategy based on highly toxic toxins, and selected relatively low-toxic camptothecin molecules as bioactive ingredients. At the same time, it adopted a high toxin-antibody ratio (DAR), such as a DAR value of 8. This type of ADC can also produce a good therapeutic effect on tumors with low expression of tumor surface antigens. Although the fourth generation of antibody-drug conjugates started late, due to its significant efficacy, it emerged as a new force and quickly gained clinical recognition. Its representative drugs Enhertu and Trodelvy have been approved for marketing by the FDA. However, the fourth generation of ADCs still have problems with poor stability or low solubility, and existing technologies lack universality. Further development of new toxin-linkers is still needed to solve these problems.

[0013] Existing antibody-drug conjugates (ADCs) typically bind to tumor cell surface antigens through the binding of the antibody in the ADC. The ADC then undergoes endocytosis and enters the endosome, where it is converted to the lysosome. Lysosomal hydrolases then dissociate the bioactive molecule (toxin or payload) from the ADC. The dissociated bioactive molecule then enters the cytoplasm and kills the tumor cell. The bioactive molecule that escapes from the killed tumor cell can further kill surrounding tumor cells that do not express or express low levels of the antigen (the so-called bystander effect). Alterations in any of these steps can lead to drug resistance and loss of therapeutic efficacy. These include changes in antigen expression, decreased or even loss of endocytosis, or altered endosome or lysosomal function. Therefore, it is crucial to develop an ADC that is stable in the bloodstream and capable of cleaving the toxin in the tumor microenvironment without endocytosis, thereby eliminating the toxin and achieving tumor killing. Such an ADC would overcome the various resistance mechanisms associated with traditional ADCs and would be of great clinical significance.

[0014] Although there is evidence that Immunomedics and Gilead's Trodelvy can be cleaved outside tumor cells without the need for endocytosis, Trodelvy is very unstable in plasma and aqueous solutions, with a plasma half-life of less than 24 hours. Therefore, this type of ADC can only be used for ADCs composed of toxins with low biological activity to avoid non-targeted toxic side effects caused by premature shedding of ADC toxins.

[0015] In addition, the function of the linker of traditional ADC is to complete enzymatic cleavage in cells or use it to regulate water solubility. How to make the linker meet the requirements of enzymatic cleavage while using the linker to achieve ADC enrichment in tumor tissue is also of great significance for reducing the toxic side effects of ADC in normal tissues.

[0016] B7H3 is a type I transmembrane protein of the B7 family, with two isoforms in humans: 2Ig-B7H3 and 4Ig-B7H3. B7H3 is widely expressed in normal tissues, constitutively expressed only in non-immune resting fibroblasts, endothelial cells, osteoblasts, and amniotic fluid stem cells, and inducibly expressed on activated T cells, NK cells, DCs, and macrophages, with no positive expression detected in lymphoid organs (Chapoval, AI, et al., B7H3: A costimulatory molecule for T cell activation and IFN production. Nature Immunology, 2001. 2(3): p. 269-274). Studies have shown that approximately 76.5% of patients with early-stage liver cancer have serum B7H3 levels about three times higher than those of healthy controls (60.79±19.45 vs. 20.52±8.46 ng / mL), but its correlation with the disease progression remains unclear (Zhao, L., et al., Early Detection of Hepatocellular Carcinoma in Patients with Hepatocirrhosis by Soluble B7H3. Journal of Gastrointestinal Surgery. 21(5): p.807-812).

[0017] Currently, there are therapeutic strategies targeting B7H3 in preclinical studies. For example, antibodies against mouse B7H3 enhance CD8-positive T cells infiltrating tumors and inhibit tumor growth (Mod Pathol. 2010 Aug; 23(8): 1104-12.). In addition, WO2008 / 066691 shows that antibodies that recognize the B7H3 variant B7H3a have anti-tumor effects on adenocarcinoma in vivo. In clinical studies, a combination of mouse B7H3 antibodies and radioactive iodine-131 can significantly inhibit the growth of neuroblastoma in patients [J Neufoocol 97(3): 409-18 (2010)]. Summary of the Invention

[0018] In order to improve the therapeutic effect of antibody-drug conjugates (ADCs) or other ligand-drug conjugates (PDCs), reduce drug toxicity and side effects, and increase the therapeutic window, the present disclosure provides a ligand-drug conjugate represented by formula (XV) or a pharmaceutically acceptable salt or solvate thereof, which contains a bioactive molecule (drug molecule), a linker, and a targeting moiety, wherein the targeting moiety is connected to the linker via an active group (e.g., a sulfhydryl group) to form a ligand-drug conjugate. The present disclosure also develops antibodies comprising a variable light chain domain and / or a variable heavy chain (VH) domain that binds to a B7H3 molecule, wherein the variable light chain domain and / or variable heavy chain (VH) domain antibodies are already derived from human antibodies.

[0019] To this end, in the first aspect of the present disclosure, the present disclosure provides a ligand drug conjugate as shown in Formula XV,

[0020]

[0021] or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

[0022] in:

[0023] Tb is a ligand or targeting moiety that binds to the target;

[0024] q is the drug-ligand coupling ratio;

[0025] D is a bioactive molecular fragment;

[0026] L1 is the extension unit;

[0027] L2 does not exist or is a linker unit; L3 is selected from an amino acid residue or a short peptide consisting of 2-10 amino acid residues;

[0028] L4 is absent or present. When L4 is present, L4 is selected from Bit 1 is connected to L3 and bit 2 is connected to D.

[0029] In addition, it should be noted that regarding "position 1 of L1 is connected to Tb via an S atom", those skilled in the art will understand that position 1 of L1 is connected to the sulfhydryl group contained in Tb (such as an antibody) after the disulfide bond is opened (for example, the disulfide bond can be opened by reducing the reducing agent TCEP to generate a sulfhydryl group -SH). In other words, the -S- between L1 and Tb is not an additional external sulfur atom. For example, In the example, -S- is not an additional external sulfur atom, but the thiol group contained in Tb itself after the disulfide bond is opened and the thiol group of L1 is connected. -S- is formed by connecting the 1 bits of

[0030] The Stretcher unit is a component of a ligand-drug conjugate, drug-linker conjugate, or linker that connects the target-binding ligand or targeting moiety to the remainder of the ligand-drug conjugate or linker. The Stretcher unit can connect the Tb unit to L2 (if present) or L3. Specific examples include, but are not limited to, (where position 1 is connected to the target-binding ligand or targeting moiety, and position 2 is connected to L2 or L3):

[0031] In some embodiments, L1 is selected from:

[0032]

[0033]

[0034]

[0035]

[0036] Each Z is independently selected from a direct bond, a carbon-carbon triple bond, a carbon-carbon double bond, a C6-10 aryl group, a 5-10 membered heteroaryl group, an amide group, a sulfonamide group, an imine group, and CF2;

[0037] Rx and Ry are independently selected from H and C1-4 alkyl;

[0038] Each m is independently selected from 0, 1, 2, 3, 4, 5 and 6;

[0039] y1, y2, y3 and y4 are independently selected from any integer between 0 and 20;

[0040] Position 1 is connected to Tb via an S atom, and position 2 is connected to L2 or L3.

[0041] The Linker is a component of a ligand-drug conjugate, drug-linker conjugate, or linker that serves to bind the Stretcher to an amino acid residue or a short peptide consisting of 2-10 amino acid residues. When present, the Linker can link L1 to L3. Specific examples include, but are not limited to, (wherein position 1 is linked to the Stretcher and position 2 is linked to L3):

[0042] In some embodiments, L2 is absent or present, and when present, L2 is selected from:

[0043]

[0044]

[0045] y1, y2, y3 and y4 are independently selected from any integer between 0 and 20, the 1st position is connected to L1, and the 2nd position is connected to L3.

[0046] In some embodiments, L1 is

[0047] In some embodiments, L1 is selected from Each Z is independently selected from a direct bond, a carbon-carbon triple bond, a carbon-carbon double bond, a C6-10 aromatic group, a 5-10 membered heteroaromatic group and an amide group (preferably selected from a direct bond, a carbon-carbon triple bond and a carbon-carbon double bond); Rx and Ry are independently selected from H and a C1-4 alkyl group; each m is independently selected from 0, 1, 2, 3, 4, 5 and 6; y1 is independently selected from any integer between 1 and 6 (such as 4, 5, 6); each y2 is independently selected from any integer between 0 and 15 (such as 6-15); each y3 is independently selected from 1, 2 and 3; each y4 is independently selected from 0 and 1; position 1 is connected to Tb through an S atom, and position 2 is connected to L2 or L3.

[0048] In some embodiments, L1 is selected from m is selected from 2, 3, and 4, y1 is selected from any integer between 1 and 6 (such as 4, 5, and 6), each y2 is independently selected from any integer between 0 and 10 (such as 6 and 10), each y3 is independently selected from 1 or 2, position 1 is connected to Tb through an S atom, and position 2 is connected to L2 or L3.

[0049] In some embodiments, L1 is selected from Position 1 is connected to Tb via an S atom, and position 2 is connected to L2 or L3.

[0050] In some embodiments, L1 is selected from

[0051] In some embodiments, L1 is selected from Position 1 is connected to Tb via an S atom, and position 2 is connected to L2 or L3.

[0052] In some embodiments, L1 is selected from Position 1 is connected to Tb via an S atom, and position 2 is connected to L2 or L3.

[0053] In some embodiments, L1 is selected from Position 1 is connected to Tb via an S atom, and position 2 is connected to L2 or L3.

[0054] In some embodiments, L2 is absent or present, and when L2 is present, L2 is selected from y1 is selected from any integer between 1-6 (such as 4, 5, 6), each y2 is independently selected from any integer between 0-10 (such as 6-10), each y3 is independently selected from 1 or 2, each y4 is independently selected from 0 or 1, position 1 is connected to L1, and position 2 is connected to L3.

[0055] In some embodiments, L2 is absent or present, and when L2 is present, L2 is selected from Bit 1 is connected to L1 and bit 2 is connected to L3.

[0056] In some embodiments, L2 is absent or present, and when L2 is present, L2 is selected from Bit 1 is connected to L1 and bit 2 is connected to L3.

[0057] In some embodiments, L2 is absent or present, and when L2 is present, L2 is selected from Bit 1 is connected to L1 and bit 2 is connected to L3.

[0058] In some embodiments, L2 is absent.

[0059] In some embodiments, L2 is selected from

[0060] In some embodiments, L3 is selected from an amino acid residue or a short peptide consisting of 2-10 amino acid residues; the amino acid residue is selected from a natural amino acid residue, a non-natural amino acid residue, or an amino acid residue represented by AA1 or a stereoisomer thereof.

[0061] In some embodiments, L3 is selected from the group consisting of amino acid residues Val, D-Val, Cit, Phe, Lys, Lys(Ac), Leu, Gly, Ala, Asn, Asp, Arg, AA 1 or 2-10 selected from Val, Cit, Phe, Lys, D-Val, Leu, Gly, Ala, Asn, Asp, AA 1 A short peptide composed of amino acid residues.

[0062] In some embodiments, L3 is selected from Val, Cit, Phe, Lys, D-Val, Leu, Gly, Ala, Asn, AA 1 , Val-Cit, Cit-Val, Cit-Ala, Val-Ala, Lys-Val, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Ala-Ala, Val-AA 1 、Ala-AA 1 、Gly-AA 1 AA 1 -Gly, Ala-Ala-Ala, Ala-Ala-Asn, Ala-Ala-Asp, Val-AA 1 -Gly, Ala-AA 1 -Gly, Gly-AA 1 -Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Gly-Phe-Gly, Gly-Gly-Phe-Gly, D-Val-Leu-Lys, Gl y-Gly-Arg, Ala-Ala-Asn, Gly-Gly-Phe, Val-Lys-Gly, Val-Lys-Gly-Gly, Val-Lys and Lys-Ala-Asn.

[0063] In some embodiments, L3 is selected from AA 1 AA 1 -Gly, Val-Cit, Val-AA 1 -Gly, AA 1 -Ala-Asn and Gly-Gly-Phe-Gly.

[0064] In some embodiments, L3 is selected from AA 1 and Val-AA 1 -Gly.

[0065] In some embodiments, L3 is selected from Val-AA 1 -Gly.

[0066] In some embodiments, L3 is selected from

[0067] X - Selected from halogen ions, carboxylate ions, sulfate ions, hydrogen sulfate ions and OH - , bit 1 is connected to L1 or L2, bit 2 is connected to L4 or D.

[0068] In some embodiments, L3 is selected from

[0069]

[0070] X - Selected from halogen ions, carboxylate ions, sulfate ions, hydrogen sulfate ions and OH - , bit 1 is connected to L1 or L2, bit 2 is connected to L4 or D.

[0071] In some embodiments, L3 is selected from X - Selected from halogen ion, carboxylate ion, sulfate ion, hydrogen sulfate ion and OH-, the 1 position is connected to L1 or L2, and the 2 position is connected to L4 or D.

[0072] In some embodiments, L3 is selected from Bit 1 is connected to L1 or L2, and bit 2 is connected to L4 or D.

[0073] In some embodiments, L3 is selected from Bit 1 is connected to L1 or L2, and bit 2 is connected to L4 or D.

[0074] In some embodiments, AA 1 The structures of the indicated amino acid residues are shown below,

[0075]

[0076] in:

[0077] R a 、R b Each independently selected from H, And R a 、R b Not at the same time H;

[0078] Or, R a With Rb Together with the carbon atoms to which they are attached, they form a 4-10 membered heterocyclic ring, which is optionally substituted by one or more R 0 replaced by;

[0079] r、r 1 are each independently selected from any integer from 0 to 20;

[0080] R m1 、R n1 Each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl and -COOR x1 ;

[0081] R x1 Selected from C1-6 alkyl;

[0082] Or, R m1 With R n1 Together with the nitrogen atom to which they are attached, they form a 4-10 membered heterocyclic ring, which is optionally substituted by one or more R 0’ replaced by;

[0083] R z Selected from C1-6 alkyl;

[0084] R 0 、R 0’ Each independently selected from C1-6 alkyl, C3-6 cycloalkyl, -NR m2 R n2 and a 4-10 membered heterocyclic group optionally substituted by a C1-6 alkyl group;

[0085] R m2 、R n2 Each is independently selected from H and C1-6 alkyl.

[0086] In some embodiments, R a 、R b Among them, any one is H, and the other is selected from

[0087] In some embodiments, R a 、R b Among them, any one is H, and the other is selected from

[0088] In some embodiments, R a With R b Together with the carbon atoms they are connected to, they form the 0 Substituted 5-6 membered heterocycle.

[0089] In some embodiments, R a With Rb Together with the carbon atoms they are connected to, they form the 0 a substituted piperidine ring or a piperazine ring.

[0090] In some embodiments, R a With R b Together with the carbon atoms they are connected to, they form the 0 Substituted piperidine ring.

[0091] In some embodiments, R a With R b Together with the carbon atoms they are connected to, they form Carbon atom No. 1 is R a and R b carbon atoms that are linked together.

[0092] In some embodiments, R a With R b Together with the carbon atoms they are connected to, they form Carbon atom No. 1 is R a and R b carbon atoms that are linked together.

[0093] In some embodiments, r, r 1 Each is independently selected from 0, 1, 2, 3, 4 and 5.

[0094] In some embodiments, r, r 1 are each independently selected from 0 and 4.

[0095] In some embodiments, r, r 1 If one of them is 0, the other one is 4.

[0096] In some embodiments, R m1 、R n1 Each is independently selected from H, methyl, ethyl, n-propyl, n-butyl, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH(CH3)2, -COOC(CH3)3 and -COOCH2CH2CH2CH3.

[0097] In some embodiments, R m1 、R n1 Each is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl and tert-butyloxycarbonyl.

[0098] In some embodiments, R m1 、R n1 Each is independently selected from H and C1-6 alkyl.

[0099] In some embodiments, R m1 、R n1 Each is independently selected from H, methyl, ethyl and n-propyl.

[0100] In some embodiments, r, r 1 In the example, r is 4, r 1 When R is 0, m1 、R n1 Each is independently selected from H, C1-6 alkyl (such as H, methyl); r is 0, r 1 When R is 4, m1 、R n1 Each is independently selected from C1-6 alkyl (such as methyl, ethyl, n-propyl), preferably selected from C2-6 alkyl (such as ethyl, n-propyl).

[0101] In some embodiments, R m1 With R n1 Together with the nitrogen atom to which they are commonly attached, they form an optionally R 0’ Substituted 5-6 membered heterocycle.

[0102] In some embodiments, R m1 With R n1 Together with the nitrogen atom to which they are commonly attached, they form an optionally R 0’ a substituted piperidine ring or a piperazine ring.

[0103] In some embodiments, R m1 With R n1 Together with the nitrogen atoms they are connected to, they form Nitrogen atom No. 1 is R m1 and R n1 Commonly linked nitrogen atoms.

[0104] In some embodiments, R z It is a methyl group.

[0105] In some embodiments, R 0 、R 0’ Each independently selected from C1-6 alkyl, -NR m2 R n2 and a 5-6 membered heterocyclic group optionally substituted by a C1-6 alkyl group.

[0106] In some embodiments, R 0 is selected from C1-6 alkyl and a 5-6 membered heterocyclic group substituted by a C1-6 alkyl group, wherein the 5-6 membered heterocyclic group is selected from piperidinyl and piperazinyl.

[0107] In some embodiments, R 0 is selected from methyl, ethyl and a 5-6 membered heterocyclic group substituted by a methyl group, wherein the 5-6 membered heterocyclic group is a piperidinyl group.

[0108] In some embodiments, R 0 is selected from methyl and a 5-6 membered heterocyclic group substituted by methyl, wherein the 5-6 membered heterocyclic group is piperidinyl.

[0109] In some embodiments, R 0 Selected from methyl, ethyl and

[0110] In some embodiments, R 0 Selected from methyl and

[0111] In some embodiments, R 0’ Selected from C1-6 alkyl and -NR m2 R n2 .

[0112] In some embodiments, R 0’ Selected from methyl and -NR m2 R n2 .

[0113] In some embodiments, R m2 、R n2 It is a methyl group.

[0114] In some embodiments, AA 1 The amino acid residues shown are selected from

[0115] In some embodiments, AA 1 The amino acid residues shown are selected from

[0116] In some embodiments, AA 1 The amino acid residues shown are selected from

[0117] In some embodiments, AA 1 The amino acid residues shown are selected from

[0118] In some embodiments, L4 is absent or present, and when L4 is present, L4 is selected from Bit 1 is connected to L3 and bit 2 is connected to D.

[0119] In some embodiments, L4 is absent or present, and when L4 is present, L4 is Bit 1 is connected to L3 and bit 2 is connected to D.

[0120] In some embodiments, L4 is absent.

[0121] In some embodiments, L4 is selected from Bit 1 is connected to L3 and bit 2 is connected to D.

[0122] In some embodiments, L4 is selected from Bit 1 is connected to L3 and bit 2 is connected to D.

[0123] In some embodiments, The structure is selected from the following structural fragments:

[0124]

[0125] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof.

[0126] In some embodiments, the antibodies or antigen-binding fragments thereof and monoclonal antibodies or antigen-binding fragments thereof include: Fab, Fab', F(ab')2, Fd, Fv (e.g., scFv), dAb, complementarity determining region fragments, non-human antibodies, humanized antibodies, chimeric antibodies, fully human antibodies, probodies, monoclonal antibodies, bispecific antibodies or multispecific antibodies.

[0127] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof having endocytic or non-endocytic activity.

[0128] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof having endocytic activity.

[0129] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has the activity of binding to free antigens in tumor tissues and / or tumor cell surface antigens.

[0130] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has the activity of being internalized by tumor cells and has the activity of binding to free antigens in tumor tissues or antigens on the surface of tumor cells.

[0131] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has the activity of being endocytosed by tumor cells and has the activity of binding to free antigens in tumor tissues and antigens on the surface of tumor cells.

[0132] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has the activity of being endocytosed by tumor cells and has no free antigen-binding activity in tumor tissues.

[0133] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has the activity of being endocytosed by tumor cells and has no activity of binding to tumor cell surface antigens.

[0134] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has no endocytosis activity or has weak endocytosis activity.

[0135] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that does not have the activity of binding to free antigens in tumor tissues and / or tumor cell surface antigens.

[0136] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has no or weak endocytosis activity by tumor cells and has binding activity to free antigens in tumor tissues or antigens on the surface of tumor cells.

[0137] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has no or weak endocytosis activity by tumor cells and has binding activity to free antigens in tumor tissues and antigens on the surface of tumor cells.

[0138] In some embodiments, Tb is an antibody or antigen-binding fragment thereof that has no or weak endocytosis activity by tumor cells and no binding activity to antigens on the surface of tumor cells. In some embodiments, Tb is an antibody or antigen-binding fragment thereof that has no or weak endocytosis activity by tumor cells and no binding activity to free antigens in tumor tissue.

[0139] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has no endocytosis activity by tumor cells and has no corresponding antigen in the human body.

[0140] In some embodiments, Tb is an antibody that does not bind to a tumor cell-associated antigen.

[0141] In some embodiments, the antibody or antigen-binding fragment thereof is selected from an IgG isotype antibody.

[0142] In some embodiments, the antibody or antigen-binding fragment thereof is selected from the group consisting of isotype IgG1, isotype IgG2, isotype IgG3, and isotype IgG4.

[0143] In some embodiments, the antibody or antigen-binding fragment thereof is an anti-chicken lysozyme human IgG1 isotype antibody.

[0144] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has the activity of binding to non-endocytic antigens (eg, ALCAM / CD166) on the surface of tumor cells.

[0145] In some embodiments, Tb is an antibody that binds to a tumor cell-associated antigen.

[0146] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has binding activity to free antigens in tumor tissues or antigens on the surface of tumor cells.

[0147] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof that has binding activity to free antigens in tumor tissues and antigens on the surface of tumor cells.

[0148] In some embodiments, Tb is an antibody or antigen-binding fragment thereof having B7H3-2Ig and / or B7H-4Ig.

[0149] In some embodiments, Tb is an antibody or antigen-binding fragment thereof having higher binding activity for B7H3-4Ig than for B7H3-2Ig.

[0150] In some embodiments of the present disclosure, Tb is a ligand or targeting moiety that binds to a target.

[0151] In some embodiments, the target of Tb is selected from targets that are expressed higher in tumor cells than in normal cells.

[0152] In some embodiments, the target of Tb is selected from targets that are highly expressed in tumor cells and lowly expressed in normal cells.

[0153] In some embodiments, the target of Tb is selected from the group consisting of: B7H3, CD20, CD19, CD30, GPNMB, Her2, Trop-2, EGFR, Her3, GD-2, CD79b and BCMA, etc.

[0154] In some embodiments, the Tb is an antibody or an antigen-binding fragment thereof.

[0155] In some embodiments, Tb is a non-human antibody, a humanized antibody, a chimeric antibody, or a fully human antibody.

[0156] In some embodiments, Tb is a monoclonal antibody, a bispecific antibody, or a multispecific antibody.

[0157] In some embodiments, Tb is a monoclonal antibody or an antigen-binding fragment thereof.

[0158] In some embodiments, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, an anti-Trop-2 antibody or an antigen-binding fragment thereof, an anti-Her 2 antibody or an antigen-binding fragment thereof, an anti-Her 3 antibody or an antigen-binding fragment thereof, or an anti-EGFR antibody or an antigen-binding fragment thereof.

[0159] In some embodiments, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, such as 1D1, 1D1-01, 2E3, 2E3-02 antibodies, enoblituzumab, mirzotamab, omburtamab, or an antigen-binding fragment thereof.

[0160] The sequence of 1D1 is shown in SEQ ID NO: 1. The VH sequence of 1D1-01 is shown in SEQ ID NO: 3, and the VL sequence is shown in SEQ ID NO: 13. The heavy chain sequence of 1D1-01 is shown in SEQ ID NO: 45, and the light chain sequence is shown in SEQ ID NO: 46. The sequence of 2E3 is shown in SEQ ID NO: 2. The VH sequence of 2E3-02 is shown in SEQ ID NO: 23, and the VL sequence is shown in SEQ ID NO: 33. The heavy chain sequence of 2E3-02 is shown in SEQ ID NO: 47, and the light chain sequence is shown in SEQ ID NO: 48.

[0161] In some embodiments, Tb is an anti-B7H3 monoclonal antibody or an antigen-binding fragment thereof.

[0162] In some embodiments, Tb is an anti-Trop-2 antibody or an antigen-binding fragment thereof, such as datopotamab, sacituzumab, or an antigen-binding fragment thereof.

[0163] In some embodiments, Tb is an anti-Trop-2 monoclonal antibody or an antigen-binding fragment thereof.

[0164] In some embodiments, Tb is an anti-Her 2 antibody or an antigen-binding fragment thereof, such as anbenitamab, coprelotamab, disitamab, gancotamab, margetuximab, pertuzumab, timigutuzumab, zanidatamab, trastuzumab, pertuzumab or an antigen-binding fragment thereof.

[0165] In some embodiments, Tb is an anti-Her 2 monoclonal antibody or an antigen-binding fragment thereof, such as trastuzumab, pertuzumab, or an antigen-binding fragment thereof.

[0166] In some embodiments, Tb is an anti-Her3 antibody or an antigen-binding fragment thereof, such as barecetamab, duligotuzumab, elgemtumab, istiratumab, lumretuzumab, patritumab, seribantumab, zenocutuzumab, 202-2-1 antibody or an antigen-binding fragment thereof.

[0167] In some embodiments, Tb is an anti-Her3 monoclonal antibody or an antigen-binding fragment thereof.

[0168] In some embodiments, Tb is an anti-EGFR antibody or an antigen-binding fragment thereof, such as demupitamab, depatuxizumab, futuximab, imgatuzumab, laprituximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, serclutamab, tomozutuximab, zalutumumab, Cetuximab or an antigen-binding fragment thereof.

[0169] In some embodiments, Tb is an anti-EGFR monoclonal antibody or an antigen-binding fragment thereof.

[0170] In some embodiments, the antibodies include antibodies that bind to antigens but do not have endocytosis activity. In some embodiments, the antibodies include antibodies that bind to antigens such as B7H3, CD20, CD19, CD30, GPNMB, Her2, Trop-2, EGFR, Her3, GD-2, CD79b, and BCMA but do not have endocytosis activity.

[0171] In some embodiments, the antibody has an antibody that binds to the B7H3 antigen but does not have endocytosis activity, such as INV721 and I7-01 of WO2021168379A1. More specifically, the anti-B7H3 antibody has a VH of SEQ ID NO: 2 and a VL of SEQ ID NO: 1 as described in WO2021168379A1.

[0172] In some embodiments, the antibody has an antibody that binds to the GD2 antigen but does not have endocytosis activity, such as INV721 and GD2-5 of WO2021168379A1. More specifically, the anti-GD2 antibody has a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 3 as described in WO2021168379A1.

[0173] In some embodiments, the antibody has an antibody that binds to the HER3 antigen but does not have endocytosis activity, such as the ANTI-HER3 21F06 antibody shown in SEQ ID NO: 22 of US10808032B2.

[0174] In some embodiments, the antibody has the ability to bind to the CD20 antigen but lacks endocytosis activity. While so-called "type II" CD20-specific antibodies have been shown to be poorly internalized by CD20-positive target cells, other so-called "type I" CD20-specific antibodies have been found to be internalized and degraded to some extent, depending on the expression levels of activating and inhibitory FcγRs on the target cells with which they interact. In some embodiments, the antibody has the ability to bind to the CD20 antigen but lacks endocytosis activity is a "type II" CD20-specific antibody, such as obinutuzumab.

[0175] In some embodiments, the antibody has the activity of binding to non-endocytic antigens (e.g., ALCAM / CD166). In some embodiments, the antibody is an antibody comprising the VH of SEQ ID No: 73 and the VL of SEQ ID No: 74, the VH of SEQ ID No: 75 and the VL of SEQ ID No: 76, the VH of SEQ ID No: 77 and the VL of SEQ ID No: 78, or the VH of SEQ ID No: 79 and the VL of SEQ ID No: 88 in EP3911682A1.

[0176] In some embodiments, the Tb is a targeting moiety, such as a ligand, a protein, a polypeptide, a non-protein agent (such as a sugar, RNA or DNA), an antibody analog, etc.

[0177] In some embodiments, q is selected from any integer between 0.1 and 16.0; in a preferred embodiment, q is selected from any integer between 0.1 and 16.0.

[0178] In some embodiments, q is selected from any integer between 0.1 and 8.0. In a preferred embodiment, q is selected from any integer between 0.1 and 8.0.

[0179] In some embodiments, q is selected from any value between 2-8.

[0180] In some embodiments, q is selected from any value between 3-8.

[0181] In some embodiments, q is selected from any value between 4-8.

[0182] In some embodiments, q is selected from any value between 6-8.

[0183] In some embodiments, q is selected from any integer between 2-8.

[0184] In some embodiments, q is selected from any integer between 3-8.

[0185] In some embodiments, q is selected from any integer between 4-8.

[0186] In some embodiments, q is selected from any integer between 6-8.

[0187] In some embodiments, q is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.

[0188] In some embodiments, q is selected from 2, 4, 6, and 8.

[0189] In this disclosure, the bioactive molecular fragments are known in the art, and are part (fragment or group) of antibody-drug conjugates (or antibody-drug conjugates (ADCs)), which can form biologically active drugs (such as small molecule cytotoxic drugs, including groups after losing an atom or atomic group) or their derivatives (such as precursors) after the linker cleavage / degradation / enzymatic cleavage between tumor tissues or within tumor cells. For the avoidance of doubt, "drugs" do not only refer to "drugs" that have been approved by medical regulatory authorities, but also include any molecules with potential therapeutic biological activity in clinical practice, or in R&D and academic research.

[0190] In some embodiments, D is a molecular fragment having anti-tumor biological activity.

