Engineered antibodies as cellular receptor-mediated molecular degraders

Abstract

To provide bifunctional compounds that can be used to promote or enhance the degradation of certain circulating proteins.SOLUTION: What is claimed is: A compound comprising Formula (I): [Ab] k' - [CON] h - [Linker] I - [CON] h' - [CRBM] j' (I) wherein: Ab is an antibody that binds to an extracellular protein; CRBM is a cell receptor binding moiety that binds to at least one receptor on the surface of a degradative cell in a subject; (I) thereby results in endocytosis and degradation of the extracellular protein; each CON is independently a bond or a group that covalently links the Ab to the CRBM, the Ab to the linker, and / or the linker to the CRBM; the linker is a group having a valence ranging from 1 to 15; k ' is an integer ranging from 1 to 15; h is an integer ranging from 0 to 15; I is an integer ranging from 0 to 15; h ' is an integer ranging from 0 to 15; and j is an integer ranging from 1 to 15.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under GM067543 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 913,679, filed October 10, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0003] Background to the disclosure One mechanism that controls the transport of molecules into cells is receptor-mediated endocytosis. In this process, a receptor on the cell surface binds to a specific ligand (or a molecule containing the specific ligand) present on the outside of the cell. This ligand can be a small molecule, metabolite, hormone, protein, or even a virus. This binding process triggers the inward budding (invagination) of the plasma membrane, forming a vesicle containing the receptor-ligand complex. The vesicle then becomes an endosome and subsequently fuses with a lysosome, where the receptor, along with its bound ligand cargo, is degraded, or the receptor is recycled to the cell surface for further collection of circulating ligand.

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

[0005] There is a need in the art for novel compounds and methods that allow for the inhibition, removal, and / or degradation of specific extracellular proteins that mediate diseases and / or disorders in a subject. The present disclosure addresses this need. Summary of the Invention

[0006] A brief summary of the disclosure The present disclosure provides compounds comprising formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof: [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) where Ab, CON, linker, CRBM, k', h, i, h', and j' are defined elsewhere herein.

[0007] The present disclosure further provides pharmaceutical compositions comprising at least one compound contemplated herein and at least one pharmaceutically acceptable excipient.

[0008] The present disclosure further provides a method of treating a disease or disorder in a subject, comprising administering a therapeutically effective amount of at least one compound contemplated herein. [Brief explanation of the drawings]

[0009] The drawings illustrate generally, by way of example, but not by way of limitation, various aspects of the present application.

[0010] As used herein, the term "REAG" refers to 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] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 2] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 3] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 4] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 5] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 6] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 7] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 8] 1 illustrates a non-limiting preparation of polymeric compounds containing mannose-6-phosphate receptor binders. [Figure 9] Non-limiting examples of R1 and / or R3 groups in ASGPRBM are shown below. [Figure 10] Non-limiting examples of R2 groups in ASGPRBM are shown below. [Figure 11A] 11A-11B show a non-limiting synthesis of the ASGPRBM group. [Figure 11B] See legend to Figure 11A. [Figure 12A] Figures 12A-12C show non-limiting syntheses of specific ASGPRBM groups. While this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 12B] See legend to Figure 12A. [Figure 12C] See legend to Figure 12A. [Figure 13A] Figures 13A-13L show non-limiting syntheses of specific ASGPRBM groups. While this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 13B] See legend to Figure 13A. [Figure 13C] See legend to Figure 13A. [Figure 13D] See legend to Figure 13A. [Figure 13E] See legend to Figure 13A. [Figure 13F] See legend to Figure 13A. [Figure 13G] See legend to Figure 13A. [Figure 13H] See legend to Figure 13A. [Figure 13I] See legend to Figure 13A. [Figure 13J] See legend to Figure 13A. [Figure 13K] See legend to Figure 13A. [Figure 13L] See legend to Figure 13A. [Figure 14A]Figures 14A-14O show non-limiting syntheses of specific ASGPRBM groups. While this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 14B] See legend to Figure 14A. [Figure 14C] See legend to Figure 14A. [Figure 14D] See legend to Figure 14A. [Figure 14E] See legend to Figure 14A. [Figure 14F] See legend to Figure 14A. [Figure 14G] See legend to Figure 14A. [Figure 14H] See legend to Figure 14A. [Figure 14I] See legend to Figure 14A. [Figure 14J] See legend to Figure 14A. [Figure 14K] See legend to Figure 14A. [Figure 14L] See legend to Figure 14A. [Figure 14M] See legend to Figure 14A. [Figure 14N] See legend to Figure 14A. [Figure 14O] See legend to Figure 14A. [Figure 15] 1 shows a non-limiting synthetic scheme that allows for labeling (derivatization) of an antibody (labeled Ab) with an azide group. [Figure 16]

[0049] Figure 16 shows a non-limiting synthetic scheme that allows for labeling (derivatization) of CRBM groups with strained alkyne-containing groups. In certain non-limiting embodiments, any azide-containing compound (including but not limited to compounds shown in Figure 15) can be reacted with a strained alkyne-containing compound (including but not limited to compounds shown in Figure 16) to produce compounds of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description 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 can be, for example, circulating proteins and / or cell surface proteins that can be bound to or embedded in a cell membrane). In certain embodiments, the extracellular proteins mediate diseases and / or disorders in a subject, and treatment or management of the disease and / or disorder requires the degradation, removal, or reduction of the concentration of the extracellular proteins in the subject. Thus, in certain embodiments, administration of a compound of the present disclosure to a subject removes the extracellular proteins and / or reduces the circulating concentration of the extracellular proteins, thereby treating, ameliorating, or preventing the disease and / or disorder in the subject.

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

[0014] In certain embodiments, the receptor is the hepatocyte asialoglycoprotein receptor (ASGPR). In that case, the binding moiety is referred to herein as an ASGPR binding moiety or ASGPRBM. The present disclosure is not limited to this receptor, but rather contemplates the use of other receptors described herein or any other endocytic receptor known in the art.

[0015] Furthermore, the present disclosure is not limited to degradation that takes place in hepatocytes, rather, the present disclosure contemplates that non-hepatic cells in the body present specific degradation receptors, which are contemplated as being within the scope of the present disclosure.

[0016] In one aspect, the compounds of the present disclosure bind to extracellular target proteins and remove them from the circulation (and the body) through the liver.Therefore, the compounds of the present disclosure utilize the body's own mechanism to degrade proteins.Without wishing to be limited by theory, the compounds of the present disclosure bind to specific receptors located in specific cells, such as but not limited to, hepatocytes, such as but not limited to, ASGPR.This binding induces the degradation of protein targets by intralysosomal proteolysis.As a result of this mechanism, the circulating level of extracellular protein targets is reduced.As a result, the corresponding disease symptoms are reduced in the subject to which the compound is administered and / or disappear from the patient.

[0017] ASPGR functions to eliminate desialylated glycoproteins with exposed non-reducing D-galactose (Gal) or N-acetylgalactosamine (GalNac) terminal groups. ASGPR is expressed at a level of approximately 500,000 per hepatocyte and is minimally present elsewhere in the body. ASGPR-mediated internalization of target glycoproteins exhibits a half-life of approximately 3 minutes. The bifunctional compounds claimed herein selectively bind 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 the intralysosomal pathway in hepatocytes via ASGPR. Endosome-bound ASPGR releases extracellular protein ligands at pH 5.4, which are then removed from the circulation by hepatocytes. However, ASPGR remains available for recycling and buds into recycling endosomes, escaping lysosomal degradation. Indeed, depending on the cell line, ASPGR can recycle up to approximately 200 times with a recirculation rate of approximately 15-20 min. ASPGR exhibits very rough ligand size requirements, possibly reaching a diameter of approximately 70 nm. In contrast, IgM pentamers are approximately 20 nm in diameter and therefore fit the ligand size requirements of ASPGR.

[0018] The disclosures of International Patent Application No. PCT / US2019 / 026260, filed April 8, 2019 (and published October 17, 2019 as WO 2019 / 199634), and International Patent Application No. PCT / US2019 / 026239, filed April 8, 2019 (and published October 17, 2019 as WO 2019 / 199621), are incorporated herein by reference in their entireties.

[0019] Without wishing to be limited by theory, the use of antibodies, such as but not limited to monoclonal antibodies, in the compounds of the present disclosure exhibits clear advantages over similar bifunctional compounds in the prior art.

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

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

[0022] In yet another aspect, the antibody interacts with neonatal Fc receptor (FcRn), also known as Brambell receptor. In humans, FcRn controls the turnover of IgG and serum albumin. FcRn extends the half-life 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 pinocytosis and are likely degraded in lysosomes. However, IgG and serum albumin are bound by FcRn at a slightly acidic pH (less than 6.5) and recycled to the cell surface, where they are released at the neutral pH of blood (greater than 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 the present disclosure can avoid ASGPR-mediated degradation while binding to ASGPRBM through binding to FcRn.

[0023] Rescue of the compounds of the present 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, modified antibodies of the present disclosure can participate in multiple rounds of protein binding and targeted degradation through recycling by FcRn. Furthermore, because the compounds of the present disclosure can participate in multiple rounds of degradation, they can be administered at relatively low doses, which is therapeutically advantageous. Furthermore, because the half-life of the compounds of the present disclosure is extended by FcRn rescue, the administration frequency of the compounds can be reduced compared to the administration frequency required when using compounds containing circulating protein small molecule binding partners.

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

[0025] As an additional advantage, the present disclosure allows for the efficient production of novel antibody-containing compounds in which an ASGPRBM is conjugated to any selected antibody (without the need to modify the antibody's amino acid sequence and / or extensively test the effects of the 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 less frequent administration regimen of the antibody-containing compounds of the present disclosure (compared to other antibody therapies) reduces overall treatment costs and lowers the financial burden on insurance companies and patients.

[0026] In accordance with the present disclosure there may be employed conventional methods of chemical synthesis and pharmaceutical formulation, as well as techniques of pharmacology, molecular biology, microbiology, and recombinant DNA within the skill of the art, which techniques are well known and are explained fully elsewhere in the literature.

[0027] Reference will now be made in detail to certain aspects of the disclosed subject matter, some examples of which are illustrated in the accompanying drawings. While the disclosed subject matter will be described in conjunction with numbered claims, it will be understood that such subject matter as illustrated is not intended to limit the scope of the claims to the disclosed subject matter.

[0028] Throughout this document, values ​​expressed in range form should be interpreted flexibly to include not only the numerical values ​​expressly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were expressly recited. For example, a range such as "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also individual values ​​(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%) within the indicated range. Unless otherwise indicated, the term "about X to Y" has the same meaning as "about X to about Y." Similarly, unless otherwise indicated, the term "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z."

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

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

[0031] In this document, the terms "a," "an," or "the" are used to include one or more unless the context clearly dictates otherwise. The term "or" is used to mean a non-exclusive "or" unless otherwise indicated. The statements "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B." Furthermore, words or terms used herein and not defined elsewhere should be understood to be for descriptive purposes only and not for limiting purposes. Any use of section headings is intended to aid in the reading and comprehension of this document and should not be construed as limiting. Information associated with a section heading may occur within or outside that particular section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, as if individually incorporated by reference.

[0032] The term "abnormal" when used in the context of an organism, tissue, cell, or component thereof means an organism, tissue, cell, or component thereof that differs in at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) from an organism, tissue, cell, or component thereof that exhibits the "normal" (expected) respective characteristic. A characteristic that is normal or expected in one cell or tissue type may be abnormal in a different cell or tissue type.

[0033] The term "acyl," as used herein, refers to a group containing a carbonyl moiety bonded through the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or to another carbon atom, which may be part of an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, a heteroaryl group, a heteroarylalkyl group, etc. The acyl group may contain 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. The acyl group may contain a double bond or a triple bond within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group may contain a heteroatom within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups. When the group containing the carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is called a "haloacyl" group. An example is the trifluoroacetyl group.

[0034] As used herein, the term "alkyl" refers to straight-chain and branched alkyl groups and 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 straight-chain 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. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched forms of alkyl. Representative substituted alkyl groups may be substituted one or more times with any of the groups enumerated herein, such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0035] As used herein, the term "alkenyl" refers to straight-chain, branched-chain, and cyclic alkyl groups, as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or from 2 to about 20 carbon atoms, or from 2 to 12 carbon atoms, or in some embodiments, from 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, among others.

[0036] The term "alkoxy" as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group can contain about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further contain double or triple bonds and heteroatoms. For example, an allyloxy group or a methoxyethoxy group is an alkoxy group within the meaning herein, as is a methylenedioxy group in the context in which two adjacent atoms of the structure are replaced thereby.

[0037] The term "alkynyl," as used herein, refers to straight- and branched-chain alkyl groups, as defined herein, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, from 2 to about 20 carbon atoms, or from 2 to 12 carbon atoms, or in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CHCH), and -CHC≡C(CHCH), among others.

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

[0039] The term "amino acid sequence variant" refers to a polypeptide having an amino acid sequence that differs to some extent from a native sequence polypeptide. Typically, amino acid sequence variants exhibit 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 exhibit 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 any of the forms -NH2, -NHR, -NR2, -NR3, where each R is independently selected. + and -NR3, which cannot be protonated. + "Amino" refers to the protonated form of each form except for the following: ##STR1## Thus, any compound substituted with an amino group can be considered an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0041] The term "aminoalkyl" as used herein 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" refers to an immunoglobulin molecule that specifically binds to an antigen. An antibody can be an intact immunoglobulin derived from natural or recombinant sources, or an immunoreactive portion of an intact immunoglobulin. Typically, an antibody is a tetramer of an immunoglobulin molecule. Antibodies in this 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, including the antigen-determining variable region of the 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 sdAbs (VL or VH), e.g., camelid antibodies (Riechmann, 1999, J. Immunol. Meth. 231:25-38), camelid VHH domains composed of a VL or VH domain that exhibits sufficient affinity for a target, and multispecific antibodies formed from antibody fragments such as bivalent fragments comprising two Fab fragments linked by a disulfide bridge at 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, intrabodies, diabodies, triabodies, tetra-antibodies, v-NARs, and bis-scFvs (see, e.g., Hollinger & Hudson, 2005, Nature Biotech. 23:1126-1136). Antigen-binding fragments may also be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (U.S. Patent No. 6,703,199, which describes fibronectin polypeptide mini-antibodies). Antibody fragments also include human or humanized antibodies, or portions of human or humanized antibodies.

[0044] As used herein, the term "antigen" or "Ag" is defined as a molecule that elicits an immune response. This immune response may involve antibody production, activation of specific immunocompetent cells, or both. Those skilled in the art will understand that any macromolecule, including virtually any protein or peptide, can serve as an antigen. Furthermore, antigens can be derived from recombinant 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 elicits an immune response, therefore, encodes an "antigen," as that term is used herein. Furthermore, those skilled in the art will understand that an antigen is not necessarily encoded solely by the full-length nucleotide sequence of a gene. It is understood that the present disclosure includes, but is not limited to, the use of partial nucleotide sequences of two or more genes, and that these nucleotide sequences may be configured in various combinations to elicit a desired immune response. Furthermore, those skilled in the art will understand that an antigen is not necessarily encoded by a "gene." It is understood that an antigen may be synthetically produced or derived from a biological sample, including, but not limited to, a tissue sample, a tumor sample, cells, or biological fluid.

