WO2015154197A1

WO2015154197A1 - Compositions and methods for glioblastoma treatment

Info

Publication number: WO2015154197A1
Application number: PCT/CA2015/050305
Authority: WO
Inventors: David F. Stojdl
Original assignee: Children's Hospital Of Eastern Ontario Research Institute Inc.
Priority date: 2014-04-11
Filing date: 2015-04-13
Publication date: 2015-10-15

Abstract

The present disclosure concerns a Farmington rhabdovirus for the treatment of cancer, for example brain cancer, such as glioblastoma. The virus has a genome that includes open reading frames that encode: proteins having sequences comprising SEQ ID NOs: 3, 4, 5, 6, 7, and at least one additional protein implicated in cell death; or variants thereof. Examples of such an additional protein include: mixed lineage kinase domain-like (MLKL), casepase 2 (CASP2), p15 BH3 interacting-domain death agonist, transcript variant 2 (BIDv2), and Bcl-2- associated death promoter (BAD). Specific examples of these proteins have the sequences shown in SEQ ID NOs: 13, 15, 17 and 19, respectively.

Description

COMPOSITIONS AND METHODS FOR GLIOBLASTOMA TREATMENT

FIELD

[0001] The present disclosure relates to Farmington rhabdovirus and its use in the treatment of cancer.

BACKGROUND

[0002] This section provides background information related to the present disclosure which is not necessarily prior art.

[0003] Brain cancer is the leading cause of cancer-related death in patients younger than age 35 and accounts for roughly 10% of all cancers diagnosed in North America.

Treatment of brain tumours is complicated by the fact that there are more than 120 different types, which range from low grade astrocytomas to high grade glioblastomas (GBM).

Malignant gliomas, such as GBM, are by far the most common brain cancer found in adults and one of the most difficult to treat. Even with aggressive single and multimodal treatment options such as surgery, chemotherapy, radiation and small molecule inhibitors, the survival has remained unchanged over the past three decades with a median survival of less than one year after diagnosis. Reasons for the failure of conventional treatments is multifactorial including the highly infiltrative/invasive nature of GBM, limitation of drug delivery through the blood brain barrier and neural parenchyma, and genetic heterogeneity resulting in intrinsic resistance to available treatments and the rise of aggressive resistant clones. Therefore, there is a dire requirement for new treatment options, which has led to the renaissance of oncolytic viral therapy for GBM.

[0004] Currently, the efficacy and safety of several oncolytic viruses with various tumour targeting strategies are being evaluated in the lab and clinic against GBM. The rhabdovirus vesicular stomatitis virus (VSV) constitutes one of these efficacious viruses being tested preclinically. However, a desired route of viral administration for GBM is intracerebral delivery, which is not currently possible with VSV due to its neurotoxicity. SUMMARY

[0005] The full-length genomic sequence for FMT has been determined. The sequence of the complementary DNA (cDNA) polynucleotide produced by FMT is shown in

SEQ ID NO: 1. The RNA polynucleotide sequence of FMT is shown in SEQ ID NO: 2. Five putative open reading frames were identified in the genomic sequence. Additional ORFs may be present in the virus that have not yet been identified. The sequences of the corresponding proteins are shown in SEQ ID NOs: 3, 4, 5, 6 and 7, and the encoding DNA sequences are shown in SEQ ID NOs: 8, 9, 10, 1 1 and 12, respectively.

[0006] It is an object of the present disclosure to obviate or mitigate at least one disadvantage of previous oncolytic viruses. For example, a Farmington rhabdovirus of the present disclosure may exhibit increased levels of cytolytic activity to one or more types of cancer cells or specific cell lines, as compared to previous oncolytic viruses. In some examples, a Farmington rhabdovirus according to the present disclosure may have increased levels of cytolytic activity, when compared to wild-type Farmington rhabdovirus, in one or more cell lines, but not in one or more other cell lines.

[0007] A Farmington rhabdovirus of the present disclosure may achieve the desired increased cytolytic activity by including an open reading frame that encodes one or more additional proteins implicated in cell death. Without wishing to be bound by theory, expression of such proteins by the infected cells are believed to increase cytolysis of the cell, for example by apoptosis, necrosis, necroptosis, or autophagy.

[0008] The additional protein encoded by a Farmington rhabdovirus of the present disclosure is selected from the group consisting of: Apoptin; Bcl-2-associated death promoter (BAD); BCL2-antagonist/killer 1 (BAK1); BCL2-associated X (BAX); p15 BH3 interacting- domain death agonist, transcript variant 2 (BIDv2); B-cell lymphoma 2 interacting mediator of cell death (BIM); Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD); caspase 2 (CASP2); caspace 3 (CASP3); caspace 8 (CASP8);

CCAAT-enhancer-binding protein homologous protein (CHOP); DNA fragmentation factor subunit alpha (DFFA); Granzyme B; activated c-Jun N-terminal kinase (JNK); Phorbol-12- myristate-13-acetate-induced protein 1 (PMAPI 1 , also referred to as NOXA); p53

upregulated modulator of apoptosis beta (PUMA beta); p53 upregulated modulator of apoptosis gamma (PUMA gamma); p53-induced death domain protein (PIDD); recombinant ADAM15 disintegrin domain (RAIDD); ubiquitin conjugated Second Mitochondrial-derived Activator of Caspases (SMAC); autophagy related 12 (ATG12); autophagy related 3 (ATG3); Beclin-1 (BECN1); solute carrier family 25 member 4 (SLC25A4); Receptor-interacting serine/threonine-protein kinase 1 (RIPK1); Receptor-interacting serine/threonine-protein kinase 3 (RIPK3); short form of Phosphoglycerate mutase family member 5 (PGAM5S); mixed lineage kinase domain-like (MLKL); Cathepsin D; Maraba M; and any variant thereof. [0009] In some examples, a Farmington rhabdovirus according to the present disclosure includes an open reading frame that encodes MLKL, or variants thereof. In specific embodiments, the Farmington rhabdovirus encodes a protein having the sequence shown in SEQ ID NO: 13. This exemplary Farmington rhabdovirus shows greater cytotoxic efficacy over wild-type Farmington rhabdovirus in a panel of three TRAIL-resistant (SF268, CT2A, U343) and one TRAIL-sensitive (U1 18) human and mouse glioma cell lines. The genome of this exemplary Farmington rhabdovirus may include an RNA nucleotide sequence shown in SEQ ID NO: 14.

[0010] In other examples, Farmington rhabdovirus according to the present disclosure includes an open reading frame that encodes CASP2, or variants thereof. In specific embodiments, the Farmington rhabdovirus encodes a protein having the sequence shown in SEQ ID NO: 15. This exemplary Farmington rhabdovirus shows greater cytotoxic efficacy over wild-type Farmington rhabdovirus in a panel of three TRAIL-resistant (SF268, CT2A, U343) and one TRAIL-sensitive (U1 18) human and mouse glioma cell lines. The genome of this exemplary Farmington rhabdovirus may include an RNA nucleotide sequence shown in SEQ ID NO: 16.

[0011] In still other examples, a Farmington rhabdovirus according to the present disclosure includes an open reading frame that encodes BIDv2, or variants thereof. In specific embodiments, the Farmington rhabdovirus encodes a protein having the sequence shown in SEQ ID NO: 17. This exemplary Farmington rhabdovirus shows greater cytotoxic efficacy over wild-type Farmington rhabdovirus in a panel of three TRAIL-resistant (SF268, CT2A, U343) and one TRAIL-sensitive (U1 18) human and mouse glioma cell lines. The genome of this exemplary Farmington rhabdovirus may include an RNA nucleotide sequence shown in SEQ ID NO: 18.

[0012] In yet other examples, a Farmington rhabdovirus according to the present disclosure includes an open reading frame that encodes BAD, or variants thereof. In specific embodiments, the Farmington rhabdovirus encodes a protein having the sequence shown in SEQ ID NO: 19. This exemplary Farmington rhabdovirus shows greater cytotoxic efficacy over wild-type Farmington rhabdovirus in a panel of three TRAIL-resistant (SF268, CT2A, U343) and one TRAIL-sensitive (U1 18) human and mouse glioma cell lines. The genome of this exemplary Farmington rhabdovirus may include an RNA nucleotide sequence shown in SEQ ID NO: 20. [0013] The present technology includes systems, methods, processes, articles, and compositions that relate to Farmington rhabdovirus, and related nucleotide and protein sequences thereof, and the use of such in oncolytic treatments, for example treatments for brain cancer, such as glioblastoma.

[0014] In another aspect, it is an object of the present disclosure to provide a modified Farmington rhabdovirus that allows for introduction of new genes into the

Farmington rhabdovirus genome. The modified Farmington rhabdovirus genome includes two restriction sites that allow cloning into the Farmington rhadbodvirus of a transgene that contains complementary restriction sequences. For example, the modified Farmington rhabdovirus genome may include a stop/start- Notl and BsiWI sequence, preferably introduced between the G and L genes. This allows cloning into the Farmington rhadbodvirus of a transgene that contains complementary Notl and BsiWI sequences. Such transgenes may be generated, for example, by amplification using a forward primer containing the Notl sequence, and a reverse primer containing the BsiWI sequence.

[0015] Other aspects and features of the present disclosure will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments in conjunction with the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Embodiments of the present disclosure will now be described, by way of example only, with reference to the attached Figures.

[0017] Figure 1. Introduction to FMT Virus: A) Region isolated; B) Amino Acid Blast alignment of 5 FMT putative open reading frames (ORFs) (N, P, G, M and L); C) SDS PAGE gel of FMT virus showing 4 of the 5 predicted FMT ORF proteins; D) Phylogenic tree of various rhabdoviruses; E) Example of a Fully replicative GFP expressing FMT strain; and F) Electron microgram of FMT virion (adapted from Tesh et al. Emerging Infect. Dis. 2002).

[0018] Figure 2. FMT Safety Profile: A) Intracranial neurotoxicity screen for rhabdoviruses; B) Motor function assessment by time on rotorod after intracerebral injection of FMT in Balb/C mice; C) FMT MTD determination in Balb/C mice injected IV with increasing doses (3e6 pfu-3e9 pfu) of FMT virus; D) No detection of viable FMT virus 3 months post- inoculation; E) Histopathology of Brain following intracerebral inoculation with FMT, VSV or PBS. [0019] Figure 3. FMT Potently and Selectively Kills Brain Tumour Cells: A) Summary of FMT virus cytotoxicity in vitro; B) FMT is a potent and selective killer of GBM cell lines; C) Assessment of FMT potency against tumour and normal cells.

[0020] Figure 4. FMT In Vivo Efficacy in Preclinical Models of GBM: A) U-87 MG Human Glioma Xenograft Model; B) Kaplan Meier survival plot of animals treated with a single dose IC (1 e5 pfu) or IV (5e8 pfu); C) Fluorescence micrograph of mock infected mouse brain (with GFP tagged U87MG tumour) versus FMT treated mouse brain; D) Late Syngeneic mouse GBM model using the CT2A cell line treated both IC and IV with FMT or PBS.

[0021] Figure 5. FMT Virus Induces Anti-Tumour Immunity: A) C57/B6 mice implanted with CT2A murine glioma cells into the striatum and treated with FMT and cured of initial tumour then challenged with CT2A cells implanted into the striatum versus Naive mice implanted with CT2A cells as a control; B) C57/B6 mice implanted with CT2A murine glioma cells into the striatum and allowed to grow tumours received either anti-CD8 polyclonal serum injections to remove CD8+ T cells or matched pre-immune serum as a control then both groups were treated with a single intracranial dose of FMT to induce tumour

regressions.

[0022] Figure 6. Novel Mechanism of Tumor Targeting: A) Viral titer determined in

Teratocarcinoma and differentiated NT2 cells infected with the indicated viruses; B)

Teratocarcinoma and differentiated NT2 cells infected with the indicated viruses and assayed for viability using Alamar blue metabolic dye; C) Western blot of several components of the cellular apoptotic signaling cascade following infection of either tumour (SNB19 or normal cells (NHA); D. Schematic of cellular apoptosis signaling cascade.

[0023] Figures 7A, 7B and 7C illustrate survival curves of FMT and HSV in patient derived glioma cells (brain tumor-initiating cells, or BTICs).

[0024] Figure 8 illustrates cumulative survival of SF268, CT2A, U343, and U1 18 cells exposed to various recombinant FMTs.

[0025] Figure 9 illustrates EC50 values of various recombinant FMTs in TRAIL susceptible cells, TRAIL resistant cells, and normal cells.

[0026] Figure 10 illustrates survival of cells at different multiplicities of infection for various recombinant FMTs.

[0027] Figure 11 shows fluorescent micrographs showing expression of green fluorescent protein and red fluorescent protein in cells exposed to a recombinant FMT expressed a bicistronic cassette that included the two transgenes separated by a sequence encoding the porcine teschovirus-1 2A self cleavage sequence.

[0028] Figure 12 illustrates cytotoxicity of exemplary FMTs according to the present disclosure (FMT-MLKL and MFT-Casp2), compared to wild-type FMT, over time in human glioma cells (U1 18).

[0029] Figure 13 illustrates cytotoxicity of exemplary FMTs according to the present disclosure (FMT-MLKL, FMT-BIDv2 and MFT-Casp2), compared to wild-type FMT, in a resistant primary patient brain tumour initiating cells (BTICs).

[0030] Figure 14 illustrates cytotoxicity of an exemplary FMT according to the present disclosure (FMT-MLKL), compared to wild-type FMT, over time in human glioma cells (U373) that are rendered resistant to apoptosis via treatment with Z-VAD-FMK (carbobenzoxy-valyl- alanyl-aspartyl-[0-methyl]- fluoromethylketone).

DESCRIPTION DEFINITIONS

[0031] Throughout the present disclosure, several terms are employed that are defined in the following paragraphs.

[0032] As used herein, the words "desire" or "desirable" refer to embodiments of the technology that afford certain benefits, under certain circumstances. However, other embodiments may also be desirable, under the same or other circumstances. Furthermore, the recitation of one or more desired embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the technology.

[0033] As used herein, the word "include," and its variants, is intended to be non- limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the materials, compositions, devices, and methods of this technology. Similarly, the terms "can" and "may" and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.

[0034] Although the open-ended term "comprising," as a synonym of non-restrictive terms such as including, containing, or having, is used herein to describe and claim embodiments of the present technology, embodiments may alternatively be described using more limiting terms such as "consisting of or "consisting essentially of." Thus, for any given embodiment reciting materials, components or process steps, the present technology also specifically includes embodiments consisting of, or consisting essentially of, such materials, components or processes excluding additional materials, components or processes (for consisting of) and excluding additional materials, components or processes affecting the significant properties of the embodiment (for consisting essentially of), even though such additional materials, components or processes are not explicitly recited in this application. For example, recitation of a composition or process reciting elements A, B and C specifically envisions embodiments consisting of, and consisting essentially of, A, B and C, excluding an element D that may be recited in the art, even though element D is not explicitly described as being excluded herein.

[0035] As referred to herein, all compositional percentages are by weight of the total composition, unless otherwise specified. Disclosures of ranges are, unless specified otherwise, inclusive of endpoints and include all distinct values and further divided ranges within the entire range. Thus, for example, a range of "from A to B" or "from about A to about B" is inclusive of A and of B. Disclosure of values and ranges of values for specific parameters (such as temperatures, molecular weights, weight percentages, etc.) are not exclusive of other values and ranges of values useful herein. It is envisioned that two or more specific exemplified values for a given parameter may define endpoints for a range of values that may be claimed for the parameter. For example, if Parameter X is exemplified herein to have value A and also exemplified to have value Z, it is envisioned that Parameter X may have a range of values from about A to about Z. Similarly, it is envisioned that disclosure of two or more ranges of values for a parameter (whether such ranges are nested, overlapping or distinct) subsume all possible combination of ranges for the value that might be claimed using endpoints of the disclosed ranges. For example, if Parameter X is exemplified herein to have values in the range of 1-10, or 2-9, or 3-8, it is also envisioned that Parameter X may have other ranges of values including 1-9, 1-8, 1-3, 1-2, 2-10, 2-8, 2-3, 3-10, and 3-9.

[0036] "A" and "an" as used herein indicate "at least one" of the item is present; a plurality of such items may be present, when possible.

[0037] "About" when applied to values indicates that the calculation or the

measurement allows some slight imprecision in the value (with some approach to exactness in the value; approximately or reasonably close to the value; nearly). If, for some reason, the imprecision provided by "about" is not otherwise understood in the art with this ordinary meaning, then "about" as used herein indicates at least variations that may arise from ordinary methods of measuring or using such parameters.

[0038] As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

[0039] As used herein, a virus that has "reduced levels of neurotoxicity" or "reduced neurotoxicity" would be understood to refer to a virus that, when injected into a mouse brain at a given dose, results in a mouse with fewer signs of neurotoxicity (for example, weigh loss, piloerection, hind leg paralysis, morbidity and mortality) than a mouse which is injected with wild-type maraba virus.

[0040] As used herein, "substantially no level of neurotoxicity" or "substantially no neurotoxicity" would be understood to refer to a virus that, when injected introcerebrally into a mouse at 1 e6 pfu, results in a mouse with no detectable signs of reduced motor function as measured by time on a rotorod compared to the mouse before injection with the virus. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0041] Of the more than 250 currently identified rhabdoviruses, several isolated wild type rhabdoviruses were determined to be effective at killing CNS tumour cell lines while retaining attenuation in normal human astrocytes and post-mitotic neurons. Several of these potent viral isolates were also determined to demonstrate remarkable attenuation, resulting in 100% survival after intracerebral inoculation. This is in striking contrast to previously tested Maraba and VSV viruses.

[0042] Generally, the present disclosure provides a Farmington rhabdovirus (FMT) for the treatment of cancer, such as brain cancer. The Farmington rhabdovirus may be used to treat cancer by directly administering the virus to a patient, or by infecting a cell with the virus and administering the infected cell to the patient to deliver the virus. The cell to be infected by the virus may be a cancer cell from the patient. In some examples, the brain cancer is a malignant glioma. One example of a malignant glioma is glioblastoma. The oncolytic virus may exhibit increased levels of cytotoxicity to the cancer cells.

[0043] Techniques for infecting a cell with a virus and using the infected cell to deliver the virus are discussed in, for example: Power AT, et al. Carrier cell-based delivery of an oncolytic virus circumvents antiviral immunity. Mol Ther. 2007 Jan; 15(1): 123-30; and Tyler MA, et al. Neural stem cells target intracranial glioma to deliver an oncolytic adenovirus in vivo. Gene Ther. 2009 Feb; 16(2):262-78. [0044] Farmington rhabdovirus has been determined to be effective at killing CNS tumour cell lines while retaining attenuation in normal human astrocytes and post-mitotic neurons. However, as discussed later, FMT infection of patient derived glioma cells (BTICs) has now been determined to be variably cytolic. It is desirable to increase the cytolyic activity the Farmington rhabdovirus.

[0045] Unlike VSV and Maraba virus, which kill target cells primarily through intrinsic apoptosis signalling, the authors of the present disclosure have determined that FMT primarily employs the extrinsic FAS, TNF and/or TRAIL death receptor pathway. Many tumour cells lose sensitivity to this apoptotic pathway, and can be infected but not killed by FMT. Oncolytic viruses expressing death genes, such as BID (and BIDv2 in particular), may deal with tumour heterogeneity and may achieve greater consistency in tumour killing across a spectrum of malignant cell types. Thus, Farmington rhabdoviruses according to the present disclosure may increase the cytotoxic activity in death receptor/ligand resistant cells.

[0046] As noted above, the sequence of the complementary DNA (cDNA)

polynucleotide produced by FMT is shown in SEQ ID NO: 1. The RNA polynucleotide of FMT is shown in SEQ ID NO: 2. Five putative open reading frames were identified in the genomic sequence. Additional ORFs may be present in the virus that have not yet been identified. The sequences of the corresponding proteins are shown in SEQ ID NOs: 3, 4, 5, 6 and 7, and the encoding DNA sequences are shown in SEQ ID NOs: 8, 9, 10, 1 1 and 12, respectively.

[0047] The Farmington rhabdovirus according to the present disclosure is an isolated viral particle having a genome that includes open reading frames that encode: a protein having a sequence comprising SEQ ID NO: 3, or a variant thereof; a protein having a sequence comprising SEQ ID NO: 4, or a variant thereof; a protein having a sequence comprising SEQ ID NO: 5, or a variant thereof; a protein having a sequence comprising SEQ ID NO: 6, or a variant thereof; a protein having a sequence comprising SEQ ID NO: 7, or a variant thereof; and at least one additional protein selected from the the group consisting of: Apoptin; Bcl-2-associated death promoter (BAD); BCL2-antagonist/killer 1 (BAK1); BCL2- associated X (BAX); p15 BH3 interacting-domain death agonist, transcript variant 2 (BIDv2); B-cell lymphoma 2 interacting mediator of cell death (BIM); Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD); caspase 2 (CASP2); caspace 3 (CASP3); caspace 8 (CASP8); CCAAT-enhancer-binding protein homologous protein (CHOP); DNA fragmentation factor subunit alpha (DFFA); Granzyme B; activated c-Jun N- terminal kinase (JNK); Phorbol-12-myristate-13-acetate-induced protein 1 (PMAPI 1 , also referred to as NOXA); p53 upregulated modulator of apoptosis beta (PUMA beta); p53 upregulated modulator of apoptosis gamma (PUMA gamma); p53-induced death domain protein (PIDD); recombinant ADAM 15 disintegrin domain (RAIDD); ubiquitin conjugated Second Mitochondrial-derived Activator of Caspases (SMAC); autophagy related 12

(ATG12); autophagy related 3 (ATG3); Beclin-1 (BECN1); solute carrier family 25 member 4 (SLC25A4); Receptor-interacting serine/threonine-protein kinase 1 (RIPK1); Receptor- interacting serine/threonine-protein kinase 3 (RIPK3); short form of Phosphoglycerate mutase family member 5 (PGAM5S); mixed lineage kinase domain-like (MLKL); Cathepsin D; Maraba M; and any variant thereof..

[0048] These additional proteins were selected as they shown in the accompanying examples to exhibit increased levels of cytolytic activity to one or more types of cancer cells, as compared to Farmington Rhabdovirus with GFP. Without wishing to be bound by theory, expression of these additional proteins by the infected cells is believed to increase cytolysis of the cell, for example by apoptosis, necrosis, necroptosis, or autophagy.

[0049] The gene encoding the additional protein is preferably inserted as a new cistron between the nucleotide sequences encoding the G protein and the nucleotide sequences encoding the L protein. However, the gene encoding the additional protein may be inserted as a new cistron between adjacent nucleotide sequences encoding any two other proteins. For example, the gene encoding the additional protein may be inserted between the nucleotide sequences encoding the N and P proteins, the P and M proteins, or the M and P proteins.

[0050] In the context of the present disclosure, Farmington rhabdovirus expressing additional proteins may generally be referred to as "recombinant Farmington rhabdovirus", "recombinant FMT", or "FMT recombinant". When the virus is modified to express a specific protein, for example 'protein X', the virus may be referred to as "Farmington rhabdovirus expressing 'protein X'", "recombinant FMT-protein X", or "FMT-'protein X'". In contrast, Farmington rhabdovirus without any of the noted additional proteins may be referred to as "Farmington rhabdovirus", "FMT", "Farmington rhabdovirus backbone", or "FMT backbone".

[0051] Although the present disclosure discusses viral particles having specific RNA sequences, during the rhabdovirus lifecycle the virus generates a reverse complement of its genome to act as a template to generate progeny viruses. Accordingly, it should be understood that the present disclosure additionally contemplates any replication competent form of the recombinant FMT virus genome. For example, the present disclosure contemplates vectors that encode the reverse complement of the specific RNA sequences since such sequences would result in the contemplated viral particles when the vectors are used to infect cells.

[0052] Sequences of specific examples of the noted additional proteins may be determined from databases such as the National Centre for Biotechnology Information. Sequences of other proteins tested in the accompanying examples may also be determined from databases such as the National Centre for Biotechnology Information. Accession numbers for genes or mRNA encoding specific examples of such proteins are shown below, and sequences of the corresponding proteins are identified by SEQ I D NO.

Table 1

ATG12 NM_004707 SEQ ID NO: 41 Maraba M HQ660076 SEQ ID NO: 66 protein id=

AEI52257.1

ATG16L1 NM_030803 SEQ ID NO: 42 Cytochrome NM_018947 SEQ ID NO: 67

C

ATG3 NM_022488 SEQ ID NO: 43

[0053] Sequences for SEQ ID NOs: 1-39, 41-63, and 65-67 are shown in Appendix

A.

[0054] An exemplary sequence of ubiquitin conjugated SMAC protein is

MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKE STLHLVLRLRGGAVPIAQKSEPHSLSNEALMRRAVSLVTDSTSTFLSQTTYALIEAITEYTKAV YTLVSLYRQYTSLLGKMNSQEEDEVWQVIIGARVEMTSKQQEYLKLETTWMTAVGLSEMAA EAAYQTGADQASITARNHIQLVKSQVQEVRQLSQKAETKLAEAQTKELHQKAQEVSDEGAD QEEEAYLREDYPI DVPDYA (SEQ ID NO: 64), which may be encoded by the nucleotide sequence:

ATGCAGATCTTCGTGAAAACCCTGACCGGCAAGACCATCACCCTGGAAGTGGAGCCCA GTGACACCATCGAAAATGTGAAGGCCAAGATCCAGGATAAAGAAGGCATCCCTCCCGA CCAGCAGAGGCTCATCTTTGCAGGCAAGCAGCTGGAAGATGGCCGCACTCTTTCTGAC TACAACATCCAGAAGGAGTCGACCCTGCACCTGGTCCTGCGTCTGAGAGGTGGTGCGG TTCCTATTGCTCAGAAATCGGAGCCTCATTCTCTCAGTAACGAAGCATTGATGAGGAGG GCTGTGTCTTTGGTAACAGATAGCACCTCTACCTTTCTGTCTCAAACCACCTACGCGCT GATTGAAGCAATCACCGAGTATACTAAGGCTGTTTACACGTTAGTGTCTCTGTACCGACA ATATACAAGTTTACTTGGGAAGATGAATTCCCAGGAGGAAGATGAGGTGTGGCAGGTAA TTATAGGAGCCAGAGTTGAGATGACTTCAAAACAGCAGGAATATTTGAAGTTGGAGACC ACTTGGATGACAGCGGTTGGCCTTTCAGAGATGGCTGCTGAGGCTGCCTATCAAACTG GAGCAGATCAGGCCTCCATAACTGCCAGGAATCACATCCAGTTGGTGAAGTCACAGGTA CAGGAGGTGCGCCAGCTCTCCCAGAAGGCAGAAACCAAGTTGGCTGAAGCACAGACAA AAGAGCTGCACCAGAAAGCACAGGAAGTGAGTGATGAGGGGGCTGACCAGGAAGAGG AGGCCTACCTGCGTGAAGATTATCCTATCGATGTCCCTGATTACGCCTAA (SEQ ID NO: 68).

[0055] An exemplary sequence of ubiquitin conjugated tBID (Ub BIDAl-60) protein is

MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKE STLHLVLRLRGGGNRSSHSRLGRIEADSESQEDIIRNIARHLAQVGDSMDRSIPPGLVNGLAL QLRNTSRSEEDRNRDLATALEQLLQAYPRDMEKEKTMLVLALLLAKKVASHTPSLLRDVFHT TVNFINQNLRTYVRSLARNGMD (SEQ ID NO: 40), which may be encoded by the nucleotide sequence:

ATGCAGATCTTCGTGAAAACCCTGACCGGCAAGACCATCACCCTGGAAGTGGAGCCCA GTGACACCATCGAAAATGTGAAGGCCAAGATCCAGGATAAAGAAGGCATCCCTCCCGA CCAGCAGAGGCTCATCTTTGCAGGCAAGCAGCTGGAAGATGGCCGCACTCTTTCTGAC TACAACATCCAGAAGGAGTCGACCCTGCACCTGGTCCTGCGTCTGAGAGGTGGTGGCA ACCGCAGCAGCCACTCCCGCTTGGGAAGAATAGAGGCAGATTCTGAAAGTCAAGAAGA CATCATCCGGAATATTGCCAGGCACCTCGCCCAGGTCGGGGACAGCATGGACCGTAGC ATCCCTCCGGGCCTGGTGAACGGCCTGGCCCTGCAGCTCAGGAACACCAGCCGGTCG GAGGAGGACCGGAACAGGGACCTGGCCACTGCCCTGGAGCAGCTGCTGCAGGCCTAC CCTAGAGACATGGAGAAGGAGAAGACCATGCTGGTGCTGGCCCTGCTGCTGGCCAAGA AGGTGGCCAGTCACACGCCGTCCTTGCTCCGTGATGTCTTTCACACAACAGTGAATTTT ATTAACCAGAACCTACGCACCTACGTGAGGAGCTTAGCCAGAAATGGGATGGACTGA

(SEQ ID NO: 69).

[0056] The isolated viral particle may be formulated for direct delivery to the central nervous system, outside the blood/brain barrier, inside the blood/brain barrier, or any combination thereof. For example the isolated viral particle may be formulated for administration via intrathecal, intravenous or intracranial injection.

[0057] An isolated viral particle according to the present disclosure may be used in a a method for treating cancer, where the method includes administering an isolated viral particle according the present disclosure to a patient having cancer. The cancer may be brain cancer, such as a glioblastoma. The isolated viral particle may be administered to the patient directly to the central nervous system, outside the blood/brain barrier, inside the blood/brain barrier, or any combination thereof. For example, the isolated viral particle may be administered intrathecal^, intravenously or via intracranial injection. The isolated viral particle may be directly administered to the patient or may be administered to the patient by infecting a cell with the virus and administering the infected cell to the patient.

[0058] An isolated viral particle according to the present disclosure may be included in a kit for the treatment of cancer in a patient, the kit including: the isolated viral particle according to the present disclosure; and instructions for administration of the isolated viral particle to the patient. The cancer may be brain cancer, such as a glioblastoma. The isolated viral particle may be formulated for direct delivery to the central nervous system, outside the blood/brain barrier, inside the blood/brain barrier, or any combination thereof. For example the isolated viral particle may be formulated for administration via intrathecal, intravenous or intracranial injection.

[0059] See Example 1 and Figure 1 for a discussion of the genetic components of

FMT. Interestingly, FMT shows little or no sequence homology to other rhabdoviruses from the six current genera and thus may constitute a seventh genus in the Rhabdoviridae. This virus was determined to exhibit reduced neurotoxicity after intracranial administration (see Example 2 and Figure 2). The FMT virus also demonstrated tumour selectivity in vitro (see Example 3 and Figure 3), and safety and efficacy following intracranial or systemic administration in syngeneic and xenograft mouse models of glioblastoma (see Example 4 and Figure 4).

[0060] As discussed above, several viruses, including Maraba (MRB), Farmington

(FMT) and Carajas (CRJ), were determined to have potent killing capacity against a variety of cancer cell lines from the NC60 cell panel. These viruses were also determined to have an ability to eradicate CNS tumour cell lines. These viruses were tested for their safety and efficacy in vitro and in vivo.

[0061] Previous viruses, such as wild type and attenuated strains of VSV, are also known to be potent killers of CNS cell lines. However, they are notably neurotoxic and treatment with such viruses often results in rapid weight loss and paralysis upon intracerebral injection at very low doses. Such neurotoxicity prevents application of VSV to treating brain cancer.

[0062] As illustrated in Example 2 and Figure 2, it was determined that, like VSV, both CRJ and MRB also resulted in neurotoxicity in Balb/C mice within a period of 2-7 days after administration. However, it was surprisingly determined that FMT demonstrated no neurotoxicity up to 30 days following direct intracranial injection (IC) of 1 e6 pfu.

[0063] FMT was determined to be able to kill GBM cells at low multiplicities of infection, and was determined to possess replication kinetics and large burst sizes that rivaled those of the highly lytic Maraba virus. FMT was also determined to be poorly cytolytic in normal human astrocytes and primary neurons (see Example 3 and Figure 3). The mechanism of tumour selectivity appears to be independent of interferon signaling, as is currently the established mechanism of selectivity governing rhabdovirus based oncolytic agents. FMT appears to infect normal cells equally to tumour cells, but only induces apoptosis in tumour cells. FMT was determined to not trigger caspase 8 in normal cells, even though there is robust virus protein synthesis. Moreover, FMT's selective cytotoxicity mechanism rendered the virus non-neurotoxic despite its strong ability to block interferon (I FN) production. This indicates that rhabdovirus infections of the CNS cannot be effectively controlled by interferon anti-virus defenses when viruses are delivered directly into the brain. When delivered peripherally, FMT was determined to be as attenuated as previously published engineered VSV deltaM51 or MR MG1 strains.

[0064] As illustrated in Example 4 and Figure 4, the FMT virus may be used to treat human xenograft and immunocompetent syngeneic models by either local regional or systemic administration. In vivo efficacy in a human orthotopic U87MG model after a single IC or IV dose of FMT is described in Example 4. In fact, IV even achieved durable cures. Notably both modes of delivery are not only able to treat the primary glioma but are able to effectively and durably treat U87MG spinal metastasis in 100% of the animals. Based on these results, it is expected that FMT virus could be used to treat other cancers, such as, for example, medulloblastomas. It is expected that FMT virus could be used to treat primary cancers as well as metastasized cancers, such as to the CNS. Although FMT virus exhibits reduced neurotoxicity and is, for that reason, suitable for use in the treatment of neurological tumors, it should be understood that the FMT virus may be used for the treatment of non- neurological cancers. It should also be understood that other viruses according to the present disclosure could be used for the treatment of non-neurological cancers.

[0065] FMT virus has been demonstrated to induce an anti-tumor immunity. As illustrated in Example 5 and Figure 5, mice previously harboring CT-2A tumors that had been successfully treated with IC FMT virus infusions were injected for a second time with CT-2A cells directly into the brain. It was determined that previously cured mice rejected the cells. When, concomitant with FMT virus treatment, cytotoxic T-lymphocytes (CTL) were removed using antibodies directed toward CD8, it was determined that mice stripped of their CD8+ T- cells all eventually re-grew the subsequently injected CT-2A cells and failed therapy. This suggests that in addition to direct tumour cell lysis and putative other mechanisms of action, the FMT virus induces an anti-tumor immunity when CTLs are present. Accordingly, it is expected that a virus according to the present disclosure may be used to induce an immune response in a patient exposed to the virus. The immune response may be, for example, an anti-cancer immune response.

[0066] Several groups have also shown impressive efficacy in U87MG model but seldom in a syngeneic immunocompetent GBM model. Moreover, GBM models are often treated at predetermined times when animals are still healthy and tumours presumably small. In the examples discussed herein, treatment was commenced 14 days post implantation, which is approximately 4-7 days before the animals displayed symptoms of their disease. In the orthoptopic CT-2A syngeneic GBM model, treatment was commenced at a stage (19 days post implantation) when animals started displaying overt symptoms of disease. These symptoms include lack of grooming, hydrocephaly, and hunched phenotype. This treatment protocol is believed to be particularly relevant to the clinical setting where patients are diagnosed and treated after presenting with symptoms. In the examples discussed herein, either a single IC dose or 6 IV doses of FMT was administered. The results demonstrated a similarly significant survival profile achieving a significant prolongation in survival and several mice in each group (20-30%) were durably cured beyond 100 days. The CT-2A model was chosen because it resulted in an aggressive infiltrative tumour and shares proliferative, metabolic, histological, and immunohistochemical profiles observed in human glioblastoma multiforme.

[0067] The FMT virus was also demonstrated to induce cell death in a manner dependent on the anti-apoptotic threshold of the infected cells, and not on the productivity of the virus infection within the infected cell (see Example 6 and Figure 6). FMT viral infection of a cell appears to initiate activation (cleavage) of caspase 8, caspase 9, BH3-interacting domain and Poly(ADP-ribose) Polymerase in tumor cells.

[0068] As noted above, FMT infects patient derived glioma cells (BTICs) but is variably cytolytic. Figures 7A, 7B and 7C show post-infection cytolysis survival curves, derived from Alamar Blue viability assays, for FMT infected cells and for oncolytic HSV virus. Fluorescent micrographs (not shown) showing GFP expression confirms viral infection and gene expression. These results are discussed in Example 7.

[0069] As previously noted, recombinant FMTs were generated with transgenes expressing an additional protein. A screen of the recombinant FMTs was performed by infecting CT2A, U343, and U1 18 cells (MOI=0.1 pfu) for 48h and assayed using Alamar blue viability assay. All of the tested recombinant FMTs showed cumulative survival rates of 300% or less as compared to control. These results are discussed in Example 8, and illustrated in Figure 8.

[0070] Specific recombinant FTMs were tested against TRAIL-resistant glioma lines

U373 and SF268 through analysis of EC50 values using an Alamar Blue assay following 48h infection by either FMT or a recombinant FMT. Similar tests were performed against TRAIL- susceptible U118 and U87MG cells. The recombinant FMTs had no effect on normal human astrocytes (NHA). Lower EC50 values correspond to less virus being required to kill 50% of cells in a given timeframe. FMT-BAX is one example of a recombinant FMT showing a lower EC50 than FMT for both TRAIL- resistant and TRAIL-suseptible cells. Although FMT can efficiently kill this TRAIL sensitive cell line, encoding BAX dramatically increased the rate of cytotoxicity. These results are discussed in Example 9, and illustrated in Figure 9.

[0071] Various exemplary recombinant FMTs were tested to determine survival of

GM38 normal fibroblasts at different multiplicities of infection in order to determine their safety profile. It was determined that the recombinant FMTs showed a similar safety profile as backbone FMT. These results are discussed in Example 10 and illustrated in Figure 10. Exemplary recombinant FMTs were also tested in vivo to determine intracranial neurotoxicity. The results are discussed in Example 1 1.

[0072] In summary, recombinant FMT-BAX is an exemplary oncolytic virus according to the present disclosure, and which has been demonstrated to have increased cytolytic activity against human brain cancer cell lines and patient samples in vitro, and which has a demonstrated potent efficacy when used to treat preclinical models of brain cancer.

Accordingly, it is expected that isolated viral particles according to the present disclosure may be used to treat cancer, such as brain cancer (for example glioblastoma). It is also expected that isolated viral particles according to the present disclosure may be used to induce an immunogenic response, such as an anti-cancer response, in a person

administered the virus.

[0073] In some situations, it may be desirable to generate recombinant FMT viruses expressing more than one additional protein. Adding additional genes to the viral genome may result in reduced virus replication or gene expression. In order to reduce the likelihood of such a reduction, the recombinant FMT can be generated expressing a multi-cistronic cassette where each protein is separated by a self cleaveage sequence, such as a porcine teschovirus-1 2A self cleavage sequence. One example of a porcine teschovirus-1 2A self cleavage sequence is: GSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 70). A restriction site BspEI (GGA(TCCGGA)) was added at the beginning of the encoding nucleotide sequence: GGATCCGGAGCCACGAACTTCTCTCTGTTAAAGCAAGCAGGAGACGTGGAAGAAAACC CCGGTCCT (SEQ ID NO: 71). The porcine teschovirus-1 2A self cleavage sequence used by the authors of the present document was discussed by A. L. Szymczak-Workman in Cold Spring Harbor Protoc; 2012; Feb 1 ; 2012(2): 199-204. [0074] A recombinant FMT expressing both green fluorescent protein and red fluorescent protein was generated by expression of a bicistronic cassette that included the two transgenes separated by a sequene encoding the porcine teschovirus-1 2A self cleavage sequence. The replication or gene expression of the resulting virus was not affected. These results are discussed in Example 12 and illustrated in Figure 1 1.

[0075] Polynucleotide and Amino Acid Sequences

[0076] The present disclosure features the identification of polynucleotide sequences, including gene sequences and coding nucleic acid sequences, and amino acid sequences. In addition to the sequences expressly provided in the accompanying sequence listing, also included are polynucleotide sequences that are related structurally and/or functionally. Also included are polynucleotide sequences that encode a protein sequence listed in the sequence listing. Also included are polynucleotide sequences that hybridize under stringent conditions to any of the polynucleotide sequences in the sequence listing, or a subsequence thereof (e.g., a subsequence comprising at least 100 contiguous nucleotides). Polynucleotide sequences also include sequences and/or subsequences configured for RNA production and/or translation, e.g., mRNA, antisense RNA, sense RNA, RNA silencing and interference configurations, etc.

[0077] Polynucleotide sequences that are substantially identical to those provided in the sequence listing can be used in the compositions and methods disclosed herein.

Substantially identical or substantially similar polynucleotide sequences are defined as polynucleotide sequences that are identical, on a nucleotide by nucleotide basis, with at least a subsequence of a reference polynucleotide. Such polynucleotides can include, e.g., insertions, deletions, and substitutions relative to any of those listed in the sequence listing. For example, such polynucleotides are typically at least about 70% identical to a reference polynucleotide selected from those in the sequence listing, or a subsequence thereof. For example, at least 7 out of 10 nucleotides within a window of comparison are identical to the reference sequence selected. Furthermore, such sequences can be at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5%, identical to the reference sequence. Subsequences of these polynucleotides can include at least about 5, at least about 10, at least about 15, at least about 20, at least about 25, at least about 50, at least about 75, at least about 100, at least about 500, about 1000 or more, contiguous nucleotides or complementary subsequences. Such subsequences can be, e.g., oligonucleotides, such as synthetic oligonucleotides, isolated oligonucleotides, or full-length genes or cDNAs. Polynucleotide sequences complementary to any of the described sequences are included.

[0078] Amino acid sequences include the amino acid sequences represented in the sequence listing, and subsequences thereof. Also included are amino acid sequences that are highly related structurally and/or functionally. Such amino acid sequences may be referred to as "variants" of the reference sequence.

[0079] For example, in addition to the amino acid sequences in the sequence listing, amino acid sequences that are substantially identical can be used in the disclosed compositions and methods. Substantially identical or substantially similar amino acid sequences are defined as amino acid sequences that are identical, on an amino acid by amino acid basis, with at least a subsequence of a reference amino acid sequence. Such amino acid sequences can include, e.g., insertions, deletions, and substitutions relative to any of the amino acid sequences in the sequence listing. For example, such amino acids are typically at least about 70% identical to a reference amino acid sequence, or a subsequence thereof. For example, at least 7 out of 10 amino acids within a window of comparison are identical to the reference amino acid sequence selected. Frequently, such amino acid sequences are at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5%, identical to the reference sequence. Subsequences of the amino acid sequences can include at least about 5, at least about 10, at least about 15, at least about 20, at least about 25, at least about 50, at least about 75, at least about 100, at least about 500, about 1000 or more, contiguous amino acids. Conservative variants of amino acid sequences or subsequences are also possible.

[0080] In view of the above, a variant of a reference protein may be a protein that has a sequence which is at least 70% to at least 99% identical, or any value therebetween (for example at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 98% identical), to the sequence of the reference protein, and where the cell viability of at least one of SF268, CT2A, U343, or U1 18 cells is less than 20% greater for cells infected with FMT virus expressing the variant protein, as compared to the cells infected with FMT virus expressing the reference protein. Cell viability is measured an assay where the cells are plated at a density of 10,000 cells/well into 96 well plates. The next day cells are infected with the FMT-va riant protein or FMT-reference protein at 0.1 multiplicity of infection. Following a 48 hour incubation, Alamar Blue (Resazurin sodium salt (Sigma-Aldrich)) is added to a final concentration of 20 μg/ml. After a 6 hour incubation the absorbance is read at a wavelength of 573 nm. If an FMT-reference protein has a cell viability of 50%, then the variant protein would be considered to have equivalent cytotoxicity if the FMT-variant protein had a cell viability of 60% or less.

[0081] Where the polynucleotide sequences are translated to form a polypeptide or subsequence of a polypeptide, nucleotide changes can result in either conservative or non- conservative amino acid substitutions. Conservative amino acid substitutions refer to the interchangeability of residues having functionally similar side chains. Conservative substitution tables providing functionally similar amino acids are well known in the art. Table 2 sets forth examples of six groups containing amino acids that are "conservative

substitutions" for one another. Other conservative substitution charts are available in the art, and can be used in a similar manner.

