Functionalized viruses and related compositions and methods

Abstract

The present invention relates to functionalized viruses (non-recombinant or recombinant) comprising a plurality of capsid-displayed drug molecules (e.g., chemotherapeutic agents), where the displayed drug molecules are attached to the capsid by a linker comprising a biocompatible polymer (e.g., PEG). In some embodiments the linker comprises a cleavable spacer, which enables release of the attached drug within and / or in close proximity to a transduced cell. In some embodiments a functionalized virus is a recombinant virus that, in addition to capsid-linked drug molecules also encodes a therapeutic agent (e.g., a protein or polynucleotide) for expression in a target cell to be transduced. Also provided are pharmaceutical compositions comprising such functionalized viruses. Also provided are methods for generating such functionalized viruses, as well as methods for their use in treatment of diseases, e.g., cancers. The present invention also relates to drug conjugates of CBL0137 and at least one stabilizing, targeting, or delivery moiety bound to the CBL0137 drug. Also provided are related compositions and methods for their use in treatment of proliferative cell diseases, e.g., cancers.

Description

[0001] FUNCTIONALIZED VIRUSES RELATED COMPOSITIONS AND METHODS RELATED APPLICATION DATA This application claims priority to United States Provisional Patent Application No. 63 / 702,272 filed on 2 October 2024; United States Provisional Application No. 63 / 743,700 filed on 10 January 2025; and United States Provisional Patent Application No. 63 / 750,467 filed on 28 January 2025, the contents of which are incorporated by reference in their entirety herein. FIELD OF THE INVENTION The specification relates generally to functionalized viruses and related compositions and methods. BACKGROUND OF THE INVENTION [1] A fundamental challenge in medicine and pharmacology is identifying treatment and dosing regimens that maximize therapeutic efficacy while minimizing potential adverse effects associated with a particular treatment or drug (AKA “therapeutic index”). This objective is particularly difficult when, due to the nature of a health condition to be treated and / or a particular therapeutic agent, systemic administration is required, as this route greatly increases the risk of both on-target and off-target adverse effects. Such considerations are especially important in diseases caused by aberrant cell proliferation, such as cancer, where in many cases the drugs used for treatment act by causing cancer cell death. Unfortunately, many, if not most, of the types of drugs deployed (e.g., chemotherapeutic agents) can kill both cancerous and non-cancerous proliferating cells throughout the body, resulting in a notoriously narrow therapeutic index for many commonly used chemotherapeutic agents. [2] Thus, there is an ongoing need for therapeutic compositions and treatment methods that, in effect, provide a greatly expanded therapeutic index for therapeutic agents that to date have had limited therapeutic success especially due to very narrow therapeutic index. SUMMARY OF THE INVENTION [3] The present inventors have surprisingly found that viruses can be effectively functionalized to display drug molecules, e.g., cancer drug molecules, on their capsid while maintaining solubility and the ability of the functionalized viral particles to transduce target cells. As the virus-displayed drugs are released in close proximity to target cells or intracellularly, the local concentration of such agents in such targeted cells is therapeutically effective, while the systemic concentration of such drugs (e.g., plasma concentration) is quite low thereby avoiding or greatly reducing the risk of drug- associated adverse effects in subject to be treated. In addition, properties of the virus itself (e.g., oncolysis and / or expression of a recombinant gene payload) when combined with displayed drug effects, unexpectedly result in synergistic effects, e.g., synergistic cancer cell killing. The present inventors have also found that a conjugate of the drug CBL0137 with a stabilizing, targeting, or delivery moiety bound to the CBL0137 presents potential advantages both as monotherapy and in combination with a recombinant virus or a functionalized virus as disclosed herein. Methods for generating and using such functionalized viruses, as well as CBL0137 drug conjugates and their use also disclosed. [4] Accordingly, in one aspect provided herein is functionalized virus comprising a plurality of drug molecules displayed on a virus wherein each displayed drug molecule is attached to the virus capsid by a linker comprising a biocompatible polymer. [5] In some embodiments the biocompatible polymer is selected from the group consisting of: a linear polyethylene glycol (PEG), a branched PEG, polysarcosine (pSar), a polysaccharide, polyvinylpyrrolidone (PVP), a synthetic poly(amino acid) (PAA), polyglutamic acid (PGA), poly(hydroxyethyl-1-asparagine) (PHEA), poly(hdryoxyethyl-1-glutamine) (PHEG), an XTEN polymer, poly(thioglycidyl glycerol) (PTTG), RAFT polymers, a dendrimer, and hydroxyethyl starch. In some embodiments the biocompatible polymer is a linear PEG or a branched PEG. In some embodiments the PEG is a branched PEG. [6] In some embodiments the attached linker comprises a disulfide bond, an amide bond, a thioamide bond, a thioether bond, a tetrazole bond, or a thioacetyl bond. In some embodiments the attached linker comprises a disulfide bond. In some embodiments the attached linker does not include a cleavable linker. In other embodiments the attached linker comprises a cleavable spacer that, upon cleavage, releases a drug molecule from the linker. In some embodiments the cleavable spacer comprises an enzymatically cleavable group or a chemically cleavable group. In some embodiments the enzymatically cleavable group is cleavable by an enzyme selected from the group consisting of: cathepsin-B, plasmin, matrix metalloprotease, pyrophosphatase, phosphatase, glucuronidase, β-galactosidase, esterase, carboxyesterase, and arylsulfatase A. [7] In some embodiments the chemically cleavable group is selected from the group consisting of: disulfide, acetal, ester, silyl ester, anhydride, carbamate, carbonate and hydrazone. [8] In some embodiments any of the foregoing functionalized viruses is a recombinant functionalized virus comprising within its genome an expression cassette for expression of one or more biotherapeutic agents. [9] In some embodiments the functionalized virus is an oncolytic virus, preferably conditionally replication-competent.

[0010] In some embodiments the functionalized virus is selected from the group consisting of: adenovirus, adeno-associated virus (AAV), Cytomegalovirus (CMV), vaccinia virus, measles virus, retrovirus, lentivirus, and Herpes Simplex virus (HSV).

[0011] In some embodiments the drug molecules displayed on the viral capsid are of a drug that has poor aqueous solubility.

[0012] In some embodiments the drug molecules are anti-cancer drug molecules. In some embodiments the anti-cancer drug molecules are of at least one type of small molecule anti-cancer drug. In some embodiments the anti-cancer drug molecules induce programmed cell death.

[0013] In some embodiments, where the functionalized virus is a recombinant functionalized virus, the one or more biotherapeutic agents are selected from the group consisting of: cytokines, cell death inducing proteins (CDIPs), a targeting polynucleotide against expression of a CDIP, a targeting polynucleotide against expression of an anti- apoptotic protein, a prodrug-converting enzyme, a chemosensitizing enzyme, a cleavable linker site protease, and antibodies. In some embodiments, where the one or more biotherapeutic agents include a prodrug-converting enzyme, the prodrug-converting enzyme is selected from the group consisting of: a carboxyesterase, a cytosine deaminase, a thymidine kinase, a nitroreductase, β-lactamase, β-glucuronidase, and alkaline phosphatase. In some embodiments the one or more biotherapeutic agents include a cytokine. In some embodiments the cytokine is interferon gamma. In some embodiments the one or more biotherapeutic agents include a CDIP. In some embodiments, where the one or more biotherapeutic agents include a targeting polynucleotide, the targeting polynucleotide is an shRNA, a guide RNA, an antisense RNA, or a miRNA. In some embodiments, where the virus is a recombinant virus, the expression cassette comprises a constitutively active promoter, a tumor-specific promoter, or a viral promoter operably linked to a nucleic acid sequence encoding the one or more biotherapeutic agents. In some embodiments the viral promoter is a viral promoter activated late in the viral infection cycle of the functionalized virus. In some embodiments the viral promoter activated late in the viral infection cycle of the functionalized virus is the adenovirus major late promoter (MLP). In some embodiments, where the functionalized virus is a recombinant virus, the expression cassette is a polycistronic expression cassette. In some embodiments the drug molecules displayed on the viral capsid are of a small molecule anti-cancer drug having poor aqueous solubility. In some embodiments the drug molecules displayed on the viral capsid are of a small molecule anti-cancer drug selected from the group consisting of: gemcitabine, CBL0137, a small molecule inhibitor of Nicotinamide phosphoribosyltransferase (NAMPTi), a GEM derivative, bortezomib, paclitaxel, 5 FU, pyrrolobenzodiazepine (PBD) dimers, and Irinotecan. In some embodiments, where small molecule anti-cancer drug molecules are displayed on the viral capsid, the drug molecules are in a prodrug form.

[0014] In some embodiments the functionalized virus also includes a cell targeting moiety. In some embodiments the targeting moiety is attached to the linker. In In some embodiments the cell targeting moiety targets a cell type selected from the group consisting of: tumour cells, myeloid cells, macrophages, myeloid-derived suppressor cells (MDSCs), T cells, stromal cells, and cancer-associated fibroblasts. In some embodiments the targeting moiety is attached to the linker. In some embodiments the linker comprises branched PEG.

[0015] In some embodiments of any of the foregoing functionalized viruses, the plurality of drug molecules comprises about 1000 drug molecules to about 5000 drug molecules.

[0016] In some embodiments the subject to be treated is a mammal. In some preferred embodiments the subject to be treated is a human.

[0017] In some embodiments provided herein is a composition comprising a functionalized virus disclosed herein and a polar aprotic solvent, wherein the functionalized virus retains infectivity. In some embodiments the polar aprotic solvent in the compositions is at a concentration of about 5% (v / v) to about 20% (v / v).

[0018] In some embodiments herein is a pharmaceutical composition comprising a functionalized virus disclosed herein and a pharmaceutically acceptable excipient.

[0019] In a related aspect provided herein is method for treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of the functionalized virus disclosed herein or a pharmaceutical composition containing a functionalized virus disclosed herein.

[0020] In a related aspect provided herein is method for treating a disease characterized by aberrant cell proliferation, comprising administering to a subject in need thereof a therapeutically effective amount of the functionalized virus disclosed herein or a pharmaceutical composition containing a functionalized virus disclosed herein. In some embodiments the functionalized virus or the pharmaceutical composition is administered systemically or locally. In some embodiments the functionalized virus or the pharmaceutical composition is administered systemically. In some embodiments the disease characterised by aberrant cell proliferation is selected from the group consisting of: a cancer, a fibrotic disease, or cutaneous warts. In some embodiments the disease characterised by aberrant cell proliferation is a cancer. In some embodiments the cancer is selected from the group consisting of: basal cell carcinoma, melanoma, lymphoma, squamous cell carcinoma, Merkel cell carcinoma, lung cancer, prostate cancer, sarcomas, medulloblastomas, cancers with desmoplastic stromas, colorectal cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, mesothelioma, mesenchymal cancer, epithelial cancer, bladder cancer, urothelial cancer, and adenocarcinomas. In some embodiments the cancer is a basal cell carcinoma (BCC). In some embodiments the subject to be treated suffers from Basal Cell Nevus Syndrome (BCNS) or sporadic BCC.

[0021] In some embodiments the cancer is a recurrent cancer or a relapsing cancer.

[0022] In some embodiments the functionalized virus or the pharmaceutical composition is administered intralesionally.

[0023] In some embodiments the cancer is resistant to one or more of: chemotherapy, radiotherapy, immune checkpoint inhibitor treatment, oncolytic virus therapy, CAR-T therapy, and Bacillus Calmette-Guerin (BCG) treatment.

[0024] In a related aspect provided herein is a functionalized virus disclosed herein for use in treatment of a medical condition.

[0025] In another aspect provided herein is a method for generating a functionalized virus, the method comprising reacting a functional group on a virus capsid with a linker comprising a biocompatible polymer attached to a drug molecule, whereby reaction of the linker with the functional group attaches the linker to generate a functionalized virus.

[0026] In some embodiments the polymer for use in the method is selected from the group consisting of: a linear polyethylene glycol (PEG), a branched PEG, polysarcosine (pSar), a polysaccharide, polyvinylpyrrolidone (PVP), a synthetic poly(amino acid) (PAA), polyglutamic acid (PGA), poly(hydroxyethyl-1-asparagine) (PHEA), poly(hdryoxyethyl-1-glutamine) (PHEG), an XTEN polymer, and poly(thioglycidyl glycerol) (PTTG), RAFT polymers, a dendrimer, and hydroxyethyl starch. In some embodiments the biocompatible polymer is a linear PEG or a branched PEG.

[0027] In some embodiments of the method the functional group on the recombinant virus capsid is selected from the group consisting of: thiol, amine, carboxyl, and a phenolic group.

[0028] In some embodiments of the method the linker does not comprise a cleavable spacer. In other embodiments the linker comprises a cleavable spacer that, upon cleavage, releases a drug molecule from the linker. In some embodiments the cleavable spacer comprises an enzymatically cleavable group or a chemically cleavable group. In some embodiments the enzymatically cleavable group is cleavable by an enzyme selected from the group consisting of: cathepsin-B, plasmin, matrix metalloprotease, pyrophosphatase, phosphatase, glucuronidase, β-galactosidase, esterase, carboxyesterase, and arylsulfatase A. In some embodiments the chemically cleavable group is selected from the group consisting of: disulfide, acetal, ester, silyl ester, anhydride, carbamate, carbonate and hydrazone. In some embodiments the reaction is conducted in the presence of 4- Dimethylaminopyridine (DMAP). In some embodiments the functionalized virus in the method is a recombinant virus. In some embodiments the functionalized virus in the method is selected from the group consisting of: adenovirus, adeno-associated virus (AAV), Cytomegalovirus (CMV), vaccinia virus, measles virus, retrovirus, lentivirus, and Herpes Simplex virus (HSV). In some embodiments the drug molecule is an anti-cancer drug molecule. In some embodiments the anti-cancer drug molecule is a small molecule anti-cancer drug. In some embodiments the small molecule anti-cancer drug has poor aqueous solubility. In some embodiments the small molecule anti-cancer drug is selected from the group consisting of: gemcitabine, CBL0137, a small molecule inhibitor of Nicotinamide phosphoribosyltransferase (NAMPTi), a GEM derivative, bortezomib, paclitaxel, pyrrolobenzodiazepine (PBD) dimers, and 5-FU. In some embodiments the linker a thiol-reactive functional group, an amine-reactive functional group, or a click chemistry functional group. In some embodiments the thiol-reactive functional group is a pyridyldithio (PDT) group, bromoacetyl, or a maleimide group. In some embodiments the amine-reactive functional group is N-Hydroxysuccinimide (NHS), Tetrafluorophenyl (TFP), or Hydroxybenzotriazole (HOBt) ester. In some embodiments the functional group on the virus capsid is a thiol. In other embodiments the functional group on the recombinant virus capsid is an amine. In some embodiments, where the functional group on the virus capsid is a thiol or an amine, the small molecule anti-cancer drug, is selected from the group consisting of gemcitabine, CBL0137, a small molecule inhibitor of Nicotinamide phosphoribosyltransferase (NAMPTi), a GEM derivative, bortezomib, paclitaxel, pyrrolobenzodiazepine (PBD) dimers, and 5-FU. In some embodiments the linker comprises a thiol-reactive functional group. In some embodiments, where the linker comprises a thiol-reactive functional group, the linker comprises a PDT functional group. In some embodiments of the method, the PDT functional group is in a molar excess of about 3 fold to 10 fold relative over the number of virus capsid thiol groups. In some embodiments the linker comprises an amine-reactive functional group. In some embodiments, where the linker comprises an amine reactive functional group, the linker comprises a TFP functional group. In some embodiments of the method, the linker is reacted at a molar ratio to viral capsid functional groups of about 4:1 to about 10:1. In some embodiments of the method, the reaction the reaction is carried out in the presence of an aprotic polar solvent. In some embodiments the aprotic polar solvent is acetonitrile. In another aspect provided herein is a method for derivatizing a virus, the method comprising reacting solvent-exposed amines on the surface of the capsid of the virus with an amine-reactive cross-linking agent to obtain a derivatized recombinant virus comprising a new functional group cross-linked to the surface of the capsid. In some embodiments the amine-reactive cross-linking agent is a thiolating agent and the new functional group is a thiol. In some embodiments the thiolating agent is 2-iminothiolane. In some embodiments the molar ratio of the thiolating agent to the viral capsid amines is about 0.1 to about 1000. In some embodiments of the method for derivatizing a virus, the method also includes a step of reacting the derivatized virus with a linker comprising (i) a functional group reactive to the new cross-linked group and (ii) a biocompatible polymer attached to a drug molecule, whereby the reaction of the linker with the derivatized recombinant virus generates a functionalized recombinant virus, comprising a plurality of drug molecules displayed on the surface of the capsid. In some embodiments of the method, where the derivatized virus is reacted with the linker, the biocompatible polymer is a linear PEG or a branched PEG.

[0029] In a related aspect provided herein is a derivatized virus corresponding to Formula I:

[0030]

[0031] wherein,

[0032] V is a viral capsid; and -NH is a viral capsid surface-derived group. In a further aspect provided herein is a drug conjugate comprising one or more CBL0137 molecules and at least one stabilizing, targeting, or delivery moiety bound to the one or more CBL10137 molecules. In some embodiments the at least one stabilizing, targeting, or delivery moiety is a peptide, protein, or non-peptide biocompatible polymer. In some embodiments at least one of the one or more CBL0137 molecules is covalently bound to the at least one stabilizing, targeting, or delivery moiety. In some embodiments at least one of the one or more CBL0137 molecules is covalently bound to the at least one stabilizing, targeting, or delivery moiety by a linker comprising a biocompatible polymer. In some embodiments the linker is a multiarm linker. In some embodiments the linker comprises a dendrimer. In some embodiments the linker comprises a biocompatible polymer selected from the group consisting of: a linear polyethylene glycol (PEG), a branched PEG, poly(2-oxazoline), poly(cyclic imino ethers), polysarcosine (pSar), a polysaccharide, polyvinylpyrrolidone (PVP), a synthetic poly(amino acid) (PAA), polyglutamic acid (PGA), poly(hydroxyethyl-1-asparagine) (PHEA), poly(hdryoxyethyl-1-glutamine) (PHEG), an XTEN polymer, poly(thioglycidyl glycerol) (PTTG), RAFT polymers, a dendrimer, and hydroxyethyl starch. In some embodiments the linker comprises a disulfide bond, an amide bond, a thioamide bond, a thioether bond, a thioester bond, a tetrazole bond, or a thioacetyl bond. In some embodiments the linker does not comprise a cleavable spacer. In other embodiments the linker comprises a cleavable spacer that, upon cleavage, releases at least one of the CBL0137 molecules from the drug conjugate. In some embodiments the enzymatically cleavable is cleavable by an enzyme selected from the group consisting of: cathepsin-B, plasmin, matrix metalloprotease, pyrophosphatase, phosphatase, glucuronidase, β galactosidase, an esterase, a carboxyesterase, and arylsulfatase A. In some embodiments the chemically cleavable group is selected from the group consisting of: disulfide, acetal, ester, silyl ester, anhydride, carbamate, carbonate, and hydrazone. In some embodiments the one or more CBL0137 molecules are non-covalently bound to the at least one stabilizing, targeting, or delivery moiety. In some embodiments, where the one or more the one or more CBL0137 molecules are non-covalently bound, the drug conjugate comprises a nanoparticle comprising a plurality of stabilizing, targeting, or delivery moieties to which the one or more CBL0137 molecules are non- covalently bound. In some embodiments the nanoparticle comprises a plurality of albumin molecules. In some embodiment the at least one stabilizing, targeting, or delivery moiety comprises a protein. In some embodiments the protein is selected from the group consisting of: albumin, an albumin fragment that retains binding to the neonatal Fc receptor (FcRn), a fusion protein comprising albumin or comprising a fragment thereof that binds to FcRn, an immunoglobulin Fc domain, an antibody, a Designed Ankryin Repeat Protein (DARPin), an XTEN polypeptide, a Proline-Alanine-Serine (PAS) polypeptide, an elastin-like polypeptide (ELP), or a fusion protein comprising any one of the foregoing. In some embodiments the protein comprises an albumin or a fragment of albumin that retains binding to FcRn. In some embodiments the protein comprises human albumin or a human albumin variant having an amino acid sequence at least 95% identical to the amino acid sequence of human, bovine, ovine, porcine, mouse, or rat albumin. In some embodiments a CBL0137 molecule is covalently bound site- specifically to the albumin via a linker at the position of a cysteine residue in the albumin. In some embodiments the position corresponds to position 34 of human albumin. In other embodiments the position corresponds to the position of a cysteine introduced by mutation into the amino acid sequence of the albumin. In other embodiments one or more CBL0137 molecules are covalently bound non-site-specifically to the albumin. In some embodiments the at least one stabilizing, targeting, or delivery moiety comprises a fusion protein comprising the albumin or the fragment thereof. In other embodiment the at least one stabilizing, targeting, or delivery moiety comprises a human immunoglobulin Fc domain. In other embodiment the at least stabilizing, targeting, or delivery moiety comprises an antibody, preferably a human antibody. In some embodiments the antibody is a monoclonal antibody, a diabody, a scFv, or a nanobody. In some embodiments the antibody is a multispecific antibody. In some embodiments the antibody is an antibody that targets human albumin. In other embodiments the antibody is an antibody that targets a cancer-enriched or tumor-enriched antigen. In some embodiments the cancer-enriched or tumor-enriched antigen targeted by the antibody is selected from the group consisting of: HER2, EGFR, VEGF, Mucin-1, integrins, estrogen receptor (ER), androgen receptor (AR), VEGFR2, EpCAM, transferrin receptor, carcinoembryonic antigen (CEA), B melanoma 1 (BAGE), G antigens (GAGEs), gp100, cancer / testis antigen 1 (CTAG1), melanoma-associated antigens (MAGEs), Nectin-4, folate receptor, CD79b, MET receptor, CD19, CD20, CD44, and CD3. In other embodiments the at least one stabilizing, targeting, or delivery moiety comprises a peptide. In some embodiments the peptide is an albumin binding peptide. In some embodiments the albumin binding peptide comprises the amino acid sequence of SEQ ID NO:1 (DICLPRWGCLW), SEQ ID NO:2 (LAEAKVLANRELDKYGVSDFYKRLINKAKTVEGVEALKLHILAALP), or SEQ ID NO:3 (EYEKpalmEYE), wherein K is palmitoylated. In some embodiments the albumin-binding peptide is selected from the group consisting of: ABD094, NbSA, and Nb80. In some embodiments the peptide is a tumor-homing or cancer-targeting peptide. In some embodiments the tumor-homing or cancer-targeting peptide is selected from the group consisting of: RGD4C, iRGD, p32-binding LyP-1 peptide, K237, VEGFR-2- binding peptide, IL4RPep-1, mUNO, Her-2 binding peptide, GE11, angiopep-2, prostate tumor-targeting peptide, and bladder tumor-targeting peptide. In other embodiments the at least one stabilizing, targeting, or delivery moiety is a non-peptide biocompatible polymer. In some embodiments the non-peptide biocompatible polymer in the at least one stabilizing, targeting, or delivery moiety is PEG and the one or more CBL0137 molecules are covalently bound to the PEG via a fluorenylmethoxycarbonyl linker. In other embodiments the non-peptide biocompatible polymer comprises a fatty acid, cholesterol, Evans blue, CRX-527, or alpha-tocopherol. In some embodiments, where the non-peptide biocompatible polymer comprises a fatty acid, the fatty acid is 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE) or octadecanoic acid. In other embodiments the non- biocompatible polymer comprises an aptamer. In some embodiments the aptamer is an albumin-binding aptamer. In some embodiments for a drug conjugate provided herein the plasma half-life (t1 / 2) of CBL0137 is greater than 40 hours when the drug conjugate is administered systemically to a human subject. In a related aspect provided herein is a pharmaceutical composition comprising any of the above-mentioned drug conjugates and a pharmaceutically acceptable excipient. In a further aspect provided herein is a method for treating a disease characterized by aberrant cell proliferation, comprising administering to a subject in need thereof a therapeutically effective amount of any of the above-mentioned drug conjugates or a pharmaceutical composition comprising any of the above-mentioned drug conjugates. In some embodiments the drug conjugate or the pharmaceutical composition is administered systemically, or locally. In some embodiments the disease characterised by aberrant cell proliferation is selected from the group consisting of: a cancer, a fibrotic disease, or cutaneous warts. In some preferred embodiments the disease characterised by aberrant cell proliferation is selected from the group consisting of: a cancer, a fibrotic disease, or cutaneous warts. In some embodiments the cancer is selected from the group consisting of: basal cell carcinoma (BCC), melanoma, lymphoma, squamous cell carcinoma, Merkel cell carcinoma, lung cancer, prostate cancer, sarcomas, medulloblastomas, cancers with desmoplastic stromas, colorectal cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, mesothelioma, mesenchymal cancer, epithelial cancer, bladder cancer, urothelial cancer, and adenocarcinomas. In some preferred embodiments the cancer to be treated is a BCC. In some embodiments the cancer to be treated is a recurrent cancer or a relapsing cancer. In some embodiments the drug conjugate or the pharmaceutical composition is administered intralesionally. In some embodiments the cancer to be treated is resistant to one or more of: chemotherapy, radiotherapy, immune checkpoint inhibitor treatment, oncolytic virus therapy, CAR-T therapy, and Bacillus Calmette-Guerin (BCG) treatment. In some embodiments a treatment method includes administration of a drug conjugate disclosed herein and a therapeutically effective amount of interferon gamma (separately or in a single formulation). In some embodiments a treatment method that includes administration of a drug conjugate disclosed herein further includes administering a therapeutically effective amount of a recombinant virus within its genome an expression cassette for expression of one or more biotherapeutic agents. In some embodiments the recombinant virus is a conditionally replication- competent virus. In some embodiments the recombinant virus is an oncolytic virus. In other embodiments the recombinant virus is a replication-deficient virus. In some embodiments the recombinant virus is selected from the group consisting of: adenovirus, adeno-associated virus (AAV), Cytomegalovirus (CMV), vaccinia virus, measles virus, retrovirus, lentivirus, and Herpes Simplex virus (HSV). In some embodiments the one or more biotherapeutic agents are selected from the group consisting of: cytokines, cell death inducing proteins (CDIPs), a targeting polynucleotide against expression of a CDIP, a targeting polynucleotide against expression of an anti-apoptotic protein, a prodrug-converting enzyme, a chemosensitizing enzyme, a cleavable linker site protease, and antibodies. In some embodiments the prodrug-converting enzyme is selected from the group consisting of: a carboxyesterase, a cytosine deaminase, a thymidine kinase, a nitroreductase, β- lactamase, β-glucuronidase, and alkaline phosphatase. In some embodiments the one or more biotherapeutic agents comprise a cytokine. In some preferred embodiments the cytokine is interferon gamma. In some embodiments, where the one or more biotherapeutic agents comprise a cytokine or interferon gamma, the recombinant virus is an adenovirus. In some embodiments the recombinant virus is ASN-002. In other embodiments the one or more biotherapeutic agents comprise at least one CDIP. In other embodiments, where the biotherapeutic agent is a targeting polynucleotide, the targeting polynucleotide is an shRNA, a guide RNA, an antisense RNA, or a miRNA. In some embodiments the expression cassette comprises a constitutively active promoter, a tumor-specific promoter, or a viral promoter operably linked to a nucleic acid sequence encoding the one or more biotherapeutic agents. In some embodiments the viral promoter is a viral promoter activated late in the viral infection cycle of the recombinant virus. In some embodiments the viral promoter activated later in the viral infection cycle is the adenovirus major late promoter (MLP). In some embodiments the expression cassette is a polycistronic expression cassette. In some embodiments the recombinant virus to be included in the treatment method also includes a cell-targeting moiety. In some embodiments the cell-targeting moiety targets a cell type selected from the group consisting of: tumour cells, myeloid cells, macrophages, myeloid-derived cells (MDSCs), T cells, stromal cells, and cancer-associated fibroblasts (CAFs). In some embodiments the recombinant virus is a functionalized virus comprising a plurality of drug molecules displayed on a virus capsid, wherein each displayed drug molecule is attached to the virus capsid by a linker comprising a biocompatible polymer. In some embodiments the treatment method includes administration of a second virus, wherein the second virus is a functionalized virus comprising a plurality of drug molecules displayed on a virus capsid, wherein each displayed drug molecule is attached to the virus capsid by a linker comprising a biocompatible polymer. In some embodiments the drug conjugate and (a) the interferon gamma or (b) the recombinant virus are administered by different routes of administration. In other embodiments the drug conjugate and (a) the interferon gamma or (b) the recombinant virus are administered by the same route of administration. In some embodiments the drug conjugate and the recombinant virus are administered contemporaneously. In other embodiments the drug conjugate and (a) the interferon gamma or (b) the recombinant virus are administered at different times. In some embodiments the drug conjugate is administered prior to administration of (a) the interferon gamma or (b) the recombinant virus. In some embodiments the drug conjugate is administered after administration of (a) the interferon gamma or (b) the recombinant virus. In another aspect provided herein is a method for treating a cancer comprising administering a therapeutically effective amount of CBL0137 and a therapeutically effective amount of interferon gamma. In a related aspect provided herein is a drug conjugate disclosed herein for use in the treatment of a cancer. In some embodiments the treatment also includes treatment with a recombinant virus comprising within its genome an expression cassette for expression of one or more biotherapeutic agents. In a further related aspect provided herein is the use of a drug conjugate disclosed herein for use in the manufacture of a medicament for treatment of a cancer in a subject in need thereof. In some embodiments of the use, the subject is to be treated in a combination therapy with the medicament and a recombinant virus comprising within its genome an expression cassette for expression of one or more biotherapeutic agents. In another related aspect provided herein is the use of a recombinant virus comprising within its genome an expression cassette for expression of one or more biotherapeutic agents for use in the manufacture of a medicament for treatment of a cancer in a subject to be treated in therapy with a drug conjugate disclosed herein. In some embodiments of the above uses, wherein a recombinant virus is used in the manufacture of a medicament or in a combination therapy, the recombinant virus is a functionalized virus comprising a plurality of drug molecules displayed on a virus capsid, wherein each displayed drug molecule is attached to the virus capsid by a linker comprising a biocompatible polymer. The steps, features, integers, compositions and / or therapeutic agents disclosed herein or indicated in the specification of this application individually or collectively, and any combinations of two or more of said steps or features.