[0045] As used herein, the term "aralkyl" refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups, as well as fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. An aralkenyl group refers to an alkenyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein.

[0046] As used herein, the term "aryl" refers to 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, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains from about 6 to about 14 carbon atoms in the ring portion of the group. Aryl groups can be unsubstituted or substituted as defined herein. Representative substituted aryl groups can be mono- or multi-substituted, such as, but 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-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or naphthyl groups substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring.

[0047] As used herein, the term "asialoglycoprotein receptor binding moiety" or "ASGPRBM" refers to a group capable of binding to at least one hepatocyte asialoglycoprotein receptor on the surface of a cell, such as, but not limited to, a hepatocyte. When the ASGPRBM, and any additional moieties to which it is attached, bind to a receptor on the surface of the hepatocyte, the molecule comprising the ASGPRBM is taken up by the hepatocyte by the phagocytic machinery, where the molecule is at least partially degraded through lysosomal degradation.

[0048] As used herein, "C 6~10 -C 6~10 The term "biaryl" refers to a C 6~10 C covalently bound to the aryl moiety 6~10 C means an aryl moiety. 6~10 The aryl moiety can be any suitable aryl group described herein. 6~10 -C 6~10 Non-limiting examples of biaryl include biphenyl and binaphthyl.

[0049] As used herein, the term "coding sequence" refers to a nucleic acid or its complement sequence, or a portion thereof, that can be transcribed and / or translated to produce mRNA and / or a polypeptide or a fragment thereof. Coding sequences include exons in genomic DNA or premature primary RNA transcripts that are joined together by the cell's biochemical machinery to produce mature mRNA. The antisense strand is the complement of the nucleic acid, from which the coding sequence can be deduced. In contrast, the term "non-coding sequence" as used herein refers to a nucleic acid or its complement sequence, or a portion thereof, that is not translated in vivo into amino acids or does not interact with tRNA to position or attempt to position amino acids. Non-coding sequences include both intron sequences in genomic DNA or premature primary RNA transcripts and gene-related 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) related by base-pairing rules. For example, the sequence "AGT" is complementary to the sequence "TCA." Complementarity can be "partial," in which only some of the bases of a nucleic acid match according to the base-pairing rules. Alternatively, there can be "complete" or "total" complementarity 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 term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to patients or subjects. There are multiple techniques for administering compounds in the art, including but not limited to intravenous administration, oral administration, aerosol administration, parenteral administration, intraocular administration, intrapulmonary administration, and topical administration.

[0052] As used herein, the term " conservative variation " or " conservative substitution " refers to replacing amino acid residue with another biologically similar residue.Conservative variation or conservative substitution may not change the shape of peptide chain.Examples of conservative variation or conservative substitution 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, such as replacing arginine with lysine, replacing glutamic acid with aspartic acid, or replacing glutamine with asparagine.

[0053] As used herein, the term "cycloalkyl" refers to cyclic alkyl groups, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups can have from 3 to about 8-12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Additionally, cycloalkyl groups include polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl, as well as fused rings, such as, but not limited to, decalinyl. Cycloalkyl groups also include rings substituted with straight- or branched-chain alkyl groups, as defined herein. Representative substituted cycloalkyl groups can be mono- or more than twice substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups or mono-, di-, or tri-substituted norbornyl or cycloheptyl groups, which may be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl," alone or in combination, refers to a cyclic alkenyl group.

[0054] "Disease" refers to a state of health in an animal where the animal is unable to maintain homeostasis and where the animal's health continues to deteriorate unless the disease is remitted.

[0055] In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's health is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily cause a further deterioration in the animal's health.

[0056] A disease or disorder is "in remission" when the severity of a symptom of the disease or disorder, the frequency with which the patient experiences the symptom, or both, is reduced.

[0057] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to produce a desired biological result. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be ascertained by one of ordinary skill in the art using routine experimentation.

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

[0059] "Encoding" refers to the inherent property of a particular sequence of nucleotides in a polynucleotide, such as a gene, cDNA, or mRNA, to serve as a template for the synthesis of other polymers and macromolecules in biological processes and to have a defined sequence of nucleotides (i.e., rRNA, tRNA, and mRNA) or a defined sequence of amino acids, and the resulting biological properties. Thus, a gene encodes a protein when the protein is produced in a cell or other biological system by 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 a sequence listing, and the non-coding strand, which is used as a template for transcription of the gene or cDNA, can be said to encode the protein or other product of the gene or cDNA.

[0060] As used herein, the term "fragment," when applied to nucleic acids, refers to a subsequence of a larger nucleic acid. A "fragment" of a nucleic acid can be at least about 15 nucleotides in length; e.g., at least about 50 nucleotides to about 100 nucleotides; at least about 100 nucleotides to about 500 nucleotides; at least about 500 nucleotides to about 1000 nucleotides; at least about 1000 nucleotides to about 1500 nucleotides; about 1500 nucleotides to about 2500 nucleotides; or about 2500 nucleotides (and any integer value therebetween). As used herein, the term "fragment" as applied to a protein or peptide refers to a subsequence of a larger protein or peptide. A "fragment" of a protein or peptide can be at least about 20 amino acids in length; e.g., at least about 50 amino acids in length; at least about 100 amino acids in length; at least about 200 amino acids in length; at least about 300 amino acids in length; or at least about 400 amino acids in length (and any integer value therebetween).

[0061] As used herein, the term "GN3" refers to the following group: TIFF2026010002000002.tif79128

[0062] As used herein, the terms "halo," "halogen," or "halide" group by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0063] As used herein, the term "haloalkyl" includes monohaloalkyl groups, polyhaloalkyl groups in which all halo atoms may be the same or different, and perhaloalkyl groups in which all hydrogen atoms are replaced with halogen atoms such as fluoro. 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 Camelidae species by immunization with an antigen and subsequent isolation of serum, or by cloning and expression of nucleic acid sequences encoding the antibody. The term "heavy chain antibody" includes immunoglobulin molecules isolated from or derived from animals with heavy chain disease. H It further encompasses immunoglobulin molecules prepared by cloning and expression of (variable heavy chain immunoglobulin) genes.

[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, heteroaryl rings can have from five to about 8-12 ring members. Heteroaryl groups refer to various heterocyclyl groups with aromatic electronic structures. A heteroaryl group referred to as 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, etc. Similarly, a C4-heteroaryl can be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, etc. The sum of the number of carbon atoms and the number of heteroatoms equals the total number of ring atoms. 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, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted or substituted with groups described herein. Representative substituted heteroaryl groups may be substituted one or more times with groups such as those enumerated 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, benzyl, benzo ... hydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), 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-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), 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]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 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) nyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), 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-benzimidazolyl, 8-benzimidazolyl), 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]azepin-1-yl, 5H-dibenzo[b,f]azepin-2-yl, 5 H-dibenzo[b,f]azepin-3-yl, 5H-dibenzo[b,f]azepin-4-yl, 5H-dibenzo[b,f]azepin-5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepine (10,11-dihydro-5H-dibenzo[b,f]azepin-1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-4-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl), but are not limited to these.

[0067] The term "heteroarylalkyl," as used herein, means an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heteroaryl group, as defined herein.

[0068] As used herein, "C 6~10 The term "5-6-membered heterobiaryl" refers to a C-membered heteroaryl moiety covalently linked through a single bond to a 5- or 6-membered heteroaryl moiety. 6~10 C means an aryl moiety. 6~10 The aryl and 5- to 6-membered heteroaryl moieties can be any suitable aryl and heteroaryl groups described herein. 6~10 Non-limiting examples of 5- to 6-membered heterobiaryls include: TIFF2026010002000003.tif20128 is an example. 6~10 When a 5- to 6-membered heterobiaryl is listed as a substituent (e.g., as an "R" group), C 6~10 -5-6 membered heterobiaryl is C 6~10 It is attached to the rest of the molecule through a moiety.

[0069] As used herein, "5-6 membered-C 6~10 The term "heterobiaryl" refers to a 5- to 6-membered -C 6~10 When heterobiaryl is recited as a substituent (e.g., as an "R" group), it is a 5- to 6-membered -C 6~10 C except that the heterobiaryl is attached to the rest of the molecule through a 5- or 6-membered heteroaryl moiety. 6~10 -The same as 5- to 6-membered 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. Thus, heterocyclyl can be cycloheteroalkyl, heteroaryl, or any combination thereof, provided it is polycyclic. In some embodiments, heterocyclyl groups contain from three to about 20 ring members, while other similar groups have from three to about 15 ring members. A heterocyclyl group referred to as a C2-heterocyclyl can be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, etc. Similarly, a C4-heterocyclyl can be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, etc. The number of carbon atoms and heteroatoms equals the total number of ring atoms. A heterocyclyl ring may contain one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species, including species containing fused aromatic and non-aromatic groups. For example, dioxolanyl rings and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted or substituted as described herein.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, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be groups such as, but not limited to, mono- or more than twice substituted piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted with groups such as those enumerated herein.

[0071] As used herein, the term "heterocyclylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group, as defined herein, is replaced with a bond to a heterocyclyl group, as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0072] As used herein, the term "immunoglobulin" or "Ig" is 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. Five members of this protein class are IgA, IgG, IgM, IgD, and IgE. IgA is the primary antibody present 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 fixation, and other antibody responses and is important in defense against bacteria and viruses. IgD is an immunoglobulin with no known antibody function but can act as an antigen receptor. IgE is an immunoglobulin that mediates immediate hypersensitivity by triggering the release of mediators from mast cells and basophils upon exposure to allergens.

[0073] As used herein, the term "independently selected from" means that the groups referenced are the same, different, or a mixture thereof, unless the context clearly dictates otherwise. Thus, based on this definition, "X 1 , X 2 , and X 3 The phrase "independently selected from the noble gases" is intended to include, for example, X 1 , X 2 , and X 3 scenario where all are the same, X 1 , X 2 , and X 3 scenario where all are different, X 1 and X 2 is the same but X 3 This would include scenarios where the .times. ...

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

[0075] "Isolated" means changed or removed from its natural state. For example, a nucleic acid or polypeptide naturally present in a living animal is not "isolated," but the same nucleic acid or polypeptide partially or completely separated from the coexisting materials of its natural state is "isolated." An isolated nucleic acid or protein may exist in a substantially purified form or may exist in a non-native environment, such as a host cell.

[0076] As used herein, the term "modulate" means to mediate a detectable increase or decrease in the activity and / or level of an mRNA, polypeptide, or response in a subject compared to the activity and / or level of the mRNA, polypeptide, or response in a subject in the absence of treatment or compound, and / or compared to the activity and / or level of the mRNA, polypeptide, or response in an otherwise identical but untreated subject. This term encompasses activating, inhibiting, and / or otherwise affecting a natural signal or response to mediate a beneficial therapeutic response in a subject, preferably a human.

[0077] As used herein, the term "monovalent" means that the substituent is connected to the substituted molecule by a single bond. If the substituent is monovalent, e.g., F or Cl, then the substituent is attached to the atom it replaces by a single bond.

[0078] As used herein, the term "organic group" refers to 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, carboxylates, and carboxylic acid esters; sulfur-containing groups such as alkylsulfide groups and arylsulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R), CN, CF, OCF, R, C(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, R, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 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, where R can be hydrogen (in instances containing other carbon atoms) or a carbon-based moiety, which may be substituted or unsubstituted.

[0079] The terms "patient," "subject," or "individual" are used interchangeably herein and refer to any animal, or cells thereof, whether in vitro or in situ, amenable to the methods described herein. In non-limiting embodiments, the patient, subject, or individual is a human.

[0080] As used herein, the term "pharmaceutically acceptable" means a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesired biological effects or deleterious interactions with any of the components of the composition contained therein.

[0081] As used herein, the phrase "pharmaceutically acceptable salts" refers to salts of the administered compound prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, as well as solvates, hydrates, or clathrates thereof.

[0082] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids, examples of which include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids, examples of which 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, saccharinic 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, alkaline earth metal salts, and transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also 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 compound, for example, by reacting the compound with an appropriate acid or base.

[0084] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound described herein within or to a patient so that it can perform its intended function. Typically, these compounds are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a formulation containing a compound described herein and not harmful to the patient. Some examples of materials which 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; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; 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 buffers; and other non-toxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds described herein and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. "Pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of the compounds described herein.Other additional ingredients 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" refers to a polymer composed of amino acid residues, related natural structural variants, and synthetic, non-natural analogs thereof, linked through peptide bonds. Synthetic polypeptides can be synthesized, for example, using an automated polypeptide synthesizer. Generally, as used herein, the term "protein" refers to a large polypeptide. As used herein, the term "peptide" refers to a short polypeptide. Conventional notation is used herein to represent polypeptide sequences: the left-hand end of a polypeptide sequence is the amino-terminus, and the right-hand end of a polypeptide sequence is the carboxyl-terminus.

[0086] As used herein, the term "efficacy" refers to the half-maximal response (ED 50 ) means the dose required to produce

[0087] As used herein, the term "REAG" refers to 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 a compound of the present disclosure, or a fragment thereof, a derivative thereof, or an intermediate thereof.

[0088] As used herein, the term "room temperature" means a temperature of about 15°C to 28°C.

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

[0090] As used herein, the term "solvent" means a liquid that can dissolve a solid, liquid, or 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.

[0092] As used herein, the term "substantially" means "a majority of" or "mostly," similarly meaning 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 free" can mean completely free or having an insignificant amount, such that the amount of material present does not affect the material properties of the composition including the material, and such that the material is between about 0% and about 5%, or between about 0% and about 1%, or not more than about 5%, or less than about 4.5%, equal to, or greater than about 4.5%, or not more than 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 not more than about 0.001% by weight of the composition. The term "substantially free" can mean having an insignificant amount, such that a material is from about 0% to about 5%, or from about 0% to about 1%, or about 5% or less, or less than about 4.5%, equal to, or greater than about 4.5%, 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, or about 0% by weight of the composition.

[0093] The term "substituted" as used herein with respect to a molecule or organic group as defined herein means that one or more hydrogen atoms therein are replaced with one or more non-hydrogen atoms. As used herein, the term "functional group" or "substituent" refers to a group that can be substituted or is substituted on a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl groups, alkoxyl groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxylic acids, carboxylates, and carboxylic acid esters; sulfur atoms in thiol groups, alkylsulfide groups and arylsulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amines, hydroxylamine, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be attached to a substituted carbon atom (or other atom) include F, Cl, Br, I, OR, OC(O)N(R), CN, NO, NO, ONO, azido, CF, OCF, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, R, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R), N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R), N(R)SOR, N(R)SON(R), N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R), N(R)C(S)N(R), N(COR)COR, N(OR)R, C(=NH)N(R), C(O)N(OR)R, and C(=NOR)R, where R can be hydrogen or a carbon-based moiety, e.g., R can be hydrogen, (C1-C 100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups attached to a nitrogen atom or adjacent nitrogen atoms can be taken together with one or more of the nitrogen atoms to form a heterocyclyl.