[0191] In some embodiments, D is a fragment of a molecule with anti-tumor biological activity, wherein the biologically active molecule is selected from a cytotoxic agent or a derivative thereof, such as a DNA topoisomerase inhibitor (e.g., a camptothecin-type biologically active molecule, such as camptothecin, DXD, a substituent-modified camptothecin, or a substituent-modified DXD) or a microtubule inhibitor (e.g., MMAF-type microtubule inhibitor, MMAE-type microtubule inhibitor).

[0192] In some embodiments, the Ligand Drug Conjugate has the structure of Formula I:

[0193]

[0194] in,

[0195] R1 and R2 are each independently selected from H, halogen, -OH, optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy, or,

[0196] R1 and R2 together with the carbon atoms to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring, wherein the heterocyclic ring contains one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof;

[0197] R3 is selected from H, halogen, -OH, -NH2, optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy, or,

[0198] R3 and X together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring containing one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof, or

[0199] R3 and R2 together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring, wherein the heterocyclic ring contains one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof;

[0200] W is absent or present. When W is present, W is selected from -O-, -S-, -NR4-, Bit 1 is connected to X, bit 2 is connected to L4 or L3;

[0201] X is selected from a direct bond, an optionally substituted -O-(CH2) n3 -、-N(R4)-(CH2) n3 -、-S-(CH2) n3 -, carbonyl-(CH2) n3 、-SO2-(CH2) n3 -、 -(CH2) n1 -, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group, the 1 position is connected to the parent ring, and the 2 position is connected to W or L4; the substituent is selected from one or more C1-4 alkyl, C3-6 cycloalkyl, or multiple C1-4 alkyl and the carbon atoms to which they are simultaneously connected together form a C3-6 cycloalkyl;

[0202] Each M is independently selected from a direct bond and -CR 5a R 5b -;

[0203] R4, R5, R 5a 、R 5b , R6, R7 are each independently selected from H, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy and optionally substituted C3-6 cycloalkyl;

[0204] n, n', n1, n2, n3 are each independently selected from any integer between 0 and 6;

[0205] L4 is absent or present. When L4 is present, L4 is selected from Bit 1 is connected to L3, and bit 2 is connected to W or X.

[0206] Tb, L1, L2, L3 and q have the meanings provided above and in any of the embodiments specifically described herein.

[0207] In some embodiments, R1 and R2 are each independently selected from H, halogen, and C1-4 alkyl.

[0208] In some embodiments, R1 and R2, together with the carbon atom to which they are attached, form a 5-6 membered heterocyclic ring containing 1, 2 or 3 O, S or N or any combination thereof.

[0209] In some embodiments, R1 is selected from H and halogen, and R2 is selected from H and C1-4 alkyl.

[0210] In some embodiments, R1 and R2 and the carbon atom to which they are attached form The dotted line indicates the position where the heterocyclic ring is fused to the benzene ring.

[0211] In some embodiments, R1 is H or F, and R2 is H or methyl.

[0212] In some embodiments, R1 is F, R2 is methyl, or R1 and R2 together with the carbon atom to which they are attached form

[0213] In some embodiments, R1 is F and R2 is methyl.

[0214] In some embodiments, R1 and R2 together with the carbon atom to which they are attached form

[0215] In some embodiments, R3 is selected from H and C1-4 alkyl.

[0216] In some embodiments, R3 and X, together with the carbon atom to which they are attached, form a 5-6 membered carbocyclic ring.

[0217] In some embodiments, R3 is H or R3 and X together with the carbon atom to which they are attached form The dotted lines indicate where the carbocyclic ring is fused to the benzene and pyridine rings.

[0218] In some embodiments, R3 is H.

[0219] In some embodiments, W is absent or present, and when W is present, W is selected from -O-, -S-, -NR4-, Bit 1 is connected to X, and bit 2 is connected to L4 or L3.

[0220] In some embodiments, W is absent or present, and when W is present, W is selected from -O-, -S-, -NR4-, Bit 1 is connected to X, and bit 2 is connected to L4 or L3.

[0221] In some embodiments, W is selected from -O-, -NR4- and Bit 1 is connected to X, and bit 2 is connected to L4 or L3.

[0222] In some embodiments, W is selected from -O- and -NR4-, position 1 is connected to X, and position 2 is connected to L4 or L3.

[0223] In some embodiments, X is selected from optionally substituted -(CH2) n1 -、 C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group, the 1 position is connected to the parent ring, and the 2 position is connected to W or L4; the substituent is selected from 1 or 2 C1-4 alkyl groups, or 2 C1-4 alkyl groups and the carbon atoms to which they are simultaneously connected form a C3-6 cycloalkyl group.

[0224] In some embodiments, X is selected from optionally substituted Position 1 is connected to the parent ring, and position 2 is connected to W or L4; the substituent is selected from 1 or 2 C1-4 alkyl groups (such as methyl), or 2 C1-4 alkyl groups (such as methyl) and the carbon atoms to which they are simultaneously connected form a C3-6 cycloalkyl group (such as cyclopropyl).

[0225] In some embodiments, X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W or L4.

[0226] In some embodiments, X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W.

[0227] In some embodiments, when W is absent, X is selected from 1 is connected to the parent ring, 2 is connected to L4; when W exists, X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W.

[0228] In some embodiments, W is selected from -O-, -NR4- and Position 1 is connected to X, position 2 is connected to L4 or L3; X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W.

[0229] In some embodiments, R4 and R5 are each independently selected from H, C1-4 alkyl and C3-6 cycloalkyl.

[0230] In some embodiments, each R4 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl, and R5 is H.

[0231] In some embodiments, each R4 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, tert-butyl, and cyclopropyl, and R5 is H.

[0232] In some embodiments, R 5a 、R 5b Each is independently selected from H and C1-4 alkyl.

[0233] In some embodiments, R 5a 、R 5b are each independently selected from H and methyl.

[0234] In some embodiments, each R7 is independently selected from H and C1-4 alkyl.

[0235] In some embodiments, R7 is H.

[0236] In some embodiments, n is selected from 1, 2, and 3.

[0237] In some embodiments, n is 1.

[0238] In some embodiments, n1 is selected from 1, 2, 3, and 4.

[0239] In some embodiments, n2 is 1.

[0240] In some embodiments, n3 is 0.

[0241] In some embodiments, L3 is selected from

[0242]

[0243] X - Selected from halogen ions, carboxylate ions, sulfate ions, hydrogen sulfate ions and OH - , bit 1 is connected to L1 or L2, bit 2 is connected to L4 or W.

[0244] In some embodiments, L3 is selected from X- Selected from halogen ion, carboxylate ion, sulfate ion, hydrogen sulfate ion and OH-, the 1 position is connected to L1 or L2, and the 2 position is connected to L4 or W.

[0245] In some embodiments, L3 is selected from X - Selected from halogen ions, carboxylate ions, sulfate ions and hydrogen sulfate ions, OH - , bit 1 is connected to L1 or L2, bit 2 is connected to L4 or W.

[0246] In some embodiments, L3 is selected from Bit 1 is connected to L1 or L2, and bit 2 is connected to L4 or W.

[0247] In some embodiments, L3 is selected from Bit 1 is connected to L1 or L2, and bit 2 is connected to L4 or W.

[0248] In some embodiments, L4 is absent or present, and when L4 is present, L4 is selected from Bit 1 is connected to L3, and bit 2 is connected to W or X.

[0249] In some embodiments, L4 is absent or present, and when L4 is present, L4 is Bit 1 is connected to L3, and bit 2 is connected to W or X.

[0250] In some embodiments, L4 is absent.

[0251] In some embodiments, L4 is selected from Bit 1 is connected to L3, and bit 2 is connected to W or X.

[0252] In some embodiments, L4 is selected from Bit 1 is connected to L3, and bit 2 is connected to W or X.

[0253] It should be noted that, as described above, W is absent or present. Therefore, when W is absent, position 1 of L4 is connected to L3 and position 2 is connected to X. When W is present, position 1 of L4 is connected to L3 and position 2 is connected to W. The following connection relationship of L4 can be understood with reference to the above content.

[0254] In some embodiments, The structure is selected from the following structural fragments:

[0255]

[0256]

[0257]

[0258]

[0259] Among them, bit 1 is connected to Tb and bit 2 is connected to W.

[0260] In some embodiments, D is The structural fragment shown; position 1 is connected to L3 or L4; for example

[0261]

[0262] In some embodiments, The structure is selected from the following structural fragments:

[0263]

[0264]

[0265]

[0266] Among them, bit 1 is connected to L4; when L4 does not exist, bit 1 is connected to L3.

[0267] In some embodiments,

[0268] W is absent or present. When W is present, W is selected from -O-, -S-, -NR4-, For example, there is no, -O-, -NR4- or R4 and R5 are each independently selected from H and C1-4 alkyl; n is independently selected from 0, 1, 2, 3 and 4;

[0269] X is selected from

[0270] R1 is selected from H, halogen, R2 is selected from H, C1-4 alkyl, or R1 and R2 and the carbon atom to which they are connected form The dotted line indicates the position where the heterocyclic ring is fused to the benzene ring;

[0271] R3 is selected from H and C1-4 alkyl, or R3 and X together with the carbon atom to which they are attached form a 5-6 membered carbocyclic ring;

[0272] Preferably, W is absent or present, and when W is present, W is selected from -O-, -NR4- (eg, -NH-, -N(CH3)-, -N(C2H5)-), R4 is independently selected from H, methyl, ethyl, isopropyl, n-propyl, tert-butyl and cyclopropyl;

[0273] When W does not exist, X is selected from 1 is connected to the parent ring; when W exists, X is selected from

[0274] AA1 wherein r is selected from 0, 1, 2, 3, 4 and 5;

[0275] R a 、R b Among them, any one is H, and the other is selected from Or, R a With R b Together with the carbon atoms they are connected to, they form the 0 substituted 5-6 membered heterocycle;

[0276] R1 is selected from H, halogen, R2 is selected from H, C1-4 alkyl, or R1 and R2 and the carbon atom to which they are connected form

[0277] R3 is selected from H and C1-4 alkyl, or R3 and X together with the carbon atom to which they are attached form R3 and X together with the carbon atom to which they are attached form

[0278] More preferably, W is selected from -O- and -NR4-, position 1 is connected to X, and position 2 is connected to L4 or L3;

[0279] X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W;

[0280] for For example

[0281] R1 is F,

[0282] R2 is methyl or R1 and R2 together with the carbon atom to which they are attached form

[0283] R3 is H.

[0284] In some embodiments, the Ligand Drug Conjugate has the structure of Formula I-1:

[0285]

[0286] wherein Tb, L1, L2, L3, L4, X, R1, R2, R3, R4 and q have the meanings provided above and in any of the embodiments specifically described herein.

[0287] In some embodiments, the Ligand Drug Conjugate has the structure of Formula I-1A or I-1B:

[0288]

[0289] wherein Tb, L2, L3, L4, X, R1, R2, R3, R4 and q have the meanings provided above and in any of the embodiments specifically described herein.

[0290] In some embodiments, the Ligand Drug Conjugate has the structure of Formula I-2:

[0291]

[0292] wherein Tb, L1, L2, L3, L4, X, R1, R2, R3 and q have the meanings provided above and in any embodiment specifically described herein.

[0293] In some embodiments, the Ligand Drug Conjugate has the structure of Formula I-2A or I-2B:

[0294]

[0295] wherein Tb, L2, L3, L4, X, R1, R2, R3 and q have the meanings provided above and in any of the embodiments specifically described herein.

[0296] In some embodiments, the Ligand Drug Conjugate has the structure of Formula I-3:

[0297]

[0298] wherein Tb, L1, L2, L3, L4, X, R1, R2, R3, R4, R5, n, and q have the meanings provided above and in any of the embodiments specifically described herein.

[0299] In some embodiments, the Ligand Drug Conjugate has the structure of Formula I-3A or I-3B:

[0300]

[0301] wherein Tb, L2, L3, L4, X, R1, R2, R3, R4 and q have the meanings provided above and in any of the embodiments specifically described herein.

[0302] In some embodiments, the Ligand Drug Conjugate has the structure of Formula IA:

[0303]

[0304] Among them, Tb, X, R1, R2, R3, R a 、R b and q have the meanings provided above and in any embodiments specifically described herein.

[0305] In some embodiments, the Ligand Drug Conjugate has the structure of Formula IB:

[0306]

[0307] Among them, Tb, X, R1, R2, R3, R a 、R b and q have the meanings provided above and in any embodiments specifically described herein.

[0308] In some embodiments, the ligand drug conjugate is selected from the group consisting of:

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329] The Tb antibodies or antigen-binding fragments thereof can be prepared by various methods known in the art, such as by genetic engineering and recombinant techniques. For example, DNA molecules encoding the heavy and light chain genes of the disclosed antibodies can be obtained by chemical synthesis or PCR amplification. The resulting DNA molecules are inserted into expression vectors, which are then transfected into host cells. The transfected host cells are then cultured under specific conditions to express the disclosed antibodies.

[0330] In some embodiments of the present disclosure, the targeting moiety is an anti-B7H3 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-B7H3 antibody includes all prior art anti-B7H3 antibodies, such as enoblituzumab, mirzotamab, omburtamab, and see CN112521512, WO2021027674, WO2021021543, WO2021006619, CN111662384, CN111454357, WO2020151384, WO2020140094, WO2020103100, WO2020102779, WO2020063673, WO2020047257, WO2020041626, CN1 10684790, CN110642948, WO2019225787, WO2019226017, US20190338030, CN110305213, WO2018209346, WO2018177393, US9150656, WO2016106004, WO2016044383, WO2016033225, WO2015181267, US20120294796, WO2011109400, CN101104639, WO2004093894, WO2002010187, WO2001018021. In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof is selected from the group consisting of: antibody numbered M30-H1-L4 in CN103687945 B and antibody numbered mAb-C-DUBA in CN 109069633 A.

[0331] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs), wherein the CDRs are defined according to the IMGT numbering system:

[0332] (a) HCDR1 of SEQ ID NO: 10, HCDR2 of SEQ ID NO: 11, and HCDR3 of SEQ ID NO: 12; and / or,

[0333] LCDR1 with the sequence of SEQ ID NO: 20, LCDR2 with the sequence of GTF, and LCDR3 with the sequence of SEQ ID NO: 22;

[0334] (b) HCDR1 with the sequence of SEQ ID NO: 10, HCDR2 with the sequence of SEQ ID NO: 11, and HCDR3 with the sequence of SEQ ID NO: 12; and / or,

[0335] LCDR1 with the sequence of SEQ ID NO: 40, LCDR2 with the sequence of GAS, and LCDR3 with the sequence of SEQ ID NO: 42;

[0336] (c) HCDR1 with the sequence of SEQ ID NO: 30, HCDR2 with the sequence of SEQ ID NO: 31, and HCDR3 with the sequence of SEQ ID NO: 32; and / or,

[0337] LCDR1 with the sequence of SEQ ID NO: 40, LCDR2 with the sequence of GAS, and LCDR3 with the sequence of SEQ ID NO: 42;

[0338] or

[0339] (d) HCDR1 with the sequence of SEQ ID NO: 30, HCDR2 with the sequence of SEQ ID NO: 31, and HCDR3 with the sequence of SEQ ID NO: 32; and / or,

[0340] The sequence of LCDR1 is SEQ ID NO: 20, the sequence of LCDR2 is GTF, and the sequence of LCDR3 is SEQ ID NO: 22.

[0341] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof, as defined by the IMGT numbering system, comprises:

[0342] a VH comprising (a) a heavy chain HCDR1, HCDR2, and HCDR3 and a VL comprising (a) a light chain LCDR1, LCDR2, and LCDR3;

[0343] a VH comprising (b) the heavy chain HCDR1, HCDR2, and HCDR3 and a VL comprising (b) the light chain LCDR1, LCDR2, and LCDR3;

[0344] A VH comprising (c) heavy chain HCDR1, HCDR2, HCDR3 and a VL comprising (c) light chain LCDR1, LCDR2, LCDR3; or

[0345] (d) VH containing heavy chain HCDR1, HCDR2, HCDR3 and (d) VL containing light chain LCDR1, LCDR2, LCDR3.

[0346] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs), wherein the CDRs are defined according to the Chothia numbering system:

[0347] (a) HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6; and / or,

[0348] LCDR1 with the sequence of SEQ ID NO: 14, LCDR2 with the sequence of SEQ ID NO: 15, and LCDR3 with the sequence of SEQ ID NO: 16;

[0349] (b) HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 25, and HCDR3 of SEQ ID NO: 26; and / or,

[0350] LCDR1 with the sequence of SEQ ID NO: 34, LCDR2 with the sequence of SEQ ID NO: 35, and LCDR3 with the sequence of SEQ ID NO: 36;

[0351] (c) HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, and HCDR3 of SEQ ID NO: 6; and / or,

[0352] LCDR1 with the sequence of SEQ ID NO: 34, LCDR2 with the sequence of SEQ ID NO: 35, and LCDR3 with the sequence of SEQ ID NO: 36;

[0353] or

[0354] (d) HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 25, and HCDR3 of SEQ ID NO: 26; and / or,

[0355] The sequence of LCDR1 is SEQ ID NO: 14, the sequence of LCDR2 is SEQ ID NO: 15, and the sequence of LCDR3 is SEQ ID NO: 16.

[0356] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof, as defined by the Chothia numbering system, comprises:

[0357] a VH comprising (a) a heavy chain HCDR1, HCDR2, and HCDR3 and a VL comprising (a) a light chain LCDR1, LCDR2, and LCDR3;

[0358] a VH comprising (b) the heavy chain HCDR1, HCDR2, and HCDR3 and a VL comprising (b) the light chain LCDR1, LCDR2, and LCDR3;

[0359] A VH comprising (c) heavy chain HCDR1, HCDR2, HCDR3 and a VL comprising (c) light chain LCDR1, LCDR2, LCDR3; or

[0360] (d) VH containing heavy chain HCDR1, HCDR2, HCDR3 and (d) VL containing light chain LCDR1, LCDR2, LCDR3.

[0361] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs), wherein the CDRs are defined according to the Kabat numbering system:

[0362] (a) HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9; and / or,

[0363] LCDR1 with the sequence of SEQ ID NO: 17, LCDR2 with the sequence of SEQ ID NO: 18, and LCDR3 with the sequence of SEQ ID NO: 19;

[0364] (b) HCDR1 of SEQ ID NO: 27, HCDR2 of SEQ ID NO: 28, and HCDR3 of SEQ ID NO: 29; and / or,

[0365] LCDR1 with the sequence of SEQ ID NO: 37, LCDR2 with the sequence of SEQ ID NO: 38, and LCDR3 with the sequence of SEQ ID NO: 39;

[0366] (c) HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9; and / or,

[0367] LCDR1 with the sequence of SEQ ID NO: 37, LCDR2 with the sequence of SEQ ID NO: 38, and LCDR3 with the sequence of SEQ ID NO: 39;

[0368] or

[0369] (d) HCDR1 of SEQ ID NO: 27, HCDR2 of SEQ ID NO: 28, and HCDR3 of SEQ ID NO: 29; and / or,

[0370] The sequence of LCDR1 is SEQ ID NO: 17, the sequence of LCDR2 is SEQ ID NO: 18, and the sequence of LCDR3 is SEQ ID NO: 19.

[0371] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof, as defined by the Kabat numbering system, comprises:

[0372] a VH comprising (a) a heavy chain HCDR1, HCDR2, and HCDR3 and a VL comprising (a) a light chain LCDR1, LCDR2, and LCDR3;

[0373] a VH comprising (b) the heavy chain HCDR1, HCDR2, and HCDR3 and a VL comprising (b) the light chain LCDR1, LCDR2, and LCDR3;

[0374] A VH comprising (c) heavy chain HCDR1, HCDR2, HCDR3 and a VL comprising (c) light chain LCDR1, LCDR2, LCDR3; or

[0375] (d) VH containing heavy chain HCDR1, HCDR2, HCDR3 and (d) VL containing light chain LCDR1, LCDR2, LCDR3.

[0376] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises:

[0377] (a) a heavy chain variable region (VH) comprising an amino acid sequence selected from the group consisting of:

[0378] (i) the sequence shown in SEQ ID NO: 3 or 23;

[0379] (ii) a sequence having one or more amino acid substitutions, deletions or additions, or any combination thereof, compared to the sequence shown in SEQ ID NO: 3 or 23 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions, or any combination thereof); or

[0380] (iii) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence set forth in SEQ ID NO: 3 or 23;

[0381] and / or

[0382] (b) a light chain variable region (VL) comprising an amino acid sequence selected from the group consisting of:

[0383] (iv) the sequence shown in SEQ ID NO: 13 or 33;

[0384] (v) a sequence having one or more amino acid substitutions, deletions or additions, or any combination thereof, compared to the sequence shown in SEQ ID NO: 13 or 33 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions, or any combination thereof); or

[0385] (vi) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence set forth in SEQ ID NO: 13 or 33.

[0386] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises the VH set forth in SEQ ID NO:3, and / or the VL set forth in SEQ ID NO:13.

[0387] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises the VH set forth in SEQ ID NO:23, and / or the VL set forth in SEQ ID NO:33.

[0388] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises the VH set forth in SEQ ID NO:3, and / or the VL set forth in SEQ ID NO:33.

[0389] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises the VH set forth in SEQ ID NO:23, and / or the VL set forth in SEQ ID NO:13.

[0390] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises:

[0391] (a) VH of SEQ ID NO: 3 and VL of SEQ ID NO: 13;

[0392] (b) VH of SEQ ID NO: 23 and VL of SEQ ID NO: 33;

[0393] (c) VH of SEQ ID NO: 3 and VL of SEQ ID NO: 13;

[0394] (d) VH of SEQ ID NO: 23 and VL of SEQ ID NO: 13;

[0395] (e) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the VH and VL described in any one of groups (a) to (d), respectively; or

[0396] (f) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof) compared to the VH and VL described in any one of groups (a) to (d), respectively. Preferably, the substitutions are conservative substitutions.

[0397] In some embodiments, the heavy chain of the anti-B7H3 antibody comprises a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof having up to 50 conservative substitutions of amino acids compared to the wild-type sequence from which it is derived (e.g., up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10, or up to 5 conservative substitutions of amino acids; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative substitutions of amino acids). In certain embodiments, the anti-B7H3 antibody light chain comprises a light chain constant region (CL) of a human immunoglobulin or a variant thereof having up to 50 conservative amino acid substitutions (e.g., up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions; e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions) compared to the wild-type sequence from which it is derived.

[0398] In some embodiments, the constant region is altered, for example, mutated, to modify the properties of the anti-B7H3 antibody molecule (e.g., to alter one or more of the following: Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, or complement function). Functional changes can be produced by replacing at least one amino acid residue in the antibody constant region with a different residue, for example, by altering the affinity of the antibody for an effector ligand (such as FcR or complement C1q), thereby altering (e.g., reducing) the effector function. The Fc region of an antibody mediates several important effector functions, such as ADCC, phagocytosis (ADCP), CDC, etc.

[0399] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof has a heavy chain constant region (CH) selected from, for example, the heavy chain constant region of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; in particular, selected from, for example, the heavy chain constant region of IgG1, IgG2, IgG3, and IgG4, more particularly selected from the heavy chain constant region of IgG1 (e.g., human IgG1). In some embodiments, the human IgG1 heavy chain constant region is as shown in SEQ ID NO: 43. In some embodiments, the antibody or antigen-binding fragment thereof of the present disclosure has a light chain constant region selected from, for example, a kappa or lambda light chain constant region, preferably a kappa light chain constant region (e.g., a human kappa light chain constant region). In some embodiments, the light chain constant region has a sequence as shown in SEQ ID NO: 44.

[0400] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises CH as set forth in SEQ ID NO:43 or a variant thereof, wherein the variant has up to 20 conservative amino acid substitutions (e.g., up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions) compared to SEQ ID NO:43, or has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to SEQ ID NO:43.

[0401] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises a light chain constant region or a variant thereof. In some embodiments, the light chain constant region comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises a light chain constant region (CL) as set forth in SEQ ID NO: 44 or a variant thereof, the variant having a conservative substitution of up to 20 amino acids compared to SEQ ID NO: 44 (e.g., a conservative substitution of up to 20, up to 15, up to 10, or up to 5 amino acids; e.g., a conservative substitution of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids), or having a sequence identity of at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% to SEQ ID NO: 44.

[0402] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) set forth in SEQ ID NO:43 and a light chain constant region (CL) set forth in SEQ ID NO:44.

[0403] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises:

[0404] (a) a heavy chain comprising an amino acid sequence selected from the group consisting of:

[0405] (i) a sequence comprising the VH sequence shown in SEQ ID NO: 3 and the CH sequence shown in SEQ ID NO: 43;

[0406] (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0407] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to the sequence shown in (i); and

[0408] (b) a light chain comprising an amino acid sequence selected from the group consisting of:

[0409] (iv) a sequence comprising the VL sequence shown in SEQ ID NO: 13 and the CL sequence shown in SEQ ID NO: 44;

[0410] (v) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (iv) (e.g., at most 50, at most 45, at most 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0411] (vi) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence shown in (iv).

[0412] In some embodiments, the substitution described in (ii) or (v) is a conservative substitution.

[0413] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises:

[0414] (a) a heavy chain comprising an amino acid sequence selected from the group consisting of:

[0415] (i) a sequence comprising the VH sequence shown in SEQ ID NO: 23 and the CH sequence shown in SEQ ID NO: 43;

[0416] (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0417] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to the sequence shown in (i); and

[0418] (b) a light chain comprising an amino acid sequence selected from the group consisting of:

[0419] (iv) a sequence comprising the VL sequence shown in SEQ ID NO: 33 and the CL sequence shown in SEQ ID NO: 44;

[0420] (v) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (iv) (e.g., at most 50, at most 45, at most 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0421] (vi) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence shown in (iv).

[0422] In some embodiments, the substitution described in (ii) or (v) is a conservative substitution.

[0423] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain,

[0424] The heavy chain comprises:

[0425] (i) the sequence shown in SEQ ID NO:45;

[0426] (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0427] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in (i); and

[0428] The light chain comprises:

[0429] (iv) the sequence shown in SEQ ID NO:46;

[0430] (v) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (iv) (e.g., at most 50, at most 45, at most 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0431] (vi) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in (iv);

[0432] Preferably, the substitutions described in (ii) or (v) are conservative substitutions.

[0433] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain,

[0434] The heavy chain comprises:

[0435] (i) the sequence shown in SEQ ID NO: 47;

[0436] (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0437] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in (i); and

[0438] The light chain comprises:

[0439] (iv) the sequence shown in SEQ ID NO:48;

[0440] (v) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (iv) (e.g., at most 50, at most 45, at most 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0441] (vi) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in (iv);

[0442] Preferably, the substitutions described in (ii) or (v) are conservative substitutions.

[0443] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof is a chimeric antibody, a humanized antibody, or a fully human antibody.

[0444] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof is selected from scFv, Fab, Fab', (Fab')2, Fv fragment, disulfide-linked Fv (dsFv), and diabody.

[0445] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof is a scFv. In certain embodiments, the scFv of the present disclosure comprises:

[0446] (a) VH of SEQ ID NO: 3 and VL of SEQ ID NO: 13;

[0447] (b) VH of SEQ ID NO: 23 and VL of SEQ ID NO: 33;

[0448] (c) VH of SEQ ID NO: 3 and VL of SEQ ID NO: 33;

[0449] (d) VH of SEQ ID NO: 23 and VL of SEQ ID NO: 13;

[0450] (e) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the VH and VL described in any one of groups (a) to (d), respectively; or

[0451] (f) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof) compared to the VH and VL described in any one of groups (a) to (d), respectively. Preferably, the substitutions are conservative substitutions.

[0452] In some embodiments, the antibodies of the present disclosure are scFvs. In certain embodiments, the scFvs of the present disclosure comprise:

[0453] (i) the sequence shown in SEQ ID NO: 1 or 2;

[0454] (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0455] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in (i);

[0456] Preferably, the substitutions described in (ii) are conservative substitutions.

[0457] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof is a scFv. In certain embodiments, the scFv of the present disclosure comprises the sequence shown in SEQ ID NO: 1 or 2.

[0458] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof is selected from the group consisting of: 1D1 antibody, 1D1-01 antibody, 2E3 antibody, and 2E3-02 antibody.

[0459] In some embodiments of the present disclosure, the targeting moiety is trastuzumab or pertuzumab. Trastuzumab is an anti-Her 2 monoclonal antibody, and its amino acid sequence is known to those skilled in the art. Its schematic sequence can be found, for example, in CN103319599. The last Lys residue is easily deleted without affecting biological activity, see Dick, LW et al., Biotechnol. Bioeng., 100: 1132-1143.

[0460] Exemplary heavy and light chain sequences of trastuzumab can be found, for example, in IMGT / mAb-DB ID 97. Exemplary heavy and light chain sequences of pertuzumab can be found in SEQ ID No. 16 and SEQ ID No. 15 of US7560111, and can also be found in IMGT / mAb-DB ID 80.

[0461] In some embodiments of the present disclosure, the targeting moiety is an anti-Her3 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-Her3 antibody includes all prior art anti-Her3 antibodies, for example, barecetamab, duligotuzumab, elgemtumab, istiratumab, lumretuzumab, patritumab, seribantumab, zenocutuzumab, 202-2-1 antibody, antibody CN 103189392 B with heavy chain SEQ ID NO: 10 and light chain SEQ ID NO: 14, and IMGT / mAb-DB SEQ ID NO: 546.

[0462] In some embodiments, the targeting moiety is an anti-Her3 antibody, wherein the anti-Her3 antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs), wherein the CDRs are defined according to the IMGT numbering system:

[0463] HCDR1 of SEQ ID NO: 56, HCDR2 of SEQ ID NO: 57, HCDR3 of SEQ ID NO: 58; and / or,

[0464] The sequence of LCDR1 is SEQ ID NO:41, the sequence of LCDR2 is AAS, and the sequence of LCDR3 is SEQ ID NO:21.

