WO2023192510A1

WO2023192510A1 - β-CATENIN ANTIBODIES

Info

Publication number: WO2023192510A1
Application number: PCT/US2023/016953
Authority: WO
Inventors: Byung-Kwon Choi; Nicholas Emerson LONG; Ziqing QIAN; Patrick Dougherty; Mahboubeh KHEIRABADI
Original assignee: Entrada Therapeutics, Inc.
Priority date: 2022-03-31
Filing date: 2023-03-30
Publication date: 2023-10-05

Abstract

β catenin antibodies or antigen binding fragments thereof are provided. The β catenin antibodies or antigen binding fragments thereof may be linked to an endosomal escape vehicle to allow delivery of the β catenin antibodies or antigen binding fragments thereof to the cytosol of cells.

Description

β-CATENIN ANTIBODIES CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Application No. No. 63/362,295 filed on March 31, 2022; U.S. Provisional Patent Application No.63/339,793 filed on May 9, 2022; U.S. Provisional Patent Application No. 63/354,382 filed on June 22, 2022; U.S. Provisional Patent Application No.63/411,852 filed on September 30, 2022; and U.S. Provisional Patent Application No. 63/426,411, filed on November 18, 2022 each of which is incorporated herein by reference in its entirety. INTRODUCTION [0002] The Wnt/β-catenin signaling pathway plays a role in the regulation of cell proliferation, differentiation, and survival. As such, abnormal regulation of the Wnt/β-catenin signaling pathway is associated with many diseases including many forms of cancer, fibrosis diseases, and metabolic diseases. The Wnt/β-catenin signaling pathway primarily regulates cellular function through β- catenin. [0003] The Wnt/β-catenin signaling pathway involves a myriad of proteins, each protein having a different function when the extracellular glycoprotein, Wnt ligand, is present or absent. In the off state (e.g., the Wnt ligand is not present), β-catenin is sequestered by a destruction complex that includes adenomatous polyposis coil protein (APC), glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), and axin. CK1α and GSK3β phosphorylate β-catenin resulting in the recognition of β-catenin by the E3 ligase TrCP, and its subsequent degradation (MacDonald, B., et al., Dev Cell, 2009, 17(1), doi:10.1016/j.devcel.2009.06.016; Liu, C., Medicine in Drug Discovery 2022, 8, dx.doi.org/10.1016/j.medidd.2020.100066; Zhang, Y., Journal of Hematology and Oncology 2020 13(16), doi.org/10.1186/s13045-020-00990-3; Suryawanshi, A., et al., Frontiers in Immunology 2016, 7, 0.3389/fimmu.2016.00460). [0004] The Wnt/β-catenin signaling pathway is activated by the binding of Wnt to the transmembrane Fizzled (FZD) and low-density lipoprotein receptor related proteins (LRP5/6) which, in turn, activate the intracellular protein disheveled (DVL). The activation of DVL disrupts the destruction complex and inhibits the ability of GSK3β to phosphorylate β-catenin. Unphosphorylated β-catenin translocates to the nucleus and interacts with T cell-specific factor (TCF)/lymphoid enhancer-binding factor (LEF) and coactivators (e.g., BCL9 and CBP) to trigger the expression of cell proliferation genes such as c-Myc, cyclin D1, and CDKN1A (MacDonald, B., et al., Dev Cell, 2009, 17(1), doi:10.1016/j.devcel.2009.06.016; Liu, C., Medicine in Drug Discovery 2022, 8, dx.doi.org/10.1016/j.medidd.2020.100066; Zhang, Y., Journal of Hematology and Oncology 2020 13(16), doi.org/10.1186/s13045-020-00990-3; Suryawanshi, A., et al., Frontiers in Immunology 2016, 7, 0.3389/fimmu.2016.00460). [0005] Drugs are being developed to target various parts of the Wnt/β-catenin signaling pathway. For example, small molecule drugs and antibodies have been developed to target porcupine, a protein that regulates the excretion of Wnt; TTCF/β-catenin complex; CBP/β-catenin complex; DVL; FZD; LRP5/6; and tankyrase, an axion regulator protein (Liu, C., Medicine in Drug Discovery 2022, 8, dx.doi.org/10.1016/j.medidd.2020.100066; Zhang, Y., Journal of Hematology and Oncology 202013(16), doi.org/10.1186/s13045-020-00990-3). However, targeting the Wnt/β- catenin signaling pathway has proven challenging and new strategies are needed. SUMMARY [0006] The present disclosure describes, among other things, E-catenin (also referred to herein as “b-catenin” and beta-catenin”) antibodies and antigen binding fragments thereof. The antibodies or antigen binding fragments thereof may be delivered to cells to modulate activity of b-catenin. The antibodies or antigen binding fragments thereof may be administered to subjects in need thereof to treat diseases associated with b-catenin. [0007] The antibodies and antigen binding fragments thereof comprises an antibody variable domain comprising an amino acid sequence comprising: (i) a CDR1 sequence comprising amino acid sequence GRTFARNV, GGALSSYR, or GGIFSTFA; (ii) a CDR2 sequence comprising amino acid sequence ISWSGAST, ISWSGDST, or ISGGGST; and (iii) a CDR3 sequence comprising amino acid sequence ISWSGAST, ISWSGDST, or ISGGGST. In embodiments, the antibody variable domain comprises an amino acid sequence comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to (i) QVQLVESGGG LVQAGDSLIL SCAASGRTFA RNVMGWFRQA PGNEAEFVAA ISWSGASTFY ADSVKGRFTI SRDNAKNTTY LQMNSLKPED TAVYYCKAVR RLRLGVDDYW GQGTQVTVSS, (ii) QVQLVETGGG LVQPGDSLRL SCAASGGALS SYRMGWFRQA PGKEREFVAA ISWSGDSTYY QHSVRGRFT ISRDNAKDT VYLQMNSLK PEDTGVYY CAVDVKSD RGSLVADF GSWGQGTQV TVSS, or (iii) QVQLQESGGG LVQPGGSLRL SCTVSGGIFS TFAMGWYRQA PGKQRELVAA ISGGGSTRYE DAVKGRFTIS RDNAGNTVYL RMNSLEPEDT AVYYCNARVW IADADEPYSF WGQGTQVTVSS. [0008] In embodiments, the present disclosure describes degradation constructs comprising a degradation moiety operably linked to a targeting moiety. The targeting moiety comprises the b- catenin antibody or an antigen binding fragment thereof. The targeting moiety binds b-catenin and brings the degradation moiety in proximity to the b-catenin. The degradation moiety facilitates degradation of the b-catenin. In embodiments, the targeting moiety includes a first targeting domain and a second targeting domain (e.g., a bispecific targeting moiety). The first targeting domain comprises the b-catenin antibody or an antigen binding fragment thereof. The second targeting domain binds to an extracellular antigen or an intracellular antigen. In embodiments, the second targeting domain is linked (e.g., conjugated or fused) to the first targeting domain. [0009] In embodiments, the degradation moiety comprises an E3 ligase, an active fragment of an E3 ligase, or an E3 ligase recruiting moiety. The E3 ligase, the active fragment of an E3 ligase, or the E3 ligase recruiting moiety cause ubiquitination or facilitate ubiquitination of the b-catenin within a cell to cause proteasomal degradation of the b-catenin. [0010] In embodiments, the present disclosure describes compounds comprising a cell penetrating peptide (CPP) and the b-catenin antibody or antigen binding fragment thereof or the degradation construct. The CPP may enhance intracellular delivery of the b-catenin antibody or antigen binding fragment thereof or the degradation construct. The CPP may be a cyclic CPP (cCPP). The compound may comprise an endosomal escape vehicle (EEV). In embodiments, the EEV comprises the cCPP. In embodiments, the EEV comprises the cCPP and an exocyclic peptide (EP) operably linked to the cCPP. The EEV facilitates intracellular delivery of the b-catenin antibody or antigen binding fragment thereof and endosomal escape to allow the b-catenin antibody or antigen binding fragment thereof to interact with intracellular b-catenin in the cytosol. [0011] In embodiments, the cCPP comprises 6 through 12 amino acids, wherein at least two amino acids of the cyclic peptide are charged amino acids; at least two amino acids of the cyclic peptide are aromatic hydrophobic amino acids; and at least two amino acids of the cyclic peptide are uncharged, and non-aromatic amino acids. In embodiments, the at least at least two aromatic hydrophobic amino acids of the cyclic peptide are phenylalanine, naphthylalanine, or combinations thereof. In embodiments, the at least two uncharged, non-aromatic amino acids are citrulline, glycine, or combinations thereof. In embodiments, the at least two charged amino acids are arginine. [0012] In embodiments, the cCPP comprises 6-12 amino acids, wherein at least two amino acids are arginine, at least two amino acids comprises a hydrophobic side chain, and at least one amino acid is a D amino acid. [0013] In embodiments, the cCPP comprises:

or a protonated form thereof, wherein: R1, R2, and R3 are each independently H or an aromatic or heteroaromatic side chain of an amino acid; at least one of R₁, R₂, and R₃ is an aromatic or heteroaromatic side chain of an amino acid; R₄, R₅, R₆, and R₇ are independently H or an amino acid side chain; at least one of R4, R5, R6, and R7 is the side chain of 3-guanidino-2- aminopropionic acid, 4-guanidino-2-aminobutanoic acid, arginine, homoarginine, N- methylarginine, N,N-dimethylarginine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, lysine, N-methyllysine, N,N-dimethyllysine, N-ethyllysine, N,N,N-trimethyllysine, 4- guanidinophenylalanine, citrulline, N,N-dimethyllysine, β-homoarginine, 3-(1- piperidinyl)alanine; AASC is an amino acid side chain; and q is 1, 2, 3 or 4. [0014] In embodiments, the cCPP comprises:

or a protonated form thereof, wherein: R1, R2, and R3 are each independently H or an aromatic or heteroaromatic side chain of an amino acid; at least one of R1, R2, and R3 is an aromatic or heteroaromatic side chain of an amino acid; R₄, R₅, R₆, and R₇ are independently H or an amino acid side chain; at least one of R4, R5, R6, and R7 is the side chain of 3-guanidino-2- aminopropionic acid, 4-guanidino-2-aminobutanoic acid, arginine, homoarginine, N- methylarginine, N,N-dimethylarginine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, lysine, N-methyllysine, N,N-dimethyllysine, N-ethyllysine, N,N,N-trimethyllysine, 4- guanidinophenylalanine, citrulline, N,N-dimethyllysine, β-homoarginine, 3-(1- piperidinyl)alanine; AA_SC is an amino acid side chain; and q is 1, 2, 3 or 4. [0015] In embodiments, the cCPP comprise:

wherein: R1, R2, R3, R4, R5, R6, and R7 are independently H or an amino acid side chain; at least two of R₁, R₂, and R₃ are independently a side chain of phenylalanine, or naphthylalanine; at least two of R4, R5, R6, and R7 are independently a side chain of arginine; AASC is an amino acid side chain; each nx is 0 or 1 and at least one nx is 1; and q is 1, 2, 3 or 4. [0016] In embodiments, the cCPP comprises:

or a protonated form thereof, wherein: each of R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are independently H or an amino acid side chain; AASC is an amino acid side chain; nx is 1; and q is 1, 2, 3 or 4. In embodiments, at least two of R1, R2, and R3 are independently a side chain of phenylalanine or naphthylalanine; and at least two of R₄, R₅, R₆, or R₇ are independently a side chain of arginine. [0017] In embodiments, the cCPP comprises:

at least one of R1, R2, R3, R4, R5, R6, and R7 is the amino acid side chain of serine or histidine; each of R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are independently H or an amino acid side chain; AA_SC is an amino acid side chain; n_x is 0 or 1; and q is 1, 2, 3 or 4. In embodiments, at least two of R₄, R₅, R₆, and R7 are independently a side chain of serine of histidine. In embodiments, at least two of R1, R2, and R3 are independently a side chain of phenylalanine or naphthylalanine; and at least two of R4, R₅, R₆, or R₇ are independently a side chain of arginine. In embodiments, at least two of R₄, R₅, R6, and R7 are independently a side chain of serine of histidine; at least two of R1, R2, and R3 are independently a side chain of phenylalanine or naphthylalanine; and at least two of R4, R5, R6, or R₇ are independently a side chain of arginine. [0018] The above summary of the present disclosure is not intended to describe each disclosed embodiment or every implementation of the present disclosure. The description that follows exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list. BRIEF DESCRIPTION OF THE FIGURES [0019] The following detailed description of illustrative embodiments of the present disclosure may be best understood when read in conjunction with the following drawings. [0020] FIG. 1A shows schematics of and IgG antibody and antigen binding fragments such as F(ab), Fv fragment, sdAb, scFv, pFc’, Fc, F(ab’)2. FIG.1B shows schematics of a camelid heavy chain IgG (hcIgG) and a sdAb from the hcIgG. [0021] FIG.2 is a schematic showing the mechanism of b-catenin degradation mediated by of the degradation compounds described herein. [0022] FIG. 3 is a plot showing the level of β-catenin after HEK293TN cells were treated with various sdAbs. [0023] FIGS. 4A-4D show generalized reaction schemes for maleimide bioconjugation (4A), succinimidyl 3-(2-pyridyldithio)propionate (SPDP) bioconjugation (4B), malemide- dibenzocylcooctyne (Mal-DBCO) bioconjugation (4C), and N-hydroxysuccinimide ester-DBCO bioconjugation (4D). [0024] FIG.5A is a plot showing the change in β-catenin levels and c-Myc levels after cells were treated with various NB03 andNB01-E3 ligase constructs. FIG.5B shows two plots showing the change in β-catenin levels and c-Myc levels after cells were treated with various nanobody-E3 ligase constructs. [0025] FIG. 6 shows Western blots illustrating that the NB01-MDM2i-1 and NB01-MDM2i-2 constructs downregulate c-Myc level in MCF-7 cells after intracellular expression of the construct. [0026] FIGS. 7A-D are various plots showing the levels of β-catenin (A), c-Myc (B), P53 (C), and MDM2 (D) after MCF-7 cells were treated with various degradation compounds. [0027] FIG.8A-8F are various plots showing the levels of β-catenin, Myc, MDM2, and P53 (A); the cell viability (B); level of β-catenin (C) over time; the level of P53 over time (D); and the level of MDM2 over time after MCF-7 cells were treated with NB01-hFc, NB01-MDM2i-1, or MDM2i- 2. [0028] FIGS.9A-9D are plots showing the result of a lysine discharge assay. The plots show the ubiquitination level of BSA alone (A), and after treatment with the NB01 sdAb (B), the NB01- UBOX-EEV construct (C), or the NB01-UBOX construct (D). [0029] FIGS. 10A-10B are plots showing the level of ubiquitinated β-catenin after exposing 10 nM β-catenin (A) and 40 nM β-catenin (B) to various concentrations of the NB01-Ubox and NB01- Ubox-EEV constructs. FIG. 10C is a plot showing the level of ubiquitinated β-catenin after exposing 5 nM, 10 nM, 20 nM, and 40 nM β-catenin to the NB01-UBOX-EEV construct. [0030] FIGS. 11A-11B are images Western blots showing the level of ubiquitinated β-catenin after 20 nM β-catenin was exposed to various concentrations of the NB01-UBOX construct in the presence of ATP, ubiquitin, and the UBE2D1 or UBE2D3 E2 ligases. FIG.11A is a gel after low exposure to an β-catenin antibody and FIG. 11B is the gel after high exposure to the β-catenin antibody. [0031] FIGS.12A-12B are images of SDS-PAGE gels showing β-catenin ubiquitination after β- catenin was exposed to the NB01-Ubox construct (A and B) or negative control RNF4 (B). [0032] FIG. 13A is an image of a western blot showing a co-immunoprecipitation study after HCT-116 cells were exposed to various concentrations of the NB01-UBOX construct or the NB01- UBOX-EEV02 construct. FIG.13B is a gel showing cellular uptake and c-Myc level modulation after HCT-116 cells were exposed to the NB01 nanobody or NB01-EEV02 construct. [0033] FIGS. 14A-14B are images of a series of western blots showing the levels of the NB01- UBOX and NB01-UBOX-EEV at various subcellular locations after HCT116 cells were treated with two varying concentrations of the two constructs. FIG. 15A is a plot showing the level of c-Myc at 2 hours, 4 hours, and 6 hours, after HCT-116 cells were exposed to 1 μM (L), 3 μM (M), and 8 μM (H), of NB01, NB01-EEV, or NB01-HIF1α- EEV. [0034] FIG.15B is a plot showing the levels of c-Myc and β-catenin at 2 hours, 6 hours, and 24, after HCT-116 cells were exposed to 2.7 μM or 8 μM of NB01 or NBO1-HIF1α -EEV. [0035] FIG. 16A-C are plots showing the ubiquitination of β-catenin (shown as relative CL intensity) for various (A) 7D12-NB03-MDM2i-2-EEV, (B) 7D12-NB02-MDM2i-2-EEV, and 7D12-sdAb-Hif1a-EEV bispecific degrader constructs. [0036] FIG.17 show the levels of β-catenin, c-Myc, p-EGFR Y1068, p-ERK1/2 after completion of a mouse model. [0037] FIGS. 18A-18C are images of Western blots showing the co-immunoprecipitation of β- catenin and the NB01 sdAbs after completion of the intratumorally (A and B) and intravenous (C) treatments of the study of a mouse model. The NB01 nanobodies in each construct each included a FLAG-tag. In FIG. 18A β-catenin was immunoprecipitated and β-catenin and the NB01 nanobody were immunoblotted. In FIG. 18B NB01 was immunoprecipitated and β-catenin and the NB01 nanobody were immunoblotted. In FIG. 18C NB01 was immunoprecipitated and β- catenin and the NB01 nanobody were immunoblotted. [0038] FIG. 19 is an image of a Western blot showing the protein levels of c-Myc, β-catenin, p- EGFR Y1068, and various constructs. [0039] FIG. 20 are Western Blots showing the level of various 7D12-NB03-EEV and 7D12- NB02-EEV constructs in the plasma upon completion of a xenograft mouse model. [0040] FIG. 21 are images of Western Blots showing the level of various 7D12-NB03-EEV and 7D12-NB02-EEV constructs in tumor tissue upon completion of a xenograft mouse model. [0041] FIG.22 is an image of a Western Blot showing the level of various 7D12-NB03-EEV and 7D12-NB02-EEV constructs in gastrocnemius tissue upon completion of a xenograft mouse model. [0042] FIG. 23A-23B are plots showing the results of a protein simple capillary electrophoresis assay that was used to quantify β-catenin levels relative to two controls, TOM20 (2A) and LRPPRC (23B) upon completion of a xenograft mouse model. [0043] The schematic drawings are not necessarily to scale. Like numbers used in the figures refer to like components, steps and the like. However, it will be understood that the use of a number to refer to a component in a given figure is not intended to limit the component in another figure labeled with the same number. In addition, the use of different numbers to refer to components is not intended to indicate that the different numbered components cannot be the same or similar to other numbered components. [0044] FIG.24 is the structure of EEV04. DETAILED DESCRIPTION [0045] The invention is defined in the claims. However, below there is provided a non-exhaustive listing of non-limiting embodiments. Any one or more of the features of these embodiments may be combined with any one or more features of another example, embodiment, or aspect described herein. Anti β-catenin antibodies [0046] This disclosure describes, among other things, antibodies and antigen binding fragments thereof that specifically bind to β-catenin, which are referred herein to as β-catenin antibodies and/or anti-β-catenin antibodies. Β-catenin (also referred to as b-catenin, β-catenin, β-Catenin, catenin β-1, and CTNNB1 protein) is a dual function protein, involved in coordinating cell-cell adhesion by interacting with cadherin in the cadherin junction formation pathway and regulating gene expression through Wnt signaling pathway. β-catenin is a 92-kDa protein, 781 amino acids in length, that is composed of two flexible tails at each of the N- and C-termini, and an intermediate structured armadillo domain (ARM) containing 12 repeats of helical segments. Because β-catenin regulates cadherin junction formation and regulates Wnt signaling, β-catenin plays important roles in many biological processes, such as embryonic development, cell division, and maintenance of pluripotency. Disorganized expression of β-catenin is associated with many diseases, including cancer and cardiovascular diseases. See, for example, McCrea et al., Science (1991); 254(5036):1359–1361; Peifer et al., Cell (1994); 76:789–791; Peifer, Trends Cell Biol (1995); 5:224–229; Xing et al., Structure (2008); 16(3):478–87; and Zhao and Xue, BMC Genomics (2016); 17(Suppl 5):484. [0047] In humans, β-catenin is encoded by the CTNNB1 gene. The human β-catenin amino acid sequence (UniProtKB - P35222) is shown below.

[0048] As used herein, a polypeptide is “structurally similar” to a reference polypeptide if the amino acid sequence of the polypeptide possesses a specified amount of identity compared to the reference polypeptide. Structural similarity of two polypeptides can be determined by aligning the residues of the two polypeptides (for example, a candidate polypeptide and the polypeptide of, for example, the β-catenin sequence) to optimize the number of identical amino acids along the lengths of their sequences; gaps in either or both sequences are permitted in making the alignment to optimize the number of identical amino acids, although the amino acids in each sequence must nonetheless remain in their proper order. A candidate polypeptide is the polypeptide being compared to the reference polypeptide (e.g., the β-catenin sequence). A candidate polypeptide can be isolated, for example, from an animal, or can be produced using recombinant techniques, or chemically or enzymatically synthesized. [0049] A pair-wise comparison analysis of amino acid sequences can be carried out using the BESTFIT algorithm in the GCG package (version 10.2, Madison WI). Alternatively, polypeptides may be compared using the Blastp program of the BLAST 2 search algorithm, as described by Tatiana et al., (FEMS Microbiol Lett, 174, 247-250 (1999)), and available on the National Center for Biotechnology Information (NCBI) website. The default values for all BLAST 2 search parameters may be used, including matrix = BLOSUM62; open gap penalty = 11, extension gap penalty = 1, gap x_dropoff = 50, expect = 10, wordsize = 3, and filter on. [0050] In the comparison of two amino acid sequences, structural similarity may be referred to by percent “identity” or may be referred to by percent “similarity.” “Identity” refers to the presence of identical amino acids. “Similarity” refers to the presence of not only identical amino acids but also the presence of conservative substitutions. A conservative substitution for an amino acid in a polypeptide may be selected from other members of the class to which the amino acid belongs. For example, it is well-known in the art of protein biochemistry that an amino acid belonging to a grouping of amino acids having a particular size or characteristic (such as charge, hydrophobicity and hydrophilicity) can be substituted for another amino acid without altering the activity of a protein, for example, in regions of the protein that are not directly associated with biological activity. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and tyrosine. Polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, or glutamine. The positively charged (basic) amino acids include arginine, lysine, or histidine. The negatively charged (acidic) amino acids include aspartic acid or glutamic acid. Conservative substitutions include, for example, lysine for arginine or vice versa to maintain a positive charge; glutamic acid for asparagine or vice versa to maintain a negative charge; serine for threonine or vice versa so that a free -OH is maintained; or glutamine for asparagine or vice versa to maintain a free -NH₂. Likewise, biologically active analogs of a polypeptide containing deletions or additions of one or more contiguous or noncontiguous amino acids that do not eliminate a functional activity of the polypeptide are also contemplated. [0051] In embodiments, the β-catenin antibodies or antigen binding fragments thereof bind to a protein that comprises an amino acid sequence that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent similarity and/or percent identity to the β-catenin sequence. In embodiments, the β-catenin antibodies of the present disclosure bind to a protein that has 80% to 100%, 90% to 100%, 95% to 100%, or 99% to 100% percent similarity and/or percent identity to the β-catenin sequence. Single-Domain Antibodies [0052] In embodiments, a β-catenin antibody or antigen binding fragment thereof as described herein includes a single domain antibody. A single domain antibody (sdAb) (also referred to interchangeably herein as VHH, V_HH, domain antibody, single variable domain antigen binding domain, NANOBODY^®, and LLAMABODY^TM) is an antibody fragment having a single monomeric variable domain (VH) of heavy-chain antibody, lacking the CH regions of an antibody heavy-chain, and completely lacking an antibody light chain. Similar to a conventional antibody, a single domain antibody is able to bind selectively to a specific antigen. [0053] The canonical antibody is a molecule composed of two heavy chains and two light chains. An intact conventional antibody molecule has two heavy (H) chain variable regions (abbreviated herein as VH or V_H) and two light (L) chain variable regions (abbreviated herein as VL or V_L). The VH and VL regions can be further subdivided into regions of hypervariability, termed “complementarity determining regions” (“CDRs”), interspersed with regions that are more conserved, termed “framework regions” (“FRs”). The extent of the FRs and CDRs has been precisely defined (see, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242, and (Chothia et al. J Mol Biol 196, 901-917 (1987))). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. [0054] Mammals from the Camelidae family, which includes dromedary camels, Bactrian camels, wild Bactrian camels, llamas, alpacas, guanaco, and vicuñas, in addition to producing a conventional antibody, produce an antibody that is composed of two identical heavy-chain polypeptides, each of which incorporates contiguous constant domains (CH2 and CH3), a hinge region, and a variable domain. This unique secondary set of single-chain antibodies (scAbs), also known as heavy chain IgG (hcIgG) or heavy chain-only antibodies (HCAbs), contain a single variable domain antigen binding domain, called the VHH region or VHH region, instead of two variable domains (VH and VL) that make up the equivalent antigen-binding fragment (Fab) of conventional IgG antibodies. FIGS. 1A-1B schematically show the structure of, among other things, human immunoglobulin, llama immunoglobulin, and a VHH single domain antibody. [0055] Each variable domain (VH) of the camelid scAb can function independently as an antigen- binding module. This single variable domain, in the absence of the constant domains (CH2 and CH3), is referred to as a single-domain antibody (sdAb). sdAbs comprise about 110 amino acids and have a molecular weight of only 12-15 kDa, compared to 150-160 kDa for a conventional antibody. The term VHH was originally introduced to indicate a VH domain derived from camelid heavy chain antibodies. The lack of a light chain does not limit or reduce the diversity of the epitopes recognized or antigen binding and VHHs demonstrate affinities and specificities for antigens comparable to conventional antibodies. [0056] More information on camelid single-chain antibodies and single-domain antibodies can be found, for example, at Wrapp et al., Cell (2020);181(6):1436-1441; Arbabi-Ghahroudi, Front Immunol (2017); 8:1589; Desmyter et al., Curr Opin Struct Biol (2015); 32:1-8; Fernandes et al., Front Immunol (2017); 8:653; Wesolowski et al., Med Microbiol Immunol (2009) 198:157-174; and WO2002085944. [0057] VHH single domain antibodies may provide benefits over traditional IgG antibodies. Due to their smaller size, VHH single domain antibodies are able to detect epitopes that may not be accessible with a conventional antibody due to steric hindrance. VHH single domain antibodies are able to penetrate tissue and enter cells more easily than conventional antibodies. VHH single domain antibodies demonstrate improved thermal stability and chemostability compared to most conventional antibodies, withstanding larger pH and temperature ranges. Unlike conventional antibodies, VHH single domain antibodies are functional at high temperatures and refold after heat denaturation and demonstrate improved stability after prolonged storage. These key characteristics, including, but not limited to, high affinity and specificity (equivalent to conventional antibodies), high thermostability, good solubility, monomeric behavior, small size, relatively low production cost, ease of genetic engineering, format flexibility or modularity, low immunogenicity, and a higher penetration rate into tissues make VHHs suitable for biotechnological and medical applications. [0058] The present disclosure also includes various β-catenin antibody fragments, also referred to as antigen binding fragments. Antigen binding fragments include only a portion of an intact antibody, generally including an antigen binding site of the intact β-catenin antibody and thus retaining the ability to bind β-catenin. The terms “antibody” and “antigen binding fragment” overlap to some extent. The term antibody includes any full-length antibody or a fragment of an antibody capable of binding to an antigen including a molecule that immunospecifically binds an antigen of interest. In contrast, an antigen binding fragment refers to a polypeptide fragment that includes at least one complementarity-determining region (CDR) of an antibody. For example, Fab, F(ab’)2, Fab’, Fv fragments, minibodies, single domain antibodies (sdAb), single-chain variable fragments (scFv), divalent scFv such as diabodies, multispecific antibodies formed from antibody fragments are both antibodies and antigen binding fragments. In contrast, an Fc and pFc’ are antibodies but not antigen binding fragments as they do not include a CDR. [0059] The techniques for preparing and using various antibody-based constructs and antigen binding fragments are well known in the art. For example, antigen binding fragments can be obtained via chemical or enzymatic treatment of an intact or complete antibody or antibody chain. Antigen binding fragments can also be obtained by recombinant means. Examples of antibody fragments include, for example, Fab, Fab', F(ab')_2, Fd, Fd', scFv (single chain Fv), single domain antibodies, linear antibodies, diabodies, and the like. [0060] β-catenin antibodies of the present disclosure may include dimeric, trimeric, and multimeric antibodies, bispecific antibodies, chimeric antibodies, human antibodies, humanized antibodies, recombinant antibodies, and engineered antibodies. For example, a β-catenin antibody of the present disclosure may be bispecific, having in addition to an antibody or antigen binding fragment thereof with binding specificity to β catenin, an antibody or antigen binding fragment thereof with specificity to an antigen other than β-catenin. [0061] In embodiments, an β-catenin antibody is “humanized.” A common method for humanization of non-human antibodies is complementary determining region (CDR) grafting in which the CDRs of non-human antibodies are grafted onto the human frameworks. In addition to CDR grafting, substituting human residues into framework regions of the grafted may be performed. The use of antibody components derived from humanized monoclonal antibodies obviates potential problems associated with immunogenicity of constant regions of antibodies from different organisms. Techniques for producing humanized monoclonal antibodies can be found, for example, in Jones et al., 1986, Nature; 321:522 and Singer et al., 1993, J Immunol: 150:2844. Single domain antibodies, including those of camelid origin, can be humanized, following, for example, methods described in Vinke et al., 2009 JBC; 284(5):3273-3285; and Soler et al., (2021) Biomolecules; 11:163, and reviewed by Rossotti et al., ((FEBS J. 2021 Mar 9. doi: 10.1111/febs.15809). [0062] The amino acid sequence of a β-catenin antibody may be modified, for example to improve binding affinity, reduce propensity for aggregation, remove T cell epitopes, CDR germlining, and/or remove charge variants. Codon optimization, a technique in which codons are replaced with synonymous ones in order to increase protein expression, may be undertaken on a nucleic acid sequence encoding an β-catenin antibody. Due to the degeneracy of the genetic code, most amino acids can be encoded by multiple synonymous codons. Synonymous codons naturally occur with different frequencies in different organisms. The choice of codons may affect protein expression, structure, and function. See, for example, Athey et al., (2017) BMC Bioinformatics; 18:391. NB01, NB02, and NB03 Antibodies [0063] As described in Examples 1 and 2, NB01 (also referred to herein as NB01VHH), NB02 (also referred to herein as NB02_VHH), and NB03 (also referred to herein as NB03_VHH), single domain VHHs were obtained from B lymphocytes obtained from a llama immunized with human β- catenin. The full amino acid sequences and the CDRs of the NB01, NB02, and NB03VHHs are shown in Table 1. Table 1: Amino acid sequences of NB01, NB02, and NB03

[0064] In embodiments, the β-catenin antibody or antigen binding fragment thereof includes a heavy chain variable region (VHH) with an amino acid sequence that has at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% percent similarity and/or percent identity to an amino acid sequence of NB01, NB02, and/or NB03. In embodiments, the β-catenin antibody or antigen binding fragment thereof has a sequence that has 80% to 100%, 90% to 100%, 95% to 100%, or 99% to 100% percent similarity and/or percent identity to NB01, NB02, and/or NB03. [0065] In embodiments, the β-catenin antibody or antigen binding fragment thereof includes an amino acid sequence includes one, two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions of the amino acid sequence of NB01, NB03, and/or NB02. In embodiments, the substitutions may be substitutions with conserved amino acids. In embodiments, the amino acid substitutions do not substantially affect binding of the antibody or antigen binding fragment thereof to β-catenin. [0066] In embodiments, the β-catenin antibody or antigen binding fragment thereof includes the amino acid sequence of NB01, NB02, and/or NB03. In embodiments, the β-catenin antibody is a sdAb that includes the amino acid sequence of NB01, NB02, and/or NB03. In embodiments, the β-catenin antibody is a sdAb that includes the amino acid sequence of NB01. In embodiments, the β-catenin antibody is a sdAb that includes the amino acid sequence of NB02. In embodiments, the β-catenin antibody is a sdAb that includes the amino acid sequence of NB03. [0067] In embodiments, an β-catenin antibody or antigen binding fragment thereof includes one, two, or three complementary determining regions (CDRs) selected from those in Table 1 or an amino acid sequence that has 90% to 100%, 95% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% sequence similarity and/or sequence identity to at least one of the CDR sequences in Table 1. [0068] In embodiments, a β-catenin antibody or antigen binding fragment thereof includes a CDR1 selected from a CDR1 in Table 1 or an amino acid sequence that has 90% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% sequence similarity and/or sequence identity to at least one of the CDR1 sequences in Table 1. In embodiments, a β-catenin antibody or antigen binding fragment thereof includes a CDR2 selected from a CDR2 in Table 1 or an amino acid sequence that has 90% to 100%, 95% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% sequence similarity and/or sequence identity to at least one sequence of a CDR2 in Table 1. In embodiments, a β-catenin antibody or antigen binding fragment thereof includes a CDR3 selected from a CDR3 in Table 1 or an amino acid sequence that has 90% to 100%, 95% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% sequence similarity and/or sequence identity to at least one CDR3 in Table 1. [0069] In embodiments, a β-catenin antibody or antigen binding fragment thereof includes a CDR1 selected from a CDR1 in Table 1 or an amino acid sequence that has 90% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% sequence similarity and/or sequence identity to at least one of the CDR1 sequences in Table 1; a CDR2 selected from a CDR2 in Table 1 or an amino acid sequence that has 90% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% sequence similarity and/or sequence identity to at least one sequence of a CDR2 in Table 1; and a CDR3 selected from a CDR3 in Table 1 or an amino acid sequence that has 90% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% sequence similarity and/or sequence identity to at least one CDR3 in Table 1. [0070] In embodiments, a β-catenin antibody or antigen binding fragment thereof includes an antibody that binds to the same β-catenin epitope as a VHH having the amino acid sequence of NB03, NB02, or NB01. Such an epitope, for example, may include amino acids 1 to 119 of human β-catenin, amino acids 120 to 683 of human β-catenin, or amino acid 684 to 781 of human β- catenin. [0071] The β-catenin antibody or antigen binding fragment thereof may include sequences from antibodies for other suitable species. For example, the antibody may include sequences from a human antibody, a mouse antibody, a rat antibody, a rabbit antibody, a goat antibody, a shark antibody, a llama antibody, etc. In embodiments, one or more of the variable regions and/or constant regions of the antibody include an antibody sequence of any suitable species (e.g., rat, rabbit, goat, shark, llama, etc.). [0072] In embodiments, a β-catenin antibody or antigen binding fragment thereof that binds to β- catenin may include at least a portion of an immunoglobulin constant region (Fc) of a human immunoglobulin, for example, the Fc region of a human IgG, IgE, IgM, or IgD antibody. In embodiments, the human Fc region may be of the IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2 subclass. In embodiments, a VHH antibody is fused to a human Fc IgG2 region. In embodiments, a VHH antibody is fused to a full or a portion of a murine IgG constant region of any isotype subclass. In embodiments, a VHH antibody is fused to a full or a portion of a goat, rabbit, chicken rat, or hamster IgG constant region of any isotype subclass. [0073] The β-catenin antibody may be of any type, any class, or any subclass. When the β-catenin antibody is a human or mouse antibody, for example, the type may include, for example, IgG, IgE, IgM, IgD, IgA and IgY; and/or the class may include, for example, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. [0074] In embodiments, the β-catenin antibody is an IgG antibody. In embodiments, the IgG antibody is a human antibody of any one of the IgG subclasses including, for example, IgG1, IgG2, IgG3 or IgG4. In embodiments, the antibody is a mouse IgG of one of the following sub-classes: IgG1, IgG2A, IgG2B, IgG2C and IgG3. In embodiments, the β-catenin antibody is a rat IgG of one of the following sub-classes: IgG1, IgG2A, IgG2B, or IgG2C. [0075] In embodiments, the β-catenin antibody is paired with a light chain, for example, a human kappa light chain or human lambda light chain. [0076] In embodiments, the β-catenin antibody includes an antibody fragment capable of binding to a biological molecule (such as an antigen or receptor) or portions thereof, including but not limited to Fab, Fab' and F(ab')₂, pFc', Fd, a single domain antibody (sdAb), a variable fragment (Fv), a single-chain variable fragment (scFv) or a disulfide-linked Fv (sdFv); a diabody or a bivalent diabody; a linear antibody; a single-chain antibody molecule; and a multispecific antibody formed from antibody fragments. [0077] In embodiments, the β-catenin antibody or antigen binding fragment thereof is a humanized antibody. An antibody that binds to β-catenin may be humanized by any suitable method. For example, humanization of the antibody may include changes to the antibody to reduce the immunogenicity of the antibody when used in humans. In embodiments, a humanized antibody that binds to β-catenin includes at least a portion of an immunoglobulin constant region (Fc) of a human immunoglobulin. Techniques for producing humanized monoclonal antibodies may be found, for example, in Jones et al. (Jones et al. Nature 321, 522-525 (1986)) and Singer et al. (Singer et al. J Immunol 150, 2844-2857 (1993)). Techniques for humanized camelid-derived monoclonal antibodies may be found, for example, in Vincke (Vincke et al, J Biol Chem.2009 Jan 30;284(5):3273-3284. doi: 10.1074/jbc.M8068892002009). [0078] In embodiments, a β-catenin monoclonal antibody includes a chimeric antibody, that is, an antibody in which different portions are derived from different animal species. A chimeric antibody may be obtained by, for example, splicing the genes from a mouse antibody molecule with appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological specificity. See, for example, Takeda et al. (Takeda et al. Nature 314, 452- 454 (1985)). Additional chimeric antibodies including genes from different species may be envisioned. [0079] In embodiments, a β-catenin antibody or antigen binding fragment thereof is constructed into a variety of formats, including, but not limited to, bivalent, multivalent, bispecific, and multispecific formats. The term bispecific antibody (bsAb) is used to describe an antibody molecule that can simultaneously bind to two different epitopes or antigens. A bispecific antibody includes two variable regions with differing antigen specificities. A multispecific antibody includes more than one variable region of differing antigen specificities, for example, two, three, four, or more variable regions. A bivalent antibody has at least two antigen-binding sites and a multivalent antibody binds to multiple sites on one target. In embodiments, an antibody includes a bivalent antibody that includes more than one variable region targeting a similar molecule. In embodiments, an antibody includes a multivalent antibody that comprises more than one variable region targeting a similar molecule. Bivalent, multivalent, bispecific and multispecific antibodies, including such llama antibodies, are described in more detail in, for example, Strokappe et al., 2019, Antibodies (Basel); 8(2):38; Beirnaert et al., 2017, Front Immunol; 8:867; Li et al., 2020, Clin Transl Med; 9(1):16; Coppieters et al., 2006, Arthritis Rheum; 54(6):1856-66; Weiss and Verrips, 2019, Vaccines (Basel); 7(3):77; Sadeghi et al., 2020, Drug Test Anal; 12(1):92-100; Hultberg et al., 2011, PLoS One; 6(4):e17665; Zhang and Mackenzie, 2012, Methods Mol Biol; 911:445-56; Stone et al., 2007, J Immunol Methods; 318(1-2):88-94; Dong et al., 202, Sci Rep; 10(1):17806; Godar et al., 2018, J Allergy Clin Immunol; 142(4):1185-1193.e4; Rozan et al., 2013, Mol Cancer Ther; 12(8):1481-91; Els Conrath et al., 2001, J Biol Chem; 276(10):7346-50; Palomo et al., 2016, Antimicrob Agents Chemother; 60(11):6498-6509; and Labrijn et al., 2019, Nature Reviews Drug Discovery; 18:585-608. [0080] In embodiments, the β-catenin antibody or antigen binding fragment thereof is produced by an animal (including, but not limited to, human, mouse, rat, rabbit, hamster, goat, horse, chicken, or turkey), produced by a cell from an animal, chemically synthesized, or recombinantly expressed. The antibody or antigen binding fragment thereof may be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (for example, ion exchange, affinity, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. In addition, an antibody or antigen binding fragment thereof may be fused to a heterologous polypeptide sequence, as described herein or otherwise known in the art, including, for example, to facilitate purification. [0081] In embodiments, an β-catenin antibody or antigen binding fragment thereof that binds to β-catenin may be made by immunizing an animal with a β-catenin protein or fragment thereof, including, for example, at least a portion of human β-catenin (UniProtKB - P3522). In embodiments, the animal may be a mammal. For example, the animal may be a rabbit, a mouse, a goat, a sheet, a llama, or a rat. In embodiments, the animal may be a chicken. [0082] A monoclonal antibody may be assayed for immunospecific binding by the methods described herein and by any suitable method known in the art. The immunoassay that may be used includes but is not limited to a competitive and/or a non-competitive assay system using a technique such as BIACORE analysis, fluorescence activated cell sorting (FACS) analysis, immunofluorescence, immunocytochemistry, Western blot, radio-immunoassay, enzyme linked immunosorbent assay (ELISA), “sandwich” immunoassay, immunoprecipitation assay, precipitin reaction, gel diffusion precipitin reaction, immunodiffusion assay, agglutination assay, complement-fixation assay, immunoradiometric assay, fluorescent immunoassay, and protein A immunoassay. Such assays are routine and well known in the art (see for example, Ausubel et al., eds, Current Protocols in Molecular Biology, Vol.1, John Wiley & Sons, Inc., N.Y. (1994)). [0083] A monoclonal antibody may be obtained by any suitable technique. In embodiments, an antibody that binds to β-catenin may be made by recombinant DNA methods, produced by phage display, and/or produced by combinatorial methods. DNA encoding an antibody that binds to β- catenin may be readily isolated and sequenced using conventional procedures. [0084] Once isolated, the DNA may be transfected into a host cell (including, for example, simian COS cells, Chinese hamster ovary (CHO) cells, human embryonic kidney cells (HEK), or myeloma cells that do not otherwise produce immunoglobulin protein) or introduced into a host cell by genome editing (for example, using a CRISPR-Cas system) to obtain the synthesis of monoclonal antibodies in a recombinant host cell. The DNA encoding an antibody that binds to β- catenin may be modified to, for example, humanize the antibody. [0085] In another embodiment, this disclosure describes an isolated polynucleotide molecule. In embodiments, the isolated polynucleotide molecule includes a nucleotide sequence encoding a β- catenin an antibody or antigen binding fragment thereof. In embodiments, the isolated polynucleotide molecule includes a nucleotide sequence that has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to nucleotide sequence encoding an antibody described herein. In embodiments, the isolated polynucleotide molecule includes polynucleotides that hybridize under high stringency to a nucleotide sequence encoding an antibody or a complement thereof. As used herein “stringent conditions” refer to the ability of a first polynucleotide molecule to hybridize, and remain bound to, a second, filter-bound polynucleotide molecule in 0.5 M NaHPO4, 7% sodium dodecyl sulfate (SDS), and 1 mM EDTA at 65°C, followed by washing in 0.2 X SSC/0.1% SDS at 42°C (see Ausubel et al. (eds.), Current Protocols in Molecular Biology, Vol.1, Green Publishing Associates, Inc., and John Wiley & Sons, Inc., N.Y. (1989), at p. 2.10.3). In embodiments, the isolated polynucleotide molecule includes polynucleotides that encode one or more of the CDRs or the variable region of an antibody of the present disclosure. [0086] General techniques for cloning and sequencing immunoglobulin variable domains and constant regions are well known. See, for example, Orlandi et al. (Orlandi et al. Proc Natl Acad Sci U S A 86, 3833-3837 (1989)). [0087] In embodiment, this disclosure describes recombinant vectors including an isolated polynucleotide of the present disclosure. The vector may be, for example, in the form of a plasmid, a viral particle, or a phage. The appropriate DNA sequence may be inserted into a vector by a variety of procedures. In general, the DNA sequence is inserted into an appropriate restriction endonuclease site(s) in a vector by procedures known in the art. Such procedures are deemed to be within the scope of those skilled in the art. Large numbers of suitable vectors and promoters are known to those of skill in the art and are commercially available. The following vectors are provided by way of example. Bacterial vectors include, for example, pQE70, pQE60, pQE-9, pBS, pD10, phagescript, psiX174, pbluescript SK, pbsks, pNH8A, pNH16a, pNH18A, pNH46A, ptrc99a, pKK223-3, pKK233-3, pDR540, and pRIT5. Eukaryotic vectors include, for example, pWLNEO, pSV2CAT, pOG44, pXT1, pSG, pSVK3, pBPV, pMSG, and pSVL. However, any other plasmid or vector may be used. [0088] In an embodiment, this disclosure includes a host cell containing at least one of the above- described vectors. The host cell may be a higher eukaryotic cell, such as a mammalian or insect cell, or a lower eukaryotic cell, such as a yeast cell. Or, the host cell may be a prokaryotic cell, such as a bacterial cell, or a plant cell. Introduction of a vector construct into the host cell may be affected by any suitable techniques, such as, for example, calcium phosphate transfection, DEAE- Dextran mediated transfection, electroporation, or nucleofection. [0089] Β-catenin antibodies or antigen binding fragments thereof may be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free translation systems may also be employed to produce such proteins using RNAs derived from the DNA constructs of the present disclosure. Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y. (1989). [0090] Also included in the present disclosure are phage display libraries expressing one or more hypervariable regions from an antibody of the present disclosure, and the clones obtained from such a phage display library. A phage display library is used to produce antibody-derived molecules. Gene segments encoding the antigen-binding variable domains of antibodies are fused to genes encoding the coat protein of a bacteriophage. Bacteriophage containing such gene fusions are used to infect bacteria, and the resulting phage particles have coats that express the antibody- fusion protein, with the antigen-binding domain displayed on the outside of the bacteriophage. Phage display libraries may be prepared, for example, using the PH.D.-7 Phage Display Peptide Library Kit (Catalog # E8100S) or the PH.D. -12 Phage Display Peptide Library Kit (Catalog # E8110S), available from New England Biolabs Inc., Ipswich, MA. See, for example, Smith and Petrenko (Smith et al. Chem Rev 97, 391-410 (1997)). [0091] In embodiments, the anti-β-catenin antibody is a monoclonal antibody. [0092] In embodiments, the antibody is an isolated antibody. In embodiments, the antibodies are isolated or purified by conventional immunoglobulin purification procedures, such as, for example, protein A- or G-sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. [0093] In embodiments, a β-catenin antibody or antigen binding fragment thereof may include a derivative of an antibody that is modified or conjugated by the covalent attachment of any type of molecule to the antibody. Such antibody derivatives include, for example, antibodies that have been modified by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, toxins, or linkage to a cellular ligand or other protein. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, and metabolic synthesis of tunicamycin. Additionally, the derivatives may contain one or more non-classical amino acids. [0094] An β-catenin antibody or antigen binding fragment thereof may be coupled directly or indirectly to a detectable marker by techniques well known in the art. A detectable marker is an agent detectable, for example, by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. Antibodies conjugated to detectable agents may be used for diagnostic or therapeutic purposes. Β-catenin targeting compounds [0095] In embodiments, β-catenin targeting compounds are provided. The β-catenin compound targets and binds to β-catenin. In embodiments, the β-catenin targeting compound inhibits the activity of β-catenin. In embodiments, the β-catenin targeting compound decreases the level of β- catenin in a cell. In embodiments, the β-catenin targeting compound modulates the level and/or activity of one or more downstream proteins, genes, and/or transcripts that are regulated by β- catenin. In embodiments, the β-catenin targeting compound decreases the level and/or activity of one or more downstream proteins, genes, and/or transcripts that are regulated by β-catenin. [0096] In embodiments, the β-catenin targeting compounds include a targeting moiety and a cell penetrating peptide (CPP). The CPP may be any suitable CPP, such as those described herein. In embodiments, the β-catenin targeting compounds include a targeting moiety and an endosomal escape vehicle (EEV). The targeting moiety binds to β-catenin. In embodiments, the targeting moiety is an antibody or antigen binding fragment thereof or a multimeric construct that includes the antibody or antigen binding fragment thereof. [0097] The targeting moiety may be any suitable β-catenin antibody or antigen binding fragment thereof, such as those disclosed herein. As used herein “β-catenin antibody or antigen binding fragment thereof” refers to an antibody or antigen binding fragment thereof that specifically binds to β-catenin. [0098] In embodiments, the targeting moiety is a bispecific targeting moiety (also referred to as a bispecific construct). A bispecific targeting moiety includes a first targeting domain and a second targeting domain. In embodiments, the first targeting domain binds to β-catenin. The first targeting domain may be any be any suitable β-catenin antibody or antigen binding fragment thereof, such as those disclosed herein. In embodiments, the second targeting domain binds a second antigen that is not β-catenin. In embodiments, the second targeting domain of a bispecific targeting moiety is an intracellular targeting domain. An intracellular targeting domain is a targeting domain that binds to an antigen located inside a cell, for example, in the cytosol of the cell or within a compartment within the cell, such as the nucleus. In embodiments, the second targeting domain of a bispecific targeting moiety is an extracellular targeting domain. An extracellular targeting domain is a targeting moiety that binds to an antigen located outside a cell, such as on the cell surface (e.g., cell surface antigen). [0099] In embodiments, the targeting moiety is a trispecific targeting construct. That is, the targeting moiety includes a first targeting domain that binds to β-catenin, a second targeting domain, and a third targeting domain. In embodiments, the second targeting domain and the third targeting domain bind to different cell surface antigens from each other. In embodiments, the second targeting domain and the third targeting domain bind to different surface antigens on the same cell. In embodiments, the second targeting domain and the third targeting domain bind to different cell surface antigens on different cells. [0100] Cancer cells can co-express multiple target antigens, and therefore a targeting moiety comprising a second targeting domain or second and third targeting domains can increase the number of target cells to which the bispecific or trispecific targeting moiety can bind. Additionally, a targeting moiety comprising second and third targeting domains can be used to bring two different cell types in close proximity to one another, such as an effector cell (e.g., a T cell, NK cell, NKT cell, neutrophil, macrophage, etc.) and a target cell (e.g., a tumor cell). In such embodiments, the bi-or tri-specific construct can direct the effector cell function (e.g., cell lysis) to the target cell. [0101] The bispecific targeting moieties described herein can be of any format that allows binding to β-catenin and to a second target antigen. For example, in embodiments, the bispecific targeting moiety is a diabody or a dual variable domain immunoglobulin (DVD-Ig). In embodiments, the bispecific targeting moiety comprises a fusion or linkage of two independent antigen-binding domains. In embodiments, the two independent antigen-binding domains are the same type (e.g., two scFvs, two nanobodies, two antibody mimetics, etc.). In embodiments, the two targeting domains are different types (e.g., an scFv and a nanobody, an scFv and an antibody mimetic, a nanobody and an antibody mimetic, etc.). [0102] In embodiments, the present disclosure describes a bispecific targeting moiety comprising a β-catenin antibody or antigen binding fragment thereof and a second targeting domain that specifically binds to the extracellular portion of the transmembrane epidermal growth factor receptor (EGFR). In embodiments, the first targeting domain is any β-catenin antibody or antigen binding fragment (e.g., such as those described herein) and the second targeting domain is the single domain antibody 7D12

