Compounds for lysosomal degradation of target proteins

Abstract

The present disclosure relates to harnessing endosomal sorting of lipids to enable targeted protein degradation via the lysosomal degradation pathway. Accordingly, provided herein are molecules for degrading target proteins, pharmaceutical compositions of such molecules, and methods of making and using such molecules.

Description

COMPOUNDS FOR LYSOSOMAL DEGRADATION OF TARGET PROTEINSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Application No. 63 / 575,520, filed April 5, 2024, the entire contents of which are incorporated herein by reference in their entireties.BACKGROUND

[0002] Targeted protein degradation is a promising new therapeutic modality that leverages endogenous degradation pathways to eliminate disease-associated proteins. The two major protein degradation pathways are the ubiquitin-proteasome pathway (UPS) and the lysosomal proteolysis pathway. Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that bring together a target protein and an E3 ligase, thereby using the UPS system to ubiquitinate and degrade the target protein. PROTACs are effective against cytosolic targets but not extracellular or membrane proteins. Bifunctional molecules are also developed to utilize the lysosomal proteolysis pathway and are comprised of a target binder linked to a binder to a cell-surface receptor that traffics to the lysosome, such as asialoglycoprotein receptor (ASGPR) or mannose-6-phosphate receptor (M6P). The receptor expression affects and limits the functioning of such bifunctional molecules targeting lysosomes.

[0003] Gangliosides and sphingolipids are important components of all animal cell membranes. The “prototype” monosialoganglioside GM1 impacts neuronal plasticity and repair mechanisms, and different GM1 species have different sorting capacities to cellular compartments such as the lysosome. GM1 and other sphingolipids are sorted differently during endomembrane trafficking.

[0004] There remains a need for new and improved therapeutic strategies to degrade extracellular and membrane proteins.SUMMARY

[0005] The present application encompasses the insight that target-binding moieties conjugated to ceramides may induce target internalization and degradation.

[0006] In one aspect, provided are compounds of Formula (I):TB— L— LPFormula (I)or a pharmaceutically acceptable salt thereof, wherein: TB is a target binding moiety capable of binding a target protein; L is absent or a linker; and LP is a ceramide moiety.

[0007] In some embodiments, the compound is capable of enhancing degradation of the target protein. In some embodiments, the target protein is an extracellular protein or a membrane protein.

[0008] In some embodiments, the ceramide comprises a C0-C30fatty acid moiety.

[0009] In some embodiments, LP is represented by Formula (II):Formula (II) wherein:— is a single bond or double bond;L1is absent or -O-, #-O-N=, #=N-O-, #-O-NH-, #-NH-O-, -C(O)-, #-C(O)NH- #-NHC(O)-, #-C(O)O-, or #-OC(O)-, wherein “#” indicates the point of attachment to L;X is absent or a sugar moiety;Rais hydrogen or hydroxyl;Rbis hydrogen or -C(O)R2;R1is C11-C27alkyl or C11-C27alkenyl, each optionally substituted with one or more hydroxyl;R2is hydrogen, C1-C30alkyl, or C2-C30alkenyl.

[0010] In some embodiments, R1is linear. In some embodiments, R1is -(CH2)14CH3, -(CH2)16CH3, or -CH=CH(CH2)12CH3.

[0011] In some embodiments, LP is represented by Formula (ILa):Formula (II- a).

[0012] In some embodiments, R2is linear. In some embodiments, R2is hydrogen, C1-C16alkyl, or C2-C16alkenyl. In some embodiments, R2is -(CH2)4CH3, -(CH2)IOCH3, -(CH2)i4CH3, or - (CH2)7CH=CH(CH2)5CH3.

[0013] In some embodiments, X is absent. In some embodiments, X is a monosaccharide. In some embodiments, X is glucose, fructose, galactose, or N-acetylgalactosamine (GalNAc).

[0014] In some embodiments, L1is -O-, #-O-N=, or -C(O)-, wherein “#” indicates the point of attachment to L.

[0015] In some embodiments, LP is represented by Formula (Il-al), (II-a2), or (II-a3):

[0016] In some embodiments, the linker comprises: a reactive group, a stretcher, a peptide, a PEG, or a self-immolative moiety, or a combination thereof.

[0017] In some embodiments, the linker comprises: a polyethylene glycol (PEG) of formulawherein g is an integer from 1 to 50; and a peptide (e.g., a monopeptide, a dipeptide, a tripeptide, or a tetrapeptide).

[0018] In some embodiments, linker is represented by Formula (IV):whereinRG1is absent or a reactive group;Lsis absent or a stretcher;Lpis absent or a peptide;LIis absent or a self-immolative moiety; and each of X1and X2is independently M, W-M, M-W, M-W-M, or W-M-W, each W is independently C1-6 alkylene or C2-6 alkenylene; and each M is independently a bond, -O-, -C(O)-, *-O-N=, *=N-O-, *-O-NH-, *-NH-O-, *-NHC(O)-, *-C(O)NH-, *-OC(O)-, *-C(O)O-, *-OP(O)(OH)-, *-P(O)(OH)O-, *-OP(O)(OH)OP(O)(OH)-, *-P(O)(OH)OP(O)(OH)O-,-OP(O)(OH)O-, *-OC(O)N(CH3)C(RM)2C(RM)2N(CH3)C(O)-, or *-C(O)N(CH3)C(RM)2C(RM)2N(CH3)C(O)O-, wherein each RMis independently selected from H, C1-6alkyl, or C3-8 cycloalkyl, and “*”indicates the point of attachment to TB or LIwhen X is M, M-W, or M-W-M, or to W when X is W-M, M-W-M, or W-M-W; and“#” indicates the point of attachment to LP, and “&” indicates the point of attachment to TB.

[0019] In some embodiments, X2is a bond, C(O)CH2-#, or -NHC(O)-#, wherein “#” indicates the point of attachment to LP.

[0020] In some embodiments, LIis absent.

[0021] In some embodiments, Lpis absent. In some embodiments, Lpis a peptide of formula wherein R is an amino acid side chain, m is an integer from 1 to 20, and “*”indicates the point of attachment to LI. In some embodiments, Lpis a monopeptide, a dipeptide, a tripeptide, or a tetrapeptide. In some embodiments, Lpis Glu-Glu. In some embodiments, Lpis Lys-Lys. In some embodiments, Lpis Ala-Ala. In some embodiments, Lpis Arg-Arg. In some embodiments, Lpis Lphas a structure ofwherein “*” indicates the point of attachment to LI.

[0022] In some embodiments, Ls is absent. In some embodiments, Ls is a stretcher of formula-(CH2)q(CH2OCH2)P(CH2)q-, wherein p and q are each independently an integer from 0 to 20. In some embodiments, Ls is -(CH2)(CH2OCH2)6(CH2)-, -(CH2)(CH2OCH2)n(CH2)-, or -(CH2)(CH2OCH2) I2(CH2)-.

[0023] In some embodiments, X1is a bond, (CH2)0-6C(0)NH-* or NHC(O)(CH2)1-6C(O)NH-*, wherein “*” indicates the point of attachment to Ls. In some embodiments, X1is a bond, -(CH2)2C(O)NH-* or -NHC(O)(CH2)1-6C(O)NH-*, wherein “*” indicates the point of attachment to Ls.

[0024] In some embodiments, RG1is absent, -CH2-, -C(O)-, &-C(O)NH-, &-C(S)NH-,, wherein “&” indicates the point ofattachment to TB, and R’ is hydrogen or C1-3alkyl.

[0025] In some embodiments, RG1— X1has one of the following structure:wherein indicates the point of attachment to Ls, and “&” indicates the point of attachment to TB.

[0026] In some embodiments, the compound is represented by Formula (V-al) or (V-a2):wherein TB, RG1, p, m, and R2are as defined above.

[0027] In some embodiments, TB comprises or is a peptide.

[0028] In some embodiments, TB comprises or is an antibody or an antigen binding fragmentthereof. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antigen binding fragment is a Fab, a Fab’, a Fab2, a F(ab’)2, Fv, a single-chain Fv (scFv), or a single domain antibody (sdAb) (e.g., a nanobody).

[0029] In some embodiments, the target protein is IgG, IgG4, IgA, IgE, IgM, IL-31, FGF23, TTR, IFN-γ, or TSLP.

[0030] In some embodiments, the target protein is IgG.

[0031] In some embodiments, IgG binding TB comprises or is a peptide comprising or having an amino acid sequence that has at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 1-51. In some embodiments, IgG binding TB comprises or is a peptide comprising or having an amino acid sequence that has at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 22. In some embodiments, IgG binding TB comprises or is a peptide comprising or having an amino acid sequence selected from SEQ ID NOs: 1-51. In some embodiments, IgG binding TB comprises or is a peptide comprising or having an amino acid sequence of SEQ ID NO: 22.

[0032] In some embodiments, IgG binding TB comprises or has one of the following structures:

[0033] In some embodiments, IgG binding TB comprises or has the following structure:

[0034] In some embodiments, the target protein is IgG4.

[0035] In some embodiments, IgG4 binding TB comprises or is an antibody or an antigen binding fragment thereof, comprising(a) ( (ii)) a heavy chain variable (VH) region comprising: heavy chain complementarity-determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 87, or a sequence differing in 1 or 2 amino acids therefrom,HCDR2 having the amino acid sequence of SEQ ID NO: 88, or a sequence differing in 1 or 2 amino acids therefrom, andHCDR3 having the amino acid sequence of SEQ ID NO: 89, or a sequence differing in 1 or 2 amino acids therefrom; and / or(ii) a light chain variable (VL) region comprising: light chain complementarity-determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 91, or a sequence differing in 1 or 2 amino acids therefrom,LCDR2 having the amino acid sequence of SEQ ID NO: 92, or a sequence differing in 1 or 2 amino acids therefrom, andLCDR3 having the amino acid sequence of SEQ ID NO: 93, or a sequence differing in 1 or 2 amino acids therefrom; or(b) (i) a VH region comprising:HCDR1 having the amino acid sequence of SEQ ID NO: 95, or a sequence differing in 1 or 2 amino acids therefrom,HCDR2 having the amino acid sequence of SEQ ID NO: 96, or a sequence differing in 1 or 2 amino acids therefrom, andHCDR3 having the amino acid sequence of SEQ ID NO: 97, or a sequence differing in 1 or 2 amino acids therefrom; and(ii) a VL region comprising:LCDR1 having the amino acid sequence of SEQ ID NO: 99, or a sequence differing in 1 or 2 amino acids therefrom,LCDR2 having the amino acid sequence of SEQ ID NO: 100, or a sequence differing in 1 or 2 amino acids therefrom, andLCDR3 having the amino acid sequence of SEQ ID NO: 101, or a sequence differing in 1 or 2 amino acids therefrom.

[0036] In some embodiments, the antibody or antigen binding fragment thereof comprises aVH comprising HCDR1, HCDR2, and HCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprise amino acid sequences that collectively differ by no more than two amino acid residues from the sequences of:(a) SEQ ID NO: 87, SEQ ID NO: 88, and SEQ ID NO: 89, respectively; or(b) SEQ ID NO: 95, SEQ ID NO: 96, and SEQ ID NO: 97, respectively.

[0037] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising LCDR1, LCDR2, and LCDR3, wherein the LCDR1, LCDR2, and LCDR3 comprise amino acid sequences that collectively differ by no more than two amino acid residues from the sequences of:(a) SEQ ID NO: 91, SEQ ID NO: 92, and SEQ ID NO: 93, respectively; or(b) SEQ ID NO: 99, SEQ ID NO: 100, and SEQ ID NO: 101, respectively.

[0038] In some embodiments, the antibody or antigen binding fragment thereof comprises(a) ((ii)) a VH region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 87,HCDR2 comprising the amino acid sequence of SEQ ID NO: 88, andHCDR3 comprising the amino acid sequence of SEQ ID NO: 89; and(ii) a VL region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 91,HCDR2 comprising the amino acid sequence of SEQ ID NO: 92, andHCDR3 comprising the amino acid sequence of SEQ ID NO: 93; or(a) (i) a VH region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 95, HCDR2 comprising the amino acid sequence of SEQ ID NO: 96, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and (ii) a VL region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 99, HCDR2 comprising the amino acid sequence of SEQ ID NO: 100, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 101.

[0039] In some embodiments, the antibody or antigen binding fragment thereof comprises (a) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 86, and / or a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 90; or(b) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 94, and / or a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 98.

[0040] In some embodiments, the antibody or antigen binding fragment thereof comprises(a) a VH region having the amino acid sequence of SEQ ID NO: 86, and / or a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 90; or(b) a VH region having the amino acid sequence of SEQ ID NO: 94, and / or a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 98.

[0041] In some embodiments, the antibody or antigen binding fragment thereof is a Fab.

[0042] In some embodiments, the Fab comprises a heavy chain (HC) that comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 102 or SEQ ID NO: 103; a light chain (EC) that comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of having the amino acid sequence of SEQ ID NO: 104.

[0043] In some embodiments, the target protein is IgA.

[0044] In some embodiments, IgA binding TB comprises or is a peptide comprising or having an amino acid sequence that has at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 52-85. In some embodiments, IgA binding TB comprises or is a peptide comprising or having an amino acid sequence that has at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 55. In some embodiments, TB comprises or is a peptide comprising or having an amino acid sequence selected from SEQ ID NOs: 52-85. In some embodiments, IgA binding TB comprises or is a peptide comprising or having an amino acid sequence of SEQ ID NO: 55.

[0045] In some embodiments, IgA binding TB comprises or is an antibody or an antigen binding fragment thereof, comprising(a) a VH region comprising:HCDR1 having the amino acid sequence of SEQ ID NO: 109, or a sequence differing in 1 or 2 amino acids therefrom,HCDR2 having the amino acid sequence of SEQ ID NO: 110, or a sequence differing in 1 or 2 amino acids therefrom, andHCDR3 having the amino acid sequence of SEQ ID NO: 111, or a sequence differing in 1 or 2 amino acids therefrom; and(b) a VL region comprising:LCDR1 having the amino acid sequence of SEQ ID NO: 114, or a sequence differing in 1 or 2 amino acids therefrom,LCDR2 having the amino acid sequence of SEQ ID NO: 115, or a sequence differing in 1 or 2 amino acids therefrom, andLCDR3 having the amino acid sequence of SEQ ID NO: 116, or a sequence differing in 1 or 2 amino acids therefrom.

[0046] In some embodiments, the antibody or antigen binding fragment thereof comprises(a) a VH region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 109, HCDR2 comprising the amino acid sequence of SEQ ID NO: 110, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 111; and(b) a VL region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 114, HCDR2 comprising the amino acid sequence of SEQ ID NO: 115, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 116.

[0047] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 108, and / or a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 113.

[0048] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH region having the amino acid sequence of SEQ ID NO: 108, and / or a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 113.

[0049] In some embodiments, the target protein is IgE.

[0050] In some embodiments, IgE binding TB comprises or is a peptide comprising or having an amino acid sequence that has at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 124-159 and 586- 588. In some embodiments, IgE binding TB comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% or 100% sequence identity to SEQ ID NO: 143 or SEQ ID NO: 159. In some embodiments, IgE binding TB comprises or is a peptide comprising or having an amino acid sequence selected from SEQ ID NOs: 124-159 and 586- 588. In some embodiments, IgE binding TB comprises or has an amino acid sequence of SEQ ID NO: 143 or SEQ ID NO: 159.

[0051] In some embodiments, IgE binding TB comprises or is an antibody or an antigenbinding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof is omalizumab, ligelizumab, quilizumab, MEDI4212, XmAb7195, or 8D6, or an antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof is omalizumab. In some embodiments, the antibody or antigen binding fragment thereof is ligelizumab. In some embodiments, the antibody or antigen binding fragment thereof binds IgE with a pH-dependent affinity. In some embodiments, the antibody or antigen binding fragment thereof comprises one or more sequences selected from SEQ ID NOs: 526-583.

[0052] In some embodiments, the target protein is IL-31.

[0053] In some embodiments, IL-31 binding TB comprises or is an antibody or an antigen binding fragment thereof, comprising(a) a VH region comprising:HCDR1 having the amino acid sequence of SEQ ID NO: 506, or a sequence differing in 1 or 2 amino acids therefrom,HCDR2 having the amino acid sequence of SEQ ID NO: 507 or 508, or a sequence differing in 1 or 2 amino acids therefrom, andHCDR3 having the amino acid sequence of SEQ ID NO: 509, or a sequence differing in 1 or 2 amino acids therefrom; and(b) a VL region comprising:LCDR1 having the amino acid sequence of SEQ ID NO: 514 or 515, or a sequence differing in 1 or 2 amino acids therefrom,LCDR2 having the amino acid sequence of SEQ ID NO: 516, or a sequence differing in 1 or 2 amino acids therefrom, andLCDR3 having the amino acid sequence of SEQ ID NO: 517, or a sequence differing in 1 or 2 amino acids therefrom.

[0054] In some embodiments, the antibody or antigen binding fragment thereof comprises(a) a VH region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 506,HCDR2 comprising the amino acid sequence of SEQ ID NO: 507 or 508, andHCDR3 comprising the amino acid sequence of SEQ ID NO: 509; and(b) a VL region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 514 or 515,HCDR2 comprising the amino acid sequence of SEQ ID NO: 516, andHCDR3 comprising the amino acid sequence of SEQ ID NO: 517.

[0055] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 510-513, and / or a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence deleted from SEQ ID NOs: 518-519.

[0056] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH region having the amino acid sequence of SEQ ID NO: 510-513, and / or a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 518-519.

[0057] In some embodiments, the antibody or antigen binding fragment thereof is an scFv. In some embodiments, the scFv comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 520-525.

[0058] In various embodiments, any of the disclosed TB may comprise or be a peptide, an antibody, or an antigen binding fragment, wherein the peptide, antibody, or antigen binding fragment is attached to L at an amino acid side chain comprising -NH2, -SH, or -OH. In some embodiments, the peptide, antibody, or antigen binding fragment is attached to L at a lysine (Lys), cysteine (Cys), or tyrosine (Tyr) residue.

[0059] In various embodiments, any of the disclosed TB may comprise or be a peptide, an antibody, or an antigen binding fragment, wherein the peptide, antibody, or antigen binding fragment is modified to comprise a reactive group. In some embodiments, the reactive group comprises an azide or alkyne group.

[0060] In some embodiments, a compound described above is capable of being internalized after contacting with a cell. In some embodiments, a compound described above is bound with the target protein. In some embodiments, a compound described above is capable of delivering the target protein into a cell.

[0061] In some embodiments, a compound described above is capable of delivering the target protein to late endosome or lysosome. In some embodiments, the delivery to late endosome or lysosome is preferable than delivery to Golgi, endoplasmic reticulum (ER), or endocytic recycling compartment (ERC).

[0062] In another aspect, provided are pharmaceutical compositions comprising a compound described above and a pharmaceutically acceptable carrier, diluent, or excipient.

[0063] In another aspect, provided are methods of delivering a target protein, comprisingcontacting a compound or pharmaceutical described above with the target protein. In some embodiments, the method delivers the target protein to late endosome or lysosome. In some embodiments, the target protein is delivered for targeted degradation.

[0064] In another aspect, provided are methods of enhancing degradation of a target protein, comprising contacting a compound or pharmaceutical described above with the target protein. In some embodiments, degradation of the target protein is enhanced relative to degradation of target protein in the absence of the compound or pharmaceutical described above. In some embodiments, the method is performed in vitro. In some embodiments, the method is performed in vivo. In some embodiments, contacting a compound or pharmaceutical described above with the target protein comprises administering an effective amount of the compound or pharmaceutical composition to a subject.

[0065] In another aspect, provided are methods of treating a disease or disorder associated with the target protein, comprising administering to a compound or pharmaceutical composition described above.

[0066] In some embodiments, any method disclosed herein may comprise multiple administrations of a compound or pharmaceutical composition described above. In some embodiments, the interval between two consecutive administrations is at least 1 week, at least2 weeks, at least 3 weeks, or at least 4 weeks. In some embodiments, the compound or pharmaceutical composition is administered no more frequent than once every week, once every 2 weeks, once every 3 weeks, or once every 4 weeks.BRIEF DESCRIPTION OF THE DRAWINGS

[0067] FIGs. 1A-1C show the increased uptake and degradation of anti-biotin IgG-Ax647 in the presence of biotin conjugated to ceramide in HEK293 cells. FIG. 1A is a schematic representation of experimental system. FIG. IB is representative SDS-PAGE gel images depicting IgG uptake in HEK293 cells incubated with anti-biotin IgG-Ax647, alone or with compounds TT5-control, TT5-C6, or TT5-C16, for 1 hour. FIG. 1C is representative SDS- PAGE images depicting IgG uptake and degradation in HEK293 cells incubated with anti- biotin IgG-Ax647, alone or with compound TT5-control, TT5-C6, or TT5-C16, for 1 hour, followed by post- incubation of 0.5, 1, 3, and 5 hours. Coomassie was used as loading control.

[0068] FIG. 2 shows the increased uptake and degradation of anti-biotin IgG-Ax647 in the presence of biotin conjugated to ceramide in MDCK-II cells. The representative SDS-PAGE images depict IgG uptake in MDCK-II cells incubated with anti-biotin IgG-Ax647, alone or with compound TT5-control, TT5-C6, TT5-C16, or TT5-FA16, for 1 hour, followed by post-incubation of 0.5, 1, 3, and 5 hours. Coomassie was used as loading control.

[0069] FIGs. 3 A and 3B show the increased uptake and degradation of human IgG-Ax488 in the presence of 4A conjugated to ceramide in HEK293 cells. FIG. 3A is a schematic representation of experimental system. FIG. 3B is representative SDS-PAGE images depicting IgG uptake and degradation in HEK293 cells incubated with human IgG-Ax488, alone or with compound 4A, 4A-TT3-C6, 4A-TT3-C12, 4A-TT3-C16, or 4A-TT3-C16:1, for 1 hour, followed by post- incubation of 1, 3, and 5 hours. Coomassie was used as loading control. HC: heavy chain; EC: light chain.

[0070] FIGs. 4A-4D show the increased uptake and lysosomal degradation of human IgG- Ax488 in the presence of 4A conjugated to ceramide in HEK293 cells. FIG. 4A is a schematic representation of experimental system. FIG. 4B is representative SDS-PAGE images depicting IgG uptake and degradation in HEK293 cells incubated with human IgG-Ax488 and compound 4A, 4A-TT3-C6, 4A-TT3-C12, or 4A-TT3-C16:1 for 1 hour, followed by post- incubation of 1, 3, and 5 hours. HEK293 cells were either pretreated with Bafilomicin A (BfA) to inhibit lysosomal degradation or not pretreated before incubation with human IgG-Ax488 and test compound. Degradation fragments were visible as low molecular weight fragments. Coomassie was used as loading control. FIG. 4C shows the quantification of normalized human IgG intensity over time based on the SDS-PAGE gels used for imaging in FIG. 4B. FIG. 4D shows IgG uptake and degradation induced by 4A-TT3-C12. 4A-TT3-C12 removed 85% of internalized IgG within 24 hrs.

[0071] FIGs. 5 A and 5B show the increased uptake and lysosomal degradation of human IgG- Ax488 in the presence of 4A conjugated to ceramide in HepG2 cells. FIG. 5A is representative SDS-PAGE images depicting IgG uptake and degradation in HepG2 cells incubated with human IgG-Ax488 and compound 4A, 4A-TT3-C6, 4A-TT3-C12, or 4A-TT3-C16:1 for 1 hour, followed by post-incubation of 1, 3, and 5 hours. HepG2 cells were either pretreated with BfA to inhibit lysosomal degradation or not pretreated before incubation with human IgG- Ax488 and test compound. Degradation fragments are visible as low molecular weight fragments. Coomassie was used as loading control. FIG. 5B shows the quantification of normalized human IgG intensity over time based on the SDS-PAGE gels used for imaging in FIG. 5 A. HC: heavy chain; EC: light chain.

[0072] FIG. 6A demonstrates the colocalization with lysosomes of internalized anti-biotin IgG-Ax647. Scale bar 50 um.

[0073] FIG. 6B shows that 4A-TT3-C12 induces IgG colocalization with lysosomal marker Lampl and increases IgG degradation after 5 hrs, which is prevented by the addition of alysosomal inhibitor.

[0074] FIGs. 7A-7H. Ceramide analogs: N-acyloxyacyl-ornitine (FIG. 7A); cerilipin (FIG. 7B); brominated mololipids, wherein R1and R2are each independently C14-20 fatty acid (FIG. 7C); iso-3-hydroxy heptadecanoic acid-containing lipid (FIG. 7D); lipstatin (FIG. 7E); N- stearoyl proline (FIG. 7F); volicitin (FIG. 7G); and N-acyl taurine (FIG. 7H).

[0075] FIG. 8 depicts GM1 oligosaccharide domain structure and replacement with approximated peptide-sugar linkers.

[0076] FIG. 9 A shows representative SDS-PAGE images and the corresponding quantification of normalized human IgG intensity over time, demonstrating that binders linked to ceramide moieties drive IgG uptake and degradation but not binders linked to a single acyl chain.

[0077] FIG. 9B depicts the quantification of normalized human IgG intensity based on the SDS-PAGE gels used for imaging, showing that a C12 ceramide-based conjugate induced IgG internalization the most strongly at all tested concentrations and demonstrating that the acyl chain length of the ceramide comprised in the conjugate affects the internalization efficiency.

[0078] FIG. 9C depicts the quantification of normalized human IgG intensity based on the SDS-PAGE gels used for imaging, showing that a conjugate comprising a negatively charged linker induced IgG degradation more strongly than the conjugate comprising a neutrally charged linker, and demonstrating that the linker characteristics and charges affect the degradation efficiency.

[0079] FIG. 9D shows representative SDS-PAGE images, depicting that a lysosome inhibitor, but not a proteasome inhibitor, prevented the IgG degradation induced by a ceramide-based IgG-binding protein degrader.

[0080] FIG. 9E shows representative SDS-PAGE images depicting the IgG uptake and degradation induced by a ceramide-based IgG-binding protein degrader in multiple cell types.

[0081] FIG. 9F shows representative SDS-PAGE images depicting the dose-dependent IgG uptake and degradation induced by additional ceramide-based IgG-binding protein degraders.

[0082] FIG. 10A and FIG. 10B are representative SDS-PAGE images depicting the ability of ceramide-based protein degrader 4A-TT3-C12 to induce the uptake and degradation of human and rabbit IgG but not rat IgG.

[0083] FIG. 11A and FIG. 11B depict the concentration of plasma human IgG in rat over time following the intravenous administration of a ceramide-based IgG-binding protein degrader.

[0084] FIG. 12A and FIG. 12B depict the plasma concentrations of a ceramide -based IgG- binding protein degrader (FIG. 12A) and human IgG (FIG. 12B) in rat over time following intravenous (IV) or subcutaneous (SC) administration of the ceramide-based IgG-bindingprotein degrader.

[0085] FIG. 13A and FIG. 13B depict the plasma concentrations of a ceramide -based IgG- binding protein degrader (FIG. 13A) and human IgG (FIG. 13B) in rat over time following SC administration of the ceramide-based IgG-binding protein degrader.

[0086] FIG. 14A and FIG. 14B depict the plasma concentrations of a ceramide -based IgG- binding protein degrader (FIG. 14A) and human IgG (FIG. 14B) in rabbit over time following IV administration of the ceramide-based IgG-binding protein degrader.

[0087] FIG. 15A shows representative SDS-PAGE images and the corresponding quantification of normalized human IgA intensity over time, demonstrating IgA uptake and degradation induced by an IgA-binding peptide conjugated to a ceramide.

[0088] FIG. 15B shows representative SDS-PAGE images depicting the IgA uptake and degradation induced by the ceramide-based IgA-binding protein degrader is dose-dependent.

[0089] FIG. 15C shows representative SDS-PAGE images and the corresponding quantification of normalized human IgA intensity over time, demonstrating that the potency of IgA uptake and degradation induced by a ceramide-based IgA-binding protein degrader is dependent on the linker comprised in the degrader.

[0090] FIG. 15D shows representative SDS-PAGE images and the corresponding quantification of normalized anti-human IgA / IgG intensity over time, demonstrating that the ceramide-based IgA-binding protein degrader is capable of internalizing immune complexes.

[0091] FIG. 16A and FIG. 16B are representatives of SDS-PAGE images and the corresponding quantification of normalized human IgE intensity over time, demonstrating IgE uptake and degradation induced by ceramide -based IgE-binding protein degrader.

[0092] FIG. 16C depict the concentration of plasma human IgE in mice over time following the intravenous administration of the ceramide-based IgE-binding protein degrader.

[0093] FIG. 17 shows representative SDS-PAGE images depicting human IgG4 uptake and degradation induced by ceramide-based IgG4-binding protein degrader.

[0094] FIG. 18A shows non-limiting examples target binding moieties capable of binding interleukin- 1 (IL-1).

[0095] FIG. 18B shows non-limiting examples target binding moieties capable of binding interleukin-2 (IL-2).

[0096] FIG. 18C shows non-limiting examples target binding moieties capable of binding interleukin-6 (IL-6).

[0097] FIG. 18D shows non-limiting examples target binding moieties capable of binding interferon- y (IFN-γ).

[0098] FIG. 18E shows non-limiting examples target binding moieties capable of binding interleukin-21 (IL-21) .

[0099] FIG. 18F shows non-limiting examples target binding moieties capable of binding interleukin-22 (IL-22).

[0100] FIG. 18G shows non-limiting examples target binding moieties capable of binding interleukin- 10 (IL- 10).

[0101] FIG. 18H shows non-limiting examples target binding moieties capable of binding interleukin-5 (IL-5).

[0102] FIG. 181 shows non-limiting examples target binding moieties capable of binding interleukin- 8 (IL-8).

[0103] FIG. 18J shows non-limiting examples target binding moieties capable of binding cholinesterase (ChE).

[0104] FIG. 18K shows non-limiting examples target binding moieties capable of binding carboxypeptidase B2 (CPB2).

[0105] FIG. 18L shows non-limiting examples target binding moieties capable of binding neutrophil elastase (NE).

[0106] FIG. 18M shows non-limiting examples target binding moieties capable of binding coagulation factor Xa (Factor Xa).

[0107] FIG. 18N shows non-limiting examples target binding moieties capable of binding coagulation factor XI (Factor XI).

[0108] FIG. 180 shows non-limiting examples target binding moieties capable of binding coagulation factor XII (Factor XII).

[0109] FIG. 18P shows non-limiting examples target binding moieties capable of binding coagulation factor XIII (Factor XIII).

[0110] FIG. 18Q shows non-limiting examples target binding moieties capable of binding Prothrombin.

[0111] FIG. 18R shows non-limiting examples target binding moieties capable of binding coagulation factor VII (Factor VII).

[0112] FIG. 18S shows non-limiting examples target binding moieties capable of binding coagulation factor IX (Factor IX).

[0113] FIG. 18T shows non-limiting examples target binding moieties capable of binding fibroblast growth factor 1 (FGF1).

[0114] FIG. 18U shows non-limiting examples target binding moieties capable of binding fibroblast growth factor 2 (FGF2).

[0115] FIG. 18V shows non-limiting examples target binding moieties capable of binding fibronectin (FN1).

[0116] FIG. 18W shows non-limiting examples target binding moieties capable of binding kallikrein 1 (KLK1).

[0117] FIG. 18X shows non-limiting examples target binding moieties capable of binding plasma kallikrein (KLKB1).

[0118] FIG. 18Y shows non-limiting examples target binding moieties capable of binding matrix metalloproteinase- 1 (MMP1).

[0119] FIG. 18Z sows non-limiting examples target binding moieties capable of binding Macrophage migration inhibitory factor (MIF), also known as glycosylation inhibiting factor (GIF), L-dopachrome isomerase, or phenylpyruvate tautomerase.

[0120] FIG. 18AA shows non-limiting examples target binding moieties capable of binding transforming growth factor beta 2 (TGF-β2, TGFB2).

[0121] FIG. 18BB shows non-limiting examples target binding moieties capable of binding thrombospondin 1 (TSP1, TSP-1, THBS1).

[0122] FIG. 18CC shows non-limiting examples target binding moieties capable of binding CD40 Ligand (CD40L).

[0123] FIG. 18DD shows non-limiting examples target binding moieties capable of binding urokinase or urokinase-type plasminogen activator (UP A, uPA).

[0124] FIG. 18EE shows non-limiting examples target binding moieties capable of binding plasminogen activator, tissue type (tPA, TPA, PLAT).

[0125] FIG. 18FF shows non-limiting examples target binding moieties capable of binding plasminogen (PLG).

[0126] FIG. 18GG shows non-limiting examples target binding moieties capable of binding plasminogen activator inhibitor- 1 (PALI), endothelial plasminogen activator inhibitor or serpin El.

[0127] FIG. 18HH shows non-limiting examples target binding moieties capable of binding placental growth factor (PGF).

[0128] FIG. 1811 shows non-limiting examples target binding moieties capable of binding phospholipases A2, for example type IB or group IB (PLA2, PA21B, PLA2G1B, PLA2-IB).

[0129] FIG. 18JJ shows non-limiting examples target binding moieties capable of binding phospholipases A2, for example type IIA or group IIA (PLA2, PLA2A, PA2IIA, PLA2G2A, PLA2-IIA).

[0130] FIG. 18KK shows non-limiting examples target binding moieties capable of bindingcomplement factor B.

[0131] FIG. 18LL shows non-limiting examples target binding moieties capable of binding complement factor D.

[0132] FIG. 18MM shows non-limiting examples target binding moieties capable of binding complement factor H.

[0133] FIG. 18NN shows non-limiting examples target binding moieties capable of binding complement component 5.

[0134] FIG. 1800 shows non-limiting examples target binding moieties capable of binding proprotein convertase subtilisin kexin 9 (PCSK-9).

[0135] FIG. 18PP shows non-limiting examples target binding moieties capable of binding transforming growth factor beta (TGF-β1).

[0136] FIG. 18QQ shows non-limiting examples target binding moieties capable of binding TNF-alpha.

[0137] FIG. 18RR shows non-limiting examples target binding moieties capable of binding vascular endothelial growth factor (VEGF).

[0138] FIG. 18SS shows non-limiting examples target binding moieties capable of binding C- C motif chemokine ligand 2 (CCL2).

[0139] FIG. 18TT shows non-limiting examples target binding moieties capable of binding prostate specific membrane antigen (PSMA).

[0140] FIG. 18UU shows non-limiting examples target binding moieties capable of binding lipoprotein lipase (LPL).

[0141] FIG. 19 shows non-limiting examples target binding moieties capable of binding immunoglobulin A (IgA).

[0142] FIG. 20 shows non-limiting examples target binding moieties capable of binding immunoglobulin G (IgG).

[0143] FIGs. 21A-21E show non-limiting examples target binding moieties capable of binding immunoglobulin E (IgE).DETAILED DESCRIPTION

[0144] The present application encompasses the insight current lysosomal protein degradation strategies based on cell receptors such as ASGPR are limited, e.g., by the receptor expressions and have drawbacks, including that the cell receptor (e.g., ASGPR) rapidly removes bifunctional molecules from circulation whether or not the target is bound, leading to short plasma half-life and limited duration of action. The present application also encompasses theinsight that GM1 and other sphingolipids are sorted in the endosome based on the structure of their ceramide domain and that lysosomal degradation strategies harnessing sphingolipid trafficking to late endosomes and lysosomes offer a new approach to degrade extracellular and membrane proteins and can provider broader therapeutic applicability and enhanced efficacy.Definitions

[0145] The terms “analog,” “variant,” and “derivative,” where used herein in connection with ceramide or sphingoid base, are used interchangeably and refer to a modified form of a ceramide or sphingoid base, e.g., comprising one or more substituents or having different lengths and / or different unsaturation degrees of the alkyl chain of the ceramide or sphingoid base.

[0146] As used herein, “antibody” refers to a polypeptide whose amino acid sequence includes immunoglobulins and fragments thereof which specifically bind to a designated antigen, or fragments thereof. Antibodies in accordance with the present invention may be of any type (e.g., IgA, IgD, IgE, IgG, or IgM) or subtype (e.g., IgAl, IgA2, IgGl, IgG2, IgG3, or IgG4). Those of ordinary skill in the art will appreciate that a characteristic sequence or portion of an antibody may include amino acids found in one or more regions of an antibody (e.g., variable region, hypervariable region, constant region, heavy chain, light chain, and combinations thereof). Moreover, those of ordinary skill in the art will appreciate that a characteristic sequence or portion of an antibody may include one or more polypeptide chains, and may include sequence elements found in the same polypeptide chain or in different polypeptide chains.

[0147] An “antigen-binding fragment” of an antibody, or an “antibody fragment,” comprises a portion of an intact antibody, which portion is still capable of antigen binding. In some embodiments, the antibody has a function in addition to that of antigen-binding, and an antigen-binding fragment retains that function. Typically, an antigen-binding fragment comprises the variable region of the antibody. In certain embodiments, papain digestion of antibodies produce two identical antigen-binding fragments, called “Fab” fragments, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire light chain along with the variable region domain of the heavy chain (VH), and the first constant domain of one heavy chain (CHI). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. In certain embodiments, pepsin treatment of an antibody yields a single large F(ab')2fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-bindingactivity and that is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CHI domain, including one or more cysteines from the antibody hinge region. Fab'-SH designates an Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2antibody fragments originally were produced as pairs of Fab' fragments having hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0148] A “complementarity determining region” (abbreviated “CDR”) is a region of hypervariability interspersed within regions that are more conserved, termed “framework regions” (abbreviated “FR”). CDRs can be determined by methods known in the art, such as under Rabat, AbM, Chothia, or any other CDR determination method. In some embodiments, the sequences of the framework regions are identical to the framework regions in human germline sequences. In some embodiments, the sequences of the framework regions are modified with respect to the human germline sequence.

[0149] As used herein, unless otherwise noted, the term “constant region,” when used in reference to an antibody or a fragment thereof (e.g., an IgGl, an IgG2, or an IgG4 constant region) is intended to encompass both wild type constant regions and variants (e.g., constant regions having at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity with a reference sequence of a wild- type constant region).

[0150] As used herein, “antibody mimetic” refers to any molecule that is capable of mimicking an antibody’s ability to bind an antigen, but which are not limited to antibody structures. Examples of antibody mimetics include, but are not limited to, Affibodies, Affilins, Affimers, Afftins, Alphabodies, Anticalins, avimers, Centyrins, DARPins, Fynomers, monobodies, nanobody, and nanoCLAMPs.

