Modified antibodies acting as molecular degradation agents via cell receptors

Abstract

This invention provides a bifunctional compound that can be used to promote or enhance the degradation of specific circulating proteins. [Solution] Compounds containing formula (I), etc.: [Ab] k’ -[CON] h -[Linker] i -[CON] h’ -[CRBM] j’ (I) In the formula, Ab is an antibody that binds to an extracellular protein; CRBM is a cell receptor binding portion that binds to at least one receptor on the surface of a degradable cell in the subject, and the binding of (I) by this portion causes endocytosis and degradation of the extracellular protein; each CON is a group that binds independently or covalently links Ab to CRBM, Ab to a linker, and / or the linker to CRBM; the linker is a group having a valency in the range of 1 to 15; k' is an integer in the range of 1 to 15; h is an integer in the range of 0 to 15; i is an integer in the range of 0 to 15; h' is an integer in the range of 0 to 15; and j is an integer in the range of 1 to 15.

Description

[Technical Field]

[0001] Description of research or development sponsored by the federal government. This invention was made possible with government support under GM067543, awarded by the U.S. National Institutes of Health. The government has certain rights in this invention.

[0002] Cross-reference of related applications This application claims priority under 119(e) of U.S. Patent Provisional Application No. 62 / 913,679, filed October 10, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0003] Background of Disclosure One mechanism that controls the transport of molecules into cells is receptor-mediated endocytosis. In this process, receptors on the cell surface bind to specific ligands (or molecules containing such ligands) located outside the cell. These ligands can be small molecules, metabolites, hormones, proteins, or even viruses. This binding process induces inward budding (invagination) of the plasma membrane, forming vesicles containing the receptor-ligand complex. These vesicles become endosomes, which then fuse with lysosomes, where the receptor is degraded along with its bound ligand cargo, or the receptor is recirculated to the cell surface for further collection of circulating ligands.

[0004] One such receptor is the asialoglycoprotein receptor (ASGPR). This receptor is a type C lectin whose primary biological role is to bind to glycoproteins (asialoglycoproteins) containing terminal galactose or N-acetylgalactosamine residues, internalize them, and subsequently remove them from circulation. ASGPR removes target glycoproteins from circulation through endocytosis and subsequent lysosomal degradation. ASGPR is highly expressed on the surface of hepatocytes, several human cancer cell lines, and liver cancer cells, and is lowly expressed by gallbladder and gastric glandular cells. These receptors are known to be involved in the removal of IgG subtypes and other antibody isotypes from circulation, removal of apoptotic cells, removal of low-density lipoprotein (LDL) and chylomicron remnants, and disposal of cellular fibronectin.

[0005] There is a need in the art for novel compounds and methods that enable the inhibition, removal, and / or degradation of specific extracellular proteins that mediate disease and / or impairment in subjects. This disclosure addresses this need. [Overview of the Initiative]

[0006] Brief summary of the disclosure This disclosure provides compounds comprising formula (I), or salts thereof, geometric isomers, stereoisomers, or solvates thereof: [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) In the formula, Ab, CON, linker, CRBM, k', h, i, h', and j' are defined elsewhere in this specification.

[0007] This disclosure further provides a pharmaceutical composition comprising at least one compound as envisioned herein and at least one pharmaceutically acceptable excipient.

[0008] This disclosure further provides a method for treating a disease or disorder in a subject, comprising the step of administering a therapeutically effective amount of at least one compound as defined herein. [Brief explanation of the drawing]

[0009] The drawings generally illustrate various aspects of this application, not as limitations.

[0010] As used herein, the term "REAG" means any reagent containing -CON, -linker, -CON-linker, -linker-CON, -CON-linker-CON, -CRBM, -CON-CRBM, -linker-CRBM, -CON-linker-CRBM, -linker-CON-CRBM, and / or -CON-linker-CON-CRBM.

[0011] [Figure 1] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 2] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 3] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 4] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 5] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 6] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 7] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 8] This demonstrates the non-limiting preparation of polymer compounds containing a mannose-6-phosphate receptor binder. [Figure 9] This shows non-restrictive examples of R1 and / or R3 groups in ASGPRBM. [Figure 10] This shows a non-restrictive example of the R2 group in ASGPRBM. [Figure 11A] Figures 11A and 11B show non-restrictive synthesis of the ASGRBM group. [Figure 11B] See the explanation in Figure 11A. [Figure 12A] Figures 12A–12C show non-restrictive synthesis of a specific ASGPRBM group. This example discloses non-restrictive Cbz protecting groups, but synthesis may be carried out using any other suitable protecting groups known to those skilled in the art. Protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 12B] See the explanation in Figure 12A. [Figure 12C] See the explanation in Figure 12A. [Figure 13A] Figures 13A to 13L show non-restrictive synthesis of a specific ASGRBM group. This example discloses non-restrictive Cbz protecting groups, but synthesis may be carried out using any other suitable protecting groups known to those skilled in the art. Protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 13B] See the explanation in Figure 13A. [Figure 13C] See the explanation in Figure 13A. [Figure 13D] See the explanation in Figure 13A. [Figure 13E] See the explanation in Figure 13A. [Figure 13F] See the explanation in Figure 13A. [Figure 13G] See the explanation in Figure 13A. [Figure 13H] See the explanation in Figure 13A. [Figure 13I] See the explanation in Figure 13A. [Figure 13J] See the explanation in Figure 13A. [Figure 13K] See the explanation in Figure 13A. [Figure 13L] See the explanation in Figure 13A. [Figure 14A]Figures 14A–14O show non-restrictive synthesis of specific ASGRBM groups. While this example discloses non-restrictive Cbz protecting groups, synthesis may be carried out using any other suitable protecting groups known to those skilled in the art. Protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 14B] See the explanation in Figure 14A. [Figure 14C] See the explanation in Figure 14A. [Figure 14D] See the explanation in Figure 14A. [Figure 14E] See the explanation in Figure 14A. [Figure 14F] See the explanation in Figure 14A. [Figure 14G] See the explanation in Figure 14A. [Figure 14H] See the explanation in Figure 14A. [Figure 14I] See the explanation in Figure 14A. [Figure 14J] See the explanation in Figure 14A. [Figure 14K] See the explanation in Figure 14A. [Figure 14L] See the explanation in Figure 14A. [Figure 14M] See the explanation in Figure 14A. [Figure 14N] See the explanation in Figure 14A. [Figure 14O] See the explanation in Figure 14A. [Figure 15] This paper presents a non-restrictive synthetic scheme that enables the labeling (derivativeization) of antibodies (labeled as Ab) using an azide group. [Figure 16] A non-limiting synthetic scheme is presented that enables the labeling (derivativeization) of CRBM groups with strain alkyne-containing groups. In certain non-limiting embodiments, any azide-containing compound (as shown in Figure 15, but not limited thereto) can react with a strain alkyne-containing compound (as shown in Figure 16, but not limited thereto) to produce the compounds of this disclosure. [Modes for carrying out the invention]

[0012] Detailed explanation of disclosure In one aspect, the present disclosure provides bifunctional compounds that can be used to promote or enhance the degradation of extracellular proteins (which may be, for example, circulating proteins and / or cell surface proteins that can bind to or embed in cell membranes). In certain embodiments, extracellular proteins mediate disease and / or impairment in a subject, and treatment or management of the disease and / or impairment requires the degradation, removal, or reduction of the concentration of extracellular proteins in the subject. Accordingly, in certain embodiments, administration of the compounds of the present disclosure to a subject removes extracellular proteins and / or reduces the circulating concentration of extracellular proteins, thereby treating, relieving, or preventing disease and / or impairment in the subject.

[0013] In certain embodiments, the compounds of the Disclosure include antibodies, such as monoclonal antibodies, capable of binding to extracellular proteins of interest. In other embodiments, the compounds of the Disclosure further include another group (such as a small molecule) that binds to a cell receptor, and this binding results in endocytosis of the compound (and / or extracellular protein-compound complex). The receptor binder and antibody may be linked by linkers, such as polyethylene glycol (PEG), any other linker described herein having an adjustable length, or any other linker described herein and containing one or more conjugation molecules referred to herein as CON. Binding of the antibody to the conjugation molecules may be achieved using any chemical reaction known to those skilled in the art, such as lysine bioconjugation using activated esters, such as NHS esters, but not limited to NHS esters. When the extracellular protein-compound complex undergoes endocytosis, the extracellular protein is ultimately degraded, and the compound may be degraded or recycled outside the cell.

[0014] In certain embodiments, the receptor is the hepatocyte asialoglycoprotein receptor (ASGPR). In this case, the binding site is referred to herein as the ASGPR binding site or ASGRBM. This disclosure is not limited to this receptor, but rather envisions the use of other receptors described herein or any other endocytosis receptor known in the art.

[0015] Furthermore, this disclosure is not limited to degradation occurring in hepatocytes. Rather, this disclosure assumes that non-hepatocytes in the body present specific degradation receptors, and such receptors are assumed to be within the scope of this disclosure.

[0016] In one aspect, the compounds of the Disclosure bind to extracellular target proteins and remove them from the body's circulation (and the body) via the liver. Thus, the compounds of the Disclosure utilize the body's own mechanisms to degrade proteins. While it is not desirable to be limited to theory, the compounds of the Disclosure bind to specific receptors located in specific cells, such as but not limited to hepatocytes, such as ASGPR. This binding induces the degradation of protein targets by intralysosomal proteolysis. As a result of this mechanism, the circulating levels of extracellular protein targets decrease. Consequently, the corresponding disease symptoms are attenuated and / or disappear from the patient in whom the compound is administered.

[0017] ASPGR has the function of eliminating desialylated glycoproteins having exposed unreduced D-galactose (Gal) or N-acetylgalactosamine (GalNac) as terminal groups. ASGPR is expressed at a level of approximately 500,000 per hepatocyte and is present only minimally in other parts of the body. Internalization of target glycoproteins by ASGPR exhibits a half-life of approximately 3 minutes. The bifunctional compound claimed herein selectively binds to extracellular proteins through the antibody portion of the compound, thereby forming a protein complex. Upon reaching the liver, the asialoglycoprotein receptor-binding portion (ASGPRBM) of the molecule engages with the hepatocyte's lysosomal pathway via ASGPR. Endosome-bound ASPGR releases the extracellular protein ligand at pH 5.4, and the ligand is removed from circulation by the hepatocyte. However, ASPGR remains available for recirculation, escaping lysosomal degradation and budding into recirculating endosomes. In fact, depending on the cell line, ASPGR can be recirculated up to approximately 200 times at a recirculation rate of about 15-20 minutes. ASPGR exhibits very coarse ligand size requirements, possibly reaching a diameter of about 70 nm. In contrast, IgM pentamers are approximately 20 nm in diameter and therefore meet the ligand size requirements of ASPGR.

[0018] The disclosures of international patent application number PCT / US2019 / 026260, filed on April 8, 2019 (and published on October 17, 2019 as WO 2019 / 199634), and international patent application number PCT / US2019 / 026239, filed on April 8, 2019 (and published on October 17, 2019 as WO 2019 / 199621), are incorporated herein by reference in their entirety.

[0019] While it is undesirable to limit ourselves to theory, the use of antibodies, including but not limited to monoclonal antibodies, within the compounds of this disclosure offers clear advantages compared to similar bifunctional compounds in the prior art.

[0020] In one aspect, the affinity of an antibody to a target is often in the pM to low nM range, which corresponds to particularly strong binding. In contrast, small molecule protein binders often exhibit affinity in the nM to μM range to their targets. Therefore, antibodies are expected to exhibit much stronger binding to molecular targets of interest.

[0021] In another context, antibodies, such as but not limited to monoclonal antibodies, are highly specific to their intended target, thereby reducing antibody toxicity due to off-target interactions.

[0022] In another aspect, antibodies interact with the neonatal Fc receptor (FcRn), also known as the Brambell receptor. In humans, FcRn regulates the turnover of IgG and serum albumin. FcRn prolongs the half-lives of IgG and serum albumin by reducing lysosomal degradation in endothelial cells and bone marrow-derived cells. IgG, serum albumin, and other serum proteins are continuously internalized through phagocytosis and would likely be degraded in lysosomes. However, IgG and serum albumin are bound by FcRn at a slightly acidic pH (below 6.5), recirculated to the cell surface, where they are released at the neutral pH of the blood (above 7.0), thereby avoiding lysosomal degradation. Interestingly, both FcRn and ASGPR are expressed on hepatocytes, the primary cell type where ASGPR-mediated degradation occurs. Therefore, the compounds of this disclosure can avoid ASGPR-mediated degradation while binding to ASGBRBM by binding to FcRn.

[0023] Rescuing the compounds of this disclosure by FcRn offers several therapeutic advantages. Generally, compounds containing circulating protein small molecule binding partners are degraded along with the circulating protein of interest. In contrast, the modified antibodies of this disclosure can participate in multiple protein binding and targeted degradation through recirculation by FcRn. Furthermore, because the compounds of this disclosure can participate in multiple degradations, they can be administered at relatively low doses, which is therapeutically advantageous. In addition, since the half-life of the compounds of this disclosure is extended by FcRn rescue, the frequency of administration of these compounds is reduced compared to the frequency required when using compounds containing circulating protein small molecule binding partners.

[0024] In fact, the antibody-containing compounds of this disclosure exhibit advantageous properties not only compared to previously described compounds containing circulating protein small molecule binding partners, but also compared to underivativeized antibodies themselves. The primary function of unmodified antibodies is to bind to and neutralize protein targets. In this situation, each unmodified antibody may participate in a single binding event. In contrast, the antibody-containing compounds of this disclosure function by degrading protein targets, and a certain percentage of these compounds, after the degradation event has occurred, are recycled by FcRn and become available to participate in another binding event. Thus, these available antibody-containing compounds of this disclosure can participate in semicatalytic proteolysis, a property facilitated by FcRn-mediated recycling.

[0025] As a further advantage, this disclosure enables the efficient generation of novel antibody-containing compounds in which ASGBRBM is conjugated to any selected antibody (without requiring modification of the amino acid sequence of the antibody and / or extensive testing of the effects of such amino acid changes on FcRn binding, protein binding, and protein release). This ease of synthesis is useful for investigating the degradation of various protein targets. In certain embodiments, using this method is less expensive than traditional antibody modification methods. In certain embodiments, the lower dosing regimens of the antibody-containing compounds of this disclosure (compared to other antibody therapies) reduce overall treatment costs and lower the financial burden on insurance companies and patients.

[0026] In accordance with this disclosure, conventional chemical synthesis and pharmaceutical formulation methods, as well as pharmacological, molecular biological, microbiological, and recombinant DNA techniques within the scope of the skills in the art, can be used. These techniques are well known and are described elsewhere in the literature.

[0027] Herein, specific aspects of the disclosed subject matter will be mentioned in detail. Some examples of these aspects are shown in the accompanying drawings. The disclosed subject matter will be described in relation to the numbered claims, but it will be understood that the illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0028] Throughout this document, values ​​expressed in the form of a range should be interpreted flexibly to include not only the numerical values ​​explicitly stated as the limits of the range, but also all individual numerical values ​​or subranges contained within that range, as if each numerical value and subrange were explicitly stated. For example, the range "approximately 0.1% to approximately 5%" or "approximately 0.1% to approximately 5%" should be interpreted to include not only approximately 0.1% to approximately 5%, but also individual values ​​within the indicated range (e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). Unless otherwise specified, the notation "approximately X to Y" is equivalent to "approximately X to approximately Y". Similarly, unless otherwise specified, the notation "approximately X, Y, or approximately Z" is equivalent to "approximately X, approximately Y, or approximately Z".

[0029] In the methods described herein, the actions may be performed in any order unless a chronological or operational order is explicitly stated. Furthermore, unless the express language of the claim states that certain actions must be performed separately, they may be performed simultaneously. For example, the action of performing X and the action of performing Y described in the claim may be performed simultaneously in a single operation, and the resulting process is within the literal scope of the process described in the claim.

[0030] definition As used herein, the term “approximately” allows for a variation in the value or range of the stated value or range within, for example, 10%, 5%, or 1% of the stated value or range limit, and includes the exact value or range stated.

[0031] In this document, unless otherwise indicated by context, the terms “a,” “an,” or “the” are used to refer to one or more items. Unless otherwise indicated, the term “or” is used to mean non-exclusive “or.” The phrases “at least one of A and B” or “at least one of A or B” are synonymous with “A, B, or A and B.” Furthermore, any words or terms used herein and not otherwise defined should be understood to be for descriptive purposes only and not to be restrictive. Any use of section headings is intended to aid in the reading of this document and should not be interpreted as restrictive. Information related to section headings may arise inside or outside that particular section. All publications, patents, and patent documents referenced herein are incorporated herein by reference in whole, as if each individual were incorporated by reference.

[0032] When used in the context of organisms, tissues, cells, or components thereof, the term “abnormal” means an organism, tissue, cell, or component thereof in which at least one observable or detectable feature (e.g., age, treatment, time, etc.) differs from that which exhibits each “normal” (expected) feature. A feature that is normal or expected in one cell type or tissue type may be abnormal in a different cell type or tissue type.

[0033] As used herein, the term “acyl” means a group containing a carbonyl moiety, bonded through a carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen atom that forms a “formyl” group, or to another carbon atom that may be part of an alkyl group, aryl group, aralkyl group, cycloalkyl group, cycloalkylalkyl group, heterocyclyl group, heterocyclylalkyl group, heteroaryl group, heteroarylalkyl group, etc. The acyl group may contain 0 to about 12, 0 to about 20, or 0 to about 40 further carbon atoms bonded to the carbonyl group. The acyl group may contain double or triple bonds within the scope of its meaning as herein. The acryloyl group is an example of an acyl group. The acyl group may contain heteroatoms within the scope of its meaning as herein. The nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the scope of its meaning as herein. Other examples include the acetyl group, benzoyl group, phenylacetyl group, pyridylacetyl group, cinnamoyl group, and acryloyl group. When a group containing a carbon atom bonded to a carbonyl carbon atom also contains a halogen, the group is called a "haloacyl" group. One example is the trifluoroacetyl group.

[0034] As used herein, the term “alkyl” means linear and branched alkyl groups, as well as cycloalkyl groups, having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbon atoms, or in some embodiments, 1 to 8 carbon atoms. Examples of linear alkyl groups include groups having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl groups, isoalkyl groups, and anteisoalkyl groups, as well as other branched alkyl groups. Typical substituted alkyl groups may be substituted once or more times with any of the groups listed herein, such as amino groups, hydroxyl groups, cyano groups, carboxyl groups, nitro groups, thio groups, alkoxy groups, and halogen groups.

[0035] As used herein, the term “alkenyl” means linear, branched, and cyclic alkyl groups, as defined herein, except that at least one double bond is present between two carbon atoms. Thus, alkenyl groups have 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl.

[0036] As used herein, the term “alkoxy” means an oxygen atom connected to an alkyl group, including cycloalkyl groups as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, and isohexyloxy. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. An alkoxy group may contain about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to an oxygen atom, and may further contain double or triple bonds, and may also contain heteroatoms. For example, the allyloxy group or methoxyethoxy group are alkoxy groups within the scope of meaning as defined herein, as is the methylenedioxy group in the context of substituting two adjacent atoms in the structure with them.

[0037] As used herein, the term "alkynyl" means linear and branched alkyl groups as defined herein, except that at least one triple bond is present between two carbon atoms. Thus, alkynyl groups have 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3).

[0038] As used herein, the term "amine" means primary, secondary, and tertiary amines having, for example, the formula N(group)3 where each group can be independently H or non-H such as alkyl or aryl. Amines include R-NH2, such as alkylamines, arylamines, alkylarylamines; R2NH where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclic amines, etc.; and R3N where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc., but are not limited thereto. The term "amine" also includes ammonium ions as used herein.

[0039] The term "amino acid sequence variant" means a polypeptide having an amino acid sequence that is somewhat different from a native sequence polypeptide. Usually, amino acid sequence variants show at least about 70% homology, at least about 80% homology, at least about 90% homology, or at least about 95% homology to the native polypeptide. Amino acid sequence variants show substitutions, deletions, and / or insertions at specific positions within the amino acid sequence of the native amino acid sequence.

[0040] As used herein, the term "amino group" refers to substituents of the forms -NH2, -NHR, -NR2, -NR3 where each R is independently selected, + and the protonated forms of each form except -NR3 that cannot be protonated. + Thus, any compound substituted with an amino group can be regarded as an amine. The "amino group" within the scope of the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. The "alkylamino" group includes monoalkylamino groups, dialkylamino groups, and trialkylamino groups.

[0041] As used herein, the term "aminoalkyl" means an amine attached to an alkyl group as defined herein. The amine group can occur at any suitable position within the alkyl chain, for example at the end of the alkyl chain or anywhere within the alkyl chain.

[0042] As used herein, the term "antibody" means an immunoglobulin molecule that specifically binds to an antigen. An antibody can be an intact immunoglobulin derived from a natural or recombinant source, or it can be an immunoreactive portion of an intact immunoglobulin. Typically, an antibody is a tetramer of immunoglobulin molecules. Antibodies in the present disclosure can exist in various forms including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab, and F(ab)2, as well as single-chain antibodies and humanized antibodies (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426).

[0043] The term "antibody fragment" refers to a portion of an intact antibody, specifically the antigen-determining variable region of an intact antibody. Examples of antibody fragments include, but are not limited to, Fab fragments, Fab' fragments, F(ab')2 fragments, and Fv fragments; linear antibodies, scFv antibodies; single-domain antibodies, such as sdAb(VL or VH), such as camel antibodies (Riechmann, 1999, J. Immunol. Meth. 231:25-38); camel VHH domains, which consist of a VL domain or VH domain that exhibits sufficient affinity for the target; and bivalent fragments containing two Fab fragments linked by disulfide crosslinks in the hinge region; as well as isolated complementarity-determining regions (CDRs) or other epitope-binding fragments of an antibody. Antigen-binding fragments may be incorporated into single-domain antibodies, maxi-antibodies, mini-antibodies, nano-antibodies, intracellular antibodies, bispecific antibodies, triplicate antibodies, quadruplicate antibodies, v-NARs, and bis-scFvs (see, for example, Hollinger & Hudson, 2005, Nature Biotech. 23:1126-1136). Antigen-binding fragments may be grafted onto polypeptide-based scaffolds such as fibronectin type III (Fn3) (see U.S. Patent No. 6,703,199, describing fibronectin polypeptide mini-antibodies). Antibody fragments may include human antibodies or humanized antibodies, or portions of human antibodies or humanized antibodies.

[0044] As used herein, the terms “antigen” or “Ag” are defined as molecules that induce an immune response. This immune response may include antibody production, activation of specific immune cells, or both. Those skilled in the art will understand that virtually any macromolecule, including any protein or peptide, can act as an antigen. Furthermore, antigens may originate from recombinant DNA or genomic DNA. Those skilled in the art will understand that any DNA containing a nucleotide sequence or partial nucleotide sequence encoding a protein that induces an immune response, therefore, encodes the term “antigen” as used herein. Furthermore, those skilled in the art will understand that antigens are not necessarily encoded only by the full-length nucleotide sequence of a gene. It is obvious that this disclosure includes, but is not limited to, the use of partial nucleotide sequences of two or more genes, and that these nucleotide sequences are composed of various combinations to induce a desired immune response. Furthermore, those skilled in the art will understand that antigens are not necessarily encoded by a “gene.” It is obvious that antigens may be synthetically produced or derived from biological samples. These biological samples may include, but are not limited to, tissue samples, tumor samples, cells, or biological fluids.