[0094] As used herein, the term "synthetic antibody" refers to an antibody produced using recombinant DNA techniques, such as an antibody expressed by a bacteriophage as described herein. The term should also be taken to mean an antibody produced by synthesis of a DNA molecule encoding the antibody and expressing the antibody protein, or by synthesis of an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence is obtained using DNA and amino acid sequence synthesis techniques that are available and well known in the art.

[0095] A "therapeutic" treatment is a treatment administered to a subject who exhibits symptoms of a pathological condition with the intent of reducing or eliminating those symptoms.

[0096] The term "thioalkyl" as used herein means a sulfur atom connected to an alkyl group, as defined herein. The alkyl group in a thioalkyl can be straight-chained or branched. Examples of straight-chain thioalkyl groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiohexyl, and the like. Examples of branched alkoxy groups include, but are not limited to, isothiopropyl, sec-thiobutyl, tert-thiobutyl, isothiopentyl, isothiohexyl, and the like. The sulfur atom can occur at any suitable position within the alkyl chain, for example, at the terminal end of the alkyl chain or anywhere within the alkyl chain.

[0097] As used herein, the terms "treat," "treating," and "treatment" refer to 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" refers to a gene or gene product isolated from a natural source. A wild-type gene is a 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 term "modified" or "mutant" refers to a gene or gene product that exhibits modified sequence and / or functional properties (i.e., altered characteristics) compared to a wild-type gene or gene product. Note that naturally occurring mutants can be isolated. Naturally occurring mutants are identified by the fact that they exhibit altered characteristics (including altered nucleic acid sequences) compared to a wild-type gene or gene product.

[0099] The term "autoimmune disease" refers to a disease or illness that occurs when the body's tissues are attacked by its own immune system. Examples of autoimmune diseases include, for example, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis, among others.

[0100] A more complete list of autoimmune diseases treatable with the compounds and pharmaceutical compositions of the present disclosure includes 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, Sjogren'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 neutrophil leukemia, and urinary tract infections. thrombocytopenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adiposity, adult Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related 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, Parsonage-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, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barrow concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, patter Streptococcus aureus-associated pediatric neuropsychiatric disorder (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff-person syndrome, Sydenham's chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan's syndrome, Graves' ophthalmopathy, intermediate uveitis, lignified conjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Susac's syndrome, sympathetic ophthalmia, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behcet's disease,Particularly including eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatoid 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, and pyoderma gangrenosum.

[0101] Throughout this specification, the terms "cancer" or "neoplasia" are used to refer to a pathological process resulting in the formation and proliferation of cancerous or malignant neoplasms, i.e., abnormal tissues that grow by cellular proliferation, often more rapidly than normal tissues, and continue to grow even after the stimuli that initiated the new growth have ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissues; most infiltrate surrounding tissues, metastasize to several sites, likely recur after attempted removal, and likely cause patient death if not treated appropriately. As used herein, the term neoplasia is used to describe all cancerous disease states and encompasses or includes the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Neoplasia includes, but is not limited to, morphological irregularities in cells in the tissues of a subject or host, and a pathological proliferation of cells in the tissues of a subject relative to normal proliferation in the same type of tissue. Furthermore, neoplasia includes benign and malignant tumors, both invasive and non-invasive (e.g., colon tumors). Malignant neoplasms (cancers) are distinguished from benign neoplasms in that the former exhibit a greater degree of anaplasia, or loss of cellular differentiation and orientation, and are invasive and metastatic.Examples of neoplasms or neoplasias from which target cells of the present disclosure may be derived include cancers (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), particularly bladder, intestinal, breast, cervical, colon, esophageal, head, kidney, liver, lung, neck, ovarian, pancreatic, prostate, and gastric cancer; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, particularly Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, and synovial sarcoma; central nervous system tumors (e.g., glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma); Germline tumors (e.g., intestinal, breast, prostate, cervical, uterine, lung, ovarian, testicular, thyroid, astrocytoma, esophageal, pancreatic, gastric, liver, colon, and melanoma); mixed neoplasias, particularly carcinosarcoma and Hodgkin's disease; and mixed origin tumors, such as Wilms' tumor and teratocarcinoma (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 are treatable using the compounds of the present disclosure.

[0102] Representative common cancers that may be treated with the compounds of the present disclosure include, for example, prostate cancer, metastatic prostate cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic 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, renal cancer, and lymphoma, among others, which may be treated with one or more compounds of the present disclosure. Because of the activity of the compounds, the present disclosure is generally applicable to treating virtually any cancer in any tissue, and therefore the compounds, compositions, and methods of the disclosure are generally applicable to the treatment of cancer and to reducing the likelihood of cancer development and / or metastasis of existing cancers.

[0103] In certain aspects of the present disclosure, the cancer to be treated is metastatic cancer, recurrent cancer, or drug-resistant cancer, and particularly includes drug-resistant cancer.Apart from this, metastatic cancer can be found in virtually any tissue of cancer patients in the late stage of the disease, and typically metastatic cancer is found in virtually any tissue, including lymphatic system / lymph nodes (lymphoma), bone, lung, bladder tissue, kidney tissue, liver tissue, and brain (brain cancer / brain tumor).Therefore, the present disclosure is generally applicable to and can be used to treat any cancer in any tissue, regardless of etiology.

[0104] The term "anticancer agent" or "additional anticancer agent" refers to a compound other than the chimeric compounds of the present disclosure that can be used in combination with the compounds of the present disclosure to treat cancer. Exemplary anticancer agents that can be co-administered in combination with one or more chimeric compounds of the present disclosure include, for example, antimetabolites, topoisomerase I and II inhibitors, alkylating agents, and microtubule inhibitors (e.g., taxol), among others. Exemplary anti-cancer compounds for use in the present 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, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab (Arzerra), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, jamatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanton, LY 317615, neuradiab, vitespan, Rta744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estrogen Stradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-j-quinolone, vatalanib, 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 to 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, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; Amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (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, levofloxacin Mysole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine,Marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody), and erbitux, cremophor-free paclitaxel, epothilone B B), BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, 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, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte-colony stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony stimulating factor Stimulatory factors, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-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, dolasetron, tropisetron, PEG-1 receptor antagonists ... Filgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib may be mentioned in particular, and immunotherapeutic agents, for example IDO inhibitors (indoleamine 2,3-dioxygenase (IDO) pathway inhibitors) such as indoximod (NLG-8187), navoximod (GDC-0919), and NLG802, PDL1 inhibitors (programmed death-ligand 1 inhibitors) including, for example, nivolumab, durvalumab, and atezolizumab, PD1 inhibitors such as pembrolizumab (Merck), and CTLA-4 inhibitors (cytotoxic T-lymphocyte-associated protein 4 / cluster of differentiation 152 inhibitors) including ipilimumab and tremelimumab, among others.

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

[0106] The term "inflammatory disease" is used to describe diseases or conditions that involve acute, but often chronic, inflammation as a primary symptom of the disease or condition. Inflammatory diseases include neurodegenerative diseases (including, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease; other ataxias); immune response disorders that cause inflammation (e.g., dysregulation of T cell maturation, B cell homeostasis, and T cell homeostasis, combating damaging inflammation); chronic inflammatory diseases including, for example, inflammatory bowel disease, including Crohn's disease, rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, Sjogren's disease; hyperglycemic disorders; and lipid metabolism disorders. Diabetes mellitus (types I and II) affecting islet function and / or structure, pancreatic beta cell death, and associated conditions including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g., Mendenhall syndrome, Werner syndrome, leprechaunism, 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) Particularly included are hyperglycemic disorders, liver disease, kidney disease (apoptosis in plaque, glomerular disease), cardiovascular disease (particularly including infarction, ischemia, stroke, pressure overload and reperfusion complications), muscle degeneration and muscle atrophy, mild inflammation, gout, silicosis, atherosclerosis, and related conditions such as cardiac and neurological symptoms (both central and peripheral), including stroke, age-related dementia and sporadic Alzheimer's disease, and psychiatric conditions, including depression, stroke and spinal cord injury, and arteriosclerosis.In these diseases, elevated MIF levels are often observed, and therefore these disease states and / or conditions respond to treatment using the compounds and / or pharmaceutical compositions of the present disclosure.It should be noted that there is some overlap between certain autoimmune diseases and inflammatory diseases described herein.

[0107] Throughout this disclosure, various aspects of the present disclosure may be presented in the form of ranges. It should be understood that the description in range form is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Thus, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, a description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and the like, as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the width of the range.

[0108] compound The present disclosure provides compounds comprising Formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof. [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I)

[0109] In certain embodiments, the compound comprises Formula (Ia), or a salt, geometric isomer, stereoisomer, or solvate thereof. [Ab]-[CON] 0~1 -[Linker]-[CON] 0~1 -[CRBM] ' (Ia)

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

[0111] In (I) or (Ia), the CRBM is a cellular receptor binding moiety that binds to at least one receptor on the surface of hepatocytes or other degradative cells in a subject, whereby binding results in endocytosis and degradation of (I) and / or (Ia) and / or the biological target. In certain embodiments, the CRBM is an ASGPRBM, which is a cellular receptor binding moiety that binds to at least one asialoglycoprotein receptor on the surface of hepatocytes or other degradative cells in a subject.

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

[0113] In (I) or (Ia), the linker is a group having a valency ranging from 1 to 15. In certain embodiments, the linker has a valency of 1 to 10. In certain embodiments, the linker has a valency of 1 to 5. In certain embodiments, the linker has a valency of 1, 2, or 3. In certain embodiments, the linker covalently links to one or more CRBM and / or Ab groups, optionally through CON, where the linker may itself include one or more CON groups.

[0114] In certain embodiments, k' is an integer ranging from 1 to 15. In certain embodiments, k' is an integer ranging from 1 to 10. In certain embodiments, k' is an integer ranging from 1 to 5. In certain embodiments, k' is an integer ranging from 1 to 3. In certain embodiments, k' is 1, 2, or 3.

[0115] In certain embodiments, j is an integer ranging from 1 to 15. In certain embodiments, j is an integer ranging from 1 to 10. In certain embodiments, j is an integer ranging from 1 to 5. In certain embodiments, j is an integer ranging from 1 to 3. In certain embodiments, j is 1, 2, or 3.

[0116] In certain embodiments, h is an integer ranging from 0 to 15. In certain embodiments, h is an integer ranging from 1 to 15. In certain embodiments, h is an integer ranging from 1 to 10. In certain embodiments, h is an integer ranging from 1 to 5. In certain embodiments, h is an integer ranging from 1 to 3. In certain embodiments, h is 1, 2, or 3.

[0117] In certain embodiments, h' is an integer ranging from 0 to 15. In certain embodiments, h' is an integer ranging from 1 to 15. In certain embodiments, h' is an integer ranging from 1 to 10. In certain embodiments, h' is an integer ranging from 1 to 5. In certain embodiments, h' is an integer ranging from 1 to 3. In certain embodiments, h' is 1, 2, or 3.

[0118] In certain embodiments, i is an integer ranging from 0 to 15. In certain embodiments, i is an integer ranging from 1 to 15. In certain embodiments, i is an integer ranging from 1 to 10. In certain embodiments, i is an integer ranging from 1 to 5. In certain embodiments, i is an integer ranging from 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 one.

[0120] In certain embodiments, k', j', h, h', and i are each 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, the CRBM is folic acid or any fragment or derivative thereof capable of binding to a folate receptor. Folate receptors bind to folic acid and reduced folate derivatives and mediate the delivery of tetrahydrofolate to the inside of cells, which is then converted from monoglutamic acid to polyglutamic acid (e.g., 5-methyltetrahydrofolate) since only the monoglutamic acid form can be transported across the cell membrane. Human proteins from this family include folate receptor 1 (adult), folate receptor 2 (fetal), and folate receptor γ.

[0123] In certain embodiments, the folate CRBM is methotrexate or a biologically active fragment thereof: Includes TIFF2026010002000004.tif29128.

[0124] In certain embodiments, the folate CRBM is pemetrexed or a biologically active fragment thereof: Includes TIFF2026010002000005.tif27128.

[0125] In certain embodiments, folate CRBM may be incorporated into compounds of the present disclosure through one of its carboxylic acids. In other embodiments, folate CRBM may be incorporated into compounds of the present disclosure using N-hydroxysuccinamidyl (NHS)-activated folic acid (similar chemistry applies to methotrexate and pemetrexed). TIFF2026010002000006.tif76128

[0126] mannose receptor In certain embodiments, the CRBM is a group that binds to the mannose receptor. In certain embodiments, the CRBM comprises the following group: TIFF2026010002000007.tif19128

[0127] In certain embodiments, the mannose receptor CRBM may be conjugated to a compound of the disclosure (such as, but not limited to, REAG) using one of the following reagents (which may be protected with an appropriate protecting group): TIFF2026010002000008.tif18128In the formula, X is S or O, and R is TIFF2026010002000009.tif19149, and 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. The molecule can include one or more independently selected mannose receptor CRBMs as part of the polymer chain. In certain embodiments, the CRBM can be incorporated into the polymer molecule using the CRBM reagents described elsewhere herein.

[0129] Mannose-6-phosphate (M6P) receptor In certain embodiments, the CRBM is a group that binds to the mannose-6-phosphate (M6P) receptor. In certain embodiments, the CRBM comprises the following group: TIFF2026010002000010.tif18128In the formula, X is O or S, and R 1 is selected from the group consisting of: TIFF2026010002000011.tif52128

[0130] In certain embodiments, a CRBM may be attached to a compound of the disclosure (such as, but not limited to, REAG) using one of the following reagents (which may be protected with an appropriate protecting group): TIFF2026010002000012.tif18128 where X and R 1 is as defined elsewhere herein, and R 2 teeth, TIFF2026010002000013.tif41150, and 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. The molecule can include one or more independently selected M6P receptor CRBMs as part of the polymer chain. In certain embodiments, the CRBM can be incorporated into the polymer molecule using the CRBM reagents described elsewhere herein. Figures 1-8 show exemplary mannose receptor binders and their preparation.

[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): TIFF2026010002000014.tif116128

[0133] In certain embodiments, the M6P receptor CRBM is one of the following (US2011 / 0110960 to Platenburg): TIFF2026010002000015.tif98156

[0134] Low-density lipoprotein receptor-related protein 1 (LRP1) receptor In certain embodiments, the CRBM is an LRP1 (low density lipoprotein receptor-related protein 1; also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER), or cluster of differentiation 91 (CD91)) binding group comprising one of the following amino acid sequences: TIFF2026010002000016.tif128158

[0135] Low-density lipoprotein receptor (LDLR) In certain embodiments, the CRBM is an LDLR (low density lipoprotein receptor) binding group comprising one of the following amino acid sequences: TIFF2026010002000017.tif41150TIFF2026010002000018.tif246154TIFF2026010002000019.tif85152

[0136] FcγRI receptor In certain embodiments, the CRBM is an FcγRI binding group comprising one of the following amino acid sequences: TIFF2026010002000020.tif245154

[0137] Transferrin receptor In certain embodiments, the CRBM is a transferrin receptor binding group comprising one of the following amino acid sequences: TIFF2026010002000021.tif115154

[0138] Macrophage scavenger receptor In certain embodiments, the CRBM is a macrophage scavenger receptor binding portion comprising one of the following amino acid sequences: TIFF2026010002000022.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 moiety. In certain embodiments, the binding moiety binds to the GPCR and induces internalization of the receptor. 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 moiety is TIFF2026010002000023.tif37128, wherein each R is independently H or C1-C6 alkyl. In certain embodiments, a CRBM may be attached to a compound of the disclosure (such as, but not limited to, REAG) using one of the following reagents (optionally protected with an appropriate protecting group): TIFF2026010002000024.tif37128In the formula, at least one R is REAG, and the remaining R are independently H or C1-C6 alkyl.

