Antibody coupling medicine and application thereof

Abstract

The present disclosure relates to antibody-drug conjugates, and more particularly to antibody-drug conjugates (ADCs) loaded with inhibitors of Ras mutations as well as compositions containing the ADC molecules and therapeutic applications thereof.

Description

Technical Field

[0001] The present disclosure relates to antibody-drug conjugates (ADCs) based on Ras mutation inhibitors, pharmaceutical compositions containing the same, and methods for their use in the treatment or prevention of diseases associated with Ras mutations. Specifically, the present disclosure relates to compounds, uses, and methods for treating or preventing related diseases such as tumors or cancers by targeting oncogenic mutants of Ras. Background Art

[0002] Ras belongs to the GTPase protein family. Under normal physiological conditions, Ras is activated by receiving growth factors and various other extracellular signals and is responsible for regulating functions such as cell growth, survival, migration, and differentiation. These regulatory functions of Ras are carried out through the conversion between the inactive GDP-bound state and the active GTP-bound state, i.e., the "molecular switch". Ras in the GDP-bound form is in an inactive state and will be activated when exposed to some growth-promoting stimuli such as guanine nucleotide exchange factors (GEFs), releasing GDP and binding to GTP, thereby transforming into the active GTP-bound state, which recruits and activates various downstream effectors to conduct signal transduction, thus controlling numerous key cellular processes such as differentiation, survival, and proliferation.

[0003] Ras has GTPase activity, which can cleave the terminal phosphate of GTP and convert it into GDP, i.e., convert itself into an inactive state. However, the endogenous GTPase activity of Ras is very low, and the conversion of GTP-Ras to GDP-Ras requires the exogenous protein GAP (GTPase-activating protein). GAP interacts with Ras and promotes the conversion of GTP to GDP. Therefore, any Ras gene mutation that affects the interaction between Ras and GAP or affects the conversion of GTP to GDP will cause Ras to be in an over-activated state, thereby continuously transmitting signals of growth and division to cells, stimulating cells to proliferate continuously, and ultimately leading to tumor formation and development. In fact, the dysregulation of the Ras signaling pathway is almost always associated with diseases. The over-activated somatic mutations of Ras are one of the most common lesions in human cancers.

[0004] Although mutations in any one of the three Ras isoforms (K-Ras, N-Ras, or H-Ras) have been shown to cause oncogenic transformation, KRas mutations are by far the most common mutations in human cancers, which are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and cholangiocarcinoma, and are also found in 25% of patients with non-small cell lung cancer. The vast majority of KRas mutations occur at codons G12, G13, and Q61, and approximately 80% of KRas mutations occur at the glycine at codon 12, such as G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, etc., and the G12D mutation is one of the most common mutations.

[0005] In view of this, Ras mutant proteins, such as KRas mutant proteins, have become very attractive anti-cancer drug targets in the pharmaceutical field, and the development of their inhibitors is also regarded as a very promising research and development direction in anti-cancer / tumor drug development. However, drug research and development targeting K-Ras mutations in the past few decades has shown that existing small molecule inhibitors of K-Ras mutations have many insurmountable defects, such as ineffective delivery to some lesions such as the colon, breast, and pancreas, severe drug resistance, poor membrane permeability, poor hydrophilicity, unsatisfactory oral pharmacokinetics, high toxicity of intravenous administration, etc. Therefore, KRas has long been considered an "undruggable" target.

[0006] Therefore, the present inventors have been dedicated to developing Ras, such as KRas mutant small molecule inhibitors with improved structural patterns. Due to the specifically designed structural fragments, these small molecule inhibitors have shown enhanced Ras, such as KRas mutant inhibitory activity and inhibitory activity against related tumors compared to existing Ras, such as KRas mutant inhibitors in the prior art, and at the same time have good oral pharmacokinetic properties, thus having good druggability, reduced side effects and toxicity, improved drug resistance and safety, and reduced risk of drug interactions.

[0007] Nevertheless, there is still an urgent need in the field of cancer treatment for new therapies that can more precisely deliver Ras, such as KRas mutant inhibitors, to the tumor environment, can be administered in a more friendly manner, and can prolong the drug effect, reduce side effects and toxicity, and drug resistance. The present disclosure meets the above needs.

[0008] Targeted conjugated drugs are a new technology for drug delivery with high efficiency and low toxicity, showing great superiority in the research and development of anti-cancer drugs. A cytotoxic molecule is linked to a targeting molecule such as an antibody or a peptide through a suitable linker. These targeting molecules can selectively deliver the conjugated molecule to tumor tissues with high expression of the targeting receptor, and selectively bring the anti-cancer drug into cancer cells through internalization. Then, the active anti-cancer molecule is cleaved and released by differential functional molecules enriched in tumor tissues and cancer cells. Since the active anti-cancer molecule can only be released and enriched inside tumor tissues with high expression of the targeting receptor and a specific "scissors", this dual-selective drug delivery method greatly reduces the toxicity of the anti-cancer drug and improves the drug efficacy.

[0009] The inventors of the present invention utilized a targeted conjugation strategy to further link a group of developed Ras, such as KRas mutation inhibitor compounds, to a targeting molecule such as an antibody or a peptide through a suitable linker, to prepare a group of ADC compounds based on targeted Ras, such as KRas mutation inhibitors. The developed ADC compounds have dual selectivity and can significantly reduce toxicity because they use a targeted Ras, such as a K-Ras enzyme inhibitor, as the ADC payload; they have increased conjugation efficiency and product purity due to specific modification of the linker unit, inhibit the aggregation of ADC macromolecules, and improve the drug efficacy; and these ADC macromolecules delay the metabolism of the loaded Ras, such as KRas mutation inhibitor, thereby further improving the systemic stability and PK properties of the drug, obtaining a longer half-life, persistent target inhibition, and extended drug efficacy in vivo, and thus delaying the emergence of drug resistance. Summary of the Invention

[0011] To meet the above needs in the art, the present disclosure has conducted in-depth research and conjugated a group of targeted Ras, such as KRas mutation inhibitor compounds with a specific structure, to a targeting molecule through a selected linker unit to obtain an antibody-drug conjugate as shown in the examples.

[0012] Currently, Ras inhibitors under research, such as KRas inhibitors, have shown many deficiencies during development and use, including ineffective delivery to certain lesions, severe drug resistance, poor membrane permeability, poor hydrophilicity, poor oral PK properties, high toxicity upon intravenous administration, etc.; while the antibody-drug conjugates of the present disclosure, through innovative structural modification of the components of the linker unit of the ADC and for the first time using this linker unit to conjugate a Ras small molecule inhibitor and an antibody targeting unit, can be rapidly and effectively endocytosed by tumor cells, and show significant antitumor growth activity and good tolerance compared to the individual antibody and the individual Ras inhibitor in animal models, well overcoming the above deficiencies, and are expected to be administered by more mature and friendly dosage forms (such as oral and parenteral), providing enhanced and prolonged drug efficacy, good pharmacokinetic properties, reduced toxic side effects and drug resistance, as well as an expanded indication and beneficiary population.

[0013] Accordingly, in a first aspect, the present disclosure provides an antibody-drug conjugate (ADC) of formula (X) or a pharmaceutically acceptable salt or solvate thereof:

[0014] [P-L] q -Ab (X)

[0015] Wherein,

[0016] P represents a Ras inhibitor, such as the Ras inhibitor defined in the P unit part of the drug of the present disclosure (such as the compounds of formula (I) and its respective sub-formulas defined in the present disclosure);

[0017] L represents a linker unit that connects P to Ab;

[0018] q represents the number of [P-L] linkers connected to Ab, for example, an integer or non-integer from 1 to 20, such as 1-10, 1-8, 2-8, 3-8, 4-8 or 6-8;

[0019] Ab represents an antibody or antigen-binding fragment.

[0020] In a second aspect, the present disclosure provides a pharmaceutical composition comprising the ADC of the present disclosure or its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, optionally at least one other therapeutic agent and optionally one or more pharmaceutically acceptable excipients.

[0021] In a third aspect, the present disclosure provides the ADC of the present disclosure or its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same, for use as a therapeutic agent for treating or preventing a disease mediated by a Ras mutant protein (such as but not limited to G12C mutant, G12D mutant, G12V mutant, G12A mutant, G12R mutant, G12S mutant, and G13D mutant proteins), more specifically for treating or preventing a hyperproliferative disease, especially for use as an anti-tumor therapeutic agent. In some specific embodiments, the Ras mutant protein is a KRas mutant protein.

[0022] In a fourth aspect, the present disclosure provides the use of the ADC of the present disclosure or its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same in preventing or treating a disease mediated by a Ras mutant protein (such as but not limited to G12C mutant, G12D mutant, G12V mutant, G12A mutant, G12R mutant, G12S mutant, and G13D mutant proteins), more specifically in treating or preventing a hyperproliferative disease, especially in tumors.

[0023] In a fifth aspect, the present disclosure provides a method for treating or preventing a disease mediated by a Ras mutant protein (such as but not limited to G12C mutant, G12D mutant, G12V mutant, G12A mutant, G12R mutant, G12S mutant, and G13D mutant proteins) in a subject, the method comprising administering to a human or an animal the ADC of the present disclosure or its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same; specifically, the present disclosure provides a method for treating or preventing a hyperproliferative disease, especially a tumor, in a subject, the method comprising administering to a human or an animal the ADC of the present disclosure or its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same.

[0024] In a sixth aspect, the present disclosure provides the use of the ADC of the present disclosure or its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same in the preparation of a drug for preventing or treating a disease mediated by a Ras mutant protein (such as but not limited to G12C mutant, G12D mutant, G12V mutant, G12A mutant, G12R mutant, G12S mutant, and G13D mutant proteins); specifically, the present disclosure provides the use of the ADC of the present disclosure or its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same in the preparation of a drug for treating or preventing a hyperproliferative disease, especially a tumor.

[0025] In a seventh aspect, the present disclosure provides a pharmaceutical combination comprising an ADC of the present disclosure or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, and at least one other therapeutic agent; the use of the combination for preventing or treating a disease mediated by a Ras mutant protein (such as but not limited to G12C mutant, G12D mutant, G12V mutant, G12A mutant, G12R mutant, G12S mutant and G13D mutant proteins), more specifically for treating or preventing a hyperproliferative disease, particularly a tumor; and a method for treating or preventing a disease mediated by a Ras mutant protein (such as G12C mutant, G12D mutant, G12V mutant, G12A mutant, G12R mutant, G12S mutant and G13D mutant proteins) in a subject, more specifically a hyperproliferative disease, particularly a tumor, the method comprising administering the pharmaceutical combination of the present disclosure to a human or an animal.

[0026] In an eighth aspect, the present disclosure also provides a method for preparing an ADC of the present disclosure or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof by conjugating a Ras inhibitor as defined herein to an antibody or an antigen-binding fragment thereof via a linker unit. The Ras inhibitor compound as defined herein can be conjugated to the antibody or antigen-binding fragment via a cleavable or non-cleavable linker unit. In a specific embodiment, when the linker unit cleaves, the Ras inhibitor is released into tumor cells, cancer-related immune cells or the tumor microenvironment.

[0027] In some embodiments of the various aspects of the present disclosure above, the Ras mutant protein is a KRas mutant protein, specifically a KRas G12D mutant protein, and correspondingly the P inhibitor compound is a KRas inhibitor, specifically a KRas G12D inhibitor; in other embodiments, the Ras mutant protein is not limited to a specific subtype and / or mutation site, i.e., it is pan-Ras, and correspondingly the P inhibitor compound is a pan-Ras inhibitor.

[0028] The present disclosure is further illustrated in the following drawings and specific embodiments. However, these drawings and specific embodiments should not be considered as limiting the scope of the present disclosure, and modifications readily contemplated by those skilled in the art will be included within the spirit of the present disclosure and the scope of the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Attached Figure 1 Showing the anti-tumor effect and body weight change in a subcutaneous xenograft BALB / c Nude mouse animal model of human colon cancer cells GP2D with KRAS-G12D mutation by some representative ADC compounds of the present disclosure (administered at a dose of 20 mg / kg, administered on D0 / 7 days, for 21 days).

[0030] AttachedFigure 2 Shown are the anti-tumor effects and body weight changes of some representative ADC compounds of the present disclosure in a BALB / c Nude mouse animal model with subcutaneous xenografts of human colon cancer cells GP2D with KRAS-G12D mutation (administered at a dose of 10 mg / kg, on day D0, for 21 days) in another batch of experiments.

[0031] Attached Figure 3 Shown are the anti-tumor effects of some representative ADC compounds of the present disclosure in a BALB / c Nude mouse animal model with subcutaneous xenografts of human colon cancer cells GP2D with KRAS-G12D mutation (administered at a dose of 10 mg / kg, on day D0, for 20 days) in another batch of experiments.

[0032] Attached Figure 4A 、 4B 、4C shows the results from the same another batch of experiments, i.e., the anti-tumor effects of some representative ADC compounds of the present disclosure in a BALB / c Nude mouse animal model with subcutaneous xenografts of human colon cancer cells GP2D with KRAS-G12D mutation (administered at a dose of 10 mg / kg, on day D0, for 20 days). For the purpose of clear display, the example compounds in this batch of experiments are separately shown in Figure 4A 、 4B and 4C.

[0033] Attached Figure 5 and attached Figure 6 respectively represent the anti-tumor effects of some representative ADC compounds, drug P units, and antibodies of the present disclosure in a BALB / c Nude mouse animal model with subcutaneous xenografts of human colon cancer cells GP2D with KRAS-G12D mutation (administered at a dose of 10 mg / kg, on days D0 and / or 7 and / or 14, for 21 days).

[0034] Attached Figure 7 Shows a schematic diagram of the linkage of the KRas mutation inhibitor, a drug payload of the ADC of the present disclosure, with the linker unit L and the antibody. Detailed Description of the Invention

[0035] Definitions

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of the present disclosure, the following terms are defined below.

[0037] When a trade name is used herein, unless the context otherwise indicates, the trade name includes the product formulation of the trade name product, the generic drug, and the active pharmaceutical ingredient.

[0038] As used herein, the term "substantially" refers to the vast majority, i.e., > about 50% of a population, mixture, sample, content, or any other numerical value, preferably greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0039] As used herein, the term "and / or" shall be understood to mean any one of the alternatives or a combination of any two or more of the alternatives.

[0040] As used herein, the term "ADC" or "conjugate" refers to an antibody-drug conjugate.

[0041] As used herein, the term "drug" refers to a substance that produces a beneficial prophylactic or therapeutic effect on a disease mediated by a Ras mutant protein, such as a KRas mutant protein (such as, but not limited to, G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, and G13D mutant protein).

[0042] As used herein, the term "Ras mutation" or "Ras mutant protein" refers to a protein encoded and expressed by a Ras gene in which one or more codons are mutated, typically including, but not limited to, a Ras protein in which glycine at codon 12, glycine at codon 13, or glutamine at codon 61 of Ras is mutated, such as mutant HRas, NRas, or KRas. These residues are located at the active site of Ras, and their mutation can impair the intrinsic or GAP-catalyzed GTPase activity of Ras, resulting in the persistent presence of GTP-bound Ras.

[0043] For the purposes of the present disclosure, "Ras mutation" or "Ras mutant protein" and "Ras" when describing inhibitory activity can be used interchangeably, e.g., referring to mutant KRas, such as, but not limited to, KRas-G12C (mutation of glycine to cysteine at codon G12), KRas-G12D (mutation of glycine to aspartic acid at codon G12), HRas-G12D, NRas-G12D, KRas-G12V (mutation of glycine to valine at codon G12), KRas-G13D (mutation of glycine to aspartic acid at codon G13); in some embodiments referring to a KRas mutant protein, more particularly to a KRas-G12C mutant protein, a KRas-G12D mutant protein, a KRas-G12V mutant protein, a G12A mutant protein, a G12R mutant protein, a G12S mutant protein, a KRas-G13D mutant protein, most particularly to KRas-G12D, and in other embodiments referring to a pan-RAS mutant protein, i.e., not limited to a specific subtype and mutation site.

[0044] As used herein, the term "Ras mutation-mediated disease" refers to a disease in which a Ras mutation promotes the occurrence and development of the disease, or in which inhibition of the Ras mutation will reduce the incidence of the disease and reduce or eliminate the symptoms of the disease. For the present disclosure, "Ras mutation-mediated disease" refers in some embodiments to a KRas mutation-mediated disease, most preferably KRas-G12D, and in other embodiments to a pan-Ras-mediated disease, such as a hyperproliferative disease such as cancer or tumor.

[0045] As used herein, the terms "cancer" or "tumor" refer to abnormal cell growth and proliferation, including solid tumors and hematogenous tumors, whether malignant or benign, and all pre-cancerous cells and cancer cells and tissues. For various aspects of the present disclosure, the cancer or tumor includes but is not limited to adenocarcinoma of the lung, lung cancer (including squamous cell carcinoma of the lung and non-small cell lung cancer, small cell lung cancer (SCLC)), bone cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, skin cancer, head and neck cancer (including squamous cell carcinoma of the head and neck), melanoma (including cutaneous or uveal melanoma), squamous cell carcinoma, cancer of the anal region, testicular cancer, urethral cancer, ureteral cancer, penile cancer, prostate cancer (including hormone-refractory prostate cancer), bladder cancer, uterine cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, gastric cancer, gastric adenocarcinoma, colon cancer, rectal cancer, colorectal cancer, liver cancer, breast cancer (including metastatic breast cancer, triple-negative breast cancer (TNBC)), esophageal cancer, small intestine cancer, lip cancer, laryngeal cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, peritoneal cancer, gastrointestinal stromal tumor, gastroesophageal junction (GEJ) cancer, mesothelioma, biliary tract cancer, hepatocellular carcinoma, seminoma, soft tissue sarcoma, osteosarcoma, urothelial carcinoma, sweat gland cancer, endocrine system cancer, thyroid cancer, medullary thyroid cancer, follicular thyroid cancer, papillary thyroid cancer, parathyroid cancer, kidney cancer, renal parenchymal cancer, renal cell carcinoma, renal pelvic cancer, adrenal cancer, brain cancer such as glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumor, glioblastoma multiforme (including glioblastoma multiforme), neuroblastoma; chronic or acute leukemia, Hodgkin's disease, lymphoma (including lymphocytic lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), primary CNS lymphoma), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CLL) and lymphocytic carcinoma, acute myelogenous leukemia (AML), myelogenous leukemia (chronic myelogenous leukemia (CML), central nervous system tumors (CNS), spinal tumors, brainstem glioma or pituitary adenoma.

[0046] For various aspects of the present disclosure, preferably, the cancer or tumor is associated with a Ras mutation, such as a KRas mutation, including but not limited to the above-mentioned tumor types and their preferred ranges. Particularly preferred tumors of the present invention include lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer, cholangiocarcinoma, leukemia, and ovarian cancer.

[0047] As used herein, the term "anti-tumor effect" refers to a biological effect that can be characterized in various forms, including but not limited to, for example, a reduction in tumor volume, a reduction in the number of tumor cells, a reduction in tumor cell proliferation, or a reduction in tumor cell survival.

[0048] As used herein, the terms "inhibit" and "reduce" or any variants of these terms refer to the ability of a bioactive agent to reduce the signal transduction activity of a target by directly or indirectly interacting with the target, and refer to any measurable reduction or complete inhibition of the activity of the target. For example, compared to normal conditions, it can be a reduction in activity (such as Ras activity, such as KRas activity) of about, at most about, or at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, or any range derivable therefrom.

[0049] The term "selective inhibition" as used herein refers to the ability of a bioactive agent to preferentially reduce the signal transduction activity of a target compared to off-target signal activities by directly or indirectly interacting with the target. For the Ras inhibitors and ADCs of the present disclosure, with respect to various mutations occurring in one or more codons of the Ras protein, it has the ability to selectively inhibit G12 or G13 mutations of the KRas protein, such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, and G13D mutation, preferably the ability to selectively inhibit the G12D mutation of the KRas protein. For example, compared to the inhibition of another specific Ras mutation, the Ras inhibitors and ADCs of the present disclosure have a higher inhibitory activity against a specific mutation such as KRas-G12D by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therefrom, or is at least 0.1-, 0.5-, 1-, 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-, or 500-fold or higher in inhibitory activity against a specific mutation such as KRas-G12D compared to the activity against another specific Ras mutation.

[0050] As used herein, the term "dual selective inhibition" refers to the ability of a conjugate drug to target and inhibit a specific Ras mutation through a small molecule targeting inhibitor on the one hand, and on the other hand, to highly selectively target and deliver the loaded Ras targeting inhibitor to tumor tissues with high expression of the guiding receptor by means of the linked guiding antibody molecule, thereby exerting a dual selective inhibitory effect.

[0051] As used herein, the term "antigen" refers to an entity that specifically binds to an antibody.

[0052] As used herein, the term "antibody" refers to a polypeptide comprising at least the immunoglobulin variable region of a light or heavy chain, the immunoglobulin variable region specifically recognizing and binding an antigen. The term encompasses various antibody structures, including but not limited to monoclonal antibodies, single-chain antibodies or multichain antibodies, monospecific or multispecific antibodies (e.g., bispecific antibodies), chimeric antibodies or humanized antibodies, full-length antibodies and antibody fragments, provided that they exhibit the desired antigen-binding activity. Antibodies can be of any class (e.g., IgG, IgE, IgM, IgD and IgA), type (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subtype.

[0053] As used herein, the terms "antibody fragment" and "antigen-binding fragment" of an antibody are used interchangeably and refer to a molecule that is not a complete antibody and that contains the portion of the complete antibody that is used to bind the antigen to which the complete antibody binds. As will be understood by those skilled in the art, antibody fragments typically contain amino acid residues from "complementary determining regions" or "CDRs" for the purpose of antigen binding. Antibody fragments can be prepared by recombinant DNA techniques, or by enzymatic or chemical cleavage of a complete antibody. Antigen-binding fragments include but are not limited to Fab, scFab, Fab’, F(ab’)2, Fab’-SH, Fv, single-chain Fv, diabody, triabody, tetrabody, minibody, single-domain antibody (sdAb); and multispecific antibodies formed from antibody fragments.

[0054] As used herein, reference to an IgG antibody means that the antibody is a heterotetrameric protein having the immunoglobulin structure of the IgG class. In an IgG antibody, typically the VH-CH1 of the heavy chain pairs with the VL-CL of the light chain to form a Fab fragment that specifically binds an antigen. Thus, an IgG antibody consists essentially of two Fab molecules and two dimerized Fc regions linked by an immunoglobulin hinge region. In some embodiments, the IgG antibody is, for example, an IgG1, IgG2, IgG3 or IgG4 antibody. In other embodiments, the IgG antibody is an IgGκ or IgGλ antibody, such as an IgG1κ or IgG1λ antibody.

[0055] In this text, the terms "complementary determining region" or "CDR region" or "CDR" or "hypervariable region" are used interchangeably and refer to the regions in the variable domains of antibodies that are highly variable in sequence and form structurally defined loops ("hypervariable loops") and / or contain antigen - contacting residues ("antigen - contact points"). CDRs are mainly responsible for binding to antigen epitopes. In this text, the CDRs of the heavy and light chains of antibodies are sequentially numbered starting from the N - terminus and are commonly referred to as CDR1, CDR2, and CDR3. The CDRs located within the variable domain of the heavy chain of an antibody are also referred to as HCDR1, HCDR2, and HCDR3, while the CDRs located within the variable domain of the light chain of an antibody are referred to as LCDR1, LCDR2, and LCDR3. In a given amino acid sequence of a variable light - chain or heavy - chain region, various well - known schemes in the art can be used to determine its CDR sequence, including CDR sequences defined based on Kabat, AbM, Chothia, Contact, and IMGT. In addition, CDRs can also be determined based on having the same Kabat - numbered positions as a reference CDR sequence.

[0056] In this text, the "variable region" or "variable domain" is the domain in the heavy or light chain of an antibody that participates in the binding of the antibody to its antigen. The heavy - chain variable region (VH) and the light - chain variable region (VL) can be further divided into hypervariable regions (HVRs, also known as complementary - determining regions (CDRs)), which are interspersed with more conserved regions (i.e., framework regions (FRs)). Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino - terminus to the carboxyl - terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some aspects, the variable regions of antibodies can be modified by CDR transplantation. Since the CDR sequences are responsible for most antibody - antigen interactions, recombinant antibody variants that mimic the properties of known antibodies can be constructed. In such antibody variants, the CDR sequences from a known antibody are transplanted onto the framework regions of different antibodies with different properties. The properties of the mutated and / or modified antibodies or ADC conjugates containing them, such as target - antigen - binding properties or other desired functional properties, such as endocytosis, pharmacokinetics, and in - vivo tumor - killing activity of the ADC, can be evaluated in in - vitro or in - vivo assay tests.

[0057] In this text, the term "isotype" refers to the type of antibody determined by the constant region of the heavy chain of the antibody. For example, according to the present disclosure, the antibody portion of the ADC can be an IgA (e.g., IgA1 or IgA2), IgG1, IgG2 (e.g., IgG2a or IgG2b), IgG3, IgG4, IgE, IgM, and IgD antibody and has the heavy - chain constant region of the said immunoglobulin type. In addition, the present disclosure contemplates not only antibodies with native - sequence constant regions but also antibodies containing variant - sequence constant regions.

[0058] As used herein, the term "epitope" includes any protein determinant capable of specific binding to an immunoglobulin or otherwise interacting with a molecule. Epitope determinants are usually composed of the chemically active surface groups of the molecule, such as amino acids or carbohydrate or sugar side chains, and may have specific three-dimensional structural features as well as specific charge features. Epitopes can be "linear" or "conformational". The difference between conformational and linear epitopes lies in the loss of binding to the former but not the latter in the presence of a denaturing solvent.

[0059] As used herein, the term "receptor-mediated endocytosis" refers to the process by which a ligand / receptor complex is internalized and delivered into the cytosol or transferred to a suitable intracellular compartment, triggered by the binding of a ligand to its corresponding receptor on the cell surface. The receptor-mediated endocytic activity of an antibody can be characterized by measuring the rate of endocytosis.

[0060] As used herein, "sequence identity" refers to the degree of sequence identity on a nucleotide-by-nucleotide or amino acid-by-amino acid basis in a comparison window. The "percent sequence identity" can be calculated by comparing two optimally aligned sequences in the comparison window, determining the number of positions at which the same nucleic acid base (e.g., A, T, C, G, I) or the same amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met) exist in both sequences to obtain the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window (i.e., window size), and multiplying the result by 100 to yield the percent sequence identity. The optimal alignment for determining percent sequence identity can be achieved in a variety of ways known in the art, e.g., using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithms required to achieve the maximum alignment over the full length of the sequences being compared or within the target sequence region.

[0061] As used herein, the term "isolated" antibody is an antibody that has been separated from the components in its natural environment. In some embodiments, the antibody is purified to greater than 90%, 95%, or 99% purity, which can be determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

[0062] In this text, the term "affinity" or "binding affinity" refers to the inherent binding affinity that reflects the interaction between members of a binding pair, such as the strength of the interaction between an antibody and an antigen at a single antigenic site. The stronger the interaction, the higher the affinity. The affinity of a molecule for its partner can generally be represented by the equilibrium dissociation constant (K D ), which is the ratio of the dissociation rate constant and the association rate constant (k dis and k on respectively). Affinity can be measured by common methods known in the art, such as ELISA assays based on antigen proteins or cells, flow cytometry assays, techniques based on biolayer interferometry (BLI), etc.

[0063] In this text, the term "K D " (M) refers to the dissociation equilibrium constant of a specific antibody-antigen interaction in this text. Affinity is inversely correlated with the K D value, that is, the higher the affinity, the smaller the K D value; conversely, the lower the affinity, the larger the K D value. Generally, the K D value depends on the dissociation rate constant (Kd or Kdis, sec -1 ) and the association rate constant (Ka, M -1 × sec -1 ) between the interacting antibody-antigen pair.

[0064] In this text, the term "binding" or "specific binding" refers to the ability of a single antibody binding site to react with one antigenic determinant and not with different antigenic determinants. In the context of antibody binding to an associated antigen, binding with an affinity having a K -6 value of approximately 10 D M or less is referred to, for example, a K D value of approximately 10 -7 M or less, or approximately 10 -8 M or less. Compared with the K D value of binding to a non-specific antigen (such as an irrelevant antigen, such as BSA), the K D value of the antibody binding to its associated antigen is preferably at least 100-fold lower or, for example, at least 1000-fold lower. Measurement of the K D value is known in the art, for example, based on biolayer interferometry (BLI) technology, in an instrument such as ForteBio , using the antibody as a ligand and the antigen as an analyte for the assay.

[0065] As used herein, the term "effector function" refers to those biological activities attributable to the Fc-region of an antibody, which vary with antibody class. It has been known that the IgG Fc region can mediate several important effector functions, such as cytokine induction, ADCC, phagocytosis, complement-dependent cytotoxicity (CDC), and the half-life / clearance rate of antibodies and antigen-antibody complexes. In some cases, depending on the therapeutic purpose, these effector functions are desirable for therapeutic antibodies, but may be unnecessary in other cases. Thus, in one embodiment, the present disclosure provides antibodies having an Fc region that elicits effector functions such as ADCC or CDC, thereby inducing tumor cell apoptosis, cell lysis, and / or inhibiting the proliferation, dissemination, and / or metastasis of tumor cells carrying the TF antigen in tumor cells carrying the TF antigen. In other embodiments, the present disclosure also provides antibodies having an Fc region with altered effector functions. The effector functions can be altered by making sequence changes to the Fc region of the antibody. Alternatively, antibodies can be prepared with an altered type of glycosylation in the Fc region. Alterations in the Fc region glycosylation pattern can be conveniently achieved by altering the amino acid sequence of the Fc region to generate or remove one or more glycosylation sites.

[0066] As used herein, the term "linker unit" or "linker" refers to a bifunctional moiety that links a drug to an antibody in an antibody-drug conjugate. The linker units of the present disclosure have multiple components, such as a self-degrading linker, a cleavable linker, a property-modulating unit, and an antibody linker.

[0067] As used herein, the term "self-degrading linker" refers to a temporary extender, spacer, or placeholder unit that links two or more molecules together by chemical bonds that break under defined conditions to release the two molecules. Generally, the self-degrading linker unit can be linear or branched, and can link two or more identical molecules together, or can link two or more different molecules together. The self-degrading unit can be defined as a bifunctional chemical group that is capable of covalently linking two spaced-apart chemical moieties together to form a generally stable molecule, releasing one of the spaced-apart chemical moieties from the molecule by enzymatic cleavage; and, after the enzymatic cleavage, spontaneously cleaving from the remaining portion of the bifunctional chemical group to release the other of the spaced-apart chemical moieties. In some embodiments, the self-degrading unit refers to a heterocyclic self-degrading moiety. Typical self-degrading linker units include, but are not limited to, His-Ala, p-aminobenzyloxycarbonyl (PABC), p-hydroxybenzyloxycarbonyl, 2,4-bis(hydroxymethyl)aniline, -NH-(CH2)4-C(O)-, and -NH-(CH2)3-C(O)-, etc.

[0068] As used herein, the term "cleavable linker" refers to the in vivo labile portion of the linker unit of an ADC. Preferably, the "cleavable linker" allows activation of the label or therapeutic agent by cleavage of the label or reagent from the remainder of the conjugate. Operationally defined, the cleavable linker is preferably cleaved by the biological environment in vivo. The cleavage can result from any process without limitation, such as enzymatic, reduction, pH, etc. Preferably, the cleavable group is selected such that activation occurs at the desired site of action, which can be a target cell (e.g., cancer cell) or a site in or near the tissue, such as a site of therapeutic action or label activity. Such cleavage can be enzymatic, and exemplary enzymatic groups include natural amino acids or peptide sequences ending with natural amino acids, and are attached to the linker unit or self-degrading linker at their carboxyl terminus.

[0069] As used herein, the term "antibody linker" refers to any chemical group designed to facilitate attachment of a drug conjugate to an antibody.

[0070] As used herein, the term "property modulating unit" refers to a functional moiety connected in a tandem or branched manner in the linker unit of an ADC, designed to modulate the properties of the ADC, such as stability in blood circulation, improved hydrophilicity, etc. Commonly used property modulating units of ADCs include, but are not limited to, polyethylene glycol (PEG), hydrophilic peptides, monosaccharides, oligosaccharides, polysaccharides, cyclodextrin units, polyamines, polyamides, dendrimers, and bifunctional hydrocarbon chains, etc. In the ADCs of the present disclosure, the property modulating unit can be connected in a tandem manner as a separate component in the linker unit, or can exist as a branched chain of each component in the linker unit. For example, the property modulating unit can be connected to a self-degrading linker, a cleavable linker, and / or an antibody linker.

[0071] Specific examples of the term "property modulating unit" as used herein include "solubilizing sugar unit", which refers to a sugar unit (directly or indirectly connected through other structural fragments) connected to the linker unit, such as the self-degrading linker portion of the linker. This sugar unit, together with the self-degrading linker, is specifically hydrolyzed in vivo by an enzyme such as β-glucuronidase or β-galactosidase, and releases the drug payload through a self-degradation reaction. In the antibody-drug conjugates of the present disclosure, introducing a glycosyl group into the linker unit helps to improve the hydrophilicity of the conjugate chain, increase the payload loading rate to the theoretical maximum value, while improving the solubility and purity of the conjugate, reducing aggregation, improving the drugability of the conjugate, and ultimately enhancing the inhibition of tumor cell proliferation.

[0072] As used herein, the "monosaccharide" as a property regulating unit refers to a polyhydroxy aldehyde (aldose) or polyhydroxy ketone (ketose) containing 3 or more carbon atoms and their derivatives, which are the basic structural units constituting saccharides and their complexes, cannot be hydrolyzed further, and do not have glycosidic linkages with other similar units. According to the number of carbon atoms in the monosaccharide, monosaccharides can also be classified into trioses (trioses), tetroses (tetroses), pentoses (pentoses), hexoses (hexoses), heptoses (heptoses), etc. Pentoses or hexoses are preferably carried in the ADCs of the present disclosure. The derivatives of the monosaccharide include, for example, phosphates of monosaccharides, sugar alcohols, sugar acids, deoxysugars, amino sugars, acylated amino sugars, and glycosides. Examples of monosaccharides or their derivatives include, but are not limited to, glyceraldehyde, glyceraldehyde phosphate, dihydroxyacetone phosphate, erythrose, erythrulose, threose, arabinose, ribose, ribulose, deoxyribose, ribitol, ribose phosphate, xylose, xylulose, xylitol, lyxose, glucose, glucosamine, N-acetylglucosamine, glucuronic acid, N-acetylglucuronic acid, glucose phosphate, mannose, mannitol, aminomannitol, N-acetylmannosamine, fructose, fructose phosphate, galactose, galactitol, galactosamine, N-acetylgalactosamine, allose, deoxyallose, altrose, deoxyaltrose, quinic sugar, rhamnose, psicose, sorbose, sorbitol, tagatose, gulose, deoxygulose, idose, talose, fucose, deoxytalose, etc.