[0033] Any embodiment herein shall be taken to apply mutatis mutandis to any other embodiment unless specifically stated otherwise.

[0034] The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the invention, as described herein.

[0035] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (e.g. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter. BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS Figure 1 – Exemplary CBL0137-linkers are shown in a schematic illustration of a non- limiting embodiment in which the cancer drug CBL0137 [1,1′-(9-(2- (isopropylamino)ethyl)-9H-carbazole-3,6-diyl)bis(ethan-1-one) (IUPAC / chemical name)] is shown conjugated to a PEG-based linker that includes a cathepsin B cleavage site, and a terminal carboxyl functional group (top panel) that can be used to crosslink the linker drug conjugate to amines on a viral capsid surface; or a PDT functional group (lower panel), which can be used to crosslink the linker drug conjugate to thiols on a viral capsid. Figure 2 – Exemplary conjugation of water-soluble carboxylic acids to amines after esterification. A schematic illustration of a non-limiting embodiment of a cross-linking reaction between a carboxylic acid functional group (e.g., on a PEG-drug conjugate) and a primary amine functional group viral capsid surface). Illustration adapted from ThermoFisher Scientific. Figure 3 – Exemplary viral capsid derivatization (capsid amine to sulfhydryl) followed by conjugation via disulfide linkage to covalently link the “displayed payload” to virus. A schematic illustration of a non-limiting embodiment of derivatization of a virus by conversion of viral capsid surface amines by a coupling reaction with the thiolating reagent, 2-Iminothiolane (“Traut’s reagent“) to provide sulfhydrl group for subsequent functionalization with a linker-drug conjugate. Subsequently, a linker-drug conjugate having a terminal pyridyldithio (PDT) on a linker- drug conjugate is reacted with the sulfhydryl groups on the derivatized virus to generate a functionalized virus having disulfide-cross-linked linker-drug conjugates displayed on the functionalized virus capsid surface. Figure 4 – Exemplary EDC-reacted Functionalized viral transduction patterns after activation with EDC. Fluorescence photomicrographs in A549 cells (top row) and HeLa cells (bottom row). In left column "mock" transduced cells (no virus). In middle column, cells transduced with unmodifed EGFP-expression adenovirus ("Ad"). In right column, cells transduced with EGFP-expression adenovirus functionalized with PEG-CBL0137 via EDC / NHS activation and crosslinking between PEG-COOH functional group and Adenovirus capsid surface amines to form amide bond ("AdPEG- CBL"). Conventional activation of COOH in the presence of EDC and NHS and subsequent crosslinking of the linker-drug conjugate to the viral capsid results in a functionalized virus with aberrant transduction patterns as visualized by host cell EGFP expression patterns (compare images in "Ad" column vs "AdPEG-CBL" column), suggesting that the reaction conditions used have a negative impact on the abiliity of PEG-CBL0137-functionalized viruses prepared by this reaction scheme to transduce cells effectively or with the expected pattern. Figure 5 – Adenovirus infectivity after aprotic polar solvent exposure. Scatter plots showing percentage of cells showing EGFP expression (assessed by flow cytometry) in Ad-EGFP-transduced A549 cells following exposure of Ad-EGFP to varying concentrations of seven different solvents as shown. From top and left to right, Acetonitrile, n-Butanol, n-Pentanol, n-Hexanol, DMSO, DMF and PEG400 (solubilizer). Of note, adenoviral infectivity / transduction efficiency appears to be relatively unaffected until a threshold concentration of reached or, the case of pentanol or hexanol- not at all. Figure 6 – Assessing coupling efficiencies using Biotin-COOH-PEG. A) Schematic, qualitative summary of results of coupling efficiency using different combinations of solvents; w = hexon only (weak signal), m = hexon only, (medium signal), s = hexon + penton + fiber (strong signal). B) Western blot image showing avidin-detected biotin coupling to hexon capsomere of adenovirus vector. C) Schematic summary of functionalized Ad-EGFP infectivity using different combinations of solvents and coupling agents after coupling of Biotin-COOH-PEG on HeLa and A549 cell lines. D) Functionalized Ad-EGFP infectivity after coupling biotin-COOH-PEG to viral capsid using different combinations of coupling agents in acetonitrile as solvent after coupling of Biotin-COOH-PEG on A549 cell line. E) Functionalized Ad-EGFP infectivity after coupling biotin-COOH-PEG to viral capsid using different combinations of coupling agents in acetonitrile as solvent after coupling of Biotin-COOH-PEG on HeLa cell line. F) Schematic, qualitative summary of combination of functionalized Ad-EGFP infectivity and coupling efficiency results demonstrating best solvent-coupling agent combinations; m = hexon only, (medium signal), s = hexon + penton + fiber (strong signal). Of note, excessive coupling efficiency to capsid could result in decreased infectivity. Figure 7 – Optimizing reaction stoichiometry of Biotin-PEG-COOH crosslinking to capsid amines with tetrafluorophenyl (TFP) TFP using acetonitrile as solvent. A) Western blot showing avidin-visualized capsid conjugation of Biotin-PEG-COOH activated in acetonitril / TFP, molar ratio of TFP:PEG ranging from 1:1 to 1:3 (shown at top) and a molar ratio of Biotin-PEG to virus capsid surface amines during coupling (18,000 amines on surface) ranging from 10:1 to 200:1 (as indicated in second row), short exposure time (ECL). B) As above, but with longer exposure time for image development C) Scatter plot illustrating transduction efficiency of Biotin-PEG- Functionalized Ad-EGFP following functionalization under conditions shown in A) above: a molar ratio of TFP:PEG ranging from 1:1 to 1:3, and a molar ratio of Biotin- PEG to virus capsid surface amines during coupling (18,000 amines on surface) ranging from 10:1 to 200:1. Note excessively high ratio of Biotin-PEG to amines results in reduced functionalized virus transduction efficiency. Figure 8 – Capsid amine coupling of PEG-COOH with modification using TFP in the presence of 4-methyl-diaminopyridine (DAP) in acetonitrile and assessment of transduction efficiency of resulting functionalized virus, using dual CsCl discontinuous gradients for pre and post-crosslinking purification. Left panel shows western blot of avidin-visualized crosslinking of Biotin-PEG-COOH to Ad-EGFP capsid proteins at a ratio of 3:1 or 17:1 molar ratio of Biotin-PEG-COOH to viral capsid surface amines. Ad-EGFP was purified in a CsCl discontinuous gradient, and biotin- PEG coupling reaction to viral capsid was conducted in CsCl. Biotin-PEG- functionalized virus was purified on a second CsCl discontinuous gradient prior to testing for infectivity. Right panel summarizes degree of modification (determined by ELISA) and infectivity of functionalized Biotin-PEG-functionalized Ad-EGFP from functionalization using different ratios of Biotin-PEG-COOH to virus amines. As shown, a 17 fold excess of Biotin-PEG to viral amines results in very high cross-linking efficiency of Biotin-PEG to viral capsid, but results in functionalized virus having no infectivity. In contrast, a three fold excess of Biotin-PEG over virus amines yields functionalized Ad-EGFP retaining a high degree of infectivity. In addition, no viral particle aggregates were formed (data not shown). Figure 9 – Transduction to assess effect of thiolating reagent, 2-Iminothiolane (“Traut’s reagent”) reaction (in different solvents) on Ad-EGFP infectivity A) left panel shows a scatter plot of functionalized virus transduction efficiency (as percentage of EGFP-positive cells on Y axis) following thiolation with Traut’s reagent in dimethylformamide (DMF) as a solvent (one hour at room temperature) followed by a viral transduction assay. X axis indicates molar excess of Traut’s reagents relative to viral capsid amines. Right panel refers to fluorescence intensity B) Scatter plots showing results of experiments similar to those in A) when conducted in dimethylsulfoxide (DMSO) as the solvent. Note increasing molar ratio of Traut’s reagent:viral capsid amines result in diminished Ad-EGFP infectivity indicating careful titration of Traut’s reagent is needed when used for functionalization of viruses to avoid significant loss of infectivity. Figure 10 – CBL-0137(CBL)-PEG-pyridyldithio (PDT) coupling to viral capsid sulfhydryl (“SH”) groups at a molar ratio of 20:1 (CBL-PEG:capsid SH groups) results in insoluble functionalized virus aggregates. Coupling of CBL-PEG-PDT to Traut reagent-derivatized Ad-EGFP (to provide capsid -SH groups, at a molar ratio of CBL-PEG to SH groups of 20:1 leads to aggregate formation of functionalized viruses, as shown in middle (“2ndand right most photographs comparing functionalized virus (aggregates) in top image as compared unmodified virus. Viral aggregates would not elute from G25 (gel filtration) sizing column. Figure 11 – Titration of molar ratios of Traut’s reagent and PDT-PEG-Biotin to viral capsid functional groups yields soluble Biotin-PEG-functionalized viral particles. Shown are photographic images of “2nd gradients“, i.e., purification gradients (glycerol) after coupling. Text above images indicates molar ratio of Traut’s reagent to viral capsid surface amines (top line) and molar ratio of PDT-PEG-biotin to viral capsid surface amines (bottom line). At the indicated ratios, a tight band of PEG-biotin functionalized viral particles was observed indicating that functionalized viral particles were soluble and free of aggregates. Optical size measurement in a nanosizer light scattering spectrometer confirmed expected functionalized viral particle size for each of the indicated reaction ratios (data not shown). Figure 12 – Exemplary optimized molar ratio of Traut’s reagent and PDT-PEG- CBL to viral capsid functional groups yields soluble PEG-CBL functionalized viral particles. Shown are photographic images of gradients (glycerol) after coupling. At a molar ratio of 5:1 Traut’s reagent:capsid amines (first line) and 6:1 PEG-CBL:capsid amines, soluble PEG-CBL- functionalized Ad-EGFP viral particles devoid of aggregates were obtained. The expected of functionalized viral particle size was confirmed by light scattering spectrometry (data not shown). Figure 13 – Assessing infectivity of PEG-CBL functionalized AdEGFP. Ad-EGFP was modified with a molar excess of 5xTraut+6xPEG-CBL over surface amines in CsCl, gradient purified, and titrated for genome copy numbers. Control Ad-EGFP “unmodified” were left untreated. HeLa cells were transduced with at the indicated multiplicity of infection (MOI) and analyzed for EGFP expression 48 hours after transduction by flow cytometry. Left panel shows percentage of EGFP-positive cells for indicated transduction groups. Right panel shows mean fluorescence intensity for corresponding transduction groups. PEG-CBL functionalized AdEGFP retains substantial transduction efficiency as measured by EGFP, although apparent reduction in transduction efficiency could be a reflection of CBL-induced cell death. Figure 14 - CBL delivered by PEG-CBL functionalized Ad-EGFP induces cell death in HeLa cells. Top panel shows a scatter plot indicating percentage of Annexin-positive cells following transduction with Ad-EGFP or PEG-CBL functionalized Ad- EGFP at the indicated MOIs. Bottom panel shows a scatter plot indicating percentage of Zombie (cell death stain)-positive cells following transduction with unmodified Ad- EGFP or PEG-CBL functionalized Ad-EGFP at the indicated MOIs. As shown, PEG- CBL functionalized Ad-EGFP induces HeLa much greater cell death (compared to Ad- EGFP at all MOIs tested. Results of statistical tests comparing Ad-EGFP vs PEG-CBL- Ad-EGFP are shown below respective plots. Figure 15 - Biophysical characterization of PEG-CBL functionalized of SP-002 (IFN-gamma-expressing Adenovirus). Following PEG-CBL functionalization using optimized conditions (5xTraut and 6x PEG-CBL relative to viral capsid amines), resulting viral particles were characterized for their hydrodynamic radius (relative to unmodified SP-002 virus), as shown in top panel. A determination of polydispersity to detect potential aggregation was conduction and it was shown that the polydispersity index of PEG-CBL functionalized SP-002 virus fell within a normal range relative to unmodified virus indicating good virus solubility without aggregate formation. Figure 16 – CBL-PEG-functionalized SP002 virus transduces normally and results in expression of IFN-gamma. Scatter plots show results of ELISA assay for interferon gamma expression in HeLa cells 48 hours after transduction with SP002 or PEG-CBL functionalized SP002. As shown, PEG-CBL functionalized SP-002 induces expression of IFN-gamma at the same level as unmodified SP002. Figure 17 – CBL-PEG-functionalized SP002 virus induces increased induction of apoptosis when displaying CBL. Scatter plots show results of Annexin V staining in HeLa cells transduced with unmodified SP002 or PEG-CBL functionalized SP002. As shown, PEG-CBL functionalized SP002 induced substantially higher levels of HeLa cell apoptosis compared to unmodified SP002 indicating that displayed CBL is likely inducing increased apoptosis. Statistical analysis results are shown below scatter plot. Figure 18 – CBL-PEG-functionalized SP002 virus exhibits complementary effects of displayed CBL payload and IFN gamma transgene on cell death. Scatter plots shows results of XTT cell viability assay 48 hours post-transduction with unmodified SP002 or CBL-PEG-functionalized SP002. The results indicate that displayed CBL in conjunction with expressed IFN-gamma payload results in greatly increased cell death. Figure 19 – Human Serum (HSA) CBL Conjugation Strategies. A schematic illustration of non-limiting embodiments of A) Indirect conjugation to HSA: Albumin binding peptides or small molecules with an affinity to albumin is used. The drug is first linked to the peptide or small molecule and when administered in vivo it will bind to albumin and circulate. The linkage to peptide should be such that active free drug is released after processing eg. pH, reduction, enzyme. B) Direct conjugation to HSA: One method of direct conjugation is site-specific: HSA has a single cysteine that can be used to site-specifically link drugs via a linker incorporating a maleimide, haloacetyl or pyridyldithio group. C) Direct conjugation to HSA: One method of direct conjugation is non-site-specific: HSA being a protein has a number of reactive functional groups present in amino acids exposed on the surface of the molecule. These are carboxylic acid and amino groups. Drugs can be directly linked to these groups directly or via a linker. The linkers should be cleavable to release active drug in the tumour microenvironment or inside the tumour cell. The functional groups on HSA can be modified into other functional groups such as azide, alkyne, SH, or PDP for reaction with various linkers. Figure 20 – Various CBL0137 linkers. A schematic illustration of non-limiting embodiments of various linkers for conjugating CBL0137 to proteins. Figure 21 – Multiarm / Dendrimeric CBL. A schematic illustration of non-limiting embodiments of dendrimeric (multiarm) CBL0137derivatives for conjugation to proteins. Figure 22 – Conjugatoin of denrimeric CBL0137 to human serum albumin (HSA). A schematic illustration of a non-limiting embodiment of conjugation of a dendrimeric structure of CBL0137 to HSA via click chemistry. Figure 23 – Conjugation of CBL0137 to antibodies. A schematic illustration of a non- limiting embodiment of conjugation of CBL0137 to and antibody via a disulphide or thioether link. Figure 24 – Various methods to link CBL to human serum albumin (HSA) or antibodies. A schematic illustration on non-limiting embodiments of methods to link CBL0137 to HSA or antibodies. Figure 25 – Conjugation of CBL0137 serum albumin (HSA). A schematic illustration of a two non-limiting embodiments of conjugating CBL0137 to HSA. Figure 26 – Conjugation of gemcitabine (GEM) to adenovirus-5 expressing human interferon gamma (AdhIg; SP002). A) schematic illustration of derivatization of adenovirus capsid amine groups by reaction with Traut’s agent followed by reaction with pyridyldithio-gemcitabine-carbonate (PDT-GEM-carbonate) linker to obtain GEM- functionalized AdhIg. B) Images of purified AdhIg bands on CsCl gradients before and after PDT-GEM coupling. C) Plots showing biophysical characterization of AdhIg before and after PDT-GEM coupling-top panel showing averaged particle diameter (Z) and bottom panel showing polydispersity of AdhIg before and after PDT-GEM coupling. D) Image of reducing and non-reducing SDS-PAGE analysis of AdhIg capsid proteins of AdhIg and AdhIg-GEM. Figure 27 – Comparison of AdhIg-GEM vs free GEM on HeLa cell viability. Line graph comparing viability of untreated HeLa cells, HeLa cells treated with AdhIg (SP-002) at increasing MOI; AdhIg-GEM (SP-002-GEM) at increasing MOI; conjugated GEM on 1500 MOI equivalent to approximately 10 nM GEM); and free GEM. SP-002- GEM-induced cytotoxicity was greater than that associated with SP-002 alone or free GEM alone and is synergistic relative to SP-002 or GEM alone at equivalent MOI or GEM concentration. Figure 28 – Comparison of AdhIg-GEM vs free GEM on HeLa cell apoptosis. Line graph comparing level of apoptosis (annexin-positive cells) in untreated HeLa cells, HeLa cells treated with AdhIg (SP-002) at increasing MOI; AdhIg-GEM (SP-002-GEM) at increasing MOI; conjugated GEM on 1500 MOI equivalent to approximately 10 nM GEM); and free GEM. SP-002-GEM-induced apoptosis was greater than that associated with SP-002 alone or free GEM alone and is synergistic relative to SP-002 or GEM alone at equivalent MOI or GEM concentration. Figure 29 – Interferon-gamma expression in HeLa cells. Bar plots showing levels of IFN-gamma expression determined by ELISA on HeLa cell supernatants 48 hours post- transduction with AdhIg and AdhIg-GEM based at various MOI (based on physical particle count). Left panel shows plots of IFN-gamma absolute concentration in media; right panel shows IFN-gamma levels normalized to average value for AdhIg transduction. DETAILED DESCRIPTION OF THE INVENTION General Techniques and Definitions Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in viral vector construction, transfection, gene knockdown, gene knockout, gene therapy, molecular genetics, cancer biology, cancer therapy, immunology, pharmacology, protein chemistry, and biochemistry). Unless otherwise indicated, any recombinant molecular biology or immunological techniques described herein are standard procedures, well known to those skilled in the art. Such techniques are described and explained throughout the literature in sources such as, J. Perbal, A Practical Guide to Molecular Cloning, John Wiley and Sons (1984), J. Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbour Laboratory Press (1989), T.A. Brown (editor), Essential Molecular Biology: A Practical Approach, Volumes 1 and 2, IRL Press (1991), D.M. Glover and B.D. Hames (editors), DNA Cloning: A Practical Approach, Volumes 1-4, IRL Press (1995 and 1996), and F.M. Ausubel et al. (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience (1988, including all updates until present), Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbour Laboratory, (1988), and J.E. Coligan et al. (editors) Current Protocols in Immunology, John Wiley & Sons (including all updates until present). As used herein, the term about, unless stated to the contrary, refers to + / - 10%, more preferably + / - 5%, of the designated value. Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. As used in this application, the term “or” is intended to mean an inclusive “or” rather than an exclusive “or.” That is, unless specified otherwise, or clear from context, “X employs A or B” is intended to mean any of the natural inclusive permutations. That is, if X employs A; X employs B; or X employs both A and B, then “X employs A or B” is satisfied under any of the foregoing instances. Further, at least one of A and B and / or the like generally means A or B or both A and B. In addition, the articles “a” and “an” as used in this application and the appended claims may generally be construed to mean “one or more” unless specified otherwise or clear from context to be directed to a singular form. The term “disease characterised aberrant cell proliferation” as used herein, refers to any disease in which cell division is characterised by a diminished response, a lack of response, or an exaggerated response to one or more regulatory signals or proteins that modulate the rate of cell division, cell survival, and / or cell death in a particular population of cells. Examples of such regulatory signals include the regulatory signals or proteins include, but are not limited to, the presence or absence of a growth factor, checkpoint proteins, tumour suppressor proteins, pro-apoptotic proteins, and anti- apoptotic proteins. Examples of diseases characterised by aberrant cell proliferation include, but are not limited to, a cancer, a fibrotic disease, or cutaneous warts. The term “viral capsid surface”, as used herein, refers to the subset of solvent- exposed functional groups of the amino acids of viral capsid proteins., e.g., amines, sulfhydryls, disulfides, and phenols. The term “functionalized virus”, as used herein, refers to a non-recombinant or recombinant, enveloped or non-enveloped, virus that has been modified by linkage of a drug (e.g., a small molecule cancer drug), peptide, polypeptide, nucleic acid, lipid, or carbohydrate, to the viral capsid via a linker (e.g., a linker comprising a linear PEG). The term “dosing period”, as used herein, refers to a defined period of time over which at one or more doses of a first and a second therapeutic agent are administered to a subject in a desired temporal phase relationship. For example, within a first dosing period, a small molecule inhibitor may be administered twice at least 10 days before the beginning of administration of a recombinant virus expressing interferon gamma. Thus, within the first dosing period the small molecule inhibitor is administered before the recombinant virus. If a second dosing period commences, and the same sequence of administration is continued, the small molecule inhibitor is still considered to be administered before the recombinant virus even though it occurs after the previous administration of recombinant virus that occurred in the first dosing period. The terms "effective amount" or "therapeutically effective amount", as used herein, refer to a sufficient amount of an administered agent (e.g., a recombinant virus, an inhibitor the Hh signalling pathway, or a purified protein) which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. A “therapeutically effective amount” of a therapeutic agent that is administered as part of a combination treatment can refer to an amount of the therapeutic agent that would be therapeutically effective when used on its own (i.e., as a monotherapy), or may refer to a reduced amount that is therapeutically effective by virtue of its combination with one or more additional therapeutic agents. The term “recombinant virus”, herein, refers to any virus that has been genetically modified by experimental intervention and is capable of expressing a biologically active RNA from the inserted sequence. This can be the insertion of a full expression cassette or the insertion of a biologically active RNA (including splice sites) without any promoter insertion. The term “derivatized virus”, as used herein refers to a naturally occurring or recombinant virus in which a plurality of capsid surface functional groups have been reacted with a cross-linking agent to provide new functional groups at one or more of the locations of the plurality of the capsid original functional groups. The term “administer” or “administered” as used herein, broadly encompasses exposing a subject to a therapeutic agent in question by direct or indirect means. In some cases, e.g., where a biotherapeutic agent such as a peptide, protein, or polynucleotide is to be administered, it can be delivered directly as an isolated purified reagent by any suitable route of administration, or, alternatively, it can be delivered indirectly by inducing expression of the biotherapeutic agent within the subject, e.g., by delivering to the subject a plasmid DNA, modified mRNA, or a recombinant virus encoding the relevant biotherapeutic agent. The term “adverse event” as used herein, refers to any undesirable clinical occurrence in a subject / patient (as compared to the subject’s baseline health) and is any untoward medical occurrence defined as an unintended disease or injury or untoward clinical signs (including abnormal laboratory findings) in a patient. More specifically, grades of adverse events, as referred to herein, include those published under the “Common Terminology Criteria for Adverse Events” published by the U.S. National Cancer Institute (version 4.03 published 14 June 2010). These include mild (grade 1) adverse events which present as mild symptoms not requiring medical intervention; moderate (grade 2) adverse events, which require minimal, local or noninvasive intervention; severe or medically significant (grade 3) adverse events, which are not immediately life-threatening, but may require hospitalization or prolongation of hospitalization; life-threatening (grade 4) adverse events requiring urgent intervention; and adverse event-related death (grade 5). Adverse events commonly associated with administration of agents for inhibiting the Hh signalling pathway for cancer therapy include, but are not limited to, myopathies, fatigue, alopecia (hair loss), dysgeusia (distortion of taste perception), weight loss, elevation of creatine phosphokinase, muscle cramps / spasms, and ovarian dysfunction, and new onset squamous cell carcinoma. The terms “encoding” “encodes” “encoded” and the like as used herein, refer to any biomolecule for which a corresponding DNA or RNA sequence can be either transcribed into one or more RNAs or into one or more peptides or proteins. Examples of such encodable biomolecules include, but are not limited to, miRNAs, siRNAs, antisense RNAs, gRNAs, proteins, and