[0151] As used herein, “ceramide” refers to a compound comprising a sphingoid base moiety, optionally a fatty acid moiety, and optionally a sugar moiety. In some embodiments, the sphingoid base moiety comprises a terminal hydroxyl group (i.e., a hydroxyl group at carbon 1). In some embodiments, the terminal hydroxyl group is functionalized, e.g., acetylated. In some embodiments, the terminal hydroxyl group is linked (e.g., covalently linked) to another molecule or moiety. In some embodiments, ceramides comprise a fatty acid moiety. In some embodiments, the fatty acid moiety is linked (e.g., covalently linked) to an amino group (e.g., at carbon 2) comprised in the sphingoid base moiety. In some embodiments, ceramides do not comprise a fatty acid moiety. In some embodiments, ceramides comprise a sugar moiety (also referred to as “glycoceramide”), e.g., a simple sugar moiety. In some embodiments, the sugarmoiety is linked (e.g., covalently linked) to a hydroxyl group (e.g., terminal hydroxyl group) comprised in the sphingoid base moiety. In some embodiments, ceramides do not comprise a sugar moiety. In some embodiments, ceramides comprise a serine residue. In other embodiments, ceramides comprise an amino acid residue other than a serine residue, such as an ornithine residue, a tyrosine residue, a glycine residue, a leucine residue, a proline residue, a glutamine residue, or a taurine residue. In some embodiments, ceramides may be substituted at one or more positions with one or more functional groups (also referred to as “ceramide derivatives”). In some embodiments, substitution(s) may be within the sphingoid base moiety, the fatty acid moiety, and / or the sugar moiety.

[0152] As used here, “ceramide analog” has the ordinary and customary meaning understood by persons of ordinary skill in the art. Nonlimiting examples of ceramide analogs include: 2- hydroxy-ceramide, diene-deoxy-ceramide, dihydroceramide, dihydroceramide phosphate, o- acyl-ceramide, ceramide phosphate, sphinganine, and methyl-sphingosine. In some embodiments, ceramide analogs are non- serine-based, i.e., the sphingoid base comprised in the ceramide analog comprises a non-serine backbone. For example, ceramide analogs may comprise an amino acid backbone containing o ithine (e.g., N-acyloxyacyl-ornitine or bacterial cerilipin, as described in Kawai et al., FEMS Immunol Med Microbial 1999, 23, 67 and Tahara et al., Agric Biol Chem 1976, 40, 243, incorporated herein by reference), tyrosine ( e.g., Brominated mololipids from sea sponge as described in Ross et al., J Nat Prod 2000, 63, 501, incorporated herein by reference), glycine (e.g., iso-3-hydroxy heptadecanoic acid- containing lipid from Cytophaga johnsonae, as described in Kawazoe et al., J Bacterial 1991, 173, 5470, incorporated herein by reference), leucine ( e.g., Lipstatin, which is an inhibitor of pancreatic protease, as described in Weibel et al., J Antibiot 1987, 1081, incorporated herein by reference), proline ( e.g., N-stearoyl praline, as described in Sivasamy et al., JAOCS 2001, 78, 897, incorporated herein by reference), glutamine (e.g., Volicitin, N-(17- hydroxylinolenoyl)-! -glutamine, as described in Pare et al., PNAS 1998, 95, 13971, incorporated herein by reference) or taurine (e.g., N-acyl taurine, as described in Saghatelian et al., Biochemistry 2006, 45, 9007, incorporated herein by reference). Non-limiting, exemplary structures of these ceramide analogs are provided in FIGs. 7A-7H.

[0153] As used herein, a “fatty acid” is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. The length and the unsaturation degree of the aliphatic chain may vary. For example, the aliphatic chain may have a length of between 0-30 carbons (C0-C30), for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbons. The aliphatic chain may comprise one or moreunsaturated bonds, such as double bonds, between backbone carbons. The aliphatic chain may be substituted at one or more positions with one or more functional groups. In some embodiments, a fatty acid may be referred to as CX:Y, wherein X is the length of the aliphatic chain (including the carboxylic acid carbon) (also referred to as the “number of backbone carbons”), and Y is the number of double bonds comprised in the aliphatic chain between the backbone carbons (also referred to as the “number of backbone double bonds”). For example, a fatty acid with 20 backbone carbons and 1 backbone double bond may be referred to as “C20:l fatty acid.” In some embodiments, fatty acids of the disclosure comprise one or more backbone double bonds. Each backbone double bond is independently a cis-double bond or a trans-double bond.

[0154] As used herein, the term “half-life” refers to a pharmacokinetic property of a molecule (e.g., a compound comprising a target binding moiety and a ceramide moiety disclosed herein). Half-life can be expressed as the time required to eliminate through biological processes (e.g., metabolism, excretion, accelerated blood clearance, etc.) fifty percent (50%) of a known quantity of the molecules in vivo, following their administration, from the subject’s body (e.g., human patient or other mammal) or a specific compartment thereof, for example, as measured in serum, i.e., circulating half-life, or in other tissues. In general, an increase in half-life results in an increase in mean residence time (MRT) in circulation for the payload molecule administered.

[0155] As used herein, the term “moiety” refers to a portion or fragment of a molecule that can be included as a part of other molecules. For example, a “fatty acid moiety” refers to any portion of a fatty acid that can be included as a part of, e.g., a ceramide. In some embodiments, a moiety may be functionalized to comprise a reactive group (e.g., a reactive group described herein).

[0156] As used herein, the phrase “reference level” generally refers to a level considered “normal” for comparison purposes, e.g., a level of an appropriate control. For example, in the context of the excessive amount of a protein, a “reference level” may refer to the level of the amount of the protein present in a healthy subject. A reference level may be determined contemporaneously or may be predetermined, e.g., known or deduced from past observations.

[0157] The term “sphingoid base” or “sphingoid backbone” as used herein refers to a compound or compound backbone comprising an aliphatic chain that comprises an amino group, typically at carbon 2 (C2), and one or more hydroxyl groups. In some embodiments, the sphingoid base comprises a hydroxyl group at carbon 1 (C1) of the aliphatic chain. In some embodiments, the sphingoid base comprises a hydroxyl group at carbon 3 (C3) of the aliphaticchain. In some embodiments, the sphingoid base comprises a hydroxyl group at both C1 and C3 of the aliphatic chain. In some embodiments, the sphingoid comprises an amino group at C2 and a hydroxyl group at both C1 and C3 of the aliphatic chain. In certain such embodiments, the sphingoid base may be synthesized from serine and a fatty acyl-CoA comprising the corresponding aliphatic chain (such sphingoid base may therefore be referred to as “serine- based” or having a “serine backbone”). In some embodiments, the sphingoid base may be synthesized from an amino acid other than serine and a fatty acyl-CoA (also referred to “non- serine-based” or having a “non-serine backbone”). In some embodiments, the hydroxyl group (e.g., the hydroxyl group and C1 and / or C3) may be functionalized, e.g., acetylated. The length, unsaturation degree, and branching level of the aliphatic chain comprised in sphingoid base may vary. In some embodiments, the aliphatic chain may have a length of between 4-40 carbons (C4-C40), for example, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, or C40.In some embodiments, the aliphatic chain may be saturated. In some embodiments, the aliphatic chain may comprise one or more unsaturated bonds. In some embodiments, the aliphatic chain comprises one or more double bonds. In some embodiments, the aliphatic chain comprises one or more triple bonds. In some embodiments, the aliphatic chain may be linear. In some embodiments, the aliphatic chain may be branched. In some embodiments, the aliphatic chain may be substituted at one or more positions with one or more functional groups. Nonlimiting examples of sphingoid bases include 6-hydroxysphingosine, phyto sphingosine (PHS), sphingadienine, sphinganine, sphingosine, and acetylated derivatives thereof.

[0158] The term “sphingolipid” refers to a compound that comprises or is constituted by a sphingoid base moiety and optionally a fatty acid moiety, which is covalently linked to an amino group comprised in the sphingoid base moiety through an amide bond. In some embodiments, hydroxyl group(s) comprised in the sphingoid base moiety may be linked (e.g., covalently linked) to another molecule, e.g., aa sugar, a phosphocholine, or a phosphoethanoamine. Nonlimiting examples of sphingolipids include ceramides, glucosylceramides (cerebrosides), inositol phosphorylceramides, mannosylinositol phosphorylceramides, and manno syldiinositol phosphorylceramides.

[0159] “Sugar” refers to any natural or unnatural monosaccharide, disaccharide, oligosaccharides, or polysaccharide. In certain embodiments, a “simple sugar” as used herein refers to a monosaccharide, e.g., glucose, fructose, and galactose.

[0160] As used herein, the term “subject” refers to a human or non-human animal (e.g., a mammal).

[0161] As used herein, the term “target binding moiety” refers to any molecule or any part of a molecule that is capable of binding to a given target.

[0162] As used herein, the phrases “therapeutically effective amount” and “effective amount” are used interchangeably and refer to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the type of disease, disease state, age, sex, and / or weight of the individual, and the ability of an immunoconjugate (or pharmaceutical composition thereof) to elicit a desired response in the individual. An effective amount may also be an amount for which any toxic or detrimental effects of the immunoconjugate or pharmaceutical composition thereof are outweighed by therapeutically beneficial effects.

[0163] As used herein, to “treat” a condition or “treatment” of the condition (e.g., the conditions described herein such as cancer) is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition (e.g., of a primary cancer and / or of a secondary metastases); delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.

[0164] As used herein, the term “variant” in the context of polynucleotides or polypeptides refers to a polynucleotide or polypeptide with a sequence differing from that of a reference polynucleotide or polypeptide, but retaining essential properties of the parental polynucleotide or polypeptide. Generally, variant polynucleotide or polypeptide sequences are overall closely similar, and, in many regions, identical to the parental polynucleotide or polypeptide. For instance, a variant polynucleotide or polypeptide may exhibit at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98% at least 99%, or at least 99.5% sequence identity compared to the parental polynucleotide or polypeptide.

[0165] The terms “a” and “an,” as used herein, mean “one or more” and include the plural unless the context is inappropriate.

[0166] As used herein, the term “about” or “approximately,” when used in reference to a quantitative value, includes the recited quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” or “approximately” refers to a ±10% variation from the recited quantitative value, unless otherwise indicated or inferred from the context.

[0167] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive and covers both “or” and “and.”

[0168] The term “and / or” where used herein is to be taken as specific disclosure of each of the specified features or components with or without the other.

[0169] The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”) unless otherwise noted. The term “consisting of’ is to be construed as close-ended.Compounds

[0170] Provided herein are compounds comprising a target binding moiety and a ceramide moiety. In some embodiments, the compound further comprises a linker. In some embodiments, the linker links the target binding moiety and the ceramide.

[0171] Compounds of the disclosure is generally represented by Formula (I):TB— L— LP (I) or a pharmaceutically acceptable salt thereof, wherein:TB is a target binding moiety capable of binding a target protein;L is a linker; andLP is a ceramide moiety.

[0172] In some embodiments, the ceramide moiety comprises a C0-C30fatty acid moiety.

[0173] In some embodiments, provided compounds are capable of internalization into a cell. Internalized materials in the early endosome can be sorted into various endosomal pathways such as the retrograde pathway, the recycling pathway, the transcytotic pathway (in polarized cells) and / or the lysosomal pathway. In some embodiments, internalized material is degraded after internalization into a cell. In some embodiments, provided compounds are sorted to the lysosome pathway.

[0174] In some embodiments, provided compounds are capable of delivering the target protein to late endosome or lysosome. In some embodiments, provided compounds preferably deliver the target protein to late endosome or lysosome rather than to Golgi, ER, or endocytic recycling compartment (ERC).

[0175] In some embodiments, provided compounds are capable of inducing degradation of the target protein. Accordingly, compounds of the present disclosure are also referred to as “protein degraders” or “degraders.” In some embodiments, provided compounds are capable of inducing targeted degradation of the target protein. “Targeted degradation” as used herein generally refers to induced degradation of one or more target proteins through the use ofcompounds (e.g., compounds of Formula (I)) that link a lysosome trafficking or targeting molecule to a target binding moiety capable of binding to the target protein such that the target protein is directed to lysosomal degradation. As used herein, a “lysosome trafficking or targeting molecule” is a molecule which, upon being linked to the target binding moiety of a disclosed compound, shuttles the compound and the target protein bound by the target binding moiety to the lysosome within a cell. The target protein is subsequently degraded by lysosomal enzymes, e.g., acid hydrolases. This way, provided compounds target the target protein for degradation, which targeting is useful in a variety of in vitro and in vivo applications.I. Target Proteins

[0176] In various embodiments, target proteins of the present disclosure are extracellular proteins. The extracellular protein may be any extracellular protein that is desired for targeted degradation, e.g., via lysosomal degradation pathway. For example, in some embodiments, the extracellular protein may be a ligand for a cell surface receptor, an antibody, a secreted protein, a cholesterol carrier, a toxin, a chemokine or cytokine, a hormone, or an allergen.

[0177] In various embodiments, target proteins of the present disclosure are membrane proteins. The membrane protein may be any membrane protein that is desired for targeted degradation, e.g., via lysosomal degradation pathway, on any cell. For example, in some embodiments, the membrane protein may be a cell surface receptor, a membrane transport protein, a membrane enzyme, or a cell adhesion molecule. In some embodiments, the membrane protein may be on a tumor cell or an immune cell.

[0178] In some embodiments, target proteins of the present disclosure may modulate or are involved in biological pathways of a disease or disorder. In some embodiments, the disease or disorder is associated with the excessive amount of the target protein compared to a reference level.

[0179] In certain embodiments, a target protein of the present disclosure is not druggable in the classic sense in that it does not have a binding pocket or an active site that can be inhibited or otherwise bound, and cannot be easily allosterically controlled. In another embodiment, a target protein of the present disclosure is druggable in the classic sense, yet for therapeutic purposes, degradation of the protein is preferred to inhibition. In various embodiments, a target protein is recruited with a target binding moiety capable of binding (e.g., specifically binding) the target protein.

[0180] In certain embodiments, a target protein of the present disclosure is a non-endogenous peptide or protein such as that from a pathogen or toxin. In another embodiment, a target proteinof the present disclosure can be an endogenous protein, e.g., an endogenous protein that mediates a disorder. An endogenous protein can be either the normal form of the protein or an aberrant form. For example, a target protein can be an extracellular mutant protein, or a protein, for example, where a partial or full gain-of-function or loss-of-function is encoded by nucleotide polymorphisms. Accordingly, in some embodiments, compounds of the present disclosure are capable of inducing targeted degradation of an aberrant form and not the normal form of a target protein.

[0181] In some embodiments, a target protein of the present disclosure is immunoglobulin G (IgG), IgG4, IgA, IgE, IgM, interleukin 31 (IL-31), fibroblast growth factor 23 (FGF23), transthyretin (TTR), interferon-gamma (IFN-γ), or thymic stromal lymphopoietin (TSLP). In some embodiments, a target protein of the present disclosure is IgG. IgG can be divided into 4 distinct subclasses (IgGl, IgG2, IgG3, and IgG4). IgG mediates a range of autoimmune, infectious, and metabolic diseases. In addition, overexpression of IgG4 is associated with IgG4-related diseases, which generally include multiple organs, and disorders, including type 1 autoimmune pancreatitis, interstitial nephritis, Riedel’s thyroiditis, storiform fibrosis, Mikulicz’s disease, Kiittner’ s tumor, inflammatory pseudotumors (in various sites of the body), mediastinal fibrosis, retroperitoneal fibrosis (Ormond’s disease), aortitis and periaortitis, proximal biliary strictures, idiopathic hypocomplementemic tubulointerstitial nephritis, multifocal fibrosclerosis, pachymeningitis, pancreatic enlargement, tumefactive lesions, pericarditis, rheumatoid arthritis (RA), inflammatory bowel disease, multiple sclerosis, myasthenia gravis, ankylosing spondylitis, primary Sjogren’s syndrome, psoriatic arthritis, systemic lupus erythematosus (SLE), sclerosing cholangitis, IgG monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), melanoma, bullous pemphigoid, Goodpasture disease, encephalitis, thrombotic thrombocytopenic purpura, immune thrombocytopenia, chronic inflammatory polyneuropathy, limbic encephalitis, neuromyotonia, Morvan syndrome, pemphigus foliaceus, pemphigus vulgaris, REM and non- REM parasomnia, and membranous nephropathy, multiple sclerosis, hyperthyroid Grave’s disease, epidermolysis bullosa acquisita, pemphigoid gestationis, anti-p200 pemphigoid, and paraneoplastic pemphigus, among others. Targeted degradation of IgG can be achieved through the use of compounds of the present disclosure (e.g., compounds of Formula (I)) that comprise a target binding moiety capable of binding IgG.

[0182] In some embodiments, a target protein of the present disclosure is immunoglobulin A (IgA). IgA can be divided into 2 subclasses, IgAl and IgA2. IgA mediates a range of autoimmune and immune-mediated disorders , including IgA nephropathy (also known asBerger's disease), celiac disease, Crohn's disease, Henoch-Sconiein purpura (HSP) (also known as IgA vasculitis), liner IgA bullous dermatosis, IgA pemphigus, dermatitis herpetiformis, inflammatory bowel disease (IBD), Sjogren's syndrome, ankylosing spondylitis, alcoholic liver cirrhosis, acquired immunodeficiency syndrome, IgA multiple myeloma, a-chain disease, IgA monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), and linear IgA bullous dermatosis, among others. Targeted degradation of IgA can be achieved through the use of compounds of the present disclosure (e.g., compounds of Formula (I)) that comprise a target binding moiety capable of binding IgA. In some embodiments, the target protein is IgAl. In some embodiments, the target protein is galactose-deficient IgAl (Gd- IgAl). In some embodiments, the target protein is IgA2.

[0183] In some embodiments, a target protein of the present disclosure is immunoglobulin E (IgE). IgE is a strong mediator of allergic disease, including but not limited to, atopic asthma, allergic rhinitis, atopic dermatitis, IgE-mediated food allergy, IgE-mediated animal allergies, allergic conjunctivitis, allergic urticaria, anaphylactic shock, nasal polyposis, keratoconjunctivitis, mastocytosis, and eosinophilic gastrointestinal disease, bullous pemphigoid, chemotherapy induced hypersensitivity reaction, seasonal allergic rhinitis, interstitial cystitis, eosinophilic esophagitis, angioedema, acute interstitial nephritis, atopic eczema, eosinophilic bronchitis, chronic obstructive pulmonary disease, gastroenteritis, hyper- IgE syndrome (Job's Syndrome), IgE monoclonal gammopathy, and monoclonal gammopathy of undetermined significance (MGUS), among others.

[0184] In some embodiments, a target protein of the present disclosure is IgM or an anti-MAG IgM autoantibody. Myelin-associated glycoprotein (MAG) is a transmembrane glycoprotein that plays a role in glial-axonal interactions in the nervous system. In some patients, IgM anti- MAG antibodies develop leading to neuropathy. Antibody levels can be as high as four-fold over normal, leading to potential nephropathy. Lowering levels of anti-MAG antibodies is associated with clinical response in polyneuropathy.

[0185] In some embodiments, a target protein of the present disclosure is interleukin 31 (IL- 31). IL-31 is an inflammatory cytokine that helps trigger cell-mediated immunity against pathogens. IL-31 is preferentially produced by Th2-cells. IL-31 sends signals through a heterodimeric receptor complex (IL-31 R or IL31 R) comprising the interleukin 31 receptor alpha (IL-31 RA or IL31 RA) and the oncostatin M receptor (OSMR), expressed in immune and epithelial cells. Binding of IL-31 to this receptor complex results in activation of the JAK / STAT and PI3K / AKT signal transduction pathways, and also activates different MARK pathways (ERK, p38, and INK). IL-31 is implicated in various chronic inflammatory diseases.For example, it has been found that IL-31 over-expression in mice results in dermatitis-like symptoms, see, Dillon, et al, Nature Immunol. 5 (2004)752-760. Furthermore, in many chronic inflammatory diseases, such as for example in atopic dermatitis (AD), IL-31 mediates activation of nerve fibers within the skin of the patients resulting in an aggressive itch- phenotype, which exacerbates the symptoms of these diseases upon patient scratching, see for example Oetjen et al., Cell 171 (2017) 217-228. Scratching can lead to skin barrier disruption, access of microbial pathogens into the skin and further promotes inflammation at the site. Also, it has been found that IL-31 is implicated in allergic asthma, allergic rhinitis, inflammatory bowel diseases, malignancies and osteoporosis, see Bagci et al., J Allergy Clin Immunol. 141 (2018):858-866. Blockage of IL-31 / 1L-3 IRA- signaling by anti-IL31RA antibodies, such as for example by the anti- IL-3 IRA antibody nemolizumab, is clinically proven to be effective at reducing itch in patients suffering from AD, see Ruzicka et al., N Engl J Med. 376 (2017): 2092-2093. Furthermore, the IL- 31 -neutralizing antibody BMS-981164 was developed to provide an effective targeted therapy for the treatment of chronic pruritic skin conditions, see Lewis et al, J Eur Acad of Dermatol Venereol. 31 (2017)142-150.

[0186] In some embodiments, a target protein of the present disclosure is FGF23. FGF23’s main function is to regulate the phosphate concentration in plasma. It does this by decreasing reabsorption of phosphate in the kidney, which means phosphate is excreted in urine. FGF23 is secreted by osteocytes in response to increased calcitriol and phosphate. FGF23 acts on the kidneys by decreasing the expression of NPT2, a sodium-phosphate cotransporter in the proximal tubule. FGF23 may also suppress 1- alpha-hydroxylase, reducing its ability to activate vitamin D and subsequently impairing calcium absorption.

[0187] Mutations in FGF23, which render the protein resistant to proteolytic cleavage, lead to its increased activity and to renal phosphate loss, in the human disease autosomal dominant hypopho sphatemic rickets. FGF23 can also be overproduced by some types of tumors, such as the benign mesenchymal neoplasm phosphaturic mesenchymal tumor causing tumor- induced osteomalacia, a paraneoplastic syndrome. Loss of FGF23 activity is thought to lead to increased phosphate levels and the clinical syndrome of familial tumor calcinosis. Mice lacking either FGF23 or the klotho enzyme age prematurely due to hyperphosphatemia. Over- expression of FGF23 has been associated with cardiovascular disease in chronic kidney disease including cardiomyocyte hypertrophy, vascular calcification, stroke, and endothelial dysfunction. FGF23 expression and cleavage is promoted by iron deficiency and inflammation. FGF23 is associated with at least 7 non-nutritional diseases of hypophosphatemia: aside from autosomal dominant hypopho sphatemic rickets, X-linkedhypophosphatemia, autosomal recessive hypopho sphatemic rickets type 1, 2, and 3, Tumor- induced osteomalacia and Hypopho sphatemic rickets with hypercalciuria.

[0188] In some embodiments, a target protein of the present disclosure is TTR. TTR is found in plasma and CSF. TTR transports the thyroid hormone thyroxine and retinol. Both wild-type and mutated TTR is known to misfold and aggregate into amyloid fibrils. Diseases associated with TTR amyloids include wild-type transthyretin amyloidosis, hereditary transthyretin amyloidosis, familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC).

[0189] In some embodiments, a target protein of the present disclosure is human interferon-y (ILN-y) (UniProtKB - Q14609 (Q14609_HUMAN)). IFN-γ is a immunoregulatory cytokine. IFN-γ has been implicated in a number of autoimmune disorders, including, but not limited to hemophagocytic lymphohistiocytosis (HLH), rheumatoid arthritis, multiple sclerosis (MS), corneal transplant rejection, and various autoimmune skin diseases such as psoriasis, alopecia areata, vitiligo, acne vulgaris, and others.

[0190] The Protein Data Bank website provides the crystal structure of IFN-γ searchable by 1HIG (Ealick, S. E., et al., Science 252, 1991, 698-702); as well as the crystal structure of IFN- y bound to various compounds searchable by 6E3K and 6E3L (Mendoza, J. L., et al., Nature, 2019, 567 56-60). Additionally, Randal et al., provides insight into the structure and activity of a monomeric interferon-y: a-chain receptor signaling complex (Randal, M., et al., Structure, 2001, 9(2), 155-163).

[0191] In some embodiments, a target protein of the present disclosure is TSLP. TSLP is an interleukin (IL)-2-like cytokine, alarmin, and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system. It shares a common ancestor with IL-7. TSLP was initially observed to have both pro-inflammatory and anti-inflammatory activity. It is now clear that this seemingly ambivalent action can actually be divided between the two transcript variants, with TSLP being pro-inflammatory and sfTSLP being anti-inflammatory. TSLP expression is linked to many disease states including asthma, inflammatory arthritis, atopic dermatitis, eczema, eosinophilic esophagitis and other allergic states. The factors inducing the activation of TSLP release are not clearly defined.

[0192] In some embodiments, a target protein of the present disclosure is human interleukin- 1 (IL-1) (UniProtKB - P01584 (IL1B_HUMAN)). IL-1 is a potent proinflammatory cytokine. Initially discovered as the major endogenous pyrogen, induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, B-cell activation and antibody production, and fibroblast proliferation and collagen production. IL-1 promotesThl7 differentiation of T-cells, and Synergizes with IL 12 / interleukin-12 to induce IFNG synthesis from T-helper 1 (Thl) cells. IL-1 has been implicated in a number of auto- inflammatory and autoimmune disorders, including, but not limited to, Blau syndrome, cryopyrin- associated periodic syndromes, familial Mediterranean fever, Majeed syndrome; mevalonate kinase deficiency syndrome, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, tumor necrosis factor receptor-associated periodic syndrome, Behcet’s Disease, Sjogren’s Syndrome, gout and chondrocalcinosis, periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (or PFAPA) syndrome, rheumatoid arthritis, Type 2 diabetes mellitus, acute pericarditis, Chronic interstitial lung diseases (ILDs), and Still’s Disease.

[0193] The Protein Data Bank website provides the crystal structure of IL-1 searchable by 9ILB (Yu, B., et al., Proc Natl Acad Sci USA, 1999, 96 103-108); 1I1B (Finzel, B. C., et al., J Mol Biol., 1989, 209 779-791); and 3 040 (Wang et al., NatTmmunoL, 2010, 11: 905-911); as well as the crystal structure of IL-I bound to various compounds searchable by 4G6J (Blech, M., et al., J Mol Biol., 2013, 425 94-111); 5BVP (Rondeau e al., MAbs, 2015, 7 1151-1160); and 3LTQ (Barthelmes, K., et al., J Am Chem. Soc., 2011, 133 808-819). Additionally, Guy et al., provides insight into the crystal structure of a small antagonist peptide bound to interleukin-1 receptor type 1 (Guy et al., The Journal OfBiological Chemistry, 2000, 275, 36927-36933).

[0194] In some embodiments, a target protein of the present disclosure is human interleukin- 2 (IL-2) (UniProtKB - P60568 (IL2_HUMAN)). IL- 2 is a potent pro-inflammatory cytokine. IL-2 has been implicated in host versus graft rejection and other autoimmune disorders.

[0195] The Protein Data Bank website provides the crystal structure of IL-2 searchable by 1M4C and 1M47 (Arkin, M. R., et al., Proc. Natl. Acad. Sci. U S A, 2003, 100: 1603-1608); as well as the crystal structure of IL- 2 bound to various compounds searchable by 4NEJ and 4NEM (Brenke, R., et al.); IQVN (Thanos, C. D., et al., Proc Natl Acad Sci USA, 2006, 103 15422-15427); 1PW6 and 1PY2 (Thanos, C. D., et al., J Am Chem Soc., 2003, 125 15280- 15281); INBP (Hyde, J., et al., Biochemistry, 2003, 42 6475-6483); and 1M48, 1M49, 1M4A, 1M4B, and 1M4C (Arkin, M. R., et al., Proc Natl Acad Sci USA, 2003, 100 1603-1608). Additionally, Stauber, D. J., et al, provides insight into the crystal structure of the IL- 2 signaling complex: paradigm for a heterotrimeric cytokine receptor (Stauber, D. J., et al., PNAS, 2006, 103(8), 2788-2793).

[0196] In some embodiments, a target protein of the present disclosure is human inteleukin-6 (IL-6) (UniProtKB - P05231 (IL6_HUMAN)). IL-6 is a cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response and plays an essential role in the final differentiation of B-cells into Ig-secreting cells. It is also involved inlymphocyte and monocyte differentiation. It also acts on B-cells, T-cells, hepatocytes, hematopoietic progenitor cells and cells of the CNS, and is required for the generation of T(H)17 cells. IL-6 has been implicated in a number Ofinflammatory diseases and cancers, including, but not limited to, Castleman’s disease, metastatic castration-associated prostate cancer, renal cell carcinoma, large-cell lung carcinoma, ovarian cancer, rheumatoid arthritis, asthma.

[0197] The Protein Data Bank website provides the crystal structure of IL-6 searchable by 1P9M (Boulanger, M. J., et al., Science, 2003, 300: 2101-2104); IALU (Somers et al., EMBO J., 1997, 16, 989-997); 1IL6 and 2IL6 (Xu, G. Y., et al., J Mol Biol., 1997, 268 468-481) and 1N26 (Varghese et al., ProcNatl Acad Sci U S A., 2002,99 15959-15964); as well as the crystal structure of IL-6 bound to various compounds searchable by 4CNI (Shaw, S., et al., Mabs, 2014, 6: 773); and 4NI7 and 4NI9 (Gelinas et al., J Biol Chem. 2014, 289(12), 8720-8734). Additionally, Gelinas et al., provides insight into the crystal structure of interleukin-6 in complex with a modified nucleic acid ligand (Gelinas, A. D., et al., J Biol Chem. 2014, 289(12), 8720-8734); and Somers et al., provides insight into the crystal structure of interleukin 6: implications for a novel mode of receptor dimerization and signaling.

[0198] In some embodiments, a target protein of the present disclosure is tau protein. The accumulation of tau in the brain causes aggregates that are associated with Alzheimer’s and other tauopathies.

[0199] In some embodiments, a target protein of the present disclosure is human interleukin-21 (IL-21) (UniProtKB - Q9HBE4 (IL21 HUMAN)). IL-21 is an Immunoregulatory cytokine. IL-21 has been implicated in a number of autoimmune disorders, including Sjogren’s syndrome, systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.

[0200] The Protein Data Bank website provides the crystal structure of IL-21 searchable by 20QP (Bondensgaard, K., et al., J Biol Chem., 2007, 28223326-23336); and 4NZD (Hamming et al.); as well as the crystal structure of IL-21 bound to various compounds searchable by 3TGX (Hamming, O. J., et al., J Biol Chem., 2012, 287(12), 9454-9460).

[0201] In some embodiments, a target protein of the present disclosure is human interleukin-22 (IL-22) (UniProtKB - Q9GZX6 (IL22_HUMAN)). IL-22 is a member of IL-IO family cytokines that is produced by many different types Oflymphocytes including both those of the innate and adaptive immune system. IL-22 has been implicated in a number of autoimmune disorders, including, but not limited to, graft versus host disease (GVHD), psoriasis, rheumatoid arthritis, atopic dermatitis, and asthma.

[0202] The Protein Data Bank website provides the crystal structure of IL-22 searchable by 1M4R (Nagem, R.A.P., et al., Structure, 2002, 10 1051-1062); as well as the crystal structure of IL- 22 bound to various compounds searchable by 3DGC (Jones, B. C. et al., Structure, 2008, 16 13331344).

[0203] In some embodiments, a target protein of the present disclosure is human interleukin- 10 (IL-10) (UniProtKB - P22301 (IL10_HUMAN)). IL-10 is an inflammatory cytokine. IL-10 has been implicated in tumor survival and protection against cytotoxic chemotherapeutic drugs.

[0204] The Protein Data Bank website provides the crystal structure of IL- 10 searchable by 2ILK (Zdanov, A et al., Protein Sci., 1996, 5 1955-1962); IILK (Zdanov, A. et al., Structure, 1995, 3 591-601); 2H24 (Yoon, S. L, et al., J Biol Chem., 2006, 281 35088-35096) and 3LQM (Yoon, S. L, et al., Structure, 2010, 18 63 8-648). Additionally, Zdanov, A., et al, provides insight into crystal structure of IL- 10 (Zdanov A., CurrentPharmaceutical design, 2004, 10, 3873-3884).

[0205] In some embodiments, a target protein of the present disclosure is human interleukin- 5 (IL-5) (UniProtKB - P05113 (IL5_HUMAN)). IL-5 is a cytokine that regulates eosinophil maturation, recruitment, and survival. IL-5 has been implicated in a number of allergic disorders, including, but not limited to, asthma, nasal polyposis, atopic dermatitis, eosinophilic esophagitis, hypereosinophilic syndrome, and Churg-Strauss syndrome.

[0206] The Protein Data Bank website provides the crystal structure of IL-5 searchable by IHUL (Milburn, M. V., Nature, 1993, 3 63, 172-176) and 3VA2 (Kusano et al., Protein Sci., 2012, 21(6), 850-864); as well as the crystal structure of IL- 5 bound to various compounds searchable by 1OBX and IOBZ (Kang, B. S., et al., Structure, 2003, 11, 845).

[0207] In some embodiments, a target protein of the present disclosure is human interleukin-8 (IL-8) (UniProtKB - P10145 (IL8_HUMAN)). IL-8 is a chemotactic factor that attracts neutrophils, basophils, and T-cells, but not monocytes. It is also involved in neutrophil activation. It is released from several cell types in response to an inflammatory stimulus. IL-8 has been implicated in the promotion of tumor progression, immune escape, epithelial- mesenchymal transition, and recruitment of myeloid-derived suppressor cells. Studies have demonstrated that high serum IL-8 levels correlate with poor prognosis in many malignant tumors. Preclinical studies have shown that IL-8 blockade may reduce mesenchymal features in tumor cells, making them less resistant to treatment.

[0208] The Protein Data Bank website provides the crystal structure of IL-8 searchable by 3IL8 (Baldwin, E. T., et al., ProcNatl Acad Sci USA, 1991, 88, 502-506); and 1IL8 and 2IL8 (Clore, G. M., et ak, Biochemistry, 1990, 29, 1689-1696); as well as the crystal structure of IL-8 boundto various compounds Searchableby IIEP and IILQ (Skelton, N, J., et al., Structure, 1999, 7, 157168); and IROD (Sticht, H., et al., Eur J Biochem., 1996, 235, 26-35); 4XDX (Ostrov et al.,) and 5WDZ (Beckamp, S., IBiomol NMR, 2017, 69, 111-121).

[0209] In some embodiments, a target protein of the present disclosure is human cholinesterase (UniProtKB - P06276 (CHLE_HUMAN)). Cholinesterase contributes to the inactivation of the neurotransmitter acetylcholine. Inhibition of cholinesterase results in increased levels of acetylcholine in the synaptic cleft (the space between two nerve endings). The main use of cholinesterase inhibitors is for the treatment of dementia in patients with Alzheimer’s disease. People with Alzheimer’s disease have reduced levels of acetylcholine in the brain. Cholinesterase inhibitors have been shown to have an effect on dementia symptoms such as cognition.

[0210] The Protein Data Bank website provides the crystal structure of cholinesterase searchable by IPOI and IPOQ (Nicolet, Y., et al., J Biol Chem., 2003, 278, 41141-41147); as well as the crystal structure of cholinesterase bound to various compounds searchable by IPOM and IPOP (Nicolet, Y., et al., J Biol Chem., 2003, 278, 41141-41147); 2J4C (Frasco, M. F., et al., FEBS J., 2007, 274 1849); 4BDT, 4BDS (Nachon, F., et al., Biochem J, 2013, 453, 393- 399); IGQR and IGQS (Bar-on, P., et al., Biochemistry, 2002, 41, 3555); 3DJY and 3DKK (Carletti, E. et al., J Am Chem Soc., 2008, 130, 16011-16020); 4AXB, 4BOO, 4B0P, and 4BBZ (Wandhammer, M., et al., Chem Biol Interact., 2013, 203, 19); 1DX6 (Greenblatt, H. M., et al., FEES Lett., 1999, 463 321); IGPK and IGPN (Dvir, H., et al., Biochemistry, 2002, 41, 10810); 6CQY (Bester, S. M., et al., Chem Res Toxicol., 2018, 31, 1405-1417 ); IXEV and IXEW (Nachon, F., et al., Biochemistry, 2005,44, 1154-1162); 2Y1K (Carletti, E., et al., Chem Res Toxicol., 2011,24, 797); and 2WIG, 2WIJ, 2WIK, 2WIE, and 2WSE (Carletti, E., et al., Biochem J., 2009, 421, 97-106). Additionally, Ahmad et al., provides insight into the isolation, crystal structure determination and cholinesterase inhibitory potential Ofisotalatizidine hydrate from delphinium denudatum (Ahmad H., et al., Journal Pharmaceutical Biology, 2016, 55(1), 680-686).

[0211] In some embodiments, a target protein of the present disclosure is human C-C motif chemokine ligand 2 (CCE2) (UniProtKB - Pl 3500 (CCE2_HUMAN)). CCE2 acts as a ligand for C-C chemokine receptor CCR2. CCE2 signals through binding and activation of CCR2 and induces a strong chemotactic response and mobilization of intracellular calcium ions. CCE2 exhibits a chemotactic activity for monocytes and basophils but not neutrophils or eosinophils. CCE2 has been implicated in the recruitment of monocytes into the arterial wall during the disease process of atherosclerosis.

[0212] In some embodiments, a target protein of the present disclosure is human carboxypeptidase B2 (UniProtKB - Q96IY4 (CBPB2_HUMAN)). Carboxypeptidase B2, also known as thrombin activatable fibrinolysis inhibitor (TAFIa), cleaves C-terminal arginine or lysine residues from biologically active peptides such as kinins or anaphylatoxins in the circulation thereby regulating their activities. It down-regulates fibrinolysis by removing C- terminal lysine residues from fibrin that has already been partially degraded by plasmin. Carboxypeptidase B2 has been implicated and targeted to inhibit thrombosis.

[0213] The Protein Data Bank website provides the crystal structure of carboxypeptidase B2 (also known as thrombin-activatable fibrinolysis inhibitor (TAFI)) searchable by 3D66 (Marx, P. F., et al., Blood, 2008, 112, 2803-2809); 3DGV (Anand, K., et al., JBC, 2008, 283, 29416- 29423); and IKWM (Barbosa Pereira, P.J., et al., J Mol Biol., 2002, 321, 537-547); as well as the crystal structure of TAFI bound to various compounds searchable by 3D67 (Marx, P. F., et al., Blood, 2008, 112, 2803-2809); 5HVF, 5HVG, 5HVH (Zhou, X., et al., J Thromb Haemost., 2016, 14, 1629-1638); and 3LMS (Sanglas, L., et al., J Thromb Haemost., 2010, 8, 1056-1065). Additionally, Schreuder et al., provides insight into the interaction of TAFI and anabaenopeptin, a highly potent inhibitor of TAFI (Schreuder, H., et al., Sci Rep., 2016, 6, 32958).

