WO1999018210A2 - Compounds and methods for immunotherapy and immunodiagnosis of prostate cancer - Google Patents

Abstract

Compounds and methods for treating and diagnosing prostate cancer are provided. The inventive compounds include polypeptides containing at least a portion of a prostate protein. Vaccines and pharmaceutical compositions for immunotherapy of prostate cancer comprising such polypeptides or DNA molecules encoding such polypeptides are also provided. The inventive polypeptides may also be used to generate antibodies useful for the diagnosis and monitoring of prostate cancer. Nucleic acid sequences for preparing probes, primers, and polypeptides are also provided.

Description

COMPOUNDS AND METHODS FOR IMMUNOTHERAPY AND IMMUNODIAGNOSIS OF PROSTATE CANCER

TECHNICAL FIELD The present invention relates generally to the treatment, diagnosis and monitoring of prostate cancer. The invention is more particularly related to polypeptides comprising at least a portion of a prostate protein. Such polypeptides may be used in vaccines and pharmaceutical compositions for treatment of prostate cancer. The polypeptides may also be used for the production of compounds, such as antibodies, useful for diagnosing and monitoring the progression of prostate cancer, and possibly other tumor types, in a patient.

BACKGROUND OF THE INVENTION

Prostate cancer is the most common form of cancer among males, with an estimated incidence of 30% in men over the age of 50. Overwhelming clinical evidence shows that human prostate cancer has the propensity to metastasize to bone, and the disease appears to progress inevitably from androgen dependent to androgen refractory status, leading to increased patient mortality. This prevalent disease is currently the second leading cause of cancer death among men in the U.S. In spite of considerable research into therapies for the disease, prostate cancer remains difficult to treat. Commonly, treatment is based on surgery and/or radiation therapy, but these methods are ineffective in a significant percentage of cases. Three prostate specific proteins - prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) - have limited diagnostic and therapeutic potential. PSA levels do not always correlate well with the presence of prostate cancer, being positive in a percentage of non-prostate cancer cases, including benign prostatic hyperplasia (BPH). Furthermore, PSA measurements correlate with prostate volume, and do not indicate the level of metastasis.

Accordingly, there remains a need in the art for improved vaccines and diagnostic methods for prostate cancer. SUMMARY OF THE INVENTION

The present invention provides compounds and methods for immunotherapy and diagnosis of prostate cancer In one aspect, polypeptides are provided comprising at least an immunogenic portion of a prostate protein having a partial sequence as provided in SEQ ID NOS 2 and 4-8, or a variant of such a protein that differs only in conservative substitutions and/or modifications, together with polypeptides comprising an immunogenic portion of a prostate protein, or a variant thereof, wherein the protein comprises an amino acid sequence encoded by a DNA sequence selected from the group consisting of sequences recited in SEQ ID NOS 11, 13-19, 58, 59 and 61-64, the complements of said sequences, and DNA sequences that hybridize to a sequence recited in SEQ ID NOS 11, 13-19, 58, 59 and 61-64, or a complement thereof under moderately stringent conditions

In related aspects, DNA molecules encoding the above polypeptides, expression vectors comprising such DNA molecules and host cells transformed or transfected with such expression vectors are also provided In preferred embodiments, the host cells are selected from the group consisting of E. coli, yeast and mammalian cells

The present invention also provides pharmaceutical compositions comprising one or more of the polypeptides of SEQ ID NOS 1-8, 20, 21, 25-31, 44-57, 60 or 61, or DNA molecules of SEQ ID NOS 9-19, 22-24, 32-43, 58, 59 or 61-64 and a physiologically acceptable carrier The invention further provides vaccines comprising one or more of such polypeptides or DNA molecules in combination with a non-specific immune response enhancer In yet another aspect, methods are provided for inhibiting the development of prostate cancer in a patient, comprising administering an effective amount of one or more of the polypeptides of SEQ ID NOS 1-8, 20, 21, 25-31, 44-57, 60 or 61, or DNA molecules of SEQ ID NOS 9-19, 22-24, 32-43, 58, 59 or 61-64 to a patient in need thereof In further aspects, methods are provided for detecting prostate cancer in a patient, comprising (a) contacting a biological sample obtained from a patient with a binding agent that is capable of binding to a polypeptide of SEQ ID NOS 1-8, 20, 21,

25-31, 44-57, 60 or 61, and (b) detecting in the sample a protein or polypeptide that binds to the binding agent

In related aspects, methods are provided for monitoring the progression of prostate cancer in a patient, comprising (a) contacting a biological sample obtained from a patient with a binding agent that is capable of binding to a polypeptide of SEQ ID NOS 1-8, 20, 21, 25-31, 44-57, 60 or 61, (b) determining in the sample an amount of a protein or polypeptide that binds to the binding agent, (c) repeating steps (a) and (b), and comparing the amounts of polypeptide detected in steps (b) and (c)

Within related aspects, the present invention provides antibodies, preferably monoclonal antibodies, that bind to the polypeptides described above, as well as diagnostic kits comprising such antibodies, and methods of using such antibodies to inhibit the development of prostate cancer

The present invention also provides methods for detecting prostate cancer comprising (a) obtaining a biological sample from a patient, (b) contacting the sample with at least two oligonucleotide primers in a polymerase chain reaction, at least one of the oligonucleotide primers being specific for a DNA sequence selected from the group consisting of SEQ ID NOS 9-19, 22-24, 32-43, 58, 59 and 61-64, and (c) detecting in the sample a DNA sequence that amplifies in the presence of the oligonucleotide primer In one embodiment, the oligonucleotide primer comprises at least about 10 contiguous nucleotides of a DNA sequence selected from the group consisting of SEQ ID NOS 9-19, 22-24, 32-43, 58, 59 and 61-64 In a further aspect, the present invention provides a method for detecting prostate cancer in a patient comprising (a) obtaining a biological sample from the patient, (b) contacting the sample with an oligonucleotide probe specific for a DNA sequence selected from the group consisting of SEQ ID NOS 9-19, 22-24, 32-43, 58, 59 and 61-64, and (c) detecting in the sample a DNA sequence that hybridizes to the oligonucleotide probe In one embodiment, the oligonucleotide probe comprises at least about 15 contiguous nucleotides of a DNA sequence selected from the group consisting of SEQ ID NOS 9-19, 22-24, 32-43, 58, 59 and 61-64

These and other aspects of the present invention will become apparent upon reference to the following detailed description and attached drawings All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually

BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1 illustrates a Western blot analysis of sera obtained from rats immunized with rate prostate extract

Fig 2 illustrates a non-reduced SDS PAGE of the rat immunizing preparation of Fig 1

Fig 3 illustrates the binding of a putative human homologue of rat steroid binding protein to progesterone and to estramustine

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention is generally directed to compositions and methods for the immunotherapy, diagnosis and monitoring of prostate cancer The inventive compositions are generally polypeptides that comprise at least a portion of a human prostate protein, the protein demonstrating immunoreactivity with human prostate sera Also included within the present invention are molecules (such as an antibody or fragment thereof) that bind to the inventive polypeptides Such molecules are referred to herein as "binding agents "

In particular, the subject invention discloses polypeptides comprising at least a portion of a human prostate protein provided in SEQ ID NOS 2 and 4-8, or a variant of such a protein that differs only in conservative substitutions and/or modifications As used herein, the term "polypeptide" encompasses amino acid chains of any length, including full length proteins, wherein the amino acid residues are linked by covalent peptide bonds Thus, a polypeptide comprising a portion of one of the above prostate proteins may consist entirely of the portion, or the portion may be present within a larger polypeptide that contains additional sequences. The additional sequences may be derived from the native protein or may be heterologous, and such sequences may be immunoreactive and/or antigenic.

As used herein, an "immunogenic portion" of a human prostate protein is a portion that reacts either with sera derived from an individual inflicted with autoimmune prostatitis or with sera derived from a rat model of autoimmune prostatitis. In other words, an immunogenic portion is capable of eliciting an immune response and as such binds to antibodies present within prostatitis sera. Autoimmune prostatitis may occur, for example, following treatment of bladder cancer by administration of Bacillus Calmette-Guerin (BCG), an avirulent strain of Mycobacterium bovis. In the rat model of autoimmune prostatitis, rats are immunized with a detergent extract of rat prostate. Sera from either of these sources may be used to react with the human prostate derived polypeptides described herein. Antibody binding assays may generally be performed using any of a variety of means known to those of ordinary skill in the art, as described, for example, in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1988. For example, a polypeptide may be immobilized on a solid support (as described below) and contacted with patient sera to allow binding of antibodies within the sera to the immobilized polypeptide. Unbound sera may then be removed and bound antibodies detected using, for example, '^I-labeled Protein A.

The compositions and methods of the present invention also encompass variants of the above polypeptides and DNA molecules. A polypeptide "variant," as used herein, is a polypeptide that differs from the recited polypeptide only in conservative substitutions and/or modifications, such that the therapeutic, antigenic and/or immunogenic properties of the polypeptide are retained. Polypeptide variants preferably exhibit at least about 70%, more preferably at least about 90% and most preferably at least about 95% identity to the identified polypeptides as determined using the computer algorithm FASTX employing default parameters. For prostate tumor polypeptides with immunoreactive properties, variants may, alternatively, be identified by modifying the amino acid sequence of one of the above polypeptides, and evaluating the immunoreactivity of the modified polypeptide. For prostate tumor polypeptides useful for the generation of diagnostic binding agents, a variant may be identified by evaluating a modified polypeptide for the ability to generate antibodies that detect the presence or absence of prostate cancer. Such modified sequences may be prepared and tested using, for example, the representative procedures described herein.

As used herein, a "conservative substitution" is one in which an amino acid is substituted for another amino acid that has similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the polypeptide to be substantially unchanged. In general, the following groups of amino acids represent conservative changes: (1) ala, pro, gly, glu, asp, gin, asn, ser, thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg, his; and (5) phe, tyr, trp, his.

Variants may also, or alternatively, contain other modifications, including the deletion or addition of amino acids that have minimal influence on the antigenic properties, secondary structure and hydropathic nature of the polypeptide. For example, a polypeptide may be conjugated to a signal (or leader) sequence at the N- terminal end of the protein which co-translationally or post-translationally directs transfer of the protein. The polypeptide may also be conjugated to a linker or other sequence for ease of synthesis, purification or identification of the polypeptide (e.g., poly-His), or to enhance binding of the polypeptide to a solid support. For example, a polypeptide may be conjugated to an immunoglobulin Fc region.

A nucleotide "variant" is a sequence that differs from the recited nucleotide sequence in having one or more nucleotide deletions, substitutions or additions. Such modifications may be readily introduced using standard mutagenesis techniques, such as oligonucleotide-directed site-specific mutagenesis as taught, for example, by Adelman et al. (DNA, 2: 183, 1983). Nucleotide variants may be naturally occurring allelic variants, or non-naturally occurring variants. Variant nucleotide sequences preferably exhibit at least about 70%, more preferably at least about 80% and most preferably at least about 90% identity to the recited sequence. Such variant nucleotide sequences will generally hybridize to the recited nucleotide sequence under stringent conditions As used herein, "stringent conditions" refers to prewashing in a solution of 6X SSC, 0 2% SDS, hybridizing at 65 °C, 6X SSC, 0 2% SDS overnight, followed by two washes of 30 minutes each in IX SSC, 0 1% SDS at 65 °C and two washes of 30 minutes each in 0.2X SSC, 0 1% SDS at 65 °C Polypeptides having one of the sequences provided in SEQ ID NOS 1 to 8, 20, 21 and 25-31 may be isolated from a suitable human prostate adenocarcinoma cell line, such as LnCap fgc ( ATCC No 1740-CRL) LnCap fgc is a prostate adenocarcinoma cell line that is a particularly good representation of human prostate cancer Like the human cancer, LnCap fgc cells form progressively growing tumors as xenografts in SCID mice, respond to testosterone, secrete PSA and respond to the presence of bone marrow components (e.g., transferrin) In particular, the polypeptides may be isolated by expression screening of a LnCap fgc cDNA library with human prostatitis sera using techniques described, for example, in Sambrook et al , Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY (and references cited therein), and as described in detail below The polypeptides of SEQ ID NOS 48 and 49 may be isolated from the LnCap/fgc cell line by screening with sera from the rat model of autoimmune prostatitis discussed above The polypeptides of SEQ ID NOS 50-56 may be isolated from the LnCap/fgc cell line by screening with human prostatitis sera as described in detail in Example 4 The polypeptides of SEQ ID NOS 44-47 may be isolated from human seminal fluid as described in detail in Example 2 The polypeptides encoded by the sequences of SEQ ID NOS 58 and 59 may be isolated by screening a prostate tumor cDNA expression library with monkey anti-prostate sera as detailed below in Example 6 Polypeptides encoded by the cDNA sequences of SEQ ID NO 61-66 may be isolated by screening a prostate tumor cell-line expression library with a prostate tumor-specific monoclonal antibody Once a DNA sequence encoding a polypeptide is obtained, any of the above modifications may be readily introduced using standard mutagenesis techniques, such as oligonucleotide-directed site-specific mutagenesis

The polypeptides disclosed herein may also be generated by synthetic or recombinant means Synthetic polypeptides having fewer than about 100 amino acids, and generally fewer than about 50 amino acids, may be generated using techniques well known to those of ordinary skill in the art For example, such polypeptides may be synthesized using any of the commercially available solid-phase techniques, such as the Merrifield solid-phase synthesis method, where amino acids are sequentially added to a growing amino acid chain See Merrifield, J. Am. Chem. Soc. 55.2149-2146, 1963 Equipment for automated synthesis of polypeptides is commercially available from suppliers such as Applied BioSystems, Inc., (Foster City, CA), and may be operated according to the manufacturer's instructions

Alternatively, any of the above polypeptides may be produced recombinantly by inserting a DNA sequence that encodes the polypeptide into an expression vector and expressing the protein in an appropriate host Any of a variety of expression vectors known to those of ordinary skill in the art may be employed to express recombinant polypeptides of this invention Expression may be achieved in any appropriate host cell that has been transformed or transfected with an expression vector containing a DNA molecule that encodes a recombinant polypeptide Suitable host cells include prokaryotes, yeast and higher eukaryotic cells Preferably, the host cells employed are E. coli, yeast or a mammalian cell line, such as CHO cells The DNA sequences expressed in this manner may encode naturally occurring polypeptides, portions of naturally occurring polypeptides, or other variants thereof In general, regardless of the method of preparation, the polypeptides disclosed herein are prepared in substantially pure form (i.e., the polypeptides are homogenous as determined by amino acid composition and primary sequence analysis) Preferably, the polypeptides are at least about 90% pure, more preferably at least about 95%> pure and most preferably at least about 99%> pure In certain preferred embodiments, described in more detail below, the substantially pure polypeptides are incorporated into pharmaceutical compositions or vaccines for use in one or more of the methods disclosed herein

In a related aspect, the present invention provides fusion proteins comprising a first and a second inventive polypeptide or, alternatively, a polypeptide of the present invention and a known prostate antigen, together with variants of such fusion proteins The fusion proteins of the present invention may also include a linker peptide between the first and second polypeptides.

A DNA sequence encoding a fusion protein of the present invention is constructed using known recombinant DNA techniques to assemble separate DNA sequences encoding the first and second polypeptides into an appropriate expression vector. The 3' end of a DNA sequence encoding the first polypeptide is ligated, with or without a peptide linker, to the 5' end of a DNA sequence encoding the second polypeptide so that the reading frames of the sequences are in phase to permit mRNA translation of the two DNA sequences into a single fusion protein that retains the biological activity of both the first and the second polypeptides.

A peptide linker sequence may be employed to separate the first and the second polypeptides by a distance sufficient to ensure that each polypeptide folds into its secondary and tertiary structures. Such a peptide linker sequence is incorporated into the fusion protein using standard techniques well known in the art. Suitable peptide linker sequences may be chosen based on the following factors: (1) their ability to adopt a flexible extended conformation; (2) their inability to adopt a secondary structure that could interact with functional epitopes on the first and second polypeptides; and (3) the lack of hydrophobic or charged residues that might react with the polypeptide functional epitopes. Preferred peptide linker sequences contain Gly, Asn and Ser residues. Other near neutral amino acids, such as Thr and Ala may also be used in the linker sequence. Amino acid sequences which may be usefully employed as linkers include those disclosed in Maratea et al., Gene 40:39-46, 1985; Murphy et al., Proc. Natl. Acad. Sci. USA 83: 8258-8262, 1986; U.S. Patent No. 4,935,233 and U.S. Patent No. 4,751,180. The linker sequence may be from 1 to about 50 amino acids in length. Peptide sequences are not required when the first and second polypeptides have non-essential N-terminal amino acid regions that can be used to separate the functional domains and prevent steric interference.