peptides. The term “expressing” or “expression” as used herein refers to the process of transcription and / or translation. The term “purified” as used herein, in relation to a protein (e.g., “purified interferon gamma” and the like) refers to a protein provided in a form that is substantially free of contaminants normally associated with the protein in a native or natural environment. The term "antibody" as used herein, includes polyclonal antibodies, monoclonal antibodies, bispecific antibodies, fusion diabodies, triabodies, heteroconjugate antibodies, chimeric antibodies including intact molecules as well as fragments thereof, and other antibody-like molecules. Antibodies include modifications in a variety of forms including, for example, but not limited to, domain antibodies including either the VH or VL domain, a dimer of the heavy chain variable region (VHH, as described for a camelid), a dimer of the light chain variable region (VLL), Fv fragments containing only the light (VL) and heavy chain (VH) variable regions which may be joined directly or through a linker, or Fd fragments containing the heavy chain variable region and the CH1 domain. The term “antigen-binding portion” as used herein, refers to a region on an antibody that binds to a specific antigen. Typically, such an antigen-binding portion will include at least a heavy chain variable domain (VL) and a light chain variable domain (VH), which together form the antigen-binding portion. An example of such an antigen- binding portion would include, e.g., single chain variable fragments (scFvs). The term “small molecule drug” as used herein, refers to a drug or molecule having a molecular weight below 2000 daltons. As used herein, the term “conjugate” or “conjugated” shall be understood to encompass both indirect and direct binding. For example, direct conjugation includes chemical conjugation, which can be non-covalent or covalent or genetic conjugation (also referred to as “fusion”). In one example, the conjugation is covalent, e.g., a disulphide bond. The term “drug conjugate” and “drug conjugation” refers to the linking of drugs or prodrugs to other molecules, for example but not limited to, polymers, peptides, and proteins, often but not necessarily through a linker, for example, a biocompatible linker. For example, drug conjugation may improve the pharmacokinetics of a drug, for example contribute to the stabilisation of the drug, extension of drug half-life, improve tolerance of a drug, facilitate targeted delivery, release, or targeted delivery and / or release under specific conditions. For example, drug conjugation may improve the efficacy of the drug, or may allow for tracking or monitoring the location and / or amount of the drug in the body of a subject. The terms “synergy” or “synergistic” as used herein refer to an effect (e.g., induction of cell death”) resulting from the use of a combination of agents where the effect is quantitatively greater than the sum of the effects resulting from the use of each agent separately. For example, if agent “A” causes 30% cell death and agent “B” causes 30% cell death, the (non-synergistic) sum of such effects would be 60%. If, in fact, the combination of agents A and B results in greater than 60% cell death, their combined effect would be considered synergistic. The terms “treating” or “treatment” as used herein, refer to both direct treatment of a subject by a medical professional (e.g., by administering a therapeutic agent to the subject), or indirect treatment, effected, by at least one party, (e.g., a medical doctor, a nurse, a pharmacist, or a pharmaceutical sales representative) by providing instructions, in any form, that (i) instruct a subject to self-treat according to a claimed method (e.g., self-administer a drug) or (ii) instruct a third party to treat a subject according to a claimed method. Also encompassed within the meaning of the term “treating” or “treatment” are prevention of relapse or reduction of the disease to be treated, e.g., by administering a therapeutic at a sufficiently early phase of disease to prevent or slow its progression. Functionalized Viruses In some embodiments provided herein is a functionalized virus comprising a plurality of drug molecules displayed on its viral capsid, wherein each displayed drug molecule is attached to the virus capsid by a linker comprising a biocompatible polymer. Linkers Suitable linkers for the functionalized viruses disclosed herein include at least a biocompatible polymer, where the attached linker is part of a conjugate with a drug molecule and is crosslinked by a particular type of bond with the surface of a viral capsid to yield a functionalized virus as disclosed herein. In some embodiments the biocompatible polymer in the linker is selected from the group consisting of a linear polyethylene glycol (PEG), a branched PEG, poly(2-oxazoline), poly(cyclic imino ethers), polysarcosine (pSar), a polysaccharide, polyvinylpyrrolidone (PVP), a synthetic poly(amino acid) (PAA), polyglutamic acid (PGA), poly(hydroxyethyl-1-asparagine) (PHEA), poly(hdryoxyethyl-1- (PHEG), an XTEN polymer, poly(thioglycidyl glycerol) (PTTG), RAFT polymers, a dendrimer, and hydroxyethyl starch. In some preferred embodiments the biocompatible polymer is a linear PEG or a branched PEG. In some embodiments, the functionalized virus comprises a structure depicted by Formula I: wherein: m is an integer between 1 and about 5000, or about 1000 to about 5000; X is a linker comprising a biocompatible polymer; D is a drug molecule. It will be appreciated that m refers to the number of -X-D moieties that are linked to or loaded on the viral capsid. D may be any drug molecule, including those described elsewhere herein. The biocompatible polymer may be any such biocompatible polymer described herein. The linker may be a divalent linking moiety. The term “divalent linking moiety” refers to any divalent group capable of linking, joining, bonding or attaching two chemical moieties. In some embodiments, X is an aliphatic group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, - C(=O)NR4-, -NR4-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R4)C(=S)N(R4)-, and – N(R4)C(=O)N(R4)-, and is optionally substituted with one or more R5, wherein: each R4is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl, each of which is optionally substituted with one or more R5; each R5is independently selected from the group consisting of H, halogen, C1- 10alkyl, OC1-10alkyl, C1-10haloalkyl, OC1-10haloalkyl, C2-10alkenyl, C2-10alkynyl, OC2- 10alkenyl, OC2-10alkynyl, 3-10 membered carbocyclyl, 3-10-membered heterocyclyl, C1-10alkyl-3-10-membered-carbocyclyl, C1-10alkyl-3-10-membered-heterocyclyl, PEG, - NO2, -CN, -SCN, -N3, =O, -N(R6)2, -C(=O)N(R6)2, -S(=O)N(R6)2, -S(=O)2N(R6)2, -OR6, - - – 10 membered-carbocyclyl, and 3-10- heterocyclyl is optionally substituted with one or more R6, and wherein PEG may comprise 1 to 100, 1 to 60, 1 to 20 or 1 to 10, monomer units; each R6is independently selected from the group consisting of H, C1-6alkyl, 3- 10 membered carbocyclyl, 3-10-membered heterocyclyl, C1-6alkyl-3-10-membered- carbocyclyl, and C1-6alkyl-3-10-membered-heterocyclyl; wherein each C1-6alkyl, 3-10- membered-carbocyclyl, and 3-10-membered heterocyclyl is optionally substituted with one or more R7; each R7is independently selected from the group consisting of H, halogen, - NO2, -N(R8)2, -CN, -SCN, -N3, =O, -C(=O)R8, -C(=O)OR8, -C(=O)N(R8)2, - N(R8)C(=O)R8, -OR8, -P(=O)(OR8)2, -P(=O)OR8(R8), -P(=O)(R8)2, C1-6alkyl, and -OC1-6alkyl; and each R8is independently selected from the group consisting of H, C1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C1-10alkyl-3-10-membered carbocyclyl, C1-10alkyl-3-10-membered heterocyclyl. In some embodiments, X is a C1-30, C1-20, C1-10, or C1-8, or C1-6, group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, -C(=O)NR4-, -NR4-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R4)C(=S)N(R4)-, and –N(R4)C(=O)N(R4)-, and is optionally substituted with one or more R5. In some embodiments, X is a C1-30, C1-20, C1-10, or C1-8, or C1-6, group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, -C(=O)O-, -C(=O)S-, or -S(=O)2-. In some embodiments, L is a C1-10, or C1-8, or C1-6, group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, or -C(=O)O-. In some embodiments, the functionalized virus comprises a structure depicted by Formula Ia, Formula Ib or Formula Ic: Formula Ic wherein: m is an integer between 1 and about 5000, or about 1000 to about 5000; D is a drug molecule; L1and L2are independently selected from an aliphatic group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, -C(=O)NR4-, -NR4-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R4)C(=S)N(R4)-, and –N(R4)C(=O)N(R4)-, and is optionally substituted with one or more R5, wherein: each R4is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl, each of which is optionally substituted with one or more R5; each R5is independently selected from the group consisting of H, halogen, C1- 10alkyl, OC1-10alkyl, C1-10haloalkyl, OC1-10haloalkyl, C2-10alkenyl, C2-10alkynyl, OC2- 10alkenyl, OC2-10alkynyl, 3-10 membered carbocyclyl, 3-10-membered heterocyclyl, C1-10alkyl-3-10-membered-carbocyclyl, C1-10alkyl-3-10-membered-heterocyclyl, PEG, - NO2, -CN, -SCN, -N3, =O, -N(R6)2, -C(=O)N(R6)2, -S(=O)N(R6)2, -S(=O)2N(R6)2, -OR6, -SR6, OC(=O)R6, –C(=O)R6, -C(=O)OR6-S(=O)R6, -S(=O)2R6, -S(=O)OR6, - S(=O)2OR6, -S(=O)(OR6)2, -OS(=O)R6, -OS(=O)2R6, -OS(=O)OR9, -OS(=O)2OR6, - OS(=O)(OR6)2, -N(R6)C(=O)R6, –N(R6)S(=O)R6, N(R6)C(=O)N(R6)2, -N(R6)S(=O)2R6, -P(=O)(OR6)2, -P(=O)OR6(R6), -P(=O)(R6)2, -OP(=O)(OR6)2, -OP(=O)OR6(R6) and – OP(=O)(R6)2,, wherein each C1-10alkyl, C1-10haloalkyl, C2-10alkenyl, C2-10alkynyl, 3-10 membered-carbocyclyl, and 3-10-membered-heterocyclyl is optionally substituted with one or more R6, and wherein PEG may comprise 1 to 100, 1 to 60, 1 to 20 or 1 to 10, monomer units; each R6is independently selected from the group consisting of H, C1-6alkyl, 3- 10 membered carbocyclyl, 3-10-membered heterocyclyl, C1-6alkyl-3-10-membered- carbocyclyl, and C1-6alkyl-3-10-membered-heterocyclyl; wherein each C1-6alkyl, 3-10- membered-carbocyclyl, and 3-10-membered heterocyclyl is optionally substituted with one or more R7; each R7is independently selected from the group consisting of H, halogen, - NO2, -N(R8)2, -CN, -SCN, -N3, =O, -C(=O)R8, -C(=O)OR8, -C(=O)N(R8)2, - C1-6alkyl, and -OC1- each R8is independently selected from the group consisting of H, C1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C1-10alkyl-3-10-membered carbocyclyl, C1-10alkyl-3-10-membered heterocyclyl. In some embodiments, L1and L2independently C1-30, C1-20, C1-10, or C1-8, or C1-6, group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, -C(=O)NR4-, -NR4-, -C(=O)O-, -C(=O)S-, -S(=O)2-, - N(R4)C(=S)N(R4)-, and –N(R4)C(=O)N(R4)-, and is optionally substituted with one or more R5. In some embodiments, L1and L2are independently C1-30, C1-20, C1-10, or C1-8, or C1-6, group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, -C(=O)O-, -C(=O)S-, or -S(=O)2-. In some embodiments, L is a C1-10, or C1-8, or C1-6, group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, or -C(=O)O-. In some embodiments, the functionalized virus comprises a structure depicted by Formula Ia, Formula Ib or Formula Ic, wherein L1and L2are independently selected from C1-C30alkyl, which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, or -C(=O)O-. In some embodiments, the functionalized virus comprises a structure depicted by Formula Ia, Formula Ib or Formula Ic, wherein L1and L2are independently selected from C1-C30alkyl, which is uninterrupted or interrupted with one or more groups selected from –O-, -C(=NH)-, - C(=O)-. In some embodiments, the functionalized virus comprises a structure depicted by Formula Ia, Formula Ib or Formula Ic, wherein L1is C1-C10 alkyl, which is uninterrupted or interrupted with -C(=NH)-, and L2is C1-C30 alkyl, which is uninterrupted or interrupted with -O- or -C(=O)-. In some embodiments, the functionalized virus comprises a structure depicted by Formula Ia. In some embodiments, the functionalized virus comprises a structure depicted by Formula Ib. In some embodiments, the functionalized virus comprises a structure depicted by Formula Ic. In some embodiments the linker, as attached to the viral capsid surface (i.e., the attached linker) comprises a disulfide bond, an amide bond, a thioamide bond, a thioether bond, a tetrazole bond, or a thioacetyl bond. In some preferred embodiments the linker comprises a disulfide bond. In some embodiments the attached linker also includes a cleavable spacer that upon cleavage releases the displayed drug molecule from the linker. In other embodiments the attached linker does not include a cleavable spacer. In some embodiments, where the attached linker includes a cleavable spacer, the cleavable spacer contains an enzymatically cleavable group or a chemically cleavable group. Suitable enzymatically cleavable include, but are not limited to, those that can be cleaved by cathepsin-B, plasmin, matrix metalloprotease, pyrophosphatase, phosphatase, glucuronidase, β galactosidase, an esterase, a carboxyesterase, and arylsulfatase A. Suitable chemically cleavable groups include, but are not limited to, disulfide, acetal, ester, silyl ester, anhydride, carbamate, carbonate, and hydrazone . Recognition sites and conditions effective for cleaving linkers are well known to the person skilled in the art, for example Sheyi et al. (2022), Tsuchikama et al. (2016), Su et al. (2021), Joubert et al. (2020), and Fuchigami et al. (2018). Types of Virus Suitable for Functionalization A variety of virus types are suitable for generation of functionalized viruses as described herein. In some embodiments a functionalized virus is a non-recombinant virus. In other embodiments a functionalized virus is a recombinant virus comprising within its genome an expression cassette for expression of one or more biotherapeutic agents. In some embodiments a functionalized virus is a conditionally replication- competent virus, i.e., a virus that can replicate only in particular cell types or in cells with a particular expression profile, e.g., p53-deficient cancer cells.. In other embodiments a functionalized virus is an oncolytic virus, which can replicate in a transduced host cell and, ultimately, lyse the host cell. In some embodiments, the functionalised virus is a DNA virus. In some embodiments, the functionalised virus is an RNA virus. In some embodiments, the functionalised virus is a non-enveloped virus. In some embodiments, the functionalised is an enveloped virus. In an embodiment, the enveloped virus has been treated to remove the envelope. For example, using a suitable nonionic detergent which removes the envelope but maintains a stable capsid. In an embodiment, the non-enveloped DNA virus is an adenovirus or an adeno- associated virus, In an embodiment, the enveloped DNA virus is a vaccinia virus, Cytomegalovirus (CMV) or Herpes Simplex virus (HSV). In an embodiment, the enveloped RNA virus is a measles virus, retrovirus or a lentivirus. In other embodiments, the type of functionalised virus is an RNA virus. Suitable types RNA viruses include, but are not limited to, Alphavirus (e.g., Sindbis or Semliki Forest Virus), Flavivirus (e.g., , Paramyxovirus (e.g., Sendai virus), Rhabdovirus (e.g., vesicular stomatitis virus), Retrovirus, Lentivirus and Orthomyxovirus (e.g., influenza A virus). Methods for design, production, and use of recombinant DNA viruses are established in the art, as exemplified in Fukazawa et al. (2010) and in “Gene Therapy Protocols” for adenovirus; “Adeno-Associated Virus: Methods and Protocols” for AAV; Cody et al. (2013) and “Herpes Simplex Virus: Methods and Protocols” for HSV; “Gene Therapy Protocols Vol. 1: Production and In Vivo Applications of Gene Transfer Vectors” and Amer et al. (2014) for retrovirus; and Merten et al. (2016) and Emeagi et al. (2013) for lentivirus. Methods for design, production, and use of such types of recombinant RNA viruses are established in the art, as exemplified in Lundstrom (2015) and Quetglas et al. (2010) for Alphavirus; Hoang-Le et al. (2009) and Usme-Ciro et al. (2013) for Flavivirus; Cattaneo (2010) for Paramyxovirus; Finke et al. (2005) and Chang et al. (2010) for Rhabdovirus; and U.S.8,475,806 for Orthomyxovirus. In some embodiments, where the functionalized virus is a recombinant functionalized virus, suitable biotherapeutic agents for expression include, but are not limited to: cytokines, cell death inducing proteins (CDIPs), a targeting polynucleotide against expression of a CDIP, a targeting polynucleotide against expression of an anti- apoptotic protein, a prodrug-converting enzyme, a chemosensitizing enzyme, a cleavable linker site protease, and antibodies. Suitable examples of prodrug-converting enzymes, depending on the prodrug substrate to be activated, include, but are not limited to, a carboxyesterase, a cytosine deaminase, a thymidine kinase, a nitroreductase, β-lactamase, β-glucuronidase, and alkaline phosphatase. Examples of anti-cancer drugs that can pair with one or more of these prodrug-converting enzymes include, but are not limited to, those disclosed in Sheikh et al (2021), Xu et al. (2001), Wierdll et al. (2008) and Martin et al. (2022). The skilled person will appreciate that expression of such prodrug-converting enzymes is particularly useful in embodiments where a recombinant functionalized virus for expression of the prodrug converting enzyme displays on its capsid prodrug molecules that are activated by the prodrug converting enzyme. In other embodiments the one or more biotherapeutic agents to be expressed include a cytokine. In some embodiments the cytokine is interferon gamma. In other embodiments the cytokine is a disulfide-stabilized IL-18 Fc-fusion protein (dsIL-18-Fc) as described in Bainbridge et al. (2025), J Immunother, 13(7):e011789. In other embodiments the one or more biotherapeutic agents to be expressed include one or more cell death-inducing proteins (CDIPs). In some embodiments the one or biotherapeutic agents include a targeting polynucleotide. In some embodiments the targeting polynucleotide is an shRNA, a guide RNA, an antisense RNA, or a miRNA. In some embodiments the expression cassette in a recombinant functionalized virus described herein includes a constitutively active promoter, a tumor-specific promoter, or a viral promoter operably linked to a nucleic acid sequence encoding the one or more biotherapeutic agents. Examples of suitable promoters for driving expression of biotherapeutic agents from a recombinant virus in a method described herein include, but are not limited to, constitutive promoters such as, CMV, CAG, EF-1-α, HSV1-TK, SV40, β-actin, and PGK promoters. In other embodiments, a promoter is an inducible promoters, such as those containing TET-operator elements. In some embodiments the promoter is a viral promoter. In some embodiments the viral promoter is a viral promoter activated late in the viral infection cycle of the functionalized virus. In some embodiments the viral promoter activated late in the viral infection cycle is the adenovirus major late promoter (MLP). While not wishing to be bound by theory, delayed expression of an encoded therapeutic agent from a recombinant functionalized virus expression is advantageous, particularly in the case of biotherapeutic agents that induce cancer host cell death, as delayed expression of such proteins will allow the infected host cell to survive long enough to permit viral replication to proceed in the case of replication-competent or conditionally replication-competent recombinant functionalized viruses as described herein. In certain embodiments, target-selective promoters are used to drive expression of biotherapeutic agents in specific cell types or specifically in cells exhibiting aberrant cell proliferation. Examples of suitable promoters useful for the methods described herein include, but are not limited to, the erb 2 promoter (breast cancer), the carcinoembryonic antigen promoter (colorectal cancer), the urokinase-type plasminogen activator receptor promoter (colorectal cancer), the tyrosinase promoter (melanoma), the melacortin receptor (melanoma); the human telomerase reverse transcriptase (hTERT) promoter (multiple cancers), the RAS-related nuclear protein promoter (multiple cancers), the breast cancer metastasis suppressor 1 promoter (multiple cancers), the Rad51C promoter (multiple cancers), and the minichromosome maintenance complex component 5 promoter (multiple cancers). In some embodiments, where two or more proteins are to be expressed from a recombinant virus, the recombinant virus contains an expression cassette encoding a polycistronic mRNA (a "polycistronic expression cassette"), which, upon translation gives rise to independent polypeptides different amino acid sequences or functionalities, e.g., interferon gamma and a protein inhibitor of the Hh signalling pathway (e.g., hSu(fu)). In some embodiments, a polycistronic expression cassette encodes a "polyprotein" comprising multiple polypeptide sequences that are separated by encoded by a picornavirus, e.g., a foot-and-mouth disease virus (FMDV) viral 2A peptide sequence. The 2A peptide sequence acts co-translationally, by preventing the formation of a normal peptide bond between the conserved glycine and last proline, resulting in ribosome skipping to the next codon, and the nascent peptide cleaving between the Gly and Pro. After cleavage, the short 2A peptide remains fused to the C- terminus of the `upstream` protein, while the proline is added to the N-terminus of the `downstream` protein. which during translation allow cleavage of the nascent polypeptide sequence into separate polypeptides (see, for example, Trichas et al., 2008). In other embodiments, a polycistronic expression cassette may incorporate one or more internal ribosomal entry site (IRES) sequences between open reading frames incorporated into the polycistronic expression cassette. IRES sequences and their use are known in the art as exemplified in, e.g., Martinez-Sales (1999). In some embodiments, a functionalized virus described herein has targeted tropism, e.g., tropism for a particular cell type as reviewed in Bucholz et al. (2015). Suitable targeting moieties, to be incorporated into a recombinant viral capsid surface, include ligands that bind to cell surface receptors that are overexpressed by overproliferating cells (e.g., cancer cells). For example, the Her2 / neu receptor, frequently overexpressed in breast cancer cells, can be targeted by incorporating a designed ankryrin repeat protein (DARPin) ligand, as has been done for lentivirus (Münch et al. 2011) in AAV (Münch et al. 2013). In another example a recombinant lentivirus is designed to target P-glycoprotein, overexpressed on the surface of melanoma cells, by incorporating an antibody into the viral capsid surface (Morizono et al.2005). In some embodiments the cell targeting moiety targets a cell type selected from the group consisting of: tumour cells, myeloid cells, macrophages, myeloid-derived suppressor cells (MDSCs), T cells, stromal cells, and cancer-associated fibroblasts. Drugs in Functionalized Viruses The skilled person will appreciate that many types of drugs can be crosslinked, via a linker, to a viral capsid to generated a functionalized virus as disclosed herein. In some embodiments the drug molecules crosslinked to the viral capsid of a functionalized virus are the same drug (i.e.., all the same molecular structure). In other embodiments the capsid-crosslinked drug molecules are of more than one type, i.e., drugs of different molecular structures. In the drug molecules consist of 2, 3, or 4 types of drug molecules. Non-limiting examples of suitable drug molecule combinations include CBL0137and gemcitabine (see Burkhart et al., 2014), CBL0137 and cis-platin (see De at al., 2018), combinations with gemcitabine (see KalantarMotamedi et al., 2021), and paclitaxel and verapamil (see Li et al., 2019). In some embodiments the drug displayed in a functionalized virus is a small molecule drug, where a small molecule drug is considered to be a drug having a molecular weight in the range of about 0.1 kDa to about 1.0 kDa. In some embodiments the drug molecules are of a drug that has poor aqueous solubility. In some embodiments the aqueous solubility of such a drug in pure form is about 0.001 mg / mL to about 0.05 mg / mL at 25 °C and neutral pH, e.g., 0.002 mg / mL, 0.004 mg / mL, 0.007 mg / mL, 0.01 mg / mL, 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / ml or another level of solubility from about 0.001 mg / mL to about 0.05 mg / mL at 25 °C and neutral pH. In some embodiments the linked drug molecules displayed in a functionalized virus are anti-cancer drug molecules. In some embodiments the anti-cancer drug molecules induce programmed cell death. In other embodiments the anti-cancer drug molecules are cytostatic. In some embodiments the anti-cancer drug molecules are small molecule anti-cancer drugs. Suitable examples of small molecule anti-cancer drugs for functionalized viruses disclosed herein include, but are not limited to, one or more of: gemcitabine, gemcitabine derivatives, derivative CBL0137 (CAS No.1197996-80-7), a small molecule inhibitor of Nicotinamide phosphoribosyltransferase (NAMPTi), bortezomib (CAS No. 179324-69-7), paclitaxel, 5-Fluorouracil (5-FU), and Irinotecan (CAS No.97682-44-5), and pyrrolobenzodiazepine (PBD) dimers, e.g., SGD-1882 (CAS No. 1222490-34-7) and SG3199 (CAS NO. 1595275-71-0). Examples of NAMPTi’s include, but are not limited to: FK866 (CAS No. 658084-64-), CHS-828 (CAS No. 200484-11-3), and OT-82 (1800487-55-1). Examples of gemcitabine derivatives include, but are not limited to: SL-01 (CAS No.26049-94-5.), and those set out in U.S. Patent No.6,384,019. The drug molecule may be linked via a cleavable moiety, including any cleavable moiety described herein, e.g. a cathepsin B cleavable moiety, e.g. Val-Ala or Val-Cit. The cleavable moiety may comprise a self-immolative moiety, which are known in the art, e.g. PAB / PABC. Accordingly, in some embodiments, the functionalized virus comprises a NAMPTi inhibitor linked to a PEG linker, such as a PEG12linker, e.g. in one example, the functionalized virus comprises: the functionalized virus comprises a structure selected from: from: . from: .