[0465] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof, as defined by the IMGT numbering system, comprises: the aforementioned VH comprising the aforementioned heavy chain HCDR1, HCDR2, and HCDR3 and the aforementioned VL comprising the aforementioned light chain LCDR1, LCDR2, and LCDR3.

[0466] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs), wherein the CDRs are defined according to the Kabat numbering system:

[0467] HCDR1 of SEQ ID NO: 53, HCDR2 of SEQ ID NO: 54, HCDR3 of SEQ ID NO: 55; and / or,

[0468] The sequence of LCDR1 is SEQ ID NO: 59, the sequence of LCDR2 is SEQ ID NO: 60, and the sequence of LCDR3 is SEQ ID NO: 21.

[0469] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof, as defined by the Kabat numbering system, comprises: the aforementioned VH comprising the aforementioned heavy chain HCDR1, HCDR2, and HCDR3 and the aforementioned VL comprising the aforementioned light chain LCDR1, LCDR2, and LCDR3.

[0470] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof comprises:

[0471] (a) a heavy chain variable region (VH) comprising an amino acid sequence selected from the group consisting of:

[0472] (i) the sequence shown in SEQ ID NO: 49;

[0473] (ii) a sequence having one or more amino acid substitutions, deletions or additions, or any combination thereof, compared to the sequence shown in SEQ ID NO: 49 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions, or any combination thereof); or

[0474] (iii) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to the sequence set forth in SEQ ID NO: 49;

[0475] and / or

[0476] (b) a light chain variable region (VL) comprising an amino acid sequence selected from the group consisting of:

[0477] (iv) the sequence shown in SEQ ID NO:50;

[0478] (v) a sequence having one or more amino acid substitutions, deletions or additions, or any combination thereof, compared to the sequence shown in SEQ ID NO: 50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions, or any combination thereof); or

[0479] (vi) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence set forth in SEQ ID NO:50.

[0480] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof comprises:

[0481] (a) VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50;

[0482] (b) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the VH and VL described in group (a), respectively; or

[0483] (c) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof) compared to the VH and VL described in group (a), respectively. Preferably, the substitutions are conservative substitutions.

[0484] In some embodiments, the heavy chain of the anti-Her3 antibody comprises a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof, which has up to 50 conservative substitutions of amino acids compared to the wild-type sequence from which it is derived (e.g., up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 conservative substitutions of amino acids; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 conservative substitutions of amino acids). In certain embodiments, the anti-B7H3 antibody light chain comprises a light chain constant region (CL) of a human immunoglobulin or a variant thereof having up to 50 conservative amino acid substitutions (e.g., up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions; e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions) compared to the wild-type sequence from which it is derived.

[0485] In some embodiments, the constant region is altered, for example, mutated, to modify the properties of the anti-Her3 antibody molecule (e.g., to alter one or more of the following: Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, or complement function). Functional changes can be produced by replacing at least one amino acid residue in the antibody constant region with a different residue, for example, by changing the affinity of the antibody for an effector ligand (such as FcR or complement C1q), thereby altering the effector function (e.g., reducing it). The Fc region of an antibody mediates several important effector functions, such as ADCC, phagocytosis (ADCP), CDC, etc.

[0486] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof has a heavy chain constant region (CH), which is selected from, for example, the heavy chain constant region of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE; in particular, it is selected from, for example, the heavy chain constant region of IgG1, IgG2, IgG3 and IgG4, more particularly, it is selected from the heavy chain constant region of IgG1 (for example, human IgG1). In some embodiments, the antibody or antigen-binding fragment thereof of the present disclosure has a light chain constant region, which is selected from, for example, a kappa or lambda light chain constant region, preferably a kappa light chain constant region (for example, a human kappa light chain constant region).

[0487] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) shown in SEQ ID NO:43 and a light chain constant region (CL) shown in SEQ ID NO:44.

[0488] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain,

[0489] The heavy chain comprises:

[0490] (i) the sequence shown in SEQ ID NO:51;

[0491] (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0492] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in (i); and

[0493] The light chain comprises:

[0494] (iv) the sequence shown in SEQ ID NO:52;

[0495] (v) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (iv) (e.g., at most 50, at most 45, at most 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0496] (vi) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in (iv);

[0497] Preferably, the substitutions described in (ii) or (v) are conservative substitutions.

[0498] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof is a chimeric antibody, a humanized antibody, or a fully human antibody.

[0499] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof is selected from scFv, Fab, Fab', (Fab')2, Fv fragment, disulfide-linked Fv (dsFv), and diabody.

[0500] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof is a scFv. In certain embodiments, the scFv of the present disclosure comprises:

[0501] (a) VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50;

[0502] (b) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the VH and VL described in group (a), respectively; or

[0503] (c) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof) compared to the VH and VL described in group (a), respectively. Preferably, the substitutions are conservative substitutions.

[0504] In some embodiments, the anti-Her3 antibody or antigen-binding fragment thereof is selected from: 202-2-1 antibody.

[0505] In some embodiments of the present disclosure, the targeting moiety is cetuximab. Cetuximab is an anti-EGFR monoclonal antibody, whose amino acid sequence is known to those skilled in the art. For its schematic sequence, see the antibody shown in IMGT / mAb-DB ID 151.

[0506] In some embodiments, the ligand drug conjugate is selected from:

[0507]

[0508]

[0509]

[0510] Wherein, Tb1 is an anti-B7H3 antibody or an antigen-binding fragment thereof, such as enoblituzumab, mirzotamab, omburtamab, 1D1-01, or 2E3-02 antibody, preferably 1D1-01 or 2E3-02 antibody; and q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6, or 8.

[0511] In some embodiments, the ligand drug conjugate is selected from:

[0512]

[0513] Wherein, Tb2 is an anti-Trop-2 antibody or an antigen-binding fragment thereof, such as datopotamab or sacituzumab, preferably sacituzumab; and q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6, or 8.

[0514] In some embodiments, the ligand drug conjugate is selected from:

[0515]

[0516] Wherein, Tb3 is an anti-Her2 antibody or an antigen-binding fragment thereof, such as anbenitamab, coprelotamab, disitamab, gancotamab, margetuximab, pertuzumab, timigutuzumab, zanidatamab, trastuzumab, pertuzumab, preferably trastuzumab or pertuzumab; q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6, or 8.

[0517] In some embodiments, the ligand drug conjugate is selected from:

[0518]

[0519] Wherein, Tb4 is an anti-Her3 antibody or an antigen-binding fragment thereof, for example, the antibodies barecetamab, duligotuzumab, elgemtumab, istiratumab, lumretuzumab, patritumab, seribantumab, zenocutuzumab, the 202-2-1 antibody, the antibody with the heavy chain represented by SEQ: 10 and the light chain represented by SEQ: 14 in CN 103189392 B, the antibody represented by IMGT / mAb-DB ID: 564, the 202-2-1 antibody; preferably the 202-2-1 antibody; q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6, or 8.

[0520] In some embodiments, the ligand drug conjugate is selected from:

[0521]

[0522] Wherein, Tb5 is an anti-EGFR antibody or an antigen-binding fragment thereof, such as demupitamab, depatuxizumab, futuximab, imgatuzumab, laprituximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, serclutamab, tomozutuximab, zalutumumab, or cetuximab; preferably cetuximab; and q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6, or 8.

[0523] In some embodiments, the ligand drug conjugate is selected from:

[0524]

[0525] Wherein, Tb6 is an antibody without tumor cell endocytosis activity or an antibody with binding activity to non-endocytic antigens (e.g., ALCAM / CD166), for example, an IgG isotype antibody for which the human body lacks the corresponding cell surface antigen, an anti-CD166 antibody, preferably an anti-chicken lysozyme human IgG1 isotype antibody; q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6, or 8.

[0526] In some embodiments, the ligand drug conjugate is selected from:

[0527]

[0528] Wherein, Tb7 is an antibody with weak or no tumor cell endocytosis activity but with tumor cell surface antigen binding activity; q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6, or 8.

[0529] In some embodiments, the antibody has an antibody that binds to the B7H3 antigen but does not have endocytosis activity, such as INV721 and I7-01 of WO2021168379A1. More specifically, the anti-B7H3 antibody has a VH of SEQ ID NO: 2 and a VL of SEQ ID NO: 1 as described in WO2021168379A1.

[0530] In some embodiments, the antibody has an antibody that binds to the GD-2 antigen but does not have endocytosis activity, such as INV721 and GD2-5 of WO2021168379A1. More specifically, the anti-GD-2 antibody has a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 3 as described in WO2021168379A1.

[0531] In some embodiments, the antibody has an antibody that binds to the HER3 antigen but does not have endocytosis activity, such as the ANTI-HER3 21F06 antibody shown in SEQ ID NO: 22 of US10808032B2.

[0532] In some embodiments, the antibody has the ability to bind to the CD20 antigen but lacks endocytosis activity. While so-called "type II" CD20-specific antibodies have been shown to be poorly internalized by CD20-positive target cells, other so-called "type I" CD20-specific antibodies have been found to be internalized and degraded to some extent, depending on the expression levels of activating and inhibitory FcγRs on the target cells with which they interact. In some embodiments, the antibody has the ability to bind to the CD20 antigen but lacks endocytosis activity is a "type II" CD20-specific antibody, such as obinutuzumab.

[0533] In some embodiments, the antibody has the activity of binding to non-endocytic antigens (e.g., ALCAM / CD166). In some embodiments, the antibody is an antibody comprising the VH of SEQ ID No: 73 and the VL of SEQ ID No: 74, the VH of SEQ ID No: 75 and the VL of SEQ ID No: 76, the VH of SEQ ID No: 77 and the VL of SEQ ID No: 78, or the VH of SEQ ID No: 79 and the VL of SEQ ID No: 88 in EP3911682A1.

[0534] In some embodiments, the ligand drug conjugate is selected from:

[0535]

[0536] Wherein, Tb8 is an antibody that has tumor cell endocytosis activity and tumor cell surface antigen binding activity, such as 1D1-01, 2E3-02, sacituzumab, pertuzumab, trastuzumab, or cetuximab; q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6, or 8.

[0537] It should also be noted that those skilled in the art will understand that L1 is linked to the sulfhydryl group contained in Tb (e.g., an antibody) after disulfide bond opening (for example, disulfide bond reduction by the reducing agent TCEP can open the disulfide bond to form a sulfhydryl group -SH). In other words, the -S- between L1 and Tb is not a separate external sulfur atom. For example, the -S- is not a separate external sulfur atom, but rather the -S- formed by the sulfhydryl group contained in Tb after disulfide bond opening connecting with L1.

[0538] In the second aspect of the present disclosure, the present disclosure provides a compound represented by formula II:

[0539]

[0540] or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a ligand-drug conjugate thereof,

[0541] in:

[0542] R1 and R2 are each independently selected from H, halogen, -OH, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or,

[0543] R1 and R2 together with the carbon atoms to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring, wherein the heterocyclic ring contains one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof;

[0544] R3 is selected from H, halogen, -OH, -NH2, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or,

[0545] R3 and X together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring, wherein the heterocyclic ring contains one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof;

[0546] R3 and R2 together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring, wherein the heterocyclic ring contains one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof;

[0547] W is absent or present. When W is present, W is selected from -OH, -SH, -NHR4, 1 bit is connected to X;

[0548] X is selected from a direct bond, an optionally substituted -O-(CH2) n3 -、-N(R4)-(CH2) n3 -、-S-(CH2) n3 -, carbonyl-(CH2) n3 、-SO2-(CH2) n3 -、-(CH2) n1 -、 C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, the 1 position is connected to the parent ring, and the 2 position is connected to W; the substituent is selected from one or more C1-4 alkyl, C3-6 cycloalkyl, or multiple C1-4 alkyl groups and the carbon atoms to which they are simultaneously connected together form a C3-6 cycloalkyl;

[0549] Each M is independently selected from a direct bond, -CR 5a R 5b -;

[0550] R4, R5, R 5a 、R 5b , R6, R 7 Each is independently selected from H, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, optionally substituted C3-6 cycloalkyl;

[0551] n, n', n1, n2, n3 are each independently selected from any integer between 0 and 6;

[0552] Among them, when R1 and R2 are both H, and X is -(CH2) n1 -, n1 is 1, 2, 3, 4, W is not -OH or -NHR4; and the compound represented by formula II does not contain

[0553]

[0554]

[0555] In some embodiments, R1 and R2 are each independently selected from H, halogen, or C1-4 alkyl.

[0556] In some embodiments, R1 and R2, together with the carbon atom to which they are attached, form a 5-6 membered heterocyclic ring containing 1, 2 or 3 O, S or N or any combination thereof.

[0557] In some embodiments, R1 is selected from H and halogen, and R2 is selected from H and C1-4 alkyl.

[0558] In some embodiments, R1 and R2 and the carbon atom to which they are attached form The dotted line indicates the position where the heterocyclic ring is fused to the benzene ring.

[0559] In some embodiments, R1 is H or F, and R2 is H or methyl.

[0560] In some embodiments, R1 and R2 together with the carbon atom to which they are attached form

[0561] In some embodiments, R1 is F, R2 is methyl; or R1 and R2 together with the carbon atom to which they are attached form

[0562] In some embodiments, R1 is F and R2 is methyl.

[0563] In some embodiments, R1 and R2 together with the carbon atom to which they are attached form

[0564] In some embodiments, R3 is selected from H and C1-4 alkyl.

[0565] In some embodiments, R3 is H.

[0566] In some embodiments, W is absent or present, and when W is present, W is selected from -OH, -SH, -NHR4, 1 bit is connected to X.

[0567] In some embodiments, W is absent or present, and when W is present, W is selected from -OH, -SH, -NHR4, 1 bit is connected to X.

[0568] In some embodiments, W is selected from -OH, -NHR4 and 1 bit is connected to X.

[0569] In some embodiments, W is selected from -OH and -NHR4, and position 1 is connected to X.

[0570] In some embodiments, X is selected from optionally substituted -(CH2) n1 -、 C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group, the 1 position is connected to the parent ring, and the 2 position is connected to W; the substituent is selected from 1 or 2 C1-4 alkyl groups, or 2 C1-4 alkyl groups and the carbon atoms to which they are simultaneously connected form a C3-6 cycloalkyl group.

[0571] In some embodiments, X is selected from optionally substituted Position 1 is connected to the parent ring, and position 2 is connected to W; the substituent is selected from 1 or 2 C1-4 alkyl groups (such as methyl), or 2 C1-4 alkyl groups (such as methyl) and the carbon atoms to which they are simultaneously connected form a C3-6 cycloalkyl group (such as cyclopropyl).

[0572] In some embodiments, X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W.

[0573] In some embodiments, X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W.

[0574] In some embodiments, when W is absent, X is selected from 1 is connected to the parent ring; when W exists, X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W.

[0575] In some embodiments, W is selected from -OH, -NHR4 and Position 1 is connected to X, position 2 is connected to L4 or L3; X is selected from Position 1 is connected to the parent ring, and position 2 is connected to W. In some embodiments, R4 and R5 are each independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl.

[0576] In some embodiments, each R4 is independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl, and R5 is H.

[0577] In some embodiments, each R4 is independently selected from H, methyl, ethyl, isopropyl, n-propyl, tert-butyl, and cyclopropyl, and R5 is H.

[0578] In some embodiments, R 5a and R 5b Each independently selected from H and C1-4 alkyl;

[0579] In some embodiments, R 5a and R 5b are each independently selected from H and methyl;

[0580] In some embodiments, each R 7 Independently selected from H and C1-4 alkyl;

[0581] In some embodiments, R 7 For H.

[0582] In some embodiments, n is 1, 2, or 3.

[0583] In some embodiments, n is 1.

[0584] In some embodiments, n1 is 1, 2, 3, or 4.

[0585] In some embodiments, n2 is 1;

[0586] In some embodiments, n3 is 0.

[0587] In some embodiments, the compound represented by Formula II is selected from any one of the following compounds:

[0588]

[0589]

[0590]

[0591]

[0592] In the third aspect of the present disclosure, the present disclosure provides a drug-linker conjugate shown in formula III,

[0593]

[0594] or a stereoisomer of the drug-linker conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

[0595] in:

[0596] R1 and R2 are each independently selected from H, halogen, -OH, optionally substituted C1-6 alkyl or optionally substituted C1-6 alkoxy, or,

[0597] R1 and R2 together with the carbon atoms to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring, wherein the heterocyclic ring contains one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof;

[0598] R3 is selected from H, halogen, -OH, -NH2, optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy, or,

[0599] R3 and X together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring containing one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof, or

[0600] R3 and R2 together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring, wherein the heterocyclic ring contains one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof;

[0601] W is absent or present. When W is present, W is selected from -O-, -S-, -NR4-, Bit 1 is connected to X, bit 2 is connected to L4 or L3;

[0602] X is selected from a direct bond, an optionally substituted -O-(CH2) n3 -、-N(R4)-(CH2) n3 -、-S-(CH2) n3 -, carbonyl-(CH2) n3 、-SO2-(CH2) n3 -、 -(CH2) n1 -, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group, the 1 position is connected to the parent ring, and the 2 position is connected to W or L4; the substituent is selected from one or more C1-4 alkyl, C3-6 cycloalkyl, or multiple C1-4 alkyl and the carbon atoms to which they are simultaneously connected together form a C3-6 cycloalkyl;

[0603] Each M is independently selected from a direct bond, -CR 5a R 5b -;

[0604] R4, R5, R 5a 、R 5b , R6 and R7 are each independently selected from H, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy and optionally substituted C3-6 cycloalkyl;

[0605] n, n', n1, n2, n3 are each independently selected from any integer between 0 and 6;

[0606] L1 is selected from:

[0607]

[0608]

[0609]

[0610] Each Z is independently selected from a direct bond, a carbon-carbon triple bond, a carbon-carbon double bond, a C6-10 aryl group, a 5-10 membered heteroaryl group, an amide group, a sulfonamide group, an imine group, or CF2; Rx and Ry are each independently selected from H or a C1-4 alkyl group; each m is independently selected from 0, 1, 2, 3, 4, 5, or 6; y1, y2, y3, and y4 are each independently selected from any integer between 0 and 20; position 1 is connected to Lg; and position 2 is connected to L2 or L3;

[0611] L2 is absent or present. When L2 is present, L2 is selected from:

[0612]

[0613]

[0614] y1, y2, y3, and y4 are each independently selected from any integer between 0 and 20, with position 1 connected to L1 and position 2 connected to L3;

[0615] L3 is selected from an amino acid residue or a short peptide consisting of 2-10 amino acid residues;

[0616] L4 is absent or present. When L4 is present, L4 is selected from

[0617] Bit 1 is connected to L3, bit 2 is connected to W or X;

[0618] Lg is a leaving group, which is selected from halogen, sulfone, tertiary amine salt (Me3N + 、Et3N + ), diazonium salt, -OMs, MeSO2-, CF3SO3-.

[0619] In some embodiments, R1 and R2 are each independently selected from H, halogen, and C1-4 alkyl.

[0620] In some embodiments, R1 and R2, together with the carbon atom to which they are attached, form a 5-6 membered heterocyclic ring containing 1, 2 or 3 O, S or N or any combination thereof.

[0621] In some embodiments, R1 is selected from H, halogen, and R2 is selected from H, C1-4 alkyl.

[0622] In some embodiments, R1 and R2 and the carbon atom to which they are attached form The dotted line indicates the position where the heterocyclic ring is fused to the benzene ring.

[0623] In some embodiments, R1 is H or F, and R2 is H or methyl.

[0624] In some embodiments, R1 is F, R2 is methyl, or R1 and R2 together with the carbon atom to which they are attached form

[0625] In some embodiments, R1 is F and R2 is methyl.

[0626] In some embodiments, R1 and R2 together with the carbon atom to which they are attached form

[0627] In some embodiments, R3 is selected from H, C1-4 alkyl.

[0628] In some embodiments, R3 and X, together with the carbon atom to which they are attached, form a 5-6 membered carbocyclic ring.

[0629] In some embodiments, R3 is H or R3 and X together with the carbon atom to which they are attached form The dotted lines indicate where the carbocyclic ring is fused to the benzene and pyridine rings.

[0630] In some embodiments, R3 is H.

[0631] In some embodiments, R3 and X together with the carbon atom to which they are attached form The dotted lines indicate where the carbocyclic ring is fused to the benzene and pyridine rings.

[0632] In some embodiments, W is absent or present, and when W is present, W is selected from -O-, -S-, -NR4-, Bit 1 is connected to X, and bit 2 is connected to L4 or L3.

[0633] In some embodiments, W is absent or present, and when W is present, W is selected from -O-, -S-, -NR4-, Bit 1 is connected to X, and bit 2 is connected to L4 or L3.

[0634] In some embodiments, W is selected from -O-, -NR4-, Bit 1 is connected to X, and bit 2 is connected to L4 or L3.

[0635] In some embodiments, W is selected from -O-, -NR4-, position 1 is connected to X, and position 2 is connected to L4 or L3.

[0636] In some embodiments, X is selected from optionally substituted -(CH2) n1 -、 C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group, the 1 position is connected to the parent ring, and the 2 position is connected to W or L4; the substituent is selected from 1 or 2 C1-4 alkyl groups, or 2 C1-4 alkyl groups and the carbon atoms to which they are simultaneously connected form a C3-6 cycloalkyl group.

[0637] In some embodiments, X is selected from optionally substituted Position 1 is connected to the parent ring, and position 2 is connected to W or L4; the substituent is selected from 1 or 2 C1-4 alkyl groups (such as methyl), or 2 C1-4 alkyl groups (such as methyl) and the carbon atoms to which they are simultaneously connected form a C3-6 cycloalkyl group (such as cyclopropyl).

[0638] In some embodiments, X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W or L4.

[0639] In some embodiments, X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W.

[0640] In some embodiments, when W is absent, X is selected from 1 is connected to the parent ring, 2 is connected to L4; when W exists, X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W.

[0641] In some embodiments, W is selected from -O-, -NR4-, Position 1 is connected to X, position 2 is connected to L4 or L3; X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W.

[0642] In some embodiments, R4 and R5 are each independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl.

[0643] In some embodiments, each R4 is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, and R5 is H.

[0644] In some embodiments, each R4 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, and R5 is H.

[0645] In some embodiments, R 5a 、R 5b Each is independently selected from H, C1-4 alkyl.

[0646] In some embodiments, R 5a 、R 5bEach is independently selected from H, methyl.

[0647] In some embodiments, each R 7 Independently selected from H, C1-4 alkyl.

[0648] In some embodiments, R 7 For H.

[0649] In some embodiments, n is selected from 1, 2, or 3.

[0650] In some embodiments, n is 1.

[0651] In some embodiments, n1 is selected from 1, 2, 3 or 4.

[0652] In some embodiments, n2 is 1.

[0653] In some embodiments, n3 is 0.

[0654] In some embodiments, L1 is selected from Each Z is independently selected from a direct bond, a carbon-carbon triple bond, a carbon-carbon double bond, a C6-10 aryl, a 5-10 membered heteroaryl, an amide group (preferably selected from a direct bond, a carbon-carbon triple bond, a carbon-carbon double bond), Rx, Ry are each independently selected from H, a C1-4 alkyl group, each m is independently selected from 0, 1, 2, 3, 4, 5, 6, y1 is selected from any integer between 1-6 (such as 4, 5, 6), each y2 is independently selected from any integer between 0-15 (such as 6-15), each y3 is independently selected from 1, 2 or 3, each y4 is independently selected from 0 or 1, 1 is independently selected from 1, 2 or 3, Position 1 is connected to Lg, and position 2 is connected to L2 or L3; for example, each Z is independently selected from a direct bond, a carbon-carbon triple bond, or a carbon-carbon double bond, Rx and Ry are each independently selected from H, a C1-4 alkyl group, each m is independently selected from 0, 1, 2, 3, 4, 5, or 6, y1 is selected from any integer between 1 and 6 (e.g., 4, 5, or 6), each y2 is independently selected from any integer between 0 and 15 (e.g., 6-15), each y3 is independently selected from 1, 2, or 3, each y4 is independently selected from 0 or 1, position 1 is connected to Lg through an S atom, and position 2 is connected to L2 or L3.

[0655] In some embodiments, L1 is selected from m is selected from 2, 3, and 4, y1 is selected from any integer between 1 and 6 (such as 4, 5, and 6), each y2 is independently selected from any integer between 0 and 10 (such as 6 and 10), and each y3 is independently selected from 1 or 2. Position 1 is connected to Lg, and position 2 is connected to L2 or L3.

[0656] In some embodiments, L1 is selected from Position 1 is connected to Lg, and position 2 is connected to L2 or L3.

[0657] In some embodiments, L1 is selected from Position 1 is connected to Lg, and position 2 is connected to L2 or L3.

[0658] In some embodiments, L1 is selected from Position 1 is connected to Lg, and position 2 is connected to L2 or L3.

[0659] In some embodiments, L1 is selected from Position 1 is connected to Lg, and position 2 is connected to L2 or L3.

[0660] In some embodiments, L2 is absent or present, and when L2 is present, L2 is selected from y1 is selected from any integer between 1-6 (such as 4, 5, 6), each y2 is independently selected from any integer between 0-10 (such as 6-10), each y3 is independently selected from 1 or 2, each y4 is independently selected from 0 or 1, position 1 is connected to L1, and position 2 is connected to L3.

[0661] In some embodiments, L2 is absent or present, and when L2 is present, L2 is selected from Bit 1 is connected to L1 and bit 2 is connected to L3.

[0662] In some embodiments, L2 is absent or present, and when L2 is present, L2 is selected from Bit 1 is connected to L1 and bit 2 is connected to L3.

[0663] In some embodiments, L2 is absent or present, and when L2 is present, L2 is selected from Bit 1 is connected to L1 and bit 2 is connected to L3.

[0664] In some embodiments, L2 is absent.

[0665] In some embodiments, L2 is selected from

[0666] In some embodiments, L3 is selected from an amino acid residue or a short peptide consisting of 2-10 amino acid residues; the amino acid residue is selected from a natural amino acid residue, a non-natural amino acid residue, an AA 1The indicated amino acid residues or stereoisomers thereof.

[0667] In some embodiments, L3 is selected from the group consisting of amino acid residues Val, D-Val, Cit, Phe, Lys, Lys(Ac), Leu, Gly, Ala, Asn, Asp, Arg, AA 1 or 2-10 selected from Val, Cit, Phe, Lys, D-Val, Leu, Gly, Ala, Asn, Asp, AA 1 A short peptide composed of amino acid residues.

[0668] In some embodiments, L3 is selected from Val, Cit, Phe, Lys, D-Val, Leu, Gly, Ala, Asn, AA 1 , Val-Cit, Cit-Val, Cit-Ala, Val-Ala, Lys-Val, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Ala-Ala, Val-AA 1 、Ala-AA 1 、Gly-AA 1 AA 1 -Gly, Ala-Ala-Ala, Ala-Ala-Asn, Ala-Ala-Asp, Val-AA 1 -Gly, Ala-AA 1 -Gly, Gly-AA 1 -Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Gly-Phe-Gly, Gly-Gly-Phe-Gly, D-Val-Leu-Lys, Gl y-Gly-Arg, Ala-Ala-Asn, Gly-Gly-Phe, Val-Lys-Gly, Val-Lys-Gly-Gly, Val-Lys, Lys-Ala-Asn.

[0669] In some embodiments, L3 is selected from AA 1 AA 1 -Gly, Val-Cit, Val-AA 1 -Gly, AA 1 -Ala-Asn, Gly-Gly-Phe-Gly.

[0670] In some embodiments, L3 is selected from AA 1 、Val-AA 1 -Gly.

[0671] In some embodiments, L3 is selected from Val-AA1 -Gly.

[0672] In some embodiments, L3 is selected from X - Selected from halogen ions, carboxylate ions, sulfate ions, hydrogen sulfate ions, OH - , bit 1 is connected to L1 or L2, bit 2 is connected to L4 or W.

[0673] In some embodiments, L3 is selected from X - Selected from halogen ions, carboxylate ions, sulfate ions, hydrogen sulfate ions, OH - , bit 1 is connected to L1 or L2, bit 2 is connected to L4 or W.

[0674] In some embodiments, L3 is selected from X - Selected from halogen ions, carboxylate ions, sulfate ions, hydrogen sulfate ions, OH - , bit 1 is connected to L1 or L2, bit 2 is connected to L4 or W.

[0675] In some embodiments, L3 is selected from Bit 1 is connected to L1 or L2, and bit 2 is connected to L4 or W.

[0676] In some embodiments, L3 is selected from Bit 1 is connected to L1 or L2, and bit 2 is connected to L4 or W.

[0677] In some embodiments, AA 1 The structures of the indicated amino acid residues are shown below,

[0678]

[0679] in:

[0680] R a 、R b Each independently selected from H, And R a 、R b Not at the same time H;

[0681] Or, R a With R bTogether with the carbon atoms to which they are attached, they form a 4-10 membered heterocyclic ring, which is optionally substituted by one or more R 0 replaced by;

[0682] r、r 1 are each independently selected from any integer from 0 to 20;

[0683] R m1 、R n1 Each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, -COOR x1 ;

[0684] R x1 Selected from C1-6 alkyl;

[0685] Or, R m1 With R n1 Together with the nitrogen atom to which they are attached, they form a 4-10 membered heterocyclic ring, which is optionally substituted by one or more R 0’ replaced by;

[0686] R z Selected from C1-6 alkyl;

[0687] R 0 、R 0’ Each independently selected from C1-6 alkyl, C3-6 cycloalkyl, -NR m2 R n2 , a 4-10 membered heterocyclic group optionally substituted by a C1-6 alkyl group;

[0688] R m2 、R n2 Each is independently selected from H, C1-6 alkyl.