[0073] It should be noted that the monosaccharides and their derivatives described in the present disclosure include their D configurations, L configurations, racemates (DL), and meso forms, and also include any optically active forms ((+), (-), (±)). The monosaccharides and their derivatives described in the present disclosure include their chain isomers, cyclic isomers, or mixtures thereof, where the cyclic forms include α-anomers and β-anomers, and also include, for example, pyranose forms or furanose forms.

[0074] As used herein, the "disaccharide" as a property regulating unit refers to a compound formed by linking two monosaccharides through a glycosidic bond and its derivatives, which are divided into two types according to different linking methods: one is a non-reducing sugar formed by dehydration of the hemiacetal (hemiketal) hydroxyl groups of two sugars to form a glycoside, which is a glycosyl glycoside; the other is a reducing sugar formed by glycosidation of the hemiacetal (hemiketal) hydroxyl group of one sugar with the non-hemiacetal (hemiketal) hydroxyl group of another sugar, which is a glycosyl sugar. The glycosidic bond can be an α-1,4 glycosidic bond, an α-1,6 glycosidic bond, a β-1,4 glycosidic bond, an α-1-2β glycosidic bond, a β-1,6 glycosidic bond, an α-1,1 glycosidic bond, a β-1,3 glycosidic bond, a β-2,1 glycosidic bond. Specific examples of disaccharides include, but are not limited to, maltose, isomaltose, lactose, sucrose, chitobiose, rutinose, trehalose, xylobiose, gentiobiose, etc., where the monosaccharide units constituting the disaccharide can be in the form of various monosaccharide derivatives as described above.

[0075] As used herein, the term "oligosaccharide" refers to a low-degree polymerized sugar and its derivatives formed by glycosidic bonds connecting 3 to 9 monosaccharides, where the monosaccharides, glycosidic bonds, and derivatives are as defined above, such as, but not limited to, mannotriose, selaginellose, gentianose, plantain sugar, stachyose, raffinose, etc.

[0076] As used herein, the term "polysaccharide" is formed by connecting 10 or more monosaccharide groups through glycosidic bonds, and the glycosidic bonds can be α-type, β-type, or α / β mixed type, and can be linear, branched, or cyclic in structure. Polysaccharides can be homopolysaccharides composed of one type of monosaccharide, and the sugar units of the homopolysaccharides are selected from trioses, tetroses, pentoses, hexoses, heptoses, octoses, or deoxysugar units, such as dextran, xylan, polysialic acid, etc.; or heteropolysaccharides composed of two or more types of monosaccharides, such as hyaluronic acid, heparin, etc. Examples of polysaccharides include, but are not limited to, dextran, levan, hyaluronic acid, cyclodextrin (α, β, γ, etc.), hydroxyethyl starch, xylan, water-soluble starch, water-soluble cellulose, carboxymethyl cellulose, galactosamine, polysialic acid, rhamnose, ganoderma lucidum polysaccharide, lentinan, chitin, chitosan, alginate, carrageenan, gellan gum, pullulan, scleroglucan, xanthan gum, xyloglucan, amylose, etc. The polysaccharides can be those that inherently carry or are structurally modified to carry one or more substituents selected from the following: carboxyl group, carboxylate group, amino group, sulfonic acid group, sulfonate group, phosphate group, phosphonate group, hydroxyethyl, hydroxypropyl, methyl, acyl group, carboxymethyl, natural amino acid group, unnatural amino acid group, etc.

[0077] As used herein, the term "derivative" used to describe sugar units mainly refers to sugar phosphates (sugar compounds formed by esterification of one or more hydroxyl groups of a sugar with phosphoric acid), sugar alcohols (sugar compounds formed by reducing the carbonyl group of a sugar to OH), sugar acids (aldonic acids formed by oxidizing the aldehyde group of an aldose to a carboxyl group, uronic acids formed by oxidizing the primary alcohol group in an aldose to a carboxyl group, and saccharic acids formed by oxidizing both the aldehyde group and the primary alcohol group of an aldose to carboxyl groups), deoxysugars (sugars in which one or two hydroxyl groups in the sugar molecule are replaced by hydrogen atoms), amino sugars (sugar derivatives in which one or more hydroxyl groups in the sugar molecule are replaced by amino groups), acylated amino sugars (sugar derivatives in which the amino group of an amino sugar is acylated), and glycoside forms (sugar derivatives formed by condensing the hemiacetal hydroxyl group of a sugar with a hydroxyl group, amino group, or mercapto group of another molecule such as an alcohol, sugar, purine, or pyrimidine, that is, derivatives formed by connecting a sugar residue (sugar minus the hemiacetal hydroxyl group) and a ligand through a glycosidic bond), preferably in the form of sugar acids, amino sugars, or acylated amino sugars.

[0078] Sugar derivatives applicable to the ADCs of the present disclosure may also be derivatives formed by derivatizing sugar molecules in one or more of the above ways. For example, acylated amino sugar acids, such as 2-acetamido-2-deoxy-D-galacturonic acid, 2-acetamido-2-deoxy-D-glucuronic acid, 2-acetamido-2-deoxy-D-mannuronic acid.

[0079] As used herein, specific examples of the term "property modulating unit" also include "PEG units". The term "PEG unit" refers to an organic moiety containing repeating ethyleneoxy subunits (PEG or PEG subunits), which may be polydisperse, monodisperse or discrete (i.e., having a discrete number of ethylene-oxy subunits). Polydisperse PEG is a non-uniform mixture of sizes and molecular weights, while monodisperse PEG is typically purified from a non-uniform mixture and thus has a single chain length and molecular weight. Preferred PEG units contain discrete PEGs, which are compounds synthesized in a stepwise manner rather than via a polymerization process. Discrete PEGs provide a single molecule with a defined and specified chain length.

[0080] The PEG units provided herein include one or more polyethylene glycol chains, each polyethylene glycol chain consisting of one or more ethyleneoxy subunits, covalently linked to each other. The polyethylene glycol chains may be linked together, for example, in a linear, branched or star configuration. Typically, prior to incorporation into the ADC conjugate, at least one polyethylene glycol chain is derivatized at one end with an alkyl moiety substituted with an electrophilic group to covalently link to the carbamate nitrogen of the methylene carbamate unit. Typically, the terminal ethyleneoxy groups in each polyethylene glycol chain that are not involved in covalently linking to the remainder of the linker unit are modified with a PEG capping unit, typically an optionally substituted alkyl group, such as -CH3, CH2CH3 or CH2CH2CO2H. Preferred PEG units have a single polyethylene glycol chain having 2 to 24 -CH2CH2O- subunits covalently linked in series.

[0081] As used herein, specific examples of the term "property modulating unit" also include "hydrophilic peptides". The term "hydrophilic peptide" may be attached, for example, to the self-cleaving linker of the linker unit, or may be attached to the antibody linker head, which may be directly attached to the linker unit or attached to the linker unit via a suitable structural fragment (such as the formula (A) or (A1) fragment as defined in the present disclosure). Specifically, a "hydrophilic peptide" refers to an organic moiety containing repeating subunits -CO-CR′R″-NR-, wherein one or more amino acids, identical or different from each other, are linked via amide bonds in a linear, branched or star configuration, and each hydrophilic peptide generally contains 1-20 amino acids, preferably 4-14 amino acids, more preferably 6-12 amino acids.

[0082] In this text, the amino acid monomers constituting the hydrophilic peptide can be natural amino acids, such as alanine (Ala), arginine (Arg), aspartic acid (Asp), asparagine (Asn), histidine (His), glycine (Gly), glutamic acid (Glu), glutamine (Gln), phenylalanine (Phe), lysine (Lys), leucine (Leu), serine (Ser), tyrosine (Tyr), threonine (Thr), isoleucine (Ile), proline (Pro), tryptophan (Trp), valine (Val), cysteine (Cys), methionine (Met). Correspondingly, in the repeating subunit -CO-CR’R”-NR-, R is H and one of R’ and R” is H, and the other corresponds to the corresponding group or fragment in each natural amino acid; preferably polar natural amino acids, such as arginine, serine, threonine, tyrosine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, histidine, glycine, tryptophan.

[0083] In this text, the amino acid monomers constituting the hydrophilic peptide can also be amino acids other than the above twenty natural amino acids, such as ornithine (Orn), β-alanine (β-Ala), citrulline (Cit), sarcosine (Sar), and those amino acids in which R, R’, and R” in the repeating subunit -CO-CR’R”-NR- are different from the corresponding groups or fragments in natural amino acids. For example, R, R’, and R” are selected from alkyl, aryl, acyl, amide, ketone, azide, hydroxyl, mercapto, hydrazine, cyano, quaternary ammonium, halogen, acylhydrazine, alkenyl, alkynyl, ether, thiol, seleno, sulfonic acid, sulfate, borate, phosphonyl, phosphate, heterocycle, enone, imine, aldehyde, ester, thioacid, hydroxylamine, amino, etc. or any combination thereof, or a group containing alkyl, aryl, acyl, amide, ketone, azide, hydroxyl, mercapto, hydrazine, cyano, quaternary ammonium, halogen, acylhydrazine, alkenyl, alkynyl, ether, thiol, seleno, sulfonic acid, sulfate, borate, phosphonyl, phosphate, heterocycle, enone, imine, aldehyde, ester, thioacid, hydroxylamine, amino, etc.; preferably those amino acids in which R, R’ and / or R” contain hydrophilic groups, such as R, R’, and R” are each independently carboxyl, sulfonic acid, sulfate, phosphate, amino, amide, quaternary ammonium, oxygen-containing group, ether group, mercapto or hydroxyl, or a group containing carboxyl, sulfonic acid, sulfate, phosphate, amino, amide, quaternary ammonium, oxygen-containing group, ether group, mercapto and / or hydroxyl, such as alkyl, such as C 1-6 alkyl.

[0084] For the ADCs of the present disclosure, when the linker unit carries a hydrophilic peptide, at least 50% to 100% of the amino acids constituting the hydrophilic peptide are hydrophilic amino acids, such as 80% - 100%, such as 60%, 70%, 80%, 90% or 100%, and the amino acids are preferably arginine, serine, threonine, tyrosine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, histidine, glycine, tryptophan, ornithine, citrulline (Cit), sarcosine (Sar).

[0085] For the ADCs of the present disclosure, the hydrophilic peptide carried by the linker unit is preferably poly(sarcosine), poly(arginine), poly(glycine) of 4 - 14 units, more preferably poly(sarcosine) of 6 - 12 units.

[0086] As used herein, the term "drug:antibody ratio" or "DAR" refers to the ratio of the drug moiety (D) conjugated to the Ab moiety described herein in an ADC conjugate to the Ab moiety. In some embodiments described herein, the DAR can be determined by q in Formula I. For example, the DAR can be an integer or non-integer of at least 1, such as about 1 to 20, such as about 2-18, 4-16, 5-12, 6-10, 1-10, 1-8, 2-8, 3-8, 2-6, 4-6, 4-8, 6-8, 6-10, such as about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. The DAR can also be calculated as the average DAR of the molecular population in the product, i.e., the overall ratio of the small molecule drug moiety (D) conjugated to the Ab moiety described herein in the product measured by a detection method (e.g., by conventional methods such as mass spectrometry, ELISA assay, electrophoresis, and / or HPLC). This DAR is referred to as the average DAR in the text. In some embodiments, the average DAR value of the conjugate of the present disclosure is about 1 to 20, such as about 2-18, 4-16, 5-12, 1-10, 1-8, 6-10, 2-8, 3-8, 2-6, 4-6, 4-8, 6-8, 6-10, such as 1.0-8.0, 2.0-6.0, such as about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0, and ranges with two of these values as endpoints.

[0087] As used herein, the term "halogen" generally refers to fluorine, chlorine, bromine, iodine, and can be, for example, fluorine or chlorine.

[0088] As used herein, the term "alkyl" refers to a straight-chain or branched-chain aliphatic saturated hydrocarbon group having a specified number of carbon atoms. Specifically, the alkyl group may have 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Suitable C 1-14 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, dimethylmethyl, dipropylmethyl, ethylbutylmethyl, diethylmethyl, methylethylmethyl, ethylpropylmethyl, diethylethyl, diethylpropyl, dipropylethyl, etc. Specific alkyl groups have 1 to 7 carbon atoms, such as 1 to 6 carbon atoms, 1 to 4 carbon atoms.

[0089] As used herein, the term "-O-alkyl" or "alkoxy" means an alkyl group as defined herein attached to the remainder of the molecule through an oxygen atom. Specifically, -O-alkyl has 1-10, for example 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, the term "-O-C 1-6 alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom, examples of which are -O-methyl, -O-ethyl, -O-propyl (including -O-n-propyl and -O-isopropyl), -O-butyl (including -O-n-butyl, -O-isobutyl, -O-sec-butyl or -O-tert-butyl), -O-pentyl (including -O-n-pentyl, -O-isopentyl, -O-neopentyl), -O-n-hexyl, 2-methylpentyl-O-, etc.

[0090] As used herein, the term "optionally halogen-substituted C 1-6 alkyl" refers to the C 1-6 alkyl group described above, wherein one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are optionally replaced by halogen. Those skilled in the art will understand that when there are more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. "Halogen-substituted C 1-6 alkyl" examples include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, -CH2CH2CF3, or -CF(CF3)2, etc.

[0091] As used herein, the term "alkenyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon group composed of carbon atoms and hydrogen atoms and containing at least one double bond. Specifically, the alkenyl has 2-8 carbon atoms, such as 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C2-C6 alkenyl" refers to a straight-chain or branched-chain alkenyl having 2 to 6 carbon atoms, such as vinyl, propenyl, allyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexadienyl, etc. The carbon atom in the alkenyl that is connected to the rest of the molecule can be saturated or an olefinic carbon atom.

[0092] As used herein, the term "alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon group composed of carbon atoms and hydrogen atoms and containing at least one triple bond. Specifically, the alkynyl has 2-8 carbon atoms, such as 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C 2-6 alkynyl" refers to a straight-chain or branched-chain alkynyl having 2 to 6 carbon atoms, such as ethynyl, propynyl, propargyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-methyl-1-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl, etc. The carbon atom in the alkynyl that is connected to the rest of the molecule can be saturated or an acetylenic carbon atom.

[0093] As used herein, the term "alkylene" refers to a divalent group obtained by removing two hydrogen atoms from the same or two different carbon atoms of a straight-chain or branched-chain saturated alkane. Specifically, the alkylene has 1-10 carbon atoms, such as 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, the term "C 1-6 alkylene" refers to a straight-chain or branched-chain alkylene having 1 to 6 carbon atoms, including but not limited to methylene, ethylene, propylene, butylene, etc.

[0094] As used herein, a specific "alkylene" refers to a divalent group obtained by removing two hydrogen atoms from the same carbon atom of a straight-chain or branched-chain saturated alkane, such as the =C(R d )2 group defined in part P of the drugs of the present disclosure, as shown in the structural fragment .

[0095] As used herein, the term "alkenylene" refers to a divalent group obtained by removing two hydrogen atoms from the same or two different carbon atoms of a straight-chain or branched-chain unsaturated alkene containing at least one double bond. Specifically, the alkenylene has 2 to 8 carbon atoms, such as 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C 2-6 alkenylene" refers to a straight-chain or branched-chain alkenylene having 2 to 6 carbon atoms, such as vinylidene, propenylene, allylidene, butenylene, pentenylene, and hexenylene.

[0096] As used herein, the term "alkynylene" refers to a divalent group obtained by removing two hydrogen atoms from the same or two different carbon atoms of a straight-chain or branched-chain unsaturated alkyne containing at least one triple bond. Specifically, the alkynylene has 2 to 8 carbon atoms, such as 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C2-C6 alkynylene" refers to a straight-chain or branched-chain alkynylene having 2 to 6 carbon atoms, such as ethynylene, propynylene, propargylidene, butynylene, pentynylene, and hexynylene.

[0097] As used herein, the term "cycloalkyl" refers to a monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic non-aromatic monovalent hydrocarbon ring structure having a specified number of ring atoms, which may be saturated or unsaturated, such as containing one or more double bonds. The cycloalkyl group may contain 3 or more, such as 3 - 18, 3 - 10, or 3 - 8 carbon atoms in the ring, such as C 3-10 cycloalkyl, C 3-8 cycloalkyl, C 3-6 cycloalkyl, C 5-6 cycloalkyl. Examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0098] As used herein, the term "heterocycle" or "heterocyclic group" refers to an aromatic or non-aromatic monocyclic, bicyclic, or polycyclic ring system having 5 to 20 members (such as 5 to 14 members, 5 to 8 members, 5 to 6 members) with 1 to 4 heteroatom ring members independently selected from N, O, or S. One or more N, C, or S atoms in the heterocycle may be oxidized. Preferably, the heterocycle is a 5 - 10 member ring system, which is monocyclic or fused bicyclic. Representative examples include, but are not limited to, pyrrolidine, azetidine, piperidine, morpholine, tetrahydrofuran, tetrahydropyran, benzofuran, benzothiophene, indole, benzopyrazole, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, pyrimidine, pyridine, pyrazine, pyridazine, isothiazole, and isoxazole.

[0099] As used herein, the term "heteroalkyl" means a monocyclic, fused polycyclic, spiro or bridged polycyclic non-aromatic saturated ring structure containing one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from O, N and S and a specified number of ring atoms, or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heteroalkyl can have 3 to 12 ring members (which can be referred to as 3- to 12-membered heteroalkyl), such as 3 to 10 ring members, 3 to 8 ring members, 3 to 7 ring members, 4 to 7 ring members, 4 to 6 ring members, 5 to 6 ring members. Heteroalkyl typically contains up to 4 (e.g., 1, 2, 3 or 4) heteroatoms, such as a 4- to 7-membered heteroalkyl containing 1 to 3 heteroatoms selected from N, O, S. Examples of suitable heteroalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothienyl (e.g., 1-tetrahydrothienyl, 2-tetrahydrothienyl and 3-tetrahydrothienyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl), morpholinyl (e.g., morpholino), thiomorpholinyl, dioxolanyl, piperazinyl or azepanyl, diazepanyl such as 1,4-diazepanyl, 3,6-diaza-bicyclo[3.1.1]heptyl or 3-aza-bicyclo[3.2.1]octyl. The atom in the heteroalkyl that is connected to the rest of the compound can be a carbon atom or a heteroatom, as long as it is chemically feasible.

[0100] As used herein, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6-20, such as 6-12, carbon atoms in the ring moiety. Preferably, aryl is a (C6-C 10 ) aryl. Non-limiting examples include phenyl, biphenyl, naphthyl or tetrahydronaphthyl, each of which can be optionally substituted with 1-4 substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroaryl-O-, amino, mercapto, alkyl-S-, aryl-S-, nitro, cyano, carboxyl, alkyl-O-C(O)-, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, heterocyclic group, etc.

[0101] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system having from 5 to 20 members (e.g., from 5 to 14 members, from 5 to 8 members, from 5 to 6 members) containing from 1 to 4 heteroatoms selected from N, O, or S, which may be substituted or unsubstituted. Preferably, the heteroaryl is a 5- to 10-membered ring system, which is monocyclic or fused bicyclic. Representative heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl.

[0102] As used herein, the term "heteroalkyl" refers to a stable straight or branched chain hydrocarbon that is fully saturated or contains from 1 to 3 degrees of unsaturation and is composed of the indicated number of carbon atoms and from one to ten, preferably from one to three, heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatoms may be optionally quaternized. The heteroatoms O, N, Si, and S may be located at any internal position of the heteroalkyl group or at the position where the heteroalkyl group is attached to the remainder of the molecule. Representative examples of heteroalkyl include –CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -NH-CH2-CH2-NH-C(O)-CH2-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-O-CH3, and –CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and –CH2-O-Si(CH3)3. Generally, C1 to C4 heteroalkyl or heteroalkylidene has 1 to 4 carbon atoms and 1 or 2 heteroatoms, and C1 to C3 heteroalkyl or heteroalkylidene has 1 to 3 carbon atoms and 1 or 2 heteroatoms. In some aspects, the heteroalkyl and heteroalkylidene are saturated.

[0103] Unless otherwise indicated, the term "substituted" as used herein to define each group means that the corresponding group can be substituted by, for example but not limited to, the following groups defined herein or conventional in the art: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, halogen, cyano, nitro, azide, carboxyl, hydroxyl, mercapto, amino, mono- or dialkylamino, mono- or dicycloalkylamino, mono- or diarylamino, mono- or dicyclic amino, mono- or diheteroarylamino, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-oxy, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-thio, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-acyl, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-acylamino, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-acyloxy, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-sulfonyl, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-sulfonyloxy, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-sulfonylamino, or the above-mentioned optionally substituted carbamoyl, and groups further substituted by the remaining optional substituents, where each type of group is as defined herein. Examples of substituents include but are not limited to one or more groups independently selected from the following: halogen, OH, SH, CN, NH2, NHCH3, N(CH3)2, NO2, N3, C(O)CH3, COOH, C(O)-amino, OCOCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO2, phenyl, piperidinyl, piperazinyl, and pyrimidinyl.

[0104] As used herein, the term "substituted" or "substitution" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom are replaced by the designated group, provided that the normal valence of the designated atom in the current situation is not exceeded and a stable compound is formed, and combinations of substituents and variables are permitted only if such combinations form stable compounds.

[0105] As used herein, the term "optionally substituted", unless otherwise indicated, means that the group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5 or more, or any range derivable therefrom) of the substituents listed for the group, where the substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents that are the same or different. In another embodiment, the optionally substituted group has 3 substituents that are the same or different. In another embodiment, the optionally substituted group has 4 substituents that are the same or different. In another embodiment, the optionally substituted group has 5 substituents that are the same or different.

[0106] Many of the groups defined herein are optionally substituted, and the lists of substituents given in the specific group definition sections are not intended to limit the substituents defined in other parts of this specification and the claims.

[0107] As used herein, the term "pharmaceutically acceptable salt" means a salt that retains the biological effects and properties of the ADC conjugates of the present disclosure and that is not biologically or otherwise undesirable. The ADC conjugates of the present disclosure may exist in their pharmaceutically acceptable salt forms, including acid addition salts and base addition salts. In the present disclosure, a pharmaceutically acceptable non-toxic acid addition salt means a salt formed by the ADC conjugates in the present disclosure with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. A pharmaceutically acceptable non-toxic base addition salt means a salt formed by the ADC conjugates in the present disclosure with an organic or inorganic base, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts formed by reaction with an organic base containing an N group.

[0108] As used herein, the term "solvate" means an association formed by one or more solvent molecules with the ADC conjugates in the present disclosure. Solvents that form solvates include but are not limited to water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. It should be understood that such solvates of the compounds of the present invention also include solvates of the pharmaceutically acceptable salts of the compounds of the present invention.

[0109] As used herein, the term "isotope variant" refers to a compound in which one or more of the atoms constituting the compound are replaced by atoms having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into one or more atoms of the compounds of the present disclosure include, for example2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S and 18 F, thus forming isotopic variants of the compounds of the present disclosure, which, whether radioactive or not, are intended to be covered within the scope of the present disclosure. In certain embodiments, the compounds of the present disclosure are provided in an unlabeled form, and in other embodiments, the compounds of the present disclosure are provided in an isotopically labeled form, such as in a form labeled with the hydrogen isotope D. In particular, one or more H in the R9, R 10 and R 11 groups in the definition of the drug P herein may be replaced by the isotope D. For example, R9 and R 10 are each independently H or D, and R 11 may be replaced by one or more D, particularly -C 1-6 alkyl substituted by one or more D.

[0110] As used herein, the term "isomer" refers to any stereoisomer, enantiomeric mixture, including racemate, diastereomeric mixture, geometric isomer, atropisomer, and / or tautomer that may exist structurally in a compound. Methods for determining and separating the stereochemistry of such isomers are well known to those skilled in the art (S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994). The present disclosure covers all possible isomeric forms of the compounds defined herein, as well as their pharmaceutically acceptable salts or solvates, unless otherwise indicated. In addition, the compounds of the present disclosure may exist as a mixture of two or more different structural forms in rapid equilibrium (commonly referred to as tautomers). It is to be understood that the scope of the present application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0111] Certain compounds of the present disclosure contain at least one (e.g., 1, 2, 3, or 4) asymmetric center and can thus be prepared in (R)- or (S)-stereoisomeric forms or as mixtures thereof.

[0112] As used in the structural formula or structural fragment of the compounds of the present disclosure represents the configuration of a stereocenter, i.e., a chiral center, and accordingly, in the naming of the compounds or intermediates provided by the present invention, the configuration of the chiral center is represented by R or S; attached to the chiral center represents the racemic form in which both configurations of the chiral center are present, such as represents a mixture of. In the definition of some compounds of the present disclosure, axial chirality can also be used to represent the configuration of the compound. The determination of these configurations uses the Cahn-Ingold-Prelog rules well-known to those skilled in the art. The absolute configurations of axial chirality in the following two exemplary structures are described as follows:

[0113]

[0114] When the linked axial chirality bond is marked with "*", it indicates that the compound has a single chiral configuration and is obtained by SFC resolution, but the absolute configuration is uncertain. For example, represents or

[0115] It should be understood that when those skilled in the art can determine that a pair of chiral isomers exist for a compound based on the compound structure shown herein and can easily resolve them based on conventional methods in the art, then the disclosure of the racemate of the compound herein (whether in the structural formula or chemical name) should be regarded as having separately disclosed each isomer of the compound.

[0116] In this article, the number of groups attached to each atom in the compound definition, compound structural formula, or structural fragment depends on the valence of the atom and does not have to be fully shown. Generally, only non-hydrogen groups are shown in the group definition, structural formula, or structural fragment, and the groups not shown generally represent H. Those skilled in the art can easily determine whether the groups not shown exist and the number thereof.

[0117] As used in the structural fragments involved herein indicates that the bond crossing therewith is the bond by which the structural fragment is connected to the rest of the molecule.

[0118] Substituents shown across chemical bonds in the cyclic structural fragments involved herein, such as in -(R 12 ) m means that the m Rs 12The substituent(s) may be attached to any chemically feasible substitution site(s) in the ring, including X when chemically feasible.

[0119] Unless otherwise specified, C in the definitions of the compounds of the present invention n-n+m or C n -C m encompasses various cases including from n to n + m carbons, such as C 1-6 including C1, C2, C3, C4, C5, and C6, and also any range from n to n + m, such as C 0-6 including C1, C2, C3, C4, C5, C6, C 0-1 , C 0-2 , C 0-3 , C 0-4 , C 0-5 , C 1-2 , C 1-3 , C 1-4 , C 2-3 , etc., C 1-6 including C 1-2 , C 1-3 , C 1-4 , C 2-6 , C 3-6 etc.

[0120] As used herein, the term "about" when used to modify a numerical value, numerical range, or parameter means that the numerical value or parameter so associated is floating ±10%, for example floating ±5%, ±2%, or ±1%. For example, the expression "about 100" as used herein includes 90 and 110 and all values therebetween (e.g., 90.5, 95, 101, 105, 109.95... etc.). For ratios, the term "about" is used to qualify each number of the given ratio. For example, the ratio "about 1:1" means a ratio of (0.9 - 1.1):(0.9 - 1.1). Again, for example, the range "about n - m" or "about n - about m" means from 90%n - 110%n to 90%m - 110%m.

[0121] Where context is not contradictory, the terms "pharmaceutically acceptable" and "medicinal" are used interchangeably herein.

[0122] As used herein, the term "pharmaceutical composition" refers to a composition that is in a form that allows the biological activity of the active ingredient(s) contained therein to be effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which the composition is administered.

[0123] As used herein, the terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier", and "therapeutically inert excipient" are used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in formulating a pharmaceutical product.

[0124] As used herein, the term "drug combination" refers to non-fixed combination products or fixed combination products, including but not limited to kits, pharmaceutical compositions. The term "non-fixed combination" means that the active ingredients, such as (i) the ADC conjugates of the present disclosure, and (ii) other therapeutic agents, are administered to a patient simultaneously, without a specific time limit, or at the same or different time intervals, sequentially, in separate entities, wherein such administration provides a prophylactically or therapeutically effective level of two or more active agents in the patient. In some embodiments, the ADC conjugates of the present disclosure and other therapeutic agents used in the drug combination are administered at levels not exceeding those at which they are used alone. The term "fixed combination" means that two or more active agents are administered to a patient in the form of a single entity. Preferably, the doses and / or time intervals of the two or more active agents are selected such that the combined use of the components produces a greater effect in treating a disease or disorder than can be achieved by using any one of the components alone. The components may each be in a separate formulation, which may be the same or different.

[0125] As used herein, the term "combination therapy" refers to the administration of two or more therapeutic agents or modalities, such as radiotherapy or surgery, to treat the diseases described herein. Such administration includes co-administering the therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration includes co-administering the individual active ingredients in multiple or separate containers (such as tablets, capsules, powders, and liquids). The powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. In addition, such administration also includes using each type of therapeutic agent in a sequential manner at approximately the same time or at different times. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the disorders or conditions described herein.

[0126] As used herein, the terms "individual" or "subject" are used interchangeably and refer to a mammal. Mammals include but are not limited to domesticated animals (such as cows, sheep, cats, dogs, and horses), primates (such as humans and non-human primates like monkeys), rabbits, and rodents (such as mice and rats). In particular, the subject is a human.

[0127] As used herein, the term "treatment" refers to slowing, interrupting, arresting, alleviating, halting, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.

[0128] As used herein, the term "prevention" includes inhibition of the occurrence or development of a disease or disorder or symptoms of a particular disease or disorder. In some embodiments, a subject with a family history of cancer is a candidate for a preventive regimen. Generally, in the context of cancer, the term "prevention" refers to administration of a medicament before the signs or symptoms of cancer occur, particularly in a subject at risk of cancer.

[0129] As used herein, the term "effective amount" refers to such an amount or dose of the antibody-drug conjugate or a composition or combination thereof of the present disclosure that, upon administration to a patient in a single or multiple doses, produces the desired effect in a patient in need of treatment or prevention.

[0130] As used herein, the term "therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic outcome at the required dose and for the required period of time. A therapeutically effective amount is also an amount in which any toxic or harmful effects of the antibody-drug conjugate or a composition or combination thereof of the present disclosure are outweighed by the therapeutic beneficial effects. Relative to an untreated individual, a "therapeutically effective amount" preferably achieves at least about 30%, even more preferably at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or even 100% inhibition of a measurable parameter (such as tumor volume).

[0131] As used herein, the term "preventively effective amount" refers to an amount effective to achieve the desired preventive outcome at the required dose and for the required period of time. Generally, since preventive doses are administered in a subject before or at an earlier stage of a disease, a preventively effective amount will be less than a therapeutically effective amount.

[0132] As used in this specification and the appended claims, the terms "comprising" and variations of that word such as "includes" and "containing" mean "including but not limited to" and are not intended to exclude, for example, other additives, ingredients, integers or steps. When an element is described as comprising a plurality of components, steps or conditions, it is understood that the element may also be described as comprising any combination of the plurality of components, steps or conditions, or "consisting of a plurality of or combined components, steps or conditions" or "consisting essentially of a plurality of or combined components, steps or conditions".

[0133] I: Antibody-Drug Conjugate

[0134] In one aspect, the present disclosure provides an antibody-drug conjugate (ADC) of formula (X) or a pharmaceutically acceptable salt or solvate thereof:

[0135] [P-L] q -Ab (X)

[0136] wherein,

[0137] P represents a Ras inhibitor, such as a KRas inhibitor;

[0138] L represents a linker unit that links P to Ab;

[0139] q represents the number of [P-L] units linked to Ab, which is an integer or non-integer of at least 1, such as q = 1 to 20, such as about 1-10, 1-8, 2-8, 3-10, 3-8, 4-10, 4-8, 6-8 or 6-10;

[0140] Ab represents an antibody or antigen-binding fragment.

[0141] In some embodiments of formula X, q represents an integer selected from 1 to 20, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some cases, the range of q is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19 or 1 to 20, or a range composed of any two values between 1 and 20, such as 2 to 10, 2 to 8, 2 to 6, 2 to 4, 3 to 8, 3 to 10, 4 to 6, 4 to 8, 4 to 10, 6 to 8 or 6 to 10. In other embodiments, formula X describes an ADC in an ADC mixture, which exhibits a q value range from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19 or 1 to 20, or a range composed of any two values between 1 and 20, such as 2 to 10, 2 to 8, 2 to 6, 2 to 4, 3 to 8, 3 to 10, 4 to 6, 4 to 8, 4 to 10, 6 to 8 or 6 to 10.

[0142] In certain embodiments, Formula X describes an ADC in an ADC mixture such that the q value of more than 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the ADCs in the mixture is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, Formula X describes an ADC in an ADC mixture such that the q value of more than 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the ADCs in the mixture ranges from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, or 1 to 20, or is a range formed by any two values between 1 and 20, such as 2 to 10, 2 to 8, 2 to 6, 2 to 4, 3 to 8, 3 to 10, 4 to 6, 4 to 8, 4 to 10, 6 to 8, or 6 to 10.

[0143] In other embodiments, Formula X describes an ADC mixture where q is "q 平均 ", which represents the average value of the q value of the mixture, or the average DAR, that is, the average number of linker units (L) attached to a given antibody (Ab) in the mixture. In such embodiments, q 平均 or the average DAR represents an integer or non-integer value from 1 to 20, such as about 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, or 1 to 20, or is an integer or decimal within a range formed by any two values between 1 and 20, such as about 2 to 10, 2 to 8, 2 to 6, 2 to 4, 3 to 8, 3 to 10, 4 to 6, 4 to 8, 4 to 10, 6 to 8, or 6 to 10.

[0144] In preferred embodiments, q in Formula (X) of the present disclosure is an integer or non-integer from 1 to 10 or is a range formed by any two values between 1 and 10, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, about 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 4 to 6, 3 to 8, 3 to 10, 4 to 8, 4 - 10, 6 to 8, or 6 to 10.

[0145] In some embodiments, q represents an average DAR of about 3. In some embodiments, q represents an average DAR of about 6. In some embodiments, q represents an average DAR of about 8.

[0146] In some embodiments, q represents an average DAR of about 1-10, 1-8, 2-8, 3-10, 3-8, 4-10, 4-8, 6-8, or 6-10.

[0147] Those skilled in the art should also understand that the various ADCs described herein can be in the form of salts or solvates, and in some specific embodiments, are pharmaceutically acceptable salts.

[0148] The following details each component of the disclosed ADC conjugate and the disclosed ADC conjugate composed thereof. Those skilled in the art can understand that the ADCs disclosed herein are inherently "modular" because each has the above-mentioned modular components Ab, L, and P. Throughout this disclosure, various specific non-limiting examples and embodiments of these modular components are described, and this disclosure encompasses specific combinations of specific embodiments of all modules, as if each specific combination were separately and explicitly described.

