Methods and compositions for epithelial targeting

Abstract

The present disclosure relates to, inter alia, compositions for site-specific delivery of nucleic acids to epithelial cells by conjugating the nucleic acids to an plgR binder capable of binding polymeric Ig receptor (plgR). The present disclosure also relates to, inter alia, methods for treating diseases.

Description

[0001] Atorney Docket No. CVL-001PC / 140489-5001

[0002] METHODS AND COMPOSITIONS FOR EPITHELIAL TARGETING

[0003] TECHNICAL FIELD

[0004] The present disclosure relates to, inter alia, compositions for site-specific delivery of nucleic acids to epithelial cells by combining them with targeting ligands, and methods for treating diseases.

[0005] PRIORITY

[0006] This Application claims the benefit of, and priority to, US Application Nos. 63 / 778,024, filed March 26, 2025; and 63 / 778,027, filed March 26, 2025, each of which is hereby incorporated by reference in its entirety.

[0007] SEQUENCE LISTING

[0008] The instant application contains a sequence listing, which has been submitted in XML format via Patent Center. The contents of the XML copy named “CVL-001PC_140489- 5001_Sequence_Listing”, which was created on March 24, 2026, and is 242,770 bytes in size, are incorporated herein by reference in their entirety.

[0009] BACKGROUND

[0010] Nucleic acid therapeutics provide novel modalities with characteristics that differ from those of small molecules and other biologies, such as antibodies and proteins. Their unique characteristics make it possible to target entities that are considered “undruggable” using small molecule or protein / antibody-based biologies. Nucleic acid drugs are also amendable to extrapolation of discovery platforms to create newer drugs against different targets. For example, with availability of modified RNA platform, mRNA vaccines against COVID-19 could be developed and administered to humans within several months of the sequencing of SARS-CoV-2 genome sequence. Similarly, RNAi and antisense RNA drugs have been rapidly identified using various platforms once target identities were determined. However, the progress of nucleic acid drugs is hindered by difficulty to deliver these drugs to desired tissues, with some exceptions. Nucleic acids are not easily taken up by cells due to their polyvalent anionic properties. When administered intravenously, they tend to accumulate in the liver and kidney. However, uptake of N- acetylgalactosamine (GalNAc) conjugates via the asialoglycoprotein receptor (ASGPR) provides an efficient delivery mechanism to hepatocytes. Thus, most of the approved and advanced nucleic 1

[0011] DB1 / 167593545.6Atorney Docket No. CVL-001PC / 140489-5001

[0012] acid drugs rely on systemic administration to target the liver (e.g., intravenous infusion of patisiran) or local administration (e.g., intravitreal administration of fomivirsen). In cases where the locus of delivery is less important (e.g., mRNA vaccines), intramuscular injection is another option. However, there are no such delivery technologies for other tissues or cell types.

[0013] Therefore, newer technologies that enable delivery of nucleic acid therapeutics to other tissues are desired.

[0014] SUMMARY

[0015] Accordingly, in various aspects, the present disclosure provides compositions and methods that are useful, inter alia, to deliver nucleic acid drugs to epithelial cells (without limitation, e.g., the epithelial cells of gastrointestinal tract, respiratory tract, urinogenital tract and kidney).

[0016] In aspects, the present disclosure provides a composition comprising: (a) a polymeric Ig receptor (plgR) binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the therapeutic nucleic acid payload is or comprises one or more of an small interfering RNA (siRNA), a microRNA (miRNA), or an antisense oligonucleotide (ASO), wherein the composition is formulated for delivering the therapeutic nucleic acid payload to an epithelial cell of a human subject in need thereof, and wherein the therapeutic nucleic acid payload is capable of entering an endosome of the epithelial cell.

[0017] In aspects, the present disclosure provides a composition comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and optionally a linker contacting both (a) and (b), wherein the composition is formulated for delivering the therapeutic nucleic acid payload to an epithelial cell of a human subject, and wherein the therapeutic nucleic acid payload is capable of entering an endosome of the epithelial cell.

[0018] In aspects, the present disclosure provides a composition comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and optionally a linker contacting both (a) and (b), wherein the composition is formulated for delivering the therapeutic nucleic acid payload to an epithelial cell of a human subject, and wherein the therapeutic nucleic acid payload is substantially retained in one or more subcellular compartments, optionally selected from nucleus, lysosome, endosome, or cytoplasm, of the epithelial cell.

[0019] DB1 / 167593545.6 2Atorney Docket No. CVL-001PC / 140489-5001

[0020] In aspects, the present disclosure provides a composition comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) a linker contacting both (a) and (b), wherein the composition is formulated for delivering the therapeutic nucleic acid payload to an epithelial cell of a human subject, and wherein the therapeutic nucleic acid payload is substantially retained in one or more subcellular compartments, optionally selected from nucleus, lysosome, endosome, or cytoplasm, of the epithelial cell.

[0021] In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a polymeric Ig receptor (plgR) binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b).

[0022] In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b), wherein the therapeutic nucleic acid payload is capable of entering an endosome of the epithelial cell.

[0023] In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b), wherein the therapeutic nucleic acid payload is substantially retained in one or more subcellular compartments, optionally selected from nucleus, lysosome, endosome and cytoplasm, of the epithelial cell. In embodiments, the retention in in one or more subcellular compartments is detected or detectable by methods known in the art, e.g., fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT- qPCR), stem-loop RT-qPCR, and biological activity of the therapeutic nucleic acid payload. In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b), wherein the therapeutic nucleic acid payload is delivered to the endosome, lysosome, nucleus, and / or cytoplasm of the epithelial cell. In embodiments, the delivery to the endosome and / or cytoplasm is detected or detectable by methods

[0024] DB1 / 167593545.6 3Atorney Docket No. CVL-001PC / 140489-5001

[0025] known in the art, e.g.. fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, and a technique that can determine the presence or ongoing biological activity of the therapeutic nucleic acid payload.

[0026] In aspects, the present disclosure provides a delivery system composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b), wherein the therapeutic nucleic acid payload does not substantially transcytose across the epithelial cell. In embodiments, the delivery to the transcytosis across the epithelial cell is detected or detectable by methods known in the art, e.g, in vitro immunological assays (e.g, fluorescence-based in vitro assays to detect the payload, plgR binder translocalization across a monolayer) and trans well assay, coupled with a detection technique known in the art such as ELISA, western blot, or a combination thereof. In embodiments, the composition or the delivery system further comprises a PEG moiety and / or a lipid moiety contacting (i) the payload or at least one of the plurality of payloads, (ii) the plgR binder, (iii) the linker or at least one of the plurality of linkers.

[0027] In embodiments, the therapeutic nucleic acid payload is or comprises one or more of small interfering RNA (siRNA), microRNA (miRNA), anti-miRNA, antisense oligonucleotide (ASO), phosphorodiamidate morpholino oligomer (PMO, e.g., an exon skipping PMO), tRNA, peptide nucleic acid (PNA), locked nucleic acid (LNA), RNA aptamer, DNA aptamer, ribozyme, circular RNA (circRNA), RNA decoy, small activating RNA (saRNA), and messenger RNA (mRNA). In embodiments, the therapeutic nucleic acid payload or the plurality of nucleic acid payloads comprises at least one inhibitory nucleic acid, and wherein the at least one inhibitory nucleic acid is capable of greater silencing of a target gene to compared to a control composition lacking the plgR binder, as measured by levels of a protein encoded by the target gene and mRNA of the target gene.

[0028] In embodiments, the composition or the delivery system comprises at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the therapeutic nucleic acid payload. In embodiments, the copies of the therapeutic nucleic acid payload have same or different sequences. In embodiments, the copies of the therapeutic nucleic acid payload are independently selected from siRNA, miRNA, anti-miRNA, ASO, PMO, tRNA, PNA, LNA,

[0029] DB1 / 167593545.6 4Atorney Docket No. CVL-001PC / 140489-5001

[0030] RNA aptamer, DNA aptamer, ribozyme, circRNA, RNA decoy, saRNA, and mRNA. In embodiments, at least one of the copies of the therapeutic nucleic acid payload is an siRNA or an ASO. In embodiments, all copies of the therapeutic nucleic acid payload are siRNA or ASO (having same or different sequences).

[0031] In embodiments, the therapeutic nucleic acid payload comprises at least one chemically modified nucleotide. In embodiments, the chemically modified nucleotide is selected from a deoxynucleotide, a 3 '-terminal deoxy -thymine (dT) nucleotide, a 2' O-methyl modified nucleotide, a 2'- fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino-modified nucleotide, a 2'-O-allyl-modified nucleotide, 2'-C-alkyl-modified nucleotide, 2'-hydroxyl-modified nucleotide, a 2 '-methoxy ethyl modified nucleotide, a2'-O-alkyl- modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural nucleobase comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5'- phosphate, a nucleotide comprising a 5 '-phosphate mimic, a glycol modified nucleotide, and a 2- O-(N-methylacetamide) modified nucleotide, and a combination any two or more thereof.

[0032] In embodiments, the antibody is a monoclonal antibody or a polyclonal antibody, or a plgR- binding fragment thereof. In embodiments, the antibody is a monoclonal antibody, or a plgR binding fragment thereof. In embodiments, the antibody-like molecule is selected from a recombinant heavy-chain-only antibody (VHH), single-domain antibody, single-chain antibody (scFv), shark heavy-chain-only antibody (VNAR), microprotein (cysteine knot protein, knottin), DARPin, Tetranectin, Affibody, Affitin, Alphabody, Gastrobody, Monobody, nanoCLAMP, Optimer, Repebody, fibronectin domain-derived antibody mimic, Centyrin, Obody, Transbody, Anticalin, AdNectin, Affilin, Affimer, Microbody, aptamer, alterase, plastic antibody, phylomer, stradobody, maxibody, evibody, fynomer, armadillo repeat protein, Kunitz domain, avimer, atrimer, probody, immunobody, triomab, troybody, pepbody, vaccibody, UniBody, DuoBody, Fv, Fab, Fab', and F(ab')2, or a plgR binding fragment thereof. In embodiments, the antibody-like molecule is a VHH.

[0033] DB1 / 167593545.6 5Atorney Docket No. CVL-001PC / 140489-5001

[0034] In embodiments, the antibody, antibody-like molecule or plgR binding fragment thereof is in form of an antibody format selected from multivalent tandem binding fragment (e.g., multivalent tandem VHHs or multivalent tandem scFvs), single a binding fragment (e.g., VHH-His or scFv- His), a monomeric Fc domain-binding fragment (e.g., VHH- monomeric Fc domain or scFv- monomeric Fc domain), binding fragment-Fc domain (e.g., VHH-Fc or scFv-Fc), IgG-binding fragment fusion (e.g., light chain-(LC)-VHH, LC-scFv, heavy chai n-(HC)- VHH or HC-scFv), a biparatopic molecule (e.g., biparatopic VHH-Fc or scFv-Fc), a tetravalent molecule (e.g., a tetravalent VHH-Fc), an IgG hexamer, a diabody (i.e., a dimeric scFv), a triabody (i.e., a trimeric scFv), a tetrabody (i.e., a tetrameric scFv), bidisulftde-bond stabilized scFv (ds-scFv), abi-speciftc antibody, DuoBody, VHH beads on a string, an Fc-heterodimeric molecule, minibody (miniAbs), Fab-IgG, IgG-Fab, and VHH-IgG-VHH.

[0035] In embodiments, the composition or the delivery system comprises at least 2, or at least 3, or at least 4 or more antibodies, antibody-like molecules or plgR binding fragments thereof per copy of the therapeutic nucleic acid payload. In embodiments, the antibody, antibody-like molecule or plgR binding fragment thereof binds same or different domains or epitopes of plgR.

[0036] In embodiments, the composition or the delivery system comprises at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the therapeutic nucleic acid payload. In embodiments, the copies of the therapeutic nucleic acid payload are independently selected from siRNA, miRNA, anti-miRNA, ASO, phosphorodiamidate PMO, tRNA, PNA, LNA, RNA aptamer, DNA aptamer, ribozyme, circRNA, RNA decoy, saRNA, and mRNA. In embodiments, at least one of the copies of the therapeutic nucleic acid payload is an siRNA or an ASO. In embodiments, all copies of the therapeutic nucleic acid payload are siRNA or ASO. In embodiments, the copies of siRNA or ASO have same or different sequences.

[0037] In embodiments, the plgR binder binds to one or more of extracellular domains DI, D2, D3, D4, D5, and the cleavage domain (also known as D6) of plgR. In embodiments, the plgR binder binds to the cleavage domain of plgR. In embodiments, the plgR binder binds plgR at or near the J chain binding site for plgR of immunoglobulin A (IgA) or IgM. In embodiments, the plgR binder reduces or inhibits cleavage of extracellular domain D6 of plgR. In embodiments, the plgR binder binds to plgR in a competitive manner with IgA and / or IgM. In embodiments, the plgR binder comprises a plgR ligand selected from IgA, IgM, or a plgR-binding fragment thereof. In embodiments, the

[0038] DB1 / 167593545.6 6Atorney Docket No. CVL-001PC / 140489-5001

[0039] plgR binder binds to pTgR with higher affinity than IgA or IgM binds to plgR. In embodiments, the plgR binder binds to plgR at an acidic pH. In embodiments, the plgR binder binds to plgR at pH of about 4.5 to about 6.5.

[0040] In embodiments, the plgR binder comprises an amino acid sequence selected from those disclosed in Table 1 or Table 2. In embodiments, the plgR binder comprises an amino acid sequence selected from an amino acid sequence selected from SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124 and 153-186.

[0041] In embodiments, the linker contacts the 5' end of the therapeutic nucleic acid payload and / or the 3' end of the therapeutic nucleic acid payload. In embodiments, the linker contacts an internal location within the therapeutic nucleic acid payload. In embodiments, the linker does not contact the 5' end and / or the 3' end of the therapeutic nucleic acid payload. In embodiments, the plgR binder is or comprises a peptide or a protein. In embodiments, the linker contacts the N-terminus of the plgR binder and / or the C-terminus of the plgR binder. In embodiments, the linker contacts an internal amino acid residue of the plgR binder. In alternative embodiments, the linker does not contact the N-terminus of the plgR binder. In additional or alternative embodiments, the linker does not contact the C-terminus of the plgR binder.

[0042] In embodiments, the linker is branched. In embodiments, the linker is capable of linking at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the plgR binder with a copy of the therapeutic nucleic acid pay load. In embodiments, the linker is capable of linking at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the therapeutic nucleic acid payload with a copy of the plgR binder.

[0043] In embodiments, the composition or the delivery system modulates the expression and / or activity of a target of the therapeutic nucleic acid payload. In embodiments, the composition or the delivery system modulates the expression and / or activity of a target of the therapeutic nucleic acid payload substantially within the epithelial cell. In embodiments, the epithelial cell is located with gastrointestinal mucosa, lung, kidney, respiratory tract mucosa, gall bladder, or urinary bladder. In embodiments, the composition or the delivery system is not substantially transported across the epithelium. In embodiments, the amount of composition transported across the epithelium is at DB1 / 167593545.6 7Atorney Docket No. CVL-001PC / 140489-5001

[0044] least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold less than an amount transported across the epithelium of a control composition lacking the plgR binder.

[0045] In embodiments, a detectable amount of the composition or the delivery system is retained inside the epithelial cell. In embodiments, the endosomal retention is detected or detectable using methods known in the art, e.g., a technique selected from fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, and biological activity of the therapeutic nucleic acid payload.

[0046] In embodiments, the composition or the delivery system is not substantially secreted by the epithelial cell. In embodiments, the secretion is detected or detectable by methods known in the art, e.g., in vitro immunological assays (e.g, fluorescence-based in vitro assays to detect the payload, plgR binder translocalization across a monolayer) and trans well assay, coupled with a detection technique known in the art such as ELISA, western blot, or a combination thereof. In embodiments, the amount of the composition or the delivery system is retained inside the epithelial cell is at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold greater than an amount retained inside the epithelial cell of a control composition lacking the plgR binder.

[0047] In embodiments, the amount of the composition or the delivery system does not substantially contact the apical side of the epithelial cell. In embodiments, the amount of the composition or the delivery system contacting the basal side of the epithelial cell is at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold greater than the amount of composition contacting the apical side of the epithelial cell.

[0048] In aspects, the present disclosure provides a pharmaceutical composition comprising the composition of any of the embodiments disclosed herein, and a pharmaceutically acceptable diluent or excipient. In aspects, the present disclosure provides a pharmaceutical composition comprising the delivery system of any of the embodiments disclosed herein, and a pharmaceutically acceptable diluent or excipient. In embodiments, the pharmaceutical composition is formulated for a parenteral administration. In embodiments, the pharmaceutical composition is formulated for an intravenous, subcutaneous, intramuscular, intradermal, intraperitoneal, epidural, or intrathecal administration.

[0049] DB1 / 167593545.6 8Atorney Docket No. CVL-001PC / 140489-5001

[0050] In aspects, the present disclosure provides a host cell comprising the composition of any of the embodiments disclosed herein. In aspects, the present disclosure provides a host cell comprising the delivery system of any of the embodiments disclosed herein.

[0051] In aspects, the present disclosure provides a method for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject comprising administering to the subject the composition of any of the embodiments disclosed herein or the delivery system of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein, or the host cell of any of the embodiments disclosed herein.

[0052] In aspects, the present disclosure provides a method for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject comprising (i) contacting a cell of the subject with the composition of any of the embodiments disclosed herein or the delivery system of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein, (ii) optionally, culturing the cell, and (iii) administering to the subject the cell. In aspects, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject the composition of any of the embodiments disclosed herein or the delivery system of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein, or the host cell of any of the embodiments disclosed herein.

[0053] In aspects, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, the method comprising (i) contacting a cell of the subject with the composition of any of the embodiments disclosed herein or the delivery system of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein, (ii) optionally, culturing the cell, and (iii) administering to the subject the cell.

[0054] Any aspect or embodiment disclosed herein can be combined with any other aspect or embodiment as disclosed herein.

[0055] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a non-limiting, schematic representation of transcytosis, endosomal retention and internalization mediated by the polymeric immunoglobulin receptor (plgR). Without wishing to be bound by theory, transcytosis of IgA dimers (and IgM pentamers) is initiated once they bind to

[0056] DB1 / 167593545.6 9Atorney Docket No. CVL-001PC / 140489-5001

[0057] plgR. The IgA-pIgR complex is internalized via clathrin-mediated endocytosis. Without wishing to be bound by theory, it is believed that the internalized IgA-pIgR complex is first trafficked to the basolateral early endosome (EE), followed by transport to the common endosome (CE), before being sorted to the apical recycling endosome (ARE) that is localized beneath the apical epithelial membrane, where the extracellular portion of plgR undergoes cleavage. The cleaved extracellular portion, which is called the secretory component (SC), remains bound to the IgA dimers. The IgA dimer-SC complex is then secreted. The composition of the present disclosure promotes endosomal retention or escape.

[0058] FIG. 2 is a non-limiting, schematic representation of the composition of the present disclosure.

[0059] FIG. 3A to FIG. 3E show flow cytometry data for expression of plgR on HEK293T cells stably transfected with human (FIG. 3A), cynomolgus (FIG. 3B) mouse (FIG. 3C), or rat plgR (FIG.

[0060] 3D) FIG. 3E shows human plgR expression on single cell clone 1B8. The light grey histogram shows wildtype HEK293T cells and the dark grey histograms are the transfected cells.

[0061] FIG. 4 shows flow cytometry data of VHH with a sortase motif binding to human plgR HEK293T clone 1B8 cells.

[0062] FIG. 5A to FIG. 5F show results of flow cytometry demonstrating internalization of an irrelevant recombinant heavy-chain-only antibody (VHH)-Srt (FIG. 5A), anti-pIgR VHH NBl-Srt (FIG.

[0063] 5B), NB2-Srt (FIG. 5C), NB3-Srt (FIG. 5D), NB4-Srt (FIG. 5E), or NB5-Srt (FIG. 5F), each VHH linked to a sortase motif labeled with a pH sensitive dye into human plgR expressing HEK293T cell clone 1B8 or wildtype HEK293T cells.

[0064] FIG. 6A and FIG. 6B show ELISA data of VHH NB 1 with a free terminal cysteine, to enable thiol-maleimide conjugation, for binding to human plgR (FIG. 6A) or mouse plgR (FIG. 6B).

[0065] Comparison was made to NB1 without a terminal cysteine. Proteins were expressed as either a monomer or a dimer.

[0066] FIG. 7A to FIG.7H demonstrate species cross-reactivity of a VHH NB 1 construct or a VHH NB2 construct as measured by flow cytometry. FIG. 7A and FIG. 7B show the binding of the VHH NB1 construct (FIG. 7A) or the VHH NB2 construct (FIG. 7B) to HEK293T cells expressing human plgR (clone 1B8 cells). FIG.7C and FIG.7D show the binding of the VHH NB 1 construct (FIG. 7C) or the VHH NB2 construct (FIG. 7D) to HEK293T stable pool cells expressing

[0067] DB1 / 167593545.6 10Atorney Docket No. CVL-001PC / 140489-5001

[0068] cynomolgus plgR. FIG. 7E and FIG. 7F show the binding of the VHH NB1 construct (FIG. 7E) or the VHH NB2 construct (FIG.7F) to HEK293T stable pool cells expressing mouse plgR. FIG.

[0069] 7G and FIG. 7H show the binding of the VHH NB1 construct (FIG. 7G) or the VHH NB2 construct (FIG. 7H) to wildtype HEK293T cells.

[0070] FIG. 8A to FIG.8D show results of an enzyme-linked immunosorbent assay (ELISA) illustrating the binding of fusion proteins of an anti-human serum albumin VHH and anti-pIgR VHHs to human serum albumin (FIG. 8A and FIG. 8B), mouse serum albumin (FIG. 8C), or cynomolgus serum albumin (FIG. 8D).

[0071] FIG. 9A to FIG.9D demonstrate in vitro activity of the conjugates of anti-pIgR VHHs and siRNA targeting housekeeping gene AHSA1 in HEK293T expressing plgR. Shown is bDNA (branched DNA) analysis for AHSA1 mRNA expression following treatment with the conjugates in parental HEK293 cells (FIG. 9A) or HEK293T cells expressing human plgR (clone 1B8, FIG. 9B). As a control, parental HEK293 cells (FIG. 9C) or HEK293T cells expressing human plgR (clone 1B8, FIG. 9D) were transfected with the conjugates.

[0072] FIG. 10A to FIG. 10D demonstrate in vitro activity of the conjugates of AHSA1 -specific siRNA with fusion proteins of an anti-human serum albumin VHH and anti-pIgR VHHs produced by various methods. Shown is bDNA (branched DNA) analysis for AHSA1 mRNA expression following treatment with the conjugates produced by various methods in parental HEK293 cells (FIG. 10A) or HEK293T cells expressing human plgR (clone 1B8, FIG. 10B). As a control, parental HEK293 cells (FIG. 10C) or HEK293T cells expressing human plgR (clone 1B8, FIG.

[0073] 10D) were transfected with the conjugates produced by various methods. Conjugation methods include sortase (-Srt-), thiol-maleimide (-C-), or glycosite specific (-Fc-) conjugation.

[0074] FIG. 11 shows bDNA analysis for AHSA1 mRNA expression in cells treated with the conjugates of AHSA1 -specific siRNA with the fusion proteins of an anti-human serum albumin VHH and anti-pIgR VHHs prepared using the thiol-maleimide method.

[0075] FIG. 12A and FIG. 12B demonstrate in vivo activity of the conjugates of AHSA1 -specific siRNA with the fusion proteins of an anti-human serum albumin VHH and anti-pIgR VHHs prepared using the thiol-maleimide method. RT-pPCR data for relative AHSA1 mRNA expression in the liver (FIG. 12A) and gut (FIG. 12B) following systemic administration of VHH-AHSA1 siRNA conjugates is shown. GalNAc3-AHSAl siRNA was used as a control for liver targeting.

[0076] DB1 / 167593545.6 11Atorney Docket No. CVL-001PC / 140489-5001

[0077] FIG. 13A and FIG. 13B shows results from a phage display peptide screen. FIG. 13A shows correlation of peptides from phage display peptide screen that bind to human and mouse plgR as measured by ELISA. FIG. 13B shows confirmation ELISA testing in triplicate of top candidates.

[0078] FIG. 14A to FIG. 14D shows binding of the indicated native peptides to human plgR as measured by ELISA.

[0079] FIG. 15 shows binding of the indicated native peptides by flow cytometry to human plgR expressing HEK293T cells clone 1B8 or wildtype HEK293T cells.

[0080] FIG. 16 shows internalization kinetics of peptides labeled with pH sensitive dye in human plgR expressing HEK293T clone 1B8 cells or wildtype HEK293T cells.

[0081] DETAILED DESCRIPTION

[0082] The present disclosure is based, in part, on the creation of a composition or a delivery system for delivering a therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) to an epithelial cell of a subject (without limitation, e.g., the epithelial cells of gastrointestinal tract, respiratory tract, urinogenital tract and kidney).

[0083] Therapeutic agents need to reach specific locations to engage with their targets and exert their therapeutic actions. Frequently, the target is located in cells of specific tissues. Small molecule drugs (generally having molecular weight < 1000 Da), which are typically hydrophobic organic compounds, can reach many parts of the body due to their small size, which allows them to easily circulate through the bloodstream. Their hydrophobic nature enables them to readily cross cell membranes and enter cells to exert their therapeutic effects. Biologies, particularly nucleic acid therapeutics, on the other hand, are large, polar or charged compounds that cannot easily circulate through the bloodstream because of their retention in the liver and kidneys. The present disclosure provides a composition or a delivery system capable of specifically delivering drugs to the epithelial cells by harnessing the activity of the polymeric Ig receptor (plgR) receptor. plgR facilitates the transcytosis of the soluble polymeric isoforms of immunoglobulin A (e.g., dimeric IgA) and immunoglobulin M (IgM) and immune complexes. Disclosed herein are delivery vehicles for therapeutic payloads (without limitations, e.g., therapeutic nucleic acid payload) that exploit the internalization induced by plgR and then divert the internalized therapeutic payloads to the intracellular environment (rather than transcytosis).

[0084] DB1 / 167593545.6 12Atorney Docket No. CVL-001PC / 140489-5001

[0085] Accordingly, in aspects, the present disclosure provides a composition comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the composition is formulated for delivering the therapeutic nucleic acid payload to an epithelial cell of a human subject, and wherein the therapeutic nucleic acid payload is capable of entering an endosome of the epithelial cell. In aspects, the present disclosure provides a composition comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and optionally a linker contacting both (a) and (b), wherein the composition is formulated for delivering the therapeutic nucleic acid payload to an epithelial cell of a human subject, and wherein the therapeutic nucleic acid payload is substantially retained in one or more subcellular compartments, optionally selected from nucleus, lysosome, endosome, or cytoplasm, of the epithelial cell.

[0086] In aspects, the present disclosure provides a composition comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) a linker contacting both (a) and (b), wherein the composition is formulated for delivering the therapeutic nucleic acid payload to an epithelial cell of a human subject, and wherein the therapeutic nucleic acid payload is substantially retained in one or more subcellular compartments, optionally selected from nucleus, lysosome, endosome, or cytoplasm, of the epithelial cell.

[0087] In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a polymeric Ig receptor (plgR) binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b).

[0088] In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b).

[0089] In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b), wherein the therapeutic nucleic acid payload is capable of entering an endosome of the epithelial cell.

[0090] DB1 / 167593545.6 13Atorney Docket No. CVL-001PC / 140489-5001

[0091] In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b), wherein the therapeutic nucleic acid payload is substantially retained in one or more subcellular compartments. In embodiments, the subcellular compartment is selected from nucleus, endosome and cytoplasm, of the epithelial cell. In embodiments, the retention in in one or more subcellular compartments is detected or detectable by methods known in the art, e.g., fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, and biological activity of the therapeutic nucleic acid payload.

[0092] In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b), wherein the therapeutic nucleic acid payload is delivered to the endosome, lysosome, nucleus, and / or cytoplasm of the epithelial cell. In embodiments, the delivery to the endosome and / or cytoplasm is detected or detectable by methods known in the art, e.g., fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, and a technique that can determine the presence or ongoing biological activity of the therapeutic nucleic acid payload.

[0093] In aspects, the present disclosure provides a delivery system composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder, (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b), wherein the therapeutic nucleic acid payload does not substantially transcytose across the epithelial cell. In embodiments, the delivery to the transcytosis across the epithelial cell is detected or detectable by methods known in the art, e.g., in vitro immunological assays (e.g., fluorescence-based in vitro assays to detect the payload, plgR binder translocalization across a monolayer) and trans well assay, coupled with a detection technique known in the art such as ELISA, western blot, or a combination thereof.

[0094] DB1 / 167593545.6 14Atorney Docket No. CVL-001PC / 140489-5001

[0095] Polymeric Immunoglobulin Receptor (plgR) Binders

[0096] In aspects, the present disclosure provides a plgR binder that that promote the internalization of a therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) in epithelial cells via the plgR-mediated internalization but then divert the internalized therapeutic payloads to the intracellular environment (rather than transcytosis).

[0097] In embodiments, the plgR binder binds to one or more of extracellular domains DI, D2, D3, D4, D5, and the cleavage domain (also known as D6) of plgR. In embodiments, the plgR binder binds to the cleavage domain of plgR. In embodiments, the plgR binder binds plgR at or near the J chain binding site for plgR of immunoglobulin A (IgA) or IgM. In embodiments, the plgR binder reduces or inhibits cleavage of extracellular domain D6 of plgR. In embodiments, the plgR binder binds to plgR in a competitive manner with IgA and / or IgM. In embodiments, the plgR binder comprises a plgR ligand selected from IgA, IgM, or a plgR-binding fragment thereof. In embodiments, the plgR binder binds to plgR with higher affinity than IgA or IgM binds to plgR.

[0098] In embodiments, the plgR binder binds to plgR with higher affinity than the affinity with which a reference molecule binds to plgR. In embodiments, the reference molecule is a reference antibody. In embodiments, the reference antibody is selected from EPR23314-256, 825724, EPR23314-78, 7C1, LS-C163718, LS-C490449, and MAB27171. In embodiments, the reference molecule is a reference peptide. In embodiments, the reference peptide has an amino acid sequence of amino acids 37-158 of Streptococcus pneumoniae secretory IgA-binding protein SpsA (SEQ ID NO: 234).

[0099] In embodiments, the affinity is measured or is measurable using methods known in the art, including enzyme-linked immunosorbent assay (ELISA), flow cytometry, surface plasmon resonance (SPR), fluorescence polarization binding assay, kinetic exclusion assay (KinExA), radioimmunoassay (RIA), or a combination thereof.

[0100] In embodiments, the plgR binder binds to plgR at an acidic pH. In embodiments, the plgR binder binds to plgR at pH of about 4.5 to about 8.5. In embodiments, the plgR binder binds to plgR at pH of about 4.5. In embodiments, the plgR binder binds to plgR at pH of about 5. In embodiments, the plgR binder binds to plgR at pH of about 5.5. In embodiments, the plgR binder binds to plgR at pH of about 6. In embodiments, the plgR binder binds to plgR at pH of about 6.5. In embodiments, the plgR binder binds to plgR at pH of about 7. In embodiments, the plgR binder DB1 / 167593545.6 15Atorney Docket No. CVL-001PC / 140489-5001

[0101] binds to plgR at pH of about 7.5. In embodiments, the plgR binder binds to plgR at pH of about 8. In embodiments, the plgR binder binds to plgR at pH of about 8.5.

[0102] In embodiments, the binding of the plgR binder to plgR at a given pH is measured or is measurable using methods known in the art, including ELISA, flow cytometry, SPR, fluorescence polarization binding assay, KinExA, RIA, or a combination thereof.

[0103] In embodiments, the plgR binder is internalized in the epithelial cells. In embodiments, the plgR binder promotes the internalization of a therapeutic pay load (without limitation, e.g. , a nucleic acid therapeutic payload) in the epithelial cells. In embodiments, at least a fraction of the plgR binder and / or the therapeutic payload is not translocalized across the epithelial cells. In embodiments, the fraction of the plgR binder and / or the therapeutic payload that is not translocated across the epithelial cells is sufficient to exert its therapeutic effect. In embodiments, the fraction of a therapeutic payload conjugated to the plgR binder (without limitation, e.g., a nucleic acid therapeutic payload) that is not translocalized across the epithelial cells is sufficient to exert its therapeutic effect. In embodiments, at least about 0.1%, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of the plgR binder and / or the therapeutic payload is not translocalized across the epithelial cells. In embodiments, at least about 0.1%, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of a therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) conjugated to the plgR binder is not translocalized across the epithelial cells.

[0104] In embodiments, internalization of the payload, the plgR binder in epithelial cells is measured or is measurable using methods known in the art, including immunocytochemistry, fluorescence microscopy (e.g., immunofluorescence microscopy), ELISA, flow cytometry, western blot, or a combination thereof. In embodiments, translocalization of the payload, the plgR binder across epithelial cells is measured or is measurable using methods known in the art, including in vitro

[0105] DB1 / 167593545.6 16Atorney Docket No. CVL-001PC / 140489-5001

[0106] immunological assays (e.g., fluorescence-based in vitro assays to detect the payload, the plgR binder translocalization across a monolayer) and trans well assay, coupled with a detection technique known in the art such as ELISA, western blot, or a combination thereof.

[0107] In embodiments, at least a fraction of the plgR binder and / or the therapeutic payload is retained in the epithelial cells. In embodiments, the retention of the payload, the plgR binder in epithelial cells is measured or is measurable using methods known in the art, including immunocytochemistry, fluorescence microscopy (e.g., immunofluorescence microscopy), ELISA, flow cytometry, western blot, or a combination thereof. In embodiments, the fraction of the plgR binder and / or the therapeutic payload that is retained in the epithelial cells is sufficient to exert its therapeutic effect. In embodiments, at least about 0.1 %, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of the plgR binder and / or the therapeutic payload is retained in the epithelial cells. In embodiments, at least about 0.1%, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of a therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) conjugated to the plgR binder is retained in the epithelial cells.

[0108] In embodiments, a fraction of the plgR binder and / or the therapeutic payload is retained in the endosomes of the epithelial cells. In embodiments, the retention of the payload, the plgR binder in the endosomes of the epithelial cells is measured or is measurable using methods known in the art, including immunocytochemistry, fluorescence microscopy (e.g., immunofluorescence microscopy showing colocalization with an endosomal marker). In embodiments, the plgR binder and / or the therapeutic payload escapes the endosomes of the epithelial cells. In embodiments, the plgR binder and / or the therapeutic payload escapes the endosomes of the epithelial cells with a slow kinetics. In embodiments, the plgR binder and / or the therapeutic payload escapes the endosomes of the epithelial cells with a kinetics that causes the escape of at least about 0.1%, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 5%, or at least about 10%, or at least about DB1 / 167593545.6 17Atorney Docket No. CVL-001PC / 140489-5001

[0109] 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of the therapeutic payload over about a 24 hours. In embodiments, the plgR binder and / or the therapeutic payload escapes the endosomes of the epithelial cells with a kinetics that causes the escape of at least about 0.1%, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of the therapeutic payload over about a week. In embodiments, the endosomal escape of the payload, the plgR binder in epithelial cells is measured or is measurable using methods known in the art, including immunocytochemistry, fluorescence microscopy (e.g., immunofluorescence microscopy showing colocalization with an endosomal marker), biological activity of the payload (e.g., evidence of silencing when the payload is siRNA) or a combination thereof.

[0110] In embodiments, the plgR binder binds to plgR at a lower affinity at pH less than about 6 compared to the affinity of binding of the plgR binder binds to plgR at a pH greater than about 6. As a consequence, in embodiments, as the endosomal pH drops, the plgR binder is released from plgR. In embodiments, the linker that attaches the plgR binder to a therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) is cleaved at a pH less than about 6. As a consequence, in embodiments, as the endosomal pH drops, the therapeutic payload is released from the plgR binder.

[0111] In embodiments, the plgR binder is a macromolecule. In embodiments, the plgR binder is selected from an antibody, an antibodydike molecule, a peptide (without limitation, e.g., selected using phage display), a protein (without limitation, e.g., a lectin, a plgR ligand such as IgA, IgM, or a pIGR-binding fragment thereof), a nucleic acid (without limitation, e.g., an aptamer), a polysaccharide, and a combination thereof.

[0112] Antibody or Antibody-Like Molecule Capable of Binding Polymeric immunoglobulin receptor (plgR)

[0113] In embodiments, the plgR binder is an antibody or an antibody-like molecule that is capable of specifically binding to plgR (e.g., an anti-pIgR antibody).

[0114] DB1 / 167593545.6 18Atorney Docket No. CVL-001PC / 140489-5001

[0115] In embodiments, the antibody is a monoclonal antibody or a polyclonal antibody, or a plgR- binding fragment thereof. In embodiments, the antibody is an anti-pIgR monoclonal antibody, or a plgR binding fragment thereof. In embodiments, the antibody comprises at least one mutation that reduces or silences Fc effector function. In embodiments, the mutation is selected from L234A, L235E, G237A, D265A, S267K, N297A, P329A, and P329G with respect to an IgGl Fc domain sequence. In embodiments, the antibody has reduced effector function. In embodiments, the antibody has reduced activity with respect to antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and / or complement-dependent cytotoxicity (CDC). In embodiments, the plgR binder (without limitation, e.g., antibody or an antibody-like molecule) does not induce a significant immune response against cells expressing plgR. In embodiments, the antibody or antibody-like molecule does not induce a significant immune response against cells expressing plgR.

[0116] In embodiments, the antibody -like molecule is selected from a recombinant heavy-chain-only antibody (VHH), single-domain antibody, single-chain antibody (scFv), shark heavy-chain-only antibody (VNAR), microprotein (cysteine knot protein, knottin), DARPin, Tetranectin, Affibody, Affitin, Alphabody, Gastrobody, Monobody, nanoCLAMP, Optimer, Repebody, fibronectin domain-derived antibody mimic, Centyrin, Obody, Transbody, Anticalin, AdNectin, Affilin, Affimer, Microbody, aptamer, alterase, plastic antibody, phylomer, stradobody, maxibody, evibody, fynomer, armadillo repeat protein, Kunitz domain, avimer, atrimer, probody, immunobody, triomab, troybody, pepbody, vaccibody, UniBody, DuoBody, Fv, Fab, Fab', and F(ab or a plgR binding fragment thereof. In embodiments, the antibody-like molecule is a VHH. In embodiments, the antibody, antibody-like molecule is in form of an antibody format selected from multivalent tandem binding fragment (e.g., multivalent tandem VHHs or multivalent tandem scFvs), single a binding fragment (e.g., VHH-His or scFv-His), a monomeric Fc domain-binding fragment (e.g., VHH- monomeric Fc domain or scFv- monomeric Fc domain), binding fragment- Fc domain (e.g., VHH-Fc or scFv-Fc), IgG-binding fragment fusion (e.g., light chain-(LC)-VHH, LC-scFv, heavy chain-(HC)-VHH or HC-scFv), a biparatopic molecule (e.g., biparatopic VHH- Fc or scFv-Fc), a tetravalent molecule (e.g., a tetravalent VHH-Fc), an IgG hexamer, a diabody (i.e., a dimeric scFv), a triabody (i.e., a trimeric scFv), a tetrabody (i.e., a tetrameric scFv), bidisulfide-bond stabilized scFv (ds-scFv), a bi-specific antibody, DuoBody, VHH beads on a

[0117] DB1 / 167593545.6 19Atorney Docket No. CVL-001PC / 140489-5001

[0118] string, an Fc-heterodimeric molecule, minibody (miniAbs), Fab-TgG, TgG-Fab, and VHH-IgG- VHH.

[0119] In embodiments, the antibody, antibody-like molecule or plgR binding fragment thereof is in form of a single a binding fragment (e.g., VHH-His or scFv-His), or binding fragment-Fc domain (e.g., VHH-Fc or scFv-Fc). In embodiments, the antibody, antibody-like molecule or plgR binding fragment thereof is in form of a multivalent tandem binding fragment. In embodiments, the antibody, antibody-like molecule or plgR binding fragment thereof is in form of a multivalent tandem VHHs format.

[0120] In embodiments, the multivalent tandem binding fragment binds same or different sequences. In embodiments, the multivalent tandem binding fragment binds at least two epitopes of plgR. In embodiments, the multivalent tandem binding fragment binds plgR and a molecule other than plgR. In embodiments, the molecule other than plgR is a serum protein, In embodiments, the molecule other than plgR is human serum albumin. In embodiments, the multivalent tandem binding fragment binds plgR and a serum protein. In embodiments, the multivalent tandem binding fragment binds plgR and human serum albumin.

