Antibody-drug conjugates for delivery of cytotoxic agents

Abstract

There is provided a compound having the structure of formula (R-l): LG-RG-LRM-MOI, or a salt thereof, where: LG is a group comprising a target binding moiety that binds to Bentuximab or a biosimilar analog thereof, LRM is a linking group comprising formula (I); and MOI is a moiety of interest that includes monomethyl aurestatin D (MMAD), monomethyl aurestatin E (MMAE), or monomethyl aurestatin F (MMAF). Also provided are a conjugate, a compound having the structure of formula (R-l) and bentuximab or a biologically similar analog thereof, and methods of using the conjugate and the compound to treat various cancerous conditions. (I)

Description

Technical Field

[0001] This invention relates to antibody-drug conjugates for delivering cytotoxic agents. Specifically, this invention relates to antibody-drug conjugates for delivering antimitotic agents to cancer cells. Background Technology

[0002] Antibody-drug conjugates can be used for a variety of purposes, such as as diagnostic reagents, therapeutic agents (e.g., antigen-targeted therapies), etc. Existing drug-antibody conjugation technologies may face various challenges. For example, the reaction of conjugating the moiety of interest (e.g., the detection moiety, the drug moiety, etc.) to the target molecule (e.g., the antibody for the antibody-drug conjugate) may be inefficient and / or have low selectivity (e.g., conjugation at various positions on the target molecule (e.g., various amino acid residues of the antibody), and the resulting conjugate compositions are often highly heterogeneous, comprising multiple separate conjugate types, each independently possessing its own copy number of the moiety of interest, conjugation position (e.g., different amino acid residues of the protein), etc.

[0003] Approved antibody-drug conjugates used for delivering cytotoxic agents to cancer cells include PADCEV (enfortumab vedotin) and ADCETRIS (brentuximab vedotin), both of which can be used to deliver monomethylolpropionate E (MMAE). Current drug-antibody conjugation techniques include conjugation via lysine residues, conjugation via reduced interchain disulfide bonds, and conjugation via engineered cysteine ​​residues. Figure 1. Each of these techniques has disadvantages. Lysine conjugation produces a wide range of drug-antibody ratios (DARs), where each lysine is a statistically probabilistic marker. The result is millions of possible drug-antibody conjugates. High DARs indicate a predisposition to CMC problems such as aggregation. Some species may readily release their conjugated drug, resulting in toxicity. Conjugation via reduced interchain disulfide bonds also produces a variety of antibody-conjugated species. Drug linkage can be reversed over time, releasing free drug. Existing techniques using engineered cysteine ​​conjugations involve a wide range of antibody manipulation or engineering.

[0004] There is a need for drug-antibody conjugates with predictable DAR and conjugation sites that do not cause "leakage" of the conjugated drug, and without the need for extensive antibody engineering. This disclosure meets the stated needs and has additional advantages. Summary of the Invention

[0005] This invention relates to site-specific antibody conjugation for generating conjugates with high homogeneity.

[0006] In one embodiment, a compound is provided having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes The linking group; and The MOI is the portion of interest that includes monomethylopilotrine D (MMAD), monomethylopilotrine E (MMAE), or monomethylopilotrine F (MMAF).

[0007] In another embodiment, a method for preparing a pharmaceutical agent having the structure of formula (PI) is provided: P-(L PM -MOI)2, (PI) or its salt, wherein: P is a portion of bentuximab or a biosimilar of it; Each L PM It includes The linking group; and Each MOI is the portion of interest that includes monomethylopilotrine D (MMAD), monomethylopilotrine E (MMAE), or monomethylopilotrine F (MMAF).

[0008] The method may include the following steps: (1) Contacting bentuximab or a bio-similar thereof with a reaction coupler having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes Linking groups; The MOI is the portion of interest including monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF); and (2) Forming a drug having the structure of formula (PI).

[0009] In another embodiment, a pharmaceutical agent is provided having the structure of formula (PI): P-(L PM -MOI)2, (PI) or its salt, wherein: P is a portion of bentuximab or a biosimilar of it; Each L PM It includes The linking group; and Each MOI is the portion of interest that includes monomethylopilotrine D (MMAD), monomethylopilotrine E (MMAE), or monomethylopilotrine F (MMAF).

[0010] In another embodiment, a method for preparing a pharmaceutical agent having a (P-II) structure is provided: P-(NH-L PM -MOI)2, (P-II) in: P-NH is a moiety of benzoxicam or a biosimilar thereof, wherein the moiety of benzoxicam or a biosimilar thereof comprises a lysine residue having a terminal NH group. L PM It includes The linking group; and MOI is or includes monomethyl aurestatin D (MMAD), monomethyl aurestatin E (MMAE), or monomethyl aurestatin F (MMAF).

[0011] The method may include the following steps: (1) Providing benzoxicam or a biosimilar thereof, said benzoxicam or a biosimilar thereof having the structure P-(NH2)2, wherein each NH2 is a terminal amino group of a lysine residue; and (2) Contacting P-(NH2)2 with a reaction coupler having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes The linking group; and MOI is the part of interest, namely monomethyl aurestatin D (MMAD), monomethyl aurestatin E (MMAE), or monomethyl aurestatin F (MMAF).

[0012] In another embodiment, a pharmaceutical agent is provided having a (P-II) structure: P-(NH-L PM -MOI)2, (P-II) in: P-NH is a biosimilar of benzoximab or the biosimilar thereof, which includes a lysine residue having a terminal NH group. L PM It includes The linking group; and The MOI is the portion of interest that includes monomethylopilotrine D (MMAD), monomethylopilotrine E (MMAE), or monomethylopilotrine F (MMAF).

[0013] In one embodiment, a compound is provided having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes The linking group; and The MOI is the portion of interest that includes monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF). The bentuximab contains an IgG heavy chain, wherein the IgG heavy chain includes K246 or K248, and The target-binding portion is configured to bind to benzoxicam such that the reactive group is close to K246 or K248 of the benzoxicam IgG heavy chain, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction comprising L RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0014] LG-RG can be .

[0015] MOI can include .

[0016] In another embodiment, a method is provided for treating Hodgkin lymphoma in a subject requiring such treatment, the method comprising administering to the subject a pharmaceutically effective amount of the aforementioned agent.

[0017] In another embodiment, a method is provided for treating a subject with systemic anaplastic large cell lymphoma who requires such treatment, the method comprising administering to the subject a pharmaceutically effective amount of the above-described agent.

[0018] In another embodiment, a method is provided for treating a subject with primary cutaneous anaplastic large cell lymphoma who requires such treatment, the method comprising administering to the subject a pharmaceutically effective amount of the above-described agent.

[0019] In another embodiment, a method is provided for treating CD30-expressing mycosis fungoides in a subject requiring such treatment, the method comprising administering to the subject a pharmaceutically effective amount of the above-described agent.

[0020] In another embodiment, a method is provided for treating cutaneous T-cell lymphoma in a subject requiring such treatment, the method comprising administering to the subject a pharmaceutically effective amount of the above-described agent.

[0021] In another embodiment, a method is provided for selectively targeting tumor cells expressing the CD30 antigen in a subject, the method comprising administering the above-described agent to the subject.

[0022] In another embodiment, a composition is provided comprising: The first compound has the structure of formula (P-II): PNL PM -MOI (P-II) in: PN is a biosimilar of benzoxicam or a biosimilar thereof, which includes lysine residues; L PM It includes The linking group; and The MOI is the portion of interest including monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF); and The second compound has the following structure: LG-OH (LG-I) LG is a group that includes a target-binding moiety that binds to bentuximab or its bio-similar analogues.

[0023] The composition may further include: A third compound, wherein the third compound has the formula (RI): LG-RG-L RM -MOI(RI) LG is a group comprising a target-binding moiety that binds to tuftuximab or its bio-similar analogues, said group being identical to LG in formula (LG-I); RG is a reactive group; L RM It is a linking group, which is identical to the LRM in formula (P-II); and MOI is the part of interest, which is the same as the MOI in equation (P-II); and The fourth compound has the formula (R-III): HO-RG-L RM -MOI (R-III) Or a combination thereof. Attached Figure Description

[0024] These and / or other aspects will become apparent and more readily understood from the following description of embodiments taken in conjunction with the accompanying drawings, wherein: Figure 1 shows the spectral characterization of the conjugate of bentuximab and reagent A according to an embodiment of the present invention; Figure 2 illustrates the properties of site-specific antibody-drug conjugates according to an embodiment of the present invention; Figure 3 illustrates the engineering and chemical activation of alternative antibody-drug conjugate proteins; Figure 4 illustrates potential best-in-class antibody-drug conjugates according to embodiments of the present invention; Figure 5 illustrates the pharmacokinetic (PK) studies of Adcetris® and antibody-drug conjugates according to embodiments of the present invention; Figure 6 illustrates the potential for superior efficacy of the antibody-drug conjugates according to embodiments of the present invention compared to Adcetris®; Figure 7 illustrates the improved survival rate in mouse models using the antibody-drug conjugate according to embodiments of the present invention, compared to Adcetris®; and Figure 8 shows the results of a single-dose, 14-day mouse tumor xenograft study in the case of an antibody-drug conjugate according to an embodiment of the present invention. Detailed Implementation

[0025] The following detailed description is provided to assist those skilled in the art in practicing the invention. Exemplary embodiments will be described in detail below. However, these embodiments are merely exemplary, and the present disclosure is not limited thereto, but is defined by the scope of the appended claims. Modifications and variations can be made to the embodiments described herein without departing from the spirit or scope of this disclosure.

[0026] Therefore, embodiments are described below only by reference to structures and schemes to explain various aspects of this specification. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. The term "or" means "and / or". Expressions such as "at least one of" modify the entire list of elements without modifying the individual elements in the list when following a list of elements.

[0027] It should be understood that when an element is referred to as being "on" another element, it can be in direct contact with said other element, or there may be an intermediate element between them. In contrast, when an element is referred to as being "directly on" another element, there is no intermediate element.

[0028] It should be understood that although the terms first, second, third, etc., may be used herein to describe various elements, components, regions, layers, and / or segments, these elements, components, regions, layers, and / or segments should not be limited by these terms. These terms are used only to distinguish one element, component, region, layer, or segment from another. Therefore, the first element, component, region, layer, or segment discussed below may be referred to as the second element, component, region, layer, or segment without departing from the teachings of the embodiments of the present invention.

[0029] It should be understood that the terms “comprises and / or comprising” or “includes and / or including”, when used in this specification, specify the presence of the stated features, regions, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0030] Unless otherwise defined, all technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for the purpose of describing particular embodiments only and is not intended to be limiting. It should also be understood that terms (such as those defined in common dictionaries) should be interpreted as having the same meaning as they have in the context of the relevant technology and this disclosure, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0031] As used herein, unless expressly specified otherwise, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application. Where a term is not expressly defined herein, it shall be given its commonly accepted meaning by one of ordinary skill in the art in the context of its application in describing the uses of the invention.

[0032] The article "a (a and an)" refers to one or more ( Right now (at least one) the grammatical object of the article, unless the context clearly indicates otherwise. For example, "an element" means one element or more elements.

[0033] As used herein, unless otherwise specifically defined, the term “substituted” means a group substituted by at least one hydrogen atom of a deuterium, halogen (-F, -Cl, -Br, -I), hydroxyl (-OH), amino (-NH2), carboxyl (-CO2H), substituted or unsubstituted C1-C10 amino, nitro (-NO2), C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C1-C10 alkoxy, C1 to C10 trifluoroalkyl or cyano (-CN) such as trifluoromethyl (-CF3), etc., rather than a substituent or compound.

[0034] As used herein, the term “bentuximab” refers to the antibody cAC10 targeting CD30. As used herein, the term “biosimilar analog of bentuximab” or “biosimilar analog” refers to a composition of substances that is substantially the same copy of bentuximab and has been formally approved by a regulatory agency in any country or jurisdiction worldwide.

[0035] Other aspects will be set forth in part in the description which follows, and will be apparent in part from the description.

[0036] The starting materials that can be used to prepare the pharmaceutical compositions of the present invention are readily available commercially or can be prepared by those skilled in the art.

[0037] A solvate is a compound formed through solvation, which is a combination of solvent molecules and solute molecules or ions. Solvation is the interaction between the solute and the solvent, which stabilizes the solute species in solution. Solvation can also refer to the solvated state in which ions in the solution recombine due to solvent molecules. The differences in the physical properties of different solvates and their polymorphic forms are caused by the different orientations of adjacent molecules in the solid and intermolecular interactions. Polymorphic forms of compounds or solvates can be distinguished by X-ray diffraction and other methods such as infrared spectroscopy or Raman spectroscopy.

[0038] In one embodiment, a compound is provided having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes The linking group; and The MOI is the portion of interest that includes monomethylopistatin D, monomethylopistatin E, or monomethylopistatin F.

[0039] LG-RG may be or may include .

[0040] L RM It can be or can include .

[0041] MOI can be or can include .

[0042] The target-binding portion can be configured to bind to benzoxicam or its biosimilars such that the reactive group is close to K246 or K248 of the benzoxicam IgG heavy chain or its biosimilars, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction of which can result in L RMThe -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0043] The target-binding portion can be configured to bind to benzoxicam or a biosimilar thereof, such that the reactive group is close to K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction comprising L RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0044] In another embodiment, a compound is provided having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; LG-RG may be or may include ; L RM It can be or can include ;and MOI can be or can include .