[0149] Ab - antibody or antigen - binding fragment

[0150] In the ADCs of the present disclosure, the antibody is an antibody or antigen-binding fragment that specifically binds to a target antigen, and its function is to target and deliver a KRas mutant inhibitor compound to a specific target cell population. Due to the presence of its targeting component or molecule, the antibody or antigen-binding fragment interacts with the specific target cell population, and then releases the free drug intracellularly (intracellular mode) or releases the free drug near the target cell (extracellular mode).

[0151] In one group of embodiments, the antibody or antigen-binding fragment is bonded to a linker unit that contains a cleavable peptide component. As described above, other linking components may also be present in the conjugates described herein to provide additional space between the Ras, such as a KRas mutant inhibitor compound, and the antibody unit, or to provide solubility-enhancing properties to the composition. In some of these embodiments, the antibody or antigen-binding fragment is bonded to the linker unit through its heteroatoms. The heteroatoms that can be present on the antibody or antigen-binding fragment for this bonding include sulfur (in one embodiment, from the mercapto group of the targeting ligand), oxygen (in one embodiment, from the carboxyl or hydroxyl group of the targeting ligand), and optionally substituted nitrogen (in one embodiment, from the primary or secondary amine functional group of the targeting ligand, or in another embodiment, from the optionally substituted amide nitrogen). These heteroatoms can exist on the antibody unit in the natural state of the ligand, such as in a naturally occurring antibody, or can be introduced into the antibody unit by chemical modification or bioengineering.

[0152] The conjugation sites on the antibody can affect the stability, pharmacokinetics, and pharmacodynamic properties of the ADC. Excess drug payloads may sometimes result in rapid plasma clearance, while ADCs with low DAR (drug-antibody ratio) may exhibit weak activity. The drug loading of the antibody can be controlled by selecting the conjugation strategy and the conjugation sites on the antibody, while maintaining the structural integrity and homogeneity of the antibody.

[0153] In some embodiments, the antibody or antigen-binding fragment has a thiol functional group such that it is bonded to the linker unit via the sulfur atom of the thiol functional group. In some other embodiments, the thiol is generated by reducing the inter-chain disulfide bond of the antibody. Accordingly, in some embodiments, the linker unit is conjugated to a cysteine residue from the reduced inter-chain disulfide bond in the antibody. In some other embodiments, the thiol group is chemically introduced into the antibody, such as introducing a cysteine residue. Correspondingly, in some embodiments, the linker unit is conjugated to the antibody or antigen-binding fragment via a cysteine residue introduced into the antibody or antigen-binding fragment.

[0154] In some other embodiments, the antibody or antigen-binding fragment has one or more lysine residues that are capable of reacting with activated esters (including but not limited to N-hydroxysuccinimide, pentafluorophenyl, and p-nitrophenyl esters) in the linker unit and thereby providing an amide bond composed of the nitrogen atom of the antibody or antigen-binding fragment and the C=O of the linker unit.

[0155] In some other embodiments, the antibody or antigen-binding fragment has one or more lysine residues that can be chemically modified to introduce one or more thiol groups. In these embodiments, the antibody or antigen-binding fragment is covalently attached to the linker unit via the sulfur atom of the thiol functional group. Reagents that can be used to modify lysine in this manner include but are not limited to N-succinimidyl-S-acetylthioacetate (SATA) and 2-iminothiolane hydrochloride (Traut reagent).

[0156] In some other embodiments, the antibody or antigen-binding fragment has one or more carbohydrate groups that can be modified to provide one or more thiol functional groups. The chemically modified antibody or antigen-binding fragment in the ADC is bonded to the linker unit via the sulfur atom of the thiol functional group.

[0157] In some other embodiments, the antibody or antigen-binding fragment has one or more carbohydrate groups that can be oxidized to provide an aldehyde (-CHO) functional group. In these embodiments, the corresponding aldehyde interacts with the reactive site on the linker unit to form a chemical bond between the linker unit and the antibody unit.

[0158] In some other embodiments, artificial attachment sites are introduced into the antibody to achieve more site-specific conjugation.

[0159] Other schemes for modifying proteins to link to linker units or related substances can be found in Coligan et al., Current Protocols in Protein Science, Vol. 2, John Wiley & Sons (2002), which is incorporated herein by reference.

[0160] In some embodiments, the antibody or antigen-binding fragment is capable of forming a covalent bond between the linker unit and the antibody or antigen-binding fragment corresponding to the antibody unit by interacting with a reactive functional group on the linker unit. The functional group capable of interacting with the antibody unit will depend on the nature of the antibody or antigen-binding fragment. In some embodiments, the reactive group is maleimide. The covalent attachment of the antibody or antigen-binding fragment to the linker unit is achieved by the interaction of the thiol functional group of the antibody or antigen-binding fragment with the maleimide functional group of the linker unit to form a sulfur-substituted succinimide. The thiol functional group can be present in the natural state of the antibody or antigen-binding fragment, such as in naturally occurring residues, or can be introduced into the antibody or antigen-binding fragment by chemical modification or by bioengineering.

[0161] The antibody constituting the ADC of the present disclosure can be polyclonal, monoclonal, genetically engineered, and / or otherwise modified, and is suitable for administration to humans, such as humanized antibodies or fully human antibodies.

[0162] In some embodiments, the Ab unit of the ADC of the present disclosure is a monospecific antibody. In some embodiments, the Ab unit of the ADC of the present disclosure is a multispecific antibody. In some embodiments, after binding to the antigen receptor expressed on the surface of tumor cells, the Ab unit triggers endocytosis mediated by the antigen receptor, thereby effectively transporting the anti-tumor drug of the ADC into the tumor cells.

[0163] In some embodiments, the Ab unit of the disclosed ADC can be a bispecific antibody, a diabody, a multichain or single-chain antibody, a single-domain antibody, a camelized antibody, an scFv-Fc antibody, a surrogate antibody, etc. In some embodiments where the Ab unit is a bispecific antibody, one specificity of the antibody can target a tumor-associated antigen to promote specific binding of the ADC to tumor cells; while the other specificity of the antibody can target a tumor cell surface receptor to further promote endocytosis and degradation of the ADC. Examples of such combinations of bispecific targets that can be mentioned include, but are not limited to, the dual-target combination of HER2 and PRLR on breast cancer cells. In some other embodiments, the two specificities of the antibody can target different tumor-associated antigens respectively to provide a mechanism against drug resistance. Examples of such combinations of bispecific targets that can be mentioned include, but are not limited to, the dual-target combination of EGFR and MET on lung cancer cells. In some other embodiments, the two specificities of the antibody can also target different epitopes of the same tumor-associated antigen respectively to increase the selectivity of the antibody for cancer cells and / or enhance internalization and transport to lysosomes by inducing clustering and cross-linking of the antigen on the surface of tumor cells. Examples of such tumor-associated antigens that can be mentioned include, but are not limited to, HER2 on breast cancer cells.

[0164] The antibody portion constituting the disclosed ADC can be in the form of a full-length antibody, which can have or be derived from any antibody isotype, including, for example, IgA, IgD, IgE, IgG, IgM or IgY. In some embodiments, the antibody constituting the ADC is IgG (such as IgG1, IgG2, IgG3 or IgG4). In some embodiments, the antibody constituting the ADC comprises all or part of the constant region of the IgG immunoglobulin.

[0165] The antibody portion constituting the disclosed ADC can be a functionally active fragment, derivative or analogue of an antibody that immunospecifically binds to a target cell (such as a cancer cell antigen, a viral antigen or a microbial antigen). In this regard, "functionally active" means that the fragment, derivative or analogue is capable of immunospecifically binding to the target cell.

[0166] Useful antibody fragments include, for example but not limited to, F(ab’)2 fragments, Fab fragments, Fvs, single-chain antibodies, diabodies, triabodies, tetra-bodies, scFv, scFv-FV or any other molecule having the same specificity as the antibody. The fragments can be obtained by molecular engineering, or by chemical or enzymatic treatment of the intact antibody or antibody chains, or by recombinant means.

[0167] Useful modified antibody analogs and derivatives include, for example but not limited to, derivatives and analogs of antibodies obtained by glycosylation, acetylation, polyethylene glycolylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, linkage to cell antibody units or other proteins, etc. Any of a number of chemical modifications can be carried out by known techniques, including but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis in the presence of tunicamycin, etc.

[0168] Target antigen and antibody

[0169] The antibody portion of the disclosed ADC can target any suitable target molecule presented on the surface of target cells, for example, a polypeptide, protein, polysaccharide, or lipid molecule. The binding of the antibody to the target molecule should be highly specific to ensure that the ADC specifically binds to the target cells and reduces off-target toxicity. In some embodiments, the binding affinity of the antibody to the target molecule can be selected at the nanomolar or sub-nanomolar level.

[0170] Suitable target antigens can be selected by searching for cell surface proteins that are highly expressed in tumors but lowly expressed or even almost not expressed in non-malignant tissues. In some embodiments, such target molecules are membrane antigens expressed on the surface of target tumor cells, such as tumor-specific antigens or tumor-associated antigens, where the tumors include hematological tumors and solid tumors, including primary and metastatic tumors. In a particularly preferred embodiment, the antibody or antigen-binding fragment in the disclosed ADC specifically binds to one or more tumor-specific antigens or tumor-associated antigens, or immune cell-related antigens.

[0171] In some embodiments, the tumor specific antigen or tumor associated antigen targeted by the antibody portion of the disclosed ADCs is selected from: HER2, Her3, HER1 (ErbB1), HER4 (ErbB4), TROP2, Nectin-4, tissue factor, PD-L1, PD-1, PD-L1 / PD-L2, MET, CLDN18.2, KIT, CTLA-4, RPR1, adrenergic A2 receptor (EphA2), folate receptor (FRa), mesothelin, endothelin receptor, GCPII, IL-13Ra, BCMA, GD2, CLL-1, CA-IX, MUC1, 5T4, AOC3, ALK, AXL, C242, CA-125, CCL11, CCR5, CD2, CD3, CD4, CDS, CD15, CA15-3, CD16, CD18, CD19, CD20, CD21, CD22, CD25, CD30, CD32, CD33, CD37, CD38, CD44, CD52, CD56, CD64, CD66e, CD70, CD72, CD74, CD79a, CD79b, CD123, CD138, CD142, CD174, CD276, CDH3, CCD79b, CLDN9 / CLDN6, CA19-9, DPEP3, AGS-16, IGF1R, IGF2R, VEGFR1, VEGFR2, VEGFR3, PDGFR-α, PDGFR-β, EGFR, EGFRvIII, ENPP3, FcRH5, FRα, KAAG1, LIV-1, Mesothelin, cMet, ROR1, SLTRK6, TF, BMPR1B, E16, TOP1, STEAP1, 0772P, MUC16, Napi3b, Sema 5b, PSCAhIg, ETBR, RNF124, Prostate cancer associated gene 1, TrpM4, Teratoma-derived growth factor 1, C3DR, FcRH2, NCA, MDP, IL20R-α, Brevican, EphB2R, ASLG659, Prostate stem cell antigen precursor, GEDA, BAFF-R, CXCR5, HLA-DOB, P2X5, LY64, FcRH1, IRTA2, TENB2, Integrin α5β6, Integrin α4β7, FGF2, FGFR1, FGFR2, FGFR3, FGFR4, PSMA, Somatostatin receptor, RANK, SLAMF7, ITGB6, CEACAM5, CA9, EGFRvlll, IL2RA, AXL receptor tyrosine kinase, TGF-βR, TNFRSF8, Cancer / testis associated antigen, CLEC14A, GRP78, Stem cell specific antigen, ASG-5, PRR4, GUCY2C, SLC39A6, TPBG, Tumor associated antigen CA242, FOLR1, GPNMB, HAVCR1, Prostate tumor target Mindin, VTCN1, PTK7 protein tyrosine kinase 7, Macrophage stimulating 1 receptor, TACSTD2, CA6, DLL3, DLL4, EpCAM, FAP, DKK-1, Endoglin, VCAM1, GPC3, DR5, ASCT2, B7H1, B7H3, B7H4.

[0172] In certain embodiments, the tumor-associated antigen and the immune cell antigen are T cell co-inhibitory molecules. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to a tumor-associated antigen selected from PD-L1, PD-L2, CD47, CD80, CD86, HVEM, UL144, CD155, CD112, CD113, Galectin-1, Galectin-3, Galectin 9, CD48, LIGHT, BTLA, and CD160. In some embodiments, the tumor-associated antigen is a molecule that binds to a T cell molecule selected from BTLA, Tim-3, PD-1, CTLA-4, TIGIT, CD244, and CD223.

[0173] In some embodiments, the antibody is an anti-PD-L1 antibody, such as atezolizumab, durvalumab, avelumab, or an antigen-binding fragment thereof, or an antibody or antigen-binding fragment thereof having an amino sequence equivalent thereto.

[0174] In some embodiments, the antibody is an anti-PD-1 antibody, such as nivolumab, Pembrolizumab, cemiplimab, anti-mouse PD-1 antibody clone J43, anti-mouse PD-1 antibody clone RMP1-14, mouse anti-PD-1 antibody clone EH12, ANB011, MDX-1106, AMP-514, AMP-224, or Pidilizumab. In some embodiments, the anti-PD-1 antibody is Pembrolizumab or nivolumab.

[0175] In some embodiments, the antibody is an anti-CTLA-4 antibody, such as ipilimumab, clone 9H10, tremelimumab, or clone BNI3.

[0176] In some embodiments, the antibody is an anti-CD47 antibody, such as Hu5F9-G4, IBI188, CC-90002, ZL1201, TTI-621, AO-176, an antibody of SGN-CD47M, an antigen-binding domain of ALX148, or an antigen-binding fragment thereof, or an antibody or an antigen-binding fragment thereof having an amino acid sequence equivalent thereto.

[0177] In other embodiments, the antibody or an antigen-binding fragment thereof specifically binds to a tumor-associated antigen, which is a growth factor receptor (GFR). In certain embodiments, the tumor-associated antigen is an EGFR / ErbB / HER family GFR. In some embodiments, the tumor-associated antigen is selected from the EGFR / HER1 (ErbB1), HER2 / c-Neu (ErbB2), Her3 (ErbB3), and Her4 (ErbB4) receptors. In certain embodiments, the tumor-associated antigen is an IGFR family GFR. In some embodiments, the cancer-associated tumor antigen is the IGF1R or IGF2R receptor. In certain embodiments, the tumor-associated antigen is a TGF-βR (TβR) family GFR. In some embodiments, the cancer-associated tumor antigen is the TβR I or TβR II receptor. In certain embodiments, the tumor-associated antigen is a VEGFR family GFR. In some embodiments, the cancer-associated tumor antigen is the VEGFR1, VEGFR2, or VEGFR3 receptor. In certain embodiments, the tumor-associated antigen is a PDGFR family GFR. In some embodiments, the cancer-associated tumor antigen is the PDGFR-α or PDGFR-β receptor. In certain embodiments, the tumor-associated antigen is an FGFR family GFR. In some embodiments, the cancer-associated tumor antigen is the FGFR1, FGFR2, FGFR3, or FGFR4 receptor.

[0178] In some embodiments, the antibody is an anti-EGFR / HER1 (ErbB1) antibody, such as cetuximab, panitumumab, necitumumab, or an antigen-binding fragment thereof, or an antibody or an antigen-binding fragment thereof having an amino acid sequence equivalent thereto. In some embodiments, the antibody is an anti-HER2 (ErbB2) antibody, such as trastuzumab, pertuzumab, or an antigen-binding fragment thereof, or an antibody or an antigen-binding fragment thereof having an amino acid sequence equivalent thereto. In some embodiments, the antibody is an anti-VEGFR2 antibody, such as ramucirumab, or an antigen-binding fragment thereof or an antibody or an antigen-binding fragment thereof having an amino acid sequence equivalent thereto. In some embodiments, the antibody is an anti-PDGFR-α antibody, such as olaratumab, or an antigen-binding fragment thereof or an antibody or an antigen-binding fragment thereof having an amino acid sequence equivalent thereto.

[0179] In other embodiments, the antibody or its antigen-binding fragment specifically binds to a lymphoma-related antigen. In certain embodiments, the lymphoma-related antigen is CD20, CD30, CD19 / CD3, CD22, or CD33. In some embodiments, the antibody is an anti-CD20 antibody, such as rituximab, ibritumomab, ofatumumab, obinutuzumab, or an antigen-binding fragment thereof or an antibody or an antigen-binding fragment thereof having an amino acid sequence equivalent thereto. In some embodiments, the antibody is an anti-CD30 antibody, such as brentuximab, or an antigen-binding fragment thereof or an antibody or an antigen-binding fragment thereof having an amino acid sequence equivalent thereto. In some embodiments, the antibody is an anti-CD19 / CD3 antibody, such as blinatumomab, or an antigen-binding fragment thereof or an antibody or an antigen-binding fragment thereof having an amino acid sequence equivalent thereto. In some embodiments, the antibody is an anti-CD22 antibody, such as inotuzumab, or an antigen-binding fragment thereof or an antibody or an antigen-binding fragment thereof having an amino acid sequence equivalent thereto. In some embodiments, the antibody is an anti-CD33 antibody, such as gemtuzumab, or an antigen-binding fragment thereof or an antibody or an antigen-binding fragment thereof having an amino acid sequence equivalent thereto.

[0180] In other embodiments, the antibody or its antigen-binding fragment specifically binds to a myeloma-associated antigen. In certain embodiments, the myeloma-associated antigen is SLAMF7 or CD38. In some embodiments, the antibody is an anti-SLAMF7 antibody, such as elotuzumab, or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an amino acid sequence equivalent thereto. In some embodiments, the antibody is an anti-CD38 antibody, such as daratumumab, or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an amino acid sequence equivalent thereto.

[0181] In other embodiments, the antibody or its antigen-binding fragment specifically binds to a germ cell tumor-associated antigen. In certain embodiments, the germ cell tumor-associated antigen is GD2. In some embodiments, the antibody is an anti-GD2 antibody, such as dinutuximab, or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an amino acid sequence equivalent thereto.

[0182] In other embodiments, the antibody or its antigen-binding fragment specifically binds to RANK ligand. In some embodiments, the antibody is an anti-RANK ligand antibody, such as denosumab, or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an amino acid sequence equivalent thereto.

[0183] In other embodiments, the antibody or its antigen-binding fragment specifically binds to TROP2. In some embodiments, the antibody is an anti-TROP2 antibody, such as Sacituzumab and Datopotamab, or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an amino acid sequence equivalent thereto.

[0184] In other embodiments, the antibody or its antigen-binding fragment specifically binds to Claudin18.2. In some embodiments, the antibody is an anti-Claudin18.2 antibody, such as Zolbetuximab, Osemitamab (TST001), CMG901, ASKB589, ZL-1211, or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an amino acid sequence equivalent thereto.

[0185] In other embodiments, the antibody or its antigen-binding fragment specifically binds to Met (also known as c-Met, or hepatocyte growth factor receptor (HGFR)). The Met gene with a pathogenic mutation will encode an abnormal Met receptor, which transmits abnormal signals and has various effects, including cell growth, survival, invasion, metastasis, angiogenesis, etc. The tumors involved in Met include non-small cell lung cancer, colorectal cancer, gastric cancer, esophageal cancer, glioma, etc. In some embodiments, the antibody is an anti-Met antibody, such as Onartuzumab or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an amino acid sequence equivalent thereto.

[0186] In other embodiments, the antibody or its antigen-binding fragment specifically binds to the Eph receptor, particularly the EphA2 receptor. EphA2 is not only a biomarker of malignant characteristics but also an active participant in malignant progression. It has been confirmed to play an important role in the regulation of cancer development and tumor progression. Human EphA2 is highly expressed in prostate cancer, lung cancer, esophageal cancer, colorectal cancer, cervical cancer, ovarian cancer, breast cancer, and skin cancer, which is associated with poor prognosis, increased metastatic potential, and reduced survival in cancer patients. In some embodiments, the antibody is an anti-EphA2 antibody or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an amino acid sequence equivalent thereto.

[0187] In other embodiments, the antibody or its antigen-binding fragment specifically binds to Nectin-4. In some embodiments, the antibody is an anti-Nectin-4 antibody, such as Enfortumab or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an amino acid sequence equivalent thereto.

[0188] In other embodiments, the antibody or its antigen-binding fragment specifically binds to both EGFR and Met (also known as c-Met). In some embodiments, the antibody is an anti-EGFR and Met bispecific antibody, such as Amivantamab or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an amino acid sequence equivalent thereto.

[0189] In some embodiments, the tumor-associated antigens specifically bound by the antibody or its antigen-binding fragment are selected from AXL, B7H1, B7H3, B7H4, BCMA, CD16, CD19, CD22, CD25, CD30, CD32, CD33, CD44, CD64, CD70, CD74, CD79, CD138, CD142, CD276, CDH3, CEACAM5, Claudin 18.2, CLDN9 / CLDN6, DPEP3, EGFR, ENPP3, EphA, FcRH5, FOLR1, FRα, GCPII, HER2, HER3, KAAG1, KIT, LIV-1, Mesothelin, c-Met, MUC1, Nectin-4, PD-L1, PD-L1 / PD-L2, PSMA, ROR1, RPR1, TF, TOP1, TROP2, etc. The corresponding antibodies are commercially available or can be prepared by techniques known in the art.

[0190] In preferred embodiments, the antibodies are those that bind to antigens that are preferentially expressed or overexpressed in cancer cells, such as HER2 (ErbB2), PD-1, PD-L1, EGFR, TROP2, Claudin 18.2, EphA-2, Nectin-4, and Met, more preferably HER2 (ErbB2), EGFR, TROP2, Claudin 18.2, Nectin-4, or a combination of EGFR and Met.

[0191] Against the tumor-associated antigens mentioned above, the ADC compounds of the present disclosure can treat tumors associated with the expression of the antigens mentioned above. The specific list of tumors can be known or determined by those skilled in the art based on the prior art.

[0192] Antibodies that are immunospecific for tumor-associated antigens can be obtained commercially or produced by any method known to those skilled in the art, such as recombinant expression techniques. The nucleotide sequences encoding immunospecific antibodies against cancer cell antigens can be obtained, for example, from the GenBank database or similar databases, literature publications, or by conventional cloning and sequencing.

[0193] Ab unit targeting HER2

[0194] In a particularly preferred embodiment, the antibody conjugate provided herein comprises an antibody or antigen-binding fragment that specifically binds to human HER2 (anti-HER2 antibody), i.e., the antibody portion specifically targets the tumor-associated antigen HER2. Thus, in some aspects, the present disclosure provides an antibody-drug conjugate (ADC) that comprises an antibody or its antigen-binding fragment that specifically binds to HER2 as the Ab unit of the ADC.

[0195] HER2 is the receptor tyrosine protein kinase ErbB2, and overexpression or gene amplification of HER2 is present in approximately 20 - 30% of breast cancers. The increase in HER2 activates multiple downstream pathways, leading to abnormal proliferation of cancer cells (Treish I, Schwartz R, Lindley C: Pharmacology and therapeutic use of trastuzumab in breast cancer. Am J Health Syst Pharm. 2000 Nov 15;57(22):2063 - 76; quiz 2077 - 9). HER2 is also overexpressed in many other types of cancers, such as gastric cancer, esophageal cancer, colon cancer, rectal cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, bladder cancer, pancreatic cancer, lung cancer, prostate cancer, osteosarcoma, neuroblastoma, or head and neck cancer.

[0196] In some embodiments, an antibody or an antibody fragment (e.g., an antigen - binding fragment) that specifically binds to human HER2 can be selected from trastuzumab, pertuzumab, margetuximab, or HT - 19, or an antibody fragment thereof, or a site - specific mutant thereof, or other anti - human HER2 antibodies that recognize the same epitope or competitively bind to human HER2.

[0197] Trastuzumab (trade name Herceptin or Herclon) is a humanized monoclonal antibody against human epidermal growth factor 2, used for the treatment of HER2 - positive breast cancer, gastrointestinal cancer, and gastric cancer. It binds to the juxtamembrane part of the extracellular domain of the HER2 receptor. The amino acid sequences of its heavy - chain and light - chain variable regions are described in U.S. Patent 5,821,337, and it interacts with three loop regions formed by human HER2 residues 557–561, 570–573, and 593–603 (Cho et al., Nature 421:756 - 760, 2003), and may interfere with HER2 signaling by preventing HER2 receptor dimerization, promoting HER2 receptor endocytosis and degradation, and inhibiting the shedding of the extracellular domain (Hudis CA, N Engl J Med. 2007;357(1):39 - 51). Another important mechanism of action of anti - HER2 antibodies is the mediation of antibody - dependent cell - mediated cytotoxicity (ADCC). In ADCC, the anti - HER2 antibody binds to tumor cells and then recruits immune cells, such as macrophages, through interaction with the Fcε receptor (FcεR). Trastuzumab was approved by the U.S. FDA in September 1998 for the treatment of metastatic breast cancer patients.

[0198] Pertuzumab (also known as 2C4, Omnitarg, Perjeta) is a humanized monoclonal antibody that binds to the extracellular domain of the HER2 receptor and inhibits the dimerization of HER2 with other HER receptors. The amino acid sequences of its heavy and light chains are described in U.S. Patent No. 7,560,111. Pertuzumab interacts primarily with residues within the 245–333 region of human HER2, particularly residues His 245, Val 286, Ser 288, Leu 295, His 296, or Lys 311 (Franklin et al., Cancer Cell 5:317–328, 2004). Pertuzumab has been shown to be more effective than trastuzumab in disrupting HER1-HER2 and HER3-HER2 complex formation in breast and prostate cancer cell lines (Agus et al., J Clin Oncol. 2005;23(11):2534-43. Epub Feb 7, 2005). For potency, pertuzumab does not require antibody-dependent cytotoxicity as the intact Fc region is not required for its activity (Agus et al., J Clin Oncol. 2005;23(11):2534-43. Epub Feb 7, 2005). Pertuzumab is approved by the U.S. FDA in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer.

[0199] Margetuximab (also known as MGAH22) is another anti-HER2 monoclonal antibody (see http: / / www.macrogenics.com / products-margetuximab.html). The Fc region of margetuximab has been optimized to increase its binding to activated FcεRs. Margetuximab is currently in clinical trials for the treatment of patients with recurrent or refractory advanced breast cancer whose tumors are found by immunohistochemistry to have HER2 expression at the 2+ level and lack evidence of HER2 gene amplification by FISH.

[0200] HT-19 is another anti-HER2 monoclonal antibody that binds to an epitope in human HER2 different from that of trastuzumab or pertuzumab and has been shown to inhibit HER2 signaling about as well as trastuzumab and to promote HER2 degradation in combination with trastuzumab and pertuzumab (Bergstrom D.A. et al., Cancer Res. 2015;75:LB-231).

[0201] Exemplary HER2-targeting antibodies that can be used in the ADCs of the present disclosure can be antibodies or antigen-binding fragments comprising all 6 CDR sequences of antibodies selected from the group consisting of (preferably, comprising the heavy chain variable region and light chain variable region sequences of antibodies selected from the group consisting of): trastuzumab (Herceptin, Genentech, US6,054,297); ATCC accession numbers PTA-10355, PTA-10356, PTA-10357, PTA 10358 (US20100119511); ATCC accession number CRL-10463 (Genentech); ATCC accession numbers HB-12215, HB-12216, CRL 10463, HB-12697; pertuzumab (Pertuzumab, Genentech, US20110117097); ATCC accession numbers HB-12215, HB-12216, CRL 10463, HB-12698 (US20090202546); ATCC accession numbers HB-12215, HB-12216 (US20060088523); ATCC accession numbers (7C2) HB-12215, (7F3) HB-12216, (4D5) CRL-10463, (2C4) HB-12697 (US20060018899); TrasGEX (Glycotope: http: / / www.glycotope.conn / pipeline). The present disclosure also contemplates anti-HER2 antibodies disclosed in the following documents: US20110177095, US20100119511, US20110117097, US20090285837, US20090202546, US20060088523, US20060018899, US2011 / 0159014, US20090187007, US20110217305.

[0202] >Trastuzumab light chain amino acid sequence (SEQ ID NO:1)

[0203] DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0204] >Amino acid sequence of the heavy chain of trastuzumab (SEQ ID NO:2)

[0205] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFT ISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS

[0206] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK。

[0207] >Amino acid sequence of the light chain LCDR1 of trastuzumab (SEQ ID NO:3)

[0208] RASQDVNTAVA

[0209] >Amino acid sequence of the light chain LCDR2 of trastuzumab (SEQ ID NO:4)

[0210] SASFLYS

[0211] >Amino acid sequence of the light chain LCDR3 of trastuzumab (SEQ ID NO:5)

[0212] QQHYTTPPT

[0213] >Amino acid sequence of the heavy chain HCDR1 of trastuzumab (SEQ ID NO:6)

[0214] DTYIH

[0215] >Amino acid sequence of the heavy chain HCDR2 of trastuzumab (SEQ ID NO:7)

[0216] RIYPTNGYTRYADSVKG

[0217] >Amino acid sequence of the heavy chain HCDR3 of trastuzumab (SEQ ID NO:8)

[0218] WGGDGFYAMDY

[0219] >Variable light chain VL of trastuzumab (SEQ ID NO:9)

[0220] DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK

[0221] >Variable heavy chain VH of trastuzumab (SEQ ID NO:10)

[0222] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS

[0223] In one embodiment, the antibody portion for the ADCs of the present disclosure comprises all 6 CDR sequences of trastuzumab. In another embodiment, the antibody portion for the ADCs of the present disclosure comprises the variable heavy chain sequence and the variable light chain sequence of trastuzumab. In yet another embodiment, the antibody portion for the ADCs of the present disclosure comprises the heavy chain sequence and the light chain sequence of trastuzumab.

[0224] In some embodiments, the Ab unit of the ADCs of the present disclosure comprises three CDRs of the variable heavy chain (VH) sequence of SEQ ID NO:10 and three CDRs of the variable light chain (VL) sequence of SEQ ID NO:9, and preferably, wherein said CDRs are defined according to Kabat or IMGT or a combination thereof.

[0225] In some embodiments, the Ab unit of the ADCs of the present disclosure comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs), wherein:

[0226] According to Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:6, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:7, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:8, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:3, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:4, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:5.

[0227] In one embodiment, the Ab unit of the disclosed ADC comprises a heavy chain variable region, wherein the heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO: 10, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0228] In one embodiment, the Ab unit of the disclosed ADC comprises a light chain variable region, wherein the light chain variable region comprises: the amino acid sequence shown in SEQ ID NO: 9, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0229] In some preferred embodiments, the Ab unit of the disclosed ADC comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 10, and wherein the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 9.

[0230] In some embodiments, the Ab unit of the disclosed ADC preferably further comprises a heavy chain constant region and / or a light chain constant region of an antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from a human immunoglobulin. Preferably, the light chain constant region is a light chain constant region derived from a human immunoglobulin. In some aspects, the heavy chain constant region comprised in the Ab unit can be of any isotype or subtype, such as a heavy chain constant region of the IgG1, IgG2, IgG3 or IgG4 isotype, and preferably an IgG1, IgG2 or IgG4 heavy chain constant region, especially a human IgG1 heavy chain constant region. In still further aspects, the light chain constant region comprised in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially a human κ light chain constant region.

[0231] In some embodiments, the Ab unit of the disclosed ADC comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 11, or an amino acid sequence having at least one, two or three, but not more than 20, 10 or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO: 11, or a sequence having at least 95-99% identity to the amino acid sequence of SEQ ID NO: 11.

[0232] An exemplary amino acid sequence of the human IgG1 heavy chain constant region (SEQ ID NO: 11)

[0233] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0234] In some embodiments, the Ab unit of the disclosed ADC comprises a human kappa light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO:12, or an amino acid sequence comprising at least one, two, or three, but no more than 20, 10, or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO:12, or a sequence having at least 95 - 99% identity to the amino acid sequence of SEQ ID NO:12.

[0235] An exemplary amino acid sequence of the human kappa light chain constant region (SEQ ID NO:12)

[0236] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0237] In some embodiments, the Ab unit of the disclosed ADC is a full - length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit has a tetrameric structure formed by two light chains and two heavy chains. In still other embodiments, the unit of the Ab is an IgG antibody, particularly an IgG1 antibody.

[0238] In some preferred embodiments, the Ab unit of the ADC of the present disclosure comprises a heavy chain and a light chain, wherein: the heavy chain comprises the amino acid sequence shown in SEQ ID NO: 2, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or consists of the same. In some other preferred embodiments, the Ab unit of the ADC of the present disclosure comprises a heavy chain and a light chain, wherein: the light chain comprises the amino acid sequence shown in SEQ ID NO: 1, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0239] In some more preferred embodiments, the Ab unit of the ADC of the present disclosure comprises:

[0240] (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2, and

[0241] (b) a light chain comprising the amino acid sequence of SEQ ID NO: 1.

[0242] Ab unit targeting TROP2

[0243] In a particularly preferred embodiment, the antibody conjugate provided herein comprises an antibody or antigen-binding fragment that specifically binds to human TROP2 (anti-TROP2 antibody), i.e., the antibody portion specifically targets the tumor-associated antigen TROP2. Thus, in some aspects, the present disclosure provides an antibody-drug conjugate (ADC) that comprises an antibody or antigen-binding fragment thereof that specifically binds to TROP2 as the Ab unit of the ADC.

[0244] Trophoblast cell surface antigen 2 (TROP2), also known as tumor-associated calcium signal transducer 2 (TACSTD2), is a type I transmembrane cell surface glycoprotein. The sequence of human TROP2 can be obtained from UniProtKB accession number P09758. It has been confirmed that TROP2 is overexpressed in many solid tumors, including, but not limited to, various human epithelial cancers, such as cervical cancer, endometrial cancer, breast cancer, urothelial cancer, lung cancer, gastric cancer, prostate cancer, colorectal cancer, and pancreatic cancer, etc. Moreover, TROP2 can play a role in tumor cell proliferation, invasion, migration, apoptosis, and treatment resistance by binding to or interacting with various molecules. These characteristics have made TROP2 an attractive pan-cancer target for cancer treatment. Ying Wen et al., A literature review of the promising future of TROP2: a potential drug therapy target, Ann Transl Med. 2022 Dec;10(24):1403, doi:10.21037 / atm-22-5976.

[0245] Antibodies targeting human TROP2 that can be used in the ADCs of the present disclosure can be prepared using antibody preparation processes known in the art. For example, anti-TROP2 antibodies can be obtained by immunizing an animal with human TROP2 (UniProtKB accession number P09758) or a polypeptide comprising the amino acid sequence of the extracellular domain of TROP2, harvesting the antibodies from the immunized animal, and purifying and preferably humanizing them. In addition, fully human sequence anti-human TROP2 antibodies can be obtained using methods such as yeast display libraries expressing human immunoglobulin sequences or transgenic animals.