Table 2

Conservative Substitution Group

1 Alanine (A) Serine (S) Threonine (T)

2 Aspartic acid (D) Glutamic acid(E)

3 Asparagine (N) Glutamine (Q)

4 Arginine (R) Lysine (K)

5 Iso leucine (I) Leucine (L) Methionine (M) Valine (V)

6 Phenylalanine (F) Tyrosine (Y) Tryptophan (W)

[0082] One of skill in the art will appreciate that many conservative substitutions yield functionally identical constructs. For example, as discussed above, owing to the degeneracy of the genetic code, "silent substitutions" (i.e., substitutions in a polynucleotide sequence which do not result in an alteration in an encoded polypeptide) are an implied feature of every polynucleotide sequence which encodes an amino acid. Similarly, "conservative amino acid substitutions," in one or a few amino acids in an amino acid sequence (e.g., about 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or more) are substituted with different amino acids with highly similar properties, are also readily identified as being highly similar to a disclosed construct. Such conservative variations of each disclosed sequence are also contemplated. [0083] Methods for obtaining conservative variants, as well as more divergent versions of the polynucleotide and amino acid sequences, are widely known in the art. In addition to naturally occurring homologues which can be obtained, e.g., by screening genomic or expression libraries according to any of a variety of well-established protocols, see, e.g., Ausubel et al. Current Protocols in Molecular Biology (supplemented through 2004) John Wiley & Sons, New York ("Ausubel"); Sambrook et al. Molecular Cloning - A Laboratory Manual (2nd Ed.), Vol. 1-3, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1989 ("Sambrook"), and Berger and Kimmel Guide to Molecular Cloning Techniques, Methods in Enzymology volume 152 Academic Press, Inc., San Diego, Calif. ("Berger"), additional variants can be produced by any of a variety of mutagenesis procedures. Many such procedures are known in the art, including site directed mutagenesis, oligonucleotide- directed mutagenesis, and many others. For example, site directed mutagenesis is described, e.g., in Smith (1985) "In vitro mutagenesis" Ann. Rev. Genet. 19:423-462, and references therein, Botstein & Shortle (1985) "Strategies and applications of in vitro mutagenesis" Science 229: 1193-1201 ; and Carter (1986) "Site-directed mutagenesis" Biochem. J. 237:1-7. Oligonucleotide-directed mutagenesis is described, e.g., in Zoller & Smith (1982) "Oligonucleotide-directed mutagenesis using M13-derived vectors: an efficient and general procedure for the production of point mutations in any DNA fragment" Nucleic Acids Res. 10:6487-6500). Mutagenesis using modified bases is described e.g., in Kunkel (1985) "Rapid and efficient site-specific mutagenesis without phenotypic selection" Proc. Natl. Acad. Sci. USA 82:488-492, and Taylor et al. (1985) "The rapid generation of oligonucleotide-directed mutations at high frequency using phosphorothioate-modified DNA" Nucl. Acids Res. 13: 8765-8787. Mutagenesis using gapped duplex DNA is described, e.g., in Kramer et al. (1984) "The gapped duplex DNA approach to oligonucleotide-directed mutation construction" Nucl. Acids Res. 12: 9441-9460). Point mismatch mutagenesis is described, e.g., by Kramer et al. (1984) "Point Mismatch Repair" Cell 38:879-887). Double- strand break mutagenesis is described, e.g., in Mandecki (1986) "Oligonucleotide-directed double-strand break repair in plasmids of Escherichia coli: a method for site-specific mutagenesis" Proc. Natl. Acad. Sci. USA, 83:7177-7181 , and in Arnold (1993) "Protein engineering for unusual environments" Current Opinion in Biotechnology 4:450-455).

Mutagenesis using repair-deficient host strains is described, e.g., in Carter et al. (1985)

"Improved oligonucleotide site-directed mutagenesis using M13 vectors" Nucl. Acids Res. 13:

4431-4443. Mutagenesis by total gene synthesis is described e.g., by Nambiar et al. (1984) "Total synthesis and cloning of a gene coding for the ribonuclease S protein" Science 223: 1299-1301. DNA shuffling is described, e.g., by Stemmer (1994) "Rapid evolution of a protein in vitro by DNA shuffling" Nature 370:389-391 , and Stemmer (1994) "DNA shuffling by random fragmentation and reassembly: In vitro recombination for molecular evolution," Proc. Natl. Acad. Sci. USA 91 : 10747-10751.

[0084] Many of the above methods are further described in Methods in Enzymology

Volume 154, which also describes useful controls for trouble-shooting problems with various mutagenesis methods. Kits for mutagenesis, library construction and other diversity generation methods are also commercially available. For example, kits are available from, e.g., Amersham International pic (Piscataway, N.J.) (e.g., using the Eckstein method above), Bio/Can Scientific (Mississauga, Ontario, CANADA), Bio-Rad (Hercules, Calif.) (e.g., using the Kunkel method described above), Boehringer Mannheim Corp. (Ridgefield, Conn.), Clonetech Laboratories of BD Biosciences (Palo Alto, Calif.), DNA Technologies

(Gaithersburg, Md.), Epicentre Technologies (Madison, Wis.) (e.g., the 5 prime 3 prime kit); Genpak Inc. (Stony Brook, N.Y.), Lemargo Inc (Toronto, CANADA), Invitrogen Life

Technologies (Carlsbad, Calif.), New England Biolabs (Beverly, Mass.), Pharmacia Biotech (Peapack, N.J.), Promega Corp. (Madison, Wis.), QBiogene (Carlsbad, Calif.), and

Stratagene (La Jolla, Calif.) (e.g., QuickChange.TM. site-directed mutagenesis kit and Chameleon. TM. double-stranded, site-directed mutagenesis kit).

[0085] Determining Sequence Relationships

[0086] Similar sequences can be objectively determined by any number of methods, e.g., percent identity, hybridization, immunologically, and the like. A variety of methods for determining relationships between two or more sequences (e.g., identity, similarity and/or homology) are available and well known in the art. Methods include manual alignment, computer assisted sequence alignment, and combinations thereof, for example. A number of algorithms (which are generally computer implemented) for performing sequence alignment are widely available or can be produced by one of skill. These methods include, e.g., the local homology algorithm of Smith and Waterman (1981) Adv. Appl. Math. 2:482; the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443; the search for similarity method of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. (USA)

85:2444; and/or by computerized implementations of these algorithms (e.g., GAP, BESTFIT,

FASTA, and TFASTA in the Wsconsin Genetics Software Package Release 7.0, Genetics

Computer Group, 575 Science Dr., Madison, Wis.). [0087] For example, software for performing sequence identity (and sequence similarity) analysis using the BLAST algorithm is described in Altschul et al. (1990) J. Mol. Biol. 215:403-410. This software is publicly available, e.g., through the National Center for Biotechnology Information on the internet at ncbi.nlm.nih.gov. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold. These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the

parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 1 1 , an expectation (E) of 10, a cutoff of 100, M=5, N=-4, and a comparison of both strands. For amino acid sequences, the BLASTP (BLAST Protein) program uses as defaults a wordlength (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see, Henikoff & Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915).

[0088] Additionally, the BLAST algorithm performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul (1993) Proc. Nat'l. Acad. Sci. USA 90:5873-5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (p(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence (and, therefore, in this context, homologous) if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.1 , or less than about 0.01 , and or even less than about 0.001. [0089] Another example of a sequence alignment algorithm is PI LEU P, which creates a multiple sequence alignment from a group of related sequences using progressive, pairwise alignments. It can also plot a tree showing the clustering relationships used to create the alignment. PILEUP uses a simplification of the progressive alignment method of Feng & Doolittle (1987) J. Mol. Evol. 35:351-360. The method used is similar to the method described by Higgins & Sharp (1989) CABIOS5: 151-153. The program can align, e.g., up to 300 sequences of a maximum length of 5,000 letters. The multiple alignment procedure begins with the pairwise alignment of the two most similar sequences, producing a cluster of two aligned sequences. This cluster can then be aligned to the next most related sequence or cluster of aligned sequences. Two clusters of sequences can be aligned by a simple extension of the pairwise alignment of two individual sequences. The final alignment is achieved by a series of progressive, pairwise alignments. The program can also be used to plot a dendogram or tree representation of clustering relationships. The program is run by designating specific sequences and their amino acid or nucleotide coordinates for regions of sequence comparison.

[0090] An additional example of an algorithm that is suitable for multiple DNA, or amino acid, sequence alignments is the CLUSTALW program (Thompson, J. D. et al. (1994) Nucl. Acids. Res. 22: 4673-4680). CLUSTALW performs multiple pairwise comparisons between groups of sequences and assembles them into a multiple alignment based on homology. Gap open and Gap extension penalties can be, e.g., 10 and 0.05 respectively. For amino acid alignments, the BLOSUM algorithm can be used as a protein weight matrix. See, e.g., Henikoff and Henikoff (1992) Proc. Natl. Acad. Sci. USA 89: 10915-10919.

[0091] Polynucleotide hybridization similarity can also be evaluated by hybridization between single stranded (or single stranded regions of) nucleic acids with complementary or partially complementary polynucleotide sequences. Hybridization is a measure of the physical association between nucleic acids, typically, in solution, or with one of the nucleic acid strands immobilized on a solid support, e.g., a membrane, a bead, a chip, a filter, etc. Nucleic acid hybridization occurs based on a variety of well characterized physico-chemical forces, such as hydrogen bonding, solvent exclusion, base stacking, and the like. Numerous protocols for nucleic acid hybridization are well known in the art. An extensive guide to the hybridization of nucleic acids is found in Tijssen (1993) Laboratory Techniques in

Biochemistry and Molecular Biology-Hybridization with Nucleic Acid Probes, part I, chapter

2, "Overview of principles of hybridization and the strategy of nucleic acid probe assays," (Elsevier, N.Y.), as well as in Ausubel et al. Current Protocols in Molecular Biology

(supplemented through 2004) John Wiley & Sons, New York ("Ausubel"); Sambrook et al. Molecular Cloning - A Laboratory Manual (2nd Ed.), Vol. 1-3, Cold Spring Harbor

Laboratory, Cold Spring Harbor, N.Y., 1989 ("Sambrook"), and Berger and Kimmel Guide to Molecular Cloning Techniques, Methods in Enzymology volume 152 Academic Press, Inc., San Diego, Calif. ("Berger"). Hames and Higgins (1995) Gene Probes 1 , IRL Press at Oxford University Press, Oxford, England (Hames and Higgins 1) and Hames and Higgins (1995) Gene Probes 2, IRL Press at Oxford University Press, Oxford, England (Hames and Higgins 2) provide details on the synthesis, labeling, detection and quantification of DNA and RNA, including oligonucleotides.

[0092] Conditions suitable for obtaining hybridization, including differential hybridization, are selected according to the theoretical melting temperature (Tm) between complementary and partially complementary nucleic acids. Under a given set of conditions, e.g., solvent composition, ionic strength, etc., the. Tm is the temperature at which the duplex between the hybridizing nucleic acid strands is 50% denatured. That is, the Tm corresponds to the temperature corresponding to the midpoint in transition from helix to random coil; it depends on the length of the polynucleotides, nucleotide composition, and ionic strength, for long stretches of nucleotides.

[0093] After hybridization, unhybridized nucleic acids can be removed by a series of washes, the stringency of which can be adjusted depending upon the desired results. Low stringency washing conditions (e.g., using higher salt and lower temperature) increase sensitivity, but can product nonspecific hybridization signals and high background signals. Higher stringency conditions (e.g., using lower salt and higher temperature that is closer to the T.sub.m) lower the background signal, typically with primarily the specific signal remaining, See, also, Rapley, R. and Walker, J. M. eds., Molecular Biomethods Handbook (Humana Press, Inc. 1998).

[0094] "Stringent hybridization wash conditions" or "stringent conditions" in the context of nucleic acid hybridization experiments, such as Southern and northern

hybridizations, are sequence dependent, and are different under different environmental parameters. An extensive guide to the hybridization of nucleic acids is found in Tijssen

(1993), supra, and in Hames and Higgins 1 and Hames and Higgins 2, supra.

[0095] An example of stringent hybridization conditions for hybridization of complementary nucleic acids which have more than 100 complementary residues on a filter in a Southern or northern blot is 2xSSC, 50% formamide at 42°C, with the hybridization being carried out overnight (e.g., for approximately 20 hours). An example of stringent wash conditions is a 0.2xSSC wash at 65°C for 15 minutes (see Sambrook, supra for a description of SSC buffer). Often, the wash determining the stringency is preceded by a low stringency wash to remove signal due to residual unhybridized probe. An example low stringency wash is 2xSSC at room temperature (e.g., 20° C for 15 minutes).

[0096] In general, a signal to noise ratio of at least 2.5^χ-5^χ (and typically higher) than that observed for an unrelated probe in the particular hybridization assay indicates detection of a specific hybridization. Detection of at least stringent hybridization between two sequences indicates relatively strong structural similarity to those provided in the sequence listings herein.

[0097] Generally, "highly stringent" hybridization and wash conditions are selected to be about 5°C or less lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH (as noted below, highly stringent conditions can also be referred to in comparative terms). Target sequences that are closely related or identical to the nucleotide sequence of interest (e.g., "probe") can be identified under stringent or highly stringent conditions. Lower stringency conditions are appropriate for sequences that are less complementary.

[0098] For example, in determining stringent or highly stringent hybridization (or even more stringent hybridization) and wash conditions, the stringency of the hybridization and wash conditions is gradually increased (e.g., by increasing temperature, decreasing salt concentration, increasing detergent concentration, and/or increasing the concentration of organic solvents, such as formamide, in the hybridization or wash), until a selected set of criteria are met. For example, the stringency of the hybridization and wash conditions is gradually increased until a probe comprising one or more of the present polynucleotide sequences, or a subsequence thereof, and/or complementary polynucleotide sequences thereof, binds to a perfectly matched complementary target, with a signal to noise ratio that is at least 2.5^χ, and optionally 5^χ, or 10^χ, or 100^χ or more, as high as that observed for hybridization of the probe to an unmatched target, as desired.

[0099] Vectors, Promoters and Expression Systems

[00100] Polynucleotide sequences of the present disclosure can be in any of a variety of forms, e.g., expression cassettes, vectors, plasmids, viral particles, or linear nucleic acid sequences. For example, vectors, plasmids, cosmids, bacterial artificial chromosomes (BACs), YACs (yeast artificial chromosomes), phage, viruses and nucleic acid segments can comprise the present nucleic acid sequences or subsequences thereof. These nucleic acid constructs can further include promoters, enhancers, polylinkers, regulatory genes, etc. Thus, the present disclosure also relates, e.g., to vectors comprising the polynucleotides disclosed herein, host cells that incorporate these vectors, and the production of the various disclosed polypeptides (including those in the sequence listing) by recombinant techniques.

[00101] In accordance with these aspects, the vector may be, for example, a plasmid vector, a single or double-stranded phage vector, or a single or double-stranded RNA or DNA viral vector. Such vectors may be introduced into cells as polynucleotides, preferably DNA, by well known techniques for introducing DNA and RNA into cells. The vectors, in the case of phage and viral vectors, also may be and preferably are introduced into cells as packaged or encapsidated virus by well known techniques for infection and transduction. Viral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.

[00102] In some examples, vectors include those useful for expression of

polynucleotides and polypeptides of the present invention. Generally, such vectors comprise cis-acting control regions effective for expression in a host, operably linked to the

polynucleotide to be expressed. Appropriate trans-acting factors are supplied by the host, supplied by a complementing vector or supplied by the vector itself upon introduction into the host.

[00103] In certain examples in this regard, the vectors provide for protein expression. Such preferred expression may be inducible expression, temporally limited expression, or expression restricted to predominantly certain types of cells, or any combination of the above. Some embodiments of inducible vectors can be induced for expression by environmental factors that are easy to manipulate, such as temperature and nutrient additives. A variety of vectors suitable to this aspect, including constitutive and inducible expression vectors for use in prokaryotic and eukaryotic hosts, are well known and employed routinely by those of skill in the art. Such vectors include, among others, chromosomal, episomal and virus-derived vectors, e.g., vectors derived from bacterial plasmids, from bacteriophage, from transposons, from yeast episomes, from insertion elements, from yeast chromosomal elements, from viruses such as rhabdoviruses, baculoviruses, papova viruses, such as SV40, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and retroviruses, and vectors derived from combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, such as cosmids and phagemids and binaries used for Agrobacterium-mediated transformations.

[00104] Vectors can include a selectable marker and a reporter gene. For ease of obtaining sufficient quantities of vector, a bacterial origin that allows replication in E. coli can be used. The following vectors, which are commercially available, are provided by way of example. Among vectors preferred for use in bacteria are pQE70, pQE60 and pQE-9, available from Qiagen; pBS vectors, Phagescript vectors, Bluescript vectors, pNH8A, pNH16a, pNH18A, pNH46A, available from Stratagene; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia. Among preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Useful plant binary vectors include BIN19 and its derivatives available from Clontech. These vectors are listed solely by way of illustration of the many commercially available and well-known vectors that are available to those of skill in the art. It will be appreciated that any other plasmid or vector suitable for, for example, introduction, maintenance, propagation or expression of one or more polynucleotides and/or polypeptides as provided in the present sequence listing, including variants thereof as described, in a host may be used.

[00105] In general, expression constructs will contain sites for transcription initiation and termination, and, in the transcribed region, a ribosome-binding site for translation when the construct encodes a polypeptide. The coding portion of the mature transcripts expressed by the constructs will include a translation-initiating AUG at the beginning and a termination codon appropriately positioned at the end of the polypeptide to be translated. In addition, the constructs may contain control regions that regulate as well as engender expression.

Generally, in accordance with many commonly practiced procedures, such regions will operate by controlling transcription, such as transcription factors, repressor binding sites and termination signals, among others. For secretion of a translated protein into the lumen of the endoplasmic reticulum, into the periplasmic space or into the extracellular environment, appropriate secretion signals may be incorporated into the expressed polypeptide. These signals may be endogenous to the polypeptide or they may be heterologous signals.

[00106] Transcription of the DNA (e.g., encoding the polypeptides) of the present invention by higher eukaryotes may be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp that act to increase transcriptional activity of a promoter in a given host cell-type. Examples of enhancers include the SV40 enhancer, which is located on the late side of the replication origin at bp 100 to 270, the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. Additional enhancers useful in the invention to increase transcription of the introduced DNA segment, include, inter alia, viral enhancers like those within the 35S promoter, as shown by Odell et al., Plant Mol. Biol. 10:263-72 (1988), and an enhancer from an opine gene as described by Fromm et al., Plant Cell 1 :977 (1989). The enhancer may affect the tissue-specificity and/or temporal specificity of expression of sequences included in the vector.

[00107] Termination regions also facilitate effective expression by ending transcription at appropriate points. Useful terminators include, but are not limited to, pinll (see An et al., Plant Cell 1 (1): 1 15-122 (1989)), glbl (see Genbank Accession #L22345), gz (see gzw64a terminator, Genbank Accession #S78780), and the nos terminator from Agrobacterium. The termination region can be native with the promoter nucleotide sequence, can be native with the DNA sequence of interest, or can be derived from another source. For example, other convenient termination regions are available from the Ti-plasmid of A. tumefaciens, such as the octopine synthase and nopaline synthase termination regions. See also: Guerineau et al. (1991) Mol. Gen. Genet. 262:141-144; Proudfoot (1991) Cell 64:671-674; Sanfacon et al. (1991) Genes Dev. 5: 141-149; Mogen et al. (1990) Plant Cell 2: 1261-1272; Munroe et al. (1990) Gene 91 : 151-158; Ballas et al. 1989) Nucleic Acids Res. 17:7891-7903; and Joshi et al. (1987) Nucleic Acid Res. 15:9627-9639.

[00108] Among known eukaryotic promoters suitable for generalized expression are the CMV immediate early promoter, the HSV thymidine kinase promoter, the early and late SV40 promoters, the promoters of retroviral LTRs, such as those of the Rous sarcoma virus ("RSV"), metallothionein promoters, such as the mouse metallothionein-l promoter and various plant promoters, such as globulin-1. The native promoters of the polynucleotide sequences listing in the sequence listing may also be used. Representatives of prokaryotic promoters include the phage lambda PL promoter, the E. coli lac, trp and tac promoters to name just a few of the well-known promoters.

[00109] Isolated or recombinant viruses, virus infected cells, or cells including one or more portions of the present polynucleotide sequences and/or expressing one or more portions of the present amino acid sequences are also contemplated.

[00110] A polynucleotide, optionally encoding the heterologous structural sequence of an amino acid sequence as disclosed, generally will be inserted into a vector using standard techniques so that it is operably linked to a promoter for expression. Operably linked, as used herein, includes reference to a functional linkage between a promoter and a second sequence, wherein the promoter sequence initiates and mediates transcription of the DNA corresponding to the second sequence. Generally, operably linked means that the polynucleotide sequence being linked is contiguous and, where necessary to join two protein coding regions, contiguous and in the same reading frame. When the polynucleotide is intended for expression of a polypeptide, the polynucleotide will be positioned so that the transcription start site is located appropriately 5' to a ribosome binding site. The ribosome- binding site will be 5' to the AUG that initiates translation of the polypeptide to be expressed. Generally, there will be no other open reading frames that begin with an initiation codon, usually AUG, and lie between the ribosome binding site and the initiation codon. Also, generally, there will be a translation stop codon at the end of the polypeptide and there will be a polyadenylation signal in constructs for use in eukaryotic hosts. Transcription termination signals appropriately disposed at the 3' end of the transcribed region may also be included in the polynucleotide construct.

[00111] For nucleic acid constructs designed to express a polypeptide, the expression cassettes can additionally contain 5' leader sequences. Such leader sequences can act to enhance translation. Translation leaders are known in the art and include: picornavirus leaders, for example: EMCV leader (Encephalomyocarditis 5' noncoding region), Elroy-Stein et al. (1989) Proc. Nat. Acad. Sci. USA 86:6126-6130; potyvirus leaders, for example, TEV leader (Tobacco Etch Virus), Allison et al. (1986); MDMV leader (Maize Dwarf Mosaic Virus), Virology 154:9-20; human immunoglobulin heavy-chain binding protein (BiP), Macejak et al. (1991) Nature 353:90-94; untranslated leader from the coat protein mRNA of alfalfa mosaic virus (AMV RNA 4), Jobling et al. (1987) Nature 325:622-625); tobacco mosaic virus leader (TMV), Gallie et al. (1989) Molecular Biology of RNA, pages 237-256; and maize chlorotic mottle virus leader (MCMV) Lommel et al. (1991) Virology 81 :382-385. See also Della- Cioppa et al. (1987) Plant Physiology 84:965-968. The cassette can also contain sequences that enhance translation and/or mRNA stability such as introns. The expression cassette can also include, at the 3' terminus of the isolated nucleotide sequence of interest, a translational termination region.

[00112] In those instances where it is desirable to have the expressed product of the polynucleotide sequence directed to a particular organelle or secreted at the cell's surface the expression cassette can further comprise a coding sequence for a transit peptide. Such transit peptides are well known in the art and include, but are not limited to: the transit peptide for the acyl carrier protein, the small subunit of RUBISCO, plant EPSP synthase, and the like.

[00113] In making an expression cassette, the various DNA fragments can be manipulated so as to provide for the polynucleotide sequences in the proper orientation and, as appropriate, in the proper reading frame. Toward this end, adapters or linkers can be employed to join DNA fragments or other manipulations can be involved to provide for convenient restriction sites, removal of superfluous DNA, removal of restriction sites, or the like. For this purpose, in vitro mutagenesis, primer repair, restriction digests, annealing, and resubstitutions such as transitions and transversions, can be employed.

[00114] Introduction of a construct into a host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, microinjection, cationic lipid- mediated transfection, electroporation, transduction, scrape loading, ballistic introduction, infection or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods in Molecular Biology, (1986) and Sambrook et al., Molecular Cloning - A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989).

[00115] Representative examples of appropriate hosts include bacterial cells, such as streptococci, staphylococci, E. coli, streptomyces and Salmonella typhimurium cells; fungal cells, such as yeast cells and Aspergillus cells; insect cells such as Drosophila S2 and

Spodoptera Sf9 cells; animal cells such as CHO, COS and Bowes melanoma cells; and plant cells.

[00116] The host cells can be cultured in conventional nutrient media, which may be modified as appropriate for, inter alia, activating promoters, selecting transformants or amplifying genes. Culture conditions, such as temperature, pH and the like, previously used with the host cell selected for expression generally will be suitable for expression of nucleic acids and/or polypeptides, as will be apparent to those of skill in the art. Mature proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the polynucleotides disclosed herein.

[00117] Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, where the selected promoter is inducible it is induced by appropriate means (e.g., temperature shift or exposure to chemical inducer) and cells are cultured for an additional period. Cells typically then are harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification. Microbial cells employed in expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents; such methods are well known to those skilled in the art.

[00118] Compositions and methods of the present disclosure can include

administering the polynucleotides and/or amino acids as provided herein. For example, treatments for glioblastoma can include administering one or more of the polynucleotides and/or amino acids. The one or more polynucleotides and/or amino acids may be in an isolated form or may be part of a composition, including a viral particle. In various

embodiments, the administering can take the following forms: intradermal, transdermal, parenteral, intravascular, intravenous, intramuscular, intranasal, subcutaneous, regional, percutaneous, intratracheal, intraperitoneal, intraarterial, intravesical, intratumoral, inhalation, perfusion, lavage, direct injection, alimentary, oral, or intracranial administration.

[00119] Materials and Methods

[00120] Cell lines: U87MG, U343, U373, SF268, SF265, SF539, SNB19, SNB75, Vero, U1 18, normal human astrocytes (NHA), CT-2A, DBT, GL261 and human GM38 primary fibroblasts (National Institute of General Medical Sciences Mutant Cell Repository, Camden, NJ) were propagated in Dulbecco's modified Eagle's medium (Hyclone, Logan, UT) supplemented with 10% fetal calf serum (Cansera, Etobicoke, Ontario, Canada).

[00121] Viability Assays: The indicated cell lines were plated at a density of 10 000 cells/well into 96 well plates. The next day cells were infected with the rMarabaWT, or FMT at various multiplicity of infections (0.0001-1 Opfu/cell). Following a 48 hour incubation Alamar Blue (Resazurin sodium salt (Sigma-Aldrich)) was added to a final concentration of 20μg/ml. After a 6 hour incubation the absorbance was read at a wavelength of 573nm.

[00122] Plaque assays: Vero cells were plated at a density of 5e5 cells per/well of a 6 well dish. The next day 1001 of serial viral dilutions were prepared and added for 1 hour to Vero cells. After viral adsorption 2ml of agarose overlay was added (1 :1 1 % agarose: 2X DMEM and 20% FCS). Plaques were counted the following day.

[00123] Interferon bioassay: PC-3 cells were infected with rMarabaWT, ΔΜ51 or FMT, at a multiplicity of infection of 3 pfu/cell for 24 hours. The following day supernatant was acid neutralized with 0.25N HCI overnight at 4°C followed by the addition of 0.25 NaOH to adjust the pH to 7. Vero cells were incubated with the neutralized supernatant for 24 hours and subsequently infected rMaraba WT with a multiplicity of infection ranging from 0.0001 to 100pfu/cell. Any interferon secreted by the PC-3 cells in response to Maraba or the attenuated mutants would subsequently protect the Vero cells from infection with Maraba. After 24 hours, survival was quantitated using a crystal violet assay. Briefly cells were incubated with 1 % crystal violet solution, washed, dried, resuspended in 1 % SDS and read at a wavelength of 595nm.

[00124] Determination of in vivo toxicity: For the intracranial (IC) route of

administration (roa), groups of 6-8 week old female BALB/c mice (n = 5/group) were given a single IC infusion of the indicated viruses in log increments per group ranging from 10² - 10⁷ pfu. For the intravenous (IV) roa, groups of five 6-8 week old female BALB/c mice were given a single IV injection of the indicated viruses into the tail vein, in half log increments per group ranging from 3 x 10⁶ - 3 x 10⁹ pfu, diluted into 100 per injection. Following IC or IV injections, mice were monitored daily for signs of distress including weight loss, piloerection, hind-limb paralysis and respiratory distress. The median lethal dose (LD50) was calculated using the Spearman Karber method, while the maximal tolerable dose (MTD) was denoted as the highest dose not resulting in a single animal death.

[00125] Imaging glioblastoma in an animal model: U87MG and CT2A cells were adapted for bioluminescent imaging by transducing with lentivirus containing firefly luciferase (FLUC) and transfecting FLUC plasmid respectively. U87MG FLUC and CT2A FLUC cells were injected IC into CD1 nude and C57BL/6 respectively. Animals with FLUC expressing tumours were monitored for tumour progression using the live imaging MS Xenogen 200 system after an IP injection of luciferin (Gold Biotechnology Inc). The animals were monitored for signs of distress including survival, weight loss, morbidity, piloerection, hind- limb paralysis and respiratory distress.

[00126] Mouse syngeneic glioblastoma tumour models: Brain tumours were established by a single stereotactic injection with CT-2A mouse glioma cells into 6-8 week old C57BL/6 animals. Five days post injection. On Day 19 C57BL/6 mice bearing CT-2A tumours were IV treated with 6 doses of FMT (5 x 10⁸ pfu/dose thrice weekly) or injected stereotactically with FMT (2 x 10⁷ in a volume of 50 μΙ) using an infusion pump (rate=3 μΙ/min). Some C57BI/6 animals were sacrificed at day 19 and images were captured on a Nikon dissecting microscope. The remaining animals were monitored for survival. [00127] Human glioblastoma xenograft model: Human ovarian U87MG cells were adapted for bioluminescent imaging at which time 1 e6 U87MG cells were injected IC into 6-8 week old athymic CD-1 nude mice. Untreated CD-1 animals develop tumours at about day 15-21. Mice were either treated with a single intravenous (tail vein) injection performed on day 14 with FMT (5 x 10⁸), or treated IC with the same viruse at a dose of 2 x 10⁷ pfu.

Animals were monitored for survival and for signs of distress including weight loss, morbidity, piloerection, hind-limb paralysis and respiratory distress. Tumour imaging was captured with a Xenogen 200 MS system (Caliper LS, USA).

[00128] Rotorod: Balb/C mice were tested for motor function/performance on a rotating rod apparatus prior to IC viral administration. Mice were placed on a rotorod for 3 trials per day for 4 consecutive days. After allowing the animals 0.5min to adjust to the apparatus, the rod was accelerated in a linear fashion 0.1 rpm/s. Latency to fall was measured in minutes. The animals were divided into groups of 3. Motor function one week post surgery in uninjected (Naive), PBS and FMT IC treated animals. Standard error of the mean was calculated.

[00129] Nucleic Acid Sequencing: FMT sequencing was performed at the Ontario Institute for Cancer research (Toronto, Canada) on FMT cDNA which was generated using a shotgun approach with random hexamers on trizol extracted and RNeasy purified FMT RNA.

[00130] Protein sequencing: FMT virus was amplified in Vero cells to high titer (~10¹¹ pfu/mL), purified, and lysed with 5 x Laemmli sample buffer (60 mM Tris-CI pH 6.8, 2% SDS, 10% glycerol, 5% β-mercaptoethanol, 0.01 % bromophenol blue) and separated on 12% SDS-PAGE gels. Replicate gels were stained with either coomasie blue or silver, and nine bands were extracted for peptide sequencing.

[00131] Manufacturing and rescuing recombinant FMT virus: Recombinant FMT was produced as described recently for Maraba virus25. Briefly, FMT virus complementary DNA

(cDNA) was amplified in three separate RT-PCR reactions yielding overlapping fragments that were stitched together using internal restriction sites. The full length -11 Kb cDNA was then cloned into a modified LC-KAN vector (Lucigen, Middleton, Wl) carrying a T7 promoter upstream of the 5'-antigenomic leader sequence and immediately downstream of the 3'- terminator a modified hepatitis delta virus ribozyme and T7 polymerase termination signal sequence. A549 lung carcinoma cells seeded at 3.0 ^χ 10⁵ cells/well in 6-well plates were infected 24 hr later with vaccinia virus (moi = 10) expressing the T7 RNA polymerase37 in

OptiMeM medium for 1.5 hours. Following removal of the vaccinia virus, each well was transfected with LC-KAN FMT (2 μg) together with pCI-Neo constructs encoding for FMT "N" (1 μg), "P" (1.25 μg), and L (0.25 μg) with lipofectamine 2000 (5 μΙ per well) according to the manufacturer's instructions. The transfection reagent was removed 5 hr later and replaced with DMEM containing 10% HI-FBS. At 48 hours following the transfection, medium was collected (pooled from two plates), filtered (0.2 μηι) to remove contaminating vaccinia virus, and 1 ml was used to infect SNB19 glioblastoma cells in each well of a 6-well plate.

Cytopathic effects and GFP expression visible 24-48 hours later were indicative of a successful rescue. Recombinant FMT underwent three rounds of plaque purification (on SNB19 cells), before scale up, purification on sucrose cushion, and resuspension in PBS containing 15% glucose.

[00132] Phylogenetic Analysis: Phylogenetic relationships between rhabdoviruses based on a Muscle alignment of L protein amino acid sequences, and using the

paramyxovirus Measles Edmonston strain as the outgroup. The tree was generated by the neighbor-joining method and bootstrap values (indicated for each branch node) were estimated using 1000 tree replicas. Branch lengths are proportional to genetic distances. The scale bar corresponds to substitutions per amino acid site.

[00133] Immunoblotting: Cells were lysed (50mM Tris-HCI; 150 mM NaCI; 1 % Triton X-100; 1 % SDS) and protein quantified using the Lowry assay (Bio-Rad). Total cell lysates were prepared in SDS sample buffer, and 5-50 μg of total protein was separated by SDS- PAGE on Bis-Tris gels (ranging from 8-15%) and transferred to nitrocellulose or PVDF membranes. Membranes were probed with primary antibodies diluted in 5% skim milk powder (SMP) or 5% Bovine Serum Albumen (BSA) overnight at 4 deg C, followed by horse radish peroxidase-conjugated secondary antibodies diluted in 5% SMP for 1 hr at room temperature. The following primary antibodies were used: rabbit anti-PARP (Cell Signaling, 9542); mouse anti-caspase 3 (Cell Signaling, 9668); mouse anti-caspase 8 (Enzo Life

Sciences, 12F5); rabbit anti-caspase 9 (Cell Signaling, 9502); rabbit anti-BID (Cell Signaling, 2002); mouse anti-GAPDH (R&D Systems). A polylonal anti-FMT antibody was generated in rabbits (Capralogics Inc.) using purified, UV-inactivated FMT virus. Protein bands were visualized using SuperSignal West Pico Chemiluminescent Substrate System (Pierce Biotechnology)

[00134] CD8+ T cell depletion: The brains of 7 week old C57BL/6 mice were stereotactically implanted with 2e5 CT2A cells that express firefly luciferase (CT2Afluc). Mice were treated with 2e7 PFU of Farmington virus at the site of tumour implantation 7 days later. For CD8+ T cell depletion studies, 200 of anti-mouse CD8 antibody (clone 2.43) was injected intraperitoneal^ (IP) one day prior to virus treatment and 100 on the day of treatment. A maintenance dose of 100 every 3 days was given for the following 2 weeks.

[00135] Statistics: For Kaplan Meier plots, survival plots were compared using Mantel- Cox Log rank analysis (Graphpad Prism).

[00136] Examples

[00137] Example 1 : Farmington virus is not a vesiculovirus

[00138] Phylogenetic analysis of the full-length genomic sequence was performed by aligning the amino acid sequence of the putative FMT L protein to the L protein sequences of representative members from the 6 genera of Rhabdoviridae (Figure 1). The alignment demonstrated that FMT did not appear to belong to the current 6 genera schema of the Rhabdoviridae family. FMT virus appears to be more divergent from the currently known rhabdoviruses. While we did detect some sequence homology (-50% identity) between a short segment of the L protein of FMT and lettuce necrosis yellow virus, we were unable to detect any homology of the 4 remaining FMT putative open reading frames (ORFs) (N, P, G, M) to any sequences in the NCBI database. This suggests that FMT, which was originally classified incorrectly as a vesiculovirus (Tesh et al. Emerging Infect. Dis. 2002), may in fact constitute the type member of a new genus within the Rhabdoviridae family (Figure 1 ; and see Table 3 and accompanying Sequence Listing file).

Table 3. Description of Sequences.

[00139] SEQ ID NO: 3 is encoded by SEQ ID NO: 8 (i.e. the encoding sequence of positions 206 to 1444 of SEQ ID NO: 1). SEQ ID NO: 4 is encoded by SEQ ID NO: 9 (i.e. the encoding sequence of positions 1640 to 2590 of SEQ ID NO: 1). SEQ ID NO: 5 is encoded by SEQ ID NO: 10 (i.e. the encoding sequence of positions 2894 to 3340 of SEQ ID NO: 1). SEQ ID NO: 6 is encoded by SEQ ID NO: 11 (i.e. the encoding sequence of positions 3603 to 5717 of SEQ ID NO: 1). SEQ ID NO: 7 is encoded by SEQ ID NO: 12 (i.e. the encoding sequence of positions 5832 to 12221 of SEQ ID NO: 1).

[00140] Figure 1 shows A) Schematic of where FMT was first isolated in 1969. B) Amino acid Blast alignment of 5 FMT ORFs reveals no sequence homology to any other sequences in the database except for the L protein which is -45% similar to plant rhabdovirus : Lettuce Necrotic yellow virus (LNYV). C) Commassie stained SDS PAGE gel of FMT virus showing 4 of the 5 predicted FMT ORF proteins. These bands were excised from the gel and their identity confirmed through protein sequencing by tandem mass

spectrometry. D) Phylogenic tree derived from the amino acid sequences of the polymerase genes of various rhabdoviruses. The Measles paramyxovirus was included as a non-family control. All previous oncolytic rhabdoviruses have been identified from the vesiculovirus genus (VSV, Maraba). Unexpectedly, Farmington virus appears to cluster with the plant infecting cytorhabdoviruses. E) We have built a recombinant system for the FMT platform that allows us complete control of the genetic make-up of the virus. We show here the generation of a fully replicative GFP expressing FMT strain as an example. F) Electron microgram of FMT bullet shaped virion measuring 55nm x 150nm. (adapted from Tesh et al. Emerging Infect. Dis. 2002).

[00141] Example 2: Farmington virus does not demonstrate neurotoxicity

[00142] FMT demonstrated profound attenuation in non-transformed cells in vitro. To ascertain whether the observed attenuation in vitro translates to safety in vivo, we injected stereotaxically into the right striatum of the brain increasing doses of rhabdoviruses and monitored for signs of neurotoxicity (including weight loss, piloerection, hind leg paralysis, morbidity and mortality). FMT had an LD₅₀ of approximately 1 x 10⁹ in contrast the other rhabdoviruses displayed LD₅₀ of approximately 10². (Figure 2A). The Maximum Tolerated Dose (MTD) was determined to be the highest dose not resulting in durable morbidity. (Figure 2A). For FMT the MTD was approximately 1 x 10^{7 5} pfu while for the other rhabdoviruses the LD₅o occurred at such a low dose of virus the MTD was impossible to determine. These animals displayed clinical signs of a CNS infection with rapid and progressive weight loss, hind leg paralysis and had significant titres of virus in their brain just prior to death (data not shown).

[00143] Although we found no acute neurotoxicity from IC treatment with FMT, we wished to assess the cognitive and motor function of the mice several days after virus infection. Therefore, we assessed the motor function before and after treatment with these wild-type FMT virus using a rotorod apparatus (Figure 2B). Specifically, we measured the latency of these animals to fall from a slowly accelerating rod. We show that there is no significant difference in the latency to fall between the mock-infected animals or virus infected animals, 1 week prior and 1 week post injection (Figure 2B). [00144] In addition to intracranial toxicity, we evaluated the toxicity of FMT when administered intravenously (IV) in immunocompetent mice with escalating doses of virus (Figure 2C). FMT is well tolerated IV and never reaches an LD₅₀ even at our highest dose 3 x 10⁹ pfu which is comparable to an attenuated version of Maraba we described in Brun, J. et al. Identification of Genetically Modified Maraba Virus as an Oncolytic Rhabdovirus. Mol Ther 18, 1440 (2010). FMT animals IV dosed at greater than 3x 10⁸ pfu displayed transient weight loss and moderate piloerection, which resolved 5-7 days post treatment (data not shown). No detectable titres were observed from brain homogenates taken from FMT treated animals 3 months post IV treatment (Figure 2D). In addition, following administration of high doses of FMT (1 x 10⁷ pfu) in the brain, we found no signs of cell death and comparable inflammatory responses to those of saline injected control mice (Figure 2E). This differed dramatically from VSV injected animals, which displayed a striking increase in inflammatory cells, condensed nuclei, and a perforated morphology. Due to its lack of neurotoxicity and potent CNS tumour killing capacity, we elected to proceed with FMT as a platform to develop as a novel oncolytic against GBM.

[00145] Figure 2 shows the FMT Safety Profile. Figure 2A shows groups of 5 Balb/C mice were injected sterotaxically into the right striatum of the brain with increasing doses of rhabdoviruses as indicated and monitored for signs of distress including weight loss, piloerection, hind leg paralysis, morbidity and mortality. Maximal Tolerable Dose (MTD) was determined to be the highest dose not resulting in durable morbidity as measured by behaviour and weight. LD₅₀ was determined using the Spearman Karber method. FMT is unique among rhabdoviruses as a non-neurotoxic virus. Figure 2B shows, to detect any cognitive deficiencies in the striatum, motor function was assessed by rotorod apparatus which measures latency to fall off an accelerating rod. Motor function is indistinguishable from controls after intracerebral injection of FMT. Figure 2C shows groups of 3-5 Balb/C mice were injected once intravenously in half log increments of virus ranging from 3 x 10⁶ pfu to 3 x 10⁹ pfu. The animals were monitored for signs of distress including weight loss, morbidity, piloerection, hind-limb paralysis and respiratory distress. FMT shows a very high MTD of 1 x 10⁹ pfu when delivered systemically. Figure 2D shows animals sacrificed 3 months post- intracerebral inoculation demonstrate no viable virus in the brain homogenates. Limit of detection is 101. Figure 2E shows Balb/C mice were inoculated intracerebral^ with the indicated viruses (1 x 10⁷ pfu) and sacrificed 2 days post treatment. Little to no inflammation is visible and no cell loss is detectable following FMT treatment. This is in contrast to VSV which shows significant neuronal loss (empty spaces, inset).

[00146] Example 3: Farmington virus potently and selectivity kills brain tumour cells

[00147] Wild-type FMT isolates demonstrate attenuation in normal primary cells while maintaining potent glioma cell killing capacity (Figure 3A). To evaluate the clinical relevance of our novel oncolytic rhabdoviruses to treat brain cancer, we examined whether FMT could kill freshly derived patient tumour samples. Cell cultures isolated from 3 patients with primary glioblastoma multiforme were infected with FMT and 48 h later, viability assays demonstrated that FMT virus was potently cytotoxic to 2 of 3 patient tumour explants (Figure 3A). To test the killing capacity of the FMT isolates we performed cell killing assays on normal human astrocytes (NHA) and 3 GBM tumour cell lines (Figure 3B). While wild type MRB was very potent against all of the GBM cell lines, it was also highly lytic against both primary normal human astrocytes (NHA). Remarkably, FMT demonstrated the greatest therapeutic index, with potency rivaling MRB in the majority of GBM lines while remaining highly attenuated in NHA and GM38 primary cell lines (Figure 3C). This demonstrates that FMT virus is a potent and selective oncolytic virus when tested against brain cancer cell lines.

[00148] In Figure 3 we show A) Summary of FMT in vitro cytotoxicity showing potent activity against primary glioblastoma patient samples and established human and mouse brain tumour cell lines, while remaining attenuated against normal cells. B) FMT is a potent and selective killer of glioblastoma cell lines. Viability was assayed using Alamar blue assay 72h post treatment. Error bars represent SEM of 4 biological replicates. C) Detailed assessment of FMT potency against tumour and normal cells. EC50 (moi = multiplicity of infection) represents the the ratio of virus:cell required to kill 50% of cultured cells in a 72 time frame as measured using an Alamar Blue viability assay.

[00149] Example 4: Farmington virus is efficacious in xenograft and syngeneic models of glioblastoma

[00150] We next sought to determine the in vivo efficacy of our candidate viruses in mouse models of glioblastoma. After adapting human U87MG glioma cells for

bioluminescent imaging, we established an intracerebral U87MG glioma model in athymic mice and we examined the IV and IC efficacy of FMT in this model (Figure 4A-B).

Specifically, animals were treated with a single FMT dose IC (1x 10⁵) or IV (5 x10⁸ pfu) 14 days post implantation. Three days after the first treatment we observed a significant decrease in tumour burden with a greater decrease observed by day 7 (Figure 4A).