[0141] Asialoglycoprotein receptor (ASGPR) The present disclosure contemplates the use of ASGPR binding moieties (ASGPRBM).

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

[0143] In certain embodiments, the ASGPRBM group has the structure: TIFF2026010002000025.tif24128 included, where X is a linker 1 to 4 atoms in length, and If X is a linker one atom long, X is O, S, N(R N1 ), or C(R N1 )(R N1 ) and If X is a linker two atoms long, not more than one atom of X may be O, S, or N(R N1 ) and When X is a linker 3 or 4 atoms in length, no more than two atoms of X are independently O, S, or N(R N1 ) As such, O, S, N(R N1 ), or C(R N1 )(R N1 ) groups.

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

[0145] In certain embodiments, when X is two atoms in length, X in the ASGPRBM 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 )-.

[0146] In certain embodiments, when X is 3 atoms in length, X in the ASGPRBM 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(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 four atoms in length, X in the ASGPRBM 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 )-.

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

[0149] In certain embodiments, X is CHO and R N1is H.

[0150] In certain embodiments, the ASGPRBM has the following structure: Includes TIFF2026010002000026.tif19128.

[0151] In certain embodiments, the ASGPRBM has the following structure: Includes TIFF2026010002000027.tif21128.

[0152] In certain embodiments, R 1 is the group shown in Figure 9. In certain embodiments, R 3 is the group shown in Figure 9. In certain embodiments, R 1 and R 3 are each independently a group shown in FIG.

[0153] In certain embodiments, R 1 and R 3 are each independently H, -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 independently selected halogens, —(CH2) K (vinyl), -O(CH2) K (vinyl), -(CH2) K (alkynyl), -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -C(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens.

[0154] In certain embodiments, R 1 and R 3 are each independently Ph(CH2) K-, which is optionally substituted with 1 to 3 independently selected halogens; C1 to C4 alkyl optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups; or C1 to C4 alkoxy optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups.

[0155] In certain embodiments, R 1 and R 3 are each independently represented by the following structure: -O-(CH2) K' -CH(OH)-(CH2)K'-R 7 where R 7 is a C1-C4 alkoxy optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxy 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 embodiments, R N3 Each occurrence of is independently H or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0159] In certain embodiments, R N4 each occurrence independently represents H, C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, or Ph-(CH2)K -It is.

[0160] In certain embodiments, R 1 and R 3 are each independently selected from the group consisting of: TIFF2026010002000028.tif27128wherein CYC represents a group consisting of: Selected from TIFF2026010002000029.tif112156, wherein: The bond shown in TIFF2026010002000030.tif1128 is -(CH2) K indicates the site on CYC to which it is connected.

[0161] In certain embodiments, L 1 is a bond, -linker, -CON-linker, or -CON-linker-CON.

[0162] In certain embodiments, R C is absent, H, C1-C4 alkyl optionally substituted with 1 to 3 optionally substituted halogens and / or 1 to 2 hydroxyl groups, or a group having the following structure: TIFF2026010002000031.tif23128, wherein R 4 , R 5 , and R 6 are independently H, F, Cl, Br, I, CN, or NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1 to 3 independently selected halogens, C1-C3 alkoxy optionally substituted with 1 to 3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens KC(=O)O-(C1-C4 alkyl), -OC(=O)-(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -C(=O)-(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens.

[0163] In certain embodiments, R N2 Each occurrence of is independently H or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0164] In certain embodiments, R C teeth The file is TIFF2026010002000032.tif25155.

[0165] In certain embodiments, R 1 and R 3 are each independently (C3-C8 saturated carbocyclic ring)-(CH2) K -, where the carbocycle is -L 1 and -R C is further substituted with

[0166] In certain embodiments, R N Each occurrence of is independently H or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0167] In certain embodiments, R 2 is the group shown in FIG.

[0168] In certain embodiments, R 2 Ha-(CH2) K -N(R N1 )-C(=O)R AM is.

[0169] In certain embodiments, R AMis H, C1-C4 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, -C(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -(CH2) K -NR N3 R N4 is.

[0170] In certain embodiments, R 2 teeth TIFF2026010002000033.tif16128, wherein: R TA H, CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 independently selected halogens, —(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens; or R TA is C3~C 10 an aryl group or a 3- to 10-membered heteroaryl group containing 1 to 5 non-carbon ring atoms, wherein the aryl group or heteroaryl group is CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogensK O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(C1-C3-alkoxy) optionally substituted with 1-3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O-(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -(CH2) optionally substituted with 1 to 3 independently selected halogens. K C(=O)-(C1-C4 alkyl), or R TA teeth TIFF2026010002000034.tif48128, which is optionally substituted with 1 to 3 C1-C3 alkyl groups, each optionally substituted with 1 to 3 independently selected halogens; or R TA teeth TIFF2026010002000035.tif29128, wherein each -(CH2) K The group is optionally substituted with 1 to 4 C1 to C3 alkyl groups which may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups.

[0171] In certain embodiments, the ASGPRBM group has the structure: TIFF2026010002000036.tif51162, During the ceremony, R A is C1-C3 alkyl optionally substituted with 1 to 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 absent, -(CH2) IM -, -C(=O)-(CH2) IM - or -C(=O)(CH2) IM -NR M - and; R M is H or C1-C3 alkyl optionally substituted with 1-2 hydroxyl groups; Each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6.

[0172] In certain embodiments, R A is methyl or ethyl, either of which may be substituted with 1 to 3 fluorines.

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

[0174] In certain embodiments, the ASGPRBM group comprises one of the following (Mamidyala, et al., 2012, J. Am. Chem. Soc. 134:1978-1981): TIFF2026010002000037.tif104163TIFF2026010002000038.tif217152TIFF2026010002000039.tif219160

[0175] In certain embodiments, the ASGPRBM group comprises one of the following (Sanhueza, et al., 2017, J. Am. Chem. Soc. 139:3528-3536): TIFF2026010002000040.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 structure: -CH2CH2(OCH2CH2) m OCH2-, -(CH2) m CH2-, -[N(R a )-CH(R b )(C=O)] m - or a polypropylene glycol group or a polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units, Each R a are independently H, C1-C3 alkyl, or C1-C6 alkanol, or R b together to form a pyrrolidine group or a hydroxypyrroline group; Each R b is 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 ranging from 1 to 15.

[0178] In certain embodiments, the linker has the structure —[N(R ' -(CH2) 1~15 —C(═O)]—, where R′ is H or C1-C3 alkyl optionally substituted with 1-2 hydroxyl groups, and m is an integer ranging from 1-100.

[0179] In certain embodiments, the linker has the structure: -ZD-Z'- Including, During the ceremony, Z and Z' each independently represent a bond; TIFF2026010002000041.tif25163; each R is independently H, C1-C3 alkyl, or C1-C6 alkanol; Each R 2 are independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N(R); In certain embodiments, each i is independently 0 to 100; in certain embodiments, 0 to 75; in certain embodiments, 1 to 60; in certain embodiments, 1 to 55; in certain embodiments, 1 to 50; in certain embodiments, 1 to 45; in certain embodiments, 1 to 40; in certain embodiments, 2 to 35; in certain embodiments, 3 to 30; in certain embodiments, 1 to 15; in certain embodiments, 1 to 10; in certain embodiments, 1 to 8; in certain embodiments, 1 to 6; in certain embodiments, 0, 1, 2, 3, 4, or 5; D is a bond, -(CH2) i -YC(=O)-Y-(CH2) i -, -(CH2) m' - or -[(CH2) n -X1)] j with the proviso that Z, Z', and D are not each simultaneously a bond; X 1 is O, S, or N(R); j is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; in certain embodiments, from 1, 2, 3, 4, or 5; m' is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; in certain embodiments, from 1, 2, 3, 4, or 5; n is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; and in certain embodiments, from 1, 2, 3, 4, or 5.

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

[0181] In certain embodiments, the linker has the structure: -PEG-CON-PEG- Including, wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON is a triazole group. The file is TIFF2026010002000042.tif14128.

[0182] In certain embodiments, CON has the structure: TIFF2026010002000043.tif85135 included, wherein R′ and R″ are each 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)- Including, In the formula, each R 1 is independently H or C1-C3 alkyl, and n'' is independently an integer from 0 to 8, and in certain embodiments 1 to 7, and in certain embodiments 1, 2, 3, 4, 5, or 6.

[0184] In certain embodiments, CON has the structure: TIFF2026010002000044.tif14128 included, During the ceremony, R 1a , R 2a , and R 3a are each independently H, -(CH2) 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 - but R 1a , R 2a , and R 3a and H are not simultaneously; 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 0 or 1; Each R 4 are independently H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), provided that the same R 1a , R 2a , and R 3a M2 and M3 in cannot all be 0 at the same time.

[0185] In certain embodiments, CON has the structure: Includes TIFF2026010002000045.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 contemplated within the scope of the present disclosure include 1-40-beta-amyloid, 5'-nucleotidase, activated F9, F10, activin receptor-like kinase 1, alpha-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-1), Bacillus anthracis anthrax, BAFF, beta-amyloid, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide alpha, Canis lupus familiaris) IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, clumping factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, Escherichia coli (E.coli Shiga toxin type 1, E. coli Shiga toxin type 2, EGFL7, endotoxin, episialin, FGF 23, fibrin II, beta chain, fibronectin extra domain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human beta-amyloid, human scatter factor receptor kinase, human TNF, IFN-α, IFN-γ, IgE, IgE Fc region, IGF1, IGF2, IGF-E, IL-17A, IL-17A and IL-17F, IL-17A, IL-17B, IL-17C, IL-17D, IL-17F ... 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 gamma, interferon Ron gamma-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), neuroapoptosis-regulating proteinase 1, NGF, NOGO-A, Notch 1, NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, tectal plate-specific spondin 3, RTN4, sclerostin, SDC1, serum amyloid A protein, serum amyloid P component, SOST, Staphylococcus aureus alpha-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 the present disclosure include abagovomab, abrezekimab, adalimumab, aducanumab, afasevikumab, afelimomab, alirocumab, altumomab, altumomab pentetate, and the like. pentetate), Andecaliximab, Anrukinzumab, Arcitumomab, Ascrinvacumab, Atezolizumab, Atidortoxumab, Atinumab, Avelumab, Bapineuzumab, Bavituximab, Belimumab, Bermekimab, Besilesomab, Bevacizumab, Biciromab, Bimetazolamide, Bimekizumab, Birtamimab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumab, Cantuzumab ravtansine, Caplacizumab, Carlumab, Cergutuzumab, Cergutuzumab amunaleukin, Certolizumab, Certolizumab pegol, Cibisatamab, Clazakizumab, Crivatuzumab, Crivatuzumab tetraxetanTetraxetan, Concizumab, Crenezumab, Dectrekumab, Denosumab, Dezamizumab, Diridavumab, Domagrozumab, Dorlimomab, Dorlimomab-alitonox Aritox, Durvalumab, Dusigitumab, Eculizumab, Edobacomab, Efungumab, Eldelumab, Elezanumab, Elsilimomab, Emactuzumab, Emapalumab, Emicizumab, Enokizumab, Epitumomab, Epitumomab-sitaxetan Cituxetan, Eptinezumab, Erenumab, Evinacumab, Evolocumab, Faricimab, Fasinumab, Fezakinumab, Ficlatuzumab, Filivumab, Fletikumab, Fontolizumab, Fremanezumab, Fresolimumab, Frovocimab, Furnevetomab Frunevetmab, Fulranumab, Galcanezumab, Gantenerumab, Gatipotuzumab, Gedivumab, Gevokizumab, Gimsilumab, Girentuximab, Golimumab, Gosuranemab, Guselkumab, Idarucizumab, Igovomab, Imalumab, Indatuximab ...Ravtansine, Infliximab, Istiratumab, Ixekizumab, Labetuzumab, Lacnotuzumab, Lampalizumab, Lanadelumab, Landogrozumab, Lebrikizumab, Remalesomab, Lendalizumab, Lenzilumab, Lerdelimumab Lerdelimumab, Lesofavumab, Ligelizumab, Lodelcizumab, Lokivetmab, Lutikizumab, Marstacimab, Mepolizumab, Metelimumab, Mirikizumab, Nacolomab, Nacolomab butafenatox Tafenatox, Namilumab, Narnatumab, Navivumab, Naxitamab, Nebacumab, Nemolizumab, NEOD, Nerelimomab, Nesvacumab, Netakimab, Nofetumomab, Nofetumomab Merpentanemerpentan, obiltoxaximab, oleclumab, olendalizumab, olokizumab, omalizumab, OMS, onartuzumab, oregovomab, orticumab, otilimab, ozanezumab, ozoralizumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, pentumomab, perakizumab, pexelizumab, Placulumab, Ponezumab, Prasinezumab, Pritoxaximab, Quilizumab, Radretumab, Ralpancizumab, Ranevetmab, Ranibizumab, Ravulizumab b), Raxibacumab, 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 vedotinvedotin, solanezumab, sontuzumab, stamulumab, sulesomab, sutimlimab, suvratoxumab, tabalumab, tacatuzumab, tacatuzumab tetraxetan, talizumab, tanezumab, tefibazumab, telimomab, telimomab alitoxin These include aritox, tesidolumab, tezepelumab, tiburizumab, tildrakizumab, timolumab, tisotumab, tisotumab vedotin, tralokinumab, trevogrumab, urtoxazumab, ustekinumab, vanucizumab, vapaliximab, varisacumab, vepalimomab, besencumab, vobarilizumab, bunakizumab, and xentuzumab.

[0189] The antibody of interest can be incorporated into the compound of the present disclosure using any method known in the art and / or any technique described or exemplified herein. For example, the antibody can be attached to the linker through a carboxylic acid group on the surface of the antibody, for example, using amide- or ester-forming chemical reactions. For example, the antibody can be attached to the linker through an amine group on the surface of the antibody, for example, using amide-forming chemical reactions. For example, the antibody can be attached to the linker through a thiol group on the surface of the antibody, for example, using nucleophilic substitution chemical reactions. In this case, the surface cysteine ​​residue can be present in the wild-type form of the Ab and / or can be introduced by mutation, for example, using site-directed mutagenesis. Linkers useful within the scope of the present disclosure can be any linkers known in the art, as long as the presence of the linker does not significantly interfere with the Ab's ability to bind to circulating proteins.