[0246] In some embodiments, an antibody or an antibody fragment (such as an antigen-binding fragment) that specifically binds to human TROP2 can be selected from Sacituzumab, Datopotamab, or an antibody fragment thereof, or other anti-human TROP2 antibodies that recognize the same epitope or competitively bind to human TROP2.

[0247] Sacituzumab, also known as sacituzumab govitecan, is the humanized form of the murine monoclonal antibody RS7 developed by Immunomedics and is a humanized IgG1κ monoclonal antibody targeting TROP2. This antibody can directly bind to cancer cells expressing TROP2 and trigger antibody endocytosis. The sequence of Sacituzumab can be found in US10179171B2.

[0248] Datopotamab is an IgG1 anti-TROP2 antibody. This antibody was generated by humanizing a mouse mAb that specifically binds to human TROP2. The sequence of Datopotamab can be found in Daisuke Okajima et al., Datopotamab Deruxtecan, a Novel TROP2-directed Antibody–drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells, Mol Cancer Ther (2021) 20(12):2329–2340.

[0249] Exemplary antibodies targeting human TROP2 that can be used in the ADCs of the present disclosure can be antibodies or antigen-binding fragments comprising all 6 CDR sequences of antibodies selected from the group consisting of (preferably, comprising the heavy chain variable region and light chain variable region sequences of antibodies selected from the group consisting of): Sacituzumab and Datopotamab. The present disclosure also contemplates anti-human TROP2 antibodies disclosed in the following documents: WO2010089782A1; US2021 / 0393792 A1; WO2008 / 144891, WO2011 / 145744, WO2011 / 155579, WO2013 / 077458, WO2003 / 074566, WO2011 / 068845, WO2013 / 068946, US 2023 / 0270870A1.

[0250] >Sacituzumab light chain amino acid sequence (SEQ ID NO:13)

[0251] DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIK

[0252] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0253] >Sacituzumab heavy chain amino acid sequence (SEQ ID NO:14)

[0254] QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMG WINTYTGEPTYTDDFKG RFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVSS

[0255] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0256] >Sacituzumab light chain LCDR1 sequence (SEQ ID NO:15)

[0257] KASQDVSIAVA

[0258] >Sacituzumab light chain LCDR2 sequence (SEQ ID NO:16)

[0259] SASYRYT

[0260] >Sacituzumab light chain LCDR3 sequence (SEQ ID NO:17)

[0261] QQHYITPLT

[0262] >Sacituzumab heavy chain HCDR1 sequence (SEQ ID NO:18)

[0263] NYGMN

[0264] >Sacituzumab heavy chain HCDR2 sequence (SEQ ID NO:19)

[0265] WINTYTGEPTYTDDFKG

[0266] >Heavy chain HCDR3 sequence of Sacituzumab (SEQ ID NO:20)

[0267] GGFGSSYWYFDV

[0268] >Variable light chain VL of Sacituzumab (SEQ ID NO:21)

[0269] DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIK

[0270] >Variable heavy chain VH of Sacituzumab (SEQ ID NO:22)

[0271] QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVSS

[0272] In one embodiment, the antibody portion for the disclosed ADCs comprises all 6 CDR sequences of Sacituzumab or Datopotamab. In another embodiment, the antibody portion for the disclosed ADCs comprises the variable heavy chain sequence and the variable light chain sequence of Sacituzumab or Datopotamab. In yet another embodiment, the antibody portion for the disclosed ADCs comprises the heavy chain sequence and the light chain sequence of Sacituzumab or Datopotamab.

[0273] In some embodiments, the Ab unit of the disclosed ADCs comprises three CDRs of the variable heavy chain (VH) sequence of SEQ ID NO:22 and three CDRs of the variable light chain (VL) sequence of SEQ ID NO:21, and preferably, wherein the CDRs are defined according to Kabat or IMGT or a combination thereof.

[0274] In some embodiments, the Ab unit of the disclosed ADCs comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs), wherein:

[0275] According to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:18, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:19, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:20, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:15, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:16, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:17.

[0276] In one embodiment, the Ab unit of the disclosed ADC comprises a heavy chain variable region, wherein the heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:22, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0277] In one embodiment, the Ab unit of the disclosed ADC comprises a light chain variable region, wherein the light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:21, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0278] In some preferred embodiments, the Ab unit of the disclosed ADC comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:22, and wherein the light chain variable region comprises the amino acid sequence shown in SEQID NO:21.

[0279] In some embodiments, the Ab unit of the disclosed ADC preferably further comprises the heavy chain constant region and / or the light chain constant region of the antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from a human immunoglobulin. Preferably, the light chain constant region is a light chain constant region derived from a human immunoglobulin. In some aspects, the heavy chain constant region comprised in the Ab unit can be any isotype or subtype, such as the heavy chain constant region of the IgG1, IgG2, IgG3 or IgG4 isotype, and preferably the IgG1, IgG2 or IgG4 heavy chain constant region, especially the human IgG1 heavy chain constant region. In still other aspects, the light chain constant region comprised in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially the human κ light chain constant region.

[0280] In some embodiments, the Ab unit of the disclosed ADC comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:23, or an amino acid sequence comprising at least one, two, or three, but no more than 20, 10, or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO:23, or a sequence having at least 95 - 99% identity to the amino acid sequence of SEQ ID NO:23.

[0281] An exemplary amino acid sequence (SEQ ID NO:23) of the human IgG1 heavy chain constant region

[0282] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0283] In some embodiments, the Ab unit of the disclosed ADC comprises a human κ light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO:12, or an amino acid sequence comprising at least one, two, or three, but no more than 20, 10, or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO:12, or a sequence having at least 95 - 99% identity to the amino acid sequence of SEQ ID NO:12.

[0284] In some embodiments, the Ab unit of the disclosed ADC is a full-length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit has a tetrameric structure formed by two light chains and two heavy chains. In still further embodiments, the Ab unit is an IgG antibody, particularly an IgG1 antibody.

[0285] In some preferred embodiments, the Ab unit of the ADC of the present disclosure comprises a heavy chain and a light chain, wherein: the heavy chain comprises the amino acid sequence shown in SEQ ID NO: 14, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or consists of the same. In some other preferred embodiments, the Ab unit of the ADC of the present disclosure comprises a heavy chain and a light chain, wherein: the light chain comprises the amino acid sequence shown in SEQ ID NO: 13, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0286] In some more preferred embodiments, the Ab unit of the ADC of the present disclosure comprises:

[0287] (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 14, and

[0288] (b) a light chain comprising the amino acid sequence of SEQ ID NO: 13.

[0289] Cancers that can be treated with the ADC of the present disclosure targeting TROP2 include, but are not limited to, adenocarcinoma, squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer, gastric adenocarcinoma, esophageal cancer, hepatocellular carcinoma, ovarian epithelial cancer, breast cancer, metastatic breast cancer, triple-negative breast cancer (TNBC), prostate cancer, hormone-refractory prostate cancer, pancreatic ductal adenocarcinoma, head and neck cancer, renal cell carcinoma, bladder tumor, cervical cancer, endometrial cancer, uterine cancer, follicular thyroid cancer, glioblastoma multiforme.

[0290] Ab unit targeting Claudin18.2

[0291] In a particularly preferred embodiment, the antibody conjugate provided herein comprises an antibody or antigen-binding fragment that specifically binds to human Claudin18.2 (anti-Claudin18.2 antibody), i.e., the antibody portion specifically targets the tumor-associated antigen Claudin18.2. Thus, in some aspects, the present disclosure provides an antibody-drug conjugate (ADC) that comprises an antibody or an antigen-binding fragment thereof that specifically binds to Claudin18.2 as the Ab unit of the ADC.

[0292] Claudin 18.2 (also abbreviated as CLDN18.2) belongs to the tight junction membrane proteins of the Claudin family. The Claudin 18.2 sequences of humans and various mammals can be found in UniProtKB. For example, the human Claudin 18.2 sequence can be found in UniProtKB accession number P56856-2. The expression of this protein in healthy tissues is mainly limited to differentiated gastric mucosal epithelial cells, but it shows abnormal overexpression in a series of malignant tumors, especially in digestive system malignancies. Therefore, Claudin 18.2 has been proposed as a promising target for the development of antibody-based ADC cancer therapeutics. Daisuke Kyuno et al., Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials, Tissue Barriers. 2022;10(1):1967080. doi:10.1080 / 21688370.2021.1967080; Jinxia Chen, Targeting CLDN18.2 in cancers of the gastrointestinal tract: New drugs and new indications, Front Oncol. 2023;13:1132319, doi:10.3389 / fonc.2023.1132319.

[0293] Antibodies targeting human Claudin 18.2 that can be used in the ADCs of the present disclosure can be prepared using antibody preparation processes known in the art. For example, anti-Claudin 18.2 antibodies can be obtained by immunizing an animal with human Claudin 18.2 (UniProtKB accession number P56856-2) or a polypeptide comprising the amino acid sequence of the extracellular domain of Claudin 18.2, harvesting the antibodies from the immunized animal, and purifying and preferably humanizing them. In addition, yeast display libraries or transgenic animals expressing human immunoglobulin sequences can be used to obtain fully human sequence anti-human Claudin 18.2 antibodies.

[0294] In some embodiments, an antibody or an antibody fragment (e.g., an antigen-binding fragment) that specifically binds to human Claudin18.2 can be selected from Zolbetuximab, Osemitamab (TST001), CMG901, ASKB589, ZL-1211, or an antibody fragment thereof, or other anti-human Claudin18.2 antibodies that recognize the same epitope or competitively bind to human Claudin18.2.

[0295] Zolbetuximab (also known as GC-182, IMAB-362, IMAB362, claudiximab) is an IgG1 antibody derived from a murine monoclonal antibody and has been chimerized to display the human IgG1 constant region for clinical use. This antibody can directly bind to cancer cells expressing CLDN18.2 and trigger antibody endocytosis. The sequence of Zolbetuximab can be found in WO2007059997 and WO2016 / 165762.

[0296] Osemitamab (TST001) is a high-affinity humanized anti-Claudin18.2 antibody. This antibody has enhanced antibody-dependent cell cytotoxicity (ADCC) and complement-dependent cell cytotoxicity (CDC), and exhibits strong anti-tumor activity in tumor xenograft models. The sequence of this antibody can be found in Inxight Drugs and INN (code 11927).

[0297] CMG901, ASKB589, and ZL-1211 are exemplary antibodies against human CLDN18.2 in clinical trials. See DOI:10.1200 / JCO.2023.41.4_suppl.352; DOI:10.1200 / JCO.2023.41.4_suppl.397; DOI:10.1200 / JCO.2023.41.16_suppl.2537.

[0298] Exemplary antibodies targeting human Claudin18.2 that can be used in the ADCs of the present disclosure can be antibodies or antigen-binding fragments comprising all 6 CDR sequences (preferably, comprising the heavy chain variable region and light chain variable region sequences) of antibodies selected from the group consisting of Zolbetuximab, Osemitamab (TST001), and CMG901.

[0299] The present disclosure also contemplates anti-human Claudin18.2 antibodies disclosed in the following documents: WO2007059997A1, CN107667118A, WO2016 / 166122, US11555070B2, WO2020 / 135674, WO2018 / 006882, CN109762067, WO2019 / 242505, WO2020 / 038404, WO2020 / 043044, WO2020 / 063988, WO2020 / 082209, WO2020 / 018852, WO2020 / 023679, WO2020 / 135674, WO2020 / 135201, WO2020 / 139956, WO2020 / 025792, WO2020160560, CN111808194, and WO2020200196.> Zolbetuximab light chain amino acid sequence (SEQ ID NO:24)

[0300] DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPFTFGSGTKLEIK

[0301] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0302] > Zolbetuximab heavy chain amino acid sequence (SEQ ID NO:25)

[0303] QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDSYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSWRGNSFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0304] >Zolbetuximab light chain LCDR1 sequence (SEQ ID NO:26)

[0305] KSSQSLLNSGNQKNYLT

[0306] >Zolbetuximab light chain LCDR2 sequence (SEQ ID NO:27)

[0307] WASTRES

[0308] >Zolbetuximab light chain LCDR3 sequence (SEQ ID NO:28)

[0309] QNDYSYPFT

[0310] >Zolbetuximab heavy chain HCDR1 sequence (SEQ ID NO:29)

[0311] SYWIN

[0312] >Zolbetuximab heavy chain HCDR2 sequence (SEQ ID NO:30)

[0313] NIYPSDSYTNYNQKFKD

[0314] >Zolbetuximab heavy chain HCDR3 sequence (SEQ ID NO:31)

[0315] SWRGNSFDY

[0316] >Zolbetuximab light chain variable region VL (SEQ ID NO:32)

[0317] DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPFTFGSGTKLEIK

[0318] >Zolbetuximab heavy chain variable region VH (SEQ ID NO:33)

[0319] QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDSYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSWRGNSFDYWGQGTTLTVSS

[0320] In one embodiment, the antibody portion for the disclosed ADC comprises all 6 CDR sequences of Zolbetuximab. In another embodiment, the antibody portion for the disclosed ADC comprises the heavy chain variable region sequence and the light chain variable region sequence of Zolbetuximab. In yet another embodiment, the antibody portion for the disclosed ADC comprises the heavy chain sequence and the light chain sequence of Zolbetuximab.

[0321] In some embodiments, the Ab unit of the disclosed ADC comprises three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:33 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:32, and preferably, wherein the CDRs are defined according to Kabat or IMGT or a combination thereof.

[0322] In some embodiments, the Ab unit of the disclosed ADC comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs), wherein:

[0323] According to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:29, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:30, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:31, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:26, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:27, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:28.

[0324] In one embodiment, the Ab unit of the ADC of the present disclosure comprises a heavy chain variable region, wherein the heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:33, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0325] In one embodiment, the Ab unit of the ADC of the present disclosure comprises a light chain variable region, wherein the light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:32, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0326] In some preferred embodiments, the Ab unit of the ADC of the present disclosure comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:33, and wherein the light chain variable region comprises the amino acid sequence shown in SEQID NO:32.

[0327] In some embodiments, the Ab unit of the ADC of the present disclosure preferably further comprises a heavy chain constant region and / or a light chain constant region of the antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from a human immunoglobulin. Preferably, the light chain constant region is a light chain constant region derived from a human immunoglobulin. In some aspects, the heavy chain constant region comprised in the Ab unit can be any isotype or subtype, such as a heavy chain constant region of the IgG1, IgG2, IgG3 or IgG4 isotype, and preferably an IgG1, IgG2 or IgG4 heavy chain constant region, especially a human IgG1 heavy chain constant region. In still further aspects, the light chain constant region comprised in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially a human κ light chain constant region.

[0328] In some embodiments, the Ab unit of the disclosed ADC comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 34, or an amino acid sequence comprising at least one, two, or three, but no more than 20, 10, or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO: 34, or a sequence having at least 95-99% identity to the amino acid sequence of SEQ ID NO: 34.

[0329] An exemplary amino acid sequence of the human IgG1 heavy chain constant region (SEQ ID NO: 34)

[0330] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0331] In some embodiments, the Ab unit of the disclosed ADC comprises a human κ light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO: 12, or an amino acid sequence comprising at least one, two, or three, but no more than 20, 10, or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO: 12, or a sequence having at least 95-99% identity to the amino acid sequence of SEQ ID NO: 12.

[0332] In some embodiments, the Ab unit of the disclosed ADC is a full-length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit has a tetrameric structure formed by two light chains and two heavy chains. In still further embodiments, the Ab unit is an IgG antibody, particularly an IgG1 antibody.

[0333] In some preferred embodiments, the Ab unit of the disclosed ADC comprises a heavy chain and a light chain, wherein: the heavy chain comprises the amino acid sequence shown in SEQ ID NO:25, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto, or consists thereof. In some other preferred embodiments, the Ab unit of the disclosed ADC comprises a heavy chain and a light chain, wherein: the light chain comprises the amino acid sequence shown in SEQ ID NO:24, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0334] In some more preferred embodiments, the Ab unit of the disclosed ADC comprises:

[0335] (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:25, and

[0336] (b) a light chain comprising the amino acid sequence of SEQ ID NO:24.

[0337] Cancers that can be treated with the disclosed ADC targeting Claudin18.2 include, but are not limited to, various digestive tract cancers, such as gastric cancer (GC), gastroesophageal junction (GEJ) cancer, esophageal cancer, and pancreatic cancer.

[0338] Ab unit targeting EGFR

[0339] In a particularly preferred embodiment, the antibody-drug conjugate provided herein comprises an antibody or antigen-binding fragment that specifically binds to human EGFR (anti-EGFR antibody), i.e., the antibody portion specifically targets the tumor-associated antigen EGFR. Thus, in some aspects, the present invention provides an antibody-drug conjugate (ADC) that comprises an antibody or antigen-binding fragment thereof that specifically binds to EGFR as the Ab unit of the ADC.

[0340] Epidermal growth factor receptor, also abbreviated as EGFR herein, is one of the members of the epidermal growth factor receptor (HER) family and is encoded by the c-erbB proto-oncogene (also known as HER-1 or Erb-B1). The EGFR sequences of humans and many of their mammals can be found in UniProtKB. For example, the human EGFR sequence can be seen in UniProtKB accession number P00533. EGFR is overexpressed in many solid tumors, including lung cancer, head and neck cancer, breast cancer, kidney cancer, gastric cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, and bladder cancer; and EGFR can induce tumor proliferation through homodimerization.

[0341] Currently, EGFR has been proposed as a promising target for antibody-based cancer therapeutics. To date, five EGFR-targeting monoclonal antibodies have been approved for clinical cancer treatment, namely cetuximab ( ), panitumumab ( ), nimotuzumab (BIOMAB- ), necitumuma and amivantamab (amivantamab-vmjw; ). In addition, three EGFR-based ADC drugs are in the clinical trial stage. However, no EGFR-based ADC has been approved for treatment yet. See Jinfeng Yu et al., Antibody-Drug Conjugates Targeting the Human Epidermal GrowthFactor Receptor Family in Cancers, Front Mol Biosci. 2022; 9:847835, doi:10.3389 / fmolb.2022.847835.

[0342] Multiple anti-EGFR monoclonal antibodies have been developed to bind to the extracellular domain of the receptor to block the interaction of the receptor with ligands or its dimerization. These antibodies are all applicable to the present invention. In addition, antibodies targeting human EGFR for use in the ADCs of the present invention can also be prepared by antibody preparation processes known in the art. For example, anti-EGFR antibodies can be obtained by immunizing animals with human EGFR (UniProtKB accession number P00533) or a polypeptide containing the amino acid sequence of the extracellular domain of EGFR, harvesting the antibodies from the immunized animals, and purifying and preferably humanizing them. In addition, yeast display libraries expressing human immunoglobulin sequences or transgenic animals can be used to obtain fully human sequence anti-human EGFR antibodies.

[0343] The antibody targeting human EGFR for use in the ADCs of the present invention can be a monospecific antibody that binds to EGFR. In some cases, the antibody targeting human EGFR for use in the ADCs of the present invention can also be a multispecific antibody, especially a bispecific antibody, such as a bispecific antibody targeting EGFR and MET; or a bispecific antibody targeting MUC1 and EGFR.

[0344] In some embodiments, the anti-human EGFR antibody or an antibody fragment thereof (such as an antigen-binding fragment) for use in the ADCs of the present invention can be selected from cetuximab ( ), panitumumab ( ) Nimotuzumab (nimotuzumab, BIOMAB- ) Necitumuma Depatuxizumab (ABT-806), NECITUMUMAB, IZALONTAMAB, BAFISONTAMAB, Petosemtamab, PIMURUTAMAB, FUTUXIMAB, MODOTUXIMAB (Zatuximab) or an antibody fragment thereof, or other anti-human EGFR antibodies that recognize the same epitope or competitively bind to human EGFR. The sequences of the above antibodies can be found in Inxight Drugs and International Nonproprietary Names (INN) codes 7906, 8499, 8545, 9083, 11030, 10263, 9083, 12022, 11851, 11136, 11309, 9612, and 9613.

[0345] Cetuximab (cetuximab, ) is a recombinant chimeric human / mouse IgG1 monoclonal antibody. This antibody binds to the extracellular domain of non-activated EGFR, and has a much higher affinity than endogenous ligands, can competitively block the binding of ligands to receptors, block the agonist effect of ligands on receptors, and can trigger the endocytosis of EGFR, downregulating the expression level of EGFR on the cell membrane. In addition, this antibody can activate antibody-dependent cell-mediated cytotoxicity (ADCC), producing a further cell killing effect. The sequence of cetuximab can be found in WO2007092453 and INN code 7906.

[0346] Panitumumab (panitumumab, ) is a recombinant humanized IgG2 monoclonal antibody. Panitumumab specifically binds to EGFR on tumor cells and competitively inhibits the binding of EGFR ligands. Preclinical studies have shown that the binding of panitumumab to EGFR can prevent ligand-induced receptor autophosphorylation and the activation of receptor-associated kinases, thereby inhibiting cell growth, inducing apoptosis, reducing the production of pro-inflammatory cytokines and vascular growth factors, and can induce EGFR internalization. The sequence of panitumumab can be found in INN code 8499.

[0347] Exemplary antibodies targeting human EGFR that can be used in the ADC of the present invention can be antibodies or antigen-binding fragments comprising all 6 CDR sequences of antibodies selected from the group consisting of (preferably, comprising the heavy chain variable region and light chain variable region sequences of antibodies selected from the group consisting of): cetuximab, panitumumab, nimotuzumab, necitumuma, deapatuxizumab, NECITUMUMAB, IZALONTAMAB, BAFISONTAMAB, Petosemtamab, PIMURUTAMAB, FUTUXIMAB, and MODOTUXIMAB.

[0348] The present invention also contemplates anti-human EGFR antibodies disclosed in the following documents: WO2023040941A1, WO2022271722A1, WO2022159576A1, WO2022128716A1, WO2022105878A1, WO2021247798A1, WO2022104697A1, WO2021066869A1, WO2020233534A1, WO2020130125A1, WO2019046858A1, WO2019046859A1, WO2019035630A2, WO2019035630A3, WO2018098035A1, WO2017214233A1, WO2017214282A1, WO2017214301A1, WO2017161206A1, WO2017139623A1, WO2017136581A1, WO2017076492A1, WO2017060322A3, WO2017025458A1, WO2017008169A1, WO2016065456A1, WO2015143382A1, WO2014143765A1, WO2014143765A8, WO2014152199A1, WO2014094355A1, WO2012143495A2, and WO2012143495A3.

[0349] >Cetuximab light chain amino acid sequence (SEQ ID NO:35)

[0350] DILLTQSPVILSVSPGERVSFSC RASQSIGTNIH WYQQRTNGSPRLLIK YASESIS GIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTT FGAGTKLELK

[0351] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0352] >Amino acid sequence of the heavy chain of Cetuximab (SEQ ID NO:36)

[0353] QVQLKQSGPGLVQPSQSLSITCTVSGFSLT NYGVH WVRQSPGKGLEWLG VIWSGGNTDYNTPFTS RLSINKDNSKSQVFFKMNSLQSNDTAIYYCAR ALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0354] >LCDR1 sequence of the light chain of Cetuximab (SEQ ID NO:37)

[0355] RASQSIGTNIH

[0356] >LCDR2 sequence of the light chain of Cetuximab (SEQ ID NO:38)

[0357] YASESIS

[0358] >LCDR3 sequence of the light chain of Cetuximab (SEQ ID NO:39)

[0359] QQNNNWPTT

[0360] >HCDR1 sequence of the heavy chain of Cetuximab (SEQ ID NO:40)

[0361] NYGVH

[0362] >Cetuximab heavy chain HCDR2 sequence (SEQ ID NO:41)

[0363] VIWSGGNTDYNTPFTS

[0364] >Cetuximab heavy chain HCDR3 sequence (SEQ ID NO:42)

[0365] ALTYYDYEFAY

[0366] >Cetuximab light chain variable region VL (SEQ ID NO:43)

[0367] DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK

[0368] >Cetuximab heavy chain variable region VH (SEQ ID NO:44)

[0369] QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA

[0370] In one embodiment, the antibody portion for the ADC of the present invention comprises all 6 CDR sequences of Cetuximab. In another embodiment, the antibody portion for the ADC of the present invention comprises the heavy chain variable region sequence and the light chain variable region sequence of Cetuximab. In yet another embodiment, the antibody portion for the ADC of the present invention comprises the heavy chain sequence and the light chain sequence of Cetuximab.

[0371] In some embodiments, the Ab unit of the ADC of the present invention comprises three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:44 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:43, and preferably, wherein said CDRs are defined according to Kabat or IMGT or a combination thereof.

[0372] In some embodiments, the Ab unit of the ADC of the present invention comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs), wherein:

[0373] According to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:40, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:41, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:42, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:37, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:38, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:39.

[0374] In one embodiment, the Ab unit of the ADC of the present invention comprises a heavy chain variable region, wherein the heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:44, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity therewith.

[0375] In one embodiment, the Ab unit of the ADC of the present invention comprises a light chain variable region, wherein the light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:43, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity therewith.

[0376] In some preferred embodiments, the Ab unit of the ADC of the present invention comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:44, and wherein the light chain variable region comprises the amino acid sequence shown in SEQID NO:43.

[0377] In some embodiments, the Ab unit of the ADC of the present invention preferably further comprises a heavy chain constant region and / or a light chain constant region of the antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from a human immunoglobulin. Preferably, the light chain constant region is a light chain constant region derived from a human immunoglobulin. In some aspects, the heavy chain constant region comprised in the Ab unit can be of any isotype or subtype, such as the heavy chain constant region of the IgG1, IgG2, IgG3 or IgG4 isotype, and preferably the IgG1, IgG2 or IgG4 heavy chain constant region, especially the human IgG1 heavy chain constant region. In still further aspects, the light chain constant region comprised in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially the human κ light chain constant region.

[0378] In some embodiments, the Ab unit of the ADC of the present invention comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:34, or an amino acid sequence having at least one, two or three, but not more than 20, 10 or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO:34, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:34.

[0379] In some embodiments, the Ab unit of the ADC of the present invention comprises a human κ light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO:12, or an amino acid sequence having at least one, two or three, but not more than 20, 10 or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO:12, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:12.

[0380] In some embodiments, the Ab unit of the ADC of the present invention is a full-length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit has a tetrameric structure formed by two light chains and two heavy chains. In still other embodiments, the unit of the Ab is an IgG antibody, particularly an IgG1 antibody.

[0381] In some preferred embodiments, the Ab unit of the ADC of the present invention comprises a heavy chain and a light chain, wherein: the heavy chain comprises the amino acid sequence shown in SEQ ID NO:36, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity therewith, or consists thereof. In some other preferred embodiments, the Ab unit of the ADC of the present invention comprises a heavy chain and a light chain, wherein: the light chain comprises the amino acid sequence shown in SEQ ID NO:35, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity therewith.

[0382] In some more preferred embodiments, the Ab unit of the ADC of the present invention comprises:

[0383] (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:36, and

[0384] (b) a light chain comprising the amino acid sequence of SEQ ID NO:35.

[0385] Cancers that can be treated with the ADCs of the present disclosure that target EGFR include, but are not limited to, various primary and metastatic solid tumors, such as lung cancer (e.g., lung adenocarcinoma, lung squamous cell carcinoma, and non-small cell lung cancer), head and neck cancer (e.g., head and neck squamous cell carcinoma), nasopharyngeal cancer, esophageal cancer, biliary tract cancer, colon cancer, colorectal cancer, pancreatic cancer, gastric cancer, and glioblastoma.

[0386] Ab unit targeting EGFR and MET

[0387] In a particularly preferred embodiment, the antibody conjugates provided herein include an antibody or antigen-binding fragment that specifically binds to human EGFR and MET (also referred to as c-Met) (anti-EGFR / MET antibody), i.e., the antibody portion specifically targets the tumor-associated antigens EGFR and MET. Thus, in some aspects, the present disclosure provides antibody-drug conjugates (ADCs) that comprise an antibody or an antigen-binding fragment thereof that specifically binds to EGFR and MET as the Ab unit of the ADC.

[0388] Drug resistance is a major challenge in targeted cancer therapy. For example, MET amplification or protein overexpression has been identified as an important mechanism of clinical resistance to EGFR inhibitors. Similarly, emerging evidence suggests that activation of the EGFR pathway may lead to resistance to c-MET targeted inhibitors. Benedettini, E., et al., Met activation in non-smallcell lung cancer is 2010associated with de novo resistance to EGFR inhibitorsand the development of brain metastasis. The American journal of pathology, 2010.177(1): p. 415-423. Bertotti, 2015Bertotti, A. and F. Sassi, Molecular Pathways: Sensitivity and Resistance to Anti-EGFR Antibodies. Clinical Cancer Research, 2015. In addition, co-expression of cMet and EGFR has been observed in a variety of cancers, including non-small cell lung cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell carcinoma, breast cancer, and esophageal-gastric cancer. Therefore, drug molecules based on multi-specific antibodies targeting EGFR and c-MET (such as bispecific antibodies) have been proposed as a promising treatment option for EGFR / cMET single-positive and double-positive tumors. Examples of EGFR / cMET dual-targeted antibodies include, but are not limited to, Amivantamab, AZD9592, Pamvatamig (MCLA-129), Bafisontamab (EMB01), and LY-3164530, which have been approved or are in clinical development.

[0389] In some embodiments, the antibody or antibody fragment (such as an antigen-binding fragment) that specifically binds to human EGFR and MET is selected from: Amivantamab, AZD9592, Pamvatamig (MCLA-129), Bafisontamab (EMB01), and LY-3164530, or an antibody fragment thereof or a site-specific mutant thereof, or other anti-human EGFR and MET antibodies that recognize the same epitope or competitively bind to human EGFR and MET. These antibodies can all promote endocytosis at the relevant target and enter tumor cells for degradation, and thus are suitable drug delivery vehicles.

[0390] Amivantamab, also known as JNJ-61186372, is an anti-EGFR-MET bispecific antibody. The antibody has an EGFR antibody arm composed of a heavy chain and a light chain and a MET antibody arm composed of a heavy chain and a light chain, with an asymmetric IgG-like structure of the 1+1 type. The antibody binds to EGFR and MET, functions as an EGFR antagonist and a MET inhibitor, and induces the internalization of EGFR and MET on the cell surface. Amivantamab is suitable for the treatment of various cancers with EGFR exon 20 insertion mutations, especially non-small cell lung cancer. Patients with non-small cell lung cancer usually develop resistance to drugs that target EGFR and MET alone. The development of Amivantamab, by targeting both EGFR and MET, reduces the likelihood of resistance development and shows superior efficacy to single EGFR inhibitors and single MET inhibitors in animal models and clinical trials. The FDA has approved the antibody for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations who have progressed after platinum-based chemotherapy. The antibody sequence of Amivantamab can be found in US20230174677A1 and CAS No.2171511-58-1.

[0391] AZD9592 is a drug molecule based on a MET-EGFR bispecific antibody that is currently in phase 1 clinical trials and is suitable for colorectal cancer, head and neck tumors, and non-small cell lung cancer. The bispecific antibody RAA22 / B09-57 targeting EGFR and cMet in this drug molecule targets both EGFR and c-Met, and is an asymmetric bispecific antibody of the 1+1 type. The antibody exerts its function by inhibiting the hepatocyte growth factor receptor MET and the epidermal growth factor receptor EGFR. The antibody sequence of RAA22 / B09-57 can be found in US2023 / 0183358A1.

[0392] Pamvatamig, also known as MCLA-129, is an asymmetric bispecific antibody of the 1+1 type. The bispecific antibody is constructed with DEKK mutations to prevent heavy chain mispairing and a common light chain to prevent light chain mispairing. Functionally, MCLA-129 can not only inhibit the phosphorylation of cMet and EGFR in tumors, but also reverse tumor resistance to erlotinib. The bispecific antibody is suitable for targeting advanced malignant solid tumors, colorectal cancer, esophageal squamous cell carcinoma, metastatic non-small cell lung cancer, head and neck squamous cell carcinoma, gastric cancer, advanced non-small cell lung cancer, and non-small cell lung cancer with EGFR mutations. The antibody sequence of Pamvatamig is disclosed under US11773170B2 and CAS No.2750004-05-6.

[0393] Bafisontamab (EMB01) is a bispecific antibody targeting EGFR and cMet constructed using the FIT- bispecific antibody platform. Structurally, EMB-01 has a 2+2 symmetric bispecific antibody structure. The anti-tumor activity induced by EMB-01 in PDX and CDX tumor models is significantly stronger than that of anti-EGFR or anti-c-Met monoclonal antibodies alone, and it exhibits significant anti-tumor activity in anti-EGFR monoclonal antibody-resistant tumor models. The antibody sequence of EMB-01 is disclosed under WO2017136820 (as molecule FIT013a) and INN code 11851.

[0394] LY-3164530 is a bispecific antibody targeting c-MET / EGFR, which fuses scFv (cetuximab) to the N-terminus of the heavy chain of emibetuzumab (LY2875358), thus forming a 2+2 symmetric bispecific antibody. This antibody is of the IgG4 subtype and therefore has almost no effector functions such as ADCC. In tumor mouse models, this bispecific antibody has a certain effect on inhibiting the growth of tumor cells. The antibody sequence of LY-3164530 is disclosed under CAS2069210-01-9.

[0395] Exemplary antibodies targeting EGFR and MET that can be used in the ADCs of the present disclosure can be antibodies or antigen-binding fragments that comprise all 6 CDR sequences specifically binding to EGFR and all 6 CDR sequences specifically binding to MET (preferably, comprising the anti-EGFR heavy and light chain variable region sequences and the anti-MET heavy and light chain variable region sequences of antibodies selected from the group consisting of): Amivantamab, AZD9592, Pamvatamig (MCLA-129), Bafisontamab (EMB01), and LY-3164530. The present disclosure also contemplates anti-EGFR and MET antibodies disclosed in the following documents: WO2019031965A1, WO2022104236A2, WO2023069888A1, WO2023122588A2, WO2023172133A1, WO2023172134A1, WO2024002938A1, and WO2024153168A2.

