THYMIDINE PHOSPHORYLASE FOR USE IN THE MODULATION OF CELLULAR PROLIFERATION OR CHEMOTAXIS

Abstract: A thymidine phosphorylase for use in medicine. The thymidine phosphorylase may be targeted to a selected location, for example by conjugating it to an antibody directed to a cell-specific antigen. The thymidine phosphorylase modulates cell growth and/or promotes chemotaxis. Cell growth can be increased for wound healing or decreased for tumour therapy.

Description: THYMIDINE PHOSPHORYLASE FOR USE IN THE MODULATION OF CELLULAR PROLIFERATION OR CHEMOTAXIS The present invention relates to compounds for use in medicine. Thymidine phosphorylase (thymine: orthophosphate deoxyribosyltransferase, EC 2.4.2.4) is a cytosolic enzyme which catalyses the reversible phosphorolysis of thymidine and other pyrimidine 2'-deoxyribosides, except for 4-amino substituted compounds such as 2'-deoxycytidine, as follows:- PyrdR + P. ^ Pyr + dR-l-P The phosphorolytic and synthetic reactions may also be used to transfer a deoxyribose moiety of one deoxynucleoside to form a second deoxynucleoside in a nucleoside deoxyribosyl transferase reaction (Schwartz, M. (1971) Eur. J. Biochem. 21, 191-198). Thymidine phosphorylase has been purified and characterised from a number of micro-organisms (Schwartz, M. (1971) Eur. J. Biochem. 21, 191-198, Schwartz, M. (1978) Methods Enzymol. 51, 442-445; Avraham, Y. et al (1990) Biochim. Biophys. Acta 1040, 287-293; Hoffee, P. A. et al (1978) Methods Enzymol. 51, 437-442) and from human tissues (Desgranges, C. et al (1981) Biochim. Biophys. Acta. 654, 211-218; Kubilus, J. et al (1978) Biochim. Biophys. Acta 527, 221-228; Yoshimura et al (1990) Biochim. Biophys. Acta 1034, 107-113). Escherichia coli thymidine phosphorylase is a dimer of 90kD composed of two identical subunits with a molecular weight of 45kD (Schwartz, M. (1978) Methods Enzymol. 51, 442-445; Walter, M. et al (1990) /. Biol. Chem. 265, 14016-14022). The three-dimensional crystal structure of Escherichia coli has been determined to resolution of 2.8 A (Walter, M. et al (1990) /. Biol. Chem. 265, 14016-14022). The monomer subunit consists of a small α-helical domain and a large a/β domain. The active site, which binds both thymidine and phosphate, has been located in a cleft between the two domains. Human thymidine phosphorylase has been identified in many tissues including lymphocytes, heart, spleen, lung and placenta (Yoshimura, A. et al (1990) Biochim. Biophys. Acta. 1034, 107-113) and purified from both placenta (Yoshimura, A. et al (1990) Biochim. Biophys. Acta. 1034, 107-113; Kubilus, J. (1978) Biochem. Biophys. Acta. 527, 221-228) and platelets (Desgranges, C. (1981) Biochim. Biophys. Acta 654, 211-218). It has been suggested that thymidine phosphorylase plays an essential role in maintaining intracellular thymidine homeostasis (Shaw, T. et al (1988) Mutant Res. 200, 99-116). The thymidine salvage pathway requires the action of a permease to transport thymidine across the lipid bilayer. Intracellular thymidine is then phosphorylated by thymidine kinase, generating thymidine monophosphate (TMP) which is further phosphorylated to generate thymidine triphosphate. Thymidine triphosphate not only regulates the thymidine salvage pathway by inhibition of thymidine kinase but also inhibits the production of other deoxyribonucleotides by allosteric effects on ribonucleotide diphosphate reductase. The action of thymidine phosphorylase may therefore be to regulate the size of the intracellular thymidine nucleotide pool and hence the size of the other nucleotide pools via ribonucleotide diphosphate reductase as suggested by Shaw, T. et al (1988) Mutant Res. 200, 99-116, and hence regulate DNA synthesis. There has been no suggestion that thymidine phosphorylase could be used as an extracellular growth factor in medicine. One aspect of the present invention provides a method of modulating cellular proliferation or promoting chemotaxis by the application of a thymidine phosphorylase to an organism. Cellular proliferation is defined herein as being any increase in cell number in the assay using CPAE cells described below in Example 5. The thymidine phosphorylase may be native thymidine phosphorylase from a prokaryotic or eukaryotic source, or a fragment of the native enzyme having thymidine phosphorylase enzymatic activity, or any other polypeptide having thymidine phosphorylase activity. Thymidine phosphorylase enzymatic activity is defined herein as phosphorolysis and/or nucleoside deoxyribosyl transferase activity. Whole thymidine phosphorylase compounds or fragments may be generated by proteolytic cleavage or by recombinant DNA techniques. Preferably, the thymidine phosphorylase has a molecular weight of at least 15 kD, preferably at least 20 kD and/or has a thymidine phosphorylase activity of at least 5%, preferably at least 50% or 90%, of the native E. coli enzyme. Suitably, the thymidine phosphorylase is not nature-identical human thymidine phosphorylase. Domains of thymidine phosphorylase can also be expressed. Preferred regions include amino acids 80-130, and analogues thereof (although such analogues preferably retain one or more of amino acids Lys 84 , His g5 , Ser g6 , Ser 95 , Ser 113 and Thr 123 ); a region including amino acids 165-220, or an analogue thereof (preferably retaining one or more of Arg 171 , Ser 186 , and Lys 190 ); or both regions 80-130 and 165-220, see Figure 1. Other preferred regions include amino acids 1-241, 79-241 and 79-440. These regions can be expressed, as individual polypeptides or as parts of larger polypeptides, as recombinant proteins in any one of a number of host expression systems including mammalian cells, Escherichia coli and Saccharomyces cerevisiae when appropriately adapted by provision of translation/transcription initiation and termination sequences. The thymidine phosphorylase may be produced by recombinant DNA techniques in heterologous hosts. Preferably, the host lacks an endogenous thymidine phosphorylase since then purification of the heterologous thymidine phosphorylase is easier. Saccharomyces cerevisiae may lack an endogenous thymidine phosphorylase. Hosts processing thymidine phosphorylase can have the endogenous thymidine phosphorylase gene deleted, for example by site- directed mutagenesis. Although rapid cellular proliferation is a hallmark of certain disease states it is also a prerequisite of many normal cellular processes, eg in response to tissue damage. Localised, rapid tissue growth and tissue remodelling are required in the wound healing process, where the growth of endothelial cells and the regeneration of a vascular network are necessary following surgical intervention, or for the treatment of burns and ulcers. Endothelial cell regeneration is also required following various surgical techniques where damage or injury results to the endothelial cell lining of the vascular network, for example balloon angioplasty or coronary by-pass surgery; or where an endothelial cell lining has to be generated de novo, for example on synthetic vascular grafts or protheses. By directing a growth- or proliferation-promoting agent to these regions the action of the agent may be localised. Further, such targeting may enable the dosage of the agent required to be reduced since, by accumulating the agent at the required site, a higher localised concentration may be achieved. Thymidine phosphorylase can be conjugated with a targeting portion by use of cross- linking agents as well as by recombinant DNA techniques whereby the thymidine phosphorylase DNA sequence, or a functional portion of it, is cloned adjacent to the DNA sequence of the ligand when the ligand is a protein, and the conjugate expressed as a fusion protein. The targeting agent can be any monoclonal antibody, or active portion thereof, eg Fab or F(ab') 2 fragment, a ligand (natural or synthetic) recognised by an endothelial cell surface receptor or a functional portion thereof, or any other agent which interacts with protein or structures of the endothelial cell. The active antibody portions, eg Fab or F(ab') fragments of antibodies, will retain antigen/target binding but have low non-specific binding. Fab or F(ab') 2 fragments may be obtained by protease digestion, for example using immobilised Protein A and pepsin/papain digestion using ImmunoPure Fab and ImmunoPure F(ab') 2 preparation kits (Pierce). Other active portions of antibodies may be obtained by reduction of the antibodies or antibody fragments into separate heavy and light chains. Molecules targeted by thymidine phosphorylase/antibody conjugates or gene fusions can be endothelial cell surface molecules, extracellular matrix components, for example collagen, fibronectin or laminin, or other blood vessel wall structures. Examples of monoclonal antibodies raised to endothelial surface antigens are Tϋk3 (Dako) and QBendlO (Serotec) which recognise CD34, a glycosylated endothelial cell surface transmembrane protein. Other monoclonal antibodies raised to endothelial cell surface antigens include 9G11, JC70, and By 126 (British Bio-technology) raised to CD31 (also known as PECAM-1) and ESIVC7 raised to the CD36 antigen, which is the thrombospondin receptor (Kuzu et al (1992) J. Clin. Pathol.45, 143-148). QBend20, QBend30 and QBend40 (Serotec) are examples of other monoclonal antibodies which recognise endothelial cell surface antigens. The endothelial cell surface molecules to which the targeting antibodies are raised can be non-specific and recognise a number of different endothelial cell types from different tissues, or can be specific for certain endothelial cell types. Antibody A10-33/1 (Serotec) recognises endothelial cells in metastatic melanomas, H4-7/33 (Serotec) recognises endothelial cells from small capillaries and a wide range of tumour cells, HM15/3 (Serotec) recognises sinusoidal endothelial cells, and IF/10 (Serotec) binds to a 250 kD surface protein on continuous endothelium. Antibodies raised to antigens involved in haemostasis and inflammation can also be used. Antibody 4D10 (Serotec) and BB11 (Benjamin etal (1990) Biochem. Biophys. Res. Commun. 171, 348-353) recognises ELAM-1 present on endothelial cells in acute inflamed tissues. Antibody 4B9 (Carlo, T. and Harlan, J. (1990) Immunol. Rev. 114, 1-24) recognises the VCAM adhesion protein. Antibody 84H10 (Makgabo, M. et al (1988) Nature 331, 86-88) recognises the ICAM1 adhesion protein. Antibody EN7/58 (Serotec) recognises antigens present on inflamed endothelium and on cells adhering to the endothelial cells. Antibody KG7/30 recognises a FVIE related protein on endothelial surfaces of inflamed tissues and tumours. The cytokines IL-1 and TNF stimulate cultured endothelial cells to acquire adhesive properties for various peripheral blood leukocytes in vitro (Bevilaqua, M. et al (1985) . Clin. Invest. 76, 2003; Schleimer, R. et al (1986) /. Immunol 136, 649; Lamas, A. et al (1988) /. Immunol. 140, 1500; Bochner, B. etal (1988) /. Clin. Invest. 81, 1355). This adhesiveness is associated with the induction on endothelial cells of a number of adhesive molecules, including ICAM-1, ELAM-1, GMP-140 (also known as PADGEM or CD62) and VCAM-L These adhesive molecules recognise counter receptors on the surface of the target cell. VCAM-1 recognises an antigen known as VLA-4, also known as CD49d/CD29 and member of the integrin family (Elices, M. et al (1990) Cell 60, 577; Schwartz, B. et al (1990) /. Clin. Invest. 85, 2019). ICAM-1 recognises an antigen known as LFA-1, also known as CD1 la/CD18, another member of the integrin family (Martin, S. et al (1987) Cell 51, 813-819 Fujita, H. et al (1991) Biochem. Biophys. Res. Comm. 177, 664-672). ELAM-1 and GMP-140 (GMP-140 is also known as CD62 or PADGEM), recognise an antigen known as LewisX, also known as CD15, or sialyl-LewisX (Larsen, E. et al (1990) Cell 63, 467-474; McEver, R. (1991) J. Cell. Biochem. 