AU2002359579A1 - Therapeutic polypeptides, nucleic acids encoding same, and methods of use - Google Patents

Description

WO 03/050245 PCT/US02/38594 THERAPEUTIC POLYPEPTIDES, NUCLEIC ACIDS ENCODING SAME, AND METHODS OF USE FIELD OF THE INVENTION The present invention relates to novel polypeptides, and the nucleic acids encoding them, having properties related to stimulation of biochemical or physiological responses in a cell, a tissue, an organ or an organism. More particularly, the novel polypeptides are gene products of novel genes, or are specified biologically active fragments or derivatives thereof. Methods of use encompass diagnostic and prognostic assay procedures as well as methods of treating diverse pathological conditions.

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WO 03/050245 PCT/USO2/38594 BACKGROUND OF THE INVENTION Eukaryotic cells are characterized by biochemical and physiological processes which under normal conditions are exquisitely balanced to achieve the preservation and propagation of the cells. When such cells are components of multicellular organisms such 5 as vertebrates, or more particularly organisms such as mammals, the regulation of the biochemical and physiological processes involves intricate signaling pathways. Frequently, such signaling pathways involve extracellular signaling proteins, cellular receptors that bind the signaling proteins, and signal transducing components located within the cells. Signaling proteins may be classified as endocrine effectors, paracrine effectors or 10 autocrine effectors. Endocrine effectors are signaling molecules secreted by a given organ into the circulatory system, which are then transported to a distant target organ or tissue. The target cells include the receptors for the endocrine effector, and when the endocrine effector binds, a signaling cascade is induced. Paracrine effectors involve secreting cells and receptor cells in close proximity to each other, for example two different classes of 15 cells in the same tissue or organ. One class of cells secretes the paracrine effector, which then reaches the second class of cells, for example by diffusion through the extracellular fluid. The second class of cells contains the receptors for the paracrine effector; binding of the effector results in induction of the signaling cascade that elicits the corresponding biochemical or physiological effect. Autocrine effectors are highly analogous to paracrine 20 effectors, except that the same cell type that secretes the autocrine effector also contains the receptor. Thus the autocrine effector binds to receptors on the same cell, or on identical neighboring cells. The binding process then elicits the characteristic biochemical or physiological effect. Signaling processes may elicit a variety of effects on cells and tissues including by 25 way of nonlimiting example induction of cell or tissue proliferation, suppression of growth or proliferation, induction of differentiation or maturation of a cell or tissue, and suppression of differentiation or maturation of a cell or tissue. Many pathological conditions involve dysregulation of expression of important effector proteins. In certain classes of pathologies the dysregulation is manifested as 30 diminished or suppressed level of synthesis and secretion of protein effectors. In other classes of pathologies the dysregulation is manifested as increased or up-regulated level of synthesis and secretion of protein effectors. In a clinical setting a subject may be suspected 2 WO 03/050245 PCT/USO2/38594 of suffering from a condition brought on by altered or mis-regulated levels of a protein effector of interest. Therefore there is a need to assay for the level of the protein effector of interest in a biological sample from such a subject, and to compare the level with that characteristic of a nonpathological condition. There also is a need to provide the protein 5 effector as a product of manufacture. Administration of the effector to a subject in need thereof is useful in treatment of the pathological condition. Accordingly, there is a need for a method of treatment of a pathological condition brought on by a diminished or suppressed levels of the protein effector of interest. In addition, there is a need for a method of treatment of a pathological condition brought on by a increased or up-regulated levels of 10 the protein effector of interest. Antibodies are multichain proteins that bind specifically to a given antigen, and bind poorly, or not at all, to substances deemed not to be cognate antigens. Antibodies are comprised of two short chains termed light chains and two long chains termed heavy chains. These chains are constituted of immunoglobulin domains, of which generally there 15 are two classes: one variable domain per chain, one constant domain in light chains, and three or more constant domains in heavy chains. The antigen-specific portion of the immunoglobulin molecules resides in the variable domains; the variable domains of one light chain and one heavy chain associate with each other to generate the antigen-binding moiety. Antibodies that bind immunospecifically to a cognate or target antigen bind with 20 high affinities. Accordingly, they are useful in assaying specifically for the presence of the antigen in a sample. In addition, they have the potential of inactivating the activity of the antigen. Therefore there is a need to assay for the level of a protein effector of interest in a biological sample from such a subject, and to compare this level with that characteristic of 25 a nonpathological condition. In particular, there is a need for such an assay based on the use of an antibody that binds immunospecifically to the antigen. There further is a need to inhibit the activity of the protein effector in cases where a pathological condition arises from elevated or excessive levels of the effector based on the use of an antibody that binds immunospecifically to the effector. Thus, there is a need for the antibody as a product of 30 manufacture. There further is a need for a method of treatment of a pathological condition brought on by an elevated or excessive level of the protein effector of interest based on administering the antibody to the subject. 3 WO 03/050245 PCT/USO2/38594 SUMMARY OF THE INVENTION The invention is based in part upon the discovery of isolated polypeptides including amino acid sequences selected from mature forms of the amino acid sequences selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77. The 5 novel nucleic acids and polypeptides are referred to herein as NOVIa, NOVlb, NOV2a, NOV2b, NOV2c, NOV2d, NOV3a, NOV3b, NOV3c, NOV3d, NOV3e, NOV3f, NOV3g, NOV3h, NOV3i, NOV3j, NOV3k, NOV31, NOV3m, NOV3n, NOV3o, NOV3p, NOV3q, NOV4a, NOV4b, NOV4c, NOV5a, NOV5b, NOV6a, NOV6b, NOV6c, NOV7a, NOV8a, NOV8b, NOV9a, NOV9b, NOV9c, NOV9d, NOV9e, NOV10a, NOV 11la, NOV12a, 10 NOV13a, NOV13b, NOV14a, NOV15a, NOV15b, NOV16a, NOV16b, NOV16c, NOV17a, NOV17b, NOV17c, NOV17d, NOV18a, NOV18b, NOV19a, NOV19b, NOV20a, NOV20b, NOV20c, NOV21a, NOV22a, NOV22b, NOV22c, NOV23a, NOV23b, NOV24a, NOV25a, NOV26a, NOV27a, NOV27b, NOV27c, NOV28a, NOV28b, NOV28c and NOV28d. These nucleic acids and polypeptides, as well as 15 derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as "NOVX" nucleic acid or polypeptide sequences. The invention also is based in part upon variants of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77, wherein any amino acid in the mature form is changed to a different 20 amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed. In another embodiment, the invention includes the amino acid sequences selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between I and 77. In another embodiment, the invention also comprises variants of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is 25 an integer between 1 and 77 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed. The invention also involves fragments of any of the mature forms of the amino acid sequences selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77, or any other amino acid sequence 30 selected from this group. The invention also comprises fragments from these groups in which up to 15% of the residues are changed. In another embodiment, the invention encompasses polypeptides that are naturally occurring allelic variants of the sequence selected from the group consisting of SEQ ID 4 WO 03/050245 PCT/USO2/38594 NO:2n, wherein n is an integer between 1 and 77. These allelic variants include amino acid sequences that are the translations of nucleic acid sequences differing by a single nucleotide from nucleic acid sequences selected from the group consisting of SEQ ID NOS: 2n-l, wherein n is an integer between 1 and 77. The variant polypeptide where any 5 amino acid changed in the chosen sequence is changed to provide a conservative substitution. In another embodiment, the invention comprises a pharmaceutical composition involving a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77 and a pharmaceutically 10 acceptable carrier. In another embodiment, the invention involves a kit, including, in one or more containers, this pharmaceutical composition. In another embodiment, the invention includes the use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease being selected from a pathology associated with a polypeptide with an amino acid 15 sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77 wherein said therapeutic is the polypeptide selected from this group. In another embodiment, the invention comprises a method for determining the presence or amount of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77 in a sample, the 20 method involving providing the sample; introducing the sample to an antibody that binds immunospecifically to the polypeptide; and determining the presence or amount of antibody bound to the polypeptide, thereby determining the presence or amount of polypeptide in the sample. In another embodiment, the invention includes a method for determining the 25 presence of or predisposition to a disease associated with altered levels of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77 in a first mammalian subject, the method involving measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and comparing the amount of the polypeptide in this sample to the 30 amount of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, the disease, wherein an alteration in the expression level of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to the disease. 5 WO 03/050245 PCT/USO2/38594 In another embodiment, the invention involves a method of identifying an agent that binds to a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77, the method including introducing the polypeptide to the agent; and determining whether the agent binds to the 5 polypeptide. The agent could be a cellular receptor or a downstream effector. In another embodiment, the invention involves a method for identifying a potential therapeutic agent for.use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer 10 between 1 and 77, the method including providing a cell expressing the polypeptide of the invention and having a property or function ascribable to the polypeptide; contacting the cell with a composition comprising a candidate substance; and determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an alteration observed in the presence of the substance is not observed when the cell is 15 contacted with a composition devoid of the substance, the substance is identified as a potential therapeutic agent. In another embodiment, the invention involves a method for screening for a modulator of activity or of latency or predisposition to a pathology associated with a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID 20 NO:2n, wherein n is an integer between 1 and 77, the method including administering a test compound to a test animal at increased risk for a pathology associated with the polypeptide of the invention, wherein the test animal recombinantly expresses the polypeptide of the invention; measuring the activity of the polypeptide in the test animal after administering the test compound; and comparing the activity of the protein in the test animal with the 25 activity of the polypeptide in a control animal not administered the polypeptide, wherein a change in the activity of the polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency of, or predisposition to, a pathology associated with the polypeptide of the invention. The recombinant test animal could express a test protein transgene or express the transgene under the control of a promoter at 30 an increased level relative to a wild-type test animal The promoter may or may not b the native gene promoter of the transgene. In another embodiment, the invention involves a method for modulating the activity of a polypeptide with an amino acid sequence selected from the group consisting of SEQ 6 WO 03/050245 PCT/USO2/38594 ID NO:2n, wherein n is an integer between 1 and 77, the method including introducing a cell sample expressing the polypeptide with a compound that binds to the polypeptide in an amount sufficient to modulate the activity of the polypeptide. In another embodiment, the invention involves a method of treating or preventing a 5 pathology associated with a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77, the method including administering the polypeptide to a subject in which such treatment or prevention is desired in an amount sufficient to treat or prevent the pathology in the subject. The subject could be human. 10 In another embodiment, the invention involves a method of treating a pathological state in a mammal, the method including administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide having the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is 15 an integer between 1 and 77 or a biologically active fragment thereof. In another embodiment, the invention involves an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide having an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between I and 77; a variant of a mature form of the 20 amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77 wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer 25 between 1 and 77; a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between I and 77, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence 30 selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77 or any variant of the polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid 7 WO 03/050245 PCT/USO2/38594 residues in the sequence are so changed; and the complement of any of the nucleic acid molecules. In another embodiment, the invention comprises an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence 5 selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 77, wherein the nucleic acid molecule comprises the nucleotide sequence of a naturally occurring allelic nucleic acid variant. In another embodiment, the invention involves an isolated nucleic acid molecule including a nucleic acid sequence encoding a polypeptide having an amino acid sequence 10 selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 77 that encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant. In another embodiment, the invention comprises an isolated nucleic acid molecule 15 having a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 77, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 2n-l, wherein n is an integer between I and 77. 20 In another embodiment, the invention includes an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 77, wherein the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of the nucleotide 25 sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77; a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so 30 changed; a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77; and a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77 is changed from 8 WO 03/050245 PCT/USO2/38594 that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed. In another embodiment, the invention includes an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence 5 selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 77, wherein the nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, or a complement of the nucleotide sequence. 10 In another embodiment, the invention includes an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 77, wherein the nucleic acid molecule has a nucleotide sequence in which any nucleotide specified in the coding sequence of the 15 chosen nucleotide sequence is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides in the chosen coding sequence are so changed, an isolated second polynucleotide that is a complement of the first polynucleotide, or a fragment of any of them. 20 In another embodiment, the invention includes a vector involving the nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 77. This vector can have a promoter operably linked to the nucleic acid molecule. This vector can be located within a 25 cell. In another embodiment, the invention involves a method for determining the presence or amount of a nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer 30 between 1 and 77 in a sample, the method including providing the sample; introducing the sample to a probe that binds to the nucleic acid molecule; and determining the presence or amount of the probe bound to the nucleic acid molecule, thereby determining the presence or amount of the nucleic acid molecule in the sample. The presence or amount of the 9 WO 03/050245 PCT/USO2/38594 nucleic acid molecule is used as a marker for cell or tissue type. The cell type can be cancerous. In another embodiment, the invention involves a method for determining the presence of or predisposition for a disease associated with altered levels of a nucleic acid 5 molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 77 in a first mammalian subject, the method including measuring the amount of the nucleic acid in a sample from the first mammalian subject; and comparing the amount of the nucleic acid in the sample of 10 step (a) to the amount of the nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease. The invention further provides an antibody that binds immunospecifically to a 15 NOVX polypeptide. The NOVX antibody may be monoclonal, humanized, or a fully human antibody. Preferably, the antibody has a dissociation constant for the binding of the NOVX polypeptide to the antibody less than 1 x 10 -9 M. More preferably, the NOVX antibody neutralizes the activity of the NOVX polypeptide. In a further aspect, the invention provides for the use of a therapeutic in the 20 manufacture of a medicament for treating a syndrome associated with a human disease, associated with a NOVX polypeptide. Preferably the therapeutic is a NOVX antibody. In yet a further aspect, the invention provides a method of treating or preventing a NOVX-associated disorder, a method of treating a pathological state in a mammal, and a method of treating or preventing a pathology associated with a polypeptide by 25 administering a NOVX antibody to a subject in an amount sufficient to treat or prevent the disorder. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those 30 described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In 10 WO 03/050245 PCT/USO2/38594 addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description and claims. 5 DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel nucleotides and polypeptides encoded thereby. Included in the invention are the novel nucleic acid sequences, their encoded polypeptides, antibodies, and other related compounds. The sequences are collectively referred to herein as "NOVX nucleic acids" or "NOVX polynucleotides" and the 10 corresponding encoded polypeptides are referred to as "NOVX polypeptides" or "NOVX proteins." Unless indicated otherwise, "NOVX" is meant to refer to any of the novel sequences disclosed herein. Table A provides a summary of the NOVX nucleic acids and their encoded polypeptides. TABLE A. Sequences and Corresponding SEQ ID Numbers SEQ ID SEQ ID NOVX Internal NO NO Homology Assignment Identification (nucleic (amino Homolo acid) acid) NOVla CG102689-01 1 2 Von Ebner's gland protein precursor NOV1b CG102689-02 3 4 Von Ebner's gland protein precursor NOV2a CG103827-01 5 6 Fibulin-2 NOV2b CG103827-02 7 8 Fibulin-2 NOV2c CG103827-03 9 10 Fibulin-2 NOV2d CG103827-04 11 12 Fibulin-2 NOV3a CG105716-09 13 14 Cartilage oligomeric matrix protein NOV3b CG105716-05 15 16 Cartilage oligomeric matrix protein NOV3c CG105716-06 17 18 Cartilage oligomeric matrix protein NOV3d CG105716-04 19 20 Cartilage oligomeric matrix protein NOV3e CG105716-03 21 22 Cartilage oligomeric matrix protein NOV3f CG105716-02 23 24 Fibulin-2 NOV3g CG105716-01 25 26 Germline oligomeric matrix protein NOV3h 207569245 27 28 Cartilage oligomeric matrix protein NOV3i 207569277 29 30 Cartilage oligomeric matrix protein NOV3j 207569281 31 32 Cartilage oligomeric matrix protein NOV3k 248644823 33 34 Cartilage oligomeric matrix protein NOV31 248644900 35 36 Cartilage oligomeric matrix protein NOV3m 248576435 37 38 Cartilage oligomeric matrix protein NOV3n 310681505 39 40 Cartilage oligomeric matrix protein NOV3o CG105716-07 41 42 Cartilage oligomeric matrix protein NOV3p CG105716-08 43 44 Cartilage oligomeric matrix protein NOV3q CG105716-10 45 46 Cartilage oligomeric matrix protein NOV4a CG153910-01 47 48 Secreted protein CGI-100 11 WO 03/050245 PCT/USO2/38594 NOV4b CG153910-02 49 50 Secreted protein CGI-100 NOV4c CG153910-03 51 52 Secreted protein CGI-100 NOV5a CG158564-02 53 54 Interferon induced transmembrane NOV5b CG158564-01 55 56 Interferon induced transmembrane NOV6a CG159093-01 57 58 Type Ib membrane protein NOV6b CG159093-02 59 60 Type Ib membrane protein NOV6c CG159093-03 61 62 Type Ib membrane protein NOV7a CG159390-01 63 64 Thrombospondin type I domain containing protein NOV8a CG159498-01 65 66 ST7L isoform 4 membrane protein NOV8b CG159498-02 67 68 ST7L isoform-4 membrane protein NOV9a CG160152-01 69 70 MS4A7 NOV9b CG160152-03 71 72 MS4A7 NOV9c CG160152-02 73 74 MS4A7 NOV9d CG160152-04 75 76 MS4A7 NOV9e CG160152-05 77 78 MS4A7 NOV10a CG160185-01 79 80 Membrane protein NOV1 1a CG160244-01 81 82 Type IIIa membrane protein Lectin C-type and SCP domain containing NOV12a CG160541-01 83 84 extracellular protein NOV13a CG161630-01 85 86 Soggy-1 protein precursor NOV13b CG161630-02 87 88 Soggy-1 protein precursor NOV14a CG161793-01 89 90 LME-4 membrane protein NOV15a CG162177-01 91 92 Folate receptor beta NOV15b CG162177-02 93 94 Folate receptor beta Advanced glycosylation end product NOV16a CG162443-02 95 96 specific receptor NOV16b CG162443-01 97 98 Advanced glycosylation end product INOV16b CG162443-01 97 98 spifcrepo specific receptor NOV16c CG162443-03 99 100 Advanced glycosylation end product NOV16c CG162443-03 99 100 spcfcreto specific receptor NOV17a CG162509-02 101 102 Leukocyte-associated IG-like receptor-2 NOV17b 306610228 103 104 Leukocyte-associated IG-like receptor-2 NOV17c 306610270 105 106 Leukocyte-associated IG-like receptor-2 NOV17d CG162509-01 107 108 Leukocyte-associated IG-like receptor-2 NOV18a CG162645-02 109 110 Cell surface receptor FDFO3-dtm NOV18b CG162645-01 111 112 Cell surface receptor FDFO3-dtm NOV19a CG162687-02 113 114 EVIN2 NOV19b CG162687-01 115 116 Membrane protei NOV20a CG162738-01 117 118 MADSO1 NOV20b CG162738-02 119 120 MADSO1 NOV20c CG162738-03 121 122 MADSO1 NOV21a CG163175-01 123 124 Type Lb membrane protein NOV22a CG163259-01 125 126 Cytokine-like factor-1 NOV22b CG163259-02 127 128 Cytokine-like factor-1 NOV22c CG163259-03 129 130 Cytokine-like factor-1 NOV23a CG163425-01 131 132 Interleukin-15 receptor alpha chain NOV23a CGl63425-01 131 132 precursor NOV23b CG163425-02 133 134 Interleukin-15 receptor alpha chain NOV23b CGl63425-02 133 134 precursor NOV24a CG163957-01 135 136 Polycystic kidney and hepatic disease 1 precursor 12 WO 03/050245 PCT/USO2/38594 NOV25a CG164482-01 137 138 4930418P06RIK rhomboid NOV26a CGl64511-01 139 140 Dora protein precursor NOV27a CG55060-03 141 142 SLPI NOV27b CG55060-01 143 144 SLP1 NOV27c CG55060-02 145 146 SLP1 NOV28a CG56972-02 147 148 NMB NOV28b CG56972-03 149 150 NMB NOV28c CG56972-01 151 152 NMB NOV28d 255623772 153 154 NMB Table A indicates the homology of NOVX polypeptides to known protein families. Thus, the nucleic acids and polypeptides, antibodies and related compounds according to 5 the invention corresponding to a NOVX as identified in column 1 of Table A will be useful in therapeutic and diagnostic applications implicated in, for example, pathologies and disorders associated with the known protein families identified in column 5 of Table A. Pathologies, diseases, disorders and condition and the like that are associated with NOVX sequences include, but are not limited to: e.g., cardiomyopathy, atherosclerosis, 10 hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), vascular calcification, fibrosis, atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, metabolic disturbances associated with obesity, transplantation, osteoarthritis, rheumatoid arthritis, osteochondrodysplasia, 15 adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, diabetes, metabolic disorders, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, glomerulonephritis, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, psoriasis, skin disorders, graft versus host disease, AIDS, bronchial asthma, lupus, Crohn's disease; inflammatory bowel disease, ulcerative colitis, multiple 20 sclerosis, treatment of Albright Hereditary Ostoeodystrophy, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias,] schizophrenia, depression, asthma, emphysema, allergies, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers, as 25 well as conditions such as transplantation, neuroprotection, fertility, or regeneration (in vitro and in vivo). NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to 13 WO 03/050245 PCT/USO2/38594 the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong. 5 Consistent with other known members of the family of proteins, identified in column 5 of Table A, the NOVX polypeptides of the present invention show homology to, and contain domains that are characteristic of, other members of such protein families. Details of the sequence relatedness and domain analysis for each NOVX are presented in Example A. 10 The NOVX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVX activity or function. Specifically, the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit diseases associated with the protein families listed in Table A. 15 The NOVX nucleic acids and polypeptides are also useful for detecting specific cell types. Details of the expression analysis for each NOVX are presented in Example C. Accordingly, the NOVX nucleic acids, polypeptides, antibodies and related compounds according to the invention will have diagnostic and therapeutic applications in the detection of a variety of diseases with differential expression in normal vs. diseased tissues, e.g. 20 detection of a variety of cancers. Additional utilities for NOVX nucleic acids and polypeptides according to the invention are disclosed herein. NOVX clones NOVX nucleic acids and their encoded polypeptides are useful in a variety of 25 applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong. 30 The NOVX genes and their corresponding encoded proteins are useful for preventing, treating or ameliorating medical conditions, e.g., by protein or gene therapy. Pathological conditions can be diagnosed by determining the amount of the new protein in a sample or by determining the presence of mutations in the new genes. Specific uses are 14 WO 03/050245 PCT/USO2/38594 described for each of the NOVX genes, based on the tissues in which they are most highly expressed. Uses include developing products for the diagnosis or treatment of a variety of diseases and disorders. The NOVX nucleic acids and proteins of the invention are useful in potential 5 diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug 10 targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) a biological defense weapon. In one specific embodiment, the invention includes an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature 15 form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 77; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 77, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of 20 the mature form are so changed; (c) an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 77; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid 25 residues in the sequence are so changed; and (e) a fragment of any of (a) through (d). In another specific embodiment, the invention includes an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence given SEQ ID NO: 2n, wherein n is an integer between 1 and 77; (b) a variant of 30 a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 77 wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) 15 WO 03/050245 PCT/USO2/38594 the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 77; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 77, in which any amino acid specified in the chosen sequence is changed to a different amino acid, 5 provided that no more than 15% of the amino acid residues in the sequence are so changed; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 77 or any variant of said polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of 10 the amino acid residues in the sequence are so changed; and (f) the complement of any of said nucleic acid molecules. In yet another specific embodiment, the invention includes an isolated nucleic acid molecule, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) the nucleotide sequence selected from the group 15 consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 77; (b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 77 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; 20 (c) a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 77; and (d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 77 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide 25 provided that no more than 15% of the nucleotides are so changed. NOVX Nucleic Acids and Polypeptides One aspect of the invention pertains to isolated nucleic acid molecules that encode NOVX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify 30 NOVX-encoding nucleic acids (e.g., NOVX mRNAs) and fragments for use as PCR primers for the amplification and/or mutation of NOVX nucleic acid molecules. As used * herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNA 16 WO 03/050245 PCT/USO2/38594 generated using nucleotide analogs, and derivatives, fragments and homologs thereof. The nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double-stranded DNA. A NOVX nucleic acid can encode a mature NOVX polypeptide. As used herein, a 5 "mature" form of a polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. 10 The product "mature" form arises, by way of nonlimiting example, as a result of one or more naturally occurring processing steps that may take place within the cell (e.g., host cell) in which the gene product arises. Examples of such processing steps leading to a "mature" form of a polypeptide or protein include the cleavage of the N-terminal methionine residue encoded by the initiation codon of an ORF, or the proteolytic cleavage 15 of a signal peptide or leader sequence. Thus a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N remaining after removal of the N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N-terminal signal sequence from residue 1 to residue M 20 is cleaved, would have the residues from residue M+I to residue N remaining. Further as used herein, a "mature" form of a polypeptide or protein may arise from a step of post-translational modification other than a proteolytic cleavage event. Such additional processes include, by way of non-limiting example, glycosylation, myristylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation 25 of only one of these processes, or a combination of any of them. The term "probe", as utilized herein, refers to nucleic acid sequences of variable length, preferably between at least about 10 nucleotides (nt), about 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences. Longer length 30 probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single stranded or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies. 17 WO 03/050245 PCT/USO2/38594 The term "isolated" nucleic acid molecule, as used herein, is a nucleic acid that is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5'- and 3'-termini of the nucleic acid) in 5 the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated NOVX nucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, I kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an "isolated" nucleic acid 10 molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium, or of chemical precursors or other chemicals. A nucleic acid molecule of the invention, e.g., a nucleic acid molecule having the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, or a complement of this nucleotide sequence, can be isolated using standard molecular biology 15 techniques and the sequence information provided herein. Using all or a portion of the nucleic acid sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, as a hybridization probe, NOVX molecules can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, et al., (eds.), MOLECULAR CLONING: A LABORATORY MANUAL 2 nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 20 NY, 1989; and Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993.) A nucleic acid of the invention can be amplified using eDNA, mRNA or alternatively, genomic DNA, as a template with appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be 25 cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to NOVX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer. As used herein, the term "oligonucleotide" refers to a series of linked nucleotide residues. A short oligonucleotide sequence may be based on, or designed from, a genomic 30 or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides comprise a nucleic acid sequence having about 10 nt, 50 nt, or 100 nt in length, preferably about 15 nt to 30 nt in length. In one embodiment of the invention, an oligonucleotide 18 WO 03/050245 PCT/USO2/38594 comprising a nucleic acid molecule less than 100 nt in length would further comprise at least 6 contiguous nucleotides of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, or a complement thereof. Oligonucleotides may be chemically synthesized and may also be used as probes. 5 In another embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule that is a complement of the nucleotide sequence shown in SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer or a fragment encoding a biologically-active portion of a NOVX polypeptide). A nucleic acid molecule 10 that is complementary to the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, is one that is sufficiently complementary to the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, that it can hydrogen bond with few or no mismatches to the nucleotide sequence shown in SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, thereby forming a stable duplex. 15 As used herein, the term "complementary" refers to Watson-Crick or Hoogsteen base pairing between nucleotides units of a nucleic acid molecule, and the term "binding" means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction 20 can be either direct or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates. A "fragment" provided herein is defined as a sequence of at least 6 (contiguous) 25 nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, and is at most some portion less than a full length sequence. Fragments may be derived from any contiguous portion of a nucleic acid or amino acid sequence of choice. 30 A full-length NOVX clone is identified as containing an ATG translation start codon and an in-frame stop codon. Any disclosed NOVX nucleotide sequence lacking an ATG start codon therefore encodes a truncated C-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 5' 19 WO 03/050245 PCT/USO2/38594 direction of the disclosed sequence. Any disclosed NOVX nucleotide sequence lacking an in-frame stop codon similarly encodes a truncated N-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 3' direction of the disclosed sequence. 5 A "derivative" is a nucleic acid sequence or amino acid sequence formed from the native compounds either directly, by modification or partial substitution. An "analog" is a nucleic acid sequence or amino acid sequence that has a structure similar to, but not identical to, the native compound, e.g. they differs from it in respect to certain components or side chains. Analogs may be synthetic or derived from a different evolutionary origin 10 and may have a similar or opposite metabolic activity compared to wild type. A "homolog" is a nucleic acid sequence or amino acid sequence of a particular gene that is derived from different species. Derivatives and analogs may be full length or other than full length. Derivatives or analogs of the nucleic acids or proteins of the invention include, but are not limited to, 15 molecules comprising regions that are substantially homologous to the nucleic acids or proteins of the invention, in various embodiments, by at least about 70%, 80%, or 95% identity (with a preferred identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable 20 of hybridizing to the complement of a sequence encoding the proteins under stringent, moderately stringent, or low stringent conditions. See e.g. Ausubel, et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993, and below. A "homologous nucleic acid sequence" or "homologous amino acid sequence," or 25 variations thereof, refer to sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences include those sequences coding for isoforms of NOVX polypeptides. Isoforms can be expressed in different tissues of the same organism as a result of, for example, alternative splicing of RNA. Alternatively, isoforms can be encoded by different genes. In the invention, 30 homologous nucleotide sequences include nucleotide sequences encoding for a NOVX polypeptide of species other than humans, including, but not limited to: vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and other organisms. Homologous nucleotide sequences also include, but are not limited to, naturally occurring 20 WO 03/050245 PCT/USO2/38594 allelic variations and mutations of the nucleotide sequences set forth herein. A homologous nucleotide sequence does not, however, include the exact nucleotide sequence encoding human NOVX protein. Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID 5 NO:2n-1, wherein n is an integer between I and 77, as well as a polypeptide possessing NOVX biological activity. Various biological activities of the NOVX proteins are described below. A NOVX polypeptide is encoded by the open reading frame ("ORF") of a NOVX nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be 10 translated into a polypeptide. A stretch of nucleic acids comprising an ORF is uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG "start" codon and terminates with one of the three "stop" codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For.an 15 ORF to be considered as a good candidate for coding for a bonafide cellular protein, a minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more. The nucleotide sequences determined from the cloning of the human NOVX genes allows for the generation of probes and primers designed for use in identifying and/or 20 cloning NOVX homologues in other cell types, e.g. from other tissues, as well as NOVX homologues from other vertebrates. The probe/primer typically comprises substantially purified oligonucleotide. The oligonucleotide typically comprises a region ofnucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutive sense strand nucleotide sequence of SEQ ID 25 NO:2n-1, wherein n is an integer between 1 and 77; or an anti-sense strand nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77; or of a naturally occurring mutant of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77. Probes based on the human NOVX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various 30 embodiments, the probe has a detectable label attached, e.g. the label can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis-express a NOVX protein, such as by measuring a level of a NOVX-encoding nucleic acid in a sample of cells 21 WO 03/050245 PCT/USO2/38594 from a subject e.g., detecting NOVX mRNA levels or determining whether a genomic NOVX gene has been mutated or deleted. "A polypeptide having a biologically-active portion of a NOVX polypeptide" refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a 5 polypeptide of the invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a "biologically-active portion of NOVX" can be prepared by isolating a portion of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, that encodes a polypeptide having a NOVX biological activity (the biological activities of the NOVX proteins are described 10 below), expressing the encoded portion of NOVX protein (e.g., by recombinant expression in vitro) and assessing the activity of the encoded portion of NOVX. NOVX Nucleic Acid and Polypeptide Variants The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, due to 15 degeneracy of the genetic code and thus encode the same NOVX proteins as that encoded by the nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a protein having an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between I and 77. 20 In addition to the human NOVX nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of the NOVX polypeptides may exist within a population (e.g., the human population). Such genetic polymorphism in the NOVX genes may exist among individuals within a population due to 25 natural allelic variation. As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame (ORF) encoding a NOVX protein, preferably a vertebrate NOVX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the NOVX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the NOVX polypeptides, 30 which are the result of natural allelic variation and that do not alter the functional activity of the NOVX polypeptides, are intended to be within the scope of the invention. Moreover, nucleic acid molecules encoding NOVX proteins from other species, and thus that have a nucleotide sequence that differs from a human SEQ ID NO:2n-1, wherein n 22 WO 03/050245 PCT/USO2/38594 is an integer between 1 and 77, are intended to be within the scope of the invention. Nucleic acid molecules corresponding to natural allelic variants and homologues of the NOVX cDNAs of the invention can be isolated based on their homology to the human NOVX nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a 5 hybridization probe according to standard hybridization techniques under stringent hybridization conditions. Accordingly, in another embodiment, an isolated nucleic acid molecule of the invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n-1, wherein n 10 is an integer between 1 and 77. In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule of the invention hybridizes to the coding region. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at 15 least about 65% homologous to each other typically remain hybridized to each other. Homologs (i.e., nucleic acids encoding NOVX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or high stringency hybridization with all or a portion of the particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning. 20 As used herein, the phrase "stringent hybridization conditions" refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5 'C lower 25 than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% of the probes complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess, at Tm, 50% of the probes are occupied at equilibrium. Typically, stringent 30 conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30 'C for short probes, primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about 60 oC for longer probes, primers and oligonucleotides. 23 WO 03/050245 PCT/USO2/38594 Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide. Stringent conditions are known to those skilled in the art and can be found in Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 5 N.Y. (1989), 6.3.1-6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6X SSC, 50 mM Tris-HC1 (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm 10 DNA at 65 0 C, followed by one or more washes in 0.2X SSC, 0.01% BSA at 50 0 C. An isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to a sequence of SEQ ID NO:2n-1, wherein n is an integer between I and 77, corresponds to a naturally-occurring nucleic acid molecule. As used herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs 15 in nature (e.g., encodes a natural protein). In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, or fragments, analogs or derivatives thereof, under conditions of moderate stringency is provided. A non-limiting example of moderate stringency 20 hybridization conditions are hybridization in 6X SSC, 5X Reinhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55 oC, followed by one or more washes in 1X SSC, 0.1% SDS at 37 0 C. Other conditions of moderate stringency that maybe used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Krieger, 1990; GENE TRANSFER 25 AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY. In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between I and 77, or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions 30 are hybridization in 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/ml denatured salmon sperm DNA, 10% (wt/vol) dextran sulfate at 40 0 C, followed by one or more washes in 2X SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDS at 50oC. Other conditions of low 24 WO 03/050245 PCT/USO2/38594 stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg, 1981. 5 Proc Natl Acad Sci USA 78: 6789-6792. Conservative Mutations In addition to naturally-occurring allelic variants of NOVX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences of SEQ ID NO:2n-1, wherein n is an 10 integer between 1 and 77, thereby leading to changes in the amino acid sequences of the encoded NOVX protein, without altering the functional ability of that NOVX protein. For example, nucleotide substitutions leading to amino acid substitutions at "non-essential" amino acid residues can be made in the sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 77. A "non-essential" amino acid residue is a residue that can be altered 15 from the wild-type sequences of the NOVX proteins without altering their biological activity, whereas an "essential" amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the NOVX proteins of the invention are predicted to be particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well-known within the art. 20 Another aspect of the invention pertains to nucleic acid molecules encoding NOVX proteins that contain changes in amino acid residues that are not essential for activity. Such NOVX proteins differ in amino acid sequence from SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, yet retain biological activity. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the 25 protein comprises an amino acid sequence at least about 40% homologous to the amino acid sequences of SEQ ID NO:2n, wherein n is an integer between 1 and 77. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 77; more preferably at least about 70% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 77; still more 30 preferably at least about 80% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 77; even more preferably at least about 90% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 77; and most preferably at least about 95% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 77. 25 WO 03/050245 PCT/USO2/38594 An isolated nucleic acid molecule encoding a NOVX protein homologous to the protein of SEQ ID NO:2n, wherein n is an integer between 1 and 77, can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, such that one or 5 more amino acid substitutions, additions or deletions are introduced into the encoded protein. Mutations can be introduced any one of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at 10 one or more predicted, non-essential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), 15 uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the NOVX protein is replaced with 20 another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of a NOVX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for NOVX biological activity to identify mutants that retain activity. Following mutagenesis of a nucleic acid of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, the 25 encoded protein can be expressed by any recombinant technology known in the art and the activity of the protein can be determined. The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved "strong" residues or fully conserved "weak" residues. The "strong" group of conserved amino acid residues may be 30 any one of the following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the "weak" group of conserved residues may be any one of the following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, 26 WO 03/050245 PCT/USO2/38594 NDEQHK, NEQHRK, HFY, wherein the letters within each group represent the single letter amino acid code. In one embodiment, a mutant NOVX protein can be assayed for (i) the ability to form protein:protein interactions with other NOVX proteins, other cell-surface proteins, or 5 biologically-active portions thereof, (ii) complex formation between a mutant NOVX protein and a NOVX ligand; or (iii) the ability of a mutant NOVX protein to bind to an intracellular target protein or biologically-active portion thereof; (e.g. avidin proteins). In yet another embodiment, a mutant NOVX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release). 10 Interfering RNA In one aspect of the invention, NOVX gene expression can be attenuated by RNA interference. One approach well-known in the art is short interfering RNA (siRNA) mediated gene silencing where expression products of a NOVX gene are targeted by specific double stranded NOVX derived siRNA nucleotide sequences that are 15 complementary to at least a 19-25 nt long segment of the NOVX gene transcript, including the 5' untranslated (UT) region, the ORF, or the 3' UT region. See, e.g., PCT applications WO00/44895, WO99/32619, WO01/75164, WO01/92513, WO 01/29058, WO01/89304, W002/16620, and W002/29858, each incorporated by reference herein in their entirety. Targeted genes can be a NOVX gene, or an upstream or downstream modulator of the 20 NOVX gene. Nonlimiting examples of upstream or downstream modulators of a NOVX gene include, e.g., a transcription factor that binds the NOVX gene promoter, a kinase or phosphatase that interacts with a NOVX polypeptide, and polypeptides involved in a NOVX regulatory pathway. According to the methods of the present invention, NOVX gene expression is 25 silenced using short interfering RNA. A NOVX polynucleotide according to the invention includes a siRNA polynucleotide. Such a NOVX siRNA can be obtained using a NOVX polynucleotide sequence, for example, by processing the NOVX ribopolynucleotide sequence in a cell-free system, such as but not limited to a Drosophila extract, or by transcription of recombinant double stranded NOVX RNA or by chemical synthesis of 30 nucleotide sequences homologous to a NOVX sequence. See, e.g., Tuschl, Zamore, Lehmann, Bartel and Sharp (1999), Genes & Dev. 13: 3191-3197, incorporated herein by reference in its entirety. When synthesized, a typical 0.2 micromolar-scale RNA synthesis 27 WO 03/050245 PCT/USO2/38594 provides about 1 milligram of siRNA, which is sufficient for 1000 transfection experiments using a 24-well tissue culture plate format. The most efficient silencing is generally observed with siRNA duplexes composed of a 21-nt sense strand and a 21-nt antisense strand, paired in a manner to have a 2-nt 5 3' overhang. The sequence of the 2-nt 3' overhang makes an additional small contribution to the specificity ofsiRNA target recognition. The contribution to specificity is localized to the unpaired nucleotide adjacent to the first paired bases. In one embodiment, the nucleotides in the 3' overhang are ribonucleotides. In an alternative embodiment, the nucleotides in the 3' overhang are deoxyribonucleotides. Using 2'-deoxyribonucleotides in 10 the 3' overhangs is as efficient as using ribonucleotides, but deoxyribonucleotides are often cheaper to synthesize and are most likely more nuclease resistant. A contemplated recombinant expression vector of the invention comprises a NOVX DNA molecule cloned into an expression vector comprising operatively-linked regulatory sequences flanking the NOVX sequence in a manner that allows for expression (by 15 transcription of the DNA molecule) of both strands. An RNA molecule that is antisense to NOVX mRNA is transcribed by a first promoter (e.g., a promoter sequence 3' of the cloned DNA) and an RNA molecule that is the sense strand for the NOVX mRNA is transcribed by a second promoter (e.g., a promoter sequence 5' of the cloned DNA). The sense and antisense strands may hybridize in vivo to generate siRNA constructs for silencing of the 20 NOVX gene. Alternatively, two constructs can be utilized to create the sense and anti-sense strands of a siRNA construct. Finally, cloned DNA can encode a construct having secondary structure, wherein a single transcript has both the sense and complementary antisense sequences from the target gene or genes. In an example of this embodiment, a hairpin RNAi product is homologous to all or a portion of the target gene. 25 In another example, a hairpin RNAi product is a siRNA. The regulatory sequences flanking the NOVX sequence may be identical or may be different, such that their expression may be modulated independently, or in a temporal or spatial manner. In a specific embodiment, siRNAs are transcribed intracellularly by cloning the NOVX gene templates into a vector containing, e.g., a RNA pol III transcription unit from 30 the smaller nuclear RNA (snRNA) U6 or the human RNase P RNA H 1. One example of a vector system is the GeneSuppressor m RNA Interference kit (commercially available from Imgenex). The U6 and HI promoters are members of the type III class of Pol III promoters. The +1 nucleotide of the U6-like promoters is always guanosine, whereas the +1 for H1 28 WO 03/050245 PCT/USO2/38594 promoters is adenosine. The termination signal for these promoters is defined by five consecutive thymidines. The transcript is typically cleaved after the second uridine. Cleavage at this position generates a 3' 1UU1 overhang in the expressed siRNA, which is similar to the 3' overhangs of synthetic siRNAs. Any sequence less than 400 nucleotides in 5 length can be transcribed by these promoter, therefore they are ideally suited for the expression of around 21-nucleotide siRNAs in, e.g., an approximately 50-nucleotide RNA stem-loop transcript. A siRNA vector appears to have an advantage over synthetic siRNAs where long term knock-down of expression is desired. Cells transfected with a siRNA expression 10 vector would experience steady, long-term mRNA inhibition. In contrast, cells transfected with exogenous synthetic siRNAs typically recover from mRNA suppression within seven days or ten rounds of cell division. The long-term gene silencing ability of siRNA expression vectors may provide for applications in gene therapy. In general, siRNAs are chopped from longer dsRNA by an ATP-dependent 15 ribonuclease called DICER. DICER is a member of the RNase III family of double-stranded RNA-specific endonucleases. The siRNAs assemble with cellular proteins into an endonuclease complex. In vitro studies in Drosophila suggest that the siRNAs/protein complex (siRNP) is then transferred to a second enzyme complex, called an RNA-induced silencing complex (RISC), which contains an endoribonuclease that is 20 distinct from DICER. RISC uses the sequence encoded by the antisense siRNA strand to find and destroy mRNAs of complementary sequence. The siRNA thus acts as a guide, restricting the ribonuclease to cleave only mRNAs complementary to one of the two siRNA strands. A NOVX mRNA region to be targeted by siRNA is generally selected from a 25 desired NOVX sequence beginning 50 to100 nt downstream of the start codon. Alternatively, 5' or 3' UTRs and regions nearby the start codon can be used but are generally avoided, as these may be richer in regulatory protein binding sites. UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNP or RISC endonuclease complex. An initial BLAST homology search for the selected siRNA 30 sequence is done against an available nucleotide sequence library to ensure that only one gene is targeted. Specificity of target recognition by siRNA duplexes indicate that a single point mutation located in the paired region of an siRNA duplex is sufficient to abolish target mRNA degradation. See, Elbashir et al. 2001 EMBO J. 20(23):6877-88. Hence, 29 WO 03/050245 PCT/USO2/38594 consideration should be taken to accommodate SNPs, polymorphisms, allelic variants or species-specific variations when targeting a desired gene. In one embodiment, a complete NOVX siRNA experiment includes the proper negative control. A negative control siRNA generally has the same nucleotide composition 5 as the NOVX siRNA but lack significant sequence homology to the genome. Typically, one would scramble the nucleotide sequence of the NOVX siRNA and do a homology search to make sure it lacks homology to any other gene. Two independent NOVX siRNA duplexes can be used to knock-down a target NOVX gene. This helps to control for specificity of the silencing effect. In addition, 10 expression of two independent genes can be simultaneously knocked down by using equal concentrations of different NOVX siRNA duplexes, e.g., a NOVX siRNA and an siRNA for a regulator of a NOVX gene or polypeptide. Availability of siRNA-associating proteins is believed to be more limiting than target mRNA accessibility. A targeted NOVX region is typically a sequence of two adenines (AA) and two 15 thymidines (TT) divided by a spacer region of nineteen (N19) residues (e.g., AA(N19)TT). A desirable spacer region has a G/C-content of approximately 30% to 70%, and more preferably of about 50%. If the sequence AA(N19)TT is not present in the target sequence, an alternative target region would be AA(N21). The sequence of the NOVX sense siRNA corresponds to (N19)TT or N21, respectively. In the latter case, conversion of the 3' end of 20 the sense siRNA to TT can be performed if such a sequence does not naturally occur in the NOVX polynucleotide. The rationale for this sequence conversion is to generate a symmetric duplex with respect to the sequence composition of the sense and antisense 3' overhangs. Symmetric 3' overhangs may help to ensure that the siRNPs are formed with approximately equal ratios of sense and antisense target RNA-cleaving siRNPs. See, e.g., 25 Elbashir, Lendeckel and Tuschl (2001). Genes & Dev. 15: 188-200, incorporated by reference herein in its entirely. The modification of the overhang of the sense sequence of the siRNA duplex is not expected to affect targeted mRNA recognition, as the antisense siRNA strand guides target recognition. Alternatively, if the NOVX target mRNA does not contain a suitable AA(N21) 30 sequence, one may search for the sequence NA(N21). Further, the sequence of the sense strand and antisense strand may still be synthesized as 5' (N19)TT, as it is believed that the sequence of the 3'-most nucleotide of the antisense siRNA does not contribute to specificity. Unlike antisense or ribozyme technology, the secondary structure of the target 30 WO 03/050245 PCT/USO2/38594 mRNA does not appear to have a strong effect on silencing. See, Harborth, et al. (2001) J. Cell Science 114: 4557-4565, incorporated by reference in its entirety. Transfection of NOVX siRNA duplexes can be achieved using standard nucleic acid transfection methods, for example, OLIGOFECTAMINE Reagent (commercially 5 available from Invitrogen). An assay for NOVX gene silencing is generally performed approximately 2 days after transfection. No NOVX gene silencing has been observed in the absence of transfection reagent, allowing for a comparative analysis of the wild-type and silenced NOVX phenotypes. In a specific embodiment, for one well of a 24-well plate, approximately 0.84 tg of the siRNA duplex is generally sufficient. Cells are typically 10 seeded the previous day, and are transfected at about 50% confluence. The choice of cell culture media and conditions are routine to those of skill in the art, and will vary with the choice of cell type. The efficiency of transfection may depend on the cell type, but also on the passage number and the confluency of the cells. The time and the manner of formation of siRNA-liposome complexes (e.g. inversion versus vortexing) are also critical. Low 15 transfection efficiencies are the most frequent cause of unsuccessful NOVX silencing. The efficiency of transfection needs to be carefully examined for each new cell line to be used. Preferred cell are derived from a mammal, more preferably from a rodent such as a rat or mouse, and most preferably from a human. Where used for therapeutic treatment, the cells are preferentially autologous, although non-autologous cell sources are also contemplated 20 as within the scope of the present invention. For a control experiment, transfection of 0.84 Ig single-stranded sense NOVX siRNA will have no effect on NOVX silencing, and 0.84 pg antisense siRNA has a weak silencing effect when compared to 0.84 jg of duplex siRNAs. Control experiments again allow for a comparative analysis of the wild-type and silenced NOVX phenotypes. To 25 control for transfection efficiency, targeting of common proteins is typically performed, for example targeting of lamin A/C or transfection of a CMV-driven EGFP-expression plasmid (e.g. commercially available from Clontech). In the above example, a determination of the fraction of lamin A/C knockdown in cells is determined the next day by such techniques as immunofluorescence, Western blot, Northern blot or other similar assays for protein 30 expression or gene expression. Lamin A/C monoclonal antibodies may be obtained from Santa Cruz Biotechnology. Depending on the abundance and the half life (or turnover) of the targeted NOVX polynucleotide in a cell, a knock-down phenotype may become apparent after 1 to 3 days, 31 WO 03/050245 PCT/USO2/38594 or even later. In cases where no NOVX knock-down phenotype is observed, depletion of the NOVX polynucleotide may be observed by immunofluorescence or Western blotting. If the NOVX polynucleotide is still abundant after 3 days, cells need to be split and transferred to a fresh 24-well plate for re-transfection. If no knock-down of the targeted 5 protein is observed, it may be desirable to analyze whether the target mRNA (NOVX or a NOVX upstream or downstream gene) was effectively destroyed by the transfected siRNA duplex. Two days after transfection, total RNA is prepared, reverse transcribed using a target-specific primer, and PCR-amplified with a primer pair covering at least one exon-exon junction in order to control for amplification of pre-mRNAs. RT/PCR of a 10 non-targeted mRNA is also needed as control. Effective depletion of the mRNA yet undetectable reduction of target protein may indicate that a large reservoir of stable NOVX protein may exist in the cell. Multiple transfection in sufficiently long intervals may be necessary until the target protein is finally depleted to a point where a phenotype may become apparent. If multiple transfection steps are required, cells are split 2 to 3 days after 15 transfection. The cells may be transfected immediately after splitting. An inventive therapeutic method of the invention contemplates administering a NOVX siRNA construct as therapy to compensate for increased or aberrant NOVX expression or activity. The NOVX ribopolynucleotide is obtained and processed into siRNA fragments, or a NOVX siRNA is synthesized, as described above. The NOVX 20 siRNA is administered to cells or tissues using known nucleic acid transfection techniques, as described above. A NOVX siRNA specific for a NOVX gene will decrease or knockdown NOVX transcription products, which will lead to reduced NOVX polypeptide production, resulting in reduced NOVX polypeptide activity in the cells or tissues. The present invention also encompasses a method of treating a disease or condition 25 associated with the presence of a NOVX protein in an individual comprising administering to the individual an RNAi construct that targets the mRNA of the protein (the mRNA that encodes the protein) for degradation. A specific RNAi construct includes a siRNA or a double stranded gene transcript that is processed into siRNAs. Upon treatment, the target protein is not produced or is not produced to the extent it would be in the absence of the 30 treatment. Where the NOVX gene function is not correlated with a known phenotype, a control sample of cells or tissues from healthy individuals provides a reference standard for determining NOVX expression levels. Expression levels are detected using the assays 32 WO 03/050245 PCT/USO2/38594 described, e.g., RT-PCR, Northern blotting, Western blotting, ELISA, and the like. A subject sample of cells or tissues is taken from a mammal, preferably a human subject, suffering from a disease state. The NOVX ribopolynucleotide is used to produce siRNA constructs, that are specific for the NOVX gene product. These cells or tissues are treated 5 by administering NOVX siRNA's to the cells or tissues by methods described for the transfection of nucleic acids into a cell or tissue, and a change in NOVX polypeptide or polynucleotide expression is observed in the subject sample relative to the control sample, using the assays described. This NOVX gene knockdown approach provides a rapid method for determination of a NOVX minus (NOVX) phenotype in the treated subject 10 sample. The NOVX phenotype observed in the treated subject sample thus serves as a marker for monitoring the course of a disease state during treatment. In specific embodiments, a NOVX siRNA is used in therapy. Methods for the generation and use of a NOVX siRNA are known to those skilled in the art. Example techniques are provided below. 15 Production of RNAs Sense RNA (ssRNA) and antisense RNA (asRNA) of NOVX are produced using known methods such as transcription in RNA expression vectors. In the initial experiments, the sense and antisense RNA are about 500 bases in length each. The produced ssRNA and asRNA (0.5 gM) in 10 mM Tris-HCl (pH 7.5) with 20 mM NaCI 20 were heated to 950 C for 1 min then cooled and annealed at room temperature for 12 to 16 h. The RNAs are precipitated and resuspended in lysis buffer (below). To monitor annealing, RNAs are electrophoresed in a 2% agarose gel in TBE buffer and stained with ethidium bromide. See, e.g., Sambrook et al., Molecular Cloning. Cold Spring Harbor Laboratory Press, Plainview, N.Y. (1989). 25 Lysate Preparation Untreated rabbit reticulocyte lysate (Ambion) are assembled according to the manufacturer's directions. dsRNA is incubated in the lysate at 300 C for 10 min prior to the addition of mRNAs. Then NOVX mRNAs are added and the incubation continued for an additional 60 min. The molar ratio of double stranded RNA and mRNA is about 200:1. 30 The NOVX mRNA is radiolabeled (using known techniques) and its stability is monitored by gel electrophoresis. 33 WO 03/050245 PCT/USO2/38594 In a parallel experiment made with the same conditions, the double stranded RNA is internally radiolabeled with a 32 P-ATP. Reactions are stopped by the addition of 2 X proteinase K buffer and deproteinized as described previously (Tuschl et al., Genes Dev., 13:3191-3197 (1999)). Products are analyzed by electrophoresis in 15% or 18% 5 polyacrylamide sequencing gels using appropriate RNA standards. By monitoring the gels for radioactivity, the natural production of 10 to 25 nt RNAs from the double stranded RNA can be determined. The band of double stranded RNA, about 21-23 bps, is eluded. The efficacy of these 21-23 mers for suppressing NOVX transcription is assayed in vitro using the same 10 rabbit reticulocyte assay described above using 50 nanomolar of double stranded 21-23 mer for each assay. The sequence of these 21-23 mers is then determined using standard nucleic acid sequencing techniques. RNA Preparation 21 nt RNAs, based on the sequence determined above, are chemically synthesized 15 using Expedite RNA phosphoramidites and thymidine phosphoramidite (Proligo, Germany). Synthetic oligonucleotides are deprotected and gel-purified (Elbashir, Lendeckel, & Tuschl, Genes & Dev. 15, 188-200 (2001)), followed by Sep-Pak C18 cartridge (Waters, Milford, Mass., USA) purification (Tuschl, et al., Biochemistry, 32:11658-11668 (1993)). 20 These RNAs (20 pM) single strands are incubated in annealing buffer (100 mM potassium acetate, 30 mM HEPES-KOH at pH 7.4, 2 mM magnesium acetate) for 1 min at 900 C followed by 1 h at 370 C. Cell Culture A cell culture known in the art to regularly express NOVX is propagated using 25 standard conditions. 24 hours before transfection, at approx. 80% confluency, the cells are trypsinized and diluted 1:5 with fresh medium without antibiotics (1-3 X 105 cells/ml) and transferred to 24-well plates (500 ml/well). Transfection is performed using a commercially available lipofection kit and NOVX expression is monitored using standard techniques with positive and negative control. A positive control is cells that naturally 30 express NOVX while a negative control is cells that do not express NOVX. Base-paired 21 and 22 nt siRNAs with overhanging 3' ends mediate efficient sequence-specific mRNA degradation in lysates and in cell culture. Different concentrations of siRNAs are used. An 34 WO 03/050245 PCT/USO2/38594 efficient concentration for suppression in vitro in mammalian culture is between 25 nM to 100 nM final concentration. This indicates that siRNAs are effective at concentrations that are several orders of magnitude below the concentrations applied in conventional antisense or ribozyme gene targeting experiments. 5 The above method provides a way both for the deduction of NOVX siRNA sequence and the use of such siRNA for in vitro suppression. In vivo suppression may be performed using the same siRNA using well known in vivo transfection or gene therapy transfection techniques. Antisense Nucleic Acids 10 Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between I and 77, or fragments, analogs or derivatives thereof. An "antisense" nucleic acid comprises a nucleotide sequence that is complementary to a "sense" nucleic acid encoding a protein 15 (e.g., complementary to the coding strand of a double-stranded eDNA molecule or complementary to an mRNA sequence). In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire NOVX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of 20 a NOVX protein of SEQ ID NO:2n, wherein n is an integer between 1 and 77, or antisense nucleic acids complementary to a NOVX nucleic acid sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, are additionally provided. In one embodiment, an antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence encoding a NOVX protein. The term 25 "coding region" refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleotide sequence encoding the NOVX protein. The term "noncoding region" refers to 5' and 3' sequences which flank the coding region that are not translated into amino acids (i.e., also referred to 30 as 5' and 3' untranslated regions). Given the coding strand sequences encoding the NOVX protein disclosed herein, antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be 35 WO 03/050245 PCT/USO2/38594 complementary to the entire coding region of NOVX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of NOVX mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of NOVX mRNA. An antisense 5 oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally-occurring nucleotides or variously modified nucleotides 10 designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids (e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used). Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, 15 xanthine, 4-acetylcytosine, 5-carboxymethylaminomethyl-2-thiouridine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 5-methoxyracil, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 20 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, 2-thiouracil, 4-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 25 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection). 30 The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a NOVX protein to thereby inhibit expression of the protein (e.g., by inhibiting transcription and/or translation). The hybridization can be by conventional 36 WO 03/050245 PCT/USO2/38594 nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. 5 Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface (e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens). The antisense nucleic 10 acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient nucleic acid molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred. In yet another embodiment, the antisense nucleic acid molecule of the invention is an a-anomeric nucleic acid molecule. An c-anomeric nucleic acid molecule forms specific 15 double-stranded hybrids with complementary RNA in which, contrary to the usual 13-units, the strands run parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl. Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (See, e.g., Inoue, et al. 1987. Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (See, e.g., Inoue, et al., 1987. FEBSLett. 215: 327-330. 20 Ribozymes and PNA Moieties Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding 25 nucleic acids in therapeutic applications in a subject. In one embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in 30 Haselhoff and Gerlach 1988. Nature 334: 585-591) can be used to catalytically cleave NOVX mRNA transcripts to thereby inhibit translation of NOVX mRNA. A ribozyme having specificity for a NOVX-encoding nucleic acid can be designed based upon the nucleotide sequence of a NOVX cDNA disclosed herein (i.e., SEQ ID NO:2n-1, wherein n 37 WO 03/050245 PCT/USO2/38594 is an integer between 1 and 77). For example, a derivative of a Tetrahymnena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a NOVX-encoding mRNA. See, e.g., U.S. Patent 4,987,071 to Cech, et al. and U.S. Patent 5,116,742 to Cech, et al. 5 NOVX mRNA can also be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., (1993) Science 261:1411-1418. Alternatively, NOVX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the NOVX nucleic acid (e.g., the 10 NOVX promoter and/or enhancers) to form triple helical structures that prevent transcription of the NOVX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene, et al. 1992. Ann. N.Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15. In various embodiments, the NOVX nucleic acids can be modified at the base 15 moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids. See, e.g., Hyrup, et al., 1996. Bioorg Med Chemn 4: 5-23. As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics (e.g., DNA mimics) in which the deoxyribose 20 phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleotide bases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomer can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al., 1996. supra; Perry-O'Keefe, et al., 1996. Proc. Natl. 25 Acad. Sci. USA 93: 14670-14675. PNAs of NOVX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of NOVX can also be used, for example, in the analysis of 30 single base pair mutations in a gene (e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., Si nucleases (See, Hyrup, et al., 199 6 .supra); or as probes or primers for DNA sequence and hybridization (See, Hyrup, et al., 1996, supra; Perry-O'Keefe, et al., 1996. supra). 38 WO 03/050245 PCT/USO2/38594 In another embodiment, PNAs of NOVX can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras of NOVX can be generated 5 that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes (e.g., RNase H and DNA polymerases) to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleotide bases, and orientation (see, Hyrup, 10 et al., 1996. supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al., 1996. supra and Finn, et al., 1996. NuclAcids Res 24: 3357-3363. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite, can be used between the 15 PNA and the 5' end of DNA. See, e.g., Mag, et al., 1989. NuclAcidRes 17: 5973-5988. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment. See, e.g., Finn, et al., 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment. See, e.g., Petersen, et al., 1975. Bioorg. Med. Chemn. Lett. 5:1119-11124. 20 In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger, et al., 1989. Proc. Natl. Acad. Sci. U.S.A. 86: 6553-6556; Lemaitre, et al., 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134). In 25 addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g., Krol, et al., 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988. Pharmn. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, and the like. 30 NOVX Polypeptides A polypeptide according to the invention includes a polypeptide including the amino acid sequence of NOVX polypeptides whose sequences are provided in any one of SEQ ID NO:2n, wherein n is an integer between 1 and 77. The invention also includes a 39 WO 03/050245 PCT/USO2/38594 mutant or variant protein any of whose residues may be changed from the corresponding residues shown in any one of SEQ ID NO:2n, wherein n is an integer between 1 and 77, while still encoding a protein that maintains its NOVX activities and physiological functions, or a functional fragment thereof. 5 In general, a NOVX variant that preserves NOVX-like function includes any variant in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues of the parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or 10 deletion is encompassed by the invention. In favorable circumstances, the substitution is a conservative substitution as defined above. One aspect of the invention pertains to isolated NOVX proteins, and biologically-active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise 15 anti-NOVX antibodies. In one embodiment, native NOVX proteins can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, NOVX proteins are produced by recombinant DNA techniques. Alternative to recombinant expression, a NOVX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques. 20 An "isolated" or "purified" polypeptide or protein or biologically-active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the NOVX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of NOVX proteins in which 25 the protein is separated from cellular components of the cells from which it is isolated or recombinantly-produced. In one embodiment, the language "substantially free of cellular material" includes preparations of NOVX proteins having less than about 30% (by dry weight) of non-NOVX proteins (also referred to herein as a "contaminating protein"), more preferably less than about 20% of non-NOVX proteins, still more preferably less than about 30 10% of non-NOVX proteins, and most preferably less than about 5% of non-NOVX proteins. When the NOVX protein or biologically-active portion thereof is recombinantly-produced, it is also preferably substantially free of culture medium, i.e., 40 WO 03/050245 PCT/USO2/38594 culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% of the volume of the NOVX protein preparation. The language "substantially free of chemical precursors or other chemicals" includes preparations of NOVX proteins in which the protein is separated from chemical 5 precursors or other chemicals that are involved in the synthesis of the protein. In one embodiment, the language "substantially free of chemical precursors or other chemicals" includes preparations of NOVX proteins having less than about 30% (by dry weight) of chemical precursors or non-NOVX chemicals, more preferably less than about 20% chemical precursors or non-NOVX chemicals, still more preferably less than about 10% 10 chemical precursors or non-NOVX chemicals, and most preferably less than about 5% chemical precursors or non-NOVX chemicals. Biologically-active portions of NOVX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences of the NOVX proteins (e.g., the amino acid sequence of SEQ ID NO:2n, wherein n is an integer 15 between 1 and 77) that include fewer amino acids than the full-length NOVX proteins, and exhibit at least one activity of a NOVX protein. Typically, biologically-active portions comprise a domain or motif with at least one activity of the NOVX protein. A biologically-active portion of a NOVX protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acid residues in length. 20 Moreover, other biologically-active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of a native NOVX protein. In an embodiment, the NOVX protein has an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 77. In other embodiments, the NOVX 25 protein is substantially homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 77, and retains the functional activity of the protein of SEQ ID NO:2n, wherein n is an integer between 1 and 77, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the NOVX protein is a protein that comprises an amino acid sequence at least about 45% 30 homologous to the amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 77, and retains the functional activity of the NOVX proteins of SEQ ID NO:2n, wherein n is an integer between 1 and 77. 41 WO 03/050245 PCT/USO2/38594 Determining Homology Between Two or More Sequences To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal 5 alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid 10 "homology" is equivalent to amino acid or nucleic acid "identity"). The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs known in the art, such as GAP software provided in the GCG program package. See, Needleman and Wunsch, 1970. JMol Biol 48: 443-453. Using GCG GAP software with 15 the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP extension penalty of 0.3, the coding region of the analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, with the CDS (encoding) part of the DNA sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77. 20 The term "sequence identity" refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the case of 25 nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The term "substantial identity" as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a 30 sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison region. 42 WO 03/050245 PCT/USO2/38594 Chimeric and Fusion Proteins The invention also provides NOVX chimeric or fusion proteins. As used herein, a NOVX "chimeric protein" or "fusion protein" comprises a NOVX polypeptide operatively-linked to a non-NOVX polypeptide. An "NOVX polypeptide" refers to a 5 polypeptide having an amino acid sequence corresponding to a NOVX protein of SEQ ID NO:2n, wherein n is an integer between 1 and 77, whereas a "non-NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially homologous to the NOVX protein, e.g., a protein that is different from the NOVX protein and that is derived from the same or a different organism. Within a NOVX 10 fusion protein the NOVX polypeptide can correspond to all or a portion of a NOVX protein. In one embodiment, a NOVX fusion protein comprises at least one biologically-active portion of a NOVX protein. In another embodiment, a NOVX fusion protein comprises at least two biologically-active portions of a NOVX protein. In yet another embodiment, a NOVX fusion protein comprises at least three biologically-active 15 portions of a NOVX protein. Within the fusion protein, the term "operatively-linked" is intended to indicate that the NOVX polypeptide and the non-NOVX polypeptide are fused in-frame with one another. The non-NOVX polypeptide can be fused to the N-terminus or C-terminus of the NOVX polypeptide. In one embodiment, the fusion protein is a GST-NOVX fusion protein in which the 20 NOVX sequences are fused to the C-terminus of the GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant NOVX polypeptides. In another embodiment, the fusion protein is a NOVX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host 25 cells), expression and/or secretion of NOVX can be increased through use of a heterologous signal sequence. In yet another embodiment, the fusion protein is a NOVX-immunoglobulin fusion protein in which the NOVX sequences are fused to sequences derived from a member of the immunoglobulin protein family. The NOVX-immunoglobulin fusion proteins of the 30 invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a NOVX ligand and a NOVX protein on the surface of a cell, to thereby suppress NOVX-mediated signal transduction in vivo. The NOVX-immunoglobulin fusion proteins can be used to affect the bioavailability of a 43 WO 03/050245 PCT/USO2/38594 NOVX cognate ligand. Inhibition of the NOVX ligand/NOVX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well as modulating (e.g. promoting or inhibiting) cell survival. Moreover, the NOVX-immunoglobulin fusion proteins of the invention can be used as immunogens to 5 produce anti-NOVX antibodies in a subject, to purify NOVX ligands, and in screening assays to identify molecules that inhibit the interaction of NOVX with a NOVX ligand. A NOVX chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional 10 techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of 15 gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g., Ausubel, et al. (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a 20 GST polypeptide). A NOVX-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the NOVX protein. NOVX Agonists and Antagonists The invention also pertains to variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists. Variants of the NOVX protein 25 can be generated by mutagenesis (e.g., discrete point mutation or truncation of the NOVX protein). An agonist of the NOVX protein can retain substantially the same, or a subset of, the biological activities of the naturally occurring form of the NOVX protein. An antagonist of the NOVX protein can inhibit one or more of the activities of the naturally occurring form of the NOVX protein by, for example, competitively binding to a 30 downstream or upstream member of a cellular signaling cascade which includes the NOVX protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. In one embodiment, treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein has fewer side 44 WO 03/050245 PCT/USO2/38594 effects in a subject relative to treatment with the naturally occurring form of the NOVX proteins. Variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists can be identified by screening combinatorial libraries of 5 mutants (e.g., truncation mutants) of the NOVX proteins for NOVX protein agonist or antagonist activity. In one embodiment, a variegated library of NOVX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of NOVX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene 10 sequences such that a degenerate set of potential NOVX sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of NOVX sequences therein. There are a variety of methods which can be used to produce libraries of potential NOVX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be 15 performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential NOVX sequences. Methods for synthesizing degenerate oligonucleotides are well-known within the art. See, e.g., Narang, 1983. Tetrahedron 39: 3; Itakura, et al., 1984. Annu. Rev. Biochem. 53: 323; 20 Itakura, et al., 1984. Science 198: 1056; Ike, et al., 1983. Nucl. Acids Res. 11: 477. Polypeptide Libraries In addition, libraries of fragments of the NOVX protein coding sequences can be used to generate a variegated population of NOVX fragments for screening and subsequent selection of variants of a NOVX protein. In one embodiment, a library of coding sequence 25 fragments can be generated by treating a double stranded PCR fragment of a NOVX coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double-stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with SI nuclease, 30 and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-terminal and internal fragments of various sizes of the NOVX proteins. 45 WO 03/050245 PCT/USO2/38594 Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of NOVX 5 proteins. The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was 10 detected. Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify NOVX variants. See, e.g., Arkin and Yourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 7811-7815; Delgrave, et al., 1993. Protein Engineering 6:327-331. 15 Anti-NOVX Antibodies Included in the invention are antibodies to NOVX proteins, or fragments of NOVX proteins. The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. 20 Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab, Fab' and F(ab'2 fragments, and an Fab expression library. In general, antibody molecules obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgGa, IgG 2 , and others. Furthermore, in 25 humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species. An isolated protein of the invention intended to serve as an antigen, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that 30 immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid 46 WO 03/050245 PCT/USO2/38594 sequence of the full length protein, such as an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between I and 77, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope. Preferably, the antigenic peptide 5 comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions. In certain embodiments of the invention, at least one epitope encompassed by the 10 antigenic peptide is a region of NOVX that is located on the surface of the protein, e.g., a hydrophilic region. A hydrophobicity analysis of the human NOVX protein sequence will indicate which regions of a NOVX polypeptide are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and 15 hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 3824-3828; Kyte and Doolittle 1982, J. Mo!. Biol. 157: 105-142, each incorporated herein by reference in their entirety. Antibodies that are specific for one or more domains within 20 an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein. The term "epitope" includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually 25 have specific three dimensional structural characteristics, as well as specific charge characteristics. A NOVX polypeptide or a fragment thereof comprises at least one antigenic epitope. An anti-NOVX antibody of the present invention is said to specifically bind to antigen NOVX when the equilibrium binding constant (KD) is 1 IpM, preferably < 100 rinM, more preferably < 10 nM, and most preferably < 100 pM to about 1 pM, as measured 30 by assays such as radioligand binding assays or similar assays known to those skilled in the art. 47 WO 03/050245 PCT/USO2/38594 A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components. Various procedures known within the art may be used for the production of 5 polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, incorporated herein by reference). Some of these antibodies are discussed below. 10 Polyclonal Antibodies For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring 15 immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin 20 inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, 25 or similar immunostimulatory agents. Additional examples of adjuvants which can be employed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate). The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known 30 techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity 48 WO 03/050245 PCT/USO2/38594 chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia PA, Vol. 14, No. 8 (April 17, 2000), pp. 25-28). Monoclonal Antibodies 5 The term "monoclonal antibody" (MAb) or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus 10 contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it. Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an 15 immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro. The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells 20 of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103). Immortalized cell lines are usually transformed mammalian cells, particularly 25 myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium 30 for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine ("HAT medium"), which substances prevent the growth of HGPRT-deficient cells. Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a 49 WO 03/050245 PCT/USO2/38594 medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia. Human myeloma and mouse-human heteromyeloma cell lines also 5 have been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63). The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen. Preferably, the 10 binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, 15 Anal. Biochem., 107:220 (1980). It is an objective, especially important in therapeutic applications of monoclonal antibodies, to identify antibodies having a high degree of specificity and a high binding affinity for the target antigen. After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods (Goding,1986). Suitable 20 culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal. The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification 25 procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., 30 by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, 50 WO 03/050245 PCT/USO2/38594 Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the 5 homologous murine sequences (U.S. Patent No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of 10 the invention to create a chimeric bivalent antibody. Humanized Antibodies The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against 15 the administered immunoglobulin. Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') 2 or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin. Humanization can be performed following the method of 20 Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S. Patent No. 5,225,539.) In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized 25 antibodies can also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human 30 immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)). 51 WO 03/050245 PCT/USO2/38594 Human Antibodies Fully human antibodies essentially relate to antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed "human antibodies", or "fully human antibodies" 5 herein. Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be 10 produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). In addition, human antibodies can also be produced using additional techniques, 15 including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in 20 humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al. (Bio/Technology 10, 779-783 (1992)); Lonberg et al. (Nature 368 856-859 (1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al,( Nature Biotechnology 14, 845-51 (1996)); Neuberger 25 (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93 (1995)). Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT 30 publication WO94/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial 52 WO 03/050245 PCT/USO2/38594 chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the 5 Xenomouse T M as disclosed in PCT publications WO 96/33735 and WO 96/34096. This animal produces B cells which secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. 10 Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules. An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. 15 Patent No. 5,939,598. It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem 20 cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker. A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Patent No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in 25 culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain. In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that 30 binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049. 53 WO 03/050245 PCT/USO2/38594 Fab Fragments and Single Chain Antibodies According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Patent No. 4,946,778). In addition, methods can be adapted for the construction of Fab 5 expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F(ab)2 fragment produced by pepsin digestion of an 10 antibody molecule; (ii) an Fab fragment generated by reducing the disulfide bridges of an F(ab)2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) Fv fragments. Bispecific Antibodies Bispecific antibodies are monoclonal, preferably human or humanized, antibodies 15 that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit. Methods for making bispecific antibodies are known in the art. Traditionally, the 20 recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the 25 correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991). Antibody variable domains with the desired binding specificities (antibody-antigen 30 combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain 54 WO 03/050245 PCT/USO2/38594 constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific 5 antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986). According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more 10 small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over 15 other unwanted end-products such as homodimers. Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab') 2 bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 20 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab') 2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intenrmolecular disulfide formation. The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then reconverted to the Fab'-thiol 25 by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes. Additionally, Fab' fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) 30 describe the production of a fully humanized bispecific antibody F(ab') 2 molecule. Each Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well 55 WO 03/050245 PCT/USO2/38594 as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets. Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies 5 have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5):1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. 10 The "diabody" technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains 15 of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994). Antibodies with more than two valencies are contemplated. For example, 20 trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991). Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, 25 CD28, or B7), or Fe receptors for IgG (FcyR), such as FcyRI (CD64), Fc'yRII (CD32) and Fc'yRIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, 30 DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF). 56 WO 03/050245 PCT/USO2/38594 Heteroconjugate Antibodies Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalentlyjoined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted 5 cells (U.S. Patent No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include 10 iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Patent No. 4,676,980. Effector Function Engineering It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For 15 example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 20 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fe regions and can thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989). 25 Immunoconjugates The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate). 30 Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A 57 WO 03/050245 PCT/USO2/38594 chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the 5 tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 2 12 Bi, 131, In, 90Y, and "'Re. Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as 10 dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 15 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026. 20 In another embodiment, the antibody can be conjugated to a "receptor" (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand" (e.g., avidin) that is in turn conjugated to a cytotoxic agent. 25 Immunoliposomes The antibodies disclosed herein can also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. 30 Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through 58 WO 03/050245 PCT/USO2/38594 filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al .,J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. 5 See Gabizon et al., J. National Cancer Inst., 81(19): 1484 (1989). Diagnostic Applications of Antibodies Directed Against the Proteins of the Invention In one embodiment, methods for the screening of antibodies that possess the desired specificity include, but are not limited to, enzyme linked immunosorbent assay (ELISA) 10 and other immunologically mediated techniques known within the art. In a specific embodiment, selection of antibodies that are specific to a particular domain of an NOVX protein is facilitated by generation of hybridomas that bind to the fragment of an NOVX protein possessing such a domain. Thus, antibodies that are specific for a desired domain within an NOVX protein, or derivatives, fragments, analogs or homologs thereof, are also 15 provided herein. Antibodies directed against a NOVX protein of the invention may be used in methods known within the art relating to the localization and/or quantitation of a NOVX protein (e.g., for use in measuring levels of the NOVX protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and 20 the like). In a given embodiment, antibodies specific to a NOVX protein, or derivative, fragment, analog or homolog thereof, that contain the antibody derived antigen binding domain, are utilized as pharmacologically active compounds (referred to hereinafter as "Therapeutics"). An antibody specific for a NOVX protein of the invention (e.g., a monoclonal 25 antibody or a polyclonal antibody) can be used to isolate a NOVX polypeptide by standard techniques, such as immunoaffinity, chromatography or immunoprecipitation. An antibody to a NOVX polypeptide can facilitate the purification of a natural NOVX antigen from cells, or of a recombinantly produced NOVX antigen expressed in host cells. Moreover, such an anti-NOVX antibody can be used to detect the antigenic NOVX protein (e.g., in a 30 cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the antigenic NOVX protein. Antibodies directed against a NOVX protein can be used diagnostically to monitor protein levels in tissue as part of a clinical testing 59 WO 03/050245 PCT/USO2/38594 procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, 5 and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, -galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or 10 phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include 1251, 131I, 35 S or 3H. Antibody Therapeutics Antibodies of the invention, including polyclonal, monoclonal, humanized and fully 15 human antibodies, may used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology in a subject. An antibody preparation, preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Such an effect may be one of two kinds, depending on the specific nature of the interaction between the 20 given antibody molecule and the target antigen in question. In the first instance, administration of the antibody may abrogate or inhibit the binding of the target with an endogenous ligand to which it naturally binds. In this case, the antibody binds to the target and masks a binding site of the naturally occurring ligand, wherein the ligand serves as an effector molecule. Thus the receptor mediates a signal transduction pathway for which 25 ligand is responsible. Alternatively, the effect may be one in which the antibody elicits a physiological result by virtue of binding to an effector binding site on the target molecule. In this case the target, a receptor having an endogenous ligand which may be absent or defective in the disease or pathology, binds the antibody as a surrogate effector ligand, initiating a 30 receptor-based signal transduction event by the receptor. A therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, 60 WO 03/050245 PCT/USO2/38594 interferes with the functioning of the target, and in other cases, promotes a physiological response. The amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is 5 administered. Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week. Pharmaceutical Compositions of Antibodies 10 Antibodies specifically binding a protein of the invention, as well as other molecules identified by the screening assays disclosed herein, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington: The Science And Practice Of 15 Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa. : 1995; Drug Absorption Enhancement: Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York. If the antigenic protein is intracellular and whole antibodies are used as inhibitors, 20 internalizing antibodies are preferred. However, liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein 25 sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the 30 composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. 61 WO 03/050245 PCT/USO2/38594 The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, 5 albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions. The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes. Sustained-release preparations can be prepared. Suitable examples of 10 sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and y 15 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT TM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels 20 release proteins for shorter time periods. ELISA Assay An agent for detecting an analyte protein is an antibody capable of binding to an analyte protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof 25 (e.g., Fab or F(ab)2) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled 30 secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term "biological 62 WO 03/050245 PCT/USO2/38594 sample", therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mRNA include 5 Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting immunoassays are described, for example in "ELISA: Theory and Practice: Methods in 10 Molecular Biology", Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, NJ, 1995; "Immunoassay", E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, CA, 1996; and "Practice and Theory of Enzyme Immunoassays", P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-an analyte protein antibody. 15 For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. NOVX Recombinant Expression Vectors and Host Cells Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a NOVX protein, or derivatives, fragments, analogs or 20 homologs thereof. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of 25 autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are 30 operatively-linked. Such vectors are referred to herein as "expression vectors". In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is 63 WO 03/050245 PCT/USO2/38594 intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions. The recombinant expression vectors of the invention comprise a nucleic acid of the 5 invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably-linked" is intended to mean that the nucleotide sequence of interest is linked to 10 the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term "regulatory sequence" is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory 15 sequences are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by 20 those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., NOVX proteins, mutant forms of NOVX proteins, fusion 25 proteins, etc.). The recombinant expression vectors of the invention can be designed for expression of NOVX proteins in prokaryotic or eukaryotic cells. For example, NOVX proteins can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further 30 in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase. 64 WO 03/050245 PCT/USO2/38594 Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such 5 fusion vectors typically serve three purposes: (i) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (iii) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein 10 from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathione S-transferase (GST), maltose E 15 binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al., (1988) Gene 69:301-315) and pET 1 d (Studier et al., GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89). 20 One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector 25 so that the individual codons for each amino acid are those preferentially utilized in E. coli (see, e.g., Wada, et al., 1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques. In another embodiment, the NOVX expression vector is a yeast expression vector. Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSec 1 30 (Baldari, et al., 1987. EMBO J. 6: 229-234), pMFa (Kurjan and Herskowitz, 1982. Cell 30: 933-943), pJRY88 (Schultz et al., 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and picZ (InVitrogen Corp, San Diego, Calif.). 65 WO 03/050245 PCT/USO2/38594 Alternatively, NOVX can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39). 5 In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly 10 used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989. 15 In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1: 20 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Imminunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Banerji, eta!., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), 25 pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the cc-fetoprotein promoter (Campes and Tilglman, 1989. Genes Dev. 3: 30 537-546). The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that 66 WO 03/050245 PCT/USO2/38594 allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to NOVX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or 5 enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a 10 discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub, et al., "Antisense RNA as a molecular tool for genetic analysis," Reviews-Trends in Genetics, Vol. 1(1) 1986. Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms "host cell" and 15 "recombinant host cell" are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. 20 A host cell can be any prokaryotic or eukaryotic cell. For example, NOVX protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or manunalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art. Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional 25 transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found 30 in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals. 67 WO 03/050245 PCT/USO2/38594 For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is 5 generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding NOVX or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection 10 (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die). A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) NOVX protein. Accordingly, the invention further provides methods for producing NOVX protein using the host cells of the invention. In one 15 embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding NOVX protein has been introduced) in a suitable medium such that NOVX protein is produced. In another embodiment, the method further comprises isolating NOVX protein from the medium or the host cell. Transgenic NOVX Animals 20 The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which NOVX protein-coding sequences have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous NOVX sequences have been introduced into their genome or 25 homologous recombinant animals in which endogenous NOVX sequences have been altered. Such animals are useful for studying the function and/or activity of NOVX protein and for identifying and/or evaluating modulators of NOVX protein activity. As used herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal 30 includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that remains in the genome of the mature animal, thereby directing the expression of an 68 WO 03/050245 PCT/USO2/38594 encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous NOVX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA 5 molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal. A transgenic animal of the invention can be created by introducing NOVX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by microinjection, retroviral infection) and allowing the oocyte to develop in a pseudopregnant 10 female foster animal. The human NOVX cDNA sequences, i.e., any one of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, can be introduced as a transgene into the genome of a non-human animal. Alternatively, a non-human homologue of the human NOVX gene, such as a mouse NOVX gene, can be isolated based on hybridization to the human NOVX eDNA (described further supra) and used as a transgene. Intronic 15 sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably-linked to the NOVX transgene to direct expression of NOVX protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and 20 are described, for example, in U.S. Patent Nos. 4,736,866; 4,870,009; and 4,873,191; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the NOVX transgene in its genome and/or expression of NOVX mRNA in tissues or 25 cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene-encoding NOVX protein can further be bred to other transgenic animals carrying other transgenes. To create a homologous recombinant animal, a vector is prepared which contains at 30 least a portion of a NOVX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the NOVX gene. The NOVX gene can be a human gene (e.g., the eDNA of any one of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77), but more preferably, is a non-human homologue of a human 69 WO 03/050245 PCT/USO2/38594 NOVX gene. For example, a mouse homologue of human NOVX gene of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, can be used to construct a homologous recombination vector suitable for altering an endogenous NOVX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous 5 recombination, the endogenous NOVX gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a "knock out" vector). Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous NOVX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby 10 alter the expression of the endogenous NOVX protein). In the homologous recombination vector, the altered portion of the NOVX gene is flanked at its 5'- and 3'-termini by additional nucleic acid of the NOVX gene to allow for homologous recombination to occur between the exogenous NOVX gene carried by the vector and an endogenous NOVX gene in an embryonic stem cell. The additional flanking NOVX nucleic acid is of sufficient 15 length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5'- and 3'-termini) are included in the vector. See, e.g., Thomas, et al., 1987. Cell 51: 503 for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced NOVX gene has 20 homologously-recombined with the endogenous NOVX gene are selected. See, e.g., Li, et al., 1992. Cell 69: 915. The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley, 1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 25 113-152. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously-recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously-recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination 30 vectors and homologous recombinant animals are described further in Bradley, 1991. Curr. Opin. Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354; WO 91/01140; WO 92/0968; and WO 93/04169. 70 WO 03/050245 PCT/USO2/38594 In another embodiment, transgenic non-humans animals can be produced that contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. For a description of the cre/loxP recombinase system, See, e.g., Lakso, et al., 1992. Proc. Natl. Acad. Sci. 5 USA 89: 6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See, O'Gorman, et al., 1991. Science 251:1351-1355. If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic 10 animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase. Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al., 1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit 15 the growth cycle and enter Go phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone of the animal from 20 which the cell (e.g., the somatic cell) is isolated. Pharmaceutical Compositions The NOVX nucleic acid molecules, NOVX proteins, and anti-NOVX antibodies (also referred to herein as "active compounds") of the invention, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions 25 suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are 30 described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles 71 WO 03/050245 PCT/USO2/38594 such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated 5 into the compositions. A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for 10 parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, 15 citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Pharmaceutical compositions suitable for injectable use include sterile aqueous 20 solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL T M (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable 25 under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a 30 coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be 72 WO 03/050245 PCT/USO2/38594 preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. 5 Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a NOVX protein or anti-NOVX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required 10 other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Oral compositions generally include an inert diluent or an edible carrier. They can 15 be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible 20 binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such 25 as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. 30 Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic 73 WO 03/050245 PCT/USO2/38594 acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. The compounds can also be prepared in the form of suppositories (e.g., with 5 conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery. In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, 10 biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to 15 viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used 20 herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular 25 therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Patent No. 5,328,470) or by 30 stereotactic injection (see, e.g., Chen, et al., 1994. Proc. Natl. Acad. Sci. USA 91: 3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene 74 WO 03/050245 PCT/USO2/38594 delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system. The pharmaceutical compositions can be included in a container, pack, or dispenser 5 together with instructions for administration. Screening and Detection Methods The isolated nucleic acid molecules of the invention can be used to express NOVX protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect NOVX mRNA (e.g., in a biological sample) or a genetic lesion in a 10 NOVX gene, and to modulate NOVX activity, as described further, below. In addition, the NOVX proteins can be used to screen drugs or compounds that modulate the NOVX protein activity or expression as well as to treat disorders characterized by insufficient or excessive production of NOVX protein or production of NOVX protein forms that have decreased or aberrant activity compared to NOVX wild-type protein (e.g.; diabetes 15 (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting disorders associated with chronic diseases and various cancers, and infectious disease(possesses anti-microbial activity) and the various dyslipidemias. In addition, the anti-NOVX antibodies of the invention can be used to detect and isolate NOVX proteins 20 and modulate NOVX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absorption of nutrients and the disposition of metabolic substrates in both a positive and negative fashion. The invention further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra. 25 Screening Assays The invention provides a method (also referred to herein as a "screening assay") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to NOVX proteins or have a stimulatory or inhibitory effect on, e.g., NOVX protein expression or NOVX protein 30 activity. The invention also includes compounds identified in the screening assays described herein. 75 WO 03/050245 PCT/USO2/38594 In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity of the membrane-bound form of a NOVX protein or polypeptide or biologically-active portion thereof. The test compounds of the invention can be obtained using any of the numerous approaches in combinatorial 5 library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the "one-bead one-compound" library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, 10 non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 1997. Anticancer Drug Design 12: 145. A "small molecule" as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, 15 carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention. Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al., 1993. Proc. Natl. Acad. Sci. US.A. 90: 6909; Erb, et al., 20 1994. Proc. Natl. Acad. Sci. US.A. 91: 11422; Zuckermann, et al., 1994. J. Med. Chemn. 37: 2678; Cho, et al., 1993. Science 261: 1303; Carrell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2059; Carell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2061; and Gallop, et al., 1994. J. Med. Chemn. 37: 1233. Libraries of compounds may be presented in solution (e.g., Houghten, 1992. 25 Biotechniques 13: 412-421), or on beads (Lam, 1991. Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Patent No. 5,223,409), spores (Ladner, U.S. Patent 5,233,409), plasmids (Cull, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al., 1990. Proc. Natl. Acad. Sci. U.S.A. 87: 6378-6382; 30 Felici, 1991. J. Mol. Biol. 222: 301-310; Ladner, U.S. Patent No. 5,233,409.). In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface is contacted with a test compound and the ability of the test compound to bind 76 WO 03/050245 PCT/USO2/38594 to a NOVX protein determined. The cell, for example, can of mammalian origin or a yeast cell. Determining the ability of the test compound to bind to the NOVX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the NOVX protein or 5 biologically-active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with 1 25 , 35 S, 14C, or 3 H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic 10 label detected by determination of conversion of an appropriate substrate to product. In one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact 15 with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX protein or a biologically-active portion thereof as compared to the known compound. In another embodiment, an assay is a cell-based assay comprising contacting a cell 20 expressing a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX or a biologically-active portion thereof can be 25 accomplished, for example, by determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule. As used herein, a "target molecule" is a molecule with which a NOVX protein binds or interacts in nature, for example, a molecule on the surface of a cell which expresses a NOVX interacting protein, a molecule on the surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal 30 surface of a cell membrane or a cytoplasmic molecule. A NOVX target molecule can be a non-NOVX molecule or a NOVX protein or polypeptide of the invention. In one embodiment, a NOVX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of 77 WO 03/050245 PCT/USO2/38594 a compound to a membrane-bound NOVX molecule) through the cell membrane and into the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with NOVX. 5 Determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by one of the methods described above for determining direct binding. In one embodiment, determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by determining the activity of the target molecule. For example, the activity of the target 10 molecule can be determined by detecting induction of a cellular second messenger of the target (i.e. intracellular Ca 2+ , diacylglycerol, IP 3 , etc.), detecting catalytic/enzymatic activity of the target an appropriate substrate, detecting the induction of a reporter gene (comprising a NOVX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or detecting a cellular response, for 15 example, cell survival, cellular differentiation, or cell proliferation. In yet another embodiment, an assay of the invention is a cell-free assay comprising contacting a NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to bind to the NOVX protein or biologically-active portion thereof. Binding of the test compound to the NOVX protein can 20 be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to 25 interact with a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX or biologically-active portion thereof as compared to the known compound. In still another embodiment, an assay is a cell-free assay comprising contacting NOVX protein or biologically-active portion thereof with a test compound and determining 30 the ability of the test compound to modulate (e.g. stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX can be accomplished, for example, by determining the ability of the NOVX protein to bind to a NOVX target molecule by one of 78 WO 03/050245 PCT/USO2/38594 the methods described above for determining direct binding. In an alternative embodiment, determining the ability of the test compound to modulate the activity of NOVX protein can be accomplished by determining the ability of the NOVX protein further modulate a NOVX target molecule. For example, the catalytic/enzymatic activity of the target 5 molecule on an appropriate substrate can be determined as described, supra. In yet another embodiment, the cell-free assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein 10 determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the NOVX protein to preferentially bind to or modulate the activity of a NOVX target molecule. The cell-free assays of the invention are amenable to use of both the soluble form or the membrane-bound form of NOVX protein. In the case of cell-free assays comprising the 15 membrane-bound form of NOVX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of NOVX protein is maintained in solution. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X- 100, Triton® X-1 14, Thesit®, 20 Isotridecypoly(ethylene glycol ether),, N-dodecyl--N,N-dimethyl-3-ammonio-l-propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-l -propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate (CHAPSO). In more than one embodiment of the above assay methods of the invention, it may be desirable to immobilize either NOVX protein or its target molecule to facilitate 25 separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Binding of a test compound to NOVX protein, or interaction of NOVX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and 30 micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix. For example, GST-NOVX fusion proteins or GST-target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized 79 WO 03/050245 PCT/USO2/38594 microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or NOVX protein, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any 5 unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra. Alternatively, the complexes can be dissociated from the matrix, and the level of NOVX protein binding or activity determined using standard techniques. Other techniques for immobilizing proteins on matrices can also be used in the 10 screening assays of the invention. For example, either the NOVX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated NOVX protein or target molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 15 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with NOVX protein or target molecules, but which do not interfere with binding of the NOVX protein to its target molecule, can be derivatized to the wells of the plate, and unbound target or NOVX protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include 20 immunodetection of complexes using antibodies reactive with the NOVX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the NOVX protein or target molecule. In another embodiment, modulators of NOVX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of 25 NOVX mRNA or protein in the cell is determined. The level of expression of NOVX mRNA or protein in the presence of the candidate compound is compared to the level of expression of NOVX mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator ofNOVX mRNA or protein expression based upon this comparison. For example, when expression of NOVX mRNA 30 or protein is greater (i.e., statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of NOVX mRNA or protein expression. Alternatively, when expression of NOVX mRNA or protein is less (statistically significantly less) in the presence of the candidate compound 80 WO 03/050245 PCT/USO2/38594 than in its absence, the candidate compound is identified as an inhibitor ofNOVX mRNA or protein expression. The level of NOVX mRNA or protein expression in the cells can be determined by methods described herein for detecting NOVX mRNA or protein. In yet another aspect of the invention, the NOVX proteins can be used as "bait 5 proteins" in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Patent No. 5,283,317; Zervos, et al., 1993. Cell 72: 223-232; Madura, et al., 1993. J. Biol. Chem. 268: 12046-12054; Bartel, et a!., 1993. Biotechniques 14: 920-924; Iwabuchi, et al., 1993. Oncogene 8: 1693-1696; and Brent WO 94/10300), to identify other proteins that bind to or interact with NOVX ("NOVX-binding proteins" or "NOVX-bp") and modulate NOVX 10 activity. Such NOVX-binding proteins are also involved in the propagation of signals by the NOVX proteins as, for example, upstream or downstream elements of the NOVX pathway. The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes 15 two different DNA constructs. In one construct, the gene that codes for NOVX is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation domain of the known transcription factor. If the "bait" and the "prey" proteins are able to 20 interact, in vivo, forming a NOVX-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated 25 and used to obtain the cloned gene that encodes the protein which interacts with NOVX. The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein. Detection Assays Portions or fragments of the cDNA sequences identified herein (and the 30 corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: (i) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (ii) identify an individual from a minute biological sample (tissue typing); 81 WO 03/050245 PCT/USO2/38594 and (iii) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below. Chromosome Mapping Once the sequence (or a portion of the sequence) of a gene has been isolated, this 5 sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments of the NOVX sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, or fragments or derivatives thereof, can be used to map the location of the NOVX genes, respectively, on a chromosome. The mapping of the NOVX sequences to chromosomes is an important first 10 step in correlating these sequences with genes associated with disease. Briefly, NOVX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the NOVX sequences. Computer analysis of the NOVX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can 15 then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the NOVX sequences will yield an amplified fragment. Somatic cell hybrids are prepared by fusing somatic cells from different mammals (e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they 20 gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or 25 a small number of human chromosomes, and a fudl set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, et al., 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions. 30 PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using a single thermal cycler. Using the NOVX sequences to design oligonucleotide 82 WO 03/050245 PCT/USO2/38594 primers, sub-localization can be achieved with panels of fragments from specific chromosomes. Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one 5 step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a DNA sequence as short as 500 or 600 10 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al., HUMAN CHROMOSOMES: A MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988). 15 Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance 20 of cross hybridizations during chromosomal mapping. Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, e.g., in McKusick, MENDELIAN INHERITANCE IN MAN, available on-line through Johns Hopkins University Welch Medical Library). The relationship between 25 genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland, et al., 1987. Nature, 325: 783-787. Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the NOVX gene, can be determined. If a 30 mutation is observed in some or all of the affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are 83 WO 03/050245 PCT/USO2/38594 visible from chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms. Tissue Typing 5 The NOVX sequences of the invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences of the invention are useful as additional DNA markers for RFLP ("restriction fragment length polymorphisms," described in U.S. Patent No. 10 5,272,057). Furthermore, the sequences of the invention can be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the NOVX sequences described herein can be used to prepare two PCR primers from the 5'- and 3'-termini of the sequences. These primers can then be 15 used to amplify an individual's DNA and subsequently sequence it. Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences of the invention can be used to obtain such identification sequences from individuals and from tissue. The NOVX 20 sequences of the invention uniquely represent portions of the human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Much of the allelic variation is due to single nucleotide polymorphisms (SNPs), which include restriction 25 fragment length polymorphisms (RFLPs). Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can 30 comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If coding sequences, such as those of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77, are used, a 84 WO 03/050245 PCT/USO2/38594 more appropriate number of primers for positive individual identification would be 500-2,000. Predictive Medicine The invention also pertains to the field of predictive medicine in which diagnostic 5 assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the invention relates to diagnostic assays for determining NOVX protein and/or nucleic acid expression as well as NOVX activity, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an 10 individual is afflicted with a disease or disorder, or is at risk of developing a disorder, associated with aberrant NOVX expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic 15 disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. For example, mutations in a NOVX gene can be assayed in a biological sample. Such 20 assays can be used for prognostic or predictive purpose to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with NOVX protein, nucleic acid expression, or biological activity. Another aspect of the invention provides methods for determining NOVX protein, nucleic acid expression or activity in an individual to thereby select appropriate therapeutic 25 or prophylactic agents for that individual (referred to herein as "pharmacogenomics"). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual examined to determine the ability of the individual to respond to a particular agent.) 30 Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX in clinical trials. These and other agents are described in further detail in the following sections. 85 WO 03/050245 PCT/USO2/38594 Diagnostic Assays An exemplary method for detecting the presence or absence of NOVX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting NOVX protein or 5 nucleic acid (e.g., mRNA, genomic DNA) that encodes NOVX protein such that the presence of NOVX is detected in the biological sample. An agent for detecting NOVX mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to NOVX mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length NOVX nucleic acid, such as the nucleic acid of SEQ ID NO:2n-1, wherein n is an integer between 10 1 and 77, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to NOVX mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein. An agent for detecting NOVX protein is an antibody capable of binding to NOVX 15 protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab') 2 ) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or 20 antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids 25 present within a subject. That is, the detection method of the invention can be used to detect NOVX mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of NOVX mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of NOVX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, 30 immunoprecipitations, and immunofluorescence. In vitro techniques for detection of NOVX genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of NOVX protein include introducing into a subject a labeled anti-NOVX 86 WO 03/050245 PCT/USO2/38594 antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test 5 subject or genomic DNA molecules from the test subject. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting NOVX protein, mRNA, or genomic DNA, such that the presence of 10 NOVX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of NOVX protein, mRNA or genomic DNA in the control sample with the presence of NOVX protein, mRNA or genomic DNA in the test sample. The invention also encompasses kits for detecting the presence of NOVX in a biological sample. For example, the kit can comprise: a labeled compound or agent 15 capable of detecting NOVX protein or mRNA in a biological sample; means for determining the amount of NOVX in the sample; and means for comparing the amount of NOVX in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect NOVX protein or nucleic acid. 20 Prognostic Assays The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject 25 having or at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant NOVX expression or activity in which a test sample is obtained from a subject and NOVX protein or nucleic 30 acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. As used herein, a "test sample" 87 WO 03/050245 PCT/USO2/38594 refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., serum), cell sample, or tissue. Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, 5 peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant NOVX expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder. Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with 10 aberrant NOVX expression or activity in which a test sample is obtained and NOVX protein or nucleic acid is detected (e.g., wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant NOVX expression or activity). The methods of the invention can also be used to detect genetic lesions in a NOVX 15 gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding a NOVX-protein, or the misexpression of the NOVX gene. 20 For example, such genetic lesions can be detected by ascertaining the existence of at least one of: (i) a deletion of one or more nucleotides from a NOVX gene; (ii) an addition of one or more nucleotides to a NOVX gene; (iii) a substitution of one or more nucleotides of a NOVX gene, (iv) a chromosomal rearrangement of a NOVX gene; (v) an alteration in the level of a messenger RNA transcript of a NOVX gene, (vi) aberrant modification of a 25 NOVX gene, such as of the methylation pattern of the genomic DNA, (vii) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of a NOVX gene, (viii) a non-wild-type level of a NOVX protein, (ix) allelic loss of a NOVX gene, and (x) inappropriate post-translational modification of a NOVX protein. As described herein, there are a large number of assay techniques known in the art which can be used for 30 detecting lesions in a NOVX gene. A preferred biological sample is'a peripheral blood leukocyte sample isolated by conventional means from a subject. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells. 88 WO 03/050245 PCT/USO2/38594 In certain embodiments, detection of the lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Patent Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran, et al., 1988. Science 241: 1077-1080; and Nakazawa, et al., 1994. 5 Proc. Natl. Acad. Sci. USA 91: 360-364), the latter of which can be particularly useful for detecting point mutations in the NOVX-gene (see, Abravaya, et al., 1995. Nucl. Acids Res. 23: 675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to a 10 NOVX gene under conditions such that hybridization and amplification of the NOVX gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations 15 described herein. Alternative amplification methods include: self sustained sequence replication (see, Guatelli, et al., 1990. Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (see, Kwoh, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 1173-1177); QP3 Replicase (see, Lizardi, et al, 1988. BioTechnology 6:1197), or any other nucleic acid 20 amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. In an alternative embodiment, mutations in a NOVX gene from a sample cell can be 25 identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes 30 (see, e.g., U.S. Patent No. 5,493,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site. In other embodiments, genetic mutations in NOVX can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high-density arrays containing 89 WO 03/050245 PCT/USO2/38594 hundreds or thousands of oligonucleotides probes. See, e.g., Cronin, et al., 1996. Human Mutation 7: 244-255; Kozal, et al., 1996. Nat. Med. 2: 753-759. For example, genetic mutations in NOVX can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, et a!., supra. Briefly, a first hybridization array of 5 probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or 10 mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene. In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the NOVX gene and detect mutations by comparing the sequence of the sample NOVX with the corresponding wild-type (control) sequence. 15 Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl. Acad. Sci. USA 74: 560 or Sanger, 1977. Proc. Natl. Acad. Sci. USA 74: 5463. It is also contemplated that any of a variety of automated sequencing , procedures can be utilized when performing the diagnostic assays (see, e.g., Naeve, et al., 1995. Biotechniques 19: 448), including sequencing by mass spectrometry (see, e.g., PCT 20 International Publication No. WO 94/16101; Cohen, et al., 1996. Adv. Chromatography 36: 127-162; and Griffin, et al., 1993. Appl. Biochemn. Biotechnol. 38: 147-159). Other methods for detecting mutations in the NOVX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers, et al., 1985. Science 230: 1242. In general, 25 the art technique of "mismatch cleavage" starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type NOVX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to basepair mismatches between the control and sample strands. 30 For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with S 1 nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched 90 WO 03/050245 PCT/USO2/38594 regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., Cotton, et al., 1988. Proc. Natl. Acad. Sci. USA 85: 4397; Saleeba, et al., 1992. Methods Enzymol. 217: 286-295. In an embodiment, the control DNA or RNA can be labeled for 5 detection. In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in NOVX cDNAs obtained from samples of cells. For example, the mutY enzyme of E. 10 coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches. See, e.g., Hsu, et al., 1994. Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, a probe based on a NOVX sequence, e.g., a wild-type NOVX sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage 15 products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Patent No. 5,459,039. In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in NOVX genes. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility 20 between mutant and wild type nucleic acids. See, e.g., Orita, et al., 1989. Proc. Natl. Acad. Sci. USA: 86: 2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Apple. 9: 73-79. Single-stranded DNA fragments of sample and control NOVX nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in 25 electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of 30 changes in electrophoretic mobility. See, e.g., Keen, et al., 1991. Trends Genet. 7: 5. In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE). See, e.g., Myers, et al., 1985. Nature 313: 495. 91 WO 03/050245 PCT/USO2/38594 When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and 5 sample DNA. See, e.g., Rosenbaum and Reissner, 1987. Biophys. Chemin. 265: 12753. Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions 10 that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al., 1986. Nature 324: 163; Saiki, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA. 15 Alternatively, allele specific amplification technology that depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, et al., 1989. Nucl. Acids Res. 17: 2437-2448) or at the extreme 3'-terminus of one primer 20 where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 11: 238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection. See, e.g., Gasparini, et al., 1992. Mol. Cell Probes 6: 1. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for 25 amplification. See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3'-terminus of the 5' sequence, making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification. The methods described herein may be performed, for example, by utilizing 30 pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a NOVX gene. 92 WO 03/050245 PCT/USO2/38594 Furthermore, any cell type or tissue, preferably peripheral blood leukocytes, in which NOVX is expressed may be utilized in the prognostic assays described herein. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells. 5 Pharmacogenomics Agents, or modulators that have a stimulatory or inhibitory effect on NOVX activity (e.g., NOVX gene expression), as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) disorders. The disorders include but are not limited to, e.g., those diseases, disorders and conditions listed 10 above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table A. In conjunction with such treatment, the pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) of the individual may be considered. Differences in metabolism of 15 therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics of the individual permnnits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages 20 and therapeutic regimens. Accordingly, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. Pharmacogenomics deals with clinically significant hereditary variations in the 25 response to drugs due to altered drug disposition and abnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol., 23: 983-985; Linder, 1997. Clin. Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering 30 the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of 93 WO 03/050245 PCT/USO2/38594 oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans. As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic 5 polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome pregnancy zone protein precursor enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the 10 extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive 15 standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification. 20 Thus, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness 25 phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a NOVX modulator, such as a modulator identified by one of the exemplary screening assays described herein. Monitoring of Effects During Clinical Trials 30 Monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described 94 WO 03/050245 PCT/USO2/38594 herein to increase NOVX gene expression, protein levels, or upregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting decreased NOVX gene expression, protein levels, or downregulated NOVX activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease NOVX gene expression, protein levels, 5 or downregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting increased NOVX gene expression, protein levels, or upregulated NOVX activity. In such clinical trials, the expression or activity of NOVX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a "read out" or markers of the immune responsiveness of a particular cell. 10 By way of example, and not of limitation, genes, including NOVX, that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) that modulates NOVX activity (e.g., identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the 15 levels of expression of NOVX and other genes implicated in the disorder. The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of NOVX or other genes. In this manner, the gene expression pattern can serve as a 20 marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent. In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, 25 peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of a NOVX protein, mRNA, or genomic DNA in the preadministration sample; (iii) obtaining one or more post-administration samples from the 30 subject; (iv) detecting the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the pre-administration sample with the NOVX protein, mRNA, or genomic DNA in the post administration sample or 95 WO 03/050245 PCT/USO2/38594 samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased administration of the agent may be desirable to increase the expression or activity of NOVX to higher levels than detected, i.e., to increase the effectiveness of the agent. Alternatively, decreased administration of the agent may be desirable to decrease 5 expression or activity of NOVX to lower levels than detected, i.e., to decrease the effectiveness of the agent. Methods of Treatment The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant 10 NOVX expression or activity. The disorders include but are not limited to, e.g., those diseases, disorders and conditions listed above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table A. These methods of treatment will be discussed more fully, below. 15 Diseases and Disorders Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner. Therapeutics that 20 may be utilized include, but are not limited to: (i) an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (ii) antibodies to an aforementioned peptide; (iii) nucleic acids encoding an aforementioned peptide; (iv) administration of antisense nucleic acid and nucleic acids that are "dysfunctional" (i.e., due to a heterologous insertion within the coding sequences of coding sequences to an aforementioned peptide) that are 25 utilized to "knockout" endogenous function of an aforementioned peptide by homologous recombination (see, e.g., Capecchi, 1989. Science 244: 1288-1292); or (v) modulators ( i.e., inhibitors, agonists and antagonists, including additional peptide mimetic of the invention or antibodies specific to a peptide of the invention) that alter the interaction between an aforementioned peptide and its binding partner. 30 Diseases and disorders that are characterized by decreased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate 96 WO 03/050245 PCT/USO2/38594 activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability. Increased or decreased levels can be readily detected by quantifying peptide and/or 5 RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or peptide levels, structure and/or activity of the expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, 10 immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot blots, in situ hybridization, and the like). Prophylactic Methods In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant NOVX expression or activity, by administering to 15 the subject an agent that modulates NOVX expression or at least one NOVX activity. Subjects at risk for a disease that is caused or contributed to by aberrant NOVX expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the NOVX aberrancy, such that a 20 disease or disorder is prevented or, alternatively, delayed in its progression. Depending upon the type of NOVX aberrancy, for example, a NOVX agonist or NOVX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections. 25 Therapeutic Methods Another aspect of the invention pertains to methods of modulating NOVX expression or activity for therapeutic purposes. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of NOVX protein activity associated with the cell. An agent that modulates NOVX protein 30 activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of a NOVX protein, a peptide, a NOVX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or 97 WO 03/050245 PCT/USO2/38594 more NOVX protein activity. Examples of such stimulatory agents include active NOVX protein and a nucleic acid molecule encoding NOVX that has been introduced into the cell. In another embodiment, the agent inhibits one or more NOVX protein activity. Examples of such inhibitory agents include antisense NOVX nucleic acid molecules and anti-NOVX 5 antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). As such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of a NOVX protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent 10 identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) NOVX expression or activity. In another embodiment, the method involves administering a NOVX protein or nucleic acid molecule as therapy to compensate for reduced or aberrant NOVX expression or activity. Stimulation of NOVX activity is desirable in situations in which NOVX is 15 abnormally downregulated and/or in which increased NOVX activity is likely to have a beneficial effect. One example of such a situation is where a subject has a disorder characterized by aberrant cell proliferation and/or differentiation (e.g., cancer or immune associated disorders). Another example of such a situation is where the subject has a gestational disease (e.g., preclampsia). 20 Determination of the Biological Effect of the Therapeutic In various embodiments of the invention, suitable in vitro or in vivo assays are performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue. In various specific embodiments, in vitro assays may be performed with 25 representative cells of the type(s) involved in the patient's disorder, to determine if a given Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects. Similarly, for in vivo testing, any of the animal model system known in the art may be used prior to 30 administration to human subjects. 98 WO 03/050245 PCT/USO2/38594 Prophylactic and Therapeutic Uses of the Compositions of the Invention The NOVX nucleic acids and proteins of the invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders. The disorders include but are not limited to, e.g., those diseases, disorders and conditions listed 5 above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table A. As an example, a cDNA encoding the NOVX protein of the invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof. By way of non-limiting example, the compositions of the invention will have 10 efficacy for treatment of patients suffering from diseases, disorders, conditions and the like, including but not limited to those listed herein. Both the novel nucleic acid encoding the NOVX protein, and the NOVX protein of the invention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. A further use 15 could be as an anti-bacterial molecule (i.e., some peptides have been found to possess anti-bacterial properties). These materials are further useful in the generation of antibodies, which immunospecifically-bind to the novel substances of the invention for use in therapeutic or diagnostic methods. The invention will be further described in the following examples, which do not 20 limit the scope of the invention described in the claims. EXAMPLES Example A: Polynucleotide and Polypeptide Sequences, and Homology Data The NOV1 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 1A. 25 Table 1A. NOV1 Sequence Analysis SEQ ID NO: 1 531 bp NOVa, ATGAAGCCCCTGCTCCTGGCCGTCAGCCTTGGCCTCATTGCTGCCCTGCAGGCCCACCACCTCCTGGC CG102689-01 CTCAGACGAGGAGATTCAGGATGTGTCAGGGACGTGGTATCTGAAGGCCATGACGGTGGACAGGGAGT TCCCTGAGATGAATCTGGAATCGGTGACACCCATGACCCTCACGACCCTGGAAGGGGGCAACCTGGAA DNA Sequence GCCAAGGTCACCATGCTGATAAGTGGCCGGTGCCAGGAGGTGAAGGCCGTCCTGGAGAAAACTGACGA GCCGGGAAAATACACGGCCGACGGGGCAAGCACGTGGCATACATCATCAGGTCGCACGTGAAGGACC ACTACATCTTTTACTGTGAGGGCGACTGCACGGGAAGCCGGTCCGAGGGGTGAAGCTCGTGGGCAGA GACCCCAAGAACAACCTGGAAGCCTTGGAGGACTTTGAGAAAGCCGCAGGAGCCCGCGGACTCAGCAC GGAGAGCATCCTCATCCCCAGGCAGAGCGAAACCTGCTCTCCAGGGAGCGATTAG I ORF Start: ATG at 1 ORF Stop: TAG at 529 99 WO 03/050245 PCT/USO2/38594 SEQ ID NO: 2 176 aa MW at 19249.8kD NOVIa, MKPLLLAVSLGLIAALQAHHLLASDEE IQDVSGTWYLKAMTVDREFPEMNLESVTPMTLTTLEGGNLE CG102689-01 AKVTMLISGRCQEVKAVLEKTDEPGKYTADGGKHVAYI IRSHVKDHYIFYCEGELHGKPVRGVKLVGR Protein DPKNNLEALEDFEKAAGARGLSTESILIPRQSETCSPGSD Sequence SEQ IDNO: 3 531bp NOV1b, CGTGGACTCAGACTCCGGAGATGAAGCCCCTGCTCCTGGCCGTCAGCCTTGGCCTCATTGCTGCCCT CG102689-02 GCAGGCCCACCACCTCCTGGCCTCAGACGAGGAGATTCAGGATGTGTCAGGGACGTGGTATCTGAAG DNA Sequen GCCATGACGGTGGACAGGGAGTTCCCTGAGAT TCTGGAATCGGTGACACCCATGACCCTCACGA sequence CCCTGGAAGGGGGCAACCTGGAAGCCAAGGTCACCATGCTGATAAGTGGCCGGTGCCAGGAGGTGAA GGCCGTCCTGGAGAAAACTGACGAGCCGGTCCGAGGGGTGAAGCTCGTGGGCAGAGACCCCAAGAAC AACCTGGAAGCCTTGGAGGACTTTGAGAAAGCCGCAGGAGCCCGCGGACTCAGCACGGAGAGCATCC TCATCCCCAGGCAGAGCGAAACCTGCTCTCCAGGGAGCGATTAGGGGCAGGGGACACCTTGGCTCCT CAGCAGCCCAAGGACGGCACCATCCAGCACCTCCGTCATTCACAGGGACATGGAAAAGCTCC ORF Start: ATG at 21 . ORF Stop: TAG at 444 SEQ ID NO: 4 1141 aa JMW at 15277.3kD NOVlb, MKPLLLAVSLGLIAALQAHHLLASDEEIQDVSGTWYLKAMTVDREFPEMNLESVTPMTLTTLEGG CG102689-02 EAKVTMLISGRCQEVKAVLEKTDEPVRGVKLVGRDPKNNLEALEDFEKAAGARGLSTESILIPRQSE Pe TCSPGSD Protemn Sequence Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table lB. Table 1B. Comparison of NOVla against NOVlb. Protein Sequence NOVla Residues/ Identities/ Match Residues Similarities for the Matched Region NOVlb 1..176 141/176 (80%) 1..141 141/176 (80%) 5 Further analysis of the NOV1 a protein yielded the following properties shown in Table 1C. Table 1C. Protein Sequence Properties NOVla SignalP Cleavage site between residues 24 and 25 analysis: 100 WO 03/050245 PCT/USO2/38594 PSORTIL PSG: a new signal peptide prediction method analysis: N-region: length 2; pos.chg 1; neg.chg 0 H-region: length 22; peak value 9.05 PSG score: 4.65 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): 1.14 possible cleavage site: between 15 and 16 >>> Seems to have a cleavable signal peptide (1 to 15) ALOM: Klein et al's method for TM region allocation Init position for calculation: 16 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood = 8.80 (at 59) ALOM score: 8.80 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 7 Charge difference: -5.0 C(-3.0) - N( 2.0) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 5.25 Hyd Moment(95): 6.66 G content: 1 D/E content: 1 S/T content: 2 Score: -4.93 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 10.8% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none 101 WO 03/050245 PCT/USO2/38594 checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 89 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 33.3 %: extracellular, including cell wall 22.2 %: mitochondrial 22.2 %: vacuolar 11.1 %: Golgi 11.1 %: endoplasmic reticulum > prediction for CG102689-01 is exc (k=9) A search of the NOVI a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 1D. 5 Table ID. Geneseq Results for NOVIa NOVla . . a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for the Expect Identifier [Patent #, Date] Match Matched Region Value Reide Matched Region Residues AAG66536 Human interferon-alpha 1..176 176/176 (100%) 2e-98 induced polypeptide, 1..176 176/176 (100%) Lipocalin 1 - Homo sapiens, 176 aa. [WO200159155-A2, 16-AUG-2001] ABG29411 Novel human diagnostic 1..170 157/170 (92%) 4e-87 protein #29402 - Homo 1..170 162/170 (94%) sapiens, 865 aa. [WO200175067-A2, 11-OCT-2001] .... AAY25670 Dog allergen Can f 1 protein 1..174 100/174 (57%) 3e-48 fragment - Canis sp, 174 aa. 1..172 122/174 (69%) [WO9934826-A1, 15-JUL-1999] AAR59987 Can fI protein allergen - 1..174 100/174 (57%) 3e-48 Canis familiaris, 174 aa. 1..172 122/174 (69%) [WO9416068-A, 21-JUL-1994] ABB84919 Human PRO1283 protein 1..173 80/174 (45%) 9e-36 1..168 109/174 (61%) 102 WO 03/050245 PCT/USO2/38594 Homo sapiens, 170 aa. [WO200200690-A2, 03-JAN-2002] In a BLAST search of public sequence databases, the NOVIa protein was found to have homology to the proteins shown in the BLASTP data in Table 1E. Table 1E. Public BLASTP Results for NOVla NOVia Protein NOVia Identities/ Residues/ SiiaiisfrteExpect Accession Protein/Organisnm/Length Match Similarities for the Expect Number Residues Matched Portion Residues P31025 Von Ebner's gland protein 1..176 176/176 (100%) 6e-98 precursor (VEG protein) (Tear 1..176 176/176 (100%) prealbumin) (TP) (Tear lipocalin) (Lipocalin 1) Homo sapiens (Human), 176 aa. P53715 Von Ebner's gland protein 1..176 103/176 (58%) 4e-52 precursor (VEG protein) (Tear 2..176 131/176 (73%) prealbumin) (TP) (Tear lipocalin) (Lipocalin-1) - Sus scrofa (Pig), 176 aa. P41244 Von Ebner's gland protein 2 1..176 107/178 (60%) 9e-51 precursor (VEG protein 2) - 1..177 127/178 (71%) Rattus norvegicus (Rat), 177 aa. P20289 Von Ebner's gland protein 1 1..176 104/178 (58%) le-49 precursor (VEG protein 1) - 1..177 125/178 (69%) Rattus norvegicus (Rat), 177 aa. 018873 Major allergen Can f 1..174 100/174 (57%) le-47 precursor (Allergen Dog 1) - 1..172 122/174 (69%) Canis familiaris (Dog), 174 aa. 5 PFam analysis predicts that the NOV1a protein contains the domains shown in the Table 1F. Table IF. Domain Analysis of NOVla IIdentities/ Pfam Domain NOVIa Match Region Similarities Expect Value for the Matched Region Clusterin 1.. 13 8/13 (62%) 0.59 12/13(92%) 103 WO 03/050245 PCT/USO2/38594 lipocalin 130.. 171 45/157 (29%) 7.e8 117/157 (75%) Example 2. The NOVW clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 2A. 5 Table 2A. NOV2 Sequence Analysis SEQ ID NO: 5 141 9 bp NOV2a, TCGCGCCGCCAGCGAGTCCCCGCCGTCTTACAGGAAGGGACCGTCCTGGCTCGCCTGAC CG1 03827-01 CATGTGCTGCTCTGGGGCCTGCGGGCCTGGCTTGCTCTGGGCCTGGCCCTGGCCCTGGGCCCCA GC@TGGCCGCAGCTGCCCCTCQQCAGGACTGCACGGGCGTGGAGTCCCGCCGCTGAGAACTGCTT DNA Sequence GAGGAGGCGCTGGAGCCGGGTGCCTGCTGTGCCACGTGTGTGCAGCAGGGCTGCGCCTGCGAGGGCTA CCAGTACTATGACTGCCTACAGGGTGGCTTCGTGCGCGGCCGCGTGCCCGCCGGTCAGTCCTATTTTG TGACTTCGGAGCACTGAGTGCTCCTGCCCACCAGCGCGCAZAGATCAGCTCCAGTTC!ATGCTG TGCCCGGAGCTGCCGCCCAACTGATCGAGGCTGTAGTGGTGGCTGACACTGCCCACAGTGCGGCCA GGTGGGCTGCGTCCACGCGGGCCACGAGTACGCCGCTGGCCACACTGTTCACCTGCCGCCCTGCCGGG CCTGCCACTGCCCTGACGCCGGTmGAGAGCTCATCTGCTACCACTCCCCGGTTCCCGGACTTC TCAGATGCCGAGGAGTc4ACCCCGAGCGACACTACGAJ4GACCCCTACAGCTATCACCGGAGGTGGC CGAGGTGGAAGCAGCAAGCCCTGGGGGGTGAGGTCAGGCGGGTGAGTCCAGGCAGGCGGGG GCCCCCCAGCTGCTCTGGAGTGGATGAGCCACTGTCCACCATCCAGGCACCCCCCTGGCCAGCT GTCCTCCCCAGGCC-AC:AGCr.GCTGCTGCCCTC3GGTCCCCCAGCCCCAGTGCAGCCAAAGCTAGGAG AGTGACCGAGACAGTGAGGAGGAAGAAGAGGAGGAGGAGGAGAGAGAGGATGGCTGTCACTGAGC AGCTGGCAGCAGGTGGCCAAGGGGGCTGGATGGGCTGCCCACTACALGCCCCAGCTGGACCCAGTCTT CCACAGGAAGCGACGGrAAGGAAGTGGAGCTAGGAC CATCCTGGATGCCCAAGCCCACGTCCCGCAGCACTGGGCCGGAGGGCGTGACGCATGCACCGAGCCTGG GCAAGGCTGCTCTCGTCCCAACTCAGGCCGTGCCTGGCTCTCCCAGGGACCCAGTCAAGCCCAGCCCC r-CAACTTCCT-CGCGTCGCTGTCACACGGATCCGA GCCGCAAGTTCTGCCCCATTCCCACGTGCAOQAGGACAGACCCCALACTCTGTCCATTCTATCCCCA GAGACCG-GCCACAGCTACGGCTCGGACG~-GATGC ATTGACGATACGAGTGCCTGGAGATCCCTGACAGTCGCACTGAGGACAACGTCTGCCGACAGCCCA GAGGCACTGCTGTCTCTCCTACTTCCAOGAGAAGAGCTGCATGCCGGCGTCCTGGAGCAGGAGG GTAACGGGCGGAACAACGCGACCCGAAGATCGGCG TGTGGCCTCGGCCTCCGCGTcGCGGGCCGAGGGCCATCGTGTGAGTCCAATCCTACCTGGGCTATCC CTGCATCATGTCATGCTCTCCTCTGTGAGGTAAAGCCTCTCATAGTACCTGAGGTTCGCCGAC CTCCAGAGCCCGCAGCTGCACCACGGAGAGTTTCAGAGGCAGAGATGGCGGGCCGAGAGGCCCTGTC'A CTGGCACAAGGCCGACTGCCGAAAGCCTGCCGGCGATGACCAGATGAGTGCCTTCTCCTCCC GGGAGACCTGTGCCAGCACCTTTGCATrCAATACTGTGGGTTCTTACCACTGTGCCTGCTTTCCTGGCT TCTCACTGCGGACGATGGCCGCACTTGCCGCCCAAGGGTCACCCTCCACAGCCGGAGCCCACG GACTCCGATAATTCCGTGCTTAACTCGTCATCGAC CAATACCTcCAAAGACAATGGACCCTGCAGCACGTGTGCAGCCTGTTGGGGGCTCAGCATATGCT CCTGTTTTCCCGGCTATGCCATCATGGCGGATGGCGTGTCCTGTGAGAATCAACcAGTGTGTGACG GACGA-AGGACGGCACCGGTACCCGGTCTCCGTCAG ACTCACCTGTGAGCCAGGCTATGCCCTCAAGTGCAGTGCAAAGACGTGGATGAGTGTGCGATGG GCACGC-ACACCTGCCAGCCGGGCTTCTTGTGCCAGAACACCAAGGGCTCCTTCTACTGCCAGCCAGG CAGCGCTGCATGGAGCTTCCTGCAGGATCCTGAAGGCAACTGTGTCGACATALCGAGTGCACGTC ACTGTCCGAGCCATGTCCGCCAGGCTAGCTGCATCCACGGTGGGCTCCTACGTGCGG ACCCGTTCCCGGCACCCACGTAGGCAGGTTGCTATA TGTGAGACAGrnTGTGCACCGCTGCGGTGAGGGCCAAGTGTGCCACAJ&CCTCCCTGGCTCCTACCGCTG TGCGAACCCTCGGGTCTCGCGGTCTGCTAT~GGTG CCTCGCCAGGCCGCCTGTGCCAGCACACGTGTGAGACCACTCGGCTCCTACCGCTGTTCCTGCGCC TCGGTCGTGACGCGACCGGAAGGAGGGGOCCGGT CGCCGGAGTCCCACATCTATGGCTCCTACCAGTGCTACTGCCGCCAGGCTACCGCTGGCTG AGCATGGGC-ACACCTGCACAGACATCGACGAGTTGCTCAGGCCCGCATCCTCTGCACCTTCCGC TGCCAGGCGGGTCATTCTGCTACGGTCCAGCGCAG GAGGTCCTGCAAGGACGTGGTGAGTGTGCACTGGGCACCCACXCTGTTCCGAGGCTGAGACCTGCC ACAACATCCAGGGTAGCTTCCGCTGCCTGCGCTTCGAGTGTCCTCCCCTATGTCATCTCCAAA ACGAGTGCGAGCGrACCACGTGCCATGACTTCCTGGAGTCCGACTCGCCAGCGCGCATCACGCA CTACCACCTCCTTCCAGACGGGCCTCCTGGTGCCTGCGATATCTTCCATTGGCCCCGCGCCAG 104 WO 03/050245 PCT/USO2/38594 CCTTCAC GGACACCATCGCCCTGAACATC-ATcAAGGCA.ATGAGGAGGGCTACTTTGGCcACGCoC AGGCTCAATGCCTACACGGGTGTGGTCTACCTGCAGCGGGCC!GTGCTGGAGCCcCCGGACTTTGCCCT GGACGTGGAGATGAAGCTCTGGAGGCAGGGCTCCGTCACCACCTTCCTGGCCAAGATGCACATCTTCT TCACCACCTTTGCCCTGTGAGGTGCCAGCACGGCC-ACCGCGGTGTGCGCAGCCAGQGCTCACAC TGCGTGGGAGGGACTGGGCACTATTGTGGTTTTTACTATAACTTTGTAAATTAACTTAATTTTGCTG ACTTGACTCCTGTGGCTTCTGGACCCCTCCTCTGCCCCGCAGGAGGAAGTTCCACGGCAGGTGGTGCG TTCCCATGTAGGCACCAGTGGAAGCTTGCACGTGGGCCACGCCGTGGCGC.TGCCCTGTGGGTGA GGCTGGGTGATGACCTGAGGACCAGAGACACGCGACCATGTTGGGGCTCTTGGACTCCTCTGGATGAC CCGTCCCCAAACGTTGACA TCCATTTCATGTTCCACTGTGATTAACTTCTTTTCTTTTTTAAAAAAT CATTTTAAAGTTTTTTGTTTAACTATAAAGTAGTACALTGTACATTATATAAAAAAA2'AGTTCAACTAG TATGAAAGGGTTATAAATAACAGAGGAAAACGCCTCTTGGTCCCTTTAAAAAAAAAAA _________ORF Start: ATO at 70 ORE Stop: TGA at 3622 ______SEQ ID NO: 6 18aa. MNW at 126542.lkD NOV2a, NIVIJWEPAGAWLALGALALGPSVAAAAPRQDCTGVECPPLENCIEEALEPGACCATCVQQGCACEGY CG1 03827-01 QYYDCLQGGFVRGRVPAQSYFVDFGSTECSCPPGGGKTSCQFMLCPELPPNCIAVVVADSCPQCGQ VGCVHAGHEYAAGHTVHLPPCRACHCPDAGGELI CYQLPGCHGNFSDAEEGDPERflYEDPYSYDQEVA Protein EVEAATrALGGEVQAGAVQAGAGGPPAALGGGSQPLSTIQAPPWPAVLPRPTAAAALGPPAPVQAKARR Sequence VTEDSEEEEEEEEEREEMAVTEQLAGrHRGLDGLPTTAPAPSLPQEERAAGARA-AARPEEN ILDAQATS1RSTGPEGVTHAPSLGKAALVPTQAVPGSPRDPVKPSPHNILSTSLPDAAWI PPTREVPRK PQVLPHSHVEEDTDPNSVHSI PRSSPEGSTKLIETCCAGQQWAIDNY2CLEIPESTEDNVCRTAQ PHCCVSYLQEKSCMAGVLGAKEGETCGAEDNDSCGISLYKOCCDCCGLGLRVRAEGOSCESNPNLGYP CNHVMLSCCEGEEPLIVPEVRRPPEPAAAPRRVSEAEMAGREALSLGTE-AELPNSLPODDQDECLLLP GELCQHL~CINTVGSYHCACFPGFSLQDDGRTCRPEGHPPQPEAPQEPALKSEFSQVASNTIPLPLPQP NTCKDNGPCKQVCSTVGGSAI CSCFPGYAIMADGVSCEDINCVTDLHTCSRGHCVNT~LGSFHCYKA LTrCEPGYALKDGECEDVDECAMGHTCQPGFLCQNTKGSYCQARQRCMDGFLQDPEC.NC'JDINECTS LSEPCRPGFSCINTVGSYTCQRNPLI CARGYEASDDGAKCVDVNECETGVHRCGEGQVCHNLPGSYRC DCKAGFQRDAFGRGCIEJVNECWASPGRLCQHTCENTLGSYRCSCASGFLLAADGKRCEDVNECEAQRC SQECAIYGSYQCYCRQGYQLAEDGHTCTDIDECAQGAGILCTFRCLNVGSYQCACPEQGYTMTANG RSCKDVDECALGTHN'CSEAETCHNIQGSFRCLRFECPPNYVQVSKTKCERTTCHDFLECQNSPARITH YQLNFQTGLLVPAHI FRI GPAPAFTGDTIALNI IIGNEEGYFGTRRLNAYTGVVYLQRAVLEPRDFAL * DVEMKLWRQGSVTTFLAKMHIFFTTFAL ________SEQ ID NO: 7 390 bp NOV2b, TCGCGGCCGCCGAGCGCAGTGCCCCGCGGGTCTTACAGGAGAGGGCACCGTCCTGGGCTGGCCTGCA CG1 03827-02 ECATGGTOCTGCTCTGGAGCCTGAGGGCCTGGCTTGCTCTGGCCTGGCCCTGGCCCTGGGCCC CAGCGTGGCCGCAGCTGCCCCTCGGCAGGACTGCACGGGCGTGGAGTGCCCGCCGCTGGAGAACTGC DNA Sequence IATTGAGGAGGCGCTGGAGCCGGGTGCCTGCTGTGCCACGTGTGTGC-AGCAGG.GCTGCGCCTGCGAGG GCTACCATACTATGACTGCCTACGGTGGCTTCTGCGCGCCCGTGCCCGCCGGTCAGTCCTA TTTTGTGGACTTCGGAGCACTAGTGCTCCTGCCCACCAGGCGGCGGCAA-GATCALOCTGCCAGTTC ATGCTGTGCCCGGAGCTGCCGCCCAACTGCATCGAGGCTGTAGTGGTGGCTGAGAGCTGCCCACAGT GCGGCCAGGTGGGCTGCGTCCACGCGGGCCACGAGTACGCCGCTGGCCACACTGTTCACCTGCCGCC CTGCCGOGCCTCCCACTGCCCTGACGCCGGTGGAGAGCTCATCTGCTACCAGCTCCCCGGTTGCCAC GGGAACTTCTCAGATGCCGAGGAGGGTGACCCCGAGCGACACTACGAAGACCCCTACAGCTATGACC AGGAGGTGGCCcGAGGTGGAAGCAGCAACAGCCCTGGGGGGTGAGGTCCAGGCGGGTGCAGTCCAGGC AGGCGCAGGGGOCCCCCCAGCTGCTCTGGGAGGTGCGAGTCAGCCACTGTCCACCATCCAGGCACCC CCCTGGCCAGCTGTCCTCCCCAGGCCCACAGCGGCTGCTGCCCTGGGTCCCCCAGCCCCAGTGCAGG CCAACCTAGGAGAGTGACCGAGGACAGTGAGGAGGAAGAAGAGGAGGAGGAGGAGAGAGAGGAAAT GGCTGTCACTGAGCAGCTGGCAOCAGG VGCCACAGOGCTGGATOOGCTGCCCACTACAGCCCCAL GCTGGACCCAGTCTTCCTATCCAGGAGGAGAGGGCAGAAGCTGGGGCA-AGGGCAGAAGCTGGGGCALA GGCCTGAAGAGAACCTCATCCTGGATGCCCAAGCCACGTCCCGC*AGCACTGGGCCGGAGGGCGTGAC GCATGCACCGACCCTGGGCAAGGCTGCTCTCGTCCCAACTCAGGCCGTGCCTGGCTCTCCCAGGGAC CCAGTCAAGCCCAGCCCCCACAACATCCTGTCCACATCACTGCCTGATGCAGCCTGGATCCCACCCA CCCGAGAAGTGCCCAGGAAGCCGCAAGTTCTGCCCCATTCCCACGTGGAGGAGGACACAOACCCCAA CTCTGTCCATTCTATCCCCAGAAGTAGCCCTGAAGGCTCCACCAAGGACCTGATCGAGACTTGCTGC GCAGCCGGACAGCAGTGGGCCATTGACAATGACGAGTGCCTGGAGATCCCTGAGAGTGGCACTGAGG ACACGTCTGCAGACAGCCCAGAGGCACTGCTGTGTCTCCTACTTGCAGGAGAAGAGCTGCATGGC CGGCGTCCTCAGCCAAGGAGGGTGAGACCTGTGOGCOCTGAQGACAACGACAGCTGCGGCATCTCC CTGTACAAGCAATGCTGTGACTGCTGTGGCCTGGGCCTCCGCGTGCGGGCCGAGGGCCAGTCGTGTG AGTCCAATCCT1AACCTOGGCTATCCCTGCAATCATGTCATGCTCTCCTGCTGTGAGGGTGAAGAGCC TCTCATAGTACCTGAGGTTCGCCGACCTCCAGAOCCCGCAGCTGCACCACGOAGAGTTTCAGAGGCA GAGATGGCGGGCCGAGAGGCCCTGTCACTGGGCACAGAGGCCGAGCTGCCGAACAGCCTGCCGGGCG ATOACCAGGATGAGTGCCTTCTCCTCCCGGGAGAGCTGTGCCAGCACCTTTGCATCAATACTGTGGG TTCTTACCACTGTGCCTGCTTTCCTGGCTTCTCACTGCAOACGATGGCCGCACTTGCCGCCCAGAG * GTCACCCTCCACAGCCGGAAGCCCCACAGGAGCCTGCACTGAAGTCAGAATTTTCCCAGGTGGCCT CTAAC-ACCATCCCGCTGCCACTGCCGCAGCCCAATACCTGCAAAGACAATGGACCCTGCAAGCAGGT ....... .GTGCAGCACTGTTGCGGGCTCACCCATATOCTCCTGTTTTCCCCCTATGCCATCATGGCGGATGGC_ 105 WO 03/050245 PCT/USO2/38594 GTGTCCTGTGAAGACATCA.ACGAGTGTGTGACGGACCTGCACACGTGCAGCCGGaGCGAGCACTGTG TGAACACACTGGGCTCCTTCCACTGCTACAAGGCACTCACCTGTGAGCCAGGCTATGCCCTCAAGGA TGGCGAGTGCGAAGACGTGGATGAGTGTGCGATGGGCACGCACACCTGCCAGCCCGGCTTCTTGTGC CAGAACACCAAGGGCTCCTTCTACTGCCAGGCCAGGCAGCGCTGCATGGATGGCTTCCTGCAGGATC CTGAAGGCAACTGTGTGGACATCAACGAGTGCACGTCACTGTCCGAGCCATGTCGGCCAGGCTTCAG CTGCATC.ACACGGTGGCTCCTACACGTCCAGAGGAACCCGCTGATCTGCCCCGCCGCTACCAC GCCAGCGATGATGGGGCCAAGTGTGTGGACGTGAATGAGTGTGAGACAGGTGTGCACCGCTGCGGTG AGGGCCAAcGTGTGCCACAACCTCCCTGGCTCCTACCGCTGTGACTGCAAAGCCGGCTTTCAGCGGGA TGCCTTCGGCCAGCGCTGCAGCCAGOAGTGTGCCAAr-ATCTATGGCTCCTACCAGTGCTACTGCCGC CAGGGCTACCAGCTGGCTGAGGATGGGCACACCTGCACAGACATCGACGAGTGTGCTCAAGGCGCCG GCAkTCCTCTGCACCTTCCGCTGTCTCAACGTGCCAGGGAGCTACCAGTGTGCATGCCCTGAGCAGGG CTACA CCATGACGGCGAACGGGAGGTCCTGCAGGACGTGATGAGTGTCACTGGTACCCAC-AAC TGTTCCGAGGCTGAGACCTGCCACAACATCCAGGGTAGCTTCCGCTGCCTGCGCTTCGAGTGTCCTC CCACTATGTCCAAGTCTCCAAACGAAGTGCGAGCGCACCACGTGCCATGACTTCCTGGAGTGCCA GAACTCGCCAGCGCGCATCACGCACTACCAGCTCAACTTCCAGACGGGCCTCCTGGTGCCTGCGCAT ATCTTCCGCATTGGCCCCGCGCCAGCCTTCACGGGGGACACCATCGCCCTGAACATCATCAAGGGCA ATGAGGAGGGCTACTTTGGCACGCGC-AGGCTCAATGCCTACACGGGTGTGGTCTACCTGCAGCGGGC CGTGCTGGAGCCCCGGGACTTTGCCCTGGACGTGGAGATGAAGCTCTGGAGGCAGGGCTCCGTC-ACC ACCTTCCTGGCCAAGATGCACATCTTCTTCACCACCTTTGCCCGTAGGTCCAGCACGGGCCACC TGCGGGTGTcGCGCAGCCAGGGCTCACACTGCGTGGGAGGGACTGGGTCACTATTGTGGTTTTTACT ATAACTTTGTAAATTAACTTAATTTTGCTGACTTGACTCCTGTGGCTTCTGGACCCCTCCTICTGCCC CGCAGGAGGAAGTTCCACGGCAGGTGGTGCGTTCCC'ATGTAGGCACCAAGTGGAAO3CTTGCACGGTG3 GGCCACGGCCGTGGCGGGTGCCCTGTGGGTGAGGCTGGGTGATGACCTGAGGACCAGAGACACGCGA CCATGTTGGGGCTCTTGGACTCCTCTGGATGACCCGTCCCCAAACGTTGACATTCCATTTC-ATGTTC * CACTGTGATTAACTTCTTTTCTTTTTTAAAAAATCATTTTAAAGTTTTTTGTTTAACTATAAAGTAG TACATGTACATTATATAAAAAAAAAGTTCAACTAGTATGAAAGGGTTATAAAGTAACAGAGGAAAAC GCCTCTTGGTCCCTTTAAAAAAAAAAA ______ORF Start: ATG at 70 .......... ORF Stop: TGA at 3463 SEQ ID NO:8 131aa M at 120816.8kD NOV2b, MVLLWEPAGAWLALGLALALGPSVAAAAPRQDCTGVECPPLENCI EEALE:PCACCATCVQQGCACEG CG103 827-02 YQYYDCLQGGFVRGRVPAGQSYFVDFGSTECSCPPGCGKISCQFMLCPELPPNCIEAVVVADSCPQC ProeinGQVGCVHAGHEYAAGHTVHLPPCRACHCPDAGGELICYQLPGCHGNFSD.AEEGDPERHYEDPYSYDQ ProteinEVAEVEAATALGGEVQAGAVQAGAGQPPAALGGGSQPLSTIQAPPWPAVLPRPTAAAALGPPAPVQA Sequence KRRVTEDSBEEEEEEEREEMAVTEQLAAGGHRGLD)GtPTTAPAGPSLPI QEE1RAEAGARAEAGAR PEENLILDAQATS1RSTGPEGVTHAPSLGKAALVPTQAVPGSPRDPVKPSPHNILSTSLPDAAWIPPT REVPRKPQVLPHSHVEEDTDPNSVHSIPRSSPEGSTKDLIETCCAAGOQWAIDNflECLEI PESGTED NVCRTAQRHCCVSYLQEKSCMAGVLr.AKEGETCGAEDNDS CGISLYKQCCDCCOLGLRVRAEGQSCE SNPNLGYPCNHVMLSCCEGEEPLIVPEVRRPPEPAAAPRRVSEAEMAGRE-ALSLGTEAELPNSLPGD DQDECLLLPGELCQHLCINTVGSYHCACFPGFSLQDDGRTCRPEGH-PPQPEAPQEPALKSEFSQVAS N~TI PLPLPQPNTCKDNCPCKQVCSTVGGSAICS CFPGYAIMADGVSCEDINECVTDLHTCSRGEHCV NTLGSFHCYKALTCEPGYALKDGECEDVDECAMGTHTCQPGFLCQNTXCGSFYCQARQRCMDGFLQDP EGNCDINECTSLSEPCRPGFSCNTVGSYTCRNPLCARGYHASDGAKCVDVNECETGVHRCGE GQVCHLPGSYRCDCAGQRDAFQRCSQECAIYGSYQCYCRQGYQLAEDGHTCTDDECAQGAG ILCTFRCLNVPGSYQCACPEQGYTMTANGRSCKDVDECALGTHNCSEAETCHNTQGSFRCLRFECPP NYVQVSKTKCERTTCHDFLECQNSPARITHYQLNFOTGLLVPAHI FRIGPAPAFTGDTIAINI IKGN EEGYFGTRRLNAYTGVVYLQRAVLEPRDFALDVEMKLWRQGSVTTFLAKMHI FFTTFAL {SEQ ID NO: 9 13240 bp NOV2c, TCGCGGCCGCCGAGCGCAGTGCCCCGCGGGTCTTACAGGAGAGGGGACCGTCCTGGGCTGGCCTGGAC CG1 03827-03 CATOGTGCTGCTCTOGOAGCCTGAGAGCCTOCTTGCTCTGGCCTGGCCCTGGCCCTGGGCCCCA GCGTGGCCGCAGCTGCCCCTCGGCAGGACTGCACGGGCGTGGAGTGCCCGCCGCTGGAGAACTGCATT DNA Sequence GAGGCCGACGGGCGTTCACTTTCGAGCGGCGGGGT CCAGTACTATGACTGCCTACAGGGTGGCTTCGTGCCCGGCCGCGTCCCGCCGGTCAGTCCTATTTTG TGGACTTCGGGAGCAC'rGAGTGCTCCTGCCCACCAGGCGGCGGCAAGATCAGCTGCCAGTTCATGCTG TGCCCGGAGCTGCCGCCCCTGCATCGAGCTGTAGTGGTGGCTGACAGCTGCCCACAGTGCGGCCA GGTGGOCTGCGTCCACCCGCCACGAGTACGCCOCTGGCCACACTCTTCACCTGCCGCCCTGCCGGG CCTGCCACTGCCCTGACGCCGGTGGAGAGCTCATCTGCTACCAGCTCCCCGGTTGCCACGGGAACTTC TCAGATGCCGAGGAGGGTGACCCCGAGCGACACTAcr.AAGAcCCCTACAGCTATGACC-AGGAQGTGGC CGAGGTGGAAGCAGCAACAGCCCTGGGGGGTGAGGTCCAGGCGGGTGCAGTCCAGOCACGCGCAGOGG GCCCCCCAGCTGCTCTGGAGGTGGGAGTCAGCCACTGTCCACCATCCAGGCACCCCCCTGGCCAGCT GTCCTCCCCAGGCCCACAGCGGCTGCTGCCCTOGGTCCCCCAGCCCCAGTGCAGCCAAAGCTAGOAG AGTGACCGAGGACAGTGAGGAGGAAGAAGAGGAGGAGGAGGAGAGAGAOgAAATGCCTGTCACTGAGC AGCTGGCAGCAGGTGGCCACAGGGGGCTGGATGGGCTGCCc-ACTACAGCCCCAGCTGGACCCAGTCTT CCTATCCAGGAGcAGAGGGC-AGAAcGCTGcGGGCAAGGCAGAAGCTGGCAAGCCCTGAACAGAACCT CATCCTGGATGCCCAAGCCACGTCCCOCAGCACTGGGCCGGAGGGCGTrGACGCATGCACCCAGCCTGG __________GCAGGCTGCTCTCGTCCCACTCAGGCCGTGCCTngCcTCTCCCAGGGACCCAGTCAAGCCCAGCcCC 106 WO 03/050245 PCT/USO2/38594 CACAACATCCTGTCCACATCACTGCCTGATGCAGCCTGGATCCCACCCACCCGAGAAGTGCCCAGGAA (CCGCAAGTTCTGCCCCATTCCCACGTGGAGGAGGACACAGACCCCAACTCTGTCCATTCTATCCCCA GAAGTAGCCCTCAAGGCTCCACCAAGGACCTGATCGACACTTGCTGCGCAGCCGGACAGCAGTGGGCC ATTGACAATGACGAGTGCCTGGAGATCCCTGAGAGTGGCACTGAGGACAACGVCTG-AGGACAGCCCA GAGGCACTGCTGTGTCTCCTACTTGCAGGAGAAGAGCTGCATGGCCGGCGTCCTGGAGCCAAGGAGG GTGAGACCTGTGGGGCTGAGGAcACGACAGCTGCGGCATCTCCCTGTACAACAATGCTrGTGACTGC TGTGGCCTGGGCCTCCGCGTGCGGGCCGAGGGCCAGTCGTGTGAGTCCAATCCTAACCTGGGCTATCC CTGCAATCATGTCATGCTCTCCTGCTGTGAGGTGAGAGCCTCTCATAGTACCTAGTTCGCCGAC CTCCAGAGCCCGCAGCTGCACCACGGAGAGTTTCAOAGGCAGAGATGGCGGGCCOAGAGGCCCTGTCA CTGGGCACAGAGGCCGAGCTGCCGAACAGCCTGCCGGGCGATGACCAGGATGAGTGCCTTCTCCTCCC GGGAGAGCTGTGCCAGCACCTTTGCATCAATACTGTGGGTTCTTACCACTGTGCCTGCTTTCCTGGCT TCTCACTGC-AGGACGATGGCCGCACTTGCCGCCCAGAGGGTCACCCTCCACAGCCGGAAGCCCCACAG GAGCCTGCACTGAAGTCAGAATTTTCCCAGGTGGCCTCTAACACCATCCCGCTGCCACTGCCGCAGCC CAATACCTGCA1XAGACAATGGACCCTGCAAGCAGGTGTGCAGCACTGTTGGGGGCTCAGCCATATGCT CCTGTTTTCCCGCCTATGCCATCATGGCCGATGCCGTGTCCTGTGAAGACATCAACGACTGTGTGACG GACCTGCACACGTGCAGCCGGGGCGAGCACTGTGTGAACACACTGGGCTCCTTCCACTGCTACAAGGC ACTCACCTGTGAGCCAGGCTATcGCCCTCAGGATGGCGATGCAAGACGTGGATGAGTGTGCGATGG GCACGCACACCTGCCAGCCGGGCTTCTTGTGCC-AGAACACCAACGGCTCCTTCTACTGCCAGGCCAGG CAGCGCTGCATGGATGGCTTCCTGCAGGATCCTGAAGGCAACTGTGTGGACATCAACGAGTGCACGTC ACTGTCCGAGCCATGTCGGCCAGGCTTCAGCTGCATCAACACGGTGGGCTCCTACACGTGCCAGAGA ACCCGCTGATCTGCCCGCGCGGCTACCACGCCAGCGATGATGGGGCCAAGTGTGTGGACGTGAATGAG TGTGAGACAGGTGTGCACCGCTGCGGTGAGGGCCAAGTGTGCCACAACCTCCCTGGCTCCTACCGCTG TGACTGCAAAGCCGcGCTTTCAGCGGGATGCCTTCGGCCGGmGCTGCATCACGTGAATAGTGCTGGG CCTCGCCAGGCCGCCTGTGCCAGCACACGTGTGAGAACACACTCGGCTCCTACCGCTGTTCCTGCGCC TCCGGGTTrCCTGCTAGCAGCGGACGGCAAGCGCTGTGAAGACATCGACGAGTGTGCTCAAGGCGCCGG CATCCTCTGCACCTTCCGCTGTCTCAACGTGCCAGGGAGCTACCAGTGTGCATGCCCTGAGCAGGGCT ACACCATGACGGCCAACCGAGGTCCTCAAGACGTGGATGAGTGTGCACTGGGTACCCACAACTGT CAGGCTGAGACCTGCCACAACATCCAGGGTAGCTTCCGCTGCCTGCGCTTCGAGTGTCCTCCCAA CATGTCCALAGTCTCCAAAACGAAGTGCGTTCCCACGCAGGCACCAAGTGGAAGCTTGrACGGTGGGC ___ORFStart: ATG at 70Stp Gat32 F ______ SEQ ID NO: 10 1051 aa M t11164.9kD NOV2c, D4VLLWEPAGAWLALGLALALPSVAAAAPRQDCTGVECPPLEMTCIEEALEPGACCATCVQQGCACEGY CG1 03827-03 QYYDCLQGGFVRGRVPAGQSYFVDFGSTECSCPPGGGKI SCQFMLCPELPPNCIEAVVVADSCPQCGQ \TGCVHAc1EYAAGHTVJLPPCRACHCPDAGGELICYQLPGCHGNFSDAEEGDPERHYEDPYSYDQEV2. Protein EVEAATALGGEVQAGAVQAGAGPPAALGGGSQPLSTI0APPWPAVLPRPTAAAALGPPAPVQAKARR Sequence VTEDSEEEEEEEEEBREEMAVTEQLAAGGURGLDGLPTTAPAGPSLPIQEERAzEAGARAEAGARPEENL ILDAQATSRSTGPEGVTF{APSLGKAALVPTQAVPGSPRDPVKPSPHNILSTSLPDAAWIPPTREVPRK PQVLPHSHVEEDTDPNSVHSIPRSPEGSTKDLIETCCAAQQWAIDNDECLEIPESGTEDNVCRTAQ RHCCVSYLQEKSCMAGVLGAKEGETCGAEDNflSCGISLYQCCDCCLGLRVRAEGQSCESNPNLGYP CNT1VMLSCCEGEEPLIVPEVRRPPEPAAAPRRVSAEMAGREALSLGTEAELPNSLPGDDQDECLLLP GELCQHLCINTVGSYHACFPGFSLQDDGRTCRPEHPPQPAQEPALKSEFSQVASNTIP LPLPQP NTCKDNGPCKQVCSTVGGSAICSCFPGYAIMADGVSCEDINECVTDLHTCSRGECVNTLGSHCYKA LTCEPGYALKDGECEDVDECAMGTHTCQPGFLCQNTKGSFYCQARQRCMDGFLQDPEGNCVDINECTS LS EPCRPGFSCINTVGSYTCQRNPLI CARGYHASDDGAKCVDVNECETGVHRCGEGQVCHNLPGSYRC DCKAGFQRDAFGRGCIDVNECWASPGRLCQHTCENTLGSYRCSCASGFLLAADCKRCEDIDECAQGAG ILCTFRCLNVPGSYQCACPEQGYTMTAGRSCKDVDECALGTHNCSEAETCHN'IQGSFRCLRFECPPN SQ ID.NO:11 .J 0 2 bp NOV2d, TCGCGGCCGCCGAGCGCAGTGCCCCGCGGGTCTTACAGGAGAGGGGACCGTCCTGGGCTGGCCTGGA CG103827-04 CATGCTGCTGCTCTGGGAGCCTGCAGGAGCCTGGCTTCTCTGGACCTGGCCCTGGCCCTGGGCCC CAGCGTGGCCGCAGCTGCCCCTCGGCAGGACTGCACGGGCGTGGAGTGCCCGCCGCTGGAGAACTGC DNA Sequence ATTGAGGAGGCGCTGGAGCCGGGTGCCTGCTGTGCCACGTGTGTGCAGCAGGGCTGCGCCTGCGAGG GCTACCAGTACTATGACTGCCTACAGGTGCTTCGTGCGCGGCCCGTCCCGCCGGTCAGTCCTA TTTTGTGGACTTCGGGAGCACTGAGTGCTCCTGCCCACCAGGCGGCGGCAAGATCAGCTGCCAGTTC ATGCTGTGCCCGGAGCTGCCGCCCAACTGCATCGAGGCTGTAGTGGTGGCTGAWAGCTGCCCACAGT GC6CCCAGGTGGGCTGCGTCCACGCCOGCCACGAGTACGCCGCTGGCCACACTGTTCACCTGCCCCC CTGCCGGGCCTGCCACTGCCCTGACGCCGGTGGAGAGCTCATCTGCTACCAGCTCCCCGGTTGCCAC GGAACTTCTCAGATGCCGAGGAGGGTGACCCCGAGCGACACTACGAAGaCCCCTACAGCTATGACC ACGAGGTGGCCGAGGTGGAOAGCACACAGCCCTOGG4GCGTGAGGTCCAGGCGGGTGCAGTCCACGC AGGCGCAGGGGGCCCCCCAGCTGCTCTGGGAGGTGGGAGTCAGCCACTGTCCACCATCCAGGCACCC CCCTGGCCAGCTGTCCTCCCCAmCCCACAGCGGCTGCTGCCCTGGGTCCCCCAGCCCCAGTGC'AGG CCAAAGCTAGGAGAGTGACCGAGGACAGTGAGAGAAAAGAGGAGGAGAGGAGAGAGAGAAAT GGCTGTCACTGAGCAGCTGGCAGCAGGTGGCCACAGGGGGCTGGATGGGCTGCCCACTACAGCCCCA GCTGGACCCAGTCTTCCTATCC-AGGAGGAGAGGCAGAAGCTGGGGCAAGGGCAGAAGCTC3GGCAA 107 WO 03/050245 PCT/US02/38594 GGCCTGAAGAGAACCTCATCCTGGATGCCCAAGCCACGTCCCGCAGCACTGGGCCGGAGGGCGTGAC GCATGCACCGGCCTGGGCAAGCTGCTCTCGTCCCACTCAGGCCGTGCCTGCTCTCCCAGGGAC CCAGTCAAGCCCAGCCCCCACAACATCCTGTCCACATCACTGCCTOATGCAOCCTGGATCCCACCCA CCCGAGAAGTGCCCAGGAAGCCGCAAGTTCTGCCCCATTCCCACGTGGAGGAGGACACAGACCCCAA CTCTGTCCA PTCTATCCCCGAAGTAGCCCTGAAGGCTCC-ACCAAGGACCTGATCGAGACTTGCTGC GCAGCCGGACAGCAGTGGGCCATTGACAATGACGAGTGCCTGGAGATCCCTGAGAGTGCACTGAGG ACAACGTCTGCAGGACAGCCCAGAGGCACTGCTGTGTCTCCTACTTGCAGGAGAAGAGCTGCATGGC CGGCTCCTGGAGCCAGGAGGTGAGACCTGTGGGGCTGAGGACACGACAGCTGCGGCATCTCC CTGTACAGCATGCTGTGACTGCTGTGGCCTGOCCCTCCGTGCGGOCCGAGGGCCAGTCGTGTG AGTCCA.ATCCTAADCCTGGGCTATCCCTGCAATCATGTCATGCTCTCCTGCTGTGAGGGTGAAGAGCC TCTCATAGTACCTGATTCGCCGACCTCCAGACGCGCTGCACCACGGAGAGTTTCAGAC GAGATGGCGGG~CGAGAGGCCCTGTCACTOGGCACAGAGGCCGAGCTGCCGAACAGCCTGCCaGGCG ATGACCAGGATGAGTGCCTTCTCCTCCCGGGAGAGCTGTGCCAGCACCTTTGCATCAATACTGTGGG TTCTTACCACTGTGCCTGCTTTCCTGGCTTCTCACTGCAGGACGATGGCCGCACTTGCCGCCCAGAG GGTCACCCTCCACAGCCGGAAGCCCCACAGGAGCCTGCALCTGAAGTCAGAATTTTCCCAGGTGGCCT CTALACACCATCCCGCTGCCACTGCCGCAGCCCAATACCTGCAAAGACAATGGACCCTGCAAGCAGGT GTGCAGCACTGTTGGGGCTCAGCCATATGCTCCTGTTTTCCCGGCTATGCCATCATGGCGGATGGC GTGTCCTGTGAAGACATCAACGAGTGTGTGACGGACCTGCAACGTGAGCCGGGGCGAGCACTGTG TGAACACACTGcGGCTCCTTCCACTGCTACAAGGCACTCACCTGTGAGCCXGGCTATGCCCTCAAGGA TGGCGAGTGCGAAGACGTGrATAGTGTGCGATGGGCACQC-ACACCTGCCAGCCGGGCTTCTTGTGC CAGAACACCAAGGGCTCCTTCTACTGCCAGCCCAGGCAGCCCTGATGGATGGCTLTCCTGCAGGATC CTGAAGGCAACTGTGTGGACATCA.ACGAGTGCACGTCACTGTCCGAGCCATGTCGGCCAGGCTTCAG CTGCATCACACGGTGGGCTCCTAACGTCCAGAGGAACCCGCTGATCTGCCGCGCGGCTACCAC GCCAGCATGATGGGQCCGTGTGTGGACGTGATAGTGTGAACAGGTGTGCACCGCTGCGGTG AGGGCCAAGTGTGCCACAACCTCCCTGGCTCCTACCGCTGTGACTGCAAAGCCGGCTTTCAGCGGGA TGCCTTCcGGCCC3GGGCTGCATCGACGTGAATGAGTGCTGGCCTCGCCAGGCCGCCTGTGCCAGCAC ACGTGTGAGAACACACTCGGCTCCTACCGCTGTTCCTG2CGCCTCCGGGTTCCTGCTAGC-AGCGGACG GCAAGCGCTGTGAAGACATCGACGAGTGTGCTCAAGGCGCCGGCATCCTCTGCACCTTCCGCTGTCT CAACGTGCCAGGGAGCTACC-AGTGT;CATGCCCTGAGCAGGGCTACACCATGACGGCCAACGGGAGG TCCTGCAAGGACGTGGATGAGTGTGCACTGTACCCACAACTGTTCCAGCTGAGACCTGCCACA ACATCCAGGGTAGCTTCCGCTGCCTGCGCTTCGAGTGTCCTCCCAACTATGTCCAAGTCTCCAAAAC GAAGTGCGAGCGCACCACGTGCCATGACTTCCTGGAGTGCCAGAACTCGCCAGCGCGCATCACGCAC TACCAGCTCAACTTCCAGACGCGCCTCCTGGTGCCTGCGCATATCTTCCGCATTGGCCCCGCGCCAG CCTTCACGGGGGACACCATCGCCCTGAACATCATCAAGGCAATGAGACTACTTTGCcACGCG CAGGCTCAATGCCTACACGGGTGTGGTCTACCTGCAGCGGGCCGTGCTGGAGCCCCGGGACTTTGCC CTGGACGTGGACATGAGCTCTGGAGCAGGGCTCCGTCACCACCTTCCTGGCCAAGATGCACATCT TCTTCACCACCTTTGCCCTGTGAGGTGCCAGACOCCACCTGCGGTGTGGCGAGCAGGCTC ACACTGCGTGGGAGGGACTGGGTCACTATTGTGGTTTTTACTATAACTTTGTAAATTAACTTAATTT TGCTGACTTGACTCCTGTGGCTTCTGGACCCCTCCTCTGCCCCCAGGAGGAAGTTCCACGGCAGGT GGTGCGTTCCCATGTAGGCACCAAGTGGAAGCTTGCACGGTGGGCCACGGCCGTGCGGGTGCCCTG TcIGGTGAGGCTGGGTGATGACCTGAGGACCAGAGACACGCGACCATGTTGGGGCTCTTGGACTCCTC TGGATGACCCGTCCCCAAACGTTGACATTCCATTTCATGTTCcACTGTGATTAACTTCTTTTCTTTT TTAAAAAATCATTTTAAAGTTTTTTGTTTAACTATAAAGTAGTACATGTACATTATATAAAAAAAAA GTTCAACTAGTATGAAAGGGTTATAAAGTAACAGAGGAAAACGCCTCTTGGTCCCTTTAAAAAAAAA ______ORF Start: AT( at 70 a30 - SEQTD NO:1 E l45a -- M t12119.4kD NOV2d, MLLWEPAGAWLALCLAALGPSVAAAPRQDCTGVECPPLECIEEALEPCACCATCVQQQr-CEG CG1 03827-04 YQYYDCLQGGFRGRVPAGQSYFVDFGSTECSCPPGGGKISCQFMLCPELPPNCIEAVVVDSCPQC GQVGCVHAGHEYAAHTVILPPCR-ACHCPDAGGELICYQLPGCHGNFSDAEEGDPERHYEDPYSYDQ Protein EVAEVFAATALGGEVQAGAVQAGAGGPPAALGGGSQPLSTIQAPPWPAVLPRPTAAA1ALGPPAPVQA Sequence KARRVTEDSEEEEEEEEEREEMAVTEQLAAGGHRGLGLPTTAPAGPSLPIQEEPAGARAEAGAR PEENLILDAQATSRSTGPEGVTHAPSLGKAALVPTQAVPGSPRDPVKPSPHNILSTSLPDAAWI PPT REVPRI(POVLP1SHVEEDTDPNSViS IPRSSPEGSTKDLITCCAACQQWAIDN'DECLEIPESGTED NVCRTAQRHCCVSYLQEKSCMAGVLGAKEGETCGAEDNDSCGISLYKQCCDCCGLGLRVRAEGQSCE SNPNLGYPCNHVMLSCCEGEEPLIVPEVRRPPEPAAAPRRVSEAEMAcREALSLGTEAELPNSLPGD DQDECLLLPGELCQHLCINTVGSYSCACFPGB'SLQDDGRTCRPEGHPPQPE-APQEPALKSEFSQVAS NTIPLPLPQPNTCKDNGPCI(QVCSTVGGSAICSCFPGYAIMADGVSCEDINECVTDLITCSRGflHCV NTLGSFUCYKALTCEPGYALKDGECEDVDECAMGTHTCQPGFLCQNTI(GSFYCQARQRCMDGFLQDP EGNCVDIUECTSLSEPCRPGFSCINTVGSYTCQRNPLI CARGYHASDDGAKCVDVN'ECETGVHRCGE CQVCHNLPGSYRCDCKAGFQPflAFGRGCIDVNECqASPGRLCQHTCE1TLGSYRCSCASGFLLAAlG KRCEDIDECAQGAGILCTFRCLWTPGSYQCACPEQGYTMTANGRSCKDVDEC-ALGTHaCSEAETCHN IQGSFRCLRFECPPNYVQVSKTKCERTTCHDFLECQNSPARITHYQLFQTGLLVPAIPRIGPAA FT@DTIALNIIKGNEEGYFGTRRLNAYTGVYLQRAVLEPRDFALDVEMKLWRQGSVTTLMHIF 108 WO 03/050245 PCT/USO2/38594 Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 2B. Table 2B. Comparison of NOV2a against NOV2b through NOV2d. NOV2a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region NOV2b 1..1184 1131/1184 (95%) 1..1131 1131/1184(95%) NOV2c 1..1071 1030/1071 (96%) 1..1032 1030/1071 (96%) NOV2d 1..1184 1145/1184 (96%) 1..1145 1145/1184(96%) 5 Further analysis of the NOV2a protein yielded the following properties shown in Table 2C. Table 2C. Protein Sequence Properties NOV2a SignalP Cleavage site between residues 28 and 29 analysis: PSORT II PSG: a new signal peptide prediction method analysis: N-region: length 6; pos.chg 0; neg.chg 1 H-region: length 23; peak value 0.00 PSG score: -4.40 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -0.40 possible cleavage site: between 25 and 26 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -3.03 Transmembrane 12 - 28 PERIPHERAL Likelihood = 2.01 (at 1168) ALOM score: -3.03 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 19 Charge difference: -2.0 C(-2.0) - N( 0.0) N >= C: N-terminal side will be inside >>> membrane topology: type 2 (cytoplasmic tail 1 to 12) MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 4.70 Hyd Moment(95)4 5.95 G content: 3 D/E content: 2 S/T content: 1 Score: -7.47 109 WO 03/050245 PCT/USO2/38594 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 40 PRQIDC NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 6.8% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: found LL at 3 checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 76.7 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 47.8 %: nuclear 21.7 %: mitochondrial 13.0 %: cytoplasmic 4.3 %: vacuolar 4.3 %: plasma membrane 4.3 %: extracellular, including cell wall 4.3 %: peroxisomal >> prediction for CG103827-01 is nuc (k=23) 110 WO 03/050245 PCT/USO2/38594 A search of the NOV2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 2D. Table 2D. Geneseq Results for NOV2a NOV2a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for the Expect Identifier [Patent #, Date] Match Matched Region Value Residues ABP63045 Human polypeptide SEQ ID 1..1184 1183/1231 (96%) 0.0 NO 482 - Homo sapiens, 1..1231 1183/1231 (96%) 1231 aa. [WO200218424-A2, 07-MAR-2002] AAM40146 Human polypeptide SEQ ID 549..1184 635/636 (99%) 0.0 NO 3291 - Homo sapiens, 1..636 636/636 (99%) 636 aa. [WO200153312-A1, 26-JUL-2001] AAM79191 Human protein SEQ ID NO 582..1184 602/603 (99%) 0.0 1853 - Homo sapiens, 603 1..603 602/603 (99%) aa. [WO200157190-A2, 09-AUG-2001] AAMI41932 Human polypeptide SEQ ID 656..1184 528/576 (91%) 0.0 NO 6863 - Homo sapiens, 1..576 528/576 (91%) 576 aa. [WO200153312-A1, 26-JUL-2001] AAM80175 Human protein SEQ ID NO 656..1184 528/576 (91%) 0.0 3821 - Homo sapiens, 576 1..576 528/576 (91%) aa. [WO200157190-A2, 09-AUG-2001] 5 In a BLAST search of public sequence datbases, the NOV2a protein was found to have homology to the proteins shown in the BLASTP data in Table 2E. Table 2E. Public BLASTP Results for NOV2a Protein NOV2a Identities/ Accession Protein/Organism/Length Residues/ Similarities for the Expect Number Match Matched Portion Value Residues P98095 Fibulin-2 precursor - Homo 1..1184 1184/1184 (100%) 0.0 _sapiens (Human), 1184 aa. 1..1184 1184/1184 (100%) 111 WO 03/050245 PCT/USO2/38594 CAD33510 Sequence 237 from Patent 1..1184 1183/1231 (96%) 0.0 W00218424 - Homo sapiens 1..1231 1183/1231 (96%) (Human), 1231 aa. AAN05436 Fibulin 2 - Homo sapiens 1..1184 1183/1231 (96%) 0.0 (Human), 1231 aa. 1..1231 1183/1231 (96%) AAN05435 Fibulin 2 - Homo sapiens 1..1184 1182/1231 (96%) 0.0 (Human), 1231 aa. 1..1231 1182/1231 (96%) Q99K58 Similar to fibulin 2 - Mus 2..1183 966/1186 (81%) 0.0 musculus (Mouse), 1174 aa. 1..1173 1029/1186 (86%) PFam analysis predicts that the NOV2a protein contains the domains shown in the Table 2F. Table 2F. Domain Analysis of NOV2a Identities/ Similarities Pfam Domain NOV2a Match Region for the Matched Expect Value Region vwc 73..134 20/87(23%) 0.16 46/87 (53%) vwc 139..189' 16/84 (19%) 0.5 30/84 (36%) ANATO 445..480 11/37 (30%) 0.42 21/37 (57%) ANATO 521..553 13/37 (35%) 0.0099 21/37 (57%) EGF 608..644 14/47 (30%) 0.0001 29/47 (62%) EGF 683..717 13/47 (28%) 0.33 22/47 (47%) EGF 862..899 13/47 (28%) 4.1le-05 27/47 (57%) EGF 905..941 16/47 (34%) 1.7e-05 27/47 (57%) TIL 899..947 16/68 (24%) 0.33 32/68 (47%) EGF 947..980 14/47 (30%) 0.0045 25/47 (53%) EGF 986..1023 14/47 (30%) 0.3 27/47 (57%) 5 112 WO 03/050245 PCT/USO2/38594 Example 3. The NOV3 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 3A. Table 3A. NOW3 Sequence Analysis ISEQ ED NO: 13 22 96_bp___ NOV3a, CACCAAGCTTCCCACCATGGTCCCCGACACCGCCTGCGTTCTTCTGCTCACCCTGGCTGCCCTCGGCG CG10516-09CGTCCGcAcAGGCcCAGAGCCCGTTGGGCTCAGACCTGcGGCCGCAcATGCTTCGGGAAkCTGCAGAA CG107 1-09ACCAACGCGGCGCTGCAGGACGTGCGGGAGCTGCTGCGGCAGCAGGTCAGGGAGATCACGTTCCTGAA DNA Sequence AAAACGTATGAGTGTGACGCGTGCGGGATGCAGCAGTAGTACGCACCGGCCTACCCAGCGTGC CGCCCCTGCTCCACTGCGCGCCCGGCTTCTGCTTCCCCGGCGTGGCCTGCATCCAGACCGAGAGCGGC GCGCGCTGCGGCCCCTGCCCCGCGGGCTTCACGGGCAACGGCTCGCACTGCACCGACGTCAACGAGTG CAACGCCCACCCCTGCTTCCCCCGAGTCCGCTGTATCAACACCAGCCCGGGGTTCCGCTGCGAGGCTL GCCCGCCGcGGTACAGCcGCCCCACCCACCAGGGCGTGGGGCTGGCTTTCGCCAAGGCCAACAAGCAG GTTTGCACGGACATCAACGAGTGTGAGACCGGGCAACATAACTGCGTCCCCAACTCCGTGTGCATCAA CACCCGGGGCTCCTTCCAGTcGCGGCCCGTGCCAGCCCGGCTTCGTGGGCGACCAGGCGTCCGGCTGCC AGCGGCGCGCACAGCGCTTCTGCCCCGACGGCTCGCCCAGCGAGTGCCACGAGCATGCAGACTGCGTC CTAGAGCGCGATGGCTCGCGGTCGTGCGTGTGTGCCGTTGGCTGGGCCGGCAACGGGATCCTCTGTGG TCGCGACACTGACCTAGACGGCTTCCCGQACGAGAAGCTGCGCTGCCCGGAGCGCCAGTGCCGTAAGG ACAACTGTTGACTGTCCCACTCAGGGCAGAGATTGGACCGGATGCATCGGAGACGCCTGC GATCCGGATGCCGACGGGGACGGGGTCCCCAATGAAAAGGACAACTGCCCCCTGGTGCGGAACCCAGA CCGCGCAACACGACGAGGACAAG'GGGGCGATGCGTGCGACAACTGCCGGTCCCAGAAGAACGACG ACCAAAAGGACACAGACCAGGACGGCCGGCGCGATGCGTGCGACGACGACATCGACGGCGACCGGATC CGCAACCAGCCCACAACTGcCCTAGGGTACCCAACTCAGACCAGAAGGACAGTGATGr.CGATGGTAT AGGGGATGCCTGTGACAACTGTCCCCAGAAGAGCAACCCGGATCAGGCGGATGTGGACCACGACTTTG TGGGAGATGCTTGTGACAGCGATCAGACCAGGATGGAACGACATCAGGACTCTCGGACAACTGT CCCACGGTGCCTAACAGTGCCCAGGAGGACTCAGACCACGATCGCCAGGGTGATGCCTGCGACGACGA CGACGACAATGACGGAGTCCCTGACAGTCGGGACAACTGCCGCCTGGTGCCTAACCCCGGCCAGGAGG ACGCC.GACAGGGACGGCGTGGGCGACGTGTCCAGGACGACTTTGATGCAACAAGGTGGTAGACAAG ATCGACGTCTGTCCGGAcAACGCTGAATCACGCTCACCGACTCAGGCCTTCCAACAG2TCGTGCT GGACCCGGAGGGTGACGCGCAGATTGACCCCAACTGGGTGGTGCTCAACCAGGGAAGGGAGATCGTGC AGACAATGACAGCGACCCAGGCCTGGCTGTGGTTACACTGCCTTCATGGCTGGACTTCGAGGGC ACGTTCCATGTGAACACGGTCACGGATGACGACTATGCGGGCTTCATCTTTGGCTACCAGGACAGCTC CAGCTTrCTACGTGGTCATGTGGAAGCAGATGG AGCAAACGTATTGGCAGGCGAAkCCCCTTCCGTGCTG TGGCCGAGCCTGGCATCCAACTCAAGGCTGTGAAGTCTTCCACAGGCCCCGGGGAACAGCTGCGGAAC GCTCTGTGCCATACAGGAGACACAGAGTCCCAGGTGCGGCTGCTGTGGAAGGACCCGCGAAACGTCGGG TTGGAAGGACAAGAAGTCCTATCGTTGGTTCCTGCAGCACCGGCCCCAAGTGGGCTACATCAGGGTGC GATTCTATAGGCCCTGACTGGTGGCCGACAGCAACGTGGTCTTGGACACAACCATGCGGGGTGGC CCCCTGGGCTCTTCTCTTCTCCCAGAGAACATCATCTGMcCCAACCTGCGTTACCGCTGCAATGA CACCATCCr-AGAGGACTATGAGACCCATCAGCTGCGGCAAGCCCTCGAGGGC___ ________ ORF Start: ATG at 17 ~OFStop: at 2288 [ SEQ ID NO: 14 .757 aa JMW at 82859.7kD NOV3a, MVPDTACVLLTLALGASGQGQSPLSDLGPQLRELQETAALQDVRELLRQQVREI TFLKNTVVME CGI 05716-09 CDACGmQQSVRTcLPSVRPLLHCAPGFCFPGVACIQTESGARCGPCPAGFTGNGSHCTDVNECNAHPC FPRVRCINTSPGFRCEACPPGYSGPTHQGVGLAFAKANKQVCTDINECETGQHNCVPNSVCINTRGS F Protein QCGPCQPGFVGDQASGCQRRAQRFCPDGSPSECHEHADCVLERDGSRS CVCAVGWAGNGILCGRDTDL Sequence DGFPDEI(L1CPERQCRKDNCVTVPNSGQEDVDRDGIGDACDPDADC1D)GVPNEKENCPLVRNPDQRNTD EDKWGDACDNCRSQK!UDDQKDTDQDGRGDACDDDIDGDRIRNQADNCPRVPNSDQCDSDGDGIGDACD