The ligated DNA sequences are operably linked to suitable transcriptional or translational regulatory elements. The regulatory elements responsible for expression of DNA are located only 5' to the DNA sequence encoding the first polypeptides Similarly, stop codons require to end translation and transcription termination signals are only present 3' to the DNA sequence encoding the second polypeptide

Polypeptides of the present invention that comprise an immunogenic portion of a prostate protein may generally be used for immunotherapy of prostate cancer, wherein the polypeptide stimulates the patient's own immune response to prostate tumor cells In further aspects, the present invention provides methods for using one or more of the immunoreactive polypeptides disclosed herein (or DNA encoding such polypeptides) for immunotherapy of prostate cancer in a patient As used herein, a "patient" refers to any warm-blooded animal, preferably a human A patient may be afflicted with a disease, or may be free of detectable disease Accordingly, the above immunoreactive polypeptides may be used to treat prostate cancer or to inhibit the development of prostate cancer The polypeptides may be administered either prior to or following surgical removal of primary tumors and/or treatment by administration of radiotherapy and conventional chemotherapeutic drugs

In these aspects, the polypeptide is generally present within a pharmaceutical composition and/or a vaccine Pharmaceutical compositions may comprise one or more polypeptides, each of which may contain one or more of the above sequences (or variants thereof), and a physiologically acceptable carrier The vaccines may comprise one or more of such polypeptides and a non-specific immune response enhancer, such as an adjuvant, biodegradable microsphere (e.g., polylactic galactide) or a liposome (into which the polypeptide is incorporated). Pharmaceutical compositions and vaccines may also contain other epitopes of prostate cell antigens, either incorporated into a combination polypeptide (i.e., a single polypeptide that contains multiple epitopes) or present within a separate polypeptide

Alternatively, a pharmaceutical composition or vaccine may contain DNA encoding one or more of the above polypeptides, such that the polypeptide is generated in situ In such pharmaceutical compositions and vaccines, the DNA may be present within any of a variety of delivery systems known to those of ordinary skill in the art, including nucleic acid expression systems, bacteria and viral expression systems Appropriate nucleic acid expression systems contain the necessary DNA sequences for expression in the patient (such as a suitable promoter) Bacterial delivery systems involve the administration of a bacterium (such as Bacillus-Calmette-Guerriή) that expresses an epitope of a prostate cell antigen on its cell surface In a preferred embodiment, the DNA may be introduced using a viral expression system (e.g., vaccinia or other pox virus, retrovirus, or adenovirus), which may involve the use of a non-pathogenic (defective), replication competent virus Suitable systems are disclosed, for example, in Fisher-Hoch et al , PNAS 86 317-321, 1989, Flexner et al , Arm. N Y. Acad. Sci. 569 86-103, 1989, Flexner et al , Vaccine 5.17-21, 1990, U.S Patent Nos NOS 4,603,112, 4,769,330, and 5,017,487, WO 89/01973, U S Patent No 4,777,127, GB 2,200,651, EP 0,345,242, WO 91/02805, Berkner, Biotechniques 6.616-621, 1988, Rosenfeld et al , Science 252 431-434, 1991, Kolls et al , PNAS 97 215-219, 1994, Kass-Eisler et al , PNAS 90 11498-1 1502, 1993, Guzman et al , Circulation 55 2838-2848, 1993, and Guzman et al , r. Res. 73 1202-1207, 1993 Techniques for incorporating DNA into such expression systems are well known to those of ordinary skill in the art The DNA may also be "naked," as described, for example, in published PCT application WO 90/11092, and Ulmer et al , Science 259 1745-1749, 1993, reviewed by Cohen, Science 259.1691-1692, 1993 The uptake of naked DNA may be increased by coating the DNA onto biodegradable beads, which are efficiently transported into the cells

Routes and frequency of administration, as well as dosage, will vary from individual to individual and may parallel those currently being used in immunotherapy of other diseases In general, the pharmaceutical compositions and vaccines may be administered by injection (e.g., intracutaneous, intramuscular, intravenous or subcutaneous), intranasally (e.g., by aspiration) or orally Between 1 and 10 doses may be administered over a 3-24 week period Preferably, 4 doses are administered, at an interval of 3 months, and booster administrations may be given periodically thereafter Alternate protocols may be appropriate for individual patients A suitable dose is an amount of polypeptide or DNA that is effective to raise an immune response (cellular and/or humoral) against prostate tumor cells in a treated patient. A suitable immune response is at least 10-50% above the basal (i.e., untreated) level. In general, the amount of polypeptide present in a dose (or produced in situ by the DNA in a dose) ranges from about 1 pg to about 100 mg per kg of host, typically from about 10 pg to about 1 mg, and preferably from about 100 pg to about 1 μg. Suitable dose sizes will vary with the size of the patient, but will typically range from about 0.01 mL to about 5 mL.

While any suitable carrier known to those of ordinary skill in the art may be employed in the pharmaceutical compositions of this invention, the type of carrier will vary depending on the mode of administration. For parenteral administration, such as subcutaneous injection, the carrier preferably comprises water, saline, alcohol, a fat, a wax and/or a buffer. For oral administration, any of the above carriers or a solid carrier, such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, and/or magnesium carbonate, may be employed. Biodegradable microspheres (e.g., polylactic glycolide) may also be employed as carriers for the pharmaceutical compositions of this invention. Suitable biodegradable microspheres are disclosed, for example, in U.S. Patent Nos. 4,897,268 and 5,075, 109.

Any of a variety of non-specific immune response enhancers may be employed in the vaccines of this invention. For example, an adjuvant may be included. Most adjuvants contain a substance designed to protect the antigen from rapid catabolism, such as aluminum hydroxide or mineral oil, and a nonspecific stimulator of immune response, such as lipid A, Bordella pertussis or Mycobacterium tuberculosis. Such adjuvants are commercially available as, for example, Freund's Incomplete Adjuvant and Complete Adjuvant (Difco Laboratories, Detroit, MI) and Merck Adjuvant 65 (Merck and Company, Inc., Rahway, NJ). Polypeptides disclosed herein may also be employed in ex vivo treatment of prostate cancer. For example, cells of the immune system, such as T cells, may be isolated from the peripheral blood of a patient, using a commercially available cell separation system, such as CellPro Incorporated's (Bothell, WA) CEPRATE™ system (see U.S. Patent No. 5,240,856; U.S. Patent No. 5,215,926; WO 89/06280; WO 91/16116 and WO 92/07243). The separated cells are stimulated with one or more of the immunoreactive polypeptides contained within a delivery vehicle, such as a microsphere, to provide antigen-specific T cells. The population of tumor antigen- specific T cells is then expanded using standard techniques and the cells are administered back to the patient. Polypeptides of the present invention may also, or alternatively, be used to generate binding agents, such as antibodies or fragments thereof, that are capable of detecting metastatic human prostate tumors.

Binding agents of the present invention may generally be prepared using methods known to those of ordinary skill in the art, including the representative procedures described herein. Binding agents are capable of differentiating between patients with and without prostate cancer, using the representative assays described herein. In other words, antibodies or other binding agents raised against a prostate protein, or a suitable portion thereof, will generate a signal indicating the presence of primary or metastatic prostate cancer in at least about 20% of patients afflicted with the disease, and will generate a signal indicating the absence of the disease in at least about 90%) of individuals without primary or metastatic prostate cancer. Suitable portions of such prostate proteins are portions that are able to generate a binding agent that indicates the presence of primary or metastatic prostate cancer in substantially all (i.e., at least about 80%>, and preferably at least about 90%) of the patients for which prostate cancer would be indicated using the full length protein, and that indicate the absence of prostate cancer in substantially all of those samples that would be negative when tested with full length protein. The representative assays described below, such as the two- antibody sandwich assay, may generally be employed for evaluating the ability of a binding agent to detect metastatic human prostate tumors. The ability of a polypeptide prepared as described herein to generate antibodies capable of detecting primary or metastatic human prostate tumors may generally be evaluated by raising one or more antibodies against the polypeptide (using, for example, a representative method described herein) and determining the ability of such antibodies to detect such tumors in patients. This determination may be made by assaying biological samples from patients with and without primary or metastatic prostate cancer for the presence of a polypeptide that binds to the generated antibodies Such test assays may be performed, for example, using a representative procedure described below Polypeptides that generate antibodies capable of detecting at least 20% of primary or metastatic prostate tumors by such procedures are considered to be able to generate antibodies capable of detecting primary or metastatic human prostate tumors Polypeptide specific antibodies may be used alone or in combination to improve sensitivity

Polypeptides capable of detecting primary or metastatic human prostate tumors may be used as markers for diagnosing prostate cancer or for monitoring disease progression in patients In one embodiment, prostate cancer in a patient may be diagnosed by evaluating a biological sample obtained from the patient for the level of one or more of the above polypeptides, relative to a predetermined cut-off value As used herein, suitable "biological samples" include blood, sera, urine and/or prostate secretions The level of one or more of the above polypeptides may be evaluated using any binding agent specific for the polypeptide(s) A "binding agent," in the context of this invention, is any agent (such as a compound or a cell) that binds to a polypeptide as described above As used herein, "binding" refers to a noncovalent association between two separate molecules (each of which may be free (i.e., in solution) or present on the surface of a cell or a solid support), such that a "complex" is formed Such a complex may be free or immobilized (either covalently or noncovalently) on a support material The ability to bind may generally be evaluated by determining a binding constant for the formation of the complex The binding constant is the value obtained when the concentration of the complex is divided by the product of the component concentrations In general, two compounds are said to "bind" in the context of the present invention when the binding constant for complex formation exceeds about 10³ L/mol The binding constant may be determined using methods well known to those of ordinary skill in the art

Any agent that satisfies the above requirements may be a binding agent For example, a binding agent may be a ribosome with or without a peptide component, an RNA molecule or a peptide In a preferred embodiment, the binding partner is an antibody, or a fragment thereof Such antibodies may be polyclonal, or monoclonal In addition, the antibodies may be single chain, chimeric, CDR-grafted or humanized Antibodies may be prepared by the methods described herein and by other methods well known to those of skill in the art

There are a variety of assay formats known to those of ordinary skill in the art for using a binding partner to detect polypeptide markers in a sample See, e g , Harlow and Lane, Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory, 1988 In a preferred embodiment, the assay involves the use of binding partner immobilized on a solid support to bind to and remove the polypeptide from the remainder of the sample The bound polypeptide may then be detected using a second binding partner that contains a reporter group Suitable second binding partners include antibodies that bind to the binding partner/polypeptide complex Alternatively, a competitive assay may be utilized, in which a polypeptide is labeled with a reporter group and allowed to bind to the immobilized binding partner after incubation of the binding partner with the sample The extent to which components of the sample inhibit the binding of the labeled polypeptide to the binding partner is indicative of the reactivity of the sample with the immobilized binding partner

The solid support may be any material known to those of ordinary skill in the art to which the antigen may be attached For example, the solid support may be a test well in a microtiter plate or a nitrocellulose or other suitable membrane Alternatively, the support may be a bead or disc, such as glass, fiberglass, latex or a plastic material such as polystyrene or polyvmylchloπde The support may also be a magnetic particle or a fiber optic sensor, such as those disclosed, for example, in U S Patent No 5,359,681 The binding agent may be immobilized on the solid support using a variety of techniques known to those of skill in the art, which are amply described in the patent and scientific literature In the context of the present invention, the term "immobilization" refers to both noncovalent association, such as adsorption, and covalent attachment (which may be a direct linkage between the antigen and functional groups on the support or may be a linkage by way of a cross-linking agent) Immobilization by adsorption to a well in a microtiter plate or to a membrane is preferred. In such cases, adsorption may be achieved by contacting the binding agent, in a suitable buffer, with the solid support for a suitable amount of time. The contact time varies with temperature, but is typically between about 1 hour and about 1 day. In general, contacting a well of a plastic microtiter plate (such as polystyrene or polyvinylchloride) with an amount of binding agent ranging from about 10 ng to about 10 μg, and preferably about 100 ng to about 1 μg, is sufficient to immobilize an adequate amount of binding agent.

Covalent attachment of binding agent to a solid support may generally be achieved by first reacting the support with a bifunctional reagent that will react with both the support and a functional group, such as a hydroxyl or amino group, on the binding agent. For example, the binding agent may be covalently attached to supports having an appropriate polymer coating using benzoquinone or by condensation of an aldehyde group on the support with an amine and an active hydrogen on the binding partner (see, e.g., Pierce Immunotechnology Catalog and Handbook, 1991, at A12-A13).

In certain embodiments, the assay is a two-antibody sandwich assay. This assay may be performed by first contacting an antibody that has been immobilized on a solid support, commonly the well of a microtiter plate, with the sample, such that polypeptides within the sample are allowed to bind to the immobilized antibody. Unbound sample is then removed from the immobilized polypeptide-antibody complexes and a second antibody (containing a reporter group) capable of binding to a different site on the polypeptide is added. The amount of second antibody that remains bound to the solid support is then determined using a method appropriate for the specific reporter group.

More specifically, once the antibody is immobilized on the support as described above, the remaining protein binding sites on the support are typically blocked. Any suitable blocking agent known to those of ordinary skill in the art, such as bovine serum albumin or Tween 20™ (Sigma Chemical Co., St. Louis, MO). The immobilized antibody is then incubated with the sample, and polypeptide is allowed to bind to the antibody The sample may be diluted with a suitable diluent, such as phosphate-buffered saline (PBS) prior to incubation In general, an appropπate contact time (/ e , incubation time) is that period of time that is sufficient to detect the presence of polypeptide within a sample obtained from an individual with prostate cancer Preferably, the contact time is sufficient to achieve a level of binding that is at least about 95%> of that achieved at equilibrium between bound and unbound polypeptide Those of ordinary skill in the art will recognize that the time necessary to achieve equilibrium may be readily determined by assaying the level of binding that occurs over a period of time At room temperature, an incubation time of about 30 minutes is generally sufficient

Unbound sample may then be removed by washing the solid support with an appropriate buffer, such as PBS containing 0 1% Tween 20™ The second antibody, which contains a reporter group, may then be added to the solid support Preferred reporter groups include enzymes (such as horseradish peroxidase), substrates, cofactors, inhibitors, dyes, radionuchdes, luminescent groups, fluorescent groups and biotin The conjugation of antibody to reporter group may be achieved using standard methods known to those of ordinary skill in the art

The second antibody is then incubated with the immobilized antibody- polypeptide complex for an amount of time sufficient to detect the bound polypeptide An appropriate amount of time may generally be determined by assaying the level of binding that occurs over a period of time Unbound second antibody is then removed and bound second antibody is detected using the reporter group The method employed for detecting the reporter group depends upon the nature of the reporter group For radioactive groups, scintillation counting or autoradiographic methods are generally appropriate Spectroscopic methods may be used to detect dyes, luminescent groups and fluorescent groups Biotin may be detected using avidin, coupled to a different reporter group (commonly a radioactive or fluorescent group or an enzyme) Enzyme reporter groups may generally be detected by the addition of substrate (generally for a specific period of time), followed by spectroscopic or other analysis of the reaction products To determine the presence or absence of prostate cancer, the signal detected from the reporter group that remains bound to the solid support is generally compared to a signal that corresponds to a predetermined cut-off value. In one preferred embodiment, the cut-off value is the average mean signal obtained when the immobilized antibody is incubated with samples from patients without prostate cancer. In general, a sample generating a signal that is three standard deviations above the predetermined cut-off value is considered positive for prostate cancer. In an alternate preferred embodiment, the cut-off value is determined using a Receiver Operator Curve, according to the method of Sackett et al., Clinical Epidemiology: A Basic Science for Clinical Medicine, Little Brown and Co., 1985, p. 106-7. Briefly, in this embodiment, the cut-off value may be determined from a plot of pairs of true positive rates (i.e., sensitivity) and false positive rates (100%-specifιcity) that correspond to each possible cut-off value for the diagnostic test result. The cut-off value on the plot that is the closest to the upper left-hand corner (i.e., the value that encloses the largest area) is the most accurate cut-off value, and a sample generating a signal that is higher than the cut-off value determined by this method may be considered positive. Alternatively, the cut-off value may be shifted to the left along the plot, to minimize the false positive rate, or to the right, to minimize the false negative rate. In general, a sample generating a signal that is higher than the cut-off value determined by this method is considered positive for prostate cancer.

In a related embodiment, the assay is performed in a flow-through or strip test format, wherein the antibody is immobilized on a membrane, such as nitrocellulose. In the flow-through test, polypeptides within the sample bind to the immobilized antibody as the sample passes through the membrane. A second, labeled antibody then binds to the antibody-polypeptide complex as a solution containing the second antibody flows through the membrane. The detection of bound second antibody may then be performed as described above. In the strip test format, one end of the membrane to which antibody is bound is immersed in a solution containing the sample. The sample migrates along the membrane through a region containing second antibody and to the area of immobilized antibody. Concentration of second antibody at the area of immobilized antibody indicates the presence of prostate cancer Typically, the concentration of second antibody at that site generates a pattern, such as a line, that can be read visually The absence of such a pattern indicates a negative result In general, the amount of antibody immobilized on the membrane is selected to generate a visually discernible pattern when the biological sample contains a level of polypeptide that would be sufficient to generate a positive signal in the two-antibody sandwich assay, in the format discussed above Preferably, the amount of antibody immobilized on the membrane ranges from about 25 ng to about lμg, and more preferably from about 50 ng to about 500 ng Such tests can typically be performed with a very small amount of biological sample

Of course, numerous other assay protocols exist that are suitable for use with the antigens or antibodies of the present invention The above descriptions are intended to be exemplary only

In another embodiment, the above polypeptides may be used as markers for the progression of prostate cancer In this embodiment, assays as described above for the diagnosis of prostate cancer may be performed over time, and the change in the level of reactive polypeptide(s) evaluated For example, the assays may be performed every 24-72 hours for a period of 6 months to 1 year, and thereafter performed as needed In general, prostate cancer is progressing in those patients in whom the level of polypeptide detected by the binding agent increases over time In contrast, prostate cancer is not progressing when the level of reactive polypeptide either remains constant or decreases with time

Antibodies for use in the above methods may be prepared by any of a variety of techniques known to those of ordinary skill in the art See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988 In one such technique, an immunogen comprising the antigenic polypeptide is initially injected into any of a wide variety of mammals (e.g., mice, rats, rabbits, sheep and goats) In this step, the polypeptides of this invention may serve as the immunogen without modification Alternatively, particularly for relatively short polypeptides, a superior immune response may be elicited if the polypeptide is joined to a carrier protein, such as bovine serum albumin or keyhole limpet hemocyanin. The immunogen is injected into the animal host, preferably according to a predetermined schedule incorporating one or more booster immunizations, and the animals are bled periodically. Polyclonal antibodies specific for the polypeptide may then be purified from such antisera by, for example, affinity chromatography using the polypeptide coupled to a suitable solid support.