[0045] The target-binding portion can be configured to bind to benzoxicam or its biosimilars such that the reactive group is close to K246 or K248 of the benzoxicam IgG heavy chain or its biosimilars, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction of which can result in L RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0046] The target-binding portion can be configured to bind to benzoxicam or its bio-analysts such that the reactive group is close to K248 of the benzoxicam IgG heavy chain or its bio-analysts, thereby enabling a reaction between K248 and the reactive group, the reaction of which can result in L RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0047] In another embodiment, a method for preparing a pharmaceutical agent having the structure of formula (PI) is provided: P-(L PM -MOI)2, (PI) or its salt, wherein: P is bentuximab or a biosimilar of it; Each L PM It includes The linking group; and Each MOI is the portion of interest that includes monomethylopistatin D (MMAD), monomethylopistatin E (MMAE), or monomethylopistatin F (MMAF). The method includes the following steps: (1) Contacting bentuximab or a bio-similar thereof with a reaction coupler having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes Linking groups; The MOI is the portion of interest including monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF); and (2) Forming a drug having the structure of formula (PI).

[0048] LG-RG may be or may include .

[0049] L RM It can be or can include .

[0050] MOI can be or can include .

[0051] The target-binding portion of the reagent conjugate can be configured to bind to benzoxicam or its bio-analysts such that the reactive group is close to K246 or K248 of the benzoxicam IgG heavy chain or its bio-analysts, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction of which can result in L RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0052] The target-binding portion of the reagent conjugate can be configured to bind to benzoxicam or a biosimilar thereof, such that the reactive group is close to K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction comprising L RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0053] The contact and formation steps can be carried out in a chemical reaction.

[0054] In another embodiment, a pharmaceutical agent is provided having the structure of formula (PI): P-(L PM -MOI) n , (PI) or its salt, wherein: P is bentuximab or a biosimilar of it; Each L PM It includes Linking groups; Each MOI is the portion of interest including monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF); and n is 1, 2, 3 or 4.

[0055] L RM It can be or can include .

[0056] MOI can include .

[0057] In another embodiment, a pharmaceutical agent is provided having the structure of formula (PI): P-(L PM -MOI)2, (PI) or its salt, wherein: P is bentuximab or a biosimilar of it; Each L PM It includes The linking group; and Each MOI is the portion of interest that includes monomethylopilotrine D (MMAD), monomethylopilotrine E (MMAE), or monomethylopilotrine F (MMAF).

[0058] L RM It can be or can include .

[0059] MOI can include .

[0060] Each L PM -MOI can be linked to K246 or K248 of the benzoxicam IgG heavy chain or its biosimilar analogue.

[0061] Each L PM -MOI can be linked to K248 of the benzoxicam IgG heavy chain or its biosimilar analogue.

[0062] In another embodiment, a method for preparing a pharmaceutical agent having a (P-II) structure is provided: P-(NH-L PM -MOI) n , (P-II) in: P-NH is a biosimilar of benzoximab or the biosimilar thereof, which includes a lysine residue having a terminal NH group. L PM It includes Linking groups; The MOI is the portion of interest including monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF); and n is 1, 2, 3, or 4. The method includes the following steps: (1) Providing benzoxicam or a biosimilar thereof, said benzoxicam or a biosimilar thereof having the structure P-(NH2)2, wherein each NH2 is a terminal amino group of a lysine residue; and (2) Make P-(NH2) nContact with the reaction partner, the reaction partner having a structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes Linking groups; The MOI is the portion of interest including monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF); and n is 1, 2, 3, and 4.

[0063] In another embodiment, a method for preparing a pharmaceutical agent having a (P-II) structure is provided: P-(NH-L PM -MOI)2, (P-II) in: P-NH is a biosimilar of benzoximab or the biosimilar thereof, which includes a lysine residue having a terminal NH group. L PM It includes The linking group; and The MOI is the portion of interest that includes monomethylopistatin D (MMAD), monomethylopistatin E (MMAE), or monomethylopistatin F (MMAF). The method includes the following steps: (1) Providing benzoxicam or a biosimilar thereof, said benzoxicam or a biosimilar thereof having the structure P-(NH2)2, wherein each NH2 is a terminal amino group of a lysine residue; and (2) Contacting P-(NH2)2 with a reaction coupler having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes The linking group; and The MOI is the portion of interest that includes monomethylopilotrine D (MMAD), monomethylopilotrine E (MMAE), or monomethylopilotrine F (MMAF).

[0064] LG-RG may be or may include .

[0065] L RM It can be or can include .

[0066] MOI can be or can include .

[0067] The target-binding portion of the reagent conjugate can be configured to bind to benzoxicam or its bio-analysts such that the reactive group is close to K246 or K248 of the benzoxicam IgG heavy chain or its bio-analysts, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction of which can result in L RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0068] The target-binding portion of the reagent conjugate can be configured to bind to benzoxicam or a biosimilar thereof, such that the reactive group is close to K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction comprising L RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0069] The contact and formation steps can be carried out in a chemical reaction.

[0070] In another embodiment, a pharmaceutical agent is provided having a (P-II) structure: P-(NH-L PM -MOI) n , (P-II) in: P-NH is a biosimilar of benzoximab or the biosimilar thereof, which includes a lysine residue having a terminal NH group. LPM It includes Linking groups; The MOI is the portion of interest including monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF); and n is 1, 2, 3 or 4.

[0071] L RM It can be or can include .

[0072] MOI can be or can include .

[0073] In another embodiment, a pharmaceutical agent is provided having a (P-II) structure: P-(NH-L PM -MOI)2, (P-II) in: P-NH is a biosimilar of benzoximab or the biosimilar thereof, which includes a lysine residue having a terminal NH group. L PM It includes The linking group; and The MOI is the portion of interest that includes monomethylopilotrine D (MMAD), monomethylopilotrine E (MMAE), or monomethylopilotrine F (MMAF).

[0074] L RM It can be or can include .

[0075] MOI can be or can include .

[0076] The lysine residue can be K246 or K248 of the benzoximab IgG heavy chain or its biosimilar.

[0077] Each lysine residue can be K248 of the benzoximab IgG heavy chain or its biosimilar analogue.

[0078] In another embodiment, a compound is provided having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG can be a group that includes a target-binding moiety that binds to bentuximab or its bio-similar analogues. RG can be a reactive group; L RM It can include The linking group; and The MOI can be the portion of interest including monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF). The bentuximab or its biosimilars may include IgG heavy chains, said IgG heavy chains including K246 or K248, and The target-binding portion can be configured to bind to benzoxicam or its bio-similar analogues such that the reactive group is close to K246 or K248 of the benzoxicam IgG heavy chain or its bio-similar analogues, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction causing L... RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0079] LG-RG may be or may include .

[0080] MOI can be or can include .

[0081] The target-binding portion can be configured to bind to benzoxicam or its bio-analysts such that the reactive group is close to K248 of the benzoxicam IgG heavy chain or its bio-analysts, thereby enabling a reaction between K248 and the reactive group, the reaction of which can result in L RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0082] Target binding part In some embodiments, the target binding portion is an antibody binding portion. In some embodiments, the provided compounds and / or agents include an antibody binding portion. Various antibody binding portions can be used according to this disclosure. In some embodiments, the antibody binding portion is a generic antibody binding portion that can bind to antibodies with different Fab regions and different specificities. Among other things, compounds including such antibody binding portions can be used for conjugation to antibodies with different specificities. In some embodiments, the antibody binding portions of this disclosure (e.g., generic antibody binding portions) bind to Fc regions. In some embodiments, the antibody binding portion is capable of binding to tuftuximab or its biosimilar analogues.

[0083] According to this disclosure, various antibody binding moieties, including a universal antibody binding moieties, can be utilized. Certain antibody binding moieties and techniques for identifying and / or evaluating antibody binding moieties are described in WO 2019 / 023501 A1 and WO 2019 / 136442 A1, and are incorporated herein by reference. Those skilled in the art will understand that other techniques in the art can be applied to identify and / or evaluate antibody binding moieties according to this disclosure. In some embodiments, the antibody binding moieties comprise one or more amino acid residues, each amino acid residue being independently natural or non-natural.

[0084] In some embodiments, the target binding portion, such as a protein binding portion (e.g., an antibody binding portion (e.g., a universal antibody binding portion)), has The structure of or a salt form of , wherein: R 1 R 3 and R 5 Each of them is independently hydrogen or a group selected from the following optional substitution groups: C 1-6 Aliphatic compounds; 3-8 membered saturated or partially unsaturated monocyclic carbon rings; phenyl; 8-10 membered bicyclic aromatic carbon rings; 4-8 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 5-6 membered monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or 8-10 membered bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: R 1 and R 1' Optionally, together with its intermediate carbon atom, it forms a 3-8 member optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-8 member saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen or sulfur. R 3 and R 3'Optionally, together with its intermediate carbon atom, it forms a 3-8 member optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-8 member saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen or sulfur. R bonded to the same carbon atom 5 Groups and R 5' The group optionally forms, together with its intermediate carbon atom, a 3-8 membered saturated or partially unsaturated spirocyclic carbide ring or a 3-8 membered saturated or partially unsaturated spirocyclic heterocycle having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur; or Two Rs 5 The group optionally forms a C with its intermediate atom. 1-10 Optionally substituted divalent straight-chain or branched saturated or unsaturated hydrocarbon chains, wherein 1-3 methylene units of the chain are independently and optionally substituted by: -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2- or -Cy 1 -, where each -Cy 1 - Independently, it is a 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1' R 3' and R 5' Each of them is independently hydrogen or an optional substituted C. 1-3 Aliphatic compounds; R 2 R 4 and R 6 Each of them is independently hydrogen or an optional substituted C. 1-4 Aliphatic compounds, or: R 2 and R 1 Optionally together with its intermediate atom, it forms a 4-8 membered saturated or partially unsaturated monocyclic heterocycle with 1-2 independently selected heteroatoms chosen from nitrogen, oxygen or sulfur; R 4 and R 3 Optionally, together with its intermediate atom, it forms a 4-8 membered, optionally substituted, saturated or partially unsaturated monocyclic heterocycle having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur; or R 6 Group and its adjacent R 5 The group may optionally form, together with its intermediate atom, a 4-8 membered, optionally substituted, saturated or partially unsaturated monocyclic heterocycle having 1-2 independent heteroatoms selected from nitrogen, oxygen or sulfur; L 1It is the trivalent connector part; and Each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0085] In some embodiments, L 1 It is selected from C1-C having 1-5 heteroatoms. 20 Aliphatic compounds or C1-C 20 The trivalent group of the heteroaliphatic compound is optionally substituted, wherein one or more methylene units of the group are optionally and independently substituted with: -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S- or -C(O)O-.

[0086] In some embodiments, the target binding portion, such as a protein binding portion (e.g., an antibody binding portion (e.g., a universal antibody binding portion)), has The structure or its salt form, in: R 7 Each of them is independently hydrogen or a group selected from the following optional substitution groups: C 1-6 Aliphatic compounds; 3-8 membered saturated or partially unsaturated monocyclic carbon rings; phenyl; 8-10 membered bicyclic aromatic carbon rings; 4-8 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 5-6 membered monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or 8-10 membered bicyclic heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: R bonded to the same carbon atom 7 Groups and R 7' The group may optionally form, together with its intermediate carbon atom, a 3-8 member optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-8 member optionally substituted saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 independently selected heteroatoms from nitrogen, oxygen or sulfur. R 7' Each of them is independently hydrogen or an optional substituted C. 1-3 Aliphatic compounds; R 8 Each of them is independently hydrogen or an optional substituted C. 1-4 Aliphatic compounds, or: R8 Group and its adjacent R 7 The group optionally forms, together with its intermediate atom, a 4-8 membered, optionally substituted, saturated or partially unsaturated monocyclic heterocycle having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur; and R 9 It is hydrogen, and the C is optionally substituted. 1-3 Aliphatic compounds or -C(O)-.

[0087] In some embodiments, the antibody-binding portion, such as a universal antibody-binding portion, is or includes a peptide portion, such as having R c The structure of -(Xaa)z- or a part of its salt form, where R c Each of , z, and Xaa is independently as described herein. In some embodiments, one or more Xaa residues are independently non-natural amino acid residues. In some embodiments, the side chains of two or more amino acid residues may be linked together to form a bridge. For example, in some embodiments, the side chains of two cysteine ​​residues may form a disulfide bridge including -SS- (as in many proteins, which can be formed by two -SH groups).

[0088] In some embodiments, the target-binding portion, such as a protein-binding portion (e.g., an antibody-binding portion (e.g., a universal antibody-binding portion)), is or includes a cyclic peptide portion, such as having The structure or salt form of a portion thereof, wherein: Each Xaa is independently an amino acid or amino acid analog residue; t is 0-50; z is 1-50; L represents the connector section; Each R c Independently is -L a -R'; Each L a Independently covalent bonds, or selected from C1-C bonds having 1-5 heteroatoms. 20 Aliphatic compounds or C1-C 20 The optional substituted divalent group of the heteroaliphatic compound, wherein one or more methylene units of the group are optionally and independently replaced by: -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S- or -C(O)O-; Each -Cy- is independently a optionally substituted divalent monocyclic, bicyclic, or polycyclic group, wherein each monocyclic group is independently selected from C 3-20 Alicyclic rings, C 6-20 Aryl ring, 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-20 membered heterocyclic ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; Each R' is independently -R, -C(O)R, -CO2R, or -SO2R; Each R is independently -H or a group selected from the following optional substitution groups: C 1-30 Aliphatic compounds, having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 Aliphatic compounds, C 6-30 Aryl, C 6-30 Aryl aliphatic compounds, having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. 6-30 Aryl heteroaliphatic compounds, 5-30 membered heteroaryl groups having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclic groups having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or The two R groups optionally and independently form a covalent bond together, or: Two or more R groups on the same atom optionally and independently form, together with the atom, a 3-30 membered monocyclic, bicyclic, or polycyclic ring having 0-10 independently substituted heteroatoms selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to the atom; or Two or more R groups on two or more atoms optionally and independently form, together with an intermediate atom, a 3-30 member monocyclic, bicyclic or polycyclic atom having optional substitutions of 0-10 heteroatoms in addition to the intermediate atom.