[0689] In some embodiments, R a 、R b Among them, any one is H, and the other is selected from

[0690] In some embodiments, R a 、R b Among them, any one is H, and the other is selected from

[0691] In some embodiments, R a With R b Together with the carbon atoms they are connected to, they form the 0 Substituted 5-6 membered heterocycle.

[0692] In some embodiments, R a With R bTogether with the carbon atoms they are connected to, they form the 0 a substituted piperidine ring or a piperazine ring.

[0693] In some embodiments, R a With R b Together with the carbon atoms they are connected to, they form the 0 Substituted piperidine ring.

[0694] In some embodiments, R a With R b Together with the carbon atoms they are connected to, they form Carbon atom No. 1 is R a and R b carbon atoms that are linked together.

[0695] In some embodiments, R a With R b Together with the carbon atoms they are connected to, they form Carbon atom No. 1 is R a and R b carbon atoms that are linked together.

[0696] In some embodiments, r, r 1 Each is independently selected from 0, 1, 2, 3, 4, and 5.

[0697] In some embodiments, r, r 1 Each is independently selected from 0, 4.

[0698] In some embodiments, r, r 1 If one of them is 0, the other one is 4.

[0699] In some embodiments, R m1 、R n1 Each is independently selected from H, methyl, ethyl, n-propyl, n-butyl, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2CH2CH2CH3.

[0700] In some embodiments, R m1 、R n1 Each is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and tert-butyloxycarbonyl.

[0701] In some embodiments, R m1 、R n1 Each is independently selected from H, C1-6 alkyl.

[0702] In some embodiments, Rm1 、R n1 Each is independently selected from H, methyl, ethyl, and n-propyl.

[0703] In some embodiments, r, r 1 In the example, r is 4, r 1 When R is 0, m1 、R n1 Each is independently selected from H, C1-6 alkyl (such as H, methyl); r is 0, r 1 When R is 4, m1 、R n1 Each is independently selected from C1-6 alkyl (such as methyl, ethyl, n-propyl), preferably selected from C2-6 alkyl (such as ethyl, n-propyl).

[0704] In some embodiments, R m1 With R n1 Together with the nitrogen atom to which they are commonly attached, they form an optionally R 0’ Substituted 5-6 membered heterocycle.

[0705] In some embodiments, R m1 With R n1 Together with the nitrogen atom to which they are commonly attached, they form an optionally R 0’ a substituted piperidine ring or a piperazine ring.

[0706] In some embodiments, R m1 With R n1 Together with the nitrogen atoms they are connected to, they form Nitrogen atom No. 1 is R m1 and R n1 Commonly linked nitrogen atoms.

[0707] In some embodiments, R z It is a methyl group.

[0708] In some embodiments, R 0 、R 0’ Each independently selected from C1-6 alkyl, -NR m2 R n2 , a 5-6 membered heterocyclic group optionally substituted by a C1-6 alkyl group.

[0709] In some embodiments, R 0 The 5-6 membered heterocyclic group is selected from C1-6 alkyl and substituted by C1-6 alkyl, wherein the 5-6 membered heterocyclic group is selected from piperidinyl and piperazinyl.

[0710] In some embodiments, R 0 It is selected from methyl, ethyl, and a 5-6 membered heterocyclic group substituted by a methyl group, wherein the 5-6 membered heterocyclic group is a piperidinyl group.

[0711] In some embodiments, R 0 The 5- to 6-membered heterocyclic group is selected from methyl and methyl-substituted 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group is piperidinyl.

[0712] In some embodiments, R 0 Selected from methyl, ethyl,

[0713] In some embodiments, R 0 Selected from methyl,

[0714] In some embodiments, R 0’ Selected from C1-6 alkyl, -NR m2 R n2 .

[0715] In some embodiments, R 0’ Selected from methyl, -NR m2 R n2 .

[0716] In some embodiments, R m2 、R n2 It is a methyl group.

[0717] In some embodiments, AA 1 The amino acid residues shown are selected from

[0718]

[0719] In some embodiments, AA 1 The amino acid residues shown are selected from

[0720] In some embodiments, AA 1 The amino acid residues shown are selected from

[0721] In some embodiments, AA 1 The amino acid residues shown are selected from

[0722] In some embodiments, L4 is absent or present, and when L4 is present, L4 is selected from Bit 1 is connected to L3, and bit 2 is connected to W or X.

[0723] In some embodiments, L4 is absent or present, and when L4 is present, L4 is Bit 1 is connected to L3, and bit 2 is connected to W or X.

[0724] In some embodiments, L4 is absent.

[0725] In some embodiments, L4 is selected from Bit 1 is connected to L3, and bit 2 is connected to W or X.

[0726] In some embodiments, L4 is selected from Bit 1 is connected to L3, and bit 2 is connected to W or X.

[0727] In some embodiments, Lg is selected from F, Cl, MeSO2-.

[0728] In some embodiments, Lg is selected from F, MeSO2-.

[0729] In some embodiments, The structure is selected from the following:

[0730]

[0731]

[0732]

[0733]

[0734] Among them, bit 1 is connected to Lg and bit 2 is connected to W.

[0735] In some embodiments, The structure is selected from the following:

[0736]

[0737]

[0738]

[0739]

[0740] Among them, bit 1 is connected to L4; when L4 does not exist, bit 1 is connected to L3.

[0741] In some embodiments, the drug-linker conjugate has the structure of Formula III-(1):

[0742]

[0743] wherein L1, L2, L3, L4, X, R1, R2, R3, R4 and Lg have the meanings provided above and in any embodiment specifically described herein.

[0744] In some embodiments, the drug-linker conjugate has a structure represented by Formula III-(1A) or III-(1B):

[0745]

[0746] wherein L2, L3, L4, X, R1, R2, R3, R4 and Lg have the meanings provided above and in any of the embodiments specifically described herein.

[0747] In some embodiments, the drug-linker conjugate has the structure of Formula III-(2):

[0748]

[0749] wherein L1, L2, L3, L4, X, R1, R2, R3 and Lg have the meanings provided above and in any embodiment specifically described herein.

[0750] In some embodiments, the drug-linker conjugate has the structure of Formula III-(2A) or III-(2B):

[0751]

[0752] wherein L2, L3, L4, X, R1, R2, R3 and Lg have the meanings provided above and in any of the embodiments specifically described herein.

[0753] In some embodiments, the drug-linker conjugate has the structure of Formula III-(3):

[0754]

[0755] wherein L1, L2, L3, L4, X, R1, R2, R3, R4, R5, n, and Lg have the meanings provided above and in any of the embodiments specifically described herein.

[0756] In some embodiments, the drug-linker conjugate has a structure represented by Formula III-(3A) or III-(3B):

[0757]

[0758] wherein Lg, L2, L3, L4, X, R1, R2, R3, R4 and Lg have the meanings provided above and in any of the embodiments specifically described herein.

[0759] In some embodiments, the drug-linker conjugate has the structure of Formula III-A:

[0760]

[0761] Among them, Lg, X, R1, R2, R3, R a and R b has the meanings provided above and in any embodiments specifically described herein.

[0762] In some embodiments, the drug-linker conjugate has the structure shown in Formula III-B:

[0763]

[0764] Among them, Lg, X, R1, R2, R3, R a and R b has the meanings provided above and in any embodiments specifically described herein.

[0765] In some embodiments, the drug-linker conjugate represented by Formula III is selected from the following structures:

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0788] In some embodiments, compounds are provided wherein the L1-L2-L3 unit of the drug-linker conjugate of Formula III has been partially cleaved, thereby leaving the drug moiety bonded to the amino acid residue.

[0789] In some embodiments, the partially released free drug is a compound of Formula III-(A):

[0790]

[0791] or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein L4, X, W, R1, R2 and R3 have the meanings provided above and in any of the embodiments specifically described herein.

[0792] In some embodiments, The structure of III-(A) is selected from the following:

[0793]

[0794]

[0795]

[0796]

[0797]

[0798] The present disclosure also provides a linker in a ligand-drug conjugate, the structure of which comprises the following fragments:

[0799]

[0800] Among them, position 2 is connected to the bioactive molecule fragment; (position 1 is connected to the ligand end, for example, when it is connected to the linker unit (such as L2), and then connected to the ligand or targeting portion (Tb) through the extension unit (such as L1); or, when the linker unit does not exist, it is directly connected to the extension unit and then further connected to the ligand);

[0801] The definitions of L3 and L4 are as described in any embodiment of the present disclosure.

[0802] In some embodiments, the structure of the linker in the ligand drug conjugate is as follows:

[0803] Among them, position 1 is connected to the ligand or targeting portion that binds to the target, and position 2 is connected to the bioactive molecular fragment;

[0804] The definitions of L1, L2, L3, and L4 are as described in any embodiment of the present disclosure;

[0805] Preferably, the target-binding ligand or targeting portion and the bioactive molecule fragment are defined as Tb and D in any embodiment of the present disclosure, respectively.

[0806] In some embodiments, the linker is connected to the antibody or antigen-binding fragment thereof at position 1 and to the biologically active molecule fragment at position 2.

[0807] In some embodiments, the linker is connected to a cysteine ​​or lysine on the antibody or antigen-binding fragment thereof at position 1, and is connected to a biologically active molecule fragment at position 2;

[0808] Preferably, the antibody or antigen-binding fragment thereof is as described in any embodiment of the present disclosure.

[0809] In the fourth aspect of the present disclosure, the present disclosure further provides a linker represented by formula III-1:

[0810] Lg-L1-L2-L3-L4-Lg1

[0811] III-1

[0812] Lg, L1, L2, L3 and L4 have the meanings provided above and in any of the embodiments specifically described herein; Lg1 is a leaving group when reacting with a drug molecule.

[0813] In some embodiments, Lg1 is preferably -OH, or halogen.

[0814] In the fifth aspect of the present disclosure, the present disclosure further provides a linker represented by formula III-2:

[0815] Lg-L1-L2-L3-Lg2

[0816] III-2

[0817] Lg, L1, L2 and L3 have the meanings provided above and in any of the embodiments specifically described herein; Lg2 is a leaving group when reacting with L4 or a fragment containing a drug molecule.

[0818] In some embodiments, Lg2 is preferably -OH, or halogen.

[0819] In a sixth aspect of the present disclosure, the present disclosure provides a method for preparing the compound (drug molecule, bioactive molecule) represented by Formula II and the drug-linker conjugate represented by Formula III.

[0820] In one aspect, the present disclosure provides a method for preparing a compound (drug molecule, biologically active molecule) represented by Formula II. Specifically:

[0821] Compound (VI) can be obtained by alkylating compound (IV) with compound (V) in the presence of an iron compound or other related Minisci reactions.

[0822]

[0823] Alternatively, compound (IV) is oxidized to compound (VII), which is then treated with a phosphorus oxyhalide to produce compound (VIII), a halogenated product of compound (IV). Compound (VIII) can be converted to compound (VI) through various reactions, such as Heck reaction, Suzuki reaction, Buchwald reaction, Nigishi reaction, Stille reaction, and the like.

[0824]

[0825] In compound (VI), R 11 Different or more complex molecules can be synthesized through a variety of chemical transformations, such as oxidation, reduction, substitution, and other methods commonly seen in textbooks.

[0826] Alternatively, compound (VI) and compound (IV) can also be obtained by a ring-closure reaction of compound (IX) and compound (X) as shown below.

[0827]

[0828] In another aspect, the present disclosure provides a method for preparing the fragments represented by Formula III-1 and Formula III-2. Specifically:

[0829] Compound III-a can react with the functional group Fg1 of compound III-b to obtain compound III-c, and compound III-c can react with the functional group Fg2 of compound III-b to obtain compound III-c. a Compound III-d can be obtained, and similar transformations can be used to obtain compounds of formula III-2 and III-1. a , Lg b, Lg1, Lg2 are reactive leaving groups, such as -OH, Or halogen, etc.

[0830]

[0831] In yet another aspect, the present disclosure provides a method for preparing a drug-linker conjugate represented by Formula III. Specifically:

[0832] The target product can be obtained by coupling fragments B and C as shown in the following reaction formula. The coupling product is subjected to some commonly used chemical modifications, such as oxidation and deprotection, to obtain the drug-linker conjugate shown in general formula III.

[0833]

[0834] In a seventh aspect of the present disclosure, the present disclosure provides a method for preparing the aforementioned ligand-drug conjugate, comprising:

[0835] Conjugate Tb with the drug linker shown in formula III Carry out the coupling reaction in a suitable solvent and conditions;

[0836] in:

[0837] Tb has the meaning provided above and in any embodiment specifically described herein;

[0838] R1, R2, R3, X, W, L1, L2, L3, L4, and Lg have the meanings provided above and in any of the embodiments specifically described herein.

[0839] In some embodiments, the method comprises conjugating Tb with a drug linker of formula III The step of forming a C-S bond by coupling reaction is carried out in a suitable solvent and conditions.

[0840] In some embodiments, the ratio of the amount of Tb to the amount of the drug-linker conjugate is 1:(1-20), such as 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:(10-20), 1:(12-20), 1:(14-20), 1:(16-20) or 1:(18-20).

[0841] In some embodiments, the coupling reaction is carried out in water and / or an organic solvent.

[0842] In some embodiments, the organic solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, nitriles (such as acetonitrile), alcohols (such as methanol, ethanol) or any combination thereof.

[0843] In some embodiments, the method further comprises the step of purifying the coupling product.

[0844] In some embodiments, the coupled product is purified by chromatography.

[0845] In some embodiments, the chromatography method comprises one or more of ion exchange chromatography, hydrophobic chromatography, reverse phase chromatography, or affinity chromatography.

[0846] In an eighth aspect of the present disclosure, the present disclosure provides an antibody or antigen-binding fragment thereof that binds to B7H3, wherein the antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs):

[0847] HCDR1 or a variant thereof, HCDR2 or a variant thereof, and HCDR3 or a variant thereof contained in the heavy chain variable region (VH) shown in SEQ ID NO: 3 or 23; and / or

[0848] LCDR1 or a sequence variant thereof, LCDR2 or a sequence variant thereof, and LCDR3 or a sequence variant thereof contained in the light chain variable region (VL) shown in SEQ ID NO: 13 or 33.

[0849] In certain embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1 or a variant of its sequence, HCDR2 or a variant of its sequence, and HCDR3 or a variant of its sequence contained in the VH shown in SEQ ID NO: 3; and / or LCDR1 or a variant of its sequence, LCDR2 or a variant of its sequence, and LCDR3 or a variant of its sequence contained in the VL shown in SEQ ID NO: 13.

[0850] In certain embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1 or a variant of its sequence, HCDR2 or a variant of its sequence, and HCDR3 or a variant of its sequence contained in the VH shown in SEQ ID NO: 3; and / or LCDR1 or a variant of its sequence, LCDR2 or a variant of its sequence, and LCDR3 or a variant of its sequence contained in the VL shown in SEQ ID NO: 33.

[0851] In certain embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1 or a variant of its sequence, HCDR2 or a variant of its sequence, and HCDR3 or a variant of its sequence contained in the VH shown in SEQ ID NO: 23; and / or LCDR1 or a variant of its sequence, LCDR2 or a variant of its sequence, and LCDR3 or a variant of its sequence contained in the VL shown in SEQ ID NO: 33.

[0852] In certain embodiments, the antibody or antigen-binding fragment thereof comprises HCDR1 or a variant of its sequence, HCDR2 or a variant of its sequence, and HCDR3 or a variant of its sequence contained in the VH shown in SEQ ID NO: 23; and / or LCDR1 or a variant of its sequence, LCDR2 or a variant of its sequence, and LCDR3 or a variant of its sequence contained in the VL shown in SEQ ID NO: 13.

[0853] In certain preferred embodiments, the sequence variant is a CDR having one or several amino acid substitutions, deletions or additions (eg, 1, 2 or 3 amino acid substitutions, deletions or additions) compared to its source CDR.

[0854] In certain preferred embodiments, the substitutions are conservative substitutions.

[0855] Preferably, the CDRs are defined according to the AbM, Chothia, Kabat or IMGT numbering systems.

[0856] In certain embodiments, the VH and / or VL of the antibody or antigen-binding fragment thereof comprises a framework region (FR) from a human immunoglobulin.

[0857] In certain embodiments, the antibody or antigen-binding fragment thereof binds to human B7H3 and / or monkey B7H3. In certain embodiments, the antibody or antigen-binding fragment thereof binds to human 2Ig B7H3. In certain embodiments, the antibody or antigen-binding fragment thereof binds to human 4Ig B7H3. In certain embodiments, the antibody or antigen-binding fragment thereof binds to monkey 4Ig B7H3. In certain embodiments, the antibody or antigen-binding fragment thereof binds to both human 2Ig B7H3 and human 4Ig B7H3, and preferentially binds to human 4Ig B7H3. In certain embodiments, the antibody or antigen-binding fragment thereof binds to human 4Ig B7H3 but does not bind to human 2Ig B7H3.

[0858] In one aspect, the present disclosure provides an antibody or antigen-binding fragment thereof capable of binding to B7H3, wherein the antibody or antigen-binding fragment thereof comprises: a heavy chain variable region (VH) and / or a light chain variable region (VL).

[0859] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable region (VH) and / or light chain variable region (VL), wherein the CDRs are defined according to the IMGT numbering system:

[0860] (a) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 10 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 11 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 12 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0861] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 20 or a sequence having one or more amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR2 having a sequence of GTF or a sequence having one or more amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR3 having a sequence of SEQ ID NO: 22 or a sequence having one or more amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom;

[0862] (b) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 30 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 31 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 32 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0863] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 40 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR2 having a sequence of GAS or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR3 having a sequence of SEQ ID NO: 42 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom;

[0864] (c) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 10 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 11 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 12 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0865] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 40 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR2 having a sequence of GAS or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR3 having a sequence of SEQ ID NO: 42 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom;

[0866] or

[0867] (d) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 30 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 31 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 32 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0868] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 20 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto, LCDR2 having a sequence of GTF or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto, LCDR3 having a sequence of SEQ ID NO: 22 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto.

[0869] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable region (VH) and / or light chain variable region (VL), wherein the CDRs are defined according to the IMGT numbering system:

[0870] (a) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 10, HCDR2 with a sequence of SEQ ID NO: 11, and HCDR3 with a sequence of SEQ ID NO: 12; and / or,

[0871] a light chain variable region (VL) comprising the following three CDRs: LCDR1 with a sequence of SEQ ID NO: 20, LCDR2 with a sequence of GTF, and LCDR3 with a sequence of SEQ ID NO: 22;

[0872] (b) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 10, HCDR2 with a sequence of SEQ ID NO: 11, and HCDR3 with a sequence of SEQ ID NO: 12; and / or,

[0873] a light chain variable region (VL) comprising the following three CDRs: LCDR1 of SEQ ID NO: 40, LCDR2 of GAS, and LCDR3 of SEQ ID NO: 42;

[0874] (c) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 30, HCDR2 with a sequence of SEQ ID NO: 31, and HCDR3 with a sequence of SEQ ID NO: 32; and / or,

[0875] a light chain variable region (VL) comprising the following three CDRs: LCDR1 of SEQ ID NO: 40, LCDR2 of GAS, and LCDR3 of SEQ ID NO: 42;

[0876] or

[0877] (d) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 30, HCDR2 with a sequence of SEQ ID NO: 31, and HCDR3 with a sequence of SEQ ID NO: 32; and / or,

[0878] The light chain variable region (VL) comprises the following three CDRs: LCDR1 with the sequence of SEQ ID NO: 20, LCDR2 with the sequence of GTF, and LCDR3 with the sequence of SEQ ID NO: 22.

[0879] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable region (VH) and / or light chain variable region (VL), wherein the CDRs are defined according to the Chothia numbering system:

[0880] (a) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 4 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 5 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 6 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0881] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 14 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR2 having a sequence of SEQ ID NO: 15 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR3 having a sequence of SEQ ID NO: 16 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom;

[0882] (b) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 4 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 5 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 6 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0883] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 34 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR2 having a sequence of SEQ ID NO: 35 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR3 having a sequence of SEQ ID NO: 36 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom;

[0884] (c) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 24 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 25 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 26 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0885] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 34 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR2 having a sequence of SEQ ID NO: 35 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR3 having a sequence of SEQ ID NO: 36 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom;

[0886] or

[0887] (d) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 24 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 25 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 26 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0888] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 14 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto, LCDR2 having a sequence of SEQ ID NO: 15 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto, LCDR3 having a sequence of SEQ ID NO: 16 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto.

[0889] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable region (VH) and / or light chain variable region (VL), wherein the CDRs are defined according to the chothia numbering system:

[0890] (a) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 4, HCDR2 with a sequence of SEQ ID NO: 5, and HCDR3 with a sequence of SEQ ID NO: 6; and / or,

[0891] a light chain variable region (VL) comprising the following three CDRs: LCDR1 of SEQ ID NO: 14, LCDR2 of SEQ ID NO: 15, and LCDR3 of SEQ ID NO: 16;

[0892] (b) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 24, HCDR2 with a sequence of SEQ ID NO: 25, and HCDR3 with a sequence of SEQ ID NO: 26; and / or,

[0893] a light chain variable region (VL) comprising the following three CDRs: LCDR1 of SEQ ID NO: 34, LCDR2 of SEQ ID NO: 35, and LCDR3 of SEQ ID NO: 36;

[0894] (c) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 4, HCDR2 with a sequence of SEQ ID NO: 5, and HCDR3 with a sequence of SEQ ID NO: 6; and / or,

[0895] a light chain variable region (VL) comprising the following three CDRs: LCDR1 of SEQ ID NO: 34, LCDR2 of SEQ ID NO: 35, and LCDR3 of SEQ ID NO: 36;

[0896] or

[0897] (d) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 24, HCDR2 with a sequence of SEQ ID NO: 25, and HCDR3 with a sequence of SEQ ID NO: 26; and / or,

[0898] The light chain variable region (VL) comprises the following three CDRs: LCDR1 with the sequence of SEQ ID NO: 14, LCDR2 with the sequence of SEQ ID NO: 15, and LCDR3 with the sequence of SEQ ID NO: 16.

[0899] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable region (VH) and / or light chain variable region (VL), wherein the CDRs are defined according to the Kabat numbering system:

[0900] (a) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 7 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 8 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 9 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0901] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 17 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR2 having a sequence of SEQ ID NO: 18 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR3 having a sequence of SEQ ID NO: 19 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom;

[0902] (b) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 27 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 28 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 29 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0903] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 37 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR2 having a sequence of SEQ ID NO: 38 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR3 having a sequence of SEQ ID NO: 39 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom;

[0904] (c) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 7 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 8 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 9 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0905] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 37 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR2 having a sequence of SEQ ID NO: 38 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, LCDR3 having a sequence of SEQ ID NO: 39 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom;

[0906] or

[0907] (d) a heavy chain variable region (VH) comprising the following three CDRs: a HCDR1 having a sequence of SEQ ID NO: 27 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR2 having a sequence of SEQ ID NO: 28 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom, a HCDR3 having a sequence of SEQ ID NO: 29 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom; and / or,

[0908] A light chain variable region (VL) comprising the following three CDRs: LCDR1 having a sequence of SEQ ID NO: 17 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto, LCDR2 having a sequence of SEQ ID NO: 18 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto, LCDR3 having a sequence of SEQ ID NO: 19 or a sequence having one or several amino acid substitutions, deletions or additions (e.g., 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto.

[0909] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable region (VH) and / or light chain variable region (VL), wherein the CDRs are defined according to the Kabat numbering system:

[0910] (a) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 7, HCDR2 with a sequence of SEQ ID NO: 8, and HCDR3 with a sequence of SEQ ID NO: 9; and / or,

[0911] a light chain variable region (VL) comprising the following three CDRs: LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19;

[0912] (b) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 27, HCDR2 with a sequence of SEQ ID NO: 28, and HCDR3 with a sequence of SEQ ID NO: 29; and / or,

[0913] a light chain variable region (VL) comprising the following three CDRs: LCDR1 of SEQ ID NO: 37, LCDR2 of SEQ ID NO: 38, and LCDR3 of SEQ ID NO: 39;

[0914] (c) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 7, HCDR2 with a sequence of SEQ ID NO: 8, and HCDR3 with a sequence of SEQ ID NO: 9; and / or,

[0915] a light chain variable region (VL) comprising the following three CDRs: LCDR1 of SEQ ID NO: 37, LCDR2 of SEQ ID NO: 38, and LCDR3 of SEQ ID NO: 39;

[0916] or

[0917] (d) a heavy chain variable region (VH) comprising the following three CDRs: HCDR1 with a sequence of SEQ ID NO: 27, HCDR2 with a sequence of SEQ ID NO: 28, and HCDR3 with a sequence of SEQ ID NO: 29; and / or,

[0918] The light chain variable region (VL) comprises the following three CDRs: LCDR1 with the sequence of SEQ ID NO: 17, LCDR2 with the sequence of SEQ ID NO: 18, and LCDR3 with the sequence of SEQ ID NO: 19.

[0919] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable region (VH) and / or light chain variable region (VL), wherein at least one CDR in the heavy chain variable region (VH) and / or light chain variable region (VL) contains a mutation compared to the CDR defined by IMGT, Chothia or Kabat, and the mutation is a substitution, deletion or addition of one or several amino acids or any combination thereof (e.g., substitution, deletion or addition of 1, 2 or 3 amino acids or any combination thereof).

[0920] Preferably, the substitutions described in the present disclosure are conservative substitutions.

[0921] In certain embodiments, the VH of the antibodies or antigen-binding fragments thereof of the present disclosure comprises a framework region (FR) derived from the heavy chain variable region (VH) of a human immunoglobulin, and / or the VL of the antibodies or antigen-binding fragments thereof comprises a framework region (FR) derived from the light chain variable region (VL) of a human immunoglobulin. Thus, in certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are humanized. In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are fully human.

[0922] In certain embodiments, the VH of the antibodies or antigen-binding fragments thereof of the present disclosure comprises a framework region (FR) derived from the heavy chain variable region (VH) of a human immunoglobulin, and / or the VL of the antibodies or antigen-binding fragments thereof comprises a framework region (FR) derived from the light chain variable region (VL) of a human immunoglobulin. Thus, in certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are humanized. In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are fully human.

[0923] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise:

[0924] (a) a heavy chain framework region of a human immunoglobulin or a variant thereof, which has up to 20 conservative substitutions of amino acids (e.g., up to 20, up to 15, up to 10, or up to 5 conservative substitutions of amino acids; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative substitutions of amino acids) compared to the amino acid sequence encoded by the germline antibody gene from which the variant is derived; and / or

[0925] (b) a light chain framework region of a human immunoglobulin or a variant thereof, which has up to 20 conservative substitutions of amino acids compared to the amino acid sequence encoded by the germline antibody gene from which the variant is derived (e.g., up to 20, up to 15, up to 10 or up to 5 conservative substitutions of amino acids; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 conservative substitutions of amino acids).

[0926] In certain embodiments, the degree of humanization of the antibodies or antigen-binding fragments thereof of the present disclosure is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0927] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise:

[0928] (a) a heavy chain variable region (VH) comprising an amino acid sequence selected from the group consisting of:

[0929] (i) the sequence shown in SEQ ID NO: 3 or 23;

[0930] (ii) a sequence having one or more amino acid substitutions, deletions or additions, or any combination thereof, compared to the sequence shown in SEQ ID NO: 3 or 23 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions, or any combination thereof); or

[0931] (iii) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence set forth in SEQ ID NO: 3 or 23;

[0932] and / or

[0933] (b) a light chain variable region (VL) comprising an amino acid sequence selected from the group consisting of:

[0934] (iv) the sequence shown in SEQ ID NO: 13 or 33;

[0935] (v) a sequence having one or more amino acid substitutions, deletions or additions, or any combination thereof, compared to the sequence shown in SEQ ID NO: 13 or 33 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions, or any combination thereof); or

[0936] (vi) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence set forth in SEQ ID NO: 13 or 33.

[0937] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the VH set forth in SEQ ID NO:3, and / or the VL set forth in SEQ ID NO:13.

[0938] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the VH set forth in SEQ ID NO:23, and / or the VL set forth in SEQ ID NO:33.

[0939] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the VH set forth in SEQ ID NO:3, and / or the VL set forth in SEQ ID NO:33.

[0940] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the VH set forth in SEQ ID NO:23, and / or the VL set forth in SEQ ID NO:13.

[0941] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise:

[0942] (a) VH of SEQ ID NO: 3 and VL of SEQ ID NO: 13;

[0943] (b) VH of SEQ ID NO: 23 and VL of SEQ ID NO: 33;

[0944] (c) VH of SEQ ID NO: 3 and VL of SEQ ID NO: 33;

[0945] (d) VH of SEQ ID NO:23 and VL of SEQ ID NO:13.

[0946] (e) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the VH and VL described in any one of groups (a) to (d), respectively; or

[0947] (f) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof) compared to the VH and VL described in any one of groups (a) to (d), respectively. Preferably, the substitutions are conservative substitutions.

[0948] In certain embodiments, the heavy chain of the antibodies or antigen-binding fragments thereof of the present disclosure comprises a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof having up to 50 conservative substitutions of amino acids compared to the wild-type sequence from which it is derived (e.g., up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10, or up to 5 conservative substitutions of amino acids; e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative substitutions of amino acids). In certain embodiments, the light chain of the antibodies or antigen-binding fragments thereof of the present disclosure comprises a light chain constant region (CL) of a human immunoglobulin or a variant thereof having up to 50 conservative substitutions of amino acids compared to the wild-type sequence from which it is derived (e.g., up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10, or up to 5 conservative substitutions of amino acids; e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative substitutions of amino acids).

[0949] In some embodiments, the constant region is altered, for example, mutated, to modify the properties of the anti-B7H3 antibody molecule (e.g., to alter one or more of the following: Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, or complement function). Functional changes can be produced by replacing at least one amino acid residue in the antibody constant region with a different residue, for example, by altering the affinity of the antibody for an effector ligand (such as FcR or complement C1q), thereby altering (e.g., reducing) the effector function. The Fc region of an antibody mediates several important effector functions, such as ADCC, phagocytosis (ADCP), CDC, etc.