which specifically binds to the extracellular portion of EGFR. [0103] In embodiments, the targeting moiety includes a β-catenin antibody or antigen binding fragment thereof. In embodiments, the β-catenin antibody or antigen binding fragment thereof is NB01, NB02, or NB03 or has a sequence that has 80% to 100%, 85% to 100%, 90% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% percent similarity and/or percent identity to NB01, NB02, or NB03. In embodiments where the targeting moiety is a bispecific targeting moiety, the second targeting domain is 7D12 or has a sequence that has 80% to 100%, 85% to 100%, 90% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% percent similarity and/or percent identity to 7D12. In embodiments where the targeting moiety is a bispecific targeting moiety, the first targeting domain (the β-catenin antibody or antigen binding fragment thereof) is NB01, NB02, or NB03 or has a sequence that has 80% to 100%, 85% to 100%, 90% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% percent similarity and/or percent identity to NB01, NB02, or NB03; and the second targeting domain is 7D12 or has a sequence that has 80% to 100%, 85% to 100%, 90% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% percent similarity and/or percent identity to 7D12. [0104] In embodiments where the targeting moiety is a bispecific targeting moiety, the first targeting domain (the β-catenin antibody or antigen binding fragment thereof) and the second targeting domain may be joined via a linker. Any suitable linker may be used such as those in Table 6 and described elsewhere herein. [0105] The β-catenin targeting compound (e.g., β-catenin antibody or antigen binding fragment thereof, or bispecific β-catenin targeting construct) includes a CPP. The targeting moiety may be conjugated to a CCP at any spot in the targeting moiety. For example, the CCP may be conjugated to the N-terminus, C-terminus, or any amino acid side chain, the β-catenin antibody or antigen binding fragment thereof, or the bispecific targeting moiety. The CCP may be any CCP as described herein. [0106] In embodiments, the targeting moiety includes a C-terminal and/or N-terminal cysteine to provide a site for conjugation to a CCP or EEV. The addition of a C-terminal and/or N-terminal cysteine may be denoted by a -cys (or -Cys) on the N-terminal and/or C-terminal side of the β- catenin antibody or fragment thereof; or the first targeting domain or the second targeting domain of a bispecific targeting moiety (e.g., NB01-cys; cys-NB01; NB02-cys; cys-NB02; NB03-cys; cys- NB03; NB01-7D12-cys, cys-NB01-7D12, cys-7D12- NB01, or 7D12- NB01-cys).

[0107] In embodiments, the present disclosure describes degradation compounds. Degradation compounds are β-catenin targeting compounds that facilitate degradation of β-catenin. In embodiments, the degradation compound facilitates proteasomal degradation of a β-catenin. In embodiments, the degradation compound facilitates autophagy mediated degradation of β-catenin. In embodiments, the degradation compound regulates the levels and/or activity of a β-catenin within a cell. In embodiments, the degradation compound decreases the level of β-catenin within a cell. In embodiments, the degradation compound increases or decreases the level and/or activity of a protein, transcript, or gene that is regulated by β-catenin. [0108] In embodiments, the degradation compound includes a degradation construct. In embodiments, the degradation compound includes a degradation construct and a CPP. In embodiments, the CPP is a cCPP. In embodiments, the degradation compounds include a degradation construct and an endosomal escape vehicle (EEV), where the EEV comprises a CPP, such as a cCPP. In embodiments, the degradation construct includes a targeting moiety (e.g., any targeting moiety describe herein) and a degradation moiety. Mechanisms of degradation [0109] To maintain homeostasis, cells regulate the degradation of proteins that are misfolded, have aberrant activity, are mutated, or have become obsolete in the cell’s current phenotype. Autophagy mediated degradation and proteasomal degradation are the two main mechanism by which cells can degrade proteins. Autophagy Degradation Mechanism [0110] Autophagy is the removal of proteins and/or organelles through a lysosome-mediated process. There are several types of autophagy including macroautophagy, microautophagy, chaperone-mediated autophagy, mitophagy, and lipophagy. Macroautophagy is the primary autophagy process used to remove cytolytic proteins. In macroautophagy a double membrane autophagosome engulfs the target protein. The autophagosome fuses with a lysosome or vacuole. Proteasomal Degradation Mechanism [0111] Proteins may be degraded by a proteasome, a protein complex of various proteases that degrade proteins via proteolysis. Degradation via the proteasome is termed proteasomal degradation. Proteins that have polyubiquitin tags may be targeted for proteasomal degradation. The process of adding a polyubiquitin tag to a protein involves several proteins and enzymatic reactions. In embodiments, degradation compounds and degradation constructs are provided that mediate the addition of a polyubiquitin tag on a target protein for proteasomal degradation of the target protein. [0112] Ubiquitin is a 76 amino acid protein that may be conjugated to proteins as a post translational modification. The process of adding ubiquitin to a target protein is termed ubiquitylation (also known as ubiquitination or ubiquitinylation). Polyubiquitylated proteins may be targeted for proteasomal degradation. A first ubiquitin is conjugated to a target protein through a covalent bond between the C-terminal carboxylate of the ubiquitin and a lysine, cysteine, serine, or threonine side chain or the N-terminus of the target protein. A second ubiquitin can be conjugated to the first ubiquitin through a covalent bond between the C-terminal carboxylate of the second ubiquitin and a lysine or methionine side chain on the first ubiquitin. The nature of the ubiquitin linkages in a polyubiquitin chain specifies the fate of the target protein. For example, chains of four or more ubiquitin molecules linked through K48 and chains of ubiquitin linked through K11 often signal for proteasomal degradation of the protein they are conjugated to. [0113] The ubiquitylation process involves three enzymes; a ubiquitin-activating enzyme, ubiquitin-conjugating enzyme, and a ubiquitin ligase colloquially termed E1, E2, and E3, respectively. E1 activates ubiquitin by catalyzing an ATP dependent reaction resulting in a thioester linkage between the C-terminus of ubiquitin and a cysteine within the active site of E1. E2 catalyzes the transfer of the activated ubiquitin to a cysteine within the active site of E2 via a transthioesterification reaction. E3 catalyzes the transfer of ubiquitin from E2 to the target protein. [0114] There are two known human E1 enzymes, 35 known E2 enzymes, and over 600 known E3 ligases. The large number of E1, E2, and E3 proteins allows for vast diversity and specificity in the ubiquitylation process. The E1 enzymes include UBA1 and UBA6. The E2 enzymes include, but are not limited to, Ube2A, Ube2B, Ube2D1, Ube2D2, Ube2D3, Ube2D4, Ube2E1, Ube2E2, Ube2E3, Ube2G1, Ube2G2, Ube2H, Ube2J1, Ube2J2, Ube2K, Ube2L3, Ube2N, Ube2NL, Ube2O, Ube2Q1, Ube2Q2, Ube2QL, Ube2R1, Ube2R2, Ube2S, Ube2T, Ube2V1, Ube2V2, Ube2W, BIRC6, Ube2F, Ube2I, Ube2L6, Ube2M, Ube2Z, ATG10, and ATG3. [0115] The E3 ligases can be classified in several categories including the homologous to E6- associated protein C-terminus (HECT) domain ligases, the Really Interesting New Gene (RING) domain ligases, and the U-box ubiquitin family of ligases (UUL). RING and UUL E3 ligases catalyze the direct transfer of ubiquitin to the target protein. In contrast, HECT E3 ligases require an intermediate step. HECT E3 ligases first catalyze the transfer of the ubiquitin from the E2 to an active cysteine on the HECT E3 ligase before catalyzing the transfer of the ubiquitin from the HECT E3 ligase to the target protein. UULs are a family of modified RING E3 ligases the do not have the full complement of Zn²⁺ binding ligands. While HECT E3 ligases have a direct role in catalysis during ubiquitination, RING and U-box E3 proteins facilitate protein ubiquitination by acting as adaptor molecules that recruit E2 and substrate molecules to promote substrate ubiquitination. Although many RING-type E3 ligases, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, may act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex (“APC”). Table 2 gives examples of E3 ligases. [0116] Some E3 ligases are E3 ligase complexes that include accessory proteins in addition to the protein that is directly involved in catalyzing ubiquitination of the target protein. For example, cullin-RING ligases (CRL) are E3 ligase complexes that catalyze ubiquitinylation of a target protein (Mahon et al., Biomolecules (2014), 13, 4(4):897-930; Jackson et al., Trends Ciochem Sci. (2009), 34(11): 562-570). CRLs include a cullin scaffold protein that recruits a RBX1 or RBX2 (E3 ligases). The cullin scaffold also binds to an adaptor protein. The adaptor protein binds to the target protein. In some cases, the adaptor protein binds to a substrate receptor protein and the substrate receptor protein binds to the target protein. There are seven cullin proteins (Cul1, Cul2, Cul3, Cul4a, Cul4b, Cul5, and Cul7). There are many adaptor proteins including, but not limited to, SKP1, elongin B/C heterodimer, and DDB1. Additionally, there are many substrate receptor proteins including but not limited to, FBP, various SOCS proteins, and various DCAF proteins. An example of a CRL is the anaphase-promoting complex. Another example of a CLR is the SKP, Cullin, F-box containing complex (SCF). SCF complexes include CUL1 as a scaffold protein, RBX1 as the RING ligase, SKP1 as an adaptor protein, and an F-box containing protein. Table 3 lists some examples of E3 ligase accessory proteins. Table 2: Examples of some E3 ligases and classes thereof

Table 3: E3 ligase complex accessory proteins

[0117] In embodiments, the degradation construct of the degradation compound includes a targeting moiety and a degradation moiety. The targeting moiety binds to at least β-catenin. The targeting moiety may be any targeting moiety described herein (e.g., a β-catenin antibody or antigen biding fragment thereof, or a bispecific targeting moiety). The degradation moiety may be an E3 ligase or a functional fragment thereof, or an E3 ligase recruiting moiety. As used herein an “E3 ligase or an active fragment thereof” includes E3 ligases and E3 ligase accessory proteins or active fragments thereof. An E3 ligase recruiting moiety includes a domain that binds to an E3 ligase, an E3 ligase complex, or an accessory E3 ligase protein. [0118] FIG. 2 shows how degradation compounds of the present disclosure that include a degradation construct mediate degradation of a β-catenin. As used herein, “mediates degradation” refers to the facilitation of ubiquitination of β-catenin leading to degradation of β-catenin by proteasomal degradation or autophagy. A degradation construct 10 of the present disclosure is conjugated to an EEV to form a degradation compound. The degradation construct includes a targeting moiety 30 and a degradation moiety 20. In embodiments, the targeting moiety is a β- catenin targeting compound such as a β-catenin antibody or antigen binding fragment thereof. The targeting moiety 30 is designed to bind to at least β-catenin 40. The degradation moiety is configured to facilitate polyubiquitylation 60 of β-catenin which leads to proteasomal degradation of β-catenin. In embodiments, where the degradation moiety 20 includes an active E3 ligase or an active fragment thereof, the degradation moiety is directly involved in catalyzing the polyubiquitylation of the target protein. In embodiments, where the degradation moiety 20 includes an E3 ligase recruiting moiety, the E3 ligase recruiting moiety interacts with an endogenous E3 ligase or an endogenous E3 ligase complex 50 to catalyze the polyubiquitylation 60 of β-catenin 40. Degradation Construct [0119] The degradation compounds include a degradation construct. In embodiments, the degradation construct includes a targeting moiety and a degradation moiety. In embodiments, the targeting moiety is any targeting moiety described herein that binds to at least β-catenin. The degradation moiety mediates proteasomal and/or autophagy mediated degradation of β-catenin. Degradation Moieties [0120] In embodiments, the degradation constructs of the degradation compounds of the present disclosure include a degradation moiety. The degradation moiety may mediate proteasomal and/or autophagy mediated degradation of β-catenin. The degradation moiety may mediate degradation through ubiquitination of the target antigen (e.g., β-catenin) leading to degradation of the target antigen by proteasomal degradation or autophagy. Ubiquitination of a peptide or protein can act as a signal for its rapid cellular degradation, and for targeting to the proteasome complex. The degradation moiety can mediate degradation of β-catenin either through direct action of the degradation moiety itself or indirectly through the recruitment of endogenous cellular proteins that mediate degradation of the target protein. [0121] The degradation moiety may be an E3 ligase or an active fragment thereof, or an E3 ligase recruiting moiety. As used herein “active fragment” or “active fragment thereof” refers to a fragment of a polypeptide that retains the function of the polypeptide, such as, for example, an E3 ligase or an E3 ligase accessory protein. As used herein an “E3 ligase or an active fragment thereof” includes E3 ligases and E3 ligase accessory proteins or active fragments thereof. The degradation moiety may be any E3 ligase or an active fragment thereof, such as those listed in Table 2. The degradation moiety may be any E3 ligase accessory protein or an active fragment thereof, such as those listed in Table 3. The degradation moiety may function to recruit any E3 ligase, such as those listed in Table 2. The degradation moiety may function to recruit any E3 ligase accessory protein or an active fragment thereof, such as those listed in Table 3. E3 ligase or an active fragment thereof [0122] In embodiments, the degradation moiety includes an E3 ligase or an active fragment thereof. E3 ligases and active fragments thereof, mediate degradation of a target antigen through direct action as E3 ligases or active fragments thereof or through acting as an accessory protein or active fragment thereof for an E3 ligase complex. The E3 ligase or fragment thereof is capable of ubiquitinating a substrate (e.g., β-catenin). In embodiments, the E3 ligase or fragment thereof comprises a U-box motif. In embodiments, the E3 ligase or fragment thereof comprises a ligase that includes a RING domain, a HECT domain, or a Ubox domain (see Table 2). In embodiments, the E3 ligase or fragment thereof participates in larger E3 ligase complexes such as a cullin-RING ligase complex (e.g., SCF or anaphase complex). [0123] In embodiments, the E3 ligase or active fragment thereof is a von Hippel-Lindau (VHL, UniProt Ref #: P40337) E3 ligase; a Cereblon (CRBN, UniProt Ref #: Q96SW2) E3 ligase; a Tripartite motif-containing protein 21 (TRIM21, UniProt Ref #: P19747) E3 ligase; and a suppressor of cytokine signaling 1 (SOCS1, UniProt Ref #: O15524) E3 ligase. Table 4 shows examples of E3 ligases and active fragments thereof that may be used as the degradation moiety. [0124] In embodiments, the E3 ligase or active fragment thereof is ODC or derived from ODC. In embodiments, the E3 ligase or active fragment thereof is UBOX or derived from UBOX. In embodiments, the E3 ligase or active fragment thereof is VIF-1 or derived from VIF-1. In embodiments, the E3 ligase or active fragment thereof is VIF-2 or derived from VIF-2. In embodiments, the E3 ligase or active fragment thereof is bTrCP or derived from bTrCP. In embodiments, the E3 ligase or active fragment thereof is FBW7 or derived from FBW7. In embodiments, the E3 ligase or active fragment thereof is hRNF4 or derived from hRNF4. [0125] In embodiments, the E3 ligase or active fragment thereof is VHL or derived from VHL. In embodiments, VHL or an active fragment of VHL includes a Y185F mutation. In embodiments, the active fragment of VHL is VHL peptide 1a (VHLpep1a(152-213)) or VHL peptide 1b (VHLpep1b(152-213; Y185F)). VHLpep1a includes amino acids 152-213 of VHL. VHLpep1b includes amino acids 152-213 of VHL and the Y185F mutation. In embodiments, the active fragment of VHL is VHL peptide 2a (VHLpep2a(157-194)) or VHL peptide 2b (VHLpep2b(157- 194; Y185F)). VHLpep2a includes amino acids 157-194 of VHL. VHLpep2b includes amino acids 157-194 of VHL and the Y185F mutation. In embodiments, the active fragment of VHL is VHL peptide 3a (VHLpep3a(113-213)) or VHL peptide 3b (VHLpep3b(113-213; Y185F)). VHLpep3a includes amino acids 113-213 of VHL. VHLpep3b includes amino acids 113-213 of VHL and the Y185F mutation. In embodiments, the active fragment of VHL is VHL peptide 4a (VHLpep4a(103-213)) or VHL peptide 4b (VHLpep4b(110-213; Y185F)). VHLpep4a includes amino acids 110-213 of VHL. VHLpep4b includes amino acids 113-213 of VHL and the Y185F mutation. [0126] In embodiments, the E3 ligase or active fragment thereof is TRIM21 or derived from TRIM21. In embodiments, the active fragment of TRIM21 is TRIM21 peptide (TRIM21pep (1- 277)). TRIM21pep includes amino acids 1-277 of TRIM21. [0127] In embodiments, the E3 ligase or active fragment thereof is SOCS1 or derived from SOCS1. In embodiments, the active fragment of SOCS1 is SOCS peptide (SOCSpep (173-211)). SOCSpep includes amino acids 173-211 of SOCS1. [0128] In embodiments, the E3 ligase or active fragment thereof is CRB or derived from CRB. [0129] In embodiments, the E3 ligase or active fragment thereof comprises a sequence that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% percent similarity and/or percent identity to any one of the sequences in Table 4. In embodiments, the E3 ligase or active fragment thereof comprises a sequence having 80% to 100%, 85% to 100%, 90% to 100%, 91% to 100%, 92% to 100%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% percent similarity and/or percent identity to any one of the sequences in Table 4. [0130] In embodiments, the E3 ligase or active fragment thereof includes a C-terminal and/or N- terminal cysteine to provide a site for conjugation of a CCP or EEV and/or a targeting moiety as described herein. The addition of a C-terminal and/or N-terminal cysteine may be denoted by a - cys (or -Cys) on the N-terminal and/or C-terminal side of the E3 ligase or active fragment thereof. In embodiments, any sequence in Table 4 may further include a C-terminal and/or a N-terminal cysteine. Table 4. Degradation moieties

E3 ligase recruiting moiety [0131] In embodiments, the degradation moiety is an E3 ligase recruiting moiety. An E3 ligase recruiting moiety is a protein, peptide, and/or small molecule that interacts with an endogenous E3 ligase, E3 ligase complex, or E3 ligase accessory protein to recruit the E3 ligase to the target protein (e.g., β-catenin). Proteins and Peptide E3 ligase recruiting domains [0132] In embodiments. the E3 ligase recruiting moiety is a protein or a peptide. The protein or peptide may interact with any E3 ligase and/or E3 ligase complex. Table 5 lists examples of proteins and peptides that may be used as an E3 ligase recruiting moiety. [0133] In embodiments, the E3 ligase recruiting moiety is an Fc domain or an active fragment thereof that interacts with an endogenous ubiquitin ligase. In embodiments, the Fc domain or active fragment thereof, interacts with TRIM21. In embodiments, the Fc domain or active fragment thereof comprises one or more mutations relative to a wild-type Fc domain. [0134] In embodiments, the E3 ligase recruiting moiety is an IgG1 Fc (also called hFc and Fc herein) domain or an active fragment thereof that interacts with an endogenous ubiquitin ligase such as TRIM21. In embodiments, the IgG1 Fc domain or active fragment thereof comprises one or more mutations relative to a wild-type IgG1 Fc domain. In embodiments, the IgG1 Fc domain or active fragment thereof comprises one or more amino acid mutations at positions 233, 234, 235, 236, 237, 238, 239, 253, 254, 255, 256, 258, 264, 265, 267, 268, 269, 270, 272, 276, 280, 285, 286, 288, 290, 293, 295, 296, 297, 298, 301, 303, 305, 307, 309, 311, 312, 315, 317, 322, 326, 327, 329, 330, 331, 332, 333, 334, 337, 338, 339, 360, 362, 376, 378, 380, 382, 392, 414, 415, 424, 430, 433, 434, 435, and/or 436 according to the EU numbering system. For example, in embodiments, the IgG1 Fc domain or active fragment thereof comprises a mutation at a position selected from 239, 297, and 433 according to the EU numbering system. [0135] In embodiments, the E3 ligase recruiting moiety is IgG1 Fc or an active fragment thereof. [0136] In embodiments, the E3 ligase recruiting moiety is IkBalpha (IκBα) or an IkBalpha peptide that binds to the β-TrCP subunit of the SCF E3 ligase complex, e.g., as described in US Pat. No. 7,208,157, which is herein incorporated by reference in its entirety. In embodiments, the E3 ligase recruiting domain is IkBalpha or an active fragment thereof. In embodiments, the active fragment of IkBalpha is IkBalphapep. [0137] In embodiments, the E3 ligase recruiting moiety comprises a sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent similarity and/or percent identity to any one of the sequences in Table 5. In embodiments, the E3 ligase recruiting domain comprises a sequence having 80% to 100%, 85% to 100%, 90% to 100%, 91% to 100%, 92% to 10%, 93% to 100%, 94% to 100%, 95% to 100%, 96% to 100%, 97% to 100%, 98% to 100%, or 99% to 100% percent similarity and/or percent identity to any one of the sequences in Table 5. [0138] In embodiments, the E3 ligase recruiting moiety includes a C-terminal and/or N-terminal cysteine to provide a site for conjugation to a CCP or an EEV and/or targeting moiety as described herein. The addition of a C-terminal and/or N-terminal cysteine may be denoted by a -cys (or-Cys) on the N-terminal and/or C-terminal side of the E3 ligase recruiting domain. In embodiments, any one of the sequences in Table 5 may further include a C-terminal and/or a N-terminal cysteine. Table 5: Protein and Peptide E3 ligase recruiting moieties.

Small molecule E3 ligase recruiting domains [0139] In embodiments, the E3 ligase recruiting moiety is a small molecule or a peptidomimetic. [0140] In embodiments, the E3 ligase recruiting moiety is a peptidomimetic. In embodiments, the peptidomimetic E3 ligase recruiter domain includes VH032 (Galdeano, et al., J. Med. Chem. (2014), 57, 20:504-513), VH101 (Ishida et al., SLAS Discov. (2021), 26(4): 484-502), VH298 (Frost et al., Nat. Commun. (2016), 6:133312), LCL161 (Troup et al., Exploration of Target Anti- tumor Therapy (2020),1:273-312. doi.org/10.37349/etat.2020.00018), methylbestin, derivatives thereof, and any combination thereof. In embodiments, VH032, VH101, VH298, derivatives thereof, and any combination thereof interact with the VHL E3 ligase. In embodiments, LCL161, methylbestin, derivatives thereof, and any combination thereof interact with the cIAP E3 ligase. [0141] In embodiments, the E3 ligase recruiting moiety is a small molecule. In embodiments, the small molecule is thalidomide, pomalidomide, lenalidomide, bardoxolone methyl, nutlin-3, nimbolide, indisulam, derivatives thereof, or any combination thereof (Ishida et al., SLAS Discov. (2021), 26(4): 484-502; Sun et al., Nature, Signal Transduction and Targeted Therapy (2019), 4(64), doi.org/10.1038/s41392-019-0101-6; Troup et al., Exploration of Target Anti-tumor Therapy (2020),1:273-312. doi.org/10.37349/etat.2020.00018). In embodiments, thalidomide, lenalidomide, pomalidomide, and derivatives thereof, interact with CRBN. In embodiments, nutlin-3 and derivatives thereof interact with MDM2. In embodiments, nimbolide and derivatives thereof interact with RNF114. [0142] In embodiments, indisulam and derivatives thereof interact with the CUL4 CLR E3 ligase complex. In embodiments, indisulam and derivatives thereof interact with substrate receptor protein DCAF15. [0143] In embodiments, the E3 ligase recruiting moiety is compound 159 or compound 160. Compound 159 binds to and recruits VHL. Compound 160 binds to and recruits CRBN.

Linkers and additional amino acid sequences [0144] The components of the β-catenin targeting compounds such as the degradation compounds and degradation construct are operably linked through one or more linkers. [0145] As used herein, the term “operably linked” refers to a direct or indirect covalent linking between the components of a compound (e.g., components of a degradation construct; components of a multivalent targeting moiety; components of a β-catenin targeting compound; components of a degradation compound). Indirect covalent linking between components generally includes a linker, such as those described herein, and/or a separator such as those described herein. [0146] The degradation moiety and the targeting moiety and/or bispecific construct that are operably linked may be directly covalently coupled to one another. Conversely, the degradation moiety and the targeting moiety and/or bispecific construct may be connected by mutual covalent linking to an intervening component (e.g., a flanking sequence, polypeptide, linker). In embodiments where the degradation construct includes a degradation moiety and a bispecific construct, the degradation moiety and the second targeting moiety may be separately linked to the first targeting moiety; or the degradation moiety may be directly linked to the first targeting moiety and the second targeting moiety may be directly linked to the degradation moiety. [0147] The term “linker” as used herein refers any bond, small molecule, peptide sequence, or other vehicle that physically links the components of a β-catenin targeting compound or degradation compound described herein (e.g., a CPP to targeting moiety; a CPP to a degradation construct; a first targeting domain to a second targeting domain; a degradation moiety to a targeting moiety).. Linkers can be susceptible to or be substantially resistant to acid-induced cleavage, light- induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and/or disulfide bond cleavage. Linkers are classified based on the presence of one or more chemical motifs such as, for example, including a disulfide group, a hydrazine group or peptide (cleavable), or a thioester group (non-cleavable). Linkers also include charged linkers, and hydrophilic forms thereof as known in the art. [0148] Suitable linkers for linking the components of the degradation constructs and/or the components of the β-catenin targeting compounds of the present disclosure include a natural linker, an empirical linker, or a combination of natural and/or empirical linkers. Natural linkers are derived from the amino acid linking sequence of multi-domain proteins, which are naturally present between protein domains. Properties of natural linkers such as, for example, length, hydrophobicity, amino acid residues, and/or secondary structure can be exploited to confer desirable properties to a multi-domain compound that includes natural linkers connecting the components of the degradation constructs and/or the components of the β-catenin targeting compounds of the present disclosure. [0149] The studies of linkers in natural multi-domain proteins have led to the generation of many empirical linkers with various sequences and conformations for the construction of recombinant fusion proteins. Empirical linkers are often classified as three types: flexible linkers, rigid linkers, and cleavable linkers. Flexible linkers can provide a certain degree of movement or interaction at the joined components. Flexible linkers typically include small, non-polar (e.g., Gly) or polar (e.g., Ser or Thr) amino acids, which provide flexibility, and allow for mobility of the connected components. Rigid linkers can successfully keep a fixed distance between the degradation moiety and the targeting moiety and/or bispecific construct of the degradation constructs to maintain their independent functions, which can provide efficient separation of the targeting moiety and the degradation moiety and/or sufficiently reduce interference between the targeting moiety and the degradation moiety. Rigid linkers can successfully keep a fixed distance between the components of a bispecific construct to maintain their independent functions, which can provide efficient separation of components of a bispecific construct and/or sufficiently reduce interference between the components of the bispecific construct. [0150] In embodiments, the degradation constructs and/or the β-catenin targeting compounds described herein comprise at least one amino acid that is used to connect components of the degradation construct and/or the β-catenin targeting compounds. The amino acid linker may be referred to as a linker peptide. The linker peptide may contain 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids. [0151] In embodiments, the degradation constructs and/or the β-catenin targeting compounds include a linker peptide. In embodiments, the degradation construct and/or the β-catenin targeting compounds includes two, three, four, or five linker peptides. For example, in embodiments where the targeting moiety is a bispecific construct, the first targeting moiety and the second targeting moiety may be connected by a peptide linker and the bispecific construct may be connected to the degradation moiety through a second linker peptide. In embodiments, the degradation construct does not include a peptide linker. In embodiments, all the components of the degradation construct and/or the β-catenin targeting compounds are directly linked. In embodiments, some components of the depredation construct are directly linked and others are linked via a peptide linker. For example, in embodiments where the targeting moiety is a bispecific construct, the first targeting moiety and the second targeting moiety may be linked via a peptide linker and the bispecific construct is directly linked to the degradation moiety. In embodiments where the targeting moiety is a bispecific construct, the first targeting moiety and the second targeting moiety may be directly linked, and the bispecific construct may be linked to the degradation construct via a peptide linker. In embodiments, the degradation construct and/or the β-catenin targeting compound includes one or more linkers of Table 6. Table 6. Polypeptide linker sequences

[0152] In embodiments, a linker is covalently attached to the targeting moiety or bispecific construct, degradation moiety, β-catenin antibody or antigen binding fragment thereof, or any combination thereof using bioconjugation chemistries. Bioconjugation chemistries are well known in the art and include but are not limited to, NHS-ester ligation, isocyanate ligation, isothiocyanate ligation, benzoyl fluoride ligation, maleimide conjugation, iodoacetamide conjugation, 2- thiopyridine disulfide exchange, 3-arylpropiolonitrile conjugation, diazonium salt conjugation, PTAD conjugation, and Mannich ligation. [0153] In embodiments, the linker, the targeting moiety or the bispecific construct, the degradation moiety, the β-catenin antibody or antigen binding fragment thereof, of any combination thereof, may include one or more unnatural amino acids that allow for bioorthogonal conjugation reactions. As used herein, “bioorthogonal conjugation” refers to a conjugation reaction that uses one or more unnatural amino acids or modified amino acids as a starting reagent. Examples of bioorthogonal conjugation reactions include but are not limited to, Staudinger ligation, copper-catalyzed azide– alkyne cycloaddition, strain promoted [3+2] cycloadditions, tetrazine ligation, metal-catalyzed coupling reactions, or oxime-hydrazone ligations. Examples of non-natural amino acids include, but are not limited to, azidohomoalanine, 2 homopropargylglycine, 3 homoallylglycine, 4 p-acetyl- phenylalanine, 5 p-azido-phenylalanine, 3-(6-acetylnaphthalen-2-ylamino)-2-aminopropanoic acid, N^ɛ-(cyclooct-2-yn-1-yloxy)carbonyl)L-lysine, N^ɛ-2-azideoethyloxycarbonyl-L-lysine, Nɛ-p- azidobenzyloxycarbonyl lysine, Propargyl-L-lysine, or trans-cyclooct-2-ene lysine. [0154] In embodiments, the linker is derived from a small molecule, such as a polymer. Example polymer linkers include but are not limited to, poly-ethylene glycol, poly(N-isopropylacrylamide), and N,N′-dimethylacrylamide-co-4-phenylazophenyl acrylate. The small molecule linkers generally include one or more reactive handles allowing conjugation to the degradation moiety, targeting moiety, or both. In embodiments, the reactive handle allows for a bioconjugation or bioorthogonal conjugation. In embodiments, the reactive handle allows for any organic reaction compatible with conjugating a linker to the targeting moiety, degradation moiety, or both. [0155] The linker may be conjugated at any amino acid location of the targeting moiety or bispecific moiety, and degradation moiety. For example, the linker may be conjugated to the N- terminus, C-terminus, or any amino acid between. [0156] In embodiments where the degradation construct includes additional domains, the additional domains may be operably linked to each other and/or the targeting moiety and/or degradation moiety using one or more of the linkers disclosed elsewhere herein. [0157] In embodiments where the degradation construct includes a targeting moiety or bispecific construct, and a degradation moiety comprised of amino acids that are operably linked by peptide linkers, the degradation construct may be produced by expression in a host cell. In embodiments where the β-catenin targeting compound includes a bispecific construct where the β-catenin targeting antibody or antigen binding fragment thereof and the second targeting moiety are operably linked by peptide linkers, the β-catenin targeting compound may be produced by expression in a host cell. [0158] In embodiments where the degradation construct includes a targeting moiety and a degradation moiety comprised of amino acids that are operably linked by peptide linkers, the degradation construct may be produced by solid phase peptide synthesis. In embodiments where the β-catenin targeting compound includes a bispecific construct where the β-catenin targeting antibody or antigen binding fragment thereof and the second targeting moiety are operably linked by peptide linkers, the β-catenin targeting compound may be produced by solid phase peptide synthesis. [0159] In embodiments, the β-catenin targeting compound, the degradation construct and/or one or more components of the degradation construct may include a protein tag. The protein tag may be a purification tag or a cell signaling tag. In embodiments, the β-catenin antibody or antigen binding fragment thereof of a β-catenin targeting compound may include a protein tag. In embodiments, the targeting moiety or the bispecific construct, degradation moiety, and/or the full degradation construct of a degradation compound may include a protein tag. [0160] In embodiments, the degradation construct and/or one or more components of the degradation construct include a protein tag such as glutathione S-transferase (GST), polyhistidine tag, a histidine peptide, hemagglutinin, and/or a FLAG tag. In embodiments, the β-catenin antibody or antigen binding fragment thereof, the bispecific construct, or a component of a bispecific construct of a β-catenin targeting compound includes a protein tag such as glutathione S-transferase (GST), poly tag, histidine, a histidine peptide, hemagglutinin, and/or a FLAG tag. Examples of some protein tags are listed in Table 7. [0161] In embodiments, the protein tag is on the N-terminus of the degradation construct and/or one or more components of the degradation construct sequence. In embodiments, the protein tag is on the C-terminus of the degradation construct and/or one or more components of the degradation construct. In embodiments, the degradation construct and/or one or more components of the degradation construct includes a protein tag of one of those in Table 7. [0162] In embodiments, the protein tag is on the N-terminus of the β-catenin antibody or antigen binding fragment thereof, the bispecific construct, or the second targeting moiety of a bispecific construct of a β-catenin targeting compound. In embodiments, the protein tag is on the C-terminus of the β-catenin antibody or antigen binding fragment thereof, the bispecific construct, or the second targeting moiety of a bispecific construct of a β-catenin targeting compound. In embodiments, the β-catenin antibody or antigen binding fragment thereof, the bispecific construct, or the second targeting moiety of a bispecific construct of a β-catenin targeting compound includes a protein tag listed in Table 7. Table 7. Examples of Polypeptide Protein Tags

Examples of Degradation Constructs [0163] One or more β-catenin antibodies of antigen binding fragments thereof may be combined with one or more degradation moieties to form a degradation construct. The targeting moiety may be combined with one or more of the degradation moieties in any suitable order, e.g., at the N- terminus or C-terminus of the targeting moiety, or on the side chain of an internal amino acid in the targeting moiety’s amino acid sequence. Similarly, the operable linkage to the degradation moiety may occur at any suitable position, e.g., at the N-terminus or C-terminus of the degradation moiety, or on the side chain of an internal amino acid in the degradation moiety’s amino acid sequence. The targeting moiety may be operably linked such as a direct linkage or linked by a peptide linker or synthetic linker to the degradation moiety described herein and/or one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids). [0164] In embodiments where the targeting moiety is a bispecific moiety, the first targeting moiety or the second targeting moiety may be operably linked to degradation moiety. In embodiments, the first targeting moiety of a bispecific construct is operably linked to the degradation moiety. In embodiments, the second targeting moiety of the bispecific construct is operably linked to the degradation moiety. [0165] Matrix 1 provides example degradation constructs that include a degradation moiety and a targeting moiety. Bispecific targeting moieties that include a β-catenin antibody and a 7D12 are included. The components of the bispecific targeting moiety may be combined in any suitable order. The sequences for the degradation moieties are provided in Table 4. The sequences for the targeting moieties are provided in Table 1. Matrix 1: Examples of Some Degradation Constructs M i _t

Endosomal Escape Vehicles (EEVs) [0166] An endosomal escape vehicle (EEV) can be used to transport a cargo across a cellular membrane, for example, to deliver the cargo to the cytosol or nucleus of a cell. Cargo can include a β-catenin antibody or antigen binding fragment thereof, a β-catenin targeting compound, a degradation construct, or a degradation compound as described herein. The EEV can comprise a cell penetrating peptide (CPP), for example, a cyclic cell penetrating peptide (cCPP). In embodiments, the EEV comprises a cCPP and an exocyclic peptide (EP). [0167] The EP can be referred to interchangeably as a modulatory peptide (MP). The EP can comprise a sequence of a nuclear localization signal (NLS). The EP can be coupled to the cargo. The EP can be coupled to the cCPP. The EP can be coupled to the cargo and the cCPP. Coupling between the EP, cargo, cCPP, or combinations thereof, may be non-covalent or covalent. The EP can be attached through a peptide bond to the N-terminus of the cCPP. The EP can be attached through a peptide bond to the C-terminus of the cCPP. The EP can be attached to the cCPP through a side chain of an amino acid in the cCPP. The EP can be attached to the cCPP through a side chain of a lysine which can be conjugated to the side chain of a glutamine in the cCPP. The EP can be coupled to a linker. The exocyclic peptide can be conjugated to an amino group of the linker. The EP can be coupled to a linker via the C-terminus of an EP and a cCPP through a side chain on the cCPP and/or EP. For example, an EP may comprise a terminal lysine which can then be coupled to a cCPP containing a glutamine through an amide bond. When the EP contains a terminal lysine, and the side chain of the lysine can be used to attach the cCPP, the C- or N-terminus may be attached to a linker on the cargo. Exocyclic Peptides [0168] The exocyclic peptide (EP) can comprise from 2 to 10 amino acid residues e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues, inclusive of all ranges and values therebetween. The EP can comprise 6 to 9 amino acid residues. The EP can comprise from 4 to 8 amino acid residues. [0169] Each amino acid in the exocyclic peptide may be a natural or non-natural amino acid. The term “non-natural amino acid” refers to an organic compound that is a congener of a natural amino acid in that it has a structure similar to a natural amino acid so that it mimics the structure and reactivity of a natural amino acid. The non-natural amino acid can be a modified amino acid, and/or amino acid analog, that is not one of the 20 common naturally occurring amino acids or the rare natural amino acids selenocysteine or pyrrolysine. Non-natural amino acids can also be the D- isomer of the natural amino acids. Examples of suitable amino acids include, but are not limited to, alanine, allosoleucine, arginine, citrulline, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, napthylalanine, phenylalanine, proline, pyroglutamic acid, serine, threonine, tryptophan, tyrosine, valine, a derivative thereof, or combinations thereof. These, and others amino acids, are listed in the Table 8 along with their abbreviations used herein. For example, the amino acids can be A, G, P, K, R, V, F, H, Nal, or citrulline. [0170] The EP can comprise at least one positively charged amino acid residue, e.g., at least one lysine residue and/or at least one amine acid residue comprising a side chain comprising a guanidine group, or a protonated form thereof. The EP can comprise 1 or 2 amino acid residues comprising a side chain comprising a guanidine group, or a protonated form thereof. The amino acid residue comprising a side chain comprising a guanidine group can be an arginine residue. Protonated forms can mean salt thereof throughout the disclosure. [0171] The EP can comprise at least two, at least three or at least four or more lysine residues. The EP can comprise 2 lysine residues. The EP can comprise 3 lysine residues. The EP can comprise 4 lysine residues. The amino group on the side chain of each lysine residue can be substituted with a protecting group, including, for example, trifluoroacetyl (-COCF₃), allyloxycarbonyl (Alloc), 1- (4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde), or (4,4-dimethyl-2,6-dioxocyclohex-1- ylidene-3)-methylbutyl (ivDde) group. The amino group on the side chain of each lysine residue can be substituted with a trifluoroacetyl (-COCF₃) group. The protecting group can be included to enable amide conjugation. The protecting group can be removed after the EP is conjugated to a cCPP. [0172] The EP can comprise at least 2 amino acid residues with a hydrophobic side chain. The amino acid residue with a hydrophobic side chain can be selected from valine, proline, alanine, leucine, isoleucine, and methionine. The amino acid residue with a hydrophobic side chain can be valine or proline. [0173] The EP can comprise at least one positively charged amino acid residue, e.g., at least one lysine residue and/or at least one arginine residue. The EP can comprise at least two, at least three, or at least four or more lysine residues and/or arginine residues. [0174] The EP can comprise KK, KR, RR, HH, HK, HR, RH, KKK, KGK, KBK, KBR, KRK, KRR, RKK, RRR, KKH, KHK, HKK, HRR, HRH, HHR, HBH, HHH, HHHH, KHKK, KKHK, KKKH, KHKH, HKHK, KKKK, KKRK, KRKK, KRRK, RKKR, RRRR, KGKK, KKGK, HBHBH, HBKBH, RRRRR, KKKKK, KKKRK, RKKKK, KRKKK, KKRKK, KKKKR, KBKBK, RKKKKG, KRKKKG, KKRKKG, KKKKRG, RKKKKB, KRKKKB, KKRKKB, KKKKRB, KKKRKV, RRRRRR, HHHHHH, RHRHRH, HRHRHR, KRKRKR, RKRKRK, RBRBRB, KBKBKB, PKKKRKV, PGKKRKV, PKGKRKV, PKKGRKV, PKKKGKV, PKKKRGV, or PKKKRKG, wherein B is β-alanine. The amino acids in the EP can have D or L stereochemistry. [0175] The EP can comprise KK, KR, RR, KKK, KGK, KBK, KBR, KRK, KRR, RKK, RRR, KKKK, KKRK, KRKK, KRRK, RKKR, RRRR, KGKK, KKGK, KKKKK, KKKRK, KBKBK, KKKRKV, PKKKRKV, PGKKRKV, PKGKRKV, PKKGRKV, PKKKGKV, PKKKRGV, or PKKKRKG. The EP can comprise PKKKRKV, RR, RRR, RHR, RBR, RBRBR, RBHBR, or HBRBH, wherein B is β-alanine. The amino acids in the EP can have D or L stereochemistry. [0176] The EP can consist of KK, KR, RR, KKK, KGK, KBK, KBR, KRK, KRR, RKK, RRR, KKKK, KKRK, KRKK, KRRK, RKKR, RRRR, KGKK, KKGK, KKKKK, KKKRK, KBKBK, KKKRKV, PKKKRKV, PGKKRKV, PKGKRKV, PKKGRKV, PKKKGKV, PKKKRGV, or PKKKRKG. The EP can consist of PKKKRKV, RR, RRR, RHR, RBR, RBRBR, RBHBR, or HBRBH, wherein B is β-alanine. The amino acids in the EP can have D or L stereochemistry. [0177] The EP can comprise an amino acid sequence identified in the art as a nuclear localization sequence (NLS). The EP can comprise an NLS comprising the amino acid sequence PKKKRKV. The EP can consist of an NLS comprising the amino acid sequence PKKKRKV. The EP can comprise an NLS comprising or consisting of an amino acid sequence selected from NLSKRPAAIKKAGQAKKKK, PAAKRVKLD, RQRRNELKRSF, RMRKFKNKGKDTAELRRRRVEVSVELR, KAKKDEQILKRRNV, VSRKRPRP, PPKKARED, PQPKKKPL, SALIKKKKKMAP, DRLRR, PKQKKRK, RKLKKKIKKL, REKKKFLKRR, KRKGDEVDGVDEVAKKKSKK, and RKCLQAGMNLEARKTKK. [0178] All exocyclic sequences can also contain an N-terminal acetyl group (Ac). Hence, for example, the EP can have the structure: Ac-PKKKRKV. Cell Penetrating Peptides (CPP) [0179] In embodiments, the cell penetrating peptide (CPP) comprises 6 to 20 amino acid residues. The cell penetrating peptide can be a cyclic cell penetrating peptide (cCPP). The cCPP is capable of penetrating a cell membrane. An exocyclic peptide (EP) can be conjugated to the cCPP, and the resulting construct can be referred to as an endosomal escape vehicle (EEV). The cCPP can direct a cargo (e.g., a照-catenin targeting compound, degradation compound, or degradation construct) to penetrate the membrane of a cell. The cCPP can deliver the cargo to the cytosol of the cell. The cCPP can deliver the cargo to a cellular location where a target (e.g., β-catenin) is located. To conjugate the cCPP to a cargo, at least one bond or lone pair of electrons on the cCPP can be replaced. [0180] The total number of amino acid residues in the cCPP is in the range of from 6 to 20 amino acid residues, e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues, inclusive of all ranges and subranges therebetween. The cCPP can comprise 6 to 13 amino acid residues. The cCPP disclosed herein can comprise 6 to 10 amino acids. By way of example, cCPP comprising 6-10 amino acid residues can have a structure according to any of Formula I-A to I-E:

, wherein AA₁, AA₂, AA₃, AA₄, AA₅, AA₆, AA₇, AA₈, AA₉, and AA₁₀ are amino acid residues. [0181] The cCPP can comprise 6 to 8 amino acids. The cCPP can comprise 8 amino acids. [0182] Each amino acid in the cCPP may be a natural or non-natural amino acid. Abbreviations used herein for some natural and non-natural amino acids are shown in Table 8. [0183] As used herein, the term "amino acid" refers to compounds having an amino group and a carboxylic acid group. Most amino acids (except for glycine) also have a side chain. As used herein, “amino acid side chain” or "side chain" refers to the characterizing substituent bound to the α-carbon of the amino acid. [0184] An “α-amino acid” is an amino acid in which the amino group is attached to the first (alpha) carbon adjacent to the carboxylic acid group, such that the carbon atom of the carbonyl is separated from the nitrogen atom of the amino group by one carbon atom. A “b-amino acid” (also called “beta-amino acid,” and “照-amino acid”) is an analog of an α -amino acid in which the amino group is attached to the second (beta) carbon, rather than the alpha-carbon, such that the carbon atom of the carbonyl is separated from the nitrogen atom of the amino group by two carbon atoms. Examples of b-amino acids include but are not limited to b-alanine and b-homophenylalanine. An “uncharged” amino acid is an amino acid that does not have a charge at a physiological pH (between 5.0 and 8.0). It is noted that histidine can exist in neutral or positively charged forms at physiological pH. [0185] A side chain that does not comprise an aryl or heteroaryl group, can be referred to herein as a “non-aryl” side chain. In embodiments, the side chain that does not comprise an aryl or heteroaryl group can be uncharged and is referred to herein as an uncharged, non-aryl side chain. Amino acids with uncharged non-aryl amino side chains include, but are not limited to, histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-Thiazolyl)-alanine, 3-(4-furanyl)-alanine, 3-(4-thienyl)-alanine, and b-amino acid derivatives thereof. Table 8. Amino Acid Abbreviations

[0186] As used herein, “polyethylene glycol” and “PEG” are used interchangeably. “PEGm,” and “PEGm,” are, or are derived from, a molecule of the formula HO(CO)-(CH2)n-(OCH2CH2)m- NH₂ where n is any integer from 1 to 5 and m is any integer from 1 to 23. In embodiments, n is 1 or 2. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 1 and m is 2. In embodiments, n is 2 and m is 2. In embodiments, n is 1 and m is 4. In embodiments, n is 2 and m is 4. In embodiments, n is 1 and m is 12. In embodiments, n is 2 and m is 12. [0187] As used herein, “miniPEGm” or “miniPEG_m” are, or are derived from, a molecule of the formula HO(CO)-(CH2)n-(OCH2CH2)m-NH2 where n is 1 and m is any integer from 1 to 23. For example, “miniPEG2” or “miniPEG₂” is, or is derived from, (2-[2-[2-aminoethoxy]ethoxy]acetic acid), and “miniPEG4” or “miniPEG₄” is, or is derived from, HO(CO)-(CH₂)_n-(OCH₂CH₂)_m- NH2 where n is 1 and m is 4. [0188] In embodiments, one or two amino acids in the CPP can have no side chain. In embodiments, all amino acids in the CPP have a side chain. As used herein, when no side chain is present, the amino acid has two hydrogen atoms on the carbon atom(s) (e.g., -CH2-) linking the amine and carboxylic acid of the amino acid residue. The amino acid having no side chain can be glycine or beta-alanine. [0189] The cCPP can comprise from 6 to 20, from 6 to 10, or from 6 to 8 amino acid residues, wherein: (i) at least one amino acid can be glycine, b-alanine, serine, histidine or 4-aminobutyric acid; (ii) at least one amino acid can have a side chain comprising an aryl or heteroaryl group; and (iii) at least one amino acid has a side chain comprising a guanidine group, or a protonated form thereof. [0190] In embodiments, one amino acid of the CPP can be glycine, b-alanine, serine, histidine, or 4-aminobutyric acid. In embodiments, two amino acids can be, independently, glycine, b-alanine, serine, histidine or 4-aminobutyric acid. In embodiments, three amino acids can be glycine, b- alanine, serine, histidine, or 4-aminobutyric acid. [0191] In embodiments, one amino acid of the CPP can have a side chain comprising an aryl or heteroaryl group. In embodiments, two amino acids of the CPP can have a side chain comprising an aryl or heteroaryl group. In embodiments, three amino acids of the CPP can have a side chain comprising an aryl or heteroaryl group. [0192] In embodiments, one amino acid of the CPP can have a side chain that does not comprise an aryl or heteroaryl group, referred to herein as a “non-aryl” side chain. In embodiments, the side chain that does not comprise an aryl or heteroaryl group can be uncharged and is referred to herein as an uncharged, non-aryl side chain. In embodiments, two amino acids of the CPP can have an uncharged, non-aryl side chain. In embodiments, three amino acids of the CPP can have an uncharged, non-aryl side chain. Amino acids with uncharged non-aryl amino side chains include, but are not limited to, histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-thiazolyl)-alanine, 3-(4-furanyl)-alanine, and 3-(4- thienyl)-alanine. [0193] The cCPP can comprise 6 to 20 amino acids, wherein: (i) at least one amino acid has a side chain comprising a guanidine group, or a protonated form thereof; (ii) at least one amino acid has

no side chain or a side chain comprising ,

, , , , or a protonated form thereof; and (iii) at least two amino acids independently have a side chain comprising an aromatic or heteroaromatic group. [0194] At least two amino acids can have no side chain or a side chain comprising

,

protonated form thereof. As used herein, when no side chain is present, the amino acid has two hydrogen atoms on the carbon atom(s) (e.g., -CH2-) linking the amine and carboxylic acid. [0195] The amino acid having no side chain can be glycine or beta-alanine. [0196] The cCPP can comprise from 6 to 20 amino acid residues which form the cCPP, wherein: (i) at least one amino acid can be glycine, b-alanine, or 4-aminobutyric acid residues; (ii) at least one amino acid can have a side chain comprising an aryl or heteroaryl group; and (iii) at least one amino acid has a side chain comprising a guanidine group,

,

, or a protonated form thereof. [0197] The cCPP can comprise from 6 to 20 amino acid residues which form the cCPP, wherein: (i) at least two amino acids can independently be glycine, b-alanine, or 4-aminobutyric acid residues; (ii) at least one amino acid can have a side chain comprising an aryl or heteroaryl group;

form thereof. [0198] The cCPP can comprise from 6 to 20 amino acid residues which form the cCPP, wherein: (i) at least three amino acids can independently be glycine, b-alanine, or 4-aminobutyric acid residues; (ii) at least one amino acid can have a side chain comprising an aromatic or heteroaromatic group; and (iii) at least one amino acid can have a side chain comprising a guanidine group,

, , , , ,

, or a protonated form thereof. [0199] The cCPP can comprise 1 or 2 amino acid residues selected from uncharged non-aryl amino acids residues. [0200] The cCPP can comprise 2 contiguous amino acids with hydrophobic side chains The cCPP can comprise 3 contiguous amino acids with hydrophobic side chains. [0201] In embodiments, one amino acid of the CPP can have a side chain that does not comprise an aryl or heteroaryl group, referred to herein as a “non-aryl” side chain. In embodiments, the side chain that does not comprise an aryl or heteroaryl group can be uncharged and is referred to herein as an uncharged, non-aryl side chain. In embodiments, two amino acids of the CPP can have an uncharged, non-aryl side chain. In embodiments, three amino acids of the CPP can have an uncharged, non-aryl side chain. Amino acids with uncharged non-aryl amino side chains include, but are not limited to, histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-thiazolyl)-alanine, 3-(4-furanyl)-alanine, and 3-(4- thienyl)-alanine. [0202] In embodiments, one amino acid of the CPP has a side chain comprising a guanidine group, or a protonated form thereof. In embodiments, two amino acids of the CPP can have a side chain comprising a guanidine group, or a protonated form thereof. In embodiments, three amino acids of the CPP can have a side chain comprising a guanidine group, or a protonated form thereof. In embodiments, four amino acids of the CPP can have a side chain comprising a guanidine group, or a protonated form thereof. Glycine and Related Amino Acid Residues [0203] The cCPP can comprise (i) 1, 2, 3, 4, 5, or 6 glycine, b-alanine, 4-aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 2 glycine, b-alanine, 4-aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 3 glycine, b-alanine, 4- aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 4 glycine, b- alanine, 4-aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 5 glycine, b-alanine, 4-aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 6 glycine, b-alanine, 4-aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 3, 4, or 5 glycine, b-alanine, 4-aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 3 or 4 glycine, b-alanine, 4-aminobutyric acid residues, or combinations thereof. [0204] The cCPP can comprise (i) 1, 2, 3, 4, 5, or 6 glycine residues. The cCPP can comprise (i) 2 glycine residues. The cCPP can comprise (i) 3 glycine residues. The cCPP can comprise (i) 4 glycine residues. The cCPP can comprise (i) 5 glycine residues. The cCPP can comprise (i) 6 glycine residues. The cCPP can comprise (i) 3, 4, or 5 glycine residues. The cCPP can comprise (i) 3 or 4 glycine residues. The cCPP can comprise (i) 2 or 3 glycine residues. The cCPP can comprise (i) 1 or 2 glycine residues. [0205] The cCPP can comprise (i) 3, 4, 5, or 6 glycine, b-alanine, 4-aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 3 glycine, b-alanine, 4-aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 4 glycine, b-alanine, 4-aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 5 glycine, b-alanine, 4- aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 6 glycine, b- alanine, 4-aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 3, 4, or 5 glycine, b-alanine, 4-aminobutyric acid residues, or combinations thereof. The cCPP can comprise (i) 3 or 4 glycine, b-alanine, 4-aminobutyric acid residues, or combinations thereof. [0206] The cCPP can comprise at least three glycine residues. The cCPP can comprise (i) 3, 4, 5, or 6 glycine residues. The cCPP can comprise (i) 3 glycine residues. The cCPP can comprise (i) 4 glycine residues. The cCPP can comprise (i) 5 glycine residues. The cCPP can comprise (i) 6 glycine residues. The cCPP can comprise (i) 3, 4, or 5 glycine residues. The cCPP can comprise (i) 3 or 4 glycine residues [0207] In embodiments, none of the glycine, b-alanine, or 4-aminobutyric acid residues in the cCPP are contiguous. Two or three glycine, b-alanine, 4-or aminobutyric acid residues can be contiguous. Two glycine, b-alanine, or 4-aminobutyric acid residues can be contiguous. [0208] In embodiments, none of the glycine residues in the cCPP are contiguous. Each glycine residue in the cCPP can be separated by an amino acid residue that is not glycine. Two or three glycine residues can be contiguous. Two glycine residues can be contiguous. Amino Acid Side Chains with an Aromatic or Heteroaromatic Group [0209] The cCPP can comprise (ii) 2, 3, 4, 5 or 6 amino acid residues independently having a side chain comprising an aromatic or heteroaromatic group. The cCPP can comprise (ii) 2 amino acid residues independently having a side chain comprising an aromatic or heteroaromatic group. The cCPP can comprise (ii) 3 amino acid residues independently having a side chain comprising an aromatic or heteroaromatic group. The cCPP can comprise (ii) 4 amino acid residues independently having a side chain comprising an aromatic or heteroaromatic group. The cCPP can comprise (ii) 5 amino acid residues independently having a side chain comprising an aromatic or heteroaromatic group. The cCPP can comprise (ii) 6 amino acid residues independently having a side chain comprising an aromatic or heteroaromatic group. The cCPP can comprise (ii) 2, 3, or 4 amino acid residues independently having a side chain comprising an aromatic or heteroaromatic group. The cCPP can comprise (ii) 2 or 3 amino acid residues independently having a side chain comprising an aromatic or heteroaromatic group. [0210] The cCPP can comprise (ii) 2, 3, 4, 5 or 6 amino acid residues independently having a side chain comprising an aromatic group. The cCPP can comprise (ii) 2 amino acid residues independently having a side chain comprising an aromatic group. The cCPP can comprise (ii) 3 amino acid residues independently having a side chain comprising an aromatic group. The cCPP can comprise (ii) 4 amino acid residues independently having a side chain comprising an aromatic group. The cCPP can comprise (ii) 5 amino acid residues independently having a side chain comprising an aromatic group. The cCPP can comprise (ii) 6 amino acid residues independently having a side chain comprising an aromatic group. The cCPP can comprise (ii) 2, 3, or 4 amino acid residues independently having a side chain comprising an aromatic group. The cCPP can comprise (ii) 2 or 3 amino acid residues independently having a side chain comprising an aromatic group. [0211] The aromatic group can be a 6- to 14-membered aryl. Aryl can be phenyl, naphthyl or anthracenyl, each of which is optionally substituted. Aryl can be phenyl or naphthyl, each of which is optionally substituted. The heteroaromatic group can be a 6- to 14-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S. Heteroaryl can be pyridyl, quinolyl, or isoquinolyl. [0212] The amino acid residue having a side chain comprising an aromatic or heteroaromatic group can each independently be bis(homonaphthylalanine), homonaphthylalanine, naphthylalanine, phenylglycine, bis(homophenylalanine), homophenylalanine, phenylalanine, tryptophan, 3-(3-benzothienyl)-alanine, 3-(2-quinolyl)-alanine, O-benzylserine, 3-(4- (benzyloxy)phenyl)-alanine, S-(4-methylbenzyl)cysteine, N-(naphthalen-2-yl)glutamine, 3-(1,1'- biphenyl-4-yl)-alanine, 3-(3-benzothienyl)-alanine or tyrosine, each of which is optionally substituted with one or more substituents. The amino acid having a side chain comprising an aromatic or heteroaromatic group can each independently be selected from:

, , ,

, , , and

, wherein the H on the N-terminus and/or the H on the C- terminus are replaced by a peptide bond. [0213] The amino acid residue having a side chain comprising an aromatic or heteroaromatic group can each be independently a residue of phenylalanine, naphthylalanine, phenylglycine, homophenylalanine, homonaphthylalanine, bis(homophenylalanine), bis-(homonaphthylalanine), tryptophan, or tyrosine, each of which is optionally substituted with one or more substituents. The amino acid residue having a side chain comprising an aromatic group can each independently be a residue of tyrosine, phenylalanine, 1-naphthylalanine, 2-naphthylalanine, tryptophan, 3- benzothienylalanine, 4-phenylphenylalanine, 3,4-difluorophenylalanine, 4- trifluoromethylphenylalanine, 2,3,4,5,6-pentafluorophenylalanine, homophenylalanine, β- homophenylalanine, 4-tert-butyl-phenylalanine, 4-pyridinylalanine, 3-pyridinylalanine, 4- methylphenylalanine, 4-fluorophenylalanine, 4-chlorophenylalanine, 3-(9-anthryl)-alanine. The amino acid residue having a side chain comprising an aromatic group can each independently be a residue of phenylalanine, naphthylalanine, phenylglycine, homophenylalanine, or homonaphthylalanine, each of which is optionally substituted with one or more substituents. The amino acid residue having a side chain comprising an aromatic group can each be independently a residue of phenylalanine, naphthylalanine, homophenylalanine, homonaphthylalanine, bis(homonaphthylalanine), or bis(homonaphthylalanine), each of which is optionally substituted with one or more substituents. The amino acid residue having a side chain comprising an aromatic group can each be independently a residue of phenylalanine or naphthylalanine, each of which is optionally substituted with one or more substituents. At least one amino acid residue having a side chain comprising an aromatic group can be a residue of phenylalanine. At least two amino acid residues having a side chain comprising an aromatic group can be residues of phenylalanine. Each amino acid residue having a side chain comprising an aromatic group can be a residue of phenylalanine. [0214] In embodiments, none of the amino acids having the side chain comprising the aromatic or heteroaromatic group are contiguous. Two amino acids having the side chain comprising the aromatic or heteroaromatic group can be contiguous. Two contiguous amino acids can have opposite stereochemistry. The two contiguous amino acids can have the same stereochemistry. Three amino acids having the side chain comprising the aromatic or heteroaromatic group can be contiguous. Three contiguous amino acids can have the same stereochemistry. Three contiguous amino acids can have alternating stereochemistry. [0215] The amino acid residues comprising aromatic or heteroaromatic groups can be L-amino acids. The amino acid residues comprising aromatic or heteroaromatic groups can be D-amino acids. The amino acid residues comprising aromatic or heteroaromatic groups can be a mixture of D- and L-amino acids. [0216] The optional substituent can be any atom or group which does not significantly reduce (e.g., by more than 50%) the cytosolic delivery efficiency of the cCPP/EEV, e.g., compared to an otherwise identical sequence which does not have the substituent. The optional substituent can be a hydrophobic substituent or a hydrophilic substituent. The optional substituent can be a hydrophobic substituent. The substituent can increase the solvent-accessible surface area (as defined herein) of the hydrophobic amino acid. The substituent can be halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, acyl, alkylcarbamoyl, alkylcarboxamidyl, alkoxycarbonyl, alkylthio, or arylthio. The substituent can be halogen. [0217] The hydrophobicity of amino acid residues can be measured and/or calculated using a variety of techniques. In embodiments, the hydrophobicity of an amino acid residue can be determined by calculating its consensus value on the consensus scale of D. Eisenberg et al., using the method described in D. Eisenberg et al., “Hydrophobic Moments and Protein Structure,” Faraday Symp. Chem. Soc. 1982, 17, 109-120 (e.g., D. Eisenberg et al.). For example, the hydrophobicity according to the consensus scale of D. Eisenberg et al. of isoleucine is 0.73; phenylalanine is 0.61; valine is 0.54; leucine is 0.53; tryptophan is 0.37; methionine is 0.26; alanine is 0.25; glycine is 0.16; cysteine is 0.4; tyrosine s 0.02; proline is -0.07; threonine is -0.18; serine is -0.26; histidine is -0.40; glutamic acid is -0.62; asparagine is -0.64; asparagine is -0.72; lysine is -1.1; and arginine is -1.8. The hydrophobicity of any amino acid residue (natural or unnatural) may be calculated according to the consensus method of D. Eisenberg et al. In embodiments, a hydrophobic amino acid residue has a hydrophobicity consensus value calculated according to D. Eisenberg et al. of 0 or greater, 0.02 or greater, 0.05 or greater, 0.07 or greater, 0.1 or greater, 0.2 or greater, 0.3 or greater, 0.4 or greater, 0.5 or greater, 0.6 or greater, 0.7 or greater, 0.8 or greater, 0.9 or greater or 1.0 or greater. A hydrophobic amino acid is an amino acid that has a hydrophobic side chain. Amino Acid Residues Having a Side Chain Comprising a Guanidine Group, Guanidine Replacement Group, or Protonated Form Thereof [0218] As used herein, guanidine refers to the structure:

. [0219] As used herein, a protonated form of guanidine refers to the structure:

. [0220] Guanidine replacement groups refer to functional groups on the side chain of amino acids that will be positively charged at or above physiological pH or those that can recapitulate the hydrogen bond donating and accepting activity of guanidinium groups. [0221] The guanidine replacement groups facilitate cell penetration and delivery of therapeutic agents while reducing toxicity associated with guanidine groups or protonated forms thereof. The cCPP can comprise at least one amino acid having a side chain comprising a guanidine or guanidinium replacement group. The cCPP can comprise at least two amino acids having a side chain comprising a guanidine or guanidinium replacement group. The cCPP can comprise at least three amino acids having a side chain comprising a guanidine or guanidinium replacement group [0222] The guanidine or guanidinium group can be an isostere of guanidine or guanidinium. The guanidine or guanidinium replacement group can be less basic than guanidine. [0223] As used herein, a guanidine replacement group refers to

,

, or a protonated form thereof. [0224] The disclosure relates to a cCPP comprising from 6 to 20 amino acids residues, wherein: (i) at least one amino acid has a side chain comprising a guanidine group, or a protonated form thereof; (ii) at least one amino acid residue has no side chain or a side chain comprising

a protonated form thereof; and (iii) at least two amino acids residues independently have a side chain comprising an aromatic or heteroaromatic group. [0225] At least two amino acids residues can have no side chain or a side chain comprising

a protonated form thereof. As used herein, when no side chain is present, the amino acid residue have two hydrogen atoms on the carbon atom(s) (e.g., -CH2-) linking the amine and carboxylic acid. [0226] The cCPP can comprise at least one amino acid having a side chain comprising one of the

,

, or a protonated form thereof. [0227] The cCPP can comprise at least two amino acids each independently having one of the following moieties

, , , , ,

, or a protonated form thereof. At least two amino acids can have a side chain comprising the same moiety selected from:

, , ,

acid can have a side chain comprising

, or a protonated form thereof. At least two amino acids can have a side chain comprising

, or a protonated form thereof. One, two, three, or four amino acids can have a side chain comprising

, or a protonated form thereof. One amino acid can have a side chain comprising

, or a protonated form thereof. Two amino acids can have a side chain comprising

, or a protonated form

, or a protonated form thereof, can be attached to the terminus of the amino acid side chain.

can be attached to the terminus of the amino acid side chain. [0228] The cCPP can comprise (iii) 2, 3, 4, 5 or 6 amino acid residues independently having a side chain comprising a guanidine group, guanidine replacement group, or a protonated form thereof. The cCPP can comprise (iii) 2 amino acid residues independently having a side chain comprising a guanidine group, guanidine replacement group, or a protonated form thereof. The cCPP can comprise (iii) 3 amino acid residues independently having a side chain comprising a guanidine group, guanidine replacement group, or a protonated form thereof. The cCPP can comprise (iii) 4 amino acid residues independently having a side chain comprising a guanidine group, guanidine replacement group, or a protonated form thereof. The cCPP can comprise (iii) 5 amino acid residues independently having a side chain comprising a guanidine group, guanidine replacement group, or a protonated form thereof. The cCPP can comprise (iii) 6 amino acid residues independently having a side chain comprising a guanidine group, guanidine replacement group, or a protonated form thereof. The cCPP can comprise (iii) 2, 3, 4, or 5 amino acid residues independently having a side chain comprising a guanidine group, guanidine replacement group, or a protonated form thereof. The cCPP can comprise (iii) 2, 3, or 4 amino acid residues independently having a side chain comprising a guanidine group, guanidine replacement group, or a protonated form thereof. The cCPP can comprise (iii) 2 or 3 amino acid residues independently having a side chain comprising a guanidine group, guanidine replacement group, or a protonated form thereof. The cCPP can comprise (iii) at least one amino acid residue having a side chain comprising a guanidine group or protonated form thereof. The cCPP can comprise (iii) two amino acid residues having a side chain comprising a guanidine group or protonated form thereof. The cCPP can comprise (iii) three amino acid residues having a side chain comprising a guanidine group or protonated form thereof. [0229] The amino acid residues can independently have the side chain comprising the guanidine group, guanidine replacement group, or the protonated form thereof that are not contiguous. Two amino acid residues can independently have the side chain comprising the guanidine group, guanidine replacement group, or the protonated form thereof can be contiguous. Three amino acid residues can independently have the side chain comprising the guanidine group, guanidine replacement group, or the protonated form thereof can be contiguous. Four amino acid residues can independently have the side chain comprising the guanidine group, guanidine replacement group, or the protonated form thereof can be contiguous. The contiguous amino acid residues can have the same stereochemistry. The contiguous amino acids can have alternating stereochemistry. [0230] The amino acid residues independently having the side chain comprising the guanidine group, guanidine replacement group, or the protonated form thereof, can be L-amino acids. The amino acid residues independently having the side chain comprising the guanidine group, guanidine replacement group, or the protonated form thereof, can be D-amino acids. The amino acid residues independently having the side chain comprising the guanidine group, guanidine replacement group, or the protonated form thereof, can be a mixture of L- or D-amino acids. [0231] Each amino acid residue having the side chain comprising the guanidine group, or the protonated form thereof, can independently be a residue of arginine, homoarginine, 2-amino-3- propionic acid, 2-amino-4-guanidinobutyric acid or a protonated form thereof. Each amino acid residue having the side chain comprising the guanidine group, or the protonated form thereof, can independently be a residue of arginine or a protonated form thereof. [0232] Each amino acid having the side chain comprising a guanidine replacement group, or protonated form thereof, can independently be

,

, or a protonated form thereof. [0233] Without being bound by theory, it is hypothesized that guanidine replacement groups have reduced basicity, relative to arginine and in some cases are uncharged at physiological pH (e.g., a -N(H)C(O)), and are capable of maintaining the bidentate hydrogen bonding interactions with phospholipids on the plasma membrane that is believed to facilitate effective membrane association and subsequent internalization. The removal of positive charge is also believed to reduce toxicity of the cCPP/EEV. [0234] Those skilled in the art will appreciate that the N- and/or C-termini of the above non-natural aromatic hydrophobic amino acids, upon incorporation into the peptides disclosed herein, form amide bonds. [0235] The cCPP can comprise a first amino acid having a side chain comprising an aromatic or heteroaromatic group and a second amino acid having a side chain comprising an aromatic or heteroaromatic group, wherein an N-terminus of a first glycine forms a peptide bond with the first amino acid having the side chain comprising the aromatic or heteroaromatic group, and a C- terminus of the first glycine forms a peptide bond with the second amino acid having the side chain comprising the aromatic or heteroaromatic group. Although by convention, the term “first amino acid” often refers to the N-terminal amino acid of a peptide sequence, as used herein “first amino acid” is used to distinguish the referent amino acid from another amino acid (e.g., a “second amino acid”) in the cCPP such that the term “first amino acid” may or may refer to an amino acid located at the N-terminus of the peptide sequence. [0236] The cCPP can comprise an N-terminus of a second glycine forms a peptide bond with an amino acid having a side chain comprising an aromatic or heteroaromatic group, and a C-terminus of the second glycine forms a peptide bond with an amino acid having a side chain comprising a guanidine group, or a protonated form thereof. [0237] The cCPP can comprise a first amino acid having a side chain comprising a guanidine group, or a protonated form thereof, and a second amino acid having a side chain comprising a guanidine group, or a protonated form thereof, wherein an N-terminus of a third glycine forms a peptide bond with a first amino acid having a side chain comprising a guanidine group, or a protonated form thereof, and a C-terminus of the third glycine forms a peptide bond with a second amino acid having a side chain comprising a guanidine group, or a protonated form thereof. [0238] The cCPP can comprise a residue of asparagine, aspartic acid, glutamine, glutamic acid, or homoglutamine. The cCPP can comprise a residue of asparagine. The cCPP can comprise a residue of glutamine. [0239] The cCPP can comprise a residue of tyrosine, phenylalanine, 1-naphthylalanine, 2- naphthylalanine, tryptophan, 3-benzothienylalanine, 4-phenylphenylalanine, 3,4- difluorophenylalanine, 4-trifluoromethylphenylalanine, 2,3,4,5,6-pentafluorophenylalanine, homophenylalanine, β-homophenylalanine, 4-tert-butyl-phenylalanine, 4-pyridinylalanine, 3- pyridinylalanine, 4-methylphenylalanine, 4-fluorophenylalanine, 4-chlorophenylalanine, 3-(9- anthryl)-alanine. [0240] While not wishing to be bound by theory, it is believed that the chirality of the amino acids in the cCPPs/EEVs may impact cytosolic uptake efficiency. The cCPP can comprise at least one D amino acid. The cCPP can comprise one to fifteen D amino acids. The cCPP can comprise one to ten D amino acids. The cCPP can comprise 1, 2, 3, or 4 D amino acids. The cCPP can comprise 2, 3, 4, 5, 6, 7, or 8 contiguous amino acids having alternating D and L chirality. The cCPP can comprise three contiguous amino acids having the same chirality. The cCPP can comprise two contiguous amino acids having the same chirality. At least two of the amino acids can have the opposite chirality. The at least two amino acids having the opposite chirality can be adjacent to each other. At least three amino acids can have alternating stereochemistry relative to each other. The at least three amino acids having the alternating chirality relative to each other can be adjacent to each other. At least four amino acids have alternating stereochemistry relative to each other. The at least four amino acids having the alternating chirality relative to each other can be adjacent to each other. At least two of the amino acids can have the same chirality. At least two amino acids having the same chirality can be adjacent to each other. At least two amino acids have the same chirality and at least two amino acids have the opposite chirality. The at least two amino acids having the opposite chirality can be adjacent to the at least two amino acids having the same chirality. Accordingly, adjacent amino acids in the cCPP can have any of the following sequences: D-L; L-D; D-L-L-D; L-D-D-L; L-D-L-L-D; D-L-D-D-L; D-L-L-D-L; or L-D-D-L-D. The amino acid residues that form the cCPP can all be L-amino acids. The amino acid residues that form the cCPP can all be D-amino acids. [0241] At least two of the amino acids can have a different chirality. At least two amino acids having a different chirality can be adjacent to each other. At least three amino acids can have different chirality relative to an adjacent amino acid. At least four amino acids can have different chirality relative to an adjacent amino acid. At least two amino acids have the same chirality and at least two amino acids have a different chirality. One or more amino acid residues that form the cCPP can be achiral. The cCPP can comprise a motif of 3, 4, or 5 amino acids, wherein two amino acids having the same chirality can be separated by an achiral amino acid. The cCPPs can comprise the following sequences: D-X-D; D-X-D-X; D-X-D-X-D; L-X-L; L-X-L-X; or L-X-L-X-L, wherein X is an achiral amino acid. The achiral amino acid can be glycine. [0242] An amino acid having a side chain comprising:

, or a protonated form thereof, can be adjacent to an amino acid having a side chain comprising an aromatic or heteroaromatic group. An amino acid having a side chain comprising:

, or a protonated form thereof, can be adjacent to at least one amino acid having a side chain comprising a guanidine or protonated form thereof. An amino acid having a side chain comprising a guanidine or protonated form thereof can be adjacent to an amino acid having a side chain comprising an aromatic or heteroaromatic group. Two amino acids having a side chain comprising:

or protonated forms thereof, can be adjacent to each other. Two amino acids having a side chain comprising a guanidine or protonated form thereof are adjacent to each other. The cCPPs can comprise at least two contiguous amino acids having a side chain can comprise an aromatic or heteroaromatic group and at least two non-adjacent amino acids having a side chain comprising:

, or a protonated form thereof. The cCPPs can comprise at least two

contiguous amino acids having a side chain comprising an aromatic or heteroaromatic group and at least two non-adjacent amino acids having a side chain comprising

, or a protonated form thereof. The adjacent amino acids can have the same chirality. The adjacent amino acids can have the opposite chirality. Other combinations of amino acids can have any arrangement of D and L amino acids, e.g., any of the sequences described in the preceding paragraph. [0243] At least two amino acids having a side chain comprising:

, , or a protonated form thereof, are alternating with at least two amino acids having a side chain comprising a guanidine group or protonated form thereof. [0244] In embodiments, the cCPP can comprise the general Formula (IA):

or a protonated form thereof, wherein: R1, R2, R3, R4, R5, R6, and R7 are independently H or an amino acid side chain; AASC is an amino acid side chain; and q is 1, 2, 3 or 4. [0245] The cCPP of the general Formula (IA) can have any configuration and/or amino acid side chain as described in the published PCT application NO. US2020/066459 (WO2021127650A1) or US Patent No.11,225,506. [0246] In embodiments, the cCPP may be of the general Formula (IA) or a protonated form thereof, wherein: R1, R2, and R3 are each independently H or an aromatic or heteroaromatic side chain of an amino acid; at least one of R₁, R₂, and R₃ is an aromatic or heteroaromatic side chain of an amino acid; R4, R5, R6, and R7 are independently H or an amino acid side chain; at least one of R₄, R₅, R₆, and R₇ is the side chain of 3-guanidino-2-aminopropionic acid, 4-guanidino-2-aminobutanoic acid, arginine, homoarginine, N-methylarginine, N,N- dimethylarginine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, lysine, N-methyllysine, N,N-dimethyllysine, N-ethyllysine, N,N,N-trimethyllysine, 4-guanidinophenylalanine, citrulline, N,N-dimethyllysine, β-homoarginine, 3-(1-piperidinyl)alanine; AASC is an amino acid side chain; and q is 1, 2, 3 or 4. [0247] In embodiments, the cCPP may be Formula (IA) where at least one of R₄, R₅, R₆, and R₇ are independently an uncharged, non-aromatic side chain of an amino acid. In embodiments, at least one of R4, R5, R6, and R7 are independently H or a side chain of citrulline. [0248] In embodiments, compounds are provided that include a cyclic peptide having 6 to 12 amino acids, wherein at least two amino acids of the cyclic peptide are charged amino acids, at least two amino acids of the cyclic peptide are aromatic hydrophobic amino acids and at least two amino acids of the cyclic peptide are uncharged, non-aromatic amino acids. In embodiments, at least two charged amino acids of the cyclic peptide are arginine. In embodiments, at least two aromatic, hydrophobic amino acids of the cyclic peptide are phenylalanine, naphtha alanine (3- Naphth-2-yl-alanine) or a combination thereof. In embodiments, at least two uncharged, non- aromatic amino acids of the cyclic peptide are citrulline, glycine or a combination thereof. In embodiments, the compound is a cyclic peptide having 6 to 12 amino acids wherein two amino acids of the cyclic peptide are arginine, at least two amino acids are aromatic, hydrophobic amino acids selected from phenylalanine, naphtha alanine and combinations thereof, and at least two amino acids are uncharged, non-aromatic amino acids selected from citrulline, glycine and combinations thereof. [0249] The cCPP of general Formula (IA) can comprise the general Formula (I):

or a protonated form thereof, wherein: R₁, R₂, and R₃ can each independently be H or an aromatic or heteroaromatic side chain of an amino acid; at least one of R1, R2, and R3 is an aromatic or heteroaromatic side chain of an amino acid; R₄ and R₆ are independently H or an amino acid side chain; AASC is an amino acid side chain; q is 1, 2, 3 or 4; and each m is independently 0 or an integer of 1, 2, or 3. [0250] In embodiments, the cCPP may be of Formula (IA) or (I) where R₁, R₂, and R₃ can each independently be H, -alkylene-aryl, or -alkylene-heteroaryl. R1, R2, and R3 can each independently be H, -C_1-3alkylene-aryl, or -C_1-3alkylene-heteroaryl. R₁, R₂, and R₃ can each independently be H or -alkylene-aryl. R₁, R₂, and R₃ can each independently be H or -C_1-3alkylene-aryl. C_1-3alkylene can be methylene. Aryl can be a 6- to 14-membered aryl. Heteroaryl can be a 6- to 14-membered heteroaryl having one or more heteroatoms selected from N, O, and S. Aryl can be selected from phenyl, naphthyl, or anthracenyl. Aryl can be phenyl or naphthyl. Aryl can be phenyl. Heteroaryl can be pyridyl, quinolyl, and isoquinolyl. R1, R2, and R3 can each independently be H, -C1- 3alkylene-Ph or -C1-3alkylene-Naphthyl. R1, R2, and R3 can each independently be H, -CH2Ph, or -CH₂Naphthyl. R₁, R₂, and R₃ can each independently be H or -CH₂Ph. [0251] In embodiments, the cCPP may be of Formula (I) or (IA) where R1, R2, and R3 can each independently be the side chain of phenylalanine, 1-naphthylalanine, 2-naphthylalanine, tryptophan, 3-benzothienylalanine, 4-phenylphenylalanine, 3,4-difluorophenylalanine, 4- trifluoromethylphenylalanine, 2,3,4,5,6-pentafluorophenylalanine, homophenylalanine, β- homophenylalanine, 4-tert-butyl-phenylalanine, 4-pyridinylalanine, 3-pyridinylalanine, 4- methylphenylalanine, 4-fluorophenylalanine, 4-chlorophenylalanine, 3-(9-anthryl)-alanine. [0252] In embodiments, the cCPP may be of Formula (I) or (IA) where R₁ can be the side chain of phenylalanine. R1 can be the side chain of 1-naphthylalanine. R1 can be the side chain of 2- naphthylalanine. R₁ can be the side chain of tryptophan. R₁ can be the side chain of 3- benzothienylalanine. R₁ can be the side chain of 4-phenylphenylalanine. R₁ can be the side chain of 3,4-difluorophenylalanine. R1 can be the side chain of 4-trifluoromethylphenylalanine. R1 can be the side chain of 2,3,4,5,6-pentafluorophenylalanine. R1 can be the side chain of homophenylalanine. R₁ can be the side chain of β-homophenylalanine. R₁ can be the side chain of 4-tert-butyl-phenylalanine. R1 can be the side chain of 4-pyridinylalanine. R1 can be the side chain of 3-pyridinylalanine. R1 can be the side chain of 4-methylphenylalanine. R1 can be the side chain of 4-fluorophenylalanine. R₁ can be the side chain of 4-chlorophenylalanine. R₁ can be the side chain of 3-(9-anthryl)-alanine. [0253] In embodiments, the cCPP may be of Formula (I) or (IA) where R2 can be the side chain of phenylalanine. R₂ can be the side chain of 1-naphthylalanine. R₁ can be the side chain of 2- naphthylalanine. R₂ can be the side chain of tryptophan. R₂ can be the side chain of 3- benzothienylalanine. R2 can be the side chain of 4-phenylphenylalanine. R2 can be the side chain of 3,4-difluorophenylalanine. R2 can be the side chain of 4-trifluoromethylphenylalanine. R2 can be the side chain of 2,3,4,5,6-pentafluorophenylalanine. R₂ can be the side chain of homophenylalanine. R2 can be the side chain of β-homophenylalanine. R2 can be the side chain of 4-tert-butyl-phenylalanine. R2 can be the side chain of 4-pyridinylalanine. R2 can be the side chain of 3-pyridinylalanine. R₂ can be the side chain of 4-methylphenylalanine. R₂ can be the side chain of 4-fluorophenylalanine. R₂ can be the side chain of 4-chlorophenylalanine. R₂ can be the side chain of 3-(9-anthryl)-alanine. [0254] In embodiments, the cCPP may be of Formula (I) or (IA) where R₃ can be the side chain of phenylalanine. R₃ can be the side chain of 1-naphthylalanine. R₃ can be the side chain of 2- naphthylalanine. R3 can be the side chain of tryptophan. R3 can be the side chain of 3- benzothienylalanine. R3 can be the side chain of 4-phenylphenylalanine. R3 can be the side chain of 3,4-difluorophenylalanine. R3 can be the side chain of 4-trifluoromethylphenylalanine. R3 can be the side chain of 2,3,4,5,6-pentafluorophenylalanine. R₃ can be the side chain of homophenylalanine. R3 can be the side chain of β-homophenylalanine. R3 can be the side chain of 4-tert-butyl-phenylalanine. R3 can be the side chain of 4-pyridinylalanine. R3 can be the side chain of 3-pyridinylalanine. R₃ can be the side chain of 4-methylphenylalanine. R₃ can be the side chain of 4-fluorophenylalanine. R₃ can be the side chain of 4-chlorophenylalanine. R₃ can be the side chain of 3-(9-anthryl)-alanine. [0255] In embodiments, the cCPP may be of Formula (I) or (IA) where R₄ can be H, -alkylene- aryl, -alkylene-heteroaryl. R₄ can be H, -C_1-3alkylene-aryl, or -C_1-3alkylene-heteroaryl. R₄ can be H or -alkylene-aryl. R4 can be H or -C1-3alkylene-aryl. C1-3alkylene can be a methylene. Aryl can be a 6- to 14-membered aryl. Heteroaryl can be a 6- to 14-membered heteroaryl having one or more heteroatoms selected from N, O, and S. Aryl can be selected from phenyl, naphthyl, or anthracenyl. Aryl can be phenyl or naphthyl. Aryl can phenyl. Heteroaryl can be pyridyl, quinolyl, and isoquinolyl. R4 can be H, -C1-3alkylene-Ph or -C1-3alkylene-Naphthyl. R4 can be H or the side chain of an amino acid in Table 8. R₄ can be H or an amino acid residue having a side chain comprising an aromatic group. R₄ can be H, -CH₂Ph, or -CH₂Naphthyl. R₄ can be H or -CH₂Ph. [0256] In embodiments, the cCPP may be of Formula (IA) where R5 can be H, -alkylene-aryl, - alkylene-heteroaryl. R₅ can be H, -C_1-3alkylene-aryl, or -C_1-3alkylene-heteroaryl. R₅ can be H or - alkylene-aryl. R₅ can be H or -C_1-3alkylene-aryl. C_1-3alkylene can be a methylene. Aryl can be a 6- to 14-membered aryl. Heteroaryl can be a 6- to 14-membered heteroaryl having one or more heteroatoms selected from N, O, and S. Aryl can be selected from phenyl, naphthyl, or anthracenyl. Aryl can be phenyl or naphthyl. Aryl can phenyl. Heteroaryl can be pyridyl, quinolyl, and isoquinolyl. R5 can be H, -C1-3alkylene-Ph or -C1-3alkylene-Naphthyl. R5 can be H or the side chain of an amino acid in Table 8 or. R4 can be H or an amino acid residue having a side chain comprising an aromatic group. R₅ can be H, -CH₂Ph, or -CH₂Naphthyl. R₄ can be H or -CH₂Ph. [0257] In embodiments, the cCPP may be of Formula (I) or (IA) where R₆ can be H, -alkylene- aryl, -alkylene-heteroaryl. R6 can be H, -C1-3alkylene-aryl, or -C1-3alkylene-heteroaryl. R6 can be H or -alkylene-aryl. R₆ can be H or -C_1-3alkylene-aryl. C_1-3alkylene can be a methylene. Aryl can be a 6- to 14-membered aryl. Heteroaryl can be a 6- to 14-membered heteroaryl having one or more heteroatoms selected from N, O, and S. Aryl can be selected from phenyl, naphthyl, or anthracenyl. Aryl can be phenyl or naphthyl. Aryl can phenyl. Heteroaryl can be pyridyl, quinolyl, and isoquinolyl. R6 can be H, -C1-3alkylene-Ph or -C1-3alkylene-Naphthyl. R6 can be H or the side chain of an amino acid in Table 8 or. R₆ can be H or an amino acid residue having a side chain comprising an aromatic group. R6 can be H, -CH2Ph, or -CH2Naphthyl. R6 can be H or -CH2Ph. [0258] In embodiments, the cCPP may be of Formula (IA) where R7 can be H, -alkylene-aryl, - alkylene-heteroaryl. R₇ can be H, -C_1-3alkylene-aryl, or -C_1-3alkylene-heteroaryl. R₇ can be H or - alkylene-aryl. R₇ can be H or -C_1-3alkylene-aryl. C_1-3alkylene can be a methylene. Aryl can be a 6- to 14-membered aryl. Heteroaryl can be a 6- to 14-membered heteroaryl having one or more heteroatoms selected from N, O, and S. Aryl can be selected from phenyl, naphthyl, or anthracenyl. Aryl can be phenyl or naphthyl. Aryl can phenyl. Heteroaryl can be pyridyl, quinolyl, and isoquinolyl. R7 can be H, -C1-3alkylene-Ph or -C1-3alkylene-Naphthyl. R7 can be H or the side chain of an amino acid in Table 8 or. R7 can be H or an amino acid residue having a side chain comprising an aromatic group. R₇ can be H, -CH₂Ph, or -CH₂Naphthyl. R₇ can be H or -CH₂Ph. [0259] In embodiments, the cCPP may be of Formula (I) or (IA) where one, two or three of R1, R2, R3, R4, R5, R6, and R7 can be -CH2Ph. One of R1, R2, R3, R4, R5, R6, and R7 can be -CH2Ph. Two of R₁, R₂, R₃, R₄, R₅, R₆, and R₇ can be -CH₂Ph. Three of R₁, R₂, R₃, R₄, R₅, R₆, and R₇ can be -CH₂Ph. At least one of R₁, R₂, R₃, R₄, R₅, R₆, and R₇ can be -CH₂Ph. No more than four of R₁, R2, R3, R4, R5, R6, and R7 can be -CH2Ph. [0260] In embodiments, the cCPP may be of Formula (I) or (IA) where one, two or three of R₁, R₂, R₃, and R₄ are -CH₂Ph. One of R₁, R₂, R₃, and R₄ is -CH₂Ph. Two of R₁, R₂, R₃, and R₄ are - CH2Ph. Three of R1, R2, R3, and R4 are -CH2Ph. At least one of R1, R2, R3, and R4 is -CH2Ph. [0261] In embodiments, the cCPP may be of Formula (I) where one, two or three of R1, R2, R3, R₄, R₅, R₆, and R₇ can be H. One of R₁, R₂, R₃, R₄, R₅, R₆, and R₇ can be H. Two of R₁, R₂, R₃, R₄, R5, R6, and R7 are H. Three of R1, R2, R3, R5, R6, and R7 can be H. At least one of R1, R2, R3, R4, R5, R6, and R7 can be H. No more than three of R1, R2, R3, R4, R5, R6, and R7 can be -CH2Ph. [0262] In embodiments, the cCPP may be of Formula (I) or (IA) where one, two or three of R₁, R₂, R₃, and R₄ are H. One of R₁, R₂, R₃, and R₄ is H. Two of R₁, R₂, R₃, and R₄ are H. Three of R₁, R2, R3, and R4 are H. At least one of R1, R2, R3, and R4 is H. [0263] In embodiments, the cCPP may be of Formula (I) or (IA) where at least one of R₄, R₅, R₆, and R₇ can be side chain of 3-guanidino-2-aminopropionic acid. At least one of R₄, R₅, R₆, and R₇ can be side chain of 4-guanidino-2-aminobutanoic acid. At least one of R4, R5, R6, and R7 can be side chain of arginine. At least one of R4, R5, R6, and R7 can be side chain of homoarginine. At least one of R4, R5, R6, and R7 can be side chain of N-methylarginine. At least one of R4, R5, R6, and R₇ can be side chain of N,N-dimethylarginine. At least one of R₄, R₅, R₆, and R₇ can be side chain of 2,3-diaminopropionic acid. At least one of R4, R5, R6, and R7 can be side chain of 2,4- diaminobutanoic acid, lysine. At least one of R4, R5, R6, and R7 can be side chain of N- methyllysine. At least one of R₄, R₅, R₆, and R₇ can be side chain of N,N-dimethyllysine. At least one of R₄, R₅, R₆, and R₇ can be side chain of N-ethyllysine. At least one of R₄, R₅, R₆, and R₇ can be side chain of N,N,N-trimethyllysine, 4-guanidinophenylalanine. At least one of R4, R5, R6, and R₇ can be side chain of citrulline. At least one of R₄, R₅, R₆, and R₇ can be side chain of N,N- dimethyllysine, , β-homoarginine. At least one of R₄, R₅, R₆, and R₇ can be side chain of 3-(1- piperidinyl)alanine. [0264] In embodiments, the cCPP may be of Formula (I) where at least two of R4, R5, R6, and R7 can be side chain of 3-guanidino-2-aminopropionic acid. At least two of R₄, R₅, R₆, and R₇ can be side chain of 4-guanidino-2-aminobutanoic acid. At least two of R4, R5, R6, and R7 can be side chain of arginine. At least two of R4, R5, R6, and R7 can be side chain of homoarginine. At least two of R₄, R₅, R₆, and R₇ can be side chain of N-methylarginine. At least two of R₄, R₅, R₆, and R₇ can be side chain of N,N-dimethylarginine. At least two of R₄, R₅, R₆, and R₇ can be side chain of 2,3-diaminopropionic acid. At least two of R4, R5, R6, and R7 can be side chain of 2,4- diaminobutanoic acid, lysine. At least two of R₄, R₅, R₆, and R₇ can be side chain of N- methyllysine. At least two of R₄, R₅, R₆, and R₇ can be side chain of N,N-dimethyllysine. At least two of R4, R5, R6, and R7 can be side chain of N-ethyllysine. At least two of R4, R5, R6, and R7 can be side chain of N,N,N-trimethyllysine, 4-guanidinophenylalanine. At least two of R4, R5, R6, and R₇ can be side chain of citrulline. At least two of R₄, R₅, R₆, and R₇ can be side chain of N,N- dimethyllysine, β-homoarginine. At least two of R4, R5, R6, and R7 can be side chain of 3-(1- piperidinyl)alanine. [0265] In embodiments, the cCPP may be of Formula (I) where at least three of R₄, R₅, R₆, and R₇ can be side chain of 3-guanidino-2-aminopropionic acid. At least three of R₄, R₅, R₆, and R₇ can be side chain of 4-guanidino-2-aminobutanoic acid. At least three of R4, R5, R6, and R7 can be side chain of arginine. At least three of R₄, R₅, R₆, and R₇ can be side chain of homoarginine. At least three of R₄, R₅, R₆, and R₇ can be side chain of N-methylarginine. At least three of R₄, R₅, R₆, and R7 can be side chain of N,N-dimethylarginine. At least three of R4, R5, R6, and R7 can be side chain of 2,3-diaminopropionic acid. At least three of R4, R5, R6, and R7 can be side chain of 2,4- diaminobutanoic acid, lysine. At least three of R4, R5, R6, and R7 can be side chain of N- methyllysine. At least three of R₄, R₅, R₆, and R₇ can be side chain of N,N-dimethyllysine. At least three of R4, R5, R6, and R7 can be side chain of N-ethyllysine. At least three of R4, R5, R6, and R7 can be side chain of N,N,N-trimethyllysine, 4-guanidinophenylalanine. At least three of R4, R5, R₆, and R₇ can be side chain of citrulline. At least three of R₄, R₅, R₆, and R₇ can be side chain of N,N-dimethyllysine, β-homoarginine. At least three of R₄, R₅, R₆, and R₇ can be side chain of 3- (1-piperidinyl)alanine. [0266] AA_SC of general Formula (IA) and (I) can be a side chain of a residue of asparagine, glutamine, or homoglutamine. AA_SC can be a side chain of a residue of glutamine. The cCPP can further comprise a linker conjugated the AASC, e.g., the residue of asparagine, glutamine, or homoglutamine. Hence, the cCPP can further comprise a linker conjugated to the asparagine, glutamine, or homoglutamine residue. The cCPP can further comprise a linker conjugated to the glutamine residue. [0267] In embodiments, the cCPP may be of Formula (I) where q can be 1, 2, or 3. q can be 1 or 2. q can be 1. q can be 2. q can be 3. q can be 4. [0268] In embodiments, the cCPP may be of Formula (I) where m can be 1, 2, or3. m can be 1 or 2. m can be 0. m can be 1. m can be 2. m can be 3. [0269] The cCPP of Formula (IA) or (I) can comprise Formula (I-a) or Formula (I-b):