Monoclonal antibodies specific for the antigenic polypeptide of interest may be prepared, for example, using the technique of Kohler and Milstein, Ewr. J. Immunol. (5:51 1-519, 1976, and improvements thereto. Briefly, these methods involve the preparation of immortal cell lines capable of producing antibodies having the desired specificity (i.e., reactivity with the polypeptide of interest). Such cell lines may be produced, for example, from spleen cells obtained from an animal immunized as described above. The spleen cells are then immortalized by, for example, fusion with a myeloma cell fusion partner, preferably one that is syngeneic with the immunized animal. A variety of fusion techniques may be employed. For example, the spleen cells and myeloma cells may be combined with a nonionic detergent for a few minutes and then plated at low density on a selective medium that supports the growth of hybrid cells, but not myeloma cells. A preferred selection technique uses HAT (hypoxanthine, aminopterin, thymidine) selection. After a sufficient time, usually about 1 to 2 weeks, colonies of hybrids are observed. Single colonies are selected and tested for binding activity against the polypeptide. Hybridomas having high reactivity and specificity are preferred.

Monoclonal antibodies may be isolated from the supematants of growing hybridoma colonies. In addition, various techniques may be employed to enhance the yield, such as injection of the hybridoma cell line into the peritoneal cavity of a suitable vertebrate host, such as a mouse. Monoclonal antibodies may then be harvested from the ascites fluid or the blood. Contaminants may be removed from the antibodies by conventional techniques, such as chromatography, gel filtration, precipitation, and extraction. The polypeptides of this invention may be used in the purification process in, for example, an affinity chromatography step. Monoclonal antibodies of the present invention may also be used as therapeutic reagents, to diminish or eliminate prostate tumors. The antibodies may be used on their own (for instance, to inhibit metastases) or coupled to one or more therapeutic agents. Suitable agents in this regard include radionuchdes, differentiation inducers, drugs, toxins, and derivatives thereof. Preferred radionuchdes include ⁹⁰Y, i23_L 125^ i3i ιs_δRe is^ 211^ _and 2i2_{βi Preferred drugs} include methotrexate, and pyrimidine and purine analogs. Preferred differentiation inducers include phorbol esters and butyric acid. Preferred toxins include ricin, abrin, diptheria toxin, cholera toxin, gelonin, Pseudomonas exotoxin, Shigella toxin, and pokeweed antiviral protein. A therapeutic agent may be coupled (e.g., covalently bonded) to a suitable monoclonal antibody either directly or indirectly (e.g., via a linker group). A direct reaction between an agent and an antibody is possible when each possesses a substituent capable of reacting with the other. For example, a nucleophilic group, such as an amino or sulfhydryl group, on one may be capable of reacting with a carbonyl- containing group, such as an anhydride or an acid halide, or with an alkyl group containing a good leaving group (e.g., a halide) on the other.

Alternatively, it may be desirable to couple a therapeutic agent and an antibody via a linker group. A linker group can function as a spacer to distance an antibody from an agent in order to avoid interference with binding capabilities. A linker group can also serve to increase the chemical reactivity of a substituent on an agent or an antibody, and thus increase the coupling efficiency. An increase in chemical reactivity may also facilitate the use of agents, or functional groups on agents, which otherwise would not be possible.

It will be evident to those skilled in the art that a variety of bifunctional or polyfunctional reagents, both homo- and hetero-functional (such as those described in the catalog of the Pierce Chemical Co., Rockford, IL), may be employed as the linker group. Coupling may be effected, for example, through amino groups, carboxyl groups, sulfhydryl groups or oxidized carbohydrate residues. There are numerous references describing such methodology, e.g., U.S. Patent No. 4,671,958, to Rodwell et al. Where a therapeutic agent is more potent when free from the antibody portion of the immuno conjugates of the present invention, it may be desirable to use a linker group which is cleavable during or upon internalization into a cell A number of different cleavable linker groups have been described The mechanisms for the intracellular release of an agent from these linker groups include cleavage by reduction of a disulfide bond (e.g., U S Patent No 4,489,710, to Spitler), by irradiation of a photolabile bond (e.g., U S Patent No 4,625,014, to Senter et al ), by hydrolysis of derivatized amino acid side chains (e.g., U.S Patent No 4,638,045, to Kohn et al ), by serum complement-mediated hydrolysis (e.g., U S Patent No 4,671,958, to Rodwell et al ), and acid-catalyzed hydrolysis (e.g., U S Patent No 4,569,789, to Blattler et al ) It may be desirable to couple more than one agent to an antibody In one embodiment, multiple molecules of an agent are coupled to one antibody molecule In another embodiment, more than one type of agent may be coupled to one antibody Regardless of the particular embodiment, immunoconjugates with more than one agent may be prepared in a variety of ways For example, more than one agent may be coupled directly to an antibody molecule, or linkers which provide multiple sites for attachment can be used Alternatively, a carrier can be used

A carrier may bear the agents in a variety of ways, including covalent bonding either directly or via a linker group Suitable carriers include proteins such as albumins (e.g., U S Patent No 4,507,234, to Kato et al ), peptides and polysaccharides such as aminodextran (e.g., U S Patent No 4,699,784, to Shih et al ) A carrier may also bear an agent by noncovalent bonding or by encapsulation, such as within a liposome vesicle (e.g., U.S Patent Nos 4,429,008 and 4,873,088) Carriers specific for radionuclide agents include radiohalogenated small molecules and chelating compounds For example, U S Patent No 4,735,792 discloses representative radiohalogenated small molecules and their synthesis A radionuclide chelate may be formed from chelating compounds that include those containing nitrogen and sulfur atoms as the donor atoms for binding the metal, or metal oxide, radionuclide For example, U.S Patent No 4,673,562, to Davison et al discloses representative chelating compounds and their synthesis A variety of routes of administration for the antibodies and immunoconjugates may be used. Typically, administration will be intravenous, intramuscular, subcutaneous or in the bed of a resected tumor. It will be evident that the precise does of the antibody/immunoconjugate will vary depending upon the antibody used, the antigen density on the tumor, and the rate of clearance of the antibody.

Diagnostic reagents of the present invention may also comprise DNA sequences encoding one or more of the above polypeptides, or one or more portions thereof. For example, at least two oligonucleotide primers may be employed in a polymerase chain reaction (PCR) based assay to amplify prostate tumor-specific cDNA derived from a biological sample, wherein at least one of the oligonucleotide primers is specific for a DNA molecule encoding a polypeptide of the present invention. The presence of the amplified cDNA is then detected using techniques well known in the art, such as gel electrophoresis. Similarly, oligonucleotide probes specific for a DNA molecule encoding a polypeptide of the present invention may be used in a hybridization assay to detect the presence of an inventive polypeptide in a biological sample.

As used herein, the term "oligonucleotide primer/probe specific for a DNA molecule" means an oligonucleotide sequence that has at least about 80% identity, preferably at least about 90%> and more preferably at least about 95%, identity to the DNA molecule in question. Oligonucleotide primers and/or probes which may be usefully employed in the inventive diagnostic methods preferably have at least about 10-40 nucleotides. In a preferred embodiment, the oligonucleotide primers comprise at least about 10 contiguous nucleotides of a DNA molecule encoding one of the polypeptides disclosed herein. Preferably, oligonucleotide probes for use in the inventive diagnostic methods comprise at least about 15 contiguous oligonucleotides of a DNA molecule encoding one of the polypeptides disclosed herein. Techniques for both PCR based assays and hybridization assays are well known in the art (see, for example, Mullis et al. Ibid; Ehrlich, Ibid). Primers or probes may thus be used to detect prostate and/or prostate tumor sequences in biological samples, preferably blood, semen or prostate and/or prostate tumor tissue.

The following Examples are offered by way of illustration and not by way of limitation.

EXAMPLES

Example 1 A. Isolation of Polypeptides from LnCap. fgc using human prostatitis sera

Representative polypeptides of the present invention were isolated by screening a human prostate cancer cell line with human prostatitis sera as follows. A human prostate adenocarcinoma cDNA expression library was constructed by reverse transcriptase synthesis from mRNA purified from the human prostate adenocarcinoma cell line LnCap. fgc (ATCC No. 1740-CRL), followed by insertion of the resulting cDNA clones in Lambda ZAP II (Stratagene, La Jolla, CA).

Human prostatitis serum was obtained from a patient diagnosed with autoimmune prostatitis following treatment of bladder carcinoma by administration of BCG. This serum was used to screen the LnCap cDNA library as described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, 1989. Specifically, LB plates were overlaid with approximately 10⁴ pfu of the LnCap cDNA library and incubated at 42°C for 4 hours prior to obtaining a first plaque lift on isopropylthio-beta-galactoside (IPTG) impregnated nitrocellulose filters. The plates were then incubated for an additional 5 hours at 42°C and a second plaque lift was prepared by incubation overnight at 37°C. The filters were washed three times with PBS-T, blocked for 1 hours with PBS (containing \% Tween 20™) and again washed three times with PBS-T, prior to incubation with human prostatitis sera at a dilution of 1 :200 with agitation overnight. The filters were then washed three times with PBS-T and incubated with ¹²³I-labeled Protein A (1 μl/15 ml PBS-T) for 1 hour with agitation Filters were exposed to film for variable times, ranging from 16 hours to 7 days Plaques giving signals on duplicate lifts were re-plated on LB plates Resulting plaques were lifted with duplicate filters and these filters were treated as above The filters were incubated with human prostatitis sera (1 200 dilution) at 4°C with agitation overnight Positive plaques were visualized with ¹²T-Protein A as described above with the filters being exposed to film for variable times, ranging from 16 hours to 11 days In vivo excision of positive human prostatitis antigen cDNA clones was performed according to the manufacturer's protocol

B Characterization of Polypeptides DNA sequence for positive clones was obtained using forward and reverse primers on an Perkin Elmer/Applied Biosystems Division Automated Sequencer Model 373A (Foster City, CA) The cDNA sequences encoding the isolated polypeptides, hereinafter referred to as HPA8, HPA13, HPA15 - HPA17, HPA20, HPA25, HPA28, HPA29, HPA32 - HP A38 and HPA41 are presented in SEQ ID NOS 32 and 33, 34 and 35, 36, 9 and 10, 11, 12, 13 and 14, 15, 37 and 38, 16, 39, 22 and 23, 17 and 18, 19, 24, 40 and 41, 42 and 43, respectively The 3' sequences of HPA16 and HPA20 are identical HPA13, HPA16, HPA20, HPA29 and HPA33 are believed to be overlapping clones with novel 5' end points Two of the positive clones were determined to be identical to HPA15 Also, HPA15, HPA34 and HPA37 were found to be overlapping clones The expected N-terminal amino acid sequences of the isolated polypeptides HPA16, HPA17, HPA20, HPA25, HPA28, HPA32, HPA35, HPA36, HPA34, HPA37, HPA8, HPA13, HPA15, HPA29, HPA33, HPA38 and HPA41, based on the determined cDNA sequences in frame with the N-terminal portion of β- galactosidase (lacZ) are presented in SEQ ID NOS 1-8, 20, 21 and 25-31, respectively

The determined cDNA and expected amino acid sequences for the isolated polypeptides were compared to known sequences in the gene bank using the

EMBL and GenBank (Release 91) databases, and also the DNA STAR system The DNA STAR system is a combination of the Swiss, PIR databases along with translated protein sequences (Release 91) No significant homologies to HPA17, HPA25, HPA28, HPA32, HPA35 and HPA36 were found

The determined cDNA sequence for HPA8 was found to have approximately 100% identity with the human proto-oncogene BMI-1 (Alkema, M J et al , Hum. Mol. Gen. 2 1597-1603, 1993) Search of the DNA database with 5' and 3' cDNA sequence encoding HPA13 revealed 100% identity with a known cDNA sequence from a human immature myeloid cell line (GenBank Ace No D63880) Search of the protein database with the deduced amino acid sequence for HPA13 revealed 100% identity with the open reading frame encoded by the same human cDNA sequence Search of the protein database with the expected amino acid sequence for HPA15, revealed high homology (60% identity) with a Saccharomyces cerevisiae predicted open reading frame (Swiss/PIR Ace No S46677), and 100% identity with a human protein from pituitary gland modulating intestinal fluid secretion (Lonnroth, I , J. Biol. Chem. 35 20615-20620, 1995) The deduced amino acid sequence for HPA38 was found to have 100% identity with human heat shock factor protein 2 (Schuetz, T j et al , Proc. Natl. Acad. Sci. USA 88 691 1-6915, 1991) Search of the DNA database with the 5' DNA sequence for HPA41 and search of the protein database with the deduced amino acid sequence revealed 100% identity with a human LIM protein (Rearden, A , Biochem. Biophys. Res. Commun. 201 1124-1131, 1994) To the best of the inventors' knowledge, except for LIM protein, none of the inventive polypeptides have been previously shown to be present in human prostate

Positive phagemid viral particles were used to infect E. coli XL-1 Blue MRF', as described in Sambrook et al , supra Induction of recombinant protein was accomplished by the addition of IPTG Induced and uninduced lysates were run in duplicate on SDS-PAGΕ and transferred to nitrocellulose filters Filters were reacted with human prostatitis sera (1 200 dilution) and a rabbit sera (1 200 or 1.250 dilution) reactive with the N-terminal 4 Kd portion of lacZ Sera incubations were performed for 2 hours at room temperature Bound antibody was detected by addition of ¹²⁵I- labeled Protein A and subsequent exposure to film for variable times ranging from 16 hours to 1 1 days The results of the immunoblots are summarized in Table I, wherein (+) indicates a positive reaction and (-) indicates no reaction

TABLE I

Human Prostatitis Anti-lacZ Protein

Antigen Sera Sera Mass/Kd

HPA8 (-) (-)

HPA13 (+) (+)

HPA15 (+) (+) 50

HPA16 (+) (+) 40

HPA17 (+) (-) 40

HPA20 (+) (+) 38

HPA25 (-) (+) 32

HPA28 (-) (-)

HPA29 (+) (+)

HPA32 (-) (-)

HPA33 (+) (+)

HPA34 not tested (+) 50

HP A35 (-) (-)

HP A36 (-) (-)

HPA37 not tested (+) 50

HP A38 (-) (-)

HPA41 not tested (+)

Positive reaction of the recombinant human prostatitis antigens with both the human prostatitis sera and anti-lacZ sera indicate that reactivity of the human prostatitis sera is directed towards the fusion protein Cloned antigens showing reactivity to the human prostatitis sera but not to anti-lacZ sera indicate that the reactive protein is likely initiating within the clone Antigens reactive with the anti-lacZ sera but not with the human prostatitis sera may be the result of the human prostatitis sera recognizing conformational epitopes, or the antigen-antibody binding kinetics may be such that the 2 hour sera exposure in the immunoblot is not sufficient Antigens not reactive with either sera are not being expressed in E coh, and reactive epitopes may be within the fusion protein or within an internal open reading frame Due to the instability of recombinant antigens from HPA13, HPA29 and HP A33, it was not possible to determine the size of the recombinant antigens

The expression of representative human prostatitis antigens was investigated by RT-PCR in four different human cell lines (including two metastatic prostate tumor lines LNCaP and DU145), normal prostate, breast, colon, kidney, stomach, lung and skeletal muscle tissue, nine different prostate tumor samples and three different breast tumor samples The results of these studies are shown in Table II

Table II Analysis of HPA clone mRNA expression by RT-PCR in human cell lines, normal tissues and tumors

Clone LNCaP DU145 MCF-12A HBL-100 Prostate Breast Colon Kidney Stomach Lung Skel . Muscle hpa-17 + ++ + + + + - - + +

£ hpa-20 +++ ++++ NT NT ± NT NT - NT + NT hpa-28 + +++ + + + + + + +

O I rπ Prostate Tumors (n=9) Breast Tumors (n=3)

Clone T Tuummoorr 11 T Tuummoorr 22 Tumor 3 Tumor 4 Tumor 5 Tumor 6 Tumor 7 Tumor 8 Tumor 9 Tumor 1 Tumor 2 Tumor 3 m hpa-17 + + + - + + + - +4- hpa-20 + + NT NT NT NT NT NT NT + hpa-28 + + + - + + ++ + ++

mRNA expression of representative antigens in LNCaP and normal prostate, kidney, liver, stomach, lung and pancreas was also investigated by RNase protection. The results of these studies are provided in Table III.

Table III Analysis of HPA clone mRNA expression by RNase protection in LNCaP and normal human tissues

Clone LNCaP Prostate Kidney Liver Stomach Lung Pancreas hpa-15 + - ++ -H- + ++ hρa-20 +++++ + + + + NT NT hpa-25 + + + + ++ ++ NT hpa-32 NT ++ + + NT ++ NT hpa-35 +++ +++ NT + + +++ + hpa-36 + + NT NT + + +

Example 2 A. Isolation and Characterization of Rat Steroid Binding Protein

Immune sera was obtained from rats immunized with rat prostate extract to generate antibodies to self prostate antigens. Specifically, rats were prebled to obtain control sera prior to being immunized with a detergent extract of rat prostate (in PBS containing 0.1 % Triton) in Freunds complete adjuvant. A boost of incomplete Freunds adjuvant was given 3 weeks after the initial immunization and sera was harvested at 6 weeks.