Interestingly the spinal metastases in this model are completely cleared in all tumour bearing animals. In contrast, animals treated with UV inactivated virus had a significant increase in tumour burden by day 7 at which point they started exhibiting neurological symptoms from their brain tumours (Figure 4B). All IV treated animals responded to treatment with 4 of 1 1 durably cured and surviving beyond 100 days post treatment. Most IC treated animals responded to treatment (10 of 16) with a significant (~ 2 fold) increase in time to death.

Moreover we also used fluorescent microscopy to visualize tumour explants of mock-infected animals and durably cured animals. While we detect a strong GFP expressing glioma tumour in mock-infected animals, there is a clear absence of GFP signal in FMT treated animals (Figure 4C). To complement our studies of viral efficacy in immunocompromised animals, we tested FMT in a mouse CT-2A syngeneic glioma model. Unlike xenograft models in which human gliomas grow expansively, CT-2A gliomas are infiltrative similar to what is observed clinically. We established the CT-2A glioma model by stereotactically injecting 2 x 10⁵ cells into the striatum (right frontal lobe) of C57BL/6 mice. Since treatments typically commence in human patients after they present with clinical symptoms of GBM, we sought to examine the effect of FMT at exactly the time when animals exhibit outward symptoms. In the CT-2A animals begin to show symptoms 15-20 days post implantation. These symptoms include increased intracranial pressure, lethargy, motor function, piloerection, and hunched posture. Accordingly, 19 days post implantation C57BL/6 animals were treated with FMT IV (5 x 10⁸ pfu thrice weekly for 2 weeks) or with a single IC dose of FMT (2 x 10⁷ pfu). Most animals responded to both the treatment regimens, durable cures achieved in 3 of 11 IC and 2 of 10 IV treated animals in this challenging model of advanced GBM (Figure 4D). Thus FMT virus demonstrates efficacy in preclinical models of brain cancer.

[00151] Figure 4 shows FMT In Vivo Efficacy in Preclinical Models of Glioblastoma. Figure 4A shows bioluminescence-adapted U87MG human gliomblatsoma cells (1 e6) were stereotxically implanted into right striatum of CD-1 nude mice. After 2 weeks animals were either treated with a single dose of FMT intravenously (IV- 5 x 10⁸ pfu) or intracranially (IC - 1 x 10⁵ pfu) and monitored by IVIS bioluminescence imaging. Disseminated tumours in all mice treated with FMT regress rapidly within 3-7 days and become undetectable in the spinal cord.

Figure 4B shows Kaplan Meir survival plot of animals treated with a single dose IC (1 x 10⁵ pfu) resulting in a doubling of mean time to death (Log rank test p=0.0001) or IV (5 x 10⁸ pfu) resulting in durable cures in 40% of animals (Log rank test p=0.0001). Figure 4C shows fluorescence micrograph of a mock infected mouse brain with an orthotopic GFP tagged U87MG tumour (top 2 panels) versus a FMT treated brain (bottom 2 panels). GFP

expressing tumour is clearly visible in sagittal sections of untreated mice, while FMT treatment results in no detectable GFP tumour signal, confirming tumour regression. Figure 4D shows syngeneic mouse glioblastoma tumour model using the CT2A cell line. Here again, tumours were allowed to establish until the point where mice began to die from their tumour burden. Both IC (one dose 2 x 10⁷pfu) and IV (6 doses 5 x 10⁸) treatment doubled mean time to death and resulted in >20% durable cures.

[00152] Example 5: Farmington virus induces anti-tumour immunity

[00153] Emerging evidence is demonstrating that the oncolytic effect of many viruses, including oncolytic rhabdoviruses, is due in part to the induction of anti-tumor immunity. To explore the possibility that FMT virus induces multiple mechanisms for tumor destruction in vivo, we asked whether treating immunocompetent tumor-bearing mice with FMT virus evokes anti-tumor immunity. To begin, we performed a "re-challenge" experiment, where C57/BL6 mice previously harboring CT-2A tumors that had been successfully treated with IC FMT virus infusions were injected for a second time with CT-2A cells directly into the brain. In these experiments, previously cured mice uniformly rejected the cells (Figure 5A), demonstrating that they had acquired long-lasting immunity towards CT-2A antigen(s). Next, we examined the role of cytotoxic T-lymphocytes (CTLs) in the anti-tumor response elicited by FMT virus. Mice were inoculated with CT-2A cells in their brain, and then CTLs were removed using antibodies directed towards CD8 concomitant with FMT virus treatment. Consistent with recent data from other labs using different oncolytic agents, these

experiments showed that FMT virus induced complete responses only when CTLs were present (Figure 5B). Thus, in addition to directly lysing MG cells, these data demonstrate that FMT virus induces a potent and long-lasting CTL-mediated anti-MG immune response in immunocompetent mice.

[00154] In Figure 5A, C57/B6 mice were implanted with CT2A murine glioma cells into the striatum (3 x 10⁵ cells). Mice were treated with a single dose of FMT (2 x 10⁷ pfu) and subsequently cured of their initial tumour. After 6 months, these mice were challenged with

CT2A cells implanted into the striatum. Naive mice were implanted with CT2A cells as a control. Bioluminescent imaging to monitor CT2A tumour growth showed that mice that had previously been cured of the tumours completely rejected subsequent CT2A tumour growth, while naive mice grew tumours with the expected kinetics. In figure 5B) C57/B6 mice were implanted with CT2A murine glioma cells into the striatum (3 x 10⁵ cells) and allowed to grow tumours for 14 days. One group mice received anti- CD8 polyclonal serum injections to remove CD8+ T cells or matched pre-immune serum as a control. Both groups were treated with a single intracranial dose of FMT (2 x 10⁷ pfu) to induce tumour regressions. All mice responded with tumour regression as measured using bioluminescent tumour imaging (not shown), but mice that had been stripped of their CD8+ T cells all eventually regrew tumours and failed therapy.

[00155] Example 6: Farmington virus selectively induces apoptosis in tumor cells

[00156] We used the NT2 cell system that consists of transformed NT2

teratocarcinoma cells which can be induced to differentiate into post mitotic neurons with retanoic acid. Following infection with wild type VSV or FMT we observed that these viruses infected and produced infectious progeny to the same degree in either cancerous or noncancerous forms of the NT2 cells (Figure 6A). However, although these viruses were potently cytotoxic to malignant NT2 cells, FMT showed almost no cytotoxicity in differentiated post mitotic NT2 cells (Figure 6B). This indicated that in contrast to other oncolytic rhabdoviruses like VSV, FMT virus appeared to have a unique mechanism of tumour selectivity functioning at the level of cytotoxicity.

[00157] Rhabdoviruses kill permissive cells by apoptosis, activated through virus- mediated degradation of key BH3-only proteins, an event which ultimately engages the apical intracellular and extracellular caspases that initiate the irreversible cell death cascade. To ascertain whether FMT virus selectively kills tumor cells via differential induction of apoptosis, we evaluated the activation status of key proteins in the apoptotic heirarchy. As expected, the surrogate apoptosis marker PARP as well as the downstream effector caspase 3 were strongly activated in SNB19 but not NHA cells treated with FMT virus (Figure 6C), indicating the presence of apoptosis. Moreover, the activator caspases 8 and 9 were engaged in the tumor cells, but not in the normal cells. The NT2 cell system data is consistent with this apoptosis data in the transformed versus normal cell lines showing that cell death induced by FMT virus is dependent not just on the productivity of the virus infection within, but also the anti-apoptotic threshold of, the infected cell. [00158] In Figure 6A, both pre and post differentiated cell types were permissive to infection by wt VSV and wt FMT virus, producing infectious particles in the 10⁶ - 10⁸ range. Figure 6B shows that only VSV was cytolytic against the neuron. Figure 6C Western blot of several components of the cellular apoptotic signaling cascade following infection of either tumour (SNB19) or normal cells (NHA). FMT appears to initiate the activation (cleavage) of Caspase 8, Caspase 9, BID, and PARP only in tumour cells. To our knowledge, this is the first report of an oncolytic virus whose activity is restricted not just at the level of infectivity, but also at the level of selective initiation of cell death. Figure 6D Schematic of cellular apoptosis signaling cascade. Proteins that are cleaved during activation are depicted in orange and correspond to those included in our western blotting array in Figure 6C.

[00159] Example 7: Farmington virus shows variable cytolyic activity in patient derived glioma cells (brain tumor-initiating cell, or BTICs).

[00160] Three different primary cell cultures established from patient derived glioma cells were plated at a density of 10 000 cells/well into 96 well plates. The next day cells were infected with the FMT at various multiplicity of infections (0.0001-10 pfu/cell). Following a 96 hour incubation Alamar Blue (Resazurin sodium salt (Sigma-Aldrich)) was added to a final concentration of 20μg/ml. After a 6 hour incubation the absorbance was read at a wavelength of 573 nm.

[00161] Example 8: Screen of recombinant FMTs in SF268, CT2A, U343, and U118 cells.

[00162] Recombinant FMTs were generated using an engineered Farmington virus genome. The engineered Farmington virus genome was modified to introduce a start/stop- Notl and BsiWI sequence between the G and L Farmington genes in order to facilitate the insertion of the transgene sequences.

[00163] Forward primers (containing Notl) and reverse primers (containing BsiWI) were designed to amplify the coding region of each open reading frame (ORF) using cDNA from either normal human fibroblast (GM38), normal human astrocytes, or human lymphocytes. With tBID (Ub BIDAl-60), a synthethized plasmid DNA from IDT was used. Wth Maraba M a plasmid containing Maraba wild type genome sequence was used. For FMT-EndoG, an In phusion recombination system was used since it has a BsiWI site. [00164] The resulting recombinant Farmington clones were then rescued, as previously described in Brun J. et al., (2010) Mol Ther 18: 1440-1449, except Farmington N, P and L was used for the rescue. The rescued viruses were plaque purified once, and subjected to opti-prep purification.

[00165] The forward and reverse primers used to amplify the coding region of each ORF are shown below in Tables 4 and 5. The sources of the cDNA to amplify the transgenes are shown in Table 6.

Table 4. Forward Primers

PUMA alpha forw ACTGGCGGCCGCATGGCCCGCGCACG PUMA NM_014417 NotI CCAGG (SEQ ID NO: 89) alpha

RAIDD forw NotI ACTGGCGGCCGCATGGAGGCCAGAGA RAIDD NM_003805

CAAACAAG (SEQ ID NO: 90)

RIPK1 forw NotI ACTGGCGGCCGCATGCAACCAGACAT RIPK1 NM_003804

GTCCTTG (SEQ ID NO: 91)

BIDvl forw NotI ACTGGCGGCCGCATGTGCAGCGGTGC BIDvl NM_197966

TGGGGTC (SEQ ID NO: 92)

BIDv2 forw NotI ACTGGCGGCCGCATGGACTGTGAGGT BIDv2 NM_001 196

CAACAAC (SEQ ID NO: 93)

Ub BIDAl-60 ACTGGCGGCCGCATGCAGATCTTCGT Ub

forw NotI GAAAACCC (SEQ ID NO: 94) BIDA1- 60

ATG12 forw NotI ACTGGCGGCCGCATGGCGGAGGAGC ATG12 NM_004707

CGCAGTC (SEQ ID NO: 95)

ATG16L1 forw ACTGGCGGCCGCATGTCGTCGGGCCT ATG16 NM_030803 NotI CCGCG (SEQ ID NO: 96) L1

ATG3 forw NotI ACTGGCGGCCGCATGCAGAATGTGAT ATG3 NM_022488

TAATACTGTGAAG (SEQ ID NO: 97)

ATG5 forw NotI ACTGGCGGCCGCATGACAGATGACAA ATG5 NM_004849

AGATGTGC (SEQ ID NO: 98)

ATG7 forw NotI ACTGGCGGCCGCATGGCGGCAGCTAC ATG7 NM_006395

GGGGG (SEQ ID NO: 99)

BECN1 forw NotI ACTGGCGGCCGCATGGAAGGGTCTAA BECN1 NM_003766

GACGTCC (SEQ ID NO: 100)

CASP2 forw NotI ACTGGCGGCCGCATGGCGGCGCCGA CASP2 NM_032982

GCGCGG (SEQ ID NO: 101)

IFNgamma forw ACTGGCGGCCGCATGAAATATACAAGT IFN NM_000619 NotI TATATCTTGGC (SEQ ID NO: 102) gamma

IGF1 R forw NotI ACTGGCGGCCGCATGAAGTCTGGCTC IGF1 R NM_000875

CGGAGG (SEQ ID NO: 103)

IRGM forw NotI ACTGGCGGCCGCATGGAAGCCATGAA IRGM NM 001 145

TGTTGAGAAAG (SEQ ID NO: 104) 805

TRAF2 forw NotI ACTGGCGGCCGCATGGCTGCAGCTAG TRAF2 NM_021 138

CGTGAC (SEQ ID NO: 105)

ATP6V1G2 forw ACTGGCGGCCGCATGGCCAGTCAGTC ATP6V NM_130463 NotI CCAAGG (SEQ ID NO: 106) 1G2

Cathepsin D forw ACTGGCGGCCGCATGCAGCCCTCCAG Cathep NM_001909 NotI CCTTC (SEQ ID NO: 107) sin D

DRP1 forw NotI ACTGGCGGCCGCATGGAGGCGCTAAT DRP1 NM_012062

TCCTGTC (SEQ ID NO: 108)

MLKL forw NotI ACTGGCGGCCGCATGGAAAATTTGAA MLKL NM_152649

GCATATTATCACC (SEQ ID NO: 109)

PARP1 forw NotI ACTGGCGGCCGCATGGCGGAGTCTTC PARP1 NM_001618

GGATAAG (SEQ ID NO: 110)

PARP2 forw NotI ACTGGCGGCCGCATGGCGGCGCGGC PARP2 NM_005484

GGCGAC (SEQ ID NO: 11 1) PGAM5-S forw ACTGGCGGCCGCATGGCGTTCCGGCA PGAM5 NM 001 170 NotI GGCGC (SEQ ID NO: 1 12) -S 544

RIPK3 forw NotI ACTGGCGGCCGCATGTCGTGCGTCAA RIPK3 NM_006871

GTTATGG (SEQ ID NO: 1 13)

SLC25A4 forw ACTGGCGGCCGCATGGGTGATCACGC SLC25 NM_001 151 NotI TTGGAGC (SEQ ID NO: 114) A4

EndoG forw NotI TCCAGAGCCGCGGCCGCATGCGGGC EndoG NM_004435

GCTGCGGGCCGG (SEQ ID NO: 115)

MRB M forw NotI ACTGGCGGCCGCATGAGCTCTCTCAA Maraba HQ660076

GAAAA I I I TGGG (SEQ ID NO: 116) M gene

Table 5. Reverse primers

Name Sequence Gene Accession #

AIF rev BsiWI ACTGCGTACGTCAGTCTTCATGAATGTT AIF NM_004208

GAATAG (SEQ ID NO: 117)

APAF1 rev BsiWI ACTGCGTACGTTATTCTAAAGTCTGTAA APAF1 NM_181861

AATATATAAAATACC (SEQ ID NO: 118)

BAD rev BsiWI ACTGCGTACGTCACTGGGAGGGGGCG BAD NM_004322

GAGC (SEQ ID NO: 1 19)

BIM rev BsiWI ACTGCGTACGTCAATGCATTCTCCACA BIM NM_138621

CCAG (SEQ ID NO: 120)

CAD rev BsiWI ACTGCGTACGTCACTGGCGTTTCCGCA CAD NM 001282

CAGG (SEQ ID NO: 121) 669

CASP3 rev ACTGCGTACGTTAGTGATAAAAATAGA CASP3 NM_004346 BsiWI GTTC I I I I GTG (SEQ ID NO: 122)

CASP8 rev ACTGCGTACGTCAATCAGAAGGGAAGA CASP8 NM 001080 BsiWI CAAG (SEQ ID NO: 123) 125

CHOP rev BsiWI ACTGCGTACGTCATGCTTGGTGCAGAT CHOP NM 001 195

TCACC (SEQ ID NO: 124) 053

CYLD rev BsiWI ACTGCGTACGTTATTTGTACAAACTCAT CYLD NM_015247

TGTTGGAC (SEQ ID NO: 125)

DFFA rev BsiWI ACTGCGTACGCTATGTGGGATCCTGTC DFFA NM_004401

TGGC (SEQ ID NO: 126)

Granzyme B rev ACTGCGTACGTTAGTAGCGTTTCATGG Granzy NM_004131 BsiWI TTTTCTTTA (SEQ ID NO: 127) me B

JNK1 a2 rev ACTGCGTACGTCATCTACAGCAGCCCA JNK1 NM_139049 BsiWI GAG (SEQ ID NO: 128) a2

JNK1 b2 rev ACTGCGTACGTCATCTACAGCAGCCCA JNK1 NM 001278 BsiWI GAGG (SEQ ID NO: 129) b2 547

NOXA rev BsiWI ACTGCGTACGTCAGGTTCCTGAGCAGA NOXA NM_021 127

AGAG (SEQ ID NO: 130)

PIDD rev BsiWI ACTGCGTACGCTAGGCCTGGGCAGGC PIDD NM_145886

TCTG (SEQ ID NO: 131)

PUMA gamma ACTGCGTACGCTACATGGTGCAGAGAA PUMA NM 001 127 rev BsiWI AGTC (SEQ ID NO: 132) gamma 240

PUMA beta rev ACTGCGTACGCTAATTGGGCTCCATCT PUMA NM 001 127 BsiWI CGGG (SEQ ID NO: 133) beta 241 PUMA alpha rev ACTGCGTACGCTAATTGGGCTCCATCT PUMA NM_014417 BsiWI CGGG (SEQ ID NO: 134) alpha

RAIDD rev BsiWI ACTGCGTACGTCACTCCAACATGTGCA RAIDD NM_003805

GGAG (SEQ ID NO: 135)

RIPK1 rev BsiWI ACTGCGTACGTTAGTTCTGGCTGACGT RIPK1 NM_003804

AAATC (SEQ ID NO: 136)

BIDvl rev BsiWI ACTGCGTACGTCAGTCCATCCCATTTC BIDvl NM_197966

TGGC (SEQ ID NO: 137)

BIDv2 rev BsiWI ACTGCGTACGTCAGTCCATCCCATTTC BIDv2 NM_001 196

TGGC (SEQ ID NO: 138)

Ub BIDAl-60 rev ACTGCGTACGTCAGTCCATCCCATTTC Ub

BsiWI TGGC (SEQ ID NO: 139) BIDA1- 60

ATG12 rev BsiWI ACTGCGTACGTCATCCCCACGCCTGAG ATG12 NM_004707

ACTTG (SEQ ID NO: 140)

ATG16L1 rev ACTGCGTACGTCAGTACTGTGCCCACA ATG16 NM_030803 BsiWI GCAC (SEQ ID NO: 141) L1

ATG3 rev BsiWI ACTGCGTACGTTACATTGTGAAGTGTC ATG3 NM_022488

TTGTGTAG (SEQ ID NO: 142)

ATG5 rev BsiWI ACTGCGTACGTCAATCTGTTGGCTGTG ATG5 NM_004849

GGATG (SEQ ID NO: 143)

ATG7 rev BsiWI ACTGCGTACGTCAGATGGTCTCATCAT ATG7 NM_006395

CGCTC (SEQ ID NO: 144)

BECN1 rev ACTGCGTACGTCATTTGTTATAAAATTG BECN1 NM_003766 BsiWI TGAGGACAC (SEQ ID NO: 145)

CASP2 rev ACTGCGTACGTCATGTGGGAGGGTGTC CASP2 NM_032982 BsiWI CTGG (SEQ ID NO: 146)

IFNgamma rev ACTGCGTACGTTACTGGGATGCTCTTC IFNga NM_000619 BsiWI GACC (SEQ ID NO: 147) mma

IGF1 R rev BsiWI ACTGCGTACGTCAGCAGGTCGAAGACT IGF1 R NM_000875

GGG (SEQ ID NO: 148)

IRGM rev BsiWI ACTGCGTACGTTAGTATTCACATACCC IRGM NM 001 145

GCTCC (SEQ ID NO: 149) 805

TRAF2 rev BsiWI ACTGCGTACGTTAGAGCCCTGTCAGGT TRAF2 NM_021 138

CCAC (SEQ ID NO: 150)

ATP6V1G2 rev ACTGCGTACGCTAGGCAGAAATCCGGT ATP6V NM_130463 BsiWI AGTTG (SEQ ID NO: 151) 1G2

Cathepsin D rev ACTGCGTACGCTAGAGGCGGGCAGCC Cathep NM_001909 BsiWI TCG (SEQ ID NO: 152) sin D

DRP1 rev BsiWI ACTGCGTACGTCACCAAAGATGAGTCT DRP1 NM_012062

CCCG (SEQ ID NO: 153)

MLKL rev BsiWI ACTGCGTACGCTACTTAGAAAAGGTGG MLKL NM_152649

AGAG I I I C (SEQ ID NO: 154)

PARP1 rev ACTGCGTACGTTACCACAGGGAGGTCT PARP1 NM_001618 BsiWI TAAAATTG (SEQ ID NO: 155)

PARP2 rev ACTGCGTACGTCACCACAGCTGAAGGA PARP2 NM_005484 BsiWI AATTAAAC (SEQ ID NO: 156) PGAM5-S rev ACTGCGTACGTCAGGATCGAGTGATCT PGAM NM 001 170 BsiWI TGTC (SEQ ID NO: 157) 5-S 544

RIPK3 rev BsiWI ACTGCGTACGTTATTTCCCGCTATGATT RIPK3 NM_006871

ATACCAAC (SEQ ID NO: 158)

SLC25A4 rev ACTGCGTACGTTAGACATATTTTTTGAT SLC25 NM_001 151 BsiWI CTCATCATAC (SEQ ID NO: 159) A4

EndoG rev BsiWI CTAGGGTTTGCGTACGTCACTTACTGC EndoG NM_004435

CCGCCGTGATG (SEQ ID NO: 160)

MRB M rev Bsiwl ACTGCGTACGTTACTTGAAATGACTAA Maraba HQ660076

TAGAGTCC (SEQ ID NO: 161) M gene

Table 6. Source of cDNA to amplify the transgene

GENE Template source

AIF GM38

APAF1 NHA

BAD GM38

BIM GM38

CAD GM38

CASP3 GM38

CASP8 GM38

CHOP GM38

CYLD GM38

DFFA GM38

Granzyme B h lymphocytes

JNK1 a2 GM38

JNK1 b2 GM38

NOXA GM38

PIDD NHA

PUMA gamma NHA

PUMA beta GM38

PUMA alpha NHA

RAIDD GM38

RIPK1 GM38

BIDvl NHA

BIDv2 GM38

Ub BIDAl-60 IDT gene synthetis

ATG12 GM38

ATG16L1 GM38

ATG3 GM38

ATG5 GM38

ATG7 GM38

BECN1 GM38

CASP2 GM38

IFNgamma h lymphocytes

IGF1 R NHA

IRGM NHA TRAF2 NHA

ATP6V1 G2 GM38

Cathepsin D GM38

DRP1 GM38

MLKL GM38

PARP1 GM38

PARP2 NHA

PGAM5-S GM38

RIPK3 GM38

SLC25A4 GM38

Maraba M Maraba wild type

genome

[00166] The generated recombinant FMTs were screened in a viability assay, as described above. Briefly, SF268, CT2A, U343, and U118 cells were plated at a density of 10,000 cells/well into 96 well plates. The next day cells were infected with the recombinant FMTs at 0.1 multiplicity of infection. Following a 48 hour incubation Alamar Blue (Resazurin sodium salt (Sigma-Aldrich)) was added to a final concentration of 20μg/ml. After a 6 hour incubation the absorbance was read at a wavelength of 573 nm. SF268, CT2A, U343 cells are TRAIL resistant. U1 18 cells are TRAIL sensitive. U343, SF268 and U118 are human glioma cells. CT2A are murine glioma cells.

[00167] The % survival of the infected cells are shown below in Table 7. The values denote % cell viability following 48h of infection of the FMT virus variants as listed. "Avg" represents the average viability across all 4 cell lines. "Normalized Total" represents the total viability across all 4 cells lines, as a percent of the total viability for FMT eGFP.

[00168] The cumulative survival percentages for the recombinant FMTs are illustrated in Figure 8.

Table 7

GLIOMA CELL LINE

DEATH Normalized

Avg

TRANSGENE total

CT2A U343 SF268 U118

Control FMT eGFP 49.9 43.8 58.9 33.4 46.5 100%

AIF 40.6 46.2 55.3 59.3 50.4 108%

APAF1 68.5 70.5 71.6 79.6 72.5 156%

BAD 20.4 9.5 21.5 0.9 13.1 28%

BIM 33.3 43.1 58.9 20.7 39.0 84%

CAD 38.9 37.7 51.3 10.4 34.6 74%

CHOP 29.0 45.7 54.4 14.0 35.8 77%

CYLD 67.5 61.0 75.1 69.1 68.2 147%

DFFA 35.4 60.4 64.2 13.3 43.3 93%

Granzyme B 36.6 53.0 24.1 7.0 30.2 65%

JNK1 a2 34.8 41.9 33.3 21.2 32.8 71 %

JNK1 b2 39.6 34.7 44.1 55.3 43.4 93%

Apoptosis NOXA 29.2 26.9 58.0 9.1 30.8 66%

PIDD 33.8 52.4 61.9 13.4 40.4 87%

PUMA

30.8 35.8 48.1 8.4 30.8 66% gamma

PUMA beta 27.0 54.3 60.5 16.9 39.7 85%

PUMA alpha 45.4 61.0 56.7 59.9 55.7 120%

RAIDD 28.4 42.0 46.2 10.2 31.7 68%

RIPK1 -0.7 47.0 36.9 4.3 21.9 47%

BIDv2 2.0 3.2 0.8 0.1 1.5 3%

CASP3 39.3 7.4 41.2 17.5 26.4 57%

CASP8 1.3 52.8 55.1 6.3 28.9 62%

CASP2 8.3 9.7 3.2 6.2 6.9 15%

TRAF2 44.6 48.4 67.5 31.0 47.9 103% Maraba M

17.7 59.8 53.3 61.0 36.2 103%

protein

ATG12 24.6 38.0 43.1 10.2 29.0 62%

ATG16L1 69.8 57.7 63.1 34.9 56.4 121 %

ATG3 46.4 64.5 61.0 22.6 48.6 105%

ATG5 70.4 49.6 73.5 58.7 63.0 136%

Autophagy

ATG7 73.5 61.1 46.5 58.4 59.9 129%

BECN1 59.7 50.7 56.9 22.0 47.3 102%

IFN gamma 40.6 46.7 57.5 29.7 43.6 94%

IRGM 52.3 51.4 60.6 31.6 49.0 105%

ATP6V1G2 57.2 59.7 56.9 49.7 55.9 120%

Cathepsin D 31.3 53.1 50.5 25.5 40.1 86%

DRP1 64.0 63.0 61.0 55.1 60.8 131 %

MLKL 3.2 20.4 6.8 0.4 7.7 17%

Necrosis /

Necroptosis PARP1 73.6 63.4 59.2 71.3 66.9 144%

PARP2 68.6 58.0 60.9 59.0 61.6 133%

PGAM5-S 27.0 48.7 62.7 26.6 41.2 89%

RIPK3 -0.8 59.7 69.0 2.1 32.5 70%

SLC25A4 58.3 61.6 62.7 16.5 49.7 107%

[00169] Example 9: Screen of specific recombinant FMTs against normal cells, TRAIL- resistant cells, and TRAIL-susceptible cells.

[00170] FMT, FMT-BAX, FMT-BAK, FMT-UbSMAC and FMT-Apoptin were tested in viability assays against: U373 cells and SF268 cells (TRAIL-resistant glioma cell lines); U118 cells and U87MG cells (TRAIL-susceptible cells); and NHA cells (normal human astrocytes).

[00171] Briefly, the cells were plated at a density of 10 000 cells/well into 96 well plates. The next day cells were infected with the recombinant FMTs at various multiplicity of infection. Following a 48 hour incubation Alamar Blue (Resazurin sodium salt (Sigma- Aldrich)) was added to a final concentration of 20μg/ml. After a 6 hour incubation the absorbance was read at a wavelength of 573 nm. The EC50 values were determined based on the amount of virus required to kill 50% of the cells.

[00172] Lower EC50 values correspond to less virus being required to kill 50% of cells in a given timeframe. FMT-BAX is one example a recombinant FMT showing a lower EC50 than FMT for both TRAIL-resistant and TRAIL-suseptible cells. Although FMT can also kill this TRAIL sensitive cell line, encoding BAX further reduced the EC50 value by increasing the cytotoxicity. These results are illustrated in Figure 9.

[00173] Example 10: Safety profile of recombinant FMTs in primary normal cells.

[00174] Primary human skin fibroblasts cells were plated at a density of 10 000 cells/well into 96 well plates and allowed to grow to a post-mitotic state (full confluence and 2% serum). Cells were infected with the recombinant FMTs at various multiplicity of infection. Following a 48 hour incubation Alamar Blue (Resazurin sodium salt (Sigma-Aldrich)) was added to a final concentration of 20μg/ml. After a 6 hour incubation the absorbance was read at a wavelength of 573 nm. Survival, as a percent of untreated controls, is shown in Figure 10.

[00175] Example 1 1 : Safety profile of recombinant FMTs in vivo.

[00176] The safety profiles of various recombinant FMTs were determined by taking groups of 6-8 week old female BALB/c mice (n = 5/group) and giving them a single intracranial infusion of the indicated viruses at the a dose of 1 e8 pfu. Following the injections, the mice were monitored daily for signs of distress including weight loss, piloerection, hind- limb paralysis and respiratory distress. The results are shown below in Table 8. Single dose LD50 (median lethan dose) was calculated using the Spearman Karber method. MTD (Maximum tolerable dose) was denoted as the highest dose not resulting in durable morbidity.

Table 8

[00177] Without wishing to be bound by theory, the authors of the present disclosure believe that FMT and recombinant FMT do not get expressed in non-cancerous cells under physiological conditions (for example in vivo), even if the virus infects the cells. Accordingly, it is believed that the additional protein is not expressed by the non-cancerous cells, which results in the toxicity of the recombinant FMT to non-cancerous cells being comparable to wild-type FMT, even though the additional protein is implicated in cell death. However, since the additional protein is expressed by infected cancerous cells, the expression of a protein implicated in cell death does increase the cytolytic activity of the recombinant FMT to cancerous cells.

[00178] Example 12: Expression of two proteins in a recombinant FMT using a bicistronic cassette.

[00179] A recombinant FMT that expressed both green fluorescent protein and red fluorescent protein was generated based on the protocol discussed by A. L. Szymczak- Workman in Cold Spring Harbor Protoc; 2012; doi: 10.1 101/pdb.ip067876. The disclosed nucleotide sequence was modified to include a restriction site BspEI (GGA(TCCGGA)) at the beginning.

[00180] The resulting FMT-GFP/RFP was used to infect cells. The infected cells were fluorescently imaged, as shown in Figure 1 1.

[00181] Example 13: Cytotoxicity of exemplary FMT rhabdoviruses over time

[00182] CT2A murine glioblastoma cell line were seeded in 96 well format at 1 e4 cell/well. 24h later, cells were infected at a MOI of 3.0 pfu with FMT-MLKL, FMT-Casp2 or wtFMT and incubated with YOYO-1 iodide reagent (100 nM; ESSEN Bioscience) during the course of infection to measure membrane integrity using an Incucyte automated

fluorescence microscope. FMT-MLKL and FMT-Casp2 are faster and more effective at killing murine CT2A glioblastoma cells than wtFMT. Results are illustrated in Figure 12.

[00183] Example 14: Cytotoxicity of exemplary FMT rhabdoviruses in refractory primary patient brain tumour initiating cells (BTICs)

[00184] Cultured human BTIC cells (Prigo 017; gift from Ian Lorimer OHRI) were seeded in 96 well plates and allowed to grow for 4 days, and then subsequently infected with FMT-MLKL, FMT-BIDv2, FMT-Casp2, FMT-ATG12 or wtFMT over a range of multiplicities of infection. Viability was measured by Alamar Blue metabolic activity assay 96h post infection. Results are illustrated in Figure 13. FMT-MLKL, FMT-BIDv2 and FMT-Casp2 are more potent at killing a resistant primary patient BTIC (sample 17) than wtFMT.

[00185] Example 15: An exemplary FMT rhabdovirus bypasses apoptotis resistance.

[00186] Human glioma cells (U373) were seeded in 96 well plates at a density of 1 e4 cells/well. After 24 hours, wells were either pre-treated with Z-VAD-FMK (carbobenzoxy- valyl-alanyl-aspartyl-[0-methyl]- fluoromethylketone) pan-caspase inhibitor (Promega, catalog#G7231) at a final concentration of 20 μΜ for 30 min, or with vehicle control and then subsequently infected with wtFMT virus or FMT-MLKL at an MOI of 0.1 pfu. Cell viability was measured by incubating the cells with membrane impermeable fluorescent YOYO-1 iodide reagent (100nM; ESSEN Bioscience) during the course of infection and measuring membrane integrity using an Incucyte automated fluorescence microscope. Results are illustrated in Figure 14. FMT-MLKL kills human U373 gliomas even when rendered resistant to apoptosis via treatment with Z-VAD-FMK.

[00187] In the preceding description, for purposes of explanation, numerous details are set forth in order to provide a thorough understanding of the examples. However, it will be apparent to one skilled in the art that these specific details are not required. Equivalent changes, modifications and variations of some examples, materials, compositions and methods can be made within the scope of the present technology, with substantially similar results. [00188] The above-described examples are intended to be exemplary only.

Alterations, modifications and variations can be effected to the particular embodiments by those of skill in the art without departing from the scope, which is defined solely by the claims appended hereto.