, or protonated form thereof, wherein AASC , R1, R2, R3, R4, and m are as defined herein relative to Formula (IA) and/or Formula (I). [0270] The cCPP of Formula (IA) or (I) can comprise the structures of (I-1), (I-2), (I-3), (I-4), (I- 5), (I-6) or (I-7): ,

, or a protonated form thereof, wherein AA_SC and

m are as defined herein relative to Formula (IA) and/or Formula (I). [0271] In embodiments, the cCPP of the general Formula (IA) is of general Formula (IX):

at least two of R1, R2, R3, R4, R5, R6, or R7 are independently the side chain of lysine, mono- methyl lysine, dimethyl lysine, trimethyl lysine, 2,4-diaminobutanoic acid, or 2,3- diaminopropionic acid; R1, R2, R3, R4, R5, R6, R7 are independently H or an amino acid side chain; AASC is an amino acid side chain; and q is 1, 2, 3 or 4. [0272] In embodiments, the CPP is of the general Formula (IX), wherein at least two of R₄, R₅, R6, or R7 are independently the amino acid side chain of lysine, mono-methyl lysine, dimethyl lysine, trimethyl lysine, 2,4-diaminobutanoic acid, or 2,3-diaminopropionic acid. [0273] In embodiments, the CPP is of the general Formula (IX), wherein at least three of R₄, R₅, R6, or R7 are independently the amino acid side chain of lysine, mono-methyl lysine, dimethyl lysine, or trimethyl lysine. [0274] In embodiments, the CPP is of the general Formula (IX), wherein R₄, R₅, R₆, R₇ are independently the amino acid side chain of lysine, mono-methyl lysine, dimethyl lysine, trimethyl lysine, 2,4-diaminobutanoic acid, or 2,3-diaminopropionic acid. [0275] In embodiments, the CPP is of the general Formula (IX), wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, or R₇ is H. [0276] In embodiments, the CPP is of the general Formula (IX), wherein at least one of R1, R2, or R₃ is H. In embodiments, the CPP is of the general Formula (IX), wherein at least one of R₄, R₅, R₆, or R₇ is H. In embodiments, the CPP is of the general Formula (IX), wherein at least two of R1, R2, R3, R4, R5, R6, or R7 are independently H. In embodiments, the CPP is of the general Formula (IX), wherein at least one of R1, R2, or R3 is H; and at least one of R4, R5, R6, or R7 is H. [0277] In embodiments, the CPP is of the general Formula (IX), wherein at least one of R1, R2, R3, R4, R5, R6, or R7 is an aromatic or heteroaromatic side chain of an amino acid. In embodiments, the CPP is of the general Formula (IX), wherein at least one of R₁, R₂, R₃, is an aromatic or heteroaromatic side chain of an amino acid. In embodiments, the CPP is of the general Formula (IX), wherein at least two of R1, R2, R3, are independently an aromatic or heteroaromatic side chain of an amino acid. [0278] In embodiments, the CPP of the general Formula (IX) is of the general formula IX(1),

or a protonated form thereof, wherein: R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are independently H or the side chain of an amino acid; at least two of R₄, R₅, R₆, or R₇ are independently the side chain of lysine, mono-methyl lysine, dimethyl lysine, trimethyl lysine, 2,4-diaminobutanoic acid, or 2,3- diaminopropionic acid; R₂ is H or an amino acid side chain; AASC is an amino acid side chain; and q is 1, 2, 3 or 4. [0279] In embodiments, the CPP is of the general Formula IX(1), wherein, R₁, R₃, or both have S stereochemistry. [0280] In embodiments, the CPP is of the general Formula IX(1), wherein R2 is H. [0281] In embodiments, the CPP is of the general Formula IX(1), wherein at least two of R₄, R₅, R₆, or R₇ are independently the amino acid side chain of lysine, mono-methyl lysine, dimethyl lysine, trimethyl lysine, 2,4-diaminobutanoic acid, or 2,3-diaminopropionic acid. [0282] In embodiments, the CPP is of the general Formula IX(1), wherein at least three of R4, R5, R6, or R7 are independently the amino acid side chain of lysine, mono-methyl lysine, dimethyl lysine, trimethyl lysine, 2,4-diaminobutanoic acid, or 2,3-diaminopropionic acid. [0283] In embodiments, the CPP is of the general Formula IX(1), wherein at least R5 and R7 are independently the side chain of lysine, mono-methyl lysine, dimethyl lysine, trimethyl lysine, 2,4- diaminobutanoic acid, or 2,3-diaminopropionic acid. [0284] In embodiments, the CPP is of the general Formula IX(1), wherein; R₂ is H; q is one; and at least R5 and R7 are independently the side chain of lysine, mono-methyl lysine, dimethyl lysine, trimethyl lysine, 2,4-diaminobutanoic acid, or 2,3-diaminopropionic acid. [0285] The AA_sc of Formula IX or IX(1) may be any AA_sc as described relative to Formula IA. AASC can be conjugated to a linker. [0286] In embodiments, the cCPP of Formula (IA), (IX), (IX(1), has the structure of IX(a), IX(b), IX(c), or a protonated form thereof:

[0287] In embodiments, the CPP of general Formula (IA), (IX), or IX(1) may comprise one of the sequences: FGFGKGK; FGFKKKK; FGFK(me2)K(me2)K(me2)K(me2); FGFGKGKQ; FGFKKKKQ; or FGFK(me2)K(me2)K(me2)K(me2)Q (Kme2 is dimethyl lysine). [0288] The cCPP can comprise one of the following sequences: FGFGRGR; GfFGrGr, FfΦGRGR; FfFGRGR; or FfΦGrGr. The cCPP can have one of the following sequences: FGFGRGRQ; GfFGrGrQ, FfΦGRGRQ, FfFGRGRQ; FfΦGrGrQ; or FfFRrRrQ. [0289] The disclosure also relates to a cCPP having the general Formula (II):

wherein: AASC is an amino acid side chain; R^1a, R^1b, and R^1c are each independently a 6- to 14-membered aryl or a 6- to 14- membered heteroaryl; R^2a, R^2b, R^2c and R^2d are independently an amino acid side chain; at least one

,

, or a protonated form thereof; at least one of R^2a, R^2b, R^2c and R^2d is guanidine or a protonated form thereof; each n” is independently an integer 0, 1, 2, 3, 4, or 5; each n’ is independently an integer from 0, 1, 2, or3; and if n’ is 0 then R^2a, R^2b, R^2b or R^2d is absent. [0290] In embodiments, the cCPP is of Formula (II) where at least two of R^2a, R^2b, R^2c and R^2d can

, or a protonated form thereof. Two or three of R^2a, R^2b, R^2c and R^2d can be

,

protonated form thereof. One of R^2a, R^2b, R^2c and R^2d can

,

, R^2b, R^2c and R^2d can be , or a protonated form thereof, and the remaining of R^2a, R^2b, R^2c and R^2d can be guanidine or a protonated form thereof. At least two of R^2a, R^2b, R^2c and R^2d can be

, or a protonated form thereof, and the remaining of R^2a, R^2b, R^2c and R^2d can be guanidine, or a protonated form thereof. [0291] In embodiments, the cCPP is of Formula (II) where all of R^2a, R^2b, R^2c and R^2d can be

a protonated form thereof. At least of R^2a, R^2b, R^2c and R^2d can be

, or a protonated form thereof, and the remaining of R^2a, R^2b, R^2c and R^2d can be guanidine or a protonated form thereof. At least two R^2a, R^2b, R^2c and R^2d groups can be

, or a protonated form thereof, and the remaining of R^2a, R^2b, R^2c and R^2d are guanidine, or a protonated form thereof. [0292] In embodiments, the cCPP is of Formula (II) where each of R^2a, R^2b, R^2c and R^2d can independently be 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, the side chains of ornithine, lysine, methyllysine, dimethyllysine, trimethyllysine, homo-lysine, serine, homo-serine, threonine, allo-threonine, histidine, 1-methylhistidine, 2-aminobutanedioic acid, aspartic acid, glutamic acid, or homo-glutamic acid. [0293] In embodiments, the cCPP is of Formula (II) where AASC can be

, wherein t can be an integer from 0 to 5. AA_SC can be

, wherein t can be an integer from 0 to 5. t can be 1 to 5. t is 2 or 3. t can be 2. t can be 3. [0294] In embodiments, the cCPP is of Formula (II) where R^1a, R^1b, and R^1c can each independently be 6- to 14-membered aryl. R^1a, R^1b, and R^1c can be each independently a 6- to 14- membered heteroaryl having one or more heteroatoms selected from N, O, or S. R^1a, R^1b, and R^1c can each be independently selected from phenyl, naphthyl, anthracenyl, pyridyl, quinolyl, or isoquinolyl. R^1a, R^1b, and R^1c can each be independently selected from phenyl, naphthyl, or anthracenyl. R^1a, R^1b, and R^1c can each be independently phenyl or naphthyl. R^1a, R^1b, and R^1c can each be independently selected pyridyl, quinolyl, or isoquinolyl. [0295] In embodiments, the cCPP is of Formula (II) where each n’ can independently be 1 or 2. Each n’ can be 1. Each n’ can be 2. At least one n’ can be 0. At least one n’ can be 1. At least one n’ can be 2. At least one n’ can be 3. At least one n’ can be 4. At least one n’ can be 5. [0296] In embodiments, the cCPP is of Formula (II) where each n” can independently be an integer from 1 to 3. Each n” can independently be 2 or 3. Each n” can be 2. Each n” can be 3. At least one n” can be 0. At least one n” can be 1. At least one n” can be 2. At least one n” can be 3. [0297] In embodiments, the cCPP is of Formula (II) where each n” can independently be 1 or 2 and each n’ can independently be 2 or 3. Each n” can be 1 and each n’ can independently be 2 or 3. Each n” can be 1 and each n’ can be 2. Each n” is 1 and each n’ is 3. [0298] The cCPP of Formula (II) can be of Formula (II-1):

are as defined herein. [0299] The cCPP of Formula (II) can be of Formula (IIa):

’ are as defined herein. [0300] The cCPP of formula (II) can be of Formula (IIb):

wherein R^2a, R^2b, AASC, and n’ are as defined herein. [0301] The cCPP can be of Formula (II) can be of Formula (IIc):

, wherein: AA_SC and n’ are as defined herein. [0302] The cCPP can be of Formula (III):

wherein: AA_SC is an amino acid side chain; R^1a, R^1b, and R^1c are each independently a 6- to 14-membered aryl or a 6- to 14- membered heteroaryl;

,

, or a protonated form thereof; R^2b and R^2d are each independently guanidine or a protonated form thereof; each n” is independently an integer from 1 to 3; each n’ is independently an integer from 1 to 5; and each p’ is independently an integer from 0 to 5. [0303] The cCPP of Formula (III) can be of Formula (III-1):

wherein: AA_SC, R^1a, R^1b, R^1c, R^2a, R^2c, R^2b, R^2d n’, n”, and p’ are as defined herein. [0304] The cCPP of Formula (III) can be of Formula (IIIa):

wherein: AASC, R^2a, R^2c, R^2b, R^2d n’, n”, and p’ are as defined herein. [0305] In Formulas (III), (III-1), and (IIIa), R^a and R^c can be H. R^a and R^c can be H and R^b and R^d can each independently be guanidine or protonated form thereof. R^a can be H. R^b can be H. p’ can be 0. R^a and R^c can be H and each p’ can be 0. [0306] In Formulas (III), (III-1), and (IIIa), R^a and R^c can be H, R^b and R^d can each independently be guanidine or protonated form thereof, n” can be 2 or 3, and each p’ can be 0. [0307] p’ can 0. p’ can 1. p’ can 2. p’ can 3. p’ can 4. p’ can be 5. [0308] The cCPP can have the structure:

or a protonated from thereof wherein m is defined herein. [0309] The cCPP of Formula (IA) can be selected from:

[0310] The cCPP of Formula (IA) can be selected from:

[0311] In embodiments, the cCPP is selected from:

Where Φ = L-naphthylalanine; ϕ = D-naphthylalanine; Ω = L-norleucine [0312] The cCPP can comprise Formula (D)

or a protonated form thereof, wherein: R1, R2, and R3 can each independently be H or an amino acid residue having a side chain comprising an aromatic group; at least one of R1, R2, and R3 is an aromatic or heteroaromatic side chain of an amino acid; R₄ and R₆ are independently H or an amino acid side chain; AA_SC is an amino acid side chain;

q is 1, 2, 3 or 4; each m is independently an integer 0, 1, 2, or 3, and each n is independently an integer 0, 1, 2, or 3. [0313] The cCPP can comprise Formula (AV):

wherein: R1, R2, R3, R4, R5, R6, R7 are independently H or an amino acid side chain; at least two of R1, R2, and R3 are independently a side chain of phenylalanine, or naphthylalanine; at least two of R4, R5, R6, or R7 are independently a side chain of arginine; AASC is an amino acid side chain; and nx is 0 or 1 and at least one nx is 1; and q is 1, 2, 3 or 4. [0314] In embodiments, the cCPP is of Formula (AV), wherein only one n_x is 1. In embodiments, the cCCP is of Formula (AV), wherein the nx associated with R1 is 1; that is, the amino acid residue of R1 is a beta amino acid. [0315] In embodiments, the cCPP is of Formula (AV), wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇ are independently H or an amino acid side chain; at least two of R1, R2, and R3 are independently a side chain of phenylalanine, naphthylalanine; at least two of R₄, R₅, R₆, or R₇ are independently a side chain of arginine; AASC is an amino acid side chain; and each nx is 1 or 0; residue R1 is a beta-amino acid (i.e., n_x associated with R₁ is 1) and q is 1, 2, 3 or 4. [0316] In embodiments, the cCPP is of Formula (AV), wherein at least one of R1, R2, R3, R4, or R7 are a B-amino acid (i.e., at least one n_x is 1). In embodiments, at least one of R₁, R₂, R₃ is a side chain of B-hF. In embodiments, at least one of R₁, R₂, R₃ is a side chain of b-alanine. In embodiments, at least one of R4, or R7 is a side chain of B-alanine. In embodiments, at least one of R₄, or R₇ is a side chain of B-hF. [0317] In embodiments, the cCPP can be of the Formula (Y1):

or a protonated form thereof, wherein: at least one of R₁, R₂, R₃, R₄, R₅, R₆, or R₇ is the amino acid side chain of serine or histidine; R1, R2, R3, R4, R5, R6, R7 are independently H or an amino acid side chain; AA_SC is an amino acid side chain; nx is 0 or 1; and q is 1, 2, 3 or 4. [0318] In embodiments the cCPP is of Formula (Y1) where at least two of R₁, R₂, R₃, R₄, R₅, R₆, or R₇ is the amino acid side chain of serine or histidine. In embodiments the cCPP is of Formula (Y1) where at least three of R1, R2, R3, R4, R5, R6, or R7 is the amino acid side chain of serine or histidine. In embodiments the cCPP is of Formula (Y1) where at least four of R₁, R₂, R₃, R₄, R₅, R₆, or R₇ is the amino acid side chain of serine or histidine. [0319] The cCPP of Formula Y1 can comprise the general Formula (Y1’):

(Y1’), or a protonated form thereof, wherein: R1, R2, R3, R4, R5, R6, R7 are independently H or an amino acid side chain; at least two of R₁, R₂, and R₃ are independently a side chain of phenylalanine, or naphthylalanine; at least two of R4, R5, R6, or R7 are independently a side chain of arginine; at least two of R4, R5, R6, or R7 are independently a side chain of serine or histidine; AA_SC is an amino acid side chain; nx is 0 or 1; and q is 1, 2, 3 or 4. [0320] In embodimetns, the cCPP is of Fromula (Y1’), where three of R₄, R₅, R₆, or R₇ are independently a side chain of serine or histidine. [0321] In embodiments, the cCPP is of formula (Y1’), wherein q is 1. [0322] In embodiments, the cCPP be of the Formula (Y2):

or a protonated form thereof, wherein: R₁, R₂, R₃, R₄, R₅, R₆, R₇ are independently H or an amino acid side chain; AASC is an amino acid side chain; n_x is 1; and q is 1, 2, 3 or 4. [0323] The cCPP of Formula Y can be of the general Formula (Y2’): (Y2’) or a protonated form thereof,

wherein: R₁, R₂, R₃, R₄, R₅, R₆, R₇ are independently H or an amino acid side chain; at least two of R1, R2, and R3 are independently a side chain of phenylalanine or naphthylalanine; at least two of R₄, R₅, R₆, or R₇ are independently a side chain of arginine; AASC is an amino acid side chain; and nx is 1; and q is 1, 2, 3 or 4. [0324] In embodiments, the CPP is of Formula (Y2) or (Y2’) wherein: R1, R2, R3, R4, R5, R6, R7 are independently H or an amino acid side chain; at least two of R₁, R₂, and R₃ are independently a side chain of phenylalanine or naphthylalanine; at least two of R₄, R₅, R₆, or R₇ are independently a side chain of arginine; at least two of R4, R5, R6, or R7 are independently a side chain of an uncharged non-aryl amino acid selected from histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-thiazolyl)-alanine, 3-(4-furanyl)-alanine, and 3-(4- thienyl)-alanine; AASC is an amino acid side chain; n_x is 0 or 1; and q is 1, 2, 3 or 4. [0325] In embodiments, the CPP is of Formula (Y2) or (Y2’) wherein: R₁, R₂, R₃, R₄, R₅, R₆, R₇ are independently H or an amino acid side chain; at least two of R₁, R₂, and R₃ are independently a side chain of phenylalanine or naphthylalanine; at least two of R4, R5, R6, or R7 are independently a side chain of arginine; at least two of R₄, R₅, R₆, or R₇ are independently a side chain of serine or histidine; AA_SC is an amino acid side chain; nx is 0 or 1; and q is 1. [0326] In embodiments, the CPP is of Formula (Y2) or (Y2’) wherein: R1, R2, R3, R4, R5, R6, R7 are independently H or an amino acid side chain; at least two of R1, R2, and R3 are independently a side chain of phenylalanine, or naphthylalanine; at least two of R₄, R₅, R₆, or R₇ are independently a side chain of arginine. at least two of R₄, R₅, R₆, or R₇ are independently a side chain of histidine or serine; AASC is an amino acid side chain; n_x is 0 or 1; and q is 1. [0327] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y1’), (Y2), or (Y2’) wherein at least one of R1, R2, or R3 is H. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y1’), (Y2), or (Y2’), wherein at least one of R₁, R₂, or R₃ is a side chain of phenylalanine. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y1’), (Y2), or (Y2’), wherein at least two of R1, R2, or R3 are a side chain of naphthylalanine. [0328] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y1’), (Y2), or (Y2’), wherein q is 1. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y1’), (Y2), or (Y2’), wherein q is 1 and nx is 1 (at least one nx of Formula Y is 1). In embodiments, the CPP is of the general Formula (AV), (Y1), (Y1’), (Y2), or (Y2’), wherein q is 1 and n_x is 0 (all n_x of Formula Y is 1). [0329] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y1’), (Y2), or (Y2’), wherein at least two of R4, R5, R6, or R7 are independently a side chain of serine or histidine. [0330] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y1’), (Y2), or (Y2’), at least two of R4, R5, R6, or R7 are independently a side chain of arginine. [0331] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R₄, R₅, R₆, R₇ are independently an uncharged, non-aryl side chain of an amino acid. In embodiments, at least two of R₄, R₅, R₆, or R₇ are independently side chains of an uncharged non-aryl amino acid (e.g., histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-Thiazolyl)-alanine, 3-(4-furanyl)- alanine, and 3-(4-thienyl)-alanine). In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least two of R4, R5, R6, or R7 are independently side chains of an uncharged non-aryl amino acid selected from histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-Thiazolyl)-alanine, 3-(4- furanyl)-alanine, and 3-(4-thienyl)-alanine. [0332] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R₄, R₅, R₆, R₇ are independently H. [0333] In embodiments, compounds are provided that include a cyclic peptide having 6 to 12 amino acids, wherein at least two amino acids of the cyclic peptide are charged amino acids, at least two amino acids of the cyclic peptide are aromatic hydrophobic amino acids and at least two amino acids of the cyclic peptide are uncharged, non-aryl amino acids. In embodiments, at least two charged amino acids of the cyclic peptide are arginine. In embodiments, at least two aromatic, hydrophobic amino acids of the cyclic peptide are phenylalanine, naphthylalanine (3- naphth-2-yl-alanine) or a combination thereof. In embodiments, at least two uncharged, non-aryl amino acids of the cyclic peptide are glycine. In embodiments, two of the uncharged amino acids are serine, histidine or a combination thereof. [0334] Is embodiments, the CPP is of the general Formula (AV), (Y1), (Y1’), (Y2), or (Y2’), wherein at least one of R₄, R₅, R₆, or R₇ is the amino acid side chain of serine or histidine. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y1’), (Y2), or (Y2’), wherein at least two of R1, R2, R3, R4, R5, R6, or R7 are independently the amino acid side chain of serine or histidine. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y1’), (Y2), or (Y2’), wherein at least two of R₄, R₅, R₆, or R₇ are independently the amino acid side chain of serine or histidine. [0335] Is embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, or R₇ is the amino acid side chain of serine or histidine; and at least one of R1, R2, R3, R4, R5, R6, or R7 is H. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R1, R2, R3, R4, R5, R6, or R7 is the amino acid side chain of serine or histidine; and at least two of R₁, R₂, R₃, R₄, R₅, R₆, or R₇ are independently H. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R1, R2, R3, R4, R5, R6, or R7 is the amino acid side chain of serine or histidine; and at least two of R₂, R₄, and R₆ are independently H. [0336] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R1, R2, R3, R4, R5, R6, or R7 is the amino acid side chain of serine or histidine; and nx is 1. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least two of R₁, R₂, R₃, R₄, R₅, R₆, or R₇ are independently the amino acid side chain of serine or histidine; and nx is 1. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least two of R4, R5, R6, or R7 are independently the amino acid side chain of serine or histidine; and n_x is 1. [0337] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R1, R2, R3, R4, R5, R6, or R7 is the amino acid side chain of serine or histidine; and R1, R₂, and R₃ are independently H or an aromatic or heteroaromatic side chain of an amino acid. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R1, R2, R3, R4, R5, R6, or R7 is the amino acid side chain of serine or histidine; R1, R2, and R3 are independently H or an aromatic or heteroaromatic side chain of an amino acid; and at least one of R1, R2, and R3 is an aromatic or heteroaromatic side chain of an amino acid. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R₁, R₂, R₃, R4, R5, R6, or R7 is the amino acid side chain of serine or histidine; and R1, R2, and R3 are independently aromatic or heteroaromatic side chain of an amino acid. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, or R₇ is the amino acid side chain of serine or histidine; two of R₁, R₂, and R₃ are independently an aromatic or heteroaromatic side chain of an amino acid; and one of R1, R2, and R3 is H. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, or R₇ is the amino acid side chain of serine or histidine; and R₁, R₂, and R3 are independently an aromatic or heteroaromatic side chain of an amino acid. [0338] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, or R₇ is the amino acid side chain of serine or histidine; and at least one of R1, R2, R3, R4, R5, R6, or R7 is the side chain of 3-guanidino-2-aminopropionic acid, 4-guanidino-2-aminobutanoic acid, arginine, homoarginine, N-methylarginine, N,N- dimethylarginine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, lysine, N-methyllysine, N,N-dimethyllysine, N-ethyllysine,, N,N,N-trimethyllysine, 4-guanidinophenylalanine, citrulline, N,N-dimethyllysine, , β-homoarginine, 3-(1-piperidinyl)alanine. [0339] In embodiments, the CPP is of the general Formula (AV), (Y-1), (Y-2), or (Y-2’) wherein at least one of R₄, R₅, R₆, R₇ are independently H. [0340] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R4, R5, R6, R7 are independently an uncharged, non-aryl side chain of an amino acid. In embodiments, at least two of R₄, R₅, R₆, or R₇ are independently side chains of an uncharged non-aryl amino acid (e.g., histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-Thiazolyl)-alanine, 3-(4-furanyl)- alanine, and 3-(4-thienyl)-alanine). In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least two of R₄, R₅, R₆, or R₇ are independently side chains of an uncharged non-aryl amino acid selected from histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-Thiazolyl)-alanine, 3-(4- furanyl)-alanine, and 3-(4-thienyl)-alanine. [0341] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R1, R2, R3, R4, R5, R6, or R7 is the amino acid side chain of serine or histidine; and at least one of R₄, R₅, R₆, or R₇ is the side chain of 3-guanidino-2-aminopropionic acid, 4-guanidino- 2-aminobutanoic acid, arginine, homoarginine, N-methylarginine, N,N-dimethylarginine, 2,3- diaminopropionic acid, 2,4-diaminobutanoic acid, lysine, N-methyllysine, N,N-dimethyllysine, N- ethyllysine,, N,N,N-trimethyllysine, 4-guanidinophenylalanine, citrulline, N,N-dimethyllysine, , β-homoarginine, 3-(1-piperidinyl)alanine. In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least one of R4, R5, R6, or R7 is the amino acid side chain of serine; and at least one of R₄, R₅, R₆, or R₇ is the side chain of 3-guanidino-2-aminopropionic acid, 4-guanidino-2-aminobutanoic acid, arginine, homoarginine, N-methylarginine, N,N- dimethylarginine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, lysine, N-methyllysine, N,N-dimethyllysine, N-ethyllysine,, N,N,N-trimethyllysine, 4-guanidinophenylalanine, citrulline, N,N-dimethyllysine, β-homoarginine, 3-(1-piperidinyl)alanine. [0342] In embodiments, the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’) wherein at least one of R4, R5, R6, R7 are independently an uncharged, non-aryl side chain of an amino acid. In embodiments the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least two of R₄, R₅, R₆, or R₇ are independently side chains of an uncharged non-aryl amino acid. In embodiments the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), wherein at least two of R₄, R₅, R₆, or R₇ are independently side chains of an uncharged non-aryl amino acid selected from histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-Thiazolyl)-alanine, 3-(4-furanyl)-alanine, and 3-(4-thienyl)- alanine. In embodiments the CPP is of the general Formula (AV), (Y1), (Y2), or (Y2’), at least two of R₄, R₅, R₆, or R₇ are independently side chains of an uncharged non-aryl amino acid selected from serine or histidine. [0343] The cCPP can comprise Formula (Y2), (Y2’), or a protonated form thereof, wherein: R₁, R₂, R₃, R₄, R₅, R₆, R₇ are independently H or an amino acid side chain; at least two of R1, R2, and R3 are independently a side chain of phenylalanine or naphthylalanine; at least two of R₄, R₅, R₆, or R₇ are independently a side chain of arginine; AASC is an amino acid side chain; and nx is 1; and q is 1, 2, 3 or 4. [0344] The cCPP may be Formula (Y-2) or a protonated form thereof, wherein: R1, R2, R3, R4, R5, R6, R7 are independently H or an amino acid side chain; at least two of R₁, R₂, or R₃ are independently a side chain of an aromatic hydrophobic amino acid, at least two of R4, R5, R6, or R7 are independently a side chain of an amino acid comprising a guanidium group; at least two of R₄, R₅, R₆, or R₇ are independently an uncharged non-aryl amino acid side chain; AASC is an amino acid side chain; n_x is 1; and q is 1, 2, 3 or 4. [0345] In embodiments, the CPP is of the general Formula (Y2) or (Y2’), wherein: R1, R2, R3, R4, R₅, R₆, R₇ are independently H or an amino acid side chain; at least two of R₁, R₂, and R₃ are independently a side chain of phenylalanine, or naphthylalanine; at least two of R₄, R₅, R₆, or R₇ are independently a side chain of arginine; at least two of R4, R5, R6, or R7 are independently a side chain of an uncharged non-aryl amino acid selected from histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-thiazolyl)-alanine, 3-(4-furanyl)-alanine, and 3-(4-thienyl)-alanine;AASC is an amino acid side chain; nx is 1; and q is 1, 2, 3 or 4. In some such embodiments, q is 1. [0346] In embodiments, the CPP is of the structure (AA(a)) or (AA(b))

[0347] In embodiments, the CPP of general Formula (AV) may comprise one of the following sequences: FGFGHGH; FGFSHSH; FGFGHGHQ; or FGFSHSHQ. [0348] The cCPP of Formula Y1 or Y2 can comprise Formula (Y-a):

or a protonated form thereof, wherein: R₁, R₂, and R₃ can each independently be H or an amino acid residue having a side chain comprising an aromatic or heteroaromatic group; at least two of R1, R2, and R3 is an aromatic or heteroaromatic side chain of an amino acid; R₄ and R₆ are independently H or an amino acid side chain; AASC is an amino acid side chain; q is 1, 2, 3 or 4; n_x is 0 or 1 (according to Formula Y1) or n_x is 1 (according to Formula Y2); and each m is independently an integer of 0, 1, 2, or 3. [0349] In embodiments the CPP is of the general Formula (Y-a), wherein R4 and R6 are independently H or the side chain of serine or histidine. In embodiments the CPP is of the general Formula (Y-a), wherein R4 and R6 are independently H or the side chain of serine or histidine and nx is 1. In embodiments the CPP is of the general Formula (Y-a), wherein R4 and R6 are independently H or the side chain of serine or histidine; n_x is 1; and q is 0 (according to Formula Y1 or Y2). In embodiments the CPP is of the general Formula (Y-a) wherein, R₄ and R₆ are independently H or the side chain of serine or histidine and nx is 0 (according to Formula Y1). In embodiments the CPP is of the general Formula (Y-a) wherein, R₄ and R₆ are independently H or the side chain of serine or histidine; n_x is 0; and q is 1 (according to Formula Y1). [0350] In embodiments, the CPP is of the general Formula (Y-a), wherein R1, R2, and R3 can each independently be H, -alkylene-aryl, or -alkylene-heteroaryl. R1, R2, and R3 can each independently be H, -C_1-3alkylene-aryl, or -C_1-3alkylene-heteroaryl. R₁, R₂, and R₃ can each independently be H or -alkylene-aryl. R1, R2, and R3 can each independently be H or -C1-3alkylene-aryl. C1-3alkylene can be methylene. Aryl can be a 6- to 14-membered aryl. Heteroaryl can be a 6- to 14-membered heteroaryl having one or more heteroatoms selected from N, O, and S. Aryl can be selected from phenyl, naphthyl, or anthracenyl. Aryl can be phenyl or naphthyl. Aryl can be phenyl. Heteroaryl can be pyridyl, quinolyl, and isoquinolyl. R1, R2, and R3 can each independently be H, -C1- ₃alkylene-Ph or -C_1-3alkylene-Naphthyl. R₁, R₂, and R₃ can each independently be H, -CH₂Ph, or -CH₂-naphthyl. R₁, R₂, and R₃ can each independently be H or -CH₂Ph. [0351] In embodiments, the CPP is of the general Formula (Y-a),wherein R1, R2, and R3 can each independently be the side chain of phenylalanine, 1-naphthylalanine, 2-naphthylalanine, tryptophan, 3-benzothienylalanine, 4-phenylphenylalanine, 3,4-difluorophenylalanine, 4- trifluoromethylphenylalanine, 2,3,4,5,6-pentafluorophenylalanine, homophenylalanine, β- homophenylalanine, 4-tert-butyl-phenylalanine, 4-pyridinylalanine, 3-pyridinylalanine, 4- methylphenylalanine, 4-fluorophenylalanine, 4-chlorophenylalanine, 3-(9-anthryl)-alanine. [0352] In embodiments, the CPP is of the general Formula (Y-a), wherein R₁ and R₂ can be side chains of phenylalanine and R3 can be a side chain of 2-naphthylalanine. [0353] In embodiments, the CPP is of the general Formula (Y-a) wherein R₄ can be H. R₄ can be H or the side chain of an amino acid in Table 8. R₄ can be a residue of an uncharged non-aryl amino acid. In embodiments, R4 is a side chain of an uncharged non-aryl amino acid selected from histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-thiazolyl)-alanine, 3-(4-furanyl)-alanine, and 3-(4-thienyl)-alanine. R4 can be a side chain of serine. R₄ can be a side chain of histidine. [0354] In embodiments, the CPP is of the general Formula (Y-a) wherein R6 can be H or the side chain of an amino acid in Table 8. R6 can be a residue of an uncharged non-aryl amino acid. In embodiments, R₆ is a side chain of an uncharged non-aryl amino acid selected from histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-thiazolyl)-alanine, 3-(4-furanyl)-alanine, and 3-(4-thienyl)-alanine. R6 can be a side chain of serine. R₆ can be a side chain of histidine. [0355] In embodiments, the CPP is of the general Formula (Y-a)wherein one, two or three of R₁, R2, R3, R4, R5, and R6 can be -CH2Ph. One of R1, R2, R3, R4, R5, R6, and R7 can be -CH2Ph. Two of R1, R2, R3, R4, R5, and R6 can be -CH2Ph. Three of R1, R2, R3, R4, R5, R6, and R7 can be -CH2Ph. At least one of R₁, R₂, R₃, R₄, R₅, and R₆ can be -CH₂Ph. No more than four of R₁, R₂, R₃, R₄, R₅, R6, and R7 can be -CH2Ph. [0356] In embodiments, the CPP is of the general Formula (Y-a) wherein ne, two or three of R1, R₂, R₃, and R₄ are -CH₂Ph. One of R₁, R₂, R₃, and R₄ is -CH₂Ph. Two of R₁, R₂, R₃, and R₄ are - CH₂Ph. Three of R₁, R₂, R₃, and R₄ are -CH₂Ph. At least one of R₁, R₂, R₃, and R₄ is -CH₂Ph. [0357] In embodiments, the CPP is of the general Formula (Y-a) wherein one, two or three of R1, R₂, R₃, R₄, R₅, and R₆ can be H. One of R₁, R₂, R₃, R₄, R₅, and R₆, can be H. Two of R₁, R₂, R₃, R₄, R₅, and R₆ are H. Three of R₁, R₂, R₃, R₅, and R₆ can be H. At least one of R₁, R₂, R₃, R₄, R₅, and R6 can be H. No more than three of R1, R2, R3, R4, R5, and R6 can be -CH2Ph. [0358] In embodiments, the CPP is of the general Formula (Y-a)wherein one, two or three of R1, R₂, R₃, and R₄ are H. One of R₁, R₂, R₃, and R₄ is H. Two of R₁, R₂, R₃, and R₄ are H. Three of R1, R2, R3, and R4 are H. At least one of R1, R2, R3, and R4 is H. [0359] In embodiments, the CPP is of the general Formula (Y-a), wherein AASC can be a side chain of a residue of asparagine, glutamine, or homoglutamine. AA_SC can be a side chain of a residue of glutamine. The cCPP can further comprise a linker conjugated the AA_SC, e.g., the residue of asparagine, glutamine, or homoglutamine. Hence, the cCPP can further comprise a linker conjugated to the asparagine, glutamine, or homoglutamine residue. The cCPP can further comprise a linker conjugated to the glutamine residue. [0360] In embodiments, the CPP is of the general Formula (Y-a) wherein q can be 1, 2, or 3. q can 1 or 2. q can be 1. q can be 2. q can be 3. q can be 4. [0361] In embodiments, the CPP is of the general Formula (Y-a) wherein m can be 1-3. m can be 1 or 2. m can be 0. m can be 1. m can be 2. m can be 3. [0362] In embodiments, the CPP is of the general Formula (Y-a) wherein nx can be 0. nx can be 1. [0363] In embodiments, the CPP is of Formula (Y-a), wherein: R₁, R₂, and R₃ can each independently be H or an amino acid residue having a side chain comprising an aromatic or heteroaromatic group; at least two of R₁, R₂, and R₃ is an aromatic or heteroaromatic side chain of an amino acid; R₄ and R₆ are independently H or side chain of serine or histidine; AASC is an amino acid side chain; q is 1, 2, 3 or 4; n_x is 1; and each m is independently an integer 0, 1, 2, or 3. [0364] In embodiments, the CPP is of Formula (Y-a), wherein R₁, R₂, and R₃ can each independently be H or an amino acid residue having a side chain comprising an aromatic or heteroaromatic group; at least two of R1, R2, and R3 is an aromatic or heteroaromatic side chain of an amino acid; R₄ and R₆ are independently a side chain of serine or histidine; AA_SC is an amino acid side chain; q is 1, 2, 3 or 4; nx is 1; and each m is independently an integer 0, 1, 2, or 3. [0365] The cCPP of Formula (Y-a) can comprise the structure of Formula (Y-aa) or Formula (Y- ab):

(Y-aa), or protonated form thereof, wherein AASC , R1, R2, R3, R4, R7, m and nx are as defined herein. [0366] The cCPP can comprise the structure of Formula (Ym), (Yn), (Yo), or (Yp), :

or a protonated form thereof, wherein AASC is as defined herein. [0367] The cCPP can comprise one of the following sequences: hFfΦGrGr; bhFfΦSRSR; or FfΦSrSr. The cCPP can comprise one of the following sequences: bhFfΦGrGrQ; bhFfΦSRSRQ; or FfΦSrSrQ. [0368] The cCPP can comprise the structure of Formula AA(c), AA(d), or AA(e). AA(c)

[0369] In embodiments, the cCPP can comprise one of the following sequences: FfFSRSR; FGFSRSR; βhFf-Nal-SRSR; FfFSRSRQ; FGFSRSRQ; or βhFf-Nal-SRSRQ. [0370] The disclosure also relates to a cCPP having the structure of Formula (A-II):

wherein: AASC is an amino acid side chain; R^1a, R^1b, and R^1c are independently a 6- to 14-membered aryl or a 6- to 14-membered heteroaryl; R^2a, R^2b, R^2c and R^2d are independently an amino acid side chain; at least one of R^2a, R^2b, R^2c and R^2d is guanidine or a protonated form thereof; each n” is independently an integer 0, 1, 2, 3, 4, or 5; each n’ is independently an integer from 0, 1, 2, or 3; nx is 0 or 1; and if n’ is 0 then R^2a, R^2b, R^2b or R^2d is absent. [0371] In embodiments where the cCPP is of Formula (A-II), ne or two of R^2a, R^2b, R^2c or R^2d are guanidine, or a protonated form thereof, and the remaining of R^2a, R^2b, R^2c or R^2d are uncharged non-aryl amino acid side chains. Amino acids with uncharged non-aryl side chains include, but are not limited to, histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-thiazolyl)-alanine, 3-(4-furanyl)-alanine, and 3-(4-thienyl)- alanine. [0372] In embodiments where the cCPP is of Formula (A-II), each of R^2a, R^2b, R^2c and R^2d can independently be serine, homo-serine, threonine, allo-threonine, histidine, or 1-methylhistidine. [0373] AASC can be

, wherein t can be an integer from 0 to 5. AASC can be

, wherein t can be 0 or an integer from 1 to 5. t can be 1 to 5. t is 2 or 3. t can be 2. t can be 3. [0374] In embodiments where the cCPP is of Formula (A-II), R^1a, R^1b, and R^1c can each independently be 6- to 14-membered aryl. R^1a, R^1b, and R^1c can be each independently a 6- to 14- membered heteroaryl having one or more heteroatoms selected from N, O, or S. R^1a, R^1b, and R^1c can each be independently selected from phenyl, naphthyl, anthracenyl, pyridyl, quinolyl, or isoquinolyl. R^1a, R^1b, and R^1c can each be independently selected from phenyl, naphthyl, or anthracenyl. R^1a, R^1b, and R^1c can each be independently phenyl or naphthyl. R^1a, R^1b, and R^1c can each be independently selected pyridyl, quinolyl, or isoquinolyl. [0375] In embodiments where the cCPP is of Formula (A-II), each n’ can independently be 1 or 2. Each n’ can be 1. Each n’ can be 2. At least one n’ can be 0. At least one n’ can be 1. At least one n’ can be 2. At least one n’ can be 3. At least one n’ can be 4. At least one n’ can be 5. [0376] In embodiments where the cCPP is of Formula (A-II), each n” can independently be an integer from 1 to 3. Each n” can independently be 2 or 3. Each n” can be 2. Each n” can be 3. At least one n” can be 0. At least one n” can be 1. At least one n” can be 2. At least one n” can be 3. [0377] In embodiments where the cCPP is of Formula (A-II), each n” can independently be 1 or 2 and each n’ can independently be 2 or 3. Each n” can be 1 and each n’ can independently be 2 or 3. Each n” can be 1 and each n’ can be 2. Each n” is 1 and each n’ is 3. [0378] In embodiments where the cCPP is of Formula (A-II), each nx can independently be 0 or 1. nx can be 0. nx can be 1. [0379] The cCPP of Formula (A-II) can have the structure of Formula (A-II-1):

wherein R^1a, R^1b, R^1c, R^2a, R^2b, R^2c, R^2d, AA_SC, n’,n”, and n_x are as defined herein. [0380] The cCPP of Formula (A-II) or (A-II-1) can have the structure of Formula (A-IIa):

wherein R^1a, R^1b, R^1c, R^2a, R^2b, R^2c, R^2d, AASC,n’, and nx are as defined herein. [0381] The cCPP of formula (A-II) or (A-II-1)can have the structure of Formula (A-IIb):

wherein R^2a, R^2b, AA_SC, n’, and n_xare as defined herein. [0382] The cCPP can have the structure of Formula (A-III):

wherein: AA_SC is an amino acid side chain; R^1a, R^1b, and R^1c are independently a 6- to 14-membered aryl or a 6- to 14-membered heteroaryl; R^2a and R^2c are independently H, or uncharged non-aryl amino acid side chain; R^2b and R^2d are independently guanidine or a protonated form thereof; each n” is independently an integer from 1 to 3; each n’ is independently an integer from 1 to 5; each n_x is 0 or 1; and each p’ is independently 0 or 1. [0383] The cCPP of Formula (A-III) can have the structure of Formula (A-III-1):

wherein: AASC, R^1a, R^1b, R^1c, R^2a, R^2c, R^2b, R^2d n’, n”, nx, and p’ are as defined herein. [0384] The cCPP of Formula (A-III) can have the structure of Formula (A-IIIa):

wherein: AASC, R^2a, R^2c, R^2b, R^2d n’, n”, nx, and p’ are as defined herein. [0385] In Formulas (A-III), (A-III-1), and (A-IIIa), R^2a and R^2c can be H. R^2a and R^2c can be H and R^2b and R^2d can each independently be guanidine or protonated form thereof. R^2a can be H. R^2b can be H. p’ can be 0. R^2a and R^2c can be H or uncharged non-aryl amino acid side chain and each p’ can be 0, or 1. [0386] In Formulas (A-III), (A-III-1), and (A-IIIa), R^2a and R^2c can be H or uncharged non-aryl amino acid side chain, R^2b and R^2d can each independently be guanidine or protonated form thereof, n” can be 2 or 3, and each p’ can be 0, or 1. [0387] In Formulas (A-III), (A-III-1), and (A-IIIa) p’ can 0. p’ can 1. [0388] In Formulas (A-III), (A-III-1), and (A-IIIa) nx can be 0. nx can be 1. [0389] The cCPP can have the structure:

[0390] The cCPP of Formula (Y) can be selected from:

(FfΦHrHrQ) [0391] The cCPP can comprise the structure of Formula (A-D)

or a protonated form thereof, wherein: R₁, R₂, and R₃ can each independently be H or an amino acid residue having a side chain comprising an aromatic group; at least one of R1, R2, and R3 is an aromatic or heteroaromatic side chain of an amino acid; R₄ and R₆ are independently H or an uncharged non-aryl amino acid side chain; AASC is an amino acid side chain;

q is 1, 2, 3 or 4; each m is independently an integer 0, 1, 2, or 3, each n is independently an integer 0, 1, 2, or 3, and nx is 0 or 1. [0392] In embodiments, the cCPP is of Formula (A-D), wherein

. [0393] In embodiments, the cCPP is of Formula (A-D), wherein

each of m and n are independently 0, 1, 2, or 3. [0394] In embodiments, the cCPP is of Formula (A-D), wherein Y is and each of m and n are independently 0, 1, 2, or 3.