[0089] In some embodiments, the heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0090] In some embodiments, the target binding portion is or includes R c -(Xaa)z- or its salt form, wherein each variable is as described herein. In some embodiments, the protein-binding portion is or includes R c -(Xaa)z- or its salt form, wherein each variable is as described herein. In some embodiments, the antibody-binding portion, such as a universal antibody-binding portion, includes R c -(Xaa)z- or its salt form, where each variable is as described herein. In some embodiments, the target binding portion is or includes Or its salt form, wherein each variable is as described herein. In some embodiments, the protein-binding portion is or includes Or its salt form, wherein each variable is as described herein. In some embodiments, the antibody-binding portion, such as a universal antibody-binding portion, is or includes Or its salt form, wherein each variable is as described herein. In some embodiments, the antibody-binding portion, such as a universal antibody-binding portion, is R. c -(Xaa)z- or Or its salt form, and is or includes a peptide unit. In some embodiments, -(Xaa)z- is or includes a peptide unit. In some embodiments, amino acid residues may form bridges, for example, optionally by a linker portion (e.g., L) formed by a side chain; for example, as in many polypeptides, cysteine ​​residues may form disulfide bridges. In some embodiments, the peptide unit includes amino acid residues (e.g., at a physiological pH of about 7.4, "positively charged amino acid residues", Xaa) P For example, an amino acid having a positively charged side chain of formula AI. In some embodiments, the peptide unit includes R. In some embodiments, at least one Xaa is R. In some embodiments, the peptide unit is or includes APAR. In some embodiments, the peptide unit is or includes RAPA. In some embodiments, the peptide unit includes an amino acid residue, such as an amino acid having a side chain of formula AI with an aromatic group (“aromatic amino acid residue”, Xaa). A In some embodiments, the peptide unit comprises positively charged amino acid residues and aromatic amino acid residues. In some embodiments, the peptide unit comprises W. In some embodiments, the peptide unit comprises positively charged amino acid residues and aromatic amino acid residues. In some embodiments, the peptide unit is or includes Xaa. A XaaXaa P Xaa P In some embodiments, the peptide unit is or includes Xaa. P Xaa P XaaXaa A In some embodiments, the peptide unit is or includes Xaa. P Xaa A Xaa P In some embodiments, the peptide unit is or comprises two or more Xaa molecules. P Xaa A Xaa P In some embodiments, the peptide unit is or includes Xaa. P Xaa A Xaa P XaaXaa P Xaa A XaaP In some embodiments, the peptide unit is or includes Xaa. P Xaa P Xaa A Xaa A Xaa P In some embodiments, the peptide unit is or includes Xaa. P Xaa P Xaa P Xaa A In some embodiments, the peptide unit is or comprises two or more Xaa molecules. A Xaa A Xaa P In some embodiments, the peptide residues include one or more proline residues.

[0091] In some embodiments, the target binding portion is or includes the optionally substituted portions of Table A-1. In some embodiments, the protein binding portion is or includes the optionally substituted portions of Table A-1. In some embodiments, the antibody binding portion, such as a universal antibody binding portion, is or includes the optionally substituted portions of Table A-1. In some embodiments, the target binding portion is selected from Capable A-1. In some embodiments, the protein binding portion is selected from Capable A-1. In some embodiments, the antibody binding portion, such as a universal antibody binding portion, is selected from Capable A-1. In some embodiments, the C-terminus and / or N-terminus are optionally capped (e.g., for the C-terminus, by converting -COOH to -C(O)N(R')2, such as -C(O)NH2; for the N-terminus, by adding R'C(O)-, such as CH3C(O)-, to an amino group).

[0092] Table A-1. Exemplary antibody binding portions. In some embodiments, the target binding portion is the antibody binding portion as described herein. In some embodiments, the protein binding portion is the antibody binding portion as described herein. In some embodiments, the amino group of -COOH and / or amino acid residues, such as the amino group located at the C-terminus or N-terminus, is optionally capped. For example, in some embodiments, the -COOH group (e.g., C-terminal -COOH) is amidated (e.g., converted to -CON(R')2, for example, -C(O)NHR (e.g., -C(O)NH2)), and in some embodiments, the amino group, such as -NH2 (e.g., N-terminal -NH2), is capped with R'- or R'C(O)- (e.g., in some embodiments, by converting -NH2 to -NHR' (e.g., -NHC(O)R, (e.g., -NHC(O)CH3)).

[0093] In some embodiments, the target binding portion is or includes optionally substituted A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, A-17, A-18, A-19, A-20, A-21, A-22, A-23, A-24, A-2 5. A-26, A-27, A-28, A-29, A-30, A-31, A-32, A-33, A-34, A-35, A-36, A-37, A-38, A-39, A-40, A-41, A-42, A-43, A-44, A-45, A-46, A-47, A-48, A-49, or A-50, each of which is optionally substituted. In some embodiments, this target-binding portion is an antibody-binding portion. In some embodiments, this target-binding portion is a universal antibody-binding portion.

[0094] In some embodiments, the target binding portion, such as a protein binding portion (e.g., an antibody binding portion (e.g., a universal antibody binding portion), comprises a peptide unit and is linked via a C-terminal linker portion of the peptide unit. In some embodiments, the target binding portion is linked to the linker portion via the N-terminus of the peptide unit. In some embodiments, the target binding portion is linked to a linker group via a side chain group of the peptide unit. In some embodiments, the antibody binding portion (e.g., a universal antibody binding portion) comprises a peptide unit and is optionally linked to the target binding portion via a linker portion via the C-terminus of the peptide unit. In some embodiments, the target binding portion, such as a protein binding portion (e.g., an antibody binding portion (e.g., a universal antibody binding portion), comprises a peptide unit and is optionally linked to the target binding portion via a linker portion via the N-terminus of the peptide unit. In some embodiments, the target binding portion, such as a protein binding portion (e.g., an antibody binding portion (e.g., a universal antibody binding portion), comprises a peptide unit and is optionally linked to the target binding portion via a linker portion via the side chain of the peptide unit.

[0095] reactive groups In some embodiments, the provided compound, such as a compound that can be used as a reactive partner, includes a reactive group (e.g., RG). As illustrated herein, in many embodiments, in the provided compound, the reactive group (e.g., RG) is positioned between a first group (e.g., LG) and the portion of interest (e.g., MOI), and is optionally and independently connected to the first group and the portion of interest by a linking group. In some embodiments, RG is a reactive group as described herein.

[0096] In some embodiments, as shown herein, when used in compounds that do not include a target-binding moiety, the reactive group reacts slowly and provides, in some embodiments, a low level of essentially no conjugation between the moiety of interest and the target agent. As shown herein, among other things, the combination of the reactive group and the target-binding moiety in the same compound (e.g., in a compound of formula RI or a salt thereof) promotes the reaction between the reactive group and the target agent, enhances reaction efficiency, reduces side reactions, and / or improves reaction selectivity (e.g., with respect to the target site in which the moiety of interest is conjugated with the target agent).

[0097] The reactive groups in the provided compounds can react with various types of groups in the target drug. In some embodiments, the reactive groups in the provided compounds selectively react with amino groups (e.g., -NH2 groups on the side chains of lysine residues of proteins) of the target drug. In some embodiments, when used in the provided compounds (e.g., compounds of formula RI or salts thereof), the reactive groups selectively react with specific sites of the target drug (e.g., K246, K248, K288, K290, K317, etc. of IgG1, K251, K253, etc. of IgG2, K239, K241, etc. of IgG4, as illustrated in the examples herein). In some embodiments, the site is K246 or K248 of the antibody heavy chain. In some embodiments, the site is K246 and / or K248 on the antibody heavy chain. In some embodiments, the site is K246 of the antibody heavy chain. In some embodiments, the site is K248 of the antibody heavy chain. In some embodiments, the site is K288 or K290 of the antibody heavy chain. In some embodiments, the site is K288 of the antibody heavy chain. In some embodiments, the site is K290 of the antibody heavy chain. In some embodiments, the site is K317. In some embodiments, the site is K414 of the antibody heavy chain. In some embodiments, the site is K185 of the antibody light chain. In some embodiments, the site is K187 of the antibody light chain. In some embodiments, the site is K251 and / or K253 of the IgG2 heavy chain. In some embodiments, the site is K251 of the IgG2 heavy chain. In some embodiments, the site is K253 of the IgG2 heavy chain. In some embodiments, the site is K239 and / or K241 of the IgG4 heavy chain. In some embodiments, the site is K239 of the IgG4 heavy chain. In some embodiments, the site is K241 of the IgG4 heavy chain. In some embodiments, conjugation selectively occurs at one or more heavy chain sites instead of light chain sites. In some embodiments, for techniques without a target binding portion, more conjugation occurs at light chain sites than at heavy chain sites (e.g., see Figure 15).

[0098] In some embodiments, the reactive group (e.g., RG) is or includes an ester group. In some embodiments, the reactive group (e.g., RG) is or includes an electrophilic group, such as a Michael acceptor.

[0099] In some embodiments, the reactive group (e.g., RG) is or includes -L RG1 -L RG2 -, where L RG1 and L RG2 Each of these is independently L as described herein. In some embodiments, the reactive group (e.g., RG) is or includes -L. LG4 -L RG1-L RG2 - where each variable is as described herein. In some embodiments, the reactive group (e.g., RG) is or includes -L LG3 -L LG4 -L RG1 -L RG2 - where each variable is as described herein. In some embodiments, the reactive group (e.g., RG) is or includes -L LG2 -L LG3 -L LG4 -L RG1 -L RG2 - where each variable is as described herein. In some embodiments, the reactive group (e.g., RG) is or includes -L LG4 -L RG2 - where each variable is as described herein. In some embodiments, the reactive group (e.g., RG) is or includes -L LG3 -L LG4 -L RG2 - where each variable is as described herein. In some embodiments, the reactive group (e.g., RG) is or includes -L LG2 -L LG3 -L LG4 -L RG2 - where each variable is as described in this article.

[0100] In some embodiments, as described herein, L LG4 Yes -O-. In some embodiments, L LG4 It is -N(R)-. In some embodiments, L LG4 It is -NH-.

[0101] In some embodiments, as described herein, L LG3 It may include, or optionally substituted, an aryl ring. In some embodiments, L LG3 It may include or contain a phenyl ring. In some embodiments, the aryl ring or phenyl ring is substituted. In some embodiments, the substituent is an electron-withdrawing group as described herein, such as -NO2, -F, etc.

[0102] In some embodiments, L RG1 It is a covalent bond. In some embodiments, L RG1 It is not a covalent bond. In some embodiments, L RG1 It is -S(O)2-.

[0103] In some embodiments, L RG2 It is -C(O)-. In some embodiments, the reactive group is or includes -L LG4 -C(O)-, where each variable is as described herein. In some embodiments, the reactive group is or includes -LLG3 -L LG4 -C(O)-, where each variable is as described herein. In some embodiments, the reactive group is or includes -L LG2 -L LG3 -L LG4 -C(O)-, where each variable is as described in this article.

[0104] In some embodiments, L RG2 Yes -L RG3 -C(=CR RG1 R RG2 )-CR RG3 R RG4 -, where R RG1 R RG2 R RG3 and R RG4 Each of them is independently -L-R', and L RG3 It is -C(O)-, -C(O)O-, -C(O)N(R')-, -S(O)-, -S(O)2-, -P(O)(OR')-, -P(O)(SR')-, or -P(O)(N(R')2)-. In some embodiments, R RG1 R RG2 R RG3 and R RG4 Each of them is independently R'. In some embodiments, R RG1 R RG2 R RG3 and R RG4 One or more of them are independently -H. In some embodiments, L RG3 It is -C(O)-. In some embodiments, L RG3 It is -C(O)O-. In some embodiments, L RG3 -O-, -N(R')-, etc., and L PM Bonding.

[0105] In some embodiments, R RG1 Yes -H. In some embodiments, R RG3 Yes, it's -H.

[0106] In some embodiments, L RG2 It is an optional replacement -L RG3 -C(=CHR RG2 )-CHR RG4 - where each variable is as described in this article.

[0107] In some embodiments, R RG2 and R RG4Together with its intermediate atom, it forms an optionally substituted ring as described herein. In some embodiments, the formed ring is an optionally substituted 3-10 member monocyclic or bicyclic ring having 0-5 heteroatoms. In some embodiments, the formed ring is an optionally substituted 3-10 member alicyclic ring. In some embodiments, the formed ring is an optionally substituted 3-8 member alicyclic ring. In some embodiments, the formed ring is an optionally substituted 5-8 member alicyclic ring. In some embodiments, the formed ring is an optionally substituted 5 member alicyclic ring. In some embodiments, the formed ring is an optionally substituted 6 member alicyclic ring. In some embodiments, the formed ring is an optionally substituted 7 member alicyclic ring. In some embodiments, the formed ring is substituted. In some embodiments, the formed ring is not substituted. In some embodiments, except C(=CHR) RG2 ) or C (=CR) RG1 R RG2 Apart from the double bonds in the ring, the ring formed does not contain any other degree of unsaturation.