[0121] In embodiments, the antibody, antibody-like molecule comprises a VH having a set of CDRs (HCDR1, HCDR2, and HCDR3) provided in Table 1. In embodiments, the antibody, antibodylike molecule comprises a VH having a set of CDRs (HCDR1, HCDR2, and HCDR3), provided in Table 1, wherein the antibody, antibody-like molecule binds plgR. In embodiments, the antibody, antibody-like molecule comprises a VH having a set of CDRs (HCDR1, HCDR2, and HCDR3), provided in Table 1, wherein the antibody, antibody-like molecule comprises an amino acid sequence that is at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identical to the amino acid sequence of the antipolymeric Ig receptor (plgR) VHH provided in Table 1. In embodiments, the antibody, antibodylike molecule comprises a VH having a set of CDRs (HCDR1, HCDR2, and HCDR3), provided in Table 1, wherein the antibody, antibody-like molecule comprises an amino acid sequence of the amino acid sequence of the anti-polymeric Ig receptor (plgR) VHH provided in Table 1.

[0122] DB1 / 167593545.6 20Attorney Docket No. CVL-001PC / 140489-5001

[0123] Table 1: Sequences of Illustrative Non-limiting Recombinant Heavy-Chain-Only Antibodies (VHH) that are Capable of Binding Polymeric Ig Receptor (plgR)

[0124] VHH CDR Sequence According to Kabat Numbering

[0125] Name Anti-Polymeric Ig Receptor (plgR) VHH Sequence HCDR1 HCDR2 HCDR3

[0126] EVQVVESGGGLVQAGGSLKLACAAPGLTF S SYRMGWFR AIDWNGRGTYY TTVLTDPRVLNE SYRMG QAPGQEREFVAAIDWNGRGTYYRYYADSVKGRSTISRD NB1 RYYADSVKG YAT

[0127] (SEQ IDNO: 1) NAKNTVYLQMNSLKPEDTAVYYCAATTVLTDPRVLNE (SEQ IDNO: 2) (SEQ IDNO: 3)

[0128] YATWGQGTQVTVSS (SEQ ID NO: 4) QLQLVESGGGLVQPGGSLRLSCAASGSIFSINVMGWYRQ RINGGGITHYAE INVMG DVFGSSGYVETY APGKQRELVARINGGGITHYAESVKGRFTISRDNAKNTV NB2 SVKG

[0129] (SEQ ID NO: 5) (SEQIDNO: 7) YLQMNSLKPEDTAAYYCKADVFGSSGYVETYWGQGTQ (SEQ IDNO: 6)

[0130] VTVSS (SEQ ID NO: 8) EVQLVESGGGLVQAGGSLRLSCAVSGSSVSSDAMGWYR FISGGGTTTYAD SDAMG PLTSR QAPGNQRAWVAFISGGGTTTYADSVKGRFTISRDNTKN NB3 SVKG

[0131] (SEQ ID NO: 9) (SEQ ID NO: 11) TVYLHMNSLKPEDTAVYYCNHPLTSRWGQGTQVTVSS (SEQ ID NO: 10)

[0132] (SEQ IDNO: 12) EVQVVESGGGLVQAGGSLRLSCAASGRTFTTYRMGWFR AIRWSGGRTLYA DLAEYSGTYSSP TYRMG QAPGKEREFVAAIRWSGGRTLYADSVKGRFTISRDNAK NB4 DSVKG ADSPAGYDY

[0133] (SEQ IDNO: 13) NT AYLQMNNLRPEDTAVYYC AADL AEYSGT YS SPAD SP (SEQ IDNO: 14) (SEQ IDNO: 15)

[0134] AGYDYWGQGTQVTVSS (SEQ ID NO: 16)

[0135]

[0136] 21

[0137] DBl / 167593545.6Atorney Docket No. CVL-001PC / 140489-5001

[0138] QVQLVETGGGLVQAGDSLRLSCAASGRTLSFNTYAMG SITWNGGSTSYA ARYYVSGTYFPA FNTYAMG WFRQAPGKEREFVASITWNGGSTSYADSVKGRFTITRDN NB5 DSVKG NY

[0139] (SEQ IDNO: 17) AKNTATLRMNSLQPDDTAVYYCAAARYYVSGTYFPAN (SEQ IDNO: 18) (SEQ IDNO: 19)

[0140] YWGQGTQVTVSS (SEQ ID NO: 20) QVQLVESGGGLVQAGGSLKLACAAPGLTF S S YRMGWFR AIDWNGRGTYY GSIDLNWYGGM SYRMG QAPGQEREFVAAIDWNGRGTYYRYYADSVKGRSTISRD NB18 RYYADSVKG DY

[0141] (SEQ IDNO: 21) NAKNTMYLQMNSLKPEDTAVYYCAAGSIDLNWYGGM (SEQ IDNO: 22) (SEQ ID NO: 23)

[0142] D YWGQGTQVTVSS (SEQ ID NO: 24) EVQVVESGGGLVQAGGSLRLSCAVSGTSVSSNAMGWY FIDRIATTTIATS SNAMG PLTAR RQAPGKQREWVGFIDRIATTTIATSVKGRFAITRDNAKN NB19 VKG

[0143] (SEQ ID NO: 25) (SEQ ID NO: 27) TVYLQMSGLKPEDTAVYYCNHPLTARWGQGTQVTVSS (SEQ ID NO: 26)

[0144] (SEQ ID NO: 28) QVQLVESGGGLVQAGGSLRLSCAASGRTFSSYAMGWFR AITWNGGTTYY SYAMG DPFNQGY QAPGKEREFVAAITWNGGTTYYADSVKGRFTISRDNAK NB20 ADSVKG

[0145] (SEQ IDNO: 29) (SEQ IDNO: 31) NTVYLQMNSLKPEDTAVYYCAADPFNQGYWGQGTQVT (SEQ ID NO: 30)

[0146] VSS (SEQ IDNO: 32) EVQVVESGGGLVQAGGSLRLACVASRSIGSINVMGWYR RITGGGSTHYAE MVNPIITAWGTI INVMG QAPGKQRDLVARITGGGSTHYAESVKGRFTISRDNAKNT NB21 SVKG GVREIPDYDY

[0147] (SEQ ID NO: 33) VYLQMNSLEPEDTAVYYCASMVNPIITAWGTIGVREIPD (SEQ ID NO: 34) (SEQ IDNO: 35)

[0148] YD YWGQGTQVTVSS (SEQ ID NO: 36)

[0149] TYRMG AISWSGGSTTYA DQRGY QVQLVESGGGLVQAGGSLRLSCAVSGRTFSTYRMGWFR NB22

[0150] (SEQ ID NO: 37) DPVKG (SEQ ID NO: 39) QAPGKERSFVAAISWSGGSTTYADPVKGRFTISRDNAKN

[0151]

[0152] DB1 / 167593545.6 22Atorney Docket No. CVL-001PC / 140489-5001

[0153] (SEQ ID NO: 38) TVYLRMNSLKPEDTAVYYCNDQRGYWGQGTLVTVSS (SEQ ID NO: 40) EVQVVESGGGLVQAGGSLRLSCAASGFTFTRYAMGWFR AISWSGSSAGYG RYAMG DPFNQGY QAPGKERSFVAAISWSGSSAGYGDSVKGRFTISRDNAKN NB23 DSVKG

[0154] (SEQ IDNO: 41) (SEQ ID NO: 43) TLYLQMNSLKPEDTAVYYCAADPFNQGYWGQGTQVTV (SEQ ID NO: 42)

[0155] SS (SEQ ID NO: 44) EVQLVESGGGLVQSGGSLRLSOAASGRAFNYYAMGWF VINWSGGTTSYA YYAMG DSIYRTSKDYNY RQAPGKERELVAVINWSGGTTSYADSVKGRFTISRSNAK NB24 DSVK

[0156] (SEQ ID NO: 45) (SEQ ID NO: 47) NT VYLQMS SLKPEDT AVYYC AAD SIYRT SKD YNYWGQ (SEQ ID NO: 46)

[0157] GTQVTVSS (SEQ ID NO: 48) EVQLVESGGGLVQAGGSLRLSCAASGRTFSNYVMGWFR AISWSGVTTYHY RGRTGSDPRKG NYVMG QAPGKEREFVAAISWSGVTTYHYSADSVKGRFTTSRDN NB25 SADS DDYDY

[0158] (SEQ IDNO: 49) DRNTAHLQMNSLKPEDTAVYYCAARGRTGSDPRKGDD (SEQ ID NO: 50) (SEQ ID NO: 51)

[0159] YDYWGQGTQVTVSS (SEQ ID NO: 52) EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRR CTSSSDGSTYYA TFGDACTVVAGI YYAIG APGKEREGVSCTSSSDGSTYYADSVKGRFTISRDNAKNT NB26 DSVK PDQYDFGS

[0160] (SEQ IDNO: 53) VYLQMNSLKPEDTAVYYCATTFGDACTVVAGIPDQYDF (SEQ ID NO: 54) (SEQ ID NO: 55)

[0161] GSWGQGTQVTVSS (SEQ ID NO: 56) EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFR CISSSDMSDGITY TFGDACTVVAGI YYAIG Q APGKEREGVSCIS S SDMSDGITYYAD S VKGRET S SRDN NB27 YA DSVKG PDQADFDS

[0162] (SEQ IDNO: 57) VKNTVYLQMNSLKPEDTAVYYCATTFGDACTVVAGIPD (SEQ ID NO: 58) (SEQ ID NO: 59)

[0163] QADFDSWGQSTQVTVSS (SEQ ID NO: 60)

[0164]

[0165] DB1 / 167593545.6 23Atorney Docket No. CVL-001PC / 140489-5001

[0166] EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYDIGWFR CTSSSDGSTYYA TFGDACTVVAGI YYDIG Q APGKEREGVSCT S S SDGST YYAD S VKGRFTISRDNAKN NB28 DSVKG POQYDFGS

[0167] (SEQ ID NO: 61) TVYLQMNSLKPEDTAVYYCATTFGDACTVVAGIPOQYD (SEQ ID NO: 62) (SEQ ID NO: 63)

[0168] FGSWGQGTQVTVSS (SEQ ID NO: 64) EVQLVESGGGLVQAGGSLRLSCEDSGRTFGDYIMGWFR AISWTGDSTYYK RTFRIDYDPRTA DYIMG QAPGKERDFVAAISWTGDSTYYKYYSDSAKGRFTASRD NB29 YYSDSAKG STYNY

[0169] (SEQ ID NO: 65) NAKNTAYLQMNGLKPEDTAVYYCAARTFRIDYDPRTAS (SEQ ID NO: 66) (SEQ ID NO: 67)

[0170] TYNYWGQGIQVTVSS (SEQ ID NO: 68) EVQLVKSGGGLVQAGDSLRLSCAASGRTSSSVTMGWFR AISWSGGSTYYA VVPSDPIIYYTDY SVTMG QAPGKERDFVAAISWSGGSTYYADSVKGRFTISRDNAK NB30 DSVKG VDYDY

[0171] (SEQ ID NO: 69) NTVYLQMNSLKPEDTAVYYCAAVVPSDPIIYYTDYVDY (SEQ ID NO: 70) (SEQ ID NO: 71)

[0172] DYWGQGTQVTVSS (SEQ ID NO: 72) EVQLVESGGGLVQAGGSLRLSCAASGFTFDDYAIGWFR CISSRDGITYYA DLVGSFPCPVAA DYAIG QAPGKEREGVSCISSRDGITYYADSVKGRFTISSDNAKNT NB31 DSVKG YDY

[0173] (SEQ ID NO: 73) VYLQMNSLKPEDTAVYYCAADLVGSFPCPVAAYDYWG (SEQ ID NO: 74) (SEQ ID NO: 75)

[0174] QGTQVTVSS (SEQ ID NO: 76) EVQLVESGGGLVQAGGSLRLSCAASGFTFDDYAIGWFR CISSRDGTTYYA DLVGSFPCPVAA DYAIG QAPGKEREGVSCISSRDGTTYYADSVKGRFTISSDNAKN NB32 DSVKG YDY

[0175] (SEQ ID NO: 77) TVYLQMNSLKPEDTAVYYCAADLVGSFPCPVAAYDYW (SEQ ID NO: 78) (SEQ ID NO: 79)

[0176] GQSTQVTVSS (SEQ ID NO: 80)

[0177] DYAIG CINNSDGSTYYA DFVGGSYCLFPT EVQLVESGGGLVQAGGSLRLSCAASGFTFDDYAIGWFR NB33

[0178] (SEQ ID NO: 81) DSVKG YNY QAPGKEREGVSCINNSDGSTYYADSVKGRFTISSDNAKN

[0179]

[0180] DB1 / 167593545.6 24Atorney Docket No. CVL-001PC / 140489-5001

[0181] (SEQ ID NO: 82) (SEQ ID NO: 83) TVYLQMNSLKPEDTAVYYCAADFVGGSYCLFPTYNYW GQCTQVTVSS (SEQ ID NO: 84) EVQLVESGGGLVQAGDSLRLSCAASGRTFSTYAMAWFR AISWSSDMTYYL GAYYAGSSTSPY TYAMA QAPGKDREFVAAISWSSDMTYYLDSVKGRFTISRDNAK NB34 DSVKG NY

[0182] (SEQ IDNO: 85) NTVFLQMNSLKPEDTAVYYCASGAYYAGSSTSPYNYW (SEQ ID NO: 86) (SEQ ID NO: 87)

[0183] GQGTQVTVSS (SEQ ID NO: 88) EVQLVESGGGLVQAGGSLRLSCAASGRTFTIYTMGWFR ALRWSGGSTYTF VDPRAPYMRPD IYTMG QAPGKAREFISALRWSGGSTYTFYADSVKGRFTISRDNA NB35 YADSVKG STDSYAY

[0184] (SEQ ID NO: 89) KNTLYLQMNSLKSEDTAIYYCGMVDPRAPYMRPDSTDS (SEQ ID NO: 90) (SEQ IDNO: 91)

[0185] YAYWGQGTQVTVSS (SEQ ID NO: 92 ) EVQLVESGGGQVQAGGSLRLSCVASERTFSYYDLAARA ASTWNGGYTYY RRAYSSDLHDY YYDLAARA WFRQAPGKERELVSASTWNGGYTYYVDSVKGRFTVST NB36 VDSVKG RTFDY

[0186] (SEQ IDNO: 93) DDAGDTMYLQMNSLEPEDTAVYYCAARRAYSSDLHDY (SEQ ID NO: 94) (SEQ ID NO: 95)

[0187] RTFDYWGQGTQVTVSS (SEQ ID NO: 96) EVQLVESGGGLVQAGGSLRLSCAASGFTFDDYAIGWFR CISRSDGSTYYA DAIGSFPCPAGV DYAIG QAPGKEREWVSCISRSDGSTYYADSVKGRFTISSDNAKN NB37 DSVKG YDY

[0188] (SEQ IDNO: 97) TVYLQMNSLKPEDTAVYHCAADAIGSFPCPAGVYDYW (SEQ ID NO: 98) (SEQ ID NO: 99)

[0189] GQGTQVTVSS (SEQ ID NO: 100) EVQLVESGGGLAQPGGSLRLSCAASGFAFSSYWMYWVR AISTGGGGTYYA DEAPTFDYSGNY SYWMY QAPGKGLEWVSAISTGGGGTYYADSVKGRFTISRDNAK NB38 DSVKG AYTGSDPNDY

[0190] (SEQ IDNO: 101) NTLYLQMNSLKPEDTARYYCARDEAPTFDYSGNYAYTG (SEQ IDNO: 102) (SEQIDNO: 103)

[0191] SDPNDYWGQGTQVTVSS (SEQ ID NO: 104)

[0192]

[0193] DB1 / 167593545.6 25Atorney Docket No. CVL-001PC / 140489-5001

[0194] EVQLVESGGGLVQPGGSLRLSCAASGFAFSRYGMYWVR TINSGGDYIIYAD GYRGSEWPPPAF RYGMY QAPGKGLEWVSTINSGGDYIIYADSVKGRFTISRDNAKN NB39 SVKG TLQRADFAS

[0195] (SEQ IDNO: 105) TLYLQMNSLKPEDTAVYYCAEGYRGSEWPPPAFTLQRA (SEQ IDNO: 106) (SEQIDNO: 107)

[0196] DFASWGQGTQVTVSS (SEQ ID NO: 108) EVQLVESGGGLVQAGGSLRLSCVASGFILREYNMGWFR AIAWTGTNSYY EGYVSNFPRSSA EYNMG QAPGKEREIVAAIAWTGTNSYYVDSVKGRFTISRDDTKN NB40 VDSVKG DEYDY

[0197] (SEQ IDNO: 109) T VYLQMNSLNPEDTGVYHC AAEGYVSNFPRS S ADEYD Y (SEQ IDNO: 110) (SEQIDNO: 111)

[0198] WGQGTQVTVSS (SEQ ID NO: 112) EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMTWVR IISGNGGSTSYAD SYAMT WDGLGTLP QGLGKCLEWVSIISGNGGSTSYADSVKGRFTISRDNAKN NB41 SVKG

[0199] (SEQ IDNO: 113) (SEQIDNO: 115) TLYLQMNSLKPEDTAVYYCAKWDGLGTLPGSQGTQVT (SEQ IDNO: 114)

[0200] VSS (SEQ IDNO: 116) EVQLVESGGGLVQAGGSLRLSCAASGSILSTNDMGWYR RISRGSSTIYTES DMLPSDLSHGY TNDMG QAPGNQRELVARISRGSSTIYTESVKGRFTISRDNAKNTV NB42 VKG YYRDY

[0201] (SEQ IDNO: 117) YLQMNSLKPEDTAVYYCNADMLPSDLSHGYYYRDYWG (SEQ IDNO: 118) (SEQIDNO: 119)

[0202] QGTQVTVSS (SEQ ID NO: 120) EVQLVESGGGLVQAGGSLRLSCAASGFTFDDYAIGWFR CISSRDGMTYYA DLVGSFPCPVAA DYAIG QAPGKEREGVSCISSRDGMTYYADSVKGRFTISSDNARN NB43 DSVKG YDY

[0203] (SEQ ID NO: 121) TVYLQMNSLKPEDTAVYYCAADLVGSFPCPVAAYDYW (SEQ IDNO: 122) (SEQIDNO: 123)

[0204] GQGTQVTVSS (SEQ ID NO: 124)

[0205]

[0206] DB1 / 167593545.6 26Atorney Docket No. CVL-001PC / 140489-5001

[0207] In embodiments, the antibody or antibody-like molecule comprises a heavy chain variable region (VH) comprising a heavy chain complementarity-determining region 1 (HCDR1) having an amino acid sequence SYRMG (SEQ ID NO: 1), a HCDR2 having an amino acid sequence AIDWNGRGTYYRYYADSVKG (SEQ ID NO: 2), and a HCDR3 having an amino acid sequence TTVLTDPRVLNEYAT (SEQ ID NO: 3). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence INVMG (SEQ ID NO: 5), a HCDR2 having an amino acid sequence RINGGGITHYAESVKG (SEQ ID NO: 6), and a HCDR3 having an amino acid sequence DVFGSSGYVETY (SEQ ID NO: 7). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SDAMG (SEQ ID NO: 9), a HCDR2 having an amino acid sequence FISGGGTTTYADSVKG (SEQ ID NO: 10), and a HCDR3 having an amino acid sequence PLTSR (SEQ ID NO: 11). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence TYRMG (SEQ ID NO: 13), a HCDR2 having an amino acid sequence AIRWSGGRTLYADSVKG (SEQ ID NO: 14), and a HCDR3 having an amino acid sequence DLAEYSGTYSSPADSPAGYDY (SEQ ID NO: 15). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence FNTYAMG (SEQ ID NO: 17), a HCDR2 having an amino acid sequence SITWNGGSTSYADSVKG (SEQ ID NO: 18), and a HCDR3 having an amino acid sequence ARYYVSGTYFPANY (SEQ ID NO: 19). In embodiments, the antibody or antibodylike molecule comprises a VH comprising a HCDR1 having an amino acid sequence SYRMG (SEQ ID NO: 21), a HCDR2 having an amino acid sequence AIDWNGRGTYYRYYADSVKG (SEQ ID NO: 22), and a HCDR3 having an amino acid sequence GSIDLNWYGGMDY (SEQ ID NO: 23). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SNAMG (SEQ ID NO: 25), a HCDR2 having an amino acid sequence FIDRIATTTIATSVKG (SEQ ID NO: 26), and a HCDR3 having an amino acid sequence PLTAR (SEQ ID NO: 27). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SYAMG (SEQ ID NO: 29), a HCDR2 having an amino acid sequence AITWNGGTTYYADSVKG (SEQ ID NO: 30), and a HCDR3 having an amino acid sequence DPFNQGY (SEQ ID NO: 31). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence INVMG (SEQ ID NO: 33), a HCDR2 having an amino acid sequence

[0208] 27

[0209] DB1 / 167593545.6Atorney Docket No. CVL-001PC / 140489-5001

[0210] RITGGGSTHYAESVKG (SEQ ID NO: 34), and a HCDR3 having an amino acid sequence MVNPIITAWGTIGVREIPDYDY (SEQ ID NO: 35). In embodiments, the antibody or antibodylike molecule comprises a VH comprising a HCDR1 having an amino acid sequence TYRMG (SEQ ID NO: 37), a HCDR2 having an amino acid sequence AISWSGGSTTYADPVKG (SEQ ID NO: 38), and a HCDR3 having an amino acid sequence DQRGY (SEQ ID NO: 39). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence RYAMG (SEQ ID NO: 41), a HCDR2 having an amino acid sequence AISWSGSSAGYGDSVKG (SEQ ID NO: 42), and a HCDR3 having an amino acid sequence DPFNQGY (SEQ ID NO: 43). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence YYAMG (SEQ ID NO: 45), a HCDR2 having an amino acid sequence VINWSGGTTSYADSVK (SEQ ID NO: 46), and a HCDR3 having an amino acid sequence DSIYRTSKDYNY (SEQ ID NO: 47). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence NYVMG (SEQ ID NO: 49), a HCDR2 having an amino acid sequence AISWSGVTTYHYSADS (SEQ ID NO: 50), and a HCDR3 having an amino acid sequence RGRTGSDPRKGDDYDY (SEQ ID NO: 51). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence YYAIG (SEQ ID NO: 53), a HCDR2 having an amino acid sequence CTSSSDGSTYYADSVK (SEQ ID NO: 54), and a HCDR3 having an amino acid sequence TFGDACTVVAGIPDQYDFGS (SEQ ID NO: 55). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence YYAIG (SEQ ID NO: 57), a HCDR2 having an amino acid sequence CISSSDMSDGITYYADSVKG (SEQ ID NO: 58), and a HCDR3 having an amino acid sequence TFGDACTVVAGIPDQADFDS (SEQ ID NO: 59). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence YYDIG (SEQ ID NO: 61), a HCDR2 having an amino acid sequence CTSSSDGSTYYADSVKG (SEQ ID NO: 62), and aHCDR3 having an amino acid sequence TFGDACTVVAGIPOQYDFGS (SEQ ID NO: 63). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence DYIMG (SEQ ID NO: 65), a HCDR2 having an amino acid sequence AISWTGDSTYYKYYSDSAKG (SEQ ID NO: 66), and a HCDR3 having an amino acid sequence RTFRIDYDPRTASTYNY (SEQ ID NO: 67). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid

[0211] DB1 / 167593545.6 28Atorney Docket No. CVL-001PC / 140489-5001

[0212] sequence SVTMG (SEQ ID NO: 69), a HCDR2 having an amino acid sequence AISWSGGSTYYADSVKG (SEQ ID NO: 70), and a HCDR3 having an amino acid sequence VVPSDPIIYYTDYVDYDY (SEQ ID NO: 71). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 73), a HCDR2 having an amino acid sequence CISSRDGITYYADSVKG (SEQ ID NO: 74), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 75). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 77), a HCDR2 having an amino acid sequence CISSRDGTTYYADSVKG (SEQ ID NO: 78), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 79). In embodiments, the antibody or antibodylike molecule comprises a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 81), a HCDR2 having an amino acid sequence CINNSDGSTYYADSVKG (SEQ ID NO: 82), and a HCDR3 having an amino acid sequence DFVGGSYCLFPTYNY (SEQ ID NO: 83). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence TYAMA (SEQ ID NO: 85), a HCDR2 having an amino acid sequence AISWSSDMTYYLDSVKG (SEQ ID NO: 86), and a HCDR3 having an amino acid sequence GAYYAGSSTSPYNY (SEQ ID NO: 87). In embodiments, the antibody or antibodylike molecule comprises a VH comprising a HCDR1 having an amino acid sequence IYTMG (SEQ ID NO: 89), a HCDR2 having an amino acid sequence ALRWSGGSTYTFYADSVKG (SEQ ID NO: 90), and a HCDR3 having an amino acid sequence VDPRAPYMRPDSTDSYAY (SEQ ID NO: 91). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence YYDLAARA (SEQ ID NO: 93), a HCDR2 having an amino acid sequence ASTWNGGYTYYVDSVKG (SEQ ID NO: 94), and a HCDR3 having an amino acid sequence RRAYSSDLHDYRTFDY (SEQ ID NO: 95). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 97), a HCDR2 having an amino acid sequence CISRSDGSTYYADSVKG (SEQ ID NO: 98), and a HCDR3 having an amino acid sequence DAIGSFPCPAGVYDY (SEQ ID NO: 99). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SYWMY (SEQ ID NO: 101), a HCDR2 having an amino acid sequence AISTGGGGTYYADSVKG (SEQ ID NO: 102), and a HCDR3 having an amino acid sequence DEAPTFDYSGNYAYTGSDPNDY (SEQ ID NO: 103). In embodiments,

[0213] DB1 / 167593545.6 29Atorney Docket No. CVL-001PC / 140489-5001

[0214] the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence RYGMY (SEQ ID NO: 105), a HCDR2 having an amino acid sequence TINSGGDYIIYADSVKG (SEQ ID NO: 106), and a HCDR3 having an amino acid sequence GYRGSEWPPPAFTLQRADFAS (SEQ ID NO: 107). In embodiments, the antibody or antibodylike molecule comprises a VH comprising a HCDR1 having an amino acid sequence EYNMG (SEQ ID NO: 109), a HCDR2 having an amino acid sequence AIAWTGTNSYYVDSVKG (SEQ ID NO: 110), and a HCDR3 having an amino acid sequence EGYVSNFPRSSADEYDY (SEQ ID NO: 111). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SYAMT (SEQ ID NO: 113), a HCDR2 having an amino acid sequence IISGNGGSTSYADSVKG (SEQ ID NO: 114), and a HCDR3 having an amino acid sequence WDGLGTLP (SEQ ID NO: 115). In embodiments, the antibody or antibody -like molecule comprises a VH comprising a HCDR1 having an amino acid sequence TNDMG (SEQ ID NO: 117), a HCDR2 having an amino acid sequence RISRGSSTIYTESVKG (SEQ ID NO: 118), and a HCDR3 having an amino acid sequence DMLPSDLSHGYYYRDY (SEQ ID NO: 119). In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 121), a HCDR2 having an amino acid sequence CISSRDGMTYYADSVKG (SEQ ID NO: 122), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 123).

[0215] In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SYRMG (SEQ ID NO: 1), a HCDR2 having an amino acid sequence AIDWNGRGTYYRYYADSVKG (SEQ ID NO: 2), and a HCDR3 having an amino acid sequence TTVLTDPRVLNEYAT (SEQ ID NO: 3), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ IS NO: 4. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence 1NVMG (SEQ ID NO: 5), a HCDR2 having an amino acid sequence RINGGGITHYAESVKG (SEQ ID NO: 6), and a HCDR3 having an amino acid sequence DVFGSSGYVETY (SEQ ID NO: 7), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 8. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence

[0216] DB1 / 167593545.6 30Atorney Docket No. CVL-001PC / 140489-5001

[0217] SDAMG (SEQ ID NO: 9), a HCDR2 having an amino acid sequence FISGGGTTTYADSVKG (SEQ ID NO: 10), and a HCDR3 having an amino acid sequence PLTSR (SEQ ID NO: 11), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 12. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence TYRMG (SEQ ID NO: 13), a HCDR2 having an amino acid sequence AIRWSGGRTLYADSVKG (SEQ ID NO: 14), and a HCDR3 having an amino acid sequence DLAEYSGTYSSPADSPAGYDY (SEQ ID NO: 15), wherein the antibody or antibody -like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 16. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence FNTYAMG (SEQ ID NO: 17), a HCDR2 having an amino acid sequence SITWNGGSTSYADSVKG (SEQ ID NO: 18), and a HCDR3 having an amino acid sequence ARYYVSGTYFPANY (SEQ ID NO: 19), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 20. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SYRMG (SEQ ID NO: 21), a HCDR2 having an amino acid sequence AIDWNGRGTYYRYYADSVKG (SEQ ID NO: 22), and a HCDR3 having an amino acid sequence GSIDLNWYGGMDY (SEQ ID NO: 23), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 24. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SNAMG (SEQ ID NO: 25), a HCDR2 having an amino acid sequence FIDRIATTTIATSVKG (SEQ ID NO: 26), and a HCDR3 having an amino acid sequence PLTAR (SEQ ID NO: 27), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 28. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SYAMG (SEQ ID NO: 29), a HCDR2 having an amino acid sequence AITWNGGTTYYADSVKG (SEQ ID NO: 30), and a HCDR3 having an amino acid sequence DPFNQGY (SEQ ID NO: 31), wherein the antibody or

[0218] DB1 / 167593545.6 31Atorney Docket No. CVL-001PC / 140489-5001

[0219] antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 32. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence INVMG (SEQ ID NO: 33), a HCDR2 having an amino acid sequence RITGGGSTHYAESVKG (SEQ ID NO: 34), and a HCDR3 having an amino acid sequence MVNPIITAWGTIGVREIPDYDY (SEQ ID NO: 35), wherein the antibody or antibodylike molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 36. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence TYRMG (SEQ ID NO: 37), a HCDR2 having an amino acid sequence AISWSGGSTTYADPVKG (SEQ ID NO: 38), and a HCDR3 having an amino acid sequence DQRGY (SEQ ID NO: 39), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 40. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence RYAMG (SEQ ID NO: 41), a HCDR2 having an amino acid sequence AISWSGSSAGYGDSVKG (SEQ ID NO: 42), and a HCDR3 having an amino acid sequence DPFNQGY (SEQ ID NO: 43), wherein the antibody or antibody -like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 44. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence YYAMG (SEQ ID NO: 45), a HCDR2 having an amino acid sequence VINWSGGTTSYADSVK (SEQ ID NO: 46), and a HCDR3 having an amino acid sequence DSIYRTSKDYNY (SEQ ID NO: 47), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 48. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence NYVMG (SEQ ID NO: 49), a HCDR2 having an amino acid sequence AISWSGVTTYHYSADS (SEQ ID NO: 50), and a HCDR3 having an amino acid sequence RGRTGSDPRKGDDYDY (SEQ ID NO: 51), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 52. In embodiments, the

[0220] DB1 / 167593545.6 32Atorney Docket No. CVL-001PC / 140489-5001

[0221] antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence YYAIG (SEQ ID NO: 53), a HCDR2 having an amino acid sequence CTSSSDGSTYYADSVK (SEQ ID NO: 54), and a HCDR3 having an amino acid sequence TFGDACTVVAGIPDQYDFGS (SEQ ID NO: 55), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 56. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence YYAIG (SEQ ID NO: 57), a HCDR2 having an amino acid sequence CISSSDMSDGITYYADSVKG (SEQ ID NO: 58), and a HCDR3 having an amino acid sequence TFGDACTVVAGIPDQADFDS (SEQ ID NO: 59), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 60. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence YYDIG (SEQ ID NO: 61), a HCDR2 having an amino acid sequence CTSSSDGSTYYADSVKG (SEQ ID NO: 62), and a HCDR3 having an amino acid sequence TFGDACTVVAGIPOQYDFGS (SEQ ID NO: 63), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 64. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence DYIMG (SEQ ID NO: 65), a HCDR2 having an amino acid sequence AISWTGDSTYYKYYSDSAKG (SEQ ID NO: 66), and a HCDR3 having an amino acid sequence RTFRIDYDPRTASTYNY (SEQ ID NO: 67), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 68. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SVTMG (SEQ ID NO: 69), a HCDR2 having an amino acid sequence AISWSGGSTYYADSVKG (SEQ ID NO: 70), and a HCDR3 having an amino acid sequence VVPSDPIIYYTDYVDYDY (SEQ ID NO: 71), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 72. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid

[0222] DB1 / 167593545.6 33Atorney Docket No. CVL-001PC / 140489-5001

[0223] sequence DYAIG (SEQ ID NO: 73), a HCDR2 having an amino acid sequence CISSRDGITYYADSVKG (SEQ ID NO: 74), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 75), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 76. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 77), a HCDR2 having an amino acid sequence CISSRDGTTYYADSVKG (SEQ ID NO: 78), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 79), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 80. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 81), a HCDR2 having an amino acid sequence CINNSDGSTYYADSVKG (SEQ ID NO: 82), and a HCDR3 having an amino acid sequence DFVGGSYCLFPTYNY (SEQ ID NO: 83), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 84. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence TYAMA (SEQ ID NO: 85), a HCDR2 having an amino acid sequence AISWSSDMTYYLDSVKG (SEQ ID NO: 86), and a HCDR3 having an amino acid sequence GAYYAGSSTSPYNY (SEQ ID NO: 87), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 88. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence IYTMG (SEQ ID NO: 89), a HCDR2 having an amino acid sequence ALRWSGGSTYTFYADSVKG (SEQ ID NO: 90), and a HCDR3 having an amino acid sequence VDPRAPYMRPDSTDSYAY (SEQ ID NO: 91), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 92. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence YYDLAARA (SEQ ID NO: 93), a HCDR2 having an amino acid sequence

[0224] DB1 / 167593545.6 34Atorney Docket No. CVL-001PC / 140489-5001

[0225] ASTWNGGYTYYVDSVKG (SEQ ID NO: 94), and a HCDR3 having an amino acid sequence RRAYSSDLHDYRTFDY (SEQ ID NO: 95), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 96. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 97), a HCDR2 having an amino acid sequence CISRSDGSTYYADSVKG (SEQ ID NO: 98), and a HCDR3 having an amino acid sequence DAIGSFPCPAGVYDY (SEQ ID NO: 99), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 100. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SYWMY (SEQ ID NO: 101), a HCDR2 having an amino acid sequence AISTGGGGTYYADSVKG (SEQ ID NO: 102), and a HCDR3 having an amino acid sequence DEAPTFDYSGNYAYTGSDPNDY (SEQ ID NO: 103), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 104. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence RYGMY (SEQ ID NO: 105), a HCDR2 having an amino acid sequence TINSGGDYIIYADSVKG (SEQ ID NO: 106), and a HCDR3 having an amino acid sequence GYRGSEWPPPAFTLQRADFAS (SEQ ID NO: 107), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 108. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence EYNMG (SEQ ID NO: 109), a HCDR2 having an amino acid sequence AIAWTGTNSYYVDSVKG (SEQ ID NO: 110), and a HCDR3 having an amino acid sequence EGYVSNFPRSSADEYDY (SEQ ID NO: 111), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 112. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence SYAMT (SEQ ID NO: 113), a HCDR2 having an amino acid sequence IISGNGGSTSYADSVKG (SEQ ID NO: 114), and a HCDR3 having an amino acid sequence

[0226] DB1 / 167593545.6 35Atorney Docket No. CVL-001PC / 140489-5001

[0227] WDGLGTLP (SEQ ID NO: 115), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 116. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence TNDMG (SEQ ID NO: 117), a HCDR2 having an amino acid sequence RISRGSSTIYTESVKG (SEQ ID NO: 118), and a HCDR3 having an amino acid sequence DMLPSDLSHGYYYRDY (SEQ ID NO: 119), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 120. In embodiments, the antibody or antibody-like molecule comprises a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 121), a HCDR2 having an amino acid sequence CISSRDGMTYYADSVKG (SEQ ID NO: 122), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 123), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 124. In embodiments, the antibody or antibody-like molecule comprises an amino acid sequence selected from the amino acid sequence of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124 and 153-186. In embodiments, the antibody or antibody-like molecule comprises an amino acid sequence provided in Table 1 or Table 2, wherein the antibody or antibody-like molecule binds plgR. In embodiments, the antibody or antibody-like molecule comprises an amino acid sequence, provided in Table 1 or Table 2, wherein the antibody or antibody-like molecule comprises one or more additional elements (e.g., amino acid sequences added at N- or C-terminus) that are known in the art to improve solubility, function, serum half-life, production, stability, purification, e.g., conjugation (e.g., PEGylation), linkers, hydrophobic residues and tags. See, e.g., Roberts et al.. Chemistry for antibody or antibody-like molecule and protein PEGylation, Advanced Drug Delivery Reviews 54: 459-476 (2002); and Islam et al., Analysis of amino acid contributions to protein solubility using short antibody or antibody-like molecule tags fused to a simplified BPTI variant, Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1824(10): 1144-1150 (2012). In embodiments, the antibody or antibody-like molecule is fused with a carrier moiety. In embodiments, the carrier moiety is a half-life extending carrier moiety.

[0228] DB1 / 167593545.6 36Atorney Docket No. CVL-001PC / 140489-5001

[0229] In embodiments, the antibody or antibody-like molecule comprises or further comprises a cysteine to facilitate thiol-maleimide conjugation. In embodiments, the antibody or antibody-like molecule comprises or further comprises one or more unpaired cysteine residues to facilitate thiol-maleimide conjugation. In embodiments, the antibody or antibody-like molecule comprises or further comprises natural or engineered glycosylation sites (e.g., N297 on IgG Fc domain) to facilitate glycosite-specific conjugation using technologies like glycan oxidation, enzymatic labeling (GalT Y289L), or click chemistry, which avoids antibody functional impairment. In embodiments, the antibody or antibody-like molecule comprises or further comprises one or more lysine residues to facilitate NHS-esters or isothiocyanate conjugation. In embodiments, the antibody or antibodylike molecule comprises or further comprises one or more glutamine residues to facilitate transglutaminase-mediated conjugation.

[0230] In embodiments, the antibody-like molecule comprises an amino acid sequence provided in Table 1, wherein the antibody-like molecule is in an antibody format VHH-His. In embodiments, the antibody-like molecule comprises an amino acid sequence provided in Table 1, wherein the antibody-like molecule is in an antibody format VHH-Fc. In embodiments, the antibody-like molecule comprises an amino acid sequence provided in Table 1, wherein the antibody-like molecule is a tetravalent molecule (e.g., a tetravalent VHH- VHH-Fc). In embodiments, the tetravalent molecule is monospecific, bispecific, trispecific or tetraspecific. In embodiments, the antibody-like molecule comprises an amino acid sequence provided in Table 1, wherein the antibody-like molecule comprises or further comprises a moiety that facilitates conjugation of the antibody-like molecule to an siRNA. In embodiments, the antibody-like molecule comprises an amino acid sequence provided in Table 1, wherein the antibody-like molecule comprises or further comprises a SLPETG (SEQ ID NO: 235) peptide tag (e.g, G4SLPETG (SEQ ID NO: 236) or G5SLPETG (SEQ ID NO: 237)) to facilitate conjugation using sortase A (SrtA) enzymes. In embodiments, the antibody -like molecule comprises an amino acid sequence provided in Table 1, wherein the antibody-like molecule comprises or further comprises a cysteine to facilitate thiol- maleimide conjugation. In embodiments, the antibody-like molecule comprises an amino acid sequence provided in Table 1, wherein the antibody-like molecule comprises or further comprises one or more unpaired cysteine residues to facilitate thiol-maleimide conjugation. In embodiments, the antibody-like molecule comprises an amino acid sequence provided in Table 1, wherein the antibody-like molecule comprises or further comprises natural or engineered glycosylation sites

[0231] DB1 / 167593545.6 37Attorney Docket No. CVL-001PC / 140489-5001

[0232] (e g., N297 on IgG Fc domain) to facilitate glycosite-specific conjugation using technologies like glycan oxidation, enzymatic labeling (GalT Y289L), or click chemistry, which avoids antibody functional impairment. In embodiments, the antibody-like molecule comprises an amino acid sequence provided in Table 1, wherein the antibody-like molecule comprises or further comprises one or more lysine residues to facilitate NHS-esters or isothiocyanate conjugation. In embodiments, the antibody-like molecule comprises an amino acid sequence provided in Table 1, wherein the antibody -like molecule comprises or further comprises one or more glutamine residues to facilitate transglutaminase-mediated conjugation.

[0233] Table 2: Sequences of Illustrative Non-limiting VHH-His or VHH-Fc Antibody Format. CDR sequences of antibodies NB-1 to NB5 are underlined and are disclosed in Table 1.