The sera thus obtained was subjected to ECL Western blot analysis (Amersham International, Arlington Heights, 111) using the manufacturer's protocol and a rat prostate protein was identified, as shown in Fig. 1. After reduction, SDS-PAGE revealed a broad silver staining band migrating at 7 kD. Without reduction, a strong band was seen at 24 kD (Fig. 2). This protein was purified by ion exchange chromatography and subjected to gel electrophoresis under reduced conditions Three bands were seen, indicating the presence of three chains within the protein a 6-8 kD chain (Cl), a 8-10 kD chain (C2) and a 10-12 kD chain (C3) The protein was further purified by reverse phase HPLC on a Delta™ C18 300 A⁰ 5 μm column, column size 3 9 x 300 mm (Waters-Millipore, Milford, MA) The sample containing 100 μg of protein was dissolved in 0 1% trifluoroacetic acid (TFA), pH 1 9 and polypeptides were eluted with a linear gradient of acetonitrile (0-60%) in 0 1% TFA pH 1 9 at a flow rate of 0 5 mL/min for 1 hour The eluent was monitored at 214 nm Two peaks were obtained, a C1-C3 dimer and a C2-C3 dimer The amino terminus of the C2 chain was found to be blocked The Cl and C3 chains were sequenced on a Perkin Elmer/ Applied Biosystems Inc Procise Model 494 protein sequencer and found to have the following amino terminal sequences (SEQ ID NOS 44 and 45, respectively)

(a) Ser-Gln-Ile-Cys-Glu-Leu-Val-Ala-His-Glu-Thr-Ile-Ser-Phe-Leu, and (b) Xaa-Xaa-Xaa-Xaa-Xaa-Ser-Ile-Leu-asp-Glu-Val-Ile-Arg-Gly-Thr, wherein Xaa may be any amino acid

These sequences were compared to known sequences in the gene bank using the databases discussed in Example 1 and were found to be identical to rat steroid binding protein, also known as estramustine-binding protein (EMBP) (Forsgren, B et al , Prog. Clin. Biol. Res. 75^.391-407, 1981, Forsgren, B et al., Proc. Natl. Acad. Sci. USA 7(5 3149-53, 1979) This protein is a major secreted protein in rat seminal fluid and has been shown to bind steroid, cholesterol and proline rich proteins EMBP has been shown to bind estramustine and estromustine, the active metabolites of estramustine phosphate Estramustine phosphate has been found to be clinically useful in treating advanced prostate cancer in patients who do not respond to standard hormone ablation therapy (see, for example, Van Poppel, H. et al , Prog. Clin. Biol. Res. 370.323-41, 1991)

B Isolation of putative human homologue to rat steroid binding protein

Purified rat steroid binding protein was obtained from freshly excised rat prostate and used to subcutaneously immunize a New Zealand white virgin female rabbit (150 μg purified rat steroid binding protein in 1 ml of PBS and 1 ml of incomplete Freund's adjuvant containing 100 μg of muramyl dipeptide (adjuvant peptide, Calbiochem, La Jolla, CA) Six weeks later the rabbit was boosted subcutaneously with the same protein dose in incomplete Freund's adjuvant Finally, the rabbit was boosted intravenously two weeks later with 100 μg protein in PBS and the sera harvested two weeks after the final immunization

The resulting rabbit antisera was used to screen the LnCap fgc cell line without success The rabbit antisera was subsequently used to screen human seminal fluid anion exchange chromatography pools using the protocol detailed below in Example 3 This analysis indicated an approximately 18-22 kD cross-reactive protein The seminal fluid fraction of interest (Fraction 1) was separated into individual components by SDS-PAGE under non-reducing conditions, blotted onto a PVDF membrane, excised and digested with CNBr in 70%> formic acid The resulting CNBr fragments were resolved on a tπcine gel system, again electroblotted to PVDF and excised The sequence for one peptide was determined as follows

Val-Val-Lys-Thr-Tyr-Leu-Ile-Ser-Ser-Ile-Pro-Leu-Gln-Gly-Ala-Phe- Asn-Tyr-Lys-Tyr-Thr-Ala (SEQ ID NO 46)

This sequence was compared to known sequences in the gene bank using the databases identified above and was unexpectedly found to be identical to gross cystic disease fluid protein, a protein whose expression was previously found to correlate with the presence of metastatic breast cancer (Murphy, L C et al , J Biol Chem 262 15236-15241, 1987) To the best of the inventors' knowledge, this protein has not been previously identified in male tissues

The ability of Fraction 1 as described above, to bind to steroid was investigated as follows Purified rat steroid binding protein (RSBP) and fraction 1 were subjected to SDS-PAGE and transferred onto nitrocellulose filters Specifically, 1 5 μg of RSBP/gel lane and 4 μg of fraction 1/gel lane were electrophoresed in parallel on a 4-20% gradient Laemmh gel (BioRad), then electrophoretically transferred to nitrocellulose After protein transfer, the nitrocellulose was blocked for 1 hour at room temperature in 1% Tween 20 in PBS, rinsed three times for 10 min each in 10 ml 0.1% Tween 20 in PBS plus 0.5 M NaCl, then probed with either 1) 0.87 μM progesterone conjugated to horseradish peroxidase (HRP, Sigma) diluted in the rinse buffer; 2) 0.87 μM progesterone HRP with 200 μM estramustine; or 3) 0.87 μM progesterone HRP plus 400 μM unlabelled progesterone and 200 μM estramustine. Each reaction mixture was incubated for 1 hour at room temperature and washed three times for 10 min each with 0.1% Tween 20 , PBS, and 0.5 M NaCl. The blots were then developed (ECL system, Amersham) to reveal progesterone HRP binding proteins that are also capable of binding estramustine.

With both rat steroid binding protein and Fraction 1, three bands were obtained that bound HRP-progesterone and that were competed out with unlabelled progesterone and estramustine (Fig. 3). These results indicate that the three bands isolated from human seminal fluid as described above bind hormone and correspond in number of polypeptides to the chains Cl, C2 and C3 of rat steroid binding protein, although slightly bigger in size, either due to primary sequence or secondary post- translational modifications.

This putative homologue of rat steroid binding protein was also identified in a subsequent screen of human seminal fluid using the rabbit antisera detailed above. Specifically a hydrophobic 22kD/65kD aggregate protein was obtained which, following CNBr digestion of the 22kD band, provided a peptide having the following sequence:

Val-Val-Lys-Thr-Tyr-Leu-Ile-Ser-Ser-Ile-Pro-Leu-Gln-Ala-Phe-Asn- Tyr-Lys-Tyr-Thr-Ala (SEQ ID NO: 47).

This peptide was found to correspond to residues 67 through 87 of gross cystic disease fluid protein and was identified again utilizing human autoimmune prostatitis sera as discussed below in Example 4. Example 3 Isolation and Characterization of Polypeptides Isolated from LnCaP fgc

Using Rat Prostatitis Sera

A LnCap fgc cell pellet was homogenized (10 gm cell pellet in 10 ml) by resuspension in PBS, 1% NP-40 and 60 μg/ml phenylmethylsulfonyl fluoride (PMSF) (Sigma, St. Louis, MO) then 10 strokes in a Dounce homogenizer This was followed by a 30 second probe sonication and another 10 strokes in the Dounce homogenizer The resulting slurry was centrifuged at 10,000 x G, and the supernatant filtered with a 0 45 μM filter (Amicon, Beverly, MA) then applied to a BioRad (Hercules, CA) Macro-Prep Q-20 anion exchange resin Proteins were eluted with a 70 minute 0 to 0 8 M NaCl gradient in 20 mM tris pH 7 5 at a flow rate of 8 ml/min Fractions were cooled, concentrated with 10 kD MWCO centriprep concentrators (Amicon) and stored at -20°C in the presence of 60 μg/ml PMSF The ion exchange pools were then examined by electrophoresis on 4-20% tris glycine Ready-Gels (BioRad) and subsequent transfer to nitrocellulose filters Ion exchange pools of interest were identified by ECL (Amersham International) Western analysis, using the rat sera described above in Example 2A This analysis indicated an approximately 65 kD protein eluting at 0.08 to 0.13 M NaCl The rat sera reactive ion exchange pool was subjected to HPLC and subsequent Western analysis to identify the protein fraction of interest This protein was then digested for 24 hours at 25°C in 70% formic acid saturated with CNBr to cleave at methionine residues.

The resulting CNBr fragments were purified by microbore HPLC using a Vydac C18 column (Hesperia, CA), column size 1x150 mM in a Perkin Elmer/ Applied Biosystems Inc (Foster City, CA) Division Model 172 HPLC Fractions were eluted from the column with a gradient of 0 to 60% of acetonitrile at a flow rate of 40 μl per minute The eluent was monitored at 214 nm The resulting fractions were loaded directly onto a Perkin Elmer/ Applied Biosystems Inc Procise 494 protein sequencer and sequenced using standard Edman chemistry from the amino terminal end Two different peptides having the following sequences were obtained (a) Xaa-Ala-Lys-Lys-Phe-Leu-Asp-Ala-Glu-His-Lys-Leu-Asn-Phe- Ala (SEQ ID NO 48), and

(b) Xaa-Xaa-Xaa-Lys-Ile-Lys-Lys-Phe-Ile-Gln-Glu-Asn-Ile-Phe- Gly, wherein Xaa may be any amino acid (SEQ ID NO 49)

These sequences were compared to known sequences in the gene bank using databases identified above, and identified as residues 286 through 300 and 228 through 242, respectively, of probable protein disulfide isomerase ER-60 precursor, hereinafter referred to as ER-60 (Bado, R J et al , Endocrinology 123 1264-1273, 1988) This antigen is also known as phosphohpase C-alpha (see PCT WO 95/08624) Residues 285 and 227 of ER-60 are methionmes, consistent with the above sequences being cyanogen bromide fractions

ER-60 is a resident endoplasmic protein with multiple biological activities, including disulfide isomerase and restricted cysteine protease activity In particular, ER-60 has been shown to preferentially degrade calnexin, a protein involved in presentation of antigens via the Class I major histocompatabihty complex, or MHC, pathway ER-60 and a related family member, ER-72, have been shown to be over- expressed in colon cancer, with truncated forms of ER-60 exhibiting increased enzymatic activity (Egea, G et al , J Cell Sci (England) 705 819-30, 1993) However, to the best of the inventors' knowledge, this polypeptide has not been previously shown to be present or overexpressed in human prostate Recently, ER-60 gene expression has been correlated with induction of contact inhibition of cell proliferation (Greene, J J et al , Cell Mol Biol 41 473-80, 1995) Thus, if ER-60 is also truncated and non-functional in prostate cancer, as it is in colon cancer, the resultant loss of contact inhibition would lead to neoplastic transformation and tumor progression Example 4

Isolation and Characterization of Polypeptides Isolated from LnCaP.fgc

Using Human Prostatitis Sera

The human prostatitis sera described above in Example 1 was used to screen the LnCaP.fgc cell line using the ion exchange techniques described above in Example 3. Reactive ion exchange pools were purified by reverse phase HPLC as described previously and the polypeptides shown in SEQ ID NOS: 50-56 were isolated utilizing cross-reactivity with said antisera as the selection criteria. Comparison of these sequences with known sequences in the gene bank using the databases described above revealed the homologies shown in Table II. However, none of these polypeptides have been previously associated with human prostate.

TABLE IV

SEO ID NO: Database Search Identification

50 glyceraldehyde-3 -phosphate- dehydrogenase

51 alpha-human fructose biphosphate aldolase

52 calreticulin

53 calreticulin

54 malate dehydrogenase

55 cystic disease fluid protein

56 cystic disease fluid protein Example 5 Isolation and Characterization of Polypeptides from Human Seminal Fluid

Polypeptides from human seminal fluid were purified to homogeneity by anion exchange chromatography. Specifically, seminal fluid samples were diluted 1 to 10 with 0.1 mM Bis-Tris propane buffer pH 7 prior to loading on the column. The polypeptides were fractionated into pools utilizing gel profusion chromatography on a Poros (Perseptive Biosystems) 146 II Q/M anion exchange column 4.6 mm x 100 mm equilibrated in 0.01 mM Bis-Tris propane buffer pH 7.5. Proteins were eluted with a linear 0-0.5 M NaCl gradient in the above buffer. The column eluent was monitored at a wavelength of 220 nm. Individual fractions were further purified by reverse phase HLPC on a Vydac (Hesperia, CA) C18 column.

The resulting fractions were sequenced as described above in Example 3. A peptide having the following N-terminal sequence was obtained: (c) Met-Asp-Ile-Pro-Gln-Thr-Lys-Gln-Asp-Leu-Glu-Leu-Pro-Lys-Leu

(SEQ ID NO:57). Comparison of this sequence with those of known sequences in the gene bank as described above revealed 100% identity with human placental protein 14 (PPM).

Example 6

Isolation of Polypeptides from a Prostate Tumor cDNA Library using Monkey Anti-Prostate Sera

A female cynomologous monkey was immunized with homogenized monkey prostate plus complete Freund's adjuvant. A booster immunization, using the same immunogen, was given one month later. Sera was taken from this monkey two months after the first immunization. This sera was pre-cleared of E. coli and phage antigens and used at a 1 :200 dilution to screen a primary prostate tumor expression library prepared in Lambda ZAP II (Stratagene). Two positive clones identified in the screen (hereinafter referred to as JF3 and JF5) were found to be non-sister clones from the same gene The clones were excised and insert size was determined by restriction digest (JF3 = 1500 bp, JF5 = 1000 bp) Complete DNA sequencing of these clones with both vector and internal primers indicated that the sequence of JF5 was found within that of JF3 Similarly, the partial open reading frame found in JF5 was found to be contained wholly within JF3 The determined cDNA sequences for JF3 and JF5 are provided in SEQ ID NO- 58 and 59, respectively, with the corresponding predicted amino acid sequence being provided in SEQ ID NO 60 Comparison of these sequences with those in the gene bank as described above revealed no significant homologies

The expression of these antigens in various tissue types was investigated using RT-PCR Over-expression was found in 2 out of 5 prostate tumor samples, 3 out of 5 normal prostate samples, 1 out of 2 breast tumor samples, and in a normal kidney sample and a normal brain sample. Northern analysis indicated that these antigens may be expressed both in prostate and testis

Example 7

Isolation of Polypeptides from a Prostate Tumor Cell-Line DNA Library by Expression Screening with Prostate Tumor-Specific Monoclonal Antibodies This example describes the isolation of polypeptides by screening a human prostate cancer cell line expression library with a monoclonal antibody known as Pro 1 5 as follows

The Pro 1 5 antibody was generated as follows High molecular weight DNA from the prostate tumor cell line LnCap was transformed into the non- tumorigenic embryonic rat cell line CREF-6 The transformed cells were then introduced into nude mice In some cases, the non-tumorigenic CREF cells were able to form tumors in the nude mice because of the presence of the high molecular weight LnCap DNA These cells were rescued and surface epitope masked using a polyclonal sera generated to non-transformed CREF-6 cells This sera masks any proteins present on the surface of the non-transformed CREF-6 cells while leaving exposed any proteins expressed on the surface of the cell due to the presence of the high molecular weight LnCap DNA These exposed proteins may represent tumor antigens expressed by the transformed CREF-6 cells The masked cells coated with the antι-CREF-6 antibody were used as an immunogen in immunocompetent mice After immunization and boosting, the mice were sacrificed and a monoclonal antibody reactive to the transformed cell-line (referred to as Pro 1 5) was generated

Pro 1 5 was determined to bind to the prostate tumor cell line Du-145 by FACS analysis and was used to screen an unamplified expression library prepared from Du- 145 RNA in Lambda ZAP Express (Stratagene) The determined partial cDNA sequences for the first of three genes isolated in this screen are provided in SEQ ID NO 61 and 62, the determined 5' and 3' sequences for a second clone are provided in SEQ ID NO 63 and 64, respectively, and the determined partial cDNA sequences for a third isolated clone are provided in SEQ ID NO 65 and 66 Comparison of these sequences with those in the gene bank revealed no significant homologies to the sequence of SEQ ID NO 61 and 62 SEQ ID NO 63 and 64 were found to show some homology to previously isolated expressed sequence tags The sequence of SEQ ID NO 65 and 66 were found to represent the known human gene amphiphysin II

Example 8 Synthesis of Polypeptides

Polypeptides may be synthesized on an Applied Biosystems 430A peptide synthesizer using FMOC chemistry with HPTU (O-Benzotπazole-N,N,N',N'- tetramethyluromum hexafluorophosphate) activation A Gly-Cys-Gly sequence may be attached to the amino terminus of the peptide to provide a method of conjugation, binding to an immobilized surface, or labeling of the peptide Cleavage of the peptides from the solid support may be carried out using the following cleavage mixture tπfluoroacetic acid ethanedithiol thioamsole water phenol (40 1 2 2 3) After cleaving for 2 hours, the peptides may be precipitated in cold methyl-t-butyl-ether The peptide pellets may then be dissolved in water containing 0 1% tπfluoroacetic acid (TFA) and lyophilized prior to purification by C18 reverse phase HPLC. A gradient of 0%-60% acetonitrile (containing 0.1 % TFA) in water (containing 0.1 % TFA) may be used to elute the peptides. Following lyophilization of the pure fractions, the peptides may be characterized using electrospray or other types of mass spectrometry and by amino acid analysis.

From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein for the purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention.

SEQUENCE LISTING

(1) GENERAL INFORMATION:

(i) APPLICANTS: Reed, Steven G.

Dillon, Davin C. Twardzik, Daniel R. Mitcham, Jennifer L.

(ii) TITLE OF INVENTION: COMPOUNDS AND METHODS FOR IMMUNOTHERAPY

AND IMMUNODIAGNOSIS OF PROSTATE CANCER

(iii) NUMBER OF SEQUENCES: 66

(iv) CORRESPONDENCE ADDRESS:

(A) ADDRESSEE: SEED and BERRY LLP

(B) STREET: 6300 Columbia Center, 701 Fifth Avenue

(C) CITY: Seattle

(D) STATE: Washington

(E) COUNTRY: USA

(F) ZIP: 98104-7092

(v) COMPUTER READABLE FORM:

(A) MEDIUM TYPE: Floppy disk

(B) COMPUTER: IBM PC compatible

(C) OPERATING SYSTEM: PC-DOS/MS-DOS

(D) SOFTWARE: Patentin Release #1.0, Version #1.30

(vi) CURRENT APPLICATION DATA:

(A) APPLICATION NUMBER:

(B) FILING DATE: 22-JUN-1998

(C) CLASSIFICATION:

(viii) ATTORNEY/AGENT INFORMATION:

(A) NAME: Maki, David J.