Appendix A

SEQ ID NO: 1

ttacgacgca taagctgaga aacataagag actatgttca tagtcaccct gtattcatta 60 ttgactttta tgacctatta ttcgtgaggt catatgtgag gtaatgtcat ctgcttatgc 120 gtttgcttat aagataaaac gatagaccct tcacgggtaa atccttctcc ttgcagttct 180 cgccaagtac ctccaaagtc agacgatggc tcgtccgcta gctgctgcgc aacatctcat 240 aaccgagcgt cattcccttc aggcgactct gtcgcgggcg tccaagacca gagccgagga 300 attcgtcaaa gatttctacc ttcaagagca gtattctgtc ccgaccatcc cgacggacga 360 cattgcccag tctgggccca tgctgcttca ggccatcctg agcgaggaat acacaaaggc 420 cactgacata gcccaatcca tcctctggaa cactcccaca cccaacgggc tcctcagaga 480 gcatctagat gccgatgggg gaggctcatt cacagcgctg cccgcgtctg caatcagacc 540 cagcgacgag gcgaatgcat gggccgctcg catctccgac tcagggttgg ggcctgtctt 600 ctatgcagcc ctcgctgctt acatcatcgg ctggtcagga agaggagaga ctagccgcgt 660 gcagcagaac ataggtcaga aatggctgat gaacctgaac gcaatcttcg gcaccacgat 720 cacccatcca acaaccgtgc gtctgccaat caacgtcgtc aacaacagcc tcgcagtgag 780 gaacggactt gctgccacac tctggctata ctaccgttca tcacctcaga gtcaggacgc 840 gttcttctat gggctcatcc gtccctgttg cagtggatat ctcggcctgc tacatcgggt 900 gcaggagatt gatgagatgg agccggactt cctcagtgac ccccggatca tccaggtgaa 960 tgaggtctac agtgcactca gagccctggt tcaactggga aacgacttca agaccgccga 1020 tgatgagccc atgcaggtct gggcgtgcag gggaatcaac aacggatatc tgacatatct 1080 ctcagaaact cctgcgaaga aaggagctgt tgtgcttatg tttgcccaat gcatgctgaa 1140 gggcgactct gaggcctgga acagctaccg cactgcaacc tgggtgatgc cctattgcga 1200 caatgtggcc ctaggagcga tggcaggcta catccaagcc cgccagaaca ccagggcata 1260 tgaggtctca gcccagacag gtctcgacgt caacatggcc gcggtcaagg actttgaggc 1320 cagttcaaaa cccaaggctg ctccaatctc gctgatccca cgccccgctg atgtcgcatc 1380 ccgcacctct gagcgcccat ctattcctga ggttgacagc gacgaagagc tcggaggaat 1440 gtaaaccaat aagcttcact gccggtagtt taggcataca cacgcagttc cgttatccat 1500 cacacccgtc ccttctttta tgctgctatt atttcagttg ctaagcttcc tgatttgatt 1560 aacaaaaaac cgtagacctc ctacgtgagg tatagctaga aattggttct atcggttgag 1620 agtctttgta ctattagcca tggaggacta tttgtctagc ttagaggccg cgagagagct 1680 cgtccggacg gagctggagc ccaagcgtaa cctcatagcc agcttagagt ccgacgatcc 1740 cgatccggta atagcgccag cggtaaaacc aaaacatccc aagccatgcc tgagcactaa 1800 agaagaggat catctcccct ctcttcgcct actattcggc gcaaaacgag acacctcggt 1860 gggcgtagag cagactctcc acaagcgtct ctgcgcttgt ctcgacggtt acctgaccat 1920 gacgaagaaa gaggccaatg cctttaaggc cgcggctgaa gcagcagcat tagcagtcat 1980 ggacattaag atggagcatc agcgccagga tctagaggat ctgaccgctg ctatccctag 2040 gatagaattc aaactcaatg ccatcctgga aaacaacaag gagatagcca aggctgtaac 2100 tgctgctaag gagatggagc gggagatgtc gtggggggaa agcgccgcca gctcgctcaa 2160 gtctgtcacc ctagatgagt cgtttagggg ccctgaagag ctttcagagt catttggcat 2220 ccgatataag gtcagaacct ggaatgagtt caagaaggcg ctggaaacca gcattgtgga 2280 cctgaggcct agccctgttt catttaggga attacggact atgtggctgt ctcttgacac 2340 ctcctttagg ctcattgggt ttgccttcat tcccacatgc gagcgcctgg agaccaaagc 2400 caaatgcaag gagacaagga ctctactccc ccttgcagag tcgatcatgc gaagatggga 2460 cctgcgggat ccaaccatct tggagaaagc ctgcgtagta atgatgatcc gtgggaatga 2520 gattgcatcg ctgaatcagg taaaagatgt tctcccgacc acaattcgtg ggtggaagat 2580 cgcttattag tcactgctcc cattagtccc actagacggc atacttccat tccgcccttt 2640 aattcccctg tcagacactc atgctccgaa atcactaacc atccttgtcc accaagcaat 2700 acgcatattc agtagcactg catctcgccc tccccctatc aagccccagc gctgcagatc 2760 ttcaccacat atatacatgc atcaactaca tgtgatttag aaaaaaccag acccttcacg 2820 ggtaatagcc taactcacga acgttcctct cgtttcgtat gataaggcct taagcattgt 2880 cgatacggtc gttatgcgtc ggttcttttt aggagagagc agtgcccctg cgagggactg 2940 ggagtccgag cgacctcccc cctatgctgt tgaggtccct caaagtcacg ggataagagt 3000 caccgggtac ttccagtgca acgagcgtcc gaaatccaag aagaccctcc acagcttcgc 3060 cgtaaaactc tgcgacgcaa ttaagccggt tcgagcggat gctcccagct tgaagatagc 3120 aatatggacg gctctagatc tggccttcgt gaaacctccc aatggaactg taacaataga 3180 tgcggcggtg aaagctacac cgctaatcgg gaacacccag tacaccgtag gcgatgaaat 3240 cttccagatg ctagggagaa ggggtggcct gatcgtcatc aggaacttac cccatgatta 3300 tcctcgaacg ttgattgagt tcgcctctcc cgagccttga gcaccagggc atcggtccgc 3360 ccgccctgtg atctcccgta gccgggctca gcgatcaagc cggcccgggt cgggggggac 3420 tggtgcaaca caaggggcgg cagtggacgc tgattaacaa aaaaccacct atatagaccc 3480 ctcacggtct tagactctgt tgccagctga caaccaacac acaagacatc tctctgattc 3540 agccgacccg atcgattcct ccccacccaa ttcctaccaa cgcactcctc acaagctcca 3600 ccatgctcag gatccagatc cctccgattg ctatcattct ggtaagtctc ctcacactcg 3660 acctgtccgg tgcaaggagg acaaccacac aaagaatccc tctccttaat gattcgtggg 3720 atttgttctc gagctatggc gacattcccg aagaacttgt cgtataccag aactacagcc 3780 acaattcctc cgagttaccc cctcctggct tcgagagatg gtacataaac cgaagagtgg 3840 cagacacttc cataccgtgc aggggcccct gtctagtgcc ctacatcctt catggcctca 3900 atgacacaac tgtctctcga cggggaggag gatggcgaag gtccggaatg aagtacccaa 3960 cccacgctgt caggctaggc ccttcaacag acgacgagag agttgaggaa gacatcggct 4020 acgtcaatgt ctccgcacta tcctgcacag ggtcgcccgt tgagatggcg ataccaacaa 4080 tccccgactg caccagtgct atccatccac gatccgaggt tactgtgccc gtcaagctcg 4140 atgtcatgag acgaaatccc aactaccctc ccattagagc gtggtcgtgc atcggacaga 4200 aaatcaccaa ccgatgtgat tgggcactct tcggcgagaa cctcatatat actcaagttg 4260 aagctagctc tctagcattc aagcacacaa gagcctctct tttgaacgaa tccaacggga 4320 tagacgctga aggacgtgca gttccctata tcctcgggga tatcgaaccc gggtactgcc 4380 gaaccctatt caacacatgg gtctctagtg agatcgtgtc atgcacgccc atcgaacttg 4440 tcctagttga cctgaaccct ttgtccccgg gacatggcgg atatgctgta ttgctgccaa 4500 acggagacaa agtggatgta cacgacaagc atgcatggga tggggacaac aaaatgtgga 4560 gatgggtgta cgagaagaaa gatccctgtg cgttcgagct ggtatccagg gaagtgtgtc 4620 ttttctcact gagtaggggt agtagactga gaggagcaac ccctccccaa ggagagctcc 4680 tcacctgccc gcattcggga aaggcatttg acctgaaggg ggcccgaagg attacaccca 4740 tttcatgcaa aatcgacatg gaatatgact tgctgtcact accaaccgga gtcatcctag 4800 gcctccacct atcagaactc gggacctcct ttggcaacct ctcaatgagt cttgaaatgt 4860 atgaacctgc cacaactctg acccctgagc aaatcaactt ctcgcttaaa gagctgggaa 4920 gctggaccga ggctcaactg aagagcctgt ctcactcaat ctgcctctcc acattctcca 4980 tatgggaact atcggttggg atgatcgatc taaaccctac cagggcagca agggccttgc 5040 tccatgatga taacatactg gcaacattcg agaacggtca cttttccatc gtcagatgtc 5100 gtccggaaat agttcaagtc ccttcgcatc ctcgagcatg tcacatggat ctccgccctt 5160 atgacaagca atcacgggca tcaaccctgg tggttcccct tgacaacagc actgccctcc 5220 tggtccccga caacatcgtg gttgaaggag tagaggccag tctatgcaac cactccgttg 5280 ccatcacgct gtcgaagaac agaactcact catacagcct ctatccccag ggtcgtcctg 5340 tgcttcgaca gaaaggtgcc gtggagctcc cgacgatagg gcccctccag ttacatcctg 5400 ccactcgagt ggacctttat acactgaaag agttccagga ggaccgaata gcgcgcagtc 5460 gagtcacaga catcaaggct gccgttgacg atctgcgtgc gaagtggcgt aaaggcaaat 5520 ttgaggcgga caccacggga gggggacttt ggtcggcgat tgtgggagtc ttcagttctc 5580 tcggggggtt cttcatgagg cccttgattg ctctcgcggc gatagtgacc tcaatcatca 5640 tcctgtatat ccttctgcgt gtactgtgtg ctgcctcatg ttcgacacac cgaagagtaa 5700 ggcaggactc ttggtaaaga ggactgcgat tgttgagtgg acaaacccta ggcctattcc 5760 gatttagaaa aaaccagacc tctcacgagg tcttttctac tagctgggtt ttcctcattc 5820 tatccagagc catggccttc gacccgaact ggcagagaga aggttatgaa tgggatccgt 5880 caagtgaggg cagaccgacc gatgagaacg aagacgacag aggtcatcgg ccaaaaacga 5940 gacttcgtac attccttgcc cgcacgttaa atagccctat ccgagcccta ttctacacaa 6000 tattcctagg aattcgagcg gtttgggacg ggttcaaaag actcctacct gtgaggaccg 6060 aaaagggtta tgcgaggttt tctgagtgcg tcacatatgg aatgatcgga tgtgatgagt 6120 gtgtaataga cccggtgagg gttgtcattg agctgaccga gatgcagtta ccgattaaag 6180 gcaaaggctc tacgaggttg agagcaatga taactgaaga ccttctcacg gggatgcgca 6240 cagccgtgcc tcagatcaga gtgagatcga agatcctagc agagcggtta gggagagcaa 6300 tcggccgaga gaccttgccg gcaatgatcc atcatgagtg ggcatttgtg atggggaaga 6360 ttctcacttt catggcagac aatgtgggta tgaacgctga cacggtcgag ggcgttctat 6420 cactatcaga ggtcacacgg cgatgggata tcggcaactc tgtgtccgca gtgttcaatc 6480 ctgatggcct tactatcaga gtagaaaaca cgggttacat catgaccaga gagactgcct 6540 gcatgatcgg agacattcat gctcaatttg caatccaata cctagctgca tacctagacg 6600 aggtgatcgg cacaaggacg tctctctcac ccgccgaact gacctctctc aaactatggg 6660 gacttaacgt cctgaaactc ctaggacgga acggttatga ggtgatcgcc tgcatggagc 6720 ccatagggta cgctgtcctg atgatgggaa gagacaggag tcctgatccc tatgtcaatg 6780 acacctattt aaacagcatc ctctcagaat tccctgtcga ctctgacgct cgagcctgcg 6840 ttgaagccct cttaactatc tatatgagct tcggcacacc ccataaagtc tcggacgcat 6900 tcggcctctt cagaatgttg ggacatccga tggttgatgg agctgacggg attgaaaaga 6960 tgcgaaggtt aagcaagaag gtcaagatcc cagaccagtc tacagcgatc gacctcgggg 7020 ctatcatggc cgaactgttt gtgcggagtt tcgtaaagaa gcacaaaagg tggcccaact 7080 gctccatcaa tctcccgcca cgacacccct tccaccacgc ccgcctatgt gggtatgtcc 7140 cggctgaaac ccatccccta aacaacactg catcctgggc ggctgtggag ttcaaccagg 7200 aattcgagcc gccgagacag tacaaccttg cagacatcat tgatgacaag tcgtgctctc 7260 ccaacaagca tgagctatat ggtgcttgga tgaagtcaaa aacagctggg tggcaggaac 7320 aaaagaagct catactccga tggttcactg agaccatggt taaaccttcg gagctcctgg 7380 aagagattga tgcacacggc ttccgagaag aggataagtt gattggatta acaccaaagg 7440 agagagagct gaaattaaca ccaagaatgt tctccttgat gacattcaag ttcagaacct 7500 accaagtcct cactgagagt atggtcgccg atgagatcct cccgcacttc ccccagatca 7560 ccatgaccat gtccaaccac gaactcacaa agaggttgat tagcagaacg agacctcaat 7620 ctggaggagg gcgtgatgtt cacatcaccg tgaacataga tttccagaaa tggaacacaa 7680 acatgagaca cggactggtc aaacatgtct tcgagcgact ggacaacctc tttggcttca 7740 ccaacttaat cagacgaact catgaatact tccaggaggc gaaatactat ctggctgaag 7800 atggaactaa tctgtcgttc gacaggaacg gggagttaat agatggccca tacgtttaca 7860 ccggatcata cggggggaac gaggggttac gacagaagcc ctggacaata gttaccgtgt 7920 gtggaatata caaggtagct agagacctga aaatcaaaca tcagatcacc ggtcagggag 7980 ataatcaggt ggtcacccta atatttccgg atcgagagtt gccttcagat ccggtggaga 8040 ggagcaagta ctgtagagac aagagcagtc agttcctgac acgtctcagt caatatttcg 8100 ctgaggttgg tttgcccgtc aagactgaag agacatggat gtcatcacgt ctctatgctt 8160 acggtaagcg catgttctta gagggagttc cacttaagat gtttctcaag aagataggca 8220 gagctttcgc cctctcgaat gagtttgtcc cgtccctcga ggaagatctg gccagagtct 8280 ggagtgccac cagcgcagcg gtagagcttg acctaactcc ctacgtagga tatgtcctcg 8340 ggtgctgctt gtctgcgcag gcgatcagaa atcacctcat ctactcccct gttctggagg 8400 gccctctgct ggttaaggcc tacgagcgta agttcattaa ctacgacgga ggaacaaagc 8460 ggggggcgat gcccggccta cgtccaacct ttgagagcct agtcaaaagt atctgctgga 8520 agccaaaggc catcggaggg tggccggtat tgatgttaga agatctcatc atcaaagggt 8580 tccctgatcc ggcgactagc gccctggctc aattgaagtc aatggtgcca tatacctctg 8640 gtatcgaccg ggagatcata ctttcctgtc tcaaccttcc cttatcgtcg gtggtatctc 8700 cgtcaatgtt gttaaaggac ccggcggcca tcaacaccat cacaaccccg tccgcgggcg 8760 acatcctgca agaggtcgcc agagactatg ttaccgatta cccactccaa aacccgcagc 8820 tcagagcagt ggtcaagaac gtgaagaccg agctagacac attggccagt gacttattca 8880 aatgtgaacc tttctttcct cctttaatga gcgatatctt ctcggcatct ctcccggcat 8940 atcaagacag gattgttcgc aagtgctcca cgacttctac aatcaggaga aaagctgccg 9000 agaggggctc cgactctctc ctcaaccgga tgaaaaggaa tgagatcaat aagatgatgt 9060 tacatctttg ggctacctgg ggaaggagcc ctctggccag attagacacc agatgtctca 9120 caacctgcac caagcaatta gcccaacagt atcggaacca gtcttgggga aagcagatcc 9180 atggagtctc agtcggccac cccttagaac tgttcggtcg aataacaccc agccatagat 9240 gcctacatga ggaggaccac ggagatttcc tgcaaacctt cgccagcgag catgtgaacc 9300 aagtggacac cgacatcacc acaactctgg ggccgttcta cccttacata ggctcggaga 9360 cgcgagaacg ggcagtcaag gttcgaaaag gagtgaatta cgtagttgag ccgcttctga 9420 aacccgcagt tcgactacta agagccatta attggttcat tcccgaggag tcagatgcgt 9480 cccatttgct gagcaatcta ttagcgtctg ttaccgacat caatcctcaa gaccactact 9540 catctaccga agtagggggg ggcaacgccg tccatcgcta cagctgccga ctatccgaca 9600 aattgagcag agtcaacaac ttatatcagt tgcatactta tttatctgtc acaacagagc 9660 ggttgaccaa gtacagtcga ggatcaaaaa acactgacgc acacttccag agcatgatga 9720 tttatgcaca aagccgtcat atagacctca tcttggagtc tctgcacacc ggagagatgg 9780 taccgttgga gtgtcatcat cacattgagt gcaatcactg tatagaggat atacccgacg 9840 agccaatcac gggggacccg gcttggactg aagtcaagtt tccttcaagt cctcaggagc 9900 cctttcttta catcaggcaa caagatctgc cggtcaaaga caaactcgag cctgtgcctc 9960 gcatgaacat cgtccgtctt gccggattgg gtccggaggc gattagtgag ctagcgcact 10020 actttgttgc attccgagtt atccgggcgt cagagacgga tgtcgaccct aacgatgttc 10080 tctcgtggac ctggctgagc cgaattgatc ctgacaaatt ggttgagtat atcgtgcatg 10140 tgttcgcttc actggaatgg catcatgtat taatgtcagg cgtgagtgtg agcgtcagag 10200 atgcattctt taagatgcta gtgtctaaaa gaatctcaga gactccgcta agttcattct 10260 attatctggc caacctgttc gttgaccctc agactcgcga agcactaatg agctctaaat 10320 acgggttcag cccccccgcc gagacagtcc ccaacgcaaa tgccgccgca gccgaaataa 10380 gaagatgctg tgcgaacagt gcgccgtcga tcttagaatc agcccttcac agccgtgagg 10440 ttgtttggat gccaggaacg aacaattatg gagacgttgt catctggtct cattacatta 10500 gattacggtt cagcgaagtt aaactagttg acattacacg atatcagcag tggtggagac 10560 agtctgagcg agacccctac gatttggtcc cggacatgca ggttcttgag agcgacctag 10620 atacgctgat gaaacggata ccgaggctca tgcgcaaggc gagacgtccc cctcttcagg 10680 taattcgaga ggacctggat gtcgcagtca tcaatgctga tcatcccgct cactctgtgc 10740 ttcagaacaa atacaggaaa ttgattttca gagagccgaa gattatcacg ggagctgtgt 10800 acaagtacct ctccctaaaa tcagagttga cagagttcac ctcagcaatg gtgatcggag 10860 acggaactgg aggtatcacc gccgccatga tggccgatgg gatagatgtg tggtatcaga 10920 cgctcgtcaa ctatgaccac gtgacacaac agggattatc cgtacaagcc ccggcagcat 10980 tggatcttct gcgcggggca ccctctggta ggctcttgaa tccgggaaga ttcgcatcat 11040 ttgggtctga cctaactgac cctcgattta cagcctactt tgatcaatat cccccgttca 11100 aggtggacac tctatggtct gacgcagagg gcgacttttg ggacaagcct tccaagttga 11160 atcaatactt tgagaacatc attgctttga gacatcggtt cgtgaagaca aatggacagc 11220 ttgtcgtgaa ggtgtatctg actcaagaca ctgctaccac aattgaagca ttcagaaaga 11280 agctgtcccc atgcgccatc atcgtgtctc tcttctcgac ggaaggctcc acagaatgct 11340 tcgtcctaag caatctcatc gcaccagaca cccctgtcga ccttgagatg gtggagaata 11400 tccctaaact aacatccctt gttccccaga ggacgacagt gaaatgctat tcccgacgag 11460 tagcgtgcat cagtaaaagg tggggacttt tcagatctcc gagcatagcc cttgaagtcc 11520 aaccgttcct tcactacatc acaaaggtca tctcagacaa aggaacacaa ctgagtctca 11580 tggcggtagc tgacacaatg atcaacagtt acaagaaggc tatctcaccc cgagtgttcg 11640 atctacaccg gcatagggcc gcactgggtt tcgggaggag atccttgcat ctcatctggg 11700 ggatgatcat ctcaccaatc gcttaccagc attttgagaa tccggccaag ttgatggatg 11760 tcctggacat gttgaccaat aacatctcag ctttcttatc gatatcgtcg tcaggatttg 11820 acctgtcatt tagtgtcagt gcagaccgag atgtccggat tgacagcaaa cttgtcagac 11880 tcccgctatt cgaaggatca gacctaaaat tcatgaaaac catcatgtct accctcggat 11940 ctgtgttcaa ccaggtcgag ccttttaagg ggatcgccat aaacccttct aaactaatga 12000 ctgtcaagag gacacaggag ttacgttaca acaacctaat ttacactaag gatgccatcc 12060 tattccccaa tgaagcggca aaaaacactg ccccgcttcg agccaacatg gtataccccg 12120 tccggggaga tctattcgcc cctaccgatc gcataccaat catgactcta gtcagcgatg 12180 agacaacacc tcagcactct cctccagagg atgaggcata actgaatcct ccctgaaggc 12240 tcacatgtcc cacgcgacgc aagatataac gacaagcaac tcgccctatt aactgtgatt 12300 aataaaaaac cgattattca gttgcttgag ggagtttcaa tccgttcagt gtatgatagg 12360 aagtttctga gatggtgggg attagggggc acctagagta tgtttgttcg ttttatgcgt 12420 cgt 12423 SEQ ID NO: 2

uuacgacgca uaagcugaga aacauaagag acuauguuca uagucacccu guauucauua 60 uugacuuuua ugaccuauua uucgugaggu cauaugugag guaaugucau cugcuuaugc 120 guuugcuuau aagauaaaac gauagacccu ucacggguaa auccuucucc uugcaguucu 180 cgccaaguac cuccaaaguc agacgauggc ucguccgcua gcugcugcgc aacaucucau 240 aaccgagcgu cauucccuuc aggcgacucu gucgcgggcg uccaagacca gagccgagga 300 auucgucaaa gauuucuacc uucaagagca guauucuguc ccgaccaucc cgacggacga 360 cauugcccag ucugggccca ugcugcuuca ggccauccug agcgaggaau acacaaaggc 420 cacugacaua gcccaaucca uccucuggaa cacucccaca cccaacgggc uccucagaga 480 gcaucuagau gccgaugggg gaggcucauu cacagcgcug cccgcgucug caaucagacc 540 cagcgacgag gcgaaugcau gggccgcucg caucuccgac ucaggguugg ggccugucuu 600 cuaugcagcc cucgcugcuu acaucaucgg cuggucagga agaggagaga cuagccgcgu 660 gcagcagaac auaggucaga aauggcugau gaaccugaac gcaaucuucg gcaccacgau 720 cacccaucca acaaccgugc gucugccaau caacgucguc aacaacagcc ucgcagugag 780 gaacggacuu gcugccacac ucuggcuaua cuaccguuca ucaccucaga gucaggacgc 840 guucuucuau gggcucaucc gucccuguug caguggauau cucggccugc uacaucgggu 900 gcaggagauu gaugagaugg agccggacuu ccucagugac ccccggauca uccaggugaa 960 ugaggucuac agugcacuca gagcccuggu ucaacuggga aacgacuuca agaccgccga 1020 ugaugagccc augcaggucu gggcgugcag gggaaucaac aacggauauc ugacauaucu 1080 cucagaaacu ccugcgaaga aaggagcugu ugugcuuaug uuugcccaau gcaugcugaa 1140 gggcgacucu gaggccugga acagcuaccg cacugcaacc ugggugaugc ccuauugcga 1200 caauguggcc cuaggagcga uggcaggcua cauccaagcc cgccagaaca ccagggcaua 1260 ugaggucuca gcccagacag gucucgacgu caacauggcc gcggucaagg acuuugaggc 1320 caguucaaaa cccaaggcug cuccaaucuc gcugauccca cgccccgcug augucgcauc 1380 ccgcaccucu gagcgcccau cuauuccuga gguugacagc gacgaagagc ucggaggaau 1440 guaaaccaau aagcuucacu gccgguaguu uaggcauaca cacgcaguuc cguuauccau 1500 cacacccguc ccuucuuuua ugcugcuauu auuucaguug cuaagcuucc ugauuugauu 1560 aacaaaaaac cguagaccuc cuacgugagg uauagcuaga aauugguucu aucgguugag 1620 agucuuugua cuauuagcca uggaggacua uuugucuagc uuagaggccg cgagagagcu 1680 cguccggacg gagcuggagc ccaagcguaa ccucauagcc agcuuagagu ccgacgaucc 1740 cgauccggua auagcgccag cgguaaaacc aaaacauccc aagccaugcc ugagcacuaa 1800 agaagaggau caucuccccu cucuucgccu acuauucggc gcaaaacgag acaccucggu 1860 gggcguagag cagacucucc acaagcgucu cugcgcuugu cucgacgguu accugaccau 1920 gacgaagaaa gaggccaaug ccuuuaaggc cgcggcugaa gcagcagcau uagcagucau 1980 ggacauuaag auggagcauc agcgccagga ucuagaggau cugaccgcug cuaucccuag 2040 gauagaauuc aaacucaaug ccauccugga aaacaacaag gagauagcca aggcuguaac 2100 ugcugcuaag gagauggagc gggagauguc guggggggaa agcgccgcca gcucgcucaa 2160 gucugucacc cuagaugagu cguuuagggg cccugaagag cuuucagagu cauuuggcau 2220 ccgauauaag gucagaaccu ggaaugaguu caagaaggcg cuggaaacca gcauugugga 2280 ccugaggccu agcccuguuu cauuuaggga auuacggacu auguggcugu cucuugacac 2340 cuccuuuagg cucauugggu uugccuucau ucccacaugc gagcgccugg agaccaaagc 2400 caaaugcaag gagacaagga cucuacuccc ccuugcagag ucgaucaugc gaagauggga 2460 ccugcgggau ccaaccaucu uggagaaagc cugcguagua augaugaucc gugggaauga 2520 gauugcaucg cugaaucagg uaaaagaugu ucucccgacc acaauucgug gguggaagau 2580 cgcuuauuag ucacugcucc cauuaguccc acuagacggc auacuuccau uccgcccuuu 2640 aauuccccug ucagacacuc augcuccgaa aucacuaacc auccuugucc accaagcaau 2700 acgcauauuc aguagcacug caucucgccc ucccccuauc aagccccagc gcugcagauc 2760 uucaccacau auauacaugc aucaacuaca ugugauuuag aaaaaaccag acccuucacg 2820 gguaauagcc uaacucacga acguuccucu cguuucguau gauaaggccu uaagcauugu 2880 cgauacgguc guuaugcguc gguucuuuuu aggagagagc agugccccug cgagggacug 2940 ggaguccgag cgaccucccc ccuaugcugu ugaggucccu caaagucacg ggauaagagu 3000 caccggguac uuccagugca acgagcgucc gaaauccaag aagacccucc acagcuucgc 3060 cguaaaacuc ugcgacgcaa uuaagccggu ucgagcggau gcucccagcu ugaagauagc 3120 aauauggacg gcucuagauc uggccuucgu gaaaccuccc aauggaacug uaacaauaga 3180 ugcggcggug aaagcuacac cgcuaaucgg gaacacccag uacaccguag gcgaugaaau 3240 cuuccagaug cuagggagaa gggguggccu gaucgucauc aggaacuuac cccaugauua 3300 uccucgaacg uugauugagu ucgccucucc cgagccuuga gcaccagggc aucgguccgc 3360 ccgcccugug aucucccgua gccgggcuca gcgaucaagc cggcccgggu cgggggggac 3420 uggugcaaca caaggggcgg caguggacgc ugauuaacaa aaaaccaccu auauagaccc 3480 cucacggucu uagacucugu ugccagcuga caaccaacac acaagacauc ucucugauuc 3540 agccgacccg aucgauuccu ccccacccaa uuccuaccaa cgcacuccuc acaagcucca 3600 ccaugcucag gauccagauc ccuccgauug cuaucauucu gguaagucuc cucacacucg 3660 accuguccgg ugcaaggagg acaaccacac aaagaauccc ucuccuuaau gauucguggg 3720 auuuguucuc gagcuauggc gacauucccg aagaacuugu cguauaccag aacuacagcc 3780 acaauuccuc cgaguuaccc ccuccuggcu ucgagagaug guacauaaac cgaagagugg 3840 cagacacuuc cauaccgugc aggggccccu gucuagugcc cuacauccuu cauggccuca 3900 augacacaac ugucucucga cggggaggag gauggcgaag guccggaaug aaguacccaa 3960 cccacgcugu caggcuaggc ccuucaacag acgacgagag aguugaggaa gacaucggcu 4020 acgucaaugu cuccgcacua uccugcacag ggucgcccgu ugagauggcg auaccaacaa 4080 uccccgacug caccagugcu auccauccac gauccgaggu uacugugccc gucaagcucg 4140 augucaugag acgaaauccc aacuacccuc ccauuagagc guggucgugc aucggacaga 4200 aaaucaccaa ccgaugugau ugggcacucu ucggcgagaa ccucauauau acucaaguug 4260 aagcuagcuc ucuagcauuc aagcacacaa gagccucucu uuugaacgaa uccaacggga 4320 uagacgcuga aggacgugca guucccuaua uccucgggga uaucgaaccc ggguacugcc 4380 gaacccuauu caacacaugg gucucuagug agaucguguc augcacgccc aucgaacuug 4440 uccuaguuga ccugaacccu uuguccccgg gacauggcgg auaugcugua uugcugccaa 4500 acggagacaa aguggaugua cacgacaagc augcauggga uggggacaac aaaaugugga 4560 gaugggugua cgagaagaaa gaucccugug cguucgagcu gguauccagg gaaguguguc 4620 uuuucucacu gaguaggggu aguagacuga gaggagcaac cccuccccaa ggagagcucc 4680 ucaccugccc gcauucggga aaggcauuug accugaaggg ggcccgaagg auuacaccca 4740 uuucaugcaa aaucgacaug gaauaugacu ugcugucacu accaaccgga gucauccuag 4800 gccuccaccu aucagaacuc gggaccuccu uuggcaaccu cucaaugagu cuugaaaugu 4860 augaaccugc cacaacucug accccugagc aaaucaacuu cucgcuuaaa gagcugggaa 4920 gcuggaccga ggcucaacug aagagccugu cucacucaau cugccucucc acauucucca 4980 uaugggaacu aucgguuggg augaucgauc uaaacccuac cagggcagca agggccuugc 5040 uccaugauga uaacauacug gcaacauucg agaacgguca cuuuuccauc gucagauguc 5100 guccggaaau aguucaaguc ccuucgcauc cucgagcaug ucacauggau cuccgcccuu 5160 augacaagca aucacgggca ucaacccugg ugguuccccu ugacaacagc acugcccucc 5220 ugguccccga caacaucgug guugaaggag uagaggccag ucuaugcaac cacuccguug 5280 ccaucacgcu gucgaagaac agaacucacu cauacagccu cuauccccag ggucguccug 5340 ugcuucgaca gaaaggugcc guggagcucc cgacgauagg gccccuccag uuacauccug 5400 ccacucgagu ggaccuuuau acacugaaag aguuccagga ggaccgaaua gcgcgcaguc 5460 gagucacaga caucaaggcu gccguugacg aucugcgugc gaaguggcgu aaaggcaaau 5520 uugaggcgga caccacggga gggggacuuu ggucggcgau ugugggaguc uucaguucuc 5580 ucgggggguu cuucaugagg cccuugauug cucucgcggc gauagugacc ucaaucauca 5640 uccuguauau ccuucugcgu guacugugug cugccucaug uucgacacac cgaagaguaa 5700 ggcaggacuc uugguaaaga ggacugcgau uguugagugg acaaacccua ggccuauucc 5760 gauuuagaaa aaaccagacc ucucacgagg ucuuuucuac uagcuggguu uuccucauuc 5820 uauccagagc cauggccuuc gacccgaacu ggcagagaga agguuaugaa ugggauccgu 5880 caagugaggg cagaccgacc gaugagaacg aagacgacag aggucaucgg ccaaaaacga 5940 gacuucguac auuccuugcc cgcacguuaa auagcccuau ccgagcccua uucuacacaa 6000 uauuccuagg aauucgagcg guuugggacg gguucaaaag acuccuaccu gugaggaccg 6060 aaaaggguua ugcgagguuu ucugagugcg ucacauaugg aaugaucgga ugugaugagu 6120 guguaauaga cccggugagg guugucauug agcugaccga gaugcaguua ccgauuaaag 6180 gcaaaggcuc uacgagguug agagcaauga uaacugaaga ccuucucacg gggaugcgca 6240 cagccgugcc ucagaucaga gugagaucga agauccuagc agagcgguua gggagagcaa 6300 ucggccgaga gaccuugccg gcaaugaucc aucaugagug ggcauuugug auggggaaga 6360 uucucacuuu cauggcagac aaugugggua ugaacgcuga cacggucgag ggcguucuau 6420 cacuaucaga ggucacacgg cgaugggaua ucggcaacuc uguguccgca guguucaauc 6480 cugauggccu uacuaucaga guagaaaaca cggguuacau caugaccaga gagacugccu 6540 gcaugaucgg agacauucau gcucaauuug caauccaaua ccuagcugca uaccuagacg 6600 aggugaucgg cacaaggacg ucucucucac ccgccgaacu gaccucucuc aaacuauggg 6660 gacuuaacgu ccugaaacuc cuaggacgga acgguuauga ggugaucgcc ugcauggagc 6720 ccauagggua cgcuguccug augaugggaa gagacaggag uccugauccc uaugucaaug 6780 acaccuauuu aaacagcauc cucucagaau ucccugucga cucugacgcu cgagccugcg 6840 uugaagcccu cuuaacuauc uauaugagcu ucggcacacc ccauaaaguc ucggacgcau 6900 ucggccucuu cagaauguug ggacauccga ugguugaugg agcugacggg auugaaaaga 6960 ugcgaagguu aagcaagaag gucaagaucc cagaccaguc uacagcgauc gaccucgggg 7020 cuaucauggc cgaacuguuu gugcggaguu ucguaaagaa gcacaaaagg uggcccaacu 7080 gcuccaucaa ucucccgcca cgacaccccu uccaccacgc ccgccuaugu ggguaugucc 7140 cggcugaaac ccauccccua aacaacacug cauccugggc ggcuguggag uucaaccagg 7200 aauucgagcc gccgagacag uacaaccuug cagacaucau ugaugacaag ucgugcucuc 7260 ccaacaagca ugagcuauau ggugcuugga ugaagucaaa aacagcuggg uggcaggaac 7320 aaaagaagcu cauacuccga ugguucacug agaccauggu uaaaccuucg gagcuccugg 7380 aagagauuga ugcacacggc uuccgagaag aggauaaguu gauuggauua acaccaaagg 7440 agagagagcu gaaauuaaca ccaagaaugu ucuccuugau gacauucaag uucagaaccu 7500 accaaguccu cacugagagu auggucgccg augagauccu cccgcacuuc ccccagauca 7560 ccaugaccau guccaaccac gaacucacaa agagguugau uagcagaacg agaccucaau 7620 cuggaggagg gcgugauguu cacaucaccg ugaacauaga uuuccagaaa uggaacacaa 7680 acaugagaca cggacugguc aaacaugucu ucgagcgacu ggacaaccuc uuuggcuuca 7740 ccaacuuaau cagacgaacu caugaauacu uccaggaggc gaaauacuau cuggcugaag 7800 auggaacuaa ucugucguuc gacaggaacg gggaguuaau agauggccca uacguuuaca 7860 ccggaucaua cggggggaac gagggguuac gacagaagcc cuggacaaua guuaccgugu 7920 guggaauaua caagguagcu agagaccuga aaaucaaaca ucagaucacc ggucagggag 7980 auaaucaggu ggucacccua auauuuccgg aucgagaguu gccuucagau ccgguggaga 8040 ggagcaagua cuguagagac aagagcaguc aguuccugac acgucucagu caauauuucg 8100 cugagguugg uuugcccguc aagacugaag agacauggau gucaucacgu cucuaugcuu 8160 acgguaagcg cauguucuua gagggaguuc cacuuaagau guuucucaag aagauaggca 8220 gagcuuucgc ccucucgaau gaguuugucc cgucccucga ggaagaucug gccagagucu 8280 ggagugccac cagcgcagcg guagagcuug accuaacucc cuacguagga uauguccucg 8340 ggugcugcuu gucugcgcag gcgaucagaa aucaccucau cuacuccccu guucuggagg 8400 gcccucugcu gguuaaggcc uacgagcgua aguucauuaa cuacgacgga ggaacaaagc 8460 ggggggcgau gcccggccua cguccaaccu uugagagccu agucaaaagu aucugcugga 8520 agccaaaggc caucggaggg uggccgguau ugauguuaga agaucucauc aucaaagggu 8580 ucccugaucc ggcgacuagc gcccuggcuc aauugaaguc aauggugcca uauaccucug 8640 guaucgaccg ggagaucaua cuuuccuguc ucaaccuucc cuuaucgucg gugguaucuc 8700 cgucaauguu guuaaaggac ccggcggcca ucaacaccau cacaaccccg uccgcgggcg 8760 acauccugca agaggucgcc agagacuaug uuaccgauua cccacuccaa aacccgcagc 8820 ucagagcagu ggucaagaac gugaagaccg agcuagacac auuggccagu gacuuauuca 8880 aaugugaacc uuucuuuccu ccuuuaauga gcgauaucuu cucggcaucu cucccggcau 8940 aucaagacag gauuguucgc aagugcucca cgacuucuac aaucaggaga aaagcugccg 9000 agaggggcuc cgacucucuc cucaaccgga ugaaaaggaa ugagaucaau aagaugaugu 9060 uacaucuuug ggcuaccugg ggaaggagcc cucuggccag auuagacacc agaugucuca 9120 caaccugcac caagcaauua gcccaacagu aucggaacca gucuugggga aagcagaucc 9180 auggagucuc agucggccac cccuuagaac uguucggucg aauaacaccc agccauagau 9240 gccuacauga ggaggaccac ggagauuucc ugcaaaccuu cgccagcgag caugugaacc 9300 aaguggacac cgacaucacc acaacucugg ggccguucua cccuuacaua ggcucggaga 9360 cgcgagaacg ggcagucaag guucgaaaag gagugaauua cguaguugag ccgcuucuga 9420 aacccgcagu ucgacuacua agagccauua auugguucau ucccgaggag ucagaugcgu 9480 cccauuugcu gagcaaucua uuagcgucug uuaccgacau caauccucaa gaccacuacu 9540 caucuaccga aguagggggg ggcaacgccg uccaucgcua cagcugccga cuauccgaca 9600 aauugagcag agucaacaac uuauaucagu ugcauacuua uuuaucuguc acaacagagc 9660 gguugaccaa guacagucga ggaucaaaaa acacugacgc acacuuccag agcaugauga 9720 uuuaugcaca aagccgucau auagaccuca ucuuggaguc ucugcacacc ggagagaugg 9780 uaccguugga gugucaucau cacauugagu gcaaucacug uauagaggau auacccgacg 9840 agccaaucac gggggacccg gcuuggacug aagucaaguu uccuucaagu ccucaggagc 9900 ccuuucuuua caucaggcaa caagaucugc cggucaaaga caaacucgag ccugugccuc 9960 gcaugaacau cguccgucuu gccggauugg guccggaggc gauuagugag cuagcgcacu 10020 acuuuguugc auuccgaguu auccgggcgu cagagacgga ugucgacccu aacgauguuc 10080 ucucguggac cuggcugagc cgaauugauc cugacaaauu gguugaguau aucgugcaug 10140 uguucgcuuc acuggaaugg caucauguau uaaugucagg cgugagugug agcgucagag 10200 augcauucuu uaagaugcua gugucuaaaa gaaucucaga gacuccgcua aguucauucu 10260 auuaucuggc caaccuguuc guugacccuc agacucgcga agcacuaaug agcucuaaau 10320 acggguucag cccccccgcc gagacagucc ccaacgcaaa ugccgccgca gccgaaauaa 10380 gaagaugcug ugcgaacagu gcgccgucga ucuuagaauc agcccuucac agccgugagg 10440 uuguuuggau gccaggaacg aacaauuaug gagacguugu caucuggucu cauuacauua 10500 gauuacgguu cagcgaaguu aaacuaguug acauuacacg auaucagcag ugguggagac 10560 agucugagcg agaccccuac gauuuggucc cggacaugca gguucuugag agcgaccuag 10620 auacgcugau gaaacggaua ccgaggcuca ugcgcaaggc gagacguccc ccucuucagg 10680 uaauucgaga ggaccuggau gucgcaguca ucaaugcuga ucaucccgcu cacucugugc 10740 uucagaacaa auacaggaaa uugauuuuca gagagccgaa gauuaucacg ggagcugugu 10800 acaaguaccu cucccuaaaa ucagaguuga cagaguucac cucagcaaug gugaucggag 10860 acggaacugg agguaucacc gccgccauga uggccgaugg gauagaugug ugguaucaga 10920 cgcucgucaa cuaugaccac gugacacaac agggauuauc cguacaagcc ccggcagcau 10980 uggaucuucu gcgcggggca cccucuggua ggcucuugaa uccgggaaga uucgcaucau 11040 uugggucuga ccuaacugac ccucgauuua cagccuacuu ugaucaauau cccccguuca 11100 agguggacac ucuauggucu gacgcagagg gcgacuuuug ggacaagccu uccaaguuga 11160 aucaauacuu ugagaacauc auugcuuuga gacaucgguu cgugaagaca aauggacagc 11220 uugucgugaa gguguaucug acucaagaca cugcuaccac aauugaagca uucagaaaga 11280 agcugucccc augcgccauc aucgugucuc ucuucucgac ggaaggcucc acagaaugcu 11340 ucguccuaag caaucucauc gcaccagaca ccccugucga ccuugagaug guggagaaua 11400 ucccuaaacu aacaucccuu guuccccaga ggacgacagu gaaaugcuau ucccgacgag 11460 uagcgugcau caguaaaagg uggggacuuu ucagaucucc gagcauagcc cuugaagucc 11520 aaccguuccu ucacuacauc acaaagguca ucucagacaa aggaacacaa cugagucuca 11580 uggcgguagc ugacacaaug aucaacaguu acaagaaggc uaucucaccc cgaguguucg 11640 aucuacaccg gcauagggcc gcacuggguu ucgggaggag auccuugcau cucaucuggg 11700 ggaugaucau cucaccaauc gcuuaccagc auuuugagaa uccggccaag uugauggaug 11760 uccuggacau guugaccaau aacaucucag cuuucuuauc gauaucgucg ucaggauuug 11820 accugucauu uagugucagu gcagaccgag auguccggau ugacagcaaa cuugucagac 11880 ucccgcuauu cgaaggauca gaccuaaaau ucaugaaaac caucaugucu acccucggau 11940 cuguguucaa ccaggucgag ccuuuuaagg ggaucgccau aaacccuucu aaacuaauga 12000 cugucaagag gacacaggag uuacguuaca acaaccuaau uuacacuaag gaugccaucc 12060 uauuccccaa ugaagcggca aaaaacacug ccccgcuucg agccaacaug guauaccccg 12120 uccggggaga ucuauucgcc ccuaccgauc gcauaccaau caugacucua gucagcgaug 12180 agacaacacc ucagcacucu ccuccagagg augaggcaua acugaauccu cccugaaggc 12240 ucacaugucc cacgcgacgc aagauauaac gacaagcaac ucgcccuauu aacugugauu 12300 aauaaaaaac cgauuauuca guugcuugag ggaguuucaa uccguucagu guaugauagg 12360 aaguuucuga gauggugggg auuagggggc accuagagua uguuuguucg uuuuaugcgu 12420 cgu 12423

SEQ ID NO: 3

MARPLAAAQH LITERHSLQA TLSRASKTRA EEFVKDFYLQ EQYSVPTIPT DDIAQSGPML 60 LQAILSEEYT KATDIAQSIL WNTPTPNGLL REHLDADGGG SFTALPASAI RPSDEANAWA 120 ARISDSGLGP VFYAALAAYI IGWSGRGETS RVQQNIGQKW LMNLNAIFGT TITHPTTVRL 180 PINVWNSLA VRNGLAATLW LYYRSSPQSQ DAFFYGLIRP CCSGYLGLLH RVQEIDEMEP 240 DFLSDPRIIQ EVYSALRA LVQLGNDFKT ADDEPMQWA CRGINNGYLT YLSETPAKKG 300 AWLMFAQCM LKGDSEAWNS YRTATWVMPY CDNVALGAMA GYIQARQNTR AYEVSAQTGL 360 DVNMAAVKDF EASSKPKAAP ISLIPRPADV ASRTSERPSI PEVDSDEELG GM 412

SEQ ID NO: 4

MEDYLSSLEA ARELVRTELE PKRNLIASLE SDDPDPVIAP AVKPKHPKPC LSTKEEDHLP 60 SLRLLFGAKR DTSVGVEQTL HKRLCACLDG YLTMTKKEAN AFKAAAEAAA LAVMDIKMEH 120 QRQDLEDLTA AIPRIEFKLN AILENNKEIA KAVTAAKEME REMSWGESAA SSLKSVTLDE 180 SFRGPEELSE SFGIRYKVRT WNEFKKALET SIVDLRPSPV SFRELRTMWL SLDTSFRLIG 240 FAFIPTCERL ETKAKCKETR TLLPLAESIM RRWDLRDPTI LEKACWMMI RGNEIASLNQ 300 VKDVLPTTIR GWKIAY 316

SEQ ID NO: 5

MRRFFLGESS APARDWESER PPPYAVEVPQ SHGIRVTGYF QCNERPKSKK TLHSFAVKLC 60 DAIKPVRADA PSLKIAIWTA LDLAFVKPPN GTVTIDAAVK ATPLIGNTQY TVGDEIFQML 120 GRRGGLIVIR NLPHDYPRTL IEFASPEP 148

SEQ ID NO:

MLRIQIPPIA IILVSLLTLD LSGARRTTTQ RIPLLNDSWD LFSSYGDIPE ELWYQNYSH 60 NSSELPPPGF ERWYINRRVA DTSIPCRGPC LVPYILHGLN DTTVSRRGGG WRRSGMKYPT 120 HAVRLGPSTD DERVEEDIGY VNVSALSCTG SPVEMAIPTI PDCTSAIHPR SEVTVPVKLD 180 VMRRNPNYPP IRAWSCIGQK ITNRCDWALF GENLIYTQVE ASSLAFKHTR ASLLNESNGI 240 DAEGRAVPYI LGDIEPGYCR TLFNTWVSSE IVSCTPIELV LVDLNPLSPG HGGYAVLLPN 300 GDKVDVHDKH AWDGDNKMWR WVYEKKDPCA FELVSREVCL FSLSRGSRLR GATPPQGELL 360 TCPHSGKAFD LKGARRITPI SCKIDMEYDL LSLPTGVILG LHLSELGTSF GNLSMSLEMY 420 EPATTLTPEQ INFSLKELGS WTEAQLKSLS HSICLSTFSI WELSVGMIDL NPTRAARALL 480 HDDNILATFE NGHFSIVRCR PEIVQVPSHP RACHMDLRPY DKQSRASTLV VPLDNSTALL 540 VPDNIWEGV EASLCNHSVA ITLSKNRTHS YSLYPQGRPV LRQKGAVELP TIGPLQLHPA 600 TRVDLYTLKE FQEDRIARSR VTDIKAAVDD LRAKWRKGKF EADTTGGGLW SAIVGVFSSL 660 GGFFMRPLIA LAAIVTSIII LYILLRVLCA ASCSTHRRVR QDSW 704

SEQ ID NO: 7

MAFDPNWQRE GYEWDPSSEG RPTDENEDDR GHRPKTRLRT FLARTLNSPI RALFYTIFLG 60 IRAVWDGFKR LLPVRTEKGY ARFSECVTYG MIGCDECVID PVRWIELTE MQLPIKGKGS 120 TRLRAMITED LLTGMRTAVP QIRVRSKILA ERLGRAIGRE TLPAMIHHEW AFVMGKILTF 180 MADNVGMNAD TVEGVLSLSE VTRRWDIGNS VSAVFNPDGL TIRVENTGYI MTRETACMIG 240 DIHAQFAIQY LAAYLDEVIG TRTSLSPAEL TSLKLWGLNV LKLLGRNGYE VIACMEPIGY 300 AVLMMGRDRS PDPYVNDTYL NSILSEFPVD SDARACVEAL LTIYMSFGTP HKVSDAFGLF 360 RMLGHPMVDG ADGIEKMRRL SKKVKIPDQS TAIDLGAIMA ELFVRSFVKK HKRWPNCSIN 420 LPPRHPFHHA RLCGYVPAET HPLNNTASWA AVEFNQEFEP PRQYNLADII DDKSCSPNKH 480 ELYGAWMKSK TAGWQEQKKL ILRWFTETMV KPSELLEEID AHGFREEDKL IGLTPKEREL 540 KLTPRMFSLM TFKFRTYQVL TESMVADEIL PHFPQITMTM SNHELTKRLI SRTRPQSGGG 600 RDVHITVNID FQKWNTNMRH GLVKHVFERL DNLFGFTNLI RRTHEYFQEA KYYLAEDGTN 660 LSFDRNGELI DGPYVYTGSY GGNEGLRQKP WTIVTVCGIY KVARDLKIKH QITGQGDNQV 720 VTLIFPDREL PSDPVERSKY CRDKSSQFLT RLSQYFAEVG LPVKTEETWM SSRLYAYGKR 780 MFLEGVPLKM FLKKIGRAFA LSNEFVPSLE EDLARVWSAT SAAVELDLTP YVGYVLGCCL 840 SAQAIRNHLI YSPVLEGPLL VKAYERKFIN YDGGTKRGAM PGLRPTFESL VKSICWKPKA 900 IGGWPVLMLE DLIIKGFPDP ATSALAQLKS MVPYTSGIDR EIILSCLNLP LSSWSPSML 960 LKDPAAINTI TTPSAGDILQ EVARDYVTDY PLQNPQLRAV VKNVKTELDT LASDLFKCEP 1020 FFPPLMSDIF SASLPAYQDR IVRKCSTTST IRRKAAERGS DSLLNRMKRN EINKMMLHLW 1080 ATWGRSPLAR LDTRCLTTCT KQLAQQYRNQ SWGKQIHGVS VGHPLELFGR ITPSHRCLHE 1140 EDHGDFLQTF ASEHVNQVDT DITTTLGPFY PYIGSETRER AVKVRKGVNY WEPLLKPAV 1200 RLLRAINWFI PEESDASHLL SNLLASVTDI NPQDHYSSTE VGGGNAVHRY SCRLSDKLSR 1260 VNNLYQLHTY LSVTTERLTK YSRGSKNTDA HFQSMMIYAQ SRHIDLILES LHTGEMVPLE 1320 CHHHIECNHC IEDIPDEPIT GDPAWTEVKF PSSPQEPFLY IRQQDLPVKD KLEPVPRMNI 1380 VRLAGLGPEA ISELAHYFVA FRVIRASETD VDPNDVLSWT WLSRIDPDKL VEYIVHVFAS 1440 LEWHHVLMSG VSVSVRDAFF KMLVSKRISE TPLSSFYYLA NLFVDPQTRE ALMSSKYGFS 1500 PPAETVPNAN AAAAEIRRCC ANSAPSILES ALHSREWWM PGTNNYGDW IWSHYIRLRF 1560 SEVKLVDITR YQQWWRQSER DPYDLVPDMQ VLESDLDTLM KRIPRLMRKA RRPPLQVIRE 1620 DLDVAVINAD HPAHSVLQNK YRKLIFREPK IITGAVYKYL SLKSELTEFT SAMVIGDGTG 1680 GITAAMMADG IDVWYQTL YDHVTQQGLS VQAPAALDLL RGAPSGRLLN PGRFASFGSD 1740 LTDPRFTAYF DQYPPFKVDT LWSDAEGDFW DKPSKLNQYF ENIIALRHRF VKTNGQLWK 1800 VYLTQDTATT IEAFRKKLSP CAIIVSLFST EGSTECFVLS NLIAPDTPVD LEMVENIPKL 1860 TSLVPQRTTV KCYSRRVACI SKRWGLFRSP SIALEVQPFL HYITKVISDK GTQLSLMAVA 1920 DTMINSYKKA ISPRVFDLHR HRAALGFGRR SLHLIWGMII SPIAYQHFEN PAKLMDVLDM 1980 LTNNISAFLS ISSSGFDLSF SVSADRDVRI DSKLVRLPLF EGSDLKFMKT IMSTLGSVFN 2040 QVEPFKGIAI NPSKLMTVKR TQELRYNNLI YTKDAILFPN EAAKNTAPLR ANMVYPVRGD 2100 LFAPTDRIPI MTLVSDETTP QHSPPEDEA 2129

SEQ ID NO:

atggctcgtc cgctagctgc tgcgcaacat ctcataaccg agcgtcattc ccttcaggcg 60 actctgtcgc gggcgtccaa gaccagagcc gaggaattcg tcaaagattt ctaccttcaa 120 gagcagtatt ctgtcccgac catcccgacg gacgacattg cccagtctgg gcccatgctg 180 cttcaggcca tcctgagcga ggaatacaca aaggccactg acatagccca atccatcctc 240 tggaacactc ccacacccaa cgggctcctc agagagcatc tagatgccga tgggggaggc 300 tcattcacag cgctgcccgc gtctgcaatc agacccagcg acgaggcgaa tgcatgggcc 360 gctcgcatct ccgactcagg gttggggcct gtcttctatg cagccctcgc tgcttacatc 420 atcggctggt caggaagagg agagactagc cgcgtgcagc agaacatagg tcagaaatgg 480 ctgatgaacc tgaacgcaat cttcggcacc acgatcaccc atccaacaac cgtgcgtctg 540 ccaatcaacg tcgtcaacaa cagcctcgca gtgaggaacg gacttgctgc cacactctgg 600 ctatactacc gttcatcacc tcagagtcag gacgcgttct tctatgggct catccgtccc 660 tgttgcagtg gatatctcgg cctgctacat cgggtgcagg agattgatga gatggagccg 720 gacttcctca gtgacccccg gatcatccag gtgaatgagg tctacagtgc actcagagcc 780 ctggttcaac tgggaaacga cttcaagacc gccgatgatg agcccatgca ggtctgggcg 840 tgcaggggaa tcaacaacgg atatctgaca tatctctcag aaactcctgc gaagaaagga 900 gctgttgtgc ttatgtttgc ccaatgcatg ctgaagggcg actctgaggc ctggaacagc 960 taccgcactg caacctgggt gatgccctat tgcgacaatg tggccctagg agcgatggca 1020 ggctacatcc aagcccgcca gaacaccagg gcatatgagg tctcagccca gacaggtctc 1080 gacgtcaaca tggccgcggt caaggacttt gaggccagtt caaaacccaa ggctgctcca 1140 atctcgctga tcccacgccc cgctgatgtc gcatcccgca cctctgagcg cccatctatt 1200 cctgaggttg acagcgacga agagctcgga ggaatg 1236