[0045] As used herein, the term "aralkyl" means an alkyl group as defined herein, in which the hydrogen or carbon bonds of the alkyl group are replaced by bonds to an aryl group as defined herein. Typical aralkyl groups include benzyl and phenylethyl groups, as well as condensed (cycloalkylaryl) alkyl groups such as 4-ethyl-indanyl. An aralkenyl group is an alkenyl group as defined herein, in which the hydrogen or carbon bonds of the alkyl group are replaced by bonds to an aryl group as defined herein.

[0046] As used herein, the term "aryl" means a cyclic aromatic hydrocarbon group that does not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylene, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains from about 6 to about 14 carbons in the ring portion of the group. The aryl group may be unsubstituted or substituted as defined herein. Representative substituted aryl groups include, but are not limited to, phenyl groups substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or naphthyl groups substituted at any one or more of the 2- to 8-positions thereof, and may be mono-substituted or multiply-substituted groups.

[0047] As used herein, the term "asialoglycoprotein receptor binding moiety" or "ASGPRBM" means a group capable of binding to at least one hepatocyte asialoglycoprotein receptor on the surface of cells including, but not limited to, hepatocytes. When an ASGPRBM, and any additional moiety to which it is attached, binds to a receptor on the surface of a hepatocyte, the molecule containing the ASGPRBM is taken up by the hepatocyte via the endocytic mechanism, where the molecule is at least partially degraded through lysosomal degradation.

[0048] As used herein, "C 6~10 -C 6~10 biaryl" means a C 6~10 aryl moiety covalently attached via a single bond to another C 6~10 aryl moiety. The C 6~10 aryl moiety can be any suitable aryl group described herein. C 6~10 6~10 Non-limiting examples of C

[0049] ​As used herein, the term “coding sequence” means a sequence or portion thereof of a nucleic acid or its complement that is transcribed and / or translateable to produce mRNA and / or polypeptides or fragments thereof. A coding sequence includes exons in genomic DNA or immature primary RNA transcripts that are joined together by the cellular biochemical mechanisms to obtain mature mRNA. The antisense strand is the complement of the nucleic acid, from which the coding sequence can be inferred. In contrast, as used herein, the term “non-coding sequence” means a sequence or portion thereof of a nucleic acid or its complement that is not translated in vivo into amino acids or does not interact in such a way that tRNA positions or attempts to position amino acids. Non-coding sequences include both intron sequences in genomic DNA or immature primary RNA transcripts and gene-associated sequences such as promoters, enhancers, and silencers.

[0050] As used herein, the terms “complementary” or “complementarity” are used in reference to polynucleotides (i.e., nucleotide sequences) linked by base pairing rules. For example, the sequence “AGT” is complementary to the sequence “TCA”. Complementarity may be “partial,” in which case only some of the bases of the nucleic acid are matched according to base pairing rules. Alternatively, “complete” or “full” complementarity may exist between nucleic acids. The degree of complementarity between nucleic acid strands has a significant impact on the efficiency and strength of hybridization between nucleic acid strands. This is particularly important in amplification reactions and detection methods that rely on binding between nucleic acids.

[0051] As used herein, the terms “composition” or “pharmaceutical composition” mean a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to a patient or subject. Multiple techniques exist in the art for administering compounds, including but not limited to intravenous, oral, aerosol, parenteral, intraocular, intrapulmonary, and topical administration.

[0052] As used herein, the terms “conservative variation” or “conservative substitution” mean the replacement of an amino acid residue with another biologically similar residue. Conservative variations or substitutions do not likely alter the shape of the peptide chain. Examples of conservative variations or substitutions include replacing one hydrophobic residue, such as isoleucine, valine, leucine, or methionine, with another hydrophobic residue, or replacing one polar residue with another polar residue, for example, replacing arginine with lysine, glutamic acid with aspartic acid, or glutamine with asparagine.

[0053] As used herein, the term "cycloalkyl" refers to cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups can have 3 to about 8 to 12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Furthermore, cycloalkyl groups include but not limited to polycyclic cycloalkyl groups, such as norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, as well as fused rings, such as dekalinyl. Cycloalkyl groups also include rings substituted with linear or branched alkyl groups as defined herein. Typical substituted cycloalkyl groups include, but are not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups, or monosubstituted, disubstituted, or trisubstituted norbornyl or cycloheptyl groups; they can be monosubstituted or two or more substituted groups, which may be substituted with, for example, amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl," alone or in combination, refers to a cyclic alkenyl group.

[0054] A "disease" is a state of animal health in which the animal is unable to maintain homeostasis, and unless the disease goes into remission, the animal's health will continue to deteriorate.

[0055] In contrast, a “disorder” in animals refers to a health condition in which the animal can maintain homeostasis, but its health is less favorable than it would be in the absence of the disorder. Leaving the disorder untreated does not necessarily lead to a further decline in the animal's health.

[0056] A disease or disorder is considered to be in "remission" when the severity of its symptoms, the frequency with which the patient experiences those symptoms, or both, decreases.

[0057] As used herein, the terms “effective dose,” “pharmaceutical effective dose,” and “therapeutic effective dose” mean an amount of an agent that is non-toxic but sufficient to produce the desired biological effect. This effect may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in the biological system. The appropriate therapeutic dose in any individual case can be determined by those skilled in the art using routine experiments.

[0058] As used herein, the term "efficacy" refers to the maximum effect achieved within the assay (E max ) means.

[0059] "Code" means that a specific sequence of nucleotides in a polynucleotide such as a gene, cDNA, or mRNA has the inherent characteristic of serving as a template for the synthesis of other polymers and macromolecules in biological processes, possessing a defined nucleotide sequence (i.e., rRNA, tRNA, and mRNA) or amino acid sequence, and the resulting biological properties. Thus, a gene codes for a protein when that protein is produced in a cell or other biological system by the transcription and translation of the mRNA corresponding to that gene. Both the coding strand, whose nucleotide sequence is identical to the mRNA sequence and is usually shown in sequence listings, and the non-coding strand, which is used as a template for the transcription of the gene or cDNA, can be said to code for the protein or other product of that gene or cDNA.

[0060] As used herein, when applied to nucleic acids, the term “fragment” means a subsequence of a larger nucleic acid. A “fragment” of nucleic acid may have a length of at least about 15 nucleotides; for example, at least about 50 to about 100 nucleotides; at least about 100 to about 500 nucleotides; at least about 500 to about 1000 nucleotides; at least about 1000 to about 1500 nucleotides; at least about 1500 to about 2500 nucleotides; or about 2500 nucleotides (and any integer value in between). As used herein, when applied to proteins or peptides, the term “fragment” means a subsequence of a larger protein or peptide. A “fragment” of protein or peptide may have a length of at least about 20 amino acids; for example, at least about 50 amino acids; at least about 100 amino acids; at least about 200 amino acids; at least about 300 amino acids; or at least about 400 amino acids (and any integer value in between).

[0061] As used herein, the term "GN3" means the following base: TIFF2026099858000002.tif79128

[0062] As used herein, the terms "halo", "halogen", or "halide" group, either by itself or as part of another substituent, means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, unless otherwise specified.

[0063] As used herein, the term "haloalkyl" group includes mono-haloalkyl groups, poly-haloalkyl groups where all the halo atoms may be the same or different, and per-haloalkyl groups where all the hydrogen atoms are replaced by halogen atoms such as fluorine. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0064] As used herein, the term "heavy chain antibody" includes immunoglobulin molecules derived from camelid species by immunization with an antigen and subsequent isolation of the serum, or by cloning and expression of the nucleic acid sequence encoding said antibody. The term "heavy chain antibody" further encompasses immunoglobulin molecules isolated from animals having heavy chain disease or prepared by cloning and expression of the V H (variable heavy chain immunoglobulin) gene.

[0065] As used herein, the term "heteroaryl" refers to an aromatic ring compound containing five or more ring members, one or more of which are heteroatoms such as, but not limited to, N, O, and S. For example, a heteroaryl ring can have five to about eight to twelve ring members. A heteroaryl group is a variety of heterocyclyl groups having an aromatic electronic structure. A heteroaryl group called a C2-heteroaryl can be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heteroaryl can be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, and so on. The sum of the number of carbon atoms and heteroatoms is equal to the total number of ring atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups may be unsubstituted or substituted with the groups described herein. Typical substituted heteroaryl groups may be substituted once or multiple times with groups such as those listed herein.

[0066] Further examples of aryl and heteroaryl groups include phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, and Nzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrrolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl) Pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyridinyl, 4-pyridinyl, 5-pyridinyl, 6-pyridinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl) ), benzo[b]furanil (2-benzo[b]furanil, 3-benzo[b]furanil, 4-benzo[b]furanil, 5-benzo[b]furanil, 6-benzo[b]furanil, 7-benzo[b]furanil), 2,3-dihydro-benzo[b]furanil (2-(2,3-dihydro-benzo[b]furanil), 3-(2,3-dihydro-benzo[b]furanil), 4-(2,3-dihydro-benzo[b]furanil), 5-(2,3-dihydro-benzo[b]furanil), 6-(2,3-dihydro-benzo[b]furanil), 7-(2,3-Dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl) 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl) Zolyl, 7-benzoimidazolyl, 8-benzoimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo[b,f]azepine (5H-dibenzo[b,f]azepine-1-yl, 5H-dibenzo[b,f]azepine-2-yl, 5 H-dibenzo[b,f]azepine-3-yl, 5H-dibenzo[b,f]azepine-4-yl, 5H-dibenzo[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepine (10,11-dihydro-5H-dibenzo[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenzo[b,Examples include, but are not limited to, azepine-5-yl (f).

[0067] As used herein, the term “heteroarylalkyl” means an alkyl group as defined herein, in which the hydrogen bonds or carbon bonds of the alkyl group are replaced by bonds to a heteroaryl group as defined herein.

[0068] When used herein, "C 6~10 The term "-5~6 member heterobiaryl" refers to a C18 covalent bond to a 5 or 6 member heteroaryl portion via a single bond. 6~10 This refers to the aryl portion. C 6~10 The aryl moiety and the 5-6 membered heteroaryl moiety may be any preferred aryl group and heteroaryl group as described herein. 6~10 - Non-exclusive examples of 5- to 6-membered heterobiaryls include: TIFF2026099858000003.tif20128 is one example. C 6~10 -When a 5- to 6-membered heterobiaryl is listed as a substituent (for example, as an "R" group), C 6~10 -5~6 member heterobiaryls are C 6~10 It is bonded to the rest of the molecule through that portion.

[0069] As used herein, "5-6 member-C" 6~10 The term "heterobiaryl" refers to a 5-6 member C 6~10 When heterobiaryls are listed as substituents (e.g., as "R" groups), they are 5-6 member-C 6~10 Aside from the fact that the heterobiaryl is bonded to the rest of the molecule through the 5-6 member heteroaryl moiety, C 6~10 - It is the same as a 5- to 6-member heterobiaryl.

[0070] As used herein, the term “heterocyclyl” refers to aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms, such as but not limited to N, O, and S. Therefore, a heterocyclyl can be a cycloheteroalkyl, heteroaryl, or any combination thereof, as long as it is polycyclic. In some embodiments, a heterocyclyl group contains 3 to about 20 ring members, while other similar groups have 3 to about 15 ring members. A heterocyclyl group called a C2-heterocyclyl may be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heterocyclyl may be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, and so on. The number of carbon atoms and heteroatoms are equal to the total number of ring atoms. A heterocyclyl ring may contain one or more double bonds. A heteroaryl ring is one embodiment of a heterocyclyl group. The term "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. For example, dioxolanyl rings and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are both heterocyclyl groups within the scope of this specification. This term also includes polycyclic systems containing heteroatoms, such as quinuclidyls, but not limited to them. Heterocyclyl groups may be unsubstituted or substituted as described herein.Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Typical substituted heterocyclyl groups include, but are not limited to, monosubstituted or two- or more substituted piperidinyl or quinolinyl groups, and these groups are 2-, 3-, 4-, 5- or 6-substituted or disubstituted with groups such as those listed herein.

[0071] As used herein, the term “heterocyclylalkyl” means an alkyl group as defined herein, in which the hydrogen or carbon bonds of the alkyl group as defined herein are replaced by bonds to a heterocyclyl group as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridine-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0072] As used herein, the terms “immunoglobulin” or “Ig” are defined as a class of proteins that function as antibodies. Antibodies expressed by B cells are sometimes called BCRs (B cell receptors) or antigen receptors. The five members of this class of proteins are IgA, IgG, IgM, IgD, and IgE. IgA is a primary antibody found in bodily secretions, such as saliva, tears, breast milk, gastrointestinal secretions, and mucous secretions of the respiratory and genitourinary tracts. IgG is the most common circulating antibody. IgM is the major immunoglobulin produced in the primary immune response in most subjects. IgM is the most efficient immunoglobulin in agglutination, complement binding, and other antibody responses and is important in defense against bacteria and viruses. IgD is an immunoglobulin that does not have known antibody function but can act as an antigen receptor. IgE is an immunoglobulin that mediates immediate-type hypersensitivity by triggering the release of mediators from mast cells and basophils upon exposure to allergens.

[0073] As used herein, the term "selected independently from" means that the groups referred to are the same group, different groups, or a mixture thereof, unless the context clearly indicates otherwise. Therefore, based on this definition, "X 1 , X 2 , and X 3 The phrase "is selected independently of noble gases" is, for example, X 1 , X 2 , and X 3 The scenario where all X is the same. 1 , X 2 , and X 3 A scenario where everything is different, X 1 and X 2 Although X is the same 3 This would include scenarios where the values ​​are different, as well as other similar permutation scenarios.

[0074] An "inducible" promoter is a nucleotide sequence that, when manipulably linked to a polynucleotide encoding or identifying a gene product, causes the gene product to be produced in the cell substantially only if an inducer corresponding to the promoter is present in the cell.

[0075] "Isolated" means that it has been altered or removed from its natural state. For example, nucleic acids or polypeptides that are naturally present in living animals are "not isolated," but the same nucleic acids or polypeptides that have been partially or completely separated from coexisting substances in their natural state are "isolated." Isolated nucleic acids or proteins may exist in a substantially purified form and may exist in a non-natural environment, such as a host cell.

[0076] As used herein, the term “modulate” means mediating a detectable increase or decrease in the activity and / or levels of mRNA, polypeptide, or response in a subject compared to the activity and / or levels of mRNA, polypeptide, or response in the absence of the treatment or compound in the subject, and compared to the activity and / or levels of mRNA, polypeptide, or response in an otherwise identical but untreated subject. This term encompasses mediating a beneficial therapeutic response in a subject, preferably a human, by activating, inhibiting, and / or otherwise influencing a native signal or native response.

[0077] As used herein, the term “monovalent” means that the substituent is attached to the substituted molecule by a single bond. When the substituent is monovalent, for example, F or Cl, the substituent is attached by a single bond to the atom it substitutes.

[0078] As used herein, the term “organic group” means any carbon-containing functional group. Examples include oxygen-containing groups such as alkoxy groups, aryloxy groups, aralkyloxy groups, and oxo(carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylate salts, and carboxylic acid esters; sulfur-containing groups such as alkyl sulfide groups and aryl sulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, O(O)R, C(O)N(R)2, O(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N( R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1~C 100 ) Hydrocarbyl is an example, where R can be hydrogen (in examples containing other carbon atoms) or a carbon-based moiety, and the carbon-based moiety may or may not be substituted.

[0079] The terms “patient,” “subject,” or “individual” are used interchangeably herein and mean any animal or its cells, whether in vitro or in situ, to which the methods described herein are permitted. In a non-limiting aspect, patient, subject, or individual is human.

[0080] As used herein, the term “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not inhibit the biological activity or biological properties of a compound and is relatively non-toxic; that is, the material can be administered to an individual without causing undesirable biological effects or harmful interactions with any components of the composition contained in the composition.

[0081] As used herein, the term "pharmaceutically acceptable salt" means a salt of a administered compound, or a solvate, hydrate, or clathrate thereof, prepared from a pharmaceutically acceptable, non-toxic acid or base, including an inorganic acid or inorganic base, or an organic acid or organic base.

[0082] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid (including sulfates and bisulfates), and phosphoric acid (including hydrogen phosphates and dihydrogen phosphates). Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid classes, and examples include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0083] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts and metal salts, including alkali metal salts such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts, alkaline earth metal salts, and transition metal salts. Examples of pharmaceutically acceptable base addition salts include organic salts made from basic amines such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of these salts can be prepared from the corresponding compounds, for example, by reacting the compound with a suitable acid or base.

[0084] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” mean a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in transporting or delivering the compound described herein into or to a patient so that it can perform its intended function. Typically, these compounds are transported or delivered from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation containing the compound described herein and is not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose, and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic and suitable substances used in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carriers” include any coatings, antimicrobial and antifungal agents, as well as absorption retarders, that are compatible with the activity and efficacy of the compounds described herein and are physiologically acceptable to patients. Supplementary active compounds may be incorporated into the composition. “pharmaceutically acceptable carriers” may further include pharmaceutically acceptable salts of the compounds described herein.Other additional components that may be included in the pharmaceutical compositions used in the methods or compounds described herein are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0085] As used herein, the term "polypeptide" means a polymer composed of amino acid residues, associated native structural variants, and their synthetic non-native analogs linked by peptide bonds. Synthetic polypeptides can be synthesized, for example, using an automated polypeptide synthesizer. Generally as used herein, the term "protein" means a large polypeptide. Generally as used herein, the term "peptide" means a short polypeptide. In this specification, the usual notation is used to represent polypeptide sequences; that is, the left end of a polypeptide sequence is the amino terminus and the right end is the carboxyl terminus.

[0086] As used herein, the term "effectiveness" means half of the maximum response (ED). 50 This refers to the amount required to produce ).

[0087] As used herein, the term "REAG" means any reagent comprising -CON, -linker, -CON-linker, -linker-CON, -CON-linker-CON, -CRBM, -CON-CRBM, -linker-CRBM, -CON-linker-CRBM, -linker-CON-CRBM, and / or -CON-linker-CON-CRBM. As described herein, REAG reacts with a protein binder to incorporate the protein binder into the compounds of this disclosure, or fragments thereof, derivatives thereof, or intermediates thereof.

[0088] As used herein, the term "room temperature" refers to a temperature between approximately 15°C and 28°C.

[0089] As used herein with respect to antibodies, the term “specifically binding” means an antibody that recognizes a particular antigen but substantially does not recognize or bind to other molecules in the sample. For example, an antibody that specifically binds to an antigen from one species may also bind to the same antigen from one or more species. However, this interspecies reactivity itself does not change the classification of the antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allele forms of the antigen. However, this cross-reactivity itself does not change the classification of the antibody as specific. In some cases, the term “specific binding” or “specifically binding” may be used with respect to the interaction between an antibody, protein, or peptide and a second chemical species to mean that the interaction depends on the presence of a specific structure on the chemical species (e.g., an antigenic determinant or epitope), for example, that the antibody recognizes and binds to a specific protein structure rather than the protein in general. If an antibody is specific to epitope “A”, the presence of a molecule containing epitope A (or free, unlabeled A) in the reaction involving labeled “A” and the antibody reduces the amount of labeled A that binds to the antibody.

[0090] As used herein, the term “solvent” means a solid, liquid, or liquid capable of dissolving a gas. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0091] As used herein, the terms “standard temperature” and “standard pressure” mean 20°C and 101 kPa, respectively.

[0092] As used herein, the term “substantially” means “a majority of” or “mostly” as equivalent to at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the term “substantially absent” may mean not having any material at all or having it in negligible amounts. Therefore, the amount of material present does not affect the material properties of the composition containing the material. Thus, the material is present in an amount of about 0% to about 5% by weight of the composition, or about 0% to about 1% by weight, or less than or equal to about 5% by weight, or less than about 4.5% by weight, equivalent to about 4.5% by weight, or greater than about 4.5% by weight, or 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or less than or equal to about 0.001% by weight. The term "substantially absent" can mean having in negligible amounts, and therefore the material is present in about 0% to about 5% by weight of the composition, or about 0% to about 1% by weight, or about 5% or less by weight, or less than about 4.5% by weight, equivalent to about 4.5% by weight, or more than about 4.5% by weight, or 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001% or less by weight, or about 0% by weight.

[0093] As used herein, the term “substituted” in relation to a molecule or organic group as defined herein means a state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. As used herein, the terms “functional group” or “substituent” mean a group that can be substituted on or performs substitution on a molecule or organic group. Examples of substituents or functional groups include halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxylic acids, carboxylates, and carboxyl groups including carboxyl groups; sulfur atoms in thiol groups, alkyl sulfide groups and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon atom (or other atom) include F, Cl, Br, I, OR, OCO(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OCO(O)R, C(O)N(R)2, OCO(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 Examples include N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, where R can be a hydrogen or carbon-based part, for example, R is hydrogen, (C1~C 100) can be hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups bonded to a nitrogen atom or multiple adjacent nitrogen atoms can combine with one or more of the nitrogen atoms to form a heterocycline.

[0094] As used herein, the term “synthetic antibody” means an antibody produced using recombinant DNA technology, for example, an antibody expressed by a bacteriophage as described herein. This term should also be interpreted to mean an antibody produced by the synthesis of a DNA molecule that encodes an antibody and expresses an antibody protein, or by the synthesis of an amino acid sequence that identifies the antibody, wherein the DNA or amino acid sequence is obtained using DNA and amino acid sequence synthesis techniques available and well known in the art.

[0095] A "therapeutic" treatment is a procedure performed on an individual exhibiting signs of a disease with the aim of reducing or eliminating those signs.

[0096] As used herein, the term "thioalkyl" means a sulfur atom connected to an alkyl group as defined herein. The alkyl group in a thioalkyl group may be linear or branched. Examples of linear thioalkyl groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, and thiohexyl. Examples of branched alkoxy groups include, but are not limited to, isothiopropyl, sec-thiobutyl, tert-thiobutyl, isothiopentyl, and isothiohexyl. The sulfur atom may appear at any preferred position within the alkyl chain, for example, at the end of the alkyl chain or at any other location within the alkyl chain.

[0097] As used herein, the terms “to treat,” “to treat,” and “treatment” mean reducing the frequency or severity of symptoms of a disease or condition experienced by a subject by administering an agent or compound to the subject.

[0098] As used herein, the term “wild-type” means a gene or gene product isolated from a natural source. A wild-type gene is the gene that is most frequently observed in a population and is therefore arbitrarily intended to be the “normal” or “wild-type” form of the gene. In contrast, the terms “modified” or “mutant” mean a gene or gene product that exhibits modifications to its sequence and / or functional properties (i.e., changes in its characteristics) compared to a wild-type gene or gene product. It should be noted that natural mutants are isolated. Natural mutants are identified by the fact that they exhibit changes in characteristics (including changes in nucleic acid sequence) compared to a wild-type gene or gene product.

[0099] The term "autoimmune disease" refers to a disease or illness that occurs when body tissues are attacked by their own immune system. Examples of autoimmune diseases include, but are not limited to, systemic lupus erythematosus, Sjögren's syndrome, Hashimoto's thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes mellitus, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis.