NCPQKSN'PIDQADVDHDFVGDACDSDQDQDGDGHQDSRDNCPTVPNSAQEDSDHDGQGDACDDDDDND

VPDSRDNCRLVPNPGQEDADRDGVGDVCQDDFDADICVVDKIDVCPENAEVTLThFRAFQTVVLDPEGD AQIDPNWLNQGRIVQTMNSDPGLAVYTANGVDFEGTFlVNTVTDDDYAGFI FGYQDSSSFYVV MWKQMEQTYWQA1PFRAVAEPGIQLKAVKSSTGPGQLRNTALWHTGDTESQVRLLWKDPRNVGWKDnKK SYRWFLQHRPQVGYIRVRFYEGPELVADSNVVLDTTMRGGRLGVFCFSQENI IWANLRYRCNDTIPED IYETHQLRQA NOV3b, CAGCACCCAGCTCCCCGCCCCGCCATGGTCCCCGACACCGCCTGCGTTCTTCTGCTCCCCTGGCTG G~i 571-05 CCCTCGGCGCGTCCGGACAGGGCCAGAGCCCGTTGGGCTCAGACCTGGGCCCGCAGATGCTTCCGAA CTGCAGGAAACCAACGCGGCGCTGCAGGACGTGCGGGACTGGCTGCGGC-AGCAGGTCAGGGAGATCAC DNA Sequence 'GTTCCTGA-CATGATGGAGTGTGACGCGTGCGATGcA.CAGTCAGTACGCACCGGCCTAC 113 WO 03/050245 PCT/USO2/38594 CCCTCGCCCCTGCTCCACTCCGCCCGGCTTCTCTTCCCCGGCGTGCCTGCATCCAGACG GAGAGCGGCGGCCGCTGCGGCCCCTGCCCCGCGGGCTTCACGGGCAACGGCTCGCACTGCACCGACGT CAACGAGTGCAACGCCCACCCCTGCTTCCCCCGAGTCCGCTGTATCAAC-ACCAGCCCGGGGTTCCGCT lGCGAGGCTTGCCCGCCGGGTACGCGGCCCCACCCACCAGGCGTGGGGCTGGCTTTCGCCAAGGCC AACAAGCAGGTTTGCACGGACAkTCAACGAGTGTGAGACCGGGCAACATAACTGCGTCCCCAACTCCGT GTCTACCCGGTCTCGGGCCGGCGCGCTGGGGCAGG CCGGCTGCCACCGCGGCGCACAGCGCTTCTOCCCCGACGGCTCCCCXGCGAGTGCCACGAGCATGCA GACTGCGTCCTAGAGCGCGATGGCTCGCGGTCGTGCGTGTGTCGCGTTGGCTGGGCCGGCAACGGGAT C'CTCTGTGGTCGCGAGCTACCTAACGGCTTCCCGAC4AGAAGCTGCGCTCCCGGAGCCGCAGT GCCGTAAGGACAACTGCGTGACTGTcCCCAACTCAGCGCAGGAGGATGTGGACCGCGATGGCATCGGA GACGCCTGCGATCCGGATGCCGACGGGGACGGGGTCCCCAATGAAAAGGACAACTGCCCGCTGGTGCG GAACCCAGACCAGCGCA-CACGACGAGGACAAGTGm3GCATCGT(CGACAACTGCCGTCCCAGA AGAACGACGACCAAAAGGACACAGACCAGGACGGCCGGGCGATGCGTGCGACGACGACATCGACGGC GACCGGATCCGCAACCAGGCCGACAACTGCCCTAGGGTACCCAACTCAGACCAGAAGGACAGTGATGG CGATGGTATAGGGGATGCCTGTGACAACTGTCCCCAAAGAGCAACCCnGATCAGGCGATGTGGACC ACGACTTTGTGGGAGATGCTTO3TGACAGCGATCAAGACCACGATGGACACGGACATCAOACTCTCGG GACAACTGTCCCACGGTGCCTAACAGTGCCCAGGAGGACTCAGACCACGATGGCCAGGGTGATGCCTG CGACGACGACGACGACAATGACGGAGTCCCTGAAGTCGGGACGGCGTGGGCGACGTGTGCCAGAC@ ACTTTGATGCAGACAAGGTGGTAGACAAGATCGACGTGTGTCCGGAAACGCTGAAGTCACGCTCACC GACTTCAGGGCCTTCCAGACAGTCGTGCTGGACCCGGAGGGTGACGCGCAGATTGACCCCAACTGGGT GGTGCTCACCAGGGAAGGAGATCGTGCAGACAATGAACAGCACCCAGGCCTGGCTGTGGGTTACA CTGCCTTCAATGGCGTGGACTTCGAGGGCACGTTCCATTGAACACGGTCCGGATGACGACTATOCG GGCTTCATCTTTGGCTACCAGGACAGCTCCAGCTTCTACGTGGTCATGTGGAAGCAGATGGAGCAAAC GTATTGGCAGGCGAACCCCTTCCGTGCTGTGGCCGAGCCTGGCATCCAACTCAAGGCTGTGAAGTCTT CCACAGGCCCCGGGGACAGCTGCGGAACGCTCTGTCGCATACAGGAACACAGAGTCCCAGGTGCGr CTGCTGTGGAAGGACCCGCGAAACGTGGGTTGGAAGGACAAGAAGTCCTATCGTTGGTTCCTGCAGCA CCGGCCCCAAGTGGGCTACATCAGGGTGCGATTCTATGAGGGCCCTGAGCTGGTGGCCGACAGCAACG TGGTCTTGGACACAACCATGCGGGGTGCCCGCCTGGOGGTCTTCTGCTTCTCCCAGAGAACATCATC TGGCCAACCTGCGTTACCGCTGCAATGACACCATCCCAGAGGACTATGAGACCCATCAGCTGCGGCAZ AGCCTAGGGACCAGGGTGAGGACCCGCCGGATGACAGCCACCCTCACCGCGGCTGGATGGGGGCTCTG .CAcCCCACCAAGGGGTGCCGTCCTGAGGCGGAAGTGAG OYStart: ATG at 26 IRF Stop: TAG at 2249 _________SEQ ID NO: 16 _ ]741 aa __MW at 81050.7kD NOV3b, MVPDTACVLLLTLAALGASGQGQSPLGSDLGPQMLRELQETAALQDVRDWLRQQVREITFLKNTVME CG10516-05 CDACGMQQSVRTGLPSVRPLLHCAPGFCFPGVACIQTESGGRCGPCPAGFTGNGSHCTDVNECNAHPC Protein FPRVRCINTSPGFRCEACPPGYSGPTHQGVGLAFAKAKQVCTDINECETGQHNSCVPNSVCINTRGSF QCGPCQPGFVGDQASGCQRGAQRFCPDGSPSECHEHADCVLERDGSRSCVCRVGWAGNGILCGPDTDL Sequence DGFPDEKLRCPEPQCRKDNCVTVPNSQEDVDRDGIGDACDPDAJGDGVPNEKDNCPLVRNPDQRNTD EDKWGDACDNCRSQKNDD)QKDTDQDGRGDACDDDIDGDRIRNQADNCPRVPNSDQKDSDGDGIGDACD NCQSPQDDDVDCSQ)DDHDRNPVNAESIDQDCDDNC VPDS1GVGDVCQDDFDADKVVDIIDVCPENAEVTLTDFRAFQTVVLDPEDAQIDPN~v-VLNQGREI VQTMNSDPGLAVGYTAFNGVDFEGTFHVNTVTDDDYAGFIFGYQDSSSFYVVMWKQMEQTYWQANPFR AVAEPGIQLKAVKSSTGPGEQLNALWHTGDTSQVRLLWKDPRNVGWKDKKSYRWFLQ1RPQVGYIR VRFYEGPELVADSNVVLDTTMRGGRLGVFCFSQENI IWANLRYRCNDTI PEDYETHQLRQA SEQ ID NO: 17 207 bp NOV3c, CAGCACCCACTCCCCGCCACCGCCATGGTCCCCGACACCGCCTGCGTTCTTCTCTCACCCTGGCTG CG1057 16-06 CCCTCGGCGCCTCCGGACAGGGCCAACCCQTTGGGCTCAGACCTGGC.CCCGCAQATGCTTCGCGAA CTGCAGGAAACCAACGCGGCGCTGCAGGACGTGCGGGACTGGCTGCGGCAGCAGGTCAGGGAGATCAC DNA Sequence GTTCCTGAAAAACACGGTGATGGAGTGTGACGCGTGCGGGATGCAGCACTCAGTACGCACCGGCCTAC CCAGCGTGCCOCCCCTGCTCCACTGCGCGCCCGGCTTCTGCTTCCCCGQCGTGGCCTGCATCCACACG GAGAGCGGCGGCCGCTGCGGCCCCTGCCCCGCGGGCTTCACGGCAACGGCTCGCACTGCACCGACGT CAACGAGTGCAACGCCCACCCCTGCTTCCCCCG2XGTCCGCTGTATCAACACCAGCCCGGGGTTCCGCT GCGAGGCTTGCCCGCCGGGGTACAGCGGCCCCACCCACCAGGGCGTGGGGCTGGCTTTCGCCAAGGCC AACAAGCAGGTTTGCACGGACATCAACGAGTGTcGAGACCGGGCAACATAACTGCGTCCCCAACTCCGT GTGCATCACACCCGQCTCCTTCCAGTCGGCCCGTGCCGCCCGGCTTCGTGGCGACCAGGCGT CCGOCTGCCGCGCGGCGCAC-AGCGCTTCTGCCCCGACGCTCGCCCAGCGAGTGCCACGAGCATGCA GACTGCGTCCTAGAGCGCGATGGCTCGCQGTCGTGCGTGTGTCGCGTTGGCTGGGCCGGCAAC~GGAT CCTCTGTGGTCGCGACACTGACCTAGACGCTTCCCGGAAAGCTGCGCTGCCCGGAC3CCGCAGT GCCCTAAGGACAACTGCGTGACTGTGCCCACTCAGGGCAGGAGGATGTGGACCGCGATGGCATCGGA GAACCCAGACCAGCGCAACACGACGACAGCQCGCTGCGTGCGACAACTCCGOTCCCAG3A AGAACGACGACCAAAAGGACACAGACCAGGACGGCCGGGGCGATGCGTGCGACGACGACATCGACGGC GACCGGATCCGCAACCAGGCCGACAACTGCCCTAGGGTACCCACTCAGCCAGAAGGACAGTGATGG CGTGAAGGTCTTAACGCCCGAACACCACGCGTTGC AACTTTGTGGGAGATGCTTGTGAAGCGATCAAGACCGrTGGAGACGGACATCAGGACTTCGG 114 WO 03/050245 PCT/USO2/38594 GACAACTGTCCCACGGTGCCTAACAGTGCCCAOGAGGACTCAGACCACGATGGCCAGGGTGATGCCTG CGACGACGACGTGTGCCAGGACGACTTTGATGC-AGACA.AGGTGGTAGACAAGATCGACGTGTGTCCGG AGAACGCTGAAGTCACGCTCCCGACTTCAGGCCTTCAGACAGTCGTGCTGACCCGGAGGGTGAC GCGCAGATTCACCCCAACTGGGTGGTGCTCAACCAGGGAAGGGAGATCGTGCAGACAATGAACAGCGA CCCAGGCCTGGCTGTGGGTTACACTGCCTTCAATGGCGTGGACTTCGAGGGCACGTTCCATGTGAACA CGGTCACGGATGACGACTATGCGGGCTTCATCTTTGGCTACCACGACAGCTCCAGCTTCTACGTGGTC ATGTGGAAGCAGATGGAGCAAACGTATTGGCAGGCGAACCCCTTCCGTGCTGTOGCCGAGCCTGGCAT CCAACTCAAGGCTGTGAAGTCTTCCACAGGCCCCGGGGAACAGCTGCGGAACGCTCTGTGGCATACAG CAGACACAGAGTCCCAGGTGCGGCTGCTGTGAAGGACCCGCGAAACGTGGTTGGAAGGACAAGAAG TCCTATCGTTGGTTCCTGCAGCACCGOCCCCAAGTGGGCTACATCAGGGTGCGATTCTATGAGGGCCC TGAGCTGGTGGCCGACAGCAACGTGGTCTTGGACACAACCATGCGGGGTGGCCGCCTGGGGGTCTTCT GCTTCTCCCAGGAGAACATCATCTGGGCCAACCTGCGTTACCGCTGCAATGACACCATCCCAGAGGAC TATGAOACCCATCAGCTGCGGCAA4GCCTAGGGACCAGGGTGAGGACCCGCCGGAkrGACAGCC-ACCCTC ORF Start: ATG at 26 IR Stop: TA G -a t 2.2 10 .4 SEQ ID NO: 18 - 726 aa 1M t 936.3D NOV3c, KVPDTACVLLLTLAALGASGQQQSPLGSDLGPQMLRELQETNAALQDVRDWLRQQVREITFLKNTVME CG10571 6-06 CDACGMQQSVRTGLPSVPLL1C-APFCFPGVACIQTESGRCGPCPAGFTGGSHCTDVNECNAHPC FPRVRCINTSPGFRCEACPPGYSGPTHQGVGLAFAKANKQVCTDINECETGQHNCVPNSVCINTRGSF Protein QCGPCQPGFVGDQASGCQRGAQRFCPDGSPSECHEHADCVLERDGSRSCVCRVGWAGNGILCGRDTDL Sequence DGPELCEQR<NVVNGEVROIDCPAG3VNKNPVNDRT EDKWGDACDNCRSQKN1DDQKDTDQDGRGDACDDDIDGDRIRNUQ2ADNCPRVPNSDQKDSDGDGIGDACD IICPQKSNPDQAIJVDHDFVGDACDSDQDQDGDGHQDSRDNCPTVPNSAQEDSDHDGQGDACDDDVCQDD FDADKOJVDKIDVCPENAEVTrLTDFRAFQTVVLDPEGDAQIDPNWVVLNQGREIVQTMNSDPGLAVGYT A FNGVOFEGTFUVNTVTDDDYAGFIFGYQDSSSFYVVMWI(0MEQTYWQANPFRAVAEPGIQLKAVKSS TGPGEQLRNALWHTGDTESQVRLLWKDPRNVGWKDKKSYRWFLQHRPQVGYIRVRFYEGPELVADSINV VLDTTMRGGRLGVFCFSQENI IWANLRYRCtNDTI PEDYETHQLRQA SEQ ID NO:19. 1374P NOV3d, CAGCACCCAGCTCCCCGCCACCGCCATGGTCCCCGACACCGCCTGCGTTCTTCTGCTCACCCTGGCTG CG10571 6-04 CCCTCGGCGrCGTCCGcGACAGGCCAGAGCCCGTTGGGCTCAGACCTGGGCCCCAGATGCTTCGGGAA CTGCAGGAAACCAACaCGGCGCTGCAGGACGTGCGGGACTGGCTGCGGCAGCAGGTCAGGGAGATCAC DNA Sequence GTTCCTGAAkAAACACGGTGATGGAGTGTGACGCGTGCGGGATGCAcGCAGTCAGTACGCACCGGCCTAC CCAGCGTrGCGGCCCCTGCTCCACTGCGCGCCCGGCTTCTGCTTCCCCGGCGTGGCCTGCATCCAGACG CAGAGCcGCGGCCGCTGCGGCCCCTGCCCCGCGGGCTTCACGGGCAACGGCTCGCACTGCACCGACGT CAACGAGTGCAACGCCCACCCCTGCTTCCCCCGAGTCCGCTGTATCAACACCAGCCCGGGGTTCCGCT cGCGAGGCTTGCCCGCCGGGGTACAGCGGCCCCACCC-ACCAGGGCGTGGGGCTGGCTTTCGCCAAGGCC AACAAGCAGGTTTGCACGGACATCAACGAGTGTGAGACCGGGCAACATAACTGCGTCCCCAACTCCGT GTGCATCA-ACACCCGGGGCTCCTTCCAGTGCGGCCCGTGCCAGCCCGGCTTCGTGGGCGACCAOGCGT CCGGCTGCCAGCGCGGCGCACAGCGCTTCTGCCCCGACGGCTCGCCCAGCGAGTGCCACGAGCATGCA GACTGCGTCCTAGAGCGCGATGGCTCGCGGTCGTGCGTGTGTCGCGTTGGCTGGGCCWGCAACGGGAT CCTCTGTGGTCGCGACACTGACCTAGACGGCTTCCCGGACGAGAAGCTGCGCTGCCCGGAGCCGCAGT QcCCTAAGGACAACTGCGTGACTGTrGCCCAACTCAGGGCAGGAGGATGTGGACCGCGATGGCATCGGA GACGCCTGCGATCCGGATGCCGACCGGGACGGGGTCCCCAATGAAAAGGACAACTGCCCGCTGGTGCG GAACCCAGACCAGCGCAACACGGACGAGGACAAGTGGGGCGATGCGTGCGACAACTcCCGGTCCCAGA AGAACGACGACCAAAAGGACACAGACCAGGACGGCCGGGGCGATGCGTGCGACGACGACATCGACGGC GACCGGATCCGCAACCAGCCGACAACTGCCCTAGGTACCCAACTCAGACCAGAAGAC'AGTGATGG CGATGGTATAGGGGATGCCTGTGACAACTGTCCCCAGAAGAGCAACCCGGATCAGGCGGATGTCGACC ACGCTTTGGGGAGATGCTTGTGACGCGATCAAGACCAGGATGGAGACGGACATCAGGACTCTCGG GACTCTCGCGACTAGACCACGATGGCCAGGTGATGCCTGCGACGACGACGACGACAATGACGGAGT CCCTGACAGTCGGGACAACTGCCGCCTGGTGCCTAACCCCGGCCAGGAGGACGCGGACAOCGACGGCC TGGGCGACGTGTGCCAGGACGACTTTGATGCAGACALAGGTGGTAGACAAGATCGACGTGTGTCCGGAG AACGCTGAAGTCACGCTCACCGACTTCAGGCCTTCCAGACAGTCGTGCTGGACCCGGAGGGTGACGC GCAGATTGACCCCAACTGGGTGGTGCTCAACCAGGGAAGGGAGATCGTGCAGACAATGAACAGCGACC CGCCTGGCTGTGGGTTACACTGCCTTGAATGCGTGACTTCGAGGGCACGTTCCATGTGAACACG GTCACGGATGACGACTATGCGGGCTTCATCTTTCGCTACCAGGACAGCTCCAGCTTCTACGTGGTCAT GTGGAAGCAiGATGGAGCAAACGTATTGGCAGGCGAACCCCTTCCGTGCTGTOGCCGAGCCTGGCATCC AACTCAGCTGTGAAGTCTTCCACAGGCCCCGGGAACACTGCGGAACGCTCTGGGCATAC!AGGA GACACAGAGTCCCAGGTGCGGCTGCTGTGGAACGrACCCGCGAA.ACGTGCGTTGAAGGACAAGAAGTC cTATCGTTGGTTCCTGCAGCACCGGCCCCAAGTGGGCTACATCAGGGTGCGATTCTATGAGGGCCCTG AGCTGGTGGCCGACAGCACGTGGTCTTGGACACACCAIGCGGGGTGGCCGCCTGGGGGTCTTCTGC TTCTCCCAGGAGAACATCATCTGGGCCAACCTGCGTTACC!GCTGCAATCACACCATCCCAGAGGACTA TGAGACCCATCAGCTGCGGCAAGCCTAGGGACCAGGGTGAGGACCCGCCGGATGACAGCCACCCTCAC ICGCGGCTGGATG(GGGGCTCTGCACCCAGCCCCAAGGGGTGGCCGTCCTGAGGGGGAAGTGAG * ORY Start: AIG at 26 ~ORF Stop: TAG at 2270 115 WO 03/050245 PCT/USO2/38594 SEQ ID NO: 20 74aa MW at 81933.6kD NOV3d, MVPDTACVLLLTLALGASGQGQSPLGSDLGPQMLRLQETNAALQDVRDWLRQQVREITFLI<NTVMa CG1 05716-04 CDACGMQQSVRTGLPSVRPLLHCAPGFCFPGVACIQTESGGRCGPCPAGFTGNGSHCTDVNECNAHPC FPRVRCINTSPGFRCEACPPGYSGTHQVGAFAKAKQVCTDINECETQHCVPNSVCIN'TRGSF Protein QCGPCQPGFVGD0ASGCQRGAQRFCPDGSPSECHEHADCVLERDGSRSCVCRVGWAGNGILCGRDTDL Sequence DGFPDEKLRCPEPQCRKDNCVTVPNSGQEDVDRDGIGDACDPDADGDGVPNEKDNCPLVRNPDQR ITD EDKWGflACD1NCRSQK&DDQKDTDQGRGDACDDDIDGDRIRNQADNCPRVPNSDQKDSDGDGIGDACD NCPQKSNPDQADVDHDFVGDACDSDQDQDGDGHQDSRDSRDSDHDGQGDACDDDDDNDGVPDSRDNCR LVPNPGQEDADRDGVGDVCQDDFDADI(VVDKIDVCPENAEVTLTDFRAFQTVVLDPEGDAQIDPNWvV LNQGREIVQTNNSCPGLAVGYTAFNGVDFEGTFHVNTVTDDDYAGFIFGYQDSSSFYVVMWKQMEQTY WQANPFAVAPGIQLKAVKSSTGPGEQLRAIWHTGDTESQVRLLWKDPRNVGWKDKKSYRWFLQHR __________PQVGYIRVRFYEGPELVADSNVVLDTTMRGGRLGVFCFSQENI IWANLRYRCNDTIPEDYETHQLRQA ISEQ ID NO: 21*29b NOV3e, CAGCACCCAGCTCCCCCCACCGCCATGGTCCCCGACACCGCCTGCGTTCTTCTGCTCACCCTGGCTG CG1 05716-03 CCCTCGGCGCGTCCGGACAGGGCCAGAGCCCGTTGGGCTCAGACCTGGGCCCGCAGATGCTTCGGGAA CTGCAGAACCAACGCGGCGCTGGGACGTGCGGACTIGCTGCGGCAG-AGTCAGGGACATCAC DNA Sequence GTTCCTGAAAA.ACACGGTGATfGGAGTGTGACGCGTCCGCGATGCAGCAGTCAGTACGCACCGCCCTAC CCAXGCGTGCGGCCCCTGCTCCACTGCGCG1CCCGGCTTCTGCTTCCCCGGCGTGGCCTGCATCCAGACG GA@AGCGGCGGCCGCTGCGGCCCCTGCCCCGCmGCTTCACGGGCAACGGCTCGCACTGCXACCGACGT CAACGAGTGCAACGCCCACCCCTGCTTCCCCCGAGTCCGCTGTATCAACACCAGCCCCGGTTCCGCT GCGAGGCTTGCCCGCCGGGGTACAGCGGCCCCACCCACCAGGGCGTGGGGCTGGCTTTCGCCAAGGCC AACA-ACAGGTTTGCACGGACATCAACGAGGTGAGACCGGGCAACATAACTGCGTCCCCAACTCCGT GTOCATCACACCCGGGCTCCTTCCATGCCCCCGTGCCAGCCCGCTTCGTGGGCGACCACGCGT CCGGCTGCCAGCGCGGCGCACAGCGCTTCTGCCCCGACGGCTCGCCCAGCGAGTGCCACGAGCATGCA GACTGCGTCCTAGAGCGCGATGGCTrCCMTCTGCGTGTGTCGCGTTGGTGGCC4GCAACGGGAT CCTCTGTGGTCGCGAACTGACCTAGACCGCTTCCCGGACGAAAGCTGCGCTGCCCGAGCCGCAGT GCCGTAAGGACAACTGCGTGACTGTGCCCAACTCAGGGCAGGAGGATGTGGACCGCGATGGCATCGGA GACGCCTGCGATCCGGATGCCGACGGGGACGGGGTCCCCAATGAAAAGGACAACTGCCCGCTmGTGCG GAACCCAGACCAGCGCAACACQGACGAGGACAAGTGGGGCGATGCGTGCGACAA-CTGCCGGTCCCAGA AGAACGACGACCAAAAGGACACAGACCAGGACGGCCGGGGCGATGCGTGCGACGACGACATCGACGGC GACCGGATCCGCAACCAGGCCGACAACTGCCCTAGGGTACCCAACTCAGACCAGAAGGACAGTGATCG CGATGGTATAGGGGATGCCTGTGACAACTGTCCCCAGAAGAGCAACCCGGATCAGGCGGATGTGGACC ACGACTTTGTGGGAGATGCTTCTGACAGCGATCAAGACCAGGATGGAGACGGACATCAGGACTCTCGG GACAACTGCCGCCTGGTGCCTAACCCCGGCCAGGAGGACGCGGACAGGGACGGCGTGGGCGACGTGTG CCAGGACGACTTTGATGCAGACAAGGTGGTAGACAGATCGACGTTGTrnCCGGAACGCTGAAGTCA CCCTCACCGACTTCACCCTTCCAQACAGTCGTGCTGGACCCGGACGCCTCACGCGCAGATTGACCCC AACTGGGTGGTGCTCAACCAGGGAAGGGAGATCGTGCAGACAATGAACAGCGACCCAGGCCTGGCTGT GGGTTACACTGCCTTCATGGCGTGGACTTCGAGGGCACWTCCATGTGAACACAGTCACGGATGACG ACTATCCCGGOCTTCATCTTTGCCTACCAGGACAGCTCCACCTTCTACTCGTCATGTGGAAOCAGATG GAGCAAACGTATTGGCAGGCGAACCCCTTCCGTGCTGTGGCCGAGCCTGGCATLCCAACTCAAGGCTGT GAAGTCTTCCACAGGCCCCGGGAACAGCTGCGGAACGCTCTGTGGCATACAGGAGACACAGAGTCCC AGOTGCQGCTGCTGTGGAAGGACCCGCGAAACGTGGGTTGGAACGACAAGAAGTCCTATCGTTGGTTC CTcGCAGCACCGGCCCCAAGTGGGCTACATCAGGGTGCGATTCTATGAGGGCCCTGAGCTGGTGGCCGA CAGCAACGTGGTCTTGGACCAACCATGCGGGn2GGCCGCCTGGQGTCTTCTGCTTCTCCCAGAGA ACATCATCTCGGCCAACCTGCGTTACCGCTGCAATGACACCATCCCAGACGACTATGAGACCCATCAG CTGCGGCAAGCCTAGGGACCAGGGTGAGGACCCGCCGGATGACAGCCACCCTCACCGCGGCTGGATGG Gm CTCTGCACCCAGCCCCAAGGGTGGCCGTCCTGAGGGGAAGTGAG ORF Str:AGat 26 ~OFStop: TAG at 2189 SEQ ID NO: 22 _721 aa ,,MW at 79058.OkD NOV3e, MVP)DTACVLLLTLAALGASGQGQS PLGSDLGPQMLRELQETNAALQDVRDWLRQQVREITLI'TVME CG1 05716-03 CDACGMQQSVRTGLPSVRPLLHCAPG1FCFPGVACIQTESGGRCGPCPAGFTGNrGSHCTrDVNECNAPC FPRVRCINTSPGFRCEACPPGYSGPTHQGVGLAFAKANKQVCTDTNECETGQRI'CVPNSVCINTRGSF Protein QCGPCQPGFVGDQASGCOQflAQRFCPDGSPSECHEHADCVLERDGSRSCVCRVGWAGNGILCGRDTDL Sequence DGFPDEKLRCPEPQCRKDCVTVPNSGQEDVDRDGIGDACDPDAGDGVPNEKNCPLVRNPDQRNTD EDKGDACDNCRSQDDQKDTDQDRGDACDDDIDwRIRNQALh1CPRVPNSDQKDSDGDIADACD NCPQKS1NPDQADVDUDFVGDACDSDQDQDDGHQDSRDNCRLVPNPQEDADRGVGDVCQDDFDAD( VVDKIDVCPEN4AEVTLTDFRAFQTVVLDPEGDAQIDPN~WVLNQGRIVQTMNSDPGLAVGYTAFGV DFEGTFRVNTVTDDDYAGFIFGYQDSSSFY-VMWKQMQTYWQANPFRAVAEPGIQLKAVKSSTGPGE QLRNALWHTGDTESQVRLLWKDPRNVCWKDKKSYRWFLQHRPQVGYIRVRFYEGPELVADSNVVLDTT ___________MRGGRtLGVFCFSQEIIWANLRYRCNDTIPEDYETHQLRQA ____________ - SEQ ID NO: 23_ 18b NOV3f, AGTCTCAGGAGGATGTGGACCGCGATGGCATCGGAGACGCCTCCATCCGGATGCCGACCGGGACGG C151-2.GGTCCCCAATGAAAAGGACAACTGCCCGCTGGTGCGAACCCAGACCAGCGCAACACGGACGAGGACA 116 WO 03/050245 PCT/USO2/38594 DNA Sequence AGGGCAGGGGC-CGCGCCGAACAGCAAGAAAACGA GGCCGGGGCGATGCGTGCGACGACGACATCGACGGCGACCGGATCCGCAGGCCGACAACTGCCC TAGGrnTACCCAACTCAGACCAGAAGGACAGTGATGGCGATGGTATAGGGATCCTGTAACTGTC CCCAGGAGAACCCGGATACGCG(ATGTGGACCACGACTTTGTGGGAGATGCTTGTGACGCGAT CAAGACCAGGATGGAGACGGACATCAGGACTCTCGGACAACTGTCCCACGGTGCCTCGTGCCCA GAGGACTAGCACGATGGCCAGGTGATGCCTGCGACGACGACGACGACATACGGAGTCCCTG ACAGTCGGGACAACTGCCGCCTGGTGCCTAACCCCGGCCAGGAGGACGCGGACAGGACGCGTGGGC GACGTGTGCCAGGACGACTTTGATGCAGACAGGTGTAGAAGATCGACGTGTGTCCGAGACGC TGAGTCACGCTCACCGACTTCAGGGCCTTCCAGACAGTCGTGCTGGACCCGAGGTGACGCGCAGA cGGATGACGACTATGCGGGCTTCATCTTTGGCTACCAGGACAGCTCCAGCTTCTACGTGGTCATGTGGA AGCAGATGGAGCAACGTATTGGCAGGCGAACCCCTTCCGTGCTGTGGCCGAGCCTGGATCCAACTC AAGGCTGTGAAGTCTTCCACAGCCCCCGGGAACAGCTA CGCTCTGTGGA4AGAC AGAGTCCCAGGTGCGGCTGCTGTGGAAGGACCCGCGAACGTGGGTTGGAAGACGAAGTCCTATC GTTCGTTCCTGCAGCACCGGCCCCAAGTGGGCTACATCAGGTGCGATTCTATAGGCCCTGAGCTG GTGCAAGACTGCTGCCACTCGGGCGCGGGCTTCTT CCAGGAGAACATCATCTGGGCCAACCTGCGTTACCGCTGCAATGACCATCCAGAGACTATGA CCCATCAGCTGCGGCAA(GCCCTCGAG -::ORF Start: at 7 ...... - ...... ORF Stop: at 1381 SEQ ID NO: 24 .458 aa JMW at 51108.lkD NOV3f, UEDDDIDCPAGGPEDCLRPQNDDWDCNRQNDKTQG CG1 05716-02 GDCDIGRRQDCRPSQDDDIDCNPKNDAVIDVDCSQ QDGDGHQDSRDNCPTVPNSAQEDSDHDGQGDACDDDDDNDGVPDSRCRLVPNPEDDRGVGDV Protein CQDDDVDIVPNETTFAQVVDEDQDNVLQRIQMSP Sequence VGTFGDETHNVDDAFFYDSSYVWQETWAPRVEGQK VKSSTGPGEQLRALWHTGDTESQVRLLWKDPRNVGWKDKKSYRWFLQHRPQVGYIRRFYEGPELVA DSNVVLDTTMPRGRLGVFCFSQENIIWANLRYRCNDTIPEDYETHQLRQA _______SEQ ID NO: 25 __ _ 2274 bp NOV3g, !T C'-G CCCCGAACGCCTGCGTTCTTCTGCTCACCCTGGCTCCCTCGCGCGTCCGACGGGCCA CG105716-01 GAGCCCGTTGGGCTCAGACCTGCCCGCAGATGCTTCGGGAACTGCAGGAACCACGCGGCGCTGC AGGACGTGCGGGACTGCTGCGCAGCAGGTCAGGAGATCACGTTCCTGACTGATGG DNA Sequence .TGTGACGCGTGCGGGATGCAGCAGTCAGTACGCACCMCCTACCCAGCC3TGCGGCCCCTGCTCCACTG CGGCGCTTCTCCGGGCTCACAAGAACGGCGTCGCC GCCCCGCGGGCTTCACGGGACGGCTCGCACTGCACCGACGTCAACGAGTACGCCCACCCCTGC TTCCCCCGAGTCCGCTGTATCAACACCAGCCCGGGTTCCCCTGCGAGCTTGCCCGCCGGGTACAG CGGCCCCACCCACAGGGCGTGGGCTGGCTTTCGCCAAGGCCAAAGCAGGTTTGACGGAATC ACGAGTGTGAGACCGGCAATAACTGCGTCCCCCTCCGTGTCATCAACCCCGGGGCTCCTTC CAGTGCGGCCCGTGCCAGCCCGGCTTCGTGGGCACCAGGCGTCCGCTGCCACGCGCGCCG CTTCTGCCCCGACGGCTCGCCCAGCGAGTGCCACGAGCATGCAGACTGCGTCCTAGAGCGCGATGGCT CGCCGTCGTGCGTGTTGCCGTTGGCTGGGCCGCAACATCCTCTGTGTCGCGACCTGACCTA GACGGCTTCCCGGACGAGAAGCTGCGCTGCCCGGAGCCCAGTGCCGTAGACACTGCGTGACTGT GCCCAACTCAGGGCAGGAGGATGTGGACCGCGATGGCATCGGAGACGCCGCGATCCGAGCCGACG GGGACcGGTCCCCAATcAAAGGACAACTGCCCGCTGGTGCGGAACCCAG-ACCAGCGCAACACGGAC GAGGACAAGTGGGGCATGCGTGCGACAACTGCCGGTCCCAGAAGAACGACGACCAAGACCAGA AACTGTCCCCAGAAGAGCAACCCGGATCAGGCGATGTGACCACGACTTTGTGGGATGCTTGTGA CAGCGATCAAGACCAGGATGGAGACGGACATCAGGACTCTCGGGACAACTGTCCCACGTGCCTAC GTGCCCGGAGACTC-AGACCACGATCOCCAGGGTGATGCCTGCGACGACGACGACGACAATGACGGA GTCCCTGACAGTCGGGACAACTGCCGCCTGGTGCCTAACCCCGGCCAGGAGACGCGACGGGACGG CGTGGGCGACGTGTGCCAGGACGACTTTGATGCAGACAAGGTGGTAGACAAGATCGACGTGTGTCCG AGACGCTGAAGTCCGCTCACCGACTTCAGCCTTCCAGACAGTCGTGCTGGATCCTGGGAT GCCCAGATCGATCCCAACTGGGTGGTCCTGAACCAGGGCATGGAGATTGTACAGACCATGAACAGTGA TCCTGGCCTGGCAGTGGGTACACAGCTTTTATGGAGTTGACTTCGAAGGGACCTTCCATGTGAATA CCCAGAAGATGATGACTATGCAaCcTTTATCTTTGOCTACCAAGATAGCTCCGCTTCTACGTGTC ATGTGGAAGCAGACGGAGCAGACATATTGGCAAGCCACCCCATTCCGAGCAGTTGCAGAACCTGGCAT TCAGCTCAACCTGTGAAGTCTAAGA-AGTCCAGrnAGCATCTCCGGAACGCTCTGTGGCATACAG GAGACACAGAGTCCCAGGTGCGCTCCTTGGAAGACCCGCGAACGTGGTTr.C-GGACAAGAAG TCCTATCGTTGGTTCCTGCAGCACCGGCCCCAAGTGGGCTACATC-AGGGTGCGATTCTATGAr.GCCC TGAGCTGGTGGCCGACAGCAACGTGGTCTTGGACACXACCATGCGGGGTGGCCGCCTGGGGGTCTTCT GCTTCTCCCAGGAGAAC-ATCATCTGGGCCAACCTCGTTACCGCTGCAATACACCATCCAGGGAC iTATGAGACCCATCAGCTGCGGCAAGCCTAG ORF Start: ATG at 1 JORF Stop: TAG at 2272 117 WO 03/050245 PCT/USO2/38594 ISEQ ID NO: 26 j77 aa 1MWat .82915.7kD NOV3g, MVPDTACVLLLTLAALGASGQGQSPLGSDLGPQMLRELQETNAALQDVRDWLRQQVREITFLKNTVME! CG105716-01i CDACGMQQSVRTGLPSVRPLLH-CAPGFCFPGVACIQTESGGRCGPCPAGFTGNGSHCTDVNECNA{PC FPRVRCIbNTSPGFRCEACPPGYSGPTQGVGLAAKANKQVCTDINECETGQEHNCVPNSVCINTRGSF Protein QCGPCQPGFVGDQASGCQRflAQRFCPDGSPSECHEHADCVLERDGSRSCVCAVGWAGNGILCGRDTDL Sequence DGFPDEKLRCPERQCRKDNCVTVPNSGQEDVDREDGIGDACDPDADGDGVPNEKDNCPLVRNPDQRNTD EDKWG.DACDNCRSQKNDDQKDTDQDGRGDACDDDIDGI)RIRNQADNCPRVPNSDQKDSDGDGIGDACD NCPQKSNPDQADVDHI)FVCDACDSDQDQDGDGHQDSRDNCPTVPNSAQEDSDDGQGDACDDDDDNDG VPDSRDNCRLVPNPGQEDAD1RDGVGDVCQDDFDADKVVDKIDVCPENAEVTLTDFRAFQTVVLDPEGD AQIDPNWVVLNQGMEIVQTMNSDPGLAVGYTAFNGVDFEGTFHVNTQTDDDYAGFIFGYQDSSSFYVV MWKQTEQTYWQATPF1RAVAEPGIQLKAVKSKTGPGELRNALWHTGDTESQVRLLWKDPRNVGWKDKK SYRWFLQHRPQVGYIRVRFYEGPELVADSNVVLDTTMRGGRLGVFCFSQENI IWANLRYRCNDTI PED YETHQLRQA SEQID NO: 27 11386bp NOV3h, AGATCTCAGGAGGATGTGGACCGCGATGGCATCGGAGACGCCTGCGATCCGGATGCCGACGGGGACGG 207569245 GGTCCCCAATGAAAAGGACACTGCCCGCTGGTGCGAACCCAGACCAGCGCAA-ACGGACGAGGACA AGTGGGCGATGCGTGCGACAACTGCCGGTCCCAGAAGAACGACGACCAAAAGGACACAGACCAGGAC DNA Sequence GGCCGGGGCGATGCGTGCGACGACGACATCGACGGCGACCGGATCCGCAACCAGGCCGACAACTGCCC TAGGGTACCCAACTCAGACCAGAAGACAGTATGCGATGTATAGGGGATGCCTGTGACAACTGTC CCCAGAAGAGCAACCCGGATCAGGCGGATGTGGACCACGACTTTGTGQGAGATGCTTGTGACAGCGAT CAAGACCAGGATGGAGACGGACATCAGGACTCTCGGGACAACTGTCCCACGGTGCCTAACAGTGCCCA GGACAGACTCAGACCACGATGGCCAGGGTGATGCCTGCGACGACGACGACGACAATGACGGAGTCCCTG ACTCGGGACACTGCCGCCTGTGCCTAACCCCGGCCAGAGACGCGGACAGGGACGGCGTGGGC GACGTGTGCCAGGACGACTTTGATGCAGACAAGGTGGTAGACAAGATCGACGTGTGTCCGGAGAACGC TGAAGTCACGCTCACCGACTTCAGGGCCTTCCAGACAGTCGTGCTGGACCCGGAGGGTGACGCGCAGA TTGACCCCAACTGGGTGGTGCTCACCAGGAGGGAGATCTGAGACAATGAACAGCGACCCAGGC CTGGCTGTGGGTTACACTGCCTTCAATGGCGTGGACTTCGAGGGCACGTTCCATGTAACACGGTCAC GGATGACGACTATGCGGGCTTCATCTTTGGCTACCAGGACAGCTCCAGCTTCTACGTGGTCATGTGGA AGCAGATGGAGCAAACGTATTGCAOCGAACCCCTTCCGTGCTGTGGCCGAGCCTGGCATCCAACTC AAGGCTGTGAAGTCTTCCA-AGCCCCGCGAACAGCTGCGAACGCTCTGTGGCATACAGGAGACAC AGAGTCCCAGGTGCGGCTGCTGTGGAAGGACCCGCGAAACGTGGGTTGGAAGGACAAGAAGTCCTATC GTTGGTTCCTGCAGCACCGGCCCCAAGTGGGCTACATC-AGGGTGCQATTCTATGAGGGCCCTGAGCTG GTGGCCGACAGCAACGTGGTCTTGGACACAACCATGCGGTGGCCGCCTGGGGGTCTTCTGCTTCTC CCAGGAGAACATCATCTGGGCCAACCTGCGTTACCGCTGCAATGACACCATCCCAGAGGACTATGAGA CCCATCAGCTGCGGCAAGCCCTCGAG ORE Start: at I ORE Stop: end of sequence SEQ ID NO: 28 1462 aa 1Wa 19.k NOV3h, RSQEDVDRDGIr.DACDPDADGDGVPNEKDNCPLVRNPDQRNTDEDKWGI)ACDNCRSQN1DQKDTDQD 207569245 *GRGDACDDDIDGDRIRNQADNCPRVPNSDQKSDGDGIGDACDNCPQKSNPDQADVDHDFVGDACDSD Protein QDQDGDGHQDSRDNCPTVPNSAQEDSDHDGQGDACDDDDDNlGVPDSRflNCRLVPNPGQEDADRDGVG Protein DVCQDDFDADKVDKIDVCPNAEVTLTDFRAFQTVVLDPEGDAQIDPNWVVLNQGREIVQTMNSDPG Sequence LAVGYTAFNGVIDEEGTFHVUTVTDDDYAGFIFGYQDSSS FYVVMWKQMEQTYWQANPFRAVAEPGIQL KAVKSSTGPGEQLRNALWHTGDTESQVRLLWKDPRNVGWKDKKSYRWFLQHRPQVGYIRVRFYEGPEL VSNVWLDTTMRGGRLVFCFSQEIIWANLYRCNlTI PEDYETHQLRQALE _______SEQ ID NO: 29 1386 bp NOV31, AGATCTCAGAGATGTGGACCGCGATGGCATCGGAGACGCCTGCGATCCGGATGCCGACGGGGACGG 207569277 GGTCCCCAATGAAAAGG-ACAACTGCCCGCTGGTGCGGAACCCAGACCAGCGCAACACGGACGAGGACA 20759277 AGTGGGGCGATGCGTGCGACAACTGCCGGTCCCAGAAGAACGACGACCAAAAGGAC2ACAGACCAcGAC DNA Sequence rncCCGGGGCGATGCGTGCGACGACGACATCGACGGCGACCGGATCCGCAACCAGGCCGACAACTGCCC TAaGTACCCACTCAGACCAAAGGACAGTGATGGCATGTATAr.GGGATGCCTGTGACAACTGTC CCCAGAAGAkGCAACCCGGATCAGGCGGATGTGGACCACGACTTTGCG.GGAGATGCTTCTGACAGCGAT CAAGACCAGGATGGAGACGGACATCAGGACTCTCGGGACAACTGTCCCACGGTGCCTAACAGTGCCCA CGAGGACTCAGACCACGATGGCCAGGGTGATGCCTGCGACGACGACGACGACAATGACG.GAGTCCCTG ACAGTCGGGACAACTCCGCCTGGTGCCTAACCCCGGCCAGGAGGACGCGGACAGCGACCCCGTCGGC GACGTGTGCCAGGACGACTTTGATGCAGACAGTGGTAGACAAGATCGACGTGTGTCCGGAGAACGC TGAADTCACCTCACCGACTTCAGGGCCTTCCAGACTCTCTGACCCGGAGGGTGACGCGCAGA TTGACCCCAACTGGGTGGTGCTCAACCAGGGAAGGGAGATCGTGCAGACAATGAACACCGACCCAGC CTGGCTGTGGGTTACACTGCCTTCAATGGCGTGACTTCGADGGGCACGTTCCATGTGAACACGGTCAC GGATC:ACGACTATGCCCGCTTCATCTTTGGCTACCAGDACAGCTCCAGCTTCTACGTr.GTCATGTGGA AGCAGATGGAGCAAACGTATTGGCAGGCGAACCCCTTCCGTGCTGTGGCCGAGCCTGGCATCCALACTC AAGQCTGTGP.AGTCTTCCACAGGCCCCGGGGA.ACAGCTGCGGAACGCTCTGTGGCATACAGGAGACAC AGAGTCCCAGGTGCGGCTGCTGTGGAAGGACCCGCGAAACGTGGGTTGGAAGGACAAGAALGTCCTATC __________GTT GTTCCTGAGCACCGGCCCCAAGTGGGCTACATCAGGGTGCGATTCTATGAGGGCCCTGAGCTG 118 WO 03/050245 PCT/USO2/38594 GTGCAACAGGTTGAAACATCGGGCGCGGGCTTCTT CCGAACTGCGGCACGGTCGCGAT~-CACCGGACAGG CCCATCAGCTGCGGCAAGCCCTCGAG ________ ORE Start: at 1IOR Stop: end of sequence ______SEQ ID NO: 30 __462 aa JMWat 5155l.6kD NOV3 j, RSQEDVDRDGIGDACDPDADGDGVPNEKDNCPLVRN~PDQRNTDEDKWGDACDN'CRSQKNDDQKIDTDQD 207569277 GRGDACDDDIDGDRIfNQADNCPRVPNSDQSDGDGIGDACDNCPQNPDQDDHFAGDACDSl QDQDGDGHQDSRDNCPTPNSAQEDSDHDGOGDACDDDDDNDGVPDSRNCRLVPNPGQEDDRGVG Protein DVCQDDFDADKVVDKIDVCPENAEVTLTDFRAFQTVVLDPEGDAQIDPNWVVLNQGREIVQTMNSDPG Sequence LAVGYTAFNGVDFEGTFIVNTVTDDDYAGFIFGYQDSSS FYVVMWKQMEQTYWQANPFRAVAEPGIQL KAVKS STGPGEQLRNALWHTGDTESQVLWKPNVGWWKKSYRWFLQHRPQVGYIRVRFYEGP 2 L VADSNVLDTTMRGGRLGVFCFSQENIVWANLRYRCNDTIPEDYETHQLRQALE ______SEQ ID NO: 31 _ 8 b NOV3j, AGATCTCAGGAGGATGTGGACCGCGATGGCATCQACGCCTGCATCCGATGCCACGGGCCG 207569281 GGTCCCCAATGAAAAAACTCCCGCTGGGCGGAACCCAGACCAGCGCAACACGGACGAGAC AGTGGGGCGATOCTGCGACAACTGCCGGTCCCAGAAACGACGACCAAAAGGACACCGGAC DNA Sequence GGCCGGGGCGATGCGTGCGACGACGATCGACGGCGACCGGATCCGCCAGCCGACACTGCCC TAGGGTACCCAACTCAQGACCAGAAGGACAGTGATGGCGATGGTATAGGGGATGCCTGTGAACTGTC CCAAGGACCGTAGGAGCrACAGzCTGGGGTCTTAACA CAGCAGTGGCGCTAGCCCGGCATTCAGTCTAATCC GGAGGACTCAGACCACGATGGCCAGGGTGATGCCTGCGACGACGACGACGACAATGACGGAGTCCCTG ACGCGPCATCGCGTCTACCGCAGGAGGAAGGCGGGG GACGTGTGCCAGGACGACTTTGATGCAGACAAGGTGGTAGACAAGATCGACGCGTGTCCGGAGACGC TGAAGTCACGCTCACCGACTTCAGGGCCTTCCAGACAGTCGTGCTGGACCCGGAGGGTGACGCGCAGA TTGACCCCAACTGGGTGGTGCTCAACCAGGGAGGGAGATCGTGCAGACAATGAACAGCGACCCGGC CTGGCTGTGGGTTACACTCCTTCAATGCGTGGACTTCGAGGCACGTTCCATGTCCGGTC GGATGACGACTATGCGGGCTTCATCTTTGGCTACCAGGACAGCTCCAGCTTCTACGTGGTCATGTCGA AGCAGATGGAGCAAACGTATTGGCAGGCGAACCCCTTCCGTGCTGTGGCCGAGCCTGGTCACTC AAGTTAGCTCCGCCGGACACGGACCCGGCTCGAAA AGAGTCCCAGGTGCGGCTGCTGTGGAAGGACCCGCGAAACGTGGGTTGGA.AGGACAAGAAGTCCTATC GTTGGTTCCTGCAGCACCGGCCCCAAGTGGGCTACATCAGGGTGCGATTCTATGAGGGCCCTGAGCTG GTGGCCGACACAACGTGTCTTGGACACACCATCCGGGGTcGCCGCCTGGGTCTTCTGCTTCTC CCGAAkACTTGCACTCTACCGATAACTCAAGCAGG ICCCATCAGCTGCGGCALAGCCCTCGAG _________ Strt atR Stp endof sequence _ ________SEQ ID NO: 32 462.. anM a1565.6kD NOV3j, RSQEDVDRDGIGDACDPDADGDGVPNEKDNCLVRNPDQRNTDEDKWGDACDNCRSQINDDQKDTDQD 20759281 GRGDACDDDIDGDRIRNQADCPRVPNSDQDSDGDGIGDACDNCPQKSNPDQDVHDFIGDACDSD QEQDGDGHQDSRNCPVPNSAQEDSDEGQGDACDDDDDNDGVPDSRDNCRLVPNPGQEDDRGVG Protein DVQDDDVDI)CEAVLDRPTVDEDQDNVLORIQMSP Sequence LAVGYTAFNGVDFEGTFHTVTDDDYAGFIFGYQDSSSFYVWKQMEQTYWQNPFRVAEPGIQL KAVI(SSTGPGEQLRNAWHTGDTESQVRLLWKDPNGWKDKSYRWFLQHRPQVGYIRVRFYECPEL VASNVVLDTTMRGGRLGVFCFSQENIIWANLRYRCND)TIPEDYETHQLRQALE - SEQ ID NO: 33......... .. 1386 bp NOV3k, AGATCTCAGGAGGA CGTGGACCGCGATGGCATCGGAGACGCCTGCGATCCcCATGCCOACGGCGACG 248644823 GGGTCCCCAATGAAAAGGACAACTGCCCGCTGGTGCGGAACCCAGACCAGCGAACACGGACGAGGA CAAGTGGGGCGATGCGTCGACAACTGCCGGTCCCAGAAGA ACGACAGACCAGACCAG DNA Sequence GACGGCCGGGGCGATGCGTGCGACGACGACATCGACGGCGACCGGATCCGCAACCAGGCCGACAACT GCCCTAGCGTACCCAACTCAGACCAGAAGGACAGTCATGGCGATGGTATAGGGGATGCCTGTGACAA CTGTCCCCAGAAGAGCAACCCGGATCAGGCGGATGTGGACCACGACTTTGTGGGAGATGCTTGTGAC AGCGATCGAGACCAGGATGGAGACGGAATCAGACTCTCGGGACAACTGTCCCACGGTGCCTAC GTGCCCAGGAGGACTCAGACCACGATGGCCAGGGTGATGCCTGCGACGACGACGACGACAATGACGG AGTCCCTGACAGTCGGGACAACTCCGCCTGGTGCCTAACCCCGGccAGAGGACGCGGACAGG~CA GGCGTGGGCGACGTGTCAGGACGACTTTGATGCAGACAAGGTGGTAGACAAGATCGACGCGTGTC CGGAGAACCTAGTCACGCTcACCGACTTCAGGCCTTCCAGACAGTCGTGCTGAcCCGAGGG AGCGACCCAGGCCTGCTGTGGGTTACACTGCCTTCAATGGCGTGGACTTCGAGGGCACGTTCCATG TGAACAGGTCACGATACGACTATGccGGCTTCATCTTTGGCTACCAGGACAGCTCCAGCTTCTA CGTGGTCATGTGGAAGCAGATGGAGCAACGTATTGGCAGGCGAACCCCTTCCGTCTGTGGCCGAG CCTGGCATCCAACTCAAGGCTGTGAAGTCTTCCACAGGCCCCGGGGAACAGCTGCGGAACGCTCTGT GGCATACAAGACACAGAGTCCAGGTGCGCTGCTGTGGAAGGACCCnCGAAACGTGGGTTGGAA GGACAAGAAGTCCTATCGTTGGTTCCTGCAGCACCGGCCCCAAGTOGCTACATCAGGGTGCGATTC ........... ,..,TATGAGGGCCCTGAGCTGGTGGCCGAcAGCPLACGTGGTCTTGGACACAACCATGCGGGGTGGCCGCCj 119 WO 03/050245 PCT/USO2/38594 ________ TGGGGGTCTTCTGCTTCTCCCAGGAGAACATCATCTGGGCCAACTGCGTTACCGCTGCAATGACAC ________ ORF Start: at I __:ORF Stop: end of sequence SEQ H) NO: 34 46 aMW at 5 1565.6kD NOV3k, RSQEDVDRDGIDACDPDADGDGVPNEKCPLVRNPDQRTDEDKWGDACDNCRSQKDDQCDTDQ 248644823 DGRGDACDDDIDGDRIRflQADNCPRVPNSDQKDSDGDGIGDACDNCPQCSNPIDQADVDIDFVGDACD SDQDQDGDGHQDSRDNCPTVPNSAQEDSDHDGQGDACDDDDDNDGVPDSRDNCRLVPNPGQEDADRD Protein GVGDVCQDDFDADnJIJKIDACPENAEVTLTDFRAFQTVVLDPEGDAQIDPNWVVLNQGREIVQTU Sequence SDPGLAVGYTAFNGVDFEGTFHVNTVTDDDYAGFIFGYQDSSSPYVVMWQMQTYWQANPFRAVAE PGIQLKAVKSSTGPGEQLRNALWHTGDTESQVRLLWKDPRNVGWKDKCSYRWFLQHRPQVGYIRVRF __________YEGPELVADSNVVLDTTM4RGGRLGVFCFSQENI IWANLRYRCNDTIPEDYETHQLRQALE _______SEQID NO: 35 _F2b NOV31, AAGCTTCAGGAGGATGTGGACCGCGATGGCATCGGAGACGCCTGCGATCCGGATGCCGACGGGGACGG 248644900 GGTCCCC-AATGAAAAGGACAACTGCCCGCTGGTGCGGAACCCAGACCAGCGCAACACGGACGAGGACA AGTCGGGCGATGCGTCACAACTGCCGGTCCCAGAAGAACGACGACCAAAGGACACAGACCAGGAC DNA Sequence GGCCGGGGCGATGCGTGCGACGACGACATCGACGGCGACCGGATCCGCAACCAGGCCGACAACTGCCC TAGGGTACCCAACTCAGACCGAAnACATGATGGCGATGTATAGGGGATGCCTGTGACAACTGTC CCCAGAAGAGCACCCGGATCAGGCGGATGTGGACCACGACTTTGTrGGGAGATGCTTGTGACAGCGAT CAAGACCAGGATGGAGACGGACATCAGGACTCTCGGGACAACTGTCCCACGGTGCCTAACAGTGCCCA GGAGGACTCAGACCACGATGGCCAGGWTGATGCCTGCGACGACQACGACGACALATGACGGAGTCCCTG ACAGTCGGGACAACTGCCGCCTGTGCCTAACCCCGCCAGAGACCGGACAGGC~CnTGaCc GACGTGTGCCAGGACGACTTTGATGCAGACAAGGTGGTAGACAAGATCGACGTGCTCGAG ORE Start: at 1 - OEStop: end of sequence SEQ ID NO: 36 ______224 aa __MW at 24274.4kD NOV31, KLQEDVDRDGIGDACDPDADGDGVPNEKNCPLVRNPDQRNTDEDKWGDACDNCRSQQ'IfDQKDTDQJ 248644900 GRGDACDDDTDCGRRNQADNCPRVPNSDQfSDGDGGDACDNCQKSNPDQADVDHDFVGDACDSD QDQDGDGUQDSRNCPTVPNSAQEDSDIDQGDACDDDDDNDGVpDSRDNCRLVPNPCAQEDADRDGVG Protein DVCQDDFDADKVVD)KIDVLE Sequence -SEQ ID NO: 37 j22bp NOV3m, AAGCTTCAGCCCAGACCCCGTTGGCCTCACATCTGGCCCCGCAGATGCTTCGGGAACTGCAGGAAA 248576435 CCAACGCGGCGCTGCAGGACGTGCGGGAGCTGCTGCGGCAGCAGGTCAGGGAGACACGTTCCcro1A AAACACGGTGATGGAGTGTGACGCGTGCGGGATGCAGCAGTCAGTACGCACCGGCCTACCCAGCGTG DNA Sequence CGGCCCCTGCTCCACTGCCCGCCCGGCTTCTGCTTCCCCGCCGTCGCCTGCATCCAGACGGAGAGCG GCGCGCGCTGCGGCCCCTGCCCCGCGGGCTTCACGGGCAACGGCTCGCACTGCACCGACGTCAACGA GTGCACGCCCACCCCTCTTCCCCCGAGTCCGCTGTATCACACCAGCCCGGGTTCCGCTCGAG GCTTGCCCGCCGGGGTACACGaCCCCACCCACCAGGCCGTGGGCCTGGCTTTCGCCAAGGCCAACA AGCAGGTTTGCACGGACATCAACGAGTGTGAGACCGGGCAACATAACTGCGTCCCCAACTCCGTG'rG CATCAACACCCrntGCTCCTTCCAGTGCGGCCCGTCCAGCCCGGCTTCGTGGCCACCAGGCGTCC GGCTGCCAGCGGCGCGCACACCGCTTCTGCCCCGACGGCTCGCCCAGCGAGTGCCACGAGCATGCAG ACTGCGTCCTAGAGCGCGATGGCTCGCGGTCGTGCGTGTGTGCCGTTGGCGGCCGGCA~CGGAT CCTCTGTGGTCaCGACACTGACCTAGACGGCTTCCCGGACGAGAAGCTGCGCTGCCCGGAGCGCCAG TGCCGTAAGGACAACTGCGTCACTGTGCCCAACTCAGGCCACGAGGATGTGGACCGCGATGGCATCG GAGACGCCTGCGATCCGGATGCCGACGGGGACGGGGTCCCCAATGAAAAGGACAACTGCCCGCTGGT G3CGGAACCCAGACCAGCGCAACACGGACGAGGAAAGTGGGGCGATGCGTGCGACAACTCCCGTCC CAGAAGAACGACGACCAAAAGGACACAGACCAGGACGGCCGGGGCGATGCGTGCGACGACGAATCG ACGGCGACCGGATCCGCAACCAGGCCGACACTGCCCTAGGGTACCCCTC'-GACCAGAGGCAG TGTGGTGAAGGTCTTAACTTCCGA-GACCGTAGGA GTGACCACGACTTTGTGGGAATGCTTGTGACAGCGATCAGACC-GGATGGAGACGACTCAGG ACTCTCGGGACAACTGTCCCACGGTGCCTAACAGTGCCCAGGAGGACTCAGACCACGATGC~CAccGG TGATGCCTGCGACGACGACGACGACAATGACGGACTCCCTGACAGTCGGGACAACTGCCCCCTGGTG CCTAACCCCGGCCAGCAGGACGCGGACAGGGACGGCGTGGGCGACGTGTGCCAGGACGACTTTGATG CAGACAAGGTGGTAGACAAGATCGACGTGTGTCCGGAGAACGCTGAAGTCACGCTCACCGACTTCAG CGCCTTCCAGACAGTCGTCTGGACCCGGAGACGCGAGATTGACCCCAACTGGTGGTGCTC AACCAGCGAAGOGAGATCGTGCAGACAATGAACAGCGACCCAGGCCTGGCTGTGGGTTACACTGCCT TCAATGGCGTGGACTTCGAGGGCACGTTCCATGTGAACACGcGTCACGGATGACGACTATGCGGGCTT CACTGCACAGCGTCOTCACTGCTTGACGTGGAAGA TCGCAGGCG-ACCCCTTCCGTGCTGTGGCCGAGCCTGGCATCCACTCAGGCTGTGAAGTCTTCCA CAGGCCCCGGGGAACAGCTGCGGA-ACCTCTGTG3nJ-TACA3GAGACACAGAGTCCCAGGTGCGGCT GTGTGGALAGGACCCGCGAAACGTGGOTTGGAAGGACUAGAAGTCCTATCGTTGTTCCT~CCACA CGCCCOAGTGGGCTACATCAGGGTGCGATTCTATGAGGGCCCTGAGCTGGTGGCCGACAGCAJCG I _____________GTGCGCGGGGCTCGCTTCCGGGAC~rA ,GGGCCACCTGCGTTACCGCTGCATGACACCATCCCAGAGGACTATGAGACCCATCAOCTGCGG' 120 WO 03/050245 PCT/USO2/38594 ,I A CCCCTCGAG 1 R t p n f s q e c JORF Start: at 1 _______SEQ ID NO: 38- .... -- 41 a MW at 81445.OkD NOV3m, - LQGQSPLGSDLGPQMLRELQETNAALQDVRELLRQQVREITFLKNTVMECDACGMQQSVRTGLPSV 248576435 LRPLLHCAPGFCFPGVACIQTESGARCGPCPAGFTGNGSHCTDVNECNAHPCFPRVRCINTSPGFRCE ACPPGYSGPTHQGVGLAFAKMIKQVCTDINECETGQHNICVPNSVCINTRGSFQCGPCQPGFVGDQAS Protein GCQRRAQRFCPDGSPSECH1EHADCVLERDGSRSCVCAVGWAGNGILCGRDTDLDGFPDEKLRCPERQ Sequence CRKDNCVTVPNSGQEDVDRDGIGDACDPDAGDGVPNKDNCPVRNPDQRNfTDEDKWGDACDNCRS QKDDQKDTDQDGRGDACUDDIDGDRIRNqQADNCPRVPNSDQKDSDGDGIGDACDNCPQKSNPDQAD VDDFVGDACDSDQDQDGDGHQDSRDCPTVPNSAQEDSDDGQGDACDDDDNGVPDSRDNCRLV PNPGQEDADRDGVGDVCQDDFDDnVVDCIDVCPENAEVTLTFAFTVDPEGDAQIDPNVV N~QGREIVQTMN~SDPLAVGYTAFNGVDFEGTFHSJNTVTDDDYAGFI FGYQDSSSFYVVMWKQMEQTY WQANPFRAVAuPGIQLKA VKSSTGPGEQLRNALW{TGDTESQVRLLWKDPRNVGWKDKKSYRWFLQH RPQVGYIRVRFYEGPELVADSNWVLDTThIRGGRLGVFCFSQENIIWANLRYRCNDTI PEDYETHQLR QALE SEQ ID NO: 39 2296 bp NOV3n, CACCAAGCTTCCCACCATGGTCCCCGACACCGCCTGCGTTCTTCTGCTCACCCTGGCTGCCCTCGGC 310681505 GCGTCCGGACAGGGCC-AGCCCGTTGGGCTCAGACCTGGGCCCGCAGATGCTTCGGGAACTGCAGG 310681505 AAACCAACaCGGCGCTGCACGACcGTGCGGGAGCTuCTGCGGCAGCAGGTCAGGGAGATCACGTTCCT DNA Sequence GAAAAACACGGTGATGGAGTGTGACGCGTGCGGGATGCAGCAGTCAGTACOCACCGGCCTACCCAGC GTGCGGCCCCTGCTCCACTGCGCGCCCGGCTTCTGCTTCCCCGGCGTGGCCTGCATCCAGACGGAGA CCGCGCGCGCTcCGGCCCCTGCCCCGCGGGCTTCACGGGCACGGCTCGCACTGCACCGACGTCAA CGAGTGCAACGCCCACCCCTGCTTCCCCCGAGTCCGCTGTATCAACACCAGCCCGGGGTTCCGCTGC GAGGCTTGCCCGCCGGGGTACAGCGGCCCCACCCACCAGGGCGTGGGGCTGGCTTTCGCCAAGGCCA ACAAGCAGGTTTGCACGGACATCAACGAGTGTGAGACCGGGCAACATAACTGCGTCCCCAACTCCGT GTGCATCAACACCCGGGGCTCCTTCCAGTGCGGCCCGTGCCAGCCCCGCTTCGTGGCGACCAGGCG TCCGCTGCCAGCGGCGCGCACAGCGCTTCTGCCCCGACGGCTCGCCCAGCGAGTGCCACGAGCATG CAGACTGCGTCCTAGAGCGCGATGGCTCGCGGTCGTGCGTGTGTGCCGTTGGCTGGGCCGGCAACGG GATCCTCTGTGGTCGCGACACTGACCTAGACCGCTTCCCGGACGAGAAGCTGCGCTG.CCCGGAC;CGC C-AGTGCCGTAAGGACAACTGTGTGACTGTGCCCALACTCAGGGCAGGAGGATGTGGACCGCGATGGCA TCGGAGACGCCTGCGATCCGGATGCCGACGQACGGGGTCCCC.AATGAAAAGGACAACTGCCCGCT GGTGCGGAACCCAGACCAGCGCACACGGACGAGGACAAGTQGGGCGATGCGTGCGACAACTGCCCG TCCCAGAAGAACGACGACCAAAAGGACACAGACCAGGACGGCCGGGGCGATGCGTGCGACACACA TCGACGGCGACCGGATCCGCALACCAGGCCGACAAkCTGCCCTAGGGTACCCALACTCAGACCAGAAGGA CAGTGATaGCGATGGTATAGGGCATGCCTGTGACAACTGTCCCCAGALAGAGCA.ACCCGGATCACGCG GATGTGGACCACGACTTTGTGGGAGATGCTTGTGACAGCGATCAAGACCAGGATGGAGACGGAATC AGGACTCTCGGGACACTTCCCACGTGCCTAACAGTGCCCAGGAGGACTCAGACCACGATGGCCA CGGTGATCCCTCCGACGACGACGACGACALATGACGGAGTCCCTGACAGTCGGGACAACTGCCGCCTG GTGCCTACCCCGGCAGGAGGACGCGGACAGGGACGGCTGGGCGACGTGTGCCAGGACGACTTTG ATGC-AGACAAGGTGGTAGACAAGATCGACGTGTGTCCGGAGAACGCTGAAGTCACGCTCACCGACTT CAGCTCAAATGGTGCCGGGGCCCGTGCCACGGGT CTCACCAGGGAAGGGAGATCGTGCGACAATGAACAGCGACCCAGGCCTGGCTGTGGGTTACACTG CCTTCAATcAGCGTGGACTTCGAGGGCACGTTCC-ATGTGAACACGGTCACGGATGACGACTATGCGGG CTTCATCTTTGGCTACCACGACAGCTCCAGCTTCTACGTGGTCATGTGGAGCAGATGAGCAAACG TATTGGCAGGCGAACCCCTTCCGTGCTGTGGCCGAGCCTGCATCCAACTAAGGCTGTtAATCTT CCACAGGCCCCGcGQAACAGCTGCGGAACGCTCTGTGGCATACAGGAGACACAGAGTCCCAGGTGCG GCT0CTGTGGAAGGACCCGCGAAACGTGGGTTGGAAGGACAAGAAGTCCTATCGTTGGTTCCTGCAG CACCGGCCCCAAGTGGGCTACATCGGGTGCGATTCTATGAGGGCCCTGAGCTGTGGCCGAAGC ACGTGGTCTTGGACACALACCALTGCGGGGTc4GCCGCCTGGGGGTCTTCTGCTTCTCCCAGGAGAACAT CTCTGGGCCA.ACCTGCGTTACCGCTGCAATGACACCATCCCAGAGGACTATGAGACCCATC-AGCTG _________RF Start: at 2 ~OFSo:end of sequence L SEQ ID NO: 40 765 at 83699.6kD NOV3n, TKLPTMVPDTACVLLTLALGASGQGQSPLGSDLGPQML~RELQETNALQDVRELLRQQVREITF'L 310681505 KTVECACGMQQSVRTGLPSVRPLLHCPGFCFPGVACIQTESGARCGPCPAQFTGGSHCTDVN ProeinECNAHPCFPRVRCINTSPGFRCEACPPGYSGPTHQGVGLAFAKANKQVCTDINECETGQNCPNSV ProteinCINTRGSFQCGPCQPGFVGDQASGCQRRAQRFCPDGSPSECHEHDCVLERDGSRSCVCAVGWAGNG Sequence ILCGRDTDLDGFPDEKRCPERQCRKcDNCVTVPNSGQEDVDRDGIGDACDPEADGDGVPNKINCPL VRNPDQRNTDEDKWGDACDN~CRSQKNDDQKDTDQDGRGDACDDDIDGDRIRNQADNCPRVPNTSDQIKD SDGDGICDACDNCPQKSNPDQADVDHDFVGDACDSDQDQDGDGE{QDSRDNCPTVPNSAQEDSDHDGQ GDACDDDDDNDGVPDSRDNCRLVPNPGQEDADRDGVGDVCQDDFADKVDKIDVCPENAEVTLTDF RAFQTVVLDPEGDAQIDPNWLNQGREIVQTMNSDPGLAVGYTAFGVDFEGTFVNTVTDDDYAG __________ IFGYQDSSSFYVVMWKQMEQTYWQANPFRAVAEPGIQLKAVKSSTG2GEQLRNALWHTGDTESQVR 121 WO 03/050245 PCT/USO2/38594 __________ IW ANLRYRCNDTI PEDYETHQLRQALEG SEQ ID NO: 41 ~ 2223bp NOV3o, AAGCTTCAGGGCCAGAGCCCGTTGOCTCAATCTGGCCCGGATGCTTCGGGACTGAGGAAA CG1 05716-07 CCACCG(CGAGCTCGACGTGGCG:GTAGAACCTCTA DNA equnceAAACACGGTGATGGAGTGTGArnCGTGCGGGATGCAGCAGTCAGTACGCACCGGCCTACCCAGCGTG DN euneCGCCGTCCGGGCGCTCGTCCGCTGCGACAAGAAC GCCCCGOCCTCCGGGTCCGCAGCCCCGACAGCAG CATCACACCCGGGGCTCCTTCCAGTGCGGCCCGTGCCAGCCCGCTTCGTGGCGACAGGCGTCC GGTCACGGGAACCTTCCGCGTGCACATCAGGAGA ACTGCGTCCTAGAGCGCGATGGCTCGCGTCGTGCGTGTGTGCCGTTGGCTGCCGC3CACGQT CCCGGTGGCCGCTGCGTCCGCAAGTCCGCGACCA TGCTAGCATCTATTCCATAGCGAGTTGCGGTGAC GAQACGCCTCGATCCGGATGCCGACGGACGGGGTCCCCTGAGGACACTGCCCGCTGC(3 GCGACAACGGACCGCAGCATGGGTCTCAACGCGC CAAGAGCACAAGCCGCAGCGCGGGTCTCAGC rAC ACGGCGACGACAGCAACGCCAGTCCAT-a.CGACAA TGTGGTGAAGGTCTTAAACGCCAAGGACCGTAGGA GTGCAGCTGGGGTCTTAACACAACGAGAAGAACG ACCCGAACGCCCGGCACGGCAGGATAACCAGCAG TGTCTCAGCAGCAATAGATCTAATGGCATCGCGT CCACCGCAGGAGGAAGAGCTGCAGGGCGAGCTGT CAAACGGTrAAGTOCTTTCGGAGTAGCCCCCGCTA GGCTCGCGCTCGACGAGTAGGAATACCATGTGGT AACGGAGAACTrAAATACACACAGCGCGGGTCCGC TCAGCTGCTGGGAGTCTTACCGCCGTAGCAGGGT CACTCCACGAACCACTTCTGCTTGACGTGCAAGA TGGCAGGCGAACCCCTTCCGTGCTGTGCCGCCTGGCCATCAGGCTTAGTCTTCCA CAGGCCCCGGGGACACTGCCGCTCTGTCTAAGAAAGAGTCCCGTGCGCCT GCGGAGACGGACTGTGAGAAGATCACTGTCTCGA CGGCCCCAAGTGGGCTAATCAGGGTGCGATTCTATGAGGCCCTAGCTGGTGGCCGAAGCACG TGTTGAAACAGGGTOCCTGGTTCGTCCCGAACTA CTGCACTCTACCGATAACACCGGAT~-GCCTACGG ICAAGCCCTCGAG {SEQ StaN: 42 aa ORF St op: at 2218 -SE ID NO:7 42 MW at 80961.4kD NOV3o, QGSLSLPMRLENAQVELQQR1FKTMCAGQSRGLSR CG1057 16-07 LLHCAPGFCFPGVACIQTESQACGPCPAGFTGNGSHCTDNECNA~PCFPRVRCINTSPGFRCEAC PPGYSGPTHQGVGLAFAKANKQVCTDINCETQHN(YJPNSVCINTRG.SFQCGPCQPGFVGDQASGC Protein QRRAQRFCPDGSPSECHEHDCVLERDGSRSCVCAVQWACNGILCGRDTDLDGFPDEKRCPERQCR Sequence KDCTPSQIVRGGADDDDVPEDCLRPQNDDWDCNRQ HDFVGDACDSDQDQDGDGHQDSDNCPPNSAQEDSDHDQGACDDDDDNDGVPDSRDNCRLVPN ISEQ ID NO: 43 223 J~9bp - - NOV3p, CACCAAGCTTCAGGGCCAGACCCGTTGGCTAGATCTGGGCCCGAGATGCTTCGGGACTGCAG CG1057 16-08 IIIGGCCCAGCTCGACGTCGACGTAGAACCTC DNA Sequence CGTGCGGCCCCTGCTCCACTGCGCGCCCGGCTTCTGCTTCCCCGGCGTGGCCTGTCAGACGCAG