[0396] > Amino acid sequence of the anti-EGFR heavy chain of Amivantamab (SEQ ID NO:45)

[0397] QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0398] >Amino acid sequence of the anti-EGFR light chain of amivantamab (SEQ ID NO:46)

[0399] AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0400] >Amino acid sequence of the anti-MET heavy chain of amivantamab (SEQ ID NO:47)

[0401] QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0402] >Amino acid sequence of the anti-MET light chain of amivantamab (SEQ ID NO:48)

[0403] DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0404] >Amino acid sequence of the anti-EGFR heavy chain HCDR1 of amivantamab (SEQ ID NO:49)

[0405] TYGMH

[0406] >Amino acid sequence of the anti-EGFR heavy chain HCDR2 of amivantamab (SEQ ID NO:50)

[0407] VIWDDGSYKYYGDSVKG

[0408] >Amino acid sequence of the anti-EGFR heavy chain HCDR3 of amivantamab (SEQ ID NO:51)

[0409] DGITMVRGVMKDYFDY

[0410] >Amino acid sequence of the anti-EGFR light chain LCDR1 of amivantamab (SEQ ID NO:52)

[0411] RASQDISSALV

[0412] >Amino acid sequence of the anti-EGFR light chain LCDR2 of amivantamab (SEQ ID NO:53)

[0413] DASSLES

[0414] >Amino acid sequence of the anti-EGFR light chain LCDR3 of amivantamab (SEQ ID NO:54)

[0415] QQFNSYPLT

[0416] >Amino acid sequence of the anti-MET heavy chain HCDR1 of amivantamab (SEQ ID NO:55)

[0417] SYGIS

[0418] >Amino acid sequence of the anti-MET heavy chain HCDR2 of amivantamab (SEQ ID NO:56)

[0419] WISAYNGYTNYAQKLQG

[0420] >Amino acid sequence of the anti-MET heavy chain HCDR3 of amivantamab (SEQ ID NO:57)

[0421] DLRGTNYFDY

[0422] >Amino acid sequence of the anti-MET light chain LCDR1 of amivantamab (SEQ ID NO:58)

[0423] RASQGISNWLA

[0424] >Amino acid sequence of the anti-MET light chain LCDR2 of amivantamab (SEQ ID NO:59)

[0425] AASSLLS

[0426] >Amino acid sequence of the anti-MET light chain LCDR3 of amivantamab (SEQ ID NO:60)

[0427] QQANSFPIT

[0428] >Amino acid sequence of the anti-EGFR heavy chain variable region VH of amivantamab (SEQ ID NO:61)

[0429] QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS

[0430] >Amino acid sequence of the anti-EGFR light chain variable region VL of amivantamab (SEQ ID NO:62)

[0431] AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK

[0432] >Amino acid sequence of the anti-MET heavy chain variable region VH of amivantamab (SEQ ID NO:63)

[0433] QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS

[0434] >Amino acid sequence of the anti-MET light chain variable region VL of amivantamab (SEQ ID NO:64)

[0435] DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK

[0436] In one embodiment, the antibody portion for the ADC of the present invention comprises all 6 CDR sequences in the anti-EGFR arm of amivantamab and all 6 CDR sequences in the anti-MET arm of amivantamab. In another embodiment, the antibody portion for the ADC of the present invention comprises the heavy chain variable region sequence and the light chain variable region sequence of the anti-EGFR arm of amivantamab and the heavy chain variable region sequence and the light chain variable region sequence of the anti-MET arm of amivantamab. In yet another embodiment, the antibody portion for the ADC of the present invention comprises the heavy chain sequence and the light chain sequence of the anti-EGFR of amivantamab and the heavy chain sequence and the light chain sequence of the anti-MET of amivantamab.

[0437] In some embodiments, the Ab unit of the ADC of the present invention comprises a first set of complementarity determining regions that bind to EGFR and a second set of complementarity determining regions that bind to MET, wherein the first set of complementarity determining regions comprises three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:61 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:62, and the second set of complementarity determining regions comprises three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:63 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:64. Preferably, the CDRs are defined according to Kabat or IMGT or a combination thereof.

[0438] In some embodiments, the Ab unit of the ADC of the present invention comprises a first set of complementarity determining regions that bind to EGFR and a second set of complementarity determining regions that bind to MET, wherein:

[0439] the first set of complementarity determining regions comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs), wherein:

[0440] According to Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:49, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:50, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:51, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:52, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:53, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:54;

[0441] the second set of complementarity determining regions comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs), wherein:

[0442] According to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:55, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:56, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:57, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:58, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:59, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:60.

[0443] In one embodiment, the Ab unit of the ADC of the present invention comprises a first heavy chain variable region and a first light chain variable region that bind to EGFR, and a second heavy chain variable region and a second light chain variable region that bind to MET. In some embodiments, the first heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:61, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto. In some embodiments, the first light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:62, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto. In some embodiments, the second heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:63, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto. In some embodiments, the second light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:64, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0444] In some embodiments, the Ab unit of the ADC of the present invention comprises a first heavy chain variable region and a first light chain variable region that bind to EGFR, and a second heavy chain variable region and a second light chain variable region that bind to MET, wherein:

[0445] the first heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:61, and the first light chain variable region comprises the amino acid sequence shown in SEQ ID NO:62; and

[0446] the second heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:63, and the second light chain variable region comprises the amino acid sequence shown in SEQ ID NO:64.

[0447] In some embodiments, the Ab unit of the disclosed ADC preferably further comprises the heavy chain constant region and / or the light chain constant region of the antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from a human immunoglobulin. Preferably, the light chain constant region is a light chain constant region derived from a human immunoglobulin. In some aspects, the heavy chain constant region included in the Ab unit can be any isotype or subtype, such as the heavy chain constant region of the IgG1, IgG2, IgG3 or IgG4 isotype, and preferably the IgG1, IgG2 or IgG4 heavy chain constant region, especially the human IgG1 heavy chain constant region. In still other aspects, the light chain constant region included in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially the human κ light chain constant region.

[0448] In some embodiments, the Ab unit of the disclosed ADC comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 65 or 66, or an amino acid sequence comprising at least one, two or three, but not more than 20, 10 or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO: 65 or 66, or a sequence having at least 95-99% identity to the amino acid sequence of SEQ ID NO: 65 or 66.

[0449] An exemplary amino acid sequence of the human IgG1 heavy chain constant region (SEQ ID NO: 65)

[0450] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0451] An exemplary amino acid sequence of the human IgG1 heavy chain constant region (SEQ ID NO: 66)

[0452] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0453] In some embodiments, the Ab unit of the disclosed ADCs comprises a human kappa light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO:12, or an amino acid sequence comprising at least one, two or three, but no more than 20, 10 or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO:12, or a sequence having at least 95-99% identity to the amino acid sequence of SEQ ID NO:12.

[0454] In some embodiments, the Ab unit of the disclosed ADCs comprises or consists of a first heavy chain, a first light chain, a second heavy chain, and a second light chain, wherein from the N-terminus to the C-terminus,

[0455] - the first heavy chain comprises an anti-EGFR heavy chain variable region and a first heavy chain constant region;

[0456] - the first light chain comprises an anti-EGFR light chain variable region and a first light chain constant region;

[0457] - the second heavy chain comprises an anti-MET heavy chain variable region and a second heavy chain constant region;

[0458] the second light chain comprises an anti-MET light chain variable region and a second light chain constant region.

[0459] In some embodiments, the first and second heavy chain constant regions are the heavy chain constant regions as defined above, preferably the human IgG1 constant region; the first and second light chain constant regions are the light chain constant regions as defined above, preferably the human kappa light chain constant region. In some embodiments, the first heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:65, and the second heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:66. In some embodiments, the first and second light chain constant regions each comprise or consist of the amino acid sequence of SEQ ID NO:12.

[0460] In some embodiments, the Ab unit of the disclosed ADC is a full-length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit has a tetrameric structure formed by two light chains and two heavy chains. In still further embodiments, the Ab unit is an IgG antibody, particularly an IgG1 antibody.

[0461] In some preferred embodiments, the Ab unit of the disclosed ADC comprises a first heavy chain, a first light chain, a second heavy chain, and a second light chain, wherein:

[0462] the first heavy chain comprises, consists of, or consists of an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence shown in SEQ ID NO:45; and the first light chain comprises, consists of, or consists of an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence shown in SEQ ID NO:46;

[0463] the second heavy chain comprises, consists of, or consists of an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence shown in SEQ ID NO:47; and the second light chain comprises, consists of, or consists of an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence shown in SEQ ID NO:48.

[0464] In some more preferred embodiments, the Ab unit of the disclosed ADC comprises:

[0465] (a) an anti-EGFR heavy chain comprising the amino acid sequence of SEQ ID NO:45 and an anti-EGFR light chain comprising the amino acid sequence of SEQ ID NO:46, and

[0466] (b) An anti-MET heavy chain comprising the amino acid sequence of SEQ ID NO: 47 and an anti-MET light chain comprising the amino acid sequence of SEQ ID NO: 48.

[0467] Cancers that can be treated with the disclosed ADCs targeting EGFR and MET are EGFR and / or MET-positive cancers, such as solid tumors and hematological malignancies, including but not limited to: non-small cell lung cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, gastric cancer, prostate cancer, head and neck tumors, liver cancer, bladder cancer, melanoma, esophageal cancer, renal tumors, thyroid cancer, cervical cancer, lymphoma, uterine cancer, skin tumors, colon cancer, sarcoma, leukemia, glioblastoma, etc. Ab unit targeting Nectin4

[0468] In a particularly preferred embodiment, the antibody conjugates provided herein comprise an antibody or antigen-binding fragment that specifically binds to human Nectin-4 (anti-Nectin-4 antibody), i.e., the antibody portion specifically targets the tumor-associated antigen Nectin-4. Thus, in some aspects, the present disclosure provides antibody-drug conjugates (ADCs) that comprise an antibody or antigen-binding fragment thereof that specifically binds Nectin-4 as the Ab unit of the ADC.

[0469] Nectin-4 (Nectin cell adhesion molecule 4), also known as poliovirus receptor-related (PRR) protein, is a type I transmembrane cell adhesion molecule belonging to the Nectin family. Nectin-4 forms physical connections between adjacent cells and is crucial for enabling intercellular communication, migration, and other important cellular processes. The Nectin-4 protein is specifically expressed in embryos and placentas and is only lowly expressed in a few normal adult tissues (including the skin), while being abnormally highly expressed in tumor tissues. Overexpression of Nectin-4 in various tumor cells has been used as a marker for cancer recurrence and metastasis and is associated with poor prognosis in multiple cancers. Cancers with overexpression of Nectin4 include, for example, breast cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, head and neck cancer, lung cancer, non-small cell lung cancer, melanoma, bladder cancer, thyroid cancer, and hepatocellular carcinoma and urothelial carcinoma, etc. Due to the specific expression of the Nectin-4 target, Nectin-4 has become a potential biomarker and a promising therapeutic target. See, for example, Jeffrey L Wong et al., Expert Opin Biol Ther. 2021 May 24; 21(7):863–873. doi:10.1080 / 14712598.2021.1929168, “Targeting nectin-4 by antibody-drug conjugates for the treatment of urothelial carcinoma”.

[0470] Antibodies targeting human Nectin-4 that can be used in the ADCs of the present disclosure can be prepared using antibody preparation processes known in the art. For example, anti-Nectin4 antibodies can be obtained by immunizing an animal with human Nectin4 (UniProtKB accession number Q96NY8) or a polypeptide comprising the amino acid sequence of the extracellular domain of Nectin-4, harvesting the antibodies from the immunized animal, and purifying and preferably humanizing them. In addition, fully human sequence anti-human Nectin4 antibodies can be obtained using methods such as yeast display libraries expressing human immunoglobulin sequences or transgenic animals.

[0471] In some embodiments, antibodies or antibody fragments (such as antigen-binding fragments) that specifically bind to human Nectin-4 can be selected from Enfortumab, LY4052031, 9MW2821, BAT8007, SBT6290, or their antibody fragments, or other anti-human Nectin4 antibodies that recognize the same epitope or competitively bind to human Nectin4.

[0472] Exemplary antibodies targeting human Nectin4 that can be used in the ADCs of the present disclosure can be antibodies or antigen-binding fragments comprising all 6 CDR sequences of antibodies selected from the group consisting of (preferably, comprising the heavy chain variable region and light chain variable region sequences of antibodies selected from the group consisting of): Enfortumab, LY4052031, 9MW2821, BAT8007, SBT6290. The present disclosure also contemplates anti-human Nectin4 antibodies disclosed in the following documents: WO2012047724, WO2022228406, WO2022228563, WO2024088390, WO2024012536, WO2024038075, WO2024017992, US12049500B2, US11179473B2, US11292837B2, US10675357B2, CN119013302A.

[0473] Enfortumab is a monospecific bivalent IgG antibody that binds to Nectin4 specifically. This antibody can directly bind to cancer cells expressing Nectin4 and trigger antibody endocytosis. Its sequence can be found in NCATS Inxight Drugs, as well as FDA UNII U1HUE4W970 and CAS NO. 1448664-46-7.

[0474] >Enfortumab light chain amino acid sequence (SEQ ID NO:67)

[0475] DIQMTQSPSSVSASVGDRVTITCRASQGISGWLAWYQQKPGKAPKFLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPPTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0476] >Enfortumab heavy chain amino acid sequence (SEQ ID NO:68)

[0477] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYNMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNSLSLQMNSLRDEDTAVYYCARAYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0478] >Enfortumab light chain LCDR1 sequence (SEQ ID NO:69)

[0479] RASQGISGWLA

[0480] >Enfortumab light chain LCDR2 sequence (SEQ ID NO:70)

[0481] AASTLQS

[0482] >Enfortumab light chain LCDR3 sequence (SEQ ID NO:71)

[0483] QQANSFPPT

[0484] >Enfortumab heavy chain HCDR1 sequence (SEQ ID NO:72)

[0485] SYNMN

[0486] >Enfortumab heavy chain HCDR2 sequence (SEQ ID NO:73)

[0487] YISSSSSTIYYADSVKG

[0488] >Enfortumab heavy chain HCDR3 sequence (SEQ ID NO:74)

[0489] AYYYGMDV

[0490] >Enfortumab light chain variable region VL (SEQ ID NO:75)

[0491] DIQMTQSPSSVSASVGDRVTITCRASQGISGWLAWYQQKPGKAPKFLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPPTFGGGTKVEIK

[0492] >Enfortumab heavy chain variable region VH (SEQ ID NO:76)

[0493] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYNMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNSLSLQMNSLRDEDTAVYYCARAYYYGMDVWGQGTTVTVSS

[0494] In one embodiment, the antibody portion for the ADC of the present disclosure comprises all 6 CDR sequences of Enfortumab. In another embodiment, the antibody portion for the ADC of the present disclosure comprises the heavy chain variable region sequence and the light chain variable region sequence of Enfortumab. In yet another embodiment, the antibody portion for the ADC of the present disclosure comprises the heavy chain sequence and the light chain sequence of Enfortumab.

[0495] In some embodiments, the Ab unit of the ADC of the present disclosure comprises three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:76 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:75, and preferably, wherein said CDRs are defined according to Kabat or IMGT or a combination thereof.

[0496] In some embodiments, the Ab unit of the ADC of the present disclosure comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs), wherein:

[0497] According to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:72, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:73, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:74, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:69, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:70, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:71.

[0498] In one embodiment, the Ab unit of the disclosed ADC comprises a heavy chain variable region, wherein the heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:76, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0499] In one embodiment, the Ab unit of the disclosed ADC comprises a light chain variable region, wherein the light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:75, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

[0500] In some preferred embodiments, the Ab unit of the disclosed ADC comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:76, and wherein the light chain variable region comprises the amino acid sequence shown in SEQID NO:75.

[0501] In some embodiments, the Ab unit of the disclosed ADC preferably further comprises the heavy chain constant region and / or the light chain constant region of the antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from a human immunoglobulin. Preferably, the light chain constant region is a light chain constant region derived from a human immunoglobulin. In some aspects, the heavy chain constant region comprised in the Ab unit can be of any isotype or subtype, such as the heavy chain constant region of the IgG1, IgG2, IgG3 or IgG4 isotype, and preferably the IgG1, IgG2 or IgG4 heavy chain constant region, especially the human IgG1 heavy chain constant region. In still further aspects, the light chain constant region comprised in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially the human κ light chain constant region.

[0502] In some embodiments, the Ab unit of the disclosed ADC comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:23, or an amino acid sequence comprising at least one, two, or three, but no more than 20, 10, or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO:23, or a sequence having at least 95 - 99% identity to the amino acid sequence of SEQ ID NO:23.

[0503] In some embodiments, the Ab unit of the disclosed ADC comprises a human κ light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO:12, or an amino acid sequence comprising at least one, two, or three, but no more than 20, 10, or 5 amino acid alterations relative to the amino acid sequence of SEQ ID NO:12, or a sequence having at least 95 - 99% identity to the amino acid sequence of SEQ ID NO:12.

[0504] In some embodiments, the Ab unit of the disclosed ADC is a full - length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit has a tetrameric structure formed by two light chains and two heavy chains. In still other embodiments, the Ab unit is an IgG antibody, particularly an IgG1 antibody.

[0505] In some preferred embodiments, the Ab unit of the disclosed ADC comprises a heavy chain and a light chain, wherein: the heavy chain comprises the amino acid sequence shown in SEQ ID NO:68, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or consists thereof. In some other preferred embodiments, the Ab unit of the disclosed ADC comprises a heavy chain and a light chain, wherein: the light chain comprises the amino acid sequence shown in SEQ ID NO:67, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0506] In some more preferred embodiments, the Ab unit of the disclosed ADC comprises:

[0507] (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:68, and

[0508] (b) a light chain comprising the amino acid sequence of SEQ ID NO:67.

[0509] The cancers that can be treated with the disclosed ADCs targeting Nectin-4 are Nectin4-positive cancers, including but not limited to breast cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, head and neck cancer, lung cancer, non-small cell lung cancer, melanoma, bladder cancer, thyroid cancer, and hepatocellular carcinoma and urothelial carcinoma.

[0510] Drug P unit

[0511] The drug P unit of the antibody-drug conjugate is also referred to herein as the payload of the ADC drug.

[0512] In some embodiments, the drug P unit that can be used in the disclosed ADCs is a KRas mutation inhibitor, including but not limited to G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, and G13D mutation inhibitors. In some embodiments, the drug P units that can be used in the disclosed ADCs are those KRas mutation inhibitors described in the PCT application PCT / CN2023 / 122129 previously completed and filed by the applicant, more specifically the KRas mutation inhibitors defined below in this document.

[0513] In other embodiments, the drug P unit that can be used in the disclosed ADCs is a pan-Ras inhibitor that can inhibit almost all Ras subtypes, regardless of the mutation status, such as some of the drug P units implemented or exemplified below in this disclosure, including but not limited to P8, P9, P12, P13, P16-23, P25-37, etc.

[0514] Embodiment 1: The drug P unit that can be used in the disclosed ADCs is specifically a compound of formula (I), its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts, or solvates,

[0515]

[0516] wherein:

[0517] M is selected from N or C-R1;

[0518] M' is selected from N or C-R1';

[0519] R1 and R1' are each independently selected from H, halogen, CN, -C 1-6 alkyl optionally substituted with halogen and -OC 1-6 alkyl;

[0520] R a is selected from H, halogen, CN, -C 1-6 alkyl optionally substituted with halogen, -C2-6 an alkynyl group and -OC optionally substituted by halogen or deuterium 1-6 alkyl group;

[0521] R b and R c together with the N to which they are attached form wherein X is selected from CH2, N and O;

[0522] R2 and R2’ are each independently selected from H, OH or -C optionally substituted by halogen 1-6 alkyl group; or R2 and R2’ attached to non-adjacent ring carbon atoms together form an in-ring bridging -(CH2) 1-2 - or -CH2=CH2-; or R2 and R2’ attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a 4-6 membered spiroalkyl group or a 4-6 membered spiroheteroalkyl group containing 1 or 2 heteroatoms selected from N and O;

[0523] Ar is selected from

[0524] R3 is selected from H, -NH2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl group)2 and -OC 1-6 alkyl group;

[0525] R4 is selected from -CN, halogen, -NO2, -C optionally substituted by halogen 2-6 alkynyl group and -C optionally substituted by halogen 1-6 alkyl group;

[0526] R5 is selected from H, -CN, halogen, -NO2 and -C substituted by halogen 1-6 alkyl group;

[0527] R6 is selected from H, halogen, CN, -C 1-6 alkyl group and -C 2-6 alkynyl group, wherein the -C 1-6 alkyl group and -C 2-6 alkynyl group are each independently optionally substituted by halogen;

[0528] R7, R7’, R8 and R8’ are each independently selected from H, halogen, CN, -NO2 and -C optionally substituted by halogen 1-6 alkyl group;

[0529] V and W are each independently selected from H, halogen, -C 1-6 alkyl group, OH and NH2;

[0530] Z is selected from O, N and CH2;

[0531] R is

[0532] R9 and R 10 are each independently selected from H, deuterium, -C 1-6 alkyl, and -(CH2) n -C 3-6 cycloalkyl, where the -C 1-6 alkyl and -C 3-6 cycloalkyl are each independently optionally substituted with deuterium, halogen, or -O-C 1-6 alkyl, or R9 and R 10 attached to the same carbon atom together with the carbon atom to which they are attached form a C 3-4 cycloalkyl;

[0533] R 11 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, and -(CH2) n -C 3-6 cycloalkyl, where the C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, or C 3-6 cycloalkyl are each independently optionally substituted with deuterium, halogen, CN, or -O-C 1-6 alkyl;

[0534] R 12 is selected from H, halogen, -CN, -OH, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -O-C 1-6 alkyl, -O-C 3-6 cycloalkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -(CH2) n -C 3-6 cycloalkyl, and =C(R d )2, where R d are each independently selected from H, halogen, and optionally halogen-substituted -C 1-6 alkyl, where each occurrence of C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, or C 3-6 cycloalkyl are each independently optionally substituted with halogen, CN, or -OC 1-6 alkyl;

[0535] R 13 is selected from H, -C 1-6 alkyl, and -(CH2) n -C 3-6A cycloalkyl group, wherein the -C 1-6 alkyl group and -C 3-6 the cycloalkyl group are each independently optionally substituted by a halogen or -O-C 1-6 alkyl group;

[0536] k is an integer selected from 0 or 1

[0537] m is an integer selected from 0 to 6; and

[0538] n is an integer selected from 0 to 2;

[0539] Therefore, formula (I) can be specifically represented as:

[0540]

[0541] Embodiment 1.1: A compound of formula (I) according to Embodiment 1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M is C-R1.

[0542] Embodiment 1.1.1: A compound of formula (I) according to Embodiment 1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1 is H.

[0543] Embodiment 1.1.2: A compound of formula (I) according to Embodiment 1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1 is a halogen, such as F, Cl.

[0544] Embodiment 1.1.3: A compound of formula (I) according to Embodiment 1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1 is CN.

[0545] Embodiment 1.1.4: A compound of formula (I) according to Embodiment 1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1 is -C 1-6 alkyl group optionally substituted by a halogen, preferably -C 1-3 alkyl group optionally substituted by a halogen, more preferably -C 1-3 alkyl group substituted by 1-3 halogens, most preferably -C 1-3An alkyl group, such as -CF3; examples of R1 include, but are not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5.

[0546] Embodiment 1.1.5: A compound of formula (I) according to Embodiment 1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1 is -OC optionally substituted by halogen 1-6 alkyl group, preferably -OC optionally substituted by halogen 1-3 alkyl group, such as -OC 1-3 alkyl group, such as -OCH3, -OCH2CH3.

[0547] Embodiment 1.1.6: A compound of formula (I) according to Embodiment 1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1 is selected from halogen and -C optionally substituted by halogen 1-6 alkyl group, preferably halogen and -C substituted by halogen 1-3 alkyl group, such as F, Cl and -CF3.

[0548] Embodiment 1.1.7: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R a is H.

[0549] Embodiment 1.1.8: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R a is CN or halogen, such as F, Cl.

[0550] Embodiment 1.1.9: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R a is -C optionally substituted by halogen 1-6 alkyl group, as generally or specifically defined in Embodiment 1.1.4.

[0551] Embodiment 1.1.10: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R a is -C 2-6 alkynyl optionally substituted by halogen, preferably -C 2-4 alkynyl optionally substituted by halogen, more preferably -C 2-4 alkynyl, such as but not limited to

[0552] Embodiment 1.1.11: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R a is -OC 1-6 alkyl optionally substituted by halogen or deuterium, preferably -OC 1-3 alkyl optionally substituted by halogen or deuterium, more preferably -OC 1-3 alkyl optionally substituted by deuterium, such as -OCH3, -OCD3, -OCH2CH3, most preferably -OCH3.

[0553] Embodiment 1.1.12: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.11, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M' is N.

[0554] Embodiment 1.1.13: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.11, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M' is C-R1'.

[0555] Embodiment 1.1.14: A compound of formula (I) according to Embodiment 1.1.13, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1' is selected from halogens, such as F, Cl, preferably F.

[0556] Embodiment 1.1.15: A compound of formula (I) according to Embodiment 1.1.13, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1' is CN.

[0557] Embodiment 1.1.16: A compound of formula (I) according to Embodiment 1.1.13, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1' is selected from -C 1-6 alkyl optionally substituted by halogen and -OC 1-6Alkyl, each as generally or specifically defined in Embodiments 1.1.4 and 1.1.5.

[0558] Embodiment 1.2: A compound of formula (I) according to Embodiment 1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M is N.

[0559] Embodiment 1.2.1: A compound of formula (I) according to Embodiment 1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R a is H.

[0560] Embodiment 1.2.2: A compound of formula (I) according to Embodiment 1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R a is CN, or R a is a halogen, such as F, Cl.

[0561] Embodiment 1.2.3: A compound of formula (I) according to Embodiment 1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R a is -C 1-6 alkyl optionally substituted with a halogen, as generally or specifically defined in Embodiment 1.1.4.

[0562] Embodiment 1.2.4: A compound of formula (I) according to Embodiment 1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R a is -C 2-6 alkynyl optionally substituted with a halogen, preferably -C 2-4 alkynyl optionally substituted with a halogen, more preferably -C 2-4 alkynyl, such as but not limited to

[0563] Embodiment 1.2.5: A compound of formula (I) according to Embodiment 1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R a is -OC 1-6 alkyl optionally substituted with a halogen or deuterium, preferably -OC 1-3 alkyl optionally substituted with a halogen or deuterium, more preferably -OC 1-3 alkyl optionally substituted with deuterium, such as -OCH3, -OCD3, -OCH2CH3, most preferably -OCH3.

[0564] Embodiment 1.2.6: A compound of formula (I) according to any one of Embodiments 1.2 to 1.2.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M' is N.

[0565] Embodiment 1.2.7: A compound of formula (I) according to any one of Embodiments 1.2 to 1.2.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M' is C-R1'.

[0566] Embodiment 1.2.8: A compound of formula (I) according to Embodiment 1.2.7, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1' is selected from halogens, such as F, Cl, preferably F.

[0567] Embodiment 1.2.9: A compound of formula (I) according to Embodiment 1.2.7, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1' is CN.

[0568] Embodiment 1.2.10: A compound of formula (I) according to Embodiment 1.2.7, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1' is selected from -C 1-6 alkyl optionally substituted by halogen and -OC 1-6 alkyl, each as generally or specifically defined in Embodiments 1.1.4 and 1.1.5.

[0569] Embodiment 1.3: A compound of formula (I) according to Embodiment 1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein the structural fragment is, for example, Specifically,

[0570] M is C-R1, wherein R1 is selected from halogens (preferably F or Cl) or -C 1-6 alkyl optionally substituted by halogen (preferably -C 1-3 alkyl, more preferably -CF3), R a is H, and M' is C-R1' and R1' is halogen, preferably F; or M is N, R a is selected from H, -C 2-6 alkynyl (preferably -C 2-4 alkynyl, more preferably -C≡CH) and -OC 1-6 alkyl (preferably -OC 1-3an alkyl group, more preferably -OCH3, -OCD3, -OCH2CH3), and M' is C-R1' and R1' is a halogen, preferably F; specific examples include but are not limited to:

[0571]

[0572] Embodiment 2.1: A compound of formula (I) according to any one of Embodiments 1 to 1.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Ar is

[0573] Embodiment 2.1.1: A compound of formula (I) according to Embodiment 2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R3 is H; or R3 is selected from -NH2, -NHC 1-6 alkyl and N(C 1-6 alkyl)2, preferably selected from -NH2, -NHC 1-3 alkyl and N(C 1-3 alkyl)2, most preferably -NH2.

[0574] Embodiment 2.1.2: A compound of formula (I) according to Embodiment 2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R3 is -OC 1-6 alkyl, preferably -OC 1-3 alkyl, such as -OCH3, -OCH2CH3.

[0575] Embodiment 2.1.3: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R4 is CN..

[0576] Embodiment 2.1.4: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R4 is a halogen, selected from F, Cl, Br, I; or R4 is NO2.

[0577] Embodiment 2.1.5: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R4 is -C 2-6 alkynyl optionally substituted with a halogen, preferably -C 2-4 alkynyl optionally substituted with a halogen, such as but not limited to

[0578] Embodiment 2.1.6: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R4 is -C 1-6 alkyl, preferably -C 1-3 alkyl optionally substituted by halogen, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5.

[0579] Embodiment 2.1.7: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein each of R7 and R7' is H; or each of R7 and R7' is halogen, preferably F.

[0580] Embodiment 2.1.8: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein one of R7 and R7' is H and the other is selected from halogen, CN and NO2, and the halogen is preferably F; for example, R7 is H and R7' is halogen, preferably F, or R7' is H and R7 is halogen, preferably F.

[0581] Embodiment 2.1.9: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein one of R7 and R7' is H and the other is selected from -C 1-6 alkyl optionally substituted by halogen, preferably -C 1-3 alkyl, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5.

[0582] Embodiment 2.1.10: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein one of R7 and R7' is selected from halogen, -NO2, CN and -C optionally substituted by halogen 1-6 alkyl, and the other is selected from -C optionally substituted by halogen 1-6 alkyl, wherein the -C optionally substituted by halogen 1-6 alkyl is preferably -C optionally substituted by halogen 1-3 alkyl, as specifically exemplified in Embodiment 2.1.9.

[0583] Embodiment 2.1.11: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.10, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein V is H.

[0584] Embodiment 2.1.12: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.10, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein V is -OH, or V is -NH2.

[0585] Embodiment 2.1.13: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.10, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein V is halogen; or V is -C 1-6 alkyl, preferably -C 1-3 alkyl.

[0586] Embodiment 2.1.14: A compound of formula (I) according to Embodiment 2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Ar is wherein R3 is H or halogen, and R4 is selected from halogen, -C 2-6 alkynyl (preferably -C 2-4 alkynyl) and -C 1-6 alkyl (preferably -C 1-3 alkyl), such as but not limited to

[0587] Embodiment 2.1.15: A compound of formula (I) according to Embodiment 2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Ar is wherein R3 is selected from -NH2, -NHC 1-6 alkyl and N(C 1-6 alkyl)2, preferably selected from -NH2, -NHC1-3 An alkyl group and N(C 1-3 (alkyl)2, most preferably -NH2; R4 is selected from -CN, halogen, -NO2, and -C 2-6 alkynyl substituted by halogen; V is selected from H, -C 1-6 (alkyl) (preferably -C 1-3 (alkyl)) and halogen, R7 and R7' are each H, or each is halogen, or one of them is H and the other is halogen or C 1-6 (alkyl) substituted by halogen (preferably halogen-substituted -C 1-3 (alkyl)), or one of them is halogen and the other is C 1-6 (alkyl) substituted by halogen (preferably halogen-substituted -C 1-3 (alkyl)), wherein the halogen is preferably F;

[0588] Preferably, Ar is V is H, R7 and R7' are each H, or one of them is H and the other is halogen, wherein the halogen is preferably F;

[0589] For example but not limited to:

[0590]

[0591] Embodiment 2.1.16: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.15, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein The starred position may optionally (e.g., depending on the values of R1 and R1') have axial chirality, including Or

[0592] Embodiment 2.2: A compound of formula (I) according to any one of Embodiments 1 to 1.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Ar is

[0593] Embodiment 2.2.1: A compound of formula (I) according to Embodiment 2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R5 is H; or R5 is halogen, selected from F, Cl, Br, I; preferably R5 is halogen, most preferably F; or R5 is NO2; or R5 is -C 1-3 alkyl substituted by halogen.

[0594] Embodiment 2.2.2: A compound of formula (I) according to Embodiment 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R6 is H; or R6 is a halogen selected from F, Cl, Br, I.

[0595] Embodiment 2.2.3: A compound of formula (I) according to Embodiment 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R6 is -C 1-6 alkyl optionally substituted by a halogen, preferably -C 1-3 alkyl, more preferably -C 1-3 alkyl, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5.

[0596] Embodiment 2.2.4: A compound of formula (I) according to Embodiment 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R6 is -C 2-6 alkynyl optionally substituted by a halogen, preferably -C 2-4 alkynyl, more preferably -C 2-4 alkynyl, such as but not limited to preferably

[0597] Embodiment 2.2.5: A compound of formula (I) according to any one of Embodiments 2.2 to 2.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R8 and R8' are each H; or R8 and R8' are each a halogen, preferably F.

[0598] Embodiment 2.2.6: A compound of formula (I) according to any one of Embodiments 2.2 to 2.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein one of R8 and R8' is H and the other is selected from a halogen, CN and NO2, and the halogen is preferably F.

[0599] Embodiment 2.2.7: A compound of formula (I), stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate according to any one of Embodiments 2.2 to 2.2.4, wherein one of R8 and R8' is H and the other is selected from -C 1-6 alkyl, preferably -C 1-3 alkyl optionally substituted with halogen, as generally or specifically defined in Embodiment 2.1.9.

[0600] Embodiment 2.2.8: A compound of formula (I), stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate according to any one of Embodiments 2.2 to 2.2.4, wherein one of R8 and R8' is selected from H, halogen, -NO2, CN and -C 1-6 alkyl optionally substituted with halogen, and the other is selected from -C 1-6 alkyl, wherein the -C 1-6 alkyl optionally substituted with halogen is preferably -C 1-3 alkyl, as generally or specifically defined in Embodiment 2.1.9.

[0601] Embodiment 2.2.9: A compound of formula (I), stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate according to any one of Embodiments 2.2 to 2.2.8, wherein W is -OH.

[0602] Embodiment 2.2.10: A compound of formula (I), stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate according to any one of Embodiments 2.2 to 2.2.8, wherein W is -NH2.

[0603] Embodiment 2.2.11: A compound of formula (I), stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate according to Embodiment 2.2, wherein Ar is wherein R5 is H or halogen, R6 is selected from halogen, -C 2-6 alkynyl and -C 1-6 alkyl; R8 and R8' are each H; or R8 and R8' are each halogen, or one of R8 and R8' is H and the other is selected from halogen, CN and NO2, or one of R8 and R8' is H and the other is selected from -C 1-6 alkyl optionally substituted with halogen, or one of R8 and R8' is selected from H, halogen, -NO2, CN and -C 1-6 alkyl optionally substituted with halogen, and the other is selected from -C 1-6 alkyl;

[0604] Preferably, Ar is wherein R5 is halogen, preferably F, and R6 is selected from -C 2-6 alkynyl (preferably -C 2-4 alkynyl), such as but not limited to

[0605] Embodiment 2.2.12: A compound of formula (I), a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof according to any one of Embodiments 2.2 to 2.2.11, wherein the marked * may optionally have axial chirality as exemplified in the definition section above.

