Engineered viral like particles (EVLPS) for the selective transduction of target cells

Abstract

The present disclosure provides compositions and methods for the selective transduction and genome editing of human cells (e.g., hematopoietic stem and progenitors cells, HSPCs) using engineered viral like particles (eVLPs). Aspects of the disclosure provide eVLP compositions comprising fusion proteins comprising a targeting moiety. In some embodiments, the fusion proteins comprise a cytokine conjugated to a transmembrane protein and / or an envelope glycoprotein. In other embodiments, the fusion proteins comprise a targeting moiety domain, a stalk protein domain, a transmembrane and / or envelope glycoprotein domain. Targeted-eVLP architectures comprising various targeting domains, stalk domains, transmembrane domains, and envelope glycoproteins are also provided herein. Other aspects of the disclosure provide eVLP compositions comprising envelope glycoproteins comprising non-natural sugars and methods of conjugating said eVLPs to various targeting moieties using bio-orthogonal click chemistry. Polynucleotides, vectors, cells, and kits useful for producing the articles, and performing the methods, described herein are also provided.

Description

ENGINEERED VIRAL LIKE PARTICLES (EVLPS) FOR THE SELECTIVE TRANSDUCTION OF TARGET CELLSGOVERNMENT SUPPORT

[0001] This invention was made with government support under Grant Nos. UG3AI150551, U01AI142756, R35GM118062, RM1HG009490, and R01EY009339 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF INVENTION

[0002] Recently developed gene editing agents, such as base editors and prime editors, enable the precise manipulation of genomic DNA in living organisms and raise the possibility of treating the root cause of many genetic diseases. The broad therapeutic application of in vivo gene editing requires safe and efficient means for delivering gene editing agents to multiple tissues and organs. Many of the most robust approaches for delivering gene editing agents in vivo reported to date involve the use of viruses, such as adeno-associated viruses (AAVs) or lentiviruses (LV), to deliver DNA encoding a gene editing agent to target tissues. However, viral delivery of DNA encoding editing agents leads to prolonged expression in transduced cells, which could increase the frequency of off-target editing. In addition, viral delivery of DNA raises the possibility of viral vector integration into the genome of transduced cells, both of which can potentially promote oncogenesis or other adverse effects. Further, despite the constant development of transfection methods and the optimization of viral and nonviral delivery vectors (e.g., AAV or LV), the efficiency of these approaches can vary dramatically, especially in primary cells that are highly sensitive to changes in their environment and may be altered in response to transfection agents and / or vectors. This effect is further exacerbated in vivo when pharmacokinetics significantly limits the accessibility of certain cell types to circulating delivery vectors.

[0003] More recently, virus-like particles (VLPs) have been engineered to deliver, for example, Cas9 proteins, base editors, and prime editors. These VLPs allow the delivery of ribonucleoproteins (RNPs) (e.g., a gene editing protein agent complexed with a guide RNA) instead of DNA to target cells. The short half-life of RNPs in cells limits the opportunity for off-target editing. These VLPs, however, utilize wild-type viral fusogen proteins, which havebeen optimized by natural evolution to transduce many different cell types. This property, which yields highly infectious VLPs, increases transduction of non-target cell types when used in vivo due to the wide natural tropism of the wild-type viral fusogen. This can be problematic when targeted gene editing (e.g., gene editing of a specific cell type) is desired. Thus, improvements are needed.SUMMARY OF INVENTION

[0004] The present disclosure provides compositions of engineered virus like particles (eVLPs) and eVLP complexes for the selective transduction and genome editing of human cells (e.g., hematopoietic stem and progenitor cells, HSPCs). Polynucleotides encoding the proteins of the eVLP and eVLP complexes, vectors comprising said polynucleotides, cells comprising the polynucleotides and / or vectors, and kits useful for producing the eVLPs and eVLP complexes are also provided. Additionally, methods of preparing eVLPs and eVLP complexes are also disclosed herein, as are methods for editing a nucleic acid molecule using said eVLPs and / or eVLP complexes. Other aspects relate to methods of delivering a cargo (e.g., a therapeutic) of interest to a target cell. For example, in some embodiments, the methods relate to using the eVLPs disclosed herein to deliver a base editor or a prime editor to a target cell to treat a disease or disorder.

[0005] Aspects of the disclosure relate to eVLPs. In some embodiments, the eVLPs disclosed herein are formed via supra-molecular assembly and comprise (a) an envelope comprising (i) a lipid membrane (e.g., single-layer or bi-layer membrane) and a (ii) viral envelope glycoprotein; and (b) a multi-protein core region enclosed by the envelope and comprising (i) a Gag protein, (ii) a Gag-Pro-Pol protein, and (iii) a Gag-cargo fusion protein (e.g., a second fusion protein) comprising a Gag protein fused to a cargo protein (e.g., a napDNAbp, base editor, or prime editor, or therapeutic protein) via a cleavable linker (e.g., a protease-cleavable linker). As described in more detail below, in some embodiments, a transmembrane domain is conjugated to a targeting domain. In other embodiments, the envelope glycoprotein is conjugated to the targeting domain.

[0006] Some aspects of the disclosure relate to eVLP compositions comprising fusion proteins comprising a targeting moiety. In some embodiments, the fusion proteins comprise a cytokine conjugated to a transmembrane protein and / or an envelope glycoprotein of the eVLP. In other embodiments, the fusion proteins comprise a targeting moiety domain, a stalk protein domain, and a transmembrane domain, and / or optionally, an envelope glycoprotein domain. Targeted-eVLP architectures comprising various combinations of targeting domains(e.g., facilitates targeted binding of the eVLP to a target cell), stalk domains (e.g., inert domains that act as spacer sequences), transmembrane domains (e.g., a peptide that spans across the lipid membrane domain of the eVLP), and / or envelope glycoproteins (e.g., proteins that facilitate binding of the eVLP to multiple cell targets). Other aspects of the disclosure provide eVLP compositions comprising envelope glycoproteins comprising non-natural moieties and methods of conjugating said eVLPs to various targeting moieties using chemistry, e.g., bio-orthogonal click chemistry.

[0007] As described herein, the inventors have discovered that eVLP compositions comprising targeting moieties on their surfaces (e.g., as fusion proteins comprising the viral envelope glycoprotein and / or transmembrane proteins) are capable of delivering payloads to specific cell types, both in vitro and in vivo, with higher transduction efficiencies than eVLPs lacking said targeting moieties.

[0008] Thus, in certain aspects, the present disclosure relates to eVLPs comprising one or more fusion proteins capable of displaying a targeting domain on the surface of eVLP. In some embodiments, the fusion protein comprises a transmembrane domain and a targeting domain. In some embodiments, the fusion protein comprises a transmembrane domain, a stalk domain, and a targeting domain. In other embodiments, the fusion protein comprises a viral envelope domain and a targeting domain. Alternatively, or additionally, the fusion protein comprises a viral envelope domain, a stalk domain, and a targeting domain.

[0009] Any two domains within the fusion protein may be optionally linked together using one or more linkers (e.g., cleavable linkers), according to some embodiments. For example, in one set of embodiments, a first linker (e.g., cleavable linker) connects the transmembrane domain and the targeting domain. In another set of embodiments, the first linker (e.g., cleavable linker) connects the transmembrane domain and the stalk domain. In a third set of embodiments, the first linker (e.g., cleavable linker) connects the stalk domain to a targeting domain. In yet another set of embodiments, a second linker (e.g., cleavable linker) connects the stalk domain to a targeting domain.

[0010] In some embodiments, the one or more linkers comprises a stalk domain. For example, in some cases, a stalk domain connects the transmembrane domain and the targeting domain.

[0011] In some embodiments, a first linker (e.g., linker) connects a viral envelope glycoprotein domain and the targeting domain. In another set of embodiments, the first linker (e.g., linker) connects the viral envelope glycoprotein domain and the stalk domain. In athird set of embodiments, the first linker (e.g., linker) connects the stalk domain to a targeting domain. In yet another set of embodiments, a second linker (e.g., linker) connects the stalk domain to a targeting domain.

[0012] In certain embodiments, the fusion protein comprises a transmembrane domain, an optional linker (e.g., linker), and a targeting domain (e.g., any domain capable of binding a target receptor on a target cell). Exemplary receptortargeting domains contemplated herein include, but are not limited to, CD110:Thrombopoientin (TPO), c-kit:Stem Cell Factor (SCF), CXCR4:CXCL12, CD46:Adenovirus F35 (AdF35), CD201:Protein C, CD150:SH2DlA / EAT-2, CD45:CMV ULll / PP14 / adenovirus E3, CD54:LFA-1, CD55:CD97, CD58:CD2, CD59:CD2, CD100:Plexin-B2, CD120:TNFa / b, CD124:IL-4, and Flk2:Flt3 ligand.

[0013] In other embodiments, the fusion protein comprises a transmembrane domain, a stalk domain, an optional linker (e.g., linker), and a targeting domain. In some embodiments, the fusion protein comprises a viral envelope glycoprotein, an optional linker (e.g., a linker), and a targeting domain. Additional embodiments include fusion proteins comprising the viral transmembrane domain, a stalk domain, an optional linker (e.g., linker), and a targeting domain.

[0014] In some embodiments, one or more domains of a fusion protein comprises a mutation. In some embodiments, the mutation reduces the affinity of an envelope glycoprotein for its target receptor while preserving its fusogenic capabilities. For example, in some embodiments, a transmembrane domain comprises a mutation. In some embodiments, a viral envelope glycoprotein domain comprises a mutation. In other embodiments, a targeting domain comprises a mutation. In other embodiments still, a stalk domain comprises a mutation.

[0015] eVEPs comprising any combination of the fusion proteins disclosed herein are also possible, according to some embodiments. For example, in some embodiments, eVEPs may comprise a first fusion protein comprising a transmembrane domain and a targeting domain and a second fusion protein comprising a viral envelope domain and a targeting domain. The person of ordinary skill in the art will understand that the eVEPs disclosed herein may comprise any suitable number of fusion proteins. Thus, in some embodiments, eVLPs may comprises a first fusion protein, a second fusion protein, a third fusion protein, a fourth fusion protein, a fifth fusion protein, and so on. In some embodiments, the eVLPs comprise at least 2 fusion proteins.

[0016] Other aspects of the disclosure relate to eVLP complexes. In some embodiments, the eVLP complexes comprise an eVLP and a small molecule, an antibody, a (poly)nucleic acid, a protein, a peptide, or the like. In some embodiments, the protein or peptide is a recombinant protein or a recombinant peptide. In some embodiments, the eVLP comprises a fusion protein comprising a targeting domain configured to bind to the small molecule, antibody, (poly)nucleic acid, protein, or peptide. In some embodiments, the eVLP comprising the fusion protein comprising the targeting domain binds to the small molecule, an antibody, a (poly)nucleic acid, a protein, a peptide, thus forming an eVLP complex. In some embodiments, the small molecule, antibody, (poly)nucleic acid, protein, or peptide facilitates binding of the eVLP complex to a target cell. In some embodiments, the eVLP complex comprises an antibody bound to thetargeting domain of the fusion protein. In some embodiments, the targeting domain is configured to bind to one or more domains of the antibody. In some embodiments, the antibody facilitates binding of the eVLP to the target cell. In some embodiments, the antibody is any antibody capable of binding to a cell surface (e.g., via a cell surface receptor).

[0017] Any known targeting domain- antibody domain complex known in the art may be used to form the eVLP complexes disclosed herein. For example, in some embodiments, the antibody domain is an IgG antibody, and the targeting domain is a Z-peptide, which is known in the art to bind IgG antibodies. Other antibodies can also be used as described herein (e.g., IgA, IgM, IgE, etc.). Other non-limiting examples are provided in the Detailed Description. Accordingly, in some embodiments, the targeting domain and / or antibody domain may be naturally occurring or non-naturally occurring.

[0018] Any of the eVLP complexes contemplated herein may be formed in vitro or in vivo. For example, in some embodiments, eVLP complexes are formed in vitro by mixing a desired antibody domain (e.g., IgG antibody) with eVLPs comprising fusion proteins comprising targeting domains (e.g., Z-peptide) capable of binding the desired antibody domain. Alternatively, eVLP complexes may be formed in vivo, for example, by administering eVLPs comprising fusion proteins comprising a targeting domain (e.g., Z- peptide) capable of binding to a desired antibody domain to a subject in need thereof, wherein antibody domain is also present within the subject in need. Notably, the subject in need may produce the antibody domain naturally or may be administered the antibody domain prior to or following administration of the eVLPs.

[0019] Other aspects of the present disclosure relate to enhancing the selective tropism of eVLPs by chemically conjugating a desired targeting domain to the surface of the eVLP (e.g., using chemical methods as opposed to genetic methods). As such, in some embodiments, the eVLPs disclosed herein comprise at least one conjugation domain capable of forming a bond with a desired targeting domain. In a first set of embodiments, the conjugation domain is a subdomain of a transmembrane domain. In a second set of embodiments, the conjugation domain is a subdomain of a viral envelope glycoprotein domain. In third set of embodiments, the conjugation domain is a subdomain of a stalk domain. In other embodiments, multiple conjugation subdomains are possible within the eVLPs (e.g., the conjugation domain is a subdomain of the transmembrane domain and the envelope glycoprotein domain).

[0020] In some embodiments, the eVLPs comprise one least one conjugation domain comprising at least one reactive group capable of forming a bond with a desired targeting domain comprising a second reactive group (e.g., -COOH + -NH2 or -N3 +-C=C-, etc.) In some embodiments, the reactive group is a chemical group that is naturally occurring in biological systems (e.g., -SH, -NH2, -COOH groups, etc.). In other embodiments, the chemical group is a chemical group that is not naturally occurring in biological systems (e.g., -N3, -C=C-, etc.). For example, in some embodiments, eVLPs comprising a viral envelope protein comprising N-azidoacetylmannosamine (ManNAz) may be reacted with a targeting domain comprising a strained alkyne group (e.g., dibenzocyclooctyne, DIBO). Such embodiments produce eVLPs comprising a viral envelope glycoprotein comprising one or more targeted domains via a 1,2,3-triazole ring linkage.

[0021] Additional aspects of the present disclosure relate to one or more polynucleotides that, collectively, encode for any one of the proteins of the eVLPs disclosed herein. In some embodiments, the one or more polynucleotides comprises a first nucleic acid encoding a first fusion protein. The fusion protein be any fusion protein disclosed herein. For example, in some embodiments the fusion protein comprises a transmembrane domain, a targeting domain, and optionally, a stalk domain. In other embodiments, the one or more polynucleotides further comprises a second nucleic acid sequence encoding a viral envelope glycoprotein. In another embodiment, the one or more polynucleotides further comprise a third nucleic acid sequence encoding a group-specific antigen (gag) protease (pro) polyprotein. In some embodiments, the one or more polynucleotides further comprises a fourth nucleic acid sequence encoding a second fusion protein encoding a base editor, a prime editor, or other protein(e.g., a therapeutic protein).

[0022] Other aspects of the present disclosure relate to one or more methods. In some embodiments, the methods relate to methods of producing the eVLPs disclosed herein. For example, in some embodiments, the methods comprise transfecting a cell (e.g., a producer cell) with one or more polynucleotides that encode for said eVLPs. Other methods are directed to methods of editing a nucleic acid molecule in a target cell using any of the eVLPs disclosed herein. In some embodiments, the methods comprise contacting the target cell with any of the eVLPs, polynucleotides, vectors, and / or cells disclosed herein, wherein the eVLPs encapsulate a gene editor (e.g., base editor or prime editor, a therapeutic, etc.), and wherein upon transduction the gene editor installs one or more modifications to the nucleic acid molecule at a target site.

[0023] In other embodiments, the methods comprise methods for treating a disease using the eVLPs disclosed herein. In some embodiments, the methods comprise contacting a target cell (e.g., hematopoietic stem and progenitor cells, HSPCs) with any of the eVLPs, polynucleotides, vectors, and / or cells or compositions thereof disclosed herein, wherein the eVLPs encapsulate a therapeutic (e.g., base editor or prime editor, RNA therapy, peptide therapy, etc.), and wherein upon transduction the gene editor installs one or more modifications to the nucleic acid molecule at a target site, and wherein the one or more modifications are associated with reducing, relieving, treating, curing, or preventing the symptoms of a disease or disorder.

[0024] Other aspects relate to pharmaceutical compositions comprising any of the eVLPs, polynucleotides, vectors, and / or cells disclosed herein, and a pharmaceutical excipient.

[0025] It should be appreciated that the foregoing concepts, and additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various nonlimiting embodiments when considered in conjunction with the accompanying Figures.

[0026] International Patent Application Nos. PCT / US2022 / 080834, PCT / US2022 / 080836, and PCT / US2022 / 080856, each of which was filed on December 2, 2022, and each of which is incorporated herein by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 shows a schematic drawing of various surface receptors with high- specificity for hematopoietic stem and progenitor cell (e.g., HSPCs) and their cognate ligand including (1) thrombonoietin receptor (e.g., CD110) / Thrombopoietin (TPO), (2) proto-oncogene c-Kit (e.g., c-Kit) / Stem Cell Factor (SCF), C-X-C chemokine receptor type 4 (e.g., CXCR-4) / stromal-derived factor 1 (e.g., CXCL-12 or SDF-1), and CD46 complement regulatory protein (e.g., CD46) / Adenovirus Finger Protein 35 (e.g., AdF35).

[0028] FIG. 2 shows exemplary eVLP constructs comprising (i) a fusion protein comprising a targeting domain and a transmembrane domain, and (ii) a mutated VSVG envelope glycoprotein domain.

[0029] FIG. 3 shows exemplary eVLP constructs comprising (i) a fusion protein comprising a targeting domain and a wild-type VSVG transmembrane domain, and (ii) a mutated VSVG envelope glycoprotein domain.

[0030] FIG. 4 shows exemplary eVLP constructs comprising (i) a fusion protein comprising a targeting domain, a CD8 alpha stalk domain, and a transmembrane domain, and (ii) a mutated VSVG envelope glycoprotein domain.

[0031] FIG. 5 shows exemplary eVLP constructs comprising (i) a fusion protein comprising a targeting domain, an IgG alpha stalk domain, and a transmembrane domain, and (ii) a mutated VSVG envelope glycoprotein domain.

[0032] FIG. 6 shows exemplary eVLP constructs comprising (i) a fusion protein comprising a targeting domain and a transmembrane domain, and (ii) a mutated VSVG envelope glycoprotein domain. The targeting domain is configured to bind to an antibody, which in turn, binds a protein on a target cell.

[0033] FIG. 7 shows an exemplary eVLP comprising a wild-type envelope glycoprotein comprising one or more non-natural moieties.

[0034] FIG. 8 shows a schematic drawing of a version 4 virus-like particle (e.g., v4 eVLP) architecture as published in Banskota, Raguram et al., Cell 185, 250-265 (2022). Vesicular stomatitis virus G protein (e.g., VSVG) is the standard envelope glycoprotein which initiates receptor-mediated endocytosis through the ubiquitously expressed LDL receptor protein (LDLR). The wide expression distribution of LDLR means that v4 eVLPs have the potential to transduce many different cell types, which often results in significant off-target effects.

[0035] FIG. 9 shows exemplary embodiments wherein genome editing agents were selectively delivered to hematopoietic stem cells using eVLPs comprising a targeting protein conjugated to a VSVGmut, a mutated version of the fusogen VSVG (K47Q, R354A) with impaired binding affinity for its natural receptor but with retained fusogenic activity. This fusogen is displayed on v4 eVLP architecture in its binding active form. Here the targetingprotein corresponds to a ligand that binds a surface receptor on HSPCs. Exemplary targeting proteins tested include TPO, SCF, CXCL12, and F35.

[0036] FIG. 10 shows a plot of the percentage of reads with the desired A>G edit at position 7 in the BCE11A +58kb enhancer in hCD34+ cells as a function of eVEPs with 50 different targeting architectures. To measure the editing efficiency, eVEPs were engineered to contain an adenine base editor (e.g., ABE8e) and a sgRNA (e.g., A>G edits at position 7 of BCE11A protospacer) as cargo.

[0037] FIG.l 1 shows additional eVEP architectures to display the targeting protein on the eVEP surface, as contemplated herein. As shown in the figure, targeting proteins may be displayed on eVEP surfaces through various transmembrane domains fused to an inert stalk domain which serves as a spacer separating the transmembrane domain from the targeting domain thus allowing access to bind membrane proximal receptors on target cells.Exemplary inert stalks, as shown, include CD8alpha and IgG.

[0038] FIG. 12A shows the use of wild type (WT) VSVG in a fusion with the targeting proteins (e.g., as opposed to the VSVGmut). Constructs comprising the pCMV-TPO-VSVG and pCMV-SCF-VSVG exhibited 15% and 10% of the editing efficiency of WT VSVG v4 eVLPs in human CD34+ cells, respectively, with no statistically significant loss in cell viability compared to VSVG-eVLPs. Constructs comprising an adenine base editor were validated by observing A>G editing at position 7 of BCL11 A protospacer.

[0039] FIG. 12B shows the viability of CD34+ cells following treatment with targeted- eVLPs as described in FIG. 7.

[0040] FIG. 13A shows an illustration of an exemplary barcoded lentivirus platform for testing viral targeting proteins in a high-throughput, pooled manner. In this screen, HIV 1 lentivirus is produced in an arrayed format (typically 96 w format) by transfecting HEK17 producer cells with pCMV- VSVGmut, psPAX2 (lentiviral packaging plasmid), a barcoded lentiviral genome containing a predefined NNNNNNNNNNNNNNNNNNNN barcode in addition to pCMV-EGFP-P2A-PuroR. FIG. 13B shows an illustration of an exemplary assay used to validate the ability of targets identified from the lentiviral screen to delivery eVEPs to target cells.

[0041] FIG. 14A shows the sequence of exemplary construct pJAQ218 identified during the lentiviral screen. Two barcodes are assigned to each targeting ligand or combination of ligands involved in the screen. FIG. 14B shows the results from an exemplary lentiviral screen using CD34+ cells. The reads assigned to each barcode are plotted in a scatterplotwith the hits defined in the upper right quadrant. The soundness of the screen can be ascertained from both the separation of the positive and negative controls (VSV-G and VSV- Gmut here) and the correlation between degenerate barcodes (distinct barcode sequences corresponding to the same targeting ligand). gDNA reads per targeting construct plotted in a scatterplot with the hits defined in the upper right quadrant. .FIGs. 14C and 14D show a plot of the reads assigned to each barcode normalized to the cDNA and gDNA, respectively. FIG. 14D shows a plot of the reads assigned to each barcode normalized to the ratio of the gDNA / cDNA. The color of the dot represents the sum of the cDNA reads between the two barcodes assigned to a single construct. This gives information on production titer achievable for a given construct.

[0042] FIG. 15 shows the results from an exemplary validation study performed using Base-editing eVLPs bearing one or more exemplary candidate targeting proteins identified using the lentiviral screen shown in FIG. 13. BE-eVLPs were screened for their ability to induce an A«T to G*C base edit in the BCL11A gene in CD34+ cells in vitro.

[0043] FIG. 16 shows the results from an exemplary validation study performed using Prime editing eVLPs (PE-eVLPs) bearing pJAQ218, which is a targeting protein identified using the lentiviral screen shown in FIG. 13. eVLP constructs used the V3 and V3b prime editor architectures. PE-eVLPs were screened for their ability to recode a 5bp substitution in the HEK gene in CD34+ cells.

[0044] FIG. 17 shows an exemplary eVLP construct comprising (i) a first fusion protein comprising a first targeting domain, a stalk domain, and a transmembrane domain, (ii) a second fusion protein comprising a second targeting domain, a stalk domain, and a transmembrane domain, and (iii) a mutated Cocal envelope glycoprotein domain. The first targeting domain is different than the second targeting domain.

[0045] FIG.18A shows a scatter plot of the reads assigned to each barcode plotted with the hits defined in the upper right quadrant. The screen was performed using lentiviruses comprisng a mutant cocal glycoenvelope protein. FIG. 18B shows a plot of the reads, normalized to the cDNA, for the data provided in FIG. 18 A.

[0046] FIGs. 19A and 19B shows the results from another exemplary lentiviral screen testing a different array of targeting proteins and VSV-Gmut against CD34+ cells. FIG. 19A shows the reads assigned to each barcode from gDNA; whereas FIG. 19B shows the reads assigned to each barcode from gDNA normalized to the cDNA.DEFINITIONS

[0047] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them unless specified otherwise.Base editors

[0048] The term “base editor (BE)” refers to an agent comprising a polypeptide that is capable of making a modification to a base (e.g., A, T, C, G, or U) within a nucleic acid sequence (e.g., DNA or RNA) that converts one base to another (e.g., A to G, A to C, A to T, C to T, C to G, C to A, G to A, G to C, G to T, T to A, T to C, or T to G). In some embodiments, the base editor is capable of deaminating a base within a nucleic acid such as a base within a DNA molecule. In the case of an adenosine base editor, the base editor is capable of deaminating an adenine (A) in DNA. Such base editors may include a nucleic acid programmable DNA binding protein (napDNAbp) fused to an adenosine deaminase. Some base editors include CRISPR-mediated fusion proteins that are utilized in the base editing methods described herein. In some embodiments, the base editor comprises a nucleaseinactive Cas9 (dCas9) fused to a deaminase which binds a nucleic acid in a guide RNA- programmed manner via the formation of an R-loop, but does not cleave the nucleic acid. For example, the dCas9 domain of the fusion protein may include a D10A and a H840A mutations described in PCT / US2016 / 058344, which published as WO 2017 / 070632 on April 27, 2017, and is incorporated herein by reference. The DNA cleavage domain of S. pyogenes Cas9 includes two subdomains, the HNH nuclease subdomain and the RuvCl subdomain. The HNH subdomain cleaves the strand complementary to the gRNA (the “targeted strand,” or the strand in which editing or deamination occurs), whereas the RuvCl subdomain cleaves the non-complementary strand containing the PAM sequence (the “non-edited strand”). The RuvCl mutant D10A generates a nick in the targeted strand, while the HNH mutant H840A generates a nick on the non-edited strand (see Jinek et al., Science, 337:816-821(2012); Qi et al., Cell. 28; 152(5): 1173-83 (2013)). In some embodiments, a base editor comprises a Cas9 nickase (nCas9) that comprises only one of the D10A or the H840A mutations.

[0049] In some embodiments, a base editor is a macromolecule or macromolecular complex that results primarily (e.g., more than 80%, more than 85%, more than 90%, more than 95%, more than 99%, more than 99.9%, or 100%) in the conversion of a base in a polynucleotide sequence into another base (i.e., a transition or transversion) using a combination of 1) a nucleotide-, nucleoside-, or base-modifying enzyme and 2) a nucleic acid binding protein that can be programmed to bind to a specific nucleic acid sequence.

[0050] In some embodiments, the base editor comprises a DNA binding domain (e.g., a programmable DNA binding domain, such as a dCas9 or nCas9) that directs it to a target sequence. In some embodiments, the base editor comprises a base modification domain fused to a programmable DNA binding domain (e.g., dCas9 or nCas9). The terms “base modifying enzyme” and “base modification domain,” which are used interchangeably herein, refer to an enzyme that can modify a base and convert one base to another (e.g., a deaminase, such as a cytidine deaminase or an adenosine deaminase). The base modifying enzyme of the base editor may target cytosine (C) bases in a nucleic acid sequence and convert the C to a thymine (T) base. In some embodiments, C to T editing is carried out by a deaminase, e.g., a cytidine deaminase. In some embodiments, A to G editing is carried out by a deaminase, e.g., an adenosine deaminase. Base editors that can carry out other types of base conversions (e.g., C to G) are also contemplated.

[0051] In some embodiments, a base editor converts a C to a T. In some embodiments, the base editor comprises a cytosine deaminase. A “cytosine deaminase”, or “cytidine deaminase,” refers to an enzyme that catalyzes the chemical reaction “cytosine + H2Ouracil + NH3” or “5-methyl-cytosine + H2Othymine + NH3.” As may be apparent from the reaction formula, such chemical reactions result in a C to U / T base change. In the context of a gene, such a nucleotide change, or mutation, may in turn lead to an amino acid change in the protein, which may affect the protein’s function, e.g., loss-of-function or gain-of-function. In some embodiments, the C to T base editor comprises a dCas9 or nCas9 fused to a cytidine deaminase. In some embodiments, the cytidine deaminase domain is fused to the N-terminus of the dCas9 or nCas9. In some embodiments, the base editor further comprises a domain that inhibits uracil glycosylase, and / or a nuclear localization signal. Such base editors have been described in the art, e.g., in Rees & Liu, Nat. Rev. Genet. 2018;19(12):770-788 and Koblan et al., Nat. Biotechnol. 2018;36(9):843-846; as well as U.S. Patent Publication No.2018 / 0073012, U.S. Patent Publication No. 2017 / 0121693, PCT Publication No. WO 2017 / 070633, U.S. Patent Publication No. 2015 / 0166980, U.S. Patent No. 9,840,699, U.S.Patent No. 10,077,453, PCT Publication No. WO 2019 / 023680, PCT Publication No. WO 2018 / 0176009, PCT Application No PCT / US2019 / 033848, PCT Application No.PCT / US2019 / 47996, PCT Application No. PCT / US2019 / 049793, PCT Application No. PCT / US2020 / 028568, PCT Application No. PCT / US2019 / 61685, PCT Application No. PCT / US2019 / 57956, and PCT Application No. PCT / US2019 / 58678, each of which is incorporated herein by reference.

[0052] In some embodiments, a base editor converts an A to a G. In some embodiments, the base editor comprises an adenosine deaminase. An “adenosine deaminase” is an enzyme involved in purine metabolism. An adenosine deaminase catalyzes hydrolytic deamination of adenosine (forming inosine, which base pairs as G) in the context of DNA. There are no known natural adenosine deaminases that act on DNA. Instead, known adenosine deaminase enzymes only act on RNA (tRNA or mRNA). Evolved deoxyadenosine deaminase enzymes that accept DNA substrates and deaminate dA to deoxyinosine have been described, e.g., in PCT Application PCT / US2017 / 045381, filed August 3, 2017, which published as WO 2018 / 027078, PCT Application No. PCT / US2019 / 033848, which published as WO 2019 / 226953, PCT Application No PCT / US2019 / 033848, filed May 23, 2019, and PCT Patent Application No. PCT / US2020 / 028568, filed April 17, 2020; each of which is incorporated herein by reference.

[0053] Exemplary adenosine and cytidine base editors are also described in Rees & Liu, Base editing: precision chemistry on the genome and transcriptome of living cells, Nat. Rev. Genet. 2018;19(12):770-788; as well as U.S. Patent Publication No. 2018 / 0073012, U.S. Patent Publication No. 2017 / 0121693, PCT Publication No. WO 2017 / 070633, U.S. Patent Publication No. 2015 / 0166980, U.S. Patent No. 9,840,699, and U.S. Patent No. 10,077,453, each of which is incorporated herein by reference.Cas9

[0054] The term “Cas9” or “Cas9 nuclease” refers to an RNA-guided nuclease comprising a Cas9 domain, or a fragment thereof (e.g., a protein comprising an active or inactive DNA cleavage domain of Cas9, and / or the gRNA binding domain of Cas9). A “Cas9 domain,” as used herein, is a protein fragment comprising an active or inactive cleavage domain of Cas9 and / or the gRNA binding domain of Cas9. A “Cas9 protein” is a full length Cas9 protein. A Cas9 nuclease is also referred to sometimes as a casnl nuclease or a CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat)-associated nuclease. CRISPR is an adaptive immune system that provides protection against mobile genetic elements (viruses,transposable elements, and conjugative plasmids). CRISPR clusters contain spacers, sequences complementary to antecedent mobile elements, and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA). In type II CRISPR systems, correct processing of pre-crRNA requires a trans-encoded small RNA (tracrRNA), endogenous ribonuclease 3 (me), and a Cas9 domain. The tracrRNA serves as a guide for ribonuclease 3-aided processing of pre-crRNA. Subsequently, Cas9 / crRNA / tracrRNA endo-nucleolytically cleaves a linear or circular dsDNA target complementary to the spacer. The target strand not complementary to crRNA is first cut endonucleolytically, then trimmed 3'-5' exonucleolytically. In nature, DNA-binding and cleavage typically requires protein and both RNAs. However, single guide RNAs (“sgRNA”, or simply “gRNA”) can be engineered so as to incorporate aspects of both the crRNA and tracrRNA into a single RNA species. See, e.g., Jinek M., Chylinski K., Fonfara I., Hauer M., Doudna J.A., Charpentier E. Science 337:816-821(2012), which is incorporated herein by reference. Cas9 recognizes a short motif in the CRISPR repeat sequences (the PAM or protospacer adjacent motif) to help distinguish self versus non-self. Cas9 nuclease sequences and structures are well known to those of skill in the art (see, e.g., “Complete genome sequence of an Ml strain of Streptococcus pyogenes.” Ferretti et al., J.J., McShan W.M., Ajdic D.J., Savic D.J., Savic G., Lyon K., Primeaux C., Sezate S., Suvorov A.N., Kenton S., Lai H.S., Lin S.P., Qian Y., Jia H.G., Najar E.Z., Ren Q., Zhu H., Song L., White J., Yuan X., Clifton S.W., Roe B.A., McLaughlin R.E., Proc. Natl. Acad. Sci. U.S.A. 98:4658- 4663(2001); “CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III.” Deltcheva E., Chylinski K., Sharma C.M., Gonzales K., Chao Y., Pirzada Z.A., Eckert M.R., Vogel J., Charpentier E., Nature 471:602-607(2011); and “A programmable dual- RNA-guided DNA endonuclease in adaptive bacterial immunity.” Jinek M., Chylinski K., Fonfara I., Hauer M., Doudna J.A., Charpentier E. Science 337:816-821(2012), each of which is incorporated herein by reference). Cas9 orthologs have been described in various species, including, but not limited to, S. pyogenes and 5. thermophilus. Additional suitable Cas9 nucleases and sequences will be apparent to those of skill in the art based on this disclosure, and such Cas9 nucleases and sequences include Cas9 sequences from the organisms and loci disclosed in Chylinski, Rhun, and Charpentier, “The tracrRNA and Cas9 families of type II CRISPR-Cas immunity systems” (2013) RNA Biology 10:5, 726-737; which is incorporated herein by reference. In some embodiments, a Cas9 nuclease comprises one or more mutations that partially impair or inactivate the DNA cleavage domain.