[0234] SEQ

[0235] Construct Amino Acid Sequence

[0236] Name ID NO NBl-His EVQ VVE SGGGL VQ AGGSLKLAC A APGLTF S SYRMGWFRQ APG 153 QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTOVTVSS GGGGSHHHHHH NB2-His QLQLVESGGGLVQPGGSLRLSCAASGSIFSINVMGWYRQAPGK 154 ORELVARINGGGITHYAESVKGRFTISRDNAKNTVYLOMNSLKP EDTAAYYCKADVFGSSGYVETYWGOGTQVTVSSGGGGSHHHH HH NB3-His EVQLVESGGGLVQAGGSLRLSCAVSGSSVSSPAMGWYRQAPG 155 NORAWVAFISGGGTTTYADSVKGRFTISRDNTKNTVYLHMNSL KPEDTAVYYCNHPLTSRWGQGTQVTVSSGGGGSHHHHHH NB4-His EVQVVESGGGLVQAGGSLRLSCAASGRTFTTYRMGWFRQAPG 251 KEREFVAAIRWSGGRTLYADSVKGRFTISRDNAKNTAYLOMNN LRPEDT A VYYC A ADLAEYSGT YS SP AD SP AGYD YWGOGTQ VT VS S GGGGSHHHHHH NB5-His OVOLVETGGGLVOAGDSLRLSCAASGRTLSFNTYAMGWFROA 156

[0237] PGKEREFVASITWNGGSTSYADSVKGRFTITRDNAKNTATLRMN

[0238]

[0239] DBl / 167593545.6 38Atorney Docket No. CVL-001PC / 140489-5001

[0240] SLQPDDTAVYYCAAARYYVSGTYFPANYWGOGTOVTVSSGGG GSHHHHHH NBl-Fc EVQVVESGGGLVQAGGSLKEACAAPGLTFSSYRMGWFRQAPG 157 QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTQVTVSS GGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQ VYTLPP SQEEMTKNQ VSLTCL VKGF YP SDI A VEWE SNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGK NB2-Fc QLQLVESGGGLVQPGGSLRLSCAASGSIFSINVMGWYRQAPGK 158 ORELVARINGGGITHYAESVKGRFTISRDNAKNTVYLOMNSLKP EDTAAYYCKADVFGSSGYVETYWGOGTOVTVSSGGGGSESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSLGK NB3-Fc EVQLVESGGGLVQAGGSLRLSCAVSGSSVSSPAMGWYRQAPG 159 NORAWVAFISGGGTTTYADSVKGRFTISRDNTKNTVYLHMNSL KPEDTAVYYCNHPLTSRWGQGTQVTVSSGGGGSESKYGPPCPP CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEV QFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK NB4-Fc EVQVVESGGGLVQAGGSLRLSCAASGRTFTTYRMGWFRQAPG 160 KEREFVAAIRWSGGRTLYADSVKGRFTISRDNAKNTAYLOMNN LRPEDT AVYYC A ADLAEYSGT YS SP AD SP AG YD YWGOGTO VT

[0241]

[0242] DB1 / 167593545.6 39Atorney Docket No. CVL-001PC / 140489-5001

[0243] VSSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PEN N YK TTP P VLD SDGSFFL YSRLTVDKSRWQEGNVF SC S VMHE ALHNHYTQKSLSLSLGK NB5-Fc OVOLVETGGGLVOAGDSLRLSCAASGRTLSFNTYAMGWFRQA 161 PGKEREFVASITWNGGSTSYADSVKGRFTITRDNAKNTATLRMN SLOPDDTAVYYCAAARYYVSGTYFPANYWGOGTQVTVSSGGG GSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS VLTVLHQD WLNGKE YKCKVSNKGLP S SIEKTISK AKGQPREPQ V YTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH YTQKSLSLSLGK NB6-Fc EVQVVESGGGLVQAGGSLKLACAAPGLTFSSYRMGWFRQAPG 162 QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTQVTVSS GGGGSEVQLVESGGGLVQAGGSLRLSCAVSGSSVSSDAMGWY ROAPGNORAWVAFISGGGTTTYADSVKGRFTISRDNTKNTVYL HMNSLKPEDTAVYYCNHPLTSRWGQGTQVTVSSGGGGSESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQD WLNGKE YKCKVSNKGLP S SIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LD SDGSFFLYSRLT VDKSRWQEGNVF SC S VMHEALHNHYTQKS LSLSLGK NB7-Fc EVQVVESGGGLVQAGGSLKLACAAPGLTFSSYRMGWFRQAPG 163 QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTOVTVSS GGGGSEVOVVESGGGLVQAGGSLRLSCAASGRTFTTYRMGWF

[0244]

[0245] DB1 / 167593545.6 40Atorney Docket No. CVL-001PC / 140489-5001

[0246] RQAPGKEREFVAAIRWSGGRTLYADSVKGRFTISRDNAKNTAY LQMNNLRPEDTAVYYCAADLAEYSGTYSSPADSPAGYDYWGO GTQVTVSSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNST YRVVS VLT VLHQDWLNGKEYKCKVSNKGLP S SIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCSVMHEALHNHYTQKSLSLSLGK NB8-Fc EVQVVESGGGLVQAGGSLKLACAAPGLTFSSYRMGWFRQAPG 164 QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTQVTVSS GGGGSOVOLVETGGGLVQAGDSLRLSCAASGRTLSFNTYAMG WFRQAPGKEREFVASITWNGGSTSYADSVKGRFTITRDNAKNT ATLRMNSLOPDDTAVYYCAAARYYVSGTYFPANYWGOGTOVT VSSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PEN N Y KTTP PVLD SDGSFFL YSRLTVDKSRWQEGNVF SC S VM HE ALHNHYTQKSLSLSLGK NB9-Fc EVQLVESGGGLVQAGGSLRLSCAVSGSSVSSPAMGWYRQAPG 165 NORAWVAF1SGGGTTTYADSVKGRFT1SRDNTKNTVYLHMNSL KPEDTAVYYCNHPLTSRWGOGTOVTVSSGGGGSEVQVVESGG GLVOAGGSLRLSCAASGRTFTTYRMGWFROAPGKEREFVAAIR WSGGRTLYADSVKGRFTISRDNAKNTAYLQMNNLRPEDTAVY YCAADLAEYSGTYS SP ADSPAGYDYWGOGTQVTVS SGGGGSES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP

[0247]

[0248] DB1 / 167593545.6 41Atorney Docket No. CVL-001PC / 140489-5001

[0249] VLD SDGSFFL YSRLT VDK SRWQEGNVF SC S VMHEALHNHYTQK SLSLSLGK NBIO-Fc EVQLVESGGGLVQAGGSLRLSCAVSGSSVSSDAMGWYRQAPG 166 NORAWVAFISGGGTTTYADSVKGRFTISRDNTKNTVYLHMNSL KPEDTAVYYCNHPLTSRWGQGTQVTVSSGGGGSQVQLVETGG GLVOAGDSLRLSCAASGRTLSFNTYAMGWFROAPGKEREFVAS ITWNGGSTSYADSVKGRFTITRDNAKNTATLRMNSLQPDDTAV YYCAAARYYVSGTYFPANYWGOGTQVTVSSGGGGSESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL SLGK NBll-Fc EVQVVESGGGLVQAGGSLRLSCAASGRTFTTYRMGWFRQAPG 167 KEREFVAAIRWSGGRTLYADSVKGRFTISRDNAKNTAYLOMNN LRPEDT A VYYC A ADLAEYSGT YS SP AD SP AGYD YWGQGTQ VT VSSGGGGSOVOLVETGGGLVQAGDSLRLSCAASGRTLSFNTYA MGWFROAPGKEREFVASITWNGGSTSYADSVKGRFTITRDNAK NTATLRMNSLOPDDTAVYYCAAARYYVSGTYFPANYWGOGTQ VTVSSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPP VLD SDGSFFL YSRLT VDK SRWQEGNVF SC SV MHEALHNHYTQKSLSLSLGK NB12-FC EVQVVESGGGLVQAGGSLKLACAAPGLTFSSYRMGWFRQAPG 168 QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTQVTVSS GGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEV

[0250] TCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR

[0251]

[0252] DB1 / 167593545.6 42Atorney Docket No. CVL-001PC / 140489-5001

[0253] VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQ VYTLPP SQEEMTKNQVSLTCL VKGF YP SDIAVEWE SNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGKGGGGSEVQLVESGGGLVQAGGSLRLSCA VSGSSVSSDAMGWYRQAPGNQRAWVAFISGGGTTTYADSVKG RFTISRDNTKNTVYLHMNSLKPEDTAVYYCNHPLTSRWGQGTQ VTVSS NB13-FC EVQVVESGGGLVQAGGSLKLACAAPGLTFSSYRMGWFRQAPG 169 QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTQ VTVSS GGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGKGGGGSEVQVVESGGGLVQAGGSLRLSCA ASGRTFTTYRMGWFRQAPGKEREFVAAIRWSGGRTLYADSVKG RFTISRDNAKNTAYLQMNNLRPEDTAVYYCAADLAEYSGTYSS PADSPAGYDYWGOGTQVTVSS NB14-Fc EVQVVESGGGLVQAGGSLKLACAAPGLTFSSYRMGWFRQAPG 170 QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTO VTVSS GGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQ VYTLPP SQEEMTKNQVSLTCL VKGF YP SDIAVEWE SNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGKGGGGSQVQLVETGGGLVQAGDSLRLSCA ASGRTLSFNTYAMGWFRQAPGKEREFVASITWNGGSTSYADSV KGRFTITRDNAKNTATLRMNSLQPDDTAVYYCAAARYYVSGTY FPANYWGOGTQVTVSS

[0254]

[0255] DB1 / 167593545.6 43Atorney Docket No. CVL-001PC / 140489-5001

[0256] NB15-Fc EVQLVESGGGLVQAGGSLRLSCAVSGSSVSSpAMGWYRQAPG 171 NORAWVAFISGGGTTTYADSVKGRFTISRDNTKNTVYLHMNSL KPEDTAVYYCNHPLTSRWGQGTQVTVSSGGGGSESKYGPPCPP CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEV QFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK GGGGSEVQVVESGGGLVQAGGSLRLSCAASGRTFTTYRMGWF RQAPGKEREFVAAIRWSGGRTLYADSVKGRFTISRDNAKNTAY LQMNNLRPEDTAVYYCAADLAEYSGTYSSPADSPAGYDYWGO GTQVTVSS NB16-Fc EVQLVESGGGLVQAGGSLRLSCAVSGSSVSSPAMGWYRQAPG 172 NORAWVAFISGGGTTTYADSVKGRFTISRDNTKNTVYLHMNSL KPEDTAVYYCNHPLTSRWGQGTQVTVSSGGGGSESKYGPPCPP CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEV QFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK GGGGSOVOLVETGGGLVQAGDSLRLSCAASGRTLSFNTYAMG WFRQAPGKEREFVASITWNGGSTSYADSVKGRFTITRDNAKNT ATLRMNSLOPDDTAVYYCAAARYYVSGTYFPANYWGOGTQVT

[0257] vss

[0258] NB17-Fc EVQVVESGGGLVQAGGSLRLSCAASGRTFTTYRMGWFRQAPG 173 KEREFVAAIRWSGGRTLYADSVKGRFTISRDNAKNTAYLQMNN LRPEDT AVYYC A ADLAEYSGT YS SP AD SP AGYD YWGOGTQ VT VSSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

[0259]

[0260] DB1 / 167593545.6 44Atorney Docket No. CVL-001PC / 140489-5001

[0261] PENNYKTTPPVLD SDGSFFL YSRLTVDKSRWQEGNVF SC S VMHE ALHNHYTQKSLSLSLGKGGGGSQVQLVETGGGLVQAGDSLRLS CAASGRTLSFNTYAMGWFRQAPGKEREFVASITWNGGSTSYAD SVKGRFTITRDNAKNTATLRMNSLOPDDTAVYYCAAARYYVSG TYFPANYWGOGTQVTVS S NBl-Srt EVOVVESGGGLVOAGGSLKLACAAPGLTFSSYRMGWFROAPG 174 QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTQVTVSS GGGGSLPETGHHHHHH NB2-Srt OLOLVESGGGLVOPGGSLRLSCAASGSIFSINVMGWYRQAPGK 175 OREL VARIN GGG1THYAESVKGRFT1SRDNAKNTVYLOMNSLKP EDTAAYYCKADVFGSSGYVETYWGOGTQVTVSSGGGGSLPET GHHHHHH NB3-Srt EVOLVESGGGLVOAGGSLRLSCAVSGSSVSSDAMGWYRQAPG 176 NORAWVAFISGGGTTTYADSVKGRFTISRDNTKNTVYLHMNSL KPEDTAVYYCNHPLTSRWGQGTQVTVSSGGGGSLPETGHHHHH H NB4-Srt EVOVVESGGGLVOAGGSLRLSCAASGRTFTTYRMGWFRQAPG 177 KEREFVAAIRWSGGRTLYADSVKGRFTISRDNAKNTAYLOMNN LRPEDT AVYYC A ADLAE YSGT YS SP AD SP AGYD YWGOGTQ VT VS S GGGGSLPETGHHHHHH NB5-Srt OVOLVETGGGLVOAGDSLRLSCAASGRTLSFNTYAMGWFRQA 178 PGKEREFVASITWNGGSTSYADSVKGRFTITRDNAKNTATLRMN SLOPDDTAVYYCAAARYYVSGTYFPANYWGOGTQVTVSSGGG GSLPETGHHHHHH NB1-C EVOVVESGGGLVOAGGSLKLACAAPGLTFSSYRMGWFROAPG 179 OEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTQVTVSS CGGGGSHHHHHH NB2-C OLOLVESGGGLVOPGGSLRLSCAASGSIFSINVMGWYROAPGK 180

[0262] ORELVARINGGGITHYAESVKGRFTISRDNAKNTVYLOMNSLKP

[0263]

[0264] DB1 / 167593545.6 45Atorney Docket No. CVL-001PC / 140489-5001

[0265] EDTAAYYCKADVFGSSGYVETYWGOGTQVTVSSCGGGGSHHH I II III NB1-NB1-C EVQVVESGGGLVQAGGSLKLACAAPGLTFSSYRMGWFRQAPG 181 QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTQVTVSS GGGGSGGGGSGGGGSEVQVVESGGGLVQAGGSLKLACAAPGL TF S S YRMGWFRQ APGQEREF VAAIDWNGRGTYYRYYAD S VKG RSTISRDNAKNTVYLQMNSLKPEDTAVYYCAATTVLTDPRVLN EYATWGOGTQVTVSSCGGGGSHHHHHH NB2-NB2-C OLOLVESGGGLVOPGGSLRLSCAASGSIFSINVMGWYRQAPGK 182 OREL VARIN GGG1THYAESVKGRFT1SRDNAKNTVYLOMNSLKP EDTAAYYCKADVFGSSGYVETYWGOGTQVTVSSGGGGSGGGG SGGGGSQLQLVESGGGLVQPGGSLRLSCAASGSIFSINVMGWYR OAPGI<ORELVARINGGGITHYAESVI<GRFTISRDNAI<NTVYLO MNSLKPEDTAAYYCKADVFGSSGYVETYWGOGTQVTVSSCGG GGSHHHHHH NB1-HSA-C EVQVVESGGGLVQAGGSLKLACAAPGLTFSSYRMGWFRQAPG 183 QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTOVTVSS GGGGSGGGGSGGGGS- EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGK GLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLR PEDT AVYYCTIGGSL SRS SQGTL VT VS S-CGGGGSHHHHHH NB2-HSA-C QLQLVESGGGLVQPGGSLRLSCAASGSIFSINVMGWYRQAPGK 184 ORELVARINGGGITHYAESVKGRFTISRDNAKNTVYLOMNSLKP EDTAAYYCKADVFGSSGYVETYWGOGTQVTVSSGGGGSGGGG SGGGGS- EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGK GLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLR PEDT AVYYCTIGGSLSRSSQGTLVTVS S -CGGGGSHHHHHH

[0266]

[0267] DB1 / 167593545.6 46Attorney Docket No. CVL-001PC / 140489-5001

[0268] NB1-HSA- EVQVVESGGGLVQAGGSLKLACAAPGLTFSSYRMGWFRQAPG 185 NBI-C

[0269] QEREFVAAIDWNGRGTYYRYYADSVKGRSTISRDNAKNTVYLO MNSLKPEDTAVYYCAATTVLTDPRVLNEYATWGOGTQVTVSS GGGGSGGGGSGGGGS- EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGK GLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLR PEDT AVYYCTIGGSL SRS SQGTL VT VS S- GGGGSGGGGSGGGGSEVQVVESGGGLVQAGGSLKLACAAPGL TFSSYRMGWFRQAPGQEREFVAAIDWNGRGTYYRYYADSVKG RSTISRDNAKNTVYLQMNSLKPEDTAVYYCAATTVLTDPRVLN EYATWGOGTQVTVSSCGGGGSHHHHHH NB2-HSA- QLQLVESGGGLVQPGGSLRLSCAASGSIFSINVMGWYRQAPGK 186 NB2-C

[0270] ORELVARINGGGITHYAESVKGRFTISRDNAKNTVYLOMNSLKP EDTAAYYCKADVFGSSGYVETYWGOGTOVTVSSGGGGSGGGG SGGGGS- EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGK GLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLR PEDT AVYYCTIGGSL SRS SQGTL VT VS S- GGGGSGGGGSGGGGSQLQLVESGGGLVQPGGSLRLSCAASGSIF SINVMGWYRQAPGKQRELVARINGGGITHYAESVKGRFTISRDN AKNTVYLOMNSLKPEDTAAYYCKADVFGSSGYVETYWGOGTQ VTVSSCGGGGSHHHHHH

[0271]

[0272] Peptides Capable of Binding Polymeric immunoglobulin receptor (plgR)

[0273] In aspects, the present disclosure provides a peptide capable of binding plgR that that promote the internalization of a therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) in epithelial cells via the plgR-mediated internalization but then divert the internalized therapeutic payloads to the intracellular environment (rather than transcytosis). In embodiments, the peptide.

[0274] DBl / 167593545.6 47Atorney Docket No. CVL-001PC / 140489-5001

[0275] In embodiments, the peptide binds to one or more of extracellular domains DI, D2, D3, D4, D5, and the cleavage domain (also known as D6) of plgR. In embodiments, the peptide binds to the cleavage domain of plgR. In embodiments, the peptide binds plgR at or near the J chain binding site for plgR of immunoglobulin A (IgA) or IgM. In embodiments, the peptide reduces or inhibits cleavage of extracellular domain D6 of plgR. In embodiments, the peptide binds to plgR in a competitive manner with IgA and / or IgM. In embodiments, the peptide binds to plgR with higher affinity than IgA or IgM binds to plgR.

[0276] In embodiments, the peptide binds to plgR with higher affinity than the affinity with which a reference peptide binds to plgR. In embodiments, the reference peptide has an amino acid sequence of amino acids 37-158 of Streptococcus pneumoniae secretory IgA-binding protein SpsA. See Braathen et al., Identification of a Polymeric Ig Receptor Binding Phage-displayed Peptide That Exploits Epithelial Transcytosis without Dimeric IgA Competition, J. Biol. Chem. 281(11): 7075- 7081. In embodiments, the Streptococcus pneumoniae SpsA has the following sequence:

[0277] MFASKSERKVHYSIRKFSIGVASVVVASLVMGSVVHATENEGSTQAATFSNMANKSQT EQGEINIERDKAKTAVSEYKEKKVSEIYTKLERDRHKDTVDLVNKLQEIKNEYLNKIVQS TSKTEIQGLITTSRSKLDEAVSKYKKAPSSSSSSGSSTKPEASDTAKPNKPTELEKKVAEA EKKVEEAKKKAKDQKEEDYRNYPTITYKTLELEIAESDVEVKKAELELVKEEAKEPRNE EKVKQAKAKVESEETEATRLEKIKTDRKKAEEEAKRKAAEEDKVKEKPAEQQAEEDYA RRSEEEYNRLTQQQPPKTEKPAQPSTPKTGWKQENGMWYFYNTDGSMATGWLQNNGS WYYLNSNGAMATGWLQNNGSWYYLNANGSMATGWLQNNGSWYYLNANGSMATG WLQYNGSWYYLNANGDMATGWLQYNGSWYYLNANGDMATGWLQYNGSWYYLNA NGDMATGWVKDGDTWYYLEASGAMKASQWFKVSDKWYYVNGSGALAVNTTVDGY GVNANGEWVN (SEQ ID NO: 234).

[0278] In embodiments, the affinity is measured or is measurable using enzyme-linked immunosorbent assay (ELISA), flow cytometry, surface plasmon resonance (SPR), fluorescence polarization binding assay, kinetic exclusion assay (KinExA), radioimmunoassay (RIA), or a combination thereof.

[0279] In embodiments, the peptide binds to plgR at an acidic pH. In embodiments, the peptide binds to plgR at pH of about 4.5 to about 8.5. In embodiments, the peptide binds to plgR at pH of about 4.5. In embodiments, the peptide binds to plgR at pH of about 5. In embodiments, the peptide

[0280] DB1 / 167593545.6 48Atorney Docket No. CVL-001PC / 140489-5001

[0281] binds to plgR at pH of about 5.5. In embodiments, the peptide binds to plgR at pH of about 6. In embodiments, the peptide binds to plgR at pH of about 6.5. In embodiments, the peptide binds to plgR at pH of about 7. In embodiments, the peptide binds to plgR at pH of about 7.5. In embodiments, the peptide binds to plgR at pH of about 8. In embodiments, the peptide binds to plgR at pH of about 8.5. In embodiments, the peptide to plgR at a given pH is measured or is measurable using methods known in the art, including ELISA, flow cytometry, SPR, fluorescence polarization binding assay, KinExA, RIA, or a combination thereof.

[0282] In embodiments, the peptide is internalized in the epithelial cells. In embodiments, the peptide promotes the internalization of a therapeutic payload (without limitation, e. ., a nucleic acid therapeutic payload) in the epithelial cells. In embodiments, at least a fraction of the peptide and / or the therapeutic payload is not translocalized across the epithelial cells. In embodiments, the fraction of the peptide and / or the therapeutic payload that is not translocated across the epithelial cells is sufficient to exert its therapeutic effect. In embodiments, the fraction of a therapeutic payload conjugated to the peptide (without limitation, e.g., a nucleic acid therapeutic payload) that is not translocalized across the epithelial cells is sufficient to exert its therapeutic effect. In embodiments, at least about 0.1%, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of the peptide and / or the therapeutic payload is not translocalized across the epithelial cells. In embodiments, at least about 0.1%, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of a therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) conjugated to the peptide is not translocalized across the epithelial cells.

[0283] In embodiments, internalization of the payload and / or the peptide in epithelial cells is measured or is measurable using methods known in the art, including immunocytochemistry, fluorescence microscopy (e.g., immunofluorescence microscopy), ELISA, flow cytometry, western blot, or a combination thereof. In embodiments, translocalization of the payload and / or the peptide across epithelial cells is measured or is measurable using methods known in the art, including iti vitro DB1 / 167593545.6 49Atorney Docket No. CVL-001PC / 140489-5001

[0284] immunological assays (e.g, fluorescence-based in vitro assays to detect the payload and / or the peptide translocalization across a monolayer) and trans well assay, coupled with a detection technique known in the art such as ELISA, western blot, or a combination thereof.

[0285] In embodiments, at least a fraction of the peptide and / or the therapeutic payload is retained in the epithelial cells. In embodiments, the retention of the payload and / or the peptide in the endosomes of the epithelial cells is measured or is measurable using methods known in the art, including immunocytochemistry, fluorescence microscopy (e.g., immunofluorescence microscopy showing colocalization with an endosomal marker). In embodiments, the retention of the payload and / or the peptide in epithelial cells is measured or is measurable using methods known in the art, including immunocytochemistry, fluorescence microscopy e.g., immunofluorescence microscopy), ELISA, flow cytometry, western blot, or a combination thereof. In embodiments, the fraction of the peptide and / or the therapeutic payload that is retained in the epithelial cells is sufficient to exert its therapeutic effect. In embodiments, at least about 0.1%, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of the peptide and / or the therapeutic payload is retained in the epithelial cells. In embodiments, at least about 0.1%, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of a therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) conjugated to the peptide is retained in the epithelial cells.

[0286] In embodiments, a fraction of the peptide and / or the therapeutic payload is retained in the endosomes of the epithelial cells. In embodiments, the peptide and / or the therapeutic payload escapes the endosomes of the epithelial cells. In embodiments, the peptide and / or the therapeutic payload escapes the endosomes of the epithelial cells with a slow kinetics. In embodiments, the peptide and / or the therapeutic payload escapes the endosomes of the epithelial cells with a kinetics that causes the escape of at least about 0.1%, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least DB1 / 167593545.6 50Atorney Docket No. CVL-001PC / 140489-5001

[0287] about 3%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of the therapeutic payload over about a 24 hours. In embodiments, the peptide and / or the therapeutic payload escapes the endosomes of the epithelial cells with a kinetics that causes the escape of at least about 0.1%, or at least about 0.2%, or at least about 0.3%, or at least about 0.5%, or at least about 0.75%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or more of the therapeutic payload over about a week. In embodiments, the endosomal escape of the payload and / or the peptide in epithelial cells is measured or is measurable using methods known in the art, including immunocytochemistry, fluorescence microscopy (e.g., immunofluorescence microscopy showing colocalization with an endosomal marker), biological activity of the payload (e.g., evidence of silencing when the payload is siRNA) or a combination thereof.

[0288] In embodiments, the peptide binds to plgR at a lower affinity at pH less than about 6 compared to the affinity of binding of the peptide binds to plgR at a pH greater than about 6. As a consequence, in embodiments, as the endosomal pH drops, the peptide is released from plgR. In embodiments, the linker that attaches the peptide to a therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) is cleaved at a pH less than about 6. As a consequence, in embodiments, as the endosomal pH drops, the therapeutic payload is released from the peptide.

[0289] In embodiments, the peptide has a length of about 4 amino acids to about 100 amino acids. In embodiments, the peptide comprises about 6 amino acids to about 60 amino acids. In embodiments, the peptide has a length of about 6 amino acids, or about 8 amino acids, or about 10 amino acids, or about 15 amino acids, or about 20 amino acids, or about 25 amino acids, or about 30 amino acids, or about 35 amino acids, or about 40 amino acids, or about 45 amino acids, or about 50 amino acids, or about 55 amino acids, or about 60 amino acids. In embodiments, the peptide has a length in the range of about 4 amino acids to about 100 amino acids, or about 6 amino acids to about 60 amino acids, or about 6 amino acids to about 40 amino acids, or about 6 amino acids to about 20 amino acids, or about 10 amino acids to about 20 amino acids, or about 15 amino acids to about 30 amino acids, or about 20 amino acids to about 40 amino acids, or about 30 amino acids to about 60 amino acids, or about 8 amino acids to about 45 amino acids, or about 10 amino DB1 / 167593545.6 51Attorney Docket No. CVL-001PC / 140489-5001

[0290] acids to about 50 amino acids, or about 15 amino acids to about 60 amino acids. In embodiments, the peptide is a linear peptide, a branched peptide, a circular peptide, or a semi-cyclic peptide. In embodiments, the peptide comprises an amino acid sequence shown in Table 3. In embodiments, the peptide comprises an amino acid sequence, provided in Table 3, i.e., one or more of SEQ ID NOs: 187-233, or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions.

[0291] Table 3: Sequences of Illustrative Non-limiting peptides that are Capable of Binding Polymeric Ig Receptor (plgR)

[0292] Peptide Sequence of the Peptide capable of binding plgR SEQ Name ID NO.

[0293] Pepl QRNPRLRLIRRHPTLRIPPI 187 Pep2 QRNPKLKLIRRHPTLRIPPI 188 Pep3 CVVWMGFQQVC 189 Pep4 TWASRQEPSQGTTTFAVTSGP 190 Pep5 RSRMFVLGVLEVDSGLLNCLCWVGVSVDGRKSSCRWTAY 191 Pep6 SAMF VPFDIAVGVRDGQQGLGGSRRKGARLREAIS S YAE 192 Pep7 IP S VTRMT VGGTLRKEFQD VVLGVIFGLVL VINRC SFL 193 Pep8 VDDLTLQSRSPPSQLNSQHLLLSQLCGYWMFRVRSRSCCG 194 Pep9 MFVCVDAKQCLLGAAGGLRLIFA 195 Pep 10 YRNYPT 196 Pepll YPTITYKT 197 Pep 12 YRNYPTITYKTLELE 198 Pep 13 CIIVPHAYAWC 199 Pep 14 CALVSEAGCLVWAA 200 Pep 15 RFWWGWY 201 Pep 16 PFVVLLV 202 Pep 17 CQDPICFCGADGACYCTSRNC 203 Pep 18 CAWHYRFCGAAHSADGACREVFLVC 204 Pep 19 CWTSGARWRLC 205

[0294]

[0295] DB1 / 167593545.6 52Atorney Docket No. CVL-001PC / 140489-5001

[0296] Pep20 CAGAWSRC 206 Pep21 LHVSQRG 207 PeplOl- APWHLSAQYSRTGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDT 208 Fc LMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSLGK

[0297] Pep 102- APWHLSSQYSATGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDT 209 Fc LMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSLGK

[0298] Pepl03- SAMFVPFDIAVGVRDGQQGLGGSRRKGARLREAISSYAEGGGGSESK 210 Fc YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKGLP S SIEKTISKAKGQPREPQ VYTLPP SQEEMTKNQ VSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVF SC SVMHE ALHNHYTQKSLSLSLGK

[0299] Pep 104- VDDLTLQSRSPPSQLNSQHLLLSQLCGYWMFRVRSRSCCGGGGGSES 211 Fc KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVF SC SVMHE ALHNHYTQKSLSLSLGK

[0300] Pep 105- QRNPRLRLIRRHPTLRIPPIGGGGSESKYGPPCPPCPAPEFLGGPSVFLFP 212 Fc PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

[0301]

[0302] DB1 / 167593545.6 53Atorney Docket No. CVL-001PC / 140489-5001

[0303] ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN HYTQKSLSLSLGK

[0304] Pep 106- QRNPKLKL1RRHPTLR1PP1GGGGSESKYGPPCPPCPAPEFLGGPSVFLFP 213 Fc PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SC SVMHEALHN HYTQKSLSLSLGK

[0305] Pep 107 FKCRGINCVK 214 Pep 108 MWCSTNHCKT 215 Pep 109 KVCINQGCHR 216 PepllO PHCATSDCRN 217 Peplll MACGSNKCRM 218 Pepll2 QICMAGPCPN 219 Pepll3 NDCKSPGCNR 220 Pepll4 PRCSAPPCKK 221 Pepll5 KACSNMRCNK 222 Pepll6 IGCTRASCLA 223 Pepll7 WGCLHKHCKA 224 Pepll8 TLCKHKTCPT 225 Pepll9 PACTKTSCKT 226 Pepl20 ARCTNLSCPQ 227 Pepl21 PTCQTRSCSQ 228 Pep 122 HVCKKMTCKK 229 Pep 123 STCKLGLCRP 230 Pep 124 WQCGEPKCRA 231 Pepl25 LRCMLNHCLK 232 Pep 126 FPCAKRTCSK 233

[0306]

[0307] DB1 / 167593545.6 54Atorney Docket No. CVL-001PC / 140489-5001

[0308] In embodiments, the peptide is or comprises Pepl07 (SEQ ID NO: 214), Pepl 10 (SEQ ID NO: 217), Pep 112 (SEQ ID NO : 219), Pep 113 (SEQ ID NO : 220), Pep 114 (SEQ ID NO : 221), Pep 115 (SEQ ID NO: 222), Pepl 16 (SEQ ID NO: 223), Pepl 17 (SEQ ID NO: 224), Pepl 19 (SEQ ID NO: 226), Pep 120 (SEQ ID NO: 227), Pepl21 (SEQ ID NO: 228), Pep 122 (SEQ ID NO: 229), Pep 124 (SEQ ID NO: 231) and Pepl25 (SEQ ID NO: 232), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions.

[0309] In embodiments, the peptide is or comprises Pepl 15 (SEQ ID NO: 222), Pepl 12 (SEQ ID NO: 219), Pepl07 (SEQ ID NO: 214), Pepl 17 (SEQ ID NO: 224), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide is or comprises Pepl 15 (SEQ ID NO: 222), Pepl 12 (SEQ ID NO: 219), Pep 107 (SEQ ID NO: 214), Pepl 17 (SEQ ID NO: 224)

[0310] In embodiments, the peptide comprises an amino acid sequence selected from the amoni acid sequence of SEQ ID NOs: 187-233. In embodiments, the peptide comprises an amino acid sequence QRNPRLRLIRRHPTLRIPPI (SEQ ID NO: 187), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence QRNPKLKLIRRHPTLRIPPI (SEQ ID NO: 188), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence CVVWMGFQQVC (SEQ ID NO: 189), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence TWASRQEPSQGTTTFAVTSGP (SEQ ID NO: 190), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence RSRMFVLGVLEVDSGLLNCLCWVGVSVDGRKSSCRWTAY (SEQ ID NO: 191), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, DB1 / 167593545.6 55Atorney Docket No. CVL-001PC / 140489-5001

[0311] insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence SAMFVPFDIAVGVRDGQQGLGGSRRKGARLREAISSYAE (SEQ ID NO: 192), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence IPSVTRMTVGGTLRKEFQDVVLGVIFGLVLVINRCSFL (SEQ ID NO: 193), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence VDDLTLQSRSPPSQLNSQHLLLSQLCGYWMFRVRSRSCCG (SEQ ID NO: 194), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence MFVCVDAKQCLLGAAGGLRLIFA (SEQ ID NO: 195), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence YRNYPT (SEQ ID NO: 196), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence YPTITYKT (SEQ ID NO: 197), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence YRNYPTITYKTLELE (SEQ ID NO: 198), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence CIIVPHAYAWC (SEQ ID NO: 199), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence CALVSEAGCLVWAA (SEQ ID NO: 200), or a variant thereofhaving at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and

[0312] DB1 / 167593545.6 56Atorney Docket No. CVL-001PC / 140489-5001

[0313] deletions. Tn embodiments, the peptide comprises an amino acid sequence RFWWGWY (SEQ ID NO: 201), or a variant thereof having at least 1, or atleast2, or atleast3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence PFVVLLV (SEQ ID NO: 202), or a variant thereofhaving at least 1, or atleast2, or atleast3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence CQDPICFCGADGACYCTSRNC (SEQ ID NO: 203), or a variant thereofhaving at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence CAWHYRFCGAAHSADGACREVFLVC (SEQ ID NO: 204), or a variant thereofhaving at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence CWTSGARWRLC (SEQ ID NO: 205), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence CAGAWSRC (SEQ ID NO: 206), or a variant thereofhaving at least 1, or atleast2, or atleast3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence LHVSQRG (SEQ ID NO: 207), or a variant thereofhaving at least 1, or atleast2, or atleast3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions.

[0314] In embodiments, the peptide comprises an amino acid sequence:

[0315] APWHLSAQYSRTGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SC S VMHEALHNHY TQKSLSLSLGK (SEQ ID NO: 208),

[0316] DB1 / 167593545.6 57Atorney Docket No. CVL-001PC / 140489-5001

[0317] or a variant thereof having at least 1 , or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence:

[0318] APWHLSSQYSATGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK (SEQ ID NO: 209),

[0319] or a variant thereof having at least 1 , or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence:

[0320] SAMFVPFDIAVGVRDGQQGLGGSRRKGARLREAISSYAEGGGGSESKYGPPCPPCPAPE FLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTL PPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLT VDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 210),

[0321] or a variant thereof having at least 1 , or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence:

[0322] VDDLTLQSRSPPSQLNSQHLLLSQLCGYWMFRVRSRSCCGGGGGSESKYGPPCPPCPAP EFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPP SQEEMTKNQ VSLTCLVKGF YP SDIAVEWESNGQPENNYKTTPP VLD SDGSFFL YSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 211),

[0323] or a variant thereof having at least 1 , or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence:

[0324] DB1 / 167593545.6 58Atorney Docket No. CVL-001PC / 140489-5001

[0325] QRNPRLRLIRRHPTLRIPPIGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEA LHNHYTQKSLSLSLGK (SEQ ID NO: 212),

[0326] or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence:

[0327] QRNPKLKLIRRHPTLRIPPIGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKG F YP SDIAVEWESNGQPENNYKTTPP VLD SDGSFFL YSRLTVDKSRWQEGNVF SC S VMHE ALHNHYTQKSLSLSLGK (SEQ ID NO: 213),

[0328] or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence FKCRGINCVK (SEQ ID NO: 214), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence MWCSTNHCKT (SEQ ID NO: 215), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence KVCINQGCHR (SEQ ID NO: 216), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence PHCATSDCRN (SEQ ID NO: 217), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence MACGSNKCRM (SEQ ID NO: 218), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently DB1 / 167593545.6 59Atorney Docket No. CVL-001PC / 140489-5001

[0329] selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence QICMAGPCPN (SEQ ID NO: 219), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence NDCKSPGCNR (SEQ ID NO: 220), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence PRCSAPPCKK (SEQ ID NO: 221), or a variant thereof having at least 1 , or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence KACSNMRCNK (SEQ ID NO: 222), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence IGCTRASCLA (SEQ ID NO: 223), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence WGCLHKHCKA (SEQ ID NO: 224), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence TLCKHKTCPT (SEQ ID NO: 225), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence PACTKTSCKT (SEQ ID NO: 226), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence ARCTNLSCPQ (SEQ ID NO: 227), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence PTCQTRSCSQ (SEQ ID NO: 228), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations

[0330] DB1 / 167593545.6 60Atorney Docket No. CVL-001PC / 140489-5001

[0331] independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence HVCKKMTCKK (SEQ ID NO: 229), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence STCKLGLCRP (SEQ ID NO: 230), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence WQCGEPKCRA (SEQ ID NO: 231), or a variant thereof having at least 1 , or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence LRCMLNHCLK (SEQ ID NO: 232), or a variant thereofhaving at least 1, oratleast2, oratleast3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence FPCAKRTCSK (SEQ ID NO: 233), or a variant thereofhaving at least 1, oratleast2, or atleast3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions. In embodiments, the peptide comprises an amino acid sequence provided in Table 3, wherein the peptide binds plgR. In embodiments, the peptide comprises an amino acid sequence, provided in Table 3, wherein the peptide comprises one or more additional elements (e.g., amino acid sequences added at N- or C-terminus) that are known in the art to improve solubility, function, serum half-life, production, stability, purification, e.g., conjugation (e.g., PEGylation), linkers, hydrophobic residues and tags. See, e.g., Roberts et al., Chemistry for peptide and protein PEGylation, Advanced Drug Delivery Reviews 54: 459-476 (2002); and Islam et al., Analysis of amino acid contributions to protein solubility using short peptide tags fused to a simplified BPTI variant, Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1824(10): 1144-1150 (2012). In embodiments, the peptide is fused with a carrier moiety. In embodiments, the carrier moiety is a half-life extending carrier moiety.

[0332] In embodiments, the carrier moiety is a polymer. In embodiments, the polymer is PEG. In embodiments, one or more amino acids present in the peptide are PEGylated. In embodiments, no amino acids present in the peptide is PEGylated. In embodiments, N- and / or C- terminal extensions are added to the peptide for PEGylation. In embodiments, one or more amino acids that are added DB1 / 167593545.6 61Atorney Docket No. CVL-001PC / 140489-5001

[0333] at the N- or C-terminus of the peptide are PEGylated. In embodiments, N- and / or C- terminal extensions comprising one or more amino acids selected from lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine and tyrosine are added to the peptide for PEGylation. In embodiments, one or more amino acids present in the peptide or added in N- and / or C-terminal extension and selected from lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine and tyrosine are PEGylated using a technique known in the art, e.g., via chemical or enzymatic conjugation. In embodiments, one or more cysteine (Cys of C) residues present in the peptide or added in N- and / or C-terminal extension are PEGylated using a technique known in the art, e.g., via thiol conjugation. In embodiments, one or more are lysine (Lys or K) residues present in the peptide or added in N- and / or C-terminal extension are PEGylated using a technique known in the art, e.g., via amine conjugation. In embodiments, one or more are glutamine (Gin or Q) residues present in the peptide or added in N- and / or C-terminal extension are PEGylated using a technique known in the art, e.g., via transglutaminase (TGase) mediated enzymatic conjugation. In embodiments, the peptide comprises or further comprises is a lipid moiety. In embodiments, carboxyl group of the lipid and an amine group of present in the peptide are coupled to form an amide bond via chemical conjugation using methods known in the art, such as a carbodiimide- coupling method. In embodiments, a thiol group present in the peptide and an amine group that are present in the lipid, or a thiol group present in the lipid and an amine group that are present in the peptide are coupled using methods known in the art, such as a maleimide -coupling method. In embodiments derivatized peptide and the lipid, one having an azide group and the other having a triphosphine grouping are coupled using methods known in the art, such as a Staudinger ligation method.