[0606] Embodiment 3.1: A compound of formula (I), a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof according to any one of Embodiments 1 to 2.2.12, wherein R b and R c together with the N to which they are attached form a wherein k is 0 and X is selected from CH2, N and O, that is, R b and R c together with the N to which they are attached form or

[0607] or k is 1 and X is selected from CH2, N and O, that is, R b and R c together with the N to which they are attached form

[0608] Embodiment 3.1.1: A compound of formula (I), a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof according to Embodiment 3.1, wherein R b and R c together with the N to which they are attached form or wherein R2 and R2' are each independently selected from H, OH and -C 1-6 alkyl optionally substituted with halogen, preferably OH and -C 1-6 alkyl optionally substituted with halogen, more preferably selected from OH and -C 1-3 alkyl; or R2 and R2' attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a 4-6 membered spiroalkyl or a 4-6 membered spiroheteroalkyl containing 1 or 2 heteroatoms selected from N and O.

[0609] Embodiment 3.1.1.1: A compound of formula (I) according to Embodiment 3.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R2 and R2' can each independently be attached to any ring carbon atom, preferably more preferably for example Further, one of R2 and R2' is -OH and the other is -C 1-6 alkyl, preferably -C 1-3 alkyl, more preferably methyl; or R2 and R2' together with the ring carbon atom to which they are attached form a 4-6 membered spiroalkyl or a 4-6 membered spiroheteroalkyl containing 1 or 2 heteroatoms selected from N and O;

[0610] Further, when chemically feasible, the substituents R2 and R2' can each exist in stereoisomeric forms, such as R or S configurations;

[0611] Specific examples include but are not limited to:

[0612]

[0613] Embodiment 3.1.2: A compound of formula (I) according to Embodiment 3.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R b and R c together with the N to which they are attached form wherein R2 and R2' attached to non-adjacent ring carbon atoms together form an intra-ring bridging -CH2-, -CH2CH2- or -CH2=CH2-; specific examples include preferably

[0614] Embodiment 4.1: A compound of formula (I) according to any one of Embodiments 1 to 3.1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Z is O; or Z is N; or Z is CH2; preferably Z is O.

[0615] Embodiment 5.1: A compound of formula (I) according to any one of Embodiments 1 to 4.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R is more preferably

[0616] Embodiment 5.1.1: A compound of formula (I) according to any one of Embodiments 1 to 5.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R9 and R 10Both are H; or one of them or both are deuterium.

[0617] Embodiment 5.1.1.1: A compound of formula (I) according to any one of Embodiments 1 to 5.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R9 and R 10 are each independently selected from H and -C 1-6 alkyl, preferably -C 1-3 alkyl, optionally substituted by deuterium, halogen or -OC 1-6 alkyl, for example one of them is H and the other is the defined alkyl, or both are the defined alkyl; the alkyl therein is for example but not limited to -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3.

[0618] Embodiment 5.1.1.2: A compound of formula (I) according to any one of Embodiments 1 to 5.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R9 and R 10 are each independently selected from H and -(CH2) n -C 3-6 cycloalkyl (preferably -C 3-6 cycloalkyl), wherein the C 3-6 cycloalkyl is optionally substituted by halogen or C 1-6 alkoxy, for example one of them is H and the other is the defined cycloalkyl; for example but not limited to

[0619]

[0620] Embodiment 5.1.1.3: A compound of formula (I) according to any one of Embodiments 1 to 5.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R9 and R attached to the same carbon atom 10 together with the carbon atom to which they are attached form C 3-4 cycloalkyl, such as cyclopropyl, cyclobutyl.

[0621] Embodiment 5.1.2: A compound of formula (I) according to any one of Embodiments 1 to 5.1.1.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is H.

[0622] Embodiment 5.1.2.1: A compound of formula (I) according to any one of Embodiments 1 to 5.1.1.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is -C 1-6 alkyl, preferably -C 1-3 alkyl, optionally substituted by deuterium, halogen, CN or -C 1-6 alkoxy, preferably optionally substituted by deuterium, halogen or -C 1-3 alkoxy; such as but not limited to -CH3, -CD3, -CH2CH3, -CH2CD3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH(CH3)CH2-OCH3, -CH2CH(CH3)-OCH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH(CH3)F, -CH(CH3)CH2F, -CH2CH(CH3)F, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -CH2CN, -CH2CH2CN; more preferably, R 11 is -C 1-3 alkyl, wherein the hydrogen atoms are optionally replaced by one or more isotopes of deuterium, such as -CH3, -CD3.

[0623] Embodiment 5.1.2.2: A compound of formula (I) according to any one of Embodiments 1 to 5.1.1.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is -C 2-6 alkenyl or -C 2-6 alkynyl, preferably -C 2-4 alkenyl or -C 2-4 alkynyl, optionally substituted by halogen, CN or -C 1-6 alkoxy; such as but not limited to vinyl, propenyl, ethynyl, each optionally substituted by halogen or -C 1-6 alkoxy.

[0624] Embodiment 5.1.2.3: A compound of formula (I) according to any one of Embodiments 1 to 5.1.1.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is -(CH2) n -C 3-6 cycloalkyl, preferably -C 3-6 cycloalkyl, said -C 3-6 cycloalkyl is optionally substituted with deuterium, halogen, CN or -C 1-6 alkoxy; such as but not limited to

[0625]

[0626] Embodiment 5.1.3: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 is H.

[0627] Embodiment 5.1.3.1: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 is halogen, such as F, Cl, Br, I, preferably F; or R 12 is CN.

[0628] Embodiment 5.1.3.2: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 is -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, wherein -C 1-6 alkyl is preferably -C 1-3 alkyl, optionally substituted with halogen, CN or -OC 1-6 alkyl.

[0629] Embodiment 5.1.3.3: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 is -OH; or R 12 is -O-C 1-6 alkyl, preferably -O-C 1-3 alkyl, wherein the alkyl is optionally substituted with halogen, CN or -OC 1-6Alkyl substitution; for example but not limited to -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)(CH3), -O-CH2CH2CH2CH3, -O-CH2CH(CH3)CH3, -O-C(CH3)3, -O-CH2Cl, -O-CH2CN, -O-CH2F, -O-CHF2, -O-CF3, -O-CCl3, -O-CH2CH2F, -O-CH2CH2CN, -O-CH2CHF2, -O-CH2CF3, -O-CH2CH2CH2F, -O-CH2CH2CHF2, -O-CH2CH2CF3, -O-C(CH3)2CF3, -O-C2F5, -O-CH2-OCH3, -O-CH2-O-CH2CH3, -O-CH2CH2-O-CH3, -O-CH2CH2-O-CH2CH3.

[0630] Embodiment 5.1.3.4: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 is -C 1-6 alkyl, preferably -C 1-3 alkyl, optionally substituted by halogen, CN or -OC 1-6 alkyl, for example but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH(CH3)CH2-OCH3, -CH2CH(CH3)-OCH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -CH2CN, -CH2CH2CN.

[0631] Embodiment 5.1.3.5: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 is -O-C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl is optionally substituted by halogen, CN or -O-C 1-6 alkyl; for example but not limited to

[0632] Embodiment 5.1.3.6: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 is -(CH2) n -C 3-6 cycloalkyl, preferably -C 3-6 cycloalkyl, said -C 3-6 cycloalkyl is optionally substituted by halogen, CN or -C 1-6 alkoxy; as exemplified in Embodiment 5.1.2.3.

[0633] Embodiment 5.1.3.7: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 is -C 2-6 alkenyl or -C 2-6 alkynyl, preferably -C 2-4 alkenyl or -C 2-4 alkynyl, optionally substituted by halogen, CN or -C 1-6 alkoxy; such as but not limited to vinyl, propenyl, ethynyl, each optionally substituted by halogen or -C 1-6 alkoxy.

[0634] Embodiment 5.1.3.8: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 is =C(R d )2, wherein R d are each independently selected from H, F, Cl, Br, I, -C 1-6 alkyl optionally substituted by halogen (preferably -C 1-3 alkyl); such as but not limited to =CH2, =CF2, =CHF, =CCl2, =C(CH3)2, =C(CF3)2.

[0635] Embodiment 5.1.3.9: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 is selected from -C 1-6 alkyl optionally substituted by halogen (preferably -C 1-3 alkyl) and =C(R d )2, wherein R d are each independently selected from H and halogen (preferably F).

[0636] Embodiment 5.1.3.10: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein m is 0, 1 or 2, preferably 1.

[0637] Embodiment 5.1.3.11: A compound of formula (I) according to any one of Embodiments 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 The attached ring carbon atom may optionally be chiral and have the R configuration or the S configuration.

[0638] Embodiment 5.1.3.12: A compound of formula (I) according to any one of Embodiments 5.1.3.8 to 5.1.3.9, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 12 When it is =C(R d )2, the double bond may have cis-trans isomerism, including the E isomer and the Z isomer, preferably the E isomer.

[0639] Embodiment 5.1.4: A compound of formula (I) according to any one of Embodiments 1 to 5.1.3.12, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 13 is H.

[0640] Embodiment 5.1.4.1: A compound of formula (I) according to any one of Embodiments 1 to 5.1.3.12, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 13 is a halogen, preferably F

[0641] Embodiment 5.1.4.2: A compound of formula (I) according to any one of Embodiments 1 to 5.1.3.12, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 13 is -C 1-6 alkyl, preferably -C 1-3 alkyl, optionally substituted by a halogen or -OC 1-6Alkyl substitution, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2 - OCH3, -CH2 - O - CH2CH3, -CH2CH2 - OCH3, -CH2CH2 - O - CH2CH3, -CH(CH3)CH2 - OCH3, -CH2CH(CH3)-OCH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5.

[0642] Embodiment 5.1.4.3: A compound of formula (I) according to any one of Embodiments 1 to 5.1.3.12, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 13 is -(CH2) n -C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl is optionally substituted by halogen or -OC 1-6 alkyl; such as but not limited to

[0643] Embodiment 5.1.4.4.: A compound of formula (I) according to any one of Embodiments 1 to 5.1.3.12, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 13 is -C 1-6 alkyl, preferably -C 1-3 alkyl, more preferably -CH3.

[0644] Embodiment 5.2: A compound of formula (I) according to any one of Embodiments 1 to 5.1.4.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R is more preferably wherein R9 and R 10 are both H, or one or both of them are deuterium; R 11 is -C 1-3 alkyl, wherein the hydrogen atoms are optionally replaced by one or more isotope deuteriums; R 12 is selected from -C 1-6 alkyl (preferably -C 1-3 alkyl) optionally substituted by halogen and =C(R d )2, wherein R dEach independently selected from H and halogen (preferably F); R 13 is -C 1-6 alkyl (preferably -C 1-3 alkyl); m is 1 or 2;

[0645] Specifically, R is wherein R 11 , R 12 and m have the defined meanings, examples of R 11 include but are not limited to methyl, ethyl, isopropyl, -CD3, -CH2CD3; and / or examples of R 12 include but are not limited to fluoromethyl, difluoromethyl, methyl, fluoromethylene, difluoromethylene, methylene.

[0646] Embodiment 5.3: A compound of formula (I) according to any one of Embodiments 1 to 5.1.4.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R is preferably wherein both R9 and R 10 are H, or one or both of them are deuterium; R 11 is -C 1-3 alkyl, wherein the hydrogen atoms are optionally replaced by one or more isotope deuteriums; R 12 is selected from -C 1-6 alkyl (preferably -C 1-3 alkyl) optionally substituted by halogen and =C(R d )2, wherein R d each independently selected from H and halogen (preferably F); R 13 is -C 1-6 alkyl (preferably -C 1-3 alkyl); m is 1 or 2;

[0647] Specifically, R is wherein R 11 , R 12 and m have the defined meanings, examples of R 11 include but are not limited to methyl, ethyl, isopropyl, -CD3, -CH2CD3; and / or examples of R 12 include but are not limited to fluoromethyl, difluoromethyl, methyl, fluoromethylene, difluoromethylene, methylene.

[0648] Embodiment 5.4: A compound of formula (I) according to any one of Embodiments 1 to 5.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein examples of R include but are not limited to

[0649]

[0650]

[0651]

[0652] Preferably

[0653] Embodiment 6.1: A compound of formula (I) according to Embodiment 1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, which has the sub-general formula shown in Table 1 below:

[0654]

[0655]

[0656]

[0657] wherein each substituent has the meaning defined generally or specifically in each of the corresponding embodiments above, and also encompasses any combination of the meanings defined generally or specifically for each substituent;

[0658] Preferably, wherein

[0659] when M is C-R1, R1 is selected from halogen (preferably F or Cl) or -C optionally substituted by halogen 1-6 alkyl (preferably -C substituted by halogen 1-3 alkyl, more preferably -CF3), R a is H, and M' is C-R1' and R1' is halogen (preferably F);

[0660] when M is N, R a is selected from H, -C 2-6 alkynyl (preferably -C 2-4 alkynyl, more preferably -C≡CH) and -OC 1-6 alkyl (preferably -OC optionally substituted by deuterium 1-3 alkyl, more preferably -OCH3, -OCD3, -OCH2CH3), and M' is C-R1' and R1' is halogen (preferably F);

[0661] R2 and R2' attached to non-adjacent ring carbon atoms together form an in-ring bridging -(CH2) 1-2 - or -CH2=CH2-;

[0662] R3 is selected from -NH2, -NHC 1-6 alkyl and N(C1-6 (alkyl)2 (preferably selected from -NH2, -NHC 1-3 alkyl and N(C 1-3 alkyl)2, more preferably -NH2); R4 is selected from -CN, halogen, -NO2 and -C substituted with halogen 2-6 alkynyl; V is selected from H, -C 1-6 alkyl (preferably -C 1-3 alkyl) and halogen; R7 and R7' are each H, or each is halogen, or one is H and the other is halogen or halogen-substituted C 1-6 alkyl (preferably halogen-substituted -C 1-3 alkyl), or one is halogen and the other is halogen-substituted C 1-6 alkyl (preferably halogen-substituted -C 1-3 alkyl), wherein the halogen is preferably F;

[0663] Preferably, R3 is -NH2, R4 is -CN, V is H, R7 and R7' are each H, or one is H and the other is halogen (preferably F);

[0664] R5 is H or halogen (preferably F); R6 is selected from halogen, -C 2-6 alkynyl (preferably -C 2-4 alkynyl) and -C 1-6 alkyl (preferably -C 1-3 alkyl);

[0665] R8 and R8' are each H, or R8 and R8' are each halogen, or one of R8 and R8' is H and the other is selected from halogen, CN and NO2, or one of R8 and R8' is H and the other is selected from -C optionally substituted with halogen 1-6 alkyl, or one of R8 and R8' is selected from H, halogen, -NO2, CN and -C optionally substituted with halogen 1-6 alkyl, and the other is selected from -C optionally substituted with halogen 1-6 alkyl; W is OH;

[0666] Preferably, R5 is halogen (preferably F), R6 is selected from -C 2-6 alkynyl (preferably -C 2-4 alkynyl), R8 and R8' are each H, and W is OH;

[0667] Z is selected from O, N and CH2;

[0668] R9 and R 10 are both H; or one or both of them are deuterium;

[0669] R 11 is -C 1-6 alkyl (preferably -C 1-3(alkyl), wherein the hydrogen atoms are optionally replaced by one or more deuterium isotopes;

[0670] R 12 is selected from -C 1-6 alkyl optionally substituted with halogen (preferably -C 1-3 alkyl) and =C(R d )2, wherein R d are each independently selected from H and halogen (preferably F);

[0671] m is 0, 1 or 2 (preferably 1 or 2);

[0672] R 13 is -C 1-6 alkyl (preferably -C 1-3 alkyl, more preferably -CH3).

[0673] Embodiment 6.2: A compound of formula (I) according to Embodiment 1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, having the sub-formula shown in Table 2 below:

[0674]

[0675]

[0676]

[0677] wherein each substituent has the meaning generally or specifically defined in the respective above embodiments, and also encompasses any combination of the meanings generally or specifically defined for each substituent;

[0678] Preferably, wherein

[0679] when M is C-R1, R1 is selected from halogen (preferably F or Cl) or -C 1-6 alkyl optionally substituted with halogen (preferably -C 1-3 alkyl substituted with halogen, more preferably -CF3), R a is H, and M' is C-R1' and R1' is halogen (preferably F);

[0680] when M is N, R a is selected from H, -C 2-6 alkynyl (preferably -C 2-4 alkynyl, more preferably -C≡CH) and -OC 1-6 alkyl (preferably -OC 1-3 alkyl optionally substituted with deuterium, more preferably -OCH3, -OCD3, -OCH2CH3), and M' is C-R1' and R1' is halogen (preferably F);

[0681] Structural fragment selected from wherein X is selected from C, N, and O; one of R2 and R2’ is -OH and the other is -C 1-6 alkyl, or R2 and R2’ together with the ring carbon atom to which they are attached form a 4- to 6-membered spiroalkyl group or a 4- to 6-membered spiroheteroalkyl group containing 1 or 2 heteroatoms selected from N and O;

[0682] preferably selected from wherein one of R2 and R2’ is -OH and the other is -C 1-3 alkyl, preferably methyl, more preferably R3 is selected from -NH2, -NHC 1-6 alkyl and N(C 1-6 alkyl)2 (preferably selected from -NH2, -NHC 1-3 alkyl and N(C 1-3 alkyl)2, more preferably -NH2); R4 is selected from -CN, halogen, -NO2, and -C 2-6 alkynyl substituted by halogen; V is selected from H, -C 1-6 alkyl (preferably -C 1-3 alkyl) and halogen; R7 and R7’ are each H, or each is halogen, or one of them is H and the other is halogen or C 1-6 alkyl substituted by halogen (preferably halogen-substituted -C 1-3 alkyl), or one of them is halogen and the other is C 1-6 alkyl substituted by halogen (preferably halogen-substituted -C 1-3 alkyl), wherein the halogen is preferably F;

[0683] preferably R3 is -NH2, R4 is -CN, V is H, R7 and R7’ are each H, or one of them is H and the other is hal

[0684] ogen (preferably F);

[0685] R5 is H or halogen (preferably F); R6 is selected from halogen, -C 2-6 alkynyl (preferably -C 2-4 alkynyl) and -C 1-6 alkyl (preferably -C 1-3 alkyl); R8 and R8’ are each H, or R8 and R8’ are each halogen, or one of R8 and R8’ is H and the other is selected from halogen, CN, and NO2, or one of R8 and R8’ is H and the other is selected from -C 1-6 alkyl optionally substituted by halogen, or one of R8 and R8’ is selected from H, halogen, -NO2, CN, and -C 1-6 alkyl optionally substituted by halogen, and the other is selected from -C 1-6Alkyl; W is OH;

[0686] Preferably, R5 is halogen (preferably F), and R6 is selected from -C 2-6 alkynyl (preferably -C 2-4 alkynyl), R8 and R8’ are each H, and W is OH;

[0687] Z is selected from O, N, and CH2;

[0688] R9 and R 10 are both H; or one or both of them are deuterium;

[0689] R 11 is -C 1-6 alkyl (preferably -C 1-3 alkyl), in which the hydrogen atoms are optionally replaced by one or more deuterium isotopes;

[0690] R 12 is selected from -C 1-6 alkyl (preferably -C 1-3 alkyl) optionally substituted by halogen and =C(R d )2, where R d are each independently selected from H and halogen (preferably F);

[0691] m is 0, 1, or 2 (preferably 1 or 2);

[0692] R 13 is -C 1-6 alkyl (preferably -C 1-3 alkyl, more preferably -CH3).

[0693] Embodiment 6.3: A compound of formula (I’), its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, having the sub-formula shown in Table 2-1 below:

[0694]

[0695]

[0696] wherein

[0697] wherein M, M’, X, Z, V, W, R1, R1’, R3, R4, R5, R6, R7, R7’, R8, R8’, R9, R 10 , R 11 , R 12 , R 13 , k, m, and n are respectively defined as in each embodiment of the compound of formula (I) above;

[0698] Structural fragment As defined above for any one of embodiments 2.1 to 2.1.16 of the compound of formula (I);

[0699] Structural fragment As defined above for any one of embodiments 2.2 to 2.2.12 of the compound of formula (I);

[0700] Structural fragment As defined above for any one of embodiments 5.1 to 5.4 of the compound of formula (I);

[0701] Y is selected from -CH2-, -CH2CH2-, -CH2OCH2- or absent;

[0702] R 14 and R 15 are each independently selected from H and -C 1-6 alkyl.

[0703] Embodiment 6.3.1: A compound of formula (I') of Embodiment 6.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein,

[0704] In fragment, when M is C-R1, R1 is selected from halogen (preferably F or Cl) or -C 1-6 alkyl optionally substituted by halogen (preferably -C 1-3 alkyl substituted by halogen, more preferably -CF3), and M' is C-R1' and R1' is halogen (preferably F); or when M is N, M' is C-R1' and R1' is halogen (preferably F);

[0705] In fragment, both Ms are C-R1, or one of Ms is N and the other is C-R1, and R1s are each independently selected from H, halogen (preferably F) and halogen-substituted -C 1-6 alkyl (preferably -C 1-3 alkyl substituted by one or more Fs, more preferably -CF3), preferably the M adjacent to R3 is selected from N and C-R1 (preferably C-halogen, more preferably C-F), and the M adjacent to R6 is C-R1 (preferably -C 1-3 alkyl substituted by halogen, more preferably -C-CF3); R3 is selected from -NH2, -NHC 1-6 alkyl and N(C 1-6 alkyl)2 (preferably selected from -NH2, -NHC 1-3 alkyl and N(C 1-3 alkyl)2, more preferably -NH2); R5 is H or halogen (preferably F); R6 is selected from halogen (preferably Cl) and -C 1-6 alkyl (preferably -C 1-3 alkyl);

[0706] In the fragment, R3 is selected from -NH2, -NHC 1-6 alkyl and N(C 1-6 alkyl)2 (preferably selected from -NH2, -NHC 1-3 alkyl and N(C 1-3 alkyl)2, more preferably -NH2); R4 is selected from -CN, halogen, -NO2 and -C 2-6 alkynyl substituted by halogen; V is selected from H, -C 1-6 alkyl (preferably -C 1-3 alkyl) and halogen; R7 and R7' are each H, or each is halogen, or one of them is H and the other is halogen or C 1-6 alkyl substituted by halogen (preferably -C 1-3 alkyl substituted by halogen), or one of them is halogen and the other is C 1-6 alkyl substituted by halogen (preferably -C 1-3 alkyl substituted by halogen), wherein the halogen is preferably F;

[0707] Preferably, R3 is -NH2, R4 is -CN, V is H, R7 and R7' are each H, or one of them is H and the other is halogen (preferably F);

[0708] In the fragment, R5 is H or halogen (preferably F); R6 is selected from halogen, -C 2-6 alkynyl (preferably -C 2-4 alkynyl) and -C 1-6 alkyl (preferably -C 1-3 alkyl); R8 and R8' are each H, or R8 and R8' are each halogen, or one of R8 and R8' is H and the other is selected from halogen, CN and NO2, or one of R8 and R8' is H and the other is selected from -C 1-6 alkyl optionally substituted by halogen, or one of R8 and R8' is selected from H, halogen, -NO2, CN and -C 1-6 alkyl optionally substituted by halogen, and the other is selected from -C 1-6 alkyl optionally substituted by halogen; W is OH;

[0709] Preferably, R5 is halogen (preferably F), R6 is selected from -C 2-6 alkynyl (preferably -C 2-4 alkynyl), R8 and R8' are each H, and W is

[0710] OH;

[0711] X is selected from O and NH;

[0712] Y is selected from -CH2CH2- and absent;

[0713] Z is selected from O;

[0714] R9 and R 10 are both H; or one or both of them are deuterium;

[0715] R 11 is -C 1-6 alkyl (preferably -C 1-3 alkyl), in which the hydrogen atoms are optionally replaced by one or more deuterium isotopes;

[0716] R 12 is selected from -C 1-6 alkyl optionally substituted by halogen (preferably -C 1-3 alkyl) and =C(R d )2, where R d are each independently selected from H and halogen (preferably F);

[0717] m is 0, 1 or 2 (preferably 1 or 2);

[0718] n, k are 0 or 1 (preferably 0);

[0719] R 13 is -C 1-6 alkyl (preferably -C 1-3 alkyl, more preferably -CH3);

[0720] R 14 and R 15 are H or -C 1-3 alkyl, more preferably -CH3.

[0721] Embodiment 6.4: The compounds of Embodiments 6.1 to 6.3.1, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein the R fragment is selected from

[0722] Embodiment 6.5: The compounds of any one of Embodiments 6.1 to 6.4, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein the Ar moiety, i.e., the left - hand fragment, optionally has axial chirality as follows:

[0723] For example

[0724] For example

[0725] For example

[0726] Embodiment 7: A KRas mutant inhibitor compound selected from the following compounds, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates,

[0727]

[0728] or its pharmaceutically acceptable salt or solvate.

[0729] It should be noted that the KRas mutant inhibitor compound defined above applicable to the ADC of the present disclosure is bonded to the linker unit L of the ADC through the ring NH when present in its fragment and / or through the OH when present on the side chain naphthalene ring or benzothiophene ring.

[0730] Embodiment 8: A Ras mutant inhibitor compound selected from the following compounds, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates,

[0731]

[0732]

[0733] wherein each Ras mutant inhibitor compound is linked to the linker unit L of the ADC through -NH2, -NH-, N or -OH in its structure; or a Ras inhibitor compound selected from the following patent disclosures, and representative compounds are as follows:

[0734] Ras protein degrader

[0735]

[0736]

[0737]

[0738] Ras molecular glue

[0739]

[0740] Tri - / tetracyclic Ras inhibitor

[0741]

[0742]

[0743] Small - molecule Ras inhibitor

[0744]

[0745]

[0746]

[0747]

[0748] Other types of small - molecule Ras inhibitors

[0749]

[0750]

[0751] It should be noted that the Ras mutant inhibitor compounds of the present disclosure cover each of the above individual embodiments or specific embodiments, and also cover the embodiments constituted by any combination or sub-combination of the above individual embodiments or specific embodiments, and also cover the embodiments constituted by any combination of the above any preferred or exemplified embodiments.

[0752] It should be noted that the present disclosure covers the ADC compounds formed by any of the above general, specific or preferred Ras mutant inhibitor compounds, linker units and antibody drugs defined herein.

[0753] Linker unit L

[0754] In the ADCs described herein, a Ras inhibitor, such as a KRas mutant inhibitor, is linked to an antibody or antigen-binding fragment through a linker unit. The linker unit links the Ras inhibitor, such as a KRas mutant inhibitor, to the antibody or antigen-binding fragment by forming a covalent bond with the Ras inhibitor, such as a KRas mutant inhibitor, at one position thereof and a covalent bond with the antibody or antigen-binding fragment at another position thereof. The linker unit can be monovalent with respect to the Ras inhibitor, such as a KRas mutant inhibitor, such that they covalently link a single Ras inhibitor, such as a KRas mutant inhibitor, to a single site on the antibody or a fragment thereof, or can be multivalent with respect to the Ras inhibitor, such as a KRas mutant inhibitor, such that they covalently link more than one Ras inhibitor, such as a KRas mutant inhibitor, to a single site on the antibody or a fragment thereof. As used herein, the expression "linker unit" is intended to include the un-conjugated, partially conjugated (i.e., conjugated only with the Ras inhibitor, such as a KRas mutant inhibitor, or only with the Ab) and fully conjugated forms (i.e., conjugated with the Ras inhibitor, such as a KRas mutant inhibitor, and the Ab) of the linker unit.

[0755] The number of Ras inhibitors, such as KRas mutation inhibitors, conjugated to the antibody or antigen-binding fragment thereof connected to the ADC can vary (referred to as "drug-antibody ratio" or "DAR"), and will be limited by the number of available conjugation sites on the antibody or antigen-binding fragment thereof and the number of Ras inhibitors, such as KRas mutation inhibitors, conjugated to a single linker. In an ADC comprising multiple Ras inhibitors, such as KRas mutation inhibitors, each Ras inhibitor, such as KRas mutation inhibitor, may be the same or different. An ADC with a DAR of 10 or even higher can be considered as long as the ADC does not exhibit an unacceptable level of aggregation under the use and / or storage conditions. In some embodiments, the ADCs described herein may have a DAR in the range of about 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, or 1 to 4. In some embodiments, the ADCs described herein may have a DAR in the range of about 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, or 2 to 4. In certain specific embodiments, the DAR of the ADC can be about 1, 2, 3, or 4. In other specific embodiments, the DAR of the ADC can be about 5, 6, 7, or 8. In some specific embodiments, the DAR of the ADC can be about 1.

[0756] The linker unit L applicable to the ADCs of the present disclosure can be any linker capable of effecting the conjugation of the drug of the present disclosure to the antibody. Suitably, the addition of the linker should ensure the sufficient stability of the ADCs of the present disclosure in the circulatory system, should not be prematurely cleaved in the circulation to trigger off-target toxicity, and can provide rapid and efficient release of the KRas mutation inhibitor at the target site (such as tumor cells or tumor environment). For example, the linker unit can be stable to the extracellular environment and serum chemistry, or can include deliberately labile linker units and can release Ras inhibitors, such as KRas mutation inhibitors, in the extracellular environment or tumor microenvironment.

[0757] In some embodiments, the linker unit includes a bond designed to release Ras inhibitors, such as KRas mutation inhibitors, after intracellular internalization of the ADC. In some specific embodiments, the linker unit includes a bond designed to be cleaved and / or digested intracellularly or otherwise degraded specifically or non-specifically.

[0758] In some embodiments, the linker unit in the ADC of formula (X) of the present disclosure is a non-degradable linker. Examples of non-degradable linker units include, but are not limited to, thioether linkers, N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and maleimidocaproyl (MC). Generally, such linkers are more stable, and ADCs containing such linkers must be internalized by cells, and the antibody portion of the ADC is degraded by intracellular lysosomal proteases to release the drug active molecule.

[0759] In some further embodiments, the linker unit in the ADC of the present disclosure formula (X) is a degradable linker unit, which comprises one or more chemically or enzymatically degradable chemical bonds. The drug release of the ADC comprising such a linker is triggered by the nature of the cleavage site in the linker. Thus, the cleavage site of such a linker can be designed according to the characteristics of the target treatment site (such as the tumor cell lysosome and / or the tumor environment).

[0760] In some embodiments, the degradable linker unit comprises a chemically labile group, which takes advantage of the differential properties between plasma and some cytoplasmic compartments, such as the acidic environment of endosomes or lysosomes or the high thiol concentration (such as glutathione) in the cytosol; in some cases, the plasma stability of the linker comprising the chemically labile group can be increased or decreased by using substituents to change the steric hindrance near the group.

[0761] In some embodiments, the chemically labile group of the degradable linker unit is an acid-labile group, which can remain intact during the neutral pH circulation of the blood and is hydrolyzed under acidic conditions to release a Ras inhibitor, such as a KRas mutant inhibitor. For example, in an acidic tumor environment or when internalized into endosomes (pH 5.0 - 6.5) and lysosomes (pH 4.5 - 5.0) cell compartments, this pH-dependent release mechanism can be optimized by chemical modification to finely regulate the release of a Ras inhibitor, such as a KRas mutant inhibitor, for a specific pH. Examples of such acid-labile groups include hydrazone, hydrazide, acetal, orthoester or imine groups.

[0762] In some embodiments, the degradable linker unit comprises a reducible group, such as a group containing a disulfide group. This group is reduced when the ADC is internalized into cells because the cytosol in the cells provides a more reducing environment (such as reduced glutathione), thereby releasing the drug. Tumor cells can induce a hypoxic state due to irregular blood flow, resulting in enhanced reductase activity and increased concentration of glutathione, which is beneficial for the linker containing a disulfide bond to selectively release the drug in tumor cells.

[0763] In some embodiments, the degradable linker unit is an enzyme-degradable linker unit and is more stable in plasma and the extracellular environment than a chemically labile linker. Such linkers can be peptide-based or include peptide regions, or non-peptide linkers such as peptidomimetics, or carbohydrates, esters, and amides. Such linkers can be cleaved by tumor-specific enzymes, such as tumor-specific proteases with increased abundance in tumors and / or the tumor environment, including but not limited to lysosomal proteases such as cathepsins (e.g., cathepsin B), legumain, MMP-2 / 9, plasmin, esterases, amidases, glutathione, etc.

[0764] Generally, the enzyme-degradable linker unit can consist of a self-decomposing linker, a cleavable linker, optionally a property-modulating unit, an optional linker unit, and an antibody linker moiety. The self-decomposing linker connects the drug P to the cleavable linker, facilitating the release of the drug active molecule from the rest of the ADC, such as p-aminobenzyl, p-hydroxybenzyl, p-aminobenzyloxycarbonyl, p-hydroxybenzyloxycarbonyl, etc.; the cleavable linker contains a peptide or peptide mimetic, esters (e.g., carbamates, sulfates), amides, disulfide-containing moieties, carbohydrates, etc. that can be recognized by enzymes under an enzyme-based release mechanism; the addition of a property-modulating unit may be beneficial for improving the properties of the ADC, such as stability in blood circulation, the pharmacodynamic effect of the ADC at the target site, and optimizing the hydrophilicity of the ADC. For example, when the drug has high hydrophobicity, the addition of a PEG unit (although not necessary) can be considered to optimize the hydrophilicity of the ADC, such as reducing precipitation and aggregation; the antibody linker connects the antibody or antigen-binding fragment targeting the antigen to the rest of the conjugate and has functional groups that can form bonds with the functional groups on the antibody.

[0765] On the one hand, the linker unit L in the ADC of formula (X) of the present disclosure has the structure of formula (II) as follows:

[0766] -A(S)-B(D 1 )-D-E(D 1 )-G- (II),

[0767] where

[0768] A is a self-decomposing linker;

[0769] S is an optionally present solubilizing sugar unit;

[0770] B is a cleavable linker, which is absent or selected from peptide residues of 2-8 amino acids, preferably dipeptides, tripeptides, or tetrapeptides; amide bond-containing fragments; carbamate bond-containing fragments; thioether bond-containing fragments;

[0771] D and D 1Each is independently an optionally present property modulating unit, which, when present, is selected from polyethylene glycol (PEG), hydrophilic peptides, cyclodextrin units, polyamines, polyamides, polysaccharides, dendrimers, and bifunctional hydrocarbon chains;

[0772] E is an optionally present linker unit;

[0773] G is an antibody linker connected to Ab.

[0774] Accordingly, the composition of the ADC of the present disclosure can be represented as: [P - A(S) - B(D 1 ) - D - E(D 1 ) - G] q -Ab.