[0190] In a non-limiting example, an antibody useful within the scope of the present disclosure can bind to a circulating protein. As will be understood by those skilled in the art, any antibody that can recognize and specifically bind to a circulating protein is useful in the present disclosure. The present disclosure should not be construed as being limited to any one known or previously unknown antibody, provided that the antibody can specifically bind to a circulating protein and 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 antibody production can be achieved by inoculating a desired animal with an antigen and isolating antibodies that specifically bind to the antigen from the animal. Monoclonal antibodies directed against full-length or peptide fragments of proteins or peptides can be prepared using any well-known monoclonal antibody preparation procedure, such as those described in Harlow et al. (1989, Antibodies, A Laboratory Manual, Cold Spring Harbor, New York) and Tuszynski et al. (1988, Blood 72:109-115). Chemical synthesis techniques can be used to synthesize large quantities of the desired peptide. Alternatively, DNA encoding the desired peptide can be cloned and expressed from an appropriate promoter sequence in cells suitable for producing large quantities of the peptide. Monoclonal antibodies directed against the peptide can be generated from mice immunized with the peptide using standard procedures referred to herein. However, the present disclosure should not be construed as being limited solely to methods and compositions comprising these antibodies, but rather as including other antibodies, as that term is defined elsewhere herein.

[0192] In some cases, it is desirable to prepare monoclonal antibodies from various mammalian hosts, such as rodents (e.g., mice), primates (e.g., humans), etc. The 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; and U.S. Patent Nos. 5,693,762; 5,693,761; 5,585,089; and 6,180,370.

[0193] Nucleic acids encoding the antibodies obtained using the procedures described herein can be cloned and sequenced using techniques available in the art and described, for example, in Wright et al. (Critical Rev. Immunol. 1992, 12:125-168) and the references cited therein. Furthermore, antibodies useful within the present disclosure can be "humanized" using the techniques described in Wright et al. (supra) and the references cited therein, and 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, e.g., hybridomas, that express the desired protein, e.g., the desired antibody, to be expressed on the surface of phage. Reverse transcriptase is used to generate cDNA copies of the mRNA. cDNAs specifying immunoglobulin fragments are obtained by PCR, and the resulting DNA is cloned into a suitable bacteriophage vector to create a bacteriophage DNA library containing DNA specifying immunoglobulin genes. Procedures for generating 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] Bacteriophage encoding a desired antibody can be engineered so that the protein is displayed on the surface of the bacteriophage, making it available for binding to its corresponding binding protein, e.g., the antigen against which the antibody is directed. Thus, when bacteriophage expressing a specific antibody are incubated in the presence of cells expressing the corresponding antigen, the bacteriophage will bind to the cells. Bacteriophage that do not express the antibody will not bind to the cells. This panning technique is well known in the art and is described, for example, in Wright et al. (Critical Rev. Immunol. 1992, 12:125-168).

[0196] Processes such as the one described herein have been developed for the production of human antibodies using M13 bacteriophage display (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, and thus the cDNA encodes, rearranged immunoglobulin genes. The amplified cDNA is cloned into an M13 expression vector, creating a library of phage that express human Fab fragments on their surface. Phage displaying the antibody of interest are selected by antigen binding and propagated in bacteria to produce soluble human Fab immunoglobulins. Thus, in contrast to traditional monoclonal antibody synthesis, this procedure immortalizes the DNA encoding the human immunoglobulin rather than the cells expressing the human immunoglobulin.

[0197] The procedure described above describes the generation of phage encoding the Fab portion of an antibody molecule. However, this disclosure should not be construed as being limited solely to the generation of phage encoding Fab antibodies. Rather, phage encoding single-chain antibodies (scFv / phage antibody libraries) are also included in this disclosure. Fab molecules contain the entire Ig light chain; i.e., Fab molecules contain both the variable and constant regions of the light chain, but only the variable region and first constant region domain (CH1) of the heavy chain. Single-chain antibody molecules contain a single chain of protein, including an Ig Fv fragment. An Ig Fv fragment contains only the variable regions of the heavy and light chains of an antibody, without the constant region. Phage libraries containing scFv DNA can be generated according to the procedure described by Marks et al. (1991, J Mol Biol 222:581-597). Panning of the phage thus generated to isolate the desired antibodies is performed in a manner similar to that described for phage libraries containing Fab DNA.

[0198] The present disclosure should also be construed to include synthetic phage display libraries capable of synthesizing heavy and light chain variable regions encompassing nearly every possible specificity (Barbas, 1995, Nature Medicine 1:837-839; de Kruif et al., 1995, J Mol Biol 248:97-105).

[0199] The present disclosure encompasses polyclonal antibodies, monoclonal antibodies, synthetic antibodies, etc. One of skill in the art will understand, based on the disclosure set forth herein, that an important characteristic of an antibody useful within the scope of the present disclosure is that the antibody specifically binds to a circulating protein.

[0200] The compounds described herein may possess one or more stereocenters, and each stereocenter may independently exist in the (R) or (S) configuration. In certain embodiments, the compounds described herein exist as optically active or racemic forms. It should be understood that the compounds described herein encompass racemates, optically active forms, regioisomers, and stereoisomers, or combinations thereof, that possess the therapeutically useful properties described herein. Preparation of optically active forms is accomplished in any suitable manner, including, but not limited to, resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases. In certain embodiments, mixtures of one or more isomers are utilized as therapeutic compounds 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 enantiomeric and / or diastereomeric mixtures. Resolution 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 include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any of the compounds described herein, as well as metabolites and active metabolites of these compounds that exhibit similar activity. Solvates include solvates with water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether), or alcohols (e.g., ethanol), as well as acetate esters. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein exist in unsolvated forms.

[0202] In certain embodiments, the compounds described herein can exist as tautomers, and all tautomers are included within the scope of the compounds presented herein.

[0203] In certain embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, the prodrug is chemically converted into the biologically, pharmaceutically, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized into the biologically, pharmaceutically, or therapeutically active form of the compound through one or more steps or processes.

[0204] In certain embodiments, sites on the aromatic ring portion of the compounds described herein, for example, are susceptible to various metabolic reactions. By incorporating appropriate substituents on the aromatic ring structure, this metabolic pathway can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions include, by way of example only, deuterium, halogen, or alkyl groups.

[0205] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or atomic mass number different from that usually found in nature. Examples of isotopes suitable for inclusion 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 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 dosage requirements). In still other embodiments, 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, is useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process that employs an appropriate isotopically labeled reagent in place of an otherwise used non-labeled reagent.

[0206] In certain aspects, the compounds described herein are labeled by 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 with different substituents, can be synthesized using the techniques and materials described herein and in other publications such as 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); March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); 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), the disclosures of which are all incorporated by reference. The general methods for the preparation of the compounds described herein are modified by the use of appropriate reagents and conditions to introduce the various moieties found in the formulas set forth 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 carboxy groups are protected to prevent their undesired participation in reactions. Protecting groups are used to block some or all reactive moieties, preventing the group from participating in chemical reactions until the protecting group is removed. In other embodiments, each protecting group is removable by a different means. The need for differential removal is met by protecting groups that are cleaved under completely different reaction conditions.

[0210] In certain embodiments, protecting groups are removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are acid labile and are used to protect carboxy- and hydroxy-reactive moieties in the presence of amino groups protected with the hydrogenolysis-removable Cbz group and the base-labile Fmoc group. Carboxylic acid- and hydroxy-reactive moieties are blocked with base-labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid-labile groups such as t-butyl carbamate, or with carbamates that are both acid- and base-stable but removable by hydrolysis.

[0211] In certain embodiments, carboxylic acid- and hydroxy-reactive moieties are blocked with hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of hydrogen bonding with acids are blocked with base-labile groups such as Fmoc. Carboxylic acid-reactive moieties are protected by conversion to simple ester compounds exemplified herein, including conversion to alkyl esters, or are blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while concurrent amino groups are blocked with fluoride-labile silyl carbamates.

[0212] Allyl blocking groups are useful in the presence of acid- and base-protecting groups because the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, allyl-blocking carboxylic acids are deprotected by palladium catalysis in the presence of acid-labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, the functional group is blocked and cannot react. Upon release from the resin, the functional group becomes available for reaction.

[0213] Typically, the blocking / protecting group may be selected from: TIFF2026010002000046.tif79136

[0214] Other protecting groups, along with detailed descriptions of techniques applicable to the creation and removal of 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, the disclosures of which are incorporated herein by reference.

[0215] composition Compositions comprising the compounds described herein include pharmaceutical compositions comprising at least one compound described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, the compositions are formulated for oral or parenteral administration, such as transdermal, transmucosal (e.g., sublingual, intralingual, buccal (buccal), urethral (urethral), intravaginal (e.g., vaginal and perivaginal), nasal (intranasal), and rectal (rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0216] Treatment method The compounds of the present disclosure can be used to treat certain diseases and / or disorders, such as, but not limited to, autoimmune diseases, cancer, inflammation, or any other disease and / or disorder described herein.

[0217] Non-limiting examples of diseases and / or disorders include acute sciatica, advanced solid tumors, allergic asthma, allergic reactions, ALS and multiple sclerosis, Alzheimer's disease, amyloidosis, anaplastic large cell lymphoma, angioedema, angiogenesis, neovascularization, ocular vascular disease, ankylosing spondylitis, psoriasis, anthrax (prevention and treatment), arthritis, asthma, asthma and leukocyte disorders, asthma, atopic dermatitis, atypical hemolytic uremic syndrome, autoimmune diseases, autoimmune disorders, B cell cancers, B cell malignancies, anthrax, bleeding, bleeding due to hemophilia, cancer, cancer (diagnosis), and the like. , 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, Escherichia coli-induced diarrhea, Duchenne muscular dystrophy, dyslipidemia, eczema, fibrosis, gastric or gastroesophageal junction adenocarcinoma, gastrointestinal cancer, geographic atrophy secondary to age-related macular degeneration, hemophilia A, hemophagocytic lymphohistiocytosis, High-risk neuroblastoma and refractory bone marrow disease, Hodgkin's lymphoma, hypercholesterolemia, idiopathic pulmonary fibrosis, focal segmental glomerulosclerosis, cancer, immune-mediated inflammatory disorders, infectious diseases / influenza A, inflammation, inflammation of the airways, skin, and gastrointestinal tract, inflammatory autoimmune diseases, inflammatory lesions and metastasis (detection), influenza A, invasive Candida infection, macular degeneration (wet type), metastatic cancer, retinopathy of prematurity, metastatic pancreatic cancer, migraine, migraine and cluster headache, multiple sclerosis, psoriasis, psoriatic arthritis, orthopedic disuse and sarcopenic muscle wasting muscle wasting disorders, muscular dystrophy, hospital-acquired pneumonia, oncological / immunological indications, osteoarthritis in dogs, osteoarthritis, rheumatoid arthritis, osteomyelitis, osteoporosis, bone metastases, etc., ovarian cancer, 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, reduction of scarring after glaucoma surgery, reduction of side effects of cardiac surgery,Recurrent or refractory cervical cancer, reversal of the anticoagulant effect of dabigatran, rheumatoid arthritis, ankylosing spondylitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, Crohn's disease, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, hemolytic disease of the newborn, psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, sepsis, sepsis caused by gram-negative bacteria, severe asthma and chronic spontaneous urticaria, SLE, dermatomyositis , 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, systemic lupus erythematosus, lupus nephritis, acute graft-versus-host disease, systemic sclerosis, thromboembolism, thrombotic thrombocytopenic purpura, thrombosis, triple-negative breast cancer, uveitis, rheumatoid arthritis, psoriasis, viral infections, wet age-related macular degeneration, X-linked hypophosphatemia,

[0218] The method described herein comprises administering to the subject a therapeutically effective amount of at least one compound described herein, which can 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 comprises administering to the subject an additional therapeutic agent for treating disease or disorder.

[0219] In certain embodiments, administration of a compound described herein to a subject allows for the administration of a lower dose of an additional therapeutic agent compared to the dose of the additional therapeutic agent alone required to achieve a similar result in treating a disease or disorder in the subject. For example, in certain embodiments, the compound described herein enhances the activity of the additional therapeutic compound, thereby reducing the dose of the additional therapeutic compound to achieve the same effect.

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

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

[0222] Combination therapy The compounds useful within the methods described herein can 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 ameliorate the symptoms of the disease or disorder and / or the side effects of the therapeutic agents used in treating the disease or disorder. These additional therapeutic agents can include compounds that are commercially available or available to those skilled in the art through 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 with one or more additional therapeutic agents or compounds. Synergistic effects can include, for example, sigmoid-E max The drug combination effect can be calculated using suitable methods, such as the concentration-effect curve (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6: 429-453), the Loewe additivity 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 above-mentioned equations to experimental data, a corresponding graph can be generated that is useful for evaluating the effect of drug combinations. The corresponding graphs associated with the above-mentioned equations are the concentration-effect curve, the isobologram curve, and the combination index curve, respectively.

[0224] Administration / Dosage / Formulation The dosing regimen can affect what constitutes an effective amount. The therapeutic formulation can be administered before or after the onset of a disease or disorder in the subject. Furthermore, several divided and staggered doses can be administered daily or sequentially, or the dose can be administered by continuous infusion or bolus injection. Furthermore, the dosage of the therapeutic formulation can be proportionally increased or decreased as required by the therapeutic or prophylactic situation.

[0225] The compositions described herein can be administered to a patient, preferably a mammal, more preferably a human, at a dosage and for a duration effective to treat the patient's disease or disorder using known procedures. The effective amount of the therapeutic compound required to achieve a therapeutic effect can vary according to factors such as the current state of the patient's disease or disorder; the patient's age, sex, and weight; and the ability of the therapeutic compound to treat the patient's disease or disorder. The administration regimen can be adjusted to achieve an optimal therapeutic response. For example, several divided doses can be administered daily, or the dose can be proportionally reduced as required by the therapeutic situation. A non-limiting example of an effective dose range for the therapeutic compounds described herein is approximately 1 to 5,000 mg / kg body weight / day. Those skilled in the art will be able to make the determination regarding the effective amount of the therapeutic compound without undue experimentation, considering the relevant factors.

[0226] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response, desired composition, and desired mode of administration for a particular patient, without being toxic to the patient.

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

[0228] A medical practitioner, e.g., a physician or veterinarian, having ordinary skill in the art can readily determine and prescribe the effective amount of the required pharmaceutical composition. For example, the physician or veterinarian can start dosages of the compounds described herein used in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0229] In certain embodiments, it is particularly advantageous to formulate the compound into unit dosage form for ease of administration and uniformity of dosage.As used herein, unit dosage form refers to a physically discrete unit suitable as a unit dosage form for the patient to be treated, each unit containing a predetermined amount of therapeutic compound calculated to produce a desired therapeutic effect, in combination with the required pharmaceutical vehicle.The unit dosage form of the compound described herein is determined by and directly depends 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 a compound described herein and a pharmaceutically acceptable carrier.

[0231] The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerin, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0232] In certain embodiments, the compositions described herein are administered to a patient at a dosing frequency ranging from 1 to 5 or more times per day. In other embodiments, the compositions described herein are administered to a patient at a dosing frequency ranging from, but not limited to, once daily, once every two days, once every three days to once a week, and once every two weeks. Those skilled in the art will appreciate that the dosing 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, gender, general health, and other factors. Therefore, administration of the compounds and compositions described herein should not be construed as limited to any particular dosing regimen; the exact dosing frequency and composition administered to any patient will be determined by the attending physician, taking into account all other factors relevant to the patient.