45, 156-161; Shimizu, Y. et al (1991) Nature 349, 799; Picker, L. et al (1991) Nature 349, 796-798; Polley, M. et al (1991) Proc. Natl Acad. Sci. USA. 88, 6224-6228; Lowe, J. et al (1990) Cell 63, 475-484; Tiemeyer, M. et al (1991) Proc. Natl Acad. Sci. USA. 88, 1138-1142). Monoclonal antibodies to either the receptor expressed on the surface of the endothelial cell or counter receptor on the surface of the responding cell have been shown to block interaction of the components necessary for this cell-cell recognition and were instrumental in establishing the mode of recognition (for references see above). A second aspect of this invention provides a conjugate of thymidine phosphorylase and a moiety which specifically binds endothelial cells. Thymidine phosphorylase can be conjugated, by crosslinking or by recombinant DNA techniques, to natural or synthetic ligands which interact with receptors on the endothelial cell surface. Such ligands include growth factors, for example vascular permeability factor (Gitay-Goren, H. et al (1992) J. Biol. Chem. 267, 6093-6098; Bikfalin, A. et al (1991) . Cell. Phys. 149, 50-59; Tischer, E. et al (1991) 266, 11947-11954; Conn, G. et al (1990) PNAS 87, 2628-2632; Keck, P. et al (1989) Science 246, 1309-1312; Leung, D.W. et al (1989) Science 246, 1306-1309); platelet-derived growth factor (Beitz, J. et al (1991) PNAS 88, 2021-2025); and well as other biomolecules such as transferrin andurokinase (Haddock, R. et al (1991) /. Biol. Chem. 266, 21466- 21473). The ligand domain of the conjugates will be recognised by the endothelial cell surface receptor for that ligand and will target the thymidine phosphorylase to the endothelium. An agent with thymidine phosphorylase activity, for example thymidine phosphorylase or a fragment of thymidine phosphorylase with thymidine phosphorylase activity, can also be directed toward a specific adhesion molecule by cross-linking the agent to the counter receptor for that adhesion molecule. In the example of ELAM-1 mediated adhesion, the counter receptor is a carbohydrate determinant known as Lewis-X or sialylated Lewis-X, the terminal structure of which is given in Figure 21. Synthetic carbohydrates with this terminal structure (Kameyama, A. et al (1991) Carbohydrate. Res. 209, C1-C4) or purified from natural sources, for example LNFIII (Calbiochem), are available. The terminal Lewis-X or sialyl Lewis-X determinant can be cross- linked to free sulphydryl groups within the thymidine phosphorylase agent as described in Example 1. This allows specific targeting of the agent to endothelial cells presenting the ELAM-1 adhesion molecule. This moiety may be a monoclonal antibody to endothelial cell surface receptors such as ICAM-1, ELAM-1, GMP-140 or VCAM-1. Alternatively, this moiety may be the counter receptor itself, or a functional portion thereof. Fusion may be achieved by i) chemical cross linking of the moiety, be it a monoclonal antibody or the counter receptor, by techniques known in the art, or ii) by recombinant DNA technology whereby the moiety, when it is a single polypeptide chain, is expressed as a gene fusion with the agent in a suitable host. A number of cell- or stage-specific antibodies have been described. These include, for example antibodies to endothelial cell adhesion molecules, including antibody BB11 (anti-ELAM, Benjamin, C. et al (1990), Biochem. Biophys. Res. Commun. 171, 348-353), antibody 4B9 (anti-VCAM, Carlo, T. and Harlan, J. (1990) Immunol. Rev. 114, 1-24) and antibody 84H10 (anti- ICAM1, Makgobo, M. et al (1988) Nature 331, 86-88). These antibodies, or antibodies like them, can be covalently joined to an agent with structural homology to thymidine phosphorylase, be it full length thymidine phosphorylase or a fragment of it with enzyme activity. This can be achieved by gene fusion whereby the DNA sequence encoding the agent with thymidine phosphorylase activity is spliced into the genes encoding either the heavy or light chain of the antibody. Alternatively the agent can be covalently cross- linked to the antibody via one of a number of bi-functional cross-linking reagent for example disuccinimidyl suberate (DSS); bis (sulfosuccinimidyl) suberate (BS 3 ); dimethyl adipimidate-2 HCl (DMA); dimethyl pimelimidate-2 HCl (DMP); dimethyl suberimidate-2 HCl (DMS) bismaleimidohexane (BMH); m- maleimidobenzoyl-N-hydroxysuccinimide ester (MBS); m-maleimido-benzoyl- N-hydroxysulfosuccinimide ester (sulfo-MBS); succinimidyl 4-(p- maleimidophenyl)butyrate (SMPB); sulfosuccinimidyl 4-(p- maleimidophenyl)butyrate (sulfo-SMPB); N-succinimidyl (4-iodoacetyl) aminobenzoate (SIAB); sulfosuccinimidyl (4-iodoacetyl) aminobenzoate (sulfo- SIAB); succinimidyl 4-(N-maleimidomethyl)cyclohexane-l-carboxylate (SMCC); sulfosuccinimidyl 4-(N-maIeimidomethyI) cyclohexane-1-carboxylate (Sulfo-SMCC) or l,5-difluoro-2,4-dinitrobenzene (DFDNB), (Pierce). While appropriate concentrations of thymidine phosphorylase can be demonstrated to stimulate mammalian cell growth, at superoptimal concentrations mitogenesis can be reduced or inhibited (Figure 19). Therefore, by targeting thymidine phosphorylase to certain cell types where rapid or uncontrolled cellular proliferation is associated with certain disease states, proliferation of these cell types can be reduced. Antibodies recognising antigens related to malignant transformation and angiogenesis can also be used: for example EN2/3 (Serotec) recognises an antigen characteristic of malignant transformed endothelial cells; EN7/44 (Serotec) recognises an angiogenesis related antigen present on proliferating, migrating and budding endothelial cells; and H3-5/47 recognises endothelial cells in angioblasts, angiomas, angiosarcomas and perivascular cells in psoriasis and arthritic tissues. Alternatively, the entity which is recognised by the targeting portion may be a suitable entity which is specifically expressed by tumour cells, which entity is not expressed, or at least not with such frequency, in cells into which one does not wish to introduce the thymidine phosphorylase. The entity which is recognised will often be an antigen. Examples of antigens include those listed in Table 1 below. Monoclonal antibodies which will bind specifically to many of these antigens are already known (for example those given in the Table) but in any case, with today's techniques in relation to monoclonal antibody technology, antibodies can be prepared to most antigens. The antigen-specific portion may be an entire antibody (usually, for convenience and specificity, a monoclonal antibody), a part or parts thereof (for example an F ab fragment, F(ab') 2 , dab or "minimum recognition unit") or a synthetic antibody or part thereof. A compound comprising only part of an antibody may be advantageous by virtue of being less likely to undergo non-specific binding due to the F c part. Suitable monoclonal antibodies to selected antigens may be prepared by known techniques, for example those disclosed in "Monoclonal Antibodies: A manual of techniques'', H. Zola (CRC Press, 1988) and in "Monoclonal Hybridoma Antibodies: Techniques and Applications'', J.G.R. HurreE (CRC Press, 1982). All references mentioned in this specification are incorporated herein by reference. Bispecific antibodies may be prepared by cell fusion, by reassociation of monovalent fragments or by chemical cross-linking of whole antibodies, with one part of the resulting bispecific antibody being directed to the cell-specific antigen and the other to the thymidine phosphorylase. The bispecific antibody can be administered bound to the thymidine phosphorylase or it can be administered first, followed by the thymidine phosphorylase. The former is preferred. Methods for preparing bispecific antibodies are disclosed in Corvalan et al (1987) Cancer Immunol Immunother. 24, 127-132 and 133-137 and 138-143. Bispecific antibodies, chimaeric antibodies and single chain antibodies are discussed generally by Williams in Tibtech, February 1988, Vol. 6, 36-42, Neuberger et al (8th International Biotechnology Symposium, 1988, Part 2, 792-799) and Tan and Morrison (Adv. Drug Delivery Reviews 2, (1988), 129-142). Suitably prepared non-human antibodies can be "humanized" in known ways, for example by inserting the CDR regions of mouse antibodies into the framework of human antibodies. IgG class antibodies are preferred. Table 1 1. Tumour Associated Antigens Antigen Antibody Existing Uses Carcino-embryonic {C46 (Amersham) Imaging & Therapy of colon/rectum tumours. Antigen {85A12 (Unipath) 10 Placental Alkaline H17E2 (ICRF, Travers Imaging & Therapy of testicular and ovarian Phosphatase & Bodmer cancers. Pan carcinoma NR-LU-10 (NeoRx Imaging & Therapy of various carcinomas 15 Corporation) incl. small cell lung cancer. Polymorphic Epithelial HMFG1 (Taylor- Imaging & Therapy of ovarian cancer, Mucin (Human milk fat Papadimitriou, ICRF) pleura! effusions. globule) ø-human Chorionic W14 Targeting of enzyme (CPG2) to human Gonadotropin xenograft choriocarcinoma in nude mice. (Searle et al (1981) Br. J. Cancer 44, 137-144). a Carbohydrate on L6 (IgG2a) 1 Targeting of alkaline phosphatase. Human Carcinomas (Senter et al (1988) P.N.A.S. 85, 4842- 10 4846. CD20 Antigen on B 1F5 (IgG2a) 2 Targeting of alkaline phosphatase. Lymphoma (normal and (Senter et al (1988) P.N.A.S. 85, 4842- and neoplastic) 4846. 15 Ηellstrδm et al (1986) Cancer Res. 46, 3917-3923 2 Clarke et al (1985) P.N.A.S. 82, 1766-1770 Other antigens include alphafoetoprotein, Ca-125 and prostate specific antigen. Immune Cell Antigens Pan T Lymphocyte OKT-3 (Ortho) As anti-rejection therapy for kidney Surface Antigen (CD3) transplants. B-lymphocyte Surface RFB4 (Janossy, Royal Immunotoxin therapy of B cell lymphoma. Antigen (CD22) Free Hospital) Pan T lymphocyte H65 (Bodmer, Knowles Immunotoxin treatment of Acute Graft 10 Surface Antigen (CD5) ICRF, Licensed to Xoma versus Host disease, Rheumatoid Arthritis. Corp., USA) If applied to the treatment of CML or ALL, the ligand binding molecules can be monoclonal antibodies against leukaemia-associated antigens. Examples of these are: anti-CALLA (common acute lymphoblastic leukaemia-associated antigen), J5, BA-3, RFB-1, BA-2, SJ-9A4Du-ALL-l, anti-3-3, anti-3-40, SN1 and CALL2, described in Foon, K.A. et al 1986 Blood 68(1), 1-31, "Review: Immunologic Classification of Leukemia and Lymphoma" . The ligand binding molecules can also be antibodies that identify myeloid cell surface antigens, or antibodies that are reactive with B or T lymphocytes, respectively. Examples of such antibodies are those which identify human myeloid cell surface antigens or those which are reactive with human B or T lymphocytes as described in Foon, K.A. Id. Additional examples are antibodies B43, CD22 and CD19 which are reactive with B lymphocytes can also be used. Alternatively, the entity which is recognised may or may not be antigenic but can be recognised and selectively bound to in some other way. For example, it may be a characteristic cell surface receptor such as the receptor for melanocyte-stimulating hormone (MSH) which is expressed in high numbers in melanoma cells. The targeting portion may then be a compound or part thereof which specifically binds to the entity in a non-immune sense, for example as a substrate or analogue thereof for a cell-surface enzyme or as a messenger. In the case of melanoma cells, the targeting portion may be MSH itself or a part thereof which binds to the MSH receptor. Such MSH peptides are disclosed in, for example, Al-Obeidi et al (1980) J. Med. Chem. 32, 174. The specificity may be indirect: a first cell-specific antibody may be administered, followed by a conjugate of the invention directed against the first antibody. Preferably, the entity which is recognised is not secreted to any relevant extent into body fluids, since otherwise the requisite specificity may not be achieved. The targeting portion of the conjugate of this embodiment of the invention may be linked to the thymidine phosphorylase by any of the conventional ways of linking compounds, for example by disulphide, amide or thioether bonds, such as those generally described in Goodchild, supra or in Connolly (1985) Nucl Acids Res. 13(12), 4485-4502 or in PCT/US85/03312. When applied topically the thymidine phosphorylase can be incorporated into an inert cream or base, to stabilise the thymidine phosphorylase, to allow even application of the thymidine phosphorylase and to maintain the agent at the site of application. This can also be achieved by incorporation of the thymidine phosphorylase, optionally