[0214] In some embodiments, a target protein of the present disclosure is human neutrophil elastase (UniProtKB - P08246 (ELNE_HUMAN)). Neutrophil elastase modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis. Neutrophil elastase has been implicated in a number of disorders, including lung disease, chronic obstructive pulmonary disease, pneumonia, respiratory distress, and acute lung injury (ALI), and cystic fibrosis, as well as chronic kidney disease.

[0215] The Protein Data Bank website provides the crystal structure of human neutrophil elastase bound to various compounds searchable by 3Q76 and 3Q77 (Hansen, G., et al., J.Mol.BioL, 2011, 409, 681-691); 5ABW (Von Nussbaum, et al., Bioorg Med Chem Lett., 2015, 25, 4370-4381); IBOF (Cregge, R. J., et al., J Med Chem., 1998, 41, 2461-2480); IH1B (Macdonald, S.J.F., et al., J Med Chem., 2002, 45, 3878); 2Z7F (Koizumi, M., et al., J Synchrotron Radiat., 2008, 15 308311); 5A09, 5A0A, 5A0B, and 5A0C (Von Nussbaum, F., et al., Chem Med Chem., 2015, 10, 1163-1173); 5A8X, 5A8Y and 5A8Z (VonNussbaum, F., et al., ChemMedChem., 2016, 11, 199206); IHNE (Navia, M. A., et al., ProcNatl Acad Sci USA, 1989, 86, 7-11); 6F5M (Hochscherf, J., et al., Acta CrystallogrF Struct Biol Commun., 2018, 74, 480-489); and 4WVP (Lechtenberg, B. C., et al., ACS Chem Biol., 2015, 10, 945- 951).

[0216] In some embodiments, a target protein of the present disclosure is human Factor Xa (UniProtKB - P00742 (FA10_HUMAN)). Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting. Factor X has been implicated in the development of deep vein thrombosis and acute pulmonary embolism, and the risk of stroke and embolism in people with nonvalvular atrial fibrillation.

[0217] The Protein Data Bank website provides the crystal structure of Factor Xa bound to various compounds searchable by 1G2L and 1G2M (Nar, H., et al., Structure, 2001, 9, 29-38); 2PR3 (Nan huis, C. A., et al., Chem Biol Drug Des., 2007, 69, 444-450); 2UWP (Young, R. J., et al., Bioorg Med Chem Lett., 2007, 17, 2927); 2VVC, 2VVV, 2VVU, 2VWL, 2VWM, 2VWN and 2VW0 (Zbinden, K. G., et al., Eur J Med Chem., 2009, 44, 2787); 4Y6D, 4Y71, 4Y7A, 4Y7B, 4zh8, 4ZHA (Convery, M.A. et al.); 4Y76, 4Y79, 2J94 and 2J95 (Chan, C., et al., J Med Chem., 2007, 50 1546-1557); IF AX (Brandstetter, H., et al., J Biol Chem., 1996, 271, 29988-29992 ); 2JKH (Salonen, L. M., et al., Angew Chem IntEdEngk, 2009, 48, 811); 2PHB (Kohrt, J. T., et al., Chem Biol Drug Des., 2007, 70, 100-112); 2W26 (Roehrig, S., et al., J Med Chem., 2005, 48, 5900); 2Y5F, 2Y5G and 2Y5H (Salonen, L.M., et al., Chemistry, 2012, 18, 213); 3Q3K (Yoshikawa, K., et al., Bioorg Med Chem Lett., 2011, 21, 2133-2140); 2BMG (Matter, K., et al., J Med Chem., 2005, 48, 3290); 2BOH, 2BQ6 2BQ7, and 2BQW (Nazare, M., et al., J Med Chem., 2005, 48, 4511); 2CJI (Watson, N.S., et al, Bioorg Med Chem Lett., 2006, 16, 3 784); 2J2U, 2J34, 2J3 8, 2J41 (Senger, S., et al., Bioorg Med Chem Lett.,2006, 16 5 731); 3IIT (Yoshikawa, K., et al., Bioorg Med Chem., 2009, 17 8221-8233); IEZQ, IFOR and IFOS (Maignan, S., et al., J Med Chem., 2000, 43, 3226-3232); IFJS (Adler, M., et al., Biochemistry, 2000, 39, 12534-12542 ); IKSN (Guertin, K. R., et al., Bioorg Med Chem Lett., 2002, 12, 1671-1674); INFU, INFW, INFX and INLY (Maignan, S., et al., J Med Chem., 2003, 46, 685-690); 2XBV, 2XBW, 2XBX, 2XBY, 2XC0, 2XC4 and 2XC5 (Anselm, L., et al., Bioorg Med Chem Lett., 2010, 20, 5313); 4A7I (Nazare, M., et al., Angew Chem Int Ed Engl., 2012, 51, 905); 4BTI, 4BTT and 4BTU (Meneyrol, L., et al., J Med Chem., 2013, 56, 9441); 3FFG, 3KQB, 3KQC, 3KQD and 3KQE (Quan, M. L., et al., Bioorg Med Chem Lett., 2010, 20, 13 73-13 77); 2P93, 2P94 and 2P95 (Qiao, J. X., et al., Bioorg Med Chem Lett.,2007, 17, 4419-4427); 1V3X (Haginoya, N., et al., J Med Chem., 2004, 47, 5167-5182); 2P16 (Pinto, D.J.P., et al., JMed Chem., 2007, 50, 5339-5356); 2RA0 (Lee, Y.K., et al., JMed Chem.,2008, 51, 282-297 ); 3SW2 (Shi, Y., et al., BioorgMed Chem Lett., 2011, 21, 7516-7521); 2VH6 (Young, R.J., et al., Bioorg Med Chem Lett., 2008, 18, 23); 2WYG and 2WYJ (Kleanthous, S., et al., BioorgMed Chem Lett., 2010, 20, 618); 2Y7X (Watson, N.S., et al.,Bioorg Med Chem Lett., 2011, 21, 1588); 2Y7Z, 2Y80, 2Y81 and 2Y82 (Young, RJ., et al., Bioorg Med Chem Lett., 2011, 21, 1582); 3KL6 (Fujimoto, T., et al., J Med Chem., 2010, 53, 3517-3531); 3LIW (Meuller, M.M., et al., Biol.Chem., 2003, 3 83, 1185); 5K0H (Schweinitz, A., et al., Med Chem., 2006, 2, 349-361); IXKA and IXKB (Kamata, K., et al., ProcNatl Acad Sei USA, 1998, 95, 6630-6635); 2EI6 and 2EI7 (Nagata, T., et al., Bioorg Med Chem Lett., 2007, 17, 4683-4688); 2P3T (Ye, B., et al., J Med Chem., 2007, 50, 2967-2980); 1MQ5 and 1MQ6 (Adler, M., et al., Biochemistry, 2002, 41, 15514-15523); 3K9X and 3HPT (Shi, Y., et al., Bioorg Med Chem Lett., 2009, 19, 6882-6889); 3CEN (Corte, J.R., et al., Bioorg Med Chem Lett., 2008, 18, 2845-2849); 2W3I and 2W3K (Van Huis, C.A., et al., Bioorg Med Chem., 2009, 17, 2501); 2H9E (Murakami, M.T., et al., J Mol Biol., 2007, 366, 602-610); IWU1 and 2D1J (Komoriya, S., et al., Bioorg Med Chem., 2005, 13, 3927-3954); 2G00 (Pinto, D J.P., et al., Bioorg Med Chem Lett., 2006, 16, 55845589); 3M36 and 3M37 (Pruitt, LR. et al., JMed Chem., 2003, 46, 5298-5315); 3CS7 (Qiao, J.X., et al., Bioorg Med Chem Lett., 2008, 18, 4118-4123); 1Z6E (Quan, M.L., et al., J Med Chem., 2005, 48, 1729-1744); 2FZZ (Pinto, D.J.P., et al., BioorgMed Chem Lett., 2006, 16, 4141-4147); and 3ENS (Shi, Y., et al., JMed Chem., 2008, 51, 7541-7551).

[0218] In some embodiments, a target protein of the present disclosure is human Factor XI UniProtKB - P03951 (FAI 1_HUMAN). Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX. Factor XI has been implicated in the development of deep vein thrombosis and acute pulmonary embolism, and the risk of stroke and embolism in people with nonvalvular atrial fibrillation.

[0219] The Protein Data Bank website provides the crystal structure of Factor XT bound to various compounds searchable by IZSL, IZTJ, IZTK, and IZTL (Nagafuji, P., et al.,); IZOM (Lin, J., et al., JMed Chem., 2006, 49, 7781-7791); 5EOK and 5E0D (Wong, S.S., et al., Blood, 2016, 127, 2915-2923 ); IZHM, IZHP and IZHR (Jin, L., et al., Acta Crystallogr D Biol Crystallogr., 2005, 61, 1418-1425 ); IZMJ, IZLR, IZML and IZMN (Lazarova, T.I., Bioorg Med Chem Lett., 2006, 16, 5022-5027); IZRK, IZSJ and IZSK (Guo, Z., et al); 4CRA, 4CRB, 4CRC, 4CRD, 4CRE, 4CRF and 4CRG (Fjellstrom, 0., et al., PLoS One, 2015, 10, 13705); 3SOR and 3S0S (Fradera, X., et al., Acta Crystallogr Sect F Struct Biol Cryst Commun., 2012, 68, 404-408); IZPB, IZPC, 2FDA (Deng, H., et. al., Bioorg Med Chem Lett., 2006, 16, 3049- 3054); 5WB6 (Wang, C., et al., Bioorg Med Chem Lett., 2017, 27, 4056-4060); 4NA7 and 4NA8 (Quan, M.L., et al., JMed Chem., 2014, 57, 955-969); 4WXI (Corte, J.R., et al., Bioorg Med Chem Lett., 2015, 25, 925-930); 5QTV, 5QTW, 5QTX and 5QTY (Fang, T., et al., BioorgMed Chem Lett., 2020, 126949-126949); 6C0S (Hu, Z., et al., Bioorg Med Chem Lett.,28, 987-992); 5QQP and 5QQ0 (Clark, C.G., et al., Bioorg Med Chem Lett., 2019, 29, 126604- 126604); 5Q0D, 5Q0E, 5Q0F, 5Q0G, and 5Q0H (Corte, J.R., et al., Bioorg Med Chem Lett., 2017, 27, 3833-3839); 5QCK, 5QCL, 5QCM, and 5QCN (Pinto, D.J.P., et al., J Med Chem., 2017, 60, 9703-9723); 5TKS and 5TKU (Corte, J.R., et al., J Med Chem., 2017, 60, 1060- 1075); IXXD and 1XX9 (Jin, Lt et al., J Biol Chem., 2005, 280, 47044712); 5QTT and 5QTU (Corte, J. R., et al., J Med Chem., 2019, 63, 784-803); 4TY6, 4TY7 (Hangeland, J.J., et al., J Med Chem., 2014, 57, 9915-9932); 4X6M, 4X6N, 4X60, and 4X6P (Pinto, D.J.P., et al., Bioorg Med Chem Lett., 2015, 25, 1635-1642); and 5EXM (Corte, J.R., et al., Bioorg Med Chem., 2016, 24, 2257-2272). Additionally, Al-Horani et al., provides insight into a review of patent literature regarding Factor Xia inhibitors (Al-Horani et al., Expert Opin Ther Pat. 2016; 26(3), 323-345).

[0220] In some embodiments, a target protein of the present disclosure is human Factor XII (UniProtKB - P00748 (FA12_HUMAN)). Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation Ofbradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor Xlla and then trypsin cleaves it to beta-factor Xlla. Alpha-factor Xlla activates factor XI to factor Xia. Factor XII has been implicated in the development of deep vein thrombosis and acute pulmonary embolism, and the risk of stroke and embolism in people with nonvalvular atrial fibrillation.

[0221] The Protein Data Bank website provides the crystal structure of factor XII bound to various compounds searchable by 4XDE and 4XE4 (Pathak, M., et al., J Thromb Haemost., 2015, 13(4), 580-591); 6GT6 and 6QF7 (Pathak, M., et al., Acta CrystallogrD StructBiok, 2019, 75, 578-591); and 6B74 and 6B77 (Dementiev, A.A., et al., Blood Adv., 2018, 2, 549- 558). Additionally, Pathak et al., provides insight into the crystal structure of factor XII (Pathak, M., et al., J Thromb Haemost., 2015, 13(4), 580-591).

[0222] In some embodiments, a target protein of the present disclosure is human Factor XIII UniProtKB - P00488 (F13A_HUMAN)). Factor XIII is activated by thrombin and calcium ion to a transglutaminase that catalyzes the formation of gamma-glutamyl-epsilon-lysine cross- links between fibrin chains, thus stabilizing the fibrin clot. Also cross-link alpha-2-plasmin inhibitor, or fibronectin, to the alpha chains of fibrin. Factor XIII has been implicated in the development of deep vein thrombosis and acute pulmonary embolism, and the risk of stroke and embolism in people with nonvalvular atrial fibrillation. The Protein Data Bank website provides the crystal structure of factor XIII searchable by IFIE (Yee, V.C., et al., Thromb Res., 1995, 78, 389-397); and 1F13 (Weiss, M.S., et al., FEES Lett., 1998, 423, 291-296); as well asthe crystal structure of factor XIII bound to various compounds searchable by 1DE7 (Sadasivan, C., et al., J Biol Chem., 2000, 275, 36942-36948); and 5MHL, 5MHM, 5MHN, and 5MH0 (Stieler, M., et al., ). Additionally, Gupta et al., provides insight into the mechanism of coagulation factor XIII activation and regulation from a Structure / functional perspective (Gupta, S., et al., Sci Rep., 2016; 6, 30105); and Komaromi et al., provides insight into the novel structural and functional aspect of factor XIII (Komaromi, Z., et al.,. J Thromb Haemost 2011, 9, 9-20).

[0223] In some embodiments, a target protein of the present disclosure is human Prothrombin (UniProtKB - P00734 (THRB_HUMAN)). Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.

[0224] Thrombin is involved in blood clot formation and arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0225] The Protein Data Bank website provides the crystal structure of prothrombin searchable by 3NXP (Chen, Z. et al., Proc Natl Acad Sci USA, 2010, 107, 19278-19283); as well as the crystal structure of prothrombin bound to various compounds searchable by 2HPP and 2HPQ (Ami, R.K., et al., Biochemistry, 1993, 32, 4727-4737); 6BJR, 6C2W (Chinnaraj, M., et al., Sci Rep., 2018, 8, 2945-2945); 5EDK, 5EDM (Pozzi, N., et al., JBiol Chem., 2016, 291, 6071- 6082); 3K65 (Adams, T.E., et al., Biochimie, 2016, 122, 23 5-242); and 6BJR and 6C2W (Chinnaraj, M. et al., Sci Rep., 2018, 8, 2945-2945). Additionally, Pozzi et al., provides insight into the mechanism and conformational flexibility for the crystal structure of prothrombin (Pozzi, N. et al., J Biol Chem., 2013, 288(31), 22734-22744); andZhiwei et al., provides insight into the crystal structure of prothrombin- 1 (Zhiwei, C. etak, PNAS, 2010, 107(45), 19278- 19283).

[0226] Prothrombin is converted to thrombin, as such the Protein Data Bank website provides the crystal structure of thrombin bound to compounds searchable by IXMN (Carter, W.J. et al., J-BioLChem., 2005, 280, 2745-2749); 4CH2and 4CH8 (Lechtenberg, B.C. et al., J Mol Biol., 2014, 426, 881); 3PO1 (Karie, M. et al., Bioorg Med Chem Lett., 2012, 22, 4839-4843); 3DA9 (Nilsson, M. et al., J Med Chem., 2009, 52, 2708-2715); 2H9T and 3BF6 (Lima, L.M.T.R. et al., Biochim Biophys Acta., 2009, 1794, 873-881); 3BEF and 3BEI (Gandhi, P.S. et al., Proc Natl Acad Sci USA, 2008, 105, 1832-1837); 3BV9 (Nieman, M.T. et al., J Thromb Haemost., 2008, 6, 837-845); 2HWL (Pineda, A.O. et al., Biophys Chem., 2007, 125, 556-559); 2AFQ (Johnson, D.J.D. et al., Biochem J., 2005, 392, 21-28); ISHH (Pineda, A.O. et al., J Biol Chem., 2004, 279, 31842-31853); IJWT (Levesque, S. et al., Bioorg Med Chem Lett., 2001, 11,3161-3164); 1G37 (Bachand, B. et al., Bioorg Med Chem Lett., 2001, 11, 287-290); IEOJ and IEOL (Slon-Usakiewicz, JJ. et al., Biochemistry, 2000, 39, 2384-2391); IAWH (Weir, M.P. et al., Biochemistry, 1998, 37, 6645-6657); IDIT (Krishnan, R. et al., Protein Sci., 1996, 5, 422-433); IHAO and IHAP (Padmanabhan, K. et al., Acta Crystallogr D Biol Crystallogr., 1996, 52, 272- 282); and IHBT (Rehse, P.H. et al., Biochemistry, 1995, 34, 11537-11544).

[0227] In some embodiments, a target protein of the present disclosure is human coagulation Factor VII (UniProtKB - P08709 (FA7_HUMAN)). Factor VII initiates the extrinsic pathway of blood coagulation. It is a serine protease that circulates in the blood in a zymogen form. Factor VII is converted to Factor Vila by Factor Xa, Factor Xlla, Factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, Factor Vila then converts Factor X to Factor Xa by limited proteolysis. Factor Vila will also convert Factor IX to Factor IXa in the presence of tissue factor and calcium. Factor VII is involved in blood clot formation and arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0228] The Protein Data Bank website provides the crystal structure of factor VII bound to various compounds searchable by 2F9B (Rai, R., et al., Bioorg Med Chem Lett., 2006, 16, 2270-2273); 5U6J (Wurtz, N.R., et al., BioorgMed Chem Lett., 2017, 27, 2650-2654); 5L2Y, 5L2Z, and 5L30 (Ladziata, .U., et al., Bioorg Med Chem Lett., 2016, 26, 5051-5057); 5146 (Glunz, P. W., et al., J Med Chem., 2016, 59,4007-4018); 4YLQ, 4Z6A, and 4ZMA (Sorensen, A.B., et al., JBiol Chem., 2016, 291, 4671-4683); 4YT6 and 4YT7 (Glunz, P.W., et al., Bioorg Med Chem Lett, 2015, 25, 2169-2173); 4NA9 (Quan, M.L., et al., J Med Chem., 2014, 57, 955-969); 4NG9 (hang, X., et al., ACS Med Chem Eett., 2014, 5, 188-192); 4JZD, 4JZE and 4JZF (Bolton, S. A., et al., Bioorg Med Chem Eett., 2013, 23, 5239-5243); 4JYU and 4JYV (Glunz, P.W., et al., Bioorg Med Chem Eett., 2013, 23, 5244-5248); 4ISH (Priestley, E.S., et al., BioorgMed Chem Eett., 2013, 23, 2432-2435); 4ISI (Zhang, X., et al., Bioorg Med Chem Eett., 2013, 23, 1604-1607); 2ZZU (Shiraishi, T., et al., Chem Pharm Bull (Tokyo), 2010, 58, 38-44); 1WV7 and IWUN (Kadono, S., et al., Biochem Biophys Res Commun., 2005, 327, 589-596); 2ZWL, 2ZP0, (Kadono, S., et al.); 2EC9 (Krishan, R., et al., Acta Crystallogr D Biol Crystallogr., 2007, 63, 689-697); 2PUQ (Earsen, K. S., et al., Biochem J., 2007, 405, 429-438); 2FER (Riggs, J. R., et al., Bioorg Med Chem Eett., 2006, 16, 3197-3200); 2C4F (Kohrt, J.T., et al., Bioorg Med Chem Eett., 2006, 16, 1060); 2AEI (Kohrt, J.T. et al., BioorgMed Chem Eett., 2005, 15,4752-4756); IWTG (Kadono, S., et al., Biochem Biophys Res Commun., 2005, 326, 859-865); IWSS (Kadono, S., et al., Acta Crystallogr Sect F Struct Biol Cryst Commun., 2005, 61, 169-173); 1W7X and 1W8B (Zbinden, K.G., et al., Bioorg Med Chem Eett., 2005, 15, 5344); IWQV (Kadono, S., et al., Biochem Biophys Res Commun., 2004, 324, 1227-1233);1Z6J (Schweitzer, B. A., et al., BioorgMed Chem Lett., 2005, 15,3006-3011); IYGC (Olivero, A. G., et al., J Biol Chem., 2005, 280, 9160-9169); 6R2W (Sorensen, A.B., et al., J Biol Chem., 2019, 295, 517-528); 5PA8, 5PA9, 5PAA, 5PAB, 5PAC, 5PAE, 5PAF, 5PAG, 5PAI, 5PAJ, 5PAK, SPAM, SPAN, 5PAO, 5PAQ, SPAR, SPAS, SPAT, 5PAU, 5PABV, 5PAW, 5PAX, SPAY, 5PB0, 5PB1, 5PB2, 5PB3, 5PB4, 5PB5, and 5PB6 (Mayweg, A.V., et al.,); and 5L0S (Li, Z., et al., Nat Commun., 2017, 8, 185-185). Additionally, Kemball-Cook, et al., provides insight into the crystal structure of active site-inhibited factor Vila (Kemball-Cook, G., et al., J Struct Biol., 1999, 127(3), 213-23).

[0229] In some embodiments, a target protein of the present disclosure is human coagulation Factor IX (UniProtKB - P00740 (FA9_HUMAN)). Lactor IX Lactor IX is a vitamin K- dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca2+ ions, phospholipids, and factor Villa. Lactor IX is involved in blood clot formation and arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0230] The Protein Data Bank website provides the crystal structure of factor IX bound to various compounds searchable by 6MV4 (Vadivel, K., et al., J Thromb Haemost., 2019, 17, 574-584); 4ZAE (Zhang, T., et al., Bioorg Med Chem Lett., 2015, 25, 4945-4949); 4YZU and 4Z0K (Parker, D.L., et al., Bioorg Med Chem Lett., 2015, 25, 2321-2325); 5TN0 and 5TNT (Sakurada, I., et al., Bioorg Med Chem Lett., 2017, 27, 2622-2628); 5JB8, 5JB9, 5JBA, 5JBB and 5JBC (Kristensen, L.H., et al., Biochem J., 2016, 473, 2395-2411); 3LC3 (Wang, S., et al, J Med Chem., 2010, 53, 1465-1472); 3LC5 (Wang, S., et al, JMedChem., 2010, 53, 1473- 1482); 3KCG (Johnson, D.J.D., et al, Proc Natl Acad Sci USA, 2010, 107, 645-650); 1NL0 (Huang, M., et al, J Biol Chem., 2004, 279, 14338-14346); IREN (Hopfner, K.P., et al., Structure, 1999, 7, 989-996); and 6REK (Sendall, T.J., et al.,).

[0231] In some embodiments, a target protein of the present disclosure is human fibroblast growth factor 1 (FGF1) (UniProtKB - P05230 (FGF1_HUMAN)). FGF1 plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. FGF1 acts as a ligand for FGFR1 and integrins, and binds to FGFR1 in the presence of heparin leading to FGFR1 dimerization and activation via sequential autophosphorylation on tyrosine residues which act as docking sites for interacting proteins, leading to the activation of several signaling cascades. LGL1 induces the phosphorylation and activation of LGLR1, FRS2, MAPK3 / ERK1, MAPK1 / ERK2 and AKT1. FGF1 can induce angiogenesis. EGE1 has been implicated in oncogenesis, cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis.

[0232] The Protein Data Bank website provides the crystal structure of FGF1 searchable by 2AFG (Blaber, M., et al., Biochemistry, 1996, 3 5, 2086-2094); and 1BAR (Zhu, X. et al., Science, 1991, 251, 90-93); as well as the crystal structure of FGF1 bound to various compounds searchable by 1AFC (Zhu, X., et al., Structure, 1993, 1, 27-34); 1AXM and 2AXM (DiGabriele, A. D., et al., Nature, 1998, 393, 812-817); 1EVT (Plotnikov, A.N., et al., Cell, 2000, 101, 413-424); 1E0O (Pellegrini, L., et al., Nature, 2000, 407, 1029); and 2ERM (Canales, A., et al., FEBS J, 2006, 273, 4716-4727).

[0233] In some embodiments, a target protein of the present disclosure is human fibroblast growth factor 2 (FGF2) (UniProtKB - P09038 (FGF2_HUMAN)). FGF2 acts as a ligand for FGFR1, FGFR2, FGFR3 and FGFR4. FGF2 also acts as an integrin ligand which is required for FGF2 signaling, and plays an important role in the regulation of cell survival, cell division, cell differentiation and cell migration. FGF2 also induces angiogenesis. FGF2 has been implicated in oncogenesis, cancer cell proliferation, resistance to anti cancer therapies, and neoangiogenesis.

[0234] The Protein Data Bank website provides the crystal structure of FGF2 bound to various compounds searchable by 40EE, 4OEF, and 40EG (Li, Y.C., et al., ACS Chem Biol., 2014, 9, 1712-1717); 1EV2 (Plotnikov, A.N., et al., Cell, 2000, 101, 413-424); and 5X1O (Tsao, Y.H.).

[0235] In some embodiments, a target protein of the present disclosure is human fibronectin 1 (FN1) (UniProtKB - P02751 (FINC_HUMAN)). Fibronectin (FN) polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblasts (MFs) after cardiac injury. Interfering with FN polymerization may attenuate MF and fibrosis and improve cardiac function after ischemia / reperfusion (I / R) injury.

[0236] The Protein Data Bank website provides the crystal structure of fibronectin- 1 bound to various compounds searchable by 3M7P (Graille, M., et al., Structure, 2010, 18, 710-718); 3MQL (Erat, M.C., et al., J Biol Chem., 2010, 285, 33764-33770); and 3EJH (Erat, M.C., et al., ProcNatl Acad Sci USA, 2009, 106, 4195-4200).

[0237] In some embodiments, a target protein of the present disclosure is human kallikrein-1 (UniProtKB - P06870 (KLK1_HUMAN)). Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin. Kallikrein has been implicated in adverse reactions in hereditary angioedema (HAE).

[0238] The Protein Data Bank website provides the crystal structure of KLK1 searchable by 1SPJ (Laxmikanthan, G., et al., Proteins, 2005, 58, 802-814); as well as the crystal structure of KLK1 bound to various compounds searchable by 5F8Z, 5F8T, 5F8X, (Xu, M., et al.,); and 6A8O (Xu, M., et al., FEES Lett., 2018, 592, 2658-2667). Additionally, Katz et al., providesinsight into the crystal structure Ofkallikrein (Katz, B.A., et al., Protein Sci., 1998, 7(4), 875- 85).

[0239] In some embodiments, a target protein of the present disclosure is human plasma kallikrein (UniProtKB - P03952 (KLKB1_HUMAN)). Plasma kallikrein cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin. Plasma kallikrein has been implicated in retinal dysfunction, the development of diabetic macular edema and hereditary angioedema (HAE).

[0240] The Protein Data Bank website provides the crystal structure of plasma kallikrein bound to various compounds searchable by 5TJX (Li, Z., et al., ACS Med Chem Lett., 2017, 8, 185- 190); 6O1G and 6O1S (Patridge, J. R., et al., J Struct Biol., 2019, 206, 170-182); 40GX and 40GY (Kenniston, J. A., et al., JBiol Chem., 2014, 289, 23596-23608); and 5F8T, 5F8X, and 5F8Z (Xu, M., et al.,).

[0241] In some embodiments, a target protein of the present disclosure is human lipoprotein lipase (UniProtKB - P06858 (LIPL_HUMAN)). Lipoprotein lipase is a key enzyme in triglyceride metabolism. It catalyzes the hydrolysis of triglycerides from circulating chylomicrons and very low density lipoproteins (VLDL), and thereby plays an important role in lipid clearance from the blood stream, lipid utilization and storage. Lipoprotein lipase mediates margination of triglyceride-rich lipoprotein particles in capillaries. Lipoprotein lipase has been implicated in the development of cardiovascular disease and obesity.

[0242] The Protein Data Bank website provides the crystal structure of lipoprotein lipase bound to various compounds searchable by 6E7K (Birrane, G., et al., Proc Natl Acad Sci U S A, 2018 116 1723-1732).

[0243] In some embodiments, a target protein of the present disclosure is human matrix metallopeptidase 1 (MMP-1) (UniProtKB - P03956 (MMP1_HUMAN)). MMP-1 cleaves collagens of types I, II, and III at one site in the helical domain. It also cleaves collagens of types VII and X. MMP-1 has been implicated in cardiovascular disease.

[0244] The Protein Data Bank website provides the crystal structure of MMP-1 searchable by 3SHI (Bertini, I., et al., LEBS Lett., 2012, 586, 557-567); as well as the crystal structure of MMP-1 bound to various compounds searchable by 4AU0 (Manka, S. W., et al., Proc Natl Acad Sci U S A, 2012, 109, 12461); 3MA2 (Grossman, M., et al., Biochemistry, 2010, 49, 6184-6192); and 2J0T (Iyer, S., et al., J. Biol. Chem., 2007, 282, 364 ). Additionally, Iyer et al., provides insight into the crystal structure of an active form of MMP- 1 (Iyer, S., et al., J MolBiol., 2006, 362(1), 78-88); and Lovejoy et al., provides insight into the crystal structure of MMP1 and the selectivity of collagenase inhibitors (Lovejoy, B., et al., Nat Struct Mol Biol., 1999, 6, 217-221).

[0245] In some embodiments, a target protein of the present disclosure is human macrophage migration inhibitory factor (MIF) (UniProtKB - P14174 (MIF_HUMAN)). MIF is a pro- inflammatory cytokine involved in the innate immune response to bacterial pathogens. The expression of MIF at sites of inflammation suggests a role as mediator in regulating the function of macrophages in host defense. It counteracts the anti-inflammatory activity of glucocorticoids. MIF has been implicated in tumor progression; systemic inflammation; atherosclerosis; rheumatoid arthritis; and systemic lupus erythematosus, among others.

[0246] The Protein Data Bank website provides the crystal structure of MIF searchable by IMIF (Sun, H-W. et al., ProcNatl Acad Sci USA, 1996, 93, 5191-5196); as well as the crystal structure of MIF bound to various compounds searchable by 6PEG (Cirillo, P.F. et al.,); 5XEJ (Fukushima, K); 6FVE and 6FVH (Sokolov, A.V., et al., Biochemistry (Mose), 2018, 83, 701- 707); 6CB5, 6CBF, 6CBG, and 6CBH (Trivedi-Parmar, V., et al., ChemMedChem., 2018, 13, 1092-1097); 6B1C, 6B1K, 6B2C, (Dawson, T.K., et al., ACS Med Chem Lett., 2017, 8, 1287- 1291); 4Z15, 4Z1T and 4Z1U (Singh, A.K., et al, J Cell Mol Med., 2017, 21, 142-153); 5HVS and 5HVT (Cisneros, J.A., et al., J Am Chem Soc., 2016, 138, 8630-8638); 4PKK (Pantouris, G., et al.,); 5J7P and 5J7Q (Cisneros, J. A., et al., Bioorg Med Chem Lett., 2016, 26, 2764- 2767); 5B4O (Kimura, H., et al., Chem Biol., 2010, 17, 1282-1294 ); 4PLU, 4TRF, 4P0H, and 4P01 (Pantouris, G., et al., Chem Biol., 2015, 22, 1197-1205); 4WR8 and 4WRB (Dziedzic, P., et al., J Am Chem Soc., 2015, 1372996-3003); 4K9G (loannou, K., etak, Int J Oncol., 2014, 45, 1457-1468); 40SF, 3WNR, 3WNS and 3WNT (Spencer, E.S., et al., EurJMed Chem., 2015, 93, 501-510); 4OYQ (Spencer, E.S. et al.,); 3SMB and 3SMC (Crichlow, G.V. et al., Biochemistry, 2012, 51, 7506-7514); 3U18 (Bai, F., et al., J Biol Chem., 2012, 287, 30653- 30663); 4F2K (Tyndall, J.D.A., et al., Acta Crystallogr Sect F Struct Biol Cryst Commun., 2012, 68, 999-1002); 3IJG and 3IJJ (Cho, Y., et al., ProcNatl Acad Sci USA, 2010, 107, 11313- 11318); 3L5P, 3L5R, 3L5S, 3L5T, 3L5U, and 3L5V (McLean, L.R. et al., BioorgMed Chem Lett., 2010, 20, 1821-1824); 3JSF, 3JSG and 3JTU (McLean, L R., et al., Bioorg Med Chem Lett., 2009, 19, 6717); 3HOF (Crawley, L., et al.); 3CE4 and 3DJI (Crichlow G.V., et al., Biochemistry, 2009, 48, 132-139); 3B9S (Winner, M. et al., Cancer Res., 2008, 68, 7253-7257 ); 2OOH, 2OOW and 2OOZ (Crichlow, G.V. et al., J Biol Chem., 2007, 282, 23089-23095); IGCZ and IGDO (Orita, M. et al., J Med Chem., 2001, 44, 540547); and 1CA7, ICGQ and IP1G (Lubetsky, J.B. et al., Biochemistry, 1999, 38, 7346-7354). Additionally, Sun et al., providesinsight into the crystal structure of MIF (Proc Natl Acad Sci U SA., 1996, 28;93(11), 5191-6).

[0247] In some embodiments, a target protein of the present disclosure is human transforming growth factor-β2 (TGF-β2) (UniProtKB - P61812 (TGFB2_HUMAN)). TGF-β2 is a multifunctional protein that regulates various processes such as angiogenesis and heart development. Once activated following release of LAP, TGF-beta-2 acts by binding to TGF- beta receptors (TGFBR1 and TGFBR2), which transduce signal. TGF-β2 expression in the tumor microenvironment has been associated with a poor prognosis, and is implicated in TGF- β2 mediated tumor suppression via T-cell exclusion. TGF-β2 expression has also been implicated in hematological malignancies and fibrosis.

[0248] The Protein Data Bank website provides the crystal structure of TGF-β2 searchable by 6I9J (Del Amo-Maestro L. et al., Sci Rep. 2019, 9, 8660-8660); as well as the crystal structure of TGF-β2 bound to various compounds searchable by 1M9Z (Boesen, C.C., et al. Structure, 2002, 10, 913-919); 5QIN (Zhang, Y. et al., ACS Med Chem Lett., 2018, 9, 1117-1122); 5E8V, 5E8Y, 5E91 and 5E92 (Tebben, A. J. et al., Acta Crystallogr D Struct Biol., 2016, 72, 658-674); 4P7U (Wangkanont, K. et al., Protein Expr Purif., 2015, 115, 19-25); 4XJJ (Wangkanont et al.); and IKTZ (Hart, PJ., et al., Nat Struct Biol., 2002, 9, 203-208).

[0249] In some embodiments, a target protein of the present disclosure is human thrombospondin- 1 (TSP-1) (UniProtKB - P61812 (TGFB2_HUMAN)). TSP1 acts as an angiogenesis inhibitor by stimulating endothelial cell apoptosis, inhibiting endothelial cell migration and proliferation, and regulating vascular endothelial growth factor bioavailability and activity. TSP1 affects tumor immune response, tumor cell behaviors including adhesion, invasion, migration, apoptosis, and proliferation. TSP-1 expression has been implicated in a number of diseases, including in promoting certain cancers such as breast cancer, prostate cancer, melanoma, SCLC, osteosarcoma, cutaneous squamous cell carcinoma, oral squamous cell carcinoma, papillary thyroid carcinoma, thyroid cancer, medulloblastoma, and fibrotic disorders such as diabetes, liver fibrosis, and in multiple myeloma.

[0250] The Protein Data Bank website provides the crystal structure of TSP -1 searchable by 1LSL (Tan, K. et al., J Cell Biol., 2002, 159, 373-382); 2ES3 (Tan, K., et al., J Biol Chem., 2008, 283, 3932-3941); 1Z78 and 2ERF (Tan, K., et al., Structure, 2006, 14, 33-42); and 3R6B (Klenotic, P.A., et al., Protein ExprPurif., 2011, 80, 253-259); as well as the crystal structure of TSP-1 bound to various compounds searchable by 20UH and 2OUJ (Tan, K., et al., J Biol Chem., 2008, 283, 3932-3941); and 1ZA4 (Tan, K., et al., Structure, 2006, 14, 33-42).

[0251] In some embodiments, a target protein of the present disclosure is human CD40 ligand (CD40L) (UniProtKB - P29965 (CD40L_HUMAN)). CD40L is a cytokine that acts as a ligandto CD40 / TNFRSF5. It costimulates T-cell proliferation and cytokine production. Its cross- linking on T-cells generates a costimulatory signal which enhances the production of IL4 and IL10 in conjunction with the TCR / CD3 ligation and CD28 co stimulation. CD40L induces the activation of NF-kappa-B, as well as kinases MAPK8 and PAK2 in T-cells. It also induces tyrosine phosphorylation of isoform 3 of CD28. CD40L mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL4, and is involved in immunoglobulin class switching.

[0252] The Protein Data Bank website provides the crystal structure of CD40L searchable by 1ALY (Karpusas, M., et al., Structure, 1995, 3, 1031-1039); as well as the crystal structure of CD40L bound to various compounds searchable by 3QD6 (An, H. J., et al., J Biol Chem., 2011, 286, 11226-11235); and 6BRB (Kamell, J. L., et al., Sci Transl Med., 2019, 11(489), 6584).

[0253] In some embodiments, a target protein of the present disclosure is human urokinase- type plasminogen activator (UPA) (UniProtKB - P00749 (UROK_HUMAN)). Urokinase-type plasminogen activator (uPA), is a serine protease present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression. Elevated expression levels of urokinase and several other components of the plasminogen activation system are found to be correlated with tumor malignancy.