[0055] A nuclease-inactivated Cas9 domain may interchangeably be referred to as a “dCas9” protein (for nuclease-“dead” Cas9). Methods for generating a Cas9 domain (or a fragment thereof) having an inactive DNA cleavage domain are known (see, e.g., Jinek et al., Science. 337:816-821(2012); Qi et al., “Repurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene Expression” (2013) Cell. 28; 152(5): 1173-83, the entire contents of each of which are incorporated herein by reference). For example, the DNA cleavage domain of Cas9 is known to include two subdomains, the HNH nuclease subdomain and the RuvCl subdomain. The HNH subdomain cleaves the strand complementary to the gRNA, whereas the RuvCl subdomain cleaves the non-complementary strand. Mutations within these subdomains can silence the nuclease activity of Cas9. For example, the mutations D10A and H840A completely inactivate the nuclease activity of S. pyogenes Cas9 (Jinek et al., Science. 337:816-821(2012); Qi et al., Cell. 28; 152(5): 1173-83 (2013)). In some embodiments, proteins comprising Cas9 or fragments thereof are referred to as “Cas9 variants.” A Cas9 variant shares homology to Cas9, or a fragment thereof. For example, a Cas9 variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, at least about 99.8% identical, at least about 99.9% or 100% identical to a wild type Cas9. In some embodiments, the Cas9 variant may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more amino acid changes compared to wild type Cas9. Fusion protein

[0056] The term “fusion protein,” as used herein, refers to a hybrid polypeptide that comprises protein domains from at least two different proteins. One protein may be located at the amino-terminal (N-terminal) portion of the fusion protein or at the carboxy-terminal (C- terminal) protein thus forming an “amino-terminal fusion protein” or a “carboxy-terminal fusion protein,” respectively. A protein may comprise different domains, for example, a nucleic acid binding domain (e.g., the gRNA binding domain of Cas9 that directs the binding of the protein to a target site) and a nucleic acid cleavage domain or a catalytic domain of a nucleic-acid editing protein. Other examples include fusion of a Cas9 or equivalent thereof to a deaminase (as in a base editor) or to a polymerase, such as a reverse transcriptase (as in a prime editor). Any of the fusion proteins provided herein may be produced by any method known in the art. For example, the fusion proteins provided herein may be produced viarecombinant protein expression and purification, which is especially suited for fusion proteins comprising a peptide linker. Methods for recombinant protein expression and purification are well known, and include those described by Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)), which is incorporated herein by reference.Group- specific antigen (gag)

[0057] Without being limited by theory, and in the context of typical envelope virus lifecycle, Gag is the primary structural protein responsible for orchestrating the majority of steps in viral assembly, including budding out of fully-formed enveloped virions having an (i) envelope (comprising a lipid membrane formed from cell membrane during budding out, and one or more glycoproteins inserted therein), and (ii) a capsid, which is the internal protein shell. Most of these assembly steps occur via interactions with three Gag subdomains - matrix (MA), capsid (CA), and nucleocapsid. These three regions have a low level of sequence conservation among the different retroviral genera, which belies the observed high level of structural conservation. Outside of these three domains, Gag proteins can vary widely. For example, HIV-1 Gag additionally codes for a C-terminal p6 protein as well as two spacer proteins, SP1 and SP2, which demarcate the CA-NC and NC-p6 junctions, but HTLV-1 contains no additional sequences outside of MA, CA, and NC (Oroszlan and Copeland, 1985; Henderson et al., 1992).

[0058] Gag is also referred to as a “viral structural protein.” As used herein, the term “viral structural protein” refers to viral proteins that contribute to the overall structure of the capsid protein or of the protein core of a virus. The term “viral structural protein” further includes functional fragments or derivatives of such viral protein contributing to the structure of a capsid protein or of the protein core of a virus. An example of viral structural protein is MMLV Gag. The viral membrane fusion proteins are not considered as viral structural proteins. Typically, said viral structural proteins are localized inside the core of the virus.

[0059] In some embodiments, the gag protein used in the eVLPs described herein (including the viral nucleocapsid portion) comprises the sequence of SEQ ID NO: 405, or a sequence at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the sequence of SEQ ID NO: 405:

[0060] MGQTVTTPLSLTLGHWKDVERIAHNQSVDVKKRRWVTFCSAEWPTFNV GWPRDGTFNRDLITQVKIKVFSPGPHGHPDQVPYIVTWEALAFDPPPWVKPFVHPKPPPPLPPSAPSLPLEPPRSTPPRSSLYPALTPSLGAKPKPQVLSDSGGPLIDLLTEDPPPYR DPRPPPSDRDGNGGEATPAGEAPDPSPMASRLRGRREPPVADSTTSQAFPLRAGGNG QLQYWPFSSSDLYNWKNNNPSFSEDPGKLTALIESVLITHQPTWDDCQQLLGTLLTG EEKQRVEEEARKAVRGDDGRPTQEPNEVDAAFPEERPDWDYTTQAGRNHEVHYRQ EEEAGEQNAGRSPTNEAKVKGITQGPNESPSAFEEREKEAYRRYTPYDPEDPGQETN VSMSFIWQSAPDIGRKEEREEDEKNKTEGDEVREAEKIFNKRETPEEREERIRRETEE KEERRRTEDEQKEKERDRRRHREMSKEEATVVSGQKQDRQGGERRRSQEDRDQCA YCKEKGHWAKDCPKKPRGPRGPRPQTSEETEDD (SEQ ID NO: 405)Group- specific antigen (gag) nuclcocapsid protein

[0061] The term “group -specific antigen nuclcocapsid protein” or “gag nuclcocapsid protein” refers to a protein that makes up the core structural component of the inner shell of many viruses, including retroviruses. The gag nuclcocapsid proteins used in the VEPs of the present disclosure may be an MMLV gag nuclcocapsid protein, an FMLV gag nuclcocapsid protein, or a nuclcocapsid protein from any other virus that produces such proteins.Group- specific antigen (gag) protease (pro) polyprotein

[0062] A “group-specific antigen (gag) protease (pro) polyprotein” or “gag-pro polyprotein” refers to a gag nuclcocapsid protein further comprising a viral protease linked thereto. Gag -pro polyproteins mediate proteolytic cleavage of gag and gag-pol polyproteins or nuclcocapsid proteins during or shortly after the release of a virion from the plasma membrane. In the VLPs described herein, the protease of a gag-pro polyprotein is responsible for cleaving a cleavable linker in the fusion protein to release a cargo protein (such as a base editor or prime editor) following delivery of the VLP to a target cell. In some embodiments, a gag-pro polyprotein is an MMLV gag-pro polyprotein or an FMLV gag-pro polyprotein.Guide RNA (“gRNA”)

[0063] As used herein, the term “guide RNA” is a particular type of guide nucleic acid which is mostly commonly associated with a Cas protein of a CRISPR-Cas9 and which associates with Cas9, directing the Cas9 protein to a specific sequence in a DNA molecule that includes complementarity to the protospacer sequence of the guide RNA. However, this term also embraces the equivalent guide nucleic acid molecules that associate with Cas9 equivalents, homologs, orthologs, or paralogs, whether naturally occurring or non-naturally occurring (e.g., engineered or recombinant), and which otherwise program the Cas9 equivalent to localize to a specific target nucleotide sequence. The Cas9 equivalents mayinclude other napDNAbp from any type of CRISPR system (e.g., type II, V, VI), including Cpfl (a type-V CRISPR-Cas system), C2cl (a type V CRISPR-Cas system), C2c2 (a type VI CRISPR-Cas system), and C2c3 (a type V CRISPR-Cas system). Further Cas-equivalents are described in Makarova et al., “C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector,” Science 2016; 353(6299), which is incorporated herein by reference.

[0064] A guide RNA is a particular type of guide nucleic acid that is most commonly associated with a Cas protein of a CRISPR-Cas9 and which associates with Cas9, directing the Cas9 protein to a specific sequence in a DNA molecule that includes complementarity to the protospacer sequence for the guide RNA. Functionally, guide RNAs associate with Cas9, directing (or programming) the Cas9 protein to a specific sequence in a DNA molecule that includes a sequence complementary to the protospacer sequence for the guide RNA. A gRNA is a component of the CRISPR / Cas system. Typically, a guide RNA comprises a fusion of a CRISPR-targeting RNA (crRNA) and a trans-activation crRNA (tracrRNA), providing both targeting specificity and scaffolding / binding ability for Cas9 nuclease. A “crRNA” is a bacterial RNA that confers target specificity and requires tracrRNA to bind to Cas9. A “tracrRNA” is a bacterial RNA that links the crRNA to the Cas9 nuclease and typically can bind any crRNA. The sequence specificity of a Cas DNA-binding protein is determined by gRNAs, which have nucleotide base-pairing complementarity to target DNA sequences. The native gRNA comprises a 20 nucleotide (nt) Specificity Determining Sequence (SDS), or spacer, which specifies the DNA sequence to be targeted, and is immediately followed by an 80 nt scaffold sequence, which associates the gRNA with Cas9. In some embodiments, the 80nt scaffold sequence comprises any one of the following sequences:

[0065] Sp Flipped:GTTTAAGAGCTAGAAATAGCAAGTTAAAATAAGGCTAGTCCGTTATCAACTTGA AAAAGTGGCACCGAGTCGGTGC (SEQ ID NO: 388)

[0066] Sp Extended:GTTTTAGAGCTATGCTGGAAACAGCATAGCAAGTTTAAATAAGGCTAGTCCGTTA TCAACTTGAAAAAGTGGCACCGAGTCGGTGC (SEQ ID NO: 389)

[0067] Sp F&E:GTTTAAGAGCTATGCTGGAAACAGCATAGCAAGTTTAAATAAGGCTAGTCCGTTA TCAACTTGAAAAAGTGGCACCGAGTCGGTGC (SEQ ID NO: 390)

[0068] Sauri 76:GTTTTAGTACTCTGGAAACAGAATCTACTAAAACAAGGCAAAATGCCGTGTTTAT CTCGTCAACTTGTTGGCGAGA (SEQ ID NO: 391)

[0069] Sauri 84:GTTTTAGTACTCTGTAATGAAAATTACAGAATCTACTAAAACAAGGCAAAATGCC GTGTTTATCTCGTCAACTTGTTGGCGAGA (SEQ ID NO: 392)

[0070] eNme2 121: GTTGTAGCTCCCTTTCTCATTTCGGAAACGAAATGAGAACCGTTGCTACAATAAG GCCGTCTGAAAAGATGTGCCGCAACGCTCTGCCCCTTAAAGCTTCTGCTTTAAGG GGCATCGTTTA (SEQ ID NO: 393)

[0071] eNme279: GTTGTAGCTCCCGAAACGTTGCTACAATAAGGCCGTCTGAAAAGACGTGCCGCA ACGCTCTGCCTTCTGGCATCGTTTA (SEQ ID NO: 394)

[0072] In some embodiments, the 80 nt scaffold sequence comprises a nucleic acid sequence that is at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5%, at least 99.8%, or 100% identical to any one of the nucleic acid sequences of SEQ ID NO:s: 388-394.

[0073] In some embodiments, an SDS spacer of the present disclosure has a length of 15 to 100 nucleotides, or more. For example, an SDS spacer may have a length of 15 to 90, 15 to 85, 15 to 80, 15 to 75, 15 to 70, 15 to 65, 15 to 60, 15 to 55, 15 to 50, 15 to 45, 15 to 40, 15 to 35, 15 to 30, or 15 to 20 nucleotides. In some embodiments, the SDS is 20 nucleotides long. For example, the SDS may be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides long.At least a portion of the target DNA sequence is complementary to the SDS of the gRNA. For Cas9 to successfully bind to the DNA target sequence, a region of the target sequence is complementary to the SDS of the gRNA sequence and is immediately followed by the correct protospacer adjacent motif (PAM) sequence (e.g., NGG for Cas9 and TTN, TTTN, or YTN for Cpfl). In some embodiments, an SDS is 100% complementary to its target sequence. In some embodiments, the SDS sequence is less than 100% complementary to its target sequence and is, thus, considered to be partially complementary to its target sequence. For example, a targeting sequence may be 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% complementary to its target sequence. In some embodiments, the SDS of template DNA or target DNA may differ from a complementary region of a gRNA by 1, 2, 3, 4, or 5 nucleotides.

[0074] In some embodiments, the guide RNA is about 15-120 nucleotides long and comprises a sequence of at least 10 contiguous nucleotides that is complementary to a target sequence. In some embodiments, the guide RNA is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120 nucleotides long. In some embodiments, the guide RNA comprises a sequence of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more contiguous nucleotides that is complementary to a target sequence. Sequence complementarity refers to distinct interactions between adenine and thymine (DNA) or uracil (RNA), and between guanine and cytosine.

[0075] As used herein, the terms “prime editing guide RNA” or “PEgRNA” or “extended guide RNA” refer to a specialized form of a guide RNA that has been modified to include one or more additional sequences for implementing the prime editing methods and compositions described herein. As described herein, the prime editing guide RNAs comprise one or more “extended regions” of nucleic acid sequence. The extended regions may comprise, but are not limited to, single- stranded RNA or DNA. Further, the extended regions may occur at the 3' end of a traditional guide RNA. In other arrangements, the extended regions may occur at the 5' end of a traditional guide RNA. In still other arrangements, the extended region may occur at an intramolecular region of the traditional guide RNA, for example, in the gRNA core region which associates and / or binds to the napDNAbp. The extended region comprises a “DNA synthesis template” which encodes (by the polymerase of the prime editor) a single- stranded DNA which, in turn, has been designed to be (a) homologous with the endogenous target DNA to be edited, and (b) which comprises at least one desired nucleotide change (e.g., a transition, a transversion, a deletion, or an insertion) to be introduced or integrated into the endogenous target DNA. The extended region may also comprise other functional sequence elements, such as, but not limited to, a “primer binding site” and a “spacer or linker” sequence, or other structural elements, such as, but not limited to, aptamers, stem loops, hairpins, toe loops (e.g., a 3' toeloop), or an RNA-protein recruitment domain (e.g., MS2 hairpin). As used herein, the “primer binding site” comprises a sequence that hybridizes to a single-strand DNA sequence having a 3 end generated from the nicked DNA of the R-loop.

[0076] In certain embodiments, the PEgRNAs have a 5' extension arm, a spacer, and a gRNA core. The 5' extension further comprises in the 5' to 3' direction a reverse transcriptase template, a primer binding site, and a linker. The reverse transcriptase template may also be referred to more broadly as the “DNA synthesis template” where the polymerase of a prime editor described herein is not an RT, but another type of polymerase.

[0077] In certain other embodiments, the PEgRNAs have a 5' extension arm, a spacer, and a gRNA core. The 5' extension further comprises in the 5' to 3' direction a reverse transcriptase template, a primer binding site, and a linker. The reverse transcriptase template may also be referred to more broadly as the “DNA synthesis template” where the polymerase of a prime editor described herein is not an RT, but another type of polymerase.

[0078] In still other embodiments, the PEgRNAs have in the 5' to 3' direction a spacer (1), a gRNA core (2), and an extension arm (3). The extension arm (3) is at the 3' end of the PEgRNA. The extension arm (3) further comprises in the 5' to 3' direction a “primer binding site” (A), an “edit template” (B), and a “homology arm” (C). The extension arm (3) may also comprise an optional modifier region at the 3' and 5' ends, which may be the same sequences or different sequences. In addition, the 3' end of the PEgRNA may comprise a transcriptional terminator sequence. These sequence elements of the PEgRNAs are further described and defined herein.

[0079] In still other embodiments, the PEgRNAs have in the 5' to 3' direction an extension arm (3), a spacer (1), and a gRNA core (2). The extension arm (3) is at the 5' end of the PEgRNA. The extension arm (3) further comprises in the 3' to 5' direction a “primer binding site” (A), an “edit template” (B), and a “homology arm” (C). The extension arm (3) may also comprise an optional modifier region at the 3' and 5' ends, which may be the same sequences or different sequences. The PEgRNAs may also comprise a transcriptional terminator sequence at the 3' end. These sequence elements of the PEgRNAs are further described and defined herein.Linkers

[0080] The term “linker,” as used herein, refers to a molecule linking two other molecules or moieties. The linker can be an amino acid sequence in the case of a linker joining two fusion proteins. For example, a Cas9 can be fused to a deaminase (e.g., an adenosine deaminase or a cytosine deaminase) by an amino acid linker sequence. A Cas9 can be fused to a reverse transcriptase by an amino acid linker sequence. The linker can also be a nucleotide sequence in the case of joining two nucleotide sequences together (e.g., in agRNA). In other embodiments, the linker is an organic molecule, group, polymer, or chemical moiety. In some embodiments, the linker is 5-200 amino acids in length, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 30-35, 35-40, 40-45, 45-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-150, or 150-200 amino acids in length. Longer or shorter linkers are also contemplated.

[0081] The protease cleavage site may be any known in the art, or any sequence yet to be discovered, so long as the corresponding protease may be co-packaged in the VLPs to allow for post-maturation cleavage within the mature VLP particles. Such cleavage sites and their corresponding proteases include but are not limited to: (a) granzyme A, which recognizes and cleaves a sequence comprising ASPRAGGK (SEQ ID NO: 339), (b) granzyme B, which recognizes and cleaves a sequence comprising YEADSLEE (SEQ ID NO: 340), (c) granzyme K, which recognizes and cleaves a sequence comprising YQYRAL (SEQ ID NO: 341), or (d) Cathepsin D, which recognizes and cleaves a sequence comprising LGVLIV (SEQ ID NO: 342). Many other combinations of specific proteases and protease cleavage sites may be used in connection with the present disclosure by co-packing a specific protease during the VLP manufacture process. Such proteases can include, without limitation, Arg-C proteinase, Asp- N Endopeptidase, Caspase 1, Caspase 2, Caspase 3, Caspase 4, Caspase 5, Caspase 7, Caspase 8, Caspase 9, Caspase 10, Chymotrypsin, Clostripain, Enterokinase, Factor Xa, Glutamyl endopeptidase, Granzyme B, Neutrophil elastase, Pepsin, Prolyl-endopeptidase, Proteinase K, Staphylococcal peptidase I, Thermolysin, Thrombin, and Trypsin. Any protease paired with its cognate recognition sequence may be used in the present disclosure proteasesensitive linkers, including any serine protease, cysteine protease, aspartic protease, threonine protease, glutamic protease, metalloprotease, or asparagine peptide lyase (which constitute major classifications of known proteases). The specific protease cleavage sites for said enzymes are well-known in the art and may be utilized in the linkers herein to provide protease-susceptible linkers. napDNAbp

[0082] As used herein, the term “nucleic acid programmable DNA binding protein” or “napDNAbp,” of which Cas9 is an example, refers to a protein that uses RNA:DNA hybridization to target and bind to specific sequences in a DNA molecule. Each napDNAbp is associated with at least one guide nucleic acid (e.g., guide RNA), which localizes the napDNAbp to a DNA sequence that comprises a DNA strand (i.e., a target strand) that is complementary to the guide nucleic acid, or a portion thereof (e.g., the protospacer of a guideRNA). In other words, the guide nucleic-acid “programs” the napDNAbp (e.g., Cas9 or equivalent) to localize and bind to a complementary sequence.

[0083] Without being bound by theory, the binding mechanism of a napDNAbp - guide RNA complex, in general, includes the step of forming an R-loop whereby the napDNAbp induces the unwinding of a double-strand DNA target, thereby separating the strands in the region bound by the napDNAbp. The guide RNA protospacer then hybridizes to the “target strand.” This displaces a “non-target strand” that is complementary to the target strand, which forms the single strand region of the R-loop. In some embodiments, the napDNAbp includes one or more nuclease activities, which then cut the DNA, leaving various types of lesions.For example, the napDNAbp may comprise a nuclease activity that cuts the non-target strand at a first location, and / or cuts the target strand at a second location. Depending on the nuclease activity, the target DNA can be cut to form a “double- stranded break” whereby both strands are cut. In other embodiments, the target DNA can be cut at only a single site, i.e., the DNA is “nicked” on one strand. Exemplary napDNAbp with different nuclease activities include “Cas9 nickase” (“nCas9”) and a deactivated Cas9 having no nuclease activities (“dead Cas9” or “dCas9”). Exemplary sequences for these and other napDNAbp are provided herein.Nuclear export sequence (NES)

[0084] The term “nuclear export sequence” or “NES” refers to an amino acid sequence that promotes transport of a protein out of the cell nucleus to the cytoplasm, for example, through the nuclear pore complex by nuclear transport. Nuclear export sequences are known in the art and would be apparent to the skilled artisan. For example, NES sequences are described in Xu, D. et al. Sequence and structural analyses of nuclear export signals in the NESdb database. Mol Biol. Cell. 2012, 23(18) 3677-3693, the contents of which are incorporated herein by reference. Exemplary NES include, but are not limited to, the following:

[0085] MEELSQALASSFSV SEQ ID NO: 406

[0086] PLQLPPLERLTL SEQ ID NO: 407

[0087] NELALKLAGLDI SEQ ID NO: 408

[0088] ERFEMFRELNEALEL SEQ ID NO: 409

[0089] DHAEKVAEKLEALSV SEQ ID NO: 410

[0090] QLVEELLKIICAFQL SEQ ID NO: 411

[0091] TNLEALQKKLEELEL SEQ ID NO: 412

[0092] DVKEEMTSALATMRV SEQ ID NO: 413

[0093] STNGSLAAEFRHLQL SEQ ID NO: 414

[0094] PSVQELTEQIHRLLM SEQ ID NO: 415

[0095] MNFKELKDFLKELNI SEQ ID NO: 416

[0096] ENFEILMKLKESLEL SEQ ID NO: 417

[0097] FETVYELTKMCTIR SEQ ID NO: 418

[0098] SGKASSSLGLQDFDL SEQ ID NO: 419

[0099] PKYSDIDVDGLCSEL SEQ ID NO: 420

[0100] VDLACTPTDVRDVDI SEQ ID NO: 893

[0101] YGEKTTQRDLTELEI SEQ ID NO: 421

[0102] RRIYDITNVLEGIGL SEQ ID NO: 422

[0103] AKIIPYSGLLLVITV SEQ ID NO: 423

[0104] LRSEEVHWLHVDMGV SEQ ID NO: 424

[0105] LQSEEVHWLHLDMGV SEQ ID NO: 425

[0106] LQVRKYSLDLASLIL SEQ ID NO: 426

[0107] AGVEAIIRILQQLLF SEQ ID NO: 427

[0108] TGVEALIRILQQLLF SEQ ID NO: 428

[0109] IVLNQLCVRFFGLDL SEQ ID NO: 429

[0110] SLGGFEITPPVVLRL SEQ ID NO: 430

[0111] EAIQDLCLAVEEVSL SEQ ID NO: 431

[0112] DELLQVLRMMVGVNI SEQ ID NO: 432

[0113] SVMLAVQEGIDLLTF SEQ ID NO: 433

[0114] LSSHFQELSI SEQ ID NO: 434

[0115] QSTHVDIRTLEDLLM SEQ ID NO: 435

[0116] ESSAEDLRTLQQLFL SEQ ID NO: 436

[0117] EFSLPTHHTVRLIRV SEQ ID NO: 437

[0118] MSSGYYLGEILRLAL SEQ ID NO: 438

[0119] DTVLDILRDFFELRL SEQ ID NO: 439

[0120] NSVNEILSEFYYVRL SEQ ID NO: 440

[0121] CAFLSVKKQFEELTL SEQ ID NO: 441

[0122] ISPEHVIQALESLGF SEQ ID NO: 442

[0123] AHWMRQLVSFQKLKL SEQ ID NO: 443

[0124] ATRELDELMASLSDF SEQ ID NO: 444

[0125] YQNIELITFINALKL SEQ ID NO: 445

[0126] FNATAVVRHMRKLQL SEQ ID NO: 446

[0127] SGIFGLVTNLEELEV SEQ ID NO: 447

[0128] EESYTLNSDLARLGV SEQ ID NO: 448

[0129] EESYDLTSHLARLGV SEQ ID NO: 449

[0130] GIQQAHAEQLANMRI SEQ ID NO: 450

[0131] DVKEEMTSALATMRV SEQ ID NO: 451

[0132] AAEPVILDLRDLFQL SEQ ID NO: 452

[0133] MEGCVSNLMV SEQ ID NO: 453

[0134] EGCVSNLMV SEQ ID NO: 454

[0135] DMDFLRNLFSQTLSL SEQ ID NO: 455

[0136] EQLLEIVHDLENLSL SEQ ID NO: 456

[0137] NVMKYFTDLFDYLPL SEQ ID NO: 457

[0138] KVYPIILRLGSNLSL SEQ ID NO: 458

[0139] YAGFSLPHAILRIDL SEQ ID NO: 459

[0140] EIVRDIKEKLCYVAL SEQ ID NO: 460

[0141] EAINKLESNLRELQI SEQ ID NO: 461

[0142] EAINKLENNLRELQI SEQ ID NO: 462

[0143] SDQKQEQLLLKKMYL SEQ ID NO: 463

[0144] KQVLWDRTFSLFQQL SEQ ID NO: 464

[0145] AQLQNLTKRIDSLPL SEQ ID NO: 465

[0146] NDENEHQLSLRTVSL SEQ ID NO: 466

[0147] ISFTEFVKVLEKVDV SEQ ID NO: 467

[0148] MESAITLWQFLLQL SEQ ID NO: 468

[0149] VPKELMQQIENFEKI SEQ ID NO: 469

[0150] QARFILEKIDGKIII SEQ ID NO: 470

[0151] QVKFIKMIIEKELTV SEQ ID NO: 471

[0152] NHRMKNLREISQLGI SEQ ID NO: 472

[0153] NHRVKKLNEISKLGI SEQ ID NO: 473

[0154] TEKHLQKYLRQDLRL SEQ ID NO: 474

[0155] RQERKRPLLDLHIEL SEQ ID NO: 475

[0156] ANMRIQDLKVSLKPL SEQ ID NO: 476

[0157] ATMRVDYEQIKIKKI SEQ ID NO: 477

[0158] LQGEEFVCLKSIILL SEQ ID NO: 478

[0159] THYGQKAILFLPLPV SEQ ID NO: 479

[0160] PSAHEITGLADSLQL SEQ ID NO: 480

[0161] VRLHDVLHSDKKLTL SEQ ID NO: 481

[0162] LINRNGELKLANFGL SEQ ID NO: 482

[0163] LEPLKKLECLKSLDL SEQ ID NO: 483

[0164] The NES examples above are not limiting. The fusion proteins delivered by the presently described VLPs may comprise any known NES sequence, including any of those described in Xu, D. et al. Sequence and structural analyses of nuclear export signals in the NESdb database. Mol. Biol. Cell. 2012, 23(18), 3677-3693; Fung, H. Y. J. et al. Structural determinants of nuclear export signal orientation in binding to exportin CRM1. eLife. 2015, 4:el0034; and Kosugi, S. et al. Nuclear Export Signal Consensus Sequences Defined Using a Localization-based Yeast Selection System. Traffic. 2008, 9(12), 2053-2062, each of which are incorporated herein by reference.

[0165] In various embodiments, the fusion proteins, constructs encoding the fusion proteins, and VLPs disclosed herein further comprise one or more, preferably, at least three nuclear export sequences. In certain embodiments, the fusion proteins comprise at least three NESs. In embodiments with at least three NESs, the NESs can be the same NESs or they can be different NESs. In certain other embodiments, the fusion proteins, constructs encoding the fusion proteins, and VLPs may comprise at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more NESs. In general, the one or more NESs are of sufficient strength to drive accumulation of the VLP proteins (e.g., the Gag-cargo) in a detectable amount respectively in the cytoplasm of a producer cell.

[0166] The location of the NES fusion can be at the N-terminus, the C-terminus, or within a sequence of a fusion protein (e.g., inserted between the encoded napDNAbp component (e.g., Cas9) and the gag nucleocapsid protein). In certain embodiments, the NES (or multiple NESs, e.g., three NESs) are positioned between the napDNAbp and the gag nucleocapsid protein such that they can be cleaved from the napDNAbp upon delivery of the fusion protein to a target cell. NES sequences may preferably be joined to a fusion protein via a cleavable linker, such as protease-cleavable linker (e.g., the Gag-Pro-Pol). In this way, theNES may be removed from the cargo protein after VLP maturation so that the cargo may be free to translocate to the nucleus once delivered to a recipient cell.

[0167] The NESs may be any known NES sequence in the art. The NESs may also be any future-discovered NESs for nuclear export. The NESs also may be any naturally-occurring NES, or any non-naturally occurring NES (e.g., an NES with one or more desired mutations).

[0168] The term “nuclear export sequence” or “NES” refers to an amino acid sequence that promotes export of a protein from the cell nucleus, for example, by nuclear transport. Nuclear export sequences are known in the art and would be apparent to the skilled artisan.

[0169] In one aspect of the disclosure, a base editor or other fusion protein may be modified with one or more nuclear export sequences (NES), preferably at least three NESs. In certain embodiments, the fusion proteins are modified with two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more NESs. The disclosure contemplates the use of any nuclear export sequence known in the art at the time of the disclosure, or any nuclear export sequence that is identified or otherwise made available in the state of the art after the time of the instant filing. A representative nuclear export sequence is a peptide sequence that directs the protein out of the nucleus of the cell in which the sequence is expressed. NESs commonly contain hydrophobic amino acid residues in the sequence LXXXLXXLXL, where L is a hydrophobic residue (frequently leucine), and X represents any amino acid. Nuclear export sequences often comprise leucine residues.

[0170] The fusion proteins delivered by the VLPs described herein may also comprise nuclear export sequences that are linked through one or more linkers, e.g., a polymeric, amino acid, nucleic acid, polysaccharide, chemical, or nucleic acid linker element. The linkers within the contemplated scope of the disclosure are not intended to have any limitations and can be any suitable type of molecule (e.g., polymer, amino acid, polysaccharide, nucleic acid, lipid, or any synthetic chemical linker domain) and can be joined to the base editor by any suitable strategy that effectuates forming a bond (e.g., covalent linkage, hydrogen bonding) between the cargo protein and the one or more NESs. In some embodiments, the linker joining one or more NES and a cargo protein is a cleavable linker, as described further herein, such the one or more NES can be cleaved from the cargo protein, e.g., upon delivery of the cargo protein to a target cell.Nuclear localization sequence (NLS)

[0171] The term “nuclear localization sequence” or “NLS” refers to an amino acid sequence that promotes import of a protein into the cell nucleus, for example, by nuclear transport. Nuclear localization sequences are known in the art and would be apparent to the skilled artisan. For example, NLS sequences are described in Plank et al., International PCT Application, PCT / EP2000 / 011690, filed November 23, 2000, published as WO / 2001 / 038547 on May 31, 2001, the contents of which are incorporated herein by reference for its disclosure of exemplary nuclear localization sequences. In some embodiments, an NLS comprises the amino acid sequence PKKKRKV (SEQ ID NO: 484), MDSLLMNRRKFLYQFKNVRWAKGRRETYLC (SEQ ID NO: 485), KRTADGSEFESPKKKRKV (SEQ ID NO: 486), or KRTADGSEFEPKKKRKV (SEQ ID NO: 487). In other embodiments, NLS comprises the amino acid sequences NLSKRPAAIKKAGQAKKKK (SEQ ID NO: 488), PAAKRVKLD (SEQ ID NO: 489), RQRRNELKRSF (SEQ ID NO: 490), or NQSSNFGPMKGGNFGGRSSGPYGGGGQYFAKPRNQGGY (SEQ ID NO: 491).

[0172] In one aspect of the disclosure, a base editor, prime editor, or other fusion protein may be modified with one or more nuclear localization sequences (NLS), preferably at least two NLSs. In certain embodiments, the fusion proteins are modified with two or more NLSs. The disclosure contemplates the use of any nuclear localization sequence known in the art at the time of the disclosure, or any nuclear localization sequence that is identified or otherwise made available in the state of the art after the time of the instant filing. A representative nuclear localization sequence is a peptide sequence that directs the protein to the nucleus of the cell in which the sequence is expressed. A nuclear localization signal is predominantly basic, can be positioned almost anywhere in a protein’s amino acid sequence, generally comprises a short sequence of four amino acids (Autieri & Agrawal, (1998) J. Biol. Chem. 273: 14731-37, incorporated herein by reference) to eight amino acids, and is typically rich in lysine and arginine residues (Magin et al., (2000) Virology 274: 11-16, incorporated herein by reference). Nuclear localization sequences often comprise proline residues. A variety of nuclear localization sequences have been identified and have been used to effect transport of biological molecules from the cytoplasm to the nucleus of a cell. See, e.g., Tinland et al., (1992) Proc. Natl. Acad. Sci. U.S.A. 89:7442-46; Moede et al., (1999) FEBS Lett. 461:229- 34, which is incorporated herein by reference. Translocation is currently thought to involve nuclear pore proteins.

[0173] Most NLSs can be classified in three general groups: (i) a monopartite NLS exemplified by the SV40 large T antigen NLS (PKKKRKV (SEQ ID NO: 484)); (ii) a bipartite motif consisting of two basic domains separated by a variable number of spacer amino acids and exemplified by the Xenopus nucleoplasmin NLS (KRXXXXXXXXXXKKKL (SEQ ID NO: 492)); and (iii) noncanonical sequences such as M9 of the hnRNP Al protein, the influenza virus nucleoprotein NLS, and the yeast Gal4 protein NLS (Dingwall and Laskey 1991).