[0100] A more complete list of autoimmune diseases treatable with the compounds and pharmaceutical compositions of this disclosure includes Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes mellitus, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, and autoimmune neutrophil Phenophobia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful steatosis, adult Still's disease, ankylosing spondylitis, Crest syndrome, drug-induced lupus, enthesitis-associated arthritis, eosinophilic fasciitis, Felty's syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatoid arthritis, Parry-Romberg syndrome, Personage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever Rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neurogenic myotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow concentric sclerosis, Vickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenia gravis, multiple sclerosis, Patter Oshtoran syndrome, pediatric autoimmune streptococcal neuropsychiatric disorders (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, generalized rigidity syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, woody conjunctivitis, Mohren's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Suzak syndrome, sympathetic ophthalmitis, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behçet's disease,This includes, in particular, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki disease, leukocytosis-destroying vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency disorders, and pyoderma gangrenosum.

[0101] Throughout this specification, the terms “cancer” or “neoplasia” are used to mean cancerous or malignant neoplasms, which are pathological processes resulting in the formation and proliferation of abnormal tissues that grow more rapidly by cell proliferation than normal tissue and continue to grow even after the stimulus that initiated the new growth has ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, mostly invading surrounding tissues, metastasizing to several sites, likely recurring after attempts at removal, and likely causing death to the patient if not properly treated. As used herein, the term neoplasia is used to describe all cancerous disease conditions and encompasses or includes pathological processes associated with malignant hematogenous neoplasms, ascites tumors, and solid tumors. Neoplasms include, but are not limited to, morphological irregularities in cells within the tissue of the subject or host, and the proliferation of cells within the tissue of the subject that is pathological compared to normal proliferation in the same type of tissue. Furthermore, neoplasms include benign and malignant tumors (e.g., colon tumors), which may be invasive or non-invasive. Malignant neoplasms (cancers) and benign neoplasms are distinguished by the fact that the former exhibit a greater degree of anaplasia, or loss of cell differentiation and orientation, and are invasive and metastatic.Examples of neoplasms or neoforms from which the target cells of this disclosure may originate include cancers (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), particularly bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas, particularly Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, and synovial sarcoma; central nervous system tumors (e.g., gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, and Schwannoma); Germline tumors (e.g., intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, and melanoma); mixed neoplasia, especially carcinosarcoma and Hodgkin's disease; and mixed origin tumors, such as Wilms' tumor and teratoma (Beers and Berkow (eds.), The Merck Manual of Diagnosis and Therapy, 17). th (ed. (Whitehouse Station, NJ: Merck Research Laboratories, 1999) 973-74, 976, 986, 988, 991). All of these neoplasms can be treated using the compounds of this disclosure.

[0102] Typical common cancers treated with the compounds of this disclosure include, for example, prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oropharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer, and lymphoma, all of which can be treated with one or more compounds of this disclosure. Due to the activity of the compound, the disclosure is generally applicable to treating substantially any cancer in any tissue, and therefore the compounds, compositions, and methods of the disclosure are generally applicable to treating cancer and reducing the likelihood of cancer development and / or metastasis of existing cancer.

[0103] In the specific aspects of this disclosure, the cancers being treated are metastatic cancers, recurrent cancers, or drug-resistant cancers, and in particular, drug-resistant cancers. Separately, metastatic cancers can be found in virtually any tissue of cancer patients in the later stages of the disease, and typically metastatic cancers are found in virtually any tissue, including the lymphatic system / lymph nodes (lymphoma), bone, lungs, bladder tissue, kidney tissue, liver tissue, and brain (brain cancer / brain tumor). Thus, this disclosure is generally applicable to and can be used to treat any cancer in any tissue, regardless of etiology.

[0104] The terms “anticancer agent” or “additional anticancer agent” mean compounds other than the chimeric compounds of the Disclosure that can be used in combination with the compounds of the Disclosure for the treatment of cancer. Exemplary anticancer agents that can be administered concurrently in combination with one or more chimeric compounds of the Disclosure include, for example, antimetabolites, topoisomerase I and II inhibitors, alkylating agents, and microtubule inhibitors (e.g., Taxol). Exemplary anticancer compounds for use in this disclosure include everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, and EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, adhesion plaque kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexide, azd2171, batabulin, ofatumumab (Arzerra), zanorimumab, edotecarin, tetrandrin, lubitecan, tesmilifene, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitide, Jaimatekan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanton, LY 317615, Neuradiab, Vitespan, Rta744, Sdx 102, Tarampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Irinotecan, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Seliclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), E Stradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperazine methyl)-indolyl j-quinolone, batalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly10] acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C 59 H 84 N 18 O i4 -(C2H4O2) X, where x = 1~2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifanib; Amifostin, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus carmette-Guélain (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine Chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, leva Misol, Lomustine, Mechloretamine, Melphalan, 6-Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Niltamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer, Procarbazine, Larcitrexed, Rituximab, Streptozocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vindesine, 13-Cis-Retinoic Acid, Phenylalanine Mustard, Uracil Mustard, Estramustine, Altretamine, Phloxuridine, 5-Deoxyuridine, Cytosine Arabinoside, 6-Mercaptopurine, Deoxycoformycin, Calcitriol, Barrubicin, Mithramycin, Vinblastine, Vinorelbine, Topotecan, Lazoxin,Marimast, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin difutitox, gefitinib, bortezimib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody), and Erbitux, cremohol-free paclitaxel, epithilone B B) BMS-247550, BMS-310705, Droloxifen, 4-Hydroxytamoxifen, Pipendoxifen, ERA-923, Alzoxifen, Fulvestrant, Acorbifen, Lasofoxifen, Idoxifen, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wartmannin, ZM336372, L-779,450, PEG-filgrastim, Darbepoetin, Erythropoietin, Granulocyte Colony-Stimulating Factor, Zolendronate, Prednisone, Cetuximab, Granulocyte Macrophage Colony Stimulating factors, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan,Androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, PEG Examples include filgrastim, erythropoietin, epoetin alfa, and darbepoetin alfa, and vemurafenib; particularly, immunotherapeutic agents, such as IDO inhibitors (indoleamine 2,3-dioxygenase (IDO) pathway inhibitors) including indoximod (NLG-8187), navoximod (GDC-0919), and NLG802; PDL1 inhibitors (programmed death ligand 1 inhibitors) including nivolumab, durvalumab, and atezolizumab; PD1 inhibitors such as pembrolizumab (Merck); and CTLA-4 inhibitors (cytotoxic T lymphocyte-associated protein 4 / surface antigen classification 152 inhibitors) including ipilimumab and tremelimumab.

[0105] In the treatment of cancer, in addition to anticancer drugs, several other agents may be administered concurrently with the chimeric compounds of this disclosure. These include active ingredients, minerals, vitamins, and nutritional supplements that have shown some efficacy in inhibiting cancer tissue or its growth, or that are otherwise useful in the treatment of cancer. For example, one or more of the following may be used in combination with the compounds to treat cancer: dietary selenium, vitamin E, lycopene, soy products, curcumin (turmeric), vitamin D, green tea, omega-3 fatty acids, and phytoestrogens including β-sitosterol.

[0106] The term "inflammatory disease" is used to describe diseases or illnesses that are characterized by inflammation, which is acute but often becomes chronic, as a major symptom of the disease or illness. Inflammatory diseases include neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, Huntington's disease; and other ataxias, for example); immunocompromised immune response diseases that cause inflammation (e.g., dysregulation of T cell maturation, B cell homeostasis, and T cell homeostasis, and counteracting damaging inflammation); inflammatory bowel disease, including Crohn's disease; chronic inflammatory diseases, including rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, and Sjögren's disease, for example; hyperglycemia disorders; and lipid metabolism disorders. Diabetes mellitus (Type 1 and Type 2), pancreatic β-cell death, and related conditions affecting the function and / or structure of the pancreatic islets, including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g., Mendenhall syndrome, Werner syndrome, pyelonephrosis, and lipoatrophic diabetes), and dyslipidemia (e.g., hyperlipidemia, high low-density lipoprotein (LDL), low high-density lipoprotein (HDL), high triglycerides, and metabolic syndrome, which occur in obese subjects). Examples of conditions that may be affected include hyperglycemia, liver disease, kidney disease (apoptosis in plaque, glomerular disease), cardiovascular disease (particularly complications during infarction, ischemia, stroke, pressure overload, and reperfusion), muscle degeneration and muscular atrophy, mild inflammation, gout, silicosis, atherosclerosis, and related conditions such as cardiac and neurological signs (both central and peripheral), including stroke, age-related dementia, and sporadic Alzheimer's disease, as well as psychiatric conditions including depression, stroke and spinal cord injury, and arteriosclerosis. Since elevated MIF levels are often observed in these diseases, these disease conditions and / or conditions respond to treatment with the compounds and / or pharmaceutical compositions of this disclosure. It should be noted that there is some overlap between the specific autoimmune diseases and inflammatory diseases described herein.

[0107] Throughout this disclosure, various aspects of the disclosure can be presented in the form of scope. It should be understood that descriptions in the form of scope are merely for convenience and conciseness and should not be interpreted as rigid limitations on the scope of the disclosure. Therefore, descriptions of scope should be considered as specifically disclosing all possible sub-scopes and the individual numbers within those scopes. For example, a description of a scope such as 1 to 6 should be considered as specifically disclosing sub-scopes such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and the individual numbers within those scopes, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the width of the scope.

[0108] compound This disclosure provides compounds comprising formula (I), or salts thereof, geometric isomers, stereoisomers, or solvates thereof. [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I)

[0109] In certain embodiments, the compound comprises formula (Ia), or its salts, geometric isomers, stereoisomers, or solvates. [Ab]-[CON] 0~1 -[Linker]-[CON] 0~1 -[CRBM] ' (Ia)

[0110] In (I) or (Ia), Ab is an antibody, such as a monoclonal antibody, that binds to a biological target, such as a circulating protein and / or an extracellular protein, such as a cell surface protein, but not limited thereto. In certain embodiments, the circulating protein mediates disease and / or impairment in the subject, and treatment or management of the disease and / or impairment requires degradation, removal, or reduction of the concentration of the circulating protein in the subject. In certain embodiments, Ab in (I) or (Ia) is capable of binding to the circulating protein in the plasma of the subject with the same or substantially similar affinity to Ab itself.

[0111] In (I) or (Ia), the CRBM is a cell receptor-binding moiety that binds to at least one receptor on the surface of hepatocytes or other degradable cells in the subject, and the binding thereto results in endocytosis and degradation of (I) and / or (Ia) and / or the biological target. In certain embodiments, the CRBM is an ASGRBM, which is a cell receptor-binding moiety that binds to at least one asial glycoprotein receptor on the surface of hepatocytes or other degradable cells in the subject.

[0112] In (I) or (Ia), each CON is a group that is independently bonded, or a group that covalently links Ab to CRBM, Ab to a linker, and / or a linker to CRBM.

[0113] In (I) or (Ia), the linker is a group having a valency in the range of 1 to 15. In certain embodiments, the valency of the linker is 1 to 10. In certain embodiments, the valency of the linker is 1 to 5. In certain embodiments, the valency of the linker is 1, 2, or 3. In certain embodiments, the linker is covalently linked to one or more CRBM and / or Ab groups, optionally via CON, where the linker itself may contain one or more CON groups.

[0114] In certain embodiments, k' is an integer in the range of 1 to 15. In certain embodiments, k' is an integer in the range of 1 to 10. In certain embodiments, k' is an integer in the range of 1 to 5. In certain embodiments, k' is an integer in the range of 1 to 3. In certain embodiments, k' is 1, 2, or 3.

[0115] In certain embodiments, j is an integer in the range of 1 to 15. In certain embodiments, j is an integer in the range of 1 to 10. In certain embodiments, j is an integer in the range of 1 to 5. In certain embodiments, j is an integer in the range of 1 to 3. In certain embodiments, j is 1, 2, or 3.

[0116] In certain embodiments, h is an integer in the range of 0 to 15. In certain embodiments, h is an integer in the range of 1 to 15. In certain embodiments, h is an integer in the range of 1 to 10. In certain embodiments, h is an integer in the range of 1 to 5. In certain embodiments, h is an integer in the range of 1 to 3. In certain embodiments, h is 1, 2, or 3.

[0117] In certain embodiments, h' is an integer in the range of 0 to 15. In certain embodiments, h' is an integer in the range of 1 to 15. In certain embodiments, h' is an integer in the range of 1 to 10. In certain embodiments, h' is an integer in the range of 1 to 5. In certain embodiments, h' is an integer in the range of 1 to 3. In certain embodiments, h' is 1, 2, or 3.

[0118] In certain embodiments, i is an integer in the range of 0 to 15. In certain embodiments, i is an integer in the range of 1 to 15. In certain embodiments, i is an integer in the range of 1 to 10. In certain embodiments, i is an integer in the range of 1 to 5. In certain embodiments, i is an integer in the range of 1 to 3. In certain embodiments, i is 1, 2, or 3.

[0119] In certain embodiments, at least one of h, h', and i is at least 1.

[0120] In certain embodiments, k', j', h, h', and i are independently 1, 2, or 3.

[0121] In certain embodiments, k' is 1 and j' is 1, 2, or 3.

[0122] CRBM Folate receptor In certain embodiments, CRBM is folate, or any fragment or derivative thereof capable of binding to the folate receptor. The folate receptor binds to folate and reduced folate derivatives, mediating the delivery of tetrahydrofolate into the cell, where it is converted from monoglutamate to polyglutamate (e.g., 5-methyltetrahydrofolate), since only the monoglutamate form can be transported across the cell membrane. Human proteins derived from this family include folate receptor 1 (adult), folate receptor 2 (fetal), and folate receptor γ.

[0123] In certain embodiments, folic acid CRBM is methotrexate or its bioactive fragment: Includes TIFF2026099858000004.tif29128.

[0124] In certain embodiments, folic acid CRBM is pemetrexed or its bioactive fragment: Includes TIFF2026099858000005.tif27128.

[0125] In certain embodiments, folate CRBM may be incorporated into the compounds of the Disclosure through one of its carboxylic acids. In other embodiments, folate CRBM may be incorporated into the compounds of the Disclosure using N-hydroxysuccinamidyl (NHS) activated folate (similar chemistry applies to methotrexate and pemetrexed). TIFF2026099858000006.tif76128

[0126] Mannose receptor In certain embodiments, CRBM is a group that binds to a mannose receptor. In certain embodiments, CRBM includes the following groups: TIFF2026099858000007.tif19128

[0127] In certain embodiments, the mannose receptor CRBM may be conjugated to the compound of the Disclosure (such as, but not limited to, REAG) using one of the following reagents (which may be protected with a suitable protecting group): In formula TIFF2026099858000008.tif18128, X is S or O, and R is Selected from the group consisting of TIFF2026099858000009.tif19149, each occurrence of "n" is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0128] In certain embodiments, the mannose receptor CRBM is part of a polymer molecule. This molecule may contain one or more independently selected mannose receptor CRBMs as part of a polymer chain. In certain embodiments, the CRBM may be incorporated into the polymer molecule using CRBM reagents described elsewhere in this specification.

[0129] Mannose-6-phosphate (M6P) receptor In certain embodiments, CRBM is a group that binds to the mannose-6-phosphate (M6P) receptor. In certain embodiments, CRBM includes the following groups: In formula TIFF2026099858000010.tif18128, X is either O or S, and R 1 The following group was selected: TIFF2026099858000011.tif52128

[0130] In certain embodiments, CRBM may be conjugated to the compound of the Disclosure (such as REAG, but not limited to REAG) using one of the following reagents (which may be protected with a suitable protecting group): In formula TIFF2026099858000012.tif18128, X and R 1 R is defined elsewhere in this specification, 2 teeth, Selected from the group consisting of TIFF2026099858000013.tif41150, each occurrence of "n" is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0131] In certain embodiments, the M6P receptor CRBM is part of a polymer molecule. This molecule may contain one or more independently selected M6P receptor CRBMs as part of the polymer chain. In certain embodiments, the CRBM may be incorporated into the polymer molecule using CRBM reagents described elsewhere in this specification. Figures 1 to 8 show exemplary mannose receptor binders and their preparations.

[0132] In certain embodiments, the M6P receptor CRBM is one of the following (Yamaguchi, et al., 2016, J. Am. Chem. Soc. 138(38):12472-12485). TIFF2026099858000014.tif116128

[0133] In certain embodiments, the M6P receptor CRBM is one of the following (US2011 / 0110960, attributed to Platenburg): TIFF2026099858000015.tif98156

[0134] Low-density lipoprotein receptor-associated protein 1 (LRP1) receptor In certain embodiments, CRBM is an LRP1 [Low-density lipoprotein receptor-associated protein 1; also known as α-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER), or surface antigen classification 91 (CD91)] binding group containing one of the following amino acid sequences. TIFF2026099858000016.tif128158

[0135] Low-density lipoprotein receptor (LDLR) In certain embodiments, CRBM is an LDLR (low-density lipoprotein receptor) binding group containing one of the following amino acid sequences. TIFF2026099858000017.tif41150TIFF2026099858000018.tif246154TIFF2026099858000019.tif85152

[0136] FcγRI receptor In certain embodiments, CRBM is an FcγRI binding group containing one of the following amino acid sequences. TIFF2026099858000020.tif245154

[0137] transferrin receptor In certain embodiments, CRBM is a transferrin receptor binding group comprising one of the following amino acid sequences. TIFF2026099858000021.tif115154

[0138] Macrophage scavenger receptors In certain embodiments, CRBM is a macrophage scavenger receptor binding site containing one of the following amino acid sequences. TIFF2026099858000022.tif85159

[0139] As used herein, Pen is penicillamine, Thz is thiazolidine-4-carboxylic acid, Sar is sarcosine, Pip is pipecolic acid, Nleu is norleucine, and NMeLeu is N-methylleucine.

[0140] G protein-coupled receptors In certain embodiments, the CRBM is a G protein-coupled receptor (GPCR) binding site. In certain embodiments, the binding site binds to the GPCR and induces receptor internalization. In certain embodiments, the receptor is CXCR7 (see, e.g., Nalawansha, et al., 2019, ACS Cent. Sci. 5(6):1079-1084). In certain embodiments, the binding site The formula includes TIFF2026099858000023.tif37128, where each R is independently H or C1-C6 alkyl. In certain embodiments, CRBM may be conjugated to a compound of the present disclosure (such as REAG, but not limited to REAG) using one of the following reagents (which may be protected with a suitable protecting group): In formula TIFF2026099858000024.tif37128, at least one R is REAG, and the remaining Rs are independently H or C1-C6 alkyl.

[0141] Asialoglycoprotein receptor (ASGPR) This disclosure assumes the use of the ASGPR coupling portion (ASGPRBM).

[0142] In certain embodiments, the ASGRBM group is any group described in Huang, et al., 2017, Bioconjugate Chem. 28:283-295, which is incorporated herein by reference in whole.

[0143] In certain embodiments, the ASGRBM group has the following structure: Including TIFF2026099858000025.tif24128, In the formula, X is a linker with a length of 1 to 4 atoms, and If X is a linker the length of one atom, then X is O, S, N(R N1 ), or C(R N1 )(R N1 ) and If X is a linker the length of two atoms, then one or fewer atoms in X are O, S, or N(R) N1 ) and When X is a linker of 3 or 4 atoms in length, no more than 2 atoms of X are independently O, S, or N(R N1 ), and are thus, including an O, S, N(R N1 ), or C(R N1 )(R N1 ) group.

[0144] In certain embodiments, each occurrence of R N1 is independently H, or C1-C3 alkyl optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups.

[0145] In certain embodiments, when X is 2 atoms in length, X in ASGPRBM is -O-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-O-, -S-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-S-, -N(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-N(R N1 )-, or -C(R N1 )(R N1 )-C(R N1 )(R N1 ).

[0146] In certain embodiments, when X is 3 atoms in length, X in ASGPRBM is -O-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-O-C(R N1 )(R N1 )-, -O-C(R N1 )(R N1 )-O-, -O-C(R N1 )(R N1 )-S-, -O-C(RN1 )(R N1 )-N(R N1 )-,-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-,-C(R N1 )(R N1 )-C(R N1 )(R N1 )-S, -SC(R N1 )(R N1 )-S-, -SC(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 )-N(R N1 )-,-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-C(R N1 )(R N1 )-N(R N1 )-,-N(R N1 )-C(R N1 )(R N1 )-N(R N1 )-, or -C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )

[0147] In certain embodiments, when X is the length of four atoms, X in ASGRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(RN1 )(R N1 )-,-C(R N1 )(R N1 )-OC(R N1 )(R N1 )-C(R N1 )(R N1 )-,-OC(R N1 )(R N1 )-OC(R N1 )(R N1 )-,-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-,-SC(R N1 )(R N1 )-SC(R N1 )(R N1 )-,-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, or -C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-is.

[0148] In certain embodiments, X is OCH2, and R N1 H is H.

[0149] In certain embodiments, X is CH2O, and R N1H is H.

[0150] In certain embodiments, the ASGRBM has the following structure: Includes TIFF2026099858000026.tif19128.

[0151] In certain embodiments, the ASGRBM has the following structure: Includes TIFF2026099858000027.tif21128.

[0152] In certain aspects, R 1 This is the base shown in Figure 9. In certain embodiments, R 3 This is the base shown in Figure 9. In certain embodiments, R 1 and R 3 These are each independent groups shown in Figure 9.

[0153] In certain aspects, R 1 and R 3 These are H and -(CH2) respectively, independently. K OH may be replaced by 1 to 3 independently selected halogens - (CH2) K O(C1-C4 alkyl), C1-C4 alkyl which may be substituted with 1-3 independently selected halogens, -(CH2) K (Vinyl), -O(CH2) K (Vinyl), -(CH2) K (Alkinyl), -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K The elements are C(=O)O(C1~C4 alkyl), -OC(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or -C(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens.

[0154] In certain aspects, R 1 and R 3 Each of these is independently Ph(CH2) K- and this may be substituted with 1 to 3 independently selected halogens; C1 to C4 alkyls which may be substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups; or C1 to C4 alkoxys which may be substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups.

[0155] In certain aspects, R 1 and R 3 Each of these has the following independent structure: -O-(CH2) K' -CH(OH)-(CH2)K'-R 7 It is the basis of, and in the formula, R 7 C1-C4 alkoxys may be substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; -NR N3 R N4 ; or -(CH2) K' -O-(CH2) K -CH2-CH=CH2

[0156] In certain embodiments, K is 0. In certain embodiments, K is 1. In certain embodiments, K is 2. In certain embodiments, K is 3. In certain embodiments, K is 4.

[0157] In certain embodiments, K' is 1. In certain embodiments, K' is 2. In certain embodiments, K' is 3. In certain embodiments, K' is 4.

[0158] In certain aspects, R N3 Each occurrence is independently a C1-C3 alkyl group which may be substituted with H, or 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0159] In certain aspects, R N4 Each occurrence may be independently substituted with H, 1-3 independently selected halogens and / or 1-2 hydroxyl groups, or C1-C3 alkyl, or Ph-(CH2)K - is

[0160] In certain aspects, R 1 and R 3 Each is independently selected from the following group: In formula TIFF2026099858000028.tif27128, CYC is the group consisting of the following: Selected from TIFF2026099858000029.tif112156, in the formula, The join described in TIFF2026099858000030.tif1128 is -(CH2) K This indicates the part of the CYC to which it is connected.