AGGCCCCGOCCTCCGGGTTAGGACGTGATCCGCT

ACGAGTGCAACGCCCACCCCTGCTTCCCQGTCCGCTGTATCACGCCCGaGTTCGT CGGCTCCCGGTCGGCCACACGGGGGCGCTCCAGC AACAAGCAGGTTTGCACCACATCGTGTGACCGACTACTCCGTCCCACTCCG TGTGCATCAACACCCGGGGCTCCTTCCAGTGCGGCCCGTGCAGCCCGGCTTCGTGGCGACCAGGC GTCGTCACGGGAACCTTCCCAGCCCCGGGGCAGGA GCGCGGCTGGCGTGTGGTCTCTTTCGTGTGCGC-C GGATCCTCTGTGGTCGCGAACTGACCTAGACGCTTCCCCGACGAGAAGCTGCGCTGCCCGGAGCG CCGGCTAGCATCTATTCCACCG~-GAGTTGCGGTG 122 WO 03/050245 PCT/USO2/38594 ATCGGAGACGCCTCATCCGGATGCCGACGGGGACGGGTCCCATGAGGAACTGCCCGC TGTCGACAACGGACCGCAGCATGGOTCTCAACGC GTCCCAGAAGAACGACGACCAAAAGGACACAGACCAGGACGGCCGGGGCGATGCGTGCGACGACGAC ATCGACGGCGACCATCCGACGCCGAACTGCCCTAGCCACTCCCGAGG ACAGTGATGGCGATGGTATAGGGATGCCTGTGACAACTGTCCCCAGAGACCCGGATAGC GGTTGCAGCTGGGGTCTTAACACAACGAGAAGAA CAGGACTCTCGGGACAACTGTCCCACGGTGCCTAACAGTGCCCAGGAGGACTCAGACCACGATGGCC AGGG GATGCCTGCGACGACGACGACGACAATGACGGAGTCCCTGAC-AGTCGGGACAACTGCCGCCT GGTGCCTAACCCCGGCCAGGAGGACGCGGACAGGGACGGCGTGGGCGACGTGTGCCAGGACACTTT GAGAAAAGGTGCAGTGCTTGCGA AGTAGCCCCCGC TAGGGCCTTCCOGACAGTCGTGCTGGACCCGGAGGGTGACGCGCAATTACCCCACTGGGTGGT GCTCACCAGGGGGGAGATCGTGCAGACATGAACAGCGACCCAGGCCTGGCTGTGGTTACACT aCCTTCAATGGCGTGGACTTCAGGCACGTTCCATGTGAAACGGTCACGGATGACGACTATGCGG GCTTCATCTTTGGCTACCAGGACACTCCACTTCTACGTGGTCATGT AGCAGATGGCC GTATTGGCGGCGAACCCCTTCCGTGCTGGGCCGAGCCTGGCATCCAACTCAAGGCTGTGAAGTCT TCCACAGGCCCCGGGAACAGCTGCGGAACGCTCTGTGGCATACAGGAGACACAGAGTCCCAGGTGC GGCTGCTGTGGAAGGACCCGCGACGTGCGTTGGAAGACAAGAAGTCCTATCGTTGTTCCTGCA GCACCGGCCCCAAGTGGGCTACATCAGGGTGCGATTCTATGAGGGCCCTGAGCTGGTGGCCGACAGC AAGGTTGAAACAGGGTGCCTGGTTCGTCCCGAAC TCTTGCACTCTACCGATAACTCAAGCAGGCCTAC GCGGCAAGCCGTCGACGGC ORF Start: at 2 '1743 Stop endo sequence SEQ ID NO: 44 74 aMW at 81575.lkD NOV3p, TKLQCQSPLGSDLGPQM4LRELQETNABALQDVRELLRQQVREITFLKTVMECDACGMQQSVRTGLPS CG10571 6-08 VRPLLHCAPGFCFPGVACIQTESARCGPCPAGFTGNGSHCTDVNEGAPCFPRVRCINTSPGFRC EACPPGYSGPTHQGVGLAFAAIQVCTDINECETGQHNCVPNSVCINTRGSFQCGPCQPG'VD)QA Protein SGCQRRAQRFCPDGSPSECHEHAflCVLERDGSRSCVCAVGWAGNGILCGRDTDLDGFPDEKLRCPER Sequence QCRKDNCVTVPNSGQEDVDRDGIGDACYDPDDDGVPNEKDNCPLVRNPQRNTDEDKWGIACDNCR SQ NDDQKDTDQDGRGDACDDDIDGDRIRNQADNCPRVPNSDQKDSDGDGIGDACDNCPQKSNPDQA DVDHDFVGDACDSDQDQDGDGHQDSRDNCPTVPNSAQEDSDHDGQGDACDDDDDNDGVPDSRDNCRL VPN~PGQEDADRDGVGDVCQDDFDADKVVDKIDVCPEN~AEVTLTDFRAFQTVVLhDPEGDAQIDPNWVV JNQGREIVQTMNSDPGLAVCYTAFNGVDFECTFHVNTVTDDDYAGFIFGYQDSSSFY!V]VKQMEQT YWQANPFRAVAEPGIQLKAVKSSTGPGEQLRNALWTGDTESQVRLLWKDPRNVGKDKKSYRWFLQ HRPQVGYIRVRFYEGPELVADSNVVLDTTMRGGRLGVFCFSQEUI

IWANLRYRCNDTIPEDYETEQL

RQAVDG SEQ ID NO: 45 12296 bp NOV3 q, CACCATCTCCCACCATGGTCCCCGACACCGCCTGCGTTCTTCTGCTCACCCTGGCTGCCCTCGGC CG1057 16-10 GCGTCCGGACAGGCCAGAGCCCGTTGGGCTCAGACCTGGGCCCGCAGATGCTTCGAACTGCAGG AAACCAACGCGGCGCTGAGGACGTGCGGGAGCTGCTGCGGCAGAOGGTGGGAATCCGTTCCT DNA Sequence GAJA-AACACGGTGATGGAGTGTGACGCGTGCGGGATGCAGCAGTCAGTACGCACCGGCCTACCCAGC GTGCCGCCCCTGCTCCACTCCCGCCCGGCTTCTGCTTCCCCGGCGTGCCTG TCCCGAG GCGGCGCGCGCTGCGGCCCCTGCCCCGCGGCTTCACGG~CACGGCTCGCACTCACCACGTC CGAGTGCAACGCCCACCCCTGCTTCCCCCGAGTCCGCTGTATCAACACCAGCCCGGGGTTCCGCTGC OACGCTTGCCCCCCGSGGTACA0CGGCCCCACCCACCAGGGCGTGGCTGGCTTTCGCCAGGCCA ACAAGCAGGTTGCACGGACATCAACGAGTGTGAGACCOGGCAACATAACTGCTCCCCACTCCGT GTGCATCAACACCCGGGGCTCCTTCCAGTGCGGCCCGTGCCAGCCCGGCTTCGTGGGCGACCAGGCG TCCGGCTGCCACCGCGCACAGCGCTTCTGCCCCGACGGCTCGCCCAGCAGTCACGAGCATG CAGACTGCGTCCTAGAGCGCGATGGCTCGCGGTCGTGCGTGTGTCCGTTGCTCCGCACGC GATCCTCTcITGcGTCGCGACACTGACCTAGACGGCTTCCCGGACGAGAAGCTGCGCTGCCCGGAGCGC CAGTGCCGTAACAACTGTGTGACTGTSCCCACTCAGGGCAGGAGGATGTGGACCGCGATGGCA TCGGAGACGCCTGCGATCCGGATGCCGACGGGGACGGGTCCCATGAGGACACTGCCCGCT GGTGCGGAACCCAGACCAGCGCAACACGGACGAGGACAAGTGGGGCGATGCGTGCGACAACTGCCGG TCCCAGAAGAACGACSACCAAAAGGAACAGACAGACGCCGGCGATCCTGCACGACGAr TCGACGGCGACCGGATCCGCAACCAGGCCGACAACTGCCCTAGGGTACCCACTCAGACCAAAG CAGTGATGGCGATGGTATAGGGGATGCCTGTGACAACTGTCCCC-AGAAGAGCAACCCGGATCAGGCG GATGTGGACCACGACTTTCTGGGAGTGCTTGTGACAGCGACAAGACCAGATGGAGACGGAATC AGATTGGCATTCAGTCTAATCCGAGCCGCACTGC GGGTGATGCCTGCGACGACGACGACGACAATGACGGAGTCCCTGACAGTCGGGACAACTGCCGCCTG GTGCCTAACCCCGGCCAGGAGCACGCGACAGCGACCOCGTGGGCG7ACGTGTGCCAGGACGACTTTG ATGCAGACAAGGTGGTAGACAAGATCGACGTGTGTCCGGAGACGCTGAAGTACGCTCACCACTT CAGGGCCTTCCAGACAGTCGTGCTGGACCCGGAGGTGACGCGAGATTGACCCCACTGGGTGGTG CTCACCACGGSAGAGATCGTGCAGACAATAACAGCGACCCAGGCCTGG.CTGTGGTTACACTG CCTTCAATGGCGTGGACTTCGAGGGCACGTTCCATGTGAACACGGTCACGGATGACGACTATGCOG . .... ..... .... . TATTGGCAGGCGAACCCCTTCCGTGCTGTGOCCGAGCCTGGCATCCAACTCAAGGCTGTGAAGTCTT 123 WO 03/050245 PCT/USO2/38594 GCTGCTGTGGAAGGACCCGCGAAACGTGGGTTGGAAGGACAAGAAGTCCTATCGTTGGTTCCTGC-AG CACCGGCCCCAAGTGGGCTACATCAGGGTGCGATTCTATGAGGCCCTGAGCTGGTGGCCGACAGCA ACGTGGTCTTGGACACAACCATGCGGGGTGGCCGCCTGGGGGTCTTCTGCTTCTCCCAGGAGAACAT CATCTGGGCCAACCTGCGTTACCGCTGCAATGACACCATCCCAGAGGACTATGAGACCC-ATCAGCTG CGGCAAGCCCTCGAGGGC fORF.Start: ATG at 17 IORF Stop: at 2288 ISEQ ID NO: 46 1757 aa 'MW at 82859.7kD NOV3q, MVPDTACVLLLTLAALGASGOGQSPLGSDLGPQMLRELQETNAALQDVRELLP.QQVREITFLKNTVM CG1 05716- 10 ECDACGMQQSVRTGLPSVRPLLHCAPGFCFPGVACIQTESGARCGPCPAGFTGNGSHCTDVNECNAH PCFPRVRCINTSPGRCEACPPGYSGPTQGVLAFAKA1KQVCTDIECETGQHNCVPNSVC1NTR Protein GSFQCGPCQPGFVGDQASGCQRRAQRFCPDGSPSECHEHADCVLERDGSRSCVCAVGWAGNGILCGR Sequence DTDLDGFPDEKLRCPERQCRKDSCVTVPNSGQEDVDRDGIDACDPDAD)GDGVPNEKDNCPLVRNPD QRNTDEDKWGDACDNCRSQKNDDQKDTDQDGRGIDACDDDIDGDRIRNQADNCPRVPNSDQKDSDGDG IGDACDNCPQKSNPDQADVDHDFVGDACDSDQDQDGDGHQDSRDNCPTVPNSAQEDSDHDGQGDACD DDDDNDGVPDSRDNCRLVPNPGQEDADRDXVGDVCQDDFDADKVVDKIDVCPENAEVTLTDFRAFQT VVLDPEGDAQIDPNWVLNQGREIVQTMSDPGLAVYTAFGVDFEGTFHVNTVTDDDYAGFIFGY QDSSSFYVVMKQMEQTYWQANPFRAVAEPGIQLYCAVKSSTGPGEQLRNALWHTGDTESQVRLLWKD PRiNVGWKDKKSYRWFLQRPQVYIRVRFYEGPELVADNVLDTTMRGGRLGVFCFSQENIIWAflL RYRCNDTIPEDYETHQLRQA Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 3B. Table 3B. Comparison of NOV3a against NOV3b through NOV3q. Protein Sequence NOV3a Residues/ Identities/ Match Residues Similarities for the Matched Region NOV3b 1 .3757 735/757 (97%) 1.3741 7361757 (97%) NOV3c 1.3757 720/757 (95%) 1.326 721/757 (95%) NOV3d 1.357 740/757 (97%/) 1.3748 742/757 (97%) NOV3e 1.357 715/757(94%) 1.3721 716/757 (94%) NOV3f 300..757 458/458 (100%) L..458 458/458 (100%) NOV3g 1.3757 748/757 (98%) L.757 749/757 (98%) NOV3h 1300..757 458/458 (100%) 1..460 45 8/458 (100%) NOV3i j300.3757 456/458 (99%) 3..460 457/458 (99%) NOV3j 1300..757 45 7/458 (99%) _____________ 3..460 457/458 (99%) NOVA 0..5 457/458 (99%) -460 45 7/458 (99%) 124 WO 03/050245 PCT/USO2/38594 NOV31 300..519 220/220(100%) 3..222 220/220 (100%) NOV3m 21..757 737/737 (100%) 3..739 737/737 (100%) NOV3n 1..757 757/757 (100%) 6..762 757/757 (100%) NOV3o 21..757 737/737(100%) 1..737 737/737 (100%) NOV3p 21..757 737/737 (100%) 4..740 737/737 (100%) NOV3q 1..757 757/757(100%) 1..757 757/757(100%) Further analysis of the NOV3a protein yielded the following properties shown in Table 3C. Table 3C. Protein Sequence Properties NOV3a SignalP Cleavage site between residues 21 and 22 analysis: PSORTII PSG: a new signal peptide prediction method analysis: N-region: length 4; pos.chg 0; neg.chg 1 H-region: length 24; peak value 0.00 PSG score: -4.40 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): 3.65 possible cleavage site: between 20 and 21 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 0 PERIPHERAL Likelihood = 1.43 (at 87) ALOM score: -1.81 (number of TMSs: 0) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 7.90 Hyd Moment(95): 5.39 G content: 4 D/E content: 2 S/T content: 5 Score: -7.28 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 8.9% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none 125 WO 03/050245 PCT/USO2/38594 ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 70.6 COIL: Lupas's algorithm to detect coiled-coil regions 32 Q 0.97 33 M 0.97 34 L 0.97 35 R 0.97 36 E 0.97 37 L 0.97 38 Q 0.97 39 E 0.97 40 T 0.97 41 N 0.97 42 A 0.97 43 A 0.97 44 L 0.97 45 Q 0.97 46 D 0.97 47 V 0.97 48 R 0.97 49 E 0.97 50 L 0.97 51 L 0.97 52 R 0.97 53 Q 0.97 54 Q 0.97 55 V 0.97 56 R 0.97 57 E 0.97 58 I 0.97 59 T 0.97 60 F 0.97 61 L 0.97 62 K 0.97 63 N 0.97 126 WO 03/050245 PCT/USO2/38594 64 T 0.84 65 V 0.73 total: 34 residues Final Results (k = 9/23): 56.5 %: nuclear 17.4 %: mitochondrial 13.0 %: extracellular, including cell wall 8.7 %: cytoplasmic 4.3 %: peroxisomal >> prediction for CG105716-09 is nuc (k=23) A search of the NOV3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3D. 5 Table 3D. Geneseq Results for NOV3a NOV3a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region ABJ05594 Breast cancer-associated 1..757 751/757 (99%) 0.0 protein 59 - Unidentified, 757 1..757 752/757 (99%) aa. [WO200259377-A2, 01-AUG-2002] AAB00044 Human cartilage oligomeric 1..757 750/757 (99%) 0.0 matrix protein (COMP) - 1..757 751/757 (99%) Homo sapiens, 757 aa. [WO200044908-A2, 03-AUG-2000] AAR56248 Xenopus thrombospondin-4 - 29..756 516/740 (69%) 0.0 Xenopus laevis, 889 aa. 150..886 602/740 (80%) [WO9413794-A, 23-JUN-1994] AAE25032 Human thrombospondin 16..753 518/752 (68%) 0.0 (TSP)4 protein - Homo 211..952 598/752 (78%) sapiens, 961 aa. [WO200239122-A2, 16-MAY-2002] AAR56249 Human thrombospondin-4 - 16..753 518/752 (68%) 0.0 Homo sapiens, 961 aa. 211..952 598/752 (78%) [WO9413794-A, 23-JTUN-1994] 127 WO 03/050245 PCT/USO2/38594 In a BLAST search of public sequence datbases, the NOV3a protein was found to have homology to the proteins shown in the BLASTP data in Table 3E. Table 3E. Public BLASTP Results for NOV3a NOV3 a Protein NOV3a Identities/ Residues/ Expect Accession Protein/Organism/Length Match Similarities for the Valuexpect Number Residues Matched Portion Residues P49747 Cartilage oligomeric matrix 1..757 751/757 (99%) 0.0 protein precursor (COMP) - 1..757 752/757 (99%) Homo sapiens (Human), 757 aa. 014592 COMPHUMAN - Homo 1..742 742/742 (100%) 0.0 sapiens (Human), 817 aa. 1..742 742/742 (100%) Q8N4T2 Similar to cartilage oligomeric 34..757 724/724 (100%) 0.0 matrix protein 1..724 724/724 (100%) (pseudoachondroplasia, epiphyseal dysplasia 1, multiple) - Homo sapiens (Human), 724 aa. Q9BG80 Cartilage oligomeric matrix 1..757 699/757 (92%) 0.0 protein - Equus caballus 1..755 717/757 (94%) (Horse), 755 aa. P35444 Cartilage oligomeric matrix 5..757 686/753 (91%) 0.0 protein precursor (COMP) - 4..755 711/753 (94%) Rattus norvegicus (Rat), 755 aa. 5 PFam analysis predicts that the NOV3a protein contains the domains shown in the Table 3F. Table 3F. Domain Analysis of NOV3a Identities/ Pfam Domain NOV3a Match Region Similarities Expect Value for the Matched Region EGF 229..266 10/47 (21%) 0.007 30/47 (64%) tsp3 300.314 11/15(73%) 0.02 13/15 (87%) tsp 3 336..350 9/15 (60%) 0.057 15/15 (100%) tsp_3 359..373 10/15(67%) 0.22 15/15 (100%) 128 WO 03/050245 PCT/US02/38594 tsp3 395..409 12/15 (80%) 0.014 ______________15/15 (100%) tsp3 1418.432 10/15 (67%) 0.042 13/15 (87%) tsp3 145 6..470 12/15 (80%) 0.25 15/15 (100%) tsp3 492..506 10/15 (67%) 0.2 1 __________________14/15 (93%) _________ Example 4. The NOV4 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 4A. 5 Table 4A. NOV4 Sequence Analysis SEQ ID NO: 47 _[S39bp NO0V5ia, CAGATTTCCCTGTCAACCACGAGGAGTCCAGAGAGGCGCGGAGGACACTACCTGACGC CG153910-01 CTCTTTCAGCCCGGGATCGCCtnGCGGGALTL'ULi.~GUCG4CAGATCTGGCTGCCCTTCCCCGTGCTCCT DNA Sequence TCACCTTTACCCTTCCCGCCGGCAGACGGAGTGCTTCTACAGCCATGCCCCTGAmCCTCGCTG GAACATCAGTTGTGGAGTTGTTGTTCTTGCCCAAG CAAAACCTTAGTTTTTaAACAAAGAATCACATGGAGTTCACCTGTAGAGACTGAGTTGGTGATT ACTTCGTTAATCTCGACTTCGGAGGTTCTGATACT GAATTGAACGCCAACAAGTGAGATTTATG~-GTTT __________AAAATGAGGCATAAAAATGCAAT ORE Start: ATG at 99 jOP-F Stop: TAA at 786 SEQ ID NO: 48 MW2at 25989.5kD NOVa, G IWPPLLPVLGAGTSSFTTPGTFQiPYSLIEQDA CG1 53910-01 GLDIDFHLASPEGKTLVFEQRKSDGVHTVETEVGDYMFCFDNTFSTI SEKVIFFELILDNGEQAQEQ EDWKKYITGTDILDD4KLEDILES INSIKRSS QLRFADRIENDVFSVL Protein VMVWVSAIQVYM4LKSLFED{RISRT Sequence SEQ ID NO: 4 ~ 1223 bp NOVOb, CAGTCGCTCACCACCCAAATCCTCGCTGGGAGAGACCAJACCCGGCGACTGCGCGCTTCGr-CTCGAG CG153910-02 TCTGCGTTAGGAAGCCTCTGACCCTTTCCCGGCCCCTGCGCGTGGCCTCGGACACACTCGA GAACC-AGCGAACCCCGGCAGCACAATTCGAACCGCCGCGGGAGCCGTTGCGACGCGCCTACCCG DNA Sequence .TCACTGTCCCGCCCCGGCGCAGACTGCGTGAGGCGCCGCCGXAGGCGCGGGGCTTGCCGGGGATCGT GGTCGGCGAGCGCGCCCGAGCCCACTAGCGCAGCCCCCCGCGACTACATTTCCcCCAATTACCOCCC ATGATGCCCATTGGTGGGGGAACCTGGQACCGGACGCCGTCAGGGGAGAGGCGGGCGGCGCTC ACGCCTGGCCTACGGCCCAGACTGAGGCGGTTGCGGWTAGGACTGCTAGCCCCGCCCAGAGTC CCTACCCTTTGGAGAACTGCGCTTCTCTTTCGGAAGTGTTCGCCGCCGCCGGGC~CccCCTC ACAACAGTACCTGACCCTCTTTACCCGGATCGCCCGGGATGGGCGAAGATCTGGCT GCCCTTCCCCGTGCTCCTTCTGGCCGCTCTCCTCCGTCTGCTCCTGCGGCCGCTTAC CCTTCCCTCGATAGCGACTTCACCTTTACCCTTCCCGCCGGCAGAGAGTGCTTCTACAGCCCA TGCCCCTGAACGCCTCGCTGGAGATCGAGTACCAGTTTTAGATGGAG-'GGATTAGATATTGATTT TGATTTTCTTTAATTAATCCTGATAATATGGGAGAAGCAGAATTGGAGA 1TAAAATAAAAATTATTAACAGCCAGAGCCTTACTAGTAATAAGTTACTGAACTAAGCATTTTAT WO 03/050245 PCT/USO2/38594 . .CTGCATTATCCAGGAAA ORF Start: ATG at 651 ORF Stop: TAA at 1137 SEQ ID NO: 50 162 aa 11.....I_MW at 18167.6klD NOV4b MGDKIWLPFPVLLLAALPPVLLPGAAGFTPSLDSDFTFTLPAGQKECFYQPMPLKASLEIEYQVLDG C153910-02 AGLDIDFHLASPEGKTLVFEQRKSDGVHTVETEVGDYMFCFDNTFSTISEKVIFFELILDNMGEQAQ CG153910-02 EQEDWKKYITGTDILDMKLEDILVSMVF Protein Sequence SEQ ID NO: 51 712 bp NOV4c, CACCGCATCCACCATGGGCGACAAGATCTGGCTGCCCTTCCCCGTGCTCCTTCTGGCCGCTCTGCCTC CG153910-03 CGGTGCTGCTGCCTGGGGCGGCCGGCTTCACACCTTCCCTCGATAGCGACTTCACCTTTACCCTTCCC GCCGGCCAGAAGGAGTGCTTCTACCAGCCCATGCCCCTGAAGGCCTCGCTGGAGATCGAGTACCAAGT DNA Sequence TTTAGATGGAGCAGGATTAGATATTGATTTCCATCTTGCCTCTCCAGAAGGCAAAACCTTAGTTTTTG AACAAAGAAAATCAGATGGAGTTCACACTGTAGAGACTGAAGTTGGTGATTACATGTTCTGCTTTGAC AATACATTCAGCACCATTTCTGAGAAGGTGATTTTCTTTGAATTAATCCTGGATAATATGGGAGAACA GGCACAAGAACAAGAAGATTGGAAGAAATATATTACTGGCACAGATATATTGGATATGAAACTGGAAG ACATCCTGGAATCCATCAACAGCATCAAGTCCAGACTAAGCAAAAGTGGGCACATACAAATTCTGCTT AGAGCATTTGAAGCTCGTGATCGAAACATACAAGAAAGCAACTTTGATAGAGTCAATTTCTGGTCTAT GGTTAATTTAGTGGTCATGGTGGTGGTGTCAGCCATTCAAGTTTATATGCTGAAGAGTCTGTTTGAAG ATAAGAGGAAAAGTAGAACTTAGGTCGACGGC .... ORF Start: ATG at 14 ORF Stop: TAG at 701 SEQ ID NO: 52 229 aa MW at 26016.6kD NOV4c, " MGDKIWLPFPVLLLAALPPVLLPGAAGFTPSLDSDFTFTLPAGQKECFYQPMPLKASLEIEYQVLDGA C0153910-03 GLDIDFHLASPEGKTLVFEQRKSDGVHTVETEVGDYMFCFDNTFSTISEKVIFFELILDNMGEQAQEQ EDWKKYITGTDILDMKLEDILESINSIKSRLSKSGHIQILLRAFEARDRNIQESNFDRVNFWSMVNLV Protein VMVVVSAIQVYMLKSLFEDKRKSRT Sequence Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 4B. Table 4B. Comparison of NOV4a against NOV4b and NOV4c. NOV4a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region NOV4b 1..160 157/160 (98%) 1..160 158/160 (98%) NOV4c 1..229 228/229 (99%) 1..229 228/229 (99%) 5 Further analysis of the NOV4a protein yielded the following properties shown in Table 4C. Table 4C. Protein Sequence Properties NOV4a SignalP Cleavage site between residues 28 and 29 analysis: PSORT II PSG: a new signal peptide prediction method analysis: N-region: length 4; pos.chg 1; neg.chg 1 H-region: length 28; peak value 9.26 PSG score: 4.86 130 WO 03/050245 PCT/USO2/38594 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -0.04 possible cleavage site: between 23 and 24 >>> Seems to have a cleavable signal peptide (1 to 23) ALOM: Klein et al's method for TM region allocation Init position for calculation: 24 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -5.89 Transmembrane 201 - 217 PERIPHERAL Likelihood = 5.62 (at 110) ALOM score: -5.89 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 11 Charge difference: -4.0 C(-3.0) - N( 1.0) N >= C: N-terminal side will be inside >>> membrane topology: type la (cytoplasmic tail 218 to 229) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 11.31 Hyd Moment(95): 8.32 G content: 3 D/E content: 2 S/T content: 2 Score: -6.89 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 9.2% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: KKXX-like motif in the C-terminus: RKSR SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none 131 WO 03/050245 PCT/USO2/38594 NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 44.4 %: endoplasmic reticulum 22.2 %: Golgi 11.1 %: plasma membrane 11.1%: vesicles of secretory system 11.1%: extracellular, including cell wall >> prediction for CG153910-01 is end (k=9) A search of the NOV4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 4D. 5 Table 4D. Geneseq Results for NOV4a NOV4a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region AAU12376 Human PRO733 polypeptide 1..229 228/229 (99%) e-129 sequence - Homo sapiens, 1..229 228/229 (99%) 229 aa. [WO200140466-A2, 07-JUN-2001] AAY94859 Human protein clone 1..229 228/229 (99%) e-129 HP02515 - Homo sapiens, 1..229 228/229 (99%) 229 aa. [WO200005367-A2, 03-FEB-2000] AAB34734 Human secreted protein 1..229 228/229 (99%) e-129 encoded by DNA clone vq20 1..229 228/229 (99%) 1 - Homo sapiens, 229 aa. [WO200055375-A1, 21-SEP-2000] AAB44310 Human PRO733 (UNQ411) 1..229 228/229 (99%) e-129 protein sequence SEQ ID L.229 228/229 (99%) NO:447 - Homo sapiens, 229 aa. [WO200053756-A2, 14-SEP-2000] AAY41754 Human PRO733 protein 1..229 228/229 (99%) e-129 sequence -Homo sapiens, 1..229 228/229 (99%) 132 WO 03/050245 PCT/USO2/38594 16-SEP-1999] In a BLAST search of public sequence datbases, the NOV4a protein was found to have homology to the proteins shown in the BLASTP data in Table 4E. Table 4E. Public BLASTP Results for NOV4a Protein NOV4a Identities/ Protein Residues/ Similarities for Expect Accession Protein/Organism/Length Match the Matched Value Number Residues Portion Q9Y3A6 Protein CGI-100 precursor - 1..229 227/229 (99%) e-128 Homo sapiens (Human), 229 1..229 227/229 (99%) aa. Q9CXE7 4432412D15Rik protein - 1..229 204/229 (89%) e-115 Mus musculus (Mouse), 229 1..229 215/229 (93%) aa. Q8VCE7 RIKEN cDNA 4432412D15 1..229 203/229 (88%) e-115 gene - Mus musculus 1..229 215/229 (93%) (Mouse), 229 aa. CAC22512 Sequence 1 fromPatent 1..158 153/158 (96%) 5e-85 WO0075321 - Cloning vector 1..158 154/158 (96%) pINT1, 169 aa. Q13445 Putative T1/ST2 receptor 17..225 120/210 (57%) le-62 binding protein precursor - 16..223 157/210 (74%) Homo sapiens (Human), 227 aa. 5 PFam analysis predicts that the NOV4a protein contains the domains shown in the Table 4F. Table 4F. Domain Analysis of NOV4a Identities/ Similarities Pfam Domain NOV4a Match Region for the Matched Expect Value Region EMP24_GP25L 13..227 80/239 (33%) 2.2e-54 180/239 (75%) 10 Example 5. The NOV5 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 5A. 133 WO 03/050245 PCT/USO2/38594 ITable 5A. NOV5 Sequence Analysis ~SEQ ID NO: 53 ~ 463 bp NOV5a, ATCCCAGTAACCCGACCACCGCTGGTCTTCACIGGACACCATGAACCACACTGTCCAAACCTTCTCTC CG1 58564-02 CTATCAACAGCGGCCAGCCCCCCAACTATGAGATGCTCAAGGAGGAGCATGAGGTGGCTGTGCTGGGG GTGGCCTACAACCCTGCTCCCCCGACGTCCACCGTGATCCACATCCGCAACGAGACCTCCGTGCCCGA DNA Sequence CCATGTTGTCTQGTCCCTGTTCAACACTCTCTTCATGAACCCCTGCTGCCTGGGCTTCATAGCATTCG CTTACTCCGTGAAGTCTAGGCAAGGAGATGGTTGGCGACCTGACTGGCCCCACGCCTATnCCTCC ACCGCCAAGTGCCTGAACATCTGGGCCCTGATTTTGGGCATCTTCATGACCATTCTGCTCATCATCAT CCCAGTGTTGATCTTCCAACCTATCAATAGATCAGGAGGCATCATTGAGCCAG ORF Start: ATG at41 ~OFSop: TAG at 437 SEQ ID NO: 54 ... 132 aa JMWatl14709lk NOV5a, MNI{TVQTFSPINSGQPPNYEMLKEEHEVAVLGVAYN1 2 APPTSTVIHIRNETSVPDSTVWSLFNTLFMN CG158564-02 PCCL GFIAFAYSVKSRHRKD4VGDLTGAQAYASTAKCLNIWALILGIFMTILLIIIPVLIFQAYQ Protein Sequence SEQ ID NO: 55 T63 bp 7 NOV5b, ATCCCAGTAACCCGACC-ACCGCTGGTCTTCACTGGACACCATGAACCAC-ACTGTCCAAACCTTCTCT CG1 58564-01 CCTATCACAQCGGCCAGCCCCCCACTATGAGATGCTCAAGGAGGAGCATGAGGTGGCTGTGCTGG GGGTGGCCTACAACCCTGCTCCCCCGACGTCC-ACCGTGATCCACATCCGCAACGAGACCTCCGTGCC DNA Sequence CGACCATGTTGTCTGGTCCCTGTTCAACACTCTCTTCATCGAACCCCTGCTGCCTGGGCTTCATAGC-A TTCGCTTACTCCGTGAAGTCTAGGCACACGAAGATGGTTGGCGACCTGACTGGCGCCCAGGCCTATG CCTCCACCGCCAAGTGCCTGAACATCTGGGCCCTGATTTTGGGCATCTTCATGACCATTCTGCTCAT CATCATCCCAGTGTTGATCTTCCAAGCCTATCAATAGATCAGGAGGCATC-ATTGAGGCCAG ORE Start: AIG at 41 ~OFStop: TAG at 43 7 ______SEQIDNO:56 _ 1___t32aa JMWat14709.lkD_ NOV5b, IMNITVQTFSPINSQPPNYEMLKEEHEVAVLGVAYNPAPPTSTVIHIRNETSVPDHVVWSLFNTLFM CGI 58564-01 NPCCLGFIAFAYSVKSRHRKMVGDLTGAQAYASTACLNIWALILGIFMTILLIIIPVLIFQAYQ Protein Sequence j Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 5B. 5 Table 5B. Comparison of NOV5a. against NOV5b. Prten eqeneNOY~a Residues! Identities/ Protin equnceMatch Residues Similarities for the Matched Region NOV5b L1.132 132/132 (100%) L.132 132/132 (100%/,) Further analysis of the NOV5a protein yielded the following properties shown in Table 5C. Table 5C. Protein Sequence Properties NOV5a SignalP No Known Signal Sequence Predicted analysis: 134 WO 03/050245 PCT/USO2/38594 PSORT II PSG: a new signal peptide prediction method analysis: N-region: length 0; pos.chg 0; neg.chg 0 H-region: length 19; peak value 4.24 PSG score: -0.16 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -9.01 possible cleavage site: between 13 and 14 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 2 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood =-13.80 Transmembrane 111 - 127 PERIPHERAL Likelihood = 6.79 (at 29) ALOM score: -13.80 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 118 Charge difference: 0.0 C( 0.0) - N( 0.0) N >= C: N-terminal side will be inside >>> Single TMS is located near the C-terminus >>> membrane topology: type Nt (cytoplasmic tail 1 to 110) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 4.44 Hyd Moment(95): 8.97 G content: 1 D/E content: 1 S/T content: 4 Score: -4.16 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: RHRK (3) at 84 pat7: none bipartite: none content of basic residues: 5.3% NLS Score: -0.29 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail 135 WO 03/050245 PCT/USO2/38594 Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: Leucine zipper pattern (PS00029): *** found *** LNIWALILGIFMTILLIIIPVL at 105 none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 26.1 %: nuclear 21.7 %: cytoplasmic 17.4 %: Golgi 8.7 %: mitochondrial 8.7 %: vesicles of secretory system 8.7 %: endoplasmic reticulum 4.3 %: extracellular, including cell wall 4.3 %: peroxisomal >> prediction for CG158564-02 is nuc (k=23) A search of the NOV5a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 5D. 5 Table 5D. Geneseq Results for NOV5a NOV5a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region ABP43105 Human ovarian antigen 1..131 122/132 (92%) 3e-67 HVCBB19, SEQ ID NO:4237 11..142 127/132 (95%) - Homo sapiens, 143 aa. [WO200200677-A1, 03-JAN-2002] AAE13797 Human lung tumour-specific 1..131 122/132 (92%) 3e-67 protein SALT-T8 - Homo 1..132 127/132 (95%) sapiens, 133 aa. [WO200172295-A2, 04-OCT-2001] AAB44456 04___T-2001_ 3e-67 S.... .... 136 136 WO 03/050245 PCT/USO2/38594 antigen encoded by cDNA 1..132 127/132 (95%) #71 - Homo sapiens, 133 aa. [WO200060077-A2, 12-OCT-2000] AAY29544 Human lung tumour protein 1..131 122/132 (92%) 3e-67 SALT-T8 predicted amino 1..132 127/132 (95%) acid sequence - Homo sapiens, 133 aa. [WO9938973-A2, 05-AUG-1999] AAY93594 Protein encoded by I-8U gene 1..131 121/132 (91%) 3e-66 from interferon-inducible 1..132 127/132 (95%) gene family - Homo sapiens, 133 aa. [WO200035473-A2, 22-JUN-2000] In a BLAST search of public sequence datbases, the NOV5a protein was found to have homology to the proteins shown in the BLASTP data in Table SE. Table SE. Public BLASTP Results for NOV5a NOV5a Identities/ Protein Residues/ Similarities for Expect Accession Protein/Organism/Length Match the Matched Value Number Residues Portion Q01628 Interferon-induced 1..131 122/132 (92%) 9e-67 transmembrane protein 3 1..132 127/132 (95%) (Interferon-inducible protein 1-8U) - Homo sapiens (Human), 133 aa. S17182 interferon-induced protein 1..131 121/132 (91%) 8e-66 1-8U - human, 133 aa. 1..132 127/132 (95%) Q01629 Interferon-induced 1..130 116/130 (89%) 8e-64 transmembrane protein 2 1..130 123/130 (94%) (Interferon-inducible protein 1-8D) - Homo sapiens (Human), 132 aa. Q95MQ3 Interferon-induced protein 1..123 83/124 (66%) 4e-43 1-8U - Bos taurus (Bovine), 1..124 104/124 (82%) 146 aa. JC1241 beta-interferon-induced 1..127 85/128 (66%) le-42 protein - rat, 137 aa. 1..128 101/128 (78%) 5 PFam analysis predicts that the NOV5a protein contains the domains shown in the Table SF. 137 WO 03/050245 PCT/USO2/38594 [Table 5F. Domain Analysis of Va Identities/ Pfam Domain NOV5a Match Region Similarities Expc au for the MatchedxpcVau Region No Significant Matches Found Example 6. The NOVW clone was analyzed, and the nucleotide and encoded polypeptide 5 sequences are shown in Table 6A. Table 6A. NOW6 Sequence Analysis SEQ ID NO: 57_ _1488 bp NOV6a, ATCTGTGGGGATTCTCACAACTTCCATTTCTGGTGA1ACAGCTGAGGTCAGAGGGAGTTGGTCCAGGC CG1 59093-01 GCATGTTCAGGTATTGAGC-AAATCACAAG-AATTGTAGTTAAGGAGATCGATGCTrAGmQGATAT diTTGCCGTTAGAAGCCTTGTTGATGCTGATAGATTCCGCTGCTTCCATCTGGTGQGGCAGAAcGAA DNA Sequence CTTTCTTTGGATGCCGGCACTACACAAAGGCCTCACCCTGATGGACATTCTGGACACAGATGGGAC AAGTGGTTAGATG.AACTGGATTCTGGGCTCCAAGGTCAAAGGCTGAGTTTCAXATTCJTGGATAATGT AGACTCAACGGGAGAGTTGATAGTGAGATTACCAAAGAATAACAATTTCAGGCAGTTTCCAGccCT TCCACC-ATCAGAAAATCAAGATATCGGAGAACCGGATATCCCAGCAGTATCTGGCTACCCTTGAAAAC AGGAAGCTGAAGAGGG-AACTACCCTTTTCATTCCGATCAATTAArACGAGAGAAAACCTGTATCTGGT (GACAGAAACTCTOcGAACGGTAACGAGAAACCCTGAAGCGACCGGCAATATAAATTTTGGACC .XGATCTCTCAGGcCCATCTCAGCTATAAAC-ACAALGGGCCAAGGGAAGTGACCATCCCCCCAAATCG GTCCTGAGCTATCGAGTAAGCAGCTTGTCTTCCCCACAAGGAGACGATGGGAATCTTTGGGTTC GAGATTCCAGAAACATGAGGAGA\GTTGGAGGACATGGAGAGTGTCCTCALAGGACCTGACAGAGG AGAAGAGAAAOCATGTGCTAAACTCCCTCGCTAAGTGCCTCGGCAAGGAGGATATTCGGCAGGATCTA GAGCAAAGAGTATCTGAGGTCCTGATTTCCAGGGAGCTACACATGGAGGACTCAGACAAGCCTCTCCT AAGCAGCCTTTTTAATGCTGCTGGGGTCTTGTAGAAGCGCGTGCAAAAGCCATTCTGQACTTCCTCG ATCCCCTGCTAGAGCTGTCTGAIAGCAGCATTTGTGCTGAGCCCTGGAGAAGGGGACCCTTCCT CTGTFTGAAGGACC-AGGTGATCTGTCATGGAGCAGAACTEGGGATGAGCTGGCCAGCAGTCCTCCTGA CATGGACTATGACCCTGAGGCACGAATTCTCTGTGCGCTGTATGTTCTTGTCTCTATCCTGCTGGAGC TGGCTGAGGGGCCTACCTCTGTCTCTTCCTAACT~ACACCCTTTCTCCCCACAACCCTCTGGGTT TTCCCTTTACCAGTCTGTCCTCACTGCCATCGCCACTACCATCCTGTCACCAGTGGGACCTCTTTAAA ACAAGCACCWCCATTCTTTqTGTATCCCATTCGCTCCATGTTAAJCATCCAACCAGCCTGGATT TCATACATGGACTTCTGATTGGGCACGTTGTCATGTTAAAAAAAA ORF Start: ATG at 72 jOFtp: TAA at 1254 ________ SEQ ID NO: 59 _ 394 aMW a45002.8kD NOV6a, MF'SVFEEITIVVKEMDAGGDMIAVRSLVDADRFRCFRILVGEKRTFFGCRiYTTGLTLMDILDTDGDK CG1 59093-01 IWLDLDSGrQGQAEFQILDNVDSTGELIVRLPKETISSFQGHQKTKI SENRISQQYLATLENP KRELPFSFRSINTRNLYLVTETLETVEETLKSDRQYKFWSQISQGHLSYYJIKGQREVTIPPNRV Protein ~ LS YRVKQLVFPNETMG1SGSEDRMKEKLEDMESVLLTEEDVLNSLAKCLGKEDIRQDLE Sequence QRVSEVLISRELMEDSDKPLLSSLFNAGVLVEAILDFLDALELSEEQQFVAEAE(GTLPL __________LKDQVKSVMEQNWDELASSPDMDYDPARILCALYVVVSILLEAEGPTSVSS jSEQ ID NO: 59 43bp NOV6b, ATCTGTGGGGATTCTCACA-CTTCCATTTCTGGTGAGCTGAGTCAGAGAGAGTTGGTCCAGG CG1 59093 -02 CGCATGTTCAGCOTATTTGAGGAIACACAAGATGTAGTTAGGAATGATGCTGGAGGGGAT ATGATTGCCGTTAGAAGCCTTGTTGATGCTGATAGATTCCGCTGCTTCCATCTGTGGGGAGAJGA DNA Sequence GAACTTTCTTTGGATGCCGaCACTACACAACAGCQCCTcACCCTr.ATGGACATTCTGGACAcAGATCG GGCATGTGTACCATTGCCAGTAAGCGGTCATCGA AATGTAGACTCAACGGGAGAGTTGATAGTGAGATTACGATAACATTTCAGGCAGTTTCC AGGGCTTCCACCATC!AGAAATCAAGATATCGAGXACCGGATATCCCAGCAGTATCTGGCTACCCT 138 WO 03/050245 PCT/USO2/38594 TTTGGAGCCAGATCTCTCAGGGCCATCTCAGCTATAAACACAGCAGAAGGATGGTGCTTCATCCTG TTTAGGAAAGTCTTTGGGTTCGGAGGATTCCAGAAACATGAAGGAGAAGTTGGAGGAATGGAGAGT GTCCTCAAGGACCTGACAGAGGAGAAGAGAAAAATGTGCTAAACTCCCTCGCTAGTGCCTCGGA AGGAGGATATTCGGCAGGATCTAGAGCAGAGTATCTGAGGTCCTGATTTGGAGCTACCA GCQAGGACTCAGACAAGCCTCTCCTAAGCAGCCTTTTTAATGCTGCTGGGGTCTTGGTAGAAGCGCGT GCAAAAGCCATTCTGGACTTCCTGGATGCCCTGCTAGAGCTGTCTGAGAGAGCGTTTGTGGCTG AGCCGAAGGACTCTTTGAGACGTAACGCLGACGAT GGATGAGCTCGCCAGCATCCTCCTGCATGGACTATGACCCTGAGGCACGATTCTCTGTGCGCTG TATGTTQTTGTCTCTATCCTGCTGGACTGCTGAGGCCTACCTCTGTCTCTTCCTACTAA.A AGCCCTTTCTCCCCCAAGCCTCTGGGTTTTCCCTTTACCAGTCTGTCCTACTCATCGCCACTA CCATCCTGTCACCAGTGACCTCTTTAAAACAAGCAGCCAACCATTCTTTGATGTATCCATTCG-C TCCATGTTAACATCCAAACCAGCCTGGATTTCATACATGACTCTGATTAGTGGAGTTGT GCATGTTA-AAAkAA _______ORF Start: ATG at 72 OR Stop: TAA at 1197 ________SEQ ID NO: 60 1375 aa JMW at 42609.9kD NOV6b, MFSVFEEITRIVWKEMDAGGDMIAVRSLVDADRFRCFHLVGEKRTFFGCRHYTTGLTLMDILDTDGD CG1 59093-02 KWLDELDSGLQcGQKAEFQIILDNVDSTGELIVRLPKEI TfSGSFQGFHHQKIYI SENRISQQYLATLE NRK]M(RELPFSFRSINTRENLYLVTETLETVKEETLKSDRQYKFWSQI SQGHLSYKHKKKDGASSCL Protein jGKSLGSEDSR NKEKLEDtESVLKDLTEEKRKDVILNSLACLGKEDIRQDLEQRVSEVLISRELuME Sequence 1 DSDKPLLSSLFNA.AGVLVEARAKAILDFLDALLELSEEQQFVAELEKGTLPLLKDQVKSVMEQNWD ELASSPPDMDYDPEARILCALYVVVSILLELAEGPTSVSS _______ SEQ ID NO: 61 1401 bp NOV~c, ATCTGTGGGGATTCTCACAAC!TTCCATTTCTGGTGAACGCTGAGGTCAGAGAGTTGTCCGGC NG15993c 0 OCAATGTTCAGCTATTTAGGAATCACAAGATTGTAGTTAAGGAGATGATGCTGAGGGGATAT GG1599303GATTGCCGTTAGAGCCTTGTTGATGCTGATAGATTCCGCTGCTTCCATCTGTGGGGAAGAGAA DNA Sequence CTTTCTTTGGATGCCGGCACTACACAACAGGCCTCACCCTGATGGACATTCTGACGATGGAC TCCACCATCAGAAAATCA.AGATATCGGAGAACCGGATATCCCAGCAGTATCTGGCTACCCTTGAAAAC AGGAAGCTAAAGGACTACCCTTTTCATTCCATCAATTAATACGAAAAACCTGTATCTGGT GACAGAAACTCTGGAGACGGTAAAGGAGGAAACCCTGAAAAGCACCCTATATTTTGAGCC AGATCTCTC-AGGGCcATCTCAGCTATAAACACA-AGAAGTCTTTGGGTTCGGAATTCAGAACTc AAGCAGAAGTTGGAGGACATGGAGAGTGTCCTCAAGGACCTGACAGAGGAGAAGAGAAAAGATGTGCT AAACTCCCTCGCTAAGTGCCTCCGCAAGGAGGATATTCGGCGGATCTAGAGACGTATCTCGG TCCTGATTTCAGGGAGCTACACATGGAGGACTCAGACAAGCCTCTCCTAAGCAGCCTTTTTATGCT GCTGGGGTCTTGGTAGAAGCGCGTGCAAAAGCCATTCTGGACTTCCTGGATGCCCTG.CTAGAGCTGTC TGAACGATTTGTAGCTGGAGGACCTCCGTAGACAGG AATCTGTCATGGAGCAGAACTGGGATGAGCTGGCCAGCAGTCCTCCTGACATGGACTATGACCCTGAn GCACGAATTCTCTGTGCGCTGTATQTTGTTGTCTCTATCCTGCTGGAGCTGGCTGAGGGGCCTACCTC TGTCTCTTCCTAACTACAAGCCCTTTCTCCCCACAGCCTCTGGGTTTTCCCTTTACCGTCTGTC CTATCACCATCACTTACGTGACCTAACACCCACTC TTGATGTATCCCATTCGCTCCATGTTACATCCAAAACCAGCCTGGATTTCATACATGGACTTCTGAT ORE Start: ATO at 72 ORE Stop -TAA at1167 _______SEQ ID NO: 62 365 aa. JMW at 41662.9kD NOV6c, MSVFEEITRIVVKEMDAGGDMIAVRSLVIDAnRFRCFHLVGEKRTFFGCRHYTTGLTLMDILDTDGDK CG1 59093-03 WLDELDSGLQGQAEFQIDNVDSTGELIVRLPITISGSFQGFHHRIKISERISQQYATLENR KLRLPFSFRSITRELYLVTETLETVKEETL(SDRQYKFWSQISQGHLSYKHKKSLaSEDSRMK Protein EKLEDMESVLKDLTEEIKRKDVLNSLAIKCLGIKEDIRQDLEQRVSEVLI SRELHMEDSDKPLLSSLFNAP Sequence rVLVEARAAIDFDALLELSEEQQFVAAEKGTLPLLKDQV5VMEQNWDELASPPDM~DYDPEA RILCALYVVVSILLELAEGPTSVSS Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 6B. Table 6B. Comparison of NOV6a against NOV6b and NOV6c. NOV6a Residues! Identities/ Proei SeueceMatch Residues Similarities for the Matched Region 139 WO 03/050245 PCT/USO2/38594 NOV6b 1.394 366/394 (92%) 1.375 369/394 (92%) NOV6c 1..394 365/394 (92%) 1..365 365/394 (92%) Further analysis of the NOV6a protein yielded the following properties shown in Table 6C. Table 6C. Protein Sequence Properties NOV6a SignalP No Known Signal Sequence Predicted analysis: PSORTII PSG: a new signal peptide prediction method analysis: N-region: length 10; pos.chg 1; neg.chg 2 H-region: length 3; peak value 0.00 PSG score: -4'40 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -9.00 possible cleavage site: between 31 and 32 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -5.68 Transmembrane 371 - 387 PERIPHERAL Likelihood = 3.50 (at 297) ALOM score: -5.68 (number of TMSS: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 378 Charge difference: 1.0 C(-2.0) - N(-3.0) C > N: C-terminal side will be inside >>> Single TMS is located near the C-terminus >>> membrane topology: type Nt (cytoplasmic tail 1 to 370) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 6.38 Hyd Moment(95): 9.01 G content: 0 D/E content: 2 S/T content: 1 Score: -6.37 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 13.2% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none 140 WO 03/050245 PCT/USO2/38594 SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: found LL at 293 LL at 319 LL at 340 checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 76.7 COIL: Lupas's algorithm to detect coiled-coil regions 221 K 0.91 222 S 0.91 223 L 0.95 224 G 0.99 225 S 0.99 226 E 0.99 227 D 0.99 228 S 0.99 229 R 0.99 230 N 0.99 231 M 0.99 232 K 0.99 233 E 0.99 234 K 0.99 235 L 0.99 236 E 0.99 237 D 0.99 238 M 0.99 239 E 0.99 240 S 0.99 241 V 0.99 242 L 0.99 243 K 0.99 244 D 0.99 245 L 0.99 246 T 0.99 247 E 0.99 248 E 0.99 249 K 0.99 250 R 0.99 251 K 0.99 141 WO 03/050245 PCT/USO2/38594 252 D 0.99 253 V 0.98 254 L 0.92 255 N 0.92 256 S 0.92 257 L 0.75 258 A 0.68 total: 38 residues Final Results (k = 9/23): 26.1 %: cytoplasmic 26.1 %: nuclear 13.0 %: Golgi 13.0 %: endoplasmic reticulum 8.7 %: mitochondrial 8.7 %: vesicles of secretory system 4.3 %: peroxisomal >> prediction for CG159093-01 is cyt (k=23) A search of the NOV6a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 6D. 5 Table 6D. Geneseq Results for NOV6a NOV6a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region ABB97522 Novel human protein SEQ ID 1..394 392/403 (97%) 0.0 NO: 790 - Homo sapiens, 403 1..403 392/403 (97%) aa. [WO200222660-A2, 21-MAR-2002] ABB90047 Human polypeptide SEQ ID 205..394 176/195 (90%) 6e-91 NO 2423 - Homo sapiens, 3..197 181/195 (92%) 197 aa. [WO200190304-A2, 29-NOV-2001] AAO17132 Human cancer cell growth 232..394 161/163 (98%) 9e-84 inhibitor related protein SEQ 1..163 161/163 (98%) ID NO: 8 - Unidentified, 163 aa. [CN1324819-A, 05-DEC-2001] AAB93904 Human protein sequence SEQ 1..389 120/497 (24%) 3e-14 ID NO:13862- Homo 1..483 204/497 (40%) sapiens, 484 aa. [EP1074617-A2, 07-FEB-2001] ABB90142 le-13 142 WO 03/050245 PCT/USO2/38594 NO 2518 - Homo sapiens, 1.427 187/441 (42%) 478 aa. [WO200190304-A2, 29-NOV-2001] In a BLAST search of public sequence datbases, the NOV6a protein was found to have homology to the proteins shown in the BLASTP data in Table 6E. Table 6E. Public BLASTP Results for NOV6a Protein NOV6a Identities/ P en Residues/ Similarities for Expect Accession Protein/Organism/Length Match the Matched Value Number Residues Portion Q9NX71 Hypothetical protein 1..394 394/403 (97%) 0.0 FLJ20402 - Homo sapiens 1..403 394/403 (97%) (Human), 403 aa. Q9P163 PRO2521 - Homo sapiens 1..394 390/394 (98%) 0.0 (Human), 394 aa. 1.394 390/394 (98%) Q8TAX9 Similar to hypothetical 1..394 394/411 (95%) 0.0 protein PRO2521 - Homo 1..411 394/411 (95%) sapiens (Human), 411 aa. CAD35038 Sequence 346 from Patent 1..394 392/403 (97%) 0.0 W00222660 - Homo sapiens 1..403 392/403 (97%) (Human), 403 aa. Q8WY76 PP4052 - Homo sapiens 232..394 161/163 (98%) 3e-83 (Human), 163 aa. 1..163 161/163 (98%) 5 PFam analysis predicts that the NOV6a protein contains the domains shown in the Table 6F. Table 6F. Domain Analysis of NOV6a Identities/ Similarities Pfam Domain NOV6a Match Region for the Matched Expect Value for the Matched IRegion 10 Example 7. The NOV7 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 7A. 143 WO 03/050245 PCT/USO2/38594 ITable 7A. NOV7 Sequence Analysis NOV7a, CCGATCCACGGGGCCCGCCCCCCGCAGG;CACTTC CG1 59390-01 CAGTGCGCTGGGGCCCTGCGCTGGGGGTGACCGGACCTGGGTCOCGGGCCCCCGTGGGAGCCCA GGCGCGCCAGGGTCCCC!ATCCACGAGCAGGTCGACCCCCCGCGAGAGGGCCTCAGCAGTGGCCCCTTC DNA Sequence CCTCCACGGGCTGCCCCGGAGCTCAGTCCCACCCCCTCCGCCGATGAGGCCATGAGGACCGACGGA CCTGGGCCAGAACCTCCTGCTCTTCCTGTGGGCCCTGCTGAACTGTGGTTTGGGGTAGTGCTCAGG GTCCGGG.CGAGTGciACCCCnTGGGTGTCCTrGGACCCGCTGCTCCAGCTCCTGCGGGCGTGGCGTCTCT GTCCGCGGTCTCGTCTOGAGACTCGGAATCAGGAC CCTCTGCAGTTGCCAGACTGCCCCCCAGGGGCTGTGCCCTTCCGAGACCTACIAGTGTCCCCTGTACA ATGGCCGCCCTGTCCTGHGGCACCCAGAGACCTACCAGTGGGTGCCCTTCCATGGGGCGCCCAACCAG TGCGACCTCAACTGCCTGGCTGAGGGGCACGCCTTCTACCACACTTCGCCGCGTCCTGACGGC CGCCTGCAGCCCGGGTGCCCAGGGGGTCTGCGTGGCTGGCCGCTGCCTTACCGCCGGCTGTCATGGGT TGTTGGGCTCGGGTGCCCTCnAGACCGCTGTGGCCGCTGCGGAGGCGCCAACGACTCGTGCCTTTTrC GTGCAGCGCGTGTTTCGTGACGCCGGTGCCTTCGCTGGTACTGGACGTGACCCTGATCCCCGAGGG CGCCAGACACATCCGCGTGGACACAGGAGCCGCAACCACCTGGGTATCCTAGATCTGATGcGG GCGATGGGCGCTACGTGCTTAATGGCACTGGGTGGTCAGCCCACCAGGGACCTACGAGGCGGCCGGC ACGCATGTCGTCTACACCCGAGACACAGGGCCCCAGAGACATTGCAGCCGGCCCACCTCCCA TGCTCCTCGTCCTCGACCACCGCTGGTGGTTGTCT GGGAGCGCTACAGCCCCTTCCAGGCTCGTGTGCAGGCCCTGGGCTGGCCCCTGAGGCAGCCTCAGCCC COGGGGCGTCOAGCCCAGCCCCCCGCAGCCCCTGCTGTCACCCCTGCAAGACCCACGCTGGCCCC AGTGTTCCGGCCCGAGTGCTGGGCCACCACCACCAGGCCCAGACCCGCTATGAGGTGCGCATCC AQCTCGTCTACAAGAACCGCTCGCCACTGCGGGCACGCGAGTACGTGTGGGCGCCAGGCCACTGCCCC TGCCCGATGCTA-CCCCACCGGACTACCTGATGGCTGCCAGCGTCTTGTCAGCCCCGACGGC ACGACGTCGTCCAGCGTCGCGCCGACCGGAGCGCC TACGCCTGACTGCCCGGCGCTGTCCTGGCTGAGCCCCTGCAGG ____ ___ _______ ORF Start: ATG at 7 1 ORF Stop: IGA at 1594 ________ SEQ ID NO: 64 1529 aa IM at 57778.9kD NOV7a, MRQLGGSLRPPRAAGAEPLPSALGPCAGGDRDLGRGTPGWEPRRARVPIHEQVflPPREGLSSGPFPP CG1 59390-01 RAAPELSPTPSADEAMRRTDL~GQNLLLFLWALLNCGLGVSAQGPGEWTPWVSWTRCSSCGRGVSVR SRRCLRLPGEEPCWGDSHEYRLCQLPDCPPGAVPFRDLQCALYNGRPVLGTQKTYQWVPFHGAPNQCD Protein LNCLAEGAFYHSGRVLDGTACSPGAQGVCVAGRCLSAGDGLLGSGLEDRCGRCGANSCLFVQ Sequence RVFRDAGAFAGYWNVTLI PEGARHIRVHS1HLGILGSLMGGDGRYLVLNGHWVVSPPGTYEAAGTH VVYTRDTGPQETLQAAGPTSHDLLLQVLLQEPNPGIEFEFWLPRE.YSPFQARVQALGWPLRQPQPRG VEPQPPAAPAVTPAQTPTLAPVFQARVLGHHQAQETRYEVRQL~VYKNRSPLRAREYVWAPGHCPCP J.MLAPURDYLMAVQRLVSPDGTQDQLLLPBAGYARPWS PAEDSRIRLTARRCPG Further analysis of the NOV7a protein yielded the following properties shown in 5 Table 7B. FTable 7B. Protein Sequence Properties NOV7a SignaiP No Known Signal Sequence Predicted analysis: PSORT Il PSG: a new signal peptide prediction method anayss:N-region: length 9; pos-chg 2; neg.chg 0 analsis:H-region: length 2; peak value -5.17 PSG score: -9.57 GvU:- von Heijoe's method for signal seq. recognition GvH score (threshold: -2.1): -6.80 possible cleavage site: between 29 and 30 >>> Seems to have no N-terminal signal peptide, AILOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of rMS(s) for the threshold 0.5: 1 144 WO 03/050245 PCT/USO2/38594 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -3.61 Transmembrane 94 - 110 PERIPHERAL Likelihood = 3-39 (at 233) ALOM score: -3.61 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 101 Charge difference: 0.5 C( 0.0) - N(-0.5) C > N: C-terminal side will be inside >>> membrane topology: type lb (cytoplasmic tail 94 to 529) MITDISC: discrimination of mitochondrial targeting seq R content: 3 Hyd Moment(75): 7.96 Hyd Moment(95): 9.93 G content: 3 D/E content: 1 S/T content: 1 Score: -2.68 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 22 PRALAH NUCDISC: discrimination of nuclear localization signals pat4: none pat7: PRRARVP (5) at 43 bipartite: none content of basic residues: 10.0% NLS Score: -0.04 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: RQLG none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: found LL at 94 LL at 95 LL at 101 LL at 248 LL at 363 LL at 364 checking 63 PROSITE DNA binding motifs: Myb DNA-binding domain repeat signature 1 (PS00037): *** found WSPAEDSRI at 512 145 WO 03/050245 PCT/USO2/38594 checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 55.5 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 39.1 %: nuclear 21.7 %: mitochondrial 17.4 %: cytoplasmic 8.7 %: vesicles of secretory system 4.3 %: vacuolar 4.3 %: endoplasmic reticulum 4.3 %: peroxisomal >> prediction for CG159390-01 is nuc (k=23) A search of the NOV7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 7C. 5 Table 7C. Geneseq Results for NOV7a NOV7a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region SABB80573 Human sbg98530TS protein 1..529 499/529 (94%) 0.0 #1 - Homo sapiens, 502 aa. 1..502 499/529 (94%) [WO200222802-A1, 21-MAR-2002] AAU74754 Human protease PRTS-14 84..529 446/470 (94%) 0.0 protein sequence - Homo 1..470 446/470 (94%) sapiens, 470 aa. [WO200198468-A2, 27-DEC-2001] ABB80574 Human sbg98530TS protein 87..529 440/443 (99%) 0.0 #2 - Homo sapiens, 451 aa. 9..451 440/443 (99%) [WO200222802-A1, 21-MAR-2002] 146 WO 03/050245 PCT/USO2/38594 AAB72282 Human ADAMTS-6 amino 114..386 113/280 (40%) 2e-52 acid sequence - Homo 511..784 149/280 (52%) sapiens, 859 aa. [WO200111074-A2, 15-FEB-2001] ABG76897 Human ADAM-TS 7-like 114..420 117/315 (37%) 3e-52 protein #2 - Homo sapiens, 624..910 162/315 (51%) 952 aa. [WO200233087-A2, 25-APR-2002] In a BLAST search of public sequence datbases, the NOV7a protein was found to have homology to the proteins shown in the BLASTP data in Table 7D. Table 7D. Public BLASTP Results for NOV7a Protein NOV7a Identities/ Accession Protein/Organis/Length Residues/ Similarities for Expect Accession Prote/Organism/Length Match the Matched Value Number Residues Portion Q9CRC7 2010109HO9Rik protein - 94..279 157/186 (84%) le-98 Mus musculus (Mouse), 244 27..212 167/186 (89%) aa. Q8JZY8 Similar to RIKEN cDNA 94..278 156/185 (84%) 5e-98 2010109H09 gene - Mus 27..211 166/185 (89%) musculus (Mouse), 215 aa. 095428 Hypothetical protein - Homo 94..389 123/309 (39%) 6e-55 sapiens (Human), 1235 aa. 3..304 162/309 (51%) Q9EPX2 Papilin - Mus musculus 116..383 111/277 (40%) 2e-52 (Mouse), 1280 aa. 30..299 147/277 (52%) Q9UKP5 ADAMTS-6 precursor (EC 114..386 113/280 (40%) 5e-52 3.4.24.-) (A disintegrin and 511.784 149/280 (52%) metalloproteinase with thrombospondin motifs 6) (ADAM-TS 6) (ADAM-TS6) - Homo sapiens (Human), 860 aa. 5 PFam analysis predicts that the NOV7a protein contains the domains shown in the Table 7E. Table 7E. Domain Analysis of NOV7a Identities/ Pfam Domain NOV7a Match Region Similarities Expect Value for the Matched Region 147 WO 03/050245 PCT/USO2/38594 tspl 117..164 19154 (35%) 9.5 e-08 32/54 (59%) Example 8. The NOV8 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 8A. 5 Table 8A. NOV8 Sequence Analysis ________SEQ ID NO: 65 _ __tI28 bp NOV8a, GGAATTCGCGGCAAGATGGCGACCGTGGCGCCGTGGGTGAAGCCGCAGCTGTTGGAGCGTCTCCTGC CG1949-01ATCTGTCCCTGGCCTAAACCCGACGCTAGGCTGGAGGGAGCGACTGCGGGCCGGGCTGGCGGGGACTG CG1 949-01 GGGCCTCGTTGTCGTTCGTGCCGGGGCTGGGQCTGCTTTACCCCTGAGGATCCCTTTGAGGCTGTGT DNA Sequence GAGAATTTGGCAGCGGTGACTGTATTTTTAAATTCTTGCACCCATTCTAGTGCCTTACAGG GACCTCTTCATTGATATCAGGACTAATATTTATATTTGATGGTGGTACTTCCATCAGCCT CTTTTATTCAGCAAGTATCTGTAGCCATTTGCAACCACTnATGGGAGGAACAGAGAGCAGATTTCA GAACCAGGTTCTCCTTCGAGGAACAGAGAAAATGAACCAGCAGAAGAATTTGTCAGATGTAAGGT ATGAGAA4CCCTCTAAATCTTTTCAGAGGAGCAGAATATAGGAGATACACTTGGGTGACTGGTAA AGCCACTTACATACTATGACATGAACCTGTCAGCTCAGGACCATCAGACCTTTTTCCCTGTGACAC GATTTTTTACGTCCTTCAGACACAGTTATGCAGAAGGCTTGGAaGAAAGAAATCCTCCAGCTCGAAkT CAAAGCAGCCTATCAAGCTTTAGAATTAAACAATGACTGTGCCACTGCATATGTTCTACTGGCTGAGG AGAAGCAACAACTATTGTAGATGCTGAAAGTTATTTAAACAGGCACTCAAGGCAGGAGAAACAATT TAACATAACGGCrCCAATCCGAGACCATAGGGTCA TGTACTGGTATATATTAAAGAAGATTGGCAATGTGTGCAAGAAAATTAGGAAGAATAAGAGAAGCAG TAAAAATAATGAGAGATTTGATGAATnAATTTCCTCCTCTTACCATGTTGAACATCC-ATGAAAALTCTC TTAcAATCACTTTTAAATTACAGGCCTATCCAGATGTTCAGCAGTCCTAGCAAAALTATGATGATAT

AAGCCTTCCAAGTCAGCAGCAATCTGTTACACAGCAGCACTGTTGAAGAGGACTGTTTAQA

AATTCTCTCCA2AAACAGCCTCCACAAGAGGATTAAGCGCAGCAGAAATTAATGCCGTGGATGCAATT CATAGAGCTGTCGAATTTAATCCTCATGTTCCAAATATTTATTAGAGATGAALATTTAATTTTACC TCCAGAACAATTCTGAACGGGGTGATAGTGAAGAATTCCTATGCTTCTTTATCTTAGCCT GGAAACGAATAGAAGGTGCTCTTAATCTGTTAAGTGTAATGGAGGAGTTTTAGATGTTCCA TACCCGTTAGAGAAGGACATCTATTTTACCCTTATCCCACTGCACAGACGCTGATAGAGCT ATTACCTAGTTTTCATCATGTTTCTGTTTACCCAAAAAGGACTTCCTTTTTCATCATTTCACAG CGGATTTTGCTCTTCTACAGCAATGATAGCCATTCTCACTCACCAGTTTCCTAAATCATGGGTATT TTTGCTAAAGCTGTAAGTATGATCTCAAGACTTGTTAGATTATTTGTAAAACCGACAT CTCTGATCTGCCTGTGCTAACCCACTGAACAATGAAATATTTGTTGTAATTAAGGATTGATT TGTATATAGTTGCTGCCATAAATACATCAAACATAAATTTTTGGTGATTTGAGCTACTTCTGTTGCTT AAAGTTTAAAGATACAATATAAGATTGTACAATATACATTATAAAGTTTGCTCTTATAGATC ORF Start: ATG at 16 JORF Stop: TAAat 1681 _______ SEQID NO:_66 1 555 aa ------ MW at 62572.2kD NOV8a, MADRGGVGEAAAVGASPASVPGLNPTLGWRERLRAGLATGSLWFVAGLGLLYALRIPLRLCMAAA CGI 949-01 VTVFLNSLTPK FYVALTGTSSLISGLI FlFEWWYFHKHGTSFIEQVSVSHLQPLMGGTESS ISEPGSP SRRENETSRQNLSECKVWRNPLNLFRGAEYRRYalhVTGKEPLTYYDMNLSAQDHQTFFTCDTDr RP Protein SDTVMQKAWRE1UNPPARI KAAYQALELUNDCATAYVLLAEEEATTIVDAERLFKQIALCAGETTYRQSQ Sequence QCQHQSPQHEAQLRRflTNVLVYIlQRRLAMC-ARKLGRIREAVKIMRDLMNEFPPLTN1LNIHENLLESLL ELQAYPDVQAVLAKYDDISLPKSAAICYTAALLKTRTVSEKFSPETASTRGLSAAEINAVDAIHRAVE FNPHPKYLLMKSLILPEHLKRGDSEAIAYAFFHLQHWKRIEGALhNLLQCTWEGSFRMIPYPLEK GI{LFYPYPS CTETADRELLPSFI4HVSVYPKKELPLFIHFTAGFCS STAMIAILTHQFPEIMGIFAKAV SMSRTCVDYL ______ ________SEQ ID NO: 67 178b NOV8b, TACTATCCCAGGATTCCCGACTCCCGGTTTCCTGTCCTTCTCCCCTCCCAGCTCCTGGCGCCTQCGAT CG159498-02 I AGCGGCAAGATGeCGACCGTG CGTGGTGAAGCCGCAGCTGTTGGAGCGTCTCCTGCATCTG TCCCTGGCCTAAACCCcACGCTAGOCTGGAGGGAGCGACTGCccccGGGCTGGCcGGCACTGGGGC DNA Sequence CTCGTTGTGGTTCGTGGCGGGGCTGGGGCTGCTTTACGCCCTGAGGATCCCTTTGAGGCTGTGTGAG 1AATTTnGCAGCCGTGACTGTATTTTTAAATTCATTGACACCCAAATTCTATGTGCACTTACAGGGA CCTCTTCATTGATATCGGACTAATATTTATATTTGATGGTGGTACTTCCATAOTGGACTC TTTTATTGAGCA AGTATCTGTA AGCCATTTCAACCACTGATGGGAGGAACAGAGAGCAGCATTT SA 148 WO 03/050245 PCT/USO2/38594 GAACCAGGTTCTCCTTCGAGGAACAGAGAAATGAAACCAGAGACAGAATTTGTCAGAATGTAAGG TATGGAGAAACCCTCTAATCTTTTCA AAGCAGAATATAGATAACTTGGTGACTGGTAA AGGCCACTTACATACTATGACATGAACCTGTCAGCTCAGGACATCGACCTTTTTCCCTGTGAC ACAGATTTTTTACGTCCTTCAGACACAGTTATGCAGAAGGCTTGGAGGGAAAGAAATCCTCCAGCTC GAATCAAAGCAGCCTATCAAGCTTTAGAATTAACATGACTGTGCACTGCTATGTTCTACTGGC TcAGuGAAGAAGCAACAACTATTGTAGATGCTGAAAGGTTATTTAAACAGGCACTCAAGGCAGGAA ACAATTTATAGGCAGTCACACAGTGCCACACCAAGTCCTCAGCATGACTCACTGAG~GAG ATCATTCGTTTTAAGAATGATTTCAAATAGAATA AGAAGCAGTAAAATAATGAGAGATTTGATGAAGAATTTCCTCCTCTTACCGTTACTCCAT ATGATGATATAGCCTTCAAGTCAGCACAATCTGTTACAGCAG~CATTTcAAGACAAGAC TGTTTCAGAAAAATTCTCTCCAGAAACAGCCTCCAGAGAGGATTAAGCAAGCAGAATTATGCC GTGGAAGCAATTCATAGAGCTGTGGAATTTAATCCTCATGTTCCAAATATTTATTAGAGATGAAA GTTTAATTTTACCTCCAGAACACATTCTGAAACGGTGATAGTGAGCAATTGCCTATGCTTTCTT TCATCTTCAGCACTGGAAACGAATAGAAGGTGCTCTTAATCTGTTACAGTGTACATGGGAAGGCACC TTTCATCATGTTTCTGTTTACCCAAAAAAGGACTTCCTTTGTTCATCATTCAGCGGATTTT GCTCTTCTACAGCAATGATAGCCATTCTCACTCACCAGTTTCCTLTATGGGTATTTTTGCTAA AGCTGTCTGGGACTCTGGTGCCCCCAACCCTGTCCTCAGGCTTTGATACGT TTGAGTCAGAGACCTAGGTTTGAGTTCTGGCTGACACGCACTGTTCATGTACCTTGC, - jORF Start: ATG at 77 OR top: TGA at 1709 ISEQ ID NO: 68 .544 aa JMW at 61110.4kD NOV8b, MADRGGVGEAAVGASPASVPGLNPTLGWERLRALAGTASLWFVAGL0.LLYALRIPLRLCENLA CG159498-02 AVTVFLNSLTPKFYVALTGTSSLISGLIFIFEWWYFHKHGTSFIEQVSVSHLQPLMGGTESSISEPG SPSRRENETSRQNhSECKVWRNPLNLFRGAEYRRYTWVTGKEPLTYYDMLSAQDHQTFFTCDTDF Protein LRSTMKWENPRKAQLLNCTYLAEATVARFQLAEI Sequence RQSQQCQHQSPQHE-AQLRRDTNVLVYI KRRLAMCARK(LGRIREAVKIMRDLMKEFPPLTD4LNIHENL LESLLELQAYPDVQAVLAKYDDISLPKSAAI CYTAALLKTRTVSEKFSPETASRRGLSTAEINAVEA IHAENHPYLMSIPEIKGSAAAFLHKIGLLQTETH VSVYPKELPLFIHFTAGFCSSTAIAILTHQFPEIMGIFAAVLGLWCPQPWASGFEENTQDLKS EDLGLSSG Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 81B. 5 Table 8B. Comparison of NOV8a against NOV8b. Prten eqeneNOV8a Residues/ Identities/ Protin equnceMatch Residues Similarities for the Matched Region NOV8b L..544 508/544 (93%) L..513 510/544 (93%) Further analysis of the NOV8a protein yielded the following properties shown in Table 8C. [Table 8C. Protein Sequence Properties Va SignalP Cleavage site between residues 64 and 65 analysis: PSORT 11 PSG: a new signal peptide, prediction method anayss:N-region: length 9; pos.chg 1; neg.chg 2 anayss:H-region: length 20; peak value 0.00 PSG score: -4.40 cGvii von Heijne's method for signal seq. recognition 149 WO 03/050245 PCT/USO2/38594 GvH score (threshold: -2.1): -2.39 possible cleavage site: between 55 and 56 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 3 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -2.66 Transmembrane 82 - 98 PERIPHERAL Likelihood = 1.80 (at 536) ALOM score: -2.66 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 89 Charge difference: -1.0 C( 0.0) - N( 1.0) N >= C: N-terminal side will be inside >>>,membrane topology: type 2 (cytoplasmic tail 1 to 82) MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 11.73 Hyd Moment(95): 8.52 G content: 3 D/E content: 2 S/T content: 0 Score: -6.50 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 10.5% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: ADRG none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: found LL at 52 checking 63 PROSITE DNA binding motifs: 150 WO 03/050245 PCT/USO2/38594 Leucine zipper pattern (PS00029): *** found *** LRRDTNVLVYIKRRLAMCARKL at 285 none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 76.7 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23) 39.1 %: mitochondrial 30.4 %: cytoplasmic 8.7 %: endoplasmic reticulum 4.3 %: Golgi 4.3 %: vacuolar 4.3 %: extracellular, including cell wall 4.3 %: nuclear 4.3 %: vesicles of secretory system > prediction for CG159498-01 is mit (k=23) A search of the NOV8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 8D. 5 Table 8D. Geneseq Results for NOV8a NOV8a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region AAM79736 Human protein SEQ ID NO 1..471 371/476 (77%) 0.0 3382 - Homo sapiens, 486 aa. 6..476 388/476 (80%) [WO200157190-A2, 09-AUG-2001] ABB71248 Drosophila melanogaster 70..544 334/503 (66%) 0.0 polypeptide SEQ ID NO 5..507 396/503 (78%) 40536 - Drosophila melanogaster, 537 aa. [WO200171042-A2, 27-SEP-2001] AAM80117 Human protein SEQ IDNO 152..546 298/404 (73%) e-170 3763 - Homo sapiens, 420 aa. 1..401 332/404 (81%) [WO200157190-A2, 09-AUG-2001] 151 WO 03/050245 PCT/USO2/38594 AAB56844 Human prostate cancer 292..543 217/252 (86%) e-125 antigen protein sequence 33..284 230/252 (91%) SEQ ID NO:1422 - Homo sapiens, 315 aa. [WO200055174-A1, 21-SEP-2000] ABB89473 Human polypeptide SEQ ID 301..543 209/243 (86%) e-121 NO 1849 - Homo sapiens, 1..243 222/243 (91%) 274 aa. [WO200190304-A2, 29-NOV-2001] In a BLAST search of public sequence datbases, the NOV8a protein was found to have homology to the proteins shown in the BLASTP data in Table 8E. Table 8E. Public BLASTP Results for NOV8a Protein NOV8a Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion Q8TDW1 ST7L isoform4 - Homo 1..555 549/555 (98%) 0.0 sapiens (Human), 555 aa. 1..555 552/555 (98%) Q8TDW4 ST7L isoform 1 - Homo 1..544 538/544 (98%) 0.0 sapiens (Human), 575 aa. 1..544 541/544 (98%) Q8TDW3 ST7L isoform 2 - Homo 1..544 521/544 (95%) 0.0 sapiens (Human), 558 aa. 1..527 524/544 (95%) Q8K4P7 Tumorsuppressor St7-like 1..555 501/559 (89%) 0.0 product - Mus musculus 1..559 529/559 (94%) (Mouse), 559 aa. Q8TDW2 ST7L isoform 3 - Homo 1..544 508/544 (93%) 0.0 sapiens (Human), 544 aa. 1..513 510/544 (93%) 5 PFam analysis predicts that the NOV8a protein contains the domains shown in the Table 8F. Table 8F. Domain Analysis of NOV8a Identities/ Pfam Domain NOV8a Match Region Similarities Expect Value for the Matched Epc au Region 152 WO 03/050245 PCT/USO2/38594 Example 9. The NOV9 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 9A. Tle 9A. NOV9 Sequence Analysis Tabe SEQ ID NO: 69 d760bp NOV9a, AATCGCCCTTCATCATGCTATTACAATCCCAACCATGGGGTTTCTCACAGCTTTACACCAAAGGGC CGl160152-01 ATCACTATCCCTCAAAGAGAGAAACCTGGACACATCTACCAAAACGAAGATTACCTGCAGAACGGGCT GCOAACAGAAACCACCGTTCTTrGGGACAGTCCAGATCCTGTGTTGCCTGTTGATTTCAAGTCTGGGGG DNA Sequence CATCTTGGTTTTTGCTCCCTACCCCTCCCACTTCAATCCAGCAATTTCCACCACTTTGATGTCTGGG TACCC-ATTTTTAGGAGCTCTG3TGTTTTGGCATTACTGATCCCTCTCAATTATCTCTGGAAAACAATC AACTAAGCCCTTTGACCTGAGCAGCTTGACCTCAAATGCAGTGAGTTCTGTTACTGCAGGAGCAGGCC TCTTCCTCCTTGCTGACAGCATGGTAGCCCTGAGGACTGCCTCTCAACATTGTC3CTCAGAAAkTGGAT TATCTATCCTCATTGCCTTATTCGAGTACTATTATCCAATATATGAAATCAAAGATTGTCTCCTGAC CAGTGTCAGTTTAACAGGTGTCCTAGTGGTGATG'CTCATCTTCACTGTGCTGGAGCTCTTATTAGCTG CAkTACAGTTCTGTCTTTTGGTGGAAACAGCTCTACTCCAACAACCCTGGGAGTTCATTTTCCTCGACC CAGTCACAAGATCATATCCAACAOGGTCAAAAAGAGTTCTTCACGGTCTTGGATATAAGTAACTCTTGG CCTCAGAGGAAG ~ORF Start: ATG at 15 FOI Stop: TAA at 735 ______SEQ ID NO: 70 240 aa JMWat 26l30.kD NOV9a, MLLQSQTMGVSHSFTPKGITPQREKPGHIMYQNEDYLQNGLPTETTVXGTVQILCCLLI SSLGAILVF CG1 60152-01 APYPSHFNPAISTTLMSCYPFLGALCFGrJTGSLSIISGKQSTKPFDLSSLTSNAVSSVTAGAGLFLLA DSMVALRTASQHCGSEMDYLSSLPYSEYYYPIYEIKCLLTSVSLTGVLVV4LIFTVLELLLAAYS SV Protein FWWKQLYSNNPGSSFSSTQSQDHIQQVKKSSSRSWI Sequence ________SEQID NO: 71 __ 61bp NOV9b, CTTCATCATGCTATTACAATCCCAAACCATGGGGGTTTCTCACACTTTACACCAAAGGGCATCACT CG1 60152-03 ATCCCTEAAAGAGAGAAACCTGGACACATGTACCAAAACGAAGATTACCTG.CAGAACGGGCTGC=A CAGAAACCACCGTTCTTGGGGACCTGAGCAGCTTGACCTCAAATGCAGTGAGTTCTGTTACTGCAGG DNA Sequence AGCAGGCCTCTTCCTCCTTGCTGACAGCATCGTAGCCCTGAGGACTGCCTCTCAACATTGTGGCTCA G AAATGGATTATCTATCCTCATTOCCTTATTCGGAGTACTATTATCCAATATATGAAATCAAAGATT GTCTCCTGACCAGTGTCAGTTTAACAGGTGTCCTAGTGGTGATGCTCATCTTCACTGTGCTGGAGCT CTTATTAGCTGCATACAGTTCTGTCTTTTGGTGGAAACAGCTCTACTCCAACAJACCCTGGGAGTTC'A TTTTCCTCACCCAGTCACAAGATCATATCCAACAGGTCAAAAAGAGTTCTTCACGGTCTTGGATAT AAGTAACTCTTGGCCTCAGAGGAAGGAAAAGCAACTCAACACTCATGGTCAAGTGTGATTAGACTTT CCTGAAATCTCTGCC ORF Start: ATO .at,8 ...... S..top: TAA at 536 _EI O 176 aa M t195.k NOV9b, MLLQSQTMGVSHSFTPKGI TIPQREKPGUD4YQNEDYLQNGLPTETTVLGDLSSLTSNAVSSVTAGAG CG1 60152-03 LFLLADSMVALRTASQHCGSE4DYLSSLPYSEYYYPIYEIKDCLLTSVSLTGVLVVALI FTVLELLL Protein AAYSSVFWWKQLYSN'NPGSSFSSTQSQDHIQQVKKSSSRSWI Sequence I _______SEQID NO: 73 *75 bp NOV9c, CTTCATCATGCTATTACAATCCCAAACCATGGGGGTTTCTCACAGCTTTACACCAAAGGGCATCACTA CG1 60152-02 TCCCTCAAAGAGAcAAACCTGGACACATGTACnAAACGAAGATTACCTGCAGAACGGGCTGCCAACA DNA equece AAACCACCGTTCTTGGCTTTCGCAT TACTGGATCCCTCTCAATTATCTCTGGAAAACAATCAACTAA DNA SquencGCCCTTTGACCTGAGCAGCTTGACCTCAAAgrGCAGTGAGTTCTGTTACTGCAGGAGCAGGCCTCTTCC TCCTTOCTGACAGCATGGTAGCCCTGAGACTGCCTCTCAAnTTGTGGCTCAGAAATGGATTATCTA TCCTCATTGCCTTATTCCGAGTACTATTATCCAATATATGAALATCAAAGATTGTCTCCTGACCAGTGT CAGTTTAACAGGTGTCCTAGTGGTGATGCTCATCTTCACTGTGCTGGAGCTCTTATTAOCTGCATACA GTTCTGTCTTTTGTGGAAACAGCTCTACTCCAAACCCTcccAGTTCATTTTCCTCACCCAGTCA CAAGATCATATCCAACAGGTCAAAAAGAGTTCTTCACGGTCTTGGATATAAGTAACTCTTGGCCTCAG AGGAAGGAAAAGCAACTCAACACTCATnGTCAGTGTGATTAGACTTTCCTGAAATCTCTGCC 'R tart: ATG at 8 JORE Stop: TAA at 593 SEQ ID NO: 74 195aa. MWat 21404.lkDj 153 WO 03/050245 PCT/USO2/38594 NOV9c, IMLLQSQTMGVSHS PTPI(GITIPQREKPGHMYQNEDYLQNGLPTETTVLGFGITGSLSI ISGKQSTKPF CG1 60152-02 DLSSTTSNAVSSVTAGAGLFLLADSMVALRTASQHCGSEMDYLSSLPYSEYYYPIYEIKDCLLTSVSL Proein TGVLJVIVLIFTVLELLLAAYSSVFWWKQLYSNNPGSSFSSTQSQDHIQQVKKSSSRSWI Sequence ____ SEQ ID NO: 75 .,,675 bp NOV9d, CTTCATCATGCTATTACAATCCCAAACCATGGGGGTTTCTCACAGCTTTACACCAAAGGGCATCACT CG1 60152-04 :ATCCCTCAAGAGAGAAACCTGGACACATGTACCAAAACGAAGATTACCTCAAACGX4GCTGCCAA CAGAAACCACCGTTCTTGGGTTTGGCATTACTGGATCCCTCTCAATTATCTCTGAAAACAATCAAC DNA Sequence TAAGCCCTTTGACCTGAGCAGCTTGACCTCAAATGCAGTGAGTTCTGTTACTG-AGGAGCAGGCCTC TTCCTCCTTGCTGACAGCATGGTAGCCCTGAGGACTGCCTCTCAACATTTGGCTCAGAAATGGATT ATCTATCCTCATTGCCTTATTCGAGTACTATTATCCAATATATGAAATCAAAGATTGTCTCCTGAC CAG CGTCAGTTTAACAGGTGTCCTAGTGGTGATGCTCATCTTCACTGTGCTGGAGCTCTTATTAGCT GCATACAGTTCTGTCTTTTGGTCGAAACAGCTCTACTCCAACAACCCTGGGAGTTCATTTTCCTCGA CCCAGTCACAAGIU'CATATCCAACAGGTCAAAAAGAGWTCTTCACGGTCTTGGATATAAGTAACTCT TGGCCTCAGAGGAAGGAAAAGCAACTCAACACTCATGGTCAAGTGTGATTAGACTTTCCTGAAATCT CTGCC ORF Start: ATG at 8 IRStop: TAA at 593 ______SEQ ID NO: 76,_ j 195 aa _M~yat 2l4q4.lkD NOV~dMLLQSQTMGVSHSFTPIKGITIPQREKPGHMYQNEDYLQNGLPTETTVLGFGITGSLSIISGKQSTKP -CG16015-04 FDLSSLTSNAVSSVTAGAGLFLLADSMVALRTASQHCGSEMDYLSSLPYSEYYYPIYEIGJCLLTSV ~Sequence ______ SEQ ID NO: 77 '747 bp NOV9e, CACCGCGGCCGCACCATGCTATTACAATCCCAAACCATGGGGGTTTCTCACAGCTTTACACCAAAGGG CG1 60152-05 CATCCTATCCCTCAAAGAGAGAAACCTQGACACATGTACCAAAACGAAGATTACCTGCAGAACGGGC TGCCAACAGAAACCACCTTCTTGGACTGTCCAGATCCTGTTTCCTGTTGATTTCAAGTCTGcci DNA Sequence GCCATCTTGGTTTTTGCTCCCTACCCCTCCCACTTCAATCCAGCAATTTPCCACCACTTTGATGTCTGG GTAcCCATTTTTAGGAGCTCT~GTG TTTcGCATTACTGGATCCCTCTCAATTATCTCTGGAAAACAAT CAACTAAGCCCTTTGACCTGAGCAGCTTGACCTCAAATGCAGTGAGTTCTGTTACTGCAGGAGCAGGC CTCTTCCTCCTTGCTGACAGCATGGTAGCCCTGAGGACTGCCTCTCAACATTGTGGCTCAGAAATCGA TTATCTATCCTCATTGCCTTATTCGGAGTACTATTATCCAATATATGAAATCAAAGATTGTCTCCTGA CCAGTGTCAGTTTAACAGGTGTCCTAGTGGTATGCTCATCTTCACTGTGCTGGAGCTCTTATTAGCT GCATACAGTTCTGTCTTTTGGTGCAAACAGCTCTACTCCAACAACCCTGCGAGTTCATTTTCCTCGAC CCAGTCACAAGATCATATCCAACAGGTCAAAAAGAGTTCTTCACGGTCTTGGATATAGGTCGACGGC ORF Start: ATG at_16 -OR Stop: TAG at 736 _______SEQ ID NO: 78 1240 aa. _.IMW at 26130.7kD NOV9e, M~LLQSQTMGVSHSFTPKGITIPQREKPGHMYQNEDYLQNGLPTETTVLGTVQILCCLLISSLGAILVF CG 160152-05 APYPSHFNPAISTTLMSGYPFLGALCFGITGSLSIISGKQSTKPFDLSSLTSNAVSSVTAGAGLFLLA DSMVAt.RTASQHCGSEMDYLSSLPYSEYYYPIYEIKflCLLTSVSLTGVLVVMLIFTVLELLLAAYSSV Protein FWWKQLYSNNPGSSFSSTQSQDHIQQVKKSSSRSWI -Sequence 5 Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 9B. Table 9B. Comparison of NOV9a against NOV9b through NOV9e. Protein Sequence JNOV9a Residues/ Identities/ Match Residues Similarities for the Matched Region NOV9b 114..240 127/127 (100%) 5.176 127/127 (100%) ____________ 11190 ____9240 ____(81%)___ 2409 195/240 (81%) _________ ______ ... .. ...... .. .... .19.240(.1% 154 WO 03/050245 PCT/USO2/38594 NOV9d 1..240 195/240 (81%) 1..195 195/240 (81%) NOV9e 1..240 2 4 0/2 4 0 (100%) 1..240 240/240 (100%) Further analysis of the NOV9a protein yielded the following properties shown in Table 9C. Table 9C. Protein Sequence Properties NOV9a SignalP analysis: Cleavage site between residues 70 and 71 PSORTII PSG: a new signal peptide prediction method analysis: N-region: length 0; pos.chg 0; neg.chg 0 H-region: length 16; peak value 5.27 PSG score: 0.87 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -4.91 possible cleavage site: between 13 and 14 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 4 INTEGRAL Likelihood =-10.19 Transmembrane 53 - 69 INTEGRAL Likelihood = -1.91 Transmembrane 89 - 105 INTEGRAL Likelihood = -1.49 Transmembrane 126 - 142 INTEGRAL Likelihood =-11.30 Transmembrane 184 - 200 PERIPHERAL Likelihood = 9.02 (at 167) ALOM score: -11.30 (number of TMSs: 4) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 60 Charge difference: 3.5 C( 0.5) - N(-3.0) C > N: C-terminal side will be inside >>>Caution: Inconsistent mtop result with signal peptide >>> membrane topology: type 3b MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 4.11 Hyd Moment(95): 1.37 G content: 2 D/E content: 1 S/T content: 6 Score: -4.06 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 4.6% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none 155 WO 03/050245 PCT/USO2/38594 SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 55.5 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues

-------------------------

Final Results (k = 9/23): 44.4 %: endoplasmic reticulum 22.2 %: vacuolar 11.1 %: Golgi 11.1 %: vesicles of secretory system 11.1 %: mitochondrial >> prediction for CG160152-01 is end (k=9) A search of the NOV9a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 9D. 5 Table 9D. Geneseq Results for NOV9a NOV9a NOV9a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for the Expect Identifier [Patent #, Date] Match Matched Region Value Residues ABP65232 Hypoxia-regulated protein 1..240 240/240 (100%) e-136 1..240 240/240 (100%) 156 WO 03/050245 PCT/USO2/38594 [WO200246465-A2, 13-JUN-2002] ABP65029 Human membrane spanning 1..240 240/240 (100%) e-136 4-domain family, subfamily 1..240 240/240 (100%) A 7 protein - Homo sapiens, 240 aa. [WO200262946-A2, 15-AUG-2002] AAM93537 Human polypeptide, SEQ ID 1..240 240/240 (100%) e-136 NO: 3283 - Homo sapiens, 1..240 240/240 (100%) 240 aa. [EP1130094-A2, 05-SEP-2001] AAM78610 Human protein SEQ ID NO 1..240 240/240 (100%) e-136 1272 - Homo sapiens, 240 aa. 1..240 240/240 (100%) [WO200157190-A2, 09-AUG-2001] AAE13063 Human CD20/IgE-receptor 1..240 240/240 (100%) e-136 like protein, agp-69406-al - 1..240 240/240 (100%) Homo sapiens, 240 aa. [WO200174903-A2, 11-OCT-2001] In a BLAST search of public sequence datbases, the NOV9a protein was found to have homology to the proteins shown in the BLASTP data in Table 9E. Table 9E. Public BLASTP Results for NOV9a NOV9a Protein NOV9aResidues/ Identities/ Accession Protein/Organism/Length Match Similarities for the Expect Number Residues Matched Portion Residues Q9GZW8 MS4A7 1..240 240/240 (100%) e-135 (CD20/FC-epsilon-RI-beta 1..240 240/240 (100%) family member 4) (Four-span transmembrane protein 2) (Membrane-spanning 4-domains, subfamily A, member 7) (High affinity immunoglobulin epsilon receptor beta subunit) - Homo sapiens (Human), 240 aa. Q99N04 MS4A7 protein - Mus 1..234 126/234 (53%) le-61 musculus (Mouse), 234 aa. 1..231 155/234 (65%) Q8R3W1 Similar to RIKEN cDNA 1..234 124/234 (52%) 5e-61 9130422110 gene- Mus 1..231 154/234 (64%) musculus (Mouse), 234 aa. Q9D2W6 91304221ORik protein - Mus 1..234 112/234 (47%) 6e-51 musculus (Mouse), 215 aa. 1..212 141/234 (59%)_.. . 157 WO 03/050245 PCT/USO2/38594 Q99N07 MS4A6D protein (RIKEN 2..235 84/234 (35%) 5e-35 cDNA 11 1005SE1 6 gene) - 5..235 1301234 (54%) Mus musculus (Mouse), 247 a. PHam analysis predicts that the NOV9a protein contains the domains shown in the Table 9F. Table 9F. Domain Analysis of NOV9a Pfam Domain NOV9a Match Region foiritestce Expect Value 5 Example 10. The NOV1 0 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 10OA Table 10A. NOV10 Sequence Analysis ~SEQID NO: 79 1257 bp NOVi 0a, GTCCCGCCCCTGCCCGGCCTGGCCCCGCCCCTGCCCGGCCCCGCCCCCCAACGTGTCTTCAGGTCTC C016085-0lTTTCCCTCCAGCCGGCCCTTAcGGACGGCTCTTGGACGTGCTCGTGAGTCCTTCGCCTGTCTGCCTTC CACCTCTCTGCAGCTCCTTCTCCAATCTCATGCTCTTCTTGAGCTTGGCCGCCCTCCACGCCCCATG DNA Seque c TGGGCTTGGTCGGTTCTGGGGTCTACCTCTCTGGCTTCATCCCTCCCACAGTTTCGAGGGTTTCCC TGTGCTCAGGCCCCTGGCAGCCGCCCCTGTGCAGACCACTGGGCAGATCCAGCTGACCTCCAGGG CACTTCCTCGGCTATCACTGGCCGGTGCTCTGCAGAATGAGCTGTGAGAGCCACTGTGGCTCGCC AGAGGGTGCC-ACTCACAGTCACTTCAGACTCACAGGAGCCTTCGTCCCGACCCCTGCATTCATCTGT GTTCTGTTTTATGTTTTTTCCCAGTCACCTGA@CTcCAGcCCTTGGTCACCCCAGACTCCTCCCTCC TGTc-ACCCTTATCCTC-ACCCCAGCACCTTTACGTCTGcCCCAGGCTCCATrTTCCCCC'rCTTCTCCCT GGATCAAACCACCCTGACTTTCCTGGGTCTTCGTGCAACAGCCTGCTCCGGCCGCTGCCTCACTGCA CCTGCAAATCCACTTGCACCCACACCCAGGCCAGGGTTTTTAALACAGAAGCCTCAcC-AGATCCCTCT *CTCTC~CAGCTCCCTGTTGAACCAC.GAAG.CAGGTCCCTGTTGAACCTCAGCATGACCCCCcCAC CCCTGCATCCCACTTCTGCTCTGGGAGCCTCTGGGTTCCTGGGCGCACCTGCTGCCCTTCCCTGTTT GTCACTGGTGACCTCCCGTCCTTGTGGnCGCTCCCGrnCCCTGTCTCGG4CCTTCTGAGGACTTG CTCTCCTGGTAGCGCCTGCTGACTGTGAGCCCAGAGAGCAGGCGTGGCTGTTGACCTTAGGTCCTCC CAGAACCTGGCGGATCGCCTGGCTCCCAGGCAGGAGGCGCTGCATGACGCCTCCAACTTCCGCCAAT CTAGCCCAAGGATGGCGTTCTAAATAAAACGCGTTCTACAGAAAAGTGTTTATTGCATTCTTCTTTG AAATAATGTAAGCATAAAAGTAATCTc2AATATTGACCAATACOGTTAATTCATTAACGTATATTTAC CTAATTGAAATATTGGGTAGATGTGAAAAAAAGTTCCAATGTTTGTAATTA - ORF Start: ATG at 374 hIRF Stop: TGA at 779 I ~ SEQ ID NO: 80 1135 aa j~fat 4547.5kD_ INOV10a, MSCESHCGWPEGATHSHFRLTGAFVPTPAFICVLFYVFSQSPELQALVTPDSSLLS PLSSPQHLYVC ICG160 185-01 PRLIHFPLFCLDQTTLTFLGLRATACSGRCLTAP2UNPLAPTPRPGFLNRSLSRSLSASSLLTQEAGP Protein Sequence: _________________________________ 158 WO 03/050245 PCT/USO2/38594 Further analysis of the NOV10a protein yielded the following properties shown in Table 10B. Table 10B. Protein Sequence Properties NOV10a SignalP analysis: No Known Signal Sequence Predicted PSORTII PSG: a new signal peptide prediction method analysis: N-region: length 11; pos.chg 0; neg.chg 2 analysis H-region: length 7; peak value 0.00 PSG score: -4.40 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -3.68 possible cleavage site: between 46 and 47 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -3.03 Transmembrane 22 - 38 PERIPHERAL Likelihood = 5.99 (at 71) ALOM score: -3.03 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 29 Charge difference: -3.5 C(-2.0) - N( 1.5) N >= C: N-terminal side will be inside >>> membrane topology: type 2 (cytoplasmic tail 1 to 22) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 4.85 Hyd Moment(95): 2.00 G content: 1 D/E content: 2 S/T content: 2 Score: -7.58 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 5.2% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none 159 WO 03/050245 PCT/USO2/38594 NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 89 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 39.1 %: nuclear 26.1 %: mitochondrial 8.7 %: Golgi 8.7 %: cytoplasmic 4.3 %: extracellular, including cell wall 4.3 %: plasma membrane 4.3 %: vesicles of secretory system 4.3 %: peroxisomal >> prediction for CG160185-01 is nuc (k=23) A search of the NOVI0a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 10C. 5 Table 10C. Geneseq Results for NOV10a NOV10a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region AAY44775 Long splice variant of human L.. 110 31/110 (28%) 0.82 Enovin - Homo sapiens, 228 8..100 36/110 (32%) aa. [WO200004050-A2, 27-JAN-2000] AAY93559 A human GDNF-related 1..110 31/110 (28%) 0.82 neurotropic factor 4 (GRNF4) 8..100 36/110 (32%) - Homo sapiens, 228 aa. [WO200034475-A2, 15-JUN-2000] 160 WO 03/050245 PCT/USO2/38594 AAG48263 Arabidopsis thaliana protein 20..85 17/66 (25%) 5.4 fragment SEQ ID NO: 60928 131..187 31/66 (46%) - Arabidopsis thaliana, 333 aa. [EP1033405-A2, 06-SEP-2000] AAG48262 Arabidopsis thaliana protein 20..85 17/66 (25%) 5.4 fragment SEQ ID NO: 60927 145..201 31/66 (46%) - Arabidopsis thaliana, 347 aa. [EP1033405-A2, 06-SEP-2000] AAG48261 Arabidopsis thaliana protein 20..85 17/66 (25%) 5.4 fragment SEQ ID NO: 60926 227..283 31/66 (46%) - Arabidopsis thaliana, 429 aa. [EP1033405-A2, 06-SEP-2000] In a BLAST search of public sequence datbases, the NOV10a protein was found to have homology to the proteins shown in the BLASTP data in Table 10D. Table 10D. Public BLASTP Results for NOV10a Protein NOV10a Identities/ esin . Residues/ Similarities for Expect Accession Protem/Organism/Length Match the Matched Value Number Residues Portion Q22001 Hypothetical 28.5 kDa protein 15..118 31/107 (28%) 8.6 - Caenorhabditis elegans, 247 131..232 45/107 (41%) Saa. 5 PFam analysis predicts that the NOV10a protein contains the domains shown in the Table 10E. Table 10E. Domain Analysis of NOV10a Identities/ Similarities Pfam Domain NOV10a Match Region for the Matched Expect Value for the Matched Region 10 Example 11. The NOV11 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 11A. 161 WO 03/050245 PCT/US02/38594 ~Table IIA. NOV11 Sequence Analysis ISEQ ID NO: 81 47b NOV11 a, GCCCTCAGCATCGGACCAGAGTACTTGGTATCTGGATGAATCGACA CTCACTGACAACATCAAAAAG CG160244-0 1 CCGAAGTTTGCCCCTTGCTATAGGATCTACGCT CCACGGAGCrCGCCACGCTGCTGATGGCATGTCTCTGCGCCCTCTGAGGGCCGTGAGCCAGA DNA Sequence GGGCGTCTGGAACCTGCTAAGCATTGTGCGGGAGATGTTCAGCGAGCGACAGCAATGCTGCCCCC TTGTTGGAAATCCTCACTGACCAGTGCCTCACCTATGAACAGATAACAGGTTGGTGGTATAGCGTAC GTACCTC-AGCCTCACACAGCAGTGCCAGTGGGCACACGGGCCGTAGCAACC3GCAGTCAGAGGTGGC AGCCCATGCCTGTGCCACCATr.TGTG.ACGAGATGGTCACACTGTGGAGGCTGGCCGTGCTGGACCCT GCACTCAGCCCCCAGCGGCGCCGGGAACTGTGTACGCAGCTGCGGCAGTGGCAACTGAAGGTGATTG AGAACGTCAAGCGGGGcCA-ACACAGAAGACGCTGQAGrnGGTCTTCCCCGGCTTCCcGGCAGCGGT GGACGCCTGCTACTTCACTCGAAGAGCCTACCCACTTCCTGGTTCACCTACAGCGGCACTGAC AGGAAGCTGGCACTGTGCTGGGCCCGGGCCCTGCCCTCTCGGCCAGGTGCCTCCCGCTCTGGGGGCC TGGAGGAATCCCGGACCGCCCCGACCCCTTCCTACTGAGCCAGCTGTGCGGCCCAAGGAGCCTGG GACCAAcCGAAAGccCTTGGGTGAGGGGGTCCCCTCATCACAGCGGOGTCCCCGCCGCCTCTC!AGCT GAAGGGGGAGATAAAGCTCTACATAAGATGGGTCCAGGTGGGGGCAALAGCCAAGGCACTGGGTGGGG CTGGCAGTGCGAGCAAGGCTCAGCAGGTGGCGGAAGCAAGCGACGCTGAGCAGCGALAGACAGCTC CCTGGAGCCAGACCTGCCCAGATGAGCCTGGATGACAGCAGCCTGGCCCTGGGCGCALGAGGCCAGC ACCTTCGGGGGATTCCCTGAGAGCCCTCCACCCTGTCCTCTCCACGGTGGCTCCCGAGGCCCTTCCA CTTTCCTTCCTGAGCCCCCAATACTTATAAGAAGATGTGGTGTGTACTTCTCGGAAGGGCCTGA GCCTCCCACAGCCTCTGTTGGCCCCCCTGGCCTACTGCCTGGGGATGTCTGTACCCAGGACGACCTC CCTTCTACAGATGAGAGTGGCAATGGGCTTCCCAAAACCAAAGAGGCAGCCCCTGCAGTTGGAGAGG AGGATGATGACTACCAGGCGTACTATCTGAATGCCCAGGATGGGGCTGGGGGCGAGGAAGAGAAGGC CGAcGGGCGGCGATGGGGAGGAGCACGACCTGTTTGCTGGGCTGAAGCCACTGAACAGGAGAGTCGC ATGGAGGTACTGTCTGCCTGTGCTGAGGCCCTGCATGCGCATGGCTATAGCAGTGAGGCCTCCCGTC TCACTGTGGAGCTTGCCCAGGATCTGCTAGCCAACCCACCCGACCTCAAGGTAGAGCCGCCCCCTGC CAAGGGCAAGAAGAACAAGGTATCCACGAGCCGTCAGACCTGGGTGGCTACCAACACCCTGAGCAAQ GCGGCCTTCCTGTTGACAGTCCTAAGTGAGCGTCCAGAGCACCACAACCTGGCCTTCCGAGTTGGCA TGTTTGCCTTGGAGCTACAGAGGCCTCCAGCTTCTACCAAGGCCTTGGAGGTGAAGCTGGCATACCA GGAGTCTGAC.GTGGCTGCCCTGCTCAAGALAGATCCCTCTGGGTCCAAGTAGATGAGTACCATGCGG TGCCGGGCAGAGGAACTTCGCGAGGGGACACTCTGTGACTATCGGCCTGTGTTGCCTCTCATaCTCG CCAGTTTCATCTTTGACGTTCTCTGTGCTCCAGTGGTTTCTCCCACAGGTTCCCGGCCCCCAAGTCG CAACTGGAACAGCGAGACACCTGGGGATGAGGAGCTTGGATTTGAAaCALGCAGTTGCTGCCTTGGGC ATGAOACAACAGTGACGAOCCAGAACATCCCCTCTTATGTGAAGGCACACGTCGGAGAAGGGTG ACCTGGCATTAGCACTAATGATCACTTACAAGGACGACCAGGCCAAGCTTAAGAAGATCTTAGACAA ACTCTTGGACCGAGAGAGCCAGACACATAAGCCACAGACGCTGAGTTCTTTCTACTCATCTAGCCGC CCAACCACAGCCAGCCAGAGGTCTCCTTCAAAGCACGGGGGCCCATCTGCCCCAGGGACCCTGCcAAC CACTGACCTCAGGCTCTGCAGGGCCTGCTCAACCAGGGAGTGTGGCAGGGGCTGGGCCAGGCCCCAC TGAGGGCTTCACAGAGAAGATGTcGCCTAGATTCCCCACATTCCCCCTGTGAGTCTTCCATCT GACGCAGCTTTGACCCC2AACCCAeGAAGGGAAGGTTCCTAGCCGCTTGGCAC'TGGCAGTCGTGGAG GCTATAATGGACGGGGATGGCGGTCCCCAGGACGGCCTAAGAAGAAGCACACAGGCATGGCCAGCAT TGACAGCAGTGCCCCTGAAACAACATCGGATAQTTCCCCCACCTTAAGCC-GAGACCACTTCAAGGG GGCTGGGCCCCCACCTCCTGOGGTCGAGGTCAGGACAGTGACAGCATTAGCAACTCTTCTTCGGACT CCCTGGGCTCCTCATCCTCCAGTGGAAGTCGCCGGGCCAGTGCCAGTGGAGGAGCCCGGGCGAAGAC TGTTGAAGTTGGC'AGGTACAAGGGCCGCCGCCCCGAGAGTCATGCCCCTCATGTACCCAATCAGCCA TCAGAGGCACCTGCACACTTCTACTTCGAGCTGGCAAGACAGTGCTGATCAAGACAGGGGCAACA GCAGCACTTCCATTTTCACACATCCATCTTCCTCAGGGGGCCACCAGGGTCCTC!ACCGCAACCTGCA CCTTTGCGCCTTCGAGATTGGGCTTTATGCCCTTGCCTCACAACTTTGTTTCTCCCAACTGGCTC TCACGTACTTATTCTTCCCACGTTTCCTGATTACAGGCCAGCCATGGAGATAGGCACCGCAGCCC TGACTATACTGGTAGAATGCTGGGATGGGCACCTGACACCCCCTGAGGTTGCATCCCTGGCTGACAG GGCATCACGGGCAAGAGACTCCAATATGGTGAGGGCGGC-AGCAGAGC PGQCCCTGAGCTGCCTGCCT CACGCCCATGCATTGAACCCTAATGAGATCCAGCGGGCCCTGTCAGTGCAAGGAACAGGACAACC TGATGTTGGAGAAGGCCTGCATGGCAGTGGAAGAGGCAGCTAAGGGTGGGGGCGTGTACCCTGAAGT GTTGTTTGAGGTTGCTCACCAGTGGTTCTGGCTATATGAGCA~AACTGC-AGGTX4CTCATCC-ACAGCC CGTGAACCGGCTACAACCTGTAOTGCCAGTGGGATCAGGGCAGGTGGGGAAGCTCGGGCCCGGTATC CTGAGGGTAGAGGGGGCCCAGGGACTGAGCCGrnTTACAGTGGCAGCGGCAGCAGTGACAGCAGCAGC CACAGTGGTGCCCGTCATATCGGTCGGGTCTAGTTTATACCCGGTCCAGACTGGGGCATGGCCAC TCCCCTGGCCTGCACCCCTACACTGCTCTACAGCCCCACCTGCCCTGTAGCCCTCAGTATCTCACTC ACCCAGCTCACCCTGCCCACCCCATGCCTCACATGCCCCGGCCTGCCGTCTTCCCTGTGCCCAGCTC TCACTTGCTGCCACTGCTGTGTCTTTCCCCGTTCCTTCCTGC~jACCCATCACAGTACATCCCTACC AOACGAGCCAGGGCTTCCACTGCCCACCAGTGTTcTAGCAGTGTCCATCCAGCATCCACGTC TCCCCATCCAGGTGCCTCACTCCTCCCCTGACCAAACCGCCCTCTGGGAGCGAGn? TTTCCACCGCCCGAGGAGGACACACACAGTCAGCCAGTCAATCCCCACAGCCTGCACCACCTCCATG

CTGCCTACCGTGTCGGAATGCTGGCACTGGAGATGCTGGGTCGCCGGGCACACACGATCACCCCAA

WO 03/050245 PCT/USO2/38594 CAACTTCTCCCGCTCCCCCCCCTACACTGATGATGTCAAATGGTTGCTGGGGCTGGCAGCAAAGCTG GGAGATCGTCATGGAGACGCTGCZAGCGGCTGAGTCCCGCTCATGCCCACAACCACCTGCGTGCCCCG GCCTTCCACCAACTGGTGCAGCGCTGCCAGCAGGCATAC!ATGCAGTACATCCACCACAGCTTGATTC ACCTGACTCCTGCGGACTACGACGACTTTGTGAATGCGATCCGGAGTGCCCGCAGCGCCTTCTGCCT GACGCCCATGGCATGATGCAGTTCAACGACATCCTACASAACCTAGCGCAGCACAGCAG GAGCTGTGGCAGCGGGTCTCACTCGAGATGGCCACCTTCTCCCCCTGAGTCTTTCACCCTTAGGGTC CTATACGGSACCCGCCTGTGCTATGGGGGCCCCTCACTCAGGGGGAGTGAAACTTGGCTGGAC AGATCATCCTCACTCAGTTCCCTGGTACCACAGACTGACAGCTGCTCTTGGGCTATAGCTTGGGGCC AAGATGTCTCACACCCTAGAAGCCTAGGGCTGGGGGAGACAGCCCTGTCTGGGAGGGGGCGTTGGGT GCCTCTGGTATTTATTTGGCATTTATAAATATATAAACTCCTTTTTTACTCT _________RF Start: ATG at 122 _IR tp A t45 _______ SEQ ID NO: 82 1579 aa _..._MW at 166990.OkD NOVI la, MYLSSTEPPAAAEWACLLRPLRGREPEGVWNLLSIVREMFKR.RDSNAAPLLEILTDQCLTYEQITGW CGI 60244-01 WIYSVRTSASHSSASGHTGRSNGQSEVAAHACASMCDEMVTLWRLAVLDPALSPQRRRELCTQLRQWQ LKVIEVKIGQKKTLERLFGFRPAVEACYFNWEEAYPLPGVTYSGTDRKLALCWARALPSRPGAS Protein Sequence RSGGLEESRDRPRPLPTEPAVRPKEPGTKRKGLGEGVPSSQRGPLSAEGGDKLKMGPGGGAK ALGGAGSGSKGSAGGGSKRRLSSEDSSLEPDLAEMSLDDSSLALGAEASTFGGFPESPPPCPLHGGS RGPSTFLPEPPDTYEEDGGVYFSEGPEPPTASVGPPGLLPGDVCTQDDLPSTDESGNGLPKTKE-AAP AVGEEDDDYQAYYLNAQDGAGGEEEKAEGGDGEEHDLFAGLKIPLEQESRMEVLSACARALHAHGYSS EASRLTVELAQDLLANPPDLKVEPPPAKGKKNKVSTSRQTWVATNTLSKAAFLLTVLSERPEHNLA FRVGMPALELQRPPASTKALEVKLAYQESEVAA.LLKKI PLGPSEMSTMRCP.AEELREG;TLCDYRPVL PLMLASFIFDVLCAPVVSPTGSRPPSRNNSETPGDELGFEAAVAALGMKTTVSEAHEHPLLCEGTR REKGDLALALMITYKDDQAKLKKILDKLLDRESQTHKPQTLSS FYSSSRPTTASQRSPSKIHGGPSAP STLQPLTSGSAGPAQPGSVAGAGPGPTEGFTEiQVPESSPHSPCELPSEAALTPRPEGKVPSRLAL GSRGGYNGRGWGSPGRPRKKHTGMASIDSSAPETTSDSSPTLSRPLQGGWAPTSWSRGQDSDS ISN SSSDSLGSSS SSGSRRASASGGAAKTVEVGRYKGRRPESHAPHV2NQPSEAAAHFYFELAKTVLIK TGGMSSTS IFTHPSSSGGHQGPHRNLHLCAFE IGLYALGLIHIFVSPNWLSRTYS SHVSWITGQAMEI GSAALTILVECWDGLTPPEVASLAflRASRAR DSNMVRAALALSCLPHAHALNPNEIQRLVQCK EQDNLMLEKACMAVEEAKGGGVYPEVLFEVAHQWFWLYEQTAGGSSTAREGATSCSASCIRACE GRGMPEGRGGPGTEPVTVAAAAVTAAATVVPVISVGSSLYPGPGLGHGHSPGLHPYTALQPHLsPCSP QYLTHPA1HPAEPMPHMPRPAVFPVPSSAYPQGVHPAFLGAQYPYSVTPPSLAATAVSFPVPSMAkPIT VHPYHTEPGLPLPTSVALSSVHPASTFPAIQGASLPALTTQPSPLVSGGFPPPEET{SQPVNPHS. HHLHAAYRVGMLALEMLGRP.AHNDHPNNFSRSPPYTDDVKWLLGLAAKLGDRHGDAAAAESRSCPQP PACPGLPPTGAALPAGIHAVHPPQLDSPDSCGLRRLCECDPECPQRLLPDAHGHDAVQRHPTEPQAQ QTDQGAVAAGLTRDGHLLPLSLSPLGSYTGTQACGYGGPSLRGSETWLDRSSSLSSLVAQTDSCSWA IAWGQDVSHPRSLGLGETALSGRGRWVASGIYLAFINI Further analysis of the NOVI 1la protein yielded the following properties shown in Table 1113. 5 [Table 11B. Protein Sequence Properties NOVila SignaiP? analysis: No Known Signal Sequence Predicted PSORTl11analysis: P3G: a new signal peptide prediction method UN-region: length 7; pos.chg 0; neg.chg I H-region: length 5; peak value 0.00 PSG score: -4.40 Gvfl: von Heijae's method for signal seq. recognition GvH score (threshold: -2-1): -3.08 possible cleavage site: between 23 and 24 >>> Seems to have no N-terminal signal peptide, ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 2 INTEGRAL Likelihood = -4.51 Transmembrane 605 - 621 INTEGRAL Likelihood = -3.98 Transmenbrane 1156 -1172 PERIPHERAL Likelihood =1.91 (at 9G6) 163 WO 03/050245 PCT/USO2/38594 ALOM score: -4.51 (number of TMSs: 2) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 612 Charge difference: 0.0 C( 0.0) - N( 0.0) N >= C: N-terminal side will be inside >>> membrane topology: type 3a MITDISC: discrimination of mitochondrial targeting seq R content: 0 Ryd Moment(75): 4.39 Hyd Moment(95): 4.58 G content: 0 D/E content: 2 S/T content: 3 Score: -6.56 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: RPKK (4) at 820 pat4: PKKK (4) at 821 pat4: KKKH (3) at 822 pat7: PQRRREL (5) at 120 pat7: PGTKRKG (4) at 227 pat7: PPAKGKK (3) at 494 pat7: PAKGKKN (4) at 495 pat7: PGRPKKK (4) at 818 pat7: PKKKHTG (5) at 821 bipartite: RKGLGEGVPSSQRGPRR at 231 content of basic residues: 9.0% NLS Score: 2.86 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 89 164 WO 03/050245 PCT/USO2/38594 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues

-------------------------

Final Results (k = 9/23): 39.1 %: mitochondrial 34.8 %: nuclear 17.4 %: endoplasmic reticulum 4.3 %: cytoplasmic 4.3 %: peroxisomal >> prediction for CG160244-01 is mit (k=23) A search of the NOV11 a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 11C. 5 Table 11C. Geneseq Results for NOV11a NOV1l1a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for the Expect Identifier [Patent #, Date] Match Matched Region Value Residues AAB41456 Human ORFX ORF1220 1..1243 1225/1243 (98%) 0.0 polypeptide sequence SEQ 41..1275 1227/1243 (98%) ID NO:2440 - Homo sapiens, 1306 aa. [WO200058473-A2, 05-OCT-2000] AAB95514 Human protein sequence 445..1390 943/954 (98%) 0.0 SEQ ID NO:18083 - Homo 2..955 944/954 (98%) sapiens, 1081 aa. [EP1074617-A2, 07-FEB-2001] AAE20837 Human gene 2 encoded 1..622 617/622 (99%) 0.0 secreted protein fragment, 90..711 618/622 (99%) SEQ ID NO:99 - Homo sapiens, 720 aa. [WO200218435-A1, 07-MAR-2002] AAB56941 Human prostate cancer 976.1390 413/415 (99%) 0.0 antigen protein sequence 76..490 413/415 (99%) SEQ ID NO:1519 - Homo sapiens, 616 aa. [WO200055174-A1, 21-SEP-2000] ............. AAB43300 Human ORFX ORF3064 995..1390 392/404 (97%) 0.0 polypeptide sequence SEQ 1..404 394/404 (97%) 165 WO 03/050245 PCT/USO2/38594 sapiens, 530 aa. [WO200058473-A2, 05-OCT-2000] In a BLAST search of public sequence datbases, the NOV1 la protein was found to have homology to the proteins shown in the BLASTP data in Table 11D. Table liD. Public BLASTP Results for NOV1la ProteinNOVila Protein O 1a Identities/ Expect Accession Protein/Organism/Length MatchResidues/ Similarities for the Value Number MatchResidues Matched Portion NumberResidues 094987 Hypothetical protein 1..1243 1222/1243 (98%) 0.0 KIAAO913 - Homo sapiens 41..1270 1224/1243 (98%) (Human), 1301 aa (fragment). Q9H8F3 Hypothetical protein 445..1390 943/954 (98%) 0.0 FLJ13680 - Homo sapiens 2..955 944/954 (98%) (Human), 1081 aa. Q9GKV3 Hypothetical 41.8 kDa 260..657 381/398 (95%) 0.0 protein - Macaca fascicularis 1..393 385/398 (96%) (Crab eating macaque) (Cynomolgus monkey), 399 aa. Q9VWN8 CG32542 protein - 429..1119 341/732 (46%) e-161 Drosophila melanogaster 852..1526 435/732(58%) (Fruit fly), 2030 aa. Q9D789 2310021P13Rik protein - 1133..1390 254/258 (98%) e-152 Mus musculus (Mouse), 384 1..258 256/258 (98%) a a . ...... ........... . 5 PFam analysis predicts that the NOV11 la protein contains the domains shown in the Table 11E. Table 11E. Domain Analysis of NOV11a Identities/ Similarities Pfam Domain NOV11a Match Region for the Matched Expect Value Region 166 WO 03/050245 PCT/USO2/38594 Example 12. The NOV12 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 12A. ~Table 12A. NOV12 Sequence Analysis ~SEQ ID NO: 83 . 1682 bp CG16541-1 CATCCAAGACCTCCCCTGGCCGGGGGCATCTCCTGGCTGTGCTCCTGGCCCTCCTTGGCACCGCCT DNA Sequene GAGTTTCTTGCTCCTCTCCCTGCACAACCGCCTGCCAGCTGCGTCCAGCCCCCTGCGGCTGACATG CGAGGCTGACTGGAGTGACAGCCTGGCCOAACTGGCTCAAGCCAGCGGCCCTCTGTGATCC CAACCCCGAGCCTGGCGTCCGGCCTGTGCGCACCCTGCAAGTGGGCTGGAACATGCAGCTGCTGCC GCCGCTGGCTGTGGGCGGCACCTGTGCTCTGCGGCCAGACAGCGATAGAGCCTTTGTCTGTGC TGTTCGCTCTGCACAGCCAGTGTCTCAGGCTGCTTAAAGCCTGrACATGCGGGGGCTCTGTG AGGTCCCCAGGATCCTTGTCGCATGACTGCCAGAACCATGGACGTCTCTAGCCTGCCA CTGCCACTGTCCCCCTGGCTACACGCAGATACTGCCGCCAGGTGCATTTTCCCTTCACCC TGGCTAGTGCGGCGTCTGGCTAAGAAACATCGGC GGATGAATGTCAGAGAAAGGCGGGGTGCTGGCCCAGATCAAGAGCCAGAAGTGCAGGACATCCT CGCCTTCTATCTGGGCCGCCTGGAGACCACCAACAGGTGATTGACATGACTTCGAGACCGAC TTTGTGGTACAAGCGCAGCCTCGTGCAAGGGACG CCTTCACCAGTTTTGCCTTTGGGCAGCCTGACAACCACGGGTTTGGACTGCGTGGAGCTGACGC TTCAGCTcICCTTCAACTGGAACAACCAGCGCTGCAAAACCCGAAACCGTTACATCTGCCAGTTTGCC CAGGAGCACATCTCCCGTGGCCCAGGGTCCTGAGCCTGACCCATGCTCCCTCGCCTGCCCT GGGAGCACCGGCTCTGCTTACCTGTCCGCCCACCTGTCTGGAACAAGGGCCAGTTGACACTG CCCTTCAGGTTAACTCCAGCGATGGAAAAGAGAG CAGTGAGGGCCAGGAGTGAGTGTTAGAAGCTGGGCCCTTCGCCTGCTTTTGATTGACT GGGCTTCAATTAGATGGCAAAGGAGAGGACACCGCCAGTGGTCCAAAAAGGCTGCTCTCTTCCACCT GGCCCAACCCTGTGGGCAGCGGAGCTTCCCTGTGGCATGAACCCCACAGGGTATTATTATA 'rCAGCTG OR tr:ATG at 6 2 IORF Stop: TGA at 1307 _______ SEQ ID NO: 84 MW at 46138.OkD NOV12a, jMHPESPGRGWLLAVLLALLGTAWAEVWPPQLOEQAPMAGALITRKESFLLLSLINRLRSWVQPPAA CG1 60541-01 ~DMLDWSDSLAQLAQAALCGIPTPSIASGLWRTLQVGNQLLPAGIASFVEVSLWFAEGQRY ISHAAGECARNATCTHYTQLVWATSSQLCCPILCSAQTAIEAFVCAYS PGGNWEVNGKTIIPYKKG Protein Sequence AWCSLCTASVSGCFKAWDHAGGLCEVPRNPCRMSCQNHGRLNI STCHCHCPPGYTGRYCQAKVHPPF H1TCDLRIDGDCFMVSSE.ADTYYRARMKCQRKGGVLAQIKSQKVQDILAFYLGRLETTNEVIDSDFET ~RNFWIGLTYKTAKDSFRWATGEHQAFTSFAFGQPDNHGFGNCVELQASAAFNWNNQRCKTPRiRYICQ FAQEHISRWGPGS Further analysis of the NOV1 2a protein yielded the following properties shown in Table 12B. Table 12B. Protein Sequence Properties NOV12a SignaiP analysis: Cleavage site between residues 27 and 28 PSORT 11 PSG: a new signal peptide prediction method anaysiN -region: length 10; pos.chg 1; neg.chg 1 analsis:H-region: length 16; peak value 10.35 PSG score: 5.95 GvH-- von IHeijne's method for signal seq. recognition GvH core(thrshol~ -21): 6.65 167 WO 03/050245 PCT/USO2/38594 possible cleavage site: between 26 and 27 >>> Seems to have a cleavable signal peptide (1 to 26) ALOM: Klein et al's method for TM region allocation Init position for calculation: 27 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 0 PERIPHERAL Likelihood = 5.52 (at 167) ALOM score: -1.12 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 13 Charge difference: -4.0 C(-2.0) - N( 2.0) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 5.31 Hyd Moment(95): 1.68 G content: 3 D/E content: 2 S/T content: 3 Score: -7.29 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 20 GRGIHL NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 9.4% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 76.7 168 WO 03/050245 PCT/USO2/38594 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 33.3 %: extracellular, including cell wall 22.2 %: vacuolar 22.2 %: mitochondrial 22.2 %: endoplasmic reticulum >> prediction for CG160541-01 is exc (k=9) A search of the NOVI 2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 12C. 5 Table 12C. Geneseq Results for NOV12a NOV12a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region AAE21077 Human T139 (TANGO-139) 1..415 413/446 (92%) 0.0 protein - Homo sapiens, 446 1..446 413/446 (92%) aa. [US2002028508-A1, 07-MAR-2002] AAB64994 Human secreted protein #2 - 1..415 413/446 (92%) 0.0 Homo sapiens, 446 aa. 1..446 413/446 (92%) [WO200075375-A1, 14-DEC-2000] AAE06575 Human protein having 1..415 413/446 (92%) 0.0 hydrophobic domain, 1..446 413/446 (92%) HP10760 - Homo sapiens, 446 aa. [WO200149728-A2, 12-JUL-2001] AAY41266 Human T139 protein - Homo 1..415 413/446 (92%) 0.0 sapiens, 446 aa. 1..446 413/446 (92%) [WO9954343-A2, 28-OCT-1999] AAM93326 Human polypeptide, SEQ ID 1..415 409/446 (91%) 0.0 NO: 2851 - Homo sapiens, 1..446 410/446 (91%) 446 aa. [EP1130094-A2, 05-SEP-2001] In a BLAST search of public sequence datbases, the NOV12a protein was found to have homology to the proteins shown in the BLASTP data in Table 12D. 169 WO 03/050245 PCT/USO2/38594 Table 12D. Public BLASTP Results for NOV12a Protein NOV12a Identities/ Accession Protein/OrganisLength Residues/ Similarities for Expect Accession ProteOrganisLength Match the Matched Value Number Residues Portion CAC51149 Sequence 25 from Patent 1..415 413/446 (92%) 0.0 WO0 149728 - Homo sapiens 1..446 413/446 (92%) (Human), 446 aa. Q8NCFO Hypothetical protein 1..415 409/446 (91%) 0.0 FLJ90292 - Homo sapiens 1..446 410/446 (91%) (Human), 446 aa. Q9BE36 Hypothetical 35.9 kDa 1..225 211/225 (93%) e-126 protein - Macaca fascicularis 1..225 213/225 (93%) (Crab eating macaque) (Cynomolgus monkey), 334 aa. Q96HH2 Hypothetical protein - Homo 341..415 72/75 (96%) 8e-39 sapiens (Human), 156 aa 82..156 73/75 (97%) (fragment). Q9ET66 Cysteine-rich protease 42..231 67/198 (33%) 3e-20 inhibitor - Mus musculus 20.. 196 89/198 (44%) (Mouse), 489 aa. PFam analysis predicts that the NOV12a protein contains the domains shown in the Table 12E. 5 Table 12E. Domain Analysis of NOV12a Identities/ Pfam Domain NOV12a Match Region Similarities Expect Value for the Matched Region SCP 52..83 17/44 (39%) 0.0011 23/44(52%) SCP 118..191 26/86(30%) 1.2e-10 49/86 (57%) EGF 225..260 15/47(32%) 0.33 26/47(55%) lectinc 285..403 34/137 (25%) 1.3e-17 84/137 (61%) 170 WO 03/050245 PCT/USO2/38594 Example 13. The NOV1 3 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 1 3A. Table 13A. NOV 13 Sequence Analysis ~SEQ ID NO: 85 _ 82T b NOVi 3a, CCGGGCTGTGGTCTAGCATAAAGCGGAGCCCAAAGAAGGGCGGGTATGGAGAAGCCTCCCCA C~l 163-01 CCTGCCCCCGCAAGGCGGCATCTGCTGGTCCTGCTGCTGCTCCTCTCTACCCTGGTGATCCCCTCCA CG1163-01 CTGrACTCCTATCATGATCTGACGCCCAGAGACTCCTTGGTCTCACAGGCCTCCAGAGCCT DNA Sequence IACTCcAACGCTTCACCCACTTTTCCTGAAGTAACCTGCTTCGGGGCATAGACAGCTTATTCTCT GCCCCCATGGACTTCCGGGGCCTCCCTGGGAACTACCACAAAGAGGAGAACCAGGAGCACCAGCTGG GGAACAACACCCTCTCCAGCCACCTCCAGATCGACAAGATGACCGACAACAAGACAGGAGAGGTGCT GATCTCCGGAATGTGGTGGCATCCATTCACCAGCGGAGGGACTTCAGGTGATTTGAAGGTA CCCAGGATGGAGGAGAAGGAGGCCCTGGTACCCATCCAGAAGGCCACGGACAGCTTCCACACAGAAC TCCATCCCCGIGTGGCCTTCTGGATCATTAAGCTGCCACGGCGGAGGTCCCACCAGGATGCCCTGGA GGGCGGCCACTGGCTCAGCGAGAAGCGACACCGCCTGCAGGCCATCCGGGATGGACTCCGCAAGGG ACCCACAAGGACGTCCTAGAAGAGGGGACCGAGAGCTCCTCCCACTCCAGGCTGTCCCCCCGAAAGA CCCACTTACTGTACATCCTCAGGCCCTCTCGGCAGCTGTAGGGGTGGGGACCGGGGAGCACCTGCCT QGTACCCCCCATCAGACCCT -_____ OR Start: ATG at 50 JORE Stop: TAG at 776 _________SEQ ID NO: 86 1242 aa JMW at 2703 6.5kD NOVI 3a, MGEASPPAPARRHLLVLLLLLSTLVIPSTAAPIHDADAQESSLGLTGLQSLLQGFSRLFLKGNLLRG CG161630-0l IDSLFSAPMDFRGLPGNYKEENQEHQLGNNTLSSHLQIDKMTDNKTGEVLISENVVASIQPAEGSF EGDLKVPRMEEKEALVPIQKATDSFHTELHPRVAFWII KLPRRRSHQDALEGGNWLSEKPXRLQAIR Protein Sequence DGLRKGTEKDVLEEGTES SSHSRLSPRKTHLLYILRPSRQL JSEQ ID NO: 87 65b NOVi 3b, CTCGAGGCCAAAATTCGGCACGAGCCOGGCTGTGCCTCTAGCATAAAGGCCGAGCCCAr.AAGAACCG CG1 61630-02 GCGGGGTATGGGAGAAGCCTCCCCACCTGCCCCCGCAAGGCGGCATCTGCTGGTCCTGCTGCTGCTC CTCTCTACCCTGGTGATcCCCTCCGCTGCAGCTCCTATCCATGATGCTGACGCCCAAGAGAGCTCCT DNA Sequence TGGGTCTCACAGGCCTCCACAGCCTACTCCAAGGCTTCACCCGACTTTTCCTGAAAGTACCCACGAT GGAGGAGAAGGAGGCCCTGGTACCCATCCAGAAGGCCACGGACAGCTTCCACACAGAACTCCATCCC CGCGTGGCCTTCTOATcATTAACTGCcACGGCGGAGGTCCCACCAGGATCCCTGAGGGCAGcC ACTGGCTCACCGAGAAGCGACACCGCCCTGCAGGCCATCCOOGATGGACTCCGCAAGGGGACCCACAA GGACGTCCTAGAAGAGGGGACCGAGAGCTCCTCCCACTCCAGGCTGTCCCCCCGAAAGACCCACTTA rCTGTACATCCTCGGCCCTCTCGCAGCTGTAGGGGTGGGGACCGGGGAGrACCTGCCTGTAGCCCC CATCAGACCCTGCCCCAAGCACCATATGGAAATAAAGTTCTTTCTTACATCT ORE Start: ATG at 75 JORE Stop: TAG at 567 SEQINO:8 14aaMW at8500.lkD NOV 13b, MGEASPPAPARRHLLVLLLLLSTLVIPSAAAPIHDADAQESSLGLTGLQSLLQGFSRLFLKVPRMEE CG1 61630-02 KE-ALVPIQ1CATDSFHTELHPRVAFWI I PRRRSHQDALEGSHWLSEKRHRLQAIRDLRKGTHXDV Proei SeueceLEEGTESSSHS1RLSPRKTHLLYILRPSRQL Sequence comparison of the above protein sequences yields the following sequence 10 relationships shown in Table 13B. Table 13B. Comparison of NOV13a against NOV13b. Prten eqeneNOV13a Residues! Identities/ Protin equnceMatch Residues Similarities for the Matched Region 171 WO 03/050245 PCT/USO2/38594 Further analysis of the NOV 13a protein yielded the following properties shown in Table 13C. Table 13C. Protein Sequence Properties NOV13a SignalP analysis: Cleavage site between residues 31 and 32 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 11; pos.chg 1; neg.chg 1 H-region: length 0; peak value 0.66 PSG score: -3.74 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): 6.42 possible cleavage site: between 30 and 31 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -7.22 Transmembrane 14 - 30 PERIPHERAL Likelihood = 7.16 (at 43) ALOM score: -7.22 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 21 Charge difference: -5.0 C(-2.5) - N( 2.5) N >= C: N-terminal side will be inside >>> membrane topology: type 2 (cytoplasmic tail 1 to 14) MITDISC: discrimination of mitochondrial targeting seq R content: 2 Hyd Moment(75): 4.91 Hyd Moment(95): 7.07 G content: 1 D/E content: 2 S/T content: 5 Score: -4.24 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 22 RRHILL NUCDISC: discrimination of nuclear localization signals pat4: PRRR (4) at 175 pat4: KRHR (3) at 193 pat7: PRRRSHQ (5) at 175 bipartite: none content of basic residues: 12.4% NLS Score: 0.40 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: found RLSPRKTHL at 224 VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: 172 WO 03/050245 PCT/USO2/38594 type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 89 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 43.5 %: nuclear 21.7 %: mitochondrial 13.0 %: cytoplasmic 8.7 %: Golgi 4.3 %: plasma membrane 4.3 %: extracellular, including cell wall 4.3 %: peroxisomal >> prediction for CG161630-01 is nuc (k=23) A search of the NOV1 3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 13D. 5 Table 13D. Geneseq Results for NOV13a NOV13a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region AAM24259 Human EST encoded protein 1..242 241/242 (99%) e-136 SEQ ID NO: 1784 - Homo 1..242 241/242 (99%) sapiens, 242 aa. [WO200154477-A2, 02-AUG-2001] AAU29184 Human PRO polypeptide 1..242 241/242 (99%) e-136 1..242 241/242 (99%) 173 WO 03/050245 PCT/USO2/38594 sapiens, 242 aa. [WO200168848-A2, 20-SEP-2001] AAB08878 A human Dickkopf 1..242 241/242 (99%) e-136 (Dkk)-related protein 1..242 241/242 (99%) designated Soggy - Homo sapiens, 242 aa. [WO200052047-A2, 08-SEP-2000] AAW73020 Human cysteine-rich secreted 1..242 241/242 (99%) e-136 protein-like-N - Homo 1..242 241/242 (99%) sapiens, 242 aa. [WO9846755-A1, 22-OCT-1998] AAY36062 Extended human secreted 1..242 232/242 (95%) e-131 protein sequence, SEQ ID 1..242 232/242 (95%) NO. 447 - Homo sapiens, 242 aa. [WO9931236-A2, 24-JUN-1999] In a BLAST search of public sequence datbases, the NOV 13a protein was found to have homology to the proteins shown in the BLASTP data in Table 13E. Table 13E. Public BLASTP Results for NOV13a Protein NOV13a Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion Q9UK85 Soggy-1 protein precursor 1..242 241/242 (99%) e-136 (SGY-1) - Homo sapiens 1..242 241/242 (99%) (Human), 242 aa. CAC50177 Sequence 25 from Patent 12..229 167/218 (76%) 2e-87 WO0146231 - Homo sapiens 2..213 182/218 (82%) (Human), 312 aa. Q9EQT4 Soggy - Mus musculus 14..242 148/230 (64%) 3e-78 (Mouse), 230 aa. 4..230 181/230 (78%) Q9ERW1 Soggy precursor (Soggy 1) - 14..242 147/230 (63%) le-77 Mus musculus (Mouse), 230 4..230 179/230 (76%) aa. Q9QZL9 Soggy-1 protein precursor 14..242 146/230 (63%) 9e-77 (SGY-1) - Mus musculus 4..230 178/230 (76%) (M ouse), 230 aa... . . . . . . . 174 174 WO 03/050245 PCT/USO2/38594 PFam analysis predicts that the NOV13a protein contains the domains shown in the Table 13F. Table 13F. Domain Analysis of NOV13a Identities/ ]Similarities Pfam Domain NOV13a Match Region Sifor the Matched Expect Value NO~t~afor the Matched IRegion 5 Example 14. The NOV14 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 14A. Table 14A. NOV14 Sequence Analysis SEQ ID NO: 89 .1239 bp NOV14a, CAGACGGTACACCCCCGTCAGGTTCTTGCTCTGGCCCAGACCCTTGGGCTTCAGGTTCACCTGCCAC CG161793-01 ACCTCACGGTGAGTTCTCCTGGAAGAAGAACCTGATGCCAGCCATCTGTCAAGGAAGACAGGAAGTA ACAGTGCAGGCTCAGTGTGCTCGGCCCCTTCATCTGTCAGCTGCAGCAATGGAATACGTGCTGGAAG DNA Sequence TGAAGAACTCTCCGCGGCACCTCCTGAAGCAATTCACAGTGTGTGACGTTCCTCTGTATGACATTTG TGACTACAACGTCTCCAGGGACCGATGCCAGGAGCTCGGGTGCTGCTTCTACGAAGGCGTCTGCTAC AAGAAAGCGGTTCCCATTTACATCCACGTGTTCTCTGCCTTGATTGTGATCATCGCTGGGGCCTTCG TCATCACCATCATCTACAGAGTCATTCAGGAGAGCAGGAAAGAAAAGGCCATCCCTGTGGATGTCGC GCTGCCACAGAAGTCCAGCGAAAAGGCGGAGTTGGCCTCATCCAGCAGCAAGTTAGGGCTGAAGCCT GCGAGTCCTGGGCCTCCAAGTGCTGGGCCCTCGATGAAGAGTGACGAGGATAAGGATGATGTAACAG GGACAATAACAGAAGCCGAAGAAACTGAGGACTGACTGAGACGCATGAAGAAGTGGAGATTGTCAGA ATTATCCAAATGAAATGGTACAGCAGGTGCACTGTTAACAGTGTGATGGAATGACCACCCAAAGAGA AACAAACAATAAAGGGGTTATTTTTTGGAAAAATTCAAACAAAAAAAAA CAAAAAAAACA ACAGAACCAAAAAAAA-ACAAAAAAAAAAAAAAGGGGGGGCGCCGCGCGCCCCAAAAGGATTTTTCCC CCCGGGAGGGGCGGCCCAAGTTTTTGGCGCCGCTCACCCCCGGTTTTGTTGGGACACAGAAGGGGGG CCCCCCTAATGAGGGGGCCGCTTTATAATAAAAGGCCCAGGCGACGGGGCCGCCCGTGTTTTAACAC CGGGCGCTCCGAGCTGGGGAGAAACCCGGGCACCGGGGGGGGAACCCGTGGGGAGGGAGACCCTCAA GACGGGGGGGGGGGGAGGAACAATAGGGGCCACACCCCCCCCACGAGAAATTAAAGCCCCCGAGGGCA CAAAATTAAGATCTCACGGGCACAAGGGCTCAACACCCAGCGCAAATTAGCCGGCGCGCCGAAAAGT TTGCCCCACGGGATAGTCTGACGACATTCTCG ............................................. . ............. ..... i 6 5: T o , -t 6 ..... . ORF Start: ATG at12ORF Stop: TGA at 636 SEQ ID NO: 90 1178 aa - MW at 19481.1kD NOV14a, MPAICQGRQEVTVQAQCARPLHLSAAAMEYVLEVKNSPRHLLKQFTVCDVPLYDICDYNVSRDRCQE CG161793-01 LGCCFYEGVCYKKAVPIYIHVFSALIVIIAGAFVITIIYRVIQESRKEKAIPVDVALPQKSSEKAEL ASSSSKLGLKPASPGPPSAGPSMKSDEDKDDVTGTITEAEETED Protein Sequence 10 Further analysis of the NOV14a protein yielded the following properties shown in Table 14B. Table 14B. Protein Sequence Properties NOV14a SignalP analysis: No Known Signal Sequence Predicted 175 WO 03/050245 PCT/USO2/38594 PSORT IIanalysis: PSG: a new signal peptide prediction method N-region: length 10; pos.chg 1; neg.chg 1 H-region: length 8; peak value 1.78 PSG score: -2.62 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -9.59 possible cleavage site: between 27 and 28 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood =-11.36 Transmembrane 89 - 105 PERIPHERAL Likelihood = 7.64 (at 68) ALOM score: -11.36 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 96 Charge difference: -0.5 C( 1.0) - N( 1.5) N >= C: N-terminal side will be inside >>> membrane topology: type 2 (cytoplasmic tail 1 to 89) MITDISC: discrimination of mitochondrial targeting seq R content: 2 Hyd Moment(75): 5.69 Hyd Moment(95): 1.83 G content: 1 D/E content: 2 S/T content: 2 Score: -5.65 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 29 ARPILH NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 10.7% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: found LL at 41 176 WO 03/050245 PCT/USO2/38594 checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 55.5 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 34.8 %: mitochondrial 21.7 %: cytoplasmic 17.4 %: Golgi 8.7 %: endoplasmic reticulum 4.3 %: vacuolar 4.3 %: extracellular, including cell wall 4.3 %: nuclear 4.3 %: vesicles of secretory system > prediction for CG161793-01 is mit (k=23) A search of the NOV14a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 14C. 5 Table 14C. Geneseq Results for NOV14a NOV14a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Datel Match the Matched Value Residues Region ABB08204 Human lipid metabolism 104..165 17/62 (27%) 0.61 enzyme-4 (LME-4) - Homo 458..519 33/62 (52%) sapiens, 1216 aa. [WO200185956-A2, 15-NOV-2001] AAB94695 Human protein sequence SEQ 104..165 17/62 (27%) 0.61 ID NO:15668 - Homo 35..96 33/62(52%) sapiens, 639 aa. [EP1074617-A2, 07-FEB-2001] AAM80177 Human protein SEQ ID NO 104..165 17/62(27%) 0.61 3823 - Homo sapiens, 1058 300..361 33/62 (52%) aa. [WO200157190-A2, 09-AUG-2001] AAM79193 0.61 177 WO 03/050245 PCT/USO2/38594 1855 - Homo sapiens, 1216 458..519 33/62 (52%) aa. [WO200157190-A2, 09-AUG-2001] AAB50134 Human brain T calcium 71..164 25/96 (26%) 0.80 channel alpha 1G subunit 6..93 40/96 (41%) gene exon 33 protein - Homo sapiens, 118 aa. [WO200070044-A2, 23-NOV-2000] In a BLAST search of public sequence datbases, the NOV14a protein was found to have homology to the proteins shown in the BLASTP data in Table 14D. Table 14D. Public BLASTP Results for NOV14a Protein NOV14a Identities/ Protein Residues/ Similarities for Expect Accession Protein/Organism/Length Match the Matched Value Number Residues Portion Q8N6KO Similar to evidence:NAS putative 28..178 151/151(100%) 4e-83 unclassifiable - Homo sapiens 1..151 151/151 (100%) (Human), 151 aa. Q9DA77 1700018L24Rik protein - Mus 28..134 64/109 (58%) 9e-32 musculus (Mouse), 186 aa. 1..109 80/109 (72%) T46339 hypothetical protein 104..165 17/62 (27%) 1.8 DKFZp434AO814.1 - human, 913 198..259 33/62 (52%) aa (fragment). A53430 1-phosphatidylinositol-4,5-bisphosp 104..165 17/62 (27%) 1.8 hate phosphodiesterase (EC 458..519 33/62 (52%) 3.1.4.11) beta-lb -rat, 1173 aa. BAA25507 KIAAO581 protein - Homo sapiens 104..165 17/62 (27%) 1.8 (Human), 1076 aa (fragment). 318..379 33/62(52%) 5 PFam analysis predicts that the NOV14a protein contains the domains shown in the Table 14E. Table 14E. Domain Analysis of NOV14a Identities/ Similarities Pfam Domain NOV14a Match Region Similarities Expect Value for the Matched Region 178 WO 03/050245 PCT/USO2/38594 Example 15. The NOV15 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 15A. Table 15A. NOV15 Sequence Analysis SEQ ID NO: 91 947 bp NOVi 5a, GCCTkCTTArAGAAGCC-ACTCAGACACAGCCGTGTATGCTCCCAGCAGCACGGGTTCAGCT G162177-01 CCGCCTGCAGGGACAGAAAGACATGGTCTGGAAATGGATGCCACTTCTGCTGCTTCTGGTCTGTGTA GCCACCATGTGCAGTGCCCAGGACAGGACTGATCTCCTCAATGTCTGTATGGATGCCAAGCACCACA DNA Sequence AGACAAAGCCAGGTCCTGAGGACAAGCTGCATGACCAATGCAGTCCCTGGAAGAAGAATGCCTGCTO CACAGCCAGCACCAGCCAGGAGCTGCACAAGGACACCTCCCGCCTGTACAACTTTAACTGGGACCAC TGCGGCAAGATGGAGCCCGCCTGCAAGCGCCACTTCATCCAGGACACCTGTCTCTATGAGTGCTCAC CCAACCTGGGGCCCTGGATCCAGCAGGTGAATCAGAGCTGGCGCAAAGAACGCTTCCTGGATGTGCC CTTATGCAAAGAGGACTGTCAGCGCTGGTGGGAGGATTGTCACACCTCCCACACGTGCAAGAGCAAC TGGCACAGAGGATGGGACTGGACCTCAGGAGTTAACAAGTGCCCAGCTGGGGCTCTCTGCCGCACCT TTGAGTCCTACTTCCCCACTCCAGCTGCCCTTTGTGAAGGCCTCTGGAGTCACTCATACAAGGTCAG CAACTACAGCCGAGGGAGCGGCCGCTGCATCCAGATGTGGTTTGATTCAGCCCAGGGCAACCCCAAC GAGGAAGTGGCGAGTTCTATGCTCAGCCATGCATGTGAATGCTGGTGAGATGCTTCATGGGACTG GGGGTCTCCTGCTCAGTCTGGCCCTGATGCTGCAACTCTGGCTCCTTGGCTGAGTTCAGTCCTCCCA AACTACCTGCCCTCAGCTTGGATAACCAGGCTGGGCTCAGCTCAGCTCCCACAAATGACAGCCCCTT AAGCATGCT ORF Start: ATGat90 ORF Stop: TGA at 855 SEQ ID NO: 92 1255 aa JMW at 29279.2kD NOV15a, MVWKWMPLLLLLVCVATMCSAQDRTDLLNVCMDAKHHKTKPGPEDKLHDQCSPWK ACCTASTSQE CG1 I LHKDTSRLYNFNWDHCGKMEPACKRHFIQDTCLYECSPNLGPWIQQVNQSWRKERFLDVPLCKEDCQ 62177-0 RWWEDCHTSHTCKSNWHRGWDWTSGVNKCPAGALCRTFESYFPTPAALCEGLWSHSYKVSNYSRGSG Protein Sequence RCIQMWFDSAQGNPNEEVARFYAAAMHVNAGEMLHGTGGLLLSLALMLQLWLLG SEQ ID NO: 93 814 bp NOV15b, GGAM C T ACGC CG CGTG TC CG162177-02 TCCGCCTGCAGGGACAGAAAGACATGGTCTGGAAATGGATGCCACTTCTGCTGCTTCTGGTCTGTGT AGCCACCATGTGCAGTGCCCAGGACAGGACTGATCTCCTCAATGTCTGTATGGATGCCAAGCACCAC DNA Sequence AAGACAAAGCCAGGTCCTGAGGACAAGCTGCATGACCAATGCAGTCCCTGGAAGAAGAATGCCTGCT GCACAGCCAGCACCAGCCAGGAGCTGCACAAGGACACCTCCCGCCTGTACAACTTTAACTOGGACCA CTGCGGCAAGATGGAGCCCGCCTGCAAGCGCCACTTCATCCAGGACACCTGTCTCTATGAGTGCTCA CCCAACCTGGGGCCCTGGATCCAGCAGGTGAATCAGAGCTGGCGCAAAGAACGCTTCCTGGATGTGC CCTTATGCAAAGAGGACTGTCAGCGCTGGTGGGAGGATTGTCACACCTCCCACACGTGCAAGAGCAA CTGGCACAGAGGATGGGACTGGACCTCAGCTGCCCTTTGTGAAGGCCTCTGGAGTCACTCATACAAG GTCAGCAACTACAGCCGAGGGAGCGGCCGCTGCATCCAGATGTGGTTTGATTCAGCCCAGGGCAACC CCAACGAGGAAGTGGCGAGGTTCTATGCTGCAGCCATGCATGTGAATGCTGGTGAGATGCTTCATGG GACTGGGGGTCTCCTGCTCAGTCTGGCCCTGATGCTGCAACTCTGGCTCCTTGGCTGAGTTCAGTCC TCCCAGACTA ORF Start: ATG at 91 ORF Stop: TGA at 793 SEQ D NO 94 234 aa MW at 27038.7kD NOV15b MVWKWMPLLLLLVCVATMCSAQDRTDLLNVCMDAKHHKTKPGPEDKLHDQCSPWKNACCTASTSQE CG162177-02 LHKTSRLYNFNHCGKMEPACKRHFIQDTCLYECSPNLPWIQQVNQSWRKERFLDVPLCKEDCQ C~l6277-02 RWWEDCHTSHTCKSNWHRGWDWTSAALCEGLWSHSYKVSNYSRGSGRCIQMWFDSAQGNPNEEVARq Protein Sequence YAAAMHVNAGEMLHGTGGLLLSLALMLQLWLLG Sequence comparison of the above protein sequences yields the following sequence 10 relationships shown in Table 15B. Table 15B. Comparison of NOV15a against NOV15b. 179 WO 03/050245 PCT/USO2/38594 NOV15a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region NOV15b 1..255 234/255 (91%) 1..234 234/255 (91%) Further analysis of the NOV1 5a protein yielded the following properties shown in Table 15C. Table 15C. Protein Sequence Properties NOV15a SignalP analysis: Cleavage site between residues 22 and 23 PSORTII PSG: a new signal peptide prediction method analysis: N-region: length 4; pos.chg 1; neg.chg 0 analysis: H-region: length 18; peak value 11.09 PSG score: 6.69 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): 5.18 possible cleavage site: between 21 and 22 >>> Seems to have a cleavable signal peptide (1 to 21) ALOM: Klein et al's method for TM region allocation Init position for calculation: 22 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -2.44 Transmembrane 239 - 255 PERIPHERAL Likelihood = 8.22 (at 219) ALOM score: -2.44 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 10 Charge difference: -2.0 C( 0.0) - N( 2.0) N >= C: N-terminal side will be inside >>> membrane topology: type la (cytoplasmic tail 255 to 255) >>> Seems to be GPI anchored MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 7.26 Hyd Moment(95): 6.46 G content: 0 D/E content: 1 S/T content: 2 Score: -4.19 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 10.2% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none 180 WO 03/050245 PCT/USO2/38594 PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 55.5 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 55.6 %: extracellular, including cell wall 22.2 %: endoplasmic reticulum 11.1%: Golgi 11.1%: plasma membrane >> prediction for CG162177-01 is exc (k=9) A search of the NOV1 5a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 15D. 5 Table 15D. Geneseq Results for NOV15a NOV15a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region AAB50286 Human folate receptor II 1..255 254/255 (99%) e-164 protein SEQ ID NO: 6 - 1..255 255/255 (99%) Homo sapiens, 255 aa. 181 WO 03/050245 PCT/USO2/38594 30-NOV-2000] ABP41366 Human ovarian antigen 8..254 187/252 (74%) e-115 HLHCI46, SEQ ID NO:2498 22..269 207/252 (81%) - Homo sapiens, 270 aa. [WO200200677-A1, 03-JAN-2002] ABG19167 Novel human diagnostic 1..231 183/238 (76%) e-112 protein #19158 - Homo 3..240 203/238 (84%) sapiens, 248 aa. [WO200175067-A2, 11-OCT-2001] ABG04155 Novel human diagnostic 50..254 141/209 (67%) 7e-81 protein #4146 - Homo 1..205 157/209 (74%) sapiens, 206 aa. [WO200175067-A2, 11-OCT-2001] AAE09454 Human sbg72825FOLATEa 5..226 131/229 (57%) 2e-80 protein - Homo sapiens, 250 4..229 158/229 (68%) aa. [WO200160850-A1, 23-AUG-2001] In a BLAST search of public sequence datbases, the NOV1 5a protein was found to have homology to the proteins shown in the BLASTP data in Table 15E. Table 15E. Public BLASTP Results for NOV15a Protein NOV15a Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion P14207 Folate receptor beta precursor 1..255 254/255 (99%) e-164 (FR-beta) (Folate receptor 2) 1..255 255/255 (99%) (Folate receptor, fetal/placental) (Placental folate-binding protein) (FBP) - Homo sapiens (Human), 255 aa. P41439 Folate receptor gamma 1..231 194/235 (82%) e-125 precursor (FR-gamma) (Folate 1..235 213/235 (90%) receptor 3) - Homo sapiens (Human), 243 aa. Q05685 Folate receptor beta precursor 1..255 196/255 (76%) e-121 (FR-beta) (Folate receptor 2) 1..251 215/255 (83%) (Folate- binding protein 2) Mus musculus (Mouse), 251 aa. 182 WO 03/050245 PCT/USO2/38594 P79388 Folate binding protein - Sus 1..254 187/254 (73%) e-120 scrofa (Pig), 253 aa. 1..252 214/254 (83%) Q9ROD3 Folate receptor alpha - 6..253 188/251 (74%) e-117 Cricetulus griseus (Chinese 7..253 210/251 (82%) Shamster), 261 aa. PFam analysis predicts that the NOV15a protein contains the domains shown in the Table 15F. Table 15F. Domain Analysis of NOV15a Identities/ Pfam Domain NOV15a Match Region Similarities Expect Value for the Matched Region Folate rec 5..246 182/247 (74%) 6.3e-174 S230/247 (93%) 5 Example 16. The NOV16 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 16A. Table 16A. NOV16 Sequence Analysis SEQ IDNO: 95 1217bp NOV16a, TTATGGCAGCCGGAACAGCAGTTGGAGCCTGGGTGCTCGTCCTCAGTCTGTGGGGGGCAGTAGTAGG CGI62443-02 TGCTCAAAACATCACAGCTCGGATTGGCGAGCCACTGGTGCTGAAGTGTAAGGGGGCCCCCAAGAAA DNA Sequence CCACCCCAGCGGCTGGAATGGAAACTGAACACAGGCCGGACAGAAGCTTGGAAGGTCCTGTCTCCCC DNA Sequence AGGGAGGAGGCCCCTGGGACAGTGTGGCTCGTGTCCTTCCCAACGGCTCCCTCTTCCTTCCGGCTGT CGGGATCCAGGATGAGGGGATTTTCCGGTGCCAGGCAATGAACAGGAATGGAAAGGAGACCAAGTCC AACTACCGAGTCCGTGTCTACCAGATTCCTGGGAAGCCAGAAATTGTAGATTCTGCCTCTGAACTCA CGGCTGGTGTTCCCAATAAGGTGGGGACATGTGTGTCAGAGGGAAGCTACCCTGCAGGGACTCTTAG CTGGCACTTGGATGGGAAGCCCCTGGTGCCTAATGAGAAGGGAGTATCTGTGAAGGAACAGACCAGG AGACACCCTGAGACAGGGCTCTTCACACTGCAGTCGGAGCTAATGGTGACCCCAGCCCGGGGAGGAG ATCCCCGTCCCACCTTCTCCTGTAGCTTCAGCCCAGGCCTTCCCCGACACCGGGCCTTGCGCACAGC CCCCATCCAGCCCCGTGTCTGGGAGCCTGTGCCTCTGGAGGAGGTCCAATTGGTGGTGGAGCCAGAA GGTGGAGCAGTAGCTCCTGGTGGAACCGTAACCCTGACCTGTGAAGTCCCTGCCCAGCCCTCTCCTC AAATCCACTGGATGAAGGATGGTGTGCCCTTGCCCCTTCCCCCCAGCCCTGTGCTGATCCTCCCTGA GATAGGGCCTCAGGACCAGGGAACCTACAGCTGTGTGGCCACCCATTCCAGC CACGGGCCCCAGGAA AGCCGTGCTGTCAGCATCAGCATCATCGAACCAGGCGAGGAGGGGCCAACTGCAGGCTCTGTGGGAG GATCAGGGCTGGGAACTCTAGCCCTGGCCCTGGGGATCCTGGGAGGCCTGGGGACAGCCGCCCTGCT CATTGGGGTCATCTTGTGGCAAAGGCGGCAACGCCGAGGAGAGGAGAGGAAGGCCCCAGAAAACCAG GAGGAAGAGGAGGAGCGTGCAGAACTGAATCAGTCGGAGGAACCTGAGGCAGGCGAGAGTAGTACTG GAGGGCCTTGA ORFStart: AT G at3 ORF Stop: TGA at 1215 ... . SEQ IDNO: 96 __ 404aa MWat42802.3kD NOV16a, MAAGTAVGAWVLVLSLWGAVVGAQNITARIGEPLVLKCKGAPKKPPQRLEWKLNTGRTEAWKVLSPQ CG162443-02 GGGPWDSVARVLPNGSLFLPAVGIQDEGIFRCQAMNRNGIETKSNYRVRVYQIPGKPEIVDSASELT Protein Sequence AGVPNKVGTCVSEGSYPAGTLSWHLDGKPLVPNEKGVSVKEQTRRHPETGLFTLQSELMVTPARGGD ProteinSequencePRPTFSCSFSPGLPRHRALRTAPIQPRVWEPVPLEEVQLVVEPEGGAVAPGGTVTLTCEVPAQPSPQ IHWMKDGVPLPLPPSPVLILPEIGPQDQGTYSCVATHSSHGPQESRPAVSISIIEPGEEGPTAGSVGG SGLGTLALALGILGGLGTAALLIGVILWQRRQRRGEERKAPENQEEEEERAELNQSEEPEAGESSTG 183 WO 03/050245 PCT/USO2/38594 SEQIDNO 97 126bp NV0 716b, 3CCAGGACCCTGGAAGGAAGCAGGATGGCAGCCGGAACAGCAGTTGGAACCTGGGTGCTGGTCCTCA CTCTGTGGGGGGCAGTAGTAGGTGCTCAAACATCACAGCCCGGATTGGCGAGCCACTGGTGCTGAA DNA62443-01 GTGTAAGGGGGCCCCCAAGAAACCACCCCAGCGGCTGGAATGGAAACTGGGAGGAGGCCCCTGGGAC DNA Sequence AGTGTGGCTCGTGTCCTTCCCAACGGCTCCCTCTTCCTTCCGGCTGTCGGGATCCAGGATGAGGGGA TTTTCCGGTGCCAGGCAATGAACAGGAATGGAAAGGAGACCAAGTCCAACTACCGAGTCCGTGTCTA CCAGATTCCTGGGAAGCCAGAAATTGTAGATTCTGCCTCTGAACTCACGGCTGGTGTTCCCAATAAG 3TGGGGACATGTGTGTCAGAGGGAAGCTACCCTGCAGGGACTCTTAGCTGGCACTTGGATGGGAAGC CCCTGGTGCCTAATGAGAAGGGAGTATCTGTGAAGGAACAGACCAGGAGACACCCTGAGACAGGGCT CTTCACACTGCAGTCGGAGCTAATGGTGACCCCAGCCCCGGGGAGGAGATCCCCGTCCCACCTTCTCC TGTAGCTTCAGCCCAGGCCTTCCCCGACACCGGGCCTTGCGCACAGCCCCCATCCAGCCCCGTGTCT GGGAGCCTGTGCCTCTGGAGGAGGTCCAATTGGTGGTGGAGCCAGAAGGTGGAGCAGTAGCTCCTGG TGGAACCGTAACCCTGACCTGTGAAGTCCCTOCCCAGCCCTCTCCTCAAATCCACTGGATGAAGGAT GGTGTGCCCTTGCCCCTTCCCCCCAGCCCTGTGCTGATCCTCCCTGAGATAGGGCCTCAGGACCAGG GAACCTACAGCTGTGTGGCCACCCATTCCAGCCACGGGCCCCAGGAAAGCCGTGCTGTCAGCATCAG CATCATCGAACCAGGCGAGGAGGGGCCAACTGCAGGCTCTGTGGGAGGATCAGGGCTGGGAACTCTA GCCCTGGCCCTGGGGATCCTGGGAGGCCTGGGGACAGCCGCCCTGCTCATTGGGGTCATCTTGTGGC AAACGCGGCAACGCCGAGGAGAGGAGAGGAAGGCCCCAGAAAACCAGGAGGAAGAGGAGGAGCGTGC AGAACTGAATCAGTCGGAGGAACCTGAGGCAGGCGAGAGTAGTACTGGAGGGCCTTGAGGGGCCCAC AGACAGATCCCATCCATCAG ORF Start: ATG at 25 IORF Stop: TGA at 1195 SEQ ID NO: 98 _390 aa MW at 41263.6kD NOVL 6b ~ MAACTAVGTWVLVLSLWGAVVCAQNITARIGEPLVLKCKGAPKKPPQRLEWKLGGGPWDSVARVLPN CXG162443-01 GSLFLPAVGIQDEGIFRCQAMNRNGKETKSNYRVRVYQIPGKPEIVDSASELTAGVPNKVGTCVSEG SYPAGTLSWHLDGKPLVPNEKGVSVKEQTRRHPETGLFTLQSELMVTPARGGDPRPTFSCSFSPGLP Protein Sequence RHRALRTAPIQPRVWEPVPLEEVQLVVEPEGGAVAPGGTVTLTCEVPAQPSPQIHWMKDGVPLPLPP SPVLILPEIGPQDQGTYSCVATHSSHGPQESRAVSISIIEPGEEGPTAGSVGGSGLGTLALALGILG GLGTAALLIGVILWQRRQRRGEERKAPENQEEEEERAELNQSEEPEAGESSTGGP SEQ ID NO: 99 1173 bp NOV16c, ATGGCAGCCGGAACAGCAGTTGGAGCCTGGGTGCTGGTCCTCAGTCTGTGGGGGCCAGTAGTAGGTG 0G162443-03 CTCAAAACATCACAGCCCGGATTGGCGAGCCACTGGTGCTGAAGTGTAAGGGGGCCCCCAAGAAACC ACCCCAGCGGCTGGAATGGAAACTGGGAGGAGGCCCCTGGGACAGTGTGGCTCGTGTCCTTCCCAAC DNA Sequence GGCTCCCTCTTCCTTCCGGCTGTCGGGATCCAGGATGAGGGGATTTTCCGGTGCCAGGCAATGAACA GGAATGGAAAGGAGACCAAGTCCAACTACCGAGTCCGTGTCTACCAGATTCCTGGGAAGCCAGAAAT TGTAGATTCTGCCTCTGAACTCACGGCTGGTGTTCCCAATAAGGTGGGGACATGTGTGTCAGAGGGA AGCTACCCTGCAGGGACTCTTAGCTGGCACTTGGATGGGAAGCCCCTGGTGCCTAATGAGAAGGGAG TATCTGTGAAGGAACAGACCAGGAGACACCCTGAGACAGGGCTCTTCACACTGCAGTCGGAGCTAAT GGTGACCCCAGCCCGGGGAGGAGATCCCCGTCCCACCTTCTCCTGTAGCTTCAGCCCAGGCCTTCCC CGACACCGGGCCTTGCGCACAGCCCCCATCCAGCCCCTGTCTGCGAGCCTGTCCTCTGGAGGAGG TCCAATTGGTGGTGGAGCCAGAAGGTGGAGCAGTAGCTCCTGGTGGAACCGTAACCCTGACCTGTGA AGTCCCTGCCCAGCCCTCTCCTCAAATCCACTCGATGAAGGATGGTGTGCCCTTGCCCCTTCCCCCC AGCCCTGTGCTGATCCTCCCTGAGATAGGGCCTCAGGACCAGGGAACCTACAGCTGTGTGGCCACCC ATTCCAGCCACGGGCCCCAGGAAAGCCGTGCTGTCAGCATCAGCATCATCGAACCAGGCGAGGAGGG GCCAACTGCAGGCTCTGTGGGAGGATCAGGGCTGGGAACTCTAGCCCTGGCCCTGGGGATCCTGGGA GGCCTGGGGACAGCCGCCCTGCTCATTGGGGTCATCTTGTGGCAAAGGCGGCAACGCCGAGGAGAGG AGAGGAAGGCCCCAGAAAACCAGGAGGAAGAGGAGGAGCGTGCAGAACTGAATCAGTCGGAGGAACC TGAGGCAGGCGAGAGTAGTACTGGACGGCCTTGA ORF Start: ATG at 1 ORF Stop: TGA at 1171 SEQ ID NO: 100 390 aa MW at 41233.5kD NOV16c, MAAGTAVGAWVLVLSLWGAVVGAQNITARIGEPLVLKCKGAPKKPPQRLEWKLGGGPWDSVARVLPN CG162443-03 GSLFLPAVGIQDEGIFRCQAMNRNGKETKSNYRVRVYQIPGKPEIVDSASELTAGVPNKVGTCVSEG SYPAGTLSWHLDGKPLVPNEKGVSVKEQTRRHPETGLFTLQSELMVTPARCGDPRPTFSCSPSPGLP Protein Sequence RHRALRTAPIQPRVWEPVPLEEVQLVVEPEGGAVAPGGTVTLTCEVPAQPSPQIEWMKDGVPLPLPP SPVLILPEIGPQDQGTYSCVATHSSHGPQESRAVSISIIEPGEEGPTAGSVGGSGLGTLALALGILG GLGTAALLIGVILWQRRQRRGEERKAPENQEEEEERAELNQSEEPEAGESSTGGP 5 Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 16B. 184 WO 03/050245 PCT/US02/38594 Table 16B. Comparison of NOV16a against NOV16b and NOV16c. SNOV16a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region NOV16b 1..404 389/404 (96%) 1..390 389/404 (96%) NOV16c 1..404 390/404(96%) 1..390 390/404 (96%) Further analysis of the NOV1 6a protein yielded the following properties shown in Table 16C. 5 Table 16C. Protein Sequence Properties NOV16a SignalP Cleavage site between residues 24 and 25 analysis: PSORTII PSG: a new signal peptide prediction method analysis: N-region: length 0; pos.chg 0; neg.chg 0 H-region: length 28; peak value 9.40 PSG score: 5.00 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): 2.36 possible cleavage site: between 22 and 23 >>> Seems to have a cleavable signal peptide (1 to 22) ALOM: Klein et al's method for TM region allocation Init position for calculation: 23 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -5.68 Transmembrane 345 - 361 PERIPHERAL Likelihood = 2.54 (at 75) ALOM score: -5.68 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 11 Charge difference: 2.0 C( 3.0) - N( 1.0) C > N: C-terminal side will be inside >>>Caution: Inconsistent mtop result with signal peptide >>> membrane topology: type la (cytoplasmic tail 362 to 404) MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 2.53 Hyd Moment(95): 0.37 G content: 5 D/E content: 1 S/T content: 3 Score: -6.73 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 58 QRLIEW NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 9.4% NLS Score: -0.47 185 WO 03/050245 PCT/USO2/38594 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 76.7 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 44.4 %: endoplasmic reticulum 22.2 %: Golgi 22.2 %: extracellular, including cell wall 11.1 %: plasma membrane >> prediction for CG162443-02 is end (k=9) A search of the NOV16a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 16D. 5 Table 16D. Geneseq Results for NOV16a 186 WO 03/050245 PCT/USO2/38594 NOV16a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for the Expect Identifier [Patent #, Date] Match Value Residues Matched Region AAB81925 Extracorporeal circulation 1..404 404/404 (100%) 0.0 material receptor protein - 1..404 404/404 (100%) Unidentified, 404 aa. [WO200118060-A1, 15-MAR-2001] AAM48745 Human RAGE protein SEQ 2..404 403/403 (100%) 0.0 ID NO 1 - Homo sapiens, 2..404 403/403 (100%) 404 aa. [WO200192892-A2, 06-DEC-2001] AAE23219 Human receptor for 2..404 402/403 (99%) 0.0 advanced glycosylation end 2..404 403/403 (99%) product (RAGE) protein Homo sapiens, 404 aa. [WO200230889-A2, 18-APR-2002] AAU77543 Human receptor for 2..404 402/403 (99%) 0.0 advanced glycosylation end 2..404 403/403 (99%) product (RAGE) - Homo sapiens, 404 aa. [WO200214519-A1, 21-FEB-2002] AAW33753 Human RAGE polypeptide 1..340 340/340 (100%) 0.0 (340 amino acid residues) - 1..340 340/340 (100%) [WO9739121-A1, 23-OCT-1997] In a BLAST search of public sequence datbases, the NOV16a protein was found to have homology to the proteins shown in the BLASTP data in Table 16E. Table 16E. Public BLASTP Results for NOV16a Protein NOV16a Identities/ Residues/ Expect Accession Protein/Organism/Length Match Similarities for the ValuExpect Number Mac Matched Portion Residues Q15109 Advanced glycosylation end 1..404 404/404 (100%) 0.0 product-specific receptor 1..404 404/404 (100%) precursor (Receptor for advanced glycosylation end products) - Homo sapiens (Human), 404 aa. 187 WO 03/050245 PCT/USO2/38594 Q28173 Advanced glycosylation end 1..404 337/417 (80%) 0.0 product-specific receptor 1..416 363/417 (86%) precursor (Receptor for advanced glycosylation end products) - Bos taurus (Bovine), 416 aa. Q62151 Advanced glycosylation end 1..404 315/404 (77%) 0.0 product-specific receptor 1..403 341/404 (83%) precursor (Receptor for advanced glycosylation end products) - Mus musculus (Mouse), 403 aa. Q63495 Advanced glycosylation end 1..404 315/404 (77%) 0.0 product-specific receptor 1..402 345/404 (84%) precursor (Receptor for advanced glycosylation end products) - Rattus norvegicus (Rat), 402 aa. 035444 RAGE - Mus musculus 1..404 316/404 (78%) 0.0 (Mouse), 402 aa. 1..402 342/404 (84%) PFam analysis predicts that the NOV16a protein contains the domains shown in the Table 16F. Table 16F. Domain Analysis of NOV16a Identities/ Similarities Pfam Domain NOV16a Match Region for the Matched Expect Value Region ig 31..101 13/73 (18%) 0.00018 44/73 (60%) ig 252..303 19/55 (35%) 5.1e-12 S39/55 (71%) 5 Example 17. The NOV17 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 17A. Table 17A. NOV17 Sequence Analysis ........ SEQ ID NO: 101 471 bp NOV17a, 'GGGACCGGGGCCATGTCTCCACACCTCACTGCTCTCCTGGGCCTAOTGCTCTGCCTGGCCCAGACCA CG162509-02 TCCACACGCAGGAGGGGGCCCTTCCCAGACCCTCCATCTCGGCTGAGCCAGGCACTGTGATCTCCCC GGGGAGCCATGTGACTTTCATGTGCCGGGGCCCGGTTGGGGTTCAAACATTCCGCCTGGAGAGGGAG DNA Sequence GATAGAGCCAAGTACAAAGATAGTTATAATGTGTTTCGACTTGGTCCATCTGAGTCAGAGGCCAGAT 188 WO 03/050245 PCT/USO2/38594 TCCACATTGACTCAGTAAGTGAAGGAAATGCCGGGCTTTATCGCTGCCTCTATTATAAGCCCCCTGG ATGGTCTGAGCACAGTGACTTCCTGGAGCTGCTGGTGAAAGAAAGCTCTGGAGGCCCGGACTCCCCG GACACAGAGCCCGGCTCCTCAGCTGGGACTGTGCCAGGCACTGAAGCCTCCGGATTTGATGCACCAT GA ORF Start: ATG at 13 ORF Stop: TGA at 469 _ _ _ SEQ ID NO: 102 152 aa MW at 16279.9kD NOV17a, MSPHLTALLGLVLCLAQTIHTQEGALPRPSISAEPGTVISPGSHVTFMCRGPVGVQTRLEREDRAK CG162509-02 YKDSYNVFRLGPSESEARFHIDSVSEGNAGLYRCLYYKPPGWSEHSDFLELLVKESSGGPDSPDTEP Protei n n Se quence SSAGTVPGTEASGFDAP Protein Sequence,______ SEQ ID NO: 103 478 bp NOV17 Tb, CACCGGATCCACCATGTCTCCACACCTCACTGCTCTCCTGGGCCTAGTGCTCTGCCTGGCCCAGACC 306610228 DNA ATCCACACGCAGGAGGGGGCCCTTCCCAGACCCTCCATCTCGGCTGAGCCAGGCACTGTGATCTCCC SCGGGGAGCCATGTGACTTTCATGTGCCGGGGCCCGGTTGGGGTTCAAACATTCCGCCTGGAGAGGGA Sequence GGATAGAGCCAAGTACAAAGATAGTTATAATGTGTTTCGACTTGGTCCATCTGAGTCAGAGGCCAGA TTCCACATTGACTCAGTAAGTGAAGGAAATGCCGGGCTTTATCGCTGCCTCTATTATAAGCCCCCTG GATGGTCTGAGCACAGTGACTTCCTGGAGCTGCTCGTGAAAGAAAGCTCTGGAGGCCCGGACTCCCC GGACACAGAGCCCGGCTCCTCAGCTGGGACTGTGCCAGGCACTGAAGCCTCCGGATTTGATGCACCA CTCGAGGGC ORF Start: at 2 ORF Stop: end of sequence ........ SEQ ID NO: 104 159 aa MW at 16925.6kD NOV17b, TGSTMS PI H L

TALLGLVLCLAQTI

H

TQEGALPRPSISAEPGTVISPG

S H

VTFMCRGPVGVQTFRLER

E 306610228 DRAKYKDSYNVFRLGPSESEARFHIDSVSEGNAGLYRCLYYKPPGWSEHSDFLELLVKESSGGPDSP Protein Sequence DTEPGSSAGTVPGTEASGFDAPLEG Protem Se.quenc SEQ ID NO: 105 427 bp NOV17c, CACCGGATCCACCATGTCTCCACACCTCACTGCTCTCCTGGGCCTAGTGCTCTGCCTGGCCCAGACC 306610270 DNA ATCCACACGCAGGAGGGGGCCCTTCCCAGACCCTCCATCTCGGCTGAGCCAGGCACTGTGATCTCCC CGGGGAGCCATGTGACTTTCATGTGCCGGGGCCCGGTTGGGGTTCAAACATTCCGCCTGGAGAGGGA Sequence GGATAGAGCCAAGTACAAAGATAGTTATAATGTGTTTCGACTTGGTCCATCTGAGTCAGAGGCCAGA TTCCACATTGACTCAGTAAGTGAAGGAAATGCCGGGCTTTATCGCTGCCTCTATTATAAGCCCCCTG GATGGTCTGAGCACAGTGACTTCCTGGAGCTGCTGGTGAAAGGGACTGTGCCAGGCACTGAAGCCTC CGGATTTGATGCACCACTCGAGGGC ORF Start: at 2 ORF Stop: end of sequence SEQ ID NO: 106 _142 aa JMW at 15367.1kD NOV17c, TGSTMSPHLTALLGLVLCLAQTIHTQEGALPRPSISAEPGTVISPGSHVTFMCRGPVGVQTFRLERE 306610270 DRAKYKDSYNVFRLGPSESEARFHIDSVSEGNAGLYRCLYYKPPGWSEHSDFLELLVKGTVPGTEAS Protein Sequence GFDAPLEG SEQ ID NO: 107 J421 bp NOV17d, GGGACCGGGGCCATGTCTCCACACCTCACTGCTCTCCTGGGCCTAGTGCTCTGCCTGGCCCAGACCA CG162509-01 TCCACACGCAGGAGGGGGCCCTTCCCAGACCCTCCATCTCGGCTGAGCCAGGCACTGTGATCTCCCC GGGGAGCCATGTGACTTTCATGTGCCGGGGCCCGGTTGGGGTTCAAACATTCCGCCTGGAGAGGGAG DNA Sequence GATAGAGCCAAGTACAAAGATAGTTATAATGTGTTTCGACTTGGTCCATCTGAGTCAGAGGCCAGAT TCCACATTGACTCAGTAAGTGAAGGAAATGCCGGGCTTTATCGCTGCCTCTATTATAAGCCCCCTGG ATGGTCTGAGCACAGTGACTTCCTGGAGCTGCTGGTGAAAGGGACTGTGCCAGGCACTGAAGCCTCC GGATTTGATGCACCATGAA ORF Start: ATG at 13 ORF Stop: TGA at 418 ~...,~Q1DN9135 aa .I a .... M at 14721.5kD. .. NOVI17d, MSPHLTALLGLVLCLAQTIHTQEGALPRPSISAEPGTVISPGSHVTFMCRGPVGVQTFRLEREDRAK CG162509-01 YKDSYNVFRLGPSESEARFHIDSVSEGNAGLYRCLYYKPPGWSEHSDFLELLVKGTVPGTEASGFDA P Protein Sequence Sequence comparison of the above protein sequences yields the following sequence 10 relationships shown in Table 17B. 189 WO 03/050245 PCT/USO2/38594 Table 17B. Comparison of NOV17a against NOV17b through NOV17d. SNOV17a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region NOV17b 1..152 152/152 (100%) 5..156 152/152 (100%) NOV17c 1..152 135/152 (88%) 5..139 135/152 (88%) NOV17d 1..152 135/152 (88%) 1..135 135/152 (88%) Further analysis of the NOV1 7a protein yielded the following properties shown in Table 17C. 5 Table 17C. Protein Sequence Properties NOV17a SignalP analysis: Cleavage site between residues 22 and 23 PSORTIl PSG: a new signal peptide prediction method analysis: N-region: length 0; pos.chg 0; neg.chg 0 H-region: length 22; peak value 10.25 PSG score: 5.85 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): 2.05 possible cleavage site: between 21 and 22 >>> Seems to have a cleavable signal peptide (1 to 21) ALOM: Klein et al's method for TM region allocation Init position for calculation: 22 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood = 9.02 (at 38) ALOM score: 9.02 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 10 Charge difference: -2.0 C(-0.5) - N( 1.5) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 3.32 Hyd Moment(95): 2.96 G content: 1 D/E content: 1 S/T content: 4 Score: -5.02 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 7.9% NLS Score: -0.47 190 WO 03/050245 PCT/USO2/38594 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 70.6 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 66.7 %: extracellular, including cell wall 22.2 %: mitochondrial 11.1 %: nuclear >> prediction for CG162509-02 is exc (k=9) A search of the NOVI17a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 17D. 5 Table 17D. Geneseq Results for NOV17a NOV17a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value _ Residues Region AAW62776 7e-73 191 WO 03/050245 PCT/USO2/38594 gamma and Fc alpha, 1..135 135/152 (88%) designated DLAIR-2 - Homo sapiens, 135 aa. [WO9824906-A2, 11-JUN-1998] ABP41696 Human ovarian antigen 1.139 115/139 (82%) 2e-62 HVVBV73, SEQ ID 36..174 123/139 (87%) NO:2828 - Homo sapiens, 322 aa. [WO200200677-Al, 03-JAN-2002] AAB58453 Lung cancer associated 1..139 115/139 (82%) 2e-62 polypeptide sequence SEQ 36..174 123/139 (87%) ID 791 - Homo sapiens, 322 aa. [WO200055180-A2, 21-SEP-2000] AAW62775 Human receptor for Fe 1..139 115/139 (82%) 2e-62 gamma and Fc alpha - Homo 1..139 123/139 (87%) sapiens, 287 aa. [WO9824906-A2, 11-JUN-1998] AAW62774 Human receptor for Fe 1..139 115/139 (82%) 2e-62 gamma and Fe alpha, 1..139 123/139 (87%) designated YE01 - Homo sapiens, 287 aa. [WO9824906-A2, 11-JUN-1998] In a BLAST search of public sequence datbases, the NOV1 7a protein was found to have homology to the proteins shown in the BLASTP data in Table 17E. Table 17E. Public BLASTP Results for NOV17a Protein NOV17a Identities/ ProteinResidues/ Similarities for Expect Accession Protein/Organism/Length Match the Matched Value Number Residues Portion AAB69325 Leukocyte-associated Ig-like 1..152 135/152 (88%) 2e-72 receptor-2 - Homo sapiens 1..135 135/152 (88%) (Human), 135 aa. AAB69324 Leukocyte-associated Ig-like 1..139 115/139 (82%) 7e-62 receptor-1 - Homo sapiens 1.139 123/139 (87%) (Human), 287 aa. AAF71275 Leukocyte-associated Ig-like 1..139 115/139 (82%) 7e-62 receptor 1D isoform - Homo 1..139 123/139 (87%) sapiens (Human), 209 aa. 192 WO 03/050245 PCT/USO2/38594 AAF17107 Leukocyte-associated Ig-like 1..127 99/127 (77%) 4e-51 receptor lb - Homo sapiens 1..127 107/127 (83%) (Human), 270 aa. AAF71274 Leukocyte-associated Ig-like 1..127 99/127 (77%) 5e-50 receptor 1C isoform - Homo l..126 107/127 (83%) sapiens (Human), 269 aa. PFam analysis predicts that the NOV17a protein contains the domains shown in the Table 17F. Table 17F. Domain Analysis of NOV17a Identities/ Similarities Pfam Domain NOV17a Match Region for the Matched Expect Value Region ig 42..103 11/66 (17%) 1.5e-05 45/66 (68%) 5 Example 18. The NOV18 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 18A. Table 18A. NOV18 Sequence Analysis SEQ ID NO: 109 800bp NOV18a, CCCCTCTCCTGCCTGGACGGCTCTGCTGGTCTCCCCGTCCCCTGGAGAAGAACAAGGCCATGGGTCG CG162645-02 GCCCCTGCTGCTGCCCCTACTGCCCCTGCTGCTGCCGCCAGCATTTCTGCAGCCTAGTGGCTCCACA GGATCTGGTCCAAGCTACCTTTATGGGGTCACTCAACCAAAACACCTCTCAGCCTCCATGGGTGGCT DNA Sequence CTGTGGAAATCCCCTTCTCCTTCTATTACCCCTGGGAGTTAGCCACAGCTCCCGACGTGAGAATATC CTGGAGACGGGGCCACTTCCACGGGCAGTCCTTCTACAGCACAAGGCCGCCTTCCATTCACAAGGAT TATGTGAACCGGCTCTTTCTGAACTGGACAGAGGGTCAGAAGAGCGGCTTCCTCAGGATCTCCAACC TGCAGAAGCAGGACCAGTCTGTGTATTTCTGCCGAGTTGAGCTGGACACACGGAGCTCAGGGAGGCA GCAGTGGCAGTCCATCGAGGGGACCAAACTCTCCATCACCCAGGGTCAGCAGCGGACTAAAGCCACA ACCCCAGCCAGGGAACCCTTCCAAAACACAGAGGAGCCATATGAGAATATCAGGAATGAAGGACAAA ATACAGATCCCAAGCTAAATCCCAAGGATGACGGCATCGTCTATGCTTCCCTTGCCCTCTCCAGCTC CACCTCACCCAGAGCACCTCCCAGCCACCGTCCCCTCAAGAGCCCCCAGAACGAGAACCTGTACTCT GTCTTAAAGGCCTAACCAATGGACAGCCCTCTCAAAACTGAATGGTGAAAGGGCGATTCCAGC ORF Start: ATG at 60 TAA at 750 SEQ ID NO: 110 230 aa MW at 25849.8kD NOVI8a, MGRPLLLPLLPLLLPPAFLQPSGSTGSGPSYLYGVTQPKHLSASMCGGSVEIPFSFYYPWELATAPDV CG162645-02 RISWRRGHFHGQSFYSTRPPSIHKDYVNRLFLNWTEGQKSGFLRISNLQKQDQSVYFCRVELDTRSS GRQQWQSIEGTKLSITQGQQRTKATTPAREPFQNTEEPYENIRNEGQNTDPKLNPKDDGIVYASLAL Protein Sequence SSSTSPRAPPSHRPLKSPQNENLYSVLKA SEQ IDNO: 111 653 bp ... NOV18b, CTGGAGAAGAACAAGGCCATGGGTCGGCCCCTGCTGCTGCCCCTACTGCCCCTGCTGCTGCCGCCAG CG162645-01 CGTTTCTGCAGCCTAGTGGCTCCACAGGATCTGGTCCAAGCTACCTTTATGGGGTCACTCAACCAAA ACACCTCTCAGCCTCCATGGGTGGCTCTGTGGAAATCCCCTTCTCCTTCTATTACCCCTGGGAGTTA DNA Sequence GCCACTTCCATTCACAAGGATTATGTGAACCGGCTCTTTCTGAACTGGACAGAGGGTCAGAAGAGCG GCTTCCTCAGGATCTCCAACCTGCAGAAGCAGGACCAGTCTGTGTATTTCTGCCGAGTTGAGCTGGA 193 WO 03/050245 PCT/USO2/38594 CACACGGAGCTCAGGGAGGCAGCAGTGGCAGTCCATCGAGGGGACCAAACTCTCCATCACCCAGGGT CAGCAGCGGACTAAAGCCACAACCCCAGCCAGGGAACCCTTCCAAAACACAGAGGAGCCATATGAGA ATATCAGGAATGAAGGACAAAATACAGATCCCAAGCTAAATCCCAAGGATGACGGCATCGTCTATGC TTCCCTTGCCCTCTCCAGCTCCACCTCACCCAGAGCACCTCCCAGCCACCGTCCCCTCAAGAGCCCC CAGAACGAGAACCTGTACTCTGTCTTAAAGGCCTAACCAATGGACAGCCC ......... ORF Start: ATG at 19 ORF Stop: TAA at 637 SEQ ID NO: 112 206aa MW at 23012.7kD NOV18b, MGRPLLLPLLPLLLPPAFLQPSGSTGSGPSYLYGVTQPKHLSASMGGSVEIPFSFYYPWELATSIHK CG162645-01 DYVRLLNWTEGQKSGLRISNLQKQDQSVYCRVELDTRSSGRQQWQSIEGTKLSITQGQQRTKA TTPAREPFQNTEEPYENIRNEGQNTDPKLNPKDDGIVYASLALSSSTSPRAPPSHRPLKSPQNENLY Protein Sequence SVLKA Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 18B. 5 Table 18B. Comparison of NOV18a against NOV18b. NOV18a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region NOV18b 1..230 206/230 (89%) 1..206 206/230 (89%) Further analysis of the NOV18a protein yielded the following properties shown in Table 18C. Table 18C. Protein Sequence Properties NOV18a SignalP analysis: Cleavage site between residues 20 and 21 PSORTII PSG: a new signal peptide prediction method analysis: N-region: length 3; pos.chg 1; neg.chg 0 H-region: length 35; peak value 8.58 PSG score: 4.18 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): 1.66 possible cleavage site: between 19 and 20 >>> Seems to have a cleavable signal peptide (1 to 19) ALOM: Klein et al's method for TM region allocation Init position for calculation: 20 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood = 8.91 (at 41) ALOM score: 8.91 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 9 Charge difference: -1.5 C( 0.5) - N( 2.0) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 10.02 Hyd Moment(95): 8.02 G content: 7 D/E content: 1 S/T content: 9 194 WO 03/050245 PCT/USO2/38594 Score: -3.94 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 13 GRPjLL NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 10.9% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: GRPL KKXX-like motif in the C-terminus: SVLK SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues

-------------------------

Final Results (k = 9/23): 44.4 %: extracellular, including cell wall 22.2 %: mitochondrial 22.2 %: nuclear 11.1 %: cytoplasmic >> prediction for CG162645-02 is exc (k=9) 195 WO 03/050245 PCT/USO2/38594 A search of the NOV1 8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 18D. Table 18D. Geneseq Results for NOV18a NOV18a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region AAB07444 A human monocyte-derived 1..230 229/230 (99%) e-134 protein FDF03DeltaTM - 1..230 229/230 (99%) Homo sapiens, 230 aa. [WO200040721-A1, 13-JUL-2000] ABG21403 Novel human diagnostic 1..179 157/179 (87%) 3e-89 protein #21394 - Homo 357..535 161/179 (89%) sapiens, 1012 aa. [WO200175067-A2, 11-OCT-2001] ABG16869 Novel human diagnostic 1..179 157/179 (87%) 3e-89 protein #16860 - Homo 357..535 161/179 (89%) sapiens, 1012 aa. [WO200175067-A2, 11-OCT-2001] ABG02851 Novel human diagnostic 1..179 157/179 (87%) 3e-89 protein #2842 - Homo 357..535 161/179 (89%) sapiens, 1012 aa. [WO200175067-A2, 11-OCT-2001] ABG00509 Novel human diagnostic 1..179 157/179 (87%) 3e-89 protein #500 - Homo sapiens, 357..535 161/179 (89%) 1012 aa. [WO200175067-A2, 11-OCT-2001] 5 In a BLAST search of public sequence datbases, the NOVI 8a protein was found to have homology to the proteins shown in the BLASTP data in Table 1 8E. Table 18E. Public BLASTP Results for NOV18a Protein NOV18a Identities/ Accession Protein/Organis/Length Residues/ Similarities for Expect NumbAccession Protein/Organism/Length r Match the Matched Value Residues Portion 196 WO 03/050245 PCT/USO2/38594 CAC01614 Cell surface receptor 1..230 229/230 (99%) e-134 FDF03-dtm precursor - 1..230 229/230 (99%) Homo sapiens (Human), 230 aa. Q8NHI1 Similar to paired 1.216 196/216 (90%) e-113 immunoglobulin-like receptor 1..212 202/216 (92%) alpha - Homo sapiens (Human), 226 aa. CAC01615 Cell surface receptor 1:.152 151/152 (99%) le-86 FDFO3-M14 precursor - 1..152 152/152 (99%) Homo sapiens (Human), 175 aa. CAC01613 Cell surface receptor FDFO3 L..169 155/169 (91%) le-86 precursor - Homo sapiens 1..164 156/169 (91%) (Human), 303 aa. Q9UKJ1 Inhibitory receptor 1..169 155/169 (91%) le-86 PILRalpha - Homo sapiens 1..164 156/169 (91%) (Human), 303 aa. PFam analysis predicts that the NOV 18a protein contains the domains shown in the Table 18F. Table 18F. Domain Analysis of NOV18a Identities/ SimIrtie Pfam Domain NOV18a Match Region Simi arities Expect Value for the Matched Region ig 65..127 10/65 (15%) 0.077 47/65 (72%) 5 Example 19. The NOV19 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 19A. Table 19A. NOV19 Sequence Analysis SEQ IDNO: 113 2203bp NOV19a, CACCGGATCCACCATGCTGCTGCCGCGGTCGGTGTCATCGGAGCGGGCCCCTGGGGTGCCGGAGCCG CG162687-02 GAGGAGCTGTGGGAGGCAGAGATGGAGCGGCTGCGCGGCTCTGGGACGCCCGTGCGTGGGCTGCCCT DNA SATGCCATGATGGACAAGCGCCTCATCTGGCAGCTGCGGGAGCCCGCGGGGGTGCAGACCTTGCGCTG DNA Sequence GCAGCGGTGGCAGCGCCGGCGGCAGACGGTGGAAAGGCGCCTGCGGGAGGCAGCGCAGCGGCTGGCC CGGGGCCTTGGGCTCTGGGAGGGGGCGCTCTACGAGATCGGGGGCCTCTTCGGCACAGGAATTCGGT CCTACTTCACCTTCCTCCGCTTCCTGCTGCTACTCAACCTGCTGAGTCTGCTGCTCACCGCAAGCTT CGTGCTGCTGCCCCTGGTCTGGCTCCGCCCCCCTGACCCAGGCCCCACCCTGAACTTGACCCTCCAG TGCCCTGGTAGCCGCCAGTCCCCGCCTGGCGTTTTGAGGTTCCACAATCAACTTTGGCATGTTTTGA CTGGCAGGGCCTTCACCAACACCTATCTCTTCTACGGTGCGTACCGAGTGGGGCCGGAGAGCAGCTC 197 WO 03/050245 PCT/USO2/38594 CGTGTACAGCATCCGCCTGACCTACCTCCTCAGCCCGCTGGCCTGCCTGCTCCTCTGCTTCTGTGGG ACTCTGCGGCGGATGGTGAAGGGGCTGCCGCAGAAGACTCTGCTGGGTCAGGGCTATCAGGCGCCTC TCAGCGCCAAGGTCTTCTCCTCATGGGACTTCTGCATCCGGGTGCAGGAAGCAGCCACCATCAAGAA GCATGAGATCAGCAACGAGTTCAAGGTGGAGCTGGAGGAGGGCCGTCGCTTCCAGCTGATGCAGCAG CAGACCCGGGCCCAGACGGCCTGCCGCCTGCTCTCCTACCTGCGGGTCAACGTACTCATCGGGCTCC TGGTGGTTGGGGCCATCAGCGCCATCTTCTGGGCTACCAAGTACTCACAGGACAACAAGGAGGAGTC CCTGTTTCTGCTGCTCCAGTACCTGCCCCCTGGGGTCATCGCCCTGGTCAACTTCCTGGGTCCCCTG CTGTTCACATTTCTGGTCCAGCTGGAGAACTACCCTCCCAACACGGAAGTCAACCTCACTCTGATCT GGTGCGTGGTGCTGAAGCTGGCCAGCTTGGGGATGTTCTCCGTCTCCCTGGGTCAGACCATACTGTG CATTGGCAGAGACAAGAGCAGCTGTGAGTCCTACGGCTACAACGTTTGTGACTATCAGTGCTGGGAG AACTCCGTGGGGGAGGAGCTGTACAAGCTGAGTATCTTCAACTTCCTCCTCACCGTGGCCTTCGCCT TCCTGGTCACCCTGCCTCGGAGGCTGCTGGTGGACCGGTTCTCAGGCCGGTTCTGGGCCTGGCTGGA ACGGGAGGAGTTCCTGGTCCCCAAGAATGTGCTGGACATCGTGGCGGGGCAGACGGTCACCTGGATG GGCCTCTTCTACTGCCCCCTGCTGCCCCTGCTGAATAGCGTCTTCCTCTTCCTCACCTTCTACATCA AGAAGTACACCCTCCTGAAGAACTCCAGGGCATCTTCGCGGCCCTTCCGTGCCTCCAGCTCCACCTT CTTCTTCCAGCTAGTGCTCCTCCTGGGCCTGCTTCTGGCTGCAGTGCCCCTGGGCTATGTGGTCAGC AGCATCCACTCCTCCTGGGACTACGGCCTCTTCACCAACTACTCAGCACCCTGGCAAGTGGTCCCGG AGCTGGTGGCCCTTGGGCTCCCGCCCATTGGCCAGCGTGCCCTCCACTACCTGGGCTCCCACGCCTT CAACTTCCCCCTCCTCATCATGCTCAGCCTTGTCCTGACGGTGTGCGTCTCCCAGACCCAGGCCAAT GCCAGGGCCATCCACAGGCTCCGGAAGCAGCTGOTGTGGCAGGTTCAGGAGAAGTGGCACCTGGTGG AGGACCTGTCGCGACTGCTGCCGGAGCCAGGCCCGAGCGACTCTCCGGGCCCCAAGTACCCTGCCTC CCAAGCTTCGCGCCCGCAGTCCTTCTGCCCCGGATGCCCATGCCCTGGCTCCCCGGGCCACCAGGCC CCGCGGCCGGGCCCCTCCGTCGTGGATGCCGCGGGACTGCGTTCCCCTTGCCCTGGACAGCACGGTG CCCCGGCCTCCGCCCGCAGATTCCGCTTCCCCAGCGGCGCGGAGCTGTAACTCGAGGGC ORF Start: ATG at 14 :ORF Stop: TAA at 2192 :S1QDNO:114 726aa MWat81756.5kD NOV19a, MLLPRSVSSERAPGVPEPEELWEAEMERLRGSGTPVRGLPYAMMDKRLIWQLREPAGVQTLRWQRWQ CG162687-02 RRRQTVERRLREAAQRLARGLGLWEGALYEIGGLFGTGIRSYFTFLRFLLLLNLLSLLLTASFVLLP LVWLRPPDPGPTLNLTLQCPGSRQSPPGVLRFHNQLWHVLTGRAFTNTYLFYGAYRVGPESSSVYSI Protein Sequence RLTYLLSPLACLLLCFCGTLRRMVKGLPQKTLLGQGYQAPLSAKVFSSWDFCIRVQFAATIKKEIS NEFKVELEEGRRFQLMQQQTRAQTACRLLSYLRVNVLIGLLVVGAISAIFWATKYSQDNKEESLFLL LQYLPPGVIALVNFLGPLLFTFLVQLENYPPNTEVNLTLIWCVVLKLASLGMFSVSLGQTILCIGRD KSSCESYGYNVCDYQCWENSVGEELYKLSIFNFLLTAFAFLVTLPRRLLVDRFSGRFWAWLEREEF LVPKNVLDIVAGQTVTWMGLFYCPLLPLLNSVFLFLTFYIKKYTLLKNSRASSRPFRASSSTFFFQL VLLLGLLLAAVPLGYVVSSIHSSWDYGLFTNYSAPWQVVPELVALGLPPIGQRALHYLGSHAFNFPL LIMLSLVLTVCVSQTQANARAIHRLRKQLVWQVQEKWHLVEDLSRLLPEPGPSDSPGPKYPASQASR PQSFCPGCPCPGSPGHQAPRPGPSVVDAAGLRSPCPGQHGAPASARRFRFPSGAEL SEQU)DND: 115 269 bp NO19b, CTGAGAAGGGGACTCCTCCAGGACTTGGTCCCTAGGTCCCCAGATGGGGAGACTGAGGCCGTGGCTG CG162687-01 TGTGTCCCTCTGAGAGTTGGAGCGGGGCTGGGCCCGAATTCGACCCCAGCAGGATTCTCTCTCATTT CTGAGCCCCGGAGGTGGCAGAGCGGCAGACCCGGGCAAGTGAACCCTAGGGCTGCAGGAGCCCAGGC DNA Sequence CCCGACGCCGGCGCAGAGGGGACGGAAGGGCCCGCCCCCAGCCCAGCGTGCACAGAGGCCATAGCCA AGGCCTTAAGGCTCATCCAACCGGGGACTCATATCCCCCCCACCGGCAGCCCGGCGCCCCAGCCTCT ACCCGTGCCCGCCGAGATGCTGCTGCCGCGGTCGGTGTCATCGGAGCGGGCCCCTGGGGTGCCGGAG CCGGAGGAGCTGTGGGAGGCAGAGATGGAGCGGCTGCGCGGCTCTGGGACGCCCGTGCGCGGGCTGC CCTATGCCATGATGGACAAGCGCCTCATCTGGCAGCTGCGGGAGCCCGCGGGGGTGCAGACCTTGCG CTGGCAGCGGTGGCAGCGCCGGCGGCAGACGGTGGAAAGGCGCCTGCGGGAGGCAGCGCAGCGGCTG GCCCGGGGCCTTGGGCTCTGGGAGGGGGCGCTCTACGAGATCGGCGGCCTCTTCGGCACAGGAATTC GGTCCTACTTCACCTTCCTCCGCTTCCTGCTGCTACTCAACCTGCTGAGCCTGCTGCTCACCGCAAG CTTCGTGCTGCTGCCCCTGGTCTGGCTCCGCCCCCCTGACCCAGGCCCCACCCTGAACTTGACCCTC CAGTGCCCTGGTAGCCGCCAGTCCCCGCCTOGCGTTTTGAGGTTCCACAATCAACTTTGGCATGTTT TGACTGGCAGGGCCTTCACCAACACCTATCTCTTCTACGGTGCGTACCGAGTGGGGCCGGAGAGCAG CTCCGTGTACAGCATCCGCCTGGCCTACCTCCTCAGCCCGCTGGCCTGCCTGCTCCTCTGCTTCTGT GGGACTCTGCGGCGGATGGTGAAGGGGCTGCCGCAGAAGACTCTGCTOGGTCAGGGCTATCAGGCGC CTCTCAGCGCCAAGGTCTTCTCCTCATGGGACTTCTGCATCCGGGTGCAGGAAGCAGCCACCATCAA GAAGCATGAGATCAGCAACGAGTTCAAGGTGGAGCTGGAGGAGGGCCGTCGCTTCCAGCTGATGCAG CAGCAGACCCGGGCCCAGACGGCCTGCCCCCTGCTCTCCTACCTGCGGGTCAACGTACTCAACGGGC TCCTGGTGGTTGGGGCCATCAGCGCCATCTTCTGGGCTACCAAGTACTCACAGGACAACAAGGAGGT GTCAGGCAACTGCATTCATTTAATCCTGGCCAGAACTGCGGGGGAGTCCCTGTTTCTGCTGCTCCAG TACCTGCCCCCTGGGGTCATCGCCCTGGTCAACTTCCTGGGTCCCCTGCTGTTCACATTTCTGGTCC AGCTGGAGAACTACCCTCCCAACACGGAGGTCAACCTCACTCTGATCTGGTGCGTGGTGCTGAAGCT GGCCAGCTTGGGGATGTTCTCCGTCTCCCTGGGTCAGACCATACTGTGCATTGGCAGAGACAAGAGC AGCTGTGAGTCCTACGGCTACAACGTTTGTGACTATCAGTGCTGGGAGAACTCCGTGGGGGAGGAGC TGTACAAGCTGAGTATCTTCAACTTCCTCCTCACCGTGGCCTTCGCCTTCCTGGTCACCCTGCCTCG 198 WO 03/050245 PCT/USO2/38594 GAGGCTGCTGGTGGACCGGTTCTCAGGCCGGTTCTGGGCCTGGCTGGAACGGGAGGAGTTCCTGGTC CCCAAGAATGTGCTGGACATCGTGGCGGGGCAGACGGTCACCTGGATGGGCCTCTTCTACTGCCCCC TGCTGCCCCTGCTGAATAGCGTCTTCCTCTTCCTCACCTTCTACATCAAGAAGTACACCCTCCTGAA GAACTCCAGGGCATCTTCGCGGCCCTTCCGTGCCTCCAGCTCCACCTTCTTCTTCCAGCTAGTGCTC CTCCTGGGCCTGCTTCTGGCTGCAGTGCCCCTGGGCTATGTGGTCAGCAGCATCCACTCCTCCTGGG ACTGCGGCCTCTTCACCAACTACTCAGCACCCTGGCAAGTGGTCCCGGAGCTGGTGGCCCTTGGGCT CCCGCCCATTGGCCAGCGTGCCCTCCACTACCTGGGCTCCCACGCCTTCAGCTTCCCCCTCCTCATC ATGCTCAGCCTTGTCCTGACGGTGTGCGTCTCCCAGACCCAGGCCAATGCCAGGGCCATCCACAGGC TCCGGAAGCAGCTGGTGTGGCAGGTTCAGGAGAAGTGGCACCTGGTGGAGGACCTGTCGCGACTGCT GCCGGAGCCAGGCCCGAGCGACTCTCCGGGCCCCAAGTACCCTGCCTCCCAAGCTTCGCGCCCGCAG TCCTTCTGCCCCGGATGCCCATGCCCTGGCTCCCCGGGCCACCAGGCCCCGCGGCCGGGCCCCTCCG TCGTGGATGCCGCGGGACTGCGTTCCCCTTGCCCTGGACAGCACGGTGCCCCGGCCTCCGCCCGCAG ATTCCGCTTCCCCAGCGGCGCGGAGCTGTAACCCCGACCCCTGCCTCCCCGAAGCCTCCCTGGGGCC CCTTCAGGCCTCCTTA .... .... .. .. ....... ...... ............ .... .. ; .. ..... ....... .... .... i .. iii i.. -.. ORF Start: ATG at 352 ORF Stop: TAA at 2575 SEQID NO: 116 741 aa MW at 83147.1kD NOV19b, MLLPRSVSSERAPGVPEPEELWEAEMERLRGSGTPVRGLPYAMMDKRLIWQLREPAGVQTLRWQRWQ CG162687-01 RRRQTVERRLREAAQRLARGLGLWEGALYEIGGLFGTGIRSYFTFLRFLLLLNLLSLLLTASFVLLP LVWLRPPDPGPTLNLTLQCPGSRQSPPGVLRFHNQLWHVLTGRAFTNTYLFYGAYRVGPESSSVYSI Protein Sequence RLAYLLSPLACLLLCFCGTLRRMVKGLPQKTLLGQGYQAPLSAKVFSSWDFCIRVQEAATIKKHEIS NEFKVELEEGRRFQLMQQQTRAQTACRLLSYLRVNVLNGLLVVGAISAIFWATRYSQDNKEVSGNCI HLILARTAGESLFLLLQYLPPGVIALVNFLGPLLFTFLVQLENYPPNTEVNLTLIWCVVLKLASLGM FSVSLGQTILCIGRDKSSCESYGYNVCDYQCWENSVGEELYKLSIFNFLLTVAFAFLVTLPRRLLVD RFSGRFWAWLEREEFLVPKNVLDIVAGQTVTWMGLFYCPLLPLLNSVFLFLTFYIKKYTLLKNSRAS SRPFRASSSTFFFQLVLLLGLLLAAVPLGYVVSSIHSSWDCGLFTNYSAPWQVVPELVALGLPPIGQ RALHYLGSHAFSFPLLIMLSLVLTVCVSQTQANARAIHRLRKQLVWQVQEKWHLVEDLSRLLPEPGP SDSPGPKYPASQASRPQSFCPGCPCPGSPGHQAPRPGPSVVDAAGLRSPCPGQHGAPASARRFRFPS GAEL Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 19B. 5 Table 19B. Comparison of NOV19a against NOV19b. NOV19a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region NOV19b 1..726 722/741 (97%) 1..741 723/741 (97%) Further analysis of the NOV1 9a protein yielded the following properties shown in Table 19C. Table 19C. Protein Sequence Properties NOV19a SignalP analysis: No Known Signal Sequence Predicted PSORT II PSG: a new signal peptide prediction method analysis: N-region: length 11; pos.chg 2; neg.chg 1 H-region: length 5; peak value -6.15 PSG score; -10.55 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -5.78 possible cleavage site: between GO60 and 61 >>> Seems to have no N-terminal signal peptide 199 WO 03/050245 PCT/USO2/38594 ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 9 INTEGRAL Likelihood = -7.48 Transmembrane 116 - 132 INTEGRAL Likelihood = -3.72 Transmembrane 203 - 219 INTEGRAL Likelihood = -8.65 Transmembrane 304 - 320 INTEGRAL Likelihood = -7.01 Transmembrane 343 - 359 INTEGRAL Likelihood = -4.04 Transmembrane 374 - 390 INTEGRAL Likelihood = -5.47 Transmembrane 430 - 446 INTEGRAL Likelihood = -3.19 Transmembrane 489 - 505 INTEGRAL Likelihood = -8.70 Transmembrane 537 - 553 INTEGRAL Likelihood = -6.69 Transmembrane 599 - 615 PERIPHERAL Likelihood = 5.04 (at 570) ALOM score: -8.70 (number of TMSs: 9) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 123 Charge difference: -2.0 C( 0.0) - N( 2.0) N >= C: N-terminal side will be inside >>> membrane topology: type 3a MITDISC: discrimination of mitochondrial targeting seq R content: 2 Hyd Moment(75): 9.58 Hyd Moment(95): 7.17 G content: 1 D/E content: 2 S/T content: 3 Score: -4.19 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 15 PRS[VS NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 9.9% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: LLPR none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none 200 WO 03/050245 PCT/USO2/38594 checking 63 PROSITE DNA binding motifs: Leucine zipper pattern (PS00029): *** found *** LSPLACLLLCFCGTLRRMVKGL at 207 LFLLLQYLPPGVIALVNFLGPL at 332 LSIFNFLLTVAFAFLVTLPRRL at 430 none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions 58 Q 0.53 59 T 0.53 60 L 0.53 61 R 0.53 62 W 0.53 63 Q 0.53 64 R 0.53 65 W 0.53 66 Q 0.53 67 R 0.53 68 R 0.53 69 R 0.53 70 Q 0.53 71 T 0.53 72 V 0.53 73 E 0.53 74 R 0.53 75 R 0.53 76 L 0.53 77 R 0.53 78 E 0.53 79 A 0.53 80 A 0.53 81 Q 0.53 82 R 0.53 83 L 0.53 84 A 0.53 85 R 0.53 total: 28 residues Final Results (k = 9/23): 77.8 %: endoplasmic reticulum 11.1 %: nuclear 11.1 %: vesicles of secretory system >> prediction for CG162687-02 is end (k=9) A search of the NOV1 9a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 19D. 5 Table 19D. Geneseq Results for NOV19a 201 WO 03/050245 PCT/USO2/38594 NOV19a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region AAB74730 Human membrane associated 35..639 225/626 (35%) 2e-90 protein MEMAP-36 - Homo 83..689 322/626 (50%) sapiens, 706 aa. [WO200112662-A2, 22-FEB-2001] AAY94906 Human secreted protein clone 83..639 212/571 (37%) 2e-87 rb649 3 protein sequence 15..572 303/571 (52%) SEQ ID NO:18 - Homo sapiens, 589 aa. [WO200009552-A1, 24-FEB-2000] AAM40237 Human polypeptide SEQ ID 128..559 161/446 (36%) 2e-62 NO 3382 - Homo sapiens, 2..436 231/446 (51%) 436 aa. [WO200153312-A1, 26-JUL-2001] AAO17232 Human secreted protein 332..639 123/309 (39%) 6e-55 homologous protein SEQ ID 10..317 176/309 (56%) NO: 131 - Homo sapiens, 334 aa. [WO200228877-A1, 11-APR-2002] ABG64736 Human albumin fusion 427..639 87/213 (40%) 5e-38 protein #1411 - Homo 1..212 124/213 (57%) sapiens, 229 aa. [WO200177137-Al, 18-OCT-2001] In a BLAST search of public sequence datbases, the NOV1 9a protein was found to have homology to the proteins shown in the BLASTP data in Table 19E. Table 19E. Public BLASTP Results for NOV19a Protein NOV19a Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Number Residues Portion AAL25837 EVIN2 - Homo sapiens 1..726 722/726 (99%) 0.0 (Human), 726 aa. 1..726 723/726 (99%) Q8NFO4 FLJ00400 protein - Homo 1..726 722/726 (99%) 0.0 sapiens (Human), 782 aa 57..782 723/726 (99%) (fragment). Q8N358 Hypothetical protein- Homo 1..228 221/228 (96%) e-128 sapiens (Human), 287 aa. 1..228 224/228 (97%) 202 WO 03/050245 PCT/USO2/38594 Q8TBS7 Similar to hypothetical 35. .639 ~225/626 (35%) 5e-90 protein FLJ21240 - Homno 83..689 322/626 (50%) ___________sapiens (Human), 706 aa. Q9H766 Hypothetical protein 260..647 1146/401 (3 6%) 2e-67 FLJ2 1240 - Homo sapiens 2..394 12641(58%) _________(Human), 402 aa. 12J/4 PFam analysis predicts that the NOVI 9a protein contains the domains shown in the Table 19F. Table 19F. Domain Analysis of NOV19a Identities/ Pfam Domain NOV19a Match Region Similarities Expc au for the MatchedxecVau Region 5 Example 20. The NOV20 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 20A. jTale i0A. NOV20 Sequence Analysis ~SEQ ID NO: 117 143 .bp NOV20a, GGCCCGGCTGGCCrACTGCTCGTCG CGGCTGC CcH 62738-01 GGTCGCCGCAGGTTGCGAATGCOCAATTTGGGGC TCCCGCAGACGGTATCTTCTGTAGACGTCACCCCCCGGAGGCTTCAACCTGCGCGGGATGTCT DNA Sequence ATATCCGAATCGCCTCTCTCCTGAGACTCTGCTGAAACGGAGGAGTGGTGCTTGTCCTCCTCC ATGGGCCGCCTCTATCACTGGC-AQAGTCCTGACATCCAC'GGTCCCGATTCCCTGGTCTGAGTTT TTGTTCAGCCAAAAACCGCTGGAGGATCTGAATT GTGGGCCCTTTATTGACCAGGTTTACGTCCTGCAAGTTACGCAGAGGGTGGAAAGAGGGACCTG GCGAAGACAAGTGACGAGCGGCCGTTATTGATGCTCCTGTACTCCGCAAGCCGAGTAC TACAGACOATCGTTTTGCCTTATGAGGAGACCAGGGGTCTAACGTCTCCTGTCTGTCCGTCCAGG GCTCAGCCTCCATCGTGGCGCCCCTGCTGCTAGAACACATCAGCCCGGTCCGTATGTTAQJAC CAGACAGGATCCCCTTCCAGGAGGACTGGATGAJGATGAGGTAAGCTGGGCTCCGCGCTAGGGGG -ATAAAACATTTTGGACTGTGACCATGTACCTTCCTTTTTAAATAACTGCTTTATGGAAGTT I___A OFStart: ATG at - 1 ORF .,S t op: TAA at 1074 ______SEQ ID NO: 118I 353 aa ,MW at4078.0kD NOV20a, MATLSFVFLLLGAVSWPPASASCQEPWPGQSAILSGAASJRYLLYDVNPPEGN.IRPRyYIRIA CG1 62738-01 SLLKTLLKTEELVLPPWGRLYHWQSPDIHQIPWEFFDLPLNIPVIEYEQFIESGPFI DQVYVLQSYAEGWKEGTWEEKVDERPCIDQLLYSQDHEYYGWWGYEETRCLNVSCLSVQGSASI Protein Sequence: VALLNSRVLPANLDYGEWDRS~AHRVDFSHNTDD .FQDWMKMsVKGSA PLGvRRRDFIwGHQ DVPSLEGAVRK MKTHRLDKVFVATDAV 203 WO 03/050245 PCT/USO2/38594 SEQ ID NO: 119 960bp NOV20b, GGCCGCCCGGGGCCATGGCGACACTCAGCTTCGTCTTCCTGCTGCTGGGGGCAGTGTCCTGGCCTCC CG162738-02 GGCTTCTGCCTCCGGCCAGGAGTTCTGGCCCGGACAATCGGCGGCCGATATTCTGTCGGGGCGGCT TCCCGCAGACGGTATCTTCTGTATGACGTCAACCCCCCGGAAGGCTTCAACCTGCGCAGGGATGTCT DNA Sequence ATATCCGAATCGCCTCTCTCCTGAAGACTCTGCTGAAGACGGAGGAGTGGGTGCTTGTCCTGCCTCC ATGGGGCCGCCTCTATCACTGGCAGAGTCCTGACATCCACCAGGTCCGGATTCCCTGGTCTGAGTTT TTTGATCTTCCAAGTCTCAATAAAAACATCCCCGTCATCGAGTATGAGCCAGTTCATCGCAGGAAGAC GCACTGCGTGTGGAGTATGCTTCGTGGTGTCTCAGTGCAGCGCCAGGGATAAAGAATCTGGTGGGCC CTTTATTGACCAGGTTTACGTCCTGCAAAGTTACGCAGAGGGGTGGAAAGAAGGGACCTGGGAAGAG AAGGTGGACGAGCGGCCGTGTATTGATCAGCCTCCTGTACTCCCAGGACAAGCACGAGTCCTCACTGA GCAGCCACTTTCCACATCTGCTAGAGGAACAGTGACATGGACACCTGTGACAGAGAGAGGACAGTTA GGAGGGACAGACAGCTCTTCCTTTCGGAGCCTGGCTAGTCTAGGACATCACCTTGCTGTGTCTTCTC AAGCTTTTAAAATTGACCCTGAACGTGTGACAGGGTCCTATGGTGTTACTCAAAGCTGTGCAGGGTA AATGATGACATATTTATTCTTTTTCCATTTGTTCTAGAAACAGTGCCTTTTTCATCAGTTGCATTTT CCAGGCTGAGAGCTGTATAAAACATTTTGGACTGTGACCATGTACCTTCCTTTTTAAGAAAAATAAA CTGCTTTATGGAAAAAAAAAAA ________ ORF Start: ATG at 15 ORF Stop: TGA at 636 SEQ ID NO: 120 207 aa MW at 23705.6kD NOV20b, MATLSPVFLLLGAVSWPPASASGQEFWPGQSAADILSGAASRRRYLLYDVNPPEGFNLRRDVYIRIA CG162738-02 SLLKTLLKTEEWVLVLPPWGRLYHWQSPDIHQVRIPWSEFFDLPSLNKNIPVIEYEQFIAGRRTACG VCFVVSQCSARDKESGGPFIDQVYVLQSYAEGWKEGTWEEVDERPCIDQLLYSQDKHESSLSSHFp Protein Sequence HLLEEQ SEQ ID NO: 121 _960 bp NOV20c, GGCCGCCCGGGCCATGGCGACACTCAGCTTCGTCTTCCTGCTGCTGGGGGCAGTGTCCTGGCCTCC CG162738-03 GGCTTCTGCCTCCGGCCAGGAGTTCTGGCCCGGACAATCGGCGGCCGATATTCTGTCGGGGGCGGCT TCCGCAGACGGTATCTTCTGTATGACGTCAACCCCCCGGAAGGCTTCAACCTGCGCAGGGATGTCT DNA Sequence ATATCCGAATCGCCTCTCTCCTGAAGACTCTGCTGAAGACCGGAGGAGTGGGTGCTTGTCCTGCCTCC ATGGGGCCGCCTCTATCACTGGCAGAGTCCTGACATCCACCAGGTCCGGATTCCCTGGTCTGAGTTT TTTGATCTTCCAAGTCTCAATAAAAACATCCCCGTCATCGAGTATGAGCAGTTCATCGCAGGAAGAC GCACTGCGTGTGGAGTATGCTTCGTGGTGTCTCAGTGCAGCGCCAGGGATAAAGAATCTGGTGGGCC CTTTATTGACCAGGTTTACGTCCTGCAAAGTTACGCAGAGGGGTGGAAAGAAGGGACCTGGGAAGAG AAGGTGGACGAGCGGCCGTGTATTGATCAGCTCCTGTACTCCCAGGACAAGCACGAGTCCTCACTGA GCAGCCACTTTCCACATCTGCTAGAGGAACAGTGACATGGACACCTGTGACAGAGAGAGGACAGTTA GGAGGGACAGACAGCTCTTCCTTTCGGAGCCTGGCTAGTCTAGGACATCACCTTGCTGTGTCTTCTC AAGCTTTTAAAATTGACCCTGAACGTGTGACAGGGTCCTATGGTGTTACTCAAAGCTGTGCAGGGTA AATGATGACATATTTATTCTTTTTCCATTTGTTCTAGAAACAGTGCCTTTTTCATCAGTTGCATTTT CCAGGCTGAGAGCTGTATAAAACATTTTGGACTGTGACCATGTACCTTCCTTTTTAAGAAAAATAAA CTGCTTTATGGAAAAAAAAAAA ORF Start: ATG at 15 ORF Stop: TGA at 636 SEQ ID NO: 122 207 aa MW at 23705.6kD NOV20c, MATLSFVFLLLGAVSWPPASASGQEFWPGQSAADILSGAASRRRYLLYDVNPPEGFNLRRDVYIRIA CG162738-03 SLLKTLLKTEEWVLVLPPWGRLYHWQSPDIHQVRIPWSEFFDLPSLNKNIPVIEYEQFIAGRRTACG VCFVVSQCSARDKESGGPFIDQVYVLQSYAEGWKEGTWEEKVDERPCIDQLLYSQDKHESSLSSHIFP Protein Sequence HLLEEQ Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 20B. Table 20B. Comparison of NOV20a against NOV20b and NOV20c. oei euence NOV20a Residues/ Identities/ Protein Sqec Match Residues Similarities for the Matched Region NOV20b L..173 173/193 (89%) 1..193 173/193 (89%) 204 WO 03/050245 PCT/USO2/38594 NOV2 0 c i1..173 173/193 (89%) 1..193 173/193 (89%) Further analysis of the NOV20a protein yielded the following properties shown in Table 20C. Table 20C. Protein Sequence Properties NOV20a SignalP analysis: Cleavage site between residues 22 and 23 PSORTIH PSG: a new signal peptide prediction method analysis: N-region: length 0; pos.chg 0; neg.chg 0 H-region: length 24; peak value 11.40 PSG score: 7.00 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): 3.12 possible cleavage site: between 21 and 22 >>> Seems to have a cleavable signal peptide (1 to 21) ALOM: Klein et al's method for TM region allocation Init position for calculation: 22 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood = 0.53 (at 190) ALOM score: 0.53 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 10 Charge difference: -3.0 C(-2.0) - N( 1.0) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 2.26 Hyd Moment(95): 1.40 G content: 2 D/E content: 1 S/T content: 5 Score: -5.53 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 12.7% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none 205 WO 03/050245 PCT/USO2/38594 type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 22.2 %: extracellular, including cell wall 22.2 %: vacuolar 22.2 %: mitochondrial 22.2 %: endoplasmic reticulum 11.1%: Golgi >> prediction for CG162738-01 is exc (k=9) A search of the NOV20a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 20D. 5 Table 20D. Geneseq Results for NOV20a NOV20a Identities/ Geneseq Protein/Organism/Length Residues/ ExpectIdentities Identifier [Patent #, Date] Match Similarities for theValuepect Residues Matched Region Residues AAB40332 Human ORFX ORF96 1..338 338/338 (100%) 0.0 polypeptide sequence SEQ 5..342 338/338 (100%) ID NO:192 - Homo sapiens, 428 aa. [WO200058473-A2, 05-OCT-2000] AAY11376 Human 5' EST secreted 1..134 130/134 (97%) 8e-72 protein SEQ ID No 198 - 1..134 130/134 (97%) Homo sapiens, 134 aa. [WO9906551-A2, 11-FEB-1999] 206 WO 03/050245 PCT/USO2/38594 ABB69800 Drosophila melanogaster 45..353 124/334 (37%) 6e-49 polypeptide SEQ ID NO 73..396 175/334 (52%) 36192 - Drosophila melanogaster, 490 aa. [WO200171042-A2, 27-SEP-2001] ABB48718 Listeria monocytogenes 56..175 29/123 (23%) 2.1 protein #1422 - Listeria 55..166 55/123 (44%) monocytogenes, 657 aa. [WO200177335-A2, 18-OCT-2001] In a BLAST search of public sequence datbases, the NOV20a protein was found to have homology to the proteins shown in the BLASTP data in Table 20E. Table 20E. Public BLASTP Results for NOV20a Protein NOV20a Identities/ Accession Protein/Organismni/Length Residues/ Similarities for the Expect Number Match Matched Portion Value Residues Matched Portion Value T14795 hypothetical protein 1..338 338/338 (100%) 0.0 DKFZp434E171.1 -human, 4..341 338/338 (100%) 383 aa (fragment). Q9Y2G5 Protein C21orf80 - Homo 1..338 338/338 (100%) 0.0 sapiens (Human), 424 aa. 1..338 338/338 (100%) Q8VHI3 Protein C2lorf80 homolog - 1..338 309/338 (91%) 0.0 Mus musculus (Mouse), 429 1..338 323/338 (95%) aa. Q8WR51 C21ORF80 - Caenorhabditis 40..338 133/305 (43%) 2e-68 elegans, 424 aa. 38..334 201/305 (65%) Q9W589 EG:BACN32G11.6 protein 45..353 124/334 (37%) 2e-48 (GH07929P) - Drosophila 73..396 175/334 (52%) melanogaster (Fruit fly), 490 aa. 5 PFam analysis predicts that the NOV20a protein contains the domains shown in the Table 20F. Table 20F. Domain Analysis of NOV20a Identities/ Pfam Domain NOV20a Match Region Similarities Expect Value for the Matched Region 207 WO 03/050245 PCT/USO2/38594 Example 21. The NOV21 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 21A. 5 Table 21A. NOV21 Sequence Analysis ~SEQ ID NO:1327 NOV21a, CTGCCCCGGTACTCACAAGCTTCTCGGCCCCGACCTTCGCCCTGGGAGGTTCTGGCCAGGTGCCGGG CG163175-01 AGGGGCGCTGTGTCGAGGGCGATCCCCCCAAAGCAGCGTCCCGTGCTAAAGGTACTGCTTAGGATGA ATATGATTTGGAGAAATTCCATTTCTTGTCTAAGGCTAGGAAAGGTGCCACACAGATACCAAAGTGG DNA Sequence TTACCACCCAGTGGCCCCTCTGGGATCAAGGATTTTAACTGACCCAGCCAAAGTTTTTGAACACAAC ATGTGGGATCACATGCAGTGGTCTAAGGAAGAAGAAGCAGCAGCCAGAAAAAAAGTAAAAGAAAACT CAGCTGTGCGAGTCCTTCTGGAAGAGCAAGTTAAGTATGAGAGAGAAGCTAGTAAATACTGGGACAC ATTTTACAAGATTCATAAGAATAAGTTTTTCAAGGATCGTAATTGGCTGTTGAGGGAATTTCCTGAA ATTCTTCCAGTTGATCAAAAACCTGAAGAGAAGGCGAGAGAATCATCATGGGATCATGTAAAAACTA GTGCTACAAATCGTTTCTCAAGAATGCACTGTCCTACTGTGCCTGATGAAAAAAATCATTATGAGAA AAGTTCTGGTTCTTCAGAAGGTCAAAGCAAAACAGAATCTGATTTTTCCAACCTAGACTCTGAAAAA CACAAAAAAGGACCTATGGAGACTGGATTGTTTCCTGGTAGCAATGCCACTTTCAGGATACTAGAGG TTGGTTGTGGAGCTGGAAATAGTGTGTTTCCAATTTTGAACACTTTGGAGAACTCTCCGGAGTCCTT TCTGTATTGTTGTGATTTTGCTTCTGGAGCTGTGGAGCTCGTAAAGTCACACTCGTCCTACAGAGCA ACCCAGTGTTTTGCCTTTGTTCATGATGTATGTGATGATGGCTTACCTTACCCTTTTCCAGATGGGA TCCTGGATGTCATTCTCCTTGTCTTTGTGCTCTCTTCTATTCATCCTGACAGGATGCAAGGTGTTGT AAACCGACTGTCCAGTTACTCAAACCTGGGGGAATGCTGTTATTTCGAGACTATGGAAGATATGAT AAGACTCAGCTTCGTTTTAAAAAGGGACATTGTTTATCTGAAAATTTTTATGTTCGAGGAGATGGTA CCAGAGCATATTTCTTTACAAAAGGGGAAGTCCACAGTATGTTCTGCAAAGCCAGTTTAGATGAAAA GCAAAATCTGGTTGATCGCCGCTTACAAGTTAATAGGAAAAAACAAGTGAAAATGCACCGAGTGTGG ATTCAAGGCAAATTCCAGAAACCATTGCACCAGACTCAGAATAGCTCCAATATGGTATCTACACTCC TTTCACAAGACTGAACTTTGTAACATGTTAAGGTACAAAGCCAGAGGACTGTGCTATTCAAGGACTA CTGTAAGTCTATTGTTTCTCAAAAGACAATGAGAAAAAAAGAAGAGAATTTGTATTTCCTGCCGTTT TGTCATAGGTGAGCTCCTTTGTGCATTTTAAGCACATGTAAGTGGTTCAGCACAGTATGCCTTTTTC TGTGCTTTGAAAACTTGATATGCTCAAGCTTGTTTGAATTTATTACATCTAACCATTTTGCTTGTTC CTTGATTTTTATAAGCATTCAATTAAGTTAGTATTATGTCAAGTAATTTTGAGAAAATGTAACTTGA CATTTTTTGCAAGTAAAAAAAATTGTTTATTTGTTTAGGCTTAGTAAACCAGTTCCCAAACACAGTC AGACTCTTCCCATTGTCATCTGATTGCAGAGAGAA.AGCACACCTTATTTCCAGGGAAAGCTACAACA AGCCCAAGGTCAAAGTGTATTATTTTTTGTCTTGTTGTTGTCTATTTTCTCCCAATTTTTTTTTGAA ATTCAGAGGCTCATATCTGAAATAGAATTTTAGTTCCTCTTTCCTTTCCTAAAATTGGGGAAGTACA GCCCATGCTGACATTATTTTCAGGCTATTCTTAGATATACAAGTTGTTAGGCCAGGTGCAATGGCTC GCACCTGTAATCCCAGCACTTTGGGGGGCTGAGGCAGGCAGATCGCTTGAGCTCAGGAGTTCAAGAC CAGCCTGGACAACATGGCAAAACCCTGTCTCTCCCAAGAATACAAAAATTAGCCAGGCATGGTGGCA CACACCTGTGGTCCCAGCTACTCAGGAGACTGAGGTGGGAGGATCGCTTGAGCCTCGGAGGCGGAGG TTGCAGTGAGCTGACATTGTACCACTGCGCTCCAAACTGGGTGACATGGTGAGACCTTGTCTCC ORF Start: ATG at 131 ORF Stop: TGA at 1352 S E SEQ ID NO: 124 aa IMIat46992.lkD NOV21a, MNMIWRNSISCLRLGKVPHRYQSGYHPVAPLGSRILTDPAKVFEHNMWDHMQWSKEEEAAARKKVKE CG163175-0 1 NSAVRVLLEEQVKYEREASKYWDTFYKIHKNKFFKDRNWLLREFPEILPVDQKPEEKARESSWDHVK TSATNRPSRMHCPTVPDEKNHYEKSSGSSEGQSKTESDFSNLDSEKHKKGPMETGLFPGSNATFRIL Protein Sequence EVGCGAGNSVFPILNTLENSPESFLYCCDFASGAVELVKSHSSYRATQCFAFVHDVCDDGLPYPFPD GILDVILLVFVLSSIHPDRMQGVVNRLSKLLKPGGMLLFRDYGRYDKTQLRFKKGHCLSERFYVRGD GTRAYFFTKGEVHSMFCKASLDEKQNLVDRRLQVNRKKQVKMHRVWIQGKFQKPLHQTQNSSNMVST LLSQD Further analysis of the NOV21 a protein yielded the following properties shown in Table 21B. 208 WO 03/050245 PCT/USO2/38594 Table 21B. Protein Sequence Properties NOV21a SignalP analysis: No Known Signal Sequence Predicted PSORT II PSG: a new signal peptide prediction method analysis: N-region: length 6; pos.chg 1; neg.chg 0 H-region: length 6; peak value -2.73 PSG score: -7.12 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -9.99 possible cleavage site: between 37 and 38 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -3.66 Transmembrane 269 - 285 PERIPHERAL Likelihood = 4.72 (at 200) ALOM score: -3.66 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 276 Charge difference: 6.5 C( 2.5) - N(-4.0) C > N: C-terminal side will be inside >>> membrane topology: type lb (cytoplasmic tail 269 to 407) MITDISC: discrimination of mitochondrial targeting seq R content: 4 Hyd Moment(75): 10.77 Hyd Moment(95): 11.10 G content: 3 D/E content: 1 S/T content: 5 Score: -0.04 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 44 SRIILT NUCDISC: discrimination of nuclear localization signals pat4: KHKK (3) at 180 pat7: none bipartite: none content of basic residues: 14.7% NLS Score: -0.29 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none 209 WO 03/050245 PCT/USO2/38594 memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: found LL at 275 LL at 298 LL at 305 LL at 403 checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 55.5 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23) 65.2 %: nuclear 17.4 %: mitochondrial 8.7 %: cytoplasmic 4.3 %: plasma membrane 4.3 %: vesicles of secretory system >> prediction for CG163175-01 is nuc (k=23) A search of the NOV21 a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 21C. 5 Table 21C. Geneseq Results for NOV21a NOV21a Identities/ Geneseq Protein/Organism/Length Residues/ i itiesExpect Identifier [Patent #, Date] Match Similarities for the Value Residues Matched Region AAB94868 Human protein sequence 51..287 237/237 (100%) e-140 SEQ ID NO:16072 - Homo 1..237 237/237 (100%) sapiens, 241 aa. [EP1074617-A2, 07-FEB-2001] AAM78551 Human protein SEQ ID NO 32..390 200/360 (55%) e-108 1213 - Homo sapiens, 415 58..410 256/360 (70%) aa. [WO200157190-A2, 09-AUG-2001] ABB80946 Human basophilic 49..390 188/343 (54%) e-100 72..407 243/343 (70%) 210 WO 03/050245 PCT/US02/38594 45.32 - Homo sapiens, 412 aa. [CN1341659-A, 27-MAR-2002] AAM79535 Human protein SEQ ID NO 49..390 188/343 (54%) e-100 3181 -Homo sapiens, 384 44..379 243/343 (70%) aa. [WO200157190-A2, 09-AUG-2001] AAB87436 Human gene 22 encoded 125..287 163/163 (100%) 3e-94 secreted protein fragment, 1..163 163/163 (100%) SEQ ID NO:177 - Homo sapiens, 167 aa. [WO200118022-A1, 15-MAR-2001] In a BLAST search of public sequence datbases, the NOV21 a protein was found to have homology to the proteins shown in the BLASTP data in Table 21D. Table 21D. Public BLASTP Results for NOV21a Protein NOV21a Identities/ Accession Protein/Organism/Length Residues/ Similarities for the Expect Number Match Matched Portion Value Residues Q9H825 Hypothetical protein 51..287 237/237 (100%) e-140 FLJ13984 - Homo sapiens 1..237 237/237 (100%) (Human), 241 aa. Q9POB5 HSPC266 - Homo sapiens 32..390 199/360 (55%) e-107 (Human), 376 aa (fragment). 19.371 255/360 (70%) Q9NUI8 Hypothetical protein 79..390 172/313 (54%) 8e-90 FLJ11350 - Homo sapiens 3..308 219/313 (69%) (Human), 313 aa. Q99KI7 Similar to hypothetical 51..287 162/238 (68%) le-87 protein FLJ13984 -Mus 1..227 183/238 (76%) musculus (Mouse), 254 aa. Q961Z6 Hypothetical protein - Homo 191..390 134/200 (67%) 2e-76 sapiens (Human), 242 aa. 39..237 164/200 (82%) 5 PFam analysis predicts that the NOV21a protein contains the domains shown in the Table 21E. Table 21E. Domain Analysis of NOV21a 211 WO 03/050245 PCT/USO2/38594 Identities/ Similarities Pfam Domain NOV21a Match Region for the Matched Expect Value Region Example 22. The NOV22 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 22A. 5 Table 22A. NOV22 Sequence Analysis SEQ ID NO: 125 1033bp NOV22a, CGCCCAGCGACGTGCGGGCGGCCTGGCCCGCGCCCTCCCGCGCCCGGCCTGCGTCCCGCGCCCTGCG CG163259-01 CCACCGCCGCCGAGCCGCAGCCCGCCGCGCGCCCCCGGCAGCGCCGGCCCCATGCCCGCCGGCCGCC GGGGCCCCGCCGCCCAATCCGCGCGGCGGCCGCCGCCGTTGCTGCCCCTGCTGCTGCTGCTCTGCGT DNA Sequence CCTCGGGGCGCCGCGAGCCGGATCAGGAGCCCACACAGCTGTGATCAGTCCCCAGGATCCCACGCTT CTCATCGGCTCCTCCCTGCTGGCCACCTGCTCAGTGCACGGAGACCCACCAGGAGCCACCGCCGAGG GCCTCTACTGGACCCTCAACGGGCGCCGCCTGCCCCCTGAGCTCTCCCGTGTACTCAACGCCTCCAC CTTGGCTCTGGCCCTGGCCAACCTCAATGGGTCCAGGCAGCGGTCGGGGGACAACCTCGTGTGCCAC GCCCGTGACGGCAGCATCCTGGCTGGCTCCTGCCTCTATGTTGGCCTGCCCCCAGAGAAACCCGTCA ACATCAGCTGCTGGTCCAAGAACATGAAGGACTTGACCTGCCGCTGGACGCCAGGGGCCCACGGGGA GACCTTCCTCCACACCAACTACTCCCTCAAGTACAAGCTTAGGTGGTATGGCCAGGACAACACATGT GAGGAGTACCACGGCGAGAGGTCCTGCCAGATAAGCTGTAGGGGCTCAGGCCACCCTCCCTGCCACG TGGAGACGCAGAGGCCGAACCCAAACTGGGGCCACCTCTGTACCCTCACTTCAGGGCACCTGAGCCA CCCTCAGCAGGAGCTOGGGTGGCCCCTGAGCTCCAACGGCCATAACAGCTCTGACTCCCACGTGAGG CCACCTTTGGGTGCACCCCAGTGGGTGTGTGTGTGTGTGTGAGGGTTGGTTGAGTTGCCTAGAACCC CTGCCAGGGCTGGGGGTGAGAAGGGGAGTCATTACTCCCCATTACCTAGGGCCCCTCCAAAAGAGTC CTTTTAAATAAATGAGCTATTTACGTGC ORF Start: ATG at 119 ORF Stop: TGA at 911 SEQ ID NO: 126 264 aa BAWat28400.9kD NOV22a, MPAGRRGPAAQSARRPPPLLPLLLLLCVLGAPRAGSGAHTAVISPQDPTLLIGSSLLATCSVHGDPP CG163259-01 GATAEGLYWTLNGRRLPPELSRVLNASTLALALANLNGSRQRSGDNLVCHARDGSILAGSCLYVGLP PEKPVNISCWSKNMKDLTCRWTPGAHGETFLHTNYSLKYKcLRWYGQDNTCEEYHGIERSCQISCRG Protein Sequence HPPCHVETQRPNPNWGHLCTLTSGHLSHPQQELGWPLSSNGHNSSDSHVRPPLGAPQWVCVCV SEQ ID NO: 127 1485 bp NOV/22b, CGCCCAGCGACGTGCGGGCGGCCTGGCCCGCGCCCTCCCGCGCCCGGCCTGCGTCCCGCGCCCTGCG CG163259-02 CACCGCCGCCGAGCCGCCCGCCCGCCCCCGGCAGCGCCGCCCATCCCGCCGGCCGCC GGGGCCCCGCCGCCCAATCCGCGCGGCGGCCGCCGCCGTTGCTGCCCCTGCTGCTGCTGCTCTGCGT DNA Sequence CCTCGGGGCGCCCGAGCCGGATCAGGAGCCCACACAGCTGTGATCAGTCCCCAGGATCCCACGCTT CTCATCOGCTCCTCCCTGCTGGCCACCTGCTCAGTGCACGGAGACCCACCAGGAGCCACCGCCGAGG GCCTCTACTGGACCCTCAACGGGCGCCGCCTGCCCCCTGAGCTCTCCCGTGTACTCAACGCCTCCAC CTTGGCTCTGGCCCTGGCCAACCTCAATGGGTCCAGGCAGCGGTCGGGGGACAACCTCGTGTGCCAC GCCCGTGACGGCAGCATCCTGGCTCTCTTTACGCCCTATGAGATCTGGGTGGAGGCCACCAACCGCC TGGGCTCTGCCCGCTCCGATGTACTCACGCTGGATATCCTGGATGTGGTGACCACGGACCCCCCGCC CGACGTGCACGTGAGCCGCGTCGGGGGCCTGGAGGACCAGCTGAGCGTGCGCTGGGTGTCGCCACCC GCCCTCAAGGATTTCCTCTTTCAAGCCAAATACCAGATCCGCTACCGAGTGGAGGACAGTGTGGACT GGAAGGTGGTGGACGATGTGAGCAACCAGACCTCCTGCCGCCTGGCCGGCCTGAAACCCGGCACCGT GTACTTCGTGCAAGTGCGCTGCAACCCCTTTGGCATCTATGGCTCCAAGAAAGCCGGGATCTGGAGT GAGTGGAGCCACCCCACAGCCGCCTCCACTCCCCGCAGTGAGCGCCCGGGCCCGGGCGGCGGGGCGT GCGAACCGCGGGGCGGAGAGCCGAGCTCGGGGCCGGTGCGGCGCGAGCTCAAGCAGTTCCTGGGCTG GCTCAGAAGCACGCGACTGCTCCAACCTCAGCTTCCGCCTCTACGACCAGTGGCGAGCCTGGATG CAGAAGTCGCACAAGACCCGCAACCAGGACGAGCGGATCCTGCCCTCGGGCAGACGGGGCACGGCGA GAGGTCCTGCCAGATAAGCTGTAGGGGCTCAGGCCACCCTCCCTGCCACGTGGAGACGCAGAGGCCG AACCCAAACTGGGGCCACCTCTGTACCCTCACTTCAGGGCACCTGAGCCACCCTCAGCAGGAGCTGG GGTGGCCCCTGAGCTCCAACGGCCATAACAGCTCTGACTCCCACGTGAGGCCACCTTTGGGTGCACC 212 WO 03/050245 PCT/USO2/38594 CCAGTGGGTGTGTGTGTGTGTOTGAGGGTTGGTTGAGTTGCCTAGAACCCCTGCCAGGGCTGGGGGT GAGAAGGGGAGTCATTACTCCCCATTACCTAGGGCCCCTCCAAAAGAGTCCTTTTAAATAAATGAGC TATTTAGGTGC ORF Start: ATG at 119 IORF Stop: TAA at 1154 SEQ ID NO: 128 345 aa MW at 37494.2kD NOV22b, MPAGRRGPAAQSARRPPPLLPLLLLLCVLGAPRAGSGAHTAVISPQDPTLLIGSSLLATCSVHGDPP CG163259-02 GATAEGLYWTLNGRRLPPELSRVLNASTLALALANLNGSRQRSGDNLVCHARDGSILALFTPYEIWV EATNRLGSARSDVLTLDILDVVTTDPPPDVHIVSRVGGLEDQLSVRWVSPPALKDFLFQAKYQIRYRV Protein Sequence EDSVDWKVVDDVSNQTSCRLAGLKPGTVYFVQVRCNPFGIYGSKKAGIWSEWSHPTAASTPRSERPG PGGGACEPRGGEPSSGPVRRELKQFLGWLKKHAYCSNLSFRLYDQWRAWMQKSHKTRNQDEGILPSG RRGTARGPAR SEQ ID NO: 129 814 bp NOV22c, CGCCCAGCGACGTGCGGGCGGCCTGGCCCGCGCCCTCCCGCGCCCGGCCTGCGTCCCGCGCCCTGCG CG163259-03 CCACCGCCGCCGAGCCGCAGCCCGCCGCGCGCCCCCGGCAGCGCCGGCCCCATGCCCGCCGGCCGCC GGGGCCCCGCCGCCCAATCCGCGCGGCGGCCGCCGCCGTTGCTGCCCCTGCTGCTGCTGCTCTGCGT DNA Sequence cCTCGGGGCGCCGCGAGCCGGATCAGGAGCCCACACAGCTGTGATCAGTCCCCAGGATCCCACGCTT CTCATCGGCTCCTCCCTGCTGGCCACCTGCTCAGTGCACGGAGACCCACCAGGAGCCACCGCCGAGG GCCTCTACTGGACCCTCAACGGGCGCCGCCTGCCCCCTGAGCTCTCCCGTGTACTCAACGCCTCCAC CTTGGCTCTGGCCCTGGCCAACCTCAATGGGTCCAGGCAGCGGTCGGGGGACAACCTCGGGCAGACG GGGCACGGCGAGAGGTCCTGCCAGATAAGCTGTAGGGGCTCAGGCCACCCTCCCTGCCACGTGGAGA CGCAGAGGCCGAACCCAAACTGGGGCCACCTCTGTACCCTCACTTCAGGGCACCTGAGCCACCCTCA GCAGGAGCTGGGGTGGCCCCTGAGCTCCAACGGCCATAACAGCTCTGACTCCCACGTGAGGCCACCT TTGGGTGCACCCCAGTGGGTGTGTGTGTGTGTGTGAGGGTTGGTTGAGTTGCCTAGAACCCCTGCCA GGGCTGGGGGTGAGAAGGGGAGTCATTACTCCCCATTACCTAGGGCCCCTCCAAAAGAGTCCTTTTA AATAAATGAG ORF Start: ATG at 119 ORF Stop: TGA at 704 SEQ ID NO: 130 195 aa MW at 20407.9kD NOV22c, MPAGRRGPAAQSARRPPPLLPLLLLLCVLGAPRAGSGAHTAVISPQDPTLLIGSSLLATCSVHGDPP CG163259-03 GATAEGLYWTLNGRRLPPELSRVLNASTLALALANLNGSRQRSGDNLGQTGHGERSCQISCRGSGHP Protein Sequence PCHVETQRPNPNWGHLCTLTSGHLSHPQQELGWPLSSNGHNSSDSHVRPPLGAPQWVCVCV Protemn Sequence.... . 5 Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 22B. Table 22B. Comparison of NOV22a against NOV22b and NOV22c. Protein Seqence NOV22a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region NOV22b 1..204 146/229 (63%) 1..226 159/229 (68%) NOV22c 1..135 119/135 (88%) 1..135 119/135 (88%) Further analysis of the NOV22a protein yielded the following properties shown in 10 Table 22C. Table 22C. Protein Sequence Properties NOV22a SignalP Cleavage site between residues 38 and 39 analysis: 213 WO 03/050245 PCT/USO2/38594 PSORT II PSG: a new signal peptide prediction method analysis: N-region: length 6; pos.chg 2; neg.chg 0 analysis H-region: length 7; peak value -5.34 PSG score: -9.74 GvH: von Heijne's method for signal seq. recognition GvK score (threshold: -2.1): 3.08 possible cleavage site: between 30 and 31 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -2.81 Transmembrane 19 - 35 PERIPHERAL Likelihood = 3.45 (at 87) ALOM score: -2.81 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 26 Charge difference: -4.5 C( 0.5) - N( 5.0) N >= C: N-terminal side will be inside >>> membrane topology: type 2 (cytoplasmic tail 1 to 19) MITDISC: discrimination of mitochondrial targeting seq R content: 5 Hyd Moment(75): 9.72 Hyd Moment(95): 9.38 G content: 5 D/E content: 1 S/T content: 4 Score: -0.72 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 43 PRAIGS NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 8.3% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: PAGR none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none 214 WO 03/050245 PCT/USO2/38594 Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues

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Final Results (k = 9/23): 39.1%: nuclear 34.8 %: mitochondrial 8.7 %: cytoplasmic 4.3 %: extracellular, including cell wall 4.3 %: Golgi 4.3 %: plasma membrane 4.3 %: peroxisomal >> prediction for CG163259-01 is nuc (k=23) A search of the NOV22a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 22D. 5 Table 22D. Geneseq Results for NOV22a NOV22a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region ABB06125 HumanNS protein sequence 1..195 192/197 (97%) e-112 SEQ ID NO:217 - Homo 1..197 192/197 (97%) sapiens, 457 aa. [WO200206315-A2, 24-JAN-2002] AAB36647 Human cytokine receptor 1..195 192/197 (97%) e-112 subunit NR6 protein SEQ ID 1..197 192/197 (97%) NO:4 - Homo sapiens, 410 aa. [WO200073451-A1, 07-DEC-2000] AAG63545 Amino acid sequence of a 1..195 192/197 (97%) e-112 human CLF-1 protein - 1..197 192/197 (97%) Homo sapiens, 422 aa. [WO200155172-A2, 02-AUG-2001] 215 WO 03/050245 PCT/USO2/38594 AAG63544 Amino acid sequence of a 1..195 192/197 (97%) e-112 human CLF-1 protein - 1..197 192/197 (97%) Homo sapiens, 445 aa. [WO200155172-A2, 02-AUG-2001] AAY44840 Human orphan cytokine 1..195 192/197 (97%) e-112 receptor-1 - Homo sapiens, 1..197 192/197 (97%) 448 aa. [WO200005370-A1, 03-FEB-2000] In a BLAST search of public sequence datbases, the NOV22a protein was found to have homology to the proteins shown in the BLASTP data in Table 22E. Table 22E. Public BLASTP Results for NOV22a Protein NOV22a Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion CAC60176 Sequence 3 from Patent 1..195 192/197 (97%) e-111 WO0155172- Homo sapiens 1..197 192/197 (97%) (Human), 445 aa. Q9UHH5 Class I cytokine receptor- 1..195 192/197 (97%) e-111 Homo sapiens (Human), 422 1..197 192/197 (97%) aa. 075462 Cytokine-like factor-1 1..195 192/197 (97%) e-111 precursor - Homo sapiens 1..197 192/197 (97%) (Human), 422 aa. Q9JM58 Cytokine receptor like 1..195 175/200 (87%) 3e-99 molecule 3 precursor - Mus 1..200 179/200 (89%) musculus (Mouse), 425 aa. CAB42575 SEQUENCE 18 FROM 48..195 136/150 (90%) 3e-78 PATENT WO9811225 - 1..150 140/150 (92%) unidentified, 278 aa (fragment). 5 PFam analysis predicts that the NOV22a protein contains the domains shown in the Table 22F. Table 22F. Domain Analysis of NOV22a Identities/ Pfam Domain NOV22a Match Region Similarities Expect Value for the Matched Expect Value Region 216 WO 03/050245 PCT/USO2/38594 Example 23. The NOV23 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 23A. 5 Table 23A. NOV23 Sequence Analysis SEQ ID NO: 131 .1375 bp NOV23a, CCCAGAGCAGCGCTCGCCACCTCCCCCCGGCCTGGGCAGCGCTCGCCCGGGGAGTCCAGCGGTGTCC CG 163425-01 TGTGGAGCTGCCGCCATGGCCCCGCGGCGGGCGCGCGGCTGCCGGACCCTCGGTCTCCCGGCGCTGC TACTGCTGCTGCTGCTCCGGCCGCCGGCGACGCGGCATCACGTGCCCTCCCCCCATGTCCGTGGA DNA Sequence ACACGCAGACATCTGGGTCAAGAGCTACAGCTTGTACTCCAGGGAGCGGTACATTTGTAACTCTGGT TTCAAGCGTAAAGCCGGCACGTCCAGCCTGACGGAGTGCGTGTTGAACAAGGCCACGAATGTCGCCC ACTGGACAACCCCCAGTCTCAAATGCATTAGAACCACAGATAAGCAGTCATGAGTCCTCCCACGG CACCCCCTCTCAGACAACAGCCAAGAACTGGGAACTCACAGCATCCGCCTCCCACCAGCCGCCAGGT GTGTATCCACAGGGCCACAGCGACACCACTGTGGCTATCTCCACGTCCACTGTCCTGCTGTGTGGGC TGAGCGCTGTGTCTCTCCTGGCATGCTACCTCAAGTCAAGGCAAACTCCCCCGCTGGCCAGCGTTGA AATGGAAGCCATGGAGGCTCTGCCGGTGACTTGGGGGACCAGCAGCAGAGATGAAGACTTGGAAAAC TGCTCTCACCACCTATGAAACTCGGGGAAACCAGCCCAGCTAAGTCCGGAGTGAAGGAGCCTCTCTG CTTTAGCTAAAGACGACTGAGAAGAGGTGCAAGGAAGCGGGCTCCAGGAGCAAGCTCACCAGGCCTC TCAGAAGTCCCAGCAGGATCTCACGGACTGCCGGGTCGGCGCCTCCTGCGCGAGGGAGCAGGTTCTC CGCATT-CCCATGGGCACCACCTGCCTGCCTGTCGTGCCTTGGACCCAGGGCCCAGCTTCCCAGGAGA GACCAAAGGCTTCTGAGCAGGATTTTTATTTCATTAAGTGTGAGCTGCCTGGAATACATGTOGTAA TGAAATAAAAACCCTGCCCCGAATCTTCCGTCCCTCATCCTAACTTTCAGTTCACAGAGAAAAGTGA CATACCCAAAGCTCTCTGTCAATTACAAGGCTTCTCCTGGCGTGGGAGACGTCTACAGGGAAGACAC CAGCGTTTGGGCTTCTAACCACCCTGTCTCCA GCTGCTCTGCACACATGGACAGGGACCTGGGAAAG GTGGGAGAGATGCTGAGCCCAGCGAATCCTCTCCATTGAAGGATTCAGGAAGAAGAAAACTCAACTC AGTGCCATTTTACGAATATATGCGTTTATATTTATACTTCCTTGTCTATTATATCTATACATTATAT ATTATTTGTATTTTGACATTGTACCTTGTATAAAC ORF Start: ATG at 83 ORF Stop: TGA at 68 SEQ ID NO: 132 21 aa MWa 12.kD NOV23a, MAPRRARGCRTLGLPALLLLLLLRPPATRGITCPPPMSVERIWVKSYSLYSRERYICNSGFKRKA CG163425-0I GTSSLTECVLNKATNVAHWTTPSLKCIRTTEISSHESSHGTPSQTTAKNWELTASASHQPPGVYPQG Prti Sqec HSDTTVAISTSTVLLCGLSAVSLLACYLKSRQTPPLASVEMEAMEALPVTWGTSSRDEDLENCSHHL Protein Sequence __ SEQ ID NO: 133 .. _.1474 bp NOV23b, CCCAGAGCAGCGCTCGCCACCTCCCCCCGGCCTGGGCAGCGCTCGCCCGGGGAGTCCAGCGGTGTCC CG163425-02 TGTGGAGCTGCCGCCATGGCCCCGCGGCGGGCGCGCGGCTGCCGGACCCTCGGTCTCCCGGCGCTGC TACTGCTGCTGCTGCTCCGGCCCCCGGCGACGCGGGGCATCACGTGCCCTCCCCCCATGTCCGTGGA DNA Sequence ACACGCAGACATCTGGGTCAAGAGCTACAGCTTGTACTCCAGGGAGCGGTACATTTGTAACTCTGGT TTCAAGCGTAAAGCCGCgACGTCCAGCCTGACGGATGCGTGTTGAACAAGGCCACGAATGTCGCCC ACTGGACAACCCCCAGTCTCAAATGCATTAAGCCCGCAGCTTCATCTCCCAGCTCAAACAACACAGC GGCCACAACAGCAGCTATTGTCCCGGGCTCCCAGCTGATGCCTTCAAAATCACCTTCCACAGGAACC ACAGAGATAAGCAGTCATGAGTCCTCCCACGGCACCCCCTCTCAGACAACAGCCAAGAACTGGGAAC TCACAGCATCCGCCTCCCACCAGCCGCCAGGTGTGTATCCACAGGGCCACAGCGACACCACTGTGGC TATCTCCACGTCCACTGTCCTGCTGTGTGGGCTGAGCGCTGTGTCTCTCCTGGCATGCTACCTCAAG TCAAGGCAAACTCCCCCGCTGGCCAGCGTTGAAATGGAAGCCATGGAGGCTCTGCCOGTGACTTGGG GGACCAGCAGCAGAGATGAAGACTTGGAAAACTGCTCTCACCACCTATGAAACTCGGGGAAACCAGC CCAGCTAAGTCCGGAGTGAAGGAGCCTCTCTGCTTTAGCTAAAGACGACTGAGAAGAGGTGCAAGGA AGCGGGCTCCAGGAGCAAGCTCACCAGGCCTCTCAGAAGTCCCAGCAGGATCTCACGGACTOCCGGG TCGGCGCCTCCTGCGCGAGGGAGCAGGTTCTCCGCATTCCCATGGGCACCACCTGCCTGCCTGTCGT GCCTTGGACCCAGGGCCCAGCTTCCCAGGAGAGACCAAAGGCTTCTGAGCAGGATTTTTATTTCATT ACAGTGTGAGCTGCCTGGAATACATGTGGTAATGAAATAAAAACCCTGCCCCGAATCTTCCGTCCCT CATCCTAACTTTCAGTTCACAGAGAAAAGTGACATACCCAAAGCTCTCTGTCAATTACAAGGCTTCT CCTGGCGTGGGAGACGTCTACAGGGAAGACACCAGCGTTTGGGCTTCTAACCACCCTGTCTCCAGCT GCTCTGCACACATGGACAGGGACCTGGGAAAGGTGGGAGAGATGCTGAGCCCAGCGAATCCTCTCCA TTGAGGATTCGGAAGAAGAAACTCAACTCAGTGCCATTTTACGAATATATGCGTTTATATTTAT 217 WO 03/050245 PCT/USO2/38594 ACTTCCTTGTCTATTATATCTATACATTATATATTATTTGTATTTTGACATTGTACCTTGTATAAAC ORF Start: ATG at 83 ORF Stop: TGA at 785 SEQ IDNO:14 234 aa W at 24869.9kD NOV23b, MAPRRARGCRTLGLPALLLLLLLRPPATRGITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKA CG163425-02 GTSSLTECVLNKATNVAHWTTPSLKCIKPAASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISS HESSHGTPSQTTAKNWELTASASHQPPGVYPQGHSDTTVAISTSTVLLCGLSAVSLLACYLKSRQTP Protein Sequence PLASVEMEAMEALPVTWGTSSRDEDLENCSHHL Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 23B. 5 Table 23B. Comparison of NOV23a against NOV23b. NOV23a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region NOV23b 1..201 200/234 (85%) 1..234 201/234 (85%) Further analysis of the NOV23a protein yielded the following properties shown in Table 23C. Table 23C. Protein Sequence Properties NOV23a SignalP Cleavage site between residues 31 and 32 analysis: PSORTII PSG: a new signal peptide prediction method analysis: N-region: length 10; pos.chg 4; neg.chg 0 anaySis H-region: length 13; peak value 11.07 PSG score: 6.67 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): 4.42 possible cleavage site: between 30 and 31 >>> Seems to have a cleavable signal peptide (1 to 30) ALOM: Klein et al's method for TM region allocation Init position for calculation: 31 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -4.73 Transmembrane 146 - 162 PERIPHERAL Likelihood = 8.80 (at 170) ALOM score: -4.73 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 15 Charge difference: -3.0 C( 2.0) - N( 5.0) N >= C: N-terminal side will be inside >>> membrane topology: type la (cytoplasmic tail 163 to 201) MITDISC: discrimination of mitochondrial targeting seq R content: 6 Hyd Moment(75): 6.07 Hyd Moment(95): 8.42 G content: 3 218 WO 03/050245 PCT/USO2/38594 D/E content: 1 S/T content: 4 Score: 0.52 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 39 TRGIIT NUCDISC: discrimination of nuclear localization signals pat4: none pat7: PRRARGC (5) at 3 bipartite: none content of basic residues: 9.5% NLS Score: -0.04 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: APRR none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23) 44.4 %: extracellular, including cell wall 22.2 %: Golgi 22.2 %: endoplasmic reticulum 11.1 %: plasma membrane >> prediction for CG163425-01 is exc (k=9) 219 WO 03/050245 PCT/USO2/38594 A search of the NOV23a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 23D. ITable 23D. Geneseq Results for NOV23a NOV23a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region AAR90844 Human interleukin-15 1..201 200/234 (85%) e-111 receptor from clone A212 - 1..234 201/234 (85%) Homo sapiens, 234 aa. [WO9530695-A, 16-NOV-1995] AAR90843 Human interleukin-15 7..201 193/279 (69%) le-99 receptor from clone P1 - 1..279 194/279 (69%) Homo sapiens, 279 aa. [WO9530695-A, 16-NOV-1995] AAR90847 Composite human 1..201 184/267 (68%) 4e-95 interleukin-15 receptor - 1..267 189/267 (69%) Homo sapiens, 267 aa. [WO9530695-A, 16-NOV-1995] AAR91594 Human interleukin-15 17..201 171/251 (68%) 5e-87 receptor - Homo sapiens, 251 1..251 175/251 (69%) aa. [WO9530695-A, 16-NOV-1995] AAR90846 Hybrid construct of IL-15R 28..165 124/204 (60%) 2e-58 alternate cytoplasmic tail - 1..204 128/204 (61%) Homo sapiens, 225 aa. [WO9530695-A, 16-NOV-1995] 5 In a BLAST search of public sequence datbases, the NOV23a protein was found to have homology to the proteins shown in the BLASTP data in Table 23E. Table 23E. Public BLASTP Results for NOV2 Protein NOV23a Identities/ Protein Residues/ Similarities for Expect Accession Protein/Organism/Length Match the Matched Value Number Residues Portion 220 WO 03/050245 PCT/USO2/38594 Q13261 Interleukin-15 receptor alpha 1..201 188/267 (70%) 3e-97 chain precursor - Homo 1..267 192/267 (71%) sapiens (Human), 267 aa. Q9ESL1 Interleukin-15 receptor alpha 1..193 110/259 (42%) 2e-45 chain precursor - Cavia 1..259 135/259 (51%) porcellus (Guinea pig), 268 aa. CAD10564 Sequence 85 from Patent 31..137 94/173 (54%) 3e-41 WO0177171 -Homo sapiens 1..173 98/173 (56%) (Human), 173 aa (fragment). Q60819 Interleukin 15 receptor 1..193 107/259 (41%) 2e-39 precursor - Mus musculus 1..259 132/259 (50%) (Mouse), 263 aa. Q8RSE4 Similar to interleukin 15 96..193 38/98 (38%) 4e-08 receptor, alpha chain - Mus 23..119 53/98 (53%) musculus (Mouse), 123 aa. PFam analysis predicts that the NOV23a protein contains the domains shown in the Table 23F. Table 23F. Domain Analysis of NOV23a Identities/ Similarities Pfam Domain NOV23a Match Region for the Matched Expect Value Region 5 Example 24. The NOV24 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 24A. Table 24A. NOV24 Sequence Analysis SEQ ID NO: 135 5940bp NOV24a, GCTCCAGCACTAGAGCCAGCTGCGAGCGGAGGGCACCAACTCCGCAGAACTGGCTTTTCAATGGGAC CG163957-01 ACCTGTGGCTCCTGGGTATTTGGGGCCTCTGTGGGCTGCTCCTGTGTGCCGCGGATCCCAGCACAGA TGGCTCTCAAATAATCCCCAAAGTCACAGAAATAATACCTAAATATGGCAGTATAAATGGAGCAACA DNA Sequence AGGCTGACTATAAGAGGGGAAGGTTTTTCTCAAGCAAACCAGTTTAACTATGGAGTTGATAACGCTG AGTTGGGAAACAGTGTGCAATTAATTTCTTCTTTCCAGTCAATTACTTGTGATGTAGAAAAAGATGC AAGTCATTCAACTCAAATTACATGCTATACTAGAGCAATGCCGGAAGATTCCTACACTGTTAGAGTC AGTGTGGACGGGGTTCCTGTTACGGAAAATAACACCTGCAAAGGTCACATCAACAGCTGGGAATGTA CCTTCAACGCAAAAAGTTTTAGAACCCCAACAATAAGAAGCATCACACCTTTATCTGGAACTCCAGG TACACTAATAACAATCCAAGGCAGAATCTTCACTGATGTCTATGGAAGTAATATTGCACTAAGCTCA AATGGGAAAAATGTTAGGATTTTGAGAGTTTACATTGGAGGAATGCCCTGTGAGCTTCTCATACCAC AATCTGATAATTTATATGGTCTAAAACTGGATCATCCAAATGGAGATATGGGTTCTATGGTTTGTAA GACGACTGGAACTTTTATTGGTCATCACAATGTCAGCTTCATCTTAGATAATGATTATGGAAGGAGT TTTCCACAGAAAATGGCATATTTTGTTTCTTCTCTCAATAAAATTGCAATGTTTCAAACATATGCAG 221 WO 03/050245 PCT/US02/38594 !GT 7- 2TCCAGACTCAGGCCAGTAATATGC TTTCTTTGATCAGACGATTTCCCCGTCGAGTTCTAGTTGGACGTCOAACCTTGTGATATTTTGAAT GTAAAATGAAGTCAAACCCAACCTTCCAATTTTC( GAGGGAGAGGCCTGAAGCTTGAGGTGTGTA TAGCCQTGCATACTTTGGAATACTGGA ATCAGAAAGCGGAAGGGCGTGTGTCGTCTTTTGT ATGGAACAAGACACATTTGTTGCACGCTTTAGTGGATTTTTGGTGCTCCGATTCTATGTTTATA GATTCTACATCAAGGGTGATGACCGTTATGCTATTTATTTTAGCGACTGGACTTCCGATA GGGGATCTTATTCATCACGTTTTCGCACCAGTAA r-TTCTTCGAGAAGAATTATAACTCGAGGAAATAT CATTTGTTGATGTTGGACTGTAC GTATC TGTTTATACTAAAAAGGATGCAGT GATAGAAGTTAACCGCAATCCAGATCGTAACTGA AATGAAACATCATAGGTCGAACAGACACCAGGCGA CTATAGTATTCAAAAATATTTAAGAAACGCTCACG TGTCTTATCTCGATACTGATACCGTTTAACGrAAT CAGATAACCAACCAACAGCAAGTAATAACATGGA = TGTTCTGTAGATGTAGGATAGCCATGAATCGAAA CAAGAACACTGGCTCCATGATGAGCTGTCAGCCCC CTTGCTAAGTATTAGACGGAGATGTGATATTCCA AATGAATTAGAGTTTGGAAATCGCATTAATATTAC GGAACTATTAACAGAGCAGAAGAAGCTGACCGATGCTTACTGTGGTCGTTATTCCCTGA AACACGTTTTATACGTTAACACGCACTTGGTTTA T* TCTAATATAGTTGAAA GTCTGCATAATGCAAT TCGACAAATGAGTATGACCGTCCGTAAAACTGTA GGACATGCTCCTCTGCTCTGTTGAGAG AAATGAA ATTTTTCGGATGTAAAACACGACrATCTTTTGTTG GTCTGAAAACAATTACTGAGATCCAAACCTCGAT * ATAG-AATCTGGATTAGTATAAC-A~kAGGCAT~, CAAACCAATATTCTGTTACCATGACTT'-TACATTGCAGTTAATATACCCTGATGGCTGTG CTTTGGGCAGATAATCACAATAGLCGAGTTTGTCTAAGGGATATTGGCCAGGC GATAAATAATAAATCACGACCACCAGGCGTTAAT AA3TAGAAATTAAGCCCGCGTTTACGAACGATTCC CCGGCGAGATGAGACCGTAAGGGG-CTTCGCAGGG AAACATG*A ACGGALGAAACTTCGTATGTCACTAT GAAAGCATTAATAAGAAAGAGGCTTCGCAAGATG AGCTCTGAACATAAACA-GGTAATTTTATGATCGTA TGTAGGCGGATAAGGTCA~-TATCCATTGCAAGCT CTAGrTCAGAACCCATTACAATGTCGATTTCATCG TGTAACAGTCTCATTGGACCAGTAGGTTGTTCTCTTCTTTCTGTGAT-GGCTCAGTGC CAGATTCTGATGGAAGTGCTCrnACATGCCCCCTTCTGTGTCATCCTATGTTGGACTAGC AGAGAGGTAGGTTCTOTATAATAACCCAACGCTAT TGACAACGTGATTCGCTATTGTTGTTAGAATAAGT TTGTGATAACGATTATACGATGAAGTACGAGCCA AAAATAGTCGTAATCGTCACAOATCACAACAGAG TTTGTTATTTCGCCATAACGTTATCAATCACAAT GGAGAAGTTAATTTAACAATT mCATTTTTATGCTCCAA-TGGCGGTGT ATTGAGAACTCAATTCCGACTAAAATGTCTTGCA GTGCCTGAAAGTTTTTGATAAATGGTTCTACAAA AATAATTCAA'ATTTTAAGGCACTTTCCAGGCCTG TTGGACGATACTACOTTGTCGAATCACGGAACTC GTAGTCTCTGATTAACTATAAATTAAATTTC~-TC ACGGAAATAGTACACAGGAGT('GAA~.TAGTTCTG CACCATCA-TTTTTGGAAATGAGCATGAAAACGTC TAAGAAGTTGATTTTTTC~,CTGATTATAGTGAAG TTAAGGAGCAATTCTAGTATTTACATATCCTGAC ATATTGACGTTTGTAGTACCATTCCAGATATATTT ACACGACAAAATCTGACGTGGGCCCGACAAAGTA GGGACGGATGATGGACCGT:CGCGCACAAACCTTC GCTACAACGGTAATCAAGTGTTTAGTC~,TTTT-C ATTTACAATCCGCATGA'AGAAGATLTAATATGCTG TTATACCCTGCATAGTCATGACACCGGCTGAAAT GTAGTCATCTTAATACTAACCACC, GTGACG,,ACG CATTATTTCACGGA~,TTA-AGTTCAGATGTGCAT GTCTTCAA-ATACGTTOCATCGACATCGATAAGGG CCTAAGTTGTTCGTCTTCGTTAATCTTGTATCCT TAATCACGGATTCGCTGAGGACTCCGTCCAACTT 222 WO 03/050245 PCT/USO2/38594 TGAAGGAGAAGGTTTGGGGACTGTTTTGGAGGACATTGCTGTTTTCATTGGAAATCAACAGTTCAGA GCAATAGAGGTTAATGAAAACAACATCACTGCTCTTGTGACTCCTCTCCCAGTTGGACATCATTCTG TTAGTGTTGTGOTGGGAAGTAALAGGCTTGGCTCTGGGAAACCTGACTGTCAGCAGCCCCCCAGTAGC ATCTCTATCACCAACTTCTGGAACCATTGGTGGTGGAACTACACTGGTGATCACAGGAAATGGCTTC TATCCAGGCAACACTACAGTCACTATTGGGGATGAACCTTGTCAAATTATTTCCATCAACCCCAATG AAGTCTACTGCCGCACTCCCGCTGGGACCACTGGAATGGTCGATGTTAAAATCTTTGTTAATACAAT TGCTTATCCACCTTTGCTTTTTACATATGCCCTGGAGGATACTCCATTTCTCAGAGGAATTATCCCA AGCAGAGGTACTCCAATATCTGCCTTATTATCTTGATATTATAGTATCGATAATATTTATTAGTATG GAATTGGAATGATATTTGTAAATAACTATTAAGGTGTGTTTATA ORF Start: ATG at 61 IORF Stop: TGA at 5863 SEQ ID NO: 136 1934 aa MW at 211824.6kD NOV24a, MGHLWLLGIWGLCGLLLCAADPSTDGSQIIPKVTEIIPKYGSINGATRLTIRGEGFSQANQFNYGVD CG163957-01 NAELGNSVQLISSFQSITCDVEKDASHSTQITCYTRAMPEDSYTVRVSVDGVPVTENNTCKGHINSW ECTFNAKSFRTPTIRSITPLSGTPGTLITIQGRIFTDVYGSNIALSSNGKNVRILRVYIGGMPCELL Protein Sequence IPQSDNLYGLKLDHPNGDMGSMVCKTTGTFIGHKNVSFILDNDYGRSFPQKMAYFVSSLNXIAMFQT YAEVTMIFPSQGSIRGGTTLTISGRFFDQTDFPVRVLVGGEPCDILNVTENSICCKTPPKPHILKTV YPGGRGLKLEVWNNSRPIRLEEILEYNEKTPGYMGASWVDSASYIWLMEQDTFVARFSGFLVAPDSD VYRFYIKGDDRYAIYFSQTGLPEDKVRIAYHSANANSYFSSPTQRSDDIHLQKGKEYYIEILLQEYR LSAFVDVGLYQYRNVYTEQQTGDAVNEEQVIKSQSTILQEVQVITLENWETTNAINEVQKIKVTSPC VEANSCSLYQYRLIYNMEKTVFLPADASEFILQSALNDLWSIKPDTVQVIRTQNPQSYVYMVTFIST RGDFDLLGYEVVEGNNVTLDITEQTKGKPNLETFTLNWDGIASKPLTLWSSEAEFQGAVEEMVSTKC PPQIANFEEGFVVKYFRDYETDFNLEHINRGQKTAETDAYCGRYSLKNPAVLFDSADVKPNRRPYGD ILLFPYNQLCLAYKGFLANYIGLKFQYQDNSKITRSTDTQFTYNFAYGNNWTYTCIDLLDLVRTKYT GTNVSLQRISLHKASESQSFYVDVVYIGHTSTISTLDEMPKRRLPALANKGIFLEHFQVNQTKTNGP TMTNQYSVTMTSYNCSYNIPMMAVSFGQIITHETENEFVYRGNNWPGESKIHIQRIQAASPPLSGSF DIQAYGHILKGLPAAVSAADLQFALQSLEGMGRISVTREGTCAGYAWNIKWRSTCGKQNLLQINDSN IIGEKANMTVTRIKEGGLPRQHVLGDLLRTPSQQPQVEVYVNGIPAKCSGDCGFTWDSNITPLVLAI SPSQGSYEEGTILTIVGSGFSPSSAVTVSVGPVGCSLLSVDEKELKCQILNGSAGRAPVAVSMADVG LAQNVGGEEFYFVYQSQISHIWPDSGSTAGGTLLTLSGFGFNENSKVLVGNETCNVIEGDLNRITCR TPKKTEGTVDISVTTNGFQATARDAFSYNCLQTPIITDFSPKVRTILGEVNLTIKGYNFGNELTQNM AVYVGGKTCQILHWNFTDIRCLLPKLSPGKHDIYVEVRNWGFASTRDKLNSSIQYVLEVTSMFPQRG SLGGTEITIRGFGFSTIPAENTVLLGSIPCNVTSSSENVIKCILHSTGNIFRITNNGKDSVHGLGY AWSPPVLNVSVGDTVAWHWQTHPFLRGIGYRIFSVSSPGSVIYDGKGPTSGRQKSTSGSFSYQFTSP GIHYYSSGYVDEAHSIFLQGVINVLPAETRHIPLHLFVGRSEATYAYGGPENLHLGSSVAGCLATEP LCSLNNTRVKNSKRLLFEVSSCFSPSISNITPSTGTVNELITIIGHGFSNLPWANKVTIGSYPCVVE ESSEDSITCHIDPQNSMDVGIRETVTLTVYNLGTAINTLSNEFDRRFVLLPNIDLVLPNAGSTTGMT SVTIKGSGFAVSSAGVKVLMGHFPCKVLSVNYTAIECETSPAAQQLVDVDLLIHGVPAQCQGNCTFS YLESITPYITGVFPNSVIGSVKVLIEGEGLGTVLEDIAVFIGNQQFRAIEVNENNITALVTPLPVGH HSVSVVVGSKGLALGNLTVSSPPVASLSPTSGSIGGGTTLVITGNGFYPGNTTVTIGDEPCQIISIN PNEVYCRTPAGTTGMVDVKIFVNTIAYPPLLFTYALEDTPFLRGIIPSRGTPISALLS Further analysis of the NOV24a protein yielded the following properties shown in Table 24B. 5 Table 24B. Protein Sequence Properties NOV24a SignalP Cleavage site between residues 21 and 22 analysis: PSORTII PSG: a new signal peptide prediction method analysis: N-region: length 0; pos.chg 0; neg.chg 0 H-region: length 201; peak value 9.31 PSG score: 4.91 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -1.16 possible cleavage site: between 20 and 21 >>> Seems to have a cleavable signal peptide (1 to 20) ALOM: Klein et al's method for TM region allocation 223 WO 03/050245 PCT/USO2/38594 Init position for calculation: 21 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 0 PERIPHERAL Likelihood = 1.11 (at 1751) ALOM score: 0.16 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 10 Charge difference: -3.5 C(-2.0) - N( 1.5) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 3.65 Hyd Moment(95): 3.01 G content: 4 D/E content: 1 S/T content: 0 Score: -7.61 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: PKRR (4) at 844 pat7: PKRRLPA (5) at 844 bipartite: none content of basic residues: 7.2% NLS Score: 0.21 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none IRNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 89 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 224 WO 03/050245 PCT/USO2/38594 30.4 %: cytoplasmic 30.4 %: nuclear 8.7 %: extracellular, including cell wall 8.7 %: vacuolar 8.7 %: mitochondrial 8.7 %: endoplasmic reticulum 4.3 %: vesicles of secretory system >prediction for CG163957-01 is cyt (k=23) A search of the NOV24a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 24C. 5 Table 24C. Geneseq Results for NOV24a NOV24a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region ABG37531 Human peptide encoded by 1598..1925 328/328 (100%) 0.0 genome-derived single exon 1..328 328/328 (100%) probe SEQ ID 27196 Homo sapiens, 328 aa. [WO200186003-A2, 15-NOV-2001] AAM03553 Peptide #2235 encoded by 1598..1925 328/328 (100%) 0.0 probe for measuring breast 1..328 328/328 (100%) gene expression - Homo sapiens, 328 aa. [WO200157270-A2, 09-AUG-2001] AAM28325 Peptide #2362 encoded by 1598..1925 328/328 (100%) 0.0 probe for measuring 1.328 328/328 (100%) placental gene expression Homo sapiens, 328 aa. [WO200157272-A2, 09-AUG-2001] AAM15815 Peptide #2249 encoded by 1598..1925 328/328 (100%) 0.0 probe for measuring cervical 1..328 328/328 (100%) gene expression - Homo sapiens, 328 aa. [WO200157278-A2, 09-AUG-2001] AAM67998 Human bone marrow 1598..1925 328/328 (100%) 0.0 expressed probe encoded 1..328 328/328 (100%) protein SEQ ID NO: 28304 Homo sapiens, 328 aa. 225 WO 03/050245 PCT/USO2/38594 09-AUG-2001] In a BLAST search of public sequence datbases, the NOV24a protein was found to have homology to the proteins shown in the BLASTP data in Table 24D. Table 24D. Public BLASTP Results for NOV24a NOV24a Protein NOV24aResidues Identities/ Accession Protein/Organism/Length Residues/ Similarities for the Expect [ ccsio roen/rgnsmLnghMatch Mthdorin Value Number Residues Matched Portion Residues Q99PS9 D86 protein - Mus musculus 1..1933 1528/1933 (79%) 0.0 (Mouse), 1944 aa. 1..1932 1699/1933 (87%) AAM93492 Polycystic kidney and 637..1895 319/1323 (24%) 3e-67 hepatic disease 1 - Homo 514..1717 536/1323 (40%) sapiens (Human), 4074 aa. Q8TCZ9 Polycystic kidney and 637..1895 319/1323 (24%) 3e-67 hepatic disease 1 precursor 514..1717 536/1323 (40%) (Fibrocystin) (Polyductin) (Tigmin) - Homo sapiens (Human), 4074 aa. AAN05018 Polyductin - Mus musculus 630..1885 308/1315 (23%) 3e-66 (Mouse), 4059 aa. 508..1703 546/1315 (41%) Q8RD81 Hypothetical protein 1062..1355 88/317 (27%) 9e-15 TTE0165 - 798..1105 143/317 (44%) Thermoanaerobacter tengcongensis, 1754 aa. 5 PFam analysis predicts that the NOV24a protein contains the domains shown in the Table 24E. Table 24E. Domain Analysis of NOV24a Identities/ Pfam Domain NOV24a Match Region Similarities Expect Value for the Matched Region TIG 31..130 26/120 (22%) 1.2e-05 74/120 (62%) TIG 146..256 28/122 (23%) 0.0019 77/122 (63%) TIG 270..362 26/111 (23%) 1.5e- 11 72/111 (65%) TIG 1067..1152 26/104 (25%) 1.8e-08 60/104 (58%) 226 WO 03/050245 PCT/USO2/38594 TIG 1155..1235 27/104 (26%) 4.1e-13 61/104 (59%) TIG 1240..1323 21/105 (20%) 0.0076 61/105 (58%) TIG 1330..1470 29/153 (19%) 4.9e-07 95/153 (62%) TIG 1566..1650 23/106 (22%) 0.064 61/106 (58%) TIG 1659..1744 28/104 (27%) 2.3e-11 65/104 (62%) TIG 1749..1829 21/106 (20%) 0.00062 58/106 (55%) TIG 1831..1911 29/104 (28%) 2.4e-12 63/104 (61%) Example 25. The NOV25 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 25A. 5 Table 25A. NOV25 Sequence Analysis SEQ ID NO: 137 1145 bp NOV25a, TGTGTTTTAGGTTCAGCCGTCTGTATATCTCCCCAGATACCTGAAACTGACCACCTGAGTACGTTTT CG164482-01 CCCATTGCTGAGCTGTTTCCCTGATATCTGGCCATGCAACGGAGATCAAGAGGGATAAATACTGGAC TTATTCTACTCCTTTCTCAAATCTTCCATGTTGGGATCAACAATATTCCACCTGTCACCCTAGCAAC DNA Sequence TTTGGCCCTCAACATCTGGTTCTTCTTGAACCCTCAGAAGCCACTGTATAGCTCCTGCCTTAGTGTG GAGAAGTGTTACCAGCAAAAAGACTGGCAGCGTTTACTGCTCTCTCCCCTTCACCATGCTGATGATT GGCATTTGTATTTCAATATGGCATCCATGCTCTGGAAAGGAATAAATCTAGAAAGAAGACTGGGAAG TAGATGGTTTGCCTATGTTATCACCGCATTTTCTGTACTTACTGGAGTGGTATACCTGCTCTTGCAA TTTGCTGTTGCCGAATTTATGGATGAACCTGACTTCAAAAGGAGCTGTGCTGTAGGTTTCTCAGGAG TTTTGTTTGCTTTGAAAGTTCTTAACAACCATTATTGCCCTGGAGGCTTTGTCAACATTTTGGGCTT TCCTGTACCGAACAGATTTGCTTGTTGGGTCGAACTTGTGGCTATTCATTTATTCTCACCACCTAGG ACTTCCTTCGCTGGGCATCTGGCTGGGATTCTTGTTGGACTAATGTACACTCAAGGGCCTCTGAAGA AAATCATGGAAGCATGTGCAGGTGGTTTTTCCTCCAGTGTTGGTTACCCAGGACGGCAATACTACTT TAATAGTTCAGGTAGCTCTGGATATCAGGATTATTATCCGCATGGCAGGCCAGATCACTATGAAGAA GCACCCAGGAACTATGACACGTACACAGCAGGACTGAGTGAAGAAGAACAGCTCGAGAGAGCATTAC AAGCCAGCCTCTGGGACGGAAATACCAGAAATAGCCCACCACCCTACGGGTTTCATCTCTCACCAGA AGAAATGAGGAGACAGCGGCTTCACAGATTCGATAGCCAGTGAGGTGGCATCTTGGGAAGACATGGC CTATTCGTGTAATTATTGCCCATTTGGCTCATTCCCCAAGCCCCTAATTCATTTTAATTCATTTTAA ACAAAA ORF Start: ATG at 101 ORF Stop: TGA at 1046 SEQ ID NO: 138 315 aa MWat35862.7kD NOV25a, MQRRSRGINTGLILLLSQIFHVGINNIPPVTLATLALNIWFFLNPQKPLYSSCLSVEKCYQQKDWQR CG164482-01 LLLSPLHHADDWHLYFNMASMLWKGINLERRLGSRWFAYVITAFSVLTGVVYLLLQFAVAEFMDEPD FKRSCAVGFSGVLFALKVLNNHYCPGGFVNILGFPVPNRFACWVELVAIHLFSPPRTSFAGHLAGIL Protein Sequence VGLMYTQGPLKKIMEACAGGFSSSVGYPGRQYYFNSSGSSGYQDYYPHGRPDHYEEAPRNYDTYTAG LSEEEQLERALQASLWDGNTRNSPPPYGFHLSPEEMRRQRLHRFDSQ Further analysis of the NOV25a protein yielded the following properties shown in Table 25B. 227 WO 03/050245 PCT/USO2/38594 Table 25B. Protein Sequence Properties NOV25a SignalP Cleavage site between residues 24 and 25 analysis: PSORTII PSG: a new signal peptide prediction method analysis: N-region: length 6; pos.chg 3; neg.chg 0 analysis: H-region: length 40; peak value 8.94 PSG score: 4.54 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -6.06 possible cleavage site: between 61 and 62 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 3 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -4.78 Transmembrane 106 - 122 PERIPHERAL Likelihood = 0.53 (at 138) ALOM score: -4.78 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 113 Charge difference: -5.0 C(-2.0) - N( 3.0) N >= C: N-terminal side will be inside >>> membrane topology: type 2 (cytoplasmic tail 1 to 106) MITDISC: discrimination of mitochondrial targeting seq R content: 3 Hyd Moment(75): 4.10 Hyd Moment(95): 10.35 G content: 3 D/E content: 1 S/T content: 8 Score: -1.05 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 16 SRGIIN NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 8.6% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: QRRS none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none 228 WO 03/050245 PCT/USO2/38594 NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: found LL at 14 LL at 15 checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 43.5 %: mitochondrial 21.7 %: cytoplasmic 13.0 %: Golgi 4.3 %: vacuolar 4.3 %: extracellular, including cell wall 4.3 %: vesicles of secretory system 4.3 %: nuclear 4.3 %: endoplasmic reticulum >> prediction for CG164482-01 is mit (k=23) A search of the NOV25a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 25C. 5 Table 25C. Geneseq Results for NOV25a NOV25a I Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for the Expect Identifier [Patent #, Date] Match Matched Region Value Residues Mth Rg AAE17492 Human secretion and 1..315 313/316 (99%) 0.0 trafficking protein-1 (SAT-1) 1..315 313/316 (99%) - Homo sapiens, 315 aa. [WO200202610-A2, 10-JAN-2002] 229 WO 03/050245 PCT/USO2/38594 ABG27447 Novel human diagnostic 1..144 144/144 (100%) 2e-81 protein #27438 - Homo 4..147 144/144 (100%) sapiens, 236 aa. [WO200175067-A2, 11-OCT-2001] ABG14559 Novel human diagnostic 171..315 139/146 (95%) 3e-76 protein #14550 - Homo 1..145 139/146 (95%) sapiens, 145 aa. [WO200175067-A2, S11-OCT-2001] ABG01637 Novel human diagnostic 1..119 119/119 (100%) 2e-66 protein #1628 - Homo 1..119 119/119 (100%) sapiens, 119 aa. [WO200175067-A2, 1 1-OCT-2001] ABG02478 Novel human diagnostic 215.314 100/101 (99%) 2e-55 protein #2469 - Homo 1..101 100/101 (99%) sapiens, 102 aa. [WO200175067-A2, 11-OCT-2001] In a BLAST search of public sequence datbases, the NOV25a protein was found to have homology to the proteins shown in the BLASTP data in Table 25D. Table 25D. Public BLASTP Results for NOV25a NOV25a Identities/ Protein Residues/ Similarities for Expect Accession Protein/Organism/Length Match the Matched Value Number Residues Portion Q8TEB9 Hypothetical protein 1..315 313/316 (99%) 0.0 FLJ23678 - Homo sapiens 1..315 313/316 (99%) (Human), 315 aa. Q99K13 Similar to RIKEN cDNA 1..315 255/316 (80%) e-152 4930418P06 gene - Mus 1..315 278/316 (87%) musculus (Mouse), 315 aa. Q9D5L8 4930418PO6Rik protein - 1..315 253/316 (80%) e-151 Mus musculus (Mouse), 315 1..315 277/316 (87%) aa. Q95LN6 Hypothetical 29.3 kDa 1..250 235/250 (94%) e-138 protein - Macaca fascicularis 1..249 243/250 (97%) (Crab eating macaque) (Cynomolgus monkey), 261 aa. AAH27900 Hypothetical protein 220..315 96/97 (98%) 2e-52 DKFZp547EO52 - Homo 10..106 96/97 (98%) sapiens (Human), 106 aa. 230 WO 03/050245 PCT/USO2/38594 PFam analysis predicts that the NOV25a protein contains the domains shown in the Table 25E. Table 25E. Domain Analysis of NOV25a Identities/ Pfam Domain NOV25a Match Region Similarities Expect Value for the Matched Region Rhomboid 59..215 44/169 (26%) 7.4e-05 102/169 (60%) UIM 269..286 9/18 (50%) 0.42 16/18(89%) 5 Example 26. The NOV26 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 26A. Table 26A. NOV26 Sequence Analysis SEQ ID NO: 139 853 bp NOV26a, AGCCAACTTTCCTTTCAAATACACACCCCAACCCGCCCCGGCATACACAGAAATGGGGACTGCGAGC CG1l64511-01 AGAAGCAACATCGCTCGCCATCTGCAAACCAATCTCATTCTATTTTGTGTCGGTGCTGTGGGCGCCT GTACTCTCTCTGTCACACAACCGTGGTACCTAGAAGTGGACTACACTCATGAGGCCGTCACCATAAA DNA Sequence GTGTACCTTCTCCGCAACCGGATGCCCTTCTGAGCAACCAACATGCCTGTGGTTTCGCTACGGTGCT CACCAGCCTGAGAACCTGTGCTTGGACGGGTGCAAAAAAATTAAGCTGCTCAGCAAGGAACTGCGGA GCTTCCTGACAGCTCTTGTATCACTGCTCTCTGTCTATGTGACCGGTGTGTGCGTGGCCTTCATACT CCTCTCCAAATCAAAATCCAACCCTCTAAGAAAGAAAGAAATAAAAGAAGACTCACAAAAGAAGAAG AGTGCTCGGCGTATTTTTCAGGAAATTGCTCAAGAACTATACCATAAGAGACATGTGGAAACAAATC AGCAATCTGAGAAAGATAACAACACTTATGAAAACAGAAGAGTACTTTCCAACTATGAAAGGCCATA GAAACGTTTTAATTTTCAATGAAGTCACTGAAAATCCAACTCCAGGAGCTATGGCAGTGTTAATGAA CATATATCATCAGGTCTTAAAAAAAAAATAAAGGTAAACTGAAAAGACAACTGGCTACAAAGAAGGA TGTCAGAATGTAAGGAAACTATAACTAATAGTCATTACCAAAATACTAAAACCCAACAAAATGCAAC TGAAAAATACCTTCCAAATTTGCCAAGAAAAAAAATTCTATTNNAAACT ORF Start: ATG at 53 ORF Stop: TAG at 602 SEQ ID NO: 140 183 aa MW at 20846.8kD NOV26a, MGTASRSNIARHLQTNLILFCVGAVGACTLSVTQPWYLEVDYTHEAVTIKCTFSATGCPSEQPTCLW CG164511-01 FRYGAHQPENLCLDGCKKIKLLSKELRSLTALVSLLSVYVTGVCVAFILLSKSKSNPLRKKEIKED SQKKKSARRIFQEIAQELYHKRHVETNQQSEKDNNTYENRRVLSNYERP Protein Sequence, Further analysis of the NOV26a protein yielded the following properties shown in Table 26B. Table 26B. Protein Sequence Properties NOV26a SignalP analysis: Cleavage site between residues 28 and 29 PSORT II analysis: PSG: a new signal peptide prediction method 231 WO 03/050245 PCT/USO2/38594 N-region: length 11; pos.chg 2; neg.chg 0 H-region: length 27; peak value 10.26 PSG score: 5.86 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -2.66 possible cleavage site: between 30 and 31 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 2 INTEGRAL Likelihood = -5.31 Transmembrane 17 - 33 INTEGRAL Likelihood = -6.95 Transmembrane 100 - 116 PERIPHERAL Likelihood = 12.04 (at 42) ALOM score: -6.95 (number of TMSs: 2) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 24 Charge difference: -5.0 C(-1.5) - N( 3.5) N >= C: N-terminal side will be inside >>> membrane topology: type 3a MITDISC: discrimination of mitochondrial targeting seq R content: 2 Hyd Moment(75): 3.52 Hyd Moment(95): 4.97 G content: 3 D/E content: 1 S/T content: 7 Score: -2.98 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 21 ARHILQ NUCDISC: discrimination of nuclear localization signals pat4: none pat7: PLRKKEI (5) at 125 bipartite: RKKEIKEDSQKKKSARR at 127 content of basic residues: 14.2% NLS Score: 0.45 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none 232 WO 03/050245 PCT/USO2/38594 checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 89 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 39.1%: mitochondrial 34.8 %: nuclear 17.4 %: endoplasmic reticulum 4.3 %: cytoplasmic 4.3 %: peroxisomal >> prediction for CG164511-01 is mit (k=23) A search of the NOV26a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 26C. 5 Table 26C. Geneseq Results for NOV26a NOV26a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region AAW60833 Human Ig-like A07C03 1..183 167/241 (69%) 4e-86 protein - Homo sapiens, 241 1..241 172/241 (71%) aa. [WO9823747-A2, 04-JUN-1998] AAW60834 Human Ig-like A07C03 1..183 167/241 (69%) 4e-86 protein - Homo sapiens, 241 1..241 172/241 (71%) aa. [WO9823747-A2, 04-JUN-1998] AAY69993 Human receptor-associated 1..183 166/241 (68%) le-85 protein from Incyte clone 1.L.241 171/241 (70%) 1220371 - Homo sapiens, 241 aa. [WO200008155-A2, 17-FEB-2000] AAY36007 Extended human secreted 1..183 166/241 (68%) le-85 protein sequence, SEQ ID 1..241 171/241 (70%) NO. 392 - Homo sapiens, 241 aa. [WO9931236-A2, 24-JUN-1999] 233 WO 03/050245 PCT/US02/38594 AAY13062 Human secreted protein 1..84 84/84 (100%) 5e-47 encoded by 5' EST SEQ ID 1..84 84/84 (100%) NO: 76 - Homo sapiens, 125 aa. [WO9906552-A2, 11-FEB-1999] In a BLAST search of public sequence datbases, the NOV26a protein was found to have homology to the proteins shown in the BLASTP data in Table 26D. Table 26D. Public BLASTP Results for NOV26a Protein NOV26a Identities/ Protemn Residues/ Similarities for Expect Accession Protein/Organism/Length Match the Matched Value Number. Number Residues Portion 095976 DORA protein precursor - 1..183 167/241 (69%) le-85 Homo sapiens (Human), 241 1..241 172/241 (71%) aa. CAC20440 Immunoglobulin superfamily 1..183 166/241 (68%) 5e-85 6 protein (IGSF6) precursor - 1..241 171/241 (70%) Homo sapiens (Human), 241 aa. Q8WWD8 Hypothetical protein - Homo 1..183 164/241 (68%) 3e-84 sapiens (Human), 241 aa. 1..241 171/241 (70%) Q9ZOK5 DORA protein precursor - 1.. 183 103/240 (42%) 7e-38 Rattus norvegicus (Rat), 238 1..238 128/240 (52%) aa. CAC20696 Immunoglobulin superfamily 1..179 93/236 (39%) 6e-29 6 protein (IGSF6) precursor - 1..233 116/236 (48%) Mus musculus (Mouse), 237 aa. 5 PFam analysis predicts that the NOV26a protein contains the domains shown in the Table 26E. Table 26E. Domain Analysis of NOV26a Identities/ Similarities Pfam Domain NOV26a Match Region Similarities Expect Value for the Matched Region 234 WO 03/050245 PCT/USO2/38594 Example 27. The NOV27 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 27A. Table 27A. NOV27 Sequence Analysis _ EQ ID N5: 141 .422 bp NOV27a, . CACGCGGCCGCACCATGAAGTCCUACGGCTCTTC CCCTTCCTccTcCTGCTTnCCCTGGACTCT CG55060-03 GGCACCTTGCTTGGAGCTCTGAAGTCCTTCAAGCTGGAGTCTGTCCTCCTAATCT DNA Sequence GTGCTAATGGrACATCTGACTTGCCCAACACAGGA GCCTGGAGTCCCAGTGACTTATGGCCALTGTTTGATGCTTAACCCCCCATTTCTGTGAGATG ____________TGAAAGCTTAGGTCGACGGC _ _ _ _ORF Start: ATG atI15 ORF Stop: TAG at 411 ______SEQ ID NO: 142 .132 aa M1W atl4325.9k NOV27a, MSSGLFPFLVLLLGTLAPWAVEGSGKSFKAGVCPPKKSAQCLRYKCPECQSDWQCPGKKRCCPDT CG55060-03 CGIKCLDPVDTPNPTRRKPGCPVTYGQCLLNPPNFCEMDGQCRDLKCCMMCGKSSPK Protein Sequence ]SEQ ID NO: 143 594 bp NOV2Th, GTCACTCCTGCCTTCACCATAGTCCGCGGCCTCTTCCCCTTCCTGTGCTGCTTCCCTGG CG55060-0 1 CTCTGGCACCTTGGGCTGTGGAGGCTCTGGAGTCCTTQACTCGAGTCTGTCCTCCTAGAA DNA Sequence AG GTTCGCCTTGACATCCGACTTGCCCAACACAG GGAAGCCTGGGAAGTGCCCAGTACTTATGGCATGTTTGATGCTTJACCCCCCATTTCTGTGA TTTCCACCCTGAGACTTGGCTCCACCACTGATATCCTCCTTTGAGGCTTnCOC 0RFStart: ATG at 19 -IRStop: TGAat 415 __________SEQ ID NO: 144 .132_ aa M t142.k NOV2Th, MKSSGLFPFLVLTLLTGTLAPWAVEGSGKSFKAGVCPPKSAQCLRYKEcQsnwQCPGKKRCCPDT CG55060-01i CGIKCLDPVDTPNPTRRKPGKCPTYGQCLMLNPNFCE]DQCKDLKCCMGMCGKSCVSPVKA Protein Sequence ISEQ ID NO:_145 1321 bp_ _______ NOV27c, TCTGGAAAGTCCTTCAAAGCTGGAGTCTGTCCTCCTMAAAATCTGCCCAGTGCCTTAGATACAAGA CG55060-02 AACCTGAGTGCCAAGTGACTGGCAGTGTCCAcAGAACATGTTGTCCTGGGA ________ TAATGCTGCAGATTGTGCGAAATCcCnTTACcCGTAGAAAGCTGAGTCATG DNA Sequence TATGGCCAATGTTTGATGCTTAACCCCCCCATTTCTGTGAGATGGATGGCCAGTGCAAOCCTGACT fSEQ ID NO: 146 110 a MWatl1725.8kD NOV27c, SGI<SFKAGVCPPKCSAQCLRYKKPECQSIDWQCPGKKRCCPDTCGIKCLDPVDTPNPTRKPGKCPVT =CG55060-02 Protein Sequence. 10 Sequence comparison Of the above protein sequences yields the following sequence relationships shown in Table 27B.

WO 03/050245 PCT/USO2/38594 NOV27a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region NOV27b 1..132 132/132 (100%) 1..132 132/132 (100%) NOV27c 26..132 107/107 (100%) 1..107 107/107 (100%) Further analysis of the NOV27a protein yielded the following properties shown in Table 27C. Table 27C. Protein Sequence Properties NOV27a SignalP analysis: Cleavage site between residues 26 and 27 PSORTII PSG: a new signal peptide prediction method analysis: N-region: length 2; pos.chg 1; neg.chg 0 H-region: length 21; peak value 10.99 PSG score: 6.59 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -1.73 possible cleavage site: between 18 and 19 >>> Seems to have a cleavable signal peptide (1 to 18) ALOM: Klein et al's method for TM region allocation Init position for calculation: 19 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood = 8.59 (at 114) ALOM score: 8.59 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 9 Charge difference: 0.0 C( 2.0) - N( 2.0) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 3.26 Hyd Moment(95): 4.32 G content: 2 D/E content: 1 S/T content: 3 Score: -5.65 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 55 LRYIKK NUCDISC: discrimination of nuclear localization signals pat4: RRKP (4) at 83 pat7: PGKKRCC (5) at 58 pat7: PNPTRRK (3) at 79 pat7: PTRRKPG (5) at 81 bipartite: KKPECQSDWQCPGKKRC at 47 content of basic residues: 15.9% NLS Score: 1.39 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: KKXX-like motif in the C-terminus: SPVK 236 WO 03/050245 PCT/USO2/38594 SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 60.9 %: nuclear 17.4 %: mitochondrial 17.4 %: extracellular, including cell wall 4.3 %: cytoplasmic >> prediction for CG55060-03 is nuc (k=23) A search of the NOV27a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 27D. 5 Table 27D. Geneseq Results for NOV27a NOV27a identities/ Geneseq Protein/Organism/Length Residues/ Identilarities for the Expect Identifier [Patent #, Date] Match SiMiarities for theValue Residues Matched Region 237Residues 237 WO 03/050245 PCT/USO2/38594 AAU11763 Human Antileukoprotease 1..132 132/132 (100%) 2e-81 protein - Homo sapiens, 132 1..132 132/132 (100%) aa. [WO200190421-A2, 29-NOV-2001] AAB66864 Human antileukoprotease - 1..132 132/132 (100%) 2e-81 Homo sapiens, 132 aa. 1..132 132/132 (100%) [WO200101998-A2, 11-JAN-2001] AAB47403 SLPI native immature form - 1..132 132/132 (100%) 2e-81 Homo sapiens, 132 aa. 1..132 132/132 (100%) [WO200148231-A2, 05-JUL-2001] ABB50282 Leukocyte protease inhibitor 1..132 132/132 (100%) 2e-81 ovarian tumour marker 1..132 132/132 (100%) protein, #54 - Homo sapiens, 132 aa. [WO200175177-A2, 11-OCT-2001] AAR84056 Secretory leukocyte protease 1..132 132/132 (100%) 2e-81 inhibitor - Homo sapiens, 1..132 132/132 (100%) 132 aa. [WO9608275-A1, 21-MAR-1996] In a BLAST search of public sequence datbases, the NOV27a protein was found to have homology to the proteins shown in the BLASTP data in Table 27E. Table 27E. Public BLASTP Results for NOV27a Protein NOV27a Residues/ Identities/Expect Accession Protein/Organism/Length Match Similarities for the Expect Number Residues Matched Portion Value P03973 Antileukoproteinase 1 1..132 132/132 (100%) 5e-81 precursor (ALP) (HUSI-1) 1..132 132/132 (100%) (Seminal proteinase inhibitor) (Secretory leukocyte protease inhibitor) (BLPI) (Mucus proteinase inhibitor) (MPI) - Homo sapiens (Human), 132 aa. CAA00747 ALP-242 PROTEIN - 26..132 106/107 (99%) 9e-66 synthetic construct, 107 aa 1..107 107/107 (99%) (fragment). CAA00748 ALP-246 PROTEIN - 26..132 105/107 (98%) le-64 synthetic construct, 107 aa 1..107 106/107 (98%) (fragment). 238 WO 03/050245 PCT/USO2/38594 CAA00743 ALP-231 PROTEIN - 26..132 103/107 (96%) le-64 synthetic construct, 107 aa 1..107 107/107 (99%) (fragment). CAA00742 ALP-240 PROTEIN - 26..132 105/107 (98%) le-64 synthetic construct, 107 aa 1..107 106/107 (98%) (fragment). PFam analysis predicts that the NOV27a protein contains the domains shown in the Table 27F. Table 27F. Domain Analysis of NOV27a Identities/ Similarities Pfam Domain NOV27a Match Region for the Matched Expect Value Region wap 31..75 23/55 (42%) 1.8e-18 45/55 (82%) wap 85..129 25/55 (45%) 7e-21 43/55 (78%) 5 Example 28. The NOV28 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 28A. Table 28A. NOV28 Sequence Analysis ISEQ ID NO: 147 ;_1542 bp NOV28a, AAACGATTTCATGATGTGCTGGGCAATGAAAGACCTTCTGCTTACATGAGGGAGCACAATCAATTAA CG56972-02 ATGGCTGGTCTTCTGATGAAAATGACTGGAATGAAAAACTCTACCCAGTGTGGAAGCGGGGAGACAT GAGGTGGAAAAACTCCTGGAAGGGAGGCCGTGTGCAGGCGGTCCTGACCAGTGACTCACCAGCCCTC DNA Sequence GTGGGCTCAAATATAACATTTGCGGTGAACCTGATATTCCCTAGATGCCAAAAGGAAGATGCCAATG GCAACATAGTCTATGAGAAGAACTGCAGAAATGAGGCTGGTTTATCTGCTGATCCATATGTTTACAA CTGGACAGCATGGTCAGAGGACAGTGACGGGGAAAATGGCACCGGCCAAAGCCATCATAACGTCTTC CCTGATGGGAAACCTTTTCCTCACCACCCCGGATGGAGAAGATGGAATTTCATCTACGTCTTCCACA CACTTGGTCAGTATTTCCAGAAATTGGGACGATGTTCAGTGAGAGTTTCTGTGAACACAGCCAATGT GACACTTGGGCCTCAACTCATGGAAGTGACTGTCTACAGAAGACATGGACGGGCATATGTTCCCATC GCACAAGTGAAAGATGTGTACGTGGTAACAGATCAGATTCCTGTGTTTGTGACTATGTTCCAGAAGA ACGATCGAAATTCATCCGACGAAACCTTCCTCAAAGATCTCCCCATTATGTTTGATGTCCTGATTCA TGATCCTAGCCACTTCCTCAATTATTCTACCATTAACTACAAGTGGAGCTTCGGGGATAATACTGGC CTGTTTGTTTCCACCAATCATACTGTGAATCACACGTATGTGCTCAATGGAACCTTCAGCCTTAACC TCACTGTGAAAGCTGCAGCACCAGGACCTTGTCCGCCACCGCCACCACCACCCAGACCTTCAAAACC CACCCCTTCTTTAGGACCTGCTGGTGACAACCCCCTGGAGCTGAGTAGGATTCCTGATGAAAACTGC CAGATTAACAGATATGGCCACTTTCAAGCCACCATCACAATTGTAGAGGGAATCTTAGAGGTTAACA TCATCCAGATGACAGACGTCCTGATGCCGGTGCCATGGCCTGAAAGCTCCCTAATAGACTTTGTCGT GACCTGCCAAGGGAGCATTCCCACGGAGGTCTGTACCATCATTTCTGACCCCACCTGCGAGATCACC CAGAACACAGTCTGCAGCCCTGTGGATGTGGATGAGATGTGTCTGCTGACTGTGAGACGAACCTTCA ATGGGTCTGGGACGTACTGTGTGAACCTCACCCTGGGCGATGACACAAGCCTGGCTCTCACGAGCAC CCTGATTTCTGTTCCTGACAGAGACCCAGCCTCGCCTTTAAGGATGGCAAACAGTGCCCTGATCTCC GTTGGCTGCTTGGCCATATTTGTCACTGTGATCTCCCTCTTGGTGTACAAAAAAcACAAGGAATACA ACCCAATAGAAAATAGTCCTGGGAATGTGGTCAGAAGCAAAGGCCTGAGTGTCTTTCTCAACCGTGC 239 WO 03/050245 PCT/USO2/38594 :_ ,OR fStiart: at 1 ORF Stop: end of sequence ______SEQ ID NO: 148 :514~ Maat57453.5kD NOV28a, KRFHDVLGNERPSAYMREHNQLNGWSSDENDWNEKLYPVWKRGDMRWKNSWKGGRVQAVLTSDSPAL CG56972-02 VGSNITFAVNLIFPRCQKEDANGNIVYEKNCRNEAGLSADPYVYNWTAWSEDSDGENGTGQSHHNVF Proei SeuecePDGKPFPHHPGWRRWNFIYVFHTLGQYFQKLGRCSVRVSVNTANVTLOPQLMEVTVYRRHGRAYVPI Protein Sequence AQVKDVYVVTDQIPVPVTMFQKNDRNSSDETFLKDLPIMPDVLIHDPSHFLNYSTINYKWSFGDNTG LPVSTNHTVNHTYVLNGTFSLNLTVKAAAPGPCPPPPPPPRPSKPTPSLGPAGDNPLELSRIPDENC QINRYGHFQATITIVEGILEVNIIQMTDVLMPVPWPESSLIDFVVTCQGSIPTEVCTIISDPTCEIT QNTVCSPVDVDEMCLLTVRRTFNGSGTYCVNLTLGDDTSLALTSTLISVPDRDPASPLRMANSALIS VGCLAIFVTVISLLVYKKHKEYNPIENSPGNVVRSKGLSVFLNRA JSEQ ID NO: 149140b NOV28b, AAACGATTTCATGATGTGCTGGGCAATGAAAGACCTTCTGCTTACATGAGGGAGCACAATCAATTAA CG56972-03 ATGGCTGGTCTTCTGATGAAAATGACTGGAATGAAAAACTCTACCCAGTGTGGAAGCGGGGAGACAT DNA Seuence AGGTGGAAAAACTCCTGGAAGGGAGGCCGTGTGCAGGCGGTCCTGACCAGTGACTCACCAGCCCTC DNA Sequence GTGGCTCAAATATAACATTTGCGGTGAACCTGATATTCCCTAGATGCCAAAAGGAAGATGCCAATG GCAACATAGTCTATGAGAAGAACTGCAGAAATGAGGCTGOTTTATCTGCTGATCCGTATGTTTACAA CTGGACAGCATGGTCAGAGGACAGTGACGGGGAAAATGGCACCGGCCAAAGCCATCATAACGTCTTC CCTGATGGGAAACCTTTTCCTCACCACCCCGGATGGAGAAGATGGAATTTCATCTACGTCTTCCACA CACTTGGTCAGTATTTCCAGAAATTGGGACGATGTTCAGTGAGAGTTTCTGTGAACACAGCCAATGT GACACTTGGGCCTCAACTCATGGAAGTGACTGTCTACAGAAGACATGGACGGGCATATGTTCCCATC GCACAAGTG;AAAGATGTOTACGTGGTAACAGATCAGATTCCTGTGTTTGTGACTATGTTCCAGAAGA ACGATCGAAATTCATCCGACGAAACCTTCCTCAAAGATCTCCCCATTATGTTTGATGTCCTGATTCA TGATCCTAGCCACTTCCTCAATTATTCTACCATTAACTACAAGTGGAGCTTCGGGGATAATACTGGC CTGTTTGTTTCCACCAATCATACTGTGAATCACACGTATGTGCTCAATGGAACCTTCAGCCTTAACC TCACTGTGAAAGCTGCAGCACC-AGGACCTTGTCCGCCACCGCCACCACCACCCAGACCTTCAAAACC CCCCCTTCTTTAGCAACTACTCTAAAATCTTATGATTCAAACACCCCAGGACCTGCTGGTGACAAC CCCCTGGAGCTGAGTAGGATTCCTGATGAAAACTGCCAGATTAACAGATATGGCCACTTTCAAGCCA CCATCACAATTGTAGAGGGAATCTTAGAGGTTAACATCATCCAGATGACAGACGTCCTGATGCCGGT 3CCATGGCCTGAAAGCTCCCTAATAGACTTTGTCGTGACCTGCCAAGGGAGCATTCCCACGGAGGTC TGTACCATCATTTCTGACCCCACCTGCGAGATCACCCAGAACACAGTCTGCAGCCCTG.TGGATGTGG ATGAGATGTGTCTGCTGACTGTGAGACGAACCTTCAATGGGTCTGGGACGTACTGTGTGAACCTCAC CCTGGGGGATGACACAAGCCTGGCTCT2CACGAGCACCCTGATTTCTGTTCCTGACAGAGACCCAGCC ORF Start: at 1 ORF -Stop: endofsqec SEQ ID NO: 150 470 aaMWa521.k NOV28b, KRPHDVLGNERPSAYMRENNG~ujitWSSDEh!ND)WN\E YPVWKRGDMRWKNSWKGGRVQAVLTSDSPAL: CG56972-03 VGSNITFAVNLIFPRCQKEDANGNIVYEKNqCRNEAGLSADPYVYNWTAWSEDSDGENGTGQSHHNVF Proei SeuecePDGKPPPHHPGWRRWNFIYVFHTLGQYFQKLGRCSVRVSVNTANVTLGPQLMEVTVYRRHGRAYVPI Proei SeueceAQVKDVYVVTDQIPVFVTMFQKNDRZNSSDETFLKDLPIMFD3VLIHDPSHPLNYSTINYKWSFGDNTG LFVSTNHTVNHTYVLNGTPSLNLTVKAAAPGPCPPPPPPPRPSKPTPSLATTLKSYDSNTPGPAGDN PLELSRIPDENCQINRYGHFQATITIVEGILEVNIIQMTDVLMPVPWPESSLIDFVVTCQGSIPTEV CTIISDPTCEITQNTVCSPVDVDEMCLLTVRRTFNGSGTYCVNLTLGDDTSLALTSTLISVPDRDPA S SEQ ID NO: 15 NOV28c, NGNCAGATGCCAG-AAGAM TGTGCTCTTGGTGGACGGCCCAGAGGAATTCAGAGTTAA-ACCTT CG56972-01 GAGTGCCTGCGTCCGTGAGAATTCAGCATGGAATGTCTCTACTATTTCCTGGGATTTCTGCTCCTGG .DNASequnceCTGCAAGATTGCCACTTGATGCCGCCAAACGATTTCATGATGTGCTGGGCAATGAAAGACCTTCTGC DNA equnceTTACATGAGGGAGCACAATCAATTAAATGGCTGGTCTTCTGATGAAAATGACTGGAATGAAAAACTC TACCCAGTGTGGAAGCGGGGAGACATGAGGTGGAAAAACTCCTGGAAGGGAGGCCGTGTGCAGGCG TCCTGACCAGTGACTCACCAGCCCTCGTGGGCTCAAATATAACATTTGCGGTGAACCTGATATTCCC TAGATGCCAAAAGGAAGATGCCAATGGCAACATAGTCTATGAGAAGAACTGCAGAAATGAGGCTGGT TTATCTCCTGATCCATATGTTTACAACTGGACAGCATGGTCAGAGGACAGTGACGGGGBAAAATGGC-A CCGGCCAAAGCCATCATAACGTCTTCCCTGATGGGAAACCTTTTCCTCACCACCCCGGATGGAGAAG ATGGAATTTCATCTACGTCTTCCACACACTTGGTCAGTATTTCCAGAAATTGGGACGATGTTCAGTG AGAGTTTCTGTGAACACAGCCAATGTGACACTTGGGCCTCAACTCATGGAAGTGACTGTCTACAGAA GACATGGACGGGCATATGTTCCCATCGCACAAGTGAAAGATGTGTACGTGGTAACAGATCAGATTCC TGTGTTTGTGACTATGTTCCAGAAGAACGATCGAAATTCATCCGACGAAACCTTCCTCAAAGATCTC CCCATTATGTTTGATGTCCTGATTCATGATCCTAGCC-ACTTCCTCAATTATTCTACCATTAACTACA AGTGGAGCTTCGGGGATAATACTGGCCTGTTTGTTTCCACCAATCATACTGTGAATCACACGTATGT GCTCAATGGAACCTTCAGCCTTAACCTCACTOTGAAAGCTGCAGCACCAGGACCTTGTCCGCCACCG ICCACCACCACCCAGACCTTCAAAACCC-ACCCCTTCTTTAGGACCTGCTGGTGACAACCCCCTGGAGC 240 WO 03/050245 PCT/USO2/38594 .. AGTAGGATTCCTGATGAAAACTGCCAGATTAACAGATATGGCCACTTTCAAGCCACCATCACAAT TGTAGAGGGAATCTTAGAGGTTAACATCATCCAGATGACAGACGTCCTGATGCCGGTGCCATCGCCT GAAAGCTCCCTAATAGACTTTGTCGTGACCTGCCAAGGGAGCATTCCCACGGAGGTCTGTACCATCA TTTCTGACCCCACCTGCGAGATCACCCAGAACACAGTCTGCAGCCCTGTGGATGTGGATGAGATGTG TCTGCTGACTGTGAGACGAACCTTCAATGGGTCTGGGACGTACTGTGTGAACCTCACCCTGGGGGAT GACACAAGCCTGGCTCTCACGAGCACCCTGATTTCTGTTCCTGACAGAGACCCAGCCTCGCCTTTAA GGATGGCAAACAGTGCCCTGATCTCCGTTGGCTGCTTGGCCATATTTGTCACTGTGATCTCCCTCTT GGTGTACAAAAAACACAAGGAATACAACCCAATAGAAAATAGTCCTGGGAATGTGGTCAGAAGCAAA GGCCTGAGTGTCTTTCTCAACCGTGCAAAAGCCGTGTTCTTCCCGGGAAACCAGGAAAAGGATCCGC TACTCAAAAACCAAGAATTTAAAGGAGTTTCTTAAATTTCGACCTTGTTTCTGAAGCTCACTTTTCA GTGCCATTATGTGAGATGTGCTGGAGTGGCTATTAACCTTTTTTTCCTAAAGATTATTGTTAAATA GATATTGTGTTTGGGGAAGTTGAATTTTTTATAGGTTAAATGTCAT ORF Start: ATG at 95 JORF Stop: TAA at 1775 SEQ ID NO: 152 _ 1560 aa MW at 62642.6kD NOV28c, MECLYY LLLAARLPLDAA PHD MR GWSSDE GD CG56972-01 RWIOTSWKGGRVQAVLTSDSPALVGSNITFAVNLIFPRCQKEDANGNIVYEKNCRNEAGLSADPYVYN WTAWSEDSDGENGTGQSHHNVFPDGKPPPHHPGWRRWNFIYVFHTLGQYFQKLGRCSVRVSVNTANV Protein Sequence TLGPQLMEVTVYRRHGRAYVPIAQVKDVYVVTDQIPVPVTMFQKNDRNSSDETFLKDLPIMFDVLIH DPSHFLNYSTINYKWSFGDNTGLFVSTNHTVNHTYVLNGTFSLNLTVKAAAPGPCPPPPPPPRPSKP TPSLGPAGDNPLELSRIPDENCQINRYGHFQATITIVEGILEVNIIQMTDVLMPVPWPESSLIDFVV TCQGSIPTEVCTIISDPTCEITQNTVCSPVDVDEMCLLTVRRTFNGSGTYCVNLTLGDDTSLALTST LISVPDRDPASPLRMANSALISVGCLAIFVTVISLLVYKKHKEYNPIENSPGNVVRSKGLSVFLNRA KAVFFPGNQEKDPLLKNQEFKGVS SEQ ID NO: 153 1393 bp NOV28d CACCGGATCCAAACGATTTCATGATGTGCTGGGCAATGAAAGACCTTCTGCTTACATGAGGGAGCAC 'D AATCAATTAAATGGCTGGTCTTCTGATGAAAATGACTGGAATGAAAAACTCTACCCAGTGTGGAAGC 255623772 DNAGGGGAGACATGAGTGAAAAACTCCTGAAGGGAGGCCGTGTCAGGCGGTCCTGACCAGTGACTC Sequence ACCAGCCCTCGTGGGCTCAAATATAACATTTGCGGTGAACCTGATATTCCCTAGATGCCAAAAGGAA GATGCCAATGGCAACATAGTCTATGAGAAGAACTGCAGAAATGAGGCTGGTTTATCTGCTGATCCGT ATGTTTACAACTGGACAGCATGGTCAGAGGACAGTGACGGGGAAAATGGCACCGGCCAAAGCCATCA TAACGTCTTCCCTGATGGGAAACCTTTTCCTCACCACCCCGGATGGAGAAGATGGAATTTCATCTAC GTCTTCCACACACTTGGTCAGTATTTCCAGAAATTGGGACGATGTTCAGTGAGAGTTTCTGTGAACA CAGCCAATGTGACACTTGGGCCTCAACTCATGGAAGTGACTGTCTACAGAAGACATGGACGGGCATA TGTTCCCATCGCACAAGTGAAAGATGTGTACGTGGTAACAGATCAGATTCCTGTGTTTGTGACTATG TTCCAGAAGAACGATCGAAATTCATCCGACGAAACCTTCCTCAAAGATCTCCCCATTATGTTTGATG TCCTGATTCATGATCCTAGCCACTTCCTCAATTATTCTACCATTAACTACAAGTGGAGCTTCGGGGA TAATACTGGCCTGTTTGTTTCCACCAATCATACTGTGAATCACACGTATGTCTCAATGGAACCTTC AGCCTTAACCTCACTGTGAAAGCTGCAGCACCAGGACCTTGTCCGCCACCGCCACCACCACCCAGAC CTTCAAAACCCACCCCTTCTTTAGGACCTGCTGGTGACAACCCCCTGGAGCTGAGTAGGATTCCTGA TGAAAACTGCCAGATTAACAGATATGGCCACTTTCAAGCCACCATCACAATTGTAGAGGGAATCTTA GAGGTTAACATCATCCAGATGACAGACGTCCTGATGCCGGTGCCATGGCCTGAAAGCTCCCTAATAG ACTTTGTCGTGACCTGCCAAGGGAGCATTCCCACGGAGGTCTGTACCATCATTTCTGACCCCACCTG CGAGATCACCCAGAACACAGTCTGCAGCCCTGTGGATGTGGATGAGATGTGTCTGCTGACTGTGAGA CGAACCTTCAATGGGTCTGGGACGTACTGTGTGAACCTCACCCTGGGGGATGACACAAGCCTGGCTC TCACGAGCACCCTGATTTCTGTTCCTGACAGAGACCCAGCCTCGCTCGAGGGC ORF Start: at 2 ORF Stop: end of sequence SEQ ID NO: 154 _ 464 aa MW at 51886.9kD NOV28d, TGSKRFHVLGNERPSAYMREHQLGWSSDENDWNEKLYPVRGDMRWKNSWKGGRVQATSDS 255623772 PALVGSNITFAVNLIPRCQKEDANIVYEKNCRNAGLSADPYVYNWTAWSEDSDGENGTGQSHH 25563772NVFPDGKPPPHHPGWRRWNFIYVFHTLGQYFQKLGRCSVRVSVNTANVTLGPQLMEVTVYRRHORAY Protein Sequence VPIAQVKDVYVVTDQIPVPVTMFQKNDRNSSDETFLKDLPIMFDVLIHDPSEFLNYSTINYKWSFGD NTGLFVSTNRTVNHTYVLNGTFSLNLTVKAAAPGPCPPPPPPPRPSKPTPSLGPAGDNPLELSRIPD ENCQINRYGHFQATITIVEGILEVNIIQMTDVLMPVPWPESSLIDFVVTCQGSIPTEVCTIISDPTC EITQNTVCSPVDVDEMCLLTVRRTFNGSGTYCVNLTLGDDTSLALTSTLISVPDRDPASLEG 5 Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 28B. 241 WO 03/050245 PCT/USO2/38594 Table 28B. Comparison of NOV28a against NOV28b through NOV28d. NOV28a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region NOV28b 1..458 458/470 (97%) 1..470 458/470 (97%) NOV28c 1..514 514/514 (100%) 23..536 514/514 (100%) NOV28d 1..458 458/458 (100%) 4..461 458/458 (100%) Further analysis of the NOV28a protein yielded the following properties shown in Table 28C. 5 Table 28C. Protein Sequence Properties NOV28a SignalP analysis: No Known Signal Sequence Predicted PSORT II PSG: a new signal peptide prediction method analysis: N-region: length 11; pos.chg 3; neg.chg 2 analysis: H-region: length 5; peak value -9.84 PSG score: -14.24 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -13.12 possible cleavage site: between 61 and 62 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood =-10.19 Transmembrane 468 - 484 PERIPHERAL Likelihood = 1.80 (at 343) ALOM score: -10.19 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 475 Charge difference: 1.5 C( 1.5) - N( 0.0) C > N: C-terminal side will be inside >>> Single TMS is located near the C-terminus >>> membrane topology: type Nt (cytoplasmic tail 1 to 467) MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 8.66 Hyd Moment(95): 14.16 G content: 1 D/E content: 2 S/T content: 0 Score: -5.32 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 12 KRFHD NUCDISC: discrimination of nuclear localization signals pat4: KKHK (3) at 486 pat7: none 242 WO 03/050245 PCT/USO2/38594 bipartite: none content of basic residues: 8.6% NLS Score: -0.29 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: RFHD none SKL: peroxisomal targeting signal in the C-terminus: NRA PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: found LL at 417 checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 76.7 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues

-------------------------

Final Results (k = 9/23): 26.1 %: cytoplasmic 26.1%: nuclear 13.0 %: Golgi 8.7 %: mitochondrial 8.7 %: vesicles of secretory system 8.7 %: peroxisomal 8.7 %: endoplasmic reticulum >> prediction for CG56972-02 is cyt (k=23) 243 WO 03/050245 PCT/USO2/38594 A search of the NOV28a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 28D. Table 28D. Geneseq Results for NOV28a NOV28a NOV28a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for the Expect Identifier [Patent #, Date] Match Matched Region Value Residues watched Region ABP61881 Human lung cancer 1..514 514/514 (100%) 0.0 associated protein sequence 23..536 514/514 (100%) SEQ ID NO:225 - Homo sapiens, 560 aa. [WO200247534-A2, 20-JUN-2002] ABB74961 Human lung tumour L528S 1..514 514/514 (100%) 0.0 protein sequence SEQ ID 23..536 514/514 (100%) NO:225 - Homo sapiens, 560 aa. [WO200200174-A2, 03-JAN-2002] AAB11329 Human lung 1..514 514/514 (100%) 0.0 cancer-associated protein 23..536 514/514 (100%) L528S - Homo sapiens, 560 aa. [WO200061612-A2, 19-OCT-2000] AAW35382 Murine metastatic nucleic 1..514 514/514 (100%) 0.0 acid sequence product - Mus 23..536 514/514 (100%) musculus, 560 aa. [WO9718454-A2, 22-MAY-1997] AAU83612 Human PRO protein, Seq ID 1..514 513/526 (97%) 0.0 No 42 - Homo sapiens, 572 23..548 513/526 (97%) aa. [WO200208288-A2, 31-JAN-2002] 5 In a BLAST search of public sequence datbases, the NOV28a protein was found to have homology to the proteins shown in the BLASTP data in Table 28E. Table 28E. Public BLASTP Results for NOV28a Protein NOV28a Identities/ Accession Protein/Organisni/Length Residues! Similarities for the Expect Number Match Matched Portion Value Residues 244 WO 03/050245 PCT/USO2/38594 Q14956 Putative transmembrane 1..514 514/514 (100%) 0.0 protein NMB precursor 23..536 514/514 (100%) (Transmembrane glycoprotein HGFIN) - Homo sapiens (Human), 560 aa. Q8N1A1 Similar to glycoprotein 1..514 514/526 (97%) 0.0 (Transmembrane) nmb - 23..548 514/526 (97%) Homo sapiens (Human), 572 aa. Q9QXA0 Putative transmembrane 1..514 375/530 (70%) 0.0 glycoprotein - Mus musculus 23..552 440/530 (82%) (Mouse), 574 aa. Q99P91 Dendritic cell-associated 1..514 375/530 (70%) 0.0 transmembrane protein 23..552 440/530 (82%) (Glycoprotein (Transmembrane) nmb) Mus musculus (Mouse), 574 aa. Q9QZF6 Osteoactivin - Rattus 1..514 369/528 (69%) 0.0 ........ norvegicus (Rat), 572 aa. 23..550 439/528 (82%) PFam analysis predicts that the NOV28a protein contains the domains shown in the Table 28F. Table 28F. Domain Analysis of NOV28a Identities/ Pfam Domain NOV28a Match Region Similarities Expect Value for the Matched Region 5 Example B: Sequencing Methodology and Identification of NOVX Clones 1. GeneCalling T M Technology: This is a proprietary method of performing differential gene expression profiling between two or more samples developed at CuraGen and described by Shimkets, et al., "Gene expression analysis by transcript profiling coupled 10 to a gene database query" Nature Biotechnology 17:198-803 (1999). cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene 15 expression, for example, growth factors, chemokines or steroids. The eDNA thus derived 245 WO 03/050245 PCT/USO2/38594 was then digested with up to as many as 120 pairs of restriction enzymes and pairs of linker-adaptors specific for each pair of restriction enzymes were ligated to the appropriate end. The restriction digestion generates a mixture of unique cDNA gene fragments. Limited PCR amplification is performed with primers homologous to the linker adapter 5 sequence where one primer is biotinylated and the other is fluorescently labeled. The doubly labeled material is isolated and the fluorescently labeled single strand is resolved by capillary gel electrophoresis. A computer algorithm compares the electropherograms from an experimental and control group for each of the restriction digestions. This and additional sequence-derived information is used to predict the identity of each differentially expressed 10 gene fragment using a variety of genetic databases. The identity of the gene fragment is confirmed by additional, gene-specific competitive PCR or by isolation and sequencing of the gene fragment. 2. SeqCalling m Technology: cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, 15 and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then sequenced using CuraGen's proprietary SeqCalling technology. Sequence traces were evaluated manually 20 and edited for corrections if appropriate. eDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each 25 assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations. 3. PathCalling M Technology: The NOVX nucleic acid sequences are derived by laboratory screening of cDNA library by the two-hybrid approach. cDNA 30 fragments covering either the full length of the DNA sequence, or part of the sequence, or both, are sequenced. In silico prediction was based on sequences available in CuraGen Corporation's proprietary sequence databases or in the public human sequence databases, and provided either the full length DNA sequence, or some portion thereof. 246 WO 03/050245 PCT/USO2/38594 The laboratory screening was performed using the methods summarized below: cDNA libraries were derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue 5 cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then directionally cloned into the appropriate two-hybrid vector (Gal4-activation domain (Gal4-AD) fusion). Such eDNA libraries as well as commercially available cDNA libraries from Clontech (Palo Alto, CA) 10 were then transferred from E.coli into a CuraGen Corporation proprietary yeast strain (disclosed in U. S. Patents 6,057,101 and 6,083,693, incorporated herein by reference in their entireties). Gal4-binding domain (Gal4-BD) fusions of a CuraGen Corportion proprietary library of human sequences was used to screen multiple Gal4-AD fusion cDNA libraries 15 resulting in the selection of yeast hybrid diploids in each of which the Gal4-AD fusion contains an individual cDNA. Each sample was amplified using the polymerase chain reaction (PCR) using non-specific primers at the eDNA insert boundaries. Such PCR product was sequenced; sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, 20 sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice 25 forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations. Physical clone: the cDNA fragment derived by the screening procedure, covering the entire open reading frame is, as a recombinant DNA, cloned into pACT2 plasmid (Clontech) used to make the eDNA library. The recombinant plasmid is inserted into the 30 host and selected by the yeast hybrid diploid generated during the screening procedure by the mating of both CuraGen Corporation proprietary yeast strains N106' and YULH (U. S. Patents 6,057,101 and 6,083,693). 247 WO 03/050245 PCT/USO2/38594 4. RACE: Techniques based on the polymerase chain reaction such as rapid amplification of eDNA ends (RACE), were used to isolate or complete the predicted sequence of the cDNA of the invention. Usually multiple clones were sequenced from one or more human samples to derive the sequences for fragments. Various human tissue 5 samples from different donors were used for the RACE reaction. The sequences derived from these procedures were included in the SeqCalling Assembly process described in preceding paragraphs. 5. Exon Linking: The NOVX target sequences identified in the present invention were subjected to the exon linking process to confirm the sequence. PCR 10 primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case of the reverse primer, until the stop codon was reached. Such 15 primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) of the DNA or protein sequence of the target sequence, or by translated hongology of the predicted exons to closely related human sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain 20 hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma -Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The PCR product derived from 25 exon linking was cloned into the pCR2.1 vector from Invitrogen. The resulting bacterial clone has an insert covering the entire open reading frame cloned into the pCR2.1 vector. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another 30 component of the assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported herein. 248 WO 03/050245 PCT/USO2/38594 6. Physical Clone: Exons were predicted by homology and the intron/exon boundaries were determined using standard genetic rules. Exons were further selected and refined by means of similarity determination using multiple BLAST (for example, tBlastN, BlastX, and BlastN) searches, and, in some instances, GeneScan and Grail. Expressed 5 sequences from both public and proprietary databases were also added when available to further define and complete the gene sequence. The DNA sequence was then manually corrected for apparent inconsistencies thereby obtaining the sequences encoding the full-length protein. The PCR product derived by exon linking, covering the entire open reading frame, 10 was cloned into the pCR2.1 vector from Invitrogen to provide clones used for expression and screening purposes. Example C. Quantitative expression analysis of clones in various cells and tissues The quantitative expression of various clones was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell lines 15 and tissues using real time quantitative PCR (RTQ PCR). RTQ PCR was performed on an Applied Biosystems ABI PRISM® 7700 or an ABI PRISM® 7900 HT Sequence Detection System. Various collections of samples are assembled on the plates, and referred to as Panel 1 (containing normal tissues and cancer cell lines), Panel 2 (containing samples derived from tissues from normal and cancer sources), Panel 3 (containing cancer cell 20 lines), Panel 4 (containing cells and cell lines from normal tissues and cells related to inflammatory conditions), Panel 5D/5I (containing human tissues and cell lines with an emphasis on metabolic diseases), AI comprehensivepanel (containing normal tissue and samples from autoinflammatory diseases), Panel CNSD.01 (containing samples from normal and diseased brains) and CNSneurodegeneration_panel (containing samples from 25 normal and Alzheimer's diseased brains). RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s: 18s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA 30 contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon. First, the RNA samples were normalized to reference nucleic acids such as constitutively expressed genes (for example, 13-actin and GAPDH). Normalized RNA (5 ul) 249 WO 03/050245 PCT/USO2/38594 was converted to cDNA and analyzed by RTQ-PCR using One Step RT-PCR Master Mix Reagents (Applied Biosystems; Catalog No. 4309169) and gene-specific primers according to the manufacturer's instructions. In other cases, non-normalized RNA samples were converted to single strand cDNA 5 (sscDNA) using Superscript II (Invitrogen Corporation; Catalog No. 18064-147) and random hexamers according to the manufacturer's instructions. Reactions containing up to 10 gg of total RNA were performed in a volume of 20 pl and incubated for 60 minutes at 42oC. This reaction can be scaled up to 50 gg of total RNA in a final volume of 100 pl. sscDNA samples are then normalized to reference nucleic acids as described previously, 10 using IX TaqMan@ Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. Probes and primers were designed for each assay according to Applied Biosystems Primer Express Software package (version I for Apple Computer's Macintosh Power PC) or a similar algorithm using the target sequence as input. Default settings were used for 15 reaction conditions and the following parameters were set before selecting primers: primer concentration = 250 nM, primer melting temperature (Tm) range = 58 0 -60 0 C, primer optimal Tm = 59 0 C, maximum primer difference = 2oC, probe does not have 5'G, probe Tm must be 10C greater than primer Tm, amplicon size 75bp to 1 00bp. The probes and primers selected (see below) were synthesized by Synthegen (Houston, TX, USA). Probes 20 were double purified by HPLC to remove uncoupled dye and evaluated by mass spectroscopy to verify coupling of reporter and quencher dyes to the 5' and 3' ends of the probe, respectively. Their final concentrations were: forward and reverse primers, 900nM each, and probe, 200nM. PCR conditions: When working with RNA samples, normalized RNA from each 25 tissue and each cell line was spotted in each well of either a 96 well or a 384-well PCR plate (Applied Biosystems). PCR cocktails included either a single gene specific probe and primers set, or two multiplexed probe and primers sets (a set specific for the target clone and another gene-specific set multiplexed with the target probe). PCR reactions were set up using TaqMan® One-Step RT-PCR Master Mix (Applied Biosystems, Catalog No. 30 4313803) following manufacturer's instructions. Reverse transcription was performed at 48 0 C for 30 minutes followed by amplification/PCR cycles as follows: 95'C 10 min, then 40 cycles of 95oC for 15 seconds, 60 0 C for 1 minute. Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, 250 WO 03/050245 PCT/USO2/38594 with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression is then obtained by taking the reciprocal of this RNA difference and multiplying by 100. 5 When working with sscDNA samples, normalized sscDNA was used as described previously for RNA samples. PCR reactions containing one or two sets of probe and primers were set up as described previously, using IX TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification was performed as follows: 95oC 10 min, then 40 cycles of 95 0 C for 15 10 seconds, 60 0 C for 1 minute. Results were analyzed and processed as described previously. Panels 1, 1.1, 1.2, and 1.3D The plates for Panels 1, 1.1, 1.2 and 1.3D include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in these panels are broken into 2 classes: samples derived from cultured cell lines 15 and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in these panels are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and 20 were cultured using the conditions recommended by the ATCC. The normal tissues found on these panels are comprised of samples derived from all major organ systems from single adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone 25 marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. In the results for Panels 1, 1.1, 1.2 and 1.3D, the following abbreviations are used: ca. = carcinoma, 30 * = established from metastasis, met = metastasis, s cell var = small cell variant, non-s = non-sm = non-small, 251 WO 03/050245 PCT/USO2/38594 squam = squamous, pl. eff = pl effusion = pleural effusion, glio = glioma, astro = astrocytoma, and 5 neuro = neuroblastoma. General_screening_panel_vl.4, vl.5, vl.6 and 1.7 The plates for Panels 1.4, 1.5, 1.6 and 1.7 include 2 control wells (genomic DNA control and chemistry control) and 88 to 94 wells containing eDNA from various samples. The samples in Panels 1.4, 1.5, 1.6 and 1.7 are broken into 2 classes: samples derived from 10 cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in Panels 1.4, 1.5, 1.6 and 1.7 are widely available through the American Type Culture Collection (ATCC), a 15 repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on Panels 1.4, 1.5, 1.6 and 1.7 are comprised of pools of samples derived from all major organ systems from 2 to 5 different adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, 20 adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. Abbreviations are as described for Panels 1, 1.1, 1.2, and 1.3D. Panels 2D, 2.2, 2.3 and 2.4 25 The plates for Panels 2D, 2.2, 2.3 and 2.4 generally include 2 control wells and 94 test samples composed of RNA or cDNA isolated from human tissue procured by surgeons working in close cooperation with the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative (NDRI) or from Ardais or Clinomics). The tissues are derived from human malignancies and in cases where 30 indicated many malignant tissues have "matched margins" obtained from noncancerous tissue just adjacent to the tumor. These are termed normal adjacent tissues and are denoted "NAT" in the results below. The tumor tissue and the "matched margins" are evaluated by two independent pathologists (the surgical pathologists and again by a pathologist at NDRI/ 252 WO 03/050245 PCT/USO2/38594 CHTN/Ardais/Clinomics). Unmatched RNA samples from tissues without malignancy (normal tissues) were also obtained from Ardais or Clinomics. This analysis provides a gross histopathological assessment of tumor differentiation grade. Moreover, most samples include the original surgical pathology report that provides information regarding the 5 clinical stage of the patient. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated "NAT", for normal adjacent tissue, in Table RR). In addition, RNA and cDNA samples were obtained from various human tissues derived from autopsies performed on elderly people or sudden death victims (accidents, etc.). These tissues were ascertained to be free of disease and were purchased 10 from various commercial sources such as Clontech (Palo Alto, CA), Research Genetics, and Invitrogen. HASS Panel v 1.0 The HASS panel v 1.0 plates are comprised of 93 cDNA samples and two controls. Specifically, 81 of these samples are derived from cultured human cancer cell lines that had 15 been subjected to serum starvation, acidosis and anoxia for different time periods as well as controls for these treatments, 3 samples of human primary cells, 9 samples of malignant brain cancer (4 medulloblastomas and 5 glioblastomas) and 2 controls. The human cancer cell lines are obtained from ATCC (American Type Culture Collection) and fall into the following tissue groups: breast cancer, prostate cancer, bladder carcinomas, pancreatic 20 cancers and CNS cancer cell lines. These cancer cells are all cultured under standard recommended conditions. The treatments used (serum starvation, acidosis and anoxia) have been previously published in the scientific literature. The primary human cells were obtained from Clonetics (Walkersville, MD) and were grown in the media and conditions recommended by Clonetics. The malignant brain cancer samples are obtained as part of a 25 collaboration (Henry Ford Cancer Center) and are evaluated by a pathologist prior to CuraGen receiving the samples. RNA was prepared from these samples using the standard procedures. The genomic and chemistry control wells have been described previously. ARDAIS Panel v 1.0 The plates for ARDAIS panel v 1.0 generally include 2 control wells and 22 test 30 samples composed of RNA isolated from human tissue procured by surgeons working in close cooperation with Ardais Corporation. The tissues are derived from human lung malignancies (lung adenocarcinoma or lung squamous cell carcinoma) and in cases where indicated many malignant samples have "matched margins" obtained from noncancerous 253 WO 03/050245 PCT/USO2/38594 lung tissue just adjacent to the tumor. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated "NAT", for normal adjacent tissue) in the results below. The tumor tissue and the "matched margins" are evaluated by independent pathologists (the surgical pathologists and again by a 5 pathologist at Ardais). Unmatched malignant and non-malignant RNA samples from lungs were also obtained from Ardais. Additional information from Ardais provides a gross histopathological assessment of tumor differentiation grade and-stage. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical state of the patient. 10 Panel 3D, 3.1 and 3.2 The plates of Panel 3D, 3.1, and 3.2 are comprised of 94 cDNA samples and two control samples. Specifically, 92 of these samples are derived from cultured human cancer cell lines, 2 samples of human primary cerebellar tissue and 2 controls. The human cell lines are generally obtained from ATCC (American Type Culture Collection), NCI or the 15 German tumor cell bank and fall into the following tissue groups: Squamous cell carcinoma of the tongue, breast cancer, prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon, lung and CNS cancer cell lines. In addition, there are two independent samples of cerebellum. These cells are all cultured under standard 20 recommended conditions and RNA extracted using the standard procedures. The cell lines in panel 3D, 3.1, 3.2, 1, 1.1., 1.2, 1.3D, 1.4, 1.5, and 1.6 are of the most common cell lines used in the scientific literature. Panels 4D, 4R, and 4.1D Panel 4 includes samples on a 96 well plate (2 control wells, 94 test samples) 25 composed of RNA (Panel 4R) or cDNA (Panels 4D/4. 1 D) isolated from various human cell lines or tissues related to inflammatory conditions. Total RNA from control normal tissues such as colon and lung (Stratagene, La Jolla, CA) and thymus and kidney (Clontech) was employed. Total RNA from liver tissue from cirrhosis patients and kidney from lupus patients was obtained from BioChain (Biochain Institute, Inc., Hayward, CA). Intestinal 30 tissue for RNA preparation from patients diagnosed as having Crohn's disease and ulcerative colitis was obtained from the National Disease Research Interchange (NDRI) (Philadelphia, PA). 254 WO 03/050245 PCT/USO2/38594 Astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, human umbilical vein endothelial cells were all purchased from Clonetics (Walkersville, 5 MD) and grown in the media supplied for these cell types by Clonetics. These primary cell types were activated with various cytokines or combinations of cytokines for 6 and/or 12-14 hours, as indicated. The following cytokines were used; IL-1 beta at approximately 1-5ng/ml, TNF alpha at approximately 5-O10ng/ml, IFN gamma at approximately 20-50ng/ml, IL-4 at approximately 5-O10ng/ml, IL-9 at approximately 5-10ng/ml, IL-13 at 10 approximately 5-10ng/ml. Endothelial cells were sometimes starved for various times by culture in the basal media from Clonetics with 0.1% serum. Mononuclear cells were prepared from blood of employees at CuraGen Corporation, using Ficoll. LAK cells were prepared from these cells by culture in DMEM 5% FCS (Hyclone), 100iM non essential amino acids (Gibco/Life Technologies, 15 Rockville, MD), 1mM sodium pyruvate (Gibco), mercaptoethanol 5.5x10-M (Gibco), and 10mM Hepes (Gibco) and Interleukin 2 for 4-6 days. Cells were then either activated with 10-20ng/ml PMA and 1-2gg/ml ionomycin, IL-12 at 5-10ng/ml, IFN gamma at 20-50ng/ml and IL-18 at 5-O10ng/ml for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone), 100pM non essential amino acids (Gibco), ImM 20 sodium pyruvate (Gibco), mercaptoethanol 5.5x10 5 "M (Gibco), and 10mM Hepes (Gibco) with PHA (phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5 pg/ml. Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from two donors, isolating the mononuclear cells using Ficoll and mixing the isolated mononuclear cells 1:1 at a final 25 concentration of approximately 2xl0 6 ells/ml in DMEM 5% FCS (Hyclone), 100jiM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol (5.5x10-sM) (Gibco), and 10mM Hepes (Gibco). The MLR was cultured and samples taken at various time points ranging from 1- 7 days for RNA preparation. Monocytes were isolated from mononuclear cells using CD14 Miltenyi Beads, +ve 30 VS selection colunms and a Vario Magnet according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone, Logan, UT), 100jM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10- 5 M (Gibco), and 10mM Hepes (Gibco), 50ng/ml 255 WO 03/050245 PCT/USO2/38594 GMCSF and 5ng/ml IL-4 for 5-7 days. Macrophages were prepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone), 100pM non essential amino acids (Gibco), 1mM sodium pyruvate (Gibco), mercaptoethanol 5.5x 10-s 5 M (Gibco), 10mM Hepes (Gibco) and 10% AB Human Serum or MCSF at approximately 50ng/ml. 5 Monocytes, macrophages and dendritic cells were stimulated for 6 and 12-14 hours with lipopolysaccharide (LPS) at 100 ng/ml. Dendritic cells were also stimulated,with anti-CD40 monoclonal antibody (Pharmingen) at 10Ig/ml for 6 and 12-14 hours. CD4 lymphocytes, CD8 lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection 10 columns and a Vario Magnet according to the manufacturer's instructions. CD45RA and CD45RO CD4 lymphocytes were isolated by depleting mononuclear cells of CD8, CD56, CDI4 and CDI9 cells using CD8, CD56, CD14 and CD19 Miltenyi beads and positive selection. CD45RO beads were then used to isolate the CD45RO CD4 lymphocytes with the remaining cells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and 15 CD8 lymphocytes were placed in DMEM 5% FCS (Hyclone), 100tM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x1 0- 5 M (Gibco), and 10mM Hepes (Gibco) and plated at 10 6 cells/ml onto Falcon 6 well tissue culture plates that had been coated overnight with 0.5jtg/ml anti-CD28 (Pharmingen) and 3ug/ml anti-CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA 20 preparation. To prepare chronically activated CD8 lymphocytes, we activated the isolated CD8 lymphocytes for 4 days on anti-CD28 and anti-CD3 coated plates and then harvested the cells and expanded them in DMEM 5% FCS (Hyclone), 100pM non essential amino acids (Gibco), 1mM sodium pyruvate (Gibco), mercaptoethanol 5.5x10- 5 M (Gibco), and 10mM Hepes (Gibco) and IL-2. The expanded CD8 cells were then activated again with 25 plate bound anti-CD3 and anti-CD28 for 4 days and expanded as before. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culture. The isolated NK cells were cultured in DMEM 5% FCS (Hyclone), 100 pM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10" 5 M (Gibco), and 10mM Hepes (Gibco) and IL-2 for 4-6 days before RNA was prepared. 30 To obtain B cells, tonsils were procured from NDRI. The tonsil was cut up with sterile dissecting scissors and then passed through a sieve. Tonsil cells were then spun down and resuspended at 10 6 cells/ml in DMEM 5% FCS (Hyclone), 100pM non essential amino acids (Gibco), 1mM sodium pyruvate (Gibco), mercaptoethanol 5.5x10-sM (Gibco), 256 WO 03/050245 PCT/USO2/38594 and 10mM Hepes (Gibco). To activate the cells, we used PWM at 5pg/ml or anti-CD40 (Pharmingen) at approximately 10 gg/ml and IL-4 at 5-10 Ong/ml. Cells were harvested for RNA preparation at 24,48 and 72 hours. To prepare the primary and secondary Thl/Th2 and Trl cells, six-well Falcon plates 5 were coated-overnight with 10g/ml anti-CD28 (Pharmingen) and 2gg/ml OKT3 (ATCC), and then washed twice with PBS. Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, MD) were cultured at 10 5 -10 6 cells/ml in DMEM 5% FCS (Hyclone), 100pM non essential amino acids (Gibco), 1mM sodium pyruvate (Gibco), mercaptoethanol 5.5x10-sM (Gibco), 10mM Hepes (Gibco) and IL-2 (4ng/ml). IL-12 10 (5ng/ml) and anti-IL4 (1 pg/ml) were used to direct to Thil, while IL-4 (5ng/ml) and anti-IFN gamma (l Ig/ml) were used to direct to Th2 and IL-10 at 5ng/ml was used to direct to Trl. After 4-5 days, the activated Thl, Th2 and Trl lymphocytes were washed once in DMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), 1001M non essential amino acids (Gibco), 1mM sodium pyruvate (Gibco), mercaptoethanol 5.5x10 5 M 15 (Gibco), 10mM Hepes (Gibco) and IL-2 (1 ng/ml). Following this, the activated Thl, Th2 and Trl lymphocytes were re-stimulated for 5 days with anti-CD28/OKT3 and cytokines as described above, but with the addition of anti-CD95L (1 [ig/ml) to prevent apoptosis. After 4-5 days, the Thl, Th2 and Trl lymphocytes were washed and then expanded again with IL-2 for 4-7 days. Activated Thl and Th2 lymphocytes were maintained in this way for a 20 maximum of three cycles. RNA was prepared from primary and secondary Thl, Th2 and Trl after 6 and 24 hours following the second and third activations with plate bound anti-CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures in Interleukin 2. The following leukocyte cells lines were obtained from the ATCC: Ramos, EOL-1, 25 KU-812. EOL cells were further differentiated by culture in 0.1mM dbcAMP at 5xlO 5 cells/ml for 8 days, changing the media every 3 days and adjusting the cell concentration to 5x10 5 cells/ml. For the culture of these cells, we used DMEM or RPMI (as recommended by the ATCC), with the addition of 5% FCS (Hyclone), 100pM non essential amino acids (Gibco), 1mM sodium pyruvate (Gibco), mercaptoethanol 5.5x10 5 M 30 (Gibco), 10mM Hepes (Gibco). RNA was either prepared from resting cells or cells activated with PMA at 10ng/ml and ionomycin at Ipg/ml for 6 and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumor line NCI-H292 were also obtained from the ATCC. Both were cultured in DMEM 5% FCS (Hyclone), 100pM non essential amino 257 WO 03/050245 PCT/USO2/38594 acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10-sM (Gibco), and 10mM Hepes (Gibco). CCD1106 cells were activated for 6 and 14 hours with approximately 5 ng/ml TNF alpha and I ng/ml IL-1 beta, while NCI-H292 cells were activated for 6 and 14 hours with the following cytokines: 5ng/ml IL-4, 5ng/ml IL-9, 5 5ng/ml IL-13 and 25ng/ml IFN gamma. For these cell lines and blood cells, RNA was prepared by lysing approximately 10 7 cells/ml using Trizol (Gibco BRL). Briefly, 1/10 volume of bromochloropropane (Molecular Research Corporation) was added to the RNA sample, vortexed and after 10 minutes at room temperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor. 10 The aqueous phase was removed and placed in a 15ml Falcon Tube. An equal volume of isopropanol was added and left at -20 0 C overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34 rotor and washed in 70% ethanol. The pellet was redissolved in 300pl of RNase-free water and 35pl buffer (Promega) 5 1 tl DTT, 7gl RNAsin and 8pl DNase were added. The tube was incubated at 37 0 C for 30 minutes to remove 15 contaminating genomic DNA, extracted once with phenol chloroform and re-precipitated with 1/10 volume of 3M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down and placed in RNase free water. RNA was stored at -80'C. AI_comprehensive panel_v1.0 The plates for AI _comprehensive panel vl.0 include two control wells and 89 test 20 samples comprised of eDNA isolated from surgical and postmortem human tissues obtained from the Backus Hospital and Clinomics (Frederick, MD). Total RNA was extracted from tissue samples from the Backus Hospital in the Facility at CuraGen. Total RNA from other tissues was obtained from Clinomics. Joint tissues including synovial fluid, synovium, bone and cartilage were obtained 25 from patients undergoing total knee or hip replacement surgery at the Backus Hospital. Tissue samples were immediately snap frozen in liquid nitrogen to ensure that isolated RNA was of optimal quality and not degraded. Additional samples of osteoarthritis and rheumatoid arthritis joint tissues were obtained from Clinomics. Normal control tissues were supplied by Clinomics and were obtained during autopsy of trauma victims. 30 Surgical specimens of psoriatic tissues and adjacent matched tissues were provided as total RNA by Clinomics. Two male and two female patients were selected between the ages of 25 and 47. None of the patients were taking prescription drugs at the time samples were isolated. 258 WO 03/050245 PCT/USO2/38594 Surgical specimens of diseased colon from patients with ulcerative colitis and Crohns disease and adjacent matched tissues were obtained from Clinomics. Bowel tissue from three female and three male Crohn's patients between the ages of 41-69 were used. Two patients were not on prescription medication while the others were taking 5 dexamethasone, phenobarbital, or tylenol. Ulcerative colitis tissue was from three male and four female patients. Four of the patients were taking lebvid and two were on phenobarbital. Total RNA from post mortem lung tissue from trauma victims with no disease or with emphysema, asthma or COPD was purchased from Clinomics. Emphysema patients 10 ranged in age from 40-70 and all were smokers, this age range was chosen to focus on patients with cigarette-linked emphysema and to avoid those patients with alpha-lanti-trypsin deficiencies. Asthma patients ranged in age from 36-75, and excluded smokers to prevent those patients that could also have COPD. COPD patients ranged in age from 35-80 and included both smokers and non-smokers. Most patients were taking 15 corticosteroids, and bronchodilators. In the labels employed to identify tissues in the AIcomprehensive panel vl.0 panel, the following abbreviations are used: AI = Autoimmunity Syn = Synovial 20 Normal = No apparent disease Rep22 /Rep20 = individual patients RA = Rheumatoid arthritis Backus = From Backus Hospital OA= Osteoarthritis 25 (SS) (BA) (MF) = Individual patients Adj = Adjacent tissue Match control = adjacent tissues -M = Male -F = Female 30 COPD = Chronic obstructive pulmonary disease AI.05 chondrosarcoma The AI.05 chondrosarcoma plates are comprised of SW 1353 cells that had been subjected to serum starvation and treatment with cytokines that are known to induce MMP 259 WO 03/050245 PCT/USO2/38594 (1, 3 and 13) synthesis (eg. ILlbeta). These treatments include: IL-lbeta (10 ng/ml), IL-lbeta + TNF-alpha (50 ng/ml), IL-lbeta + Oncostatin (50 ng/ml) and PMA (100 ng/ml). The SW1353 cells were obtained from the ATCC (American Type Culture Collection) and were all cultured under standard recommended conditions. The SW1353 cells were plated 5 at 3 x10 5 cells/ml (in DMEM medium-10 % FBS) in 6-well plates. The treatment was done in triplicate, for 6 and 18 h. The supernatants were collected for analysis of MMP 1, 3 and 13 production and for RNA extraction. RNA was prepared from these samples using the standard procedures. Panels 5D and 51 10 The plates for Panel 5D and 51 include two control wells and a variety of cDNAs isolated from human tissues and cell lines with an emphasis on metabolic diseases. Metabolic tissues were obtained from patients enrolled in the Gestational Diabetes study. Cells were obtained during different stages in the differentiation of adipocytes from human mesenchymal stem cells. Human pancreatic islets were also obtained. 15 In the Gestational Diabetes study subjects are young (18 - 40 years), otherwise healthy women with and without gestational diabetes undergoing routine (elective) Caesarean section. After delivery of the infant, when the surgical incisions were being repaired/closed, the obstetrician removed a small sample (<1 cc) of the exposed metabolic tissues during the closure of each surgical level. The biopsy material was rinsed in sterile 20 saline, blotted and fast frozen within 5 minutes from the time of removal. The tissue was then flash frozen in liquid nitrogen and stored, individually, in sterile screw-top tubes and kept on dry ice for shipment to or to be picked up by CuraGen. The metabolic tissues of interest include uterine wall (smooth muscle), visceral adipose, skeletal muscle (rectus) and subcutaneous adipose. Patient descriptions are as follows: 25 Patient 2: Diabetic Hispanic, overweight, not on insulin Patient 7-9: Nondiabetic Caucasian and obese (BMI>30) Patient 10: Diabetic Hispanic, overweight, on insulin Patient 11: Nondiabetic African American and overweight Patient 12: Diabetic Hispanic on insulin 30 Adiocyte differentiation was induced in donor progenitor cells obtained from Osirus (a division of Clonetics/BioWhittaker) in triplicate, except for Donor 3U which had only two replicates. Scientists at Clonetics isolated, grew and differentiated human mesenchymal stem cells (HuMSCs) for CuraGen based on the published protocol found in 260 WO 03/050245 PCT/USO2/38594 Mark F. Pittenger, et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells Science Apr 2 1999: 143-147. Clonetics provided Trizol lysates or frozen pellets suitable for mRNA isolation and ds cDNA production. A general description of each donor is as follows: 5 Donor 2 and 3 U: Mesenchymal Stem cells, Undifferentiated Adipose Donor 2 and 3 AM: Adipose, AdiposeMidway Differentiated Donor 2 and 3 AD: Adipose, Adipose Differentiated Human cell lines were generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: 10 kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver HepG2 cancer cells, heart primary stromal cells, and adrenal cortical adenoma cells. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. All samples were processed at CuraGen to produce single stranded cDNA. 15 Panel 51 contains all samples previously described with the addition of pancreatic islets from a 58 year old female patient obtained from the Diabetes Research Institute at the University of Miami School of Medicine. Islet tissue was processed to total RNA at an outside source and delivered to CuraGen for addition to panel 51. In the labels employed to identify tissues in the SD and 5I panels, the following 20 abbreviations are used: GO Adipose = Greater Omentum Adipose SK = Skeletal Muscle UT = Uterus PL= Placenta 25 AD = Adipose Differentiated AM= Adipose Midway Differentiated U= Undifferentiated Stem Cells Panel CNSD.01 The plates for Panel CNSD.01 include two control wells and 94 test samples 30 comprised of eDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80 0 C in 261 WO 03/050245 PCT/USO2/38594 liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology. Disease diagnoses are taken from patient records. The panel contains two brains from each of the following diagnoses: Alzheimer's disease, Parkinson's disease, 5 Huntington's disease, Progressive Supernuclear Palsy, Depression, and "Normal controls". Within each of these brains, the following regions are represented: cingulate gyms, temporal pole, globus palladus, substantia nigra, Brodman Area 4 (primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9 (prefrontal cortex), and Brodman area 17 (occipital cortex). Not all brain regions are represented in all cases; e.g., Huntington's 10. disease is characterized in part by neurodegeneration in the globus palladus, thus this region is impossible to obtain from confirmed Huntington's cases. Likewise Parkinson's disease is characterized by degeneration of the substantia nigra making this region more difficult to obtain. Normal control brains were examined for neuropathology and found to be free of any pathology consistent with neurodegeneration. 15 In the labels employed to identify tissues in the CNS panel, the following abbreviations are used: PSP = Progressive supranuclear palsy Sub Nigra = Substantia nigra Glob Palladus= Globus palladus 20 Temp Pole = Temporal pole Cing Gyr = Cingulate gyrus BA 4= Brodman Area 4 Panel CNS_Neurodegeneration_V1.0 The plates for Panel CNS Neurodegeneration_V1.0 include two control wells and 25 47 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean Hospital) and the Human Brain and Spinal Fluid Resource Center (VA Greater Los Angeles Healthcare System). Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80 0 C in liquid nitrogen vapor. All brains are sectioned and 30 examined by neuropathologists to confirm diagnoses with clear associated neuropathology. Disease diagnoses are taken from patient records. The panel contains six brains from Alzheimer's disease (AD) patients, and eight brains from "Normal controls" who 262 WO 03/050245 PCT/USO2/38594 showed no evidence of dementia prior to death. The eight normal control brains are divided into two categories: Controls with no dementia and no Alzheimer's like pathology (Controls) and controls with no dementia but evidence of severe Alzheimer's like pathology, (specifically senile plaque load rated as level 3 on a scale of 0-3; 0 = no 5 evidence of plaques, 3 = severe AD senile plaque load). Within each of these brains, the following regions are represented: hippocampus, temporal cortex (Brodman Area 21), parietal cortex (Brodman area 7), and occipital cortex (Brodman area 17). These regions were chosen to encompass all levels of neurodegeneration in AD. The hippocampus is a region of early and severe neuronal loss in AD; the temporal cortex is known to show 10 neurodegeneration in AD after the hippocampus; the parietal cortex shows moderate neuronal death in the late stages pf the disease; the occipital cortex is spared in AD and therefore acts as a "control" region within AD patients. Not all brain regions are represented in all cases. In the labels employed to identify tissues in the CNSNeurodegeneration V1.0 15 panel, the following abbreviations are used: AD = Alzheimer's disease brain; patient was demented and showed AD-like pathology upon autopsy Control = Control brains; patient not demented, showing no neuropathology Control (Path) = Control brains; patient not demented but showing sever AD-like 20 pathology SupTemporal Ctx = Superior Temporal Cortex Inf Temporal Ctx = Inferior Temporal Cortex A. CG103827-03: Fibulin-2-like Protein. Expression of gene CG103827-03 was assessed using the primer-probe set Ag6712, 25 described in Table AA. Results of the RTQ-PCR runs are shown in Tables AB, AC and AD. Table AA. Probe Name Ag6712 Primers Length Start SEQ ID , I Position No Forward a'-cgcttgaagacatcgacg-3 ' 19 2887 155 Probe TET-5'-atcctctgcaccttccgctgtctcaa 6 156 Probe -3 '-TAM I - I....26 22 1 263 WO 03/050245 PCT/US02/38594 Reverse 5'-ggtacCcagtgcacactcat-3' 20 13032 .157 Table AB. CNS neurodegeneration v1.0 ... Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag6712, issue Name Ag6712, Run Run 276596839 276596839 AD 1 Hippo 25.5 Control (Path) 3 Temporal Ctx 12.2 AD 2 Hippo 19.1 Control (Path) 4 Temporal Ctx 30.8 AD 3 Hippo 12.2 .AD 1 Occipital Ctx 5.1 AD 4 Hippo 32.5 AD 2 Occipital Ctx (Missing) 0.0 AD 5 Hippo 28.3 AD 3 Occipital Ctx 7.2 AD 6 Hippo 1 l00.0 AD 4 Occipital Ctx 29.9 Control 2 Hippo 50.7 AD 5 Occipital Ctx 33.9 Control 4 Hippo 18.4 . AD 6 Occipital Ctx 122.7 Control (Path) 3 Hippo 19.5 Control I Occipital Ctx 38.7 AD 1 Temporal Ctx 12.2 Control 2 Occipital Ctx 148.6 AD 2 Temporal Ctx 22.4 Control 3 Occipital Ctx 111.3 AD 3 Temporal Ctx 3.5 Control 4 Occipital Ctx 14.6 AD 4 Temporal Ctx .25.2 Control (Path) 1 Occipital Ctx 24.1 AD 5 Inf Temporal Ctx 45.7 Control (Path) 2 Occipital Ctx 21.9 AD 5 Sup Temporal Ctx 67.8 Control (Path) 3 Occipital Ctx 7.9 AD 6 Inf Temporal Ctx 15.5 Control (Path) 4 Occipital Ctx 12.3 AD 6 Sup Temporal Ctx 81.2 Control 1 Parietal Ctx 21.9 Control 1 Temporal Ctx 19.3 Control 2 Parietal Ctx 126.2 Control 2 Temporal Ctx 4.7 Control 3 Parietal Ctx 7.7 Control 3 Temporal Ctx 20.4 Control (Path) 1 Parietal Ctx 61.1 Control 3 Temporal Ctx 115.0 Control (Path) 2 Parietal Ctx 52.5 Control (Path) 1 Temporal Ctx 40.1 Control (Path) 3 Parietal Ctx 3.4 Control (Path) 2 Temporal Ctx 120.3 ]Control (Path) 4 Parietal Ctx 22.1 Table AC. General screening panel vl.6 Rel. Rel. Exp.(%) !Exp.(%) Tissue Name Ag6712, issue Name Ag6712, Run Run 277261484 277261484 Adipose 5.5 Renal ca. TK-10 0.0 Melanoma* Hs688(A).T _ 34.4 Bladder 2.7 Melanoma* Hs688(B).T 33.0 IGastric ca. (liver met.) NCI-N87 0.0 Melanoma* M14 0.0 IGastric ca. KATO III 0.0 Melanoma* LOXIMVI 0.0 Colon ca. SW-948 0.0 Melanoma* SK-MEL-5 10.0 .Colon ca. SW480 0.1 Squamous cell carcinoma SCC-4 0.0 Colon ca.* (SW480 met) SW620 0.0 264 WO 03/050245 PCT/US02/38594 Testis Pool 11.1 Colon ca. HT29 0.1 Prostate ca.* (bone met) PC-3 0.1 Colon ca. HCT- 116 0.0 Prostate Pool 3.1 Colon ca. CaCo-2 4.0 Placenta 8.9 . Colon cancer tissue 10.6 Uterus Pool 1.5 Colon ca. SW1116 0.0 Ovarian ca. OVCAR-3 2.0 Colon ca. Colo-205 0.0 Ovarian ca. SK-OV-3 14.0 Colon ca. SW-48 0.0 Ovarian ca. OVCAR-4 0.9 Colon Pool 3.8 Ovarian ca. OVCAR-5 0.0 Small Intestine Pool 1.6 Ovarian ca. IGROV-1 1.4 Stomach Pool 2.5 Ovarian ca. OVCAR-8 2.9 Bone Marrow Pool 2.7 Ovary 0.9 Fetal Heart 3.0 Breast ca. MCF-7 0.1 Heart Pool 3.5 Breast ca. MDA-MB-231 0.0 Lymph Node Pool 3.1 Breast ca. BT 549 100.0 Fetal Skeletal Muscle 1.9 Breast ca. T47D 0.0 Skeletal Muscle Pool 2.7 Breast ca. MDA-N 0.0 Spleen Pool 0.7 Breast Pool 3.1 Thymus Pool 3.0 Trachea 5.5 CNS cancer (glio/astro) U87-MG 0.1 Lung 0.5 CNS cancer (glio/astro) U-118-MG 0.4 Fetal Lung 5.7 CNS cancer (neuro;met) SK-N-AS 3.3 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 0.0 Lung ca. LX-1 0.2 CNS cancer (astro) SNB-75 0.2 Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 1.4 Lung ca. SHP-77 0.0 CNS cancer (glio) SF-295 16.0 Lung ca. A549 0.2 Brain (Amygdala) Pool 0.5 Lung ca. NCI-H526 0.0 Brain (cerebellum) 1.6 Lung ca. NCI-H23 .......... 6.6 Brain (fetal) 1.0 Lung ca. NCI-H460 0.0 JBrain (Hippocampus) Pool 1.0 Lung ca. HOP-62 0.9 Cerebral Cortex Pool 0.9 Lung ca. NCI-H522 0.1 Brain (Substantia nigra) Pool 0.7 Liver 0.1 Brain (Thalamus) Pool 0.7 Fetal Liver 1.7 Brain (whole) 2.1 Liver ca. HepG2 0.0 Spinal Cord Pool 0.6 Kidney Pool 4.5 Adrenal Gland 1.4 Fetal Kidney 1.1 Pituitary gland Pool 0.1 Renal ca. 786-0 0.0 Salivary Gland 1.4 Renal ca. A498 0.1 Thyroid (female) 3.3 Renal ca. ACHN 0.0 Pancreatic ca. CAPAN2 0.0 Renal ca. UO-31 0.2 Pancreas Pool 1.0 265 WO 03/050245 PCT/US02/38594 Table AD. Panel 4.1D Rel. Rel. Ep.(%) Exp.(%) Tissue Name Ag6712, Tissue Name Ag6712, Run Run 276596876 276596876 Secondary Thl act 0.0 HUVEC IL-lbeta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 Secondary Trl act 0.0 HUVEC TNF alpha + IFN gamma 0.0 Secondary Thl rest 0.0 HUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 0.0 Secondary Trl rest 0.0 Lung Microvascular EC none 0.0 Primary Thl act 0.0 Lung Microvascular EC TNFalpha 0.0 + IL-lbeta Primary Th2 act 0.0 Microvascular Dermal EC none 0.0 Primary Trl act 0.0 Microsvasular Dermal EC 0.0 TNFalpha + IL-1beta Primary Thl rest 0.0 Bronchial epithelium TNFalpha + 0.0 ILlbeta Primary Th2 rest 0.0 Small airway epithelium none 0.0 Primary Trl rest 0.0 Small airway epithelium TNFalpha 1.5 + IL-lbeta CD45RA CD4 lymphocyte act 15.0 Coronery artery SMC rest 13.4 CD45RO CD4 lymphocyte act 0.0 Coronery artery SMC TNFalpha + 14.5 IL-lbeta CD8 lymphocyte act 0.0 Astrocytes rest 0.0 Secondary CD8 lymphocyte rest 10.0 Astrocytes TNFalpha + IL-lbeta 0.0 Secondary CD8 lymphocyte act 0.0 KU-812 (Basophil) rest 0.0 ~KU-812 (Basophil) CD4 lymphocyte none 0.0 KU-12 (Basophil) 0.0 PMA/ionomycin 2 ry Thl/Th2fTrl anti-CD95 CH11 - 0.0 CCD 1106 (Keratinocytes) none 12.1 LAK cells rest 0.0 CCD1106 (Keratinocytes) 6.1 TNFalpha + IL-lbeta LAK cells IL-2 0.0 ILiver cirrhosis 2.4 LAK cells IL-2+IL-12 0.0 NCI-H292 none 0.0 LAK cells IL-2+IFN gamma 0.0 NCI-H292 IL-4 0.0 LAK cells IL-2+ L-18 0.0 NCI-H292 IL-9 0.0 LAK cells PMA/ionomycin 0.0 NCI-H292 IL-13 0.0 NK Cells IL-2 rest 0.0 NCI-H292 IFN gamma 0.0 Two Way MLR 3 day 0.0 HPAEC none 0.0 Two Way MLR 5 day 0.0 HPAEC TNF alpha + IL-1 beta 0.0 Two Way MLR 7 day 0.0 Lung fibroblast none 7.7 IPBMC rest 0.0 Lung fibroblast TNF halpha + L-1 0.5 beta PBMC PWM 0.0 Lung fibroblast IL-4 18.4 266 WO 03/050245 PCT/USO2/38594 PBMC PHA-L 0.0 Lung fibroblast IL-9 4.7 Ramos (B cell) none 0.0 Lung fibroblast IL-13 3.6 Ramos (B cell) ionomycin 0.0 Lung fibroblast IFN gamma 16.0 B lymphocytes PWM .. . 0.0 Dermal fibroblast CCD1070 rest 56.3 Dermal fibroblast CCD1070 TNF B lymphocytes CD40L and IL-4 0.0 Dermal fibroblast CCD17 TNF 39.0 Dermal fibroblast CCD1070 IL- 41 EOL-1 dbcAMP 0.0 41.2 beta EOL-1 dbcAMP EOL dbcAMP 0.0 Dermal fibroblast IFN gamma 51.8 PMA/ionomycin Dendritic cells none 0.0 Dermal fibroblast IL-4 100.0 Dendritic- cells LPS 0.0 IDermal.Fibroblasts rest 52.5 Dendritic cells anti-CD40 0.0 INeutrophils TNFa+LPS 0.0 Monocytes rest 0.0 INeutrophils rest 0.0 Monocytes LPS 0.0 Colon 1.8 Macrophages rest 0.0 Lung 6.5 Macrophages LPS 0.0 Thymus 1.9 HUVEC none _ 0.0 Kidney 1.1 HUVEC starved 0.0 CNSneurodegenerationvl.0 Summary: Ag6712 This panel does not show differential expression of this gene in Alzheimer's disease. However, this profile confirms the expression of this gene at low levels in the brain. Please see Panel 1.6 for discussion of utility of this gene in the central nervous system. 5 Generalscreeningpanelvl.6 Summary: Ag6712 Highest expression of this gene is seen in a breast cancer cell line (CT=26.4). Moderate levels of expression are also seen in brain, melanoma, and ovarian cancer cell lines. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the 10 expression or function of this gene may be effective in the treatment of breast, brain, melanoma, and ovarian cancers. Low but significant levels of expression are seen in pancreas, adrenal, thyroid, adult and fetal skeletal muscle and heart, fetal liver, and adipose. This widespread expression among these tissues suggests that this gene product may play a role in normal 15 neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes. This gene is also expressed at low levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the 267 WO 03/050245 PCT/USO2/38594 treatment of neurological disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy. In addition, this gene is expressed at much higher levels in fetal lung and liver tissue (CTs=30.5-32.5) when compared to expression in the adult counterpart (CTs=34-35). Thus, 5 expression of this gene may be used to differentiate between the fetal and adult source of these tissues. Furthermore, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance organ growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the GPCR encoded by this gene could be useful in treatment of lung or liver related 10 diseases. Panel 4.1D Summary: Ag6712 Expression of this gene is most prominent in a cluster sf samples derived from dermal fibroblasts, with highest expression in IL-4 treated dermal fibroblasts (CT=32.3). Thus, expression of this gene could be used as a marker of this cell type and to differentiate between these samples and other samples on this panel. 15 This expression also suggests that this gene product may be involved in inflammatory conditions of the skin, including psoriasis. B. CG105716-01, CG105716-02, CG105716-03, CG105716-04, CG105716-05 and CG105716-06: Cartilage oligomeric matrix protein precursor-like Protein. Expression of gene CG105716-01, CG105716-02, CG105716-03, CG105716-04, 20 CG105716-05, and CG105716-06 was assessed using the primer-probe sets Ag2362, Ag5922, Ag5924, Ag5928, Ag5936 and Ag6846, described in Tables BA, BB, BC, BD, BE and BF. Results of the RTQ-PCR runs are shown in Tables BG, BH, BI, BJ, BK, BL, BM, BN, BO, BP and BQ. Please note that probe-primer sets Ag5922 is specific for CG105716-03, Ag5924 is specific for CG105716-04, Ag5928 is specific for CG105716-05 25 and Ag5936 is specific for CG105716-06. Table BA. Probe Name Ag2362 Primers ength tart SEQ ID Position No Forward 5 '-gtataggggatgcctgtgaca-3' 21 1230 158 Probe TET-5' -actgtccccagaagagcaacccg-3 23 1251 159 S- TAMRA Reverse 5 ' -cacaagcatctcccacaaa-3' 19 1298 160 268 WO 03/050245 PCT/USO2/38594 Table BB. Probe Name Ag5922 .......... SLength Start ]SEQ ID Primers Sequencs eng Position No Forward 5'-gactctcgggacaactgccg-3' 20 1352 161 Probe TET-5 1 -tctgcatcaaagtcgtcctggcacacg 2 8 1422 162 t-3'-TAMRA Reverse 5 ' -cggacacacgtcgatcttgt-3' 20 1461 163 STable BC. Probe Name Ag5924 _......... Start SEQ ID Primers Sequence Length Position No .... Position No Forward 5'-gactttgtgggagatgcttgt-3' 21 1295 164 Probe TET-5'-atgtccgtctccatcctggtcttgat 26 1323 165 Prob -3'-TAMRA 13 65 Reverse 5-tggtctgagtcccgagagt-3' 19 1362 166 5 Table RD. Probe Name Ag5928 1'.egtF Start ]SEQ ID) Primers Sequencs Length start SEQ ID jPosition INo. Forward 5'-ctgacagtcgggacggcgt-3' 19 1458 167 Pbe TET-5' -tccagcacgactgtctggaaggccctg28 11569 168 Probe a-3'-TAMRA ..