[0174] Nuclear localization sequences appear at various points in the amino acid sequences of proteins. NLS have been identified at the N-terminus, the C-terminus, and in the central region of proteins. Thus, the disclosure provides fusion proteins that may be modified with one or more NLSs at the C-terminus and / or the N-terminus, as well as at internal regions of the fusion protein. The residues of a longer sequence that do not function as component NLS residues should be selected so as not to interfere, for example, tonically or sterically, with the nuclear localization signal itself. Therefore, although there are no strict limits on the composition of an NLS-comprising sequence, in practice, such a sequence can be functionally limited in length and composition.

[0175] The present disclosure contemplates any suitable means by which to modify a fusion protein to include one or more NLSs. In one aspect, the fusion proteins may be engineered to express a fusion protein that is translationally fused at its N-terminus or its C- terminus (or both) to one or more NLSs, i.e., to form a base editor or prime editor-NLS fusion construct. In other embodiments, a fusion protein-encoding nucleotide sequence may be genetically modified to incorporate a reading frame that encodes one or more NLSs in an internal region of the encoded base editor or prime editor. In addition, the NLSs may include various amino acid linkers or spacer regions encoded between the base editor and the N- terminally, C-terminally, or internally-attached NLS amino acid sequence, e.g., and in the central region of proteins. Thus, the present disclosure also provides for nucleotide constructs, vectors, and host cells for expressing fusion proteins that comprise a base editor or prime editor and one or more NLSs, among other components.

[0176] The fusion proteins delivered by the VLPs described herein may also comprise nuclear localization sequences that are linked to the fusion protein through one or more linkers, e.g., a polymeric, amino acid, nucleic acid, polysaccharide, chemical, or nucleic acid linker element. The linkers within the contemplated scope of the disclosure are not intended to have any limitations and can be any suitable type of molecule (e.g., polymer, amino acid,polysaccharide, nucleic acid, lipid, or any synthetic chemical linker domain) and can be joined to the fusion protein by any suitable strategy that effectuates forming a bond (e.g., covalent linkage, hydrogen bonding) between the fusion protein and the one or more NLSs.Nucleic acid molecule

[0177] The term “nucleic acid,” as used herein, refers to a polymer of nucleotides. The polymer may include natural nucleosides (i.e., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxy cytidine), nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, C5 bromouridine, C5 fluorouridine, C5 iodouridine, C5 propynyl uridine, C5 propynyl cytidine, C5 methylcytidine, 7 deazaadenosine, 7 deazaguanosine, 8 oxoadenosine, 8 oxoguanosine, 0(6) methylguanine, 4-acetylcytidine, 5- (carboxyhydroxymethyl)uridine, dihydrouridine, methylpseudouridine, 1 -methyl adenosine, 1-methyl guanosine, N6-methyl adenosine, and 2-thiocytidine), chemically modified bases, biologically modified bases (e.g., methylated bases), intercalated bases, modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, 2'-O-methylcytidine, arabinose, and hexose), or modified phosphate groups (e.g., phosphorothioates and 5' N phosphoramidite linkages).Nucleocapsid protein

[0178] The term “nucleocapsid protein” refers to a protein that makes up the core structural component of the inner shell of many viruses, including retroviruses. A nucleocapsid protein makes up part of the gag protein. The nucleocapsid proteins used in the VLPs of the present disclosure may be an MMLV gag nucleocapsid protein, an FMLV gag nucleocapsid protein, or a nucleocapsid protein from any other virus that produces such proteins.Prime editor

[0179] The term “prime editor” refers to fusion constructs comprising a napDNAbp (e.g., Cas9 nickase) and a reverse transcriptase that are capable of carrying out prime editing on a target nucleotide sequence in the presence of a PEgRNA (or “extended guide RNA”). The term “prime editor” may refer to the fusion protein or to the fusion protein complexed with a PEgRNA, and / or further complexed with a second-strand nicking sgRNA. In some embodiments, the prime editor may also refer to the complex comprising a fusion protein (reverse transcriptase fused to a napDNAbp) and a PEgRNA.

[0180] Prime editors may be used to carry out prime editing, which is an approach for gene editing using napDNAbps, a polymerase (e.g., a reverse transcriptase), and specialized guide RNAs that include a primer binding site and a DNA synthesis template for encoding desired new genetic information (or deleting genetic information) that is then incorporated into a target DNA sequence. Prime editing is described in Anzalone, A. V. et al., Search- and- replace genome editing without double-strand breaks or donor DNA. Nature 576, 149-157 (2019), which is incorporated herein by reference. See also International PCT Application, PCT / US2020 / 023721, filed March 19, 2020, and published as WO 2020 / 191239, which is incorporated herein by reference.

[0181] Prime editing represents a platform for genome editing that is a versatile and precise method to directly write new genetic information into a specified DNA site using a nucleic acid programmable DNA binding protein (“napDNAbp”) working in association with a polymerase (i.e., in the form of a fusion protein or otherwise provided in trans with the napDNAbp), wherein the prime editing system is programmed with a prime editing (PE) guide RNA (“PEgRNA”) that both specifies the target site and templates the synthesis of the desired edit in the form of a replacement DNA strand by way of an extension (either DNA or RNA) engineered onto a guide RNA (e.g., at the 5' or 3' end, or at an internal portion of a guide RNA). The replacement strand containing the desired edit (e.g., a single nucleobase substitution) shares the same sequence as the endogenous strand (or is homologous to it) immediately downstream of the nick site of the target site to be edited (with the exception that it includes the desired edit). Through DNA repair and / or replication machinery, the endogenous strand downstream of the nick site is replaced by the newly synthesized replacement strand containing the desired edit. Cas protein-reverse transcriptase fusions or related systems are used to target a specific DNA sequence with a guide RNA, generate a single strand nick at the target site, and use the nicked DNA as a primer for reverse transcription of an engineered DNA synthesis template that is integrated with the guide RNA. However, while the concept begins with prime editors that use reverse transcriptase as the DNA polymerase component, the prime editors described herein are not limited to reverse transcriptase but may include the use of virtually any DNA polymerase. Indeed, while the application throughout may refer to prime editors with “reverse transcriptase,” it is set forth here that reverse transcriptase are only one type of DNA polymerase that may work with prime editing. Thus, wherever the specification mentions a “reverse transcriptase,” the person having ordinary skill in the art should appreciate that any suitable DNA polymerase may beused in place of the reverse transcriptase. Thus, in one aspect, the prime editors may comprise Cas9 (or an equivalent napDNAbp), which is programmed to target a DNA sequence by associating it with a specialized guide RNA (i.e., PEgRNA) containing a spacer sequence that anneals to a complementary sequence (the complementary sequence to an endogenous protospacer sequence) in the target DNA. The PEgRNA also contains new genetic information in the form of an extension that encodes a replacement strand of DNA containing a desired nucleotide change which is used to replace a corresponding endogenous DNA strand at the target site. To transfer information from the PEgRNA to the target DNA, the mechanism of prime editing involves nicking the target site in one strand of the DNA to expose a 3 '-hydroxyl group. The exposed 3 '-hydroxyl group can then be used to prime the DNA polymerization of the edit-encoding extension on PEgRNA directly into the target site. In various embodiments, the extension — which provides the template for polymerization of the replacement strand containing the edit — can be formed from RNA or DNA. In the case of an RNA extension, the polymerase of the prime editor can be an RNA-dependent DNA polymerase (such as a reverse transcriptase). In the case of a DNA extension, the polymerase of the prime editor may be a DNA-dependent DNA polymerase. The newly synthesized strand (i.e., the replacement DNA strand containing the desired nucleotide edit) that is formed by the prime editor would be homologous to the genomic target sequence (i.e., have the same sequence as), except for the inclusion of one or more desired nucleotide changes (e.g., a single nucleotide substitution, a deletion, or an insertion, or a combination thereof). The newly synthesized (or replacement) strand of DNA may also be referred to as a single strand DNA flap, which would compete for hybridization with the complementary homologous endogenous DNA strand, thereby displacing the corresponding endogenous strand. Resolution of the hybridized intermediate (also referred to as a heteroduplex, comprising the single strand DNA flap synthesized by the reverse transcriptase hybridized to the endogenous DNA strand with the exception of mismatches at positions where desired nucleotide edits are installed in the edit strand) can include removal of the resulting displaced flap of endogenous DNA (e.g., with a 5' end DNA flap endonuclease, FEN1), ligation of the synthesized single strand DNA flap to the target DNA, and assimilation of the desired nucleotide changes as a result of cellular DNA repair and / or replication processes.Producer cell

[0182] The term “producer cell” refers to any cell type that can be used to make the VLPs described herein. One or more polynucleotides encoding the components of a VLP aretransfected, transduced, electroporated, or otherwise inserted into a producer cell. In some embodiments, a single vector comprises polynucleotides encoding all components of the VLP, and in other embodiments, polynucleotides encoding each component of the VLP are split over two, three, or four different vectors. Once the producer cell expresses the polynucleotides, the various components of the VLPs self-assemble spontaneously within the producer cells. Assembly of the VLPs relies on multimerization of the gag polyproteins encoded on the polynucleotides as described above. The gag polyproteins (some of which are fused to a cargo molecule such as a protein) multimerize at the cell membrane of a producer cell and are subsequently released into the producer cell supernatant spontaneously. Producer cell lines include, but are not limited to, Gesicle 293T cells, HEK 293T, 293G, 293SF, 293FT, 293TN, Eent-X 293T, and inducible custom cell lines with lentivirally integrated VEP genes.Protease cleavage site

[0183] The term “protease cleavage site,” as used herein, refers to an amino acid sequence that is recognized and cleaved by a protease, i.e., an enzyme that catalyzes proteolysis and breaks down proteins into smaller polypeptides, or single amino acids. In some embodiments, a protease cleavage site is included in a cleavable linker in a fusion protein, as described herein. In certain embodiments, a protease cleavage site is cleaved by the protease of a gag-pro polyprotein. In some embodiments, a protease cleavage site comprises an MMLV protease cleavage site or an FMLV protease cleavage site. In certain embodiments, a protease cleavage site comprises one of the amino acid sequences TSTLLMENSS (SEQ ID NO: 334), PRSSLYPALTP (SEQ ID NO: 335), VQALVLTQ (SEQ ID NO: 336), PLQVLTLNIERR (SEQ ID NO: 337), or an amino acid sequence at least 90% identical to any one of SEQ ID NO:s: 1-4. In some embodiments, a protease cleavage site comprises an amino acid sequence of any one of SEQ ID NO:s: 1-8, or an amino acid sequence at least 90% identical to any one of SEQ ID NO:s: 1-8.Protein, peptide, and polypeptide

[0184] The terms “protein,” “peptide,” and “polypeptide” are used interchangeably herein and refer to a polymer of amino acid residues linked together by peptide (amide) bonds. The terms refer to a protein, peptide, or polypeptide of any size, structure, or function. Typically, a protein, peptide, or polypeptide will be at least three amino acids long. A protein, peptide, or polypeptide may refer to an individual protein or a collection of proteins. One or more of the amino acids in a protein, peptide, or polypeptide may be modified, for example, by theaddition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a famesyl group, an isofamesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modification, etc. A protein, peptide, or polypeptide may also be a single molecule or may be a multi-molecular complex. A protein, peptide, or polypeptide may be just a fragment of a naturally occurring protein or peptide. A protein, peptide, or polypeptide may be naturally occurring, recombinant, or synthetic, or any combination thereof. Any of the proteins provided herein may be produced by any method known in the art. For example, the proteins provided herein may be produced via recombinant protein expression and purification, which is especially suited for fusion proteins comprising a peptide linker. Methods for recombinant protein expression and purification are well known, and include those described by Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)), the contents of which are incorporated herein by reference.Subject

[0185] The term “subject,” as used herein, refers to an individual organism, for example, an individual mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a non-human primate. In some embodiments, the subject is a rodent. In some embodiments, the subject is a sheep, a goat, a cattle, a cat, or a dog. In some embodiments, the subject is a vertebrate, an amphibian, a reptile, a fish, an insect, a fly, or a nematode. In some embodiments, the subject is a research animal. In some embodiments, the subject is genetically engineered, e.g., a genetically engineered non-human subject. The subject may be of either sex and at any stage of development.Substitution

[0186] The term “substitution,” as used herein, refers to replacement of a residue within a sequence, e.g., a nucleic acid or amino acid sequence, with another residue, or a deletion or insertion of one or more residues within a sequence. The term “mutation” may also be used throughout the present disclosure to refer to a substitution (i.e., a “nucleic acid mutation” or an “amino acid mutation”). Substitutions are typically described herein by identifying the original residue followed by the position of the residue within the sequence and the identity of the newly mutated / substituted residue. Various methods for making the amino acid substitutions provided herein are well known in the art, and are provided by, for example, Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th ed., Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y. (2012)). In some embodiments, a substitution is in a viral nucleocapsid protein, which may be part of a VLP as described herein.Target cell

[0187] A “target cell” refers to any cell type to which a VLP is delivered. In some embodiments, a VLP is used to deliver a particular cargo to a target cell. For example, a VLP may be used to deliver a gene editing agent such as a napDNAbp (e.g., a Cas9 protein), a base editor, or a prime editor to a target cell. Once the VLP enters the target cell, the cargo is released and may perform its function, for example, by editing the genome of the target cell. Target cell types include any cell to which a person of ordinary skill in the art may want to deliver a VLP as described herein. In some embodiments, VLPs are delivered into human embryonic kidney (HEK) cells (e.g., HEK 293 or HEK 293T cells). In some embodiments, VLPs are delivered into stem cells (e.g., human stem cells) such as, for example, pluripotent stem cells (e.g., human pluripotent stem cells including human induced pluripotent stem cells (hiPSCs)).

[0188] Target cell types contemplated by the present disclosure include, but are not limited to, stem and progenitor cells (e.g., embryonic stem cells, hematopoietic stem cells, mesenchymal stem cells, neural crest cells, etc.), endothelial cells, muscle cells, myocardial cells, smooth and skeletal muscle cells, mesenchymal cells, epithelial cells, hematopoietic cells, lymphocytes such as T-cells (e.g., Thl T cells, Th2 T cells, ThO T cells, cytotoxic T cells) and B cells (e.g., pre-B cells), monocytes, dendritic cells, neutrophils, macrophages, natural killer cells, mast cells, adipocytes, immune cells, neurons, hepatocytes, and cells involved with particular organs (e.g., thymus, endocrine glands, pancreas, brain, neurons, glia, astrocytes, dendrocytes, osteoblasts, osteoclasts, gametes, fat cells, and genetically modified cells thereof).

[0189] In some embodiments, VLPs are delivered into a cell line, such as, but not limited to, 293-T, 3T3, 4T1, 721, 9L, A-549, A172, A20, A253, A2780, A2780ADR, A2780cis, A431, ALC, B16, B35, BCP-1, BEAS-2B, bEnd.3, BHK-21, BR 293, BxPC3, C2C12, C3H- 10T1 / 2, C6, C6 / 36, Cal-27, CGR8, CHO, CML Tl, CMT, COR-L23, COR-L23 / 5010, COR- L23 / CPR, COR-L23 / R23, COS-7, COV-434, CT26, D17, DH82, DU145, DuCaP, E14Tg2a, EL4, EM2, EM3, EMT6 / AR1, EMT6 / AR10.0, FM3, H1299, H69, HB54, HB55, HCA2, Hepalclc7, High Five cells, HL-60, HMEC, HT-29, HUVEC, J558L cells, Jurkat, JY cells, K562 cells, KCL22, KG1, Ku812, KY01, LNCap, Ma-Mel 1, 2, 3....48, MC-38, MCF-10A, MCF-7, MDA-MB-231, MDA-MB-435, MDA-MB-468, MDCK II, MG63, MONO-MAC 6,MOR / 0.2R, MRC5, MTD-1A, MyEnd, NAEM-1, NCI-H69 / CPR, NCI-H69 / LX10, NCI- H69 / LX20, NCI-H69 / LX4, NIH-3T3, NW- 145, OPCN / OPCT Peer, PNT-1A / PNT 2, PTK2, Raji, RBL cells, RenCa, RIN-5F, RMA / RMAS, S2, Saos-2 cells, Sf21, Sf9, SiHa, SKBR3, SKOV-3, T-47D, T2, T84, THP1, U373, U87, U937, VCaP, WM39, WT-49, X63, YAC-1, or YAR cells.Treatment

[0190] The terms “treatment,” “treat,” and “treating,” refer to a clinical intervention aimed to reverse, alleviate, delay the onset of, or inhibit the progress of a disease or disorder, or one or more symptoms thereof, as described herein. As used herein, the terms “treatment,” “treat,” and “treating” refer to a clinical intervention aimed to reverse, alleviate, delay the onset of, or inhibit the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed and / or after a disease has been diagnosed. In other embodiments, treatment may be administered in the absence of symptoms, e.g., to prevent or delay onset of a symptom or inhibit onset or progression of a disease. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.Variant

[0191] As used herein, the term “variant” should be taken to mean the exhibition of qualities that have a pattern that deviates from what occurs in nature, e.g., a variant nucleocapsid protein is a nucleocapsid protein comprising one or more changes in amino acid residues as compared to a wild type nucleocapsid protein amino acid sequence. The term “variant” encompasses homologous proteins having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with a reference sequence and having the same or substantially the same functional activity or activities as the reference sequence. The term also encompasses mutants, truncations, or domains of a reference sequence that display the same or substantially the same functional activity or activities as the reference sequence.Vector

[0192] The term “vector,” as used herein, refers to a nucleic acid that can be modified to encode a gene of interest and that is able to enter a host cell and replicate within the host cell, and then transfer a replicated form of the vector into another host cell. Exemplary suitable vectors include viral vectors, such as retroviral vectors or bacteriophages and filamentous phage, and conjugative plasmids. Additional suitable vectors will be apparent to those of skill in the art based on the instant disclosure.Viral envelope glycoprotein

[0193] The term “viral envelope glycoprotein” refers to oligo saccharide-containing proteins that form a part of the viral envelope, i.e., the outermost layer of many types of viruses that protects the viral genetic materials when traveling between host cells. Glycoproteins may assist with identification and binding to receptors on a target cell membrane so that the viral envelope fuses with the membrane, allowing the contents of the viral particle (which may be, e.g., a VLP as described herein) to enter the host cell. This property may also be referred to as “tropism.” The viral envelope glycoproteins used in the VLPs of the present disclosure may comprise any glycoprotein from an enveloped virus. In some embodiments, a viral envelope glycoprotein is an adenoviral envelope glycoprotein, an adeno-associated viral envelope glycoprotein, a retroviral envelope glycoprotein, or a lentiviral envelope glycoprotein. In certain embodiments, a viral envelope glycoprotein is a vesicular stomatitis virus G protein (VSVG), a baboon retroviral envelope glycoprotein (BaEVRless), a FuG-B2 envelope glycoprotein, an HIV-1 envelope glycoprotein, or an ecotropic murine leukemia virus (MLV) envelope glycoprotein, or a mutant form thereof.Virus-like particles (VLPs)

[0194] As used herein, a “virus-like particle (VLP)” (or “engineered virus-like particle (eVLP),” which is used interchangeably with the term “VLP” herein) consists of a supra- molecular assembly comprising (a) an envelope comprising (i) a lipid membrane (e.g., singlelayer or bi-layer membrane) and a (ii) viral envelope glycoprotein, and (b) a multi-protein core region comprising (ii) a Gag protein, (ii) a first fusion protein comprising a Gag protein and Pro-Pol, and (iii) a second fusion protein comprising a Gag protein fused to a cargo protein via a protease-cleavable linker. In some embodiments, the gag protein comprises a nucleocapsid protein variant as described herein. In various embodiments, the cargo protein is a napDNAbp (e.g., Cas9). In other embodiments, the cargo protein is a base editor. In other embodiments, the cargo protein is a prime editor. In various other embodiments, the multiprotein core region of the VLPs further comprises one or more guide RNA molecules whichare complexed with a napDNAbp, base editor, or prime editor to form a ribonucleoprotein (RNP). In some embodiments, the guide RNA molecule comprises a barcode sequence as described herein (e.g., a barcode sequence associated with a nucleocapsid protein variant that forms part of the gag protein). In various embodiments, the VLPs are prepared in a producer cell that is transiently transformed with plasmid DNA that encodes that various protein and nucleic acid (sgRNA) components of the VLPs. The components self-assemble at the cell membrane and bud out in accordance with the naturally occurring mechanism of retroviral budding in order to release from the cell fully-matured VLPs. Once formed, the Pol-Pro cleaves the protease- sensitive linker joining the Gag-cargo linker (e.g., the linker joining a Gag to a napDNAbp RNP) to release the cargo within the VLP. Once the VLP is administered to a recipient target cell and taken up by said target cell, the contents of the VLP are released, including free cargo (e.g., a napDNAbp, base editor, or prime editor). Once in the cell, the cargo may translocate to the nuclease of the cell (in particular, where NLSs are included on an RNP cargo), where DNA editing may occur at target sites specified by the guide RNA.

[0195] In some embodiments, the protease-cleavable linker is optimized to improve cleavage efficiency after VLP maturation. In some embodiments, the Gag-cargo fusion (e.g., Gag::BE) further comprises one or more nuclear export signals at one or more locations along the length of the fusion polypeptide protein which may be joined by a cleavable linker such that during VLP assembly in the producer cell, the Gag-cargo fusions (due to presence of competing NLS signals) do not accumulate in the nucleus of the producer cells but instead are available in the cytoplasm to undergo the VLP assembly process at the cell membrane. Once inside the matured VLPs following release from the producer cell, the NES may be cleaved by Pro-Pol, thereby separating the cargo (e.g., napDNAbp, base editor, or prime editor) from the NES. Upon delivery to a recipient cell, therefore, the cargo (e.g., napDNAbp, base editor, or prime editor, typically flanked with one or more NLS elements) will not comprise an NES element, which may otherwise prohibit the transport of the cargo into the nucleus and hinder gene editing activity.

[0196] In some embodiments, an optimized stoichiometry ratio of Gag-cargo fusion to Gag-Pro-Pol fusion protein is used, which balances the amount of Gag-cargo available to be packaged into VLPs with the amount of retrovirus protease (the “Pro” in the Gag-Pro-Pol fusion) required for VLP maturation. In some embodiments, the optimized ratio of Gag-cargo fusion to Gag-Pro-Pol fusion protein is achieved by the appropriate ratio of plasmidsencoding each component which are transiently delivered to the producer cells. In some embodiments, the optimal gag-cargo:gag-pro-pol stoichiometry is 25% gag-cargo:75% gag- pro-pol.

[0197] In some embodiments, a VLP comprises additional agents for targeting the VLP for delivery to particular cell types. For example, such additional targeting agents may be incorporated into the outer lipid membrane encapsulation layer of the VLP. In some embodiments, the additional targeting agent is a protein. In certain embodiments, the additional targeting agent is an antibody.

[0198] Thus, as used herein, a virus-derived particle comprises a virus-like particle formed by one or more virus-derived protein(s), which virus-derived particle is substantially devoid of a viral genome such that the VLP is replication-incompetent when delivered to a recipient cell.Wild type

[0199] As used herein the term “wild type” is a term of the art understood by skilled persons and means the typical form of an organism, strain, gene or characteristic as it occurs in nature as distinguished from mutant or variant forms.Click Chemistry

[0105] The term “click chemistry” refers to a chemical synthesis technique introduced by K. Barry Sharpless of The Scripps Research Institute, describing chemistry tailored to generate covalent bonds quickly and reliably by joining small units comprising reactive groups together. See, e.g., Kolb, Finn and Sharpless Angewandte Chemie International Edition (2001) 40: 2004-2021; Evans, Australian Journal of Chemistry (2007) 60: 384-395).Exemplary coupling reactions (some of which may be classified as “click chemistry”) include, but are not limited to, formation of esters, thioesters, amides (e.g., such as peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g., such as nucleophilic displacement of a halide or ring opening of strained ring systems); azidealkyne Huisgen cycloaddition; thiol-yne addition; imine formation; Michael additions (e.g., maleimide addition); and Diels- Alder reactions (e.g., tetrazine [4 + 2] cycloaddition).Exemplary click chemistry reactions include, but are not limited to, azide-alkyne Huisgen cycloaddition; and Diels-Alder reactions (e.g., tetrazine [4 + 2] cycloaddition). In some embodiments, click chemistry reactions are modular, wide in scope, give high chemical yields, generate inoffensive byproducts, are stereospecific, exhibit a large thermodynamic driving force > 84 kJ / mol to favor a reaction with a single reaction product, and / or can becarried out under physiological conditions. In some embodiments, a click chemistry reaction exhibits high atom economy, can be carried out under simple reaction conditions, use readily available starting materials and reagents, uses no toxic solvents or use a solvent that is benign or easily removed (preferably water), and / or provides simple product isolation by non- chromatographic methods (crystallization or distillation).

[0106] The term “click chemistry handle,” as used herein, refers to a reactant, or a reactive group, that can partake in a click chemistry reaction. For example, a strained alkyne, e.g., a cyclooctyne, is a click chemistry handle, since it can partake in a strain-promoted cycloaddition (see, e.g., Table 1). In general, click chemistry reactions require at least two molecules comprising click chemistry handles that can react with each other. Such click chemistry handle pairs that are reactive with each other are sometimes referred to herein as partner click chemistry handles. For example, an azide is a partner click chemistry handle to a cyclooctyne or any other alkyne. Exemplary click chemistry handles suitable for use according to some aspects of this invention are described herein, for example, in Tables 1 and 2. In some embodiments, click chemistry handles are used that can react to form covalent bonds in the presence of a metal catalyst, e.g., copper (II). In some embodiments, click chemistry handles are used that can react to form covalent bonds in the absence of a metal catalyst. Additional suitable click chemistry handles are well known to those of skill in the art, and such click chemistry handles include, but are not limited to, the click chemistry reaction partners, groups, and handles described in Becer, Hoogenboom, and Schubert, Click Chemistry beyond Metal-Catalyzed Cycloaddition, Angewandte Chemie International Edition (2009) 48: 4900 - 4908 and PCT / US2012 / 044584 and references therein, which references are incorporated herein by reference for click chemistry handles and methodology.Table 1: Exemplary click chemistry handles and reactions.Table 2: Exemplary click chemistry handles and reactions (from Becer, Hoogenboom, andSchubert, Click Chemistry Beyond Metal-Catalyzed Cycloaddition, Angewandte ChemieInternational Edition (2009) 48: 4900 - 4908.).DETAILED DESCRIPTION

[0200] The present disclosure provides articles and methods for the selective transduction and genome editing of human cells (e.g., hematopoietic stem and progenitors cells, HSPCs) using engineered viral like particles (e.g., eVLPs). Aspects of the disclosure provide eVLPs comprising fusion proteins comprising a targeting moiety. In some embodiments, the fusion proteins comprise a cytokine conjugated to a transmembrane protein and / or an envelope glycoprotein. In other embodiments, the fusion proteins comprise a targeting moiety domain, a stalk protein domain, a transmembrane domain and / or envelope glycoprotein domain. Targeted-eVLP architectures comprising fusion proteins comprising various targeting domains, stalk domains, transmembrane domains, and envelope glycoproteins are also provided herein. In some embodiments, the eVLP comprise a second fusion protein comprising various targeting domains, stalk domains, and transmembrane domains or envelope glycoprotein domain. In some embodiments, the first fusion protein and second fusion protein comprise the same targeting domains, stalk domains, and transmembrane or envelope glycoprotein domains. In some embodiments, the first fusion protein and second fusion protein comprise different targeting domains, stalk domains, and transmembrane or envelope glycoprotein domains. In some embodiments, the different targeting domains are configured to bind the same, or different, target (e.g., receptor) on a target cell (e.g., they both target the same cell type, such as HSPC or immune cells).

[0201] Other aspects of the disclosure provide eVLP compositions comprising envelope glycoproteins comprising non-natural sugars and methods of conjugating various targeting moieties to said eVLPs using bio-orthogonal click chemistry. Polynucleotides, vectors, cells, and kits useful for producing the articles, and performing the methods, described herein are also provided.

[0202] As described elsewhere herein, current eVLP architectures (e.g., v4 eVLPs) use VSVG as the standard envelope glycoprotein. VSVG initiates receptor- mediated endocytosis through the ubiquitously expressed LDL receptor protein (LDLR). The wide expression distribution of LDLR means that v4 eVLPs have the potential to transduce many cell types. While this has obvious benefits especially in an ex vivo context, this property increases transduction in off-target cell types, especially in the liver. Therefore, the effective dose reaching the target cell population for a given disease is much lower than the administered dose since off-target cells act as a sink for the high-activity eVLPs.

[0203] The inventors of the present disclosure have now discovered that eVLP architectures comprising a targeting domain increases the effective dose of a therapeutic (e.g.,genome editors) reaching a target cell. For example, eVLPs carrying genome editors permit delivery of gene editors to correct disease-associated alleles only in the cell types where they exert the most substantial phenotypic effect. Importantly, the inventors have surprisingly shown that non- viral targeting domains (e.g., cytokines) may be incorporated into eVLP architectures thus greatly enhancing the specificity of transduction both in vitro and in vivo. As such, aspects of the present disclosure are generally directed toward compositions of eVLPs comprising one or more targeting domains and methods of making the same, both in vitro and in vivo. The following is a description of various elements that permit the targeted delivery of eVLPs as contemplated herein. eVLP Constructs

[0204] The core components used to assemble the eVLPs of the present disclosure are discussed elsewhere herein, but in general include one or more retrovirus-derived structural protein(s) and optionally one or more virus-derived envelope protein(s) or mutated variants thereof. FIG. 2 shows an exemplary embodiment of an eVLP comprising a fusion protein comprising a transmembrane (TM) domain, a targeting domain, and a linker. FIG 2 also shows other eVLP components including the (i) lipid membrane e.g., single-layer or bi-layer membrane), a mutant viral envelope glycoprotein (e.g., VSVG-mut) and a multi-protein core region enclosed by the envelope and comprising a Gag protein, a Gag-Pro-Pol protein, and a Gag-cargo fusion protein. Thus, in some embodiments, the fusion protein is conjugated to a transmembrane domain, and the envelope glycoprotein is a mutant envelope glycoprotein (e.g., VSVG-mutant, Cocal-mutant, Nipah virus mutant). Such embodiments may be useful, for example, for ablating the native cellular tropism associated with the VSVG glycoprotein while retaining fusogenic activity and enhancing selective tropism toward a specific cell type. Other envelope glycoproteins and / or mutant envelope glycoproteins are also contemplated. For example, in some embodiments, the envelope glycoprotein is derived from the vesicular stomatitis virus G (e.g., VSVG), the Cocal, virus and / or Nipah virus. In some embodiments, the mutant envelope protein comprises an envelope glycoprotein derived from the vesicular stomatitis virus (e.g., VSVG), Cocal virus, and / or Nipah virus. The fusion protein may comprise other domains (e.g., stalk domain) and / or combinations of domains (e.g., targeting domains) according to other embodiments.

[0205] FIG. 3 shows an exemplary embodiment of an eVLP comprising a fusion protein comprising a wild type envelope glycoprotein domain, a targeting domain, and a linker. The eVLP construct in FIG. 3 also comprises a mutant envelope glycoprotein, e.g., VSVG-mutantthat possesses impaired binding affinity to the LDLR but retains its fusogenic activity. Such embodiments may be useful, for example, for increasing the transduction efficiency of the eVLPs into in a target cell type. The fusion protein may comprise other domains (e.g., stalk domain) and / or combinations of domains (e.g., targeting domains) according to other embodiments.

[0206] FIGs. 4 and 5 show exemplary embodiments of an eVLP comprising a fusion protein comprising a transmembrane (TM) domain, a stalk domain, and a targeting domain. Again, the eVLP construct in FIGs. 4 and 5 also comprises a mutant envelope glycoprotein, e.g., VSVG-mutant that possesses impaired binding affinity to the LDLR but retains its fusogenic activity. In some embodiments, the stalk domains are inert and serve as linkers (or spacers) to separate the transmembrane domain, which incorporates into the eVLP capsid, from the targeting protein. In some embodiments, the stalk domain comprises CD8-alpha or a fragment thereof (e.g., FIG. 4). In other embodiments, the stalk domain comprises IgG, or a fragment thereof (e.g., FIG. 5). Again, such embodiments, are useful for increasing the transduction efficiency of the eVLPs. The fusion protein may comprise other domains and / or combinations of domains (e.g., targeting domains) according to other embodiments.

[0207] FIG. 6 shows an exemplary embodiment of an eVLP comprising a fusion protein comprising a transmembrane (TM) domain, a targeting domain, and a linker. In this set of embodiments, however, the targeting domain binds to a second targeting domain, which in turn binds to a target receptor on a target cell (e.g., HSBC cell). For example, in certain embodiments, the targeting domain comprises an IgG binding peptide configured to bind to an IgG antibody (e.g., an anti-CDl 10 IgG antibody). Such embodiments are useful, for example, to enhance the targeting specificity of the eVLP construct. The fusion protein may comprise other domains (e.g., stalk domain) and / or combinations of domains (e.g., targeting domains) according to other embodiments.

[0208] FIG. 7 shows an exemplary eVLP comprising a non-natural moiety (e.g., an azido (-N3) functionality) and an exemplary method of producing the same. It will be appreciated that general methods are known in the art for incorporating non-natural moieties (e.g., N-(4- pentynoyl mannosamine, N-azidoacetylmannosamine, etc.) into cell surface glycoproteins (e.g., such as VSVG). Thus, in some embodiments, eVLPs of the present disclosure comprise an envelope glycoprotein with one or more azido functionalities. In other embodiments, the eVLPs comprises an envelope glycoprotein with one or more alkyne or strained alkyne functionalities.