[0161] In certain aspects, L 1 It is a linker, a CON-linker, or a CON-linker-CON.

[0162] In certain aspects, R C is absent, H, a C1-C4 alkyl group which may be substituted with 1-3 substituted halogens and / or 1-2 hydroxyl groups, or the following structure: This is the basis for TIFF2026099858000031.tif23128, in the formula, R 4 , R 5 , and R 6 Each of these is independently H, F, Cl, Br, I, CN, NR N1 R N2 ,-(CH2) K OH may be replaced by 1 to 3 independently selected halogens - (CH2) K O(C1-C4 alkyl), C1-C3 alkyl which may be substituted with 1-3 independently selected halogens, C1-C3 alkoxy which may be substituted with 1-3 independently selected halogens, -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) KThe elements are C(=O)O-(C1~C4 alkyl), OC(=O)-(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or -C(=O)-(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens.

[0163] In certain aspects, R N2 Each occurrence is independently a C1-C3 alkyl group which may be substituted with H, or 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0164] In certain aspects, R C teeth The filename is TIFF2026099858000032.tif25155.

[0165] In certain aspects, R 1 and R 3 Each of these is independently (C3~C8 saturated carbon ring)-(CH2) K - and here the carbon ring is -L 1 and -R C It is further replaced by [this].

[0166] In certain aspects, R N Each occurrence is independently a C1-C3 alkyl group which may be substituted with H, or 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0167] In certain aspects, R 2 This is the base shown in Figure 10.

[0168] In certain aspects, R 2 ha-(CH2) K -N(R N1 )-C(=O)R AM That is the case.

[0169] In certain aspects, R AMC1-C4 alkyl, -(CH2) which may be substituted with H, 1-3 independently selected halogens and / or 1-2 hydroxyl groups. K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K C(=O)O(C1~C4 alkyl), -OC(=O)(C1~C4 alkyl), -C(=O)(C1~C4 alkyl), -C(=O)(C1~C4 alkyl), or -(CH2) K -NR N3 R N4 That is the case.

[0170] In certain aspects, R 2 teeth The filename is TIFF2026099858000033.tif16128, and in the formula, R TA H, CN, NR N1 R N2 ,-(CH2) K OH may be replaced by 1 to 3 independently selected halogens - (CH2) K O(C1-C4 alkyl), C1-C4 alkyl which may be substituted with 1-3 independently selected halogens, -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K C(=O)O(C1~C4 alkyl), -OC(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or -C(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or R TA C3~C 10 An aryl group, or a 3-10 membered heteroaryl group containing 1-5 non-carbon ring atoms, where the aryl group or heteroaryl group is designated as CN or NR, respectively. N1 R N2 ,-(CH2) K OH may be replaced by 1 to 3 independently selected halogens - (CH2)K O(C1-C4 alkyl), C1-C3 alkyl which may be substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(C1-C3 alkoxy), -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K C(=O)O-(C1~C4 alkyl), which may be substituted with 1 to 3 independently selected halogens-OC(=O)(C1~C4 alkyl), or which may be substituted with 1 to 3 independently selected halogens-(CH2) K It may be substituted with 1 to 3 groups independently selected from C(=O)-(C1~C4 alkyl), or R TA teeth TIFF2026099858000034.tif48128, which may be substituted with 1 to 3 independently selected halogens or 1 to 3 C1-C3 alkyl groups, or R TA teeth TIFF2026099858000035.tif29128, and in the formula, each -(CH2) K The group may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups, or with 1 to 4 C1-C3 alkyl groups.

[0171] In certain embodiments, the ASGRBM group has the following structure: Including TIFF2026099858000036.tif51162, During the ceremony, R A is a C1-C3 alkyl which may be substituted with 1-5 independently selected halogens; Z A ha-(CH2) IM -, -O-(CH2) IM -, -S-(CH2) IM -, -NR M -(CH2) IM-, -C(=O)-(CH2) IM - A PEG group containing 1 to 8 ethylene glycol residues, or -C(O)(CH2) IM NR M -and; Z B is nonexistent, -(CH2) IM -, -C(=O)-(CH2) IM -, or -C(=O)(CH2) IM -NR M -and; R M is a C1-C3 alkyl group which may be substituted with H or 1-2 hydroxyl groups; Each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6.

[0172] In certain aspects, R A is methyl or ethyl, and both may be substituted with 1 to 3 fluorine atoms.

[0173] In certain aspects, Z A This is a PEG group containing 1 to 4 ethylene glycol residues.

[0174] In certain embodiments, the ASGPRBM group includes one of the following (Mamidyala, et al., 2012, J. Am. Chem. Soc. 134:1978-1981): TIFF2026099858000037.tif104163TIFF2026099858000038.tif217152TIFF2026099858000039.tif219160

[0175] In certain embodiments, the ASGPRBM group includes one of the following (Sanhueza, et al., 2017, J. Am. Chem. Soc. 139:3528-3536): TIFF2026099858000040.tif121155

[0176] Linker and CON In certain embodiments, the linker is a polyethylene glycol-containing linker having 1 to 12 ethylene glycol residues.

[0177] In certain embodiments, the linker has the following structure: -CH2CH2(OCH2CH2) m OCH2-, -(CH2) m CH2-, -[N(R a )-CH(R b )(C=O)] m - Alternatively, it may contain a polypropylene glycol group or a polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units. Each R a is independently H, C1-C3 alkyl, or C1-C6 alkanol, or R b Together with other groups, they form a pyrrolidine group or a hydroxypyrroline group; Each R b These are independently selected from the group consisting of hydrogen, methyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)3-guanidine, -CH2C(=O)NH2, -CH2C(=O)OH, -CH2SH, -(CH2)2C(=O)NH2, -(CH2)2C(=O)OH, -(CH2)imidazole, -(CH2)4NH2, -CH2CH2SCH3, benzyl, -CH2OH, -CH(OH)CH3, -(CH2)imidazole, or -(CH2)phenol; m is an integer in the range of 1 to 15.

[0178] In certain embodiments, the linker is structured -[N(R ' -(CH2) 1~15 The formula contains -C(=O)]-, where R' is H, or a C1-C3 alkyl which may be substituted with 1-2 hydroxyl groups, and m is an integer in the range of 1-100.

[0179] In certain embodiments, the linker has the following structure: -ZD-Z'- Includes, During the ceremony, Z and Z' are joined independently. The filename is TIFF2026099858000041.tif25163; Each R is independently H, C1-C3 alkyl, or C1-C6 alkanol; Each R 2 These are independently H or C1-C3 alkyl groups; Each Y is independently a bond, O, S, or N(R); Each i is independently 0 to 100; in certain aspects 0 to 75; in certain aspects 1 to 60; in certain aspects 1 to 55; in certain aspects 1 to 50; in certain aspects 1 to 45; in certain aspects 1 to 40; in certain aspects 2 to 35; in certain aspects 3 to 30; in certain aspects 1 to 15; in certain aspects 1 to 10; in certain aspects 1 to 8; in certain aspects 1 to 6; in certain aspects 0, 1, 2, 3, 4, or 5; D represents a bond, -(CH2) i -YC(=O)-Y-(CH2) i -,-(CH2) m' -, or -[(CH2) n -X1)] j -However, Z, Z', and D cannot be combined at the same time; X 1 is O, S, or N(R); j is an integer in the range of 1 to 100; in certain aspects 1 to 75; in certain aspects 1 to 60; in certain aspects 1 to 55; in certain aspects 1 to 50; in certain aspects 1 to 45; in certain aspects 1 to 40; in certain aspects 2 to 35; in certain aspects 3 to 30; in certain aspects 1 to 15; in certain aspects 1 to 10; in certain aspects 1 to 8; in certain aspects 1 to 6; in certain aspects an integer in the range of 1, 2, 3, 4, or 5; m' is an integer in the range of 1 to 100; in certain aspects 1 to 75; in certain aspects 1 to 60; in certain aspects 1 to 55; in certain aspects 1 to 50; in certain aspects 1 to 45; in certain aspects 1 to 40; in certain aspects 2 to 35; in certain aspects 3 to 30; in certain aspects 1 to 15; in certain aspects 1 to 10; in certain aspects 1 to 8; in certain aspects 1 to 6; in certain aspects an integer in the range of 1, 2, 3, 4, or 5; n is an integer in the range of 1 to 100; in certain aspects 1 to 75; in certain aspects 1 to 60; in certain aspects 1 to 55; in certain aspects 1 to 50; in certain aspects 1 to 45; in certain aspects 1 to 40; in certain aspects 2 to 35; in certain aspects 3 to 30; in certain aspects 1 to 15; in certain aspects 1 to 10; in certain aspects 1 to 8; in certain aspects 1 to 6; and in certain aspects an integer in the range of 1, 2, 3, 4, or 5.

[0180] In certain embodiments, the linker has the following structure: -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n' CH2CH2-, or -(CH2CH2CH2O) n - Includes, In the formula, each n and n' is an integer in the range of 1 to 25 independently; in certain embodiments, 1 to 15; in certain embodiments, 1 to 12; in certain embodiments, 2 to 11; in certain embodiments, 2 to 10; in certain embodiments, 2 to 8; in certain embodiments, 2 to 6; in certain embodiments, 2 to 5; in certain embodiments, 2 to 4; in certain embodiments, 2 or 3; and in certain embodiments, an integer in the range of 1, 2, 3, 4, 5, 6, 7, or 8.

[0181] In certain embodiments, the linker has the following structure: -PEG-CON-PEG- Includes, In the formula, each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON is a triazole group. The filename is TIFF2026099858000042.tif14128.

[0182] In certain configurations, CON has the following structure: Including TIFF2026099858000043.tif85135, In the formula, R' and R'' are independently H, methyl, or a bond.

[0183] In certain embodiments, CON has the following diamide structure: -C(=O)-N(R 1 )-(CH2) n'' -N(R 1 )C(=O)-, -N(R 1 )-C(=O)(CH2) n'' -C(=O)N(R 1 )-,or -N(R 1 )-C(=O)(CH2) n'' -N(R 1 )C(=O)- Includes, In the formula, each R 1 n'' is independently H or C1-C3 alkyl, and n'' is independently an integer from 0 to 8, in certain embodiments from 1 to 7, and in certain embodiments from 1, 2, 3, 4, 5, or 6.

[0184] In certain configurations, CON has the following structure: Includes TIFF2026099858000044.tif14128, During the ceremony, R 1a , R 2a , and R 3a These are H and -(CH2) respectively, independently. M1 -,-(CH2) M2 C(=O) M3 (NR 4 ) M3 -(CH2) M2 -,-(CH2) M2 (NR 4 ) M3 C(O) M3 -(CH2) M2 -, or -(CH2) M2 O-(CH2) M1 -C(O)NR4 -However, R 1a , R 2a , and R 3a It is not possible for both to be H at the same time; Each M1 is independently 1, 2, 3, or 4, and in certain embodiments, 1 or 2; Each M2 is independently 0, 1, 2, 3, or 4, and in certain embodiments, 0, 1, or 2; Each M3 is independently either 0 or 1; Each R 4 These are independently H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), however, the same R 1a , R 2a , and R 3a It is not possible for both M2 and M3 within the same variable to be 0 at the same time.

[0185] In certain configurations, CON has the following structure: Includes TIFF2026099858000045.tif46128.

[0186] Ab Any antibody (Ab) that binds to an extracellular protein is useful within the scope of this disclosure. In certain non-limiting embodiments, the antibody is a monoclonal antibody.

[0187] Non-limiting examples of extracellular proteins envisioned within the scope of this disclosure include 1-40-β-amyloid, 5'-nucleotidase, activated F9, F10, activin receptor-like kinase 1, α-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3(VAP-1), Bacillus anthracis anthrax, BAFF, β-amyloid, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide α, and canine (Canis lupus) familiaris) IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, clamping factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, Escherichia coli (E. coli)E. coli Shiga toxin type 1, E. coli Shiga toxin type 2, EGFL7, endotoxin, epicyalin, FGF 23, fibrin II, β chain, fibronectin extradomain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth and differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human β-amyloid, human cell dispersion factor receptor kinase, human TNF, IFN-α, IFN-γ, IgE, IgE Fc region, IGF1, IGF2, IGHE, IL 17A, IL 17A and IL 17F, IL 20, IL-1, IL-12, IL-23, IL-13, IL-17, IL-1β, IL-22, IL-4, IL-5, IL-6, IL17A and IL17F, IL1A, IL2, IL23, IL23A, IL31RA, IL6, IL6R, IL9, ILGF2, influenza A hemagglutinin, influenza A virus hemagglutinin, influenza A virus hemagglutinin HA, interferon γ, interferon Ron-γ-inducing protein, interleukin-1α, interleukin-13, interleukin-17α, interleukin-17α, TNF, interleukin-17A, kallikrein, LOXL2, LRRC15, LTA, MASP-2, MCP-1, MIF, MST1R (also known as RON), MUC1, myostatin, NACP, NCA-90 (granulocyte antigen), neuronal apoptosis-regulating proteinase 1, NGF, NOGO-A, Notch Examples include 1, NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, lid-specific spongein 3, RTN4, sclerostin, SDC1, serum amyloid A protein, serum amyloid P component, SOST, Staphylococcus aureus α-toxin, tau protein, TFPI, TGFβ1, TGFβ2, TGF-β, TNF-α, TROP-2, TSLP, VEGF-A, VEGF-A and Ang-2, VEGFA, and VWF.

[0188] Non-limiting examples of antibodies useful within the scope of this disclosure include avagovomab, abrezekimab, adalimumab, aducanumab, afasevikumab, aferimomab, alirocumab, altumomab, and altumomab pentetate. pentetate), andecaliximab, anrukinzumab, alsitumomab, ascrinvacumab, atezolizumab, atidortoxumab, atinumab, avelumab, bapineuzumab, bavituximab, belimumab, bermekimab, besilesomab, bevacizumab, bicilomab, bime Bimekizumab, Birtamimab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumab, Cantuzumabrabutansine ravtansine), caplacizumab, carlumab, cergutuzumab, cergutuzumab amunaleukin, certolizumab, certolizumab pegol, cibisatamab, clazakizumab, cribatuzumab, cribatuzumab tetraxetantetraxetan), concizumab, crenezumab, dectrekumab, denosumab, dezamizumab, diridavumab, domagrozumab, dorlimomab, dorlimomab aritox aritox), durvalumab, dusigitumab, eculizumab, edobacomab, efungumab, eldelumab, elezanumab, elsilimomab, emactuzumab, emapalumab, emicizumab, enokizumab, epitumomab, epitumomab situxetan cituxetan), eptinezumab, erenumab, evinacumab, evolocumab, faricimab, facinumab, fezakinumab, ficlatuzumab, firivumab, fletikumab, fontrizumab, fremanezumab, fresolimumab, phlovocimab, flunebetomab ( Frunevetmab, Fulranumab, Galcanezumab, Gantenerumab, Gatipotuzumab, Gedivumab, Gebokizumab, Gimsilumab, Girentuximab, Golimumab, Gosuranemab, Guselkumab, Idarucizumab, Igovomab, Imalumab, Indatuximab, Indatuximab tansineravtansine), infliximab, istiratumab, ixekizumab, rabetsumab, lacnotuzumab, lampalizumab, lanadelumab, landogrozumab, lebrikizumab, lemalesomab, lensalizumab, lensilumab, reldelimumab ( Lerdelimumab, Lesofavumab, Ligelizumab, Lodelcizumab, Lokivetmab, Lutikizumab, Marstacimab, Mepolizumab, Metelimumab, Mirikizumab, Nacolomab, Nacolomabutafenatox Tafenatox), Namilumab, Narnatumab, Navivumab, Naxitamab, Nevacumab, Nemolizumab, NEOD, Nerelimomab, Nesvacumab, Netakimab, Nofetumomab, Nofetumomab merpentanMerpentan), Obiltoxaximab, Oleclumab, Olendalizumab, Olokizumab, Omalizumab, OMS, Onartuzumab, Olegobomab, Orticumab, Otilimab, Ozanezumab, Ozoralizumab, Parsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab, Pemtumomab, Perakizumab, Pexelizumab, Placulumab, ponezumab, prasinezumab, pritoxaximab, quilizumab, radretumab, ralpancizumab, ranevetmab, ranibizumab, ravulizumab b) Laxibakumab, REGN-EB, Remtolumab, Reslizumab, Rilotumumab, Risankizumab, Romilkimab, Romosozumab, Rontalizumab, Rosmantuzumab, Sacituzumab, Sacituzumab-Govitecan govitecan), Samrotamab, Samrotamab vedotin, Sarilumab, Secukinumab, Setoxaximab, Setrusumab, Sifalimumab, Siltuximab, Simtuzumab, Silkumab, Sofituzumab, Sofituzumab, Sofituzumab vedotinVedotin), solanezumab, sontuzumab, stamulumab, sulesomab, sutimlimab, suvizumab, supratoxumab, tabarumab, tacatuzumab, tacatuzumab tetraxetan, talizumab, tanezumab, tefibazumab, telimomab, telimomab aritox Examples include aritox, tesidolumab, tezeperumab, tibrizumab, tildrakizumab, timolumab, tisotumab, tisotumab vedotin, tralokinumab, trevogrumab, urtoxazumab, ustekinumab, vanucizumab, vapaliximab, varisacumab, bepalimomab, besencumab, vobarilizumab, vunakizumab, and xentuzumab.

[0189] An antibody of interest can be incorporated into a compound of the Disclosure by any method known in the Art and / or any technique described or illustrated herein. For example, an antibody can be linked to a linker via a carboxylic acid group on the surface of the antibody, for example, by using an amide or esterification reaction. For example, an antibody can be linked to a linker via an amine group on the surface of the antibody, for example, by using an amide formation reaction. For example, an antibody can be linked to a linker via a thiol group on the surface of the antibody, for example, by using a nucleophilic substitution reaction. In this case, the surface cysteine ​​residue may be present in the wild type of Ab and / or may be introduced by a mutation using, for example, site-directed mutagenesis. A linker useful within the scope of the Disclosure may be any linker known in the Art, as long as the presence of the linker does not significantly impede Ab's ability to bind to a circulating protein.

[0190] In non-limiting examples, antibodies useful within the scope of this disclosure may bind to circulating proteins. As those skilled in the art will understand, any antibody capable of recognizing and specifically binding to a circulating protein is useful in this disclosure. This disclosure should not be construed as being limited to any single antibody, whether known or previously unknown, provided that such antibody specifically binds to a circulating protein and can prevent or minimize the biological activity of the circulating protein.

[0191] Methods for producing and using these antibodies are well known in the art. For example, polyclonal antibodies can be produced by inoculating a desired animal with an antigen and isolating an antibody that specifically binds to the antigen from the animal. Monoclonal antibodies directed to full-length or peptide fragments of proteins or peptides can be prepared using any well-known monoclonal antibody preparation procedure, for example, the procedure described by Harlow et al. (1989, Antibodies, A Laboratory Manual, Cold Spring Harbor, New York) and Tuszynski et al. (1988, Blood 72:109-115). Large quantities of the desired peptide may be synthesized using chemical synthesis techniques. Alternatively, the DNA encoding the desired peptide can be cloned from a suitable promoter sequence in cells suitable for producing large quantities of the peptide and expressed. Monoclonal antibodies directed to the peptide are produced from mice immunized with the peptide using the standard procedures referred to herein. However, this disclosure should not be construed as merely limiting to methods and compositions comprising these antibodies, but rather as including other antibodies as defined elsewhere herein.

[0192] In some cases, it is desirable to prepare monoclonal antibodies from various mammalian hosts, such as rodents (e.g., mice) and primates (e.g., humans). Techniques for preparing these monoclonal antibodies are well known and are described, for example, in Harlow et al., ANTIBODIES: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1988); Harlow et al., Using Antibodies: A Laboratory Manual, (Cold Spring Harbor Press, New York, 1998); Breitling et al., Recombinant Antibodies (Wiley-Spektrum, 1999); and Kohler et al., 1997 Nature 256: 495-497; as well as U.S. Patents 5,693,762; 5,693,761; 5,585,089; and 6,180,370.

[0193] The nucleic acids encoding antibodies obtained using the procedures described herein can be cloned and sequenced using techniques available in the art, such as those described by Wright et al. (Critical Rev. Immunol. 1992, 12:125-168) and the references cited herein. Furthermore, antibodies useful within the scope of this disclosure can be "humanized" using techniques described by Wright et al. (opposite cited) and the references cited herein, as well as by Gu et al. (Thrombosis and Hematocyst 1997, 77:755-759).

[0194] Alternatively, antibodies can be generated using phage display technology. To create a phage display library, a cDNA library is first obtained from mRNA isolated from cells expressing the desired protein to be expressed on the phage surface, such as a hybridoma, for example, the cell expressing the desired antibody. A cDNA copy of the mRNA is generated using reverse transcriptase. CDNA identifying immunoglobulin fragments is obtained by PCR, and the obtained DNA is cloned into a suitable bacteriophage vector to create a bacteriophage DNA library containing DNA identifying immunoglobulin genes. Procedures for constructing bacteriophage libraries containing heterologous DNA are well known in the art and are described, for example, in Sambrook et al. (1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York).

[0195] A bacteriophage encoding a desired antibody can be manipulated so that the protein is presented on the surface of the bacteriophage so that it is available for binding to its corresponding binding protein, for example, the antigen to which the antibody is directed. Thus, when a bacteriophage expressing a particular antibody is incubated in the presence of cells expressing the corresponding antigen, the bacteriophage binds to the cells. A bacteriophage that does not express an antibody does not bind to cells. This panning technique is well known in the art and is described, for example, by Wright et al. (Critical Rev. Immunol. 1992, 12:125-168).

[0196] Processes such as the one described herein for the production of human antibodies using M13 bacteriophage display have been developed (Burton et al., 1994, Adv. Immunol. 57:191-280). Essentially, a cDNA library is created from mRNA obtained from a population of antibody-producing cells. The mRNA encodes the reconstituted immunoglobulin gene, and therefore the cDNA encodes it. By cloning the amplified cDNA into an M13 expression vector, a library of phages expressing human Fab fragments on its surface is created. Phages presenting the antibody of interest are selected by antigen binding and propagated into bacteria to produce soluble human Fab immunoglobulin. Thus, in contrast to conventional monoclonal antibody synthesis, this procedure immortalizes the DNA encoding human immunoglobulin rather than the cells expressing human immunoglobulin.

[0197] The procedure described above describes the generation of a phage encoding the Fab portion of an antibody molecule. However, this disclosure should not be interpreted as being limited only to the generation of phages encoding Fab antibodies. Rather, phages encoding single-chain antibodies (scFv / phage antibody libraries) are also included in this disclosure. A Fab molecule contains the entire Ig light chain; that is, a Fab molecule contains both the variable and constant regions of the light chain, but only the variable region and the first constant region domain (CH1) of the heavy chain. A single-chain antibody molecule contains a single chain of protein containing an Ig Fv fragment. The Ig Fv fragment contains only the variable regions of the heavy and light chains of the antibody, and does not contain the constant region. A phage library containing scFv DNA can be prepared by following the procedure described by Marks et al. (1991, J Mol Biol 222:581-597). Panning of the phages thus prepared for the isolation of the desired antibody is performed in a manner similar to that described for the phage library containing Fab DNA.