8 168 Reverse .5'-cttccctggttgagcaccac-3' . 20 1631 169 Table BE. Probe Name Ag5936 Start jSEQID Primers Sequenes Length Position No Forwnvard 5'-ctgcgacgacgacgtgtgc-3' 19 1426 170 Probe TET-5' -agaacgctgaagtcacgctcaccgact 30 1497 171 tca-3'-TAMRA Reverse 5'-tctcccttccctggttgagc-3' 120 1591 172 Table BF. Probe Name Ag6846 Start SEQ ID Primers Length Position No Forward 5'-aacataactgcgtccccaact-3' 21 3588 173 Probe TET-5'-ccttccagtgcggcccgtgcca-3 22 633 174 -TAMRA Reverse 5'-cctggtcgcccacgaa-3' 16 662 175 10 269 WO 03/050245 PCT/US02/38594 Table BG. AI.05 chondrosarcoma __ _ _ _ _ _ _ _ Rel. Rel. Exp.(%) Exp.(%) Tissue Name g2362, Tissue Name Ag2362, Run Run 316264541 316264541 138353_ (l8hr) 0.3 138346 IL-lbeta + Oncostatin M 0.2 138353_PMA (18hrs) 0.3 hr)-0.2 (6hrs) 138352_IL-lbeta + Oncostatin M 0.5 138345 IL-lbeta+TNFa (6hrs) 0.1 (18hrs) 138351 IL-lbeta+TNFa (18hrs) 6.6 138344_IL-lbeta (6hrs) 0.1 138349 Untreated-secum starved 138350_IL-lbeta (18hrs) 1.1 138349-Untreated-serum starved 68.8

-

(6hrs) 138354_Untreated-complete 0.0 138348 Untreated-complete 100.0 medium (18hrs) medium (6hrs) 138347 PMA (6hrs) 0.7 Table BH. AI comprehensive panel vl.0 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag2362, issue Name Ag2362, Run Run 255325334 255325334 110967 COPD-F 0.0 112427 Match Control Psoriasis-F 0.0 110980 COPD-F 0.0 112418 Psoriasis-M 0.0 110968 COPD-M 0.0 112723 Match Control Psoriasis-M 0.0 110977 COPD-M 0.0 112419 Psoriasis-M 0.0 110989 Emphysema-F .. 0 1 12424 Match Control Psoriasis-M 0.0 110992 Emphysema-F 0.3 112420 Psoriasis-M 0.0 110993 Emphysema-F 0.0 112425 Match Control Psoriasis-M 0.0 110994 Emphysema-F 10.0 104689 (MF) OA Bone-Backus 1.2 1099 Emph a.4 - 104690 (MF) Adj "Normal" 2.0 110995 Emphysema-F 0Bone-Backus 2.0 110996 Emphysema-F 0.1 104691 (MF) OA Synovium-Backus 2.0 110997 Asthma-M 0.0 104692 (BA) OA Cartilage-Backus 100.0 111001 Asthma-F 0.0 104694 (BA) OA Bone-Backus 2.0 111002 Asthma-F 0.0 104695 (BA) Adj 'Normal" 7.1 Bone-Backus 111003 Atopic Asthma-F 0.0 104696 (BA) OA Synovium-Backus 2.0 111004 Atopic Asthma-F 0.0 104700 (SS) OA Bone-Backus 1.8 104701 (SS) Adj "Normal" 7.0 111005 Atopic Asthma-F 0.0 Bone-Backus 7 111006 Atopic Asthma-F 0.0 104702 (SS) OA Synovium-Backus 13.0 11417 Allergy-M 0.0 117093 OA Cartilage Rep7 0.0 112347 Allergy-M 0.0 112672 OA Bone5 0.0 112349 Normal Lung-F 0.0 112673 OA Synovium5 0.0 270 WO 03/050245 PCT/USO2/38594 12357 Nonrmnal Lung-F 0.0 112674 OA Synovial Fluid ceils5 0.0 112354 Normal Lung-M 0.0 117100 OA Cartilage Repl4 0.0 112374 Crohns-F 0.1 112756 OA Bone9 0.0 112389 Match Control Crohns-F 1.1 112757 OA Synovium 0.0 12375 Crohns-F 0.0 112758 OA Synovial Fluid Cells9 0.0 112732 Match Control Crohns-F 0.0 117125 RA Cartilage Rep2 0.0 112725 Crohns-M 0.0 113492 Bone2 RA 0.0 112387 Match Control{ Crohns-M 0.0 113493 Synovium2 RA 0.0 Crohns-M0. 112378 Crohns-M 0.0 113494 Syn Fluid Cells RA 0.0 112390 Match Control K:_.. Crohns-M 0.0 113499 Cartilage4 RA 0.0 112726 Crohns-M 0.0 113500 Bone4 RA - 0.0 112731 Match Control 0.0 Synovium Crohns-M 0.0 113501 Synovium4 RA 0.0 112380 Ulcer Col-F 0.0 113502 Syn Fluid Cells4 RA 0.0 112734 Match Control Ulcer 0.0 i13495 Cartilage3 RA . Col-F 0 113495 Cartilage3 RA 0.0 112384 Ulcer Col-F 0.1 113496 Bone3 RA 0.0 112737 Match Control Ulcer 0.0 113497 Synovium3 RA ClF0.0 113497 Synovium3 RA 0.0 Col-F 0.0 112386 Ulcer Col-F 0.2 . 113498 Syn Fluid Cells3 RA . 0.0 112738 Match Control Ulcer 127Col-F8 Match Control Ulcer 0.0 117106 Normal Cartilage Rep20 0.0 112381 Ulcer Col-M 0.0 113663 Bone3 Normal 0.0 112735 Match Control Ulcer 13664 Sovium3 Normal Col-M 0.0 113664 Synovium.3 Normal 0.0 112382 Ulcer Col-M 0.2 113665 Syn Fluid Cells3 Normal 0.0 112394 Match Control Ulcer 117107 Normal Cartilage Rep22 0.0 Col-M 0.0 117107 Normal Cartilage Rep22 0.0 112383 Ulcer Col-M 0.1 113667 Bone4 Normal 0.0 112736 Match Control Ulcer 0.3 113668 Synoviu,4 Normal. Col-M 0.3 13668 Synovium4 Normal 0.0 112423 Psoriasis-F 0. 113669 Syn Fluid Cells4 Normal 0.0 Table BI. General screening panel v .5 Rel. Rel. Rel. Rel. Rel. Rel. Exp.(%) Ag2362 Exp. %) Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag2362, Ag5922, Ag5924, Ag5928, Ag5936, 24815646 Run Run Run Run 24815646 247608955 247608957 247834910 248102147 Adipose 1.7 0.4 0.3 0.3 0.7 Melanoma* Hs688(A).T 100.0 100.0 100.0 100.0 100.0 Melanoma* Hs688(B).T 81.2 85.9 76.3 81.2 80.7 Melanoma* M14 0.0 0.0 0.0 0.0 0.0 271 WO 03/050245 PCT/USO2/38594 Melanoma* LOXIMVI 0.0 0.0 0.0 0.0 0.0 Melanoma* SK-MEL-5 0.0 0.0 0.0 0.0 0.0 Squamous cell carcinoma SCC-4 0.0 0.0 0 0 0.0 0.0 Testis Pool 3.2 2.0 1.8 1.1 1.2 Prostate ca.* (bone met) PC-3 0.0 0.0 9.0 0.0 0.0 Prostate Pool 1.0 0.4 0.3 0.2 0.0 Placenta 0.6 0.8 0.3 0.8 0.6 Uterus Pool 0.0 0.1 0.0 0.0 0.0 Ovarian ca. OVCAR-3 0.0 O.0 0.0 0.0 0.0 Ovarian ca. SK-OV-3 0.0 0.0 0.0 o.0 0.0 Ovarian ca. OVCAR-4 0.0 0.0 0.0 0.0 0.0 Ovarian ca. OVCAR-5 0.1 0.0 0.0 0.0 0.0 Ovarian ca. IGROV-1 0.0 0.0 0.0 0.0 0.0 Ovarian ca. OVCAR-8 0.0 0.0 0.0 0.0 0.0 Ovary 0.5 0.0 0.4 0.0 0.0 Breast ca. MCF-7 0.0 0.0 0.0 0.0 0.0 Breast ca. MDA-MB-231 0.0 0.0 0.0 0.0 0.0 Breast ca. BT 549 0.0 0.0 0.0 0.0 0.0 Breast ca. T47D 0.0 0.0 0.0 0.0 0.0 Breast ca. MDA-N 0.0 0.0 0.0 _0.0 0.0 Breast Pool 0.1 0.0 0.0 0.0 0.0 Trachea 4.1 3.1 2.2 2.2 5.4 Lung 0.1 0.0 0.0 0.0 0.0 Fetal Lung 0.0 0.0 0.0 0.0 0.0 Lung ca. NCI-N417 0.0 0.0 0.0 0.0 0.0 Lung ca. LX-1 0.4 0.2 0.2 0.1 0.0 Lung ca. NCI-H146 0.0 0.0 0.0 0.0 0.0 Lung ca. SHP-77 0.0 0.0 0.0 0.0 0.0 Lung ca. A549 0.0 0.0 0.0 0.0 0.0 Lung ca. NCI-H526 0.0 0.0 0.0 0.0 0.0 Lung ca. NCI-H23 0.1 0.0 0.0 0.0 0.0 Lung ca. NCI-H460 0.0 0.0 0.0 0.0 0.0 Lung ca. HOP-62 0.0 0.0 0.0 0.0 0.0 Lung ca. NCI-H522 0.0 0.0 0.0 0.0 0.0 Liver 0.0 0.0 0.0 0.0 0.0 Fetal Liver 0.0 0.0 0.0 0.0 0.0 Liver ca. HepG2 0.8 0.9 0.7 '0.7 0.5 Kidney Pool 0.2 0.1 0.1 0.0 0.0 Fetal Kidney 0.0 0,0 0. 0 0.0 0.0 Renal ca. 786-0 0.0 0.0 0.0 0.0 0.0 Renal ca. A498 0.0 0.1 0.0 0.0 0.0 Renal ca. ACHN 0.0 0.0 0.0 0.0 0.0 Renal ca. U3-1 0.0 ~0.0 0~.2 Renal ca. TK-10 0.4 0.1 10.2 10.0 0.3 272 WO 03/050245 PCT/US02/38594 Bladder 7.5 3.5 5.0 3.7 6.6 Gastric ca. (liver met.) NCI-N87 0.0 0.0 0.0 0.0 0.0 Gastric ca. KATO III 0.0 0.0 0.0 0.0 0.0 Colon ca. SW-948 0.0 0.0 0.0 0.0 0.0 Colon ca. SW480 0.0 0.1 0.0 0.0 0.0 Colon ca.* (SW480 met) SW620 0.0 0.0 0.0 0.0 0.0 Colon ca. HT29 0.0 0.0 0.0 0.0 0.0 Colon ca. HCT-116 0.0 0.0 0.0 0.0 0.0 Colon ca. CaCo-2 0.1 0.0 0.0 0.0 0.0 Colon cancer tissue 16.6 14.2 18.2 16.2 20.9 Colon ca. SW1116 0.0 0.0 0.0 0.0 0.0 Colon ca. Colo-205 0.0 0.0 0.0 0.0 0.0 Colon ca. SW-48 0.0 0.0 0.0 0.0 0.0 Colon Pool 0.2 0.0 0.0 0.0 0.1 Small Intestine Pool 0.0 0.0 0.0 0.0 0.0 Stomach Pool 0.5 0.3 0.2 0.1 0.0 Bone Marrow Pool 0.2 0.0 0.0 0.0 0.0 Fetal Heart 0.1 0.0 0.1 0.0 0.0 Heart Pool 0.0 0.1 0.0 0.0 0.0 Lymph Node Pool 0.0 0.0 0. 0.0 0.0 0.0 Fetal Skeletal Muscle 0.7 0.2 0.3 0.3 0.0 Skeletal Muscle Pool 0.2 0.1 0.2 0. 0.0 Spleen Pool 0.0 0.1 0.0 0.0 0.0 Thymus Pool 0.1 0.0 0.0 0.0 0.0 CNS cancer (glio/astro) U87-MG 0.0 0.0 0.0 0.0 0.0 CNS cancer (glio/astro) U-118-MG 0.6 0.6 0.3 0.4 0.7 CNS cancer (neuro;met) SK-N-AS 0.0 0.0 0.0 0.0 0.0 CNS cancer (astro) SF-539 0.0 0.0 0.0 0.0 0.0 CNS cancer (astro) SNB-75 0.0 0.1 0.0 0.0 0.0 CNS cancer (glio) SNB-19 0.0 . 0.0 0.0 0.0 CNS cancer (glio) SF-295 0.0 0.0 0.0 0.0 0.0 Brain (Amygdala) Pool 0.0 0.0 0.0 0.0 0.0 Brain (cerebellum) 1.4 0.6 1.1 0.4 0.9 Brain (fetal) 0.0 0.0 0.0 0.0 0.0 Brain (Hippocampus) Pool 0.1 0.0 0.0 0.0 0.0 Cerebral Cortex Pool 0.0 0.0 0.0 0.0 0.0 Brain (Substantia nigra) Pool 0.0 0.0 0.0 0.0 0.0 Brain (Thalamus) Pool 0.0 0.0 0.0 0.0 0.0 Brain (whole) 0.0 0.0 0.0 0.0 0.0 Spinal Cord Pool 0.0 0.1 0.0 __ 0.0 0.2 Adrenal Gland 0.0 0.0 0.0 0.0 0.0 Pituitary gland Pool 0.0 0.0 0.0 0.0 0.0 Salivary Gland 0.1 0.0 0.0 0.0 0.0 Thyroid (female) 0.3 0.2 0.7 0.2 0.0 273 WO 03/050245 PCT/USO2/38594 IPancreatic ca. CAPAN2 . 0.0 0.0 00 0.0 Pancreas Pool 7.4 6.7 5.8 5.1 6.9 Table BJ. General screening panel v1.6 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag6846, issue Name Ag6846, Run Run 278391621 278391621 Adipose 0.2 Renal ca. TK-10 0.1 Melanoma* Hs688(A).T 100.0 Bladder 2.1 Melanoma* Hs688(B).T 92.0 Gastric ca. (liver met.) NCI-N87 0.0 Melanoma* M14 0.0 Gastric ca. KATO III 0.0 Melanoma* LOXIM4VI 0.0 Colon ca. SW-948 0.0 Melanoma* SK-MEL-5 0.0 Colon ca. SW480 0.0 Squamous cell carcinoma SCC-4 0.0 Colon ca.* (SW480 met) SW620 0.0 Testis Pool 2.1 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 0.0 Prostate Pool 0.2 Colon ca. CaCo-2 0.1 Placenta 0.3 Colon cancer tissue 9.1 Uterus Pool 0.0 Colon ca. SW1 116 0.0 Ovarian ca. OVCAR-3 0.0 Colon ca. Colo-205 0.0 Ovarian ca. SK-OV-3 0.0 Colon ca. SW-48 0.0 Ovarian ca. OVCAR-4 [0.0 Colon Pool 0.1 Ovarian ca. OVCAR-5 0.0 Small Intestine Pool 0.0 Ovarian ca. IGROV-1 0.0 Stomach Pool 0.6 Ovarian ca. OVCAR-8 0.0 Bone Marrow Pool 0.0 Ovary 0.1 Fetal Heart 0.0 Breast ca. MCF-7 0.0 Heart Pool 0.0 Breast ca. MDA-MB-231 0.0 Lymph Node Pool 0.0 Breast ca. BT 549 0.0 Fetal Skeletal Muscle 0.1 Breast ca. T47D 0.0 Skeletal Muscle Pool 0.0 Breast ca. MDA-N 0.0 Spleen Pool 0.0 Breast Pool 0.0 Thymus Pool 0.1 Trachea 1.4 CNS cancer (glio/astro) U87-MG 0.0 Lung 0.0 CNS cancer (glio/astro) U-118-MG 0.2 Fetal Lung 0.0 CNS cancer (neuro;met) SK-N-AS 0.0 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 0.0 Lung ca. LX-1 0.0 CNS cancer (astro) SNB-75 0.0 Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 0.0 Lung ca. SHP-77 0.0 CNS cancer (glia) SF-295 0.0 Lung ca. A549 0.0 Brain (Amygdala) Pool 0.0 Lung ca. NCI-H526 0.0 Brain (cerebellum) 0.7 Lung ca. NCI-H23 0.0 Brain (fetal) 0.0 274 WO 03/050245 PCT/USO2/38594 Lung ca. NCI-H460 0.0 Brain (Hippocampus) Pool 0.1 Lung ca. HOP-62 0.0 Cerebral Cortex Pool 0.0 Lung ca. NCI-H522 0.0 Brain (Substantia nigra) Pool 0.0 Liver 0.0 Brain (Thalamus) Pool 0.0 Fetal Liver 0.0 Brain (whole) 0.0 Liver ca. HepG2 0.3 Spinal Cord Pool 0.0 Kidney Pool 0.2 Adrenal Gland 0.0 F ~~~~~~~~~~~~ .eta.!. K i ne ........................................ .. . iu t r .l d . o ................ ........................... Fetal Kidney 0.0 Pituitary gland Pool 0.0 Renal ca. 786-0 0.0 Salivary Gland ]0.0 Renal ca. A498 0.0 Thyroid (female) 0_.2 Renal ca. ACHN 0.0 Pancreatic ca. CAPAN2 0.0 Renal ca. UO-31 0.0 Pancreas Pool' 0.1 Table BK. HASS Panel vl.0 Rel. Rel. Exp.(% Exp.(%) Tissue Name Ag2362, Tissue Name Ag2362, Run Run 268623699 268623699 MCF-7 C1 0.0 U87-MG F1 (B) 0.0 MCF-7 C2 0.2 U87-MG F2 0.0 MCF-7 C3 0.4 U87-MG F3 0.0 MCF-7 C4 0.6 U87-MG F4 0.0 MCF-7 C5 0.6 U87-MG F5 .0.0 MCF-7 C6 0.3 U87-MG F6 0.0 MCF-7 C7 10.0 U87-MG F7 0.0 MCF-7 C9 0.0 U87-MG F8 0.0 MCF-7 C10 0.0 U87-MG F9 0.1 MCF-7 C11 0.0 U87-MG F10 0.0 MCF-7 C12 0.0 U87-MG F 1 0.0 MCF-7 C13 0.1 U87-MG Fl2 0.0 MCF-7 C15 0.0 U87-MG F13 0.0 MCF-7 C16 0.3 U87-MG F14 0.0 MCF-7 C17 0.0 U87-MG F15 0.0 T24 D1 0.0 U87-MG F16 0.0 T 2 . 1 ............. ...... . . .: ...... . ............................. ----- I 1 6 . ]0 .0.. ....... T24 D2 0.2 U87-MG F17 0.4 T24 D3 0.5 LnCAP A1 0.4 T24 D4 0.0 LnCAP A2 0.0 T24 D5 0.2 LnCAP A3 0.8 T24 D6 0.0 LnCAP A4 0.5 T24 D7 0.0 LnCAP A5 0.7 T24 D9 0.0 LnCAP A6 0.3 T24D1O 0.3 LnCAP A7 2.0 T24 D11 0.0 LnCAP A8 4.9 275 WO 03/050245 PCT/USO2/38594 T24 D12 0.3 LnCAP A9 2.4 T24 D13 0.3 LnCAP A10 12.6 T24 D15 0.0 LnCAP All 16.7 T24 D16 0.9 LnCAP A12 0.3 T24 D17 0.0 LnCAP A13 0.7 CAPaN B1 0.0 LnCAP A14 1.4 CAPaN B2 0.0 LnCAP A15 3.0 CAPaN B3 0.0 LnCAP A16 0.3 CAPaN B4 0.0 LnCAP A17 5.5 CAPaN B5 0.3 Primary Astrocytes 100.0 B60.0 Primary Renal Proximal Tubule Epithelial cell 0.0 CAPaN B6 0.0 0.0 A2 CAPaN B7 0.1 Primary melanocytes A5 0.0 CAPaN B8 0.0 126443 - 341 medullo 0.5 CAPaN B9 0.0 126444 -487 medullo 0.0 CAPaN B10 0.0 126445 - 425 medullo 0.0 CAPaN B11 0.0 126446 -690 medullo 1.2 CAPaN B12 0.0 126447 -54 adult glioma 0.0 CAPaN B13 0.0 126448 - 245 adult glioma 0.3 CAPaN B 14 0.3 126449 - 317 adult glioma 0.0 CAPaN B15 0.0 126450 -212 glioma 0.0 CAPaN B16 0.0 126451 -456 glioma 0.0 CAPaN B17 0.0 Table BL. Panel 1.3D Rel. Rel. Rel. Rel. Exp.(%) Exp.(%) Exp.(%) Exp.(%) Tissue Name g2362, Ag2362, Tissue Name Ag2362, Ag2362, Run Run Run Run 166013008 167966893 166013008 167966893 nLiver 0.3 1.2 Kidney (fetal) - 0.0 2.8 adenocarcinoma ... ... . ... ....... .. . .. .... ........ .... .. ....... ...... .. .. .. .... .... .. .. ..... .... .. .. .... .. .. .. ... Pancreas 0.5 0.6 Renal ca. 786-0 0.0 0.0 Pia ncreatic ca. ", .. l..... . .. .. 0.0 10.0 Renal ca. A498 0.0 0.1 CAPAN 2 Adrenal gland . 0.3 - 0.0 Renal ca. RXF 393 0.0 0.0 . Thyroid 10.5 1.5 Renal ca. ACHN 10.0 0.2 Salivary gland 1.8 0.2 Renal ca. UO-31 0.0 0.0 Pituitary gland .0 00 Renal ca.0 10 ... 0.0 Brain (fetal) 0.0 .. 0 Liver 10.0 0.0 Brain (whole) 0.2 1.4 Liver (fetal) 0.0 0.0 ~~Liver ca. 1 Brain (amygdala) 0.0 0.0 Liver ca. 6.4HepG2 9.5 (hepatoblast) HepG2 Brain(cerebellum) 5.4 4.6 Lung 0.9 1.6 Brain (hippocampus) 0.0 0.2 Lung (fetal) 12.2 5.3 276 WO 03/050245 PCT/USO2/38594 Brain (substantia 1.6 0.9 Lung ca. (small cell) 1.6 2.0 nigra) LX-1 Lung ca. (small cell) Brain (thalamus) 0.0 0.0 NCI-H69 0.0 0.0 Cerebral Cortex 0.0 0.0 Lung ca. (s.cell var.) 0.0 0.0 SHP-77 Lung ca. (large Spinal cord 0.6 0.6 cell)NCI-H460 0.4 0.0 cell)NCI-H460 Lung ca. (non-sin. glio/astro U87-MG 0.0 0.0 cl50.0 0.3 cell) A549 glio/astro U-118-MG 2.3 1.6 Lung ca. (non-s.cell) 0.0 0.4 NCI-H23 astrocytoma 0. Lung ca. (non-s.cell) 00 asrcyoa 0.0 0.0 0.0 0.0 SW1783 HOP-62 neuro*; met 0.0 0.1 Lung ca. (non-s.cl) 0.0 0.3 SK-N-AS NCI-H522 astrocytoma SF-539 0.0 0.0 Lung ca. (squam.) 0.0 0.0 ... rc3 ... ... . .... .SW 900 astrocytoma SNB-75 0.0 0.3 nHca. (squam.) 0.0 0.3 glioma SNB-19 00.0 .0 Mammary gland 2.8 1.4 100 0.0 Breast ca.* (pl.ef) glioma U251 MCF-7 0.0 0.0 MCF-7 glioma SF-295 0.3 0.0 Breast ca.* (pl.et) 0.0 0.0 MDA-MB-231 Breast ca.* (pl.ef) Heart (fetal) 5.4 16.5 T47D 0.0 0.0 Heart 4.9 12.9 Breast ca. BT-549 0.0 0.0 Skeletal muscle 22.7 69.7 Breast ca. MDA-N 0.0 0.0 (fetal) Skeletal muscle 35.4 52.5 Ovary 0.2 1.5 Ovarian ca. Bone marrow 6.4 11.2 0.0 0.0 OVCAR-3 Ovarian ca. Thymus 0.0 0.2 OVCAR-4 0.0 0.0 OVCAR-4 Ovarian ca Spleen 0.3 0.0 OVCAR-5 0.0 0.0 OVCAR-5 Lymph node 0.3 0.0 V a .0.0 0.0 OVCAR-8 .90 Ovarian ca. Colorectal 0.0 0.2 O a 0.0 0.0 IGROV-1 ~Ovarian ca.* 0.00 Stomach 1.2 .0.6 Ovarian ca.* 0.0 0.0 (ascites) SK-OV-3 Small intestine 0.0 0.7 Uterus 1.3 2.6 Colon ca. SW480 0.0 0.0 Placenta 20.3 1.2 Colon ca.o Colonca.*_03 1Prostate 1.8 2.7 SW620(SW480 met) .3 1.5 277 WO 03/050245 PCT/USO2/38594 Colon ca. HT29 0.0 0.0 Prostate ca.* (bone .0 0.0 met)PC-3 Colon ca. HCT-116 0.0 0.0 Testis - 17.6 21.9 Colon ca. CaCo-2 0.0 0.0 Melanoma 68.8 91.4 Hs688(A).T _4 Colon ca. 100.0 99.3 Melanoma* (met) 71.70. tissue(ODO3866) 1 99.3 _ Hs688(B).T 71.7 0.0 Colon ca. HCC-2998 .0 0. 0 Melanoma 0.0 0.0 0.0__ 'UACC-62 Gastric ca.* (liver met) NCI-N87 0.3 0.0 Melanoma M14 0.0 0.0 met) NCI-N87 ____ ____10.0 Bladder 31.9 45.7 Melanoma LOX 0.0 0.0 Trachea 7.8 '14.1 Melanoma* (met) 0.0 0.0 . ]~SK -MEL-5 .. . Ki.dn.ey.. ........ 0.3 0.7 Adipose 11.7 128.1 Table BM. Panel 2D el. Rel. SEx.(%) Exp.(%) Tissue Name Ag2362, Tissue Name Ag2362, Run Run 164151688 164151688 Normal Colon 1.2- Kidney Margin 8120608 0.8 CC Well to Mod Diff(ODO3866) 54.0 Kidney Cancer 8120613 0.0 CC Margin (0DO3866)_ 0.9 Kidney Margin 8120614 0.9 CC Gr.2 rectosigmoid (ODO3868) 3.2 Kidney Cancer 9010320 12.8 CC Margin (ODO3868) 10.2 Kiney Margi 9010321 .8 CC ModDiff (ODO3920) . ... 04 Normal Uterus 2.9 C Margin (ODO3920) 0.3 Uterus Cancer 064011 0.9 CC Gr.2 ascend colon (ODO3921) 11.5 -Normal Thyroid 1.7 CC Margin (OD03921) 9.4 Thyroid Cancer 064010 1.4 CC from Partial Hepatectomy

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oidCancer 22.8 (ODO4309) Mets 46.3 Thyroid Cancer A302152 22.8 Liver Margin (OD04309) 0.0 Thyroid Margin A302153 0.3 Colon mets to lung (OD04451-01) 2.2 Normal Breast 2.6 Lung Margin (OD04451-02) 0.1 . . Breast Cancer (OD04566) 21.9 Normal Prostate 6546-1 12.0 .Breast Cancer (OD04590-01) 173.2 Prostate Cancer (ODO_4410) 36.6 Breast Cancer Mets 100.0 Prostate Cancer (D04410) 36.6 (OD04590-03) Prostate Margin (OD04410) 18.2 Breast Cancer Metastasis (OD04655-05) 9 Prostate Cancer (OD04720-01) 11.9 Breast Cancer 064006 35.8 Prostate Margin (OD04720-02) 2.3 Breast Cancer 1024 21.5 Normal Lung 061010 5.4 Breast Cancer 9100266 44.4 LungMet to Muscle (ODO4286) 57 . Breast Margin 9100265 21.3 278 WO 03/050245 PCT/USO2/38594 Muscle Margin (ODO4286) 19.6 Breast Cancer A209073 44.4 Lung Malignant Cancer (OD03126) 16.0 Breast Margin A209073 4.9 Lung Margin (OD03126) 4.5 Normal Liver 0.0 Lung Cancer (OD04404) 5.2 Liver Cancer 064003 0.0 Lung Margin (OD04404) 110.7 Liver Cancer 1025 0.0 Lung Cancer (OD04565) 22.5 Liver Cancer 1026 2.9 Lung Margin (OD04565) 1.0 Liver Cancer 6004-T 0.0 Lung Cancer (OD04237-01) 15.5 Liver Tissue 6004-N 0.5 Lung Margin (OD04237-02) 12.2 Liver Cancer 6005-T 3.3 Ocular Mel Met to Liver (OD4310) 0.3 Liver Tissue 6005-N 0.0 (ODO43 10)00 Liver Margin (OD04310) 0.0 Normal Bladder 52.5 Melanoma Mets to Lung 0.1 Bladder Cancer 1023 20.9 (OD04321) . Bladder Cancer 1023 20.9 Lung Margin (OD04321) 0.6 Bladder Cancer A302173 19.1 Normal Kidney 0.8 Bladder Cancer (OD04718-01) 5.2 Kidney Ca, Nuclear grade 2 1.1 Bladder Normal Adjacent 34.9 (OD04338) (ODO4718-03) . . .. 3. Kidney Margin (OD04338) 3.4 Normal Ovary 0.6 Kidney Ca Nuclear grade 1/2 Cancer 0.1 Ovarian Cancer 064008 71.2 (OD04339) Kidney Margin (OD04339) 1.3 Ovarian Cancer (OD04768-07) 0.6 Kidney Ca, Clear cell type Margin 19 (OD04340) 0.3 Ovary Margin (OD04768-08) 19.2 Kidney Margin (OD04340) 2.5 Normal Stomach 0.3 Kidney Ca, Nuclear grade 3 Kidney C2.9 Gastric Cancer 9060358 4.0 (OD04348) Kidney Margin (OD04348) 0.7 Stomach Margin 9060359 1.0 Kidney Cancer (OD04622-01) 3.7 Gastric Cancer 9060395 4.1 Kidney Margin (OD04622-03) 0.2 Stomach Margin 9060394 2.5 Kidney Cancer (OD04450-01) 0.0 Gastric Cancer 9060397 184.1 Kidney Margin (OD04450-03) 2.5 Stomach Margin 9060396 0.9 Kidney Cancer 8120607 16.8 Gastric Cancer 064005 11.1 Table BN. Panel 3D Rel. Rel. Ex.(%) Exp.(%) Tissue Name Ag2362, Tissue Name Ag2362, Run Run 168032574 168032574 Daoy- Medulloblastoma 0.0 Ca Ski- Cervical epidermoid 0.0 Do-Mdlolsoa00.carcinoma (metastasis) TE671- Medulloblastoma 8.0 ES-2- Ovarian clear cell carcinoma 0.0 D283 Med- Medulloblastoma 0.6 Ramos- Stimulated with 0.0 . PMA/ionomycin 6h __ 279 WO 03/050245 PCT/US02/38594 PFSK-1- Primitive Ramos- Stimulated with 0.0 0).6 Neuroectodermal PMA/ionomycin 14h XF-498- CNS 0.0 MEG-01- Chronic myelogenous 0).0 leukemia (megokaryoblast) SNB-78- Glioma 2.2 Raji- Burkitt's lymphoma 0.0 SF-268- Glioblastoma 0.0 Daudi- Burkitt's lymphoma 0.0 T98G- Glioblastoma 0.0 U266- B-cell plasmacytoma 0.7 SK-N-SH- Neuroblastoma 26 CA46-Burkittslyphoma 0.0 (metastasis) 12.6 CA46- Burkitt's lymphoma 0.0 SF-295- Glioblastoma 0.0 RL- non-Hodgkin's B-cell 0.0 lymphoma Cerebellum 31.6 JM1 - pre-B-cell lymphoma 0.0 Cerebellum 100.0 Jurkat- T cell leukemia 0.0 NCI-H292- Mucoepidermoid TF 0.0 lungcarcnoma0.0 TF- 1- Erythroleukemia 0.0 lung carcinoma DMS-l14- Small cell lung 57.0 HUT 78- T-cell lymphoma 0.0 cancer DMS-79- Small cell lung cancer 29.7 U937- Histiocytic lymphoma 0.0 NCI-H146- Small cell lung 6.7 KU-812- Myelogenous leukemia 0.7 cancer NCI-H526- Small cell lung 0.0 769-P- Clear cell renal carcinoma 0.0 cancer NCI-N417- Small cell lung 0.0 Caki-2- Clear cell renal carcinoma 0.0 cancer NCI-H82- Small cell lung cancer 0.0 SW 839- Clear cell renal carcinoma 0.0 NCI-H157- Squamous cell lung NCI-57- Squamous cell lung 0.0 Rhabdoid kidney tumor 2.3 cancer (metastasis) NCI-H 1155- Large cell lung 0.5 Hs766T- Pancreatic carcinoma (LN 0.6 cancer metastasis) NCI-H1299- Large cell lung 0.7 CAPAN-1- Pancreatic 0.0 cancer adenocarcinoma (liver metastasis) NCI-H727- Lung carcinoid 85.9 SU86.86- Pancreatic carcinoma 1.4 (liver metastasis) NCI-UMC-11- Lung carcinoid 0.0 BxPC-3- Pancreatic 2.7 adenocarcinoma LX-- cSmall ll lung cacer 11.5 HPAC- Pancreatic adenocarcinoma 0.0 Colo-205- Colon cancer 0.0 MIA PaCa-2- Pancreatic carcinoma 0.0 ~CFPAC-1- Pancreatic ductal KM12- Colon cancer 0.0 CFPAC-- Pancreatic du0tal .0 adenocarcinoma KM20L2- Colon cancer 0.0 PANC-1- Pancreatic epithelioid 6.2 ductal carcinoma NCI-H716- Colon cancer 9

.

5 T24- Bladder carcinma (transitional 0.0 .W C o ao ... . 5. cell) SW-48- Colon adenocarcinoma 0.0 5637- Bladder carcinoma 0.0 SW1116- Colon adenocarcinoma 0.0 HT-1197- Bladder carcinoma 0.0 UM-UC-3- Bladder carcinma LS 174T- Colon adenocarcinoma 0.0 UM-UC-3- Bladder carinma (transitional cell) 280 WO 03/050245 PCT/USO2/38594 SW-948- Colon adenocarcinoma 0.0 A204- Rhabdomyosarcoma 2.4 SW-480- Colon adenocarcinoma 0.0 HT-1080- Fibrosarcoma 0.0 NCI-SNU-5- Gastric carcinoma 1.4 MG-63- Osteosarcoma 14.1 KATO III- Gastric carcinoma 0.0 SK-LMS-1- Leiomyosarcoma 0.0 ___ -__ ast___armom _(vulva) NCI-SNU-16- Gastric carcinoma 0.0 SJRH30- Rhabdomyosarcoma (met 0.0 to bone marrow) .. .. NCI-SNU-1- Gastric carcinoma 0.0 A431- Epidermoid carcinoma 0.0 RF-1- Gastric adenocarcinoma 0.0 WM266-4- Melanoma 0.5 RF-48- Gastric adenocarcinoma 4.5 DU 145- Prostate carcinoma (brain 0.0 RF-48Gasticadnocrinom 4.5metastasis) MKN-45- Gastric carcinoma 0.0 MDA-MB-468- Breast 0.0 adenocarcinoma NCI-N87- Gastric carcinoma 0.0 SCC-4- Squamous cell carcinoma of 0.0 _ _ _ _ _ _ Ltongue OVCAR-5- Ovarian carcinoma 0.0 SCC-9- Squamous cell carcinoma o 0.0 ........ . .. . ...... . . . .. .... to n g u e RL95-2- Uterine carcinoma 0.0 SCC-15- Squamous cell carcinoma 0.0 of tongue HelaS3- Cervical 1.4 CAL 27- Squamous cell carcinoma 0.0 adenocarcinoma of tongue Table BO. Panel 4.1D Rel. Rel. Rel. Rel. ReL Rel. Exp.(%) Exp.(%) Exp.(%) Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag2362, Ag5922, Ag6846, Tissue Name Ag2362, Ag5922, Ag6846, Run Run Run Run Run Run 1698382 2475799 2790291 16983820 24757994 27902912 00 44 21 0 4 1 Secondary Thl act 0.0 0.0 0.0 HUVEC.9 0.0 0.0 F-- IL-1beta HUVEC IFN Secondary Th2 act 0.0 0.0 .0 I 0.0 0.0 0.0 gamma HUVEC TNF Secondary Trl act 0.0 0.0 0.0 alpha + IFN 0.0 0.0 0.0 ganmma Secondary ThI rest 0.0 0.0 0.0 HUVECTNF 0.0 0.0 0.0 alpha + IL4 Secondary Th2 rest 0.0 0.0 0.0 HUVEC IL-I1 0.0 0.0 0.0 Lung Secondary Trl rest 0.0 0.0 0.0 Microvascular 0.0 0.0 1.4 EC none Lung Primary Thl act 0.0 0.0 0.0 Microvascular 0.0 0.0 0.0 EC TNFalpha + IL-lbeta Primary Th2 act 0.0 0.0 0.0 Microvascular 00 . 0.0 Pr.mary....act..0 0.0 {0* Dermal EC none 281 WO 03/050245 PCT/US02/38594 Microsvasular Dermal EC Primary Trl act 0.0 0.0 0.0 DeTNFrmal Epha+ 0.0 0.0 0.0 0 ~ TNFalpha + IL-1beta Bronchial epithelium0.00 00 Primary Thl rest 00 00 0.0 epitheum 0.0 0.0 0.0 TNFalpha + ILIbeta Primary Th2 rest 0.0 0.0 0.0 Small airway 0.0 0.0 1.4 epithehium none Small airway epithelium Primary Trl rest 0.0 0.0 0.0 1 Ih + 0.0 0.0 0.0 Primary'TNFalpha + . IL-Ibeta CD45RA CD4 3.8 0.0 4.0 Coronery artery 0.0 0 .0 0.0 lymphocyte act SMC rest CD45RO CD4 Coronery artery pc yt c 0.0 0.0 0.0 SMC TNFalpha 0.4 0.0 0.0 lymphocyte act + IL-lbeta CD8 lymphocyte 0.0 0.0 0.0 Astrocytes rest 8.6 0.0 4.1 act Secndry...Astrocytes Secondary CD8 0.0 0.0 0.0 KU-812 0.0 0.0 0.0 0.0 ____10.0 0.0 T~~h.+76 2. lymphocyte act __ (Basophil) rest KU-812 CD4 lymphocyte 0.0 0.0 0.0 (Basophil) 0.0 0.0 0.0 none none PMA/ionomycin 2ry CCD 1106 Thl/Th2/Trl_anti- 0.0 0.0 0.0 (Keratinocytes) 0.0 0.0 0.0 CD95 CHII __ none CCD1106 LAK cells rest 0.6 0.0 0.0 (Keratinocytes) 0.5 0.0 0.0 TNFalpha + IL-1beta LAK cells IL-2 0.0 10.0 0.0 Liver cirrhosis ]6.2 0.0 2.4 cels . 0.0 0.0 0o.o NCI-H292 none 0.4 0.0 0.0 IL-2+IL-12__ LAK cells 0. 00 0.0 0.0 0.0 NCI-H292 IL-4 .. 0.0 0.0 0.0 IL-2+IFN gamma LAK cells IL-2+ 0.0 0.0 0.0 NCI-H292 IL-9 0.0 0.0 0.0 IL-18 LAK cells A c i 0.0 0.0 0.0 NCI-H292 IL-13 0.9 0.0 0.0 PMAionomycm. NK Cells IL-2 rest 0.4 0.0 0.0 NCI

-

H292 IFN 0.

0 0.0 0.0 E____ -gamma SWay MLR o0.0 0.0 0.0 HPAEC none o0.0 0.0 da282 282 WO 03/050245 PCT/USO2/38594 Two Way MLR 5 0 00 HPAEC TNF 0.0 .0.0 0.0 0.0 0.0 0.0 day alpha + IL-1 beta 0 ___ Two Way MLR 7 00 0.0 0.0 Lung fibroblast 0. 00 1. 0.0 0.0 0.0 day none Lung fibroblast PBMC rest 0.0 0.0 0.0 TNF alpha + 1.2 0.0 2.4 IL-1 beta PBMC PWM 0.

4 0.0 0.0 Lung fibroblast 0.8 0.0 0.0 IL-4 __ _ __ _ _ __ _ _ __1 ung fbroblast .................... .... PBMC PHA-L 0.0 0.0 0.0 Lung fibroblast 0.5 0.0 0.0 IL-9 Ramos (B cell) 0.5 0.0 0.0 Lung fibroblast 0.6 2.8 0.0 none IL-13 Ramos (B cell) . 0.0 0.0 Lung fibroblast 0.0 tonmyin 0.0 0"0 0.0 FNgma 0.5 0.0 0.0 ionomycin IFN gamma Dermal B lymphocytes Dermal lyphyes 0.0 0.0 0.0 fibroblast 52.1 100.0 80.7 CCD1070 rest Dermal B lymphocytes fibroblast CD40L and IL-4 00 0.0 0.0 CCD1070 TNF 14.6 14.5 20.4 alpha Dermal EOL-1 dbcAMP 0.6 0.0 0.0 fibroblast 26.2 25.3 27.5 CCD1070 IL-1I beta EOL-1 dbcAMP Dermal PMA/ionoycin 0.0 0.0 0.0 fibroblast IFN 85.3 69.3 100.0 PMA/ionomycmngma________ ___ gamma Dendritic cells 0.0 0.0 0.0 Dermal 100.0 87.7 92.0 none fibroblast IL-4 Dendritic cells LPS 0.0 0.0 0.0 Dermal 53.6 23.5 30.4 Fibroblasts rest Dendritic cells 0.4 0.0 0.0 N eutr o phi ls 0.0 0.0 0.0 anti-CD40 TNFa+LP S Monocytes rest 0.0 0.0 0.0 Neutrophils rest 0.1 0.0 0.0 Monocytes LPS 0.0 0.0 0.0 Colon 0.5 0.0 0.0 Macrophages rest 0.0 0.0 0.0 Lung 50.0 4.9 0.0 Macrophages LPS 0.4 0.0 0.0 Thymus 0.0 0.0 0.0 HUVEC none 0.0 0.0 0.0 Kidney 1.6 2.0 0.0 HUVEC starved 0.0 0.0 0.0 283 WO 03/050245 PCT/US02/38594 Table BP. Panel 4D Rel. Rel. xp.(%) Exp.(%) Tissue Name Ag2362, Tissue Name Ag2362, Run Run 164155977 164155977 Secondary Thil act 0.0 HUVEC IL-Ibeta 0.0 Secondary Th2 act 0.0 HUVEC gama 00 Secondary Trl act 0.0 HUVEC TNF alpha + IFN gamma 0.0 Secondary Thl rest 0.0 IUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 0.0 C IL-11 0 Secondary Trl rest 0.0 Lung Microvascular EC none 0.0 Primary Thl act 0.0 Lung Microvascular EC TNFalpha 0.0 + IL-lbeta Primary Th2 act 0.0 Microvascular Dermal EC none 0.9 Primary Trl act 0.3 Microsvasular Dermal EC Primary T act 0 TNFalpha + IL-lbeta 0.0 Primary Thl rest 0.0 Bronchial epithelium TNFalpha + 0.0 ILlbeta Primary T rest0.5 Small airway epithelium none 0.0 Primary Trl rest 0.0 Small airway epithelium TNFalpha 0.8 + IL-lbeta CD45RA CD4 lymphocyte act 4.8 Coronery artery SMC rest 0.0 CD45RO CD4 lymphocyte act 0.1 Coronery artery SMC TNFalpha + 0.0 IL-1 beta CD8 lymphocyte act 0.1 Astrocytes rest 11 Secondary CD8 lymphocyte rest 0.0 Astrocytes TNFalpha + IL-lbeta 30.1 Secondary CD8 lymphocyte act 0.0 KU-812 (Basophil) rest0.0 KU81T(asophil) rs CD4 lymphocyte none 0.0 KU-812 (Basophil) 0.0 r PMA/ionomycin ry CHlt iTrlanti-C95 0.0 CCD1106 (Keratinocytes) none 0.2 LAK cells rest 0.0 CCD 1106 (Keratinocytes) 0.0 TNFalpha + IL-1beta LAK cells IL-2 0.0 Liver cirrhosis 3.3 LAK cells IL-2+IL-12 0.0 Lupus kidney 26.4 LAK cl L-2+IFN gamma 0o.0 NCI-H292 none 0.0 LAK cells IL-2+ IL-18 0.0 NCI-H292 IL-4 10.0 LA 1 ce lsPMA/ionomycin 0.0 NCI-H292 IL-9 0.0 NK Cells IL-2 rest 0.0 NCI-H292 IL-13 0.0 Two Way MLR 3 day 0.0 NCIF292 IFN gamma 0.0 Two Way MLR 5 day 0.0 HPAEC none 0.0 Two Way MLR 7 day 0.0 HPAEC TNF alpha + IL-I beta 0.0 PBMC rest 0.0 Lung fibroblast none 0.4 PBMC PWVM 0.0 Lung fibroblast TNF alpha + IL-1 1.7 284beta 284 WO 03/050245 PCT/USO2/38594 PBMC PHA-L 0.0 Lung fibroblast IL-4 0.8 Ramos (B cell) none 0.0 Lung fibroblast IL-9 1.0 Ramos (B cell) ionomycin 0.0 Lung fibroblast IL-13 1.2 B lymphocytes PWM 1.2 Lung fibroblast IFN gamma 0.1 B lymphocytes CD40L and IL-4 0.0 Dermal fibroblast CCD1070 rest 94.6 ........... EOL-1 dbcAMP 03 IDermal fibroblast CCD1070 TNF 25.2 EOL-1 dbcAMP 0.3 25.2.--alh alpha EOL-1 dbcAMP 0.4 Dermal fibroblast CCD1070 IL- 21.6 PMA/ionomycin beta 2. Dendritic cells none 0.0 Dermal fibroblast IFN gamma 76.3 Dendritic cells LPS 0.0 Dermal fibroblast IL-4 100.0 Dendritic cells anti-CD40 0.0 IBD Colitis 2 0.0 Monocytes rest 0.0 IBD Crohn's 1.8 Monocytes LPS 0.0 Colon 2.6 Macrophages rest 0.0 Lung 52.5 Macrophages LPS 0.0 Thymus 0.9 HUVEC none 0.0 Kidney 0.9 [HUVEC starved 0.0................. Table BQ. Panel 5D .. _Rl Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag262, Tissue Name Ag2362, Run Run 172171201 172171201 97457 Patient-02goadipose 0.3 94709 Donor 2 AM - A adipose 17.8 97476 Patient-07sk skeletal 8.8 94710 Donor 2 AM - Badipose 10.6 muscl 94710_Donor 2 M-B adipose 10.6 muscle 97477_Patient-07ut uterus 0.1 94711 Donor 2 AM - C adipose 7.9 97478 Patient-07plplacenta 0.1 94712_Donor 2 AD - A adipose 52.5 97481 _Patient-08skskeletal 11.0 94713 Donor 2 AD - Badipose 73.2 muscle 97482 Patient-08ut uterus 0.7 94714_Donor 2 AD - C adipose 61.1 94742 Donor 3 U - AMesenchymal 97483 Patient-08pl placenta 0.1 Stem Cells 3.5 97486_Patient-09skskeletal 2.2 94743 Donor 3 U - BMesenchymal4.7 muscle Stem Cells 97487 Patient-09ututerus 0.2 94730 Donor 3 AM - A adipose 28.5 j97488_Patient-09plplacenta 0.2 94731 Donor 3 AM - B adipose 18.9 97492 Patient-10ut uterus 0.6 94732 Donor 3 AM - Cadipose 19.5 97493 Patient-10plplacenta 0.1 -94733 Donor 3 AD - Aadipose 100.0 97495 Patient-1lgoadipose 0.0 94734_Donor 3 AD - B adipose 69.3 97496_Patient-1 lskskeletal 0.1 94735 Donor 3 AD - Cadipose 82.4 muscle 97497 Patient-11 ut uterus 0.3 77138 LiverHepG2untreated 2.6 285 WO 03/050245 PCT/USO2/38594 97498 Patient-1 lplplacenta . 73556 Heart Cardiac stromal cells . -_ ..... _ ple 0, primary) 97500 Patient-12go_adipose 0.1 81735 Small Intestine 0.3 97501 Patient-12sk skeletal 0.2 72409 Kidney Proximal Convoluted muscle Tubule 0.0 97502 Patient-12ut uterus 0.2 82685 Small intestine Duodenum 0.0 97503 Patient-12pllacenta 0.1 '90650_Adrenal Adrenocortical .0 adenoma 94721 Donor 2 U A Mesenchymal Stem Cells 4.7 72410 Kidney HRCE .0 94722_Donor 2 U - 7411Kidn B Mesenchymal Stem Cells 3.6 7241 -KidneyHRE.0 94723 Donor 2 U - 73139 Uterus Uterine smooth C Mesenchymal Stem Cells muscle cells0.0 AI.05 chondrosarcoma Summary: Ag2362 Highest expression of this gene is detected in untreated chondrosarcoma cell line (SW1353) grown in complete media (CT=25.7). High expression of this gene is also detected in untreated serum starved cells. Interestingly, expression of this gene appears to be somewhat down regulated upon IL-1 5 treatment, a potent activator of pro-inflammatory cytokines and matrix metalloproteinases which participate in the destruction of cartilage observed in Osteoarthritis (OA). Modulation of the expression of this transcript in chondrocytes by either small molecules or antisense might be important for preventing the degeneration of cartilage observed in OA. AI comprehensive panel_vl.0 Summary: Ag2362 Highest expression of the 10 CG105716-01 gene is detected in cartilage from osteoarthritis patient (CT=19). In addition, high expression of this gene is also seen in synovium and bone samples from the osteoarthritis patient. Furthermore, low but significant expression of this gene is also detected in synovium, bone and cartilage samples of rheumatoid arthritis patients. The CG105716-01 gene codes for cartilage oligomeric matrix protein (COMP). COMP is a 15 noncollagenous extracellular matrix (ECM) protein which consists of five identical glycoprotein subunits, each with EGF-like and calcium-binding (thrombospondin-like) domains. COMP has been implicated in inflammatory diseases including osteochondrodysplasias and arthritis (Neidhart et al., 1997, Br J Rheumatol 36(11):1151-60, PMID: 9402858; Baitner et al, 2000, J Pediatr Orthop 20(5):594-605, 20 PMID: 11008738; Clark et al., 1999, Arthritis Rheum 1999 Nov;42(11):2356-64, PMID: 10555031). Therefore, therapeutic modulation of this gene product through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of inflammatory diseases such as rheumatoid and osteoarthritis, and osteochondrodysplasia. 286 WO 03/050245 PCT/USO2/38594 Generalscreening_panel_v1.5 Summary: Ag2362/Ag5922/Ag5924/Ag5928/Ag5936 Multiple experiments with different probe-primer sets are in good agreement. Highest expression of this gene is detected in melanoma sample (CTs=24-30). Thus, expression of this gene can be used to 5 distinguish this sample from other samples in this panel. In addition, significant expression of this gene is seen in colon cancer tissue, a colon cancer, lung cancer, liver cancer, and CNS cancer cell line. This gene codes for cartilage oligomeric matrix protein (COMP). Cartilage oligomeric matrix protein (COMP) is a noncollagenous extracellular matrix (ECM) protein which consists of five identical glycoprotein subunits, each with EGF-like 10 and calcium-binding (thrombospondin-like) domains. COMP contains an RGD sequence. The RGD domain in other proteins has been shown to affect cell adhesion, migration, survival and proliferation. Mutations of COMP can cause the osteochondrodysplasias pseudochondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) (Kleerekoper et al., 2002, J Biol Chem 15 2002 Jan 8; [epub ahead of print], PMID: 11782471). Based on this profile, COMP may play a role in tumor cell growth and survival based upon the cells ability to interact with the extracellular matrix. Thus, therapeutic targeting with a human monoclonal antibody might block the interaction of cancer cells, or supporting stromal elements, with extracellular matrix and thus promote cell death rather than cell survival especially in these cancers. 20 Additionally, this gene is expressed in two melanoma cell lines that mimic some of characteristics of activated tumor endothelial cells. Hence, antibody directed against this gene may affect endothelial growth and survival in the tumor and prevent tumor growth. In addition, recently COMP has also been implicated in vascular calcification and fibrosis especially associated with with advanced complicated atherosclerosis (Canfield et 25 al., 2002, J Pathol 196(2):228-34, PMID: 11793375). Therefore, therapeutic modulation of this gene could also be beneficial in the treatement of vascular calcification and fibrosis. Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adipose, thyroid, skeletal muscle, heart, and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may 30 prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. General_screening_panel_vl.6 Summary: Ag6846 Highest expression of this gene is detected in melanoma sample (CT=26). The expression profile seen in this panel is 287 WO 03/050245 PCT/USO2/38594 in agreement with panel 1.5. Please see panel 1.5 for further discussion on the utility of this gene. IHASS Panel vl.0 Summary: Ag2362 The expression of this gene appears to be highest in astrocytes (Ct-28.95). There is a slight induction in expression of this gene when 5 LnCAP cells are serum-starved and subjected to a reduced oxygen concentration and a decreased pH. These conditions resemble those typically found in tumors and suggest that in the tumors from which LnCAp cells are derived, expression of this gene may be regulated by these conditions. Panel 1.3D Summary: Ag2362 Two experiments with same primer and probe set 10 are in excellent agreement, with highest expression of the CG105716-01 gene in colon cancer ODO3866 sample (CTs=29). High expression of this gene are also associated with melanoma, and a liver cancer cell line. In addition, moderate expression of this gene is also seen adipose, brain, bone marrow, skeletal muscle heart, placenta, lung, testis and prostate. Please see panel 1.4 for the utility of this gene. 15 Panel 2D Summary: Ag2362 The expression of this gene appears to be highest in a sample derived from a breast cancer(CT=27). In addition, there appears to be substantial expression in other samples derived from breast cancer, gastric cancer, ovarian cancer, bladder cancer, thyroid cancer, kidney cancer, lung cancer, prostate cancer, liver cancer and colon cancer. Therapeutic modulation of this gene, through the use of small molecule 20 drugs, protein therapeutics or antibodies could be of benefit in the treatment of breast, gastric, ovarian, bladder, thyroid, kidney, lung, prostate, liver or colon cancer. Panel 3D Summary: Ag2362 Highest expression of the CG105716-01 gene is detected in cerebellum (CT=27). Low to moderate expression of this gene is associated with small cell lung cancer, lung carcinoid, and osteosarcoma. Please see panel 1.4 for the 25 utility of this gene. Panel 4.1D Summary: Ag2362/Ag5922/Ag6846 Multiple experiment with different probe-primer sets are in good agreement. Highest expression of this gene is detected in resting, IL-4 and IFN-gamma treated dermal fibroblasts (CTs=29-33). Expression of this gene is in agreement with panel 4D, please see panel 4D for further 30 discussion on the utility of this gene. Panel 4D Summary: Ag2362 Highest expression of the CG105716-01 gene is detected in IL4 treated dermal fibroblast cells (CT=29.2). High expression of this gene is 288 WO 03/050245 PCT/USO2/38594 seen in all the dermal fibroblast samples (CTs=29-31). Thus expression of this gene can be used to distinguish the dermal fibroblast from other samples used in this panel. Furthermore, therapeutic modulation of this gene product could be beneficial in the treatment of skin disorders, including psoriasis. 5 In addition, low to moderate expression of this gene is also with lung and colon. Therefore therapeutic modulation of this gene could be useful in treatment of lung and colon related diseases such as lupus and glomerulonephritis, and inflammatory bowel diseases. Panel 5D Summary: Ag2362 Highest expression of the CG105716-01 gene is 10 detected in a adipose sample (CT=25). In addition, high expression of this gene is seen in other adipose samples, as well as skeletal muscle. Thus, expression of this gene could be used to distinguish this sample from other samples in this panel. C. CG153910-02: Secreted protein CGI-100 precursor-like Protein. Expression of gene CG153910-02 was assessed using the primer-probe sets 15 Ag2642, Ag2849 and Ag2811, described in Tables CA, CB and CC. Results of the RTQ-PCR runs are shown in Tables CD, CE, CF, CG and CH. Table CA. Probe Name Ag2642 Start SEQ ID Primers Length Position No Forward . 5'-cttctctttcggagggagtg-3' 20 491 176 Probe TET-5' -gccacctggagtttcttcagactcca 26 529 177 -3'-TAMRA Reverse 5' -ttcct" cttggactcccgt-3' 20 571 J178 Table CB. Probe Name Ag2849 - .... Start ISEQ ID riders Sequence L e n g t h Position No Forward 5'-cttctctttggag9gagtg-3' 20 491 179 TET-5 ' -gccacctggagtttcttcagactcca2 Probe26 529 1180 -3'-TAMRA Reverse 5' -ttcctctctggactcctcgt- 3 ' :2 1 181 20 Table CC. Probe Name Ag2811 ....... Start ]SEQ ED 1Primers [ ~ .ngth 4 1 [8 riders Position No Forward 5'-cttctctttcggagggagtg-3' 20 491 182 289 WO 03/050245 PCT/USO2/38594 Probe TET-5'-gccacctggagtttettcagactcca 2 2 8 jProbe 26 529 1183 -3'-TAMRA Reverse 5'-ttcctctctggactcctcgt-3' 20 571 184 Table CD. Panel 1.3D Rel. Rel. Exp.0 Exp.(%) Tissue Name Ag2642, Tissue Name Ag2642, Run Run 167615898 167615898 Liver adenocarcinoma _15.1 . Kidney (fetal) 72.2 Pancreas 4.8 Renal ca. 786-0 37.9 Pancreatic ca. CAPAN 2 21.2 IRenal ca. A498 24.7 Adrenal gland 7.5 ]Renal ca. RXF 393 35.4 Thyroid 7.3 Renal ca. ACHN 21.3 Salivary gland 3.4 Renal ca. UO-31 25.2 Pituitary gland 8.4 Renal ca. TK-10 52.1 Brain (fetal) 9.0 Liver 19.8 Brain (whole) 7.8 Liver (fetal) ... . 12.1 Brain (amygdala) 5.8 Liver ca. (hepatoblast) HepG2 41.5 Brain (cerebellum) 13.3 Lung 6.1 Brain (hippocampus) 6.5 Lung (fetal) 10.6 Brain (substantia nigra) 11.9 Lung ca. (small cell) LX-1 21.8 Brain (thalamus) 7.2 Lung ca. (small cell) NCI-H69 13.0 Cerebral Cortex 110.1 Lung ca. (s.cell var.) SHP-77 84.7 Spinal cord 14.4 .Lung ca. (large cell)NCI-H460 3.3 glio/aslro U87-MG 20.9 Lung ca. (non-sm. cell) A549 42.6 glo/astro U- 18-MG 40.3 Lung ca. (non-s.cell) NCI-H23 14.4 astrocytoma SW1 783 50.3 Lung ca. (non-s.cell) HOP-62 15.3 neuro*; met SK-N-AS 17.3 Lung ca. (non-s.cl) NCI-H522 30.4 astrocytoma SF-539 26.1 Lung ca. (squam.) SW 900 27.9 astrocytoma SNB-75 36.3 Lung ca. (squamr.) NCI-H596 20.6 glioma SNB-19 23.0 Mammary gland 6.8 glioma U251 57.0 Breast ca.* (pl.ef) MCF-7 18.8 glioma SF-295 _125.9 Breast ca.* (pl.ef) MDA-MB-231 31.4 Heart (fetal) 1.9 Breast ca.* (plef) T47D 52.9 Heart 7.9 Breast ca. BT-549 29.5 ..... Skeletal muscle (fetal) 3.2 Breast ca. MDA-N 9.5 Skeletal muscle 34.6 Ovary 4.6 Bone marrow 5.5 Ovarian ca. OVCAR-3 7. 1 Thymus 12.1 Ovarian ca. OVCAR-4 17.3 Spleen 7.0 Ovarian ca. OVCAR-5 100.0 Lymph node 12. ....... 1 Ovarian ca. OVCAR-8 20.2 Colorectal 10.8 Ovarian ca. IGROV-1 15.6 Stomach 4.1 Ovarian ca.* (ascites) SK-OV-3 34.4 290 WO 03/050245 PCT/USO2/38594 Small intestine 3.3 Uterus 6.2 Colon ca. SW480 12.7 Placenta 1.3 Colon ca.* SW620(SW480 met) 48.3 . Prostate 15.7 Colon ca. HT29 18.6 Prostate ca.* (bone met)PC-3 20.9 Colon ca. HCT-116 17.2 Testis 5.2 Colon ca. CaCo-2 33.2 Melanoma Hs688(A).T 5.4 Colon ca. tissue(ODO3866) 10.5 Melanoma* (met) Hs688(B).T 8.7 Colon ca. HCC-2998 25.0 Melanoma UACC-62 7.8 Gastric ca.* (liver met) NCI-N87 26.1 Melanoma M14 7.9 Bladder 20.7 Melanoma LOX RIMVI 14.7 Trachea 3.8 Melanoma* (met) SK-MEL-5 111.7 Kidney 23.2 Adipose 132.1 Table CE. Panel 2.2 Rel. Rel. Ex.(%) Exp.(%) Tissue Name Ag2642, Tissue Name Ag2642, Run Run 175135978 175135978 Normal Colon 18.2 Kidney Margin (OD04348) 100.0 Colon cancer (OD06064) 34.2 Kidney malignant cancer 22.8 (OD06204B) Colon Margin (OD06064) 24.8 Kidney normal adjacent tissue 36.9 (OD06204E) Colon cancer (OD06159) 4.9 Kidney Cancer (OD04450-01) 53.6 Colon Margin (OD06159) 12.9 Kidney Margin (OD04450-03) 19.8 Colon cancer (OD06297-04) 4.9 - Kidney Cancer 8120613 2.8 Colon Margin (OD06297-05) 20.0 Kidney Margin 8120614 11.0 CC Gr.2 ascend colon (ODO3921) 9.4 Kidney Cancer 9010320 5.8 CC Margin (ODO3921) 8.1 Kidney Margin 9010321 10.3 Colon cancer metastasis 9.7 Kidney Cancer 8120607 20.0 (OD06104) Lung Margin (OD06104) 15.6 Kidney Margin 8120608 9.3 Colon mets to lung (OD04451-01) 26.6 Normal Uterus 19.9 Lung Margin (OD04451-02) 31.6 Uterine Cancer 064011 7.9 Normal Prostate 10.4 Normal Thyroid 4.9 Prostate Cancer (OD04410) 4.9 Thyroid Cancer 064010 8.4 Prostate Margin (OD04410) 7.9 Thyroid Cancer A302152 426.2 Normal Ovary 4.4 Thyroid Margin A302153 9.8 Ovarian cancer (OD06283-03) 12.2 Normal Breast 19.9 Ovarian Margin (OD06283-07) 10.4 Breast Cancer (OD04566) 8.5 Ovarian Cancer 064008 4.4 Breast Cancer 1024 16.6 Ovarian cancer (OD06145) 11.6 Breast Cancer (OD04590-01) 42.9 Ovarian Margin (D06145) 13.8 Breast Cancer Mets Ovarian Margin (OD6145) 13.8 (OD04590-03) 19.8 291 WO 03/050245 PCT/US02/38594 Ovarian cancer (D06455-03) 8.4 Breast Cancer Metastasis Ovarian cancer (ODO6455-03) 8.4 (OD04655-05) 19.8 Ovarian Margin (OD06455-07) 5.6 Breast Cancer 064006 17.1 Normal Lung 16.8 Breast Cancer 9100266 5.3 Invasive poor diff. lung adeno 8.9 Breast Margin 9100265 4.5 (ODO4945-01 Lung Margin (ODO4945-03) 13.9 Breast Cancer A209073 7.7 Lung Malignant Cancer 10.2 Breast Margin A2090734 11.0 (O D 0 3126)........................ Lung Margin (OD03126) 7.5 Breast cancer (OD06083) 37.1 Lung Cancer (D05014A) 20.2 Breast cancer node metastasis 295 _Lung Cancer (OD05014A) 20.2_ (OD06083)29.5 Lun Margin (OD05014B) 19.5 Normal Liver 31.2 Lung cancer (OD06081) 8.7 Liver Cancer 1026 8.5 Lung Margin (OD06081) 14.0 Liver Cancer 1025 133.0 Lung Cancer (OD04237-01) 5.5 Liver Cancer 6004-T 125.3 Lung Margin (OD04237-02) 39.8 Liver Tissue 6004-N 17.0 Ocular Melanoma Metastasis 14.7 Liver Cancer 6005-T 21.6 Ocular Melanoma Margin (Liver) 20.9 Liver Tissue 6005-N 82.9 Melanoma Metastasis 11.4 Liver Cancer 064003 84.1 Melanoma Margin (Lung) 14.1 Normal Bladder 5.5 Normal Kidney 11.1 Bladder Cancer 1023 4.8 Kidney Ca, Nuclear grade 2 43.2 Bladder Cancer A302173 17.2 (OD04338) Kidney Margin (OD04338) 14.5 Normal Stomach 33.7 i(oD043 39) 1ula rae12 39.8 Gastric Cancer 9060397 12.4 Kidney Ca Nuclear grade 1/2 39.8 Gastn Cancer 9060397 2.4 Kidney Margin (OD04339) 29.3 Stomach Margin 9060396 10.8 Kidney Ca, Clear cell type KiOdney0 Ca,..Clear .. cell .. 20.3 !Gastric Cancer 9060395 14.8 (ODO4340) I Kidney Margin (OD04340) 26.4 Stomach Margin 9060394 21.2 Kidney Ca, Nuclear grade 3 10.4 c Cancer 064005 ______________ 10.4 iGastric Cancer 064005 10.8 (ODO4348) Table CF. Panel 4D Rel. Rel. Exp (%) Exp.(%) Tissue Name Ag2642, Tissue Name Ag2642, Run Run 165242421 165242421 Secondary Thl act 20.7 HUVEC IL-ibeta -- ,110.0 Secondary Th2 act 23.0 HUVEC IFN ganma _15.1 Secondary TrI act .21.6 _ HUVEC TNF alpha + IFN gamma 116.2 Secondary Thl rest 6.7 HUVEC TNF alpha + IL4 14.6 Secondary Th2 rest 9.9 HUVEC IL-1 1 8.9 Secondary Trl rest 11.6 Lung Microvascular EC none 14.5 292 WO 03/050245 PCT/USO2/38594 Primary Thl act 13.2 Lung Mirovascular EC TNFalpha 16.7 + IL-lbeta Primary Th2 act 12.8 Microvascular Dermal EC none 20.7 Primary Trl act 15.4 Microsvasular Dermal EC TNFalpha + IL-1beta 19.3 Primary Thl rest 30.8 Bronchial epithelium TNFalpha + . ji~ibeta16.5 ILlbeta Primary Th2 rest 17.6 Small airway epithelium none 7.2 Primary Trl rest 14.0 Small airway epithelium TNFalpha 2.8 + IL-lbeta , CD45RA CD4 lymphocyte act 9.9 Coronery artery SMC rest 17.3 CD45RO CD4 lymphocyte act 17.9 Coronery artery SMC TNFalpha + 11.3 IL-lbeta CD8 lymphocyte act 9.9 Astrocytes rest 10.2 Secondary CD8 lymphocyte rest .13.4 Astrocytes TNFalpha + IL-lbeta .1 Secondary CD8 lymphocyte act 9.2 KU-812 (Basophil) rest 13.7 CD4 lymphocyte none 6.7 KU-812 (Basophil) 50.3 .PMA ionomycin 2ryThlf/Th2/Trl anti-CD95 CH11 9

.

5 CCD1106 (Keratinocytes) none 9.5 HHD 10 Ktno cts LAK cells rest .2 .. . . 1 O6i..........s. 33 -- 1 ] ~t N ~ lp ta + IL-lbeta " LAK cells IL-2 22.8 Liver cirrhosis .5 LAKcells IL-2+IL- 12 1[22.1 Lupus kidney 4.4 LAK cells IL-2+IFN gamma 27.2 NCI-H292 none 14.9 LAK cells IL-2+ IL-i 8 .19.3 NCI-H292 IL-4 24.5 LAK cells PMA/ionomycin 27.9 NCI-H292 IL-9 12.4 NK Cells IL-2 rest 16.3 NCI-H292 IL-13 11.3 Two Way MLR 3 day 24.0 NCI-H292 IFN gamma 10.8 Two Way MLR 5 day 14.4 HPAEC none 11.2 Two Way MLR 7 day 10.7 HPAEC TNF alpha+ IL-1 beta 18.9 PBMC rest 9.5 ng fibroblast none 11.2 PBMC PWM 51.1 Lung fibroblast TNF alpha + IL-i 13.7 _ ... ... ........ .b eta 1 . PBMC PHA-L 20.7 Lung fibroblast IL-4 17.7 Ramos (B cell) none 25.9 Lung fibroblast IL-9 18.2 Ramos (B cell) ionomycin 100.0 Lung fibroblast IL-13 10.5 lymphocytes PWM 53.6 Lung fibroblast IFN gamma 21.9 B lymphocytes CD40L and IL4 23.5 Dermal fibroblast CCD 1070 rest 24.3 EOL- 1 dbcAMP 11.3 Dermal fibroblast CCD 1070 TNF -alpha 44.8 EOL-1 dbcAMP 15.3 Dermal fibroblast CCD1070 IL-I PMA/ionomycin beta 0.9 Dendritic cells none 33.0 Dermal fibroblast IFN gamma - 0.2 Dendritic cells LPS .21.3 Dermal fibroblast IL-4 19.6 Dendritic cells anti-CD40 30.1 IBD Colitis 2 1 293 WO 03/050245 PCT/USO2/38594 Monocytes rest 23.8 IBD Crohn's 11.8 Monocytes LPS 36.9 Colon 11.5 Macrophages rest 39.2 Lung 113.3 Ma crophages LPS 30.1 - Thymus 125.7 HUVEC none 15.3 Kidney 15.8 HUVEC starved 30.1 Table CG. Panel 5 Islet Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag2849 Tissue Name Ag2849, Run Run 247609778 247609778 97457 Patient-02go adipose 24.0 94709 Donor 2 AM -A adipose 14.7 97476_Patient-07skskeletal 8.8 94710_Donor 2 AM - Badipose 9.9 muscle 97477_ Patient-07ut uterus 4.3 94711_Donor 2 AM - C adipose 9.5 97478 Patient-07pl placenta 14.1 94712 Donor 2 AD - Aadipose 23.8 99167 Bayer Patient 1 25.0 94713 Donor 2 AD - B adipose 18.2 97482 Patient-08ut uterus 7.3 94714 Donor 2 AD - C_adipose 114.8 97483Patient-8plplacenta 1.7 94742 Donor 3 U - A Mesenchymal 6.9 97483 Patient-08plplaenta 11.7 Stem Cells - 6.9 97486_Patient-09sk skeletal 3.4 94743 Donor 3 U - BMesenchymal 20.7 muscle Stem Cells 97487 Patient-09ut uterus 7.2 194730 Donor 3 AM - A_adipose 29.5 97488 Patient-09pl_placenta 6.8 94731 Donor 3 AM - B adipose 12.5 97492 Patient-10ut uterus 9.5 94732 Donor 3 AM - C adipose 13.8 97493_Patient-10plplacenta 22.1 94733 Donor 3 AD - A_adipose 20.3 97495_Patient-11 go adipose 15.2 94734_Donor 3 AD - Badipose 7.9 .97496_Patient-I lsk skeletal 97496_Patient-1skskeletal 19.1 94735 Donor 3 AD - Cadipose 38.2 muscle 97497 Patient-1 lut uterus 17.2 77138 Liver HepG2untreated 100.0 97498Patient- lplplacenta 11.8 73556 Heart Cardiac stromal cells 16.2 97498_Patient-11lpl placenta 11.8 .piay -16.2 -- _ (primary) 97500_Patient-12go adipose 21.2 81735_Small Intestine 22.1 97501_Patient-12skskeletal 22.7 72409_Kidney Proximal Convoluted 8.0 muscle Tubule 97502 Patient-12ututerus 16.3 82685 Small intestine _Duodenum 5.1 90650 Adrenal Adrenocortical 97503_Patient-12pl_placenta 14.6 adenoma l-UHU il 17.3 adenoma.. 94721_Donor 2 U- 11.5 72410_Kidney HRCE 68.8 A Mesenchymal Stem Cells 94722-Donor 2 U - 5.9 72411 Kidney HRE 19.8 B Mesenchymal Stem Cells __ 94723 Donor 2 U - 99 73139 UterusUterine smooth C Mesenchymal Stem Cells muscle cells15 294 WO 03/050245 PCT/USO2/38594 .Table CH. general oncology screening panel v 2.4 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag2811, Tissue Nine Ag2811, Run Run 264980323 _ _264980323 Colon cancer 1 24.3 Bladder NAT 2 0.4 Colon NAT 1 12.3 Bladder NAT 3 0.6 Colon cancer 2 25.7 Bladder NAT 4 4.4 Colon NAT 2 16.6 Prostate adenocarcinoma 1 27.4 Colon cancer 3 48.3 Prostate adenocarcinoma 2 4.3 Colon NAT 3 21.2 Prostate adenocarcinoma 3 20.2 Colon malignant cancer 4 57.0 Prostate adenocarcinoma 4 16.3 Colon NAT 4 11.5 Prostate NAT 5 8.7 Lung cancer 1 16.7 Prostate adenocarcinoma 6 6.8 Lung NAT 1 1.8 Prostate adenocarcinoma 7 7.7 Lung cancer 2 49.3 Prostate adenocarcinoma 8 2.3 Lung NAT 2 2.6 Prostate adenocarcinoma 9 32.5 Squamous cell carcinoma 3 29.9 Prostate NAT 10 3.8 Lung NAT 3 2.4 Kidney cancer 1 41.2 Metastatic melanoma 1 21.9 Kidney NAT 1 11.3 Melanoma 2 2.8 Kidney cancer 2 100.0 Melanoma 3 2.4 _ Kidney NAT 2 30.1 Metastatic melanoma 4 56.6 Kidney cancer 3 135.4 iMetastatic melanoma 5 55.1 Kidney NAT 3 9.9 Bladder cancer 1 0.9 Kidney cancer 4 47.6 Bladder NAT 1 0.0 Kidney NAT 4 26.8 Bladder cancer 2 6.7 Panel 1.3D Summary: Ag2642 Highest expression of this gene is detected in ovarian cancer OVCAR-5 cell line (CT=31.8). Moderate to low levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, 5 liver, renal, breast, ovarian, prostate, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of pancreatic, gastric, colon, lung, liver, renal, breast, ovarian, prostate, melanoma and brain cancers. 10 Among tissues with metabolic or endocrine function, this gene is expressed at low levels in adipose and skeletal muscle. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. 295 WO 03/050245 PCT/USO2/38594 In addition, this gene is expressed at low levels in cerebellum, substantia nigra and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. 5 Panel 2.2 Summary: Ag2642 Highest expression of this gene is detected in kidney sample (CT=30.8). In addition, moderate to low levels of expression of this gene is also detected in normal and cancer samples derived from colon, lung, prostate, ovary, lung, liver, kidney, thyroid, breast bladder and stomach. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of colon, lung, prostate, 10 ovarian, liver, kidney, thyroid, breast, bladder and stomach cancers. Panel 4D Summary: Ag2642 Highest expression of this gene is detected in ionomycin treated Ramos B cells (CT=28.9). This gene is expressed at low to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, 15 macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. Therefore, modulation of the gene product with a functional therapeutic may lead to the 20 alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. Panel 5 Islet Summary: Ag2849 Highest expression of this gene is detected in 25 liver HepG2 cell line (CT=31.3). This gene shows a widespread moderate to low expression in this panel, especially adipose, skeletal muscle, placenta, cardiac stromal cells and small intestine from diabetic and non-diabetic patients. Therefore, therapeutic modulation of this gene may be useful in the treatment of diabetic and obesity. general oncology screening panelv_2.4 Summary: Ag2811 Highest expression 30 of this gene is detected in kidney cancer (CT=30.4). In addition, moderate expression of this gene is also seen in normal and cancer samples derived from colon, lung, metastatic melanoma, and prostate. Expression of this gene is consistently higher in cancer samples compared to adjacent normal tissue. Therefore, expression of this gene may be used as 296 WO 03/050245 PCT/USO2/38594 diagnostic marker to detect the presence of these cancers. In addition, therapeutic modulation of this gene or its protein product through the use of antibody or small molecule drug may be useful in the treatment of colon, lung, metastatic melanoma, and prostate cancers. 5 D. CG158564-01 and CG158564-02: Interferon induced transmembrane protein-like Protein. Expression of gene CG158564-01 and CGl158564-02 was assessed using the primer-probe set Ag5736, described in Table DA. Results of the RTQ-PCR runs are shown in Table DB. Please note that CG158564-02 represents a full-length physical clone of the 10 CG158564-01 gene, validating the prediction of the gene sequence. Table DA. Probe Name Ag5736 ... Start SEQ ID Primers Length Start SEQ ID ... ..... Position 1N o Forward 5'-tggtcttcactggacaccat-3 ' 20 23 185 TET-5'-aaccttctctcctatcaacagcggcc 26 58 186 Probe 26 58 1186 -3' -TAMRA Reverse 5' -ctcctccttgagcatctcatag-3I' 122 94 187 Table DB. General screening panel v1.5 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5736, issue Name Ag5736, Run Run 245385010 245385010 Adipose 0.2 Renal ca. TK-10 0.6 Melanoma* Hs688(A).T __ 0.0 Bladder 100.0 Melanoma* Hs688(B).T 0.0 Gastric ca. (liver met.) NCI-N87 0.0 Melanoma* M14 0.0 Gastric ca. KATO III 0.0 Melanoma* LOXIMVI 0.0 Colon ca. SW-948 0.0 Melanoma* SK-MEL-5 9.3 Colon ca. SW480 0.0 Squamous cell carcinoma SCC-4 .0.0 Colon ca.* (SW480 met) SW620 .0 Testis Pool 0.0 lColon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 14.2 Colonca. HCT-116 0.0 Prostate Pool 0.0 Colon ca. CaCo-2 1.2 Placenta 0.0 Colon cancer tissue 0.0 Uterus Pool 0.6 Colon ca. SW 116 0.0 Ovarian ca. OVCAR-3 0.1 Colon ca. Colo-205 0.0 Ovarian ca. SK-OV-3 29.5 Colon ca. SW-48 0.0 Ovarian ca. OVCAR-4 0.0 Colon Pool 0.0 Ovarian ca. OVCAR-5 0.0 Small Intestine Pool 0.0 297 WO 03/050245 PCT/USO2/38594 Ovarian ca. IGROV-1 4.1 Stomach Pool 0.0 Ovarian ca. OVCAR-8 0.0 Bone Marrow Pool 0.0 Ovary 0.0 Fetal Heart 1.5 Breast ca. MCF-7 0.0 Heart Pool 0.0 Breast ca. MDA-MB-231 0.0 Lymph Node Pool 1.0 Breast ca. BT 549 0.0 Fetal Skeletal Muscle 0.0 Breast ca. T47D 3.1 Skeletal Muscle Pool 0.0 Breast ca. MDA-N .3 Spleen Pool 0.0 Breast Pool 0.0 Thymus Pool 0.0 Trachea 0.0 CNS cancer (glio/astro) U87-MG 0.6 Lung 0.0 CNS cancer (glio/astro) U-118S-MG 0.1 Fetal Lung 3.6 CNS cancer (neuro;met) SK-N-AS 27.0 Lung ca. NCI-N417 1.5 CNS cancer (astro) SF-539 21.6 Lung ca. LX-1 6.1 CNS cancer (astro) SNB-75 0.0 Lung ca. NCI-H146 8.5 CNS cancer (glio) SNB-19 3.1 Lung ca. SHP-77 18.8 CNS cancer (glio) SF-295 0.0 Lung ca. A549 6.7 Brain (Amygdala) Pool 0.0 Lung ca. NCI-H526 4.0 Brain (cerebellum) 0.7 Lung ca. NCI-H23 0.9 Brain (fetal) 0.0 Lung ca. NCI-H460 0.0 Brain (Hippocampus) Pool 0.0 Lung ca. HOP-62 0.0 Cerebral Cortex Pool 0.0 Lung ca. NCI-H522 0.0 Brain (Substantia nigra) Pool 0.0 Liver 0.0 Brain (Thalamus) Pool 0.0 Fetal Liver 0.0 Brain (whole) 0.0 Liver ca. HepG2 9.3 Spinal Cord Pool 0.0 Kidney Pool 0.0 Adrenal Gland 0.0 Fetal Kidney 0.7 Pituitary gland Pool 0.0 Renal ca. 786-0 0.0 Salivary Gland 0.0 Renal ca. A498 10.0 Thyroid (female) 0.0 Renal ca. ACHN 41.2 Pancreatic ca. CAPAN2 0.0 Renal ca. UO-3 1 0.0 Pancreas Pool 0.0 Generalscreening_panel_vl.5 Summary: Ag5736 Highest expression of this gene is detected in bladder (CT=27). Therefore, expression of this gene may be used to distinguish bladder from other samples used in this panel. In addition, low expression of this gene is also detected in number of cancer cell 5 lines derived from melanoma, renal, liver, lung, breast, ovarian, colon, and prostate cancer. Therefore, expression of this gene may be used as diagnostic marker to detect presence of these cancers and therapeutic modulation of this gene may be useful in the treatment of these cancers. 298 WO 03/050245 PCT/USO2/38594 E. CG159093-01, CG159093-02 and CG159093-03: Type Ib membrane protein like Protein. Expression of gene CG159093-01, CG159093-02 and CG159093-03 was assessed using the primer-probe sets Ag5738, Ag6690 and Ag6714, described in Tables EA, EB and 5 EC. Results of the RTQ-PCR runs are shown in Tables ED, EE and EF. Please note that probe-primer set Ag5738 is specific for CG159093-01. Table EA. Probe Name Ag5738 Primer Seqenc Le. Start SEQID Primers Sequence Length Position No Forward 5' -tcgagtaaagcagcttgtcttc-3' 22 692 188 Probe TET-5' -acccaaagactttcccatcgtctcct 26 721 189 -3 ' -TAMRA Reverse 5'-cttctccttcatgtttctggaa -3 122755 .190 Table EB. Probe Name Ag6690 ....... ..... Start SEQ ID Primers Sequence Length Position No Forward 5'-acccttttcattccgatcaa-3' 20 497 191 Probe TET-5' -tgtcaccagatacag9ttttctctcg 26 523 192 1-3'-TAMRA ..... Reverse .. 5'-tcctttaccgtctccagagttt-3' .. 22 550 1193.I 10 Table EC. Probe Name Ag6714 Primers Sequence Start SEQ ID Primers Sequence Length Position No Forward 5'-acccttttcattccgatcaa-3' 20 497 194 Probe TET-5' -tgtcaccagatacaggtttt ctctcg 26 523 195 Probe -31'-TAMRA1252 19 Reverse 5 -ctcctttaccgtctcca9agtt-3' 22 551 196 Table ED. CNS neurodegeneration v1.0 Rel. Rel. Rel. Rel. Exp.(%) Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag6690, Ag6714, issue Name Ag6690, Ag6714, Run Run Run Run 276247142 276596842 276247142 276596842 AD 1 Hippo 117.4 13.5 Control (Path) 3 8.8 j6.2 Temporal Ctx 8 AD 2 Hippo 15.1 14.6 ]Temporal Ctx 4 32.8 35.1 AD 3 Hippo 18.2 8.3 lAD 1 Occipital Ctx 61.1 46.0 AD 4 Hippo 17.0 5.7 AD 2 Occipital Ctx ~__AD 4 Hippo 7.0 5.7" ](Missing) 0.0 0.0 299 WO 03/050245 PCT/USO2/38594 Hiplpo. 100.0 (a100.0 AD 3 Occipital Ctx 19.3 17.3 AD 6 Hippo t 62.9 58.2 oAD 4 Occipital Ctx 24.8 17.6 Control 2 Hippo 18.7 19.5 AD 5 Occipital Ctx 21.2 36.9 control 4 Hippo -9.2 8.7 AD 6 Occipital Ctx 26.1 24.0 Control (Path) 3 6.5 3.0 Control 3 Occipital 3.1 4.5 Hippo Ctx _ Control 2 Occipital490 40 AD 1 Temporal Ctx 37.1 32.3 Ctx 49.0 47.0 AD 2 Temporal Ctx 28.3 31.4 Control 3 Occipital 44.8 33.9 Ctx ' ~Control 4 Occipital8.58 AD 3 Temporal Ctx 21.9 17.6 Control 4 Occipital 8.7 5.8 Control (Path) 1 82.9 15. AD 4 Temporal Ctx 31.9 22.4 Occipitarl (Path) 1 82.9 65.5 ______________ _________ _________Occipital Clx _____ AD 5 Inf Temporal 51.4 58.6 Control (Path) 2 31.4 11.2 Ctx .4Occipital Ctx . . . AD 5 Sup Temporal 25.2 25.7 Control (Path) 3 2.6 3.3 Ctx Occipital Ctx AD 6 nf Temporal 22.5 70.7 Control (Path) 4 24.5 25.2 Ctx 2.0 Occipital Ctx AD 6 Sup Temporal 829 79.6 Control 1 Parietal 1 4

.

2 10.0 Ctx 82.9 79.6 Ctx Control 1 Temporal 6.4 10.0 Control 2 Parietal 51.1 44.4 Ctx Ctx Control 2 Temporal 22.8 18.7 Control 3 Parietal 24.1 12.2 Ctx .

Ctx Control 3 Temporal 27.7 275 Control (Path) 1 42.3 54.7 Ctx 7.7 . Parietal Ctx Control 3 Temporal 10.7 10.2 Control (Path) 2 3 1

.

9 29.7 Ctx Parietal Ctx Control (Path) 1 41.8 39.8 Control (Path) 3 5.6 6.3 Temporal Ctx P___ arietal Ctx Control (Path) 2 62.9 62.0 Control (Path) 4 35.8 299 Temporal Ctx Parietal Ctx Table EE. General screening panel v1.6 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag6690, issue Name Ag6690, Run Run 27725930.0 277259300 Adipose 2.9 Renal ca. TK-10 8.9 Melanoma* Hs688(A).T 2.2 _ Bladder 11.3 Melanoma* Hs688(B).T 2.1 _ Gastrc ca. (liver met.) NCI-N87 100.0 Melanoma* M14 06 G astric ca. KATO III 6.6 [Melanoma* LOXIMVI 10.5 Colon ca. SW-948 4.0 300 WO 03/050245 PCT/USO2/38594 Melanoma* SK-MEL-5 0.5 Colon ca. SW480 0.0 Squamous cell carcinoma SCC-4 1.1 Colon ca.* (SW480 met) SW620 5.0 Testis Pool 0.9 Colon ca. HT29 3.1 Prostate ca.* (bone met) PC-3 5.8 Colon ca. HCT-116 7.1 Prostate Pool 0.9 Colon ca. CaCo-2 6.7 Placenta 1.1 Colon cancer tissue 16.5 Uterus Pool 0.2 Colon ca. SW1116 0.5 Ovarian ca. OVCAR-3 1.9 Colon ca. Colo-205 9.6 Ovarian ca. SK-OV-3 4.7 Colon ca. SW-48 12.1 Ovarian ca. OVCAR-4 0.5 Colon Pool 3.0 Ovarian ca. OVCAR-5 28.3 Small Intestine Pool 1.5 Ovarian ca. IGROV-1 1.9 Stomach Pool 2.4 Ovarian ca. OVCAR-8 0.8 Bone Marrow Pool 0.1 Ovary 2.2 Fetal Heart 1.9 Breast ca. MCF-7 1.2 Heart Pool 0.8 Breast ca. MDA-MB-231 0.3 Lymph Node Pool 2.9 Breast ca. BT 549 6.0 Fetal Skeletal Muscle 1.0 Breast ca. T47D 2.5 Skeletal Muscle Pool 0.5 Breast ca. MDA-N 0.1 Spleen Pool 3.7 Breast Pool- 2.6 Thymus Pool 14.8 Trachea 3.6 CNS cancer (glio/astro) U87-MG 0.7 Lung 0.4 CNS cancer (glio/astro) U-118-MG 3.4 Fetal Lung 8.2 CNS cancer (neuro;met) SK-N-AS 2.6 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 1.8 Lung ca. LX-1 7.8 CNS cancer (astro) SNB-75 5.0 Lung ca. NCI-H11146 0.3 CNS cancer (glio) SNB-19 2.9 Lung ca. SHP-77 0.6 CNS cancer (glio) SF-295 20.9 Lung ca. A549 4.0 Brain (Amygdala) Pool 0.7 Lung ca. NCI-H526 0.1 Brain (cerebellum) 8.1 Lung ca. NCI-H23 .7.1 Brain (fetal) 5.3 Lung ca. NCI-H460 1.4 Brain (Hippocampus) Pool 0.7 L u n g ca .H O P -6 2 2 18 ...................................... & ; .;X .. .i ;.. ............... ...................... 1 " Lung ca. HOP-62 '28 Cerebral Cortex Pool 1.6 Lung ca. NCI-H522 4.2 Brain (Substantia nigra) Pool 1.2 Liver 0.4 Brain (Thalamus) Pool 1.5 Fetal Liver 5.0 Brain (whole) 12.2 Liver ca. HepG2 . _2.5 Spinal Cord Pool 1.4 Kidney Pool 2.8 Adrenal Gland 0.4 Fetal Kidney 12.9 Pituitary gland Pool 0.3 Renal ca. 786-0 1.9 Salivary Gland 0.7 Renal ca. A498 18.6 Thyroid (female) 0.3 Renal ca. ACHN 2.0 Pancreatic ca. CAPAN2 110.7 Renal ca. UO-31 !. 2.1 Pancreas Pool 7.3 301 WO 03/050245 PCT/US02/38594 Table EF. Panel 4.1D Rel. Rel. Exp.0 Exp.(%) Tissue Name Ag6690, Tissue Name Ag6690, Run Run 276043961 276043961 Secondary Thl act 57.0 HUVEC IL-Ibeta 6.8 Secondary Th2 act 75.8 HUVEC IFN gamma 7.4 Secondary Trl act 29.9 HUVEC TNF alpha + IFN gamma 1.5 Secondary Thl rest 24.3 HUVEC TNF alpha+ IL4 0.8 Secondary Th2 rest 28.9 .HUVEC IL-11 3--9 Secondary Trl rest 12.9 Lung Microvascular EC none 23.0 Primary Th act 6.4 Lung Microvascular EC TNFalpha 5.9 Primary Thl_ act 6.4 + IL-lbeta Primary Th2 act 39.0 Microvascular Dermal EC none 0.6 m Microsvasular Dermal EC Primary Trl act 28.9 TNFalpha + IL-lbeta 2.1 Primary rest 5.5 Bronchial epithelium TNFalpha + 5.1 Primary Th1 rest 5.5 ILlbeta Primary Th2 rest 9.0 _ Small airway epithelium none 3.3 Primary T rest 10.7 Small airway epithelium TNFalpha 12.8 Primary Trl rest 10.7 + IL-lbeta CD45RA CD4 lymphocyte act 22.8 Coronery artery SMC rest 5.6 CD45RO CD4 lymphocyte act 65.1 Coronery artery SMC TNFalpha + 8.8 CD45RO CD4 lymphocyte act 65.1 IL-lbeta 8.8 CD8 lymphocyte act 23.0 Astrocytes rest Secondary CD8 lymphocyte rest 9.6 Astrocytes TNFalpha + IL-lbeta 7.0 Secondary CD8 lymphocyte act 16.0 KU-812 (Basophil) rest 4.0 CD4 lymphocyte none 156 KU-812 (Basophil) 2.8 CD4 lymphocyte none 15.6 PMA/ionomycin 2 ry Thl/Th2/Trlanti-CD95 19.5 CCD1106 (Keratinocytes) none 10.2 CH11 LAK cells rest 11.0 CCD1 106 (Keratinocytes) 18.0 TNFalpha + IL-lbeta LAK cells IL-2 40.9 Liver cirrhosis 27.2 LAK cells IL-2+IL-12 4.2 NCI-H292 none 7.7 LAK cells IL-2+IFN gamma 28.1 NCI-H292 IL-4 6.2 LAK cells IL-2+ IL-18 12.8 NCI-H292 IL-9 10.7 LAK cells PMA/ionomycin 4.3 NCI-H292 IL-13 6.4 NK Cells IL-2 rest 92.7 NCI-H292 IFN gamma 9.5 Two Way MLR 3 day 58.6 HPAEC none 3.4 Two Way MLR 5 day 4.9 HPAEC TNF alpha + IL-1 beta 2.5 Two Way MLR 7 day 21.0 Lung fibroblast none _15.7 PBMC rest 1.4 Lung fibroblast TNF alpha + IL- 8.1 PBMC rest 1.4 b8.1 beta 302 WO 03/050245 PCT/USO2/38594 PBMC PWM 15.1 Lung fibroblast IL-4 2.8 PBMC PHA-L 23.7 . Lung fibroblast IL-9 6.3 Ramos (B cell) none 1.5 . Lung fibroblast IL-13 3.2 Ramos (B cell) ionomycin _, 7.3 Lung fibroblast IFN gamma 6.0 B lymphocytes PWM 13.4 Dermal fibroblast CCD1 O70 re st 8.1 Dermal fibroblast CCD1070 TNF 9. B lymphocytes CD40L and IL-4 100.0 Dealpha fibroblast CCD17 TNF 946 EOL-1 dbcAMP 8.7 Dermal fibroblast CCD1070 IL-1 5.7 EOL-1 dbcAMP 8.7 beta EOL-1 dbcAMP 5.8 Dermal fibroblast IFN gamma 1.7 PMA/ionomycin Dendritic cells none 6.7 Dermal fibroblast IL-4 5.4 Dendciritic cells LPS 2.9 Dermal Fibroblasts rest 2.3 Dendritic cells anti-CD40 1.2 Neutrophils TNFa+LPS 1.6 Monocytes rest 0.5 Neutrophils rest 17.2 Monocytes LPS 8.0 Colon 21.5 Macrophages rest 2.3 Lung 0.0 Macrophages LPS 0.0 Thiymus 54.7 UVEC .none 1.4 Kidney 6.9 HUVEC starved 6.6] . ... CNSneurodegenerationvl.0 Summary: Ag6690/Ag6714 Two experiments with same probe-primer sets are in good agreement. This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem 5 brains and those of non-demented controls in this experiment. Please see Panel 1.6 for a discussion of the potential utility of this gene in treatment of central nervous system disorders. General_screeningpanel_vl.6 Summary: Ag6690 Highest expression of this gene is detected in a gastric cancer NCI-N87 cell line (CT=27.4). High to moderate 10 expression of this gene is also seen in cancer cell lines derived from melanoma, pancreatic, brain, colon, renal, lung ovarian, breast, and prostate cancers. Therefore, therapeutic modulation of this gene may be useful in the treatment of these cancers. Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, fetal skeletal muscle, heart, fetal liver and the 15 gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. 303 WO 03/050245 PCT/USO2/38594 Interestingly, this gene is expressed at much higher levels in fetal (CTs=31) when compared to adult lung and liver (CTs=35). This observation suggests that expression of this gene can be used to distinguish fetal from adult lung and liver, respectively. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein 5 product may enhance lung and liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of lung and liver related diseases. In addition, this gene is expressed at low levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, 10 cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Panel 4.1D Summary: Ag6690 Highest expression of this gene is detected in 15 CD40L and IL-4 treated B lymphocytes (CT=31.9). In addition, moderate to low level of expression of this gene is also detected in thymus, TNF alpha activated dermal fibroblast, IL-2 treated resting NK cells, 2 way MLR, lung fibroblast, liver cirrhosis, activated keratinocytes, activated LAK cells, activated bronchial and small airway epithelium, lung microvascular endothelial cells, activated primary and secondary polarized T cells, naive 20 and memory T cells, PWM treated B cells, and activated lymphocytes. Therefore, therapeutic modulation of this gene product may reduce or eliminate the symptoms in patients with several types of autoimmune and inflammatory diseases, such as lupus erythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, or psoriasis. 25 F. CG159390-01: Thrombospondin type 1 domain containing protein-like Protein. Expression of gene CG159390-01 was assessed using the primer-probe set Ag5800, described in Table FA. Results of the RTQ-PCR runs are shown in Table FB. 304 WO 03/050245 PCT/US02/38594 Table FA. Probe Name Ag5800_ _ _ _ Primer Lent Start SEQ ID _______Primers _ Length Position No Forward 5' -actggaacgtgaccctgatC-3' 20 857 197 Probe TET-5' -agacacatccgcgtggaacacag-3 23 889 198 Probe ' ' 23 ~ 889 1198 '-TAMRA Reverse 15 -ccccatcagtgatcctagga-3' 120 932 19 5 Table FB. General screening panel v1....................... Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5800, issue Name Ag5800, Run Run 246267831 246267831 Adipose 0.0 Renal ca. TK-10 -1.4 Melanoma* Hs688(A).T 16.4 Bladder i1.1 Melanoma* Hs688(B).T ..... 41.2 JGastric ca. (liver met.) NCI-N87 1.1 Melanoma* M14 0.0 Gastric ca. KATO III 27.2 Melanoma* LOXIMVI 0.0 Colon ca. SW-948 2.7 Melanoma* SK-MEL-5 30.8 Colon ca. SW480 8.8 Squamous cell carcinoma SCC-4 12.8 Colon ca.* (SW480 met) SW620 _ - 19.5 Testis Pool 0.0 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 11.3 Prostate Pool 0.0 Colon ca. CaCo-2 35.6 Placenta 0.0 Colon cancer tissue 6.3 Uterus Pool 9.5 Colon ca. SW1116 0.8 Ovarian ca. OVCAR-3 6.1 Colon ca. Colo-205 3.7 Ovarian ca. SK-OV-3 14.4 Colon ca. SW-48 7.2 Ovarian ca. OVCAR-4 0.0 Colon Pool 1.0 Ovarian ca. OVCAR-5 39.5 Small Intestine Pool 1.1 Ovarian ca. IGROV-1 10.0 Stomach Pool __0 __.0 Ovarian ca. OVCAR-8 100.0 Bone Marrow Pool 4.3 Ovary 0.0 Fetal Heart 28.3 Breast ca. MCF-7 0.0 Heart Pool 0.8 Breast ca. MDA-MB-231 54.0 Lymph Node Pool 6.2 Breast ca. BT 549 0.0 Fetal Skeletal Muscle 3.8 Breast ca. T47D 2.3 Skeletal Muscle Pool 0.0 Breast ca. MDA-N 0.8 Spleen Pool 0.8 Breast Pool 0.0 Thymus Pool 0.0 Trachea 0.0 CNS cancer (glio/astro) U87-MG 0.0 Lung 0.0 CNS cancer (glio/astro) U-118-MG 65.1 Fetal Lung 0.0 CNS cancer (neuro;met) SK-N-AS 0.0 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 4.1 305 WO 03/050245 PCT/USO2/38594 Lung ca. LX-1 49.7 CNS cancer (astro) SNB-75 10.2 Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 0.0 Lung ca. SHP-77 0.0 CNS cancer (glio) SF-295 4.7 Lung ca. A549 0.0 Brain (Amygdala) Pool 0.9 Lung ca. NCI-H526 0.0 Brain (cerebellum) 5.3 Lung ca. NCI-H23 0.0 Brain (fetal) 0.0 Lung ca. NCI-H460 0.0 Brain (Hippocampus) Pool 0.0 Lung ca. HOP-62 12.3 Cerebral Cortex Pool 0.0 Lung ca. NCI-H522 23.5 Brain (Substantia nigra) Pool 0.0 Liver 0.0 Brain (Thalamus) Pool 0.7 Fetal Liver 0.0 Brain (whole) 2.7 Liver ca. HepG2 0.0 Spinal Cord Pool 0.7 Kidney Pool 20.7 Adrenal Gland 0.0 Fetal Kidney 0.0 Pituitary gland Pool 1.1 Renal ca. 786-0 2.2 Salivary Gland 0.0 Renal ca. A498 2.7 Thyroid (female) 1.0 Renal ca. ACHN 11.2 Pancreatic ca. CAPAN2 0.0 Renal ca. UO-31 7.6 Pancreas Pool 0.0 General screening_panel_vl.5 Summary: Ag5800 Highest expression of this gene is detected in a ovarian cancer OVCAR-8 cell line (CT=32). Moderate to low levels of expression of this gene is also seen in ovarian cancer OVCAR-5 cell line, melanoma Hs688(B).T and SK-MEL-5 cell lines, Breast cancer MDA-MB-231 cell line, lung cancer 5 LX-1 cell line, gastric cancer KATO III cell line, colon cancer CaCo-2 cell line, and brain cancer U-118-MG cell lines. Therefore, expression of this gene may be used as diagnostic marker to detect the presence of melanoma, ovarian, breast, lun, gastric, colon and brain cancers. In addition, therapeutic modulation of this gene or its protein product through the use of antibodies or small molecule drug may be useful in the treatment of these cancers. 10 Low expression of this gene is also seen in fetal heart. Interestingly, this gene is expressed at much higher levels in fetal (CT=34.6) when compared to adult heart (CT=39.7). This observation suggests that expression of this gene can be used to distinguish fetal from adult heart. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance heart growth or development in 15 the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of heart related diseases. G. CG159498-01: ST71 membrane protein-like Protein. 306 WO 03/050245 PCT/USO2/38594 Expression of gene CG159498-01 was assessed using the primer-probe sets Ag5546 and Ag8056, described in Tables GA and GB. Results of the RTQ-PCR runs are shown in Tables GC, GD and GE. Table GA. Probe Name Ag5546 F IStart ISEQ ID Primers Sequence Length Start SEQ ED Position No Forward 5'-tctctgatctgcctgtgctaac-3' 22 1700 200 Probe TET-5' -caacaaatatcttccattgttcagctg 28 1722 201 g-3 '-TAMRA R-everse~ ~ ~ ~ ~ ~ ~ ~~~~~~~~..... ...... 5-' tqgtgtt- ~''''gca-S - ................. -......... . -- 17 0 Reverse 5'-tttgatgtatttatggcagcaa-3 22 1778 202 5 Table GB. Probe Name Ag8056 Start SEQ ID Primers Length st IS Position No Forward 5'-cctttgaggctgtgtgagaa-3' 20 190 203 Probe T~TET-5'-aaaatacagtcacgctgccaaa-3J 23 ' A210 204 Probe ,23 210 204 Reverse j5'-ggtccctgtaagtgccacata-3' 21 1256 1205 10 Table GC. CNS neurodegeneration v.0 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5546, issue Name Ag5546, Run Run 247121694 247121694 AD 1 Hippo 11.3 Control (Path) 3 Temporal Ctx 8.1 AD 2 Hippo 9.5 Control (Path) 4 Temporal Ctx 26.4 AD 3 Hippo 1.8 AD 1 Occipital Ctx 14.8 AD 4 Hippo 6.0 AD 2 Occipital Ctx (Missing) 10.0 AD 5 hippo 62.4 AD 3 Occipital Ctx 5.1 AD 6 Hippo _39.5 AD 4 Occipital Ctx 14.1 Control 2 Hippo 11.9 AD 5 Occipital Ctx 16.0 Control4 Hippo 6.1 AD 6 Occipital Ctx 20.7 Control (Path) 3 Hippo 1.2 Control 1 Occipital Cx 0.3 AD 1 Temporal Ctx 6.4 Control 2 Occipital Ctx 50.3 AD 2 Temporal Ctx 0.0 Control 3 Occipital Ctx 17.8 AD 3 Temporal Ctx 7.6 Control 4 Occipital Ctx 6.0 AD 4Temppral C x 1 4

.

3 Control (Path) 1 Occipital Ctx 87.7 AD 5 Inf Temporal Ctx 100.0 Control (Path) 2 Occipital Ctx 6.3 AD5 SupTemporal Ctx 33.7 Control (Path) 3 Occipital Ctx 4.6 AD 6 Inf Temporal Ctx 62.0 Control (Path) 4 Occipital Ctx 5.5 AD 6 Sup Temporal Ctx 50.0 Control 1 Parietal Ctx 7.3 307 WO 03/050245 PCT/USO2/38594 Control 1 Temporal Ctx 4.6 Control 2 Parietal Ctx 125.2 Control 2 Temporal Ctx 41.2 Control 3 Parietal Ctx 116.0 Control 3 Temporal Ctx 2.1 Control (Path) 1 Parietal Ctx 53.2 Control4 Temporal Ctx 5.4 Control (Path) 2 Parietal Ctx 14.6 Control (Path) I Temporal Ctx 66.9 Control (Path)3 Parietal Ctx 4.3 Control (Path) 2 Temporal Ctx 122.5 Control (Path) 4 Parietal Ctx 23.0 Table GD. General screening panel v1.7 ... Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5546, issue Name Ag5546, Run Run 318350003 318350003 Adipose 23.5 Gastric ca. (liver met.) NCI-N87 J0.5 HUVEC 5.4 Stomach 10.2 Melanoma* Hs688(A).T 0.0 Colon ca. SW-948 1.3 Melanoma* Hs688(B).T 9.8 Colon ca. SW480 0.3 Melanoma (met) SK-MEL-5 2.5 Colon ca. (SW480 met) SW620 23.5 Testis 8.4 Colon ca. HT29 13.8 Prostate ca. (bone met) PC-3 0.3 Colon ca. HCT-116 26.4 Prostate ca. DU145 4.5 Colon cancer tissue 0.2 Prostate pool 2.4 Colon ca. SW 116 1.4 Uterus pool 1.8 Colon ca. Colo-205 2.3 Ovarian ca. OVCAR-3 2.4 Colon ca. SW-48 1.7 Ovarian ca. (ascites) SK-OV-3 1.7 Colon 8.7 Ovarian ca. OVCAR-4 6.0 Small Intestine 3.5 Ovarian ca. OVCAR-5 13.5 Fetal Heart 7.4 Ovarian ca. IGROV-1 9.2 Heart 1.4 Ovarian ca. OVCAR-8 24.8 Lymph Node pool 1 2.7 Ovary 13.3 Lymph Node pool 2 25.5 Breast ca. MCF-7 3.0 Fetal Skeletal Muscle 4.3 Breast ca. MDA-MB-231 38.2 Skeletal Muscle pool 0.8 Breast ca. BT-549 2.5 Skeletal Muscle 10.4 Breast ca. T47D 3.2 Spleen 8.4 Breast pool 7.2 1Thymus 4.6 Trachea 28.7 CNS cancer (glio/astro) SF-268 2.8 Lung 30.6 CNS cancer (glio/astro) T98G 12.8 Fetal Lung 21.2 CNS cancer (neuro;met) SK-N-AS 1.0 Lung ca. NCI-N417 2.8 CNS cancer (astro) SF-539 18.4 Lung ca. LX-1 2.9 CNS cancer (astro) SNB-75 13.9 Lung ca. NCI-H146 6.9 CNS cancer (glio) SNB -19 12.2 Lung ca. SHP-77 39.2 CNS cancer (glio) SF-295 2.9 Lung ca. NCI-H23 22.8 Brain (Amygdala) 7.2 308 WO 03/050245 PCT/USO2/38594 Lung ca. NCI-H460 6.7 Brain (Cerebellum) 33.9 Lung ca. HOP-62 14.7 Brain (Fetal) 18.0 Lung ca. NCI-H522 21.9 Brain (Hippocampus) 5.7 Lung ca. DMS-114 2.9 Cerebral Cortex pool 6.2 Liver 0.1 IBrain (Substantia nigra) 2.3 Fetal Liver 0.6 Brain (Thalamus) 9.6 Kidney pool 19.3 IBrain (Whole) 100.0 Fetal Kidney 3 .3 Spinal Cord . .. 2.1 Renal ca. 786-0 13.6 Adrenal Gland 10.3 Renal ca. A498 0.7 Pituitary Gland 4.6 Renal ca. AC.HN 5.....0 Salivary Gland 1.9 Renal ca. UO-31 4.0 Thyroid 24.1 Renal ca. TK-10 19.8 Pancreatic ca. PANC-1 12.4 Bladder 12.4 Pancreas pool ...... 1.4 Table GE. Panel 4.1D Rel. Rel. Ep.(%) Exp.(%) Tissue Name Ag5546, Tissue Name Ag5546, Run Run 246950177 246950177 Secondary Thl act ]7.4 HUVEC IL-lbeta 15.3 Secondary Th2 act 47.3 HUVEC IFN gamma 39.0 .Secondary Trl act . 4 HUVEC TNF alpha + IFN gamma 0.0 Secondary Thl rest 0.0 HUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 3.2 Secondary Trl rest 0.0 Lung Microvascular EC none 51.4 Primary Thil act 2.8 Lung Microvascular EC TNFalpha 7.2 + IL-lbeta Primary Th2 act 8.6 Microvascular Dermal EC none 0.0 .m a7.5 Microsvasular Dermal EC 138 Primary Tr act TNFalpha + IL-lbeta Primary Thl rest 0.0 Bronchial epithelium TNFalpha + 12.2 Primary Th rest . ILlbeta Primary Th2 rest .0.0 Small airway epithelium none 9.5 Primary T rest Small airway epithelium TNFalpha 31.0 Primary Trl rest 1.1 + IL-lbeta 3 CD45RA CD4 lymphocyte act 16.3 Coronery artery SMC rest 12.2 CD45RO CD4 lymphocyte act 20.2 Coronery artery SMC TNFalpha + 4.5 IIL- Ibeta_____ CD CD4Dph cyte o e act 0.21 2 L- (b a so.................rest........................ CD8 lymphocyte act 0.0 Astrocytes rest 4.5 Secondary CD8 lymphocyte rest 8.2 Astrocytes TNFalpha + IL-lbeta 0.0 Secondary CD8 lymphocyte act 0.0 KU-812 (Basophil) rest 11.1 CD4 lymphocyte none 1.5 KU-812 (Basophil) 28.3 3PMA/ionomyci 309 WO 03/050245 PCT/US02/38594 2ry Tlfh2/Trlanti-CD95 2.7 CCD1106 (Keratinocytes) none 13.2 CH11 CCD1116(Keratinocytes) LAK cells rest 8.

1 CCD1 106 (Keratinocytes) 10.5 LAKcllsrst_ 8.

T

NFalpha + IL-lbeta LAK cells IL-2 0.7 Liver cirrhosis 3.0 LAK cells IL-2+IL-12 3.8 NCI-H292 none 3.6 LAK cells IL-2+IFN gamma 4.4 NCI-H292 IL-4 13.4 LAK cells IL-2+ IL-18 3.3 NCI-H292 IL-9 19.8 LAK cells PMA/ionomycin 16.0 NCI-H292 IL-13 30.4 NK Cells IL-2 rest 55.1 . NCI-H292 IFN gamma 18.9 Two Way MLR 3 day I.I ,,,HPAEC none 8.0 Two Way MLR 5 day .0.5 HPAEC TNF alpha + IL-1 beta 45.1 Two Way MLR 7 day 3.2 Lung fibroblast none 17.6 PBMC rest 0.0 Lung fibroblast TNF alpha + IL-1 12.9 PBMC rest 0.0 12.9 beta PBMC PWM 3.3 Lung fibroblast IL-4 21.8 PBMC PHA-L 6.0 Lung fibroblast IL-9 15.3 Ramos (B cell) none 0.0 Lung fibroblast IL-13 1.2 Ramos (B cell) ionomycin 7.2 Lung fibroblast IFN gamma 61.6 B lymphocytes PWM 9.1 Dermal fibroblast CCD1070 rest 44.1 ]Dermal fibroblast CCD1070 TNF10. B lymphocytes CD40L and IL-4 12.7 Dermalpha fibroblast CCD17 TNF 100.0 EOL-1 dbcA 21.6 Dermal fibroblast CCD1070 IL-1 17.2 EOL-1 dbcAMP 21.6 17.2 a beta EOL-1 dbcAMP 13.3 Dermal fibroblast IFN gamma 8.2 PMA/ionomycin. Dendritic cells none 18.2 Dermal fibroblast IL-4 25.7 Dendritic cells LPS 4

.

7 Dermal Fibroblasts rest 13.0 Dendritic cells anti-CD40 0.0 Neutrophils TNFa+LPS 1.6 Monocytes rest 1.2 . Neutrophils rest 1.7 Monocytes LPS 28.5 IColon 0.9 Macrophages rest 1.9 9Lung 1.4 Macrophages LPS 6.2 . Thymus 5.8 HUVEC none 18.7 Kidney 26.6 HUVEC starved 21.6 CNS neurodegeneration_vl.0 Summary: Ag5546 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please 5 see Panel 1.7 for a discussion of the potential utility of this gene in treatment of central nervous system disorders. 310 WO 03/050245 PCT/USO2/38594 General_screeningpanel vl.7 Summary: Ag5546 Highest expression of this gene is detected in whole brain (CT=26.4). In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, 5 therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Moderate to low levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, liver, renal, breast, ovarian, prostate, 10 melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of pancreatic, gastric, colon, lung, liver, renal, breast, ovarian, prostate, melanoma and brain cancers. Among tissues with metabolic or endocrine function, this gene is expressed at 15 moderate to low levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. Interestingly, this gene is expressed at much higher levels in fetal (CT=33.8) when 20 compared to adult liver (CT=36.9). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in 25 treatment of liver related diseases. Panel 4.1D Summary: Ag5546 Highest expression of this gene is detected in TNF alpha activated dermal fibroblast (CT=31.4). Moderate to low expression of this gene is detected in activated primary and secondary Th2 cells, activated memory and naive T cells, resting IL-2 treated NK cells, resting eosinophils and dendritic cells, activated mononcytes, 30 HUVEC, lung microvascular endothelial cells, bronchial and small airway epithelial cells, basophils and keratinocytes, activated mucoepidermoid NCI-H292 cells, activated HPAEC, resting and activated lung and dermal fibroblasts, and kidney. Therefore, therapeutic modulation of this gene may be useful in the treatment of autoimmune and inflammatory 311 WO 03/050245 PCT/USO2/38594 diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. H. CG160152-03: MS4A7-like Protein. 5 Expression of gene CG160152-03 was assessed using the primer-probe set Ag6881, described in Table HA. Results of the RTQ-PCR runs are shown in Table HB. Table HA. Probe Name Ag6881 I Start ISEQ ID Primers Sequeces Length PoStart SEQ D __ Position No Forward 5'-tttcttggggacctgagca-3' 9 146 206 Probe TET-5' -tgcagtaacagaactcactgcatttgag 33 167 207 e gtcaa-3 ' -TAMRA 167 207 Reverse 5'-gctgtcagcaaggaggaagag-3' 21 209 208 Table HB. General screening anel vl.6 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag6881, issue Name Ag6881, Run Run 278388060 278388060 Adipose 30.1 . Renal ca. TK-1i0 0.0 Melanoma* Hs688(A).T 0.0 Bladder 100i.0 Melanoma* Hs688(B).T 0.0 Gastric ca. (liver met.) NCI-N87 0.0 Melanoma* M14 0.0 Gastric ca. KATO III 0.0 Melanoma* LOXIM I 0.0 Colon ca. SW-948 0. Melanoma* SK-MEL-5 0.0 Colon ca. SW480 0.0 Squamous cell carcinoma SCC-4 0.0 Colon ca.* (SW480 met) SW620 0.0 Testis Pool 4.3 Colon ca. HT29 0.0 Prostate ca* (bone met) PC-3 0.0 Colon ca. HCT-116 0.0 Prostate Pool 9.0 Colon ca. CaCo-2 0.0 Placenta 5.9 Colon cancer tissue 18- 3.5 Uterus Pool 1.4 Colon ca. SWI116 0.0 Ovarian ca. OVCAR-3 0.0 Colon ca. Colo-205 0.0 Ovarian ca. SK-OV-3 0.0 Colon ca. SW-48 0.0 Ovarian ca. OVCAR-4 0.0 Colon Pool 24.5 Ovarian ca. OVCAR-5 0.0 Small Intestine Pool 6.0 Ovarian ca. IGROV-1 0.0 Stomach Pool 9.6 Ovarian ca. OVCAR-8 0.0 :Bone Marrow Pool 19.2 Ovay 17.8 Fetal Heart 5.5 Breast ca. MCF-7 0.0 Heart Pool 5.8 Breast ca. MDA-MB-231 0.0 Lymph Node Pool 14.5 312 WO 03/050245 PCT/USO2/38594 Breast ca. BT 549 0.0 Fetal Skeletal Muscle 5.3 Breast ca. T47D 0.0 Skeletal Muscle Pool 1.6 Breast ca. MDA-N 1.2 Spleen Pool 78.5 Breast Pool 23.7 Thymus Pool 23.7 Trachea 11.5 CNS cancer (glio/astro) U87-MG 0.0 Lung 4.5 CNS cancer (glio/astro) U-118-MG 0.0 Fetal Lung 25.2 CNS cancer (neuro;met) SK-N-AS 0.0 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 0.0 Lung ca. LX-1 0.0 CNS cancer (astro) SNB-75 0.0 Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 0.0 Lung ca. SHP-77 0.0 CNS cancer (glio) SF-295 0.0 Lung ca. A549 0.0 Brain (Amygdala) Pool 2.9 Lung ca. NCI-H526 0.0 Brain (cerebellum) 5.3 Lung ca. NCI-H23 0.0 Brain (fetal) 0.6 Lung ca. NCI-H460 0.0 Brain (Hippocampus) Pool 9.0 Lung ca. HOP-62 0.0 Cerebral Cortex Pool 5.4 Lung ca. NCI-H522 0.0 Brain (Substantia nigra) Pool 2.5 Liver 7.2 Brain (Thalamnus) Pool 4.5 Fetal Liver 33.9 Brain (whole) 6.9 Liver ca. HepG2 0.0 Spinal Cord Pool 7.1 Kidney Pool 19.1 Adrenal Gland 16.2 Fetal Kidney 3.0 Pituitary gland Pool 0.4 Renal ca. 786-0 0.0 Salivary Gland 1.9 Renal ca. A498 0.0 Thyroid (female) 7.6 Renal ca. ACHN 0.0 Pancreatic ca. CAPAN2 0.0 Renal ca. UO-31 0.0 Pancreas Pool 8.1 General_screening_panel_vl.6 Summary: Ag6881 Highest expression of this gene is detected mainly in bladder. Therefore, expression of this gene may be used to distinguish bladder from other samples in this panel and also, therapeutic modulation of this gene may be useful in the treatment of bladder related diseases. 5 In addition, moderate to low levels of expression of this gene is also seen in spleen, thymus, colon, lymph node, kidney, ovary, breast, fetal lung and fetal liver. Therefore, therapeutic modulation of this gene may be useful in the treatment of diseases that affect these tissues. Moderate expression of this gene is also detected in colon cancer tissue sample. 10 Therefore, expression of this gene may be used as diagnostic marker to detect the presence of colon cancer. Furthermore, therapeutic modulation of this gene or its protein product may be useful in the treatment of colon cancer. 313 WO 03/050245 PCT/USO2/38594 I. CG160185-01: membrane protein-like Protein. Expression of gene CG160185-01 was assessed using the primer-probe set Ag7844, described in Table IA. Results of the RTQ-PCR runs are shown in Tables IB and IC. Table IA. Probe Name Ag7844 e S n Start SEQ ID Primers SLength Position No Forward 5'-tccctcctgtcacccttatc-3' 20 530 209 TET-5' -ctttacgtctgccccaggctccattt 26 563 210 Probe -3 ' -TAMRA Reverse 5' -aggaaagtcagggtggtttg-3' 20 608 211 . 5 Table IB. Al comprehensive panel vl.0...... ......... Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag7844, issue Name Ag7844, Run Run 317419925 317419925 110967 COPD-F 1.8 112427 Match Control Psoriasis-F 34.2 110980 COPD-F 2.4 112418 Psoriasis-M 3.1 110968 COPD-M 6.0 112723 Match Control Psoriasis-M 14.1 110977 COPD-M 27.7 112419 Psoriasis-M 5.6 110989 Emphysema-F 18.2 112424 Match Control Psoriasis-M 6.6 110992 Emphysema-F 4.9 112420 Psoriasis-M 22.7 10993 Emphysemna-F 0.0 112425 Match Control Psoriasis-M 4.0 110994 Emphysema-F 2.0 104689 (MF) OA Bone-Backus 3.6 110995 Emphysema-F 9.2 104690 (MF) Adj "Nonnrmal" 110995_mphysea-F9. Bone-Backus 4.2 110996 Emphysema-F 2.0 104691 (MF) OA Synovium-Backus 5.7 110997 Asthma-M 0.5 104692 (BA) OA Cartilage-Backus 0.0 111001 Astluhma-F 3.1 104694 (BA) OA Bone-Backus 0.4 111002 Asthma-F 5.3 104695 (BA) Adj "Normal" 1.5 Bone-Backus 111003 Atopic Asthma-F 12.2 104696 (BA) OA Synovium-Backus 2.8 111004 Atopic Asthma-F 6.1 104700 (SS) OA Bone-Backus 1.5 104701 (SS) Adj "Normal" 111005 Atopic Asthma-F 6.4 104701 (SS) Adj "Normal" 1.9 Bone-Backus 111006 Atopic Asthma-F 1.8 104702 (SS) OA Synovium-Backus 1.4 111417 Allergy-M 1.5 117093 OA Cartilage Rep7 10.2 112347 Allergy-M 0.2 112672 OA Bone5 2.0 112349 Normal Lung-F 0.1 112673 OA Synovium5 2.8 112357 Normal Lung-F 60.3 112674 OA Synovial Fluid cells5 1.7 112354 Normal Lung-M 32.1 117100 OA Cartilage Repl4 3.6 112374 Crohns-F 28.3 112756 OA Bone9 100.0 314 WO 03/050245 PCT/USO2/38594 112389 Match Control Crohns-FI 1.9 112757 OA Synovium9 2.0 112375 Crohns-F 16.6 112758 OA Synovial Fluid Cells9 3.8 112732 Match Control Crohns-F 0.9 117125 RA Cartilage Rep2 6.8 112725 Crohns-M 3.4 113492 Bone2 RA 1.7 112387 Match Control 1.4 Synovium2 1.4 113493 Synovium2 RA 1.8 Crohns-M 112378 Crohns-M 0.4 113494 Syn Fluid Cells RA) 3.2 112390 Match Control 39.0 13499 39.0 113499 Cartilage4 RA 1.5 Crohns-M 112726 Crohns-M 2.9 113500 Bone4 RA 2.7 112731 Match Control. 112731 Match Control 3.3 113501 Synovium4 RA 2.9 Crohns-M 112380 Ulcer Col-F 6.9 113502 Syn Fluid Cells4 RA 1.3 112734 Match Control Ulcer 113495 Cartilage3 A 2.9 3.7 113495 Cartilage3 RA 2.9 Col-F 112384 Ulcer Col-F 18.8 113496 Bone3 RA 2.8 112737 Match Control Ulcer 113497 Synovium3 A 2 2.5 113497 Synovium3 RA 2.3 Col-F 112386 Ulcer Col-F 3.0 113498 Syn Fluid Cells3 RA 5.1 112738 Match Control Ulcer Cl 1.5 117106 Normal Cartilage Rep20 4.0 Col-F 112381 Ulcer Col-M 0.0 113663 Bone3 Normal 0.0 112735 Match Control Ulcer 1.7 113664 Synovium3 Normal 0.0 Col-M 112382 Ulcer Col-M 3.0 113665 Syn Fluid Cells3 Normal 0.2 112394 Match Control Ulcer ClM2.6 117107 Normal Cartilage Rep22 1.7 Col-M 112383 Ulcer Col-M 19.8 113667 Bone4 Normal 5.4 112736 Match Control Ulcer 1.1 113668 Synovium4 Normal 8.2 Col-M 112423 Psoriasis-F 3.7 113669 Syn Fluid Cells4 Normal 7.1 Table IC.General screening panel v1.7. Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag7844, issue Name Ag7844, Run Run 318010060 318010060 Adipose 0.2 Gastric ca. (liver met.) NCI-N87 0.0 HUVEC 0.0 Stomach 0.0 Melanoma* Hs688(A).T 0.0 Colon ca. SW-948 0.2 Melanoma* Hs688(B).T 0.7 Colon ca. SW480 0.0 Melanoma (met) SK-MEL-5 1.3 Colon ca. (SW480 met) SW620 9.9 Testis 0.4 Colon ca. HT29 0.0 Prostate ca. (bone met) PC-3 0.0 Colon ca. HCT-116 2.7 Prostate ca. DU145 2.4 Colon cancer tissue 0.0 315 WO 03/050245 PCT/USO2/38594 Prostate pool 0.1 Colon ca. SW1116 0.0 Uterus pool 0.0 Colon ca. Colo-205 __0.0 Ovarian ca. OVCAR-3 0.0 Colon ca. SW-48 . .0.0. Ovarian ca. (ascites) SK-OV-3 0.0 Colon ... 0.1 Ovarian ca. OVCAR-4 1.0 Small Intestine 0.1... Ovarian ca. OVCAR-5 0.8 Fetal Heart 0.0 Ovarian ca. IGROV-1 1.2 Heart 0.0" Ovarian ca. OVCAR-8 10.1 Lymph Node pool 1 0.0 Ovary 0.2 Lymph Node pool 2 10.1 Breast ca. MCF-7 0.2 Fetal Skeletal Muscle 0.0 Breast ca. MDA-MB-231 0.0 'Skeletal Muscle pool .0.0_ Breast ca. BT-549 0.3 Skeletal Muscle 0.0 Breast ca. T47D 0.3 Spleen 0.0 Breast pool 0.1 Thymus 0.0 Trachea 0.7 CNS cancer (glio/astro) SF-268 0.0 Lung 0.1 CNS cancer (glio/astro) T98G 0.1 Fetal Lung 0.1 CNS cancer (neuro;met) SK-N-AS 0.0 Lung ca. NCI-N417 3.7 _ CNS cancer (astro) SF-539 0.2 Lung ca. LX-1 0.1 CNS cancer (astro) SNB-75 0.