[0950] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure have a heavy chain constant region (CH) selected from, for example, the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; particularly selected from, for example, the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4, more particularly selected from the heavy chain constant regions of IgG1 (e.g., human IgG1). In some embodiments, the human IgG1 heavy chain constant region is as shown in SEQ ID NO: 43. In some embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure have a light chain constant region selected from, for example, a kappa or lambda light chain constant region, preferably a kappa light chain constant region (e.g., a human kappa light chain constant region). In some embodiments, the light chain constant region has a sequence as shown in SEQ ID NO: 44.

[0951] In some embodiments, the antibody or antigen-binding fragment thereof comprises the CH set forth in SEQ ID NO: 43 or a variant thereof, which has up to 20 conservative amino acid substitutions (e.g., up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions) compared to SEQ ID NO: 43, or has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to SEQ ID NO: 43.

[0952] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain constant region or a variant thereof. In some embodiments, the light chain constant region comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises a light chain constant region (CL) as set forth in SEQ ID NO: 44 or a variant thereof, the variant having a conservative substitution of up to 20 amino acids compared to SEQ ID NO: 44 (e.g., a conservative substitution of up to 20, up to 15, up to 10, or up to 5 amino acids; for example, a conservative substitution of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids), or having a sequence identity of at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% compared to SEQ ID NO: 16;

[0953] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) shown in SEQ ID NO:43 and a light chain constant region (CL) shown in SEQ ID NO:44.

[0954] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise:

[0955] (a) a heavy chain comprising an amino acid sequence selected from the group consisting of:

[0956] (i) a sequence comprising the VH sequence shown in SEQ ID NO: 3 and the CH sequence shown in SEQ ID NO: 43;

[0957] (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0958] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to the sequence shown in (i); and

[0959] (b) a light chain comprising an amino acid sequence selected from the group consisting of:

[0960] (iv) a sequence comprising the VL sequence shown in SEQ ID NO: 13 and the CL sequence shown in SEQ ID NO: 44;

[0961] (v) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (iv) (e.g., at most 50, at most 45, at most 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0962] (vi) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence shown in (iv).

[0963] In certain embodiments, the substitution described in (ii) or (v) is a conservative substitution.

[0964] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise:

[0965] (a) a heavy chain comprising an amino acid sequence selected from the group consisting of:

[0966] (i) a sequence comprising the VH sequence shown in SEQ ID NO: 23 and the CH sequence shown in SEQ ID NO: 43;

[0967] (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0968] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to the sequence shown in (i); and

[0969] (b) a light chain comprising an amino acid sequence selected from the group consisting of:

[0970] (iv) a sequence comprising the VL sequence shown in SEQ ID NO: 33 and the CL sequence shown in SEQ ID NO: 44;

[0971] (v) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (iv) (e.g., at most 50, at most 45, at most 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0972] (vi) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the sequence shown in (iv).

[0973] In certain embodiments, the substitution described in (ii) or (v) is a conservative substitution.

[0974] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain and a light chain,

[0975] The heavy chain comprises:

[0976] (i) the sequence shown in SEQ ID NO:45;

[0977] (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0978] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in (i); and

[0979] The light chain comprises:

[0980] (iv) the sequence shown in SEQ ID NO:46;

[0981] (v) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (iv) (e.g., at most 50, at most 45, at most 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0982] (vi) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in (iv);

[0983] Preferably, the substitutions described in (ii) or (v) are conservative substitutions.

[0984] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain and a light chain,

[0985] The heavy chain comprises:

[0986] (i) the sequence shown in SEQ ID NO: 47;

[0987] (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0988] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in (i); and

[0989] The light chain comprises:

[0990] (iv) the sequence shown in SEQ ID NO:48;

[0991] (v) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (iv) (e.g., at most 50, at most 45, at most 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[0992] (vi) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence set forth in (iv);

[0993] Preferably, the substitutions described in (ii) or (v) are conservative substitutions.

[0994] In certain embodiments, the antibodies of the present disclosure are chimeric, humanized, or fully human antibodies. In certain embodiments, the antibodies of the present disclosure or their antigen-binding fragments are selected from the group consisting of scFv, Fab, Fab', (Fab')2, Fv fragments, disulfide-linked Fv (dsFv), and diabodies.

[0995] In certain embodiments, the antibodies of the present disclosure are scFvs. In certain embodiments, the scFvs of the present disclosure comprise:

[0996] (a) VH of SEQ ID NO: 3 and VL of SEQ ID NO: 13;

[0997] (b) VH of SEQ ID NO: 23 and VL of SEQ ID NO: 33;

[0998] (c) VH of SEQ ID NO: 3 and VL of SEQ ID NO: 33;

[0999] (d) VH of SEQ ID NO:23 and VL of SEQ ID NO:13.

[1000] (e) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the VH and VL described in any one of groups (a) to (d), respectively; or

[1001] (f) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) and the light chain variable region (VL) independently have one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof) compared to the VH and VL described in any one of groups (a) to (d), respectively. Preferably, the substitutions are conservative substitutions.

[1002] In certain embodiments, the antibodies of the present disclosure are scFvs. In certain embodiments, the scFvs of the present disclosure comprise:

[1003] (i) the sequence shown in SEQ ID NO: 1 or 2;

[1004] (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof); or

[1005] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in (i);

[1006] Preferably, the substitutions described in (ii) are conservative substitutions.

[1007] In certain embodiments, the antibodies of the disclosure are scFvs.

[1008] In certain embodiments, the scFv of the present disclosure comprises the sequence shown in SEQ ID NO: 1 or 2.

[1009] Antibody derivatives

[1010] The antibodies or antigen-binding fragments thereof disclosed herein may be derivatized, for example, by being linked to another molecule (e.g., another polypeptide or protein). Generally, derivatization (e.g., labeling) of an antibody or antigen-binding fragment thereof will not adversely affect its binding to B7H3 (particularly human B7H3). Therefore, the antibodies or antigen-binding fragments thereof disclosed herein are also intended to include such derivatized forms. For example, an antibody or antigen-binding fragment thereof disclosed herein may be linked (by chemical coupling, genetic fusion, non-covalent linkage, or other means) to one or more other molecular groups, such as another antibody (e.g., to form a bispecific antibody), a detection reagent, a pharmaceutical agent, and / or a protein or polypeptide capable of mediating binding of the antibody or antigen-binding fragment thereof to another molecule (e.g., an avidin or polyhistidine tag).

[1011] One type of derivatized antibody (e.g., bispecific antibody) is produced by cross-linking two or more antibodies (of the same type or different types). Methods for obtaining bispecific antibodies are well known in the art, and examples thereof include, but are not limited to, chemical cross-linking, cell engineering (hybridoma method), or genetic engineering.

[1012] Another type of derivatized antibody is a labeled antibody. For example, the antibody of the present disclosure or its antigen-binding fragment can be connected to a detectable label. The detectable label described in the present disclosure can be any substance that can be detected by fluorescence, spectroscopy, photochemistry, biochemistry, immunology, electricity, optics or chemical means. Such labels are well known in the art, and examples thereof include, but are not limited to, enzymes (e.g., horseradish peroxidase, alkaline phosphatase, β-galactosidase, urease, glucose oxidase, etc.), radionuclides (e.g., 3H, 125I, 35S, 14C or 32P), fluorescent dyes (e.g., fluorescein isothiocyanate (FITC), fluorescein, tetramethylrhodamine isothiocyanate (TRITC), phycoerythrin (PE), Texas Red, rhodamine, quantum dots or cyanine dye derivatives (e.g., Cy7, Alexa750)), acridinium ester compounds, magnetic beads (e.g., ), calorimetric labels such as colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads, and biotin for binding to avidin (e.g., streptavidin) modified with the above labels. Patents teaching the use of such labels include, but are not limited to, U.S. Patents 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241 (all of which are incorporated herein by reference). Detectable labels such as those described above can be detected by methods known in the art. For example, radioactive labels can be detected using photographic film or a scintillation counter, and fluorescent labels can be detected using a photodetector to detect emitted light. Enzyme labels are generally detected by providing a substrate to the enzyme and detecting the reaction product produced by the action of the enzyme on the substrate, and calorimetric labels are detected by simple visualization of a colored label. In certain embodiments, such labels can be suitable for immunological detection (e.g., enzyme-linked immunosorbent assay, radioimmunoassay, fluorescent immunoassay, chemiluminescent immunoassay, etc.). In certain embodiments, the detectable labels described above can be linked to the antibodies or antigen-binding fragments thereof of the present disclosure via linkers of varying lengths to reduce potential steric hindrance.

[1013] In addition, the antibodies or antigen-binding fragments thereof of the present disclosure can also be derivatized with chemical groups, such as polyethylene glycol (PEG), methyl or ethyl groups, or glycosyl groups. These groups can be used to improve the biological properties of the antibodies, such as increasing serum half-life.

[1014] The antigen-binding fragments disclosed herein can be obtained by hydrolyzing intact antibody molecules (see Morimoto et al., J. Biochem. Biophys. Methods 24:107-117 (1992) and Brennan et al., Science 229:81 (1985)). Alternatively, these antigen-binding fragments can be produced directly from recombinant host cells (reviewed in Hudson, Curr. Opin. Immunol. 11:548-557 (1999); Little et al., Immunol. Today, 21:364-370 (2000)). For example, Fab' fragments can be obtained directly from host cells; Fab' fragments can be chemically coupled to form F(ab')2 fragments (Carter et al., Bio / Technology, 10:163-167 (1992)). In addition, Fv, Fab, or F(ab')2 fragments can also be directly isolated from recombinant host cell culture fluid. Other techniques for preparing such antigen-binding fragments are well known to those of ordinary skill in the art.

[1015] The IgG isotype control antibodies disclosed herein are well known to those skilled in the art and can be purchased or prepared. For example, human anti-hen egg lysosomal IgG (anti-HEL, such as human IgG1, abbreviated as hIgG1) is derived from the variable region sequence of Fab F10.6.6 in the study "Affinity maturation increases the stability and plasticity of the Fv domain of anti-protein antibodies" published by Acierno et al. (Acierno et al. J Mol Biol. 2007; 374(1): 130-46). The preparation method is as follows: Nanjing GenScript Biopharmaceuticals was commissioned to perform amino acid codon optimization and gene synthesis for the heavy and light chain genes (full sequence or variable region) of a human IgG antibody. Following the standard techniques described in the "Molecular Cloning Laboratory Manual (3rd Edition)", standard molecular cloning techniques such as PCR, enzyme digestion, DNA gel recovery, ligation transformation, colony PCR, or enzyme digestion identification were used to subclone the heavy and light chain genes into mammalian expression systems for antibody heavy and light chain expression vectors, respectively. The heavy and light chain genes in the recombinant expression vectors were then sequenced and analyzed. After sequencing verification, large quantities of endotoxin-free expression plasmids were prepared and transiently co-transfected into HEK293 cells for recombinant antibody expression. After 7 days of culture, the cell culture medium was collected and affinity purified using an rProtein A column (GE). The harvested antibody sample was then quality-assured using standard analytical techniques such as SDS-PAGE and SEC-HPLC.

[1016] In a ninth aspect, the present disclosure provides a multispecific antibody comprising the antibody or antigen-binding fragment thereof according to any one of the eighth aspects of the present disclosure, and another antibody or fragment thereof or antibody analog.

[1017] In certain embodiments, the multispecific antibody is a bispecific antibody, a trispecific antibody, or a tetraspecific antibody.

[1018] Therefore, in a tenth aspect, the present disclosure provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding an antibody or antigen-binding fragment thereof, or a heavy chain variable region and / or a light chain variable region, or one or more CDRs thereof. According to codon degeneracy known in the art, in certain embodiments, the nucleotide sequence is replaceable according to codon degeneracy. In certain embodiments, the nucleotide sequence is codon-optimized.

[1019] In certain embodiments, the isolated nucleic acid molecules of the present disclosure comprise: (i) a first nucleic acid and a second nucleic acid encoding the heavy chain variable region and the light chain variable region of the antibody or antigen-binding fragment thereof of the present disclosure, respectively, or (ii) a first nucleic acid encoding the heavy chain variable region and the heavy chain constant region, and a second nucleic acid encoding the light chain variable region and the light chain constant region, respectively, or (iii) a first nucleic acid and a second nucleic acid encoding the heavy chain and the light chain of the antibody or antigen-binding fragment thereof of the present disclosure, respectively. In certain embodiments, the first nucleic acid and the second nucleic acid comprise a degenerate sequence or a substantially identical sequence to any of the first nucleic acid and the second nucleic acid in (i)-(iii) above. In certain embodiments, the degenerate sequence or substantially identical sequence refers to a sequence having at least about 85%, 90%, 95%, 99% or higher sequence identity or a sequence having one or more nucleotide substitutions, or a sequence that differs by no more than 3, 6, 15, 30 or 45 nucleotides compared to the nucleic acid molecules of (i)-(iii).

[1020] In an eleventh aspect, a vector (e.g., a cloning vector or an expression vector) is provided, comprising an isolated nucleic acid molecule of the present disclosure. In certain embodiments, the vector of the present disclosure is, for example, a plasmid, a cosmid, a phage, a lentivirus, etc. In certain embodiments, the vector is capable of expressing the antibody or antigen-binding fragment thereof of the present disclosure in a subject (e.g., a mammal, such as a human).

[1021] A twelfth aspect provides a host cell comprising an isolated nucleic acid molecule of the present disclosure or a vector of the present disclosure. The host cell can be a eukaryotic cell (e.g., a mammalian cell, an insect cell, a yeast cell) or a prokaryotic cell (e.g., an E. coli). Suitable eukaryotic cells include, but are not limited to, NSO cells, Vero cells, Hela cells, COS cells, CHO cells, HEK293 cells, BHK cells, and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells. In certain embodiments, the host cell of the present disclosure is a mammalian cell, such as CHO (e.g., CHO-K1, CHO-S, CHO DXB11, CHO DG44).

[1022] In a thirteenth aspect, a method for preparing the antibody or antigen-binding fragment thereof, or multispecific antibody of the present disclosure is provided, comprising culturing the host cell of the present disclosure under conditions that allow expression of the antibody or antigen-binding fragment thereof, or multispecific antibody, and recovering the antibody or antigen-binding fragment thereof from the cultured host cell culture.

[1023] In a fourteenth aspect, an antibody-drug conjugate is provided, wherein the antibody is the anti-B7H3 antibody described above, and is connected to a coupling moiety via a linker. The coupling moiety is selected from the group consisting of a detectable label, a radioisotope, a fluorescent substance, a luminescent substance, a colored substance, an enzyme, polyethylene glycol (PEG), a nuclide, a nucleic acid, a small molecule toxin, a polypeptide with binding activity, a protein, a receptor, a ligand, and other active substances that inhibit tumor cell growth or promote tumor cell apoptosis or necrosis.

[1024] In some embodiments, the antibody-drug conjugate comprises an anti-B7H3 antibody drug conjugate (B7H3-ADC) of the formula:

[1025] Ab-(LD)n,

[1026] in:

[1027] Ab is the antibody or antigen-binding fragment thereof of the eighth aspect, and;

[1028] D is a small molecule toxin drug moiety;

[1029] L is a bond or linking molecule that covalently links Ab and D;

[1030] n is an integer between 1-16 and represents the number of LDs covalently linked to the Ab.

[1031] In some embodiments, L of the antibody-drug conjugate comprises an amino acid residue or a short peptide consisting of 2-10 amino acid residues; the amino acid residue is selected from natural amino acid residues, non-natural amino acid residues, AA 1 the indicated amino acid residue or its stereoisomers;

[1032]

[1033] AA 1 Among the amino acid residues shown:

[1034] R a1 and R b Each independently selected from H,

[1035] Or, R a1 With R b Together with the carbon atoms they are commonly connected to form a 4-10 membered heterocyclic ring, wherein the heteroatoms in the 4-10 membered heterocyclic ring are selected from 1, 2, 3 or 4 of O, N and S; the 4-10 membered heterocyclic ring is optionally replaced by one or more R 0 replaced by;

[1036] r、r 1 、r 1a and r 1bEach independently represents an integer from 0 to 20;

[1037] R m1 、R n1 、R m1a 、R n1a 、R m1b and R n1b Each independently is H, C 1-6 Alkyl, C 3-6 Cycloalkyl or -COOR x1 , where R x1 C 1-6 alkyl;

[1038] Or, R m1 and R n1 、R m1a and R n1a , and R m1b and R n1b Together with the nitrogen atom they are connected to, they form a 4-10 membered heterocyclic ring, wherein the heteroatoms in the 4-10 membered heterocyclic ring are selected from 1, 2, 3 or 4 of O, N and S; the 4-10 membered heterocyclic ring is optionally replaced by one or more R 0’ replaced by;

[1039] R z Selected from C 1-6 alkyl;

[1040] R 0 、R 0’ Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -NR m2 R n2 and optionally C 1-6 Alkyl-substituted 4-10 membered heterocyclic group; in the 4-10 membered heterocyclic ring, the heteroatoms are selected from 1, 2, 3 or 4 of O, N and S;

[1041] R m2 and R n2 Each independently selected from H and C 1-6 alkyl.

[1042] In some embodiments, AA 1 Among the amino acid residues shown, R a1 With R b Together with the carbon atoms they are connected to form a 5-6 membered heterocyclic ring, wherein the heteroatom in the 5-6 membered heterocyclic ring is N and the number of heteroatoms is 1 or 2; the 5-6 membered heterocyclic ring is optionally replaced by one or more R 0 The 5-6 membered heterocyclic ring is preferably a piperidine ring or a piperazine ring, and more preferably a piperidine ring, for example Carbon atom No. 1 is R a1 and R b carbon atoms that are linked together.

[1043] In some embodiments, r, r 1 、r 1a and r 1b are independently 0, 1, 2, 3, 4 or 5; preferably, r, r 1 、r 1a and r 1b Each independently is 0 or 4; more preferably, r is 0, r 1 、r 1a and r 1b is 4; or r is 4, r 1 、r 1a and r 1b is 0.

[1044] In some embodiments, r, r 1 、r 1a and r 1b Not 0 at the same time.

[1045] In some embodiments, R m1 、R n1 、R m1a 、R n1a 、R m1b and R n1b Each independently is H, C 1-6 Alkyl or -COOR x1 , where R x1 C 1-6 Alkyl; preferably, each independently H, methyl, ethyl, n-propyl, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH(CH3)2, -COOC(CH3)3 or -COOCH2CH2CH2CH3.

[1046] In some embodiments, R m1 and R n1 、R m1a and R n1a , and R m1b and R n1b Together with the nitrogen atom they are connected to form a 5-6 membered heterocyclic ring, wherein the heteroatom in the 5-6 membered heterocyclic ring is selected from 1 or 2 N atoms; the 5-6 membered heterocyclic ring is optionally replaced by one or more R 0’ substituted; the 5-6 membered heterocyclic ring is preferably a piperidine ring or a piperazine ring; further preferably Nitrogen atom No. 1 is R m1 and Rn1 Commonly linked nitrogen atoms.

[1047] In some embodiments, R z Preferably C 1-6 Alkyl; more preferably methyl.

[1048] In some embodiments, R 0 and R 0’ Each independently is C 1-6 Alkyl, -NR m2 R n2 Or optionally C 1-6 Alkyl-substituted 5-6 membered heterocyclic group; in the 5-6 membered heterocyclic ring, the heteroatom is selected from 1 or 2 N atoms.

[1049] In some embodiments, R 0 Preferably C 1-6 Alkyl or C 1-6 Alkyl-substituted 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is piperidinyl or piperazinyl; further preferably methyl or piperidinyl substituted by methyl; for example methyl or

[1050] In some embodiments, R 01’ Each independently preferably is C 1-6 Alkyl, -NR m2 R n2 Or optionally C 1-6 Alkyl-substituted 5-6 membered heterocyclic group; in the 5-6 membered heterocyclic ring, the heteroatom is 1 or 2 N; more preferably C 1-6 Alkyl or -NR m2 R n2 More preferably, methyl or -NR m2 R n2 , where R m2 and R n2 Each independently is preferably H or C 1-6 Alkyl, more preferably methyl.

[1051] In some embodiments, R 0’ Preferably C 1-6 Alkyl or -NR m2 R n2 ; R m2 and R n2 Each independently is preferably H or C 1-6 Alkyl (eg, methyl).

[1052] In some embodiments, AA 1 Among the amino acid residues shown, R a1 and R b Either one is H, the other is Preferably, R a1 and R b Any one of them is H, and the other is selected from

[1053] In some embodiments, AA 1 The amino acid residues shown are preferably More preferably More preferably

[1054] Most preferably

[1055] In some embodiments, the antibody-drug conjugate consists of antibody-linker-drug, wherein the drug is selected from: microtubule blocking drugs, DNA damaging drugs, Bcl-xL inhibitors, etc.

[1056] In some embodiments, the antibody-drug conjugate consists of antibody-linker-drug, wherein the drug is selected from: Auristatins (e.g., MMAF, MMAE), maytansine derivatives (e.g., DM1, DM4), tubulysin, cryptocolistin, anti-mitotic inhibitors, pyrrole benzazepines and indolechlorobenzazepines, dukamycin, camptothecin, calicheamicin, etc.

[1057] In some embodiments, the antibody-drug conjugate consists of antibody-linker-drug, wherein the drug is selected from camptothecin (CPT) and its derivatives.

[1058] In some embodiments, the antibody-drug conjugate consists of antibody-linker-drug, wherein the drug is selected from topoisomerase I inhibitors.

[1059] In some embodiments, the antibody-drug conjugate consists of antibody-linker-drug, wherein the drug is selected from: SN-38, DXd.

[1060] In some embodiments, in the antibody-drug conjugate, D is a drug unit having Formula II:

[1061]

[1062] in,

[1063] R1 is H or F,

[1064] R2 is H or methyl;

[1065] Or R1 and R2 together with the carbon atom to which they are attached form

[1066] R3 is H;

[1067] R4 is selected from H, -(C1-C4 alkyl)-OH, -(C1-C4 alkenyl)-OH, -(C1-C4 alkyl)-NH2, or -(C1-C4 alkenyl)-NH2;

[1068] wherein L is linked via the hydroxyl or amine group present on D.

[1069] In some embodiments, L of the antibody-drug conjugate is selected from:

[1070]

[1071] Wherein, position 1 is connected to Ab, position 2 is connected to D; AA1 is as defined above.

[1072] It should also be noted that those skilled in the art will understand that L is linked to the sulfhydryl group contained in Ab (e.g., an antibody) after disulfide bond opening (e.g., reduction of disulfide bonds by the reducing agent TCEP can open disulfide bonds to form sulfhydryl groups -SH). In other words, the -S- between L and Ab is not a separate external sulfur atom. For example, in , the -S- is not a separate external sulfur atom, but rather the -S- formed by the sulfhydryl group contained in Tb after disulfide bond opening connecting with L.

[1073] In some preferred embodiments, the antibody-drug conjugate is selected from:

[1074]

[1075]

[1076]

[1077] wherein Ab is the B7H3 antibody 1D1-01 or 2E3-02, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, and q is preferably 1, 2, 3, 4, 5, 6, 7, or 8.

[1078] In a fifteenth aspect of the present disclosure, the present disclosure provides a ligand-drug conjugate comprising the aforementioned ligand-drug conjugate or the aforementioned antibody-drug conjugate, wherein the ligand-drug conjugate has two or more q values, and the antibody-drug conjugate has two or more n values. The ligand-drug conjugate is a ligand-drug conjugate or antibody-drug conjugate (ADC) comprising a heterogeneous DAR distribution.

[1079] In some embodiments, when the ligand drug conjugates having one q value or n value account for the majority, the q value or n value is close to the DAR.

[1080] In some embodiments, the drug to antibody ratio (DAR) in the ligand drug conjugate is an integer or decimal selected from 1-10.

[1081] In some embodiments, the drug to antibody ratio (DAR) in the ligand drug conjugate is selected from the group consisting of 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.2, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.7, 8.9, and 9.

[1082] In some embodiments, the LDC ADC comprises ADCs having a distribution of DARs of 1 to 8, for example, 1.5, 2, 4, 6, and 8 (i.e., 1.5, 2, 4, 6, and 8 drug loading species). Of note, degradation products may be produced such that the LDC may also contain DARs of 1, 3, 5, and 7. Furthermore, the ADCs in the LDC may also have a DAR greater than 8. The LDC is produced by reducing interchain disulfides followed by conjugation. In some embodiments, the LDC comprises both: a LDC having a DAR of 4 or less (i.e., a drug loading species of 4 or less) and a LDC having a DAR of 6 or greater (i.e., a drug loading species of 6 or greater).

[1083] In another aspect, the present disclosure provides a use of an antibody or antigen-binding fragment thereof in preparing a kit for detecting the presence or level of B7H3 in a sample. In another aspect, the present disclosure provides a diagnostic or therapeutic kit comprising one or more of the following: an antibody or antigen-binding fragment thereof, a nucleic acid, a vector, a host cell, a multispecific antibody, a conjugate, or a pharmaceutical composition described herein. Optionally, the diagnostic or therapeutic kit also includes instructions for use.

[1084] In the sixteenth aspect of the present disclosure, the present disclosure provides a pharmaceutical composition comprising substance A, and optionally one or more pharmaceutical excipients; the substance A is the aforementioned ligand-drug conjugate, or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or the aforementioned antibody or antigen-binding fragment thereof, nucleic acid molecule, vector, host cell, multispecific antibody, and / or ligand-drug conjugate, conjugate, or the aforementioned antibody-drug conjugate, or the aforementioned compound, or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The substance A may be in a therapeutically effective amount.

[1085] In certain embodiments, the pharmaceutical compositions of the present disclosure comprise the antibodies or antigen-binding fragments thereof of the present disclosure, and a pharmaceutically acceptable carrier and / or excipient.

[1086] In certain embodiments, the pharmaceutical composition of the present disclosure comprises the host cell of the present disclosure, and a pharmaceutically acceptable carrier and / or excipient, wherein the host cell comprises the isolated nucleic acid molecule or vector as described above.

[1087] In certain embodiments, the pharmaceutical compositions of the present disclosure comprise the multispecific antibodies of the present disclosure, and a pharmaceutically acceptable carrier and / or excipient.

[1088] In certain embodiments, pharmaceutical compositions of the present disclosure comprise a conjugate of the present disclosure and a pharmaceutically acceptable carrier and / or excipient.

[1089] In a seventeenth aspect of the present disclosure, the present disclosure provides the use of the aforementioned substance A or the aforementioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing a disease associated with abnormal cell activity (e.g., a cancer disease). The substance A or the aforementioned pharmaceutical composition may be in a therapeutically effective amount.

[1090] In some embodiments, provided are uses of the antibodies or antigen-binding fragments thereof, nucleic acids, vectors, host cells, antibody-drug conjugates, or multispecific antibodies of the present disclosure in the preparation of drugs for modulating (inhibiting or blocking) the activity of B7H3.

[1091] In some embodiments, provided are uses of the antibodies or antigen-binding fragments thereof, nucleic acids, vectors, host cells, antibody-drug conjugates, or multispecific antibodies of the present disclosure in the preparation of medicaments for treating or preventing diseases associated with the activity of B7H3.

[1092] In some embodiments, provided are uses of the antibodies or antigen-binding fragments thereof, nucleic acids, vectors, host cells, antibody-drug conjugates, or multispecific antibodies of the present disclosure in the preparation of medicaments for treating or preventing tumors associated with B7H3 activity.

[1093] In some embodiments, the cancer disease is selected from esophageal cancer (e.g., esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, or lung adenocarcinoma), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer (e.g., human colon adenocarcinoma), rectal cancer, colorectal cancer, liver cancer, kidney cancer, urothelial carcinoma, epidermal cancer, non-Hodgkin's lymphoma, central nervous system tumor (e.g., glioma, glioblastoma multiforme, glioma, or sarcoma), prostate cancer, or thyroid cancer.

[1094] In some embodiments, the cancer disease is a cancer disease associated with Trop-2, Her 2, B7H3, Her 3, or EGFR. In some embodiments, the cancer disease is a cancer disease associated with Trop-2 or Her 2.

[1095] In some embodiments, the cancer disease is a cancer disease associated with Trop-2.

[1096] In some embodiments, the cancer disease is a Her 3-associated cancer disease.

[1097] In some embodiments, the cancer disease is a cancer disease associated with EGFR.

[1098] In some embodiments, the cancer disease is a B7H3-associated cancer disease.

[1099] In some embodiments, the cancer disease is a solid tumor.

[1100] In some embodiments, the cancer disease is breast cancer or lung cancer (preferably non-small cell lung cancer).

[1101] In the seventeenth aspect of the present disclosure, the present disclosure provides the aforementioned substance A or the aforementioned pharmaceutical composition, which is used to treat and / or prevent diseases associated with abnormal cell activity (such as cancer diseases).

[1102] In some embodiments, the cancer disease is selected from esophageal cancer (e.g., esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, or lung adenocarcinoma), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer (e.g., human colon adenocarcinoma), rectal cancer, colorectal cancer, liver cancer, kidney cancer, urothelial carcinoma, epidermal cancer, non-Hodgkin's lymphoma, central nervous system tumor (e.g., glioma, glioblastoma multiforme, glioma, or sarcoma), prostate cancer, or thyroid cancer.

[1103] In some embodiments, the cancer disease is a cancer disease associated with Trop-2, Her 2, B7H3, Her 3, or EGFR. In some embodiments, the cancer disease is a cancer disease associated with Trop-2 or Her 2.

[1104] In some embodiments, the cancer disease is a cancer disease associated with Trop-2.

[1105] In some embodiments, the cancer disease is a Her 3-associated cancer disease.

[1106] In some embodiments, the cancer disease is a cancer disease associated with EGFR.

[1107] In some embodiments, the cancer disease is a B7H3-associated cancer disease.