[0209] FIG. 17 shows an exemplary embodiment of an eVLP comprising a fusion protein comprising a transmembrane (TM) domain (e.g., ICAM1), a stalk domain (e.g., CD8a), and two different targeting domains (e.g., a-CD4 scFV and a-CD8 scFV). The eVLP construct comprises a mutant envelope glycoprotein, e.g., Cocal mut that possesses impaired binding affinity that reduces its broad tropism but retains its fusogenic activity. In some embodiments, the stalk domains are inert and serve as linkers (or spacers) to separate the transmembrane domain, which incorporates into the eVLP capsid, from the targeting protein. In some embodiments, the stalk domain is CD8-alpha. In other embodiments, the stalk domain is IgG. Again, such embodiments, are useful for increasing the transduction efficiency of the eVLPs. The fusion protein may comprise other domains and / or combinations of domains (e.g., targeting domains) according to other embodiments.

[0210] In some embodiments, a virus-like particle comprises a fusion protein comprising a transmembrane domain, a stalk domain, and a targeting domain, wherein the targeting domain is not a viral envelope glycoprotein, an antibody, or an antibody fragment.

[0211] In some embodiments, a virus-like particle comprises a fusion protein comprising a transmembrane domain, a stalk domain, and two or more targeting domains, wherein the targeting domains are not a viral envelope glycoprotein, an antibody, or an antibody fragment.

[0212]

[0213] In some embodiments, a virus-like particle comprises a fusion protein comprising a transmembrane domain and a targeting domain, wherein the targeting domain is not a viral envelope glycoprotein, an antibody, or an antibody fragment.

[0214] In some embodiments, a virus-like particle comprises (a) a fusion protein comprising (i) a transmembrane domain and (ii) a targeting domain, and (b) an antibody domain, wherein the targeting domain of the fusion protein binds to the antibody domain to form a virus-like particle-antibody complex, and wherein, the targeting domain is not an envelope glycoprotein, an antibody, or a fragment of an antibody.

[0215] In some embodiments, a virus-like particle comprises (a) a fusion protein comprising (i) a transmembrane domain, (ii) a stalk domain, and (iii) a targeting domain, and (b) an antibody domain, wherein the targeting domain of the fusion protein binds to the antibody domain to form a virus-like particle-antibody complex, and wherein, the targeting domain is not an envelope glycoprotein, an antibody, or a fragment of an antibody.

[0216] In some embodiments, the virus-like particle comprises at least one conjugation domain.Fusion proteins

[0217] One strategy, contemplated herein, for enhancing the selective tropism of eVLPs is to genetically engineer the eVLP to display a targeting domain on the surface of the viral capsid. As such, in some embodiments, eVLPs of the present disclosure comprise a fusion protein comprising a targeting domain. In some embodiments, the fusion protein comprises a transmembrane domain and a targeting domain. In some embodiments, the eVLP comprises a fusion protein comprising a transmembrane domain, a stalk domain, and a targeting domain. Additionally, the fusion protein may further, optionally comprise one or more linkers (e.g., linkers), for example, between the transmembrane domain and the targeting domain, between the transmembrane domain and the stalk domain, between the stalk domain and the targeting domain, and / or between the targeting domain and a signaling peptide. In some embodiments, the one or more linkers is a first linker, a second linker, a third linker, and so on. In some embodiments, the one or more linkers may be used to link any two domains. For example, in some embodiments, an optional first linker (e.g., flexible) connects the transmembrane domain and the targeting domain and an optional second linker (e.g., flexible) connects the stalk domain to targeting domain. Other compositions are also possible in other embodiments, for example, a fusion protein may comprise a targeting domain and an envelope glycoprotein domain (e.g., VSVG). In some embodiments, an eVLP may comprise more than one fusion protein comprising any one of the domains described above. In some embodiments, the domains of the more than one fusion proteins are the same; in other embodiments, the domains of the more than one fusion proteins are different. For example, in some embodiments, an eVLP comprises a first fusion protein comprising an ICAM1 transmembrane domain, a CD8a stalk domain, and a aCD4 scFv targeting domain and a second fusion protein comprising comprising an ICAM1 transmembrane domain, a CD8a stalk domain, and a aCD8-scFv targeting domain (FIG. 17). In some embodiments, the eVLP targets HSC cells. In other embodiments, the eVLPs target immune cells, such as CD4+ or CD8+ T cells. The fusion protein may have any suitable structure and / or orientation known in the art. For example, in some embodiments, the fusion proteins comprise the following structures:

[0218] N-terminus- [Transmembrane domain or envelope glycoprotein domain]- [Targeting domain] -[optional signal peptide] -C-terminus.

[0219] C-terminus-[Transmembrane domain or envelope glycoprotein domain]- [Targeting domain] -[optional signal peptide]-N-terminus.

[0220] N-terminus- [Transmembrane domain or envelope glycoprotein domain] -[optional linker] -[Targeting domain] -[optional signal peptide] -C-terminus.

[0221] C-terminus-[Transmembrane domain or envelope glycoprotein domain] -[optional linker] -[Targeting domain] -[optional signal peptide]-N-terminus.

[0222] N-terminus- [Transmembrane domain or envelope glycoprotein domain] -[Stalk domain] -[Targeting domain] -[optional signal peptide] -C-terminus.

[0223] C-terminus-[Transmembrane domain or envelope glycoprotein domain] -[Stalk domain] -[Targeting domain] -[optional signal peptide]-N-terminus.

[0224] N-terminus- [Transmembrane domain or envelope glycoprotein domain] -[optional linker] -[Stalk domain] -[Targeting domain]-[ optional signal peptide] -C-terminus.

[0225] C-terminus-[Transmembrane domain or envelope glycoprotein domain] -[optional linker] -[Stalk domain] -[Targeting domain]- [optional signal peptide] -N-terminus.

[0226] N-terminus- [Transmembrane domain or envelope glycoprotein domain] -[Stalk domain] -[optional linker] -[Targeting domain]- [optional signal peptide] -C-terminus.

[0227] C-terminus-[Transmembrane domain or envelope glycoprotein domain] -[Stalk domain] -[optional linker] -[Targeting domain] -[optional signal peptide]-N-terminus.

[0228] N-terminus- [Transmembrane domain or envelope glycoprotein domain] -[optional linker] -[Stalk domain] -[optional linker] -[Targeting domain] -[optional signal peptide] -C- terminus.

[0229] C-terminus-[Transmembrane domain or envelope glycoprotein domain] -[optional linker] -[Stalk domain] -[optional linker] -[Targeting domain] -[optional signal peptide]-N- terminus.Transmembrane domain

[0230] In some embodiments, the eVLPs comprise a fusion protein comprising a transmembrane domain. Any suitable transmembrane domain known to one of ordinary skill in the art may be used to make the fusion proteins contemplated herein. In some embodiments, the transmembrane domain is selected from the group consisting of CD28, CD43, CD49d, CD62L, CD162, HLA-A2, HLA-DRA, ICAM1, LFA-1, mCD3z, mCD4, mCD8a, hCD8a, hCD8a, and VSVG-TM. Non-limiting exemplary embodiments of possible transmembrane domains for use in any of the fusion proteins disclosed herein include:

[0231] CD28FWVLVVVGGVLACYSLLVTVAFIIFWV (SEQ ID NO: 363)

[0232] CD43GMLPVAVLVALLAVIVLVALLLLWRRRQKRRT (SEQ ID NO: 364)

[0233] CD49dIVIISSSLLLGLIVLLLISYVMWKAGFFKRQYKS (SEQ ID NO: 365)

[0234] CD62LPLFIPVAVMVTAFSGLAFIIWLARRLKKGKKSKR (SEQ ID NO: 366)

[0235] CD 162LLAILILALVATIFFVCTVVLAVRLSRKGHMYPVRN (SEQ ID NO: 367)

[0236] HLA-A2IVGIIAGLVLFGAVITGAVVAAVMWRRKSSDRKG (SEQ ID NO: 368)

[0237] HLA-DRANVVCALGLTVGLVGIIIGTIFIIKGLRKSNAAERRGPL (SEQ ID NO: 369)

[0238] ICAM1IVIITVVAAAVIMGTAGLSTYLYNRQRKIKKYRL (SEQ ID NO: 370)

[0239] LFA-1YLYVLSGIGGLLLLLLIFIVLYKVGFFKRNLK (SEQ ID NO: 371)

[0240] mCD3zLCYLLDGILFIYGVIITALYL (SEQ ID NO: 372)

[0241] mCD4VFLACVLGGSFGFLGFLGLCILC (SEQ ID NO: 373)

[0242] mCD8aIWAPLAGICVALLLSLIITLI (SEQ ID NO: 374)

[0243] hCD8aIWAPLAGTCGVLLLSLVITLY (SEQ ID NO: 375)

[0244] VSVG-TMIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK (SEQ ID NO: 376)

[0245] VSVGss-TM:GTNPIELVEGWFSSWKSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMN RLGKV (SEQ ID NO: 493)

[0246] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of any SEQ ID NO:s: 363-376 or 493.Viral envelope glycoprotein domain

[0247] In some embodiments, the eVLPs comprise a fusion protein comprising a viral envelope glycoprotein domain. Any suitable viral envelope glycoprotein domain known to one of ordinary skill in the art may be used to make the fusion proteins contemplated herein. In some embodiments, the viral envelope glycoprotein comprises one or more mutations, for example, a mutation that decreases the glycoproteins binding affinity for its native target receptor. In some embodiment, the mutation does not substantially reduce the fugsionic properties (e.g., the ability to induce endocytic transduction). Non-limiting exemplary embodiments of possible viral envelope glycoprotein domains for use in any of the fusion proteins disclosed herein include:

[0248] VSV-Gmut amino acid sequence (K47Q / R354A, del 1-16, VSVGTMASP)KFTIVFPHNQKGNWKNVPSNYHYCPSSSDLNWHNDLIGTALQVKMPQSHKAIQADG WMCHASKWVTTCDFRWYGPKYITHSIRSFTPSVEQCKESIEQTKQGTWLNPGFPPQS CGYATVTDAEAVIVQVTPHHVLVDEYTGEWVDSQFINGKCSNYICPTVHNSTTWHS DYKVKGLCDSNLISMDITFFSEDGELSSLGKEGTGFRSNYFAYETGGKACKMQYCK HWGVRLPSGVWFEMADKDLFAAARFPECPEGSSISAPSQTSVDVSLIQDVERILDYSL CQETWSKIRAGLPISPVDLSYLAPKNPGTGPAFTIINGTLKYFETRYIRVDIAAPILSRMVGMISGTTTEAELWDDWAPYEDVEIGPNGVLRTSSGYKFPLYMIGHGMLDSDLHLSSKAQVFEHPHIQDAASQLPDDESLFFGDTGLSKNPIELVEGWFSSWKSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK (SEQ ID NO: 377)

[0249] VSV-Gmut amino acid sequence (K47Q / R354A):MKCLLYLAFLFIGVNCKFTIVFPHNQKGNWKNVPSNYHYCPSSSDLNWHNDLIGTALQVKMPQSHKAIQADGWMCHASKWVTTCDFRWYGPKYITHSIRSFTPSVEQCKESIEQTKQGTWLNPGFPPQSCGYATVTDAEAVIVQVTPHHVLVDEYTGEWVDSQFINGKCSNYICPTVHNSTTWHSDYKVKGLCDSNLISMDITFFSEDGELSSLGKEGTGFRSNYFAYETGGKACKMQYCKHWGVRLPSGVWFEMADKDLFAAARFPECPEGSSISAPSQTSVDVSLIQDVERILDYSLCQETWSKIRAGLPISPVDLSYLAPKNPGTGPAFTIINGTLKYFETRYIRVDIAAPILSRMVGMISGTTTEAELWDDWAPYEDVEIGPNGVLRTSSGYKFPLYMIGHGMLDSDLHLSSKAQVFEHPHIQDAASQLPDDESLFFGDTGLSKNPIELVEGWFSSWKSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK (SEQID NO: 378)

[0250] VSVG amino acid sequence:MKCLLYLAFLFIGVNCKFTIVFPHNQKGNWKNVPSNYHYCPSSSDLNWHNDLIGTALQVKMPKSHKAIQADGWMCHASKWVTTCDFRWYGPKYITHSIRSFTPSVEQCKESIEQTKQGTWLNPGFPPQSCGYATVTDAEAVIVQVTPHHVLVDEYTGEWVDSQFINGKCSNYICPTVHNSTTWHSDYKVKGLCDSNLISMDITFFSEDGELSSLGKEGTGFRSNYFAYETGGKACKMQYCKHWGVRLPSGVWFEMADKDLFAAARFPECPEGSSISAPSQTSVDVSLIQDVERILDYSLCQETWSKIRAGLPISPVDLSYLAPKNPGTGPAFTIINGTLKYFETRYIRVDIAAPILSRMVGMISGTTTERELWDDWAPYEDVEIGPNGVLRTSSGYKFPLYMIGHGMLDSDLHLSSKAQVFEHPHIQDAASQLPDDESLFFGDTGLSKNPIELVEGWFSSWKSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK (SEQID NO: 379)

[0251] VSVGmut2 (K47Q, R354Q):MKCLLYLAFLFIGVNCKFTIVFPHNQKGNWKNVPSNYHYCPSSSDLNWHNDLIGTALQVKMPQSHKAIQADGWMCHASKWVTTCDFRWYGPKYITHSIRSFTPSVEQCKESIEQTKQGTWLNPGFPPQSCGYATVTDAEAVIVQVTPHHVLVDEYTGEWVDSQFINGKCSNYICPTVHNSTTWHSDYKVKGLCDSNLISMDITFFSEDGELSSLGKEGTGFRSNYFAYETGGKACKMQYCKHWGVRLPSGVWFEMADKDLFAAARFPECPEGSSISAPSQTS VDVSLIQDVERILDYSLCQETWSKIRAGLPISPVDLSYLAPKNPGTGPAFTIINGTLKY FETRYIRVDIAAPILSRMVGMISGTTTEQELWDDWAPYEDVEIGPNGVLRTSSGYKFP LYMIGHGMLDSDLHLSSKAQVFEHPHIQDAASQLPDDESLFFGDTGLSKNPIELVEG WFSSWKSSIASFFFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK (SEQ ID NO: 494)

[0252] Cocal:MNFLLLTFIVLPLCSHAKFSIVFPQSQKGNWKNVPSSYHYCPSSSDQNWHNDLLGIT MKVKMPKTHKAIQADGWMCHAAKWITTCDFRWYGPKYITHSIHSIQPTSEQCKESI KQTKQGTWMSPGFPPQNCGYATVTDSVAVVVQATPHHVLVDEYTGEWIDSQFPNG KCETEECETVHNSTVWYSDYKVTGLCDATLVDTEITFFSEDGKKESIGKPNTGYRSNYFAYEKGDKVCKMNYCKHAGVRLPSGVWFEFVDQDVYAAAKLPECPVGATISAPT QTSVDVSLILDVERILDYSLCQETWSKIRSKQPVSPVDLSYLAPKNPGTGPAFTIINGT LKYFETRYIRIDIDNPIISKMVGKISGSQTERELWTEWFPYEGVEIGPNGILKTPTGYKF PLFMIGHGMLDSDLHKTSQAEVFEHPHLAEAPKQLPEEETLFFGDTGISKNPVELIEG WFSSWKSTVVTFFFAIGVFILLYVVARIVIAVRYRYQGSNNKRIYNDIEMSRFRK (SEQ ID NO: 495)

[0253] Cocalmut:MNFLLLTFIVLPLCSHAKFSIVFPQSQKGNWKNVPSSYHYCPSSSDQNWHNDLLGIT MKVKMPQTHKAIQADGWMCHAAKWITTCDFRWYGPKYITHSIHSIQPTSEQCKESI KQTKQGTWMSPGFPPQNCGYATVTDSVAVVVQATPHHVLVDEYTGEWIDSQFPNG KCETEECETVHNSTVWYSDYKVTGLCDATLVDTEITFFSEDGKKESIGKPNTGYRSNYFAYEKGDKVCKMNYCKHAGVRLPSGVWFEFVDQDVYAAAKLPECPVGATISAPT QTSVDVSLILDVERILDYSLCQETWSKIRSKQPVSPVDLSYLAPKNPGTGPAFTIINGT LKYFETRYIRIDIDNPIISKMVGKISGSQTEAELWTEWFPYEGVEIGPNGILKTPTGYKF PLFMIGHGMLDSDLHKTSQAEVFEHPHLAEAPKQLPEEETLFFGDTGISKNPVELIEG WFSSWKSTVVTFFFAIGVFILLYVVARIVIAVRYRYQGSNNKRIYNDIEMSRFRK (SEQ ID NO: 496)

[0254] Nipah-G:MPAENKKVRFENTTSDKGKIPSKVIKSYYGTMDIKKINEGLLDSKILSAFNTVIALLGSIVIIVMNIMIIQNYTRSTDNQAVIKDALQGIQQQIKGLADKIGTEIGPKVSLIDTSSTITIPANIGLLGSKISQSTASINENVNEKCKFTLPPLKIHECNISCPNPLPFREYRPQTEGVSNLVGLPNNICLQKTSNQILKPKLISYTLPVVGQSGTCITDPLLAMDEGYFAYSHLERIGSCSRGVSKQRIIGVGEVLDRGDEVPSLFMTNVWTPPNPNTVYHCSAVYNNEFYYVLCAVSTVGDPILNSTYWSGSLMMTRLAVKPKSNGGGYNQHQLALRSIEKGRYDKVMPYGPSGIKQGDTLYFPAVGFLVRTEFKYNDSNCPITKCQYSKPENCRLSMGIRPNSHYILRSGLLKYNLSDGENPKVVFIEISDQRLSIGSPSKIYDSLGQPVFYQASFSWDTMIKFGDVLTVNPLVVNWRNNTVISRPGQSQCPRFNTCPEICWEGVYNDAFLIDRINWISAGVFLDSNQTAENPVFTVFKDNEILYRAQLASEDTNAQKTITNCFLLKNKIWCISLVEIYDTGDNVIRPKLFAVKIPEQCT (SEQ ID NO: 497)

[0255] Nipah-Gmut:MPAENKKVRFENTTSDKGKIPSKVIKSYYGTMDIKKINEGLLDSKILSAFNTVIALLGSIVIIVMNIMIIQNYTRSTDNQAVIKDALQGIQQQIKGLADKIGTEIGPKVSLIDTSSTITIPANIGLLGSKISQSTASINENVNEKCKFTLPPLKIHECNISCPNPLPFREYRPQTEGVSNLVGLPNNICLQKTSNQILKPKLISYTLPVVGQSGTCITDPLLAMDEGYFAYSHLERIGSCSRGVSKQRIIGVGEVLDRGDEVPSLFMTNVWTPPNPNTVYHCSAVYNNEFYYVLCAVSTVGDPILNSTYWSGSLMMTRLAVKPKSNGGGYNQHQLALRSIEKGRYDKVMPYGPSGIKQGDTLYFPAVGFLVRTEFKYNDSNCPITKCQYSKPENCRLSMGIRPNSHYILRSGLLKYNLSDGENPKVVFIEISDQRLSIGSPSKIYDSLGQPVFYQASFSWDTMIKFGDVLTVNPLVVNWRNNTVISRPGQSQCPRFNTCPAICAEGVYNDAFLIDRINWISAGVFLDSNATAANPVFTVFKDNEILYRAQLASEDTNAQKTITNCFLLKNKIWCISLVEIYDTGDNVIRPKLFAVKIPEQCT (SEQ ID NO: 498)

[0256] Nipah-Gmut trunc:MKKINEGLLDSKILSAFNTVIALLGSIVIIVMNIMIIQNYTRSTDNQAVIKDALQGIQQQIKGLADKIGTEIGPKVSLIDTSSTITIPANIGLLGSKISQSTASINENVNEKCKFTLPPLKIHECNISCPNPLPFREYRPQTEGVSNLVGLPNNICLQKTSNQILKPKLISYTLPVVGQSGTCITDPLLAMDEGYFAYSHLERIGSCSRGVSKQRIIGVGEVLDRGDEVPSLFMTNVWTPPNPNTVYHCSAVYNNEFYYVLCAVSTVGDPILNSTYWSGSLMMTRLAVKPKSNGGGYNQHQLALRSIEKGRYDKVMPYGPSGIKQGDTLYFPAVGFLVRTEFKYNDSNCPITKCQYSKPENCRLSMGIRPNSHYILRSGLLKYNLSDGENPKVVFIEISDQRLSIGSPSKIYDSLGQPVFYQASFSWDTMIKFGDVLTVNPLVVNWRNNTVISRPGQSQCPRFNTCPAICAEGVYNDAFLIDRINWISAGVFLDSNATAANPVFTVFKDNEILYRAQLASEDTNAQKTITNCFLLKNKIWCISLVEIYDTGDNVIRPKLFAVKIPEQCT (SEQ ID NO: 499)

[0257] Nipah-F:MVVILDKRCYCNLLILILMISECSVGILHYEKLSKIGLVKGVTRKYKIKSNPLTKDIVI KMIPNVSNMSQCTGSVMENYKTRLNGILTPIKGALEIYKNNTHDLVGDVRLAGVIM AGVAIGIATAAQITAGVALYEAMKNADNINKLKSSIESTNEAVVKLQETAEKTVYVL TALQDYINTNLVPTIDKISCKQTELSLDLALSKYLSDLLFVFGPNLQDPVSNSMTIQAI SQAFGGNYETLLRTLGYATEDFDDLLESDSITGQIIYVDLSSYYIIVRVYFPILTEIQQA YIQELLPVSFNNDNSEWISIVPNFILVRNTLISNIEIGFCLITKRSVICNQDYATPMTNN MRECLTGSTEKCPRELVVSSHVPRFALSNGVLFANCISVTCQCQTTGRAISQSGEQTL LMIDNTTCPTAVLGNVIISLGKYLGSVNYNSEGIAIGPPVFTDKVDISSQISSMNQSLQ QSKDYIKEAQRLLDTVNPSLISMLSMIILYVLSIASLCIGLITFISFIIVEKKRNTYSRLED RRVRPTSSGDLYYIGT (SEQ ID NO: 500)

[0258] BaEVRLess:MGFTTKIIFLYNLVLVYAGFDDPRKAIELVQKRYGRPCDCSGGQVSEPPSDRVSQVT CSGKTAYLMPDQRWKCKSIPKDTSPSGPLQECPCNSYQSSVHSSCYTSYQQCRSGNK TYYTATLLKTQTGGTSDVQVLGSTNKLIQSPCNGIKGQSICWSTTAPIHVSDGGGPLD TTRIKSVQRKLEEIHKALYPELQYHPLAIPKVRDNLMVDAQTLNILNATYNLLLMSN TSLVDDCWLCLKLGPPTPLAIPNFLLSYVTRSSDNISCLIIPPLLVQPMQFSNSSCLFSPS YNSTEEIDLGHVAFSNCTSITNVTGPICAVNGSVFLCGNNMAYTYLPTNWTGLCVLA TLLPDIDIIPGDEPVPIPAIDHFIYRPKRAIQFIPLLAGLGITAAFTTGATGLGVSVTQYT KLSNQLISDVQILSSTIQDLQDQVDSLAEVVLQNRRGLDLLTAEQGGICLALQEKCCF YVNKSGIVRDKIKTLQEELERRRKDLASNPLWTGLQGLLPYLLPFLGPLLTLLLLLTIG PCIFNRLTAFINDKLNIIHAM (SEQ ID NO: 501)

[0259] In some embodiments, the viral envelope glycoprotein domain comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of any SEQ ID NO:s: 377-379 or 494- 501.Stalk domainIn some embodiments, the eVLPs comprise a fusion protein comprising a stalk domain. Any suitable stalk domain known to one of ordinary skill in the art may be used to make the fusion proteins contemplated herein. In some embodiments, the stalk domain is selected from the group consisting of hCD8a-l, hCD8a-2, hIgG4-CH3, mCD3z, mCD4, mCD8a-l, mCD8a-2, hCD8a’, mCD28, hCD8, CD8 hinge region, Siglec-4:12, Siglec-1, Siglec-2, Siglec-3, Siglec- 7, IgGl-CH3, IgG4-CH2CH3, IgGl-CH2CH3, IgGl-1, IgGl-2, IgG2, IgG3, and IgG4. In some embodiments, the stalk domain is selected from the group consisting of hCD8a-l, hCD8a-2, hIgG4-CH3, mCD3z, mCD4, mCD8a-l, mCD8a-2, hCD8a’, mCD28, hCD8, Siglec-4:12, IgGl-CH3, IgG4-CH2CH3, IgGl-CH2CH3, IgGl-1, IgGl-2, IgG2, IgG3, and IgG4. In some embodiments, the stalk domain is selected from the group consisting of mmIgG2_l, mmIgG2_2, and mmIgG2_3. In some embodiments, the stalk domain is selected from the group consisting of IgG3_l, IgG3_2, IgG3_3, IgG3_4, IgG3_5, IgG3_6, IgGl_3, IgGl_4, IgG3_7, IgG2_l, and IgGl_3. In some embodiments, stalk domain is selected from the group consisting of IgAl_l, IgAl_2, IgAl_3, IgAl_4, IgA2_l, IgA2_2, IgA2_3, and IgA2_4. In some embodiments, the stalk domain is selected from the group consisting of IgD_l, IgD_2, IgD_3, IgD_4, IgE, IgM_l, IgM_2, IgM_3, and IgGl_4.

[0260] Non-limiting exemplary embodiments of possible stalk domains for use in any of the fusion proteins disclosed herein include:

[0261] COMP:GQSPLGSDLGPQMLRELQETNAALQDVRELLRQQVREITFLKNTVMECDACGMQQS VRTGLPSVR (SEQ ID NO: 502)

[0262] CD 8 a trunc:TTTPAPRPPTPAPTIASQPLSLRPEAC (SEQ ID NO: 503)

[0263] CD8 hinge region(TTTPAPRPPTPAPTIASQPLSLRPEAC) (SEQ ID NO: 894)

[0264] hCD8a-lTTTPAPRPPTPAPTIASQPLSLRPEACRPAAAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCS (SEQ ID. NO. 29)

[0265] hCD8a-2TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI (SEQ ID. NO. 30)

[0266] hIgG4 CH3PGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKS (SEQID. NO. 31)

[0267] mCD3zQSFGLLDPK (SEQ ID. NO. 32)

[0268] mCD4LSEGDKVKMDSRIQVLSRGVNQT (SEQ ID. NO. 33)

[0269] mCD8a-lNISNSVMYFSSVVPVLQKVNSTTTKPVLRTPSPVHPTGTSQPQRPEDCRPRGSVKGTGLDFACDIY (SEQ ID. NO. 34)

[0270] mCD8a-2TTTKPVLRTPSPVHPTGTSQPQRPEDCRPRGSVKGTGLDFACD (SEQ ID. NO. 35)

[0271] hCD8a’KPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY (SEQ ID. NO.36)

[0272] mCD28IEFMYPPPYLDNERSNGTIIHIKEKHLCHTQSSPKL (SEQ ID. NO. 37)

[0273] hCD8IEVMYPPPYLDNERSNGTIIHVKGKHLCPSPLFPGPSKP (SEQ ID. NO. 38)

[0274] Siglec-4:12PPVIVEMNSSVEAIEGSHVSLLCGADSNPPPLLTWMRDGTVLREAVAESLLLELEEVTPAEDGVYACLAENAYGQDNRTVGLSVMYAPWKPTVNGTMVAVEGETVSILCSTQSNPDPILTIFKEKQILSTVIYESELQLELPAVSPEDDGEYWCVAENQYGQRATAFNLSVEFAPVLLLESHCAAARDTVQCLCVVKSNPEPSVAFELPSRNVTVNESEREFVYSERSGLVLTSILTLRGQAQAPPRVICTARNLYGAKSLELPFQGAHRLMWAKIGPVGAV (SEQID. NO. 39)

[0275] Siglec 1MGFLPKLLLLASFFPAGQASWGVSSPQDVQGVKGSCLLIPCIFSFPADVEVPDGITAIWYYDYSGQRQVVSHSADPKLVEARFRGRTEFMGNPEHRVCNLLLKDLQPEDSGSYNFRFEISEVNRWSDVKGTLVTVTEEPRVPTIASPVELLEGTEVDFNCSTPYVCLQEQVRLQWQGQDPARSVTFNSQKFEPTGVGHLETLHMAMSWQDHGRILRCQLSVANHRAQSEIHLQVKYAPKGVKILLSPSGRNILPGELVTLTCQVNSSYPAVSSIKWLKDGVRLQ TKTGVLHLPQAAWSDAGVYTCQAENGVGSLVSPPISLHIFM (SEQ ID NO: 896).

[0276] Siglec 2MHLLGPWLLLLVLEYLAFSDSSKWVFEHPETLYAWEGACVWIPCTYRALDGDLESFILFHNPEYNKNTSKFDGTRLYESTKDGKVPSEQKRVQFLGDKNKNCTLSIHPVHLNDSGQLGLRMESKTEKWMERIHLNVSERPFPLHIQLPPEIQESQEVTLTCLLNFSCYGYPIQLQWLLEGVPMRQAAVTSTSLTIKSVFTRSELKFSPQWSHHGKIVTCQLQDADGKFLSNDTVQLNVKHTPKLEIKVTPSDAIVREGDSVTMTCEVSSSNPEYTTVSWLKDGTSLKKQNTFTLNLREVTKDQSGKYCCQVSNDVGPGRSEEVFLQVQYA (SEQ ID NO: 897).

[0277] Siglec 3MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLVPCTFFHPIPYYDKNSPVHGYWFREGAIISRDSPVATNKLDQEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFRMERGSTKYSYKSPQLSVHVTDLTHRPKILIPGTLEPGHSKNLTCSVSWACEQGTPPIFSWLSAAPTSLGPRTTHSSVLIITPRPQDHGTNLTCQVKFAGAGVTTERTIQLN (SEQ ID NO: 898)

[0278] Siglec 7MLPLQLPPLLWGRERVEGQKSNRKDYSLTMQSSVTVQEGMCVHVRCSFSYPVDSQTDSDPVHGYWFRAGNDISWKAPVATNNPAWAVQEETRDRFHLLGDPQTKNCTLSIRD ARMSDAGRYFFRMEKGNIKWNYKYDQLSVNVTALTHRPNILIPGTLESGCFQNLTCS VPWACEQGTPPMISWMGTSVSPLHPSTTRSSVLTLIPQPQHHGTSLTCQVTLPGAGVT TNRTIQLNVSYPPQNLTVTVFQGEGTASTALGNSSSLSVLEGQSLRLVCAVDSNPPAR LSWTWRSLTLYPSQPSNPLVLELQVHLGDEGEFTCRAQNSLGSQHVSLNLSL (SEQ ID NO: 899).