2 Lung ca. NCI-H146 11.0 CNS cancer (glio) SNB-19 0.0 Lung ca. SHP-77 8.7 CNS cancer (glio) SF-295 0.2 Lung ca. NCI-H23 __ 1.9 Brain (Amygdala) 8.7 Lung ca. NCI-H460 0.1 Brain (Cerebellum) 68.3 Lung ca. HOP-62 0.6 Brain (Fetal) 100.0 Lung ca. NCI-H522 16.5 Brain (Hippocampus) 6.3 Lung ca. DMS-114 1.7 Cerebral Cortex pool 6.4 Liver 0.0 Brain (Substantia nigra) 3.5 Fetal Liver 0.0 Brain (Thalamus) 11.8 Kidney pool 0.0 Brain (Whole) 62.0 Fetal Kidney 0.0 Spinal Cord 1.3 Renal ca. 786-0 10.1 Adrenal Gland 1.3 Renal ca. A498 1.4 Pituitary Gland 2.9 Renal ca. ACHN 0.1 Salivary Gland 0.7 Renal ca. UO-31 0.0 Thyroid 0.2 Renal ca. TK-10 0.6 IPancreatic ca. PANC-1 1.3 Bladder 0.0 Pancreas pool 0.0 Al comprehensive panel vl.0 Summary: Ag7844 Highest expression of this gene is detected in orthoarthritis (OA) bone (CT=29). In addition, low levels of expression of this gene is also seen in samples derived from normal and OA/ rheumatoid arthritis bone and adjacent bone, cartilage, synovium and synovial fluid samples, from normal lung, 5 COPD lung, emphysema, atopic asthma, Crohn's disease (normal matched control and diseased), ulcerative colitis(normal matched control and diseased), and psoriasis (normal 316 WO 03/050245 PCT/USO2/38594 matched control and diseased). Therefore, therapeutic modulation of this gene product may ameliorate symptoms/conditions associated with autoimmune and inflammatory disorders including psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis 5 General_screeningpanel_vl.7 Summary: Ag7844 Highest expression of this gene is detected in fetal brain (CT=23.7). High expression of this gene is seen mainly in all the brain region including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's 10 disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Low expression of this gene is also seen in number of cancer cell lines derived from pancreatic, colon, lung, liver, renal, breast, ovarian, prostate, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene 15 may be effective in the treatment of pancreatic, colon, lung, liver, renal, breast, ovarian, prostate, melanoma and brain cancers. Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in adipose, adrenal gland, thyroid, pituitary gland, and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the 20 treatment of endocrine/metabolically related diseases, such as obesity and diabetes. J. CG160244-01: Type IIIa membrane protein-like Protein. Expression of gene CG160244-01 was assessed using the primer-probe set Ag7845, described in Table JA. Results of the RTQ-PCR runs are shown in Tables JB, JC and JD. Table JA. Probe Name Ag7845 Primers Length Start SEQ ID _ ~ Position No Forward 5'-agtgtgccttgagcagtg-3 19 3983 212 Probe TET-5' -ccatccagcatccacgtttccagc- 24 4003 213 3' -TAMRA24 4003 213 Reverse 5 ' -ggtcagggcaggcagt-3,' 16 4042 214 25 317 WO 03/050245 PCT/US02/38594 Table JB. CNS neurodegeneration v1.0 ... Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag7845, issue Name Ag7845, Run Run 319510461 319510461 AD 1 Hippo 23.0...... Control (Path) 3 Temporal Ctx .7.4 AD 2 Hippo 35.1 Control (Path) 4 Temporal Ctx 46.0 AD 3 Hippo 14.0 AD I Occipital Ctx 25.0 AD 4 Hippo 18.4 AD 2 Occipital Ctx (Missing) 0.0 AD 5 hippo 100.0 AD 3 Occipital Ctx 9.9.. AD 6 Hippo 62.9 AD 4 Occipital Ctx .. 43.2 Control 2 Hippo 32.1 AD 5 Occipital Ctx 23.0 Control 4 Hippo 20.0 AD 6 Occipital Ctx 46.7... Control (Path) 3 Hippo 7.7 Control 1 Occipital Ctx 6.2 AD 1 Temporal Ctx 37.1 Control 2 Occipital Ctx 66.0 AD 2 Temporal Ctx 38.4 Control 3 Occipital Ctx 31.6 AD 3 Temporal Ctx 15.7 Control 4 Occipital Ctx 10.5 AD 4 Temporal Ctx 44.4 Control (Path) 1 Occipital Ctx 99.3 AD 5 InfTemporal Ctx~ 97.3 Control (Path) 2 Occipital Ctx 18.0 AD 5 SupTemporal Ctx 62.0 Control (Path) 3 Occipital Ctx 16.9 AD 6 Inf Temporal Ctx 59.9 Control (Path) 4 Occipital Ctx 24.1 AD 6 Sup Temporal Ctx 61.6 Control 1 Parietal Ctx 14.3 Control 1 Temporal Ctx 10.2 Control 2 Parietal Ctx 76.8 Control 2 Temporal Ctx 31.6 Control 3 Parietal Ctx 26.4 Control 3 Temporal Ctx 33.0 Control (Path) 1 Parietal Ctx 70.2 Control 4 Temporal Ctx 22.2 Control (Path) 2 Parietal Ctx 31.2 Control (Path) 1 Temporal Ctx 66.4 Control (Path) 3 Parietal Ctx 6.7 Control (Path) 2 Temporal Ctx 44.8 Control (Path) 4 Parietal Ctx 45.7 Table JC. General screening panel v1.7 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag7845, issue Name Ag7845, Run Run 318010062 318010062 Adipose 64.6 Gastricca. (liver met.) NCI-N87 3.0 HUVEC 45.7 Stomach 3.9 Melanoma* Hs688(A).T 0.0 .Colon ca. SW-948 12.6 Melanoma* Hs688(B).T 23.0 Colon ca. SW480 2.2 Melanoma (met) SK-MEL-5 24.7 Colon ca. (SW480 met) SW620 32.1 Testis 27.7 Colon ca. HT29 24.3 Prostate ca. (bone met) PC-3 0.9 Colon ca. HCT-116 _ 23.8 Prostate ca. DU145 28.9 Colon cancer tissue 2.9 Prostate pool 26.1 Colon ca. SW I 611.7 318 WO 03/050245 PCT/US02/38594 Uterus pool 5.1 Colon ca. Colo-205 4.9 Ovarian ca. OVCAR-3 6.9 Colon ca. SW-48 4.1 Ovarian ca. (ascites) SK-OV-3 3.2 Colon 23.0 Ovarian ca. OVCAR-4 35.1 Small Intestine 6.7 Ovarian ca. OVCAR-5 12.7 Fetal Heart 9.3 Ovarian ca. IGROV-1 42.9 Heart 9.0 Ovarian ca. OVCAR-8 40.1 Lymph Node pool 1 15.6 Ovary 30.4 Lymph Node pool 2 152.1 Breast ca. MCF-7 17.0 IFetal Skeletal Muscle 12.2 Breast ca. MDA-MB-231 43.2 Skeletal Muscle pool 4.7 Breast ca. BT-549 59.9 Skeletal Muscle 20.2 Breast ca. T47D 46.3 ISpleen 17.7 Breast pool 21.8 jThymus 23.3 Trachea 48.6 CNS cancer (glio/astro) SF-268 8.0 Lung 52.9 CNS cancer (glio/astro) T98G 12.7 Fetal Lung 71.2 CNS cancer (neuro;met) SK-N-AS 9.0 Lung ca. NCI-N417 5.4 CNS cancer (astro) SF-539 39.5 Lung ca. C 4.9 CNS cancer (astro) SNB-75 20.7 Lung ca. NCI-H146 17.3 CNS cancer (glio) SNB-19 21.9 Lung ca. SHP-77 21.3 CNS cancer (glio) SF-295 7.7 Lung ca. NCI-H23 25.7 Brain (Amygdala) 15.2 Lung ca. NCI-H460 15.5 Brain (Cerebellum) 46.7 Lung ca. HOP-62 63.7 Brain (Fetal) 82.9 Lung ca. NCI-H522 20.3 Brain (Hippocampus) 15.2 Lung ca. DMS-114 13.9 Cerebral Cortex pool 14.0 Liver 14.8 Brain (Substantia nigra) 6.8 Fetal Liver 30.1 Brain (Thalamus) 18.3 Kidney pool 73.2 Brain (Whole) 100.0 Fetal Kidney 27.2 Spinal Cord 8.5 Renal ca. 786-0 40.9 Adrenal Gland 57.8 Renal ca.A498 49.0 Pituitary Gland 34.9 Renal ca. ACHN 30.6 Salivary Gland 24.0 Renal ca. UO-31 39.0 Thyroid 59.9 Renal ca. TK-10 30.1 Pancreatic ca. PANC-1 18.3 Bladder 39.2 Pancreas pool 7.5 Table JD. Panel 4.11D Rel. Rel. Exp.0 Exp.(%) Tissue Name Ag7845, Tissue Name Ag7845, Run Run 313916921 313916921 Secondary Thl act 55.5 HUVEC IL-lbeta 44.8 Secondary Th2 act 82.9 HUVEC IFN gamma 55.1 319 WO 03/050245 PCT/USO2/38594 Secondary Tr act 28.5 HUVEC TNF alpha+ IFN gamma 13.5 Secondary Thl rest 4.8 HUVEC TNF alpha + IL4 20.2 Secondary Th2 rest 10.4 HUVEC IL-11 42.9 Secondary Trl rest 10.9 Lung Microvascular EC none 70.7 Primary ThI act 6.9 Lung Microvascular EC TNFalpha 27.9 + IL-lbeta Primary Th2 act 34.6 Microvascular Dermal EC none l10.2 Primary T act 24.8 Microsvasular Dermal EC 159 Primary Trl act 24.8 TNFalpha + IL-lbeta .. t... Bronchial epithelium TNFalpha + 14.6 Primary Thl rest 1.9 ILlIbeta 14.6 Primary Th2 rest 5.5 Small airway epithelium none 71-_. m Small airway epithelium TNFalpha 42.3 Primary Trl rest 1.7 + IL-lbeta CD45RA CD4 lymphocyte act 272 Coronery artery SMC rest 35.6 CD45RO CD4 lymphocyte act 460 Coronery artery SMC TNFalpha + 31.6 OCD4 lymphocyte act 46.0 IL-1beta I31. CD8 lymphocyte act 7.5 Astrocytes rest 20.7 Secondary CD8 lymphocyte rest 7.1 Astrocytes TNFalpha + IL-lbeta 11.6 Secondary CD8 lymphocyte act 4.8 KU-812 (Basophil) rest 14.2 CD4 lymphocyte none 6.4 KU-812 (Basophil) 16.6 CD4 lymphocyte none 6.4 PMA/ionomycin 2ry Thl/Th2/Trlanti-CD95 19.3 CCD1106 (Keratinocytes) none 25.3 CH11... C1 CCD1106 (Keratinocytes) 11.0 LAK cells rest 19.5 TNFalpha + IL-lbeta 11.0 LAKcells IL-2 9.2 Liver cirrhosis 18.3 LAK cells IL-2+IL-12 1.9 CI-H292 none 28.5 LAK cells IL-2+IFN gamma 6.0 NCI-H292 IL-4 33.2 LAK cells IL-2+ IL-18 4.7 NCI-H292 IL-9 34.9 LAK cells PMA/ionomycin 40.1 NCI-H292 IL-13 41. NK Cells IL-2 rest 62.0 NCI-H292 IFN gamma 12.9 Two Way MLR 3 day 28.9 HPAEC none 19.2 Two Way MLR 5 day 3.9 HPAEC TNF alpha + IL-1 beta 77.4 Two Way MLR 7 day 9.6 Lung fibroblast none 61.1 PBMC rest 4.2 Lung fibroblast TNF alpha+ IL-1 52.5 BMC rest 4.2 beta PBMC PWM 11.7 Lung fibroblast IL-4 21.0 PBMC PHA-L 8.5 Lung fibroblast IL-9 20.6 Ramos (B cell) none .7 Lung fibroblast IL-13 13.5 Ramos (B cell) ionomycin 8.2 Lung fibroblast IFN gamma 51.4 B lymphocytes PWM 7.7 Dermal fibroblast CCD 1070 rest 40.1 Dermal fibroblast CCD 1070 TNF lymphocytes CD40L and IL-4 40.9 alpha 95.3 L dA2Dermal fibroblast CCD 1070 IL- 1 38.4 EOL-1 dbcAMP 20.9 bet a .38.4 320 WO 03/050245 PCT/US02/38594 EOL-1 dbcAMP . PMA/ionomycin 5.4 Dermal fibroblast IFN gamma 27.0 Dendritic cells none 18.2 Dermal fibroblast IL-4 40.1 Dendritic cells LPS 10.0 Dermal Fibroblasts rest 42.6 Dendritic cells anti-CD40 11.4 Neutrophils TNFa+LPS 14.6 Monocytes rest 21.8 Neutrophils rest 87.7 Monocytes LPS _100.0 Colon 9.0 Macrophages rest 11.4 Lung 2.0 Macrophages LPS 13.1 Thymus 17.4 HUVEC none 18.2 Kidney 52.1 HUVEC starved 35.6 CNS_neurodegeneration_vl.0 Summary: Ag7845 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please 5 see Panel 1.7 for a discussion of the potential utility of this gene in treatment of central nervous system disorders. Generalscreening_panel_ vl.7 Summary: Ag7845 Highest expression of this gene is seen in a sample derived from the whole brain (CT=23.8). This gene is also expressed at high levels in all regions of the CNS examined on this panel, including the 10 hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy. This gene is widely expressed in this panel, with high levels of expression seen in 15 brain, colon, gastric, lung, breast, ovarian, and melanoma cancer cell lines. This expression profile suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer. Among tissues with metabolic function, this gene is expressed at high levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, 20 heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes. 321 WO 03/050245 PCT/USO2/38594 Panel 4.1D Summary: Ag7845 Highest expression of this gene is seen in LPS treated monocytes (CT=29.2). This gene is also expressed at moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and 5 peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in Generalscreeningpanel_v1.7 and also suggests a 10 role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. 15 K. CG162177-02: Folate receptor beta-like Protein. Expression of gene CG162177-02 was assessed using the primer-probe set Ag5905, described in Table KA. Results of the RTQ-PCR runs are shown in Tables KB and KC. Table KA. Probe Name Ag5905 ... Primers Length Start SEQ ID . ... .. ... .. . .. . . . .. . . . . .. ..P o sitio n N o Forward 5' -acctcccgcctgtacaac-3' 18 304 215 Probe TET-5' -atcttgccgcagtggtcccagttaaa 26 322 216 P r o b e ~ 3 2 22 1 6 -3 -TAMRA I Reverse 5'-catagagacaggtgtcctggat-3' 22 373 217 20 Table KB. A comprehensive anel vl.O Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5905, issue Name Ag5905, Run Run 247682891 247682891 110967 COPD-F 5.7 112427 Match Control Psoriasis-F 9.6 110980 COPD-F 5.9 112418 Psoriasis-M 10.2 110968 COPD-M 6.9 112723 Match Control Psoriasis-M 2.0 110977 COPD-M 9.9 112419 Psoriasis-M 9.5 110989 Emphysema-F 3.4 .112424 Match Control Psoriasis-M 2.6 110992 Emphysema-F 5.8 112420 Psoriasis-M 10.9 322 WO 03/050245 PCT/US02/38594 110993 Emphysema-F 2.0 112425 Match Control Psoriasis-M 6.4 110994 Emphysema-F 2.0 104689 (ME) O A Bone-Backus 31.6 19 104690 (MF) Adj "Normal" 13 110995 Emphysema-F 5

.

8 Bone-Backus 13.3 110996 Emphysema-F 4.0 104691 (MF) OA Synovium-Backus 100.0 110997 Asthma-M 4.4 104692 (BA) OA Cartilage-Backus 2.3 111001 Asthma-F 6.7 104694 (BA) OA Bone-Backus 37.6 1104695 (BA) Adj "Normal" 111002 Asthma-F 4.6 104695 (BA) Adj "Normal" 26.6 Bone-Backus 111003 Atopic Asthma-F 4.4 . 104696 (BA) OA Synovium-Backus 90.1 111004 Atopic Asthma-F 4.4 . 104700 (SS) OA Bone-Backus 1 2.8 104701 (SS) Adj "Normal" 111005 Atopic Asthma-F 4.5 BoneBackusi33.0 111006 Atopic Asthma-F 1.0 104702 (SS) OA Synovium-Backus 79.0 111417 Allergy-M 2.7 .117093 OA Cartilage Rep7 2.1 112347 Allergy-M 0.0 112672 OA Bone5 9.7 112349 Normal Lung-F 0.0 112673 OA Synovium5 4.0 112357 Normal Lung-F 2.9 112674 OA Synovial Fluid cells5 3.7 112354 Normal Lung-M 1.6 117100 OA Cartilage Repl4 2.6 112374 Crohns-F 4.9 112756 OA Bone9 2.9 112389 Match Control Crohns-F 5.1 112757 OA Synovium9 1.4 112375 Crohns-F 2.8 112758 OA Synovial Fluid Cel s9 8.8 112732 Match Control Crohns-F 2.8 117125 RA Cartilage Rep2 16.7 112725 Crohns-M 1.0 113492 Bone2 RA 5.6 112387 Match Control 1.8 113493 Synovium2 RA 2.6 Crohns-M Synovium2RA 2.6 112378 Crons-M 0.1 113494 Syn Fluid Cells RA 3.0 112390 Match Control C30Ma 11.5 113499 Cartilage4 RA 2.4 Crohns-M 1127726 Crohns-M . 1.8 113500 Bone4 RA 2.7 112731 Match Control 11731achCotrl4.5 113501 Synovium4 RA 2.3 Crohns-M 112380 Ulcer Col-F 0.7___ 113502 Syn Fluid Cells4 RA 1.4 112734 Match Control Ulcer 12.3 113495 Cartilage3 RA .4 Col-F 112384 Ulcer Col-F .2.7 113496 Bone3 RA 5.1 112737 Match Control Ulcer Col-F0.6 113497 Synovium3 RA 2.2 Col-F] 112386 Ulcer Col-F 1.1 113498 Syn Fluid Cells3 RA 6.4 112738 Match Control Ulcer Col-F 2.3 117106 Normal Cartilage Rep20 3.1 Col-F 112381 Ulcer Col-M 0.7 113663 Bone3 Normal 1.9 112735 Match Control Ulcer 8.8 8.8 113664 Synovium3 Normal 0.0 Col-M 112382 Ulcer Col-M 5.1 113665 Syn Fluid Cells3 Normal 0.0 323 WO 03/050245 PCT/USO2/38594 112394 Match Control Ulcer 1.4 117107 Normal Cartilage Rep22 2.6 Col-M . 112383 Ulcer Col-M 3.2 113667 Bone4 Normal 1.0 112736 Match Control Ulcer ....... 112736 Match Control Ulcer 5.1 113668 Synovium4 Normal 2.0 Col-M 112423 Psoriasis-F 4.0 113669 Syn Fluid Cells4 Normal 3.5 Table KC. General screening panel v1.5 Rel. Rel. Tissue Name Ag5905, issue Name Ag5905, Run Run 247453527 247453527 Adipose 62.4 Renal ca. TK-10 0.0 Melanoma* Hs688(A).T 0.0 Bladder 40.6 Melanoma* Hs688(B).T 0.0 Gastric ca. (liver met.) NCI-N87 0.0 Melanoma* M14 0.0 Gastric ca. KATO III 0.0 Melanoma* LOXIMVI 0.0 Colon ca. SW-948 0.0 Melanoma* SK-MEL-5 0.0 Colon ca. SW480 0.0 Squamous cell carcinoma SCC-4 0.0 Colon ca.* (SW480 met) SW620 0.0 Testis Pool 11.1 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-1 16 0.0 Prostate Pool 9.8 Colon ca. CaCo-2 0.0 Placenta 62.0 Colon cancer tissue 37.6 Uterus Pool 4.9 Colon ca. SW1116 0.0 Ovarian ca. OVCAR-3 0.0 _Colon ca. Colo-205 0.0 O v , ca.. ... V - . 0 C olo ..... IW ........ ....... ........................... Ovarian ca. SK-OV-3 0.0 Colon ca. SW-48 0.0 Ovarian ca. OVCAR-4 0.0 Colon Pool 35.8 Ovarian ca. OVCAR-5 0.0 .Small Intestine Pool _ 12.2 Ovarian ca. IGROV-1 0.0 Stomach Pool 17.1 Ovarian ca. OVCAR-8 0.0 Bone Marow Pool 17.6 Ovary 31.0 Fetal Heart 4.3 Breast ca. MCF-7 - 0.0 Heart Pool 18.8 Breast ca. MDA-MB-231 0.0 Lymph Node Pool 19.3 Breast ca. BT 549 0.0 Fetal Skeletal Muscle 18.9 Breast ca. T47D 0.0 -........ Skeletal Muscle Pool .... 13.... ................. Breast ca. MDA-N 10.0 Spleen Pool 4.3 Breast Pool _24.5 Thymus Pool 16.7 Trachea 6.0 CNS cancer (glio/astro) U87-MG 0.0 Lung 4.4 CNS cancer (glio/astro) U-118-MG 0.0 Fetal Lung 24.0 CNS cancer (neuro;met) SK-N-AS 0.0 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 0.0 Lung ca. LX-1 0.0 CNS cancer (astro) SNB-75 0.0 324 WO 03/050245 PCT/USO2/38594 Lung ca. NCI-H146 0.5 CNS cancer (glio) SNB-19 0.0 Lung ca. SHP-77 0.0 CNS cancer (glio) SF-295 ... 0.0 Lung ca. A549 . 0.0 Brain (Amygdala) Pool 3.5 Lung ca. NCI-H526 0.0 Brain (cerebellum) 9.0 Lung ca. NCI-H23 - 0.0 Brain (fetal) 6.3 Lung ca. NCI-H460 0.0 Brain (Hippocampus) Pool 6.6 Lung ca. HOP-62 0. Cerebral Cortex Pool 6.7 Lung ca. NCI-H522 0.0 Brain (Substantia nigra) Pool 8.8 Liver 12.4 Brain (Thalamus) Pool 6.2 Fetal Liver 45.4 Brain (whole) 20.6 Liver ca. HepG2 0.0 Spinal Cord Pool 12.0 dney Pool 42.6 Adrenal Gland 33.2 Fetal Kidney 10.4 Pituitary gland Pool 5.8 Renal ca. 786-0 0.0 Salivary Gland 3.8 Renal ca. A498 100.0 Thyroid (female) 3.4 Renal ca. ACHN 0.0 Pancreatic ca. CAPAN2 0.0 Renal ca. UO-31 0.0 Pancreas Pool 31.4 AI_comprehensive panel vl.0 Summary: Ag5905 Highest expression is seen in a sample of OA synovium (CT=26.7). In addition, this gene is expressed at high to moderate levels in a cluster of samples derived from OA. Thus, expression of this gene could be used to differentiate between the OA derived samples and other samples on this 5 panel and as a marker of OA. Furthermore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of OA. General_screeningpanel_vl.5 Summary: Ag5905 Highest expression is seen in a renal cancer cell line (CT=31.9), with low levels seen in a sample derived from a colon cancer. Thus, expression of this gene may be used to differentiate between the renal cell 10 line and other samples on this panel. Low levels of expression are also seen in whole brain, spinal cord, pancreas, adrenal, fetal and adult skeletal muscle, heart, liver and fetal liver, and adipose. This suggests that this gene product may be involved in diseases that involve these organs. Panel 4.1D Summary: Ag5905 Expression of this gene is limited to the lung and 15 liver cirrhosis. L. CG162443-01: Advanced Glycosylation end product-specific receptor precursor-like Protein. 325 WO 03/050245 PCT/USO2/38594 Expression of gene CG162443-01 was assessed using the primer-probe set Ag6685, described in Table LA. Results of the RTQ-PCR runs are shown in Tables LB and LC. Please note that CG162443-02 represents a full-length physical clone of the CG162443-01 gene, validating the prediction of the gene sequence. 5 Table LA. Probe Name Ag6685 ...... .. _ _ Start ISEQ ID Primers Length Start SEQ ID 1 Position No Forward j5'-cagcatcagcatcatcgaa-3' 19 930 218 Probe TET-5'-ctaccacagagcctgcagttgge-3 2 6 1 fProbe ~ 23 963 j219 ' -TAMR A Reverse 5'-tagagttcccagccctgatc-3' 20 1986 1220 Table LB. General screening panel v1.6 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag6685, issue Name Ag6685, Run Run .277259221 277259221 Adipose 0.2 Renal ca. TK-10 0.9 Melanoma* Hs688(A).T 0.5 Bladder 1.1 Melanoma* Hs688(B).T 0.4 Gastric ca. (liver met.) NCI-N87 0.4 Melanoma* M14 1.1 Gastric ca. KATO III 1.0 Melanoma* LOXIMVI 0.7 Colonca. SW-948 0.9 Melanoma* SK-MEL-5 0.0 Colon ca. SW480 0.8 Squamous cell carcinoma SCC-4. 0.0 ... Co.lon ca.. (SW480 met) SW620 .8 Testis Pool 0.3 jColon ca. HT29 0.5 Prostate ca.* (bone met) PC-3 0.1 Colon ca. HCT- 16 0.4 Prostate Pool 1.2 Colon ca. CaCo-2 0.7 Placenta 0.4 Colon cancer tissue 0.3 Run _ 1 00Run. Uterus Pool 1.4 Colon ca. SW1116 0.4 Ovarian ca. OVCAR-3 1.1 Colon ca. Colo-205 0.0 Ovarian ca. SK-OV-3 1.3 Colon ca. SW-48 0.5 Ovarian ca. OVCA- 0.0 Colon Pool 1 .5 Ovarian ca. OVCAR-5 2.7 Small Intestine Pool 1.6 Ovarian ca. IGROV-1 1.8 Stomach Pool 1.3 Ovarian ca. OVCAR-8 3.1 Bone Marrow Pool 0.8 Ovary 0.2 IFetal Heart 1.9 Breast ca. MCF-7 2.3 Heart Pool 0.8 Breast ca. MDA-MB-231 0.5 Lymph Node Pool 2.2 Breast ca. BT 549 4.2 Fetal Skeletal Muscle 0.8 Breast ca. T47D 0.9 Skeletal Muscle Pool 0.6 Breast ca. MDA-N 0.2 Spleen Pool 1.7 Breast Pool 1.5 Thymus Pool 6.4 326 WO 03/050245 PCT/USO2/38594 Trachea 0.3 CNS cancer (glio/astro) U87-MG 0.1 Lung 0.4 CNS cancer (glio/astro) U- 18-MG 2.6 Fetal Lung 100.0 CNS cancer (neuro;met) SK-N-AS 1.4 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 0.4 Lung ca. LX-1 0.6 CNS cancer (astro) SNB-75 1.0 Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 3.6 Lung ca. SHP-77 0.3 CNS cancer (glio) SF-295 2.8 Lung ca. A549 0.6 Brain (Amygdala) Pool 0.6 Lung ca. NCI-H526 0.0 Brain (cerebellum) 0.9 Lung ca. NCI-H23 0.9 Brain (fetal) 0.6 Lung ca. NCI-H460 0.2 Brain (Hippocampus) Pool 0.8 Lung ca. HOP-62 0.8 Cerebral Cortex Pool 0.4 Lung ca. NCI-H522 0.8 Brain (Substantia nigra) Pool 0.0 Liver 0.0 Brain (Thalamus) Pool 1.3 Fetal Liver 0.5 Brain (whole) 0.8 Liver ca. HepG2 1.7 Spinal Cord Pool 0.6 Kidney Pool 4.6 Adrenal Gland 0.4 Fetal Kidney 5.9 Pituitary gland Pool _ O.9 Renal ca. 786-0 0.1 Salivary Gland 0.0 Renal ca. A498 0.0 Thyroid (female) 2.6 Renal ca. ACHN 0.0 Pancreatic ca. CAPAN2 10.3 Renal ca. UO-31 2.7 Pancreas Pool 1.3 Table LC. Panel 5 Islet Rel. Rel. Exp.0 Exp.(%) Tissue Name Ag6685, Tissue Name Ag6685, Run Run 279519420 279519420 97457_Patient-02go_adipose 11.8 94709 Donor 2 AM -A adipose 125.3 S l Patient-o7skskeletal 0.0 94710 Donor 2 AM - B adipose 42.3 muscle 97477 Patient-07ut uterus 23.3 94711 Donor 2 AM - C adipose 12.5 97478 Patient-07plplacenta 51.8 94712_Donor 2 AD - Aadipose 14.8 99167 Bayer Patient 1 43.8 94713_ Donor 2 AD - B adipose 15.9 97482 Patient-08ut uterus 3.3 94714 Donor 2 AD - C adipose 12.3 94742 Donor 3 U - AMesenchymal 00 97483_Patient-08pl_placenta 58.6 Stem Cells 0 Stem Cells 97486 Patient-09sk skeletal 11.3 94743 Donor 3 U- B Mesenchyrnal 0.0 muscle _ Stem Cells 97487 Patient-09ut uterus 61.6 94730 Donor 3 AM - A adipose 0.0 97488_Patient-09plplacenta 10.4 94731 _Donor 3 AM - B adipose 17.9 97492 Patient-10ut uterus 23.2 94732_Donor 3 AM - Cadipose 0.0 97493 Patient- O1plplacenta 37.1 94733 Donor 3 AD - Aadipose 25.5 97495_Patient-1 I go adipose 23.5 94734_Donor 3 AD - B adipose 0.0 327 WO 03/050245 PCT/USO2/38594 musc97496-Patient- 11 skskeletal 25.7 94735_Donor 3 AD - C adipose 0.0 muscle 97497 Patient-1i lut uterus 2.1 77138 Liver HepG2untreated 33.2 ' 73556 Heart Cardiac stromal cells 97498_Patient-1 lplplacenta 25.2 73556 HeartCardiac stromal cells 0.0 - (primary) _ _ 97500 Patient- 12go adipose 36.9 81735 Small Intestine 10.8 97501_Patient-12sk_skeletal 8.8 72409 Kidney ProximalConvoluted 24.7 muscle Tubule 97502 Patient-12ut uterus 25.9 82685 Small intestine Duodenum 12.7 l ~ ~90650 AdrenalAdreno cortical 1. 97503_Patient- 12pl_placenta 12.2 adenom enalAdrenocortical 12.9 94721_Donor 2 U - 87.1 72410 Kidney HRCE 0.0 A Mesenchymal Stem Cells . . ... .... . ...... . . . .. . .. 94722 Donor 2 U - 45.7 72411 KidneyHRE 0.0 BMesenchymal Stem Cells 94723 Donor 2 U - 100.0 73139_UterusUterine smooth 24.8 C Mesenchymal Stem Cells muscle cells General screeningpanel_vl.6 Summary: Ag6685 Highest expression of this gene is seen in the fetal lung (CT=27). Interestingly, this gene is expressed at much higher levels in the fetal tissue when compared to the level of expression in the adult lung (CT = 35). This observation suggests that expression of this gene can be used to distinguish 5 between the fetal and adult sources of this tissue. In addition, the relative overexpression of this gene in fetal lung suggests that the protein product may enhance lung growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of lung related diseases. 10 Panel 5 Islet Summary: Ag6685 Expression of this gene on this panel is limited to samples derived from mesenchymal stem cells (CTs=34). Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker of these cells. M. CG162509-02: Leukocyte-associated IG-like receptor-2-like Protein. 15 Expression of gene CG162509-02 was assessed using the primer-probe set Ag5910, described in Table MA. Results of the RTQ-PCR runs are shown in Tables MB, MC, MD and ME. Table MA. Probe Name Ag5910 Leth IStart SEQ ID i ILength Position INo 328 WO 03/050245 PCT/USO2/38594 Forward 5' -agctgctggtgaaagaaagc-3' 20 362 221 Probe TET-5 '-ctcctcagctgggactgtgccag-3 23 417 222 Reverse 5'-caaatccggaggcttcag-3' 18 443 223 Table MB. AI comprehensive panel vl.0 . Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5910, issue Name Ag5910, Run Run 247842189 247842189 110967 COPD-F 9.0 112427 Match Control Psoriasis-F 12.9 110980 COPD-F __ 3.4 112418 Psoriasis-M 4.2 110968 COPD-M 21.8 112723 Match Control Psoriasis-M 0.0 110977 COPD-M 11.2 112419 Psoriasis-M 9.5 110989 Emphysema-F 14.2 112424 Match Control Psoriasis-M 13.0 110992 Emphysema-F 10.4 112420 Psoriasis-M 11.3 110993 Emphysema-F 0.0 112425 Match Control Psoriasis-M 9.3 110994 Emphysema-F 0.0 104689 (MF) OA Bone-Backus 39.2 110995 Emphysema-F 4.7 104690 (MF) Adj "Normal" Bone-Backus 58.2 110996 Emphysema-F 4.2 104691 (MF) OA Synovium-Backus 36.1 110997 Asthma-M 4.0 104692 (BA) OA Cartilage-Backus 2.8 111001 Asthma-F 3.5 104694 (BA) OA Bone-Backus 18.7 111002 Asthma-F 5.0 104695 (BA) Adj "Normal" 24.5 Bone-Backus 111003 Atopic Asthma-F 13.6 104696 (BA) OA Synovium-Backus 30.4 111004 Atopic Asthma-F 6.7 104700 (SS) OA Bone-Backus 19.9 111005 Atopic Asthma-F 9.6 104701 (SS) Adj "Normal" 28.1 Bone-Backus 2 111006 Atopic Asthma-F 0.0 104702 (SS) OA Synovium-Backus 45.1 111417 Allergy-M 2.5 117093 OA Cartilage Rep7 7.3 112347 Allergy-M 0.0 112672 OA Bone5 14.0 112349 Normal Lung-F 0.0 112673 OA Synovium5 6.8 112357 Normal Lung-F 0.0 112674 OA Synovial Fluid cells5 2.4 112354 Normal Lung-M 0.0 117100 OA Cartilage Rep14 3.4 12374 Crohns-F 0.0 112756 OA Bone9 44.1 112389 Match Control Crohns-F 1.3 112757 OA Synovium9 0.0 112375 Crohns-F 3.3 112758 OA Synovial Fluid Cells9 2.5 12732 Match Control Crohns-F 28.7 117125 RA Cartilage Rep2 3.3 112725 Crohns-M 0.0 113492 Bone2 RA 19.8 112387 Match Control 6.9 113493 Synovm2 RA 12.8 Crohns-M 6.9 113493 Synovium2 112378 Crohns-M 0.0 113494 Syn Fluid Cells RA 14.4 329 WO 03/050245 PCT/USO2/38594 112390 Match Control 112390 Match Control 5.4 113499 Cartilage4 RA 29.5 Crohns-M 112726 Crohns-M 2.3 113500 Bone4 RA 17.0 112731 Match Control 8.4 113501 Synovium4 RA 43.8 Crohns-M,. .. l. . 112380 Ulcer Col-F 0.0 113502 Syn Fluid Cells4 RA 18.4 112734 Match Control Ulcer I 12734 ach Control Ulcer 100.0 113495 Cartilage3 RA 16.7 Col-F 12384 UlcerCol-F 3.5 113496 Bone3RA 34.2 ..... ............ ........ ......... . . .. ........ ............ ... 0 .... v i m 3 112737 Match Control Ulcer 0.0 113497 Synovium3 RA 5.9 Col-F 112386 Ulcer Col-F 0.0 113498 Syn Fluid Cells3 RA 15.9 112738 Match Control Ulcer 19.3 117106 Normal Cartilage Rep20 0.0 Col-F 112381 Ulcer Col-M 0.0 113663 Bone3 Normal 0.0 112735 Match Control Ulcer 0.0 113664 Synovium3 Normal 0.0 Col-M 112382 Ulcer Col-M 0.0 113665 Syn Fluid Cells3 Normal 1.1 112394 Match Control Ulcer ] 112394 Match Control Ulcer 0.0 117107 Normal Cartilage Rep22 0.0 Col-M 112383 Ulcer Col-M . _ 8.7 113667 Bone4 Normal 5.3 112736 Match Control Ulcer 2.2 113668 Synovium4 Normal 0.0 Col-M 112423- Psoriasis-F 0.0 113669 Syn Fluid Cells4 Normal 8.6 Table MC. General screening panel v1.5 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5910, issue Name Ag5910, Run Run 247583780 247583780 Adipose 4.3 Renal ca. TK-10 3.9 Melanoma* Hs688(A).T 0.0 Bladder 10.0 Melanoma* Hs688(B).T 0.0 Gastric ca. (liver met.) NCI-N87 0.0 Melanoma* M14 0.0 Gastric ca. KATO III 0.2 Melanoma* LOXIMVI 0.0 Colon ca. SW-948 10.0 Melanoma* SK-MEL-5 0.2 Colon ca. SW480 0.2 Squamous cell carcinoma SCC-4 0.0 Colon ca.* (SW480 met) SW620 0.0 Testis Pool 1.0 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 0.0 Prostate Pool 1.4 Colon ca. CaCo-2 0.0 Placenta 5.6 Colon cancer tissue 100.0 Uterus Pool 0.2 Colon ca. SW116 0.0 Ovarian ca. OVCAR-3 0.0 Colon ca. Colo-205 0.0 Ovarian ca. SK-OV-3 0.0 Colon ca. SW-48 0.0 330 WO 03/050245 PCT/USO2/38594 Ovarian ca. OVCAR-4 0.0 Colon Pool 0.6 Ovarian ca. OVCAR-5 0.0 Small Intestine Pool 0.3 Ovarian ca. IGROV-1 0.0 Stomach Pool 1.5 Ovarian ca. OVCAR-8 0.0 Bone Marrow Pool 0.4 Ovary 0.5 Fetal Heart 0.2 Breast ca. MCF-7 0.0 Heart Pool 0.6 Breast ca. MDA-MB-231 0.1 Lymph Node Pool 1.2 Breast ca. BT 549 0.0 Fetal Skeletal Muscle 0.7 Breast ca. T47D 0.0 Skeletal Muscle Pool 1.1 Breast ca. MDA-N 0.0 Spleen Pool 5.7 Breast Pool 1.0 Thymus Pool 6.1 Trachea 0.4 CNS cancer (glio/astro) U87-MG 0.0 Lung 0.5 CNS cancer (glio/astro) U-118-MG 0.0 Fetal Lung 2.4 CNS cancer (neuro;met) SK-N-AS 0.0 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 0.1 Lung ca. LX-1 2.7 CNS cancer (astro) SNB-75 0.0 Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 0.0 Lung ca. SHP-77 1.8 CNS cancer (glio) SF-295 0.0 Lung ca. A549 0.0 Brain (Amygdala) Pool 1.8 Lung ca. NCI-H526 0.0 Brain (cerebellum) 0.9 Lung ca. NCI-H23 0.3 Brain (fetal) 0.5 Lung ca. NCI-H460 0.0 Brain (Hippocampus) Pool 3.1 Lung ca. HOP-62 0.0 Cerebral Cortex Pool 1.6 Lung ca. NCI-H522 0.0 Brain (Substantia nigra) Pool 1.4 Liver 0.1 Brain (Thalamus) Pool 3.6 Fetal Liver 0.6 Brain (whole) 0.2 Liver ca. HepG2 4.5 Spinal Cord Pool 2.1 Kidney Pool 2.4 Adrenal Gland 2.0 Fetal Kidney 0.0 Pituitary gland Pool 1.9 Renal ca. 786-0 0.0 Salivary Gland 0.1 Renal ca. A498 0.0 Thyroid (female) 0.2 Renal ca. ACHN 0.0 Pancreatic ca. CAPAN2 0.0 Renal ca. UO-31 0.0 Pancreas Pool 1.6 Table MD. Panel 4.1D Rel. Rel. Exp.

0 Exp.(%) Tissue Name Ag5910, Tissue Name Ag5910, Run Run 247578007 247578007 Secondary Th act 28 IHUVYEC IL-ibeta 0.0 Secondary Th2 act 100.0 HUVEC IFN gamma 0.0 Secondary Trl act 19.5 HUVEC TNF alpha + IFN gamma 0.0 331 WO 03/050245 PCT/USO2/38594 Secondary Thl rest 1.4 JHUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 1.8 IHUVEC IL-11l 0.0 Secondary Trl rest 1.2 Lung Microvascular EC none ]0.0 Primary Th act 0.0 Lung Microvascular EC TNFalpha 0.0 Primary Th act .0+ IL-lbeta Primary Th2 act 31.0 Microvascular Dermal EC none 0.0 Primary Trl act 20.9 Microsvasular Dermal EC 0.0 PrimryTl _ac20. _TNFalpha + IL-lbeta 0 Primary Thl rest 1.0 Bronchial epithelium TNFalpha + 0.0 ILlbeta Primary Th2 rest 2.9 Small ainvrway epithelium none 0.0 Primary Tl rest 0.0 Small airway epithelium TNFalpha 0.0 + IL-1beta CD45RA CD4 lymphocyte act 2.6 Coronery artery SMC rest 0.0 CD45RO CD4 lymphocyte act 16.3 Coronery artery SMC TNFalpha + 0.0 IL-lbeta CD8 lymphocyte act 0.6 Astrocytes rest 0.0 Secondary CD8 lymphocyte rest 2.8 Astrocytes TNFalpha + IL-1beta 0.0 Secondary CD8 lymphocyte act 2.0 KU-812 (Basophil) rest 0.0 CD4 lymphocyte none 1.0 KU-812 (Basophil) 0.2 PMA/ionomycin 2ry Thl/Th2/Trl anti-CD95 'C1O 2ry Thl 2/Trlanti-cD95 3.3 CCD1106 (Keratinocytes) none 0.0 CHI1I LAK cells rest 4

.

2 CCD1106 (Keratinocytes) 0.0 TNFalpha + IL-1beta LAK cells IL-2 7.6 Liver cirrhosis 0.0 LAK cells IL-2+IL-12 1.7 NCI-H292 none 0.0 LAK cells IL-2+IFN gamma 4.1 NCI-H292 IL-4 0.0 LAK cells IL-2+ IL-18 2.0 NCI-H292 IL-9 0.0 LAK cells PMA/ionomycin 5.4 NCI-H292 IL-13 0.0 NK Cells IL-2 rest 32.1 NCI-H292 IFN gamma 0.0 Two Way MLR 3 day . 1.2 HPAEC none 0.0 Two Way MLR 5 day 0.0 HPAEC TNF alpha + IL-1 beta 0.0 Two Way MLR 7 day 0.3 Lung fibroblast none 10.0 PBMC rest 0.9 Lung fibroblast TNF alpha + IL-1 0.0 beta PBMC PWM 0.0 Lung fibroblast IL-4 0.0 PBMC PHA-L 03 Lung fibroblast IL-9 0.0 Ramos (B cell) none 0.0 Lung fibroblast IL-13 0.0 Ramos (B cell) ionomycin 0.0 Lung fibroblast IFN gamma 0.0 B lymphocytes PWM 1.3 Dermal fibroblast CCD1070 rest 0.0 B lymphocytes CD40L and IL-4 1.2 Dermal fibroblast CCD 1070 TNF 18.2 alpha ..... - dbcAMP 8.0 Dermal fibroblast CCD1070 IL-1 0.0 beta 332 WO 03/050245 PCT/USO2/38594 EOL-1 dbcAMP 0.0 Dermal fibroblast IFN gamma 0.0 PMA/ionomycin Dendritic cells none 3.6 Dermal fibroblast IL-4 0.0 Dendritic cells LPS 1.7 Dermal Fibroblasts rest 0.0 Dendritic cells anti-CD40 1.2 Neutrophils TNFa+LPS 0.5 Monocytes rest 0.3 Neutrophils rest 0.7 Monocytes LPS 53.2 Colon 0.5 Macrophages rest 1.8 Lung 0.0 Macrophages LPS 2.5 Thymus 0.3 HUVEC none 0.0 Kidney 0.5 HUVEC starved 0.0 Table ME. Panel 5 Islet Rel. Rel. Exp.(% Exp.(%) Tissue Name Ag5910, Tissue Name Ag5910, Run Run 247609827 247609827 97457 Patient-02go adipose 10.7 94709_Donor 2 AM - A adipose 3.9 97476_Patient-07skskeletal 3.0 94710 Donor 2 AM - B adipose 0.0 muscle 97477 Patient-07ut uterus 0.0 94711 Donor 2 AM - Cadipose 0.0 97478 Patient-07plplacenta i100.0 94712_Donor 2 AD - Aadipose 16.6 99167 Bayer Patient 1 00 . 194713 Donor 2 AD - B_adipose 0.8 97482 Patient-08ut uterus 8.8 94714Donor 2 AD - C -adipose 18.9 97483Patient-8plplacenta 94742 Donor 3 U - A _Mesenchymal 0.0 7483_Patient-08pllacenta 7.9 Stem Cells 0 _____ __________9473 Donor 3 U -B Meseyma 97486 Patient-09sk skeletal 0.0 94743_Donor 3 U - BMesenchymal 0.0 muscle Stem Cells 97487 Patient-09ut uterus 0.0 94730 Donor 3 AM - A adipose 0 .7488_Patient-09pl_placenta 33.7 94731 Donor 3 AM - B adipose 0.0 97492 Patient-10ut uterus 6.3 94732 Donor 3 AM - C adipose _3.0 97493 Patient-10pl_placenta. 14.7 94733.Donor 3 AD - A adipose 77.4 97495 Patient-1 lgo adipose 1.2 94734 Donor 3 AD - B adipose 0.0 97496 Patient-i lsk skeletal 1.1 94735-Donor 3 AD - C adipose 0.0 muscle 97497 Patient-i ut uterus 1.1 77138 Liver HepG2untreated _,9.8 73556_Heart Cardiac stromal cells ] 97498_Patient-1 lpl_placenta 2.0 73556HeartCardiac stromal cells 0.0 (pimary)_______ 97500 Patient-12go adipose 7.1 81735 Small Intestine 25.9 97501 Patient-12sk skeletal 6.4 72409 Kidney Proximal Convoluted ... muscle -Tubule 97502 Patient-12ut uterus 1.7 82685 Small intestine Duodenum 10.0 90650_AdrenalAdrenocortical 97503Patient-12plplacenta 2.3 _adenoma

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4_. .. 333 WO 03/050245 PCT/US02/38594 94721 Donor 2 U- 0.0 72410 Kidney HRCE 0.0 A_Mesenchymal Stem Cells 94722 Donor 2 U - 0.0 72411 Kidney HRE 0.0 B Mesenchymal Stem Cells_ 94723 Donor 2 U - 0.0 73139_Uterus Uterine smooth 0.0 C Mesenchymal Stem Cells 1 muscle cells AI_comprehensive panel vl.0 Summary: Ag5910 Highest expression is seen in a match control sample of ulcerative colitis (CT=32.2). Low but significant levels of expression are seen in clusters of samples derived from OA and RA. Thus, modulation of 5 this gene product may be useful in the treatment of these diseases. Generalscreening_panel_vl.5 Summary: Ag5910 Highest expression is seen in a colon cancer tissue (CT=28.5). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker of this disease. 10 Low but significant levels of expression are also seen in the hippocampus, cerebral cortex, substantia nigra, thalamus, pituitary, pancreas, adrenal, fetal skeletal muscle, and adipose. This expression suggests that this gene may be involved in the pathogenesis of diseases of these tissues. Panel 4.1D Summary: Ag5910 Highest expression of this gene is seen in 15 chronically activated Th2 cells (CT=29.7). Prominent levels of expression are also seen in chronically activated Thl and Trl cells, as well as in acutely activated Th2 and Trl cells, CD45RO CD4 lymphocytes, LPS activated monocytes, and resting NK cells. Since lung inflammatory diseases such as asthma and chronic obstructive pulmonary diseases are mediated by Th2 cells, this protein may be involved in the lung pathology associated with 20 these Th2 T cells. Therefore, therapeutics designed against the protein encoded by this gene may be useful for the treatment of lung inflammatory diseases. Meyaard et al. have proposed that the Leukocyte-associated IG-like receptor family, which includes LAIR-1 and LAIR-2, may be pivotal in regulation of the mucosal immune response (J Exp Med 2001 194(1):107-12). Thus LAIR-2 encoded by this gene may function in vivo in the 25 normal establishment of tolerance. Modulation of the function of this gene or LAIR-2 encoded by this gene with a therapeutic antibody directed to the extracellular domain or with a protein therapeutic comprising the extracellular domain may be useful under chosen conditions in the stimulation or suppression of the immune response. Such therapeutics 334 WO 03/050245 PCT/USO2/38594 may have beneficial effects in treating diseases such as asthma, IBD, psoriasis, and arthritis in which T cells are chronically stimulated. Panel 5 Islet Summary: Ag5910 Highest expression is seen in the placenta (CT=32). Low but significant levels of expression are also seen in samples derived from 5 adipose and small intestine. N. CG162687-01: membrane protein-like Protein. Expression of gene CG162687-01 was assessed using the primer-probe set Ag5906, described in Table NA. Results of the RTQ-PCR runs are shown in Tables NB, NC and 10 ND. Table NA. Probe Name Ag 5906. .. . . . Start SEQ ID Primers Sequenes Length Position No Forward 5'-gctgaatagcgtcttcctcttc-3' 22 11887 224 Probe TET-5 '-ccttctacatcaagaagtacaccctcc 30 19 13 2 tga-3'-TAMRA Reverse 5'-cgaagatgccctggagtt-3' 18 1945 226 Table NB. AI comprehensive panel v1.0 Rel. Rel. Rel. Rel. Exp.(%) Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag5906, Ag5906, issue Name Ag5906, Ag5906, Run Run Run Run 247682906 256261784 247682906 256261784 112427 Match Control 110967 COPD-F 1.4 2.5 112427 Match Control 3.0 1.9 Psoriasis-F 110980 COPD-F 0.7 1.4 112418 Psoriasis-M 0.7 1.9 110968 COPD-M 1.4 3.1 112723 Match Control 0.1 1.1 Psoriasis-M 110977 COPD-M 2.7 4.1 1112419 Psoriasis-M 2.2 1.4 110989 1 40 112424 Match Control 0.3 0.8 2.1 4.0 0.3 0.8 Emphysema-F Psoriasis-M 110992 12 7 1109 2.5 3.6 1 12420 Psoriasis-M 4.0 7.1 Emphysema-F 110993 2.0 2.6 112425 Match Control 3.0 2.1 Emphysema-F I_ Psoriasis-M 302 110994 0.9 0.1 104689 (MF) OA 5.9 7.2 Emphysema-F_ _ Bone-Backus 110995 1 104690 (MF) Adj 7Emphyse.a-F 7.7 11.7 '"Normal" 2.1 2.7 ..... Emphysema-F .Bone-Backus ..... 335 WO 03/050245 PCT/USO2/38594 110996 104691 (MF) OA 211.1 3.5 3.8 Emphysema-F 2.1 1Synovium-Backus .5. 104692 (BA) OA 110997 Asthma-M 2.7 1.5 104692 (BA) OA 0.1 (0.1 Cartilage-Backus 104694 (BA) OA 1.31 111001 Asthma-F 2.2 0.8 104694 (BA) A 1.9 3.1 Bone-Backus 104695 (BA) Adj 111002Asthma-F 2.7 4.8 "Normal" 1.7 0.7 Bone-Backus 111003 Atopic 2.4 1.8 104696 (BA) OA 2.4 1.1 Asthma-F 2.4 Synovium-Backus 241 111004 Atopic 13 3.2 104700 (SS) OA 5.7 7.3 Asthma-F . . . . .... Bone-Backus .. 104701 (SS) Adj 111005 Atopic 0.8 1.8 "Normal" 2.0 3.4 Asthma-F IBone-Backus 111006 Atopic 0.1 4.7 104702 (SS) OA 1.8 4.8 Asthma-F Synovium-Backus 111417 Allergy-M 0.8 1.7 Rep117093 OA Cartilage 2.1 2.9 112347 Allergy-M 0.0 0.0 112672 OA Bone5 5.3 7.3 112349 Normal 00 100 112673 OA 1.5 1.9 Lung-F Synovium5 112357Normal 1 112674 OA Synovial 1 Lung-F 05 1.8 Fluid cells5 1.7 3.6 112354 Normal 03 0.4 117100 OA Cartilage 1.1 1.4 Lung-M Repl4 112374 Crohns-F 0.9 0.6 112756 OA Bone9 1.5 2.7 112389 Match 112757 OA Co, ol , o1s~ . 0 .t" t: ,.: _. .. ................... 2.0 0.7 0.5 ControlCrohns-F Synovium9 _ n112758 OA Synovial 1.22.2 112375 Crohns-F 0.6 0.4 Fi O li 1.2 2.2 Fluid Cells9 112732 Match 117125 RA Cartilage 1.7 1.8 Control Crohns-F Rep2 112725 Crohns-M 0.2 0.7 13492 Bone2 RA 2.8 7.9 112387 Match 07 1.6 113493 Synovium2 1.8 2.2 Control Crohns-M . RA • ' ' _ 113494 Syn Fluid 112378 Crohns-M 0.0 0.0 cellsRA 3.8 3.0 Cells RA 112390 Match 1.8 3.2 113499 Cartilage4 RA 4.0 7.3 Control Crohns-M 112726 Crohns-M 0.6 3.2 113500 Bone4 RA 4.5 7.6 112731 Match 1.0 2.4 113501 Synovium4 2.3 3.4 Control Crohns-M RA 112380 Ulcer 1.0113502 Syn Fluid 18 1.7 Col-F Cells4 RA 336 WO 03/050245 PCT/USO2/38594 112734 Match Control Ulcer 100.0 100.0 113495 Cartilage3 RA 2.4 3.6 Col-F 112384 Ulcer 6.8 14.1 113496 Bone3 RA 4.4 5.8 Col-F 112737 Match1 112737 Match 113497 Synovium3 Control Ulcer 0.8 0.4 RA2.7 3.0 Col-F 112386 Ulcer 0.0 0.9 113498 Syn Fluid 3.6 18.3 Col-F Cells3 RA 112738 Match 117106 Normal Control Ulcer 2.1 4.2 Cartilage Rep20 1.4 0.3 Col-F 112381 Ulcer 0.1 0.0 113663 Bone3 Normal 2.8 0.0 Col-M 112735 Match 113664 Synovium3 Control Ulcer 0.7 1.2 Normal 0.0 0.0 Normal Col-M 112382 Ulcer 1.3 1.5 113665 Syn Fluid 0.1 0.0 Col-M 1.3 1.5 Cells3 Normal . 0.0 112394 Match 77Normal 117107 Normal Col-M 112383 Ulcer 3.8 3.8 113667 Bone4 Normal 0.5 1.0 Col-M 112736 Match 113668 Synovium4 0 Control Ulcer 1.0 1.6 Normal0.9 1.0 Col-M ... 3 .9 1 113669 Syn Fluid 112423 Psoriasis-F 0.9 1.7 Cells4 Normal 2.2 3.0 Table NC. General screening Panel v1.5 Rel. Rel. Rel. Rel. Exp.(%) Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag5906, Ag5906, issue Name Ag5906, Ag5906, Run Run Run Run 247453559 255877137 247453559 255877137 Adipose 7.3 8.1 _ Renal ca. TK-10 4.7 _ _ 8.0 --

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R Melanoma* 0.0 0.0 Bladder 15.1 17.2 Hs688(A).T Melanoma* 0.0 0.0 Gastric ca. (liver 7.5 9.1 Hs688(B).T met.) NCI-N87 . Melanomrna*M14 0.3 0.1 stric ca. KATO 13.1 18.0 Melanoma* 0.2 0.1 Colon ca. SW-948 1.3 1.6 LOXIMVI Melanoma* 1.6 2.3 Colon ca. SW480 6A 11.0 Melanoma*Conjl SK-MEL-5 I... 337 WO 03/050245 PCT/USO2/38594 Squamous cell 0.2 0.4 Colon ca.* (SW480 3.2 2.6 carcinoma SCC-4 met) SW620 Testis Pool 1.6 1.6 Colon ca. HT29 9.5 10.3 Prostate ca.* (bone 0.0 0.4 Colon ca. HCT-116 5.0 9.0 met) PC-3 Prostate Pool 3.8 3.2 Colon ca. CaCo-2 0.0 0.2 Placenta 5.1 7.0 Colon cancer tissue 22.7 23.0 Uterus Pool 1.4 0.9 Colon ca. SW1116 0.0 0.1 Ovarian ca.J Ovarian ca. 4.8 3.8 Colon ca. Colo-205 1.1 0.7 OVCAR-3 Ovarian ca. SK-OV-3 0.0 0.0 Colon ca. SW-48 1.2 1.3 Ovarian ca. 0.0 0.2 Colon Pool 5.6 6.0 Ovarian ca. OVCAR-4 Ovarian ca. 66.9 80.1 Small Intestine Pool 6.3 3.8 OVCAR-5 Ovarian ca. 0.5 0.2 Stomach Pool 4.7 5.0 IGROV-1 Ovarian ca. 0.3 0.4 Bone Marrow Pool 6.1 3.9 OVCAR-8 SOvary 2.6 3.2 Fetal Heart 2.0 2.6 Breast ca. MCF-7 1.0 0.8 Heart Pool 2.2 2.2 Breast ca. 2.7 2.0 Lymph Node Pool 9.0 7.1 MDA-MB-231 Breast ca. BT 549 0.0 0.0 Fetal Skeletal 2.6 2.5 Muscle Skeletal M uscle................... ........... ... .. Breast ca. T47D 5.3 4.2 Skeletal Muscle 0.7 0.6 Pool Breast ca. MDA-N 0.2 0.4 Spleen Pool 52.9 1100.0 Breast Pool 4.4 6.6 Thymus Pool 100.0 76.8 CNS cancer Trachea 9.8 14.2 (glio/astro) 0.0 0.1 U87-MG CNS cancer Lung 0.7 0.6 (glio/astro) 0.0 0.0 U-118-MG CNS cancer Fetal Lung 23.0 20.6 (neuro;met) 0.0 0.2 SK-N-AS CNS cancer (astro) 0.0 Lung ca. NCI-N417 0.0 0.0 SF-539 0.0 Lung ca. LX-1 14.1 16.2 CNS cancer (astro) 0.0 0.1 I SNB-75 Lung ca. NCI-H146 0.0 0.2 NS cancer (glio) 0.3 0.3 _______SNB-19 Lung ca. SHP-77 1.1 1.4 CNS cancer (glio) 0.0 0.1 SF-295 Lung ca. A549 0.3 0.2 Brain (Amygdala) 8 3.3 Pool 1.8 3.3 338 WO 03/050245 PCT/US02/38594 Lung ca. NCI-H526 0.0 0.2 Brain (cerebellum) 1.8 2.1 Lung ca. NCI-H23 1.2 1.2 Brain (fetal) 3.3 3.0 Brain Lung ca. NCI-H460 0.0 0.2 (Hippocampus) 3.8 3.9 Pool Cerebral Cortex Lung ca. HOP-62 2.6 4.6 PooCerebral Coex 1.0 1.4 Lung ca. NCI-H522 0.0 0.1 Brain (Substantia 2.5 38 Lung ca. NCI-H522 0.0 .1 nigra) Pool 2.5 3.8 Liver 2.9 4.0 Brain (Thalamus) 53 3.8 Liver 2.9 4.0 Pool . Fetal Liver 44.4 49.0 Brain (whole) 3.8 2.1 Liver ca. HepG2 16.3 16.7 Spinal Cord Pool 7.9 4.5 Kidney Pool 8.4 10.5 Adrenal Gland 4.5 4.4 Fetal Kidney 1.7 2.2 Pituitary gland Pool 0.0 0.3 Renal ca. 786-0 0.0 0.0 Salivary Gland 7.3 5.7 Renal ca. A498 0.0 0.0 Thyroid (female) 1.8 2.9 Pancreatic ca. Renal ca. ACHN 0.0 0.4 CAPAN2 2.1 2.7 Renal ca. UO-31 1.1 1.7 Pancreas Pool 12.9 15.6 Table ND. Panel 4.1D Rel. Rel. Rel. Rel. Exp.(% Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag5906, Ag5906, Tissue Name Ag5906, Ag5906, Run Run Run Run 247576174 255877310 247576174 255877310 Secondary ThI act 47.6 60.3 -HUVEC IL-lbeta 0.0 0.0 Secondary Th2 act 66.4 84.7 HUVEC IFN gamma 0.0 0.0 ] ... .. !8.

7 152.

9 HUVEC TNF alpha +. 1. Secondary Trl act 18.7 52.9 HUVIFNECTNF alpha 0.0 0.0 Secondary Thl rest 0.8 20.3 HUVEC TNF alpha0.0 0.0 ILA Secondary Th2 rest 2.8 19.2 . HUVEC L-11 0.1 0.1 Secondary T rest 2.7 27.4 Lung Microvascular 0.0 0.3 Secondary Trl rest 2.7 27.4 EC none . 03 Lung Microvascular Primary Thl act 0.3 8.0 EC TNFalpha + 0.0 0.0 IL-lbeta ]~Microvascular O Primary Th2 act 54.3 52.9 Microvascular .0 0.0 Dermal EC none Microsvasular Primary Trl act 41.2 46.7 Dermal EC 0.0 0.0 TNFalpha + IL-lbeta fBroncileihlu Primary Thl rest 3.6 11.1 B r nchial epithelium 0.0 0.0 339,TNFalpha+lLlbeta 0.. 339' WO 03/050245 PCT/US02/38594 Primary Th2 rest 12.3 19.5 Small airway 0.1 0.0 m rs 1239.epithelium none Small airway Primary Trl rest 2.9 14.9 epithelium TNFalpha 0.0 0.0 + IL-lbeta CD45RA CD4 27.5 28.7 Coronery artery SMC 0.0 0.0 lymphocyte act rest CD45RO CD4 58.6 59.5 Coronery artery SMC 00 0.0 lymphocyte act TNFalpha + IL-lbeta CD8 lymphocyte act 4.8 21.5 Astrocytes rest 0.0 0.0 1' ...... .................. ....... ° ° .... Secondary CD8 34.2 25.3 Astrocytes TNFalpha 0.0 0.0 lymphocyte rest + IL-1beta Secondary CD8 3.7 10.6 KU-812 (Basophil) 15.7 22.7 lymphocyte act 37. rest KU-812 (Basophil) CD4 lymphocyte none 5.0 24.1 KU-812(aophil) 19.1 27.9 PMA/ionomycin 2ry CCD1106 Thl/Th2/Trl anti-CD95 11.3 32.8 C io 0.4 0.5 CH11 (Keratinocytes) none CCD1106 LAK cells rest 12.0 18.8 (Keratinocytes) 0.0 0.1 TNFalpha + IL-lbeta LAK cells IL-2 10.4 24.7 Liver cirrhosis 0.9 1.6 LAK cells IL-2+IL-12 j1.7 3.9 NCI-H292 none 0.1 0.2 LAK cells IL-2+IFN 7.7 11.3 NCI-H292 IL-4 0.1 0.1 ga ................................--.-.---....-.. .......................-............................. .................................... gamma _ __ __ ______ LAK cells IL-2+ IL-18 4.4 11.4 NCI-H292 IL-9 0.2 0.0 LAK cells ! 5 7 !04 ] LA cells 15.7 15.5 NCI-H292 IL-13 0.4 0.2 PMA/ionomycin NK Cells IL-2 rest 100.0 100.0 NCI-H292IFN 0.1 02 gamma Two Way MLR 3 day 6.7 15.3 HPAEC none 0.1 0.1 HPAEC TNF alpha + Two Way MLR 5 day 1.7 7.9 IL-1 beta 0.1 0.1 IL-1 beta0.01 Two Way MLR 7 day 4.2 7.1 Lung fibroblast none 0.0 0.0 ]~Lung fibroblast TNF PBMC rest 2.9 14.1 Lung fibroblast TNF 0.0 0.0 alpha + IL-1 beta PBMC PWM 4.0 8.7 Lung fibroblast IL-4 0.0 _ 0.0 PBMC PHA-L 5.6 18.3 Lung fibroblast IL-9 0.0 0.0 Ramos (B cell) none 2.1 6.6 Lung fibroblast IL-13 0.0 0.0 Ramos (B cell) 25.7 31.9 Lung fibroblast IFN 0.0 0.0 ionomycin . ganmna B lymphocytes PWM 17.2 15.3 Dermal fibroblast 00 0.0 ______ _ "CCD1070 res t B lymphocytes CD40L 42.6 54.3 Dermal fibroblast 42. 14361 '6 82.9 and IL-4 CCD1070 TNF alpha EOL- dbcAMP 5.1 4.8 Dermal fibroblast 0.0 00 4CCD1070 IL-1 beta 340 WO 03/050245 PCT/US02/38594 EOL-1 dbcAMP 62 Dermal fibroblast 0.0 0.8 6.2 0.0 0.0 PMA/ionomycin IFN gamma , , ,., ,., Dermal fibroblast 0.00 Dendritic cells none 9.0 14.7 Dermal fibroblast 0.0 0.0 ......... ............... . . . .. D erm al Fibroblasts Dendritic cells LPS 0.2 0.9 Dermal Fibroblasts 0.0 0.0 rest Dendritic cells 1.0 4.5 Neutrophils 1.5 3.1 Monocytes rest 1.3 11.4 Neutrophils rest 13.4 14.0 Monocytes LPS 1.3 1.9 Colon 0.2 0.4 Macrophages rest 2.4 3.4 Lung 0.3 0.2 Macrophages LPS 0.3 0.2 Thymus 6.3 9.0 HUVEC none 0.0 0.0 Kidney 0.2 102 HUVEC starved 0.0 0.0 1 AI_ecomprehensive panel_vl.0 Summary: Ag5906 Two experiments with the same probe and primer produce results that are in excellent agreement. Highest expression is seen in a match control sample from ulcerative colitis (CTs=27-28), with prominent expression also seen in a match control sample from Crohn's. Thus, expression of this gene 5 could be used to differentiate between these samples and other samples on this panel and as a marker of these diseases. Modulation of the expression or function of this gene may also be useful for the treatment of ulcerative colitis and Crohn's disease. Generalscreeningpanel_v1.5 Summary: Ag5906 Two experiments with the same probe and primer produce results that are in very good agreement. Highest expression 10 is seen in the spleen and thymus (CTs=28-30). Moderate levels of expression are also seen in an ovarian cancer cell line and fetal liver, with low but significant expression seen in adipose, thyroid, pancreas, adrenal, thyroid, and regions of the brain, including cerebellum, cerebral cortex, amygdala, hippocampus, thalamus, and substantia nigra. Therefore, expression of this gene maybe used to identify thymic and splenic 15 tissue. Furthermore, drugs that inhibit the function of this protein may regulate T cell development in the thymus and reduce or eliminate the symptoms of T cell mediated autoimmune or inflammatory diseases, including asthma, allergies, inflammatory bowel disease, lupus erythematosus, or rheumatoid arthritis. Additionally, small molecule or antibody therapeutics designed against this putative protein may disrupt T cell development 20 in the thymus and function as an immunosuppresant for tissue transplant. The expression profile suggests that this gene product may also be involved in metabolic and neurodegenerative diseases, such as obesity, diabetes, Parkinson's, and Alzheimer's. 341 WO 03/050245 PCT/USO2/38594 Panel 4.1D Summary: Ag5906 Two experiments with the same probe and primer produce results that are in excellent agreement. Highest expression is seen in resting NK cells (CTs=28). This gene is also expressed by T lymphocytes prepared under a number of conditions at moderate levels, B cells, LAK cells, dendritic cells, basophils, monocytes, 5 macrophages, and TNF-a treated dermal fibroblasts. Therefore, therapeutics designed with the protein encoded by this transcript may help to regulate T cell function and be effective in treating T cell mediated diseases such as asthma, arthritis, psoriasis, IBD, and lupus. O. CG162738-01: splice variant of MADSO1-like Protein. Expression of gene CG162738-01 was assessed using the primer-probe set Ag5851, 10 described in Table OA. Table OA. Probe Name A25851 Primers Length Start SEQ ID Position No Forward 15'-gccgtcagaaaggaaacagt-3' 20 1014 227 Probe TET-5'-tttcatcagttgcattttccaggctg 26 1039 228 Probe -_3'-TAMRA26 ..... Reverse 5'-gtcacagtccaaaatgttttatacag-3' 26 1069 229 P. CG162738-02: splice variant of MADSO1-like Protein. 15 Expression of gene CG162738-02 was assessed using the primer-probe set Ag5860, described in Table PA. Table PA. Probe Name Ag5860 Primers Sequencs Length Start SEQ D Position No Forward 5' -gagcagttcategcaggaa-3 ' '20 381 230 Probe TET-5' -tgggagtacaggagctgatcaatacac 28 231 _Probe g-3'-TAMPA 28553 231 Reverse 5'-cagtgaggactcgtgcttgtc-3' 21 582 232 Q. CG163175-01: Type Ib membrane protein-like Protein. 20 Expression of gene CG163175-01 was assessed using the primer-probe set Ag5907, described in Table QA. Results of the RTQ-PCR runs are shown in Tables QB, QC, QD, QE and QF. 342 WO 03/050245 PCT/US02/38594 Table QA. Probe Name Ag5907 Start SEQ ID Primers Sequence Length Start inSEQ Position No Forward 5'-gtaaaccgactqtccaagttactg- 24 1004 233 Probe TET-5' -ccatagtctcgaaataacagcattCC 28 1035 234 c-3'-TAMRA Reverse 5'-taaaacgaagctgagtcttatcatatct-3' 28 1064 .235 Table QB. AI comprehensive pvanel v1.

0 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5907, issue Name Ag5907, Run Run 247842186 247842186 110967 COPD-F 34.6 112427 Match Control Psoriasis-F 65.1 110980 COPD-F 44.8 112418 Psoriasis-M 30.4 110968 COPD-M 27.7 112723 Match Control Psoriasis-M 8.6 110977 COPD-M 66.0 112419 Psoriasis-M 50.3 110989 Emphysema-F 64.6 112424 Match Control Psoriasis-M 22.7 10992 Emphysema-F 26.4 112420 Psoriasis-M 76.8 110993 Emphysemna-F 38.4 112425 Match Control Psoriasis-M 60.7 110994 Emphysema-F 17.0 104689 (MF) OA Bone-Backus 51.8 109 104690 (MF) Adj "Normal" 33.0 110995 Emphysema-F 77.9 Bone-Backus 33.0 110996 Emphysema-F . 13.1 . 104691 (MF) OA Synovium-Backus 42.3 110997 Asthma-M 13.2 104692 (BA) OA Cartilage-Backus 18.2 111001 Asthma-F 48.6 104694 (BA) OA Bone-Backus 36.3 .. 111002 Asthma-F 45. 7 104695 (BA) Adj "Normal" 301 111002 Asthma-F 45.7 Bone-Backus 30 . 111003 Atopic Asthma-F 27.4 104696 (BA) OA Synovium-Backus 44.4 111004 Atopic Asthma-F -.-. 42.6 104700 (SS) OA Bone-Backus -12.7 111005 Atopic Asthma-F 33.2 104701 (SS) Adj "Normal" 0.4 111005 Atopic Asthma-F 33.2 Bone-Backus30.4 111006 Atopic Asthma-F 8.7 104702 (SS) OA Synovium-Backus 64.2 111417 Allergy-M .28.5 117093 OA Cartilage Rep7 49.3 112347 Allergy-M 15.4 112672 OA Bone5 57.4 112349 Normal Lung-F 15.5 112673 OA Synovium5 17.1 112357 Normal Lung-F 53.2 112674 OA Synovial Fluid cells 24.5 112354 Normal Lung-M 19.6 117100 OA Cartilage Repl4 10.1 -F 1. 112756 OA Bone9 763 112389 Match Control Crohns-F 44.1 112757 QA SYovium9 14.3 112375 Crohns-F 16.2 112758 OA Synovial Fluid Cells9 21.3 112732 Match Control Crohns-F 147.3 117125 RA Cartilage Rep2 47.3 112725 Crohns-M 8.1 113492 Bone2 RA 20.2 343 WO 03/050245 PCT/US02/38594 112387 Match Control Cr27Ma 16.0 113493 Synovium2 RA 8.6 Crohns-M 112378 Crohns-M 16.5 113494 Syn Fluid Cells RA 13.4 112390 Match Control 58.2 113499 Cartilage4 RA 15.8 Crohns-M 112726Crohns-M 41.2 113500 Bone4 RA 17.7 112731 Match Control _ _ _ ___._ 112731 Match Control 29.5 113501 Synovium4 RA 14.0 Crohns-M 112380 Ulcer Col-F 35.

6 113502 Syn Fluid Cells4 RA 8.1 112734 Match Control Ulcer 100.0 113495 Cartilage3 RA 14.6 Col-F 112384 Ulcer Col-F 78.5 113496 Bone3 RA 11.2 112737 Match Control Ulcer Col-F [20.3 113497 Synovium3 RA 9.9 Col-F 112386 Ulcer Col-F [4.9 113498 Syn Fluid Cells3 RA 18.3 112738 Match Control Ulcer 19.6 117106 Normal Cartilage Rep20 5.1 Col-F 112381 Ulcer Col-M 12.9 113663 Bone3 Normal 14.3 112735 Match Control Ulcer 33.0 113664 Snovium3 Normal 5.6 Col-M Synovium3 Normal 112382 Ulcer Col-M 44.8 113665 Syn Fluid Cells3 Normal 8.0 112394 Match Control Ulcer 13.4 117107 Normal Cartilage Rep22 21.5 Col-M 112383 Ulcer Col-M 64.2 113667 Bone4 Normal 15.2 112736 Match Control Ulcer 21.9 113668 Synovium4 Normal 24.7 Col-M _ 112423 Psoriasis-F 29.7 113669 Syn Fluid Cells4 Normal 33.9 Table OC. General screening panel vl.5 .... Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5907, issue Name Ag5907, Run Run 248163366 248163366 Adipose 8.9 Renal ca. TK-10 45.4 Melanoma* Hs688(A).T 19.8 Bladder 13.9 Melanoma Hs688(B).T 23.8 Gastric ca. (liver met.) NCI-N87 36.6 Melanoma* M14 36.9 Gastric ca. KATO II 58.6 Melanoma* LOXIMVI 56.6 Colon ca. SW-948 26.4 Melanoma* SK-MEL-5 30.8 Colon ca. SW480 49.7 Squamous cell carcinoma SCC-4 28.1 Colon ca.* (SW480 met) SW620 35.4 Testis Pool 14.2 Colon ca. HT29 13.5 Prostate ca.* (bone met) PC-3 19.8 Colon ca. HCT-116 100.0 Prostate Pool 16.2 Colon ca. CaCo-2 153.2 Placenta 1.7 Colon cancer tissue 17.4 Uterus Pool 15.1 Colon ca. SW1116 114.7 344 WO 03/050245 PCT/US02/38594 Ovarian ca. OVCAR-3 27.9 Colon ca. Colo-205 7.3 Ovarian ca. SK-OV-3 30.8 Colon ca. SW-48 7.6 Ovarian ca. OVCAR-4 19.5 Colon Pool 13.9 Ovarian ca. OVCAR-5 29.7 Small Intestine Pool 18.7 Ovarian ca. IGROV-1 22.4 Stomach Pool 12.3 Ovarian ca. OVCAR-8 7.3 Bone Marrow Pool 7.5 Ovary 8.9 Fetal Heart 7.1 Breast ca. MCF-7 27.7 Heart Pool 9.0 Breast ca. MDA-MB-231 56.3 Lymph Node Pool 25.9 Breast ca. BT 549 55.5 Fetal Skeletal Muscle 5.0 Breast ca. T47D 22.5 Skeletal Muscle Pool 18.2 Breast ca. MDA-N 24.3 Spleen Pool 22.1 Breast Pool 15.4 .Thymus Pool 15.5 Trachea 9.0 CNS cancer (glio/astro) U87-MG 45.1 Lung 3.2 CNS cancer (glio/astro) U-118-MG 65.1 Fetal Lung 18.3 CNS cancer (neuro;met) SK-N-AS 28.7 Lung ca. NCI-N417 12.4 CNS cancer (astro) SF-539 15.7 Lung ca. LX-1 60.7 CNS cancer (astro) SNB-75 40.1 Lung ca. NCI-H146 7.9 CNS cancer (glio) SNB-19 17.1 Lung ca. SHP-77 17.4 CNS cancer (glio) SF-295 38.2 Lung ca. A549 53.2 Brain (Amygdala) Pool 15.8 Lung ca. NCI-H526 6.0 Brain (cerebellum) 27.5 Lung ca. NCI-H23 44.4 Brain (fetal) 18.0 Lung ca. NCI-H460 . 15.3 Brain (Hippocampus) Pool 17.8 Lung ca. HOP-62 10.0 Cerebral Cortex Pool 16.6 Lung ca. NCI-H522 60.7 Brain (Substantia nigra) Pool 112.6 Liver 1.0 Brain (Thalamus) Pool 23.0 Fetal Liver 17.1 Brain (whole) 7.7 Li ;reT ~~~~~~~epG 2~~~ ................ , iiii -]a a................. p l"o aP a

"

....... ....... . .. 9... . - -.... Liver ca. HepG2 34.4 Spinal Cord Pool 17.9 Kidney Pool 28.3 Adrenal Gland 11.7 Fetal Kidney 15.6 Pituitary gland Pool 3.2 Renal ca. 786-0 154 Salivary Gland 1.8 Renal ca. A498 16.3 Thyroid (female) 3.3 Renal ca. ACHN 31.9 Pancreatic ca. CAPAN2 19.8 Renal ca. UO-31 29.9 Pancreas Pool 18.4 Table OD. Panel 4.1D Rel. Rel. Exp.

0 Exp.(%) Tissue Name Ag5907, Tissue Name Ag5907, Run Run 247576176 ,247576176 Secondary Thl act 31.6 HUVEC IL-lbeta 38.4 Secondary Th2 act 38.4 HUVEC FN gamma 38.2 345 WO 03/050245 PCT/USO2/38594 Secondary Trl act 10.4 HUVEC TNF alpha+ IFN gamma 2.6 Secondary Thl rest 0.4 HUVEC TNF alpha + IL4 2.7 Secondary Th2 rest 0.4 HIUVEC IL-11 20.7 Secondary Trl rest 0.7 Lung Microvascular EC none 54.7 Primary Th act 3.6 Lung Microvascular EC TNFalpha 1.3 Primary Th1 act 3.6 + IL-lbeta1 Primary Th2 act 32.8 Microvascular Dermal EC none 1.6 Primary T act 39.8 Microsvasular Dermal EC8.5 Primary Trl act 39.8 TNFalpha + IL-lbeta 8.5 Primary Thl rest 0.5 Bronchial epithelium TNFalpha + 14.8 Primary Th rest ILbeta Primary Th2 rest 3.1 Small airway epithelium none 15.7 SSmall airway epithelium TNFalpha 40.1 Primary Trl rest 1.0 + IL-lbeta CD45RA CD4 lymphocyte act 37.1 Coronery artery SMC rest 14.4 Coronery artery SMC TNFalpha + 19.5 CD45RO CD4 lymphocyte act 84.7 .IL-lbeta 19.5 CD8 lymphocyte act 9.2 Astrocytes rest 2.8 Secondary CD8 lymphocyte rest 41.5 Astrocytes TNFalpha + IL-lbeta 2.9 Secondary CD8 lymphocyte act 8.2 KU-812 (Basophil) rest 32.8 CD4 lymphocyte none .6 KU-812 (Basophil) 39.0 CD4 lymphocyte none 0.6 PMA/ionomycin 2ry Thl/Th2/Trlani-CD95 3.4 CCD1106 (Keratinocytes) none 60.3 CH11 LAK cells rest 99 CCD 1106 (Keratinocytes) 28.1 LAK cells rest 9 TNFalpha + IL-lbeta LAK cells IL-2 9.5 Liver cirrhosis 9.6 LAK cells IL-2+IL-12 2.9 NCI-H292 none 19.6 LAK cells IL-2+IFN gamma 5.6 NCI-H292 IL-4 33.0 LAK cells IL-2+ IL-18 4.5 NCI-H292 IL-9 40.1 LAK cells PMA/ionomycin 13.6 NCI-H292 IL-13 34.4 NK Cells IL-2 rest 27.2 NCI-H292 IFN gamma 14.8 Two Way MLR 3 day 8.0 HPAEC none 11.4 Two Way MLR 5 day 1.2 HPAEC TNF alpha + IL-1 beta 34.4 Two Way MLR 7 day 6.9 Lung fibroblast none 21.3 PM rs2.Lung fibroblast TNF alpha + IL-1 20.7 PBMC rest 2.0 beta PBMC PWM 4.1 Lung fibroblast IL-4 19.5 PBMC PHA-L 5.9 Lung fibroblast IL-9 15.0 Ramos (B cell) none 142 Lung fibroblast IL-13 2.7 Ramos 03(B cell) ionomycin 100.0 Lung fibroblast IFN gamma 41.2 B lymphocytes PWM 64.2 Dermal fibroblast CCD1070 rest 40.3 Dermal fibroblast CCD1070 TNF 4. B lymphocytes CD40L and IL-4 24.0 Dermal fibroblast CCD1070 TF 41.5 EOL-1__ _ bD35 ermal fibroblast CCD1070 IL- 13.5 346EOL-1 dbcAMP 35.1 beta 346 WO 03/050245 PCT/USO2/38594 EOL-1 dbcAMP 0.2 Dermal fibroblast IFN gamma 15.5 PMA/ionomycin Dendritic cells none 7.0 Dermal fibroblast IL-4 39.5 Dendritic cells LPS 1.5 Dermal Fibroblasts rest 17.3 Dendritic cells anti-CD40 1.5 Neutrophils TNFa+LPS 0.2 Monocytes rest 0.1 Neutrophils rest 0.5 Monocytes LPS 11.8 Colon 1.5 Macrophages rest 3.5 Lung 0.9 Macrophages LPS 3.0 Thymus 2.7 HUVEC none 26.6 Kidney 18.0 HUVEC starved 22.1 .Table QE. Panel 5D Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag507, Tissue Name Ag5907, Run Run 248193678 248193678 97457 Patient-02go_adipose 45.1 94709 Donor 2 AM - A adipose 39.0 7muscl6 Patient-07skskeletal 35.4 94710_Donor 2 AM - B adipose 23.5 muscle 97477 Patient-07ut uterus _ 40.1 94711Donor 2 AM - C adipose 15.5 97478 Patient-07plplacenta 14.7 94712_Donor 2 AD - Aadipose 41.5 97481Patient-08sk_skeletal 40.3 94713_Donor 2 AD - Badipose 50.7 muscle 97482 Patient-08ut uterus 24.7 94714 Donor 2 AD - Cadipose 52.9 ............. 97483 Patient-08pl_placenta 5.3 94742_Donor 3 U - AMesenchymal 19.2 - Stem Cells 97486 Patient-09skskeletal 2.6 94743 Donor 3 U - B_Mesenchymal 19.9 muscle Stemn Cells 97487_Patient-09ututerus 35.4 94730 Donor 3 AM - Aadipose 47.3 97488_Patient-09pl_placenta 7.2 94731 Donor 3 AM - Badipose 38.2 97492 Patient-10ut uterus 48.3 94732 Donor 3 AM - C adipose 26.6 97493_Patient-10plplacenta 19.2 94733 Donor 3 AD - A adipose 48.6 97495 Patient-11 lgo adipose 17.7 94734_Donor 3 AD - B adipose 29.1 97496 Patient-1 lsk skeletal 12.3 94735_Donor 3 AD - C adipose 35.4 muscle 97497 Patient-1 lut uterus 39.0 77138 Liver HepG2untreated 100.0 ~~~73556_IHeartCardiac stromal cells 2. '(primary) 97498_Patient-I1 lplplacenta 115.6 (7356iart da tomlcls 2. 97500_ Patient-12go adipose __ 32.3 81735 Small Intestine 49.7 97501_Patient-12sk skeletal 29.7 72409 Kidney Proximal Convoluted 13.6 muscle Tubule 97502_Patient-12ututerus 50.0 82685_Small intestineDuodenum 13.5 _ _ 90650_Adrenal Adrenocortical 97503_Patient-12pl_placenta 10.0 5.4 adenoma 347 WO 03/050245 PCT/US02/38594 94721_Donor 2 U - 28.5 1 72410 Kidney HRCE 62.0 AMesenchymal Stem Cells _- -__ 6. _ 94722_Donor 2 U - 13.8 72411 Kidney HRE 37.1 B Mesenchymal Stem Cells 1 94723_Donor 2 U - 16.2 73139 Uterus Uterine smooth 9.0 C Mesenchymal Stem Cells musclecells Table OF. general oncolovgy screening panel v 2.4 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5907, Tissue ame Ag5907, Run Run 260316170 260316170 Colon cancer 1 21.3 Bladder cancer NAT 2 0.9 Colon cancer NAT 1 110.9 IBladder cancer NAT3 0.2 Colon cancer 2 39.2 Bladder cancer NAT 4 5.6 Colon cancer NAT 2 8.2 Prostate adenocarcinoma 1 29.3 Colon cancer 3 43.2 Prostate adenocarcinoma 2 12.6 Colon cancer NAT 3 27.0 Prostate adenocarcinoma 3 6.4 Colonmalignant cancer 4 77.4 Prostate adenocarcinoma 4 119.1 Colon normal adjacent tissue 4 3.3 Prostate cancer NAT 5 5.2 Lung cancer 1 112.4 Prostate adenocarcinoma 6 3.8 Lung NAT 1 0.5 Prostate adenocarcinoma 7 8.6 Lung cancer 2 90.8 Prostate adenocarcinoma 8 0.9 Lung NAT 2 3.1 Prostate adenocarcinoma 9 22.2 Squamous cell carcinoma 3 61.1 Prostate cancer NAT 10 2.4 Lung NAT 3 0.8 Kidney cancer 1 16.7 metastatic melanoma 1 . 10.4 KidneyNAT 1 7.9 Melanoma 2 3.3 JKidney cancer 2 100.0 Melanoma 3 4.3 Kidney NAT 2 12.2 metastatic melanoma 4 21.2 Kidney cancer 3 18.6 metastatic melanoma 5 31.6 Kidney NAT 3 4.6 Bladder cancer 1 2.9 Kidney cancer 4 12.7 Bladder cancer NAT 1 0.0 Kidney NAT 4 4.9 Bladder cancer 2 4.3 AI_comprehensive panel_v1.0 Summary: Ag5907 Highest expression of this gene is detected in matched control sample for ulcerative colitis (CT=29.5). This gene 5 shows ubiquitous expression in this panel, with moderate to low expression seen in samples derived from normal and orthoarthitis/ rheumatoid arthritis bone and adjacent bone, cartilage, synovium and synovial fluid samples, from normal lung, COPD lung, emphysema, atopic asthma, asthma, allergy, Crohn's disease (normal matched control and diseased), ulcerative colitis(normal matched control and diseased), and psoriasis (normal 10 matched control and diseased). Therefore, therapeutic modulation of this gene product may 348 WO 03/050245 PCT/USO2/38594 ameliorate symptoms/conditions associated with autoimmune and inflammatory disorders including psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis. General_screeningpanel_v1.5 Summary: Ag5907 Highest expression of this 5 gene is detected in colon cancer HCT-116 cell line (CT=27.4). Moderate to high expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, liver, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or 10 function of this gene may be effective in the treatment of pancreatic, gastric, colon, lung, liver, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal 15 muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, 20 cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Interestingly, this gene is expressed at much higher levels in fetal (CT=29.9) when 25 compared to adult liver (CT=33.9). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in 30 treatment of liver related diseases. Panel 4.1D Summary: Ag5907 Highest expression of this gene is detected in ionomycin treated Ramos B cells (CT=29). This gene shows a wide spread expression in this panel, with moderate to low expression in a wide range of cell types of significance in 349 WO 03/050245 PCT/USO2/38594 the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by thymus and kidney. Interestingly, expression of this gene is upregulated 5 upon activation of polarized T cells and Ramos B cells. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflanunmmatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. 10 - Panel 5D Summary: Ag5907 Highest expression of this gene is detected in liver cancer HepG2 cell line (CT=31.3): This gene shows a wide spread expression in this panel, with moderate to low expression in adipose, skeletal muscle, uterus, placenta, heart stromal cells, small intestine and kidney. Please see panel 1.5 for further discussion on the utility of this gene. 15 general oncology screening panelv_2.4 Summary: Ag5907 Highest expression of this gene is detected in kidney cancer (CT=28.2). Moderate to low expression of this gene is detected in normal and cancer samples derived from kidney, colon, lung, prostate, and melanoma. Expression of this gene is consistently higher in cancer samples as compared to adjacent normal tissue. Therefore, expression of this gene may be used as 20 diagnostic marker to detect the presence of these cancer and also therapeutic modulation of this gene or its protein product may be useful in the treatment of melanoma, kidney, colon, lung, and prostate cancers. R. CG163259-01: splice variant of cytokine-like factor-l-like Protein. Expression of gene CG163259-01 was assessed using the primer-probe set Ag5863, 25 described in Table RA. Results of the RTQ-PCR runs are shown in Table RB. Table RA. Probe Name Ag5863 .. . Start SEQ ID Primers Sequence Length Position No _______ Position No Forward 5'-gaggagtaccacggcgagag-3' 20 1671 236 Probe TET-5'-ctgccagataagctgtaggggctcag 27 694 237 g-3 -TAMRA .............. Reverse 5' -cctgaagtgagggtacagaggt-3, 22 771 1238 -- 350 WO 03/050245 PCT/USO2/38594 Table RB. General screening panel v1.5 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5863, issue Name Ag5863, Run Run 246285252 246285252 Adipose 0.0 Renal ca. TK-10 27.0 Melanoma* Hs688(A).T 14.1 Bladder 0.1 Melanoma* Hs688(B).T 20.6 Gastric ca. (liver met.) NCI-N87 0.0 Melanoma* M14 0.3 Gastric ca. KATO III 0.2 Melanoma* LOXIMVI 0.0 Colon ca. SW-948 0.0 Melanoma* SK-MEL-5 0.2 Colon ca. SW480 0.4 Squamous cell carcinoma SCC-4 0.0 Colon ca.* (SW480 met) SW620 0.0 Testis Pool 0.5 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 4.9 Prostate Pool 0.0 Colon ca. CaCo-2 0.0 Placenta 0.2 Colon cancer tissue 0.7 Uterus Pool 0.0 Colon ca. SW1116 0.3 Ovarian ca. OVCAR-3 0.4 Colon ca. Colo-205 0.0 Ovarian ca. SK-OV-3 1.9 Colon ca. SW-48 0.0 Ovarian ca. OVCAR-4 0.0 Colon Pool 0.3 Ovarian ca. OVCAR-5 2.7 Small Intestine Pool 0.0 Ovarian ca. IGROV-1 1.2 Stomach Pool 0.2 Ovarian ca. OVCAR-8 0.8 Bone Marrow Pool 0.0 Ovary 0.0 Fetal Heart 0.0 Breast ca. MCF-7 2.8 Heart Pool 0.2 Breast ca. MDA-MB-231 0.0 Lymph Node Pool 0.3 Breast ca. BT 549 0.1 Fetal Skeletal Muscle 0.0 Breast ca. T47D 0.8 Skeletal Muscle Pool 1.3 Breast ca. MDA-N 0.0 Spleen Pool 0.3 Breast Pool 0.2 Thymus Pool 0.1 Trachea 1.1 CNS cancer (glio/astro) U87-MG 0.0 Lung 0.0 CNS cancer (glio/astro) U-1 18-MG 8.9 Fetal Lung 0.2 CNS cancer (neuro;met) SK-N-AS 0.0 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 1.9 Lung ca. LX-1 0.0 CNS cancer (astro) SNB-75 0.0 Lung Ca. NCI-H146 0.1 CNS cancer (glio) SNB-19 2.0 Lung ca. SHP-77 0.2 CNS cancer (glio) SF-295 2.7 Lung ca.AS49 0.3 Brain (Amygdala) Pool 0.4 Lung ca. NCI-H526 0.0 Brain (cerebellum) 0.3 Lung ca. NCI-H23 0.5 Brain (fetal) 0.0 Lung ca. NCI-H460 5.3 Brain (Hippocampus) Pool 0.5 Lung ca. HOP-62 .. 0.2 Cerebral Cortex Pool 2.1 351 WO 03/050245 PCT/USO2/38594 Lung ca. NCI-H522 1.6 Brain (Substantia nigra) Pool 21.4 Liver 0.0 Brain (Thalamus) Pool 0.4 Fetal Liver 0.0 Brain (whole) 0.9 Liver ca. HepG2 100.0 Spinal Cord Pool 0.3 Kidny Pool 0. Adrenal Gland 0.5 Fetal Kidney 0.0 Pituitary gland Pool 0.3 Renal ca. 786-0 0.0 Salivary Gland 0.5 Renal ca. A498 1.0 Thyroid (female) . 1. Renal ca. ACHN 0.0 Pancreatic ca. CAPAN2 0.4 Renal ca. UO-31 .0 Pancreas Pool 0.4 General_screeningpanel_vl.5 Summary: Ag5863 Highest expression of this gene is detected in liver cancer HepG2 cell line (CT=29.8). Moderate to low levels of expression of this gene is mainly seen in a brain cancer U-118-MG cell line, colon cancer HCT-116 cell line, lung cancer NCI-H460 cell line, renal cancer TK-10 cell line, and two 5 melanoma cell lines. Therefore, expression of this gene may be used as diagnostic marker to detect the presence of melanoma, brain, colon, lung and renal cancers. Furthermore, therapeutic modulation of this gene or its protein product through the use of antibodies or small molecule drug may be useful in the treatment of melanoma, brain, colon, lung and renal cancers. 10 S. CG163259-02: splice variant of cytokine-like factor-i-like Protein. Expression of gene CG163259-02 was assessed using the primer-probe set Ag5917, described in Table SA. Results of the RTQ-PCR runs are shown in Table SB. Table SA. Probe Name Ag5917 Primers Sequenes Length Start SEQ ID Position No Forward 5' -gcagcatcctggctctctt-3' 19 480 239 TET-5' -cgatgtactcacgctggatatcctgga 29 553 240 tg-3 ' -TAMRA Reverse 5'-ggatctggtatttggcttga-3' 20 691 241 15 Table SB. General screening panel vl.5 Rel. Rel. Tissue Name Ag5917, issue Name Ag5917, Run Run 247834853 247834853 352 WO 03/050245 PCT/USO2/38594 Adipose 0.0 Renal ca. TK-10 13.3 Melanoma* Hs688(A).T 57.4 Bladder 0.0 Melanoma* Hs688(B).T 100.0 Gastric ca. (liver met.) NCI-N87 0.0 Melanoma* M14 0.0 Gastric ca. KATO III 0.0 Melanoma* LOXIMVI 0.0 Colon ca. SW-948 0.0 Melanoma* SK-MEL-5 0.0 Colon ca. SW480 0.0 Squamous cell carcinoma SCC-4 0.0 Colon ca.* (SW480 met) SW620 0.0 Testis Pool 0.0 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 0.0 Prostate Pool 0.0 Colon ca CaCo-2 0.0 Placenta 0.0 Colon cancer tissue 0.0 Uterus Pool 0.0 Colon ca. SW1 116 0.0 Ovarian ca. OVCAR-3 0.0 Colon ca. Colo-205 0.0 Ovarian ca. SK-OV-3 0.0 Colon ca. SW-48 0.0 Ovarian ca. OVCAR-4 0.0 Colon Pool 0.0 Ovarian ca. OVCAR-5 0.0 Small Intestine Pool 0.0 Ovarian ca. IGROV-1 0.0 Stomach Pool 0.0 Ovarian ca. OVCAR-8 0.0 Bone Marrow Pool 10.0 Ovary0.0 Fetal Heart 0.0 Breast ca. MCF-7 0.0 Heart Pool 0.0 Breast ca. MDA-MB-231 0.0 Lymph Node Pool 0.0 Breast ca. BT 549 0.0 Fetal Skeletal Muscle 0.0 Breast ca. T47D 0.0 Skeletal Muscle Pool 0.0 Breast Ca. MDA-N 0.0 Spleen Pool 0.0 Breast Pool 0.0 Thymus Pool 0.0 Trachea 0.0 CNS cancer (glio/astro) U87-MG 0.0 Lung 0.0 CNS cancer (glio/astro) U-118-MG 13.6 Fetal Lung 0.0 CNS cancer (neuro;met) SK-N-AS 0.0 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 5.1 Lung ca. LX-1 0.0 CNS cancer (astro) SNB-75 0.0 Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 0.0 Lung ca. SHP-77 0.0 CNS cancer (glio) SF-295 0.0 Lung ca. A549 0.0 Brain (Amygdala) Pool 0.0 Lung ca. NCI-H526 0.0 Brain (cerebellum) 0.0 Lung ca. NCI-H23 0.0 Brain (fetal) 10.0 Lung ca. NCI-H460 0.0 Brain (Hippocampus) Pool 0.0 Lung ca. HOP-62 0.0 Cerebral Cortex Pool 0.0 Lung ca. NCI-H522 0.0 Brain (Substantia nigra) Pool 0.0 Liver 0.0 Brain (Thalamus) Pool 0.0 Fetal Liver 0.0 Brain (whole) 0.0 Liver ca. HepG2 82.4 Spinal Cord Pool 0.0 Kidney Pool 0.0 Adrenal Gland 0.

0 Fetal Kidney 0.0 Pituitary gland Pool .0 Renal ca. 786-0 00............ Salivary Gland -0.0 353 WO 03/050245 PCT/USO2/38594 Renal ca. A498 2.3 Thyroid (female) .0.0 Renal ca. ACHN 10.0 Pancreatic ca. CAPAN2 0.0 Renal ca. UO-31 0.0 Pancreas Pool 0.0 Generalscreening_panel_vl.5 Summary: Ag5917 Low expression of this gene is seen exclusively in a melanoma and a liver cancer cell line samples (CT=34.4-34.7). Therefore, expression of this gene may be used as diagnostic marker to detect the presence of these cancers and also, therapeutic modulation of this gene may be useful in the 5 treatment of these cancers. T. CG163259-03: splice variant of cytokine-like factor-l-like Protein. Expression of gene CG163259-03 was assessed using the primer-probe set Ag5921, described in Table TA. Table TA. Probe Name Ag5921 ]~Start SEQ ID Primers Sequenes Length Start SEQ ED Position No Forward 5'-gggacaacctcgggcagac-3' 19 450 242 Pro TET-5' -agcccctacagcttatctggcaggacc 30 Probe 30, '.TN 480 243 tot-31'-TAMRA Reverse 5 ' -ggtgccctgaagtgagggta-3 '20 571 244 10 U. CG163425-01: Interleukin-15 receptor alpha chain precursor-like Protein. Expression of gene CG163425-01 was assessed using the primer-probe set Ag5904, described in Table UA. Results of the RTQ-PCR runs are shown in Tables UB, UC and 15 UD. Table UA. Probe Name Ag5904 .......... Start SEQ ID Primers Length ]Position No Forward 5' -caaagattagaaccacagag ' 23 355 245 TET-5 ' -taagcagtcatgagtcctcccacgg Probe 3' -TAMA 25 378 246 Reverse 5'-agttcttggctgttgtctgaga-3' 22 410 247 354 WO 03/050245 PCT/USO2/38594 ................... able LB. Al comrehesiVe anel v1.O Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5904, issue Name Ag5904, Run Run 247947768 247947768 110967 COPD-F 11.6 112427 Match Control Psoriasis-F 66.4 110980 COPD-F _27.4 112418 Psoriasis-M 6.0 110968 COPD-M 31.4 112723 MatchControlPsoriasis-M 0.0 110977 COPD-M 100 0 112419 Psoriasis-M 7.6 110989 Emphysema-F 27.5 112424 Match Control Psoriasis-M 4.0 110992 Emphysema-F 10.1 112420 Psoriasis-M 60.7 110993 Emphysema-F 5.0 12425 Match Control Psoriasis-M 49.7 110994 Emphysema-F .0 104689 (MF) OA Bone-Backus 5.8 110995 Emphysema-F 15.9 104690 (MF) Adj "Normal" 0.0 Bone-Backus 110996 Emphysema-F4.0 104691 (MF) OA Synovium-Backus 0.0 110997 Asthma-M 2.3 . 104692 (BA) OA Cartilage-Backus 9.5 111001 Asthma-F 11.3 104694 (BA) OA Bone-Backus 11.0 111002 Asthma-F 20.7 104695 (BA) Adj "Nonnrmal" 14.3 Bone-Backus 4 111003 Atopic Asthma-F 17.6 104696 (BA) OA Synovium-Backus 19.9 111004 Atopic Asthma-F 16.4 104700 (SS) OA Bone-Backus 21.8 111005 Atopic Asthma-F 5.1 104701 (SS) Adj "Normal" 3.4 Bone-Backus 111006 Atopic Asthma-F 7.7 104702 (SS) OA Synovium-Backus 18.2 111417 Allergy-M 5.8 117093 OA Cartilage Rep7 18.0 112347 Allergy-M 0.0 112672 OA Bone5 28.9 112349 Normal Lung-F 0.0 112673 OA Synovium5 24.0 112357 Normal Lung-F 15.4 112674 OA Synovial Fluid cells5 4.6 112354 Normal Lung-M 0.0 117100 OA Cartilage Repl4 18.6 112374 Crohns-F 20.7 112756 OA Bone9 0.0 112389 Match Control Crohns-F 2.7 112757 OA Synovium9 5.8 112375 Crohns-F 24.7 112758 OA Synovial Fluid Cells9 10.3 112732 Match Control Crohns-F 18.7 117125 RA Cartilage Rep2 18.6 Magypg h 7117125 RA Cartilage Rep2 .. 18.6 112725 Crohns-M 0.0 113492 Bone2 RA 12.6 112387 Match Control 13493 Crohns-M 8.2 113493 Synovium2 RA7.6 _112378 Crohns-M ... 0.0 113494 Syn Fluid Cells RA 3.2 112390 Match Control 11.6 113499 Cartilage4 RA 12.8 Crolns-M 112726 Crohns-M 43.2 113500 Bone4 RA 14.4 112731 Match Control . Crons-M 14.8113501 Synovium4 35.6 112380 Ulcer Col-F 8.8 113502 Syn Fluid Cells4 RA 8.5 355 WO 03/050245 PCT/US02/38594 112734 Match Control Ulcer 1 Col-F 13.9 113495 Cartilage3 RA 6.6 112384 Ulcer Col-F 53.2 113496 Bone3 RA14.7 112737 Match Control Ulcer 90 11397 Soviu3 RA . Col-F 9.0 113497 Synovium3 RA 3.1 112386 Ulcer Col-F 0.0 113498 Syn Fluid Cells3 RA 25.2 112738 Match Control Ulcer Col-F 17.8 117106 Normal Cartilage Rep20 8.6 112381 Ulcer Col-M 0.0 113663 Bone3 Normal 4.1 112735 Match Control Ulcer . Col-M 12.9 113664 Synovium3 Normal 0.0 112382 Ulcer Col-M 10.8 113665 Syn Fluid Cells3 Normal 00 112394 Match Control Ulcer Col-M 3.8 117107 Normal Cartilage Rep22 28.7 112383 Ulcer Col-M .65.1 113667 Bone4 Normal 15.9 112736 Match Control Ulcer 0. CO WT ............................... 113668 Synovium 4 N orm al 1 . 112 423 Psoriasis-F 3.7 113669 Syn Fluid Cells4 Normal 22.7 Table UC. General sreeninZ Ianel vl.5 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5904, issue Name Ag5904, Run Run 247946847 247946847 Adipos e 2.8 Renal ca. TK-10 8.5 Melanoma* Hs688(A).T 3.5 Bladder 12.1 Melanoma* Hs68(B).T 1.2 Gastric ca. (liver met.) NCI-N87 i100.0 Melanoma* M14 0.0 Gastric ca. KATO III 21.0 Melanoma* LOXIMVI 4.2 Colon ca. SW-948 .2 Melanoma* SK-MEL-5 0.0 Colon ca. SW480 28.7 Squamous cell carcinoma SCC-4 76 .Colon ca.* (SW480 met) SW620 0.8 Testis Pool 3.0 Colon ca. HT29 2.7 Prostate ca.* (bone met) PC-3 2.7 Colon ca. HCT-116 9.8 Prostate Pool 2.1 Colon ca. CaCo-2 0.0 Placenta 3.5 Colon cancer tissue 19.8 Uterus Pool 1.2 Colon ca. SW1 16 4.3 Ovarian ca. OVCAR-3 4.6 Colon ca. Colo-205 2.3 Ovarian ca. SK-OV-3 55.9 Colon ca. SW-48 0.4 Ovarian ca. OVCAR-4 5.0 Colon Pool 2.2 Ovarian ca. OVCAR-5 72.2 Small Intestine Pool 11.6 Ovarian ca. IGROV-1 8.9 Stomach Pool 2.7 Ovarian ca. OVCAR-8 4.1 Bone Marrow Pool 2.3 Ovary 1.2 Fetal Heart 0.0 Breast ca. MCF-7 2.2 Heart Pool 1.3 Breast ca. MDA-MB-231 25.9 Lymph Node Pool 6.5 356 WO 03/050245 PCT/USO2/38594 Breast ca. BT 549 3.8 Fetal Skeletal Muscle 0.7 Breast ca. T47D 1.5 4Skeletal Muscle Pool 12.0 Breast ca. MDA-N 0.3 Spleen Pool 16.8 Breast Pool 8.1 Thymus Pool 2.6 jTrachea - 9.5 CNS cancer (glio/astro) U87-MG 12.2 Lung 0.3 CNS cancer (glio/astro) U-118-MG* 8.2 Fetal Lung 18.2 CNS cancer (neuro;met) SK-N-AS 7.6 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 3.8 Lung ca. LX-1 5.0 CNS cancer (astro) SNB-75 8.6 Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 0.8 Lung ca. SHP-77 0.0 CNS cancer (glio) SF-295 60.3 Lung ca. A549 0.0 Brain (Amygdala) Pool 0.7 Lung ca. NCI-H526 0.0 Brain (cerebellum) 0.8 Lung ca. NCI-H23 5.1 Brain (fetal) 0.0 Lung ca NCIH4i60 4.4 Brain (HIippocampus) Pool 0.0 Lungca. HOP-62 4.4 Cerebral Cortex Pool 3.3 Lung ca. NCI-H522 4 .7 Brain (Substantia nigra) Pool 0.0 Liver 1.8 Brain (halamus) Pool 0.0 Fetal Liver 8.5 Brain (whole) 3.1 Liver ca. HepG2 0.0 Spinal Cord Pool 2.0 Kidney Pool 16.4 Adrenal Gland 5.5 Fetal Kidney 0.0 Pituitary gland Pool 0.0 Renal ca. 786-0 2.8 Salivary Gland 1.8 Renal ca. A498 10.1 Thyroid (female) 0.0 Renal ca. ACHIN 0.0 Pancreatic ca. CAPAN2 33.2 Renal ca. UO-31 8.1 Pancreas Pool 13.9 Table UD. Panel 4.1D Rel. Rel. Exp.0 Exp.(%) Tissue Name Ag5904, Tissue Name Ag5904, Run Run 247574996 247574996 Secondary Thl act . 25.9 UVEC IL-lbeta 22.5 Secondary Th2 act 47.6 HUVEC IFN gamma 344.... Secondary TrI act 5.2 HUVEC TNF alpha + IFN gamma 15.9 Secondary Thl rest .0.0 HUVEC TNF alpha +l. ..... L4....... . Secondary Th2 rest 0.0 HUVEC IL-11 n5o2 Secondary Trl est 0.0 Lung Microvascular EC none 8.5 Primary l act Lung Microvascular EC TNFalpha 6.1 Primary Th1 act 0.0 + IL-beta 6 1 Primary Th2 act i_ __12.2 Microvascular Dermal EC none 1.8 Primary T act 14.1 Microsvasular Dermal EC 17.1 Primary Trl act 14.1 TNFalpha + L-lbeta 17.1 357 WO 03/050245 PCT/USO2/38594 .Primary Th rest 0. Bronchial epithelium TNFalpha + 0.0 Primary Thl rest 0.0 ]ILlbeta Primary Th2 rest 0.0 Small airway epithelium none 3.0 Small airway epithelium TNFalpha 4.0 Primary Trl rest 0.0 + IL-lbeta CD45RA CD4 lymphocyte act 29.5 Coronery artery SMC rest 1.6 CD45RO CD4 lymphocyte act 112 Coronery artery SMC TNFalpha + 11.1 CD45RO CD4 lymphocyte act 11.2 Astrocytes rest . Secondary CD8 lymphocyte rest 11.5 Astrocytes TNFalpha + IL-lbeta 0.0 Secondary CD8 lymphocyte act 0.9 KU-812 (Basophil) rest 4.0 KU-812 (Basophil) CD4 lymphocyte none 0.0 PMA/ionomycin 7.5 2ry Thl/Th2/Trlanti-CD95 0.0 CCD 1106 (Keratinocytes) none 1.7 CH1 1 LAK cells rest 10.2 CCD 1106 (Keratinocytes) 15.9 TNFalpha + IL-1beta . LAK cells IL-2 1.6 Liver cirrhosis 3.3 LAK cells IL-2+IL-12 j7.3 N.... CI-H292 none 1.6 LAK cells IL-2+IFN gamma 1.7 NCI-H292 IL-4 8.0 LAK cells IL-2+ IL-18 1.6 NCI-H292 IL-9 19.8 LAK cells PMA/ionomycin 29.7 N1CI-H292 IL-13 9.2 NK Cells IL-2 rest 9.2 NCI-H292 IFN gamma 2.9 Two Way MLR 3 day 10.7 HPAEC none 6.0 Two Way MLR 5 day 0.7 HPAEC TNF alpha + IL-1 beta 76.8 Two Way MLR 7 day 0.6 Lung fibroblast none 9.5 Srt.Lung fibroblast TNF alpha + IL- 1423 PBMC rest 0.0 beta beta PBMC PWM .0 . Lung fibroblast IL-4 0.0 PBMC PHA-L 4.7 Lung fibroblast IL-9 1.3 Ramos (B cell) none 0.0 Lung fibroblast IL-13 0.0 Ramos (B cell) ionomycin 4.5 Lung fibroblast IFN gamma 54.7 B lymphocytes PWM 14.6 Dermal fibroblast CCD1070 rest 1.5 Dermal fibroblast CCD1070 TNF B lymphocytes CD40L and IL-4 9.0 alpha ibroblast CCD 070 TNF 12.1 EOL- dbcAMP 0.5 Dermal fibroblast CCD 1070 IL-1 . EOL-1 dbcAMP 0.5 bea0.0 beta EOL-1 dbcAMP 0.0 Dermal fibroblast IFN gamma 35.8 PMA/ionomycin Dendritic cells none 3.4 Dermal fibroblast IL-4 22.4 Dendritic cells LPS 1.8 Dermal Fibroblasts rest 2.7 Dendritic cells anti-CD40 0.0 Neutrophils TNFa+LPS 0.0 Monocytes rest 0.0 Neutrophils rest 0.0 Monocytes LPS 100.0 Colon 0.0 Macrophages rest 0.0 Lung 0.0 Macrophages LPS 26.6 Thymus 0.0 358 WO 03/050245 PCT/USO2/38594 HUVEC none 1.6 Kidney 3.0 HUVEC starved 2.9 AI comprehensive panel_v1.0 Summary: Ag5904 Detectable expression is limited to a COPD sample (CT=34.4). General_screeningpanel_vl.5 Summary: Ag5904 Highest expression is seen in a gastric cancer cell line (CT=31.7). Moderate to low levels of expression are also seen in 5 cell lines derived from breast cancer, ovarian cancer, pancreatic cancer, and brain cancer. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker of these cancers. Panel 4.1D Summary: Ag5904 Highest expression is seen in LPS treated monocytes (CT=32.4). Low but significant levels are also seen in IFN gamma treated lung 10 and dermal fibroblasts, TN-F-a/IL1-b treated HPAECs and lung fibroblasts, LPS treated macrophages, chronically activated Thl and Th2 cells, and PMA/ionomycin treated LAK cells. Upon activation with pathogens such as LPS, monocytes contribute to the innate and specific immunity by migrating to the site of tissue injury and releasing inflammatory 15 cytokines. This release contributes to the inflammation process. Therefore, modulation of the expression of the protein encoded by this transcript may prevent the recruitment of monocytes and the initiation of the inflammatory process, and reduce the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, or rheumatoid arthritis. 20 V. CG163957-01: D86-like Protein. Expression of gene CG163957-01 was assessed using the primer-probe sets Ag5873 and Ag7796, described in Tables VA and VB. Results of the RTQ-PCR runs are shown in Tables VC and VD. Table VA. Probe Name Ag5873.. .. . ... .. .. Start SEQ ID Primers Sequenes Length Start SEQ ID Position No Forward 5'-aggtgaaccttgtgatattttgaa-3' 24 981 248 Probe TET-5' -cagaaaatagtatatgttgcaagacac 30 1010 249 ccc-3' -TAMRA Reverse 5'-gatatacagttttgagaatatgaggtttg-3 29 141 250 25 359 WO 03/050245 PCT/USO2/38594 Table VB. Probe Name Ag7796 Prmer s Lent Start SEQ ID Primers Length Position No Forward 5' -aatgaatttgataggcgatttg-3' 22 005 251 Probe TET-5' -ccaaacattgacctggtgttgcca- 24 5035 252 3 ' -TAMRA Reverse 5' -cttgtcattcctgtagttgatcct-3' 24 5064 253 Table VC. CNS neurodegeneration V1.0. Rel. Rel. Rel. Rel. Exp.(%) Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag5873, Ag7796, issue Name Ag5873, Ag7796, Run Run Run Run 247854047 312372410 247854047 312372410 AD IHippo .0 11.7 IControl (Path)3 392 2.2 _AD 1 Hippo 0.0 11.7 Temporal Ctx AD 2 Hippo 31.6 0.0 Control (Path) 4 41.8 4.1 AD 2 Hippo 31.6 .0 Temporal Ctx AD 3 Hippo 72.2 0.5 AD 1 Occipital Ctx 0.0 6.9 p00 AD 2 Occipital Ctx AD 4 Hippo 0.0 0.0 (Missing) 0.0 0.0 AD 5 Hippo 46.3 0.0 AD 3 Occipital Ctx 0.0 4.3 AD 6 Hippo 24.3 100.0 AD 4 Occipital Ctx 16.0 0.0 Control 2 Hippo 0.0 7.2 AD 5 Occipital Ctx 19.5 4.7 Control 4 Hippo 26.2 0.0 AD 6 Occipital Ctx 41.5 13.4 Control (Path) 3 25.0 Control 1 Occipital 0.0 10.5 Hpo100.0 25.0 t 0.0 10.5 Hippo Ctx Control 2 Occipital 1. . AD 1 Temporal Ctx 92.7 6.0 Control 2 Occipital 18.3 2.2 AD 2 Temporal Ctx 47.0 3.3 Control 3 Occipital 19.9 0.0 Ctx 4 Control 4 Occipital AD 3 Temporal Ctx 16.6 8.9 Ctl 36.9 4.9 Control (Path)1 AD 4 Temporal Ctx 0.0 1.4 Occipitarl (Path) 1 18.6 11.7 __________Occipital Ctx _____ AD 5 Inf Temporal 16.0 0.7 Control (Path) 2 42.9 8.2 Ctx Occipital Ctx AD 5 Sup Temporal 80.1 0.0 Control (Path) 3 20.7 2.2 Ctx Occipital Ctx AD 6 Inf Temporal 48.6 2.0 Control (Path) 4 20.4 13.1 Ctx Occipital Ctx AD 6 Sup Temporal 31.2 14.2 Control 1 Parietal 57.4 4.4 Ctx Ctx Control 1 Temporal 18.2 3.8 Control 2 Parietal 22.5 0.0 Ctx Ctx Control 2 Temporal 11.0 1.7 Control 3 Parietal 0.0 0.0 Ctx Ctx 360 WO 03/050245 PCT/US02/38594 Control 3 Temporal 43.2 2.6 Control (Path) 1 0.0 00 Ctx ... 2 Parietal Ctx 0.. Control 3 Temporal 0.0 0.0 Control (Path) 2 93.3 7.7 Ctx 0.0 00 Parietal Ctx 9. Control (Path) 1 20.3 0.0 Control (Path) 3 0.0 2.0 Temporal Ctx Parietal Ctx _" Control (Path) 2 91.4 2.4 Control (Path) 4 59.5 5.9 Temporal Ctx Parietal Ctx Table VD. Panel 4.1D Rel. Rel. Rel. Rel. Exp.(%) Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag5873, Ag7796, Tissue Name Ag5873, Ag7796, Run Run Run Run 247850137 312355982 247850137 312355982 Secondary Th1 act 0.0 0.0 HUVEC IL-lbeta 1.0 0.0 Secondary Th2 act 0.0 0.0 HUVEC IFN gamma 6.3 2.7 HSecondary Trl act 0.0 0.0 UVEC TNF alpha + 0.0 1.0 IFN gamma Secondary Trl act 0.0 00[Ngma1. . HUVEC TNF alpha +1 Secondary Thl rest 0.0 0.0 ILVEC TN alpha +0.0 0.0 Seco ndary Th2 rest 0.0 0.0 HUVEC IL-11 14.2 0.8 Secondary Tr rest 0.0 0.0 Lung Microvascular 100.0 47.6 EC none Lung Microvascular Primary Thl act 0.0 0.0 EC TNFalpha + 18.3 7.4 IL-lbeta Primary Th2 act 0.0 0.0 Microvascular 3.6 1.5 Dermal EC none Microsvasular Primary Trl act .0 0 0.0 Dermal EC TNFalpha 5.5 1.6 + IL-lbeta Primary Thl rest 0.0 0.0 Bronchial epithelium 00 .0 ......... TNFalpha+ ILlbeta 00. Primary Th2 rest 0.0 0.0 e airway 0.0 0.0 epithelium none Small airway Primary Trl rest 0.0 0.0 epithelium TNFalpha 0.0 0.0 + IL-lbeta CD45RA CD4 0.0 0.0 Coronery artery SMC 0.0 0.0 lymphocyte act rest CD45RO CD4 0.0 0.0 Coronery artery SMC 00 0.0 lymphocyte act 7TNFalpha + IL-lbeta 0.00 CD8 lymphocyte act 0.0 01.0 Astrocytes rest 0. 0 0.0 Secondary CD8 0.0 0.0 Astrocytes TNFalpha 0.0 0.0 lymphocyte rest + IL-lbeta Secondary CD8 0.0 0.0 KU-812 (Basophil) 00 0.0 lymphocyte act rest 0 361 WO 03/050245 PCT/USO2/38594 CD4 lymphocyte none 0.0 100.0 KU-812 (Basophil) 3.8 1.7 PMA/ionomycin 2ry CCD1106 Thl/Th2/Trlanti-CD95 0.0 0.0 (Keratinocytes) none 0.5 0.0 CH11 (Keratinocytes) none CHI 1 CCD1106 LAK cells rest 0.0 0.0 (Keratinocytes) 0.0 0.0 I TNFalpha + IL-1beta . LAK cells IL-2 0.0 0.0 Liver cirrhosis 8.4 3.8 LAK cells IL-2+IL-12 0. 0 0.0 NCI-H292 none 0.0 0.0 LAK cells IL-2+IFN 0.0 0.0 NCI-H292 IL-4 0.0 0.0 gamma LAK cells IL-2+ IL-18 0.0 0.0 NCI-H292 IL-9 0.0 0.0 LAK cells PA/oc 0.0 0.0 NCI-H292 IL-13 0.0 0.0 PMA/ionomycin 0 0 ]0 0NCI-H292 IFN 0 NK Cells IL-2 rest 0.0 0.0 gamma N 0.0 0.0 gamma Two Way MLR 3 day 0.0 0.0 HPAEC none 9.2 3.0 Two Way MLR 5 day 0.0 0.0 HPAEC TNF alpha + 2.7 1.3 IL-I beta Two Way MLR 7 day 0.0 0.0 Lung fibroblast none 0.8 0.0 ]Lung fibroblast TNF PBMC rest 0.0 0.2 Lung fibroblast TNF 0.0 0.0 alpha + IL-1 beta PBMC PWM jo.o 0.0 Lung fibroblast IL-4 o0.0 0.0 PBMC PHA-L 0.0 0.0 Lung fibroblast IL-9 0.0 0.0 Ramos (B cell) none 0.0 0.0 Lung fibroblast IL-13 0.0 0.0 Ramos (B cell) 0.0 0.0 Lung fibroblast IFN 0.0 0.0 ionomycmn gamma ... ............ Ranmsycell 0.0 0.0 lugfibroblast LIFN1 B lymphocytes PWM 0.0 0.0 Dermal fibroblast 0.0 0.0 By oe W.CCD1070 rest . . B lymphocytes CD40L 0.0 0.0 Dermal fibroblast 00 0.0 and IL-4 . 0 CCD1070 TNF alpha . EOL-1 dbcAMP 0.0 0.0 Dermal fibroblast 0.0 0.0 CCD1070 IL-1 beta EOL-1 dbcAMP Dermal fibroblast 0.0 0.0 0.0 0.0 PMA/ionomycin IFN gamma Dermal fibroblast Dendritic cells none 10.0 0.0 Dm0.0 0.0fbo IL-4 Dendritic cells LPS 0.0 0.0 Dermal Fibroblasts 0.0 0.0 rest Dendritic cells 0.0 0.0 Neutrophils 0.0 0.0 anti-CD40 TNFa+LPS I I Monocytes rest 0.0 0.0 Neutrophils rest 0.0 0.0 Monocytes LPS 0.0 0.0 Colon 0.0 0.6 acrophages rest 1. 0..0 Lung 1.2 0 .3 Macrophages LPS 10.0 0.0 Thymus 0.0 0.0 UVEC none ... 6 0.0 Kidney 2.2 10.6 362 WO 03/050245 PCT/USO2/38594 HUVEC starved 0.0 0.0 CNS_neurodegeneration_vl.0 Summary: Ag5873/Ag7796 Two experiments with two different probe and primer sets show that this gene is not differentially expressed in Alzheimer's disease. However, this profile does show that this gene is expressed at low levels in the brain. Therefore, therapeutic modulation of the expression or function of this 5 gene may be useful in the treatment of neurological disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy. Panel 4.1D Summary: Ag5873 Highest expression of this gene is seen in untreated lung microvascular endothelial cells (CT=29). Lower levels of expression are seen in these cells treated with TNF-a/IL-lb. Endothelial cells are known to play important 10 roles in inflammatory responses by altering the expression of surface proteins that are involved in activation and recruitment of effector inflammatory cells. This expression suggests a role for this gene in the maintenance of the integrity of the microvasculature. Therefore, therapeutics designed for this putative protein could be beneficial for the treatment of diseases associated with damaged microvasculature including heart diseases or 15 inflammatory diseases, such as psoriasis, asthma, and chronic obstructive pulmonary diseases. In addition, this expression in lung microvascular endothelial cells suggests that the protein encoded by this transcript may also be involved in lung disorders including asthma, allergies, chronic obstructive pulmonary disease, and emphysema. Therefore, therapeutic 20 modulation of the protein encoded by this gene may lead to amelioration of symptoms associated with psoriasis, asthma, allergies, chronic obstructive pulmonary disease, and emphysema. A related murine cDNA (AccNo AB055648.1) was found to be 83% identical at the protein level and the protein encoded by this cDNA was identified as a lymphocyte 25 secretion product. The difference between tissues that express the murine and human protein suggest that D86 protein encoded by this gene, as well as the murine protein, may be involved in selective processes in the immune response and thus be suitable targets for therapeutic intervention at these sites. W. CG164482-01: 4930418P06RIK Homolog with Rhomboid domain-like 30 Protein. 363 WO 03/050245 PCT/USO2/38594 Expression of gene CG164482-01 was assessed using the primer-probe sets Ag776, Ag6089 and Ag6090, described in Tables WA, WB and WC. Results of the RTQ-PCR runs are shown in Tables WD, WE, WF and WG. Table WA. Probe Name Ag776 Start SEQ ID Primers Sequence Length Position No Forward 5'-aacggagatcaagagggataaa-3' 22 105 254 TET-5 ' -tcctttctcaaatcttccatgttggg 27 144 255 Probe 1 a3'TNA27 144 25 a-3 '-TAMRAI reverse 5. 5'-tagggtgacaggtggaatattg-3' 22 175 2j56 ......... ....... T e W ~ ,P r b a a 0 9 ..................... ...................... ...... ..... .... 5 Table WB. Probe Name Ag6089 Start SEQ ID Primers Sequencs Length Position No Forward 5'-aataaatctagaaagaagactgggaagtag 30 376 257 -3' Probe TET-5'-atggtttgcctatgttatcaccgcat 26 406 258 -3 ' -TAMRA 5 '-aggtataccactccagtaagtacagaaa-3 2 .5 Reverse 28 432 259 Table WC. Probe Name Ag6090 IS , ,, Start SEQ ID Primers Sequencs Length Start SEQ D SPosition No Forward 5' -aataaatctagaaagaagactgggaagtag 30 376 260 -3' Probe TET-5'-atggtttgcctatgttatcaccgcat 26 406 261 -3 ' -TAMRA 5-Reverse -aggtataccactccagtaagtacagaaa-3 Reverse 128 432 1262 10 Table WD. CNS neurodegeneration v1.0 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag6090, issue Name Ag6090, Run Run 248386492 248386492 AD 1 Hippo 24.0 Control (Path) 3 Temporal Ctx 112.6 AD 2 Hippo 33.2 Control (Path) 4 Temporal Ctx 29.3 AD 3 Hippo 13.6 AD 1 Occipital Ctx 18.0 AD 4 Hippo 7.8 AD2 Occipital Ctx (Missing) 0.0 AD 5 hippo __ 67.4 AD 3 Occipital Ctx _11.3. AD 6 Hippo 76.3 AD 4 Occipital Ctx Control 2 Hippo 22.4 AD 5 Occipital C tx 20.6 364 WO 03/050245 PCT/USO2/38594 Control 4 Hippo 14.9 AD 6 Occipital Ctx 37.6 Control (Path) 3 Hippo 21.0 Control 1 Occipital Ctx 10.4 AD 1 Temporal Ctx 28.1 Control 2 Occipital Ctx 47.0 AD 2 Tempora C 38.2 Cntrol 3 Occipital Ctx 20.7 .AD 3 Temporal Ctx 10.0 Control 4 Occipital Ctx 14.1 AD 4 Temporal Ctx 25.2 Control (Path) 1 Occipital Ctx 69.7 AD 5 Inf Temporal Ctx 1100.0 Control (Path) 2 Occipital Ctx 14.2 AD 5 SupTemporal Ctx 137.1 iControl (Path) 3 Occipital Ctx 9 AD 6 Inf Temporal Ctx 169.7 Control (Path) 4 Occipital Ctx 15.7 AD 6 Sup Temporal Ctx 67.8 Control 1 Parietal Ctx 12.7 Control 1 Temporal Ctx 1.3.4 Control 2 Parietal Ctx 59.5 Control 2 Temporal Ctx 33.0 Control 3 Parietal Ctx 16.3 Control 3 Temporal Ctx 20.4 Control (Path) 1 Parietal Ctx 44.8 Control 4 Temporal Ctx 13.7 Control (Path) 2 Parietal Ctx 27.5 Control (Path) 1 Temporal Ctx 43.5 Control (Path) 3 Parietal Ctx 13.7 Control (Path) 2 Temporal Ctx 34.4 Control (Path) 4 Parietal Ctx 33.2 Table WE. General screening panel v1.5 Exp.(%) Exp.(%) Tissue Name Ag6089, issue Name Ag6089, Run Run 246733787 246733787 Adipose 16.8 Renal ca. TK-10 27.4 Melanoma* Hs688(A).T 51.8 Bladder 26.6 Melanoma* Hs688(B).T 57.0 Gastric ca. (liver met.) NCI-N87 36.1 Melanoma* M14 26.2 Gastric ca. KATO 1II 29.1 Melanoma* LOXIMVI 31.6 Colon ca. SW-948 13.9 Melanoma* SK-MEL-5 37.1 Colon ca. SW480 19.6 Squamous cell carcinomaSCC-4 19.6 Colon ca.* (SW480 met) SW620 41.8 Testis Pool 20.4 Colon ca. HT29 11.3 Prostate ca.* (bone met) PC-3 73.7 Colon ca. HCT-116 58.2 Prostate Pool 119.9 Colon ca. CaCo-2 14.2 Placenta 113.6 Colon cancer tissue 20.9 Uterus Pool 31.2 Colon ca. SWI116 3.8 Ovarian ca. OVCAR-3 22.7 Colon ca. Colo-205 4.9 Ovarian ca. SK-OV-3 50.7 Colon ca. SW-48 6.2 Ovarian ca. OVCAR-4 11.3 Colon Pool 29.1 Ovarian ca. OVCAR-5 56.3 Small Intestine Pool 34.9 Ovarian ca. IGROV-1 21.8 IStomach Pool 19.5 Ovarian ca. OVCAR-8 14.9 IBone Marrow Pool 12.4 Ovary .250 IFetal Heart 102 Breast ca. MCF-7 37.9 Heart Pool 14.0 365 WO 03/050245 PCT/USO2/38594 Breast ca. MDA-MB-231 16.7 Lymph Node Pool 29.7 Breast ca. BT 549 20.7 Fetal Skeletal Muscle 5.6 Breast ca. T47D 7.2 Skeletal Muscle Pool 21.8 Breast ca. MDA-N 4.9 Spleen Pool 21.3 Breast Pool 25.7 Thymus Pool 28.1 Trachea 36.1 CNS cancer (glio/astro) U87-MG 47.6 Lung 5.9 CNS cancer (glio/astro) U-118-MG 27.5 Fetal Lung 36.9 CNS cancer (neuro;met) SK-N-AS 24.5 Lung ca. NCI-N417 6.2 CNS cancer (astro) SF-539 26.1 Lung ca. LX-1 73.2 CNS cancer (astro) SNB-75 36.3 Lung ca. NCI-H146 7.9 CNS cancer (glio) SNB-19 23.0 Lung ca. SHP-77 25.9 CNS cancer (glio) SF-295 100.0 Lung ca. A549 27.7 Brain (Amygdala) Pool 22.4 Lung ca. NCI-H526 4.3 Brain (cerebellum) 77.9 Lung ca. NCI-H23 48.6 Brain (fetal) 21.5 Lung ca. NCI-H1460 55.9 Brain (Hippocampus) Pool 24.0 Lung ca. HOP-62 18.7 Cerebral Cortex Pool 19.1 Lung ca. NCI-H522 46.0 Brain (Substantia nigra) Pool 21.6 Liver 4.8 Brain (Thalamus) Pool 28.9 Fetal Liver 50.3 Brain (whole) 25.9 Liver ca. HepG2 0.0 Spinal Cord Pool 23.7 Kidney Pool 54.3 Adrenal Gland 24.0 Fetal Kidney 20.4 Pituitary gland Pool 5.1 Renal ca. 786-0 25.9 Salivary Gland 13.9 Renal ca. A498 9.5 Thyroid (female) 23.3 Renal ca. ACHN 32.1 Pancreatic ca. CAPAN2 28.9 Renal ca. UO-31 18.9 Pancreas Pool 29.1 Table WF. Panel 1.2 Rel. Rel. Exp (%) Exp.(%) Tissue Name Ag776, Tissue Name Ag776, Run Run 116762332 116762332 elial cells 23.0 Renal ca. 786-0 9.3 Heart (Fetal) 45.7 Renal ca. A498 125.7 Pancreas . 51.8 Renal ca. RXF 393 1.5_5 ............. Pancreatic ca. CAPAN 2 7.7 Renal ca. ACHN 27.7 Adrenal Gland 30.8 Renal ca. UO-31 8.8 Thyroid 37.1 Renal ca. TK-10 18.7 Salivary gland . . 26.6 Liver . . 16.3 Pituitary gland 21.2 Liver (fetal) 24.8 Brain (fetal) 11.3 Liver ca. (hepatoblast) HepG2 0.0 Brain (whole) 21.8 Lung 9.6 366 WO 03/050245 PCT/USO2/38594 Brain (amygdala) 10.5 Lung (fetal) 11.4 Brain (cerebellum) 9.0 Lung ca. (small cell) LX-1 65.5 Brain (hippocampus) 15.6 Lung ca. (small cell) NCI-H69 15.3 Brain (thalamus) 10.5 Lung ca. (s.cell var.) SHP-77 5.8 Cerebral Cortex 67.4 Lung ca. (large cell)NCI-H460 100.0 Spinal cord 14.0 Lung ca. (non-sm. cell) A549 44.4 glio/astro U87-MG 38.2 Lung ca. (non-s.cell) NCI-H23 19.9 glio/astro U- 18-MG 6.9 Lung ca. (non-s.cell) HOP-62 30.8 astrocytoma SW1783 6.4 Lung ca. (non-s.cl) NCI-H522 95.9 neuro*; met SK-N-AS 27.9 Lung ca. (squam.) SW 900 12.5 astrocytoma SF-539 9.4 Lung ca. squarem.) NCI-H596 15.8 astrocytoma SNB-75 4.1 Mammary gland 23.2 glioma SNB-19 25.2 Breast ca.* (pl.ef) MCF-7 26.4 glioma U251 10.2 Breast ca.* (pl.ef) MDA-MB-231 8.3 glioma SF-295 0.6 Breast ca.* (pl. ef) T47D 52.1 Heart 28.9 Breast ca. BT-549 8.4 Skeletal Muscle 69.3 Breast ca. MDA-N 6.3 Bone marrow 19.3 Ovary 64.2 Thymus 11.6 Ovarian ca. OVCAR-3 24.7 Spleen 10.9 Ovarian ca. OVCAR-4 16.5 Lymph node 22.1 Ovarian ca. OVCAR-5 57.4 Colorectal Tissue 9.4 Ovarian ca. OVCAR-8 15.6 Stomach 22.2 Ovarian ca. IGROV-1 21.5 Small intestine 26.6 Ovarian ca. (ascites) SK-OV-3 44.8 Colon ca. SW480 2.8 Uterus 11.5 Colon ca.* SW620 (SW480 met) 25.5 Placenta 21.3 Colon ca. HT29 7.5 Prostate 21.8 Colon ca. HCT-116 0.3 Prostate ca.* (bone met) PC-3 61.1 Colon ca. CaCo-2 8.4 Testis 55.9 Colon ca. Tissue (ODO3866) 3.1 Melanoma Hs688(A).T 13.0 Colon ca. HCC-2998 36.6 Melanoma* (met) Hs688(B).T 15.7 Gastric ca.* (liver met) NCI-N87 72.7 Melanoma UACC-62 44.8 Bladder 73.2 Melanoma M14 12.2 Trachea 4.7 Melanoma LOX IMVI 10.4 Kidney 22.1 Melanoma* (met) SK-MEL-5 20.9 Kidney (fetal) 16.8 Table WG. Panel 4.1D Rel. Rel. Exp.O Exp.(%) Tissue Name Ag6089, Tissue Name Ag6089, Run Run 247582904 247582904 367 WO 03/050245 PCT/USO2/38594 Secondary Thl act 68.8 HUVEC IL-lbeta 28.7 Secondary Th2 act 100.0 HUVEC IFN gamma 32.8 Secondary Tr act 17.1 HUVEC TNF alpha + IFN gamma 7.7 Secondaryhl rest 0.8 HUVEC TNF alpha + IL4 4.0 Secondary Th2 rest 2.7 HUJVEC IL-11 16.4 Secondary Trl rest 1.1 Lung Microvascular EC none 37.9 Primary Thl act 1.4 Lung Microvascular EC TNFalpha 10.7 + IL-lbeta PrimaryTh2 act 52.5 Microvascular Dermal EC none 6.0 Primary Tr act 43.5 Microsvasular Dermal EC 9.2 Primary T act 43.5 ITNFalpha + IL-1beta Primary ThI rest 0.9 Bronchial epithelium TNFalpha + 37.