[1108] In some embodiments, the cancer disease is a solid tumor.In some embodiments, the cancer disease is breast cancer or lung cancer (preferably non-small cell lung cancer).

[1109] In the eighteenth aspect of the present disclosure, the present disclosure provides a method for preventing and / or treating diseases associated with abnormal cell activity (such as cancer diseases), which comprises: administering a preventive and / or therapeutically effective amount of the aforementioned substance A, or the aforementioned pharmaceutical composition, to an individual in need.

[1110] In some embodiments, the cancer disease is selected from esophageal cancer (e.g., esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, or lung adenocarcinoma), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer (e.g., human colon adenocarcinoma), rectal cancer, colorectal cancer, liver cancer, kidney cancer, urothelial carcinoma, epidermal cancer, non-Hodgkin's lymphoma, central nervous system tumor (e.g., glioma, glioblastoma multiforme, glioma, or sarcoma), prostate cancer, or thyroid cancer.

[1111] In some embodiments, the cancer disease is a cancer disease associated with Trop-2, Her 2, B7H3, Her 3, or EGFR.

[1112] In some embodiments, the cancer disease is a cancer disease associated with Trop-2 or Her 2.

[1113] In some embodiments, the cancer disease is a cancer disease associated with Trop-2.

[1114] In some embodiments, the cancer disease is a Her 3-associated cancer disease.

[1115] In some embodiments, the cancer disease is a cancer disease associated with EGFR.

[1116] In some embodiments, the cancer disease is a B7H3-associated cancer disease.

[1117] In some embodiments, the cancer disease is a solid tumor.

[1118] In some embodiments, the cancer disease is breast cancer or lung cancer (preferably non-small cell lung cancer).

[1119] In another aspect, the present disclosure provides the following embodiments:

[1120] 1. A ligand-drug conjugate of formula XV,

[1121]

[1122] or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

[1123] in:

[1124] Tb is a ligand or targeting moiety that binds to the target;

[1125] q is the drug-ligand coupling ratio;

[1126] D is a bioactive molecular fragment;

[1127] L1 is the extension unit;

[1128] L2 does not exist or is a connecting unit;

[1129] L3 is selected from an amino acid residue or a short peptide consisting of 2-10 amino acid residues;

[1130] L4 is absent or present. When L4 is present, L4 is selected from Bit 1 is connected to L3 and bit 2 is connected to D.

[1131] 2. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to embodiment 1, characterized in that it satisfies one or more of the following conditions:

[1132] (1) Tb is an antibody or an antigen-binding fragment thereof;

[1133] (2) q is selected from any value between 0.1 and 16.0;

[1134] (3) D is a molecular fragment with anti-tumor biological activity;

[1135] (4) L1 is selected from:

[1136]

[1137]

[1138]

[1139] Each Z is independently selected from a direct bond, a carbon-carbon triple bond, a carbon-carbon double bond, a C6-10 aryl group, a 5-10 membered heteroaryl group, an amide group, a sulfonamide group, an imine group, and CF2;

[1140] Rx and Ry are each independently selected from H and C1-4 alkyl;

[1141] Each m is independently selected from 0, 1, 2, 3, 4, 5 and 6;

[1142] y1, y2, y3 and y4 are each independently selected from any integer between 0 and 20;

[1143] Position 1 is connected to Tb via an S atom, and position 2 is connected to L2 or L3;

[1144] (5) L2 is absent or present. When L2 is present, L2 is selected from:

[1145]

[1146]

[1147] y1, y2, y3 and y4 are each independently selected from any integer between 0 and 20, y1 is connected to L1, and y2 is connected to L3;

[1148] (6) L3 is selected from amino acid residues or short peptides consisting of 2-10 amino acid residues; the amino acid residues are selected from natural amino acid residues, non-natural amino acid residues, or AA 1the indicated amino acid residue or its stereoisomers;

[1149] AA 1 The structures of the indicated amino acid residues are shown below,

[1150]

[1151] Where: R a 、R b Each independently selected from H, And R a 、R b Not at the same time H;

[1152] Or, R a With R b Together with the carbon atoms to which they are attached, they form a 4-10 membered heterocyclic ring, which is optionally substituted by one or more R 0 replaced by;

[1153] r、r 1 are each independently selected from any integer from 0 to 20;

[1154] R m1 、R n1 Each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl and -COOR x1 ;

[1155] R x1 Selected from C1-6 alkyl;

[1156] Or, R m1 With R n1 Together with the nitrogen atom to which they are attached, they form a 4-10 membered heterocyclic ring, which is optionally substituted by one or more R 0’ replaced by;

[1157] R z Selected from C1-6 alkyl;

[1158] R 0 、R 0’ Each independently selected from C1-6 alkyl, C3-6 cycloalkyl, -NR m2 R n2 and a 4-10 membered heterocyclic group optionally substituted by a C1-6 alkyl group;

[1159] R m2 、R n2 Each independently selected from H and C1-6 alkyl;

[1160] (7) L4 is absent or present. When L4 is present, L4 is selected from

[1161] Bit 1 is connected to L3 and bit 2 is connected to D.

[1162] 3. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to embodiment 2, characterized in that it satisfies one or more of the following conditions:

[1163] (1) Tb is an antibody or an antigen-binding fragment thereof that satisfies one or more of the following conditions:

[1164] (i) the antibody or antigen-binding fragment thereof includes Fab, Fab', F(ab')2, Fd, Fv, dAb, complementarity determining region fragment, non-human antibody, humanized antibody, chimeric antibody, fully human antibody, pro-antibody, monoclonal antibody, bispecific antibody or multispecific antibody;

[1165] (ii) Tb is a monoclonal antibody or an antigen-binding fragment thereof;

[1166] (iii) Tb is an antibody or antigen-binding fragment thereof that undergoes endocytosis, does not undergo endocytosis, or undergoes weak endocytosis;

[1167] (iv) Tb is an antibody or antigen-binding fragment thereof that has the activity of binding to free antigens in tumor tissue and / or antigens on the surface of tumor cells;

[1168] (v) Tb is an antibody or antigen-binding fragment thereof that does not have the activity of binding to free antigens in tumor tissue and / or antigens on the surface of tumor cells;

[1169] (2) q is selected from 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and any value therebetween;

[1170] (3) In the bioactive molecule fragment, the bioactive molecule is a DNA topoisomerase inhibitor or a microtubule inhibitor;

[1171] (4) L1 is selected from Each Z is independently selected from a direct bond, a carbon-carbon triple bond, a carbon-carbon double bond, a C6-10 aryl group, a 5-10 membered heteroaryl group, and an amide group; Rx and Ry are each independently selected from H and a C1-4 alkyl group; each m is independently selected from 0, 1, 2, 3, 4, 5, and 6; y1 is selected from any integer between 1 and 6; each y2 is independently selected from any integer between 0 and 15; each y3 is independently selected from 1, 2, and 3; each y4 is independently selected from 0 and 1; position 1 is connected to Tb through an S atom, and position 2 is connected to L2 or L3;

[1172] (5) L2 is absent or present. When L2 is present, L2 is selected from

[1173] y1 is selected from any integer between 1 and 6, each y2 is independently selected from any integer between 0 and 10, each y3 is independently selected from 1 and 2, each y4 is independently selected from 0 and 1, position 1 is connected to L1, and position 2 is connected to L3;

[1174] (6) L3 is selected from the group consisting of amino acid residues Val, D-Val, Cit, Phe, Lys, Lys(Ac), Leu, Gly, Ala, Asn, Asp, Arg, and AA 1 or 2-10 selected from Val, Cit, Phe, Lys, D-Val, Leu, Gly, Ala, Asn, Asp and AA 1 A short peptide composed of amino acid residues;

[1175] (7)AA 1 Among the amino acid residues, R a 、R b Among them, any one is H, and the other is selected from

[1176] Or, AA 1 Among the amino acid residues, R a With R b Together with the carbon atoms they are connected to, they form the 0 substituted 5-6 membered heterocycle;

[1177] (8)AA 1 Among the amino acid residues, r, r 1 Each independently selected from 0, 1, 2, 3, 4 and 5;

[1178] (9)AA 1 Among the amino acid residues, R m1 、R n1 Each is independently selected from H, methyl, ethyl, n-propyl, n-butyl, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH(CH3)2, -COOC(CH3)3 and -COOCH2CH2CH2CH3; or, R m1 With R n1 Together with the nitrogen atoms they are connected to, they form the 0’ substituted 5-6 membered heterocycle;

[1179] (10)AA 1 Among the amino acid residues, R z is methyl;

[1180] (11)AA 1 Among the amino acid residues, R 0 、R 0’ Each independently selected from C1-6 alkyl, -NR m2 R n2 and a 5-6 membered heterocyclic group optionally substituted by a C1-6 alkyl group;

[1181] (12) L4 is absent or present. When L4 is present, L4 is selected from Bit 1 is connected to L3 and bit 2 is connected to D.

[1182] 4. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to embodiment 3, characterized in that it satisfies one or more of the following conditions:

[1183] (1) Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, an anti-Trop-2 antibody or an antigen-binding fragment thereof, an anti-Her2 antibody or an antigen-binding fragment thereof, an anti-Her3 antibody or an antigen-binding fragment thereof, an anti-EGFR antibody or an antigen-binding fragment thereof, or an IgG1 isotype antibody anti-chicken lysozyme antibody;

[1184] (2) q is selected from any value between 0.1, 1, 2, 3, 4, 5, 6, 7, 8 and so on;

[1185] (3) When the bioactive molecule in the bioactive molecule fragment is a DNA topoisomerase inhibitor, the DNA topoisomerase inhibitor is a camptothecin bioactive molecule;

[1186] (4) When the bioactive molecule in the bioactive molecule fragment is a tubulin inhibitor, the tubulin inhibitor is an MMAF type tubulin inhibitor or an MMAE type tubulin inhibitor;

[1187] (5) In L1, each Z is independently selected from a direct bond, a carbon-carbon triple bond, and a carbon-carbon double bond;

[1188] (6) In L1, y1 is 4, 5, or 6;

[1189] (7) In L1, each y2 is independently selected from any integer between 6 and 10;

[1190] (8) L2 is absent or present. When L2 is present, L2 is selected from Bit 1 is connected to L1, bit 2 is connected to L3;

[1191] (9) L3 is selected from Val, Cit, Phe, Lys, D-Val, Leu, Gly, Ala, Asn, AA 1 , Val-Cit, Cit-Val, Cit-Ala, Val-Ala, Lys-Val, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Ala-Ala, Val-AA 1 、Ala-AA 1 、Gly-AA 1 AA 1 -Gly, Ala-Ala-Ala, Ala-Ala-Asn, Ala-Ala-Asp, Val-AA 1 -Gly, Ala-AA 1 -Gly, Gly-AA 1 -Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Gly-Phe-Gly, Gly-Gly-Phe-Gly, D-Val-Leu-Lys, Gl y-Gly-Arg, Ala-Ala-Asn, Gly-Gly-Phe, Val-Lys-Gly, Val-Lys-Gly-Gly, Val-Lys and Lys-Ala-Asn;

[1192] (10)AA 1 Among the amino acid residues shown, R a 、R b Among them, any one is H, and the other is selected from or, R a With R b Together with the carbon atoms they are connected to, they form the 0 The substituted 5-6 membered heterocyclic ring is R 0 a substituted piperidine ring or piperazine ring;

[1193] (11)AA 1 Among the amino acid residues, r, r 1 Each independently selected from 0 and 4;

[1194] (12)AA 1 Among the amino acid residues, R m1 、R n1 are each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl and tert-butyloxycarbonyl; or, R m1 With R n1 Together with the nitrogen atoms they are connected to, they form the 0’ a substituted piperidine ring or piperazine ring;

[1195] (13)AA1 Among the amino acid residues, R 0 is selected from C1-6 alkyl and a 5-6 membered heterocyclic group substituted by a C1-6 alkyl, wherein the 5-6 membered heterocyclic group is selected from piperidinyl and piperazinyl;

[1196] (14)AA 1 Among the amino acid residues, R 0’ Selected from C1-6 alkyl and -NR m2 R n2 ;

[1197] (15)AA 1 Among the amino acid residues, R m2 、R n2 is methyl;

[1198] (16) L4 does not exist or exists. When L4 exists, L4 is Bit 1 is connected to L3 and bit 2 is connected to D.

[1199] 5. The ligand drug conjugate or a stereoisomer of the ligand drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 1 to 4, characterized in that it satisfies one or more of the following conditions:

[1200] (1) q is selected from any value among 2, 3, 4, 5, 6, 7, 8 and so on;

[1201] (2) Tb is any of the following:

[1202] (i) Tb is an anti-Her 2 antibody or an antigen-binding fragment thereof, wherein the anti-Her 2 antibody is anbenitamab, coprelotamab, disitamab, gancotamab, margetuximab, pertuzumab, timigutuzumab, zanidatamab, trastuzumab, pertuzumab or an antigen-binding fragment thereof;

[1203] (ii) Tb is an anti-Trop-2 antibody or an antigen-binding fragment thereof, wherein the anti-Trop-2 antibody is datopotamab, Sacituzumab or an antigen-binding fragment thereof; or

[1204] (iii) Tb is an anti-EGFR antibody or an antigen-binding fragment thereof, wherein the anti-EGFR antibody is demupitamab, depatuxizumab, futuximab, imgatuzumab, laprituximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, serclutamab, tomozutuximab, zalutumumab, cetuximab, or an antigen-binding fragment thereof; or

[1205] (iv) Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, wherein the anti-B7H3 antibody is enoblituzumab, mirzotamab, omburtamab, 1D1-01, 2E3-02 antibody or an antigen-binding fragment thereof; or

[1206] (v) Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, wherein the anti-B7H3 antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs), wherein the CDRs are defined according to the Kabat numbering system:

[1207] (a) HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9; and / or,

[1208] LCDR1 with the sequence of SEQ ID NO: 17, LCDR2 with the sequence of SEQ ID NO: 18, and LCDR3 with the sequence of SEQ ID NO: 19;

[1209] (b) HCDR1 of SEQ ID NO: 27, HCDR2 of SEQ ID NO: 28, and HCDR3 of SEQ ID NO: 29; and / or,

[1210] LCDR1 with the sequence of SEQ ID NO: 37, LCDR2 with the sequence of SEQ ID NO: 38, and LCDR3 with the sequence of SEQ ID NO: 39;

[1211] (c) HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9; and / or,

[1212] LCDR1 with the sequence of SEQ ID NO: 37, LCDR2 with the sequence of SEQ ID NO: 38, and LCDR3 with the sequence of SEQ ID NO: 39;

[1213] or (d) HCDR1 of SEQ ID NO: 27, HCDR2 of SEQ ID NO: 28, and HCDR3 of SEQ ID NO: 29; and / or,

[1214] LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19; or

[1215] (vi) Tb is an anti-Her3 antibody or an antigen-binding fragment thereof, wherein the anti-Her3 antibody is barecetamab, duligotuzumab, elgemtumab, lumretuzumab, patritumab, seribantumab, 202-2-1 or an antigen-binding fragment thereof; or

[1216] (vii) Tb is an anti-Her3 antibody or an antigen-binding fragment thereof, wherein the anti-Her3 antibody or the antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs), wherein the CDRs are defined according to the Kabat numbering system:

[1217] HCDR1 of SEQ ID NO: 53, HCDR2 of SEQ ID NO: 54, HCDR3 of SEQ ID NO: 55; and / or,

[1218] LCDR1 with the sequence of SEQ ID NO: 59, LCDR2 with the sequence of SEQ ID NO: 60, and LCDR3 with the sequence of SEQ ID NO: 21;

[1219] (viii) antibodies or antigen-binding fragments thereof that have tumor cell endocytosis activity and binding activity to free antigens in tumor tissues and / or tumor cell surface antigens;

[1220] (ix) antibodies or antigen-binding fragments thereof that have weak or no tumor cell endocytosis activity and that have binding activity to free antigens in tumor tissue and / or tumor cell surface antigens;

[1221] (x) An antibody or antigen-binding fragment thereof that has weak or no endocytic activity in tumor cells and no binding activity to free antigens in tumor tissue or antigens on the surface of tumor cells; for example, Tb is an anti-chicken lysozyme human IgG1 isotype antibody

[1222] (xi) antibodies or antigen-binding fragments thereof that bind to non-endocytosed antigens; for example, ALCAM / CD166;

[1223] (3) L1 is selected from m is selected from 2, 3 and 4, y1 is selected from any integer between 1 and 6, each y2 is independently selected from any integer between 0 and 10, each y3 is independently selected from 1 or 2, position 1 is connected to Tb through an S atom, and position 2 is connected to L2 or L3;

[1224] (4) L2 is absent or present. When L2 is present, L2 is selected from Bit 1 is connected to L1, bit 2 is connected to L3;

[1225] (5) L3 is selected from AA 1 AA 1 -Gly, Val-Cit, Val-AA 1 -Gly, AA 1 -Ala-Asn and Gly-Gly-Phe-Gly;

[1226] (6)AA 1 Among the amino acid residues shown, R a With R b Together with the carbon atoms they are connected to, they form the 0 The substituted 5-6 membered heterocyclic ring is R 0 substituted piperidine ring;

[1227] (7)AA 1 Among the amino acid residues, r, r 1 In the equation, either one is 0 and the other is 4;

[1228] (8)AA 1 Among the amino acid residues, R m1 、R n1 are each independently selected from H and C1-6 alkyl; or, R m1 With R n1 Together with the nitrogen atoms they are connected to, they form the 0’ substituted piperidine ring;

[1229] (10)AA 1 Among the amino acid residues, R 0 is selected from methyl, ethyl and a 5-6 membered heterocyclic group substituted by a methyl group, wherein the 5-6 membered heterocyclic group is a piperidinyl group;

[1230] (11)AA 1 Among the amino acid residues, R 0’ Selected from methyl and -NRm2 R n2 ;

[1231] (12) When the bioactive molecule in the bioactive molecule fragment is a DNA topoisomerase inhibitor and the DNA topoisomerase inhibitor is a camptothecin bioactive molecule, the camptothecin bioactive molecule is camptothecin, DXD, camptothecin with modified substituents, or DXD with modified substituents.

[1232] 6. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 1-4, characterized in that it satisfies one or more of the following conditions:

[1233] (1) q is selected from any value among 3, 4, 5, 6, 7, 8 and so on;

[1234] (2) Tb is any of the following:

[1235] (vi) Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, wherein the anti-B7H3 antibody or the antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs), wherein the CDRs are defined according to the Kabat numbering system:

[1236] (a) HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9; and / or,

[1237] LCDR1 with the sequence of SEQ ID NO: 17, LCDR2 with the sequence of SEQ ID NO: 18, and LCDR3 with the sequence of SEQ ID NO: 19;

[1238] (b) HCDR1 of SEQ ID NO: 27, HCDR2 of SEQ ID NO: 28, and HCDR3 of SEQ ID NO: 29; and / or,

[1239] LCDR1 with the sequence of SEQ ID NO: 37, LCDR2 with the sequence of SEQ ID NO: 38, and LCDR3 with the sequence of SEQ ID NO: 39;

[1240] (c) HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9; and / or,

[1241] LCDR1 with the sequence of SEQ ID NO: 37, LCDR2 with the sequence of SEQ ID NO: 38, and LCDR3 with the sequence of SEQ ID NO: 39;

[1242] or (d) HCDR1 of SEQ ID NO: 27, HCDR2 of SEQ ID NO: 28, and HCDR3 of SEQ ID NO: 29; and / or,

[1243] LCDR1 with the sequence of SEQ ID NO: 17, LCDR2 with the sequence of SEQ ID NO: 18, and LCDR3 with the sequence of SEQ ID NO: 19;

[1244] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a VH comprising a set of heavy chain CDRs in (a)-(d) above and a VL comprising a set of light chain CDRs in (a)-(d);

[1245] (ii) Tb is an anti-Her3 antibody or an antigen-binding fragment thereof,

[1246] The anti-Her3 antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs), wherein the CDRs are defined according to the Kabat numbering system:

[1247] HCDR1 of SEQ ID NO: 53, HCDR2 of SEQ ID NO: 54, HCDR3 of SEQ ID NO: 55; and / or,

[1248] LCDR1 with the sequence of SEQ ID NO: 59, LCDR2 with the sequence of SEQ ID NO: 60, and LCDR3 with the sequence of SEQ ID NO: 21;

[1249] The anti-Her3 antibody or antigen-binding fragment thereof comprises a VH comprising the above set of heavy chain CDRs and a VL comprising the above set of light chain CDRs;

[1250] (3) L1 is selected from Position 1 is connected to Tb via an S atom, and position 2 is connected to L2 or L3;

[1251] (4) L2 is absent or present. When L2 is present, L2 is selected from Bit 1 is connected to L1, bit 2 is connected to L3;

[1252] (5) L3 is selected from AA 1 、Val-AA 1 -Gly;

[1253] (6)AA 1 Among the amino acid residues, R 0 Selected from methyl, ethyl and

[1254] 7. The ligand drug conjugate or a stereoisomer of the ligand drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 1 to 4, characterized in that it satisfies one or more of the following conditions:

[1255] (1) q is selected from any value among 4, 5, 6, 7, 8 and so on;

[1256] (2) Tb is any of the following:

[1257] (i) Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, wherein the anti-B7H3 antibody or the antigen-binding fragment thereof comprises: a VH as shown in SEQ ID NO: 3 or 23, and / or a VL as shown in SEQ ID NO: 13 or 33;

[1258] (ii) Tb is an anti-Her3 antibody or an antigen-binding fragment thereof, wherein the anti-Her3 antibody or the antigen-binding fragment thereof comprises: VH shown in SEQ ID NO: 49, and / or VL shown in SEQ ID NO: 50;

[1259] (3) L1 is selected from Position 1 is connected to Tb via an S atom, and position 2 is connected to L2 or L3;

[1260] (4) L2 does not exist or

[1261] (5) L3 is selected from Val-AA 1 -Gly;

[1262] (6)AA 1 Among the amino acid residues shown, R a With R b Together with the carbon atoms they are connected to, they form Carbon atom No. 1 is R a and R b Commonly linked carbon atoms;

[1263] (7)r、r 1 In the example, r is 4, r 1 When R is 0, m1 、R n1 Each independently selected from H and C1-6 alkyl; r is 0, r1 When R is 4, m1 、R n1 Each independently selected from C1-6 alkyl, or, R m1 With R n1 Together with the nitrogen atoms they are connected to, they form Carbon atom No. 1 is R a and R b carbon atoms that are linked together.

[1264] 8. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to embodiment 7, characterized in that:

[1265] (1) q is selected from any value among 6, 7, 8 and 10;

[1266] (2) Tb is any of the following:

[1267] (i) Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, wherein the anti-B7H3 antibody or the antigen-binding fragment thereof comprises: a VH as shown in SEQ ID NO: 3 or 23, and / or a VL as shown in SEQ ID NO: 13 or 33;

[1268] Further including:

[1269] (a) a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof; and / or

[1270] (b) a light chain constant region (CL) of a human immunoglobulin or a variant thereof,

[1271] (ii) Tb is an anti-Her3 antibody or an antigen-binding fragment thereof, wherein the anti-Her3 antibody or the antigen-binding fragment thereof comprises: VH shown in SEQ ID NO: 49, and / or VL shown in SEQ ID NO: 50;

[1272] Further including:

[1273] (a) a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof; and / or

[1274] (b) a light chain constant region (CL) of a human immunoglobulin or a variant thereof;

[1275] (3)r、r 1 In the example, r is 4, r 1 When R is 0, m1 、R n1 Each independently selected from H and C1-6 alkyl; r is 0, r 1 When R is 4, m1、R n1 Each independently selected from C2-6 alkyl;

[1276] (4) L1 is selected from Position 1 is connected to Tb via an S atom, and position 2 is connected to L2 or L3; for example, L1 is selected from Position 1 is connected to Tb via an S atom, and position 2 is connected to L2 or L3.

[1277] 9. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to embodiment 8, characterized in that:

[1278] (1) Tb is any of the following:

[1279] (i) Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, wherein the anti-B7H3 antibody or the antigen-binding fragment thereof comprises:

[1280] VH shown in SEQ ID NO: 3, CH shown in SEQ ID NO: 43 or a variant thereof, and / or VL shown in SEQ ID NO: 13, CL shown in SEQ ID NO: 44 or a variant thereof;

[1281] VH shown in SEQ ID NO: 23, CH shown in SEQ ID NO: 43 or a variant thereof, and / or VL shown in SEQ ID NO: 33, CL shown in SEQ ID NO: 44 or a variant thereof;

[1282] Preferably, the B7H3 antibody or antigen-binding fragment thereof comprises:

[1283] The heavy chain shown in SEQ ID NO:45, and / or the light chain shown in SEQ ID NO:46;

[1284] The heavy chain shown in SEQ ID NO:47, and / or the light chain shown in SEQ ID NO:48;

[1285] (ii) Tb is an anti-Her3 antibody or an antigen-binding fragment thereof, wherein the anti-Her3 antibody or the antigen-binding fragment thereof comprises:

[1286] VH shown in SEQ ID NO:49, CH shown in SEQ ID NO:43 or a variant thereof, and / or VL shown in SEQ ID NO:50, CL shown in SEQ ID NO:44 or a variant thereof;

[1287] Preferably, the anti-Her3 antibody or antigen-binding fragment thereof comprises:

[1288] The heavy chain shown in SEQ ID NO:51, and / or the light chain shown in SEQ ID NO:52;

[1289] (2)R m1 、R n1 Each is independently selected from C1-6 alkyl, wherein the C1-6 alkyl is selected from methyl, ethyl and n-propyl; or R m1 、R n1 Each is independently selected from C2-6 alkyl, wherein the C2-6 alkyl is selected from ethyl and n-propyl.

[1290] 10. The ligand drug conjugate or a stereoisomer of the ligand drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 1 to 9, characterized in that it satisfies one or more of the following conditions:

[1291] (1) When Tb is an antibody or an antigen-binding fragment thereof, and the antibody or antigen-binding fragment thereof comprises a single-chain antibody, the single-chain antibody is scFv;

[1292] (2) Tb is an antibody or antigen-binding fragment thereof with endocytic activity;

[1293] (3)AA 1 The amino acid residues shown are selected from

[1294] Preferably, AA 1 The amino acid residues shown are selected from

[1295] More preferably, AA 1 The amino acid residues shown are selected from

[1296] Most preferably, AA 1 The amino acid residues shown are selected from

[1297] 11. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 1 to 10, characterized in that:

[1298] L3 is selected from

[1299]

[1300] X - Selected from halogen ions, carboxylate ions, sulfate ions, hydrogen sulfate ions and OH - , bit 1 is connected to L1 or L2, bit 2 is connected to L4 or D;

[1301] Preferably, L3 is selected from

[1302]

[1303] X - Selected from halogen ions, carboxylate ions, sulfate ions, hydrogen sulfate ions and OH - , bit 1 is connected to L1 or L2, bit 2 is connected to L4 or D;

[1304] More preferably, L3 is selected from X - Selected from halogen ions, carboxylate ions, sulfate ions, hydrogen sulfate ions and OH - , bit 1 is connected to L1 or L2, bit 2 is connected to L4 or D;

[1305] Also preferably, L3 is selected from Position 1 is connected to L1 or L2, and position 2 is connected to L4 or D;

[1306] Most preferably, L3 is selected from Position 1 is connected to L1 or L2, and position 2 is connected to L4 or D;

[1307] For example The structure is selected from the following structural fragments:

[1308]

[1309] 12. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 1 to 11, characterized in that:

[1310] in The structure is selected from the following:

[1311]

[1312]

[1313]

[1314]

[1315] Among them, bit 1 is connected to Tb and bit 2 is connected to D.

[1316] 13. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 1 to 12, characterized in that:

[1317] Wherein, the ligand-drug conjugate has a structure as shown in Formula I:

[1318]

[1319] wherein: Tb, L1, L2, L3, L4 and q are as defined in any one of embodiments 1-12;

[1320] R1 and R2 are each independently selected from H, halogen, -OH, optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy, or,

[1321] R1 and R2 together with the carbon atoms to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring, wherein the heterocyclic ring contains one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof;

[1322] R3 is selected from H, halogen, -OH, -NH2, optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy, or,

[1323] R3 and X together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring containing one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof, or

[1324] R3 and R2 together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring, wherein the heterocyclic ring contains one or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof;

[1325] W is absent or present. When W is present, W is selected from -O-, -S-, -NR4-, Bit 1 is connected to X, bit 2 is connected to L4 or L3;

[1326] X is selected from a direct bond, an optionally substituted -O-(CH2) n3 -、-NR4-(CH2) n3 -、-S-(CH2) n3 -, carbonyl-(CH2)n3 -, -SO2-(CH2) n3 -、-(CH2) n1 -、 C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, the 1 position is connected to the parent ring, and the 2 position is connected to W or L4; the substituent is selected from one or more C1-4 alkyl, C3-6 cycloalkyl, or multiple C1-4 alkyl groups and the carbon atoms to which they are simultaneously connected together form a C3-6 cycloalkyl;

[1327] Each M is independently selected from a direct bond and -CR 5a R 5b -;

[1328] R4, R5, R 5a 、R 5b , R6, R7 are each independently selected from H, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy and optionally substituted C3-6 cycloalkyl;

[1329] n, n', n1, n2, n3 are each independently selected from any integer between 0 and 6;

[1330] Position 1 is connected to the camptothecin nucleus, and position 2 is connected to W or L4.