(B) REGISTRATION NUMBER: 31,392

(C) REFERENCE/DOCKET NUMBER: 210121.424C2

(ix) TELECOMMUNICATION INFORMATION:

(A) TELEPHONE: (206) 622-4900

(B) TELEFAX: (206) 682-6031

(2) INFORMATION FOR SEQ ID NO : 1 : (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 89 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS :

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 1 :

Ala Arg Ala Ser Val Met Leu Leu Gly Met Met Ala Arg Gly Lys Pro

1 5 10

15

Glu lie Val Gly Ser Asn Leu Asp Thr Leu Met Ser lie Gly Leu Asp

20 25 30

Glu Lys Phe Pro Gin Asp Tyr Arg Leu Ala Gin Gin Val Cys His Ala

35 40 45 lie Ala Asn lie Ser Asp Arg Arg Lys Pro Ser Leu Gly Lys Arg His

50 55 60

Pro Pro Phe Arg Leu Pro Gin Glu His Arg Leu Phe Glu Arg Leu Arg

65 70 75

80

Glu Thr Val Thr Lys Gly Phe Val His

85

(2) INFORMATION FOR SEQ ID NO : 2 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 89 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 2 :

Ala Arg Gly Arg Phe Gly Arg Leu Gly Val Gly Gly Glu Pro His Pro

1 5 10

15

Arg Arg Asn Pro Ala Leu Pro Thr Glu Leu Ala Glu Leu Thr Pro Gin 20 25 30

Val Arg Arg Ala Ala Xaa Lys Thr Gin Arg Ser Gin Val Lys Pro Arg

35 40 45

His Arg Arg Gly Trp Pro Pro Thr Val Pro Leu Ala Gly Arg Leu Glu

50 55 60

Glu Leu Lys Thr Pro Arg Ser Pro Arg Pro Pro Glu Gin Gly Leu Asp

65 70 75

80

Pro Ser Pro Cys Ser Leu Pro Ser Pro

85

(2) INFORMATION FOR SEQ ID NO : 3 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 858 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 3 :

Gin Glu Ser Glu Pro Phe Ser His lie Asp Pro Glu Glu Ser Glu Glu

1 5 10

15

Thr Arg Leu Leu Asn lie Leu Gly Leu lie Phe Lys Gly Pro Ala Ala

20 25 30

Ser Thr Gin Glu Lys Asn Pro Arg Glu Ser Thr Gly Asn Met Val Thr

35 40 45

Gly Gin Thr Val Cys Lys Asn Lys Pro Asn Met Ser Asp Pro Glu Glu

50 55 60

Ser Arg Gly Asn Asp Glu Leu Val Lys Gin Glu Met Leu Val Gin Tyr

65 70 75

80

Leu Gin Asp Ala Tyr Ser Phe Ser Arg Lys lie Thr Glu Ala He Gly

85 90

95 He He Ser Lys Met Met Tyr Glu Asn Thr Thr Thr Val Val Gin Glu

100 105 110

Val He Glu Xaa Phe Val Met Val Phe Gin Phe Gly Val Pro Gin Ala

115 120 125

Leu Phe Gly Val Arg Arg Met Leu Pro Leu He Trp Ser Lys Glu Pro

130 135 140

Gly Val Arg Glu Ala Val Leu Asn Ala Tyr Arg Gin Leu Tyr Leu Asn

145 150 155

160

Pro Lys Gly Asp Ser Ala Arg Ala Lys Ala Gin Ala Leu He Gin Asn

165 170

175

Leu Ser Leu Leu Leu Val Asp Ala Ser Val Gly Thr He Gin Cys Leu

180 185 190

Glu Glu He Leu Cys Glu Phe Val Gin Lys Asp Glu Leu Lys Pro Ala

195 200 205

Val Thr His Leu Leu Trp Glu Arg Ala Thr Glu Lys Val Ala Cys Cys

210 215 220

Pro Leu Glu Arg Cys Ser Ser Val Met Leu Leu Gly Met Met Ala Arg

225 230 235

240

Arg Lys Pro Glu He Val Gly Ser Asn Leu Asp Thr Leu Met Ser He

245 250

255

Gly Leu Asp Glu Lys Phe Pro Gin Asp Tyr Arg Leu Ala Gin Gin Val

260 265 270

Cys His Ala He Ala Asn He Ser Asp Arg Arg Lys Pro Ser Leu Gly

275 280 285

Lys Arg His Pro Pro Phe Arg Leu Pro Gin Glu His Arg Leu Phe Glu

290 295 300

Arg Leu Arg Glu Thr Val Thr Lys Gly Phe Val His Pro Asp Pro Leu 305 310 315

320

Trp He Pro Phe Lys Glu Val Ala Val Thr Leu He Tyr Gin Leu Ala

325 330

335

Glu Gly Pro Glu Val He Cys Ala Gin He Leu Gin Gly Cys Ala Lys

340 345 350

Gin Ala Leu Glu Lys Leu Glu Glu Lys Arg Thr Ser Gin Glu Asp Pro

355 360 365

Lys Glu Ser Pro Ala Met Leu Pro Thr Phe Leu Leu Met Asn Leu Leu

370 375 380

Ser Leu Ala Gly Asp Val Ala Leu Gin Gin Leu Val His Leu Glu Gin

385 390 395

400

Ala Val Ser Gly Glu Leu Cys Arg Arg Arg Val Leu Arg Glu Glu Gin

405 410

415

Glu His Lys Thr Lys Asp Pro Lys Glu Lys Asn Thr Ser Ser Glu Thr

420 425 430

Thr Met Glu Glu Glu Leu Gly Leu Val Gly Ala Thr Ala Asp Asp Thr

435 440 445

Glu Ala Glu Leu He Arg Gly He Cys Glu Met Glu Leu Leu Asp Gly

450 455 460

Lys Gin Thr Leu Ala Ala Phe Val Pro Leu Leu Leu Lys Val Cys Asn

465 470 475

480

Asn Pro Gly Leu Tyr Ser Asn Pro Asp Leu Ser Ala Ala Ala Ser Leu

485 490

495

Ala Leu Gly Lys Phe Cys Met He Ser Ala Thr Phe Cys Asp Ser Gin

500 505 510

Leu Arg Leu Leu Phe Thr Met Leu Glu Lys Ser Pro Leu Pro He Val 515 520 525

Arg Ser Asn Leu Met Val Ala Thr Gly Asp Leu Ala He Arg Phe Pro

530 535 540

Asn Leu Val Asp Pro Trp Thr Pro His Leu Tyr Ala Arg Leu Arg Asp

545 550 555

560

Pro Ala Gin Gin Val Arg Lys Thr Ala Gly Leu Val Met Thr His Leu

565 570

575

He Leu Lys Asp Met Val Lys Val Lys Gly Gin Val Ser Glu Met Ala

580 585 590

Val Leu Leu He Asp Pro Glu Pro Gin He Ala Ala Leu Ala Lys Asn

595 600 605

Phe Phe Asn Glu Leu Ser His Lys Gly Asn Ala He Tyr Asn Leu Leu

610 615 620

Pro Asp He He Ser Arg Leu Ser Asp Pro Glu Leu Gly Val Glu Glu

625 630 635

640

Glu Pro Phe His Thr He Met Lys Gin Leu Leu Ser Tyr He Thr Lys

645 650

655

Asp Lys Gin Thr Glu Ser Leu Val Glu Lys Leu Cys Gin Arg Phe Arg

660 665 670

Thr Ser Arg Thr Glu Arg Gin Gin Arg Asp Leu Ala Tyr Cys Val Ser

675 680 685

Gin Leu Pro Leu Thr Glu Arg Gly Leu Arg Lys Met Leu Asp Asn Phe

690 695 700

Asp Cys Phe Gly Asp Lys Leu Ser Asp Glu Ser He Phe Ser Ala Phe

705 710 715

720

Leu Ser Val Val Gly Lys Leu Arg Arg Gly Ala Lys Pro Glu Gly Lys

725 730 735

Ala He He Asp Glu Phe Glu Gin Lys Leu Arg Ala Cys His Thr Arg

740 745 750

Gly Leu Asp Gly He Lys Glu Leu Glu He Gly Gin Ala Gly Ser Gin

755 760 765

Arg Ala Pro Ser Ala Lys Lys Pro Ser Thr Gly Ser Arg Tyr Gin Pro

770 775 780

Leu Ala Ser Thr Ala Ser Asp Asn Asp Phe Val Thr Pro Glu Pro Arg

785 790 795

800

Arg Thr Thr Arg Arg His Pro Asn Thr Gin Gin Arg Ala Ser Lys Lys

805 810

815

Lys Pro Lys Val Val Phe Ser Ser Asp Glu Ser Ser Glu Glu Asp Leu

820 825 830

Ser Ala Glu Met Thr Glu Asp Glu Thr Pro Lys Lys Thr Thr Pro He

835 840 845

Leu Arg Ala Ser Ala Arg Arg His Arg Ser 850 855

(2) INFORMATION FOR SEQ ID NO : 4 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 127 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 4 :

Ala Arg Asp Arg Leu Val Ala Ser Lys Thr Asp Gly Lys He Val Gin

1 5 10

15

Tyr Glu Cys Glu Gly Asp Thr Cys Gin Glu Glu Lys He Asp Ala Leu

20 25 30

Gin Leu Glu Tyr Ser Tyr Leu Leu Thr Ser Gin Leu Glu Ser Gin Arg

35 40 45

He Tyr Trp Glu Asn Lys He Val Arg He Glu Lys Asp Thr Ala Glu

50 55 60

Glu He Asn Asn Met Lys Thr Lys Phe Lys Glu Thr He Xaa Xaa Cys

65 70 75

80

Asp Asn Leu Glu His Xaa Leu Asn Asp Leu Leu Lys Glu Lys Gin Ser

85 90

95

Val Glu Arg Lys Cys Thr Gin Leu Asn Thr Lys Val Ala Lys Leu Thr

100 105 110

Asn Glu Leu Lys Glu Glu Gin Glu Met Asn Lys Cys Leu Arg Ala

115 120 125

(2) INFORMATION FOR SEQ ID NO : 5 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 43 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 5 :

Ala Arg Ala Glu Val Gin Arg Trp Arg Arg Leu Val Ala Gly Arg Arg

1 5 10

15

Arg Ala Gly Gly Asp Gly Gly Asn Ser Gly Ser Cys Ser Arg Trp Gly

20 25 30

Gly Phe Thr Ser Tyr Pro Trp Asp Arg Glu He 35 40

(2) INFORMATION FOR SEQ ID NO : 6 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 751 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS:

(D) TOPOLOGY : linear

(xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 6 :

Pro Ala Glu Ala His Ser Asp Ser Leu He Asp Thr Phe Pro Glu Cys

1 5 10

15

Ser Thr Glu Gly Phe Ser Ser Asp Ser Asp Leu Val Ser Leu Thr Val

20 25 30

Asp Val Asp Ser Leu Ala Glu Leu Asp Asp Gly Met Ala Ser Asn Gin

35 40 45

Asn Ser Pro He Arg Thr Phe Gly Leu Asn Leu Ser Ser Asp Ser Ser

50 55 60

Ala Leu Gly Ala Val Ala Ser Asp Ser Glu Gin Ser Lys Thr Glu Glu

65 70 75

80

Glu Arg Glu Ser Arg Ser Leu Phe Pro Gly Ser Leu Lys Pro Lys Leu

85 90

95

Gly Lys Arg Asp Tyr Leu Glu Lys Ala Gly Glu Leu He Lys Leu Ala

100 105 110

Leu Lys Lys Glu Glu Glu Asp Asp Tyr Glu Ala Ala Ser Asp Phe Tyr

115 120 125

Arg Lys Gly Val Asp Leu Leu Leu Glu Gly Val Gin Gly Glu Ser Ser

130 135 140

Pro Thr Arg Arg Glu Ala Val Lys Arg Arg Thr Ala Glu Tyr Leu Met

145 150 155

160

Arg Ala Glu Ser He Ser Ser Leu Tyr Gly Lys Pro Gin Leu Asp Asp

165 170

175

Val Ser Gin Pro Pro Gly Ser Leu Ser Ser Arg Pro Leu Trp Asn Leu 180 185 190

Arg Ser Pro Ala Glu Glu Leu Lys Ala Phe Arg Val Leu Gly Val He

195 200 205

Asp Lys Val Leu Leu Val Met Asp Thr Arg Thr Glu His Thr Phe He

210 215 220

Leu Xaa Gly Leu Arg Lys Ser Ser Glu Tyr Ser Arg Asn Arg Lys Thr

225 230 235

240

He Xaa Pro Arg Cys Val Pro Xaa Met Val Cys Leu His Lys Tyr He

245 250

255

He Ser Glu Glu Ser Xaa Phe Leu Val Leu Gin His Ala Glu Xaa Gly

260 265 270

Lys Leu Trp Ser Tyr He Ser Lys Phe Leu Asn Arg Ser Pro Glu Glu

275 280 285

Ser Phe Asp He Lys Glu Val Lys Lys Pro Thr Leu Ala Lys Val His

290 295 300

Leu Gin Gin Pro Thr Ser Ser Pro Gin Asp Ser Ser Ser Phe Glu Ser

305 310 315

320

Arg Gly Ser Asp Gly Gly Ser Met Leu Lys Ala Leu Pro Leu Lys Ser

325 330

335

Ser Leu Thr Pro Ser Ser Gin Asp Asp Ser Asn Gin Glu Asp Asp Gly

340 345 350

Gin Asp Ser Ser Pro Lys Trp Pro Asp Ser Gly Ser Ser Ser Glu Glu

355 360 365

Glu Cys Thr Thr Ser Tyr Leu Thr Leu Cys Asn Glu Tyr Gly Gin Glu

370 375 380

Lys He Glu Pro Gly Ser Leu Asn Glu Glu Pro Phe Met Lys Thr Glu

385 390 395

400 Gly Asn Gly Val Asp Thr Lys Ala He Lys Ser Phe Pro Ala His Leu

405 410

415

Ala Ala Asp Ser Asp Ser Pro Ser Thr Gin Leu Arg Ala His Glu Leu

420 425 430

Lys Phe Phe Pro Asn Asp Asp Pro Glu Ala Val Ser Ser Pro Arg Thr

435 440 445

Ser Asp Ser Leu Ser Arg Ser Lys Asn Ser Pro Met Glu Phe Phe Arg

450 455 460

He Asp Ser Lys Asp Ser Ala Ser Glu Leu Leu Gly Leu Asp Phe Gly

465 470 475

480

Glu Lys Leu Tyr Ser Leu Lys Ser Glu Pro Leu Lys Pro Phe Phe Thr

485 490

495

Leu Pro Asp Gly Asp Ser Ala Ser Arg Ser Phe Asn Thr Ser Glu Ser

500 505 510

Lys Val Glu Phe Lys Ala Gin Asp Thr He Ser Arg Gly Ser Asp Asp

515 520 525

Ser Val Pro Val He Ser Phe Lys Asp Ala Ala Phe Asp Asp Val Ser

530 535 540

Gly Thr Asp Glu Gly Arg Pro Asp Leu Leu Val Asn Leu Pro Gly Glu

545 550 555

560

Leu Glu Ser Thr Arg Glu Ala Ala Ala Met Gly Pro Thr Lys Phe Thr

565 570

575

Gin Thr Asn He Gly He He Glu Asn Lys Leu Leu Glu Ala Pro Asp

580 585 590

Val Leu Cys Leu Arg Leu Ser Thr Glu Gin Cys Gin Ala His Glu Glu

595 600 605

Lys Gly He Glu Glu Leu Ser Asp Pro Ser Gly Pro Lys Ser Tyr Ser

610 615 620

He Thr Glu Lys His Tyr Ala Gin Glu Asp Pro Arg Met Leu Phe Val

625 630 635

640

Ala Xaa Val Asp His Ser Ser Ser Gly Asp Met Ser Leu Leu Pro Ser

645 650

655

Ser Asp Pro Lys Phe Gin Gly Leu Gly Val Val Glu Ser Xaa Val Thr

660 665 670

Ala Asn Asn Thr Glu Glu Ser Leu Phe Arg He Cys Ser Pro Leu Ser

675 680 685

Gly Ala Asn Glu Tyr He Ala Ser Thr Asp Thr Leu Lys Thr Glu Glu

690 695 700

Val Leu Leu Phe Thr Asp Gin Thr Asp Asp Leu Ala Lys Glu Glu Pro

705 710 715

720

Thr Ser Leu Phe Xaa Arg Asp Ser Glu Thr Lys Gly Glu Ser Gly Leu

725 730

735

Val Leu Glu Gly Asp Lys Glu He His Gin He Phe Glu Gly Pro

740 745 750

(2) INFORMATION FOR SEQ ID NO : 7 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 6 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 7 :

Ala Arg Gly Ser Thr Gin 1 5

(2) INFORMATION FOR SEQ ID NO : 8 : (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 16 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 8 :

Ala Arg Gly Ser Ser Gin Val Arg Val Lys Ser Trp Arg Gly Asp Met

1 5 10

15

(2) INFORMATION FOR SEQ ID NO : 9 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 271 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 9 :