[0108] In some embodiments, -C(=CHR) RG2 )-CHR RG4 or -C(=CR) RG1 R RG2 )-CR RG3 R RG4 It is an optional replacement In some embodiments, -C(=CHR) RG2 )-CHR RG4 or -C(=CR) RG1 R RG2 )-CR RG3 R RG4 yes In some embodiments, -C(=CHR) RG2 )-CHR RG4 -L RG3 -or-C(=CR) RG1 R RG2 )-CR RG3 R RG4 -L RG3 - It is an optional replacement. In some embodiments, -C(=CHR) RG2 )-CHR RG4 -L RG3 -or-C(=CR) RG1 R RG2 )-CR RG3 R RG4 -L RG3 -yes In some embodiments, -L RG1 -C(=CHR RG2)-CHR RG4 -L RG3 -or-L RG1 -C(=CR RG1 R RG2 )-CR RG3 R RG4 -L RG3 - It is an optional replacement. In some embodiments, -L RG1 -C(=CHR RG2 )-CHR RG4 -L RG3 -or-L RG1 -C(=CR RG1 R RG2 )-CR RG3 R RG4 -L RG3 - It is an optional replacement. .

[0109] In some embodiments, the reactive group is a structure selected from the table below. In some embodiments, -L LG2 -L LG3 -L LG4 -L RG1 -L RG2 - is a structure selected from the table below. In some embodiments, -L LG2 -L LG3 -L LG4 -RG- is a structure selected from the table below.

[0110] Table RG-1. Some structures as examples. and .

[0111] In some embodiments, -L LG4 -L RG2 - is -OC(O)-. In some embodiments, -L LG4 -L RG2 - is -SC(O)-. In some embodiments, -L LG4 -L RG1 -L RG2 -is-SC(O)-.

[0112] In some embodiments, -L LG4 -L RG2 - is -N(-)-C(O)-, where N is an optional substituted ring atom of a heteroaryl ring. In some embodiments, -L LG4 -L RG2 - is -N(-)-C(O)-, where N is L LG4 The ring atom, wherein the ring atom is or includes optionally substituted heteroaryl rings. In some embodiments, -L LG4 -L RG2 - is -N(-)-C(O)-O-, where N is L LG4 The ring atom, wherein the ring atom is or includes optionally substituted heteroaryl rings.

[0113] In some embodiments, L RG2 It is an optionally substituted -CH2-C(O)-, wherein -CH2- is bonded to an electron-withdrawing group including or connected to the target-binding portion. In some embodiments, L RG2 It is an optionally substituted -CH2- bonded to an electron-withdrawing group including or connected to the target-binding portion. In some embodiments, L RG1 It is an electron-withdrawing group. In some embodiments, L RG1 It is -C(O)-. In some embodiments, L RG1 It is -S(O)-. In some embodiments, L RG1 It is -S(O)2-. In some embodiments, L RG1 It is -P(O(OR)-. In some embodiments, L RG1 It is -P(O(SR)-. In some embodiments, L RG1 It is -P(O(N(R)2)-. In some embodiments, L RG1 It is -OP(O(OR)-. In some embodiments, L RG1 It is -OP(O(SR)-. In some embodiments, L RG1 It is -OP(O(N(R)2)-.

[0114] In some embodiments, L RG2 It is an optionally substituted -CH2-C(O)-, wherein -CH2- is bonded to a leaving group including or connected to the target-binding moiety. In some embodiments, L RG2 It is an optionally substituted -CH2- bonded to a leaving group including or connected to the target-binding portion. In some embodiments, L RG1 It is -OC(O)-. In some embodiments, L RG1It is -OS(O)2-. In some embodiments, L RG1 It is -OP(O(OR)-. In some embodiments, L RG1 It is -OP(O(SR)-. In some embodiments, L RG1 It is -OP(O(N(R)2)-.

[0115] In some embodiments, the reactive group reacts with the amino group of the target drug. In some embodiments, the amino group is a -NH2 group on the side chain of a lysine residue.

[0116] In some embodiments, the target agent is a protein agent. In some embodiments, the target agent is an antibody agent. In some embodiments, the reactive group reacts with an amino acid residue of the protein agent or antibody agent. In some embodiments, the amino acid residue is a lysine residue. In some embodiments, the reactive group reacts with the -NH2 group of the side chain of the lysine residue. In some embodiments, the reactive group is or includes -C(O)-O-, which reacts with (e.g., the -NH2 group of the side chain of the lysine residue) and forms an amide group -C(O)-O- with the -NH2 group.

[0117] Linking group In some embodiments, the linking group L RM This may include lysosomal-cleavable peptide linkers. Lysosomal-cleavable peptide linkers are described, for example, in Balamkundu et al., “Lysosomal-Cleavable Peptide Linkers in Antibody-Drug Conjugates,” *Biomedical*. Biomedicines In the reference cited in ( ), 2023, 11, 3080, the entire reference is incorporated herein by reference. In some embodiments, the linking group L RM It may include a cathepsin-cleavable peptide linker. In some embodiments, the linker group L RM It may include a valine-citrulline-p-aminobenzylcarbamate (ValCitPABC) group, wherein the p-aminobenzyl group may be substituted or unsubstituted. Linking group L RM It may further include formula *-(CH2) n The linker portion of -C(=O)-*', where n is an integer from 1 to 10, * is the linking point with the reactive group RG, and *' is the linking point with the valine group ValCitPABC. In some embodiments, the linking group L RM It can have a formula .

[0118] In some embodiments, the linker group may include Val-Cit. In some embodiments, the linker group may include Phe-Lys. In some embodiments, the linker group may include Val-Lys. See, for example, BinQing Wei et al., “Discovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity,” *Journal of Medicinal Chemistry*, 2018, 61, 3, 989-1000, which is incorporated herein by reference in its entirety.

[0119] Various linking groups that may be present in antibody-drug conjugates according to embodiments of the present invention are described, for example, in WO 2022 / 246086 A1, which is incorporated herein by reference in its entirety.

[0120] The part of concern Those skilled in the art who read this disclosure will understand that, according to this disclosure, various types of the fractions of interest, including monomethyl guanystatin E (MMAE) or closely analogous thereof, can be used for a variety of purposes.

[0121] In some embodiments of this disclosure, the part of interest is or includes MMAE. MMAE is an antitumor agent used in drug-antibody conjugates (e.g., MAB-MMAE conjugates). MMAE is linked to a monoclonal antibody via a linker group that can be cleaved when the drug-antibody conjugate is linked to tumor cells. The linker group will be discussed below. (MMAE) In some embodiments of this disclosure, the portion of interest is or includes monomethylolpropionate D (MMAD): (MMAD) In some embodiments of this disclosure, the portion of interest is or includes MMAF, namely monomethyloiristatin F or desmethyloiristatin F, the linkage structure of which is shown below: (MMAF) In some embodiments, the portion of interest that is or includes monomethyloripstatin E may be the following: Among them, the wavy line " "" indicates the connection point with the linking group.

[0122] In some embodiments, the portion of interest that is or includes monomethyloripatin D may be the following: Among them, the wavy line " "" indicates the connection point with the linking group.

[0123] In some embodiments, the portion of interest that is or includes monomethyloripartin F may be the following: Among them, the wavy line " "" indicates the connection point with the linking group.

[0124] In one embodiment, a compound is provided having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; LG-RG is ; L RM It has a formula The linking group; and MOI is a formula The part that is of interest.

[0125] In one aspect, the target-binding portion may be configured to bind to benzoxicam or a biosimilar thereof such that the reactive group is adjacent to K246 or K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction causing L... RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0126] In another aspect, the target-binding portion can be configured to bind to benzoxicam or a biosimilar thereof, such that the reactive group is proximate to K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction comprising L RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0127] In one embodiment, a method for preparing a pharmaceutical agent having the structure of formula (PI) is provided: P-(L PM -MOI)2, (PI) or its salt, wherein: P is bentuximab or a biosimilar of it; Each L PM It includes The linking group; and Each MOI is a formula The part that is of interest.

[0128] The method may include the following steps: (1) Contacting bentuximab or a bio-similar thereof with a reaction coupler having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; LG-RG is ; L RM It has a formula Linking groups; MOI is a formula The part that is of concern, and (2) Forming a drug having the structure of formula (PI).

[0129] In one aspect, the target-binding portion of the reagent conjugate may be configured to bind to benzoxicam or a biosimilar thereof, such that the reactive group is adjacent to K246 or K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction comprising L RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0130] In another aspect, the target-binding portion of the reagent conjugate may be configured to bind to benzoxicam or a biosimilar thereof, such that the reactive group is brought into contact with K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction comprising L RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0131] In another aspect, the contact and formation steps can be carried out in a chemical reaction.

[0132] In another embodiment, a pharmaceutical agent is provided having the structure of formula (PI): P-(L PM -MOI)2, (PI) or its salt, wherein: P is bentuximab or a biosimilar of it; Each L PM It includes The linking group; and Each MOI is a formula The part that is of interest.

[0133] In one aspect, each L PM -MOI can be linked to K246 or K248 of the benzoxicam IgG heavy chain or its biosimilar analogue.

[0134] In another aspect, each L PM -MOI can be linked to K248 of the benzoxicam IgG heavy chain or its biosimilar analogue.

[0135] In another embodiment, a method for preparing a pharmaceutical agent having a (P-II) structure is provided: P-(NH-L PM -MOI)2, (P-II) in: P-NH is a biosimilar of benzoximab or the biosimilar thereof, which includes a lysine residue having a terminal NH group. L PM yes ;and MOI is .

[0136] The method may include the following steps: (1) Providing benzoxicam or a biosimilar thereof, said benzoxicam or a biosimilar thereof having the structure P-(NH2)2, wherein each NH2 is a terminal amino group of a lysine residue; and (2) Contacting P-(NH2)2 with a reaction coupler having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; LG-RG is ; L RM It has a formula The linking group; and MOI is a formula The part that is of interest.

[0137] In one aspect, the target-binding portion of the reagent conjugate may be configured to bind to benzoxicam or a biosimilar thereof, such that the reactive group is adjacent to K246 or K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction comprising L RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0138] In another aspect, the target-binding portion of the reagent conjugate may be configured to bind to benzoxicam or a biosimilar thereof, such that the reactive group is brought into contact with K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction comprising L RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0139] In one aspect, the contact and formation steps can be carried out in a chemical reaction.

[0140] In another embodiment, a pharmaceutical agent is provided having a (P-II) structure: P-(NH-L PM -MOI)2, (P-II) in: P-NH is a biosimilar of benzoximab or the biosimilar thereof, which includes a lysine residue having a terminal NH group. L PM It has a formula The linking group; and MOI is a formula The part that is of interest.

[0141] The lysine residue can be K246 or K248 of the benzoximab IgG heavy chain or its biosimilar.

[0142] Each lysine residue can be K248 of the benzoximab IgG heavy chain or its biosimilar analogue.

[0143] In one embodiment, a compound is provided having the structure of formula (RI): LG-RG-L RM -MOI, (RI) or its salt, wherein: LG is a group that includes a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes The linking group; and MOI is the part of interest that includes monomethylolpropionate E (MMAE). The bentuximab or its biosimilars include IgG heavy chains, said IgG heavy chains including K246 or K248, and The target-binding portion may be configured to bind to benzoxicam or a biosimilar thereof, such that the reactive group is close to K246 or K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction causing L to be included. RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0144] LG-RG can be .

[0145] MOI can include .

[0146] In one aspect, the target-binding portion can be configured to bind to benzoxicam or a biosimilar thereof, such that the reactive group is brought into contact with K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction causing L... RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

[0147] Antibody According to embodiments of the present invention, the antibodies used in the composition and method may be antibodies known for treating or preventing cancer. Antibodies with immune specificity against cancer cell antigens may be commercially available or produced by any method known to those skilled in the art (e.g., chemical synthesis or recombinant expression techniques). 。 Nucleotide sequences encoding antibodies with immune specificity against cancer cell antigens can be obtained, for example, from GenBank or similar databases, literature publications, or through routine cloning and sequencing. Examples of antibodies that can be used to treat cancer include, but are not limited to, HERCEPTIN (trastuzumab; Genentech, CA), a humanized anti-HER2 monoclonal antibody used to treat patients with metastatic breast cancer (Stebbing, J., Copson, E., and O'Reilly, S. "Herceptin (trastuzumab) in advanced breast cancer" *Cancer Treatment Review*). Cancer Treat Rev. (26, 287-90, 2000); RITUXAN (rituximab; Genentech), a chimeric anti-CD20 monoclonal antibody for the treatment of patients with non-Hodgkin's lymphoma; OvaRex (AltaRex Corporation, MA, Massachusetts), a murine antibody for the treatment of ovarian cancer; Panorex (Glaxo Wellcome, NC, North Carolina), a murine IgG for the treatment of colorectal cancer. 2aAntibodies; BEC2 (Imclone Systems Inc., NY), a mouse IgG antibody for the treatment of lung cancer; IMC-C225 (ImClone Systems, NY), a chimeric IgG antibody for the treatment of head and neck cancer; Vitaxin (MedImmune, Inc., MD), a humanized antibody for the treatment of sarcoma; Camppath I / H (Leukosite, MA), a humanized IgG1 antibody for the treatment of chronic lymphocytic leukemia (CLL); Smart MI95 (Protein Design Labs, Inc., CA), a humanized IgG antibody for the treatment of acute myeloid leukemia (AML); LymphoCide (Immunomedics, Inc., NJ), a humanized IgG antibody for the treatment of non-Hodgkin's lymphoma; Smart ID10 (a protein design lab in California) is a humanized antibody for the treatment of non-Hodgkin's lymphoma; Oncolym (Techniclone, Inc., CA) is a murine antibody for the treatment of non-Hodgkin's lymphoma; Allomune (BioTransplant, CA) is a humanized anti-CD2 antibody for the treatment of Hodgkin's disease or non-Hodgkin's lymphoma. mAb; anti-VEGF (Genentech, California), a humanized antibody for the treatment of lung and colorectal cancer; CEAcide (Immunomedics, New Jersey), a humanized anti-CEA antibody for the treatment of colorectal cancer; IMC-1C11 (ImClone Systems, New Jersey), an anti-KDR chimeric antibody for the treatment of colorectal cancer, lung cancer, and melanoma; and cetuximab (ImClone Systems, New Jersey), an anti-EGFR chimeric antibody for the treatment of epidermal growth factor-positive cancers.