[0233] The compounds described herein for administration may be administered in doses ranging from about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about 40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg to about 7,500 mg, about 200 μg to about 7,000 mg, about 350 μg to about 6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000 mg, about 1 mg to about 3,000 mg, or about 2 mg to about 4,000 mg. The dose may be within the range of about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all integer or decimal increments therebetween.

[0234] In some embodiments, the dosage of the compounds described herein is from about 1 mg to about 2,500 mg. In some embodiments, the dosage of the compounds described herein used in the compositions 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, and any and all integer or fractional increments thereof.

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

[0236] The preparations can be used in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances, suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable administration mode known in the art. The pharmaceutical preparations may be sterilized and, if desired, may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring substances, flavoring substances, and / or aromatic substances. If desired, they may be combined with other effective agents, such as other analgesics.

[0237] The administration route of any composition described herein includes oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical.The compound used in the composition described herein can be formulated for administration by any suitable route, for example, oral or parenteral administration, for example, transdermal, transmucosal (for example, sublingual, intralingual, buccal (transbuccal), urethral (transurethral), intravaginal (for example, vaginal and perivaginal), intranasal (intranasal), and rectal (transrectal)), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, 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, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, electuaries, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosol formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions described herein.

[0239] Oral administration For oral application, tablets, dragees, liquids, drops, suppositories, or capsules, caplets, and gel capsules are particularly suitable. 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 pharmaceutical excipients suitable for tablet manufacture. These excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as cornstarch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques to improve appearance or delay the release of the active ingredient. Oral preparations may be presented as hard gelatin capsules in which the active ingredient and inert diluents are mixed.

[0240] For oral administration, the compounds described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binders (e.g., polyvinylpyrrolidone, hydroxypropyl cellulose, or hydroxypropylmethylcellulose); fillers (e.g., corn starch, lactose, microcrystalline 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 can be coated using a suitable method and coating material, such as the OPADRY™ film coating system (e.g., OPADRY™ Type OY, Type OYC, organic enteric-coated Type OY-P, aqueous enteric-coated Type OY-A, Type OY-PM, and OPADRY™ White, 32K18400), available from Colorcon, West Point, Pennsylvania. Liquid formulations for oral administration can be in the form of solutions, syrups, or suspensions. Liquid formulations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or gum acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and 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, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles, which may contain other formulatory agents such as suspending agents, stabilizers, and / or dispersing agents, can be used.

[0242] Sterile injectable forms 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 dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile, fixed oils are typically used as solvents or suspending media. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Swiss Pharmacopoeia or similar alcohols.

[0243] Further dosage forms Additional 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. Additional dosage forms suitable for use with the compounds and compositions described herein also include those described in U.S. Patent Application Publication Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compounds and compositions described herein also include those described in PCT Application Nos. 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 can be, but are not limited to, short-term release formulations, rapid release formulations, and controlled release formulations, including sustained release formulations, delayed release formulations, and pulsed release formulations.

[0245] The term sustained release is used in its ordinary sense to refer to a drug formulation that gradually releases drug over an extended period of time and that can, but does not necessarily, produce substantially constant blood levels of drug over an extended period of time, which can be as long as one month or more and should be a longer release than the same amount of agent administered in bolus form.

[0246] For sustained release, the compound can be formulated with a suitable polymer or hydrophobic material that provides sustained release to the compound.Therefore, the compound used in the methods described herein can be administered in the form of microparticles, for example, by injection, or in the form of wafers or disks, by implantation.

[0247] In some cases, the dosage form used can be realized as the slow release or controlled release of one or more active ingredients in dosage form, for example, by using hydropropylmethylcellulose, other polymer matrices, gel, osmotic membrane, osmotic system, multi-layer coating, microparticles, liposomes or microspheres, or their combinations in various proportions to achieve desired release profile.Suitable controlled release formulations known to those skilled in the art, including those described herein, can be easily selected for use in the pharmaceutical compositions described herein.Therefore, the single unit dosage form suitable for oral administration, such as tablets, capsules, gel capsules and caplets, which are adapted for controlled release, are included in the compositions and dosage forms described herein.

[0248] Most controlled-release preparations have a common goal of improving drug therapy compared to the drug therapy achieved by the corresponding non-controlled preparation. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by the minimum amount of active pharmaceutical ingredient used to cure or control the condition in the minimum amount of time. The advantages of controlled-release preparations include prolonged drug activity, reduced dosing frequency, and increased patient compliance. Furthermore, controlled-release preparations can be used to affect the onset time of action or other characteristics such as the blood level of the drug, and therefore can affect the occurrence of side effects.

[0249] Most controlled-release formulations are designed to initially release an amount of drug that rapidly produces the desired therapeutic effect, and then gradually and continuously release other amounts of drug that maintain this level of therapeutic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace 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 component" is defined herein as a compound, including but not limited to, a polymer, a polymer matrix, a gel, an osmotic membrane, a liposome or a microsphere, or a combination thereof, that facilitates the controlled release of the active ingredient.In one embodiment, the compound described herein is administered to a patient alone or in combination with another drug using a sustained release formulation.In one embodiment, the compound described herein is 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 ordinary sense to refer to a drug formulation that provides for initial release of drug after some delay following drug administration, which may include, but is not necessarily, from about 10 minutes to about 12 hours.

[0252] The term pulsatile release is used herein in its ordinary sense to refer to a drug formulation that provides release of drug in a manner that produces a pulsatile plasma profile of the drug following drug administration.

[0253] The term immediate release is used in its ordinary sense to refer to a drug formulation that provides for release of drug immediately after drug administration.

[0254] As used herein, short term means any period of time up to 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, and any and all integer or fractional increments thereof.

[0255] As used herein, rapidly means any period of time up to 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 after drug administration, and any and all integer or fractional increments thereof.

[0256] Administration The therapeutically effective amount or dose of the compounds described herein depends on the age, sex, and weight of the patient, 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 dosage depending on these and other factors.

[0257] Suitable doses of the compounds described herein can range from about 0.01 mg to about 5,000 mg per day, e.g., from about 0.1 mg to about 1,000 mg per day, e.g., from about 1 mg to about 500 mg, e.g., from about 5 mg to about 250 mg. Doses can be administered as a single dose or multiple doses, e.g., from 1 to 4 or more times per day. When multiple doses are used, the amounts in each dose can be the same or different. For example, a 1 mg dose per day can be administered as two 0.5 mg doses, with an interval of about 12 hours between the doses.

[0258] It will be understood that the amount of compound administered per day can be administered, in non-limiting examples, every day, every other day, every two days, every three days, every four days, or every five days. For example, for every other day administration, a dose of 5 mg per day can be administered starting on Monday, a first subsequent dose of 5 mg per day can be administered on Wednesday, and a second subsequent dose of 5 mg per day can be administered on Friday.

[0259] If the patient's condition improves, at the physician's discretion, administration of the compounds described herein may continue, or the dose of the administered drug may be temporarily reduced or temporarily discontinued for a length of time (i.e., a "drug holiday"). The length of the drug holiday may optionally vary from 2 days to 1 year, and includes, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during drug holidays include 10% to 100%, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0260] When improvement of the patient's condition occurs, a maintenance dose is administered if necessary. The dosage or frequency of administration, or both, is then reduced to a level at which improvement in the disease is maintained. In certain embodiments, patients may require long-term intermittent treatment for any recurrence of symptoms and / or infection.

[0261] The compounds described herein can be formulated in unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as unitary dosage forms for patients receiving treatment, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect, optionally in combination with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily administration or for one of multiple daily administrations (e.g., about 1 to 4 or more times per day). When multiple daily administrations are used, the unit dosage form can be the same or different for each administration.

[0262] The toxicity and therapeutic efficacy of the therapeutic regimen in question are optionally determined in cell culture or experimental animals, and the LD 50 (a dose lethal to 50% of the population) and ED 50These include, but are not limited to, determining the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 and ED 50 The data obtained from cell culture assays and animal studies may be used in formulating a range of dosages for use in humans. The dosage of these compounds is determined to be sufficient to achieve the ED with minimal toxicity. 50 The dosage amount optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0263] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. These equivalents are considered to be within the scope of this disclosure and are considered to be covered by the claims appended hereto. For example, it should be understood that modification of reaction conditions, including but not limited to reaction time, reaction size / volume, experimental reagents such as solvents, catalysts, pressure, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, using art-recognized substitutes and no more than routine experimentation, is within the scope of this application.

[0264] Wherever values ​​and ranges are given herein, it should be understood that all values ​​and ranges subsumed within those values ​​and ranges are intended to be encompassed within the scope of the present disclosure. Moreover, all values ​​within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

[0265] The following examples further illustrate aspects of the present disclosure, but in no way limit the teachings or disclosure of the present disclosure set forth herein. [Example]

[0266] Experimental Example The present disclosure will now be described with reference to the following examples, which are presented for illustrative purposes only, and the present disclosure should in no way be construed as being limited to these examples, but rather as encompassing any variations that become evident as a result of the teachings set forth herein.

[0267] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following examples, make and utilize the disclosed compounds, and practice the claimed methods. The following examples therefore, illustrate specific embodiments of the disclosure, and are not to be construed as limiting in any way the remainder of the disclosure.

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

[0269] 11A-11B show a non-limiting synthesis of the ASGPRBM group.

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

[0271] Figures 13A-13L show non-limiting syntheses of specific ASGPRBM groups. While this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product can be deprotected as appropriate.

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

[0273] FIG. 15 shows a non-limiting synthetic scheme that allows for the labeling (derivatization) 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 allows for the labeling (derivatization) of CRBM groups with strained alkyne-containing groups. In certain non-limiting embodiments, any azide-containing compound (including but not limited to, compounds shown in Figure 15) can be reacted with a strained alkyne-containing compound (including but not limited to, compounds shown in Figure 16) to produce compounds of the present disclosure.