SEQ ID NO: 9

atggaggact atttgtctag cttagaggcc gcgagagagc tcgtccggac ggagctggag 60 cccaagcgta acctcatagc cagcttagag tccgacgatc ccgatccggt aatagcgcca 120 gcggtaaaac caaaacatcc caagccatgc ctgagcacta aagaagagga tcatctcccc 180 tctcttcgcc tactattcgg cgcaaaacga gacacctcgg tgggcgtaga gcagactctc 240 cacaagcgtc tctgcgcttg tctcgacggt tacctgacca tgacgaagaa agaggccaat 300 gcctttaagg ccgcggctga agcagcagca ttagcagtca tggacattaa gatggagcat 360 cagcgccagg atctagagga tctgaccgct gctatcccta ggatagaatt caaactcaat 420 gccatcctgg aaaacaacaa ggagatagcc aaggctgtaa ctgctgctaa ggagatggag 480 cgggagatgt cgtgggggga aagcgccgcc agctcgctca agtctgtcac cctagatgag 540 tcgtttaggg gccctgaaga gctttcagag tcatttggca tccgatataa ggtcagaacc 600 tggaatgagt tcaagaaggc gctggaaacc agcattgtgg acctgaggcc tagccctgtt 660 tcatttaggg aattacggac tatgtggctg tctcttgaca cctcctttag gctcattggg 720 tttgccttca ttcccacatg cgagcgcctg gagaccaaag ccaaatgcaa ggagacaagg 780 actctactcc cccttgcaga gtcgatcatg cgaagatggg acctgcggga tccaaccatc 840 ttggagaaag cctgcgtagt aatgatgatc cgtgggaatg agattgcatc gctgaatcag 900 gtaaaagatg ttctcccgac cacaattcgt gggtggaaga tcgcttat 948

SEQ ID NO: 10

atgcgtcggt tctttttagg agagagcagt gcccctgcga gggactggga gtccgagcga 60 cctcccccct atgctgttga ggtccctcaa agtcacggga taagagtcac cgggtacttc 120 cagtgcaacg agcgtccgaa atccaagaag accctccaca gcttcgccgt aaaactctgc 180 gacgcaatta agccggttcg agcggatgct cccagcttga agatagcaat atggacggct 240 ctagatctgg ccttcgtgaa acctcccaat ggaactgtaa caatagatgc ggcggtgaaa 300 gctacaccgc taatcgggaa cacccagtac accgtaggcg atgaaatctt ccagatgcta 360 gggagaaggg gtggcctgat cgtcatcagg aacttacccc atgattatcc tcgaacgttg 420 attgagttcg cctctcccga gcct 444

SEQ ID NO: 11

atgctcagga tccagatccc tccgattgct atcattctgg taagtctcct cacactcgac 60 ctgtccggtg caaggaggac aaccacacaa agaatccctc tccttaatga ttcgtgggat 120 ttgttctcga gctatggcga cattcccgaa gaacttgtcg tataccagaa ctacagccac 180 aattcctccg agttaccccc tcctggcttc gagagatggt acataaaccg aagagtggca 240 gacacttcca taccgtgcag gggcccctgt ctagtgccct acatccttca tggcctcaat 300 gacacaactg tctctcgacg gggaggagga tggcgaaggt ccggaatgaa gtacccaacc 360 cacgctgtca ggctaggccc ttcaacagac gacgagagag ttgaggaaga catcggctac 420 gtcaatgtct ccgcactatc ctgcacaggg tcgcccgttg agatggcgat accaacaatc 480 cccgactgca ccagtgctat ccatccacga tccgaggtta ctgtgcccgt caagctcgat 540 gtcatgagac gaaatcccaa ctaccctccc attagagcgt ggtcgtgcat cggacagaaa 600 atcaccaacc gatgtgattg ggcactcttc ggcgagaacc tcatatatac tcaagttgaa 660 gctagctctc tagcattcaa gcacacaaga gcctctcttt tgaacgaatc caacgggata 720 gacgctgaag gacgtgcagt tccctatatc ctcggggata tcgaacccgg gtactgccga 780 accctattca acacatgggt ctctagtgag atcgtgtcat gcacgcccat cgaacttgtc 840 ctagttgacc tgaacccttt gtccccggga catggcggat atgctgtatt gctgccaaac 900 ggagacaaag tggatgtaca cgacaagcat gcatgggatg gggacaacaa aatgtggaga 960 tgggtgtacg agaagaaaga tccctgtgcg ttcgagctgg tatccaggga agtgtgtctt 1020 ttctcactga gtaggggtag tagactgaga ggagcaaccc ctccccaagg agagctcctc 1080 acctgcccgc attcgggaaa ggcatttgac ctgaaggggg cccgaaggat tacacccatt 1140 tcatgcaaaa tcgacatgga atatgacttg ctgtcactac caaccggagt catcctaggc 1200 ctccacctat cagaactcgg gacctccttt ggcaacctct caatgagtct tgaaatgtat 1260 gaacctgcca caactctgac ccctgagcaa atcaacttct cgcttaaaga gctgggaagc 1320 tggaccgagg ctcaactgaa gagcctgtct cactcaatct gcctctccac attctccata 1380 tgggaactat cggttgggat gatcgatcta aaccctacca gggcagcaag ggccttgctc 1440 catgatgata acatactggc aacattcgag aacggtcact tttccatcgt cagatgtcgt 1500 ccggaaatag ttcaagtccc ttcgcatcct cgagcatgtc acatggatct ccgcccttat 1560 gacaagcaat cacgggcatc aaccctggtg gttccccttg acaacagcac tgccctcctg 1620 gtccccgaca acatcgtggt tgaaggagta gaggccagtc tatgcaacca ctccgttgcc 1680 atcacgctgt cgaagaacag aactcactca tacagcctct atccccaggg tcgtcctgtg 1740 cttcgacaga aaggtgccgt ggagctcccg acgatagggc ccctccagtt acatcctgcc 1800 actcgagtgg acctttatac actgaaagag ttccaggagg accgaatagc gcgcagtcga 1860 gtcacagaca tcaaggctgc cgttgacgat ctgcgtgcga agtggcgtaa aggcaaattt 1920 gaggcggaca ccacgggagg gggactttgg tcggcgattg tgggagtctt cagttctctc 1980 ggggggttct tcatgaggcc cttgattgct ctcgcggcga tagtgacctc aatcatcatc 2040 ctgtatatcc ttctgcgtgt actgtgtgct gcctcatgtt cgacacaccg aagagtaagg 2100 caggactctt gg 2112 SEQ ID NO: 12

atggccttcg acccgaactg gcagagagaa ggttatgaat gggatccgtc aagtgagggc 60 agaccgaccg atgagaacga agacgacaga ggtcatcggc caaaaacgag acttcgtaca 120 ttccttgccc gcacgttaaa tagccctatc cgagccctat tctacacaat attcctagga 180 attcgagcgg tttgggacgg gttcaaaaga ctcctacctg tgaggaccga aaagggttat 240 gcgaggtttt ctgagtgcgt cacatatgga atgatcggat gtgatgagtg tgtaatagac 300 ccggtgaggg ttgtcattga gctgaccgag atgcagttac cgattaaagg caaaggctct 360 acgaggttga gagcaatgat aactgaagac cttctcacgg ggatgcgcac agccgtgcct 420 cagatcagag tgagatcgaa gatcctagca gagcggttag ggagagcaat cggccgagag 480 accttgccgg caatgatcca tcatgagtgg gcatttgtga tggggaagat tctcactttc 540 atggcagaca atgtgggtat gaacgctgac acggtcgagg gcgttctatc actatcagag 600 gtcacacggc gatgggatat cggcaactct gtgtccgcag tgttcaatcc tgatggcctt 660 actatcagag tagaaaacac gggttacatc atgaccagag agactgcctg catgatcgga 720 gacattcatg ctcaatttgc aatccaatac ctagctgcat acctagacga ggtgatcggc 780 acaaggacgt ctctctcacc cgccgaactg acctctctca aactatgggg acttaacgtc 840 ctgaaactcc taggacggaa cggttatgag gtgatcgcct gcatggagcc catagggtac 900 gctgtcctga tgatgggaag agacaggagt cctgatccct atgtcaatga cacctattta 960 aacagcatcc tctcagaatt ccctgtcgac tctgacgctc gagcctgcgt tgaagccctc 1020 ttaactatct atatgagctt cggcacaccc cataaagtct cggacgcatt cggcctcttc 1080 agaatgttgg gacatccgat ggttgatgga gctgacggga ttgaaaagat gcgaaggtta 1140 agcaagaagg tcaagatccc agaccagtct acagcgatcg acctcggggc tatcatggcc 1200 gaactgtttg tgcggagttt cgtaaagaag cacaaaaggt ggcccaactg ctccatcaat 1260 ctcccgccac gacacccctt ccaccacgcc cgcctatgtg ggtatgtccc ggctgaaacc 1320 catcccctaa acaacactgc atcctgggcg gctgtggagt tcaaccagga attcgagccg 1380 ccgagacagt acaaccttgc agacatcatt gatgacaagt cgtgctctcc caacaagcat 1440 gagctatatg gtgcttggat gaagtcaaaa acagctgggt ggcaggaaca aaagaagctc 1500 atactccgat ggttcactga gaccatggtt aaaccttcgg agctcctgga agagattgat 1560 gcacacggct tccgagaaga ggataagttg attggattaa caccaaagga gagagagctg 1620 aaattaacac caagaatgtt ctccttgatg acattcaagt tcagaaccta ccaagtcctc 1680 actgagagta tggtcgccga tgagatcctc ccgcacttcc cccagatcac catgaccatg 1740 tccaaccacg aactcacaaa gaggttgatt agcagaacga gacctcaatc tggaggaggg 1800 cgtgatgttc acatcaccgt gaacatagat ttccagaaat ggaacacaaa catgagacac 1860 ggactggtca aacatgtctt cgagcgactg gacaacctct ttggcttcac caacttaatc 1920 agacgaactc atgaatactt ccaggaggcg aaatactatc tggctgaaga tggaactaat 1980 ctgtcgttcg acaggaacgg ggagttaata gatggcccat acgtttacac cggatcatac 2040 ggggggaacg aggggttacg acagaagccc tggacaatag ttaccgtgtg tggaatatac 2100 aaggtagcta gagacctgaa aatcaaacat cagatcaccg gtcagggaga taatcaggtg 2160 gtcaccctaa tatttccgga tcgagagttg ccttcagatc cggtggagag gagcaagtac 2220 tgtagagaca agagcagtca gttcctgaca cgtctcagtc aatatttcgc tgaggttggt 2280 ttgcccgtca agactgaaga gacatggatg tcatcacgtc tctatgctta cggtaagcgc 2340 atgttcttag agggagttcc acttaagatg tttctcaaga agataggcag agctttcgcc 2400 ctctcgaatg agtttgtccc gtccctcgag gaagatctgg ccagagtctg gagtgccacc 2460 agcgcagcgg tagagcttga cctaactccc tacgtaggat atgtcctcgg gtgctgcttg 2520 tctgcgcagg cgatcagaaa tcacctcatc tactcccctg ttctggaggg ccctctgctg 2580 gttaaggcct acgagcgtaa gttcattaac tacgacggag gaacaaagcg gggggcgatg 2640 cccggcctac gtccaacctt tgagagccta gtcaaaagta tctgctggaa gccaaaggcc 2700 atcggagggt ggccggtatt gatgttagaa gatctcatca tcaaagggtt ccctgatccg 2760 gcgactagcg ccctggctca attgaagtca atggtgccat atacctctgg tatcgaccgg 2820 gagatcatac tttcctgtct caaccttccc ttatcgtcgg tggtatctcc gtcaatgttg 2880 ttaaaggacc cggcggccat caacaccatc acaaccccgt ccgcgggcga catcctgcaa 2940 gaggtcgcca gagactatgt taccgattac ccactccaaa acccgcagct cagagcagtg 3000 gtcaagaacg tgaagaccga gctagacaca ttggccagtg acttattcaa atgtgaacct 3060 ttctttcctc ctttaatgag cgatatcttc tcggcatctc tcccggcata tcaagacagg 3120 attgttcgca agtgctccac gacttctaca atcaggagaa aagctgccga gaggggctcc 3180 gactctctcc tcaaccggat gaaaaggaat gagatcaata agatgatgtt acatctttgg 3240 gctacctggg gaaggagccc tctggccaga ttagacacca gatgtctcac aacctgcacc 3300 aagcaattag cccaacagta tcggaaccag tcttggggaa agcagatcca tggagtctca 3360 gtcggccacc ccttagaact gttcggtcga ataacaccca gccatagatg cctacatgag 3420 gaggaccacg gagatttcct gcaaaccttc gccagcgagc atgtgaacca agtggacacc 3480 gacatcacca caactctggg gccgttctac ccttacatag gctcggagac gcgagaacgg 3540 gcagtcaagg ttcgaaaagg agtgaattac gtagttgagc cgcttctgaa acccgcagtt 3600 cgactactaa gagccattaa ttggttcatt cccgaggagt cagatgcgtc ccatttgctg 3660 agcaatctat tagcgtctgt taccgacatc aatcctcaag accactactc atctaccgaa 3720 gtaggggggg gcaacgccgt ccatcgctac agctgccgac tatccgacaa attgagcaga 3780 gtcaacaact tatatcagtt gcatacttat ttatctgtca caacagagcg gttgaccaag 3840 tacagtcgag gatcaaaaaa cactgacgca cacttccaga gcatgatgat ttatgcacaa 3900 agccgtcata tagacctcat cttggagtct ctgcacaccg gagagatggt accgttggag 3960 tgtcatcatc acattgagtg caatcactgt atagaggata tacccgacga gccaatcacg 4020 ggggacccgg cttggactga agtcaagttt ccttcaagtc ctcaggagcc ctttctttac 4080 atcaggcaac aagatctgcc ggtcaaagac aaactcgagc ctgtgcctcg catgaacatc 4140 gtccgtcttg ccggattggg tccggaggcg attagtgagc tagcgcacta ctttgttgca 4200 ttccgagtta tccgggcgtc agagacggat gtcgacccta acgatgttct ctcgtggacc 4260 tggctgagcc gaattgatcc tgacaaattg gttgagtata tcgtgcatgt gttcgcttca 4320 ctggaatggc atcatgtatt aatgtcaggc gtgagtgtga gcgtcagaga tgcattcttt 4380 aagatgctag tgtctaaaag aatctcagag actccgctaa gttcattcta ttatctggcc 4440 aacctgttcg ttgaccctca gactcgcgaa gcactaatga gctctaaata cgggttcagc 4500 ccccccgccg agacagtccc caacgcaaat gccgccgcag ccgaaataag aagatgctgt 4560 gcgaacagtg cgccgtcgat cttagaatca gcccttcaca gccgtgaggt tgtttggatg 4620 ccaggaacga acaattatgg agacgttgtc atctggtctc attacattag attacggttc 4680 agcgaagtta aactagttga cattacacga tatcagcagt ggtggagaca gtctgagcga 4740 gacccctacg atttggtccc ggacatgcag gttcttgaga gcgacctaga tacgctgatg 4800 aaacggatac cgaggctcat gcgcaaggcg agacgtcccc ctcttcaggt aattcgagag 4860 gacctggatg tcgcagtcat caatgctgat catcccgctc actctgtgct tcagaacaaa 4920 tacaggaaat tgattttcag agagccgaag attatcacgg gagctgtgta caagtacctc 4980 tccctaaaat cagagttgac agagttcacc tcagcaatgg tgatcggaga cggaactgga 5040 ggtatcaccg ccgccatgat ggccgatggg atagatgtgt ggtatcagac gctcgtcaac 5100 tatgaccacg tgacacaaca gggattatcc gtacaagccc cggcagcatt ggatcttctg 5160 cgcggggcac cctctggtag gctcttgaat ccgggaagat tcgcatcatt tgggtctgac 5220 ctaactgacc ctcgatttac agcctacttt gatcaatatc ccccgttcaa ggtggacact 5280 ctatggtctg acgcagaggg cgacttttgg gacaagcctt ccaagttgaa tcaatacttt 5340 gagaacatca ttgctttgag acatcggttc gtgaagacaa atggacagct tgtcgtgaag 5400 gtgtatctga ctcaagacac tgctaccaca attgaagcat tcagaaagaa gctgtcccca 5460 tgcgccatca tcgtgtctct cttctcgacg gaaggctcca cagaatgctt cgtcctaagc 5520 aatctcatcg caccagacac ccctgtcgac cttgagatgg tggagaatat ccctaaacta 5580 acatcccttg ttccccagag gacgacagtg aaatgctatt cccgacgagt agcgtgcatc 5640 agtaaaaggt ggggactttt cagatctccg agcatagccc ttgaagtcca accgttcctt 5700 cactacatca caaaggtcat ctcagacaaa ggaacacaac tgagtctcat ggcggtagct 5760 gacacaatga tcaacagtta caagaaggct atctcacccc gagtgttcga tctacaccgg 5820 catagggccg cactgggttt cgggaggaga tccttgcatc tcatctgggg gatgatcatc 5880 tcaccaatcg cttaccagca ttttgagaat ccggccaagt tgatggatgt cctggacatg 5940 ttgaccaata acatctcagc tttcttatcg atatcgtcgt caggatttga cctgtcattt 6000 agtgtcagtg cagaccgaga tgtccggatt gacagcaaac ttgtcagact cccgctattc 6060 gaaggatcag acctaaaatt catgaaaacc atcatgtcta ccctcggatc tgtgttcaac 6120 caggtcgagc cttttaaggg gatcgccata aacccttcta aactaatgac tgtcaagagg 6180 acacaggagt tacgttacaa caacctaatt tacactaagg atgccatcct attccccaat 6240 gaagcggcaa aaaacactgc cccgcttcga gccaacatgg tataccccgt ccggggagat 6300 ctattcgccc ctaccgatcg cataccaatc atgactctag tcagcgatga gacaacacct 6360 cagcactctc ctccagagga tgaggca 6387

SEQ ID NO: 13

MENLKHIITL GQVIHKRCEE MKYCKKQCRR LGHRVLGLIK PLEMLQDQGK RSVPSEKLTT 60

AMNRFKAALE EANGEIEKFS NRSNICRFLT ASQDKILFKD RKLSDVWK ELSLLLQVEQ 120

RMPVSPISQG ASWAQEDQQD ADEDRRAFQM LRRDNEKIEA SLRRLEINMK EIKETLRQYL 180

PPKCMQEIPQ EQIKEIKKEQ LSGSPWILLR ENEVSTLYKG EYHRAPVAIK VFKKLQAGSI 240

AIVRQTFNKE IKTMKKFESP NILRIFGICI DETVTPPQFS IVMEYCELGT LRELLDREKD 300

LTLGKRMVLV LGAARGLYRL HHSEAPELHG KIRSSNFLVT QGYQVKLAGF ELRKTQTSMS 360

LGTTREKTDR VKSTAYLSPQ ELEDVFYQYD VKSEIYSFGI VLWEIATGDI PFQGCNSEKI 420

RKLVAVKRQQ EPLGEDCPSE LREIIDECRA HDPSVRPSVD EILKKLSTFS K 471 SEQ ID NO:

aaugcugcgu auucgacucu uuguauucuc ugauacaagu aucaguggga cauaaguaau 60 aacugaaaau acuggauaau aagcacucca guauacacuc cauuacagua gacgaauacg 120 caaacgaaua uucuauuuug cuaucuggga agugcccauu uaggaagagg aacgucaaga 180 gcgguucaug gagguuucag ucuugcuacc gagcaggcga ucgacgacgc guuguagagu 240 auuggcucgc aguaagggaa guccgcugag acagcgcccg cagguucugg ucucggcucc 300 uuaagcaguu ucuaaagaug gaaguucucg ucauaagaca gggcugguag ggcugccugc 360 uguaacgggu cagacccggg uacgacgaag uccgguagga cucgcuccuu auguguuucc 420 ggugacugua ucggguuagg uaggagaccu ugugagggug uggguugccc gaggagucuc 480 ucguagaucu acggcuaccc ccuccgagua agugucgcga cgggcgcaga cguuagucug 540 ggucgcugcu ccgcuuacgu acccggcgag cguagaggcu gagucccaac cccggacaga 600 agauacgucg ggagcgacga auguaguagc cgaccagucc uucuccucuc ugaucggcgc 660 acgucgucuu guauccaguc uuuaccgacu acuuggacuu gcguuagaag ccguggugcu 720 aguggguagg uuguuggcac gcagacgguu aguugcagca guuguugucg gagcgucacu 780 ccuugccuga acgacggugu gagaccgaua ugauggcaag uaguggaguc ucaguccugc 840 gcaagaagau acccgaguag gcagggacaa cgucaccuau agagccggac gauguagccc 900 acguccucua acuacucuac cucggccuga aggagucacu gggggccuag uagguccacu 960 uacuccagau gucacgugag ucucgggacc aaguugaccc uuugcugaag uucuggcggc 1020 uacuacucgg guacguccag acccgcacgu ccccuuaguu guugccuaua gacuguauag 1080 agagucuuug aggacgcuuc uuuccucgac aacacgaaua caaacggguu acguacgacu 1140 ucccgcugag acuccggacc uugucgaugg cgugacguug gacccacuac gggauaacgc 1200 uguuacaccg ggauccucgc uaccguccga uguagguucg ggcggucuug uggucccgua 1260 uacuccagag ucgggucugu ccagagcugc aguuguaccg gcgccaguuc cugaaacucc 1320 ggucaaguuu uggguuccga cgagguuaga gcgacuaggg ugcggggcga cuacagcgua 1380 gggcguggag acucgcgggu agauaaggac uccaacuguc gcugcuucuc gagccuccuu 1440 acauuugguu auucgaagug acggccauca aauccguaug ugugcgucaa ggcaauaggu 1500 agugugggca gggaagaaaa uacgacgaua auaaagucaa cgauucgaag gacuaaacua 1560 auuguuuuuu ggcaucugga ggaugcacuc cauaucgauc uuuaaccaag auagccaacu 1620 cucagaaaca ugauaaucgg uaccuccuga uaaacagauc gaaucuccgg cgcucucucg 1680 agcaggccug ccucgaccuc ggguucgcau uggaguaucg gucgaaucuc aggcugcuag 1740 ggcuaggcca uuaucgcggu cgccauuuug guuuuguagg guucgguacg gacucgugau 1800 uucuucuccu aguagagggg agagaagcgg augauaagcc gcguuuugcu cuguggagcc 1860 acccgcaucu cgucugagag guguucgcag agacgcgaac agagcugcca auggacuggu 1920 acugcuucuu ucuccgguua cggaaauucc ggcgccgacu ucgucgucgu aaucgucagu 1980 accuguaauu cuaccucgua gucgcggucc uagaucuccu agacuggcga cgauagggau 2040 ccuaucuuaa guuugaguua cgguaggacc uuuuguuguu ccucuaucgg uuccgacauu 2100 gacgacgauu ccucuaccuc gcccucuaca gcaccccccu uucgcggcgg ucgagcgagu 2160 ucagacagug ggaucuacuc agcaaauccc cgggacuucu cgaaagucuc aguaaaccgu 2220 aggcuauauu ccagucuugg accuuacuca aguucuuccg cgaccuuugg ucguaacacc 2280 uggacuccgg aucgggacaa aguaaauccc uuaaugccug auacaccgac agagaacugu 2340 ggaggaaauc cgaguaaccc aaacggaagu aaggguguac gcucgcggac cucugguuuc 2400 gguuuacguu ccucuguucc ugagaugagg gggaacgucu cagcuaguac gcuucuaccc 2460 uggacgcccu agguugguag aaccucuuuc ggacgcauca uuacuacuag gcacccuuac 2520 ucuaacguag cgacuuaguc cauuuucuac aagagggcug guguuaagca cccaccuucu 2580 agcgaauaau cagugacgag gguaaucagg gugaucugcc guaugaaggu aaggcgggaa 2640 auuaagggga cagucuguga guacgaggcu uuagugauug guaggaacag gugguucguu 2700 augcguauaa gucaucguga cguagagcgg gagggggaua guucgggguc gcgacgucua 2760 gaaguggugu auauauguac guaguugaug uacacuaaau cuuuuuuggu cugggaagug 2820 cccauuaucg gauugagugc uugcaaggag agcaaagcau acuauuccgg aauucguaac 2880 agcuaugcca gcaauacgca gccaagaaaa auccucucuc gucacgggga cgcucccuga 2940 cccucaggcu cgcuggaggg gggauacgac aacuccaggg aguuucagug cccuauucuc 3000 aguggcccau gaaggucacg uugcucgcag gcuuuagguu cuucugggag gugucgaagc 3060 ggcauuuuga gacgcugcgu uaauucggcc aagcucgccu acgagggucg aacuucuauc 3120 guuauaccug ccgagaucua gaccggaagc acuuuggagg guuaccuuga cauuguuauc 3180 uacgccgcca cuuucgaugu ggcgauuagc ccuugugggu cauguggcau ccgcuacuuu 3240 agaaggucua cgaucccucu uccccaccgg acuagcagua guccuugaau gggguacuaa 3300 uaggagcuug caacuaacuc aagcggagag ggcucggaac ucgugguccc guagccaggc 3360 gggcgggaca cuagagggca ucggcccgag ucgcuaguuc ggccgggccc agcccccccu 3420 gaccacguug uguuccccgc cgucaccugc gacuaauugu uuuuuggugg auauaucugg 3480 ggagugccag aaucugagac aacggucgac uguugguugu guguucugua gagagacuaa 3540 gucggcuggg cuagcuaagg aggggugggu uaaggauggu ugcgugagga guguucgagg 3600 ugguacgagu ccuaggucua gggaggcuaa cgauaguaag accauucaga ggagugugag 3660 cuggacaggc cacguuccuc cuguuggugu guuucuuagg gagaggaauu acuaagcacc 3720 cuaaacaaga gcucgauacc gcuguaaggg cuucuugaac agcauauggu cuugaugucg 3780 guguuaagga ggcucaaugg gggaggaccg aagcucucua ccauguauuu ggcuucucac 3840 cgucugugaa gguauggcac guccccgggg acagaucacg ggauguagga aguaccggag 3900 uuacuguguu gacagagagc ugccccuccu ccuaccgcuu ccaggccuua cuucaugggu 3960 ugggugcgac aguccgaucc gggaaguugu cugcugcucu cucaacuccu ucuguagccg 4020 augcaguuac agaggcguga uaggacgugu cccagcgggc aacucuaccg cuaugguugu 4080 uaggggcuga cguggucacg auagguaggu gcuaggcucc aaugacacgg gcaguucgag 4140 cuacaguacu cugcuuuagg guugauggga ggguaaucuc gcaccagcac guagccuguc 4200 uuuuaguggu uggcuacacu aacccgugag aagccgcucu uggaguauau augaguucaa 4260 cuucgaucga gagaucguaa guucgugugu ucucggagag aaaacuugcu uagguugccc 4320 uaucugcgac uuccugcacg ucaagggaua uaggagcccc uauagcuugg gcccaugacg 4380 gcuugggaua aguuguguac ccagagauca cucuagcaca guacgugcgg guagcuugaa 4440 caggaucaac uggacuuggg aaacaggggc ccuguaccgc cuauacgaca uaacgacggu 4500 uugccucugu uucaccuaca ugugcuguuc guacguaccc uaccccuguu guuuuacacc 4560 ucuacccaca ugcucuucuu ucuagggaca cgcaagcucg accauagguc ccuucacaca 4620 gaaaagagug acucaucccc aucaucugac ucuccucguu ggggaggggu uccucucgag 4680 gaguggacgg gcguaagccc uuuccguaaa cuggacuucc cccgggcuuc cuaauguggg 4740 uaaaguacgu uuuagcugua ccuuauacug aacgacagug augguuggcc ucaguaggau 4800 ccggaggugg auagucuuga gcccuggagg aaaccguugg agaguuacuc agaacuuuac 4860 auacuuggac gguguugaga cuggggacuc guuuaguuga agagcgaauu ucucgacccu 4920 ucgaccuggc uccgaguuga cuucucggac agagugaguu agacggagag guguaagagg 4980 uauacccuug auagccaacc cuacuagcua gauuugggau ggucccgucg uucccggaac 5040 gagguacuac uauuguauga ccguuguaag cucuugccag ugaaaaggua gcagucuaca 5100 gcaggccuuu aucaaguuca gggaagcgua ggagcucgua caguguaccu agaggcggga 5160 auacuguucg uuagugcccg uaguugggac caccaagggg aacuguuguc gugacgggag 5220 gaccaggggc uguuguagca ccaacuuccu caucuccggu cagauacguu ggugaggcaa 5280 cgguagugcg acagcuucuu gucuugagug aguaugucgg agauaggggu cccagcagga 5340 cacgaagcug ucuuuccacg gcaccucgag ggcugcuauc ccggggaggu caauguagga 5400 cggugagcuc accuggaaau augugacuuu cucaaggucc uccuggcuua ucgcgcguca 5460 gcucaguguc uguaguuccg acggcaacug cuagacgcac gcuucaccgc auuuccguuu 5520 aaacuccgcc uguggugccc ucccccugaa accagccgcu aacacccuca gaagucaaga 5580 gagcccccca agaaguacuc cgggaacuaa cgagagcgcc gcuaucacug gaguuaguag 5640 uaggacauau aggaagacgc acaugacaca cgacggagua caagcugugu ggcuucucau 5700 uccguccuga gaaccauuuc uccugacgcu aacaacucac cucggccguu ugggauccgg 5760 auaaggcuaa aucuuuuuug gucuggagag ugcuccagaa aagaugaucg acccaaaagg 5820 aguaagauag gucucggcgc cggcguaccu uuuaaacuuc guauaauagu gggaaccggu 5880 ccaguaggug uuugccacac uucucuacuu uaugacguuc uuugucacgg ccgcggaccc 5940 gguggcgcag gagccggacu aguucggaga ccucuacgag guccugguuc cuuucuccuc 6000 gcacgggaga cucuucaauu ggugucggua cuuggcgaag uuccgacggg accuccuccg 6060 auuaccccuc uaucuuuuca agucguuauc uagguuauag acguccaaag auugucguuc 6120 gguccuguuu uaugagaagu uccugcacuu guccuucgac ucacuacaga ccuuccucga 6180 gagcgacaau gaaguccaac ucguugcgua cggacaaagu ggguauucgg uuccucgcag 6240 gacccguguc cuucuagucg uccuacgucu gcuucugucc gcucgaaagg ucuacgauuc 6300 uucucuauua cuuuuuuauc uucgaaguga cucugcuaau cuuuaguugu acuuucuuua 6360 guuccuuuga aacuccguca uaaauggugg uuuuacguac guccucuagg gcguucucgu 6420 uuaguuccuc uaguucuucc ucgucgaaag uccuaggggc accuaagacg auucccuuuu 6480 acuucagucg ugugaaauau uuccucuuau ggugucucga ggucaccggu auuuucauaa 6540 guuuuuugag guccgaccgu cguaacguua ucacuccguc ugaaaguuau uccucuaguu 6600 uugguacuuc uuuaagcuua gaggguugua ggacgcauau aaacccuaaa cguaacuacu 6660 uugucacuga ggcggaguua agagguaaca guaccucaug acacuugagc ccugggacuc 6720 ccucgacaac cuaucccuuu uucuggagug ugaaccguuc gcguaccagg aucaggaccc 6780 ccgucgggcu ccggauaugg ccgauguggu aagucuucgu ggacuugagg ugccuuuuua 6840 gucuucgagu uugaaggacc auugaguucc gaugguucac uucgaacguc cuaaacucaa 6900 cuccuuuugu gucugaaggu acucaaaccc uugaugcucu cuuuucuguc ugucucaguu 6960 uagaugucgu auagagagug gaguccuuga ccuucuacau aaaauaguua uacuacauuu 7020 cagacuuuau augucgaaac cuuagcagga gacccuuuag cggugaccuc uauagggcaa 7080 aguuccgaca uuaagacucu ucuaggcguu cgaccaccga cacuucgccg ucguccucgg 7140 ugacccacuu cugacgggaa gucucgacgc ccucuaguaa cuacucacgg cccggguacu 7200 agggagacac gccgggagac accuacuuua gaauuucuuu gagaggugga aaagauucau 7260 cgcaugcguu ugggauccgg auaaggcuaa aucuuuuuug gucuggagag ugcuccagaa 7320 aagaugaucg acccaaaagg aguaagauag gucucgguac cggaagcugg gcuugaccgu 7380 cucucuucca auacuuaccc uaggcaguuc acucccgucu ggcuggcuac ucuugcuucu 7440 gcugucucca guagccgguu uuugcucuga agcauguaag gaacgggcgu gcaauuuauc 7500 gggauaggcu cgggauaaga uguguuauaa ggauccuuaa gcucgccaaa cccugcccaa 7560 guuuucugag gauggacacu ccuggcuuuu cccaauacgc uccaaaagac ucacgcagug 7620 uauaccuuac uagccuacac uacucacaca uuaucugggc cacucccaac aguaacucga 7680 cuggcucuac gucaauggcu aauuuccguu uccgagaugc uccaacucuc guuacuauug 7740 acuucuggaa gagugccccu acgcgugucg gcacggaguc uagucucacu cuagcuucua 7800 ggaucgucuc gccaaucccu cucguuagcc ggcucucugg aacggccguu acuagguagu 7860 acucacccgu aaacacuacc ccuucuaaga gugaaaguac cgucuguuac acccauacuu 7920 gcgacugugc cagcucccgc aagauaguga uagucuccag ugugccgcua cccuauagcc 7980 guugagacac aggcgucaca aguuaggacu accggaauga uagucucauc uuuugugccc 8040 aauguaguac uggucucucu gacggacgua cuagccucug uaaguacgag uuaaacguua 8100 gguuauggau cgacguaugg aucugcucca cuagccgugu uccugcagag agagugggcg 8160 gcuugacugg agagaguuug auaccccuga auugcaggac uuugaggauc cugccuugcc 8220 aauacuccac uagcggacgu accucgggua ucccaugcga caggacuacu acccuucucu 8280 guccucagga cuagggauac aguuacugug gauaaauuug ucguaggaga gucuuaaggg 8340 acagcugaga cugcgagcuc ggacgcaacu ucgggagaau ugauagauau acucgaagcc 8400 guguggggua uuucagagcc ugcguaagcc ggagaagucu uacaacccug uaggcuacca 8460 acuaccucga cugcccuaac uuuucuacgc uuccaauucg uucuuccagu ucuagggucu 8520 ggucagaugu cgcuagcugg agccccgaua guaccggcuu gacaaacacg ccucaaagca 8580 uuucuucgug uuuuccaccg gguugacgag guaguuagag ggcggugcug uggggaaggu 8640 ggugcgggcg gauacaccca uacagggccg acuuugggua ggggauuugu ugugacguag 8700 gacccgccga caccucaagu ugguccuuaa gcucggcggc ucugucaugu uggaacgucu 8760 guaguaacua cuguucagca cgagaggguu guucguacuc gauauaccac gaaccuacuu 8820 caguuuuugu cgacccaccg uccuuguuuu cuucgaguau gaggcuacca agugacucug 8880 guaccaauuu ggaagccucg aggaccuucu cuaacuacgu gugccgaagg cucuucuccu 8940 auucaacuaa ccuaauugug guuuccucuc ucucgacuuu aauugugguu cuuacaagag 9000 gaacuacugu aaguucaagu cuuggauggu ucaggaguga cucucauacc agcggcuacu 9060 cuaggagggc gugaaggggg ucuaguggua cugguacagg uuggugcuug aguguuucuc 9120 caacuaaucg ucuugcucug gaguuagacc uccucccgca cuacaagugu aguggcacuu 9180 guaucuaaag gucuuuaccu uguguuugua cucugugccu gaccaguuug uacagaagcu 9240 cgcugaccug uuggagaaac cgaagugguu gaauuagucu gcuugaguac uuaugaaggu 9300 ccuccgcuuu augauagacc gacuucuacc uugauuagac agcaagcugu ccuugccccu 9360 caauuaucua ccggguaugc aaauguggcc uaguaugccc cccuugcucc ccaaugcugu 9420 cuucgggacc uguuaucaau ggcacacacc uuauauguuc caucgaucuc uggacuuuua 9480 guuuguaguc uaguggccag ucccucuauu aguccaccag ugggauuaua aaggccuagc 9540 ucucaacgga agucuaggcc accucuccuc guucaugaca ucucuguucu cgucagucaa 9600 ggacugugca gagucaguua uaaagcgacu ccaaccaaac gggcaguucu gacuucucug 9660 uaccuacagu agugcagaga uacgaaugcc auucgcguac aagaaucucc cucaagguga 9720 auucuacaaa gaguucuucu auccgucucg aaagcgggag agcuuacuca aacagggcag 9780 ggagcuccuu cuagaccggu cucagaccuc acgguggucg cgucgccauc ucgaacugga 9840 uugagggaug cauccuauac aggagcccac gacgaacaga cgcguccgcu agucuuuagu 9900 ggaguagaug aggggacaag accucccggg agacgaccaa uuccggaugc ucgcauucaa 9960 guaauugaug cugccuccuu guuucgcccc ccgcuacggg ccggaugcag guuggaaacu 10020 cucggaucag uuuucauaga cgaccuucgg uuuccgguag ccucccaccg gccauaacua 10080 caaucuucua gaguaguagu uucccaaggg acuaggccgc ugaucgcggg accgaguuaa 10140 cuucaguuac cacgguauau ggagaccaua gcuggcccuc uaguaugaaa ggacagaguu 10200 ggaagggaau agcagccacc auagaggcag uuacaacaau uuccugggcc gccgguaguu 10260 gugguagugu uggggcaggc gcccgcugua ggacguucuc cagcggucuc ugauacaaug 10320 gcuaaugggu gagguuuugg gcgucgaguc ucgucaccag uucuugcacu ucuggcucga 10380 ucuguguaac cggucacuga auaaguuuac acuuggaaag aaaggaggaa auuacucgcu 10440 auagaagagc cguagagagg gccguauagu ucuguccuaa caagcguuca cgaggugcug 10500 aagauguuag uccucuuuuc gacggcucuc cccgaggcug agagaggagu uggccuacuu 10560 uuccuuacuc uaguuauucu acuacaaugu agaaacccga uggaccccuu ccucgggaga 10620 ccggucuaau cuguggucua cagaguguug gacgugguuc guuaaucggg uugucauagc 10680 cuuggucaga accccuuucg ucuagguacc ucagagucag ccggugggga aucuugacaa 10740 gccagcuuau ugugggucgg uaucuacgga uguacuccuc cuggugccuc uaaaggacgu 10800 uuggaagcgg ucgcucguac acuugguuca ccuguggcug uagugguguu gagaccccgg 10860 caagauggga auguauccga gccucugcgc ucuugcccgu caguuccaag cuuuuccuca 10920 cuuaaugcau caacucggcg aagacuuugg gcgucaagcu gaugauucuc gguaauuaac 10980 caaguaaggg cuccucaguc uacgcagggu aaacgacucg uuagauaauc gcagacaaug 11040 gcuguaguua ggaguucugg ugaugaguag auggcuucau ccccccccgu ugcggcaggu 11100 agcgaugucg acggcugaua ggcuguuuaa cucgucucag uuguugaaua uagucaacgu 11160 augaauaaau agacaguguu gucucgccaa cugguucaug ucagcuccua guuuuuugug 11220 acugcgugug aaggucucgu acuacuaaau acguguuucg gcaguauauc uggaguagaa 11280 ccucagagac guguggccuc ucuaccaugg caaccucaca guaguagugu aacucacguu 11340 agugacauau cuccuauaug ggcugcucgg uuagugcccc cugggccgaa ccugacuuca 11400 guucaaagga aguucaggag uccucgggaa agaaauguag uccguuguuc uagacggcca 11460 guuucuguuu gagcucggac acggagcgua cuuguagcag gcagaacggc cuaacccagg 11520 ccuccgcuaa ucacucgauc gcgugaugaa acaacguaag gcucaauagg cccgcagucu 11580 cugccuacag cugggauugc uacaagagag caccuggacc gacucggcuu aacuaggacu 11640 guuuaaccaa cucauauagc acguacacaa gcgaagugac cuuaccguag uacauaauua 11700 caguccgcac ucacacucgc agucucuacg uaagaaauuc uacgaucaca gauuuucuua 11760 gagucucuga ggcgauucaa guaagauaau agaccgguug gacaagcaac ugggagucug 11820 agcgcuucgu gauuacucga gauuuaugcc caagucgggg gggcggcucu gucagggguu 11880 gcguuuacgg cggcgucggc uuuauucuuc uacgacacgc uugucacgcg gcagcuagaa 11940 ucuuagucgg gaagugucgg cacuccaaca aaccuacggu ccuugcuugu uaauaccucu 12000 gcaacaguag accagaguaa uguaaucuaa ugccaagucg cuucaauuug aucaacugua 12060 augugcuaua gucgucacca ccucugucag acucgcucug gggaugcuaa accagggccu 12120 guacguccaa gaacucucgc uggaucuaug cgacuacuuu gccuauggcu ccgaguacgc 12180 guuccgcucu gcagggggag aaguccauua agcucuccug gaccuacagc gucaguaguu 12240 acgacuagua gggcgaguga gacacgaagu cuuguuuaug uccuuuaacu aaaagucucu 12300 cggcuucuaa uagugcccuc gacacauguu cauggagagg gauuuuaguc ucaacugucu 12360 caaguggagu cguuaccacu agccucugcc uugaccucca uaguggcggc gguacuaccg 12420 gcuacccuau cuacacacca uagucugcga gcaguugaua cuggugcacu guguuguccc 12480 uaauaggcau guucggggcc gucguaaccu agaagacgcg ccccguggga gaccauccga 12540 gaacuuaggc ccuucuaagc guaguaaacc cagacuggau ugacugggag cuaaaugucg 12600 gaugaaacua guuauagggg gcaaguucca ccugugagau accagacugc gucucccgcu 12660 gaaaacccug uucggaaggu ucaacuuagu uaugaaacuc uuguaguaac gaaacucugu 12720 agccaagcac uucuguuuac cugucgaaca gcacuuccac auagacugag uucugugacg 12780 augguguuaa cuucguaagu cuuucuucga cagggguacg cgguaguagc acagagagaa 12840 gagcugccuu ccgagguguc uuacgaagca ggauucguua gaguagcgug gucugugggg 12900 acagcuggaa cucuaccacc ucuuauaggg auuugauugu agggaacaag gggucuccug 12960 cugucacuuu acgauaaggg cugcucaucg cacguaguca uuuuccaccc cugaaaaguc 13020 uagaggcucg uaucgggaac uucagguugg caaggaagug auguaguguu uccaguagag 13080 ucuguuuccu uguguugacu cagaguaccg ccaucgacug uguuacuagu ugucaauguu 13140 cuuccgauag aguggggcuc acaagcuaga uguggccgua ucccggcgug acccaaagcc 13200 cuccucuagg aacguagagu agacccccua cuaguagagu gguuagcgaa uggucguaaa 13260 acucuuaggc cgguucaacu accuacagga ccuguacaac ugguuauugu agagucgaaa 13320 gaauagcuau agcagcaguc cuaaacugga caguaaauca cagucacguc uggcucuaca 13380 ggccuaacug ucguuugaac agucugaggg cgauaagcuu ccuagucugg auuuuaagua 13440 cuuuugguag uacagauggg agccuagaca caaguugguc cagcucggaa aauuccccua 13500 gcgguauuug ggaagauuug auuacugaca guucuccugu guccucaaug caauguuguu 13560 ggauuaaaug ugauuccuac gguaggauaa gggguuacuu cgccguuuuu ugugacgggg 13620 cgaagcucgg uuguaccaua uggggcaggc cccucuagau aagcggggau ggcuagcgua 13680 ugguuaguac ugagaucagu cgcuacucug uuguggaguc gugagaggag gucuccuacu 13740 ccguauugac uuaggaggga cuuccgagug uacagggugc gcugcguucu auauugcugu 13800 ucguugagcg ggauaauuga cacuaauuau uuuuuggcua auaagucaac gaacucccuc 13860 aaaguuaggc aagucacaua cuauccuuca aagacucuac caccccuaau cccccgugga 13920 ucucauacaa acaagcaaaa uacgcagca 13949