[0002] In some embodiments, functionalized virus comprises a pyrrolobenzodiazepine dimer (PBD) linked to a PEG linker. In some exemplary embodiments, a PBD-linker is one of the following: R = Ma 5leimide or Pyridyldithio In some embodiments the anti-cancer drug crosslinked to the capsid in a functionalized virus is a pro-drug form of the anti-cancer drug. The pro-drug form of the anti-cancer drug (or any other drug described herein) may include any suitable promoiety which can be metabolized. Non-limiting examples of reagents comprising the prodrug form of the anticancer drug to be crosslinked to the capsid in a functionalized virus include: Enzyme Prodrug Reagent Active Drug ne ne ne Cathepsin / Cytosine 5- deaminase Fluorouracil il , y g be crosslinked to a viral capsid as well as the total number and density of drug molecules displayed on the capsid of a functionalized virus have an impact on the solubility and / or transducibility / infectivity of a functionalized virus. Accordingly, in some embodiments, the number of drug molecules per capsid in a functionalized virus is about 1,000 molecules to about 15,000 molecules, e.g., 1,200 molecules, 1,300 molecules, 1,500 molecules, 1,700 molecules, 2,000 molecules, 2,500 molecules, 3,000 molecules, 3,500 molecules, 4,000 molecules, 4,500 molecules, 5,000 molecules, 6,000 molecules, 7,000 molecules, 8,000 molecules, 9,000 molecules, 10,000 molecules, 12,000 molecules, 14,000 molecules, another number of drug molecules per capsid from about 1,000 molecules to about 15,000 molecules per capsid. In some embodiments, particularly where a drug molecule crosslinked to a viral capsid has low aqueous solubility, the number of drug molecules is about 1000 molecules to about 5,000 molecules, e.g., molecules, 1,200 molecules, 1,500 molecules, 1,700 molecules, 2,000 molecules, 2,200 molecules, 2,500 molecules, 2,700 molecules, 3,000 molecules, 3,200 molecules, 3,500 molecules, 4,000 molecules, 4,500 molecules, or another number of drug molecules per capsid from about 1,000 molecules to about 5,000 drug molecules per capsid. A surprising finding as disclosed herein is that aprotic polar solvents, useful for cross-linking a linker-drug conjugate to viral capsids, particularly those having poor aqueous solubility, when used within the disclosed concentration ranges preserve the ability of a functionalized virus to transduce and / or infect cells. As disclosed herein, in some preferred embodiments a functionalized virus by cross-linking a linker-drug conjugate to a viral capsid is performed in the presence of a polar aprotic solvent. In some embodiments the concentration of the polar aprotic solvent is about 5%(v / v) to about 20% (v / v), e.g., 6%, 6.5%, 7%, 7.5%, 8%, 9%, 10%, 12%, 14%, 15%, 16%, 17%, 18%, or another concentration of a polar aprotic solvent from about 5% (v / v) to about 20% (v / v). In some embodiments the polar aprotic solvent is acetonitrile. Accordingly, provided herein are compositions comprising a functionalized virus and a polar aprotic solvent, wherein the functionalized virus retains infectivity despite exposure to the aprotic polar solvent. Targeting Moieties for Functionalized Viruses In some embodiments a functionalized virus disclosed herein also includes a cell-targeting moiety that confers cell type-selective tropism and / or infectivity to the functionalized virus. In some embodiments the cell-targeting moiety targets a functionalized virus to a cell type selected from the group consisting of: tumour cells, myeloid cells, macrophages, myeloid-derived suppressor cells (MDSCs), T cells, stromal cells, and cancer-associated fibroblasts. Examples of suitable targeting moieities for linkage to the capsid of a functionalized virus include, but are not limited to, DNA aptamers, RNA aptamers, peptides, DARPins, single-chain variable fragments (scFvs) of antibodies, nanobodies, glycooligomers, small molecule ligands, and genetically modified capsid proteins of the functionalized virus. Methods for modifying viral capsids to direct viral tropism are known in the art as taught in, e.g., Puzzo et al. (2023), Chen et al. (2024) and Freitag et al. (2022). In some embodiments a targeting moiety targets a cell surface antigen selected from the group consisting of: HER2, EGFR, HER3, TROP-2, B7-H3, CD25, EGFRvIII, cMET, FGFR-2, FGFR3, AXL, CD70, CD166, CEACAM5, GPNMB, Mesothelin, LIV1A, NaPi2b, CD71, CD228, FRα, CD33, CD79b, nectin-4, PSMA, STEAP1, P Cadherin, SLITRK6, LAMP1, CA9, GPR20, CLDN18.2, LRRC15, ANTXR1, TM4SF1, CD205, HLA-DR, DLK-1, DLL3, EFNA4, PTK7, ROR1, 5T4, and KAAG1. See, e.g., Boni et al. (2020). In some embodiments the targeting moiety is an antibody. In some embodiments the targeting moiety is a nanobody (see, for example, Eichoff et al., 2019). In some embodiments a cell-targeting moiety is attached to the linker rather than directly to the surface of the viral capsid. In some embodiments, where the cell-targeting moiety is attached to the linked in a functionalized virus, the linker comprises branched PEG. Derivatized Viruses The skilled person will appreciate that viral capsids commonly have a number of functional groups on their surface, which functional groups are useful for undergoing cross-linking reactions with a linker-conjugate as disclosed herein. In some embodiments, such capsid surface functional groups, e.g., an amine group are, prior to cross-linking, reacted with a reagent that, yields a derivative on the surface of the capsid in place of the native functional group, where the derivative comprises a different functional group useful for a subsequent crosslinking reaction with a linker-drug conjugate. In some embodiments, the functional group to be derivatized is an viral capsid amine group, e.g., reaction of an amine group with a thiolating agent to obtain a derivatized virus. In some embodiments a derivatized virus is a derivatized virus corresponding to the structure depicted in Formula I: wherein, n is an integer between 1 and 20000; and R comprises a reactive crosslinking moiety. It will be appreciated that n refers to the number of “R” moieties that are linked to or loaded on the viral capsid. In some embodiments, n is an integer between 1 and 20000, between 1 and 15000, between 1 and 10000, or between 1 and 5000. It will further be appreciated that the bond between R and the viral capsid may be to or via any surface- derived group of the viral capsid, for example a group on a surface protein of the viral capsid. For example, and without limitation, the surface-derived group may be a group on a side chain of an amino acid, for example and without limitation, that of lysine, cysteine, tyrosine, methionine, histidine, tryptophan, serine, threonine, aspartic acid, glutamine, glutamic acid, or arginine. The reactive crosslinking moiety (comprised by R) may be any functional group useful for a subsequent crosslinking reaction with a drug or linker-drug conjugate. Such functional groups are known by persons skilled in the art. Suitable examples include, but are not limited to, amines, thiols or sulfhydryls, selenols, alcohols, esters, anhydrides, alkenes, alkynes, azides, tetrazines, phenols, imidazoles, terminal amides, and thioethers. A derivatised virus with a reactive crosslinking moiety may be formed in a variety of ways as the person skilled in the art will appreciate, for example, the reactive crosslinking moiety may be engineered into a surface exposed protein of the viral capsid (for example, by engineering an unnatural amino acid comprising the reactive crosslinking moiety). In another non-limiting example, the reactive crosslinking moiety may be incorporated to form a derivatized virus by reacting a comprising the reactive crosslinking moiety (or a protected form thereof), with an existing functional group on a virus or derivatised virus, in order to “convert” an exposed reactive functional group from one type of functional group to another. Modification of an existing functional group on a virus or derivatised virus may be assisted by means of enzymatic catalysis. Reactive functional groups may therefore be native, or incorporated by chemical, enzymatic, or engineered means. It will be appreciated that the person skilled in the art has a variety of options available for incorporating a reactive functional group by means of residue-specific amino acid side chain modification. For example, a variety of methods are known for the modification of amino acid side chain, including but not limited to the amino acids lysine, cysteine, tyrosine, methionine, histidine, tryptophan, serine, threonine, aspartic acid, glutamine, glutamic acid, and arginine. Again, it will be appreciated that such amino acids may be native to the precursor viral capsid, or be engineered to a viral capsid by any suitable known method. The person skilled in the art will be aware that there are a variety of known methods for the modification of amino acids (e.g. lysine), such as those disclosed in: Tantipanjaporn, A.; Wong, M.-K. Development and Recent Advances in Lysine and N-Terminal Bioconjugation for Peptides and Proteins. Molecules 2023, 28, 1083, the entire contents of which is hereby incorporated by reference herein. Such methods may be utilised or adapted by the person skilled in the art to arrive at e.g. derivatised viruses of Formula II. The derivatisation of the viral capsid may be via a cysteine residue. Reagents for cysteine modification are well known, and for example include, but are not limited to, maleimides, bromomaleimides, iodoacetamides, carbonylacrylic reagents, sulfones, phosphonamidates, vinylphosphonites, ethynylbenziodoxolones, N-alkyl vinylpyridine salts, vinylheteroaryls including vinylpyrimidines and vinyltriazines. Such reagents may be commercially available with the desired reactive functional group (or a protected form thereof) for incorporating to the derivatised virus, or they may be suitably functionalised to comprise the reactive functional group, or some other intermediate moiety that may be further manipulated to incorporate the desired derivatised virus. The derivatisation of the viral capsid may be via a tyrosine residue. Methods for tyrosine modification are well known in the art, and include, but are not limited to those disclosed in Szijj et al., (2020), the contents of which is hereby incorporated by reference herein. Suitable strategies for tyrosine modification include Mannich-type reactions (e.g. with a pre-formed imine, or aryl-amine and formaldehyde), diazonium reagents, diazodicarboxyamides, SuFEx chemistry, triazole exchange, O-glycosylation, or enzyme catalysed approaches. Such reagents be commercially available with the desired reactive functional group (or a protected form thereof) for incorporating to the derivatised virus, or they may be suitably functionalised to comprise the reactive functional group, or some other intermediate moiety that may be further manipulated to incorporate the desired derivatised virus. The derivatisation of the viral capsid may be via a lysine amine, such as a native lysine amine or engineered lysine amine. Suitable methods for lysine amine modification include, but are not limited to N-hydroxysuccinimide (NHS)-ester amidation or acylation, amide coupling reagent mediated ester amidation, isothiocyanate or isocyanate addition, reductive amination, iridium catalyzed reduction alkylation, allyl isothiocyanate addition, iminoborate, squaric acid diester mediated sequential amidation, diazonium capture, phthalimidine formation, azaphilones, divinylcyclopropane- cycloheptadiene rearrangements, or iminothiolanes (e.g. Traut’s reagent), or other crosslinking reagents including formaldehyde, NHS-maleimides (e.g. SMCC, or Sulfo- SMCC), NHS-disulfides, NHS-pyridyldithiols (e.g. SPDP or LC-SPDP). Reagents for such reactions are readily available from commercial suppliers. Other suitable methods will be apparent to the skilled person. Thus, in some embodiments a derivatized virus is a derivatized virus corresponding to the structure depicted in Formula II: wherein, n is an integer between 1 and 20000; R comprises a reactive crosslinking moiety; and -NH is a viral capsid surface-derived group. R and n may be any such as described above. The viral capsid surface-derived - NH may be derived from any surface amine of the viral capsid. In some embodiments, the viral capsid surface derived -NH is derived from an amine of a lysine residue. In some embodiments, the viral capsid surface derived -NH is derived from an amine of a native lysine residue. In some embodiments, the viral capsid surface derived -NH is derived from an amine of an engineered lysine residue. In some embodiments a derivatized virus is a derivatized virus corresponding to the structure depicted in Formula III: wherein, n is an integer between 1 and 20000; L comprises divalent linking moiety which is uninterrupted or interrupted, and optionally substituted; and -NH is a viral capsid surface-derived group. The -NH viral capsid surface-derived and n may be any such as described above. The term “divalent linking moiety” refers to any divalent group capable of linking, joining, bonding or attaching two chemical moieties (for example N and S). In some embodiments, L is an aliphatic group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, - C(=O)NR4-, -NR4-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R4)C(=S)N(R4)-, and – N(R4)C(=O)N(R4)-, and is optionally substituted with one or more R5, wherein: each R4is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl, each of which is optionally substituted with one or more R5; each R5is independently selected from the group consisting of H, halogen, C1-10alkyl, OC1-10alkyl, C1-10haloalkyl, OC1-10haloalkyl, C2-10alkenyl, C2-10alkynyl, OC2-10alkenyl, OC2-10alkynyl, 3-10 membered carbocyclyl, 3-10-membered heterocyclyl, C1-10alkyl-3-10-membered-carbocyclyl, C1-10alkyl-3-10- membered-heterocyclyl, PEG, -NO2, -CN, -SCN, -N3, =O, -N(R6)2, - C(=O)N(R6)2, -S(=O)N(R6)2, -S(=O)2N(R6)2, -OR6, -SR6, OC(=O)R6, –C(=O)R6, -C(=O)OR6-S(=O)R6, -S(=O)2R6, -S(=O)OR6, -S(=O)2OR6, -S(=O)(OR6)2, - OS(=O)R6, -OS(=O)2R6, -OS(=O)OR9, -OS(=O)2OR6, -OS(=O)(OR6)2, - N(R6)C(=O)R6, –N(R6)S(=O)R6, N(R6)C(=O)N(R6)2, -N(R6)S(=O)2R6, - P(=O)(OR6)2, -P(=O)OR6(R6), -P(=O)(R6)2, -OP(=O)(OR6)2, -OP(=O)OR6(R6) and –OP(=O)(R6)2, wherein each C1-10alkyl, C1-10haloalkyl, C2-10alkenyl, C2- 10alkynyl, 3-10 membered-carbocyclyl, and 3-10-membered-heterocyclyl is optionally substituted with one R6, and wherein PEG may comprise 1 to 100, 1 to 60, 1 to 20 or 1 to 10, monomer units; each R6is independently selected from the group consisting of H, C1-6alkyl, 3-10 membered carbocyclyl, 3-10-membered heterocyclyl, C1-6alkyl-3-10-membered- carbocyclyl, and C1-6alkyl-3-10-membered-heterocyclyl; wherein each C1-6alkyl, 3-10-membered-carbocyclyl, and 3-10-membered heterocyclyl is optionally substituted with one or more R7; each R7is independently selected from the group consisting of H, halogen, -NO2, -N(R8)2, -CN, -SCN, -N3, =O, -C(=O)R8, -C(=O)OR8, -C(=O)N(R8)2, - N(R8)C(=O)R8, -OR8, -P(=O)(OR8)2, -P(=O)OR8(R8), -P(=O)(R8)2, C1-6alkyl, and -OC1-6alkyl; and each R8is independently selected from the group consisting of H, C1-10alkyl, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C1-10alkyl-3-10-membered carbocyclyl, C1-10alkyl-3-10-membered heterocyclyl. In some embodiments, L is a C1-30, C1-20, C1-10, or C1-8, or C1-6, group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, -C(=O)NR4-, -NR4-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R4)C(=S)N(R4)-, and –N(R4)C(=O)N(R4)-, and is optionally substituted with one or more R5. In some embodiments, L is a C1-30, C1-20, C1-10, or C1-8, or C1-6, group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, -C(=O)O-, -C(=O)S-, or -S(=O)2-. In some embodiments, L is a C1-10, or C1-8, or C1-6, group which is uninterrupted or interrupted with one or more groups selected from –O-, -S-, -C(=NH)-, -C(=O)-, or -C(=O)O-. In one example, Traut’s reagent may be used to convert a native or engineered lysine residue and arrive at a derivatised virus having a thiol or sulfhydryl reactive group. Thus, in some embodiments a derivatized virus is a derivatized virus corresponding to the structure depicted in Formula IV: -NH is a viral capsid surface-derived group. The -NH viral capsid surface-derived group and n may be any such as described above. CBL0137 Drug conjugates In some embodiments, provided herein is a drug conjugate comprising one or more CBL0137 molecules and at least one stabilizing, targeting, or delivery moiety bound to the one or more CBL10137 molecules. The stabilising, targeting, or delivery moiety may perform one or more of those functions, i.e. stabilising, targeting and delivery are not necessarily mutually exclusive. For example, CBL may be conjugated to a protein that both targets specific cells and also improves the stability of CBL. For example, human serum albumin has been shown to extend half-life of drugs and be also preferentially taken up by tumour cells. For example, a moiety that delivers a drug to a general tissue area, may also target, for example, specific receptors. Numerous examples exist and the skilled person will be aware of moieties suitable for any specific application. For example, the at least one stabilizing, targeting, or delivery moiety is a peptide. For example, the at least one stabilizing, targeting, or delivery moiety is a protein. For example, the at least one stabilizing, targeting, or delivery moiety is a non-peptide biocompatible polymer. In some embodiments, the stabilizing, targeting, or delivery moiety improves the efficacy of the drug. In some embodiments, the stabilizing, targeting, or delivery moiety allows for tracking or monitoring the location and / or amount of CBL0137 is in the body of a subject. In some embodiments, provided herein is a drug conjugate comprising one or more CBL0137 molecules and at least one pharmacokinetic modifier. For example, a pharmacokinetic modifier is any molecule or substance that can influence the absorption, distribution, metabolism, or excretion of a drug. For example, a pharmacokinetic modifier may contribute to the stabilisation of the drug, extension of drug half-life, improve tolerance of a drug, facilitate delivery, targeted release, or targeted delivery and / or release under specific conditions. In some embodiments, conjugation improves the plasma half-life (t1 / 2) of CBL0137 by 5 to 100%, by 5 to 90%, by 5 to 80%, by 5 to 70%, by 5 to 60%, by 5 to 50%, by 5 to 40%, by 5 to 30%, by 5 to 20%, by 5 to 15%, or by 5 to 10%. For example, the plasma half-life is improved by more than 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments the plasma half-life is improved by up to 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In some embodiments, the plasma half-life (t1 / 2) of CBL0137 is greater than 20, 25, 30, 35, 40, 45, 50, 60, 65, 70 hours when conjugated. In some embodiments, the plasma half-life (t1 / 2) of CBL0137 is greater than 40 hours when the drug conjugate is administered systemically to a human subject. In some embodiments, the protein is albumin. In some embodiments, the protein is an albumin fragment that retains binding to the neonatal Fc receptor (FcRn). In some embodiments, the protein is a fusion protein comprising albumin or comprising a fragment thereof that binds to FcRn, an immunoglobulin Fc domain. In some embodiments, the protein is an antibody. In some embodiments, the protein is a Designed Ankryin Repeat Protein (DARPin). In some embodiments, the protein is an XTEN polypeptide. In some embodiments, the protein is a Proline-Alanine-Serine (PAS) polypeptide. In some embodiments, the protein is an elastin-like polypeptide (ELP). In some embodiments, the protein is a fusion protein comprising any one or more of albumin, an albumin fragment that retains binding to the neonatal Fc receptor (FcRn), a fusion protein comprising albumin or comprising a fragment thereof that binds to FcRn, an immunoglobulin Fc domain, an antibody, a Designed Ankryin Repeat Protein (DARPin), an XTEN polypeptide, a Proline-Alanine-Serine (PAS) polypeptide, or an elastin-like polypeptide (ELP). In some embodiments the at least one stabilizing, targeting, or delivery moiety, and / or the pharmacokinetic modifier comprises an antibody. For example, the antibody is a monoclonal antibody. For example, the antibody is a diabody. For example, the antibody is a scFv. For example, the antibody is a nanobody. For example, the antibody is a multispecific antibody. In some embodiments, the antibody targets human albumin or a variation thereof. In some embodiments, the antibody targets a cancer-enriched or tumour-enriched antigen. For example, the cancer enriched or tumor-enriched antigen is selected from the group consisting of: HER2, EGFR, VEGF, Mucin-1, integrins, estrogen receptor (ER), androgen receptor (AR), VEGFR2, EpCAM, transferrin receptor, carcinoembryonic antigen (CEA), B melanoma 1 G antigens (GAGEs), gp100, cancer / testis antigen 1 (CTAG1), melanoma-associated antigens (MAGEs), Nectin-4, folate receptor, CD79b, MET receptor, CD19, CD20, CD44, and CD3. In some embodiments, the at least one stabilizing, targeting, or delivery moiety, and / or the pharmacokinetic modifier comprises a human immunoglobulin Fc domain. In some embodiments, the at least one stabilizing, targeting, or delivery moiety, and / or the pharmacokinetic modifier is itself a conjugate. For example, a protein comprising an antibody variable region is conjugated to a detectable label. For example, CBL0137 is conjugated to a fusion protein. In some embodiments, the at least one stabilizing, targeting, or delivery moiety, and / or the pharmacokinetic modifier is an albumin-binding peptide. For example, the albumin-binding peptide comprises the amino acid sequence: DICLPRWGCLW. For example, the albumin-binding peptide comprises the amino acid sequence: LAEAKVLANRELDKYGVSDFYKRLINKAKTVEGVEALKLHILAALP. For example, the albumin-binding peptide comprises ABD094. For example, the albumin- binding peptide comprises NbSA. For example, the albumin-binding peptide comprises Nb80 (see, for example, Linciano et al., 2024). In some embodiments, the peptide is a tumour-homing or cancer-targeting peptide. For example, the tumour-homing or cancer-targeting peptide comprises RGD4C. For example, the tumour-homing or cancer-targeting peptide comprises iRGD. For example, the tumour-homing or cancer-targeting peptide comprises p32-binding LyP-1 peptide. For example, the tumour-homing or cancer-targeting peptide comprises K237. For example, the tumour-homing or cancer-targeting peptide comprises VEGFR- 2-binding peptide. For example, the tumour-homing or cancer-targeting peptide comprises IL4RPep-1. For example, the tumour-homing or cancer-targeting peptide comprises mUNO. For example, the tumour-homing or cancer-targeting peptide comprises Her-2 binding peptide. For example, the tumour-homing or cancer-targeting peptide comprises GE11. For example, the tumour-homing or cancer-targeting peptide comprises angiopep-2. For example, the tumour-homing or cancer-targeting peptide comprises prostate tumour-targeting peptide. For example, the tumour-homing or cancer- targeting peptide comprises bladder tumour-targeting peptide (see, for example, Murugan et al., 2023). In some embodiments, the non-peptide biocompatible polymer is PEG. In some embodiments, the one or more CBL0137 molecules are covalently bound to PEG via a fluorenylmethoxycarbonyl linker (see, for example, Santi et al., 2012). In some embodiments, the non- biocompatible polymer comprises a fatty acid. For example, the fatty acid is 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE). For example, the fatty acid is octadecanoic acid. In some embodiments, the non-peptide biocompatible polymer comprises a cholesterol. In some embodiments, the non-peptide biocompatible polymer comprises Evans blue. In some embodiments, the non-peptide biocompatible polymer comprises CRX-527. In some embodiments, the non-peptide biocompatible polymer comprises alpha-tocopherol. In some embodiments, the non-peptide biocompatible polymer comprises an aptamer. Linkers In some embodiments, one or more CBL0137 molecules are covalently bound to the at least one stabilizing, targeting, or delivery moiety by a linker. In some embodiments, one or more CBL0137 molecules are covalently bound to the at least one pharmacokinetic modifier by a linker. Suitable linkers for the CBL drug conjugates disclosed herein include at least a biocompatible polymer, where the attached linker is part of a conjugate with a drug molecule and is crosslinked by a particular type of bond with the one or more CBL0137 molecules to yield a CBL0137 drug conjugate as disclosed herein. Linkers comprising the polymer and drug may be synthesized by any known method in the art, and / or are available commercially. For example, and without limitation, a linker comprising a polymer and drug may be synthesised by a method comprising a step of attaching the drug to the polymer by, e.g. amide coupling, esterification, or click chemistry. In some embodiments, the linker comprises a biocompatible polymer. In some embodiments the biocompatible polymer in the linker is selected from the group consisting of a linear polyethylene glycol (PEG), a branched PEG, poly(2- oxazoline), poly(cyclic imino ethers), polysarcosine (pSar), a polysaccharide, polyvinylpyrrolidone (PVP), a synthetic poly(amino acid) (PAA), polyglutamic acid (PGA), poly(hydroxyethyl-1-asparagine) (PHEA), poly(hdryoxyethyl-1-glutamine) (PHEG), an XTEN polymer, poly(thioglycidyl glycerol) (PTTG), RAFT polymers, a dendrimer, and hydroxyethyl starch. In some embodiments, the linker comprises a disulfide bond, an amide bond, a thioamide bond, a thioether bond, a thioester bond, a tetrazole bond, or a thioacetyl bond. For example, the linker comprises a disulphide bond. For example, the linker comprises an amide bond. For example, the linker comprises a thioamide bond. For example, the linker comprises a thioether bond. For the linker comprises a tetrazole bond. For example, the linker comprises a thioacetyl bond. In some embodiments the linker to be used does not comprise a cleavable spacer. In other embodiments the linker comprises a cleavable spacer that, upon cleavage, releases at least one of the CBL0137 molecules from the linker., and thereby from the drug conjugate. Where a cleavable spacer is present in a linker, the cleavable spacer includes an enzymatically cleavable group or a chemically cleavable group. In some embodiments the enzymatically cleavable group is cleavable by an enzyme selected from the group consisting of: cathepsin-B, plasmin, matrix metalloprotease, pyrophosphatase, phosphatase, glucuronidase, β-galactosidase, esterase, carboxyesterase, and arylsulfatase A. In some embodiments the chemically cleavable group is selected from the group consisting of: disulfide, acetal, ester, silyl ester, anhydride, carbamate, carbonate, and hydrazone. The skilled person will be aware of suitable linkers and methods for linker design, and any suitable linker is contemplated for use in the present disclosure. Figures 20–25 describe non-limiting examples of suitable linkers. In some embodiments, the linker is selected from the linkers depicted in Figure 20. In some embodiments, the linker comprises a linear linker. In some embodiments, the linker comprises a multiarm linker. In some embodiments, the linker comprises a dendrimer. In some embodiments, Dendrimeric CBL-derivatives are conjugated to proteins. For example, according to Figure 21. In some embodiments, a dendrimeric structure of CBL0137 is conjugated via click chemistry. For example, CBL0137 is conjugated to human serum albumin (HSA) via click chemistry, for example, as per Figure 22. In some embodiments, CBL0137 is conjugated to antibodies, for example, via a linker. In some embodiments, CBL0137 is disulphide linked. In some embodiments, CBL0137 is thioesther linked. For example, CBL0137 is conjugated to antibodies as per Figure 23. The skilled person will be aware of numerous suitable ways to link drugs to proteins, for example HSA or antibodies, and any suitable method can be used to link CBL0137 and generate the CBL drug conjugates described herein. In some embodiments, CBL is linked to HSA using the methods shown in Figure 24. In some embodiments, CBL is linked to antibodies using the methods shown in Figure 24. Two detailed, non-limiting examples of CBL0137 conjugation to HSA is provided in Figure 25. In some embodiments, at least one of the one or more CBL0137 molecules is covalently bound to the at least one stabilizing, targeting, or delivery moiety. In some embodiments, at least one of the one or CBL0137 molecules is covalently bound to the at least one pharmacokinetic modifier. In some embodiments, all of the one or more CBL0137 molecules are covalently bound to the at least one stabilizing, targeting, or delivery moiety. In some embodiments, all of the one or more CBL0137 molecules are covalently bound to the at least one pharmacokinetic modifier. In some embodiments, the drug conjugate comprises a nanoparticle comprising a plurality of stabilizing, targeting, or delivery moieties. In some embodiments, a nanoparticle is the pharmacokinetic modifier. Albumin as a delivery agent Albumin (Gene ID: 213) is a very soluble protein, and with several synthetic derivatives. The three-dimensional structure of albumin, including hydrophilic and hydrophobic domains and charged amino acids, enables it to deliver drugs with different physicochemical properties, and there are several well-known surface binding sites, for example, carboxyl groups on the surface of albumin for polymers or ligands, or subdomain IA and IB in Domain I, subdomain IIA and IIB in Domain II and subdomain IIIA and IIIB in Domain III for binding with various endogenous and exogenous ligands, also utilises for drug delivery. Albumin is readily available, nontoxic, transported readily in the blood, is biodegradable, non-immunogenic, and preferentially accumulates and is taken up by tumour cells and inflamed tissue. Human albumin is also known as human serum albumin (HSA). Generally, the HSA-based therapeutics systems can be divided into four categories, i.e. HSA-drug nanoparticles, HSA-drug conjugates, HSA-binding prodrugs, and HSA-based recombinant fusion proteins: the latter mainly include antibody (domain)- and cytokine- fusion proteins. For a detailed review see, for example, Tao et al. (2021). In some embodiments, CBL0137 is conjugated to a protein comprising human albumin. In some embodiments, CBL0137 is conjugated to a protein comprising a human albumin variant having an amino acid sequence at least 95% identical to the amino acid sequence of human, bovine, ovine, porcine, mouse, rat albumin, or a fragment of any thereof that retains binding to FcRn. For example, the protein comprises a human albumin variant having an amino acid sequence 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of human albumin, or a fragment thereof that retains binding to FcRn. For example, the protein comprises a human albumin variant having an amino acid sequence 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of bovine albumin or a fragment thereof that retains binding to FcRn. For example, the protein comprises a human variant having an amino acid sequence 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of ovine albumin, or a fragment thereof that retains binding to FcRn. For example, the protein comprises a human albumin variant having an amino acid sequence 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of porcine albumin, or a fragment thereof that retains binding to FcRn. For example, the protein comprises a human albumin variant having an amino acid sequence 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of mouse albumin, or a fragment thereof that retains binding to FcRn. For example, the protein comprises a human albumin variant having an amino acid sequence 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of rat albumin, or a fragment thereof that retains binding to FcRn. In some embodiments, a CBL0137 molecule is covalently bound site-specifically to the albumin via a linker at the position of a cysteine residue in the albumin. In some embodiments, the position corresponds to position 34 of the mature / processed human albumin The GenBank accession number for the preprotein NP_000468.1. The mature protein begins at residue 25 of the preprotein sequence, and cysteine 34 refers to the position after the 24 N-terminal residues of the albumin preprotein have been cleaved / removed. Obviously, any corresponding free Cysteine in albumin sequence variants is contemplated by the foregoing). In some embodiments, one or more CBL0137 molecules are covalently bound non-site-specifically to the albumin. In some embodiments, the protein is a fusion protein comprising the albumin or the fragment thereof. Nanoparticles Nanostructures can be utilised as delivery agents of drugs generally and CBL0137 specifically, by encapsulation and / or attachment. Nanoparticles and nanostructures can be used to increase efficacy of CBL0137, to deliver CBL0137 to target tissues, to protect or stabilise CBL0137 as it circulates in the body, and to enable controlled release and / or a longer half-life. Nanoparticles are generally defined as being between 1 to 100 nanometers (nm), but there is use in the field of nanostructures of up to 1000 nm. Ideally, nanoparticles for delivery of CBL0137 should have the following properties: specific targeting, drug release controllability, carrier non-toxic, and biodegradable / biocompatible. As used herein, the term “nanoparticle” shall be understood to refer to particles having at least one dimension on the order of nanometers (e.g., 1–1,000 nm) and which comprises a compound of any herein. In some embodiments, the nanoparticle is an albumin nanoparticle, for example human serum albumin or a synthetic derivative. In some embodiments, the nanoparticle is a lipid nanoparticle. For example, the lipid nanoparticle may be of any lipid composition, including, may be selected from, but not limited to, liposomes or vesicles, where an aqueous volume is encapsulated by amphipathic lipid bilayers (e.g., single; unilamellar or multiple; multilamellar), micelle- like lipid nanoparticles having a non-aqueous core and solid lipid nanoparticles, wherein solid lipid nanoparticles lack lipid bilayers. In some embodiments, wherein the nanoparticle comprises a plurality of albumin molecules. Suitable methods for synthesising albumin nanoparticles for conjugation to CBL0137 are known in the art, and include those described in e.g. Tao et al. (2021), and Qu et al. (2024). DARPins Designed ankyrin repeat proteins (DARPins) are a class of non-immunoglobulin proteins that can offer advantages over antibodies for target binding. DARPins are small, genetically engineered antibody mimetic proteins which can be selected to bind any given target protein with high affinity and specificity. DARPins have been in use for almost two decades, and the skilled person will be aware of methods for synthesising and conjugating DARPins suitable for the CBL0137 drug conjugate described herein. For example, Construction of polypeptide-DARPin fusion proteins containing a single C- terminal cysteine for drug conjugation including conjugation of CBL0137, is described in Brandl et al. (2020). Pharmaceutical Compositions Any of the functionalized viruses and / or drug conjugates described herein can be formulated for administration to a subject via any conventional means including, but not limited to, intralesional, parenteral (e.g., intravenous, subcutaneous, intramuscular, intraperitoneal, or intrapleural), oral, or transdermal administration routes. Thus, in some embodiments provided herein is pharmaceutical composition comprising a functionalized virus as disclosed herein and a pharmaceutically acceptable excipient. Therapeutic agents can be formulated into any suitable dosage form, including but not limited to, injectable formulations, aqueous oral dispersions, liquids, mists, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated, solid oral dosage forms, controlled release formulations, lyophilized formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more of the therapeutic agents described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Pharmaceutical solid dosage forms can include, in addition to the therapeutic agents, one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like. Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like. In order to release the therapeutic agents from a solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage forms are compressed with Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel®or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®PH101, Avicel®PH102, Avicel®PH105, Elcema®P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®.), cross- linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross- linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum®HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like. Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone®CL, Kollidon®CL, Polyplasdone®XL-10, and Povidone®K-12), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like. In general, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common. Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like. Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like. Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like. Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic®(BASF), and the like. Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like. It should be appreciated that there is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired. Liquid formulation dosage forms for oral administration can be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. The aqueous suspensions and dispersions described herein can remain in a homogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. The homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition. In one embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 1 minute. In another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 30 seconds. In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion. In addition to the additives listed above, the liquid formulations can also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like. Formulations suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin. For intravenous injections, therapeutic agents described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, appropriate formulations may include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art. Parenteral injections may involve bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical composition described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the therapeutic agents in water-soluble form. Additionally, suspensions of the therapeutic agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of a therapeutic agent to allow for the preparation of highly concentrated solutions. Alternatively, the therapeutic agent may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. agents described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more therapeutic agents. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi- dose containers, with an added preservative. Also provided herein are controlled release pharmaceutical compositions. Controlled release refers to the release of therapeutic agents from a dosage form in which they are incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of a therapeutic agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations. The controlled release pharmaceutical compositions provided herein allow the release profile of an active agent within the combination formulation to be customised so that release of one or more of these active agents occurs over a preferred time interval. In some preferred embodiments, the agent that inhibits the Hh signalling pathway in the controlled release pharmaceutical composition is a small molecule inhibitor of Hh signalling pathway. In some embodiments the pharmaceutical composition comprises from about 150 mg to about 3000 mg of a small molecule inhibitor of the Hh signalling pathway per day, e.g., 200 mg, 300 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1600 mg, 1800 mg, 2000 mg, 2400 mg, 2800 mg, or another dose from about 100 mg to about 3000 mg of the small molecule inhibitor. In some embodiments the controlled release pharmaceutical composition comprises from about 200 mg to about 1400 mg of the small molecule inhibitor. In other embodiments the controlled release pharmaceutical composition comprises from about to about 1000 mg of the small molecule inhibitor. In some embodiments, one or more of the active agents is released over a time period ranging from about one hour to about five weeks, e.g., 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 5 days, 1 week, 10 days, 2 weeks, 18 days, 3 weeks, 4 weeks, or another period from about one hour to about five weeks. In some embodiments, the controlled release profile has a release rate higher at the beginning of the release period following administration, and then decreases over time (first order release kinetics). In other embodiments, the release rate progressively increases over the release period following administration. In preferred embodiments, the release profile remains relatively constant over the entire release period following administration until all of the active agent is released (zero order release kinetics). In preferred embodiments the release profile of a small molecule inhibitor of the Hh signalling pathway upon administration of the controlled release pharmaceutical composition is adapted to avoid induction of at least one adverse event in the subject (e.g., a human subject). In some embodiments, the release rate of a small molecule inhibitor of the Hh signalling pathway is about 0.5% of the total dose / day to about 10% of the total dose per day, e.g., 0.6%, 0.8%, 1%, 1.1%, 1.2%, 1.5%, 1.8%, 2%, 2.5%, 2.75%, 3%, 3.5%, 4%, 6%, 7%, 8%, 9% or another percentage of the total dose per day from about 0.5% to about 10% per day. In some embodiments, the rate of release (as a percentage of total dose) of a small molecule inhibitor in the controlled release formulation is distinct from that the release profile of another active agent in the formulation (e.g., a recombinant virus, a polynucleotide, or a purified protein or peptide). Where at least one recombinant virus is to be included in a pharmaceutical composition described herein, such pharmaceutical compositions described herein may comprise a range of functionalized viral titers, expressed as a 50% tissue culture infective dose (TCID50) / ml and / or viral particles (vp) / ml, depending on a number of considerations including the type(s) of drugs displayed on the functionalized viruses to be administered, the number of drug molecules per capsid, the condition to be treated, the subject to be treated, a desired release rate and the desired treatment period per dose. In some embodiments the pharmaceutical compositions described herein have a titer of about 1 x 109TCID50 / ml to about 3 x 1010TCID50 / ml, e.g., 1.5 x 109TCID50 / ml, 1.8 x 109TCID50 / ml, 2.0 x 109TCID50 / ml, 3.0 x 109TCID50 / ml, 4.0 x 109TCID50 / ml, 5.0 x 109TCID50 / ml, 5.5 x 109TCID50 / ml, 6.0 x 109TCID50 / ml, 6.5 x 109TCID50 / ml, 7.0 x 109 TCID50 / ml, 7.5 x 109TCID50 / ml, 8.0 x TCID50 / ml, 8.5 x 109TCID50 / ml, 9.0 x 109TCID50 / ml, 1.0 x 1010TCID50 / ml, 1.5 x 1010TCID50 / ml, 2.0 x 1010TCID50 / ml, 2.5 x 1010TCID50 / ml, or another TCID50 / ml value from about 1 x 109TCID50 / ml to about 3 x 1010TCID50 / ml. In some preferred embodiments, the TCID50 / ml is about 4 x 109TCID50 / ml to 8 x 109TCID50 / ml. In some embodiments the equivalence of vp / TCID50 is approximately 20 to 100 vp / TCID50. Accordingly, in some embodiments the pharmaceutical compositions described herein have a titer of about 2 x 1010vp / ml to about 3 x 1012vp / ml, e.g., 2 x 1010vp / ml, 3 x 1010vp / ml, 4 x 1010vp / ml, 5 x 1010vp / ml, 6 x 1010vp / ml, 7 x 1010vp / ml, 8 x 1010vp / ml, 9 x 1010vp / ml, 1 x 1011vp / ml, 2 x 1011vp / ml, 3 x 1011vp / ml, 4 x 1011vp / ml, 5 x 1011vp / ml, 6 x 1011vp / ml, 7 x 1011vp / ml, 8 x 1011vp / ml, 9 x 1011vp / ml, 1 x 1012vp / ml, 2 x 1012vp / ml, or another titer from about 2 x 1010vp / ml to about 3 x 1012vp / ml. In some preferred embodiments the titer is from about 3 x 1010vp / ml to about 8 x 1011vp / ml. In other preferred embodiments the titer of the pharmaceutical composition is about 3 x 1010viral particles / ml to about 5 x 1012viral particles / ml. Suitable controlled release matrices for controlled release pharmaceutical compositions have been described in art. In some embodiments, the controlled release composition comprises a SiO2hydrogel-microparticle matrix. The SiO2matrix hydrogel is a bioresorbable sol-gel derived Tetraethyl orthosilicate (AKA “tetrathoxysilane” or “TEOS”) Si (OC2H5)4 matrix gel (“SiO2 matrix gel”). This technology has been commercialised by DelSiTech Ltd (Turku, Finland). Such a bioresorbable SiO2 matrix gel is useful for sustained delivery of active therapeutic agents including small molecule drugs and recombinant viruses as described in international patent application publications WO2005082781 entitled “Method for Preparing Adjustably Bioresorbable Sol-Gel Derived SiO2” and WO2007135224 entitled “Method for Storing Silica-Based Material, Package Produced with the Method, and Use of Package for Packaging of Silica-Based Products”. This technology has been commercialised by DelSiTech Ltd (Turku, Finland).