[0148] Other antibodies that can be used to treat cancer include, but are not limited to, antibodies against the following antigens: CA125 (ovarian), CA15-3 (cancer), CA19-9 (cancer), L6 (cancer), Lewis Y (cancer), Lewis X (cancer), alpha-fetoprotein (cancer), CA 242 (colorectal), placental alkaline phosphatase (cancer), prostate-specific antigen (prostate), prostate acid phosphatase (prostate), epidermal growth factor (cancer), MAGE-1 (cancer), MAGE-2 (cancer), MAGE-3 (cancer), MAGE 4 (cancer), anti-transferrin receptor (cancer), p97 (melanoma), MUC1-KLH (breast cancer), CEA (colorectal cancer), gp100 (melanoma), MART1 (melanoma), PSA (prostate cancer), IL-2 receptor (T-cell leukemia and lymphoma), CD20 (non-Hodgkin's lymphoma), CD52 (leukemia), CD33 (leukemia), CD22 (lymphoma), human chorionic gonadotropin (cancer), CD38 (multiple myeloma), CD40 (lymphoma), mucin (cancer), P21 (cancer), MPG (melanoma), and Neu oncogene product (cancer). Some specific useful antibodies include, but are not limited to, BR96 mAb (Trail, PA, Willner, D., Lasch, SJ, Henderson, AJ, Hofstead, SJ, Casazza, AM, Firestone, RA, Hellström, I., Hellström, KE, "Cure of Xenografted Human Carcinomas by BR96-Doxorubicin Immunoconjugates" Science). Science( )》 1993, 261, 212-215), BR64 (Trail, Pa., Willner, D, Knipe, J., Henderson, AJ, Lasch, SJ, Zoeckler, ME, Trailsmith, MD, Doyle, TW, King, HD, Casazza, AM, Braslawsky, GR, Brown, JP, Hofstead, SJ, Greenfield, III. S., Firestone, RA, Mosure, K., Kadow, DF, Yang, MB, Hellstrom, K E. and Hellstrom, I. "Effect of Linker Variation on the Stability, Potency, and Efficacy of Carcinoma-reactive BR64-Doxorubicin Immunoconjugates" Cancer Research ( ) 1993, 261, 212-215), BR64 (Trail, Pa., Willner, D, Knipe, J., Henderson, AJ, Lasch, SJ, Zoeckler, ME, Trailsmith, MD, Doyle, TW, King, HD, Casazza, AM, Braslawsky, GR, Brown, JP, Hofstead, SJ, Greenfield, III. S., Firestone, RA, Mosure, K., Kadow, DF, Yang, MB, Hellstrom, K E. and Hellstrom, I. "Effect of Linker Variation on the Stability, Potency, and Efficacy of Carcinoma-reactive BR64-Doxorubicin Immunoconjugates" Cancer Research ( ) Cancer Research ( )》 1997, 57, 100-105), mAbs targeting the CD40 antigen, such as S2C6 mAb (Francisco, JA, Donaldson, KL, Chace, D., Siegall, CB and Wahl, AF "Agonistic properties and in vivo antitumor activity of the anti-CD-40 antibody, SGN-14" Cancer Research 2000, 60, 3225-3231), mAbs targeting the CD70 antigen (such as 1F6 mAb), and mAbs targeting the CD30 antigen (such as AC10) (Bowen, MA, Olsen, KJ, Cheng, L., Avila, D. and Podack, ER "Functional effects of CD30 on a large granular lymphoma cell line YT"). YT) "Journal of Immunology" J. Immunol.(1993) 151, 5896-5906. Many other internalizing antibodies that bind to tumor-associated antigens can be used in this invention and have been reviewed (Franke, AE, Sievers, EL and Scheinberg, DA, “Cell surface receptor-targeted therapy of acute myeloid leukemia: a review”, Cancer Biotherapy and Radiopharmaceuticals ( ) Cancer Biother Radiopharm. ( )》2000, 15, 459-76; Murray, JL, “Monoclonal antibody treatment of solid tumors: a coming of age”, Oncology Symposium ( Semin Oncol. )》 2000, 27, 64-70; Breitling, F. and Dubel, S., "Recombinant Antibodies ( Recombinant Antibodies (John Wiley, and Sons, New York, 1998).

[0149] In some embodiments, the antibody is benzoxicam or a biosimilar of benzoxicam.

[0150] Pharmaceutical Composition This disclosure also provides a composition comprising an effective amount of a compound according to embodiments of the invention and a pharmaceutically acceptable carrier or mediator. The composition is suitable for veterinary or human administration.

[0151] The composition may be in any form that permits its administration to humans or animals. For example, the composition may be in solid, liquid, or gaseous (aerosol) form. Typical routes of administration include, but are not limited to, oral, topical, parenteral, sublingual, rectal, vaginal, ocular, and intranasal administration. Parenteral administration includes subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion techniques. In some embodiments, the composition is administered parenterally. The pharmaceutical composition may be formulated to allow the compound to be bioavailable when administered to humans or animals. The composition may be in the form of one or more dose units, wherein, for example, a tablet may be a single dose unit, and a container for a compound in aerosol form may contain multiple dose units.

[0152] The materials used to prepare the pharmaceutical composition may be non-toxic in the amounts used. It will be apparent to those skilled in the art that the optimal dosage of the active ingredient in a pharmaceutical composition will depend on a variety of factors. These factors include, but are not limited to, the type of organism (e.g., human or animal), the specific form of the compound, the method of administration, and the composition used.

[0153] Pharmaceutically acceptable carriers or mediators can be microparticles, thus the composition may be in the form of tablets or powders, for example. In the case of a composition that is, for example, an oral syrup or injectable liquid, the carrier may be liquid. Alternatively, the carrier may be gaseous to provide an aerosol composition suitable for, for example, inhalation administration.

[0154] When intended for oral administration, the composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are included in the forms considered as solid or liquid herein.

[0155] As a solid composition intended for oral administration, the composition can be formulated into powder, microparticles, compressed tablets, pills, capsules, chewing gum, crystals, etc. Such solid compositions typically contain one or more inert diluents. Additionally, one or more of the following may be present: binders, such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, or gelatin; excipients, such as starch, lactose, or dextrin; disintegrants, such as alginate, sodium alginate, Primogel, corn starch, etc.; lubricants, such as magnesium stearate or Sterotex; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; flavoring agents, such as peppermint, methyl salicylate, or orange flavoring; and coloring agents.

[0156] When the composition is in capsule form (e.g., gelatin capsule), it may contain liquid carriers such as polyethylene glycol, cyclodextrin or fatty oils, in addition to the materials of the types described above.

[0157] The composition may be in liquid form, such as an elixir, syrup, solution, emulsion, or suspension. The liquid may be intended for oral administration or delivery by injection. When intended for oral administration, the composition may include one or more of sweeteners, preservatives, dyes / colorants, and flavor enhancers. In compositions intended for injection administration, one or more of surfactants, preservatives, wetting agents, dispersants, suspending agents, buffers, stabilizers, and isotonic agents may also be included.

[0158] Liquid compositions according to embodiments of the invention, whether in solution, suspension, or other similar form, may include one or more of the following: sterile diluents, such as water for injection, saline solution, preferably physiological saline, Ringer's solution, or isotonic sodium chloride; fixed oils, such as synthetic monoglycerides or diglycerides that can act as solvents or suspending media; polyethylene glycol, glycerol, cyclodextrin, propylene glycol, or other solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate, or phosphate; and agents for adjusting tension, such as sodium chloride or dextran. Parenteral compositions may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass, plastic, or other materials. Physiological saline is a preferred adjuvant. Injectable compositions are preferably sterile.

[0159] The amount of compound effective in treating a specific condition or symptom will depend on the nature of the condition or symptom and can be determined using standard clinical techniques. Additionally, in vitro or in vivo assays may be optionally used to help identify the optimal dosage range. The precise dosage to be used in the composition will also depend on the route of administration and the severity of the disease or symptom, and should be determined based on the practitioner's judgment and the individual patient's situation.

[0160] The composition comprises an effective amount of compound such that a suitable dosage is obtained. Typically, this amount is at least about 0.01% of the compound by weight of the composition. When intended for oral administration, this amount can vary from about 0.1% to about 80% by weight of the composition. Preferred oral compositions may comprise about 4% to about 50% of the compound by weight of the composition. Preferred compositions are prepared such that the parenteral dosing unit contains about 0.01% to about 2% by weight of the compound.

[0161] For intravenous administration, the composition may comprise about 1 mg to about 250 mg of the compound per kg of animal body weight. For example, the amount administered may be in the range of about 4 mg / kg body weight to about 25 mg / kg body weight of the compound.

[0162] Typically, the dosage of a compound administered to a human or animal is typically from about 0.1 mg / kg to about 250 mg / kg of human or animal body weight. For example, the dosage administered to a human or animal is between about 0.1 mg / kg and about 20 mg / kg of human or animal body weight, such as from about 1 mg / kg to about 10 mg / kg of human or animal body weight.

[0163] The compound or composition may be administered via any convenient route (e.g., by infusion or bolus injection, absorption through the epithelial or mucosal skin layer, such as the oral mucosa, rectal and intestinal mucosa). Administration may be systemic or local. Various delivery systems are known, such as encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and may be used to administer the compound or composition. In some embodiments, more than one compound or composition may be administered to a human or animal. Methods of administration include, but are not limited to, oral and parenteral administration; parenteral administration includes, but is not limited to, intradermal, intramuscular, intraperitoneal, intravenous, and subcutaneous administration; intranasal, epidural, sublingual, intranasal, intracerebral, intraventricular, intrathecal, intravaginal, intravaginal, percutaneous, rectal, inhalation, or local administration to the ear, nose, eye, or skin. Preferred administration methods are determined by the practitioner and will depend in part on the site of the medical condition (e.g., the site of cancer or autoimmune disease).

[0164] In some embodiments, the compounds or compositions of the present invention are administered parenterally.

[0165] In some embodiments, the compounds or compositions of the present invention are administered intravenously.

[0166] In some embodiments, it may be desirable to apply one or more compounds or compositions topically to the area requiring treatment. This can be achieved, for example, but not limited to, by: local infusion during surgery; topical application, for example, in combination with a wound dressing after surgery; by injection; by means of a catheter; by means of a suppository; or by means of an implant, which is a porous, non-porous, or gel-like material, including membranes or fibers such as silicone rubber membranes. In some embodiments, application can be performed by direct injection at the site (or previous site) of cancer, tumor, or neoplastic or pretumoral tissue. In some other embodiments, application can be performed by direct injection at the site (or previous site) of an autoimmune disease manifestation.

[0167] In some embodiments, it may be desirable to introduce one or more compounds or compositions into the central nervous system via any suitable route, including intraventricular injection and intrathecal injection. Intraventricular injection can be facilitated, for example, by an intraventricular catheter connected to a reservoir such as the Ommaya reservoir.

[0168] Lung administration can also be achieved, for example, by using an inhaler or nebulizer and formulations containing aerosols, or by perfusion with fluorocarbons or synthetic pulmonary surfactants. 。 In some embodiments, the compound or composition may be formulated into a suppository together with conventional adhesives and carriers such as triglycerides.

[0169] In some embodiments, the compound can be delivered in vesicles (particularly liposomes) (see Langer, Science 249:1527-1533 (1990); Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see also...). Same as above ).

[0170] In some embodiments, the compound or composition may be delivered in a controlled-release system. In some embodiments, a pump may be used (see Langer, ibid.; Sefton, Critical Review of Biomedical Engineering (CRC Crit. RevBiomed. Eng.) 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In some embodiments, polymeric materials may be used (see *Medical Applications of Controlled Release*, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); *Controlled Drug Bioavailability, Drug Product Design and Performance*, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, *J. Macromol. Sci. Rev. Macromol. Chem.* 23:61 (1983); see also Levy et al., *Science* 228:190 (1985); During et al., *Ann. Neurol.* 25:351 (1989); Howard et al., *J. Neurosurg.* 71:105 (1989)). In some embodiments, the controlled-release system may be placed close to the target of the compound or composition, such as the brain, thereby requiring only a small fraction of the systemic dose (see, for example, Goodson, Medical Applications of Controlled Release, ibid., Vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in Langer's review (Science 249:1527-1533 (1990)) may be used.