SEQ ID NO: 15

MAAPSAGSWS TFQHKELMAA DRGRRILGVC GMHPHHQETL KKNRWLAKQ LLLSELLEHL 60

LEKDIITLEM RELIQAKVGS FSQNVELLNL LPKRGPQAFD AFCEALRETK QGHLEDMLLT 120

TLSGLQHVLP PLSCDYDLSL PFPVCESCPL YKKLRLSTDT VEHSLDNKDG PVCLQVKPCT 180

PEFYQTHFQL AYRLQSRPRG LALVLSNVHF TGEKELEFRS GGDVDHSTLV TLFKLLGYDV 240

HVLCDQTAQE MQEKLQNFAQ LPAHRVTDSC IVALLSHGVE GAIYGVDGKL LQLQEVFQLF 300

DNANCPSLQN KPKMFFIQAC RGDETDRGVD QQDGKNHAGS PGCEESDAGK EKLPKMRLPT 360

RSDMICGYAC LKGTAAMRNT KRGSWYIEAL AQVFSERACD MHVADMLVKV NALIKDREGY 420

APGTEFHRCK EMSEYCSTLC RHLYLFPGHP PT 452

SEQ ID NO: 16

aaugcugcgu auucgacucu uuguauucuc ugauacaagu aucaguggga cauaaguaau 60 aacugaaaau acuggauaau aagcacucca guauacacuc cauuacagua gacgaauacg 120 caaacgaaua uucuauuuug cuaucuggga agugcccauu uaggaagagg aacgucaaga 180 gcgguucaug gagguuucag ucuugcuacc gagcaggcga ucgacgacgc guuguagagu 240 auuggcucgc aguaagggaa guccgcugag acagcgcccg cagguucugg ucucggcucc 300 uuaagcaguu ucuaaagaug gaaguucucg ucauaagaca gggcugguag ggcugccugc 360 uguaacgggu cagacccggg uacgacgaag uccgguagga cucgcuccuu auguguuucc 420 ggugacugua ucggguuagg uaggagaccu ugugagggug uggguugccc gaggagucuc 480 ucguagaucu acggcuaccc ccuccgagua agugucgcga cgggcgcaga cguuagucug 540 ggucgcugcu ccgcuuacgu acccggcgag cguagaggcu gagucccaac cccggacaga 600 agauacgucg ggagcgacga auguaguagc cgaccagucc uucuccucuc ugaucggcgc 660 acgucgucuu guauccaguc uuuaccgacu acuuggacuu gcguuagaag ccguggugcu 720 aguggguagg uuguuggcac gcagacgguu aguugcagca guuguugucg gagcgucacu 780 ccuugccuga acgacggugu gagaccgaua ugauggcaag uaguggaguc ucaguccugc 840 gcaagaagau acccgaguag gcagggacaa cgucaccuau agagccggac gauguagccc 900 acguccucua acuacucuac cucggccuga aggagucacu gggggccuag uagguccacu 960 uacuccagau gucacgugag ucucgggacc aaguugaccc uuugcugaag uucuggcggc 1020 uacuacucgg guacguccag acccgcacgu ccccuuaguu guugccuaua gacuguauag 1080 agagucuuug aggacgcuuc uuuccucgac aacacgaaua caaacggguu acguacgacu 1140 ucccgcugag acuccggacc uugucgaugg cgugacguug gacccacuac gggauaacgc 1200 uguuacaccg ggauccucgc uaccguccga uguagguucg ggcggucuug uggucccgua 1260 uacuccagag ucgggucugu ccagagcugc aguuguaccg gcgccaguuc cugaaacucc 1320 ggucaaguuu uggguuccga cgagguuaga gcgacuaggg ugcggggcga cuacagcgua 1380 gggcguggag acucgcgggu agauaaggac uccaacuguc gcugcuucuc gagccuccuu 1440 acauuugguu auucgaagug acggccauca aauccguaug ugugcgucaa ggcaauaggu 1500 agugugggca gggaagaaaa uacgacgaua auaaagucaa cgauucgaag gacuaaacua 1560 auuguuuuuu ggcaucugga ggaugcacuc cauaucgauc uuuaaccaag auagccaacu 1620 cucagaaaca ugauaaucgg uaccuccuga uaaacagauc gaaucuccgg cgcucucucg 1680 agcaggccug ccucgaccuc ggguucgcau uggaguaucg gucgaaucuc aggcugcuag 1740 ggcuaggcca uuaucgcggu cgccauuuug guuuuguagg guucgguacg gacucgugau 1800 uucuucuccu aguagagggg agagaagcgg augauaagcc gcguuuugcu cuguggagcc 1860 acccgcaucu cgucugagag guguucgcag agacgcgaac agagcugcca auggacuggu 1920 acugcuucuu ucuccgguua cggaaauucc ggcgccgacu ucgucgucgu aaucgucagu 1980 accuguaauu cuaccucgua gucgcggucc uagaucuccu agacuggcga cgauagggau 2040 ccuaucuuaa guuugaguua cgguaggacc uuuuguuguu ccucuaucgg uuccgacauu 2100 gacgacgauu ccucuaccuc gcccucuaca gcaccccccu uucgcggcgg ucgagcgagu 2160 ucagacagug ggaucuacuc agcaaauccc cgggacuucu cgaaagucuc aguaaaccgu 2220 aggcuauauu ccagucuugg accuuacuca aguucuuccg cgaccuuugg ucguaacacc 2280 uggacuccgg aucgggacaa aguaaauccc uuaaugccug auacaccgac agagaacugu 2340 ggaggaaauc cgaguaaccc aaacggaagu aaggguguac gcucgcggac cucugguuuc 2400 gguuuacguu ccucuguucc ugagaugagg gggaacgucu cagcuaguac gcuucuaccc 2460 uggacgcccu agguugguag aaccucuuuc ggacgcauca uuacuacuag gcacccuuac 2520 ucuaacguag cgacuuaguc cauuuucuac aagagggcug guguuaagca cccaccuucu 2580 agcgaauaau cagugacgag gguaaucagg gugaucugcc guaugaaggu aaggcgggaa 2640 auuaagggga cagucuguga guacgaggcu uuagugauug guaggaacag gugguucguu 2700 augcguauaa gucaucguga cguagagcgg gagggggaua guucgggguc gcgacgucua 2760 gaaguggugu auauauguac guaguugaug uacacuaaau cuuuuuuggu cugggaagug 2820 cccauuaucg gauugagugc uugcaaggag agcaaagcau acuauuccgg aauucguaac 2880 agcuaugcca gcaauacgca gccaagaaaa auccucucuc gucacgggga cgcucccuga 2940 cccucaggcu cgcuggaggg gggauacgac aacuccaggg aguuucagug cccuauucuc 3000 aguggcccau gaaggucacg uugcucgcag gcuuuagguu cuucugggag gugucgaagc 3060 ggcauuuuga gacgcugcgu uaauucggcc aagcucgccu acgagggucg aacuucuauc 3120 guuauaccug ccgagaucua gaccggaagc acuuuggagg guuaccuuga cauuguuauc 3180 uacgccgcca cuuucgaugu ggcgauuagc ccuugugggu cauguggcau ccgcuacuuu 3240 agaaggucua cgaucccucu uccccaccgg acuagcagua guccuugaau gggguacuaa 3300 uaggagcuug caacuaacuc aagcggagag ggcucggaac ucgugguccc guagccaggc 3360 gggcgggaca cuagagggca ucggcccgag ucgcuaguuc ggccgggccc agcccccccu 3420 gaccacguug uguuccccgc cgucaccugc gacuaauugu uuuuuggugg auauaucugg 3480 ggagugccag aaucugagac aacggucgac uguugguugu guguucugua gagagacuaa 3540 gucggcuggg cuagcuaagg aggggugggu uaaggauggu ugcgugagga guguucgagg 3600 ugguacgagu ccuaggucua gggaggcuaa cgauaguaag accauucaga ggagugugag 3660 cuggacaggc cacguuccuc cuguuggugu guuucuuagg gagaggaauu acuaagcacc 3720 cuaaacaaga gcucgauacc gcuguaaggg cuucuugaac agcauauggu cuugaugucg 3780 guguuaagga ggcucaaugg gggaggaccg aagcucucua ccauguauuu ggcuucucac 3840 cgucugugaa gguauggcac guccccgggg acagaucacg ggauguagga aguaccggag 3900 uuacuguguu gacagagagc ugccccuccu ccuaccgcuu ccaggccuua cuucaugggu 3960 ugggugcgac aguccgaucc gggaaguugu cugcugcucu cucaacuccu ucuguagccg 4020 augcaguuac agaggcguga uaggacgugu cccagcgggc aacucuaccg cuaugguugu 4080 uaggggcuga cguggucacg auagguaggu gcuaggcucc aaugacacgg gcaguucgag 4140 cuacaguacu cugcuuuagg guugauggga ggguaaucuc gcaccagcac guagccuguc 4200 uuuuaguggu uggcuacacu aacccgugag aagccgcucu uggaguauau augaguucaa 4260 cuucgaucga gagaucguaa guucgugugu ucucggagag aaaacuugcu uagguugccc 4320 uaucugcgac uuccugcacg ucaagggaua uaggagcccc uauagcuugg gcccaugacg 4380 gcuugggaua aguuguguac ccagagauca cucuagcaca guacgugcgg guagcuugaa 4440 caggaucaac uggacuuggg aaacaggggc ccuguaccgc cuauacgaca uaacgacggu 4500 uugccucugu uucaccuaca ugugcuguuc guacguaccc uaccccuguu guuuuacacc 4560 ucuacccaca ugcucuucuu ucuagggaca cgcaagcucg accauagguc ccuucacaca 4620 gaaaagagug acucaucccc aucaucugac ucuccucguu ggggaggggu uccucucgag 4680 gaguggacgg gcguaagccc uuuccguaaa cuggacuucc cccgggcuuc cuaauguggg 4740 uaaaguacgu uuuagcugua ccuuauacug aacgacagug augguuggcc ucaguaggau 4800 ccggaggugg auagucuuga gcccuggagg aaaccguugg agaguuacuc agaacuuuac 4860 auacuuggac gguguugaga cuggggacuc guuuaguuga agagcgaauu ucucgacccu 4920 ucgaccuggc uccgaguuga cuucucggac agagugaguu agacggagag guguaagagg 4980 uauacccuug auagccaacc cuacuagcua gauuugggau ggucccgucg uucccggaac 5040 gagguacuac uauuguauga ccguuguaag cucuugccag ugaaaaggua gcagucuaca 5100 gcaggccuuu aucaaguuca gggaagcgua ggagcucgua caguguaccu agaggcggga 5160 auacuguucg uuagugcccg uaguugggac caccaagggg aacuguuguc gugacgggag 5220 gaccaggggc uguuguagca ccaacuuccu caucuccggu cagauacguu ggugaggcaa 5280 cgguagugcg acagcuucuu gucuugagug aguaugucgg agauaggggu cccagcagga 5340 cacgaagcug ucuuuccacg gcaccucgag ggcugcuauc ccggggaggu caauguagga 5400 cggugagcuc accuggaaau augugacuuu cucaaggucc uccuggcuua ucgcgcguca 5460 gcucaguguc uguaguuccg acggcaacug cuagacgcac gcuucaccgc auuuccguuu 5520 aaacuccgcc uguggugccc ucccccugaa accagccgcu aacacccuca gaagucaaga 5580 gagcccccca agaaguacuc cgggaacuaa cgagagcgcc gcuaucacug gaguuaguag 5640 uaggacauau aggaagacgc acaugacaca cgacggagua caagcugugu ggcuucucau 5700 uccguccuga gaaccauuuc uccugacgcu aacaacucac cucggccguu ugggauccgg 5760 auaaggcuaa aucuuuuuug gucuggagag ugcuccagaa aagaugaucg acccaaaagg 5820 aguaagauag gucucggcgc cggcguaccg ccgcggcucg cgccccagaa ccagguggaa 5880 ggucguguuc cucgacuacc ggcgacuguc cccugcgucc uauaacccuc acacaccgua 5940 cguaggagua guaguccuuu gagauuuuuu cuuggcucac cacgaucggu uugucgacaa 6000 caacucgcuu aacaaucuug uagaagaccu cuuccuguag uaguggaacc uuuacucccu 6060 cgaguagguc cgguuucacc cgucaaaguc ggucuuacac cuugaggagu ugaacgacgg 6120 auucucccca gggguucgaa aacuacggaa gacacuucgu gacucccucu gguucguucc 6180 gguggaccuc cuauacaacg agugguggga aagacccgaa gucguacaug aggguggcaa 6240 cucgacacug augcugaacu cagagggaaa aggccacaca cucaggacag gggaaauguu 6300 cuucgaggcg gacagcuguc uaugacaccu ugugagggau cuguuauuuc uaccaggaca 6360 gacggaaguc cacuucggaa cgugaggacu uaaaauaguu ugugugaagg ucgaccguau 6420 auccaacguc agagccggag caccggaucg ugaccacaac ucguuacacg ugaagugacc 6480 ucucuuucuu gaccuuaaag cgagaccucc ccuacaccug gugucaugag aucaguggga 6540 gaaguucgaa aacccgauac ugcagguaca agauacacug gucugacgug uccuuuacgu 6600 ucucuuugac gucuuaaaac gugucaaugg acguguggcu cagugccuga ggacguagca 6660 ccgugaggag agcguaccac accucccgcg guagauacca caccuacccu uugacgaggu 6720 cgagguucuc caaaaagucg agaaacuguu gcgguugacg gguucggaug ucuuguuugg 6780 uuuuuacaag aaguaggucc ggacggcacc ucuacucuga cuagcacccc aacugguugu 6840 ucuaccuuuc uuggugcguc cuaggggacc cacgcuccuc ucacuacggc cauuucuuuu 6900 caacggcuuc uacucugacg ggugcgcgag ucuguacuau acgccgauac ggacggaguu 6960 ucccugacgg cgguacgccu ugugguuugc uccaaggacc auguagcucc gagaacgagu 7020 ucacaaaaga cucgcccgaa cacuauacgu gcaccggcug uacgaccaau uccacuugcg 7080 ugaauaguuc cuagcccuuc caauacgagg accgugucuu aagguggcca cguuccucua 7140 cagacuuaug acgucgugag acacggcggu ggagauggac aaggguccug ugggagggug 7200 uacugcaugc guuugggauc cggauaaggc uaaaucuuuu uuggucugga gagugcucca 7260 gaaaagauga ucgacccaaa aggaguaaga uaggucucgg uaccggaagc ugggcuugac 7320 cgucucucuu ccaauacuua cccuaggcag uucacucccg ucuggcuggc uacucuugcu 7380 ucugcugucu ccaguagccg guuuuugcuc ugaagcaugu aaggaacggg cgugcaauuu 7440 aucgggauag gcucgggaua agauguguua uaaggauccu uaagcucgcc aaacccugcc 7500 caaguuuucu gaggauggac acuccuggcu uuucccaaua cgcuccaaaa gacucacgca 7560 guguauaccu uacuagccua cacuacucac acauuaucug ggccacuccc aacaguaacu 7620 cgacuggcuc uacgucaaug gcuaauuucc guuuccgaga ugcuccaacu cucguuacua 7680 uugacuucug gaagagugcc ccuacgcgug ucggcacgga gucuagucuc acucuagcuu 7740 cuaggaucgu cucgccaauc ccucucguua gccggcucuc uggaacggcc guuacuaggu 7800 aguacucacc cguaaacacu accccuucua agagugaaag uaccgucugu uacacccaua 7860 cuugcgacug ugccagcucc cgcaagauag ugauagucuc cagugugccg cuacccuaua 7920 gccguugaga cacaggcguc acaaguuagg acuaccggaa ugauagucuc aucuuuugug 7980 cccaauguag uacuggucuc ucugacggac guacuagccu cuguaaguac gaguuaaacg 8040 uuagguuaug gaucgacgua uggaucugcu ccacuagccg uguuccugca gagagagugg 8100 gcggcuugac uggagagagu uugauacccc ugaauugcag gacuuugagg auccugccuu 8160 gccaauacuc cacuagcgga cguaccucgg guaucccaug cgacaggacu acuacccuuc 8220 ucuguccuca ggacuaggga uacaguuacu guggauaaau uugucguagg agagucuuaa 8280 gggacagcug agacugcgag cucggacgca acuucgggag aauugauaga uauacucgaa 8340 gccguguggg guauuucaga gccugcguaa gccggagaag ucuuacaacc cuguaggcua 8400 ccaacuaccu cgacugcccu aacuuuucua cgcuuccaau ucguucuucc aguucuaggg 8460 ucuggucaga ugucgcuagc uggagccccg auaguaccgg cuugacaaac acgccucaaa 8520 gcauuucuuc guguuuucca ccggguugac gagguaguua gagggcggug cuguggggaa 8580 gguggugcgg gcggauacac ccauacaggg ccgacuuugg guaggggauu uguugugacg 8640 uaggacccgc cgacaccuca aguugguccu uaagcucggc ggcucuguca uguuggaacg 8700 ucuguaguaa cuacuguuca gcacgagagg guuguucgua cucgauauac cacgaaccua 8760 cuucaguuuu ugucgaccca ccguccuugu uuucuucgag uaugaggcua ccaagugacu 8820 cugguaccaa uuuggaagcc ucgaggaccu ucucuaacua cgugugccga aggcucuucu 8880 ccuauucaac uaaccuaauu gugguuuccu cucucucgac uuuaauugug guucuuacaa 8940 gaggaacuac uguaaguuca agucuuggau gguucaggag ugacucucau accagcggcu 9000 acucuaggag ggcgugaagg gggucuagug guacugguac agguuggugc uugaguguuu 9060 cuccaacuaa ucgucuugcu cuggaguuag accuccuccc gcacuacaag uguaguggca 9120 cuuguaucua aaggucuuua ccuuguguuu guacucugug ccugaccagu uuguacagaa 9180 gcucgcugac cuguuggaga aaccgaagug guugaauuag ucugcuugag uacuuaugaa 9240 gguccuccgc uuuaugauag accgacuucu accuugauua gacagcaagc uguccuugcc 9300 ccucaauuau cuaccgggua ugcaaaugug gccuaguaug ccccccuugc uccccaaugc 9360 ugucuucggg accuguuauc aauggcacac accuuauaug uuccaucgau cucuggacuu 9420 uuaguuugua gucuaguggc cagucccucu auuaguccac cagugggauu auaaaggccu 9480 agcucucaac ggaagucuag gccaccucuc cucguucaug acaucucugu ucucgucagu 9540 caaggacugu gcagagucag uuauaaagcg acuccaacca aacgggcagu ucugacuucu 9600 cuguaccuac aguagugcag agauacgaau gccauucgcg uacaagaauc ucccucaagg 9660 ugaauucuac aaagaguucu ucuauccguc ucgaaagcgg gagagcuuac ucaaacaggg 9720 cagggagcuc cuucuagacc ggucucagac cucacggugg ucgcgucgcc aucucgaacu 9780 ggauugaggg augcauccua uacaggagcc cacgacgaac agacgcgucc gcuagucuuu 9840 aguggaguag augaggggac aagaccuccc gggagacgac caauuccgga ugcucgcauu 9900 caaguaauug augcugccuc cuuguuucgc cccccgcuac gggccggaug cagguuggaa 9960 acucucggau caguuuucau agacgaccuu cgguuuccgg uagccuccca ccggccauaa 10020 cuacaaucuu cuagaguagu aguuucccaa gggacuaggc cgcugaucgc gggaccgagu 10080 uaacuucagu uaccacggua uauggagacc auagcuggcc cucuaguaug aaaggacaga 10140 guuggaaggg aauagcagcc accauagagg caguuacaac aauuuccugg gccgccggua 10200 guugugguag uguuggggca ggcgcccgcu guaggacguu cuccagcggu cucugauaca 10260 auggcuaaug ggugagguuu ugggcgucga gucucgucac caguucuugc acuucuggcu 10320 cgaucugugu aaccggucac ugaauaaguu uacacuugga aagaaaggag gaaauuacuc 10380 gcuauagaag agccguagag agggccguau aguucugucc uaacaagcgu ucacgaggug 10440 cugaagaugu uaguccucuu uucgacggcu cuccccgagg cugagagagg aguuggccua 10500 cuuuuccuua cucuaguuau ucuacuacaa uguagaaacc cgauggaccc cuuccucggg 10560 agaccggucu aaucuguggu cuacagagug uuggacgugg uucguuaauc ggguugucau 10620 agccuugguc agaaccccuu ucgucuaggu accucagagu cagccggugg ggaaucuuga 10680 caagccagcu uauugugggu cgguaucuac ggauguacuc cuccuggugc cucuaaagga 10740 cguuuggaag cggucgcucg uacacuuggu ucaccugugg cuguaguggu guugagaccc 10800 cggcaagaug ggaauguauc cgagccucug cgcucuugcc cgucaguucc aagcuuuucc 10860 ucacuuaaug caucaacucg gcgaagacuu ugggcgucaa gcugaugauu cucgguaauu 10920 aaccaaguaa gggcuccuca gucuacgcag gguaaacgac ucguuagaua aucgcagaca 10980 auggcuguag uuaggaguuc uggugaugag uagauggcuu cauccccccc cguugcggca 11040 gguagcgaug ucgacggcug auaggcuguu uaacucgucu caguuguuga auauagucaa 11100 cguaugaaua aauagacagu guugucucgc caacugguuc augucagcuc cuaguuuuuu 11160 gugacugcgu gugaaggucu cguacuacua aauacguguu ucggcaguau aucuggagua 11220 gaaccucaga gacguguggc cucucuacca uggcaaccuc acaguaguag uguaacucac 11280 guuagugaca uaucuccuau augggcugcu cgguuagugc ccccugggcc gaaccugacu 11340 ucaguucaaa ggaaguucag gaguccucgg gaaagaaaug uaguccguug uucuagacgg 11400 ccaguuucug uuugagcucg gacacggagc guacuuguag caggcagaac ggccuaaccc 11460 aggccuccgc uaaucacucg aucgcgugau gaaacaacgu aaggcucaau aggcccgcag 11520 ucucugccua cagcugggau ugcuacaaga gagcaccugg accgacucgg cuuaacuagg 11580 acuguuuaac caacucauau agcacguaca caagcgaagu gaccuuaccg uaguacauaa 11640 uuacaguccg cacucacacu cgcagucucu acguaagaaa uucuacgauc acagauuuuc 11700 uuagagucuc ugaggcgauu caaguaagau aauagaccgg uuggacaagc aacugggagu 11760 cugagcgcuu cgugauuacu cgagauuuau gcccaagucg ggggggcggc ucugucaggg 11820 guugcguuua cggcggcguc ggcuuuauuc uucuacgaca cgcuugucac gcggcagcua 11880 gaaucuuagu cgggaagugu cggcacucca acaaaccuac gguccuugcu uguuaauacc 11940 ucugcaacag uagaccagag uaauguaauc uaaugccaag ucgcuucaau uugaucaacu 12000 guaaugugcu auagucguca ccaccucugu cagacucgcu cuggggaugc uaaaccaggg 12060 ccuguacguc caagaacucu cgcuggaucu augcgacuac uuugccuaug gcuccgagua 12120 cgcguuccgc ucugcagggg gagaagucca uuaagcucuc cuggaccuac agcgucagua 12180 guuacgacua guagggcgag ugagacacga agucuuguuu auguccuuua acuaaaaguc 12240 ucucggcuuc uaauagugcc cucgacacau guucauggag agggauuuua gucucaacug 12300 ucucaagugg agucguuacc acuagccucu gccuugaccu ccauaguggc ggcgguacua 12360 ccggcuaccc uaucuacaca ccauagucug cgagcaguug auacuggugc acuguguugu 12420 cccuaauagg cauguucggg gccgucguaa ccuagaagac gcgccccgug ggagaccauc 12480 cgagaacuua ggcccuucua agcguaguaa acccagacug gauugacugg gagcuaaaug 12540 ucggaugaaa cuaguuauag ggggcaaguu ccaccuguga gauaccagac ugcgucuccc 12600 gcugaaaacc cuguucggaa gguucaacuu aguuaugaaa cucuuguagu aacgaaacuc 12660 uguagccaag cacuucuguu uaccugucga acagcacuuc cacauagacu gaguucugug 12720 acgauggugu uaacuucgua agucuuucuu cgacaggggu acgcgguagu agcacagaga 12780 gaagagcugc cuuccgaggu gucuuacgaa gcaggauucg uuagaguagc guggucugug 12840 gggacagcug gaacucuacc accucuuaua gggauuugau uguagggaac aaggggucuc 12900 cugcugucac uuuacgauaa gggcugcuca ucgcacguag ucauuuucca ccccugaaaa 12960 gucuagaggc ucguaucggg aacuucaggu uggcaaggaa gugauguagu guuuccagua 13020 gagucuguuu ccuuguguug acucagagua ccgccaucga cuguguuacu aguugucaau 13080 guucuuccga uagagugggg cucacaagcu agauguggcc guaucccggc gugacccaaa 13140 gcccuccucu aggaacguag aguagacccc cuacuaguag agugguuagc gaauggucgu 13200 aaaacucuua ggccgguuca acuaccuaca ggaccuguac aacugguuau uguagagucg 13260 aaagaauagc uauagcagca guccuaaacu ggacaguaaa ucacagucac gucuggcucu 13320 acaggccuaa cugucguuug aacagucuga gggcgauaag cuuccuaguc uggauuuuaa 13380 guacuuuugg uaguacagau gggagccuag acacaaguug guccagcucg gaaaauuccc 13440 cuagcgguau uugggaagau uugauuacug acaguucucc uguguccuca augcaauguu 13500 guuggauuaa augugauucc uacgguagga uaagggguua cuucgccguu uuuugugacg 13560 gggcgaagcu cgguuguacc auauggggca ggccccucua gauaagcggg gauggcuagc 13620 guaugguuag uacugagauc agucgcuacu cuguugugga gucgugagag gaggucuccu 13680 acuccguauu gacuuaggag ggacuuccga guguacaggg ugcgcugcgu ucuauauugc 13740 uguucguuga gcgggauaau ugacacuaau uauuuuuugg cuaauaaguc aacgaacucc 13800 cucaaaguua ggcaagucac auacuauccu ucaaagacuc uaccaccccu aaucccccgu 13860 ggaucucaua caaacaagca aaauacgcag ca 13892

SEQ ID NO: 17

MDCE NGSS LRDECITNLL VFGFLQSCSD NSFRRELDAL GHELPVLAPQ WEGYDELQTD 60 GNRSSHSRLG RIEADSESQE DIIRNIARHL AQVGDSMDRS IPPGLVNGLA LQLRNTSRSE 120 EDRNRDLATA LEQLLQAYPR DMEKEKTMLV LALLLAKKVA SHTPSLLRDV FHTT FINQ 180 NLRTYVRSLA RNGMD 195 SEQ ID NO: li

aaugcugcgu auucgacucu uuguauucuc ugauacaagu aucaguggga cauaaguaau 60 aacugaaaau acuggauaau aagcacucca guauacacuc cauuacagua gacgaauacg 120 caaacgaaua uucuauuuug cuaucuggga agugcccauu uaggaagagg aacgucaaga 180 gcgguucaug gagguuucag ucuugcuacc gagcaggcga ucgacgacgc guuguagagu 240 auuggcucgc aguaagggaa guccgcugag acagcgcccg cagguucugg ucucggcucc 300 uuaagcaguu ucuaaagaug gaaguucucg ucauaagaca gggcugguag ggcugccugc 360 uguaacgggu cagacccggg uacgacgaag uccgguagga cucgcuccuu auguguuucc 420 ggugacugua ucggguuagg uaggagaccu ugugagggug uggguugccc gaggagucuc 480 ucguagaucu acggcuaccc ccuccgagua agugucgcga cgggcgcaga cguuagucug 540 ggucgcugcu ccgcuuacgu acccggcgag cguagaggcu gagucccaac cccggacaga 600 agauacgucg ggagcgacga auguaguagc cgaccagucc uucuccucuc ugaucggcgc 660 acgucgucuu guauccaguc uuuaccgacu acuuggacuu gcguuagaag ccguggugcu 720 aguggguagg uuguuggcac gcagacgguu aguugcagca guuguugucg gagcgucacu 780 ccuugccuga acgacggugu gagaccgaua ugauggcaag uaguggaguc ucaguccugc 840 gcaagaagau acccgaguag gcagggacaa cgucaccuau agagccggac gauguagccc 900 acguccucua acuacucuac cucggccuga aggagucacu gggggccuag uagguccacu 960 uacuccagau gucacgugag ucucgggacc aaguugaccc uuugcugaag uucuggcggc 1020 uacuacucgg guacguccag acccgcacgu ccccuuaguu guugccuaua gacuguauag 1080 agagucuuug aggacgcuuc uuuccucgac aacacgaaua caaacggguu acguacgacu 1140 ucccgcugag acuccggacc uugucgaugg cgugacguug gacccacuac gggauaacgc 1200 uguuacaccg ggauccucgc uaccguccga uguagguucg ggcggucuug uggucccgua 1260 uacuccagag ucgggucugu ccagagcugc aguuguaccg gcgccaguuc cugaaacucc 1320 ggucaaguuu uggguuccga cgagguuaga gcgacuaggg ugcggggcga cuacagcgua 1380 gggcguggag acucgcgggu agauaaggac uccaacuguc gcugcuucuc gagccuccuu 1440 acauuugguu auucgaagug acggccauca aauccguaug ugugcgucaa ggcaauaggu 1500 agugugggca gggaagaaaa uacgacgaua auaaagucaa cgauucgaag gacuaaacua 1560 auuguuuuuu ggcaucugga ggaugcacuc cauaucgauc uuuaaccaag auagccaacu 1620 cucagaaaca ugauaaucgg uaccuccuga uaaacagauc gaaucuccgg cgcucucucg 1680 agcaggccug ccucgaccuc ggguucgcau uggaguaucg gucgaaucuc aggcugcuag 1740 ggcuaggcca uuaucgcggu cgccauuuug guuuuguagg guucgguacg gacucgugau 1800 uucuucuccu aguagagggg agagaagcgg augauaagcc gcguuuugcu cuguggagcc 1860 acccgcaucu cgucugagag guguucgcag agacgcgaac agagcugcca auggacuggu 1920 acugcuucuu ucuccgguua cggaaauucc ggcgccgacu ucgucgucgu aaucgucagu 1980 accuguaauu cuaccucgua gucgcggucc uagaucuccu agacuggcga cgauagggau 2040 ccuaucuuaa guuugaguua cgguaggacc uuuuguuguu ccucuaucgg uuccgacauu 2100 gacgacgauu ccucuaccuc gcccucuaca gcaccccccu uucgcggcgg ucgagcgagu 2160 ucagacagug ggaucuacuc agcaaauccc cgggacuucu cgaaagucuc aguaaaccgu 2220 aggcuauauu ccagucuugg accuuacuca aguucuuccg cgaccuuugg ucguaacacc 2280 uggacuccgg aucgggacaa aguaaauccc uuaaugccug auacaccgac agagaacugu 2340 ggaggaaauc cgaguaaccc aaacggaagu aaggguguac gcucgcggac cucugguuuc 2400 gguuuacguu ccucuguucc ugagaugagg gggaacgucu cagcuaguac gcuucuaccc 2460 uggacgcccu agguugguag aaccucuuuc ggacgcauca uuacuacuag gcacccuuac 2520 ucuaacguag cgacuuaguc cauuuucuac aagagggcug guguuaagca cccaccuucu 2580 agcgaauaau cagugacgag gguaaucagg gugaucugcc guaugaaggu aaggcgggaa 2640 auuaagggga cagucuguga guacgaggcu uuagugauug guaggaacag gugguucguu 2700 augcguauaa gucaucguga cguagagcgg gagggggaua guucgggguc gcgacgucua 2760 gaaguggugu auauauguac guaguugaug uacacuaaau cuuuuuuggu cugggaagug 2820 cccauuaucg gauugagugc uugcaaggag agcaaagcau acuauuccgg aauucguaac 2880 agcuaugcca gcaauacgca gccaagaaaa auccucucuc gucacgggga cgcucccuga 2940 cccucaggcu cgcuggaggg gggauacgac aacuccaggg aguuucagug cccuauucuc 3000 aguggcccau gaaggucacg uugcucgcag gcuuuagguu cuucugggag gugucgaagc 3060 ggcauuuuga gacgcugcgu uaauucggcc aagcucgccu acgagggucg aacuucuauc 3120 guuauaccug ccgagaucua gaccggaagc acuuuggagg guuaccuuga cauuguuauc 3180 uacgccgcca cuuucgaugu ggcgauuagc ccuugugggu cauguggcau ccgcuacuuu 3240 agaaggucua cgaucccucu uccccaccgg acuagcagua guccuugaau gggguacuaa 3300 uaggagcuug caacuaacuc aagcggagag ggcucggaac ucgugguccc guagccaggc 3360 gggcgggaca cuagagggca ucggcccgag ucgcuaguuc ggccgggccc agcccccccu 3420 gaccacguug uguuccccgc cgucaccugc gacuaauugu uuuuuggugg auauaucugg 3480 ggagugccag aaucugagac aacggucgac uguugguugu guguucugua gagagacuaa 3540 gucggcuggg cuagcuaagg aggggugggu uaaggauggu ugcgugagga guguucgagg 3600 ugguacgagu ccuaggucua gggaggcuaa cgauaguaag accauucaga ggagugugag 3660 cuggacaggc cacguuccuc cuguuggugu guuucuuagg gagaggaauu acuaagcacc 3720 cuaaacaaga gcucgauacc gcuguaaggg cuucuugaac agcauauggu cuugaugucg 3780 guguuaagga ggcucaaugg gggaggaccg aagcucucua ccauguauuu ggcuucucac 3840 cgucugugaa gguauggcac guccccgggg acagaucacg ggauguagga aguaccggag 3900 uuacuguguu gacagagagc ugccccuccu ccuaccgcuu ccaggccuua cuucaugggu 3960 ugggugcgac aguccgaucc gggaaguugu cugcugcucu cucaacuccu ucuguagccg 4020 augcaguuac agaggcguga uaggacgugu cccagcgggc aacucuaccg cuaugguugu 4080 uaggggcuga cguggucacg auagguaggu gcuaggcucc aaugacacgg gcaguucgag 4140 cuacaguacu cugcuuuagg guugauggga ggguaaucuc gcaccagcac guagccuguc 4200 uuuuaguggu uggcuacacu aacccgugag aagccgcucu uggaguauau augaguucaa 4260 cuucgaucga gagaucguaa guucgugugu ucucggagag aaaacuugcu uagguugccc 4320 uaucugcgac uuccugcacg ucaagggaua uaggagcccc uauagcuugg gcccaugacg 4380 gcuugggaua aguuguguac ccagagauca cucuagcaca guacgugcgg guagcuugaa 4440 caggaucaac uggacuuggg aaacaggggc ccuguaccgc cuauacgaca uaacgacggu 4500 uugccucugu uucaccuaca ugugcuguuc guacguaccc uaccccuguu guuuuacacc 4560 ucuacccaca ugcucuucuu ucuagggaca cgcaagcucg accauagguc ccuucacaca 4620 gaaaagagug acucaucccc aucaucugac ucuccucguu ggggaggggu uccucucgag 4680 gaguggacgg gcguaagccc uuuccguaaa cuggacuucc cccgggcuuc cuaauguggg 4740 uaaaguacgu uuuagcugua ccuuauacug aacgacagug augguuggcc ucaguaggau 4800 ccggaggugg auagucuuga gcccuggagg aaaccguugg agaguuacuc agaacuuuac 4860 auacuuggac gguguugaga cuggggacuc guuuaguuga agagcgaauu ucucgacccu 4920 ucgaccuggc uccgaguuga cuucucggac agagugaguu agacggagag guguaagagg 4980 uauacccuug auagccaacc cuacuagcua gauuugggau ggucccgucg uucccggaac 5040 gagguacuac uauuguauga ccguuguaag cucuugccag ugaaaaggua gcagucuaca 5100 gcaggccuuu aucaaguuca gggaagcgua ggagcucgua caguguaccu agaggcggga 5160 auacuguucg uuagugcccg uaguugggac caccaagggg aacuguuguc gugacgggag 5220 gaccaggggc uguuguagca ccaacuuccu caucuccggu cagauacguu ggugaggcaa 5280 cgguagugcg acagcuucuu gucuugagug aguaugucgg agauaggggu cccagcagga 5340 cacgaagcug ucuuuccacg gcaccucgag ggcugcuauc ccggggaggu caauguagga 5400 cggugagcuc accuggaaau augugacuuu cucaaggucc uccuggcuua ucgcgcguca 5460 gcucaguguc uguaguuccg acggcaacug cuagacgcac gcuucaccgc auuuccguuu 5520 aaacuccgcc uguggugccc ucccccugaa accagccgcu aacacccuca gaagucaaga 5580 gagcccccca agaaguacuc cgggaacuaa cgagagcgcc gcuaucacug gaguuaguag 5640 uaggacauau aggaagacgc acaugacaca cgacggagua caagcugugu ggcuucucau 5700 uccguccuga gaaccauuuc uccugacgcu aacaacucac cucggccguu ugggauccgg 5760 auaaggcuaa aucuuuuuug gucuggagag ugcuccagaa aagaugaucg acccaaaagg 5820 aguaagauag gucucggcgc cggcguaccu gacacuccag uuguugccaa ggucggaguc 5880 ccuacucacg uaguguuugg augaccacaa accgaaggag guuucgacaa gacuguuguc 5940 gaaggcgucu cucgaccugc gugacccggu gcucgacggu cacgaccgag gggucacccu 6000 cccgaugcua cucgacgucu gacuaccguu ggcgucgucg gugagggcga acccuucuua 6060 ucuccgucua agacuuucag uucuucugua guaggccuua uaacgguccg uggagcgggu 6120 ccagccccug ucguaccugg caucguaggg aggcccggac cacuugccgg accgggacgu 6180 cgaguccuug uggucggcca gccuccuccu ggccuugucc cuggaccggu gacgggaccu 6240 cgucgacgac guccggaugg gaucucugua ccucuuccuc uucugguacg accacgaccg 6300 ggacgacgac cgguucuucc accggucagu gugcggcagg aacgaggcac uacagaaagu 6360 guguugucac uuaaaauaau uggucuugga ugcguggaug cacuccucga aucggucuuu 6420 acccuaccug acugcaugcg uuugggaucc ggauaaggcu aaaucuuuuu uggucuggag 6480 agugcuccag aaaagaugau cgacccaaaa ggaguaagau aggucucggu accggaagcu 6540 gggcuugacc gucucucuuc caauacuuac ccuaggcagu ucacucccgu cuggcuggcu 6600 acucuugcuu cugcugucuc caguagccgg uuuuugcucu gaagcaugua aggaacgggc 6660 gugcaauuua ucgggauagg cucgggauaa gauguguuau aaggauccuu aagcucgcca 6720 aacccugccc aaguuuucug aggauggaca cuccuggcuu uucccaauac gcuccaaaag 6780 acucacgcag uguauaccuu acuagccuac acuacucaca cauuaucugg gccacuccca 6840 acaguaacuc gacuggcucu acgucaaugg cuaauuuccg uuuccgagau gcuccaacuc 6900 ucguuacuau ugacuucugg aagagugccc cuacgcgugu cggcacggag ucuagucuca 6960 cucuagcuuc uaggaucguc ucgccaaucc cucucguuag ccggcucucu ggaacggccg 7020 uuacuaggua guacucaccc guaaacacua ccccuucuaa gagugaaagu accgucuguu 7080 acacccauac uugcgacugu gccagcuccc gcaagauagu gauagucucc agugugccgc 7140 uacccuauag ccguugagac acaggcguca caaguuagga cuaccggaau gauagucuca 7200 ucuuuugugc ccaauguagu acuggucucu cugacggacg uacuagccuc uguaaguacg 7260 aguuaaacgu uagguuaugg aucgacguau ggaucugcuc cacuagccgu guuccugcag 7320 agagaguggg cggcuugacu ggagagaguu ugauaccccu gaauugcagg acuuugagga 7380 uccugccuug ccaauacucc acuagcggac guaccucggg uaucccaugc gacaggacua 7440 cuacccuucu cuguccucag gacuagggau acaguuacug uggauaaauu ugucguagga 7500 gagucuuaag ggacagcuga gacugcgagc ucggacgcaa cuucgggaga auugauagau 7560 auacucgaag ccgugugggg uauuucagag ccugcguaag ccggagaagu cuuacaaccc 7620 uguaggcuac caacuaccuc gacugcccua acuuuucuac gcuuccaauu cguucuucca 7680 guucuagggu cuggucagau gucgcuagcu ggagccccga uaguaccggc uugacaaaca 7740 cgccucaaag cauuucuucg uguuuuccac cggguugacg agguaguuag agggcggugc 7800 uguggggaag guggugcggg cggauacacc cauacagggc cgacuuuggg uaggggauuu 7860 guugugacgu aggacccgcc gacaccucaa guugguccuu aagcucggcg gcucugucau 7920 guuggaacgu cuguaguaac uacuguucag cacgagaggg uuguucguac ucgauauacc 7980 acgaaccuac uucaguuuuu gucgacccac cguccuuguu uucuucgagu augaggcuac 8040 caagugacuc ugguaccaau uuggaagccu cgaggaccuu cucuaacuac gugugccgaa 8100 ggcucuucuc cuauucaacu aaccuaauug ugguuuccuc ucucucgacu uuaauugugg 8160 uucuuacaag aggaacuacu guaaguucaa gucuuggaug guucaggagu gacucucaua 8220 ccagcggcua cucuaggagg gcgugaaggg ggucuagugg uacugguaca gguuggugcu 8280 ugaguguuuc uccaacuaau cgucuugcuc uggaguuaga ccuccucccg cacuacaagu 8340 guaguggcac uuguaucuaa aggucuuuac cuuguguuug uacucugugc cugaccaguu 8400 uguacagaag cucgcugacc uguuggagaa accgaagugg uugaauuagu cugcuugagu 8460 acuuaugaag guccuccgcu uuaugauaga ccgacuucua ccuugauuag acagcaagcu 8520 guccuugccc cucaauuauc uaccggguau gcaaaugugg ccuaguaugc cccccuugcu 8580 ccccaaugcu gucuucggga ccuguuauca auggcacaca ccuuauaugu uccaucgauc 8640 ucuggacuuu uaguuuguag ucuaguggcc agucccucua uuaguccacc agugggauua 8700 uaaaggccua gcucucaacg gaagucuagg ccaccucucc ucguucauga caucucuguu 8760 cucgucaguc aaggacugug cagagucagu uauaaagcga cuccaaccaa acgggcaguu 8820 cugacuucuc uguaccuaca guagugcaga gauacgaaug ccauucgcgu acaagaaucu 8880 cccucaaggu gaauucuaca aagaguucuu cuauccgucu cgaaagcggg agagcuuacu 8940 caaacagggc agggagcucc uucuagaccg gucucagacc ucacgguggu cgcgucgcca 9000 ucucgaacug gauugaggga ugcauccuau acaggagccc acgacgaaca gacgcguccg 9060 cuagucuuua guggaguaga ugaggggaca agaccucccg ggagacgacc aauuccggau 9120 gcucgcauuc aaguaauuga ugcugccucc uuguuucgcc ccccgcuacg ggccggaugc 9180 agguuggaaa cucucggauc aguuuucaua gacgaccuuc gguuuccggu agccucccac 9240 cggccauaac uacaaucuuc uagaguagua guuucccaag ggacuaggcc gcugaucgcg 9300 ggaccgaguu aacuucaguu accacgguau auggagacca uagcuggccc ucuaguauga 9360 aaggacagag uuggaaggga auagcagcca ccauagaggc aguuacaaca auuuccuggg 9420 ccgccgguag uugugguagu guuggggcag gcgcccgcug uaggacguuc uccagcgguc 9480 ucugauacaa uggcuaaugg gugagguuuu gggcgucgag ucucgucacc aguucuugca 9540 cuucuggcuc gaucugugua accggucacu gaauaaguuu acacuuggaa agaaaggagg 9600 aaauuacucg cuauagaaga gccguagaga gggccguaua guucuguccu aacaagcguu 9660 cacgaggugc ugaagauguu aguccucuuu ucgacggcuc uccccgaggc ugagagagga 9720 guuggccuac uuuuccuuac ucuaguuauu cuacuacaau guagaaaccc gauggacccc 9780 uuccucggga gaccggucua aucugugguc uacagagugu uggacguggu ucguuaaucg 9840 gguugucaua gccuugguca gaaccccuuu cgucuaggua ccucagaguc agccgguggg 9900 gaaucuugac aagccagcuu auuguggguc gguaucuacg gauguacucc uccuggugcc 9960 ucuaaaggac guuuggaagc ggucgcucgu acacuugguu caccuguggc uguaguggug 10020 uugagacccc ggcaagaugg gaauguaucc gagccucugc gcucuugccc gucaguucca 10080 agcuuuuccu cacuuaaugc aucaacucgg cgaagacuuu gggcgucaag cugaugauuc 10140 ucgguaauua accaaguaag ggcuccucag ucuacgcagg guaaacgacu cguuagauaa 10200 ucgcagacaa uggcuguagu uaggaguucu ggugaugagu agauggcuuc aucccccccc 10260 guugcggcag guagcgaugu cgacggcuga uaggcuguuu aacucgucuc aguuguugaa 10320 uauagucaac guaugaauaa auagacagug uugucucgcc aacugguuca ugucagcucc 10380 uaguuuuuug ugacugcgug ugaaggucuc guacuacuaa auacguguuu cggcaguaua 10440 ucuggaguag aaccucagag acguguggcc ucucuaccau ggcaaccuca caguaguagu 10500 guaacucacg uuagugacau aucuccuaua ugggcugcuc gguuagugcc cccugggccg 10560 aaccugacuu caguucaaag gaaguucagg aguccucggg aaagaaaugu aguccguugu 10620 ucuagacggc caguuucugu uugagcucgg acacggagcg uacuuguagc aggcagaacg 10680 gccuaaccca ggccuccgcu aaucacucga ucgcgugaug aaacaacgua aggcucaaua 10740 ggcccgcagu cucugccuac agcugggauu gcuacaagag agcaccugga ccgacucggc 10800 uuaacuagga cuguuuaacc aacucauaua gcacguacac aagcgaagug accuuaccgu 10860 aguacauaau uacaguccgc acucacacuc gcagucucua cguaagaaau ucuacgauca 10920 cagauuuucu uagagucucu gaggcgauuc aaguaagaua auagaccggu uggacaagca 10980 acugggaguc ugagcgcuuc gugauuacuc gagauuuaug cccaagucgg gggggcggcu 11040 cugucagggg uugcguuuac ggcggcgucg gcuuuauucu ucuacgacac gcuugucacg 11100 cggcagcuag aaucuuaguc gggaaguguc ggcacuccaa caaaccuacg guccuugcuu 11160 guuaauaccu cugcaacagu agaccagagu aauguaaucu aaugccaagu cgcuucaauu 11220 ugaucaacug uaaugugcua uagucgucac caccucuguc agacucgcuc uggggaugcu 11280 aaaccagggc cuguacgucc aagaacucuc gcuggaucua ugcgacuacu uugccuaugg 11340 cuccgaguac gcguuccgcu cugcaggggg agaaguccau uaagcucucc uggaccuaca 11400 gcgucaguag uuacgacuag uagggcgagu gagacacgaa gucuuguuua uguccuuuaa 11460 cuaaaagucu cucggcuucu aauagugccc ucgacacaug uucauggaga gggauuuuag 11520 ucucaacugu cucaagugga gucguuacca cuagccucug ccuugaccuc cauaguggcg 11580 gcgguacuac cggcuacccu aucuacacac cauagucugc gagcaguuga uacuggugca 11640 cuguguuguc ccuaauaggc auguucgggg ccgucguaac cuagaagacg cgccccgugg 11700 gagaccaucc gagaacuuag gcccuucuaa gcguaguaaa cccagacugg auugacuggg 11760 agcuaaaugu cggaugaaac uaguuauagg gggcaaguuc caccugugag auaccagacu 11820 gcgucucccg cugaaaaccc uguucggaag guucaacuua guuaugaaac ucuuguagua 11880 acgaaacucu guagccaagc acuucuguuu accugucgaa cagcacuucc acauagacug 11940 aguucuguga cgaugguguu aacuucguaa gucuuucuuc gacaggggua cgcgguagua 12000 gcacagagag aagagcugcc uuccgaggug ucuuacgaag caggauucgu uagaguagcg 12060 uggucugugg ggacagcugg aacucuacca ccucuuauag ggauuugauu guagggaaca 12120 aggggucucc ugcugucacu uuacgauaag ggcugcucau cgcacguagu cauuuuccac 12180 cccugaaaag ucuagaggcu cguaucggga acuucagguu ggcaaggaag ugauguagug 12240 uuuccaguag agucuguuuc cuuguguuga cucagaguac cgccaucgac uguguuacua 12300 guugucaaug uucuuccgau agaguggggc ucacaagcua gauguggccg uaucccggcg 12360 ugacccaaag cccuccucua ggaacguaga guagaccccc uacuaguaga gugguuagcg 12420 aauggucgua aaacucuuag gccgguucaa cuaccuacag gaccuguaca acugguuauu 12480 guagagucga aagaauagcu auagcagcag uccuaaacug gacaguaaau cacagucacg 12540 ucuggcucua caggccuaac ugucguuuga acagucugag ggcgauaagc uuccuagucu 12600 ggauuuuaag uacuuuuggu aguacagaug ggagccuaga cacaaguugg uccagcucgg 12660 aaaauucccc uagcgguauu ugggaagauu ugauuacuga caguucuccu guguccucaa 12720 ugcaauguug uuggauuaaa ugugauuccu acgguaggau aagggguuac uucgccguuu 12780 uuugugacgg ggcgaagcuc gguuguacca uauggggcag gccccucuag auaagcgggg 12840 auggcuagcg uaugguuagu acugagauca gucgcuacuc uguuguggag ucgugagagg 12900 aggucuccua cuccguauug acuuaggagg gacuuccgag uguacagggu gcgcugcguu 12960 cuauauugcu guucguugag cgggauaauu gacacuaauu auuuuuuggc uaauaaguca 13020 acgaacuccc ucaaaguuag gcaagucaca uacuauccuu caaagacucu accaccccua 13080 aucccccgug gaucucauac aaacaagcaa aauacgcagc a 13121