as a component of an inert cream or base, into a bandage or dressing. Alternatively, the thymidine phosphorylase can be applied topically in the form of an aerosol where the thymidine phosphorylase has been previously dissolved or resuspended in, for example, a saline solution. Such formulations can be used either to promote wound healing or to combat tumours. The pharmaceutical carrier may take the form of a graft, to which the thymidine phosphorylase is cross-linked. More specifically in the case of combatting tumours, injectable formulations of the thymidine phosphorylase can be prepared. The anti-tumour conjugates of the invention may be administered in any suitable way, usually parenterally, for example intravenously, intraperitoneally or, preferably (for bladder cancers), intra-vesically (ie into the bladder), or directly into the tumour, in standard sterile, non-pyrogenic formulations of diluents and carriers, for example isotonic saline (when administered intravenously). If needed, because the compound of the invention may be immunogenic, cyclosporin or some other immunosuppressant can be administered to provide a longer period for treatment but usually this will not be necessary. Particular tumours suitable for treatment in accordance with the invention include cancers of the uterine cervix, head, neck, brain gliomas, breast, colon, oesophagus, stomach, liver, pancreas and metastatic forms of any of these. Preferred aspects of the invention will now be described by way of example and with reference to the accompanying drawings in which: Figure 1 shows the amino acid sequence of E. coli thymidine phosphorylase; Figure 2 shows the respective nucleotide sequences of Oligonucleotides 1 to 40; Figure 3 shows the construction of plasmid pDTPl; Figure 4 shows the nucleotide sequence ligated into pUC19 to form pDTPl (Figure 3); Figures 5 to 17 show the construction of plasmids pDTP2, pDTP3, pDTP4, pDTP5, pAYE333, pAYE334, pAYE328, pAYE335, pDBP5, pDBP6, pDTP6, pDTP7 and ρDTP8, respectively; Figure 18 shows the amino acids in various regions of E. coli thymidine phosphorylase, together with corresponding PCR primers; Figure 19 shows the effect of thymidine phosphorylase on HUVE cell mitogenesis (• represents CPAE cells grown in the absence of thymidine phosphorylase; ■ represents cells grown in presence of 100 ng/ml thymidine phosphorylase); Figure 20 shows the effect of thymidine phosphorylase on CPAE cell proliferation; and Figure 21 shows the terminal structure of the LewisX and sialylated LewisX counter receptor. Example 1: Expression of an agent with thymidine phosphorylase activity Unless otherwise stated, all procedures were carried out as described by Maniatis, Fritsch and Sambrook, "Molecular Cloning: A Laboratory Handbook", Cold Spring Harbor Laboratory (1982). The primary amino acid sequence of Escherichia coli thymidine phosphorylase, Figure 1, has been described (Walter, M. et al (1990) . Biol Chem. 265, 14016-14022). A double stranded cDNA was prepared by annealing 40 overlapping single-stranded oligonucleotides. These were designed to encode the amino acid sequence of thymidine phosphorylase, as described by Walter, M. et al (1990), see above. The DNA sequence (5'-*3') of oligonucleotides 1 to 40 is given in Figure 2. Oligonucleotides 1 to 8 were prepared on an Applied Biosystems 380B DNA synthesiser. The oligonucleotides were phosphorylated by T4 polynucleotide kinase. Phosphorylated oligonucleotides 1 to 8 (25 pmol each) were annealed in water for 5 min at 60 °C, following which the solution was allowed to cool to 15°C over the next 60 min. The mixture was made up to 50 mM Tris HCl pH7.5, 10 mM MgCl 2 , 10 mM dithiothreitol, 1 mM ATP (DNA ligase buffer) and T4 DNA Iigase added. The ligation was incubated at 15°C for 18 hours. The ligated product (oligonucleotide duplex I) was purified from a 10% polyacrylamide gel, electrophoresed under nondenaturin conditions. Oligonucleotides 9 to 20 were phosphorylated and ligated in a similar way to generate oligonucleotide duplex It, while oligonucleotides 21 to 40, when phosphorylated and ligated, generated oligonucleotide duplex IE. Oligonucleotide duplexes I, π and HI were ligated into the Smal site of pUC19, generating plasmid pDTPl (Figure 3). The sequence of the DNA insert is shown in Figure 4. Two double-stranded oligonucleotide adapters, oligonucleotide duplexes IV and V, were prepared by annealing oligonucleotides 41 and 42, and oligonucleotides 43 and 44 respectively. Oligonucleotide duplex IV 5'-CATGTTATTC -3 oligonucleotide 41 3'- AATAAGAAT-5' oligonucleotide 42 Oligonucleotide duplex V 5'-ATCTGAATAAC -3 oligonucleotide 43 3'-TAGACTTATTGGTAC-5' oligonucleotide 44 These two adaptors, along with the 1.35 kbp Ddel-EcόKV thymidine phosphorylase DNA sequence from plasmid pDTPl, were ligated into the Escherichia coli expression vector pTrc99A (Pharmacia), digested with Ncol to generate plasmid pDTP2 (Figure 5). The 1.34 kbp Ncol DΝA insert encodes Escherichia coli thymidine phosphorylase with a translation initiation codon, 5'-ATG-3', inserted 5' to the leucine codon at amino acid position 1 (see Figure 1) and a translation termination codon, 5'-TAA-3', inserted 3' to the glutamic acid codon at amino acid position 440 (see Figure 1). Following the introduction of plasmid pDTP2 into Escherichia coli and selection for ampicillin-resistant transformants, thymidine phosphorylase can be expressed from the strong trc promoter. By introducing EcόKL restriction recognition sites at each end of the synthetic thymidine phosphorylase DNA sequence, thymidine phosphorylase can be expressed from the IPTG inducible tac promoter system present in plasmid pKK223-3 (Pharmacia). This was achieved by the same methodology as described above for the trc promoter system. Two double-stranded oligonucleotide adaptors, oligonucleotide duplex Vt and VH, were prepared by . annealing oligonucleotides 45 and 46 and oligonucleotides 47 and 48, respectively. Oligonucleotide duplex VI: 5'-AATTCATGTTATTC -3' oligonucleotide 45 3'- GTACAATAAGAAT-5' oligonucleotide 46 Oligonucleotide duplex VII: 5'-ATCTGAATAAG -3 oligonucleotide 47 3'-TAGACTTATTCTTAA-5' oligonucleotide 48 The two adaptors, along with the 1.315 kbp Ddel-EcoRV thymidine phosphorylase DNA sequence from plasmid pDTPl, were ligated into the Escherichia coli expression vector pKK223-3 (Pharmacia) digested with .EcoRI, to generate plasmid pDTP3 (Figure 6). To facilitate expression of recombinant thymidine phosphorylase in mammalian cells, the 1.34 kbp EcoRI synthetic thymidine phosphorylase DNA sequence from plasmid pDTP3 was purified and ligated into the .EcoRI site of the mammalian expression vector pcDNAI (Invitrogen Corporation), linearised with EcoRI. The resultant plasmid, pDTP4 (Figure 7), once transfected into mammalian cells, for example CHO or COS-7, directs the expression of recombinant thymidine phosphorylase from the CMV promoter. Example 2: Expression in yeast Saccharomyces cerevisiae can be used as an alternative expression host. This host may offer distinct advantages over mammalian- or Escherichia co/t ' -based heterologous expression systems in that Saccharomyces cerevisiae lacks any thymidine kinase activity (Grivell, A.R. and Jackson, J.F. (1968), /. Gen. Microbiol 54, 307-317). Saccharomyces cerevisiae is therefore unable to salvage thymidine and may also lack any thymidine phosphorylase activity. Saccharomyces cerevisiae is a preferred organism for the heterologous expression of thymidine phosphorylase since the heterologous protein would not be contaminated with endogenously produced thymidine phosphorylase. To facilitate the expression of thymidine phosphorylase in the yeast Saccharomyces cerevisiae, HindUl sites were incorporated at the 5' and 3' ends of the synthetic thymidine phosphorylase DNA. Two double-stranded oligonucleotide adaptors, oligonucleotide duplexes Viπ and IX, were prepared by annealing oligonucleotides 49 and 50, and oligonucleotides 51 and 52 respectively: Oligonucleotide duplex VOL 5'-AGCTTAACCTAATTCTAACAAGCAAAGATGTTATTC -3 ' oligO 49 3 '- ATTGGATTAAGATTGTTCGTTTCTACAATAAGAAT-5 ' oligO 50 Oligonucleotide duplex IX: 5'-ATCTGAATAAA -3 ' oligonucleotide 51 3 ' -TAGACTTATTTTCGA-5 ' oligonucleotide 52 These two adaptors and the 1.315 kbp Ddel-EcoRV synthetic thymidine phosphorylase DNA sequence from plasmid pDTPl were ligated into the Saccharomyces cerevisiae expression vector pDBP6 (EP 424 117), linearised with Hindm, to generate plasmid ρDTP5, Figure 8. The expression vector pAYE335 was constructed as follows. A 1.434 kbp Hϋndlll-EcoRI DNA fragment containing the protease B promoter was cloned into the polylinker of the M13 bacteriophage mpl8 (Yanish-Perron et al (1985) Gene 33, 103-119), generating plasmid pAYE333 Figure 9. Plasmid pAYE333 was linearised by partial digestion with SnaBl and the double stranded oligonucleotide duplex X inserted by ligation at the SnaBl site within the PRB1 promoter. Oligonucleotide duplex X: 5 ' -GCGGCCGC-3 ' oligonucleotide 56 3 ' -CGCCGGCG-5 ' oligonucleotide 57 Oligonucleotide sequences 56 and 57 are the same. This generates a Notl restriction site at the 5' end of the protease B promoter. The promoter element was further modified by site directed mutagenesis (oligonucleotide direct in vitro mutagenesis system-Version 2, Amersham) according to the manufacturer's instructions. Mutagenesis with the 31-mer oligonucleotide 5'-CGCCAATAAAAAAACAAGCTTAACCTAATTC-3' (oligo 58, SEQ53) introduces a Ht ' ndlll restriction site close to the ATG translation initiation codon: CGCCAATAAAAAAACAAACTAAACCTAATTCTAACAAGCAAAGATG unmodified [ | Met (Oligo 59, SEQ54) | | * * CGCCAATAAAAAAACAAGCTTAACCTAATTCTAACAAGCAAAGATG modified ' ' Met (oligo 60, SEQ55) Hinάm Plasmid pAAH5 (Goodey etal 1987: In Yeast Biotechnology, 401-429, Edited by Berry, D.R., Russell, I, and Stewart, G.G. Published by Allen and Unwin) was linearised by partially digesting with BamHI. The 5' protruding ends were blunt-ended with T4 DNA polymerase and dNTPs and ligated with the double- stranded oligonucleotide duplex X. A recombinant plasmid pAYE334 (Figure 10) was selected in which a Notl restriction site had replaced the BamHI site at the 3' end of the ADHI terminator. Plasmid pAT153 (Twigg & Sherratt (1980) Nature 283, 216-218) was digested with EcόBI/BamHL and the larger 3.36 kbp DNA fragment purified. The 5' protruding ends were blunt-ended with T4 DNA polymerase and dNTPs and recircularised with the double-stranded oligonucleotide duplex X, generating plasmid pAYE328 (Fig 11). The 0.8 kbp Notl-HindJR modified protease B promoter sequence was placed upstream of the 0.45 kbp HindUl-Notl ADHL transcription terminator on the ρAT153 based plasmid ρAYE328 to generate ρAYE335 (Figure 12). The large 6.38 kbp Htwdlll-ifømHI fragment from the yeast E. coli shuttle vector pJDB207 (Beggs, J.D. 1981 Molecular Genetics in Yeast, Alfred Benzon Symposium 16, 383-395) was treated with the Klenow fragment of E. coli DNA polymerase to create flush ends and ligated with the double stranded oligonucleotide duplex X to generate plasmid pDBP5 (Figure 13). The 1.25 kbp Notl Protease B promoter/ Hl terminator cassette from plasmid pAYE335 (Figure 12) was introduced into the unique Notl site of plasmid pDBP5 generating pDBP6 (Figure 14). Transcription initiation and termination sequences are provided by the PRB1 promoter and ADHl terminator respectively. The thymidine phosphorylase expression plasmid was introduced into the Saccharomyces cerevisiae strain DS569 (MATa, leu∑ pSAC3 (EP 424 117), by the method described by Beggs, J.D. (1978) Nature 275, 104-109. Transformants were selected on a minimal medium lacking leucine (0.15% (w/v) yeast nitrogen base without amino acids and ammonium sulphate (Difco), 5% (w/v) ammonium sulphate, 0.1M citric acid/Na 2 HP0 4 , 12H 2 0 pH6.5, 2% (w/v) sucrose). Transformants were grown for 72 hours at 30°C, 200 rpm in 2000 ml flasks containing either 1000 ml of complex (YEP, 1 % (w/v) yeast extract, 2% (w/v) bactopeptone and 2% (w/v) sucrose), or defined (0.15% (w/v) yeast nitrogen base without amino acids and ammonium sulphate (Difco), 0.5% (w/v) ammonium sulphate, 0.1M citric acid/Na 2 HP0 4 12H 2 0 pH6.5, 2% (w/v) sucrose) liquid