[0334] In embodiments, the carrier moiety is a carrier protein selected from an Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant thereof. In embodiments, the composition or the delivery system comprises at least 2, or at least 3, or at least 4 or more peptides or plgR binding fragments thereof per copy of the therapeutic nucleic acid payload. In embodiments, the peptide is conjugated with an Fc domain to form a peptibody (i.e., a peptide-Fc fusion) or a bi-peptibody. In embodiments, the peptibody comprises an N- terminal fusion of the peptide with anFc domain (e.g., fused at the C-terminus of a signal sequence, if any), a C-terminal fusion of the peptide with an Fc domain, a peptide insertion within an Fc domain or a combination thereof. In embodiments, the peptibody comprises at least 1, or at least DB1 / 167593545.6 62Atorney Docket No. CVL-001PC / 140489-5001

[0335] 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the peptide per copy of the therapeutic nucleic acid payload. In embodiments, the peptides are fused in tandem. In embodiments, the peptides are fused in tandem via a flexible linker (e.g., a Gly and Ser rich flexible linker), at one, or two, or three, or more locations within the Fc domain. In embodiments, the peptide of any of the embodiments disclosed herein is conjugated with at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the therapeutic nucleic acid payload. In embodiments, the peptide is conjugated with about 1 to about 10, or about 1 to about 5, or about 1 to about 3, of about 2 to about 10, or about 2 to about 7, or about 2 to about 5, or about 3 to about 10, of about 3 to about 5, or about 3 to about 8, or about 4 to about 10, or about 4 to about 6, or about 4 to about 8, or about 5 to about 10, or about 5 to about 8 copies of the therapeutic nucleic acid payload. In embodiments, the copies of the therapeutic nucleic acid payload are independently selected from siRNA, miRNA, anti- miRNA, ASO, phosphorodiamidate PMO, tRNA, PNA, LNA, RNA aptamer, DNA aptamer, ribozyme, circRNA, RNA decoy, saRNA, and mRNA. In embodiments, at least one of the copies of the therapeutic nucleic acid payload is an siRNA or an ASO. In embodiments, all copies of the therapeutic nucleic acid payload are siRNA. In embodiments, the copies of siRNA have same or different sequences.

[0336] In embodiments, the therapeutic nucleic acid payload is conjugated with at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the peptide. In embodiments, the therapeutic nucleic acid payload is conjugated with about 1 to about 10, or about 1 to about 5, or about 1 to about 3, of about 2 to about 10, or about 2 to about 7, or about 2 to about 5, or about 3 to about 10, of about 3 to about 5, or about 3 to about 8, or about 4 to about 10, or about 4 to about 6, or about 4 to about 8, or about 5 to about 10, or about 5 to about 8 peptides. In embodiments, the copies of the peptide have sequences independently selected from SEQ ID NOs: 187-233. In embodiments, one or more copies of the peptide (without limitation, e.g., all copies) are fused with a carrier moiety. In embodiments, the carrier moiety is a half-life extending carrier moiety. In embodiments, the carrier moiety is a polymer. In embodiments, the polymer is PEG of any of the embodiments disclosed herein.

[0337] In embodiments, the carrier moiety is a carrier protein selected from an Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant

[0338] DB1 / 167593545.6 63Atorney Docket No. CVL-001PC / 140489-5001

[0339] thereof. In embodiments, the peptide is conjugated with an Fc domain to form a peptibody (z.e., a peptide-Fc fusion) or a bi-peptibody. In embodiments, the therapeutic nucleic acid payload is conjugated with at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the peptibody. In embodiments, copies of the peptibody independently comprise an N-terminal fusion of the peptide with an Fc domain (e.g., fused at the C-terminus of a signal sequence, if any), a C-terminal fusion of the peptide with an Fc domain, a peptide insertion within an Fc domain or a combination thereof. In embodiments, the copies of the peptibody independently comprise at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the peptide. In embodiments, the peptides are fused in tandem. In embodiments, the peptides are fused in tandem via a flexible linker (e.g., a Gly and Ser rich flexible linker), at one, or two, or three, or more locations within the Fc domain. In embodiments, the copies of the peptibody independently comprise peptides binds same or different domains or epitopes of plgR. In embodiments, the peptides bind same or different domains or epitopes of plgR. In embodiments, the peptides independently bind to one or more of extracellular domains DI, D2, D3, D4, D5, and the cleavage domain (also known as D6) of plgR. In embodiments, at least one of the peptides binds to the cleavage domain of plgR. In embodiments, at least one of the peptides binds at or near the J chain binding site for plgR of immunoglobulin A (IgA) or IgM. In embodiments, at least one of the peptides binds reduces or inhibits cleavage of extracellular domain D6 of plgR. In embodiments, at least one of the peptides binds to plgR in a competitive manner with IgA and / or IgM. In embodiments, at least one of the peptides binds to plgR with higher affinity than IgA or IgM binds to plgR.

[0340] In embodiments, the peptide comprises an amino acid sequence provided in Table 3, wherein the peptide is in an antibody format peptide-His. In embodiments, the peptide comprises an amino acid sequence provided in Table 3, wherein the peptide is in an antibody format peptide-Fc. In embodiments, the peptide comprises an amino acid sequence provided in Table 3, wherein the peptide is a tetravalent molecule (e.g., a tetravalent peptide-peptide-Fc). In embodiments, the tetravalent molecule is monospecific, bispecific, trispecific or tetraspecific. In embodiments, the peptide comprises an amino acid sequence provided in Table 3, wherein the peptide comprises or further comprises a moiety that facilitates conjugation of the peptide to an siRNA. In embodiments, the peptide comprises an amino acid sequence provided in Table 3, wherein the peptide comprises or further comprises a SLPETG (SEQ ID NO: 235) peptide tag (e.g., G4SLPETG (SEQ ID NO:

[0341] DB1 / 167593545.6 64Atorney Docket No. CVL-001PC / 140489-5001

[0342] 236) or G5SLPETG (SEQ ID NO: 237)) to facilitate conjugation using sortase A (SrtA) enzymes. In embodiments, the peptide comprises an amino acid sequence provided in Table 3, wherein the peptide comprises or further comprises a cysteine to facilitate thiol-maleimide conjugation. In embodiments, the peptide comprises an amino acid sequence provided in Table 3, wherein the peptide comprises or further comprises one or more unpaired cysteine residues to facilitate thiol- maleimide conjugation. In embodiments, the peptide comprises an amino acid sequence provided in Table 3, wherein the peptide comprises or further comprises natural or engineered glycosylation sites (e.g., N297 on IgG Fc domain) to facilitate glycosite-specific conjugation using technologies like glycan oxidation, enzymatic labeling (GalT Y289L), or click chemistry, which avoids antibody functional impairment. In embodiments, the peptide comprises an amino acid sequence provided in Table 3, wherein the peptide comprises or further comprises one or more lysine residues to facilitate NHS-esters or isothiocyanate conjugation. In embodiments, the peptide comprises an amino acid sequence provided in Table 3, wherein the peptide comprises or further comprises one or more glutamine residues to facilitate transglutaminase-mediated conjugation. In embodiments, the carrier moiety is a polymer. In embodiments, the polymer is polyethylene glycol (PEG). In embodiments, one or more amino acids present in the plgR binder are PEGylated. In embodiments, no amino acids present in the plgR binder is PEGylated. In embodiments, N- and / or C- terminal extensions are added to the plgR binder for PEGylation. In embodiments, one or more amino acids that are added at the N- or C-terminus of the plgR binder are PEGylated. In embodiments, N- and / or C- terminal extensions comprising one or more amino acids selected from lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine and tyrosine are added to the plgR binder for PEGylation. In embodiments, one or more amino acids present in the plgR binder or added in N- and / or C-terminal extension and selected from lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine and tyrosine are PEGylated using a technique known in the art, e.g., via chemical or enzymatic conjugation. In embodiments, one or more cysteine (Cys of C) residues present in the plgR binder or added in N- and / or C-terminal extension are PEGylated using a technique known in the art, e.g., via thiol conjugation. In embodiments, one or more are lysine (Lys or K) residues present in the plgR binder or added in N- and / or C-terminal extension are PEGylated using a technique known in the art, e.g., via amine conjugation. In embodiments, one or more are glutamine (Gin or Q) residues present in the plgR

[0343] DB1 / 167593545.6 65Atorney Docket No. CVL-001PC / 140489-5001

[0344] binder or added in N- and / or C-terminal extension are PEGylated using a technique known in the art, e.g., via transglutaminase (TGase) mediated enzymatic conjugation.

[0345] In embodiments, the plgR binder comprises or further comprises is a lipid moiety. In embodiments, carboxyl group of the lipid and an amine group of present in the plgR binder are coupled to form an amide bond via chemical conjugation using methods known in the art, such as a carbodiimide- coupling method. In embodiments, a thiol group present in the plgR binder and an amine group that are present in the lipid, or a thiol group present in the lipid and an amine group that are present in the plgR binder are coupled using methods known in the art, such as a maleimide -coupling method. In embodiments derivatized plgR binder and the lipid, one having an azide group and the other having a triphosphine grouping are coupled using methods known in the art, such as a Staudinger ligation method.

[0346] In embodiments, the plgR binder of any of the embodiments disclosed herein is conjugated with at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the therapeutic nucleic acid payload. In embodiments, the plgR binder is conjugated with about 1 to about 10, or about 1 to about 5, or about 1 to about 3, of about 2 to about 10, or about 2 to about 7, or about 2 to about 5, or about 3 to about 10, of about 3 to about 5, or about 3 to about 8, or about 4 to about 10, or about 4 to about 6, or about 4 to about 8, or about 5 to about 10, or about 5 to about 8 copies of the therapeutic nucleic acid payload. In embodiments, the copies of the therapeutic nucleic acid payload are independently selected from siRNA, miRNA, anti-miRNA, ASO, phosphorodiamidate PMO, tRNA, PNA, LNA, RNA aptamer, DNA aptamer, ribozyme, circRNA, RNA decoy, saRNA, and mRNA. In embodiments, at least one of the copies of the therapeutic nucleic acid payload is an siRNA or an ASO. In embodiments, all copies of the therapeutic nucleic acid payload are siRNA or ASO. In embodiments, the copies of siRNA or ASO have same or different sequences.

[0347] In embodiments, the composition or the delivery system comprises at least 2, or at least 3, or at least 4 or more antibodies, antibody-like molecules or plgR binding fragments thereof per copy of the therapeutic nucleic acid payload. In embodiments, the antibodies are monoclonal antibodies, or polyclonal antibodies or plgR binding fragments thereof; and / or the antibody-like molecule is selected from a recombinant heavy-chain-only antibody (VHH), single-domain antibody, singlechain antibody (scFv), shark heavy-chain-only antibody (VNAR), microprotein (cysteine knot

[0348] DB1 / 167593545.6 66Atorney Docket No. CVL-001PC / 140489-5001

[0349] protein, knottin), DARPin, Tetranectin, Afftbody, Affitin, Alphabody, Gastrobody, Monobody, nanoCLAMP, Optimer, Repebody, fibronectin domain-derived antibody mimic, Centyrin, Obody, Transbody, Anticalin, AdNectin, Affilin, Afftmer, Microbody, aptamer, alterase, plastic antibody, phylomer, stradobody, maxibody, evibody, fynomer, armadillo repeat protein, Kunitz domain, avimer, atrimer, probody, immunobody, triomab, troybody, pepbody, vaccibody, UniBody, DuoBody, Fv, Fab, Fab', and F(ab')2, or a plgR binding fragment thereof. In embodiments, the antibodies, antibody-like molecules or plgR binding fragments thereof bind same or different domains or epitopes of plgR. In embodiments, the antibodies, antibody-like molecules or plgR binding fragments thereof independently bind to one or more of extracellular domains DI, D2, D3, D4, D5, and the cleavage domain (also known as D6) of plgR. In embodiments, at least one of the antibodies, antibody-like molecules or plgR binding fragments thereof binds to the cleavage domain of plgR. In embodiments, at least one of the antibodies, antibody-like molecules or plgR binding fragments thereof binds at or near the J chain binding site for plgR of immunoglobulin A (IgA) or IgM. In embodiments, at least one of the antibodies, antibody-like molecules or plgR binding fragments thereof binds reduces or inhibits cleavage of extracellular domain D6 of plgR. In embodiments, at least one of the antibodies, antibody-like molecules or plgR binding fragments thereof binds to plgR in a competitive manner with IgA and / or IgM. In embodiments, at least one of the antibodies, antibody-like molecules or plgR binding fragments thereof binds to plgR with higher affinity than IgA or IgM binds to plgR.

[0350] The Therapeutic Nucleic Acid Payload

[0351] In aspects, the present disclosure provides a therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) that is delivered to epithelial cells by the virtue of its conjugation with a plgR binder and promoting the internalization of the conjugate in epithelial cells via the plgR- mediated internalization. In embodiments, the internalized conjugate is then diverted to the intracellular environment (rather than transcytosis).

[0352] In embodiments, the therapeutic payload is a macromolecule. In embodiments, the therapeutic payload is a nucleic acid, a protein, a peptide, an antibody and a polysaccharide, or a combination thereof. In embodiments, the therapeutic payload is a nucleic acid therapeutic payload.

[0353] In embodiments, the therapeutic nucleic acid payload comprises at least one chemically modified nucleotide. In embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at

[0354] DB1 / 167593545.6 67Atorney Docket No. CVL-001PC / 140489-5001

[0355] least 6, or at least 7, or at least 8, or at least 9, or at least 10, or at least 11 , or at least 12, or at least 13, or at least 14, or at least 15, or at least 16, or at least 17, or at least 18 or more nucleotides of the therapeutic nucleic acid payload are chemically modified nucleotides. In embodiments, at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or more nucleotides of the therapeutic nucleic acid payload are chemically modified nucleotides. In embodiments, all or substantially all of the nucleotides of the sense strand and / or all or substantially all of the nucleotides of the antisense strand are modified nucleotides.

[0356] In embodiments, the chemically modified nucleotide is selected from a deoxy -nucleotide, a d'terminal deoxy-thymine (dT) nucleotide, a 2' O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'- amino-modified nucleotide, a 2'-O-allyl-modified nucleotide, 2'-C-alkyl-modified nucleotide, 2'- hydroxyl-modified nucleotide, a 2 '-methoxy ethyl modified nucleotide, a 2’-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural nucleobase comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5 '-phosphate, a nucleotide comprising a 5'-phosphate mimic, a glycol modified nucleotide, and a 2-O-(N-methylacetamide) modified nucleotide, and a combination any two or more thereof.

[0357] In embodiments, the modified nucleotide is selected from a 2 '-deoxy -2 '-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, 3 '-terminal deoxythimidine nucleotides (dT), a locked nucleotide, an abasic nucleotide, a 2'-amino-modified nucleotide, a 2'-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, and a non-natural nucleobase comprising nucleotide. In embodiments, the modified nucleotide comprises a short sequence of 3 '-terminal deoxythimidine nucleotides (dT).

[0358] In embodiments, the therapeutic nucleic acid payload comprises or further comprises at least one phosphorothioate intemucleotide linkage. In embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 7, or at least 8, or at least 9, or at least 10, or at least 11, or at least 12, or at least 13, or at least 14, or at least 15, or at least 16, or at least 17, or at least

[0359] DB1 / 167593545.6 68Attorney Docket No. CVL-001PC / 140489-5001

[0360] 18 or more phosphorothioate intemucleotide linkages. In embodiments, at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or more of the internucleotide linkages are phosphorothioate internucleotide linkages. In embodiments, all or substantially all of the nucleotides of the sense strand and all of the internucleotide linkages are phosphorothioate intemucleotide linkages.

[0361] In embodiments, the therapeutic nucleic acid payload is or comprises one or more of small interfering RNA (siRNA), microRNA (miRNA), anti-miRNA, antisense oligonucleotide (ASO), phosphorodiamidate morpholino oligomer (PMO, e.g., an exon skipping PMO), tRNA, peptide nucleic acid (PNA), locked nucleic acid (LNA), RNA aptamer, DNA aptamer, ribozyme, circular RNA (circRNA), RNA decoy, small activating RNA (saRNA), and messenger RNA (mRNA). In embodiments, the therapeutic nucleic acid payload or the plurality of nucleic acid payloads comprises at least one inhibitory nucleic acid, and wherein the at least one inhibitory nucleic acid is capable of greater silencing of a target gene to compared to a control composition lacking the plgR binder, as measured by levels of a protein encoded by the target gene and mRNA of the target gene.

[0362] In embodiments, the therapeutic nucleic acid payload is an siRNA. Table 4 provides illustrative, non-limiting siRNA sequences that form the therapeutic nucleic acid payloads.

[0363] Table 4: Sequences of Illustrative Non-limiting siRNA Sequences of the Present Disclosure Target Sense Strand Sequence Antisense Strand Sequence Activator of Hsp90 GGAUGAAGUGGAGAUUAGUdTs ACUAAUCUCCACUUCAUCCdTs ATPase 1 (AHA1) dT (SEQ ID NO: 125) dT (SEQ ID NO: 126)

[0364] AUAUCAUGGCCGACAAGCAdTs

[0365] Green Fluorescent UGCUUGUCGGCCAUGAUAUdTs dT

[0366] Protein (GFP) dT (SEQ ID NO: 128)

[0367] (SEQ ID NO: 127)

[0368] CAUUUUAAUCCUCACUCUAAA

[0369] Superoxide UUUAGAGUGAGGAUUAAAAU dTsdT

[0370] Dismutase (SOD1) GAGdTsdT (SEQ ID NO: 130)

[0371] (SEQ ID NO: 129)

[0372] Non-targeting AUGUAUUGGCCUGUAUUAGdTs CUAAUACAGGCCAAUACAUdTs Control dT dT (SEQ ID NO: 132)

[0373]

[0374] DBl / 167593545.6 69Atorney Docket No. CVL-001PC / 140489-5001

[0375] (SEQ ID NO: 131)

[0376]

[0377] s = phosphorothioate; dT = deoxy thymidine, dTsdT = a motif of 3’ unpaired deoxy thymidine- phosphorothioate-deoxy thymidine.

[0378] In embodiments, the therapeutic nucleic acid payload comprises nucleotide sequences provided in Table 4. In embodiments, the therapeutic nucleic acid payload comprises siRNA comprising a sense strand and an antisense strand. In embodiments, the therapeutic nucleic acid payload comprises siRNA comprising a sense strand and an antisense strand comprising nucleotide sequences provided in Table 4. In embodiments, the therapeutic nucleic acid payload comprises siRNA comprising a chemically modified version of a sense strand (“chemically modified sense strand,” z.e., harboring at least one chemically modified nucleotide of any of the embodiments disclosed herein infra and supra) and / or chemically modified version of an antisense strand (“chemically modified antisense strand,” i.e., harboring at least one chemically modified nucleotide of any of the embodiments disclosed herein infra and supra) comprising nucleotide sequences provided in Table 4. In embodiments, the chemically modified sense strand and / or the chemically modified antisense strand comprise one or more chemical modifications selected from 5 ’-phosphate modifications, internal intemucleotide linkage modifications, ribose modifications and nucleobase modifications. In embodiments, the chemically modified sense strand and / or the chemically modified antisense strand comprise internal internucleotide linkage modifications independently selected from phosphorothioate (e.g., Rp isomer, Sp isomer or a combination thereof), phosphorodithioate, methylphosphonate, phosphotriester, phosphoramidate, methoxypropylphosphonate, and a combination thereof. In embodiments, the chemically modified sense strand and / or the chemically modified antisense strand comprise 5’-phosphate modifications independently selected from 5”-(E)-vinylphosphonate, 5 ’-methyl phosphonate, (s)-5’-C-methyl with phosphate, 5 ’-phosphorothioate, and a peptide nucleic acid (PNA). In embodiments, the chemically modified sense strand and / or the chemically modified antisense strand comprise ribose modifications independently selected from 2’-O-methyl (2’-0Me), 2’-O-methoxyethyl (2’-O- MOE), 2’-deoxy-2’-fluoro (2’-F), 2’-arabino-fluoro (2’-Ara-F), 2’-O-benzyl, 2’-O-methyl-4- pyridine (2’-O-CH2Py(4)), Locked Nucleic Acid (LNA), (S)-cEt-BNA, Tricyclo-DNA,(tcDNA), PMO, Unlocked Nucleic Acid (UNA), Glycol Nucleic Acid (GNA), and a combination thereof. In embodiments, the chemically modified sense strand and / or the chemically modified antisense strand comprise nucleobase modifications independently selected from pseudouridine (y), 2’- DBl / 167593545.6 70Atorney Docket No. CVL-001PC / 140489-5001

[0379] thiouridine (s2U), N6’-methyladenosine (m6A), 5 ’-methyl cytidine (m5C), 5’-fluoro- 2’ deoxyuridine, N-ethylpiperidine 7’-EAA triazole modified adenine, N-ethylpiperidine 6’- triazole modified adenine, 6’-phenylpyrrolocytosine (PhpC), 2’,4’-difluorotoluyl ribonucleoside (rF), 5 ’-nitroindole, and a combination any two or more thereof.

[0380] In embodiments, the chemically modified sense strand and / or the chemically modified antisense strand independently comprise at least about 2, or at least about 4, or at least about 6, or at least about 8, or at least about 10, or at least about 12, or at least about 14, or at least about 16, or at least about 18, or at least about 20, or more 2’-0Me modifications. In embodiments, the chemically modified sense strand and / or the chemically modified antisense strand are fully modified with 2’- OMe modifications. In embodiments, the chemically modified sense strand and the chemically modified antisense strand are fully modified with 2’-OMe modifications. In embodiments, the chemically modified sense strand and / or the chemically modified antisense strand independently comprise at least about 2, or at least about 4, or at least about 6, or at least about 8, or at least about 10, or at least about 12, or at least about 14, or at least about 16, or at least about 18, or at least about 20, or more 2’-F modifications. In embodiments, the chemically modified sense strand and / or the chemically modified antisense strand are fully modified with 2’-F modifications. In embodiments, the chemically modified sense strand and the chemically modified antisense strand are fully modified with 2’-F modifications. In embodiments, the chemically modified sense strand and / or the chemically modified antisense strand independently comprise at least about 2, or at least about 4, or at least about 6, or at least about 8, or at least about 10, or at least about 12, or at least about 14, or at least about 16, or at least about 18, or at least about 20, or more 2’-deoxythymidine (dT) modifications. In embodiments, the chemically modified sense strand and / or the chemically modified antisense strand are fully modified with 2’ -deoxythymidine (dT) modifications. In embodiments, the chemically modified sense strand and the chemically modified antisense strand are fully modified with 2 ’-deoxy thy mi dine (dT) modifications.

[0381] In embodiments, the siRNA comprises a sense strand represented by the formula:

[0382] 5 ’ -nP-Na-(X-X-X)1-Nb- Y-Y- Y-Nb-(Z-Z-Z)j-Na-nq-3 ’ ; and an antisense strand represented by the formula:

[0383] 3’-np’-Na’-(X’-X’-X’)k-Nb’-Y’-Y’-Y’-Nb’-(Z’Z’Z’)i-Na’-nq’-5’.

[0384] DB1 / 167593545.6 71Atorney Docket No. CVL-001PC / 140489-5001

[0385] In embodiments, i, j, k, and 1 are each independently 0 or 1. Tn embodiments, p, p’, q, and q’ are each independently 0-6. In embodiments, each of Na and each Na’ independently represents an oligonucleotide sequence comprising 0 to about 25 nucleotides. In embodiments, each of Na and each Na’ independently comprise about 2 to about 20 modified nucleotides. In embodiments, each of the sense strand and antisense strand comprises at least two differently modified nucleotides. In embodiments, the at least two differently modified nucleotides that are present in each of the sense strand and anti-sense strand are independently selected from 2’-O-methyl, 2’-fluoro, and 2’- deoxythymidine (dT). In embodiments, each Nb and each Nb’ independently represents an oligonucleotide sequence comprising 0 to about 10 nucleotides. In embodiments, each of Nb and each Nb’ independently comprise about 1 to about 10 modified nucleotides In embodiments, each of Nb and each Nb’ independently comprise modified nucleotides selected from 2’-O-methyl, 2’- fluoro, and 2’ -deoxythymidine (dT). In embodiments, the siRNA comprises at least one phosphorothioate or methylphosphonate internucleotide linkage. In embodiments, each of the nP, nP’, nq, and nq’ are independently present or absent. In embodiments, each of the nP, nP’, nq, and / or nq’ represents an overhang nucleotide. In embodiments, each of X-X-X, Y-Y-Y, Z-Z-Z, X’-X’-X’, Y’-Y’-Y’, and Z’-Z’-Z’ independently represent motifs of three identical nucleotide modifications on three consecutive nucleotides. In embodiments, X-X-X is complementary to X’-X’-X’. In embodiments, Y-Y-Y is complementary to Y’-Y’-Y’. In embodiments, and Z-Z-Z is complementary to Z’-Z’-Z’. In embodiments, the sense strand is conjugated to one or more antibodies or antibody-like molecules capable of binding plgR of any of the embodiments disclosed herein.

[0386] In embodiments, the siRNA comprises a sense strand represented by the formula:

[0387] 5’-nP-Na-Y-Y-Y-Na-nq-3’; and

[0388] an antisense strand represented by the formula:

[0389] 3 ’ -nP’ -Na’ - Y’ - Y’ - Y’ -Na’ -nq’ -5 ’ .

[0390] In embodiments, each of the nP, nP’, nq, and nq’ are independently present or absent. In embodiments, one of the nP, nP’, nq, and / or nq’ represents an overhang nucleotide. In embodiments, p, p’ q, and q’ are each independently 0-6. In embodiments, nP’>0 and at least one nP’ is linked to a neighboring nucleotide via a phosphorothioate linkage In embodiments, each Naand each Na’ independently represents an oligonucleotide sequence comprising 0 to about 25 nucleotides. In DB1 / 167593545.6 72Atorney Docket No. CVL-001PC / 140489-5001

[0391] embodiments, each Na and each Na’ independently about 2 to about 20 modified nucleotides In embodiments, each Na and each Na’ independently the modified nucleotides are each independently selected from 2’-O-methyl, 2’-fluoro, and 2’ -deoxythymidine (dT). In embodiments, Y-Y-Y and Y’-Y’-Y’ represent one motif independently of three identical modifications on three consecutive nucleotides. In embodiments, the modifications are 2’-O- methyl or 2’-fluoro modifications. In embodiments, Y-Y-Y is complementary to Y’-Y’-Y’. In embodiments, the sense strand comprises at least one phosphorothioate linkage. In embodiments, the sense strand is conjugated to one or more antibodies or antibody-like molecules capable of binding plgR of any of the embodiments disclosed herein.

[0392] In embodiments, the siRNA comprises a sense strand and an antisense strand. In embodiments, the siRNA comprises at least one modified nucleotide selected from 2’-O-methyl, 2’-fluoro, and 2’ -deoxythymidine (dT). In embodiments, the antisense strand comprises two phosphorothioate internucleotide linkages between the 3 ’-end three terminal nucleotides and two phosphorothioate internucleotide linkages between the 5’ end three terminal nucleotides. In embodiments, the sense strand comprises two phosphorothioate internucleotide linkages between the 5’ end three terminal nucleotides. In embodiments, the sense strand is conjugated to one or more antibodies or antibodylike molecules capable of binding plgR of any of the embodiments disclosed herein.

[0393] In embodiments, the siRNA comprises a sense strand and an antisense strand. In embodiments, at least one nucleotide of the antisense strand is a modified nucleotide; and at least one nucleotide of the sense strand is a modified nucleotide. In embodiments, each nucleotide of the antisense and sense strands is a modified nucleotide. In embodiments, the modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a 5 '-terminal modified phosphate group. In embodiments, the modified nucleotide comprising a modified sugar moiety is selected from a 2'-fluoro nucleotide, a 2'-O-methyl nucleotide, a 2'-O-methoxyethyl nucleotide, and a bicyclic sugar nucleotide. In embodiments, the first one, or the first two, or the first three, or the first four, or the first five, or the first six or more internucleotide linkages at the 5' terminus of the sense strand are phosphorothioate internucleotide linkages. In embodiments, the last one, or the last two, or the last three, or the last four, or the last five, or the last six or more internucleotide linkages at the 3' terminus of the sense strand are phosphorothioate intemucleotide linkages. In embodiments, the first one, or the first two, or the first three, or the first four, or the first five, or the first six or more internucleotide linkages at the 5' terminus of the antisense strand are DBl / 167593545.6 73Atorney Docket No. CVL-001PC / 140489-5001

[0394] phosphorothioate internucleotide linkages. Tn embodiments, the last one, or the last two, or the last three, or the last four, or the last five, or the last six or more internucleotide linkages at the 3' terminus of the antisense strand are phosphorothioate intemucleotide linkages. In embodiments, the first two intemucleotide linkages at the 5' terminus of the sense strand and the last two internucleotide linkages at the 3' terminus of the sense strand are phosphorothioate intemucleotide linkages; and / or the first two intemucleotide linkages at the 5' terminus of the antisense strand and the last two intemucleotide linkages at the 3 ' terminus of the antisense strand are phosphorothioate intemucleotide linkages. In embodiments, the first two intemucleotide linkages at the 5' terminus of the sense strand and the last two intemucleotide linkages at the 3' terminus of the sense strand are phosphorothioate intemucleotide linkages; and the first two intemucleotide linkages at the 5' terminus of the antisense strand and the last two intemucleotide linkages at the 3' terminus of the antisense strand are phosphorothioate intemucleotide linkages. In embodiments, the 5'-terminal modified phosphate group is a 5'-(E)-vinylphosphonate. In embodiments, the siRNA comprises a combination of two of the modified sugar moieties at defined pattens. Illustrative modifications and their patterns are disclosed in US Patent Application Publication Nos. US20170275626, US20160017335, and US20240360447, which are herein incorporated by reference in their entirety.

[0395] In embodiments, the siRNA has the following structure:

[0396] / L — R1\

[0397] [ A-) — f— L3— L4— C R3

[0398] \ I /

[0399]

[0400] \ L6— R2' / t

[0401] In embodiments, A is the antisense strand and / or the sense strand of the siRNA. In embodiments, t is an integer from 1 to 5. In embodiments, L3and L4are independently selected from a bond, - N(R4)-, -O-, -S-, -C(O)-, -N(R4)C(O)-, -C(O)N(R5)-, -N(R4)C(O)N(R5)-, -C(O)O-, -OC(O)-, - N(R4)C(O)O-, -OC(O)N(R5)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R6)-O-, -O-P(S)(R6)-O-, -O- P(O)(NR4R5)-N-, -O-P(S)(NR4R5)-N-, -O-P(O)(NR4R5)-O-, -O-P(S)(NR4R5)-O-, -P(O)(NR4R5)- N-, -P(S)(NR4R5)-N-, -P(O)(NR4R5)-O-, -P(S)(NR4R3)-O-, -S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or

[0402] DB1 / 167593545.6 74Atorney Docket No. CVL-001PC / 140489-5001

[0403] substituted or unsubstituted heteroarylene. In embodiments, each R4, R3and R6is independently hydrogen or unsubstituted Ci-Cio alkyl. In embodiments, L5is -L3A-L5B-L5C-L5D-L5E-. In embodiments, L6is -L6A-L6B-L6C-L6D-L6E. In embodiments, L5A, L5B, L3C, L5D, L5E, L6A, L6B, L6C,6D, and L6Eare independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O- , -OC(O)-, -C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. In embodiments, R1, R2, and R3are independently the plgR-binding plgR binder capable of any of the embodiments disclosed herein.

[0404] In embodiments, the chemically modified sense strand comprises a 2’-0Me modification at positions 1-6, 8, and 12-21 and a 2’-F modification at positions 7 and 9-11 counted from 5’ end of the strand; and / or the chemically modified antisense strand comprises 2’-OMe modifications at positions 1, 3-5, 7, 10-13, 15, and 17-23, and a 2’-F modification at positions 2, 6, 8-9, 14 and 16 counted from 5’ end of the strand. In embodiments, the chemically modified sense strand comprises a 2’-0Me modification at positions 1-6, 8, and 12-21 and a 2’-F modification at positions 7 and 9-11 counted from 5’ end of the strand; and the chemically modified antisense strand comprises 2’-0Me modifications at positions 1, 3-5, 7, 10-13, 15, and 17-23, and a 2’-F modification at positions 2, 6, 8-9, 14 and 16 counted from 5’ end of the strand. In embodiments, the chemically modified sense strand comprises a 2’-0Me modification at positions 1-6, 8, and 12-21 and a 2’-F modification at positions 7 and 9-11 counted from 5’ end of the strand; and / or the chemically modified antisense strand comprises 2’-0Me modifications at positions 1, 3-5, 7- 13, 15, and 17-23, and a 2’-F modification at positions 2, 6, 14 and 16 counted from 5’ end of the strand. In embodiments, the chemically modified sense strand comprises a 2’-OMe modification at positions 1-6, 8, and 12-21 and a 2’-F modification at positions 7 and 9-11 counted from 5’ end of the strand; and the chemically modified antisense strand comprises 2’-OMe modifications at positions 1, 3-5, 7-13, 15, and 17-23, and a 2’-F modification at positions 2, 6, 14 and 16 counted from 5’ end of the strand. Illustrative modifications and their patterns are disclosed in Hu et al., Therapeutic siRNA: state of the art, Signal Transduction and Targeted Therapy 5: 101 (2020). Illustrative modifications and their patterns are disclosed in US Patent Application Publication Nos. US20170275626, US20160017335, and US20240360447, which is herein incorporated by reference in its entirety.

[0405] DB1 / 167593545.6 75Atorney Docket No. CVL-001PC / 140489-5001

[0406] In embodiments, the therapeutic nucleic acid payload comprises siRNA comprising a sense strand comprising a nucleotide sequence of SEQ ID NO: 125, or a chemically modified derivative thereof according to any of the embodiments disclosed herein, and an antisense strand comprising a nucleotide sequence of SEQ ID NO: 126, or a chemically modified derivative thereof according to any of the embodiments disclosed herein. In embodiments, the therapeutic nucleic acid payload comprises siRNA comprising a sense strand comprising a nucleotide sequence of SEQ ID NO: 127, or a chemically modified derivative thereof according to any of the embodiments disclosed herein, and an antisense strand comprising a nucleotide sequence of SEQ ID NO: 128, or a chemically modified derivative thereof according to any of the embodiments disclosed herein. In embodiments, the therapeutic nucleic acid payload comprises siRNA comprising a sense strand comprising a nucleotide sequence of SEQ ID NO: 129, or a chemically modified derivative thereof according to any of the embodiments disclosed herein, and an antisense strand comprising a nucleotide sequence of SEQ ID NO: 130, or a chemically modified derivative thereof according to any of the embodiments disclosed herein. In embodiments, the therapeutic nucleic acid payload comprises a non-targeting siRNA comprising a sense strand comprising a nucleotide sequence of SEQ ID NO: 131, or a chemically modified derivative thereof according to any of the embodiments disclosed herein, and an antisense strand comprising a nucleotide sequence of SEQ ID NO: 132, or a chemically modified derivative thereof according to any of the embodiments disclosed herein. In embodiments, the therapeutic nucleic acid payload comprises siRNA comprising a sense strand and an antisense strand comprising s provided in Table 4.

[0407] Table 5 provides illustrative, non-limiting siRNA modifications of SOD1 siRNA (SEQ ID NOs: 129 and 130)

[0408] Table 5: Illustrative Non-limiting siRNA Modifications of the present disclosure.

[0409] siRNA Modification Sense Strand Sequence Antisense Strand Sequence ESC c*a*uuu(C I 6u)AaUCCucacucua*a*a VPu*U*uag AgU GaggaUu A aaaug* a* g (SEQ ID NO: 133) (SEQ ID NO: 134) ESC+ c,a*uuu(C16u)AaUCCucacucua,a*a VPu’U^uagaGugaggaUuAaaaug’a^g (SEQ ID NO: 135) (SEQ ID NO: 136) Partially modified c,cz*uuu(C 16u)aauccuazcucua*a*a VPu* u*uagagugaggauuaaacmg* a»g (SEQ ID NO: 137) (SEQ ID NO: 138)

[0410]

[0411] DBl / 167593545.6 76Attorney Docket No. CVL-001PC / 140489-5001

[0412] no C16 c*a*uuuuAaUCCucacucua*a*a VPu*U*uag AgU GaggaUu Aaaaug* a* g (SEQ ID NO: 139) (SEQ ID NO: 140) no VP c* a*uuu(C 16u) AaUCCucacucua* a* a u*U*uagAgUGaggaUuAaaaug*a*g (SEQ ID NO: 141) (SEQ ID NO: 142) no C16 / no VP c*a*uuuuAaUCCucacucua*a*a u*U *uag AgU GaggaUu Aaaaug* a*g (SEQ ID NO: 143) (SEQ ID NO: 144)

[0413]

[0414] Upper-case and lower-case letters indicate 2’-deoxy-2’-fluoro (2’-F) and 2’-O-methyl (2’-0Me) sugar modifications, respectively; italicized lower-case letters indicate 2’ -hydroxyl (RNA) nucleotides; • indicate phosphorothioate (PS) linkage; (C 16u) indicate 2’-O-C16 ligand conjugated uracil nucleotide (see structure below); VP indicate 5 ’ -(E)-vinylphosphonate (see structure below). In embodiments, the therapeutic nucleic acid payload comprises a 2’-O-C16 ligand conjugated a nucleotide having the following structure:

[0415]

[0416] In embodiment, the therapeutic nucleic acid payload comprises one or more of the antibodies or antibody-like molecules that are conjugated to the side chain of 2’-O-C 16.

[0417] In embodiments, the therapeutic nucleic acid payload comprises a 5’-(E)-vinylphosphonate, which has the following structure:

[0418] O~

[0419] o=p-o"

[0420]

[0421] h

[0422] In embodiments, the therapeutic nucleic acid payload comprises siRNA comprising a sense strand comprising a nucleotide sequence of SEQ ID NO: 125, or a chemically modified derivative thereof according to any of the embodiments disclosed herein, and an antisense strand comprising a

[0423] DBl / 167593545.6 77Atorney Docket No. CVL-001PC / 140489-5001

[0424] nucleotide sequence of SEQ ID NO: 126, or a chemically modified derivative thereof according to any of the embodiments disclosed herein.

[0425] In embodiments, the therapeutic nucleic acid payload comprises siRNA disclosed in Table 6. Table 6: Illustrative Non-limiting Modified siRNA Used for Testing.

[0426] Patent Terminology Sequence 5' --> 3'

[0427] AHSA1 siRNA sense uscsUfcGfuGfgCfcUfuAfaUfgAfaAfs(invdT) (SEQ ID NO: 238) strand

[0428] AHSA1 siRNA (vinu)sUfsuCfaUfuAfaGfgCfcAfcGfaGfasusu (SEQ ID NO: 239) antisense strand

[0429] Nomenclature (invdN): inverted deoxynucleotide

[0430] Nf: 2’-F residues

[0431] n: 2’-0Me residues

[0432] s: phosphorothioate backbone modification

[0433]

[0434] (vinu): 5’-vinylphosphonate-2’-O-methyl ribonucleotide

[0435] In embodiments, the therapeutic nucleic acid payload comprises siRNA comprising a sense strand comprising a nucleotide sequence of SEQ ID NO: 238, or a chemically modified derivative thereof according to any of the embodiments disclosed herein, and an antisense strand comprising a nucleotide sequence of SEQ ID NO: 239, or a chemically modified derivative thereof according to any of the embodiments disclosed herein.

[0436] In embodiments, the therapeutic nucleic acid payload comprises siRNA comprising a sense strand and an antisense strand comprising s provided in Table 4 that are modified as provided in Table 5. In embodiments, the therapeutic nucleic acid payload comprises siRNA comprising a sense strand and an antisense strand comprising s provided in Table 4 that are modified as provided in Table 5 or Table 6.

[0437] In embodiments, the therapeutic nucleic acid payload is an antisense oligonucleotide (ASO). Table 7 provides illustrative, non-limiting ASO sequences that form the therapeutic nucleic acid payloads.

[0438] Table 7: Sequences of Illustrative Non-limiting Antisense Oligonucleotide (ASO) Sequences of the Present Disclosure

[0439] Target Antisense Strand Sequence

[0440]

[0441] DBl / 167593545.6 78Attorney Docket No. CVL-001PC / 140489-5001

[0442] TCACACTAATCTC (SEQ ID NO: 145) TbsCbsdAsdCsdAsdCsdTsdAsdAsdTsCbsTbsCb (SEQ ID NO: 146) AHA1

[0443] wherein Ab, Cb, Gb and Tb = LNA, dA, dC, dG and dT = 2’-deoxy nucleotide, s = phosphorothioate linkage

[0444] GTCGCCCTTCAGCACGCACA (SEQ ID NO: 147)

[0445] SOD1

[0446] CCGTCGCCCTTCAGCACGCA (SEQ ID NO: 148)

[0447] GAGCTGCACGCTGCCGTC (SEQ ID NO: 149)

[0448] GFP TTGCCGGTGGTGCAGATAAA (SEQ ID NO: 150)

[0449]

[0450] In embodiments, the therapeutic nucleic acid payload comprises a nucleotide sequence provided in Table 7. In embodiments, the therapeutic nucleic acid payload comprises a chemically modified ASO, which is a chemically modified version of a nucleotide sequence provided in Table 7 (i.e., harboring at least one chemically modified nucleotide of any of the embodiments disclosed herein infra and supra).