[0279] IgGl-CH3GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID.NO. 40)

[0280] IgG4-CH2CH3FLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID. NO. 41)

[0281] IgGl-CH2CH3GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID. NO. 42)

[0282] IgGl-1EPKSPDKTHTCPPCP (SEQ ID. NO. 43)

[0283] IgGl-2YVTVSSQDPAEPKSPDKTHTCPPCP (SEQ ID. NO. 44)

[0284] IgG2ERKCCVEVPPCP (SEQ ID. NO. 45)

[0285] IgG3ELKTPLGDTHTCPRCP (SEQ ID. NO. 46)

[0286] IgG4ESKYGPPCPPCP (SEQ ID. NO. 47)

[0287] Linker C2ETIRESKYGPPCPPCPGGGGSVP (SEQ ID. NO. 48)

[0288] CAR Spacer XSYVTVSSQDPAEPKSPDKTHTCPPCPKGKHLCPSPLFPGPSKP (SEQ ID. NO. 49)

[0289] CAR Spacer ISYVTVSSQDPAEPKSPDKTHTCPPCPGGGGSAKPSAPWSGPAARATPQHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPVGESVSYSIHSTAKVVLTREDVHSQVICEVAHVTLQGDPLRGTANLS (SEQ ID. NO. 50)

[0290] CAR Spacer 2SYVTVSSQDPAEPKSPDKTHTCPPCPGGGGSVPPTLEVTQQPVRAENQVNVTCQVRKFYPQRLQL TWLENGNVSRTETASTVTENKDGTYNWMSWLLVNVSAHRDDVKLTCQVEHDGQPAVSKSHDLKVS (SEQ ID. NO. 51)

[0291] CAR spacer XISYVTVSSQDPAEPKSPDKTHTCPPCPGGGGSAKPSAPWSGPAARATPQHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPVGESVSYSIHSTAKVVLTREDVHSQVICEVAHVTLQGDPLRGTANLSGGGGSKGKHLCPS PLFPGPSKP (SEQ ID. NO. 52)

[0292] CAR spacer X2SYVTVSSQDPAEPKSPDKTHTCPPCPGGGGSVPPTLEVTQQPVRAENQVNVTCQVRKFYPQRLQL TWLENGNVSRTETASTVTENKDGTYNWMSWLLVNVSAHRDDVKLTCQVEHDGQPAVSKSHDLKVSKGKHLCPSPLFP GPSKP(SEQ ID. NO. 53)

[0293] CAR spacer MYVTVSSQDPAEPKSPDKTHTCPPCPGGGGSAKPSAPWSGPAARATPQ HTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPVGESVSYSIHST AKVVLTREDVHSQVICEVAHVTLQGDPLRGTANLSETIRVPPTLEVTQQ PVRAENQVNVTCQVRKFYPQRLQLTWLENGNVSRTETASTVTENKDG TYNWMSWLLVNVSAHRDDVKLTCQVEHDGQPAVSKSHDLKVS (SEQ ID. NO. 54)

[0294] CAR spacer XMYVTVSSQDPAEPKSPDKTHTCPPCPGGGGSAKPSAPWSGPAARATPQ HTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPVGESVSYSIHST AKVVLTREDVHSQVICEVAHVTLQGDPLRGTANLSETIRVPPTLEVTQQ PVRAENQVNVTCQVRKFYPQRLQLTWLENGNVSRTETASTVTENKDG TYNWMSWLLVNVSAH RDDVKL TCQVEHDGQPAVSKSHDLKVSKGKH LCPSPLFPG PSKP (SEQ ID. NO. 55)

[0295] CAR spacer LYVTVSSQDPAEPKSPDKTHTCPPCPGGGGSVPPTLEVTQQPVRAENQ VNVTCQVRKFYPQRLQL TWLENGNVSRTETASTVTENKDGTYNWMS WLLVNVSAH RDDVKL TCQVEHDGQPAVSKSH DLKVSGGGGSAKPSAP WSGPAARATPQHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVD PVGESVSYSIHSTAKWLTREDVHSQVICEVAHVTLQGDPLRGTANLSE TIRVPPTLEVTQQPVRAENQVNVTCQVRKFYPQRLQL TWLENGNVSR TET ASTVTENKDGTYNWMSWLLVNVSAHRDDVKL TCQVEH DGQPAV SKSHDLKVS (SEQ ID. NO. 56)

[0296] CAR spacer XLYVTVSSQDPAEPKSPDKTHTCPPCPGGGGSVPPTLEVTQQPVRAENQ VNVTCQVRKFYPQRLQL TWLENGNVSRTETASTVTENKDGTYNWMS WLLVNVSAH RDDVKL TCQVEHDGQPAVSKSH DLKVSGGGGSAKPSAP WSGPAARATPQHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPVGESVSYSIHSTAKWLTREDVHSQVICEVAHVTLQGDPLRGTANLSETIRVPPTLEVTQQPVRAENQVNVTCQVRKFYPQRLQL TWLENGNVSR TET ASTVTENKDGTYNWMSWLLVNVSAHRDDVKL TCQVEH DGQPAV SKSHDLKVSKGKHLCPSPLFPGPSKP (SEQ ID. NO. 57)

[0297] mmIgG2_lKPCPPCKCP (SEQ ID. NO. 58)

[0298] mmIgG2_2KPCPPCKCPAP (SEQ ID. NO. 59)

[0299] mmIgG2_3GPTIKPCPPCKCPAP (SEQ ID. NO. 60)

[0300] IgG3_lELKTPLGDTTHTCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPAP (SEQ ID. NO. 61)

[0301] IgG3_2CPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPAP (SEQ ID.NO. 62)

[0302] IgG3_3EPKSCDTPPPCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPAP (SEQ ID. NO. 63)

[0303] IgG3_4EPKSCDTPPPCPRCPEPKSCDTPPPCPRCPAP (SEQ ID. NO. 64)

[0304] IgG3_5CPRCPEPKSCDTPPPCPRCPAP (SEQ ID. NO. 65)

[0305] IgG3_6EPKSCDTPPPCPRCPAP (SEQ ID. NO. 66)

[0306] IgGl_3EPKSCDKTHTCPPCPAP (SEQ ID. NO. 67)

[0307] IgGl_4PKSCDKTHTCPPCPAP (SEQ ID. NO. 68)

[0308] IgG3_7PCPRCPAP (SEQ ID. NO. 69)

[0309] IgG2_lPCPAPPVAG PS (SEQ ID. NO. 70)

[0310] IgGl_3PPKPKDT (SEQ ID. NO. 71)

[0311] IgAl_lTVPCPVPSTPPTPSPSTPPTPSPSCCHP (SEQ ID. NO. 72)

[0312] IgA 1_2TVPCPVPSTP (SEQ ID. NO. 73)

[0313] IgA 1_3TPSPSTPPTP (SEQ ID. NO. 74)

[0314] IgA 1_4TPSPSCCHP (SEQ ID. NO. 75)

[0315] IgA2_lVPCPVPPPPPCCHPR (SEQ ID. NO. 76)

[0316] IgA2_2VPCPVPP (SEQ ID. NO. 77)

[0317] IgA2_3PPPCCHP (SEQ ID. NO. 78)

[0318] IgA2_4PCPVPPPPPCCHP (SEQ ID. NO. 79)

[0319] IgD_lRWPESPKAQASSVPTAQPQAEGSLAKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPE CP5HTQPLGVYLLTP (SEQ ID. NO. 80)

[0320] IgD_2KTPECPSHTQPLGVYLLTP (SEQ ID. NO. 81)

[0321] IgD_3PECPSHTQPLGVYLLTP (SEQ ID. NO. 82)

[0322] IgD_4RWPESPKAQASSVP (SEQ ID. NO. 83)

[0323] IgESVCSRDFTPP (SEQ ID. NO. 84)

[0324] IgM_lPLPVIAELPPKVSVFVPPRDGFFGNP (SEQ ID. NO. 85)

[0325] IgM_2PLPVIAELPP (SEQ ID. NO. 86)

[0326] IgM_3ELPPKVSVFVPP (SEQ ID. NO. 87)

[0327] IgGl_4AEPKSPDKTHTCPPCPKDPK (SEQ ID. NO. 88)

[0328] PDGFRWSACRDLKRCPRELPPTLLGNSSEEESQLETNVTYWEEEQEFEVVSTLR (SEQ ID NO: 404)

[0329] In some embodiments, the stalk domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of any SEQ ID NO:s: 29-88, 404, 502-503, 894, or 896-899.Targeting domain

[0330] In some embodiments, the eVLPs comprise a fusion protein comprising a targeting domain. Any suitable targeting domain known to one of ordinary skill in the art may be used to make the fusion proteins contemplated herein. In some embodiments, the targeting domain is a cytokine. In some embodiments, the targeting domain is a protein. Other targeting domains are possible in other embodiments. For example, in certain embodiments, the targeting domain is a (poly)nucleic acid, a glycoprotein, a protein, a peptide, or a small molecule. In some embodiments, the targeting domain comprises an antibody or an aptamer.

[0331] In some embodiments, the targeting domain is not a viral envelope glycoprotein. In other embodiments the targeting domain is not a fragment of an antibody domain.

[0332] In some embodiments, the targeting domain is configured to bind to a specific target, e.g., a receptor on a specific cell type. The target domain, according to some embodiments, preferentially binds to human hematopoietic stem and progenitor cell (e.g., HSPCs). Without wishing to be bound by any particular theory, it is believed that HSPCs comprise a plurality of cell types. In some embodiments, the target cell type within the family of HSPC cells is the long term HSCs (LT-HSCs) which have both self-renewal and multi-lineage potential. Other target cells within the HSPC family of cells include short term HSCs (ST-HSCs), Multi-Potent Progenitor cells (MPPs), Common Myeloid Progenitor cells (CMPs), Common Lymphoid Progenitor cells (CLPs), Megakaryocyte-erythroid progenitor cells (MEPs), granulocyte-monocyte progenitor cells (GMPs), neutrophils, megakaryocytes,platelets, erythrocytes, monocytes, macrophages, basophils, lymphocytes, dendritic cells, T cells, B cells, according to other embodiments.

[0333] Again, without wishing to be bound by any particular theory, it is believed that the cells within the HSPC family may be identified by various surface markers. For example, cells expressing CD201+CD150+CD48- Lin‘ c-Kit+Sca-l+or CD34-Flk2_Lin-c-Kit+Sca-l+are considered in the art to be LT-HSC cells, according to some embodiments. LT-HSC cells can be further differentiated into ST-HSC cells which express CD34+Flk2-Lin-c-Kit+Sca-l+, in other embodiments. ST-HSC cells may then differentiate into MPP cells expressing CD34+Flk2+Lin-c-Kit+Sca-l+or CD150-CD48-Lin_c-Kit+Sca-l+, according to certain embodiments. MPP cells may then either differentiate into CMP cells (e.g., expressing CD34+FcyRIVIIIlowLin_c-Kit+Sca-l-) or CLP cells (e.g., expressing Lin-c-KitlowSca- llowIL7Ra+Flk2+), according to another set of embodiments. CMP cells may further differentiate into MEP cells (e.g., expressing CD34+FcyRIFIIl-Lin-c-Kit+Sca-l-) or GMP cells (e.g., expressing CD34+FcyRIFIII+Lin-c-Kit+Sca-l-); whereas CLP cells further differentiate into dendritic cells, T-cells, NK cells, and B-cells. MEP cells are known to further differentiate into megakaryocytes and erythrocytes; whereas GMP cells may differentiate into basophils, neutrophils, eosinophils, monocytes, and dendritic cells.Monocytes may also further differentiate into macrophages and monocyte derived dendritic cells.

[0334] In some embodiments, the targeting domain binds to target proteins on T cells and / or B cells. Exemplary targeting domains and their target receptor on T cells are shown below:Exemplary targeting domains and their target receptor on B cells are shown below:

[0335] In some embodiments, the targeting domain may bind to any known “receptor” on a target cell surface. Those of skill in the art will understand that the term “receptor” as used herein does not require any signaling event to occur upon binding of the targeting domain to the target receptor, although such a signaling event is not precluded from occurring. As such, the receptor may be any moiety present on the cell surface, including but not limited to glycoproteins, proteins (e.g., globular proteins, lipid anchored proteins, peripheral proteins), carbohydrates, glycolipids, lipids, and / or complexes formed therefrom. Exemplary receptor: targeting domains contemplated herein include, but are not limited to, CD110:Thrombopoientin (TPO), c-kit:Stem Cell Factor (SCF), CXCR4:CXCL12, CD46:Adenovirus F35 (AdF35), CD201:Protein C, CD150:SH2DlA / EAT-2, CD45:CMV ULll / PP14 / adenovirus E3, CD54:LFA-1, CD55:CD97, CD58:CD2, CD59:CD2, CD100:Plexin-B2, CD120:TNFa / b, CD124:IL-4, and Flk2:Flt3.

[0336] Non-limiting exemplary embodiments of possible targeting domains for use in any of the fusion proteins disclosed herein include:

[0337] CALR-del52

[0338] LLSVPLLLGLLGLAVAEPAVYFKEQFLDGDGWTSRWIESKHKSDFGKFVL SSGKFYGDEEKDKGLQTSQDARFYALSASFEPFSNKGQTLVVQFTVKHEQNIDCGGG YVKLFPNSLDQTDMHGDSEYNIMFGPDICGPGTKKVHVIFNYKGKNVLINKDIRCKD DEFTHLYTLIVRPDNTYEVKIDNSQVESGSLEDDWDFLPPKKIKDPDASKPEDWDER AKIDDPTDSKPEDWDKPEHIPDPDAKKPEDWDEEMDGEWEPPVIQNPEYKGEWKPR QIDNPDYKGTWIHPEIDNPEYSPDPSIYAYDNFGVLGLDLWQVKSGTIFDNFLITNDE AYAEEFGNETWGVTKAAEKQMKDKQDEEQRTRRMMRTKMRMRRMRRTRRKMRR KMSPARPRTSCREACLQGWTEA (SEQ ID NO: 343)

[0339] CALR-ins5

[0340] LLSVPLLLGLLGLAVAEPAVYFKEQFLDGDGWTSRWIESKHKSDFGKFVL SSGKFYGDEEKDKGLQTSQDARFYALSASFEPFSNKGQTLVVQFTVKHEQNIDCGGG YVKLFPNSLDQTDMHGDSEYNIMFGPDICGPGTKKVHVIFNYKGKNVLINKDIRCKD DEFTHLYTLIVRPDNTYEVKIDNSQVESGSLEDDWDFLPPKKIKDPDASKPEDWDER AKIDDPTDSKPEDWDKPEHIPDPDAKKPEDWDEEMDGEWEPPVIQNPEYKGEWKPR QIDNPDYKGTWIHPEIDNPEYSPDPSIYAYDNFGVLGLDLWQVKSGTIFDNFLITNDEAYAEEFGNETWGVTKAAEKQMKDKQDEEQRLKEEEEDKKRKEEEEAEDNCRRMMRTKMRMRRMRRTRRKMRRKMSPARPRTSCREACLQGWTEA (SEQ ID NO: 344)

[0341] CXCL12

[0342] NAKVVVVLVLVLTALCLSDGKPVSLSYRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQVCIDPKLKWIQEYLEKALNK (SEQ ID NO: 345)

[0343] AdF35TKRVRLSDSFNPVYPYEDESTSQHPFYNPGFISPNGFTQSPDGVLTLKCLTPLTTTGGSLQLKVGGGLTVDDTDGTLQENIRATAPITKNNHSVELSIGNGLETQNNKLCAKLGNGLKFNNGDICIKDSINTLWTGINPPPNCQIVENTNTNDGKLTLVLVKNGGLVNGYVSLV GVSDTVNQMFTQKTANIQLRLYFDSSGNLLTEESDLKIPLKNKSSTATSETVASSKAF MPSTTAYPFNTTTRDSENYIHGICYYMTSYDRSLFPLNISIMLNSRMISSNVAYAIQFEWNLNASESPESNIATLTTSPFFFSYITEDDN (SEQ ID NO: 346)

[0344] mSCF solubleEICGDPVTDNVKDITKLVANLPNDYMITLNYVAGMDVLPSHCWLRDMLIQLSLSLTTLLDKLSNISEGLSNYSIIHKLGIIVDDLFFCMEENAPKNRKEFPKRPETRSFTPEEFFSIFNRSIDAFKDFMVASDTSDCVLSSTLGPEKDSRVSVTKPFMLPPVAAS (SEQ ID NO: 347)

[0345] mSCF soluble (V49L / F63L)EICGDPVTDNVKDITKLVANLPNDYMITLNYVAGMDVLPSHCWLRDMLIQLSLSLTTLLDKLSNISEGLSNYSIIHKLGIIVDDLFFCMEENAPKNIKEFPKRPETRSFTPEEFFSIFN RSIDAFKDFMVASDTSDCVLSSTLGPEKDSRVSVTKPFMLPPVAAS (SEQ ID NO: 387)

[0346] SCFKKTQTWILTCIYLQLLLFNPLVKTEGICRNRVTNNVKDVTKLVANLPKDYMITLKYVPGMDVLPSHCWISEMVVQLSDSLTDLLDKFSNISEGLSNYSIIDKLVNIVDDLVECVK ENSSKDLKKSFKSPEPRLFTPEEFFRIFNRSIDAFKDFVVASETSDCVVSSTLSPEKDSR VSVTKPFMLPPVAASSLRNDSSSSNRKAKNPPGDSSLHWAAMALPALFSLIIGFAFGA LYWKKRQPSLTRAVENIQINEEDNEISMLQEKEREFQEV (SEQ ID NO: 348)

[0347] SCF mutant (V49L / F63L / K91E / I98R)KKTQTWILTCIYLQLLLFNPLVKTEGICRNRVTNNVKDVTKLVANLPKDYMITLKYV PGMDVLPSHCWISEMLVQLSDSLTDLLDKLSNISEGLSNYSIIDKLVNIVDDLVECVE ENSSKDRKKSFKSPEPRLFTPEEFFRIFNRSIDAFKDFVVASETSDCVVSSTLSPEKDSR VSVTKPFMLPPVAASSLRNDSSSSNRKAKNPPGDSSLHWAAMALPALFSLIIGFAFGALYWKKRQPSLTRAVENIQINEEDNEISMLQEKEREFQEV (SEQ ID NO: 349)

[0348] SCF mutant (V49L / F63L / K9 IE)KKTQTWILTCIYLQLLLFNPLVKTEGICRNRVTNNVKDVTKLVANLPKDYMITLKYV PGMDVLPSHCWISEMLVQLSDSLTDLLDKLSNISEGLSNYSIIDKLVNIVDDLVECVE ENSSKDLKKSFKSPEPRLFTPEEFFRIFNRSIDAFKDFVVASETSDCVVSSTLSPEKDSR VSVTKPFMLPPVAASSLRNDSSSSNRKAKNPPGDSSLHWAAMALPALFSLIIGFAFGALYWKKRQPSLTRAVENIQINEEDNEISMLQEKEREFQEV (SEQ ID NO: 350)

[0349] SCF mutant (V49L / F63L)KKTQTWILTCIYLQLLLFNPLVKTEGICRNRVTNNVKDVTKLVANLPKDYMITLKYV PGMDVLPSHCWISEMLVQLSDSLTDLLDKLSNISEGLSNYSIIDKLVNIVDDLVECVK ENSSKDLKKSFKSPEPRLFTPEEFFRIFNRSIDAFKDFVVASETSDCVVSSTLSPEKDSR VSVTKPFMLPPVAASSLRNDSSSSNRKAKNPPGDSSLHWAAMALPALFSLIIGFAFGALYWKKRQPSLTRAVENIQINEEDNEISMLQEKEREFQEV (SEQ ID NO: 351)

[0350] SCF solubleEGICRNRVTNNVKDVTKLVANLPKDYMITLKYVPGMDVLPSHCWISEMVVQLSDSL TDLLDKFSNISEGLSNYSIIDKLVNIVDDLVECVKENSSKDLKKSFKSPEPRLFTPEEFF RIFNRSIDAFKDFVVASETSDCVVSSTLSPEKDSRVSVTKPFMLPPVAA (SEQ ID NO:352)

[0351] SCF soluble mutant (V49L / F63L / K91E / I98R)EGICRNRVTNNVKDVTKLVANLPKDYMITLKYVPGMDVLPSHCWISEMLVQLSDSL TDLLDKLSNISEGLSNYSIIDKLVNIVDDLVECVEENSSKDRKKSFKSPEPRLFTPEEFF RIFNRSIDAFKDFVVASETSDCVVSSTLSPEKDSRVSVTKPFMLPPVAA (SEQ ID NO:353)

[0352] SCF soluble mutant (V49L / F63L / K9 IE)EGICRNRVTNNVKDVTKLVANLPKDYMITLKYVPGMDVLPSHCWISEMLVQLSDSLTDLLDKLSNISEGLSNYSIIDKLVNIVDDLVECVEENSSKDLKKSFKSPEPRLFTPEEFFRIFNRSIDAFKDFVVASETSDCVVSSTLSPEKDSRVSVTKPFMLPPVAA (SEQ ID NO:354)

[0353] SCF soluble mutant (V49L / F63L)EGICRNRVTNNVKDVTKLVANLPKDYMITLKYVPGMDVLPSHCWISEMLVQLSDSLTDLLDKLSNISEGLSNYSIIDKLVNIVDDLVECVKENSSKDLKKSFKSPEPRLFTPEEFFRIFNRSIDAFKDFVVASETSDCVVSSTLSPEKDSRVSVTKPFMLPPVAA (SEQ ID NO:355)

[0354] TPO-157ELTELLLVVMLLLTARLTLSSPAPPACDLRVLSKLLRDSHVLHSRLSQCPEVHPLPTPVLLPAVDFSLGEWKTQMEETKAQDILGAVTLLLEGVMAARGQLGPTCLSSLLGQLSGQVRLLLGALQSLLGTQLPPQGRTTAHKDPNAIFLSFQHLLR (SEQ ID NO: 356)

[0355] TPO-163ELTELLLVVMLLLTARLTLSSPAPPACDLRVLSKLLRDSHVLHSRLSQCPEVHPLPTPVLLPAVDFSLGEWKTQMEETKAQDILGAVTLLLEGVMAARGQLGPTCLSSLLGQLSGQVRLLLGALQSLLGTQLPPQGRTTAHKDPNAIFLSFQHLLRGKVRFL (SEQ ID NO: 357)

[0356] TPO-171ELTELLLVVMLLLTARLTLSSPAPPACDLRVLSKLLRDSHVLHSRLSQCPEVHPLPTPVLLPAVDFSLGEWKTQMEETKAQDILGAVTLLLEGVMAARGQLGPTCLSSLLGQLSGQVRLLLGALQSLLGTQLPPQGRTTAHKDPNAIFLSFQHLLRGKVRFLMLVGGSTL(SEQ ID NO: 358)

[0357] TPOELTELLLVVMLLLTARLTLSSPAPPACDLRVLSKLLRDSHVLHSRLSQCPEVHPLPTPVLLPAVDFSLGEWKTQMEETKAQDILGAVTLLLEGVMAARGQLGPTCLSSLLGQLSGQVRLLLGALQSLLGTQLPPQGRTTAHKDPNAIFLSFQHLLRGKVRFLMLVGGSTLC VRRAPPTTAVPSRTSLVLTLNELPNRTSGLLETNFTASARTTGSGLLKWQQGFRAKIP GLLNQTSRSLDQIPGYLNRIHELLNGTRGLFPGPSRRTLGAPDISSGTSDTGSLPPNLQ PGYSPSPTHPPTGQYTLFPLPPTLPTPVVQLHPLLPDPSAPTPTPTSPLLNTSYTHSQNL SQEG (SEQ ID NO: 359)

[0358] CXCL11MSVKGMAIALAVILCATVVQGFPMFKRGRCLCIGPGVKAVKVADIEKASIMYPSNN DKIEVIITLKENKGQRCLNPKSKQARLIIKKVERKNF(SEQ ID NO: 360)

[0359] CXCL4MSSAAGFCASRPGLLFLGLLLLPLVVAFASAEAEEDGDLQCLCVKTTSQVRPRHITSL EVIKAGPHCPTAQLIATLKNGRKICLDLQAPLYKKIIKKLLES (SEQ ID NO: 361)

[0360] CXCL14 (SEQ ID NO: 362)MRLLAAALLLLLLALYTARVDGSKCKCSRKGPKIRYSDVKKLEMKPKYPHCEEKM VIITTKSVSRYRGQEHCLHPKLQSTKRFIKWYNAWNEKRRVYEE (SEQ ID NO: 362)

[0361] 53E11 a-hCD8 DARPinMDLGKKLLEAARAGQDDEVRILMTNGADVNALDQAGSTPLHLAAWHGHLEIVEVL LKYGADVNASDIIGQTPLHLAALNGHLEIVEVLLKNGADVNARDRLGETPLHLAAFD GHLEIVEVLLKYDADVNAQDKFGKTPFDLAIDNGNEDIAEVLQKAA (SEQ ID NO: 900).

[0362] CD8 51.1-Xencor-H1L1 scFvMQIQLVQSGAEVKKPGASVKVSCKASGYSFTNFGMIWRQAPGQGLEWMGWINTYT GEPTYADGFTGRFVFSLQTSVNTAYLQISSLKAEDTAVYFCARKQYAGFFDYWGQG TLVTVSSGGGGSGGGGSGGGGSDILMTQSPSSLSASVGDRVTITCQASQDIGSNMGW LQQKPGKSFKALIYHGINLEYGVPSRFSGSGSGADYTLTISSLQPEDFATYYCVQFAQ FPYTFGGGTKVEIK (SEQ ID NO: 901).

[0363] 53F6 a-hCD8 DARPinDLGKKLLEASRAGQDDEVRILMANGADVNAQDRYGTTPLHLAAWHGHLEIVEVLL KHGADVNANDVKGNTPLHLAANVGHLEIVEVLLKYGADVNAADNWGHTPLHLAA FWGHLEIVEVLLKYGADVNAQDKFGKTPFDLAIDNGNEDIAEVLQKAA (SEQ ID NO: 902).

[0364] 53F6 a-hCD8 DARPinDLGKKLLEASRAGQDDEVRILMANGADVNAQDRYGTTPLHLAAWHGHLEIVEVLL KHGADVNANDVKGNTPLHLAANVGHLEIVEVLLKYGADVNAADNWGHTPLHLAA FWGHLEIVEVLLKYGADVNAQDKFGKTPFDLAIDNGNEDIAEVLQKAA (SEQ ID NO: 903).

[0365] 63A4 a-hCD8 DARPinMDLGKKLLEAVRAGKDDEVRILMANGADVNAEDTQGNTPLHLVAWHGHLEIVEVL LKYGADVNASDIIGQTPLHLAALNGHLEIVEVLLKYGADVNAWDRHGHTPLHLAAY FGHLEIVEVLLKNGADVNAQDKFGKTPFDLAIDNGNEDIAEVLQKAA (SEQ ID NO: 904).

[0366] AcapatamabCDQVQLVESGGGLVKPGESLRLSCAASGFTFSDYYMYWVRQAPGKCLEWVAIISDG GYYTYYSDIIKGRFTISRDNAKNSLYLQMNSLKAEDTAVYYCARGFPLLRHGAMDY WGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVD TNVAWYQQKPGQAPCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATY YADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWG QGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGN YPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYY CVLWY (SEQ ID NO: 905).

[0367] Acapatamab Vh-VkQVQLVESGGGLVKPGESLRLSCAASGFTFSDYYMYWVRQAPGKCLEWVAIISDGGY YTYYSDIIKGRFTISRDNAKNSLYLQMNSLKAEDTAVYYCARGFPLLRHGAMDYWG QGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVDTNVAWYQQKPGQAPCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVR (SEQ ID NO: 906).

[0368] Acapatamab Vh-VlEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISY WAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTG AVTSGNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPE DEAEYYCVLWYSNRWVFGGGTKLTVL (SEQ ID NO: 907).

[0369] CD3 DARPin-C7vl4MDLGQKLLEAAWAGQDDEVRILLAAGADVNAKNSRGWTPLHTAAQTGHLEIFEVL LKAGADVNAKNDKRVTPLHLAAALGHLEIVEVLLKAGADVNARDSWGTTPADLAA KYGHGDIAEVLQKAA (SEQ ID NO: 908).

[0370] CD3 DARPin-C7v 118MDLGQKLLEAAWAGQDDEVRELLKAGADVNAKDSQGWTPLHTAAQTGHLEIFEVL LKAGADVNAKDDKGVTPLHLAAALGHLEIVEVLLKAGADVNAQDSWGTTPADLAA KYGHEDIAEVLQKAA (SEQ ID NO: 909).

[0371] CD3 DARPin-C7vll9MDLGQKLLEAAWAGQDDEVRELLKAGADVNAKNSRGWTPLHTAAQTGHLEIFEVL LKAGADVNAKDDKGVTPLHLAAALGHLEIVEVLLKAGADVNAQDSWGTTPADLAA KYGHEDIAEVLQKAA (SEQ ID NO: 910).

[0372] CD3 DARPin-C7vl22MDLGQKLLEAAWAGQDDEVRELLKAGADVNAKNSRGWTPLHTAAQTGHLEIFEVL LKAGADVNAKNDKRVTPLHLAAALGHLEIVEVLLKAGADVNARDSWGTTPADLAA KYGHQDIAEVLQKAA (SEQ ID NO: 911).

[0373] CD3 DARPin-C7vl27MDLGQKLLEAAWAGQLDEVRILLKAGADVNAKNSRGWTPLHTAAQTGHLEIFEVL LKAGADVNAKTNKRVTPLHLAAALGHLEIVEVLLKAGADVNARDTWGTTPADLAA KYGHRDIAEVLQKAA (SEQ ID NO: 912).

[0374] scFv-CD3-lMEVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPY KGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYF DVWGAGTTVTVSSGGGGSGGGGSGGGGSDIQMTQTTSSLSASLGDRVTISCRASQDI RNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYF CQQGNTLPWTFAGGTKLEIK (SEQ ID NO: 913).

[0375] scFv-CD3-2DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSG VPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIKGGGGSGGG GSGGGGSEVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSHGKNLEWM GLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGD SDWYFDVWGAGTTVTVSS (SEQ ID NO: 914).

[0376] scFv-CD3-3MQVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPS RGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYW GQGTTLTVSSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSSVSYM NWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQ QWSSNPFTFGSGTKLEIN (SEQ ID NO: 915).

[0377] scFv-CD3-4MEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSK YNNYATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYIS YWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQP EDEAEYYCVLWY (SEQ ID NO: 916).

[0378] scFv-CD4-lQVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYND GTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAY WGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERVTMNCKSSQSLL YSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAE DVAVYYCQQYYSYRTFGGGTKLEIK (SEQ ID NO: 917).

[0379] scFv-CD4-2MDIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIY WASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIK GGGGSGGGGSGGGGSQVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQK PGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYC AREKDNYATGAWFAYWGQGTLVTVSS (SEQ ID NO: 918).

[0380] Sana CD 19 scFv FMC63 G4S linkerDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGV PSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGG SGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVI WGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAM DYWGQGTSVTVSS (SEQ ID NO: 919).

[0381] Sana CD22 scFv m971-L7QVQLQQSGPGMVKPSQTLSLTCAISGDSVSSNSVAWNWIRQSPSRGLEWLGRTYYR STWYNDYAVSMKSRITINPDTNKNQFSLQLNSVTPEDTAVYYCAREVTGDLEDAFDI WGQGTMVTVSSGGGGSGGGGSGGGGSDIQMIQSPSSLSASVGDRVTITCRASQTIWS YLNWYRQRPGEAPNLLIYAASSLQSGVPSRFSGRGSGTDFTLTISSLQAEDFATYYCQQSYSIPQTFGQGTKLEIK (SEQ ID NO: 920).

[0382] CD28 scFvDIQMNQSPSSLSASLGDTITITCHASQNIYVWLNWYQQKPGNIPKLLIYKASNLHTGV PSRFSGSGSGTGFTLTISSLQPEDIATYYCQQGQTYPYTFGGGTKLEIKRADAAPTVSI FPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYS MSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNGGGGSGGGGSGGGGSSQVQLQQSGPELVKPGTSVRISCEASGYTFTSYYIHWVKQRPGQGLEWIGCIYPGNVNTNY NEKFKDKATLIVDTSSNTAYMQLSRMTSEDSAVYFCTRSHYGLDWNFDVWGAGTT VTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHT FPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDC (SEQ ID NO: 921).

[0383] hCDl 17 scFv Ab54 CA3079215A1QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGT ANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLDTDEFDLWGRGT LVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSINSYLNWY QQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVSDI TFGGGTKVEIK (SEQ ID NO: 922).

[0384] hCDl 17 scFv Ab55 CA3079215A1QVQLVQSGAEVKKPGSSVKVSCKASGGTFRIYAISWVRQAPGQGLEWMGGIIPDFG VANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLDTDEFDLWGRG TLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSINSYLNW YQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVS DITFGGGTKVEIK (SEQ ID NO: 923).

[0385] hCDl 17 scFv Ab56 CA3079215A1QVQLVQSGAEVKKPGSSVKVSCKASGGTFSLYAISWVRQAPGQGLEWMGGIIPAFG TANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLDTDEFDLWGRG TLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSINSYLNW YQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVS DITFGGGTKVEIK (SEQ ID NO: 924).

[0386] hCDl 17 scFv Ab57 CA3079215A1QVQLVQSGAEVKKPGSSVKVSCKASGGTFSLYAISWVRQAPGQGLEWMGGIIPHFG LANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLDTDEFDLWGRG TLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSINSYLNW YQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVS DITFGGGTKVEIK (SEQ ID NO: 925).

[0387] hCD117 scFv Ab61 CA3079215A1EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYVMIWVRQAPGKGLEWVSSISGDSVT TYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGPPTYHTNYYYMDV WGKGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGISS WLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ QTNSFPYTFGGGTKVEIK (SEQ ID NO: 926).

[0388] hCDl 17 scFv Ab66 CA3079215A1EVQLVESGGGLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPGKGLEWVGRTRNKA SSYTTEYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCAREPKYWIDFDLW GRGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQS YIAPYTFGGGTKVEIK (SEQ ID NO: 927).

[0389] hCDl 17 scFv Ab67 CA3079215A1EVQLVESGGGLVQPGGSLRLSCAASGFTFSDADMDWVRQAPGKGLEWVGRTRNKA GSYTTEYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCAREPKYWIDFDLW GRGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQS YIAPYTFGGGTKVEIK (SEQ ID NO: 928).

[0390] hCDl 17 scFv Ab68 CA3079215A1EVQLVESGGGLVQPGRSLRLSCTASGFTFSDHDMNWVRQAPGKGLEWVGRTRNAA GSYTTEYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCAREPKYWIDFDLW GRGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQS YIAPYTFGGGTKVEIK (SEQ ID NO: 929).

[0391] hCDl 17 scFv Ab69 CA3079215A1EVQLVESGGGLVQPGGSLRLSCAASGFTFVDHDMDWVRQAPGKGLEWVGRTRNKL GSYTTEYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCAREPKYWIDFDLW GRGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYIAPYTFGGGTKVEIK (SEQ ID NO: 930).

[0392] USPTO 6,054,297 genentech hCDl 17 scFvEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYAMSWVRQAPGKGLEWVAVISENGS DTYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDRGGAVSYFDVWG QGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDVSSYL AWYQQKPGKAPKLLIYAASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQY NSLPYTFGQGTKVEIKRT (SEQ ID NO: 931).

[0393] Sana CD8 scFv form 1QVQLVQSGAEVKKPGASVKVSCKASSYYIHMHWVRQAPGQGLEWMGRRINPKSGR TYYAQNFQGNYAQKFQGRVTSTRDTSISTAYMELSRLRSDDTVVYYCLTEGIPDYW GQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQNIGTW LAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQTFGPGTKVDIKRFGGGTKVEIK (SEQ ID NO: 932).

[0394] Sana CD8 scFv form 2QVQLVQSGAEVKKPGASVKVSCKASSYYIHMHWVRQAPGQGLEWMGRRINPKSGR TYYAQNFQGNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTVVYYCLTEGIPDYW GQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQNIGTW LAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SYSTPQTFGPGTKVDIKRFGGGTKVEIK (SEQ ID NO: 933).

[0395] Sana CD8 scFv form 3QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIRINPK SGRTYYAQNFQGSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCLTEGIP DYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQNI GTWLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY CQQSYSTPQTFGPGTKVDIKRFGGGTKVEIK (SEQ ID NO: 934).