[0275] Numbered Aspects Numbered aspects are presented below, but the numbering should not be construed as indicating a level of importance. Aspect 1 provides the following: A compound comprising formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof: [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) During the ceremony, Ab is an antibody that binds to an extracellular protein; The CRBM is a cell receptor binding moiety that binds to at least one receptor on the surface of a degradative cell in a subject, whereby binding of (I) results in endocytosis and degradation of the extracellular protein; each CON is independently a bond or a group that covalently links an Ab to a CRBM, an Ab to a linker, and / or a linker to a CRBM; The linker is a group having a valence ranging from 1 to 15; k' is an integer ranging from 1 to 15; h is an integer ranging from 0 to 15; i is an integer ranging from 0 to 15; h' is an integer ranging from 0 to 15; j is an integer ranging from 1 to 15. Aspect 2 provides the following: The compound of embodiment 1, wherein the linker has a valency of 1, 2, or 3. Aspect 3 provides the following: The compound of any one of embodiments 1-2, wherein k′ is 1, 2, or 3. Aspect 4 provides the following: The compound of any one of embodiments 1 to 3, wherein j is 1, 2, or 3. Aspect 5 provides the following: The compound of any one of embodiments 1 to 4, wherein h is 1, 2, or 3. Aspect 6 provides the following: The compound of any one of embodiments 1 to 5, wherein h′ is 1, 2, or 3. Aspect 7 provides the following: The compound of any one of embodiments 1 to 6, wherein i is 1, 2, or 3. Aspect 8 provides the following: The compound of any one of embodiments 1 to 7, wherein at least one of h, h', and i is at least 1. Aspect 9 provides the following: The compound of any one of embodiments 1-8, wherein k′, j′, h, h′, and i are each independently 1, 2, or 3. Aspect 10 provides the following: The compound of any one of embodiments 1-9, wherein k' is 1 and j' is 1, 2, or 3. Aspect 11 provides the following: [Ab]-[CON] 0~1 -[Linker]-[CON] 0~1 The compound of any one of embodiments 1-10, wherein the compound is [CRBM] (Ia). Aspect 12 provides the following: The compound of any one of embodiments 1-11, wherein the degradative cells comprise hepatocytes. Aspect 13 provides the following: 13. The compound of any one of embodiments 1-12, wherein the 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. Aspect 14 provides the following: The compound of any one of embodiments 1-13, wherein the CRBM is: (a) a folate receptor binder comprising at least one of folic acid, methotrexate, pemetrexed, or a biologically active fragment thereof; (b) a mannose receptor binder comprising at least one of the following: TIFF2026010002000047.tif19128 (wherein X is S or O, and R is TIFF2026010002000048.tif17137, wherein 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: TIFF2026010002000049.tif19128 (wherein X is O or S, and R 1 teeth, TIFF2026010002000050.tif52128; R 2 teeth, TIFF2026010002000051.tif41128, wherein 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); The polymer molecules shown in Figure 8; below Compounds selected from TIFF2026010002000052.tif116128; below Compounds selected from TIFF2026010002000053.tif134128; (d) a low-density lipoprotein receptor-related protein 1 (LRP1) receptor binder comprising at least one amino acid sequence of SEQ ID NOs: 1-9; (e) a low-density lipoprotein receptor (LDLR) binder comprising at least one amino acid sequence of SEQ ID NO: 10-35; (f) an FcγRI receptor binder comprising at least one amino acid sequence of SEQ ID NOs: 36-52; (g) a transferrin receptor binder comprising at least one amino acid sequence of SEQ ID NOs: 53-59 and 67; (h) a macrophage scavenger receptor binder comprising at least one amino acid sequence of SEQ ID NO: 60 to 65; (i) a G protein-coupled receptor binder comprising at least one of the following: TIFF2026010002000054.tif36128 wherein each occurrence of R is independently H or C1-C6 alkyl; (j) an asialoglycoprotein receptor (ASGPR) binder, comprising: TIFF2026010002000055.tif24128 (in the formula, X is a linker 1 to 4 atoms in length, and If X is a linker one atom long, X is O, S, N(R N1 ), or C(R N1 )(R N1 ) and If X is a linker two atoms long, not more than one atom of X may be O, S, or N(R N1 ) and When X is a linker 3 or 4 atoms in length, no more than two atoms of X are independently O, S, or N(R N1 ) As such, O, S, N(R N1 ), or C(R N1 )(R N1 ) group, where R N1 each occurrence is independently H, or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; R 1 and R 3 are each independently H, -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 independently selected halogens, —(CH2) K (vinyl), -O(CH2) K (vinyl), -(CH2) K (alkynyl), -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens; or R 1 and R 3 are each independently Ph(CH2) K-, which is optionally substituted with 1 to 3 independently selected halogens; C1 to C4 alkyl optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups; or C1 to C4 alkoxy optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups; or R 1 and R 3 are each independently represented by the following structure: -O-(CH2) K' -CH(OH)-(CH2)K'-R 7 is the basis of During the ceremony, R 7 is a C1-C4 alkoxy optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxy 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 C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; R N4 each occurrence independently represents H, C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, or Ph-(CH2) K -is; or R 1 and R 3 are each independently TIFF2026010002000056.tif27128, wherein CYC is selected from the group consisting of: TIFF2026010002000057.tif112144; During the ceremony, The bond marked in TIFF2026010002000058.tif1128 is -(CH2) K indicates the site on the CYC that is connected; L 1 is a bond, -linker, -CON-linker, or -CON-linker-CON; R C is absent, H, C1-C4 alkyl optionally substituted with 1 to 3 optionally substituted halogens and / or 1 to 2 hydroxyl groups, or a group having the following structure: Based on TIFF2026010002000059.tif52128, During the ceremony, R 4 , R 5 , and R 6 are independently H, F, Cl, Br, I, CN, or NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1 to 3 independently selected halogens, C1-C3 alkoxy optionally substituted with 1 to 3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O-(C1-C4 alkyl), -OC(=O)-(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)-(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens; R N each occurrence is independently H, or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; R N2 each occurrence of is independently H or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; or R 1 and R 3 are each independently (C3-C8 saturated carbocyclic ring)-(CH2) K -, where the carbocycle is -L 1 and -R C is further substituted with; R 2 Ha-(CH2) K -N(R N1 )-C(=O)R AM where: R AM is H, C1-C4 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, -C(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -(CH2) K -NR N3 R N4 or R 2 teeth TIFF2026010002000060.tif16128, wherein: R TA H, CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 independently selected halogens, —(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens KC(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens; or R TA is C3~C 10 an aryl group or a 3- to 10-membered heteroaryl group containing 1 to 5 non-carbon ring atoms, wherein the aryl group or heteroaryl group is CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(C1-C3-alkoxy) optionally substituted with 1-3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O-(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -(CH2) optionally substituted with 1 to 3 independently selected halogens. K C(=O)-(C1-C4 alkyl), or R TA teeth TIFF2026010002000061.tif48128, which is optionally substituted with 1 to 3 C1-C3 alkyl groups, each of which is optionally substituted with 1 to 3 independently selected halogens; or R TA teeth TIFF2026010002000062.tif28128, wherein each -(CH2) K The group is optionally substituted with 1 to 4 C1-C3 alkyl groups, which may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups). Aspect 15 provides the following: If X is two atoms long, then X in the ASGPRBM 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 three atoms long, then X in the ASGPRBM 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 ) or If X is four atoms long, then X in the ASGPRBM 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, A compound of any one of embodiments 1 to 14. Aspect 16 provides the following: X is OCH2 and R N1 is H, or X is CHO and R N1 The compound of any one of embodiments 1 to 15, wherein Aspect 17 provides the following: ASGPRBM has the following structure: 17. The compound of any one of embodiments 14-16, comprising TIFF2026010002000063.tif22128. Aspect 18 provides the following: A compound of any one of embodiments 14-17, wherein the ASGPRBM group comprises: TIFF2026010002000064.tif75128 (in the formula, R A is C1-C3 alkyl optionally substituted with 1 to 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 absent, -(CH2) IM -, -C(=O)-(CH2) IM - or -C(=O)(CH2) IM -NR M - and R M is H or C1-C3 alkyl optionally substituted with 1 to 2 hydroxyl groups, each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6); TIFF2026010002000065.tif98149TIFF2026010002000066.tif213120 (where R = CH3, CF3, or CH2CF3); TIFF2026010002000067.tif186151TIFF2026010002000068.tif187156. Aspect 19 provides the following: The compound of any one of embodiments 1-18, wherein the linker is a polyethylene glycol-containing linker having 1 to 12 ethylene glycol residues. Aspect 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 - or a polypropylene glycol group or a polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units, Each R a are independently H, C1-C3 alkyl, or C1-C6 alkanol, or R b together to form a pyrrolidine group or a hydroxypyrroline group; Each R b is 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 ranging from 1 to 15; or The linker has the following structure: -[N(R ' -(CH2) 1~15 -C(=O)]- (wherein R' is H or C1-C3 alkyl optionally substituted with 1 to 2 hydroxyl groups, and m is an integer ranging from 1 to 100) contains; or The linker has the following structure: -ZD-Z'- (In the formula, Z and Z' each independently represent a bond; TIFF2026010002000069.tif18161; each R is independently H, C1-C3 alkyl, or C1-C6 alkanol; Each R 2 are independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N(R); Each i is independently between 0 and 100; D is a bond, -(CH2) i-YC(=O)-Y-(CH2) i -, -(CH2) m' - or -[(CH2) n -X1)] j with the proviso that Z, Z', and D are not each simultaneously a bond; X 1 is O, S, or N(R); j is an integer ranging from 1 to 100; m' is an integer ranging from 1 to 100; n is an integer ranging from 1 to 100. contains; or The linker has the following structure: -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n' CH2CH2-, or -(CH2CH2CH2O) n - (wherein each n and n' is independently an integer ranging from 1 to 25) contains; or The linker has the following structure: -PEG-CON-PEG- (wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON is a triazole group) TIFF2026010002000070.tif14128) Including, The compound of any one of embodiments 1 to 19. Aspect 21 provides the following: CON has the following structure: TIFF2026010002000071.tif86157 (wherein R' and R'' are each independently H, methyl, or a bond). contains; 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 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, 1, 2, 3, 4, 5, or 6. contains; or CON has the following structure: TIFF2026010002000072.tif14128 (in the formula, R 1a , R 2a , and R 3a are each independently H, -(CH2) 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 - but R 1a , R 2a , and R 3a and H are not simultaneously; each M1 is independently 1, 2, 3, or 4; each M2 is independently 0, 1, 2, 3, or 4; each M3 is independently 0 or 1; Each R 4 are independently H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), provided that the same R 1a , R 2a , and R 3a (M2 and M3 in the contains; or CON has the following structure: Including TIFF2026010002000073.tif46128, The compound of any one of embodiments 1 to 20. Aspect 22 provides the following: Extracellular proteins include 1-40-beta-amyloid, 5'-nucleotidase, activated F9, F10, activin receptor-like kinase 1, alpha-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-1), Bacillus anthracis anthrax, BAFF, beta-amyloid, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide alpha, canine (Canis lupus familiaris) IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, clumping factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, and Escherichia coli (E.coli Shiga toxin type 1, E. coli Shiga toxin type 2, EGFL7, endotoxin, episialin, FGF 23, fibrin II, beta chain, fibronectin extra domain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human beta-amyloid, human scatter factor receptor kinase, human TNF, IFN-α, IFN-γ, IgE, IgE Fc region, IGF1, IGF2, IGF-E, IL-17A, IL-17A and IL-17F, IL-17A, IL-17B, IL-17C, IL-17D, IL-17F ... 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 gamma, interferon Ron gamma-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), neuroapoptosis-regulating proteinase 1, NGF, NOGO-A, Notch 22. The compound of any one of embodiments 1-21, comprising: NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, tectal plate-specific spondin 3, RTN4, sclerostin, SDC1, serum amyloid A protein, serum amyloid P component, SOST, Staphylococcus aureus alpha-toxin, tau protein, TFPI, TGFβ1, TGFβ2, TGF-β, TNF-α, TROP-2, TSLP, VEGF-A, VEGF-A, and Ang-2, VEGFA, or VWF. Aspect 23 provides the following: The compound of any one of embodiments 1 to 22, wherein Ab is a monoclonal antibody. Aspect 24 provides the following: The antibody is selected from the group consisting of abagovomab, abrezekimab, adalimumab, aducanumab, afasevikumab, afelimomab, alirocumab, altumomab, and altumomab pentetate. pentetate), Andecaliximab, Anrukinzumab, Arcitumomab, Ascrinvacumab, Atezolizumab, Atidortoxumab, Atinumab, Avelumab, Bapineuzumab, Bavituximab, Belimumab, Bermekimab, Besilesomab, Bevacizumab, Biciromab, Bimetazolamide, Bimekizumab, Birtamimab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumab, Cantuzumab ravtansine, Caplacizumab, Carlumab, Cergutuzumab, Cergutuzumab amunaleukin, Certolizumab, Certolizumab pegol, Cibisatamab, Clazakizumab, Crivatuzumab, Crivatuzumab tetraxetanTetraxetan, Concizumab, Crenezumab, Dectrekumab, Denosumab, Dezamizumab, Diridavumab, Domagrozumab, Dorlimomab, Dorlimomab-alitonox Aritox, Durvalumab, Dusigitumab, Eculizumab, Edobacomab, Efungumab, Eldelumab, Elezanumab, Elsilimomab, Emactuzumab, Emapalumab, Emicizumab, Enokizumab, Epitumomab, Epitumomab-sitaxetan Cituxetan, Eptinezumab, Erenumab, Evinacumab, Evolocumab, Faricimab, Fasinumab, Fezakinumab, Ficlatuzumab, Filivumab, Fletikumab, Fontolizumab, Fremanezumab, Fresolimumab, Frovocimab, Furnevetomab Frunevetmab, Fulranumab, Galcanezumab, Gantenerumab, Gatipotuzumab, Gedivumab, Gevokizumab, Gimsilumab, Girentuximab, Golimumab, Gosuranemab, Guselkumab, Idarucizumab, Igovomab, Imalumab, Indatuximab ...Ravtansine, Infliximab, Istiratumab, Ixekizumab, Labetuzumab, Lacnotuzumab, Lampalizumab, Lanadelumab, Landogrozumab, Lebrikizumab, Remalesomab, Lendalizumab, Lenzilumab, Lerdelimumab Lerdelimumab, Lesofavumab, Ligelizumab, Lodelcizumab, Lokivetmab, Lutikizumab, Marstacimab, Mepolizumab, Metelimumab, Mirikizumab, Nacolomab, Nacolomab butafenatox Tafenatox, Namilumab, Narnatumab, Navivumab, Naxitamab, Nebacumab, Nemolizumab, NEOD, Nerelimomab, Nesvacumab, Netakimab, Nofetumomab, Nofetumomab Merpentanemerpentan, obiltoxaximab, oleclumab, olendalizumab, olokizumab, omalizumab, OMS, onartuzumab, oregovomab, orticumab, otilimab, ozanezumab, ozoralizumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, pemtumomab, perakizumab, pexelizumab, Placulumab, Ponezumab, Prasinezumab, Pritoxaximab, Quilizumab, Radretumab, Ralpancizumab, Ranevetmab, Ranibizumab, Ravulizumab b), Raxibacumab, 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 vedotinvedotin, solanezumab, sontuzumab, stamulumab, sulesomab, sutimlimab, suvratoxumab, tabalumab, tacatuzumab, tacatuzumab tetraxetan, talizumab, tanezumab, tefibazumab, telimomab, telimomab alitoxin 24. The compound of any one of embodiments 1-23, comprising Aritox, Tesidolumab, Tezepelumab, Tiburizumab, Tildrakizumab, Timolumab, Tisotumab, Tisotumab vedotin, Tralokinumab, Trevogrumab, Urtoxazumab, Ustekinumab, Vanucizumab, Vapaliximab, Varisacumab, Vepalimomab, Besencumab, Vobarilizumab, Bunakizumab, or Xentuzumab. Embodiment 25 provides the following: A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one compound of any one of embodiments 1-24. Embodiment 26 provides the following: 26. The pharmaceutical composition of embodiment 25, further comprising another therapeutically active compound. Aspect 27 provides the following: A method of treating a disease or disorder in a subject, comprising administering a therapeutically effective amount of at least one compound of any one of embodiments 1-24 and / or at least one pharmaceutical composition of any one of embodiments 25-26. Embodiment 28 provides the following: The method of embodiment 27, wherein the disease or disorder comprises an autoimmune disease, cancer, or inflammation. Aspect 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 (APIS), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cholangiocarcinoma (MMD), and cholangiocarcinoma (CHD). Oglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adiposity dolorosa, adult Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatoid arthritis, Parry-Romberg syndrome, Parsonage-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, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barrault concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, pattern II, Oshtoran syndrome, pediatric autoimmune streptococcal-associated neuropsychiatric disorder (PANDA) S), progressive inflammatory neuropathy, restless legs syndrome, stiff-person syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan's syndrome, Graves' ophthalmopathy, intermediate uveitis, lignified conjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Susac syndrome, sympathetic ophthalmia, 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),29. The method of embodiment 28, comprising IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatoid 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. Aspect 30 provides the following: 30. The method of embodiment 28, wherein the cancer comprises 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's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic 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, renal cancer, or lymphoma. Aspect 31 provides the following: 30. The method of embodiment 28, wherein the inflammation comprises neurodegenerative inflammatory diseases, immune-compromised response diseases causing inflammation, chronic inflammatory diseases, hyperglycemic disorders, diabetes (type I and type II), pancreatic beta cell death and associated hyperglycemic disorders, liver disease, kidney disease, cardiovascular disease, muscle degeneration and muscle atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury, or arteriosclerosis. Aspect 32 provides the following: The method of any one of embodiments 27-31, wherein at least one additional therapeutic agent that treats or prevents said disease or disorder is further administered to the subject. Aspect 33 provides the following: The method of any one of embodiments 27 to 32, wherein the subject is a mammal. Embodiment 34 provides the following: The method of any one of embodiments 27 to 33, wherein the subject is a human.

[0276] The disclosures of all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. Although the present disclosure has been disclosed with reference to certain embodiments, it is clear that those skilled in the art can devise other embodiments and variations of the present disclosure without departing from the true spirit and scope of the present disclosure. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

[0277] Sequence information SEQUENCE LISTING <110> Yale University <120> Engineered Antibodies as Molecular Degraders through Cellular Receptors <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> Chemically synthesized <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. A compound comprising formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof: [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) During the ceremony, Ab is an antibody that binds to an extracellular protein; The CRBM is a cell receptor binding moiety that binds to at least one receptor on the surface of a degradative cell in a subject, whereby binding of (I) results in endocytosis and degradation of the extracellular protein; each CON is independently a bond or a group that covalently links an Ab to a CRBM, an Ab to a linker, and / or a linker to a CRBM; The linker is a group having a valence ranging from 1 to 15; k' is an integer ranging from 1 to 15; h is an integer ranging from 0 to 15; i is an integer ranging from 0 to 15; h' is an integer ranging from 0 to 15; j is an integer ranging from 1 to 15.

2. 2. The compound of claim 1, wherein the linker has a valency of 1, 2, or 3.

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

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

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

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

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

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

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

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

11. [Ab]-[CON] 0～1 -[Linker]-[CON] 0～1 2. The compound of claim 1, wherein the compound is -[CRBM] (Ia).

12. 10. The compound of claim 1, wherein the degradative cells comprise hepatocytes.