[0451] In embodiments, the chemically modified ASO comprises one or more chemical modifications selected from intemucleotide linkage modifications, ribose modifications and nucleobase modifications. In embodiments, the chemically modified ASO comprises intemucleotide linkage modifications independently selected from phosphorothioate (e.g., Rp isomer, Sp isomer or a combination thereof), phosphorodithioate, methylphosphonate, methoxypropylphosphonate, phosphotriester, phosphoramidate, and a combination thereof. In embodiments, the chemically modified ASO comprises at least one, or at least about 2, or at least about 4, or at least about 6, or at least about 8, or at least about 10, or at least about 12, or at least about 15, or at least about 18, or at least about 20 phosphorothioate intemucleotide linkages. In embodiments, the chemically modified ASO comprises all phosphorothioate intemucleotide linkages. In embodiments, the chemically modified ASO comprises ribose modifications that, e.g., include addition of substitutent groups (including 5’ and 2’ substituent groups, bridging of non-geminal ring atoms to form bicyclic nucleic acids (BNA), replacement of the ribosyl ring oxygen atom with S, N(R), or

[0452] DB1 / 167593545.6 79Atorney Docket No. CVL-001PC / 140489-5001

[0453] C(RI)(R.2) (illustrative R, Ri and R2 are each independently selected from H, C1-C12 alkyl or a protecting group) and combinations thereof. In embodiments, the chemically modified ASO comprises ribose modifications independently selected from modified sugar moieties comprising 5’-vinyl, 5’-methyl (R or S), 4-S, 2’-F, 2’-OCH3, 2’-OCH2CH3, 2’-OCH2CH2F and 2’- O(CH2)2OCH3substituent groups. In embodiments, the bicyclic nucleic acids (BNA) comprise a bridge between the 4’ and the 2’ ribosyl ring atoms. In embodiments, the 4’ to 2’ bridged bicyclic nucleosides have a formula selected from 4’-(CH2)-O-2’ (LNA); 4’-(CH2)-S-2’; 4’-(CH2)2-O-2’ (ENA); 4’-CH(CH3)-O-2’ and 4’-CH(CH2OCH3)-O-2’; 4’-C(CH3)(CH3)-O-2’; 4’-CH2-N(OCH3)- 2’; 4’-CH2-O-N(CH3)-2’; 4’-CH2-N(R)-O-2’, wherein R is H, C1-C12 alkyl, or a protecting group; 4’-CH2-C(H)(CH3)-2’; and 4’-CH2-C-(=CH2)-2’. In embodiments, the chemically modified ASO comprises ribose modifications comprising a substitution at the 2’ position other than OH. In embodiments, the substitution at the 2’ position is selected from H (deoxy), allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3, O-(CH2)2O-CH3, 2’-O(CH2)2SCH3, O-(CH2)2-O-N(Rm)(Rn), or O-CH2-C(=O)-N(Rm)(Rn), where each Ri, Rmand Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl, and a combination thereof. In embodiments, the chemically modified ASO comprises ribose modifications comprising a substitution at the 2’ position selected from 2’- Floro (2’-F), 2’-0me (z.c., 2’-OCH3, or 2’-O-methyl, 2’-0me), 2’-M0E” (z.e., 2’-O-methoxyethyl or 2’-OCH2CH2OCH3). Illustrative modifications and their patterns are disclosed in US Patent Application Publication Nos. US20100197762, US20170175116, US20170182084 and US20220064636, which are herein incorporated by reference in their entirety.

[0454] In embodiments, the chemically modified ASO comprises ribose modification comprising has a 2'-deoxynucleoside modification. In embodiments, the 2'-modification is selected from 2'-fluoro, 2 '-deoxy-2 '-fluoro, 2'-O-methyl, 2'-O-methoxyethyl (2'-0-M0E), 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-0-DMA0E), 2'-O-dimethylaminopropyl (2'-O-DMAP), 2'-O- dimethylaminoethyloxyethyl (2'-O-DMAEOE), and 2'-O-N-methylacetamido (2'-0-NMA). In embodiments, the 2 '-modification is 2'-O-methoxyethyl (2'-0-M0E).

[0455] In embodiments, the chemically modified ASO comprises at least one, or at least about 2, or at least about 4, or at least about 6, or at least about 8, or at least about 10, or at least about 12, or at least about 15, or at least about 18, or at least about 20 2'-deoxynucleoside modifications. In embodiments, the chemically modified ASO is completely modified with 2'-deoxynucleoside modification. In embodiments, the chemically modified ASO comprises at least one, or at least DB1 / 167593545.6 80Atorney Docket No. CVL-001PC / 140489-5001

[0456] about 2, or at least about 4, or at least about 6, or at least about 8, or at least about 10, or at least about 12, or at least about 15, or at least about 18, or at least about 20 continuous 2'- deoxynucleoside modifications. In embodiments, the chemically modified ASO comprises at least five contiguous 2'-deoxynucleosides. In embodiments, the chemically modified ASO comprises blocks of '-deoxynucleoside modifications. In embodiments, a block of nucleotides 1-n, n-m and m- the last nucleotide independently do not have a have a 2'-deoxynucleoside modification (i.e., they harbor a 2'-deoxynucleosides) or same type of modification. In embodiments, n is a number in the range of about 2 to about 20, and m is a number in the sage of about 3 to about 20. In embodiments, when the ASO is 20 nucleotides long, nucleotides 1-6, 7-12 and 13-20 do not have a have a 2'-deoxynucleoside modification or have same type of modification independently selected from 2'-0-M0E, 2'-0-Me and 2’-F. In embodiments, when the ASO is 20 nucleotides long, nucleotides 1-4, 5-16 and 17-20 do not have a have a 2'-deoxynucleoside modification or have same type of modification independently selected from 2'-0-M0E, 2'-0-Me and 2’-F. In embodiments, when the ASO is 20 nucleotides long, nucleotides 1-7, 8-14 and 15-20 do not have a have a 2'-deoxynucleoside modification or have same type of modification independently selected from 2'-0-M0E, 2'-0-Me and 2’-F. In embodiments, when the ASO is 20 nucleotides long, nucleotides 1-5, 6-15 and 16-20 do not have a have a 2'-deoxynucleoside modification or have same type of modification independently selected from 2'-0-M0E, 2'-0-Me and 2’-F. In embodiments, when the ASO is 20 nucleotides long, nucleotides 1-5 and 16-20 have a 2'-0-M0E modifications, and 6-15 do not have a have a 2'-deoxynucleoside modification. In embodiments, when the ASO is 20 nucleotides long, nucleotides 1-5 and 16-20 have a 2'-F modifications, and 6- 15 do not have a have a 2'-deoxynucleoside modification. In embodiments, when the ASO is 20 nucleotides long, nucleotides 1-5 and 16-20 have a 2'-0Me modifications, and 6-15 do not have a have a 2'-deoxynucleoside modification.

[0457] In embodiments, the therapeutic nucleic acid payload comprises an antisense oligonucleotide comprising a nucleotide sequence of SEQ ID NO: 145, or a chemically modified derivative thereof according to any of the embodiments disclosed herein. An illustrative, non-limiting modified derivative of SEQ ID NO: 145 is SEQ ID NO: 146. In embodiments, the therapeutic nucleic acid payload comprises an antisense oligonucleotide comprising a nucleotide sequence of SEQ ID NO: 147, or a chemically modified derivative thereof according to any of the embodiments disclosed herein. In embodiments, the therapeutic nucleic acid payload comprises an antisense

[0458] DB1 / 167593545.6 81Atorney Docket No. CVL-001PC / 140489-5001

[0459] oligonucleotide comprising a nucleotide sequence of SEQ ID NO: 148, or a chemically modified derivative thereof according to any of the embodiments disclosed herein. In embodiments, the therapeutic nucleic acid payload comprises an antisense oligonucleotide comprising a nucleotide sequence of SEQ ID NO: 149, or a chemically modified derivative thereof according to any of the embodiments disclosed herein. In embodiments, the therapeutic nucleic acid payload comprises an antisense oligonucleotide comprising a nucleotide sequence of SEQ ID NO: 150, or a chemically modified derivative thereof according to any of the embodiments disclosed herein. In embodiments, the therapeutic nucleic acid payload is an mRNA, which is optionally a modified mRNA (z.e., harboring at least one chemically modified nucleotide of any of the embodiments disclosed herein infra and supra). In embodiments, the mRNA or the modified mRNA encodes a detection marker or reporter, which is optionally selected from green fluorescent protein (GFP), yellow fluorescent protein (YFP), cyan fluorescent protein (CFP), red fluorescent protein (RFP), luciferase, chloramphenicol acetyltransferase (CAT), 0-galactosidase (lacZ), secreted alkaline phosphatase (SEAP) and analogs or derivatives thereof. In embodiments, the mRNA or the modified mRNA encodes an enhanced green fluorescent protein (EGFP).

[0460] An illustrative, non-limiting mRNA encodes an EGFP having the following sequence:

[0461] MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWP TLVTTLTYGVQCFSRYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEG DTLVNRIELKGIDFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSV QLADHYQQNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGITLGMD ELYK (SEQ ID NO: 151).

[0462] In embodiments, the mRNA or the modified mRNA encodes an EGFP having the amino acid sequence of SEQ ID NO: 151. In embodiments, the mRNA or the modified mRNA encodes an EGFP having an amino acid sequence that is at least about 90%, or about 92%, or about 95%, or about 97%, or about 98%, or about 99% identical to the amino acid sequence of SEQ ID NO: 151. An illustrative, non-limiting mRNA comprises an open reading frame encoding EGFP having the following sequence:

[0463] ATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCT GGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGAT

[0464] DB1 / 167593545.6 82Atorney Docket No. CVL-001PC / 140489-5001

[0465] GCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTG CCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTAC CCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTC CAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGT GAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCA AGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAA CGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCC GCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACC CCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCC GCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGT GACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAG (SEQ ID NO: 152). In embodiments, the mRNA or the modified mRNA comprises the nucleotide sequence of SEQ ID NO: 152. In embodiments, the mRNA or the modified mRNA comprises a nucleotide sequence that is at least about 90%, or about 92%, or about 95%, or about 97%, or about 98%, or about 99% identical to the nucleotide sequence of SEQ ID NO: 152.

[0466] In embodiments, the mRNA or the modified mRNA comprises the nucleotide sequence of SEQ ID NO: 152. In embodiments, the mRNA or the modified mRNA comprises a nucleotide sequence that is at least about 90%, or about 92%, or about 95%, or about 97%, or about 98%, or about 99% identical to the nucleotide sequence of SEQ ID NO: 152. In embodiments, the mRNA or the modified mRNA comprises a chemically modified version of a nucleotide sequence that is at least about 90%, or about 92%, or about 95%, or about 97%, or about 98%, or about 99% identical to the nucleotide sequence of SEQ ID NO: 152 (z.e., harboring at least one chemically modified nucleotide of any of the embodiments disclosed herein infra and supra). In embodiments, the mRNA or the modified mRNA comprises an improved version (without limitation, e.g, codon optimized) of the nucleotide sequence of SEQ ID NO: 152. Illustrative methods of generating improved versions are disclosed in US Patent Application Publication Nos. US20050032730, US20150104476, US20180256741, and US20210366574, which are herein incorporated by reference in their entirety.

[0467] In embodiments, the mRNA or the modified mRNA comprises one or more stop codon that is inframe fused to the open reading frame, optionally via a nucleotide linker that encodes one or more

[0468] DB1 / 167593545.6 83Atorney Docket No. CVL-001PC / 140489-5001

[0469] amino acids (e.g., having a nucleotide sequence UAA, UAG and UGA or a chemically modified version thereof). In embodiments, the nucleotide linker has a length that is multiple of 3 (e.g., capable of encoding one or more codons). In embodiments, the nucleotide linker encodes one amino acid, or about 1 to about 5 amino acids, or about 4 to about 10 amino acids, or about 5 to about 15 amino acids, or about 10 to about 20 amino acids, or about 15 to about 30 amino acids, or about 20 to about 50 amino acids, or about 30 to about 60 amino acids, or about 40 to about 75 amino acids, or about 1 to about 100 amino acids, or more. In embodiments, the mRNA or the modified mRNA comprises a ribosome binding site and / or an internal ribosome entry site.

[0470] In embodiments, the modified mRNA comprises one or more regulatory elements that modulate gene expression. In embodiments, the regulatory elements are from a 5’ cap, an intron, a poly A tail, a 5’ untranslated region (UTR), G-C-rich elements and a 3’ UTR. In embodiments, the modified mRNA comprises at least two, or at least three, or at least four or all five of a 5’ cap, a poly A tail, a 5’ untranslated region (UTR), G-C-rich elements and a 3’ UTR. In embodiments, a 5’ cap is selected from m7G(5')ppp(5')G, 7mG(5’)ppp(5’)NlpN2p, 7mG(5’)ppp(5’)NlmpNp, and 7mG(5’)-ppp(5’)NlmpN2mp. In embodiments, a 5’ cap is 7mG(5’)ppp(5’)NlmpNp. Illustrative regulatory elements are disclosed in US Patent Application Publication Nos. US20050032730, US20150104476, US20180044687, US20190071682, US20200197510, US20200282046, US20220162618, US20210163928, US20230295215, and PCT International Patent Application Publication No. WO2017066789, which are herein incorporated by reference in their entirety. In embodiments, the modified mRNA comprises one or more nucleotide modifications selected from a ribose modifications, a nucleobase modifications, and a internucleotide linkage (e.g., modification of a phosphodiester linkage) modifications. In embodiments, the ribose modification is 2'-O-methylribose. In embodiments, the a ribose modification is substantially absent from the modified mRNA. In embodiments, the internucleotide linkage is phosphorothiate. In embodiments, the phosphorothiate modification is present in the 5’ cap. In embodiments, a phosphorothiate modification is substantially absent from the open reading frame of the modified mRNA. In embodiments, the a ribose modification is substantially absent from the modified mRNA.

[0471] In embodiments, the nucleobase modification is selected from 2-methylthio-N6-(cis- hydroxyisopentenyl)adenosine; 2-methylthio-N6-methyladenosine; 2-methylthio-N6-threonyl

[0472] DB1 / 167593545.6 84Atorney Docket No. CVL-001PC / 140489-5001

[0473] carbamoyladenosine; N6-glycinylcarbamoyladenosine; N6-isopentenyladenosine; N6- methyladenosine; N6-threonylcarbamoyladenosine; l,2’-O-dimethyladenosine; 1- methyladenosine; 2’-O-methyladenosine; 2’ -O-ribosyladenosine (phosphate); 2-methyladenosine; 2-methylthio-N6 isopentenyladenosine; 2-methylthio-N6-hydroxynorvalyl carbamoyladenosine; 2’-O-methyladenosine; 2’ -O-ribosyladenosine (phosphate); Isopentenyladenosine; N6-(cis- hydroxyisopentenyl)adenosine; N6,2’-O-dimethyladenosine; N6,2’-O-dimethyladenosine; N6,N6,2’-O-trimethyladenosine; N6,N6-dimethyladenosine; N6-acetyladenosine; N6- hydroxynorvalylcarbamoyladenosine; N6-methyl-N6-threonylcarbamoyladenosine; 2- methyladenosine; 2-methylthio-N6-isopentenyladenosine; 7-deaza-adenosine; N1 -methyladenosine; N6,N6 (dimethyl)adenine; N6-cis-hydroxy-isopentenyl-adenosine; a-thio-adenosine; 2 (amino)adenine; 2 (aminopropyl)adenine; 2 (methylthio) N6 (isopentenyl)adenine; 2- (alkyl)adenine; 2-(aminoalkyl)adenine; 2-(aminopropyl)adenine; 2-(halo)adenine; 2- (halo)adenine; 2-(propyl)adenine; 2’-amino-2’-deoxy-adenosine; 2’-azido-2’-deoxy-adenosine; 2’ -deoxy-2’ aminoadenosine; 2’-deoxy-2’azidoadenosine; 6-(alkyl)adenine; 6-(methyl)adenine; 7- (deaza)adenine; 8-(alkenyl)adenine; 8-(alkynyl)adenine; 8-(amino)adenine; 8-(thioalkyl)adenine; 8-(alkyl)adenine; 8-(halo)adenine; 8-(hydroxyl)adenine; 8-(thiol)adenine; 8-azido-adenosine; 8- aza adenine; 1 -deaza adenine; 7-deaza adenine; N6 (methyl)adenine; N6-(isopentyl)adenine; 7- deaza-8-aza-adenosine; 7-methyladenine; 1 -deazaadenosine; 2’-fluoro-N6-benzoyl- deoxyadenosine; 2’-OMe-2-amino-adenosine; 2’O-methyl-N6-benzoyl-deoxyadenosine; 2’ethynyladenosine; 2-aminoadenosine; 2’trifluoromethyladenosine; 2-azidoadenosine; 2’ethynyladenosine; 2-Bromoadenosine; 2’trifluoromethyladenosine; 2-Chloroadenosine; 2’- Deoxy-2’,2’-difluoroadenosine; 2 ’-Deoxy-2 ’mercaptoadenosine; 2’-Deoxy- 2’thiomethoxyadenosine; 2’-Deoxy-2’aminoadenosine; 2’-Deoxy-2’azidoadenosine; 2’-Deoxy- 2 ’bromoadenosine; 2’-Deoxy-2’chloroadenosine; 2 ’-Deoxy-2 ’fluoroadenosine; 2’-Deoxy- 2’iodoadenosine; 2’-Deoxy-2’mercaptoadenosine; 2’-Deoxy-2’thiomethoxyadenosine; 2- Fluoroadenosine; 2-lodoadenosine; 2-Mercaptoadenosine; 2-methoxy-adenine; 2-methylthio- adenine; 2-Trifluoromethyladenosine; 3 -Deaza-3 -bromoadenosine; 3-Deaza-3-chloroadenosine; 3 -Deaza-3 -fluoroadenosine; 3 -Deaza-3 -iodoadenosine; 3-Deazaadenosine; 4’-Azidoadenosine; 4’ -Carbocyclic adenosine; 4’-Ethynyladenosine; 5 ’-Homo-adenosine; 8-Aza-adenosine; 8-bromo- adenosine; 8-Trifluoromethyladenosine; 9-Deazaadenosine; 2-aminopurine; 7-deaza-2,6- diaminopurine; 7-deaza-8-aza-2,6-diaminopurine; 7-deaza-8-aza-2-aminopurine; 2,6-

[0474] DB1 / 167593545.6 85Atorney Docket No. CVL-001PC / 140489-5001

[0475] diaminopurine; 7-deaza-8-aza-adenine, 7-deaza-2-aminopurine; 2-thiocytidine; 3-methylcytidine; 5-formylcytidine; 5-hydroxymethylcytidine; 5 -methylcytidine; N4-acetylcytidine; 2’-O- methylcytidine; 2’-O-methylcytidine; 5,2’ -O-dimethylcyti dine; 5-formyl-2’-O-methylcytidine; Lysidine; N4,2’-O-dimethylcytidine; N4-acetyl-2’-O-methylcytidine; N4-methylcytidine; N4,N4- Dimethyl-2’-OMe-Cytidine; 4-methylcytidine; 5-aza-cytidine; Pseudo-iso-cytidine; pyrrolo- cytidine; a-thio-cytidine; 2-(thio)cytosine; 2’-Amino-2’-deoxy-CTP; 2’-Azido-2’-deoxy-CTP; 2’- Deoxy-2’aminocytidine; 2’ -Deoxy -2’ azidocytidine; 3 (deaza) 5 (aza)cytosine; 3 (methyl)cytosine; 3-(alkyl)cytosine; 3-(deaza) 5 (aza)cytosine; 3-(methyl)cytidine; 4,2’-O-dimethylcytidine; 5 (halo)cytosine; 5 (methyl)cytosine; 5 (propynyl)cytosine; 5 (trifluoromethyl)cytosine; 5- (alkyl)cytosine; 5-(alkynyl)cytosine; 5-(halo)cytosine; 5-(propynyl)cytosine; 5- (trifluoromethyl)cytosine; 5-bromo-cytidine; 5-iodo-cytidine; 5-propynyl cytosine; 6- (azo)cytosine; 6-aza-cytidine; aza cytosine; deaza cytosine; N4 (acetyl)cytosine; 1 -methyl- 1- deaza-pseudoisocytidine; 1-methyl-pseudoisocytidine; 2-methoxy-5-methyl-cytidine; 2-methoxy- cytidine; 2-thio-5-methyl-cytidine; 4-methoxy- 1-methyl-pseudoisocytidine; 4-methoxy- pseudoisocytidine; 4-thio- 1 -methyl- 1 -deaza-pseudoisocytidine; 4-thio- 1 -methyl- pseudoisocytidine; 4-thio-pseudoisocytidine; 5-aza-zebularine; 5-methyl-zebularine; pyrrolo- pseudoisocytidine; Zebularine; (E)-5-(2-Bromo-vinyl)cytidine; 2,2’ -anhydro-cytidine TP hydrochloride; 2’Fluor-N4-benzoyl-cytidine; 2’Fluoro-N4-Acetyl-cytidine; 2’-O-Methyl-N4- Acetyl-cytidine; 2’O-methyl-N4-benzoyl-cytidine; 2’Ethynylcytidine; 2’Trifluoromethylcytidine; 2’Ethynylcytidine; 2’Trifluoromethylcytidine; 2’-Deoxy-2’,2’-difluorocytidine; 2’-Deoxy- 2’mercaptocytidine; 2’-Deoxy-2’thiomethoxycytidine; 2’-Deoxy-2’aminocytidine; 2’-Deoxy- 2’ azidocytidine; 2’-Deoxy-2’bromocytidine; 2’-Deoxy-2’chlorocytidine; 2’-Deoxy- 2’fluorocytidine; 2’-Deoxy-2’iodocytidine; 2’-Deoxy-2’mercaptocytidine; 2’-Deoxy- 2’thiomethoxycytidine; 2’-O-Methyl-5-(l-propynyl)cytidine; 3’-Ethynylcytidine; 4’- Azidocytidine; 4’ -Carbocyclic cytidine; 4’-Ethynylcytidine; 5-(l-Propynyl)ara-cytidine; 5-(2- Chloro-phenyl)-2-thiocytidine; 5-(4-Amino-phenyl)-2-thiocytidine; 5-Aminoallyl-CTP; 5- Cyanocytidine; 5-Ethynylara-cytidine; 5-Ethynylcytidine; 5 ’-Homo-cytidine; 5-Methoxycytidine; 5-Trifluoromethyl-Cytidine; N4-Amino-cytidine; N4-Benzoyl-cytidine; Pseudoisocytidine; 7- methylguanosine; N2,2’-O-dimethylguanosine; N2-methylguanosine; Wyosine; l,2’-O- dimethylguanosine; 1 -methylguanosine; 2’-O-methylguanosine; 2’-O-ribosylguanosine (phosphate); 2’-O-methylguanosine; 2’-O-ribosylguanosine (phosphate); 7-aminomethyl-7-

[0476] DB1 / 167593545.6 86Atorney Docket No. CVL-001PC / 140489-5001

[0477] deazaguanosine; 7-cyano-7-deazaguanosine; Archaeosine; Methylwyosine; N2,7- dimethylguanosine; N2,N2,2’-O-trimethylguanosine; N2,N2,7-trimethylguanosine; N2,N2- dimethylguanosine; N2,7,2’-O-trimethylguanosine; 6-thio-guanosine; 7-deaza-guanosine; 8-oxo- guanosine; Nl-methyl-guanosine; a-thio-guanosine; 2 (propyl)guanine; 2-(alkyl)guanine; 2’- Amino-2’-deoxy-GTP; 2’-Azido-2’-deoxy-GTP; 2’-Deoxy-2’aminoguanosine; 2’-Deoxy- 2’ azidoguanosine; 6 (methyl)guanine; 6-(alkyl)guanine; 6-(methyl)guanine; 6-methyl -guanosine; 7 (alkyl)guanine; 7 (deaza)guanine; 7 (methyl)guanine; 7-(alkyl)guanine; 7-(deaza)guanine; 7- (methyl)guanine; 8 (alkyl)guanine; 8 (alkynyl)guanine; 8 (halo)guanine; 8 (thioalkyl)guanine; 8- (alkenyl)guanine; 8-(alkyl)guanine; 8-(alkynyl)guanine; 8-(amino)guanine; 8-(halo)guanine; 8- (hydroxyl)guanine; 8-(thioalkyl)guanine; 8-(thiol)guanine; aza guanine; deaza guanine; N (methyl)guanine; N-(methyl)guanine; l-methyl-6-thio-guanosine; 6-methoxy -guanosine; 6-thio- 7-deaza-8-aza-guanosine; 6-thio-7-deaza-guanosine; 6-thio-7-methyl-guanosine; 7-deaza-8-aza- guanosine; 7-methyl-8-oxo-guanosine; N2,N2-dimethyl-6-thio-guanosine; N2-methyl-6-thio- guanosine; 1-Me-GTP; 2’Fluoro-N2-isobutyl-guanosine; 2’O-methyl-N2-isobutyl-guanosine; 2’Ethynylguanosine; 2’ Trifluoromethylguanosine; 2’Ethynylguanosine; 2’ Trifluoromethylguanosine; 2’-Deoxy-2’,2’-difluoroguanosine; 2’ -Deoxy - 2 ’mercaptoguanosine; 2’-Deoxy-2’thiomethoxyguanosine; 2 ’-Deoxy-2’ aminoguanosine; 2’- Deoxy-2’azidoguanosine; 2’-Deoxy-2’bromoguanosine; 2’-Deoxy-2’chloroguanosine; 2’-Deoxy- 2’fluoroguanosine; 2’-Deoxy-2’iodoguanosine; 2’-Deoxy-2’mercaptoguanosine; 2’-Deoxy- 2 ’thiometh oxy guanosine; 4’ -Azidoguanosine; 4’-Carbocyclic guanosine; 4’-Ethynylguanosine; 5 ’-Homo-guanosine; 8-bromo-guanosine; 9-Deazaguanosine; N2-isobutyl-guanosine; 1- methylinosine; Inosine; l,2’-O-dimethylinosine; 2’-O-methylinosine; 7-methylinosine; 2’-O- methylinosine; Epoxyqueuosine; galactosyl-queuosine; Mannosylqueuosine; Queuosine; allyamino-thymidine; aza thymidine; deaza thymidine; deoxy-thymidine; 2’ -O-m ethyluridine; 2- thiouridine; 3 -methyluridine; 5-carboxymethyluridine; 5-hydroxyuridine; 5 -methyluridine; 5- taurinomethyl-2-thiouridine; 5-taurinomethyluridine; Dihydrouridine; Pseudouridine; (3-(3- amino-3-carboxypropyl)uridine; l-methyl-3-(3-amino-5-carboxypropyl)pseudouridine; 1- methylpseduouridine; 1-methyl-pseudouridine; 2’-O-methyluridine; 2’-O-methylpseudouridine; 2’-O-methyluridine; 2-thio-2’-O-methyluridine; 3-(3-amino-3-carboxypropyl)uridine; 3,2’-O- dimethyluridine; 3-Methyl-pseudo-Uridine; 4-thiouridine; 5-(carboxyhydroxymethyl)uridine; 5- (carboxyhydroxymethyl)uridine methyl ester; 5,2’ -O-dimethyluri dine; 5,6-dihydro-uridine; 5-

[0478] DB1 / 167593545.6 87Atorney Docket No. CVL-001PC / 140489-5001

[0479] aminomethyl-2-thiouridine; 5-carbamoylmethyl-2’-O-methyluridine; 5-carbamoylmethyluridine; 5-carboxyhydroxymethyluridine; 5-carboxyhydroxymethyluridine methyl ester; 5- carboxymethylaminomethyl-2’-O-methyluridine; 5-carboxymethylaminomethyl-2-thiouridine; 5- carboxymethylaminomethyl-2 -thiouridine; 5-carboxymethylaminomethyluridine; 5- carboxymethylaminomethyluridine; 5-Carbamoylmethyluridine; 5-methoxycarbonylmethyl-2’- O-methyluridine; 5-methoxycarbonylmethyl-2-thiouridine; 5-methoxycarbonylmethyluridine; 5- methoxyuridine; 5-methyl-2-thiouridine; 5-methylaminomethyl-2-selenouridine; 5- methylaminomethyl-2-thiouridine; 5-methylaminomethyluridine; 5 -Methyl dihydrouridine; 5- Oxyacetic acid-Uridine; 5-Oxyacetic acid-methyl ester-Uridine; Nl-methyl-pseudo-uridine; uridine 5-oxyacetic acid; uridine 5-oxyacetic acid methyl ester; 3-(3-Amino-3-carboxypropyl)- Uridine; 5-(iso-Pentenylaminomethyl)-2-thiouridine; 5-(iso-Pentenylaminomethyl)-2’-O- methyluridine; 5-(iso-Pentenylaminomethyl)uridine; 5-propynyl uracil; a-thio-uridine; 1 (aminoalkylamino-carbonylethylenyl)-2(thio)-pseudouracil; 1 (aminoalkylaminocarbonylethylenyl)-2,4-(dithio)pseudouracil; 1 (aminoalkylaminocarbonylethylenyl)-4 (thio)pseudouracil; 1 (aminoalkylaminocarbonylethylenyl)-pseudouracil; 1 (aminocarbonylethylenyl)-2(thio)- pseudouracil; 1 (aminocarbonylethylenyl)-2,4-(dithio)pseudouracil; 1 (aminocarbonylethylenyl)- 4 (thio)pseudouracil; 1 (aminocarbonylethylenyl)-pseudouracil; 1 substituted 2(thio)- pseudouracil; 1 substituted 2,4-(dithio)pseudouracil; 1 substituted 4 (thio)pseudouracil; 1 substituted pseudouracil; l-(aminoalkylamino-carbonylethylenyl)-2-(thio)-pseudouracil; 1- Methyl-3 -(3 -amino-3 -carboxypropyl) pseudouridine; l-Methyl-3 -(3 -amino-3 - carboxypropyl)pseudo-UTP; 1-Methyl-pseudo-UTP; 2 (thio)pseudouracil; 2’ deoxy uridine; 2’ fluorouridine; 2-(thio)uracil; 2,4-(dithio)psuedouracil; 2’ methyl, 2’amino, 2’ azido, 2’fluro- guanosine; 2’-Amino-2’-deoxy-UTP; 2’-Azido-2’-deoxy-UTP; 2’-Azido-deoxyuridine; 2’-O- methylpseudouridine; 2’ deoxy uridine; 2’ fluorouridine; 2’ -Deoxy-2’ aminouridine; 2’ -Deoxy - 2’ azidouridine; 2-methylpseudouridine; 3 (3 amino-3 carboxypropyl)uracil; 4 (thio)pseudouracil; 4-(thio)pseudouracil; 4-(thio)uracil; 4-thiouracil; 5 (l,3-diazole-l-alkyl)uracil; 5 (2- ami nopropyl )uracil; 5 (aminoalkyl)uracil; 5 (dimethylaminoalkyl)uracil; 5 (guanidiniumalkyl)uracil; 5 (methoxycarbonylmethyl)-2-(thio)uracil; 5 (methoxycarbonyl- methyl)uracil; 5 (methyl) 2 (thio)uracil; 5 (methyl) 2,4 (dithio)uracil; 5 (methyl) 4 (thio)uracil; 5 (methylaminomethyl)-2 (thio)uracil; 5 (methylaminomethyl)-2,4 (dithio)uracil; 5

[0480] DB1 / 167593545.6 88Atorney Docket No. CVL-001PC / 140489-5001

[0481] (methyl am inom ethyl )-4 (thio)uracil; 5 (propynyl)uracil; 5 (trifluoromethyl)uracil; 5-(2- aminopropyl)uracil; 5-(alkyl)-2-(thio)pseudouracil; 5-(alkyl)-2,4 (dithio)pseudouracil; 5-(alkyl)-4 (thio)pseudouracil; 5-(alkyl)pseudouracil; 5-(alkyl)uracil; 5-(alkynyl)uracil; 5-(allylamino)uracil; 5-(cyanoalkyl)uracil; 5-(dialkylaminoalkyl)uracil; 5-(dimethylaminoalkyl)uracil; 5- (guanidiniumalkyl)uracil; 5-(halo)uracil; 5-(l,3-diazole-l-alkyl)uracil; 5 -(m ethoxy )uracil; 5- (methoxycarbonylmethyl)-2-(thio)uracil; 5-(methoxycarbonyl-methyl)uracil; 5-(methyl) 2(thio)uracil; 5-(methyl) 2,4 (dithio)uracil; 5-(methyl) 4 (thio)uracil; 5-(methyl)-2- (thio)pseudouracil; 5-(methyl)-2,4 (dithio)pseudouracil; 5-(methyl)-4 (thio)pseudouracil; 5- (methyl)pseudouracil; 5-(methylaminomethyl)-2 (thio)uracil; 5-(methylaminomethyl)- 2,4(dithio)uracil; 5-(methylaminomethyl)-4-(thio)uracil; 5-(propynyl)uracil; 5- (trifluoromethyl)uracil; 5-aminoallyl-uridine; 5-bromo-uridine; 5-iodo-uridine; 5-uracil; 6 (azo)uracil; 6-(azo)uracil; 6-aza-uridine; ally amino-uracil; aza uracil; deaza uracil; N3 (methyl)uracil; Pseudo-UTP-l-2-ethanoic acid; Pseudouracil; 4-Thio-pseudo-UTP; 1- carboxymethyl-pseudouridine; 1 -methyl- 1-deaza-pseudouridine; 1-propynyl-uridine; 1- taurinom ethyl- 1 -methyl -uridine; l-taurinomethyl-4-thio-uridine; 1-taurinomethyl-pseudouridine; 2-methoxy-4-thio-pseudouridine; 2-thio- 1 -methyl- 1 -deaza-pseudouridine; 2-thio- 1 -methyl- pseudouridine; 2-thio-5-aza-uridine; 2-thio-dihydropseudouridine; 2-thio-dihydrouridine; 2-thio- pseudouridine; 4-methoxy-2-thio-pseudouridine; 4-methoxy-pseudouridine; 4-thio-l -methylpseudouridine; 4-thio-pseudouridine; 5 -aza-uridine; Dihydropseudouridine; (±) l-(2- Hydroxypropyl)pseudouridine; (2R)-l-(2-Hydroxypropyl)pseudouridine; (2S)-l-(2- Hydroxypropyl)pseudouridine; (E)-5-(2-Bromo-vinyl)ara-uridine; (E)-5-(2-Bromo-vinyl)uridine; (Z)-5-(2-Bromo-vinyl)ara-uridine; (Z)-5-(2-Bromo-vinyl)uridine; l-(2,2,2-Trifluoroethyl)- pseudo-UTP; l-(2,2,3,3,3-Pentafluoropropyl)pseudouridine; 1 -(2,2- Diethoxyethyl)pseudouridine; l-(2,4,6-Trimethylbenzyl)pseudouridine; l-(2,4,6-Trimethyl- benzyl)pseudo-UTP; 1 -(2,4,6-Trimethyl-phenyl)pseudo-UTP; 1 -(2-Amino-2- carboxyethyl)pseudo-UTP; l-(2-Amino-ethyl)pseudo-UTP; l-(2-Hydroxyethyl)pseudouridine; 1- (2-Methoxyethyl)pseudouridine; l-(3,4-Bis-trifluoromethoxybenzyl)pseudouridine; l-(3,4- Dimethoxybenzyl)pseudouridine; l-(3-Amino-3-carboxypropyl)pseudo-UTP; l-(3-Amino- propyl)pseudo-UTP; l-(3-Cyclopropyl-prop-2-ynyl)pseudouridine; l-(4-Amino-4- carboxybutyl)pseudo-UTP; l-(4-Amino-benzyl)pseudo-UTP; l-(4-Amino-butyl)pseudo-UTP; 1- (4-Amino-phenyl)pseudo-UTP; 1 -(4-Azidobenzyl)pseudouridine; 1 -(4-

[0482] DB1 / 167593545.6 89Atorney Docket No. CVL-001PC / 140489-5001

[0483] Bromobenzyl)pseudouridine; l-(4-Chlorobenzyl)pseudouridine; l-(4- Fluorobenzyl)pseudouridine; l-(4-Iodobenzyl)pseudouridine; l-(4- Methanesulfonylbenzyl)pseudouridine; 1 -(4-Methoxybenzyl)pseudouridine; 1 -(4-Methoxy- benzyl)pseudo-UTP; l-(4-Methoxy-phenyl)pseudo-UTP; l-(4-Methylbenzyl)pseudouridine; 1- (4-Methyl-benzyl)pseudo-UTP; 1 -(4-Nitrobenzyl)pseudouridine; 1 -(4-Nitro-benzyl)pseudo-UTP; 1 (4-Nitro-phenyl)pseudo-UTP; 1 -(4-Thiomethoxybenzyl)pseudouridine; 1 -(4- Trifluoromethoxybenzyl)pseudouridine; l-(4-Trifluoromethylbenzyl)pseudouridine; l-(5-Amino- pentyl)pseudo-UTP; l-(6-Amino-hexyl)pseudo-UTP; 1,6-Dimethyl-pseudo-UTP; l-[3-(2-{2-[2- (2-Aminoethoxy)-ethoxy]-ethoxy}-ethoxy)-propionyl]pseudouridine; l-{3-[2-(2-Aminoethoxy)- ethoxy]-propionyl} pseudouridine; 1-Acetylpseudouridine; l-Alkyl-6-(l-propynyl)-pseudo-UTP; 1 -Alkyl-6-(2-propynyl)-pseudo-UTP; 1 -Alkyl-6-allyl-pseudo-UTP; 1 -Alkyl-6-ethynyl-pseudo- UTP; l-Alkyl-6-homoallyl-pseudo-UTP; l-Alkyl-6-vinyl-pseudo-UTP; 1 -Allylpseudouridine; 1- Aminomethyl-pseudo-UTP; 1-Benzoylpseudouridine; 1-Benzyloxymethylpseudouridine; 1- Benzyl-pseudo-UTP; l-Biotinyl-PEG2-pseudouridine; 1-Biotinylpseudouridine; 1-Butyl-pseudo- UTP; 1-Cyanom ethylpseudouridine; 1-Cyclobutylmethyl-pseudo-UTP; 1-Cyclobutyl-pseudo- UTP; 1-Cycloheptylmethyl-pseudo-UTP; 1-Cycloheptyl-pseudo-UTP; 1-Cyclohexylmethyl- pseudo-UTP; 1-Cyclohexyl-pseudo-UTP; 1-Cyclooctylmethyl-pseudo-UTP; 1 -Cyclooctyl - pseudo-UTP; 1-Cyclopentylmethyl-pseudo-UTP; 1-Cyclopentyl-pseudo-UTP; 1- Cyclopropylmethyl-pseudo-UTP; 1-Cyclopropyl-pseudo-UTP; 1-Ethyl-pseudo-UTP; 1-Hexyl- pseudo-UTP; 1 -Homoallylpseudouridine; 1 -Hydroxymethylpseudouridine; 1-iso-propyl-pseudo- UTP; l-Me-2-thio-pseudo-UTP; l-Me-4-thio-pseudo-UTP; 1-Me-alpha-thio-pseudo-UTP; 1- Methanesulfonylmethylpseudouridine; 1-Methoxymethylpseudouridine; l-Methyl-6-(2,2,2- Trifluoroethyl)pseudo-UTP; l-Methyl-6-(4-morpholino)-pseudo-UTP; l-Methyl-6-(4- thiomorpholino)-pseudo-UTP; l-Methyl-6-(substituted phenyl)pseudo-UTP; l-Methyl-6-amino- pseudo-UTP; l-Methyl-6-azido-pseudo-UTP; l-Methyl-6-bromo-pseudo-UTP; l-Methyl-6- butyl-pseudo-UTP; l-Methyl-6-chloro-pseudo-UTP; l-Methyl-6-cyano-pseudo-UTP; 1-Methyl- 6-dimethylamino-pseudo-UTP; 1 -Methyl-6-ethoxy-pseudo-UTP; 1 -Methyl-6-ethylcarboxylate- pseudo-UTP; l-Methyl-6-ethyl-pseudo-UTP; l-Methyl-6-fluoro-pseudo-UTP; l-Methyl-6- formyl-pseudo-UTP; 1 -Methyl-6-hydroxyamino-pseudo-UTP; 1 -Methyl-6-hydroxy-pseudo- UTP; l-Methyl-6-iodo-pseudo-UTP; l-Methyl-6-iso-propyl-pseudo-UTP; l-Methyl-6-methoxy- pseudo-UTP; l-Methyl-6-methylamino-pseudo-UTP; l-Methyl-6-phenyl-pseudo-UTP; 1-