[0254] The Protein Data Bank website provides the crystal structure of UPA bound to various compounds searchable by 5ZA7, 5ZAJ, 5ZA8, 5ZA9, 5ZAE, 5ZAF, 5ZAG, 5ZAH, and 5ZC5 (Buckley, B.J. et al., J Med Chem., 2018, 61, 8299-8320); 5LHP, 5LHQ, 5LHR, and 5LHS (Kromann-Hansen, T. et al., Sci Rep., 2017, 7, 3385-3385); 2VNT (Fish, P.V. et al. J Med Chem., 2007, 50, 2341); 10WD, 10WE, 10WH, 1OWI, 1OWJ, and 10WK (Wendt, M.D. et al., J Med Chem., 2004, 47, 303-324); 1SQA, 1SQO, and 1SQT (Wendt, M.D., et al., Bioorg Med Chem Lett., 2004, 14, 3063-3068); 1U6Q (Bruncko, M. et al., BioorgMed Chem Lett., 2005, 15, 93-98); 30X7, 3OY5 and 3OY6 (Jiang, L.G. et al., J Mol Biol., 2011, 412, 235-250); 4OS1, 4OS2, 4OS4, 4OS5, 4OS6 and 4OS7 (Chen, S. et al., Nat Chem., 2014, 6, 1009-1016); 31G6 (West, C.W. et al., Bioorg Med Chem Lett., 2009, 19, 5712-5715); 4X0W and 4X1P (Jiang, L. et al., Int J Biochem Cell Biol., 2015, 62, 88-92); 4X1N, 4X1Q, 4X1R and 4X1S (Zhao, B. et al., PLoS One, 2014, 9, e 115872-e 115872); 5WX0 and 5WXP (Jiang, L. et al., Biochim Biophys Acta., 2018, 1862, 2017-2023); 4MNV, 4MNW, 4MNX, and 4MNY (Chen,S., et al., Angew Chem Int Ed Engl., 2014, 53, 1602-1606); 4GLY (Chen, S., et al., J Am Chem Soc., 2013, 135, 6562-6569); 4JK5 and 4JK5 (Chen, S., et al., Chembiochem., 2013, 14, 1316- 1322); 3QN7 (Angelini, A. et al., ACS Chem Biol., 2012, 7, 817-821); 2NWN (Zhao, G. et al., J StructBioL, 2007, 160, 1-10); 6NMB (Wu, G et al.,BloodAdv.,2019, 3, 729-73 3); IWOZ, 1W10, 1W11, 1W12, 1W13, and 1W14 (Zeslawska, E. et al., J Mol Biol., 2003, 328, 109); 4DVA (Jiang, L et al., Biochem J., 2013, 449, 161-166); 6A8G 6A8N (Wang, D. et al., J Med Chem., 2019, 62, 2172-2183); 2VIN, 2VIO, 2VIP, 2VIQ, 2VIV, and 2VIW (Frederickson, M. et al., J Med Chem., 2008, 51, 183); IEJN (Speri, S., et al., ProcNatl Acad Sci USA, 2000, 97, 5113-5118); 3PB1 (Lin, Z. et al., J Biol Chem., 2011, 286, 7027-7032); 3U73 (Xu, X. et al., J Mol Biol., 2012, 416, 629-641); 1C5W, 1C5X, 1C5Y and IC5Z (Katz, B.A., et al., Chem Biol., 2000, 7, 299-312); 5XG4 (Xue, G. et al., Food Funct, 2017, 8, 243 7-2443); 5WXF (Jiang, L. et al., Biochim Biophys Acta., 2018, 1862, 2017-2023); 5WXS, 4ZKS, 5WXQ, 5WXT, 5YC6, 5YC7, 5Z1C, (Jiang, L. et al.); 4H42 (Yu, H.Y. et al.,); 6AG3 and 6AG9 (Buckley, B. et al); 3KGP, 3KHV, 3KID, 3M61, 3MHW, and 3MWI (Jiang, L.G. et al.,); 4ZKN, 4ZK0 and 4ZKR (Jiang, L. et al.); 2O8T, 2O8U, 2O8W (Zhao, G. et al.,); and 4FU7, 4FU8, 4FU9, 4FUB, 4FUC, 4FUD, 4FUE, 4FUF, 4FUG, 4FUH, 4FUI, and 4FUJ (Kang, Y.N. et al.).

[0255] In some embodiments, a target protein of the present disclosure is human plasminogen activator, tissue type (TPA) (UniProtKB - P00750 (TPA_HUMAN)). TPA converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg- Vai bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation, in cell migration and many other physiopathological events. TPA plays a direct role in facilitating neuronal migration. PEA has been shown activated in various cancers including oral malignancy.

[0256] The Protein Data Bank website provides the crystal structure of TPA searchable by 1VR1 (Dekker, R.J. et al., J Mol Biol., 1999, 293, 613-627); as well as the crystal structure of TPA bound to various compounds searchable by IRTF (Lamba, D. et al., J Mol Biol., 1996, 258, 117-135); 1A5H (Renatus, M. et al., J Biol Chem., 1997, 272, 21713-21719); and 1BDA (Renatus, M. et al., EMBO J., 1997, 16, 4797-4805).

[0257] In some embodiments, a target protein of the present disclosure is human plasminogen (PEG) (UniProtKB - P00747 (PLMN_HUMAN)). PEG dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4.

[0258] The Protein Data Bank website provides the crystal structure of PEG searchable by 1DDJ (Wang, X. et al., J. Mol. Biol., 2000, 295, 903-914); and 4DUR and 4DUU (Law, R.H.P., et al., Cell Rep., 2012, 1, 185-190).

[0259] In some embodiments, a target protein of the present disclosure is human plasminogen activator inhibitor 1 (PALI) (UniProtKB - P05121 (PAI1_HUMAN)). PALI is a serine protease inhibitor, and a primary inhibitor of tissue-type plasminogen activator (PLAT) and urokinase-type plasminogen activator (PLAU). As PLAT inhibitor, it is required for fibrinolysis down-regulation and is responsible for the controlled degradation of blood clot. As PLAU inhibitor, it is involved in the regulation of cell adhesion and spreading, and acts as a regulator of cell migration, independently of its role as protease inhibitor. Overexpression of PAL 1 favors angiogenesis, metastasis, and poor prognosis in tumors, including, but not limited to, oral cancers and breast cancers.

[0260] The Protein Data Bank website provides the crystal structure of PALI searchable by 3Q02 and 3Q03 (Jensen, J. K. et al., J Biol Chem., 2011, 286, 29709-29717); 1B3K (Sharp, A. M. et al., Structure, 1999, 7, 111-118); 1C5G (Tucker, H. M. et al., Nat Struct Biol., 1995, 2, 442-445); IDVM (Stout, T. J. et al., Biochemistry, 2000, 3 9, 8460-8469); and 3UT3 (Lin, Z. H. et al.,); as well as the crystal structure of PALI bound to various compounds searchable by 4AQH (Fjellstrom, O. et al., J Biol Chem., 2013, 288, 873); 3R4L (Jankun, J. et al., Int J Mol Med., 2012, 29 61-64); 1A7C (Xue, Y., et al., Structure, 1998, 6, 627-636); 1OC0 (Zhou, A. et al., Nat Struct Biol., 2003, 10, 541); 6I8S (Vousden, K. A. et al., Sci Rep., 2019, 9, 1605- 1605 ); 4G8O and 4G8R (Li, S H et al., Proc Natl Acad Sci U S A, 2013, 110, E494LE4949); 6GWQ, 6GWN and 6GWP (Sillen, M. et al., J Thromb Haemost, 2019); and 4IC0 (Hong, Z. B. et al.,).

[0261] In some embodiments, a target protein of the present disclosure is human placental growth factor (PGF) (UniProtKB - P49763 (PLGF_HUMAN)). PGF is growth factor active in angiogenesis and endothelial cell growth, stimulating their proliferation and migration. It binds to the receptor FLT1 / VEGFR-1. Isoform P1GF-2 binds NRPl / neuropilin- 1 andNRP2 / neuropilin-2 in a heparin-dependent manner. PGF also promotes cell tumor growth, and has been implicated in age-related macular degeneration (AMD) and choroidal neovascularization (CNV).

[0262] The Protein Data Bank website provides the crystal structure of PIGF searchable by 1FZV (Iyer, S. et al., J Biol Chem., 2001, 276, 12153-12161 ); as well as the crystal structure of PIGF bound to various compounds searchable by 1RV6 (Christinger, H. W., J Biol Chem., 2004, 279, 10382-10388). Additionally, De Falco provides insight into the discovery andbiological activity of placenta growth factor (De Falco, Exp Mol Med., 2012, 44, 1-9).

[0263] In some embodiments, a target protein of the present disclosure is human phospholipase A2, Group IB (PA21B) (UniProtKB - P04054 (PA21B_HUMAN)). PA21B cleaves phospholipids preferentially at the sn-2 position, liberating free fatty acids and lysophospholipids. PA21B has been implicated in a number of diseases, including cardiovascular diseases, atherosclerosis, immune disorders and cancer.

[0264] The Protein Data Bank website provides the crystal structure of PA21B Searchable by 3FVJ and 3FVI (Pan, Y. H. et al., Biochim Biophys.Acta., 2010, 1804, 1443-1448).

[0265] In some embodiments, a target protein of the present disclosure is human phospholipase A2, Group IIA (PA2GA) (UniProtKB - P04054 (PA21B_HUMAN)). PA2GA catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-phosphoglycerides. It is thought to participate in the regulation of phospholipid metabolism in biomembranes including eicosanoid biosynthesis. Independent of its catalytic activity, it also acts as a ligand for integrins. PA2GA Induces cell proliferation in an integrin-dependent manner. PA2GA has been implicated in a number of diseases, including cardiovascular diseases, atherosclerosis, immune disorders, and cancer.

[0266] The Protein Data Bank website provides the crystal structure of PA2GA bound to various compounds searchable by 2ARM and 1SV3 (Singh, N. et al., Proteins, 2006, 64, 89- 100); 5G3M and 5G3N (Giordanetto, F., et al. ACS Med Chem Lett., 2016, 7, 884); 1KQU (Jansford, K.A., et al., Chembiochem., 2003, 4 ,181-185); and 1ZYX (Singh, N. et al.,). Additionally, Singh et al., provides insight into the crystal structure of the complexes of a group IIA phospholipase A2 with two natural anti-inflammatory agents, anisic acid, and atropine reveal a similar mode of binding (Singh, N. et al., Proteins, 2006, 64(l):89-100); and Kitadokoro et al also provides insight into the crystal structure of human secretory phospholipase A2-IIA complex with the potent indolizine inhibitor 120-1032 (Kitadokoro, K. et al., J Biochem., 1998, 123(4), 619-23).

[0267] In some embodiments, a target protein of the present disclosure is human Complement factor B (UniProtKB - P00751 (CFAB_HUMAN)). Complement factor B, which is part of the alternate pathway of the complement system, is cleaved by factor D into 2 fragments: Ba and Bb. Bb, a serine protease, then combines with complement factor 3b to generate the C3 or C5 convertase. It has also been implicated in proliferation and differentiation of preactivated B- lymphocytes, rapid spreading of peripheral blood monocytes, stimulation of lymphocyte blastogenesis and lysis of erythrocytes. Ba inhibits the proliferation of preactivated B- lymphocytes.

[0268] The Protein Data Bank website provides the crystal structure of Complement Factor B searchable by 2OK5 (Milder, F J., et al., Nat Struct Mol Bio 2007, 14, 224-228); as well as the crystal structure of Complement factor B bound to various compounds searchable by 6QSW, 6QSX, and 6RAV (Schubart, A., et al., Proc Natl Acad Sci 2019, 116, 7926-7931); 6T8U, 6T8W, and 6T8V (Mainolfi, N., et al, J Med Chem 2020, 63, 5697-5722); and 7JTN (Xu, X., et al., J Immunol 2021, 206, doi: 10.4049 / jimmunol.2001260).

[0269] In some embodiments, a target protein of the present disclosure is human Complement factor D (UniProtKB - P00746 (CFAD_HUMAN)). Factor D cleaves factor B when the latteris complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of Cis in the classical pathway.

[0270] The Protein Data Bank website provides the crystal structure of Complement factor D bound to various compounds searchable by 6FTZ, 6FUT, 6FUH, 6FUG, 6FUJ, and 6FUI (Vulpetti, A., et al., ACS Med Chem Lett 2018, 9, 490-495); 5TCA and 5TCC (Yang, C. Y., et al., ACS Med Chem Lett 2016, 7, 1092-1096); 5MT4 (Vulpetti, A., et al., J Med Chem 2017, 60, 1946-195 8); IDFP (Cole, L. B., et al., Acta Crystallogr D Biol Crystallogr 1997, 53, 143- 150); IDIC (Cole, L. B., etal, Acta Crystallogr D Biol Crystallogr 1998, 54, 711-717); 6QMR and 6QMT (Karki,R.G., et al., J Med Chem 2019, 62, 4656-4668).

[0271] In some embodiments, a target protein of the present disclosure is human complement factor H (UniProtKB - P08603 (CFAH_HUMAN)). Complement factor Hisa glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation. Acts as a soluble inhibitor of complement, where its binding to self- markers such as glycan structures prevents complement activation and amplification on cell surfaces. Complement factor H accelerates the decay of the complement alternative pathway (AP) C3 convertase C3bBb, thus preventing local formation of more C3b, the central player of the complement amplification loop. As a cofactor of the serine protease factor I, CFH also regulates proteolytic degradation of already-deposited C3b. In addition, it mediates several cellular responses through interaction with specific receptors. For example, CFH interacts with CR3 / ITGAM receptor and thereby mediates the adhesion of human neutrophils to different pathogens. In turn, these pathogens are phagocytosed and destroyed.

[0272] The Protein Data Bank website provides the crystal structure of highly similar mutants of complement factor H searchable by 3KXV and 3KZJ (Bhattacharjee, A., et al., Mol Immunol 2010, 47, 1686-1691); as well as the crystal structure of wild type complement factor H bound to various compounds searchable by 2UWN (Prosser, B.E., et al., J Exp Med 2007, 204, 2277);5WTB (Zhang, Y., et al., Biochem J 2017, 474, 1619-1631); 5032 and 5035 (Xue, X., et al., Nat StructMol Biol 2017, 24, 643-651); 40NT (Blaum, B.S., et al., Nat Chem Biol 2015, 11, 77-82); and 4ZH1 (Blaum, B.S., et al., Glycobiology 2016, 26, 532-539).

[0273] In some embodiments, a target protein of the present disclosure is human complement component 5 (C5) (UniProtKB - P01031 (C05_HUMAN)). Activation of C5 by a C5 Convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the foundation upon which the lytic complex is assembled.

[0274] The Protein Data Bank website provides the crystal structure of Complement Component 5 searchable by 3CU7 (Fredslund, F., Nat Immunol 2008, 9, 753-760); as well as the crystal structure of Complement Component 5 bound to various compound searchable by 5I5K (Schatz-Jakobsen, J.A., et al, J Immunol 2016, 197, 337-344); 3PVM and 3PRX (Eaursen, N.S., et al., EMBO J 2011, 30, 606-616); and 3 KES (Laursen, N. S., et al., Proc Natl Acad Sci 2010, 107, 3681-3686).

[0275] In certain embodiments, a target protein of the present disclosure is complement Cis.

[0276] In certain embodiments, a target protein of the present disclosure is MASP-1 or MASP- 2.

[0277] In certain embodiments, a target protein of the present disclosure is Factor Xia.

[0278] In some embodiments, a target protein of the present disclosure is an autoantibody that binds PLA2R. Phospolipase A2 Receptor- 1 (PLA2R) is a major target in autoimmune membranous nephropathy. Membranous nephropathy is one of the leading causes of nephrotic syndrome, with most patients progressing to end-stage renal disease. Current treatment regimes with anti-CD20 antibodies can be ineffective at generating a complete remission. PLA2R is a transmembrane glycoprotein with a cysteine-rich N-terminal extracellular domain. This domain contains the epitope where autoantibodies bind. Reduction of autoantibody levels may provide relief to patients and complete elimination of the autoantibodies could be required to produce a durable remission. The Protein Data Bank provides the crystal structure of the CTLD7 domain of PLA2R, the region where autoantibodies bind (6JLI; Yu et al. J. Struct. Biol. 207, 295-300).

[0279] In some embodiments, a target protein of the present disclosure is complement C3. Complement C3 is one of the major proteins involved in the complement response, a significant factor in both innate and adaptive immunity. Elevated C3 is associated with Paroxysmal nocturnal hemoglobinuria (PNH), immune complex membranoproliferative glomerulonephritis (IC-MPGN), C3 glomerulopathy (C3G), geographic (GA), age-relatedmacular degeneration (AMD), periodontitis, amyotrophic lateral sclerosis (ALS), hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT- TMA), cold agglutinin disease (CAD) and host attack in gene therapies. Reduction of C3 levels may ameliorate some of the symptoms or complications that arise from these inflammatory diseases.

[0280] The Protein Data Bank website provides the crystal structure of complement C3, searchable by 2A73 (Janssen, B. J. Nature, 2005, 505-511). Complement C3 bound to a nanobody inhibitor can be found with PDB accession code 6EHG (Jensen, R.K. et al. J Biol Chem, 2018, 293, 62696281).

[0281] In some embodiments, a target protein of the present disclosure is Complement Clq. The complement system is part of the innate immune system and clears apoptotic cells and pathogens. Activation of this pathway begins with binding the C1 complex to an immunoglobulin that has bound to an antigen. The C1 complex consists of Clq and a tetramer of proteases (C1r and C1s). C Iq mediates the binding of complement to IgG or IgM. Following the binding event, the proteases are activated, and they cleave C4 which sets off the remainder of the pathway that ends in opsonization. Overactivity of this pathway can lead to a number of inflammatory pathologies including allograft rejection, neuromyelitis optica, generalized myasthenia gravis, and cold agglutinin disease. Degradation of Clq may reduce the symptoms associated with these inflammatory diseases.

[0282] The Protein Data Bank website provides the crystal structure of Complement Clq searchable by 2JG9 (Paidassi, H. et al., J. Immunol, 2008, 180, 2329-2338), 1PK6 (Gaboriaud, C., J. Biol. Chern, 2003, (278) 46974-46982), 5HZF (Moreau, C. et al., Front. Immunol, 2016, (7) 79), 2WNV and 2WNU (Garlatti, V. et. al., J. Immunol. 2010, (185), 808). Also provided on the PDB website is the structure of complement Clq with a ligand bound, searchable by 6Z67 (Laursen, N. et al. Front. Immunol., 2020, (11), 1504)

[0283] In some embodiments, a target protein of the present disclosure is human interleukin- 17 (IL-17) (UniProtKB - Q16552 (IL17HUMAN)). Interleukin- 17 is a 35 kDa homodimeric glycoprotein and is an important cytokine for the inflammatory response. IL- 17 is secreted by a distinct class of Helper T cells (known as Thl 7 cells) which mediates tissue inflammation. A characteristic effect of IL- 17 production is the expansion of neutrophils, and in healthy tissue it is responsible for neutrophil homeostasis. IL- 17 has been implicated as a major factor in psoriasis as well as other autoimmune diseases. Other diseases where IL-17 therapies may be of benefit include but are not limited to asthma, rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, and inflammatory bowel disease. Inflammation caused by IL- 17 has been shown tohamper recovery post-stroke.

[0284] The Protein Data Bank website provides the crystal structure of IL- 17, searchable by 4NUX (Zhang, B. et al. (2014) Acta Crystallogr D Biol Crystallogr 70: 1476-1483), 4HSA (Liu, S. et al. (2013) Nat Commun 4: 1888-1888), 4QHU (unpublished), 6WIR (Lieu, R. et al. (2020) PLoS One 15: e0232311-e0232311), 5VB9 (Ting, LP. et al. (2018) PLoS One 13: e0190850-e0190850), 4NUX (Zhang, et al. (2014) Acta Crystallogr D Biol Crystallogr 70: 1476-1483), 3IVF (Ely, L.K. et al. (2009) Nat Immunol 10: 1245-1251), 5N9B (unpublished), 2VXS (Gerhardt, S. et al. (2009) JMol Biol 394: 905).

[0285] In some embodiments, a target protein of the present disclosure is anti-piAR autoantibodies and it is related to heart failure, for example cardiomyopathy or dilated cardiomyopathy .

[0286] In some embodiments, a target protein of the present disclosure is human proprotein Convertase subtilisin / kexin type 9 (PCSK-9) (UniProtKB - Q8NBP7 (PCSK9HUMAN)). PCSK-9 is a crucial player in the regulation of plasma cholesterol homeostasis. PCSK-9 binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1 / AP0ER) and apolipoprotein receptor 2 (LRP8 / APOER2), and promotes their degradation in intracellular acidic compartments. It acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP 1 / ARH-mediated pathway, and may prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. PCSK-9 has been implicated in high blood cholesterol and the development of cardiovascular disease. The Protein Data Bank website provides the crystal structure of PCSK- 9 searchable by 2P4E (Cunningham, D., et al., Nat Struct Mol Biol., 2007, 14413-419); as well as the crystal structure of PCSK-9 bound to various compounds searchable by 3BPS (Kwon, H. J., et al., Proc Natl Acad Sci USA, 2008, 105 1820-1825); 6U26, 6U2N, 6U2P, 6U36, 6U38, and 6U3X (Petrilli, W. L., et al., Cell Chem Biol., 2019, 27 32-40.e3); 50CA (Gustafsen, C., et al., Nat Commun., 2017, 8 503-503); 4NE9 (Schroeder, C. I., et al., Chem Biol., 2014, 21 284-294); 4OV6 (Mitchell, T., et al., JPharmacol Exp Ther., 2014, 350 412-424); and 4NMX (Zhang, Y., et al., JBiol Chem., 2014, 289 942-955). Additionally, Piper et al., provides insight into the crystal structure of PCSK9 (Piper, D. E., et al., Structure, 2007, 15(5), 545-52).

[0287] In some embodiments, a target protein of the present disclosure is a human complement factor H-related protein, such as human complement factor H-related protein 3 (FHR-3). Factor H (EH), a major negative regulator of alternative complement pathway activation, belongs to a family that also includes five other related family members thought to have arisen fromnonallelic homologous recombination and interlocus gene conversion including: complement factor H-related protein 1 (FHR1), complement factor H-related protein 2 (FHR2), complement factor H-related protein 3 (FHR3), complement factor H-related protein 4 with isoforms 4A and 4B (FHR4A and FHR4B) and complement factor H-related protein 5 (FHR5).

[0288] FHR3, unlike factor H, lacks the complement regulatory domains essential for complement inactivation and also competes with factor H, resulting in complement over- activation. Thus, the present invention provides compounds for use in modulating the concentration of complement factor H-proteins, specifically FHR3, to remove factor H’s competitor and thereby restore factor H-mediated regulation to treat disorders caused by excessive complement activation.

[0289] Due to the central role that factor H plays in the regulation of complement, there are many clinical implications arising from aberrant FH activity. Loss of function mutation in factor H increase susceptibility to the renal diseases, atypical hemolytic uremic syndrome (aHUS) and dense deposit disease (ODD), whilst polymorphic variation of complement factor H has been strongly associated with important human diseases, including age-related macular degeneration (AMO) and meningococcal sepsis (Clin Exp Immunol 151(2):210-230; Immunobiology 217(11): 1034-1046).

[0290] In certain embodiments, the FHR3 mediated disease or disorder is a complement- related diseases, disorders of complement dysregulation, autoimmune diseases, kidney disease, retinal degenerative diseases, Rheumatic Diseases, associated degenerative diseases, autoimmune renal disease, dense deposit disease (ODD), and systemic autoimmune diseases.

[0291] In certain embodiments, nonlimiting examples of FHR3 mediated diseases or disorders include nephropathy, age-related macular degeneration, atypical hemolytic uremic syndrome (aHUS), autoimmune form of hemolytic uremic syndrome, hepatocellular carcinoma (HOC), C3 glomerulopathy, paroxysmal nocturnal hemoglobinuria, Polymyalgia rheumatica, rheumatoid arthritis, meningococcal sepsis, and SEE (Systemic lupus erythematosus).

[0292] In some embodiments, a target protein of the present disclosure is human vascular epithelial growth factor (VEGF) (UniProtKB - P15692 (VEGFA_HUMAN)). VEGF is a growth factor active in angiogenesis, vasculogenesis, and endothelial cell growth. VEGF induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. VEGF has been implicated in the vascularization and angiogenesis of tumors.

[0293] The Protein Data Bank website provides the crystal structure of VEGF searchable by 3QTK (Mandal, K., et al., Angew Chem Int Ed Engl., 2011, 50 8029-8033); and 4KZN (Shenet al.); as well as the crystal structure of VEGF bound to various compounds searchable by 5O4E (Lobner, E., et al., MAbs, 2017, 9 1088-1104); 4QAF (Giese, T., et al.,); 5DN2 (Tsai, Y.C.I., et al., FEES, 2017, J 283 1921-1934); 4GLS (Mandal, K., et al., Proc Natl Acad Sci USA, 2012, 109 14779-14784); and 1KMX (Stauffer, M. E. et al., J Biomol NMR, 2002, 23 57-61). Additionally, Mueller, Y. A., et al, provides insight into the Crystal structure and functional mapping of the kinase domain receptor binding site of VEGF (Mueller, Y. A., et al., Proc Natl Acad Sci U S A., 1997 Jul 8; 94(14): 7192-7197).

[0294] In some embodiments, a target protein of the present disclosure is human transforming growth factor-01 (TGF-β1) (UniProtKB - P01137 (TGFB1 HUMAN)) TGF-β1 is a multifunctional protein that regulates the growth and differentiation of various cell types and is involved in various processes, such as normal development, immune function, microglia function and responses to neurodegeneration. TGF-β1 can promote either T-helper 17 cells (Thl7) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner. TGF-β1 expression in the tumor microenvironment has been associated with a poor prognosis, and is implicated in TGF-β1 mediated tumor suppression via T-cell exclusion. TGF- β1 expression has also been implicated in hematological malignancies and fibrosis.

[0295] The Protein Data Bank website provides the crystal structure of TGF-β1 searchable by 5E8S, 5E8T, and 5E8U (Tebben, A. J., et al., Acta Crystallogr D Struct Biol., 2016, 72 658- 674); 2L5S (Zuniga, J. E., et al, J Mol Biol., 2011, 412 601-618); and 2PJY (Groppe, J., et al., Mol Cell, 2008, 29 157-168); as well as the crystal structure of TGF-β1 bound to various compounds searchable by 5QIK, 5QIL and 5QIM, (Zhang, Y., et al., ACS Med Chem Lett., 2018, 9 1117-1122); 6B8Y (Harikrishnan, L. S., et al., Bioorg Med Chem., 2018, 26 1026- 1034); 5E8W, 5E8X, 5E8Z, and 5E90 (Tebben, A. J., et al., Acta Crystallogr D Struct Biol., 2016, 72658-674); 3TZM (Ogunjimi, A.A. et al., Cell Signal, 2012, 24476-483); 2X70 (Roth, G. J., et al., J Med Chem., 2010, 53 7287); 3KCF (Guckian, K., et al., Bioorg Med Chem Lett., 2010, 20 326-329); 3FAA (Bonafoux, D., et al., Bioorg Med Chem Lett., 2009, 19 912-916); 1VJY (Gellibert, F, J., et al., J Med Chem., 2004 47 4494-4506); and 1PY5 (Sawyer, J. S., et al., Bioorg Med Chem Lett., 2004, 14 3581-3584). Additionally, Hinck et al., provides insight into the structural studies of the TGF-0S and their receptors and further insight into evolution of the TGF-0 superfamily (Hinck, A., FEES, 2012, 586(14), 1860-1870).

[0296] In some embodiments, a target protein of the present disclosure is human TNF-a (UniProtKB - P01375 (TNFA_HUMAN)). TNF-a is a pro-inflammatory cytokine active in the bodily immune response and serious inflammatory diseases. TNF-a has been implicated in a number of disorders, including but not limited to rheumatoid arthritis, inflammatory boweldisease, graft-vs-host disease, ankylosing spondylitis, psoriasis, hidradenitis suppurativa, refractory asthma, systemic lupis erthyematosus, diabetes, and the induction of cachexia.

[0297] The Protein Data Bank website provides the crystal structure of TNF-a searchable by 6RMJ (Valentinis, B., et al., Int. J. Mol. Sci., 2019, 20); 5UUI (Carrington et al., Biophys J.,2017, 113 371-380); 6OOY, 6OOZ and 6OPO (O’Connell, J., et al., Nat. Commun., 2019, 10 5795-5795); and 5TSW (Cha, S. S., J Biol Chem., 1998, T13 2153-2160); as well as the crystal structure of TNF-a bound to various compounds searchable by 5YOY (Ono et al., Protein Sci.,2018, 27 103 8-1046 ); 2AZ5 (He., M. M., et al., Science, 2005, 310: 1022-1025); 5WUX (Lee, J. U., Int J Mol Sci., 2017, 18); 5MU8 (Blevitt et al., J Med Chem., 2017, 60 3 511-3 517); 4Y6O (Feldman J. L., et al., Biochemistry, 2015, 54 3037-3050); 3WD5 (Hu, S., et al., J Biol Chem, 2013, 288 2705927067); and 4G3Y (Liang, S. Y., J Biol Chem., 2013, 288 13799- 13807).

[0298] In some embodiments, a target protein of the present disclosure is human prostate specific membrane antigen (UniProtKB - Q04609 (FOLH! HUMAN)), also known as Glutamate carboxypeptidase II (GCPII), N-acetyl-L-aspartyl-L-glutamate peptidase I (NAALADase I), and NAAG peptidase. PSMA is an enzyme that catalyzes the reaction of N- Acetyl aspartylglutamate to glutamate and N-acetylaspartate. PSMA inhibitors have been shown to decrease the levels of glutamate in the nervous system, protecting from neural degeneration in models of stroke, amyotrophic lateral sclerosis (ALS) and neuropathic pain.

[0299] In some embodiments, a target protein of the present disclosure is envelope glycoprotein GP120. In certain embodiments, the Target Protein is selected from Serum amyloid P component, amyloid precursor protein, C reactive protein (CRP), an N-methyl-D- aspartate (NMD A) receptor, a-synuclein, IAPP, transthyretin, and combinations thereof. In some embodiments, the Target Protein is selected from a calcitonin gene -related peptide (CGRP), a CGRP receptor, an N-methyl-D-aspartate (NMD A) receptor, myeloperoxidase (MPO), IAPP, transthyretin, extracellular tau, beta-amyloid, amyloid precursor protein, prion protein, and a-synuclein. In some embodiments, the target binding moiety of the present disclosure is capable of binding to extracellular tau, beta-amyloid, amyloid precursor protein, prion protein, a-synuclein, or a combination thereof.

[0300] In some embodiments, a target protein of the present disclosure is autoantibodies to the Pl adrenergic receptor (anti-P 1 AR antibodies).

[0301] In some embodiments, a target protein of the present disclosure is CD 16a. In some embodiments, CD 16a is a high-affinity form, e.g., 158V. In some embodiments, CD 16a is a low-affinity form, e.g., 158F.

[0302] In some embodiments, a target protein of the present disclosure is a toll-like receptor. Toll-like receptors (TLRs) are receptors that recognize pathogens via pathogen-associated molecular patterns. These receptors are a major component of immune response, and activation of TLRs results in proinflammatory signaling. Decreasing TLR activity may be beneficial in the treatment of diseases such as rheumatoid arthritis and systemic lupus erythematosus.

[0303] In some embodiments, a target protein of the present disclosure is a soluble FLT-1. Soluble fms-like tyrosine kinase 1 (sFLT-1), an anti angiogenic protein implicated in the pathogenesis of preeclampsia. This receptor binds VEGFA, VEGFB, and placental growth factor and controls angiogenesis in healthy and diseased tissues. sFLT-1 is upregulated in women with preeclampsia and high levels of sFLT-1 is a cause of maternal hypertension of proteinuria. During placentation, a critical process is remodeling of certain arteries to support the pregnancy. One such artery is the spiral artery (SpA). SpA remodeling involves apoptosis of certain mother cells followed by the production of specialized fetal trophoblast cells in combination with uterine natural killer (uNK) cells Surrpounding the SpAs. In preeclampsia pregnancies, SpA remodeling is poor and the reduced vasodilation during preeclampsia affects placental perfusion.

[0304] In some embodiments, a target protein of the present disclosure is a soluble endoglin (sEng). sEng (soluble Eng), caused by Eng shedding from endothelial cell surface, has antiangiogenic effects in pregnant women, which can lead to preeclampsia. It has been hypothesized that this occurs via binding to circulating TGF-pi, a protein involved in homeostasis of angiogenic processes. sEng is used as a biomarker of preeclampsia during pregnancy, in particular during the second trimester.

[0305] In certain embodiments, a target protein of the present disclosure is selected from the group consisting of 1-40-β-amyloid, 5 ’-nucleotidase, activated F9, F1O, activin receptor-like kinase 1, alpha-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-I), Bacillus anthracis anthrax, BAFF, beta amyloid, c-Met, Cis, 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, E. coli shiga toxin type-1, E. coli shiga toxin type-2, EGFL7, EGER, 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, EFN-I, IFN-U, IgE, IgE Fc region, IGF1, IGF2, IGHE, IL 17A, IL 17A and IL17F, IL 20, IL-1, IL-12, IL-23, IL-13, IL-17, IL-lu, IL-22, IL-4, IL-5, IL-6, IL17A and IL17F,ILIA, IL2, IL23, IL23A, IL31RA, IL6, IL6R, IL9, ILGF2, Influenza A hemagglutinin, influenza A virus hemagglutinin, influenza A virus hemagglutinin HA, interferon gamma, interferon gamma- induced protein, interleukin 1 alpha, interleukin 13, interleukin 17 alpha, interleukin 17 alpha, TNF, interleukin 17 A, kallikrein, LOXL2, LRRC15, LTA, M ASP-2, MCP-1, MIF, MST1R (aka RON), MUC1, myostatin, NACP, NCA-90 (granulocyte antigen), neural apoptosis-regulated proteinase 1, NGF, NOGO- A, Notch 1, NRP1, oxLDL, PCSK9, PD- Ll, phosphatidylserine, RANKL, RGMA, root plate- specific spondin 3, RTN4, sclerostin, SDC1, serum amyloid A protein, serum amyloid P component, SOST, Staphylococcus aureus alpha toxin, tau protein, TFPI, TGF beta 1, TGF beta 2, TGF-it, TNF- J, TROP-2, TSLP, VEGF- A, VEGF-A and Ang-2, VEGFA, and VWF.

[0306] In certain embodiments, the target protein is TNFa, HER2, EGFR, HER3, VEGFR, CD20, CD 19, CD22, anb3 integrin, CEA, CXCR4, MUC1, LCAM1, EphA2, PD-1, PD-L1, TIGIT, TIM3, CTLA4, VISTA, Notch receptors, EGF, c-MET, CCL2, CCR2, Frizzled receptors, Wnt, LRP5 / 6, CSF-IR, SIRPa, CD38, CD73, TGF-b, Bombesin R, CAIX, CD13, CD44v6, Emmprin, Endoglin, EpCAM, FAP-a, Folate R, GRP78, IGF-IR, Matriptase, Mesothelin, sMET / HGFR, MT1-MMP, MT6-MMP, PSCA, PSMA, Tn antigen, and uPAR, TSHRa, Myelin oligodendrocyte glycoprotein (MOG), AChR-al, noncollagen domain 1 of the a3 chain of type IV collagen (a3NCl), AD AMTS 13, Desmoglein-1 / 3, or GPIb / IX, GPIIb / IIIa, GPIa / IIa, NMD A receptor, glutamic acid decarboxylase (GAD), amphiphysin and gangliosides GM1, GD3, GQ1B, LILRB1, LILRB2, VEGF-R, CXCR4, CXCL12, CSF-1, CD47, aggregated light chain, or aggregated transthyretin.

[0307] In certain embodiments, the target protein is an antibody that binds to TSHRa, MOG, AChR-al, noncollagen domain 1 of the a3 chain of type IV collagen (a3NCl), AD AMTS 13, Desmoglein-1 / 3, or GPIb / IX, GPIIb / IIIa, GPIa / IIa, NMD A receptor, glutamic acid decarboxylase (GAD), amphiphysin, or gangliosides GM1, GD3, or GQ1B.

[0308] In certain embodiments, the target protein is SIRPa, CCR2, CSF-IR, LILRB1, LILRB2, VEGF-R, or CXCR4. In other embodiments, the target protein associated with TAMs comprises CCL2, CXCL12, CSF-I, or CD47.

[0309] In certain embodiments, the target protein of the present disclosure is upregulated in cancer or involved in cancer progression. In some embodiments, the target protein upregulated in cancer or involved in cancer progression comprises HER2, EGFR, HER3, VEGFR CD20, CD 19, CD22, anb3 integrin, CEA, CXCR4, MUC1, EC AMI, EphA2, PD-1, PD-L1, TIGIT, TIM3, CTLA4, VISTA, Notch receptors, EGF, c-MET, CCL2, CCR2, Frizzled receptors, Wnt,LRP5 / 6, CSF-1R, SIRPa, CD38, CD73, or TGF-b.

[0310] In certain embodiments, the target protein is an autoantibody of an autoimmune disease. In some embodiments, the target protein is an autoantigen in an autoimmune disease. In some embodiments, the autoimmune disease is selected from Graves’ Disease, Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), Myasthenia Gravis, Anti-GBM Disease, Immune Thrombotic Thrombocytopenic Purpura, Acquired Pemphigus Vulgaris, Immune Thrombocytopenia, autoimmune encephalitis, Guillain-Barre Syndrome, and Membranous Nephropathy.

[0311] In certain embodiments, the target protein is an autoantibody which itself binds disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), steroidogenic cytochrome P450 enzyme 21 -hydroxylase, N-methyl-d- aspartate-(NMDA)-receptor, erythrocytes, anti-smooth muscle antibodies (ASMAs), actin, platelet, signal recognition particle (SRP), 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), myosin, sperm, amylase alpha2, type XVII collagen (col 17), kallikrein 13, type VII collagen (col7), myeloperoxidase (MPO), type IV collagen, proteinase 3 (PR3), thyrotropin receptor (TSHR), thyroglobulin, thyroid peroxidase (TPO), thyroglobulin, thyroid peroxidase (TPO), platelets, myeloperoxidase (MPO), muscle nicotinic acetylcholine receptors, muscle- specific kinase (MuSK), low-density lipoprotein receptor protein 4 (LRP4), myosin, betal adrenergic receptor, adenine-nucleotide translocase, aquaporin-4, myelin oligodendrocyte glycoprotein (MOG), heat shock protein 90 (HSP90), heat shock protein A5 (HSPA5), desmoglein-3, parietal cells, mitochondria, phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7 A (THSD7A), cyclic Citrullinated proteins, RNA binding proteins (Ros), La, double -stranded DNA (dsDNA), angiotensin II type 1 receptor (AT1R), endothelin-1 type A receptor (ETAR), insulin, glutamic acid decarboxylase, or protein tyrosine phosphatase.