[1331] 14. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to embodiment 13, characterized in that it satisfies one or more of the following conditions:

[1332] (1) R1 and R2 are each independently selected from H, halogen, or C1-4 alkyl; or, R1 and R2, together with the carbon atom to which they are attached, form a 5-6 membered heterocyclic ring containing 1, 2, or 3 O, S, or N atoms or any combination thereof;

[1333] (2) R3 is selected from H, C1-4 alkyl; or, R3 and X together with the carbon atom to which they are attached form a 5-6 membered carbocyclic ring;

[1334] (3) W is absent or present. When W is present, W is selected from -O-, -S-, -NR4-, Bit 1 is connected to X, bit 2 is connected to L4 or L3;

[1335] (4) X is selected from optionally substituted -(CH2) n1 -、 C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group, the 1 position is connected to the parent ring, and the 2 position is connected to W or L4; the substituent is selected from 1 or 2 C1-4 alkyl groups, or 2 C1-4 alkyl groups and the carbon atoms to which they are simultaneously connected together form a C3-6 cycloalkyl group;

[1336] (5) R4 and R5 are each independently selected from H, C1-4 alkyl and C3-6 cycloalkyl;

[1337] (6)R 5a 、R 5b Each independently selected from H and C1-4 alkyl;

[1338] (7) each R7 is independently selected from H and C1-4 alkyl;

[1339] (8) n is selected from 1, 2 and 3;

[1340] (9) n1 is selected from 1, 2, 3 and 4;

[1341] (10) n2 is 1;

[1342] (10)n3 is 0.

[1343] 15. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to embodiment 13 or 14, characterized in that it satisfies one or more of the following conditions:

[1344] (1) R1 is selected from H and halogen, R2 is selected from H and C1-4 alkyl; or, R1 and R2 and the carbon atom to which they are attached form The dotted line indicates the position where the heterocyclic ring is fused to the benzene ring;

[1345] (2) R3 is H; or, R3 and X together with the carbon atom to which they are attached form The dotted lines indicate where the carbon ring is fused to the benzene ring and the pyridine ring;

[1346] (3) W is absent or present. When W is present, W is selected from -O-, -S-, -NR4-, Bit 1 is connected to X, bit 2 is connected to L4 or L3;

[1347] (4) each R4 is independently selected from H, C1-4 alkyl and C3-6 cycloalkyl, and R5 is H;

[1348] (5)R 5a 、R 5b are each independently selected from H and methyl;

[1349] (6) R7 is H;

[1350] (7)n is 1.

[1351] 16. The ligand drug conjugate or a stereoisomer of the ligand drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 13 to 15, characterized in that it satisfies one or more of the following conditions:

[1352] (1) R1 is H or F, R2 is H or methyl; or, R1 and R2 together with the carbon atom to which they are attached form The dotted line indicates the position where the heterocyclic ring is fused to the benzene ring;

[1353] (2) W is selected from -O-, -NR4- and Bit 1 is connected to X, bit 2 is connected to L4 or L3;

[1354] (3) each R4 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, tert-butyl and cyclopropyl, and R5 is H;

[1355] (4) X is selected from optionally substituted Position 1 is connected to the parent ring, and position 2 is connected to W or L4; the substituent is selected from 1 or 2 C1-4 alkyl groups, or 2 C1-4 alkyl groups and the carbon atoms to which they are simultaneously connected form a C3-6 cycloalkyl group; the C1-4 alkyl group is such as methyl; the C3-6 cycloalkyl group is such as cyclopropyl.

[1356] 17. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 13-16, characterized in that:

[1357] (1) W is selected from -O- and -NR4-;

[1358] (2)X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W or L4.

[1359] 18. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 13 to 17, characterized in that:

[1360] When W does not exist, X is selected from 1 is connected to the parent ring, 2 is connected to L4; when W exists, X is selected from Position 1 is connected to the mother ring, and position 2 is connected to W.

[1361] 19. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 13 to 18, characterized in that:

[1362] The structure is selected from the following:

[1363]

[1364]

[1365]

[1366] Among them, bit 1 is connected to L4; when L4 does not exist, bit 1 is connected to L3.

[1367] 20. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 13-19, wherein the ligand-drug conjugate has a structure of Formula I-1, Formula I-2, or Formula I-3:

[1368]

[1369] wherein Tb, L1, L2, L3, L4, X, R1, R2, R3, R4, and q are as defined in any one of Embodiments 13-19;

[1370]

[1371] wherein Tb, L1, L2, L3, L4, X, R1, R2, R3, and q are as defined in any one of Embodiments 13-19;

[1372]

[1373] wherein Tb, L1, L2, L3, L4, X, R1, R2, R3, R4, R5, n, and q are as defined in any one of Embodiments 13-19.

[1374] 21. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 13-20, characterized in that the ligand-drug conjugate has a structure represented by Formula I-1A, Formula I-1B, Formula I-2A, Formula I-2B, Formula I-3A, or Formula I-3B:

[1375]

[1376] wherein Tb, L2, L3, L4, X, R1, R2, R3, R4, and q are as defined in any one of Embodiments 13-19;

[1377]

[1378] wherein Tb, L2, L3, L4, X, R1, R2, R3, and q are as defined in any one of Embodiments 13-19;

[1379]

[1380] wherein Tb, L2, L3, L4, X, R1, R2, R3, R4 and q are as defined in any one of Embodiments 13-19.

[1381] 22. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 13-21, characterized in that the ligand-drug conjugate has a structure of Formula IA or Formula IB:

[1382]

[1383] Among them, Tb, X, R1, R2, R3, R a 、R b and q is as defined in any one of embodiments 13-19;

[1384]

[1385] Among them, Tb, X, R1, R2, R3, R a 、R b and q are as defined in any one of embodiments 13-19.

[1386] 23. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 1 to 22, characterized in that the ligand-drug conjugate is selected from the following:

[1387]

[1388]

[1389]

[1390]

[1391]

[1392]

[1393]

[1394]

[1395]

[1396]

[1397]

[1398]

[1399]

[1400]

[1401]

[1402]

[1403]

[1404]

[1405]

[1406]

[1407] 24. The ligand-drug conjugate or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 1 to 23, characterized in that the ligand-drug conjugate is selected from:

[1408]

[1409]

[1410]

[1411] wherein Tb1 is an anti-B7H3 antibody or an antigen-binding fragment thereof, such as enoblituzumab, mirzotamab, omburtamab, 1D1-01, or 2E3-02 antibodies; q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8, and more preferably, q is 2, 4, 6, or 8;

[1412]

[1413]

[1414] wherein Tb2 is an anti-Trop-2 antibody or an antigen-binding fragment thereof, such as datopotamab, sacituzumab; q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8, and more preferably, q is 2, 4, 6 or 8;

[1415]

[1416]

[1417] wherein Tb3 is an anti-Her2 antibody or an antigen-binding fragment thereof, such as anbenitamab, coprelotamab, disitamab, gancotamab, margetuximab, pertuzumab, timigutuzumab, zanidatamab, or trastuzumab; q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8, and more preferably, q is 2, 4, 6, or 8;

[1418]

[1419]

[1420] wherein Tb4 is an anti-Her3 antibody or an antigen-binding fragment thereof, such as barecetamab, duligotuzumab, elgemtumab, lumretuzumab, patritumab, seribantumab, or the antibody represented by IMGT / mAb-DB ID: 546; q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8, and more preferably, q is 2, 4, 6, or 8;

[1421]

[1422] wherein Tb5 is an anti-EGFR antibody or an antigen-binding fragment thereof, such as demupitamab, depatuxizumab, futuximab, imgatuzumab, laprituximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, serclutamab, tomozutuximab, zalutumumab, or cetuximab; and q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8, and more preferably, q is 2, 4, 6, or 8;

[1423]

[1424] Wherein, Tb6 is an antibody without tumor cell endocytosis activity and without tumor cell surface antigen binding activity, or an antibody with binding activity to non-endocytic antigens (e.g., ALCAM / CD166), for example, an IgG isotype antibody for which there is no corresponding cell surface antigen in the human body, an anti-CD166 antibody; more specifically, an anti-chicken lysozyme human IgG1 isotype antibody; q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8, and more preferably, q is 2, 4, 6, or 8;

[1425]

[1426] Wherein, Tb7 is an antibody having weak or no tumor cell endocytosis activity but having tumor cell surface antigen binding activity; for example, the antibody has the ability to bind to B7H3, Her3, GD-2, Trop-2, EGFR, CD19, CD30, GPNMB, CD20, CD79b and BCMA antigens but has no endocytosis activity; q is selected from any value between 0.1 and 16.0, preferably any value between 2 and 8, and more preferably, q is 2, 4, 6 or 8;

[1427]

[1428] Wherein, Tb8 is an antibody having tumor cell endocytosis activity and tumor cell surface antigen binding activity, such as 1D1-01, 2E3-02 antibody, sacituzumab, pertuzumab, trastuzumab or cetuximab antibody; q is selected from any value between 0.1-16.0, preferably any value between 2-8, and more preferably, q is 2, 4, 6 or 8.

[1429] 25. A linker in a ligand-drug conjugate, comprising the following fragment:

[1430]

[1431] Among them, position 2 is connected to the bioactive molecular fragment;

[1432] L3 and L4 are as defined in any one of Embodiments 1-24;

[1433] Preferably, its structure is as follows:

[1434]

[1435] Among them, position 1 is connected to the ligand or targeting portion that binds to the target, and position 2 is connected to the bioactive molecular fragment;

[1436] L3 and L4 are as defined in any one of Embodiments 1-24;

[1437] Preferably, the target-binding ligand or targeting moiety and the biologically active molecule fragment are defined as Tb and D in any one of embodiments 1-24, respectively.

[1438] 26. The compound represented by formula II:

[1439]

[1440] or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a ligand-drug conjugate thereof,

[1441] wherein R1, R2, R3 and X are as defined in any one of Embodiments 13-24;

[1442] W is absent or present. When W is present, W is selected from -OH, -SH, -NHR4, 1 bit is connected to X;

[1443] Preferably, W is absent or present, and when W is present, W is selected from -OH, -SH, -NHR4, 1 bit is connected to X;

[1444] When W does not exist, X is connected to H; wherein, when R1 and R2 are both H, and X is -(CH2) n1 -, when n1 is 1, 2, 3, or 4, W is not -OH or -NHR4; and the compound represented by formula II does not contain

[1445]

[1446] 27. The compound of embodiment 26, wherein the compound represented by formula II is selected from the following:

[1447]

[1448]

[1449]

[1450]

[1451] 28. The drug-linker conjugate of formula III,

[1452]

[1453] or a stereoisomer of the drug-linker conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,

[1454] in:

[1455] R1, R2, R3, X, L1, L2, L3 and L4 are as defined in any one of Embodiments 1-24; W is as defined in any one of Embodiments 13-24; position 1 of L1 is connected to Lg;

[1456] Lg is a leaving group, which is selected from halogen, sulfone, tertiary amine salt (Me3N + 、Et3N + ), diazonium radicals, -OMs, MeSO2- and CF3SO3-;

[1457] Preferably, Lg is selected from F, Cl and MeSO2-; the tertiary amine salt group is selected from Me3N + and Et3N + ;

[1458] More preferably, Lg is selected from F and MeSO2-.

[1459] 29. The drug-linker conjugate or a stereoisomer of the drug-linker conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to embodiment 28, characterized in that it has a structure represented by Formula III-(1), Formula III-(2), or Formula III-(3):

[1460]

[1461] wherein L1, L2, L3, L4, X, R1, R2, R3, R4 and Lg are as defined in Embodiment 28;

[1462]

[1463] wherein L1, L2, L3, L4, X, R1, R2, R3 and Lg are as defined in Embodiment 28,

[1464]

[1465] wherein L1, L2, L3, L4, X, R1, R2, R3, R4, R5, n, and Lg are as defined in Embodiment 28.

[1466] 30. The drug-linker conjugate or a stereoisomer of the drug-linker conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to embodiment 28 or 29, characterized in that it has a structure represented by Formula III-(1A), III-(1B), III-(2A), III-(2B), III-(3A), or III-(3B);

[1467] The structure represented by formula III-(1A) or III-(1B):

[1468]

[1469] wherein L2, L3, L4, X, R1, R2, R3, R4 and Lg are as defined in embodiment 28 or 29;

[1470] The structure represented by formula III-(2A) or III-(2B):

[1471]

[1472] wherein L2, L3, L4, X, R1, R2, R3 and Lg are as defined in embodiment 28 or 29;

[1473] The structure represented by formula III-(3A) or III-(3B):

[1474]

[1475] wherein L2, L3, L4, X, R1, R2, R3, R4 and Lg are as defined in embodiment 28 or 29.

[1476] 31. The drug-linker conjugate or a stereoisomer of the drug-linker conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 28 to 30, characterized in that the drug-linker conjugate has a structure represented by Formula III-A or Formula III-B:

[1477]

[1478] Among them, Lg, X, R1, R2, R3, R a 、R b and q is as defined in any one of embodiments 28-30;

[1479]

[1480] Among them, Lg, X, R1, R2, R3, R a 、R b and q are as defined in any one of Embodiments 28-30.

[1481] 32. The drug-linker conjugate or a stereoisomer of the drug-linker conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of embodiments 28 to 31, wherein the drug-linker conjugate is selected from the following:

[1482]

[1483]

[1484]

[1485]

[1486]

[1487]

[1488]

[1489]

[1490]

[1491]

[1492]

[1493]

[1494]

[1495]

[1496]

[1497]

[1498]

[1499]

[1500]

[1501]

[1502]

[1503]

[1504] 33. A method for preparing the ligand drug conjugate of any one of embodiments 28-32, comprising:

[1505] Conjugate Tb with the drug linker shown in formula III Carry out the coupling reaction in a suitable solvent and conditions;

[1506] in:

[1507] L1, L2, L3, L4, Tb are as defined in any one of Embodiments 1-24;

[1508] R1, R2, R3, X, and W are as defined in Embodiments 13-24;

[1509] Lg is as defined in any one of Embodiments 28-32.

[1510] 34. The method of embodiment 33, wherein the method comprises conjugating Tb with a drug linker of formula III The step of performing a coupling reaction to form a C-S bond in a suitable solvent and conditions;

[1511] Preferably, the molar ratio of the Tb to the drug-linker conjugate is 1:(1-20);

[1512] Preferably, the coupling reaction is carried out in water and / or an organic solvent; preferably, the organic solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, nitriles (such as acetonitrile), alcohols (such as methanol, ethanol) or any combination thereof; the nitrile may be acetonitrile, and the alcohol may be methanol or ethanol;

[1513] Preferably, the method further comprises a step of purifying the coupled product; preferably, the coupled product is purified by a chromatography method; preferably, the chromatography method comprises one or more of ion exchange chromatography, hydrophobic chromatography, reverse phase chromatography or affinity chromatography.

[1514] 35. An antibody or antigen-binding fragment thereof that binds to B7H3, comprising the following complementarity determining regions (CDRs):

[1515] (a) HCDR1 or a variant thereof, HCDR2 or a variant thereof, and HCDR3 or a variant thereof contained in the heavy chain variable region VH shown in SEQ ID NO: 3 or 23; and / or

[1516] (b) LCDR1 or a variant thereof, LCDR2 or a variant thereof, and LCDR3 or a variant thereof contained in the light chain variable region VL shown in SEQ ID NO: 13 or 33;

[1517] Preferably, the sequence variant is a CDR having one or several amino acid substitutions, deletions or additions compared to its source CDR, such as 1, 2 or 3 amino acid substitutions, deletions or additions; preferably, the substitutions are conservative substitutions.

[1518] 36. The antibody or antigen-binding fragment thereof of embodiment 35, wherein the antibody or antigen-binding fragment thereof comprises:

[1519] (1) VH and / or VL, where defined according to the IMGT numbering system:

[1520] (a) the VH comprises: a HCDR1 of SEQ ID NO: 10, a HCDR2 of SEQ ID NO: 11, and a HCDR3 of SEQ ID NO: 12; and / or,

[1521] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 20, LCDR2 with a sequence of GTF, and LCDR3 with a sequence of SEQ ID NO: 22;

[1522] (b) the VH comprises: a HCDR1 of SEQ ID NO: 10, a HCDR2 of SEQ ID NO: 11, and a HCDR3 of SEQ ID NO: 12; and / or,

[1523] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 40, LCDR2 with a sequence of GAS, and LCDR3 with a sequence of SEQ ID NO: 42;

[1524] (c) the VH comprises: a HCDR1 of SEQ ID NO: 30, a HCDR2 of SEQ ID NO: 31, and a HCDR3 of SEQ ID NO: 32; and / or,

[1525] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 40, LCDR2 with a sequence of GAS, and LCDR3 with a sequence of SEQ ID NO: 42;

[1526] or

[1527] (d) the VH comprises: a HCDR1 of SEQ ID NO: 30, a HCDR2 of SEQ ID NO: 31, and a HCDR3 of SEQ ID NO: 32; and / or,

[1528] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 20, LCDR2 with a sequence of GTF, and LCDR3 with a sequence of SEQ ID NO: 22;

[1529] (2) VH and / or VL, where defined by the chothia numbering system:

[1530] (a) the VH comprises: a HCDR1 of SEQ ID NO: 4, a HCDR2 of SEQ ID NO: 5, and a HCDR3 of SEQ ID NO: 6; and / or,

[1531] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 14, LCDR2 with a sequence of SEQ ID NO: 15, and LCDR3 with a sequence of SEQ ID NO: 16;

[1532] (b) the VH comprises: a HCDR1 of SEQ ID NO: 24, a HCDR2 of SEQ ID NO: 25, and a HCDR3 of SEQ ID NO: 26; and / or,

[1533] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 34, LCDR2 with a sequence of SEQ ID NO: 35, and LCDR3 with a sequence of SEQ ID NO: 36;

[1534] (c) the VH comprises: a HCDR1 of SEQ ID NO: 4, a HCDR2 of SEQ ID NO: 5, and a HCDR3 of SEQ ID NO: 6; and / or,

[1535] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 34, LCDR2 with a sequence of SEQ ID NO: 35, and LCDR3 with a sequence of SEQ ID NO: 36;

[1536] or

[1537] (d) the VH comprises: a HCDR1 of SEQ ID NO: 24, a HCDR2 of SEQ ID NO: 25, and a HCDR3 of SEQ ID NO: 26; and / or,

[1538] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 14, LCDR2 with a sequence of SEQ ID NO: 15, and LCDR3 with a sequence of SEQ ID NO: 16;

[1539] (3) VH and / or VL, where defined according to the Kabat numbering system:

[1540] (a) the VH comprises: a HCDR1 of SEQ ID NO: 7, a HCDR2 of SEQ ID NO: 8, and a HCDR3 of SEQ ID NO: 9; and / or,

[1541] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 17, LCDR2 with a sequence of SEQ ID NO: 18, and LCDR3 with a sequence of SEQ ID NO: 19;

[1542] (b) the VH comprises: a HCDR1 of SEQ ID NO: 27, a HCDR2 of SEQ ID NO: 28, and a HCDR3 of SEQ ID NO: 29; and / or,

[1543] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 37, LCDR2 with a sequence of SEQ ID NO: 38, and LCDR3 with a sequence of SEQ ID NO: 39;

[1544] (c) the VH comprises: a HCDR1 of SEQ ID NO: 7, a HCDR2 of SEQ ID NO: 8, and a HCDR3 of SEQ ID NO: 9; and / or,

[1545] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 37, LCDR2 with a sequence of SEQ ID NO: 38, and LCDR3 with a sequence of SEQ ID NO: 39;

[1546] or

[1547] (d) the VH comprises: a HCDR1 of SEQ ID NO: 27, a HCDR2 of SEQ ID NO: 28, and a HCDR3 of SEQ ID NO: 29; and / or,

[1548] The VL comprises: LCDR1 with a sequence of SEQ ID NO: 17, LCDR2 with a sequence of SEQ ID NO: 18, and LCDR3 with a sequence of SEQ ID NO: 19;

[1549] Optionally, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable region VH and / or light chain variable region VL, wherein at least one CDR in the heavy chain variable region VH and / or light chain variable region VL contains a mutation compared to the CDR defined by IMGT, Chothia or Kabat, and the mutation is a substitution, deletion or addition of one or several amino acids or any combination thereof, such as a substitution, deletion or addition of one, two or three amino acids or any combination thereof; preferably, the substitution is a conservative substitution;

[1550] More preferably, the antibody or antigen-binding fragment thereof binds to human B7-H3 and / or monkey B7-H3.

[1551] 37. The antibody or antigen-binding fragment thereof of embodiment 35 or 36, wherein the antibody or antigen-binding fragment thereof comprises:

[1552] (a) VH shown in SEQ ID NO: 3 or 23, and / or VL shown in any one of SEQ ID NO: 13 or 33;

[1553] (b) a VH having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to any VH in (a); and / or a VL having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to any VL in (a); or

[1554] (c) a VH having one or several amino acid substitutions, deletions or additions or any combination thereof, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof, compared to any VH in (a); and / or a VL having one or several amino acid substitutions, deletions or additions or any combination thereof, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof, compared to any VL in (a); preferably, the substitutions are conservative substitutions.

[1555] 38. The antibody or antigen-binding fragment thereof of any one of embodiments 35-37, wherein the antibody or antigen-binding fragment thereof comprises:

[1556] (a) VH of SEQ ID NO: 3 and VL of SEQ ID NO: 13;

[1557] (b) VH of SEQ ID NO: 23 and VL of SEQ ID NO: 33;

[1558] (c) VH of SEQ ID NO: 3 and VL of SEQ ID NO: 33;

[1559] (d) VH of SEQ ID NO: 23 and VL of SEQ ID NO: 13;

[1560] (e) a VH and a VL having a VH that is at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the VH and VL of any of groups (a) to (d); and / or a VL that is at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the VH and VL of any of groups (a) to (d); or

[1561] (f) VH and VL, compared with the VH and VL in any one of groups (a) to (d), its VH has one or several amino acid substitutions, deletions or additions or any combination thereof, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof; and / or, its VL has one or several amino acid substitutions, deletions or additions or any combination thereof, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof; preferably, the substitutions are conservative substitutions.

[1562] 39. The antibody or antigen-binding fragment thereof according to any one of embodiments 35-38, wherein the antibody or antigen-binding fragment thereof is a chimeric antibody, a humanized antibody, or a fully human antibody;

[1563] Optionally, the antibody or antigen-binding fragment thereof is selected from scFv, Fab, Fab', (Fab')2, Fv fragment, disulfide-linked Fv (dsFv), diabody and multispecific antibody;

[1564] Optionally, the scFv comprises:

[1565] (i) the sequence shown in SEQ ID NO: 1 or 2;

[1566] (ii) a sequence having one or several amino acid substitutions, deletions or additions, or any combination thereof, compared to the sequence shown in (i) (e.g., up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions, or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions, or any combination thereof); or

[1567] (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in (i);

[1568] Preferably, the substitutions described in (ii) are conservative substitutions.

[1569] 40. The antibody or antigen-binding fragment thereof of any one of embodiments 35-39, wherein the antibody or antigen-binding fragment thereof further comprises:

[1570] (a) a heavy chain constant region CH of a human immunoglobulin or a variant thereof; and / or

[1571] (b) a light chain constant region CL of a human immunoglobulin or a variant thereof,

[1572] wherein the variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the wild-type sequence from which it is derived; or, the variant has one or more amino acid substitutions, deletions or additions or any combination thereof, such as up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof, compared to the wild-type sequence from which it is derived; preferably, the substitutions are conservative substitutions;

[1573] Preferably, the heavy chain constant region is an IgG heavy chain constant region, such as an IgG1, IgG2, IgG3 or IgG4 heavy chain constant region; and / or, the light chain constant region is a kappa or lambda light chain constant region;

[1574] More preferably, the antibody or antigen-binding fragment thereof comprises a human IgG1 heavy chain constant region; and / or the antibody or antigen-binding fragment thereof comprises a human κ light chain constant region.

[1575] 41. The antibody or antigen-binding fragment thereof of embodiment 40, wherein:

[1576] The heavy chain constant region comprises a CH as set forth in SEQ ID NO: 43 or a variant thereof, wherein the variant has up to 20 conservative substitutions of amino acids compared to SEQ ID NO: 43, such as up to 20, up to 15, up to 10 or up to 5 conservative substitutions of amino acids, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 conservative substitutions of amino acids; or has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to SEQ ID NO: 43; and / or

[1577] the light chain constant region comprises the CL set forth in SEQ ID NO:44 or a variant thereof having up to 20 conservative amino acid substitutions, such as up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions, compared to SEQ ID NO:44, or having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to SEQ ID NO:44;

[1578] Preferably, the antibody or antigen-binding fragment thereof comprises the heavy chain constant region CH shown in SEQ ID NO:43 and the light chain constant region CL shown in SEQ ID NO:44.

[1579] 42. The antibody or antigen-binding fragment thereof of any one of embodiments 35-41, wherein the antibody comprises:

[1580] (a) a heavy chain comprising the VH shown in SEQ ID NO: 3 and the CH shown in SEQ ID NO: 43, and a light chain comprising the VL shown in SEQ ID NO: 13 and the CL shown in SEQ ID NO: 44; preferably comprising the heavy chain shown in SEQ ID NO: 45 and the light chain shown in SEQ ID NO: 46;

[1581] (b) a heavy chain comprising VH shown in SEQ ID NO: 23 and CH shown in SEQ ID NO: 43, and a light chain comprising VL shown in SEQ ID NO: 33 and CL shown in SEQ ID NO: 44; preferably comprising a heavy chain shown in SEQ ID NO: 47 and a light chain shown in SEQ ID NO: 48.

[1582] 43. A multispecific antibody comprising the antibody or antigen-binding fragment thereof according to any one of embodiments 35-42, and another antibody or fragment thereof or antibody analog;

[1583] Preferably, the multispecific antibody is a bispecific antibody, a trispecific antibody or a tetraspecific antibody.

[1584] 44. An isolated nucleic acid molecule encoding the antibody or antigen-binding fragment thereof of any one of embodiments 35-42, or the multispecific antibody of embodiment 43.

[1585] 45. A vector comprising the isolated nucleic acid molecule of embodiment 44; preferably, the vector is a cloning vector or an expression vector.

[1586] 46. ​​A host cell comprising the isolated nucleic acid molecule of embodiment 44 or the vector of embodiment 45.

[1587] 47. A method for preparing the antibody or antigen-binding fragment thereof of any one of embodiments 35-42, or the multispecific antibody of embodiment 43, comprising culturing the host cell of embodiment 46 under conditions that allow expression of the antibody or antigen-binding fragment thereof, and recovering the antibody or antigen-binding fragment thereof, or the multispecific antibody from the cultured host cell culture.

[1588] 48. An antibody-drug conjugate, wherein the antibody is the antibody or antigen-binding fragment thereof according to any one of embodiments 35-42, or the multispecific antibody according to embodiment 43, and is connected to a coupling moiety via a linker, wherein the coupling moiety is selected from the group consisting of: a detectable label, a radioisotope, a fluorescent substance, a luminescent substance, a colored substance, an enzyme, polyethylene glycol, a nuclide, a nucleic acid, a small molecule toxin, a polypeptide with binding activity, a protein, a receptor, a ligand, and other active substances that inhibit tumor cell growth or promote tumor cell apoptosis or necrosis.

[1589] 49. A ligand drug conjugate comprising the ligand drug conjugate of any one of embodiments 1-28, wherein the ligand drug conjugate has two or more q values;

[1590] Optionally, the drug to antibody ratio (DAR) in the ligand drug conjugate is an integer or decimal selected from 1-10;

[1591] Preferably, the drug to antibody ratio (DAR) in the ligand drug conjugate is selected from 1.5-2.5, 3.5-4.5, 5.5-6.5 and 7.5-8.5;

[1592] Preferably, the drug to antibody ratio (DAR) in the ligand drug conjugate is selected from about 2.0, 4.0, 6.0 and 8.0;

[1593] Preferably, the drug to antibody ratio (DAR) in the ligand drug conjugate is selected from the group consisting of 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.2, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.7, 8.9 and 9.

[1594] 50. A pharmaceutical composition comprising substance A, and optionally one or more pharmaceutical excipients, wherein substance A is a ligand-drug conjugate as described in any one of embodiments 1-24, or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, or a compound as described in any one of embodiments 26 or 27, or a drug-linker conjugate as described in any one of embodiments 28-32, or an antibody or antigen-binding fragment thereof as described in any one of embodiments 35-42, or a multispecific antibody as described in embodiment 43, or a nucleic acid molecule as described in embodiment 44, or a vector as described in embodiment 45, or a host cell as described in embodiment 46, or a ligand-drug conjugate as described in embodiment 49; preferably, the composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[1595] 51. Use of a substance A or the pharmaceutical composition of embodiment 50 in the preparation of a medicament for treating and / or preventing a disease associated with abnormal cell activity; wherein the substance A is the ligand-drug conjugate of any one of embodiments 1-24, or a stereoisomer of the ligand-drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, or the compound of embodiment 26 or 27, or the drug-linker conjugate of any one of embodiments 28-32, or the antibody or antigen-binding fragment thereof of any one of embodiments 35-42, or the multispecific antibody of embodiment 43, or the nucleic acid molecule of embodiment 44, or the vector of embodiment 45, or the host cell of embodiment 46, or the ligand-drug conjugate of embodiment 49; and the disease associated with abnormal cell activity may be cancer.

[1596] Preferably, the cancer disease is selected from esophageal cancer, brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, kidney cancer, urothelial carcinoma, epidermal cancer, non-Hodgkin's lymphoma, central nervous system tumor, prostate cancer or thyroid cancer; the esophageal cancer is such as esophageal adenocarcinoma or esophageal squamous cell carcinoma; the lung cancer is such as small cell lung cancer, non-small cell lung cancer or lung adenocarcinoma; the central nervous system tumor is such as glioma, glioblastoma multiforme, glioma or sarcoma; the colon cancer is such as human colon adenocarcinoma;

[1597] Preferably, the cancer disease is selected from colon cancer, colorectal cancer, colon adenocarcinoma, lung cancer, breast cancer, prostate cancer, and esophageal squamous cell carcinoma;

[1598] More preferably, the cancer disease is a cancer disease associated with B7H3;

[1599] More preferably, the cancer disease is a cancer disease associated with Her3;

[1600] More preferably, the cancer disease is a cancer disease associated with EGFR;

[1601] More preferably, the cancer disease is a cancer disease associated with Trop-2 or Her 2;

[1602] Most preferably, the cancer disease is breast cancer or the lung cancer is non-small cell lung cancer.