[0036] In brief, the SiO2matrix gel sol-gel is prepared by the sol-gel process wherein the SiO2matrix gel is prepared from a sol comprising SiO2that has turned to a gel. Sol-gel derived SiO2is typically prepared from alkoxides or inorganic silicates that via hydrolysis form a sol that contains either partly hydrolysed silica species or fully hydrolysed silicic acid. Consequent condensation reactions of SiOH containing species lead to formation of larger silica species with increasing amount of siloxane bonds. Furthermore, the species aggregate, form nanosized particles and / or larger aggregates until a gel is formed. In the form of a gel, the solid state dominates, but the system still contains varying amounts of liquids material is typically soft and viscoelastic before drying and hard and brittle if it is extensively dried. In the form of a sol, liquid state dominates, but the system contains varying amounts of solid phase(s) and the material is still flowable. The time from when the SiO2 sol is prepared until the sol turns to a gel is referred to as sol ageing time. Spontaneous drying typically occurs when the sol is aged so that the system allows evaporation in ambient conditions. Generation of the controlled release pharmaceutical composition is achieved by adding to the sol, before gel formation, the desired amounts of the active therapeutic agents to be included in the pharmaceutical composition (e.g., recombinant virus expressing interferon gamma and a small molecule inhibitor of the Hh signalling pathway). As an end result of this process, a pharmaceutical composition is obtained which contains a SiO2 matrix hydrogel that contains one or more functionalized viruses. In some embodiments the functionalized viruses are recombinant functionalized viruses that serve as expression vectors for expression of a biotherapeutic agent, e.g., expression of a Type I or Type II interferon. Release rates of the active agents in SiO2gel-based controlled release pharmaceutical compositions can be adjusted as needed. Generally, the maximum dissolution rate of the SiO2gel matrix and release rate of the active agents occurs for SiO2 gels having a molar ratio of water to alkoxide of about 2, with ratios lower or higher than this resulting in slower dissolution and release rates. Further, It should also be noted that large amounts of active agent comprised within the SiO2 gel matrix increases dissolution of the matrix and the release rate(s) of the active agents. The controlled release pharmaceutical compositions can be prepared as nano- and microspheres mainly for oral, parenteral, pulmonary, topical, transdermal and surgically implantable administration. In some embodiments the rate of recombinant virus release (rate of dissolution) observed for a pharmaceutical composition described herein occurs at approximately ten times the rate in vitro than it does in vivo. In exemplary, non-limiting embodiments, the pH of a water and tetraethyl orthosilicate (TEOS) mixture at an initial molar ratio of about 100:1 to 150:1 is adjusted to pH 2 with hydrochloric acid and vigorously stirred at room temperature for 25 min. The pH of the sol is then adjusted to the desired pH (6, 6.5 or 7) by adding 0.1 M NaOH. The sol is cooled in an ice-water bath and the desired amounts of the active agents to be included are added. In some embodiments the SiO2 matrix hydrogel in the pharmaceutical composition comprise water and TEOS in a final molar ratio of about 5:1 to about 4,000:1, e.g., 10:1, 25:1, 50:1, 75:1, 150:1, 200:1, 300:1, 400:1, 500:1, 750:1, 1,000:1, 2,000:1, 3,000:1, or another final molar ratio of water to TEOS from about 50:1 to about 700:1, or about 5:1 to about 1,000:1. In some preferred embodiments the final molar ratio of water to TEOS is about 400:1. Many other types of controlled release systems known to those of ordinary skill in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include, e.g., polymer-based systems, such as polylactic and polyglycolic acid, plyanhydrides and polycaprolactone; porous matrices, nonpolymer- based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. See, e.g., US 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014 and 6,932,983. In some embodiments a pharmaceutical composition described herein is generated as a depot formulation. Methods Methods for Generating Functionalized Viruses Also disclosed herein are methods for generating a functionalized virus, where the method includes reacting a functional group on a virus capsid with a linker, which linker includes a biocompatible polymer attached to a drug molecule, whereby reaction of the linker with the functional group on the capsid attaches the linker and the associated drug molecule to generate a functionalized virus. In some embodiments a “functional group on a virus capsid” refers to a naturally occurring functional group on the outer surface of a viral capsid, e.g., a functional group associated with an amino acid, e.g., an amine group from a lysine, a phenol ring from a tyrosine residue, or a sulfhydryl group from a cysteine. In other embodiments a functional group on a virus capsid is a functional group introduced onto the viral capsid surface by derivatization, e.g., by use of a thiolating agent, to obtain a derivatized virus as disclosed herein.