[0171] The term "carrier" refers to a diluent, adjuvant, or excipient that is administered with a compound. Such drug carriers can be liquids, such as water and oils, including petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Carriers can also be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Additionally, adjuvants, stabilizers, thickeners, lubricants, and colorants can be used. In some embodiments, when administered to humans or animals, the compound or composition and the pharmaceutically acceptable carrier are sterile. When administering the compound intravenously, water may be a preferred carrier. Saline solutions and aqueous solutions of glucose and glycerol can also be used as liquid carriers, especially for injectable solutions. Suitable drug carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, ethylene glycol, water, ethanol, etc. If desired, the compositions of the present invention may also contain small amounts of wetting agents, emulsifiers, or pH buffers.

[0172] The compositions of the present invention may be in the form of solutions, suspensions, emulsions, tablets, pills, granules, capsules, liquid-containing capsules, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other suitable form for use. In some embodiments, a pharmaceutically acceptable carrier is a capsule (see, for example, U.S. Patent No. 5,698,155). Other examples of suitable drug carriers are described in EW Martin’s Remington Pharmaceutical Sciences.

[0173] In some embodiments, the compounds are formulated according to conventional procedures into pharmaceutical compositions suitable for intravenous administration to animals, particularly humans. Typically, the carrier or mediator for intravenous administration is a sterile isotonic buffered aqueous solution. If necessary, the composition may also include a solubilizer. Compositions for intravenous administration may optionally include a local anesthetic, such as lidocaine for relieving pain at the injection site. Generally, the components are provided separately or mixed together in unit dosage forms, for example, as a lyophilized powder or anhydrous concentrate in a hermetically sealed container such as an ampoule or capsule indicating the amount of active agent. When the compound is to be administered by infusion, it may be dispensed, for example, using an infusion bottle containing sterile pharmaceutical-grade water or saline. When the compounds of the present invention are administered by injection, ampoules of sterile water for injection or saline may be provided, allowing the components to be mixed prior to administration.

[0174] For example, compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Orally administered compositions may contain one or more optional pharmaceutical agents for providing a pharmaceutically palatable formulation, such as sweeteners like fructose, aspartame, or saccharin; flavoring agents like peppermint, wintergreen oil, or cherry; coloring agents; and preservatives. Furthermore, in the case of tablets or pills, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over an extended period. Selective permeation membranes surrounding osmotically driven compounds are also suitable for orally administered compounds. In these latter platforms, fluid from the capsule's surrounding environment is absorbed by the driven compound, which swells to displace the pharmaceutical agent or pharmaceutical composition through the pores. In contrast to the spiked spectra of immediate-release formulations, these delivery platforms can provide a substantially zero-order delivery spectrum. Time-delaying materials such as glyceryl monostearate or glyceryl stearate may also be used. Oral compositions may include standard carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. These carriers are preferably pharmaceutical grade.

[0175] The composition may be intended for topical application, in which case the carrier may be in the form of a solution, emulsion, ointment, or gel matrix. For example, the matrix may include one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickeners may be present in the composition for topical application. If intended for transdermal application, the composition may be in the form of a transdermal patch or an iontophoresis device. Topical formulations may include compounds of the present invention at concentrations of about 0.1% w / v to about 10% w / v (weight per unit volume of composition).

[0176] The composition may be intended for rectal administration, for example, in the form of a suppository, which dissolves in the rectum and releases the compound. Compositions for rectal administration may contain an oily matrix as a suitable, non-irritating excipient. Such matrices include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol.

[0177] The composition may include a variety of materials that alter the physical form of the solid or liquid dosage unit. For example, the composition may include a material that forms a coating around the active ingredient. The material forming the coating is typically inert and may be selected from, for example, sugars, shellac, and other enteric coating agents. Alternatively, the active ingredient may be encapsulated in gelatin capsules.

[0178] The composition may consist of gaseous dosing units, for example, it may be in the form of an aerosol. The term aerosol is used to refer to a wide range of systems, from colloidal systems to systems consisting of pressurized packaging. Delivery can be carried out by liquefying or compressing gases or by a suitable pump system dispensing the active ingredient. Aerosols of compounds can be delivered in single-phase, two-phase, or three-phase systems to deliver the compound. Aerosol delivery includes necessary containers, activators, valves, sub-containers, spacers, etc., which together can form a kit. Preferred aerosols can be determined by those skilled in the art without excessive experimentation.

[0179] Whether in solid, liquid, or gaseous form, compositions according to embodiments of the present invention may include agents for treating cancer, autoimmune diseases, or infectious diseases.

[0180] Pharmaceutical compositions can be prepared using methods well-known in the pharmaceutical field. For example, compositions intended for injection can be prepared by combining the compound with water to form a solution. Surfactants can be added to promote the formation of a homogeneous solution or suspension. A surfactant is a compound that non-covalently interacts with the compound according to embodiments of the invention to promote the dissolution or homogeneous suspension of the active compound in an aqueous delivery system.

[0181] Cancer treatment The compounds according to embodiments of the present invention can be used to treat cancer. The compounds according to embodiments of the present invention can be used to inhibit the proliferation of tumor cells or cancer cells, or to treat cancer in humans or animals. Accordingly, the compounds can be used in various settings to treat various animal cancers. Antibody-drug conjugates can be used to deliver drugs or drug units to tumor cells or cancer cells. Not bound by theory, in some embodiments, the portion of the compound of interest binds to or associates with a cancer cell or tumor cell-associated antigen, and the compound can be taken up within tumor cells or cancer cells via receptor-mediated endocytosis. The antigen can be linked to tumor cells or cancer cells, or it can be an extracellular matrix protein associated with tumor cells or cancer cells. While intracellular, one or more specific peptide sequences within the linker group are hydrolyzed and cleaved by one or more tumor cell or cancer cell-associated proteases, thereby releasing the drug or drug unit. The released drug or drug unit then migrates freely in the cytosol and induces cytotoxic activity. In some alternative embodiments, the drug or drug unit is cleaved from the compound outside the tumor cells or cancer cells, and the drug or drug unit subsequently penetrates the cell.

[0182] In some embodiments, the portion of interest binds to tumor cells or cancer cells.

[0183] In another embodiment, the portion of interest binds to tumor cell or cancer cell antigens located on the surface of tumor cells or cancer cells.

[0184] In another embodiment, the portion of interest binds to tumor cell or cancer cell antigens of extracellular matrix proteins that are associated with tumor cells or cancer cells.

[0185] In some embodiments, tumor cells or cancer cells belong to a type of tumor or cancer in humans or animals that requires treatment or prevention.

[0186] For identifying the most effective tumor or cancer to treat, the specificity of the target component to specific tumor cells or cancer cells can be important. For example, compounds containing the BR96 ligand unit can be used to treat antigen-positive cancers, including lung cancer, breast cancer, colon cancer, ovarian cancer, and pancreatic cancer. Compounds containing anti-CD30 or anti-CD40 ligand units can be used to treat hematologic malignancies.

[0187] Other specific types of cancer that can be treated with compounds include solid tumors, including but not limited to fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chondroma, angiosarcoma, endothelial sarcoma, lymphosarcoma, lymphangioendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, gastric cancer, oral cancer, nasal cancer, laryngeal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, and Wilms' tumor. Tumors, cervical cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, epithelial cancer, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma; hematogenous cancers, including but not limited to acute lymphoblastic leukemia (ALL), acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute medulloblastic leukemia (AML), acute promyelocytic leukemia, etc. Acute leukemia (APL), acute monocytic leukemia, acute erythrocytic leukemia, acute megakaryocytic leukemia, acute myeloid monocytic leukemia, acute non-lymphocytic leukemia, acute undifferentiated leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, multiple myeloma, acute and chronic leukemia: lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, myeloid leukemia, lymphoma: Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, Waldenström's macroglobulinemia, heavy chain disease, and polycythemia vera. Compounds according to embodiments of the present invention can also be used as chemotherapeutic agents in a non-targeted form. For example, the compounds can be used to treat ovarian cancer, CNS, renal cancer, lung cancer, colon cancer, melanoma, or hematologic malignancies or tumors.

[0188] The compounds provide conjugation-specific tumor or cancer targeting, thereby reducing the general toxicity of these compounds. The linking groups stabilize the compounds in the bloodstream but allow them to be cleaved by tumor-specific proteases within cells, releasing the drug or drug unit.

[0189] Cancer, including but not limited to tumors, metastases, or any disease or condition characterized by uncontrolled cell growth, can be treated or prevented by applying the compounds disclosed herein.

[0190] Other embodiments provide methods for treating or preventing cancer, the methods comprising administering an effective amount of a compound and a chemotherapeutic agent to an animal in need. In some embodiments, the chemotherapeutic agent is a treatment-resistant chemotherapeutic agent for a cancer that has not yet been identified. In other embodiments, the chemotherapeutic agent is a treatment-resistant chemotherapeutic agent for a cancer that has been identified. The compounds disclosed herein can be administered to humans or animals that have undergone surgery as a treatment for cancer.

[0191] In some embodiments, an additional treatment method is radiation therapy.

[0192] In some embodiments, the compounds of the present invention are administered in parallel with chemotherapy or radiotherapy. In some embodiments, the chemotherapy or radiotherapy is administered before or after the application of the compound, for example, at least one hour, five hours, 12 hours, one day, one week, one month, or for example several months (e.g., up to three months) before or after the application of the compound.

[0193] Chemotherapy agents can be administered within a range of activities, and any one or a combination of the chemotherapeutic agents listed below can be used. Regarding radiation, any radiation therapy regimen can be used depending on the type of cancer to be treated. For example, but not as a limitation, X-ray radiation can be administered; specifically, high-energy megavolts (radiation with energies greater than 1 MeV) can be used for deep tumors, and electron beam and positive voltage X-ray radiation can be used for skin cancer. Gamma rays emitting radioactive isotopes (such as radium, cobalt, and radioactive isotopes of other elements) can also be administered.

[0194] Additionally, some embodiments provide methods for treating cancer with compounds as an alternative to chemotherapy or radiation therapy, wherein chemotherapy or radiation therapy has been shown or could be shown to be too toxic, for example, causing unacceptable or intolerable side effects for the treated subject. The treated person or animal may optionally be treated with another cancer treatment such as surgery, radiation therapy, or chemotherapy, depending on which treatment is found to be acceptable or tolerable.

[0195] The compound can also be used in vitro or ex vivo, such as for the treatment of certain cancers, including but not limited to leukemia and lymphoma, where such treatment involves autologous stem cell transplantation. This can involve a multi-step process in which autologous hematopoietic stem cells are harvested from an animal and all cancer cells are removed. The remaining bone marrow cell population is then eradicated by administering high doses of the compound, with or without accompanying high-dose radiation therapy, and the stem cell graft is infused back into the animal. Supportive care is then provided as bone marrow function recovers and the person or animal recovers.

[0196] Some embodiments include methods for treating cancer, the methods comprising administering an effective amount of a compound and another therapeutic agent as an anticancer agent to an animal in need. Suitable anticancer agents include, but are not limited to, methotrexate, taxol, L-asparaginase, mercaptopurine, thioguanine, hydroxyurea, vidarabine, cyclophosphamide, ifosfamide, nitrosourea, cisplatin, carboplatin, mitomycin, dacarbazine, procarbazine, topotecan, nitrogen mustard, cytoxan, etoposide, 5-fluorouracil, BCNU, irinotecan, camptothecin, bleomycin, doxorubicin, idarubicin, daunorubicin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel, and docetaxel. In some embodiments, anticancer agents include, but are not limited to, the following drugs: alkylating agents; nitrogen mustard: cyclophosphamide, ifosfamide, trofosfamide, chlorambucil; nitrosourea: carmustine (BCNU), lomustine (CCNU); alkyl sulfonates: busulfan, treosulfan; triazene: dacarbazine; platinum-containing compounds: cisplatin, carboplatin; plant alkaloids such as vinca alkaloids: vincristine, vinblastine, vindesine, vinorelbine; taxanes: paclitaxel, docetaxel, DNA topoisomerase inhibitors; epipodophyllotoxin (epi) Podophyllins: etoposide, teniposide, topotecan, 9-aminocamptothecin, camptothecin, cristatol; Mitomycin C: mitomycin C, antimetabolites; Antifolate: DHFR inhibitors: methotrexate, trimetrexate; IMP dehydrogenase inhibitors: mycophenolic acid, tiazofurin, ribavirin, EICAR; Ribonucleotide reductase inhibitors: hydroxyurea, deferoxamine; Pyrimidine analogs: uracil analogs: 5-fluorouracil, fluorouracil, doxifluridine, ratitrexed; Cytosine analogs: ara C, cytosinearabinoside, fludarabine; Purine analogs: mercaptopurine, thioguanine.Hormone therapy: receptor antagonists; anti-estrogens: tamoxifen, raloxifene, megestrol; LHRH agonists: goserelin, leuprolide acetate; anti-androgens: flutamide, bicalutamide, retinol / deltoid; vitamin D3 analogs: EB 1089, CB 1093, KH 1060; Photodynamic therapy: Vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, demethoxy-pyridoxine A (2BA-2-DMHA); Cytokines: Interferon-α, Interferon-γ, tumor necrosis factor; and isoprenoidation inhibitors such as: Lovastatin; Dopaminergic neurotoxins: 1-methyl-4-phenylpyridinium cation; Cell cycle inhibitors: staurosporine, actinomycins: actinomycin D, bleomycin; Bleomycin: bleomycin A2, bleomycin B2, peplomycin; Anthracyclines: daunorubicin, doxorubicin (doxorubicin), idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone; MDR inhibitors: verapamil; and Ca2+ ATPase inhibitors: carotenoids.

[0197] In some embodiments, another therapeutic agent may be an anti-PD-1 antibody, such as nivolumab, pembrolizumab, and pidilizumab.