13. The compound of claim 1, wherein the 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. 10. The compound of claim 1, wherein the CRBM is: (a) a folate receptor binder comprising at least one of folic acid, methotrexate, pemetrexed, or a biologically active fragment thereof; (b) a mannose receptor binder comprising at least one of the following: wherein X is S or O and R is wherein 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: (wherein X is O or S, and R 1 teeth, selected from the group consisting of R 2 teeth, wherein 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; The polymer molecules shown in Figure 8; A compound selected from the following: ; A compound selected from the following: ; (d) a low-density lipoprotein receptor-related protein 1 (LRP1) receptor binder comprising at least one amino acid sequence of SEQ ID NOs: 1-9; (e) a low-density lipoprotein receptor (LDLR) binder comprising at least one amino acid sequence of SEQ ID NOs: 10-35; (f) an FcγRI receptor binder comprising at least one amino acid sequence of SEQ ID NOs: 36-52; (g) a transferrin receptor binder comprising at least one amino acid sequence of SEQ ID NOs: 53-59 and 67; (h) a macrophage scavenger receptor binder comprising at least one amino acid sequence of SEQ ID NO: 60-65; (i) a G protein-coupled receptor binder comprising at least one of the following: wherein each occurrence of R is independently H or C 1 ~C 6 is alkyl; (j) an asialoglycoprotein receptor (ASGPR) binder, comprising: (In the formula, X is a linker 1 to 4 atoms in length, and If X is a linker one atom long, X is O, S, N(R N1 ), or C(R N1 )(R N1 ) and If X is a linker two atoms long, not more than one atom of X may be O, S, or N(R N1 ) and When X is a linker 3 or 4 atoms in length, no more than two atoms of X are independently O, S, or N(R N1 ) As such, O, S, N(R N1 ), or C(R N1 )(R N1 ) group, where R N1 each occurrence of is independently H, or C optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups 1 ~C 3 is alkyl; R 1 and R 3 are each independently H, -(CH 2 ) K OH, -(CH 2 ) K O(C 1 ~C 4 alkyl), C optionally substituted with 1 to 3 independently selected halogens 1 ~C 4 Alkyl, -(CH 2 ) K (vinyl), -O(CH 2 ) K (vinyl), -(CH 2 ) K (alkynyl), -(CH 2 ) K COOH, -(CH 2 ) K C(=O)O(C 1 ~C 4 alkyl), optionally substituted with 1 to 3 independently selected halogens -OC(=O)(C 1 ~C 4 alkyl), or —C(═O)(C 1 ~C 4 alkyl); or R 1 and R 3 are each independently Ph(CH 2 ) K -, which is optionally substituted with 1 to 3 independently selected halogens; C, which is optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups 1 ~C 4 alkyl; or C optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups 1 ~C 4 optionally substituted with alkoxy; or R 1 and R 3 are each independently represented by the following structure: -O-(CH 2 ) K' -CH(OH)-(CH 2 )K'-R 7 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 hydroxy 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 of is independently H, or C optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups 1 ~C 3 is alkyl; R N4 each occurrence of C is optionally 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 are each independently wherein CYC is selected from the group consisting of: selected from the group consisting of During the ceremony, The bond marked with is -(CH 2 ) K indicates the site on the CYC that is connected; L 1 is a bond, -linker, -CON-linker, or -CON-linker-CON; R C is absent, H, C optionally substituted with 1 to 3 optionally substituted halogens and / or 1 to 2 hydroxyl groups 1 ~C 4 Alkyl, or the following structure: is the basis of During the ceremony, R 4 , R 5 , and R 6 are independently H, F, Cl, Br, I, CN, or NR N1 R N2 , -(CH 2 ) K OH, -(CH 2 ) K O(C 1 ~C 4 alkyl), C optionally substituted with 1 to 3 independently selected halogens 1 ~C 3 alkyl, C optionally substituted with 1 to 3 independently selected halogens 1 ~C 3 -alkoxy, -(CH 2 ) K COOH, -(CH 2 ) K C(=O)O-(C 1 ~C 4 alkyl), OC(=O)-(C 1 ~C 4 alkyl), or —C(═O)—(C 1 ~C 4 alkyl); R N each occurrence of is independently H, or C optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups 1 ~C 3 is alkyl; R N2 each occurrence of is independently H, or C optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups 1 ~C 3 is alkyl; or R 1 and R 3 are each independently (C 3 ~C 8 Saturated carbocycle)-(CH 2 ) K -, where the carbocycle is -L 1 and -R C is further substituted with; R 2 Ha-(CH 2 ) K -N(R N1 )-C(=O)R AM wherein: R AM is optionally substituted with H, 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups; 1 ~C 4 Alkyl, -(CH 2 ) K COOH, -(CH 2 ) K C(=O)O(C 1 ~C 4 alkyl), optionally substituted with 1 to 3 independently selected halogens -OC(=O)(C 1 ~C 4 alkyl), optionally substituted with 1 to 3 independently selected halogens -C(=O)(C 1 ~C 4 alkyl), or -(CH 2 ) K -NR N3 R N4 or R 2 teeth wherein: R TA H, CN, NR N1 R N2 , -(CH 2 ) K OH, -(CH 2 ) K O(C 1 ~C 4 alkyl), C optionally substituted with 1 to 3 independently selected halogens 1 ~C 4 Alkyl, -(CH 2 ) K COOH, -(CH 2 ) K C(=O)O(C 1 ~C 4 alkyl), optionally substituted with 1 to 3 independently selected halogens -OC(=O)(C 1 ~C 4 alkyl), or —C(═O)(C 1 ~C 4 alkyl), or R TA is C 3 ~C 10 an aryl group or a 3- to 10-membered heteroaryl group containing 1 to 5 non-carbon ring atoms, wherein the aryl or heteroaryl group is CN, NR N1 R N2 , -(CH 2 ) K OH, -(CH 2 ) K O(C 1 ~C 4 alkyl), optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups; 1 ~C 3 alkyl, optionally 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), optionally substituted with 1 to 3 independently selected halogens -OC(=O)(C 1 ~C 4 alkyl), or -(CH 2 ) K C(=O)-(C 1 ~C 4 alkyl), or R TA teeth and 1 to 3 C optionally substituted with 1 to 3 independently selected halogens. 1 ~C 3 may be substituted with an alkyl group, or R TA teeth wherein each -(CH 2 ) K The group is a 1-4 C alkyl group optionally substituted with 1-3 fluoro groups or 1-2 hydroxyl groups. 1 ~C 3 may be substituted with an alkyl group).

15. If X is two atoms long, then X in the ASGPRBM 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 three atoms long, then X in the ASGPRBM 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 ) or If X is four atoms long, then X in the ASGPRBM 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, 15. The compound of claim 14.

16. X is OCH 2 and R N1 is H or X is CH 2 O and R N1 15. The compound of claim 14, wherein is H.

17. ASGPRBM has the following structure:

15. The compound of claim 14, comprising:

18. 15. The compound of claim 14, wherein the ASGPRBM group comprises: (In the formula, R A is C optionally substituted with 1 to 5 independently selected halogens 1 ~C 3 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 absent, -(CH 2 ) IM -, -C(=O)-(CH 2 ) IM - or -C(=O)(CH 2 ) IM -NR M - and R M is H or C optionally substituted with 1 to 2 hydroxyl groups 1 ~C 3 is alkyl, each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6); (where R = CH 3 , C.F. 3 , or CH 2 CF 3 is); 。

19. 2. The compound of 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 - or a polypropylene glycol group or a polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units, Each R a are independently H, C 1 ~C 3 Alkyl, or C 1 ~C 6 alkanol, or R b together to form a pyrrolidine group or a hydroxypyrroline group; Each R b are independently hydrogen, methyl, isopropyl, -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 ) phenols; m is an integer ranging from 1 to 15; or The linker has the following structure: -[N(R ' -(CH 2 ) 1～15 -C(=O)]- (wherein R' is H or C optionally substituted with 1 to 2 hydroxyl groups) 1 ~C 3 alkyl, and m is an integer ranging from 1 to 100. contains; or The linker has the following structure: -ZD-Z'- (In the formula, Z and Z' each independently represent a bond; and; Each R is independently H, C 1 ~C 3 Alkyl, or C 1 ~C 6 It is an alkanol; Each R 2 are independently H or C 1 ~C 3 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 with the proviso that Z, Z', and D are not each simultaneously a bond; X 1 is O, S, or N(R); j is an integer ranging from 1 to 100; m' is an integer ranging from 1 to 100; n is an integer ranging from 1 to 100) contains; 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 - wherein each n and n' is independently an integer ranging from 1 to 25. contains; or The linker has the following structure: -PEG-CON-PEG- where 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 of claim 1.

21. CON has the following structure: wherein R′ and R″ are each independently H, methyl, or a bond. contains; 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 are independently H or C 1 ~C 3 alkyl, and n'' is independently an integer from 0 to 8, in certain embodiments from 1 to 7, and in certain embodiments, 1, 2, 3, 4, 5, or 6. contains; or CON has the following structure: (In the formula, R 1a , R 2a , and R 3a are each independently H, -(CH 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 - but R 1a , R 2a , and R 3a and H are not simultaneously; each M1 is independently 1, 2, 3, or 4; each M2 is independently 0, 1, 2, 3, or 4; each M3 is independently 0 or 1; Each R 4 are independently H, C 1 ~C 3 Alkyl, C 1 ~C 6 Alkanol, or -C(=O)(C 1 ~C 3 alkyl), but the same R 1a , R 2a , and R 3a (M2 and M3 in the contains; or CON has the following structure: Including, The compound of claim 1.

22. Extracellular proteins include 1-40-beta-amyloid, 5'-nucleotidase, activated F9, F10, activin receptor-like kinase 1, alpha-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-1), Bacillus anthracis anthrax, BAFF, beta-amyloid, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide alpha, canine (Canis lupus familiaris) IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, clumping factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, and Escherichia coli (E.coli Shiga toxin type 1, E. coli Shiga toxin type 2, EGFL7, endotoxin, episialin, FGF 23, fibrin II, beta chain, fibronectin extra domain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human beta-amyloid, human scatter factor receptor kinase, human TNF, IFN-α, IFN-γ, IgE, IgE Fc region, IGF1, IGF2, IGF-E, IL-17A, IL-17A and IL-17F, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F ... 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 gamma, interferon Ron gamma-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), neuroapoptosis-regulating proteinase 1, NGF, NOGO-A, Notch 1, NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, tectal plate-specific spondin 3, RTN4, sclerostin, SDC1, serum amyloid A protein, serum amyloid P component, SOST, Staphylococcus aureus alpha-toxin, tau protein, TFPI, TGFβ1, TGFβ2, TGF-β, TNF-α, TROP-2, TSLP, VEGF-A, VEGF-A and Ang-2, VEGFA, or VWF.

23. 2. The compound of claim 1, wherein the Ab is a monoclonal antibody.

24. The antibody is selected from the group consisting of abagovomab, abrezekimab, adalimumab, aducanumab, afasevikumab, afelimomab, alirocumab, altumomab, and altumomab pentetate. pentetate), Andecaliximab, Anrukinzumab, Arcitumomab, Ascrinvacumab, Atezolizumab, Atidortoxumab, Atinumab, Avelumab, Bapineuzumab, Bavituximab, Belimumab, Bermekimab, Besilesomab, Bevacizumab, Biciromab, Bimetazolamide, Bimekizumab, Birtamimab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumab, Cantuzumab ravtansine, Caplacizumab, Carlumab, Cergutuzumab, Cergutuzumab amunaleukin, Certolizumab, Certolizumab pegol, Cibisatamab, Clazakizumab, Crivatuzumab, Crivatuzumab tetraxetanTetraxetan, Concizumab, Crenezumab, Dectrekumab, Denosumab, Dezamizumab, Diridavumab, Domagrozumab, Dorlimomab, Dorlimomab-alitonox Aritox, Durvalumab, Dusigitumab, Eculizumab, Edobacomab, Efungumab, Eldelumab, Elezanumab, Elsilimomab, Emactuzumab, Emapalumab, Emicizumab, Enokizumab, Epitumomab, Epitumomab-sitaxetan Cituxetan, Eptinezumab, Erenumab, Evinacumab, Evolocumab, Faricimab, Fasinumab, Fezakinumab, Ficlatuzumab, Filivumab, Fletikumab, Fontolizumab, Fremanezumab, Fresolimumab, Frovocimab, Furnevetomab Frunevetmab, Fulranumab, Galcanezumab, Gantenerumab, Gatipotuzumab, Gedivumab, Gevokizumab, Gimsilumab, Girentuximab, Golimumab, Gosuranemab, Guselkumab, Idarucizumab, Igovomab, Imalumab, Indatuximab ...Ravtansine, Infliximab, Istiratumab, Ixekizumab, Labetuzumab, Lacnotuzumab, Lampalizumab, Lanadelumab, Landogrozumab, Lebrikizumab, Remalesomab, Lendalizumab, Lenzilumab, Lerdelimumab Lerdelimumab, Lesofavumab, Ligelizumab, Lodelcizumab, Lokivetmab, Lutikizumab, Marstacimab, Mepolizumab, Metelimumab, Mirikizumab, Nacolomab, Nacolomab butafenatox Tafenatox, Namilumab, Narnatumab, Navivumab, Naxitamab, Nebacumab, Nemolizumab, NEOD, Nerelimomab, Nesvacumab, Netakimab, Nofetumomab, Nofetumomab Merpentanemerpentan, obiltoxaximab, oleclumab, olendalizumab, olokizumab, omalizumab, OMS, onartuzumab, oregovomab, orticumab, otilimab, ozanezumab, ozoralizumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, pemtumomab, perakizumab, pexelizumab, Placulumab, Ponezumab, Prasinezumab, Pritoxaximab, Quilizumab, Radretumab, Ralpancizumab, Ranevetmab, Ranibizumab, Ravulizumab b), Raxibacumab, 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 vedotinvedotin, solanezumab, sontuzumab, stamulumab, sulesomab, sutimlimab, suvratoxumab, tabalumab, tacatuzumab, tacatuzumab tetraxetan, talizumab, tanezumab, tefibazumab, telimomab, telimomab alitoxin 10. The compound of claim 1, comprising: aritox, tesidolumab, tezepelumab, tiburizumab, tildrakizumab, timolumab, tisotumab, tisotumab vedotin, tralokinumab, trevogrumab, urtoxazumab, ustekinumab, vanucizumab, vapaliximab, varisacumab, vepalimomab, besencumab, vobarilizumab, bunakizumab, or xentuzumab.

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

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

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

28. 28. The method of claim 27, wherein the disease or disorder comprises 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 (APIS), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cholangiocarcinoma (MMD), and cholangiocarcinoma (CHD). Oglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, steatohepatitis dolorosa, 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, Parsonage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler's syndrome, systemic lupus erythematosus , undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barrow concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, pattern II, Oshtoran syndrome, pediatric autoimmune streptococcal-associated neuropsychiatric disorder (PANDA) S), progressive inflammatory neuropathy, restless legs syndrome, stiff-body syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan's syndrome, Graves' ophthalmopathy, intermediate uveitis, lignified conjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Susac syndrome, sympathetic ophthalmia, 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),29. The method of claim 28, comprising IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatoid 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. 29. The method of claim 28, wherein the cancer comprises prostate cancer, metastatic prostate cancer, stomach 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's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic 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, renal cancer, or lymphoma.

31. 29. The method of claim 28, wherein the inflammation comprises neurodegenerative inflammatory diseases, immune response disorders causing inflammation, chronic inflammatory diseases, hyperglycemic disorders, diabetes (types I and II), pancreatic beta cell death and related hyperglycemic disorders, liver disease, kidney disease, cardiovascular disease, muscle degeneration and muscle atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury, or arteriosclerosis.

32. 28. The method of claim 27, wherein at least one additional therapeutic agent that treats or prevents said disease or disorder is further administered to the subject.

33. 28. The method of claim 27, wherein the subject is a mammal.

34. 28. The method of claim 27, wherein the subject is a human.

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