[0037] Accordingly, in some embodiments the functional group on the virus capsid is selected from the group consisting of: thiol, amine, carboxyl, and a phenolic group. In some embodiments the functional group on the viral capsid to be reacted with a linker is a thiol group. In some embodiments the functional group on the viral capsid to be reacted with a linker is a cysteine thiol group. In other embodiments the functional group on the viral capsid to be reacted is an amine In other embodiments the functional group on the viral capsid to be reacted is a lysine amine group. In some embodiments the linker to be reacted with the functional group on the viral capsid comprises a thiol-reactive functional group, an amine-reactive functional group, or a click chemistry functional group. Amine-reactive functional groups include, but are not limited to, halides, acyl halides, isocyanates, epoxy, anhydrides, N-hydroxysuccinimide (NHS)-esters, amide coupling reagents (e.g. HATU, HBTU, HOBt), isothiocyanate or isocyanates, activated carboxylic acids or aldehydes, iridium catalyzed reduction alkylation, allyl isothiocyanates, iminoborate, fluorophenyls, diazoniums, azaphilones, iminothiolanes (e.g. Traut’s reagent), formaldehyde, NHS-maleimides (e.g. SMCC, or Sulfo-SMCC), NHS-disulfides, NHS-pyridyldithiols (e.g. SPDP or LC-SPDP), pyridyldithiols. Thiol- reactive functional groups include, but are not limited to, maleimides, bromomaleimides, iodoacetamides, carbonylacrylic reagents, sulfones, phosphonamidates, vinylphosphonites, ethynylbenziodoxolones, N-alkyl vinylpyridine salts, vinylheteroaryls including vinylpyrimidines and vinyltriazines. Suitable click chemistry functional groups include, but are not limited to, alkenes, alkynes, azides, thiols, epoxy groups, isocyanates, and tetrazines. In some embodiments, wherein the linker functional group to be reacted is a thiol- reactive functional group, the thiol-reactive functional group is pyridyldithio (PDT) group, bromoacetyl, or a maleimide group. In other embodiments, where the linker functional group to be reacted is an amine-reactive functional group, the amine-reactive functional group is N- Hydroxysuccinimide (NHS), Tetrafluorophenyl (TFP), or Hydroxybenzotriazole (HOBt) ester. In some embodiments, where the functional group on the linker is a carboxyl group and the functional group on the viral capsid surface is an amine, reaction of the linker with a functional group on the viral capsid is conducted in the presence of an amide coupling reagent. There is no particular limitation on amide coupling reagents that may be used in the present method. Suitable amide coupling reagents include, but are not limited to, HATU, HBTU, TBTU, EDC, DCC, PyBOP, DDQ, or CDI. In some embodiments, where the functional group on the linker is a carboxyl group and the functional group on the viral capsid surface is an amine, reaction of the linker with a functional group on the viral capsid is conducted in the presence of 1-Ethyl-3-[3- dimethylaminopropyl]carbodiimide hydrochloride) (EDC) and N Hydroxysuccinimide (NHS). In some embodiments such a reaction is conducted in the presence of a catalyst, for example a basic catalyst. Suitable include, but are not limited to piperidine, or 4-dimethylaminopyridine (DMAP) as a catalyst. In some embodiments such a reaction is conducted in the presence of 4-dimethylaminopyridine (DMAP) as a catalyst. In some preferred embodiments, where the linker comprises a thiol-reactive group, the thiol-reactive group is PDT. In some embodiments, where the linker comprises PDT, the PDT thiol-reactive group is in a molar excess of about 2 fold to about 20 fold over the number of recombinant virus capsid reactive thiol groups, e.g., 2.5 fold, 2.7 fold, 3 fold, 3.4 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 8.5 fold, 9 fold, 10 fold, 12 fold, 14 fold, 15 fold, 16 fold, 18 fold, or another fold excess over the virus capsid reactive thiol groups from about 2 fold to about 20 fold molar excess. In some embodiments the molar excess is about 3 fold to about 10 fold molar excess. In other embodiments the linker comprises an amine-reactive functional group. In some embodiments, where the linker includes an amine-reactive functional group, the amine- reactive functional group is tetrafluorophenyl (TFP). A number of suitable biocompatible polymers for inclusion in a functionalized virus are disclosed herein. Suitable example of biocompatible polymers for use in a linker used to functionalize a virus as disclosed herein include, but are not limited, to a linear polyethylene glycol (PEG), a branched PEG, polysarcosine (pSar), a polysaccharide, polyvinylpyrrolidone (PVP), a synthetic poly(amino acid) (PAA), polyglutamic acid (PGA), poly(hydroxyethyl-1-asparagine) (PHEA), poly(hdryoxyethyl-1-glutamine) (PHEG), an XTEN polymer, and poly(thioglycidyl glycerol) (PTTG), RAFT polymers, a dendrimer, and hydroxyethyl starch. In some preferred embodiments a biocompatible polymer in the linker to be reacted is a linear PEG or a branched PEG. In some embodiments the linker to be used does not comprise a cleavable spacer. In other embodiments the linker comprises a cleavable spacer that, upon cleavage, releases a drug molecule from the linker. Where a cleavable spacer is present in a linker, the cleavable spacer includes an enzymatically cleavable group or a chemically cleavable group. In some embodiments the enzymatically cleavable group is cleavable by an enzyme selected from the group consisting of: cathepsin-B, plasmin, matrix metalloprotease, pyrophosphatase, phosphatase, glucuronidase, β-galactosidase, esterase, carboxyesterase, and arylsulfatase A. In some embodiments the chemically cleavable group is selected from the group consisting of: disulfide, acetal, ester, silyl ester, anhydride, carbamate, carbonate, and hydrazone. In some embodiments the linker, comprising the drug to be displayed on the surface of a functionalized virus capsid, is reacted at a molar ratio of linker to viral capsid functional groups of about 3:1 to about e.g., 3.5:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, 15:1, 16:1, 18:1, 19:1, or another molar ratio of linker to viral capsid functional groups to be reacted. In some embodiments the drug, which forms part of the linker to be reacted with a viral capsid, is an anti-cancer drug molecule. In some embodiments the anti-cancer drug molecule is a small molecule anti-cancer drug, generally having a molecular weight no greater than about 1 kDa. In some embodiments the small molecule anti-cancer drug is one that has poor aqueous solubility, which advantageously based on the methods disclosed herein can be used to generate a functionalized virus despite such low aqueous solubility. Suitable examples of small molecule anti-cancer drugs include, but are not limited to, gemcitabine, CBL0137, a small molecule inhibitor of Nicotinamide phosphoribosyltransferase (NAMPTi), a GEM derivative, bortezomib, paclitaxel, a pyrrolobenzodiazepine (PBD) dimer, and 5-FU. In some embodiments, where the functional group on the virus capsid is a thiol or an amine, the small molecule anti-cancer drug on the linker to be reacted is selected from among gemcitabine, CBL0137, a small molecule inhibitor of Nicotinamide phosphoribosyltransferase (NAMPTi), a GEM derivative, bortezomib, paclitaxel, and 5-FU. In some embodiments the small molecule anti-cancer drug is CBL0137. In other embodiments the small molecule anti-cancer drug is gemcitabine. As disclosed herein, in some embodiments, particularly where a linker comprises a drug that has poor aqueous solubility, cross-linking of the linker with a virus capsid functional group is carried out in the presence of an aprotic polar solvent at a concentration that maintains solubility of the linker / drug as well as the resulting functionalized virus. Surprisingly, it has been found that at the selected concentrations, the aprotic polar solvent does not prevent the ability of the functionalized virus being generated from transducing and / or infecting its target cells. In some embodiments, the functionalized virus exposed generated in the presence of an aprotic polar solvent retains at least 30% transduction capability compared to the equivalent unmodified virus, e.g., 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 87%, 90%, 92%, 95%, or another percent of the transducibility or infectivity relative to a corresponding non- functionalized virus that was not exposed to the aprotic polar solvent. Examples of suitable aprotic polar solvents for the above-described reactions include, but are not limited to, acetonitrile, dimethylsulfoxide (DMSO), and dimethylformamide (DMF). In some preferred embodiments the above-mentioned cross-linking reaction is conducted in the presence of a polar aprotic solvent at a concentration of about 5% (v / v) to about 20% (v / v), e.g., 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 17%, 18%, 19%, or another of a polar aprotic solvent from about 5% (v / v) to about 20% (v / v). In some preferred embodiments the polar aprotic solvent to be used in the reaction is acetonitrile. In some embodiments a virus used for the methods disclosed herein is a non- recombinant virus. In other embodiments a virus to be used for functionalization is a recombinant virus. In some embodiments, the linker is selected from:

[0003] OH O O HO O N . . In some embodiments, the linker is selected from: limitation, a linker comprising a polymer and drug may be synthesised by a method comprising a step of attaching the drug to the polymer by, e.g. amide coupling, esterification, or click chemistry. Click chemistry may be advantageous in the generation of branched linkers comprising multiple drugs, such as those produced from the following branched polymeric structure: . (e.g. with further spacers such as PEG, and / or cleavable moieties) may be suitability functionalised with a reactive group that can react with a reactive group on the polymer, so that when the groups are reacted, a functionalised linker-drug reagent is provided, which may then be used to form the functionalised virus. For example, it will be appreciated that an analogue of the above described linkers could be by a skilled person, to contain a group that is reactive with another reactive group that is on a polymer. For example, a tetrazine functionalised drug or linker-drug could be produced, in order to react with the above depicted azide-containing branched polymer, via an SPAAC reaction. Other suitable pairings of reactive groups will be known to the person skilled in the art. Methods for Generating Derivatized Viruses Also disclosed herein are methods for generating derivatized viruses, whereby virus capsid functional groups are reacted to convert a native functional group, particularly amines, to a different functional group to facilitate generation of a functionalized virus as disclosed herein, or to provide a cross-linking / bridging agent that reacts with a native functional group, and provides a functional group with which a linker and its conjugated drug can react to form a functionalized virus as disclosed herein. Accordingly provided herein is a method for derivatizing a virus, the method comprising reacting solvent-exposed amines on the surface of the capsid of the virus with an amine-reactive cross-linking agent to obtain a derivatized virus comprising a new functional group cross-linked to the surface of the capsid. In some embodiments the amine-reactive cross-linking agent is a thiolating agent, whereby the new functional group is a thiol. In some embodiments the thiolating agent is a reagent comprising an amine-reactive group and a thiol group or protected thiol. Thiol / cysteine protecting groups are well known in the art, such as those disclosed in Spears et al., (2021), in particular those listed in Table 1 therein, the entire contents of each of which is hereby incorporated by reference herein. In some embodiments the thiolating agent is 2-iminothiolane (AKA “Traut’s reagent”). In some embodiments, where a thiolating agent is utilized to generate a derivatized virus as disclosed herein, the molar ratio of the thiolating agent to viral capsid amines is about 0.1 to about 1000, e.g., 0.3:1, 0.5:1, 0.7:1, 1:1, 1.2:1, 1.5:1, 2:1, 3:1, 5:1, 10:1, 50:1, 75:1, 100:1, 200:1, 250:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, or another molar ratio of the thiolating agent to viral capsid amines from about 0.1:1 to about 1000:1. In some embodiments after obtaining a derivatized virus, the derivatized virus is used to generate a functionalized virus by reacting the derivatized virus with a linker comprising (i) a functional group reactive to the new cross-linked functional group made available on the viral capsid by the derivatization reaction and (ii) a biocompatible polymer attached to a drug molecule, whereby the reaction of the linker with the derivatized recombinant virus generates a functionalized recombinant virus, comprising a plurality of drug molecules displayed on the surface of the capsid. In some preferred embodiments the biocompatible the just-mentioned linker is a linear PEG or a branched PEG. Methods of Treatment The methods described herein relate to treating a disease or health condition by administration of a functionalized virus as disclosed herein or a related composition (e.g., a pharmaceutical composition) comprising such a functionalized virus, and / or by administration of a drug conjugate as disclosed herein or a related composition (for example a pharmaceutical composition) comprising such drug conjugate. In some embodiment the methods described herein relate to treating a disease characterized by aberrant cell proliferation, comprising administering to a subject in need thereof a therapeutically effective amount of a functionalized virus as disclosed herein or a pharmaceutical composition comprising such a functionalized virus; and / or of a drug conjugate as disclosed herein or a related composition (for example a pharmaceutical composition) comprising such drug conjugate In some embodiments the disease characterized by aberrant cell proliferation is a cancer, a fibrotic disease, or cutaneous warts. In some embodiments the disease characterised by aberrant cell proliferation is a cancer. Cancers suitable for treatment with the compositions disclosed herein include, but are not limited to, basal cell carcinoma, melanoma, lymphoma, squamous cell carcinoma, Merkel cell carcinoma, lung cancer, prostate cancer, sarcomas, medulloblastomas, cancers with desmoplastic stromas, colorectal cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, mesothelioma, mesenchymal cancer, epithelial cancer, bladder cancer, urothelial cancer, or adenocarcinomas. In some embodiments the cancer to be treated is a basal cell carcinoma (BCC). In some embodiments, where the cancer is BCC, the subject suffering from BCC suffers from Basal Cell Nevus Syndrome (BCNS) or sporadic BCC. Fibrotic diseases that can be treated by the methods provided herein include, but are not limited to, Keloids, Scleroderma / systemic sclerosis, Nephrogenic systemic fibrosis, adhesive capsulitis, Dupuytren’s contracture, and Arthrofibrosis. In some embodiments the cancer to be treated is a recurrent cancer or a relapsing cancer. In some embodiments the cancer to be treated is a cancer that has been identified as resistant to one or more of: chemotherapy, radiotherapy, immune checkpoint inhibitor treatment, oncolytic virus therapy, CAR-T therapy, and Bacillus Calmette-Guerin (BCG) treatment. Also disclosed herein is the use functionalized virus disclosed herein and / or the drug conjugate as disclosed herein in the manufacture of a medicament for treatment of a health condition. In some embodiments the medicament is for treatment of a cancer as disclosed herein (e.g., BCC). In some embodiments the functionalized virus or the pharmaceutical composition; and / or the drug conjugate as disclosed herein or a related composition (for example a pharmaceutical composition) comprising such drug conjugate is administered systemically, or locally. In some embodiments where the subject to be treated is suffering from a BCC, a functionalized virus or pharmaceutical composition disclosed herein is administered intralesionally. In some embodiments the treatment methods described herein are performed on a mammalian subject such as a cow, sheep, horse, cat, mouse, rat, guinea pig, dog, pig, non-human primate, or a human. In some preferred embodiments the subject to be treated is a human subject. Symptoms, diagnostic tests, and prognostic tests for various types diseases characterised by aberrant cell proliferation are known in the art. See, e.g., the website of the National Comprehensive Cancer Network: (nccn.org / professionals / physician_gls / f_guidelines.asp), and British Medical Journal (BMJ) Best Practice (website at: bestpractice.bmj.com), respectively. Dosing Regimes The person of ordinary skill in the art will appreciate that a suitable therapeutically effective dose of a functionalized virus, as described herein, will depend upon factors such as the particular displayed drug payload, expression of a therapeutic agent, the replication capacity of the functionalized virus, the development of adverse effects of the treatment, the disease stage, the characteristics of the subject or host in need of treatment (e.g., weight), the properties of the particular type of disease to be treated, the proposed route of administration, etc., but can nevertheless be determined in a manner known in the art. As disclosed herein functionalized viruses disclosed herein provide a number of advantages, particularly for cancer treatment. Functionalized viruses enable delivery of multiple therapeutic modalities in one “delivery package”, i.e., localized, potentially cell- targeted delivery of a drug, viral oncolysis, expression of a therapeutic agent (in the case of recombinant viruses). These properties afford the ability to deliver drug doses at a local concentration (e.g., within a tumour or cancerous lesion) that is substantially higher than what could be achieved by the systemic administration commonly used for many cancer drugs. Thus, in some transduction of cancer cells with functionalized viruses disclosed herein allows localized, intracellular or proximal extracellular release of a drug payload from a functionalized virus, (e.g., by chemical or enzymatic cleavage) to achieve, potentially, a cancer cell-selective concentration of a released anti-cancer drug at a much higher effective local concentration than could otherwise be achieved by systemic administration of the same anti-cancer drug due to the adverse effects that would typically be expected with high systemic concentrations of anti-cancer drugs that induce cell death, particularly those that are not cancer cell- specific. Further, in some embodiment, where a cancer is to be treated, administration of a functionalized virus disclosed herein achieves a synergistic effect, whereby delivery of an anti-cancer drug that acts on one programmed cell death pathway in combination with expression of a therapeutic agent that acts on separate / orthogonal cell death pathway with or without oncolytic virus replication provides a synergistic effect, whereby greater cancer cell death is achieved by administration of a dose of a functionalized virus displaying a particular type of anti-cancer drug than the sum of the effect of equivalent doses of the virus or anti-cancer drug administered as monotherapies or even in a treatment combination where each is administered separately. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day. The time period between the multiple administration steps may range from, a few minutes to several days, depending upon the properties of the therapeutic components of a functionalized virus disclosed herein, such as displayed drug potency and solubility. Circadian variation of various physiological parameters may also be evaluated to determine the optimal dose interval. Initial administration can be via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over 5 minutes to about 5 hours, topical application, transdermal patch, sub-dermal depot release, and the like, or combination thereof. In some embodiments, administration is subcutaneous, such as intralesional injection perilesional injection, or injection in close proximity to a lesion (for example within about 5 cm or within about 1cm). In some preferred embodiments, e.g., where the subject to be treated presents with lesions / tumours amenable to direct local administration (e.g., basal cell carcinoma), administration is intralesional. In some embodiments a functionalized virus or a pharmaceutical composition comprising such a functionalized virus is administered multiple times during a first dosing period. In some embodiments is at a frequency of between about once per week to about once per day during a first dosing period, e.g., once per five days, once per four days, once per three days, once per two days, or another frequency from about once per week to about once per day. In some embodiments, a subject to be treated is administered a treatment as described herein over multiple dosing periods including at least first and second dosing periods. The number of dosing periods may range from 1 to 14, e.g., 2, 3, 4, 5, 6, 8, 10, 12, or another number of dosing periods from 1 to 14. In some embodiments the treatment includes at least first and second dosing periods. Where a subject is treated over multiple dosing periods, the total aggregate dose of a functionalized virus may be varied among different dosing periods. In some embodiments different functionalized viruses are used over different dosing periods. For example, during an initial dosing period, a first functionalized virus is administered; and in a second dosing period a second functionalized virus is administered, wherein the second functionalized virus differs from the first functionalized virus in one or more of: displayed drug, encoded therapeutic agent to be expressed, viral replicative capacity, or type of virus (e.g., adenovirus vs HSV). Monotherapy for cell proliferation diseases (e.g., cancer) with anti-cancer drugs, particularly small molecule anti-cancer drugs and chemotherapeutic agents are generally acknowledged to cause adverse events especially over prolonged dosing periods and at the doses of these agents typically required for an effective response. Adverse effects can result in patients stopping treatment with such agents before a full course of treatment has been completed. Accordingly, in some embodiments the therapeutically effective amount or dose of a drug administered as a drug displayed on a functionalized virus disclosed herein is about 0.01% to about 50% of a therapeutically effective dose (or dose range) of the same drug that would be used typically for monotherapy for the same condition to be treated, e.g., 0.02%, 0.03%, 0.04%, 0.05%, 0.07%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.7%, 0.8%, 1%, 2%, 3%, 4%, 5%, 7%, 10%, 11%, 12%, 15%, 17%, 20%, 25%, 27%, 30%, 33%, 35%, 38%, 40%, 42%, 45%, 47%, or another percentage from about 0.01% to about 50% of a therapeutically effective dose of the drug when used on its own as a monotherapy to treat the same condition. In some embodiments, where the subject to be treated is suffering from basal cell carcinoma, the dosing period comprises 2-3 administrations of (i) in a single week and daily administration of (ii). In other embodiments, where the subject to be treated is suffering from basal cell carcinoma, a dosing period comprises 2-3 administrations in two weeks. In some embodiments a which includes all dosing periods, is from about 3 weeks to about 40 weeks, e.g., 4 weeks, 5 weeks, 8 weeks, 12 weeks, 16 weeks, 18 weeks, 20 weeks, 24 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, or another treatment duration from about 3 weeks to about 40 weeks. In some embodiments, the administered intralesional total dose of recombinant virus is from about 1 x 107functionalized viral particles / lesion to about 1 x 1012functionalized viral particles / lesion, e.g., 2 x 107, 3 x 107, 4 x 107, 5 x 107, 6 x 107, 8 x 107, 1 x 108, 1.5 x 108, 2 x 108, 3 x 108, 4 x 108, 6 x 108, 8 x 108, 9 x 108, 1 x109, 2 x 109, 3 x 109, 4 x 109, 5 x 109, 6 x 109, 8 x 109, 1 x1010, 2 x 1010, 3 x 1010, 4 x 1010, 5 x 1010, 6 x 1010, 8 x 1010, 9 x 1010, 1 x1011, 2 x 1011, 3 x 1011, 4 x 1011, 5 x 1011, 6 x 1011, 8 x 1011, 9 x 1011, or another number of functionalized viral particles / lesion from about 1 x 107viral particles / lesion to about 1 x 1012functionalized viral particles / lesion. In some embodiments, the intralesional viral dose ranges from about 2 x 1010functionalized viral particles / lesion to about 3 x 1011functionalized viral particles / lesion. In some embodiments a functionalized virus is administered as at least 5 x 107functionalized viral particles to about 5 x 109functionalized viral particles per lesion per dosing day. In some embodiments a functionalized virus disclosed herein is administered as at least 1 x 108functionalized viral particles to about 1 x 109functionalized viral particles per lesion per dosing day. In some preferred embodiments the functionalized virus is administered as at least 1 x 109functionalized viral particles per lesion per dosing day. In some embodiments, the subject to be treated is administered multiple doses of functionalized virus in each dosing period. In other embodiments, where administration of the recombinant virus is intralesional, the total aggregate dose of recombinant viral particles per dosing period ranges from about 1 x 108functionalized viral particles / lesion to about 1 x 1013functionalized viral particles / lesion, e.g., 2 x 108, 3 x 108, 4 x 108, 5 x 108, 6 x 108, 8 x 108, 1 x 109, 1.5 x 109, 2 x 109, 3 x 109, 4 x 109, 6 x 109, 8 x 109, 9 x 109, 1 x1010, 2 x 1010, 3 x 1010, 4 x 1010, 5 x 1010, 6 x 1010, 8 x 1010, 1 x 1011, 2 x 1011, 3 x 1011, 4 x 1011, 5 x 1011, 6 x 1011, 8 x 1011, 9 x 1011, 1 x 1012, 1.5 x 1012, 2 x 1012, 3 x 1012, 4 x 1012, 5 x 1012, 6 x 1012, 8 x 1012, 9 x 1012or another number of total viral particles per dosing period from about 1 x 108viral particles / lesion to about 1 x 1013viral particles / lesion. In some embodiments, where administration of a functionalized virus disclosed herein is by systemic, intraperitoneal, or intrapleural administration, the total aggregate viral dose per dosing period for a functionalized virus is about 1 x 109viral particles to about 1 x 1014functionalized viral particles per dosing period, e.g., 2 x 109, 3 x 109, 4 x 109, 5 x 109, 6 x 109, 8 x 109, 1 x 1010, 2 x 1010, 3 x 1010, 4 x 1010, 5 x 1010, 6 x 1010, 8 x 1010, 9 x 1010, 1 x 1011, 1.5 x 1011, 2 x 3 x 1011, 4 x 1011, 6 x 1011, 8 x 1011, 9 x 1011, 1 x 1012, 2 x 1012, 3 x 1012, 4 x 1012, 5 x 1012, 6 x 1012, 8 x 1012, 9 x 1012, 1 x 1013, 2 x 1013, 3 x 1013, 4 x 1013, 5 x 1013, 6 x 1013, 8 x 1013, 9 x 1013or another number of total functionalized viral particles per dosing period from about 1 x 109functionalized viral particles to about 1 x 1014functionalized viral particles. In some embodiments, depending on the number of functionalized viral particles administered and the corresponding multiplicity of infection (MOI) achieved, and the average number of displayed drug molecules per functionalized viral particle, and the number of drug molecules released from the functionalized viral capsid, the intracellular concentration of a drug (e.g., in cancer cells), in some embodiments is about 5 nM to about 1,000 nM, e.g., 10 nM, 12 nM, 18 nM, 20 nM, 25 nM, 30 nM, 50 nM, 100 nM, 70 nM, 80 nM, 100 nM, 200 nM, 300 nM, 350 nM, 400 nM, 500 nM, 600 nM, 800 nM, 900 nM, or another intracellular concentration of the displayed drug from about 5 nM to about 1,000 nM. Combination Therapies The functionalized virus as disclosed herein or a related composition (e.g., a pharmaceutical composition) comprising such a functionalized virus, and the drug conjugates as disclosed herein or a related composition (for example a pharmaceutical composition) comprising such drug conjugate can be used in combination with each other, and can also be used in combination with other agents of therapeutic value. For example, the functionalized virus as disclosed herein or a related composition (e.g., a pharmaceutical composition) comprising such a functionalized virus can be used in combination with other agents of therapeutic value, including the pharmaceutical composition) comprising such drug conjugate. For example, the drug conjugates as disclosed herein or a related composition (for example a pharmaceutical composition) comprising such drug conjugate can be used in combination with other agents of therapeutic value, including the functionalized virus as disclosed herein or a related composition (e.g., a pharmaceutical composition) comprising such a functionalized virus. In general, other agents do not necessarily have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, preferably be administered by different routes. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition as the functionalised virus and / or the drug conjugate is well within the knowledge of the skilled clinician. The initial administration of other agents in combination with the virus and / or the drug conjugate can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician. The functionalised virus and / or the drug conjugate and an additional therapeutic agent may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature and phase of the symptoms ro condition to be treated, the condition of the patient, and the actual choice of therapeutic agents used. The determination of the order of administration of the functionalised virus and / or the drug conjugate and any other additional treatment and the number of repetitions of administration of each therapeutic agent during a treatment protocol is well within the knowledge of the skilled physician after evaluation of the disease being treated, the condition of the patient, and the disclosures of the present application. It is known to those of skill in the art that therapeutically-effective dosages can vary when the drugs are used in treatment combinations. Methods for experimentally determining therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimise toxic side effects, has been described extensively in the literature. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient. For combination therapies, dosages of co-administered therapeutic agents will of course vary depending on the type of co-agents employed, the condition of the patient, and the condition to be treated. Combination therapy may also include administration of the functionalised virus and / or the drug conjugate in combination with surgical interventions. For example, in cancer treatment. In some embodiments, the functionalised virus and / or the drug conjugate are administered prior to any other treatment. In some embodiments, the functionalised virus and / or the drug conjugate are administered simultaneously with or approximately contemporaneously with any other treatment, In some embodiments, the functionalised virus and / or the drug conjugate are administered after any other treatment. In some embodiments, any treatment may comprise several different treatments, which treatments may occur at different time points, and the functionalised virus and / or the drug conjugate may be given prior to, contemporaneously or after any one or more of those treatments as either a single dose or as several doses and / or on several different occasions. In some embodiments, the combination treatment comprises at least one of the functionalised virus and / or the drug conjugate and chemotherapy, radiotherapy, immune checkpoint inhibitor treatment, oncolytic virus therapy, CAR-T therapy, and Bacillus Calmette-Guerin (BCG) treatment. In some embodiments, the combination treatment comprises a mechanical intervention, such as a surgical intervention. The functionalised virus and / or the drug conjugate and additional therapeutic agent which make up a combination therapy disclosed herein may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration. The two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents. The time period between the multiple administration steps may range from, a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent. Circadian variation of various physiological parameters may also be evaluated to determine the optimal dose interval. In some embodiments, a disease to be treated, as described herein, includes treatment by systemic administration of a functionalized virus. In other embodiments, the administration is intraperitoneal administration. In some embodiments, the administration is intrapleural administration. In some embodiments, a disease to be treated, as described herein, includes treatment by systemic administration of a drug conjugate or related composition as described herein. In some embodiments, the administration is intraperitoneal administration. In some embodiments, the administration is intrapleural administration. In some embodiments, the drug conjugate or the pharmaceutical composition is administered intralesionally. In some embodiments, methods of treatment include a CBL0137 drug conjugate in combination with administration of any recombinant virus. In some embodiments, methods of treatment include a conjugate in combination with administration of SP-002. In some embodiments, methods of treatment include a CBL0137 drug conjugate in combination with administration of interferon gamma. In some embodiments, methods of treatment include administration of a unconjugated CBL0137 and administration of interferon gamma. EXAMPLES Example 1 – CBL0137 derivatives To covalently couple CBL-0137 to the surface of the adenoviral gene transfer vectors, CBL-derivatives had to be designed (Figure 1). The derivatives included linkers that include functional groups for coupling to the adenoviral vector surface and spacers to enable for cleavage of the CBL0137 compound. The first derivative (CBL0137-PEG-COOH) included CBL0137 linked to a spacer containing a cathepsin B cleavage site and a 12 unit PEG terminated by carboxylic acid (COOH). This derivative had to be activated by esterification of the terminating COOH by reacting with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and sulfo- N-hydroxysuccinimide (sulfo-NHS) prior to coupling to the virus using. After activation it could react with viral vector surface amine groups to form biologically stable amide bonds, illustrated schematically in Figure 2. The second derivative (CBL0137-PEG-PDT) included CBL0137 linked to a spacer containing a cathepsin B cleavage site and a 12 unit PEG spacer terminated by a pyridyldithio group (PDT). This group is reactive towards thiols without the need for an activation step. This is illustrated schematically in Figure 3. Example 2 – Optimization of PEG-CBL and functionalized virus solubilities Activation of CBL0137-PEG-COOH was performed using conventional protocols involving EDC and NHS to form the active ester in aqueous solutions prior to coupling with the virus (Figure 2). These protocols are standard for the modification of biological substances. However, despite PEGylation, CBL0137-PEG-COOH remained insoluble in water. Solubility tests demonstrated good solubility in organic solvents such as DMSO and DMF (data not shown). Unexpectedly, dissolving CBL0137-PEG-COOH in dimethylformamide (DMF) or dimethylsulfoxide (DMSO) and subsequently adding this solution to an aqueous suspension of adenoviral gene transfer for covalent surface coupling resulted in the rapid formation of a highly viscous gel. This gel's viscosity was so high that it was not amenable to pipetting. Briefly, CBL0137-PEG-COOH was dissolved in DMSO. Activation of PEG was performed with EDC at an EDC:PEG ratio of 10:1, or with NHS at an NHS:PEG ratio of 25:1. This reaction was performed with 50 mM HEPES pH 6 and 150 mM NaCl, for 10 minutes at room temperature. Following this quenching was performed with β-mercaptoethanol (ß-ME) and NaOH at a ß-ME:PEG ratio of 10:1, for 10 minutes at room temperature. Coupling to a virus encoding green fluorescent protein (AdEGFP) with a PEG:amine ratio of 100:1, for two hours, rotating at room temperature. A549 and HeLa cells were transduced at 300 MOI. Fluorescence microscopic analysis was performed 24 hours post-transduction. Notably, the infectivity of vector particles within the gel was preserved, but aberrant transduction patterns indicated severely limited diffusion of the gel-entrapped viral particles (Figure 4). Consequently, the use of these gel-entrapped viral particles in vitro and in vivo was not feasible. Analysis of the extent of surface modification of the adenoviral vector particles revealed relatively low modification efficiency, even with large molar excesses of activated PEG-CBL0137 over vector surface amines during coupling. Importantly, gel formation occurred even at the minimal concentrations required for coupling to the adenoviral vector surface (data not shown). As a potential solution, the activation of CBL0137-PEG-COOH was performed via Steglich esterification (data not shown). However, the low stability of the activated ester in aqueous solutions precludes purification of the activated ester and subsequent resuspension in water / buffer prior to coupling to the viral vector particle surface. Therefore, it was necessary to develop a protocol that utilizes organic solvents for the activation process while still permitting coupling of the activated ester to the viral vector surface without denaturing the virus or compromising its infectivity by exposure to an organic solvent. Example 3 – Optimization of organic solvent for ester stabilization A series of organic (aprotic polar) solvents were tested for their compatibility with maintenance of subsequent adenoviral infectivity (Figures 5A-C). Briefly, AdEGFP was diluted 10:1 in AdBuffer pH 8.0 to get a final concentration of 5.49 x 108vp / μL. 1 μL of AdEGFP-Dilution was added to each tube and mixed carefully. Tubes were incubated for two hours at room temperature.180 μL of medium was added to each tube. A549 cells were transduced in triplicate by adding 9.1 μL of a sample to a well (MOI1000) containing 100 μL of media. Plates were incubated for 20 hours and analyzed by flow cytometry. Following wells were washed three times with 100 μL of DPBS.30 μL of trypsin / EDTA solution was added to each well and incubated for five minutes at 37°C. The trypsin was inactivated with 150 μL of medium and samples were transferred to a Flat-Bottom 96-well plate for measurement. Surprisingly, several organic solvents, including DMSO, DMF, and acetonitrile, were identified as not interfering with adenovirus infectivity at specific solvent concentrations. Notably, acetonitrile was found to be compatible with vector infectivity at concentrations up to 10% (v / v) for a duration of two hours (Figure 5A). The unexpected identification of compatible organic solvents enabled the use of chemical protocols previously thought to compromise viral infectivity. Example 4 – Optimization of PEG to viral capsid coupling efficiency A series of experiments were conducted using Biotin-PEG-COOH as a model molecule to assess coupling efficiencies (Figure 6). Most modification protocols resulted in undetectable or weak surface modification of the adenoviral particles. Through these experiments, acetonitrile and DMF were identified as the most suitable solvents. The presence of 4-Dimethylaminopyridine (DMAP) as a catalyst improved coupling efficiencies significantly. However, even with the optimal combination of reaction conditions, large molar excesses of the activated PEG-CBL derivative (100-500x over viral vector surface amines) were necessary for efficient coupling. This requirement likely stems from the instability of the activated ester derivatives, which may vary significantly between different substances, with potentially higher instability for CBL derivatives compared to others such as gemcitabine, NMAPti, and 5-FU. However, in the context of CBL such high molar excesses would increase the problem of gel formation. Notably, the best coupling efficiency was achieved using acetonitrile (Figures 6A, 6F). However, the modified viruses exhibited a significant loss in their ability to transduce cells (Figure 6B-E). It was hypothesized that this might be due to overmodification, which could shield the vector particles from binding to their receptors on the cell surface. To address this, the experiments were repeated using lower molar excesses over vector surface amines during coupling and analyzed coupling efficiencies by Western blot (by avidin binding) to detect the coupled biotin moiety (Figures 7A, 7B). Briefly, transduction was performed 1, or 2, or 3-fold molar excess of TFP over Biotin-PEG-COOH, 1.1-fold molar excess of DCC over Biotin-PEG-COOH, 0.1-fold DMAP over Biotin-PEG-COOH. Incubated for 3 hours at room temperature, then centrifuged for 10 minutes at 30,000g. Microscopic analysis was performed to check for precipitate. Coupling to virus at 10- molar excess over 18,000 surface amines in HEPES, 150 mM NaCl, pH 8.0. The refined protocol with lower molar excesses still enabled efficient capsid modification (Figure 7C), and importantly, the infectivity of the modified vector particles was maintained (Figure 8). Adenoviral vectors are typically prepared from infected cells by ultracentrifugation in CsCl, involving either one discontinuous step gradient followed by a continuous CsCl gradient or two discontinuous step gradients. To further characterize the coupling efficiency of the acetonitrile / TFP method, Biotin-PEG-COOH activated in acetonitrile / TFP / DMAP was coupled to the viral vector in CsCl after the first gradient. This coupling was performed for 60 minutes at room temperature with 3- and 17-fold molar excesses over viral vector surface amines, followed by purification of the modified vectors through a second discontinuous CsCl gradient. Coupling efficiency was quantified by Western blot and ELISA (Figure 8). The data demonstrated that (i) up to 100% of the capsid surface amines could be modified, (ii) the hexon, fiber, and penton capsid proteins were modified, and (iii) a 3-fold excess of Biotin-PEG-COOH when reacted in CsCl allowed for the maintenance of vector particle infectivity. Thus, the refined protocol using acetonitrile / DMAP / TFP enabled to use significantly smaller molar excesses compared to the DMF / DMAP / HOBt protocol. Therefore, the protocol might allow to mitigate problems stemming from a limited solubility of the payload to be displayed. Example 5: Vector modification using Traut’s reagent In order to convert adenoviral vector surface amines to thiols for modification with CBL0137-PEG- pyridyldithio (PDT) (illustrated in Figure 3), Traut’s reagent was titrated to assess potential effects on viral vector infectivity. It was known from literature that small inorganic molecules can destroy vector infectivity by diffusion into and reactivity with viral particles. The titration revealed that adenoviral vector particles were in fact sensitive to Traut’s reagent (Figure 9). However, at smaller molar excesses, infectivity was largely maintained in both solvents tested: DMSO and DMF.