medium. Thymidine phosphorylase was purified from Escherichia coli as described by Cook, W. et al (1987) J. Biol. Chem. 262, 3788-3789. Thymidine phosphorylase was purified from mammalian cells by disrupting the cells as described previously (Desgranges, C. et al (1981) Biochim. Biophys. Acta. 654, 211-218), and the enzyme purified as described by Cook et al (1987) /. Biol Chem. 262, 3788-3789. Thymidine phosphorylase was purified from Saccharomyces cerevisiae by centrifuging the culture and resuspending the culture in an equal volume per weight of 50 mM Tris/HCl pH7.6. Cells were lysed by vortexing after the addition of glass beads (40 mesh). The soluble proteins were harvested by centrifugation and the thymidine phosphorylase purified as described by Cook et al (1987) /. Biol. Chem. 262, 3788-3789. Example 3: Expression of three thymidine phosphorylase domains Two double-stranded oligonucleotide adaptors, oligonucleotide duplexes XI and XII, were prepared by annealing oligonucleotides 61 and 62, and oligonucleotides 63 and 64 respectively: Oligonucleotide duplex XI 5'-AGCTTAACCTAATTCTAACAAGCAAAGATGGGTCCAATTG -3' 3'- ATTGGATTAAGATTGTTCGTTTCTACCCAGGTTAACAGCT-5' oligonucleotide 61, SEQ56 oligonucleotide 62, SEQ57 Oligonucleotide duplex XII: 5 '- CGTTGGTGTTGCTAACGGTGCTGGTGTTAGAACTACTGCTTT 3'-TAGCAACCACAACGATTGCCACGACCACAATCTTGATGACGAAA ATTAACTGATTAAA -3 ' oligonucleotide 63, SE 58 TAATTGACTAATTTTCGA-5 ' oligonucleotide 64, SEQ59 To facilitate expression of a domain comprising amino acids 1-241, oligonucleotide duplexes VIII and XII and the 0.66 kbp Ddel-Pvul synthetic thymidine phosphorylase DNA sequence from plasmid pDTPl were ligated into the Saccharomyces cerevisiae expression vector pDBP6 (EP 424 117), linearised with HindDI, to generate plasmid pDTP6 (Figure 15). To facilitate expression of a domain comprising amino acids 79-241 oligonucleotide duplexes XI and XII, and the 0.42 kbp Sat -Pvul synthetic thymidine phosphorylase DNA sequence from plasmid pDTPl were likewise ligated into the Saccharomyces cerevisiae expression vector pDB6 to generate plasmid pDTP7 (Figure 16). To facilitate expression of a domain comprising amino acids 79-440, oligonucleotide duplexes XI and IX and the 1.07 kbp SalL-EcόRV synthetic thymidine phosphorylase DNA sequence from plasmid pDTPl were likewise ligated into vector pDB6 to generate plasmid pDTP8 (Figure 17). Transcription initiation and termination sequences are provided by the PRB1 promoter and ADHl terminator respectively. Plasmids pDTP6, pDTP7 and pDTP8 were independently introduced into the Saccharomyces cerevisiae strain DS569 and cultured as described above. Example 4: Cloning of thymidine phosphorylase from other organisms This can be achieved by designing degenerate single-stranded oligonucleotides based upon the Escherichia coli thymidine phosphorylase amino acid sequence. The preferred regions are amino acids 82-92; 110-133 and 171-196, based on the amino acid sequence described in Figure 1. Within these regions, degenerate DNA sequences can be generated that will encode the amino acids from this region (Figure 18). From these six degenerate DNA sequences, oligonucleotides can be designed that are greater than 10 base pairs in length and have the lowest degeneracy, for example: From domain 82-92 5 ' -GTNGAYAARCAY S-3 ' SEQ 60 3 ' -CANCTRTTYGTRWS-5 ' SEQ 61 33 From domain 110-133 5 ' -CCNATGATHWSNGG-3 ' SEQ 3 ' -GGNTACTADWSNCC-5 ' SEQ From domain 171-196 5 ' -MGNGAYATHACNGC- 3 ' SEQ 3 ' -KCNCTRTADTGNCG-5 ' SEQ These single-stranded DNA primers can be used to amplify regions of t thymidine phosphorylase gene from a number of different species by t polymerase chain reaction (PCR). If the organism is prokaryotic, the PC amplification can be performed on the genomic DNA according to t manufacturer's instruction (GeneAmp, Perkin Elmer Cetus). However, if t organism is eukaryotic, then the PCR amplification should preferably performed on total RNA or mRNA from the desired species. This can achieved by reverse transcribing the mRNA into cDNA/RNA hybrid. This c then be used as a template for PCR amplification according to t manufacturer's instructions (RNA PCR, Perkin Elmer Cetus). The primers (SEQ60-SEQ65) should be used in pairs, SEQ60 with SEQ63 65; SEQ62 with SEQ61 or 65; SEQ64 with SEQ61 or 63; SEQ61 with SE or 64; SEQ63 with SEQ60 or 64; and SEQ65 with SEQ60 or 62. The P amplification cycle conditions should be set to maximise the amplification the desired product. For example, 94°C for 1 min; 37°C for 2 min, 74°C 3 min, 40 cycles of amplification, extending the 74°C incubation by 10 secon every cycle. Alternatively, to reduce spurious priming during ge amplification, touchdown PCR methodologies can be employed, as describ in Don et al (1991) Nucleic Acids Research 19, 4008. Briefly, this procedu employs one relatively stringent annealing temperature (eg 55°C) which reduced by 1°C per cycle for the first 10 cycles of amplification. The fin annealing temperature would then be 45°C. This annealing temperature is th maintained for another 20 to 25 cycles while the amplification portion of t cycle (72°C for 3 min) is extended by 10 seconds per cycle. The PCR amplification product can be blunt-ended with the Klenow fragme of Escherichia coli DNA polymerase and cloned into the Smdi site of pUC19 E. coli can be transformed to ampicillin resistance with the PCR/pUC1 ligation and transformants containing the thymidine phosphorylase DNA o cDNA sequence identified by DNA sequencing. Such a sequence can be use as a hybridisation probe to identify and clone the full length thymidin phosphorylase gene and/or cDNA from appropriate libraries. The full lengt thymidine phosphorylase gene or cDNA can then be tailored for expression from any one of the expression vectors described in Example 1. A full length thymidine phosphorylase DNA clone (cDNA or genomic) can also be identified by standard hybridisation techniques using 5' 32 P end labelled oligonucleotides. These oligonucleotides can be the sequences described earlier, namely SEQ60-65. These are firstly end labelled with [γ- 32 P]ATP and T4 polynucleotide kinase and then used as probes to identify potential thymidine phosphorylase genomic or cDNA clones from within appropriate genomic/cDNA libraries prepared in phage or plasmid vectors. Once identified, the thymidine phosphorylase gene or cDNA can be tailored for expression as before. Example 5: Thymidine phosphorylase stimulates endothelial cell proliferation HUVE cells were supplied by the American Type Culture Collection (ATCC number CRL1730). Reagents were supplied by Sigma Chemical Co Ltd unless otherwise stated. Routine HUVE cell cultivation was performed in Ml 99 containing Earle's salts and sodium bicarbonate, 20% (v/v) Foetal Bovine Serum (FBS), 2 mM L-glutamine, 90 μg/ml endothelial cell growth supplement and 100 μg/ml heparin. HUVE cells were maintained in tissue culture flasks (Falcon) coated with type I collagen from calf skin, cross-linked with 1 cyclohexyl-3-(2-morpholinoethyl)-carbodiimide-metho-p-toluene sulphonat (Macklis et al (1985) In Vitro 21, 189-194). HUVE cells were grown a 36.5°C, 5% C0 2 in a LEEC humidified incubator. HUVE cells were subcultured at a ratio of 1:3 whenever confluent, cells bein disassociated using a 0.5 g l" 1 trypsin, 0.2 g l "1 EDTA solution in Ca 2+ /Mg 2+ free Dulbecco's phosphate buffered saline (DPBS) (0.2 g l '1 KC1, 0.2 g l "1 KH 2 P0 4 , 8 g I' 1 NaCl, 1.15 g l "1 Na 2 HP0 4 ). There was no evidence o transformation or loss of the endothelial morphology under these conditions. A confluent HUVE ceE monolayer was trypsinised, washed and resuspended in M199 (including 2 mM L-glutamine and 20% (v/v) FBS). Duplicate haemocytometer counts were made and the cells were diluted to 4 x 10 4 cells/ml M199 (containing 2 mM L-glutamine and 20% (v/v) FBS). A collagen-coated cluster plate (24 flat bottomed 16 mm diameter wells, Costar) was seeded with approximately 2 x 10 4 cells/well (0.5 ml/well) and incubated for 8 hours at 36.5 °C in an atmosphere which included 5% C0 2 to allow cell attachment and growth factor depletion. Escherichia coli thymidine phosphorylase was added to the wells and cells were incubated for another 18 hours. Sterile [6- 3 H]-thymidine (1.0 μCi/well, 29 Ci/mmol, Amersham International pic) diluted to 10 μl with DPBS was added and the cells were incubated for a further 4 hours. The medium was discarded, the cells washe gently with 3 ml DPBS and the DNA was fixed with 0.5 ml 5% w/ trichloroacetic acid (20 min, ice cold). The trichloroacetic acid was discarded the wells were washed with 3 ml Milli-Q water and the DNA was solubilise with 0.3 ml IM sodium hydroxide (20 min, room temperature, gentl agitation), neutralised with 0.3 ml IM hydrochloric acid and then transferre to vials containing 10 ml scintillation fluid (Aqualuma, Lumac). The tritiu radioactivity was measured by liquid scintillation counting (10 min/vial) usin a Packard Tri-Carb 1500 liquid scintillation analyser (Figure 19). Thymidine phosphorylase stimulates [ 3 H]-thymidine incorporation by HUV cells. A bell-shaped dose-response curve was derived, with maxima stimulation being observed around 40 ng/ml. Thymidine phosphorylase is therefore mitogenic towards endothelial cells. The effect of E. coli thymidine phosphorylase addition on endothelial cell proliferation was determined over an eight day period by the acid phosphatase assay for endothelial cell number, Connolly et al (1986) Anal. Biochem. 152, 136-140. CPAE cells were maintained as previously described by Finnis et al (1992) Yeast 8, 57-60. Cluster plates (24 flat bottomed, 16 mm diameter wells, Costar) were seeded with CPAE cells (10 4 per well) in 0.5 ml minimal essential medium containing 2% heat inactivated (65 °C, 30 min) dialysed (1 kDa cut-off) FBS. 100 μM thymidine, non-essential amino acids and antibiotics. E. coli thymidine phosphorylase in 10 μl DPBS was added to each well to achieve a final concentration of 100 ng/ml. Cells were grown at 36.5°C in an atmosphere which included 5% C0 2 in a humidified incubator. To determine endothelial cell number, the culture medium was discarded and the cells were washed with 1 ml DPBS. Cells were then incubated for 2 hours with a medium containing 0.5 ml 10 mM p-nitrophenyl phosphate (SIGMA 104), 0.1% (v/v) Triton X-100 and 0. IM sodium acetate pH5.5, and the reaction was stopped by the addition of 50 μl IM sodium hydroxide. The absorbance at 405 nm minus the absorbance at 620 nm (A 405 -A 620 ) was determined for each well in the absence of cells and subtracted from the A 405 -A 620 in the presence of cells (Figure 20). In the absence of thymidine phosphorylase, cell number, as indicated by the corrected absorbance, declines. However, in the presence of 100 ng/ml thymidine phosphorylase, the cell number increases. Example 6: Expression of a fusion of thymidine phosphorylase and antibody region Thymidine phosphorylase, or a functional portion thereof, can be expressed as a fusion protein with a functional variable-region of a monoclonal antibody which will direct the thymidine phosphorylase to the chosen location. Total RNA is prepared from 1 x 10 8 hybridoma cells expressing the desired monoclonal antibody. Total RNA was used for first strand cDNA syn using Moloney murine leukaemia virus reverse transcriptase and ra primers at 37°C for 1 hour as described by Chaudhary, V. et al (1990) 87, 1066-1070. The variable light (VJ and (V H ) regions of the an cDNA were amplified by polymerase chain reaction (PCR) using primer 5', V L -3', V H -5' and V H -3') and conditions described by Chaudhary, V. (1990, see above). The V L and V H cDNA segments, when ligated in the 5'_V L _V H -3', are linked by a short peptide linker region. By using appro double-stranded oligonucleotide linkers, this functional antibody variable r can be cloned upstream of the synthetic thymidine phosphorylase describ Figures 1 and 4. The DNA insert encoding the V L -V H -thymidine fusion p was inserted into the HmdIII site of pDBP6 (Figure 14) with the aid of su double-stranded oligonucleotide linkers. The V L -V Η -thymidine phosphor fusion protein can then be expressed from the S. cerevisiae PRB1 pro unless the expression vector is used to transform a suitable host strain, su DS569 (MATa, leul) pSAC3 (EP 424 117). Transformants were selecte cultured as described in Example 2. Example 7: Conjugation An example will now be given of how thymidine phosphorylase, or a funct portion thereof, can be conjugated to antibodies by various coupling/c linking reagents, although this methodology equally applies to the coupling of thymidine phosphorylase to any other protein which would act as a ligand to target thymidine phosphorylase. 