[0312] In some embodiments, the autoantibody in an autoimmune disease is an antibody binding to TSHRa, Myelin oligodendrocyte protein (MOG), AChR-al, or noncollagen domain 1 of the a3 chain of type IV collagen (a3NCl), AD AMTS 13, Desmoglein-1 / 3, GPIb / IX, GPIIb / IIIa, GPIa / IIa, NMDA receptor, glutamic acid decarboxylase (GAD), amphiphysin, or gangliosides GM1, GD3 orGQIB.

[0313] In some embodiments, the target protein of the present disclosure is upregulated or expressed in a neurodegenerative disease. In some embodiments, the target protein upregulated or expressed in a neurodegenerative disease is alpha- synuclein, amyloid beta or complement cascade component.

[0314] In some embodiments, the target protein of the present disclosure is upregulated in amyloidosis. In some embodiments, the amyloidosis can be systemic amyloidosis. In other embodiments, the amyloidosis can be localized amyloidosis. In some embodiments, the protein upregulated in systemic amyloidosis can be transthyretin.

[0315] In some embodiments, the target protein of the present disclosure is an immune checkpoint protein. In some embodiments, the target protein comprises a cancer antigen. In certain embodiments, the cancer antigen comprises HER2, EGER, CDCP1, CD38, IGF-1R, MMP14, and TROP2.

[0316] In some embodiments, the target protein of the present disclosure is an immunomodulatory protein. In certain embodiments, the immunomodulatory protein comprises PD-L1, PD-1, CTLA-4, B7-H3, B7-H4, LAG3, NKG2D, TIM-3, VISTA, CD39, CD73 (NT5E), A2AR, SIGLEC7, and SIGLEC15. In some embodiments, the target protein comprises a B cell antigen. In some exemplary embodiments, the B cell antigen comprises CD 19 and CD20.

[0317] In some embodiments, the target protein of the present disclosure is a soluble target protein. In some embodiments, the soluble target protein comprises an inflammatory cytokine, a growth factor (GF), a toxic enzyme, a target associated with metabolic diseases, a neuronal aggregate, or an autoantibody. In certain embodiments, the inflammatory cytokine comprises lymphotoxin, interleukin- 1 (IL-1), IL-2, IL-5, IL-6, IL-12, IL-13, IL-17, IL-18, IL-23, tumor necrosis factor alpha (TNF-a), interferon gamma (IFNy), and granulocyte-macrophage colony stimulating factor (GM-CSF). In certain embodiments, the growth factor comprises EGF, FGF, NGF, PDGF, VEGF, IGF, GMCSF, GCSF, TGF, RANK-L, erythropieitn, TPO, BMP, HGF, GDF, neurotrophins, MSF, SGF, GDF, and an isoform thereof. In certain embodiments, the toxic enzyme comprises a protein arginine deiminase 1 (PAD1), PAD2, PAD3, PAD4, and PAD6, leucocidin, hemolysin, coagulase, treptokinase, hyaluronidase. In certain embodiments, the toxic enzyme comprises PAD2 or PAD4. In some embodiments, the neuronal aggregate comprises Ab, TTR, a-synuclein, TAO, and prion. In certain embodiments, the autoantibody comprises IgA, IgE, IgG, IgMand IgD.

[0318] In some embodiments, the target protein of the present disclosure is a growth factor, a cytokine, a chemokine, a hormone, a neurotransmitter, a capsid, a soluble receptor, an extracellular secreted protein, an antibody, a lipoprotein, an exosome, a virus, a cell, or a plasma membrane protein, wherein the bifunctional compounds of the invention can then be used to direct the extracellular target molecule to lysosomes for degradation. Examples of such target molecules which can be directed for degradation using the bifunctional compound of theinvention include, but are not limited to, LDL (ApoB), Lp(a), ApoCIII, ANGPTL3, ANGPTL4, ANGPTL8, Factor 11, GDF15, LPL, PCSK9, IL1 p, IL17, Complement Factor B, Complement Factor D, MPO, IgE, IL7, IL12A, IL23, TNFA, CXCR4, MAPT, FHR3, TIMP1, Apelin, BMP6, BMP9 / GDF2, CSF-1, EPO, IL5, MFGE8, TSLP, TSP, C5, CXCL10, FGF23, IGF1, IL10, IL13, IL2, IL6, VEGFA, NKG2D, ZNFR3, ADA2, suPAR, TGF-β1, IL4 receptor, sToll receptor, histamine, Tau, proglanulin, Alpha-synuclein, toxins, venoms, HBV soluble antigen, viral antigens, prion protein, scFV, AAV and anti-AAV antibodies. In certain embodimenst, the extracellular target molecules which can be directed for degradation using the bifunctional compound of the invention are PCSK9and FHR3.

[0319] In some embodiments, the target protein of the present disclosure is a protein selected from proprotein convertase subtilisin / kexin type 9 (PCSK9), tumor necrosis factor receptor 1 (TNFR1), interleukin- 1 receptor (ILIR), low density lipoproteins, very low density lipoproteins, chylomicrons, apolipoprotein B (ApoB), lipoprotein(a) (Lp(a)), apolipoprotein C3 (ApoCIII), angiopoietin-like 3 (ANGPTL3), angiopoietin-like 4 (ANGPTL4), angiopoietin-like 8 (ANGPTL8), Factor 11, growth differentiation factor 15 (GDF15), lipoprotein lipase (LPL), interleukin 1-beta (IL 113), interleukin 17 (IL 17), complement Eactor B, complement Factor D, myeloperoxidase (MPO), immunoglobulin A (IgA), immunoglobulin E (IgE), programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), interleukin 7 (IL7), interleukin 12A (IL12A), interleukin 23 (IL23), tumor necrosis factor A (TNFA), microtubule associated protein tau (MAPT), complement factor H-related protein 3 (FHR3), tissue inhibitor of metalloproteinases 1 (TIMPI), Apelin, bone morphogenetic protein 6 (BMP6), bone morphogenetic protein 9 / growth differentiation factor 2 (BMP9 / GDF2), colony stimulating factor 1 receptor (CSF-1), erythropoietin (EPO), interleukin 5 (IL5), milk fat globule-EGF Factor 8 protein (MFGE8), thymic stromal lymphopoietin (TSLP), thrombospondin (TSP), complement component 5 (C5), C-X-C motif chemokine ligand 10 (CXCL10), fibroblast growth factor 23 (FGF23), insulin-like growth factor 1 (IGF1), interleukin 10 (IL 10), interleukin 13 (IL 13), interleukin 2 (IL2), interleukin 6 (IL6), vascular endothelial growth factor A (VEGF-A), adenosine deaminase 2 (ADA2), soluble urokinase - type plasminogen activator receptor (suPAR), transforming growth factor beta 1 (TGF-pi), progranulin, alpha-synuclein, a toxin, a venom, an HBV soluble antigen, a viral antigen, a prion protein, a scFv, an AAV, and an anti-AAV antibody.

[0320] In some embodiments, the target protein of the present disclosure is a protein selected from ADA2, ANGPTL3, ANGPTL4, ANGPTL8, Apelin, ApoC3, APP, BMP6, BMP9 / GDF2, C2, C5, CCL2, CD40L, CD71, CD98, ChE, CPB2, CSF-1, CXCL10 / IP- 10, CXCR4, EGER,EPO, factor B, factor D, factor H, factor IX, factor VII, factor Xa, factor XI, factor XII, factorXIII, FGF1, FGF2, FGFR1-4, FHR3, FN1, GDF15 / MIC-1, GLP1R, GPR75, H4R, HER2, IFN-γ, IgA, IgE, IGF1, IgG, IgM, IL1, IL1 β, IL10, IL12A, IL13, IL17, IL2, IL21, IL22, IL23, IL31, IL33, IL4r, IL5, IL6, IL8, Kallikrein, LP(a), LPL, MAPT, MFGE8, MIE, MMP1, MPO, MuSK, NE, NKG2D, PAI-1, PCSK-9, PD1, PDL1, PGF, Prion, proglanulin, sPLA2, sToll receptor, suPAR, Tau, TfR, TGF-β1, TGF-β2, TIMP1, TL1A, TNFa, tPA, TSLP, TSP1, TTR, uPA, VEGF, VEGFA, ZNFR3, a-syn, avB6, avB8, or TMPRSS6.II. Target Binding Moieties

[0321] Target binding moieties include any molecule or any part of a molecule that is capable of binding (e.g., capable of specifically binding) to a given target. Such molecules may be, but are not limited to, polypeptides or proteins (e.g., antibodies or antigen-binding fragments thereof or antibody mimetics), small molecules, aptamers, etc.

[0322] In some embodiments, a target binding moiety binds a target protein in a non-covalent fashion. In other embodiments, a target binding moiety binds a target protein in a covalent manner that can be irreversible or reversible.

[0323] In some embodiments, a target binding moiety of the present disclosure is not a therapeutic moiety, i.e., the moiety by itself does not confer a therapeutic benefit.

[0324] In some embodiments, a target binding moiety of the present disclosure comprises a small molecule.

[0325] In some embodiments, a target binding moiety of the present disclosure comprises a polypeptide or a protein. In some embodiments, the target binding moiety has a molecular weight of at least about 5 kDa, at least about 10 kDa, at least about I5kDa, at least about 20 kDa, at least about 25 kDa, at least about 30 kDa, at least about 40 kDa, at least about 50 kDa, at least about 75 kDa, at least about 100 kDa, at least about 125 kDa, at least about 150 kDa, at least about 175 kDa, at least about 200 kDa, at least about 225 kDa, at least about 250 kDa, at least about 275 kDa, or at least about 300 kDa. In some embodiments, the target binding moiety has a molecular weight of at most about 5 kDa, at most about 10 kDa, at most about 15kDa, at most about 20 kDa, at most about 25 kDa, at most about 30 kDa, at most about 40 kDa, at most about 50 kDa, at most about 75 kDa, at most about 100 kDa, at most about 125 kDa, at most about 150 kDa, at most about 175 kDa, at most about 200 kDa, at most about 225 kDa, at most about 250 kDa, at most about 275 kDa, or at most about 300 kDa. In some embodiments, the polypeptide is 5 to 200 amino acids in length, such as 5 to 175, 5 to 150, 5 to 125, 5 to 100, 5 to 90, 5 to 80, 5 to 70, 5 to 60, 5 to 50, 5 to 45, 5 to 40, 5 to 35, 5 to 30, 5 to25, 5 to 20, 5 to 15, 5 to 10, 10 to 200, 10 to 175, 10 to 150, 10 to 125, 10 to 100, 10 to 90, 10 to 80, 10 to 70, 10 to 60, 10 to 50, 10 to 45, 10 to 40, 10 to 35, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 200, 15 to 175, 15 to 150, 15 to 125, 15 to 100, 15 to 90, 15 to 80, 15 to 70, 15 to60, 15 to 50, 15 to 45, 15 to 40, 15 to 35, 15 to 30, 15 to 25, 15 to 20, 20 to 200, 20 to 175, 20 to 150, 20 to 125, 20 to 100, 20 to 90, 20 to 80, 20 to 70, 20 to 60, 20 to 50, 20 to 45, 20 to 40,20 to 35, 20 to 30, 20 to 25, 25 to 200, 25 to 175, 25 to 150, 25 to 125, 25 to 100, 25 to 90, 25 to 80, 25 to 70, 25 to 60, 25 to 50, 25 to 45, 25 to 40, 25 to 35, 25 to 30, 30 to 200, 30 to 175,30 to 150, 30 to 125, 30 to 100, 30 to 90, 30 to 80, 30 to 70, 30 to 60, 30 to 50, 30 to 45, 30 to40, 30 to 35, 35 to 200, 35 to 175, 35 to 150, 35 to 125, 35 to 100, 35 to 90, 35 to 80, 35 to 70,35 to 60, 35 to 50, 35 to 45, 35 to 40, 40 to 200, 40 to 175, 40 to 150, 40 to 125, 40 to 100, 40 to 90, 40 to 80, 40 to 70, 40 to 60, 40 to 50, 40 to 45, 45 to 200, 45 to 175, 45 to 150, 45 to 125,45 to 100, 45 to 90, 45 to 80, 45 to 70, 45 to 60, 45 to 50, 50 to 200, 50 to 175, 50 to 150, 50 to 125, 50 to 100, 50 to 90, 50 to 80, 50 to 70, 50 to 60, 60 to 200, 60 to 175, 60 to 150, 60 to125, 60 to 100, 60 to 90, 60 to 80, 60 to 70, 70 to 200, 70 to 175, 70 to 150, 70 to 125, 70 to100, 70 to 90, 70 to 80, 80 to 200, 80 to 175, 80 to 150, 80 to 125, 80 to 100, 80 to 90, 90 to200, 90 to 175, 90 to 150, 90 to 125, 90 to 100, 100 to 200, 100 to 175, 100 to 150, 100 to 125,125 to 200, 125 to 175, 125 to 150, 150 to 200, 150 to 175, or 175 to 200 amino acids in length. In some embodiments, the polypeptide is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids in length.

[0326] In some embodiments, a target binding moiety comprising a polypeptide or protein is linked to a ceramide moiety (e.g., a ceramide moiety disclosed herein), optionally via a liner (e.g., a linker disclosed herein), at a terminal amine comprised in the polypeptide or protein. In some embodiments, a target binding moiety comprising a polypeptide or protein is linked to a ceramide moiety (e.g., a ceramide moiety disclosed herein), optionally via a liner (e.g., a linker disclosed herein), at a terminal carboxylic acid comprised in the polypeptide or protein. In some embodiments, a target binding moiety comprising a polypeptide or protein is linked to a ceramide moiety (e.g., a ceramide moiety disclosed herein), optionally via a liner (e.g., a linker disclosed herein), at an amine, hydroxyl, or carboxylic acid side chain comprised in the polypeptide or protein. For example, a target binding moiety comprising a peptide having the amino acid sequence MLKKIE (SEQ ID NO: 584) may be linked to a ceramide moiety, optionally via a linker, at the following non-limiting examples of locations:

[0327] In some embodiments, a target binding moiety of the present disclosure is an antibody or an antigen-binding fragment thereof. The antibody or antigen-binding fragment thereof may be monospecific, bispecific, or multispecific. In some embodiments, the antibody or antigen- binding fragment thereof is murine, chimeric, humanized, or human. In some embodiments, the antibody is a monoclonal antibody. Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2), or subclass. An “antigen-binding fragment” of an antibody may be any one or more fragments of the antibody that retain the target-binding ability. Nonlimiting examples of antigen-binding fragments include a Fab, an scFab (single-chain Fab), a F(ab’)2, a Fab’, a single-chain Fv (scFv), an Fv fragment, a diabody (a dimer of scFv), a single domain antibody (sdAb, such as a nanobody), or an isolated complementarity determining region (CDR). In some embodiments, the target binding moiety is an scFv.

[0328] In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody constant region or a fragment or variant thereof. In some embodiments, the antibody constant region is a heavy chain constant region (e.g., heavy chain constant region of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, or IgE). In some embodiments, the antibody constant region or fragment or variant thereof has an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a heavy chainconstant region of, e.g., the heavy chain constant region of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, or IgE. In In some embodiments, the antibody constant region is a light chain constant region chosen (e.g., light chain constant region of kappa or lambda). The constant region can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, and / or complement function). In certain embodiments, the antibody or antigen-binding fragment thereof has effector function and / or can fix complement. In other embodiments, the antibody or antigen-binding fragment thereof does not recruit effector cells or fix complement. In certain embodiments, the antibody or antigen-binding fragment thereof has reduced or no ability to bind an Fc receptor. In other embodiments, the antibody or antigen-binding fragment thereof has increased ability to bind an Fc receptor. In certain embodiments, the antibody or antigen-binding fragment thereof has reduced or abolished effector function. In other embodiments, the antibody or antigen-binding fragment thereof has enhanced effector function.

[0329] In some embodiments, the antibody or antigen-binding fragment thereof may be conjugated or fused to another moiety, e.g., a therapeutic moiety, a cytotoxic moiety, an enzyme, a label, or a moiety that increases serum half-life (e.g., a polyethylene glycol (PEG) moiety).

[0330] In some embodiments, the target binding moiety is an antibody mimetic, such as an Affibody, an Affilin, an Affimer, an afftin, an Alphabody, an Anticalin, an avimer, a camelid nanobody, a Centyrin, a DARPin, a Fynomer, a monobody, or a nanoCEAMP. The antibody mimetic may be monospecific, bispecific, or multispecific.

[0331] In some embodiments, a target binding moiety disclosed herein is optionally substituted with 1, 2, 3, or 4 is optionally substituted with 1, 2, 3, or 4 optional substituents independently selected from alkyl (including C1-C4alkyl), alkenyl (including C2-C4alkenyl), alkynyl (including C2-C4alkynyl), haloalkyl (including C1-C4haloalkyl), — OR6, F, Cl, Br, I, — NR6R7, cyano, nitro, C(O)R3, wherein the optional substituent isselected such that a stable compound results.

[0332] Any target binding moiety disclosed herein with stereochemistry is contemplated without stereochemistry. For example, in certain embodiments of a target binding moiety being, the target binding moiety beingis also contemplated.

[0333] In certain embodiments, a target binding moiety of the present disclosure is selected from IgA, IgG, IgE, TNF-alpha, IL-1, IL-2, IL-6, IFN-γ, VEGF, TGF-β1, PCSK-9, CPB2, ChE, CCL2, Factor VII, Factor IX, CD40L, Factor Xa, Factor XI, Factor Xia, Factor XII,Factor XIII, FGF1, FGF2, FN1, IL-5, IL-8, IL-10, IL-21, IL-22, Kallikrein 1, LPL, MMP1,MIF, GIF, L-dopachrome isomerase, or phenylpyruvate tautomerase, neutrophil elastase,Prothrombin, KLKB1, PLG, PAI-1, endothelial plasminogen activator inhibitor, serpin El, phospholipases A2, PLA2, PA21B, PLA2G1B, PLA2-IB, PLA2, PLA2A, PA2IIA, PLA2G2A, PLA2-IIA, PGF, plasminogen activator, tissue type (tPA, PLAT), Transforming growth factor beta 2 (TGF-β2, TGFB2), thrombospondin 1, Urokinase, Urokinase-type plasminogen activator, complement factor B, complement factor D, target complement factor H, and complement component 5.

[0334] In certain embodiments, a target binding moiety of the present disclosure is a ligand for a protein selected from IgA, IgG, IgE, TNF-alpha, IL-1, IL-2, IL-6, IFN-γ, VEGF, TGF-P1, PCSK-9, CPB2, ChE, CCL2, Factor VII, Factor IX, CD40L, Factor Xa, Factor XI, Factor Xia,Factor XII, Factor XIII, FGF1, FGF2, FN1, IL-5, IL-8, IL-10, IL-21, IL-22, Kallikrein 1, LPL,MMP1, MIF, GIF, L-dopachrome isomerase, or phenyl pyruvate tautomerase, neutrophil elastase, Prothrombin, KLKB1, PLG, PALI, endothelial plasminogen activator inhibitor, serpin El, phospholipases A2, PLA2, PA21B, PLA2G1B, PLA2-IB, PLA2, PLA2A, PA2IIA, PLA2G2A, PLA2-IIA, PGF, plasminogen activator, tissue type (tPA, PLAT), Transforming growth factor beta 2 (TGF-β2, TGFB2), thrombospondin 1, Urokinase, Urokinase-type plasminogen activator, complement factor B, complement factor D, target complement factor H, and complement component 5. In certain embodiments, a target binding moiety of the present disclosure is a ligand for anti-BlAR. a. Target Binding Moieties Capable of Binding IgG

[0335] In some embodiments, target binding moieties of the present disclosure are capable of binding IgG. In some embodiments, target binding moieties of the present disclosure are capable of specifically binding IgG (accordingly, also referred to as “IgG-specific target binding moieties”). In some embodiments, specific degradation of IgG can be accomplished through the use of an IgG-specific target binding moiety.

[0336] In some embodiments, a target binding moiety binds to the Fc region of IgG. In some embodiments, an IgG-specific target binding moiety is an Fc-binding peptide. In certain embodiments, an IgG-specific target binding moiety is Fc-BP2. In certain embodiments, an IgG-specific target binding moiety is Fc-III.

[0337] In certain embodiments, the target binding moiety capable of binding IgG comprises or is represented by one of the following:

[0338] In certain embodiments, the target binding moiety capable of binding IgG comprises or is represented by one of the following:

[0339] In certain embodiments, the target binding moiety capable of binding IgG is represented by one of the following:

[0340] In certain embodiments, the target binding moiety capable of binding IgG comprises or is represented by one of the following:

[0341] In certain embodiments, the target binding moiety capable of binding IgG is represented by one of the following:or

[0342] In certain embodiments, the target binding moiety capable of binding IgG comprises or is represented by one of the following:Menadione Carboxy ethyl Lysine (R1 = Me) wherein XRis O, S, NH, or N-C1-C3alkyl; and XMis O, S, NH, or N-C1-C3alkyl.

[0343] In certain embodiments, the target binding moiety capable of binding IgG comprises or is represented by one of the following:

[0344] In certain embodiments, the target binding moiety capable of binding IgG comprises or is represented by:wherein RNO2is a dinitrophenyl group optionally linked through CH2, S(O), S(O)2, S(O)2O, OS(O)2, or OS(O)2O.

[0345] In certain embodiments, the target binding moiety capable of binding IgG comprises or is represented by:, wherein X100is selected from O, CH2, NH, N -C1-C3alkyl, NC(O)C1-C3alkyl, S(O), S(O)2, — S(O)2O, — OS(O)2, or OS(O)2O.

[0346] In certain embodiments, the target binding moiety capable of binding IgG comprises or is represented by: where k"" is 1-4 (preferably 2-3, most often 3) or agroup.

[0347] In some embodiments, the target binding moiety capable of binding IgG comprises or is a peptide. In some embodiments, the peptide comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from Table 1. In some embodiments, the peptide comprises or has an amino acid sequence selected from Table 1.Table 1. Exemplary Target Binding Moieties Capable of Binding IgG

[0348] In certain embodiments, the target binding moiety capable of binding IgG comprises or is represented by:

[0349] In certain embodiments, the target binding moiety capable of binding IgG comprises or has a structure shown in FIG. 20.

[0350] In some embodiments, the target binding moiety capable of binding IgG comprises or is an IgG targeting ligand described in international patent publications WO 2021 / 155317, WO 2022 / 235699, and WO 2024 / 098039, the contents of each of which are incorporated herein by reference.Target binding moieties capable of binding lgG4

[0351] In some embodiments, target binding moieties of the present disclosure are capable of binding IgG4. In some embodiments, target binding moieties of the present disclosure are capable of specifically binding IgG4. In some embodiments, target binding moieties of the present disclosure are capable of specifically binding IgG4 (accordingly, also referred to as “IgG4- specific target binding moieties”). In some embodiments, specific degradation of IgG4 can be accomplished through the use of an IgG4- specific target binding moiety.

[0352] In some embodiments, the target binding moiety capable of binding IgG4 comprises or is an antibody or antigen binding fragment thereof.

[0353] In some embodiments, the antibody or antigen binding fragment thereof is capable of binding to human IgG4 with a dissociation constant of 5.0 x 10-10or less. In some embodiments, the antibody or antigen binding fragment thereof binds to an epitope of positions 221 to 3T1 of a human IgG4 heavy chain constant region represented by SEQ ID NO: 585, and has glutamic acid at position 299.

[0354] IgG4 heavy chain constant region sequence:ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 585).

[0355] In some embodiments, the antibody is produced by a hybridoma MaI4-08. In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 86, and / or a light chain variable region (VL) that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100%) identical to SEQ ID NO: 90. In some embodiments, the antibodies or antigen-binding fragments comprise the complementarity determining regions CDR1, CDR2, and CDR3, determined under Rabat, IMGT, Chothia, or any other CDR determination method known in the art, of the VH sequence of SEQ ID NO: 86, and / or the complementarity determining regions CDR1, CDR2, and CDR3, determined under Rabat, IMGT, Chothia, or any other CDR determination method known in the art, of the VH and VL sequences of SEQ ID NO: 90. In some embodiments, the VH comprises CDR1, CDR2, and CDR3, comprising the amino acid sequences of SEQ ID NOs: 87, 88, 89, respectively. In some embodiments, the VL comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 91, 92, 93, respectively. In some embodiments, the antibodies or antigen-binding fragments comprise (a) a VH that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 87, 88, 89, respectively; and (b) a VL that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 91, 92, 93, respectively.

[0356] In some embodiments, the antibody is produced by a hybridoma MaI4-09. In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 94, and / or a light chain variable region (VL) that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100%) identical to SEQ ID NO: 98. In some embodiments, the antibodies or antigen-binding fragments comprise the complementarity determining regions CDR1, CDR2, and CDR3, determined under Rabat, IMGT, Chothia, or any other CDR determination method known in the art, of the VH sequence of SEQ ID NO: 94, and / or the complementarity determining regions CDR1, CDR2, and CDR3, determined under Rabat, IMGT, Chothia, or any other CDR determination method known in the art, of the VH and VL sequences of SEQID NO: 98. In some embodiments, the VH comprises CDR1, CDR2, and CDR3, comprising the amino acid sequences of SEQ ID NOs: 95, 96, 97, respectively. In some embodiments, the VL comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 99, 100, 101, respectively. In some embodiments, the antibodies or antigen-binding fragments comprise (a) a VH that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 95, 96, 97, respectively; and (b) a VL that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 99, 100, 101, respectively.

[0357] In some embodiments, the target binding moiety capable of binding IgG4 comprises or is an antigen binding fragment, such as a Fab, an scFab, a F(ab’)2, a Fab’, an scFv, an Fv fragment, a diabody, or a single domain antibody. In some embodiments, the target binding moiety is a Fab. In some embodiments, the Fab comprises a heavy chain variable region (VH) that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 94, and / or a light chain variable region (VL) that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100%) identical to SEQ ID NO: 98. In some embodiments, the Fab comprises the complementarity determining regions CDR1, CDR2, and CDR3, determined under Rabat, IMGT, Chothia, or any other CDR determination method known in the art, of the VH sequence of SEQ ID NO: 94, and / or the complementarity determining regions CDR1, CDR2, and CDR3, determined under Rabat, IMGT, Chothia, or any other CDR determination method known in the art, of the VH and VL sequences of SEQ ID NO: 98. In some embodiments, the VH comprises CDR1, CDR2, and CDR3, comprising the amino acid sequences of SEQ ID NOs: 95, 96, 97, respectively. In some embodiments, the VL comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 99, 100, 101, respectively. In some embodiments, the antibodies or antigen-binding fragments comprise (a) a VH that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 95, 96, 97, respectively; and (b) a VL that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 99, 100, 101, respectively. In some embodiments, the Fab comprises a heavy chain (HC) that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 102, and / or a light chain (EC) that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100%) identical to SEQ ID NO: 104.Table 2. Exemplary Target Binding Moieties Capable of Binding IgG4

[0358] In some embodiments, the target binding moiety capable of binding IgG4 comprises or is an antibody or an antigen binding fragment thereof described in U.S. Pat. No. 11,372,001, the contents of which are incorporated herein by reference.

[0359] In some embodiments, the target binding moiety capable of binding IgG4 comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from Table 3. In some embodiments, the target binding moiety capable of specifically binding IgG4 comprises or has an amino acid sequence selected from Table 3.Table 3. Exemplary Target Binding Moieties Capable of Binding IgG4

[0360] In certain embodiments, the target binding moiety capable of specifically binding IgG4 is described in Gunnarsson et al. Biomol Eng. 2006, 23(2-3): 111-7, the contents of which are incorporated herein by reference. b. Target Binding Moieties Capable of Binding IgA

[0361] In some embodiments, target binding moieties of the present disclosure are capable of binding IgA. In some embodiments, target binding moieties of the present disclosure are capable of specifically binding IgA (accordingly, also referred to as “IgA-specific target binding moieties”). In some embodiments, specific degradation of IgA can be accomplished through the use of an IgA- specific target binding moiety. In some embodiments, the IgA is IgAl. In some embodiments, the IgAl galactose-deficient IgAl (Gd-IgAl). In some embodiments, the IgA is IgA2.

[0362] In certain embodiments, the target binding moiety capable of binding IgA (e.g., IgAl and / or IgA2, such as Gd-IgAl) comprises or is represented by one of the following:

[0363] In certain embodiments, the target binding moiety capable of binding IgA is represented by:

[0364] In some embodiments, the target binding moiety capable of binding IgA (e.g., IgAl and / or IgA2, such as Gd-IgAl) is a peptide. In some embodiments, the peptide comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from Table 4. In some embodiments, the peptide comprises or has an amino acid sequence selected from Table 4.Table 4. Exemplary Target Binding Moieties Capable of Binding IgA

[0365] In some embodiments, the target binding moiety capable of binding Gd-IgAl comprises or is an antibody or antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof is derived from Km55. For example, in some embodiments, the antibody or antigen binding fragment thereof comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 108, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 113. In some embodiments, the antibody or antigen binding fragment thereof comprises the HCDR1, HCDR2, and HCDR3, and LCDR1, LCDR2, and LCDR3, determined under Rabat, IM GT, Chothia, or any other CDR determination method known in the art, of the VH and VL sequences of SEQ ID NOs: 108 and 113, respectively. In some embodiments, the VH comprises HCDR1, HCDR2, and HCDR3, comprising the amino acid sequences of SEQ ID NOs: 109, 110, and 111, respectively. In some embodiments, the VL comprises LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 114, 115, and 116, respectively. In some embodiments, the antibody or antigen binding fragment thereof comprises (a) a VH that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 109, 110, and 111, respectively; and (b) a VL that comprises LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 114, 115, and 116, respectively. In certain embodiments, the antibody or antigen binding fragment thereof comprises an HC that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence selected from of SEQ ID NOs: 107 and 117-122, and an EC that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 112. In some embodiments, the antibody or antigen binding fragment thereof is derived from humanized Km55.Table 5. Exemplary Target Binding Moieties Capable of Binding Dg-IgAl

[0366] In some embodiments, the target binding moiety capable of binding IgA (e.g., IgAl and / or IgA2, such as Gd-IgAl) is jacalin and comprises or has an amino acid sequence of: YYALSDAKEEEPRYKALRGENQDLREKERKYQDKIKKLEEKEKNLEKKS (SEQ ID NO: 123), or a fragment thereof.

[0367] In certain embodiments, the target binding moiety capable of binding IgA comprises or has a structure shown in FIG. 19.

[0368] In some embodiments, the target binding moiety capable of binding IgA (e.g., IgAl and / or IgA2, such as Gd-IgAl) comprises or is a IgA targeting ligand described in international patent publications WO 2021 / 155317, WO 2022 / 235699, WO 2024 / 098039, WO 2024 / 228935, the contents of each of which are incorporated herein by reference.

[0369] In some embodiments, the target binding moiety capable of binding IgA (e.g., IgAl and / or IgA2, such as Gd-IgAl) is a peptide ligand found in Heineke et al. Fur J Immunol. 2017;47(10):1835-45. c. Target Binding Moieties Capable of Binding IgE

[0370] In some embodiments, target binding moieties of the present disclosure are capable of binding IgE. In some embodiments, target binding moieties of the present disclosure are capable of specifically binding IgE (accordingly, also referred to as “IgE-specific target binding moieties”). In some embodiments, specific degradation of IgG can be accomplished through the use of an IgE-specific target binding moiety.

[0371] In some embodiments, a target binding moiety capable of binding IgE comprises or is an antibody mimetic, such as an Affibody, an Affilin, an Affimer, an afftin, an Alphabody, an Anticalin, an avimer, a camelid nanobody, a Centyrin, a DARPin, a Fynomer, a monobody, or a nanoCLAMP. In some embodiments, a target binding moiety capable of binding IgE comprises or is a DARPin, such as DE53-Fc (Eggel et al. Allergy. 201 l;66(7):961-68), bi53_79 (Eggel et al. J Allergy Clin Immunol. 2014; 133(6): 1709- 19.e8), E2_79 (Kim et al. Nature. 2012;491(7425):613-17), or E3_53 (Pennington et al. J Allergy Clin Immunol. 2021; 148(4): 1049-60).Table 6a. Exemplary Target Binding Moieties Capable of Binding IgE

[0372] In some embodiments, a target binding moiety capable of binding IgE comprises or is an Fc fusion protein, such as GE2 (Zhu et al. Nat Med. 2002;8(5):518-21).

[0373] In some embodiments, a target binding moiety capable of binding IgE comprises or is an antibody or an antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof is derived from omalizumab, ligelizumab, quilizumab, MEDI4212, XmAb7195, or 8D6. In some embodiments, the antibody or antigen binding fragment thereof is omalizumab, ligelizumab, quilizumab, MEDI4212, XmAb7195, or 8D6, or a antigen binding fragment thereof.

[0374] In some embodiments, the target binding moiety capable of binding IgE comprises or is an antibody or antigen binding fragment thereof. In some embodiments, the antibody is omalizumab. In some embodiments, the antibody is ligelizumab.

[0375] In some embodiments, the target binding moiety capable of binding IgE comprises or is an antibody or antigen binding fragment thereof that is engineered so as to be pH-dependent (e.g., in accordance with the methods described in WO 2018 / 206748, incorporated herein by reference). In some embodiments, the antibody or antibody fragment thereof has a binding affinity for the target protein that is pH dependent. In some embodiments, the antibody or antibody fragment thereof has higher binding affinity for the target protein at neutral pHcompared to low pH. In some embodiments, the antibody or antibody fragment thereof has a binding affinity for the target protein that is calcium dependent.

[0376] In some embodiments, the antibody or antibody fragment thereof has one or more mutations that impart pH-dependent binding affinity for the target molecule. In some embodiments, the target binding moiety is an antibody or antibody fragment thereof that has been mutated from the wild-type with one or more histidine substitutions. In some embodiments, the one or more histidine substitutions are located in the variable region of the antibody or antibody fragment. In some embodiments, the one or more histidine substitutions are located in the CDR region of the antibody or antibody fragment. In some embodiments, the six heavy chain and light chain CDRs combined may consist of a total of 1-10 histidine substitutions, such as 1-5 histidine substitutions, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 histidine substitutions. Non-histidine substitutions may also be incorporated into variable domains, particularly the CDRs, of the pH-dependent antibodies described herein. For example, certain antibodies or fragment thereof can include one or more mutations from the following table:

[0377] In examples described herein, numbering for omalizumab followed a simple sequence number, that is, for omalizumab S35H-LC, Y57H-LC, residue 35 corresponds to Rabat number 31 and residue 57 corresponds to Rabat number 53. Numbering for ligelizumab (e.g. W33H- HC / Y50H-LC / N100bH-HC / W94H-LC) followed the Rabat numbering scheme.

[0378] In some embodiments, the target binding moiety has a higher binding affinity for the target protein extracellularly than intraendosomaly. In some embodiments, the target binding moiety has a higher binding affinity for the target protein at an extracellular pH than at an intraendosomal pH. In some embodiments, the target binding moiety has a higher binding affinity for the target protein at a pH between about 6.5 and about 7.5 than at a pH between about 6.5 and 4.5. In some embodiments, the target binding moiety has a higher binding affinity for the target protein at a pH between about 7.0 and about 7.5 than at a pH between about 6.5 and 4.5. In some embodiments, the target binding moiety a higher binding affinity for the target protein at a pH of about 7.4 than at a pH of about 6.0. In some embodiments, the target binding moiety has a higher binding affinity for the target protein at an extracellular Ca2+concentration than at an intraendosomal Ca2+concentration. In some embodiments, the target binding moiety has a higher binding affinity for the target protein at an Ca2+concentration between about 1-2 mM than at an Ca2+concentration between about 0-1μM.

[0379] Exemplary pH-dependent antibodies or antigen binding fragments thereof are described below comprising specific CDR, VH and / or VL sequences. In some embodiments, pH- dependent antibodies or antigen binding fragments thereof comprise: a HCDR3 comprising or consisting of ATHYFGHWHFAV (SEQ ID NO: 569); a HCDR2 comprising or consisting of SIHYDHSTNYNPSVKG (SEQ ID NO: 568); a HCDR1 comprising or consisting of SGHRWE (SEQ ID NO: 567); a LCDR3 comprising or consisting of QQNAEDPYT (SEQ ID NO: 572); a LCDR2 comprising or consisting of WGSYLRS (SEQ ID NO: 571); and a LCDR1 comprising or consisting of RASQSVDYDGDHYMN (SEQ ID NO: 570).

[0380] In some embodiments, pH-dependent antibodies or antigen binding fragments thereof comprise: a HCDR3 comprising or consisting of ATHYFGHHHFAV (SEQ ID NO: 574); a HCDR2 comprising or consisting of SIHYDGSTNYNPSVKG (SEQ ID NO: 573); a HCDR1 comprising or consisting of SGHRWE (SEQ ID NO: 567); a LCDR3 comprising or consisting of QQNAEDPYT (SEQ ID NO: 577); a LCDR2 comprising or consisting of WGSYLRS (SEQ ID NO: 576); and a LCDR1 comprising or consisting of RASQSVDYDGDSYMN (SEQ ID NO: 575).

[0381] In some embodiments, pH-dependent antibodies or antigen binding fragments thereof comprise: a HCDR3 comprising or consisting of FSHFSGSNHDYFDY (SEQ ID NO: 580); a HCDR2 comprising or consisting of EIDPGTFTTNYNEKFKA (SEQ ID NO: 579); a HCDR1 comprising or consisting of WYHLE (SEQ ID NO: 578); a LCDR3 comprising or consisting of QQSWSWPTT (SEQ ID NO: 583); a LCDR2 comprising or consisting of YASESIS (SEQ ID NO: 582); and a LCDR1 comprising or consisting of RASQSIGTNIH (SEQ ID NO: 581).

[0382] In certain embodiments, the antibodies or antigen binding fragments thereof comprise or consist of a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 552 or an amino acid sequence having at least 80%, 90%, 95%, 98% 99% identity thereto, and a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 553 or an amino acid sequence having at least 80%, 90%, 95%, 98% 99% identity thereto. In certain embodiments, the antibodies or antigen binding fragments thereof comprise or consist of a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 552, and a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 553.