[0004] Example 6: Optimization of coupled vector solubility It was shown that conjugating CBL0137-PEG-PDT molecules to an adenoviral vector at a density of approximately 4000 molecules per particle rendered the vector particles largely insoluble instead of enhancing the solubility of the displayed CBL payload (Figure 10). Although no gel formation was observed, visible aggregates formed, which were subsequently lost during purification by gel filtration chromatography. This indicated that solving solubility issues during the activation and coupling processes does not necessarily guarantee the production of soluble and monodisperse viral vector particles, which are required for successful gene transfer in vivo. To address this issue, the titration of CBL molecules on the adenoviral vector surface was optimized to prevent aggregate formation. Using Biotin-PEG-PDT as a reference, it was determined that 5- to 8-fold molar excesses over surface amines of the adenoviral vector particles, along with 5- to 6-fold excesses of Biotin-PEG-PDT, enabled successful coupling without aggregate formation. Notably, after coupling, the particles could be purified by gel filtration chromatography without loss. Biophysical characterization, including size measurement and determination of the polydispersity index, revealed that the particle solutions were monodisperse (PI<0.2), with a slight increase in particle size due to the displayed payload (Figure 11). After a series of optimizations, it was found that CBL0137-PEG-PDT could be conjugated to the adenoviral vector particles without aggregate formation using a 5- to 8-fold excess of Traut's reagent and a simultaneous 6-fold molar excess of CBL0137- PEG-PDT relative to capsid amines (Figure 12). Example 7: Analysis of biological activity Using replication-defective adenoviral vectors carrying either EGFP or IFN-γ as a transgene and displaying CBL0137 as a payload, a series of experiments were performed to analyze the biological activity of the displayed payload and potential complementing effects of payload and transgene in tumor cells. Figure 13 demonstrates that the infectivity of AdEGFP following modification with CBL0137-PEG-PDT (5xTraut + 6xCBL0137-PEG-PDT) on virus vector surface amines) was largely preserved in HeLa cells. The number of EGFP-positive cells was comparable between the functionalized virus (Ad-CBL) and the unmodified control (unmodified Ad). However, differences in the level of transgene expression were observed after 48 hours, which may be attributed to the activity of CBL. To evaluate the biological of CBL, HeLa cells were transduced and analyzed for apoptosis via annexin staining (Figure 14, top panel) and for cell death via zombie dye staining (Figure 14, lower panel) 48 hours post-transduction. The data collectively revealed that CBL transported into HeLa cells by the Ad vectors induced apoptosis and increased cell death. In summary, the modified vectors retained their ability to transduce cells and mediate transgene expression, while the displayed CBL maintained its biological activity. To investigate complementary effects of displayed CBL with IFN-γ as a vector- encoded transgene, a replication-defective adenoviral vector expressing IFN-γ under the control of an hCMV promoter (SP-002) was conjugated with CBL0137-PEG-PDT (5xTraut, 6xCBL0137-PEG-PDT) and subjected to quality control. SDS-PAGE revealed redox-sensitive coupling of CBL (data not shown) and, notably, a significant increase in the hydrodynamic diameter confirmed the display of CBL (Figure 15, top panel). Additionally, the polydispersity index of the vector particle solution remained below 0.2, indicating the absence of aggregate formation (Figure 15, bottom panel). To evaluate its biological activity, the modified vector and its unmodified control were used to transduce HeLa cells at different multiplicities of infection (MOIs). Supernatants from the cultures were collected 48 h after transduction, and the IFN-γ protein content was measured by ELISA (Figure 16). Vector titers were recalculated based on IFN-γ levels and used to transduce HeLa cells. HeLa cells were subjected to annexin staining 48 hours post-transduction (Figure 17). This experiment demonstrated an increased rate of apoptosis in cells transduced with the CBL-display vector compared to cells transduced with SP-002. This corroborated complementary effects between the payload display and the transgene. Finally, the vectors were used to transduce the human macrophage cell line THP-1. This cell line is largely refractory to human adenovirus type 5-based vectors. Therefore, polybrene was used as transduction enhancer. Surprisingly, in the presence of polybrene, the CBL display vectors reached transduction efficiencies of up to 60% despite modification of their capsids with CBL. Analysis of cell viability by an XTT assay revealed complementary effects of IFN-γ as a transgene and CBL as a display payload that increased macrophage cell line (Figure 18) death. The results indicate that using PDT-CBL, 1200–1500 CBL molecules per particle were coupled (extrapolated from biotin coupling using the procedures and concentrations). The assays using HeLa cells as shown in this document use 2E03 cells per well and a culture volume of 100 µl medium per well. Therefore, the CBL concentration in an experiment using 1000 MOI (vp / cell) can be calculated by: 2 x 103cells x 1000 vp / cell = 2 x vp 2 x 106vp x 1500 CBL molecules / vp = 3 x 109CBL molecules 3 x 109CBL molecules / 100 µl medium = 3 x 1010molecules / ml = 3 x 1013molecules / l 3 x 1013molecules = 5 x 10-11mole = 5 x 10-8mmole = 5 x 10-5µmol = 5 x 10-2nmole = 0.05 nmole = 50 pmoles Therefore, the total CBL concentration in the medium is 50 picomolar when using 1000 viral vector particles and, thus, far below the typical effective concentration of CBL which was found to be 0.5-2 µM on HeLa cells. These calculations suggest that for the vector-mediated transport of CBL into cells far lower concentrations can be applied as opposed to free drug. Example 8: Human serum albumin (HSA) CBL conjugation strategies Strategies for the conjugation of CBL to HSA were identified: Non-covalent incorporation Free drug is entrapped in an albumin nanoparticle. Active drug release is by degradation in the tumour microenvironment or by phagocytosis into the cell. Entry into tumour is via the enhanced penetration retention (EPR) effect due to the leaky vasculature of tumours. Albumin nanoparticles are synthesised according to the methods described in Qu et al. (2024). Indirectly conjugated to HSA Albumin binding peptides or small molecules with an affinity to albumin is used. The drug is first linked to the peptide or small molecule and when administered in vivo it will bind to albumin and circulate. The linkage to peptide should be such that active free drug is released after processing eg. pH, reduction, enzyme (Figure 19 A). Directly conjugated to HSA, Site-specific HSA has a single cysteine that can be used to site-specifically link drugs via a linker incorporating a maleimide, haloacetyl or pyridyldithio group (Figure 19 B). Directly conjugated to HSA, Non-site-specific HSA being a protein has a number of reactive functional groups present in amino acids exposed on the surface of the molecule. These are carboxylic acid and amino groups. Drugs can be directly linked to groups directly or via a linker. The linkers should be cleavable to release active drug in the tumour microenvironment or inside the tumour cell. The functional groups on HSA can be modified into other functional groups such as azide, alkyne, SH, or PDP for reaction with various linkers (Figure 19C). Various linker synthesis schemes and conjugate configurations are illustrated in Figures 20-2e5 Example 9: In vitro characterization, in vitro activity and in vivo efficacy of adenovirus-5 expressing human interferon-gamma (SP-002 / AdhIg) and GEM conjugated Ad5hIg (GEM-SP-002) Conjugation of gemcitabine (GEM) to SP-002 The cytotoxic drug gemcitabine (GEM) was conjugated to SP-002 (“AdhIg”) using the sulfhydryl reactive GEM linker pyridyldithio-GEM-carbonate (PDT-GEM- carbonate) as shown schematically in Figure 26A. AdhIg was reacted with Traut’s reagent (5x molar excess to amine) to introduce sulfhydryl groups and then reacted with the the pyridyldithio group of the GEM linker (x7 molar excess to amine). The intracellular reduction of the disulphide leads to spontaneous release of the cytotoxic drug GEM. The conjugated virus was purified by ultracentrifugation on a CsCl gradient and physicochemical characterization assays did not indicate any aggregation (Figures 26B and 26C). Reduced and non-reduced SDS-PAGE indicated modification of capsid proteins (Figure 26D). In vitro cytotoxic activity of AdhIg-GEM The cytotoxicity of the resulting AdhIg-GEM was tested by flow cytometry using Zombie and Annexin. As shown in Figure 27, GEM-conjugated virus kills HeLa cells more effectively than free GEM or unconjugated virus at equivalent GEM concentration and viral MOI. In addition, the proportion of cells undergoing apoptosis was also significantly more than drug or virus alone (Figure 28). Expression of IFN-gamma in Hela cells transduced with AdhIg and AdhIg-GEM The levels of expression of hIFN-gamma in supernatants from HeLa cell cultures transduced with the modified and unmodified virus were determined using a quantitative ELISA assay. As shown in Figure 29 HeLa cells transduced with either virus secreted IFN-gamma however, the levels in cells transduced with AdhIg-GEM were approximately 60% of the levels observed for AdhIg. It will be appreciated by persons in the art that numerous variations and / or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. All publications discussed and / or referenced herein are incorporated herein in their entirety. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

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Claims

CLAIMS 1. A functionalized virus comprising a plurality of drug molecules displayed on a virus capsid, wherein each displayed drug molecule is attached to the virus capsid by a linker comprising a biocompatible polymer.

2. The functionalized virus according to claim 1, wherein the biocompatible polymer is selected from the group consisting of: a linear polyethylene glycol (PEG), a branched PEG, poly(2-oxazoline), poly(cyclic imino ethers), polysarcosine (pSar), a polysaccharide, polyvinylpyrrolidone (PVP), a synthetic poly(amino acid) (PAA), polyglutamic acid (PGA), poly(hydroxyethyl-1- asparagine) (PHEA), poly(hdryoxyethyl-1-glutamine) (PHEG), an XTEN polymer, poly(thioglycidyl glycerol) (PTTG), RAFT polymers, a dendrimer, and hydroxyethyl starch.

3. The functionalized virus according to claim 1 or claim 2, wherein the biocompatible polymer is a linear PEG or a branched PEG.

4. The functionalized virus according to any one of claims 1 to 3, wherein the attached linker comprises a disulfide bond, an amide bond, a thioamide bond, a thioether bond, a tetrazole bond, or a thioacetyl bond.

5. The functionalized virus according to any one of claims 1 to 4, wherein the attached linker comprises a disulfide bond.

6. The functionalized virus according to any one of claims 1 to 5, wherein the attached linker does not comprise a cleavable spacer.

7. The functionalized virus according to any one of claims 1 to 6, wherein the attached linker comprises a cleavable spacer that, upon cleavage, releases the displayed drug molecule from the linker.

8. The functionalized virus according to claim 7, wherein the cleavable spacer comprises an enzymatically cleavable group or a chemically cleavable group.

9. The functionalized virus to claim 8, wherein the enzymatically cleavable group is cleavable by an enzyme selected from the group consisting of: cathepsin-B, plasmin, matrix metalloprotease, pyrophosphatase, phosphatase, glucuronidase, β-galactosidase, an esterase, a carboxyesterase, and arylsulfatase A.

10. The functionalized virus according to claim 8, wherein the chemically cleavable group is selected from the group consisting of: disulfide, acetal, ester, silyl ester, anhydride, carbamate, carbonate, and hydrazone.

11. The functionalized virus according to any one of claims 1 to 10, wherein the functionalized virus is a recombinant functionalized virus comprising within its genome an expression cassette for expression of one or more biotherapeutic agents.

12. The functionalized virus according to any one of claims 1 to 11, wherein the functionalized virus is a conditionally replication-competent virus.

13. The functionalized virus according to any one of claims 1 to 11, wherein the functionalized virus is an oncolytic virus.

14. The functionalized virus according to any one of claims 1 to 13, wherein the functionalized virus is selected from the group consisting of: adenovirus, adeno- associated virus (AAV), Cytomegalovirus (CMV), vaccinia virus, measles virus, retrovirus, lentivirus, and Herpes Simplex virus (HSV).

15. The functionalized virus according to any one of claims 1 to 14, wherein the drug molecules are of a drug that has poor aqueous solubility.

16. The functionalized virus according to any one of claims 1 to 15, wherein the drug molecules are anti-cancer drug molecules.

17. The functionalized virus according to claim 15, wherein the anti-cancer drug molecules are of at least one type of small molecule anti-cancer drug.

18. The functionalized virus to claim 15 or claim 17, wherein the anti-cancer drug molecules induce programmed cell death.

19. The functionalized virus according to any one of claims 11 to 18, wherein the one or more biotherapeutic agents are selected from the group consisting of: cytokines, cell death inducing proteins (CDIPs), a targeting polynucleotide against expression of a CDIP, a targeting polynucleotide against expression of an anti-apoptotic protein, a prodrug-converting enzyme, a chemosensitizing enzyme, a cleavable linker site protease, and antibodies.

20. The functionalized virus according to claim 19, wherein the prodrug-converting enzyme is selected from the group consisting of: a carboxyesterase, a cytosine deaminase, a thymidine kinase, a nitroreductase, β-lactamase, β-glucuronidase, and alkaline phosphatase.

21. The functionalized virus according to claim 19, wherein the one or more biotherapeutic agents comprises a cytokine.

22. The functionalized virus according to claim 21, wherein the cytokine is interferon gamma.

23. The functionalized virus according to claim 19, wherein the one or more biotherapeutic agents comprise at least one CDIP.

24. The functionalized virus according to claim 19, wherein the targeting polynucleotide is an shRNA, a guide RNA, an antisense RNA, or a miRNA.

25. The functionalized virus according to any one of claims 11 to 24, wherein the expression cassette comprises a constitutively active promoter, a tumor-specific promoter, or a viral promoter operably linked to a nucleic acid sequence encoding the one or more biotherapeutic agents.

26. The functionalized virus according to claim 25, wherein the viral promoter is a viral promoter activated late in the viral infection cycle of the functionalized virus.

27. The functionalized virus claim 26, wherein the viral promoter is the adenovirus major late promoter (MLP).

28. The functionalized virus according to any one of claims 1 to 27, wherein the expression cassette is a polycistronic expression cassette.

29. The functionalized virus according to any one of claims 17 to 28, wherein, the small molecule anti-cancer drug has poor aqueous solubility.

30. The functionalized virus according to any one of claims 17 to 29, wherein the plurality of drug molecules comprise at least one anti-cancer drug selected from the list consisting of: gemcitabine, CBL0137, a small molecule inhibitor of Nicotinamide phosphoribosyltransferase (NAMPTi), a GEM derivative, bortezomib, paclitaxel, a pyrrolobenzodiazepine dimer (PBD), 5-FU, and Irinotecan.