[0396] Sana CD8 scFv form 4QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGRINPK SGRTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTVVYYCARLTEGIPDYWGQG TTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQNIGTWLAW YQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYST PQTFGPGTKVDIKRFGGGTKVEIK (SEQ ID NO: 935).

[0397] Sana CD8 scFv form 5QVQEVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGEEWMGIINPKS GRTSYAQKFQGRVTMTRDTSTSTVYMEESSERSEDTAVYYCARETEGIPDYWGQGT TVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSESASVGDRVTITCRASQNIGTWEAWY QQKPGKAPKEEIYAASTEQSGVPSRFSGSGSGTDFTETISSEQPEDFATYYCQQSYSTP QTFGPGTKVDIKRFGGGTKVEIK (SEQ ID NO: 936).

[0398] Sana CD8 scFv form 6DIQMTQSPSSLSASVGDRVTITCRASQNIGTWLAWYQQKPGKAPKLLIYAASTLQSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQTFGPGTKVDIKRFGGGTKVE IKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASSYYIHMHWVRQAP GQGLEWMGRRINPKSGRTYYAQNFQGNYAQKFQGRVTSTRDTSISTAYMELSRLRS DDTVVYYCARLTEGIPDYWGQGTTVTVSS (SEQ ID NO: 937).

[0399] Sana CD8 scFv form 7DIQMTQSPSSLSASVGDRVTITCRASQNIGTWLAWYQQKPGKAPKLLIYAASTLQSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQTFGPGTKVDIKRFGGGTKVE IKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASSYYIHMHWVRQAP GQGLEWMGRRINPKSGRTYYAQNFQGNYAQKFQGRVTMTRDTSISTAYMELSRLRS DDTVVYYCARLTEGIPDYWGQGTTVTVSS (SEQ ID NO: 938).

[0400] Sana CD8 scFv form 8DIQMTQSPSSLSASVGDRVTITCRASQNIGTWLAWYQQKPGKAPKLLIYAASTLQSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQTFGPGTKVDIKRFGGGTKVE IKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIRINPKSGRTYYAQNFQGSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLTEGIPDYWGQGTTVTVSS (SEQ ID NO: 939).

[0401] Sana CD8 scFv form 9DIQMTQSPSSLSASVGDRVTITCRASQNIGTWLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQTFGPGTKVDIKRFGGGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVR QAPGQGLEWMGRINPKSGRTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTVVY YCARLTEGIPDYWGQGTTVTVSS (SEQ ID NO: 940).

[0402] Sana CD8 scFv form 10DIQMTQSPSSLSASVGDRVTITCRASQNIGTWLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPQTFGPGTKVDIKRFGGGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVR QAPGQGLEWMGIINPKSGRTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVY YCARLTEGIPDYWGQGTTVTVSS (SEQ ID NO: 941).

[0403] Sana CD8 VHH form 1QVQLVESGGGLVQPGGSLRLSCSASGYVMGMHWVRQAPGKGLEYVSAAISRGGLS TSYADSVKGYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCDRSDLYEIT AASNIDSWGQGTTVTVSS (SEQ ID NO: 942).

[0404] Sana CD8 VHH form 2QVQLQQWGAGLLKPSETLSLTCAVYGRTFSGYVWSWIRQPPGKGLEWIGEISRGGLS TNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAADRSDLYEITAASNIDSW GQGTTVTVSS (SEQ ID NO: 943).

[0405] Sana CD8 VHH form 3QVQLVESGGGLVQPGGSLRLSCSASGRTFSGYMHWVRQAPGKGLEYVSAVISRGGL STAAYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCDRSDLYEITAASNID SWGQGTTVTVSS (SEQ ID NO: 944).

[0406] CD117 scFv AHI:QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGVIYSGN GDTSYNQKFKGKATLTADKSSSTAYMQINSLTSEDSAVYYCARERDTRFGNWGQGT LVTVSAGGGGSGGGGSGGGGSNIVLTQSPASLAVSLGLRATISCRASESVDIYGNSFM HWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDAATYYCQQ NNEDPYTFGGGTKLEIK(SEQ ID NO: 504).

[0407] CD 117 scFv AH2:NIVLTQSPASLAVSLGLRATISCRASESVDIYGNSFMHWYQQKPGQPPKLLIYLASNL ESGVPARFSGSGSRTDFTLTIDPVEADDAATYYCQQNNEDPYTFGGGTKLEIKGGGG SGGGGSGGGGSQVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGVIYSGNGDTSYNQKFKGKATLTADKSSSTAYMQINSLTSEDSAVYYCARER DTRFGNWGQGTLVTVSA (SEQ ID NO: 505).

[0408] CD 117 scFv 2Dl:DIVMTQSHKFMSTSVGDRVSITCKASQDVSTTVAWYQQKPGQSPKLLIYSASYRYTG VPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYSTPPTFGGGTKLEIKGGGGSGG GGSGGGGSQVQLQQSDAELVKPGASVKISCKASGYTFTDHAIHWVKQRPEQGLEWI GCISPGNGDIKYNEKFKGKATLSADKSSSTAYMQLNSLTSEDSAVYFCKRWDYFDY WGQGTTLTVSS (SEQ ID NO: 506).

[0409] CD 117 scFv 2D2:QVQLQQSDAELVKPGASVKISCKASGYTFTDHAIHWVKQRPEQGLEWIGCISPGNGDIKYNEKFKGKATLSADKSSSTAYMQLNSLTSEDSAVYFCKRWDYFDYWGQGTTLTV SSGGGGSGGGGSGGGGSDIVMTQSHKFMSTSVGDRVSITCKASQDVSTTVAWYQQK PGQSPKLLIYSASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYSTPPT FGGGTKLEIK (SEQ ID NO: 507).

[0410] CD117 scFv 4Fl:DIVMTQSHKFMSTSVGDRVSITCKASQDVSTTVAWYQQKPGQSPKLLIYSASYRYTG VPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYSTPPTFGGGTKLEIKGGGGSGG GGSGGGGSEVQLQESGPSLVKPSQTLSLTCSVTGDSITSGYWNWIRKFPGNKLEYMGYINYSGSTYYNPSLKSQISITRDTSKNQYYLQLNSVTTEDAATYYCARGGNYFAMDY WGQGTSVTVSS (SEQ ID NO: 508).

[0411] CD 117 scFv 4F2:EVQLQESGPSLVKPSQTLSLTCSVTGDSITSGYWNWIRKFPGNKLEYMGYINYSGSTYYNPSLKSQISITRDTSKNQYYLQLNSVTTEDAATYYCARGGNYFAMDYWGQGTSV TVSSGGGGSGGGGSGGGGSDIVMTQSHKFMSTSVGDRVSITCKASQDVSTTVAWYQ QKPGQSPKLLIYSASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYSTP PTFGGGTKLEIK (SEQ ID NO: 509).

[0412] CD 117 scFv 4k94:EVQLVESGGGLVQPGGSLRLSCAASGFNISSYSMHWVRQAPGKGLEWVASIYPYSGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYVYHALDYWGQGT LVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWY QQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQWAVH SLITFGQGTKVEIK (SEQ ID NO: 510).

[0413] CD117 scFv 54:QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGT ANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLDTDEFDLWGRGT LVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSINSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVSDI TFGGGTKVEIK (SEQ ID NO: 511).

[0414] CD117 scFv 55:QVQLVQSGAEVKKPGSSVKVSCKASGGTFRIYAISWVRQAPGQGLEWMGGIIPDFG VANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLDTDEFDLWGRG TLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSINSYLNW YQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVS DITFGGGTKVEIK (SEQ ID NO: 512).

[0415] CD117 scFv 56:QVQLVQSGAEVKKPGSSVKVSCKASGGTFSLYAISWVRQAPGQGLEWMGGIIPAFG TANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLDTDEFDLWGRG TLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSINSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVSDITFGGGTKVEIK (SEQ ID NO: 513).

[0416] CD117 scFv 57:QVQLVQSGAEVKKPGSSVKVSCKASGGTFSLYAISWVRQAPGQGLEWMGGIIPHFG LANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLDTDEFDLWGRG TLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSINSYLNW YQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVS DITFGGGTKVEIK (SEQ ID NO: 514).

[0417] CD117 scFv 58EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSAISGSGG STYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGPPTYHTNYYYMD VWGKGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGIS SWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQTNSFPYTFGGGTKVEIK (SEQ ID NO: 515).

[0418] CD117 scFv 61:EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYVMIWVRQAPGKGLEWVSSISGDSVT TYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGPPTYHTNYYYMDV WGKGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGISS WLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ QTNSFPYTFGGGTKVEIK (SEQ ID NO: 516).

[0419] CD117 scFv 66:EVQLVESGGGLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPGKGLEWVGRTRNKA SSYTTEYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCAREPKYWIDFDLW GRGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQS YIAPYTFGGGTKVEIK (SEQ ID NO: 517).

[0420] CD117 scFv 67:EVQLVESGGGLVQPGRSLRLSCTASGFTFSDHDMNWVRQAPGKGLEWVGRTRNAA GSYTTEYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCAREPKYWIDFDLW GRGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQS YIAPYTFGGGTKVEIK (SEQ ID NO: 518).

[0421] CD117 scFv 68:EVQLVESGGGLVQPGRSLRLSCTASGFTFSDHDMNWVRQAPGKGLEWVGRTRNAA GSYTTEYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCAREPKYWIDFDLW GRGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQS YIAPYTFGGGTKVEIK (SEQ ID NO: 519).

[0422] CD117 scFv 69:EVQLVESGGGLVQPGGSLRLSCAASGFTFVDHDMDWVRQAPGKGLEWVGRTRNKL GSYTTEYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCAREPKYWIDFDLW GRGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQS YIAPYTFGGGTKVEIK (SEQ ID NO: 520).

[0423] CD117 scFv 70:EVQLVESGGGLVQPGGSLRLSCAASGFTFVDHDMDWVRQAPGKGLEWVGRTRNKL GSYTTEYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCAREPKYWIDFDLW GRGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYL NWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQS YIAPYTFGGGTKVEIK (SEQ ID NO: 521).

[0424] CD 117 SRI scFv:QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGVIYSGN GDTSYNQKFKGKATLTADKSSSTAYMQINSLTSEDSAVYYCARERDTRFGNWGQGT LVTVSAAKTTGGGGSGGGGSGGGGSIVLTQSPASLAVSLGLRATISCRASESVDIYGN SFMHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDAATYY CQQNNEDPYTFGGGTKLEIK (SEQ ID NO: 522).

[0425] CXCR4 scFv 1:EVQLVESGGGLVQPGGSLRLSCAAAGFTFSSYSMNWVRQAPGKGLEWVSYISSRSRTIYYADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCARDYGGQPPYYYYYG MDVWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQ GISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFVTY YCQQYNSYPRTFGQGTKVEIK (SEQ ID NO: 527).

[0426] CXCR4 scFv 2:DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGV PSRFSGSGSGTDFTLTISSLQPEDFVTYYCQQYNSYPRTFGQGTKVEIKGGGGSGGGG SGGGGSEVQLVESGGGLVQPGGSLRLSCAAAGFTFSSYSMNWVRQAPGKGLEWVS YISSRSRTIYYADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCARDYGGQPPY YYYYGMDVWGQGTTVTVSS (SEQ ID NO: 528).

[0427] CD90 scFv 1:QVQLLQPGAELVRPGASVRLSCKTSGYTFTSYWINWVKQRPGQGLEWIGKIFPSDSH TNYNQKFKDKATLTVDKSSSTAYMQLISPTSEDSAVYYCTRDFDTQFYAMEYWGQ GTSVTVSSGSDSNAGHASAGNTSQIVLTQSPTIMSASPGQKVTINCSAISSVNYMHWY QQKPGSSPKLWIYATSKLTLGVPARFSGSGSGTSYSLTVNSMVTEDATSYFCHQWSS YPPTFGAGTKLELK (SEQ ID NO: 529).

[0428] CD90 scFv 2:QVQLLQPGAELVRPGASVRLSCKTSGYTFTSYWINWVKQRPGQGLEWIGKIFPSDSHTNYNQKFKDKATLTVDKSSSTAYMQLISPTSEDSAVYYCTRDFDTQFYAMEYWGQ GTSVTVSSGGGGSGGGGSGGGGSDIQMTQTTSSLSASLGDRVTISCRASQDISNYLN WYQQKPDGTFKLLIYYTSRLHSGVPSRFSGGGSGTDYSLTISNLEKEDIATYFCQQGN TLPRTFGGGTRLEVK (SEQ ID NO: 530).

[0429] CD 133 scFv 1:AEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISRTGGVTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRTRRFDYWCQGTLVTVSSSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYSASDLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTANSPSTFGQGTKVEI (SEQ ID NO: 531).

[0430] CD 133 scFv 2:DIVLSQSPAIMSASPGEKVTISCSASSSVSYMYWYQQKPGSSPKPWIYRTSNLASGVP ARFSGSGSGTSYSLTISSMEAEDAATYYCQQYHSYPPTFGAGTKLELKSSGGGGSGG GGGGSSRSSLEVKLVESGPELKKPGETVKISCKASGYTFTDYSMKWVNQAPGKGLK WMGWINTETGEPSYADDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCATDYGD YFDYWGQGTTLTVSS (SEQ ID NO: 532).

[0431] FLT3L:DCSFQHSPISSDFAVKIRELSDYLLQDYPVTVASNLQDEELCGGLWRLVLAQRWMER LKTVAGSKMQGLLERVNTEIHFVTKCAFQPPPSCLRFVQTNISRLLQETSEQLVALKP WITRQNFSRCLELQCAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP (SEQ ID NO: 533).

[0432] In some embodiments, the targeting domain comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of any SEQ ID NO:s: 343-362, 387, 900-944, 504-522, or 527- 533.

[0433] In some embodiments, the targeting domain is selected from the group consisting of CALR-del52, CALR-ins5, CXCL12, AdF35, mSCF soluble, SCF, SCF mutant (V49L / F63L / K91E / I98R), SCF mutant (V49L / F63L / K91E), SCF mutant (V49L / F63L), SCF soluble, SCF soluble mutant (V49L / F63L / K91E / I98R), SCF soluble mutant (V49L / F63L / K91E), SCF soluble mutant (V49L / F63L), TPO-157, TPO-163, TPO-171, TPO, CXCL1 1, CXCL4, and CXCL14Signaling peptides

[0434] In some embodiments, the eVLPs comprising a fusion protein may further comprise an optional signaling peptide. Any suitable signaling peptide known to one of ordinary skill in the art may be used to make the fusion proteins contemplated herein. Without wishing to be bound by any particular theory, it is believed that signaling peptides(also referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence, or leader peptide) is a short peptide (e.g., typically between 16-30 amino acids long) present at the N-terminus (or occasionally non-classically at the C-terminus or internally within the peptide sequence) of most newly synthesized proteins that are destined toward the secretory pathway. Functionally, signaling peptides prompt a cell to translocate the protein to a desired location (e.g., to the cell membrane). In some embodiments, the signaling peptide is cleaved from the fusion protein following translocation; however, in other embodiments, the signaling peptide is not cleaved from the fusion protein following translocation.

[0435] VSVG:MKCLLYLAFLFIGVNC (SEQ ID. NO. 6)

[0436] hCD4:MNRGVPFRHLLLVLQLALLPAATQG (SEQ ID. NO. 7)

[0437] hCD45:MYLWLKLLAFGFAFLDTEVFVTG (SEQ ID. NO. 8)

[0438] hCD8a:MSLPVTALLLPLALLLHAARP (SEQ ID. NO. 9)

[0439] hCD8a-lMALPVTALLLPLALLLHAARP (SEQ ID. NO. 10)

[0440] hCD8b:MRPRLWLLLAAQLTVLHGNSV (SEQ ID. NO. 11)

[0441] hCD2:MSFPCKFVASFLLIFNVSSKGAVS (SEQ ID. NO. 12)

[0442] hCD5:MPMGSLQPLATLYLLGMLVASCLG (SEQ ID. NO. 13)

[0443] hCD7:MAGPPRLLLLPLLLALARGLPGALA (SEQ ID. NO. 14)

[0444] hTYRPl:MSAPKLLSLGCIFFPLLLFQQARA (SEQ ID. NO. 15)

[0445] hLALBa:MRFFVPLFLVGILFPAILA (SEQ ID. NO. 16)

[0446] hBGAL:MPGFLVRILPLLLVLLLLGPTRG (SEQ ID. NO. 17)

[0447] hCD52:MKRFLFLLLTISLLVMVQIQTGLS (SEQ ID. NO. 18)

[0448] hCD109:MQGPPLLTAAHLLCVCTAALA (SEQ ID. NO. 19)

[0449] hCO3:MGPTSGPSLLLLLLTHLPLALG (SEQ ID. NO. 20)

[0450] hGRAB:MQPILLLLAFLLLPRADA (SEQ ID. NO. 21)

[0451] hKV310:MEAPAQLLFLLLLWLPDTTR (SEQ ID. NO. 22)

[0452] hKV401:MVLQTQVFISLLLWISGAYG (SEQ ID. NO. 23)

[0453] hLV605:MAWAPLLLTLLAHCTDCWA (SEQ ID. NO. 24)

[0454] hIL2RG:MLKPSLPFTSLLFLQLPLLGVG (SEQ ID. NO. 25)

[0455] hBPILl:MAWASRLGLLLALLLPVVGA (SEQ ID. NO. 26)

[0456] hFCGRN:MGVPRPQPWALGLLLFLLPGSLG (SEQ ID. NO. 27)

[0457] mlgK:MAVPTQVLGLLLLWLTOA (SEQ ID. NO. 28)

[0458] B2M signal peptideMSRSVALAVLALLSLSGLEA (SEQ ID NO: 395

[0459] In some embodiments, the signaling peptide comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of any SEQ ID NO:s: 6-28.Fusion protein sequences

[0460] In some embodiments the fusion proteins comprise at least one of the following non-limiting structures:(1) [Signaling peptide] -[TPO]- [optional linker] -[VS VGTM];(2) [Signaling peptide]- [SCFK9iEmono]- [optional linker] -[ VS VGmut];(3) [Signaling peptide]- [ADF35]-[optional linker] -[VS VGTM];(4) [Signaling peptide] -[SCF]- [optional linker] -[ VS VG];(5) [Signaling peptide] -[SCF] -[optional linker] -[IgG4]- [optional linker] -[CD62];(6) [Signaling peptide] -[SCF] -[optional linker] -[CD8]- [optional linker] -[CD43];(7) [Signaling peptide] -[SCF] -[optional linker] -[CD8]- [optional linker]- [CD62];(8) [Signaling peptide] -[SCF] -[optional linker] -[CD8]- [optional linker] -[HL A- A2];(9) [Signaling peptide] -[SCF] -[optional linker] -[CD8]- [optional linker]-[HLA-DRA];(10) [Signaling peptide] -[SCF] -[optional linker] -[CD8]- [optional linker] -[LFA-1].(11) [TPO] -[optional linker] -[VS VGTM] ;(12) [SCFK9iEmono]- [optional linker] -[VS VGmut];(13) [ADF35]-[optional linker] -[ VS VG™];(14) [SCF]- [optional linker] -[ VS VG];(15) [SCF] -[optional linker] -[IgG4]- [optional linker] -[CD62];(16) [SCF] -[optional linker] -[CD8]- [optional linker] -[CD43];(17) [SCF] -[optional linker] -[CD8]- [optional linker]- [CD62];(18) [SCF] -[optional linker] -[CD8]- [optional linker] -[HLA-A2];(19) [SCF] -[optional linker] -[CD8]- [optional linker]-[HLA-DRA];(20) [SCF] -[optional linker] -[CD8]- [optional linker] -[LFA-1](21) [SCF(V49L / F63L)]- [optional linker] -[ VS VG™](22). [SCF (V49L / F63L / K91E)]-[optional linker] -[ VS VGMUTASP].

[0461] Construct 106GAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAACGCCAAGGTCGTGGTCGTGCTGGTCCTCGTGCTGACCGCGCTCTGCCTCAGCGACGGGAAGCCCGTCAGCCTGAGCTACAGATGCCCATGCCGATTCTTCGAAAGCCATGTTGCCAGAGCCAACGTCAAGCATCTCAAAATTCTCAACACTCCAAACTGTGCCCTTCAGATTGTAGCCCGGCTGAAGAACAACAACAGACAAGTGTGCATTGACCCGAAGCTAAAGTGGATTCAGGAGTACCTGGAGAAAGCTTTAAACAAGAGCGGTGGGAGCGGCGGGAGCGGCGGTAGCATGAAGTGCCTTTTGTACTTAGCCTTTTTATTCATTGGGGTGAATTGCAAGTTCACCATAGTTTTTCCACACAACCAAAAAGGAAACTGGAAAAATGTTCCTTCTAATTACCATTATTGCCCGTCAAGCTCAGATTTAAATTGGCATAATGACTTAATAGGCACAGCCTTACAAGTCAAAATGCCCCAGAGTCACAAGGCTATTCAAGCAGACGGTTGGATGTGTCATGCTTCCAAATGGGTCACTACTTGTGATTTCCGCTGGTATGGACCGAAGTATATAACACATTCCATCCGATCCTTCACTCCATCTGTAGAACAATGCAAGGAAAGCATTGAACAAACGAAACAAGGAACTTGGCTGAATCCAGGCTTCCCTCCTCAAAGTTGTGGATATGCAACTGTGACGGATGCCGAAGCAGTGATTGTCCAGGTGACTCCTCACCATGTGCTGGTTGATGAATACACAGGAGAATGGGTTGATTCACAGTTCATCAACGGAAAATGCAGCAATTACATATGCCCCACTGTCCATAACTCTACAACCTGGCATTCTGACTATAAGGTCAAAGGGCTATGTGATTCTAACCTCATTTCCATGGACATCACCTTCTTCTCAGAGGACGGAGAGCTATCATCCCTGGGAAAGGAGGGCACAGGGTTCAGAAGTAACTACTTTGCTTATGAAACTGGAGGCAAGGCCTGCAAAATGCAATACTGCAAGCATTGGGGAGTCAGACTCCCATCAGGTGTCTGGTTCGAGATGGCTGATAAGGATCTCTTTGCTGCAGCCAGATTCCCTGAATGCCCAGAAGGGTCAAGTATCTCTGCTCCATCTCAGACCTCAGTGGATGTAAGTCTAATTCAGGACGTTGAGAGGATCTTGGATTATTCCCTCTGCCAAGAAACCTGGAGCAAAATCAGAGCGGGTCTTCCAATCTCTCCAGTGGATCTCAGCTATCTTGCTCCTAAAAACCCAGGAACCGGTCCTGCTTTCACCATAATCAATGGTACCCTAAAATACTTTGAGACCAGATACATCAGAGTCGATATTGCTGCTCCAATCCTCTCAAGAATGGTCGGAATGATCAGTGGAACTACCACAGAAGCGGAACTGTGGGATGACTGGGCACCATATGAAGACGTGGAAATTGGACCCAATGGAGTTCTGAGGACCAGTTCAGGATATAAGTTTCCTTTATACATGATTGGACATGGTATGTTGGACTCCGATCTTCATCTTAGCTCAAAGGCTCAGGTGTTCGAACATCCTCACATTCAAGACGCTGCTTCGCAACTTCCTGATGATGAGAGTTTATTTTTTGGTGATACTGGGCTATCCAAAAATCCAATCGAGCTTGTAGAAGGTTGGTTCAGTAGTTGGAAAAGCTCTATTGCCTCTTTTTTCTTTATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCGAGTTGGTATCCATCTTTGCATTAAATTAAAGCACACCAAGAAAAGACAGATTTATACAGACATAGAGATGAACCGACTTGGAAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGA(SEQ ID. NO. 89)

[0462] Construct 113GAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGAAGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGACCAAAAGAGTGCGGCTGTCTGATAGCTTCAATCCTGTGTACCCCTACGAGGACGAGAGCACCTCCCAGCACCCCTTCTACAACCCCGGCTTCATCAGCCCTAATGGCTTTACCCAAAGCCCAGATGGCGTGCTGACCCTGAAGTGCCTGACCCCTCTCACCACCACAGGCGGCTCCCTGCAACTGAAGGTGGGCGGAGGACTGACCGTGGACGACACCGACGGCACACTGCAGGAGAACATCAGAGCCACCGCCCCTATCACCAAGAACAACCACAGCGTGGAACTGAGCATCGGCAACGGCCTGGAAACCCAGAACAACAAGCTGTGCGCCAAGCTGGGCAATGGCCTGAAGTTCAACAACGGAGATATCTGTATCAAGGACTCTATCAACACCCTGTGGACCGGAATCAACCCTCCACCTAATTGCCAGATCGTGGAAAACACCAATACCAACGACGGCAAGCTGACACTCGTGCTGGTTAAGAACGGAGGCCTGGTCAACGGCTACGTGTCCCTGGTCGGCGTGTCCGATACAGTGAACCAGATGTTCACACAGAAGACCGCTAATATTCAGCTGAGACTGTATTTCGACTCCAGTGGCAACCTGCTGACAGAGGAATCTGACCTGAAAATCCCCCTGAAAAACAAGAGCAGCACCGCCACATCTGAGACAGTGGCCAGCAGCAAGGCCTTCATGCCTAGCACCACAGCTTATCCTTTTAACACCACCACACGGGACAGCGAGAACTACATCCACGGCATCTGCTACTACATGACCAGCTACGACAGAAGCCTGTTCCCCCTGAACATTAGCATCATGCTGAACAGCAGGATGATCAGCAGCAACGTGGCTTACGCCATCCAGTTCGAGTGGAACCTGAACGCCAGCGAGAGCCCTGAGTCTAATATCGCCACACTGACCACATCTCCTTTTTTCTTCAGCTACATCACCGAAGATGACAACAGCGGTGGGAGCGGCGGGAGCGGCGGTAGCAAGTGCCTTTTGTACTTAGCCTTTTTATTCATTGGGGTGAATTGCAAGTTCACCATAGTTTTTCCACACAACCAAAAAGGAAACTGGAAAAATGTTCCTTCTAATTACCATTATTGCCCGTCAAGCTCAGATTTAAATTGGCATAATGACTTAATAGGCACAGCCTTACAAGTCAAAATGCCCAAGAGTCACAAGGCTATTCAAGCAGACGGTTGGATGTGTCATGCTTCCAAATGGGTCACTACTTGTGATTTCCGCTGGTATGGACCGAAGTATATAACACATTCCATCCGATCCTTCACTCCATCTGTAGAACAATGCAAGGAAAGCATTGAACAAACGAAACAAGGAACTTGGCTGAATCCAGGCTTCCCTCCTCAAAGTTGTGGATATGCAACTGTGACGGATGCCGAAGCAGTGATTGTCCAGGTGACTCCTCACCATGTGCTGGTTGATGAATACACAGGAGAATGGGTTGATTCACAGTTCATCAACGGAAAATGCAGCAATTACATATGCCCCACTGTCCATAACTCTACAACCTGGCATTCTGACTATAAGGTCAAAGGGCTATGTGATTCTAACCTCATTTCCATGGACATCACCTTCTTCTCAGAGGACGGAGAGCTATCATCCCTGGGAAAGGAGGGCACAGGGTTCAGAAGTAACTACTTTGCTTATGAAACTGGAGGCAAGGCCTGCAAAATGCAATACTGCAAGCATTGGGGAGTCAGACTCCCATCAGGTGTCTGGTTCGAGATGGCTGATAAGGATCTCTTTGCTGCAGCCAGATTCCCTGAATGCCCAGAAGGGTCAAGTATCTCTGCTCCATCTCAGACCTCAGTGGATGTAAGTCTAATTCAGGACGTTGAGAGGATCTTGGATTATTCCCTCTGCCAAGAAACCTGGAGCAAAATCAGAGCGGGTCTTCCAATCTCTCCAGTGGATCTCAGCTATCTTGCTCCTAAAAACCCAGGAACCGGTCCTGCTTTCACCATAATCAATGGTACCCTAAAATACTTTGAGACCAGATACATCAGAGTCGATATTGCTGCTCCAATCCTCTCAAGAATGGTCGGAATGATCAGTGGAACTACCACAGAAAGGGAACTGTGGGATGACTGGGCACCATATGAAGACGTGGAAATTGGACCCAATGGAGTTCTGAGGACCAGTTCAGGATATAAGTTTCCTTTATACATGATTGGACATGGTATGTTGGACTCCGATCTTCATCTTAGCTCAAAGGCTCAGGTGTTCGAACATCCTCACATTCAAGACGCTGCTTCGCAACTTCCTGATGATGAGAGTTTATTTTTTGGTGATACTGGGCTATCCAAAAATCCAATCGAGCTTGTAGAAGGTTGGTTCAGTAGTTGGAAAAGCTCTATTGCCTCTTTTTTCTTTATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCGAGTTGGTATCCATCTTTGCATTAAATTAAAGCACACCAAGAAAAGACAGATTTATACAGACATAGAGATGAACCGACTTGGAAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGA (SEQ ID.NO. 90)

[0463] Construct 114GAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGGAACTTACAGAACTGCTGCTGGTCGTGATGCTGCTGCTGACCGCCAGGCTGACCCTGTCCAGCCCGGCTCCTCCAGCCTGCGACCTGCGGGTGCTGAGCAAGCTGCTGAGAGATAGCCACGTGCTGCACTCCAGACTGTCTCAATGTCCTGAGGTGCACCCTCTGCCTACCCCTGTGCTGCTCCCTGCCGTGGACTTCAGCCTGGGCGAGTGGAAGACCCAGATGGAAGAGACAAAGGCCCAGGACATCCTGGGCGCCGTGACCCTGCTGCTTGAGGGCGTGATGGCCGCTCGGGGCCAGCTGGGACCTACCTGCCTGTCCAGCCTGCTCGGACAGCTGAGTGGACAGGTGCGCCTGCTGCTGGGCGCCCTGCAGAGCCTGCTGGGGACCCAACTCCCACCTCAGGGCAGAACAACCGCACATAAGGACCCCAACGCCATTTTCCTGAGCTTCCAGCACCTGCTGCGGGGCAAGGTGCGGTTTCTGATGCTGGTGGGCGGCTCCACCCTGTGCGTGCGGAGAGCCCCTCCTACCACCGCCGTGCCCAGCCGGACATCTCTGGTTCTCACCCTGAACGAGCTGCCTAATAGAACGAGCGGCCTGCTGGAAACCAACTTCACCGCCAGCGCCAGAACCACAGGCTCTGGTCTGCTGAAATGGCAGCAGGGCTTCAGAGCTAAAATCCCCGGCCTGCTGAACCAGACATCTAGAAGCCTTGATCAGATCCCTGGCTACCTGAACAGAATCCACGAGCTGCTGAACGGCACCAGAGGCCTCTTCCCCGGACCCTCTAGAAGAACCCTGGGAGCTCCTGATATCAGCAGCGGCACAAGCGACACCGGCAGCCTGCCACCTAACCTGCAACCTGGATATAGCCCCAGCCCCACTCACCCCCCCACAGGCCAGTACACCCTGTTTCCTCTGCCTCCTACACTGCCAACACCCGTGGTCCAGCTGCACCCCCTGCTGCCTGACCCTAGCGCCCCTACCCCAACCCCCACCTCTCCTCTGCTGAATACCAGCTACACACACAGCCAGAACCTGTCTCAGGAGGGCAGCGGTGGGAGCGGCGGGAGCGGCGGTAGCATGAAGTGCCTTTTGTACTTAGCCTTTTTATTCATTGGGGTGAATTGCAAGTTCACCATAGTTTTTCCACACAACCAAAAAGGAAACTGGAAAAATGTTCCTTCTAATTACCATTATTGCCCGTCAAGCTCAGATTTAAATTGGCATAATGACTTAATAGGCACAGCCTTACAAGTCAAAATGCCCAAGAGTCACAAGGCTATTCAAGCAGACGGTTGGATGTGTCATGCTTCCAAATGGGTCACTACTTGTGATTTCCGCTGGTATGGACCGAAGTATATAACACATTCCATCCGATCCTTCACTCCATCTGTAGAACAATGCAAGGAAAGCATTGAACAAACGAAACAAGGAACTTGGCTGAATCCAGGCTTCCCTCCTCAAAGTTGTGGATATGCAACTGTGACGGATGCCGAAGCAGTGATTGTCCAGGTGACTCCTCACCATGTGCTGGTTGATGAATACACAGGAGAATGGGTTGATTCACAGTTCATCAACGGAAAATGCAGCAATTACATATGCCCCACTGTCCATAACTCTACAACCTGGCATTCTGACTATAAGGTCAAAGGGCTATGTGATTCTAACCTCATTTCCATGGACATCACCTTCTTCTCAGAGGACGGAGAGCTATCATCCCTGGGAAAGGAGGGCACAGGGTTCAGAAGTAACTACTTTGCTTATGAAACTGGAGGCAAGGCCTGCAAAATGCAATACTGCAAGCATTGGGGAGTCAGACTCCCATCAGGTGTCTGGTTCGAGATGGCTGATAAGGATCTCTTTGCTGCAGCCAGATTCCCTGAATGCCCAGAAGGGTCAAGTATCTCTGCTCCATCTCAGACCTCAGTGGATGTAAGTCTAATTCAGGACGTTGAGAGGATCTTGGATTATTCCCTCTGCCAAGAAACCTGGAGCAAAATCAGAGCGGGTCTTCCAATCTCTCCAGTGGATCTCAGCTATCTTGCTCCTAAAAACCCAGGAACCGGTCCTGCTTTCACCATAATCAATGGTACCCTAAAATACTTTGAGACCAGATACATCAGAGTCGATATTGCTGCTCCAATCCTCTCAAGAATGGTCGGAATGATCAGTGGAACTACCACAGAAAGGGAACTGTGGGATGACTGGGCACCATATGAAGACGTGGAAATTGGACCCAATGGAGTTCTGAGGACCAGTTCAGGATATAAGTTTCCTTTATACATGATTGGACATGGTATGTTGGACTCCGATCTTCATCTTAGCTCAAAGGCTCAGGTGTTCGAACATCCTCACATTCAAGACGCTGCTTCGCAACTTCCTGATGATGAGAGTTTATTTTTTGGTGATACTGGGCTATCCAAAAATCCAATCGAGCTTGTAGAAGGTTGGTTCAGTAGTTGGAAAAGCTCTATTGCCTCTTTTTTCTTTATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCGAGTTGGTATCCATCTTTGCATTAAATTAAAGCACACCAAGAAAAGACAGATTTATACAGACATAGAGATGAACCGACTTGGAAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGA (SEQ ID. NO. 91)