[0383] In certain embodiments, the antibodies or antigen binding fragments thereof comprise or consist of a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 554 or an amino acid sequence having at least 80%, 90%, 95%, 98% 99% identity thereto, and a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 555 or an amino acid sequence having at least 80%, 90%, 95%, 98% 99% identity thereto. In certain embodiments, the antibodies or antigen binding fragments thereof comprise or consist of a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 554, and a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 555.

[0384] In certain embodiments, the antibodies or antigen binding fragments thereof comprise or consist of a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 556 or an amino acid sequence having at least 80%, 90%, 95%, 98% 99% identity thereto, and a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 557 or an amino acid sequence having at least 80%, 90%, 95%, 98% 99% identity thereto. In certain embodiments, the antibodies or antigen binding fragments thereof comprise or consist of a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 556, and a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 557.

[0385] In some embodiments, target binding moieties capable of binding IL-31 comprise (1) a VH comprising an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of a VH described in Table 6b; and (2) a VL comprising an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98%, or at least 99% identical to the amino acid sequence of a VL described in Table 6b. In some embodiments, target binding moieties capable of binding IL-31 comprise a VH sequence as described in Table 6b and a VL sequence as described in Table 6b.Table 6b. Exemplary Target Binding Moieties Capable of Binding IgE

[0386] In some embodiments, the target binding moiety capable of binding IL-31 comprises or is an anti-IL-31 antibody or antigen binding fragment thereof described in international patent publications WO 2024 / 155746 or WO 2020 / 208177, the contents of each of which are incorporated herein by reference.

[0387] In some embodiments, the target binding moiety capable of binding IgE comprises or is an antigen binding fragment. In some embodiments, the target binding moiety capable of binding IgE comprises or is a single domain antibody (sdAb). In some embodiments, the target binding moiety capable of binding IgE comprises or is an immunoglobulin single variable domain (also referred to as “anti-IgE ISV”). In some embodiments, the target binding moiety capable of binding IgE comprises or is a nanobody (or VHH) (also refereed to as “anti-IgE VHH”).

[0388] Non-limiting examples of anti-IgE VHH that may be used with the present disclosure are described in WO 2004 / 0041865 and WO 2004 / 0041867, including VHH#2C3, VHH#4G12, VHH#2C1, VHH#2H3, VHH#2D12, VHH#2G4, VHH#4C5, VHH#4A2,VHH#2D4, VHH#2B6, or VHH#2H11, or humanized and / or sequence optimized variants of the same. Additional examples of anti-IgE VHH that may be used with the present disclosure are described in WO 2012 / 175740, including 39B02, 39D8, 42D7, 42G5, and 36G5, or humanized and / or sequence-optimized version of the same, and in particular 39D11 and “39Dl l-type sequences” such as humanized and / or sequence-optimized variants of 39D11, such as IGE026.

[0389] In some embodiments, a target binding moiety capable of binding IgE comprises or is 39D 11. In some embodiments, a target binding moiety capable of binding IgE comprises or is IGE026.

[0390] In some embodiments, a target binding moiety capable of binding IgE comprises or is a 39Dl l-type sequence. As used herein, a “39Dl l-type sequence” refers to an immunoglobulin single variable domain (ISV), and in particular a nanobody, that is such that (i) it competes with 39D 11 for binding to (human) IgE (for example, in a suitable binding assay, such as a BIAcore assay); and / or (ii) it binds to the same epitope on (human) IgE as 39D11;and / or (iii) it interferes with the binding of 39D11 to IgE. In some embodiments, a “39D11- type sequence” is further such that it (i) inhibits the human IgE and human FcεRI interaction (e.g., in the ELISA assay) with an IC50better than 8.10-10M, preferably better than 6.1O-10M, such as better than 10-10M, better than 5.10-11M, better than 2.10-11M, or even better than 10-11M; and / or (ii) inhibits the human IgE and human FcεRII interaction (e.g., in the ELISA assay) with an IC50value better than 5.10-8M, preferably better than 2.10-8M, such as better than 10-8M, better than 5.10-9M, better than 2.10-9M, better than 10-9M, better than 5. IO-10M, or better than 2.1O-10M; and / or (iii) inhibits IgE-mediated degranulation (e.g., in a degranulation assay) with an IC50better than 100 nM, preferably better than 50 nM, more preferably better than 20nM, such as better than 5nM, better than 1 nM, or even better than 0.5 nM.

[0391] In some embodiments, a target binding moiety capable of binding IgE comprises or is a 39Dl l-like sequence. As used herein, a “39Dl l-like sequence” refers to an ISV that comprises: a) a CDR1 which comprises or essentially consists of either(i) the amino acid sequence SYDMS (SEQ ID NO: 161) or the amino acid sequence NYDMA (SEQ ID NO: 168), or(ii) an amino acid sequence that has only 3, 2 or 1 amino acid difference(s) with the amino acid sequence SYDMS (SEQ ID NO: 161) or the amino acid sequence NYDMA (SEQ ID NO: 168); and / or b) a CDR2 which comprises or essentially consists of either(i) the amino acid sequence SIDTGGDITHYADSVKG (SEQ ID NO: 163), or(ii) an amino acid sequence that has at least 80%, such as at least 85%, for example at least 90% or more than 95% sequence identity with the amino acid sequence SIDTGGDITHYADSVKG (SEQ ID NO: 163), or(iii) an amino acid sequence that has only 7, 6, 5, 4, 3, 2 or 1 amino acid difference(s) with the amino acid sequence SIDTGGDITHYADSVKG (SEQ ID NO: 163); and / or c) a CDR3 which comprises or essentially consists of either(i) the amino acid sequence DEDYALGPNEYDY (SEQ ID NO: 165) or the amino acid sequence DEEYALGPNEFDY (SEQ ID NO: 171), or(ii) an amino acid sequence that has at least 80%, such as at least 85%, for example at least 90% or more than 95% sequence identity with the amino acid sequence DEDYALGPNEYDY (SEQ ID NO: 165) or the amino acid sequence DEEYALGPNEFDY (SEQ ID NO: 171), or(iii) an amino acid sequence that has only 7, 6, 5, 4, 3, 2 or 1 amino acid difference(s) withthe amino acid sequence DEDYALGPNEYDY (SEQ ID NO: 165) or the amino acid sequence DEEYALGPNEFDY (SEQ ID NO: 171); in which the framework sequences present in such an ISV are as further described herein, and in which CDR1, CDR2 and CDR3 are preferably such that the 39D11-like ISV (i) inhibits the human IgE and human FcεRI interaction (e.g., in the ELISA assay) with an IC50better than 8.10-10M, preferably better than 6.1O-10M, such as better than 10-10M, better than 5.10-11M, better than 2.10-11M, or even better than 10- 11M; and / or (ii) inhibits the human IgE and human FcεRII interaction 25 (e.g., in the ELISA assay) with an IC50value better than 5.10-8M, preferably better than 2.10-8M, such as better than 10-8M, better than 5.10-9M, better than 2.10-9M, better than 10-9M, better than 5. IO-10M, or better than 2. IO-10M; and / or (iii) inhibits IgE-mediated degranulation (e.g., in a degranulation assay) with an IC50better than 100 nM, preferably better than 50 nM, more preferably better than 20nM, such as better than 5nM, better than 1 nM, or 30 even better than 0.5 nM.

[0392] In some embodiments, a 39D11-like sequence comprises CDR1 and CDR2 as defined under a) and b), respectively; or CDR1 and CDR3 as defined under a) and c), respectively; or CDR2 and CDR3 as defined under b) and c), respectively. In some embodiments, a 39D11- like sequence comprises CDR1, CDR2, and CDR3 all as defined under a), b) and c), respectively.

[0393] In some embodiments, a 39D11-like sequence comprises CDR1 comprising or essentially consisting of the amino acid sequence SYDMS (SEQ ID NO: 161) and preferably the amino acid sequence NYDMA (SEQ ID NO: 168) (with CDR2 and CDR3 being as defined under b) and c), respectively); and / or CDR2 comprising or essentially consisting of the amino acid sequence SIDTGGDITHYADSVKG (SEQ ID NO: 163) (with CDR1 and CDR3 being as defined under a) and c), respectively); and / or CDR3 may comprise or essentially consist of the amino acid sequence DEDYALGPNEYDY (SEQ ID NO: 165) and preferably the amino acid sequence DEEYALGPNEFDY (SEQ ID NO: 171) (with CDR1 and CDR2 being as defined under a) and b), respectively).

[0394] In some embodiments, a 39D11-like sequence comprises:(i) CDR1 comprising or essentially consisting of the amino acid sequence SYDMS (SEQ ID NO: 161) and preferably the amino acid sequence NYDMA (SEQ ID NO: 168), and CDR2 comprising or essentially consisting of the amino acid sequence SIDTGGDITHYADSVKG (SEQ ID NO: 163) (with CDR3 being as defined under c) above); and / or(ii) CDR1 comprising or essentially consisting of the amino acid sequence SYDMS (SEQ ID NO: 161) and preferably the amino acid sequence NYDMA (SEQ ID NO: 168) and CDR3comprising or essentially consisting of the amino acid sequence DEDYALGPNEYDY (SEQ ID NO: 165) and preferably of the amino acid sequence DEEYALGPNEFD (SEQ ID NO: 171) (with CDR2 being as defined under b) above); and / or(iii) CDR2 comprising or essentially consisting of the amino acid sequence SIDTGGDITHYADSVKG (SEQ ID NO: 161) and CDR3 comprising or essentially consisting of the amino acid sequence DEDYALGPNEYDY (SEQ ID NO: 165) and preferably the amino acid sequence DEEYALGPNEFD Y (SEQ ID NO: 171) (with CDR1 being as defined under a) above).

[0395] In some embodiments, a 39D11-like sequence comprises: CDR1 comprising or essentially consisting of the amino acid sequence SYDMS (SEQ ID NO: 161) and preferably the amino acid sequence NYDMA (SEQ ID NO: 168), CDR2 comprising or essentially consisting of the amino acid sequence SIDTGGDITHYADSVKG (SEQ ID NO: 163); and CDR3 comprising or essentially consisting of the amino acid sequence DEDYALGPNEYDY (SEQ ID NO: 165) and preferably the amino acid sequence DEEYALGPNEFD (SEQ ID NO: 171).

[0396] In all the 39D11-like sequence described herein, the FR1, FR2, FR3 and FR4 sequences, respectively, are preferably such that taken together, these framework sequences have at least 80%, such as at least 85%, for example at least 90%, such as at least 95% sequence identity with the framework sequences of 39D11 (SEQ ID NOs: 160, 162, 164 and 166, respectively) or the framework sequences of IGE026 (SEQ ID NOs: 167, 169, 170 and 172, respectively). For example and without limitation, each of the FR1, FR2, FR3 and FR4 sequences in a 39Dl l- like sequence may have between 0 and 7, such as between 0 and 5, such as 1, 2, 3 or 4 (suitable) amino acid differences with the FR1, FR2, FR3 and FR4 sequence, respectively, of 39D11 and / or with the FR1, FR2, FR3 and FR4 sequence, respectively, of IGE026. Other suitable framework sequences may essentially be as described on pages 273 to 291 of WO 2009 / 068627 (described for nanobodies against IL-23). Reference is for example made to Tables A- 10 to A-25 of WO 2009 / 068627, as well as the various humanizing substitutions described in Tables A-6 to A-9 of WO 2009 / 068627.

[0397] In some embodiments, a 39D11-like sequence has at least 70%, such as at least 80%, at least 85%, at least 90%, at least 95%, or more than 95%, sequence identity with the amino acid sequence of 39D11. In some embodiments, a 39D11-like sequence may be a humanized and / or sequence optimized variant of 39D11. In one embodiment, these may for example and without limitation contain (any suitable combination of) one or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and essentially up to all, of the following mutations compared to the amino acidsequence of 39D11: EID, V5L, E6Q, F29Y, S31N, S35A or S36G, G44R, N73K, M77T or M77L, K83R, W91A, D97E, YlOOeF, and / or Q108L (with the numbering according to Rabat, see for example Tables A- 5 to A-8 of WO 2008 / 020079; and with each letter denominating an amino acid residue in accordance with the standard one-letter amino acid code, for which reference is made to Table A-2 of WO 2008 / 020079). In another embodiment, these may for example and without limitation contain (any suitable combination of) one or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and essentially up to all, of the following mutations compared to the sequence of 39D11: EID, V5L, E6Q, F29Y, S31N, S35A or S35G, G44R, N75K, M77T or M77L, K83R, W91Y, D97E, YlOOeF and / or Q108L (with the numbering according to Rabat, see for example Tables A-5 to A-8 of WO 2008 / 020079; and with each letter denominating an amino acid residue in accordance with the standard one-letter amino acid code, for which reference is made to Table A-2 of WO 2008 / 020079). As will be clear to the skilled person, some of these mutations are in the CDRs and may improve affinity of the ISV of IgE, potency, activity, and / or other biological properties of the 39Dl l-like sequence (compared to 39D11). Other suitable humanizing and / or sequence optimizing substitutions will be clear to the skilled person, for example from the further disclosure herein and / or from comparing the sequence of 39D11 with a human VH sequence (for which reference is again for example made to Tables A-5 to A-8 of WO 2008 / 020079).

[0398] In some embodiments, a 39Dl l-like sequence is selected from any of SEQ ID NOs: 130-143 or an ISV that has at least 70%, such at least 80%, for example at least 85%, such as at least 90% or more than 95% sequence identity with any of SEQ ID NOs: 130-143. In some embodiments, a 39Dl l-like sequence is SEQ ID NO: 138 or SEQ ID NO: 139.

[0399] In some embodiments, anti-IgE ISVs of the present disclosure are selected from IGE026 and variants of IGE026 that have at least one amino acid difference with the amino acid sequence of IGE026. In some embodiments, the variants of IGE026 have 1 to 5, such as e.g. 1, 2, 3, 4 or 5 amino acid differences compared to the amino acid sequence of IGE026.

[0400] Accordingly, in some embodiments, an anti-IgE ISV of the present disclosure comprises or has an amino acid sequence selected from: a) SEQ ID NO: 138; and b) amino acid variants that have no more than 5, preferably no more than 4, no more than 3, more preferably no more than 2, most preferably no more than one amino acid difference with SEQ ID NO: 138, provided that: (i) the amino acid variant binds IgE with the same, about the same, or a higher affinity (e.g., as measured by surface plasmon resonance or RinExA) and / or (ii) the amino acid variant has the same, about the same, or a higher potency(e.g., as determined in a degranulation assay) compared to SEQ ID NO: 138.

[0401] In a preferred aspect, the variant of IGE026 has an amino acid difference with the amino acid sequence of IGE026 which is a substitution in the framework 1 region and / or in the CDR1 region, preferably at one or more of positions 1, 6, 29, 31, and 35. In a preferred aspect, the variant of IGE026 has an amino acid difference with the amino acid sequence of IGE026 selected from: GlulAsp, Glu6GIn, Phe29Tyr, Asn31Ser, Asn31Pro, Ala35Gly, and a combination thereof, such as(i) Glu6Gln (SEQ ID NO: 139),(ii) Glu6Gln and Ala35Gly (SEQ ID NO: 140),(iii) Glu6Gln and Asn31Ser (SEQ ID NO: 141),(iv) Glu6Gln and Phe29Tyr (SEQ ID NO: 142),(v) GlulAsp (SEQ ID NO: 143),(vi) GlulAsp and Glu6Gln (SEQ ID NO: 144),(vii) GlulAsp, Glu6Gln, and Ala35Gly (SEQ ID NO: 145),(viii) GlulAsp, Glu6Gln, and Asn31Ser (SEQ ID NO: 146),(ix) GlulAsp, Glu6Gln, and Phe29Tyr (SEQ ID NO: 147).Accordingly, in a preferred aspect, the anti-IgE ISV comprises or consists of any of SEQ ID NOs: 138-147.

[0402] Accordingly, in some embodiments, an anti-IgE ISV of the present disclosure comprises or has an amino acid sequence selected from: a) SEQ ID NO: 143; and b) amino acid variants that have no more than 4, preferably no more than 3, more preferably more than 2, most preferably no more than one amino acid difference with SEQ ID NO: 143, provided that:(i) the amino acid variant has an Aspartic acid (Asp, D) at position 1 (said position determined according to Kabat numbering); and(ii) the amino acid variant binds IgE with the same, about the same, or a higher affinity (e.g., as measured by surface plasmon resonance or KinExA) and / or the amino acid variant has the same, about the same, or a higher potency (e.g., as determined in a degranulation assay) compared to SEQ ID NO: 143.

[0403] In a preferred aspect, the variant of SEQ ID NO: 143 has an amino acid difference with SEQ ID NO: 143 which is a substitution in the framework 1 and / or in the CDR1 region, preferably at one or more of positions 6, 29, 31 , and 35. In another preferred aspect, the variant of the invention has an amino acid difference with SEQ ID NO: 143 selected from one or moreof: Glu6Gln, Phe29Tyr, Asn31Ser, Asn31Pro and Ala35Gly, such as Glu6Gln (SEQ ID NO: 144), Glu6Gln and Ala35Gly (SEQ ID NO: 145), Glu6Gln and Asn31Ser (SEQ ID NO: 146), Glu6Gln and Phe29Tyr (SEQ ID NO: 147). Preferably, the anti-IgE ISV comprises or essentially consists of any of SEQ ID NOs: 143-147.

[0404] In various embodiments, anti-IgE ISVs of the disclosure can bind IgE with an affinity (suitably measured and / or expressed as a KD-value (actual or apparent), or alternatively as an IC50value), preferably such that they bind to IgE with a dissociation constant (KD) of 10 nM to 0.01 nM or less, preferably 1 nM to 0.01 nM or less, more preferably 0.1 nM to 0.01 nM or less, such as 0.05 nM or less or 0.02 nM or less (e.g. as measured by KinExA).

[0405] In some embodiments, anti-IgE ISVs of the disclosure are capable of modulating, and in particular inhibiting or blocking (fully or partially), the interaction between (human) IgE and the (human) FcεRI (the high affinity IgE receptor). In some embodiments, anti-IgE ISVs are capable of inhibiting the interaction between human IgE and human FcεRI with an IC50value of 5.10-10M or lower, preferably 2.1O-10M or lower, such as 10-10M or lower, 5.10-11M or lower, 2.10-11M or lower, or even 10-11M or lower.

[0406] In some embodiments, anti-IgE ISVs of the disclosure are also capable of modulating, and in particular inhibiting or blocking (fully or partially), the interaction between (human) IgE and the (human) FcεRII (the low affinity IgE receptor). In some embodiments, anti-IgE ISVs are capable of inhibiting the interaction between human IgE and human FcεRII with an IC50value of 5.10-8M or lower, preferably 2.10-8M or lower, such as 10-8M or lower, 5.10-9M or lower, 2.10-9M or lower, 10-9M or lower, 5.10-10M or lower, or 2.1O-10M or lower.

[0407] In some embodiments, anti-IgE ISVs of the disclosure are capable of inhibiting degranulation (e.g., in a degranulation assay) with an IC50value of 100 nM or less, preferably 50 nM or less, more preferably 20nM or less, such as 5nM or less, 1 nM or less, or even 0.5 nM or less.

[0408] In some embodiments, anti-IgE ISVs of the disclosure may or may not further comprise one or more other groups, residues, moieties, or binding units. If present, such further groups, residues, moieties or binding units may or may not provide further functionality to the ISV and may or may not modify the properties of the ISV. In some embodiments, such further groups, residues, moieties, or binding units may be one or more additional amino acid sequences.

[0409] In some embodiments, one, two, or more anti-IgE ISVs and one or more groups, residues, moieties, or binding units may be linked directly to each other and / or via one or more suitable linkers or spacers. In some embodiments, when the one or more groups, residues, moieties, or binding units are amino acid sequences, the linkers may also be amino acidsequences, so that the resulting polypeptide is a fusion (protein) or fusion (polypeptide). The one or more further groups, residues, moieties, or binding units may be any suitable and / or desired amino acid sequences. The further amino acid sequences may or may not change, alter, or otherwise influence the (biological) properties of the fusion polypeptide, and may or may not add further functionality to the fusion polypeptide. Preferably, the further amino acid sequence is such that it confers one or more desired properties or functionalities to the fusion polypeptide.

[0410] Example of such amino acid sequences will be clear to the skilled person, and may generally comprise all amino acid sequences that are used in peptide fusions based on conventional antibodies and fragments thereof (including but not limited to ScFvs and single domain antibodies). Reference is for example made to the review by Holliger and Hudson (Nat Biotechnol. 2005, 23(9): 1126-36).

[0411] For example, such an amino acid sequence may be an amino acid sequence that increases the half-life, the solubility, or the absorption, reduces the immunogenicity or the toxicity, eliminates or attenuates undesirable side effects, and / or confers other advantageous properties to and / or reduces the undesired properties of the (fusion) polypeptide, compared to the anti-IgE ISV per se. Some non-limiting examples of such amino acid sequences are serum proteins, such as human serum albumin (see for example WO 2000 / 027435) or haptenic molecules (for example haptens that are recognized by circulating antibodies, see for example WO 1998 / 022141).

[0412] In some embodiments, the target binding moiety capable of binding IgE comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from Table 6c. In some embodiments, the target binding moiety capable of binding IgE comprises or has an amino acid sequence selected from Table 6c.Table 6c. Exemplary Target Binding Moieties Capable of Binding IgETable 6d. CDR and ER Sequences of Exemplary 39D11-Like Sequences

[0413] In some embodiments, the target binding moiety capable of binding IgE comprises or is a VHH against IgE described in international patent publications WO 2004 / 041865, WO2004 / 041867, WO 2014 / 087010, and WO 2012 / 175740, the contents of each of which are incorporated herein by reference.

[0414] In certain embodiments, the target binding moiety capable of binding IgE comprises or is represented by:

[0415] In certain embodiments, the target binding moiety capable of binding IgE comprises or is represented by one of the following:

[0416] In certain embodiments, the target binding moiety capable of binding IgE comprises or is represented by one of the following:and

[0417] In certain embodiments, the target binding moiety capable of binding IgE comprises or has a structure shown in FIG. 21A-21E.

[0418] In certain embodiments, the target binding moiety capable of binding IgE comprises or is an IgE targeting ligand described in international patent publications WO 2021 / 155317, WO 2022 / 235699, and WO 2024 / 098039, the contents of each of which are incorporated herein by reference. d. Target Binding Moieties Capable of Binding IgM Autoantibodies

[0419] In some embodiments, target binding moieties of the present disclosure are capable of binding IgM or an anti-MAG IgM autoantibody.

[0420] In certain embodiments, the target binding moiety capable of binding anti-MAG IgM autoantibody is selected from:HSO3-3GlcAβ1-3 Ga1β1-4GlcNAcβ1-3Ga1β1-4G1cβ1-Cer;HSO3-3GlcAβ1-3Ga1β1-4GlcNAcβ1-3Ga1β1-4GlcNAcβ1-3Ga1β1-4G1cβ1-Cer;HSO3-3GlcAβ1-3Ga1β1-4GlcNAc-X;

[0421] Additional IgM autoantibodies that can be used in the present invention are describedin Herrendorff, R. et al. 2017 PNAS Early Edition, doi / 10.1073 / pnas.1619386114, WO 2018 / 167230, US Pat. Nos. 9,056,081; 9,994,605; Volshol et al. J. Biol. Chem 1996; Wang et al. 2020; WO 2000 / 050447; WO 2015 / 136027; Bunyatov et al. “Synthetic HNK-I containing glycans provide insight into binding properties of serum antibodies from MAG-neuropathy patients” BioRxiv, 2022; Aliu et al. “Selective inhibition of anti-MAG IgM autoantibody binding to myelin by an antigen- specific glycopolymer” Journal Of Neurochemistry 2020; WO 2022 / 081895; and Simon-Haldi, M. et al. “Identification of a peptide mimic of the L2 / HNK-1 carbohydrate epitope” Journal Of Neurochemistry 2002, 83, 1380-1388.

[0422] In certain embodiments, the target binding moiety capable of binding IgM comprises or has a structure selected from one of the following:wherein nE is 1 to 10;XAA3is selected from H, SO3-, SO3H, and SOsNa; andXAA4is selected from H or Na.

[0423] In certain embodiments, the target binding moiety capable of binding IgM comprises or has a structure selected from one of the following:whereinRAA1is selected from a sialic acid group and an optionally substituted carboxymethyl group; xAA1is selected from O, S, NRAA2;., C(RAA2':)2; XAA2is selected from H and SCLNa;RAA2is independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, benzyl, CH2CH2C6H5, OCH2C6H5, and OCH2CH2C6H5;ArAis selected from an optionally substituted aryl and an optionally substituted heteroaryl.

[0424] In certain embodiments the Targeting Ligand that binds to IgM is a compound of Formulawherein areindependently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)- , -P(O)(R3)O-, -P(O)(R3)-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2- [O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-JII-, -[O-(CH2)2JII-, -[O-CH(CH3)C(O)J11-, -[C(O)-CH(CH3)-OJII-, -[O-CH2C(O)J11-, -[C(O)-CH2-OJH-, a divalentresidue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or di-carboxylic acid, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21;RQisW1is selected from H, SO3-, SO3H, and SO3Na; and W2is selected from H or Na;is selected from aryl, heteroaryl, and cycloalkyl;RAAIis selected from a sialic acid group and an optionally substituted carboxymethyl group;XAA2is selected from O, S, NRAA2, C(RAA2' XAA2is selected from H and SO3Na;RAA2is independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, benzyl, -CH2- benzyl, -O-benzyl, and -O-CH2-benzyl;R5is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl. nA is 10-90% of the polymer and nB is 100%-nA; nC is 1-500;

[0425] In certain embodiments nC is 150-300, 70-150, 40-60, 30-70, 15-30, or 4-5. In certain embodiments, nC is at least about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150. In certain embodiments, nC is about 75, 80, 85, 90, 95, or 100.

[0426] In certain embodiments, the target binding moiety capable of binding IgM comprises or has a structure selected from one of the following:

[0427] In certain embodiments, the target binding moiety capable of binding IgM comprises or has a structure selected from one of the following:

[0428] In certain embodiments, the target binding moiety capable of binding IgM comprises or has a structure selected from one of the following:

[0429] In certain embodiments, the target binding moiety capable of binding IgM comprises or has a structure selected from one of the following:e. Additional Target Binding Moieties Capable of Binding Immunoglobulin

[0430] In certain embodiments, a target binding moiety capable of binding immunoglobulin comprises or has one of the following structures:wherein XMIS (CH2)0-6, — O— (CH2)0-6, S— (CH2)0-6, NRM— (CH2)0-6, C(O)— (CH2)0-6, a PEG group containing from 1 to 8, preferably 1-4 ethylene glycol residues, or a — C(0)(CH2)o-6NRM group; RM is H or a C1-C3 alkyl group which is optionally substituted with one or two hydroxyl groups, where 0-6 is preferably 1, 2, 3, or 4, more preferably 1.

[0431] In certain embodiments, a target binding moiety capable of binding immunoglobulin comprises or has one of the following structures:wherein DNP is a 2,4-dinitrophenyl group or a group according to the chemical structure:, wherein Y' is H or NO2 (preferably H ): X101is ( ). CH2:. S.NR101, S(O), S(O)2, . S(O)2O, OS(O)2, or OS(O)2O; and R101is H, a C1-C3alkyl group, or a -C(O)(C1-C3alkyl) group.

[0432] In certain embodiments, a target binding moiety capable of binding immunoglobulin comprises or has one of the following structures:wherein X102is CH, O, N- R101, or S, preferably 0; R101is H or C1-C3alkyl; and X100is a bond, a monosaccharide, disaccharide, oligosaccharide, more preferably a sugar group selected from the monosaccharides, including aldoses and ketoses, and disaccharides, including those described herein. Exemplary monosaccharide aldoses include aldotriose (D- glyceraldehyde, among others), aldotetroses (D-erythrose and D-Threose, among others), aldopentoses, (D- ribose, D-arabinose, D- xylose, D-lyxose, among others), aldohexoses (D-allose, D-altrose, D- Glucose, D-Mannose, D-gulose, D-idose, D-galactose and D-Talose, among others), and die monosaccharide ketoses include monosaccharides such as ketotriose (dihydroxy acetone, among others), ketotetrose (D-erythrulose, among others), ketopentose (D-ribulose and D- xylulose, among others), ketohexoses (D-Psicone, D-Fructose, D-Sorbose, D-Tagatose, among others), aminosugars, including galactoseamine, sialic acid, N-acetylglucosamine, among others and sulfosugars, including sulfoquinovose, among others. Exemplary disaccharides include sucrose (which may have the glucose optionally N-acetylated), lactose (which may have the galactose and / or the glucose optionally N-acetylated), maltose (which may have one or both of the glucose residues optionally N-acetylated), trehalose; (which may have one or both of the glucose residues optionally N-acetylated), cellobiose (which may have one or both of the glucose residues optionally N-acetylated), kojibiose (which may have one or both of the glucose residues optionally N-acetylated), nigerose (which may have one or both of the glucose residues optionally N-acetylated), isomaltose (which may have one or both of the glucose residues optionally N-acetylated), b,b-trehalose (which may have one or both of the glucose residues optionally N-acetylated), sophorose (which may have one or both of the glucose residues optionally' N-acetylated), lamlnaribiose (which may have one or both of the glucose residues optionally N-acetylated), gentiobiose (which may have one or both of the glucose residues optionally N-acetylated), turanose (which may have the glucose residue optionally N- acetylated), maltulose (which may have the glucose residue optionally N-acetylated),palatinose (which may have the glucose residue optionally N-acetylated), gentiobiluose (which may have the glucose residue optionally N-acetylated), mannobiose, melibiose (which may have the glucose residue and / or the galactose residue optionally N-acetylated), melibiulose (which may have the galactose residue optionally N-acetylated), rutinose, (which may have the glucose residue optionally N-acetylated), rutinulose and xylobiose, among others.

[0433] In certain embodiments, a target binding moiety capable of binding immunoglobulin comprises or is an antibody binding moiety described in international patent publication WO 2019 / 023501, the contents of which are incorporated by reference herein. f. Target Binding Moieties Capable of Binding IL-31

[0434] In some embodiments, target binding moieties of the present disclosure are capable of binding IL-31.

[0435] In some embodiments, a target binding moiety capable of binding IL-31 comprises or is an antibody or an antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof is derived from nemolizumab, BMS-981164, NM26-2198, or ATTO-1310 or a antigen binding fragment thereof.

[0436] In some embodiments, the target binding moiety capable of binding IL-31 comprises or is an antigen binding fragment, such as a Fab, an scFab, a F(ab’)2, a Fab’, an scFv, an Fv fragment, a diabody, or a single domain antibody.

[0437] In some embodiments, the target binding moiety is an scFv. In some embodiments, the scFv is derived from monoclonal rabbit antibody clone 50-09-D07 are able to potently block IL-31 signaling while exhibiting excellent stability. In some embodiments, the scFvs derived from clone 50-09-D07 (1) bind to IL-31 with a dissociation constant (KD) of well below 1 nM, (2) can neutralize the IL-31 -induced signaling with an IC50of below 30 ng / ml, and / or (3) can be stored at a concentration of 10 mg / mL over a period of 4 weeks at 4°C and 40°C without significant loss in protein content and monomeric content.

[0438] In some embodiments, the target binding moiety capable of binding IL-31 comprises or is an antibody or antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof is derived from 50-09-D07. In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence selected from SEQ ID NOs: 510-513, and / or a light chain variable region (VL) that comprises an amino acid sequence at least 90% (e.g., at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence selected from SEQ ID NO: 518 or 519. In some embodiments, the antibodies or antigen-binding fragments comprise the complementarity determining regions CDR1, CDR2, and CDR3, determined under Rabat, IMGT, Chothia, or any other CDR determination method known in the art, of the VH sequence selected from SEQ ID NOs: 510-513, and / or the complementarity determining regions CDR1, CDR2, and CDR3, determined under Rabat, IMGT, Chothia, or any other CDR determination method known in the art, of the VL sequence selected from SEQ ID NO: 518 or 519. In some embodiments, the VH comprises CDR1, CDR2, and CDR3, comprising the amino acid sequences of SEQ ID NOs: 506, 507 or 508, and 509, respectively. In some embodiments, the VL comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 514 or 515, 516, and 517, respectively. In some embodiments, the antibody or antigen-binding fragment comprises (a) a VH that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 506, 507 or 508, and 509, respectively; and (b) a VL that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 514 or 515, 516, and 517, respectively.

[0439] In some embodiments, the antibody or antigen-binding fragment comprises (a) a VH that comprises, from N-terminus to C-terminus, the regions HFW1-HCDR1-HFW2-HCDR2- HFW3-HCDR3-HFW4, wherein each HEW designates a heavy chain framework region, and each HCDR designates a heavy chain complementarity-determining region, and wherein said HCDR1, HCDR2, and HCDR3 have the amino acid sequences of SEQ ID NOs: 506, 507 or 508, and 509, respectively; and (b) a VL that comprises, from N-terminus to C-terminus, the regions LFW1-LCDR1-LFW2-LCDR2-LFW3-LCDR3-LFW4, wherein each LEW designates a light chain framework region, and each LCDR designates a light chain complementarity- determining region, and wherein said LCDR1, LCDR2, and LCDR3 have the amino acid sequences of SEQ ID NOs: 514 or 515, 516, and 517, respectively. In some embodiments, the VH is a VH3 chain, and / or the VL is a VKI light chain.

[0440] In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100%) identical to an amino acid sequence selected from of SEQ ID NOs: 510-513, and a VL that comprises an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 518 or 519. In some embodiments, the antibody or antigen bindingfragment thereof comprises:(1) a VH having an amino acid sequence SEQ ID NO: 510 and a VL having an amino acid sequence of SEQ ID NO: 518; or (2) a VH having an amino acid sequence SEQ ID NO: 511 and a VL having an amino acid sequence of SEQ ID NO: 518; or (3) a VH having an amino acid sequence SEQ ID NO: 512 and a VL having an amino acid sequence of SEQ ID NO: 518; or (4) a VH having an amino acid sequence SEQ ID NO: 510 and a VL having an amino acid sequence of SEQ ID NO: 519.

[0441] In some embodiments, the antibody or antigen-binding fragment thereof is a Fab, an Fv, an scFv and a dsFv, in particular from a Fab, an scFv, or a dsFv. In some embodiments, the antibody or antigen-binding fragment thereof is a scFv. In some embodiments, the scFv comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 520- 525. In some embodiments, the antibody or antigen-binding fragment thereof is a scFv. In some embodiments, the scFv comprises or has an amino acid sequence selected from SEQ ID NOs: 520-525.Table 20. Exemplary Target Binding Moieties Capable of Binding IL-31

[0442] In some embodiments, the target binding moiety capable of binding IL-31 comprises or is an antibody variable domains that binds IL-31 described in international patent publications WO 2022 / 136672 and WO 2022 / 136669, the contents of each of which are incorporated herein by reference. g- Target Binding Moieties Capable of Binding Fibroblast Growth Factor 23 (FGF23)

[0443] In some embodiments, target binding moieties of the present disclosure are capable of binding fibroblast growth factor 23.

[0444] In certain embodiments, the target binding moiety capable of binding FGF23 comprises or is an antibody or antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof is borosumab or a antigen binding fragment thereof. h. Target Binding Moieties Capable of Binding Transthyretin (TTR)

[0445] In some embodiments, target binding moieties of the present disclosure are capable of binding transthyretin.

[0446] In certain embodiments, the target binding moiety capable of binding TTR is derived from tafamidis or acoramidis. In certain embodiments, the target binding moiety capable of binding TTR comprises or is a tafamidis or acoramidis moiety.i. Target Binding Moieties Capable of Binding Interferon-y (IFN-7)

[0447] In some embodiments, target binding moieties of the present disclosure are capable of binding human interferon-y (IFN-γ).

[0448] In certain embodiments, the target binding moiety capable of binding IFN-γ comprises or has a structure described in FIG. 18D. In certain embodiments, the target binding moiety capable of binding IFN-γ can be found in, for example, J Med Chem 57: 4511-20 (2014), the contents of which are incorporated by reference herein. j. Target Binding Moieties Capable of Binding Thymic Stromal Lymphopoietin (TSLP)

[0449] In some embodiments, target binding moieties of the present disclosure are capable of binding thymic stromal lymphopoietin.

[0450] In certain embodiments, the target binding moiety capable of binding TSLP is derived from, comprises, or has the following structure:wherein AA1, AA2, AA3, AA4, AA5, AA6, AA7, AA8, AA9, and R are selected from the following table:

[0451] In some embodiments, the target binding moiety capable of binding TSLP is derived from, comprises, or has the following structure:

[0452] In some embodiments, the target binding moiety capable of binding TSLP is derived from, comprises, or is a bicyclic peptide described in Narjes et al. J Med Chem. 2024;67(3):2220-35.

[0453] In certain embodiments, the target binding moiety capable of binding TSLP comprises or is an antibody or antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof is tezepelumab, TQC2731, , ecleralimab, BSL045B, UPB- 101, or AIO-OOl, or an antigen binding fragment thereof.

[0454] In certain embodiments, the target binding moiety capable of binding TSLP comprises or is an antigen binding fragment, such as a Fab, an scFab, a F(ab’)2, a Fab’, an scFv, an Fv fragment, a diabody, or a single domain antibody. In some embodiments, the target binding moiety comprises or is a nanobody. In some embodiments, the target binding moiety is derived from, comprises, or is lunsekimig.

[0455] In some embodiments, the target binding moiety comprises or has a structure of a fusion protein TSLP-trap described in Verstraete et al. Nat. Comm. 2017, 8, 14937, the contents of which are incorporated herein by reference. k. Target Binding Moieties Capable of Binding Interleukin-1 (IL-1)

[0456] In some embodiments, target binding moieties of the present disclosure are capable of binding human interleukin- 1.

[0457] In certain embodiments, the target binding moiety capable of binding IL-1 are direct or indirect inhibitors of IL-1. In some embodiments, the direct or indirect inhibitor of IL-1 comprises or has a structure described in FIG. 18A.

[0458] In certain embodiments, the target binding moiety capable of binding IL-1 is an IL-1 targeting ligand found in, for example, US Pat. No. 9,694,015, the contents of which are incorporated herein by reference.

[0459] In certain embodiments, the target binding moiety capable of binding IL-1 comprises or is rilanocept or a binding fragment thereof (J Rheumatol. 2012;39:720-727 (2012). In certain embodiments, the target binding moiety capable of binding IL-1 comprises or is canakinumab or a binding fragment thereof (J Rheumatol. 2004; 31:1103 -1111).