[0198] Furthermore, this disclosure should be interpreted as including a synthetic phage display library capable of synthesizing heavy chain and light chain variable regions containing virtually all possible specificities (Barbas, 1995, Nature Medicine 1:837-839; de Kruif et al., 1995, J Mol Biol 248:97-105).

[0199] This disclosure includes polyclonal antibodies, monoclonal antibodies, synthetic antibodies, and the like. Those skilled in the art will understand, based on this disclosure, that a key feature of antibodies useful within the scope of this disclosure is that they specifically bind to circulating proteins.

[0200] The compounds described herein may have one or more stereocenters, each stereocenter independently existing in either the (R) or (S) configuration. In certain embodiments, the compounds described herein exist as optically active or racemic compounds. It should be understood that the compounds described herein encompass racemic compounds, optically active compounds, positional isomers, and stereoisomers, or combinations thereof, having the therapeutically useful properties described herein. Preparation of optically active compounds is achieved in any preferred manner, including, but not limited to, recrystallization techniques for racemic separation, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomers is used as the therapeutic compound described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. The separation of compounds and their isomers can be achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0201] The methods and formulations described herein involve the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound described herein, as well as metabolites and active metabolites of these compounds exhibiting similar activity. Examples of solvates include solvates of water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether), or alcohols (e.g., ethanol), and acetic acid esters. In certain embodiments, the compounds described herein exist in solvated forms with water and pharmaceutically acceptable solvents such as ethanol. In other embodiments, the compounds described herein exist in non-solvated forms.

[0202] In certain embodiments, the compounds described herein may exist as tautomers. All tautomers fall within the range of compounds presented herein.

[0203] In certain embodiments, the compounds described herein are prepared as prodrugs. “Prodrug” means an agent that is converted to the parent drug in vivo. In certain embodiments, at in vivo administration, the prodrug is chemically converted to a biological, pharmaceutical, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized to a biological, pharmaceutical, or therapeutically active form of the compound by one or more steps or processes.

[0204] In certain embodiments, a portion of the compounds described herein, such as an aromatic ring, is susceptible to various metabolic reactions. By incorporating appropriate substituents onto the aromatic ring structure, these metabolic pathways can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents to reduce or eliminate the susceptibility of the aromatic ring to metabolic reactions are, to name just a few, deuterium, halogens, or alkyl groups.

[0205] The compounds described herein also include isotope-labeled compounds in which one or more atoms are replaced by atoms having the same number of atoms but with atomic masses or atomic mass numbers different from those commonly found in nature. Examples of isotopes suitably included in the compounds described herein include: 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S is one example, but is not limited to it. In certain embodiments, isotope-labeled compounds are useful in drug distribution studies and / or substrate tissue distribution studies. In other embodiments, substitution with heavy isotopes such as deuterium results in increased metabolic stability (e.g., increased in vivo half-life or reduced required dose). In yet another embodiment, 11 C, 18 F, 15 O, and 13 Substitution with positron-emitting isotopes such as 1N is useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotope-labeled compounds are prepared by any suitable method or by a process that uses a suitable isotope-labeled reagent instead of a separately used unlabeled reagent.

[0206] In certain embodiments, the compounds described herein are labeled by means of other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0207] The compounds described herein, and other related compounds having different substituents, can be synthesized using the techniques and materials described herein, and refer to Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), and March, Advanced Organic Chemistry 4. th The compounds are synthesized as described, for example, in Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001) and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference). The general methods for preparing the compounds described herein are modified by the use of appropriate reagents and conditions to introduce the various parts found in the formulas shown herein.

[0208] The compounds described herein are synthesized using any suitable procedure starting from compounds available from commercial sources, or prepared using the procedures described herein.

[0209] In certain embodiments, reactive functional groups such as hydroxyl, amino, imino, thio, or carboxyl groups are protected to avoid their undesirable involvement in the reaction. Protecting groups are used to block some or all of the reactive parts, preventing the group from participating in the chemical reaction until the protecting group is removed. In other embodiments, each protecting group can be removed by different means. The need for differential removal is satisfied by protecting groups that cleave under completely different reaction conditions.

[0210] In certain embodiments, protecting groups are removed by acids, bases, reducing conditions (e.g., hydrolysis), and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetals, and t-butyldimethylsilyl are acid-unstable and are used to protect carboxyl and hydroxyl reactive moieties in the presence of amino groups protected with Cbz groups, which are also removable by hydrolysis, and amino groups protected with base-unstable Fmoc groups. Carboxylic acid and hydroxyl reactive moieties are blocked with base-unstable groups such as methyl, ethyl, and acetyl in the presence of amines blocked with acid-unstable groups such as t-butylcarbamates, or with carbamates that are both acid-stable and base-stable but removable by hydrolysis.

[0211] In certain embodiments, the carboxylic acid-reactive and hydroxyl-reactive moieties are blocked by hydrolytically removable protecting groups such as benzyl groups, while the amine group capable of hydrogen bonding with acids is blocked by a base-unstable group such as Fmoc. The carboxylic acid-reactive moiety is protected by conversion to simple ester compounds as exemplified herein, including conversion to alkyl esters, or blocked by oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while the simultaneously present amino group is blocked by a fluoride-unstable silylcarbamate.

[0212] Allyl blocking groups are useful in the presence of acid protecting groups and base protecting groups, because the former are stable and can subsequently be removed by metal or π-acid catalysts. For example, allyl blocking carboxylic acids are deprotected by palladium-catalyzed reactions in the presence of acid-unstable t-butylcarbamate or base-unstable acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate binds. As long as the residue is bound to the resin, its functional group is blocked and does not react. When released from the resin, the functional group becomes available for reaction.

[0213] Typically, blocking / protecting groups can be selected from the following: TIFF2026099858000046.tif79136

[0214] Other protecting groups are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference, along with a detailed description of the techniques applicable to the preparation and removal of protecting groups.

[0215] composition A composition comprising the compounds described herein comprises a pharmaceutical composition comprising at least one compound described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, the composition is formulated for oral or parenteral administration, for example, through routes of administration such as transdermal, transmucosal (e.g., sublingual, intralingual, buccal), urethral (transurethral), intravaginal (e.g., transvaginal and perivaginal), transnasal (intranasal), and rectal (transrectal), intrabladder, intrapulmonary, intraduodenal, intragastric, subarachnoid, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0216] Treatment method The compounds disclosed herein can be used to treat certain diseases and / or disorders, including but not limited to autoimmune diseases, cancer, inflammation, or any other diseases and / or disorders described herein.

[0217] Non-limiting examples of diseases and / or disorders include acute sciatica, progressive solid tumors, allergic asthma, allergic reactions, ALS and multiple sclerosis, Alzheimer's disease, amyloidosis, anaplastic large cell lymphoma, angioedema, angiogenesis, neovascularization, ocular vascular diseases, ankylosing spondylitis, psoriasis, anthrax (prevention and treatment), arthritis, asthma, asthma and leukocyte disorders, atopic dermatitis, atypical hemolytic uremic syndrome, autoimmune diseases, autoimmune disorders, B-cell carcinoma, B-cell malignancies, anthrax, bleeding, bleeding due to hemophilia, cancer, cancer (diagnosis), cancer, etc. Viral infections, chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, renal clear cell carcinoma, clinical signs of atopic dermatitis in dogs, cold agglutinin disease, colorectal cancer, Crohn's disease, psoriasis, psoriatic arthritis, and asthma, rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, ulcerative colitis, cryopyrin-associated periodic fever syndrome, diabetes, diagnostic agents, diarrhea caused by Escherichia coli, Duchenne muscular dystrophy, dyslipidemia, eczema, fibrosis, gastric cancer or gastroesophageal junction adenocarcinoma, gastrointestinal cancer, geographic atrophy secondary to age-related macular degeneration, hemophilia A, hemophagocytic lymphohistiocytosis, High-risk neuroblastoma and refractory myelomedullary diseases, Hodgkin lymphoma, hypercholesterolemia, idiopathic pulmonary fibrosis, focal segmental glomerulosclerosis, cancer, immune-mediated inflammatory disorders, infectious diseases / influenza A, inflammation, inflammation of the respiratory tract, skin, and gastrointestinal tract, inflammatory autoimmune diseases, inflammatory lesions and metastases (detection), influenza A, invasive candidiasis, macular degeneration (wet type), metastatic cancer, retinopathy of prematurity, metastatic pancreatic cancer, migraine, migraines and cluster headaches, multiple sclerosis, psoriasis, psoriatic arthritis, orthopedic disuse and sarcopenia-related muscle atrophy Muscle atrophy, muscle wasting disorder, muscular dystrophy, hospital-acquired pneumonia, oncological / immunological signs, osteoarthritis in dogs, osteoarthritis, rheumatoid arthritis, osteomyelitis, osteoporosis, bone metastases, etc., ovarian cancer, pain, pain and inflammatory diseases, pancreatic and colorectal cancer, pancreatic cancer, Parkinson's disease, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, atypical HUS, psoriasis vulgaris, primary systemic amyloidosis, progressive supranuclear palsy, psoriasis, inflammatory bowel disease, multiple sclerosis, reduced scarring after glaucoma surgery, reduced side effects of cardiac surgery,Relapsed or refractory cervical cancer, reversal of dabigatran anticoagulant effect, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, Crohn's disease, psoriasis vulgaris, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, neonatal hemolytic disease, psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, sepsis, sepsis caused by Gram-negative bacteria, severe asthma and chronic spontaneous urticaria, SLE, dermatomyositis These include polymyositis, solid malignancies, solid tumors, spinal cord injury and multiple sclerosis, Staphylococcus aureus infection, systemic lupus erythematosus, systemic lupus erythematosus without renal or CNS involvement, lupus nephritis, acute graft-versus-host disease, systemic scleroderma, thromboembolism, thrombotic thrombocytopenic purpura, thrombosis, triple-negative breast cancer, uveitis, rheumatoid arthritis and psoriasis, viral infections, wet age-related macular degeneration, and X-linked hypophosphatemia.

[0218] The methods described herein include a step of administering a therapeutically effective amount of at least one compound described herein, which may be formulated in a pharmaceutical composition. In various embodiments, the therapeutically effective amount of at least one compound described herein present in the pharmaceutical composition is the only therapeutically active compound in the pharmaceutical composition. In certain embodiments, the method further includes a step of administering an additional therapeutic agent that treats a disease or disorder.

[0219] In certain embodiments, administering the compounds described herein to a subject allows for the administration of a lower dose of an additional therapeutic agent compared to the dose of that additional therapeutic agent alone required to achieve similar results in treating a disease or disorder in that subject. For example, in certain embodiments, the compounds described herein reduce the dose of the additional therapeutic agent required to achieve the same effect by enhancing the activity of the additional therapeutic agent.

[0220] In certain embodiments, the compounds and therapeutic agents described herein are administered simultaneously to the subject. In other embodiments, the compounds and therapeutic agents described herein are formulated simultaneously and administered simultaneously to the subject.

[0221] In certain aspects, the subject is a mammal. In other aspects, the mammal is a human.

[0222] Combination therapy Compounds useful within the scope of the methods described herein may be used in combination with one or more additional therapeutic agents useful for treating a disease or disorder, and / or additional therapeutic agents that reduce or alleviate the symptoms of the disease or disorder, and / or the side effects of therapeutic agents used in treating the disease or disorder. These additional therapeutic agents may include compounds that are commercially available or available to those skilled in the art by synthesis. When additional therapeutic agents useful for treating a disease or disorder are used, these additional therapeutic agents are known to treat the disease or disorder or reduce its symptoms.

[0223] In various embodiments, synergistic effects are observed when the compounds described herein are administered together with one or more additional therapeutic agents or therapeutic compounds. These synergistic effects include, for example, sigmoid-E max The effects can be calculated using, for example, preferred methods such as the equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6: 429-453), the Loewe additive equation (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326), and the median effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). By applying each of the equations mentioned above to experimental data, corresponding graphs useful for evaluating the effects of drug combinations can be created. The corresponding graphs associated with the equations mentioned above are the concentration-effect curve, the isobologram curve, and the combination exponential curve, respectively.

[0224] Dosage / Prescription The administration regimen may influence what constitutes an effective dose. Therapeutic formulations may be administered before or after the onset of disease or disability. Furthermore, several divided and staggered doses may be administered daily or sequentially, or the dose may be administered by continuous infusion or bolus injection. In addition, the dose of the therapeutic formulation may be increased or decreased proportionally as needed depending on the treatment or preventive situation.

[0225] The administration of the compositions described herein to patients, preferably mammals, more preferably humans, can be carried out using known procedures in doses and for durations effective in treating the disease or disorder in the patient. The effective amount of the therapeutic compound required to achieve a therapeutic effect may vary depending on factors such as the current state of the disease or disorder in the patient; the patient's age, sex, and weight; and the therapeutic compound's ability to treat the disease or disorder in the patient. The administration regimen can be adjusted to achieve an optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as needed depending on the treatment situation. Non-limiting examples of the effective dose range of the therapeutic compounds described herein are about 1 to 5,000 mg / kg body weight / day. Those skilled in the art will be able to determine the effective dose of the therapeutic compound without excessive experimentation by considering the relevant factors.

[0226] The actual dose level of the active ingredient in the pharmaceutical compositions described herein can be varied to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response, desired composition, and desired mode of administration for a particular patient, without causing toxicity to the patient.

[0227] In particular, the selected dosage level depends on a variety of factors, including the activity of the specific compound used, the time of administration, the rate of elimination of the compound, the duration of treatment, other drugs, compounds, or materials used in combination with the compound, the age, sex, weight, physical condition, overall health, and medical history of the patient being treated, as well as similar factors well known in the medical field.

[0228] A physician with ordinary skills in the art, such as an internist or veterinarian, can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, an internist or veterinarian can start with a dose of the compound described herein used in the pharmaceutical composition at a level lower than the level required to obtain the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0229] In certain embodiments, it is particularly advantageous to formulate the compound in unit dosage forms to facilitate administration and ensure uniformity of dosage. As used herein, a unit dosage form means a physically separate unit suitable as a unit dosage form for a patient being treated, each unit containing a predetermined amount of the therapeutic compound calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical medium. The unit dosage forms of the compounds described herein are determined and directly depend on (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the field of compounding / formulating the therapeutic compound.

[0230] In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the compound described herein and a pharmaceutically acceptable carrier.

[0231] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by the use of a surfactant. Inhibition of microbial activity can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, such as sugars, sodium chloride, or polyhydric alcohols such as mannitol and sorbitol, in the composition. Long-term absorption of the injectable composition can be achieved by incorporating absorption-delaying agents, such as aluminum monostearate or gelatin, into the composition.

[0232] In certain embodiments, the compositions described herein are administered to a patient at a frequency ranging from one to five times or more per day. In other embodiments, the compositions described herein are administered to a patient at a frequency ranging from once daily, once every two days, once every three days to once a week, and once every two weeks, but not limited to these. It will be obvious to those skilled in the art that the administration frequency of the various combination compositions described herein will vary from individual to individual depending on many factors, including but not limited to age, the disease or disorder being treated, sex, general health, and other factors. Therefore, the administration of the compounds and compositions described herein should not be construed as being limited to any particular administration regime, and the exact administration frequency and composition to be administered to any patient will be determined by the attending physician, taking into account all other factors concerning the patient.

[0233] The compounds described herein for administration are approximately 1 μg to 10,000 mg, approximately 20 μg to 9,500 mg, approximately 40 μg to 9,000 mg, approximately 75 μg to 8,500 mg, approximately 150 μg to 7,500 mg, approximately 200 μg to 7,000 mg, approximately 350 μg to 6,000 mg, approximately 500 μg to 5,000 mg, approximately 750 μg to 4,000 mg, and approximately 1 mg to 3,000 mg. The ranges are mg, approximately 10 mg to 2,500 mg, approximately 20 mg to 2,000 mg, approximately 25 mg to 1,500 mg, approximately 30 mg to 1,000 mg, approximately 40 mg to 900 mg, approximately 50 mg to 800 mg, approximately 60 mg to 750 mg, approximately 70 mg to 600 mg, and approximately 80 mg to 500 mg, as well as any and all integer or decimal increments between them.

[0234] In some embodiments, the dose of the compound described herein is about 1 mg to about 2,500 mg. In some embodiments, the dose of the compound described herein used in the composition described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dose of the second compound described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, as well as any and all of these in integer or decimal increments.

[0235] In certain embodiments, the composition described herein is a packaged pharmaceutical composition comprising a container for holding a therapeutically effective amount of the compound described herein, either alone or in combination with a second agent, and instructions for using the compound in a patient to treat a disease or disorder or to reduce one or more of its symptoms.

[0236] The formulations can be used as mixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carriers, suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration known in the art. The pharmaceutical formulations may be sterile and, if desired, may be mixed with adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, flavoring agents, and / or aromatic agents. If desired, they may be combined with other effective agents, such as other analgesics.

[0237] Routes of administration for any composition described herein include oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical administration. Compounds used in the compositions described herein can be formulated for administration by any preferred route, for example, oral or parenteral administration, percutaneous, transmucosal (e.g., sublingual, intralingual, buccal, urethral (transurethral), vaginal (e.g., transvaginal and perivaginal), nasal (intranasal, and rectal (transrectal)), intravesical, intrapulmonary, intraduodenal, intragastric, subarachnoid, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0238] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, lozenges, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma preparations, licks, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosol preparations for inhalation, and compositions and preparations for intravesical administration. It should be understood that the preparations and compositions described herein are not limited to the specific preparations and compositions described herein.

[0239] Oral administration For oral administration, tablets, sugars, solutions, drops, suppositories, or capsules, caplets, and gel capsules are particularly preferred. Compositions intended for oral use can be prepared according to any method known in the art, and these compositions may contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Examples of these excipients include inert diluents such as lactose; granulators and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or coated by known techniques for aesthetic purposes or to delay the release of the active ingredient. Oral formulations may also be presented as hard gelatin capsules containing a mixture of the active ingredient and an inert diluent.

[0240] For oral administration, the compounds described herein may be in the form of tablets or capsules, prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose); fillers (e.g., corn starch, lactose, crystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). If desired, tablets may be coated using suitable methods and coating materials, such as the OPADRY® film coating system available from Colorcon, West Point, Pennsylvania (e.g., OPADRY® OY type, OYC type, organic enteric OY-P type, aqueous enteric OY-A type, OY-PM type, and OPADRY® White, 32K18400). Liquid formulations for oral administration may be in the form of solutions, syrups, or suspensions. Liquid formulations can be prepared by conventional means with suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fat); emulsifiers (e.g., lecithin or gum arabic); non-aqueous media (e.g., almond oil, oily esters, or ethyl alcohol); and pharmaceutically acceptable additives such as preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid).

[0241] Parenteral administration For parenteral administration, the compounds described herein can be formulated for injection or infusion, such as intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in bolus doses and / or for continuous infusion. Suspensions, solutions, or emulsions in an oily or aqueous medium may be used, which may contain other formulation agents such as suspending agents, stabilizers, and / or dispersants.

[0242] The sterile injectable formulations of the compositions described herein may be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile non-volatile oils are commonly used as solvents or suspensions. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Fatty acids, such as oleic acid and its glyceride derivatives, as well as pharmaceutically acceptable natural oils such as olive oil or castor oil, particularly their polyoxyethylated derivatives, are useful in the preparation of injectable formulations. These oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Swiss Pharmacopoeia or similar alcohols.

[0243] Further forms of administration Further dosage forms suitable for use with the compounds and compositions described herein include those described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Further dosage forms suitable for use with the compounds and compositions described herein include those described in U.S. Patent Publication Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Further dosage forms suitable for use with the compounds and compositions described herein include those described in PCT applications WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0244] Controlled-release formulations and drug delivery systems In certain embodiments, the formulations described herein may, but are not limited to, short-release formulations, rapid-release formulations, and controlled-release formulations, such as sustained-release formulations, delayed-release formulations, and pulsed-release formulations.

[0245] The term "sustained-release," as it is commonly used, refers to a drug formulation that releases the drug gradually over a long period, and can, if not necessarily, maintain a substantially constant level of the drug in the blood over that period. The duration can be longer than one month and should be longer than the release of the same amount of drug administered in bolus form.

[0246] For sustained release, the compound can be formulated with a suitable polymer or hydrophobic material that imparts sustained release properties to the compound. Therefore, the compound used in the method described herein can be administered, for example, by injection in the form of a microparticle, or by embedding in the form of an edible film or disc.

[0247] In some cases, the dosage form used can be realized as a slow or controlled release of one or more active ingredients in the dosage form, for example, by using hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres, or combinations thereof in various proportions to achieve a desired release profile. Suitable controlled-release formulations known to those skilled in the art, including those described herein, are readily selectable for use in the pharmaceutical compositions described herein. Accordingly, single unit dosage forms suitable for oral administration, such as tablets, capsules, gel capsules, and caplets, adapted for controlled release, are included in the compositions and dosage forms described herein.

[0248] Most controlled-release formulations share the common goal of improving drug therapy compared to the corresponding uncontrolled formulations. Ideally, the use of optimally designed controlled-release formulations in medical procedures is characterized by a minimal amount of active pharmaceutical ingredient used to cure or control a condition in the shortest amount of time. Advantages of controlled-release formulations include prolonged drug activity, reduced dosing frequency, and increased patient compliance. Furthermore, controlled-release formulations can be used to influence other characteristics such as the time of action or drug blood levels, and therefore, the occurrence of side effects.

[0249] Most controlled-release formulations are designed to release an initial amount of drug that rapidly produces the desired therapeutic effect, and then gradually and continuously release other amounts of the drug to maintain this level of therapeutic effect over a longer period. To maintain this constant drug level in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug being metabolized and excreted from the body.

[0250] The controlled release of the active ingredient can be stimulated by various inducers, such as pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled-release ingredient" is defined herein as a compound including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes or microspheres, or combinations thereof that facilitate the controlled release of the active ingredient. In one embodiment, the compounds described herein are administered to a patient alone or in combination with another drug using a sustained-release formulation.

[0251] The term "delayed release" is used herein in its usual sense, meaning a drug formulation that releases the drug after some delay following administration, which may or may not include a delay of approximately 10 minutes to approximately 12 hours.

[0252] The term pulsed release is used herein in its usual sense and refers to a drug formulation that releases the drug in such a way that it generates a pulsed plasma profile of the drug after administration.

[0253] The term "immediate release," as it is commonly used, refers to a drug formulation that releases the drug immediately after administration.

[0254] As used herein, "short-term" means any period of time including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, as well as any and all integer or decimal increments thereof.

[0255] As used herein, "rapid" means approximately 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 40 minutes, 20 minutes, or 10 minutes after drug administration, as well as any period of time less than or equal to any integer or decimal increment thereto.

[0256] Administration The therapeutically effective dose or amount of the compounds described herein depends on the patient's age, sex, and weight, the patient's current medical condition, and the progression of the disease or disorder in the patient being treated. Those skilled in the art can determine the appropriate dose in accordance with these and other factors.