[0395] In embodiments, the cCPP is of Formula (A-D), wherein Y is and each of m

and n are independently 0, 1, 2, or 3. [0396] AA_SC can be conjugated to a linker. Linker [0397] Two or more components of the β-catenin targeting compounds, degradation constructs, and/or degradation compounds of the present disclosure may be operably linked through one or more linkers. For example, a β-catenin antibody or antigen binding fragment thereof, a targeting moiety, a degradation moiety or a degradation construct may be operably linked to a cCPP through a linker. A cCPP may be operably linked to an exocyclic peptide of the present disclosure through a linker; thereby forming an EEV. An EEV may be operably linked to a targeting moiety, degradation moiety, or degradation construct through a linker. [0398] The cCPP of the disclosure can be conjugated to a linker. The linker can link a cargo (e.g., a β-catenin antibody or antigen binding fragment thereof, a β-catenin targeting compound, a degradation construct, or a degradation compound) to the cCPP. The linker can be attached to the side chain of an amino acid of the cCPP, and the cargo can be attached at a suitable position on linker. [0399] The linker can be any appropriate moiety which can conjugate a cCPP to one or more additional moieties, e.g., an exocyclic peptide (EP) and/or a cargo. Prior to conjugation to the cCPP and one or more additional moieties, the linker has two or more functional groups, each of which are independently capable of forming a covalent bond to the cCPP and one or more additional moieties. If the cargo is a peptide or protein, the linker can be covalently bound to the N-terminus or the C-terminus of the cargo. The linker can be covalently bound to the backbone of the peptide cargo. The linker can be covalently bound to the side chain or one or more amino acids of a peptide (or protein) cargo. The linker can be any appropriate moiety which conjugates a cCPP described herein to a cargo such as an peptide (or protein; e.g., a β-catenin targeting compound, a degradation construct, or a degradation compound) or small molecule. [0400] The linker can comprise hydrocarbon linker. [0401] The linker can comprise a cleavage site. The cleavage site can be a disulfide that can be reduced under appropriate conditions, or caspase-cleavage site (e.g, Val-Cit-PABC). [0402] The linker can comprise: (i) one or more D or L amino acids, each of which is optionally substituted; (ii) optionally substituted alkylene; (iii) optionally substituted alkenylene; (iv) optionally substituted alkynylene; (v) optionally substituted carbocyclyl; (vi) optionally substituted heterocyclyl; (vii) one or more -(R^1-J-R²)z”- subunits, wherein each of R¹ and R², at each instance, are independently selected from alkylene, alkenylene, alkynylene, carbocyclyl, and heterocyclyl, each J is independently C, NR³, -NR³C(O)-, S, and O, wherein R³ is independently selected from H, alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl, each of which is optionally substituted, and z” is an integer from 1 to 50; (viii) -(R^1-J)z”- or -(J-R¹)z”-,, wherein each of R¹, at each instance, is independently alkylene, alkenylene, alkynylene, carbocyclyl, or heterocyclyl, each J is independently C, NR³, -NR³C(O)-, S, or O, wherein R³ is H, alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, each of which is optionally substituted, and z” is an integer from 1 to 50; or (ix) the linker can comprise one or more of (i) through (x). [0403] The linker can comprise one or more D or L amino acids and/or -(R^1-J-R²)z”-, wherein each of R¹ and R², at each instance, are independently alkylene, each J is independently C, NR³, - NR³C(O)-, S, and O, wherein R⁴ is independently selected from H and alkyl, and z” is an integer from 1 to 50; or combinations thereof. [0404] The linker can comprise a -(OCH₂CH₂)_z’- (e.g., as a spacer), wherein z’ is an integer from 1 to 23, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. “- (OCH2CH2) z’ can also be referred to as polyethylene glycol (PEG). [0405] The linker can comprise one or more amino acids. The linker can comprise a peptide. The linker can comprise a -(OCH₂CH₂)_z’-, wherein z’ is an integer from 1 to 23, and a peptide. The peptide can comprise from 2 to 10 amino acids. [0406] In embodiments, the linker may comprise a reactive handle that is a cooperative reactive handle (as described elsewhere herein) with a reactive handle on an exocyclic peptide, cCPP, EEV, β-catenin antibody, targeting moiety, degradation moiety, or degradation construct. The cooperative reactive handles may react in a conjugation reaction (e.g., a bioconjugation reaction) to from a reaction product. For examples, the linker can further comprise a functional group (FG) capable of reacting with an appropriate functional group on the cCPP or cargo to form a covalent bond between the linker and the cCPP or the cargo. In embodiments, the linker comprises a functional group (FG) capable of reacting through click chemistry. The FG capable of reacting through click chemistry can be an azide or alkyne, and a triazole is formed when the cargo or cCPP is conjugated to the linker. [0407] The linker can comprise (i) a β alanine residue and lysine residue; (ii) -(J-R¹)z”; or (iii) a combination thereof. Each R¹ can independently be alkylene, alkenylene, alkynylene, carbocyclyl, or heterocyclyl, each J is independently C, NR³, -NR³C(O)-, S, or O, wherein R³ is H, alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, each of which is optionally substituted, and z” can be an integer from 1 to 50. Each R¹ can be alkylene and each J can be O. [0408] The linker can comprise (i) residues of β-alanine, glycine, lysine, 4-aminobutyric acid, 5- aminopentanoic acid, 6-aminohexanoic acid or combinations thereof; and (ii) -(R^1-J)z”- or -(J- R¹)z”. Each R¹ can independently be alkylene, alkenylene, alkynylene, carbocyclyl, or heterocyclyl, each J is independently C, NR³, -NR³C(O)-, S, or O, wherein R³ is H, alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, each of which is optionally substituted, and z” can be an integer from 1 to 50. Each R¹ can be alkylene and each J can be O. The linker can comprise glycine, β-alanine, 4-aminobutyric acid, 5-aminopentanoic acid, 6-aminohexanoic acid, or a combination thereof. [0409] The linker can be a trivalent linker. The linker can have the structure:

,

wherein A₁, B₁, and C₁, can independently be a hydrocarbon linker (e.g., NRH-(CH2)n-COOH), a PEG linker (e.g., NRH-(CH2O)n-COOH, wherein R is H, methyl or ethyl) or one or more amino acid residue, and Z is independently a protecting group. The linker can also incorporate a cleavage site, including a disulfide [NH2- (CH2O)n-S-S-(CH2O)n-COOH], or caspase-cleavage site (Val-Cit-PABC). [0410] The hydrocarbon can be a residue of glycine or β-alanine. [0411] The linker can be bivalent and link the cCPP to a cargo. The linker can be bivalent and link the cCPP to an exocyclic peptide (EP). The linker can be a bivalent linker and link an EEV (comprising a cCPP and an exocyclic peptide) to a cargo. [0412] The linker can be trivalent and link the cCPP to a cargo and to an EP. [0413] In embodiments, the compound (and EEV) may include two to more cCPPs (e.g, 2, 3, 4, 5, 6, 7, 8, 9, or 10). As such, the linker can be multivalent and link two or more cCPPs to a cargo and EP. In embodiments, the compound may include two or more linkers that allow for two or more cCPPs, one or more EPs, and one or more cargos to be linked in a single compound. For example, the compound can comprise (cCPP)-linker¹-K(cCPP)-linker²-FG where linker¹ and linker² may be distinct linkers or a single linker and FG is a functional group that is a part of a linker. The compound can comprise EP-linker¹-K(cCPP)-linker²-k(cCPP)-linker³-FG where the linkers may be distinct linkers or two or more linkers may be a part of the same linker and FG is a functional group that is a part of a linker. [0414] In embodiments, the EEV can be (cyclo[EhF-f-)-GrGrQ])-PEG2-k(cyclo[EhF-f-)- GrGrQ])-PEG12-OH. In embodiments, the EEV can be (cyclo[Ff-^) -SrSrQ])-PEG2-k(cyclo[Ff- ^) -SrSrQ])-PEG₁₂-OH. In embodiments, the EEV can be (cyclo[EhF-F-^)-SRSRQ])-PEG₂- k(cyclo[EhF-F-^)-SRSRQ])-PEG₁₂-OH.The linker can be a bivalent or trivalent C₁-C₅₀ alkylene, wherein 1-25 methylene groups are optionally and independently replaced by -N(H)-, -N(C₁-C₄ alkyl)-, -N(cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(C1-C4 alkyl)-, - S(O)2N(cycloalkyl)-, -N(H)C(O)-, -N(C1-C4 alkyl)C(O)-, -N(cycloalkyl)C(O)-, -C(O)N(H)-, - C(O)N(C₁-C₄ alkyl), -C(O)N(cycloalkyl), aryl, heterocyclyl, heteroaryl, cycloalkyl, or cycloalkenyl. The linker can be a bivalent or trivalent C₁-C₅₀ alkylene, wherein 1-25 methylene groups are optionally and independently replaced by -N(H)-, -O-, -C(O)N(H)-, or a combination thereof. [0415] The linker can have the structure of L1:

wherein: each AA is independently an amino acid residue; * is the point of attachment to the AASC, and AASC is side chain of an amino acid residue of the cCPP; x is an integer from 1- 10; y is an integer from 1-5; and z is an integer from 1-10. x can be an integer from 1-5. x can be an integer from 1-3. x can be 1. y can be an integer from 2-4. y can be 4. z can be an integer from 1-5. z can be an integer from 1-3. z can be 1. Each AA can independently be selected from glycine, b-alanine, 4-aminobutyric acid, 5-aminopentanoic acid, and 6-aminohexanoic acid. [0416] The cCPP can be attached to the cargo through a linker (“L”). The linker can be conjugated to the cargo through a bonding group (“M”). [0417] In embodiments, the bonding group is the reaction product between a functional group on the linker and a functional group on the EP or cargo. In embodiments, the bonding group includes the reaction product of a conjugation reaction (e.g., a bioconjugation reaction). In some such embodiments, the bonding group includes or is the reaction product between a first cooperative reactive handle on the linker and a second cooperative reactive handle on the cargo. Conjugation reaction products between two cooperative handles are known in the art. The bonding group may be or include any reaction product of a conjugation reaction (e.g., bioconjugation reaction) such as those described elsewhere herein. [0418] In embodiments where two components of a

-catenin targeting compound or degradation compound are coupled using a bifunctional bioconjugation compound (as described elsewhere herein) and two bioconjugation reactions, the bonding group (M) connecting the two components includes the reaction products of the two conjugation reactions and any chemical group of the bifunctional bioconjugation compound that separates the two reactive handles of the bifunctional bioconjugation compound (e.g., see the discussion of FIG.4A, 4B, and 4C). [0419] The linker can have the structure of L2: [

wherein: x is an integer from 1-10; y is an integer from 1-5; z is an integer from 1-10; each AA is independently an amino acid residue; * is the point of attachment to the AASC, and AASC is side chain of an amino acid residue of the cCPP; and M is a bonding group defined herein. [0421] The linker can have the structure of L3: [0422]

(L3), wherein: x’ is an integer from 1-23; y is an integer from 1-5; z’ is an integer from 1-23; * is the point of attachment to the AA_SC, and AA_SC is a side chain of an amino acid residue of the cCPP; and M is a bonding group defined herein. [0423] The linker can have the structure of (L4): [0424]

wherein: x’ is an integer from 1-23; y is an integer from 1-5; and z’ is an integer from 1- 23; * is the point of attachment to the AA_SC, and AA_SC is a side chain of an amino acid residue of the cCPP. [0425] The linker can have the structure of L5a or L6a:

where FG is reactive handle that is cooperative with a reactive handle on a cargo or exocyclic peptide; x’ is an integer from 1-23; y is an integer from 1-5; and z’ is an integer from 1-23; * is the point of attachment to the AA_SC, and AA_SC is a side chain of an amino acid residue of the cCPP. In embodiments, FG is an azide. In embodiments, FG is OH. In embodiments, FG is SH. In embodiments, FG is NH2. [0426] Following a conjugation reaction where the FG of linker L-A or L-B reacts with a cooperative reactive handle on a cargo or exocyclic peptide, the linker may can have the structure of L5 or L6:

[0427] wherein: x’ is an integer from 1-23; y is an integer from 1-5; and z’ is an integer from 1- 23; * is the point of attachment to the AA_SC, and AA_SC is a side chain of an amino acid residue of the cCPP. In L1 and L2, x can be an integer from 1-10, e.g.,1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, inclusive of all ranges and subranges therebetween. [0428] In L1 and L2, y can be an integer from 1-5, e.g., 1, 2, 3, 4, or 5, inclusive of all ranges and subranges therebetween. y can be an integer from 2-5. y can be an integer from 3-5. y can be 3 or 4. y can be 4 or 5. y can be 3. y can be 4. y can be 5. [0429] In L1 and L2, z can be an integer from 1-10, e.g.,1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, inclusive of all ranges and subranges therebetween. [0430] In L3, L4, L5a, L5, L6a, and L6, x’ can be an integer from 1-23, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, inclusive of all ranges and subranges therebetween. x’ can be an integer from 5-15. x’ can be an integer from 9-13. x’ can be an integer from 1-5. x’ can be 1. [0431] In L3, L4, L5a, L5, L6a, and L6, z’ can be an integer from 1-23, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, inclusive of all ranges and subranges therebetween. z’ can be an integer from 5-15. z’ can be an integer from 9-13. z’ can be 11. [0432] In L3, L4, L5a, L5, L6a, and L6, as discussed above, the linker or M (wherein M is part of the linker) can be covalently bound to cargo at any suitable location on the cargo. The linker or M (wherein M is part of the linker) can be covalently bound to the N-terminus or the C-terminus of a peptide (or protein; e.g., a β-catenin targeting compound, a degradation construct, or a degradation compound) cargo. The linker or M (wherein M is part of the linker) can be covalently bound to the backbone of a peptide (or protein) cargo. The linker of M (wherein M is a part of the linker) can be covalently bound to side chain of any amino acid of a peptide or protein cargo (e.g., a β-catenin targeting compound, a degradation construct, or a degradation compound). [0433] The linker can be bound to the side chain of aspartic acid, glutamic acid, glutamine, asparagine, or lysine, or a modified side chain of glutamine or asparagine (e.g., a reduced side chain having an amino group), on the cCPP. The linker can be bound to the side chain of lysine on the cCPP. [0434] The linker can be bound to the side chain of aspartic acid, glutamic acid, glutamine, asparagine, or lysine, or a modified side chain of glutamine or asparagine (e.g., a reduced side chain having an amino group), on a peptide (or protein) cargo. The linker can be bound to the side chain of lysine on the peptide (or protein) cargo. [0435] The linker can have a structure of L7:

wherein M is a group that conjugates L to a cargo (bonding group), for example, a peptide of protein (e.g., a β-catenin targeting compound, a degradation construct, or a degradation compound) ; AAs is a side chain or terminus of an amino acid on the cCPP; each AAx is independently an amino acid residue; o is an integer from 0 to 10; and p is an integer from 0 to 5. [0436] The linker can have a structure of L8: [0437]

wherein M is a group that conjugates L to a cargo; AA_s is a side chain or terminus of an amino acid on the cCPP; each AAx is independently an amino acid residue; s is an integer from 0 to 15 (e.g., 1, 2, 11, or 12); o is an integer from 0 to 10; and p is an integer from 0 to 5. [0438] M can comprise an alkylene, alkenylene, alkynylene, carbocyclyl, or heterocyclyl, each of which is optionally substituted. M can be selected from:

,

alkenyl, alkynyl, carbocyclyl, or heterocyclyl. [0439] M can be selected from:

. wherein: R¹⁰ is alkylene, cycloalkyl, or

, wherein a is 0 to 10. [0440] M can be , R¹⁰ can be and a is 0 to 10. M can be

.

[0441] M can be a heterobifunctional crosslinker, e.g.,

is disclosed in Williams et al. Curr. Protoc Nucleic Acid Chem. 2010, 42, 4.41.1-4.41.20, incorporated herein by reference its entirety. [0442] M can be -C(O)-. [0443] AA_s can be a side chain or terminus of an amino acid on the cCPP. Non-limiting examples of AA_s include aspartic acid, glutamic acid, glutamine, asparagine, or lysine, or a modified side chain of glutamine or asparagine (e.g., a reduced side chain having an amino group). AAs can be any AASC as defined herein. [0444] Each AA_x is independently a natural or non-natural amino acid. One or more AA_x can be a natural amino acid. One or more AAx can be a non-natural amino acid. One or more AAx can be a beta-amino acid. The beta-amino acid can be beta-alanine. [0445] o can be an integer from 0 to 10, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. o can be 0, 1, 2, or 3. o can be 0. o can be 1. o can be 2. o can be 3. [0446] p can be 0 to 5, e.g., 0, 1, 2, 3, 4, or 5. p can be 0. p can be 1. p can be 2. p can be 3. p can be 4. p can be 5. [0447] The linker can have the structure:

, wherein M, AAs, each -(R¹-J-R²)z”-, o and z” are defined herein; r can be 0 or 1. [0449] r can be 0. r can be 1. [0450] The linker can have the structure: [

, wherein each of M, AA_s, o, p, q, r and z” can be as defined herein. [0452] z” can be an integer from 1 to 50, e.g., 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, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, inclusive of all ranges and values therebetween. z” can be an integer from 5-20. z” can be an integer from 10-15. [0453] The linker can have the structure:

, wherein: M, AAs and o are as defined herein. [0454] Other non-limiting examples of suitable linkers include:

wherein M and AA_s are as defined herein. [0455] Provided herein is a compound comprising a cCPP and an β-catenin targeting anitobdy or antigen binding fragment thereof and/or a degradation construct further comprising L, wherein the linker is conjugated to the a β-catenin targeting antibody or antigen binding fragment thereof and/or a degradation construct through a bonding group (M), wherein

. [0456] Provided herein is a compound comprising a cCPP and a cargo that comprises a β-catenin targeting antibody or antigen binding fragment thereof and/or a degradation construct compound further comprises L, wherein the linker is conjugated to the AC through a bonding group (M), wherein M is selected from:

, wherein: R¹ is alkylene, cycloalkyl,

, wherein t’ is 0 to 10 wherein each R is independently an alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, wherein R¹ is

, and t’ is 2. [0457] The linker can have the structure: [0458]

wherein AAs is as defined herein, and m’ is 0-10. [0459] The linker can be of the formula:

. [0460] The linker can be covalently bound to a cargo at any suitable location on the cargo. [0461] The linker can be bound to the side chain of aspartic acid, glutamic acid, glutamine, asparagine, or lysine, or a modified side chain of glutamine or asparagine (e.g., a reduced side chain having an amino group), on the cCPP. The linker can be bound to the side chain of lysine on the cCPP. cCPP-linker conjugates [0462] The cCPP can be conjugated to a linker defined herein. The linker can be conjugated to an AASC of the cCPP as defined herein. [0463] The linker can comprise a -(OCH2CH2)z’- subunit (e.g., as a spacer), wherein z’ is an integer from 1 to 23, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23. “- (OCH2CH2)z’ is also referred to as PEG. The cCPP-linker conjugate can have a structure selected from Table 9: Table 9: cCPP-linker conjugates

[0464] The linker can comprise a -(OCH₂CH₂)_z’- subunit, wherein z’ is an integer from 1 to 23, and a peptide subunit. The peptide subunit can comprise from 2 to 10 amino acids. The cCPP- linker conjugate can have a structure selected from Table 10: Table 10: EP-cCPP-linker conjugates

[0465] EEVs comprising a cyclic cell penetrating peptide (cCPP), linker and exocyclic peptide (EP) are provided. An EEV can comprise the structure of Formula (X):

wherein EP, AA, x, z, y, and M are defined elsewhere herein; AAsc is an amino acid side chain a residue in the cCPP; and the cCPP may be any cCPP having any combination of amino acid residues as described herein. [0466] EEVs comprising a cyclic cell penetrating peptide, a linker, and an EP are provided having the general formula EP-linker(a)-cCPP-linker(b), wherein linker(a) and linker(b) are a part of the same trivalent linker. The linker can be conjugated to the cCPP through the AAsc of the CCP. The linker may be conjugated to the EP through a conjugation reaction between a functional group on the EP and a functional group on the linker. In embodiments, the linker is conjugated to the EP through a reaction with a functional group on the EP that is at or is near (e.g., the size chain of the C-terminal amino acid) the C-terminus of the EP. Linker(b) may have a functional group that can react in a conjugation reaction (e.g., a bioconjugation reaction) with a functional group on a cargo to form a compound of the general formula EP-linker(a)-cCPP-linker(b)-cargo. [0467] EEVs comprising a cyclic cell penetrating peptide (cCPP), linker and exocyclic peptide (EP) are provided. An EEV can comprise the structure of Formula (J1), (J2), or (J3):

wherein EP is any exocyclic peptide disclosed herein; y is an integer from 1 to 5; x’ is an integer from 1-20; z’ is an integer from 1-23; cCPP is any cCPP disclosed herein; AA_sc is any AA_sc as disclosed herein; o is an integer from 1 to 5; and FG is a functional group configured to react with a functional group on a cargo to form any bonding group (M) disclosed herein. The stereochemistry of the stereocenters may be S or R. [0468] In embodiments, the EEV is of Formula (J1), (J2), or (J3), wherein x’ is 1 or 2. In embodiments, the EEV is of Formula (J1), (J2), or (J3), wherein z’ is 1, 2, 11, or 12. In embodiments, the cCPP is of Formula (IA), (I), (I-a), (I-b), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (IX), (IX1), (IX(a)), (IX(b)), (IX(c)), (II), (II-1), (IIa), (IIc), (III), (III-1), (IIIa), (D), (AV), (Y1), (Y1’), (Y2), (Y2’), (AA(a)), (AA(b)), (Y-a), (Y-aa), (Y-ab), (Ym), (Yn), (Yo), (Yp), (AA(c)), (AA(d)), (AA(e)), (A-II), (A-II-1), (A-IIa), (A-IIb), (A-III), (A-III-1), (A-IIIa), or derivatives having the specified characteristics described herein. [0469] EEVs comprising a cyclic cell penetrating peptide (cCPP), linker and exocyclic peptide (EP) are provided. An EEV can comprise the structure of Formula (B):

protonated form thereof, wherein: R₁, R₂, and R₃ are each independently H or an aromatic or heteroaromatic side chain of an amino acid; R4 and R7 are independently H or an amino acid side chain; EP is an exocyclic peptide as defined herein; each m is independently an integer from 0-3; n is an integer from 0-2; x’ is an integer from 1-20; y is an integer from 1-5; q is 1-4; and z’ is an integer from 1-23. [0470] R₁, R₂, R₃, R₄, R₇, EP, m, q, y, x’, z’ are as described herein. [0471] n can be 0. n can be 1. n can be 2. [0472] The EEV can comprise the structure of Formula (B-a) or (B-b):

or a protonated form

thereof, wherein EP , R¹, R², R³, R⁴, m and z’ are as defined above in Formula (B). [0473] The EEV can comprises the structure of Formula (B-c):

or a protonated form thereof, wherein EP, R¹, R², R³, R⁴, and m are as defined above in Formula (B); AA is an amino acid as defined herein; M is as defined herein; n is an integer from 0-2; x is an integer from 1-10; y is an integer from 1-5; and z is an integer from 1-10. [0474] The EEV can have the structure of Formula (B-1), (B-2), (B-3), or (B-4):

or a protonated form thereof, wherein EP is as defined above in Formula (B). [0475] The EEV can comprise Formula (B) and can have the structure: Ac-PKKKRKV-AEEA- K(cyclo[FGFGRGRQ])-PEG12-OH or Ac-PKKKRKV-AEEA-K(cyclo[GfFGrGrQ])-PEG12-OH. [0476] EEVs comprising a cyclic cell penetrating peptide (cCPP), linker and exocyclic peptide (EP) are provided. An EEV can comprise the structure of Formula (C): (C), or a protonated form thereof,

wherein: R1, R2, R3, R4, R5, and R6, are independently H or an amino acid side chain; at least two of R1, R2, and R3 are independently an aromatic or heteroaromatic side chain of an amino acid; R₄ and R₆ are independently an uncharged, non-aryl amino acid side chain selected from histidine, threonine, serine, leucine, isoleucine, valine, neopentylglycine, alanine, homoalanine, homoserine, 3-(4-Thiazolyl)-alanine, 3-(4-furanyl)-alanine, and 3-(4-thienyl)-alanine; AA_SC is an amino acid side chain; n_x is 0 or 1; q is 1, 2, 3 or 4; EP is an exocyclic peptide as defined herein; each m is independently an integer from 0-3; n is an integer from 0-2; x’ is an integer from 1-20; y is an integer from 1-5; and z’ is an integer from 1-23. [0477] In embodiments, at least two of R₁, R₂, and R₃ are independently a side chain of phenylalanine or naphthylalanine. [0478] In embodiments, R4 and R6 are independently serine or histidine. [0479] In embodiments, at least two of R₁, R₂, and R₃ are independently a side chain of phenylalanine or naphthylalanine and R₄ and R₆ are independently serine or histidine. An EEV can comprise the structure of Formula (C), or a protonated form thereof, wherein: R₁, R₂, R₃, R₄, R₅, and R₆, are independently H or an amino acid side chain; at least two of R1, R2, and R3 are independently a side chain of phenylalanine, or naphthylalanine; R₄ and R₆ are independently a side chain of serine or histidine; AA_SC is an amino acid side chain; nx is 0 or 1; q is 1, 2, 3 or 4; EP is an exocyclic peptide as defined herein; each m is independently an integer from 0-3; n is an integer from 0-2; x’ is an integer from 1-20; y is an integer from 1-5; and z’ is an integer from 1-23. [0480] EEVs comprising a cyclic cell penetrating peptide (cCPP), linker and exocyclic peptide (EP) are provided. An EEV can comprise the structure of Formula (C), or a protonated form thereof, wherein: R₁, R₂, R₃, R₄, and R₆, are independently H or an amino acid side chain; at least two of R₁, R₂, and R₃ are independently a side chain of phenylalanine, or naphthylalanine; AASC is an amino acid side chain; n_x is 1; q is 1, 2, 3 or 4; EP is an exocyclic peptide as defined herein; each m is independently an integer from 0-3; n is an integer from 0-2; x’ is an integer from 1-20; y is an integer from 1-5; and z’ is an integer from 1-23. [0481] R1, R2, R3, R4, R6, EP, m, q, y, x’, z’ are as described herein. [0482] n can be 0. n can be 1. n can be 2. [0483] n_x can be 0. n_x can be 1. [0484] R4 and R6 can be a side chain of serine or histidine. [0485] The EEV can comprise the structure of Formula (C-a) or (C-b):

or a protonated

form thereof, wherein EP, R1, R2, R3, R4, R6, m, nx, and z’ are as defined in Formula (C). [0486] The EEV can comprises the structure of Formula (C-B-c):

or a protonated form thereof, wherein EP, R₁, R₂, R₃, R₄, R₆, n_x, and m are as defined above in Formula (B); AA is an amino acid as defined herein; M is as defined herein; n is an integer from 0-2; x is an integer from 1-10; y is an integer from 1-5; and z is an integer from 1- 10. [0487] The EEV can have the structure of Formula:



or a protonated form thereof, wherein EP is as defined above in Formula (C). [0488] The EEV can comprise Formula (C) and can have the structure: Ac-PKKRKV-AEEA- K(cyclo[bhF-f-F-GrGrQ])-AEEA-K(N₃)-NH₂; Ac-PKKKRKV-AEEA-K(cyclo[Ff- F -SrSrQ])- AEEA-K(N3)-NH2, or Ac-PKKKRKV-AEEA-K(cyclo[bhF-F- F-SRSRQ])-PEG12-OH. [0489] The EEV can comprise two or more cCPP conjugated to the cargo. In embodiments, the EEV can be (cCPP)-linker-k(cCPP)-linker-OH. In embodiments, the EEV can be (cyclo[bhF-f-F- GrGrQ])-PEG2-k(cyclo[bhF-f-F-GrGrQ])-PEG12-OH. In embodiments, the EEV can be (cyclo[Ff- F -SrSrQ])-PEG2-k(cyclo[Ff- F -SrSrQ])-PEG12-OH. In embodiments, the EEV can be (cyclo[bhF-F- F-SRSRQ])-PEG₂-k(cyclo[bhF-F- F-SRSRQ])-PEG₁₂-OH. [0490] The EEV can comprise a cCPP of formula:

[0491] The EEV can comprise formula: Ac-PKKKRKV-miniPEG₂-Lys(cyclo(FfFGRGRQ)- PEG2-K(N3)). [0492] The EEV can be Ac-P-K(Tfa)-K(Tfa)-K(Tfa)-R-K(Tfa)-V-AEEA-K- (cyclo[FGFGRGRQ])-PEG12-OH. The EEV can be:

[0493] The EEV can be Ac-PKKKRKV-AEEA-Lys-(cyclo[FGFGRGRQ])-PEG12-OH. The EEV can be:

[0494] The EEV can be selected from Ac-rr-miniPEG2-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG12-OH Ac-frr-PEG2-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG12-OH Ac-rfr-PEG₂-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG₁₂-OH Ac-rbfbr-PEG₂-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG₁₂-OH Ac-rrr-PEG2-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG12-OH Ac-rbr-PEG2-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG12-OH Ac-rbrbr-PEG₂-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG₁₂-OH Ac-hh-PEG2-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG12-OH Ac-hbh-PEG2-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG12-OH Ac-hbhbh-PEG2-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG12-OH Ac-rbhbh-PEG₂-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG₁₂-OH Ac-hbrbh-PEG2-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-PEG12-OH Ac-rr-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-frr-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-rfr-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-rbfbr-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-rrr-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-rbr-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-rbrbr-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-hh-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-hbh-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-hbhbh-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-rbhbh-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-hbrbh-Dap(cyclo[FfΦ-Cit-r-Cit-rQ])-b-OH Ac-KKKK-miniPEG₂-Lys(cyclo[FfΦGrGrQ])-miniPEG₂-K(N₃)-NH₂ Ac-KGKK-miniPEG2-Lys(cyclo[FfΦGrGrQ])-miniPEG2-K(N3)-NH2 Ac-KKGK-miniPEG2-Lys(cyclo[FfΦGrGrQ])-miniPEG2-K(N3)-NH2 Ac-KKK-miniPEG₂-Lys(cyclo[FfΦGrGrQ])-miniPEG₂-K(N₃)-NH₂ Ac-KK-miniPEG₂-Lys(cyclo[FfΦGrGrQ])-miniPEG₂-K(N₃)-NH₂ Ac-KGK-miniPEG2-Lys(cyclo[FfΦGrGrQ])-miniPEG2-K(N3)-NH2 Ac-KBK-miniPEG2-Lys(cyclo[FfΦGrGrQ])-miniPEG2-K(N3)-NH2 Ac-KBKBK-PEG₂-Lys(cyclo[FfΦGrGrQ])-PEG₂-K(N₃)-NH₂ Ac-KR-miniPEG₂-Lys(cyclo[FfΦGrGrQ])-miniPEG₂-K(N₃)-NH₂ Ac-KBR-miniPEG2-Lys(cyclo[FfΦGrGrQ])-miniPEG2-K(N3)-NH2 Ac-PKKKRKV-miniPEG2-Lys(cyclo[FfΦGrGrQ])-miniPEG2-K(N3)-NH2 Ac-PKKKRKV-miniPEG₂-Lys(cyclo[FfΦGrGrQ])-miniPEG₂-K(N₃)-NH₂ Ac-PGKKRKV-miniPEG₂-Lys(cyclo[FfΦGrGrQ])-miniPEG₂-K(N₃)-NH₂ Ac-PKGKRKV-miniPEG2-Lys(cyclo[FfΦGrGrQ])-miniPEG2-K(N3)-NH2 Ac-PKKGRKV-miniPEG2-Lys(cyclo[FfΦGrGrQ])-miniPEG2-K(N3)-NH2 Ac-PKKKGKV-miniPEG₂-Lys(cyclo[FfΦGrGrQ])-miniPEG₂-K(N₃)-NH₂ Ac-PKKKRGV-miniPEG₂-Lys(cyclo[FfΦGrGrQ])-miniPEG₂-K(N₃)-NH₂ Ac-PKKKRKG-miniPEG2-Lys(cyclo[FfΦGrGrQ])-miniPEG2-K(N3)-NH2 Ac-KKKRK-miniPEG2-Lys(cyclo[FfΦGrGrQ])-miniPEG2-K(N3)-NH2 Ac-KKRK-miniPEG₂-Lys(cyclo[FfΦGrGrQ])-miniPEG₂-K(N₃)-NH₂ and Ac-KRK-miniPEG₂-Lys(cyclo[FfΦGrGrQ])-miniPEG₂-K(N₃)-NH₂. [0495] The EEV can be selected from: Ac-PKKKRKV-Lys(cyclo[FfΦGrGrQ])-PEG12-K(N3)-NH2 Ac-PKKKRKV-miniPEG₂-Lys(cyclo[FfΦGrGrQ])-PEG₂-K(N₃)-NH₂ Ac-PKKKRKV-miniPEG2-Lys(cyclo[FGFGRGRQ])-miniPEG2-K(N3)-NH2 Ac-PKKKRKV-miniPEG2-Lys(cyclo[GfFGrGrQ])-miniPEG2-K(N3)-NH2 Ac-PKKKRKV-miniPEG2-Lys(cyclo[FfFGrGrQ])-miniPEG2-K(N₃)-NH₂ Ac-PKKKRKV-miniPEG2-Lys(cyclo[FGFRRRRQ])-miniPEG2-K(N3)-NH2 Ac-PKKKRKV-Lys(cyclo(Ff-Nal-RrRrQ) Ac-KR-PEG₂-K(cyclo[FGFGRGRQ])-PEG₂-K(N₃)-NH₂ Ac-PKKKGKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-K(N3)-NH2 Ac-PKKKRKG-PEG2-K(cyclo[FGFGRGRQ])-PEG2-K(N3)-NH2 Ac-KKKRK-PEG₂-K(cyclo[FGFGRGRQ])-PEG₂-K(N₃)-NH₂ Ac-PKKKRKV-miniPEG₂-Lys(cyclo[FFΦGRGRQ])-miniPEG₂-K(N₃)-NH₂ Ac-PKKKRKV-miniPEG2-Lys(cyclo[βhFfΦGrGrQ])-miniPEG2-K(N3)-NH2 Ac-PKKKRKV-miniPEG₂-Lys(cyclo[FfΦSrSrQ])-miniPEG₂-K(N₃)-NH₂. [0496] The EEV can be selected from: Ac-PKKKRKV-miniPEG2-Lys(cyclo(GfFGrGrQ])-PEG12-OH Ac-PKKKRKV-miniPEG2-Lys(cyclo[FGFKRKRQ])-PEG12-OH Ac-PKKKRKV-miniPEG₂-Lys(cyclo[FGFRGRGQ])-PEG₁₂-OH Ac-PKKKRKV-miniPEG2-Lys(cyclo[FGFGRGRGRQ])-PEG12-OH Ac-PKKKRKV-miniPEG2-Lys(cyclo[FGFGRrRQ])-PEG12-OH Ac-PKKKRKV-miniPEG₂-Lys(cyclo[FGFGRRRQ])-PEG₁₂-OH and Ac-PKKKRKV-miniPEG₂-Lys(cyclo[FGFRRRRQ])-PEG₁₂-OH. [0497] The EEV can be selected from: Ac-KKKRKG-miniPEG₂-K(cyclo[FGFGRGRQ])-PEG₁₂-OH Ac-KKKRK-miniPEG₂-K(cyclo[FGFGRGRQ])-PEG₁₂-OH Ac-KKRKK-PEG4-K(cyclo[FGFGRGRQ])-PEG12-OH Ac-KRKKK-PEG4-K(cyclo[FGFGRGRQ])-PEG12-OH Ac-KKKKR-PEG₄-K(cyclo[FGFGRGRQ])-PEG₁₂-OH Ac-RKKKK-PEG4-K(cyclo[FGFGRGRQ])-PEG12-OH and Ac-KKKRK-PEG4-K(cyclo[FGFGRGRQ])-PEG12-OH. [0498] The EEV can be selected from: Ac-PKKKRKV-PEG₂-K(cyclo[FGFGRGRQ])-PEG₂-K(N₃)-NH₂ Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG12-OH Ac-PKKKRKV-PEG₂-K(cyclo[GfFGrGrQ])-PEG₂-K(N₃)-NH₂ and Ac- PKKKRKV-PEG₂-K(cyclo[GfFGrGrQ])-PEG₁₂-OH . [0499] The cargo can be a protein and the EEV can be selected from: Ac-PKKKRKV-PEG2-K(cyclo[FfΦGrGrQ])-PEG12-OH Ac-PKKKRKV-PEG2-K(cyclo[FfΦCit-r-Cit-rQ])-PEG12-OH Ac-PKKKRKV-PEG₂-K(cyclo[FfFGRGRQ])-PEG₁₂-OH Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG12-OH Ac-PKKKRKV-PEG2-K(cyclo[GfFGrGrQ])-PEG12-OH Ac-PKKKRKV-PEG₂-K(cyclo[FGFGRRRQ])-PEG₁₂-OH Ac-PKKKRKV-PEG₂-K(cyclo[FGFRRRRQ])-PEG₁₂-OH Ac-rr-PEG2-K(cyclo[FfΦGrGrQ])-PEG12-OH Ac-rr-PEG₂-K(cyclo[FfΦCit-r-Cit-rQ])-PEG₁₂-OH Ac-rr-PEG₂-K(cyclo[FfF-GRGRQ])-PEG₁₂-OH Ac-rr-PEG2-K(cyclo[FGFGRGRQ])-PEG12-OH Ac-rr-PEG2-K(cyclo[GfFGrGrQ])-PEG12-OH Ac-rr-PEG₂-K(cyclo[FGFGRRRQ])-PEG₁₂-OH Ac-rr-PEG2-K(cyclo[FGFRRRRQ])-PEG12-OH Ac-rrr-PEG₂-K(cyclo[FfΦGrGrQ])-PEG₁₂-OH Ac-rrr-PEG₂-K(cyclo[FfΦCit-r-Cit-rQ])-PEG₁₂-OH Ac-rrr-PEG2-K(cyclo[FfFGRGRQ])-PEG12-OH Ac-rrr-PEG₂-K(cyclo[FGFGRGRQ])-PEG₁₂-OH Ac-rrr-PEG₂-K(cyclo[GfFGrGrQ])-PEG₁₂-OH Ac-rrr-PEG2-K(cyclo[FGFGRRRQ])-PEG12-OH Ac-rrr-PEG2-K(cyclo[FGFRRRRQ])-PEG12-OH Ac-rhr-PEG2-K(cyclo[FfΦGrGrQ])-PEG12-OH Ac-rhr-PEG2-K(cyclo[FfΦCit-r-Cit-rQ])-PEG12-OH Ac-rhr-PEG₂-K(cyclo[FfFGRGRQ])-PEG₁₂-OH Ac-rhr-PEG₂-K(cyclo[FGFGRGRQ])-PEG₁₂-OH Ac-rhr-PEG2-K(cyclo[GfFGrGrQ])-PEG12-OH Ac-rhr-PEG₂-K(cyclo[FGFGRRRQ])-PEG₁₂-OH Ac-rhr-PEG₂-K(cyclo[FGFRRRRQ])-PEG₁₂-OH Ac-rbr-PEG2-K(cyclo[FfΦGrGrQ])-PEG12-OH Ac-rbr-PEG2-K(cyclo[FfΦCit-r-Cit-rQ])-PEG12-OH Ac-rbr-PEG₂-K(cyclo[FfFGRGRQ])-PEG₁₂-OH Ac-rbr-PEG2-K(cyclo[FGFGRGRQ])-PEG12-OH Ac-rbr-PEG2-K(cyclo[GfFGrGrQ])-PEG12-OH Ac-rbr-PEG₂-K(cyclo[FGFGRRRQ])-PEG₁₂-OH Ac-rbr-PEG₂-K(cyclo[FGFRRRRQ])-PEG₁₂-OH Ac-rbrbr-PEG₂-K(cyclo[FfΦGrGrQ])-PEG₁₂-OH Ac-rbrbr-PEG₂-K(cyclo[FfΦCit-r-Cit-rQ])-PEG₁₂-OH Ac-rbrbr-PEG2-K(cyclo[FfFGRGRQ])-PEG12-OH Ac-rbrbr-PEG2-K(cyclo[FGFGRGRQ])-PEG12-OH Ac-rbrbr-PEG₂-K(cyclo[GfFGrGrQ])-PEG₁₂-OH Ac-rbrbr-PEG2-K(cyclo[FGFGRRRQ])-PEG12-OH Ac-rbrbr-PEG2-K(cyclo[FGFRRRRQ])-PEG12-OH Ac-rbhbr-PEG₂-K(cyclo[FfΦGrGrQ])-PEG₁₂-OH Ac-rbhbr-PEG2-K(cyclo[FfΦCit-r-Cit-rQ])-PEG12-OH Ac-rbhbr-PEG₂-K(cyclo[FfFGRGRQ])-PEG₁₂-OH Ac-rbhbr-PEG₂-K(cyclo[FGFGRGRQ])-PEG₁₂-OH Ac-rbhbr-PEG2-K(cyclo[GfFGrGrQ])-PEG12-OH Ac-rbhbr-PEG2-K(cyclo[FGFGRRRQ])-PEG12-OH Ac-rbhbr-PEG₂-K(cyclo[FGFRRRRQ])-PEG₁₂-OH Ac-hbrbh-PEG2-K(cyclo[FfΦGrGrQ])-PEG12-OH Ac-hbrbh-PEG₂-K(cyclo[FfΦCit-r-Cit-rQ])-PEG₁₂-OH Ac-hbrbh-PEG₂-K(cyclo[FfFGRGRQ])-PEG₁₂-OH Ac-hbrbh-PEG2-K(cyclo[FGFGRGRQ])-PEG12-OH Ac-hbrbh-PEG₂-K(cyclo[GfFGrGrQ])-PEG₁₂-OH Ac-hbrbh-PEG₂-K(cyclo[FGFGRRRQ])-PEG₁₂-OH Ac- hbrbh -PEG2-K(cyclo[FGFRRRRQ])-PEG12-OH, wherein b is β-alanine, and the exocyclic sequence can be D or L stereochemistry [0500] The EEV can be selected from: cyclo(FGFGHGHQ)-PEG₁₂-K(N₃)-NH₂ cyclo(FGFSHSHQ)-PEG12-K(N3)-NH2 cyclo(FfFGRGRQ)-PEG12-K(N3)-NH2 cyclo(FfFSRSRQ)-PEG₁₂-K(N₃)-NH₂ cyclo(FGFSRSRQ)-PEG₁₂-K(N₃)-NH₂ cyclo(FGFGRGRQ)-PEG12-K(N3)-NH2 cyclo(FGFGKGKQ)-PEG12-K(N₃)-NH₂ cyclo(FGFGKGKQ)-PEG₁₂-K(N₃)-NH₂ cyclo(FGFKKKK)-PEG12-K(N3)-NH2 cyclo(FGFK(me2)K(me2)K(me2)K(me2)Q)-PEG12-K(N3)-N2 Ac-RBRBR-PEG₂-K(cyclo[Ff-Nal-GrGrQ]-PEG₁₂-K(N₃)-NH₂ Ac-RBRBR-PEG2-K(cyclo[βhFf-Nal-SRSRQ]-PEG12-K(N3)-NH2 Ac-RBRBR-PEG2-K(cyclo[FGFSRSRQ]-PEG12-K(N3)-NH2 Ac-RBRBR-PEG₂-K(cyclo[FGFGRGRQ]-PEG₁₂-K(N₃)-NH₂ Ac-RBRBR-PEG₁₂-K[cyclo(FGFSHSHQ)]-PEG₁₂-K(N₃)-NH₂ Ac-KKKK-miniPEG2-Lys(cyclo(FGFGRGRQ))-miniPEG2-K(N3)-NH2 Ac-KBKBK-miniPEG2-Lys(cyclo(FGFGRGRQ))-miniPEG2-K(N₃)-NH₂ Ac-KBK-miniPEG2-Lys(cyclo(FGFGRGRQ))-miniPEG2-K(N₃)-NH₂ Cargo [0501] The cell penetrating peptide (CPP), such as a cyclic cell penetrating peptide ( cCPP), can be conjugated to a cargo. As used herein, “cargo” is a compound or moiety for which delivery into a cell is desired (e.g., β-catenin antibody or antigen binding fragment thereof, β-catenin targeting moiety; degradation construct). The cargo can be conjugated to a terminal carbonyl group of a linker. At least one atom of the cyclic peptide can be replaced by a cargo or at least one lone pair can form a bond to a cargo. The cargo can be conjugated to the cCPP by a linker. The cargo can be conjugated to an AASC by a linker. At least one atom of the cCPP can be replaced by a β-catenin antibody or antigen binding fragment thereof, a targeting moiety, a degradation construct, or at least one lone pair of the cCPP forms a bond to a β-catenin antibody or antigen binding fragment thereof, targeting moiety, or degradation construct. A hydroxyl group on an amino acid side chain of the cCPP can be replaced by a bond to the cargo. A hydroxyl group on a glutamine side chain of the cCPP can be replaced by a bond to the cargo. The cargo can be conjugated to the cCPP by a linker. The cargo can be conjugated to an AA_SC by a linker. [0502] In embodiments, the amino acid side chain of the cCPP comprises a chemically reactive group to which the linker or cargo is conjugated comprises. The chemically reactive group can comprise an amine group, a carboxylic acid, an amide, a hydroxyl group, a sulfhydryl group, a guanidinyl group, a phenolic group, a thioether group, an imidazolyl group, or an indolyl group. In embodiments, the amino acid (i.e., the AAsc) of the cCPP to which the cargo is conjugated comprises lysine, arginine, aspartic acid, glutamic acid, asparagine, glutamine, homoglutamine, serine, threonine, tyrosine, cysteine, arginine, methionine, histidine or tryptophan. [0503] The cargo can comprise one or more one or more β-catenin antibody or antigen binding fragment thereof, one or more degradation constructs, one or more targeting moieties, or any combination thereof. In embodiments, the cargo comprises a degradation construct (the degradation construct comprising a degradation moiety and a targeting moiety). In embodiments, the cargo comprises a targeting moiety (e.g., a照-catenin antibody or antigen binding fragment thereof or a bispecific construct).澳In embodiments, the cargo comprises a β-catenin antibody or antigen binding fragment thereof. Cyclic cell penetrating peptides (cCPPs) and EEVs conjugated to a cargo moiety [0504] The cyclic cell penetrating peptide (cCPP) can be conjugated to a cargo. [0505] The cargo can be conjugated to the linker at the terminal carbonyl group to provide the following structure:

, wherein: EP is an exocyclic peptide and M, AASC, Cargo, x’, y, and z’ are as defined above, * is the point of attachment to the AASC of any cCPP disclosed herein. x’ can be 1. y can be 4. z’ can be 11. -(OCH₂CH₂)_x’- and/or -(OCH₂CH₂)_z’- can be independently replaced with one or more amino acids, including, for example, glycine, β-alanine, 4-aminobutyric acid, 5-aminopentanoic acid, 6-aminohexanoic acid, or combinations thereof. An EEV-cargo conjugate may be of the Formula (J1c), (J2c), (J3c), (J4c), (J5c);

wherein EP is any exocyclic peptide disclosed herein; y is an integer from 1 to 5; x’ is an integer from 1-20; z’ is an integer from 1-23; cCPP is any cCPP disclosed herein; AA_sc is any AA_sc as disclosed herein; o is an integer from 1 to 5; M is any bonding group disclosed herein; and cargo is any cargo disclosed herein (e.g., a beta catenin antibody or antigen fragment thereof; a targeting moiety; a degradation moiety; or a degradation construct). The stereochemistry of each of the stereocenters may be S or R. [0506] In embodiments, the compound is of Formula (J1c), (J2c), (J3c), (J4c), or (J5c) wherein x’ is 1 or 2. In embodiments, the EEV is of Formula (J1c), (J2c), or (J3c), wherein z’ is 1, 2, 11, or 12. In embodiments, the cCPP is of Formula (IA), (I), (I-a), (I-b), (I-2), (I-3), (I-4), (I-5), (I-6), (I- 7), (IX), (IX1), (IX(a)), (IX(b)), (IX(c)), (II), (II-1), (IIa), (IIc), (III), (III-1), (IIIa), (D), (AV), (Y1), (Y1’), (Y2), (Y2’), (AA(a)), (AA(b)), (Y-a), (Y-aa), (Y-ab), (Ym), (Yn), (Yo), (Yp), (AA(c)), (AA(d)), (AA(e)), (A-II), (A-II-1), (A-IIa), (A-IIb), (A-III), (A-III-1), (A-IIIa), or derivatives having the specified characteristics described herein. [0507] An endosomal escape vehicle (EEV) can comprise a cyclic cell penetrating peptide (cCPP), an exocyclic peptide (EP) and linker, and can be conjugated to a cargo to form an EEV-conjugate comprising the structure of Formula (C):

or a protonated form thereof, wherein: R1, R2, and R3 can each independently be H or an amino acid residue having a side chain comprising an aromatic group; R₄ is H or an amino acid side chain; EP is an exocyclic peptide as defined herein; Cargo is a moiety as defined herein; each m is independently an integer from 0-3; n is an integer from 0-2; x’ is an integer from 2-20; y is an integer from 1-5; q is an integer from 1-4; and z’ is an integer from 2-20. [0508] R₁, R₂, R_3, R₄, EP, cargo, m, n, x’, y, q, and z’ are as defined herein. [0509] The EEV can be conjugated to a cargo and the EEV-conjugate can comprise the structure of Formula (C-a) or (C-b):

protonated form thereof, wherein EP, m and z are as defined above in Formula (C). [0510] The EEV can be conjugated to a cargo and the EEV-conjugate can comprise the structure of Formula (C-c):

or a protonated form thereof, wherein EP, R¹, R², R³, R⁴, and m are as defined above in Formula (III); AA can be an amino acid as defined herein; n can be an integer from 0-2; x can be an integer from 1-10; y can be an integer from 1-5; and z can be an integer from 1-10. [0511] An endosomal escape vehicle (EEV) can comprise a cyclic cell penetrating peptide (cCPP), an exocyclic peptide (EP) and linker, and can be conjugated to a cargo to form an EEV-conjugate comprising the structure of Formula (A-C):

[0512]

or a protonated form thereof, wherein: R₁, R₂, and R₃ can each independently be H or an amino acid residue having a side chain comprising an aromatic or heteroaromatic group; R4 or R6 is independently H or an amino acid side chain; EP is an exocyclic peptide as defined herein; Cargo is a moiety as defined herein; each m is independently an integer from 0-3; n is an integer from 0-2; n_x is 1; x’ is an integer from 2-20; y is an integer from 1-5; q is an integer from 1-4; and z’ is an integer from 2-20. [0513] R1, R2, R3, R4, EP, cargo, m, n, nx, x’, y, q, and z’ are as defined herein. [0514] The EEV can be conjugated to a cargo and the EEV-conjugate can comprise the structure of Formula (A-C-a) or (A-C-b):

[0515]

[0516] (A-C-b), or a protonated

form thereof, wherein EP, m and z are as defined above in Formula (A-C). [0517] The EEV can be conjugated to a cargo and the EEV-conjugate can comprise the structure of Formula (A-C-c):

or a protonated form thereof, wherein EP, R¹, R², R³, R⁴, and m are as defined above in Formula (III); AA can be an amino acid as defined herein; n can be an integer from 0-2; x can be an integer from 1-10; y can be an integer from 1-5; and z can be an integer from 1-10. [0518] The EEV can be conjugated to a cargo and the EEV-cargo conjugate can comprise a structure of Formula:

[0519]

[0520]

. [0521] In embodiments, the degradation compound includes a cCPP or an EEV conjugated to one or more elements of a degradation construct (e.g., the targeting moiety and/or the degradation moiety). In embodiments, the cCPP or EEV is conjugated to the targeting moiety of a degradation construct. In embodiments, the cCPP or EEV is conjugated to the degradation moiety of a degradation construct. In embodiments where the cCPP or EEV is conjugated the degradation moiety of the degradation construct, the cCPP or EEV may be conjugated to the degradation moiety through a disulfide bond (e.g., a disulfide bond between a cysteine reside in the degradation moiety and a cysteine residue in the cCPP or EEV). In embodiments where the degradation moiety includes a peptide or a protein, the N-terminus of the cCPP or EEV may be conjugated to the C- terminus of the degradation moiety. In embodiments where the degradation moiety includes a peptide or a protein, the N-terminus of the cCPP or EEV may be conjugated to the N-terminus of the degradation moiety. In embodiments where the degradation moiety includes a peptide or a protein, the C-terminus of the cCPP or EEV may be conjugated to the N-terminus of the degradation moiety. In embodiments where the degradation moiety includes a peptide or a protein, the C-terminus of the cCPP or EEV may be conjugated to the C-terminus of the degradation moiety. [0522] In embodiments, a cCPP or EEV conjugated to a degradation construct may be selected from: Ac-K(N3)-PEG4-PEG4-DLDLEMLAPYIPMDDDFQLGS-C-C-PEG12-K(cyclo(FfΦRrRrQ))- NH2; Ac-K(N3)-PEG4-PEG4- TSFAEYWNLLSPG-C-C-PEG12-K(cyclo(FfΦRrRrQ))-NH2; ;

; or

where the peptide portions are written from N to C; the EEV is underlined; C-C or S-S represents a disulfide bond; and the portion not underlined is includes the degradation moiety. In some such embodiments, a reactive group on the targeting moiety is reacted with the azide (N3) of the above constructs to from a covalent bond thereby forming the degradation compound. Cytosolic Delivery Efficiency [0523] Modifications to a cyclic cell penetrating peptide (cCPP) may improve cytosolic delivery efficiency. Improved cytosolic uptake efficiency can be measured by comparing the cytosolic delivery efficiency of a cCPP having a modified sequence to a control sequence. The control sequence does not include a particular replacement amino acid residue in the modified sequence (including, but not limited to arginine, phenylalanine, and/or glycine), but is otherwise identical. [0524] As used herein cytosolic delivery efficiency refers to the ability of a cCPP to traverse a cell membrane and enter the cytosol of a cell. Cytosolic delivery efficiency of the cCPP is not necessarily dependent on a receptor or a cell type. Cytosolic delivery efficiency can refer to absolute cytosolic delivery efficiency or relative cytosolic delivery efficiency. [0525] Absolute cytosolic delivery efficiency is the ratio of cytosolic concentration of a cCPP (or a cCPP-cargo conjugate) over the concentration of the cCPP (or the cCPP-cargo conjugate) in the growth medium. Relative cytosolic delivery efficiency refers to the concentration of a cCPP in the cytosol compared to the concentration of a control cCPP in the cytosol. Quantification can be achieved by fluorescently labeling the cCPP (e.g., with a FITC dye) and measuring the fluorescence intensity using techniques well-known in the art. [0526] Relative cytosolic delivery efficiency is determined by comparing (i) the amount of a cCPP of the invention internalized by a cell type (e.g., HeLa cells) to (ii) the amount of a control cCPP internalized by the same cell type. To measure relative cytosolic delivery efficiency, the cell type may be incubated in the presence of a cCPP for a specified period of time (e.g., 30 minutes, 1 hour, 2 hours, etc.) after which the amount of the cCPP internalized by the cell is quantified using methods known in the art, e.g., fluorescence microscopy. Separately, the same concentration of the control cCPP is incubated in the presence of the cell type over the same period of time, and the amount of the control cCPP internalized by the cell is quantified. [0527] Relative cytosolic delivery efficiency can be determined by measuring the IC₅₀ of a cCPP having a modified sequence for an intracellular target and comparing the IC50 of the cCPP having the modified sequence to a control sequence (as described herein). Methods of Making [0528] The cCPPs, EEVs, and compounds comprising the cCPPs and EEVs described herein can be prepared in a variety of ways known to one skilled in the art of organic synthesis or variations thereon as appreciated by those skilled in the art. The compounds described herein can be prepared from readily available starting materials. Reaction conditions can vary with the reactants or solvents used, but such conditions can be determined by one skilled in the art. [0529] For example, the cCPPs of the present disclosure may be prepared using methods similar to those described in WO2015179691A1 (Published PCT Application No. PCT/US2015/032043). [0530] Briefly, the cCPPs and/or the exocyclic peptides can be prepared using solid phase peptide synthesis using, resins, protecting groups, reaction conditions, deprotection conditions, purification conditions, commonly practiced in the art such as those described in WO2015179691A1 (Published PCT Application No. PCT/US2015/032043). [0531] Variations on the compounds described herein include the addition, subtraction, or movement of the various constituents as described for each compound. Similarly, when one or more chiral centers are present in a molecule, the chirality of the molecule can be changed. Additionally, compound synthesis can involve the protection and deprotection of various chemical groups. The use of protection and deprotection, and the selection of appropriate protecting groups can be determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, 2006, which is incorporated herein by reference in its entirety. [0532] Polymers, such as PEG groups, can be attached to a cCPP, an EEV, or a compound comprising a cCPP or an EEV, under any suitable conditions. Any means known in the art can be used, including via acylation, reductive alkylation, Michael addition, thiol alkylation or other chemoselective conjugation/ligation methods through a reactive group on the PEG moiety (e.g., an aldehyde, amino, ester, thiol, D-haloacetyl, maleimido or hydrazino group) to a reactive group on a cCPP, an EEV, or a compound comprising an EEV (e.g., an aldehyde, amino, ester, thiol, D- haloacetyl, maleimido or hydrazino group). Activating groups which can be used to link the water soluble polymer to one or more proteins include without limitation sulfone, maleimide, sulfhydryl, thiol, triflate, tresylate, azidirine, oxirane, 5-pyridyl, and alpha-halogenated acyl group (e.g., D- iodo acetic acid, D-bromoacetic acid, D-chloroacetic acid). If attached to a cCPP, an EEV, or a compound comprising an EEV by reductive alkylation, the polymer selected should have a single reactive aldehyde so that the degree of polymerization is controlled. See, for example, Kinstler et al., Adv. Drug. Delivery Rev. (2002), 54: 477-485; Roberts et al., Adv. Drug Delivery Rev. (2002), 54: 459-476; and Zalipsky et al., Adv. Drug Delivery Rev. (1995), 16: 157-182. [0533] Two or more components of a β-catenin targeting compound (e.g., targeting moiety; cCPP or EEV), or a degradation compound (e.g., degradation construct; degradation moiety; targeting moiety; cCPP or EEV) may be covalently coupled using conjugation chemistries such as bioconjugation chemistries. The reaction product of a conjugation chemistry reaction may be the bonding group (M) connecting a linker to a cCPP, EEV, degradation construct, degradation moiety, targeting moiety, or β-catenin antibody or fragment thereof. [0534] Bioconjugation chemistries are chemistries that allow for the conjugation of at least two molecules, at least one of which is a biomolecule (e.g., peptide, protein, antibody, carbohydrate, and the like). Bioconjugation chemistries are well known in the art and include but are not limited to, native chemical ligation; NHS-ester ligation, isocyanate ligation, isothiocyanate ligation, benzoyl fluoride ligation, maleimide ligation, iodoacetamide ligation, 2-thiopyridine disulfide exchange, 3-arylpropiolonitrile ligation, tetrazine ligation, diazonium salt conjugation, PTAD conjugation, copper mediated click ligation, copper free click ligation (e.g., strain-promoted azide- alkyne cycloaddition), tetrazine-alkene ligation, and Mannich ligation. Bioconjugation reactions may be orthogonal; that is, the chemistry is selective such that only two reactive groups react to form a new covalent bond even when additional reactive groups may be present. Orthogonal bioconjugation reactions are useful because they allow for multiple selective bioconjugation reactions to take place in series or in parallel. [0535] The reaction products of bioconjugation reactions, such as those described herein, are known in the art. Such reaction products may be included in a bonding group (M) that covalently links a linker to a cCPP, EEV, degradation construct, degradation moiety, targeting moiety, or β- catenin antibody or fragment thereof. [0536] To accomplish bioconjugation reactions, the two or more components being conjugated each include a reactive handle, such that the reactive handles are cooperative functional reactive handles. Cooperative functional handles are two or more reactive groups that when exposed to each other under favorable conditions, a bioconjugation reaction occurs to form a new covalent bond between the cooperative functional handles. Examples of cooperative reactive handles include an amine and an NHS-ester; a thiol and a maleimide; a disulfide and a thiol; an azide and an alkyne (azide and a linear alkyne in the presence of Cu(I); an azide and a cyclic alkyne such as cyclooctyne, difluorinated cyclooctyne, dibenxocyclooctyne, TMTH-SulfoxImine, biarylazacyclooctynone, or bicyclo[6.1.0]nonyne); an amine and an isocyanate; an amine and an isothiocyanate, a amine and a benzoyl fluoride; a thiol and a iodoacetamide; a thiol and a bromoacetamide; a disulfide and 2-thiopyridine; a thiol and 3-arylpropiolonitirle; a phenol and a diazonium salt; a phenol and 4-phenyl-1,2,4-triazoline-3,5-dione; a phenol, an aldehyde, and a aniline; an N-terminal amino acid having an OH group (serine or threonine) and sodium periodate; an N-terminal thiol (cysteine) and an iodoacetamide; the N-terminus and a pyridoxal phosphate; an azide and a functionalized triphenyl phosphine; a tetrazine and a strained alkene; and the like. In some cases, a bioconjugation reaction is preceded by a reaction to attach a ketone or an aldehyde to a protein or polypeptide. Such reactions include oxidation of N-terminal serine residues or transamination with pyridoxal phosphate. Unnatural amino acids containing a ketone, or an aldehyde may also be incorporated into a protein or polypeptide. Upon inclusion of a ketone in a protein or polypeptide, the ketone can be reacted with an alkoxyamine to produce an oxime. Upon inclusion of an aldehyde in a protein or polypeptide, the aldehyde can be reacted with a hydrazine to form a hydrazone. [0537] In embodiments where the cCPP or EEV containing compounds is a β-catenin targeting compound, one reactive handle of a cooperative reactive handle pair may be on a cCPP-linker or EEV-linker conjugate and the second reactive handle may be on the targeting moiety or the β- catenin antibody or antigen binding fragment thereof. In such embodiments, the reaction product of the two reactive handles forms the bonding group (M) thereby connecting the targeting moiety or the β-catenin antibody or antigen binding fragment thereof to the cCPP-linker or EEV-linker conjugate forming the β-catenin targeting compound. [0538] In embodiments where the cCPP or EEV containing compounds is a degradation compound, one reactive handle of a cooperative reactive handle pair may be on a cCPP-linker or EEV-linker conjugate and the second reactive handle may be on the degradation construct (e.g., on the targeting moiety or the degradation moiety). In such embodiments, the reaction product of the two reactive handles forms the bonding group (M) thereby connecting the degradation moiety to the cCPP-linker or EEV-linker conjugate forming the degradation compound. [0539] Traditional bioconjugation chemistries may include reaction conditions that are incompatible with certain molecules for certain applications. For example, bioconjugation reactive handles may have multiple cooperative functional handle counterparts, which may lead to non- specific bioconjugation reactions or multiple conjugations to a single molecule that includes the cooperative functional handles. Some bioconjugation chemistries may include reaction conditions that are incompatible with certain small molecules (e.g., cCPP or EEVs) and/or biomolecules such as proteins (e.g., antibodies) or peptides. For example, the reaction conditions may promote the unfolding, degradation, or precipitation of biomolecules and/or promote other functional groups on the compound to degrade or react nonspecifically. In some instances, bioconjugation reactive handles are unstable prior to reaction with a respective cooperative handle, making them challenging to handle. [0540] Common bioconjugation chemistries include maleimide and NHS-ester bioconjugation reactions. Maleimide bioconjugation reactions include the reaction between a maleimide and a thiol or thiolate (see FIG. 4A). The thiolate may be a part of a small molecule or a biomolecule such as a protein or peptide (e.g., the thiol of a cysteine residue). In cases where a protein or peptide is involved, the maleimide bioconjugation is often conducted in disulfide reducing conditions to expose a thiol or a thiolate on the protein or peptide. The reducing conditions are tailored to allow for reduction of non-structural disulfides and inter-protein disulfides but not the reduction of structural intra-protein disulfides. Additionally, maleimide bioconjugation reactions are often performed at a pH of 6.5 to 9, which may not be compatible with particular compounds (e.g., cCPPs or EEVs) and/or proteins or peptides. Furthermore, the maleimide functional handle is prone to hydrolysis. As such, solutions of compounds that include a free maleimide group may not be stable for extended periods of time. [0541] NHS-ester bioconjugation reactions (also called NHS-ester ligation) include the reaction between an NHS-ester and an amine (see the first reaction of FIG 4D). The amine may be an amino acid side chain (e.g., the amine of lysine) of a cCPP or EEV or a biomolecule such as protein (e.g., antibody). Many proteins and small molecules include multiple amines that can participate in a bioconjugation reaction with an NHS-ester which makes controlling the location, specificity, and number of the bioconjugation reactions on a protein or small molecule challenging. Additionally, NHS-ester bioconjugation reactions are often performed at a pH of 6.5 to 9, which may not be compatible with particular compounds (e.g., cCPPs or EEVs) and/or proteins. [0542] Developing a bioconjugation strategy for two components (e.g., two components of a β- catenin targeting compound, or a degradation compound) may be challenging due to the caveats of various bioconjugation chemistries including the reactivity and stability of the components under a given set of reaction conditions. In embodiments, two components (e.g., two components of a β-catenin targeting compound, or a degradation compound) are covalently coupled using a direct bioconjugation reaction or an indirect bioconjugation reaction. [0543] In embodiments, two components (e.g., two components of a β-catenin targeting compound, or a degradation compound) are covalently coupled using a direct bioconjugation reaction. A direct bioconjugation reaction is a reaction in which the two components that are being covalently linked have the proper cooperative functional handles without the need for an intermediary bifunctional bioconjugation compound (discussed elsewhere herein). Direct bioconjugation reactions can be accomplished using any of the cooperative functional handles disclosed herein. An example of a direct bioconjugation reaction is shown in FIG. 4A. FIG. 4A is a maleimide ligation. In the bioconjugation reaction, a first component A having a thiol is reacted with a second component B having a maleimide group to form a new covalent bond between the sulfur atom of the thiol and a carbon atom of the alkene (now an alkane). Components A and B may be any EEV, cCPP, EEV-linker conjugate, cCPP-linker conjugate, protein, peptide, or other group (e.g., targeting moiety, bispecific targeting moiety, degradation moiety, and the like). [0544] In embodiments, two components (e.g., two components of a β-catenin targeting compound, or a degradation compound) are covalently coupled using a bifunctional bioconjugation compound in an indirect bioconjugation reaction. An indirect bioconjugation reaction, is the conjugation of two components through an intermediary bifunctional bioconjugation compound. A bifunctional bioconjugation compound includes a first reactive handle and a second reactive handle that are configured to react with cooperative functional handles on the components to be conjugated. Examples of pairs of reactive handles on a bifunctional bioconjugation compound include NHS-ester and an alkyne, a maleimide and an NHS-ester, an NHS ester and a disulfide, a dibenzocyclooctyne (DBCO) and an NHS ester, DBCO and a tetrafluophenyl ester, and the like. Indirect bioconjugation reactions often include two consecutive bioconjugation reactions; a first bioconjugation reaction to attach a first component to the bifunctional bioconjugation compound and a second bioconjugation reaction to attach the second component to the bifunctional bioconjugation compound. Generally, the two bioconjugation reactions are orthogonal. The first component has a reactive handle that is cooperative with a first reactive handle on the bifunctional bioconjugation compound, and the second component has a reactive handle that is cooperative with a second reactive handle on the bifunctional bioconjugation compound. Generally, the two pairs of cooperative functional handles allow for orthogonal bioconjugation reactions. Any bioconjugation chemistry and any two pairs of cooperative functional handles described herein may be used. [0545] In embodiments where two components of a β-catenin targeting compound or degradation compound are coupled using a bifunctional bioconjugation compound and two bioconjugation reactions, the bonding group (M) connecting the two components includes the reaction products of the two conjugation reactions and any chemical group of the bifunctional bioconjugation compound that separated the two reactive handles bifunctional bioconjugation compound (e.g., see FIG.4A, 4B, and 4C). [0546] FIG. 4B, 4C, and 4D show examples of indirect bioconjugation reactions where components A and B are conjugated via an intermediary bifunctional bioconjugation compound. FIG.4B shows a succinimidyl 3-(2-pyridyldithio)propionate (SPDP) bifunctional bioconjugation compound and the corresponding conjugation reactions. In a first bioconjugation reaction, the NHS-ester portion of SPDP reacts with the amine on component B to form an intermediate that includes component B and the pyridyldithio reactive handle of SPDP. In a second bioconjugation reaction, component A that includes a thiol undergoes a disulfide exchange reaction with the pyridyldithio reactive handle of the intermediate to form the final product; that is, a compound in which components A and B are conjugated. The intervening chemical group separating A and B following the two conjugation reactions may be a bonding group (M) as described elsewhere herein. Components A and B may be any protein, peptide, EEV, or other group (e.g., targeting moiety, bispecific targeting moiety, degradation moiety, and the like). Components A and B may be any EEV, cCPP, EEV-linker conjugate, cCPP-linker conjugate, protein, peptide, or other group (e.g., targeting moiety, bispecific targeting moiety, degradation moiety, and the like). [0547] FIG. 4C shows a maleimide (Mal) and DBCO (dibenzocyclooctyne) containing bifunctional bioconjugation compound and the corresponding conjugation reactions. In a first bioconjugation reaction, the thiol of component A reacts with the maleimide of the bifunctional bioconjugation compound to form an intermediate that includes covalent bond between the bifunctional bioconjugation compound and component A. In a second bioconjugation reaction, the azide of component B undergoes a click reaction with the alkyne of the DBCO reactive handle of the intermediate to form a triazole and the final product; that is, a compound in which components A and B are conjugated. The intervening chemical group separating A and B following the two conjugation reactions may be a bonding group (M) as described elsewhere herein. Components A and B may be any EEV, cCPP, EEV-linker conjugate, cCPP-linker conjugate, protein, peptide, or other group (e.g., targeting moiety, bispecific targeting moiety, degradation moiety, and the like). [0548] FIG.4D shows a DBCO and NHS ester containing bifunctional bioconjugation compound as well as a DBCO and tetrafluophenyl (TFP) containing bifunctional bioconjugation compound and the corresponding bioconjugation reactions. In a first bioconjugation reaction, the amine of component A reacts with the NHS ester or the TFP of the bifunctional bioconjugation compound to form an intermediate that includes an amide covalent bond between the bifunctional bioconjugation compound and component A. In a second bioconjugation reaction, the azide of component B undergoes a click reaction with the alkyne of the DBCO reactive handle of the intermediate to form a triazole and the final product; that is, a compound in which components A and B are conjugated. The intervening chemical group separating A and B following the two conjugation reactions may be a bonding group (M) as described elsewhere herein. Components A and B may be any protein, peptide, EEV, or other group (e.g., targeting moiety, bispecific targeting moiety, degradation moiety, and the like). [0549] The caveats of bioconjugation chemistries may be amplified when a bifunctional bioconjugation compound is used because the number of variables increases. Both the identity of bioconjugation reactive handles and/or the order of the reactions may impact the final product. The first component that is conjugated to the bifunctional bioconjugation compound in the first bioconjugation reaction should be able to withstand the bioconjugation reaction conditions of the second bioconjugation reaction. In the case of conjugating a cCPP or EEV to a targeting moiety or a degradation construct, the buffer conditions and stability of the cCPP or EEV and the targeting moiety or degradation construct should also be considered. [0550] In embodiments, a bifunctional bioconjugation compounds that included an alkyne (e.g., DBCO) and a maleimide, an NHS ester, or a TFP may be used to conjugate a cCPP, EEV, cCPP- linker conjugate, or an EEV-linker conjugate to a targeting moiety or a degradation construct. In some such embodiments, the maleimide, NHS ester, or TFP bioconjugation chemistry is used to conjugate the targeting moiety or degradation construct to the bifunctional bioconjugation compound followed by click chemistry of the DCO group of the bifunctional bioconjugation compound with the cCPP or EEV. Through experimentation, it was found that click chemistry is more widely compatible with cCPPs and EEVs than NHS-ester chemistry or maleimide chemistry. As such, using this synthetic scheme allowed for the creation of bulk bioconjugation compound – targeting moiety or degradation construct conjugates that were conjugated to a variety of EEVs for screening purposes. In embodiments, a reactive handle may be installed on an appropriate amino acid residue of the cCPP or EEV through reaction with an organic derivatizing agent that is capable of reacting with a selected side chain or the N- or C-termini of an amino acid. Reactive groups on the peptide or conjugate moiety include, e.g., an aldehyde, amino, ester, thiol, D-haloacetyl, maleimido or hydrazino group. Derivatizing agents include, for example, maleimidobenzoyl sulfosuccinimide ester (conjugation through cysteine residues), N-hydroxysuccinimide (through lysine residues), glutaraldehyde, succinic anhydride or other agents known in the art. [0551] Non-limiting examples of compounds that include a cCPPs and a reactive group useful for conjugation of components of a β-catenin targeting compound or a degrader compound are shown in Table 11. Example linker groups are also shown. Example reactive groups include tetrafluorophenyl ester (TFP), free carboxylic acid (COOH), an azide (N3), thiols, and an alkyne (e.g., a cyclooctyne). In Table 11, n is an integer from 0 to 20; Pipa6 is AcRXRRBRRXRYQFLIRXRBRXRB wherein B is β-Alanine; X is aminohexanoic acid; Dap is 2,3-diaminopropionic acid; NLS is a nuclear localization sequence; βA is β alanine; -ss- is a disulfide; PABC is poly(A) binding protein C-terminal domain; C_x where x is a number is an alkyl chain of length x; and BCN is bicyclo [6.1.0]nonyne. Table 11. Compounds that include a CPPs and a reactive group

Polynucleotides and Expression Vectors [0552] In another embodiment, this disclosure describes an isolated polynucleotide molecule. In embodiments, the isolated polynucleotide molecule includes a nucleotide sequence encoding a β- catenin antibody or antigen binding fragment thereof, bispecific construct, and/or a degradation construct described herein. In embodiments, the isolated polynucleotide molecule includes a nucleotide sequence that has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to nucleotide sequence encoding a β-catenin antibody or antigen binding fragment thereof, bispecific construct and/or a degradation construct described herein. In embodiments, the isolated polynucleotide molecule includes polynucleotides that hybridize under high stringency to a nucleotide sequence encoding an antibody or a complement thereof. As used herein “stringent conditions” refer to the ability of a first polynucleotide molecule to hybridize, and remain bound to, a second, filter-bound polynucleotide molecule in 0.5 M NaHPO₄, 7% sodium dodecyl sulfate (SDS), and 1 mM EDTA at 65°C, followed by washing in 0.2 X SSC/0.1% SDS at 42°C (see Ausubel et al. (eds.), Current Protocols in Molecular Biology, Vol. 1, Green Publishing Associates, Inc., and John Wiley & Sons, Inc., N.Y. (1989), at p. 2.10.3). In embodiments, the isolated polynucleotide molecule includes polynucleotides that encode one or more of the CDRs or the variable region of a β-catenin antibody or antigen binding fragment thereof and/or a degradation construct described herein. General techniques for cloning and sequencing immunoglobulin variable domains and constant regions are well known. See, for example, Orlandi et al. (Orlandi et al. Proc Natl Acad Sci U S A 86, 3833-3837 (1989)). [0553] In another embodiment, this disclosure describes recombinant vectors including an isolated polynucleotide of the present disclosure. The vector may be, for example, in the form of a plasmid, a viral particle, or a phage. The appropriate DNA sequence may be inserted into a vector by a variety of procedures for example, electroporation, sonoporation, lipofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, nanoparticles, polycation or lipid:nucleic acid conjugates, naked DNA, artificial virions, DEAE-dextran-mediated transfer, gene gun, and heat- shock. In general, the DNA sequence is inserted into an appropriate restriction endonuclease site(s) in a vector by procedures known in the art. Such procedures are deemed to be within the scope of those skilled in the art. Large numbers of suitable vectors and promoters are known to those of skill in the art and are commercially available. The following vectors are provided by way of example. Bacterial vectors include, for example, pQE70, pQE60, pQE-9, pBS, pD10, phagescript, psiX174, pbluescript SK, pbsks, pNH8A, pNH16a, pNH18A, pNH46A, ptrc99a, pKK223-3, pKK233-3, pDR540, and pRIT5. Eukaryotic vectors include, for example, pWLNEO, pSV2CAT, pOG44, pXT1, pSG, pSVK3, pBPV, pMSG, and pSVL. However, any other plasmids or vectors may be used. [0554] In a further embodiment, this disclosure also describes a host cell containing at least one of the above-described vectors. In embodiments, the host cell is a higher eukaryotic cell, such as a mammalian or insect cell, or a lower eukaryotic cell, such as a yeast cell. In embodiments, the host cell is a prokaryotic cell, such as a bacterial cell, or a plant cell. Introduction of a vector construct into the host cell may be effected by any suitable techniques, such as, for example, calcium phosphate transfection, DEAE-Dextran mediated transfection, electroporation, or nucleofection. [0555] β-catenin antibodies or antigen binding fragments thereof, targeting moieties, bispecific constructs, and/or degradation constructs of the present disclosure may be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free translation systems may also be employed to produce such proteins using RNAs derived from the DNA constructs of the present disclosure. Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y. (1989). [0556] As an alternative, β-catenin antibodies or antigen binding fragments thereof, targeting moieties, bispecific constructs, degradation moieties, and/or degradation constructs of the present disclosure can be synthesized by exclusive solid phase synthesis, partial solid phase methods, fragment condensation or classical solution synthesis. These synthesis methods are well-known to those of skill in the art (see, for example, Merrifield, J. Am. Chem. Soc.85:2149 (1963), Stewart et al., “Solid Phase Peptide Synthesis” (2nd Edition), (Pierce Chemical Co. 1984), Bayer and Rapp, Chem. Pept. Prot.3:3 (1986), Atherton et al., Solid Phase Peptide Synthesis: A Practical Approach (IRL Press 1989), Fields and Colowick, “Solid-Phase Peptide Synthesis,” Methods in Enzymology Volume 289 (Academic Press 1997), and Lloyd-Williams et al., Chemical Approaches to the Synthesis of Peptides and Proteins (CRC Press, Inc.1997)). Variations in total chemical synthesis strategies, such as “native chemical ligation” and “expressed protein ligation” are also standard (see, for example, Dawson et al., Science 266:776 (1994), Hackeng et al., Proc. Nat'l Acad. Sci. USA 94:7845 (1997), Dawson, Methods Enzymol.287: 34 (1997), Muir et al, Proc. Nat'l Acad. Sci. USA 95:6705 (1998), and Severinov and Muir, J. Biol. Chem.273:16205 (1998)). In one example of expressed protein ligation, a recombinantly expressed protein is cleaved from an intein and the protein is ligated to a peptide containing an N-terminal cysteine having an unoxidized sulfhydryl side chain, by contacting the protein with the peptide in a reaction solution containing a conjugated thiophenol. This forms a C-terminal thioester of the recombinant protein which spontaneously rearranges intramolecularly to form an amide bond linking the protein to the peptide. See, generally, Muir, TW et al Expressed Protein Ligation: A General Method for Protein Engineering, PNAS (1998) 95(12)6705-6710; US Pat. No.6,849,428; US Pub.2002/0151006; Bondalapati, et al., Expanding the chemical toolbox for the synthesis of large and uniquely modified proteins. (2016) Nature Chemistry volume 8, pages 407–418; Amy E. Rabideau and Bradley Lether Pentelute, Delivery of Non-Native Cargo into Mammalian Cells Using Anthrax Lethal Toxin. ACS Chem. (2016) Biol., 11(6) 1490-1501; and Weidmann et al., Copying Life: Synthesis of an Enzymatically Active Mirror-Image DNA-Ligase Made of D- Amino Acids. Cell Chemical Biology, (2019 May 16) 26(5); 616-619. [0557] Also included in the present disclosure are phage display libraries expressing one or more hypervariable regions from a β-catenin antibody of the present disclosure, and the clones obtained from such a phage display library. A phage display library is used to produce antibody-derived molecules. Gene segments encoding the antigen-binding variable domains of antibodies are fused to genes encoding the coat protein of a bacteriophage. Bacteriophage containing such gene fusions are used to infect bacteria, and the resulting phage particles have coats that express the antibody- fusion protein, with the antigen-binding domain displayed on the outside of the bacteriophage. Phage display libraries may be prepared, for example, using the PH.D.-7 Phage Display Peptide Library Kit (Catalog # E8100S) or the PH.D. -12 Phage Display Peptide Library Kit (Catalog # E8110S), available from New England Biolabs Inc., Ipswich, MA. See, for example, Smith and Petrenko (Smith et al. Chem Rev 97, 391-410 (1997)). [0558] In embodiments, the anti-β-catenin antibody is a monoclonal antibody. [0559] In embodiments, the β-catenin antibody is an isolated antibody. In embodiments, the β- catenin antibodies are isolated or purified by conventional immunoglobulin purification procedures, such as, for example, protein A- or G-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. [0560] In embodiments, a β-catenin antibody or antigen binding fragment thereof, bispecific construct, targeting moiety, degradation moiety, degradation construct, and/or degradation compound may be coupled directly or indirectly to a detectable marker by techniques well known in the art. A detectable marker is an agent detectable, for example, by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. Useful detectable markers include, but are not limited to, fluorescent dyes, chemiluminescent compounds, radioisotopes, electron-dense reagents, enzymes, coenzymes, colored particles, biotin, or dioxigenin. Compositions and Methods of Administration [0561] In embodiments, this disclosure describes compositions that include a β-catenin antibody or antigen binding fragment thereof, a β-catenin targeting compound, a degradation construct, targeting moiety, and/or a degradation compound as described herein. In embodiments, the composition is a pharmaceutical composition. [0562] A β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, degradation compound, targeting moiety, and pharmaceutical compositions thereof described herein can be administered to a subject to treat or prevent a disease or condition, or one or more symptoms of a disease or condition. In embodiments, a therapeutically-effective amount of a β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, degradation compound, targeting moiety, or pharmaceutical composition thereof may be administered to a subject to treat and/or prevent a disease or condition or progression thereof. [0563] The amount, duration and frequency of administration of a pharmaceutical composition or β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, targeting moiety, and/or degradation compound described herein can depend on several factors including, but not limited to, the health of the subject, the disease or condition being treated, the grade or level of a specific disease or condition of the patient, whether the subject has been administered any additional therapeutics, and the like. [0564] The β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, targeting moiety, and/or degradation compound described herein, and compositions containing them, may be administered by any suitable method and technique presently or prospectively known to those skilled in the art. For example, the disclosed β-catenin antibodies or antigen binding fragment thereof, β-catenin targeting compound, degradation constructs, targeting moieties, and/or degradation compounds can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art including, for example, oral and parenteral routes of administration. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection. Administration of the disclosed compounds or compositions can be a single administration, or at continuous or distinct intervals as can be readily determined by a person skilled in the art. [0565] The β-catenin antibodies or antigen binding fragments thereof, β-catenin targeting compound, degradation constructs, targeting moieties, and/or degradation compounds described herein, and compositions comprising them, can also be administered utilizing liposome technology, slow release capsules, implantable pumps, and biodegradable containers. These delivery methods can, advantageously, provide a uniform dosage over an extended period of time. The β-catenin antibodies or antigen binding fragments thereof, β-catenin targeting compound, degradation constructs, targeting moieties, and/or degradation compounds described herein can also be administered in their salt derivative forms. [0566] The β-catenin antibodies or antigen binding fragments thereof, β-catenin targeting compound, degradation constructs, targeting moieties, and/or degradation compounds described herein can be formulated according to known methods for preparing pharmaceutically acceptable compositions. Formulations are described in detail in a number of sources which are well known and readily available to those skilled in the art. For example, Remington’s Pharmaceutical Science by E.W. Martin (2020) describes formulations that can be used in connection with the disclosed methods. In general, the β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, targeting moiety, and/or degradation compound disclosed herein can be formulated such that an effective amount of the β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, targeting moiety, and/or degradation compound is combined with a suitable carrier in order to facilitate effective administration of β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, targeting moiety, and/or degradation compound described herein. The compositions used can also be in a variety of forms. These include, for example, solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspension, injectable and infusible solutions, and sprays. The form depends on the intended mode of administration and therapeutic application. In embodiments, the constructs are formulated as a liquid dosage form, such as an injectable and infusible solutions. [0567] In embodiments, the compositions also include pharmaceutically-acceptable carriers and diluents. Examples of carriers or diluents for use with the compounds include ethanol, dimethyl sulfoxide, glycerol, alumina, starch, saline, and equivalent carriers and diluents. To provide for the administration of such dosages for the desired therapeutic treatment, compositions disclosed herein can advantageously comprise between about 0.1% and 100% by weight of the total of one or more of the subject constructs based on the weight of the total composition including carrier or diluent. [0568] Formulations suitable for parenteral administration include, for example, aqueous sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions, which can include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze dried (lyophilized) condition requiring only the condition of the sterile liquid carrier, for example, water for injections, prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powder, granules, tablets, etc. It should be understood that in addition to the ingredients mentioned above, the compositions disclosed herein can include other agents conventional in the art having regard to the type of formulation in question. [0569] β-catenin antibodies or antigen binding fragments thereof, β-catenin targeting compounds, degradation constructs, targeting moieties, and/or degradation compounds and compositions disclosed herein can be administered intravenously, intramuscularly, or intraperitoneally by infusion or injection. Solutions of the β-catenin antibodies or antigen binding fragments thereof, β-catenin targeting compounds, degradation constructs, targeting moieties, and/or degradation compounds or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms. [0570] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient, which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. Optionally, the prevention of the action of microorganisms can be brought about by various other antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases isotonic agents, for example, sugars, buffers or sodium chloride may be included. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents that delay absorption, for example, aluminum monostearate and gelatin. [0571] Sterile injectable solutions may be prepared by incorporating a β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, targeting moiety, and/or degradation compound disclosed herein in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation including vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. [0572] Useful dosages of the β-catenin antibodies or antigen binding fragments thereof, β-catenin targeting compounds, degradation constructs, targeting moieties, and/or degradation compounds and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art. [0573] The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex, and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. [0574] Also disclosed are kits that comprise a β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, targeting moiety, and/or degradation compound described herein in one or more containers. The disclosed kits can optionally include pharmaceutically acceptable carriers and/or diluents. In embodiments, a kit includes one or more other components, adjuncts, or adjuvants as described herein. In embodiments, a kit includes one or more anti-cancer agents, such as those agents described herein. In embodiments, a kit includes instructions or packaging materials that describe how to administer a compound or composition of the kit. Containers of the kit can be of any suitable material, e.g., glass, plastic, metal, etc., and of any suitable size, shape, or configuration. In embodiments, a compound and/or agent disclosed herein is provided in the kit as a solid, such as a tablet, pill, or powder form. In embodiments, a β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, targeting moiety, and/or degradation compound disclosed herein is provided in the kit as a liquid or solution. In embodiments, the kit comprises an ampoule or syringe containing a β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, targeting moiety, and/or degradation compound described herein in liquid or solution form. [0575] The β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, targeting moiety, and/or degradation compound described herein may be used to treat a wide range of diseases. In embodiments, the β-catenin antibodies or antigen binding fragments thereof, β-catenin targeting compound, degradation constructs, targeting moieties, and/or degradation compounds disclosed herein can be used in the treatment of a wide range of diseases associated with β-catenin. the β-catenin antibodies or antigen binding fragments thereof, β-catenin targeting compound, degradation constructs, targeting moeites, and/or degradation compounds disclosed herein can be used to treat diseases associated with upregulation of β- catenin, upregulation and/or downregulation of genes and/or proteins regulated by β-catenin, aberrant activity of β-catenin, and/or dysfunctional β-catenin. In embodiments, the β-catenin antibodies or antigen binding fragments thereof, β-catenin targeting compound, degradation constructs, and/or degradation compounds disclosed herein may be used to treat cardiac diseases including dilated cardiomyopathy, coronary disease, and congenital heart disorders and/or metabolic disorders including Type II diabetes and obesity. [0576] In embodiments, β-catenin antibody or antigen binding fragment thereof, β-catenin targeting compound, degradation construct, targeting moiety, and/or degradation compound described herein may be used to treat various cancers. The cancers may be selected from primary tumors (e.g., cancer cells at the originating site), local invasion (cancer cells which penetrate and infiltrate surrounding normal tissues in the local area), and metastatic (or secondary) tumors – e.g., tumors that have formed from malignant cells which have circulated through the bloodstream (haematogenous spread) or via lymphatics or across body cavities (trans-coelomic) to other sites and tissues in the body. Examples of cancers (and their benign counterparts) which may be treated (or inhibited) include, but are not limited to tumors of epithelial origin (adenomas and carcinomas of various types including adenocarcinomas, squamous carcinomas, transitional cell carcinomas and other carcinomas) such as carcinomas of the bladder and urinary tract, breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, bowel, colon, rectum and anus), liver (hepatocellular carcinoma), gall bladder and biliary system, exocrine pancreas, kidney (renal cell carcinoma), lung (for example adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas and mesotheliomas), head and neck (for example cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity and paranasal sinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis, cervix, myometrium, endometrium, thyroid (for example thyroid follicular carcinoma), adrenal, prostate, skin and adnexae (for example melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic naevus); haematological malignancies (i.e. leukemias, lymphomas) and premalignant haematological disorders and disorders of borderline malignancy including haematological malignancies and related conditions of lymphoid lineage (for example acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukaemia (CML), B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL), Pre-B acute lymphoblastic leukaemia, Pre-B lymphomas, Large B-cell lymphomas, B-Cell acute lymphoblastic leukaemia, Philadelphia chromosome positive acute lymphoblastic leukaemia, Philadelphia chromosome positive chronic myeloid leukaemia, follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, T-cell lymphomas and leukaemias, T-lineage acute lymphoblastic leukaemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukaemia, natural killer (NK) cell lymphomas, Hodgkin's lymphomas, Non-Hodgkin's lymphomas, hairy cell leukaemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorders), and haematological malignancies and related conditions of myeloid lineage (for example acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome, myeloproliferative disorders such as polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (for example sarcomas of soft tissue, bone or cartilage such as osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, myosarcoma, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumors, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; neural crest cell-derived tumors including melanocytic tumors (for example, malignant melanoma or uveal melanoma), tumors of peripheral and cranial nerves, peripheral neuroblastic tumors (for example, neuroblastoma), embryonal tumors of the CNS, paraganglioma; tumors of the central or peripheral nervous system (for example, astrocytomas, gliomas and glioblastomas, gangliogliomas, ganglioneuromas, oligodendroglioma, meningiomas, ependymomas, pineal tumors and schwannomas); endocrine tumors (for example, pituitary tumors, adrenal tumors, islet cell tumors, parathyroid tumors, carcinoid tumors and medullary carcinoma of the thyroid); ocular and adnexal tumors (for example, retinoblastoma); germ cell and trophoblastic tumors (for example, teratomas, seminomas, dysgerminomas, hydatidiform moles and choriocarcinomas); and pediatric and embryonal tumors (for example medulloblastoma, neuroblastoma, Wilms tumor, and primitive neuroectodermal tumors); or syndromes, congenital or otherwise, which leave the patient susceptible to malignancy (for example, Xeroderma Pigmentosum). [0577] Specific types of cancers or malignant tumors, either primary or secondary, that can be treated using the disclosed degradation compounds include breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gall bladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuronms, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fimgoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and other sarcoma, malignant hypercalcemia, renal cell tumor, polycythemia vera, adenocarcinoma, glioblastoma multiforma, leukemias, lymphomas, malignant melanomas, epidermoid carcinomas, and other carcinomas and sarcomas Certain Definitions [0578] Terms used herein will be understood to take on their ordinary meaning in the relevant art unless specified otherwise. Several terms used herein and their meanings are set forth below. [0579] “b”, “beta”, and “E” are used herein interchangeably in the context of a beta-amino acid or beta-catenin. [0580] As used in the description and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions, reference to “an agent” includes mixtures of two or more such agents, reference to “the component” includes mixtures of two or more such components, and the like. [0581] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, …”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range. [0582] As used herein, “cell penetrating peptide” or “CPP” refers to a peptide that facilitates delivery of a cargo, e.g., a β-catenin antibody or antigen binding fragment thereof, degradation compound, or β-catenin targeting compound into a cell. In embodiments, the CPP is cyclic, and is represented as “cCPP”. In embodiments, the cCPP is capable of directing a cargo (e.g., a β-catenin antibody or antigen binding fragment thereof, degradation compound, or β-catenin targeting compound) to penetrate the membrane of a cell. In embodiments, the cCPP delivers the therapeutic moiety to the cytosol of the cell. [0583] As used herein, the term “endosomal escape vehicle” (EEV) refers to a cCPP that is conjugated by a chemical linkage (i.e., a covalent bond or non-covalent interaction) to a linker and/or an exocyclic peptide (EP). [0584] As used herein, the term “EEV-conjugate” refers to an endosomal escape vehicle defined herein conjugated by a chemical linkage (i.e., a covalent bond or non-covalent interaction) to a cargo. The cargo can be a therapeutic moiety (e.g., a β-catenin antibody or antigen binding fragment thereof, degradation compound, or β-catenin targeting compound) that can be delivered into a cell by the EEV. [0585] As used herein, the term “cCPP-linker conjugate” refers to a cCPP that is covalently attached to a linker, such as, for example, a divalent linker. Similarly, the term “EEV-linker conjugate” refers to an EEV that is covalently attached to a linker of the present disclosure. An EEV-linker conjugate may include a cCPP and an exocyclic peptide both covalently linked to a linker, such as, for example, a trivalent linker. A cCPP-linker conjugate and an EEV-linker conjugate can be further conjugated to a cargo (e.g., a β-catenin antibody or antigen binding fragment thereof, degradation compound, or β-catenin targeting compound) [0586] As used herein, the term "exocyclic peptide" (EP) and “modulatory peptide” (MP) may be used interchangeably to refer to two or more amino acid residues linked by a peptide bond that can be conjugated to (e.g., through a linker) a cyclic cell penetrating peptide (cCPP) disclosed herein. The EP, when conjugated to a cyclic peptide disclosed herein, may alter the tissue distribution and/or retention of the compound. Typically, the EP comprises at least one positively charged amino acid residue, e.g., at least one lysine residue and/or at least one arginine residue. Non- limiting examples of EP are described herein. The EP can be a peptide that has been identified in the art as a “nuclear localization sequence” (NLS). Non-limiting examples of nuclear localization sequences include the nuclear localization sequence of the SV40 virus large T-antigen, the minimal functional unit of which is the seven amino acid sequence PKKKRKV, the nucleoplasmin bipartite NLS with the sequence NLSKRPAAIKKAGQAKKKK, the c-myc nuclear localization sequence having the amino acid sequence PAAKRVKLD or RQRRNELKRSF, the sequence RMRKFKNKGKDTAELRRRRVEVSVELRKAKKDEQILKRRNV of the IBB domain from importin-alpha, the sequences VSRKRPRP and PPKKARED of the myoma T protein, the sequence PQPKKKPL of human p53, the sequence SALIKKKKKMAP of mouse c-abl IV, the sequences DRLRR and PKQKKRK of the influenza virus NS1, the sequence RKLKKKIKKL of the Hepatitis virus delta antigen and the sequence REKKKFLKRR of the mouse Mxl protein, the sequence KRKGDEVDGVDEVAKKKSKK of the human poly(ADP-ribose) polymerase and the sequence RKCLQAGMNLEARKTKK of the steroid hormone receptors (human) glucocorticoid. International Publication No. 2001/038547 describes additional examples of NLSs and is incorporated by reference herein in its entirety. [0587] As used herein, “linker” or “L” refers to a moiety that operably links through one or more covalently bonds two or more moieties together. In embodiments, a linker operably couples, through a covalently bond, one or more moieties (e.g., an exocyclic peptide (EP) and/or a cargo,) to the cyclic cell penetrating peptide (cCPP). The linker can comprise a natural or non-natural amino acid or polypeptide. The linker can be a synthetic compound containing two or more appropriate functional groups suitable to bind to another functional group of compounds disclosed herein (e.g., the linker can include two or more functional groups to operably couple the cCPP to a cargo). The linker can be a polypeptide that operably couples a first targeting domain to a second targeting domain or a degradation moiety to a targeting moiety. The linker can comprise a polyethylene glycol (PEG) moiety. The linker can comprise one or more amino acids. The cCPP may be covalently bound to a cargo via a linker. [0588] The terms “peptide,” “protein,” and “polypeptide” are used interchangeably to refer to a natural or synthetic molecule comprising two or more amino acids linked by the carboxyl group of one amino acid to the alpha amino group of another. Two or more amino acid residues can be linked by the carboxyl group of one amino acid to the alpha amino group. Two or more amino acids of the polypeptide can be joined by a peptide bond. The polypeptide can include a peptide backbone modification in which two or more amino acids are covalently attached by a bond other than a peptide bond. The polypeptide can include one or more non-natural amino acids, amino acid analogs, or other synthetic molecules that are capable of integrating into a polypeptide. The term polypeptide includes naturally occurring and artificially occurring amino acids. The term polypeptide includes peptides, for example, that include from about 2 to about 100 amino acid residues as well as proteins, that include more than about 100 amino acid residues, or more than about 1000 amino acid residues, including, but not limited to therapeutic proteins such as antibodies, enzymes, receptors, soluble proteins and the like. [0589] As used herein in relation to amino acids, the term “contiguous” refers to two amino acids, which are connected by a covalent bond. For example, in the context of a representative cyclic cell penetrating peptide (cCPP) such