[0198] In some embodiments, another therapeutic agent may be an anti-PD-L1 antibody, such as BMS-936559, durvalumab, atezolizumab, avelumab, and MDX-1105.

[0199] In some embodiments, another therapeutic agent may be an anti-CTLA-4 antibody, such as ipilimumab and tremelimumab.

[0200] In some embodiments, a method is provided for treating Hodgkin's lymphoma in a subject requiring such treatment, the method comprising administering to the subject a pharmaceutically effective amount of the above-described agent.

[0201] In another embodiment, a method is provided for treating a subject with systemic anaplastic large cell lymphoma who requires such treatment, the method comprising administering to the subject a pharmaceutically effective amount of the above-described agent.

[0202] In another embodiment, a method is provided for treating a subject with primary cutaneous anaplastic large cell lymphoma who requires such treatment, the method comprising administering to the subject a pharmaceutically effective amount of the above-described agent.

[0203] In another embodiment, a method is provided for treating CD30-expressing mycosis fungoides in a subject requiring such treatment, the method comprising administering to the subject a pharmaceutically effective amount of the above-described agent.

[0204] In another embodiment, a method is provided for treating cutaneous T-cell lymphoma in a subject requiring such treatment, the method comprising administering to the subject a pharmaceutically effective amount of the above-described agent.

[0205] In another embodiment, a method is provided for selectively targeting tumor cells expressing the CD30 antigen in a subject, the method comprising administering the aforementioned agent to the subject. Antibody-drug conjugates according to embodiments of the invention can also be used to treat autoimmune diseases and infectious diseases. Such diseases are listed, for example, in WO 2004 / 010957 A2, which is incorporated herein by reference in its entirety.

[0206] Process fingerprint composition In another embodiment, a composition is provided comprising: The first compound has the structure of formula (P-II): PNL PM -MOI (P-II) in: PN is a biosimilar of benzoxicam or a biosimilar thereof, which includes lysine residues; L PM It includes The linking group; and The MOI is the portion of interest including monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF); and The second compound has the following structure: LG-OH (LG-I) LG is a group that includes a target-binding moiety that binds to bentuximab or its bio-similar analogues.

[0207] The composition may further include: A third compound, wherein the third compound has the formula (RI): LG-RG-L RM -MOI(RI) LG is a group comprising a target-binding moiety that binds to tuftuximab or its bio-similar analogues, said group being identical to LG in formula (LG-I); RG is a reactive group; L RM It is a linking group, which is identical to the LRM in formula (P-II); and MOI is the part of interest, which is the same as the MOI in equation (P-II); and The fourth compound has the formula (R-III): HO-RG-L RM -MOI (R-III) Or a combination thereof.

[0208] The present invention is further illustrated by the following non-limiting examples.

[0209] Example Synthesis of reagent A Reagent A Synthesis and purification of BH3816 Synthesis of the reactive group containing 3-fluoro-4-hydroxybenzylamine (compound 4) The mixture of intermediate 1 (10 g, 64.45 mmol) in HBr / H2O (40% HBr, 300 mL total) was stirred at 140 °C for 16 h. The solvent was removed under reduced pressure at 70 °C, and the residue was wet-milled in MeCN (50 mL) for 10 min. After filtration, the solid was lyophilized to provide intermediate 2 (13.0 g, 58.5 mmol, 90.8% yield, HBr salt) as a brown solid. 1H NMR: (400 MHz DMSO-d6) 5 ppm 10.04 (s, 1 H) 8.18 (s, 3 H)7.32 (dd, J = 12.17, 1.88 Hz, 1 H) 7.11 (dd, J = 8.28, 1.51 Hz, 1 H) 6.96 -7.03 (m, 1 H) 3.93 (q, J = 5.52 Hz, 2 H). EDCI (12.35 g, 64.4 mmol, 1.1 equivalent) was added to a mixture of intermediate 2 (13.0 g, 58.5 mmol, 1 equivalent), intermediate 2a (24.1 g, 58.5 mmol, 1 equivalent), DIEA (3.78 g, 29.2 mmol, 5.10 mL, 0.5 equivalent), and HOBt (11.87 g, 87.8 mmol, 1.5 equivalent) in DMF (200 mL) at 15 °C, and the mixture was stirred at 15 °C for 3 hours. The mixture was then added dropwise to 0.5 M HCl (cold, 1 L), and a white solid precipitated. After filtration, the solid was lyophilized to give intermediate 3 (31 g, crude product) as a white solid.

[0210] Alternatively, the reaction can be carried out at 20 °C using 60.0 g of compound 2 as a starting material. After precipitation with HCl and filtration, the solid can be dissolved in DCM (2 L), washed with 0.5 M HCl (800 mL), H2O (800 mL), and brine (800 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 20 / 1) to give intermediate compound 3 as a white solid (120.0 g, 90% purity, containing a small amount of DMF, 83.3% yield). 1H NMR (400 MHz, DMSO-d) 6 ppm 9.70 (s, 1 H) 8.34 (t, J = 5.77 Hz, 1 H)7.90 (d, J = 7.53 Hz, 2 H) 7.71 (d, J = 7.53 Hz, 2 H) 7.61 (d, J = 8.28 Hz, 1H) 7.39 - 7.47 (m, 2 H) 7.29 - 7.36 (m, 2 H) 7.02 (d, J = 12.30 Hz, 1 H) 6.85- 6.92 (m, 2 H) 4.20 - 4.39 (m, 4 H) 4.11 - 4.19 (m, 2 H) 1.36 (s, 9 H). Compound 3 (30 g, 56.12 mmol, 1.0 equivalent) was stirred in a mixture of TFA (300 mL) and DCM (300 mL) at 15 °C for 0.5 h. The solvent was removed under reduced pressure. The residue was purified directly by passing it through a fast C18 column (ISCO®; 120 g SepaFlash® C18 fast column, elution with a 0-90% MeCN / H2O gradient at 75 mL / min) to give compound 4 (18 g, 37.6 mmol, 67.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm9.69 (s, 1 H) 8.34 (t,J = 5.90 Hz, 1 H) 7.90 (d, J = 7.28 Hz, 2 H) 7.71 (d, J= 7.53 Hz, 2 H) 7.54 (d, J = 6.53 Hz, 1 H) 7.42 (t, J = 7.40 Hz, 2 H) 7.27 -7.37 (m, 1 H) 7.27 - 7.37 (m, 1 H) 7.02 (d, J = 12.05 Hz, 1 H) 6.82 - 6.93(m, 2 H) 4.35 - 4.43 (m, 1 H) 4.20 - 4.31 (m, 3 H) 4.13 - 4.19 (m, 2 H).

[0211] Procedure for preparing the antibody-binding moiety (intermediate compound 5a) coupled to the reactive group. Peptides were synthesized using standard Fmoc chemical synthesis.

[0212] 1) Resin preparation: DIEA (4.00 equivalents) was added dropwise to a container containing 30 mL of DCM containing CTC resin (3.0 mmol, 3.0 g, 1.00 mmol / g) and Fmoc-Thr(tBu)-OH (1.19 g, 3.0 mmol, 1.00 equivalents), and the mixture was bubbled with N2 at 15°C for 2 hours. Then MeOH (3.0 mL) was added, and the mixture was bubbled with N2 for another 30 minutes. The resin was washed with DMF (60 mL), followed by the addition of DMF containing 20% ​​piperidine (60 mL), and bubbled with N2 at 15°C for 30 minutes to achieve Fmoc deprotection.

[0213] Filter the mixture and wash the resin with DMF (60 ml) before proceeding to the next step. Alternatively, this reaction can be carried out at 20°C.

[0214] 2) Coupling: 5.25 g of Fmoc-Cys(Trt)-OH (3.00 g) was added to the mixture. equivalent HBTU (3.24 g, 2.85 g) equivalent The solution in DMF (30 mL) was added to the resin via N2 bubbling. Then DIEA (6.00) was added. equivalent Add the ninhydrin dropwise to the mixture and bubble with N2 for 30 minutes at 15°C (or 20°C). Monitor the coupling reaction by the ninhydrin test; if it is colorless, the coupling is complete. Then wash the resin with DMF (60 mL).

[0215] 3) Deprotection: Add 60 mL of DMF containing 20% ​​piperidine to the resin and bubble the mixture with N2 at 15°C for 30 minutes. Monitor the deprotection reaction by ninhydrin test; if a blue or other brownish-red color appears, the reaction is complete. Then wash the resin with 60 mL of DMF.

[0216] 4) Repeat steps 2 and 3 for amino acids (3-13 in the table below).

[0217] 5) Coupling of compounds: Compound 4 (2.87 g, 2.00 g) was coupled with other compounds. equivalent) DIC (0.76 g, 2.00 equivalent) and HOBt (0.82 g, 2.00 equivalent) equivalent A solution in DMF (30 mL) was added to the resin at 15°C by bubbling with N2 for 60 minutes. The coupling reaction was monitored by a ninhydrin test; if the result was colorless, the coupling was complete. The resin was then washed with DMF (60 mL).

[0218] 6) Repeat step 3 to remove Fmoc protection.

[0219] 7) Repeat steps 5 and 6 for amino acids (10-13 in the table below).

[0220] 8) Acetylation: A solution of 10% Ac₂O / 5% NMM / 85% DMF (60 mL) was added to the resin, and the mixture was bubbled with N₂ for 20 minutes. The acetylation reaction was monitored by a ninhydrin test; if a colorless result was observed, the coupling was complete. The resin was then washed with DMF (60 mL) to obtain intermediate 5a. The procedure used to prepare BH-0003816. 1) Coupling: Dihydrogen- ions were added to a mixture of compound 5a (CTC resin, 0.50 mmol), DIEA (387.7 mg, 3.00 mmol, 522.53 μL, 6.00 equivalents), and DMAP (183.26 mg, 1.50 mmol, 3.00 equivalents) in anhydrous DMF (10 mL) by bubbling with N2 at 20 °C. 2H -pyran-2,6(3H)-dione (342.3 mg, 3.00 mmol, 6.00 equivalents). The mixture was then bubbled through N2 for 2 hours. LCMS showed completion after microcutting assay. The peptide resin ( Intermediate 30 Wash with DMF (20 mL, 5x) and use directly in the next step. LCMS: Retention time = 1.21 min, MS calculated value: M av =1789.95, [M + 2H] 2+ = 896.48. 2) TFP Ester Formation: A solution of TFP (830.37 mg, 5.00 mmol, 10.00 equivalent) and DIC (631.00 mg, 5.00 mmol, 774.23 μL, 10.00 equivalent) in anhydrous DMF (5 mL) was added to the resin-bound peptide (intermediate 30) by bubbling with N2 at 20 °C. The mixture was then bubbled with N2 for 2 hours. LCMS showed completion after microcutting assay. The resin was washed with DMF (20 mL, 5x) and 2-isopropoxypropane (20 mL, 3x) and dried by bubbling with N2 to give intermediate 31 (CTC resin, 0.5 mmol) as a bright yellow solid.

[0221] 3) Cutting: Add the cutting solution (TFA / Tis / H2O, 95 / 2.5 / 2.5, v / v / v, 20 mL) to a flask containing the side-chain protected peptide at room temperature and stir for 1 hour. After filtration, precipitate the filtrate with isopropyl ether (cold, 100 mL). After filtration, wash the solid twice more with isopropyl ether (cold, 50 mL) and dry under reduced pressure for 2 hours.

[0222] 4) Cycling: The crude peptide was dissolved in HOAc / MeCN / H2O (4 / 3 / 3, v / v / v, 500 mL). Then, 0.1 M I2 / AcOH was added dropwise to the mixture until the yellow color persisted, and the mixture was stirred at 20°C for 5 minutes. The mixture was quenched by adding 0.1 M Na2S2O3 aqueous solution dropwise until the yellow color disappeared. After filtration, the filtrate was purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to give intermediate 32 (73.0 mg, 89.2% purity, 6.7% yield) as a white solid. LCMS: Retention time = 1.31 min, MS calculated value: M av = 1935.99, [M + 2H] 2+ = 968.03.

[0223] preparation Intermediate 32 (20.0 mg, 10.6 μmol, 1.00 equivalent) and DIEA (6.82 mg, 53.0 μmol, 5.00 equivalent) were added to a solution of vcMMAE (11.9 mg, 10.6 μmol, 1.00 equivalent) in DMSO (400 μL) at 20 °C. The mixture was stirred at 20 °C for 2 h. LC-MS showed that the starting material was completely consumed. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (TFA conditions) to obtain a white solid (16.8 mg, 5.89 μmol, 55.8% yield, 96.8% purity). LC-MS: Retention time = 1.118 min, MS calculated value: M av = 2893.35, [M + 2H] 2+ =1447.20, [M + 3H] 3+ = 965.15.

[0224] Preparative HPLC conditions Joining methods Bentoximab (“Antibody A”) was buffer-exchanged in 8 dilution volumes (DV) using 50 mM HEPES buffer at pH 7.5. The target antibody concentration after buffer exchange was >14 mg / mL. A 10 mM stock solution of Reagent A in DMSO was then prepared for conjugation (Reagent A: ( S)-3-acetamido-4-(((4R,7S,10S,13S,16S,22S,25S,28S,31S,34R)-7,28-bis((1H-indol-3-yl)methyl)-25-(2-((4-((5-(((S)-1-(((S)-1-((4-((5S,8S,11S,12R)-11- ((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylprop-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,1 3-Dioxa-4,7,10-triazatetradecyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-5-oxopentanoyl)oxy)-3-fluorobenzyl)amino)-2-oxoethyl)-4-(((1S,2R)-1-carboxy-2-hydroxypropyl)carbamoyl)-16-(2-carboxyethyl)-13,22-diisobutyl-10-isopropyl-31-methyl-6,9,12,15,18,21,24,27,30,33-decoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentanetriacontane-34-yl)amino)-4-oxobutyric acid).