1 mg of antibody in 0.5 ml 30 mM HEPES pH7.4 was reacted with 50 μl sulpho-SMCC at 50 mg/ml in 30 mM HEPES pH7.4 (Pierce) for 30 min at 4°C. The sulphydryl reactive antibody was isolated by dialysis into 30 mM HEPES pH7.4. 1 mg thymidine phosphorylase in 0.5 ml in degassed 30 mM HEPES ρH7.4, 1 mM EDTA, was then reacted with the activated antibody at 4°C for 5 min. The thymidine phosphorylase antibody conjugate was isolated by gel filtration. This same procedure can be employed to cross-link thymidine phosphorylase and antibodies if sulpho-MBS is employed as the cross-linking group instead of sulpho-SMCC. SMCC or MBS (Pierce) can also be used as the cross-linking group instead of sulpho-SMCC or sulpho-MBS, in which case the SMCC or MBS should be dissolved in DMSO before use. Thus, 1.5 mg MBS or SMCC was dissolved in 50 μl DMSO. 0.5 mg of thymidine phosphorylase and 0.5 mg of the antibody were added to phosphate buffered saline pH6.0 to a final concentration of 1 mg/ml and mixed in a 10 ml conical flask at 22°C. The MBS or SMCC solution was added to the protein solution and shaken for a further 30 minutes at 22°C. The derivatised protein was desalted by FPLC using a G25 superfine column into PBS pH7.4. Peak fractions were pooled. Where necessary, free sulphydryl groups on the antibody can be blocked with N-ethyl-maleimide and primary amines on the thymidine phosphorylase moiety can be modified by Trant's Reagent (Pierce) to introduce sulphohydryl groups allowing coupling to the activated antibody. Using the same cross-linking groups eg sulfo-SMCC, sulfo-MBS, SMCC and MBS it is also possible to activate the thymidine phosphorylase moiety first as described above and then cross-link the sulphohydryl groups on the targeting ligand, for example the antibody. Thymidine phosphorylase or a functional portion thereof can also be conjugated to synthetic carbohydrates with the Lewis-X or sialyl Lewis-X determinant, Figure 21, or purified natural carbohydrates containing this determinant, eg LNFπi (Calbiochem) by procedures involving chemical spacers like p- aminophenyl, aminophenylethyl and acetyl phenylenediamine as described by Berg, E. et al (1991) J. Biol Chem. 266, 14869-14872. Example 8: Formulation of an agent with thymidine phosphorylase activity Thymidine phosphorylase prepared as above was made up as a 0.01% w/v solution in water-for-injection containing 4.5% w/v human albumin, for injection into a vein adjacent an ulcer or other target site. Alternatively, the thymidine phosphorylase, made up as a 0.01% (w/v) solution in water-for- injection, can be applied to the target site in the form of an aerosol. Example 9: Bioactive graft Thymidine phosphorylase was cross-linked to Dacron vascular prosthetic grafts and human-albumin-coated Dacron grafts, (Hake, V. et al (1991) Thorac. Cardiovasc. Surgeon 39, 208-213). This procedure enhances the rate of endothelial cell growth and hence reduces the time taken to form a confluent endothelium. Thymidine phosphorylase at 2 mg/ml in 30 mM HEPES pH7.4 was reacted with sulpho-SMCC 50 mg/ml in 30 mM HEPES ρH7.4 for 30 min at 4°C in the presence of the vascular prostheses. The thymidine phosphorylase conjugated vascular prostheses were then implanted as required. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Delta Biotechnology Limited (ii) TITLE OF INVENTION: Medicine (iii) NUMBER OF SEQUENCES: 76 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Eric Potter Clar son (B) STREET: St Mary's Court, St Mary's Gate (C) CITY: Nottingham (D) STATE: Nottinghamshire (E) COUNTRY: United Kingdom (F) ZIP: NG7 1LE (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: PatentIn Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: GB 9121815.6 (B) FILING DATE: 14-OCT-1991 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Bassett, Richard S (C) REFERENCE/DOCKET NUMBER: DELF/P9851PC (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (0602) 585800 (B) TELEFAX: (0602) 588122 (C) TELEX: 37540 Potter G (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 440 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: Escherichia coli (B) STRAIN: K12 (ix) FEATURE: (A) NAME/KEY: Protein (B) LOCATION: 1..440 (D) OTHER INFORMATION: /note= "Figure 1" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: Leu Phe Leu Ala Gin Glu lie lie Arg Lys Lys Arg Asp Gly His Ala 1 5 10 15 Leu Ser Asp Glu Glu lie Arg Phe Phe lie Asn Gly lie Arg Asp Asn 20 25 30 Thr lie Ser Glu Gly Gin lie Ala Ala Leu Ala Met Thr He Phe Phe 35 40 45 His Asp Met Thr Met Pro Glu Arg Val Ser Leu Thr Met Ala Met Arg 50 55 60 Asp Ser Gly Thr Val Leu Asp Trp Lys Ser Leu His Leu Asn Gly Pro 65 70 75 80 He Val Asp Lys His Ser Thr Gly Gly Val Gly Asp Val Thr Ser Leu 85 90 95 Met Leu Gly Pro Met Val Ala Ala Cys Gly Gly Tyr He Pro Met He 100 105 110 Ser Gly Arg Gly Leu Gly His Thr Gly Gly Thr Leu Asp Lys Leu Glu 115 120 125 Ser He Pro Gly Phe Asp He Phe Pro Asp Asp Asn Arg Phe Arg Glu 130 135 140 He He Lys Asp Val Gly Val Ala He He Gly Gin Thr Ser Ser Leu 145 150 155 160 Ala Pro Ala Asp Lys Arg Phe Tyr Ala Thr Arg Asp He Thr Ala Thr 165 170 175 Val Asp Ser He Pro Leu He Thr Ala Ser He Leu Ala Lys Lys Leu 180 185 190 Ala Glu Gly Leu Asp Ala Leu Val Met Asp Val Lys Val Gly Ser Gly 195 200 205 Ala Phe Met Pro Thr Tyr Glu Leu Ser Glu Ala Leu Ala Glu Ala He 210 215 220 Val Gly Val Ala Asn Gly Ala Gly Val Arg Thr Thr Ala Leu Leu Thr 225 230 235 240 Asp Met Asn Gin Val Leu Ala Ser Ser Ala Gly Asn Ala Val Glu Val 245 250 255 Arg Glu Ala Val Gin Phe Leu Thr Gly Glu Tyr Arg Asn Pro Arg Leu 260 265 270 Phe Asp Val Thr Met Ala Leu Cys Val Glu Met Leu He Ser Gly Lys 275 280 285 Leu Ala Lys Asp Asp Ala Glu Ala Arg Ala Lys Leu Gin Ala Val Leu 290 295 300 Asp Asn Gly Lys Ala Ala Glu Val Phe Gly Arg Met Val Ala Ala Gin 305 310 315 320 Lys Gly Pro Thr Asp Phe Val Glu Asn Tyr Ala Lys Tyr Leu Pro Thr 325 330 335 Ala Met Leu Thr Lys Ala Val Tyr Ala Asp Thr Glu Gly Phe Val Ser 340 345 350 Glu Met Asp Thr Arg Ala Leu Gly Met Ala Val Val Ala Met Gly Gly 355 360 365 Gly Arg Arg Gin Ala Ser Asp Thr He Asp Tyr Ser Val Gly Phe Thr 370 375 380 Asp Met Ala Arg Leu Gly Asp Gin Val Asp Gly Gin Arg Pro Leu Ala 385 390 395 400 Val He His Ala Lys Asp Glu Asn Asn Trp Gin Glu Ala Ala Lys Ala 405 410 415 Val Lys Ala Ala He Lys Leu Ala Asp Lys Ala Pro Glu Ser Thr Pro 420 425 430 Thr Val Tyr Arg Arg He Ser Glu 435 440 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..71 (D) OTHER INFORMATION: /function= "oligonucleotide 1" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: CTTAGCTCAA GAAATTATTA GAAAAAAAAG AGATGGTCAT GCTTTATCTG ATGAAGAAAT 60 TAGATTCTTC A 71 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..71 (D) OTHER INFORMATION: /function= "oligonucleotide 2" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: TTAACGGTAT TAGAGATAAC ACTATTTCTG AAGGTCAAAT TGCTGCTTTA GCTATGACTA 60 TTTTCTTCCA T 71 (2) INFORMATION FOR SEQ ID NO: : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs . (B) TYPEt nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 3" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: GATATGACTA TGCCAGAAAG AGTTTCTTTA ACTATGGCTA TGAGAGATTC TGGTACTGTT 60 TTAGATTGGA 70 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 27 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..27 (D) OTHER INFORMATION: /function= "oligonucleotide 4" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: AATCTTTACA TTTAAACGGT CCAATTG 27 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 42 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..42 (D) OTHER INFORMATION: /£unction= "oligonucleotide 5" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: TCGACAATTG GACCGTTTAA ATGTAAAGAT TTCCAATCTA AA 42 (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 6" ( i) SEQUENCE DESCRIPTION: SEQ ID NO:7: ACAGTACCAG AATCTCTCAT AGCCATAGTT AAAGAAACTC TTTCTGGCAT AGTCATATCA 60 TGGAAGAAAA 70 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 7" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: TAGTCATAGC TAAAGCAGCA ATTTGACCTT CAGAAATAGT GTTATCTCTA ATACCGTTAA 60 TGAAGAATCT 70 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 61 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME /KEY: misc_feature (B) LOCATION: 1. .61 (D) OTHER INFORMATION: /function= "oligonucleotide 8" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: AATTTCTTCA TCAGATAAAG CATGACCATC TCTTTTTTTT CTAATAATTT CTTGAGCTAA 60 G 61 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 73 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSEϊ NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..73 (D) OTHER INFORMATION: /function= "oligonucleotide 9" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: TCGACAAACA TTCTACTGGT GGTGTTGGTG ATGTTACTTC TTTAATGTTA GGTCCAATGG 60 TTGCTGCTTG TGG 73 (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 10" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: TGGTTACATT CCAATGATTT CTGGTAGAGG TTTAGGTCAT ACTGGTGGTA CTTTAGATAA 60 ATTAGAATCT 70 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 11" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: ATTCCAGGTT TCGATATTTT CCCAGATGAT AACAGATTCA GAGAAATTAT TAAAGATGTT 60 GGTGTTGCTA 70 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 12" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: TTATTGGTCA AACTTCTTCT TTAGCTCCAG CTGATAAAAG ATTCTACGCT ACTAGAGATA 60 TTACTGCTAC 70 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 13" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: TGTTGATTCT ATTCCATTAA TTACTGCTTC TATTTTAGCT AAAAAATTAG CTGAAGGTTT 60 AGATGCTTTA 70 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 74 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..74 (D) OTHER INFORMATION: /function= "oligonucleotide 14" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: GTTATGGATG TTAAAGTTGG TTCTGGTGCT TTCATGCCAA CTTACGAATT ATCTGAAGCC 60 TTGGCTGAAG CGAT 74 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 62 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..62 (D) OTHER INFORMATION: /function= "oligonucleotide 15" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: CGCTTCAGCC AAGGCTTCAG ATAATTCGTA AGTTGGCATG AAAGCACCAG AACCAACTTT 60 AA 62 (2) INFORMATION FOR SEQ ID NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 16" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: CATCCATAAC TAAAGCATCT AAACCTTCAG CTAATTTTTT AGCTAAAATA GAAGCAGTAA 60 TTAATGGAAT 70 (2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 17" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: AGAATCAACA GTAGCAGTAA TATCTCTAGT AGCGTAGAAT CTTTTATCAG CTGGAGCTAA 60 AGAAGAAGTT 70 (2) INFORMATION FOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 18" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: TGACCAATAA TAGCAACACC AACATCTTTA ATAATTTCTC TGAATCTGTT ATCATCTGGG 60 AAAATATCGA 70 (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 19" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: AACCTGGAAT AGATTCTAAT TTATCTAAAG TACCACCAGT ATGACCTAAA CCTCTACCAG 60 AAATCATTGG 70 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 79 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..79 (D) OTHER INFORMATION: /function= "oligonucleotide 20" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: AATGTAACCA CCACAAGCAG CAACCATTGG ACCTAACATT AAAGAAGTAA CATCACCAAC 60 ACCACCAGTA GAATGTTTG 79 (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 66 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..66 (D) OTHER INFORMATION: /function= "oligonucleotide 21" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: CGTTGGTGTT GCTAACGGTG CTGGTGTTAG AACTACTGCT TTATTAACTG ATATGAACCA 60 AGTTTT 66 (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE : (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 22" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: AGCTTCTTCT GCTGGTAACG CTGTTGAAGT TAGAGAAGCT GTTCAATTCT TAACTGGTGA 60 ATACAGAAAC 70 (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 23" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: CCAAGATTAT TCGATGTTAC TATGGCTTTA TGTGTTGAAA TGTTAATTTC TGGTAAATTA 60 GCTAAAGATG 70 (2) INFORMATION FOR SEQ ID NO:25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 24" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: ATGCTGAAGC TAGAGCTAAA TTACAAGCTG TTTTAGATAA CGGTAAAGCT GCTGAAGTTT 60 TCGGTAGAAT 70 (2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 25" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: GGTTGCTGCT CAAAAAGGTC CAACTGATTT CGTTGAAAAC TACGCTAAAT ACTTACCAAC 60 TGCTATGTTA 70 (2) INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 26" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: ACTAAAGCTG TTTACGCTGA TACTGAAGGT TTCGTTTCTG AAATGGATAC TAGAGCTTTA 60 GGTATGGCTG 70 (2) INFORMATION FOR SEQ ID NO:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 27" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: TTGTTGCTAT GGGTGGTGGT AGAAGACAAG CCTCTGATAC TATTGATTAC TCTGTTGGTT 60 TCACTGATAT 70 (2) INFORMATION FOR SEQ ID NO:29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 28" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: GGCTAGATTA GGTGATCAAG TTGATGGTCA AAGACCATTA GCTGTTATTC ATGCTAAAGA 60 TGAAAACAAC 70 (2) INFORMATION FOR SEQ ID NO:30: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 60 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..60 (D) OTHER INFORMATION: /function= "oligonucleotide 29" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30: TGGCAAGAAG CTGCTAAAGC TGTTAAAGCT GCTATTAAAT TAGCTGATAA AGCTCCAGAA 60 (2) INFORMATION FOR SEQ ID NO:31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..29 (D) OTHER INFORMATION: /function= "oligonucleotide 30" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: TCTACTCCAA CTGTTTACAG AAGGATATC 29 (2) INFORMATION FOR SEQ ID NO:32: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..40 (D) OTHER INFORMATION: /function= "oligonucleotide 31" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: GATATCCTTC TGTAAACAGT TGGAGTAGAT TCTGGAGCTT 40 (2) INFORMATION FOR SEQ ID NO:33: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 60 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO ( ix) FEATURE : (A) NAME/KEY: misc_feature (B) LOCATION: 1..60 (D) OTHER INFORMATION: /functions "oligonucleotide 32" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: TATCAGCTAA TTTAATAGCA GCTTTAACAG CTTTAGCAGC TTCTTGCCAG TTGTTTTCAT 60 (2) INFORMATION FOR SEQ ID NO:34: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 69 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..69 (D) OTHER INFORMATION: /function= "oligonucleotide 33" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: CTTTAGCATG AATAACAGCT AATGGTCTTT GACCATCAAC TTGATCACCT AATCTAGCCA 60 TATCAGTGA 69 (2) INFORMATION FOR SEQ ID NO:35: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..71 .(D) OTHER INFORMATION: /function= "oligonucleotide 34" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35: AACCAACAGA GTAATCAATA GTATCAGAGG CTTGTCTTCT ACCACCACCC ATAGCAACAA 60 CAGCCATACC T 71 (2) INFORMATION FOR SEQ ID NO:36: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 35" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36: AAAGCTCTAG TATCCATTTC AGAAACGAAA CCTTCAGTAT CAGCGTAAAC AGCTTTAGTT 60 AACATAGCAG 70 (2) INFORMATION FOR SEQ ID NO:37: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 36" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: TTGGTAAGTA TTTAGCGTAG TTTTCAACGA AATCAGTTGG ACCTTTTTGA GCAGCAACCA 60 TTCTACCGAA 70 (2) INFORMATION FOR SEQ ID NO:38: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 37" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: AACTTCAGCA GCTTTACCGT TATCTAAAAC AGCTTGTAAT TTAGCTCTAG CTTCAGCATC 60 ATCTTTAGCT 70 (2) INFORMATION FOR SEQ ID NO:39: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 69 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..69 (D) OTHER INFORMATION: /£unction= "oligonucleotide 38" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: AATTTACCAG AAATTAACAT TTCAACACAT AAAGCCATAG TAACATCGAA TAATCTTGGG 60 TTTCTGTAT 69 (2) INFORMATION FOR SEQ ID NO:40: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..71 (D) OTHER INFORMATION: /function= "oligonucleotide 39" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40: TCACCAGTTA AGAATTGAAC AGCTTCTCTA ACTTCAACAG CGTTACCAGC AGAAGAAGCT 60 AAAACTTGGT T 71 (2) INFORMATION FOR SEQ ID NO:41: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 57 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..57 (D) OTHER INFORMATION: /function= "oligonucleotide 40" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41: CATATCAGTT AATAAAGCAG TAGTTCTAAC ACCAGCACCG TTAGCAACAC CAACGAT 57 (2) INFORMATION FOR SEQ ID NO:42: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..10 (D) OTHER INFORMATION: /function= "oligonucleotide 41" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42: CATGTTATTC 10 (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..11 (D) OTHER INFORMATION: /function= "oligonucleotide 43" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: ATCTGAATAA C H (2) INFORMATION FOR SEQ ID NO:44: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..15 (D) OTHER INFORMATION: /function= "oligonucleotide 44" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: CATGGTTATT CAGAT 15 (2) INFORMATION FOR SEQ ID NO:45: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..14 (D) OTHER INFORMATION: /function= "oligonucleotide 45" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45: AATTCATGTT ATTC 14 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..13 (D) OTHER INFORMATION: /function= "oligonucleotide 46" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46: TAAGAATAAC ATG 13 (2) INFORMATION FOR SEQ ID NO:47: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..11 (D) OTHER INFORMATION: /function= "oligonucleotide 47" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: ATCTGAATAA G 11 (2) INFORMATION FOR SEQ ID NO:48: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Delta Biotechnology Limited (ii) TITLE OF INVENTION: Medicine (iii) NUMBER OF SEQUENCES: 76 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Eric Potter Clarkson (B) STREET: St Mary's Court, St Mary's Gate (C) CITY: Nottingham (D) STATE: Nottinghamshire (E) COUNTRY: United Kingdom (F) ZIP: NG7 1LE (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: PatentIn Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: GB 9121815.6 (B) FILING DATE: 14-OCT-1991 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Bassett, Richard S (C) REFERENCE/DOCKET NUMBER: DELF/P9851PC (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (0602) 585800 (B) TELEFAX: (0602) 588122 (C) TELEX: 37540 Potter G (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 440 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: Escherichia coli (B) STRAIN: K12 (ix) FEATURE: (A) NAME/KEY: Protein (B) LOCATION: 1..440 (D) OTHER INFORMATION: /note= "Figure 1" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: l : Leu Phe Leu Ala Gin Glu He He Arg Lys Lys Arg Asp Gly His Ala 1 5 10 15 Leu Ser Asp Glu Glu He Arg Phe Phe He Asn Gly He Arg Asp Asn 20 25 30 Thr He Ser Glu Gly Gin He Ala Ala Leu Ala Met Thr He Phe Phe 35 40 45 His Asp Met Thr Met Pro Glu Arg Val Ser Leu Thr Met Ala Met Arg 50 55 60 Asp Ser Gly Thr Val Leu Asp Trp Lys Ser Leu His Leu Asn Gly Pro 65 70 75 80 He Val Asp Lys His Ser Thr Gly Gly Val Gly Asp Val Thr Ser Leu 85 90 95 Met Leu Gly Pro Met Val Ala Ala Cys Gly Gly Tyr He Pro Met He 100 105 110 Ser Gly Arg Gly Leu Gly His Thr Gly Gly Thr Leu Asp Lys Leu Glu 115 120 125 Ser He Pro Gly Phe Asp He Phe Pro Asp Asp Asn Arg Phe Arg Glu 130 135 140 He He Lys Asp Val Gly Val Ala He He Gly Gin Thr Ser Ser Leu 145 150 155 160 Ala Pro Ala Asp Lys Arg Phe Tyr Ala Thr Arg Asp He Thr Ala Thr 165 170 175 Val Asp Ser He Pro Leu He Thr Ala Ser He Leu Ala Lys Lys Leu 180 185 190 Ala Glu Gly Leu Asp Ala Leu Val Met Asp Val Lys Val Gly Ser Gly 195 200 205 Ala Phe Met Pro Thr Tyr Glu Leu Ser Glu Ala Leu Ala Glu Ala He 210 215 220 Val Gly Val Ala Asn Gly Ala Gly Val Arg Thr Thr Ala Leu Leu Thr 225 230 235 240 Asp Met Asn Gin Val Leu Ala Ser Ser Ala Gly Asn Ala Val Glu Val 245 250 255 Arg Glu Ala Val Gin Phe Leu Thr Gly Glu Tyr Arg Asn Pro Arg Leu 260 265 270 Phe Asp Val Thr Met Ala Leu Cys Val Glu Met Leu He Ser Gly Lys 275 280 285 Leu Ala Lys Asp Asp Ala Glu Ala Arg Ala Lys Leu Gin Ala Val Leu 290 295 300 Asp Asn Gly Lys Ala Ala Glu Val Phe Gly Arg Met Val Ala Ala Gin 305 310 315 320 Lys Gly Pro Thr Asp Phe Val Glu Asn Tyr Ala Lys Tyr Leu Pro Thr 325 330 335 Ala Met Leu Thr Lys Ala Val Tyr Ala Asp Thr Glu Gly Phe Val Ser 340 345 350 Glu Met Asp Thr Arg Ala Leu Gly Met Ala Val Val Ala Met Gly Gly 355 360 365 Gly Arg Arg Gin Ala Ser Asp Thr He Asp Tyr Ser Val Gly Phe Thr 370 375 380 SUBSTITUTE SHEET Asp Met Ala Arg Leu Gly Asp Gin Val Asp Gly Gin Arg Pro Leu Ala 385 390 395 400 Val He His Ala Lys Asp Glu Asn Asn Trp Gin Glu Ala Ala Lys Ala 405 410 415 Val Lys Ala Ala He Lys Leu Ala Asp Lys Ala Pro Glu Ser Thr Pro 420 425 430 Thr Val Tyr Arg Arg He Ser Glu 435 440 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..71 (D) OTHER INFORMATION: /function= "oligonucleotide 1" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: CTTAGCTCAA GAAATTATTA GAAAAAAAAG AGATGGTCAT GCTTTATCTG ATGAAGAAAT 60 TAGATTCTTC A 71 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..71 (D) OTHER INFORMATION: /function= "oligonucleotide 2" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: TTAACGGTAT TAGAGATAAC ACTATTTCTG AAGGTCAAAT TGCTGCTTTA GCTATGACTA 60 TTTTCTTCCA T 71 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 3" ( i) SEQUENCE DESCRIPTION: SEQ ID NO:4: GATATGACTA TGCCAGAAAG AGTTTCTTTA ACTATGGCTA TGAGAGATTC TGGTACTGTT 60 TTAGATTGGA 70 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 27 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..27 (D) OTHER INFORMATION: /function= "oligonucleotide 4" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: AATCTTTACA TTTAAACGGT CCAATTG 27 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 42 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO SUBSTITUTE SHEET (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..42 (D) OTHER INFORMATION: /£unction= "oligonucleotide 5" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: TCGACAATTG GACCGTTTAA ATGTAAAGAT TTCCAATCTA AA 42 (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 6" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: ACAGTACCAG AATCTCTCAT AGCCATAGTT AAAGAAACTC TTTCTGGCAT AGTCATATCA 60 TGGAAGAAAA 70 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 7" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: TAGTCATAGC TAAAGCAGCA ATTTGACCTT CAGAAATAGT GTTATCTCTA ATACCGTTAA 60 TGAAGAATCT 70 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 61 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..61 (D) OTHER INFORMATION: /function= "oligonucleotide 8" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: AATTTCTTCA TCAGATAAAG CATGACCATC TCTTTTTTTT CTAATAATTT CTTGAGCTAA 60 G 61 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 73 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..73 (D) OTHER INFORMATION: /function= "oligonucleotide 9" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: TCGACAAACA TTCTACTGGT GGTGTTGGTG ATGTTACTTC TTTAATGTTA GGTCCAATGG 60 TTGCTGCTTG TGG 73 (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO ( ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 10" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: TGGTTACATT CCAATGATTT CTGGTAGAGG TTTAGGTCAT ACTGGTGGTA CTTTAGATAA 60 ATTAGAATCT 70 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 11" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: ATTCCAGGTT TCGATATTTT CCCAGATGAT AACAGATTCA GAGAAATTAT TAAAGATGTT 60 GGTGTTGCTA 70 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 12" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: TTATTGGTCA AACTTCTTCT TTAGCTCCAG CTGATAAAAG ATTCTACGCT ACTAGAGATA 60 TTACTGCTAC 70 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 13" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: TGTTGATTCT ATTCCATTAA TTACTGCTTC