[0460] In certain embodiments, the target binding moiety capable of binding IL-1 comprises or has one of the following structures:I. Target Binding Moieties Capable of Binding Interleukin-2 (IL-2)

[0461] In some embodiments, target binding moieties of the present disclosure are capable of binding human interleukin-2.

[0462] In certain embodiments, the target binding moiety capable of binding IL-2 comprises or has a structure described in FIG. 18B. In certain embodiments, the target binding moiety capable of binding IL-2 can be found in, for example, US Pat. Nos. 8,802,721; 9,682,976; 9,708,268; Eur J Med Chem 83: 294-306 (2014); J Med Chem 60: 6249-6272 (2017); Nature 450: 1001-1009 (2007); the contents of each of which are incorporated by reference herein.

[0463] In certain embodiments, the target binding moiety capable of binding IL-2 comprises or has the following structure:m. Target Binding Moieties Capable of Binding Interleukin-6 (IL-6)

[0464] In some embodiments, target binding moieties of the present disclosure are capable of binding human interleukin- 6.

[0465] In certain embodiments, the target binding moiety capable of binding IL-6 are direct or indirect inhibitors of IL-6. In some embodiments, the direct or indirect inhibitor of IL-6 comprises or has a structure described in FIG. 18C. In other embodiments, direct or indirect inhibitors of IL-6 can be found in, for example, US Pat. Nos. 8,901,310; 10,189,796; 9,694,015, the contents of each of which are incorporated herein by reference.

[0466] In certain embodiments, the target binding moiety capable of binding IL-6 comprises or is AvimarC326 or a binding fragment thereof (Nat Biotechnol 23, 1556-1561 (2005).

[0467] In certain embodiments, the target binding moiety capable of binding IL-6 can be found in, for example, US Pat. Nos. 10,633,423; 10,669,314; US Publication No. 2004 / 0092720, and Ranganath, S. et al. Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo. PLoS ONE 10(1 l):e0141330.

[0468] In some embodiments, the target binding moiety capable of binding IL-6 comprises or has an amino acid sequence of a IL-6 binding protein described in U.S. Pat. No. 7,786,262, the contents of which are incorporated herein by reference.

[0469] In some embodiments, the target binding moiety capable of binding IL-6 comprises or is a peptide. In some embodiments, the peptide comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from Table 8. In some embodiments, the peptide comprises or has an amino acid sequence selected from Table 8.Table 8. Exemplary Target Binding Moieties Capable of Binding IL-6

[0470] In certain embodiments, the target binding moiety capable of binding IL-6 comprises or has an amino acid sequence selected from any one of the following:(i) IVVTLPADLWDWIRA (SEQ ID NO: 181), or(ii) EEX3X4AWX7EIHX11LPNLX16X17X18QX20X21AFIX25X26LX28X29(SEQ ID NO:182) wherein, independently from each other,X3 is selected from A, F, H, K, Q, R, S, W and Y ;X4is selected from A, D, E, F, H, I, K, L, M, N, Q, R, S, T, V and Y;X7is selected from F, H, I, K, L, M, N, R, S, T, V, W and Y;X11is selected from A, I, K, L, M, N, R, S, T and V;X16is selected from N and T;X17selected from A, I, T and V;X18is selected from D, E, G, H, K, N, Q, R, S and T;X20is selected from I, L, M, R, T and V ;X21is selected from A, S, T and V;X25is selected from I, M, Q, S, T, V and W;X26is selected from K and S,X28is selected from F, L, M and Y ; andX29is selected from D and R;(iii) EEX3X4AWX7EIHX11LPNLX16X17X18QX20X21AFIX25X26LX28X29(SEQ ID NO: 183) wherein, independently from each other,X3is selected from A, F, H, K, Q, R, S, W and Y ;X4is selected from A, D, E, F, H, I, K, L, M, N, Q, R, S, T, V and Y;X7is selected from F, H, I, K, L, M, N, R, S, T, V, W and Y;X11is selected from A, I, K, L, M, N, R, S, T and V;X16is selected from N and T;X17selected from A, I, T and V;X18is selected from D, E, G, H, K, N, Q, R, S and T;X20is selected from I, L, M, R, T and V ;X21is selected from A, S, T and V;X25is selected from I, M, Q, S, T, V and W;X26is selected from K and S;X28is selected from F, L, M and Y ; andX29is selected from D and R;

[0471] In certain embodiments, the target binding moiety capable of binding IL-6 can be found in, for example, US Pat. Nos. 10, 633,423; 10, 669,314, the contents of each of which are incorporated by reference herein.

[0472] In certain embodiments, the target binding moiety is useful for treating an IL-6 mediated disease and capable of binding to gpl30. Accordingly, in certain embodiments, target binding moieties of the present disclosure are capable of binding gpl30.

[0473] In certain embodiments, the target binding moiety capable of binding gpl30 can be found in, for example, Ahn, S-H. et al. In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor 2020 Asian-Australas J AnimSci. 33:670-677, Aqel, S I. Novel small molecule IL-6 inhibitor suppresses autoreactive Thl7 development and promotes Treg development. (2019) Clinical and Experimental Immunology, 196:215-225, Hong, S.-S. et al. A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor beta Subunit, Glycoprotein 130. 2015 J Immunol 195:23 7-245.

[0474] In certain embodiments, the target binding moiety capable of binding gpl30 comprises or has one of the following structures:n. Target Binding Moieties Capable of Binding Tan Protein

[0475] In some embodiments, target binding moieties of the present disclosure are capable of binding tau protein.

[0476] In certain embodiments, the target binding moiety capable of binding tau protein comprises or has one of the following structures::o. Target Binding Moieties Capable of Binding Interleukin-21 (IL-21)

[0477] In some embodiments, target binding moieties of the present disclosure are capable of binding human interleukin-21.

[0478] In certain embodiments, the target binding moiety capable of binding IL-21 comprises or has a structure described in FIG. 18E. In certain embodiments, the target binding moiety capable of binding IL-21 can be found in, for example, US Pat. No. 9,701,663, the contents of which are incorporated herein by reference. p. Target Binding Moieties Capable of Binding Interleukin-22 (IL-22)

[0479] In some embodiments, target binding moieties of the present disclosure are capable of binding human interleukin-22.

[0480] In certain embodiments, the target binding moiety capable of binding IL-21 comprises or has a structure described in FIG. 18F. In certain embodiments, the target binding moiety capable of binding IL-22 can be found in, for example, US Pat. No. 9,701,663, the contents of which are incorporated herein by reference. q. Target Binding Moieties Capable of Binding Interleukin-10 (IL-10)

[0481] In some embodiments, target binding moieties of the present disclosure are capable of binding human interleukin- 10.

[0482] In certain embodiments, the target binding moiety capable of binding IL- 10 comprises or has a structure described in FIG. 18G. In certain embodiments, the target binding moiety capable of binding IL- 10 can be found, for example, in ACS Chem Biol 11: 2105-11 (2016), the contents of which are incorporated herein by reference. r. Target Binding Moieties Capable of Binding Interleukin-5 (IL-5)

[0483] In some embodiments, target binding moieties of the present disclosure are capable of binding human interleukin- 5.

[0484] In certain embodiments, the target binding moiety capable of binding IL-5 comprises or has a structure described in FIG. 18H. In certain embodiments, the target binding moiety capable of binding IL-5 can be found, for example, in Bioorg Med Chem 18: 4441-5 (2010); Bioorg Med Chem 18: 4625-9 (2011); Bioorg Med Chem 21: 2543-50 (2013); Eur J Med Chem 59: 31-8 (2013); Bioorg Med Chem 23: 2498-504 (2015); Bioorg Med Chem 20: 5757-62 (2012); the contents of each of which are incorporated by reference herein.s. Target Binding Moieties Capable of Binding Interleukin-8 (IL-8)

[0485] In some embodiments, target binding moieties of the present disclosure are capable of binding human interleukin- 8.

[0486] In certain embodiments, the target binding moiety capable of binding IL-8 comprises or has a structure described in FIG. 181. In certain embodiments, the target binding moiety capable of binding IL-8 can be found in, for example, Bioorg Med Chem Lett 19: 4026-30 (2009), the contents of which are incorporated by reference herein. t. Target Binding Moieties Capable of Binding Cholinesterase

[0487] In some embodiments, target binding moieties of the present disclosure are capable of binding cholinesterase.

[0488] In certain embodiments, the target binding moiety capable of binding IL-21 comprises or has a structure described in FIG. 18J. In certain embodiments, the target binding moiety capable of binding cholinesterase can be found in, for example, ACS Med Chem Lett 4: 1178- 82 (2013); J Med Chem 49: 3421-5 (2006); EurJMed Chem 55: 23-31 (2012); JMed Chem 51: 3154-70 (2008); J Med Chem 46: 1-4 (2002); Eur J Med Chem 126: 652-668 (2017); Biochemistry 52: 7486-99 (2013); Bioorg Med Chem 23: 1321-40 (2015); the contents of each of which are incorporated herein by reference. u. Target Binding Moieties Capable of Binding C-C motif Chemokine ligand 2 (CCL2)

[0489] In some embodiments, target binding moieties of the present disclosure are capable of binding human C-C motif chemokine ligand 2 (CCL2) (UniProtKB - Pl 3500 (CCL2_HUMAN)).

[0490] In certain embodiments, the target binding moiety capable of binding CCL2 comprises or has a structure described in FIG. 18SS. In certain embodiments, the target binding moiety capable of binding CCL2 can be found in, for example, J Med Chem 56: 7706-14 (2013), which is incorporated herein by reference. v. Target Binding Moieties Capable of Binding Carboxypeptidase B2

[0491] In some embodiments, target binding moieties of the present disclosure are capable of binding human carboxypeptidase B2 (UniProtKB - Q96IY4 (CBPB2_HUMAN)).

[0492] In certain embodiments, the target binding moiety capable of binding B2 comprises or has a structure described in FIG. 18K. In certain embodiments, the target binding moiety capable of binding B2 can be found in, for example, Bioorg Med Chem Lett 20: 92-6 (2010), J Med Chem 50: 6095-103 (2007), Bioorg Med Chem Lett 14: 2141-5 (2004), J Med Chem58: 4839-44 (2015), J Med Chem 55: 7696-705 (2012), J Med Chem 59: 9567-9573 (2016), Bioorg Med Chem Lett 17: 1349-54 (2007), US Pat. Nos. 9,662,310; 8,609,710; 9,688,645; J Med Chem 46: 5294-7 (2003), each of which is incorporated herein by reference. w. Target Binding Moieties Capable of Binding Neutrophil Elastase

[0493] In some embodiments, target binding moieties of the present disclosure are capable of binding human neutrophil elastase (UniProtKB - P08246 (ELNE_HUMAN)).

[0494] In certain embodiments, the target binding moiety capable of binding neutrophil elastase comprises or has a structure described in FIG. 18L. In certain embodiments, the target binding moiety capable of binding neutrophil elastase can be found in, for example, J Med Chem 53: 241-53 (2010), J Med Chem 38: 739-44 (1995), J Med Chem 37: 2623-6 (1994), J Med Chem 38: 468792 (1995), J Med Chem 45: 3 878-90 (2002), Bioorg Med Chem Lett 5: 105-109 (1995), Bioorg Med Chem Lett 11: 243-6 (2001), J Med Chem 40: 1906-18 (1997), Bioorg Med Chem Lett 25: 4370-81 (2015), US Pat. Nos. 8,569,314; 9,174,997; 9,290,457, each of which is incorporated herein by reference. x. Target Binding Moieties Capable of Binding Factor Xa

[0495] In some embodiments, target binding moieties of the present disclosure are capable of binding human Factor Xa (UniProtKB - P00742 (FA10_HUMAN)).

[0496] In certain embodiments, the target binding moiety capable of binding Factor Xa comprises or has a structure described in FIG. 18M. In certain embodiments, the target binding moiety capable of binding Factor Xa can be found in, for example, Bioorg Med Chem Lett 20: 5313-9 (2010), Bioorg Med Chem Lett 13: 679-83 (2003), J Med Chem 44: 566-78 (2001), J Med Chem 50: 2967-80 (2007), J Med Chem 38: 1511-22 (1995), Bioorg Med Chem Lett 18: 2845-9 (2008), J Med Chem 53: 6243-74 (2010), Bioorg Med Chem Lett 18: 2845-9 (2008), Bioorg Med Chem 16: 1562-95 (2008), each of which is incorporated herein by reference. y. Target Binding Moieties Capable of Binding Factor XI

[0497] In some embodiments, target binding moieties of the present disclosure are capable of binding human Factor XI (UniProtKB - P03951 (FAI 1_HUMAN)).

[0498] In certain embodiments, the target binding moiety capable of binding Factor XI comprises or has a structure described in FIG. 18N. In certain embodiments, the target binding moiety capable of binding Factor XI can be found in, for example, US Pat. Nos. 9,453,018; 9,783,530; 10,143,681; 10,214,512; ACS Med Chem Lett 6: 590-5 (2015), J Med Chem 60: 9703-9723 (2017), J Med Chem 60: 9703-9723 (2017), JMed Chem 60: 1060-1075 (2017), JMed Chem 57: 955-69 (2014), each of which is incorporated herein by reference.

[0499] In certain embodiments, the target binding moiety capable of binding Factor XI is selected from:

[0500] In certain embodiments, the target binding moiety capable of binding Factor XI is one described in J Med Chem 61 (17), 7425-7447 (2018) or J Med Chem (2020) Structure-based design and pre-clinical characterization of selective and orally bioavailable Factor Xia inhibitors: demonstrating the power of an integrated SI protease family approach.z. Target Binding Moieties Capable of Binding Factor XII

[0501] In some embodiments, target binding moieties of the present disclosure are capable of binding human Factor XII (UniProtKB - P00748 (FA12_HUMAN)).

[0502] In certain embodiments, the target binding moiety capable of binding Factor XII comprises or has a structure described in FIG. 180. In certain embodiments, the target binding moiety capable of binding Factor XII can be found in, for example, J Med Chem 60: 1151- 1158 (2017), J Med Chem 48: 2906-15 (2005), J Med Chem 50: 5727-34 (2007), J Med Chem 50: 1876-85 (2007), Chembiochem 18: 387-395 (2017), each of which is incorporated herein by reference. aa. Target Binding Moieties Capable of Binding Factor XIII

[0503] In some embodiments, target binding moieties of the present disclosure are capable of binding human Factor XIII UniProtKB - P00488 (F13A_HUMAN)).

[0504] In certain embodiments, the target binding moiety capable of binding Factor XIII comprises or has a structure described in FIG. 18P. In certain embodiments, the target binding moiety capable of binding Factor XIII can be found in, for example, Eur J Med Chem 98: 49- 53 (2015), J Med Chem 55: 1021-46 (2012), J Med Chem 48: 2266-9 (2005), each of which is incorporated herein by reference. bb. Target Binding Moieties Capable of Binding Prothrombin

[0505] In some embodiments, target binding moieties of the present disclosure are capable of binding human Prothrombin (UniProtKB - P00734 (THRB_HUMAN)).

[0506] In certain embodiments, the target binding moiety capable of binding prothrombin comprises or has a structure described in FIG. 18Q. In certain embodiments, the target binding moiety capable of binding prothrombin can be found in, for example, J Med Chem 46: 3 612- 22 (2003), Bioorg Med Chem Lett 12: 1017-22 (2002), J Med Chem 40: 830-2 (1997), Bioorg Med Chem Lett 15: 2771-5 (2005), J Med Chem 42: 3109-15 (1999), J Med Chem 47: 2995- 3008 (2004), Bioorg Med Chem 16: 1562-95 (2008), J Med Chem 42: 3109-15 (1999), each of which is incorporated herein by reference. cc. Target Binding Moieties Capable of Binding Coagulation Factor VII

[0507] In some embodiments, target binding moieties of the present disclosure are capable of binding human coagulation Factor VII (UniProtKB - P08709 (FA7_HUMAN)).

[0508] In certain embodiments, the target binding moiety capable of binding Factor VII comprises or has a structure described in FIG. 18R. In certain embodiments, the target bindingmoiety capable of binding Factor VII can be found in, for example, US Pat. No. 9,174,974, Bioorg Med Chem Lett 26: 5051-5057 (2016), Bioorg Med Chem Lett IL 2253-6 (2001), Bioorg Med Chem Lett 15: 3006-11 (2005), Bioorg Med Chem Lett 12: 2883-6 (2002), each of which is incorporated herein by reference. dd. Target Binding Moieties Capable of Binding Coagulation Factor IX

[0509] In some embodiments, target binding moieties of the present disclosure are capable of binding human coagulation Factor IX (UniProtKB - P00740 (FA9_HUMAN)).

[0510] In certain embodiments, the target binding moiety capable of binding Factor IX comprises or has a structure described in FIG. 18S. In certain embodiments, the target binding moiety capable of binding Factor IX can be found in, for example, US Pat. Nos. 9,409,908; 10,189,819; Bioorg Med Chem Lett 25: 543 7-43 (2015), each of which is incorporated herein by reference. ee. Target Binding Moieties Capable of Binding Fibroblast Growth Factor 1 (FGF1)

[0511] In some embodiments, target binding moieties of the present disclosure are capable of binding human fibroblast growth factor 1 (FGF1) (UniProtKB - P05230 (FGF1_HUMAN)).

[0512] In certain embodiments, the target binding moiety capable of binding FGF1 comprises or has a structure described in FIG. 18T. In certain embodiments, the target binding moiety capable of binding FGF1 can be found in, for example, Bioorg Med Chem Lett 18: 344-9 (2008), Chembiochem 6: 1882-90 (2005), J Med Chem 55: 3804-13 (2012), J Med Chem 47: 1683-93 (2004), J Med Chem 53: 1686-99 (2010, ) each of which is incorporated herein by reference. ff Target Binding Moieties Capable of Binding Fibroblast Growth Factor 2 (FGF2)

[0513] In some embodiments, target binding moieties of the present disclosure are capable of binding human fibroblast growth factor 2 (FGF2) (UniProtKB - P09038 (FGF2_HUMAN)).

[0514] In certain embodiments, the target binding moiety capable of binding FGF2 comprises or has a structure described in FIG. 18U. In certain embodiments, the target binding moiety capable of binding FGF2 can be found in, for example, US Pat. No. 8,933,099; Bioorg Med Chem Lett 12: 3287-90 (2002), Chem Biol Drug Des 86: 1323-9 (2015), Bioorg Med Chem Lett 25: 1552-5 (2015), each of which is incorporated herein by reference. gg. Target Binding Moieties Capable of Binding Fibronectin-1

[0515] In some embodiments, target binding moieties of the present disclosure are capable ofbinding human fibronectin 1 (FN1) (UniProtKB - P02751 (FINC_HUMAN)).

[0516] In certain embodiments, the target binding moiety capable of binding FN comprises or has a structure described in FIG. 18V. In certain embodiments, the target binding moiety capable of binding FN can be found in, for example, Bioorg Med Chem Lett 18: 2499-504 (2008), which is incorporated herein by reference. hh. Target Binding Moieties Capable of Binding Kallikrein-I (KLKI)

[0517] In some embodiments, target binding moieties of the present disclosure are capable of binding human kallikrein- 1 (UniProtKB - P06870 (KLK1_HUMAN)).

[0518] In certain embodiments, the target binding moiety capable of binding KLKI comprises or has a structure described in FIG. 18W. In certain embodiments, the target binding moiety capable of binding KLKI can be found in, for example, US Pat. Nos. 9,783,530; 9,234,000; 10,221,161; 9,687,479; 9,670,157; 9,834,513, 10,214,512; J Med Chem 38: 2521-3 (1995), J Med Chem 38: 1511-22 (1995), each of which is incorporated herein by reference. ii. Target Binding Moieties Capable of Binding Plasma Kallikrein

[0519] In some embodiments, target binding moieties of the present disclosure are capable of binding human plasma kallikrein (UniProtKB - P03952 (KLKB1_HUMAN)).

[0520] In certain embodiments, the target binding moiety capable of binding plasma kallikrein comprises or has a structure described in FIG. 18X. In certain embodiments, the target binding moiety capable of binding plasma kallikrein can be found in, for example, J Med Chem 61: 2823-2836 (2018), J Med Chem 55: 1171-80 (2012), US Pat. Nos. 8,598,206; 9,738,655; 9,409,908; 10,144,746; 9,290,485; Bioorg Med Chem Lett 16: 2034-6 (2006), each of which is incorporated herein by reference. jj. Target Binding Moieties Capable of Binding Matrix Metallopeptidase 1 (MMP-1 )

[0521] In some embodiments, target binding moieties of the present disclosure are capable of binding human matrix metallopeptidase 1 (MMP-1) (UniProtKB - P03956(MMP1_HUMAN)).

[0522] In certain embodiments, the target binding moiety capable of binding MMP-1 comprises or has a structure described in FIG. 18Y. In certain embodiments, the target binding moiety capable of binding MMP-1 can be found in, for example, Bioorg Med Chem Lett 5: 1415-1420 (1995), Bioorg Med Chem Lett 16: 2632-6 (2006), Bioorg Med Chem Lett 8: 837- 42 (1999), Eur J Med Chem 60: 89-100 (2013), J Med Chem 54: 4350-64 (2011), Bioorg Med Chem Lett 8: 3251-6 (1999), J Med Chem 42: 4547-62 (1999), J Med Chem 61: 2166-2210(2018), J Med Chem 41: 1209-17 (1998), which is incorporated herein by reference. kk. Target Binding Moieties Capable of Binding Macrophage Migration InhibitoryFactor (MIF)

[0523] In some embodiments, target binding moieties of the present disclosure are capable of binding human macrophage migration inhibitory factor (MIF) (UniProtKB - P14174 (MIF_HUMAN)).

[0524] In certain embodiments, the target binding moiety capable of binding MIF comprises or has a structure described in FIG. 18Z. In certain embodiments, the target binding moiety capable of binding MIF can be found in, for example, ACS Med Chem Lett 8: 124-127 (2017), J Med Chem 44: 540-7 (2001), J Med Chem 52: 416-24 (2009), J Med Chem 50: 1993-7 (2007), which is incorporated herein by reference. ll. Target Binding Moieties Capable of Binding Transforming Growth Factor- (β2 (TGF- β2)

[0525] In some embodiments, target binding moieties of the present disclosure are capable of binding human transforming growth factor-p2 (TGF-β2) (UniProtKB P61812 (TGFB2_HUMAN)).

[0526] In certain embodiments, the target binding moiety capable of binding TGF-β2 comprises or has a structure described in FIG. 18AA. mm. Target Binding Moieties Capable of Binding Thrombospondin-1 (TSP-1)

[0527] In some embodiments, target binding moieties of the present disclosure are capable of binding human thrombospondin-1 (TSP-1) (UniProtKB - P61812 (TGFB2_HUMAN)).

[0528] In certain embodiments, the target binding moiety capable of binding TSP-1 comprises or has a structure described in FIG. 18BB. nn. Target Binding Moieties Capable of Binding CD40 Ligand (CD40L)

[0529] In some embodiments, target binding moieties of the present disclosure are capable of binding human CD40 ligand (CD40L) (UniProtKB - P29965 (CD40L_HUMAN)).

[0530] In certain embodiments, the target binding moiety capable of binding CD40L comprises or has a structure described in FIG. 18CC. oo. Target Binding Moieties Capable of Binding Urokinase-Type Plasminogen Activator (UP A)

[0531] In some embodiments, target binding moieties of the present disclosure are capable ofbinding human urokinase-type plasminogen activator (UPA) (UniProtKB P00749 (UROK_HUMAN)).

[0532] In certain embodiments, the target binding moiety capable of binding UPA comprises or has a structure described in FIG. 18DD. In certain embodiments, the target binding moiety capable of binding UPA can be found in, for example, J Med Chem 38: 1511-22 (1995), Bioorg Med Chem Lett 11: 2253-6 (2001), Bioorg Med Chem Lett 14: 3063-8 (2004), J Med Chem 52: 3159-65 (2009), CSAR 1: (2012), Bioorg Med Chem 22: 3187-203 (2014), J Med Chem 50: 2341-51 (2007), J Mol Biol 329: 93-120 (2003), Bioorg Med Chem Lett2: 1399- 1404 (1992), J Med Chem 35: 4297-305 (1992), J Med Chem 35: 4150-9 (1992), J Med Chem 49: 5785-93 (2006), Bioorg Med Chem 23: 3696-704 (2015), Bioorg Med Chem Lett 10: 983-7 (2000), J Med Chem 49: 5785-93 (2006), each of which is incorporated by reference herein. pp. Target Binding Moieties Capable of Binding Plasminogen Activator, Tissue Type(TP A)

[0533] In some embodiments, target binding moieties of the present disclosure are capable of binding human plasminogen activator, tissue type (TPA) (UniProtKB - P00750 (TPA_HUMAN)).

[0534] In certain embodiments, the target binding moiety capable of binding TPA comprises or has a structure described in FIG. 18EE. In certain embodiments, the target binding moiety capable of binding TPA can be found in, for example, Bioorg Med Chem Lett 15: 4411-6 (2005), Bioorg Med ChemLett 13: 2781-4 (2003), BioorgMed Chem Lett 6: 2913-2918 (1996), JMed Chem 44: 2753-71 (2001), J Med Chem 41: 5445-56 (1999), Bioorg Med Chem Lett 12: 3183-6 (2002), US Pat. No. 10,118,930; J Biol Chem 285: 7892-902 (2010), each of which is incorporated by reference herein. qq. Target Binding Moieties Capable of Binding Plasminogen (PLG)

[0535] In some embodiments, target binding moieties of the present disclosure are capable of binding human plasminogen (PLG) (UniProtKB - P00747 (PLMN_HUMAN)).

[0536] In certain embodiments, the target binding moiety capable of binding PLG comprises or has a structure described in FIG. 18FF. In certain embodiments, the target binding moiety capable of binding PLG can be found in, for example, J Med Chem 35: 4297-305 (1992), J Med Chem 38: 1511-22 (1995), J Med Chem 56: 820-31 (2013), US Pat. Nos. 8,598,206; 8,921,319; J Med Chem 55: 1171-80 (2012), Bioorg Med Chem Lett 12: 3183-6 (2002), Bioorg Med Chem 23: 3696-704 (2015), Bioorg Med Chem Lett 13: 723-8 (2003), Bioorg Med ChemLett 7: 331-336 (1997), each of which is incorporated by reference herein. rr. Target Binding Moieties Capable of Binding Plasminogen Activator Inhibitor-1 (PAI-1)

[0537] In some embodiments, target binding moieties of the present disclosure are capable of binding human plasminogen activator inhibitor 1 (PAI-1) (UniProtKB - P05121 (PAILHUMAN)).

[0538] In certain embodiments, the target binding moiety capable of binding PAI-1 comprises or has a structure described in FIG. 18GG. In certain embodiments, the target binding moiety capable of binding PAI-1 can be found in, for example, J Biol Chem 285: 7892-902 (2010), US Pat. Nos. 9,120,744; 9,718,760; Bioorg Med Chem Lett 13: 3361-5 (2003), Bioorg Med Chem Lett 12: 1063-6 (2002), BioorgMedChemLett 13: 1705-8 (2003), Bioorg Med Chem Lett 11: 2589-92 (2001), each of which is incorporated by reference herein. ss. Target Binding Moieties Capable of Binding Placenta Growth Factor (PGF)

[0539] In some embodiments, target binding moieties of the present disclosure are capable of binding human placental growth factor (PGF) (UniProtKB - P49763 (PLGF_HUMAN)).

[0540] In certain embodiments, the target binding moiety capable of binding PGF comprises or has a structure described in FIG. 18HH. In certain embodiments, the target binding moiety capable of binding PGF can be found in, for example, J Med Chem 54: 1256-65 (2011), J Nat Prod 76: 29-35 (2013), each of which is incorporated by reference herein. tt. Target Binding Moieties Capable of Binding Phospholipase A2, Group IB (PA21B)

[0541] In some embodiments, target binding moieties of the present disclosure are capable of binding human phospholipase A2, Group IB (PA21B) (UniProtKB P04054 (PA21B_HUMAN)).

[0542] In certain embodiments, the target binding moiety capable of binding PA21B comprises or has a structure described in FIG. 1811. In certain embodiments, the target binding moiety capable of binding PA21B can be found in, for example, J Med Chern 39: 3636-58 (1996), Chembiochem 4: 181-5 (2003), J Med Chem 39: 5159-75 (1997), J Med Chem 51: 4708-14 (2008), each of which is incorporated by reference herein. uu. Target Binding Moieties Capable of Binding Phospholipase A2, Group 111 A (PA2GA)

[0543] In some embodiments, target binding moieties of the present disclosure are capable ofbinding human phospholipase A2, Group IIA (PA2GA) (UniProtKB P04054 (PA21B_HUMAN)).

[0544] In certain embodiments, the target binding moiety capable of binding PA2GA comprises or has a structure described in FIG. 18JJ. In certain embodiments, the target binding moiety capable of binding PA2GA can be found in, for example, J Med Chem 48: 893-6 (2005), J Med Chem 39: 5159-75 (1997), each of which is incorporated by reference herein. vv. Target Binding Moieties Capable of Binding Factor B

[0545] In some embodiments, target binding moieties of the present disclosure are capable of binding human complement factor B (UniProtKB - P00751 (CFAB_HUMAN)).

[0546] In certain embodiments, the target binding moiety capable of binding factor B comprises or has a structure described in FIG. 18KK. In certain embodiments, the target binding moiety capable of binding factor B can be found in, for example, US Patent Nos. 9,682,968; 9,475,806; 9,452,990; Proc Natl Acad Sci 116: 7926-7931 (2019), J Med Chem 52: 6042-6052 (2009), and J Med Chem 63: 5697-5722 (2020), each of which is incorporated by reference herein.

[0547] In certain embodiments, the target binding moiety capable of binding Factor B comprises or has one of the following structures:; each of which is optionally substituted with1, 2, 3, or 4 substituents independently selected from R21.

[0548] In certain embodiments, the target binding moiety capable of binding Factor B is selected from a ligand described in: Mainolfi, N. et. al. Discovery of 4-((2 S ,4 S )-4-Ethoxy-l- ((5-Methoxy-7-Methyl-lH-Indol-4-Yl)Methyl)Piperidin-2-Yl)Benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases. J. Med. Chem. 2020, 63 (11), 5697-5722; W02020 / 016749; WO2018 / 005552; WO2013 / 192345; or WO2015009616. ww. Target Binding Moieties Capable of Binding Factor D

[0549] In some embodiments, target binding moieties of the present disclosure are capable of binding human complement factor D (UniProtKB - P00746 (CFAD_HUMAN)).

[0550] In certain embodiments, the target binding moiety capable of binding complement factor D comprises or has a structure described in FIG. 18LL. In certain embodiments, the target binding moiety capable of binding Complement factor D can be found in, for example, J Med Chem 60: 57175735 (2017), Nat Chem Biol 12: 1105-1110 (2016), US Pat. Nos. 9,598,446; 9643986; 9,663,543; 9,695,205; 9,732,103; 9,732,104; 9,758,537; 9,796,741;9,828,396; 10,000,516; 10,005,802; 10,011,612; 10,081,645; 10,087,203; 10,092,584;10,100,072; 10,106,563; 10,138,225; 10,189,869; 10,253,053; 10,287,301; 10,301,336;10,370,394; 10,385,097; 10,428,094; 10,428,095; 10,464,956; 10,550,140; 10,660,876;10,662,175; 10,689,409; 10,807,952; 10,822,352; 9,464,081; and Hematological 102: 466-475 (2017), each of which is incorporated by reference herein.

[0551] In some embodiments, the target binding moiety capable of binding complement factor D comprises or has an amino acid sequence of a factor D binding aptamer described in U.S. Pat. No. 11,274,307, the contents of which are incorporated herein by reference.

[0552] In certain embodiments, the target binding moiety capable of binding complement factor D is selected from:wherein:R21a, R21bR , R ,R21e, R21f, , and R21gare independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, C1, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR6R7, -NR8SO2R3, -NR8S(O)R3, haloalkyl, aryl, heteroaryl, heterocyclyl, -SR3, -C(O)OR3, -C(O)NR6NR7, -OR3, and heterocycle;R201, R202, R202-, and R203are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C6alkyl, C1-C6alkenyl, C1-C6alkoxy, C2-C6alkynyl, C2-C6alkanoyl, C1- C6thioalkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, -C0-C4alkylNR9R10, -C(O)OR9, -OC(O)R9, -NR9C(O)R10, -C(O)NR9R10, -OC(O)NR9R10, -O(heteroaryl), -NR9C(O)OR10, C1-C2haloalkyl, -C0-C4alkyl(C3-C7cycloalkyl) and -0-C0-C4alkyl(C3-C7cycloalkyl), and C1-C2haloalkoxy, where R209and R210are independently chosen at each occurrence from hydrogen, C1-C6alkyl, and (C3-C7cycloalkyl)C0-C4alkyl; or R202and R202may be taken together to form a 3- to 6-membered spiro ring optionally substituted with 1 or more substituents independently chosen from halogen, hydroxyl, cyano, -COOH, C1-C4alkyl (including in particular methyl), C2-C4alkenyl, C2-C4alkynyl, C1- C4alkoxy, C2-C4alkanoyl, hydroxyC1-C4alkyl, (mono- and di- C1-C4alkylamino)C0-C4alkyl, - C0-C4alkyl(C3-C7cycloalkyl), -0- C0-C4alkyl(C3-C7cycloalkyl), C1-C2haloalkyl, and C1- C2haloalkoxy. or R201and R202may be taken together to form a 3-membered carbocyclic ring, optionally substituted with 1, 2, or 3 substituents selected from R21. or R201and R202may be taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S, optionally substituted with 1, 2, or 3 substituents selected from R21.R202and R203may be taken together to form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents selected from R21.L100is selected fromwherein R217is hydrogen or C1-C6alkyl and R218and R218are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and mm is O, 1, 2, or 3;B100is a cycloalkyl, heterocycle group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, a C2-C6alkenyl, C2-C6alkynyl group, -(C0-C4alkyl)(aryl), -(C0- C4alkyl)(heteroaryl), or -(C0-C4alkyl)(biphenyl), each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21.

[0553] In certain embodiments, the target binding moiety capable of binding complement factor D is selected from:each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21.

[0554] In certain embodiments, the target binding moiety capable of binding complement factor D is selected from a ligand described in US Pat. Nos. 9,796,74; Patent 10,011,612; WO2018 / 160889; WO2019 / 195720; WO2019 / 057946; Karki, R. G. et al. Design, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement Pathway. J. Med. Chem. 2019, 62 (9), 4656-4668; or Belanger, D. B. et al.; W02015 / 009977, the contents of each of which are incorporated by reference herein.

[0555] In certain embodiments, the target binding moiety capable of binding complementfactor D is selected from:XX. Target Binding Moieties Capable of Binding Factor H

[0556] In some embodiments, target binding moieties of the present disclosure are capable of binding human complement factor H (UniProtKB - P08603 (CFAH_HUMAN)).

[0557] In certain embodiments, the target binding moiety capable of binding complement factor H comprises or has a structure described in FIG. 18MM. In certain embodiments, the target binding moiety capable of binding complement factor H can be found in, for example, J Immunol 182: 63 94-6400 (2009), PLoS Pathogens 4: e!000250 (2008), PLoS Pathogens 6: 61001027 (2010), US Pat. Nos. 10,865,238; 8,962,795; US Pub. Nos. 2016 / 0317573; 2019 / 0315842, each of which is incorporated by reference herein. yy. Target Binding Moieties Capable of Binding Complement Component 5 (C5)

[0558] In some embodiments, target binding moieties of the present disclosure are capable of binding human complement component 5 (C5) (UniProtKB - P01031 (C05_HUMAN)).

[0559] In certain embodiments, the target binding moiety capable of binding complement C5 comprises or has a structure described in FIG. 18NN. In certain embodiments, the target binding moiety capable of binding complement C5 can be found in, for example, J Immunol 197: 337-344 (2016), Ther Adv Hematol 10: 1-11 (2019), BioDrugs 34: 149-158 (2020), Blood 135: 884-885 (2020), US Pub. Nos. 2017 / 0342139; 2020 / 0095307, each of which is incorporated by reference herein.

[0560] In certain embodiments, the target binding moiety capable of binding complement C5 is selected from:, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21.

[0561] In certain embodiments, the target binding moiety capable of binding complement C5 is selected from a ligand described in Jendza, K. et al. A Small-Molecule Inhibitor of C5 Complement Protein. Nat Chem Biol 2019, 15 (7), 666-668; or Zhang, M.; Yang, X.-Y.; Tang, W.; Groeneveld, T. W. L.; He, P.-L.; Zhu, F.-H,; Li, J.; Lu, W.; Blom, A. M.; Zuo, J.-P.; Nan,F.-J. Discovery and Structural Modification of I-Phenyl-S-(I-Phenylethyl)Urea Derivatives as Inhibitors of Complement. ACS Med. Chem. Lett. 2012, 3 (4), 317-321, the contents of each of which are incorporated by reference herein.

[0562] In certain embodiments, the target binding moiety capable of binding complement C5 is selected from:

[0563] In certain embodiments, the target binding moiety capable of binding complement C5 is selected from:zz. Target Binding Moieties Capable of Binding Complement Cis

[0564] In some embodiments, target binding moieties of the present disclosure are capable of binding human complement Cis.

[0565] In certain embodiments, the target binding moiety capable of binding complement Cis is selected from a ligand described in W02020 / 198062 or US Patent No. 6,683,055, the contents of each of which are incorporated by reference herein.

[0566] In certain embodiments, the target binding moiety comprises or has the followingstructure:

[0567] In certain embodiments, the target binding moiety is selected from OMS721, Amy 101, APL2, ACH-4471, LNP023, eculizumab, and avacopan. In other embodiments, the target binding moiety is selected from C1-INH, rhucin, TP10, CAB-2, eculizumab, pexelizumab, ofatumumab, compstatin, PMX-53, and rhMBL. In other embodiments, the target binding moiety is selected from BCX1470, TP-20, mirococept, TNX-234, TNX-558, TA106, neutrazumab, anti-properdin, HuMAX-CD38, ARC1905, and JPE-1375. aaa. Target Binding Moieties Capable of Binding MASP

[0568] In some embodiments, target binding moieties of the present disclosure are capable of binding MASP.