[0225] The conjugation of reagent A with antibody A (40 mg, 0.27 μol) was performed at 25°C using 4 equivalents of reagent A (1.07 μmol, 3.12 mg) in 50 mM HEPES buffer (pH 7.5) at an antibody concentration of 10 mg / mL with 20% (v / v) DMSO and stirred for 48 hours.

[0226] The drug-to-antibody ratio (DAR) of the conjugation reaction was analyzed by LC-MS every 24 hours. When the DAR reached >1.9, buffer exchange with PBS at pH 7.4 was performed over 30 DV using UFDF to achieve a final concentration range of approximately 7 mg / mL. The mass of reagent A was then analyzed under various conditions. The results are shown in Table 1.

[0227] Table 1. Analytical Data. DAR calculation: Figure 1 shows the spectral characterization of the conjugate of bentuximab and reagent A.

[0228] Figure 2 illustrates the properties of site-specific antibody-drug conjugates according to an embodiment of the present invention.

[0229] Figure 3 illustrates the activation of protein engineering and chemistry for alternative antibody-drug conjugates.

[0230] Figure 4 illustrates a potential best-in-class antibody-drug conjugate according to an embodiment of the present invention.

[0231] Figure 5 illustrates the pharmacokinetic (PK) studies of Adcetris® and antibody-drug conjugates according to embodiments of the present invention.

[0232] Figure 6 illustrates the potential for superior efficacy of antibody-drug conjugates according to embodiments of the present invention compared to Adcetris®.

[0233] Figure 7 illustrates the improved survival rate in mouse models with antibody-drug conjugates according to embodiments of the present invention, compared to Adcetris®.

[0234] Figure 8 shows the results of a single-dose, 14-day mouse tumor xenograft study in the case of an antibody-drug conjugate according to an embodiment of the present invention.

[0235] Throughout this application, various publications are cited by author name and date, or by patent number or patent publication number. The disclosures of these publications are thereby incorporated herein in their entirety by reference in order to provide a more comprehensive description of prior art known to those skilled in the art up to the date of the invention described and claimed herein. However, references herein should not be construed as an admission that such references are prior art to this invention.

[0236] Those skilled in the art will recognize or be able to determine many equivalents of the specific procedures described herein using experiments not exceeding those of conventional methods. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and examples herein may be used. Furthermore, it is contemplated that specific items within the list of items or sub-clusters of items within larger groups of items may be combined with other specific items, sub-clusters of items, or larger groups of items, regardless of whether specific disclosures herein identify such combinations.

Claims

1. A compound having the structure of formula (RI): LG-RG-L RM -ME, (RI) or its salt, wherein: LG is a group containing a target-binding moiety that binds to brentuximab or its biosimilar analogues. RG is a reactive group; L RM It includes The linking group; and The MOI is the portion of interest that includes monomethylopilotrine D (MMAD), monomethylopilotrine E (MMAE), or monomethylopilotrine F (MMAF).

2. The compound of claim 1, wherein LG-RG is or comprises 。 3. The compound according to claim 1 or 2, wherein L RM Yes or include 。 4. The compound according to any one of claims 1 to 3, wherein the MOI is or comprises 。 5. The compound according to any one of claims 1 to 4, wherein the target-binding portion is configured to bind to benzoxicam or a biosimilar thereof such that the reactive group is adjacent to K246 or K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction causing the L-containing compound to... RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

6. The compound according to any one of claims 1 to 5, wherein the target-binding portion is configured to bind to benzoxicam or a biosimilar thereof such that the reactive group is proximate to K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction causing the L-containing compound to... RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

7. A compound having the structure of formula (RI): LG-RG-L RM -ME, (RI) or its salt, wherein: LG is a group containing a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; LG-RG is or contains ; L RM Yes or include ;and MOI is or contains .

8. The compound of claim 7, wherein the target-binding portion is configured to bind to benzoxicam or a biosimilar thereof such that the reactive group is proximate to K246 or K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction causing the L-containing... RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

9. The compound of claim 7 or 8, wherein the target-binding portion is configured to bind to benzoxicam or a biosimilar thereof such that the reactive group is proximate to K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction resulting in the inclusion of L RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

10. A method for preparing a pharmaceutical agent having the structure of formula (PI): P-(L PM -ME)2, (PI) or its salt, wherein: P is bentuximab or a biosimilar of it; Each L PM It includes The linking group; and Each MOI is the portion of interest containing monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF). The method includes the following steps: (1) Contacting bentuximab or a bio-similar thereof with a reaction coupler having the structure of formula (RI): LG-RG-L RM -ME, (RI) or its salt, wherein: LG is a group containing a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes Linking groups; The MOI is the portion of interest containing monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF), and (2) Forming a drug having the structure of formula (PI).

11. The method of claim 10, wherein LG-RG is or comprises 。 12. The method according to claim 10 or 11, wherein L RM Yes or include 。 13. The method according to any one of claims 10 to 12, wherein the MOI is or comprises 。 14. The method according to any one of claims 10 to 13, wherein the target-binding portion of the reagent conjugate is configured to bind to benzoxicam or a bio-similar thereof such that the reactive group is brought into contact with K246 or K248 of the benzoxicam IgG heavy chain or a bio-similar thereof, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction causing L to be contained in the benzoxicam IgG heavy chain or a bio-similar thereof. RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

15. The method according to any one of claims 10 to 14, wherein the target-binding portion of the reagent conjugate is configured to bind to benzoxicam or a bio-similar thereof such that the reactive group is brought into contact with K248 of the benzoxicam IgG heavy chain or a bio-similar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction causing L to be contained in the benzoxicam IgG heavy chain or a bio-similar thereof. RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

16. The method according to any one of claims 10 to 15, wherein the contacting and forming steps are carried out in a chemical reaction.

17. A pharmaceutical preparation having the structure of formula (PI): P-(L PM -ME)2, (PI) or its salt, wherein: P is bentuximab or a biosimilar of it; Each L PM It includes The linking group; and Each MOI is the portion of interest containing monomethylopistatin D (MMAD), monomethylopistatin E (MMAE), or monomethylopistatin F (MMAF).

18. The pharmaceutical preparation according to claim 17, wherein L RM Yes or include 。 19. The pharmaceutical agent according to claim 17 or 18, wherein the MOI is or comprises 。 20. The pharmaceutical agent according to any one of claims 17 to 19, wherein each L PM -MOI is linked to K246 or K248 of the benzoxicam IgG heavy chain or its biosimilar analogue.

21. The pharmaceutical agent according to any one of claims 17 to 20, wherein each L PM -MOI is linked to K248 of the benzoxicam IgG heavy chain or its biosimilar analogue.

22. A method for preparing a pharmaceutical agent having a (P-II) structure: P-(NH-L PM -ME)2, (P-II) in: P-NH is a benzoximab or a biosimilar thereof, which contains a lysine residue having a terminal NH group. L PM It includes The linking group; and The MOI is the portion of interest that includes monomethylopistatin D (MMAD), monomethylopistatin E (MMAE), or monomethylopistatin F (MMAF). The method includes the following steps: (1) Providing benzoxicam or a biosimilar thereof, said benzoxicam or a biosimilar thereof having the structure P-(NH2)2, wherein each NH2 is a terminal amino group of a lysine residue; and (2) Contacting P-(NH2)2 with a reaction coupler having the structure of formula (RI): LG-RG-L RM -ME, (RI) or its salt, wherein: LG is a group containing a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes The linking group; and The MOI is the portion of interest that includes monomethylopilotrine D (MMAD), monomethylopilotrine E (MMAE), or monomethylopilotrine F (MMAF).

23. The method of claim 22, wherein LG-RG is or comprises 。 24. The method according to claim 22 or 23, wherein L RM Yes or include 。 25. The compound according to any one of claims 22 to 24, wherein the MOI is or comprises 。 26. The method according to any one of claims 22 to 25, wherein the target-binding portion of the reagent conjugate is configured to bind to benzoxicam or a bio-similar thereof such that the reactive group is proximate to K246 or K248 of the benzoxicam IgG heavy chain or a bio-similar thereof, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction causing L to be contained in the benzoxicam IgG heavy chain or a bio-similar thereof. RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

27. The method according to any one of claims 22 to 26, wherein the target-binding portion of the reagent conjugate is configured to bind to benzoxicam or a bio-similar thereof such that the reactive group is brought into contact with K248 of the benzoxicam IgG heavy chain or a bio-similar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction causing the L-containing RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

28. The method according to any one of claims 22 to 27, wherein the contacting and forming steps are carried out in a chemical reaction.

29. A pharmaceutical agent having a (P-II) structure: P-(NH-L PM -ME)2, (P-II) in: P-NH is a benzoximab or a biosimilar thereof, which contains a lysine residue having a terminal NH group. L PM It includes The linking group; and The MOI is the portion of interest that includes monomethylopilotrine D (MMAD), monomethylopilotrine E (MMAE), or monomethylopilotrine F (MMAF).

30. The pharmaceutical preparation according to claim 29, wherein L RM Yes or include 。 31. The pharmaceutical agent according to claim 29 or 30, wherein the MOI is or comprises 。 32. The pharmaceutical preparation according to any one of claims 29 to 31, wherein the lysine residue is K246 or K248 of the benzoxicam IgG heavy chain or its biosimilar analogue.

33. The pharmaceutical preparation according to any one of claims 28 to 32, wherein each lysine residue is K248 of the benzoxicam IgG heavy chain or a biosimilar thereof.

34. A compound having the structure of formula (RI): LG-RG-L RM -ME, (RI) or its salt, wherein: LG is a group containing a target-binding moiety that binds to bentuximab or its biolike analogues. RG is a reactive group; L RM It includes The linking group; and The MOI is the portion of interest that includes monomethylopistatin D (MMAD), monomethylopistatin E (MMAE), or monomethylopistatin F (MMAF). The bentuximab or its biosimilars contain an IgG heavy chain, wherein the IgG heavy chain contains K246 or K248, and The target-binding portion is configured to bind to benzoxicam or a biosimilar thereof such that the reactive group is brought into contact with K246 or K248 of the benzoxicam IgG heavy chain or a biosimilar thereof, thereby enabling a reaction between K246 or K248 and the reactive group, the reaction causing the L-containing... RM The -MOI portion is connected to K246 or K248, and causes the group containing the target-binding portion to be expelled from the compound.

35. The compound of claim 34, wherein LG-RG is or comprises 。 36. The compound according to claim 34 or 35, wherein the MOI is or comprises 。 37. The compound according to any one of claims 34 to 36, wherein the target-binding portion is configured to bind to benzoxicam or a bio-similar thereof such that the reactive group is brought into contact with K248 of the benzoxicam IgG heavy chain or a bio-similar thereof, thereby enabling a reaction between K248 and the reactive group, the reaction causing the L-containing compound to... RM The -MOI portion is connected to K248, and causes the group containing the target-binding portion to be expelled from the compound.

38. A method of treating a subject with Hodgkin lymphoma who requires such treatment, the method comprising administering to the subject a pharmaceutically effective amount of any one of claims 17 to 21 or 29 to 37.

39. A method of treating a subject with systemic anaplastic large cell lymphoma who requires such treatment, the method comprising administering to the subject a pharmaceutically effective amount of any one of claims 17 to 21 or 29 to 37.

40. A method of treating a subject with primary cutaneous anaplastic large cell lymphoma who requires such treatment, the method comprising administering to the subject a pharmaceutically effective amount of any one of claims 17 to 21 or 29 to 37.

41. A method of treating a subject with CD30-expressing mycosis fungoides in need of such treatment, the method comprising administering to the subject a pharmaceutically effective amount of any one of claims 17 to 21 or 29 to 37.

42. A method of treating a subject with cutaneous T-cell lymphoma requiring such treatment, the method comprising administering to the subject a pharmaceutically effective amount of any one of claims 17 to 21 or 29 to 37.

43. A method for selectively targeting tumor cells expressing the CD30 antigen in a subject, the method comprising administering to the subject an agent according to any one of claims 17 to 21 or 29 to 37.

44. A composition comprising: The first compound has the structure of formula (P-II): NLP PM -ME (P-II) in: PN is a biosimilar of benzoxicam or a biosimilar thereof, which contains lysine residues; L PM It includes The linking group; and The MOI is the portion of interest containing monomethylolpropionate D (MMAD), monomethylolpropionate E (MMAE), or monomethylolpropionate F (MMAF); and The second compound has the following structure: LG-OH (LG-I) LG is a group containing a target-binding moiety that binds to bentuximab or its bio-similar analogues.

45. The composition according to claim 44, further comprising: A third compound, wherein the third compound has the formula (RI): LG-RG-L RM -ME(LAUGH) LG is a group comprising a target-binding moiety that binds to bentuximab or its bio-similar analogues, said group being identical to LG in formula (LG-I); RG is a reactive group; L RM It is a linking group, which is identical to the LRM in formula (P-II); and MOI is the part of interest, which is the same as the MOI in equation (P-II); and The fourth compound has the formula (R-III): HO-RG-L RM -MOI(R-III) Or a combination thereof.

46. ​​The compound according to claim 44 or 45, wherein LG-RG is or comprises 。 47. The compound according to any one of claims 44 to 46, wherein L RM Yes or include 。 48. The compound according to any one of claims 44 to 47, wherein the MOI is or comprises 。

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