TATTTTAGCT AAAAAATTAG CTGAAGGTTT 60 AGATGCTTTA 70 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 74 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..74 (D) OTHER INFORMATION: /function= "oligonucleotide 14" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: GTTATGGATG TTAAAGTTGG TTCTGGTGCT TTCATGCCAA CTTACGAATT ATCTGAAGCC 60 TTGGCTGAAG CGAT 74 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 62 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO SUBSTITUTE SHEET (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..62 (D) OTHER INFORMATION: /function= "oligonucleotide 15" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: CGCTTCAGCC AAGGCTTCAG ATAATTCGTA AGTTGGCATG AAAGCACCAG AACCAACTTT 60 AA 62 (2) INFORMATION FOR SEQ ID NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 16" ( i) SEQUENCE DESCRIPTION: SEQ ID NO:17: CATCCATAAC TAAAGCATCT AAACCTTCAG CTAATTTTTT AGCTAAAATA GAAGCAGTAA 60 TTAATGGAAT 70 (2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 17' (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: AGAATCAACA GTAGCAGTAA TATCTCTAGT AGCGTAGAAT CTTTTATCAG CTGGAGCTAA 60 AGAAGAAGTT 70 (2) INFORMATION FOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 18" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: TGACCAATAA TAGCAACACC AACATCTTTA ATAATTTCTC TGAATCTGTT ATCATCTGGG 60 AAAATATCGA 70 (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 19" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: AACCTGGAAT AGATTCTAAT TTATCTAAAG TACCACCAGT ATGACCTAAA CCTCTACCAG 60 AAATCATTGG 70 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 79 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..79 (D) OTHER INFORMATION: /function= "oligonucleotide 20" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: AATGTAACCA CCACAAGCAG CAACCATTGG ACCTAACATT AAAGAAGTAA CATCACCAAC 60 ACCACCAGTA GAATGTTTG 79 (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 66 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..66 (D) OTHER INFORMATION: /function= "oligonucleotide 21" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: CGTTGGTGTT GCTAACGGTG CTGGTGTTAG AACTACTGCT TTATTAACTG ATATGAACCA 60 AGTTTT 66 (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 22" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: AGCTTCTTCT GCTGGTAACG CTGTTGAAGT TAGAGAAGCT GTTCAATTCT TAACTGGTGA 60 ATACAGAAAC 70 (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 23" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: CCAAGATTAT TCGATGTTAC TATGGCTTTA TGTGTTGAAA TGTTAATTTC TGGTAAATTA 60 GCTAAAGATG 70 (2) INFORMATION FOR SEQ ID NO:25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 24" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: ATGCTGAAGC TAGAGCTAAA TTACAAGCTG TTTTAGATAA CGGTAAAGCT GCTGAAGTTT 60 TCGGTAGAAT 70 (2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear SUBSTITUTE SHEET (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 25" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: GGTTGCTGCT CAAAAAGGTC CAACTGATTT CGTTGAAAAC TACGCTAAAT ACTTACCAAC 60 TGCTATGTTA 70 (2) INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 26" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: ACTAAAGCTG TTTACGCTGA TACTGAAGGT TTCGTTTCTG AAATGGATAC TAGAGCTTTA 60 GGTATGGCTG 70 (2) INFORMATION FOR SEQ ID NO:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function^ "oligonucleotide 27" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: TTGTTGCTAT GGGTGGTGGT AGAAGACAAG CCTCTGATAC TATTGATTAC TCTGTTGGTT 60 TCACTGATAT 70 (2) INFORMATION FOR SEQ ID NO:29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 28" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: GGCTAGATTA GGTGATCAAG TTGATGGTCA AAGACCATTA GCTGTTATTC ATGCTAAAGA 60 TGAAAACAAC 70 (2) INFORMATION FOR SEQ ID NO:30: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 60 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..60 (D) OTHER INFORMATION: /function= "oligonucleotide 29" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30: TGGCAAGAAG CTGCTAAAGC TGTTAAAGCT GCTATTAAAT TAGCTGATAA AGCTCCAGAA 60 (2) INFORMATION FOR SEQ ID NO:31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear SUBSTITUTE SHEET (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..29 (D) OTHER INFORMATION: /function= "oligonucleotide 30" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: TCTACTCCAA CTGTTTACAG AAGGATATC 29 (2) INFORMATION FOR SEQ ID NO:32: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..40 (D) OTHER INFORMATION: /function= "oligonucleotide 31" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: GATATCCTTC TGTAAACAGT TGGAGTAGAT TCTGGAGCTT 40 (2) INFORMATION FOR SEQ ID NO:33: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 60 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..60 (D) OTHER INFORMATION: /function= "oligonucleotide 32" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: TATCAGCTAA TTTAATAGCA GCTTTAACAG CTTTAGCAGC TTCTTGCCAG TTGTTTTCAT 60 (2) INFORMATION FOR SEQ ID NO:34: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 69 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..69 (D) OTHER INFORMATION: /function= "oligonucleotide 33" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: CTTTAGCATG AATAACAGCT AATGGTCTTT GACCATCAAC TTGATCACCT AATCTAGCCA 60 TATCAGTGA 69 (2) INFORMATION FOR SEQ ID NO:35: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..71 (D) OTHER INFORMATION: /function= "oligonucleotide 34" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35: AACCAACAGA GTAATCAATA GTATCAGAGG CTTGTCTTCT ACCACCACCC ATAGCAACAA 60 CAGCCATACC T 71 (2) INFORMATION FOR SEQ ID NO:36: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: CDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 35" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36: AAAGCTCTAG TATCCATTTC AGAAACGAAA CCTTCAGTAT CAGCGTAAAC AGCTTTAGTT 60 AACATAGCAG 70 (2) INFORMATION FOR SEQ ID NO:37: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 36" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: TTGGTAAGTA TTTAGCGTAG TTTTCAACGA AATCAGTTGG ACCTTTTTGA GCAGCAACCA 60 TTCTACCGAA 70 (2) INFORMATION FOR SEQ ID NO:38: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..70 (D) OTHER INFORMATION: /function= "oligonucleotide 37' (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: AACTTCAGCA GCTTTACCGT TATCTAAAAC AGCTTGTAAT TTAGCTCTAG CTTCAGCATC 60 ATCTTTAGCT 70 (2) INFORMATION FOR SEQ ID NO:39: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 69 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..69 (D) OTHER INFORMATION: /function= "oligonucleotide 38" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: AATTTACCAG AAATTAACAT TTCAACACAT AAAGCCATAG TAACATCGAA TAATCTTGGG 60 TTTCTGTAT 69 (2) INFORMATION FOR SEQ ID NO:40: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..71 (D) OTHER INFORMATION: /function= "oligonucleotide 39" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40: TCACCAGTTA AGAATTGAAC AGCTTCTCTA ACTTCAACAG CGTTACCAGC AGAAGAAGCT 60 AAAACTTGGT T 71 (2) INFORMATION FOR SEQ ID NO:41: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 57 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..57 (D) OTHER INFORMATION: /function= "oligonucleotide 40" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41: CATATCAGTT AATAAAGCAG TAGTTCTAAC ACCAGCACCG TTAGCAACAC CAACGAT 57 (2) INFORMATION FOR SEQ ID NO:42: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..10 (D) OTHER INFORMATION: /function= "oligonucleotide 41" ( i) SEQUENCE DESCRIPTION: SEQ ID NO:42: CATGTTATTC 10 (2) INFORMATION FOR SEQ ID NO:43: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..11 (D) OTHER INFORMATION: /function^ "oligonucleotide 43' (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: ATCTGAATAA C 11 (2) INFORMATION FOR SEQ ID NO:44: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..15 (D) OTHER INFORMATION: /function= "oligonucleotide 44" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: CATGGTTATT CAGAT 15 (2) INFORMATION FOR SEQ ID NO:45: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..14 (D) OTHER INFORMATION: /function= "oligonucleotide 45" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45: AATTCATGTT ATTC 14 (2) INFORMATION FOR SEQ ID NO:46: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..13 (D) OTHER INFORMATION: /function= "oligonucleotide 46" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46: TAAGAATAAC ATG 13 (2) INFORMATION FOR SEQ ID NO:47: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..11 (D) OTHER INFORMATION: /function= "oligonucleotide 47" ( i) SEQUENCE DESCRIPTION: SEQ ID NO:47: ATCTGAATAA G 11 (2) INFORMATION FOR SEQ ID NO:48: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..15 (D) OTHER INFORMATION: /function= "oligonucleotide 48" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: AATTCTTATT CAGAT 15 (2) INFORMATION FOR SEQ ID NO:49: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 36 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..36 (D) OTHER INFORMATION: /function= "oligonucleotide 49' (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: AGCTTAACCT AATTCTAACA AGCAAAGATG TTATTC 36 (2) INFORMATION FOR SEQ ID NO:50: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 35 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: CDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..35 (D) OTHER INFORMATION: /function= "oligonucleotide 50" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50: TAAGAATAAC ATCTTTGCTT GTTAGAATTA GGTTA 35 (2) INFORMATION FOR SEQ ID NO:51: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..11 (D) OTHER INFORMATION: /function= "oligonucleotide 51" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51: ATCTGAATAA A 11 (2) INFORMATION FOR SEQ ID NO:52: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..15 (D) OTHER INFORMATION: /function= "oligonucleotide 52" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: AGCTTTTATT CAGAT 15 (2) INFORMATION FOR SEQ ID NO:53: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..31 (D) OTHER INFORMATION: /function= "oligonucleotide 58" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: CGCCAATAAA AAAACAAGCT TAACCTAATT C 31 (2) INFORMATION FOR SEQ ID NO:54: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 46 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..46 (D) OTHER INFORMATION: /function= "oligonucleotide 59" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54: CGCCAATAAA AAAACAAACT AAACCTAATT CTAACAAGCA AAGATG 46 (2) INFORMATION FOR SEQ ID NO:55: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 46 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: CDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..46 (D) OTHER INFORMATION: /function= "oligonucleotide 60" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55: CGCCAATAAA AAAACAAGCT TAACCTAATT CTAACAAGCA AAGATG 46 (2) INFORMATION FOR SEQ ID NO:56: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..40 (D) OTHER INFORMATION: /function= "oligonucleotide 61" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56: AGCTTAACCT AATTCTAACA AGCAAAGATG GGTCCAATTG 40 (2) INFORMATION FOR SEQ ID NO:57: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA SUBSTITUTE SHEET (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: I..40 (D) OTHER INFORMATION: /function= "oligonucleotide 62" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57: TCGACAATTG GACCCATCTT TGCTTGTTAG AATTAGGTTA 40 (2) INFORMATION FOR SEQ ID NO:58: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 56 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..56 (D) OTHER INFORMATION: /function= "oligonucleotide 63" ( i) SEQUENCE DESCRIPTION: SEQ ID NO:58: CGTTGGTGTT GCTAACGGTG CTGGTGTTAG AACTACTGCT TTATTAACTG ATTAAA 56 (2) INFORMATION FOR SEQ ID NO:59: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 62 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..62 (D) OTHER INFORMATION: /function= "oligonucleotide 64" ( i) SEQUENCE DESCRIPTION: SEQ ID NO:59: AGCTTTTAAT CAGTTAATAA AGCAGTAGTT CTAACACCAG CACCGTTAGC AACACCAACG 60 AT 62 (2) INFORMATION FOR SEQ ID NO:60: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: CDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..14 (D) OTHER INFORMATION: /function= "SEQ 70" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60: GTNGAYAARC AYWS 14 (2) INFORMATION FOR SEQ ID NO:61: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..14 (D) OTHER INFORMATION: /function= "SEQ 71" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61: SWRTGYTTRT CNAC 14 (2) INFORMATION FOR SEQ ID NO:62: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: SUBSTITUTE SHEET (A) NAME/KEY: misc_feature (B) LOCATION: 1..14 (D) OTHER INFORMATION: /function= "SEQ 72" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62: CCNATGATHW SNGG 14 (2) INFORMATION FOR SEQ ID NO:63: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..14 (D) OTHER INFORMATION: /function= "SEQ 73" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63: CCNSWDATCA TNGG 14 (2) INFORMATION FOR SEQ ID NO:64: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..14 (D) OTHER INFORMATION: /function= "SEQ 74" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64: MGNGAYATHA CNGC 14 (2) INFORMATION FOR SEQ ID NO:65: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..14 (D) OTHER INFORMATION: /function= "SEQ 75" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65: GCNGTDATRT CNCK 14 (2) INFORMATION FOR SEQ ID NO:66: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1311 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..1311 (D) OTHER INFORMATION: /function= "Figure 4" (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 2..1311 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66: C TTA GCT CAA GAA ATT ATT AGA AAA AAA AGA GAT GGT CAT GCT TTA 46 Leu Ala Gin Glu He He Arg Lys Lys Arg Asp Gly His Ala Leu 1 5 10 15 TCT GAT GAA GAA ATT AGA TTC TTC ATT AAC GGT ATT AGA GAT AAC ACT 94 Ser Asp Glu Glu He Arg Phe Phe He Asn Gly He Arg Asp Asn Thr 20 25 30 ATT TCT GAA GGT CAA ATT GCT GCT TTA GCT ATG ACT ATT TTC TTC CAT 142 He Ser Glu Gly Gin He Ala Ala Leu Ala Met Thr He Phe Phe His 35 40 45 GAT ATG ACT ATG CCA GAA AGA GTT TCT TTA ACT ATG GCT ATG AGA GAT 190 Asp Met Thr Met Pro Glu Arg Val Ser Leu Thr Met Ala Met Arg Asp 50 55 60 TCT GGT ACT GTT TTA GAT TGG AAA TCT TTA CAT TTA AAC GGT CCA ATT 238 Ser Gly Thr Val Leu Asp Trp Lys Ser Leu His Leu Asn Gly Pro He 65 70 75 GTC GAC AAA CAT TCT ACT GGT GGT GTT GGT GAT GTT ACT TCT TTA ATG 286 Val Asp Lys His Ser Thr Gly Gly Val Gly Asp Val Thr Ser Leu Met SUBSTITUTE SHEET 80 85 90 95 TTA GGT CCA ATG GTT GCT GCT TGT GGT GGT TAC ATT CCA ATG ATT TCT 334 Leu Gly Pro Met Val Ala Ala Cys Gly Gly Tyr He Pro Met He Ser 100 105 110 GGT AGA GGT TTA GGT CAT ACT GGT GGT ACT TTA GAT AAA TTA GAA TCT 382 Gly Arg Gly Leu Gly His Thr Gly Gly Thr Leu Asp Lys Leu Glu Ser 115 120 125 ATT CCA GGT TTC GAT ATT TTC CCA GAT GAT AAC AGA TTC AGA GAA ATT 430 He Pro Gly Phe Asp He Phe Pro Asp Asp Asn Arg Phe Arg Glu He 130 135 140 ATT AAA GAT GTT GGT GTT GCT ATT ATT GGT CAA ACT TCT TCT TTA GCT 478 He Lys Asp Val Gly Val Ala He He Gly Gin Thr Ser Ser Leu Ala 145 150 155 CCA GCT GAT AAA AGA TTC TAC GCT ACT AGA GAT ATT ACT GCT ACT GTT 526 Pro Ala Asp Lys Arg Phe Tyr Ala Thr Arg Asp He Thr Ala Thr Val 160 165 170 175 GAT TCT ATT CCA TTA ATT ACT GCT TCT ATT TTA GCT AAA AAA TTA GCT 574 Asp Ser He Pro Leu He Thr Ala Ser He Leu Ala Lys Lys Leu Ala 180 185 190 GAA GGT TTA GAT GCT TTA GTT ATG GAT GTT AAA GTT GGT TCT GGT GCT 622 Glu Gly Leu Asp Ala Leu Val Met Asp Val Lys Val Gly Ser Gly Ala 195 200 205 TTC ATG CCA ACT TAC GAA TTA TCT GAA GCC TTG GCT GAA GCG ATC GTT 670 Phe Met Pro Thr Tyr Glu Leu Ser Glu Ala Leu Ala Glu Ala He Val 210 215 220 GGT GTT GCT AAC GGT GCT GGT GTT AGA ACT ACT GCT TTA TTA ACT GAT 718 Gly Val Ala Asn Gly Ala Gly Val Arg Thr Thr Ala Leu Leu Thr Asp 225 230 235 ATG AAC CAA GTT TTA GCT TCT TCT GCT GGT AAC GCT GTT GAA GTT AGA 766 Met Asn Gin Val Leu Ala Ser Ser Ala Gly Asn Ala Val Glu Val Arg 240 245 250 255 GAA GCT GTT CAA TTC TTA ACT GGT GAA TAC AGA AAC CCA AGA TTA TTC 814 Glu Ala Val Gin Phe Leu Thr Gly Glu Tyr Arg Asn Pro Arg Leu Phe 260 265 270 GAT GTT ACT ATG GCT TTA TGT GTT GAA ATG TTA ATT TCT GGT AAA TTA 862 Asp Val Thr Met Ala Leu Cys Val Glu Met Leu He Ser Gly Lys Leu 275 280 285 GCT AAA GAT GAT GCT GAA GCT AGA GCT AAA TTA CAA GCT GTT TTA GAT 910 Ala Lys Asp Asp Ala Glu Ala Arg Ala Lys Leu Gin Ala Val Leu Asp 290 295 300 AAC GGT AAA GCT GCT GAA GTT TTC GGT AGA ATG GTT GCT GCT CAA AAA 958 Asn Gly Lys Ala Ala Glu Val Phe Gly Arg Met Val Ala Ala Gin Lys 305 310 315 GGT CCA ACT GAT TTC GTT GAA AAC TAC GCT AAA TAC TTA CCA ACT GCT 1006 Gly Pro Thr Asp Phe Val Glu Asn Tyr Ala Lys Tyr Leu Pro Thr Ala 320 325 330 335 ATG TTA ACT AAA GCT GTT TAC GCT GAT ACT GAA GGT TTC GTT TCT GAA 1054 Met Leu Thr Lys Ala Val Tyr Ala Asp Thr Glu Gly Phe Val Ser Glu 340 345 350 ATG GAT ACT AGA GCT TTA GGT ATG GCT GTT GTT GCT ATG GGT GGT GGT 1102 Met Asp Thr Arg Ala Leu Gly Met Ala Val Val Ala Met Gly Gly Gly 355 360 365 AGA AGA CAA GCC TCT GAT ACT ATT GAT TAC TCT GTT GGT TTC ACT GAT 1150 Arg Arg Gin Ala Ser Asp Thr He Asp Tyr Ser Val Gly Phe Thr Asp 370 375 380 ATG GCT AGA TTA GGT GAT CAA GTT GAT GGT CAA AGA CCA TTA GCT GTT 1198 Met Ala Arg Leu Gly Asp Gin Val Asp Gly Gin Arg Pro Leu Ala Val 385 390 395 ATT CAT GCT AAA GAT GAA AAC AAC TGG CAA GAA GCT GCT AAA GCT GTT 1246 He His Ala Lys Asp Glu Asn Asn Trp Gin Glu Ala Ala Lys Ala Val 400 405 410 415 AAA GCT GCT ATT AAA TTA GCT GAT AAA GCT CCA GAA TCT ACT CCA ACT 1294 Lys Ala Ala He Lys Leu Ala Asp Lys Ala Pro Glu Ser Thr Pro Thr 420 425 430 GTT TAC AGA AGG ATA TC 1311 Val Tyr Arg Arg He 435 (2) INFORMATION FOR SEQ ID NO:67: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 436 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67: Leu Ala Gin Glu He He Arg Lys Lys Arg Asp Gly His Ala Leu Ser 1 5 10 15 Asp Glu Glu He Arg Phe Phe He Asn Gly He Arg Asp Asn Thr He 20 25 30 Ser Glu Gly Gin He Ala Ala Leu Ala Met Thr He Phe Phe His Asp 35 40 45 Met Thr Met Pro Glu Arg Val Ser Leu Thr Met Ala Met Arg Asp Ser 50 55 60 Gly Thr Val Leu Asp Trp Lys Ser Leu His Leu Asn Gly Pro He Val 65 70 75 80 Asp Lys His Ser Thr Gly Gly Val Gly Asp Val Thr Ser Leu Met Leu 85 90 95 Gly Pro Met Val Ala Ala Cys Gly Gly Tyr He Pro Met He Ser Gly 100 105 110 Arg Gly Leu Gly His Thr Gly Gly Thr Leu Asp Lys Leu Glu Ser He 115 120 125 Pro Gly Phe Asp He Phe Pro Asp Asp Asn Arg Phe Arg Glu He He 130 135 140 Lys Asp Val Gly Val Ala He He Gly Gin Thr Ser Ser Leu Ala Pro 145 150 155 160 SUBSTITUTE SHEET Ala Asp Lys Arg Phe Tyr Ala Thr Arg Asp He Thr Ala Thr Val Asp 165 170 175 Ser He Pro Leu He Thr Ala Ser He Leu Ala Lys Lys Leu Ala Glu 180 185 190 Gly Leu Asp Ala Leu Val Met Asp Val Lys Val Gly Ser Gly Ala Phe 195 200 205 Met Pro Thr Tyr Glu Leu Ser Glu Ala Leu Ala Glu Ala He Val Gly 210 215 220 Val Ala Asn Gly Ala Gly Val Arg Thr Thr Ala Leu Leu Thr Asp Met 225 230 235 240 Asn Gin Val Leu Ala Ser Ser Ala Gly Asn Ala Val Glu Val Arg Glu 245 250 255 Ala Val Gin Phe Leu Thr Gly Glu Tyr Arg Asn Pro Arg Leu Phe Asp 260 265 270 Val Thr Met Ala Leu Cys Val Glu Met Leu He Ser Gly Lys Leu Ala 275 280 285 Lys Asp Asp Ala Glu Ala Arg Ala Lys Leu Gin Ala Val Leu Asp Asn 290 295 300 Gly Lys Ala Ala Glu Val Phe Gly Arg Met Val Ala Ala Gin Lys Gly 305 310 315 320 Pro Thr Asp Phe Val Glu Asn Tyr Ala Lys Tyr Leu Pro Thr Ala Met 325 330 335 Leu Thr Lys Ala Val Tyr Ala Asp Thr Glu Gly Phe Val Ser Glu Met 340 345 350 Asp Thr Arg Ala Leu Gly Met Ala Val Val Ala Met Gly Gly Gly Arg 355 360 365 Arg Gin Ala Ser Asp Thr He Asp Tyr Ser Val Gly Phe Thr Asp Met 370 375 380 Ala Arg Leu Gly Asp Gin Val Asp Gly Gin Arg Pro Leu Ala Val He 385 390 395 400 His Ala Lys Asp Glu Asn Asn Trp Gin Glu Ala Ala Lys Ala Val Lys 405 410 415 Ala Ala He Lys Leu Ala Asp Lys Ala Pro Glu Ser Thr Pro Thr Val 420 425 430 Tyr Arg Arg He 435 (2) INFORMATION FOR SEQ ID NO:68: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 33 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..33 (D) OTHER INFORMATION: /function= "Fig.18 - region 82-92' (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..33 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68: GTNGAYAARC AYWSNACNGG NGGNGTNGGN GAY 33 (2) INFORMATION FOR SEQ ID NO:69: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Region (B) LOCATION: 1..11 (D) OTHER INFORMATION: /note= "Fig.18 - Amino acid sequence encoded by region 82-92" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69: Val Asp Lys His Ser Thr Gly Gly Val Gly Asp 1 5 10 (2) INFORMATION FOR SEQ ID NO:70: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 72 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..72 (D) OTHER INFORMATION: /function= 'Fig.18 - region 110-133" (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..72 SUBSTITUTE SHEET (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70: CCNATGATHW SNGGNMGNGG NYTNGGNCAY ACNGGNGGNA CNYTNGAYAA RYTNGARWSN 60 ATHCCNGGNT TY 72 (2) INFORMATION FOR SEQ ID NO:71: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Region (B) LOCATION: 1..24 (D) OTHER INFORMATION: /note= "Fig.18 - amino acid sequence encoded by region 110-133" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71: Pro Met He Ser Gly Arg Gly Leu Gly His Thr Gly Gly Thr Leu Asp 1 5 10 15 Lys Leu Glu Ser He Pro Gly Phe 20 (2) INFORMATION FOR SEQ ID NO:72: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 78 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..78 (D) OTHER INFORMATION: /function= "Fig.18 - region 171-196" (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..78 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72: MGNGAYATHA CNGCNACNGT NGAYWSNATH CCNYTNATHA CNGCNWSNAT HYTNGCNAAR 60 AARYTNGCNG ARGGNYTN 78 (2) INFORMATION FOR SEQ ID NO:73: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Region (B) LOCATION: 1..26 (D) OTHER INFORMATION: /note= "Fig.18 - amino acid sequence encoded by region 171-196" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73: Arg Asp He Thr Ala Thr Val Asp Ser He Pro Leu He Thr Ala Ser 1 5 10 15 He Leu Ala Lys Lys Leu Ala Glu Gly Leu 20 25 (2) INFORMATION FOR SEQ ID NO:74: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 33 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..33 (D) OTHER INFORMATION: /function= "Fig.18 - anti-sense to region 82-92" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74: RTCNCCNACN CCNCCNGTNS WRTGYTTRTC NAC 33 (2) INFORMATION FOR SEQ ID NO:75: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 72 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES SUBSTITUTE SHEET (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..72 (D) OTHER INFORMATION: /function= "Fig.18 - anti-sense to region 110-133" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75: RAANCCNGGD ATNSWYTCNA RYTTRTCNAR NGTNCCNCCN GTRTGNCCNA RNCCNCKNCC 60 NSWDATCATN GG 72 (2) INFORMATION FOR SEQ ID NO:76: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 78 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 1..78 (D) OTHER INFORMATION: /function= "Fig.18 - anti-sense to region 171-196" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76: NARNCCYTCN GCNARYTTYT TNGCNARDAT NSWNGCNGTD ATNARNGGDA TNSWRTCNAC 60 NGTNGCNGTD ATRTCNCK 78

Claims: CLAIMS 1. A thymidine phosphorylase for use in medicine. s 2. A thymidine phosphorylase for use in the modulation of cellular proliferation or chemotaxis. 3. A thymidine phosphorylase according to Claim 1 or 2 which is Escherichia coli thymidine phosphorylase, or a functional portion thereof. 4. A conjugate of a thymidine phosphorylase and a targeting portion adapted to target the conjugate to a specific cell type or a specific anatomical location. 5. A pharmaceutically acceptable composition containing a thymidine phosphorylase and a carrier. 6. A method of modulating cellular proliferation or promoting chemotaxis by the application of a thymidine phosphorylase to an organism. SUBSTITUTE SHEET 7. A method of promoting wound healing by the application of a thymidine phosphorylase to an organism having a wound. 8. A method of inhibiting tumour growth by the application of a thymidine phosphorylase to an organism having a tumour.

Inventors: BALLANCE DAVID JAMES, COURTNEY MICHAEL GEORGE, FINNIS CHRISTOPHER JOHN ARTHUR, SLEEP DARRELL, BALLANCE, DAVID, JAMES, COURTNEY, MICHAEL, GEORGE, FINNIS, CHRISTOPHER, JOHN, ARTHUR, SLEEP, DARRELL
Applicants: DELTA BIOTECHNOLOGY LTD, DELTA BIOTECHNOLOGY LIMITED
Application year: 1992
Main classification: A61K47
IPC codes: A61K38, A61K47, A61P1, A61P29, A61P35, C12N9, C12N15, C12R1