9 ILlbeta Primary Th2 rest 2.3 Small airway epithelium none 22.7 Primary Trl rest 1.6 Small airway epithelium TNFalpha 43.8 + IL-lbeta CD45RA CD4 lymphocyte act 52.1 Coronery artery SMC rest 21.0 CD45RO CD4 lymphocyte act 61.6 Coronery artery SMC TNFalpha + 27.9 SIL-lbeta CD8 lymphocyte act 5.3 Astrocytes rest 5.3 Secondary CD8 lymphocyte rest 22.7 Astrocytes TNFalpha + IL-lbeta 6.6 Secondary CD8 lymphocyte act 6.3 KU-812 (Basophil) rest 30.1 CD4 lymphocyte none 2.6 KU-812 (Basophil) 49.3 PMA/ionomycin 2ry TlMh2/Trl anti-CD95 CH11 - 2.9 CCD1 106 (Keratinocytes) none 40.6 LAK cells rest 27.5 CCD 1106 (Keratinocytes) 26.1 LAK cells rest 27.5 TNFalpha + IL-lbeta _1 LAK cells IL-2 13.3 Liver cirrhosis 13.2 LAK cells IL-2+IL-12 4.0 NCI-H292 none 27.9 LAK cells IL-2+IFN gamma 14.8 NCI-H292 IL-4 25.9 LAK cells IL-2+ IL-18 9.7 NCI-H292 IL-9 37.6 LAK cells PMA/ionomycin 79.0 NCI-H292 IL-13 39.8 NK Cells IL-2 rest 67.8 NCI-H292 IFN gamma 24.8 Two Way MLR 3 day 20.6 HPAEC none 5.2 Two Way MLR 5 day 1.1 HPAEC TNF alpha + IL-1 beta 40.3 Two Way MLR 7 day 6.0 Lung fibroblast none 41.2 PLung fibroblast TNF alpha + IL-1 PBMC rest 5.2 b40.1 beta PBMC PWM 4.7 Lung fibroblast IL-4 29.1 PBMC PHA-L 6.7 Lung fibroblast IL-9 44.8 Ramos (B cell) none 9.5 Lung fibroblast IL-13 3.7 Ramos (B cell) ionomycin 60.3 Lung fibroblast IFN gamma 61.1 B lymphocytes PWM 34.2 Dermal fibroblast CCD1070 rest 64.2 B lymphocytes CD40L and IL-4 97.3 Dermal fibroblast CCD1070 TNF 89.5 alpha 368 WO 03/050245 PCT/USO2/38594 EOL- dbcAMP 12.4 Dermal fibroblast CCDIO70 IL-1 34.4 EOL-1 dbcAMP 12.4 34e4 lbetaI EOL-1 dbcAMP 1.2 Dermal fibroblast IFN gamma 43.2 PMA/ionomycin Dendritic cells none 29.7 Dermal fibroblast IL-4 59.0 Dendritic cells LPS 14.7 'Dermal Fibroblasts rest 48.6 Dendritic cells anti-CD40 6.9 Neutrophils TNFa+LPS 2.6 Monocytes rest 30 Neutrophils rest 12.3 Monocytes LPS 40.1 Colon 3.4 Macrophages rest 13.1 I Lung 1.6 Macrophages LPS .4.7 hymus . 108 HUVEC none 9.8 Kidney . 136.3 HUVEC starved 17.8 1 ......... CNSneurodegenerationvl.0 Summary: Ag6090 This panel confirms the expression of this gene at moderate levels in the brain in an independent group of individuals. This gene appears to be slightly upregulated in the temporal cortex of Alzheimer's disease patients. Therefore, therapeutic modulation of the expression or 5 function of this gene may decrease neuronal death and be of use in the treatment of this disease. Generalscreeningpanel_vl.5 Summary: Ag6089 Highest expression of this gene is seen in a brain cancer cell line (CT=28.3). This gene is widely expressed in this panel, with moderate expression seen in brain, colon, gastric, lung, breast, ovarian, and 10 melanoma cancer cell lines. This expression profile suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer. Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal 15 muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes. SInterestingly, this gene is expressed at much higher levels in the fetal liver 20 (CT=29.3) when compared to the level of expression in the adult tissue (CT=32.6). This observation suggests that expression of this gene can be used to distinguish between the fetal and adult sources of this tissue. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance growth or development of this 369 WO 03/050245 PCT/USO2/38594 organ in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases. This gene is also expressed at moderate levels in the CNS, including the 5 hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy. Panel 1.2 Summary: Ag776 Expression of this gene is widespread in this panel, 10 with highest expression detected in a lung cancer cell line (T=25). Please see Panel 1.5 for further discussion of expression and utility of this gene. Panel 4.1D Summary: Ag6089 Highest expression of this gene is seen in chronically activated Th2 cells (CT=30.2). This gene is also expressed at moderate levels in a wide range of cell types of significance in the immune response in health and disease. 15 These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in 20 agreement with the expression profile in Generalscreening_panelvl.5 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel 25 disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. X. CG164511-01: DORA protein precursor-like Protein. Expression of gene CG164511-01 was assessed using the primer-probe set Ag5882, described in Table XA. Table XA. Probe Name A25882 IL Start ISEQ ID Primers Sequence Length Position SEQNo D Forward 5' -gCCttcatactcctctccaaat-3' 22 392 263 370 WO 03/050245 PCT/USO2/38594 Probe TET-5'-caaaatcaaccctctaagaaagaaag 28 414 '264 a-3'-TAMRA Reverse 5'-gccgagcactcttcttcttt-3' 20 460 265 Y. CG55060-01: SLPI-like Protein. Expression of gene CG55060-01 was assessed using the primer-probe set Ag588, described in Table YA. Results of the RTQ-PCR runs are shown in Tables YB, YC, YD, 5 YE, YF, YG and YH. Table YA. Probe Name Ag588 Start SEQ ID Primers Sequence Length ]Position No Forward 5'-tgccttcaccatgaagtcca-3' 20 9 266 Probe TET-5'-cttcctggtgctgcttgccctgg- 3 23 42 267 Reverse 5'-agcccaaggtgccagagtt3' 19 66 268 Table YB. CNS neurodegeneration v1.0 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag588, issue Name Ag588, Run Run 224758452 224758452 AD Hippo 8.1 Control (Path) 3 Temporal Ctx 5.2 AD 2 Hippo 75.8 Control (Path)4 Temporal Ctx 2.2 AD 3 Hippo . 100.0 AD 1 Occipital Ctx7.9 AD 4 Hippo 15.7 AD 2 Occipital Ctx (Missing) 0.0 AD 5 Hippo 16.7 AD 3 Occipital Ctx 12.6 AD 6 Hippo 11.3 AD 4 Occipital Ctx 6.2 Control 2 Hippo 2.3 AD 5 Occipital Ctx 11.7 Control 4 Hippo 11.3 AD 6 Occipital Ctx 8.8 Control (Path) 3 Hippo 25.7 Control 1 Occipital Ctx 11.1 AD 1 Temporal Ctx 17.2 Control 2 Occipital Ctx 1.9 AD 2 Temporal Ctx 23.0 Control 3 Occipital Ctx 2.6 AD 3 Temporal Ctx 14.5 Control 4 Occipital Ctx 2.1 AD 4 Temporal Ctx 6.9 Control (Path) 1 Occipital Ctx 3.3 AD 5 Inf Temporal Ctx 12.3 Control (Path) 2 Occipital Ctx 2.8 AD5 Sup Temporal Ctx 14.8 Control (Path) 3 Occipital Ctx 10.6 6 Inf Temporal Ctx 9.7 Control (Path) 4 Occipital Ctx 2.0 AD 6 Sup Tentporal Ctx 19.2 Control 1 Parietal Ctx 16.0 Control 1 Temporal Ctx 15.1 Control 2 Parietal Ctx 9.0 Control 2 Temporal Ctx 0.9 Control 3 Parietal Ctx 3.4 Control 3 Temporal Ctx 4.9 Control (Path) 1 Parietal Ctx 9.9 371 WO 03/050245 PCT/USO2/38594 Control 3 Temporal Ctx 13.2 Control (Path) 2 Parietal Ctx 14.5 Control (Path) 1 Temporal Ctx 4.3 Control (Path) 3 Parietal Ct x 7.9 Control (Path) 2 Temporal Ctx 8.1 Control (Path) 4 Parietal Ctx _ 12.0 Table YC. General screening panel v1.5 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag588, issue Name Ag588, Run Run 248445830 248445830 Adipose 10.9 jRenal ca. TK-10 jO.

0 Melanoma* Hs688(A).T 0.0 _ Bladder 1.0 Melanoma* Hs688(B).T 0.0 Gastric ca. (liver met.) NCI-N87 6.3 Melanoma* M14 0.0 Gastric ca. KATO III 0.2 Melanoma* LOXIMVI 0.0 Colon ca. SW-948 10.7 Melanoma* SK-MEL-5 0.0 Colon ca. SW480 0.2 Squamous cell carcinoma SCC-4 2.6 Colon ca.* (SW480 met) SW620 0.0 Testis Pool 0.2 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.6 Colon ca. HCT-l 16 0.0 Prostate Pool 0.1 Colon ca. CaCo-2 0.2 PlacEenta .0.0 Colon cancer tissue 0.8 Uterus Pool 0.4 Colon ca. SW1 116 10.0 Ovarian ca. OVCAR-3 6.5 Colon ca. Colo-205 0.3 Ovarian ca. SK-OV-3 11.3 Colon ca. SW-48 1.4 Ovarian ca. OVCAR-4 6.4 Colon Pool 0.1 Ovarian ca. OVCAR-5 -4.4 Small Intestine Pool 1.0 Ovarian ca. IGROV-1 4.5 Stomach Pool 0.2 Ovarian ca. OVCAR-8 0.1 Bone Marrow Pool 3.3 . ..- ..... . .. .. . . .. .. . . .... - 3J j . . ... . ... .... .... ... . Ovary 0.9 Fetal Heart 0.0 Breast ca. MCF-7 0.1 Heart Pool 0.0 Breast ca. MDA-MB-231 0.0 Lymph Node Pool 0.1 Breast ca. BT 549 0.0 Fetal Skeletal Muscle 0.0 Breast ca. T47D 0 Skeletal Muscle Pool 0.2 Breast ca. MDA-N 0.0 Spleen Pool 0.0 Breast Pool 0.4 Thymus Pool 0.3 Trachea 100.0 CNS cancer (glio/astro) U87-MG 0.0 Lung 0.0 CNS cancer (glio/astro) U-118-MG 0.1 Fetal Lug 3.6 CNS cancer (neuro;met) SK-N-AS 0.0 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 0.0 Lung ca. LX-1 1.9 CNS cancer (astro) SNB-75 2.0 Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 2_ 2.8 Lung ca. SHP-77 0.0 CNS cancer (glio) SF-295 36.6 Lung ca. A549 0.4 Brain (Amygdala) Pool 0.0 372 WO 03/050245 PCT/USO2/38594 Lung ca. NCI-H526 0.0 Brain (cerebellum) 0.0 Lung ca. NCI-H23 0.3 Brain (fetal) 0.0 Lung ca. NCI-H460 2.2 Brain (Hippocamrnpus) Pool 0.0 Lung ca. HOP-62 0.3 Cerebral Cortex Pool (0. Lung ca. NCI-H522 0.0 Brain (Substantia nigra) Pool 0.0 Liver 0.3 Brain (Thalamus) Pool 0.0 Fetal Liver 0.0 Brain (whole)_. . 0.0 Liver ca. HepG2 0.2 Spinal Cord Pool 0.3 Kidney Pool 0.1 Adrenal Gland 0.1 Fetal Kidney 0.0 Pituitary gland Pool 0.7 Renal ca. 786-0 0.0 Salivary Gland 20.4 Renal ca. A498 0.5 Thyroid (female) 0.1 Renal ca. ACHN 0.0 Pancreatic ca. CAPAN2 5.1 Renal ca. UO-31 10.3 Pancreas Pool 2.4 Table YD. Oncology cell line screening panel v3.1 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag588, Tisse Name Ag588, Run Run 225138983 225138983 Ca Ski Cervical epidermoid Daoy Medulloblastoma/Cerebellum 0.3 carcinoma (metastasis) 8.8 carcinoma (metastasis) TE671 Medulloblastom/Cerebellum 0.2 ES-2 Ovarian clear cell carcinoma 0.0 D283 Med 0.0 Ramos/6h stim_ Stimulated with 0.0 Medulloblastoma/Cerebellum PMA/ionomycin 6h PFSK-1 Primitive 0.0 Ramos/14h stim_ Stimulated with 0.0 Neuroectodermal/Cerebellum PMA/ionomycin 14h XF-498CNS 0.0 MEG-01_Chronic myelogenous 0.2 XF-498 CNS 00 leukemia (megokaryoblast) .2 SNB-78_CNS/glioma 0.0 RajiBurkitt's lymphoma 0.0 SF-268_CNS/glioblastoma 0.0 Daudi Burkitt's lymphoma T98GGlioblastoma 6.2 U266 B-cell _T98G_Glioblastoma 6.2 plasmacytoma/myeloma 0.0 SK-N-SH _Neuroblastoma 0.0 CA46 Burkitt's lymphoma 0.0 (metastasis ) SF-295_CNS/glioblastoma 9.3 RL non-Hodgkin's B-cell lymphoma 0.0 Cerebellum 0.1 JM1_pre-B-cell lymphoma/leukemia 0.0 Cerebellum 0.3 JurkatT cell leukemia 0.0 NCI-H292_Mucoepidermoid lung 24.7 TF-l_Erythroleukemia 0.0 ca. __ DMS-114 Small cell lung cancer 0.0 HUT 78_T-cell lymphoma 0.0 DMS-79_Small cell lung 0.0 U937_Histiocytic lymphoma 2.3 cancer/neuroendocrine NCI-H146 Small cell lung 0.0 KU- Myelogenous leukemia 0.0 cancer/neuroendocrinelogenous 0.0 373 WO 03/050245 PCT/USO2/38594 NCI-H526_Small cell lung 0.0 76 9 -P Clear cell renal ca. 0.0 cancer/neuroendocrine. . .. .. NCI-N417_Small cell lung 0.0 Caki-2 Clear cell renal ca. 0.4 cancer/neuroendocrine NCI-H82_Small cell lung0.831 NCI-82Small cell lung 0.0 SW 839 Clear cell renal ca. 0.0 cancer/neuroendocrine NCI-H157 Squamous cell lung 0.0 G401 Wilms' tumor 0.0 cancer (metastasis) NCI-H1 155 Large cell lung 0.1 s766TPancreatic ca. (LN 14.3 cancer/neuroendoorine metastasis) NCI-H1299 Large cell lung 0.0 CAPAN-l_Pancreatic 15.6 cancer/neuroendocrine adenocarcinoma (liver metastasis) I . SU86.86 Pancreatic carcinoma NCI-H727_Lung carcinoid 0.4 SU86.86Pancreatic carcinoma 30.8 (liver metastasis) NCI-UMC-11 _Lung carcinoid 0.0 " BxPC-3 Pancreatic adenocarcinoma 18.9 LX-1_Small cell lung cancer 0.8 HPAC Pancreatic adenocarcinoma 7.5 Colo-205_ Colon cancer 4.6 MIA PaCa-2 Pancreatic ca. 0.0 CFPAC-1_Pancreatic ductal KM12 Colon cancer 0.2 adenocarcinoma 10.9 .... ...... ~ ~denocar cinoma.. .. .. KM , CPANC-1_Pancreatic epithelioid 0.1 KM20L2_Colon cancer 0.6 ductal ca. .1 - ductal ca. NCI-H716 Colon cancer 0.0 T24 Bladder ca. (transitional cell) 5.1 SW-48 Colon adenocarcinoma 17.3 5637 Bladder ca. 26.4 SWI 116 Colon adenocarcinoma 0.1 HT-1197 Bladder ca. 1.4 • JUM-UC-3 Bladder ca. (transitional LS 174TColon adenocarcinoma 5.0 UM -UC-3Bladder ca. (transitional 0.0 __ __ _ - _ _.. .... ... .__ _. ..... cell)...1 SW-948 Colon adenocarcinoma 8.0 A204 Rhabdomyosarcoma 0.0 SW-480 Colon adenocarcinoma 1.5 HT-1080 Fibrosarcoma 0.0 NCI-SNU-5_Gastric ca. 0.1 MG-63 Osteosarcoma (bone) 0.6 KATO III Stomach 0.5 SK-LMS-1_Leiomyosarcoma 0.0 - (vulva) Ic 0.0 SJRH30_Rhabdomyosarcoma (met 0.0 NCI-SNU-16 Gastric ca. 0.0 to bone marrow) Ito bone marrow) NCI-SNU-1_Gastric ca. 1.8 A431 _Epidermoid ca. 18.9 RF-1 Gastric adenocarcinoma 0.2 WM266-4 Melanoma 0.0 RF-48 Gastric adenocarcinoma 0.3 DU 145 Prostate 2.0 MDA-MB-468_Breast MKN-45 Gastric ca. 13.8 MA-MB-468Breast 34.9 adenocarcinoma NCI-N87_Gastric ca. 13.1 SSC-4 Tongue 18.6 OVCAR-5 Ovarian ca. 14.9 SSC-9 Tongue 11.8 RL95-2 Uterine carcinoma 100.0 SSC-15 Tongue 24.7 -- 7 CAL 27_Squamous cell ca. of 2. HelaS3 Cervical adenocarcinoma 25.7 27Squanous cell ca. of 21.3 tongue 374 WO 03/050245 PCT/US02/38594 Table YE. Panel 1.1 Rel. Rel. Ex.(%) Exp.(%) Tissue Name Ag588, Tissue Name Ag588, Run Run 108446724 108446724 Adrenal gland 0.1 Renal ca. UO-31 0.0 Bladder 3.6 Renal ca. RXF 393 0.0 Brain (amygdala) 0.0 Liver 1.6 Brain (cerebellum) 0.0 Liver (fetal) 0.2 Brain (hippocapus) 0.0 Liver ca. (hepatoblast) HepG2 0.0 rain (substantia nigra) .1 Lung 8.6 Brain (thalamus) 0.0 Lung (fetal) 3.0 cerebral Cortex 0.0 Lung ca. (non-s.cell) HOP-62 0.5 Brain (fetal) 0.0 Lung ca. (large cell)NCI-H460 2.6 Brain (whole) 0.0 Lung ca. (non-s.cell) NCI-H23 0.2 glio/astro U-118-MG 0.0 Lung ca. (non-s.cl) NCI-H522 0.0 astrocytoma SF-539 0.0 Lung ca. (non-sm. cell) A549 1.6 astrocytoma SNB-75 0.2 Lung ca. (s.cell var.) SHP-77 _0.0 astrocytoma SW1783 0.0 Lung ca. (small cell) LX-1 1.6 glioma U251 0.0 Lung ca. (small cell) NCI-H69 0.1 glioma SF-295 13.8 Lung ca. (squam.) SW 900 0.4 glioma SNB-19 0.0 Lung ca. (squam.) NCI-H596 0.0 glio/astro U87-MG 0.0 Lymph node 0.3 neuro*; met SK-N-AS 0.0 Spleen 0.0 Mammary gland 1.8 Thymus 0.2 Breast ca. BT-549 0.1 Ovary 0.5 Breast ca. MDA-N 0.0 Ovarian ca. IGROV-1 4.6 Breast ca.* (pl.ef) T47D 0.1 Ovarian ca. OVCAR-3 5.4 Breast ca.* (pl.ef) MCF-7 0.1 Ovarian ca. OVCAR-4 16.5 Breast ca.* (pl.ef) MDA-MB-231 0.0 Ovarian ca. OVCAR-5 2.6 Small intestine 0.4 Ovarian ca. OVCAR-8 0.2 Colorectal 0.4 Ovarian ca.* (ascites) SK-OV-3 7.9 Colon ca. HT29 0.0 Pancreas 0.4 Colon ca. CaCo-2 0.0 Pancreatic ca. CAPAN 2 1.2 Colon ca. HCT-15 0.4 Pituitary gland 4.3 Colon ca. HCT-116 0.0 Placenta .1 Colon ca. HCC-2998 1.4 Prostate 1.2 Colon ca. SW480 0.0 Prostate ca.* (bone met) PC-3 0.6 Colon ca.* SW620 (SW480 met) 0.0 Salivary gland 64.2 Stomach 1.1 Trachea 100.0 Gastric ca. (liver met) NCI-N87 4.3 Spinal cord 1.6 Heart 0.9 Testis 0.3 Skeletal muscle (Fetal) 0.0 Thyroid 0.4 Skeletal muscle 1.5 Uterus 0.4 375 WO 03/050245 PCT/USO2/38594 Endothelial cells 0.0 Melanoma M14 0.0 Heart (Fetal) .0.0 Melanoma LOX IMVI 0.0 Kidney 0.6 Melanoma UACC-62 0.0 Kidney (fetal) 0.0 Melanoma SK-MEL-28 0.0 Renal ca. 786-0 0.0 Melanoma* (met) SK-MEL-5 0.0 Renal ca. A498 1.0 Melanoma Hs688(A).T 0.0 Renal ca. ACHN 0.0 Melanoma* (met) Hs688(B).T 0.0 Renal ca. TK-10 0.0 Table YF. Panel 2D Rel. Rel. Rel. Rel. Exp.(% Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag588, Ag588, Tissue Name Ag588, Ag588, Run Run Run Run 144773993 144872213 144773993 144872213 Normal Colon 4.8 4.4 Kidney Margin 1.7 2.1 8120608 CC Well to Mod Diff 1.3 1.2 Kidney Cancer 0.0 0.0 (ODO3866) 8120613 CC Margin 0.9 0.8 Kidney Margin 0.9 0.7 (ODO3866 ) 8120614 CC Gr.2 rectosigmoid 1.8 1.8 Kidney Cancer 27.4 26.8 (ODO3868) 9010320 CC Margin 0.0 0.1 Kidney Margin 2.4 2.2 (ODO3868) 9010321 CC Mod Diff 3.1 2.9 Normal Uterus 0.1 0.1 (ODO3920) CC Margin 0.5 0.4 Uterus Cancer 63.3 61.6 (ODO3920) 064011 CC Gr.2 ascend colon 2.3 1.8 Normal Thyroid 1.7 1.6 (ODO3921) CC Margin 0.4 0.4 Thyroid Cancer 13.8 12.3 (ODO3921) 064010 CC from Partial Thyroid Cancer Thyroid Cancer . Hepatectomy 1.8 2.0 A302152 1.3 1.0 (ODO4309) Mets A302152 Liver Margin 2.4 2.2 Thyroid Margin 0.5 0.5 (ODO4309) A302153 Colon mets to lung 5.3 5.1 Normal Breast 5.5 5.4 (OD04451-01) Lung Margin 32.8 35.8 Breast Cancer 0.0 0.0 (OD04451-02) (OD04566) Normal Prostate 5.0 4.8 Breast Cancer 0.9 0.9 6546-1 (OD04590-01) Prostate Cancer 0.3 0.2 Breast Cancer Mets 0.7 0.8 (0D04410) . . (O D 4 5 9 0 -0 3 ) 376 WO 03/050245 PCT/USO2/38594 Breast Cancer Prostate MarginBratCne Prostate Margin 0.2 0.2 Metastasis 0.1 0.2 (D4410) (OD04655-05) Prostate Cancer 0.7 0.8 Breast Cancer 1.2 0.9 (OD04720-01) 0 64006 Prostate Margin 1.8 1.5 Breast Cancer 1024 4.1 3.7 (OD04720-02) __ Breast Cancer Normal Lung 061010 56.3 55.1 . 9100266 1 .6 Lung Met to Muscle 0.0 0.0 Breast Margin 1.6 1.3 (ODO4286) 9100265 Muscle Margin 24.5 26.1 Breast Cancer 12.9 12.4 (ODO4286) A209073 . Lung Malignant 42.0 41.8 Breast Margin 6.1 6.0 Cancer (OD03126) A209073 Lung Margin 40.3 42.9 Normal Liver 1.0 1.0 (OD03126) Lung Cancer 27.4 28.9 Liver Cancer 14.4 14.2 (OD04404) 064003 Lung Margin 42.6 39.2 Liver Cancer 1025 2.5 2.4 (oD0po4404) Lung Cancer 13.7 12.8 Liver Cancer 1026 4.2 4.7 (OD04565) ___ Lung Margin 18.3 18.4 Liver Cancer 5.3 4.7 (OD04565) 6004-T . Lung Cancer 6.4 6.2 Liver Tissue 0.1 0.1 (OD04237-01) 6004-N Lung Margin 12.8 12.2 Liver Cancer 5.1 4.8 (OD04237-02) 6005-T Ocular Mel Met to 0.0 0.0 Liver Tissue 1.4 1.4 Liver (ODO4310) 6005-N Liver Margin 3.6 3.6 Normal Bladder 2.7 2.3 (ODO4310) Melanoma Mets to 0.4 0.4 Bladder Cancer 2.7 2.8 Lung (OD04321) 1023 Lung Margin 77.9 76.3 Bladder Cancer 8.2 7.3 (OD04321) A302173 Normal Kidney 1.6 1.5 Bladder Cancer Normal Kidney 1.6 1.5 (OD04718-01) 2.0 1.8 Kidney Ca, Nuclear Bladder Normal Kidney Ca, Nuclear3.3 3.2 Adjacent 0.9 0.9 grade 2 (OD04338) (OD04718-03) Kidney Margin 3.0 3.0 Normal Ovary 0.6 0.5 1OD04338) Kidney Ca Nuclear 67 6.7Ovarian Cancer 100.0 1000 grade 1/2 (OD04339) 064008. Kidney Margin Ovarian Cancer20.7 "OD04339) 0.7 0.6 ( an1ce 21.9 20.7 (ODO339) (OD477 6807) 377 WO 03/050245 PCT/USO2/38594 Kidney Ca, Clear cell 0.0 0.0 Ovary Margin 4.1 3.7 type (OD04340) (OD04768-08) _ Kidney Margin 2.5 2.3 Normal Stomach 2.3 2.0 (OD04340) Kidney Ca, Nuclear 7.1 6.8 Gastric Cancer 0.5 0.4 grade 3 (OD04348) - 9060358 Kidney Margin 1.8 1.8 Stomach Margin 2.6 2.2 (OD04348) 18_ _90603592.22 Kidney Cancer 0.3 0.2 Gastric Cancer 5.4 5.7 (OD04622-01) 9060395 Kidney Margin 2.3 2.4 Stomach Margin 4.9 4.7 (0D04622-03) 23.9060394. . Kidney Cancer 9.2 8.5 Gastric Cancer 14.1 13.9 (OD04450-01) 9060397 . Kidney Margin 1.5 1.5 Stomach Margin 5.1 4.4 (OD04450-03) 15 _ .. 190603965.44 Kidney Cancer 33.2 30.8 Gastric Cancer 0.2 0.2 8120607 064005 8 12 0 6 0 7. 0 64 0 0 ............................................... Table YG. Panel 4D Rel. Rel. Exp (%) Exp.(%) Tissue Name Ag588, Tissue Name Ag588, Run Run 163588119 163588119 Secondary Thl act 0.0 HUVEC IL-lbeta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 Secondary Trl act 0.0 HUVEC TNF alpha + IFN gamma 0.0 Secondary Thl rest 0.0 HUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 0.0 Secondary Trl rest 0.0 Lung Microvascular EC none 0.0 .Primary Thl Lung Microvascular EC TNFalpha 0.0 Primary Th act 0.0 + IL-lbeta Primary Th2 act 0.0 Microvascular Dermal EC none 0.0 Microsvasular Dermal EC Primary Trl act 0.0 TNFalpha + IL-1beta .0 Bronchial epithelium TNFalpha + 3.7 Primary Thl rest 0.0 ILIbeta 3 Primary Th2 rest 0.0 Small airway epithelium none 53.6 P Small airway epithelium TNFalpha 100.0 Primary Trl rest 0.0 + IL-lbeta CD45RA CD4 lymphocyte act O0.0 Coronery artery SMC rest 0.0 CD45RO CD4 lymphocyte act . Coronery artery SMC TNFalpha + 0.0 CD45RO CD4 lymphocyte act 0.0 IL-1beta CD8 lymphocyte act 1.4 Astrocytes rest 0.0 Secondary CD8 lymphocyte rest 0.0 Astrocytes TNFalpha + IL-1beta 0.9 Secondary CD8 lymphocyte act 0.0 KU-812 (Basophil) rest 0.0 378 WO 03/050245 PCT/US02/38594 D4 lymphocyte none 0.0 KU-812 (Basophil) 0.0 CD4 lymphocyte none 0.0 PMA/ionomycin 2ry Thl/Th2/Trlanti-CD95 0.0 CCD1106 (Keratinocytes) none 0.7 CH 11 c r00 CCD 1106 (Keratinocytes) 0.6 LAK cells rest 0.0 TNFalpha + IL- beta . LAK cells IL-2 0.0 Liver cirrhosis 1.7 LAK cells IL-2+IL-12 0.0 Lupus kidney 9.9 LAK cells IL-2+IFN gamma 0.0 NCI-H292 none 49.0 LAK cells IL-2+ IL-18 0.0 NCI-H292 IL-4 61.6 LAK cells PMA/ionomycin 10.0 NCI-H292 IL-9 83.5 NK Cells IL-2 rest 0.0 NCI-H292 IL-13 37.4 Two Way MLR 3 day 0.0 NCI-H11292 IFN gamma 43.2 Two Way MLR 5 day 0.0 HPAEC none 0.0 Two Way MLR 7 day 0.0 HPAEC TNF alpha + IL-1 beta 0.0 PBMC rest 0.0 Lung fibroblast none 0.0 PBMCPM 02 Lung fibroblast TNF alpha + IL-1 0.0 PBMC PWM 0.2 0.0a beta PBMC PHA-L 0.0 Lung fibroblast IL-4 0.0 Ramos (B cell) none 0.0 Lung fibroblast IL-9 10.0 Ramos (B cell) ionomycin 0.0 Lung fibroblast IL-13 0.0 B lymphocytes PWM 0.2 Lung fibroblast IFN gamma 0.0 B lymphocytes CD40L and IL-4 0.0 Dermal fibroblast CCD1070 rest 0.0 EO- dc10AP.2 Dermal fibroblast CCD1070 TNF 0.0 EOL-1 dbcAMP 0.2 0.0h alpha EOL-1 dbcAMP 0.0 Dermal fibroblast CCD1070 IL-1 0.0 PMA/ionomycin beta Dendritic cells none 0.0 Dermal fibroblast IFN garimma 0.0 Dendritic cells LPS 0.0 Dermal fibroblast IL-4 0.0 Dendritic cells anti-CD40 0.0 IBD Colitis 2 0.0 Monocytes rest 0.0 IBD Crohn's 0.1 Monocytes LPS 0.1 Colon 0.7 Macrophages rest 0.0 Lung 36.3 Macrophages LPS 0.0 Thymus 1.4 HUVEC none 0.0 Kidney 3.9 HUVEC starved 0.0 Table YHI. Panel 5D Rel. Rel. Exp (%) Exp.(%) Tissue Name Ag588, Tissue Name Ag588, Run Run 248989995 248989995 97457_Patient-02go adipose 100.0 94709 Donor 2 AM - A adipose 18 379 WO 03/050245 PCT/USO2/38594 .97476 _Patient-07sk skeletal L~~ 97476Patient-07skskeletal 7.8 94710 Donor 2 AM -B adipose 1.2 muscle 97477 Patient-07ut uterus 0.3 94711 Donor 2 AM - C adipose 1.0 97478 Patient-07plplacenta 1.8 94712 Donor 2 AD - A adipose 2.6 9748 lPatient-08skskeletal 9.0 94713 Donor 2 AD - B adipose 3.6 muscle 994 97482 Patient-08ut uterus 0.4 94714_Donor 2 AD - Cadipose 3.0 94742 Donor 3 U -A Mesenchymal . 97483_Patient-08plplacenta 1.1 94742 Donor 3 U - AMesenchral 0.0 - __Stem Cells 97486_Patient-09sk skeletal 7.6 94743-Donor 3 U - B_Mesenchymal 0.2 muscle Stem Cells 97487 Patient-09ut uterus 1.5 94730 Donor 3 AM - Aadipose 2.4 97488 Patient-09pl_..placenta 0.4 94731 Donor 3 AM - B adipose 1.0 97492 Patient-O10ut uterus 7.1 94732 Donor 3 AM - C adipose 1.4 97493 Patient-10plplacenta 0.3 94733_Donor 3 AD -A adipose 2.8 97495_Patient-1 lgoadipose 63.3 94734_Donor 3 AD - Badipose 1.1 97496_Patient-1 lskskeletal 6.9 94735Donor 3 AD -Cadipose 2.8 6994734 Donor 3 AD - B adipose 1.1 muscle 97497 Patient- 11lut uterus 1.0 77138 Liver HepG2untreated 0.1 97498 Patient- plplacenta 0.5 73556_Heart Cardiac stromal cells 0.0 97498_Patient-11lpl31lacenta 0.5 prmy) -0.0 (primary) 97500 Patient-12go adipose 52.5 81735_Small Intestine 58.2 97501 Patient-12sk skeletal 1. 72409 Kidney Proximal Convoluted 13.0 muscle .Tubule 97502 Patient-12ut uterus 0.2 82685 Small intestine _Duodenum 0.2 97503 0.1 90650 Adrenal Adrenocortical 0.1 97503_Patient-12plplacenta 0.1 adenoma - 0.1 adenoma 94721_ Donor 2 U - 0.0 72410 Kidney HRCE 15.4 A Mesenchymal Stem Cells 2410Kidney 94722_Donor 2 U - 0.1 72411 KidneyHRE 3.9 B _M esenchymal Stem Cells ......... _ __............. 94723_Donor 2 U - 0.0 73139_UterusUterine smooth 0.0 C_Mesenchymal Stem Cells I muscle cells CNSneurodegeneration_vl.0 Summary: Ag588 This panel confirms the expression of this gene at moderate levels in the brain in an independent group of individuals. This gene appears to be slightly upregulated in the temporal cortex of Alzheimer's disease patients. Therefore, therapeutic modulation of the expression or 5 function of this gene may decrease neuronal death and be of use in the treatment of this disease. Generalscreening_panelvl.5 Summary: Ag588 Highest expression of this gene is seen in the trachea (CT=18). High levels of expression are also seen in a cluster of ovarian cancer cell line samples, as well as in cell line samples derived from pancreatic 380 WO 03/050245 PCT/USO2/38594 cancer, brain cancer, colon cancer, gastric cancer, and squamous cell carcinoma. Thus, this gene product may be involved in these diseases. Oncology_cell line_screening_panelv3.1 Summary: Ag588 Highest expression is seen in a uterine cancer cell lien (CT=22.8). High levels of expression are also seen in 5 brain, gastric, colon, ovarian, pancreatic, breast, and bladder cancer cell lines. Panel 1.1 Summary: Ag588 Highest expression of this gene is seen in the trachea (CT= 8). Overall, expression is in agreement with Panel 1.5. Please see that panel for discussion of utility of this gene. Panel 2D Summary: Ag588 Two experiments with the same probe and primer 10 produce results that are in excellent agreement. Highest expression is seen in an ovarian cancer sample (CTs=22). In addition, this gene appears to be overexpressed in samples from ovarian, uterine, thyroid and kidney cancers when compared to expression in normal adjacent tissue. Conversely, this gene appears to be more highly expressed in normal lung tissue than in adjacent lung tumor. This gene encodes secretory leucocyte protease inhibitor 15 (SLPI), a potent inhibitor of granulocyte elastase and cathepsin G, as well as pancreatic enzymes like trypsin, chymotrypsin and pancreatic elastase. SLPI has also been shown to inhibit HIV-1 infections by blocking viral DNA synthesis. Antileucoprotease (ALP) is generally considered as a specific marker for glandular serous cells that plays a major role in the defence of the respiratory tract against proteolytic damage. Goselink et al. 20 demonstrated that the COOH-terminal domain of ALP contains proteinase inhibitory activity and illustrated that proteinase inhibitors play an important role in the in vitro growth of hematopoietic cells by the neutralization of proteinases produced by bone marrow accessory cells. (J Exp Med 1996 Oct 1;184(4):1305-12) Thus, the over-expression of this gene in these tumors suggests that expression of this gene could be used to 25 differentiate between these cancer samples and other samples on this panel and as a marker of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of ovarian, uterine, thyroid, and kidney cancers. Panel 4D Summary: Ag588 Highest expression is seen in TNF-a/ILI-b treated small airway epithelium. High levels of expression are also seen in untreated small airway 30 epithelium,normal lung, and a cluster of treated and untreated samples derived from the NCI-H292 cell line, a human airway epithelial cell line that produces mucins. Mucus overproduction is an important feature of bronchial asthma and chronic obstructive pulmonary disease samples. The expression of the transcript in this mucoepidermoid cell 381 WO 03/050245 PCT/USO2/38594 line that is often used as a model for airway epithelium (NCI-H292 cells) and in small airway epithelium suggests that this transcript may be important in the proliferation or activation of airway epithelium. Therefore, therapeutics designed with the protein encoded by the transcript may reduce or eliminate symptoms caused by inflammation in lung 5 epithelia in chronic obstructive pulmonary disease, asthma, allergy, and emphysema. Panel 5D Summary: Ag588 Prominent expression of this gene is seen in adipose (CTs=26-27). Thus, expression of this gene could be used to differentiate between the adipose derived samples and other samples on this panel and as a marker of this tissue. Furthermore, modulation of this gene product may be useful in the treatment of obesity and 10 diabetes. Z. CG56972-01, CG56972-02 and CG56972-03: NMB-soluble-like Protein. Expression of gene CG56972-01, CG56972-02 and CG56972-03 was assessed using the primer-probe sets Ag817 and Ag5968, described in Tables ZA and ZB. Results of the RTQ-PCR runs are shown in Tables ZC, ZD, ZE, ZF, ZG, ZH, ZI, ZJ, ZK, ZL, ZM, ZN 15 and ZO. Please note that CG56972-02 represents a full-length physical clone of the CG56972-01 gene, validating the prediction of the gene sequence. Also, Ag5968 is specific for CG56972-03. Table ZA. Probe Name Ag817 jStart SEQ ID Primers Sequence Length Position No Forward 5 ' -tcaatggaaccttcagcctta- 3 ' 21 543 269 Probe TET-5' -ctcactgtgaaagctgcagcaccag- 25 516 270 3 ' -TAMRA Reverse 5'-gaaggggtgggttttgaag-3' 19 464 271 20 Table ZB. Probe Name Ag5968 Lth Start SEQ ID Primers Sequencs Length Position No t Position LNo Forward !5,-cagttttcatcaggaatcctact c- 31 :24 .............. 371 t272 ........... TET-5 ' -tatgattcaaacaccccaggacctgc Probe 26 416 273 -31'-TAMRA Reverse 5'-ccctttttagcaactactctaaaatct-3 28 442 382............. 382 WO 03/050245 PCT/US02/38594 Table ZC. AI comprehensive panel vl.0O Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag817, issue Name Ag817, Run Run 247834306 247834306 110967 COPD-F 37.1 112427 Match Control Psoriasis-F 53.2 110980 COPD-F 25.3 112418 Psoriasis-M 35.8 110968 COPD-M 34.6 112723 Match Control Psoriasis-M 0.8 110977 COPD-M 50.3 112419 Psoriasis-M 53.2 110989 Emphysema-F 33.7 112424 Match Control Psoriasis-M 12.2 110992 Emphysema-F 16.6 112420 Psoriasis-M 47.3 110993 Emphysema-F 29.7 112425 Match Control Psoriasis-M 39.0 110994 Emphysema-F 113.3 104689 (MF) OA Bone-Backus 24.8 110995 Emphysema-F 25.9 1 04690 (MF) Adj "Normal" 55 110995 Emphysema-F 25.9 Bone-Backus 110996 Emphysema-F 6.1 104691 (MF) OA Synovium-Backus 54.3 110997 Asthma-M 24.5 104692 (BA) OA Cartilage-Backus 1.9 111001 Asthma-F 23.8 104694 (BA) OA Bone-Backus 41.2 111002 Asthma-F 24.8 104695 (BA) Adj "Normal" 4.2 111002 Asthma-F 24.8 BoeBa4s.2 Bone-Backus 111003 Atopic Asthma-F 25.5 104696 (BA) OA Synovium-Backus 82.4 111004 Atopic Asthma-F 13.9 104700 (SS) OA Bone-Backus 5.0 10.5 104701 (SS) Adj "Normal" 111005 Atopic Asthma-F 10.5 104701 (SS) Adj ormal" 16.4 Bone-Backus 111006 Atopic Asthma-F 3.4 104702 (SS) OA Synovium-Backus 81.8 111417 Allergy-M 14.5 117093 OA Cartilage Rep7 27.2 112347 Allergy-M 0.5 112672 OA Bone5 100.0 112349 Normal Lung-F 0.4 112673 OA Synovium5 45.7 112357 Normal Lung-F 11.4 112674 OA Synovial Fluid cells5 42.0 112354 Normal Lung-M 10.9 . 117100 OA Cartilage Repl4 21.8 112374 Crohns-F 13.2 112756 OA Bone9 2.6 112389 Match Control Crohns-F 42.3 112757 OA Synovium9 3.6 112375 Crohns-F 14.6 112758 OA Synovial Fluid Cells9 14.6 112732 Match Control Crohns-F 5.0 117125 RA Cartilage Rep2 31.9 112725 Crohns-M 0.9 113492 Bone2 RA 17.7 112387 Match Control o 20.0 113493 Synovium2 RA 11.9 Crohns-M 112378 Crohns-M 0.8 113494 Syn Fluid Cells RA 14.4 112390 Match Control 1o65.5 113499 Cartilage4 RA 14.2 Crohns-M 112726 Crohns-M 21.2 113500 Bone4 RA 14.0 112731 Match Control 19.5 113501 Synovium4 RA 11.7 Crolms-M 112380 Ulcer Col-F 17.3 113502 Syn Fluid Cells4 RA 6.6 383 WO 03/050245 PCT/US02/38594 112734 Match Control Ulcer 12.4 113495 Cartilage3 RA 21.8 ClF1.1145Cartilage3 RA 21.8 Col-F 112384 Ulcer Col-F 32.3 113496 Bone3 RA 21.9 112737 Match Control Ulcer 186 113497S oviuRA 11.3 Col-F 113497 Synovium3 RA 11.3 112386 Ulcer Col-F 4.4 113498 Syn Fluid Cells3 RA 25.3 112738 Match Control Ulcer I Col-F 3.0 117106 Normal Cartilage Rep20 14.8 112381 Ulcer Col-M 35.8 113663 Bone3 Normal 0.5 112735 Match Control Ulcer N aj C1l M 5.4 113664 Synovium3 Normal 0.1 112382 Ulcer Col-M 33.4 113665 Syn Fluid Cells3 Normal 0.2 112394 Match Control Ulcer Col-M 15.0 117107 Normal Cartilage Rep22 12.9 112383 Ulcer Col-M 27.5 113667 Bone4 Normal 13.1 112736 Match Control Ulcer o112736 Match Control Ulcer 32.1 113668 Synovium4 Normal 20.0 112423 Psoriasis-F 17.8 113669 Syn Fluid Cells4 Normal 124.8 Table ZD. Ardais Panel v.1.0 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Agl7, Tissue Name Ag817, Run Run 263526495 263526495 136799 Lung cancer(362) 91.4 136787lung cancer(356) 7.0 136800_LungNAT(363) 85.9 136788 lung NAT(357) 18.2 136813 Lung cancer(372) 100.0 136806 Lung cancer(36B) 14.3 136814 LungNAT(373) 5.6 136807 Lung NAT(36C) 10.9 136815 Lung cancer(374) 6.0 136789 lung cancer(358) . 20.6 136816 Lung NAT(375) 1 2

.

7 136802 Lung cancer(365) 10.4 136791_ung cancer(35A) 30.1 136803 Lung cancer(368)4.5 136795_Lung cancer(35E) 20.7 136804 Lung cancer(369) 25.0 136797 Lung cancer(360) 10.7 1136811 Lung cancer(370) 13.8 136794 lung NAT(35D) 9.9 1136810 Lung NAT(36F) 122.4 136818 LungNAT(377) 3.6 5 Table ZE. CNS neurodegeneration v1.0 Rel. Rel. Exp.(%) Exp.(%) Tissue Name Ag5968, issue Name Ag5968, Run Run 248589036 248589036 AD l Hippo nr. .. ..... . ol (Path) 3 Temporal Ctx 9.5 AD 2 Hippo 71.2 Control (Path) 4 Temporal Ctx 31.9 384 WO 03/050245 PCT/USO2/38594 AD 3 Hippo 29.1 AD 1 Occipital Ctx 24.3 AD 4 Hippo 15.1 AD 2 Occipital Ctx (Missing) 0.3 AD 5 Hippo 57.4 AD 3 Occipital Ctx 8.8 AD 6 Hippo 614.2 AD 4 Occipital Ctx 20.4 Control 2 Hippo 19.2 AD 5 Occipital Ctx 17.0 Control 4 Hippo 29.5 AD 6 Occipital Ctx 38.7 Control (Path) 3 Hippo 35.1 Control 1 Occipital Ctx 1.6 AD I Temporal Ctx 34.6 Control 2 Occipital Ctx 17.4 AD 2 Temporal Ctx 50.0 Control 3 Occipital Ctx 13.8 AD 3 Temporal Ctx 14.5 Control 4 Occipital Ctx 14.7 AD 4 Temporal Ctx 25.0 Control (Path) 1 Occipital Ctx 36.9 AD 5 Inf Temporal Ctx 79.0 Control (Path) 2 Occipital Ctx 18.3 AD 5 Sup Temporal Ctx 80.1 Control (Path) 3 Occipital Ctx 1.1 AD 6 lnf Temporal Ctx 100.0 Control (Path) 4 Occipital Ctx 23.0 AD 6 Sup Temporal Ctx 98.6 Control 1 Parietal Ctx 7.7 Control 1 Temporal Ctx 28.5 Control 2 Parietal Ctx 83.5 Control 2 Temporal Ctx 20.4 Control 3 Parietal Ctx 11.0 Control 3 Temporal Ctx 23.7 Control (Path) 1 Parietal Ctx 36.1 Control 3 Temporal Ctx 20.9 Control (Path) 2 Parietal Ctx 34.2 Control (Path) 1 Temporal Ctx 38.4 Control (Path) 3 Parietal Ctx 0.7 Control (Path) 2 Temporal Ctx 41.2 Control (Path) 4 Parietal Ctx .. 27.4' Table ZF. General screening panel vl.5 Rel. Rel Rel.l. Rel. Exp.(%) Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag5968, Ag817, issue Name Ag5968, Ag817, Run RRun un Run 248220123 248592794 248220123 248592794 Adipose 4.2 12.3 Renal ca. TK-10 0.0 0.0 MelHs688(A).T 2.0 11.0 Bladder 2.4 11.0 Hs688(A).TI Melanoma* 1.5 7.9 Gastric ca. (liver 2.1 12.4 Hs688(B).T 15met.) NCI-N87 12 Melanoma* M14 29.1 100.0 Gastric ca. KATO 0.0 III Melanoma* LOXIMVI 0.0 0.1 Colon ca. SW-948 0.0 0.0 LOXIVI Melanoma*7ca Melanoma 12.2 72.2 Colon ca. SW480 0.0 0.0 SK-MEL-5 Squamous cell 0.1 .6 Colon ca.* (SW480 0.0 0.0 carcinoma SCC-4 met) SW620 Testis Pool 1.0 6.7 Colon ca. HT29 0.0 " .0.0 Prostate ca.* (bone i.. Prostate ca.* (bone 0.0 10.0 Colon ca. HCT-1 16 0.0 0.0 met) PC-3 Prostate Pool 0.7 3.1 Colon ca. Co .0 0.0 385 WO 03/050245 PCT/US02/38594 Placenta 3.8 16.8 Colon cancer tissue 4.0 16.6 Uterus Pool 5.0 31.2 Colon ca. SW1116 0.0 0.0 Ovarian ca. 0.4 2.1 Colon ca. Colo-205 0.0 0.0 O V CA R-3 ........... ............. Ovarian ca. SK-OV-3 0.0 0.0 Colon ca. SW-48 0.0 0.0 Ovarian ca. Ovarian a. 0.1 1.0 Colon Pool 3.8 18.2 OVCAR-4 Ovarian ca. 0.1 0.5 Small Intestine Pool 2.5 11.5 OVCAR-5 Ovarian ca. 01 0.4 Stomach Pool 1.4 6.2 IGROV-1 0.1 .4 Stomach Pool 6.2 Ovarian ca. 0.2 0.9 Bone Marrow Pool 2.7 16.6 OVCAR-8 Ovary 0.5 2.3 Fetal Heart 4.3 23.0 Breast ca. MCF-7 0.0 0.0 Heart Pool 2.6 13.7 Breast ca. BasBa 0.0 0.0 Lymph Node Pool 3.7 18.8 MDA-MB-231 Fetal Skeletal Breast ca. BT 549 0.3 1.5 Fetal Skeletal 0.4 1.8 Muscle Breast ca. T47D 0.3 2.0 Skeletal Muscle 0.5 2.9 Pool Breast ca. MDA-N 2.1 12.4 Spleen Pool 0.3 0.8 Breast Pool 3.7 15.0 Thymus Pool 1.5 7.3 CNS cancer Trachea 1.5 4.2 (glio/astro) 3.6 12.5 U87-MG CNS cancer Lung 0.7 2.8 (glio/astro) 4.0 14.9 U-118-MG CNS cancer Fetal Lung 0.3 1.1 (neuro;met) 0.0 0.3 SK-N-AS CNS cancer (astro) Lung ca. NCI-N417 0.0 0.0 r 3.7 23.0 SF-539 CNS cancer (astro) Lung ca. LX-1 0.0 0.0 3.4 17.3 SNB-75 Lung ca. NCI-H146 0.0 0.0 CNS cancer (glio) 0.1 0.4 CNS cancer (glio) Lung ca. SHP-77 0.0 0.0 12.2 16.6 SF-295 Brain (Amygdala) 0.0.0. Lung ca. A549 0.0 0.0 Pool0.1 0.3 Lung ca. NCI-H526 0.0 0.0 Brain (cerebellum) 0.1 0.5 Lung ca.NCI-H23 0.0 0.0 Brain (fetal) 0.2 0.7 Brain Lung ca. NCI-H460 0.0 0.0 (Hippocampus) 0.2 1.2 Pool 386 WO 03/050245 PCT/USO2/38594 Lung ca. HOP-62 0.0 0.4 PooCerebral Cortex 0.3 1.3 Brain (Substantia Lung ca. NCI-H522 0.0 0.0 Brain (Substantia 0.2 0.5 nigra) Pool LBrain (Thalamus) Liver 0.1 0.3 Poo (Thalamus) 0.3 0.8 Pool Fetal Liver 0.2 0.5 Brain (whole) 0.2 1.5 Liver ca. HepG2 . 0.0 0.0 Spinal Cord Pool 100._ 0 2.2 Kidney Pool 6.4 24.7 _ Adrenal Gland _0.5 2.5 Fetal Kidney 0.5 2.8 Pituitary gland Pool 0.1 0.4 Renal ca. 786-0 '0.0 0.0 Salivary Gland 0.4 0.6 Renal ca. A498 0.8 6.4 Thyroid (female) 10.4 1.6 Pancreatic ca. Renal ca. ACHN 0.0 0.0 Pancreatic ca. 0.0 0.0 I _ CAPAN2 Renal ca. UO-31 1.3 4.4 Pancreas Pool 2.8 11.0 Table ZG. IASS Panel vl.O Rel. Rel. Exp.(% Exp.(%) Tissue Name Ag817, Tissue Name Ag817, Run Run 248122701 248122701 MCF-7 C1 0.0 U87-MG F1 (B) 3.3 MCF-7 C2 0.0 U87-MG F2 1.7 MCF-7 C3 0.2 U87-MG F3 . 3.9 MCF-7 C4 0.1 U87-MG F4 3.5 MCF-7 C5 0.2 U87-MG F5 17.6 MCF-7 C6 0.0 U87-MG F6 51.8 MCF-7 C7 0.1 U87-MG F7 11.3 MCF-7 C9 0.0 U87-MG F8 31.6 MCF-7 C10 0.0 U87-MG F9 16.7 MCF-7 C11 0.0 U87-MG F10 8.4 MCF-7 C12 0.0 U87-MG Fl1 34.9 MCF-7 C13 0. 1 U87-MG F12 16.8 MCF-7 C15 0.0 U87-MG F13 13.7 MCF-7 C16 0.3 U87-MG F14 44.1 MCF-7 C17 0.1 U87-MG F15 26.6 1T24 D1 0.0 U87-MG F16 28.3 T24 D2 0.0 U87-MG F17 25.7 T24 D3 0.0 LnCAP A1 0.4 T24 D4 0.0 LnCAP A2 0.2 T24 D5 .0.0 LnCAP A3 1.4 T24 D6 0.0 LnCAP A4 0.5 T24 D7 0.0 LnCAP A5 1.1 387 WO 03/050245 PCT/USO2/38594 T24 D9 0.0 LnCAP A6 0.5 T24 D10 0.0 LnCAP A7 0.8 T24 D11 0.0 LnCAP A8 2.5 T24 D12 0.0 LnCAP A9 1.6 T24 D13 0.0 LnCAP A10 0.2 T24 D15 0.0 LnCAP A 11 1.0 T24 D16 0.0 LnCAP A12 0.1 T24 D17 0.0 LnCAP A13 0.1 CAPaN B1 0.0 LnCAP A14 0.2 CAPaN B2 0.0 LnCAP A15 0.2 CAPaN B3 0.0 LnCAP A16 1.5 CAPaN B4 0.0 LnCAP A17 0.7 CAPaN B5 0.0 Primary Astrocytes 1.1 CAPaN B6 00 Primary Renal Proximal Tubule Epithelial cell 1.6 CAPaN B6 0.0 1.6 CAPaN B7 0.0 Primary melanocytes A5 100.0 CAPaN B8 0.0 126443 - 341 medullo 0.1 CAPaN B9 0.0 126444 - 487 medullo 0.9 CAPaN B10 0.0 126445 - 425 medullo 0.0 CAPaN B11 0.0 126446 - 690 medullo 0.1 CAPaN B12 0.0 126447 - 54 adult glioma 0.6 GAPaN B13 0.0 126448 - 245 adult glioma 38.7 CAPaN B 14 0.0 126449 - 317 adult glioma 0.2 CAPaN B15 0.0 126450- 212 glioma 62.9 CAPaN B16 0.0 126451 - 456 glioma 0.6 CAPaN B17 0.0 Table ZH. Panel 1.2 Rel. Rel. Rel. Rel. Exp.(% Exp.(%) Exp.(%) Exp.(%) Tssue Name Ag817, Ag817, Tissue Name Ag817, Ag817, Run Run Run Run 118348964 121027514 118348964 121027514 Endothelial cells 0.0 0.0 Renal ca. 786-0 0.0 0.0 Heart (Fetal) 6.3 13.1 Renal ca. A498 4.2 2.9 Pancreas 6.4 6.6 _ Renal ca. RXF 393 0.7 0.5 Pancreatic ca. 0.0 0.0 Renal ca. ACHN 0.0 0.0 CAPAN 2 Adrenal Gland 6.3 7.4 Renal ca. UO-31 1.4 2.8 yroid 21.0 19.8 Renal ca. TK-10 0.0 0.0 Salivary gland 8.0 8.7 Liver 4.3 5.0 Pituitary gland 5.3 5.2 Liver (fetal) 2.5 1.4 Brain (fetal) 10.9 JLiver ca. 0.0 0.0 Brain (fetal) 0.9 0.6 (hepatoblast) HepG2 Brain (whole) 3.7 2.8 Lung 20.6 14.5 388 WO 03/050245 PCT/USO2/38594 Brain (amygdala) 2.3 3.6 Lung (fetal) 4.7 3.1 Brain (cerebellum) 0.4 .7 Lung ca. (small cell) 0.0 0.0 - 1 LX-1 Lung ca. (small cell)0.00 Brain (hippocampus) 3.2 2.5 NCI-H69 0.1 0.0 Lun Ca.(smll.0... ~ Lung ca. (s.cell var.) 0.0 0.0 Brain (thalamus) 1.5 1.1 SHP-77 00. Cerebral Cortex 3.0 2.3 Lung ca. (large 0.0 0.0 cell)NCI-H460 Lung ca. (non-sm. .00 Spinal cord 9.5 6.2 Lung ca. (non-sm. 0.0 0.0 cell) A549 Lung ca. (non-s.cell) .00 glio/astro U87-MG 18.2 15.1 Lung Ca. (non-s.cel)0 0.0 NCI-H23 glio/astro U- 8MG9.9 6.7 Lung ca. (non-s.cell) 1.3 2.0 glio/astro U-118-MG 9.9 6.7 HOP-62 astrocytoma 0.2 0.2 Lung ca. (non-s.cl) 0.0 0.0 SW1783 NCI-H522 neuro*; met 0.6 0.6 Lung ca. (squam.) 6.9 6.7 SK-N-AS SW 900 astrocytoma SF-539 33.4 25.2 Lung ca. (squam.) 0.1 0.0 astrocytoma SF-539 33.4 25.2 NCI-H596 0 astrocytoma SNB-75 3.6 0.5 Mammary gland 31.4 32.1 glioma SNB-19 1.6 1.2 Breast ca.* (pl.ef) 0.0 g S1 MCF-7 _ gliomaU25 3.3 4.0 Breast ca.* (pl.ef) 0.0 0.0 gliomaa U251 3.3 4.0 MDA-MB-231 00. IBreast ca.* (pl. ef) glioma SF-295 8.9 10.7 Breast ca.* (pl. e47D) 3.9 2.9 T47D Heart 54.0 67.4 Breast ca. BT-549 2.0 1.0 Skeletal Muscle 12.0 10.2 Breast ca. MDA-N 41.8 33.2 Bone marrow 0.5 0.7 Ovary 17.3 19.5 Thymus 6.7 7.0 Ovarian ca. 5.6 2.8 ....... . OVCAR-3 Spleen 4.4 4.0 Ov nca. 7.5 8.7 Lymph node 23.8 17.8 Ovarian ca. 0.3 0.2 OVCAR-5 Ovarian ca. Colorectal Tissue 8.2 5.0 OVCAR-8 0.2 0.2 Stomach 10.5 9.3 Ovarian ca. 0.1 0.0 _tomah__. . _IGROV-1 01 0.0 I ~Ovarian ca. (ascites) Small intestine 17.2 10.6 Ovarian ca. (ascites) 0.0 0.0 SK-OV-3 Colon ca. SW480 0.0 0.0 Uterus 30.8 28.1 Colon ca.* SW620 0.0 0.0 Placenta 100.0 100.0 (SW480 met) Colon ca. HT29 0.0 0.0 Prostate 5.2 4.6 389 WO 03/050245 PCT/USO2/38594 Colon Prostate ca.* (bone 0.0 0.0 Colon ca. HCT-116 0.0 0.0 met) PC-3 0.0 met) PC-3 Colon ca. CaCo-2 0.0 0.0 Testis 5.9 7.3 Colon ca. Tissue 4.7 3.0 Melanoma 72 4.7 3.0 7.2 !7.5 (OD03866) _ _Hs688(A).T Melanoma* (met) Colon ca. HCC-2998 0.1 0.0 Melanoma* (met) 8.7 8.5 Hs688(B).T Gastric ca.* (liver 2 Melanoma 20.9 17.4 66.92 78.5__ ______ met) NCI-N87 UACC-626. 75 Bladder 34.2 36.6 Melanoma M14 29.9 36.6 Trachea 8.8 9.7 Melanoma LOX 0.1 0.2 IMVI Kidney 7.5 6.1 Melanoma* (met) 47.6 39.0 Kidn ,-_ __,SK-MEL-5 Kidney (fetal) 14.7 6

.

2 ...... Table ZI. Panel 2.2 Rel. Rel. Rel. Rel. Exp.(% Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag817, Ag817, Tissue Name Ag817, Ag817, Run un Run Run 176283476 184372254 176283476 184372254 Normal Colon 18.0 9.3 Kidney Margin 8.8 2.2 .. . ..... ... .. (OD04348) _ _ _ _ Colon cancer Kidney malignant (ODO6064) 39.8 26.1 cancer 0.6 0.6 _OD0064)(OD06204B) Colon Margin Kidney normal on 18.7 0.0 adjacent tissue 4.9 4.9 (D06(OD06204E) Colon cancer 1.5 2.6 Kidney Cancer 48.6 40.6 (OD06159) (OD04450-01) Colon Margin 15.3 13.5 Kidney Margin 4.1 8.0 (OD06159) (OD04450-03) Colon cancer 2.8 2.6 Kidney Cancer 1.4 4.4 (OD06297-04) 8120613 Colon Margin 16.5 9.3 Kidney Margin 2.4 1.1 (OD06297-05) 8120614 CC Gr.2 ascend colon 2.6 3.6 Kidney Cancer 21.9 21.8 (ODO3921) 9010320 CC Margin 2.5 2.3 Kidney Margin 6.7 1.0 (ODO3921) 9010321 Colon cancer metastasis 5.6 9.2 Kidney Cancer 30.4 33.9 (OD06104) _1____0 ..... ..-- Lung Margin 7.3 9.7 Kidney Margin 0.7 1.2 (OD06104) 8120608 390 WO 03/050245 PCT/US02/38594 Colon mets to lung 15.1 10.2 Normal Uterus 59.5 42.0 (OD04451-01) Lung Margin 56.3 12.5 Uterine Cancer 3.2 8.8 (OD04451-02) 064011 Normal Prostate 1.8 7.9 Normal Thyroid 1.1 7.2 Prostate Cancer 1.1 3.9 Thyroid Cancer 7.6 17.4 (OD04410) 064010 Prostate Margin 0.7 1.8 Thyroid Cancer 9.0 15.0 (OD04410) A302152 Normal Ovary 13.5 14.8 Thyroid Margin 2.4 7.3 A302153 Ovarian cancer 16.8 19.8 Normal Breast 27.9 17.9 (OD06283-03) Ovarian Margin 10.0 4.9 Breast Cancer 7.9 10.4 (OD06283-07) (OD04566) Ovarian Cancer 4.0 8.7 Breast Cancer 1024 12.0 18.0 064008 Ovarian cancer 2.9 4.9 Breast Cancer 20.0 0.0 (OD06145) (OD04590-01) Ovarian Margin 4.4 3.9 Breast Cancer Mets 12.2 17.3 (OD06145) (OD04590-03) j Breast Cancer Ovarian cancer Breast Cancer Ovaria c1.8 1.4 Metastasis 2.7 3.6 006455-03) (OD04655-05) Ovarian Margin 11.0 0.0 Breast Cancer 10.7 17.6 (OD06455-07) 064006 NormalLung 25.3 28.1 Breast Cancer 8.6 13.3 Normal Lung 253 2 8 . 9100266 861 Invasive poor diff. Breast Margin lung adeno 33.2 26.2 9100265 22.7 15.1 (ODO4945-01 906 Lung Margin 13.4 9.8 Breast Cancer 3.3 6.3 (OD04945-03) A209073 Lung Malignant 23.7 19.3 Breast Margin 3.8 7.9 Cancer (OD03126) A2090734 Lung Margin 5.7 34.6 Breast cancer 30.6 17.9 (OD03126) (OD06083) Lung Cancer Breast cancer node (D05014A) 15.0 40.1 metastasis 33.0 42.0 (OD5014A) (OD06083) Lung Margin 100.0 80.1 Normal Liver 2.3 2.3 (OD05014B) Lung cancer Cancer (ODO6081) 6.6 7.0 Liver Cancer 1026 5.0 7.4 (_OD0608 1) -~ie ~Lung Margin 3. T]C1 . (D06081) 3.4 Liver Cancer 1025 3.8 .3 Lung Cancer 5.5 6.8 Liver Cancer 7.5 2.4 (OD04237-01) 6004-T 391 WO 03/050245 PCT/US02/38594 Lung Margin 23.3 18.2 Liver Tissue 3.6 5.1 (OD04237-02) 6004-N Ocular Melanoma 33.4 60.3 Liver Cancer 11.0 9.7 Metastasis 6005-T Ocular Melanoma 3.4 5.3 Liver Tissue 16.3 8.9 Margin (Liver) 3 5.3 6005-N I~Liver Cancer Melanoma Metastasis 31.2 28.9 Liver Cancer 4.6 2.9 064003 1 Melanoma Margin 22.2 17.0 Normal Bladder 5.6 10.3 (Lung) (Lung) ~~Bladder cer__ 10. Normal Kidney 1.7 3.1 Bladder Cancer 4.5 6.0 1 1023 Kidney Ca, Nuclear 5.3 4.4 Bladder Cancer 22.4 30.8 grade 2 (OD04338) I. A302173 Kidney Margin 22.7 84.1 Normal Stomach 9.7 10.6 (OD04338) , ra c .7 Kidney Ca Nuclear 927 1000 Gastric Cancer 4.3 15.5 grade 1/2 (OD04339) _270 9060397 -...... ..... Kidney Margin 4.4 2.5 Stomach Margin 3.1 4.5 (OD04339) 2.5 9060396 . Kidney Ca, Clear cell 5.6 11.5 Gastric Cancer 10.1 12.4 type (ODO4340) 9060395 Kidney Margin 3.3 2.4 Stomach Margin 20.0 20.3 (OD04340) 3.. 9060394 Kidney Ca, Nuclear 5.4 8.6 Gastric Cancer 4.0 7.5 grade 3 (OD04348) 064005 Table ZJ. Panel 2D Rel. Rel. xp.(%) Ag817, Exp.(%) Tissue Name Run Tissue Name Ag817, - ~Rnn Run 150811736 Run 150811736 Normal Colon 18.9 Kidney Margin 8120608 1.2 CC Well to Mod Diff (ODO3866) 8.6 Kidney Cancer 8120613 9.2 CC Margin (OD03866) 3.1 Kidney Margin 8120614 1.7 CC Gr.2 rectosigmoid (OD03868) 2.1 Kidney Cancer 9010320 26.6 CC Margin (0DO3868) 0.7 Kidney Margin 9010321 1.9 CC Mod Diff (0D03920) . 0.7 INormal Uterus j8.3 CC Margin (ODO3920) 2.5 Uterus Cancer 064011 9.9 CC Gr.2 ascend colon (ODO3921) 1 1.9 Normal Thyroid 5.4_ CC Margin (ODO3921) 2.2 thyroid Cancer 064010 2.0 CC from Partial Hepatectomy 33.0 Thyroid Cancer A302152 7.1 (ODO4309) Mets Liver Margin (ODO4309) 9.2 Thyroid Margin A302153 8.3 Colon mets to lung (OD04451-01) 10.4 Normal Breast 12.5 392 WO 03/050245 PCT/USO2/38594 Lung Margin (OD04451-02) 11.2 Breast Cancer (OD04566) 12.9 Normal Prostate 6546-1 2.8 Breast Cancer (OD04590-01) 16.7 Prostate Cancer (D04410) 87 Breast Cancer Mets 22.8 Prostate Cancer (OD4410) 8.7 (OD04590-03) 22.8 Prostate Margin (D04410) Breast Cancer Metastasis 4 Prostate Margin (ODO4410) 2.4 (OD04655-05) 4.4 Prostate Cancer (OD04720-01) 10.7 Breast Cancer 064006 19.2 Prostate Margin (OD04720-02) 19.6 Breast Cancer 1024 15.5 Normal Lung 061010 66.4 Breast Cancer 9100266 9.7 Lung Met to Muscle (ODO4286) 14.7 Breast Margin 9100265 12.8 Muscle Margin (ODO4286) 10.4 Breast Cancer A209073 14.9 Lung Malignant Cancer (OD03126) 45.7 Breast Margin A209073 6.0 Lung Margin (OD03126) 34.6 Normal Liver 1.1 Lung Cancer (OD04404) 100.0 Liver Cancer 064003 4.0 Lung Margin (OD04404) 13.7 Liver Cancer 1025 1.5 Lung Cancer (OD04565) 50.0 Liver Cancer 1026 7.8 Lung Margin (OD04565) 12.7 Liver Cancer 6004-T 2.0 Lung Cancer (OD04237-01) 29.5 Liver Tissue 6004-N 10.8 Lung Margin (OD04237-02) 17.3 Liver Cancer 6005-T 7.8 Ocular Mel Met to Liver 56.3 Liver Tissue 6005-N 2.5 (ODO4310) Liver Margin (ODO4310) 3.8 Normal Bladder 16.4 Melanoma Mets to Lung (OD04321) 58.2 Bladder Cancer 1023 7.4 Lung Margin (OD04321) 18.7 Bladder Cancer A302173 33.0 Normal Kidney 10.0 . _Bladder Cancer (OD04718-01) 8.6 Kidney Ca, Nuclear grade 2 79.0 Bladder Normal Adjacent 7.9 (OD04338) (OD04718-03) Kidney Margin (OD04338) 3.1 Normal Ovary 9.7 Kidney Ca Nuclear grade 1/2 80.1 Ovarian Cancer 064008 21.0 (OD04339) 8.1 OviCancer 064008 21.0 Kidney Margin (OD04339) 4.2 Ovarian Cancer (OD04768-07) 15.1 Kidney Ca, Clear cell type 22.8 Ovary Margin (OD04768-08) 4.7 (OD04340) Kidney Margin (OD04340) 6.7 Normal Stomach 7.4 Kidney Ca, Nuclear grade 3 7.5 Gastric Cancer 9060358 6.5 (OD04348) ... Kidney Margin (OD04348) 2.4 Stomach Margin 9060359 4.5 Kidney Cancer (OD04622-01) 49.0 Gastric Cancer 9060395 17.3 Kidney Margin (OD04622-03) 1.0 Stomach Margin 9060394 11.4 Kidney Cancer (OD04450-01) 32.5 Gastric Cancer 9060397 25.5 Kidney Margin (OD04450-03) 4.2 Stomach Margin 9060396 2.2 Kidney Cancer 8120607 21.8 IGastric Cancer 064005 9.9 393 WO 03/050245 PCT/US02/38594 Table ZK. Panel 3D Rel. Rel. Exp (%) Exp.(%) Tissue Name Ag817, Tissue Name Ag817, Run Run 164729916 164729916 Daoy- Medulloblastoma 1.1 Ca Ski- Cervical epidermoid carcinoma (metastasis) 0 TE671- Medulloblastoma 0.3 ES-2- Ovarian clear cell carcinoma 0.4 Ramos- Stimulated with D283 Med- Medulloblastoma 0.8 Ramos- Stimulated with 0.0 PMA/ionomycin 6h PFSK-1- Primitive 0.8 Ramos- Stimulated with 0.8 0.0 Neuroectodermal PMA/ionomycin 14h XF-498- CNS 65.5 MEG-01- Chronic myelogenous 0.0 leukemia (megokaryoblast) SNB-78- Glioma 17.9 Raji- Burkitt's lymphoma 0.0 SF-268- Glioblastoma 0.5 Daudi- Burkitt's lymphoma 0.0 T98G- Glioblastoma 1.5 U266- B-cell plasmacytoma 0.1 SK-N-SH- Neuroblastoma SK-N-SH- Neuroblastoma 0.6 CA46- Burkidtt's lymphoma 0.0 (metastasis) _ RL- non-Hodgkin's B-cell10 SF-295- Glioblastoma 3.7 RL- non-Hodgn's B-cell 0.0 lymphoma Cerebellum 0.7 JM1- pre-B-cell lymphoma 0.0 Cerebellum 0.4 Jurkat- T cell leukemia 0.0 NCI-H1292- Mucoepidermoid 0.0 TF-1- Erythroleukemia 0.0 lung carcinoma DMS-114- Small cell lung 1.7 HUT 78- T-cell lymphoma 0.0 cancer DMS-79- Small cell lung cancer 0.5 U937- Histiocytic lymphoma 12.4 NCI-H146- Small cell lung 0 cancer .1 0 KU-812- Myelogenous leukemia 0.0 NCI-H526- Small cell lung 0.0 769-P- Clear cell renal carcinoma 0.0 cancer NCI-N417- Small cell lung 0.0 Caki-2- Clear cell renal carcinoma 4.0 cancer NCI-H82- Small cell lung cancer 0.0 SW 839- Clear cell renal carcinoma 1.9 NCI-H157- Squamous cell lung . Rhabdoid kidney tumor 1.9 cancer (metastasis) 0.0 Rhabdoid kidney tumor 1.9 NCI-H1155- Large cell lung 0.0 Hs766T- Pancreatic carcinoma (LN 0.4 cancer metastasis) NCI-H1299- Large cell lung 0.0 CAPAN-1- Pancreatic 0.2 cancer adenocarcinoma (liver metastasis) NCI-H727- Lung carcinoid 0.0 SU86.86- Pancreatic carcinoma 0.1 NC_-H27-_Lng__aini _.0(liver metastasis) BxPC-3- Pancreatic 0.2 NCI-UMC-11- Lung carcinoid 0.0 adenocarcinoma0.2 adenocarcinomna LX-1- Small cell lung cancer 0.0 HPAC- Pancreatic adenocarcinoma 0.0 Colo-205- Colon cancer 0.0 MIA PaCa-2- Pancreatic carcinoma 0.0 394 WO 03/050245 PCT/US02/38594 Co cCFPAC-1- Pancreatic ductal .0 KM12- Colon cancer 0.0 0.0encrcnm adenocarcinoma KM20L2- Colon cancer 0.0 PANC-1- Pancreatic epithelioid .0 ductal carcinoma NCI-716- Colon cancer 0.0 T24- Bladder carcinmna (transitional .0 NCI-H71 6- Colon cancer :0.0 cel 0.0 cell) SW-48- Colon adenocarcinoma 0.0 5637- Bladder carcinoma 0.0 SW1116- Colon adenocarcinoma 0.0 HT-1197- Bladder carcinoma 0.7 UM-UC-3- Bladder carcinma LS 174T- Colon adenocarcinoma 0.0 (rsio a c0.0 (transitional cell) SW-948- Colon adenocarcinoma 0.0 A204- Rhabdomyosarcoma 0.0 SW-480- Colon adenocarcinoma 0.0 HT-1080- Fibrosarcoma 0.6 NCI-SNU-5- Gastric carcinoma '0.0 MG-63- Osteosarcoma 4.7 SK-LMS-1- Leiomyosarcoma KATO III- Gastric carcinoma 0.0 (l 5.4 (vulva) Go 84 SJRH30- Rhabdomyosarcoma (met NCI-SNU-16- Gastric carcinoma 8.4 .tobone marrow) 0. 0 1

NCI

7 S~-to bone marrow).

NCI-SNU-1- Gastric carcinoma 0.0 A431- Epidermoid carcinoma 1.0 RF-1- Gastric adenocarcinoma 0.0 WM266-4- Melanoma 100.0 .F 1 ............ a...cr.io m .. .............. e......... .......... .... .. ............ .... ..... ...... DU 145- Prostate carcinoma (brain RF-48- Gastric adenocarcinoma 0.0 1 st0.0a metastasis) MKN-45- Gastric carcinoma 0.0 MDA-MB-468- Breast0.4 adenocarcinoma ISCC-4- Squamous cell carcinoma NCI-N87- Gastric carcinoma 0.1 SCC-4- Squamous cell carcinoma 0.0 of tongue ISCC-9- Squamous cell carcinoma O0 OVCAR-5- Ovarian carcinoma 0.0 SCC-9- Squaous cell carcinoma 0.0 of tongue RL95-2- Uterine carcinoma SCC-15- Squamous cell carcinoma 0.0 RL95-2- Uterine carcinoma 5.4 0.0ogu of tongue HelaS3- Cervical 0.0 CAL 27- Squamous cell carcinoma 0.2 adenocarcinoma . of tongue 0..... . Table ZL. Panel 4.1D Rel. Rel. Rel. Rel. Exp.(% Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag5968, Ag817, Tissue Name Ag5968, Ag817, Run Run Run Run 248173663 247683512 248173663 247683512 Secondary Th act 0.0 0.0 HUVEC IL-lbeta 0.0 0.0 Secondary Th2 act 10.0 0.0 HUVEC IFN gamma 0.0 0.0 1 1 HUVEC TNF alpha + Secondary Trl act 0.0 gamma lpha+ 0.

0 0.0 IFN ganuna Secondary Thl rest 0.0 0 alpha + 0.0 0.2 Secondary Th2 rest 0.0 0.0 HUVEC IL-11 0.0 0.0 Lung Microvascular ^ Secondary Trl rest 0.0 0.0 Lung Microvascular 0.1 0.3 EC none 395 WO 03/050245 PCT/US02/38594 Lung Microvascular Primary Thl act 0.0 0.0 EC TNFalpha + 0.0 0.0 IL-lbeta Primary Th2 act 0.0 0.0 Microvascula 0.0 0.0 Dermnal EC none Microsvasular Primary Trl act 0.0 0.0 Dermal EC 0.0 0.0 TNFalpha + IL-lbeta .... i~Bronchial epithelium ^ Primary Thl rest 0.0 0.0 Bronchial epithelum 3.2 3.6 TNFalpha + IMbeta Primary Th2 rest 0.0 0.0 Small airwnoneay 1.1 2.5 epithelium none Small airway Primary Trl rest 0.0 0.0 epithelium TNFalpha 1.1 1.8 +IL-1beta I ........... .. ........................ .. .... e t ..... ..... .. ....... ............. CD45RA CD4 0.4 0.5 Coronery artery SMC 0

.

2 0.6 lymphocyte act 040 rest 0 0 CD45RO CD4 0.0 0.0 Coronery artery SMC 06 1.0 lymphocyte act 0.0TNFalpha + IL-lbeta.6 1.0 CD8 lymphocyte act 0.0 0.0 Astrocytes rest 0.0 0.0 Secondary CD8 0.0 0.0 Astrocytes TNFalpha 0.0 0.0 lymphocyte rest + IL-lbeta1 Secondary CD8 0.0 0.0 KU-812 (Basophil) 0.0 0.0 lymphocyte act rest KU-812 (Basophil) CD4 lymphocyte none 0.0 0.0 K812(Basophil) 0.0 0.0 PMA/ionomycin 2ry CCD1106 Thl/Th2/Trl anti-CD95 0.0 0.0 (Keratinocytes) none0.9 0.9 CH11 ... CCD 1106 LAK cells rest 29.7 17.4 (Keratinocytes) 0.4 0.7 TNFalpha + IL-lbeta LAK cells IL-2 0.0 0.0 Liver cirrhosis 1.9 2.4 LAK cells IL-2+IL-12 0.0 0.1 NCI-H11292 none 0.0 0.1 L-AK cells IL-2+IFN LAK cells IL-2+N 0.2 0.2 NCI-H292 IL-4 0.0 0.1 gamma LAK cells IL-2+ IL-18 0.3 0.1 NCI-H292 IL-9 0.1 0.1 LAK cells .AK cells 63.3 36.3 NCI-H292 IL-13 0.0 0.2 PMA/ionomycin NK Cells IL-2 rest 0.0 0.0 NCI-H292 0.0 0.1 gamma Two Way MLR 3 day 3.2_ 1.4 HPAEC none 0.0 . 0.0 HPAEC TNF alpha + Two Way MLR 5 day 1.0 0.3 IL-1 beta 0 .0 0.1 ___________________ _________ V jL-1 beta]_____ Two Way MLR 7 day 0.1 0.1 Lung fibroblast none 4.3 8.7 Lung fibroblast TNF PBMC rest 0.0 0.0 1.7 2.0 alpha +IL-1I beta PBMC PWM 0.0 0.0 Lung fibroblast IL-4 j1.2 2.6 396 WO 03/050245 PCT/US02/38594 PBMC PHA-L 0.0 0.0 Lung fibroblast IL-9 3.1 2.2 Ramos (B cell) none 0.0 0.0 Lung fibroblast IL-13 1.4 1.6 Ramos (B cell) 0.0 0.0 Lung fibroblast IFN 4.8 5.53 ionomycin gamma Dermal fibroblast B lymphocytes PWM 0.0 0.0 CCDIO70 rest 1.5 3.3 B lymphocytes CD40L 0.1 0.0 Dermal fibroblast 1.4 2.1 and IL-4 CCD1070 TNF alpha SDermal fibroblast1.3 EOL-1dbcAMP 0.0 0.0 1.C0D1070 IL- beta .3 CCDIO70 IL-1 beta AEOL-1 dbcAMP 0.0 0.0 Dermal fibroblast 19.

5 17.0 PMA/ionomycin IFN gamma Dermal fibroblast Dendritic cells none 100.0 70.2 Dermal fibroblast 48.6 25.3 IL-4 Dermal Fibroblasts Dendritic cells LPS 19.8 14.3 Deal Fibroblasts 76.3 19.5 rest Dendritic cells 18.8 24.8 Neutrophils 0.0 0.0 anti-CD40 TNFa+LPS I Monocytes rest 0.0 0.0 Neutrophils rest 10.0 - 0.0 Monocytes LPS . 17.9 119.2 Colon 10.1 0.1 Macrophages rest 26.8 19.5 Lung 1.9 j1.0 cropi....... ........................... 5.2 100.0 .... T y u .. . ... 2 ....... _ Macrophages LPS 5.2 100.( Thymus 1.2 0.5 HUVEC none 0.0 . 0.0 Kidney 1.4 0.7 HUVEC starved 0.0 0.0 C s arv e !9 . Io ~ ! ................................................................................. Table ZM. Panel 4D Exp.(% Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag817, Ag817, Tissue Name Ag817, Ag817, Run Run Run Run 139579600 139892411 139579600 139892411 Secondary Th! act 0.0 0.0 HUVEC IL-lbeta 0.0 0.0 Secondary Th2 act 0.0 0.0 HUVEC IFN gamma 0.0 0.0 HUVEC TNF alpha +0. 00 Secondary Trl act 0.0 0.0 HVECNF alpha 0.0 0.0 IFN gamma Secondary Thl rest 0.0 0 .0 0IECTFla .

0 0.0 Secondary Th2 rest 0.0 0.0 _ _UVEC IL-11_1 0.0 0.0 S eco dary T h2 est .0 ....... .. 0 ....................... C :!.I .... ........... o.o ........................ 0........................ Secondary Trl rest 0.0 0.0 ung Microvascular 0.0 0.0 Lung Microvascular Primary Thl act 0.0 0.0 EC TNFalpha + 0.0 0.0 IL-lbeta Primary Th2 act 0.0 0.0 Microvascular 0.0 . 397Dermal EC none 397 WO 03/050245 PCT/USO2/38594 Microsvasular Primary Trl act 0.0 0.0 Dermal EC 0.0 0.0 TNFalpha + IL-lbeta Primary Th rest 0.0 Bronchial epithelium 80 11.6 Primary Thl rest 0.0 0.0 TNFalpha + ILlbeta 8.0 11.6 Salairway 11.4 1. Primary Th2 rest 0.0 0.0 Spi1ium none 1.4 1.1 Small airway Primary Trl rest 0.0 0.0 epithelium TNFalpha 2.0 2.3 + IL-lbeta CD45RA CD4 0.3 0.3 Coronery artery SMC 0.3 0.4 lymphocyte act rest CD45RO CD4 0.0 0.0 Coronery artery SMC 0.5 0.7 lymphocyte act TNFalpha + IL- beta CD8 lymphocyte act 0.0 0.0 Astrocytes rest 0.0 0.0 Secondary CD8 0.0 0.0 Astrocytes TNFalpha 0.0 0.0 lymphocyte rest + IL-lbeta Secondary CD8 0.0 0.0 KU-812 (Basophil) 0.0 0.0 lymphocyte act rest KU-812 (Basophil) CD4 lymphocyte none 0.0 0.0 -812 (Basophil) 0.0 0.0 ~PMA/ionomycin 2ry CCD1 106 Thl/Th2/Trl anti-CD95 0.0 0.0 0.4 0.7 Ci1(Keratinocytes) none CH11 CCD1106 LAK cells rest 32.3 39.5 (Keratinocytes) 3.8 4.6 TNFalpha + IL-lbeta LAK cells IL-2 0.0 10.0 Liver cirrhosis 0.6 1.4 LAK cells IL-2+IL-12 0.3 0.4 Lupus kidney 0.6 0.9 LAK cells IL-2+IFN 0.4 0.6 NCI-H292 none 0.1 0.1 gamma LAK cells IL-2+ IL-18 0.3 0.3 NCI-H292 IL-4 0.1 0.1 LAK cells 23.3 33.2 NCI-H292 IL-9 0.1 0.1 PMA/ionomycin NK Cells IL-2 rest 0.0 .0.0 NCI-H292 IL-13 0.0 0.1 NCI-H292 IFN Two Way MLR 3 day 1.2 1.9 NCI-H292 0.0 0.0 gamma Two Way MLR5 day H0.8 1.1 IPAEC none 0.0 0.0 HPAEC TNF alpha + Two Way MLR 7 day 0.3 0.4 IL-1 beta 0.0 0.0 PBMC rest 0.0 0.0 Lung fibroblast none 1.6 2.8 Lung fibroblast TNF1017 PBMC PWM 0.0 0.0 Lung fibroblast TNF 0.4 0.7 alpha + IL-1 beta PBMC PHA-L 0.1 0.2 Lung fibroblast IL-4 11.8 2.8 Ramos (B cell) none 0.0 0.0 Lung fibroblast IL-9 11.0 1.8 IRamos (B cell) j~ Ramos(Bcell) 0.0 0.0 Lung fibroblast IL-13 3.4 4.8 39onomyc8 398 WO 03/050245 PCT/US02/38594 Lung fibroblast IFN B lymphocytes PWM 0.0 0.0 Lnfirba 2.9 3.7 gamma B lymphocytes CD40L 0.0 0.0 Dermal fibroblast 1.5 2.0 and IL-4 CCD1070 rest ]Dermal fibroblast EOL-1 dbcAMvP 0.0 0.0 Dermal fibroblast 0.9 1.5 E CCD1070 TNF alpha EOL-1 dbcAMP Dermal fibroblast PMA/ionomycin 0.0 0.0 b a 0.8 1.1 PMA/ionomycin CCD1070 IL-1 beta 13 Dermal fbroblast + Dendritic cells none 39.0 51.8 Dermal fibroblast . 9.4 IFN gamma Dermal fibroblast ]93 2. Dendritic cells LPS 15.2 18.7 Dermal fibroblast 19.3 27.7 IL-4 Dendritic cells 33.4 44.1 BD Colitis 2 0.1 0.2 anti-CD40 Monocytes rest 0o.0 0.0 IBD Crohn's 0.3 0.5 Monocytes LPS 11.6 16.7 Colon 1.2 1.6 Macrophages rest 00.

0 . 100.0 Lung 8.7 12.0 Macrophages LPS 39.0 40.3 _ Thymus 2.2 3.3 HUVEC none 0.0 0.0 Kidney 138 4.6 UVEC starved 0.0 0.0 . . Table ZN. Panel 4R Rel. Rel. Ex.(%) Exp.(%) Tissue Name Ag817, Tissue Name Ag817, Run Run 140125854 140125854 Secondary Thl act 0.0 HUVEC IL-lbeta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 Secondary Trl act 0.0 HUVEC TNF alpha + IFN gamma 0.0 Secondary Thl rest 0.0 HUVEC TNF alpha + IL4 .0 Secondary Th2 rest 0.0 HUVEC IL -11 0.0 Secondary Trl rest 0.0 Lung Microvascular EC none 0.0 Primary mil act 0.0 Lung Microvascular EC TNFalpha 0.0 Primary Th1 act 0.0 + IL-lbeta Primary Th2 act 0.0 Microvascular Dermal EC none 0.0 Primary T act 0.0 Microsvasular Dermal EC 0.0 TPrimary Trl act 0.0 NFalpha + IL-lbeta. Primary Th rest 0.0 Bronchial epithelium TNFalpha + 13.9 PrimaryThrest 13.9 Primary Trl rest . ep TNFalpha 8.5 CD45RA CD4 lymphocyte act 0.8 Coronery artery SMC rest 0.8 '- ............................................. I ...... Coroner artery SM C TN Fal pha + 1 CD45RO CD4 lymphocyte act 0.0 oIL-broney artery M TNFlpha + 2.4 CD8 lymphocyte act 0.0 Astrocytes rest 0.0 399 WO 03/050245 PCT/USO2/38594 Secondary CD8 lymphocyte rest 0.0 Astrocytes TNFalpha+ IL-Ibeta 0.3 Secondary CD8 lymphocyte act 0.0 KU-812 (Basophil) rest 0.0 l cIKU-812 (Basophil) CD4 lymphocyte none 0.0 ]PMA/ionomycin 0

.

0 2ry ThlTh2/Trlanti-CD95 0.0 CCD1106 (Keratinocytes) none 1.6 CHI 1 LAK cells rest 55.9 CCD1106 (Keratinocytes) 24.1 TNFalpha + IL-lbeta 1 LAK cells IL-2 0.0 Liver cirrhosis 4.0 LAK cells IL-2+IL-12 0.9 Lupus kidney 2.2 LAK cells IL-2+IFN gamma 1.2 NCI-H292 none 0.6 LAK cells IL-2+ IL-18 1.1 NCI-H292 IL-4 0.9 LAK cells PMA/ionomrnycin 58.6 NCI-H292 IL-9 0.7 NK Cells IL-2 rest 0.0 NCI-H292 IL-13 0.2 Two Way MLR 3 day 3.3 NCI-H292 IFN gamma 0.1 Two Way MLR 5 day 1.7 HPAEC none 0.1 Two Way MLR 7 day 1.2 HPAEC TNF alpha + IL-1 beta 0.0 PBMC rest 0.1 Lung fibroblast none 10.4 Lung fibroblast TNF alpha + IL-1 PBMC PWM 0.0 1.6 beta PBMC PHA-L 0.3 . Lung fibroblast IL-4 3.1 Ramos (B cell) none .0.0 Lung fibroblast IL-9 2.9 Ramos (B cell) ionomycin 0.0 Lung fibroblast IL-13 1.6 B lymphocytes PWM 0.1 Lung fibroblast IFN gamma 3.0 B lymphocytes CD40L and IL-4 0.2 Dermal fibroblast CCD1070 rest 4.7 EOL-1 dbcAMP . Dermal fibroblast CCD1070 TNF 5.1 EOL-1 dbcAMP 0.0 5.1 alpha EOL-1 dbcAMP .1 Dermal fibroblast CCD1070 IL-1 1.6 PMA/ionomycin beta Dendritic cells none 95.3 Dermal'fibroblast IFN gamma 43.8 Dendritic cells LPS 35.4 Dermal fibroblast IL-4 28.5 Dendritic cells anti-CD40 68.3 IBD Colitis 1 2.3 Monocytes rest 0.0 .IBD Colitis 2 0.2 Monocytes LPS 30.8 IBD Crohn's 1. Macrophages rest 100.0 Colon 5.5 Macrophages LPS LLLLL87.1 Lung 48.3 HUVEC none 0.0 Thymus 4.3 HUVEC starved 0.0 Kidney 23.3 400 WO 03/050245 PCT/US02/38594 Table ZO. general oncology screening panel v 2.4 Rel. Rel. Rel. Rel. Rel. Rel. Exp.(%) Exp.(%) Exp.(%) Exp.(%) Exp.(%) Exp.(%) Tissue Name Ag817, Ag817, Ag817, issue Name Ag817, Ag817, Ag817, Run Run Run Run Run Run 25805211 25868098 25973317 25805211 25868098 25973317 0 9 0 0 9 0 Bladder cne Colon cancer 1 5.0 6.6 6.2 cNAT 2 e 1.0 0.9 0.9 NAT 2 ______ ___ f 66 6 Bladder cancer 0 093 D. Colon cancer 2.6 2.1 2.4 Bladder cancer 0.3 0.3 0.2 NAT 1 NAT 3 ABladder cancer Colon cancer 2 25.5 23.2 26.6 dr cancer 9.1 7.9 6.3 Colon cancer Prostate Colon cancer 5.6 4.3 4.4 adenocarcinoma 10.0 8.6 8.8 NAT 2 1 1 Prostate Colon cancer 3 14.2 14.6 10.6 adenocarcinoma 1.3 1.5 1.2 2 Prostate Colon cancer 63 Pott Colon cancer 7.6 7.1 6.3 adenocarcinomna 2.2 2.0 1.2 NAT 33 3 Colon Prostate malignant 29.1 29.7 32.1 adenocarcinoma 11.1 10.4 11.2 cancer 4 4 Colon normal Prostate cancer adjacent tissue 5.1 4.4 3.5 NAT 5 1.3 1.5 1.2 4 Prostate Lung cancer 1 28.5 24.5 27.7 adenocarcinoma 1.7 1.5 1.3 6 Prostate Lung NAT 1 12.2 10.4 9.2 adenocarcinoma 1.6 2.0 1.3 7 Prostate Lung cancer 2 22.7 20.0 24.5 adenocarcinoma 0.7 0.6 0.6 8 Prostate Lung NAT 2 4.9 5.1 5.2 adenocarcinoma 4.0 4.1 4.3 9 Squamous cell 646 60.3 47.3 Prostate cancer1.3 1.4 13 carcinoma 3 6 6 47.3 NAT 10 1 1 1.3 LungA 3 4.3 3.7 6.1 Kidney cancer 1 44.1 40.3 . 44.1 metastatic 18.8 16.6 17.6 KidneyNAT 1 2.4 2.4 2.7 melanoma 1 Melanoma 2 20.6 19.3 _ 17.7 Kidney cancer 2 23.2 23.0 26.4 Melanoma 3 14.8 13.5 113.0 Kidney NAT 2 4.7 j4.7 5.1 metastatic 100.0 100.0 100.0 KiCdney cancer 3 9.6 8.4 6.3 melanoma 4t . 401 WO 03/050245 PCT/US02/38594 metastatic 1 metastatc 40.9 38.7 46.3 Kidney NAT 3 1.2 1.2 1.2 melanoma 5 Bladder cancer 4.9 5.3 4.4 Kidney cancer 4 5.3 3.9 5.3 Bladder cancer 0.0 0.0 0.0 KidneyNAT 4 1.1 1.0 1.1 NAT 1 I I I I Bladder cancer 113 13.5 14.2 21 AIcomprehensive panel_vl.O0 Summary: Ag817 Highest expression of this gene is detected in a orthoarthritis bone (CT=24.3). This gene shows a wide spread expression profile in this panel. High to moderate expression of the gene is seen in in samples derived from normal and orthoarthitis/ rheumatoid arthritis bone and adjacent bone, cartilage, 5 synovium and synovial fluid samples, from normal lung, COPD lung, emphysema, atopic asthma, asthma, allergy, Crohn's disease (normal matched control and diseased), ulcerative colitis(nonrmal matched control and diseased), and psoriasis (normal matched control and diseased). Interestingly, expression of this gene is upregulated in bone and synovium from OA patients. Therefore, therapeutic modulation of this gene product may ameliorate 10 symptoms/conditions associated with autoimmune and inflammatory disorders including psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis. Ardais Panel v.1.0 Summary: Ag817 Highest expression of this gene is detected in a lung cancer (372) sample (CT=20.1). High expression of this gene is seen both in 15 normal adjacent and cancer samples from lung. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of lung cancer. CNSneurodegeneration vl.0 Summary: Ag5968 This panel confirms the expression of this gene at low levels in the brain in an independent group of individuals. This gene is found to be slightly upregulated in the temporal cortex of Alzheimer's disease 20 patients. Therefore, therapeutic modulation of the expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease. Generalscreening_panel_v1.5 Summary: Ag817 Highest expression of this gene is detected in melanoma M14 cell line (CT=22). High expression of this gene is also seen in colon cancer and number of cell lines derived from melanoma, ovarian, breast, 25 renal, and brain cancer. This gene codes for a putative transmembrane protein NMB precursor (GPNMB). Using the GeneCalling study at CuraGen the mouse ortholog of GPNMB has been shown to be highly upregulated in a Neural Stem Cell (NSC) line 402 WO 03/050245 PCT/USO2/38594 derived from the TSC2 knockout, a model for the Tuberous Sclerosis Complex syndrome. This tumor suppressor gene is involved in the regulation of cell growth, shape and interaction with the extracellular matrix. The NSC cells are a model for the CNS phenotypes associated with TSC (giant cell astrocytoma among others). Riggins's group at 5 Duke identified GPNMB as one of 7 most highly expressed genes in glioblastoma multiforme with specific induction in tumors (Loging WT, Lal A, Siu IM, Loney TL, Wikstrand CJ, Marra MA, Prange C, Bigner DD, Strausberg RL, Riggins GJ. Genome Res. 2000 Sep; 10(9):1393-402). Therefore, based on this and the expression profile, therapeutic modulation of this gene through the use of antibodies or small molecule may be beneficial 10 in the treatment of melanoma, ovarian, breast, renal, and brain cancers including glioblastoma multiforme. Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the 15 activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene 20 product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. HASS Panel vl.0 Summary: Ag817 This gene is a target in brain cancer -specifically gliomas as it is expressed at a 25 higher level in gliomas than medulloblastomas. It is induced by serum -starvation in U87-MG cells (wells 50 and 52) and was induced by treating serum-starved cells for 12 hrs with serum containing media (well 53). Therapeutic modulation of the expression or function of this gene may alleviate brain cancer; specifically gliomas and be of use in the treatment of this disease. 30 Panel 1.2 Summary: Ag817 Two experiments with same probe-primer sets are in good agreement, with highest expression of this gene seen in placenta (CTs=20.8). High to moderate expression of this gene is seen in normal tissues and number of cancer cell line. 403 WO 03/050245 PCT/USO2/38594 The expression correlates with expression profile seen in panel 1.5. Please see panel 1.5 for further discussion on the utility of this gene. Panel 2.2 Summary: Ag817 Two experiments with same probe-primer sets are in good agreement. Highest expression of this gene is detected in kidney cancer and control 5 lung sample (CTs=22-25). This gene shows widespread expression in this panel with high expression in cancer and corresponding normal adjacent tissues. Please see panel 1.5 and 2.4 for further discussion on the utility of this gene. Panel 2D Summary: Ag817 Highest expression of this gene is detected in lung cancer sample (CT=23.7). This gene shows widespread expression in this panel with high 10 expression in cancer and corresponding normal adjacent tissues. Please see panel 1.5 and 2.4 for further discussion on the utility of this gene. Panel 3D Summary: Ag817 Highest expression of this gene is detected in melanoma WM266-4 cell line (CT=24.5). High to moderate expression of this gene is also detected in number of cancer cell lines derived from brain, gastric, uterine, ovarian, 15 cervical, histiocytic lymphoma, renal, bladder, pancreatic, bone, vulva and tongue cancers. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of these cancers. Panel 4.1D Summary: Ag5968/Ag817 Two experiments with different probe and primer sets are in good agreement. Highest expression of this gene is detected in resting 20 dendritic cells and activated macrophage (CTs=25-26.5). The expression profile seen in this panel correlates with that seen in panel 4D. Please see panel 4D for further discussion on the utility of this gene. Panel 4D Summary: Ag817 Two experiments with same probe and primer sets are in excellent agreement with highest expression of this gene seen in resting macrophage 25 (CTs=21). High expression of this gene is mainly seen in activated monocytes, resting and activated dendritic cells, macrophages and LAK cells. Moderate to high expression of this gene is also seen in two way MLR, PHA-L activated PBMC cells, cytokine activated bronchial epithelium and coronary artery SMC, resting and activated small airway epithelium, activated astrocytes, keratinocytes, mucoepidermoid NCI-H292 cells, HPAEC, 30 lung and dermal fibroblasts, liver cirrhosis, lupus kidney, IBD Crohn's colitis, normal tissues represented by colon, lung, thymus and kidney. Recent data published in JBC (Shikano et. al., 276( 11l):8125-34) demonstrated that the mouse ortholog of NMB (DC-HIL) was expressed on a mouse Dendritic cell-like line (DC are myeloid lineage cells 404 WO 03/050245 PCT/USO2/38594 that specialize in presentation of antigen to T cells), and proposed that it was involved in DC migration (transendothelial migration). Therefore, therapeutic modulation of this gene or its protein product through the use of antibodies or small molecule drug may be useful in the treatment of diseases in which dendritic cells and macrophages play an important role, 5 such as, but not limited to, including Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, lupus erythematosus, or psoriasis. Panel 4R Summary: Ag817 Highest expression of this gene is detected in resting macrophage (CT=24.3). The expression profile seen in this panel correlates with that seen 10 in panel 4D. Please see panel 4D for further discussion on the utility of this gene. general oncology screening panelv_2.4 Summary: Ag817 Three experiments with same probe-primer sets are in excellent agreement with highest expression of this gene seen in metastatic melanoma (CTs=22-24.8). High to moderate expression of this gene is seen in both normal adjacent and cancer samples derived from colon, prostate, lung, 15 kidney, bladder and melanoma. Interestingly, expression of this gene is higher in cancer samples compared to the adjacent normal tissue. Therefore, expression of this gene may be used as diagnostic marker to detect the presence of melanoma, metastatic melanoma, and colon, prostate, lung, kidney, bladder cancers. Furthermore, therapeutic modulation of this gene through the use of antibodies or small molecule drug may be useful in the treatment of 20 melanoma, metastatic melanoma, and colon, prostate, lung, kidney, bladder cancers. Example D: Identification of Single Nucleotide Polymorphisms in NOVX nucleic acid sequences Variant sequences are also included in this application. A variant sequence can 25 include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a eDNA. A SNP can arise in several ways. For example, a SNP may be due to a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a transversion. A SNP can also arise from a deletion of a 30 nucleotide or an insertion of a nucleotide, relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration of the amino acid encoded by the gene at the position of the SNP. Intragenic SNPs may also be 405 WO 03/050245 PCT/USO2/38594 silent, when a codon including a SNP encodes the same amino acid as a result of the redundancy of the genetic code. SNPs occurring outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation of the expression pattern. Examples include alteration in 5 temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message. SeqCalling assemblies produced by the exon linking process were selected and extended using the following criteria. Genomic clones having regions with 98% identity to all or part of the initial or extended sequence were identified by BLASTN searches using 10 the relevant sequence to query human genomic databases. The genomic clones that resulted were selected for further analysis because this identity indicates that these clones contain the genomic locus for these SeqCalling assemblies. These sequences were analyzed for putative coding regions as well as for similarity to the known DNA and protein sequences. Programs used for these analyses include Grail, Genscan, BLAST, 15 HMMER, FASTA, Hybrid and other relevant programs. Some additional genomic regions may have also been identified because selected SeqCalling assemblies map to those regions. Such SeqCalling sequences may have overlapped with regions defined by homology or exon prediction. They may also be included because the location of the fragment was in the vicinity of genomic regions 20 identified by similarity or exon prediction that had been included in the original predicted sequence. The sequence so identified was manually assembled and then may have been extended using one or more additional sequences taken from CuraGen Corporation's human SeqCalling database. SeqCalling fragments suitable for inclusion were identified by the CuraToolsTM program SeqExtend or by identifying SeqCalling fragments mapping to the 25 appropriate regions of the genomic clones analyzed. The regions defined by the procedures described above were then manually integrated and corrected for apparent inconsistencies that may have arisen, for example, from miscalled bases in the original fragments or from discrepancies between predicted exon junctions, EST locations and regions of sequence similarity, to derive the final 30 sequence disclosed herein. When necessary, the process to identify and analyze SeqCalling assemblies and genomic clones was reiterated to derive the full length sequence (Alderborn et al., Determination of Single Nucleotide Polymorphisms by Real-time Pyrophosphate DNA Sequencing. Genome Research. 10 (8) 1249-1265, 2000). 406 WO 03/050245 PCT/USO2/38594 Variants are reported individually but any combination of all or a select subset of variants are also included as contemplated NOVX embodiments of the invention. NOV 27b: SNP Variants for SLPI-like Protein CG055060-01. 5 Variant Nucleotides Amino Acids Position Initial Modified Position Initial Modified 13374945 38 T C 7 Phe Ser 13377692 53 T C 12 Leu Pro 13376226 169 T C 51 Cys Arg 13374947 173 A G 52 Gin Arg 13374948 188 G A 57 Cys Tyr 13374949 193 G A 59 Gly Arg NOV 28c: SNP Variants for NMB-like Protein CG056972-01. Variant Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13375128 233 T C 47 Trp Arg 13375127 263 A G 57 Lys Glu 13375129 425 A G 111 Asn Asp 13381799 484 A G 130 Pro Pro 13375130 555 A G 154 Asn Ser 13375131 578 T C 162 Phe Leu 13375132 975 C T 294 Ser Phe 13375133 1065 C T 324 Pro Leu 13381798 1474 T C 460 Asp Asp 13381797 1555 T C 487 Ser Ser 13381796 1672 C A 526 Ser Arg 13381810 1832 T C 0 13381795 1899 G A 0 10 NOV 1b: SNP Variant for von Ebner's gland protein precursor-like Protein CG102689-02. Variant Nucleotides Amino Acids 407 WO 03/050245 PCT/US2/38594 Position Initial Modified Position Initial Modified 13381709 205 T C 62 Leu Pro NOV 2b: SNP Variants for Fibulin-2-like Protein CG103827-02. Variant Nucleotides Amino Acids Position Initial Modified Position Initial Modified 13381701 3006 T C 979 Gly Gly 13381704 3733 T A 0 13381705 3740 C A 0 5 NOV 3g: SNP Variant for germline oligomeric matrix protein-like Protein CG105716-01. Variant Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13378855 1304 A G 435 Asp Gly 10 NOV 4b: SNP Variants for Protein CGI-100 precursor-like Protein CG153910-02. Variant Nucleotides Amino Acids Position Initial Modified Position Initial Modified 13381722 462 C A 0 13381716 825 G T 59 Glu End 13381715 1005 G A 119 Val Met 15 NOV 6a: SNP Variants for Type Ib membrane protein-like Protein CG159093-01. Variant Nucleotides Amino Acids Position Initial Modified Position Initial Modified 13381719 915 A G 282 Arg Gly 13381718 936 T C 289 Ser Pro 13381717 1069 T C 333 Leu Pro 408 WO 03/050245 PCT/USO2/38594 NOV 9b: SNP Variant for MS4A7-like Protein CG160152-03. Variant Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13381738 408 T A 134 Leu End 5 NOV 1la: SNP Variants for Type IIIa membrane protein-like Protein CG160244-01. Variant Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13381741 1716 A G 532 His Arg 13381736 3451 A G 1110 Leu Leu 13381742 3661 G A 1180 Pro Pro 13381743 4799 G C 1560 Ala Pro NOV 12a: SNP Variants for Lectin C-type and SCP domains containing extracellular 10 protein-like Protein CG160541-01 Variant Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13381753 39 T C 0 13381752 439 A G 126 Leu Leu 13381751 513 C T 151 Thr Met 13381750 1207 T C 382 Ala Ala 13381748 1367 C T 0 13381745 1560 A G 0 13381744 1658 A G 0 NOV 13b: SNP Variants for Soggy-1 protein precursor-like Protein CG161630-02 15 Variant Nucleotides Amino Acids Position Initial Modified Position Initial Modified 13381733 159 G A 29 Ala Thr 13381732 399 A G 109 Ser Gly 13381731 480 G A 136 Glu Lys 409 WO 03/050245 PCT/USO2/38594 NOV 15b: SNP Variants for Folate receptor beta-like Protein CG162177-02 Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13381761 687 G T 199 Ala Ala 13381760 698 C A 203 Ala Asp 5 NOV 17a: SNP Variant for Leukocyte-associated IG-like receptor-2-like Protein CG162509-02. Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13376537 380 G C 123 Ser Thr 10 NOV 18b: SNP Variants for Cell surface receptor FDFO3-dtm precursor-like Protein CG162645-01 Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13381770 314 A G 99 Tyr Cys 13381769 458 A G 147 Glu Gly 13381768 527 T C 170 Ile Thr 15 NOV 19b: SNP Variant for membrane protein-like Protein CG162687-01 Variant Nucleotides Amino Acids Position Initial Modified Position Initial Modified 13381767 163 A G 0 20 NOV 21a: SNP Variants for membrane protein-like Protein CG163175-01 Variant Nucleotides Amino Acids Position Initial Modified Position Initial Modified 13381808 217 C T 29 Ala Ala 13381789 742 T C 204 Gly Gly 410 WO 03/050245 PCT/USO2/38594 13381788 760 T C 210 Ser Ser 13381787 796 G A 222 Pro Pro 13381786 803 T C 225 Phe Leu 13381785 826 T G 232 Ala Ala NOV 22a: SNP Variants for Cytokine-like factor-l-like Protein CG163259-01 Variant Nucleotides Amino Acids Position Initial Modified Position Initial Modified 13381803 281 T C 55 Ser Pro 13381812 355 C T 79 Asn Asn 13381814 777 G A 220 Cys Tyr 13381815 814 G A 232 Gln Gin 5 NOV 25a: SNP Variants for 4930418P06RIK Homolog with Rhomboid domain-like Protein CG164482-01 Variant Nucleotides Amino Acids Position Initial Modified Position Initial Modified 13381800 319 T C 73 Leu Leu 13381811 392 A G 98 Arg Gly 13381801 503 T C 135 Phe Leu 10 NOV 26a: SNP Variant for DORA protein precursor-like Protein CG164511-01. Variant Nucleotides Amino Acids Position Initial Modified Position Initial Modified 13381790 740 T C 0 15 OTHER EMBODIMENTS Although particular embodiments have been disclosed herein in detail, this has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope of the appended claims, which follow. In particular, it is 411 WO 03/050245 PCT/USO2/38594 contemplated by the inventors that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as defined by the claims. The choice of nucleic acid starting material, clone of interest, or library type is believed to be a matter of routine for a person of ordinary skill in the art with 5 knowledge of the embodiments described herein. Other aspects, advantages, and modifications considered to be within the scope of the following claims. The claims presented are representative of the inventions disclosed herein. Other, unclaimed inventions are also contemplated. Applicants reserve the right to pursue such inventions in later claims. 412

Claims (45)

1. An isolated polypeptide comprising the mature form of an amino acid sequenced selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77.

2. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between I and 77.

3. An isolated polypeptide comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77.

4. An isolated polypeptide, wherein the polypeptide comprises an amino acid sequence comprising one or more conservative substitutions in the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77.

5. The polypeptide of claim 1 wherein said polypeptide is naturally occurring.

6. A composition comprising the polypeptide of claim I and a carrier.

7. A kit comprising, in one or more containers, the composition of claim 6.

8. The use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease selected from a pathology associated with the polypeptide of claim 1, wherein the therapeutic comprises the polypeptide of claim 1.

9. A method for determining the presence or amount of the polypeptide of claim 1 in a sample, the method comprising: 413 WO 03/050245 PCT/USO2/38594 (a) providing said sample; (b) introducing said sample to an antibody that binds immunospecifically to the polypeptide; and (c) determining the presence or amount of antibody bound to said polypeptide, thereby determining the presence or amount of polypeptide in said sample.

10. A method for determining the presence of or predisposition to a disease associated with altered levels of expression of the polypeptide of claim 1 in a first mammalian subject, the method comprising: a) measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and b) comparing the expression of said polypeptide in the sample of step (a) to the expression of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, said disease, wherein an alteration in the level of expression of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to said disease.

11. A method of identifying an agent that binds to the polypeptide of claim 1, the method comprising: (a) introducing said polypeptide to said agent; and (b) determining whether said agent binds to said polypeptide.

12. The method of claim 11 wherein the agent is a cellular receptor or a downstream effector.

13. A method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of the polypeptide of claim 1, the method comprising: (a) providing a cell expressing the polypeptide of claim 1 and having a property or function ascribable to the polypeptide; (b) contacting the cell with a composition comprising a candidate substance; and 414 WO 03/050245 PCT/USO2/38594 (c) determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition in the absence of the substance, the substance is identified as a potential therapeutic agent.

14. A method for screening for a modulator of activity of or of latency or predisposition to a pathology associated with the polypeptide of claim 1, said method comprising: (a) administering a test compound to a test animal at increased risk for a pathology associated with the polypeptide of claim 1, wherein said test animal recombinantly expresses the polypeptide of claim 1; (b) measuring the activity of said polypeptide in said test animal after administering the compound of step (a); and (c) comparing the activity of said polypeptide in said test animal with the activity of said polypeptide in a control animal not administered said polypeptide, wherein a change in the activity of said polypeptide in said test animal relative to said control animal indicates the test compound is a modulator activity of or latency or predisposition to, a pathology associated with the polypeptide of claim 1.

15. The method of claim 14, wherein said test animal is a recombinant test animal that expresses a test protein transgene or expresses said transgene under the control of a promoter at an increased level relative to a wild-type test animal, and wherein said promoter is not the native gene promoter of said transgene.

16. A method for modulating the activity of the polypeptide of claim 1, the method comprising contacting a cell sample expressing the polypeptide of claim 1 with a compound that binds to said polypeptide in an amount sufficient to modulate the activity of the polypeptide.

17. A method of treating or preventing a pathology associated with the polypeptide of claim 1, the method comprising administering the polypeptide of claim 1 to 415 WO 03/050245 PCT/USO2/38594 a subject in which such treatment or prevention is desired in an amount sufficient to treat or prevent the pathology in the subject.

18. The method of claim 17, wherein the subject is a human.

19. A method of treating a pathological state in a mammal, the method comprising administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77 or a biologically active fragment thereof.

20. An isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77.

21. The nucleic acid molecule of claim 20, wherein the nucleic acid molecule is naturally occurring.

22. A nucleic acid molecule, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 77.

23. An isolated nucleic acid molecule encoding the mature form of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 77.

24. An isolated nucleic acid molecule comprising a nucleic acid selected from the group consisting of 2n-1, wherein n is an integer between 1 and 77.

25. The nucleic acid molecule of claim 20, wherein said nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group 416 WO 03/050245 PCT/USO2/38594 consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 77, or a complement of said nucleotide sequence.

26. A vector comprising the nucleic acid molecule of claim 20.

27. The vector of claim 26, further comprising a promoter operably linked to said nucleic acid molecule.

28. A cell comprising the vector of claim 26.

29. An antibody that immunospecifically binds to the polypeptide of claim 1.

30. The antibody of claim 29, wherein the antibody is a monoclonal antibody.

31. The antibody of claim 29, wherein the antibody is a humanized antibody.

32. A method for determining the presence or amount of the nucleic acid molecule of claim 20 in a sample, the method comprising: (a) providing said sample; (b) introducing said sample to a probe that binds to said nucleic acid molecule; and (c) determining the presence or amount of said probe bound to said nucleic acid molecule, thereby determining the presence or amount of the nucleic acid molecule in said sample.

33. The method of claim 32 wherein presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type.

34. The method of claim 33 wherein the cell or tissue type is cancerous.

35. A method for determining the presence of or predisposition to a disease associated with altered levels of expression of the nucleic acid molecule of claim 20 in a first mammalian subject, the method comprising: 417 WO 03/050245 PCT/USO2/38594 a) measuring the level of expression of the nucleic acid in a sample from the first mammalian subject; and b) comparing the level of expression of said nucleic acid in the sample of step (a) to the level of expression of the nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of expression of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

36. A method of producing the polypeptide of claim 1, the method comprising culturing a cell under conditions that lead to expression of the polypeptide, wherein said cell comprises a vector comprising an isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77.

37. The method of claim 36 wherein the cell is a bacterial cell.

38. The method of claim 36 wherein the cell is an insect cell.

39. The method of claim 36 wherein the cell is a yeast cell.

40. The method of claim 36 wherein the cell is a mammalian cell.

41. A method of producing the polypeptide of claim 2, the method comprising culturing a cell under conditions that lead to expression of the polypeptide, wherein said cell comprises a vector comprising an isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 77.

42. The method of claim 41 wherein the cell is a bacterial cell.

43. The method of claim 41 wherein the cell is an insect cell. 418 WO 03/050245 PCT/US02/38594

44. The method of claim 41 wherein the cell is a yeast cell.

45. The method of claim 41 wherein the cell is a mammalian cell. 419