exemplify pairs of contiguous amino acids. [0590] A residue of a chemical species, as used herein, refers to a derivative of the chemical species that is present in a particular product. To form the product, at least one atom of the species is replaced by a bond to another moiety, such that the product contains a derivative, or residue, of the chemical species. For example, the cyclic cell penetrating peptides (cCPP) described herein have amino acids (e.g., arginine) incorporated therein through formation of one or more peptide bonds. The amino acids incorporated into the cCPP may be referred to residues, or simply as an amino acid. Thus, arginine or an arginine residue refers t

. [0591] The term “protonated form thereof” refers to a protonated form of an amino acid. For example, the guanidine group on the side chain of arginine may be protonated to form a guanidinium group. The structure of a protonated form of arginine

[0592] As used herein, the term “chirality” refers to a molecule that has more than one stereoisomer that differs in the three-dimensional spatial arrangement of atoms, in which one stereoisomer is a non-superimposable mirror image of the other. Amino acids, except for glycine, have a chiral carbon atom adjacent to the carboxyl group. The term “enantiomer” refers to stereoisomers that are chiral. The chiral molecule can be an amino acid residue having a “D” and “L” enantiomer. Molecules without a chiral center, such as glycine, can be referred to as “achiral.” [0593] As used herein, the term “hydrophobic” refers to a moiety that is not soluble in water or has minimal solubility in water. Generally, neutral moieties and/or non-polar moieties, or moieties that are predominately neutral and/or non-polar are hydrophobic. Hydrophobicity can be measured by one of the methods disclosed herein. [0594] As used herein “aromatic” refers to an unsaturated cyclic molecule having 4n + 2 π electrons, wherein n is any integer. The term “non-aromatic” refers to any unsaturated cyclic molecule which does not fall within the definition of aromatic. [0595] “Alkyl”, “alkyl chain” or “alkyl group” refer to a fully saturated, straight or branched hydrocarbon chain radical having from one to forty carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 40 are included. An alkyl comprising up to 40 carbon atoms is a C1-C40 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl and an alkyl comprising up to 5 carbon atoms is a C₁-C₅ alkyl. A C₁-C₅ alkyl includes C₅ alkyls, C₄ alkyls, C₃ alkyls, C₂ alkyls and C₁ alkyl (i.e., methyl). A C₁-C₆ alkyl includes all moieties described above for C1-C5 alkyls but also includes C6 alkyls. A C1-C10 alkyl includes all moieties described above for C₁-C₅ alkyls and C₁-C₆ alkyls, but also includes C₇, C₈, C₉ and C₁₀ alkyls. Similarly, a C₁-C₁₂ alkyl includes all the foregoing moieties, but also includes C₁₁ and C₁₂ alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n- dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted. [0596] “Alkylene”, “alkylene chain” or “alkylene group” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, having from one to forty carbon atoms. Non-limiting examples of C₂-C₄₀ alkylene include ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted. [0597] “Alkenyl”, “alkenyl chain” or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to forty carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl groups comprising any number of carbon atoms from 2 to 40 are included. An alkenyl group comprising up to 40 carbon atoms is a C₂-C₄₀ alkenyl, an alkenyl comprising up to 10 carbon atoms is a C₂- C10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C₃ alkenyls, and C₂ alkenyls. A C₂-C₆ alkenyl includes all moieties described above for C₂-C₅ alkenyls but also includes C₆ alkenyls. A C₂-C₁₀ alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, C8, C9 and C10 alkenyls. Similarly, a C₂-C₁₂ alkenyl includes all the foregoing moieties, but also includes C₁₁ and C₁₂ alkenyls. Non-limiting examples of C₂-C₁₂ alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1- heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3- octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5- decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4- undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1- dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8- dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted. [0598] “Alkenylene”, “alkenylene chain” or “alkenylene group” refers to a straight or branched divalent hydrocarbon chain radical, having from two to forty carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C₂-C₄₀ alkenylene include ethene, propene, butene, and the like. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally. [0599] “Alkoxy” or “alkoxy group” refers to the group -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl as defined herein. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted. [0600] “Acyl” or “acyl group” refers to groups -C(O)R, where R is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, as defined herein. Unless stated otherwise specifically in the specification, acyl can be optionally substituted. [0601] “Alkylcarbamoyl” or “alkylcarbamoyl group” refers to the group -O-C(O)-NRaRb, where R_a and R_b are the same or different and are independently an alkyl, alkenyl, alkynyl, aryl, heteroaryl, as defined herein, or RaRb can be taken together to form a cycloalkyl group or heterocyclyl group, as defined herein. Unless stated otherwise specifically in the specification, an alkylcarbamoyl group can be optionally substituted. [0602] “Alkylcarboxamidyl” or “alkylcarboxamidyl group” refers to the group –C(O)-NR_aR_b, where Ra and Rb are the same or different and are independently an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, or heterocyclyl group, as defined herein, or R_aR_b can be taken together to form a cycloalkyl group, as defined herein. Unless stated otherwise specifically in the specification, an alkylcarboxamidyl group can be optionally substituted. [0603] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include aryl radicals that are optionally substituted. [0604] “Heteroaryl” refers to a 5- to 20-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted. [0605] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, acyl, alkylcarbamoyl, alkylcarboxamidyl, alkoxycarbonyl, alkylthio, or arylthio) wherein at least one atom is replaced by a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” also means any of the above groups in which one or more atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, - ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. “Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more atoms are replaced by an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group. “Substituted” can also mean an amino acid in which one or more atoms on the side chain are replaced by alkyl, alkenyl, alkynyl, acyl, alkylcarboxamidyl, alkoxycarbonyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents. [0606] As used herein, the symbol “

” (hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example, “

” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound CH3-R³, wherein R³ is H or “

” infers that when R³ is “XY”, the point of attachment bond is the same bond as the bond by which R³ is depicted as being bonded to CH₃. [0607] As used herein, by a “subject” is meant an individual. Thus, the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds. “Subject” can also include a mammal, such as a primate or a human. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician. [0608] The terms “inhibit”, “inhibiting” or “inhibition” refer to a decrease in an activity, expression, function or other biological parameter and can include, but does not require complete ablation of the activity, expression, function or other biological parameter. Inhibition can include, for example, at least about a 10% reduction in the activity, response, condition, or disease as compared to a control. In embodiments, expression, activity or function of a gene or protein is decreased by a statistically significant amount. In embodiments, activity or function is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, and up to about 60%, about 70%, about 80%, about 90% or about 100%. In embodiments, the expression, activity or function of IRF-5 is inhibited. [0609] By “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control (e.g., an untreated tumor). [0610] The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to reducing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. [0611] The term “therapeutically effective” refers to the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination. [0612] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio. [0613] The term “carrier” means a compound, composition, substance, or structure that, when in combination with a compound or composition, aids or facilitates preparation, storage, administration, delivery, effectiveness, selectivity, or any other feature of the compound or composition for its intended use or purpose. For example, a carrier can be selected to reduce degradation of the active ingredient and to reduce any adverse side effects in the subject. [0614] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier suitable for administration to a patient. A pharmaceutically acceptable carrier can be a sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. [0615] The term “pharmaceutically acceptable salts” include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. [0616] The term “pharmaceutically acceptable salts” also includes those obtained by reacting the active compound functioning as an acid, with an inorganic or organic base to form a salt, for example salts of ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, and the like. Non limiting examples of inorganic or metal salts include lithium, sodium, calcium, potassium, magnesium salts and the like. [0617] As used herein, the term "parenteral administration," refers to administration through injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous administration, intravenous administration, or intramuscular administration. [0618] As used herein, the term "subcutaneous administration" refers to administration just below the skin. "Intravenous administration" means administration into a vein. [0619] As used herein, the term "dose" refers to a specified quantity of a pharmaceutical agent provided in a single administration. In embodiments, a dose may be administered in two or more boluses, tablets, or injections. In embodiments, where subcutaneous administration is desired, the desired dose requires a volume not easily accommodated by a single injection. In such embodiments, two or more injections may be used to achieve the desired dose. In embodiments, a dose may be administered in two or more injections to reduce injection site reaction in a patient. [0620] As used herein, the term "dosage unit" refers to a form in which a pharmaceutical agent is provided. In embodiments, a dosage unit is a vial that includes lyophilized antisense oligonucleotide. In embodiments, a dosage unit is a vial that includes reconstituted antisense oligonucleotide. [0621] The terms “modulate”, “modulating” and “modulation” refer to a perturbation of expression, function or activity when compared to the level of expression, function or activity prior to modulation. Modulation can include an increase (stimulation or induction) or a decrease (inhibition or reduction) in expression, function or activity. In embodiments, the compound disclosed herein includes a therapeutic moiety (TM) that decreases IRF-5 expression, function and/or activity. In embodiments, IRF-5 activity is modulated by modulating IRF-5 expression. [0622] “Amino acid” refers to an organic compound that includes an amino group and a carboxylic acid group and has the general formula where R can be any organic group. An

amino acid may be a naturally occurring amino acid or non-naturally occurring amino acid. An amino acid may be a proteogenic amino acid or a non-proteogenic amino acid. An amino acid can be an L-amino acid or a D- amino acid. The term "amino acid side chain" or "side chain" refers to the characterizing substituent (“R”) bound to the α-carbon of a natural or non-natural α-amino acid. An amino acid may be incorporated into a polypeptide via a peptide bond. [0623] The term “antigen-binding domain” as used herein refers to a polypeptide that binds to an antigen. The antigen-binding domain may be an antibody, an antigen-binding fragment, or an antibody mimetic. [0624] The term “antibody” as used herein refers to a molecule that contains at least one antigen binding site that immunospecifically binds to an antigen target of interest. The term “antibody” thus includes but is not limited to a full-length antibody and/or its variants, a fragment thereof, an antigen binding fragment thereof, peptibodies and variants thereof, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (for example, bispecific antibodies) formed from at least two intact antibodies, human antibodies, humanized antibodies, and antibody mimetics that mimic the structure and/or function of an antibody or a specified fragment or portion thereof, including single chain antibodies and fragments thereof. Binding of an antibody to a target can cause a variety of effects, such as but not limited to where such binding modulates, decreases, increases, antagonizes, agonizes, mitigates, alleviates, blocks, inhibits, abrogates and/or interferes with at least one target activity or binding, or with receptor activity or binding, in vitro, in situ, and/or in vivo. An antibody of the present disclosure encompasses antibody fragments capable of binding to an antigen target of interest (i.e., and antigen binding fragment of an antibody), including but not limited to Fab; Fab'; F(ab')₂; pFc'; Fd; a single domain antibody (sdAb); a variable fragment (Fv); a single-chain variable fragment (scFv); a disulfide-linked Fv (sdFv); a diabody or a bivalent diabody; a linear antibody; a single- chain antibody molecule; and a multispecific antibody formed from antibody fragments. The antibody may be of any type, any class, or any subclass. [0625] When the antibody is a human or mouse antibody, the type may include, for example, IgG, IgE, IgM, IgD, IgA and IgY, and the class may include, for example, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. When the antibody is an IgG antibody, the antibody includes two light chains and two heavy chains. The light chains include two variable regions (VL) and two conserved regions (CL). The heavy chain includes two variable regions (VH) and three conserved regions (CH1, CH2, CH3). Each of the heavy chains associate with a light chain by virtue of interchain disulfide bonds between the heavy and light chain to form two heterodimeric proteins or polypeptides (i.e., a protein comprised of two heterologous polypeptide chains). The two heterodimeric proteins then associate by virtue of additional interchain disulfide bonds between the heavy chains to form an Ig molecule (See FIG.1A). [0626] When the antibody is a camelid antibody, the type may include, for example, camelid heavy chain IgG (hcIgG), camelid single N-terminal variable domain heavy chain (VHH) region, or single domain antibody comprising the VHH (See FIG.1B).The term “antigen-binding fragment” as used herein refers to a polypeptide fragment that contains at least one complementarity- determining region (CDR) of an immunoglobulin heavy and/or light chain that binds to at least one epitope of the antigen of interest. In this regard, an antigen-binding fragment of the herein described antibodies may comprise 1, 2, 3, 4, 5, or all 6 CDRs of a variable heavy chain (VH) and variable light chain (VL) sequence from antibodies that specifically bind to a target molecule. The antigen-binding fragment of the herein described camelid antibodies may comprise 1, 2, or 3 of the CDRs of a camelid VHH region. The antigen-binding fragment of the herein described camelid antibodies may be a single domain antibody (VHH). Antigen-binding fragments include proteins that comprise at least a portion of a full length antibody, generally the antigen binding or variable region thereof, such as Fab; F(ab’)2; Fab’; Fv fragments; minibodies; single domain antibodies (dAb); single-chain variable fragments (scFv); divalent scFv such as diabodies; multispecific antibodies formed from antibody fragments; and any other modified configuration of the immunoglobulin molecule that comprises an antigen-binding site or fragment of the required specificity (See FIG. 1A/B). A single domain antibody may be referred to as an antibody or an antigen binding fragment of an antibody. [0627] The term “β-catenin antibody or antigen binding fragment thereof” refers to an antibody (as defined herein) or antigen binding fragment thereof (as defined herein) that has an affinity for and can bind to β-catenin (i.e., β-catenin is the antigen). The β-catenin antibody or antigen binding fragment thereof may bind to any portion of β-catenin. For example, a β-catenin antibody or antigen binding fragment thereof may bind to an epitope of β-catenin that includes one or more residues of residue 1 through residue119 of β-catenin, residue 120 through residue 683 of β- catenin, residue 684 through residue 781 of β-catenin, or combinations thereof. The β-catenin antibody or antigen binding fragment thereof may bind to a β-catenin that has variations from the sequence of wild type β-catenin. [0628] The term “antibody mimetic” refers to a polypeptide that can specifically bind an antigen but is not structurally related to an antibody. Examples of antibody mimetics include monobodies, affibody molecules (constructed on a scaffold of the Z-domain of Protein A, See, Nygren, FEBS J. (2008), 275 (11): 2668–76), affilins (constructed on a scaffold of gamma-B crystalline or ubiquitin, See Ebersbach H et al., J. Mol. Biol. (2007), 372 (1): 172–85), affimers (constructed on a Crystatin scaffold, See Johnson A et al., Anal. Chem. (2012), 84 (15): 6553–60), affitins (constructed on a Sac7d from S. acidocaldarius scaffold, See Krehenbrink M et al., J. Mol. Biol. (2008), 383 (5): 1058–68), alphabodies (constructed on a triple helix coiled coil scaffold, See Desmet, J et al., Nature Communications (2014), 5: 5237), anticalins (constructs on scaffold of lipocalins, See Skerra A., FEBS J. (2008), 275 (11): 2677–83), avimers (constructed on scaffolds of various membrane receptors, See Silverman J. et al., Nat. Biotechnol. (2005), 23 (12): 1556– 61), DARPins (constructed on scaffolds of ankyrin repeat motifs, See Stumpp et al., Drug Discov. Today (2008), 3 (15–16): 695–701), fynomers (constructed on a scaffold of the SH3 domain of Fyn, See Grabulovski et al., J Biol Chem. (2007), 282 (5): 3196–3204), Kunitz domain peptides (constructed on scaffolds of the Kunitz domains of various protease inhibitors, See Nixon et. al., Curr. Opin. Drug. Discov. Dev. (2006), 9 (2): 261–8), and monobodies (constructed on scaffolds of type III domain of fibronectin, See Koide et al (2007). [0629] The term “monobody” refers to a synthetic binding protein constructed using a fibronectin type III domain (FN3) as a molecular scaffold. [0630] The term “minibody” refers to a CH3 domain fused or linked to an antigen-binding fragment (e.g., a CH3 domain fused or linked to an scFv, a domain antibody, etc.). In embodiments, the term “Mb” signifies a CH3 single domain. In embodiments, a CH3 domain signifies a minibody. (S. Hu et al., Cancer Res., 56, 3055-3061, 1996). See e.g., Ward, E. S. et al., Nature 341, 544-546 (1989); Bird et al., Science, 242, 423-426, 1988; Huston et al., PNAS USA, 85, 5879-5883, 1988); PCT/US92/09965; WO94/13804; P. Holliger et al., Proc. Natl. Acad. Sci. USA 906444-6448, 1993; Y. Reiter et al., Nature Biotech, 14, 1239-1245, 1996; S. Hu et al., Cancer Res., 56, 3055-3061, 1996. [0631] The term “F(ab)” refers to two of the protein fragments resulting from proteolytic cleavage of IgG molecules by the enzyme papain. Each F(ab) comprises a covalent heterodimer of the VH chain and VL chain and includes an intact antigen-binding site. Each F(ab) is a monovalent antigen-binding fragment. [0632] The term “F(ab’)2” refers to a protein fragment of IgG generated by proteolytic cleavage by the enzyme pepsin. Each F(ab’)2 fragment comprises two F(ab’) fragments linked by disulfide bonds in the hinge region and is therefore a bivalent antigen-binding fragment. The term “Fab’” refers to a fragment derived from F(ab’)2 and may contain a small portion of the Fc. Each Fab’ fragment is a monovalent antigen-binding fragment. [0633] An “Fv fragment” refers to a non-covalent VH::VL heterodimer which includes an antigen- binding site that retains much of the antigen recognition and binding capabilities of the native antibody molecule, but lacks the CH1 and CL domains contained within a Fab. Inbar et al. (1972) Proc. Nat. Acad. Sci. USA 69:2659-2662; Hochman et al. (1976) Biochem 15:2706-2710; and Ehrlich et al. (1980) Biochem 19:4091-4096. [0634] “Fc region” or “Fc domain” refers to a polypeptide sequence corresponding to or derived from the portion of an antibody that is capable of binding to Fc receptors on cells and/or the C1q component or complement, thereby mediating the effector function of an antibody. Fc stands for “fragment crystalline,” the fragment of an antibody that will readily form a protein crystal. Distinct protein fragments, which were originally described by proteolytic digestion, can define the overall general structure of an immunoglobulin protein. As originally defined in the literature, the Fc region is a homodimeric protein comprising two polypeptides that are associated by disulfide bonds, and each comprising a hinge region, a CH2 domain, and a CH3 domain. However, more recently the term has been applied to the single chain monomer component consisting of CH3, CH2, and at least a portion of the hinge sufficient to form a disulfide-linked dimer with a second such chain. As such, and depending on the context, use of the terms “Fc region” or “Fc domain” will refer herein to either the dimeric form or the individual monomers that associate to form the dimeric protein. For a review of immunoglobulin structure and function, see Putnam, The Plasma Proteins, Vol. V (Academic Press, Inc., 1987), pp. 49-140; and Padlan, Mol. Immunol. 31:169- 217, 1994. As used herein, the term Fc domain includes variants of naturally occurring sequences. [0635] A pFc’ fragment refers to an Fc region that is not covalently coupled. [0636] A “single domain antibody” (sdAb) refers to an antibody fragment comprising a single monomeric heavy chain variable domain. In embodiments, where the antibody fragment is from a camelid heavy chain IgG, the variable domain may be the VHH. [0637] The term “antigen” refers to a molecule or a portion of a molecule capable of being bound by an antibody or an antigen-binding fragment thereof and additionally capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. [0638] Antigens include, but are not limited to, proteins, polysaccharides, lipids, or glycolipids. In embodiments, an antigen is an antigen of an infectious agent. In embodiments, the antigen is an extracellular antigen. In embodiments, the antigen is a cell surface antigen. In embodiments, the antigen is an intracellular antigen. An antigen may have one or more epitopes. [0639] The term “epitope” refers to a region of an antigen that is bound by an antibody. Epitope determinants can include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl and may have specific three-dimensional structural characteristics, and/or specific charge characteristics. [0640] The terms “light chain variable region” (also referred to as “light chain variable domain” or “VL”) and “heavy chain variable region” (also referred to as “heavy chain variable domain” or “VH”) refer to the variable binding region from an antibody light and heavy chain, respectively. The variable binding regions are made up of discrete, well-defined sub-regions known as “complementarity determining regions” (CDRs) and “framework regions” (FRs). [0641] The term “immunoglobulin light chain constant region” (also referred to as “light chain constant region” or “CL”) is a constant region from an antibody light chain. [0642] The term “immunoglobulin heavy chain constant region” (also referred to as “heavy chain constant region” or “CH”) refers to the constant region from the antibody heavy chain. The CH is further divisible, depending on the antibody isotype into CH1, CH2, and CH3 (IgA, IgD, IgG), or CH1, CH2, CH3, and CH4 domains (IgE, IgM). [0643] The term “single-chain variable fragment (scFv) refers to fusion between a VH and VL. Generally. The N-terminus of the VH and the C-terminus of the VL or the N-terminus of the VL and the C-terminus of the VH are coupled through a linker peptide. [0644] The term “variable region of heavy chain only” or “variable region of hcIgG” (VHH) refers to the variable region of an hcIgG such as those from camelids. A VHH includes 3 CDRs. [0645] Divalent single chain variable fragment (di-scFv) refers to the association of two or more scFvs either through covalent bonds or non-covalent means such as dimerization. A diabody is a dimer of two scFv where the scFv comprise a VH and VL linked by a peptide linker that is too short to allow for intramolecular association. [0646] As used herein, the term “complementarity determining region” or “CDR” refer to an immunoglobulin (antibody) molecule. There are three CDRs per variable domain: CDR1, CDR2 and CDR3 in the variable domain of the light chain and CDR1, CDR2 and CDR3 in the variable domain of the heavy chain. In camelid antibodies and antigen binding fragments thereof, there are three CDRs per VHH. [0647] As used herein “active fragment” or “active fragment thereof” refers to a fragment of a polypeptide that retains the function of the polypeptide. Functions include but are not limited to, binding and or/enzymatic activity. The binding affinity of an active fragment need not be the same as the full polypeptide. [0648] The term “specifically binds” refers to the ability of an antibody or antigen-binding fragment thereof to bind a target antigen with a binding affinity (Ka) of at least 10⁵ M^-1 while not significantly binding other components or antigens present in a mixture. [0649] Binding affinity (Ka) refers to an equilibrium association of an interaction expressed in the units of 1/M or M^-1. Antibodies or antigen-binding antibody fragments thereof can be classified as “high affinity” antibodies or antigen-binding fragments thereof and “low affinity” antibodies or antigen-binding fragments thereof. “High affinity” antibodies or antigen-binding fragments thereof refer to those antibodies or antigen-binding fragments thereof with a Ka of at least 10⁷ M- ¹, at least 10⁸ M^-1, at least 10⁹ M^-1, at least 10¹⁰ M^-1, at least 10¹¹ M^-1, at least 10¹² M^-1, or at least 10¹³ M^-1. “Low affinity” antibodies or antigen-binding fragments thereof refer to those antibodies or antigen-binding fragments thereof with a Ka of up to 10⁷ M^-1, up to 10^{6 5 -1}

up to 10 M . Alternatively, affinity can be defined as an equilibrium dissociation constant (Kd) of a binding interaction with units of M (e.g., 10^-5 M to 10^-13, or about 500 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 25 nM, about 10 nM, or about 5 nM). Affinities of binding domain polypeptides and single chain polypeptides according to the present disclosure can be readily determined using conventional techniques (see, e.g., Scatchard et al. (1949) Ann. N.Y. Acad. Sci. 51:660; and U.S. Patent Nos. 5,283,173, 5,468,614, or the equivalent). [0650] Association constant (K_a) refers to an equilibrium association of an interaction expressed in the units of 1/M or M^-1. Antibodies or antigen-binding fragments thereof can be classified as “high affinity” antibodies or antigen-binding fragments thereof and “low affinity” antibodies or antigen-binding fragments thereof. “High affinity” antibodies or antigen-binding fragments thereof refer to those antibodies or antigen-binding fragments thereof with a Ka of at least 10⁷ M- ¹, at least 10⁸ M^-1, at least 10⁹ M^-1, at least 10¹⁰ M^-1, at least 10¹¹ M^-1, at least 10¹² M^-1, or at least 10¹³ M^-1. “Low affinity” antibodies or antigen-binding fragments thereof refer to those antibodies or antigen-binding fragments thereof with a Ka of up to 10⁷ M^-1, up to 10⁶ M^-1, up to 10⁵ M^-1. Alternatively, affinity can be defined as an equilibrium dissociation constant (Kd or KD) of a binding interaction with units of M (e.g., 10^-5 M to 10^-13, or about 500 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 25 nM, about 10 nM, or about 5 nM). Affinities of binding domain polypeptides and single chain polypeptides according to the present disclosure can be readily determined using conventional techniques (see, e.g., Scatchard et al. (1949) Ann. N.Y. Acad. Sci. 51:660; and U.S. Patent Nos. 5,283,173, 5,468,614, or the equivalent). [0651] The term “infectious agent” refers to a pathogenic microorganism, including, but not limited to, bacteria, viruses, fungi, or intracellular or extracellular parasites. [0652] The term "infection" refers to a pathological process caused by the invasion of normally sterile tissue or fluid by an infectious agent including, but not limited to, infection by bacteria, viruses, fungi, and/or parasites. An infection can be local or systemic. A subject suffering from an infection can suffer from more than one source of infection simultaneously. For example, a subject can suffer from a bacterial infection and viral infection; a viral infection and fungal infection; a bacterial and fungal infection; a bacterial infection, a fungal infection and a viral infection; or a mixture of one or more infections. A subject can suffer from one or more bacterial infections, one or more viral infections, one or more fungal infections and/or one or more parasitic infections, simultaneously or sequentially. [0653] The term “variant” or “variants” as used herein 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 about 70%, at least about 80%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% at least about 99%, or at least about 99.5% sequence identity compared to the parental polynucleotide or polypeptide. [0654] As used herein, the term “sequence identity” refers to a relationship between two or more polynucleotide sequences or between two or more polypeptide sequences. When a position in one sequence is occupied by the same nucleic acid base or amino acid residue in the corresponding position of the comparator sequence, the sequences are said to be “identical” at that position. The percentage sequence identity is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of identical positions. The number of identical positions is then divided by the total number of positions in the comparison window and multiplied by 100 to yield the percentage of sequence identity. Percentage of sequence identity is determined by comparing two optimally aligned sequences over a comparison window. The comparison window for polynucleotide sequences can be, for instance, at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 or more nucleic acids in length. The comparison window for polypeptide sequences can be, for instance, at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300 or more amino acids in length. In order to optimally align sequences for comparison, the portion of a polynucleotide or polypeptide sequence in the comparison window can comprise additions or deletions termed gaps while the reference sequence is kept constant. An optimal alignment is that alignment which, even with gaps, produces the greatest possible number of “identical” positions between the reference and comparator sequences. Percentage “sequence identity” between two sequences can be determined using the version of the program “BLAST 2 Sequences” which was available from the National Center for Biotechnology Information as of September 1, 2004, which program incorporates the programs BLASTN (for nucleotide sequence comparison) and BLASTP (for polypeptide sequence comparison), which programs are based on the algorithm of Karlin and Altschul (Proc. Natl. Acad. Sci. USA 90(12):5873-5877, 1993). When utilizing “BLAST 2 Sequences,” parameters that were default parameters as of September 1, 2004, can be used for word size (3), open gap penalty (11), extension gap penalty (1), gap dropoff (50), expect value (10) and any other required parameter including but not limited to matrix option. Two nucleotide or amino acid sequences are considered to have “substantially similar sequence identity” or “substantial sequence identity” if the two sequences have at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity relative to each other. [0655] The term “substantially identical” refers to a polypeptide sequence that contains a sufficient number of identical amino acids to a second polypeptide sequence such that the first and second polypeptide sequence have similar activity. Polypeptides that are substantially identical are at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% identical in amino acid sequence. [0656] The term “polynucleotide” as referred to herein means single-stranded or double-stranded nucleic acid polymers. In embodiments, the nucleotides comprising the polynucleotide can be RNA or DNA or a modified form of either type of nucleotide, such as a modified messenger RNA. Said modifications may include, but are not limited to, base modifications such as bromouridine, ribose modifications such as arabinoside and 2',3'-dideoxyribose and internucleotide linkage modifications such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate and phosphoroamidate. The term “polynucleotide” specifically includes single and double stranded forms of DNA. [0657] As used herein, a “polypeptide” or “protein” refers to a single, linear, and contiguous arrangement of covalently linked amino acids. Polypeptides can form one or more intrachain disulfide bonds. The terms polypeptide and protein also encompass embodiments where two polypeptide chains link together in a non-linear fashion, such as via an interchain disulfide bond. Herein, a protein or polypeptide may be an antibody or an antigen-binding fragment of an antibody. [0658] The term “degradation construct” refers to a compound or complex or portion or part thereof that binds to a target protein (e.g., b-catenin) and elicits degradation of the target protein. The degradation construct comprises a targeting moiety and degradation moiety. The targeting moiety binds to at least the target protein. In some embodiments, the targeting moiety comprises a first targeting domain that binds to the target protein and a second targeting domain that binds to an intracellular or extracellular target that is not the target protein. The degradation moietyelicits degradation of the target protein. In embodiments, the degradation construct comprising the targeting moiety and the degradation moiety is a complex of two or more proteins in which at least one protein comprises the targeting moiety and at least one other protein comprises the degradation moiety. In embodiments, the construct comprising the targeting moiety and the degradation moiety is a fusion protein containing both a targeting moiety and a degradation moiety. [0659] For any method disclosed herein that includes discrete steps, the steps may be conducted in any feasible order. And, as appropriate, any combination of two or more steps may be conducted simultaneously. [0660] All publications, patents and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications, patents and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. EXAMPLES [0661] The present disclosure is illustrated by the following examples. It is to be understood that the examples, materials, amounts, and procedures are to be interpreted broadly in accordance with the scope and spirit of the disclosure as set forth herein. [0662] Table 12 shows the EEV sequences for various EEVs (EEV00-EEV29) and constructs (C30-C33) that include an EEV used throughout the Examples. Table 13 shows the sequences of various antibodies and antibody fragments used throughout the Examples. The structure of EEV04 is shown in FIG.24. Table 12: Sequences of EEVs and constructs including and EEV used in the Examples

Table 13: Sequences of EEVs used in the Examples

Example 1. Isolation and Characterization of Camelid Single-Domain Antibodies Specific to β-Catenin [0663] To obtain camelid single domain antibodies specific to the human β-catenin protein, a llama was immunized with full length human β-catenin protein of the following sequence

Blood lymphocytes were isolated from heparinized llama blood and used to prepare a phage display library, following the general methodology first described by Ghahroudi et al. (Ghahroudi et al., FEBS Lett. (1997), 414(3):521–526) and panned with the immunizing antigen, β-catenin, to identify clones that bind to human β-catenin. Forty-nine clones were identified for further characterization. [0664] In order to test intracellular solubility of 49 sdAbs (VHHs) (all positive β-catenin binders), the C-terminal mCherry fusion with each β-catenin VHH was constructed in a pcDNA3.1 vector. The resulting constructs (endotoxin free 1ug of each construct) were transiently transfected into HEK239TN cells in a 24 well plate. After 1 day incubation at 37 °C, the transfected cells were analyzed for mCherry signal under a microscope. It was confirmed that 32 out of 49 VHHs were soluble intercellularly including clones NB01, NB02, and NB03 (see Table 13; data note shown). These 32 VHHs were selected to evaluate β-catenin target engagement. [0665] The 32 intracellularly soluble sdAbs (VHHs) were constructed in pcDNA3.1 with truncated VHL139-213 (E3 ligase; see Table 13) fusion at each VHH C-terminus and a FLAG tag at the N-terminus. Written N to C the constructs had the format (DYKDDDDKDYKDDDDK)₂- GGGS-sdAb-GGGGSGGGGS-VHL(139-213). The constructs were transiently transfected into HEK293TN cells. The cells were harvested after 24 hr. incubation at 37 °C, and analyzed for the construct expression by anti-flag antibody and the amount of β-catenin change by β-catenin antibody. FIG.3 shows the levels of β-catenin for select constructs. Constructs A, NB01 and NB02 showed the lowest level of β-catenin. NB01, NB02, and NB03 were selected for further characterization (sequences are shown in Table 12). [0666] In vitro target binding screening of the selected sdAbs to human β-catenin was performed using BIACORE. The KD (nM) of the VHH (single domain antibodies) of NB01, NB02, NB03, and NB04 (KD = 9.84 nM; ka = 1.13 × 10⁶ M^-1s^-1; kd = 1.11 × 10^-2 s^-1; a positive control), as determined by BIACORE. Single-domain antibodies NB02 (K_D= 4.81 nM; k_a = 3.23 × 10⁶ M^-1s- ¹; k_d = 1.56 × 10^-2 s^-1), NB01 (K_D = 9.53: k_a = 6.06 × 10⁵ M^-1s^-1; k_d = 5.77 × 10^-3 s^-1), and NB03 (KD = 3.34 nM: ka = 3.18 × 10⁶ M^-1s^-1; kd = 1.06 × 10^-2 s^-1) all display low nM β-catenin binding constants. [0667] Epitope Mapping for the binding of the NB01, NB02, and NB03 single-domain antibodies and positive control NB04 to the β-catenin fragments amino acids 1-119, amino acids 120-683, and amino acids 684-781 is shown in Table 14. Epitope mapping revealed that the three single- domain antibodies do not all bind in the same location on β-catenin. NB03 binds near residues 120-683 of β-catenin. NB01 and NB02 bind proximate the C-terminus (residues 684-781) of β- catenin. The positive control NB04 binds proximate the N-terminus (residues 1-119) of β-catenin. Table 14: Sequences of regions of β-catenin used for epitope mapping

[0668] Binding of the NB01, NB02, and NB03 single-domain antibodies and the NB04 positive control to E-cadherin and phosphorylated β-catenin was determined using ELISA. E-cadherin is associated with β-catenin -catenin on the membrane (cytosolic side). As such, binding to E- cadherin would indicate non-specific binding to β-catenin. Phosphorylated β-catenin (proximate the N-terminus) is naturally degraded by E3 ubiquitin ligase (β-TrCP1). NB01, NB02, and NB03 have a similar or less binding to E-cadherin when compared with the NB04 positive control. NB01, NB02, and NB03 show no significant binding to phosphorylated-β-catenin when compared with the blank. Binding affinities are shown in Table 15. Table 15: Binding affinity of various sdAb binding E-cadherin and phosphorylated β-catenin

Example 2. Illustrative conjugation reactions for preparing sdAbs-EEV conjugates [0669] EEV02 (see Table 12) was conjugated to a C-terminal cysteine added to NB01 using two different conjugation chemistries: cysteine-maleimide (Mal) conjugation and cysteine -N- succinimidyl 3-(2-pyridyldithio) propionate (SPDP) conjugation (chemistries described elsewhere herein). [0670] The reaction conditions were as follows. [0671] 1) Maleimide Chemistry (FIG.4A): a reaction of one equivalent of NB01-Cys (1 in FIG. 4A) and 2 equivalents EEV02-Mal (2 in FIG. 4A) in aqueous sodium phosphate (100 mM) and sodium chloride (500 mM) at pH 6.5 was left to incubate at 4 ˚C for two hours. Results were analyzed via SDS-PAGE and LC/MS. Yield = 85% conjugated, 95% recovery. [0672] 2) SPDP Chemistry (FIG. 4B): First an EEV02 (1 in FIG. 4B) is reacted with SPDP to form EEV-SPDP. Five equivalents EEV-SPDP and one equivalent of NB01-Cys (2 in FIG. 4B) in aqueous sodium phosphate (100 mM) and sodium chloride (137 mM) at pH 7 was left to incubate at 4 ˚C for six hours. Results were analyzed via SDS-PAGE and LC/MS. Yield = 95% conjugated, 60% recovery. Example 3. Evaluation of sdAbs-E3 ligase constructs [0673] Various sdAbs from Example 1 were fused to various E3 ligases or truncated E3 ligases to assess their ability to degrade β-catenin. The sequences of the constructs are shown in Table 16. Table 16: Sequences of E3 ligases and truncated E3 ligases

[0674] FIGS.5A-B show the ability of various sdAb-E3 ligase fusions to down regulate the levels of β-catenin and c-Myc. The UBOX, VHL(1-213), VHL(139-213), and HIF1αPep fusions gave the largest responses. Example 4. Evaluation of sdAbs-MDM2i constructs [0675] Various sAb-MDM2i-1 and sAb-MDM2i-2 constructs were evaluated in MCF-7 cells to assess if they can degrade β-catenin (Table 17). The sequences for MDM2i-1 and MDM2i-2 are shown in Table 16. The single domain antibodies NBX and NBY were used as negative controls. Table 17: Sequences of E3 ligases and truncated E3 ligases

[0676] FIG.6 shows that the NB01-MDM2i-1 and NB01-MDM2i-2 constructs can downregulate the c-Myc level in MCF-7 cells where the expression of the construct was induced with doxycycline. FIGS. 7A-D show the ability of the various nanobodies and nanobody-MDM2i constructs of FIG.7 to regulate the levels of β-catenin (A), c-Myc (B), P53 (C), and MDM (D) in MCF-7 cells. Generally, the sdAb-MDM2i constructs showed changes in proteins levels while the sdAbs showed little to no change in protein levels. A reduction in c-Myc levels was observed for constructs C01, C02, C04, C05, C09, and C10 (FIG.7B). Constructs C02, and C04 had the largest P53 level changes (FIG. 7C). Most constructs showed an increase in MDM2 levels (FIG. 7D). There were no large changes in β-catenin levels for most constructs, except constructs C07, a negative control (FIG.7A). [0677] The increase in MDM2 levels may be due to the negative feedback loop between the tumor suppressor p53 and MDM2. In cells, P53 activates MDM2 transcription and MDM2 targets P53 for degradation. As such, an increase in P53 levels generally leads to an increase in MDM2 levels. The MDM2i-sdAbs recruit MDM2 such that the higher level of MDM2 may be due to the MDM2- p53 negative feedback loop. Increases in MDM2 and P53 suggests that endosomal escaped degradation compounds interact with endogenous MDM2 and modulate the relevant signals. In terms of the β-catenin level, there are membrane associated β-catenin that contributes to level of β-catenin on the analysis. The sdAbs are likely interacting with cytosol β-catenin. [0678] The impact of NB01-MDM2 constructs (NB01-MDM2i-1 and NB01-MDM2i-2) on the β- catenin/Myc signal transduction pathway in MCF-7 cells was further explored (FIG.8A-8F). FIG. 8B shows that NB01-hFc construct suppresses MCF-7 cell growth, indicating that NB01 may suppress the WNT signaling pathway. The NB01-MDM2i-2 construct showed greater suppression of cell growth, likely due to MDM2-P53 activation. FIG. 8C indicates that the NB01-MDM2i-2 construct can degrade endogenous β-catenin over time. FIG. 8D indicates that all constructs can reduce Myc levels over time, with the NB01-MDM2i-2 showing the largest decrease in Myc levels. FIG. 8E and 8F show an increase in p53 and MDM2 levels for the NB01-MDM2i-2 construct. Example 5. Evaluation of sdAbs-UBOX-EEV and sdAb-EEV constructs. [0679] Various sdAbs, sdAb-E3 ligase constructs, and sdAbs-E3 ligase-EE constructs were evaluated for their ability to degrade β-catenin and regulate the levels of downstream proteins that are regulated by β-catenin. The constructs include NB01, NB01-EEV02, NB01-GGGGSAAA- UBOX-PEG12-EEV02 (NB01-UBOX-EEV02) (cyclo(FfΦRrRrQ)-PEG12) and NB01- GGGGSAAA-UBOX (NB01-UBOX). [0680] The UBOX sequence was:

[0681] The NB01-UBOX construct was expressed in cells, purified, and checked for quality via SDS-PAGE and LC-MS. Size exclusion chromatography showed the presence of dimers, trimers, and tetramers of the NB01-UBOX fusion. UBOX includes two cysteines and readily forms dimers. Under reducing conditions, an SDS-PAGE showed a relatively pure NB01-UBOX fusion product. [0682] EEV02 was conjugated to the NB01-UBOX to form the NB01-UBOX-EEV02 construct using SPDP chemistry (see Example 2). LC-MS post reaction showed evidence of unreacted NB01-UBOX, NB01-UBOX with one EEV02 conjugated, and NB01-UBOX with two EEV02s conjugated. The K_D for the NB01-UBOX-EEV02 construct was measured at 250 nM and 500 nM of the construct. The association and dissociation rate of the two concentrations gave a global fit KD of 71.8 nM. [0683] A lysine discharge assay was performed to evaluate if the constructs are able to induce polyubiquitylation of BSA. The assay was performed similarly to Adel, F. M., et al., Molecular Cell (2020), 79:155-166. The NB01-UBOX and NB01-UBOX-EEV02 constructs were able to induce ubiquitylation of free lysine on BSA (FIG.9C-D). The NB01 nanobody alone showed no ubiquitylation of BSA (FIG.9B). [0684] A tandem ubiquitin binding entities (TUBEs) assay (Lifesensors Inc.) was used to determine which E2 ligase paired best with the UBOX E3 ligase. Table 18 shows the results. The readout is relative cathodoluminescence intensity (relative to no E2). UBE2D1 had the highest level of ubiquitination when paired with the NB01-UBOX construct. Table 18: E2 ligase ubiquitination levels when paired with NB01-UBOX

[0685] The TUBEs assay (Lifesensors) using UBE2D1 was used assess the ability of NB01- UBOX and NB01-UBOX-EEV02 to ubiquitinate β-catenin. Both NB01-UBOX and NB01- UBOX-EE02 showed dose dependent ubiquitination of β-catenin when β-catenin was present at 10 nM and 40 nM (FIGS. 10A-B). A hook effect was observed a high concentration of NB01- UBOX and NB01-UBOX-EEV02. Additionally, NB01-UBOX-EEV02 showed dose dependent ubiquitination of β-catenin when β-catenin was present a 5 nM, 10 nM, 20 nM, and 40 nM (FIG. 10C). [0686] A gel based in vitro ubiquitylation assay showed that the NB01-UBOX construct is able to ubiquitinate β-catenin in the presence of β-catenin, ATP, and UBE2D3 (FIG.11A-B). The smears above the β-catenin band are characteristic of poly-ubiquitination. Peak ubiquitination was observed at 12.5 nM NB01-UBOX. [0687] FIG. 12A-B show dose dependent ubiquitination of β-catenin after treatment with the NB01-UBOX (A) or NB01-UBOX-EEV02 (B) constructs. RNF4 is an E3 ligase used as a positive control for ubiquitination assays. [0688] A co-immunoprecipitation assay was used to demonstrate intracellular target engagement of the NB01-UBOX and NB01-UBOX-EEV02 constructs. HCT-116 (human colon carcinoma cell line) cells were treated with 1.8 μM or 9.0 μM of NB01-UBOX or NB01-UBOX-EEV02 for 4 hours at 37 °C. Briefly, within the cell, the NB01 nanobody of the NB01-UBOX-EEV02 engages with β-catenin. The NB01 nanobody included a FLAG-tag allowing for antibody pull down assays. β-catenin antibodies are used to immunoprecipitate β-catenin. If the NB01-UBOX-EEV02 construct is engaging a β-catenin protein, the entire complex will be isolated. Following β-catenin immunoprecipitation, both β-catenin and FLAG tag are blotted for. A gel that includes a band for both β-catenin and the FLAG tag is indicative of target engagement. FIG. 13A shows target engagement for the NB01-UBOX-EEV02 construct at 9.0 μM. No target engagement was observed for NB01-UBOX construct. The difference in target engagement may be due to the EEV02 facilitating cell entrance and endosomal escape. [0689] A western blot analysis was used to evaluate cellular uptake of the NB01 sdAb, the NB01- EEV02 construct, the NB01-UBOX construct, and the NB01-UBOX-EEV02 construct. HCT-116 cells were treated with the various constructs at various concentrations for 4 hours. The whole cell lysates were characterized by Western blot. Each NB01 nanobody included a FLAG tag. The presence of the NB01 nanobody (serving as a conduit for the full NB01-UBOX and NB01-UBOX- EEV02 constructs) was confirmed by anti-FLAG tag antibody. Increased penetration & cellular uptake was observed for constructs having the EEV02 (FIG.13B). [0690] FIG.14A-B shows the subcellular distribution of the NB01-UBOX (Nb-E3) construct and NB01-UBOX-EEV02 (Nb-E3-EEV) construct. HCT116 cells were treated with NB01-UBOX or NB01-UBOX-EEV02 at various concentrations for 4 hours, and different cell fractions were prepared and analyzed by western blot. The subcellular distribution of the NB01-UBOX-EEV02 construct further confirmed the successful intracellular delivery. Example 6. Evaluation of sdAbs, sdAbs-degradation moiety, and sdAbs- degradation moiety- EEV constructs at regulating cMyc levels [0691] sdAb NB01, and the NB01-EEV (Maleimide-PEG12-EEV12) and NB01 HIF1αPep-EEV (Ac-K(N3)-PEG4-PEG4-DLDLEMLAPYIPMDDDFQLGS-C-C-PEG12-K(cyclo(FfΦRrRrQ))- NH2) constructs were evaluated for regulation of cMyc levels and β-catenin levels. HCT-116 cells were treated with 1 μM (L), 3 μM (M), and 9 μM (H), of the degradation compounds. The levels of β-catenin and cMyc were evaluated at 2, 4, and 6 hours post treatment. [0692] FIG. 15A shows a robust time dependent c-Myc level modulation with increased cellular uptake in HCT-116 cells with the NB01-EEV construct over the NB01 nanobody alone. FIG.15B indicates that the NB01-HIF1αPep-EEV construct modulates the β-catenin/c-Myc pathway. Dose dependent c-Myc inhibition was observed and was the most pronounced after 24 hours. Under these experimental conditions, the NB01-HIF1α-EEV did not show degradation of β-catenin. Example 7. Design and testing of various bispecific degradation constructs [0693] Bispecific degradation constructs were designed and tested. A bispecific degradation construct includes an intracellular targeting agent, an extracellular targeting agent, and degradation moiety. The intracellular targeting agent was a β-catenin binding nanobody. The extracellular targeting agent was 7D12.7D12 is known nanobody that binds to epidermal growth factor receptor (EGFR) on the surface of cells. The degradation moiety was an E3 ligase peptide. The bispecific degradation compound also included an EEV conjugated to the E3 ligase peptide. [0694] The components of the bispecific constructs were arranged in a variety of ways. Table 19 provides example constructs that may be synthesized. The degradation moiety included MDM2i- 1, MDM2i-2, or Hif1apep (see Table 17 for sequences). The azide (N3) of the construct was (or may be) conjugated to a sdAbs-7D12 (N to C) or 7D12-sdAbs (N to C) construct that includes a dibenzocyclooctyne (DBCO) group via copper free click chemistry. As shown in the table, the EEV (underlined in Table 19) is conjugated to the E3 ligase peptide (in italics in Table 19) through SPDS chemistry (shown as a C-C disulfide in Table 19) Table 19: Example bispecific degradation compound constructs

[0695] Various bispecific degradation constructs were synthesized and tested for their ability to degrade β-catenin (Table 20). See Table 12 for the sequence of C30, C32, C33, and C34. C32, C33, and C34 all included the MDM2i-2 degradation peptide (see Table 15 for MDM2i-2 sequence). C30 included the Hif1a peptide (see Table 17). Each 7D12-sdAbs (7D12-NB03 and 7D12 NB02) included a DBCO group at or near the C terminus. The EEV construct (C32, C33, or C4) included an azide group. The EEVs and the 7D12-sdABs were coupled via copper free click chemistry. Table 20: Bispecific degradation constructs tested

[0696] A tandem ubiquitin binding entities (TUBEs) assay (Lifesensors Inc.) was used to determine if the constructs were able to mediate the ubiquitination β-catenin. The constructs that included the MDM2i-2 degradation peptide showed more β-catenin ubiquitination than the constructs that included the Hif1a peptide (FIG. 16A and 16B vs FIG. 16C). Of the constructs that included the MDM2i-2 peptide, those that included C32 and C34 showed the highest β-catenin ubiquitination levels (FIG.16A and FIG.16B). Example 8. Cytosolic delivery EEV screen [0697] Various EEVs were screened in 7D12-NB02-EEV and 7D12-NB03-EEV constructs to determine their ability to enter the cytosol of various cell lines (see Table 21). The constructs were made, and the β-catenin KD and EGFR KD were determined using BIACORE. An immunofluorescence assay and a split GFP assay were used to ascertain which EEVs facilitate entry of the constructs into the cytosol of cells. [0698] For the immunofluorescence assay, HEK293 cells and HCT116 cells were treated with 1 μM of the construct. Images were taken 6 hours and 24 hours post treatment. Table 21 shows the results of the assay. HEK293 cells treated with the controls (7D12-NB02 and 7D12-NB03) did not show cytosolic delivery. Generally, the HEK29324 hour time point showed less cytosolic delivery of the constructs than the 6 hour time point. HCT116 cells treated with the controls (7D12-NB02 and 7D12-NB03) showed evidence of the constructs binding to the exterior of the cells (manifested as a ring around the cells), presumably through interaction of the 7D12 nanobody with the EGFR receptor on the cell surface. The HCT11624 hour time point showed relatively the same cytosolic delivery of the constructs as the 6 hour time point. [0699] A split GFP assay was done to determine which constructs are escaping the endosome upon endocytosis. For the split GFP assay, the constructs included a portion of GFP (GPF11) attached to the 7D12 nanobody. HEK293 cells and HCT116 cells were engineered to express a second portion of GFP (GFP1-10). GPF1-10 is inactive (not fluorescent) until GFP11 binds and activates green fluorescence. As such, a construct that is endocytosed and escapes the endosome may activate and turn on GFP which can be seen using microscopy. A construct that is either not endocytosed or does not escape the endosome will not activate GFP. To complete this assay, HEK293 cells and HCT116 cells were treated with 10 μM of various constructs. One hour post treatment, the cells were imaged. A GFP signal is indicative of endocytosis followed by endosomal escape. The results can be seen in Table 21. Table 21: EVV screen constructs and data

Example 9. Assessment of bispecific compounds (EGFR targeting with a β-catenin nanobody) in a first xenograft mouse model [0700] Mice inflicted with HCT-116-Luc tumor cell line were treated with 12 nmoles of sdAbs NB01, a NB01-EEV construct, a NB01-7D12 construct (7D12 is an EGFR targeting domain), or a NB01-7D12-EEV construct (see Table 22). Following completion of the study, construct uptake levels and various protein levels were investigated. [0701] sdAb NB01 and NB01-7D12 were recombinantly expressed using similar methods as described earlier. The NB01-7D12 included a GGGGSSAAA linker (NB01-GGGGSSAAA- 7D12). EEV02 was conjugated to NB01 (NB01-cysto a terminal cysteine) using maleimide chemistry giving a 58.3% yield. The EEV02 was conjugated to the NB01-7D12 through Mal- DBCO reactions (see FIG. 4C and discussion elsewhere herein). Material characterization is shown in Table 22. The 7D12-NB01-EEV02 construct retains a low nM binding affinity to EGFR and β-catenin. Table 22: Material characterization

[0702] Following 1 week of adaption, mice were subcutaneously or intravenously injected with 5 × 10⁶ HCT-116-Luc cells into the right flank. The mice were monitored for 2-3 weeks. The tumor sizes grew to 100-150 mm³. Treatment groups were randomized, and the mice were dosed with a single dose of 12 nmoles of the respective treatment. Single doses were administered every other day until the mice had received three doses. Six hours following the last dose, the mice were euthanized, and tumors harvested for downstream analysis. [0703] Western blot analysis and quantification showed that c-Myc, β-catenin, p-ERK1/2, and pEGFR Y1068 levels were modulated in the mice treated intratumorally with the 7D12-NB01- EEV02 construct (FIG. 17). Co-immunoprecipitation of mice treated intratumorally with the 7D12-NB01 construct or the 7D12-NB01-EEV construct shows that both constructs can bind to β-catenin in vivo, demonstrating clear target engagement (FIG. 18A-B). Additionally, co- immunoprecipitation of mice treated by intravenous injection of the 7D12-NB01 construct shows that 7D12-NB01 binds β-catenin in vivo (FIG.18C). [0704] FIG.19 is a western blot showing the protein levels of c-Myc, β-catenin, p-EGFR Y1068, and various constructs. There are two proposed c-Myc signal change pathways that may be induced by the NB01 nanobody.1) The complex of β-catenin and NB01 nanobody remains in the cytosol rather than being transported to the nucleus, resulting in reduction of Wnt/β-catenin dependent transcription in the nucleus (e.g., cMyc, Cycline D1 etc.).2) The transported β-catenin and NB01 nanobody complex transports into the nucleus. Once in the nucleus, the complex inhibits Wnt/β- catenin dependent transcription due to the disruption of TCF/LEF and its co-activators binding. The proposed mechanism of action of the 7D12-NB01-EEV02 construct is as follows. The 7D12 domain binds to the extracellular portion of EGFR. After binding EGFR, the entire construct is internalized. Once in the intracellular space, the NB01 nanobody domain binds to β-catenin and the Wnt/β-catenin dependent transcription pathways can be modulated as described herein. Example 10. Assessment of bispecific compounds (EGFR targeting with a β-catenin nanobody) in a second xenograft mouse model [0705] Athymic nude mice inflicted with HCT-116-Luc tumor cell line were treated with various 7D12-NB (β-catenin binding nanobody); 7D12-sdAb-EEV; and 7D12-sdAb-E3pep-EEV (sdAb is a nanobody that binds β-catenin; E3pep is a degradation moiety that is an E3 ligase peptide) constructs. Cetuximab, an EGFR inhibitor, was included as a control. The treatment groups are shown in Table 23. Following completion of the study, construct uptake levels and various protein levels were investigated. [0706] Constructs having 7D12 coupled to a nanobody included a GGGGSGGGGSAAA linker. Each sdAb included an engineered C-terminal cysteine. Constructs including an E3 ligase peptide include either the MDM2i-1 (TSFAEYWNLLSP) or MDM2i-2 (PRFWEYWLRLME) peptides couple to an EEV through a disulfide bond (these constructs are denoted as C instead of EEV; see Table 13; 7D12-NB03-C32 and 7D12-NB03-C33). The EEV-E3 ligase peptide compounds were coupled to 7D12-sdAB compounds via click chemistry. 7D12-sdAb compounds were coupled to an EEV (not an EEV-E3-ligase compound) using a DBCO-Mal compound. The azide group on the EEV reacts with DBCO of the DBCO-Mal compound via click chemistry; and the Mal of the DBCO-Mal compound reacts with a C-terminal cysteine on the NB. Table 23: List of Constructs

[0707] The study was completed similar to Example 7. Briefly, mice were injected with 4-10 x10⁶ HCT-116 cells into their right flanks and monitored for two to three weeks until the tumor size was palpable. Mice were dosed with 12 mpk of the construct via intravenous injection or intrathecal injection (7D12-NB02-EEV02 and 7D12-NB02-EEV16 were injected in mice both ways). Mice were sacrificed 3 hours post treatment. [0708] Plasma samples from each treatment group were analyzed via Western Blot for the presence of the construct in the plasma (FIG. 20; 25 μL plasma/mL buffer dilution; 100% of the dose in the plasma would be ~ 4 ng/μL for 10 mpk). All of the constructs that included NB03 (7D12-NB03-various EEVs) were visible in the plasma with 7D12-NB03-C32, 7D12-NB03-C33, and 7D12-NB03-C34 present in the highest amount. [0709] Of the constructs that included NB02 (7D12-NB02-various EEVs), there were no 7D12- NB02-EEV constructs that showed levels in the plasma that were greater than other 7D12-NB02- EEV constructs. The intrathecal injection (IT) treatment showed higher levels of the construct in the plasma than the IV injection treatment of the same construct (7D12-NB02-EEV15). Constructs 7D12-NB03-EEV15 and 7D12-NB03-EEV19 showed the lowest level in the plasma. [0710] Tumor samples from each treatment group were analyzed via Western Blot for the presence of the construct in the tumor (FIG.21.) Tumor cells were lysed with SDS either reducing or non- reducing sample loading buffer (~ 25 mg/mL total tissue)(5-10% ID/g here would be 0.3-0.6 ng/μL). Most of the constructs that included NB03 (7D12-NB03-EEV) were present in the tumor at reasonable levels. The IV treatments of constructs that included NB02 (7D12-NB02-EEV) seemed to be present in the tumor cells at lower levels than the constructs that included NB03 (7D12-NB03-EEV). The IV treatments of constructs that included NB02 (7D12-NB02-EEV) showed high levels of the construct in the tumor, even at lower exposure. [0711] Quantification can be used to compare the levels of the constructs in the tumor cells to literature values of various compounds in tumor cells. For example, the literature indicates that 5- 10% ID/g in tumor is expected for treatment with 7D12. Additionally, the literature indicates that ~7-18% ID/g in tumor is expected for full mAb’s. [0712] Gastrocnemius samples from various treatment group were analyzed via Western Blot for the presence of the construct in the gastrocnemius tissue (FIG. 22). Gastrocnemius samples were processed in reducing SDS buffer (25 mg/mL). There are none-specific binding events at the location of the construct in the Western Blot; however, there is no clear, distinct construct band for any of the treatment groups. Thus, the gastrocnemius muscle does not seem to be a construct sink. [0713] Protein simple capillary electrophoresis method was used to quantify β-catenin levels relative to two controls, TOM20 (FIG.23A) and LRPPRC (FIG.23B). The level of β-catenin was compared between constructs that included a E3 ligase peptide (degraders; 7D12-NB03-C32, 7D12-NB03-C33, 7D12-NB03-C34) and various constructs that did not include an E3 ligase peptide (no degrader). A trend toward β-catenin reduction for mice treated with degraders versus mice treated with constructs that were not degraders was observed. A similar experiment was done to compare c-Myc levels between degraders and not degraders. There did not seem to be any difference in the c-Myc levels of degraders and not degraders; however, mice were only treated for three hours so a large difference may not have been possible.

Claims

CLAIMS 1. An antibody or antigen binding fragment thereof comprising an antibody variable domain comprising an amino acid sequence comprising: a CDR1 sequence comprising: the amino acid sequence GRTFARNV, amino acid sequence GGALSSYR; or amino acid sequence GGIFSTFA; a CDR2 sequence comprising: amino acid sequence ISWSGAST, amino acid sequence ISWSGDST, or amino acid sequence ISGGGST; and a CDR3 sequence comprising: amino acid sequence KAVRRLRLGVDDY, amino acid sequence AVDVKSDRGSLVADFGS, or amino acid sequence NARVWIADADEPYSF.

2. The antibody or antigen binding fragment thereof of claim 1, wherein the CD1 comprises GRTFARNV, the CDR2 comprises ISWSGAST, and the CDR3 comprises KAVRRLRLGVDDY.

3. The antibody or antigen binding fragment thereof of claim 2, wherein the antibody variable domain comprises an amino acid sequence comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to

4. The antibody or antigen binding fragment thereof of claim 1, wherein the CD1 comprises GGALSSYR, the CDR2 comprises ISWSGDST, and the CDR3 comprises AVDVKSDRGSLVADFGS.

5. The antibody or antigen binding fragment thereof of claim 4, wherein the antibody variable domain comprises an amino acid sequence comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to

6. The antibody or antigen binding fragment thereof of claim 1, wherein the CD1 comprises GGIFSTFA, the CDR2 comprises ISGGGST, and the CDR3 comprises NARVWIADADEPYSF.

7. The antibody or antigen binding fragment thereof of claim 6, wherein the antibody variable domain comprises an amino acid sequence comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to

8. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof specifically binds human β- catenin.

9. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof specifically binds to an epitope comprising amino acids 1 to 119 of human β-catenin, amino acids 120 to 683 of human β-catenin, or amino acid 684 to 781 of human β-catenin.

10. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof, comprises a heavy-chain variable domain (VHH) single-domain antibody (sdAb).

11. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof is humanized.

12. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof further comprises a human immunoglobulin constant region.

13. A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of any one of claims 1 through 12.

14. A compound comprising: a targeting moiety comprising an antibody or antigen binding fragment thereof according to any one of claims 1 through 12; and a cell penetrating peptide (CPP) operably linked to the antibody or antigen binding fragment thereof.

15. The compound of claim 14, wherein the targeting moiety is a bispecific targeting moiety comprising a first targeting domain and a second targeting domain, the first targeting domain comprising the antibody or antigen binding fragment thereof.

16. The compound of claim 15, wherein the second targeting domain is an extracellular targeting domain.

17. The compound of claim 16, wherein the extracellular targeting domain binds to epithelial growth factor receptor (EGFR).

18. The compound of claim 17, wherein the extracellular targeting domain comprises the amino acid sequence

19. A degradation compound comprising: a cell penetrating peptide (CCP); a targeting moiety comprising an antibody or antigen binding fragment thereof according to any one of claims 1 to 12; and a degradation moiety comprising an E3 ligase, an active fragment of an E3 ligase, or an E3 ligase recruiting moiety, wherein the targeting moiety, the degradation moiety, and the CPP are operably connected.

20. The degradation compound of claim 19, wherein the E3 ligase or active fragment thereof comprises at least a portion of an amino acid sequence of ODC, UBOX, VIF-1, VIF02, bTrCP, FBW7, hRNF4, HifaPep, VHL, TRIM21, SOCS1, CRB, or MDM2.

21. The degradation compound of claim 20, wherein the E3 ligase or active fragment thereof comprises any one of sequences: i) PAWQLMQQFQNPDFPPEVEEQDASTLPVSCAWESGMDRHPAACA SASINV, ii) DIPDYLCGKISFELMREPCITPSGITYDRKDIEEHLQRVGHFDPVTRS PLTQEQLIPNLAMKEVIDAFISENGWVEDY, iii) PELADQLIHLYYFDCFSDSAIRKALLGHIVSPRCEYQAGHNKVGSL QYLALAALITPKKIKP, iv) PDLADQLIHLHYFDCFSESAIRNTILGRIVSPRCEYQAGHNKVGSLQ YLALAALIKPKQIKP, v) SPAIMLQRDFITALPARGLDHIAENILSYLDAKSLCAAELVCKEWY RVTSDGMLWKKL, vi) DFISLLPKELALYVLSFLEPKDLLQAAQTCRYWRILAEDNLLWREK vii) DEGATGLRPSGTVSCPICMDGYSEIVQNGRLIVSTECGHVFCSQCL RDSLKNANTCPTCRKKINH, viii) DLDLEMLAPYIPMDDDFQL, ix) MPRRAENWDEAEVGAEEAGVEEYGPEEDGGEESGAEESGPEESGP EELGAEEEMEAGRPRPVLRSVNSREPSQVIFCNRSPRVVLPVWLNF DGEPQPYPTLPPGTGRRIHSYRGHLWLFRDAGTHDGLLVNQTELF VPSLNVDGQPIFANITLPVYTLKERCLQVVRSLVKPENYRRLDIVR SLYEDLEDHPNVQKDLERLTQERIAHQRMGD, x) TLPVYTLKERCLQVVRSLVKPENYRRLDIVRSLYEDLEDHPNVQK DLERLTQERIAHQRMGD, xi) TLPVYTLKERCLQVVRSLVKPENYRRLDIVRSLFEDLEDHPNVQK DLERLTQERIAHQRMGD, xii) TLKERCLQVVRSLVKPENYRRLDIVRSLYEDLEDHPNV, xiii) TLKERCLQVVRSLVKPENYRRLDIVRSLFEDLEDHPNV, xiv) RGHLWLFRDAGTHDGLLVNQTELFVPSLNVDGQPIFANITLPVYTL KERCLQVVRSLVKPENYRRLDIVRSLYEDLEDHPNVQKDLERLTQ ERIAHQRMGD, xv) RGHLWLFRDAGTHDGLLVNQTELFVPSLNVDGQPIFANITLPVYTL KERCLQVVRSLVKPENYRRLDIVRSLFDLEDHPNVQKDLERLTQE RIAHQRMGD, xvi) HSYRGHLWLFRDAGTHDGLLVNQTELFVPSLNVDGQPIFANITLPV YTLKERCLQVVRSLVKPENYRRLDIVRSLYEDLEDHPNVQKDLER LTQERIAHQRMGD, xvii) HSYRGHLWLFRDAGTHDGLLVNQTELFVPSLNVDGQPIFANITLPV YTLKERCLQVVRSLVKPENYRRLDIVRSLFEDLEDHPNVQKDLER LTQERIAHQRMGD, xviii) PSLNVDGQPIFANITLPVYTLKERCLQVVRSLVKPENYRRLDIVRSL YEDLEDHPNVQKDLERLTQERIAHQRMGD, xix) PSLNVDGQPIFANITLPVYTLKERCLQVVRSLVKPENYRRLDIVRSL FEDLEDHPNVQKDLERLTQERIAHQRMGD, xx) MEAGRPRPVLRSVNSREPSQVIFCNRSPRVVLPVWLNFDGEPQPYP TLPPGTGRRIHSYRGHLWLFRDAGTHDGLLVNQTELFVPSLNVDG QPIFANITLPVYTLKERCLQVVRSLVKPENYRRLDIVRSLYEDLEDH PNVQKDLERLTQERIAHQRMGD, xxi) MEAGRPRPVLRSVNSREPSQVIFCNRSPRVVLPVWLNFDGEPQPYP TLPPGTGRRIHSYRGHLWLFRDAGTHDGLLVNQTELFVPSLNVDG QPIFANITLPVYTLKERCLQVVRSLVKPENYRRLDIVRSLFEDLEDH PNVQKDLERLTQERIAHQRMGD, xxii) MASAARLTMMWEEVTCPICLDPFVEPVSIECGHSFCQECISQVGKG GGSVCPVCRQRFLLKNLRPNRQLANMVNNLKEISQEAREGTQGER CAVHGERLHLFCEKDGKALCWVCAQSRKHRDHAMVPLEEAAQE YQEKLQVALGELRRKQELAEKLEVEIAIKRADWKKTVETQKSRIH AEFVQQKNFLVEEEQRQLQELEKDEREQLRILGEKEAKLAQQSQA LQELISELDRRCHSSALELLQEVIIVLERSESWNLKDLDITSPELRSV CHVPGLKKMLRTCAVHITLDPDTANPWLILSEDRRQVRLGDTQQS IPGNEERFDSYPMVLGAQHFHSGKHYWEVDVTGKEAWDLGVCR DSVRRKGHFLLSSKSGFWTIWLWNQKYEAGTYPQTPLHLQVPPCQ VGIFLDYEAGMVSFYNITDHGSLIYSFSECAFTGPLRPFFSPGFNDG GKNTAPLTLCPLNIGSQGSTDY, xxiii) MASAARLTMMWEEVTCPICLDPFVEPVSIECGHSFCQECISQVGKG GGSVCPVCRQRFLLKNLRPNRQLANMVNNLKEISQEAREGTQGER CAVHGERLHLFCEKDGKALCWVCAQSRKHRDHAMVPLEEAAQE YQEKLQVALGELRRKQELAEKLEVEIAIKRADWKKTVETQKSRIH AEFVQQKNFLVEEEQRQLQELEKDEREQLRILGEKEAKLAQQSQA LQELISELDRRCHSSALELLQEVIIVLERSESWNLKDLDITSPELRSV CHVPG, xxiv) MVAHNQVAADNAVSTAAEPRRRPEPSSSSSSSPAAPARPRPCPAVP APAPGDTHFRTFRSHADYRRITRASALLDACGFYWGPLSVHGAHE RLRAEPVGTFLVRDSRQRNCFFALSVKMASGPTSIRVHFQAGRFHL DGSRESFDCLFELLEHYVAAPRRMLGAPLRQRRVRPLQELCRQRI VATVGRENLARIPLNPVLRDYLSSFPFQI, xxv) PLQELCRQRIVATVGRENLARIPLNPVLRDYLSSFPFQI, xxvi) MAGEGDQQDAAHNMGNHLPLLPAESEEEDEMEVEDQDSKEAKK PNIINFDTSLPTSHTYLGADMEEFHGRTLHDDDSCQVIPVLPQVMM ILIPGQTLPLQLFHPQEVSMVRNLIQKDRTFAVLAYSNVQEREAQF GTTAEIYAYREEQDFGIEIVKVKAIGRQRFKVLELRTQSDGIQQAK VQILPECVLPSTMSAVQLESLNKCQIFPSKPVSREDQCSYKWWQK YQKRKFHCANLTSWPRWLYSLYDAETLMDRIKKQLREWDENLK DDSLPSNPIDFSYRVAACLPIDDVLRIQLLKIGSAIQRLRCELDIMNK CTSLCCKQCQETEITTKNEIFSLSLCGPMAAYVNPHGYVHETLTVY KACNLNLIGRPSTEHSWFPGYAWTVAQCKICASHIGWKFTATKKD MSPQKFWGLTRSALLPTIPDTEDEISPDKVILCL, xxvii) TSFAEYWNLLSP, xxviii) PRFWEYWLRLME, or a sequence that has at least 95% similarity and/or identity to any one of the sequences listed in i) through xxviii).

22. The degradation compound of claim 19, wherein the E3 ligase recruiting moiety comprises a peptide.

23. The degradation compound of claim 22, wherein the E3 ligase recruiting moiety comprises at least a portion of an amino acid sequence of IgG1 Fc or nuclear factor kappa B inhibitor alpha (IkBalpha).

24. The degradation compound of claim 23, wherein the E3 ligase recruiting moiety comprises any one of sequences: i) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK, ii) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K, iii) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALANHYTQKSLSLSPG K, iv) DKTHTCPPCPAPELLGGPCVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K, v) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALANHYTQKSLSLSPG, vi) DKTHTCPPCPAPELLGGPCVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK, vii) DKTHTCPPCPAPELLGGPCVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALANHYTQKSLSLSP GK, viii) DKTHTCPPCPAPELLGGPCVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALANHYTQKSLSLSP GK, ix) MFQAAERPQEWAMEGPRDGLKKERLLDDRHDSGLDSMKDEEYE QMVKELQEIRLEPQEVPRGSEPWKQQLTEDGDSFLHLAIIHEEKAL TMEVIRQVKGDLAFLNFQNNLQQTPLHLAVITNQPEIAEALLGAGC DPELRDFRGNTPLHLACEQGCLASVGVLTQSCTTPHLHSILKATNY NGHTCLHLASIHGYLGIVELLVSLGADVNAQEPCNGRTALHLAVD LQNPDLVSLLLKCGADVNRVTYQGYSPYQLTWGRPSTRIQQQLGQ LTLENLQMLPESEDEESYDTESEFTEFTEDELPYDDCVFGGQRLTL, x) DRHDSGLDSM, or a sequence that has at least 95% similarity and/or identity to any one of sequences i) through x).

25. The degradation compound of any one of claim 19 wherein the E3 ligase recruiting moiety is a small molecule.

26. The degradation compound of claim 25, wherein the small molecule is compound 159 or 160:

.

27. The degradation compound of any of claims 19 through 26, wherein the targeting moiety is a bispecific targeting moiety comprising a first targeting domain and a second targeting domain, the antibody or antigen binding fragment thereof comprising the first targeting domain.

28. The degradation compound of claims 27, wherein the second targeting domain is an extracellular targeting domain.

29. The degradation compound of claim 28, wherein the extracellular targeting domain binds to EGFR.

30. The degradation compound of claim 29, wherein the extracellular targeting domain comprises the amino acid sequence QVKLEESGGGSVQTGGSLRLTCAASGRTSRSYGMGWFRQAPGKEREFVSGISWR GDSTGYADSVKGRFTISRDNAKNTVDLQMNSLKPEDTAIYYCAAAAGSAWYGT LYEYDYWGQGTQVTVSS.

31. The compound of any one of claims 14 through 18 or the degradation compound of any one of claims 19 through 30, wherein the CPP is a cyclic CPP (cCPP).

32. The compound or degradation compound of claim 31, wherein the cCPP comprises 6 through 12 amino acids, wherein at least two amino acids of the cyclic peptide are charged amino acids; at least two amino acids of the cyclic peptide are aromatic hydrophobic amino acids; and at least two amino acids of the cyclic peptide are uncharged, and non-aromatic amino acids.

33. The compound or degradation compound of claim 32, wherein the at least at least two aromatic hydrophobic amino acids of the cyclic peptide are phenylalanine, naphthylalanine, or combinations thereof.

34. The compound or degradation compound of claim 32 or 33, wherein the at least two uncharged, non-aromatic amino acids are citrulline, glycine, or combinations thereof.

35. The compound or degradation compound of any one of claims 32 through 34, where the at least two charged amino acids are arginine.

36. The compound or degradation compound of claim 31, wherein the cCPP comprises 6-12 amino acids, wherein at least two amino acids are arginine, at least two amino acids comprises a hydrophobic side chain, and at least one amino acid is a D amino acid.

37. The compound or degradation compound of claim 31, wherein the cCPP comprises:

or a protonated form thereof, wherein: R1, R2, and R3 are each independently H or an aromatic or heteroaromatic side chain of an amino acid; at least one of R1, R2, and R3 is an aromatic or heteroaromatic side chain of an amino acid; R₄, R₅, R₆, and R₇ are independently H or an amino acid side chain; at least one of R₄, R₅, R₆, and R₇ is the side chain of 3-guanidino-2-aminopropionic acid, 4-guanidino-2-aminobutanoic acid, arginine, homoarginine, N-methylarginine, N,N-dimethylarginine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, lysine, N-methyllysine, N,N-dimethyllysine, N-ethyllysine, N,N,N- trimethyllysine, 4-guanidinophenylalanine, citrulline, N,N-dimethyllysine, , β- homoarginine, 3-(1-piperidinyl)alanine; AA_SC is an amino acid side chain; and q is 1, 2, 3 or 4.

38. The compound or degradation compound of claim 37, wherein the cCPP comprises:

or a protonated form or salt thereof, wherein each m is independently an integer from 0-3.

39. The compound or degradation compound of claim 37 or 38, wherein R₁, R₂, and R₃ are independently H or a side chain comprising an aryl group.

40. The compound or degradation compound of claim 39, wherein the side chain comprising an aryl group is a side chain of phenylalanine, 1-naphthylalanine, 2-naphthylalanine, tryptophan, 3-benzothienylalanine, 4-phenylphenylalanine, 3,4-difluorophenylalanine, 4- trifluoromethylphenylalanine, 2,3,4,5,6-pentafluorophenylalanine, homophenylalanine, β- homophenylalanine, 4-tert-butyl-phenylalanine, 4-pyridinylalanine, 3-pyridinylalanine, 4- methylphenylalanine, 4-fluorophenylalanine, 4-chlorophenylalanine, or 3-(9-anthryl)- alanine.

41. The compound or degradation compound of claim 40, wherein the side chain comprising an aryl group is a side chain of phenylalanine.

42. The compound or degradation compound of any one of claims 37 to 41, wherein two of R1, R2, and R3 are a side chain of phenylalanine.

43. The compound or degradation compound of any one of claims 37 to 42, wherein two of R1, R2, R3, and R4 are H.

44. The compound or degradation compound of claim 31 wherein the cCPP is

protonated form thereof, wherein each m is independently an integer from 0-3 and AAsc is an amino acid side chain.

45. The compound or degradation compound of claim 31, wherein the cCPP comprises:

or a protonated form thereof, wherein: at least two of R1, R2, R3, R4, R5, R6, and R7 are independently the side chain of lysine; mono-methyl lysine; dimethyl lysine; trimethyl lysine; 2,4-diaminobutanoic acid; or 2,3- diaminopropionic acid; each of R1, R2, R3, R4, R5, R6, and R7 are independently H or an amino acid side chain; AASC is an amino acid side chain; and q is 1, 2, 3 or 4.

46. The compound or degradation compound of claim 45, wherein at least two of R₁, R₂, R₃, R4, R5, R6, and R7 are phenylalanine.

47. The compound or degradation compound of claim 45 or 46, wherein at least one of R1, R2, R3, R4, R5, R6, and R7 is glycine.

48. The compound or degradation compound of claim 31, wherein the cCCP is:

,

, or a protonated form thereof.

49. The compound or degradation compound of any claim 31, wherein the cCPP comprises:

R1, R2, R3, R4, R5, R6, and R7 are independently H or an amino acid side chain; at least two of R1, R2, and R3 are independently a side chain of phenylalanine, or naphthylalanine; at least two of R4, R5, R6, and R7 are independently a side chain of arginine; AASC is an amino acid side chain; and each n_x is 0 or 1 and at least one n_x is 1; and q is 1, 2, 3 or 4.

50. The compound or degradation compound of claim 49, wherein nx associated with R1 is 1.

51. The compound or degradation compound of claim 31, wherein the cCPP comprises:

or a protonated form thereof, wherein: each of R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are independently H or an amino acid side chain; AA_SC is an amino acid side chain; nx is 1; and q is 1, 2, 3 or 4.

52. The compound or degradation compound of claim 31, wherein the cCPP comprises:

at least one of R1, R2, R3, R4, R5, R6, and R7 is the amino acid side chain of serine or histidine; each of R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are independently H or an amino acid side chain; AA_SC is an amino acid side chain; nx is 0 or 1; and q is 1, 2, 3 or 4.

53. The compound or degradation compound of claim 51 of 52, wherein: at least two of R1, R2, and R3 are independently a side chain of phenylalanine, or naphthylalanine; and at least two of R₄, R₅, R₆, or R₇ are independently a side chain of arginine.

54. The compound or degradation compound of any one of claims 51 through 53, wherein at least two of R4, R5, R6, or R7 are independently a side chain of serine or histidine.

55. The compound or degradation compound of any one of claims 49 through 54, wherein R₁ and R₃ are the side chain of phenylalanine,

56. The compound or degradation compound of any one of claims 49 through 54, wherein R1 is the side chain of phenylalanine and R₃ is the side chain of naphthylalanine.

57. The compound or degradation compound of any one of claims 49 through 56, wherein R₅ and R7 are the side chain of arginine.

58. The compound or degradation compound of any one of claims 49 through 56, wherein R4 and R₆ are the side chain of serine or histidine.

59. The compound or degradation compound of claim 31, wherein the cCPP comprises:

.

60. The compound or degradation compound of claim 31, wherein the cCPP comprises:

,

61. The compound or degradation compound of any one of claims 37 through 47 or 49 through 58, wherein AASC is a side chain of an asparagine residue, aspartic acid residue, glutamic acid residue, homoglutamic acid residue, or homoglutamate residue.

62. The compound or degradation compound of any one of claims 37 through 47 or 49 through 58, wherein AASC is a side chain of a glutamic acid residue.

63. The compound or degradation compound of any one of claims 37 through 47 or 49 through 58, wherein AASC is:

, wherein t is an integer from 0 to 5.

64. The compound or degradation compound of any one of claims 37 through 47 or 49 through 58, wherein at least one atom on the AASC or at least one lone pair forms a bond to a linker.

65. The compound or degradation compound of 64, wherein the linker comprises a - (OCH2CH2)z’- subunit, wherein z’ is an integer from 1 to 23.

66. The compound or degradation compound of claim 64 or 65, wherein the linker comprises: (i) a -(OCH2CH2)z- subunit, wherein z’ is an integer from 1 to 23; (ii) one or more amino acid residues, such as a residue of glycine, b-alanine, 4- aminobutyric acid, 5-aminopentoic acid or 6-aminohexanoic acid, or combinations thereof; or (iii) combinations of (i) and (ii).

67. The compound or degradation compound of claim 64, wherein the linker comprises a bivalent or trivalent C₁-C₅₀ alkylene, wherein 1-25 methylene groups are optionally and independently replaced by -N(H)-, -N(C₁-C₄ alkyl)-, -N(cycloalkyl)-, -O-, -C(O)-, - C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(C1-C4 alkyl)-, -S(O)2N(cycloalkyl)-, -N(H)C(O)-, - N(C₁-C₄ alkyl)C(O)-, -N(cycloalkyl)C(O)-, -C(O)N(H)-, -C(O)N(C₁-C₄ alkyl), - C(O)N(cycloalkyl), aryl, heteroaryl, cycloalkyl, or cycloalkenyl.

68. The compound or degradation compound of any one of claims 14 through 67, wherein the compound further comprises an exocyclic peptide.

69. The compound or degradation compound of claim 68, wherein the linker is a trivalent linker having the structure

wherein: x’ is an integer from 1-23; y is an integer from 1-5; z’ is an integer from 1-23; * is the point of attachment to the AASC, AASC is a side chain of an amino acid residue of the cyclic peptide; M is a bonding group that covalently attaches the targeting moiety or the degradation construct to the linker; and exocyclic peptide is conjugated to the linker at the amino end of the linker.

70. The compound or degradation compound of claim 69, wherein z’ is 11.

71. The compound or degradation compound of claim 69 or 70, wherein x’ is 1.

72. The compound or degradation compound of any one of claims 69 through 71, wherein M comprises a reaction product of a bioconjugation reaction.

73. The compound or degradation compound of any one of claims 69 through 71, wherein M comprises a reaction product of a first bioconjugation reaction, a reaction product of a second bioconjugation reaction, and a chemical moiety separating the reaction products.

74. The compound or degradation compound of any one of claims 69 through 71, wherein M , , , ,

, , ,

75.

.

76. The compound or degradation compound of any one of claims 68 through 75, wherein the exocyclic peptide comprises from 2 to 10 amino acid residues.

77. The compound or degradation compound of claim 76, wherein the exocyclic peptide comprises from 4 to 8 amino acid residues.

78. The compound or degradation compound of claim 76 or 77, wherein the exocyclic peptide comprises 1 or 2 amino acid residues comprising a side chain comprising a guanidine group, or a protonated form or salt thereof.

79. The compound or degradation compound of any one of claims 76 to 78, wherein the exocyclic peptide comprises 2, 3, or 4 lysine residues.

80. The compound or degradation compound of claim 79, wherein the amino group on the side chain of each lysine residue is substituted with a trifluoroacetyl (-COCF3), allyloxycarbonyl (Alloc), 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde), or (4,4- dimethyl-2,6-dioxocyclohex-1-ylidene-3)-methylbutyl (ivDde) group.

81. The compound or degradation compound of any one of claims 76 to 80, wherein the exocyclic peptide comprises at least 2 amino acid residues with a hydrophobic side chain.

82. The compound or degradation compound of claim 81, wherein the amino acid residue with a hydrophobic side chain is selected from valine, proline, alanine, leucine, isoleucine, and methionine.

83. The compound or degradation compound of claim 81 or 82, wherein the exocyclic peptide comprises one of the following sequences: KK, KR, RR, HH, HK, HR, RH, KKK, KGK, KBK, KBR, KRK, KRR, RKK, RRR, KKH, KHK, HKK, HRR, HRH, HHR, HBH, HHH, HHHH, KHKK, KKHK, KKKH, KHKH, HKHK, KKKK, KKRK, KRKK, KRRK, RKKR, RRRR, KGKK, KKGK, HBHBH, HBKBH, RRRRR, KKKKK, KKKRK, RKKKK, KRKKK, KKRKK, KKKKR, KBKBK, RKKKKG, KRKKKG, KKRKKG, KKKKRG, RKKKKB, KRKKKB, KKRKKB, KKKKRB, KKKRKV, RRRRRR, HHHHHH, RHRHRH, HRHRHR, KRKRKR, RKRKRK, RBRBRB, KBKBKB, PKKKRKV, PGKKRKV, PKGKRKV, PKKGRKV, PKKKGKV, PKKKRGV or PKKKRKG, wherein B is β-alanine.

84. A compound comprising: a targeting moiety comprising a β-catenin antibody or antigen binding fragment thereof; and a cyclic cell penetrating peptide (cCPP) operably linked to the antibody or antigen binding fragment thereof, wherein the cCPP comprises:

wherein: each of R1, R2, R3, R4, R5, R6, and R7 are independently H or an amino acid side chain; at least two of R1, R2, and R3 are independently a side chain of phenylalanine, or naphthylalanine; at least two of R₄, R₅, R₆, and R₇ are independently a side chain of arginine; AASC is an amino acid side chain; and nx is 0 or 1 and at least one nx is 1; and q is 1, 2, 3 or 4.

85. A compound comprising: a targeting moiety comprising a β-catenin antibody or antigen binding fragment thereof; and a cyclic cell penetrating peptide (cCPP) operably linked to the antibody or antigen binding fragment thereof, wherein the cCPP comprises:

or a protonated form thereof, wherein: each of R1, R2, R3, R4, R5, R6, and R7 are independently H or an amino acid side chain; at least two of R₁, R₂, and R₃ are independently a side chain of phenylalanine, or naphthylalanine; at least two of R4, R5, R6, and R7 are independently a side chain of arginine; at least two of R4, R5, R6, and R7 are independently a side chain of serine or histidine; AA_SC is an amino acid side chain; nx is 0 or 1; and q is 1, 2, 3 or 4.

86. A compound comprising: a targeting moiety comprising a β-catenin antibody or antigen binding fragment thereof; and a cyclic cell penetrating peptide (cCPP) operably linked to the antibody or antigen binding fragment thereof, wherein the cCPP comprises:

protonated form thereof, wherein: each of R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are independently H or an amino acid side chain; at least two of R1, R2, and R3 are independently a side chain of phenylalanine or naphthylalanine; at least two of R₄, R₅, R₆, and R₇ are independently a side chain of arginine; AASC is an amino acid side chain; and nx is 1; and q is 1, 2, 3 or 4.

87. A composition comprising the antibody or antigen binding fragment thereof, degradation compound, or compound of any one of claims 1 through 12 or 14 through 86.

88. The composition of claim 87, the composition further comprising a pharmaceutically acceptable carrier.

89. A method of delivering a b-catenin antibody or antigen binding fragment to a cytosol of a cell, comprising: contacting an exterior of the cell with the compound, the degradation compound, or the composition of any one of claims 14 to 88 to cause the compound to enter the cytosol.

90. A method comprising administering the composition of claim 87 or 88 to a subject.

91. A polynucleotide having a sequence encoding the antibody or antigen binding fragment thereof of any one of claims 1 to 13.

92. An expression vector comprising the polynucleotide of claim 91.

93. A host cell transformed with the polynucleotide sequence of claim 91 or the expression vector of claim 92.

94. A method for producing an antibody or antigen binding fragment thereof or degradation construct, the method comprising culturing the host cell of claim 93 under conditions that allow the host cell to translate the nucleotide sequence encoding the antibody or antigen binding fragment thereof.

95. The method of claim 94, further comprising harvesting, purifying and/or isolating the antibody or antigen binding fragment thereof.