[0484] DB1 / 167593545.6 90Atorney Docket No. CVL-001PC / 140489-5001

[0485] Methyl-6-propyl-pseudo-UTP; 1 -Methyl -6-tert-butyl-pseudo-UTP; 1 -Methyl-6- trifluoromethoxy-pseudo-UTP; 1 -Methyl-6-trifluoromethyl-pseudo-UTP; 1 - Morpholinomethylpseudouridine; 1-Pentyl-pseudo-UTP; 1-Phenyl-pseudo-UTP; 1- Pivaloylpseudouridine; 1-Propargylpseudouridine; 1-Propyl-pseudo-UTP; 1-propynyl- pseudouridine; 1-p-tolyl-pseudo-UTP; 1-tert-Butyl-pseudo-UTP; 1- Thiomethoxymethylpseudouridine; 1 -Thiomorpholinom ethylpseudouridine; 1 - Trifluoroacetylpseudouridine; 1-Trifluoromethyl-pseudo-UTP; 1-Vinylpseudouridine; 2,2’- anhydro-uridine; 2’-bromo-deoxyuridine; 2’-F-5-Methyl-2’-deoxy-UTP; 2’-OMe-5-Me-UTP; 2’- OMe-pseudo-UTP; 2’Ethynyluridine; 2’Trifluoromethyluridine; 2’Ethynyluridine; 2’Trifluoromethyluridine; 2’-Deoxy-2’,2’-difluorouridine; 2’-Deoxy-2’mercaptouridine; 2’- Deoxy-2’thiomethoxyuridine; 2’-Deoxy-2’aminouridine; 2’-Deoxy-2’azidouridine; 2’-Deoxy- 2’bromouridine; 2’ -Deoxy-2’ chlorouridine; 2’-Deoxy-2’fluorouridine; 2’-Deoxy-2’iodouridine; 2’-Deoxy-2’mercaptouridine; 2’-Deoxy-2’thiomethoxyuridine; 2-methoxy-4-thio-uridine; 2- methoxyuridine; 2’-O-Methyl-5-(l-propynyl)uridine; 3-Alkyl-pseudo-UTP; 4’-Azidouridine; 4’- Carbocyclic uridine; 4’-Ethynyluridine; 5-(l-Propynyl)ara-uridine; 5-(2-Furanyl)uridine; 5- Cyanouridine; 5-Dimethylaminouridine; 5 ’-Homo-uridine; 5-iodo-2’-fluoro-deoxyuridine; 5- Phenylethynyluridine; 5-Trideuteromethyl-6-deuterouridine; 5-Trifluoromethyl-Uridine; 5- Vinylarauridine; 6-(2,2,2-Trifluoroethyl)-pseudo-UTP; 6-(4-Morpholino)-pseudo-UTP; 6-(4- Thiomorpholino)-pseudo-UTP; 6-(Substituted-Phenyl)-pseudo-UTP; 6-Amino-pseudo-UTP; 6- Azido-pseudo-UTP; 6-Bromo-pseudo-UTP; 6-Butyl-pseudo-UTP; 6-Chloro-pseudo-UTP; 6- Cyano-pseudo-UTP; 6-Dimethylamino-pseudo-UTP; 6-Ethoxy-pseudo-UTP; 6-Ethyl carb oxy late- pseudo-UTP; 6-Ethyl-pseudo-UTP; 6-Fluoro-pseudo-UTP; 6-Formyl-pseudo-UTP; 6- Hydroxyamino-pseudo-UTP; 6-Hydroxy-pseudo-UTP; 6-Iodo-pseudo-UTP; 6-iso-Propyl- pseudo-UTP; 6-Methoxy-pseudo-UTP; 6-Methylamino-pseudo-UTP; 6-Methyl-pseudo-UTP; 6- Phenyl-pseudo-UTP; 6-Phenyl-pseudo-UTP; 6-Propyl-pseudo-UTP; 6-tert-Butyl-pseudo-UTP; 6- Trifluoromethoxy-pseudo-UTP; 6-Trifluoromethyl-pseudo-UTP; Alpha-thio-pseudo-UTP; Pseudouridine l-(4-methylbenzenesulfonic acid); Pseudouridine l-(4-methylbenzoic acid); Pseudouridine TP l-[3-(2-ethoxy)]propionic acid; Pseudouridine TP l-[3-{2-(2-[2-(2-ethoxy)- ethoxy]-ethoxy)-ethoxy}]propionic acid; Pseudouridine TP l-[3-{2-(2-[2-{2(2-ethoxy)-ethoxy}- ethoxy]-ethoxy)-ethoxy}]propionic acid; Pseudouridine TP l-[3-{2-(2-[2-ethoxy]-ethoxy)- ethoxy}] propionic acid; Pseudouridine TP l-[3-{2-(2-ethoxy)-ethoxy}] propionic acid;

[0486] DB1 / 167593545.6 91Atorney Docket No. CVL-001PC / 140489-5001

[0487] Pseudouridine TP 1-methylphosphonic acid; Pseudouridine TP 1-methylphosphonic acid diethyl ester; Pseudo-UTP-N 1-3 -propionic acid; Pseudo-UTP-Nl-4-butanoic acid; Pseudo-UTP-Nl-5- pentanoic acid; Pseudo-UTP-Nl-6-hexanoic acid; Pseudo-UTP-N 1-7-heptanoic acid; Pseudo- UTP-Nl-methyl-p-benzoic acid; Pseudo-UTP-Nl-p-benzoic acid; Wybutosine; Hydroxywybutosine; Isowyosine; Peroxywybutosine; undermodified hydroxywybutosine; 4- demethylwyosine; 2,6-(diamino)purine; l-(aza)-2-(thio)-3-(aza)-phenoxazin-l-yl: l,3-(diaza)-2- (oxo)-phenthiazin-l-yl; l,3-(diaza)-2-(oxo)-phenoxazin-l-yl; l,3,5-(triaza)-2,6-(dioxa)- naphthalene; 2 (amino)purine; 2,4,5-(trimethyl)phenyl; 2’ methyl, 2’amino, 2’azido, 2’fluro- cytidine; 2’ methyl, 2’ amino, 2’azido, 2’fluro-adenine; 2’methyl, 2’amino, 2’ azido, 2’fluro- uridine; 2’-amino-2’-deoxyribose; 2-amino-6-Chloro-purine; 2-aza-inosinyl; 2’-azido-2’- deoxyribose; 2’fluoro-2’-deoxyribose; 2’-fluoro-modifted bases; 2’-O-methyl-ribose; 2-oxo-7- aminopyridopyrimidin-3-yl; 2-oxo-pyridopyrimidine-3-yl; 2-pyridinone; 3 nitropyrrole; 3- (methyl)-7-(propynyl)isocarbostyrilyl; 3-(methyl)isocarbostyrilyl; 4-(fluoro)-6- (methyl)benzimidazole; 4-(methyl)benzimidazole; 4-(methyl)indolyl; 4,6-(dimethyl)indolyl; 5 nitroindole; 5 substituted pyrimidines; 5-(methyl)isocarbostyrilyl; 5-nitroindole; 6- (aza)pyrimidine; 6-(azo)thymine; 6-(methyl)-7-(aza)indolyl; 6-chloro-purine; 6-phenyl-pyrrolo- pyrimidin-2-on-3-yl; 7-(aminoalkylhydroxy)-l-(aza)-2-(thio)-3-(aza)-phenthiazin-l-yl; 7- (aminoalkylhydroxy)-l-(aza)-2-(thio)-3-(aza)-phenoxazin-l-yl; 7-(aminoalkylhydroxy)-l,3- (diaza)-2-(oxo)-phenoxazin-l-yl; 7-(aminoalkylhydroxy)-l,3-(diaza)-2-(oxo)-phenthiazin-l-yl; 7-(aminoalkylhydroxy)-l,3-(diaza)-2-(oxo)-phenoxazin-l-yl; 7-(aza)indolyl; 7-(guanidinium alkylhydroxy)-l-(aza)-2-(thio)-3-(aza)-phenoxazinl-yl; 7-(guanidiniumalkylhydroxy)-l-(aza)-2- (thio)-3-(aza)-phenthiazin-l-yl; 7-(guanidiniumalkylhydroxy)-l-(aza)-2-(thio)-3-(aza)- phenoxazin- 1 -yl ; 7-(guanidiniumalkylhy droxy)- 1 , 3 -(diaza)-2-(oxo)-phenoxazin- 1 -yl ; 7- (guanidiniumalkyl-hydroxy)- 1 ,3 -(diaza)-2-(oxo)-phenthiazin- 1 -yl; 7-(guanidiniumalkyl hydroxy) -l,3-(diaza)-2-(oxo)-phenoxazin-l-yl; 7-(propynyl)isocarbostyrilyl; 7-(propynyl) isocarbostyrilyl, propynyl-7-(aza)indolyl ; 7-deaza-inosinyl ; 7-sub stituted 1 -(aza)-2-(thio)-3 -(aza)-phenoxazin- 1 - yl; 7-substituted l,3-(diaza)-2-(oxo)-phenoxazin-l-yl; 9-(methyl)-imidizopyridinyl; Aminoindolyl; Anthracenyl; bis-ortho-(aminoalkylhy droxy )-6-phenyl-pyrrolo-pyrimidin-2-on-3- yl; bis-ortho-substituted-6-phenyl-pyrrolo-pyrimidin-2-on-3-yl; Difluorotolyl; Hypoxanthine; Imidizopyridinyl; Inosinyl; Isocarbostyrilyl; Isoguanisine; N2-substituted purines; N6-methyl-2- amino-purine; N6-substituted purines; N-alkylated derivative; Napthalenyl; Nitrobenzimidazolyl;

[0488] DB1 / 167593545.6 92Atorney Docket No. CVL-001PC / 140489-5001

[0489] Nitroimidazolyl; Nitroindazolyl; Nitropyrazolyl; Nubularine; 06-substituted purines; O-alkylated derivative; ortho-(aminoalkylhydroxy)-6-phenyl-pyrrolo-pyrimidin-2-on-3-yl; ortho-substituted- 6-phenyl-pyrrolo-pyrimidin-2-on-3-yl; Oxoformycin; para-(aminoalkylhydroxy)-6-phenyl- pyrrolo-pyrimidin-2-on-3-yl; para-substituted-6-phenyl-pyrrolo-pyrimidin-2-on-3-yl; Pentacenyl; Phenanthracenyl; Phenyl; propynyl-7-(aza)indolyl; Pyrenyl; pyridopyrimidin-3-yl; pyridopyrimidin-3-yl, 2-oxo-7-amino-pyridopyrimidin-3-yl; pyrrolo-pyrimidin-2-on-3-yl; Pyrrolopyrimidinyl; Pyrrolopyrizinyl; Stilbenzyl; substituted 1,2,4-triazoles; Tetracenyl; Tubercidine; Xanthine; Xanthosine-5’-TP; 2-thio-zebularine; 5-aza-2-thio-zebularine; 7-deaza-2- amino-purine; pyridin-4-one ribonucleoside; 2-Amino-riboside-TP; Formycin A; Formycin B; Pyrrolosine; 2’-OH-ara-adenosine; 2’-OH-ara-cytidine; 2’-OH-ara-uridine; 2’-OH-ara-guanosine; 5-(2-carbomethoxyvinyl)uridine; and N6-(19-Amino-pentaoxanonadecyl) adenosine TP.

[0490] In embodiments, the modified nucleobase is a modified uracil. In embodiments, the modified uracil is selected from pseudouridine (\| / ), pyridin-4-one ribonucleoside, 5-aza-uridine, 6-aza- uridine, 2-thio-5-aza-uridine, 2-thio-uridine (s2U), 4-thio-uridine (s4U), 4-thio-pseudouridine, 2- thio-pseudouridine, 5-hydroxy-uridine (ho5U), 5-aminoallyl-uridine, 5-halo-uridine (e.g., 5-iodo- uridineor 5-bromo-uridine), 3-methyl-uridine (m3U), 5-methoxy-uridine (mo5U), uridine 5- oxyacetic acid (cmo5U), uridine 5-oxyacetic acid methyl ester (mcmo5U), 5-carboxymethyl- uridine (cm5U), 1-carboxymethyl-pseudouridine, 5-carboxyhydroxymethyl-uridine (chm5U), 5- carboxyhydroxymethyl-uridine methyl ester (mchm5U), 5-methoxycarbonylmethyl-uridine (mcm5U), 5-methoxycarbonylmethyl-2-thio-uridine (mcm5s2U), 5-aminomethyl-2-thio-uridine (nm’s2U), 5-methylaminomethyl-uridine (mnm5U), 5-methylaminomethyl-2-thio-uridine (mnm5s2U), 5-methylaminomethyl-2-seleno-uridine (mnm5se2U), 5-carbamoylmethyl-uridine (ncm5U), 5-carboxymethylaminomethyl-uridine (cmnm’U), 5-carboxymethylaminomethyl-2- thio-uridine (cmnm5s2U), 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyl -uridine (rm5U), 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine (rm5s2U), 1- taurinomethyl-4-thio-pseudouridine, 5-methyl-uridine (m5U, i.e., having the nucleobase deoxythymine), 1-methyl-pseudouridine (m1! ), 5-methyl-2-thio-uridine (m5s2U), l-methyl-4- thio-pseudouridine (m tit), 4-thio- 1-methyl-pseudouridine, 3-methyl-pseudouridine (m3), 2- thio- 1-methyl-pseudouridine, 1 -methyl- 1 -deaza-pseudouridine, 2-thio-l -methyl- 1 -deazapseudouridine, dihydrouridine (D), dihydropseudouridine, 5,6-dihydrouridine, 5-methyl- dihydrouridine (m5D), 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxy-uridine, 2-

[0491] DB1 / 167593545.6 93Atorney Docket No. CVL-001PC / 140489-5001

[0492] methoxy -4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, N1 -methylpseudouridine, 3-(3-amino-3-carboxypropyl)uridine (acp3U), l-methyl-3-(3-amino-3- carboxypropyl)pseudouridine (acp3y), 5-(isopentenylaminomethyl)uridine (inm5U), 5- (isopentenylaminomethyl)-2-thio-uridine (inm5s2U), a-thio-uridine, 2’-O-methyl-uridine (Um), 5,2’-O-dimethyl-uridine (m5Um), 2’-O-methyl-pseudouridine (\| / m), 2-thio-2’-O-methyl-uridine (s2Um), 5-methoxycarbonylmethyl-2’-O-methyl-uridine (mcm5Um), 5-carbamoylmethyl-2’-O- methyl-uridine (ncm’Urn), 5-carboxymethylaminomethyl-2’-O-methyl-uridine (cmnm’Um), 3,2’- O-dimethyl-uridine (m3Um), and 5-(isopentenylaminomethyl)-2’-O-methyl-uridine (inm5Um), 1- thio-uridine, deoxythymidine, 2’-F-ara-uridine, 2’-F-uridine, 2’-0H-ara-uridine, 5-(2- carbomethoxyvinyl) uridine, and 5-[3-(l-E-propenylamino)]uridine.

[0493] In embodiments, the modified nucleobase is a modified cytosine. In some embodiments, the modified cytosine is selected from 5 -aza-cytidine, 6-aza-cytidine, pseudoisocytidine, 3-methyl- cytidine (m3C), N4-acetyl-cytidine (ac4C), 5 -formyl -cytidine (f’C), N4-methyl-cytidine (m4C), 5- methyl-cytidine (m5C), 5-halo-cytidine (e.g., 5-iodo-cytidine), 5-hydroxymethyl-cytidine (hm5C), 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine (s2C), 2- thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-l-methyl-pseudoisocytidine, 4-thio-l- m ethyl- 1-deaza-pseudoisocyti dine, 1 -methyl- 1-deaza-pseudoisocytidine, zebularine, 5-aza- zebularine, 5-methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, 4-m ethoxy- 1-methyl- pseudoisocytidine, lysidine (I C), a-thio-cytidine, 2’-O-methyl-cytidine (Cm), 5,2’-O-dimethyl- cytidine (m’Cm), N4-acetyl-2’-O-methyl-cytidine (ac4Cm), N4,2’-O-dimethyl-cytidine (m4Cm), 5-formyl-2’-O-methyl-cytidine (f’Cm), N4,N4,2’-O-trimethyl-cytidine (m Cm), 1-thio- cytidine, 2’-F-ara-cytidine, 2’-F-cytidine, and 2’-0H-ara-cytidine. In embodiments, the modified uridine is selected from pseudouridine, N1 -methylpseudouridine, N1 -ethylpseudouridine, 2- thiouridine, 4’ -thiouridine, 5 -methylcytosine, 5-methyluridine, 2-thio-l -methyl- 1 -deazapseudouridine, 2 -thio- 1 -methyl -pseudouridine, 2-thio-5-aza-uridine, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio- pseudouridine, 4-methoxy-pseudouridine, 4-thio-l-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methoxyuridine and 2’-O-methyl uridine. In embodiments, the modified uridine is N1 -methylpseudouridine or N1 -ethylpseudouridine. In embodiments, the modified uridine is N1 -methylpseudouridine.

[0494] DB1 / 167593545.6 94Atorney Docket No. CVL-001PC / 140489-5001

[0495] In embodiments, the modified nucleobase is a modified adenine. In embodiments, the modified adenine is selected from 2-amino-purine, 2,6-diaminopurine, 2-amino-6-halo-purine (e.g., 2- amino-6-chloro-purine), 6-halo-purine (e.g., 6-chloro-purine), 2-amino-6-methyl-purine, 8-azido- adenosine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-amino-purine, 7-deaza-8-aza-2- amino-purine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyl-adenosine (nfA), 2-methyl-adenine (m2A), N6-methyl-adenosine (m6A), 2-methylthio-N6-methyl- adenosine (ms2m6A), N6-isopentenyl-adenosine (i6A), 2-methylthio-N6-isopentenyl-adenosine (ms2i6A), N6-(cis-hydroxyisopentenyl)adenosine (io6A), 2-methylthio-N6-(cis- hydroxyisopentenyl)adenosine (ms2io6A), N6-glycinylcarbamoyl-adenosine (g6A), N6- threonylcarbamoyl-adenosine (t6A), N6-methyl-N6-threonylcarbamoyl-adenosine (m6t6A), 2- methylthio-N6-threonylcarbamoyl-adenosine (ms2g6A), N6,N6-dimethyl-adenosine (m62 A), N6- hydroxynorvalylcarbamoyl-adenosine (hn6A), 2-methylthio-N6-hydroxynorvalylcarbamoyl- adenosine (ms2hn6A), N6-acetyl-adenosine (ac6A), 7-methyl-adenine, 2-methylthio-adenine, 2- methoxy-adenine, a-thio-adenosine, 2’-O-methyl-adenosine (Am), N6,2’-O-dimethyl-adenosine (m6Am), N6,N6,2’-O-trimethyl-adenosine (m62 Am), l,2’-O-dimethyl-adenosine (m'Am), 2’-O- ribosyladenosine (phosphate) (Ar(p)), 2-amino-N6-methyl-purine, 1 -thio-adenosine, 8-azido- adenosine, 2’-F-ara-adenosine, 2’-F-adenosine, 2’-0H-ara-adenosine, and N6-(19-amino- pentaoxanonadecyl)-adenosine.

[0496] In embodiments, the modified nucleobase is a modified guanine. In embodiments, the modified guanine is selected from inosine (I), 1-methyl-inosine (m1!), wyosine (imG), methylwyosine (mimG), 4-dem ethyl -wyosine (imG-14), isowyosine (imG2), wybutosine (yW), peroxywybutosine (o2yW), hydroxywybutosine (OhyW), undermodified hydroxywybutosine (OhyW*), 7-deaza-guanosine, queuosine (Q), epoxyqueuosine (oQ), galactosyl-queuosine (galQ), mannosyl-queuosine (manQ), 7-cyano-7-deaza-guanosine (preQo), 7-aminomethyl-7-deaza- guanosine (preQi), archaeosine (G±), 7-deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza- guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine (m7G), 6-thio-7-methyl- guanosine, 7-methyl-inosine, 6-methoxy -guanosine, 1-methyl-guanosine (m’G), N2-methyl- guanosine (m2G), N2,N2-dimethyl-guanosine (m22G), N2,7-dimethyl-guano sine (m2,7G), N2,N2,7-dimethyl-guanosine (m2’2,7G), 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, l-methyl-6- thio-guanosine, N2-methyl-6-thio-guanosine, N2,N2-dimethyl-6-thio-guanosine, a-thio- guanosine, 2’-O-methyl-guanosine (Gm), N2-methyl-2’-O-methyl-guanosine (m2Gm), N2,N2-

[0497] DB1 / 167593545.6 95Atorney Docket No. CVL-001PC / 140489-5001

[0498] dimethyl-2’-O-methyl-guanosine (m22Gm), l-methyl-2’-O-methyl-guanosine (m'Gm), N2,7- dimethyl-2’-O-methyl-guanosine (m2-7Gm), 2’-O-methyl-inosine (Im), l,2’-O-dirnethyl-inosine (m^m), 2’-O-ribosylguanosine (phosphate) (Gr(p)), 1 -thio-guanosine, 06-methyl-guanosine, 2’- F-ara-guanosine, and 2’-F-guanosine.

[0499] In embodiments, the modified mRNA comprises substitution of at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 92%, or at least about 95%, or at least about 98%, or at least about 99%, or more uracils with Nl-methyl- psuedouridine. In embodiments, the modified mRNA comprises substitution of 100% of uracils with N 1 -methyl-psuedouridine.

[0500] In embodiments, the therapeutic nucleic acid payload is conjugated with at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the plgR binder. In embodiments, the therapeutic nucleic acid payload is conjugated with about 1 to about 10, or about 1 to about 5, or about 1 to about 3, of about 2 to about 10, or about 2 to about 7, or about 2 to about 5, or about 3 to about 10, of about 3 to about 5, or about 3 to about 8, or about 4 to about 10, or about 4 to about 6, or about 4 to about 8, or about 5 to about 10, or about 5 to about 8 antibodies or antibody-like molecules.

[0501] In embodiments, the composition or the delivery system comprises at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the therapeutic nucleic acid payload. In embodiments, the copies of the therapeutic nucleic acid payload are independently selected from siRNA, miRNA, anti-miRNA, ASO, phosphorodiamidate PMO, tRNA, PNA, LNA, RNA aptamer, DNA aptamer, ribozyme, circRNA, RNA decoy, saRNA, and mRNA. In embodiments, at least one of the copies of the therapeutic nucleic acid payload are chemically modified according to any of the embodiments disclosed herein. In embodiments, at least one of the copies of the therapeutic nucleic acid payload is an siRNA or an ASO. In embodiments, all copies of the therapeutic nucleic acid payload are siRNA or ASO. In embodiments, the copies of siRNA or ASO have same or different sequences. In embodiments, the copies of siRNA or ASO are chemically modified according to any of the embodiments disclosed herein.

[0502] DB1 / 167593545.6 96Atorney Docket No. CVL-001PC / 140489-5001

[0503] In embodiments, the therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) comprises or further comprises is a polymer, which is conjugated with the therapeutic payload. In embodiments, the polymer is polyethylene glycol (PEG). In embodiments, one or more thiol group present in or added to the therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) are PEGylated using a technique known in the art, e.g., via thiol conjugation. In embodiments, one or more are amino groups present in or added to the therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) are PEGylated using a technique known in the art, e.g., via amine conjugation.

[0504] In embodiments, the therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) comprises or further comprises is a lipid moiety. In embodiments, carboxyl group of the lipid and an amine group of present in or added to the therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) are coupled to form an amide bond via chemical conjugation using methods known in the art, such as a carbodiimide-coupling method. In embodiments, a thiol group present in or added to the therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) and an amine group that are present in or added to the lipid, or a thiol group present in or added to the lipid and an amine group that are present in or added to the therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) are coupled using methods known in the art, such as a maleimide -coupling method. In embodiments derivatized therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) and the lipid, one having an azide group and the other having a triphosphine grouping are coupled using methods known in the art, such as a Staudinger ligation method.

[0505] The Linker

[0506] In aspects, the present disclosure provides a linker that connects a therapeutic payload (without limitation, e. ., a nucleic acid therapeutic payload) with a plgR binder.

[0507] In embodiments, the linker is branched. In embodiments, the linker is capable of linking at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the plgR binder with a copy of the therapeutic nucleic acid payload. In embodiments, the linker is capable of linking each copy of the therapeutic nucleic acid payload with a number of the antibodies or antibody-like molecules in the range of about 1 to about 10, or about 1 to about 5, or about 1 to about 3, of about 2 to about 10, or about 2 to about 7, or about 2 to about 5, or about 3

[0508] DB1 / 167593545.6 97Atorney Docket No. CVL-001PC / 140489-5001

[0509] to about 10, of about 3 to about 5, or about 3 to about 8, or about 4 to about 10, or about 4 to about 6, or about 4 to about 8, or about 5 to about 10, or about 5 to about 8.

[0510] In embodiments, the linker is capable of linking at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the therapeutic nucleic acid payload with a copy of the plgR binder. In embodiments, the linker is capable of linking each copy of the plgR binder with a number of the therapeutic nucleic acid payloads in the range of about 1 to about 10, or about 1 to about 5, or about 1 to about 3, of about 2 to about 10, or about 2 to about 7, or about 2 to about 5, or about 3 to about 10, of about 3 to about 5, or about 3 to about 8, or about 4 to about 10, or about 4 to about 6, or about 4 to about 8, or about 5 to about 10, or about 5 to about 8.

[0511] In embodiments, the linker is or comprises a direct bond or an atom such as oxygen or sulfur, a unit such as NRi, C(O), C(0)NH, SO, SO2, SO2NH or a chain of atoms selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenyl aryl alkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl al kenyl heteroaryl al keny 1 , al keny 1 h eteroary 1 al ky ny 1 , al kyny I heteroaryl al ky 1 alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, al kenyl heteroaryl, alkynylhereroaryl, which one or more methylenes can be interrupted or terminated by O, S, S(O), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where Ri is hydrogen, acyl, aliphatic or substituted aliphatic. Additional suitable linkers are disclosed in US Patent Application Publication Nos. US20160376585, US20170327524, US20190144488, US20230295630, which are herein incorporated by reference in their entirety.

[0512] In embodiments, the linker has the following structure:

[0513] DBl / 167593545.6 98Atorney Docket No. CVL-001PC / 140489-5001

[0514]

[0515] In embodiments, A is the therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) of any of the embodiments disclosed herein. In embodiments, t is an integer from 1 to 5. In embodiments, L3and L4are independently selected from a bond, -N(R4)-, -O-, -S-, -C(O)-, - N(R4)C(O)-, -C(O)N(R5)-, -N(R4)C(O)N(R5)-, -C(O)O-, -OC(O)-, -N(R4)C(O)O-, -OC(O)N(R5)- , -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R6)-O-, -O-P(S)(R6)-O-, -O-P(O)(NR4R5)-N-, -O- P(S)(NR4R5)-N-, -O-P(O)(NR4R5)-O-, -O-P(S)(NR4R5)-O-, -P(O)(NR4R5)-N-, -P(S)(NR4R5)-N-, -P(O)(NR4R5)-O-, -P(S)(NR4R5)-O-, -S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. In embodiments, each R4, R?and R6is independently hydrogen or unsubstituted Ci-C 10 alkyl. In embodiments, L5is -L5A-L3B-L5C-L5D-L5E-. In embodiments, L6is - L6A-L6B-L6C-L6D-L6E. In embodiments, L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6Eare independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, - C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. In embodiments, R1, R2, and R3are independently the plgR-binding plgR binder of any of the embodiments disclosed herein. Additional suitable linkers are disclosed in US Patent Application Publication Nos. US20230108783, US20230I58I50, US20240360447, US20240279267, and US20250027082, which are herein incorporated by reference in their entirety.

[0516] In embodiments, the linker is or comprises a peptide linker. In embodiments, the linker is cleavable. In embodiments, the linker is cleavable by a protease. In embodiments, the linker is non-cleavable.

[0517] In embodiments, the linker contacts the 5' end of the therapeutic nucleic acid payload and / or the 3' end of the therapeutic nucleic acid payload. In embodiments, the linker contacts an internal location within the therapeutic nucleic acid payload. In embodiments, the linker does not contact

[0518] DBl / 167593545.6 99Atorney Docket No. CVL-001PC / 140489-5001

[0519] the 5' end and / or the 3' end of the therapeutic nucleic acid payload. Tn embodiments, the linker contacts the N-terminus of the plgR binder and / or the C-terminus of the plgR binder. In embodiments, the linker contacts an internal amino acid residue of the plgR binder. In embodiments, the linker does not contact the N-terminus of the plgR binder. In embodiments, the linker does not contact the C-terminus of the plgR binder.

[0520] In embodiments, the linker comprises or further comprises is a polymer, which is conjugated with the linker. In embodiments, the polymer is polyethylene glycol (PEG). In embodiments, one or more thiol group present in the linker are PEGylated using a technique known in the art, e.g., via thiol conjugation. In embodiments, one or more are amino groups present in the linker are PEGylated using a technique known in the art, e.g., via amine conjugation.

[0521] In embodiments, where the linker is a peptide linker, one or more amino acids present in the linker are PEGylated. In embodiments, one or more amino acids present in the linker and selected from lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine and tyrosine are PEGylated using a technique known in the art, e.g., via chemical or enzymatic conjugation. In embodiments, one or more cysteine (Cys of C) residues present in the linker are PEGylated using a technique known in the art, e.g., via thiol conjugation. In embodiments, one or more are lysine (Lys or K) residues present in the linker are PEGylated using a technique known in the art, e.g., via amine conjugation. In embodiments, one or more are glutamine (Gin or Q) residues present in the linker are PEGylated using a technique known in the art, e.g., via transglutaminase (TGase) mediated enzymatic conjugation.

[0522] In embodiments, the linker comprises or further comprises is a lipid moiety. In embodiments, carboxyl group of the lipid and an amine group of present in the linker are coupled to form an amide bond via chemical conjugation using methods known in the art, such as a carbodiimide- coupling method. In embodiments, a thiol group present in the linker and an amine group that are present in the lipid, or a thiol group present in the lipid and an amine group that are present in the linker are coupled using methods known in the art, such as a maleimide -coupling method. In embodiments derivatized linker and the lipid, one having an azide group and the other having a triphosphine grouping are coupled using methods known in the art, such as a Staudinger ligation method.

[0523] DB1 / 167593545.6 100Attorney Docket No. CVL-001PC / 140489-5001

[0524] Selection of Polymeric Immunoglobulin Receptor (plgR) Binders

[0525] In aspects, the present disclosure provides a polymeric immunoglobulin receptor (plgR) binder that that promote the internalization of a therapeutic payload (without limitation, e.g., a nucleic acid therapeutic payload) in epithelial cells via the plgR-mediated internalization but then divert the internalized therapeutic payloads to the intracellular environment (rather than transcytosis). In embodiments, the plgR binder is selected based on binding to a plgR in a solution-based assay. Illustrative methods are known to skilled personnel and include, but are not limited to, enriching plgR binders from a library based on binding to a column having immobilized plgR (e.g., extracellular domain of plgR or a domain or a fragment thereof) or a fusion protein comprising plgR or a domain or a fragment thereof. In embodiments, the plgR binder is selected based on binding to a plgR in a cell-based assay based on binding to cells expressing plgR or a domain or a fragment thereof, or a fusion protein comprising plgR or a domain or a fragment thereof. In embodiments, the plgR binder is selected based on binding to a plgR using a phage display technology based on binding to cells expressing plgR or a domain or a fragment thereof, or a fusion protein comprising plgR or a domain or a fragment thereof. Illustrative fusion proteins comprising plgR or a domains or a fragments thereof are shown in Table 8.

[0526] Table 8: Sequences of Illustrative Non-limiting Fusion Proteins Comprising plgR or a Domain Thereof.

[0527] Details Amino Acid Sequence KSPIFGPEEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGCITLISS EGYVSSKYAGRANLTNFPENGTFVVNIAQLSQDDSGRYKCGLGINSRGLS FDVSLEVSQGPGLLNDTKVYTVDLGRTVTINCPFKTENAQKRKSLYKQIG LYPVLVIDSSGYVNPNYTGRIRLDIQGTGQLLFSVVINQLRLSDAGQYLCQ AGDDSNSNKKNADLQVLKPEPELVYEDLRGSVTFHCALGPEVANVAKFL

[0528] human plgR- CRQ S SGENCD VVVNTLGKRAPAFEGRILLNPQDKDGSF S VVITGLRKED A

[0529] Fc

[0530] GRYLCGAHSDGQLQEGSPIQAWQLFVNEESTIPRSPTVVKGVAGGSVAVL CPYNRKESKSIKYWCLWEGAQNGRCPLLVDSEGWVKAQYEGRLSLLEEP GNGTFTVILNQLTSRDAGFYWCLTNGDTLWRTTVEIKIIEGEPNLKVPGNV TAVLGETLKVPCHFPCKFSSYEKYWCKWNNTGCQALPSQDEGPSKAFVN CDENSRLVSLTLNLVTRADEGWYWCGVKQGHFYGETAAVYVAVEERKA

[0531]

[0532] DBl / 167593545.6 101Atorney Docket No. CVL-001PC / 140489-5001

[0533] AGSRDVSLAKADAAPDEKVLDSGFREIENKAIQDPRLFAEEKAVADTRDQ ADGSRASVDSGSSEEQGGSSRGGGGSEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGK (SEQ ID NO: 240) KSPVFGPQEVSSVEGNSVSIKCYYPPTSVNRHTRKYWCRKGASGRCITLVS SEGYVSSNYAGRANLTNFPENGTFVVNTAQLSRDDSGHYKCGLGINSRGL SFDVSLEVSQGPELPNGTEVYTVDVGRTVTIKCPFKTENAPKTKALYKKIG QTSVLVIDSRNYVNPNYKDRIRLRIPGTGQLIFTVVIDRLRLSDHGLYLCQA GDGSNRDEKNADLQVLEPEPELVYEDLRGSVTFHCALGLEVANVAKFLC RVNSRETCD VVINTLGKRD S AFEGRILLNPQDKDG SF S VVITGLRKEDEGR YLCGAHSDGQLQEGWPIQAWQLFVNEESTIPRSPTVVKGVAGGSVAVLCP YNPKE SQSLKYWCLWEGAQNGRCPLL VE SQGL VQEQ YEGRL SLLQEPGN

[0534] cynomolgus GTFTVILNQLTTQDAGFYWCLTNGDTRWRTTVEIKIIEGEPNLKVPGNVTA plgR-Fc VLGETLNIPCHFPCKFSSYEKYWCKWSNTGCQTLPSQDEGPSEAFVNCDE NSRLVSLTLNPVTRADEGWYWCGVKQGHFYGETAAVYVAVEEKKVAGS RDVSPAKADAAPDEKVLDSGVREIENKAIQDPRLFAEEKVVADTGDQAG GSRASVDSSSSEEQGGSSKGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGK (SEQ ID NO: 241) KSPIFGPQEVSSIEGDSVSITCYYPDTSVNRHTRKYWCRQGASGMCTTLISS NGYLSKEYSGRANLINFPENNTFVINIEQLTQDDTGSYKCGLGTSNRGLSF

[0535] mouse plgR- DVSLEVSQVPELPSDTHVYTKDIGRNVTIECPFKRENAPSKKSLCKKTNQS Fc CELVIDSTEKVNPSYIGRAKLFMKGTDLTVFYVNISHLTHNDAGLYICQAG EGP S ADKKN VDLQ VL APEPELL YKDLRS S VTFECDLGREVANEAK YLCR MNKETCDVIINTLGKRDPDFEGRILITPKDDNGRFSVLITGLRKEDAGHYQ

[0536]

[0537] DBl / 167593545.6 102Attorney Docket No. CVL-001PC / 140489-5001

[0538] CGAHSSGLPQEGWPIQTWQLFVNEESTIPNRRSVVKGVTGGSVAIACPYN PKESSSLKYWCRWEGDGNGHCPVLVGTQAQVQEEYEGRLALFDQPGNG TYTVILNQLTTEDAGFYWCLTNGDSRWRTTIELQVAEATREPNLEVTPQN ATAVLGETFTVSCHYPCKFYSQEKYWCKWSNKGCHILPSHDEGARQSSV SCDQSSQLVSMTLNPVSKEDEGWYWCGVKQGQTYGETTAIYIAVEERTR GS SHVNPTD AN ARAKVALEEEVVD S SI SEKENKAIPNPGPF ANEREIQNVG DQAQENRASGDAGSADGQSRSSSSKGGGGSEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLD SDGSFFL YSKLTVDK SRWQQGNVF SC S VMHEALHN HYTQKSLSLSPGK (SEQ ID NO: 242) QSPIFGPQDVSSIEGNSVSITCYYPDTSVNRHTRKYWCRQGANGYCATLIS SNGYLSKDYSGRASLINFPENSTFVINIAHLTQEDTGSYKCGLGTTNRGLFF DVSLEVSQVPEFPNDTHVYTKDIGRTVTIECRFKEGNAHSKKSLCKKRGES CEVVIDSTEYVDPSYKDRATLFMKGTSRDVFYVTISHLMPSDAGLYVCQA GEGPSADKNNADLQVLEPEPELLYKDLRSSVTFECDLGHEVANDAKYLC RKNKETCDVIINTLGKRDPAFEGRILLTPRDGKGRFSVLITGLRKEDAGHY QCGAHSSGLPQEGWPIQAWQLFVNEESTIPNTRSVVKGVTGGSVAIVCPY NPKESSSLKYWCHWEADENGRCPVLVGTQALVQEGYEGRLALFDQPGSG AYTVILNQLTTQDSGFYWCLTNGDSRWRSTIELQVAEATKKPDLEVTPQN

[0539] rat plgR-Fc ATAVIGETFTISCHYPCKFYSQEKYWCKWSNDGCHILPSHDEGARQSSVS CDQ S SQIVSMTLNP VKKEDEGW YWCGVKEGQ VYGETT AIYVA VEERTRG SPHINPTDANARAKVAPEEEVVESSVSENENKANLDPRLFADEREIQNAG DQAQENRASGNAGSAGGQSGSSKGGGGSEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK (SEQ ID NO: 243)

[0540]

[0541] DBl / 167593545.6 103Atorney Docket No. CVL-001PC / 140489-5001

[0542] EEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGCITLISSEGYVSS KYAGRANLTNFPENGTFVVNIAQLSQDDSGRYKCGLGINSRGLSFDVSLE VGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC

[0543] Domain 1 hu VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL plgR-Fc HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 244) KVYTVDLGRTVTINCPFKTENAQKRKSLYKQIGLYPVLVIDSSGYVNPNY TGRIRLDIQGTGQLLFSVVINQLRLSDAGQYLCQAGDGGGGSEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

[0544] Domain 2 hu FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC

[0545] plgR-Fc

[0546] KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 245) ELVYEDLRGSVTFHCALGPEVANVAKFLCRQSSGENCDVVVNTLGKRAP AFEGRILLNPQDKDGSFSVVITGLRKEDAGRYLCGAHGGGGSEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

[0547] Domain 3 hu FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGKEYI<C plgR-Fc

[0548] KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YP SDIA VEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDK SRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 246) TVVKGVAGGSVAVLCPYNRKESKSIKYWCLWEGAQNGRCPLLVDSEGW VKAQYEGRLSLLEEPGNGTFTVILNQLTSRDAGFYWCLTNGDTLWRTTVE IKIIEGEPNLKVPGNVTAVLGETLKVPCHFPCKFSSYEKYWCKWNNTGCQ

[0549] Domains 4 ALPSQDEGPSKAFVNCDENSRLVSLTLNLVTRADEGWYWCGVKGGGGSE and 5 hu PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS plgR-Fc HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 247)

[0550] DBl / 167593545.6 104Attorney Docket No. CVL-001PC / 140489-5001

[0551] GNVTAVLGETLKVPCHFPCKFSSYEKYWCKWNNTGCQALPSQDEGPSKA FVNCDENSRLVSLTLNLVTRADEGWYWCGVKGGGGSEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY

[0552] Domain 5 hu VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK

[0553] plgR-Fc

[0554] ALP APIEKTISKAKGQPREPQ VYTLPP SRDELTKNQ VSLTCLVKGF YP SDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 248) EEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGCITLISSEGYVSS KYAGRANLTNFPENGTFVVNIAQLSQDDSGRYKCGLGINSRGLSFDVSLE VSQGPGLLNDTKVYTVDLGRTVTINCPFKTENAQKRKSLYKQIGLYPVLV ID S SGYVNPNYTGRIRLDIQGTGQLLF S VVINQLRLSD AGQ YLCQ AGDD SN

[0555] Domains 1-4 SNKKNADLQVLKPEPELVYEDLRGSVTFHCALGPEVANVAKFLCRQSSGE hu plgR-His NCDVVVNTLGKRAPAFEGRILLNPQDKDGSFSVVITGLRKEDAGRYLCGA HSDGQLQEGSPIQAWQLFVNEESTIPRSPTVVKGVAGGSVAVLCPYNRKE SKSIKYWCLWEGAQNGRCPLLVDSEGWVKAQYEGRLSLLEEPGNGTFTV ILNQLTSRDAGFYWCLTNGDTLWRTTVEIKIIEGEPNLKVPGGGGSHHHH HH (SEQ ID NO: 249) ELVYEDLRGSVTFHCALGPEVANVAKFLCRQSSGENCDVVVNTLGKRAP AFEGRILLNPQDKDGSFSVVITGLRKEDAGRYLCGAHSDGQLQEGSPIQA WQLFVNEESTIPRSPTVVKGVAGGSVAVLCPYNRKESKSIKYWCLWEGA QNGRCPLL VD SEGWVKAQ YEGRL SLLEEPGNGTFT VILNQLT SRD AGF Y

[0556] Domains 3-6

[0557] WCLTNGDTLWRTTVEIKIIEGEPNLKVPGNVTAVLGETLKVPCHFPCKFSS

[0558] hu plgR-His

[0559] YEKYWCKWNNTGCQ ALP SQDEGP SK AF VNCDENSRLVSLTLNL VTRADE GWYWCGVKQGHFYGETAAVYVAVEERKAAGSRDVSLAKADAAPDEKV LDSGFREIENKAIQDPRLFAEEKAVADTRDQADGSRASVDSGSSEEQGGG GSHHHHHH (SEQ ID NO: 250)

[0560] In embodiments, the plgR binder is selected based on binding to a plgR in a cell-based assay based on binding to cells expressing plgR or a domain thereof, or a fusion protein comprising plgR or a domain or a fragment thereof having an amino acid sequence selected from the amino acid sequence of SEQ ID NOs: 240-250 or a variant thereof having at least about 70%, or at least about

[0561] DBl / 167593545.6 105Atorney Docket No. CVL-001PC / 140489-5001

[0562] 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

[0563] The Composition for Delivering a Therapeutic Pay load to an Epithelial Cell

[0564] In aspects, the present disclosure provides a composition for delivering a therapeutic to an epithelial cell of a subject, comprising: (a) a plgR binder of any of the embodiments disclosed herein, (b) a therapeutic nucleic acid payload of any of the embodiments disclosed herein, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b) of any of the embodiments disclosed herein.