[0257] The preferred doses of the compounds described herein may range from about 0.01 mg to about 5,000 mg per day, for example, from about 0.1 mg to about 1,000 mg per day, for example, from about 1 mg to about 500 mg, for example, from about 5 mg to about 250 mg. The dose can be administered as a single dose or in multiple doses, for example, one to four times or more times per day. When multiple doses are used, the amount in each dose may be the same or different. For example, a dose of 1 mg per day can be administered as two 0.5 mg doses with an interval of about 12 hours between the two doses.

[0258] It should be understood that the amount of the compound administered per day can, in non-limiting cases, be daily, every other day, every two days, every three days, every four days, or every five days. For example, with every-other-day administration, a dose of 5 mg per day could be started on Monday, followed by a first subsequent dose of 5 mg per day on Wednesday, and a second subsequent dose of 5 mg per day on Friday.

[0259] If the patient's condition improves, the physician may, at their discretion, continue administering the compounds described herein, or temporarily reduce or discontinue the dose of the administered drug for a certain period of time (i.e., a “drug-free day”). The length of the drug-free day can vary arbitrarily from 2 days to 1 year, and examples include 2, 3, 4, 5, 6, 7, 10, 12, 15, 20, 28, 35, 50, 70, 100, 120, 150, 180, 200, 250, 280, 300, 320, 350, or 365 days. Dose reductions during drug-free days include 10% to 100%, and examples include 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0260] When the patient's condition improves, administer a maintenance dose if necessary. Subsequently, reduce the dose, frequency, or both to a level that maintains the improvement in the disease. In certain cases, the patient may require long-term intermittent treatment for any recurrence of symptoms and / or infection.

[0261] The compounds described herein can be formulated into unit dosage forms. The term "unit dosage form" means a physically separate unit suitable as a unit dosage form for a patient receiving treatment, each unit containing a predetermined amount of the active substance, calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical carrier, if applicable. Unit dosage forms may be for once-daily administration or for single-dose administration of multiple daily doses (e.g., approximately 1 to 4 times or more per day). When used for multiple daily doses, the unit dosage forms may be the same or different for each dose.

[0262] The toxicity and therapeutic efficacy of the treatment regimen in question may be determined optionally in cell culture medium or experimental animals, and the LD (Low-Depth) 50 (A lethal dose for 50% of the population) and ED 50This includes, but is not limited to, determining the dose that is therapeutically effective in 50% of the population. The dose ratio between the toxic effect and the therapeutic effect is used as the therapeutic index, which is the LD (Low Life Quantity). 50 and ED 50 It is expressed as a ratio between [value] and [value]. Data obtained from cell culture assays and animal studies may be used to determine the range of doses used in humans. The doses of these compounds are ED with minimal toxicity. 50 It is preferable that the circulating concentration is within the range that includes [the substance]. The dosage may vary arbitrarily within this range depending on the dosage form used and the route of administration used.

[0263] Those skilled in the art will recognize, or can verify, numerous equivalents of the specific procedures, embodiments, claims, and examples described herein. These equivalents are considered to be within the scope of this disclosure and are covered by the claims appended herein. For example, it should be understood that modifying reaction conditions, including but not limited to reaction time, reaction size / volume, experimental reagents such as solvents, catalysts, pressure, atmospheric conditions such as nitrogen atmosphere, and reducing / oxidizing agents, using substitutes recognized in the art and through mere routine experiments, is within the scope of this application.

[0264] Wherever values ​​and ranges are shown herein, it should be understood that all values ​​and ranges encompassed within those values ​​and ranges are intended to be included within the scope of this disclosure. Furthermore, all values ​​within these ranges, as well as any upper or lower limits on the ranges of values, are also assumed by this application.

[0265] The following examples illustrate further aspects of the present disclosure. However, they do not in any way limit the teachings or disclosures relating to the present disclosure as described herein. [Examples]

[0266] Experimental example Herein, the present disclosure will be described with reference to the following examples. These examples are provided for illustrative purposes only and should not be construed as limiting the present disclosure to these examples, but rather as encompassing any variations that become apparent as a result of the teachings provided herein.

[0267] Those skilled in the art will likely be able to use the compounds of the Disclosure and carry out the claimed methods without further explanation by using the foregoing description and the following examples. Accordingly, the following examples illustrate specific aspects of the Disclosure and should not be construed as limiting the remainder of the Disclosure.

[0268] The materials and methods used in the experiments shown in this example are described herein.

[0269] Figures 11A and 11B show non-restrictive synthesis of the ASGRBM group.

[0270] Figures 12A–12C show non-restrictive synthesis of a specific ASGPRBM group. This example discloses non-restrictive Cbz protecting groups, but synthesis may be carried out using any other suitable protecting groups known to those skilled in the art. Protecting groups in each intermediate and / or final product can be deprotected as appropriate.

[0271] Figures 13A to 13L show non-restrictive synthesis of a specific ASGRBM group. This example discloses non-restrictive Cbz protecting groups, but synthesis may be carried out using any other suitable protecting groups known to those skilled in the art. Protecting groups in each intermediate and / or final product can be deprotected as appropriate.

[0272] Figures 14A–14O show non-restrictive synthesis of specific ASGRBM groups. While this example discloses non-restrictive Cbz protecting groups, synthesis may be carried out using any other suitable protecting groups known to those skilled in the art. Protecting groups in each intermediate and / or final product can be deprotected as appropriate.

[0273] Figure 15 shows a non-restrictive synthetic scheme that enables the labeling (derivativeization) of an antibody (labeled Ab) with an azide group, where pBpa represents p-benzoyl-phenylalanine.

[0274] Figure 16 shows a non-limiting synthetic scheme that enables labeling (derivative formation) of CRBM groups with strain alkyne-containing groups. In certain non-limiting embodiments, any azide-containing compound (as shown in Figure 15, but not limited thereto) can react with a strain alkyne-containing compound (as shown in Figure 16, but not limited thereto) to produce the compounds of the present disclosure.

[0275] Numbered aspects The following numbered aspects are shown, but the numbering should not be interpreted as indicating a level of importance. Embodiment 1 provides the following: Compounds containing formula (I), or their salts, geometric isomers, stereoisomers, or solvates: [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) During the ceremony, Ab is an antibody that binds to extracellular proteins; CRBM is a cell receptor-binding portion that binds to at least one receptor on the surface of a degradable cell in question, and the binding of (I) by it leads to endocytosis and degradation of extracellular proteins; Each CON is a group that independently bonds, or covalently links Ab to CRBM, Ab to the linker, and / or the linker to CRBM; A linker is a group having a valency in the range of 1 to 15; k' is an integer in the range of 1 to 15; h is an integer in the range of 0 to 15; i is an integer in the range of 0 to 15; h' is an integer in the range of 0 to 15; j is an integer in the range of 1 to 15. Embodiment 2 provides the following: A compound according to embodiment 1, wherein the linker valency is 1, 2, or 3. Embodiment 3 provides the following: A compound according to any one of embodiments 1 to 2, wherein k' is 1, 2, or 3. Embodiment 4 provides the following: A compound according to any one of embodiments 1 to 3, wherein j is 1, 2, or 3. Embodiment 5 provides the following: A compound according to any one of embodiments 1 to 4, wherein h is 1, 2, or 3. Embodiment 6 provides the following: A compound according to any one of embodiments 1 to 5, wherein h' is 1, 2, or 3. Embodiment 7 provides the following: A compound according to any one of embodiments 1 to 6, wherein i is 1, 2, or 3. Embodiment 8 provides the following: A compound according to any one of embodiments 1 to 7, wherein at least one of h, h', and i is at least 1. Embodiment 9 provides the following: A compound according to any one of embodiments 1 to 8, wherein k', j', h, h', and i are each independently 1, 2, or 3. Embodiment 10 provides the following: A compound according to any one of embodiments 1 to 9, wherein k' is 1 and j' is 1, 2, or 3. Embodiment 11 provides the following: [Ab]-[CON] 0~1 -[Linker]-[CON] 0~1 -[CRBM] (Ia), one of any one of embodiments 1 to 10. Embodiment 12 provides the following: A compound according to any one of embodiments 1 to 11, wherein the degradable cells include hepatocytes. Embodiment 13 provides the following: A compound according to any one of embodiments 1 to 12, wherein CRBM is a folate receptor binder, a mannose receptor binder, a mannose-6-phosphate (M6P) receptor binder, a low-density lipoprotein receptor-related protein 1 (LRP1) receptor binder, a low-density lipoprotein receptor (LDLR) binder, an FcγRI receptor binder, a transferrin receptor binder, a macrophage scavenger receptor binder, a G protein-coupled receptor binder, or an asialoglycoprotein receptor (ASGPR) binder. Embodiment 14 provides the following: One of the compounds in any of embodiments 1 to 13, wherein CRBM is as follows: (a) A folate receptor binder comprising at least one of folate, methotrexate, pemetrexed, or a bioactive fragment thereof; (b) A mannose receptor binder comprising at least one of the following: TIFF2026099858000047.tif19128(In the formula, X is S or O, and R is, Selected from the group consisting of TIFF2026099858000048.tif17137, where each occurrence of "n" is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and Polymer molecules shown in Figures 1 to 7; (c) A mannose-6-phosphate (M6P) receptor binder comprising at least one of the following: TIFF2026099858000049.tif19128(In the formula, X is O or S, R 1 teeth, Selected from the group consisting of TIFF2026099858000050.tif52128, R 2 teeth, Selected from the group consisting of TIFF2026099858000051.tif41128, each occurrence of "n" is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); Polymer molecules shown in Figure 8; below Compounds selected from TIFF2026099858000052.tif116128; below Compounds selected from TIFF2026099858000053.tif134128; (d) Low-density lipoprotein receptor-associated protein 1 (LRP1) receptor binder containing at least one amino acid sequence with SEQ ID NO:1-9; (e) A low-density lipoprotein receptor (LDLR) binder containing at least one amino acid sequence with SEQ ID NO: 10-35; (f) FcγRI receptor binder containing at least one amino acid sequence with SEQ ID NO:36-52; (g) A transferrin receptor binder containing at least one amino acid sequence of SEQ ID NO: 53-59 and 67; (h) Macrophage scavenger receptor binder containing at least one amino acid sequence with SEQ ID NO:60-65; (i) A G protein-coupled receptor binder containing at least one of the following: In formula TIFF2026099858000054.tif36128, each occurrence of R is independently H or C1-C6 alkyl; (j) Asialoglycoprotein receptor (ASGPR) binders including the following: TIFF2026099858000055.tif24128 (in the formula, X is a linker with a length of 1 to 4 atoms, and If X is a linker the length of one atom, then X is O, S, N(R N1 ), or C(R N1 )(R N1 ) and If X is a linker the length of two atoms, then one or fewer atoms in X are O, S, or N(R) N1 ) and If X is a linker with a length of 3 or 4 atoms, then 2 or fewer atoms of X are independently O, S, or N(R) N1 ) As such, O, S, N(R N1 ), or C(R N1 )(R N1 ) containing a group, Here R N1 Each occurrence is independently H, or a C1-C3 alkyl which may be substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; R 1 and R 3 These are H and -(CH2) respectively, independently. K OH may be replaced by 1 to 3 independently selected halogens - (CH2) K O(C1-C4 alkyl), C1-C4 alkyl which may be substituted with 1-3 independently selected halogens, -(CH2) K (Vinyl), -O(CH2) K (Vinyl), -(CH2) K (Alkinyl), -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K C(=O)O(C1~C4 alkyl), -OC(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or -C(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens; or, R 1 and R 3 Each of these is independently Ph(CH2) K- and this is substituted with 1 to 3 independently selected halogens; C1 to C4 alkyls which may be substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups; or C1 to C4 alkoxys which may be substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups; or, R 1 and R 3 Each of these has the following independent structure: -O-(CH2) K' -CH(OH)-(CH2)K'-R 7 It is the basis of, During the ceremony, R 7 C1-C4 alkoxys may be substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; -NR N3 R N4 ; or -(CH2) K' -O-(CH2) K -CH2-CH=CH2; K is 0, 1, 2, 3, or 4; K' is 1, 2, 3, or 4; R N3 Each occurrence is independently H, or a C1-C3 alkyl which may be substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; R N4 Each occurrence may be independently substituted with H, 1-3 independently selected halogens and / or 1-2 hydroxyl groups, or C1-C3 alkyl, or Ph-(CH2) K -is; or, R 1 and R 3 Each is independent Selected from the group consisting of TIFF2026099858000056.tif27128, where CYC is, Selected from the group consisting of TIFF2026099858000057.tif112144, During the ceremony, The join described in TIFF2026099858000058.tif1128 is -(CH2) K This indicates the part of the CYC to which it is connected; L 1 -Linker, -CON-linker, or -CON-linker-CON; R C is absent, H, a C1-C4 alkyl group which may be substituted with 1-3 substituted halogens and / or 1-2 hydroxyl groups, or the following structure: This is the basis for TIFF2026099858000059.tif52128, During the ceremony, R 4 , R 5 , and R 6 Each of these is independently H, F, Cl, Br, I, CN, NR N1 R N2 ,-(CH2) K OH may be replaced by 1 to 3 independently selected halogens - (CH2) K O(C1-C4 alkyl), C1-C3 alkyl which may be substituted with 1-3 independently selected halogens, C1-C3 alkoxy which may be substituted with 1-3 independently selected halogens, -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K C(=O)O-(C1~C4 alkyl), OC(=O)-(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or -C(=O)-(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens; R N Each occurrence is independently H, or a C1-C3 alkyl which may be substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; R N2 Each occurrence is independently H, or a C1-C3 alkyl which may be substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; or, R 1 and R 3 Each of these is independently (C3~C8 saturated carbon ring)-(CH2) K - and here the carbon ring is -L 1 and -R C It is further replaced by; R 2 ha-(CH2) K -N(R N1 )-C(=O)R AM And in the formula, R AM C1-C4 alkyl, -(CH2) which may be substituted with H, 1-3 independently selected halogens and / or 1-2 hydroxyl groups. K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K C(=O)O(C1~C4 alkyl), -OC(=O)(C1~C4 alkyl), -C(=O)(C1~C4 alkyl), -C(=O)(C1~C4 alkyl), or -(CH2) K -NR N3 R N4 is; or, R 2 teeth The file is TIFF2026099858000060.tif16128, and in the formula, R TA H, CN, NR N1 R N2 ,-(CH2) K OH may be replaced by 1 to 3 independently selected halogens - (CH2) K O(C1-C4 alkyl), C1-C4 alkyl which may be substituted with 1-3 independently selected halogens, -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) KC(=O)O(C1~C4 alkyl), -OC(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or -C(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or R TA C3~C 10 An aryl group, or a 3-10 membered heteroaryl group containing 1-5 non-carbon ring atoms, where the aryl group or heteroaryl group is designated as CN or NR, respectively. N1 R N2 ,-(CH2) K OH may be replaced by 1 to 3 independently selected halogens - (CH2) K O(C1-C4 alkyl), C1-C3 alkyl which may be substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(C1-C3 alkoxy), -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K C(=O)O-(C1~C4 alkyl), which may be substituted with 1 to 3 independently selected halogens-OC(=O)(C1~C4 alkyl), or which may be substituted with 1 to 3 independently selected halogens-(CH2) K It may be substituted with 1 to 3 groups independently selected from C(=O)-(C1~C4 alkyl), or R TA teeth TIFF2026099858000061.tif48128, which may be substituted with 1 to 3 independently selected halogens or 1 to 3 C1-C3 alkyl groups, or R TA teeth TIFF2026099858000062.tif28128, and in the formula, each -(CH2) K The group may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups, or 1 to 4 C1-C3 alkyl groups. Embodiment 15 provides the following: If X is the length of two atoms, then X in ASGRBM is -OC(R N1 )(R N1 )-,-C(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 )-,-C(R N1 )(R N1 )-S-, -N(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-N(R N1 )-, or -C(R N1 )(R N1 )-C(R N1 )(R N1 )-is; If X is the length of three atoms, then X in ASGRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-OC(R N1 )(R N1 )-,-OC(R N1 )(R N1 )-O-, -OC(R N1 )(R N1 )-S-, -OC(R N1 )(R N1 )-N(R N1 )-,-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-,-C(R N1 )(R N1 )-C(R N1 )(R N1 )-S, -SC(R N1 )(R N1 )-S-, -SC(RN1 )(R N1 )-O-, -SC(R N1 )(R N1 )-N(R N1 )-,-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-C(R N1 )(R N1 )-N(R N1 )-,-N(R N1 )-C(R N1 )(R N1 )-N(R N1 )-, or -C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ) is; or, If X is the length of four atoms, then X in ASGRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-OC(R N1 )(R N1 )-C(R N1 )(R N1 )-,-OC(R N1 )(R N1 )-OC(R N1 )(R N1 )-,-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1)-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-,-SC(R N1 )(R N1 )-SC(R N1 )(R N1 )-,-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, or -C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-is, Compounds according to embodiments 1 to 14. Embodiment 16 provides the following: X is OCH2, and R N1 is H, or X is CH2O, R N1 A compound from any one of embodiments 1 to 15, wherein the element is H. Embodiment 17 provides the following: ASGPRBM has the following structure: A compound comprising any one of embodiments 14 to 16, including TIFF2026099858000063.tif22128. Embodiment 18 provides the following: A compound comprising any one of embodiments 14 to 17, wherein the ASGPRBM group is as follows: TIFF2026099858000064.tif75128 (in the formula, R A is a C1-C3 alkyl which may be substituted with 1-5 independently selected halogens. Z A ha-(CH2) IM -, -O-(CH2) IM -, -S-(CH2) IM -, -NR M -(CH2) IM -, -C(=O)-(CH2) IM - A PEG group containing 1 to 8 ethylene glycol residues, or -C(O)(CH2) IM NR M -and, Z B is nonexistent, -(CH2) IM -, -C(=O)-(CH2) IM -, or -C(=O)(CH2) IM -NR M -and, R M is a C1-C3 alkyl group which may be substituted with H or 1-2 hydroxyl groups. Each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6; TIFF2026099858000065.tif98149TIFF2026099858000066.tif213120(wherein R = CH3, CF3, or CH2CF3); TIFF2026099858000067.tif186151TIFF2026099858000068.tif187156. Embodiment 19 provides the following: A compound according to any one of embodiments 1 to 18, wherein the linker is a polyethylene glycol-containing linker having 1 to 12 ethylene glycol residues. Embodiment 20 provides the following: The linker has the following structure: -CH2CH2(OCH2CH2) m OCH2-, -(CH2) m CH2-, -[N(R a )-CH(R b )(C=O)] m - Alternatively, it may contain a polypropylene glycol group or a polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units. Each R a is independently H, C1-C3 alkyl, or C1-C6 alkanol, or R b Together with other groups, they form a pyrrolidine group or a hydroxypyrroline group; Each R b These are independently selected from the group consisting of hydrogen, methyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)3-guanidine, -CH2C(=O)NH2, -CH2C(=O)OH, -CH2SH, -(CH2)2C(=O)NH2, -(CH2)2C(=O)OH, -(CH2)imidazole, -(CH2)4NH2, -CH2CH2SCH3, benzyl, -CH2OH, -CH(OH)CH3, -(CH2)imidazole, or -(CH2)phenol; m is an integer in the range of 1 to 15; or, The linker has the following structure: -[N(R ' -(CH2) 1~15 -C(=O)]- (In the formula, R' is H, or a C1-C3 alkyl which may be substituted with 1-2 hydroxyl groups, and m is an integer in the range of 1-100) including; or, The linker has the following structure: -ZD-Z'- (In the formula, Z and Z' are joined independently. The filename is TIFF2026099858000069.tif18161; Each R is independently H, C1-C3 alkyl, or C1-C6 alkanol; Each R 2 These are independently H or C1-C3 alkyl groups; Each Y is independently a bond, O, S, or N(R); Each i is independently between 0 and 100; D represents a bond, -(CH2) i-YC(=O)-Y-(CH2) i -,-(CH2) m' -, or -[(CH2) n -X1)] j -However, Z, Z', and D cannot be combined at the same time; X 1 is O, S, or N(R); j is an integer in the range of 1 to 100; m' is an integer in the range of 1 to 100; (n is an integer in the range of 1 to 100) including; or, The linker has the following structure: -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n' CH2CH2-, or -(CH2CH2CH2O) n - (In the formula, each n and n' is an integer in the range of 1 to 25.) including; or, The linker has the following structure: -PEG-CON-PEG- (In the formula, each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON is a triazole group) (TIFF2026099858000070.tif14128) including, A compound according to any one of embodiments 1 to 19. Embodiment 21 provides the following: CON has the following structure: TIFF2026099858000071.tif86157 (wherein R' and R'' are independently H, methyl, or a bond) including; or, CON has the following structure: -C(=O)-N(R 1 )-(CH2) n'' -N(R 1 )C(=O)-, -N(R 1)-C(=O)(CH2) n'' -C(=O)N(R 1 )-,or -N(R 1 )-C(=O)(CH2) n'' -N(R 1 )C(=O)- (In the formula, each R 1 (where n'' is independently H or C1-C3 alkyl, and n'' is independently an integer from 0 to 8, in certain embodiments from 1 to 7, and in certain embodiments from 1, 2, 3, 4, 5, or 6) including; or, CON has the following structure: TIFF2026099858000072.tif14128 (in the formula, R 1a , R 2a , and R 3a These are H and -(CH2) respectively, independently. M1 -,-(CH2) M2 C(=O) M3 (NR 4 ) M3 -(CH2) M2 -,-(CH2) M2 (NR 4 ) M3 C(O) M3 -(CH2) M2 -, or -(CH2) M2 O-(CH2) M1 -C(O)NR 4 -However, R 1a , R 2a , and R 3a It is not possible for both to be H at the same time; Each M1 is independently 1, 2, 3, or 4; Each M2 is independently 0, 1, 2, 3, or 4; Each M3 is independently either 0 or 1; Each R 4 These are independently H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), however, the same R 1a , R 2a , and R 3a (M2 and M3 within the same object cannot all be 0 at the same time.) including; or, CON has the following structure: Including TIFF2026099858000073.tif46128, A compound according to any one of embodiments 1 to 20. Embodiment 22 provides the following: Extracellular proteins include 1-40-β-amyloid, 5'-nucleotidase, activated F9, F10, activin receptor-like kinase 1, α-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-1), Bacillus anthracis anthrax, BAFF, β-amyloid, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide α, canine (Canis lupus familiaris) IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, clamping factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, and Escherichia coli (E. coli).E. coli Shiga toxin type 1, E. coli Shiga toxin type 2, EGFL7, endotoxin, epicyalin, FGF 23, fibrin II, β chain, fibronectin extradomain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth and differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human β-amyloid, human cell dispersion factor receptor kinase, human TNF, IFN-α, IFN-γ, IgE, IgE Fc region, IGF1, IGF2, IGHE, IL 17A, IL 17A and IL 17F, IL 20, IL-1, IL-12, IL-23, IL-13, IL-17, IL-1β, IL-22, IL-4, IL-5, IL-6, IL17A and IL17F, IL1A, IL2, IL23, IL23A, IL31RA, IL6, IL6R, IL9, ILGF2, influenza A hemagglutinin, influenza A virus hemagglutinin, influenza A virus hemagglutinin HA, interferon γ, interferon Ron-γ-inducing protein, interleukin-1α, interleukin-13, interleukin-17α, interleukin-17α, TNF, interleukin-17A, kallikrein, LOXL2, LRRC15, LTA, MASP-2, MCP-1, MIF, MST1R (also known as RON), MUC1, myostatin, NACP, NCA-90 (granulocyte antigen), neuronal apoptosis-regulating proteinase 1, NGF, NOGO-A, Notch One compound from any one of embodiments 1 to 21, comprising 1, NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, lid-specific spongein 3, RTN4, sclerostin, SDC1, serum amyloid A protein, serum amyloid P component, SOST, Staphylococcus aureus α toxin, tau protein, TFPI, TGFβ1, TGFβ2, TGF-β, TNF-α, TROP-2, TSLP, VEGF-A, VEGF-A and Ang-2, VEGFA, or VWF. Embodiment 23 provides the following: A compound according to any one of embodiments 1 to 22, wherein Ab is a monoclonal antibody. Embodiment 24 provides the following: The aforementioned antibodies include avagovomab, abrezekimab, adalimumab, aducanumab, afasevikumab, aferimomab, alirocumab, altumomab, and altumomab pentetate. pentetate), andecaliximab, anrukinzumab, alsitumomab, ascrinvacumab, atezolizumab, atidortoxumab, atinumab, avelumab, bapineuzumab, bavituximab, belimumab, bermekimab, besilesomab, bevacizumab, bicilomab, bime Bimekizumab, Birtamimab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumab, Cantuzumabrabutansine ravtansine), caplacizumab, carlumab, cergutuzumab, cergutuzumab amunaleukin, certolizumab, certolizumab pegol, cibisatamab, clazakizumab, cribatuzumab, cribatuzumab tetraxetantetraxetan), concizumab, crenezumab, dectrekumab, denosumab, dezamizumab, diridavumab, domagrozumab, dorlimomab, dorlimomab aritox aritox), durvalumab, dusigitumab, eculizumab, edobacomab, efungumab, eldelumab, elezanumab, elsilimomab, emactuzumab, emapalumab, emicizumab, enokizumab, epitumomab, epitumomab situxetan cituxetan), eptinezumab, erenumab, evinacumab, evolocumab, faricimab, facinumab, fezakinumab, ficlatuzumab, firivumab, fletikumab, fontrizumab, fremanezumab, fresolimumab, phlovocimab, flunebetomab ( Frunevetmab, Fulranumab, Galcanezumab, Gantenerumab, Gatipotuzumab, Gedivumab, Gebokizumab, Gimsilumab, Girentuximab, Golimumab, Gosuranemab, Guselkumab, Idarucizumab, Igovomab, Imalumab, Indatuximab, Indatuximab tansineravtansine), infliximab, istiratumab, ixekizumab, rabetsumab, lacnotuzumab, lampalizumab, lanadelumab, landogrozumab, lebrikizumab, lemalesomab, lensalizumab, lensilumab, reldelimumab ( Lerdelimumab, Lesofavumab, Ligelizumab, Lodelcizumab, Lokivetmab, Lutikizumab, Marstacimab, Mepolizumab, Metelimumab, Mirikizumab, Nacolomab, Nacolomabutafenatox Tafenatox), Namilumab, Narnatumab, Navivumab, Naxitamab, Nevacumab, Nemolizumab, NEOD, Nerelimomab, Nesvacumab, Netakimab, Nofetumomab, Nofetumomab merpentanMerpentan), Obiltoxaximab, Oleclumab, Olendalizumab, Olokizumab, Omalizumab, OMS, Onartuzumab, Olegobomab, Orticumab, Otilimab, Ozanezumab, Ozoralizumab, Parsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab, Pemtumomab, Perakizumab, Pexelizumab, Placulumab, ponezumab, prasinezumab, pritoxaximab, quilizumab, radretumab, ralpancizumab, ranevetmab, ranibizumab, ravulizumab b) Laxibakumab, REGN-EB, Remtolumab, Reslizumab, Rilotumumab, Risankizumab, Romilkimab, Romosozumab, Rontalizumab, Rosmantuzumab, Sacituzumab, Sacituzumab-Govitecan govitecan), Samrotamab, Samrotamab vedotin, Sarilumab, Secukinumab, Setoxaximab, Setrusumab, Sifalimumab, Siltuximab, Simtuzumab, Silkumab, Sofituzumab, Sofituzumab, Sofituzumab vedotinVedotin), solanezumab, sontuzumab, stamulumab, sulesomab, sutimlimab, suvizumab, supratoxumab, tabarumab, tacatuzumab, tacatuzumab tetraxetan, talizumab, tanezumab, tefibazumab, telimomab, telimomab aritox A compound comprising any one of embodiments 1 to 23, including aritox), tesidolumab, tezeperumab, tibrizumab, tildrakizumab, timolumab, tisotumab, tisotumab vedotin, tralokinumab, trevogrumab, urtoxazumab, ustekinumab, vanucizumab, bapaliximab, valisacumab, bepalimomab, besencumab, vobarilizumab, vunakizumab, or xentuzumab. Embodiment 25 provides the following: A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one compound from any one of embodiments 1 to 24. Embodiment 26 provides the following: A pharmaceutical composition according to embodiment 25, further comprising another therapeutically active compound. Embodiment 27 provides the following: A method for treating a disease or disorder in a subject, comprising the step of administering a therapeutically effective amount of at least one compound from any one of embodiments 1 to 24 and / or at least one pharmaceutical composition from any one of embodiments 25 to 26. Embodiment 28 provides the following: The method according to embodiment 27, wherein the disease or disorder includes an autoimmune disease, cancer, or inflammation. Embodiment 29 provides the following: Autoimmune diseases include Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, and essential mixed purpura. Oglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful steatosis, adult Still's disease, ankylosing spondylitis, Crest syndrome, drug-induced lupus, enthesitis-associated arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatoid arthritis, Parry-Romberg syndrome, Personage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus Undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neurogenic myotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow concentric sclerosis, Vickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenia dysthenia syndrome, multiple sclerosis, pattern II, Oshtoran syndrome, pediatric autoimmune streptococcal-associated neuropsychiatric disorders (PANDA). S) Progressive inflammatory neuropathy, restless legs syndrome, generalized rigidity syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, woody conjunctivitis, Mollen's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Suzak syndrome, sympathetic ophthalmitis, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA),The method of embodiment 28, including IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytosis-destroying vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, or pyoderma gangrenosum. Embodiment 30 provides the following: The method of aspect 28, wherein the cancer includes prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer, or lymphoma. Embodiment 31 provides the following: The method of aspect 28, wherein the inflammation includes neurodegenerative inflammatory diseases, immunocompromised immune response diseases that cause inflammation, chronic inflammatory diseases, hyperglycemic disorders, diabetes mellitus (type 1 and type 2), pancreatic β-cell death and associated hyperglycemic disorders, liver diseases, kidney diseases, cardiovascular diseases, muscle degeneration and muscular atrophy, mild inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury, or arteriosclerosis. Embodiment 32 provides the following: Any one of embodiments 27 to 31, wherein at least one additional therapeutic agent for treating or preventing the disease or disorder is further administered to the subject. Embodiment 33 provides the following: One of the methods described in embodiments 27 to 32, wherein the subject is a mammal. Embodiment 34 provides the following: One of the methods described in embodiments 27 to 33, wherein the subject is a human.