31. The functionalized virus according to any one of claims 17 to 30, wherein the drug molecules are in a prodrug form.

32. The functionalized virus according to any one of claims 2 to 31, wherein the PEG is branched PEG.

33. The functionalized virus according to any one of claims 1 to 32, further comprising a cell-targeting moiety.

34. The functionalized virus according to claim 33, wherein the cell targeting moiety targets a cell type selected from the group consisting of: tumour cells, myeloid cells, macrophages, myeloid-derived suppressor cells (MDSCs), T cells, stromal cells, and cancer-associated fibroblasts (CAFs).

35. The functionalized virus according to claim 33 or claim 34, wherein the cell- targeting moiety is attached to the linker.

36. The functionalized virus according to claim 35, wherein the linker comprises branched PEG.

37. The functionalized virus to any one of claims 1 to 36, wherein the plurality of drug molecules comprises about 1000 drug molecules to about 5000 drug molecules.

38. A composition comprising the functionalized virus according to any one of claims 1 to 37 and a polar aprotic solvent, wherein the functionalized virus retains infectivity.

39. The composition according to claim 38, wherein the polar aprotic solvent is at a concentration of about 5% (v / v) to about 20% (v / v).

40. A pharmaceutical composition comprising the functionalized virus according to any one of claims 1 to 36 and a pharmaceutically acceptable excipient.

41. The pharmaceutical composition according to claim 40, further comprising a second virus, wherein the second virus is a recombinant virus comprising within its genome an expression cassette for expression of one or more biotherapeutic agents, and wherein the second virus is not a functionalized virus.

42. A method for treating a disease characterized by aberrant cell proliferation, comprising administering to a subject in need thereof a therapeutically effective amount of the functionalized virus according to any one of claims 1 to 36, or the pharmaceutical composition according to claim 40 or claim 41.

43. The method according to claim 42, wherein the functionalized virus or the pharmaceutical composition is administered systemically, or locally.

44. The method according to claim 43 wherein the functionalized virus or the pharmaceutical composition is administered systemically.

45. The method according to any one of claims 42 to 44, wherein the disease characterised by aberrant cell proliferation is selected from the group consisting of: a cancer, a fibrotic disease, or cutaneous warts.

46. The method according to claim 45, wherein the disease characterised by aberrant cell proliferation is a cancer.

47. The method according to claim 46, wherein the cancer is selected from the group consisting of: basal cell carcinoma, melanoma, lymphoma, squamous cell carcinoma, Merkel cell carcinoma, lung cancer, prostate cancer, sarcomas, medulloblastomas, cancers with desmoplastic stromas, colorectal cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, mesothelioma, mesenchymal cancer, epithelial cancer, bladder cancer, urothelial cancer, and adenocarcinomas.

48. The method according to claim 47, wherein the cancer is a basal cell carcinoma (BCC).

49. The method according to claim 48, wherein the subject suffers from Basal Cell Nevus Syndrome (BCNS) or sporadic BCC.

50. The method according to any one of claims 46 to 49, wherein the cancer is a recurrent cancer or a relapsing cancer.

51. The method according to any one of claims 48 to 50, wherein the functionalized virus or the pharmaceutical composition is administered intralesionally.

52. The method according to any one of claims 46 to 50, wherein the cancer is resistant to one or more of: chemotherapy, radiotherapy, immune checkpoint inhibitor treatment, oncolytic virus therapy, CAR-T therapy, and Bacillus Calmette-Guerin (BCG) treatment.

53. A functionalized virus according to any one of claims 1 to 37, for use in treatment of a health condition.

54. The functionalized virus according to claim 53, wherein the health condition is cancer.

55. Use of a functionalized virus according to any one of claims 1 to 37 in the manufacture of a medicament for treatment of a cancer.

56. A method for generating a virus, the method comprising reacting a functional group on a virus capsid with a linker comprising a biocompatible polymer attached to a drug molecule, whereby reaction of the linker with the functional group attaches the linker to generate a functionalized virus.

57. The method according to claim 56, wherein the biocompatible polymer is selected from the group consisting of: a linear polyethylene glycol (PEG), a branched PEG, polysarcosine (pSar), a polysaccharide, polyvinylpyrrolidone (PVP), a synthetic poly(amino acid) (PAA), polyglutamic acid (PGA), poly(hydroxyethyl- 1-asparagine) (PHEA), poly(hdryoxyethyl-1-glutamine) (PHEG), an XTEN polymer, and poly(thioglycidyl glycerol) (PTTG), RAFT polymers, a dendrimer, and hydroxyethyl starch.

58. The method according to claim 56 or claim 57, wherein the biocompatible polymer is a linear PEG or a branched PEG.

59. The method according to any one of claims 56 to 58, wherein the functional group on the virus capsid is selected from the group consisting of: thiol, amine, carboxyl, and a phenolic group.

60. The method according to any one of claims 56 to 59, wherein the linker does not comprise a cleavable spacer.

61. The method according to any one of claims 56 to 59, wherein the linker comprises a cleavable spacer that, upon cleavage, releases a drug molecule from the linker.

62. The method according to claim 61, wherein the cleavable spacer comprises an enzymatically cleavable group or a chemically cleavable group.

63. The method according to claim 62, wherein the enzymatically cleavable group is cleavable by an enzyme selected from the group consisting of: cathepsin-B, plasmin, matrix metalloprotease, pyrophosphatase, phosphatase, glucuronidase, β-galactosidase, esterase, carboxyesterase, and arylsulfatase A.

64. The method according to claim wherein the chemically cleavable group is selected from the group consisting of: disulfide, acetal, ester, silyl ester, anhydride, carbamate, carbonate and hydrazone.

65. The method according to any one of claims 56 to 64, wherein the reaction is conducted in the presence of 4-Dimethylaminopyridine (DMAP).

66. The method according to any one of claims 56 to 65, wherein the functionalized virus is a recombinant virus.

67. The method according to any one of claims 56 to 66, wherein the functionalized virus is selected from the group consisting of: adenovirus, adeno-associated virus (AAV), Cytomegalovirus (CMV), vaccinia virus, measles virus, retrovirus, lentivirus, and Herpes Simplex virus (HSV).

68. The method according to any one of claims 56 to 67, wherein the drug molecule is an anti-cancer drug molecule.

69. The method according to claim 68, wherein the anti-cancer drug molecule is a small molecule anti-cancer drug.

70. The method according to claim 69, wherein the small molecule anti-cancer drug has poor aqueous solubility.

71. The method according to claim 69 or claim 70, wherein the small molecule anti- cancer drug is selected from the group consisting of: gemcitabine, CBL-0137, a small molecule inhibitor of Nicotinamide phosphoribosyltransferase (NAMPTi), a GEM derivative, bortezomib, paclitaxel, a pyrrolobenzodiazepine dimer (PBD), and 5-FU.

72. The method according to any one of claims 56 to 71, wherein the linker comprises a thiol-reactive functional group, an amine-reactive functional group, or a click chemistry functional group.

73. The method according to claim 72, wherein the thiol-reactive functional group is a pyridyldithio (PDT) group, bromoacetyl, or a maleimide group.

74. The method according to claim 72, wherein the amine-reactive functional group is N-Hydroxysuccinimide (NHS), Tetrafluorophenyl (TFP), or Hydroxybenzotriazole (HOBt) ester.

75. The method according to any one of claims 56 to 71, wherein the functional group on the virus capsid is a thiol.

76. The method according to any one of claims 56 to 71, wherein the functional group on the virus capsid is an amine.

77. The method according to claim 75 or claim 76, wherein the small molecule anti- cancer drug is selected from the group consisting of gemcitabine, CBL-0137, a small molecule inhibitor of Nicotinamide phosphoribosyltransferase (NAMPTi), a GEM derivative, bortezomib, paclitaxel, a pyrrolobenzodiazepine dimer (PBD), and 5-FU.

78. The method according to claim 75 or claim 77, wherein the linker comprises a thiol-reactive functional group.

79. The method according to claim 78, wherein the linker comprises a PDT functional group.

80. The method according to claim 78 or claim 79, wherein the PDT functional group is in a molar excess of about 3 fold to about 10 fold relative over the number of recombinant virus capsid thiol groups.

81. The method according to claim 75 or claim 76, wherein the linker comprises an amine-reactive functional group.

82. The method according to claim 81, wherein the linker comprises a TFP functional group.

83. The method according to any one of claims 56 to 82, wherein the linker is reacted at a molar ratio of linker to viral capsid functional groups of about 4:1 to about 10:1.

84. The method according to any one of claims 56 to 83, wherein the reaction is carried out in the presence of an aprotic polar solvent.

85. The method according to claim 84, wherein the aprotic polar solvent is acetonitrile.

86. A method for derivatizing a virus, the method comprising reacting solvent- exposed amines on the surface of the capsid of the virus with an amine-reactive cross-linking agent to obtain a derivatized virus comprising a new functional group cross-linked to the surface of the capsid.

87. The method according to claim 86, wherein the amine-reactive cross-linking agent is a thiolating agent and the new functional group is a thiol.

88. The method according to claim 87, wherein the thiolating agent is 2-iminothiolane.

89. The method according to claim 87 or claim 88, wherein the molar ratio of the thiolating agent to the viral capsid amines is about 0.1:1 to about 1000:

1.

90. The method according to any one of claims 86 to 89, further comprising reacting the derivatized virus with a linker comprising (i) a functional group reactive to the new cross-linked functional group and (ii) a biocompatible polymer attached to a drug molecule, whereby the reaction of the linker with the derivatized recombinant virus generates a functionalized recombinant virus, comprising a plurality of drug molecules displayed on the surface of the capsid.

91. The method according to claim 90, wherein the biocompatible polymer is a linear PEG or a branched PEG.

92. A derivatized virus corresponding to Formula I:wherein, V is a viral capsid; and-NH is a viral capsid derived group.

93. A drug conjugate comprising one or more CBL0137 molecules and at least one stabilizing, targeting, or delivery moiety bound to the one or more CBL10137 molecules.

94. The drug conjugate according to claim 93, wherein the at least one stabilizing, targeting, or delivery moiety is a peptide, protein, or non-peptide biocompatible polymer.

95. The drug conjugate according to claim 93, wherein at least one of the one or more CBL0137 molecules is covalently bound to the at least one stabilizing, targeting, or delivery moiety.

96. The drug conjugate according to claim 95, wherein all of the one or more CBL0137 molecules are covalently bound to the at least one stabilizing, targeting, or delivery moiety.

97. The drug conjugate according to claim 95 or claim 96, wherein the one or more CBL0137 molecules are covalently bound to the at least one stabilizing, targeting, or delivery moiety by a linker comprising a biocompatible polymer.

98. The drug conjugate according to claim 97, wherein the linker is a multiarm linker.

99. The drug conjugate according to claim 97 or claim 98, wherein the linker comprises a dendrimer.

100. The drug conjugate according to any one of claims 97 to 99, wherein the linker comprises a biocompatible polymer selected from the group consisting of: a linear polyethylene glycol (PEG), a branched PEG, poly(2-oxazoline), poly(cyclic imino ethers), polysarcosine (pSar), a polysaccharide, polyvinylpyrrolidone (PVP), a synthetic poly(amino acid) (PAA), polyglutamic acid (PGA), poly(hydroxyethyl-1-asparagine) (PHEA), poly(hdryoxyethyl-1- glutamine) (PHEG), an XTEN polymer, poly(thioglycidyl glycerol) (PTTG), RAFT polymers, a dendrimer, and hydroxyethyl starch.

101. The drug conjugate according one of claims 97 to 100, wherein the linker comprises a disulfide bond, an amide bond, a thioamide bond, a thioether bond, a thioester bond, a tetrazole bond, or a thioacetyl bond.

102. The drug conjugate according to any one of claims 97 to 101, wherein the linker does not comprise a cleavable spacer.

103. The drug conjugate according to any one of claims 97 to 101, wherein the linker comprises a cleavable spacer that, upon cleavage, releases at least one of the CBL0137 molecules from the drug conjugate.

104. The drug conjugate according to claim 103, wherein the cleavable spacer comprises an enzymatically cleavable group or a chemically cleavable group.

105. The drug conjugate according to claim 104, wherein the enzymatically cleavable group is cleavable by an enzyme selected from the group consisting of: cathepsin-B, plasmin, matrix metalloprotease, pyrophosphatase, phosphatase, glucuronidase, β-galactosidase, an esterase, a carboxyesterase, and arylsulfatase A.

106. The drug conjugate according to claim 104, wherein the chemically cleavable group is selected from the group consisting of: disulfide, acetal, ester, silyl ester, anhydride, carbamate, carbonate, and hydrazone.

107. The drug conjugate according to any one of claims 93 to 96, wherein the one or more CBL0137 molecules are non-covalently bound to the at least one stabilizing, targeting, or delivery moiety.

108. The drug conjugate according to claim 107, wherein the drug conjugate comprises a nanoparticle comprising a plurality of stabilizing, targeting, or delivery moieties.

109. The drug conjugate according to any one of claims 94 to 108, wherein the at least one stabilizing, targeting, or delivery moiety comprises a protein.

110. The drug conjugate according to 108 or claim 109, wherein the nanoparticle comprises a plurality of albumin molecules.

111. The drug conjugate according to claim 109, wherein the protein is selected from the group consisting of: albumin, an albumin fragment that retains binding to the neonatal Fc receptor (FcRn), a fusion protein comprising albumin or comprising a fragment thereof that binds to FcRn, an immunoglobulin Fc domain, an antibody, a Designed Ankryin Repeat Protein (DARPin), an XTEN polypeptide, a Proline-Alanine-Serine (PAS) polypeptide, an elastin-like polypeptide (ELP), or a fusion protein comprising any one of the foregoing.

112. The drug conjugate according to claim 111, wherein the protein comprises an albumin or a fragment of albumin that retains binding to FcRn.

113. The drug conjugate according to claim 111 or claim 112, wherein the protein comprises human albumin or a human albumin variant having an amino acid sequence at least 95% identical to the amino acid sequence of human, bovine, ovine, porcine, mouse, rat albumin, or a fragment of any thereof that retains binding to FcRn.

114. The drug conjugate according to claim 112 or claim 113, wherein a CBL0137 molecule is covalently bound site-specifically to the albumin via a linker at the position of a cysteine residue in the albumin.

115. The drug conjugate according to claim 114, wherein the position corresponds to position 34 of human albumin.

116. The drug conjugate according to claim 112, wherein one or more CBL0137 molecules are covalently bound non-site-specifically to the albumin.

117. The drug conjugate according to any one of claims 111 to 116, wherein the protein is a fusion protein comprising the albumin or the fragment thereof.

118. The drug conjugate according to claim 111, wherein the protein comprises a human immunoglobulin Fc domain.

119. The drug conjugate according 111, wherein the protein comprises an antibody.

120. The drug conjugate according to claim 120, wherein the antibody is a monoclonal antibody, a diabody, a scFv, or a nanobody.

121. The drug conjugate according to claim 120 or claim 121, wherein the antibody is a multispecific antibody.

122. The drug conjugate according to any one of claims 119 to 121, wherein the antibody targets human albumin.

123. The drug conjugate according to any one of claims 119 to 121, wherein the antibody targets a cancer-enriched or tumor-enriched antigen.

124. The drug conjugate according to claim 123, wherein the cancer enriched or tumor-enriched antigen is selected from the group consisting of: HER2, EGFR, VEGF, Mucin-1, integrins, estrogen receptor (ER), androgen receptor (AR), VEGFR2, EpCAM, transferrin receptor, carcinoembryonic antigen (CEA), B melanoma 1 (BAGE), G antigens (GAGEs), gp100, cancer / testis antigen 1 (CTAG1), melanoma-associated antigens (MAGEs), Nectin-4, folate receptor, CD79b, MET receptor, CD19, CD20, CD44, and CD3.

125. The drug conjugate according to any one of claims 94 to 107, wherein the at least one stabilizing, targeting, or delivery moiety comprises a peptide.

126. The drug conjugate according to claim 125, wherein the peptide is an albumin- binding peptide.

127. The drug conjugate according to claim 126, wherein the albumin-binding peptide comprises the amino acid sequence of: SEQ ID NO:1 (DICLPRWGCLW), SEQ ID NO:2 (LAEAKVLANRELDKYGVSDFYKRLINKAKTVEGVEALK LHILAALP), or SEQ ID NO:3 (EYEKpalmEYE), wherein K is palmitoylated.

128. The drug conjugate according to 126, wherein the albumin-binding peptide is selected from the group consisting of: ABD094, NbSA, and Nb80.

129. The drug conjugate according to claim 125, wherein the peptide is a tumor- homing or cancer-targeting peptide.

130. The drug conjugate according to claim 129, wherein the tumor-homing or cancer- targeting peptide is selected from the group consisting of: RGD4C, iRGD, p32- binding LyP-1 peptide, K237, VEGFR-2-binding peptide, IL4RPep-1, mUNO, Her-2 binding peptide, GE11, angiopep-2, prostate tumor-targeting peptide, and bladder tumor-targeting peptide.

131. The drug conjugate according to any one of claims 94 to 107, wherein the at least one stabilizing, targeting, or delivery moiety is a non-peptide biocompatible polymer.

132. The drug conjugate according to claim 131, wherein the non-peptide biocompatible polymer is PEG and the one or more CBL0137 molecules are covalently bound to the PEG via a fluorenylmethoxycarbonyl linker.

133. The drug conjugate according to claim 131, wherein the non-peptide biocompatible polymer comprises a fatty acid, cholesterol, Evans blue, CRX-527, or alpha-tocopherol.

134. The drug conjugate according to claim 133, wherein the fatty acid is: 1,2- distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE) or octadecanoic acid.

135. The drug conjugate according to claim 131, wherein the non-peptide biocompatible polymer comprises an aptamer.

136. The drug conjugate according to claim 135, wherein the aptamer is an albumin- binding aptamer.

137. The drug conjugate according to any one of claims 93 to 135, wherein the plasma half-life (t1 / 2) of CBL0137 is greater than 40 hours when the drug conjugate is administered systemically to a human subject.

138. A pharmaceutical composition comprising the drug conjugate according to any one of claims 93 to 137 and a pharmaceutically acceptable excipient.

139. A method for treating a disease characterized by aberrant cell proliferation, comprising administering to a subject in need thereof a therapeutically effective amount of the drug conjugate according to any one of claims 93 to 137, or the pharmaceutical composition according to claim 138.

140. The method according to claim 139, wherein the drug conjugate or the pharmaceutical composition is administered systemically, or locally.

141. The method according to claim 140 wherein the drug conjugate or the pharmaceutical composition is administered systemically.

142. The method according to any one of claims 139 to 141, wherein the disease characterised by aberrant cell proliferation is selected from the group consisting of: a cancer, a fibrotic disease, or cutaneous warts.

143. The method according to claim 142, wherein the disease characterised by aberrant cell proliferation is a cancer.

144. The method according to claim 143, wherein the cancer is selected from the group consisting of: basal cell carcinoma (BCC), melanoma, lymphoma, squamous cell carcinoma, Merkel cell carcinoma, lung cancer, prostate cancer, sarcomas, medulloblastomas, cancers with desmoplastic stromas, colorectal cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, mesothelioma, mesenchymal cancer, epithelial cancer, bladder cancer, urothelial cancer, and adenocarcinomas.

145. The method according to claim 144, wherein the cancer is a BCC.

146. The method according to claim 144, wherein the cancer is pancreatic cancer.

147. The method according to any one of claims 143 to 146, wherein the cancer is a recurrent cancer or a relapsing cancer.

148. The method according to any one of claims 145 to 147, wherein the drug conjugate or the pharmaceutical composition is administered intralesionally.

149. The method according to any one of claims 145 to 148, wherein the cancer is resistant to one or more of: chemotherapy, radiotherapy, immune checkpoint inhibitor treatment, oncolytic virus therapy, CAR-T therapy, and Bacillus Calmette-Guerin (BCG) treatment.

150. The method according to any one of claims 139 to 149, further comprising administering a therapeutically effective amount of interferon gamma.

151. The method according to any one of claims 139 to 149, further comprising administering a therapeutically effective amount of a recombinant virus comprising within its genome an expression cassette for expression of one or more biotherapeutic agents.

152. The method according to claim 151, wherein the recombinant virus is a conditionally replication-competent virus.

153. The method according to claim 151, wherein the recombinant virus is an oncolytic virus.

154. The method according to any one of claim 151 or claim 152, wherein the recombinant virus is selected from the group consisting of: adenovirus, adeno- associated virus (AAV), Cytomegalovirus (CMV), vaccinia virus, measles virus, retrovirus, lentivirus, and Herpes Simplex virus (HSV).

155. The method according to any one of claims 151 to 154, wherein the one or more biotherapeutic agents are selected from the group consisting of: cytokines, cell death inducing proteins (CDIPs), a targeting polynucleotide against expression of a CDIP, a targeting polynucleotide against expression of an anti-apoptotic protein, a prodrug-converting enzyme, a chemosensitizing enzyme, a cleavable linker site protease, and antibodies.

156. The method according to claim wherein the prodrug-converting enzyme is selected from the group consisting of: a carboxyesterase, a cytosine deaminase, a thymidine kinase, a nitroreductase, β-lactamase, β-glucuronidase, and alkaline phosphatase.

157. The method according to claim 155, wherein the one or more biotherapeutic agents comprise a cytokine.

158. The method according to claim 157, wherein the cytokine is interferon gamma.

159. The method according to claim 157 or claim 158, wherein the recombinant virus is an adenovirus.

160. The method according to claim 158 or claim 159, wherein the recombinant virus is ASN-002.

161. The method according to claim 155, wherein the one or more biotherapeutic agents comprise at least one CDIP.

162. The method according to claim 155, wherein the targeting polynucleotide is an shRNA, a guide RNA, an antisense RNA, or a miRNA.

163. The method according to any one of claims 151 to 162, wherein the expression cassette comprises a constitutively active promoter, a tumor-specific promoter, or a viral promoter operably linked to a nucleic acid sequence encoding the one or more biotherapeutic agents.

164. The recombinant virus according to claim 163, wherein the viral promoter is a viral promoter activated late in the viral infection cycle of the recombinant virus.

165. The method according to claim 164, wherein the viral promoter is the adenovirus major late promoter (MLP).

166. The method according to any one of claims 151 to 165 wherein the expression cassette is a polycistronic expression cassette.

167. The method according to any claims 151 to 166, wherein the recombinant virus further comprises a cell-targeting moiety.

168. The method according to claim 167, wherein the cell-targeting moiety targets a cell type selected from the group consisting of: tumour cells, myeloid cells, macrophages, myeloid-derived suppressor cells (MDSCs), T cells, stromal cells, and cancer-associated fibroblasts (CAFs).

169. The method according to any one of claims 151 to 168, wherein the recombinant virus is a functionalized virus comprising a plurality of drug molecules displayed on a virus capsid, wherein each displayed drug molecule is attached to the virus capsid by a linker comprising a biocompatible polymer.

170. The method according to any one of claims 151 to 168, further comprising administration of a second virus, wherein the second virus is a functionalized virus comprising a plurality of drug molecules displayed on a virus capsid, wherein each displayed drug molecule is attached to the virus capsid by a linker comprising a biocompatible polymer.

171. The method according to any one of claims 150 to 170, wherein the drug conjugate and (a) the interferon gamma or (b) the recombinant virus are administered by different routes of administration.

172. The method according to any one of claims 150 to 170, wherein the drug conjugate and (a) the interferon gamma or (b) the recombinant virus are administered by the same route of administration.

173. The method according to any one of claims 150 to 172, wherein the drug conjugate and (a) the interferon gamma or (b) the recombinant virus are administered contemporaneously.

174. The method according to any one of claims 150 to 172, wherein the drug conjugate and (a) the interferon gamma or (b) the recombinant virus are administered at different times.

175. The method according to claim 174, wherein the drug conjugate is administered prior to administration of (a) the interferon gamma or (b) the recombinant virus.

176. The method according to claim 174, wherein the drug conjugate is administered after administration of (a) the interferon gamma or (b) the recombinant virus.

177. A method for treating a cancer comprising administering a therapeutically effective amount of CBL0137 and a therapeutically effective amount of interferon gamma.

178. A drug conjugate according to any one of claims 93 to 137, for use in treatment of a cancer in a subject in need thereof.

179. The drug conjugate for use according to claim 178, wherein the treatment further comprises treatment with a recombinant virus comprising within its genome an expression cassette for expression of one or more biotherapeutic agents.

180. Use of a drug conjugate according to any one of claims 93 to 137 in the manufacture of a medicament for treatment of a cancer.

181. The use according to claim 180, wherein the subject is to be treated in a combination therapy with the medicament and a recombinant virus comprising within its genome an expression cassette for expression of one or more biotherapeutic agents.

182. Use of a recombinant virus comprising within its genome an expression cassette for expression of one or more biotherapeutic agents for use in the manufacture of a medicament for treatment of a cancer in a subject to be treated in combination therapy with a drug conjugate according to any one of claims 93 to 137.

183. The use according to any one of claims 179, 180, or 182, wherein the recombinant virus is a functionalized virus comprising a plurality of drug molecules displayed on a virus capsid, wherein each displayed drug molecule is attached to the virus capsid by a linker comprising a biocompatible polymer.

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