[0464] Construct 115TCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCATGAAGTGCCTTTTGTACTTAGCCTTTTTATTCATTGGGGTGAATTGCAAGTTCACCATAGTTTTTCCACACAACCAAAAAGGAAACTGGAAAAATGTTCCTTCTAATTACCATTATTGCCCGTCAAGCTCAGATTTAAATTGGCATAATGACTTAATAGGCACAGCCTTACAAGTCAAAATGCCCAAGAGTCACAAGGCTATTCAAGCAGACGGTTGGATGTGTCATGCTTCCAAATGGGTCACTACTTGTGATTTCCGCTGGTATGGACCGAAGTATATAACACATTCCATCCGATCCTTCACTCCATCTGTAGAACAATGCAAGGAAAGCATTGAACAAACGAAACAAGGAACTTGGCTGAATCCAGGCTTCCCTCCTCAAAGTTGTGGATATGCAACTGTGACGGATGCCGAAGCAGTGATTGTCCAGGTGACTCCTCACCATGTGCTGGTTGATGAATACACAGGAGAATGGGTTGATTCACAGTTCATCAACGGAAAATGCAGCAATTACATATGCCCCACTGTCCATAACTCTACAACCTGGCATTCTGACTATAAGGTCAAAGGGCTATGTGATTCTAACCTCATTTCCATGGACATCACCTTCTTCTCAGAGGACGGAGAGCTATCATCCCCGGGAAAGGAGGGCACAGGGTTCAGAAGTAACTACTTTGCTTATGAAACTGGAGGCAAGGCCTGCAAAATGCAATACTGCAAGCATTGGGGAGTCAGACTCCCATCAGGTGTCTGGTTCGAGATGGCTGATAAGGATCTCTTTGCTGCAGCCAGATTCCCTGAATGCCCAGAAGGGTCAAGTATCTCTGCTCCATCTCAGACCTCAGTGGATGTAAGTCTAATTCAGGACGTTGAGAGGATCTTGGATTATTCCCTCTGCCAAGAAACCTGGAGCAAAATCAGAGCGGGTCTTCCAATCTCTCCAGTGGATCTCAGCTATCTTGCTCCTAAAAACCCAGGAACCGGTCCTGCTTTCACCATAATCAATGGTACCCTAAAATACTTTGAGACCAGATACATCAGAGTCGATATTGCTGCTCCAATCCTCTCAAGAATGGTCGGAATGATCAGTGGAACTACCACAGAAAGGGAACTGTGGGATGACTGGGCACCATATGAAGACGTGGAAATTGGACCCAATGGAGTTCTGAGGACCAGTTCAGGATATAAGTTTCCTTTATACATGATTGGACATGGTATGTTGGACTCCGATCTTCATCTTAGCTCAAAGGCTCAGGTGTTCGAACATCCTCACATTCAAGACGCTGCTTCGCAACTTCCTGATGATGAGAGTTTATTTTTTGGTGATACTGGGCTATCCAAAAATCCAATCGAGCTTGTAGAAGGTTGGTTCAGTAGTTGGAAAAGCTCTATTGCCTCTTTTTTCTTTATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCGAGTTGGTATCCATCTTTGCATTAAATTAAAGCACACCAAGAAAAGACAGATTTATACAGACATAGAGATGAACCGACTTGGAAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCCGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCG (SEQ ID. NO. 92)

[0465] Construct 117GAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGAAGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGA (SEQ ID. NO. 93)

[0466] Construct 130GAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGGCCCTGCCTGTGACCGCCCTGCTGCTCCCCCTGGCCCTGCTGCTGCACGCCGCTAGACCTAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGCTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGCTGAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGGAGGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCATGAAGTGCCTTTTGTACTTAGCCTTTTTATTCATTGGGGTGAATTGCAAGTTCACCATAGTTTTTCCACACAACCAAAAAGGAAACTGGAAAAATGTTCCTTCTAATTACCATTATTGCCCGTCAAGCTCAGATTTAAATTGGCATAATGACTTAATAGGCACAGCCTTACAAGTCAAAATGCCCCAGAGTCACAAGGCTATTCAAGCAGACGGTTGGATGTGTCATGCTTCCAAATGGGTCACTACTTGTGATTTCCGCTGGTATGGACCGAAGTATATAACACATTCCATCCGATCCTTCACTCCATCTGTAGAACAATGCAAGGAAAGCATTGAACAAACGAAACAAGGAACTTGGCTGAATCCAGGCTTCCCTCCTCAAAGTTGTGGATATGCAACTGTGACGGATGCCGAAGCAGTGATTGTCCAGGTGACTCCTCACCATGTGCTGGTTGATGAATACACAGGAGAATGGGTTGATTCACAGTTCATCAACGGAAAATGCAGCAATTACATATGCCCCACTGTCCATAACTCTACAACCTGGCATTCTGACTATAAGGTCAAAGGGCTATGTGATTCTAACCTCATTTCCATGGACATCACCTTCTTCTCAGAGGACGGAGAGCTATCATCCCTGGGAAAGGAGGGCACAGGGTTCAGAAGTAACTACTTTGCTTATGAAACTGGAGGCAAGGCCTGCAAAATGCAATACTGCAAGCATTGGGGAGTCAGACTCCCATCAGGTGTCTGGTTCGAGATGGCTGATAAGGATCTCTTTGCTGCAGCCAGATTCCCTGAATGCCCAGAAGGGTCAAGTATCTCTGCTCCATCTCAGACCTCAGTGGATGTAAGTCTAATTCAGGACGTTGAGAGGATCTTGGATTATTCCCTCTGCCAAGAAACCTGGAGCAAAATCAGAGCGGGTCTTCCAATCTCTCCAGTGGATCTCAGCTATCTTGCTCCTAAAAACCCAGGAACCGGTCCTGCTTTCACCATAATCAATGGTACCCTAAAATACTTTGAGACCAGATACATCAGAGTCGATATTGCTGCTCCAATCCTCTCAAGAATGGTCGGAATGATCAGTGGAACTACCACAGAAGCGGAACTGTGGGATGACTGGGCACCATATGAAGACGTGGAAATTGGACCCAATGGAGTTCTGAGGACCAGTTCAGGATATAAGTTTCCTTTATACATGATTGGACATGGTATGTTGGACTCCGATCTTCATCTTAGCTCAAAGGCTCAGGTGTTCGAACATCCTCACATTCAAGACGCTGCTTCGCAACTTCCTGATGATGAGAGTTTATTTTTTGGTGATACTGGGCTATCCAAAAATCCAATCGAGCTTGTAGAAGGTTGGTTCAGTAGTTGGAAAAGCTCTATTGCCTCTTTTTTCTTTATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCGAGTTGGTATCCATCTTTGCATTAAATTAAAGCACACCAAGAAAAGACAGATTTATACAGACATAGAGATGAACCGACTTGGAAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGA (SEQ ID. NO. 94)

[0467] Construct 131GAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGGCCCTGCCTGTGACCGCCCTGCTGCTCCCCCTGGCCCTGCTGCTGCACGCCGCTAGACCTAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGCTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGCTGAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGGAGGAGAACAGCTCCAAGGACCGGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCATGAAGTGCCTTTTGTACTTAGCCTTTTTATTCATTGGGGTGAATTGCAAGTTCACCATAGTTTTTCCACACAACCAAAAAGGAAACTGGAAAAATGTTCCTTCTAATTACCATTATTGCCCGTCAAGCTCAGATTTAAATTGGCATAATGACTTAATAGGCACAGCCTTACAAGTCAAAATGCCCCAGAGTCACAAGGCTATTCAAGCAGACGGTTGGATGTGTCATGCTTCCAAATGGGTCACTACTTGTGATTTCCGCTGGTATGGACCGAAGTATATAACACATTCCATCCGATCCTTCACTCCATCTGTAGAACAATGCAAGGAAAGCATTGAACAAACGAAACAAGGAACTTGGCTGAATCCAGGCTTCCCTCCTCAAAGTTGTGGATATGCAACTGTGACGGATGCCGAAGCAGTGATTGTCCAGGTGACTCCTCACCATGTGCTGGTTGATGAATACACAGGAGAATGGGTTGATTCACAGTTCATCAACGGAAAATGCAGCAATTACATATGCCCCACTGTCCATAACTCTACAACCTGGCATTCTGACTATAAGGTCAAAGGGCTATGTGATTCTAACCTCATTTCCATGGACATCACCTTCTTCTCAGAGGACGGAGAGCTATCATCCCTGGGAAAGGAGGGCACAGGGTTCAGAAGTAACTACTTTGCTTATGAAACTGGAGGCAAGGCCTGCAAAATGCAATACTGCAAGCATTGGGGAGTCAGACTCCCATCAGGTGTCTGGTTCGAGATGGCTGATAAGGATCTCTTTGCTGCAGCCAGATTCCCTGAATGCCCAGAAGGGTCAAGTATCTCTGCTCCATCTCAGACCTCAGTGGATGTAAGTCTAATTCAGGACGTTGAGAGGATCTTGGATTATTCCCTCTGCCAAGAAACCTGGAGCAAAATCAGAGCGGGTCTTCCAATCTCTCCAGTGGATCTCAGCTATCTTGCTCCTAAAAACCCAGGAACCGGTCCTGCTTTCACCATAATCAATGGTACCCTAAAATACTTTGAGACCAGATACATCAGAGTCGATATTGCTGCTCCAATCCTCTCAAGAATGGTCGGAATGATCAGTGGAACTACCACAGAAGCGGAACTGTGGGATGACTGGGCACCATATGAAGACGTGGAAATTGGACCCAATGGAGTTCTGAGGACCAGTTCAGGATATAAGTTTCCTTTATACATGATTGGACATGGTATGTTGGACTCCGATCTTCATCTTAGCTCAAAGGCTCAGGTGTTCGAACATCCTCACATTCAAGACGCTGCTTCGCAACTTCCTGATGATGAGAGTTTATTTTTTGGTGATACTGGGCTATCCAAAAATCCAATCGAGCTTGTAGAAGGTTGGTTCAGTAGTTGGAAAAGCTCTATTGCCTCTTTTTTCTTTATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCGAGTTGGTATCCATCTTTGCATTAAATTAAAGCACACCAAGAAAAGACAGATTTATACAGACATAGAGATGAACCGACTTGGAAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGA (SEQ ID. NO. 95)

[0468] Construct 132GAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCATGAAGTGCCTTTTGTACTTAGCCTTTTTATTCATTGGGGTGAATTGCAAGTTCACCATAGTTTTTCCACACAACCAAAAAGGAAACTGGAAAAATGTTCCTTCTAATTACCATTATTGCCCGTCAAGCTCAGATTTAAATTGGCATAATGACTTAATAGGCACAGCCTTACAAGTCAAAATGCCCCAGAGTCACAAGGCTATTCAAGCAGACGGTTGGATGTGTCATGCTTCCAAATGGGTCACTACTTGTGATTTCCGCTGGTATGGACCGAAGTATATAACACATTCCATCCGATCCTTCACTCCATCTGTAGAACAATGCAAGGAAAGCATTGAACAAACGAAACAAGGAACTTGGCTGAATCCAGGCTTCCCTCCTCAAAGTTGTGGATATGCAACTGTGACGGATGCCGAAGCAGTGATTGTCCAGGTGACTCCTCACCATGTGCTGGTTGATGAATACACAGGAGAATGGGTTGATTCACAGTTCATCAACGGAAAATGCAGCAATTACATATGCCCCACTGTCCATAACTCTACAACCTGGCATTCTGACTATAAGGTCAAAGGGCTATGTGATTCTAACCTCATTTCCATGGACATCACCTTCTTCTCAGAGGACGGAGAGCTATCATCCCTGGGAAAGGAGGGCACAGGGTTCAGAAGTAACTACTTTGCTTATGAAACTGGAGGCAAGGCCTGCAAAATGCAATACTGCAAGCATTGGGGAGTCAGACTCCCATCAGGTGTCTGGTTCGAGATGGCTGATAAGGATCTCTTTGCTGCAGCCAGATTCCCTGAATGCCCAGAAGGGTCAAGTATCTCTGCTCCATCTCAGACCTCAGTGGATGTAAGTCTAATTCAGGACGTTGAGAGGATCTTGGATTATTCCCTCTGCCAAGAAACCTGGAGCAAAATCAGAGCGGGTCTTCCAATCTCTCCAGTGGATCTCAGCTATCTTGCTCCTAAAAACCCAGGAACCGGTCCTGCTTTCACCATAATCAATGGTACCCTAAAATACTTTGAGACCAGATACATCAGAGTCGATATTGCTGCTCCAATCCTCTCAAGAATGGTCGGAATGATCAGTGGAACTACCACAGAAGCGGAACTGTGGGATGACTGGGCACCATATGAAGACGTGGAAATTGGACCCAATGGAGTTCTGAGGACCAGTTCAGGATATAAGTTTCCTTTATACATGATTGGACATGGTATGTTGGACTCCGATCTTCATCTTAGCTCAAAGGCTCAGGTGTTCGAACATCCTCACATTCAAGACGCTGCTTCGCAACTTCCTGATGATGAGAGTTTATTTTTTGGTGATACTGGGCTATCCAAAAATCCAATCGAGCTTGTAGAAGGTTGGTTCAGTAGTTGGAAAAGCTCTATTGCCTCTTTTTTCTTTATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCGAGTTGGTATCCATCTTTGCATTAAATTAAAGCACACCAAGAAAAGACAGATTTATACAGACATAGAGATGAACCGACTTGGAAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGA (SEQ ID. NO. 96)

[0469] Construct 133GAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGGCCCTGCCTGTGACCGCCCTGCTGCTCCCCCTGGCCCTGCTGCTGCACGCCGCTAGACCTGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCATGAAGTGCCTTTTGTACTTAGCCTTTTTATTCATTGGGGTGAATTGCAAGTTCACCATAGTTTTTCCACACAACCAAAAAGGAAACTGGAAAAATGTTCCTTCTAATTACCATTATTGCCCGTCAAGCTCAGATTTAAATTGGCATAATGACTTAATAGGCACAGCCTTACAAGTCAAAATGCCCCAGAGTCACAAGGCTATTCAAGCAGACGGTTGGATGTGTCATGCTTCCAAATGGGTCACTACTTGTGATTTCCGCTGGTATGGACCGAAGTATATAACACATTCCATCCGATCCTTCACTCCATCTGTAGAACAATGCAAGGAAAGCATTGAACAAACGAAACAAGGAACTTGGCTGAATCCAGGCTTCCCTCCTCAAAGTTGTGGATATGCAACTGTGACGGATGCCGAAGCAGTGATTGTCCAGGTGACTCCTCACCATGTGCTGGTTGATGAATACACAGGAGAATGGGTTGATTCACAGTTCATCAACGGAAAATGCAGCAATTACATATGCCCCACTGTCCATAACTCTACAACCTGGCATTCTGACTATAAGGTCAAAGGGCTATGTGATTCTAACCTCATTTCCATGGACATCACCTTCTTCTCAGAGGACGGAGAGCTATCATCCCTGGGAAAGGAGGGCACAGGGTTCAGAAGTAACTACTTTGCTTATGAAACTGGAGGCAAGGCCTGCAAAATGCAATACTGCAAGCATTGGGGAGTCAGACTCCCATCAGGTGTCTGGTTCGAGATGGCTGATAAGGATCTCTTTGCTGCAGCCAGATTCCCTGAATGCCCAGAAGGGTCAAGTATCTCTGCTCCATCTCAGACCTCAGTGGATGTAAGTCTAATTCAGGACGTTGAGAGGATCTTGGATTATTCCCTCTGCCAAGAAACCTGGAGCAAAATCAGAGCGGGTCTTCCAATCTCTCCAGTGGATCTCAGCTATCTTGCTCCTAAAAACCCAGGAACCGGTCCTGCTTTCACCATAATCAATGGTACCCTAAAATACTTTGAGACCAGATACATCAGAGTCGATATTGCTGCTCCAATCCTCTCAAGAATGGTCGGAATGATCAGTGGAACTACCACAGAAGCGGAACTGTGGGATGACTGGGCACCATATGAAGACGTGGAAATTGGACCCAATGGAGTTCTGAGGACCAGTTCAGGATATAAGTTTCCTTTATACATGATTGGACATGGTATGTTGGACTCCGATCTTCATCTTAGCTCAAAGGCTCAGGTGTTCGAACATCCTCACATTCAAGACGCTGCTTCGCAACTTCCTGATGATGAGAGTTTATTTTTTGGTGATACTGGGCTATCCAAAAATCCAATCGAGCTTGTAGAAGGTTGGTTCAGTAGTTGGAAAAGCTCTATTGCCTCTTTTTTCTTTATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCGAGTTGGTATCCATCTTTGCATTAAATTAAAGCACACCAAGAAAAGACAGATTTATACAGACATAGAGATGAACCGACTTGGAAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGA (SEQ ID. NO. 97)

[0470] Construct 134TCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCGGCATGCTGCCTGTGGCTGTGCTGGTGGCCCTGCTCGCCGTGATCGTGCTGGTCGCCCTGCTGCTGCTGTGGCGGAGAAGACAGAAGAGACGGACCTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCCGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCG (SEQID. NO. 98)

[0471] Construct 136TCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCATCGTGATCATCTCTAGCAGCCTGCTGCTGGGCCTGATCGTGCTGCTGCTGATCAGCTACGTGATGTGGAAGGCCGGCTTCTTCAAAAGACAGTACAAGTCCTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCCGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCG (SEQ ID. NO. 99)

[0472] Construct 138TCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCCCTCTGTTCATCCCCGTGGCCGTGATGGTGACCGCCTTCAGCGGCCTGGCTTTTATCATCTGGCTGGCCAGAAGACTGAAGAAGGGCAAGAAATCTAAGCGGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCCGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCG (SEQ ID. NO. 100)

[0473] Construct 140TCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCCTGCTGGCTATCCTGATCCTGGCCCTGGTCGCCACAATCTTCTTCGTGTGCACCGTGGTGCTGGCCGTGAGACTGAGCAGAAAGGGCCACATGTACCCTGTGCGGAACTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCCGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCG (SEQ ID NO: 101)

[0474] Construct 142TCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCATCGTGGGCATCATCGCCGGACTGGTGCTGTTCGGCGCCGTCATCACCGGCGCTGTGGTGGCCGCCGTGATGTGGCGGAGAAAGTCTAGCGACAGAAAGGGCTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCCGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCG (SEQ ID NO: 102)

[0475] Construct 144TCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCAACGTGGTGTGCGCCCTGGGCCTGACCGTGGGCCTGGTCGGCATCATCATTGGAACAATCTTCATCATCAAGGGCCTGAGAAAGAGCAACGCCGCTGAGCGGAGAGGCCCTCTGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCCGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCG (SEQ ID NO: 103)

[0476] Construct 146TCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCATCGTGATCATCACCGTGGTCGCCGCCGCTGTGATCATGGGCACAGCCGGCCTGAGCACCTACCTGTACAACAGACAGAGAAAGATCAAGAAATACCGGCTGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCCGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCG (SEQ ID NO: 104)

[0477] Construct 148TCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCTACCTGTACGTGCTGAGCGGCATCGGCGGACTGCTGCTGCTGCTCCTGATCTTCATCGTGCTGTACAAGGTGGGCTTTTTCAAAAGAAACCTGAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCCGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCG (SEQID NO: 105)

[0478] Construct 153GAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAAAAAAACCCAGACCTGGATCCTGACATGCATCTACCTCCAACTGCTCCTGTTTAACCCTCTGGTGAAGACCGAGGGCATCTGCAGAAATCGGGTGACCAACAACGTGAAGGACGTGACAAAGCTGGTGGCTAATCTGCCCAAGGACTACATGATCACCCTGAAGTACGTGCCTGGCATGGACGTGCTGCCCAGCCACTGTTGGATCAGCGAGATGGTGGTGCAGCTGAGCGATTCTCTGACAGATCTGCTGGACAAGTTCAGCAACATTTCTGAAGGCCTGAGCAATTACAGCATCATCGACAAGCTGGTCAACATCGTGGACGACCTGGTTGAGTGCGTGAAAGAGAACAGCTCCAAGGACCTGAAAAAGTCTTTCAAGAGCCCCGAGCCAAGACTGTTCACCCCTGAGGAATTCTTCAGAATCTTCAACCGGAGTATCGACGCCTTTAAGGACTTCGTGGTGGCCTCTGAGACATCTGATTGCGTGGTCAGCAGCACCCTGTCCCCTGAAAAGGATAGCAGAGTGTCCGTGACCAAGCCATTCATGCTGCCTCCTGTGGCCGCCAGCTCCCTTAGAAACGACAGCAGCAGCTCTAATAGAAAGGCCAAGAACCCCCCTGGAGATAGCAGCCTGCACTGGGCCGCTATGGCCCTGCCTGCCCTGTTCAGCCTGATCATCGGCTTCGCCTTCGGCGCTCTGTATTGGAAGAAAAGACAGCCTAGCCTGACCAGGGCCGTGGAAAACATCCAGATTAACGAGGAAGATAACGAGATCAGCATGCTGCAGGAGAAGGAACGGGAATTTCAGGAGGTGAGCGGTGGGAGCGGCGGGAGCGGTGGGAGCATGAAGTGCCTTTTGTACTTAGCCTTTTTATTCATTGGGGTGAATTGCAAGTTCACCATAGTTTTTCCACACAACCAAAAAGGAAACTGGAAAAATGTTCCTTCTAATTACCATTATTGCCCGTCAAGCTCAGATTTAAATTGGCATAATGACTTAATAGGCACAGCCTTACAAGTCAAAATGCCCCAGAGTCACAAGGCTATTCAAGCAGACGGTTGGATGTGTCATGCTTCCAAATGGGTCACTACTTGTGATTTCCGCTGGTATGGACCGAAGTATATAACACATTCCATCCGATCCTTCACTCCATCTGTAGAACAATGCAAGGAAAGCATTGAACAAACGAAACAAGGAACTTGGCTGAATCCAGGCTTCCCTCCTCAAAGTTGTGGATATGCAACTGTGACGGATGCCGAAGCAGTGATTGTCCAGGTGACTCCTCACCATGTGCTGGTTGATGAATACACAGGAGAATGGGTTGATTCACAGTTCATCAACGGAAAATGCAGCAATTACATATGCCCCACTGTCCATAACTCTACAACCTGGCATTCTGACTATAAGGTCAAAGGGCTATGTGATTCTAACCTCATTTCCATGGACATCACCTTCTTCTCAGAGGACGGAGAGCTATCATCCCTGGGAAAGGAGGGCACAGGGTTCAGAAGTAACTACTTTGCTTATGAAACTGGAGGCAAGGCCTGCAAAATGCAATACTGCAAGCATTGGGGAGTCAGACTCCCATCAGGTGTCTGGTTCGAGATGGCTGATAAGGATCTCTTTGCTGCAGCCAGATTCCCTGAATGCCCAGAAGGGTCAAGTATCTCTGCTCCATCTCAGACCTCAGTGGATGTAAGTCTAATTCAGGACGTTGAGAGGATCTTGGATTATTCCCTCTGCCAAGAAACCTGGAGCAAAATCAGAGCGGGTCTTCCAATCTCTCCAGTGGATCTCAGCTATCTTGCTCCTAAAAACCCAGGAACCGGTCCTGCTTTCACCATAATCAATGGTACCCTAAAATACTTTGAGACCAGATACATCAGAGTCGATATTGCTGCTCCAATCCTCTCAAGAATGGTCGGAATGATCAGTGGAACTACCACAGAAGCGGAACTGTGGGATGACTGGGCACCATATGAAGACGTGGAAATTGGACCCAATGGAGTTCTGAGGACCAGTTCAGGATATAAGTTTCCTTTATACATGATTGGACATGGTATGTTGGACTCCGATCTTCATCTTAGCTCAAAGGCTCAGGTGTTCGAACATCCTCACATTCAAGACGCTGCTTCGCAACTTCCTGATGATGAGAGTTTATTTTTTGGTGATACTGGGCTATCCAAAAATCCAATCGAGCTTGTAGAAGGTTGGTTCAGTAGTTGGAAAAGCTCTATTGCCTCTTTTTTCTTTATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCGAGTTGGTATCCATCTTTGCATTAAATTAAAGCACACCAAGAAAAGACAGATTTATACAGACATAGAGATGAACCGACTTGGAAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGA (SEQ ID NO: 106)

[0479] Construct 154GAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGAACGCCAAGGTCGTGGTCGTGCTGGTCCTCGTGCTGACCGCGCTCTGCCTCAGCGACGGGAAGCCCGTCAGCCTGAGCTACAGATGCCCATGCCGATTCTTCGAAAGCCATGTTGCCAGAGCCAACGTCAAGCATCTCAAAATTCTCAACACTCCAAACTGTGCCCTTCAGATTGTAGCCCGGCTGAAGAACAACAACAGACAAGTGTGCATTGACCCGAAGCTAAAGTGGATTCAGGAGTACCTGGAGAAAGCTTTAAACAAGAGCGGTGGGAGCGGTGGGAGCATTGCCTCTTTTTTCTTTATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCGAGTTGGTATCCATCTTTGCATTAAATTAAAGCACACCAAGAAAAGACAGATTTATACAGACATAGAGATGAACCGACTTGGAAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACGGATCGGCCGCAATTCGTAATCATGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAA (SEQ ID NO: 107)

[0480] Construct 155GAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTAAATTGTAAGCGTTAATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTCCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAGCGCGCGTAATACGACTCACTATAGGGCGAATTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGGTCGACCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACACCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAATGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTCTTTCCTACAGCTCCTGGGCAACGTGCTGGTTGTTGTGCTGTCTCATCATTTTGGCAAAGAATTCCTCGACGGATCCCTCGAGGAATTCTGACACTATGACCAAAAGAGTGCGGCTGTCTGATAGCTTCAATCCTGTGTACCCCTACGAGGACGAGAGCACCTCCCAGCACCCCTTCTACAACCCCGGCTTCATCAGCCCTAATGGCTTTACCCAAAGCCCAGATGGCGTGCTGACCCTGAAGTGCCTGACCCCTCTCACCACCACAGGCGGCTCCCTGCAACTGAAGGTGGGCGGAGGACTGACCGTGGACGACACCGACGGCACACTGCAGGAGAACATCAGAGCCACCGCCCCTATCACCAAGAACAACCACAGCGTGGAACTGAGCATCGGCAACGGCCTGGAAACCCAGAACAACAAGCTGTGCGCCAAGCTGGGCAATGGCCTGAAGTTCAACAACGGAGATATCTGTATCAAGGACTCTATCAACACCCTGTGGACCGGAATCAACCCTCCACCTAATTGCCAGATCGTGGAAAACACCAATACCAACGACGGCAAGCTGACACTCGTGCTGGTTAAGAACGGAGGCCTGGTCAACGGCTACGTGTCCCTGGTCGGCGTGTCCGATACAGTGAACCAGATGTTCACACAGAAGACCGCTAATATTCAGCTGAGACTGTATTTCGACTCCAGTGGCAACCTGCTGACAGAGGAATCTGACCTGAAAATCCCCCTGAAAAACAAGAGCAGCACCGCCACATCTGAGACAGTGGCCAGCAGCAAGGCCTTCATGCCTAGCACCACAGCTTATCCTTTTAACACCACCACACGGGACAGCGAGAACTACATCCACGGCATCTGCTACTACATGACCAGCTACGACAGAAGCCTGTTCCCCCTGAACATTAGCATCATGCTGAACAGCAGGATGATCAGCAGCAACGTGGCTTACGCCATCCAGTTCGAGTGGAACCTGAACGCCAGCGAGAGCCCTGAGTCTAATATCGCCACACTGACCACATCTCCTTTTTTCTTCAGCTACATCACCGAAGATGACAACAGCGGTGGGAGCGGTGGGAGCATTGCCTCTTTTTTCTTTATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCGAGTTGGTATCCATCTTTGCATTAAATTAAAGCACACCAAGAAAAGACAGATTTATACAGACATAGAGATGAACCGACTTGGAAAGTAACTCAAATCCTGCACAACAGATTCTTCATGTTTGGACCAAATCAACTTGTGATACCATGCTCAAAGAGGCCTCAATTATATTTGAGTTTTTAATTTTTATGAAAAAAAAAAAAAAAAACGGAATTCCTCGAGGGATCCGTCGAGGAATTCACTCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATACCACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCT...

Claims

CLAIMSWhat is claimed is:

1. A virus-like particle comprising: a fusion protein, wherein the fusion protein comprises:(i) a transmembrane domain; and(ii) a targeting domain, wherein the targeting domain is not a viral envelope glycoprotein, an antibody, or an antibody fragment.

2. The virus-like particle of claim 1, wherein the transmembrane domain is selected from the group consisting of CD28, CD43, CD49d, CD62L, CD 162, HLA-A2, HLA-DRA, ICAM1, LFA-1, mCD3z, mCD4, mCD8a, hCD8a, hCD8a, and VSVG-TM.

3. The virus-like particle of claim 1, wherein the transmembrane domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5%, or 100% identical to the amino acid sequence of SEQ ID NO: 371 (LFA-1).

4. The virus-like particle of claim 1 wherein the transmembrane domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5%, or 100% identical to the amino acid sequence of SEQ ID NO: 369 (HLA-DRA).

5. The virus-like particle of claim 1, wherein the transmembrane domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 368 (HLA-A2).

6. The virus-like particle of claim 1, wherein the transmembrane domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 366 (CD62L).

7. The virus-like particle of claim 1, wherein the transmembrane domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 364 (CD43).

8. The virus-like particle of claim 1, wherein the transmembrane domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 376 (VSVGTM).

9. The virus-like particle of claim 1, wherein the transmembrane domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 377 (VSVGTMASP).

10. The virus-like particle of claim 1, wherein the transmembrane domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of any one of SEQ ID NOs.: 363-376 or 493.

11. The virus-like particle of claim 1, wherein the targeting domain is selected from the group consisting of CALR-del52, CALR-ins5, CXCL12, AdF35, mSCF soluble, mSCF soluble (V49L / F63L), SCF, SCF mutant (V49L / F63L / K91E / I98R), SCF mutant (V49L / F63L / K91E), SCF mutant (V49L / F63L), SCF soluble, SCF soluble mutant (V49L / F63L / K91E / I98R), SCF soluble mutant (V49E / F63E / K91E), SCF soluble mutant (V49E / F63E), TPO-157, TPO-163, TPO-171, TPO, CXCE11, CXCE4, CXCE14, 53E11 a- hCD8 DARPin, CD8 51.1-Xencor-H1E1 scFv, 53F6 a-hCD8 DARPin, 53F6 a-hCD8 DARPin, 63A4 a-hCD8 DARPin, Acapatamab CD, Acapatamab Vh-Vk, Acapatamab Vh-Vl, CD3 DARPin-C7vl4, CD3 DARPin-C7vl l8, CD3 DARPin-C7vl l9, CD3 DARPin-C7vl22, CD3 DARPin-C7vl27, scFv-CD3-l, scFv-CD3-2, scFv-CD3-3, scFv-CD3-4, scFv-CD4-l,scFv-CD4-2, Sana CD19 scFv FMC63 G4S linker, Sana CD22 scFv m971-L7, CD28 scFv, hCD117 scFv Ab54 CA3079215A1, hCD117 scFv Ab55 CA3079215A1, hCD117 scFv Ab56 CA3079215A1, hCD117 scFv Ab57 CA3079215A1, hCD117 scFv Ab61 CA3079215A1, hCD117 scFv Ab66 CA3079215A1, hCD117 scFv Ab67 CA3079215A1, hCD117 scFv Ab68 CA3079215A1, hCD117 scFv Ab69 CA3079215A1, USPTO 6,054,297 genentech hCD117 scFv, Sana CD8 scFv form 1, Sana CD8 scFv form 2, Sana CD8 scFv form 3, Sana CD8 scFv form 4, Sana CD8 scFv form 5, Sana CD8 scFv form 6, Sana CD8 scFv form 7, Sana CD8 scFv form 8, Sana CD8 scFv form 9, Sana CD8 scFv form 10, Sana CD8 VHH form 1, Sana CD8 VHH form 2, and Sana CD8 VHH form 3.

12. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5%, or 100% identical to the amino acid sequence of SEQ ID NO: 359 (TPO).

13. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 358 (TPO- 171).

14. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 357 (TPO- 163).

15. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 356 (TPO- 157).

16. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 347 (mSCF soluble).

17. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 348 (SCF).

18. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 349 (SCF mutant (V49L / F63L / K91E / I98R).

19. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 350 (SCF mutant (V49L / F63L / K91E)).

20. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 351 (SCF mutant (V49L / F63L).

21. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 352 (SCF soluble).

22. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 353 (SCF soluble mutant (V49L / F63L / K91E / I98R).

23. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 354 (SCF soluble mutant (V49L / F63L / K91E).

24. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 355 (SCF soluble mutant (V49L / F63L).

25. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 346 (AdF35).

26. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 345 (CXCL12).

27. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 360 (CXCL11).

28. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 361 (CXCL4).

29. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 362 (CXCL14).

30. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 344 (CALR-ins5).

31. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 343 (CALR-del52).

32. The virus-like particle of claim 1, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 343-362, 387, 900-944, 504-522, or 527-533.

33. The virus-like particle of claim 1-32, wherein the fusion protein comprises the structure:[optional signaling protein] -[TPO]- [optional linker] -[VS VGTM].

34. The virus-like particle of any one of claims 1-32, wherein the fusion protein comprises the structure:[optional signaling protein]- [SCFK9iEmono]- [optional linker] -[ VS VGmut].

35. The virus-like particle of any one of claims 1-32, wherein the fusion protein comprises the structure:[optional signaling protein]- [ADF35]- [optional linker] -[VS VGTM].

36. The virus-like particle of any one of claims 1-32, wherein the fusion protein comprises the structure:[optional signaling protein]- [SCF]- [optional linker] -[ VS VG].

37. The virus-like particle of any one of claim 1-32, wherein the fusion protein comprises the structure:[optional signaling protein]- [SCF(V49L / F63L)]-[optional linker]-[VSVG TM].

38. The virus like particle of any one of claims 1-32, wherein the fusion protein comprises the structure:[optional signaling protein]- [SCF V49L / F63L / K9 IE] -[optional linker]- [VS VGmutASP].

39. The virus like particle of any one of claim 1-32, wherein the fusion protein comprises the structure:[VSVG Signal Peptide]-[SCF soluble]-[SGGSGGSGGS linker]-[VSVG TM],40. The virus like particle of any one of claim 1-32, wherein the fusion protein comprises the structure:[optional signaling protein] -[CXCL 12] -[optional linker] -[ VS VGmut del SP].

41. The virus like particle of any one of claim 1-32, wherein the fusion protein comprises the structure:[VSVG Signal Peptide]-[SCF soluble (V49L / F63L / K91E / I98R)]-[SGGSGGSGGS linker]-[VSVG TM],42. The virus like particle of any one of claim 1-32, wherein the fusion protein comprises the structure:[optional signaling protein]- [SCF soluble] -[optional linker] -[VS VGmut del SP].

43. The virus-like particle of any one of claims 1-42, further comprising a first linker that connects (i) and (ii), wherein the first linker is selected from the group consisting of SEQ ID NO:s. 309-342.

44. The virus-like particle of any one of claims 1-43, further comprising a second fusion protein comprising a transmembrane domain, a targeting domain, and optionally, a stalk domain, wherein the targeting domain is not a viral envelope glycoprotein, an antibody, or an antibody fragment.

45. The virus-like particle of claim 44, wherein a targeting domain of the second fusion protein is different than the targeting domain of the first fusion protein.

46. A virus-like particle comprising a fusion protein, wherein the fusion protein comprises:(i) a transmembrane domain;(ii) a stalk domain; and(iii) a targeting domain, wherein the targeting domain is not a viral envelope glycoprotein, an antibody, or an antibody fragment.

47. The virus-like particle of claim 46, wherein the transmembrane domain is selected from the group consisting of CD28, CD43, CD49d, CD62L, CD 162, HLA-A2, HLA-DRA, ICAM1, LFA-1, mCD3z, mCD4, mCD8a, hCD8a, hCD8a, and VSVG-TM.

48. The virus-like particle of claim 46, wherein the transmembrane domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to any one of the amino acid sequences of SEQ ID NO:s: 363-376 or 493.

49. The virus-like particle of claim 46, wherein the targeting domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to any one of the amino acid sequences of SEQ ID NO:s: 343- 362, 387, 900-944, 504-522, or 527-533.

50. The virus-like particle of claim 46, wherein the targeting domain is selected from the group consisting of CALR-del52, CALR-ins5, CXCL12, AdF35, mSCF soluble, SCF, SCF mutant (V49L / F63L / K91E / I98R), SCF mutant (V49E / F63E / K91E), SCF mutant (V49E / F63E), SCF soluble, SCF soluble mutant (V49E / F63E / K91E / I98R), SCF soluble mutant (V49E / F63E / K91E), SCF soluble mutant (V49E / F63E), TPO-157, TPO-163, TPO- 171, TPO, CXCE11, CXCE4, CXCE14, 53E11 a-hCD8 DARPin, CD8 51.1-Xencor-H1E1 scFv, 53F6 a-hCD8 DARPin, 53F6 a-hCD8 DARPin, 63A4 a-hCD8 DARPin, Acapatamab CD, Acapatamab Vh-Vk, Acapatamab Vh-Vl, CD3 DARPin-C7vl4, CD3 DARPin-C7vl l8, CD3 DARPin-C7vl l9, CD3 DARPin-C7vl22, CD3 DARPin-C7vl27, scFv-CD3-l, scFv- CD3-2, scFv-CD3-3, scFv-CD3-4, scFv-CD4-l, scFv-CD4-2, Sana CD19 scFv FMC63 G4S linker, Sana CD22 scFv m971-E7, CD28 scFv, hCD117 scFv Ab54 CA3079215A1, hCD117scFv Ab55 CA3079215A1, hCD117 scFv Ab56 CA3079215A1, hCD117 scFv Ab57 CA3079215A1, hCD117 scFv Ab61 CA3079215A1, hCD117 scFv Ab66 CA3079215A1, hCD117 scFv Ab67 CA3079215A1, hCD117 scFv Ab68 CA3079215A1, hCD117 scFv Ab69 CA3079215A1, USPTO 6,054,297 genentech hCD117 scFv, Sana CD8 scFv form 1, Sana CD8 scFv form 2, Sana CD8 scFv form 3, Sana CD8 scFv form 4, Sana CD8 scFv form 5, Sana CD8 scFv form 6, Sana CD8 scFv form 7, Sana CD8 scFv form 8, Sana CD8 scFv form 9, Sana CD8 scFv form 10, Sana CD8 VHH form 1, Sana CD8 VHH form 2, and Sana CD8 VHH form 3.

51. The virus-like particle of claim 46 wherein the stalk domain is selected from the group consisting of hCD8a-l, hCD8a-2, h!gG4-CH3, mCD3z, mCD4, mCD8a-l, mCD8a-2, hCD8a’, mCD28, hCD8, Siglec-4:12, IgGl-CH3, IgG4-CH2CH3, IgGl-CH2CH3, IgGl-1, IgGl-2, IgG2, IgG3, and IgG4.

52. The virus-like particle of claim 46, wherein stalk domain is selected from the group consisting of hCD8a-l, hCD8a-2, h!gG4-CH3, mCD3z, mCD4, mCD8a-l, mCD8a-2, hCD8a’, mCD28, hCD8, Siglec-4:12, IgGl-CH3, IgG4-CH2CH3, IgGl-CH2CH3, IgGl-1, IgGl-2, IgG2, IgG3, and IgG4.

53. The virus-like particle of claim 46, wherein the stalk domain is selected from the group consisting of mmIgG2_l, mmIgG2_2, and mmIgG2_3.

54. The virus-like particle of claim 46, wherein the stalk domain is selected from the group consisting of IgG3_l, IgG3_2, IgG3_3, IgG3_4, IgG3_5, IgG3_6, IgGl_3, IgGl_4, IgG3_7, IgG2_l, and IgGl_3.

55. The virus-like particle of claim 46, wherein the stalk domain is selected from the group consisting of IgAl_l, IgAl_2, IgAl_3, IgAl_4, IgA2_l, IgA2_2, IgA2_3, and IgA2_4.

56. The virus-like particle of claim 46, wherein the stalk domain is selected from the group consisting of IgD_l, IgD_2, IgD_3, IgD_4, IgE, IgM_l, IgM_2, IgM_3, and IgGl_4.

57. The virus-like particle of claim 46, wherein the stalk domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to any one of the amino acid sequences of SEQ ID NOs.: 29-47. or SEQ ID NO: 404.

58. The virus-like particle of claim 46, wherein the stalk domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to any one of the amino acid sequences of SEQ ID NO:s: 48-57.

59. The virus-like particle of claim 46, wherein the stalk domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to any one of the amino acid sequences of SEQ ID NO:s: 58-60.

60. The virus-like particle of claim 46, wherein the stalk domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to any one of the amino acid sequences of SEQ ID NO:s: 61-71.

61. The virus-like particle of claim 46, wherein the stalk domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to any one of the amino acid sequences of SEQ ID NO:s: 72-79.

62. The virus-like particle of claim 46, wherein the stalk domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to any one of the amino acid sequences of SEQ ID NO:s: 80-88.

63. The virus-like particle of claim 46, wherein the stalk domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to any one of the amino acid sequences of SEQ ID NO:s: 502-503, 894, or 896-899.

64. The virus-like particle of claim 46, wherein the stalk domain comprises IgG4.

65. The virus-like particle of claim 46, wherein the stalk domain comprises CD8a.

66. The virus-like particle of claim 46-65, wherein the fusion protein comprises a structure selected from the group consisting of [SCF]- [optional linker] -[IgG4]- [optional linker] -[CD62], [SCF] -[optional linker] -[CD8]- [optional linker] -[CD43], [SCF] -[optional linker] -[CD8]- [optional linker] -[CD62], [SCF] -[optional linker] -[CD8]- [optional linker]- [HLA-A2], [SCF] -[optional linker] -[CD8]- [optional linker] -[HLA-DRA], and [SCF]- [optional linker] -[CD8]- [optional linker]-[LFA-l].

67. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[CD8 Signal Peptide]- [CD 117 scFv 67]-[CD8a trunc stalk]-[ICAMl TM],68. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[CD8 Signal Peptide]-[SCF]-[CD8a trunc stalk]-[CD62 TM],69. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[B2M Signal Peptide]-[SCF]-[CD8a trunc stalk]-[CD49 TM],70. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[CD8 Signal Peptide]-[TPO]-[CD8a trunc stalk]-[ICAMl TM],71. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[CD8 Signal Peptide] -[AdF35]-[CD8a trunc stalk]-[CD62 TM],72. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[B2M Signal Peptide]-[SCF]-[CD8 trunc stalk]-[LFAl TM],73. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[CD8 Signal Peptide] -[CXCL 12] -[CD 8 a trunc stalk]-[ICAMl TM],74. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[CD8 Signal Peptide] -[CXCL 12] -[CD 8 a trunc stalk]-[HLA A2 TM],75. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[CD90 scFv]-[CD8a trunc stalk]-[ICAMl TM],76. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[CD8 Signal Peptide] -[CXCL 12] -[CD 8 a trunc stalk]-[CD49 TM],77. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[CD8 Signal Peptide]- [CXCL 12] -[ CD8a trunc stalk]-[LFAl TM],78. The virus like particle of any one of claims 46-65, wherein the fusion protein comprises the structure:[CD90 scFv]-[CD8a trunc stalk]-[LFAl TM],79. The virus-like particle of claim 46-78, wherein a first linker connects (i) and (ii) and is selected from the group consisting of SEQ ID NOs.: 309-342.

80. The virus-like particle of claim 46-79, wherein a second linker connects (ii) and (iii) and is selected from the group consisting of SEQ ID NOs:. 309-342.

81. The virus-like particle of any one of claims 46-80, further comprising a second fusion protein comprising a transmembrane domain, a targeting domain, and optionally, a stalkdomain, wherein the targeting domain is not a viral envelope glycoprotein, an antibody, or an antibody fragment.

82. The virus-like particle of claim 81, wherein a targeting domain of the second fusion protein is different than the targeting domain of the first fusion protein.

83. A virus-like particle comprising:(a) a fusion protein, wherein the fusion protein comprises:(i) a transmembrane domain; and(ii) a targeting domain; and(b) an antibody domain, wherein the targeting domain of the fusion protein binds to the antibody domain to form a virus-like particle-antibody complex, and wherein the targeting domain is not an envelope glycoprotein, an antibody, or an antibody fragment.

84. A virus-like particle comprising:(a) a fusion protein, wherein the fusion protein comprises:(i) a transmembrane domain;(ii) a stalk domain; and(iii) a targeting domain; and(b) an antibody domain, wherein the targeting domain binds to the antibody domain to form a virus-like particle-antibody complex, and wherein the targeting domain is not an envelope glycoprotein, an antibody, or an antibody fragment.

85. The virus-like particle of claim 84, wherein the stalk domain is IgG4 or CD8a.

86. The virus-like particle of claims 83 or 84, wherein the transmembrane domain is selected from the group consisting of CD28, CD43, CD49d, CD62L, CD 162, HLA-A2, HLA-DRA, ICAM1, LFA-1, mCD3z, mCD4, mCD8a, hCD8a, and VSVG-TM.

87. The virus-like particle of claim 83 or 84, wherein the transmembrane domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to any one of the amino acid sequences of SEQ ID NO:s: 363-376 or 493.

88. The virus-like particle of claims of claim 83 or 84, wherein the targeting domain binds to the antibody domain to form the virus-like particle complex.

89. The virus-like particle claims of claim 83 or 84, wherein the targeting domain comprises an IgG-binding peptide.

90. The virus-like particle of claim 89, wherein the IgG-binding peptide has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to any one of the amino acid sequences of SEQ ID NO:s. 200- 307.

91. The virus-like particle of claim 89 or 90, wherein the IgG-binding peptide binds to one or more IgG protein domains of an IgG antibody.

92. The virus-like particle of 91, wherein the IgG antibody further binds to an antigen on a target cell.

93. The virus-like particle of claim 92, wherein the antigen on the target cell comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 384 (Seal).

94. The virus-like particle of claim 92, wherein the antigen on the target cell comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 381 or 396CD117).

95. The virus-like particle of claim 92, wherein the antigen on the target cell comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO:385 or 397 (CD150).

96. The virus-like particle of claim 92, wherein the antigen on the target cell comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO:382 or 398 (CXCR4).

97. The virus-like particle of claim 92, wherein the antigen on the target cell comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO:383 or 401 (CD46).

98. The virus-like particle of claims 83-97, wherein the fusion protein comprises the structure selected from the group consisting of: [targeting domain] -[optional linker] -[stalk domain] -[optional linker] -[transmembrane domain] or [Z peptide] -[optional linker] -[IgG4 Fc CH3]- [optional linker]-[CD28].

99. A virus-like particle comprising at least one conjugation domain.

100. The virus-like particle of claim 99, further comprising a targeting domain linked to a transmembrane domain or a viral envelope glycoprotein domain via the conjugation domain.

101. The virus-like particle of claim 100, wherein the targeting domain is selected from the group consisting of antibodies, nucleic acids, aptamers, fluorophores, glycoproteins, proteins, peptides, and small molecules.

102. The virus-like particle of claim 100 or 101, wherein the targeting domain comprises a click chemistry handle.

103. The virus-like particle of claim 102, wherein the click chemistry handle is selected from the group consisting of azides, dibenzoazacyclooctyne (DIB AC or DBCO), biarylazacyclooctynone (BARAC), dibenzocyclooctyne (DIBO), difluorinated cyclooctyne (DIFO), bicyclononyne (BCN), dimethoxyazacyclooctyne (DIMAC), monofluorinated cyclooctyne (MOFO), cyclooctyne (OCT), and / or aryl-less cyclooctyne (ALO).

104. The virus-like particle of any one of claims 100-103, wherein the linkage between the targeting domain and the transmembrane domain or envelope glycoprotein domain comprises a 1,2,3-triazole ring.

105. The virus-like particle of any one of claims 99-104, wherein the conjugation domain is selected from the group consisting of one or more N-azidoacetylglucosamine (GlcNAz) or an acetylated variant thereof, one or more N-azidoacetylmannosamine (ManNAz) or an acetylated variant thereof, one or more N-azidoacetylgalactosamine (GalNAz) or an acetylated variant thereof, one or more 6-azidofucose (6AzFuc) or an acetylated variant thereof, one or more N-azidoacetylneuraminic acid (SiaNAz) or an acetylated variant thereof, one or more N-(4-pentynoyl mannosamine) (ManNAl) or an acetylated variant thereof, one or more N-(4-pentynoyl galactosamine) (GalNAl) or an acetylated variant thereof, one or more N-(4-pentynoyl glucosamine) (GlcNAl) or an acetylated variant thereof, one or more N- (4-pentynoyl neuraminic acid) (SiaNAl) or an acetylated variant thereof and one or more 6- alkynyl fucose or an acetylated variant thereof.

106. The virus-like particle of claim 1, 38, 83-84 or 99, further comprising a viral envelope glycoprotein and / or a mutated version thereof.

107. The virus-like particle of claim 106, wherein the viral envelope glycoprotein and / or mutated version thereof is an adenoviral envelope glycoprotein, an adeno-associated viral envelope glycoprotein, a retroviral envelope glycoprotein, or a lentiviral envelope glycoprotein.

108. The virus-like particle of claim 106, wherein the viral envelope glycoprotein and / or a mutated version thereof is a retroviral envelope glycoprotein.

109. The virus-like particle of claim 106, wherein the viral envelope glycoprotein and / or a mutated version thereof is a vesicular stomatitis virus G protein (VSVG), a baboon retroviral envelope glycoprotein (BaEVRless), a FuG-B2 envelope glycoprotein, an HIV-1 viral envelope glycoprotein, a Cocal virus envelope glycoprotein, or an ecotropic murine leukemia virus (MLV) envelope glycoprotein.

110. The virus-like particle of claim 106-109, wherein the mutated viral envelope glycoprotein retains its fusogenic activity.

111. The virus-like particle of claim 106- 110, wherein the mutated viral envelope glycoprotein does not bind to its native ligand.

112. The virus-like particle of claim 1, 38, 83-84 or 99, further comprising a group- specific antigen (gag) protease (pro) polyprotein.

113. The virus-like particle of claim 112, wherein the gag-pro polyprotein comprises an MMLV gag-pro polyprotein or an FMLV gag-pro polyprotein.

114. The virus-like particle of claim 1, 38, 83-84 or 99, further comprising a second fusion protein comprising a group specific antigen (gag) nucleocapsid protein, cargo protein, a cleavable linker, and a nuclear export sequence.

115. The virus like particle of claim 114, wherein the second fusion protein further comprises a domain selected from the group consisting of polymerases, recombinases, integrases, adenine oxides, guanine oxidases, guanine methyltransferases, transglycosylases, adenosine methyltransferases, glycosylases, and thymine alkyltransferases.

116. The virus-like particle of claim 114, wherein the gag nucleocapsid protein comprises an MMLV gag nucleocapsid protein or an FMLV gag nucleocapsid protein.

117. A cell comprising the virus-like particle of any one of claims 1-116.

118. One or more polynucleotides comprising(i) a first nucleic acid sequence encoding a first fusion protein, wherein the first fusion protein comprises:(1) a transmembrane domain;(2) optionally, a stalk domain, and(3) a targeting domain, wherein the targeting domain is not a viral envelope glycoprotein, an antibody, or an antibody fragment.

119. The one or more polynucleotides of claim 118, further comprising a second nucleic acid sequence encoding a viral envelope glycoprotein.

120. The one or more polynucleotides of claim 119, wherein the viral envelope glycoprotein is an adenoviral envelope glycoprotein, an adeno-associated viral envelope glycoprotein, a retroviral envelope glycoprotein, or a lentiviral envelope glycoprotein.

121. The one or more polynucleotides of claim 119, wherein the viral envelope glycoprotein is a retroviral envelope glycoprotein.

122. The one or more polynucleotides of claim 119, wherein the viral envelope glycoprotein is a vesicular stomatitis virus G protein (VSVG), a baboon retroviral envelope glycoprotein (BaEVRless), a FuG-B2 envelope glycoprotein, an HIV-1 viral envelope glycoprotein, or an ecotropic murine leukemia virus (MLV) envelope glycoprotein.

123. The one or more polynucleotides of claim 118-122, further comprising a third nucleic acid sequence encoding a mutated viral envelope glycoprotein.

124. The one or more polynucleotides of claim 123, wherein the mutated viral envelope glycoprotein retains its fusogenic activity.

125. The one or more polynucleotides of claim 123 or 124, wherein the mutated viral envelope glycoprotein does not bind to its native ligand.

126. The one or more polynucleotides of any one of claims 123-125, wherein the mutated viral envelope glycoprotein is a mutated version of an adenoviral envelope glycoprotein, anadeno-associated viral envelope glycoprotein, a retroviral envelope glycoprotein, or a lentiviral envelope glycoprotein.

127. The one or more polynucleotides of any one of claims 123-125, wherein the mutated viral envelope glycoprotein is a mutated version of a retroviral envelope glycoprotein.

128. The one or more polynucleotides of any one of claims 123-125, wherein the mutated viral envelope glycoprotein is a mutated version of a vesicular stomatitis virus G protein (VSVG), a baboon retroviral envelope glycoprotein (BaEVRless), a FuG-B2 envelope glycoprotein, an HIV-1 viral envelope glycoprotein, or an ecotropic murine leukemia virus (MLV) envelope glycoprotein.

129. The one or more polynucleotides of claim 118-128, further comprising a fourth nucleic acid sequence encoding a group-specific antigen (gag) protease (pro) polyprotein.

130. The one or more polynucleotides of claim 129, wherein the gag-pro polyprotein comprises an MMLV gag-pro polyprotein or an FMLV gag-pro polyprotein.

131. The one or more polynucleotides of any one of claims 118-130, further comprising a fifth nucleic acid sequence encoding a second fusion protein comprising a group specific antigen (gag) nucleocapsid protein, a cargo protein, a cleavable linker, and a nuclear export sequence.

132. The one or more polynucleotides of claim 131, wherein the cargo protein is a base editor or a prime editor.

133. The one or more polynucleotides of claim 131 or 132, wherein the second fusion protein further comprises a domain selected from the group consisting of polymerases, recombinases, integrases, adenine oxides, guanine oxidases, guanine methyltransferases, transglycosylases, adenosine methyltransferases, glycosylases, and thymine alkyltransferases.

134. The one or more polynucleotides of claim 131-133, wherein the gag nucleocapsid protein comprises an MMLV gag nucleocapsid protein or an FMLV gag nucleocapsid protein.

135. The one or more polynucleotides of any one of claims 118-134, further comprising a sixth nucleic acid sequence encoding a third fusion protein, wherein the third fusion protein comprises:(1) a transmembrane domain;(2) optionally, a stalk domain; and(3) a targeting domain, wherein the targeting domain is not a viral envelope glycoprotein, an antibody, or an antibody fragment;136. The one or more polynucleotides of any one of claims 118-135, wherein the first nucleic acid sequence encoding the first fusion protein has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 601 (pJAQ222), and wherein the sixth nucleic acid sequence encoding the third fusion protein has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 602 (pJAQ223).

137. The one or more polynucleotides of any one of claims 118-135, wherein the first nucleic acid sequence encoding the first fusion protein has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 597 (pJAQ218), and wherein the sixth nucleic acid sequence encoding the third fusion protein has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 601 (pJAQ222).

138. The one or more polynucleotides of any one of claims 118-135, wherein the first nucleic acid sequence encoding the first fusion protein has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 671 (pJAQ300), and wherein the sixth nucleic acid sequence encoding the third fusion protein has a nucleic acid sequence that is atleast 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 713 (pJAQ342).

139. The one or more polynucleotides of any one of claims 118-135, wherein the first nucleic acid sequence encoding the first fusion protein has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 671 (pJAQ300), and wherein the sixth nucleic acid sequence encoding the third fusion protein has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 718 (pJAQ347).

140. One or more vectors comprising the one or more polynucleotides of any one of claims 118-139.

141. The one or more vectors of claim 140, wherein each of the first, second, third, fourth, fifth, and sixth polynucleotides are on separate vectors.

142. The one or more vectors of claim 140, wherein one or more of the first, second, third, fourth, fifth, or sixth polynucleotides are on the same vector.

143. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 109 ([TPO]- [optional linker] -[ VS VGTM]).

144. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 112 [SCFK9 iEmono]- [optional linker] -[VS VGmut].

145. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, atleast 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 133 [ADF35]- [optional linker] -[ VS VG™].

146. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 92 [SCF]- [optional linker] -[ VS VG],147. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 123 ([SCF]-[optional linker] -[IgG4]- [CD 62]).

148. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 113 ([SCF]-[optional linker]-[CD8a]-[CD43]).

149. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 115 ([SCF]-[optional linker] -[CD 8 a] -[CD 62]).

150. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 117 ([SCF]-[optional linker] -[CD 8 a] -[HL A- A2]).

151. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 118 ([SCF]-[optional linker]-[CD8a]-[HLA-DRA]).

152. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 120 ([SCF]-[optional linker] -[CD8a]-[LFAl]).

153. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 197 [Z peptide] -[optional linker]-[IgG4 Fc CH3]- [optional linker]-[CD28].

154. The one or more vectors of any one of claims 140-142, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 534-945.

155. A cell comprising the virus-like particles of any one of claims 1-116, the one or more polynucleotides of any one of claims 118-139, or the one or more vectors of any one of claims 140-154.

156. One or more polynucleotides comprising(i) a first nucleic acid sequence encoding a first fusion protein, wherein the first fusion protein comprises:(1) a transmembrane domain;(2) optionally, a stalk domain;(3) a targeting domain, wherein the targeting domain is not a viral envelope glycoprotein, an antibody, or an antibody fragment;(ii) a second nucleic acid sequence encoding a viral envelope glycoprotein; and(iii) a third nucleic acid sequence encoding a group- specific antigen (gag) protease (pro) polyprotein.

157. The one or more polynucleotides of claim 156, further comprising a fourth nucleic acid sequence encoding a second fusion protein comprising group specific antigen (gag) nucleocapsid protein, a cargo protein, a cleavable linker, and a nuclear export sequence.

158. The one or more polynucleotides of claim 157, wherein the cargo protein is a base editor or a prime editor.

159. The one or more polynucleotides of claim 157 or 158, wherein the second fusion protein further comprises a domain selected from the group consisting of polymerases, recombinases, integrases, adenine oxides, guanine oxidases, guanine methyltransferases, transglycosylases, adenosine methyltransferases, glycosylases, and thymine alkyltransferases.

160. The one or more polynucleotides of any one of claims 156-159, wherein the gag nucleocapsid protein comprises an MMLV gag nucleocapsid protein or an FMLV gag nucleocapsid protein.

161. The one or more polynucleotides of any one of claims 156-160, wherein the gag-pro polyprotein comprises an MMLV gag-pro polyprotein or an FMLV gag-pro polyprotein.

162. The one or more polynucleotides of any one of claims 156-161, wherein the viral envelope glycoprotein is an adenoviral envelope glycoprotein, an adeno-associated viral envelope glycoprotein, a retroviral envelope glycoprotein, or a lentiviral envelope glycoprotein.

163. The one or more polynucleotides of any one of claims 156-161, wherein the viral envelope glycoprotein is a retroviral envelope glycoprotein.

164. The one or more polynucleotides of any one of claims 156-161, wherein the viral envelope glycoprotein is a vesicular stomatitis virus G protein (VSVG), a baboon retroviral envelope glycoprotein (BaEVRless), a FuG-B2 envelope glycoprotein, an HIV-1 viral envelope glycoprotein, or an ecotropic murine leukemia virus (MLV) envelope glycoprotein.

165. The one or more polynucleotides of claim 156-164, further comprising a fifth nucleic acid sequence encoding a mutated viral envelope glycoprotein.

166. The one or more polynucleotides of claim 165, wherein the mutated viral envelope glycoprotein retains its fusogenic activity.

167. The one or more polynucleotides of claim 165 or 166, wherein the mutated viral envelope glycoprotein does not bind to its native ligand.

168. The one or more polynucleotides of any one of claims 165-167, wherein the mutated viral envelope glycoprotein is a mutated version of an adenoviral envelope glycoprotein, an adeno-associated viral envelope glycoprotein, a retroviral envelope glycoprotein, or a lentiviral envelope glycoprotein.

169. The one or more polynucleotides of any one of claims 165-167, wherein the mutated viral envelope glycoprotein is a mutated version of a retroviral envelope glycoprotein.

170. The one or more polynucleotides of any one of claims 165-167, wherein the mutated viral envelope glycoprotein is a mutated version of vesicular stomatitis virus G protein (VSVG), a baboon retroviral envelope glycoprotein (BaEVRless), a FuG-B2 envelope glycoprotein, an HIV-1 viral envelope glycoprotein, or an ecotropic murine leukemia virus (MLV) envelope glycoprotein.

171. One or more vectors comprising the one or more polynucleotides of any one of claims 156-170.

172. The one or more vectors of claim 171, wherein each of the first, second, third, fourth, fifth, and sixth polynucleotides are on separate vectors.

173. The one or more vectors of claim 171, wherein one or more of the first, second, third, fourth, fifth and sixth polynucleotides are on the same vector.

174. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 109 ([TPO]- [optional linker] -[VS VGTM]).

175. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 112 [SCFK9 iEmono]- [optional linker] -[VS VGmut].

176. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 133 [ADF35]- [optional linker] -[VS VGTM].

177. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 92 [SCF]- [optional linker] -[ VS VG],178. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 123 ([SCF]-[optional linker] -[IgG4]- [CD 62]).

179. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 113 ([SCF]-[optional linker]-[CD8a]-[CD43]).

180. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, atleast 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 115 ([SCF]-[optional linker] -[CD 8 a] -[CD 62]).

181. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 117 ([SCF]-[optional linker] -[CD 8 a] -[HL A- A2]).

182. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 118 ([SCF]-[optional linker]-[CD8a]-[HLA-DRA]).

183. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the nucleic acid sequence of SEQ ID NO: 120 ([SCF]-[optional linker] -[CD8a]-[LFAl]).

184. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 197 [Z peptide] -[optional linker]-[IgG4 Fc CH3]- [optional linker]-[CD28].

185. The one or more vectors of any one of claims 171-173, wherein the one or more polynucleotides has a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 99.5% or 100% identical to the amino acid sequence of SEQ ID NO: 534-945.

186. A cell comprising the virus-like particles of any one of claims 1-116, the one or more polynucleotides of any one of claims 118-139 or 156-170, or the one or more vectors of any one of claims 140-154 or 171-185.

187. A method of delivering a viral-like particle to a target cell comprising preparing the viral-like particles of any one of claims 1-116, the polynucleotides of any one of claims 118- 139 or 156-170, the vectors of any one of claims 140-154 or 171-185, or the cells of claims117, 155 or 186 and contacting a target cell with one or more of said compositions.

188. The method of claim 187, wherein the cell type is selected from the group consisting of hematopoietic stem and progenitor cells (HPSCs), immune cells, neural cells, or retinal pigment epithelium cells.

189. The method of claim 187 or 188, wherein the targeting domain of the fusion protein targets the eVLP to a particular cell type.

190. The method of any one of claims 187-189, wherein the viral envelope glycoprotein does not target the eVLP to a particular cell type.

191. The method of any one of claim 187-190, wherein the mutated viral envelope glycoprotein retains fusogenic activity.

192. The method of any one of claims 187-191, wherein the mutated viral envelope has a reduced affinity for its native receptor.

193. A method of preparing a virus-like particle comprising transfecting the polynucleotides of any one of claims 118-139 or 156-170, the vectors of any one of claims 140-154 or 171-185 into a producer cell.

194. The method of claim 193, wherein the producer cell is selected from the group consisting of Gesicle 293T cells, HEK 293T, 293G, 293SF, 293FT, 293TN, Eent-X 293T, and inducible custom cell lines with lentivirally integrated VEP genes.

195. A method for editing a nucleic acid molecule in a target cell comprising contacting the target cell with the virus-like particle of any one of claims 118-139 or 156-170, the vectors of any one of claims 140-154 or 171-185, or the cells of claims 117, 155 or 186, thereby installing one or more modification to the nucleic acid molecule at a target site.

196. The method of claim 195, wherein the cell is a mammalian cell.

197. The method of claim 195 or 196, wherein the cell is a human cell.

198. The method of any one of claims 195-197, wherein the cell is in a subject.

199. The method of claim 198, wherein the subject is a human.

200. The method of claim 198, wherein the subject is a non-human.

201. The method of claim 195, wherein the cell is a plant cell.

202. The method of any one of claims 195-201, wherein the one or more modifications to the nucleic acid molecule are associated with reducing, relieving, or preventing the symptoms of a disease or disorder.

203. The method of any one of claims 195-202, wherein the disease or disorder is a CNS disorder, liver disorder, or ocular disorder.

204. A method of treating a disease, comprising, contacting a target cell with the virus-like particle of any one of claims 1-116, the polynucleotides of any one of claims 118-139 or 156- 170, the vectors of any one of claims 140-154 or 171-185, or the cells of claims 117, 155 or 186 wherein contacting the target cells results in reducing, relieving, curing or preventing the symptoms of a disease or disorder.

205. A method of treating a disease by editing a nucleic acid molecule in a target cell, comprising, contacting the target cell with the virus-like particle of any one of claims 1-116, the polynucleotides of any one of claims 118-139 or 156-170, the vectors of any one of claims 140-154 or 171-185, or the cells of claims 117, 155 or 186, wherein the edits introduce one or more modifications to the nucleic acid molecule and, wherein the one or more modifications are associated with reducing, relieving, or preventing the symptoms of a disease or disorder.

206. The method of claim 205, wherein the disease or disorder is selected from the group consisting of CNS disorders, liver disorders and ocular disorders.

207. A pharmaceutical composition comprising the virus-like particle of any one of claims 1-116, the polynucleotides of any one of claims 118-139 or 156-170, the vectors of any one of claims 140-154 or 171-185, or the cells of claims 117, 155 or 186, and a pharmaceutical excipient.

208. The virus-like particle of claim 114, wherein the cargo protein is a base editor or a prime editor.

209. The method of any one of claims 187-194, wherein the method is performed in vivo or in vitro.

210. A fusion protein comprising a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 100% identical to the nucleic acid sequence of any one of SEQ ID NOs: 89-199 or 534-892.

211. A polynucleotide encoding the fusion protein of claim 210.

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