CCGCACGAGC CTCTGTCATG CTTCTTGGCA TGATGGCACG AGGAAAGCCA

GAAATTGTGG 60

GAAGCAATTT AGACACACTG ATGAGCATAG GGCTGGATGA GAAGTTTCCA

CAGGACTACA 120

GGCTGGCCCA GCAGGTGTGC CATGCCATTG CCAACATCTC GGACAGGAGA

AAGCCTTCTC 180

TGGGCAAACG TCACCCCCCC TTCCGGCTGC CTCAGGAACA CAGGTTGTTT

GAGCGACTGC 240

GGGAGACAGT CACAAAAGGC TTTGTCCACC C

271

(2) INFORMATION FOR SEQ ID NO: 10:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 403 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10: GGGTGGATAA CCTGAGGTAG GGAGTTCGAG ACCAGCCTGA CCAACATGGA

GAAACCCCAT 60

CTCTACTAAA AATAAAAAAT TAGCCGGCGT ATTGGCGTGC GCCTGTAATC

CCAGCTACTC 120

AAGAGGCTGA GGCAGGAGAA TCGCCTGAAC CCAGAGGCGG AGGTTGTAGT

GAGCCGAAAT 180

CACACCATTG CACTCCAGCT TGGGCAACAA TAGCGAACCT CCATCTCAAA

TTAAAAAAAA 240

AATGCCTACA CGCTTCTTTA AAATGCAAGG CTTTCTCTTA AATTAGCCTA

ACTGAACTGC 300

GTTGAGCTGC TTCAACTTTG GAATATATGT TTGCCAATCT CCTTGTTTTC

TAATGAATAA 360

ATGTTTTTAT ATACTTTTAA AAAAAAAAAA AAAAAAACTC GAG

403

(2) INFORMATION FOR SEQ ID NO: 11:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2276 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11:

GGAGGTTTGG GCGGCTTGGC GTCGGAGGAG AGCCCCACCC GCGGAGGAAC

CCAGCCTTGC 60

CAACGGAGCT GGCGGAGCTC ACTCCTCAGG TCAGGCGGGC GGCGTANAAA

ACGCAGCGGA 120

GCCAGGTGAA ACCAAGGCAC CGCCGTGGCT GGCCCCCGAC AGTTCCTCTA

GCCGGGAGGT 180

TGGAGGAGCT GAAAACGCCG CGGAGCCCTC GGCCGCCCGA GCAGGGGCTG

GACCCCAGCC 240

CTTGCAGCCT CCCTTCTCCT GGCACCCAAG TGCAGTCCTG GCTGCAGAAG

GGGCCGCGGG 300

CGCACTGAGT TTCCAACCTC CGTTCAGCCT GTCTGTCTCA GGGTGCAGCC

TTAATGAGAG 360

GTGATTCCTA AGCTGCTGGG AACCTGAGGT TGTCAAAGGG GCGGCAGGAA

ATGGACAGCA 420

GTATAAAACC CAGAAGCAGA ACTTGAAGGT TAAACCACTA GCCCATTTCA

CAGAATGTTT 480

CATCCATTTG TGGACCAAAA GATGGAGTTG GTTTTTATTT TTAAAAAGAT

AATGTTAATG 540

ATCTGATACC ACTACAAATA TTTACGTGAG AAGATTCATG GACTTGTCTT

TTGGTTGGAC 600 TGTCACTCAT TTCTGAAAGT TTCTTCAGCC ACAATTTCTA TTTGAAAATT

CAAGTATCAA 660

AGGATACCAG GTTTAGAATG GTATAATGAT GTATTTTGTC TGAGGACTGC

AAATTTTATA 720

GAGACCACAG TTGGATTCCA GTGATATTCT GCAATCAAAG TGATTTGATA

AACCTAATTT 780

TGAAGCATTT TATATTTATA AGCGACATCA AAAGATGGGA GAAAAAAATG

GCGATGCAAA 840

AACTTTCTGG ATGGAGCTAG AAGATGATGG AAAAGTGGAC TTCATTTTTG

AACAAGTACA 900

AAATGTGCTG CAGTCACTGA AACAAAAGAT CAAAGATGGG TCTGCCACCA

ATAAAGAATA 960

CATCCAAGCA ATGATTCTAG TGAATGAAGC AACTATAATT AACAGTTCAA

CATCAATAAA 1020

GGATCCTATG CCTGTGACTC AGAAGGAACA GGAAAACAAA TCCAATGCAT

TTCCCTCTAC 1080

ATCATGTGAA AACTCCTTTC CAGAAGACTG TACATTTCTA ACAACAGGAA

ATAAGGAAAT 1140

TCTCTCTCTT GAAGATAAAG TTGTAGACTT TAGAGAAAAA GACTCATCTT

CGAATTTATC 1200

TTACCAAAGT CATGACTGCT CTGGTGCTTG TCTGATGAAA ATGCCACTGA

ACTTGAAGGG 1260

AGAAAACCCT CTGCAGCTGC CAATCAAATG TCACTTCCAA AGACGACATG

CAAAGACAAA 1320

CTCTCATTCT TCAGCACTCC ACGTGAGTTA TAAAACCCCT TGTGGAAGGA

GTCTACGAAA 1380

CGTGGAGGAA GTTTTTCGTT ACCTGCTTGA GACAGAGTGT AACTTTTTAT

TTACAGATAA 1440

CTTTTCTTTC AATACCTATG TTCAGTTGGC TCGGAATTAC CCAAAGCAAA

AAGAAGTTGT 1500

TTCTGATGTG GATATTAGCA ATGGAGTGGA ATCAGTGCCC ATTTCTTTCT

GTAATGAAAT 1560

TGACAGTAGA AAGCTCCCAC AGTTTAAGTA CAGAAAGACT GTGTGGCCTC

GAGCATATAA 1620

TCTAACCAAC TTTTCCAGCA TGTTTACTGA TTCCTGTGAC TGCTCTGAGG

GCTGCATAGA 1680

CATAACAAAA TGTGCATGTC TTCAACTGAC AGCAAGGAAT GCCAAAACTT

CCCCCTTGTC 1740

AAGTGACAAA ATAACCACTG GATATAAATA TAAAAGACTA CAGAGACAGA

TTCCTACTGG 1800

CATTTATGAA TGCAGCCTTT TGTGCAAATG TAATCGACAA TTGTGTCAAA

ACCGAGTTGT 1860

CCAACATGGT CCTCAAGTGA GGTTACAGGT GTTCAAAACT GAGCAGAAGG

GATGGGGTGT 1920

ACGCTGTCTA GATGACATTG ACAGAGGGAC ATTTGTTTGC ATTTATTCAG GAAGATTACT 1980

AAGCAGAGCT AACACTGAAA AATCTTATGG TATTGATGAA AACGGGAGAG

ATGAGAATAC 2040

TATGAAAAAT ATATTTTCAA AAAAGAGGAA ATTAGAAGTT GCATGTTCAG

ATTGTGAAGT 2100

TGAAGTTCTC CCATTAGGAT TGGAAACACA TCCTAGAACT GCTAAAACTG

AGAAATGTCC 2160

ACCAAAGTTC AGTAATAATC CCAAGGAGCT TACTATGGAA ACGAAATATG

ATAATATTTC 2220

AAGAATTCAG TATCATTCAG TTATTAGAGA TCCTGAATCC AAGACAGCCA TTTTTC

2276

(2) INFORMATION FOR SEQ ID NO: 12:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 3114 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12:

CAGGAGTCCG AACCCTTCAG TCATATAGAC CCAGAGGAGT CAGAGGAGAC

CAGGCTCTTG 60

AATATCTTAG GACTTATCTT CAAAGGCCCA GCAGCTTCCA CACAAGAAAA

GAATCCCCGG 120

GAGTCTACAG GAAACATGGT CACAGGACAG ACTGTCTGTA AAAATAAACC

CAATATGTCG 180

GATCCTGAGG AATCCAGGGG AAATGATGAA CTAGTGAAGC AGGAGATGCT

GGTACAGTAT 240

CTGCAGGATG CCTACAGCTT CTCCCGGAAG ATTACAGAGG CCATTGGCAT

CATCAGCAAG 300

ATGATGTATG AAAACACAAC TACAGTGGTG CAGGAGGTGA TTGAATNCTT

TGTGATGGTC 360

TTCCAATTTG GGGTACCCCA GGCCCTGTTT GGGGTGCGCC GTATGCTGCC

TCTCATCTGG 420

TCTAAGGAGC CTGGTGTCCG GGAAGCCGTG CTTAATGCCT ACCGCCAACT

CTACCTCAAC 480

CCCAAAGGGG ACTCTGCCAG AGCCAAGGCC CAGGCTTTGA TTCAGAATCT

CTCTCTGCTG 540

CTAGTGGATG CCTCGGTTGG GACCATTCAG TGTCTTGAGG AAATTCTCTG

TGAGTTTGTG 600

CAGAAGGATG AGTTGAAACC AGCAGTGACC CATCTGCTGT GGGAGCGGGC

CACCGAGAAG 660

GTCGCCTGCT GTCCTCTGGA GCGCTGTTCC TCTGTCATGC TTCTTGGCAT GATGGCACGA 720

AGAAAGCCAG AAATTGTGGG AAGCAATTTA GACACACTGA TGAGCATAGG

GCTGGATGAG 780

AAGTTTCCAC AGGACTACAG GCTGGCCCAG CAGGTGTGCC ATGCCATTGC

CAACATCTCG 840

GACAGGAGAA AGCCTTCTCT GGGCAAACGT CACCCCCCCT TCCGGCTGCC

TCAGGAACAC 900

AGGTTGTTTG AGCGACTGCG GGAGACAGTC ACAAAAGGCT TTGTCCACCC

AGACCCACTC 960

TGGATCCCAT TCAAAGAGGT GGCAGTGACC CTCATTTACC AACTGGCAGA

GGGCCCCGAA 1020

GTGATCTGTG CCCAGATATT GCAGGGCTGT GCAAAACAGG CCCTGGAGAA

GCTAGAAGAG 1080

AAGAGAACCA GTCAGGAGGA CCCGAAGGAG TCCCCCGCAA TGCTCCCCAC

TTTCCTGTTG 1140

ATGAACCTGC TGTCCCTGGC TGGGGATGTG GCTCTGCAGC AGCTGGTCCA

CTTGGAGCAG 1200

GCAGTGAGTG GAGAGCTCTG CCGGCGCCGA GTTCTCCGGG AAGAACAGGA

GCACAAGACC 1260

AAAGATCCCA AGGAGAAGAA TACGAGCTCT GAGACCACCA TGGAGGAGGA

GCTGGGGCTG 1320

GTTGGGGCAA CAGCAGATGA CACAGAGGCA GAACTAATCC GTGGCATCTG

CGAGATGGAA 1380

CTGTTGGATG GCAAACAGAC ACTGGCTGCC TTTGTTCCAC TCTTGCTTAA

AGTCTGTAAC 1440

AACCCAGGCC TCTATAGCAA CCCAGACCTC TCTGCAGCTG CTTCACTTGC

CCTTGGCAAG 1500

TTCTGCATGA TCAGTGCCAC TTTCTGCGAC TCCCAGCTTC GTCTTCTGTT

CACCATGCTG 1560

GAAAAGTCTC CACTTCCCAT TGTCCGGTCT AACCTCATGG TTGCCACTGG

GGATCTGGCC 1620

ATCCGCTTTC CCAATCTGGT GGACCCCTGG ACTCCTCATC TGTATGCTCG

CCTCCGGGAC 1680

CCTGCTCAGC AAGTGCGGAA AACAGCGGGG CTGGTGATGA CCCACCTGAT

CCTCAAGGAC 1740

ATGGTGAAGG TGAAGGGGCA GGTCAGTGAG ATGGCGGTGC TGCTCATCGA

CCCCGAGCCT 1800

CAGATTGCTG CCCTGGCCAA GAACTTCTTC AATGAGCTCT CCCACAAGGG

CAACGCAATC 1860

TATAATCTCC TTCCAGATAT CATCAGCCGC CTGTCAGACC CCGAGCTGGG

GGTGGAGGAA 1920

GAGCCTTTCC ACACCATCAT GAAACAGCTC CTCTCCTACA TCACCAAGGA

CAAGCAGACA 1980

GAGAGCCTGG TGGAAAAGCT GTGTCAGCGG TTCCGCACAT CCCGAACTGA

GCGGCAGCAG 2040 CGAGACCTGG CCTACTGTGT GTCACAGCTG CCCCTCACAG AGCGAGGCCT

CCGTAAGATG 2100

CTTGACAATT TTGACTGTTT TGGAGACAAA CTGTCAGATG AGTCCATCTT

CAGTGCTTTT 2160

TTGTCAGTTG TGGGCAAGCT GCGACGTGGG GCCAAGCCTG AGGGCAAGGC

TATAATAGAT 2220

GAATTTGAGC AGAAGCTTCG GGCCTGTCAT ACCAGAGGTT TGGATGGAAT

CAAGGAGCTT 2280

GAGATTGGCC AAGCAGGTAG CCAGAGAGCG CCATCAGCCA AGAAACCATC

CACTGGTTCT 2340

AGGTACCAGC CTCTGGCTTC TACAGCCTCA GACAATGACT TTGTCACACC

AGAGCCCCGC 2400

CGTACTACCC GTCGGCATCC AAACACCCAG CAGCGAGCTT CCAAAAAGAA

ACCCAAAGTT 2460

GTCTTCTCAA GTGATGAGTC CAGTGAGGAA GATCTTTCAG CAGAGATGAC

AGAAGACGAG 2520

ACACCCAAGA AAACAACTCC CATTCTCAGA GCATCGGCTC GCAGGCACAG

ATCCTAGGAA 2580

GTCTGTTCCT GTCCTCCCTG TGCAGGGTAT CCTGTAGGGT GACCTGGAAT

TCGAATTCTG 2640

TTTCCCTTGT AAAATATTTG TCTGTCTCTT TTTTTTAAAA AAAAAAAAGG

CCGGGCACTG 2700

TGGCTCACGC CTGTAATCCC AGCACTTTGC GATACCAAGG CGGGTGGATA

ACCTGAGGTA 2760

GGGAGTTCGA GACCAGCCTG ACCAACATGG AGAAACCCCA TCTCTACTAA

AAATAAAAAA 2820

TTAGCCGGGC GTATTGGCGT GCGCCTGTAA TCCCAGCTAC TCAAGAGGCT

GAGGCAGGAG 2880

AATCGCCTGA ACCCAGAGGC GGAGGTTGTA GTGAGCCGAA ATCACACCAT

TGCACTCCAG 2940

CTTGGGCAAC AATAGCGAAC CTCCATCTCA AATTAAAAAA AAAATGCCTA

CACGCTCTTT 3000

AAAATGCAAG GCTTTCTCTT AAATTAGCCT AACTGAACTG CGTTGAGCTG

CTTCAACTTT 3060

GGAATATATG TTTGCCAATC TCCTTGTTTT CTAATGAATA AATGTTTTTA TATA

3114

(2) INFORMATION FOR SEQ ID NO: 13:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1797 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO : 13 :

CGGCACGAGA TCGACTGGTT GCAAGTAAAA CAGATGGAAA AATAGTACAG

TATGAATGTG 60

AGGGGGATAC TTGCCAGGAA GAGAAAATAG ATGCCTTACA GTTAGAGTAT

TCATATTTAC 120

TAACAAGCCA GCTGGAATCT CAGCGAATCT ACTGGGAAAA CAAGATAGTT

CGGATAGAGA 180

AGGACACAGC AGAGGAAATT AACAACATGA AGACCAAGTT TAAAGAAACA

ATTGAGAAGT 240

GTGATAATCT AGAGCACAAA CTAAATGATC TCCTAAAAGA AAAGCAGTCT

GTGGAAAGAA 300

AGTGCACTCA GCTAAACACA AAAGTGGCCA AACTCACCAA CGAGCTCAAA

GAGGAGCAGG 360

AAATGAACAA GTGTTTGCGA GCCAACCAAG TCCTCCTGCA GAACAAGCTA

AAAGAGGAGG 420

AGAGGGTGCT GAAGGAGACC TGTGACCAAA AAGATCTGCA GATCACCGAG

ATCCAGGAGC 480

AGCTGCGTGA CGTCATGTTC TACCTGGAGA CACAGCAGAA GATCAACCAT

CTGCCTGCCG 540

AGACCCGGCA GGAAATCCAG GAGGGACAGA TCAACATCGC CATGGCCTCG

GCCTCGAGCC 600

CTGCCTCTTC GGGGGGCAGT GGGAAGTTGC CCTCCAGGAA GGGCCGCAGC

AAGAGGGGCA 660

AGTGACCTTC AGAGCAACAG ACATCCCTGA GACTGTTCTC CCTGACACTG

TGAGAGTGTG 720

CTGGGACCTT CAGCTAAATG TGAGGGTGGG CCCTAATAAG TACAAGTGAG

GATCAAGCCA 780

CAGTTGTTTG GCTCTTTCAT TTGCTAGTGT GTGATGTANT GAATGTAAAG

GGTGCTGACT 840

GGAGAGCTGA TAGAAAGGCG CTGCGTTCGA AAAGGTCTTA ANAGTTCACT

AACCTCACAT 900

TCTAATGACC ATTTTGCCTT CCTGCTTGGT AGAAGCCCCA ACTCTGCTGT

GCATTTTTCC 960

ATTGTATTTA TGGAGTTGGC GTATTTGACA TTCAGTTCTG GGGTAGGTTT

AAGATGTTAA 1020

GTTATTTCTT GTAACCTCAA AGGTAAGGTT ATCTAGCACT AAAGCACCAA

ACCTCTCTGA 1080

GGGCATAACA GCTGCTTTAA AGAGAGGTTT CCATTGGCTA TTAAGGAGTT

ATGAAAACTC 1140

CCTAGCAATA GTGTCATATC ATTATCATCT CCCCCTTCCT CTGGGGAGTG

GAAGAATTGC 1200

TTGAATGTTA TCTGAAAAGA GGCCTGGTAG TAAACCAGGC CCTGGCTCTT

TACCAGCAGT 1260

CATCTCTTCT TGCTCTGGGG CCAGCCAGGA AAAACAAACA ACCCGGGGCA CATTGGGTAG 1320

ACTCAGTGTA GGAAAAATGG TGGCAGCTCC ACTGTTTATT TTTGGTGACT

TCGTACGTCA 1380

TTATGAACCG CAATTAAGGA GGAGGCTTAA TGGCTGTTCC CAAACTCAAA

TCTCAGAGTG 1440

GGTATCCTAG CATCTAGCAA NACTGAGTGG GGAGATTTCT CATCCGTGTG

AAAATGTAGA 1500

GTGAGGCCTC TGACTAGCTN ATTGTGTATT TTGTTGGGTT TAGTATTTTC

TAAATGTTTA 1560

CAAAATATTG GGCTGCATGT TCAGGTTGCA GCTANAGGGA GCTTGGGCAN

ATTTTCAATT 1620

ACGCTTTCAA GATATAACCA AAAGCTGTTT CTAAATCCTA AAATTAGAAT

TTCAACAGAN 1680

CCCCCTTTAG AACAGTCATA TAACGCTTGT GTGGGCCAAC AGANGGGCTG

TGTACTCTCT 1740

CTGGAACCAT AAATGTCAAA TAATTTATAA CCTGCANTAA TTGAGCAACT TAAATAA

1797

(2) INFORMATION FOR SEQ ID NO: 14:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 720 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