[0569] In certain embodiments, the target binding moiety capable of binding MASP is selected from a ligand described in Heja, D. et al. Monospecific Inhibitors Show That Both Mannan-Binding Lectin- Associated Serine Protease-I (MASP-I) and -2 Are Essential for Lectin Pathway Activation and Reveal Structural Plasticity of MASP-2. Journal Of Biological Chemistry 2012, 287 (24), 20290-20300; Dobo, J.; Kocsis, A.; Gal, P. Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases. Pront. Immunol. 2018, 9, 1851; or WO 2014 / 144542, the contents of each of which are incorporated by reference herein.

[0570] In certain embodiments, the target binding moiety capable of binding MSAP-1 is SGMI-1 peptide, linked through the N- or C-terminus.

[0571] In certain embodiments, the target binding moiety capable of binding MSAP-1 is SGMI-2 peptide, linked through the N- or C-terminus.

[0572] In certain embodiments, the target binding moiety capable of binding MSAP-1 is TFMI-3 peptide, linked through the N- or C-terminus. bbb. Target Binding Moieties Capable of Binding Factor Xia

[0573] In some embodiments, target binding moieties of the present disclosure are capable of binding factor Xia.

[0574] In certain embodiments, the target binding moiety capable of binding factor Xia is selected from a ligand described in: Lorthiois, E. et al. Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Pactor Xia Inhibitors: Demonstrating the Power of an Integrated SI Protease Pamily Approach. J. Med. Chem. 2020, 63 (15), 8088-8113, the contents of which are incorporated by reference herein.

[0575] In certain embodiments, the target binding moiety capable of binding factor Xia is selected from a ligand described in: Quan, M. L. et al. Factor Xia Inhibitors as New Anticoagulants. J. Med. Chem. 2018, 61 (17), 7425-7447, the contents of which are incorporated by reference herein.

[0576] In certain embodiments, the target binding moiety capable of binding factor Xia is selected from a ligand described in: Yang, W. et al. Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species. J. Med. Chem. 2020, 63 (13), 7226-7242, the contents of which are incorporated by reference herein.

[0577] In certain embodiments, the target binding moiety capable of binding factor Xia comprises or has the following structure:

[0578] In certain embodiments, the target binding moiety capable of binding factor Xia is selected from:where an anchor bond is placed at any suitable location with or without functionalization.

[0579] In certain embodiments, the target binding moiety capable of binding Factor Xia is selected from:ccc. Target Binding Moieties Capable of Binding Phospholipase A2 Receptor-1 (PLA2R)Autoantibodies

[0580] In some embodiments, target binding moieties of the present disclosure are capable of binding to an autoantibody that binds PLA2R.

[0581] In some embodiments, the target binding moiety capable of binding PLA2R autoantibody comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%,96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from Table 9.In some embodiments, the target binding moiety capable of binding PLA2R autoantibody comprises or has an amino acid sequence selected from Table 9.Table 9. Exemplary Target Binding Moieties Capable of Binding PLA2R Autoantibody

[0582] In some embodiments, the target binding moiety capable of binding an epitope of PLA2R autoantibody, wherein the epitope comprises an amino acid sequence selected from one of the following:S- V-L-T-XH 1 -E-N-XH2 (SEQ ID NO: 244)XH3-I-XH4-XH5-E-XH6 (SEQ ID NO: 245)XH1-E-N-XH2-K (SEQ ID NO: 246)S-V-L-T-XH1-E-N-C-K (SEQ ID NO: 247)XH3-I-XH4-XH5-E-XH6-L-K (SEQ ID NO: 248) wherein XH1, XH2, XH3, XH4, XH5, and XH6 are each independently any natural amino acid or other amino acid described herein. ddd. Target Binding Moieties Capable of Binding Complement C3

[0583] In some embodiments, target binding moieties of the present disclosure are capable of binding complement C3.

[0584] In some embodiments, the target binding moiety capable of binding complement C3 comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from Table 10. In some embodiments, the target binding moiety capable of binding complement C3 comprises or has an amino acid sequence selected from Table 10.Table 10. Exemplary Target Binding Moieties Capable of Binding Complement C3

[0585] In some embodiments, the target binding moiety capable of binding complement C3 is

[0586] In certain embodiments, the target binding moiety capable of binding complement C3 comprises or has one of the following structures:oreee. Target Binding Moieties Capable of Binding Complement Clq

[0587] In some embodiments, target binding moieties of the present disclosure are capable of binding complement C1q.

[0588] In some embodiments, the target binding moiety capable of binding complement C1q comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from Table 11. In some embodiments, the target binding moiety capable of binding complement C1q comprises or has an amino acid sequence selected from Table 11.

[0589] In some embodiments, the target binding moiety capable of binding complement C1q comprises or is a nanobody. In some embodiments, the nanobody is C1qNb75 (Laursen et al. Front Immunol. 2020;! 1:1504).Table 11. Exemplary Target Binding Moieties Capable of Binding Complement C1qfff. Target Binding Moieties Capable of Binding Interleukin-17

[0590] In some embodiments, target binding moieties of the present disclosure are capable of binding human interleukin- 17 (IL-17) (UniProtKB - Q16552 (IL17HUMAN)).

[0591] In certain embodiments, the target binding moiety capable of binding IL- 17 can be found in, for example, W02012101263A1, WO2020163554A1, WO2021055376A1, WO2020146194A1, WO2020127685A1, US20150005319, WO2014066726A2,WO2019223718A1, WO2020135872A1, WO2020146194A1, WO2021027721 Al,WO2021027724, WO2021027729A1, W02021067191A1, CN104069102A,CN105601617B, CN108299256B, Liu et al. “Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists” 2016, Scientific Reports, 6:30859., Liu et al. “Inhibiting complex IL-17AA and IL-17RA interactions with a linear peptide” 2016, Scientific Reports 6:26071. Wang, W. et al. “Artificial macrocycles as IL-17A / IL-17RA antagonists”. Med. Chern. Comm. 2018, 9, 22. Liu, C. et al. “The flavonoid cyanidin blocks binding of the cytokine interleukin- 17A to the IL-17RA subunit to alleviate inflammation in vivo” Science Signaling 10, eaaf8823 (2017), the contents of each of which are incorporated herein by reference..

[0592] In some embodiments, the target binding moiety capable of binding IL- 17 comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from Table 12. In some embodiments, the target binding moiety capable of binding IL- 17 autoantibody comprises or has an amino acid sequence selected from Table 12.Table 12. Exemplary Target Binding Moieties Capable of Binding IL- 17

[0593] In some embodiments, the target binding moiety capable of binding IL- 17 comprises or has one of the following structures:each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21.

[0594] In certain embodiments, the target binding moiety capable of binding IL- 17 comprises or is represented by the following formula:whereinXDis CH or N;RD1is -CH3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CF3, -CH(CH3)2, CH2CHF2, CH2CH2F, -CF(CH3)2, CF2CH3, -OCH3,RD2is -H or -CH2OCH3.

[0595] In certain embodiments, the target binding moiety capable of binding IL- 17 comprises or is represented by the following:wherein,REIis alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl -ORE8or -NRE9RE1° or an F pocket substituent;RE2i LS alkyl, substituted alkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, fused cycloalkylaryl, substituted fused cycloalkylaryl, heteroaryl, substituted heteroaryl or a D pocket substituent; each RE3is independently hydrogen, (C1-C7) alkyl, (C1-C7) substituted alkyl or - ORE32; mEis 0, 1 or 2; each RE4is independently hydrogen, (C1-C7) alkyl, (C1-C7) substituted alkyl, cycloalkyl substituted cycloalkyl, heterocycle or substituted heterocycle; kEis 0 or 1 ;XE1, XE2, XE3andXE4are independently -N- or -CR’1’-provided that no more than two of XE1, XE2, XE3and XE4are nitrogen; each RE5is independently hydrogen, (C1-C7) alkyl, (C1-C7) substituted alkyl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, heterocyclealkyl, substituted heterocyclealkyl, -NRE12RE13, -NRE14C(O)RE15, -NHSO2RE31, OH or a B pocket substituent;RE6is hydrogen or alkyl;RE7is heterocycle, substituted heterocycle, -(CHRE16)oRE17or -(CHRE18)PRE19or RE6and RE7taken together with the nitrogen atom to which they are attached form piperazine,substituted, piperazine, heterocycle or substituted heterocycle,, or an A pocket substituent;RE8is (C1-C7) alkyl, (C1-C7) substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; each RE11is independently hydrogen, alkyl, substituted alkyl, -ORE20, -NRE21RE22, halo., -CN,, --CO22RE23, -CONRE24RE25, or -SRE26; nEis 1, 2 or 3; oEis 1, 2 or 3; pEis 1, 2 or 3; each RE16is independently hydrogen, (C1-C7) alkyl or (C1-C7) substituted alkylRE17iseach RE18is independently hydrogen, (C1-C7) alkyl, or (C1-C7) substituted alkyl;R719is -NRE27RE28;RE27and RE28together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle ring orRE9RE10RE13RE14RE15RE 18RE19RE20RE21RE22RE31, and RE32are independently selected at each instance from hydrogen, alkyl, substituted alkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or alternatively, independently, RE9and RE10, RE21and RE22and RE24and RE23together with atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;RE28is hydrogen or alkyl.

[0596] In some embodiments, the A-pocket substituent is selected from the group consisting of

[0597] In some embodiments, the B-pocket substituent is selected from the group consisting of

[0598] In some embodiments, the D-pocket substituent is selected from the group consisting of

[0599] In some embodiments, the F-pocket substituent is selected from the group consisting ofwherein each optional substituent for the above Formula is independently selected from halogen, -ORF12, -SRF12, -N(RF12)2, -C(O)RF12, -C(O)N(RF12)2, N(RF12)C(O)RF12, -C(O)ORF12, - OC(O)RF12, -S(O)RF12, -S(O)2RF12, -NO2, =0, =S, =N(RF12), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF12,- N(RF12)2, -C(O)RF12, -C(O)N(RF12)2, -N(RF12)C(O)RF12, -C(O)ORF12, -OC(O)RF125-NO, =0, =N(RF11) and -CN.

[0600] In certain embodiments, the target binding moiety capable of binding IL- 17 comprises or is represented by one of the following formula:

[0601] In certain embodiments, the target binding moiety capable of binding IL- 17 comprises or is represented by the following formula:wherein,is selected from an optionally substituted C3-12 carbocycle and optionally substituted 3- to 12-membered heterocycle wherein substituents on Ring AF are independently selected at each occurrence from: halogen, -ORF11, -SRFn, -N(RF11)2, -C(O)RF11, -C(O)N(RF11)2, N(RF11)C(O)RF11, - N(RF11)S(O)2RF11, -C(O)ORFU, -OC(O)RF11, -S(O)RF11, -S(O)2RF11, -NO2, =0, =S, =N(RF11)j - CN; andCI-IO alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORF11, -SRF11, -N(RF11)2, -C(O)RF11, -C(O)N(RF11)2, N(RF11)C(O)RF11, -C(O)ORF11, -OC(O)RF11, -S(O)RF11, -S(O)2RF11, -NO2, =0, =S, =N(RF11), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF11, -N(RF11)2, -C(O)RF11, -C(O)N(RF11)2, - N(RF11)C(O)RF11, -C(O)ORn, -OC(O)Rn, -NO2, =0 =N(Rn)and -CN andC3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -ORF11, -SRF11, -N(RF11)2, -C(O)RF11, -C(O)N(RF11)2, N(RF11)C(O)RF11, -C(O)ORF11, -OC(O)RF11, -NO2, -CN, C1-6 alkyl and C 1-6 haloalkyl;is selected from an optionally substituted C3-10 carbocycle and optionally substituted 3- to 12-membered heterocycle each substituent on Ring B are independently selected at each occurrence from: halogen, -ORF12, -SRF12, -N(RF12)2, -C(O)RF12, -C(O)N(RF12)2, -N(RF12)C(O)RF 12, -C(O)ORFH, -OC(O)RFH, -S(O)RFH, -S(O)2RF12, -NO2, =0, =S, =N(RF12), -CN; andC1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORF12, -SRF12, -N(RF12)I, -C(O)RF12, -C(O)N(RF12)2, N(RF12)C(O)RF12, -C(O)ORF12, -OC(O)RF12, -S(O)RF12, -S(O)2RF12, -NO2, =0, =S, =N(RF12)S -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF12-N(RF12)2, -C(O)RF12, -C(O)N(RF12)2, - N(RF12)C(O)RF12, -C(O)ORF12, -OC(O)RF12, -NO, =0, =N(RFU) and -CN;RF4is selected from -C(O)N(RF23)(RF24) and C(O)heterocycle, wherein heterocycle is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, -ORF13, -SRF13, - N(RF13)2, -C(O)RF13, -C(O)N(RF13)2, -N(RF13)C(O)RF13, -C(O)ORF13, -OC(O)RF13, -S(O)RF13, - S(O)2RF13, -NO2, =0, =S, =N(RF13) -CN; andC1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0RF13, -SRF13, -N(RF13)2, -C(0)RF13, -C(O)N(RF13)2, N(RF13)C(O)RF13, -C(0)0RF13, -0C(0)RF13, -S(O)RF13, -S(O)2RF13, -NO2, =0, =S, =N(RF13)5 -CN5 C3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF13, -N(RF13)2, -C(O)RF13, -C(O)N(RF13)2, - N(RF13)C(O)RF13, -C(O)ORF13, -OC(O)RF13, -NO2, =0, =N(RF13) , and -CN;LFis bond or selected from -O-and -NH-;RFAis selected from hydrogen, halogen, -ORF14, -N(RF14)2, -C(O)RF14, -C(O)N(RF14)2, N(RF14)C(O)RF14, -C(O)ORF14, -OC(O)RF14, -NO2, -CNs and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents selected from: halogen, ORF14, -N(RF14)2, -C(O)RF14, NO2, =0, and -CN;R™ is selected from hydrogen, halogen, -ORF15, -N(RF13)2, -C(O)RF15, -C(O)N(RF15)2, N(RF15)C(O)RF15, -C(O)ORF15, -OC(O)RF15, -NO2, -CN, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents selected from: halogen, ORF15,-N(RF15)2, -C(O)RF15, NO2, =0, and -CN, wherein at least one of RAor RBis not hydrogen;RF’ and RF” are independently selected from: hydrogen, halogen, -ORF16, and C1 -6 alkyl; wherein the C1 -6 alkyl is optionally substituted with one or more substituents selected from: halogen, -ORF16, -N(RF16)2, -C(O)RF16, -NO2, =0, and -CN;RF1is selected from -0RF21, -N(RF21)(RF22), -N(RF21)C(O)RF22, -N(RF21)C(O)ORF22, - N(RF21)C(O)N(RF21)(RF22), -N(RF21)S(=O)2N(RF21)(RF22), and -N(RF21)S(=O)2(RF22);each RF2and RF3are independently selected from: hydrogen, halogen, -ORF17C1-6 alkyl, and C3-6 cycloalkyl; wherein the C1 -6 alkyl and C3-6 cycloalkyl are optionally substituted with one or more substituents selected from: halogen, -ORF17, -N(RF17)2, -CIO / ’17, -NO2, =0, and -CN; orRF2and RF3bound to the same carbon come together to form a C3-6 cycloalkyl optionally substituted with one or more substituents selected from halogen, -ORF17, -N(RF17)2, -C(O)RF17, -NO2, =0, and -CN;RF21is independently selected at each occurrence from hydrogen and C1-C6 alkyl optionally substituted by one or more substituents independently selected from halogen, - ORF17, -N(RF17)2, -C(O)RF17, -NO2, =0, and -CN;RF22is selected from: C1- 10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - ORF18, -SRF18, -N(RF18)2, -C(O)R"S, -C(O)N(RF18)2, -N(RF18)C(O)RF18, -C(O)ORF18, -OC(O)RF18, -S(O)RF18, -S(O)2RF18, -NO2, =0, =S, =N(RF18), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -0RF18, -N(RF18)2, -C(O)RF18, -C(O)N(RF18)2, N(RF18)C(O)RF18, -C(O)ORF18, -OC(O)RF18, -NO2, =0, =N(RF18), and -CN; and C3-C12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, - 0RF18, -SRF18, -N(RF18)2, -C(0)RF18, -C(O)N(RF18)2, -N(RF18)C(O)RF18, -C(0)0RF18, - 0C(0)RF18, -S(O)RF18, -S(O)2RF18, -NO2, =0, =S, =N(RF18), -CN; andC1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0RF18, -SRF18, -N(RF18)2, - C(0)RF18, -C(O)N(RF18)2, -N(RF18)C(O)RF18, -C(0)0RF18, -0C(0)RF18, -S(O)RF18, -S(O)2RF18, - NO2, =0, =S, =N(RF18), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -0RF18, -N(RF18)2, -C(0)RF18, -C(O)N(RF18)2, - N(RF18)C(O)RF18, -C(0)0RF18, -0C(0)RF18, -N02, =0, =N(RF18), and -CN; andC3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -0RF18, -N(RF18)2, -C(0)RF18, - C(O)N(RF18)2, N(RF18)C(O)RF18, -C(0)0RF18, -0C(0)RF18, -NO2, =0, =N(RF18), and -CN;RF23is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -ORF19, -SRF19, -N(RF19)2, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-memberedheterocycle are each optionally substituted with one or more substituents selected from: halogen, -0RF19, -N(RF19)2, =0, C1-C6 alkyl, C1-C6 haloalkyl, and -CN; andC3-12 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -0RF19, - N(RF19)2, =0, C1-C6 alkyl, C1-C6 haloalkyl, and -CN;RF24is selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -0RF19, -SRF19, -N(RF19)2, -NO2, -CN, C3-6carbocycle and 3- to 6-membered heterocycle;RF1 1RF12RF13RF14RF15RF16RF17RF18, and RF19are independently selected at each occurrence from hydrogen; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =0, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10- membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =0, and -CN; andC3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1- C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =0, -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl -NH2, -NO2, =0, and -CN; nFis selected from 0 and 1 ; and mFis selected from 0, 1, and 2.

[0602] In certain embodiments, the target binding moiety capable of binding IL- 17 comprises or is represented by one of the following formula:

[0603] In certain embodiments, the target binding moiety capable of binding IL- 17 comprises or is represented by the following formula:wherein,RG1 is selected from the group consisting of 5-or 6-membered heteroaryl, 9-or 10- membered bicyclic heteroaryl, phenyl, (C1-C6)alkoxy, (C3-C7)cycloalkoxy, (C1-C6)alkyl, phenyl- (C1-C4)alkyl, (C1-C7)Cycloalkyl, 4-6-membered heterocycloalkyl and -NRGCRGD, wherein said 5- or 6-membered heteroaryl, 9-or 10-membered bicyclic heteroaryl, phenyl, (C1-C6)alkoxy, (C3- C7)Cycloalkoxy, (C1-C6)alkyl, phenyl-(C1-C4)alkyl, (C3-C7)cycloalkyl and 4-6-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from RGA;RGArepresents ddeeuutteerriiuumm,, halogen, hydroxy, --NNRRGCRGD, (C1-C6)alkyl, (Ci- C6)alkylcarbonyl, (C3-C7)cycloalkyl, phenyl, 5-or 6-membered heteroaryl or, 4-6-membered heterocycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3-C7...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:TB is a target binding moiety capable of binding a target protein;L is absent or a linker; andLP is a ceramide moiety.

2. The compound of claim 1, the compound is capable of enhancing degradation of the target protein.

3. The compound of claim 1 or 2, wherein target protein is an extracellular protein or a membrane protein.

4. The compound of any one of claims 1-3, wherein the ceramide comprises a C0-C30fatty acid moiety.

5. The compound of any one of claims 1-4, wherein LP is represented by Formula (II):Formula (II) wherein:— is a single bond or double bond; L1is absent or -O-, #-O-N=, #=N-O-, #-0-NH-, #-NH-0-, -C(O)-, #-C(O)NH- #-NHC(O)-, #-C(O)O- or #-OC(O)-, wherein “#” indicates the point of attachment to L;X is absent or a sugar moiety;Rais hydrogen or hydroxyl;Rb is hydrogen or -C(O)R2;R1is C11-C27alkyl or C11-C27alkenyl, each optionally substituted with one or more hydroxyl;R.2is hydrogen, C1-C30alkyl, or C2-C30alkenyl.

6. The compound of claim 5, wherein R1is linear.

7. The compound of claim 5 or 6, wherein R1is -(CH2)14CH3, -(CH2)16CH3, or CH=CH(CH2)I2CH3.

8. The compound of any one of claims 5-7, wherein LP is represented by Formula (Il-a):Formula (Il-a).

9. The compound of any one of claims 5-8, wherein R2is linear.

10. The compound of any one of claims 5-9, wherein R2is hydrogen, C1-C16alkyl, or C2-C16alkenyl.

11. The compound of any one of claims 5-10, wherein R2is -(CH2)4CH3-(CH2)10CH3, (CH2)14CH3, or -(CH2)7CH=CH(CH2)5CH3.

12. The compound of any one of claims 5-11, wherein X is absent.

13. The compound of any one of claims 5-11, wherein X is a monosaccharide.

14. The compound of claim 13, wherein X is glucose, fructose, galactose, or N- acetylgalactosamine (GalNAc).

15. The compound of any one of claims 5-14, wherein L1is -O-, #-O-N=, or -C(O)-, wherein “#” indicates the point of attachment to L.

16. The compound of any one of claims 5-15, wherein LP is represented by Formula (II- al), (II-a2), or (II-a3):

17. The compound of any one of claims 1-16, wherein the linker comprises: a reactive group, a stretcher, a peptide, a PEG, or a self-immolative moiety, or a combination thereof.

18. The compound of claim 17, wherein the linker comprises: a polyethylene glycol (PEG) of formula wherein g is an integer from 1to 50; and a peptide (e.g., a monopeptide, a dipeptide, a tripeptide, or a tetrapeptide.

19. The compound of any one of claims 1-18, wherein the linker is represented by Formula(IV):Formula (IV) wherein RG1is absent or a reactive group;Ls is absent or a stretcher; Lpis absent or a peptide; LIis absent or a self-immolative moiety; each of X1and X2 is independently M, W-M, M-W, M-W-M, or W-M-W, wherein each W is independently C1-6alkylene or C2-6alkenylene; and each M is independently a bond, -O-, -C(O)-, *-O-N=, *=N-O-, * *-0-NH-*. -NH-0-, *-NHC(O)-, *-C(O)NH-, *-OC(O)-, *-C(O)O-, *-OP(O)(OH)- *-P(O)(OH)O- *-OP(O)(OH)OP(O)(OH)-, *-P(O)(OH)OP(O)(OH)O- -OP(O)(OH)O-, *-OC(O)N(CH3)C(RM)2C(RM)2N(CH3)C(O)-, or *-C(O)N(CH3)C(RM)2C(RM)2N(CH3)C(O)O-, wherein each RMis independently selected from H, C1-6alkyl, or C3-8 cycloalkyl, and “*”indicates the point of attachment to RG1or LIwhen X is M, M-W, or M-W-M, or to W when X is W-M, M-W-M, or W- M-W; and“#” indicates the point of attachment to LP, and “&” indicates the point of attachment to TB.

20. The compound of claim 19, wherein X2is a bond, -C(O)CH2-#, or -NHC(O)-#, wherein “#” indicates the point of attachment to LP.

21. The compound of claim 19 or 20, wherein LIis absent.

22. The compound of any one of claims 19-21, wherein Lpis absent.

23. The compound of any one of claims 19-21, wherein Lpis a peptide of formula wherein R is an amino acid side chain, m is an integer from 1 to 20, andindicates the point of attachment to LI.

24. The compound of claim 23, wherein Lpis a monopeptide, a dipeptide, a tripeptide, or a tetrapeptide.

25. The compound of claim 23 or 24, wherein Lpis a dipeptide selected from the group consisting of Glu-Glu, Lys-Lys, Ala-Ala, and Arg-Arg.

26. The compound of claim 25, wherein Lphas a structure ofwherein indicates the point of attachment to LI.

27. The compound of any one of claims 19-26, wherein Ls is absent.

28. The compound of any one of claims 19-26, wherein Ls is a stretcher of formula (CH2)q(CH2OCH2)p(CH2)q-, wherein p and q are each independently an integer from 0 to 20.

29. The compound of claim 28, wherein Ls is (CH2)(CH2OCH2)6(CH2)-, (CH2)(CH2OCH2)11(CH2)-, or -(CH2)(CH2OCH2)12(CH2)-.

30. The compound of any one of claims 19-29, wherein X1is a bond, -(CH2)0-6C(0)NH-* or -NHC(O)(CH2)1-6C(O)NH-*, wherein indicates the point of attachment to Ls.

31. The compound of claim 30, wherein X1is a bond, -(CH2)2C(O)NH-* or NHC(O)(CH2)1-6C(O)NH-*, wherein indicates the point of attachment to Ls.

32. The compound of any one of claims 19-31, wherein RG1is absent, -CH2-, -C(O)-, &C(O)NH- &-C(S)NH- S-,whereinindicates the point of attachment to TB, and R’ is hydrogen or C1-3alkyl.

33. The compound of any one of claims 19-32, wherein RG1— X1has one of the following structure:wherein indicates thepoint of attachment to Ls, and “&” indicates the point of attachment to TB.

34. The compound of any one of claims 19-33, wherein the compound is represented by Formula (V-a1) or (V-a2):Formula (V-al)Formula (V-a2) wherein TB, RG1, p, m, and R2are as defined in any one of claims 1-35.

35. The compound of any one of claims 1-34, wherein TB comprises or is a peptide.

36. The compound of any one of claims 1-35, wherein TB comprises or is an antibody or an antigen binding fragment thereof.

37. The compound of claim 36, wherein the antibody is a humanized antibody.

38. The compound of claim 36 or 37, wherein the antigen binding fragment is a Fab, a Fab’, a Fab2, a F(ab’)2, Fv, a single-chain Fv (scFv), or a single domain antibody (sdAb) (e.g., a nanobody).

39. The compound of any one of claims 1-38, wherein the target protein is IgG, IgG4, IgA, IgE, IgM, IL-31, FGF23, TTR, IFN-γ, or TSLP.

40. The compound of any one of claims 1-39, wherein the target protein is IgG.

41. The compound of claim 40, wherein TB comprises or is a peptide comprising or having an amino acid sequence that has at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 1-51.

42. The compound of claim 41, wherein TB comprises or is a peptide comprising or having an amino acid sequence selected from SEQ ID NOs: 1-51.

43. The compound of claim 40, wherein TB comprises or has one of the following structures:The compound of claim 43, wherein TB comprises or has the following structure .

45. The compound of any one of claims 1-39, wherein the target protein is IgG4.

46. The compound of claim 45, wherein TB comprises or is an antibody or an antigen binding fragment thereof, comprising(a) ((ii)) a heavy chain variable (VH) region comprising: heavy chain complementarity-determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 87, or a sequence differing in 1 or 2 amino acids therefrom,HCDR2 having the amino acid sequence of SEQ ID NO: 88, or a sequence differing in 1 or 2 amino acids therefrom, andHCDR3 having the amino acid sequence of SEQ ID NO: 89, or a sequence differing in 1 or 2 amino acids therefrom; and / or(ii) a light chain variable (VL) region comprising: light chain complementarity-determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 91, or a sequence differing in 1 or 2 amino acids therefrom,LCDR2 having the amino acid sequence of SEQ ID NO: 92, or a sequence differing in 1 or 2 amino acids therefrom, andLCDR3 having the amino acid sequence of SEQ ID NO: 93, or a sequence differing in 1 or 2 amino acids therefrom; or(b) (i) a VH region comprising:HCDR1 having the amino acid sequence of SEQ ID NO: 95, or a sequence differing in 1 or 2 amino acids therefrom,HCDR2 having the amino acid sequence of SEQ ID NO: 96, or a sequence differing in 1 or 2 amino acids therefrom, andHCDR3 having the amino acid sequence of SEQ ID NO: 97, or a sequence differing in 1 or 2 amino acids therefrom; and(ii) a VL region comprising:LCDR1 having the amino acid sequence of SEQ ID NO: 99, or a sequence differing in 1 or 2 amino acids therefrom,LCDR2 having the amino acid sequence of SEQ ID NO: 100, or a sequence differing in 1 or 2 amino acids therefrom, andLCDR3 having the amino acid sequence of SEQ ID NO: 101, or a sequence differing in 1 or 2 amino acids therefrom.

47. The compound of claim 46, wherein the antibody or antigen binding fragment thereof comprises a VH comprising HCDR1, HCDR2, and HCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprise amino acid sequences that collectively differ by no more than two amino acid residues from the sequences of:(a) SEQ ID NO: 87, SEQ ID NO: 88, and SEQ ID NO: 89, respectively; or(b) SEQ ID NO: 95, SEQ ID NO: 96, and SEQ ID NO: 97, respectively.

48. The compound of claim 46 or 47, wherein the antibody or antigen binding fragment thereof comprises a VH comprising LCDR1, LCDR2, and LCDR3, wherein the LCDR1, LCDR2, and LCDR3 comprise amino acid sequences that collectively differ by no more than two amino acid residues from the sequences of:(a) SEQ ID NO: 91, SEQ ID NO: 92, and SEQ ID NO: 93, respectively; or(b) SEQ ID NO: 99, SEQ ID NO: 100, and SEQ ID NO: 101, respectively.

49. The compound of any one of claims 46-48, wherein the antibody or antigen binding fragment thereof comprises(a) (i) a VH region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 87,HCDR2 comprising the amino acid sequence of SEQ ID NO: 88, andHCDR3 comprising the amino acid sequence of SEQ ID NO: 89; and (ii) a VL region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 91, HCDR2 comprising the amino acid sequence of SEQ ID NO: 92, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 93; or(a) (i) a VH region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 95, HCDR2 comprising the amino acid sequence of SEQ ID NO: 96, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and (ii) a VL region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 99, HCDR2 comprising the amino acid sequence of SEQ ID NO: 100, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 101.

50. The compound of any one of claims 46-49, wherein the antibody or antigen binding fragment thereof comprises(a) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 86, and / or a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 90; or(b) a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 94, and / or a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 98.

51. The compound of any one of claims 46-50, wherein the antibody or antigen binding fragment thereof comprises(a) a VH region having the amino acid sequence of SEQ ID NO: 86, and / or a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 90; or(b) a VH region having the amino acid sequence of SEQ ID NO: 94, and / or a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 98.

52. The compound of any one of claims 46-51, wherein the antibody or antigen binding fragment thereof is a Fab.

53. The compound of claim 51, wherein the Fab comprises a heavy chain (HC) that comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 102 or SEQ ID NO: 103; a light chain (EC) that comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of having the amino acid sequence of SEQ ID NO: 104.

54. The compound of any one of claims 1-39, wherein the target protein is IgA.

55. The compound of claim 54, wherein TB comprises or is a peptide comprising or having an amino acid sequence that has at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 52-85, optionally wherein TB comprises or has an amino acid sequence that has at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 55.

56. The compound of claim 54 or 55, wherein TB comprises or is a peptide comprising or having an amino acid sequence selected from SEQ ID NOs: 52-85, optionally wherein TB comprises or has an amino acid sequence of SEQ ID NO: 55.

57. The compound of claim 54, wherein TB comprises or is an antibody or an antigen binding fragment thereof, comprising(a) a VH region comprising:HCDR1 having the amino acid sequence of SEQ ID NO: 109, or a sequence differing in 1 or 2 amino acids therefrom,HCDR2 having the amino acid sequence of SEQ ID NO: 110, or a sequence differing in 1 or 2 amino acids therefrom, andHCDR3 having the amino acid sequence of SEQ ID NO: 111, or a sequence differing in 1 or 2 amino acids therefrom; and(b) a VL region comprising:LCDR1 having the amino acid sequence of SEQ ID NO: 114, or a sequence differing in 1 or 2 amino acids therefrom,LCDR2 having the amino acid sequence of SEQ ID NO: 115, or a sequence differing in 1 or 2 amino acids therefrom, andLCDR3 having the amino acid sequence of SEQ ID NO: 116, or a sequence differing in 1 or 2 amino acids therefrom.

58. The compound of claim 57, wherein the antibody or antigen binding fragment thereof comprises(a) a VH region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 109, HCDR2 comprising the amino acid sequence of SEQ ID NO: 110, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 111; and(b) a VL region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 114, HCDR2 comprising the amino acid sequence of SEQ ID NO: 115, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 116.

59. The compound of claim 57 or 58, wherein the antibody or antigen binding fragment thereof comprises a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 108, and / or a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 113.

60. The compound of any one of claims 57-59, wherein the antibody or antigen binding fragment thereof comprises a VH region having the amino acid sequence of SEQ ID NO: 108, and / or a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 113.

61. The compound of any one of claims 1-39, wherein the target protein is IgE.

62. The compound of claim 61, wherein TB comprises or is a peptide comprising or having an amino acid sequence that has at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 124-159 and 586-588, optionally wherein TB comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% or 100% sequence identity to SEQ ID NO: 143 or SEQ ID NO: 159.

63. The compound of claim 61 or 62, wherein TB comprises or is a peptide comprising or having an amino acid sequence selected from SEQ ID NOs: 124-159 and 586-588, optionally wherein TB comprises or has an amino acid sequence of SEQ ID NO: 143 or SEQ ID NO: 159.

64. The compound of claim 61, wherein TB comprises or is an antibody or an antigen binding fragment thereof, optionally wherein antibody or antigen binding fragment thereof is omalizumab, ligelizumab, quilizumab, MEDI4212, XmAb7195, or 8D6, or an antigen binding fragment thereof.

65. The compound of claim 64, wherein the antibody or antigen binding fragment thereof binds IgE with a pH-dependent affinity.

66. The compound of claim 64 or 65, wherein the antibody or antigen binding fragment thereof comprises one or more sequences selected from SEQ ID NOs: 526-583.

67. The compound of any one of claims 1-39, wherein the target protein is IL-31.

68. The compound of claim 67, wherein TB comprises or is an antibody or an antigen binding fragment thereof, comprising(a) a VH region comprising:HCDR1 having the amino acid sequence of SEQ ID NO: 506, or a sequence differing in 1 or 2 amino acids therefrom,HCDR2 having the amino acid sequence of SEQ ID NO: 507 or 508, or a sequence differing in 1 or 2 amino acids therefrom, andHCDR3 having the amino acid sequence of SEQ ID NO: 509, or a sequence differing in 1 or 2 amino acids therefrom; and(b) a VL region comprising:LCDR1 having the amino acid sequence of SEQ ID NO: 514 or 515, or a sequence differing in 1 or 2 amino acids therefrom,LCDR2 having the amino acid sequence of SEQ ID NO: 516, or a sequence differing in 1 or 2 amino acids therefrom, andLCDR3 having the amino acid sequence of SEQ ID NO: 517, or a sequence differing in 1 or 2 amino acids therefrom.

69. The compound of claim 68, wherein the antibody or antigen binding fragment thereof comprises(a) a VH region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 506,HCDR2 comprising the amino acid sequence of SEQ ID NO: 507 or 508, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 509; and(b) a VL region comprising:HCDR1 comprising the amino acid sequence of SEQ ID NO: 514 or 515, HCDR2 comprising the amino acid sequence of SEQ ID NO: 516, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 517.

70. The compound of claim 68 or 69, wherein the antibody or antigen binding fragment thereof comprises a VH region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 510-513, and / or a VL region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence deleted from SEQ ID NOs: 518-519.

71. The compound of any one of claims 68-70, wherein the antibody or antigen binding fragment thereof comprises a VH region having the amino acid sequence of SEQ ID NO:510-513, and / or a VL region having the amino acid sequence of the amino acid sequence of SEQ ID NO: 518-519.

72. The compound of any one of claims 68-71, wherein the antibody or antigen binding fragment thereof is an scFv, optionally wherein the the scFv comprises or has an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 520-525.

73. The compound of any one of claims 1-72, wherein TB comprises or is a peptide, an antibody, or an antigen binding fragment, wherein the peptide, antibody, or antigen binding fragment is attached to L at an amino acid side chain comprising -NH2, -SH, or -OH.

74. The compound of claim 73, wherein the peptide, antibody, or antigen binding fragment is attached to L at a lysine (Lys), cysteine (Cys), or tyrosine (Tyr) residue.

75. The compound of any one of claims 1-74, wherein TB comprises or is a peptide, an antibody, or an antigen binding fragment, wherein the peptide, antibody, or antigen binding fragment is modified to comprise a reactive group.

76. The compound of claim 75, wherein the reactive group comprises an azide or alkyne group.

77. The compound of any one of claims 1-76, wherein the compound is capable of being internalized after contacting with a cell.

78. The compound of claim 77, wherein the compound is bound with the target protein.

79. The compound of any one of claims 1-78, wherein the compound is capable of delivering the target protein into a cell.

80. The compound of claim 79, wherein the compound is capable of delivering the target protein to late endosome or lysosome.

81. The compound of claim 80, wherein the delivery to late endosome or lysosome is preferable than delivery to Golgi, endoplasmic reticulum (ER), or endocytic recycling compartment (ERC).

82. A pharmaceutical composition, comprising a compound of any one of claims 1-81 and a pharmaceutically acceptable carrier, diluent, or excipient.

83. A method of delivering a target protein, comprising contacting a compound of any one or claims 1-81 or a pharmaceutical composition of claim 82 with the target protein.

84. The method of claim 83, wherein the method delivers the target protein to late endosome or lysosome.

85. The method of claim 83 or 84, wherein the target protein is delivered for targeted degradation.

86. A method of enhancing degradation of a target protein, comprising contacting a compound of any one of claims 1-81 or a pharmaceutical composition of claim 82 with the target protein.

87. The method of claim 86, wherein degradation of the target protein is enhanced relative to degradation of target protein in the absence of the compound or pharmaceutical composition.

88. The method of any one of claims 83-87, wherein the method is performed in vitro.

89. The method of any one of claims 83-87, wherein the method is performed in vivo.

90. The method of claim 86, wherein contacting the compound or pharmaceutical composition with the target protein comprises administering an effective amount of the compound or pharmaceutical composition to a subject.

91. A method of treating a disease or disorder associated with the target protein, comprising administering to a subject an effective amount of a compound of any one of claims 1-81 or pharmaceutical composition of claim 82.

92. The method of any one of claims 83-91, comprising multiple administrations of a compound of any one of claims 1-81 or pharmaceutical composition of claim 82.

93. The method of claim 92, wherein the interval between two consecutive administrations is at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks.

94. The method of claim 92, wherein the compound or pharmaceutical composition is administered no more frequent than once every week, once every 2 weeks, once every 3 weeks, or once every 4 weeks.

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