[1603] In this disclosure, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the laboratory procedures for cell culture, molecular genetics, nucleic acid chemistry, and immunology used herein are conventional procedures widely used in the relevant fields. To facilitate a better understanding of this disclosure, definitions and explanations of relevant terms are provided below.

[1604] As used herein, examples of the term "pharmaceutically acceptable salts" are organic acid addition salts formed with organic acids that form pharmaceutically acceptable anions, including but not limited to formates, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates, ascorbates, α-ketoglutarate, α-glycerophosphates, alkylsulfonates, or arylsulfonates; preferably, the alkylsulfonate is methylsulfonate or ethylsulfonate; and the arylsulfonate is benzenesulfonate or p-toluenesulfonate. Suitable inorganic salts may also be formed, including but not limited to hydrochlorides, hydrobromides, hydroiodides, nitrates, bicarbonates, carbonates, sulfates, or phosphates.

[1605] As used herein, the term "pharmaceutically acceptable carriers and / or excipients" refers to carriers and / or excipients that are pharmacologically and / or physiologically compatible with the subject and the active ingredient, which are well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and include, but are not limited to: pH adjusters, surfactants, adjuvants, ionic strength enhancers, diluents, agents for maintaining osmotic pressure, agents for delaying absorption, preservatives.

[1606] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid affording a pharmaceutically acceptable anion.

[1607] For the purposes of this disclosure, pharmaceutical excipients refer to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These substances, in addition to the active ingredients, have been reasonably evaluated for safety and are included in pharmaceutical preparations. In addition to providing shape, acting as carriers, and improving stability, pharmaceutical excipients also have important functions such as solubilization, dissolution enhancement, and sustained-release control. They are important components that may affect the quality, safety, and efficacy of drugs. Based on their source, they can be categorized as natural, semi-synthetic, and fully synthetic. According to their functions and uses, they can be divided into: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, etc. According to their route of administration, they can be divided into oral, parenteral, mucosal, transdermal or topical administration, nasal or oral inhalation administration, and ocular administration, etc. The same pharmaceutical excipient can be used in pharmaceutical preparations for different routes of administration and have different functions and uses.

[1608] The pharmaceutical composition can be prepared into various suitable dosage forms according to the route of administration, such as tablets, capsules, granules, oral solutions, oral suspensions, oral emulsions, powders, tinctures, syrups, injections, suppositories, ointments, creams, pastes, ophthalmic preparations, pills, implants, aerosols, powder sprays, sprays, etc. The pharmaceutical composition or suitable dosage form can contain 0.01 mg to 1000 mg of the compound of the present disclosure or a pharmaceutically acceptable salt or conjugate thereof, preferably 0.1 mg to 800 mg, preferably 0.5-500 mg, preferably 0.5 to 350 mg, and particularly preferably 1-250 mg.

[1609] The pharmaceutical composition can be administered in the form of an injection, including an injection solution, sterile powder for injection, and concentrated solution for injection. Among them, the carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils such as monoglycerides or diglycerides can also be used as solvents or suspending media.

[1610] As used herein, the term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or causing side effects due to the disease. As used herein, "treat" encompasses any treatment of a disease in a patient, including: (a) preventing the onset of a disease or symptom in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) suppressing the symptoms of a disease, i.e., arresting its development; or (c) relieving the symptoms of a disease, i.e., causing regression of the disease or symptom.

[1611] In the present disclosure, the term "individual" includes humans and non-human animals. Exemplary human individuals include human individuals suffering from a disease (e.g., a disease described herein) (referred to as a patient) or normal individuals. The term "non-human animal" in the present disclosure includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[1612] As used herein, the term "effective dose" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the condition being treated.

[1613] In the present disclosure, the term "ligand drug conjugate" refers to a substance obtained by connecting a bioactive molecule (drug molecule) to a targeting portion. In some embodiments of the present disclosure, the bioactive molecule is connected to the targeting portion via a connector. The connector can be broken in a specific environment (e.g., hydrolases and / or low pH environments within a tumor) or under a specific action (e.g., the action of lysosomal proteases), thereby separating the bioactive molecule from the targeting portion. In some embodiments of the present disclosure, the connector comprises a cleavable or non-cleavable unit, such as a peptide or a disulfide bond. In some embodiments of the present disclosure, the bioactive molecule is directly connected to the targeting portion via a covalent bond, and the covalent bond can be broken under a specific environment or action, thereby separating the bioactive molecule from the targeting portion. In some embodiments of the present disclosure, the ligand drug conjugate comprises a targeting portion, a connector, and a fragment of a compound of formula II of the present disclosure.

[1614] In the present disclosure, the term "bioactive substance", "bioactive molecule" or "drug molecule" refers to a substance that inhibits or prevents cell function and / or causes cell death or destruction. In some embodiments of the present disclosure, the bioactive substance, bioactive molecule or drug molecule in the conjugate is a molecule with anti-tumor biological activity. For example: radioactive isotopes, such as At 211 , I 131 , I 125 、Y 90 、Re 186 、Re188 、Sm 153 、Bi 212 、P 32 , Pb 212 and radioactive isotopes of Lu; metal complexes, such as metal platinum complexes, metal gold complexes, oxaliplatin, etc.; glycopeptide antibiotics, such as bleomycin and bleomycin; DNA topoisomerase inhibitors, such as topoisomerase I inhibitors, camptothecin, hydroxycamptothecin, 9-aminocamptothecin, SN-38, irinotecan, topotecan, belotecan, rubitecan, topoisomerase II inhibitors, actinomycin D, doxorubicin, doxorubicin, duocarmycin, daunorubicin, mitoxantrone, podophyllotoxin, etoposide, etc.; drugs that interfere with DNA synthesis, such as methotrexate, 5-fluorouracil, cytarabine, gemcitabine, mercaptopurine, pentostatin, fludarabine, cladribine, nelarabine, etc.; drugs that act on structural proteins, such as tubulin inhibitors, vinca alkaloids, vincristine, vinblastine, paclitaxel, polyoxazine Citaxel, Cabazitaxel, etc.; tumor signaling pathway inhibitors, such as serine / threonine kinase inhibitors, tyrosine kinase inhibitors, aspartate kinase inhibitors or histidine kinase inhibitors; also including proteasome inhibitors, histone deacetylase inhibitors, tumor angiogenesis inhibitors, cell cycle protein inhibitors, maytansine derivatives, calicheamicin derivatives, auristatin derivatives, pyrrolobenzodiazepines (PBD) derivatives, melphalan, mitomycin C, chlorambucil, or other active substances that inhibit tumor cell growth, promote tumor cell apoptosis and necrosis; enzymes and fragments thereof, such as nucleolytic enzymes; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof; growth inhibitors; drug moieties. The term "toxin" refers to a substance that can have a deleterious effect on cell growth or proliferation.

[1615] In this disclosure, the term "small molecule" refers to a small molecule drug with biological activity. The term "small molecule toxin" refers to a state in which a small molecule toxin has cell-damaging activity, i.e., a state in which a pathological change in a cell is caused in some form. Cell damage is not limited to direct damage, but includes all types of damage to the structure and function of the cell, such as DNA cleavage, base-dimer formation, chromosome cleavage, damage to the cell division machinery, and a decrease in the activity of various enzymatic enzymes.

[1616] In the present disclosure, the term "linker" refers to a fragment that connects a biologically active molecule (drug molecule) to a targeting moiety.

[1617] In this disclosure, the term "targeting moiety" refers to a portion of a conjugate that is capable of specifically binding to a target (or portion of a target) on the cell surface. Through the interaction of the targeting moiety with the target, the conjugate can be delivered to a specific cell population.

[1618] In the present disclosure, when the targeting moiety in the conjugate is an antibody, the conjugate may be referred to as a "drug-antibody conjugate."

[1619] In the present disclosure, antibodies or antigen-binding fragments thereof include derivatized antibodies or antigen-binding fragments thereof, such as antibodies or antigen-binding fragments thereof having sulfhydryl groups, wherein the derivatization provides the antibody with a group or ability to react with a drug-linker conjugate. The sulfhydryl group (SH) can be derivatized by opening a disulfide bond (e.g., by reduction with the reducing agent TCEP).

[1620] As used herein, the terms "cancer" and "tumor" are used synonymously.

[1621] The term "gene" used herein includes not only DNA but also its mRNA, its cDNA, and its cRNA.

[1622] As used herein, the term "polynucleotide" is used with the same meaning as nucleic acid, and also includes DNA, RNA, probes, oligonucleotides, and primers.

[1623] The term "Tb" used herein is an abbreviation for "target binding", including antibodies or any molecules that bind...

Claims

1. An antibody or antigen-binding fragment thereof that binds to B7H3, wherein the antibody or antigen-binding fragment thereof comprises the following complementary determining region (CDR): (a) HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region VH shown in SEQ ID NO: 23; and LCDR1, LCDR2 and LCDR3 contained in the light chain variable region VL shown in SEQ ID NO: 33; or (b) HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region VH shown in SEQ ID NO:3; and LCDR1, LCDR2 and LCDR3 contained in the light chain variable region VL shown in SEQ ID NO:

13.

2. An antibody or antigen-binding fragment thereof that binds to B7H3, wherein: The antibody or antigen-binding fragment thereof comprises: (1) VH and VL, where defined according to the IMGT numbering system: (a) the VH comprises: a HCDR1 whose sequence comprises or is SEQ ID NO: 30, a HCDR2 whose sequence comprises or is SEQ ID NO: 31, and a HCDR3 whose sequence comprises or is SEQ ID NO: 32; and, The VL comprises: LCDR1 whose sequence comprises or is SEQ ID NO: 40, LCDR2 whose sequence is GAS, and LCDR3 whose sequence comprises or is SEQ ID NO: 42; or (b) the VH comprises: a HCDR1 whose sequence comprises or is SEQ ID NO: 10, a HCDR2 whose sequence comprises or is SEQ ID NO: 11, and a HCDR3 whose sequence comprises or is SEQ ID NO: 12; and, The VL comprises: LCDR1 whose sequence comprises or is SEQ ID NO: 20, LCDR2 whose sequence is GTF, and LCDR3 whose sequence comprises or is SEQ ID NO: 22; (2) VH and VL, which are defined according to the chothia numbering system: (a) the VH comprises: a HCDR1 whose sequence comprises or is SEQ ID NO: 24, a HCDR2 whose sequence comprises or is SEQ ID NO: 25, and a HCDR3 whose sequence comprises or is SEQ ID NO: 26; and, The VL comprises: LCDR1 whose sequence comprises or is SEQ ID NO: 34, LCDR2 whose sequence comprises or is SEQ ID NO: 35, LCDR3 whose sequence comprises or is SEQ ID NO: 36; or (b) the VH comprises: a HCDR1 whose sequence comprises or is SEQ ID NO: 4, a HCDR2 whose sequence comprises or is SEQ ID NO: 5, and a HCDR3 whose sequence comprises or is SEQ ID NO: 6; and, The VL comprises: LCDR1 whose sequence comprises or is SEQ ID NO: 14, LCDR2 whose sequence comprises or is SEQ ID NO: 15, and LCDR3 whose sequence comprises or is SEQ ID NO: 16; (3) VH and VL, which are defined according to the Kabat numbering system: (a) the VH comprises: a HCDR1 whose sequence comprises or is SEQ ID NO: 27, a HCDR2 whose sequence comprises or is SEQ ID NO: 28, and a HCDR3 whose sequence comprises or is SEQ ID NO: 29; and, The VL comprises: LCDR1 whose sequence comprises or is SEQ ID NO: 37, LCDR2 whose sequence comprises or is SEQ ID NO: 38, LCDR3 whose sequence comprises or is SEQ ID NO: 39; or (b) the VH comprises: a HCDR1 whose sequence comprises or is SEQ ID NO: 7, a HCDR2 whose sequence comprises or is SEQ ID NO: 8, and a HCDR3 whose sequence comprises or is SEQ ID NO: 9; and, The VL comprises: LCDR1 whose sequence comprises or is SEQ ID NO: 17, LCDR2 whose sequence comprises or is SEQ ID NO: 18, and LCDR3 whose sequence comprises or is SEQ ID NO: 19; Wherein, the antibody or antigen-binding fragment thereof binds to human B7-H3 and / or monkey B7-H3.

3. The antibody or antigen-binding fragment thereof according to claim 1 or 2, wherein The antibody or antigen-binding fragment thereof comprises VH and VL, wherein the VH (a) comprising or consisting of the amino acid sequence shown in SEQ ID NO: 3 or 23; (b) a VH having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to any VH in (a); or (c) compared to any VH in (a), it has one or several amino acid substitutions, deletions or additions or any combination thereof, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof; and / or wherein the VL (a) comprising or consisting of the amino acid sequence shown in SEQ ID NO: 13 or 33; (b) a VL having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to any of the VLs in (a); or (c) compared with any VL in (a), it has one or several amino acid substitutions, deletions or additions or any combination thereof, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof; Preferably, the antibody or antigen-binding fragment thereof comprises: (a) a VH comprising the sequence shown in SEQ ID NO: 23 and / or a VL comprising the sequence shown in SEQ ID NO: 33; or (b) a VH comprising the sequence shown in SEQ ID NO: 3 and / or a VL comprising the sequence shown in SEQ ID NO: 13; More preferably, the antibody or antigen-binding fragment thereof comprises: (a) the VH sequence shown in SEQ ID NO: 23 and the VL sequence shown in SEQ ID NO: 33; or (b) VH of the sequence shown in SEQ ID NO:3 and VL of the sequence shown in SEQ ID NO:

13.

4. An antibody or antigen-binding fragment thereof that binds to B7H3, wherein: The antibody or antigen-binding fragment thereof comprises (a) a VH comprising the sequence shown in SEQ ID NO: 23 and a VL comprising the sequence shown in SEQ ID NO: 33; or (b) a VH comprising the sequence shown in SEQ ID NO: 3 and a VL comprising the sequence shown in SEQ ID NO: 13; Preferably, the antibody or antigen-binding fragment thereof comprises (a) the VH sequence shown in SEQ ID NO: 23 and the VL sequence shown in SEQ ID NO: 33; or (b) VH of the sequence shown in SEQ ID NO:3 and VL of the sequence shown in SEQ ID NO:

13.

5. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, wherein: The antibody or antigen-binding fragment thereof is a chimeric antibody, a humanized antibody or a fully human antibody; Optionally, the antibody or antigen-binding fragment thereof is selected from scFv, Fab, Fab', (Fab')2, Fv fragment, disulfide-linked Fv (dsFv), diabody and multispecific antibody; Optionally, the scFv comprises: (i) the sequence shown in SEQ ID NO: 1 or 2; (ii) a sequence having one or several amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., substitutions, deletions or additions of up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acids or any combination thereof; for example, substitutions, deletions or additions of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids or any combination thereof); or (iii) a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the sequence shown in (i); Preferably, the substitutions described in (ii) are conservative substitutions.

6. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, wherein The antibody or antigen-binding fragment thereof further comprises: (a) a heavy chain constant region CH of a human immunoglobulin or a variant thereof; and / or (b) a light chain constant region CL of a human immunoglobulin or a variant thereof, wherein the variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the wild-type sequence from which it is derived; or, the variant has one or more amino acid substitutions, deletions or additions or any combination thereof, such as up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10 or up to 5 amino acid substitutions, deletions or additions or any combination thereof, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof, compared to the wild-type sequence from which it is derived; preferably, the substitutions are conservative substitutions; Preferably, the heavy chain constant region is an IgG heavy chain constant region, such as an IgG1, IgG2, IgG3 or IgG4 heavy chain constant region; and / or, the light chain constant region is a κ or λ light chain constant region; More preferably, the antibody or antigen-binding fragment thereof comprises a human IgG1 heavy chain constant region; and / or the antibody or antigen-binding fragment thereof comprises a human κ light chain constant region; Optionally, the heavy chain constant region includes a CH having a sequence as shown in SEQ ID NO: 43, or a variant of the CH, wherein the variant has up to 20 conservative substitutions of amino acids compared to SEQ ID NO: 43, such as up to 20, up to 15, up to 10 or up to 5 conservative substitutions of amino acids, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 conservative substitutions of amino acids; or has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to SEQ ID NO: 43; and / or The light chain constant region includes a CL having a sequence as shown in SEQ ID NO:44 or a variant thereof, wherein the variant has up to 20 conservative substitutions of amino acids compared to SEQ ID NO:44, such as up to 20, up to 15, up to 10 or up to 5 conservative substitutions of amino acids, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 conservative substitutions of amino acids, or has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to SEQ ID NO:44; Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region CH shown in SEQ ID NO:43 and a light chain constant region CL shown in SEQ ID NO:

44.

7. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, wherein The antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein (a) the heavy chain comprises a VH having a sequence as shown in SEQ ID NO:23 or consisting of the sequence thereof and a CH having a sequence as shown in SEQ ID NO:43 or consisting of the sequence thereof, and the light chain comprises a VL having a sequence as shown in SEQ ID NO:33 or consisting of the sequence thereof and a CL having a sequence as shown in SEQ ID NO:44 or consisting of the sequence thereof; or (b) the heavy chain comprises a VH having a sequence shown in SEQ ID NO: 3 or consisting of the sequence shown and a CH having a sequence shown in SEQ ID NO: 43 or consisting of the sequence shown, and the light chain comprises a VL having a sequence shown in SEQ ID NO: 13 or consisting of the sequence shown and a CL having a sequence shown in SEQ ID NO: 44 or consisting of the sequence shown; Preferably, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain comprising or consisting of the sequence shown in SEQ ID NO:47 and a light chain comprising or consisting of the sequence shown in SEQ ID NO:48; or (b) a heavy chain comprising or consisting of the sequence shown in SEQ ID NO:45 and a light chain comprising or consisting of the sequence shown in SEQ ID NO:

46.

8. An antibody or antigen-binding fragment thereof that binds to B7H3, wherein: The antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein (a) the heavy chain comprises a VH having a sequence as shown in SEQ ID NO:23 or consisting of the sequence thereof and a CH having a sequence as shown in SEQ ID NO:43 or consisting of the sequence thereof, and the light chain comprises a VL having a sequence as shown in SEQ ID NO:33 or consisting of the sequence thereof and a light chain having a CL having a sequence as shown in SEQ ID NO:44 or consisting of the sequence thereof; or (b) the heavy chain comprises a VH having a sequence shown in SEQ ID NO: 3 or consisting of the sequence shown and a CH having a sequence shown in SEQ ID NO: 43 or consisting of the sequence shown, and the light chain comprises a VL having a sequence shown in SEQ ID NO: 13 or consisting of the sequence shown and a CL having a sequence shown in SEQ ID NO: 44 or consisting of the sequence shown; Preferably, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain comprising or consisting of the sequence shown in SEQ ID NO:47 and a light chain comprising or consisting of the sequence shown in SEQ ID NO:48; or (b) a heavy chain comprising or consisting of the sequence shown in SEQ ID NO:45 and a light chain comprising or consisting of the sequence shown in SEQ ID NO:

46.

9. A multispecific antibody comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, and another antibody or fragment thereof; Preferably, the multispecific antibody is a bispecific antibody or a trispecific antibody or a tetraspecific antibody.

10. An isolated nucleic acid molecule encoding the antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, or the multispecific antibody according to claim 9.

11. A vector comprising the isolated nucleic acid molecule of claim 10; preferably, the vector is a cloning vector or an expression vector.

12. A host cell comprising the isolated nucleic acid molecule of claim 10 or the vector of claim 11.

13. A method for preparing the antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, or the multispecific antibody according to claim 9, comprising culturing the host cell according to claim 12 under conditions that allow expression of the antibody or antigen-binding fragment thereof, or the multispecific antibody, and recovering the antibody or antigen-binding fragment thereof, or the multispecific antibody from the cultured host cell culture. 14 . An antibody-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the antibody is the antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, or the multispecific antibody according to claim 9.

15. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 14, wherein the antibody-drug conjugate comprises an anti-B7-H3 antibody-drug conjugate of the following formula: Ab-(LD)n, in: Ab is the antibody or antigen-binding fragment thereof of any one of claims 1 to 9; D is a small molecule toxin drug moiety; L is a bond or linking molecule that covalently links Ab and D; n is an integer between 1-16 and represents the number of LDs covalently linked to the Ab.

16. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 14 or 15, wherein: L comprises an amino acid residue or a short peptide consisting of 2-10 amino acid residues; the amino acid residue is selected from a natural amino acid residue, a non-natural amino acid residue, or an amino acid residue represented by AA1 or a stereoisomer thereof; AA 1 Among the amino acid residues shown: R a1 and R b Each independently selected from H, Or, R a1 With R b Together with the carbon atoms connected to them, they form a 4-10 membered heterocyclic ring, wherein the heteroatoms in the 4-10 membered heterocyclic ring are selected from 1, 2, 3 or 4 of O, N and S; the 4-10 membered heterocyclic ring is optionally replaced by one or more R 0 replaced by; r、r 1 、r 1a and r 1b Each independently is any integer from 0 to 20; R m1 , R n1 , R m1a , R n1a , R m1b and R n1b Each independently is H, C 1-6 Alkyl, C 3-6 Cycloalkyl or -COOR x1 , where R x1 C 1-6 alkyl; Or, R m1 and R n1 , R m1a and R n1a , and R m1b and R n1b Together with the nitrogen atom they are connected to, they form a 4-10 membered heterocyclic ring, wherein the heteroatoms in the 4-10 membered heterocyclic ring are selected from 1, 2, 3 or 4 of O, N and S; the 4-10 membered heterocyclic ring is optionally replaced by one or more R 0’ replaced by; R z Selected from C 1-6 alkyl; R 0 , R 0’ Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -NR m2 R n2 , optional C 1-6 An alkyl-substituted 4-10-membered heterocyclic group; in the 4-10-membered heterocyclic ring, the heteroatoms are selected from 1, 2, 3 or 4 of O, N and S; R m2 and R n2 Each independently selected from H and C 1-6 alkyl; Preferably, L comprises a moiety selected from Val, D-Val, Cit, Phe, Lys, Lys(Ac), Leu, Gly, Ala, Asn, Asp, Arg, AA 1 or 2 to 10 amino acid residues selected from Val, Cit, Phe, Lys, D-Val, Leu, Gly, Ala, Asn, Asp, AA 1 A short peptide composed of amino acid residues; Preferably, L comprises Val, Cit, Phe, Lys, D-Val, Leu, Gly, Ala, Asn, AA 1 , Val-Cit, Cit-Val, Cit-Ala, Val-Ala, Lys-Val, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Ala-Ala, Val-AA 1 , Ala-AA 1 , Gly-AA 1 , AA 1 -Gly, Ala-Ala-Ala, Ala-Ala-Asn, Ala-Ala-Asp, Val-AA 1 -Gly, Ala-AA 1 -Gly, Gly-AA 1 -Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Gly-Phe-Gly, Gly-Gly-Phe-Gly, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala-Asn, Gly-Gly-Phe, Val-Lys-Gly, Val-Lys-Gly-Gly, Val-Lys and Lys-Ala-Asn; Preferably, L comprises AA 1 AA 1 -Gly, Val-Cit, Val-AA 1 -Gly, AA 1 -Ala-Asn and Gly-Gly-Phe-Gly; Preferably, L comprises Val-AA 1 -Gly.

17. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 16, wherein: AA 1 The amino acid residues shown are Preferably, AA 1 The amino acid residues are selected from More preferably, AA 1 The amino acid residues are selected from Most preferably, AA 1 The amino acid residues are selected from 18. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 17, wherein L is Position 1 is connected to Ab, position 2 is connected to D; L1 is selected from Position 1 is connected to Ab, position 2 is connected to L3; L1 is preferably Position 1 is connected to Ab, position 2 is connected to L3; L2 does not exist; L3 is selected from AA 1 、AA 1 -Gly, Val-Cit, Val-AA 1 -Gly, AA 1 -Ala-Asn, Gly-Gly-Phe-Gly; L4 does not exist or exists. When L4 exists, L4 is Bit 1 is connected to L3, bit 2 is connected to D; Preferably Selected from:

19. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 18, wherein: The drug of the antibody-drug conjugate is selected from: microtubule blocking drugs, DNA damaging drugs, Bcl-xL inhibitors; Preferably, the drug of the antibody-drug conjugate is selected from: auristatins such as MMAF, MMAE, maytansine derivatives such as DM1, DM4, tubulysin, cryptocolistin, anti-mitotic inhibitors, pyrrole benzazepines and indolechlorobenzazepines, dukamycin, camptothecin, calicheamicin; More preferably, the drug of the antibody-drug conjugate is selected from camptothecin (CPT) and its derivatives; More preferably, the drug of the antibody-drug conjugate is selected from: SN-38, DXd.

20. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 18, wherein: D is a drug unit having formula II: in, R1 is H or F, R2 is H or methyl; Or R1 and R2 together with the carbon atom to which they are attached form R3 is H; R4 is selected from H, -(C1-C4 alkyl)-OH, -(C1-C4 alkenyl)-OH, -(C1-C4 alkyl)-NH2, or -(C1-C4 alkenyl)-NH2; Wherein L is linked via the hydroxyl or amine group present on D.

21. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 20, wherein: L is a linker having the following formula: Wherein, position 1 is connected to Ab, and position 2 is connected to D; AA1 is as defined in claim 16 or 17.

22. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 21, wherein: The antibody-drug conjugate is selected from the following: wherein Ab is the antibody or antigen-binding fragment thereof of claims 1-9, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16; Preferably, n is selected from 1, 2, 3, 4, 5, 6, 7 and 8; More preferably, the antibody-drug conjugate is selected from the following: wherein Ab is the antibody or antigen-binding fragment thereof of claims 1-9, and n is selected from 1, 2, 3, 4, 5, 6, 7 and 8.

23. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 14, wherein: The antibody-drug conjugate is selected from the following: n is selected from 2, 4, 6 and 8; Ab contains: (a) the VH sequence shown in SEQ ID NO: 3 and the VL sequence shown in SEQ ID NO: 13; or (b) VH of the sequence shown in SEQ ID NO:23 and VL of the sequence shown in SEQ ID NO:

33.

24. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 23, wherein: The Ab comprises a heavy chain constant region CH shown in SEQ ID NO:43 and a light chain constant region CL shown in SEQ ID NO:

44. Preferably, the Ab comprises: (a) a heavy chain comprising or consisting of the sequence shown in SEQ ID NO:47 and a light chain comprising or consisting of the sequence shown in SEQ ID NO:48; or (b) a heavy chain comprising or consisting of the sequence shown in SEQ ID NO:45 and a light chain comprising or consisting of the sequence shown in SEQ ID NO:

46.

25. An antibody-drug conjugate or a pharmaceutically acceptable salt thereof, comprising the antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 24, wherein the antibody-drug conjugate or a pharmaceutically acceptable salt thereof has a plurality of n values; Optionally, the drug to antibody ratio (DAR) in the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is an integer or decimal selected from 1-10; Preferably, the drug to antibody ratio (DAR) in the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is selected from 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.2, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.7, 8.9, 9.

26. A pharmaceutical composition comprising substance A, and optionally one or more pharmaceutical excipients, wherein substance A is the antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, or the multispecific antibody according to claim 9, or the nucleic acid molecule according to claim 10, or the vector according to claim 11, or the host cell according to claim 12, or the antibody-drug conjugate according to any one of claims 14 to 25, or a pharmaceutically acceptable salt thereof; Preferably, it further comprises a pharmaceutically acceptable carrier and / or excipient.

27. Use of a substance A or the pharmaceutical composition of claim 26 in the preparation of a drug for treating and / or preventing a disease associated with abnormal cell activity; the substance A is the antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, or the multispecific antibody according to claim 9, or the nucleic acid molecule according to claim 10, or the vector according to claim 11, or the host cell according to claim 12, or the antibody-drug conjugate according to any one of claims 14 to 25, or a pharmaceutically acceptable salt thereof, Preferably, the disease associated with abnormal cell activity is cancer; Preferably, the cancer disease is selected from esophageal cancer, brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, kidney cancer, urothelial carcinoma, epidermal cancer, non-Hodgkin's lymphoma, central nervous system tumors, prostate cancer or thyroid cancer; Preferably, the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma; the lung cancer is small cell lung cancer, non-small cell lung cancer or lung adenocarcinoma; the central nervous system tumor is glioma, glioblastoma multiforme, glioma or sarcoma; the colon cancer is human colon adenocarcinoma; Preferably, the cancer disease is selected from colon cancer, colorectal cancer, colon adenocarcinoma, lung cancer, breast cancer, prostate cancer, esophageal squamous cell carcinoma; Preferably, the cancer disease is a cancer disease associated with B7H3; Preferably, the cancer disease is breast cancer or lung cancer; or Preferably, the cancer disease is non-small cell lung cancer.

28. A method for preparing the antibody-drug conjugate according to any one of claims 14 to 25, comprising: Conducting a coupling reaction between the drug-linker conjugate and the antibody or antigen-binding fragment thereof according to any one of claims 1 to 8 or the multispecific antibody according to claim 9 under a suitable solvent and conditions; Preferably, the method comprises the step of coupling the antibody or antigen-binding fragment thereof according to any one of claims 1 to 8 or the multispecific antibody according to claim 9 with a drug-linker conjugate in a suitable solvent and conditions to form a CS bond; Further preferably, the ratio of the amount of the antibody or antigen-binding fragment thereof according to any one of claims 1 to 8 or the multispecific antibody according to claim 9 to the drug-linker conjugate is 1:(1-20), such as 1:2, 1:4, 1:6, 1:8, 1:10, 1:12, 1:14, 1:16, 1:18, 1:(10-20), 1:(12-20), 1:(14-20), 1:(16-20) or 1:(18-20); Optionally, the coupling reaction is carried out in water and / or an organic solvent.

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