[0775] On the other hand, the linker unit L in the ADC of formula (X) of the present disclosure has the structure of the following formula (II’):

[0776] -J - B(D 1 ) - D - E(D 1 ) - G - (II’),

[0777] wherein

[0778] J is a self - cleaving linker;

[0779] B is a cleavable linker, which is absent or selected from peptide residues of 2 - 8 amino acids, preferably dipeptides, tripeptides, or tetrapeptides; amide - containing fragments; carbamate - containing fragments; sulfide - containing fragments;

[0780] D and D 1 Each is independently an optionally present property modulating unit, which, when present, is selected from polyethylene glycol (PEG), hydrophilic peptides, cyclodextrin units, polyamines, polyamides, polysaccharides, dendrimers, and bifunctional hydrocarbon chains;

[0781] E is an optionally present linker unit;

[0782] G is an antibody linker connected to Ab.

[0783] Accordingly, the composition of the ADC of the present disclosure can be represented as: [P - J - B(D 1 ) - D - E(D 1 ) - G] q -Ab.

[0784] The following provides general, specific, or preferred embodiments for each possible component of the linker unit L. It should be noted that the present disclosure encompasses the linker unit L obtained by any combination of the general, specific, or preferred embodiments of each of these components with the general, specific, or preferred embodiments of any one or more of the remaining components; correspondingly, the present disclosure encompasses the ADC compound obtained by any combination of the linker unit obtained by the above-mentioned any combination with the general, specific, or preferred embodiments of the antibody and the drug moiety defined in the present disclosure.

[0785] G - antibody linker

[0786] The function of the antibody linker is to connect the antibody or antigen-binding fragment targeting the antigen to the rest of the conjugate, and it has a functional group capable of forming a bond with the functional group on the antibody.

[0787] In some embodiments, the antibody linker has a nucleophilic group capable of interacting with the reactive electrophilic group on the antibody to form a covalent bond between the antibody and the linker unit. The electrophilic groups on the antibody include, but are not limited to, aldehyde and ketone carbonyl groups, and the nucleophilic groups on the antibody linker include, but are not limited to, hydrazide, hydroxylamine, amino, hydrazine, thiosemicarbazone, carboxylic acid hydrazide, and aryl hydrazide.

[0788] In other embodiments, the antibody linker has an electrophilic group capable of interacting with the reactive nucleophilic group on the antibody to form a covalent bond between the antibody and the linker unit. The nucleophilic groups on the antibody include, but are not limited to, thiol, hydroxyl, or amino functional groups, and the electrophilic groups on the antibody linker include, but are not limited to, maleimide, haloacetamide group, activated disulfide, active ester such as NHS ester or HOBt ester, haloformate, acyl halide, alkyl halide, or benzyl halide such as haloacetamide. In some embodiments, the bond formed between the antibody linker and the antibody is a thioether, amide, ester, carbamate, carbonate, urea, disulfide, or ether.

[0789] G in the linker unit L of formula (II) or formula (II’) of the ADC of the present disclosure has the following structure:

[0790] -G1-G2-G3-, where:

[0791] G1 is a bonding atom from Ab, such as an S, N, or C atom;

[0792] G2 is selected from:

[0793] ·a 5- to 10-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, S, and O, and the ring carbon atoms therein are optionally oxidized;

[0794] ·

[0795] ·

[0796] ·

[0797] ·

[0798] · where the * on the left represents the connection point to G1, and the right represents the connection point to G3;

[0799] G3 is selected from a bond, -C 1-10 alkylene-C(=O)-, -C 3-10 alkynylene-C(=O)-, -C 3-10 alkenylene-C(=O)-, -C 1-10 heteroalkylidene-C(=O)-, -C 3-8 cycloalkylidene-C(=O)-, -O-C 1-10 alkylene-C(=O)-, -C 6-10 arylidene-C(=O)-, -C 1-10 alkylene-C 6-10 arylidene-C(=O)-, -C 6-10 arylene-C 1-10 alkylene-C(=O)-, -C 1-10 alkylene-C 3-8 cycloalkylidene-C(=O)-, -C 3-8 cycloalkylene-C 1-10 alkylene-C(=O)-, -C 3-8 heterocyclidene-C(=O)-, -C 1-10 alkylene-C 3-8 heterocyclidene-C(=O)-, -C 3-8 heterocyclylene-C 1-10 alkylene-C(=O)-, -C 1-10 alkylene-C(=O)-NH-C 1-10 alkylene-O-C 1-10 alkylene-C(=O)-, -C 3-10 alkynylene-C(=O)-NH-C 1-10 alkylene-O-C 1-10 alkylene-C(=O)-, -C 3-10 alkenylene-C(=O)-NH-C 1-10 alkylene-O-C 1-10 alkylene-C(=O)-, -C 1-10 heteroalkylidene-C(=O)-NH-C 1-10 alkylene-O-C 1-10 alkylene-C(=O)-, -C3-8 Subcycloalkyl-C(=O)-NH-C 1-10 Alkylene-O-C 1-10 Alkylene-C(=O)-, -O-C 1-10 Alkylene-C(=O)-NH-C 1-10 Alkylene-O-C 1-10 Alkylene-C(=O)-, -C6- 10 Arylene-C(=O)-NH-C 1-10 Alkylene-O-C 1-10 Alkylene-C(=O)-, -C 1-10 Alkylene-C 6-10 Arylene-C(=O)-NH-C 1-10 Alkylene-O-C 1-10 Alkylene-C(=O)-, -C 6-10 Arylene-C 1-10 Alkylene-C(=O)-NH-C 1-10 Alkylene-O-C 1-10 Alkylene-C(=O)-, -C 1-10 Alkylene-C 3-8 Subcycloalkyl-C(=O)-NH-C 1-10 Alkylene-O-C 1-10 Alkylene-C(=O)-, -C 3-8 Subcycloalkyl-C 1-10 Alkylene-C(=O)-NH-C 1-10 Alkylene-O-C 1-10 Alkylene-C(=O)-, -C 3-8 Hetrocycloalkyl-C(=O)-NH-C 1-10 Alkylene-O-C 1-10 Alkylene-C(=O)-, -C 1-10 Alkylene-C 3-8 Hetrocycloalkyl-C(=O)-NH-C 1-10 Alkylene-O-C 1-10 Alkylene-C(=O)-, -C 3-8 Hetrocycloalkyl-C 1-10 Alkylene-C(=O)-NH-C 1-10 Alkylene-O-C 1-10 Alkylene-C(=O)-, -C 1-10 Alkylene-NH-, -C 1-10 Heteroalkylene-NH-, -C 3-8 Subcycloalkyl-NH-, -O-C 1-10 Alkylene-NH-, -C 6-10 Arylene-NH-, -C 1-10 Alkylene-C 6-10Arylene-NH-, -C 6-10 Arylene-C 1-10 Alkylene-NH-, -C 1-10 Alkylene-C 3-8 Cycloalkylene-NH-, -C 3-8 Cycloalkylene-C 1-10 Alkylene-NH-, -C 3-8 Heteroarylene-NH-, -C 1-10 Alkylene-C 3-8 Heteroarylene-NH- and -C 3-8 Heteroarylene-C 1-10 Alkylene-NH-, wherein each group in G3 connected to -C(=O)- or -NH- is optionally substituted by Bu, and G3 is connected to the linker unit E (when present) or the property modulating unit D (when present and E is absent) or the cleavable linker B (when both E and D are absent) through its -C(=O)- or -NH-, and the other end group is connected to G2.

[0800] In some embodiments, each group in G3 connected to -C(=O)- or -NH- is optionally substituted by the following Bu groups: H, deuterium, halogen, NO2, CN, -OR h , -OR h , -N(R h )2, -COR h , -CO2R h , -C-(O)C(O)R h , -C(O)CH2C(O)R h , -S(O)R h , -SO2R h , C(O)N(R h )2, -SO2N(R h )2, -OC(O)R h , -N(R h )SO2R h and -C 1-6 alkyl optionally substituted by the foregoing groups, wherein R h is H or -C 1-6 alkyl optionally substituted by halogen, or wherein two R h groups connected to the same N atom and the nitrogen to which they are attached together form a 4-7 membered heteroaryl group. Preferably, the substituent of G3 is an aminoalkyl moiety, such as -(CH2) 1- 6NH2, -(CH2) 1-6 NHR h or -(CH2) 1-6 N(R h )2, or wherein two R hThe group, together with the nitrogen to which it is attached, forms an azetidinyl, pyrrolidinyl or piperidinyl group.

[0801] In some other embodiments, each group attached to -C(=O)- or -NH- in G3 is optionally substituted with a Bu group of formula (A): wherein,

[0802] T0 is -C 1-6 alkylene-;

[0803] T is selected from -C(R a )2-, -O-, -NR a -, or absent;

[0804] Q is selected from -CO-, -O-, -NR a -, or absent;

[0805] U is selected from a glycosyl or its derivative, and a hydrophilic peptide containing ;

[0806] R a is selected from H or -C 1-6 alkyl, preferably H or -CH3;

[0807] The subunit is selected from natural amino acid residues and unnatural amino acid residues;

[0808] p is an integer from 0 to 4, such as 0 - 2, 1 - 2, 2 - 4;

[0809] t is an integer from 0 to 20, such as 0 - 8, 0 - 6, 0 - 4, 0 - 2, 1 - 20, 1 - 10, 2 - 10, 2 - 8, 2 - 6, 2 - 4, 4 - 14, 6 - 10, 6 - 12, 8 - 10, 8 - 14.

[0810] The glycosyl or its derivative in the substituents carried by G3 as the antibody linker of the present disclosure ADC is selected from monosaccharide, disaccharide, oligosaccharide or polysaccharide or their derivatives, preferably the monosaccharide or disaccharide or their derivatives generally, specifically or preferably defined for the solubilizing sugar unit S in the "linker unit L" part herein, more preferably the monosaccharide or disaccharide or their derivatives exemplified in Tables 3 and 4.

[0811] In some embodiments, U is the monosaccharide or disaccharide or their derivatives defined herein and is linked by a glycosidic bond (-O-sugar residue); in some other embodiments, U is the amino sugar or its derivative defined herein and is linked by an amino group, preferably the amino sugar derivative of the monosaccharide or disaccharide; in some other embodiments, U is the sugar acid or uronic acid or their derivatives defined herein and is linked by a carbonyl group.

[0812] In the hydrophilic peptides carried by the ADCs of the present disclosure, the amino acid residues as subunits can be any of the 20 conventional natural amino acids. Correspondingly, the value combinations of R, R', and R'' in the repeating subunit -CO-CR’R”-NR- correspond to the corresponding values of alanine (Ala), arginine (Arg), aspartic acid (Asp), asparagine (Asn), histidine (His), glycine (Gly), glutamic acid (Glu), glutamine (Gln), phenylalanine (Phe), lysine (Lys), leucine (Leu), serine (Ser), tyrosine (Tyr), threonine (Thr), isoleucine (Ile), proline (Pro), tryptophan (Trp), valine (Val), cysteine (Cys), and methionine (Met). Preferred are preferably polar natural amino acids, such as arginine, serine, threonine, tyrosine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, histidine, glycine, and tryptophan. The hydrophilic peptide can be a single-unit repetition or a mixed repetition of different subunits.

[0813] In the hydrophilic peptides carried by the ADCs of the present disclosure, the amino acid residues as subunits can also be amino acids other than the 20 conventional natural amino acids, such as ornithine (Orn), β-alanine (β-Ala), citrulline (Cit), sarcosine (Sar), and those amino acids in which R, R', and R'' in the repeating subunit -CO-CR’R”-NR- are different from the corresponding groups or segments among the 20 amino acids, for example, R, R', and R'' are selected from alkyl, aryl, acyl, amido, ketone, azide, hydroxyl, mercapto, hydrazine, cyano, quaternary ammonium, halogen, acylhydrazide, alkenyl, alkynyl, ether, thiol, seleno, sulfonic acid, sulfate, borate, phosphonyl, phosphate, heterocycle, enone, imine, aldehyde, ester, thioacid, hydroxylamine, amino, etc. or any combination thereof, or groups containing alkyl, aryl, acyl, amido, ketone, azide, hydroxyl, mercapto, hydrazine, cyano, quaternary ammonium, halogen, acylhydrazide, alkenyl, alkynyl, ether, thiol, seleno, sulfonic acid, sulfate, borate, phosphonyl, phosphate, heterocycle, enone, imine, aldehyde, ester, thioacid, hydroxylamine, amino, etc.; preferably those amino acids in which R, R', and / or R'' contain hydrophilic groups, for example, R, R', and R'' are each independently carboxyl, sulfonic acid, sulfate, phosphate, amino, amido, quaternary ammonium, ether, mercapto, or hydroxyl, or are groups containing carboxyl, sulfonic acid, sulfate, phosphate, amino, amido, quaternary ammonium, ether, mercapto, and / or hydroxyl, such as alkyl or aryl, such as C 1-6 alkyl.

[0814] In some embodiments, the amino acid units of the hydrophilic peptide comprise natural amino acid repeat units, and the amino acids are preferably selected from arginine, serine, threonine, tyrosine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, histidine, glycine, tryptophan; in other embodiments, the hydrophilic peptide comprises amino acid repeat units other than the above-listed 20 natural amino acids, such as ornithine (Orn), citrulline (Cit), sarcosine (Sar); in other embodiments, the hydrophilic peptide is a mixed hydrophilic peptide comprising the natural amino acids and the non-conventional amino acids.

[0815] In some embodiments, in the subunit preferably, R, R', and R" are each independently H, -C1-6 alkyl, carboxyl, sulfonic acid group, sulfate group, phosphate group, amino group, amide group, quaternary ammonium group, ether group, mercapto group, or hydroxyl group, or are groups comprising hydrophilic groups such as carboxyl, sulfonic acid group, sulfate group, phosphate group, amino group, amide group, quaternary ammonium group, ether group, mercapto group, and / or hydroxyl group, such as aryl or C 1-6 alkyl; more preferably, R, R', and R" are each independently H, -C 1-6 alkyl, carboxyl, sulfonic acid group, phosphate group, amino group, amide group, quaternary ammonium group, mercapto group, or hydroxyl group, or are groups comprising hydrophilic groups such as carboxyl, sulfonic acid group, phosphate group, amino group, amide group, quaternary ammonium group, mercapto group, and / or hydroxyl group, such as aryl or C 1-6 alkyl.

[0816] In some embodiments, the G3 moiety of the antibody linker of the present disclosure ADC is substituted by the Bu group of formula (A), and U in formula (A) is the hydrophilic peptide as defined generally or specifically above and comprising thereof.

[0817] In some embodiments, the hydrophilic peptide is linked through the carboxyl terminus, and in other embodiments, the hydrophilic peptide is linked through the amino terminus.

[0818] It should be noted that the present disclosure context involves hydrophilic peptides in the definition of multiple structural fragments, and their definitions are all applicable to the definition given herein for the fragment of formula (A).

[0819] For the present disclosure ADC, the carried hydrophilic peptide is, for example but not limited to, linked through the carboxyl terminus or linked through the amino terminus, where R is as defined above, including but not limited to the amino residues of various amino acids listed herein for the hydrophilic peptide, and R a is selected from H or -C 1-6 alkyl, preferably H or -CH3; preferably poly(sarcosine), poly(arginine), poly(glycine) comprising 4 - 14 units, and more preferably poly(sarcosine) comprising 6 - 12 units.

[0820] It should be noted that each example of the hydrophilic peptide hereinafter is respectively a specific example of the hydrophilic peptide, especially wherein when R on N in the repeating unit a is methyl, it represents poly(sarcosine) preferably carried by the ADC of the present disclosure.

[0821] In some embodiments, U is selected from and the hydrophilic peptide linked through the amino terminus, such as In other embodiments, U is selected from and the hydrophilic peptide linked through the carboxyl terminus, such as wherein R a is selected from H or -C 1-6 alkyl, preferably H or -CH3.

[0822] In some embodiments, T0 is -C 1-4 alkylene-, preferably -C 1-2 alkylene-, more preferably methylene.

[0823] In some embodiments, in the fragment, T is -O-, such as ), or T is -C(R a )2-, such as ), or T is -NR a -, such as ), or T is absent, such as

[0824] In some embodiments, in the fragment, T is absent, p is 0 - 4, such as 0 - 2, and Q is -CO-, that is or T is -C(R a )2-, p is 0 - 4, such as 0 - 2, and Q is -CO-, that is For example but not limited to Furthermore, in such embodiments, U is preferably selected from and the hydrophilic peptide such as or the amino sugar or its derivative as defined herein and linked through the amino group, preferably the amino sugar derivative of monosaccharide or disaccharide, more preferably the amino sugar or its derivative shown in Table 3 or Table 4.

[0825] In some embodiments, in the In the fragment, T is absent, p is from 0 to 4, for example from 0 to 2, and Q is selected from -O- or -NR a -, that is Or T is -C(R a )2-, p is from 0 to 4, for example from 0 to 2, and Q is selected from -O- and -NR a -, that is For example but not limited to Furthermore, in such embodiments, U is preferably selected from the sugar acids or their derivatives as defined herein and is linked by a carbonyl group, preferably a sugar acid derivative of a monosaccharide or disaccharide, more preferably a sugar acid derivative shown in Table 3 or Table 4; And hydrophilic peptides such as

[0826] In some embodiments, Q is absent, The fragment is selected from Where p is from 0 to 4, preferably from 1 to 4, for example from 1 to 2, for example Furthermore, in such embodiments, U can be a sugar group or its derivative and is linked by a glycosidic bond, for example The sugar residue is linked by ethylene glycol; or U is an amino sugar or its derivative and is linked by an amino group, for example

[0827] In some embodiments, t is an integer from 1 to 20, for example 2 - 10, 2 - 8, 2 - 6, 2 - 4, 4 - 10, 4 - 14, 6 - 10, 6 - 12, 8 - 10, 8 - 14.

[0828] In some embodiments, G1 is an S atom; in some other embodiments, G1 is an N atom; in some other embodiments, G1 is a C atom. In the ADCs of the present disclosure, the preferred G1 is the sulfur atom of the Ab.

[0829] In some embodiments, G2 is a 5 - 10 membered heterocyclic group, preferably a 5 - 6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, and S, and the ring carbon atoms therein are optionally oxidized, for example but not limited to Where the left * represents the connection point with G1 and the right wavy line represents the connection point with G3.

[0830] In some embodiments, G2 is selected from Is the acid - amide moiety formed after partial hydrolysis of the succinimide moiety.

[0831] In a preferred embodiment, G2 is a maleimide group In another preferred embodiment, G2 is

[0832] In some embodiments, G2 is selected from preferably selected from

[0833] In some embodiments, G3 is selected from -C 1-10 alkylene-C(=O)-, -C 3-10 alkynylene-C(=O)-, -C 3-10 alkenylene-C(=O)-, -C 1-10 heteroalkylene-C(=O)-, -C 3-8 cycloalkylene-C(=O)-, -O-C 1-10 alkylene-C(=O)-, -C6- 10 arylene-C(=O)-, -C 1-10 alkylene-C 6-10 arylene-C(=O)-, -C 6-10 arylene-C 1-10 alkylene-C(=O)-, -C 1-10 alkylene-C 3-8 cycloalkylene-C(=O)-, -C 3-8 cycloalkylene-C 1-10 alkylene-C(=O)-, -C 3-8 heterocyclylene-C(=O)-, -C 1-10 alkylene-C 3-8 heterocyclylene-C(=O)-, -C 3-8 heterocyclylene-C 1-10 alkylene-C(=O)-, -C 1-10 alkylene-NH-, -C 1-10 heteroalkylene-NH-, -C 3-8 cycloalkylene-NH-, -O-C 1-10 alkylene-NH-, -C 6-10 arylene-NH-, -C 1-10 alkylene-C 6-10 arylene-NH-, -C 6-10 arylene-C 1-10 alkylene-NH-, -C 1-10 alkylene-C 3-8 cycloalkylene-NH-, -C 3-8 cycloalkylene-C 1-10 alkylene-NH-, -C 3-8 heterocyclylene-NH-, -C 1-10 alkylene-C 3-8 heterocyclylene-NH- and -C 3-8 heterocyclylene-C 1-10 alkylene-NH-; preferably selected from -C1-10 Alkylene-C(=O)-, -C 3-10 Alkynylene-C(=O)-, -C 3-10 Alkenylene-C(=O)-, -C 1-10 Heteroalkylidene-C(=O)-, -C 1-10 Alkylene-C 6-10 Arylene-C(=O)-, -C 6-10 Arylene-C 1-10 Alkylene-C(=O)-, -C 1-10 Alkylene-C 3-8 Cycloalkylidene-C(=O)-, -C 3-8 Cycloalkylidene-C 1-10 Alkylene-C(=O)-, -C 1-10 Alkylene-C 3-8 Heterocyclidene-C(=O)-, -C 3-8 Heterocyclidene-C 1-10 Alkylene-C(=O)-; more preferably -C 1-10 Alkylene-C(=O)-; wherein each group in G3 that is linked to -C(=O)- or NH is optionally substituted by Bu as defined above for G3, and G3 is linked through its -C(=O)- or NH to the linker unit E (when present) or the property modulating unit D (when present and E is absent) or the cleavable linker B (when both E and D are absent), and the other end group is linked to G2.

[0834] In some embodiments, G3 is -C 1-10 Alkylene-C(=O)-, preferably -C 1-5 Alkylene-C(=O)-, wherein the alkylene moiety is optionally substituted by the above-mentioned Bu moiety.

[0835] In some embodiments, G3 is -C 1-10 Alkylene-NH, preferably -C 1-5 Alkylene-NH-, wherein the alkylene moiety is optionally substituted by the above-mentioned Bu moiety.

[0836] In exemplary embodiments, -G2-G3- can be the following groups:

[0837] For example

[0838] For example

[0839] wherein G3 and Bu are each as generally or preferably defined above;

[0840] G3’ and G3” are each independently selected from -C 1-10 alkylene, -C 3-10 alkynylene, -C 3-10 alkenylene, -C 1-10 heteroalkylene, -C 3-8 cycloalkylene, -C 6-10 arylene, -C 1-10 alkylene-C 6-10 arylene, -C 6-10 arylene-C 1-10 alkylene, -C 1-10 alkylene-C 3-8 cycloalkylene, -C 3-8 cycloalkylene-C 1-10 alkylene, -C 3-8 heterocyclylene, -C 1-10 alkylene-C 3-8 heterocyclylene, -C 3-8 heterocyclylene-C 1-10 alkylene;

[0841] Preferably, G3’ and G3” are each independently selected from -C 1-10 alkylene, -C 3-10 alkynylene, -C 3-10 alkenylene, -C 1-10 heteroalkylene, -C 1-10 alkylene-C 6-10 arylene, -C 6-10 arylene-C 1-10 alkylene, -C 1-10 alkylene-C 3-8 cycloalkylene, -C 3-8 cycloalkylene-C 1-10 alkylene, -C 1-10 alkylene-C 3-8 heterocyclylene, -C 3-8 heterocyclylene-C 1-10 alkylene;

[0842] More preferably, G3’ is -C 1-10 alkylene-, preferably -C 1-5 alkylene-; G3” is -C 1-5 alkylene-, preferably -C 1-2 alkylene-; wherein G3’ and G3” are optionally substituted by the Bu moiety defined as above generally or preferably;

[0843] wherein the left * represents the point of attachment to G1, and the right represents the point of attachment to E (when present) or the property-modulating unit D (when present and E is absent) or the cleavable linker B (when both E and D are absent).

[0844] In some embodiments, -G2-G3- is wherein G3’ is -C 1-10 alkylene-, preferably -C 1-5 alkylene-, Bu is absent or is a structural fragment of formula (A).

[0845] In a specific embodiment, -G2-G3- can be For example or -G2-G3- can be For example wherein T0, T, Q, U, p, and the fragment of formula (A) are respectively defined generally or specifically as formula (A) above.

[0846] In a further specific embodiment, -G2-G3- is For example wherein T0 is -C 1-4 alkylene-(such as -C 1-2 alkylene-, such as methylene), T is absent and p is 0-4 (such as 0-2) and Q is selected from -O- or -NR a -, or T0 is -C 1-4 alkylene-(such as -C 1-2 alkylene-, such as methylene), T is -C(R a )2-, p is 0-4 (such as 0-2) and Q is -NR a - or -O-, and U is preferably selected from sugar acids (preferably sugar acids of monosaccharides or disaccharides) or their derivatives and is linked by a carbonyl group, hydrophilic peptides such as or wherein T0 is -C 1-4 alkylene-(such as -C 1-2 alkylene-, such as methylene), T is absent and p is 0-4 (such as 0-2) and Q is -CO-, or T0 is -C 1-4 alkylene-(such as -C 1-2 alkylene-, such as methylene), T is -C(R a )2-, p is 0-4 (such as 0-2) and Q is -CO-, and U is preferably selected from amino sugars (preferably amino monosaccharides or amino disaccharides) or their derivatives and is linked by an amino group, or hydrophilic peptides such as or

[0847] wherein T0 is -C 1-4 alkylene-(such as -C 1-2 alkylene-, such as methylene), T is selected from -C(R a )2-, -O-, -NRa - or absent, Q is absent, p is 0 - 4 (e.g., 0 - 2, 1 - 2), and U is preferably selected from a glycosyl group (preferably a monosaccharide or disaccharide) or a derivative thereof and is linked by a glycosidic bond, or an amino sugar (preferably an amino monosaccharide or amino disaccharide) or a derivative thereof and is linked by an amino group;

[0848] wherein t is an integer from 1 to 20, such as 2 - 10, 2 - 8, 2 - 6, 2 - 4, 4 - 10, 4 - 14, 6 - 10, 6 - 12, 8 - 10, 8 - 14.

[0849] In some embodiments, -G1-G2-G3- is selected from the following groups:

[0850] For example Specifically

[0851] For example Specifically wherein G3, G3’ and Bu are as generally or preferably defined above; the * on the left represents the connection point to the rest of the antibody, and the on the right represents the connection point to the linker unit E (when present) or the property modulating unit D (when present and E is absent) or the cleavable linker B (when both E and D are absent).

[0852] In some embodiments, -G1-G2-G3- is wherein G3’ is -C 1-10 alkylene-, preferably -C 1-5 alkylene-, Bu is absent or is a structural fragment of formula (A).

[0853] In a specific embodiment, -G1-G2-G3- can be For example or -G1-G2-G3- can be For example wherein T0, T, Q, U, p and the fragment of formula (A) are as generally or specifically defined for formula (A) above.

[0854] In a further specific embodiment, -G1-G2-G3- is For example wherein T0 is -C 1-4 alkylene- (e.g., -C 1-2 alkylene-, such as methylene), T is absent and p is 0 - 4 (e.g., 0 - 2) and Q is selected from -O- or -NRa -, or T0 is -C 1-4 Alkylene-(e.g., -C 1-2 Alkylene-, such as methylene), T is -C(R a )2-, p is 0-4 (e.g., 0-2) and Q is -NR a - or -O-, and U is preferably selected from sugar acids (preferably sugar acids of monosaccharides or disaccharides) or their derivatives and is linked by a carbonyl group, Hydrophilic peptides such as or wherein T0 is -C 1-4 Alkylene-(e.g., -C 1-2 Alkylene-, such as methylene), T is absent and p is 1-4 (e.g., 1-2) and Q is -CO-, or T0 is -C 1-4 Alkylene-(e.g., -C 1-2 Alkylene-, such as methylene), T is -C(R a )2-, p is 0-4 (e.g., 0-2) and Q is -CO-, and U is preferably selected from amino sugars (preferably amino monosaccharides or amino disaccharides) or their derivatives and is linked by an amino group, or hydrophilic peptides such as or

[0855] wherein T0 is -C 1-4 Alkylene-(e.g., -C 1-2 Alkylene-, such as methylene), T is selected from -C(R a )2-, -O-, -NR a -, or is absent, Q is absent, p is 0-4 (e.g., 0-2, 1-2), and U is preferably selected from glycosyl groups (preferably monosaccharides or disaccharides) or their derivatives and is linked by a glycosidic bond, or amino sugars (preferably amino monosaccharides or amino disaccharides) or their derivatives and is linked by an amino group;

[0856] wherein t is an integer from 1 to 20, such as 2-10, 2-8, 2-6, 2-4, 4-10, 4-14, 6-10, 6-12, 8-10, 8-14.

[0857] In an exemplary embodiment, G (-G1-G2-G3-) in Formula (II) or Formula (II’) of the present disclosure has the following structure:

[0858]

[0859]

[0860] In some preferred embodiments, G in Formula (II) or Formula (II’) of the present disclosure has the following structure:

[0861]

[0862]

[0863] and the maleimide moiety is each of the above - shown segments, such as and the like.

[0864] E - linker unit

[0865] In the linker unit L of the linker unit E in the formula (II) or formula (II’) of the disclosed ADC, the linker unit E connects the antibody linker G to the property - modulating unit D, or when D is absent, connects the antibody linker G to the cleavable linker B, for increasing an additional distance between the antibody linker and the cleavable linker B, which may contribute to the activation of B.

[0866] In some embodiments, the linker unit E is selected from a directly - connecting bond, - C 1-5 alkylene -, - NH -, - NH - C 1-5 alkylene - heteroaryl (such as a 5 - or 6 - membered nitrogen - containing heteroaryl, such as triazolyl), and the following groups:

[0867]

[0868] wherein when present, E is connected to the property - modulating unit D (when present) or the cleavable linker B through its - C(=O)- or - NH - terminus as appropriate, and the other end is also connected to G3 through - C(=O)- or - NH - as appropriate;

[0869] R g each independently selected from H and - C 1-6 alkyl, preferably H or - C 1-3 alkyl;

[0870] R f selected from - C 1-6 alkylene -, - arylene -, - C 1-10 heteroalkylene -, - C 3-8 heterocycloalkyl -, - C 1-10 alkylene - C 6-10 arylene -, - C 6-10 arylene - C 1-10 alkylene -, - C 1-10 alkylene - C 3-8 cycloalkyl -, - C 3-8 cycloalkyl - C 1-10 alkylene -, - C 1-10 alkylene - C 3-8 heterocycloalkyl -, - C 3-8 heterocycloalkyl - C 1-10 alkylene -;

[0871] It should be noted that when present, each of the above specific definitions of E can be continuously repeated 1 - 10 times, preferably 1 - 4 times, such as 1 time, 2 times, 3 times, and 4 times, head - to - tail in different directions.

[0872] In a specific embodiment, the linker unit E is where R f is independently selected from -C 1-6 alkylene-, preferably -C 2-4 alkylene, R g is H or C 1-3 alkyl, for example where the left wavy line is connected to the cleavable linker B, and the right wavy line is connected to the antibody linker G.

[0873] In another specific embodiment, the linker unit E is a directly connected bond; in another specific embodiment, the linker unit E is -C 1-4 alkylene-; in another specific embodiment, the linker unit E is -NH-.

[0874] D and D 1 — Property adjustment unit

[0875] The addition of the property - modulating unit D or D' in the linker unit L of formula (II) or formula (II') of the disclosed ADC may be beneficial for improving the properties of the ADC, such as stability in blood circulation, improved hydrophilicity, resulting in reduced clearance and increased exposure. However, an increase in the number of D or D' will also lead to an increase in the molecular weight of the ADC and an increase in the hydrodynamic radius, thereby resulting in reduced diffusion, and the reduced diffusion rate may reduce the ability of the ADC to penetrate tumors. Due to these two competing pharmacokinetic effects, an appropriate amount of D or D' 1 needs to be used to reduce the clearance of the ADC, thereby increasing plasma exposure, but not so much as to reduce its diffusivity to the extent that it interferes with the ability of the ADC to reach the intended target cell population. 1 is required to reduce the clearance of the ADC, thereby increasing plasma exposure, but not so much as to reduce its diffusivity to the extent that it interferes with the ability of the ADC to reach the intended target cell population. 1 to reduce the clearance of the ADC, thereby increasing plasma exposure, but not so...

Claims

1. An antibody-drug conjugate of formula (X) or a pharmaceutically acceptable salt or solvate thereof: [P-L] q -Ab(X) Wherein, Ab represents an antibody or antigen-binding fragment that binds to a target antigen; q represents the number of [P-L] units linked to Ab, which is an integer or non-integer of at least 1; L represents a linker unit that links P to Ab; P represents a Ras mutant inhibitor compound.

2. The antibody-drug conjugate according to claim 1, wherein the Ras mutant inhibitor compound is a compound represented by the following formula (I), or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: M is selected from N or C-R1; M' is selected from N or C-R1'; R1 and R1’ are each independently selected from H, halogen, CN, -C 1-6 alkyl optionally substituted with halogen and -OC 1-6 alkyl; R a selected from H, halogen, CN, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkynyl and -OC 1-6 alkyl optionally substituted by halogen or deuterium; X is selected from CH2, N and O; R2 and R2’ are each independently selected from H, OH or -C which is optionally substituted by halogen 1-6 alkyl; or R2 and R2’ which are attached to non-adjacent ring carbon atoms together form an endocyclic bridging -(CH2) 1-2 - or -CH2=CH2-; or R2 and R2’ which are attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a 4- to 6-membered spiroalkyl group or a 4- to 6-membered spiroheteroalkyl group containing 1 or 2 heteroatoms selected from N and O; R3 is selected from H, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 and -OC 1-6 alkyl; R4 is selected from -CN, halogen, -NO2, -C≡C- optionally substituted by halogen and -C 2-6 alkyl optionally substituted by halogen; 1-6 alkyl; R5 is selected from H, -CN, halogen, -NO2 and halogen-substituted -C 1-6 alkyl; R6 is selected from H, halogen, CN, -C 1-6 alkyl and -C 2-6 alkynyl, wherein the -C 1-6 alkyl and -C 2-6 alkynyl are each independently optionally substituted by halogen; R7, R7’, R8 and R8’ are each independently selected from H, halogen, CN, -NO2 and -C alkyl optionally substituted by halogen; 1-6 alkyl; V and W are each independently selected from H, halogen, -C 1-6 alkyl, OH, and NH2; Z is selected from O, N and CH2; R9 and R 10 are each independently selected from H, deuterium, -C 1-6 alkyl, and -(CH2) n -C 3-6 cycloalkyl, wherein the -C 1-6 alkyl and -C 3-6 cycloalkyl are each independently optionally substituted with deuterium, halogen, or -O-C 1-6 alkyl, or R9 and R which are attached to the same carbon atom 10 together with the carbon atom to which they are attached form a C 3-4 cycloalkyl; R 11 selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -(CH2) n -C 3-6 cycloalkyl, wherein the C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-6 cycloalkyl is each independently optionally substituted with deuterium, halogen, CN or -O-C 1-6 alkyl; R 12 selected from H, halogen, -CN, -OH, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -O-C 1-6 alkyl, -O-C 3-6 cycloalkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -(CH2) n -C 3-6 cycloalkyl and =C(R d )2, wherein R d are each independently selected from H, halogen and -C 1-6 alkyl optionally substituted by halogen, wherein each occurrence of C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-6 cycloalkyl is each independently optionally substituted by halogen, CN or -OC 1-6 alkyl; R 13 Selected from H, -C 1-6 alkyl and -(CH2) n -C 3-6 cycloalkyl, wherein the -C 1-6 alkyl and -C 3-6 cycloalkyl are each independently optionally substituted by halogen or -O-C 1-6 alkyl; k is an integer selected from 0 or 1 m is an integer from 0 to 6; n is an integer from 0 to 2; wherein the compound of formula (I) is bonded to the linker unit L through the ring NH when present in its fragment, and / or through the OH when present on the side-chain naphthalene ring or benzothiophene ring.