SEQ ID NO: 19

MFQIPEFEPS EQEDSSSAER GLGPSPAGDG PSGSGKHHRQ APGLLWDASH QQEQPTSSSH 60

HGGAGAVEIR SRHSSYPAGT EDDEGMGEEP SPFRGRSRSA PPNLWAAQRY GRELRRMSDE 120

FVDSFKKGLP RPKSAGTATQ MRQSSSWTRV FQSWWDRNLG RGSSAPSQ 168

SEQ ID NO: 20

aaugcugcgu auucgacucu uuguauucuc ugauacaagu aucaguggga cauaaguaau 60 aacugaaaau acuggauaau aagcacucca guauacacuc cauuacagua gacgaauacg 120 caaacgaaua uucuauuuug cuaucuggga agugcccauu uaggaagagg aacgucaaga 180 gcgguucaug gagguuucag ucuugcuacc gagcaggcga ucgacgacgc guuguagagu 240 auuggcucgc aguaagggaa guccgcugag acagcgcccg cagguucugg ucucggcucc 300 uuaagcaguu ucuaaagaug gaaguucucg ucauaagaca gggcugguag ggcugccugc 360 uguaacgggu cagacccggg uacgacgaag uccgguagga cucgcuccuu auguguuucc 420 ggugacugua ucggguuagg uaggagaccu ugugagggug uggguugccc gaggagucuc 480 ucguagaucu acggcuaccc ccuccgagua agugucgcga cgggcgcaga cguuagucug 540 ggucgcugcu ccgcuuacgu acccggcgag cguagaggcu gagucccaac cccggacaga 600 agauacgucg ggagcgacga auguaguagc cgaccagucc uucuccucuc ugaucggcgc 660 acgucgucuu guauccaguc uuuaccgacu acuuggacuu gcguuagaag ccguggugcu 720 aguggguagg uuguuggcac gcagacgguu aguugcagca guuguugucg gagcgucacu 780 ccuugccuga acgacggugu gagaccgaua ugauggcaag uaguggaguc ucaguccugc 840 gcaagaagau acccgaguag gcagggacaa cgucaccuau agagccggac gauguagccc 900 acguccucua acuacucuac cucggccuga aggagucacu gggggccuag uagguccacu 960 uacuccagau gucacgugag ucucgggacc aaguugaccc uuugcugaag uucuggcggc 1020 uacuacucgg guacguccag acccgcacgu ccccuuaguu guugccuaua gacuguauag 1080 agagucuuug aggacgcuuc uuuccucgac aacacgaaua caaacggguu acguacgacu 1140 ucccgcugag acuccggacc uugucgaugg cgugacguug gacccacuac gggauaacgc 1200 uguuacaccg ggauccucgc uaccguccga uguagguucg ggcggucuug uggucccgua 1260 uacuccagag ucgggucugu ccagagcugc aguuguaccg gcgccaguuc cugaaacucc 1320 ggucaaguuu uggguuccga cgagguuaga gcgacuaggg ugcggggcga cuacagcgua 1380 gggcguggag acucgcgggu agauaaggac uccaacuguc gcugcuucuc gagccuccuu 1440 acauuugguu auucgaagug acggccauca aauccguaug ugugcgucaa ggcaauaggu 1500 agugugggca gggaagaaaa uacgacgaua auaaagucaa cgauucgaag gacuaaacua 1560 auuguuuuuu ggcaucugga ggaugcacuc cauaucgauc uuuaaccaag auagccaacu 1620 cucagaaaca ugauaaucgg uaccuccuga uaaacagauc gaaucuccgg cgcucucucg 1680 agcaggccug ccucgaccuc ggguucgcau uggaguaucg gucgaaucuc aggcugcuag 1740 ggcuaggcca uuaucgcggu cgccauuuug guuuuguagg guucgguacg gacucgugau 1800 uucuucuccu aguagagggg agagaagcgg augauaagcc gcguuuugcu cuguggagcc 1860 acccgcaucu cgucugagag guguucgcag agacgcgaac agagcugcca auggacuggu 1920 acugcuucuu ucuccgguua cggaaauucc ggcgccgacu ucgucgucgu aaucgucagu 1980 accuguaauu cuaccucgua gucgcggucc uagaucuccu agacuggcga cgauagggau 2040 ccuaucuuaa guuugaguua cgguaggacc uuuuguuguu ccucuaucgg uuccgacauu 2100 gacgacgauu ccucuaccuc gcccucuaca gcaccccccu uucgcggcgg ucgagcgagu 2160 ucagacagug ggaucuacuc agcaaauccc cgggacuucu cgaaagucuc aguaaaccgu 2220 aggcuauauu ccagucuugg accuuacuca aguucuuccg cgaccuuugg ucguaacacc 2280 uggacuccgg aucgggacaa aguaaauccc uuaaugccug auacaccgac agagaacugu 2340 ggaggaaauc cgaguaaccc aaacggaagu aaggguguac gcucgcggac cucugguuuc 2400 gguuuacguu ccucuguucc ugagaugagg gggaacgucu cagcuaguac gcuucuaccc 2460 uggacgcccu agguugguag aaccucuuuc ggacgcauca uuacuacuag gcacccuuac 2520 ucuaacguag cgacuuaguc cauuuucuac aagagggcug guguuaagca cccaccuucu 2580 agcgaauaau cagugacgag gguaaucagg gugaucugcc guaugaaggu aaggcgggaa 2640 auuaagggga cagucuguga guacgaggcu uuagugauug guaggaacag gugguucguu 2700 augcguauaa gucaucguga cguagagcgg gagggggaua guucgggguc gcgacgucua 2760 gaaguggugu auauauguac guaguugaug uacacuaaau cuuuuuuggu cugggaagug 2820 cccauuaucg gauugagugc uugcaaggag agcaaagcau acuauuccgg aauucguaac 2880 agcuaugcca gcaauacgca gccaagaaaa auccucucuc gucacgggga cgcucccuga 2940 cccucaggcu cgcuggaggg gggauacgac aacuccaggg aguuucagug cccuauucuc 3000 aguggcccau gaaggucacg uugcucgcag gcuuuagguu cuucugggag gugucgaagc 3060 ggcauuuuga gacgcugcgu uaauucggcc aagcucgccu acgagggucg aacuucuauc 3120 guuauaccug ccgagaucua gaccggaagc acuuuggagg guuaccuuga cauuguuauc 3180 uacgccgcca cuuucgaugu ggcgauuagc ccuugugggu cauguggcau ccgcuacuuu 3240 agaaggucua cgaucccucu uccccaccgg acuagcagua guccuugaau gggguacuaa 3300 uaggagcuug caacuaacuc aagcggagag ggcucggaac ucgugguccc guagccaggc 3360 gggcgggaca cuagagggca ucggcccgag ucgcuaguuc ggccgggccc agcccccccu 3420 gaccacguug uguuccccgc cgucaccugc gacuaauugu uuuuuggugg auauaucugg 3480 ggagugccag aaucugagac aacggucgac uguugguugu guguucugua gagagacuaa 3540 gucggcuggg cuagcuaagg aggggugggu uaaggauggu ugcgugagga guguucgagg 3600 ugguacgagu ccuaggucua gggaggcuaa cgauaguaag accauucaga ggagugugag 3660 cuggacaggc cacguuccuc cuguuggugu guuucuuagg gagaggaauu acuaagcacc 3720 cuaaacaaga gcucgauacc gcuguaaggg cuucuugaac agcauauggu cuugaugucg 3780 guguuaagga ggcucaaugg gggaggaccg aagcucucua ccauguauuu ggcuucucac 3840 cgucugugaa gguauggcac guccccgggg acagaucacg ggauguagga aguaccggag 3900 uuacuguguu gacagagagc ugccccuccu ccuaccgcuu ccaggccuua cuucaugggu 3960 ugggugcgac aguccgaucc gggaaguugu cugcugcucu cucaacuccu ucuguagccg 4020 augcaguuac agaggcguga uaggacgugu cccagcgggc aacucuaccg cuaugguugu 4080 uaggggcuga cguggucacg auagguaggu gcuaggcucc aaugacacgg gcaguucgag 4140 cuacaguacu cugcuuuagg guugauggga ggguaaucuc gcaccagcac guagccuguc 4200 uuuuaguggu uggcuacacu aacccgugag aagccgcucu uggaguauau augaguucaa 4260 cuucgaucga gagaucguaa guucgugugu ucucggagag aaaacuugcu uagguugccc 4320 uaucugcgac uuccugcacg ucaagggaua uaggagcccc uauagcuugg gcccaugacg 4380 gcuugggaua aguuguguac ccagagauca cucuagcaca guacgugcgg guagcuugaa 4440 caggaucaac uggacuuggg aaacaggggc ccuguaccgc cuauacgaca uaacgacggu 4500 uugccucugu uucaccuaca ugugcuguuc guacguaccc uaccccuguu guuuuacacc 4560 ucuacccaca ugcucuucuu ucuagggaca cgcaagcucg accauagguc ccuucacaca 4620 gaaaagagug acucaucccc aucaucugac ucuccucguu ggggaggggu uccucucgag 4680 gaguggacgg gcguaagccc uuuccguaaa cuggacuucc cccgggcuuc cuaauguggg 4740 uaaaguacgu uuuagcugua ccuuauacug aacgacagug augguuggcc ucaguaggau 4800 ccggaggugg auagucuuga gcccuggagg aaaccguugg agaguuacuc agaacuuuac 4860 auacuuggac gguguugaga cuggggacuc guuuaguuga agagcgaauu ucucgacccu 4920 ucgaccuggc uccgaguuga cuucucggac agagugaguu agacggagag guguaagagg 4980 uauacccuug auagccaacc cuacuagcua gauuugggau ggucccgucg uucccggaac 5040 gagguacuac uauuguauga ccguuguaag cucuugccag ugaaaaggua gcagucuaca 5100 gcaggccuuu aucaaguuca gggaagcgua ggagcucgua caguguaccu agaggcggga 5160 auacuguucg uuagugcccg uaguugggac caccaagggg aacuguuguc gugacgggag 5220 gaccaggggc uguuguagca ccaacuuccu caucuccggu cagauacguu ggugaggcaa 5280 cgguagugcg acagcuucuu gucuugagug aguaugucgg agauaggggu cccagcagga 5340 cacgaagcug ucuuuccacg gcaccucgag ggcugcuauc ccggggaggu caauguagga 5400 cggugagcuc accuggaaau augugacuuu cucaaggucc uccuggcuua ucgcgcguca 5460 gcucaguguc uguaguuccg acggcaacug cuagacgcac gcuucaccgc auuuccguuu 5520 aaacuccgcc uguggugccc ucccccugaa accagccgcu aacacccuca gaagucaaga 5580 gagcccccca agaaguacuc cgggaacuaa cgagagcgcc gcuaucacug gaguuaguag 5640 uaggacauau aggaagacgc acaugacaca cgacggagua caagcugugu ggcuucucau 5700 uccguccuga gaaccauuuc uccugacgcu aacaacucac cucggccguu ugggauccgg 5760 auaaggcuaa aucuuuuuug gucuggagag ugcuccagaa aagaugaucg acccaaaagg 5820 aguaagauag gucucggcgc cggcguacaa ggucuagggu cucaaacucg gcucacucgu 5880 ccuucugagg ucgagacguc ucuccccgga cccggggucg gggcgucccc ugcccgggag 5940 uccgaggccg uucguaguag cgguccgggg uccggaggac acccugcggu caguggucgu 6000 ccucgucggu uggucgucgu cgguaguacc uccgcgaccc cgacaccucu aggccucagc 6060 ggugucgagg auggggcgcc ccugccuccu gcugcuuccc uacccccucc ucgggucggg 6120 gaaagccccg gcgagcgcga gccgcggggg guuggagacc cgucgugucg cgauaccggc 6180 gcucgaggcc uccuacucac ugcucaaaca ccugaggaaa uucuucccug aaggagcggg 6240 cuucucgcgc ccgugucguu gcgucuacgc cguuucgagg ucgaccugcg cucagaaggu 6300 caggaccacc cuagccuuga acccgucccc uucgaggcgg gggaggguca cugcaugcgu 6360 uugggauccg gauaaggcua aaucuuuuuu ggucuggaga gugcuccaga aaagaugauc 6420 gacccaaaag gaguaagaua ggucucggua ccggaagcug ggcuugaccg ucucucuucc 6480 aauacuuacc cuaggcaguu cacucccguc uggcuggcua cucuugcuuc ugcugucucc 6540 aguagccggu uuuugcucug aagcauguaa ggaacgggcg ugcaauuuau cgggauaggc 6600 ucgggauaag auguguuaua aggauccuua agcucgccaa acccugccca aguuuucuga 6660 ggauggacac uccuggcuuu ucccaauacg cuccaaaaga cucacgcagu guauaccuua 6720 cuagccuaca cuacucacac auuaucuggg ccacucccaa caguaacucg acuggcucua 6780 cgucaauggc uaauuuccgu uuccgagaug cuccaacucu cguuacuauu gacuucugga 6840 agagugcccc uacgcguguc ggcacggagu cuagucucac ucuagcuucu aggaucgucu 6900 cgccaauccc ucucguuagc cggcucucug gaacggccgu uacuagguag uacucacccg 6960 uaaacacuac cccuucuaag agugaaagua ccgucuguua cacccauacu ugcgacugug 7020 ccagcucccg caagauagug auagucucca gugugccgcu acccuauagc cguugagaca 7080 caggcgucac aaguuaggac uaccggaaug auagucucau cuuuugugcc caauguagua 7140 cuggucucuc ugacggacgu acuagccucu guaaguacga guuaaacguu agguuaugga 7200 ucgacguaug gaucugcucc acuagccgug uuccugcaga gagagugggc ggcuugacug 7260 gagagaguuu gauaccccug aauugcagga cuuugaggau ccugccuugc caauacucca 7320 cuagcggacg uaccucgggu aucccaugcg acaggacuac uacccuucuc uguccucagg 7380 acuagggaua caguuacugu ggauaaauuu gucguaggag agucuuaagg gacagcugag 7440 acugcgagcu cggacgcaac uucgggagaa uugauagaua uacucgaagc cguguggggu 7500 auuucagagc cugcguaagc cggagaaguc uuacaacccu guaggcuacc aacuaccucg 7560 acugcccuaa cuuuucuacg cuuccaauuc guucuuccag uucuaggguc uggucagaug 7620 ucgcuagcug gagccccgau aguaccggcu ugacaaacac gccucaaagc auuucuucgu 7680 guuuuccacc ggguugacga gguaguuaga gggcggugcu guggggaagg uggugcgggc 7740 ggauacaccc auacagggcc gacuuugggu aggggauuug uugugacgua ggacccgccg 7800 acaccucaag uugguccuua agcucggcgg cucugucaug uuggaacguc uguaguaacu 7860 acuguucagc acgagagggu uguucguacu cgauauacca cgaaccuacu ucaguuuuug 7920 ucgacccacc guccuuguuu ucuucgagua ugaggcuacc aagugacucu gguaccaauu 7980 uggaagccuc gaggaccuuc ucuaacuacg ugugccgaag gcucuucucc uauucaacua 8040 accuaauugu gguuuccucu cucucgacuu uaauuguggu ucuuacaaga ggaacuacug 8100 uaaguucaag ucuuggaugg uucaggagug acucucauac cagcggcuac ucuaggaggg 8160 cgugaagggg gucuaguggu acugguacag guuggugcuu gaguguuucu ccaacuaauc 8220 gucuugcucu ggaguuagac cuccucccgc acuacaagug uaguggcacu uguaucuaaa 8280 ggucuuuacc uuguguuugu acucugugcc ugaccaguuu guacagaagc ucgcugaccu 8340 guuggagaaa ccgaaguggu ugaauuaguc ugcuugagua cuuaugaagg uccuccgcuu 8400 uaugauagac cgacuucuac cuugauuaga cagcaagcug uccuugcccc ucaauuaucu 8460 accggguaug caaauguggc cuaguaugcc ccccuugcuc cccaaugcug ucuucgggac 8520 cuguuaucaa uggcacacac cuuauauguu ccaucgaucu cuggacuuuu aguuuguagu 8580 cuaguggcca gucccucuau uaguccacca gugggauuau aaaggccuag cucucaacgg 8640 aagucuaggc caccucuccu cguucaugac aucucuguuc ucgucaguca aggacugugc 8700 agagucaguu auaaagcgac uccaaccaaa cgggcaguuc ugacuucucu guaccuacag 8760 uagugcagag auacgaaugc cauucgcgua caagaaucuc ccucaaggug aauucuacaa 8820 agaguucuuc uauccgucuc gaaagcggga gagcuuacuc aaacagggca gggagcuccu 8880 ucuagaccgg ucucagaccu cacggugguc gcgucgccau cucgaacugg auugagggau 8940 gcauccuaua caggagccca cgacgaacag acgcguccgc uagucuuuag uggaguagau 9000 gaggggacaa gaccucccgg gagacgacca auuccggaug cucgcauuca aguaauugau 9060 gcugccuccu uguuucgccc cccgcuacgg gccggaugca gguuggaaac ucucggauca 9120 guuuucauag acgaccuucg guuuccggua gccucccacc ggccauaacu acaaucuucu 9180 agaguaguag uuucccaagg gacuaggccg cugaucgcgg gaccgaguua acuucaguua 9240 ccacgguaua uggagaccau agcuggcccu cuaguaugaa aggacagagu uggaagggaa 9300 uagcagccac cauagaggca guuacaacaa uuuccugggc cgccgguagu ugugguagug 9360 uuggggcagg cgcccgcugu aggacguucu ccagcggucu cugauacaau ggcuaauggg 9420 ugagguuuug ggcgucgagu cucgucacca guucuugcac uucuggcucg aucuguguaa 9480 ccggucacug aauaaguuua cacuuggaaa gaaaggagga aauuacucgc uauagaagag 9540 ccguagagag ggccguauag uucuguccua acaagcguuc acgaggugcu gaagauguua 9600 guccucuuuu cgacggcucu ccccgaggcu gagagaggag uuggccuacu uuuccuuacu 9660 cuaguuauuc uacuacaaug uagaaacccg auggaccccu uccucgggag accggucuaa 9720 ucuguggucu acagaguguu ggacgugguu cguuaaucgg guugucauag ccuuggucag 9780 aaccccuuuc gucuagguac cucagaguca gccggugggg aaucuugaca agccagcuua 9840 uugugggucg guaucuacgg auguacuccu ccuggugccu cuaaaggacg uuuggaagcg 9900 gucgcucgua cacuugguuc accuguggcu guaguggugu ugagaccccg gcaagauggg 9960 aauguauccg agccucugcg cucuugcccg ucaguuccaa gcuuuuccuc acuuaaugca 10020 ucaacucggc gaagacuuug ggcgucaagc ugaugauucu cgguaauuaa ccaaguaagg 10080 gcuccucagu cuacgcaggg uaaacgacuc guuagauaau cgcagacaau ggcuguaguu 10140 aggaguucug gugaugagua gauggcuuca uccccccccg uugcggcagg uagcgauguc 10200 gacggcugau aggcuguuua acucgucuca guuguugaau auagucaacg uaugaauaaa 10260 uagacagugu ugucucgcca acugguucau gucagcuccu aguuuuuugu gacugcgugu 10320 gaaggucucg uacuacuaaa uacguguuuc ggcaguauau cuggaguaga accucagaga 10380 cguguggccu cucuaccaug gcaaccucac aguaguagug uaacucacgu uagugacaua 10440 ucuccuauau gggcugcucg guuagugccc ccugggccga accugacuuc aguucaaagg 10500 aaguucagga guccucggga aagaaaugua guccguuguu cuagacggcc aguuucuguu 10560 ugagcucgga cacggagcgu acuuguagca ggcagaacgg ccuaacccag gccuccgcua 10620 aucacucgau cgcgugauga aacaacguaa ggcucaauag gcccgcaguc ucugccuaca 10680 gcugggauug cuacaagaga gcaccuggac cgacucggcu uaacuaggac uguuuaacca 10740 acucauauag cacguacaca agcgaaguga ccuuaccgua guacauaauu acaguccgca 10800 cucacacucg cagucucuac guaagaaauu cuacgaucac agauuuucuu agagucucug 10860 aggcgauuca aguaagauaa uagaccgguu ggacaagcaa cugggagucu gagcgcuucg 10920 ugauuacucg agauuuaugc ccaagucggg ggggcggcuc ugucaggggu ugcguuuacg 10980 gcggcgucgg cuuuauucuu cuacgacacg cuugucacgc ggcagcuaga aucuuagucg 11040 ggaagugucg gcacuccaac aaaccuacgg uccuugcuug uuaauaccuc ugcaacagua 11100 gaccagagua auguaaucua augccaaguc gcuucaauuu gaucaacugu aaugugcuau 11160 agucgucacc accucuguca gacucgcucu ggggaugcua aaccagggcc uguacgucca 11220 agaacucucg cuggaucuau gcgacuacuu ugccuauggc uccgaguacg cguuccgcuc 11280 ugcaggggga gaaguccauu aagcucuccu ggaccuacag cgucaguagu uacgacuagu 11340 agggcgagug agacacgaag ucuuguuuau guccuuuaac uaaaagucuc ucggcuucua 11400 auagugcccu cgacacaugu ucauggagag ggauuuuagu cucaacuguc ucaaguggag 11460 ucguuaccac uagccucugc cuugaccucc auaguggcgg cgguacuacc ggcuacccua 11520 ucuacacacc auagucugcg agcaguugau acuggugcac uguguugucc cuaauaggca 11580 uguucggggc cgucguaacc uagaagacgc gccccguggg agaccauccg agaacuuagg 11640 cccuucuaag cguaguaaac ccagacugga uugacuggga gcuaaauguc ggaugaaacu 11700 aguuauaggg ggcaaguucc accugugaga uaccagacug cgucucccgc ugaaaacccu 11760 guucggaagg uucaacuuag uuaugaaacu cuuguaguaa cgaaacucug uagccaagca 11820 cuucuguuua ccugucgaac agcacuucca cauagacuga guucugugac gaugguguua 11880 acuucguaag ucuuucuucg acagggguac gcgguaguag cacagagaga agagcugccu 11940 uccgaggugu cuuacgaagc aggauucguu agaguagcgu ggucuguggg gacagcugga 12000 acucuaccac cucuuauagg gauuugauug uagggaacaa ggggucuccu gcugucacuu 12060 uacgauaagg gcugcucauc gcacguaguc auuuuccacc ccugaaaagu cuagaggcuc 12120 guaucgggaa cuucagguug gcaaggaagu gauguagugu uuccaguaga gucuguuucc 12180 uuguguugac ucagaguacc gccaucgacu guguuacuag uugucaaugu ucuuccgaua 12240 gaguggggcu cacaagcuag auguggccgu aucccggcgu gacccaaagc ccuccucuag 12300 gaacguagag uagacccccu acuaguagag ugguuagcga auggucguaa aacucuuagg 12360 ccgguucaac uaccuacagg accuguacaa cugguuauug uagagucgaa agaauagcua 12420 uagcagcagu ccuaaacugg acaguaaauc acagucacgu cuggcucuac aggccuaacu 12480 gucguuugaa cagucugagg gcgauaagcu uccuagucug gauuuuaagu acuuuuggua 12540 guacagaugg gagccuagac acaaguuggu ccagcucgga aaauuccccu agcgguauuu 12600 gggaagauuu gauuacugac aguucuccug uguccucaau gcaauguugu uggauuaaau 12660 gugauuccua cgguaggaua agggguuacu ucgccguuuu uugugacggg gcgaagcucg 12720 guuguaccau auggggcagg ccccucuaga uaagcgggga uggcuagcgu augguuagua 12780 cugagaucag ucgcuacucu guuguggagu cgugagagga ggucuccuac uccguauuga 12840 cuuaggaggg acuuccgagu guacagggug cgcugcguuc uauauugcug uucguugagc 12900 gggauaauug acacuaauua uuuuuuggcu aauaagucaa cgaacucccu caaaguuagg 12960 caagucacau acuauccuuc aaagacucua ccaccccuaa ucccccgugg aucucauaca 13020 aacaagcaaa auacgcagca 13040