[0276] Any patents, patent applications, and publications cited herein are incorporated herein in their entirety by reference. While this disclosure has been made with reference to specific embodiments, it will be apparent to those skilled in the art that other embodiments and variations of this disclosure can be devised without departing from the spirit and scope of this disclosure. The appended claims are intended to be construed as encompassing all such embodiments and equivalent variations.

[0277] Sequence information SEQUENCE LISTING <110> Yale Plaza <120> Engineered Antibodies as Molecular Degraders through Cellular Recepten <150> US 62 / 913,679 <151> 2019-10-10 <160> 67 <170> PatentIn version 3.5 <210> 1 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Chemicals are <220> <221> misc_feature <222> (1)..(1) <223> N-acetylated <220> <221> misc_feature <222> (11)..(11) <223> Xaa = norleucin <220> <221> misc_feature <222> (17)..(17) <223> terminus is C(=O)NH2 <400> 1 Val Lys Phe Asn Lys Pro Phe Val Phe Leu Xaa Ile Glu Gln Asn Thr 1 5 10 15 Lys <210> 2 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 2 Val Lys Phe Asn Lys Pro Phe Val Phe Leu Met Ile Glu Gln Asn Thr 1 5 10 15 Lys <210> 3 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 3 Thr Trp Pro Lys His Phe Asp Lys His Thr Phe Tyr Ser Ile Leu Lys 1 5 10 15 Leu Gly Lys His 20 <210> 4 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 4 Thr Phe Phe Tyr Gly Gly Ser Arg Gly Lys Arg Asn Asn Phe Lys Thr 1 5 10 15 Glu Glu Tyr <210> 5 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 5 Leu Arg Lys Leu Arg Lys Arg Leu Leu Arg Asp Ala Asp Asp Leu Leu 1 5 10 15 Arg Lys Leu Arg Lys Arg Leu Leu Arg Asp Ala Asp Asp Leu 20 25 30 <210> 6 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 6 Thr Glu Glu Leu Arg Val Arg Leu Ala Ser His Leu Arg Lys Leu Arg 1 5 10 15 Lys Arg Leu Leu 20 <210> 7 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 7 Glu Ala Lys Ile Glu Lys His Asn His Tyr Gln Lys 1 5 10 <210> 8 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 8 Glu Ala Lys Ile Glu Lys His Asn His Tyr Gln Lys Gln Leu Glu Ile 1 5 10 15 Ala His Glu Lys Leu Arg 20 <210> 9 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 9 Thr Phe Phe Tyr Gly Gly Ser Arg Gly Lys Arg Asn Asn Phe Lys Thr 1 5 10 15 Glu Glu Tyr <210> 10 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(1) <223> D-amino acid <220> <221> misc_feature <222> (1)..(8) <223> Cys and Pen form a ring <220> <221> misc_feature <222> (3)..(3) <223> Xaa = thiazolidine-4-carboxylic acid <220> <221> misc_feature <222> (8)..(8) <223> Xaa = Penicillamine <400> 10 Cys Met Xaa Arg Leu Arg Gly Xaa 1 5 <210> 11 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(8) <223> Cys and Cys form a ring <400> 11 Cys Met Pro Arg Leu Arg Gly Cys 1 5 <210> 12 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(9) <223> Cys and Cys form a ring <400> 12 His Leu Asp Cys Met Pro Arg Gly Cys Phe Arg Asn 1 5 10 <210> 13 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(9) <223> Cys and Cys form a ring <400> 13 Cys Gln Val Lys Ser Met Pro Arg Cys 1 5 <210> 14 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(9) <223> Cys and Cys form a ring <400> 14 Cys Thr Thr Pro Met Pro Arg Leu Cys 1 5 <210> 15 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(9) <223> Cys and Cys form a ring <400> 15 Cys Lys Ala Pro Gln Met Pro Arg Cys 1 5 <210> 16 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(9) <223> Cys and Cys form a ring <400> 16 Cys Leu Asn Pro Ser Met Pro Arg Cys 1 5 <210> 17 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 17 Cys Leu Val Ser Ser Met Pro Arg Cys 1 5 <210> 18 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(9) <223> Cys and Cys form a ring <400> 18 Cys Leu Gln Pro Met Pro Arg Leu Cys 1 5 <210> 19 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(9) <223> Cys and Cys form a ring <400> 19 Cys Pro Val Ser Ser Met Pro Arg Cys 1 5 <210> 20 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(9) <223> Cys and Cys form a ring <400> 20 Cys Gln Ser Pro Met Pro Arg Leu Cys 1 5 <210> 21 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(9) <223> Cys and Cys form a ring <400> 21 Cys Leu Thr Pro Met Pro Arg Leu Cys 1 5 <210> 22 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (5)..(12) <223> Cys and Cys form a ring <400> 22 Asp Ser Gly Leu Cys Met Pro Arg Leu Arg Gly Cys Asp Pro Arg 1 5 10 15 <210> 23 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 23 Thr Pro Ser Ala His Ala Met Ala Leu Gln Ser Leu Ser Val Gly 1 5 10 15 <210> 24 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(1) <223> N-acetylated <220> <221> misc_feature <222> (5)..(12) <223> Cys and Cys form a ring <220> <221> misc_feature <222> (15)..(15) <223> terminus is C(=O)NH2 <400> 24 Asp Ser Gly Leu Cys Met Pro Arg Leu Arg Gly Cys Asp Pro Arg 1 5 10 15 <210> 25 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(8) <223> Cys and Cys form a ring <220> <221> misc_feature <222> (1)..(1) <223> N-propionylated <220> <221> misc_feature <222> (8)..(8) <223> terminus is C(=O)NH2 <400> 25 Cys Met Pro Arg Leu Arg Gly Cys 1 5 <210> 26 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(8) <223> Cys and Cys form a ring <220> <221> misc_feature <222> (1)..(1) <223> N-propionylated D-amino acid <220> <221> misc_feature <222> (8)..(8) <223> terminus is C(=O)NH2 <400> 26 Cys Met Pro Arg Leu Arg Gly Cys 1 5 <210> 27 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(8) <223> Cys and Pen form a ring <220> <221> misc_feature <222> (1)..(1) <223> N-propionylated D-amino acid <220> <221> misc_feature <222> (3)..(3) <223> Xaa = thiazolidine-4-carboxylic acid <220> <221> misc_feature <222> (8)..(8) <223> Xaa = Penicillamine <220> <221> misc_feature <222> (8)..(8) <223> terminus is C(=O)NH2 <400> 27 Cys Met Xaa Arg Leu Arg Gly Xaa 1 5 <210> 28 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(7) <223> Cys and Cys form a ring <220> <221> misc_feature <222> (1)..(1) <223> N-acetylated <220> <221> misc_feature <222> (7)..(7) <223> terminus is C(=O)NH2 <400> 28 Cys Met Pro Arg Leu Gly Cys 1 5 <210> 29 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(8) <223> Cys and Cys form a ring <220> <221> misc_feature <222> (1)..(1) <223> N-acetylated D-amino acid <220> <221> misc_feature <222> (8)..(8) <223> terminus is C(=O)NH2 <400> 29 Cys Met Pro Arg Leu Arg Gly Cys 1 5 <210> 30 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(1) <223> N-acetylated <220> <221> misc_feature <222> (2)..(2) <223> Xaa = Penicillamine <220> <221> misc_feature <222> (2)..(9) <223> Pen and Cys form a ring <220> <221> misc_feature <222> (4)..(4) <223> Xaa = thiazolidine-4-carboxylic acid <220> <221> misc_feature <222> (9)..(9) <223> terminus is C(=O)NH2 <400> 30 Asp Xaa Met Xaa Arg Leu Arg Gly Cys 1 5 <210> 31 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(1) <223> N-propionylated D-amino acid <220> <221> misc_feature <222> (1)..(8) <223> Cys and Pen form a ring <220> <221> misc_feature <222> (3)..(3) <223> Xaa = thiazolidine-4-carboxylic acid <220> <221> misc_feature <222> (8)..(8) <223> Xaa =Penicillamine, terminus is C(=O)NH2 <400> 31 Cys Met Xaa Arg Leu Arg Gly Xaa 1 5 <210> 32 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(1) <223> N-propionylated D-amino acid <220> <221> misc_feature <222> (1)..(8) <223> Cys and Pen form a ring <220> <221> misc_feature <222> (3)..(3) <223> Xaa = thiazolidine-4-carboxylic acid <220> <221> misc_feature <222> (7)..(7) <223> Xaa = Sarcosine <220> <221> misc_feature <222> (8)..(8) <223> Xaa = Penicillamine, terminus is C(=O)NH2 <400> 32 Cys Met Xaa Arg Leu Arg Xaa Xaa 1 5 <210> 33 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(1) <223> N-propionylated D-amino acid <220> <221> misc_feature <222> (1)..(8) <223> Cys and Cys form a ring <220> <221> misc_feature <222> (3)..(3) <223> Xaa = Pipecolic group <220> <221> misc_feature <222> (7)..(7) <223> Xaa = Sarcosine <220> <221> misc_feature <222> (8)..(8) <223> terminus is C(=O)NH2 <400> 33 Cys Met Xaa Arg Leu Arg Xaa Cys 1 5 <210> 34 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(8) <223> Cys and Pen form a ring <220> <221> misc_feature <222> (1)..(1) <223> N-propionylated D-amino acid <220> <221> misc_feature <222> (3)..(3) <223> Xaa = Pipecolic group <220> <221> misc_feature <222> (8)..(8) <223> Xaa = penicillamine, terminus is C(=O)NH2 <400> 34 Cys Met Xaa Arg Leu Arg Gly Xaa 1 5 <210> 35 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (1)..(1) <223> N-propionylated D-amino acid <220> <221> misc_feature <222> (1)..(8) <223> Cys and Pen form a ring <220> <221> misc_feature <222> (3)..(3) <223> Xaa = Pipecolic group <220> <221> misc_feature <222> (7)..(7) <223> Xaa = sarcosine <220> <221> misc_feature <222> (8)..(8) <223> Xaa = penicillamine, terminus is C(=O)NH2 <400> 35 Cys Met Xaa Arg Leu Arg Xaa Xaa 1 5 <210> 36 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 36 Thr Asp Thr Cys Leu Met Leu Pro Leu Leu Leu Gly Cys Asp Glu Glu 1 5 10 15 <210> 37 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 37 Asp Pro Ile Cys Trp Tyr Phe Pro Arg Leu Leu Gly Cys Thr Thr Leu 1 5 10 15 <210> 38 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 38 Trp Tyr Pro Cys Tyr Ile Tyr Pro Arg Leu Leu Gly Cys Asp Gly Asp 1 5 10 15 <210> 39 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 39 Gly Asn Ile Cys Met Leu Ile Pro Gly Leu Leu Gly Cys Ser Tyr Glu 1 5 10 15 <210> 40 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 40 Val Asn Ser Cys Leu Leu Leu Pro Asn Leu Leu Gly Cys Gly Asp Asp 1 5 10 15 <210> 41 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 41 Thr Pro Val Cys Ile Leu Leu Pro Ser Leu Leu Gly Cys Asp Thr Gln 1 5 10 15 <210> 42 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 42 Thr Val Leu Cys Ser Leu Trp Pro Glu Leu Leu Gly Cys Pro Pro Glu 1 5 10 15 <210> 43 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 43 Thr Phe Ser Cys Leu Met Trp Pro Trp Leu Leu Gly Cys Glu Ser Leu 1 5 10 15 <210> 44 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 44 Phe Gly Thr Cys Tyr Thr Trp Pro Trp Leu Leu Gly Cys Glu Gly Phe 1 5 10 15 <210> 45 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 45 Ser Leu Phe Cys Arg Leu Leu Leu Thr Pro Val Gly Cys Val Ser Gln 1 5 10 15 <210> 46 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 46 His Leu Leu Val Leu Pro Arg Gly Leu Leu Gly Cys Thr Thr Leu Ala 1 5 10 15 <210> 47 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 47 Thr Ser Leu Cys Ser Met Phe Pro Asp Leu Leu Gly Cys Phe Asn Leu 1 5 10 15 <210> 48 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 48 Ser His Pro Cys Gly Arg Leu Pro Met Leu Leu Gly Cys Ala Glu Ser 1 5 10 15 <210> 49 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 49 Thr Ser Thr Cys Ser Met Val Pro Gly Pro Leu Gly Ala Val Ser Thr 1 5 10 15 Trp <210> 50 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 50 Lys Asp Pro Cys Thr Arg Trp Ala Met Leu Leu Gly Cys Asp Gly Glu 1 5 10 15 <210> 51 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 51 Ile Met Thr Cys Ser Val Tyr Pro Phe Leu Leu Gly Cys Val Asp Lys 1 5 10 15 <210> 52 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (4)..(13) <223> Cys and Cys form a ring <400> 52 Ile His Ser Cys Ala His Val Met Arg Leu Leu Gly Cys Trp Ser Arg 1 5 10 15 <210> 53 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 53 Cys Gly Gly Gly Pro Phe Trp Trp Trp Pro 1 5 10 <210> 54 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 54 Cys Gly Gly Gly His Lys Tyr Leu Arg Trp 1 5 10 <210> 55 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 55 Cys Gly Gly Gly Lys Arg Ile Phe Met Val 1 5 10 <210> 56 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 56 Cys Gly Gly Gly Lys Trp His Tyr Leu Arg 1 5 10 <210> 57 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 57 Thr His Arg Pro Pro Met Trp Ser Pro Val Trp Pro 1 5 10 <210> 58 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 58 Thr His Arg Pro Pro Met Trp Ser Pro Val Trp Pro 1 5 10 <210> 59 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 59 Thr His Arg Pro Pro Met Trp Ser Pro Val Trp Pro 1 5 10 <210> 60 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 60 Leu Ser Leu Glu Arg Phe Leu Arg Cys Trp Ser Asp Ala Pro Ala 1 5 10 15 <210> 61 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 61 Leu Glu Arg Phe Leu Arg Cys Trp Ser Asp Ala Pro Ala 1 5 10 <210> 62 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 62 Arg Phe Leu Arg Cys Trp Ser Asp Ala Pro Ala 1 5 10 <210> 63 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 63 Leu Arg Cys Trp Ser Asp Ala Pro Ala 1 5 <210> 64 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 64 Cys Trp Ser Asp Ala Pro Ala 1 5 <210> 65 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 65 Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu 1 5 10 15 Ala Phe <210> 66 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <220> <221> misc_feature <222> (10)..(10) <223> Phe phenyl is para substituted with benzoyl <400> 66 Asp Cys Ala Trp His Leu Gly Glu Leu Phe Trp Cys Thr 1 5 10 <210> 67 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Chemically synthesized <400> 67 His Ala Ile Tyr Pro Arg His 1 5

Claims

1. Compounds containing formula (I), or their salts, geometric isomers, stereoisomers, or solvates: [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) During the ceremony, Ab is an antibody that binds to extracellular proteins; CRBM is a cell receptor-binding portion that binds to at least one receptor on the surface of a degradable cell in question, and the binding of (I) by it leads to endocytosis and degradation of extracellular proteins; Each CON is a group that independently bonds, or covalently links Ab to CRBM, Ab to the linker, and / or the linker to CRBM; A linker is a group having a valency in the range of 1 to 15; k' is an integer in the range of 1 to 15; h is an integer in the range of 0 to 15; i is an integer in the range of 0 to 15; h' is an integer in the range of 0 to 15; j is an integer in the range of 1 to 15.

2. The compound according to claim 1, wherein the linker valency is 1, 2, or 3.

3. The compound according to claim 1, wherein k' is 1, 2, or 3.

4. The compound according to claim 1, wherein j is 1, 2, or 3.

5. The compound according to claim 1, wherein h is 1, 2, or 3.

6. The compound according to claim 1, wherein h' is 1, 2, or 3.

7. The compound according to claim 1, wherein i is 1, 2, or 3.

8. The compound according to claim 1, wherein at least one of h, h', and i is at least 1.

9. The compound according to claim 1, wherein k', j', h, h', and i are each independently 1, 2, or 3.

10. The compound according to claim 1, wherein k' is 1 and j' is 1, 2, or 3.

11. [Ab]-[CON] 0～1 -[Linker]-[CON] 0～1 -[CRBM] (Ia), the compound according to claim 1.