3. The antibody-drug conjugate of claim 2, wherein the structural fragment in formula (I) is Preferably, M is C-R1 and M' is C-R1', where R1 is selected from halogen or -C 1-6 alkyl optionally substituted by halogen, R a is H, and R1' is halogen, or M is N and M' is C-R1', where R a is selected from H, -C 2-6 alkynyl and -OC 1-6 alkyl, and R1' is halogen, More preferably, M is C-R1 and M' is C-R1', where R1 is selected from F or Cl, or a -C alkyl group substituted by halogen, R 1-3 is H, and R1' is F, or M is N and M' is C-R1', where R a is selected from H, -C a alkynyl and optionally deuterium-substituted -OC 2-4 alkyl, and R1' is F; 1-3 ​ and / or Among them, the structural fragment in formula (I) in which, R3 is selected from -NH2, -NHC 1-6 alkyl and N(C 1-6 alkyl)2; R4 is selected from -CN, halogen, -NO2 and -C 2-6 alkynyl substituted by halogen; V is selected from H, -C 1-6 alkyl and halogen, R7 and R7' are each H, or each is halogen, or one of them is H and the other is halogen or C 1-6 alkyl substituted by halogen, or one of them is halogen and the other is C 1-6 alkyl substituted by halogen, Preferably, the structural fragment is V is H, R7 and R7' are each H, or one of them is H and the other is halogen, or Among them, the structural fragment in formula (I) wherein W is OH; R5 is H or halogen, and R6 is selected from halogen, -C 2-6 alkynyl and -C 1-6 alkyl; R8 and R8' are each H; or R8 and R8' are each halogen, or one of R8 and R8' is H and the other is selected from halogen, CN and NO2, or one of R8 and R8' is H and the other is selected from -C 1-6 alkyl optionally substituted by halogen, or one of R8 and R8' is selected from H, halogen, -NO2, CN and -C 1-6 alkyl optionally substituted by halogen, and the other is selected from -C 1-6 alkyl optionally substituted by halogen, Preferably, the structural fragment is wherein R5 is halogen and R6 is selected from -C 2-6 alkynyl; and / or wherein the structural fragment in formula (I) is wherein R2 and R2', which are attached to non-adjacent ring carbon atoms, together form an internal bridging group -CH2-, -CH2CH2- or -CH2=CH2-, preferably and / or where Z is O, and the structural fragment connected to Z is preferably more preferably 4. The antibody-drug conjugate of claim 2 or 3, wherein R9 and R 10 are both H, or one or both of them are deuterium; and / or wherein R 11 is -C 1-6 alkyl, in which the hydrogen atoms are optionally replaced by one or more deuterium isotopes; and / or wherein R 12 is selected from -C 1-6 alkyl optionally substituted by halogen and =C(R d )2, where each R d is independently selected from H and halogen, and m is 1 or 2; and / or wherein R 13 is -C 1-6 alkyl, preferably -C 1-3 alkyl, more preferably -CH3.

5. The antibody-drug conjugate according to any one of claims 1 to 4, wherein the structural fragment is selected from 6. The antibody-drug conjugate of any one of claims 1 to 5, wherein the compound of formula (I) has any of the following sub-formulas: wherein R1, R1’, R a , R3, R4, R5, R6, R7, R7’, W, V, R9, R 10 , R 11 , R 12 , R 13 , and m are respectively defined as corresponding ones in claims 1 to 11; preferably When M is C-R1 and M' is C-R1', R1 is selected from F or Cl, or a -C alkyl group substituted by halogen, R 1-3 is H, and R1' is F, or when M is N and M' is C-R1', where R a is selected from H, -C a alkynyl and optionally deuterium-substituted -OC 2-4 alkyl, and R1' is F; 1-3 ​ R3 is -NH2, R4 is -CN, V is H, R7 and R7' are each H, or one of them is H and the other is a halogen; R5 is a halogen, R6 is selected from -C 2-6 alkynyl, R8 and R8' are each H, and W is OH; R9 and R 10 are both H, or one or both of them are deuterium; R 11 is -C 1-3 alkyl, in which the hydrogen atoms are optionally replaced by one or more deuterium isotopes; R 12 selected from optionally halogen-substituted -C 1-3 alkyl and =C(R d )2, where R d are each independently selected from H and halogen; m is 1 or 2; R 13 is -C 1-3 alkyl.

7. The antibody-drug conjugate of any one of claims 1 to 6, wherein the Ras inhibitor compound is selected from: Their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates.

8. The antibody-drug conjugate of claim 1, wherein the Ras inhibitor compound has any of the following sub-formulas: or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein M, M’, X, Z, V, W, R1, R1’, R3, R4, R5, R6, R7, R7’, R8, R8’, R9, R 10 、R 11 、R 12 、R 13 、k, m, n, structural moiety are as defined in any one of claims 2 to 6, respectively; Y is selected from -CH2-, -CH2CH2-, -CH2OCH2- or absent; R 14 and R 15 each independently selected from H and -C 1-6 alkyl; Preferably, In the fragment, when M is C-R1, R1 is selected from halogen (preferably F or Cl) or -C optionally substituted by halogen 1-6 alkyl (preferably -C alkyl substituted by halogen 1-3 alkyl, more preferably -CF3), and M' is C-R1' and R1' is halogen (preferably F); or when M is N, M' is C-R1' and R1' is halogen (preferably F); In the fragment, each of the two Ms is C-R1, or one of the Ms is N and the other M is C-R1, and each R1 is independently selected from H, halogen (preferably F), and halogen-substituted -C 1-6 alkyl (preferably one or more F-substituted -C 1-3 alkyl, more preferably -CF3), preferably the M adjacent to R3 is selected from N and C-R1 (preferably C-halogen, more preferably C-F), and the M adjacent to R6 is C-R1 (preferably C-halogen-substituted -C 1-3 alkyl, more preferably -C-CF3); R3 is selected from -NH2, -NHC 1-6 alkyl, and N(C 1-6 alkyl)2 (preferably selected from -NH2, -NHC 1-3 alkyl, and N(C 1-3 alkyl)2, more preferably -NH2); R5 is H or halogen (preferably F); R6 is selected from halogen (preferably Cl) and -C 1-6 alkyl (preferably -C 1-3 alkyl); In the fragment, R3 is selected from -NH2, -NHC 1-6 alkyl and N(C 1-6 alkyl)2 (preferably selected from -NH2, -NHC 1-3 alkyl and N(C 1-3 alkyl)2, more preferably -NH2); R4 is selected from -CN, halogen, -NO2 and halogen-substituted -C 2-6 alkynyl; V is selected from H, -C 1-6 alkyl (preferably -C 1-3 alkyl) and halogen; R7 and R7’ are each H, or each is halogen, or one of them is H and the other is halogen or halogen-substituted C 1-6 alkyl (preferably halogen-substituted -C 1-3 alkyl), or one of them is halogen and the other is halogen-substituted C 1-6 alkyl (preferably halogen-substituted -C 1-3 alkyl), wherein the halogen is preferably F; Preferably R3 is -NH2, R4 is -CN, V is H, R7 and R7' are each H, or one of them is H and the other is a halogen (preferably F); In the fragment, R5 is H or a halogen (preferably F); R6 is selected from a halogen, -C 2-6 alkynyl (preferably -C 2-4 alkynyl) and -C 1-6 alkyl (preferably -C 1-3 alkyl); R8 and R8' are each H, or R8 and R8' are each a halogen, or one of R8 and R8' is H and the other is selected from a halogen, CN, and NO2, or one of R8 and R8' is H and the other is selected from -C 1-6 alkyl optionally substituted with a halogen, or one of R8 and R8' is selected from H, a halogen, -NO2, CN, and -C 1-6 alkyl optionally substituted with a halogen, and the other is selected from -C 1-6 alkyl optionally substituted with a halogen; W is OH; Preferably, R5 is halogen (preferably F), and R6 is selected from -C 2-6 alkynyl (preferably -C 2-4 alkynyl), R8 and R8' are each H, and W is OH; X is selected from O and NH; Y is selected from -CH2CH2- and absent; Z is selected from O; R9 and R 10 are both H; or one or both of them are deuterium; R 11 is -C 1-6 alkyl (preferably -C 1-3 alkyl), wherein the hydrogen atoms are optionally replaced by one or more deuteriums; R 12 selected from optionally halogen-substituted -C 1-6 alkyl (preferably -C 1-3 alkyl) and =C(R d )2, where R d are each independently selected from H and halogen (preferably F); m is 0, 1 or 2 (preferably 1 or 2); n, k are 0 or 1 (preferably 0); R 13 is -C 1-6 alkyl (preferably -C 1-3 alkyl, more preferably -CH3); R 14 and R 15 is H or -C 1-3 alkyl (preferably -CH3).

9. The antibody-drug conjugate of claim 1, wherein the Ras inhibitor compound is selected from: or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

10. The antibody-drug conjugate of any one of claims 1 to 9, wherein the linker unit L has: -A(S)-B-G-(II-3) or -B-G-(II-5) Wherein: A is selected from Preferably One end marked with * is connected to drug P, and the N or O marked with * is an atom from drug P; Y1 are each independently NH or O; R 16 is H; R 17 is H; S is selected from optionally present glucose, galactose, mannose, glucosamine, galactosamine, mannosamine, galacturonic acid, glucuronic acid, mannuronic acid, N-acetylgalactosamine, N-acetylglucosamine, N-acetylmannosamine, N-acetylgalacturonic acid, N-acetylglucuronic acid, N-acetylmannuronic acid, glucosaminaldehyde, galactosaminaldehyde, mannosaminaldehyde; lactose, maltose or their respective amino derivatives, N-acetyl derivatives, uronic acid derivatives, amino uronic acid derivatives, N-acetyl uronic acid derivatives; preferably S is selected from D-glucose, D-galactose, D-mannose, D-galacturonic acid, D-glucuronic acid, D-mannuronic acid, 2-acetamido-2-deoxy-D-galactose, 2-acetamido-2-deoxy-D-glucose, 2-acetamido-2-deoxy-D-mannose, 2-acetamido-2-deoxy-D-galacturonic acid, 2-acetamido-2-deoxy-D-glucuronic acid, 2-acetamido-2-deoxy-D-mannuronic acid; D-lactose, D-maltose, D-sucrose or their respective 2-acetamido and / or 6-carboxy derivatives; B is of formula (B-2): -(AA) d -, where d is an integer from 2 to 12, preferably an integer from 2 to 4; AA is an amino acid selected from the following: alanine, glycine, asparagine, valine, phenylalanine, citrulline, glutamic acid; preferably -(AA) d - is the following polypeptide from the C-terminus to the N-terminus: Ala-Ala, Cit-Val, Ala-Val, Glu-Gly, Asn-Ala-Ala, Cit-Ala-Glu, Gly-Phe-Gly-Gly; wherein the N-terminus of the peptide is connected to the G moiety, and the C-terminus of the peptide is connected to the self-cleaving linker A; G is selected from wherein the *-end represents the attachment point to the antibody Ab, and the -end represents the attachment point to B; Specifically, the linker unit L has the formula (II-3-1): and the maleimide moiety therein is the corresponding general formula fragment, wherein the -O- in -O-S is the O that forms a glycosidic bond with the benzene ring in the solubilizing sugar unit, or Specifically, when the solubilizing sugar unit S is absent, the linker unit L has the following formula: and the maleimide moiety therein is the corresponding general formula fragment; or The linker unit L has the following formula: and the maleimide moiety therein is the corresponding general formula fragment of 11. The antibody-drug conjugate of claim 10, wherein the solubilizing sugar unit in the linker unit is selected from: Among them, The wavy line shows the linking bond of the solubilizing sugar unit to the self-cleavable linker A, and the connected O is the O in the solubilizing sugar unit that forms a glycosidic bond with the benzene ring. The dotted line at the 1-position bond of the solubilizing sugar unit indicates that the configuration of this glycosidic bond can be α-type, β-type or a mixed form thereof.

12. The antibody-drug conjugate of any one of claims 10-11, wherein B in the linker unit is selected from the following polypeptides: Wherein the left-end carbonyl is connected to the self-cleavable linker A or the drug P, and the right-end N is connected to the G moiety.

13. The antibody-drug conjugate of claim 1, wherein the [P-L] conjugate fragment has any of the following general formulas: and the maleimide moiety therein is the corresponding general formula fragment of or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein M, M’, R in the drug P unit a , R3, R4, R5, R6, R7, R7’, R8, R8’, R9, R 10 , R 11 , R 12 , R 13 , W, V, m, and each structural fragment respectively have the meanings defined in claims 2-9 correspondingly, and A, S, B, G, AA, d in the linker unit L respectively have the meanings defined in claims 10-12 correspondingly; The wavy line represents the connection point to the Ab; the atom marked with an asterisk is the site in the drug P unit that is connected to the linker unit.

14. The antibody-drug conjugate of claim 1, which has any of the following general formulas selected from: and the maleimide moiety therein is the corresponding conjugate, or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein: M, M’, R in the drug P unit a , R3, R4, R5, R6, R7, R7’, R8, R8’, R9, R 10 , R 11 , R 12 , R 13 , W, V, m, and each structural fragment respectively have the meanings defined in claims 2 - 9; A, S, B, G, AA, d in the linker unit L respectively have the meanings defined in claims 10 - 12; The atom marked with an asterisk is the site in the drug P unit that is connected to the linker unit; q is an integer or non-integer from 1 to 10 or a range composed of any two values between 1 and 10; preferably q is the average DAR value of a range from 1 to 8 or a range composed of any two values between 1 and 8.

15. The antibody-drug conjugate of any one of claims 1 to 9, wherein the linker unit L has the structure of formula (II’-3), -J-B-G-(II’-3) Wherein, J is selected from -J1-, -J2-, -J1-J2-, -J2-J1-, wherein -J1- is selected from where the asterisk indicates the point of attachment to drug P or -J2-, and the wavy line indicates the point of attachment to cleavable linker B; -J2 - selected from where the asterisk indicates the point of attachment to drug P or -J1-, and the wavy line indicates the point of attachment to cleavable linker B; Each occurrence of X’ is independently selected from CH or N; Each occurrence of Y1’ is independently selected from -NH-, -NC 1-6 alkyl- or -O-; Each occurrence of R 16 ’ is independently selected from H and -C 1-6 alkyl, preferably H or C 1-3 alkyl, more preferably H; Each occurrence of R 17 is independently selected from H, -NO2, -NH2, -CF3 or a fragment of formula (A1): Each occurrence of R 18 is independently selected from -C 1-6 alkyl, preferably C 1-3 alkyl, more preferably methyl; T is selected from -C(R a )2-, -O-, -NR a -, or is absent; T1 is selected from -C(R a )2-, -O-, -NR a -; T2 is selected from -CR a - and -N-; T3 is a peptide formed by 2 to 6 amino acids with the carboxyl terminus connected to N; Q is selected from -CO-, -O-, -NR a - or is absent; U is selected from a glycosyl group or its derivative, and a hydrophilic peptide containing ; Subunit selected from natural amino acid residues and unnatural amino acid residues; R a each independently selected from H or -C 1-6 alkyl, preferably H or -CH3; p is an integer from 0 to 4, such as 0-2, 1-4, 1-2, 2-4; t is an integer from 0 to 10, such as 0-8, 0-6, 0-4, 0-2, 1-10, 2-10, 2-8, 2-6, 2-4, 6-10, 8-10; B is of the formula (B-2): -(AA) d -, where d is an integer from 2 to 12, preferably an integer from 2 to 4, preferably -(AA) d - is the following polypeptide from the C-terminus to the N-terminus: Ala-Ala, Cit-Val, Ala-Val, Glu-Gly, Asn-Ala-Ala, Cit-Ala-Glu, Gly-Phe-Gly-Gly, where the N-terminus of the peptide is connected to the G part of the linker unit and the C-terminus of the peptide is connected to J; G is wherein G1 is the atom in Ab responsible for connecting with L, and G3’ is -C 1-10 alkylene-, preferably -C 1-5 alkylene-, Bu is absent or is a structural fragment of formula (A) wherein T0 is -C 1-6 alkylene-, preferably -C 1-2 alkylene-, more preferably methylene, and p, Q, U are each defined as above.

16. The antibody-drug conjugate of claim 15, wherein J is selected from where the * indicates the point of attachment to the drug P, and the wavy line indicates the point of attachment to the rest of the linker unit; Each occurrence of X’ is independently selected from -N- or -CH-; Each occurrence of Y1’ is independently selected from -NH- or -O-; where Y1’ attached to the six-membered aromatic ring is attached at the para or ortho position to the other attachment point of the ring; Each occurrence of R 16 ’ is independently selected from H or -C 1-3 alkyl, preferably H; Each occurrence of R 17 ’ is independently selected from H or a fragment of formula (A1) Each occurrence of R 18 is independently selected from -C 1-3 alkyl, preferably methyl; Each occurrence of T is selected from -O-, -NR a - or is absent; Each occurrence of T1 is selected from -CH2-, -O-, -NCH3-; Each occurrence of T2 is selected as -N-; Each occurrence of T3 is a 2-4 peptide with a carboxyl terminus attached to N, selected from Ala-Ala, Cit-Val, Ala-Val, Glu-Gly, Asn-Ala-Ala, Cit-Ala-Glu, Gly-Phe-Gly-Gly; Each occurrence of Q is absent or is -NR a - or -O-; Each occurrence of U is selected from a hydrophilic peptide such as or a glycosyl group (preferably a monosaccharide or disaccharide or its uronic acid) or a derivative thereof, preferably a hydrophilic peptide, where t is from 2 to 14, such as from 4 to 14, from 6 to 12, preferably 10; each occurrence of p is from 0 to 4, preferably from 0 to 2; For example, the self-cleaving linker J is selected from:

17. The antibody-drug conjugate of claim 15 or 16, wherein G is wherein T0 is -C 1-4 alkylene-(e.g., -C 1-2 alkylene-, e.g., methylene), T is absent or is -C(R a )2-, p is 0 - 4 (e.g., 0 - 2) and Q is selected from -O- or -NR a -, and U is selected from uronic acid (preferably uronic acid of monosaccharide or disaccharide) or its derivative and is linked by a carbonyl group, a hydrophilic peptide such as or wherein T0 is -C 1-4 alkylene-(e.g., -C 1-2 alkylene-, e.g., methylene), T is absent or is -C(R a )2-, p is 0 - 4 (e.g., 0 - 2) and Q is -CO-, U is selected from amino sugar (preferably amino monosaccharide or amino disaccharide) or its derivative and is linked by an amino group, or a hydrophilic peptide such as or wherein T0 is -C 1-4 alkylene-(e.g., -C 1-2 alkylene-, e.g., methylene), T is selected from -C(R a )2-, -O-, -NR a -, or is absent, Q is absent, p is 0 - 4 (e.g., 0 - 2, 1 - 2), and U is selected from glycosyl (preferably monosaccharide or disaccharide) or its derivative and is linked by a glycosidic bond, or amino sugar (preferably amino monosaccharide or amino disaccharide) or its derivative and is linked by an amino group; wherein t is an integer from 1 to 20, e.g., 2 - 10, 2 - 8, 2 - 6, 2 - 4, 4 - 10, 4 - 14, 6 - 10, 6 - 12, 8 - 10, 8 - 14.

18. An antibody-drug conjugate according to any one of claims 15-17, wherein B is as defined in claim 12, and / or the subunit of the hydrophilic peptide corresponds to the residues of arginine, serine, threonine, tyrosine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, histidine, glycine, tryptophan, ornithine, citrulline, sarcosine, or R, R', R" are each independently additionally a group comprising a carboxyl group, a sulfonic acid group, a phosphoric acid group, an amino group, an amide group, a quaternary ammonium group, a mercapto group and / or a hydroxyl group; Preferably, the hydrophilic peptide comprises poly(sarcosine), poly(arginine), poly(glycine) of 4-14 units, preferably poly(sarcosine) of 6-12 units.

19. The antibody-drug conjugate of any one of claims 1-9 and 15-18, wherein the linker unit has the following formula: where each variable is defined as in any one of claims 15-18; For example, the linker unit L is selected from the structural fragments shown in Table 7 of the specification.

20. The antibody-drug conjugate of claim 1, wherein the [P-L] conjugate fragment has any of the following general formulas: wherein the -J-B-G- fragment is as defined in any one of claims 15 to 19, preferably as defined in claim 19, the pharmaceutical P unit is a Ras inhibitor compound as defined in any one of claims 1 to 9, preferably a Ras inhibitor compound as defined in claim 7 or 9, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof; Preferably, the [P-L] conjugate fragment is the conjugate fragment shown in Table 8-1 of the specification.

21. The antibody-drug conjugate of claim 1, having a general formula selected from: where the -J-B-G- fragment is defined as in any one of claims 15-19, preferably as defined in claim 19; The drug P unit is a Ras inhibitor compound defined in any one of claims 1 to 9, preferably a Ras inhibitor compound defined in claim 7 or 9, or its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate; q is from 1 to 10, or is the average DAR value of a range composed of any two numerical values between 1 and 10, such as about 1-10, 1-8, 2-8, 3-10, 3-8, 4-10, 4-8, 6-8 or 6-10.

22. The drug-antibody conjugate according to any one of claims 1 to 21, wherein Ab is an antibody or an antigen-binding fragment thereof that binds to a tumor-specific antigen or a tumor-associated antigen, and the tumor-specific antigen or tumor-associated antigen is selected from: HER2, Her3, HER1 (ErbB1), HER4 (ErbB4), TROP2, Nectin-4, tissue factor, PD-L1, PD-1, PD-L1 / PD-L2, MET, CLDN18.2, KIT, CTLA-4, RPR1, adrenergic A2 receptor (EphA2), folate receptor (FRα), mesothelin, endothelin receptor, GCPII, IL-13Ra, BCMA, GD2, CLL-1, CA-IX, MUC1, 5T4, AOC3, ALK, AXL, C242, CA-125, CCL11, CCR5, CD2, CD3, CD4, CDS, CD15, CA15-3, CD16, CD18, CD19, CD20, CD21, CD22, CD25, CD30, CD32, CD33, CD37, CD38, CD44, CD52, CD56, CD64, CD66e, CD70, CD72, CD74, CD79a, CD79b, CD123, CD138, CD142, CD174, CD276, CDH3, CCD79b, CLDN9 / CLDN6, CA19-9, DPEP3, AGS-16, IGF1R, IGF2R, VEGFR1, VEGFR2, VEGFR3, PDGFR-α, PDGFR-β, EGFR, EGFRvIII, ENPP3, FcRH5, FRα, KAAG1, LIV-1, Mesothelin, cMet, ROR1, SLTRK6, TF, BMPR1B, E16, TOP1, STEAP1, 0772P, MUC16, Napi3b, Sema 5b, PSCAhIg, ETBR, RNF124, prostate cancer associated gene 1, TrpM4, teratoma-derived growth factor 1, C3DR, FcRH2, NCA, MDP, IL20R-α, Brevican, EphB2R, ASLG659, prostate stem cell antigen precursor, GEDA, BAFF-R, CXCR5, HLA-DOB, P2X5, LY64, FcRH1, IRTA2, TENB2, integrin α5β6, integrin α4β7, FGF2, FGFR1, FGFR2, FGFR3, FGFR4, PSMA, Somatostatin receptor, RANK, SLAMF7, ITGB6, CEACAM5, CA9, EGFRvlll, IL2RA, AXL receptor tyrosine kinase, TGF-βR, TNFRSF8, cancer / testis associated antigen, CLEC14A, GRP78, stem cell specific antigen, ASG-5, PRR4, GUCY2C, SLC39A6, TPBG, tumor associated antigen CA242, FOLR1, GPNMB, HAVCR1, prostate tumor target Mindin, VTCN1, PTK7 protein tyrosine kinase 7, macrophage stimulating 1 receptor, TACSTD2, CA6, DLL3, DLL4, EpCAM, FAP, DKK-1, Endoglin, VCAM1, GPC3, DR5, ASCT2, B7H1, B7H3, B7H4, or any combination thereof; Preferably, the tumor-specific antigen or tumor-associated antigen is selected from AXL, B7H1, B7H3, B7H4, BCMA, CD16, CD19, CD22, CD25, CD30, CD32, CD33, CD44, CD64, CD70, CD74, CD79, CD138, CD142, CD276, CDH3, CEACAM5, Claudin 18.2, CLDN9 / CLDN6, DPEP3, EGFR, ENPP3, EphA, FcRH5, FOLR1, FRα, GCPII, HER2, HER3, KAAG1, KIT, LIV-1, Mesothelin, cMet, MUC1, Nectin-4, PD-L1, PD-L1 / PD-L2, PSMA, ROR1, RPR1, TF, TOP1, TROP2, or any combination thereof; More preferably, the tumor-specific antigen or tumor-associated antigen is selected from HER2, Claudin 18.2, EGFR, TROP2, Nectin-4, or a combination of EGFR and Met.

23. The drug-antibody conjugate of any one of claims 1 to 22, wherein: The Ab comprises three heavy-chain complementarity-determining regions (HCDRs) that specifically bind to HER2 and three light-chain complementarity-determining regions (LCDRs), wherein: according to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 6, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 7, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 8, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 3, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 4, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 5; or the Ab comprises three heavy-chain complementarity-determining regions (HCDRs) that specifically bind to Trop2 and three light-chain complementarity-determining regions (LCDRs), wherein: according to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 18, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 19, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 20, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 15, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 16, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 17; or the Ab comprises three heavy-chain complementarity-determining regions (HCDRs) that specifically bind to Claudin18.2 and three light-chain complementarity-determining regions (LCDRs), wherein: according to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:29, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:30, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:31, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:26, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:27, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:28; or said Ab comprises three heavy chain complementarity determining regions (HCDRs) that specifically bind to EGFR and three light chain complementarity determining regions (LCDRs), wherein: according to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:40, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:41, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:42, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:37, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:38, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:39; or said Ab comprises three heavy chain complementarity determining regions (HCDRs) that specifically bind to Nectin4 and three light chain complementarity determining regions (LCDRs), wherein: according to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:72, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:73, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:74, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:69, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:70, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:71; or said Ab comprises a first set of complementarity determining regions that specifically bind to EGFR and a second set of complementarity determining regions that specifically bind to MET, wherein, said first set of complementarity determining regions comprises three heavy chain complementarity determining regions (HCDRs) and three light chain complementarity determining regions (LCDRs), wherein: according to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:49, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:50, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:51, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:52, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:53, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:54, The second set of complementarity-determining regions comprises 3 heavy-chain complementarity-determining regions (HCDRs) and 3 light-chain complementarity-determining regions (LCDRs), wherein: according to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:55, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:56, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:57, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:58, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:59, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:

60.

24. The drug-antibody conjugate of any one of claims 1 to 22, wherein the Ab comprises a heavy-chain variable region and a light-chain variable region, wherein the heavy-chain variable region comprises the amino acid sequence of SEQ ID NO:10, and wherein the light-chain variable region comprises the amino acid sequence shown in SEQ ID NO:9; or wherein the heavy-chain variable region comprises the amino acid sequence of SEQ ID NO:22, and wherein the light-chain variable region comprises the amino acid sequence shown in SEQ ID NO:21; or wherein the heavy-chain variable region comprises the amino acid sequence of SEQ ID NO:33, and wherein the light-chain variable region comprises the amino acid sequence shown in SEQ ID NO:32; or wherein the heavy-chain variable region comprises the amino acid sequence of SEQ ID NO:44, and wherein the light-chain variable region comprises the amino acid sequence shown in SEQ ID NO:43; or wherein the heavy-chain variable region comprises the amino acid sequence of SEQ ID NO:76, and wherein the light-chain variable region comprises the amino acid sequence shown in SEQ ID NO:75; or wherein the Ab comprises a first heavy-chain variable region and a first light-chain variable region and a second heavy-chain variable region and a second light-chain variable region, wherein the first heavy-chain variable region and the first light-chain variable region respectively comprise the amino acid sequences of SEQ ID NO:61 and SEQ ID NO:62, and wherein the second heavy-chain variable region and the second light-chain variable region respectively comprise the amino acid sequences shown in SEQ ID NO:63 and SEQ ID NO:

64.

25. The drug-antibody conjugate of any one of claims 1 to 22, wherein the Ab comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:2, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:1; or (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:14, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:13; or (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:25, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:24; or (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (b) A light chain comprising the amino acid sequence of SEQ ID NO:35; or (a) A heavy chain comprising the amino acid sequence of SEQ ID NO:76, and (b) A light chain comprising the amino acid sequence of SEQ ID NO:75, or (a) A first heavy chain comprising the amino acid sequence of SEQ ID NO:45, (b) A first light chain comprising the amino acid sequence of SEQ ID NO:46, (c) A second heavy chain comprising the amino acid sequence of SEQ ID NO:47, and (d) A second light chain comprising the amino acid sequence of SEQ ID NO:

48.

26. The drug - antibody conjugate according to any one of claims 1 to 22, wherein the Ab is selected from trastuzumab or an antibody fragment thereof, or another anti - human HER2 antibody that recognizes the same epitope or competes with it for binding to human HER2, preferably trastuzumab; or wherein the Ab is selected from sacituzumab or an antibody fragment thereof, or another anti - human TROP2 antibody that recognizes the same epitope or competes with it for binding to human TROP2, preferably sacituzumab; or wherein the Ab is selected from zotuximab or an antibody fragment thereof, or another anti - human Claudin18.2 antibody that recognizes the same epitope or competes with it for binding to human Claudin18.2, preferably zotuximab; or wherein the Ab is selected from cetuximab or an antibody fragment thereof, or another anti - human EGFR antibody that recognizes the same epitope or competes with it for binding to human EGFR, preferably cetuximab; or wherein the Ab is selected from Enfortumab or an antibody fragment thereof, or another anti - human Nectin4 antibody that recognizes the same epitope or competes with it for binding to human Nectin4, preferably Enfortumab; or wherein the Ab is selected from amivantamab or an antibody fragment thereof, or another anti - human EGFR and MET antibody that recognizes the same epitope or competes with it for binding to human EGFR and MET, preferably amivantamab.

27. The drug - antibody conjugate, which is selected from: or its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates; Preferably, the drug - antibody conjugate of Examples 1 - 94 or its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates.

28. A pharmaceutical composition comprising the drug - antibody conjugate according to any one of claims 1 - 27 and one or more pharmaceutically acceptable excipients.

29. The pharmaceutical composition of claim 28, which is administered intravenously, intratumorally, subcutaneously, intramuscularly, orally, intranasally, intrathecally, transdermally or topically, preferably by intravenous, intraperitoneal, subcutaneous or intramuscular administration.

30. The antibody - drug conjugate according to any one of claims 1 - 27 or the pharmaceutical composition according to claims 28 or 29, for the treatment or prevention of diseases mediated by Ras mutant proteins, such as KRas mutant proteins, specifically KRas G12D mutant proteins, preferably for the treatment or prevention of hyperproliferative diseases, more preferably for the treatment or prevention of tumors.

31. Use of an antibody-drug conjugate according to any one of claims 1-27 or a pharmaceutical composition according to claim 28 or 29 for treating or preventing a disease mediated by a Ras mutant protein, such as a KRas mutant protein, specifically a KRas G12D mutant protein, preferably a hyperproliferative disease, more preferably a tumor.

32. Use of an antibody-drug conjugate according to any one of claims 1-27 or a pharmaceutical composition according to claim 28 or 29 for preparing a medicament for treating or preventing a disease mediated by a Ras mutant protein, such as a KRas mutant protein, specifically a KRas G12D mutant protein, preferably a hyperproliferative disease, more preferably a tumor.

33. A method for treating or preventing a disease mediated by a Ras mutant protein, such as a KRas mutant protein, specifically a KRas G12D mutant protein, preferably a hyperproliferative disease, more preferably a tumor, which comprises administering to a human or an animal an antibody-drug conjugate according to any one of claims 1-27 or a pharmaceutical composition according to claim 28 or 29.

34. The antibody-drug conjugate of claim 30, or the pharmaceutical composition of claim 28 or 29, the use of claim 31 or 32, or the method of claim 33, wherein the proliferative disease or tumor includes solid tumors and hematogenous tumors, and all pre-cancerous cells, cancer cells and tissues, selected from lung adenocarcinoma, lung cancer (including lung squamous cell carcinoma and non-small cell lung cancer, small cell lung cancer), bone cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, skin cancer, head and neck cancer (including head and neck squamous cell carcinoma), melanoma (including cutaneous or uveal melanoma), squamous cell carcinoma, anal area cancer, testicular cancer, urethral cancer, ureteral cancer, penile cancer, prostate cancer (including hormone-refractory prostate cancer), bladder cancer, uterine cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, gastric cancer, gastric adenocarcinoma, colon cancer, rectal cancer, colorectal cancer, liver cancer, breast cancer (including metastatic breast cancer, triple-negative breast cancer (TNBC)), esophageal cancer, small intestine cancer, lip cancer, laryngeal cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, peritoneal cancer, gastrointestinal stromal tumor, gastroesophageal junction (GEJ) cancer, mesothelioma, biliary tract cancer, hepatocellular tumor, seminoma, soft tissue sarcoma, osteosarcoma, urothelial carcinoma, sweat gland cancer, endocrine system cancer, thyroid cancer, medullary thyroid cancer, follicular thyroid cancer, papillary thyroid cancer, parathyroid cancer, renal cancer, renal parenchymal cancer, renal cell carcinoma, renal pelvic cancer, adrenal cancer, brain cancer such as glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral primitive neuroectodermal tumor, glioblastoma multiforme (including glioblastoma multiforme), neuroblastoma; chronic or acute leukemia, Hodgkin's disease, lymphoma (including lymphocytic lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt lymphoma, adult T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), primary CNS lymphoma), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CLL) and lymphocytic carcinoma, acute myelogenous leukemia (AML), myelogenous leukemia (chronic myelogenous leukemia (CML), central nervous system tumors (CNS), spinal tumors, brainstem glioma or pituitary adenoma.

35. The antibody-drug conjugate or pharmaceutical composition, use, or method of claim 34, wherein the tumor is selected from lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer, bile duct cancer, leukemia, and ovarian cancer.

36. A compound fragment having any of the general formulas (II'-3'-1) to (II'-3'-12) and (II'-4'-1) defined in claim 19, preferably the structural fragments shown in Table 7 of the specification.

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