[0565] In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: ((a) a plgR binder of any of the embodiments disclosed herein, (b) a therapeutic nucleic acid payload of any of the embodiments disclosed herein, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b) of any of the embodiments disclosed herein, wherein the therapeutic nucleic acid payload is capable of entering an endosome of the epithelial cell.

[0566] In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder of any of the embodiments disclosed herein, (b) a therapeutic nucleic acid payload of any of the embodiments disclosed herein, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b) of any of the embodiments disclosed herein, wherein the therapeutic nucleic acid payload is substantially retained in one or more subcellular compartments, optionally selected from nucleus, lysosome, endosome and cytoplasm, of the epithelial cell. In embodiments, the retention in in one or more subcellular compartments is detected or detectable by methods known in the art, e.g., fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT- qPCR), stem-loop RT-qPCR, and biological activity of the therapeutic nucleic acid payload. In aspects, the present disclosure provides a composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder of any of the embodiments disclosed herein, (b) a therapeutic nucleic acid payload of any of the embodiments disclosed herein, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b) of any of the embodiments disclosed herein, wherein the therapeutic nucleic acid payload is DB1 / 167593545.6 106Atorney Docket No. CVL-001PC / 140489-5001

[0567] delivered to the endosome, lysosome, nucleus, and / or cytoplasm of the epithelial cell. In embodiments, the delivery to the endosome and / or cytoplasm is detected or detectable by methods known in the art, e.g., fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, and biological activity of the therapeutic nucleic acid payload.

[0568] In aspects, the present disclosure provides a delivery system composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising: (a) a plgR binder of any of the embodiments disclosed herein, (b) a therapeutic nucleic acid payload of any of the embodiments disclosed herein, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b) of any of the embodiments disclosed herein, wherein the therapeutic nucleic acid payload does not substantially transcytose across the epithelial cell. In embodiments, the delivery to the transcytosis across the epithelial cell is detected or detectable by methods known in the art, e.g., in vitro immunological assays (e.g., fluorescence-based in vitro assays to detect the payload, the plgR binder translocalization across a monolayer) and trans well assay, coupled with a detection technique known in the art such as ELISA, western blot, or a combination thereof. In embodiments, the composition or the delivery system delivers the therapeutic nucleic acid payload to preferentially epithelial cells compared to non-epithelial cells compared to a control composition lacking the plgR binder. In embodiments, the delivery to epithelial cells and / or non- epithelial cells is detected or detectable by methods known in the art, e.g., fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, and biological activity of the therapeutic nucleic acid payload.

[0569] In embodiments, the composition or the delivery system modulates the expression and / or activity of a target of the therapeutic nucleic acid payload. In embodiments, the composition or the delivery system modulates the expression and / or activity of a target of the therapeutic nucleic acid payload substantially within the epithelial cell. In embodiments, the epithelial cell is located with gastrointestinal mucosa, lung, kidney, respiratory tract mucosa, gall bladder, or urinary bladder. In embodiments, the composition or the delivery system is not substantially transported across the epithelium. In embodiments, the amount of composition transported across the epithelium is at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold less than an amount transported across the epithelium of a control composition

[0570] DB1 / 167593545.6 107Atorney Docket No. CVL-001PC / 140489-5001

[0571] lacking the plgR binder. In embodiments, the amount of composition transported across the epithelium is at about 2-fold to about 10-fold, about 2-fold to about 4-fold, about 2-fold to about 6-fold, about 3-fold to about 6-fold, about 3-fold to about 10-fold, about 4-fold to about 8-fold, about 5-fold to about 10-fold less than an amount transported across the epithelium of a control composition lacking the plgR binder.

[0572] In embodiments, the amount of composition transported across the epithelium is less by at least about 5%, or at least about 10%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 33%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 66%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 99% compared to an amount of a control composition lacking the plgR binder transported across the epithelium. In embodiments, the amount of composition transported across the epithelium is less by about 5% to about 99%, or about 5% to about 75%, or about 5% to about 50%, or about 5% to about 66%, or about 10% to about 99%, or about 10% to about 75%, or about 10% to about 50%, or about 10% to about 66%, or about 25% to about 99%, or about 25% to about 75%, or about 25% to about 50%, or about 25% to about 66%, or about 33% to about 99%, or about 33% to about 75%, or about 33% to about 50%, or about 33% to about 66% compared to an amount of a control composition lacking the plgR binder transported across the epithelium.

[0573] In embodiments, a detectable amount of the composition or the delivery system is retained inside the epithelial cell. In embodiments, the endosomal retention is detected or detectable using methods known in the art, e.g., a technique selected from fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, and biological activity of the therapeutic nucleic acid payload.

[0574] In embodiments, the biological activity of the therapeutic nucleic acid payload is measured using techniques known in the art, e.g., detection of expression or activity of a gene as detected using RT-qPCR, ELISA, Western blotting, or a combination thereof; and a reporter-based assay to detect function of a nucleic acid in the cell. In embodiments, the methods include using cells that express a gene expressing a reporter (without limitation, e.g., firefly luciferase, Renilla luciferase, chloramphenicol acetyltransferase, and P-galactosidase), wherein the expression of the gene expressing the reporter is sensitive to activity of the nucleic acid payload.

[0575] DB1 / 167593545.6 108Atorney Docket No. CVL-001PC / 140489-5001

[0576] In embodiments, the composition or the delivery system is not substantially secreted by the epithelial cell. In embodiments, the secretion is detected or detectable using methods known in the art, c. ., using in vitro immunological assays (e.g., fluorescence-based in vitro assays to detect the payload, the plgR binder translocalization across a monolayer) and trans well assay, coupled with a detection technique known in the art such as ELISA, western blot, or a combination thereof. In embodiments, the amount of the composition or the delivery system is retained inside the epithelial cell is at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold greater than an amount retained inside the epithelial cell of a control composition lacking the plgR binder. In embodiments, the amount of the composition or the delivery system is retained inside the epithelial cell is at least about 2-fold to about 10-fold, about 2-fold to about 4-fold, about 2-fold to about 6-fold, about 3-fold to about 6-fold, about 3-fold to about 10-fold, about 4-fold to about 8-fold, about 5-fold to about 10-fold greater than an amount retained inside the epithelial cell of a control composition lacking the plgR binder.

[0577] In embodiments, the amount of the composition or the delivery system does not substantially contact the apical side of the epithelial cell. In embodiments, the amount of the composition or the delivery system contacting the basal side of the epithelial cell is at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold greater than the amount of composition contacting the apical side of the epithelial cell. In embodiments, the amount of the composition or the delivery system does not substantially contact the apical side of the epithelial cell. In embodiments, the amount of the composition or the delivery system contacting the basal side of the epithelial cell is at least about 2-fold to about 10-fold, about 2-fold to about 4-fold, about 2-fold to about 6-fold, about 3 -fold to about 6-fold, about 3 -fold to about 10-fold, about 4-fold to about 8-fold, about 5-fold to about 10-fold greater than the amount of composition contacting the apical side of the epithelial cell.

[0578] Pharmaceutical Compositions

[0579] In aspects, the present disclosure provides a pharmaceutical composition comprising the composition of any of the embodiments disclosed herein, and a pharmaceutically acceptable diluent or excipient. In aspects, the present disclosure provides a pharmaceutical composition comprising the delivery system of any of the embodiments disclosed herein, and a pharmaceutically acceptable diluent or excipient. In embodiments, the pharmaceutical

[0580] DB1 / 167593545.6 109Atorney Docket No. CVL-001PC / 140489-5001

[0581] composition is formulated for a parenteral administration. In embodiments, the pharmaceutical composition is formulated for an intravenous, subcutaneous, intramuscular, intradermal, intraperitoneal, epidural, or intrathecal administration.

[0582] In embodiments, the pharmaceutical composition comprises the composition or delivery system of any of the embodiments disclosed herein and a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, glidant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: water or other solvents, buffer or buffering agents (without limitation, e.g., a physiologically buffered saline), glycols, glycerol, oils, injectable organic ester, diluents, vehicles, solubilizers, stabilizers, bulking agents, cryoprotectants, isotonicity agents, dispersion media, coatings, antibacterial agents, antifungal agents, absorption delaying agents, glidants, cake forming agents, thickening agents, fdlers, disintegrating agents, adjuvants, binders, lubricants, gelatin, lactose, starch, cocoa butter, dextrose, sucrose, sorbitol, mannitol, gum acacia, alginates, cellulose, talc, magnesium stearate, polyoxyethylene sorbitan monolaurate, polyvinylpyro-lidone (PVP), and flavoring agents In embodiments, the pharmaceutical composition comprises the composition or delivery system of any of the embodiments disclosed herein and one or more of a sugar, optionally selected from lactose, glucose and sucrose; a starch, optionally selected from com starch and potato starch; a cellulose derivatives, optionally selected from sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; a lubricating agent, optionally selected from magnesium state, sodium lauryl sulfate and talc; an excipient, optionally selected from cocoa butter and suppository waxes; an oil, optionally selected from peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; a glycol, optionally selected from propylene glycol; a polyol, optionally selected from glycerin, sorbitol, mannitol and polyethylene glycol; an ester, optionally selected from ethyl oleate and ethyl laurate; agar; a buffering agent, optionally selected from phosphate (without limitation, e.g, phosphate buffered saline), acetate, citrate, prolamine, carbonate, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates or polyanhydrides; a bulking agent, optionally selected from polypeptides and amino acids; a serum component, optionally selected from serum albumin, HDL and LDL; and another non-toxic compatible substance employed in pharmaceutical formulations.

[0583] DB1 / 167593545.6 110Atorney Docket No. CVL-001PC / 140489-5001

[0584] In embodiments, the pharmaceutical composition is formulated for parenteral administration. In embodiments, the pharmaceutical composition is formulated for intradermal, intramuscular, intraperitoneal, intraarticular, intravenous, subcutaneous, intraarterial or transdermal administration.

[0585] In embodiments, the composition or delivery system of any of the embodiments disclosed herein that is introduced into cells by various transfection methods such as, e.g., methods that employ lipid particles. In embodiments, the pharmaceutical composition comprises the composition or delivery system of any of the embodiments disclosed herein and a delivery particle. In embodiments, the delivery particle comprises a lipid-based particle (e g., a lipid nanoparticle (LNP)), cationic lipid, or a biodegradable polymer). Lipid nanoparticle (LNP) delivery of gene transfer construct provides certain advantages, including transient, non-integrating expression to limit potential off-target events and immune responses, and efficient delivery with the capacity to transport large cargos. LNPs have been used for delivery of small interfering RNA (siRNA) and mRNA, and for in vitro and in vivo delivering CRISPR / Cas9 components to hepatocytes and the liver. For example, U.S. Pat. No. 10,195,291 describes the use of LNPs for delivery of RNA interference (RNAi) therapeutic agents.

[0586] In embodiments, the pharmaceutical composition in accordance with embodiments of the present disclosure is in the form of a LNP. In embodiments, the LNP comprises one or more lipids selected from l,2-dioleoyl-3-trimethylammonium propane (DOTAP); N,N-di oleyl -N,N- dimethylammonium chloride (DODAC); N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA); N,N-distearyl-N,N-dimethylammonium bromide (DDAB), a cationic cholesterol derivative mixed with dimethylaminoethane-carbamoyl (DC-Chol), phosphatidylcholine (PC), triolein (glyceryl trioleate), and l,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-[carboxy(poly ethylene glycol)-2000] (DSPE-PEG), 1,2-dimyristoyl-rac- glycero-3-methoxypolyethyleneglycol - 2000 (DMG-PEG 2K), and 1,2 distearol-sn-glycerol- 3phosphocholine (DSPC).

[0587] In embodiments, the pharmaceutical composition can have a lipid and a polymer in various ratios, wherein the lipid can be selected from, e g., DOTAP, DC-Chol, PC, Triolein, DSPE-PEG, and wherein the polymer can be, e.g., PEI or Poly Lactic-co-Glycolic Acid (PLGA). Any other lipid and polymer can be used additionally or alternatively. In embodiments, the ratio of the lipid and

[0588] DB1 / 167593545.6 111Atorney Docket No. CVL-001PC / 140489-5001

[0589] the polymer is about 0.5:1, or about 1:1, or about 1 :1.5, or about 1 :2, or about 1 :2.5, or about 1 :3, or about 3:1, or about 2.5:1, or about 2:1, or about 1.5:1, or about 1:1, or about 1:0.5.

[0590] In embodiments, the LNP comprises a cationic lipid, non-limiting examples of which include N,N- dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(I-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(I-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N,N-dimethyl-2,3- dioleyloxy)propylamine (DODMA), l,2-DiLinoleyloxy-N,N-dimethylaminopropane (DLinDMA), l,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 1,2- Dilinoleylcarbamoyloxy-3 -dimethylaminopropane (DLin-C-DAP), 1,2-Dilinoley oxy-3 - (dimethylamino)acetoxypropane (DLin-DAC), l,2-Dilinoleyoxy-3-morpholinopropane (DLin- MA), l,2-Dilinoleoyl-3 -dimethylaminopropane (DLinDAP), l,2-Dilinoleylthio-3- dimethylaminopropane (DLin-S-DMA), l-Linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), l,2-Dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.Cl), 1,2- Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.Cl), l,2-Dilinoleyloxy-3-(N- methylpiperazino)propane (DLin-MPZ), or 3-(N,N-Dilinoleylamino)-l,2-propanediol (DLinAP), 3-(N,N-Dioleylamino)-l,2-propanedio (DOAP), l,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLinDMA), 2,2-Dilinoleyl-4-dimethylaminomethyl-[l,3]-dioxolane (DLin-K-DMA) or analogs thereof, (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z, 12Z)-octadeca-9, 12-dienyl)tetrahydro-3aH- cyclopenta[d][l,3]dioxol-5-amine (ALN100), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen- 19-yl 4-(dimethylamino)butanoate (MC3), l,l'-(2-(4-(2-((2-(bis(2-‘)amino)ethyl)(2 hydroxy dodecyl)amino)ethyl) piperazin- l-yl)ethylazanediyl)didodecan-2-ol (Tech Gl), 1,2- Dilinoleyloxo-3-(2-N,N-dimethylamino) ethoxypropane (DLin-EG-DMA), or a mixture thereof. In embodiments, the LNP comprises one or more molecules selected from polyethylenimine (PEI) and poly(lactic-co-glycolic acid) (PLGA), and N-Acetylgalactosamine (GalNAc), which are suitable for hepatic delivery.

[0591] In embodiments, the composition or delivery system of any of the embodiments disclosed herein is formulated or complexed with PEI or a derivative thereof, such as polyethyleneimine- polyethyleneglycol-N-acetylgalactosamine (PELPEG-GAL) or poly ethyleneiminepoly ethyleneglycol -tri-N-acetylgalactosamine (PEI-PEG-triGAL) derivatives.

[0592] DB1 / 167593545.6 112Atorney Docket No. CVL-001PC / 140489-5001

[0593] In embodiments, the lipid nanoparticle comprises lipids selected from an ionizable lipid (e.g. an ionizable cationic lipid selected from DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin-MC3- DMA, 98N12-5, and C12-200); a structural lipid (e.g. distearoylphosphatidylcholine (DSPC)); cholesterol, and a polyethyleneglycol (PEG)-lipid (e.g. a PEG-di acylglycerol (DAG), a PEG- dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof, or a PEG-di lauryl oxy propyl (C12, a PEG-dimyristyloxypropyl (C14), a PEG-dipalmityloxypropyl (Cl 6), or a PEG-di stearyl oxy propyl (Cl 8)); l,2-dioleoyl-3-trimethylammoniumpropane (DOTAP); dioleoylphosphatidylethanolamine (DOPE); and the nucleic acid, e.g., the mmRNA. In embodiments, the LNP comprises a molar ratio of about 20-60% ionizable amino lipid, about 5-25% phospholipid, about 25-55% structural lipid, and about 0.5-1.5% PEG lipid. In embodiments, the ionizable amino lipid comprises the following formula:

[0594] In embodiments, the lipid nanoparticle comprises lipids selected from an ionizable lipid; a structural lipid; cholesterol, and a polyethyleneglycol (PEG)-lipid; l,2-dioleoyl-3- trimethylammoniumpropane (DOTAP); dioleoylphosphatidylethanolamine (DOPE); and the nucleic acid, e.g., the mmRNA. In embodiments, the ionizable lipid is an ionizable cationic lipid selected from DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin-MC3-DMA, 98N12-5, and C12-200. In embodiments, the polyethyleneglycol (PEG)-lipid is selected from a PEG- diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof, or a PEG-di lauryl oxypropyl (e.g., C12, a PEG-dimyristyloxypropyl (C14), a PEG-dipalmityloxypropyl (C16), or a PEG-distearyloxypropyl (C18)).

[0595] In embodiments, the LNP is a conjugated lipid, non-limiting examples of which include a polyethyleneglycol (PEG)-lipid including, without limitation, a PEG-diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof. The PEG-DAA conjugate may be, for example, a PEG-dilauryloxypropyl (C12, a PEG- dimyristyloxypropyl (C14), a PEG-dipalmityloxypropyl (C16), or a PEG-distearyloxypropyl (Cl 8).

[0596] In embodiments, the LNP formulations may further contain a phosphate conjugate, which can increase in vivo circulation times and / or increase the targeted delivery of the nanoparticle. Phosphate conjugates can be made by the methods described in, e.g., PCT International Patent Application Publication No. WO 2013 / 033438 or U.S. Pub. No. US 2013 / 0196948. The LNP

[0597] DB1 / 167593545.6 113Atorney Docket No. CVL-001PC / 140489-5001

[0598] formulation can also contain a polymer conjugate (e.g., a water-soluble conjugate) as described in, e.g., U.S. Patent Application Publication Nos. US 2013 / 0059360, US 2013 / 0196948, and US 2013 / 0072709, each of the references is herein incorporated by reference in its entirety.

[0599] In embodiments, the LNP formulations may comprise a carbohydrate carrier. As a non-limiting example, the carbohydrate carrier can include, but is not limited to, an anhydride-modified phytoglycogen or glycogen-type material, phytoglycogen octenyl succinate, phytoglycogen betadextrin, anhydride-modified phytoglycogen beta-dextrin (e.g., PCT International Patent Application Publication No. WO 2012 / 109121, herein incorporated by reference in its entirety). In embodiments, the LNP formulations can be coated with a surfactant or polymer to improve the delivery of the particle. In some embodiments, the LNP can be coated with a hydrophilic coating such as, but not limited to, PEG coatings and / or coatings that have a neutral surface charge as described in U.S. Patent Application Publication No. US 2013 / 0183244, herein incorporated by reference in its entirety. In embodiments, the LNP formulations can be engineered to alter the surface properties of particles so that the lipid nanoparticles can penetrate the mucosal barrier as described in U.S. Pat. No. 8,241,670 or PCT International Patent Application Publication No. WO 2013 / 110028, each of which is herein incorporated by reference in its entirety. In embodiments, the mucus penetrating LNP can be a hypotonic formulation comprising a mucosal penetration enhancing coating. The formulation can be hypotonic for the epithelium to which it is being delivered. Non-limiting examples of hypotonic formulations can be found in, e.g., PCT International Patent Application Publication No. WO 2013 / 110028, herein incorporated by reference in its entirety.

[0600] In embodiments, the composition or delivery system of any of the embodiments disclosed herein is formulated as a solid lipid nanoparticle (SLN), which can be spherical with an average diameter between 10 to 1000 nm. SLN possess a solid lipid core matrix that can solubilize lipophilic molecules and can be stabilized with surfactants and / or emulsifiers. Exemplary SLN can be those as described in PCT International Patent Application Publication No. WO 2013 / 105101, herein incorporated by reference in its entirety.

[0601] In embodiments, a nanoparticle is a particle having a diameter of less than about 1000 nm. In embodiments, nanoparticles of the present disclosure have a greatest dimension (e.g., diameter) of about 500 nm or less, or about 400 nm or less, or about 300 nm or less, or about 200 nm or less,

[0602] DB1 / 167593545.6 114Atorney Docket No. CVL-001PC / 140489-5001

[0603] or about 100 nm or less. In embodiments, nanoparticles of the present disclosure have a greatest dimension ranging between about 50 nm and about 150 nm, or between about 70 nm and about 130 nm, or between about 80 nm and about 120 nm, or between about 90 nm and about 110 nm. In embodiments, the nanoparticles of the present disclosure have a greatest dimension (e.g., a diameter) of about 100 nm.

[0604] In embodiments, the pharmaceutical composition comprising the composition or delivery system of any of the embodiments disclosed herein is formulated for sustained release, which, as used herein, refers to a pharmaceutical composition or compound that conforms to a release rate over a specific period of time. In embodiments, the period of time may include, but is not limited to, hours, days, weeks, months and years. As a non-limiting example, the sustained release nanoparticle of the mRNAs described herein can be formulated as disclosed in PCT International Patent Application Publication No. WO 2010 / 075072 and U.S. Patent Application Publication Nos. US 2010 / 0216804, US 2011 / 0217377, US 2012 / 0201859 and US 2013 / 0150295, each of which is herein incorporated by reference in their entirety.

[0605] Methods of Treatment

[0606] In aspects, the present disclosure provides a method for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject comprising administering to the subject the composition of any of the embodiments disclosed herein or the delivery system of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein, or the host cell of any of the embodiments disclosed herein.

[0607] In aspects, the present disclosure provides a host cell comprising the composition of any of the embodiments disclosed herein. In aspects, the present disclosure provides a host cell comprising the delivery system of any of the embodiments disclosed herein.

[0608] In aspects, the present disclosure provides a method for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject comprising (i) contacting a cell of the subject with the composition of any of the embodiments disclosed herein or the delivery system of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein, (ii) optionally, culturing the cell, and (iii) administering to the subject the cell.

[0609] DB1 / 167593545.6 115Atorney Docket No. CVL-001PC / 140489-5001

[0610] In aspects, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject the composition of any of the embodiments disclosed herein or the delivery system of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein, or the host cell of any of the embodiments disclosed herein.

[0611] In aspects, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, the method comprising (i) contacting a cell of the subject with the composition of any of the embodiments disclosed herein or the delivery system of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein, (ii) optionally, culturing the cell, and (iii) administering to the subject the cell.

[0612] Methods for Evaluating Receptor-Mediated Delivery of Therapeutic Nucleic Acid Payload to Epithelial Cells

[0613] In aspects, the present disclosure provides a method for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject comprising administering to the subject a composition comprising: (a) a polymeric immunoglobulin receptor (plgR) binder of any of the embodiments disclosed herein, (b) a therapeutic nucleic acid payload of any of the embodiments disclosed herein, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b) of any of the embodiments disclosed herein. In embodiments, the delivery is mediated by plgR- mediated internalization of the composition. In embodiments, the delivery is intracellular. In embodiments, the method comprises evaluating the delivery of the therapeutic nucleic acid payload to the epithelial cell. In embodiments, the method comprises evaluating the extent of delivery of the therapeutic nucleic acid payload to the epithelial cell.

[0614] In aspects, the present disclosure provides a method for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject comprising administering to the subject a delivery system comprising: (a) a polymeric immunoglobulin receptor (plgR) binder of any of the embodiments disclosed herein, (b) a therapeutic nucleic acid payload of any of the embodiments disclosed herein, and (c) optionally, a linker contacting both (a) and (b), wherein the linker connects (a) and (b) of any of the embodiments disclosed herein. In embodiments, the delivery is mediated by plgR- mediated internalization of the delivery system. In embodiments, the delivery is intracellular. In embodiments, the method comprises evaluating the delivery of the therapeutic nucleic acid

[0615] DB1 / 167593545.6 116Atorney Docket No. CVL-001PC / 140489-5001

[0616] payload to the epithelial cell. In embodiments, the method comprises evaluating the extent of delivery of the therapeutic nucleic acid payload to the epithelial cell.

[0617] In embodiments, the intracellular delivery of therapeutic nucleic acid payload to epithelial cells expressing the plgR is evaluated in vitro. In embodiments, the intracellular delivery of the therapeutic nucleic acid payload to epithelial cells expressing plgR is evaluated in vivo in a mammalian subject. In embodiments, the therapeutic nucleic acid payload is according to any of the embodiments disclosed herein. In embodiments, the therapeutic nucleic acid payload is or comprises a biologically active nucleic acid constructs capable of modulating gene expression within a target cell. In embodiments, the therapeutic nucleic acid payload is or comprises a nucleic acid therapeutic, including but not limited to small interfering RNA (siRNA), antisense oligonucleotides (ASO), microRNA modulators, messenger RNA (mRNA), guide RNA, and a gene editing component. In embodiments, the therapeutic nucleic acid payload is delivered intracellularly to a target cell (e.g., a plgR-expressing cell such as an epithelial cell).

[0618] In embodiments, the composition or the delivery system comprising the therapeutic nucleic acid payload comprises a plgR binder (e g., a plgR-targeting moiety) is operably linked to or conjugated to the therapeutic nucleic acid payload. In embodiments, the plgR binder comprises a receptorbinding ligand capable of binding plgR and mediating receptor-dependent internalization and / or transcytosis across epithelial barriers. In embodiments, the plgR binder comprises antibody fragments, single-domain antibodies, nanobodies, VHH domains, receptor-binding peptides, engineered scaffold proteins, ligands, or other molecules capable of specifically engaging plgR. In embodiments, the composition or the delivery system is administered to the subject systemically, for example by intravenous, subcutaneous, or other systemic routes of administration. In embodiments, a control subject (or a control group) is administered a nontargeted constructs (e.g., constructs lacking a plgR binder). In embodiments, a control subject (or a control group) is administered a construct directed to an alternative receptor. In embodiments, a control subject (or a control group) is administered a hepatocyte-targeted therapeutic nucleic acid payload. In embodiments, a control subject (or a control group) is administered a GalNAc-linked the therapeutic nucleic acid payload. In embodiments, a control subject (or a control group) is administered a vehicle control formulations.

[0619] DB1 / 167593545.6 117Atorney Docket No. CVL-001PC / 140489-5001

[0620] In embodiments, a biological sample comprising epithelial cell populations are collected for analysis following administration. In embodiments, the biological sample comprises a tissue that includes, but are not limited to, liver, kidney, lung, gastrointestinal tissues, spleen, and skeletal muscle. In embodiments, a portion of the tissue sample is preserved for whole-tissue molecular analysis. In embodiments, a portion of the tissue sample is processed to generate single-cell suspensions through mechanical disruption and / or enzymatic dissociation.

[0621] In embodiments, epithelial cell populations are enriched from dissociated tissues, optionally using magnetic separation, antibody-based sorting, density-based separation, negative selection strategies, or a combination thereof. In embodiments, the enrichment of epithelial cells is confirmed through detection of epithelial-associated markers, optionally EPCAM or a related marker. In embodiments, an expression of the targeting receptor (e.g., plgR) is verified through detection of plgR transcripts or protein in the enriched cell populations.

[0622] In embodiments, one or more total RNA samples are isolated from tissues or enriched cellular fractions, optionally using organic extraction, column purification, magnetic bead-based purification, or other suitable nucleic acid isolation techniques. In embodiments, the RNA samples are reverse transcribed to generate complementary DNA (cDNA), and expression levels of one or more target genes are quantified, optionally using quantitative polymerase chain reaction (qPCR), digital PCR, sequencing-based methods, hybridization-based assays, or other transcript quantification approaches.

[0623] In embodiments, one or more target transcript levels are normalized relative to one or more housekeeping genes. In embodiments, one or more target transcript levels (e.g., normalized target transcript levels) are analyzed relative to a baseline reference condition, such as untreated subjects or subjects receiving a control construct. In embodiments, the functional intracellular delivery of the nucleic acid payload is demonstrated by reduction of target gene expression in epithelial cell populations, as indicated by changes in threshold cycle values (ACt or AACt), transcript copy number, or other quantitative measures of gene expression inhibition.

[0624] In embodiments, the administration of the plgR-targeted composition or the plgR-targeted delivery system composition or system results in measurable knockdown of the target transcript in epithelial tissues of treated subjects. For example, in embodiments, reduction of the target gene expression in liver tissue following administration of plgR-targeted conjugates is shown in FIG. 12A.

[0625] DB1 / 167593545.6 118Atorney Docket No. CVL-001PC / 140489-5001

[0626] Similarly, knockdown of the target transcript in intestinal tissues, including a mixture of small intestine and large intestine samples enriched for epithelial cells, is demonstrated in FIG. 12B.

[0627] In embodiments, the method is used to evaluate receptor-mediated delivery, tissue distribution, cellular targeting specificity, and functional gene silencing or gene modulation mediated by plgR- targeted delivery constructs. The described approaches may further be used to compare delivery efficiency of receptor-targeted constructs relative to alternative delivery strategies, including hepatocyte-targeted oligonucleotide conjugates or non-targeted formulations.

[0628] Subjects and Animals

[0629] In embodiments, the subject and / or animal is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In embodiments, the subject and / or animal is a non-mammal, such, for example, a zebrafish. In embodiments, the subject and / or animal may comprise fluorescently-tagged cells (with e.g., GFP). In embodiments, the subject and / or animal is a transgenic animal comprising a fluorescent cell.

[0630] In embodiments, the subject and / or animal is a human. In embodiments, the human is a pediatric human. In embodiments, the human is an adult human. In embodiments, the human is a geriatric human. In embodiments, the human may be referred to as a patient.

[0631] In certain embodiments, the human has an age in a range of from about 0 months to about 6 months old, from about 6 to about 12 months old, from about 6 to about 18 months old, from about 18 to about 36 months old, from about 1 to about 5 years old, from about 5 to about 10 years old, from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old.

[0632] DB1 / 167593545.6 119Atorney Docket No. CVL-001PC / 140489-5001

[0633] In embodiments, the subject is a non-human animal, and therefore the disclosure pertains to veterinary use. In a specific embodiment, the non-human animal is a household pet. In another specific embodiment, the non-human animal is a livestock animal.

[0634] Kits

[0635] The disclosure provides kits that can simplify the administration of any agent described herein. An illustrative kit of the disclosure comprises the composition or delivery system of any of the embodiments disclosed herein in unit dosage form. In embodiments, the unit dosage form is a container, such as a pre-filled syringe, which can be sterile, containing any agent described herein and a pharmaceutically acceptable carrier, diluent, excipient, or vehicle. The kit can further comprise a label or printed instructions instructing the use of any agent described herein. The kit may also include a lid speculum, topical anesthetic, and a cleaning agent for the administration location. The kit can also further comprise one or more additional agent described herein. In embodiments, the kit comprises a container containing an effective amount of a composition of the disclosure and an effective amount of another composition, such those described herein.

[0636] EMBODIMENTS

[0637] Embodiment 1. A composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising:

[0638] (a) an antibody or antibody-like molecule capable of binding polymeric Ig receptor (plgR), (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and

[0639] (c) a linker contacting both (a) and (b).

[0640] Embodiment 2. A composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising:

[0641] (a) an antibody or antibody-like molecule capable of binding plgR,

[0642] (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and

[0643] (c) a linker contacting both (a) and (b),

[0644] wherein the therapeutic nucleic acid payload is capable of entering an endosome of the epithelial cell.

[0645] Embodiment s. A composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising:

[0646] DB1 / 167593545.6 120Atorney Docket No. CVL-001PC / 140489-5001

[0647] (a) an antibody or antibody-like molecule capable of binding plgR,

[0648] (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and

[0649] (c) a linker contacting both (a) and (b),

[0650] wherein the therapeutic nucleic acid payload is substantially retained in one or more subcellular compartments, optionally selected from nucleus, lysosome, endosome and cytoplasm, of the epithelial cell.

[0651] Embodiment 4. The composition of embodiment 3, wherein the retention in in one or more subcellular compartments is detected or detectable by one or more of fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, and a technique that can determine the presence or ongoing biological activity of the therapeutic nucleic acid payload.

[0652] 5. A composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising:

[0653] (a) an antibody or antibody-like molecule capable of binding plgR,

[0654] (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and

[0655] (c) a linker contacting both (a) and (b),

[0656] wherein the therapeutic nucleic acid payload is delivered to the endosome, lysosome, nucleus, and / or cytoplasm of the epithelial cell.

[0657] Embodiment 6. The composition of embodiment 5, wherein the delivery to the endosome and / or cytoplasm is detected or detectable by one or more of fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, or a technique that can determine the presence or ongoing biological activity of the therapeutic nucleic acid payload.

[0658] Embodiment 7. A delivery system composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising:

[0659] (a) an antibody or antibody-like molecule capable of binding plgR,

[0660] (b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and

[0661] (c) a linker contacting both (a) and (b),

[0662] wherein the therapeutic nucleic acid payload does not substantially transcytose across the epithelial cell.

[0663] DB1 / 167593545.6 121Atorney Docket No. CVL-001PC / 140489-5001

[0664] Embodiment 8. The delivery system of embodiment 7, wherein the delivery to the transcytosis across the epithelial cell is detected or detectable by an in vitro immunological assay and / or a trans well assay.

[0665] Embodiment 9. The composition of any one of embodiments 1-6 or the delivery system of embodiment 7 or embodiment 8, further comprising a PEG moiety and / or a lipid moiety contacting (i) the payload or at least one of the plurality of payloads, (ii) the antibody or antibody-like molecule, (iii) the linker or at least one of the plurality of linkers.

[0666] Embodiment 10. The composition of any one of embodiments 1-6 or embodiment 9, or the delivery system of any one of embodiments 7-9, wherein the therapeutic nucleic acid payload is one or more of small interfering RNA (siRNA), microRNA (miRNA), anti-miRNA, antisense oligonucleotide (ASO), pho sphorodi ami date morpholino oligomer (PMO, e.g, an exon skipping PMO), tRNA, peptide nucleic acid (PNA), locked nucleic acid (LNA), RNA aptamer, DNA aptamer, ribozyme, circular RNA (circRNA), RNA decoy, small activating RNA (saRNA), and messenger RNA (mRNA).

[0667] Embodiment 11. The composition of any one of embodiments 1-6 or embodiment 9 or embodiment 10, or the delivery system of any one of embodiments 7-10, wherein the therapeutic nucleic acid payload or the plurality of nucleic acid payloads comprises at least one inhibitory nucleic acid, and wherein the at least one inhibitory nucleic acid is capable of greater silencing of a target gene to compared to a control composition lacking the antibody or antibody-like molecule, as measured by levels of a protein encoded by the target gene and mRNA of the target gene. Embodiment 12. The composition or the delivery system of embodiment 11, wherein the therapeutic nucleic acid payload is an siRNA or an ASO.

[0668] Embodiment 13. The composition or the delivery system of embodiment 11 or embodiment 12, wherein the therapeutic nucleic acid payload comprises at least one chemically modified nucleotide.

[0669] Embodiment 14. The composition or the delivery system of embodiment 13, wherein the chemically modified nucleotide is selected from a deoxy -nucleotide, a 3 '-terminal deoxy -thymine (dT) nucleotide, a 2' O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy- modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted

[0670] DB1 / 167593545.6 122Atorney Docket No. CVL-001PC / 140489-5001

[0671] nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino-modifted nucleotide, a 2'-O-allyl-modified nucleotide, 2'-C-alkyl-modified nucleotide, 2'-hydroxyl-modified nucleotide, a 2 '-tn ethoxy ethyl modified nucleotide, a 2'-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural nucleobase comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5'-phosphate, a nucleotide comprising a 5'- phosphate mimic, a glycol modified nucleotide, and a 2-O-(N-methylacetamide) modified nucleotide, and a combination any two or more thereof.

[0672] Embodiment 15. The composition of any one of embodiments 1-6 or 9-14 or the delivery system of any one of embodiments 7-14, wherein the antibody is a monoclonal antibody or a polyclonal antibody, or a plgR-binding fragment thereof.

[0673] Embodiment 16. The composition or the delivery system of embodiment 15, whe...

Claims

1. Attorney Docket No. CVL-001PC / 140489-5001CLAIMS1. A composition comprising:(a) a polymeric Ig receptor (plgR) binder,(b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and(c) optionally, a linker contacting both (a) and (b),wherein the therapeutic nucleic acid payload is or comprises one or more of an small interfering RNA (siRNA), a microRNA (miRNA), or an antisense oligonucleotide (ASO), wherein the composition is formulated for delivering the therapeutic nucleic acid payload to an epithelial cell of a human subject in need thereof, andwherein the therapeutic nucleic acid payload is capable of entering an endosome of the epithelial cell.

2. A composition comprising:(a) a plgR binder,(b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and optionally a linker contacting both (a) and (b),wherein the composition is formulated for delivering the therapeutic nucleic acid payload to an epithelial cell of a human subject, andwherein the therapeutic nucleic acid payload is capable of entering an endosome of the epithelial cell.

3. A composition comprising:(a) a plgR binder,(b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and(c) a linker contacting both (a) and (b),wherein the composition is formulated for delivering the therapeutic nucleic acid payload to an epithelial cell of a human subject, andwherein the therapeutic nucleic acid payload is substantially retained in one or more subcellular compartments, optionally selected from nucleus, lysosome, endosome, or cytoplasm, of the epithelial cell.177DB1 / 167593545.6Attorney Docket No. CVL-001PC / 140489-50014. The composition of claim 3, wherein the retention in in one or more subcellular compartments is detected or detectable by one or more of fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, or a technique that can determine the presence or ongoing biological activity of the therapeutic nucleic acid payload.

5. A composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising:(a) a plgR binder,(b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and(c) optionally, a linker contacting both (a) and (b),wherein the therapeutic nucleic acid payload is delivered to the endosome, lysosome, nucleus, and / or cytoplasm of the epithelial cell.

6. The composition of claim 5, wherein the delivery to the endosome and / or cytoplasm is detected or detectable by one or more of fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, or a technique that can determine the presence or ongoing biological activity of the therapeutic nucleic acid payload.

7. A delivery system composition for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject, comprising:(a) a plgR binder,(b) a therapeutic nucleic acid payload or a plurality of nucleic acid payloads, and(c) optionally, a linker contacting both (a) and (b),wherein the therapeutic nucleic acid payload does not substantially transcytose across the epithelial cell.

8. The delivery system of claim 7, wherein the delivery to the transcytosis across the epithelial cell is detected or detectable by an in vitro immunological assay and / or a trans well assay.DBl / 167593545.6 178Attorney Docket No. CVL-001PC / 140489-50019. The composition of any one of claims 1-6 or the delivery system of claim 7 or claim 8, further comprising a PEG moiety and / or a lipid moiety contacting (i) the payload or at least one of the plurality of payloads, (ii) the plgR binder, (iii) the linker or at least one of the plurality of linkers.

10. The composition of any one of claims 1-6 or claim 9, or the delivery system of any one of claims 7-9, wherein the therapeutic nucleic acid payload is or comprises one or more of small interfering RNA (siRNA), microRNA (miRNA), anti-miRNA, antisense oligonucleotide (ASO), phosphorodiamidate morpholino oligomer (PMO, e.g., an exon skipping PMO), tRNA, peptide nucleic acid (PNA), locked nucleic acid (LNA), RNA aptamer, DNA aptamer, ribozyme, circular RNA (circRNA), RNA decoy, small activating RNA (saRNA), and messenger RNA (mRNA).

11. The composition of any one of claims 1-6 or claim 9 or claim 10, or the delivery system of any one of claims 7-10, wherein the therapeutic nucleic acid payload or the plurality of nucleic acid payloads comprises at least one inhibitory nucleic acid, and wherein the at least one inhibitory nucleic acid is capable of greater silencing of a target gene to compared to a control composition lacking the plgR binder, as measured by levels of a protein encoded by the target gene and mRNA of the target gene.

12. The composition or the delivery system of claim 11, wherein the therapeutic nucleic acid payload is an siRNA or an ASO.

13. The composition or the delivery system of claim 11 or claim 12, wherein the therapeutic nucleic acid payload comprises at least one chemically modified nucleotide.