SEQ ID NO: 21

MFRCGGLAAG ALKQKLVPLV RTVCVRSPRQ RNRLPGNLFQ RWHVPLELQM TRQMASSGAS 60

GGKIDNSVLV LIVGLSTVGA GAYAYKTMKE DEKRYNERIS GLGLTPEQKQ KKAALSASEG 120

EEVPQDKAPS HVPFLLIGGG TAAFAAARSI RARDPGARVL IVSEDPELPY MRPPLSKELW 180

FSDDPNVTKT LRFKQWNGKE RSIYFQPPSF YVSAQDLPHI ENGGVAVLTG KKWQLDVRD 240

NMVKLNDGSQ ITYEKCLIAT GGTPRSLSAI DRAGAEVKSR TTLFRKIGDF RSLEKISREV 300

KSITIIGGGF LGSELACALG RKARALGTEV IQLFPEKGNM GKILPEYLSN WTMEKVRREG 360

VKVMPNAIVQ SVGVSSGKLL IKLKDGRKVE TDHIVAAVGL EPNVELAKTG GLEIDSDFGG 420

FR AELQAR SNIWVAGDAA CFYDIKLGRR RVEHHDHAW SGRLAGENMT GAAKPYWHQS 480

MFWSDLGPDV GYEAIGLVDS SLPTVGVFAK ATAQDNPKSA TEQSGTGIRS ESETESEASE 540

ITIPPSTPAV PQAPVQGEDY GKGVI FYLRD KVWGIVLWN IFNRMPIARK IIKDGEQHED 600

LNEVAKLFNI HED 613

SEQ ID NO: 22

MDAKARNCLL QHREALEKDI KTSYIMDHMI SDGFLTISEE EKVRNEPTQQ QRAAMLIKMI 60

LKKDNDSYVS FYNALLHEGY KDLAALLHDG IPWSSSSGK DSVSGITSYV RTVLCEGGVP 120

QRPWFVTRK KLVNAIQQKL SKLKGEPGWV TIHGMAGCGK SVLAAEAVRD HSLLEGCFPG 180

GVHWVSVGKQ DKSGLLMKLQ NLCTRLDQDE SFSQRLPLNI EEAKDRLRIL MLRKHPRSLL 240

ILDDVWDSWV LKAFDSQCQI LLTTRDKSVT DSVMGPKYW PVESSLGKEK GLEILSLFVN 300

MKKADLPEQA HSIIKECKGS PLWSLIGAL LRDFPNRWEY YLKQLQNKQF KRIRKSSSYD 360

YEALDEAMSI SVEMLREDIK DYYTDLSILQ KDVKVPTKVL CILWDMETEE VEDILQEFVN 420

KSLLFCDRNG KSFRYYLHDL QVDFLTEKNC SQLQDLHKKI ITQFQRYHQP HTLSPDQEDC 480

MYWYNFLAYH MASAKMHKEL CALMFSLDWI KAKTELVGPA HLIHEFVEYR HILDEKDCAV 540

SENFQEFLSL NGHLLGRQPF PNIVQLGLCE PETSEVYQQA KLQAKQEVDN GMLYLEWINK 600

KNITNLSRLV VRPHTDAVYH ACFSEDGQRI ASCGADKTLQ VFKAETGEKL LEIKAHEDEV 660

LCCAFSTDDR FIATCSVDKK VKIWNSMTGE LVHTYDEHSE QVNCCHFTNS SHHLLLATGS 720

SDCFLKLWDL NQKECRNTMF GHTNSVNHCR FSPDDKLLAS CSADGTLKLW DATSANERKS 780

INVKQFFLNL EDPQEDMEVI VKCCSWSADG ARIMVAAKNK IFLFDIHTSG LLGEIHTGHH 840

STIQYCDFSP QNHLAWALS QYCVELWNTD SRSKVADCRG HLSWVHGVMF SPDGSSFLTS 900

SDDQTIRLWE TKKVCKNSAV MLKQEVDWF QENEVMVLAV DHIRRLQLIN GRTGQIDYLT 960

EAQVSCCCLS PHLQYIAFGD ENGAIEILEL VNNRIFQSRF QHKKTVWHIQ FTADEKTLIS 1020

SSDDAEIQVW NWQLDKCIFL RGHQETVKDF RLLKNSRLLS WSFDGTVKVW NIITGNKEKD 1080

FVCHQGTVLS CDISHDATKF SSTSADKTAK IWSFDLLLPL HELRGHNGCV RCSAFSVDST 1140

LLATGDDNGE IRIWNVSNGE LLHLCAPLSE EGAATHGGWV TDLCFSPDGK MLISAGGYIK 1200

WWNWTGESS QTFYTNGTNL KKIHVSPDFK TYVTVDNLGI LYILQTLE 1248

SEQ ID NO: 23

MAKQPSDVSS ECDREGRQLQ PAERPPQLRP GAPTSLQTEP QGNPEGNHGG EGDSCPHGSP 60

QGPLAPPASP GPFATRSPLF IFMRRSSLLS RSSSGYFSFD TDRSPAPMSC DKSTQTPSPP 120

CQAFNHYLSA MASMRQAEPA DMRPEIWIAQ ELRRIGDEFN AYYARRVFLN NYQAAEDHPR 180 MVILRLLRYI VRLVWRMH 198

SEQ ID NO: 24

MLQKPKSVKL RALRSPRKFG VAGRSCQEVL RKGCLRFQLP ERGSRLCLYE DGTELTEDYF 60

PSVPDNAELV LLTLGQAWQG CEWQGLWRMC LLLDRHLLFV PLVADVSDIR RFLSAFHEPQ 120

VGLIQAAQQL LCDEQAPQRQ RLLADLLHNV SQNIAAETRA EDPPWFEGLE SRFQSKSGYL 180

RYSCESRIRS YLREVSSYPS TVGAEAQEEF LRVLGSMCQR LRSMQYNGSY FDRGAKGGSR 240

LCTPEGWFSC QGPFDMDSCL SRHSINPYSN RESRILFSTW NLDHIIEKKR TIIPTLVEAI 300

KEQDGREVDW EYFYGLLFTS ENLKLVHIVC HKKTTHKLNC DPSRIYKPQT RLKRKQPVRK 360

RQ 362

SEQ ID NO: 25

MENTENSVDS KSIKNLEPKI IHGSESMDSG ISLDNSYKMD YPEMGLCIII NNKNFHKSTG 60

MTSRSGTDVD AANLRETFRN LKYEVRNKND LTREEIVELM RDVSKEDHSK RSSFVCVLLS 120

HGEEGIIFGT NGPVDLKKIT NFFRGDRCRS LTGKPKLFII QACRGTELDC GIETDSGVDD 180

DMACHKIPVE ADFLYAYSTA PGYYSWRNSK DGSWFIQSLC AMLKQYADKL EFMHILTRVN 240

RKVATEFESF SFDATFHAKK QIPCIVSMLT KELYFYH 277

SEQ ID NO: 26

MEGGRRARW IESKRNFFLG AFPTPFPAEH VELGRLGDSE TAMVPGKGGA DYILLPFKKM 60

DFSRNLYDIG EQLDSEDLAS LKFLSLDYIP QRKQEPIKDA LMLFQRLQEK RMLEESNLSF 120

LKELLFRINR LDLLITYLNT RKEEMERELQ TPGRAQISAY RVMLYQISEE VSRSELRSFK 180

FLLQEEISKC KLDDDMNLLD IFIEMEKRVI LGEGKLDILK RVCAQINKSL LKIINDYEEF 240

SKERSSSLEG SPDEFSNGEE LCGVMTISDS PREQDSESQT LDKVYQMKSK PRGYCLIINN 300

HNFAKAREKV PKLHSIRDRN GTHLDAGALT TTFEELHFEI KPHDDCTVEQ IYEILKIYQL 360

MDHSNMDCFI CCILSHGDKG IIYGTDGQEA PIYELTSQFT GLKCPSLAGK PKVFFIQACQ 420

GDNYQKGIPV ETDSEEQPYL EMDLSSPQTR YIPDEADFLL GMATVNNCVS YRNPAEGTWY 480

IQSLCQSLRE RCPRGDDILT ILTEVNYEVS NKDDKKNMGK QMPQPTFTLR KKLVFPSD 538

SEQ ID NO: 27

MELVPATPHY PADVLFQTDP TAEMAAESLP FSFGTLSSWE LEAWYEDLQE VLSSDENGGT 60

YVSPPGNEEE ESKIFTTLDP ASLAWLTEEE PEPAEVTSTS QSPHSPDSSQ SSLAQEEEEE 120

DQGRTRKRKQ SGHSPARAGK QRMKEKEQEN ERKVAQLAEE NERLKQEIER LTREVEATRR 180

ALIDRMVNLH QA 192

SEQ ID NO: 28

MSSGLWSQEK VTSPYWEERI FYLLLQECSV TDKQTQKLLK VPKGSIGQYI QDRSVGHSRI 60

PSAKGKKNQI GLKILEQPHA VLFVDEKDW EINEKFTELL LAITNCEERF SLFKNRNRLS 120

KGLQIDVGCP VKVQLRSGEE KFPGWRFRG PLLAERTVSG IFFGVELLEE GRGQGFTDGV 180

YQGKQLFQCD EDCGVFVALD KLELIEDDDT ALESDYAGPG DTMQVELPPL EINSRVSLKV 240

GETIESGTVI FCDVLPGKES LGYFVGVDMD NPIGNWDGRF DGVQLCSFAC VESTILLHIN 300

DIIPALSESV TQERRPPKLA FMSRGVGDKG SSSHNKPKAT GSTSDPGNRN RSELFYTLNG 360

SSVDSQPQSK SKNTWYIDEV AEDPAKSLTE ISTDFDRSSP PLQPPPVNSL TTENRFHSLP 420

FSLTKMPNTN GSIGHSPLSL SAQSVMEELN TAPVQESPPL AMPPGNSHGL EVGSLAEVKE 480

NPPFYGVIRW IGQPPGLNEV LAGLELEDEC AGCTDGTFRG TRYFTCALKK ALFVKLKSCR 540

PDSRFASLQP VSNQIERCNS LAFGGYLSEV VEENTPPKME KEGLEIMIGK KKGIQGHYNS 600

CYLDSTLFCL FAFSSVLDTV LLRPKEKNDV EYYSETQELL RTEIVNPLRI YGYVCATKIM 660

KLRKILEKVE AASGFTSEEK DPEEFLNILF HHILRVEPLL KIRSAGQKVQ DCYFYQIFME 720

KNEKVGVPTI QQLLEWSFIN SNLKFAEAPS CLIIQMPRFG KDFKLFKKIF PSLELNITDL 780

LEDTPRQCRI CGGLAMYECR ECYDDPDISA GKIKQFCKTC NTQVHLHPKR LNHKYNPVSL 840

PKDLPDWDWR HGCIPCQNME LFAVLCIETS HYVAFVKYGK DDSAWLFFDS MADRDGGQNG 900

FNIPQVTPCP EVGEYLKMSL EDLHSLDSRR IQGCARRLLC DAYMCMYQSP TMSLYK 956

SEQ ID NO: 29 MEVTGDAGVP ESGEIRTLKP CLLRRNYSRE QHGVAASCLE DLRSKACDIL AIDKSLTPVT 60

LVLAEDGTIV DDDDYFLCLP SNTKFVALAS NEKWAYNNSD GGTAWISQES FDVDETDSGA 120

GLKWKNVARQ LKEDLSSIIL LSEEDLQMLV DAPCSDLAQE LRQSCATVQR LQHTLQQVLD 180

QREEVRQSKQ LLQLYLQALE KEGSLLSKQE ESKAAFGEEV DAVDTGISRE TSSDVALASH 240

ILTALREKQA PELSLSSQDL ELVTKEDPKA LAVALNWDIK KTETVQEACE RELALRLQQT 300

QSLHSLRSIS ASKASPPGDL QNPKRARQDP T 331

SEQ ID NO: 30

MQPILLLLAF LLLPRADAGE IIGGHEAKPH SRPYMAYLMI WDQKSLKRCG GFLIRDDFVL 60

TAAHCWGSSI NVTLGAHNIK EQEPTQQFIP VKRPIPHPAY NPKNFSNDIM LLQLERKAKR 120

TRAVQPLRLP SNKAQVKPGQ TCSVAGWGQT APLGKHSHTL QEVKMTVQED RKCESDLRHY 180

YDSTIELCVG DPEIKKTSFK GDSGGPLVCN KVAQGIVSYG RNNGMPPRAC TKVSSFVHWI 240

KKTMKRY 247

SEQ ID NO: 31

MSRSKRDNNF YSVEIGDSTF TVLKRYQNLK PIGSGAQGIV CAAYDAILER NVAIKKLSRP 60

FQNQTHAKRA YRELVLMKCV NHKNIIGLLN VFTPQKSLEE FQDVYIVMEL MDANLCQVIQ 120

MELDHERMSY LLYQMLCGIK HLHSAGIIHR DLKPSNIWK SDCTLKILDF GLARTAGTSF 180

MMTPYWTRY YRAPEVILGM GYKENVDLWS VGCIMGEMVC HKILFPGRDY IDQWNKVIEQ 240

LGTPCPEFMK KLQPTVRTYV ENRPKYAGYS FEKLFPDVLF PADSEHNKLK ASQARDLLSK 300

MLVIDASKRI SVDEALQHPY INVWYDPSEA EAPPPKIPDK QLDEREHTIE EWKELIYKEV 360

MDLEERTKNG VIRGQPSPLG AAVINGSQHP SSSSSVNDVS SMSTDPTLAS DTDSSLEAAA 420

GPLGCCR 427

SEQ ID NO: 32

MSRSKRDNNF YSVEIGDSTF TVLKRYQNLK PIGSGAQGIV CAAYDAILER NVAIKKLSRP 60

FQNQTHAKRA YRELVLMKCV NHKNIIGLLN VFTPQKSLEE FQDVYIVMEL MDANLCQVIQ 120

MELDHERMSY LLYQMLCGIK HLHSAGIIHR DLKPSNIWK SDCTLKILDF GLARTAGTSF 180

MMTPYWTRY YRAPEVILGM GYKENVDIWS VGCIMGEMIK GGVLFPGTDH IDQWNKVIEQ 240

LGTPCPEFMK KLQPTVRTYV ENRPKYAGYS FEKLFPDVLF PADSEHNKLK ASQARDLLSK 300

MLVIDASKRI SVDEALQHPY INVWYDPSEA EAPPPKIPDK QLDEREHTIE EWKELIYKEV 360

MDLEERTKNG VIRGQPSPLG AAVINGSQHP SSSSSVNDVS SMSTDPTLAS DTDSSLEAAA 420

GPLGCCR 427

SEQ ID NO: 33

MPGKKARKNA QPSPARAPAE LEVECATQLR RFGDKLNFRQ KLLNLISKLF CSGT 54 SEQ ID NO: 34

MAATVEGPEL EAAAAAGDAS EDSDAGSRAL PFLGGNRLSL DLYPGGCQQL LHLCVQQPLQ 60

LLQVEFLRLS THEDPQLLEA TLAQLPQSLS CLRSLVLKGG QRRDTLGACL RGALTNLPAG 120

LSGLAHLAHL DLSFNSLETL PACVLQMRGL GALLLSHNCL SELPEALGAL PALTFLTVTH 180

NRLQTLPPAL GALSTLQRLD LSQNLLDTLP PEIGGLGSLL ELNLASNRLQ SLPASLAGLR 240

SLRLLVLHSN LLASVPADLA RLPLLTRLDL RDNQLRDLPP ELLDAPFVRL QGNPLGEASP 300

DAPSSPVAAL IPEMPRLFLT SDLDSFPVTP QGCSVTLACG VRLQFPAGAT ATPITIRYRL 360

LLPEPGLVPL GPHDALLSHV LELQPHGVAF QQDVGLWLLF TPPQARRCRE VWRTRNDNS 420

WGDLETYLEE EAPQRLWAHC QVPHFSWFLV VSRPVSNACL VPPEGTLLCS SGHPGVKVIF 480

PPGATEEPRR VSMQWRMAG RELQALLGEP EAAVSPLLCL SQSGPPSFLQ PVTVQLPLPS 540

GITGLSLDRS RLHLLYWAPP AATWDDITAQ WLELTHLYA RFQVTHFSWY WLWYTTKNCV 600

GGLARKAWER LRLHR LIA LQRRRDPEQV LLQCLPRNKV DATLRRLLER YRGPEPSDTV 660

EMFEGEEFFA AFERGIDVDA DRPDCVEGRI CFVFYSHLKN VKEVYVTTTL DREAQAVRGQ 720

VSFYRGAVPV RVPEEAEAAR QRKGADALWM ATLPIKLPRL RGSEGPRRGA GLSLAPLNLG 780

DAETGFLTQS NLLSVAGRLG LDWPAVALHL GVSYREVQRI RHEFRDDLDE QIRHMLFSWA 840

ERQAGQPGAV GLLVQALEQS DRQDVAEEVR AVLELGRRKY QDSIRRMGLA PKDPALPGSS 900

APQPPEPAQA 910 SEQ ID NO: 35

MKFGMGSAQA CPCQVPRAAS TTWVPCQICG PRERHGPRTP GGQLPGARRG PGPRRPAPLP 60

ARPPGALGSV LRPLRARPGC RPRRPHPAAR CLPLRPHRPT RRHRRPGGFP LAWGSPQPAP 120

RPAPGRSSAL ALAGGAAPGV ARAQRPGGSG GRSHPGGPGS PRGGGTVGPG DRGPAAADGG 180

RPQRTVRAAE TRGAAAAPPL TLEGPVQSHH GTPALTQGPQ SPRDGAQLGA CTRPVDVRDS 240

GGRPLPPPDT LASAGDFLCT M 261

SEQ ID NO: 36

MKFGMGSAQA CPCQVPRAAS TTWVPCQICG PQPSLSLAEQ HLESPVPSAP GALAGGPTQA 60

APGVRGEEEQ WAREIGAQLR RMADDLNAQY ERRRQEEQQR HRPSPWRVLY NLIMGLLPLP 120

RGHRAPEMEP N 131

SEQ ID NO: 37

MARARQEGSS PEPVEGLARD GPRPFPLGRL VPSAVSCGLC EPGLAAAPAA PTLLPAAYLC 60

APTAPPAVTA ALGGSRWPGG PRSRPRGPRP DGPQPSLSLA EQHLESPVPS APGALAGGPT 120

QAAPGVRGEE EQWAREIGAQ LRRMADDLNA QYERRRQEEQ QRHRPSPWRV LYNLIMGLLP 180

LPRGHRAPEM EPN 193

SEQ ID NO: 38

MEARDKQVLR SLRLELGAEV LVEGLVLQYL YQEGILTENH IQEINAQTTG LRKTMLLLDI 60

LPSRGPKAFD TFLDSLQEFP WVREKLKKAR EEAMTDLPAG DRLTGIPSHI LNSSPSDRQI 120

NQLAQRLGPE WEPMVLSLGL SQTDIYRCKA NHPHNVQSQV VEAFIRWRQR FGKQATFQSL 180

HNGLRAVEVD PSLLLHMLE 199

SEQ ID NO: 39

MCSGAGVMMA RWAARGRAGW RSTVRILSPL GHCEPGVSRS CRAAQAMDCE VNNGSSLRDE 60

CITNLLVFGF LQSCSDNSFR RELDALGHEL PVLAPQWEGY DELQTDGNRS SHSRLGRIEA 120

DSESQEDIIR NIARHLAQVG DSMDRSIPPG LWGLALQLR NTSRSEEDRN RDLATALEQL 180

LQAYPRDMEK EKTMLVLALL LAKKVASHTP SLLRDVFHTT WFINQNLRT YVRSLARNGM 240

D 241

SEQ ID NO: 41

MCSGAGVMMA RWAARGRAGW RSTVRILSPL GHCEPGVSRS CRAAQAMDCE WNGSSLRDE 60

CITNLLVFGF LQSCSDNSFR RELDALGHEL PVLAPQWEGY DELQTDGNRS SHSRLGRIEA 120

DSESQEDIIR NIARHLAQVG DSMDRSIPPG LWGLALQLR NTSRSEEDRN RDLATALEQL 180

LQAYPRDMEK EKTMLVLALL LAKKVASHTP SLLRDVFHTT WFINQNLRT YVRSLARNGM 240

D 241

SEQ ID NO: 42

MSSGLRAADF PRWKRHISEQ LRRRDRLQRQ AFEEIILQYN KLLEKSDLHS VLAQKLQAEK 60

HDVPNRHEIS PGHDGTWNDN QLQEMAQLRI KHQEELTELH KKRGELAQLV IDLNNQMQRK 120

DREMQMNEAK IAECLQTISD LETECLDLRT KLCDLERANQ TLKDEYDALQ ITFTALEGKL 180

RKTTEENQEL VTRWMAEKAQ EANRLNAENE KDSRRRQARL QKELAEAAKE PLPVEQDDDI 240

EVIVDETSDH TEETSPVRAI SRAATKRLSQ PAGGLLDSIT NIFGRRSVSS FPVPQDNVDT 300

HPGSGKEVRV PATALCVFDA HDGEWAVQF SPGSRLLATG GMDRRVKLWE VFGEKCEFKG 360

SLSGSNAGIT SIEFDSAGSY LLAASNDFAS RIWTVDDYRL RHTLTGHSGK VLSAKFLLDN 420

ARIVSGSHDR TLKLWDLRSK VCIKTVFAGS SCNDIVCTEQ CVMSGHFDKK IRFWDIRSES 480

IVREMELLGK ITALDLNPER TELLSCSRDD LLKVIDLRTN AIKQTFSAPG FKCGSDWTRV 540

VFSPDGSYVA AGSAEGSLYI WSVLTGKVEK VLSKQHSSSI NAVAWSPSGS HWSVDKGCK 600

AVLWAQY 607

SEQ ID NO: 43

MQNVINTVKG KALEVAEYLT PVLKESKFKE TGVITPEEFV AAGDHLVHHC PTWQWATGEE 60 LKVKAYLPTG KQFLVTKNVP CYKRCKQMEY SDELEAIIEE DDGDGGWVDT YHNTGITGIT 120

EAVKEITLEN KDNIRLQDCS ALCEEEEDED EGEAADMEEY EESGLLETDE ATLDTRKIVE 180

ACKAKTDAGG EDAILQTRTY DLYITYDKYY QTPRLWLFGY DEQRQPLTVE HMYEDISQDH 240

VKKTVTIENH PHLPPPPMCS VHPCRHAEVM KKIIETVAEG GGELGVHMYL LIFLKFVQAV 300

IPTIEYDYTR HFTM 314

SEQ ID NO: 44

MTDDKDVLRD VWFGRIPTCF TLYQDEITER EAEPYYLLLP RVSYLTLVTD KVKKHFQKVM 60

RQEDISEIWF EYEGTPLKWH YPIGLLFDLL ASSSALPWNI TVHFKSFPEK DLLHCPSKDA 120

IEAHFMSCMK EADALKHKSQ VINEMQKKDH KQLWMGLQND RFDQFWAINR KLMEYPAEEN 180

GFRYIPFRIY QTTTERPFIQ KLFRPVAADG QLHTLGDLLK EVCPSAIDPE DGEKKNQVMI 240

HGIEPMLETP LQWLSEHLSY PDNFLHISII PQPTD 275

SEQ ID NO: 45

MAAATGDPGL SKLQFAPFSS ALDVGFWHEL TQKKLNEYRL DEAPKDIKGY YYNGDSAGLP 60

ARLTLEFSAF DMSAPTPARC CPAIGTLYNT NTLESFKTAD KKLLLEQAAN EIWESIKSGT 120

ALENPVLLNK FLLLTFADLK KYHFYYWFCY PALCLPESLP LIQGPVGLDQ RFSLKQIEAL 180

ECAYDNLCQT EGVTALPYFL IKYDENMVLV SLLKHYSDFF QGQRTKITIG VYDPCNLAQY 240

PGWPLRNFLV LAAHRWSSSF QSVEWCFRD RTMQGARDVA HSIIFEVKLP EMAFSPDCPK 300

AVGWEKNQKG GMGPRMVNLS ECMDPKRLAE SSVDLNLKLM CWRLVPTLDL DKWSVKCLL 360

LGAGTLGCNV ARTLMGWGVR HITFVDNAKI SYSNPVRQPL YEFEDCLGGG KPKALAAADR 420

LQKIFPGVNA RGFNMSIPMP GHPVNFSSVT LEQARRDVEQ LEQLIESHDV VFLLMDTRES 480

RWLPAVIAAS KRKLVINAAL GFDTFWMRH GLKKPKQQGA GDLCPNHPVA SADLLGSSLF 540

ANIPGYKLGC YFCNDWAPG DSTRDRTLDQ QCTVSRPGLA VIAGALAVEL MVSVLQHPEG 600

GYAIASSSDD RMNEPPTSLG LVPHQIRGFL SRFDNVLPVS LAFDKCTACS SKVLDQYERE 660

GFNFLAKVFN SSHSFLEDLT GLTLLHQETQ AAEIWDMSDD ETI 703

SEQ ID NO: 46

MEGSKTSNNS TMQVSFVCQR CSQPLKLDTS FKILDRVTIQ ELTAPLLTTA QAKPGETQEE 60

ETNSGEEPFI ETPRQDGVSR RFIPPARMMS TESANSFTLI GEASDGGTME NLSRRLKVTG 120

DLFDIMSGQT DVDHPLCEEC TDTLLDQLDT QLNVTENECQ NYKRCLEILE QMNEDDSEQL 180

QMELKELALE EERLIQELED VEKNRKIVAE NLEKVQAEAE RLDQEEAQYQ REYSEFKRQQ 240

LELDDELKSV ENQMRYAQTQ LDKLKKTNVF NATFHIWHSG QFGTINNFRL GRLPSVPVEW 300

NEINAAWGQT VLLLHALANK MGLKFQRYRL VPYGNHSYLE SLTDKSKELP LYCSGGLRFF 360

WDNKFDHAMV AFLDCVQQFK EEVEKGETRF CLPYRMDVEK GKIEDTGGSG GSYSIKTQFN 420

SEEQWTKALK FMLTNLKWGL AWVSSQFYNK 450

SEQ ID NO: 47

MKYTSYILAF QLCIVLGSLG CYCQDPYVKE AENLKKYFNA GHSDVADNGT LFLGILKNWK 60

EESDRKIMQS QIVSFYFKLF KNFKDDQSIQ KSVETIKEDM NVKFFNSNKK KRDDFEKLTN 120

YSVTDLNVQR KAIHELIQVM AELSPAAKTG KRKRSQMLFR GRRASQ 166

SEQ ID NO: 48

MKSGSGGGSP TSLWGLLFLS AALSLWPTSG EICGPGIDIR NDYQQLKRLE NCTVIEGYLH 60

ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVIF 120

EMTNLKDIGL YNLRNITRGA IRIEKNADLC YLSTVDWSLI LDAVSNNYIV GNKPPKECGD 180

LCPGTMEEKP MCEKTTINNE YNYRCWTTNR CQKMCPSTCG KRACTENNEC CHPECLGSCS 240

APDNDTACVA CRHYYYAGVC VPACPPNTYR FEGWRCVDRD FCANILSAES SDSEGFVIHD 300

GECMQECPSG FIRNGSQSMY CIPCEGPCPK VCEEEKKTKT IDSVTSAQML QGCTIFKGNL 360

LINIRRGNNI ASELENFMGL IEWTGYVKI RHSHALVSLS FLKNLRLILG EEQLEGNYSF 420

YVLDNQNLQQ LWDWDHRNLT IKAGKMYFAF NPKLCVSEIY RMEEVTGTKG RQSKGDINTR 480

NNGERASCES DVLHFTSTTT SKNRIIITWH RYRPPDYRDL ISFTVYYKEA PFKNVTEYDG 540

QDACGSNSWN MVDVDLPPNK DVEPGILLHG LKPWTQYAVY VKAVTLTMVE NDHIRGAKSE 600

ILYIRTNASV PSIPLDVLSA SNSSSQLIVK WNPPSLPNGN LSYYIVRWQR QPQDGYLYRH 660 NYCSKDKIPI RKYADGTIDI EEVTENPKTE VCGGEKGPCC ACPKTEAEKQ AEKEEAEYRK 12 VFENFLHNSI FVPRPERKRR DVMQVANTTM SSRSRNTTAA DTYNITDPEE LETEYPFFES 7E RVDNKERTVI SNLRPFTLYR IDIHSCNHEA EKLGCSASNF VFARTMPAEG ADDIPGPVTW 84 EPRPENSIFL KWPEPENPNG LILMYEIKYG SQVEDQRECV SRQEYRKYGG AKLNRLNPGN 9C YTARIQATSL SGNGSWTDPV FFYVQAKTGY ENFIHLIIAL PVAVLLIVGG LVIMLYVFHR 9i KRNNSRLGNG VLYAS PEY FSAADVYVPD EWEVAREKIT MSRELGQGSF GMVYEGVAKG 102 WKDEPETRV AIKT EAAS MRERIEFLNE ASVMKEFNCH HWRLLGWS QGQPTLVIME 10E LMTRGDLKSY LRSLRPEMEN NPVLAPPSLS KMIQMAGEIA DGMAYLNANK FVHRDLAARN 114 CMVAEDFTVK IGDFGMTRDI YETDYYRKGG KGLLPVRWMS PESLKDGVFT TYSDVWSFGV 12C VLWEIATLAE QPYQGLSNEQ VLRFVMEGGL LDKPDNCPDM LFELMRMCWQ YNPKMRPSFL 12i EIISSIKEEM EPGFREVSFY YSEENKLPEP EELDLEPENM ESVPLDPSAS SSSLPLPDRH 132 SGHKAENGPG PGVLVLRASF DERQPYAHMN GGRKNERALP LPQSSTC 13i

SEQ ID NO: 49

MEAMNVEKAS ADGNLPEVIS NIKETLKIVS RTP ITMAG DSGNGMSTFI SALRNTGHEG KASPPTELVK ATQRCASYFS SHFSNWLWD LPGTGSATTT LENYLMEMQF NRYDFIMVAS 12 AQFSMNHVML AKTAEDMGKK FYIVWTKLDM DLSTGALPEV QLLQIRENVL ENLQKERVCE IE IE

SEQ ID NO: 50

MAAASVTPPG SLELLQPGFS KTLLGTKLEA KYLCSACRNV LRRPFQAQCG HRYCSFCLAS ILSSGPQNCA ACVHEGIYEE GISILESSSA FPDNAARREV ESLPAVCPSD GCTWKGTLKE 12 YESCHEGRCP LMLTECPACK GLVRLGEKER HLEHECPERS LSCRHCRAPC CGADVKAHHE IE VCPKFPLTCD GCGKKKIPRE KFQDHVKTCG KCRVPCRFHA IGCLETVEGE KQQEHEVQWL 24 REHLAMLLSS VLEAKPLLGD QSHAGSELLQ RCESLEKKTA TFENIVCVLN REVERVAMTA 3C EACSRQHRLD QDKIEALSSK VQQLERSIGL KDLAMADLEQ KVLEMEASTY DGVFIWKISD 3i FARKRQEAVA GRIPAIFSPA FYTSRYGYKM CLRIYLNGDG TGRGTHLSLF FWMKGPNDA 42 LLRWPFNQKV TLMLLDQNNR EHVIDAFRPD VTSSSFQRPV NDMNIASGCP LFCPVSKMEA 4E KNSYVRDDAI FIKAIVDLTG L 5C

SEQ ID NO: 51

MASQSQGIQQ LLQAEKRAAE KVADARKRKA RRLKQAKEEA QMEVEQYRRE REHEFQSKQQ ί AAMGSQGNLS AEVEQATRRQ VQGMQSSQQR NRERVLAQLL GMVCDVRPQV HPNYRISA 1]

SEQ ID NO: 52

MQPSSLLPLA LCLLAAPASA LVRIPLHKFT SIRRTMSEVG GSVEDLIAKG PVSKYSQAVP AVTEGPIPEV LKNYMDAQYY GEIGIGTPPQ CFTWFDTGS SNLWVPSIHC KLLDIACWIH 12 HKYNSDKSST YVKNGTSFDI HYGSGSLSGY LSQDTVSVPC QSASSASALG GVKVERQVFG IE EATKQPGITF IAAKFDGILG MAYPRISVNN VLPVFDNLMQ QKLVDQNIFS FYLSRDPDAQ 24 PGGELMLGGT DSKYYKGSLS YLNVTRKAYW QVHLDQVEVA SGLTLCKEGC EAIVDTGTSL 3C MVGPVDEVRE LQKAIGAVPL IQGEYMIPCE KVSTLPAITL KLGGKGYKLS PEDYTLKVSQ 3i AGKTLCLSGF MGMDIPPPSG PLWILGDVFI GRYYTVFDRD NNRVGFAEAA RL 4]

SEQ ID NO: 53

MEALIPVINK LQDVFNTVGA DIIQLPQIW VGTQSSGKSS VLESLVGRDL LPRGTGIVTR RPLILQLVHV SQEDKRKTTG EENGVEAEEW GKFLHTKNKL YTDFDEIRQE IENETERISG 12 NNKGVSPEPI HLKIFSPNW NLTLVDLPGM TKVPVGDQPK DIELQIRELI LRFISNPNSI IE ILAVTAANTD MATSEALKIS REVDPDGRRT LAVITKLDLM DAGTDAMDVL MGRVI PVKLG 24 IIGWNRSQL DINNKKSVTD SIRDEYAFLQ KKYPSLANRN GTKYLARTLN RLLMHHIRDC 3C LPELKTRINV LAAQYQSLLN SYGEPVDDKS ATLLQLITKF ATEYCNTIEG TAKYIETSEL 3i CGGARICYIF HETFGRTLES VDPLGGLNTI DILTAIRNAT GPRPALFVPE VSFELLVKRQ 42 IKRLEEPSLR CVELVHEEMQ RIIQHCSNYS TQELLRFPKL HDAIVEWTC LLRKRLPVTN 4E EMVHNLVAIE LAYINTKHPD FADACGLMNN NIEEQRRNRL ARELPSAVSR DKSSKVPSAL 54 APASQEPSPA ASAEADGKLI QDSRRETKNV ASGGGGVGDG VQEPTTGNWR GMLKTSKAEE 6C LLAEEKSKPI PIMPASPQKG HA LLDVPV PVARKLSARE QRDCEVIERL IKSYFLIVRK 660

NIQDSVPKAV MHFL HVKD TLQSELVGQL YKSSLLDDLL TESEDMAQRR KEAADMLKAL 720

QGASQIIAEI RETHLW 736

SEQ ID NO: 54

MAESSDKLYR VEYAKSGRAS CKKCSESIPK DSLRMAIMVQ SPMFDGKVPH WYHFSCFWKV 60

GHSIRHPDVE VDGFSELRWD DQQKVKKTAE AGGVTGKGQD GIGSKAEKTL GDFAAEYAKS 120

NRSTCKGCME KIEKGQVRLS KKMVDPEKPQ LGMIDRWYHP GCFVKNREEL GFRPEYSASQ 180

LKGFSLLATE DKEALKKQLP GVKSEGKRKG DEVDGVDEVA KKKSKKEKDK DSKLEKALKA 240

QNDLIWNIKD ELKKVCSTND LKELLIFNKQ QVPSGESAIL DRVADGMVFG ALLPCEECSG 300

QLVFKSDAYY CTGDVTAWTK CMVKTQTPNR KEWVTPKEFR EISYLKKLKV KKQDRIFPPE 360

TSASVAATPP PSTASAPAAV NSSASADKPL SNMKILTLGK LSRNKDEVKA MIEKLGGKLT 420

GTANKASLCI STKKEVEKMN KKMEEVKEAN IRWSEDFLQ DVSASTKSLQ ELFLAHILSP 480

WGAEVKAEPV EWAPRGKSG AALSKKSKGQ VKEEGINKSE KRMKLTLKGG AAVDPDSGLE 540

HSAHVLEKGG KVFSATLGLV DIVKGTNSYY KLQLLEDDKE NRYWIFRSWG RVGTVIGSNK 600

LEQMPSKEDA IEHFMKLYEE KTGNAWHSKN FTKYPKKFYP LEIDYGQDEE AVKKLTVNPG 660

TKSKLPKPVQ DLIKMIFDVE SMKKAMVEYE IDLQKMPLGK LSKRQIQAAY SILSEVQQAV 720

SQGSSDSQIL DLSNRFYTLI PHDFGMKKPP LLNNADSVQA KVEMLDNLLD IEVAYSLLRG 780

GSDDSSKDPI DVNYEKLKTD IKWDRDSEE AEIIRKYVKN THATTHNAYD LEVIDIFKIE 840

REGECQRYKP FKQLHNRRLL WHGSRTTNFA GILSQGLRIA PPEAPVTGYM FGKGIYFADM 900

VSKSANYCHT SQGDPIGLIL LGEVALGNMY ELKHASHISK LPKGKHSVKG LGKTTPDPSA 960

NISLDGVDVP LGTGISSGVN DTSLLYNEYI VYDIAQVNLK YLLKLKFNFK TSLW 1014

SEQ ID NO: 55

MAARRRRSTG GGRARALNES KRVNNGNTAP EDSSPAKKTR RCQRQESKKM PVAGGKANKD 60

RTEDKQDGMP GRSWASKRVS ESVKALLLKG KAPVDPECTA KVGKAHVYCE GNDVYDVMLN 120

QTNLQFNNNK YYLIQLLEDD AQRNFSVWMR WGRVGKMGQH SLVACSGNLN KAKEIFQKKF 180

LDKTKNNWED REKFEKVPGK YDMLQMDYAT NTQDEEETKK EESLKSPLKP ESQLDLRVQE 240

LIKLICNVQA MEEMMMEMKY NTKKAPLGKL TVAQIKAGYQ SLKKIEDCIR AGQHGRALME 300

ACNEFYTRIP HDFGLRTPPL IRTQKELSEK IQLLEALGDI EIAIKLVKTE LQSPEHPLDQ 360

HYRNLHCALR PLDHESYEFK VISQYLQSTH APTHSDYTMT LLDLFEVEKD GEKEAFREDL 420

HNRMLLWHGS RMSNWVGILS HGLRIAPPEA PITGYMFGKG IYFADMSSKS ANYCFASRLK 480

NTGLLLLSEV ALGQCNELLE ANPKAEGLLQ GKHSTKGLGK MAPSSAHFVT LNGSTVPLGP 540

ASDTGILNPD GYTLNYNEYI VYNPNQVRMR YLLKVQFNFL QLW 583

SEQ ID NO: 56

MAFRQALQLA ACGLAGGSAA VLFSAVAVGK PRAGGDAEPR PAEPPAWAGG ARPGPGVWDP 60

NWDRREPLSL INVRKRNVES GEEELASKLD HYKAKATRHI FLIRHSQYHV DGSLEKDRTL 120

TPLGREQAEL TGLRLASLGL KFNKIVHSSM TRAIETTDII SRHLPGVCKV STDLLREGAP 180

IEPDPPVSHW KPEAVYYEDG ARIEAAFRNY IHRADARQEE DSYEIFICHA NVIRYIVCRA 240

LQFPPEGWLR LSLNNGSITH LVIRPNGRVA LRTLGDTGFM PPDKITRS 288

SEQ ID NO: 57

MQPDMSLNVI KMKSSDFLES AELDSGGFGK VSLCFHRTQG LMIMKTVYKG PNCIEHNEAL 60

LEEAKMMNRL RHSRWKLLG VIIEEGKYSL VMEYMEKGNL MHVLKAEMST PLSVKGRIIL 120

EIIEGMCYLH GKGVIHKDLK PENILVDNDF HIKIADLGLA SFKMWSKLNN EEHNELREVD 180

GTAKKNGGTL YYMAPEHLND AKPTEKSD VYSFAWLWA IFANKEPYEN AICEQQLIMC 240

IKSGNRPDVD DITEYCPREI ISLMKLCWEA NPEARPTFPG IEEKFRPFYL SQLEESVEED 300

VKSLKKEYSN ENAWKRMQS LQLDCVAVPS SRSNSATEQP GSLHSSQGLG MGPVEESWFA 360

PSLEHPQEEN EPSLQSKLQD EANYHLYGSR MDRQTKQQPR QNVAYNREEE RRRRVSHDPF 420

AQQRPYENFQ NTEGKGTAYS SAASHGNAVH QPSGLTSQPQ VLYQNNGLYS SHGFGTRPLD 480

PGTAGPRWY RPIPSHMPSL HNIPVPETNY LGNTPTMPFS SLPPTDESIK YTIYNSTGIQ 540

IGAYNYMEIG GTSSSLLDST NTNFKEEPAA KYQAIFDNTT SLTDKHLDPI RENLGKHWKN 600

CARKLGFTQS QIDEIDHDYE RDGLKEKVYQ MLQKWVMREG IKGATVGKLA QALHQCSRID 660 LLSSLIYVSQ N

SEQ ID NO: 5i

MSCVKLWPSG APAPLVSIEE LENQELVGKG GFGTVFRAQH RKWGYDVAVK IWSKAISRE VKAMASLDNE FVLRLEGVIE KWWDQDPKP ALVTKFMENG SLSGLLQSQC PRPWPLLCRL LKEWLGMFY LHDQNPVLLH RDLKPSNVLL DPELHVKLAD FGLSTFQGGS QSGTGSGEPG GTLGYLAPEL FWWRKAST ASDVYSFGIL MWAVLAGREV ELPTEPSLVY EAVCNRQNRP SLAELPQAGP ETPGLEGLKE LMQLCWSSEP KDRPSFQECL PKTDEVFQMV ENNMNAAVST VKDFLSQLRS SNRRFSIPES GQGGTEMDGF RRTIENQHSR NDVMVSEWLN KLNLEEPPSS VPKKCPSLTK RSRAQEEQVP QAWTAGTSSD SMAQPPQTPE TSTFRNQMPS PTSTGTPSPG PRGNQGAERQ GMNWSCRTPE PNPVTGRPLV NIYNCSGVQV GDNNYLTMQQ TTALPTWGLA PSGKGRGLQH PPPVGSQEGP KDPEAWSRPQ GWYNHSGK

SEQ ID NO: 59

MGDHAWSFLK DFLAGGVAAA VSKTAVAPIE RVKLLLQVQH ASKQISAEKQ YKGIIDCWR IPKEQGFLSF WRGNLANVIR YFPTQALNFA FKDKYKQLFL GGVDRHKQFW RYFAGNLASG GAAGATSLCF VYPLDFARTR LAADVGKGAA QREFHGLGDC IIKIFKSDGL RGLYQGFNVS VQGIIIYRAA YFGVYDTAKG MLPDPKNVHI FVSWMIAQSV TAVAGLVSYP FDTVRRRMMM QSGRKGADIM YTGTVDCWRK IAKDEGAKAF FKGAWSNVLR GMGGAFVLVL YDEIKKYV

SEQ ID NO: 60

MRALRAGLTL ASGAGLGAW EGWRRRREDA RAAPGLLGRL PVLPVAAAAE LPPVPGGPRG PGELAKYGLP GLAQLKSRES YVLCYDPRTR GALWWEQLR PERLRGDGDR RECDFREDDS VHAYHRATNA DYRGSGFDRG HLAAAANHRW SQKAMDDTFY LSNVAPQVPH LNQNAWNNLE KYSRSLTRSY QNVYVCTGPL FLPRTEADGK SYVKYQVIGK NHVAVPTHFF KVLILEAAGG QIELRTYVMP NAPVDEAIPL ERFLVPIESI ERASGLLFVP NILARAGSLK AITAGSK

SEQ ID NO: 61

MASGQGPGPP RQECGEPALP SASEEQVAQD TEEVFRSYVF YRHQQEQEAE GVAAPADPEM

VTLPLQPSST MGQVGRQLAI IGDDINRRYD SEFQTMLQHL QPTAENAYEY FTKIATSLFE

SGINWGRWA LLGFGYRLAL HVYQHGLTGF LGQVTRFWD FMLHHCIARW IAQRGGWVAA

LNLGNGPILN VLWLGWLL GQFWRRFFK S

SEQ ID NO: 62

MDGSGEQPRG GGPTSSEQIM KTGALLLQGF IQDRAGRMGG EAPELALDPV PQDASTKKLS

ECLKRIGDEL DSNMELQRMI AAVDTDSPRE VFFRVAADMF SDGNFNWGRV VALFYFASKL

VLKALCTKVP ELIRTIMGWT LDFLRERLLG WIQDQGGWVR LLKPPHPHHR ALTTAPAPPS

LPPATPLGPW AFWSRSQWCP LPIFRSSDW YNAFSLRV

SEQ ID NO: 63

MNALQEDTPP GPSTVFRPPT SSRPLETPHC REIRIGIAGI TITLSLCGCA NARAPTLRSA

TADNSESTGF KNVPDLRTDQ PKPPSKKRSC DPSEYRVSEL KESLITTTPS RPRTAKRRIR

SEQ ID NO: 65

MQMPAMMSLL LVSVGLMEAL QAQSHPITRR DLFSQEIQLD MALASFDDQY AGCAAAMTAA LPDLNHTEFQ ANQVYADSWT LASSQWQERQ ARWPEWSLSP TRPSPPPLGF RDEHGVALLA YTANSPLHKE FNAAVREAGR SRAHYLHHFS FKTLHFLLTE ALQLLGSGQR PPRCHQVFRG VHGLRFRPAG PRATVRLGGF ASASLKHVAA QQFGEDTFFG IWTCLGAPIK GYSFFPGEEE VLIPPFETFQ VINASRLAQG PARIYLRALG KHSTYNCEYI KDKKCKSGPC HLDNSAMGQS PLSAWSLLL LLWFLWRAF PDGPGLL

SEQ ID NO: 66

MSSLKKILGI KGKGKKSKKL GMAPPPYEEE TPMEYSPSAP YDKSLFGVED MDFHDQRQLR YEKFHFSLKM TVRSNKPFRN YDDVAAAVSN WDHMYIGMAG KRPFYKILAF MGSTLLKATP 120

AVLADQGQPE YHAHCEGRAY LPHRLGPTPP MLNVPEHFRR PFNIGLFRGT IDITLVLFDD 180

ESVDSAPVIW DHFNASRLSS FREKALLFGL ILEKKATGNW VLDSISHFK 229

SEQ ID NO: 67

MGDVEKGKKI FIMKCSQCHT VEKGGKHKTG PNLHGLFGRK TGQAPGYSYT AANKNKGIIW 60

GEDTLMEYLE NPKKYIPGTK MIFVGIKKKE ERADLIAYLK KATNE 105

Claims

WHAT IS CLAIMED IS:

1. An isolated viral particle having a genome comprising open reading frames that encode:

a protein having a sequence comprising SEQ ID NO: 3, or a variant thereof;

a protein having a sequence comprising SEQ ID NO: 4, or a variant thereof;

a protein having a sequence comprising SEQ ID NO: 5, or a variant thereof;

a protein having a sequence comprising SEQ ID NO: 6, or a variant thereof;

a protein having a sequence comprising SEQ ID NO: 7, or a variant thereof; and a protein selected from the group consisting of: Apoptin; Bcl-2-associated death promoter (BAD); BCL2-antagonist/killer 1 (BAK1); BCL2-associated X (BAX); p15 BH3 interacting-domain death agonist, transcript variant 2 (BIDv2); B-cell lymphoma 2 interacting mediator of cell death (BIM); Carbamoyl-phosphate synthetase 2, aspartate

transcarbamylase, and dihydroorotase (CAD); caspase 2 (CASP2); caspace 3 (CASP3); caspace 8 (CASP8); CCAAT-enhancer-binding protein homologous protein (CHOP); DNA fragmentation factor subunit alpha (DFFA); Granzyme B; activated c-Jun N-terminal kinase (JNK); Phorbol-12-myristate-13-acetate-induced protein 1 (PMAPI 1 , also referred to as NOXA); p53 upregulated modulator of apoptosis beta (PUMA beta); p53 upregulated modulator of apoptosis gamma (PUMA gamma); p53-induced death domain protein (PIDD); recombinant ADAM15 disintegrin domain (RAIDD); ubiquitin conjugated Second

Mitochondrial-derived Activator of Caspases (SMAC); autophagy related 12 (ATG12);

autophagy related 3 (ATG3); Beclin-1 (BECN1); solute carrier family 25 member 4

(SLC25A4); Receptor-interacting serine/threonine-protein kinase 1 (RIPK1); Receptor- interacting serine/threonine-protein kinase 3 (RIPK3); short form of Phosphoglycerate mutase family member 5 (PGAM5S); mixed lineage kinase domain-like (MLKL); Cathepsin D; Maraba M; and any variant thereof.

2. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes mixed lineage kinase domain-like (MLKL), for example a protein having the sequence of SEQ ID NO: 13, or a variant thereof.

3. An isolated viral particle having a genome comprising an RNA polynucleotide sequence of SEQ ID NO: 14.

4. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes casepase 2 (CASP2), for example a protein having the sequence of SEQ ID NO: 15, or a variant thereof.

5. An isolated viral particle having a genome comprising an RNA polynucleotide sequence of SEQ ID NO: 16.

6. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes p15 BH3 interacting-domain death agonist, transcript variant 2 (BIDv2), for example a protein having the sequence of SEQ ID NO: 17, or a variant thereof.

7. An isolated viral particle having a genome comprising an RNA polynucleotide sequence of SEQ ID NO: 18.

8. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes Bcl-2-associated death promoter (BAD), for example a protein having the sequence of SEQ ID NO: 19, or a variant thereof.

9. An isolated viral particle having a genome comprising an RNA polynucleotide sequence of SEQ ID NO: 20.

10. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes B-cell lymphoma 2 interacting mediator of cell death (BIM), for example a protein having the sequence of SEQ ID NO: 23, or a variant thereof.

11. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes carbamoyl-phosphate synthetase 2, aspartate

transcarbamylase, and dihydroorotase (CAD), for example a protein having the sequence of SEQ ID NO: 24, or a variant thereof.

12. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes caspace 3 (CASP3), for example a protein having the sequence of SEQ ID NO: 25, or a variant thereof.

13. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes caspace 8 (CASP8), for example a protein having the sequence of SEQ ID NO: 26, or a variant thereof.

14. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes CCAAT-enhancer-binding protein homologous protein

(CHOP), for example a protein having the sequence of SEQ ID NO: 27, or a variant thereof.

15. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes DNA fragmentation factor subunit alpha (DFFA), for example a protein having the sequence of SEQ ID NO: 29, or a variant thereof.

16. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes Granzyme B, for example a protein having the sequence of SEQ ID NO: 30, or a variant thereof.

17. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes activated c-Jun N-terminal kinase alpha2 (JNK a2), for example a protein having the sequence of SEQ ID NO: 31 , or a variant thereof.

18. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes activated c-Jun N-terminal kinase beta2 (JNK b2), for example a protein having the sequence of SEQ ID NO: 32, or a variant thereof.

19. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes Phorbol-12-myristate-13-acetate-induced protein 1

(PMAPI 1 , also referred to as NOXA), for example a protein having the sequence of SEQ ID NO: 33, or a variant thereof.

20. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes p53-induced death domain protein (PIDD), for example a protein having the sequence of SEQ ID NO: 34, or a variant thereof.

21. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes p53 upregulated modulator of apoptosis gamma (PUMA-γ), for example a protein having the sequence of SEQ ID NO: 35, or a variant thereof.

22. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes p53 upregulated modulator of apoptosis beta (PUMA-β), for example a protein having the sequence of SEQ ID NO: 36, or a variant thereof.

23. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes recombinant ADAM 15 disintegrin domain (RAIDD), for example a protein having the sequence of SEQ ID NO: 38, or a variant thereof.

24. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes autophagy related 12 (ATG12), for example a protein having the sequence of SEQ ID NO: 41 , or a variant thereof.

25. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes autophagy related 3 (ATG3), for example a protein having the sequence of SEQ ID NO: 43, or a variant thereof.

26. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes Beclin-1 (BECN1), for example a protein having the sequence of SEQ ID NO: 46, or a variant thereof.

27. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes Cathepsin D, for example a protein having the sequence of SEQ ID NO: 52, or a variant thereof.

28. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes short form of Phosphoglycerate mutase family member 5 (PGAM5S), for example a protein having the sequence of SEQ ID NO: 56, or a variant thereof.

29. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes Receptor-interacting serine/threonine-protein kinase 1 (RIPK1), for example a protein having the sequence of SEQ ID NO: 57, or a variant thereof.

30. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes Receptor-interacting serine/threonine-protein kinase 3

(RIPK3), for example a protein having the sequence of SEQ ID NO: 58, or a variant thereof.

31. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes solute carrier family 25 member 4 (SLC25A4), for example a protein having the sequence of SEQ ID NO: 59, or a variant thereof.

32. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes BCL2-associated (BAK), for example a protein having the sequence of SEQ ID NO: 61 , or a variant thereof.

33. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes BCL2-associated X (BAX), for example a protein having the sequence of SEQ ID NO: 62, or a variant thereof.

34. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes Apoptin, for example a protein having the sequence of SEQ ID NO: 63, or a variant thereof.

35. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes ubiquitin conjugated Second Mitochondrial-derived

Activator of Caspases (SMAC), for example a protein having the sequence of SEQ ID NO: 64, or a variant thereof.

36. The isolated viral particle according to claim 1 , wherein the genome comprises an open reading frame that encodes Maraba M, for example a protein having the sequence of SEQ ID NO: 66, or a variant thereof.

37. An isolated viral particle having a genome comprising open reading frames that encode: a protein having a sequence comprising SEQ ID NO: 3;

a protein having a sequence comprising SEQ ID NO: 4;

a protein having a sequence comprising SEQ ID NO: 5;

a protein having a sequence comprising SEQ ID NO: 6;

a protein having a sequence comprising SEQ ID NO: 7; and

a protein having a sequence comprising SEQ ID NO: 13.

38. An isolated viral particle having a genome comprising open reading frames that encode:

a protein having a sequence comprising SEQ ID NO: 3;

a protein having a sequence comprising SEQ ID NO: 4;

a protein having a sequence comprising SEQ ID NO: 5;

a protein having a sequence comprising SEQ ID NO: 6;

a protein having a sequence comprising SEQ ID NO: 7; and

a protein having a sequence comprising SEQ ID NO: 15.

39. An isolated viral particle having a genome comprising open reading frames that encode:

a protein having a sequence comprising SEQ ID NO: 3;

a protein having a sequence comprising SEQ ID NO: 4;

a protein having a sequence comprising SEQ ID NO: 5;

a protein having a sequence comprising SEQ ID NO: 6;

a protein having a sequence comprising SEQ ID NO: 7; and

a protein having a sequence comprising SEQ ID NO: 17.

40. An isolated viral particle having a genome comprising open reading frames that encode:

a protein having a sequence comprising SEQ ID NO: 3;

a protein having a sequence comprising SEQ ID NO: 4;

a protein having a sequence comprising SEQ ID NO: 5;

a protein having a sequence comprising SEQ ID NO: 6;

a protein having a sequence comprising SEQ ID NO: 7; and

a protein having a sequence comprising SEQ ID NO: 19.

41. Use of an isolated viral particle according to any one of claims 1-40 for the treatment of cancer.

42. The use according to claim 41 wherein the cancer is a brain cancer, such as a glioblastoma.

43. The use according to claim 41 or 42 wherein the isolated viral particle is formulated for direct delivery to the central nervous system, outside the blood/brain barrier, inside the blood/brain barrier, or any combination thereof.

44. The use according to claim 43 wherein the isolated viral particle is formulated for administration via intrathecal, intravenous or intracranial injection.

45. The use according to claim 41 or 42 wherein the isolated viral particle is used to infect a cell and the infected cell is used for the treatment of the cancer.

46. The use according to claim 45 wherein the infected cell is formulated for direct delivery to the central nervous system, outside the blood/brain barrier, inside the blood/brain barrier, or any combination thereof.

47. The use according to claim 45 or 46 wherein the infected cell is formulated for administration via intrathecal, intravenous or intracranial injection.

48. The use according to any one of claims 41-47, wherein the cancer comprises apoptosis-resistant cancer cells.

49. A method for treating cancer comprising administering an isolated viral particle according to any one of claims 1-40 to a patient having cancer.

50. The method according to claim 49 wherein the cancer is brain cancer, such as a glioblastoma.

51. The method according to claim 49 or 50 wherein the isolated viral particle is administered to the patient directly.

52. The method according to claim 51 wherein the isolated viral particle is administered directly to the central nervous system, outside the blood/brain barrier, inside the blood/brain barrier, or any combination thereof.

53. The method according to claim 52 wherein the isolated viral particle is administered to the patient intrathecal^, intravenously or via intracranial injection.

54. The method according to claim 49 or 50 wherein a cell is infected with the isolated viral particle and the infected cell is administered to the patient.

55. The method according to claim 54 wherein the infected cell is administered directly to the central nervous system, outside the blood/brain barrier, inside the blood/brain barrier, or any combination thereof.

56. The method according to claim 55 wherein the infected cell is administered to the patient intrathecal ly, intravenously or via intracranial injection.

57. The method according to any one of claims 49-56, wherein the cancer comprises apoptosis-resistant cancer cells.

58. A kit for the treatment of cancer in a patient, the kit comprising:

the isolated viral particle according to any one of claims 1-40; and

instructions for administration of the isolated viral particle to the patient.

59. The kit according to claim 58, wherein the cancer is brain cancer, such as a glioblastoma.

60. The kit according to claim 58 or 59 wherein the isolated viral particle is formulated for direct delivery to the central nervous system, outside the blood/brain barrier, inside the blood/brain barrier, or any combination thereof.

61. The kit according to claim 60 wherein the isolated viral particle is formulated for administration via intrathecal, intravenous or intracranial injection.

62. The kit according to claim 58 or 59 wherein the isolated viral particle is formulated for infection of a cell and the cell is for delivery to the central nervous system, outside the blood/brain barrier, inside the blood/brain barrier, or any combination thereof.

63. The kit according to claim 62 wherein the cell is for administration via intrathecal, intravenous or intracranial injection.

64. A replication competent form of a virus genome comprising an RNA polynucleotide sequence of SEQ ID NO: 14.

65. A replication competent form of a virus genome comprising an RNA polynucleotide sequence of SEQ ID NO: 16.

66. A replication competent form of a virus genome comprising an RNA polynucleotide sequence of SEQ ID NO: 18.

67. A replication competent form of a virus genome comprising an RNA polynucleotide sequence of SEQ ID NO: 20.