12. The compound according to claim 1, wherein the degradable cells include hepatocytes.

13. The compound according to claim 1, wherein CRBM is a folate receptor binder, a mannose receptor binder, a mannose-6-phosphate (M6P) receptor binder, a low-density lipoprotein receptor-related protein 1 (LRP1) receptor binder, a low-density lipoprotein receptor (LDLR) binder, an FcγRI receptor binder, a transferrin receptor binder, a macrophage scavenger receptor binder, a G protein-coupled receptor binder, or an asialoglycoprotein receptor (ASGPR) binder.

14. The compound according to claim 1, wherein CRBM is as follows: (a) A folate receptor binder comprising at least one of folate, methotrexate, pemetrexed, or a bioactive fragment thereof; (b) A mannose receptor binder comprising at least one of the following: (In the formula, X is S or O, and R is, (Selected from the group consisting of, where each occurrence of "n" is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); and Polymer molecules shown in Figures 1 to 7; (c) A mannose-6-phosphate (M6P) receptor binder containing at least one of the following: (In the formula, X is O or S, and R 1 teeth, Selected from the group consisting of, R 2 is (Selected from the group consisting of, where each occurrence of "n" is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); Polymer molecules shown in Figure 8; The following compounds can be selected: ; The following compounds can be selected: ; (d) Low-density lipoprotein receptor-associated protein 1 (LRP1) receptor binder containing at least one amino acid sequence with SEQ ID NO:1-9; (e) A low-density lipoprotein receptor (LDLR) binder containing at least one amino acid sequence with SEQ ID NO: 10–35; (f) FcγRI receptor binder containing at least one amino acid sequence with SEQ ID NO:36-52; (g) A transferrin receptor binder containing at least one amino acid sequence of SEQ ID NO: 53-59 and 67; (h) Macrophage scavenger receptor binder containing at least one amino acid sequence with SEQ ID NO: 60–65; (i) A G protein-coupled receptor binder containing at least one of the following: In the formula, each occurrence of R is independent of H or C. 1 ~C 6 It is alkyl; (j) Asialoglycoprotein receptor (ASGPR) binders including the following: (In the formula, X is a linker with a length of 1 to 4 atoms, and If X is a linker the length of one atom, then X is O, S, N(R N1 ), or C(R N1 )(R N1 ) and If X is a linker the length of two atoms, then one or fewer atoms in X are O, S, or N(R) N1 ) and If X is a linker with a length of 3 or 4 atoms, then 2 or fewer atoms of X are independently O, S, or N(R) N1 ) As such, O, S, N(R N1 ), or C(R N1 )(R N1 ) containing a group, Here R N1 Each occurrence may be independently substituted with H, or with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups. 1 ~C 3 It is alkyl; R 1 and R 3 H and -(CH) are independent of each other. 2 ) K OH may be replaced by 1 to 3 independently selected halogens - (CH 2 ) K O(C 1 ~C 4 C may be substituted with alkyl, or one to three independently selected halogens. 1 ~C 4 Alkyl, -(CH 2 ) K (Vinyl), -O(CH 2 ) K (Vinyl), -(CH 2 ) K (Alkinyl), -(CH 2 ) K COOH may be replaced by 1 to 3 independently selected halogens - (CH 2 ) K C(=O)O(C 1 ~C 4 Alkyl) may be substituted with 1 to 3 independently selected halogens -OC(=O)(C 1 ~C 4 -C(=O)(C) may be substituted with alkyl, or one to three independently selected halogens. 1 ~C 4 Alkyl) is; or, R 1 and R 3 Each of them independently determines Ph(CH) 2 ) K - and this is substituted with 1 to 3 independently selected halogens; C may be substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups. 1 ~C 4 Alkyl; or C which may be substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups. 1 ~C 4 It may be substituted with an alkoxy; or, R 1 and R 3 Each of these has the following independent structure: -O-(CH 2 ) K' -CH(OH)-(CH 2 )K'-R 7 It is the basis of, During the ceremony, R 7 C may be substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups. 1 ~C 4 Alkoxy; -NR N3 R N4 ; or -(CH 2 ) K' -O-(CH 2 ) K -CH 2 -CH=CH 2 and; K is 0, 1, 2, 3, or 4; K' is 1, 2, 3, or 4; R N3 Each occurrence may be independently substituted with H, or with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups. 1 ~C 3 It is alkyl; R N4 Each occurrence may be independently substituted with H, 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups. 1 ~C 3 Alkyl, or Ph-(CH 2 ) K -is; or, R 1 and R 3 Each is independent Selected from the group consisting of, where CYC is, Selected from the group consisting of, During the ceremony, The bond indicated by -(CH 2 ) K This indicates the part of the CYC to which it is connected; L 1 -Linker, -CON-linker, or -CON-linker-CON; R C is absent, H, 1 to 3 optionally substituted halogens and / or C which may be substituted with 1 to 2 hydroxyl groups 1 ~C 4 Alkyl, or the following structure: It is the basis of, During the ceremony, R 4 、R 5 、and R 6 are each independently H, F, Cl, Br, I, CN, NR N1 R N2 、-(CH 2 ) K OH, -(CH 2 ) K O(C 1 ~C 4 alkyl) which may be substituted with 1 to 3 independently selected halogens, C 1 ~C 3 alkyl which may be substituted with 1 to 3 independently selected halogens, C 1 ~C 3 -alkoxy, -(CH 2 ) K COOH, -(CH 2 ) K C(=O)O-(C 1 ~C 4 alkyl) which may be substituted with 1 to 3 independently selected halogens, O-C(=O)-(C 1 ~C 4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or -C(=O)-(C 1 ~C 4 alkyl) which may be substituted with 1 to 3 independently selected halogens; R N Each occurrence may be independently substituted with H, or with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups. 1 ~C 3 It is alkyl; R N2 Each occurrence may be independently substituted with H, or with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups. 1 ~C 3 It is alkyl; or, R 1 and R 3 Each is independent of (C 3 ~C 8 Saturated carbocycle)-(CH 2 ) K - and here the carbon ring is -L 1 and -R C It is further replaced by; R 2 ha-(CH 2 ) K -N(R N1 )-C(=O)R AM And in the formula, R AM C may be substituted with H, 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups. 1 ~C 4 Alkyl, -(CH 2 ) K COOH may be replaced by 1 to 3 independently selected halogens - (CH 2 ) K C(=O)O(C 1 ~C 4 Alkyl) may be substituted with 1 to 3 independently selected halogens -OC(=O)(C 1 ~C 4 Alkyl) may be substituted with 1 to 3 independently selected halogens -C(=O)(C 1 ~C 4 Alkyl), or -(CH 2 ) K -NR N3 R N4 is; or, R 2 teeth And in the formula, R TA H, CN, NR N1 R N2 ,-(CH 2 ) K OH may be replaced by 1 to 3 independently selected halogens - (CH 2 ) K O(C 1 ~C 4 C may be substituted with alkyl, or one to three independently selected halogens. 1 ~C 4 Alkyl, -(CH 2 ) K COOH may be replaced by 1 to 3 independently selected halogens - (CH 2 ) K C(=O)O(C 1 ~C 4 Alkyl) may be substituted with 1 to 3 independently selected halogens -OC(=O)(C 1 ~C 4 -C(=O)(C) may be substituted with alkyl, or one to three independently selected halogens. 1 ~C 4 Alkyl) or, R TA C 3 ~C 10 An aryl group, or a 3-10 membered heteroaryl group containing 1-5 non-carbon ring atoms, where the aryl group or heteroaryl group is designated as CN or NR, respectively. N1 R N2 ,-(CH 2 ) K OH may be replaced by 1 to 3 independently selected halogens - (CH 2 ) K O(C 1 ~C 4 C may be substituted with alkyl, 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups. 1 ~C 3 Alkyl, may be substituted with 1 to 3 independently selected halogens - (C 1 ~C 3 -alkoxy), -(CH 2 ) K COOH may be replaced by 1 to 3 independently selected halogens - (CH 2 ) K C(=O)O-(C 1 ~C 4 Alkyl) may be substituted with 1 to 3 independently selected halogens -OC(=O)(C 1 ~C 4 (alkyl) or may be substituted with 1 to 3 independently selected halogens - (CH 2 ) K C(=O)-(C 1 ~C 4 It may be substituted with 1 to 3 groups independently selected from alkyl groups, or R TA teeth and may be substituted with 1 to 3 independently selected halogens, and 1 to 3 C 1 ~C 3 It may be substituted with an alkyl group, or R TA teeth And in the formula, each -(CH 2 ) K The group may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups, or 1 to 4 C groups. 1 ~C 3 (May be substituted with an alkyl group.)

15. If X is the length of two atoms, then X in ASGRBM is -OC(R N1 )(R N1 )-,-C(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 )-,-C(R N1 )(R N1 )-S-, -N(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-N(R N1 )-, or -C(R N1 )(R N1 )-C(R N1 )(R N1 )-is; If X is the length of three atoms, then X in ASGRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-OC(R N1 )(R N1 )-,-OC(R N1 )(R N1 )-O-, -OC(R N1 )(R N1 )-S-, -OC(R N1 )(R N1 )-N(R N1 )-,-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-,-C(R N1 )(R N1 )-C(R N1 )(R N1 )-S, -SC(R N1 )(R N1 )-S-, -SC(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 )-N(R N1 )-,-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-C(R N1 )(R N1 )-N(R N1 )-,-N(R N1 )-C(R N1 )(R N1 )-N(R N1 )-, or -C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ) is; or, If X is the length of four atoms, then X in ASGRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-OC(R N1 )(R N1 )-C(R N1 )(R N1 )-,-OC(R N1 )(R N1 )-OC(R N1 )(R N1 )-,-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-,-C(R N1 )(R N1 )-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-,-SC(R N1 )(R N1 )-SC(R N1 )(R N1 )-,-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, or -C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-is, The compound according to claim 14.

16. X is OCH 2 And R N1 If H is, or if X is CH 2 O and R N1 The compound according to claim 14, wherein is H.

17. ASGPRBM has the following structure: The compound according to claim 14, comprising:

18. The compound according to claim 14, comprising the following ASGPRBM groups: (In the formula, R A C may be replaced with 1 to 5 independently selected halogens. 1 ~C 3 It is alkyl, Z A ha-(CH 2 ) IM -, -O-(CH 2 ) IM -, -S-(CH 2 ) IM -, -NR M -(CH 2 ) IM -, -C(=O)-(CH 2 ) IM -, a PEG group containing 1 to 8 ethylene glycol residues, or -C(O)(CH 2 ) IM NR M -and, Z B is nonexistent, -(CH 2 ) IM -, -C(=O)-(CH 2 ) IM -, or -C(=O)(CH 2 ) IM -NR M -and, R M C may be substituted with H or 1-2 hydroxyl groups. 1 ~C 3 It is alkyl, Each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6; (where R = CH 3 , CF 3 , or CH 2 CF 3 (is); 。

19. The compound according to claim 1, wherein the linker is a polyethylene glycol-containing linker having 1 to 12 ethylene glycol residues.

20. The linker has the following structure: -CH 2 CH 2 (AND 2 CH 2 ) m AND 2 -、-(CH 2 ) m CH 2 -、-[N(R a )-CH(R b )(C=O)] m - Alternatively, it may contain a polypropylene glycol group or a polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units. Each R a H and C are independent of each other. 1 ~C 3 Alkyl, or C 1 ~C 6 It is alkanol, or R b Together with other groups, they form a pyrrolidine group or a hydroxypyrroline group; Each R b These are independently hydrogen, methyl, isopropyl, and -CH(CH 3 )CH 2 CH 3 ,-CH 2 CH(CH 3 ) 2 ,-(CH 2 ) 3 -Guanidine, -CH 2 C(=O)NH 2 ,-CH 2 C(=O)OH, -CH 2 SH, -(CH 2 ) 2 C(=O)NH 2 ,-(CH 2 ) 2 C(=O)OH, -(CH 2 ) Imidazole, -(CH 2 ) 4 NH 2 ,-CH 2 CH 2 SCH 3 , benzyl, -CH 2 OH, -CH(OH)CH 3 ,-(CH 2 ) Imidazole, or -(CH 2 Selected from the group consisting of phenols; m is an integer in the range of 1 to 15; or, The linker has the following structure: -[N(R ' -(CH 2 ) 1～15 -C(=O)]- (In the formula, R' may be substituted with H or 1-2 hydroxyl groups.) 1 ~C 3 (It is an alkyl group, and m is an integer in the range of 1 to 100.) including; or, The linker has the following structure: -ZD-Z'- (In the formula, Z and Z' are joined independently. and; Each R is independent of H and C 1 ~C 3 Alkyl, or C 1 ~C 6 It is alkanor; Each R 2 H or C 1 ~C 3 It is alkyl; Each Y is independently a bond, O, S, or N(R); Each i is independently between 0 and 100; D is a bond, -(CH 2 ) i -YC(=O)-Y-(CH 2 ) i -,-(CH 2 ) m' -, or -[(CH 2 ) n -X 1 )] j -However, Z, Z', and D cannot be conjugated simultaneously; X 1 is O, S, or N(R); j is an integer in the range of 1 to 100; m' is an integer in the range of 1 to 100; n is an integer in the range of 1 to 100. including; or, The linker has the following structure: -CH 2 -(OH 2 CH 2 ) n -CH 2 -、-(CH 2 CH 2 ABOUT) n' CH 2 CH 2 -、または-(CH 2 CH 2 CH 2 ABOUT) n - (In the formula, each n and n' is an integer in the range of 1 to 25.) including; or, The linker has the following structure: -PEG-CON-PEG- (In the formula, each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON is a triazole group) (is) including, The compound according to claim 1.

21. CON has the following structure: (In the formula, R' and R'' are independently H, methyl, or a bond.) including; or, CON has the following structure: -C(=O)-N(R 1 )-(CH 2 ) n'' -N(R 1 )C(=O)-、 -N(R 1 )-C(=O)(CH 2 ) n'' -C(=O)N(R 1 )-,or -N(R 1 )-C(=O)(CH 2 ) n'' -N(R 1 )C(=O)- (In the formula, each R 1 H or C 1 ~C 3 (It is an alkyl group, and n'' is independently an integer between 0 and 8, in certain embodiments between 1 and 7, and in certain embodiments between 1, 2, 3, 4, 5, or 6.) including; or, CON has the following structure: (In the formula, R 1a , R 2a , and R 3a H and -(CH) are independent of each other. 2 ) M1 -,-(CH 2 ) M2 C(=O) M3 (NR 4 ) M3 -(CH 2 ) M2 -,-(CH 2 ) M2 (NR 4 ) M3 C(O) M3 -(CH 2 ) M2 -, or -(CH 2 ) M2 O-(CH 2 ) M1 -C(O)NR 4 -However, R 1a , R 2a , and R 3a It is not possible for both to be H at the same time; Each M1 is independently 1, 2, 3, or 4; Each M2 is independently 0, 1, 2, 3, or 4; Each M3 is independently either 0 or 1; Each R 4 H and C are independent of each other. 1 ~C 3 Alkyl, C 1 ~C 6 Alkanol, or -C(=O)(C 1 ~C 3 Alkyl) However, the same R 1a , R 2a , and R 3a (M2 and M3 within the same object cannot all be 0 at the same time.) including; or, CON has the following structure: including, The compound according to claim 1.

22. Extracellular proteins include 1-40-β-amyloid, 5'-nucleotidase, activated F9, F10, activin receptor-like kinase 1, α-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-1), Bacillus anthracis anthrax, BAFF, β-amyloid, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide α, canine (Canis lupus familiaris) IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, clamping factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, and Escherichia coli (E. coli).E. coli Shiga toxin type 1, E. coli Shiga toxin type 2, EGFL7, endotoxin, epicyalin, FGF 23, fibrin II, β chain, fibronectin extradomain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth and differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human β-amyloid, human cell dispersion factor receptor kinase, human TNF, IFN-α, IFN-γ, IgE, IgE Fc region, IGF1, IGF2, IGHE, IL 17A, IL 17A and IL 17F, IL 20, IL-1, IL-12, IL-23, IL-13, IL-17, IL-1β, IL-22, IL-4, IL-5, IL-6, IL17A and IL17F, IL1A, IL2, IL23, IL23A, IL31RA, IL6, IL6R, IL9, ILGF2, influenza A hemagglutinin, influenza A virus hemagglutinin, influenza A virus hemagglutinin HA, interferon γ, interferon Ron-γ-inducing protein, interleukin-1α, interleukin-13, interleukin-17α, interleukin-17α, TNF, interleukin-17A, kallikrein, LOXL2, LRRC15, LTA, MASP-2, MCP-1, MIF, MST1R (also known as RON), MUC1, myostatin, NACP, NCA-90 (granulocyte antigen), neuronal apoptosis-regulating proteinase 1, NGF, NOGO-A, Notch The compound according to claim 1, comprising 1, NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, lid-specific spongein 3, RTN4, sclerostin, SDC1, serum amyloid A protein, serum amyloid P component, SOST, Staphylococcus aureus α toxin, tau protein, TFPI, TGFβ1, TGFβ2, TGF-β, TNF-α, TROP-2, TSLP, VEGF-A, VEGF-A and Ang-2, VEGFA, or VWF.

23. The compound according to claim 1, wherein Ab is a monoclonal antibody.

24. The aforementioned antibodies include avagovomab, abrezekimab, adalimumab, aducanumab, afasevikumab, aferimomab, alirocumab, altumomab, and altumomab pentetate. pentetate), andecaliximab, anrukinzumab, alsitumomab, ascrinvacumab, atezolizumab, atidortoxumab, atinumab, avelumab, bapineuzumab, bavituximab, belimumab, bermekimab, besilesomab, bevacizumab, bicilomab, bime Bimekizumab, Birtamimab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumab, Cantuzumabrabutansine ravtansine), caplacizumab, carlumab, cergutuzumab, cergutuzumab amunaleukin, certolizumab, certolizumab pegol, cibisatamab, clazakizumab, cribatuzumab, cribatuzumab tetraxetantetraxetan), concizumab, crenezumab, dectrekumab, denosumab, dezamizumab, diridavumab, domagrozumab, dorlimomab, dorlimomab aritox aritox), durvalumab, dusigitumab, eculizumab, edobacomab, efungumab, eldelumab, elezanumab, elsilimomab, emactuzumab, emapalumab, emicizumab, enokizumab, epitumomab, epitumomab situxetan cituxetan), eptinezumab, erenumab, evinacumab, evolocumab, faricimab, facinumab, fezakinumab, ficlatuzumab, firivumab, fletikumab, fontrizumab, fremanezumab, fresolimumab, phlovocimab, flunebetomab ( Frunevetmab, Fulranumab, Galcanezumab, Gantenerumab, Gatipotuzumab, Gedivumab, Gebokizumab, Gimsilumab, Girentuximab, Golimumab, Gosuranemab, Guselkumab, Idarucizumab, Igovomab, Imalumab, Indatuximab, Indatuximab tansineravtansine), infliximab, istiratumab, ixekizumab, rabetsumab, lacnotuzumab, lampalizumab, lanadelumab, landogrozumab, lebrikizumab, lemalesomab, lensalizumab, lensilumab, reldelimumab ( Lerdelimumab, Lesofavumab, Ligelizumab, Lodelcizumab, Lokivetmab, Lutikizumab, Marstacimab, Mepolizumab, Metelimumab, Mirikizumab, Nacolomab, Nacolomabutafenatox Tafenatox), Namilumab, Narnatumab, Navivumab, Naxitamab, Nevacumab, Nemolizumab, NEOD, Nerelimomab, Nesvacumab, Netakimab, Nofetumomab, Nofetumomab merpentanMerpentan), Obiltoxaximab, Oleclumab, Olendalizumab, Olokizumab, Omalizumab, OMS, Onartuzumab, Olegobomab, Orticumab, Otilimab, Ozanezumab, Ozoralizumab, Parsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab, Pemtumomab, Perakizumab, Pexelizumab, Placulumab, ponezumab, prasinezumab, pritoxaximab, quilizumab, radretumab, ralpancizumab, ranevetmab, ranibizumab, ravulizumab b) Laxibakumab, REGN-EB, Remtolumab, Reslizumab, Rilotumumab, Risankizumab, Romilkimab, Romosozumab, Rontalizumab, Rosmantuzumab, Sacituzumab, Sacituzumab-Govitecan govitecan), Samrotamab, Samrotamab vedotin, Sarilumab, Secukinumab, Setoxaximab, Setrusumab, Sifalimumab, Siltuximab, Simtuzumab, Silkumab, Sofituzumab, Sofituzumab, Sofituzumab vedotinVedotin), solanezumab, sontuzumab, stamulumab, sulesomab, sutimlimab, suvizumab, supratoxumab, tabarumab, tacatuzumab, tacatuzumab tetraxetan, talizumab, tanezumab, tefibazumab, telimomab, telimomab aritox The compound according to claim 1, comprising aritox), tesidolumab, tezeperumab, tibrizumab, tildrakizumab, timolumab, tisotumab, tisotumab vedotin, tralokinumab, trevogrumab, urtoxazumab, ustekinumab, vanucizumab, bapariximab, varisacumab, bepalimomab, besencumab, vobarilizumab, vunakizumab, or xentuzumab.

25. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one compound according to claim 1.

26. The pharmaceutical composition according to claim 25, further comprising another therapeutically active compound.

27. A method for treating a disease or disorder in a subject, comprising the step of administering a therapeutically effective amount of at least one compound according to claim 1.

28. The method according to claim 27, wherein the disease or disorder includes an autoimmune disease, cancer, or inflammation.

29. Autoimmune diseases include Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, and essential mixed purpura. Oglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful steatosis, adult Still's disease, ankylosing spondylitis, Crest syndrome, drug-induced lupus, enthesitis-associated arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatoid arthritis, Parry-Romberg syndrome, Personage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus Undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neurogenic myotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenia dysthenia syndrome, multiple sclerosis, pattern II, Oshtoran syndrome, pediatric autoimmune streptococcal-associated neuropsychiatric disorders (PANDA). S) Progressive inflammatory neuropathy, restless legs syndrome, generalized rigidity syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, woody conjunctivitis, Mohlen's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Suzak syndrome, sympathetic ophthalmitis, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA),The method according to claim 28, comprising IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytosis-destroying vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, or pyoderma gangrenosum.

30. The method according to claim 28, wherein the cancer includes prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer, or lymphoma.

31. The method according to claim 28, wherein the inflammation includes neurodegenerative inflammatory diseases, immunocompromised immune response diseases that cause inflammation, chronic inflammatory diseases, hyperglycemic disorders, diabetes mellitus (type 1 and type 2), pancreatic β-cell death and associated hyperglycemic disorders, liver diseases, kidney diseases, cardiovascular diseases, muscle degeneration and muscular atrophy, mild inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury, or arteriosclerosis.

32. The method according to claim 27, wherein at least one additional therapeutic agent for treating or preventing the disease or disorder is further administered to the subject.

33. The method according to claim 27, wherein the subject is a mammal.

34. The method according to claim 27, wherein the subject is a human.

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