14. The composition or the delivery system of claim 13, wherein the chemically modified nucleotide is selected from a deoxy -nucleotide, a 3 '-terminal deoxy-thymine (dT) nucleotide, a 2' O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino-modified nucleotide, a 2'-O-allyl-modified nucleotide, 2'-C-alkyl-modified nucleotide, 2'-hydroxyl-modified nucleotide, a 2'-methoxyethylDBl / 167593545.6 179Attorney Docket No. CVL-001PC / 140489-5001modified nucleotide, a 2'-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural nucleobase comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5 '-phosphate, a nucleotide comprising a 5 '-phosphate mimic, a glycol modified nucleotide, and a 2-O-(N-methylacetamide) modified nucleotide, and a combination any two or more thereof.

15. The composition of any one of claims 1-6 or 9-14 or the delivery system of any one of claims 7-14, wherein the composition or the delivery system comprises at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the therapeutic nucleic acid payload per copy of the plgR binder, optionally wherein the copies of the therapeutic nucleic acid payload are independently selected from siRNA, miRNA, anti-miRNA, ASO, PMO, tRNA, PNA, LNA, RNA aptamer, DNA aptamer, ribozyme, circRNA, RNA decoy, saRNA, and mRNA.

16. The composition or the delivery system of claim 15, wherein at least one of the copies of the therapeutic nucleic acid payload is an siRNA or an ASO.

17. The composition or the delivery system of claim 15 or claim 16, wherein all copies of the therapeutic nucleic acid payload are siRNA or ASO.

18. The composition or the delivery system of claim 17, wherein the copies of siRNA or ASO have same or different sequences.

19. The composition of any one of claims 1-6 or 9-18 or the delivery system of any one of claims 7-18, wherein the composition or the delivery system comprises at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the plgR binder per copy of the therapeutic nucleic acid payload.DBl / 167593545.6 180Attorney Docket No. CVL-001PC / 140489-500120. The composition or the delivery system of claim 19, wherein the copies of plgR binder have same or different structure and / or sequence.

21. The composition of any one of claims 1-6 or 8-20 or the delivery system of any one of claims 7-20, wherein the plgR binder binds to one or more of extracellular domains DI, D2, D3, D4, D5, and the cleavage domain (also known as D6) of plgR.

22. The composition or the delivery system of claim 21, wherein the plgR binder binds to the cleavage domain of plgR.

23. The composition or the delivery system of claim 21 or claim 22, wherein the plgR binder binds plgR at or near the J chain binding site for plgR of immunoglobulin A (IgA) or IgM.

24. The composition or the delivery system of any one of claims 1 to 23, wherein the plgR binder reduces or inhibits cleavage of extracellular domain D6 of plgR.

25. The composition or the delivery system of any one of claims 1 to 24, wherein:the plgR binder binds to plgR in a competitive manner with IgA and / or IgM, or the plgR binder comprises a plgR ligand selected from IgA, IgM, or a plgR-binding fragment thereof.

26. The composition or the delivery system of any one of claims 1 to 25, wherein the plgR binder binds to plgR with higher affinity than IgA or IgM binds to plgR.

27. The composition or the delivery system of any one of claims 1 to 26, wherein the plgR binder binds to plgR with higher affinity than the affinity with which a reference molecule that binds to plgR, optionally wherein:the reference molecule is a reference antibody, optionally selected from EPR23314-256, 825724, EPR23314-78, 7C1, LS-C163718, LS-C490449, and MAB27171, orDBl / 167593545.6 181Attorney Docket No. CVL-001PC / 140489-5001the reference molecule is a reference peptide, optionally having an amino acid sequence of amino acids 37-158 of Streptococcus pneumoniae secretory IgA-binding protein SpsA (SEQ ID NO: 234).

28. The composition or the delivery system of claim 26 or claim 27, wherein the affinity is measured or is measurable using enzyme-linked immunosorbent assay (ELISA), flow cytometry, surface plasmon resonance (SPR), fluorescence polarization binding assay, kinetic exclusion assay (KinExA), radioimmunoassay (RIA), or a combination thereof.

29. The composition of any one of claims 1-6 or 8-28 or the delivery system of any one of claims 7-28, wherein the plgR binder binds to plgR at an acidic pH.

30. The composition or the delivery system of claim 29, wherein the plgRbinder binds to plgR at pH of about 4.5 to about 6.5.

31. The composition of any one of claims 1-6 or 8-30 or the delivery system of any one of claims 7-30, wherein the plgR binder is an antibody or antibody-like molecule.

32. The composition or the delivery system of claim 31, wherein the antibody is a monoclonal antibody or a polyclonal antibody, or a plgR-binding fragment thereof.

33. The composition or the delivery system of claim 32, wherein the antibody is a monoclonal antibody, or a plgR binding fragment thereof.

34. The composition or the delivery system of claim 31, wherein the antibody -like molecule is selected from a recombinant heavy-chain-only antibody (VHH), single-domain antibody, singlechain antibody (scFv), shark heavy-chain-only antibody (VNAR), microprotein (cysteine knot protein, knottin), DARPin, Tetranectin, Affibody, Affitin, Alphabody, Gastrobody, Monobody, nanoCLAMP, Optimer, Repebody, fibronectin domain-derived antibody mimic, Centyrin, Obody, Transbody, Anticalin, AdNectin, Affilin, Affimer, Microbody, aptamer, alterase, plastic antibody, phylomer, stradobody, maxibody, evibody, fynomer, armadillo repeat protein, Kunitz domain,DBl / 167593545.6 182Attorney Docket No. CVL-001PC / 140489-5001avimer, atrimer, probody, immunobody, triomab, troybody, pepbody, vaccibody, UniBody, DuoBody, Fv, Fab, Fab', and F(ab')2, or a plgR binding fragment thereof.

35. The composition or the delivery system of claim 34, wherein the antibody-like molecule is a VHH.

36. The composition or the delivery system of claim 35, wherein the antibody or antibody-like molecule comprises:a heavy chain variable region (VH) comprising a HCDR1 having an amino acid sequence SYRMG (SEQ ID NO: 1), a HCDR2 having an amino acid sequence AIDWNGRGTYYRYYADSVKG (SEQ ID NO: 2), and a HCDR3 having an amino acid sequence TTVLTDPRVLNEYAT (SEQ ID NO: 3);a VH comprising a HCDR1 having an amino acid sequence INVMG (SEQ ID NO: 5), a HCDR2 having an amino acid sequence RINGGGITHYAESVKG (SEQ ID NO: 6), and a HCDR3 having an amino acid sequence DVFGSSGYVETY (SEQ ID NO: 7);a VH comprising a HCDR1 having an amino acid sequence SDAMG (SEQ ID NO: 9), a HCDR2 having an amino acid sequence FISGGGTTTYADSVKG (SEQ ID NO: 10), and a HCDR3 having an amino acid sequence PLTSR (SEQ ID NO: 11);a VH comprising a HCDR1 having an amino acid sequence TYRMG (SEQ ID NO: 13), a HCDR2 having an amino acid sequence AIRWSGGRTLYADSVKG (SEQ ID NO: 14), and a HCDR3 having an amino acid sequence DLAEYSGTYSSPADSPAGYDY (SEQ ID NO: 15);a VH comprising a HCDR1 having an amino acid sequence FNTYAMG (SEQ ID NO: 17), a HCDR2 having an amino acid sequence SITWNGGSTSYADSVKG (SEQ ID NO: 18), and a HCDR3 having an amino acid sequence ARYYVSGTYFPANY (SEQ ID NO: 19); a VH comprising a HCDR1 having an amino acid sequence SYRMG (SEQ ID NO: 21), a HCDR2 having an amino acid sequence AIDWNGRGTYYRYYADSVKG (SEQ ID NO: 22), and a HCDR3 having an amino acid sequence GSIDLNWYGGMDY (SEQ ID NO: 23);DBl / 167593545.6 183Atorney Docket No. CVL-001PC / 140489-5001a VH comprising a HCDR1 having an amino acid sequence SNAMG (SEQ ID NO: 25), a HCDR2 having an amino acid sequence FIDRIATTTIATSVKG (SEQ ID NO: 26), and a HCDR3 having an amino acid sequence PLTAR (SEQ ID NO: 27);a VH comprising a HCDR1 having an amino acid sequence SYAMG (SEQ ID NO: 29), aHCDR2 having an amino acid sequence AITWNGGTTYYADSVKG (SEQ ID NO: 30), and a HCDR3 having an amino acid sequence DPFNQGY (SEQ ID NO: 31);a VH comprising a HCDR1 having an amino acid sequence INVMG (SEQ ID NO: 33), a HCDR2 having an amino acid sequence RITGGGSTHYAESVKG (SEQ ID NO: 34), and a HCDR3 having an amino acid sequence MVNPIITAWGTIGVREIPDYDY (SEQ ID NO: 35);a VH comprising a HCDR1 having an amino acid sequence TYRMG (SEQ ID NO: 37), a HCDR2 having an amino acid sequence AISWSGGSTTYADPVKG (SEQ ID NO: 38), and a HCDR3 having an amino acid sequence DQRGY (SEQ ID NO: 39);a VH comprising a HCDR1 having an amino acid sequence RYAMG (SEQ ID NO: 41), a HCDR2 having an amino acid sequence AISWSGSSAGYGDSVKG (SEQ ID NO: 42), and a HCDR3 having an amino acid sequence DPFNQGY (SEQ ID NO: 43);a VH comprising a HCDR1 having an amino acid sequence YYAMG (SEQ ID NO: 45), a HCDR2 having an amino acid sequence VINWSGGTTSYADSVK (SEQ ID NO: 46), and a HCDR3 having an amino acid sequence DSIYRTSKDYNY (SEQ ID NO: 47);a VH comprising a HCDR1 having an amino acid sequence NYVMG (SEQ ID NO: 49), a HCDR2 having an amino acid sequence AISWSGVTTYHYSADS (SEQ ID NO: 50), and aHCDR3 having an amino acid sequence RGRTGSDPRKGDDYDY (SEQ ID NO: 51);a VH comprising a HCDR1 having an amino acid sequence YYAIG (SEQ ID NO: 53), a HCDR2 having an amino acid sequence CTSSSDGSTYYADSVK (SEQ ID NO: 54), and a HCDR3 having an amino acid sequence TFGDACTVVAGIPDQYDFGS (SEQ ID NO: 55);a VH comprising a HCDR1 having an amino acid sequence YYAIG (SEQ ID NO: 57), a HCDR2 having an amino acid sequence CISSSDMSDGITYYADSVKG (SEQ ID NO: 58), and aHCDR3 having an amino acid sequence TFGDACTVVAGIPDQADFDS (SEQ ID NO: 59);a VH comprising a HCDR1 having an amino acid sequence YYDIG (SEQ ID NO: 61), a HCDR2 having an amino acid sequence CTSSSDGSTYYADSVKG (SEQ ID NO: 62), and a HCDR3 having an amino acid sequence TFGDACTVVAGIPOQYDFGS (SEQ ID NO: 63);DBl / 167593545.6 184Atorney Docket No. CVL-001PC / 140489-5001a VH comprising a HCDR1 having an amino acid sequence DYIMG (SEQ ID NO: 65), a HCDR2 having an amino acid sequence AISWTGDSTYYKYYSDSAKG (SEQ ID NO: 66), and a HCDR3 having an amino acid sequence RTFRIDYDPRTASTYNY (SEQ ID NO: 67);a VH comprising a HCDR1 having an amino acid sequence SVTMG (SEQ ID NO: 69), aHCDR2 having an amino acid sequence AISWSGGSTYYADSVKG (SEQ ID NO: 70), and a HCDR3 having an amino acid sequence VVPSDPIIYYTDYVDYDY (SEQ ID NO: 71);a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 73), a HCDR2 having an amino acid sequence CISSRDGITYYADSVKG (SEQ ID NO: 74), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 75);a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 77), a HCDR2 having an amino acid sequence CISSRDGTTYYADSVKG (SEQ ID NO: 78), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 79);a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 81), a HCDR2 having an amino acid sequence CINNSDGSTYYADSVKG (SEQ ID NO: 82), and a HCDR3 having an amino acid sequence DFVGGSYCLFPTYNY (SEQ ID NO: 83);a VH comprising a HCDR1 having an amino acid sequence TYAMA (SEQ ID NO: 85), a HCDR2 having an amino acid sequence AISWSSDMTYYLDSVKG (SEQ ID NO: 86), and a HCDR3 having an amino acid sequence GAYYAGSSTSPYNY (SEQ ID NO: 87); a VH comprising a HCDR1 having an amino acid sequence IYTMG (SEQ ID NO: 89), a HCDR2 having an amino acid sequence ALRWSGGSTYTFYADSVKG (SEQ ID NO: 90), and a HCDR3 having an amino acid sequence VDPRAPYMRPD STDS YAY (SEQ ID NO: 91);a VH comprising a HCDR1 having an amino acid sequence YYDLAARA (SEQ ID NO: 93), a HCDR2 having an amino acid sequence ASTWNGGYTYYVDSVKG (SEQ ID NO: 94), and a HCDR3 having an amino acid sequence RRAYSSDLHDYRTFDY (SEQ ID NO: 95);a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 97), a HCDR2 having an amino acid sequence CISRSDGSTYYADSVKG (SEQ ID NO: 98), and a HCDR3 having an amino acid sequence DAIGSFPCPAGVYDY (SEQ ID NO: 99);a VH comprising a HCDR1 having an amino acid sequence SYWMY (SEQ ID NO: 101), a HCDR2 having an amino acid sequence AISTGGGGTYYADSVKG (SEQ ID NO:DBl / 167593545.6 185Attorney Docket No. CVL-001PC / 140489-5001102), and a HCDR3 having an amino acid sequence DEAPTFDYSGNYAYTGSDPNDY (SEQ ID NO: 103);a VH comprising a HCDR1 having an amino acid sequence RYGMY (SEQ ID NO: 105), a HCDR2 having an amino acid sequence TINSGGDYIIYADSVKG (SEQ ID NO: 106), and a HCDR3 having an amino acid sequence GYRGSEWPPPAFTLQRADFAS (SEQ ID NO: 107);a VH comprising a HCDR1 having an amino acid sequence EYNMG (SEQ ID NO: 109), a HCDR2 having an amino acid sequence AIAWTGTNSYYVDSVKG (SEQ ID NO: 110), and a HCDR3 having an amino acid sequence EGYVSNFPRSSADEYDY (SEQ ID NO: in);a VH comprising a HCDR1 having an amino acid sequence SYAMT (SEQ ID NO: 113), a HCDR2 having an amino acid sequence IISGNGGSTSYADSVKG (SEQ ID NO: 114), and a HCDR3 having an amino acid sequence WDGLGTLP (SEQ ID NO: 11 );a VH comprising a HCDR1 having an amino acid sequence TNDMG (SEQ ID NO: 117), a HCDR2 having an amino acid sequence RISRGSSTIYTESVKG (SEQ ID NO: 118), and a HCDR3 having an amino acid sequence DMLPSDLSHGYYYRDY (SEQ ID NO: 119); ora VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 121), a HCDR2 having an amino acid sequence CISSRDGMTYYADSVKG (SEQ ID NO: 122), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 123).

37. The composition or the delivery system of claim 36, wherein the antibody or antibody-like molecule comprises:a VH comprising a HCDR1 having an amino acid sequence SYRMG (SEQ ID NO: 1), a HCDR2 having an amino acid sequence AIDWNGRGTYYRYYADSVKG (SEQ ID NO: 2), and a HCDR3 having an amino acid sequence TTVLTDPRVLNEYAT (SEQ ID NO: 3), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 4;DBl / 167593545.6 186Attorney Docket No. CVL-001PC / 140489-5001a VH comprising a HCDR1 having an amino acid sequence INVMG (SEQ TD NO: 5), a HCDR2 having an amino acid sequence RINGGGITHYAESVKG (SEQ ID NO: 6), and a HCDR3 having an amino acid sequence DVFGSSGYVETY (SEQ ID NO: 7), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 8;a VH comprising a HCDR1 having an amino acid sequence SDAMG (SEQ ID NO: 9), a HCDR2 having an amino acid sequence FISGGGTTTYADSVKG (SEQ ID NO: 10), and a HCDR3 having an amino acid sequence PLTSR (SEQ ID NO: 11), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 12;a VH comprising a HCDR1 having an amino acid sequence TYRMG (SEQ ID NO: 13), a HCDR2 having an amino acid sequence AIRWSGGRTLYADSVKG (SEQ ID NO: 14), and a HCDR3 having an amino acid sequence DLAEYSGTYSSPADSPAGYDY (SEQ ID NO: 15), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 16;a VH comprising a HCDR1 having an amino acid sequence FNTYAMG (SEQ ID NO: 17), a HCDR2 having an amino acid sequence SITWNGGSTSYADSVKG (SEQ ID NO: 18), and a HCDR3 having an amino acid sequence A YYVSGTYFPANY (SEQ ID NO: 19), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 20;a VH comprising a HCDR1 having an amino acid sequence SYRMG (SEQ ID NO: 21), a HCDR2 having an amino acid sequence AIDWNGRGTYYRYYADSVKG (SEQ ID NO: 22), and a HCDR3 having an amino acid sequence GSIDLNWYGGMDY (SEQ ID NO: 23), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 24;DBl / 167593545.6 187Attorney Docket No. CVL-001PC / 140489-5001a VH comprising a HCDR1 having an amino acid sequence SNAMG (SEQ ID NO: 25), a HCDR2 having an amino acid sequence FIDRIATTTIATSVKG (SEQ ID NO: 26), and a HCDR3 having an amino acid sequence PLTAR (SEQ ID NO: 27), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 28;a VH comprising a HCDR1 having an amino acid sequence SYAMG (SEQ ID NO: 29), aHCDR2 having an amino acid sequence AITWNGGTTYYADSVKG (SEQ ID NO: 30), and a HCDR3 having an amino acid sequence DPFNQGY (SEQ ID NO: 31), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 32;a VH comprising a HCDR1 having an amino acid sequence INVMG (SEQ ID NO: 33), a HCDR2 having an amino acid sequence RITGGGSTHYAESVKG (SEQ ID NO: 34), and a HCDR3 having an amino acid sequence MVNPIITAWGTIGVREIPDYDY (SEQ ID NO: 35), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 36;a VH comprising a HCDR1 having an amino acid sequence TYRMG (SEQ ID NO: 37), a HCDR2 having an amino acid sequence AISWSGGSTTYADPVKG (SEQ ID NO: 38), and a HCDR3 having an amino acid sequence DQRGY (SEQ ID NO: 39), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 40;a VH comprising a HCDR1 having an amino acid sequence RYAMG (SEQ ID NO: 41), a HCDR2 having an amino acid sequence AISWSGSSAGYGDSVKG (SEQ ID NO: 42), and a HCDR3 having an amino acid sequence DPFNQGY (SEQ ID NO: 43), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 44;DBl / 167593545.6 188Attorney Docket No. CVL-001PC / 140489-5001a VH comprising a HCDR1 having an amino acid sequence YYAMG (SEQ ID NO: 45), a HCDR2 having an amino acid sequence VINWSGGTTSYADSVK (SEQ ID NO: 46), and a HCDR3 having an amino acid sequence DSIYRTSKDYNY (SEQ ID NO: 47), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 48;a VH comprising a HCDR1 having an amino acid sequence NYVMG (SEQ ID NO: 49), a HCDR2 having an amino acid sequence AISWSGVTTYHYSADS (SEQ ID NO: 50), and a HCDR3 having an amino acid sequence RGRTGSDPRKGDDYDY (SEQ ID NO: 51), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 52;a VH comprising a HCDR1 having an amino acid sequence YYAIG (SEQ ID NO: 53), a HCDR2 having an amino acid sequence CTSSSDGSTYYADSVK (SEQ ID NO: 54), and a HCDR3 having an amino acid sequence TFGDACTVVAGIPDQYDFGS (SEQ ID NO: 55), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 56;a VH comprising a HCDR1 having an amino acid sequence YYAIG (SEQ ID NO: 57), a HCDR2 having an amino acid sequence CISSSDMSDGITYYADSVKG (SEQ ID NO: 58), and aHCDR3 having an amino acid sequence TFGDACTVVAGIPDQADFDS (SEQ ID NO: 59), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 60;a VH comprising a HCDR1 having an amino acid sequence YYDIG (SEQ ID NO: 61), a HCDR2 having an amino acid sequence CTSSSDGSTYYADSVKG (SEQ ID NO: 62), and a HCDR3 having an amino acid sequence TFGDACTVVAGIPOQYDFGS (SEQ ID NO: 63), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 64;DBl / 167593545.6 189Attorney Docket No. CVL-001PC / 140489-5001a VH comprising a HCDR1 having an amino acid sequence DYIMG (SEQ ID NO: 65), a HCDR2 having an amino acid sequence AISWTGDSTYYKYYSDSAKG (SEQ ID NO: 66), and a HCDR3 having an amino acid sequence RTFRIDYDPRTASTYNY (SEQ ID NO: 67), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 68;a VH comprising a HCDR1 having an amino acid sequence SVTMG (SEQ ID NO: 69), aHCDR2 having an amino acid sequence AISWSGGSTYYADSVKG (SEQ ID NO: 70), and a HCDR3 having an amino acid sequence VVPSDPIIYYTDYVDYDY (SEQ ID NO: 71), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 72;a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 73), a HCDR2 having an amino acid sequence CISSRDGITYYADSVKG (SEQ ID NO: 74), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 75), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 76;a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 77), a HCDR2 having an amino acid sequence CISSRDGTTYYADSVKG (SEQ ID NO: 78), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 79), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 80;a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 81), a HCDR2 having an amino acid sequence CINNSDGSTYYADSVKG (SEQ ID NO: 82), and a HCDR3 having an amino acid sequence DFVGGSYCLFPTYNY (SEQ ID NO: 83), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 84;DBl / 167593545.6 190Attorney Docket No. CVL-001PC / 140489-5001a VH comprising a HCDR1 having an amino acid sequence TYAMA (SEQ ID NO: 85), a HCDR2 having an amino acid sequence AISWSSDMTYYLDSVKG (SEQ ID NO: 86), and a HCDR3 having an amino acid sequence GAYYAGSSTSPYNY (SEQ ID NO: 87), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 88;a VH comprising a HCDR1 having an amino acid sequence IYTMG (SEQ ID NO: 89), a HCDR2 having an amino acid sequence ALRWSGGSTYTFYADSVKG (SEQ ID NO: 90), and a HCDR3 having an amino acid sequence VDPRAPYMRPDSTDSYAY (SEQ ID NO: 91), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 92 ;a VH comprising a HCDR1 having an amino acid sequence YYDLAARA (SEQ ID NO: 93), a HCDR2 having an amino acid sequence ASTWNGGYTYYVDSVKG (SEQ ID NO: 94), and a HCDR3 having an amino acid sequence RRAYSSDLHDYRTFDY (SEQ ID NO: 95), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 96;a VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 97), a HCDR2 having an amino acid sequence CISRSDGSTYYADSVKG (SEQ ID NO: 98), and a HCDR3 having an amino acid sequence DAIGSFPCPAGVYDY (SEQ ID NO: 99), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 100;a VH comprising a HCDR1 having an amino acid sequence SYWMY (SEQ ID NO: 101), a HCDR2 having an amino acid sequence AISTGGGGTYYADSVKG (SEQ ID NO: 102), and a HCDR3 having an amino acid sequence DEAPTFDYSGNYAYTGSDPNDY (SEQ ID NO: 103), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 104;DBl / 167593545.6 191Attorney Docket No. CVL-001PC / 140489-5001a VH comprising a HCDR1 having an amino acid sequence RYGMY (SEQ ID NO: 105), a HCDR2 having an amino acid sequence TINSGGDYIIYADSVKG (SEQ ID NO: 106), and a HCDR3 having an amino acid sequence GYRGSEWPPPAFTLQRADFAS (SEQ ID NO: 107), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 108;a VH comprising a HCDR1 having an amino acid sequence EYNMG (SEQ ID NO: 109), a HCDR2 having an amino acid sequence AIAWTGTNSYYVDSVKG (SEQ ID NO: 110), and a HCDR3 having an amino acid sequence EGYVSNFPRSSADEYDY (SEQ ID NO: 111), wherein the antibody or antibody -like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 112;a VH comprising a HCDR1 having an amino acid sequence SYAMT (SEQ ID NO: 113), a HCDR2 having an amino acid sequence IISGNGGSTSYADSVKG (SEQ ID NO: 114), and a HCDR3 having an amino acid sequence WDGLGTLP (SEQ ID NO: 115), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 116;a VH comprising a HCDR1 having an amino acid sequence TNDMG (SEQ ID NO: 117), a HCDR2 having an amino acid sequence RISRGSSTIYTESVKG (SEQ ID NO: 118), and a HCDR3 having an amino acid sequence DMLPSDLSHGYYYRDY (SEQ ID NO: 119), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 120; ora VH comprising a HCDR1 having an amino acid sequence DYAIG (SEQ ID NO: 121), a HCDR2 having an amino acid sequence CISSRDGMTYYADSVKG (SEQ ID NO: 122), and a HCDR3 having an amino acid sequence DLVGSFPCPVAAYDY (SEQ ID NO: 123), wherein the antibody or antibody-like molecule comprises and amino acid sequence that is at least about 90%, or at least about 95%, or at least about 98% identical with the amino acid sequence of SEQ ID NO: 124.DBl / 167593545.6 192Attorney Docket No. CVL-001PC / 140489-500138. The composition or the delivery system of claim 36 or claim 37, wherein the antibody or antibody-like molecule comprises an amino acid sequence selected from the amino acid sequence of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124 and 153-186.

39. The composition or the delivery system of any one of claims 31-38, wherein the composition or the delivery system comprises at least 2, or at least 3, or at least 4 or more antibodies, antibody -like molecules or plgR binding fragments thereof per copy of the therapeutic nucleic acid payload.

40. The composition or the delivery system of claim 39, wherein:the antibodies are independently monoclonal antibodies, or polyclonal antibodies or plgR binding fragments thereof; and / orthe antibody-like molecule is independently selected from a recombinant heavy-chain-only antibody (VHH), single-domain antibody, single-chain antibody (scFv), shark heavy-chain-only antibody (VNAR), microprotein (cysteine knot protein, knottin), DARPin, Tetranectin, Affibody, Affitin, Alphabody, Gastrobody, Monobody, nanoCLAMP, Optimer, Repebody, fibronectin domain-derived antibody mimic, Centyrin, Obody, Transbody, Anticalin, AdNectin, Affilin, Affimer, Microbody, aptamer, alterase, plastic antibody, phylomer, stradobody, maxibody, evibody, fynomer, armadillo repeat protein, Kunitz domain, avimer, atrimer, probody, immunobody, triomab, troybody, pepbody, vaccibody, UniBody, DuoBody, Fv, Fab, Fab', and F(ab')2, or a plgR binding fragment thereof.

41. The composition or the delivery system of any one of claims 31-40, wherein the antibody, antibody-like molecule or plgR binding fragment thereof is in form of an antibody format selected from multivalent tandem binding fragment (e.g., multivalent tandem VHHs or multivalent tandem scFvs), single a binding fragment (e.g., VHH-His or scFv-His), a monomeric Fc domain-binding fragment (e.g., VHH- monomeric Fc domain or scFv- monomeric Fc domain), binding fragment- Fc domain (e.g., VHH-Fc or scFv-Fc), IgG-binding fragment fusion (e.g., light chain-(LC)-VHH, LC-scFv, heavy chain-(HC)-VHH or HC-scFv), a biparatopic molecule (e.g., biparatopic VHH- Fc or scFv-Fc), a tetravalent molecule (e.g., a tetravalent VHH-Fc), an IgG hexamer, a diabodyDBl / 167593545.6 193Attorney Docket No. CVL-001PC / 140489-5001(i.e ., a dimeric scFv), a triabody (i.e., a trimeric scFv), a tetrabody (i.e., a tetrameric scFv), bidisulfide-bond stabilized scFv (ds-scFv), a bi-specific antibody, DuoBody, VHH beads on a string, an Fc-heterodimeric molecule, minibody (miniAbs), Fab-IgG, IgG-Fab, and VHH-IgG- VHH.

42. The composition or the delivery system of claim 41, wherein the antibody, antibody-like molecule or plgR binding fragment thereof is in form of a single a binding fragment (e.g., VHH- His or scFv-His), or binding fragment-Fc domain (e.g., VHH-Fc or scFv-Fc).

43. The composition or the delivery system of claim 41, wherein the antibody, antibody -like molecule or plgR binding fragment thereof is in form of a multivalent tandem binding fragment, optionally a multivalent tandem VHHs format.

44. The composition or the delivery system of claim 42 or claim 43, wherein the multivalent tandem binding fragment binds same or different sequences.

45. The composition or the delivery system of any one of claims 42 to 44, wherein the multivalent tandem binding fragment binds at least two epitopes of plgR.

46. The composition or the delivery system of any one of claims 42 to 45, wherein the multivalent tandem binding fragment binds a molecule other than plgR.

47. The composition or the delivery system of claim 46, wherein the molecule other than plgR is a serum protein, optionally human serum albumin.

48. The composition of any one of claims 1-6 or 8-30 or the delivery system of any one of claims 7-30, wherein the plgR binder is a peptide.

49. The composition or the delivery system of claim 48, wherein the peptide comprises about 6 amino acids to about 60 amino acids.DBl / 167593545.6 194Attorney Docket No. CVL-001PC / 140489-500150. The composition or the delivery system of claim 48 or claim 49, wherein the peptide is a linear peptide, a branched peptide, a circular peptide, or a semi-cyclic peptide.

51. The composition or the delivery system of claim 50, wherein the peptide comprises an amino acid sequence selected from the amino acid sequence provided in Table 3, or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions.

52. The composition or the delivery system of claim 51, wherein the peptide comprises an amino acid sequence selected from the amino acid sequence of Pepl 15 (SEQ ID NO: 222), Pepl 12 (SEQ ID NO : 219), Pep 107 (SEQ ID NO : 214), Pep 117 (SEQ ID NO : 224), Pep 110 (SEQ ID NO : 217), Pepl 13 (SEQ ID NO: 220), Pepl 14 (SEQ ID NO: 221), Pepl 16 (SEQ ID NO: 223), Pepl 19 (SEQ ID NO: 226), Pepl20 (SEQ ID NO: 227), Pepl21 (SEQ ID NO: 228), Pepl22 (SEQ ID NO: 229), Pepl24 (SEQ ID NO: 231) and Pepl25 (SEQ ID NO: 232), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions.

53. The composition or the delivery system of claim 52, wherein the peptide comprises an amino acid sequence selected from the amino acid sequence of Pepl 15 (SEQ ID NO: 222), Pepl 12 (SEQ ID NO: 219), Pepl07 (SEQ ID NO: 214), Pepl 17 (SEQ ID NO: 224), or a variant thereof having at least 1, or at least 2, or at least 3 or more or more mutations therefrom, the mutations independently selected from amino acid substitutions, insertions, and deletions.

54. The composition or the delivery system of claim 53, wherein the peptide comprises an amino acid sequence selected from the amino acid sequence of Pepl 15 (SEQ ID NO: 222), Pepl 12 (SEQ ID NO: 219), Pepl07 (SEQ ID NO: 214), or Pepl 17 (SEQ ID NO: 224).

55. The composition or the delivery system of any one of claims 48-54, wherein the peptide is fused with a carrier moiety, optionally a life-extending carrier moiety.DBl / 167593545.6 195Attorney Docket No. CVL-001PC / 140489-500156. The composition or the delivery system of claim 55, wherein the carrier moiety is a polymer, optionally PEG.

57. The composition or the delivery system of claim 56, wherein the carrier moiety is a carrier protein selected from an Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant thereof.

58. The composition or the delivery system of claim 57, wherein the peptide is conjugated with an Fc domain to form a peptibody (i.e., a peptide-Fc fusion) or a bi-peptibody, optionally wherein the peptibody comprises an N-terminal fusion of the peptide with Fc domain (e.g., fused at the C- terminus of a signal sequence, if any), a C-terminal fusion of the peptide with Fc domain, a peptide insertion within an Fc domain or a combination thereof.

59. The composition of claim 58, wherein the peptibody comprises at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the peptide per copy of the therapeutic nucleic acid pay load, optionally wherein the peptides are fused in tandem, optionally via a flexible linker (e.g., a Gly and Ser rich flexible linker), at one, or two, or three, or more locations within the Fc domain.

60. The composition of any one of claims 1-6 or 8-59 or the delivery system of any one of claims 7-59, wherein the linker is capable of linking at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the plgR binder with a copy of the therapeutic nucleic acid payload.

61. The composition of any one of claims 1-6 or 8-60 or the delivery system of any one of claims 7-60, wherein the linker is capable of linking at least 1, or at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 8, or at least 10, or more copies of the therapeutic nucleic acid payload with a copy of the plgR binder62. The composition or the delivery system of claim 61, wherein the linker is branched.DBl / 167593545.6 196Attorney Docket No. CVL-001PC / 140489-500163. The composition or the delivery system of any one of claims 60-62, wherein the linker is or comprises a direct bond or an atom such as oxygen or sulfur, a unit such as NRi, C(O), C(O)NH, SO, SO2, SO2NH or a chain of atoms selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenyl aryl alkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl alkynylheteroarylalkynyl, alkyl heterocy cly 1 alky 1 , alkyl heterocy cly lalkeny 1 alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alky ny lheterocy cly 1 alkenyl alkynylheterocyclylalkynyl, alkyl aryl, alkenyl aryl, alkynylaryl, alkylheteroaryl alkenylheteroaryl, alkynylhereroaryl, which one or more methylenes can be interrupted or terminated by O, S, S(O), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where Ri is hydrogen, acyl, aliphatic or substituted aliphatic.

64. The composition or the delivery system of any one of claims 60-62, wherein the linker has the following structure:wherein:A is the therapeutic payload;t is an integer from 1 to 5;L3and L4are independently selected from a bond, -N(R4)-, -O-, -S-, -C(O)-, - N(R4)C(O)-, -C(O)N(R5)-, -N(R4)C(O)N(R5)-, -C(O)O-, -OC(O)-, -N(R4)C(O)O-, -DBl / 167593545.6 197Attorney Docket No. CVL-001PC / 140489-5001OC(O)N(R5)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R6)-O-, -O-P(S)(R6)-O-, -O- P(O)(NR4R5)-N-, -O-P(S)(NR4R5)-N-, -O-P(O)(NR4R5)-O-, -O-P(S)(NR4R5)-O-, - P(O)(NR4R5)-N-, -P(S)(NR4R5)-N-, -P(O)(NR4R5)-O-, -P(S)(NR4R5)-O-, -S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene, wherein each R4, R5and R6is independently hydrogen or unsubstituted Ci- C10 alkyl and wherein L5is -L5A-L5B-L5C-L5D-L5E-; L6is -L6A-L6B-L6C-L6D-L6E; L5A, L5B, I?c,5D, L5E, L6A, L6B, L6C, L6D, and L6Eare independently a bond, -NH-, -O-, -S-, -C(O)- , -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; andR1, R2, and R3are independently the antibody or antibody like molecule.

65. The composition or the delivery system of any one of claims 60-62, wherein the linker is or comprises a peptide linker.

66. The composition or the delivery system of any one of claims 60-65, wherein the linker is cleavable, optionally by a protease.

67. The composition or the delivery system of any one of claims 60-66, wherein the linker is non-cleavable.

68. The composition or the delivery system of any one of claims 60-67, wherein the linker contacts the 5' end of the therapeutic nucleic acid payload and / or the 3' end of the therapeutic nucleic acid payload.

69. The composition or the delivery system of any one of claims 60-68, wherein the linker contacts an internal location within the therapeutic nucleic acid payload.DBl / 167593545.6 198Attorney Docket No. CVL-001PC / 140489-500170. The composition or the delivery system of any one of claims 60-69, wherein the linker does not contact the 5' end and / or the 3' end of the therapeutic nucleic acid payload.

71. The composition of any one of claims 1-6 or 8-70 or the delivery system of any one of claims 7-70, wherein the linker contacts the N-terminus of the plgR binder and / or the C-terminus of the plgR binder.

72. The composition of any one of claims 1-6 or 8-71 or the delivery system of any one of claims 7-71, wherein the linker does not contact the N-terminus and / or the C-terminus of the plgR binder.

73. The composition of any one of claims 1-6 or 8-72 or the delivery system of any one of claims 7-72, wherein the linker contacts an internal amino acid residue of the plgR binder.

74. The composition of any one of claims 1-6 or 8-73 or the delivery system of any one of claims 7-73, wherein the composition or the delivery system delivers the therapeutic nucleic acid payload to preferentially epithelial cells compared to non-epithelial cells compared to a control composition lacking the plgR binder, optionally wherein the delivery to epithelial cells and / or non- epithelial cells is detected or detectable by one or more of fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, and a technique that can determine the presence or ongoing biological activity of the therapeutic nucleic acid payload.

75. The composition of any one of claims 1-6 or 8-74 or the delivery system of any one of claims 7-74, wherein the composition or the delivery system modulates the expression and / or activity of a target of the therapeutic nucleic acid payload.

76. The composition of any one of claims 1-6 or 8-75 or the delivery system of any one of claims 7-75, wherein the composition or the delivery system modulates the expression and / or activity of a target of the therapeutic nucleic acid payload substantially within the epithelial cell.DBl / 167593545.6 199Attorney Docket No. CVL-001PC / 140489-500177. The composition of any one of claims 1-6 or 8-76 or the delivery system of any one of claims 7-76, wherein the epithelial cell is located with gastrointestinal mucosa, lung, kidney, respiratory tract mucosa, gall bladder, or urinary bladder.

78. The composition of any one of claims 1-6 or 8-77 or the delivery system of any one of claims 7-77, wherein the composition or the delivery system is not substantially transported across the epithelium.

79. The composition of any one of claims 1-6 or 8-78 or the delivery system of any one of claims 7-78, wherein the amount of composition transported across the epithelium is at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10- fold less than an amount transported across the epithelium of a control composition lacking the plgR binder.

80. The composition of any one of claims 1-6 or 8-79 or the delivery system of any one of claims 7-79, wherein a detectable amount of the composition or the delivery system is retained inside the epithelial cell, optionally wherein the endosomal retention is detected or detectable using a technique selected from fluorescence microscopy, in situ hybridization, quantitative reverse transcriptase-PCR (RT-qPCR), stem-loop RT-qPCR, and a technique that can determine the presence or ongoing biological activity of the therapeutic nucleic acid payload.

81. The composition of any one of claims 1-6 or 8-80 or the delivery system of any one of claims 7-80, wherein the composition or the delivery system is not substantially secreted by the epithelial cell, optionally wherein the secretion is detected or detectable using an in vitro immunological assay and / or a trans well assay.

82. The composition of any one of claims 1-6 or 8-81 or the delivery system of any one of claims 7-81, wherein the amount of the composition or the delivery system is retained inside the epithelial cell is at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold greater than an amount retained inside the epithelial cell of a control composition lacking the plgR binder.DBl / 167593545.6 200Attorney Docket No. CVL-001PC / 140489-500183. The composition of any one of claims 1-6 or 8-82 or the delivery system of any one of claims 7-82, wherein the amount of the composition or the delivery system does not substantially contact the apical side of the epithelial cell.

84. The composition of any one of claims 1-6 or 8-83 or the delivery system of any one of claims 7-83, wherein the amount of the composition or the delivery system contacting the basal side of the epithelial cell is at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold greater than the amount of composition contacting the apical side of the epithelial cell.

85. A pharmaceutical composition comprising the composition of any one of claims 1-6 or 8- 84 or the delivery system of any one of claims 7-84, and a pharmaceutically acceptable diluent or excipient.

86. The pharmaceutical composition of claim 85, wherein the pharmaceutical composition is formulated for a parenteral administration.

87. The pharmaceutical composition of claim 86, wherein the pharmaceutical composition is formulated for an intravenous, subcutaneous, intramuscular, intradermal, intraperitoneal, epidural, or intrathecal administration.

88. A host cell comprising the composition of any one of claims 1-6 or 8-84 or the delivery system of any one of claims 7-84.

89. A method for delivering a therapeutic nucleic acid payload to an epithelial cell of a subject comprising:(a) administering to the subject the composition of any one of claims 1-6 or 8-84 or the delivery system of any one of claims 7-84, or the pharmaceutical composition of any one of claims 85-87, or the host cell of claim 88; or(b)DBl / 167593545.6 201Attorney Docket No. CVL-001PC / 140489-5001(i) contacting a cell of the subject with the composition of any one of claims 1-6 or 8-84 or the delivery system of any one of claims 7-84, or the pharmaceutical composition of any one of claims 85-87, or the host cell of claim 88, (ii) optionally, culturing the cell, and(iii) administering to the subject the cell.

90. A method of treating a disease or disorder in a subject in need thereof, the method comprising:(a) administering to the subject the composition of any one of claims 1-6 or 8-84 or the delivery system of any one of claims 7-84, or the pharmaceutical composition of any one of claims 85-87, or the host cell of claim 88, or the host cell of claim 68; or(b)(i) contacting a cell of the subject with the composition of any one of claims 1-6 or 8-84 or the delivery system of any one of claims 7-84, or the pharmaceutical composition of any one of claims 85-87, or the host cell of claim 88, (ii) optionally, culturing the cell, and(iii) administering to the subject the cell.DBl / 167593545.6 202

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