( i) SEQUENCE DESCRIPTION: SEQ ID NO : 14 :

TAATCACCAT CTGTTTTTGT GGGATGTGCT GCAGCATTTC CCAAAAAACT

TNACGTGTAA 60

TGTTGCAAAA TGAATGTACT CAGACATTNT TAATTTTTAC TTAGGGCAGA

CCAACTCTTT 120

GAGTCTCTCT TGGACTTATA TATACAGATA TCTTAAGAGT GGGAATGTAA

AGCATAACCT 180

AATTNTCTTT CCTATAGAGA TTCTATTTTA TTTAAAATNT ATTTNTACAC

TAGTTAGAAT 240

CCTGCTGTTT TGGCCAAGTA CTTGTCTTGC ATGTCTGACC TTGCAGAAGC

TGGGGTGGAT 300

CATAGCATAC TAATGAAGAG AATTAGAAGT AGTTTACAAA GCTCGCTCAC

TCCTCATTTC 360

TCTGTGATCC CTTCTATCCA GTGGCCCCAC CACCACCTGG GAAAACAGAT

TTTTCAGTAC 420

AGGTGGGATA AATGCTCTGA AAGGCTGTGC CCAGAGGAAT GAGCAAATAG

GCAAGTGTTT 480

CCAAACTACT TGGAGGTTTA CAAAAAATAT GTCCCAGAAA AAAAAAAAAT CTTACCAAGA 540

TACGTAAAGA AAAAAAAATT TTTTTTTAAA CAGTCAAAGA GTCATGTTTG

AATTTCACAA 600

AATCACATCA GACAGAAGTT GTTTTCTTCA GGAGGGAAAT GAACCACTTA

ATATACCCAT 660

ACTACCTTGA ACAATGAAAT TGAATTAAAA TAGCCAAACT TTGAAAAAAA

AAAAAAAAAA 720

(2) INFORMATION FOR SEQ ID NO: 15:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1996 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 15 :

CAGAAGTGCA GCGGTGGCGG CGGCTGGTTG CGGGCCGGCG GCGGGCTGGC

GGAGATGGAG 60

GTAACTCAGG ATCTTGTTCA AGATGGGGTG GCTTCACCAG CTACCCCTGG

GACCGGGAAA 120

TCTAAGCTGG AAACATTGCC CAAAGAAGAC CTCATCAAGT TTGCCAAGAA

ACAGATGATG 180

CTAATACAGA AAGCTAAATC AAGGTGTACA GAATTGGAGA AAGAAATTGA

AGAACTCAGA 240

TCAAAACCTG TTACTGAAGG AACTGGTGAT ATTATTAAGG CATTAACTGA

ACGTCTGGAT 300

GCTCTTCTTC TGGAAAAAGC AGAGACTGAG CAACAGTGTC TTTCTCTGAA

AAAGGAAAAT 360

ATAAAAATGA AGCAAGAGGT TGAGGATTCT GTAACAAAGA TGGGAGATGC

ACATAAGGAG 420

TTGGAACAAT CACATATAAA CTATGTGAAA GAAATTGAAA ATTTGAAAAA

TGAGTTGATG 480

GCAGTACGTT CCAAATACAG TGAAGACAAA GCTAACTTAC AAAAGCAGCT

GGAAGAACAA 540

TGAATACGCA ATTAGAACTT TCAGAACAAC TTAAATTTCA GAACAACTCT

GAAGATAATG 600

TTAAAAAACT ACAAGAAGAG ATTGAGAAAA TTAGGCCAGG CTTTGAGGAG

CAAATTTTAT 660

ATCTGCAAAA GCAATTAGAC GCTACCACTG ATGAAAAGAA GGAAACAGTT

ACTCAACTCC 720

AAAATATCAT TGAGGCTAAT TCTCAGCATT ACCAAAAAAA TATTAATAGT

TTGCAGGAAG 780

AGCTTTTACA GTTGAAAGCT ATACACCAAG AAGAGGTGAA AGAGTTGATG TGCCAGATTG 840

AAGCATCAGC TAAGGAACAT GAAGCAGAGA TAAATAAGTT GAACGAGCTA

AAAGAGAACT 900

TAGTAAAACA ATGTGAGGCA AGTGAAAAGA ACATCCAGAA GAAATATGAA

TGTGAGTTAG 960

AAAATTTAAG GAAAGCCACC TCAAATGCAA ACCAAGACAA TCAGATATGT

TCTATTCTCT 1020

TGCAAGAAAA TACATTTGTA GAACAAGTAG TAAATGAAAA AGTCAAACAC

TTAGAAGATA 1080

CCTTAAAAGA ACTTGAATCT CAACACAGTA TCTTAAAAGA TGAGGTAACT

TATATGAATA 1140

ATCTTAAGTT AAAACTTGAA ATGGATGCTC AACATATAAA GGATGAGTTT

TTTCATGAAC 1200

GGGAAGACTT AGAGTTTAAA ATTAATGAAT TATTACTAGC TAAAGAAGAA

CAGGGCTGTG 1260

TAATTGAAAA ATTAAAATCT GAGCTAGCAG GTTTAAATAA ACAGTTTTGC

TATACTGTAG 1320

AACAGCATAA CAGAGAAGTA CAGAGTCTTA AGGAACAACA TCAAAAAGAA

ATATCAGAAC 1380

TAAATGAGAC ATTTTTGTCA GATTCAGAAA AAGAAAAATT AACATTAATG

TTTGAAATAC 1440

AGGGTCTTAA GGAACAGTGT GAAAACCTAC AGCAAGAAAA GCAAGAAGCA

ATTTTAAATT 1500

ATGAGAGTTT ACGAGAGATT ATGGAAATTT TACAAACAGA ACTGGGGGAA

TCTGCTGGAA 1560

AAATAAGTCA AGAGTTCGAA TCAATGAAGC AACAGCAAGC ATCTGATGTT

CATGAACTGC 1620

AGCAGAAGCT CAGAACTGCT TTTACTGAAA AAGATGCCCT TCTCGAAACT

GTGAATCGCC 1680

TCCAGGGAGA AAATGAAAAG TTACTATCTC AACAAGAATT GGTACCAGAA

CTTGAAAATA 1740

CCATAAAGAA CCTTCAAGAA AAGAATGGAG TATACTTACT TAGTCTCAGT

CAAAGAGATA 1800

CCATGTTAAA AGAATTAGAA GGAAAGATAA ATTCTCTTAC TGAGGAAAAA

GATGATTTTA 1860

TAAATAAACT GAAAAATTCC CATGAAGAAA TGGATAATTT CCATAAGAAA

TGTGAAAGGG 1920

AAGAAAGATT GATTCTTGAA CTTGGGAAGA AAGTAGAGCA AACTATCCAG

TACAACAGTG 1980

AACTAGAACA AAAGGT

1996

(2) INFORMATION FOR SEQ ID NO: 16:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3642 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16:

GTCCTGCTGA AGCTCACTCA GATTCCCTCA TTGATACCTT TCCTGAGTGT

AGTACGGAAG 60

GCTTCTCCAG TGACAGTGAT CTGGTATCTC TTACTGTTGA TGTGGATTCT

CTTGCTGAGT 120

TAGATGATGG AATGGCTTCC AATCAAAATT CTCCCATTAG AACTTTTGGT

CTCAATCTTT 180

CTTCGGATTC TTCAGCACTA GGGGCTGTTG CTTCTGACAG TGAACAGAGC

AAAACAGAAG 240

AAGAACGGGA AAGTCGTAGC CTCTTTCCTG GCAGTTTAAA GCCGAAGCTT

GGCAAGAGAG 300

ATTATTTGGA GAAAGCAGGA GAATTAATAA AGCTGGCTTT AAAAAAGGAA

GAAGAAGACG 360

ACTATGAAGC TGCTTCTGAT TTTTATAGGA AGGGAGTTGA TTTACTCCTA

GAAGGTGTTC 420

AAGGAGAGTC AAGCCCTACC CGTCGAGAAG CTGTGAAGAG AAGAACAGCC

GAGTACCTCA 480

TGCGGGCAGA AAGTATCTCT AGTCTTTATG GGAAACCTCA GCTTGATGAT

GTATCTCAGC 540

CTCCAGGATC ACTAAGTTCA AGGCCCCTTT GGAACCTAAG GAGCCCTGCC

GAGGAGCTGA 600

AGGCCTTCAG AGTCCTTGGG GTGATTGACA AGGTTTTACT TGTAATGGAC

ACAAGGACAG 660

AACACACTTT CATTTTAANA GGTCTAAGGA AAAGCAGTGA ATACAGCAGG

AACAGAAAGA 720

CCATCCNCCC CCGCTGTGTG CCCANCATGG TGTGTCTGCA TAAGTACATC

ATCTCTGAAG 780

AGTCANTATT TCTTGTGCTG CAGCATGCGG AANGTGGCAA ACTGTGGTCA

TATATCAGTA 840

AATTTCTAAA CAGAAGTCCT GAAGAAAGCT TTGACATCAA GGAAGTGAAA

AAACCTACAC 900

TTGCAAAAGT TCACCTGCAG CAGCCAACTT CTAGTCCTCA GGACAGCAGT

AGCTTTGAAT 960

CCAGAGGAAG TGATGGTGGA AGCATGCTTA AAGCTCTGCC TTTGAAGAGT

AGTCTTACTC 1020

CAAGTTCTCA AGATGACAGC AACCAGGAAG ATGATGGCCA AGATAGCTCT

CCAAAGTGGC 1080

CAGATTCTGG TTCAAGTTCA GAAGAAGAAT GTACTACTAG TTATTTAACA

TTATGCAATG 1140 AATATGGGCA AGAAAAGATT GAACCAGGGT CTTTGAATGA GGAGCCCTTC

ATGAAGACTG 1200

AAGGGAATGG TGTTGATACA AAAGCTATTA AAAGCTTCCC AGCACACCTT

GCTGCTGACA 1260

GTGACAGCCC CAGCACACAG CTGAGAGCTC ACGAGCTGAA GTTCTTCCCC

AACGATGACC 1320

CAGAAGCAGT TAGTTCTCCA AGAACATCAG ATTCCCTCAG TAGATCAAAA

AATAGCCCCA 1380

TGGAATTCTT TAGGATAGAC AGTAAGGATA GCGCAAGTGA ACTCCTGGGA

CTTGACTTTG 1440

GAGAAAAATT GTATAGTCTA AAATCAGAAC CTTTGAAACC ATTCTTTACT

CTTCCAGATG 1500

GAGACAGTGC TTCTAGGAGT TTTAATACTA GTGAAAGCAA GGTAGAGTTT

AAAGCTCAGG 1560

ACACCATTAG CAGGGGCTCA GATGACTCAG TGCCAGTTAT TTCATTTAAA

GATGCTGCTT 1620

TTGATGATGT CAGTGGTACT GATGAAGGAA GACCTGATCT TCTTGTAAAT

TTACCTGGTG 1680

AATTGGAGTC AACAAGAGAA GCTGCAGCAA TGGGACCTAC TAAGTTTACA

CAAACTAATA 1740

TAGGGATAAT AGAAAATAAA CTCTTGGAAG CCCCTGATGT TTTATGCCTC

AGGCTTAGTA 1800

CTGAACAATG CCAAGCACAT GAGGAGAAAG GCATAGAGGA ACTGAGTGAT

CCCTCTGGGC 1860

CCAAATCCTA TAGTATAACA GAGAAACACT ATGCACAGGA GGATCCCAGG

ATGTTATTTG 1920

TAGCANCTGT TGATCATAGT AGTTCAGGAG ATATGTCTTT GTTACCCAGC

TCAGATCCTA 1980

AGTTTCAAGG ACTTGGAGTG GTTGAGTCAN CAGTAACTGC AAACAACACA

GAAGAAAGCT 2040

TATTCCGTAT TTGTAGTCCA CTCTCAGGTG CTAATGAATA TATTGCAAGC

ACAGACACTT 2100

TAAAAACAGA AGAAGTATTG CTGTTTACAG ATCAGACTGA TGATTTGGCT

AAAGAGGAAC 2160

CAACTTCTTT ATTCCANAGA GACTCTGAGA CTAAGGGTGA AAGTGGTTTA

GTGCTAGAAG 2220

GAGACAAGGA AATACATCAG ATTTTTGAAG GACCTTGATA AAAAATTAGC

ACTANCCTCC 2280

AGGTTTTACA TCCCAGAGGG CTGCATTCAA AGNTGGGCAG CTGAAATGGT

GGTAGCCCTT 2340

NGATGCTTTA ACATAGAGAG GGAATTGTGT GCCGCGATTG AACCCAAACA

ANATNTTATT 2400

GAATGATAGA GGACACATTC AGNTAACGTA TTTTAGCAGG TGGAGTGAGG

TTGAAGATTC 2460

CTGTGACAGC GATGCCATAG AGAGAATGTA CTGTGCCCCA GAGGTTGGAG CAATCACTGA 2520

AGAAACTGAA GCCTGTGATT GGTGGAGTTT GGGTGCTGTC CTCTTTGAAC

TTNTCACTGG 2580

CAAGACTCTG GTTGAATGCC ATCCAGCAGG AATAAATACT CACACTACTT

TGAACATGCC 2640

AGAATGTGTC TCTGAAGAGG CTCGCTCACT CATTCAACAG CTCTTGCAGT

TCAATCCTCT 2700

GGAACGACTT GGTGCTGGAG TTGCTGGTGT TGAAGATATC AAATCTCATC

CATTTTTTAC 2760

CCCTGTGGAT TGGGCAGAAC TGATGAGATG AACGTAATGC AGGGTTATCT

TCACACATTC 2820

TGATCTTCTC TGTGACAGGC ATCTCCAGCA CTGAGGCACC TCTGACTCAC

AGTTACTTAT 2880

GGAGCACCAA AGCATTTGGA TAAGGACCGT TATAGGAAAT GGGGGGGAAA

TGGCTAAAAG 2940

AGAACAATTT GTTTACAATT ACAAGATATT AGCTAATTGT GCCAGGGGCT

GTTATATACA 3000

TATATACACA ACCAAGGTGT GATCTGAATT TAATCCACAT TTGGTGTTGC

AGATGAGTTG 3060

TAAAGCCAAC TGAAAGAGTT CCTTCAAGAA GTTCCTCTGA TAGGAAGCTA

GAAGTGTAGA 3120

ATGAAGTTTT ACTTGACAGA AGGACCTTTA CATGGCAGCT AACAGTGCTT

TTTGCTGACC 3180

AGGATTGGTT TATATGATTA AATTAATATT TGCTTAATAA TACACTAAAA

GTATATGAAC 3240

AATGTCATCA ATGAAACTTA AAAGCGAGAA AAAAGAATAT ACACATAATT

TCTGACGGAA 3300

AACCTGTACC CTGATGCTGT ATAATGTATG TTGAATGTGG TCCCAGATTA

TTTCTGTAAG 3360

AAGACACTCC ATGTTGTCAG CTTTGTACTC TTTGTTGATA CTGCTTATTT

AGAGAAGGGT 3420

TCATATAAAC ACTCACTCTG TGTCTTCAAC AGCATCTTTC TTTCCCCATC

TTTCTATTTT 3480

CTGCACCCTC TGCTTGTTCC CTCATATTCT GTTCTTCCGA CTCCTGCTAA

CACACATGCA 3540

ACAAAAAAGG GAAGGGAGTG CTTATTTCCC TTTGTGTAAG GACTAAGAAA

TCATGATATC 3600

AAATAAACAT GGTGAAACAT TNANAAAAAA AAAAAAAAAA AA

3642

(2) INFORMATION FOR SEQ ID NO: 17:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1397 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17:

GTTCAACTCA ATAGAAGATG ACGTTTGCCA GCTAGTGTAT GTGGAAAGAG

CTGAAGTGCT 60

CAAATCTGAA GATGGCGCCA GCCTCCCAGT GATGGACCTG ACTGAACTCC

CCAAGTGCAC 120

GGTGTGTCTG GAGCGCATGG ACGAGTCTGT GAATGGCATC CTCACAACGT

TATGTAACCA 180

CATCTTCCAC AGCCAGTGTC TACAGCGCTG GGACGATACC ACGTGTCCTG

TTTGCCGGTA 240

CTGTCAAACG CCCGAGCCAG TAGAAGAAAA TAAGTGTTTT GAGTGTGGTG

TTCAGGAAAA 300

TCTTTGGATT TGTTTAATAT GCGGCCACAT AGGATGTGGA CGGTATGTCA

GTCGACATGC 360

TTATAAGCAC TTTGAGGAAA CGCAGCACAC GTATGCCATG CAGCTTACCA

ACCATCGAGT 420

CTGGGACTAT GCTGGAGATA ACTATGTTCA TCGACTGGTT GCAAGTAAAA

CAGATGGAAA 480

AATAGTACAG TATGAATGTG AGGGGGATAC TTGCCAGGAA GAGAAAATAG

ATGCCTTACA 540

GTTAGAGTAT TCATATTTAC TAACAAGCCA GCTGGAATCT CAGCGAATCT

ACTGGGAAAA 600

CAAGATAGTT CGGATAGAGA AGGACACAGC AGAGGAAATT AACAACATGA

AGACCAAGTT 660

TAAAGAAACA ATTGAGAAGT GTGATAATCT AGAGCACAAA CTAAATGATC

TCCTAAAAGA 720

AAAGCAGTCT GTGGAAAGAA AGTGCACTCA GCTAAACACA AAAGTGGCCA

AACTCACCAA 780

CGAGCTCAAA GAGGAGCAGG AAATGAACAA GTGTTTGCGA GCCAACCAAG

TCCTCCTGCA 840

GAACAAGCTA AAAGAGGAGG AGAGGGTGCT GAAGGAGACC TGTGACCAAA

AAGATCTGCA 900

GATCACCGAG ATCCAGGAGC AGCTGCGTGA CGTCATGTTC TACCTGGAGA

CACAGCAGAA 960

AGATCAACCA TCTGCCTGCC GAGACCCGGC AGGAAATCCA GGAGGGACAG

ATCAACATCG 1020

CCATGGCCTC GGCCTCGAGC CCTGCCTCTT CGGGGGGCAG TGGGAAGTTG

CCCTCCAGGA 1080

AGGGCCGCAG CAAGAGGGGC AAGTGACCTT CAGAGCAACA GACATCCCTG

AGACTGTTCT 1140

CCCTGACACT GTGAGAGTGT GCTGGGACCT TCAGCTAAAT GTGAGGGTGG

GCCCTAATAA 1200 GTACAAGTGA GGATCAAGCC ACAGTTGTTT GGCTCTTTCA TTTGCTAGTG

TGTGATGTAG 1260

TGAATGTAAA GGGTGCTGAC TGGAGAGCTG ATAGAAAGGC GCTGCGTTCG

AAAAGGTCTT 1320

AAGAGTTCAC TAACCTCACA TTCTAATGAC CANTTTGCCT TCCTGCTTGG

TAGAAGCCCC 1380

ACACTCTGCT GTGCATT

1397

(2) INFORMATION FOR SEQ ID NO: 18:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 800 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18:

CGGTAATTGA GCANACTTAA AATAAGACCT GTGTTGGAAT TTAGTTTCCT

CTGAAGAGGT 60

AGAGGGATAG GTTAGTAAGA TGTATTGTTA AACAACAGGT TTTAGTTTTT

GCTTTTATAA 120

TTAGCCACAG GTTTTCAAAT GATCACATTT CAGAATAGGT TTTTAGCCTG

TAATTAGGCC 180

TCATCCCCTT TGACCTAAAT GTCTTACATG TTACTTGTTA GCACATCAAC

TGTATCACTA 240

ATCACCATCT GNTTTTGTGG GATGTGCTGC AGCATTTCCC AAAAAACTTT

ACGTGTAATG 300

TTGCAAAATG AATGTACTCA GACATTCTTA ATTTTTACTT AGGGCAGACC

AACTCTTTGA 360

GTCTCTCTTG GACTTATATA TACAGATATC TTAAGAGTGG GAATGTAAAG

CATAACCTAA 420

TTCTCTTTCC TATAGAGATT CTATTTTATT TAAAATCTAT TTTTACACTA

GTTAGAATCC 480

TGCTGTTTTG GCCAAGTACT TGTCTTGCAT GTCTGACCTT GCAGAAGCTG

GGGTGGATCA 540

TAGCATACTA ATGAAGAGAA TTAGAAGTAG TTTACAAAGC TCGCTCACTC

CTCATTTCTC 600

TGTGATCCCT TCTATCCAGT GGCCCCACCA CCACCTGGGA AAACAGATTT

TTCAGTACAG 660

GTGGGATAAA TGCTCTGAAA GGCTGTGCCC AGAGGAATGA GCAAATAGGC

AAGTGTTTCC 720

AAACTACTTG GAGGTTTACA AAAAATATGT CCCAGAAAAA AAAAAAATCT

TACCAAGATA 780 CGTAAAAAAA AAAAAAAAAA 800

(2) INFORMATION FOR SEQ ID NO: 19:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1810 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19:

GCAGCTCCCA GGTGCGTGTT AAAAGCTGGA GGGGGGATAT GTGATCCCAG

GACCAAAAGC 60

GCGGGGCCAG ACTCATCGGT TCATTCAACA ACCAGTATTT AGTGCCTGCT

GTGTTCTGCA 120

GGCCCTGCCA TAGGCGCTTG ATACAGCGGT GCATAGCGTA TGAAAAAGAT

CTGTCCTGGC 180

TGAGCATCCG TAATATAAAA ATCTGAAATC TGAAATGCTC CAAAATCCTA

AACTTTTTGA 240

GTGCTGACAT TATGCCACAA ATGGAAAATT TCATACCTGA CCTTATGTGG

GTTGCANTCA 300

AAACACAGGT GCACAACACC CAGTTCATGC AACATCCCCA ATGGGAAAAA

AGACCCCCCC 360

AGCTCTCTTC TGCTGCAGTT TTTCTGCTCA CACCTGGATT TCCCCATGCA

TTCCCACAAA 420

AAGTAATTAA ATGGCATGCG TGCAGGCTGG ACACGCCAAC AACAGGTTTC

CCACAATGCC 480

CCACATGGGG CCAAGACCTG TGTGCATTAC TCATTGCATT TTTTTGCTTA

TTCTCTGCTG 540

TGTGGTATAA ATATATTGTT GAAAATGTCA AAAAGACCTA AAGATACCCC

TGTGAATATC 600

AGTGATAAGA AAAAGAGGAA GCATTTATGT TTATCTATAG CACAGAAAGT

CAAGTTGTTG 660

GAGAAACTGG ACAGTGGTGT AAGTGTGAAA CATCTTACAG AAGAGTATGG

TGTTGGAATG 720

ACCACCATAT ATGACCTGAA GAAACAGAAG GATAAACTGT TGAAGTTTTA

TGCTGAAAGT 780

GATGAGCAGA TATTAATGAA AAATAGAAAA ACACTTCATA AAGCTAAAAA

TGAAGATCTT 840

GATCGTGTAT TGAAAGAGTG GATCCGTCAG CGTCGCAGTG AACACATGCC

ACTTAATGGT 900

ATGCTGATCA TGAAACAAGC AAAGATATAT CACAATGAAC TAAAAATTGA

GGGGAACTGT 960 GAATATTCAA CAGGCTGGTT GCAGAAATTT AAGAAAAGAC ATGGCATTAA

ATTTTTAAAG 1020

ACTTGTGGCA ATAAAGCATC TGCTGGTCAT GAAGCAACAG AGAAGTTTAC

TGGCAATTTC 1080

AGTAATGATG ATGAACAAGA TGGTAACTTT GAAGGATTCA NTATGTCAAG

TGAGAAAAAA 1140

ATAATGTCTG ACCTCCTTAC ATATACAAAA AATATACATC CAGAGACTGT

CAGTAAGCTG 1200

GAAGAAGAGG ATATCTTTNA TGTTTTTAAC AGTAATAATG AGGCTCCAGT

TGTTCATTCA 1260

TTGTCCAATG GTGAAGTAAC AAAAATGGTT CTGAATCAAG ATGATCATGA

TGATAATGAT 1320

AATGAAGATG ATGTTAACAC TGCAGAAAAA GTGCCTATAG ACGACATGGT

AAAAATGTGT 1380

GATGGGCTTA TTAAAGGACT AGAGCAGCAT GCATTCATAA CAGAGCAAGA

AATCATGTCA 1440

GTTTATAAAA TCAAAGAGAG ACTTCTAAGA CAAAAAGCAT CATTAATGAG

GCAGATGACT 1500

CTGAAAGAAA CATTTAAAAA AGCCATCCAG AGGAATGCTT CTTCCTCTCT

ACAGGACCCA 1560

CTTCTTGGTC CCTCAACTGC TTCTGATGCT TCTTCTCACC TAAAAATAAA

ATAAAATACA 1620

GTGTACAGTA ACCTTTTAGT CAAAACAGCA TCATACTTGG AAACTGAAAG

CCTACTGTTA 1680

TTTGTTATTG TTGCTTAACA GCTGATACAG GTATTCTGGT GACACTACTG

TGCTGGCTTA 1740

CTTAACCTGA ATACACTATT TTTTTCGTTG TAAAAAAAAA AAAAAAANAA

NAAAAAAAAA 1800

AAAAAANANA

1810

(2) INFORMATION FOR SEQ ID NO: 20:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 70 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20:

Ala Arg Glu Gly Gly Lys Met Val Leu Glu Ser Thr Met Val Cys Val

1 5 10

15 Asp Asn Ser Glu Tyr Met Arg Asn Gly Asp Phe Leu Pro Thr Arg Leu

20 25 30

Gin Ala Gin Gin Asp Ala Val Asn He Xaa Cys His Ser Lys Thr Arg

35 40 45

Ser Asn Pro Glu Asn Asn Val Gly Leu He Thr Leu Ala Asn Asp Cys

50 55 60

Glu Val Leu Thr Thr Leu 65 70

(2) INFORMATION FOR SEQ ID NO: 21:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 100 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21:

Ala Arg Glu Ser Thr Met Val Cys Val Asp Asn Ser Glu Tyr Met Arg

1 5 10

15

Asn Gly Asp Phe Leu Pro Thr Arg Leu Gin Ala Gin Gin Asp Ala Val

20 25 30

Asn He Val Cys His Ser Lys Thr Arg Ser Asn Pro Glu Asn Asn Val

35 40 45

Gly Leu He Thr Leu Ala Asn Asp Cys Glu Val Leu Thr Thr Leu Thr

50 55 60

Pro Asp Thr Gly Arg He Leu Ser Lys Leu His Thr Val Gin Pro Lys

65 70 75

80

Gly Lys He Thr Phe Cys Thr Gly He Arg Val Ala His Leu Ala Leu

85 90

95

Lys His Arg Gin 100 (2) INFORMATION FOR SEQ ID NO: 22:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 214 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22:

CGGCACGAGA AGGTGGCAAG ATGGTGTTGG AAAGCACTAT GGTGTGTGTG

GACAACAGTG 60

AGTATATGCG GAATGGAGAC TTCTTACCCA CCAGGCTGCA GGCCCAGCAG

GATGCTGTCA 120

ACATANTTTG TCATTCAAAG ACCCGCAGCA ACCCTGAGAA CAACGTGGGC

CTTATCACAC 180

TGGCTAATGA CTGTGAAGTG CTGACCACAC TCAC

214

(2) INFORMATION FOR SEQ ID NO: 23:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 375 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23:

TATGGACACA TTTGAGCCAG CCAAGGAGGA GGATGATTAC GACGTGATGC

AGGACCCCGA 60

GTTCCTTCAG AGTGTCCTAG AGAACCTCCC AGGTGTGGAT CCCAACAATG

AAGCCATTCG 120

AAATGNTATG GGCTCCCTGG CCTCCCAGGC CACCAAGGAC GGCAAGAAGG

ACAAGAAGGA 180

GGAAGACAAG AAGTGAGACT GGAGGGAAAG GGTAGCTGAG TCTGCTTAGG

GGACTGCATG 240

GGAAGCACGG AATATAGGGT TAGATGTGTG TTATCTGTAA CCATTACAGC

CTAAATAAAG 300

CTTGGCAACT TTTTAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA

AAAAAAAAAA 360

AAAAAAAAAC TCGAG

375 (2) INFORMATION FOR SEQ ID NO: 24:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 304 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24:

CGGCACGAGA AAGCACTATG GTGTGTGTGG ACAACAGTGA GTATATGCGG

AATGGAGACT 60

TCTTACCCAC CAGGCTGCAG GCCCAGCAGG ATGCTGTCAA CATAGTTTGT

CATTCAAAGA 120

CCCGCAGCAA CCCTGAGAAC AACGTGGGCC TTATCACACT GGCTAATGAC

TGTGAAGTGC 180

TGACCACACT CACCCCAGAC ACTGGCCGTA TCCTGTCCAA GCTACATACT

GTCCAACCCA 240

AGGGCAAGAT CACCTTCTGC ACGGGCATCC GCGTTGCCCA TCTGGCTCTG

AAGCACCGAC 300

AAGG

304

(2) INFORMATION FOR SEQ ID NO: 25:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 25:

Val Arg Gly Gly Gly Gly Gly Gly Pro Gly Gly Gly Gly Val Gly Gly

1 5 10

15

Arg Cys Gly Gly Gly Gly 20

(2) INFORMATION FOR SEQ ID NO: 26:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 78 amino acids

(B) TYPE: amino acid ( C) STRANDEDNESS :

(D) TOPOLOGY : linear

(xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 26 :

Ala Arg Ala Ala Arg Ala Lys Ala Gin Ala Leu He Gin Asn Leu Ser

1 5 10

15

Leu Leu Leu Val Asp Ala Ser Val Gly Thr He Gin Cys Leu Glu Glu

20 25 30

He Leu Cys Glu Phe Val Gin Lys Asp Glu Leu Lys Pro Ala Val Thr

35 40 45

Xaa Leu Leu Trp Glu Arg Ala Thr Glu Lys Val Ala Cys Cys Pro Leu

50 55 60

Glu Arg Cys Ser Ser Val Met Leu Leu Gly Met Met Ala Arg

65 70 75

(2) INFORMATION FOR SEQ ID NO: 27:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 384 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27:

Lys Met Val Leu Glu Ser Thr Met Val Cys Val Asp Asn Ser Glu Tyr

1 5 10

15

Met Arg Asn Gly Asp Phe Leu Pro Thr Arg Leu Gin Ala Gin Gin Asp

20 25 30

Ala Val Asn He Val Cys His Ser Lys Thr Arg Ser Asn Pro Glu Asn

35 40 45

Asn Val Gly Leu He Thr Leu Ala Asn Asp Cys Glu Val Leu Thr Thr

50 55 60

Leu Thr Pro Asp Thr Gly Arg He Leu Ser Lys Leu His Thr Val Gin

65 70 75

80

Pro Lys Gly Lys He Thr Phe Cys Thr Gly He Arg Val Ala His Leu

85 90

95

Ala Leu Lys His Arg Gin Gly Lys Asn His Lys Met Arg He He Ala

100 105 110

Phe Val Gly Ser Pro Val Glu Asp Asn Glu Lys Asp Leu Val Lys Leu

115 120 125

Ala Lys Arg Leu Lys Lys Glu Lys Val Asn Val Asp He He Asn Phe

130 135 140

Gly Glu Glu Glu Val Asn Thr Glu Lys Leu Thr Ala Phe Val Asn Thr

145 150 155

160

Leu Asn Gly Lys Asp Gly Thr Gly Ser His Leu Val Thr Val Pro Pro

165 170

175

Gly Pro Ser Leu Ala Asp Ala Leu He Ser Ser Pro He Leu Ala Gly

180 185 190

Glu Gly Gly Ala Met Leu Gly Leu Gly Ala Ser Asp Phe Glu Phe Gly

195 200 205

Val Asp Pro Ser Ala Asp Pro Glu Leu Ala Leu Ala Leu Arg Val Ser

210 215 220

Met Glu Glu Gin Arg Gin Arg Gin Glu Glu Glu Ala Arg Arg Ala Ala

225 230 235

240

Ala Ala Ser Ala Ala Glu Ala Gly He Ala Thr Thr Gly Thr Glu Asp

245 250

255

Ser Asp Asp Ala Leu Leu Lys Met Thr He Ser Gin Gin Glu Phe Gly

260 265 270

Arg Thr Gly Leu Pro Asp Leu Ser Ser Met Thr Glu Glu Glu Gin He

275 280 285

Ala Tyr Ala Met Gin Met Ser Leu Gin Gly Ala Glu Phe Gly Gin Ala

290 295 300

Glu Ser Ala Asp He Asp Ala Ser Ser Ala Met Asp Thr Ser Glu Pro

305 310 315

320

Ala Lys Glu Glu Asp Asp Tyr Asp Val Met Gin Asp Pro Glu Phe Leu

325 330

335

Gin Ser Val Leu Glu Asn Leu Pro Gly Val Asp Pro Asn Asn Glu Ala

340 345 350

He Arg Asn Ala Met Gly Ser Leu Pro Pro Arg Pro Pro Arg Thr Ala

355 360 365

Arg Arg Thr Arg Arg Arg Lys Thr Arg Ser Glu Thr Gly Gly Lys Gly

370 375 380

(2) INFORMATION FOR SEQ ID NO: 28:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 68 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 28 :

Ala Arg Asp Ala Tyr Ser Phe Ser Arg Lys He Thr Glu Ala He Gly

1 5 10

15

He He Ser Lys Met Met Tyr Glu Asn Thr Thr Thr Val Val Gin Glu

20 25 30

Val He Glu Phe Phe Val Met Val Phe Gin Phe Gly Val Pro Gin Ala

35 40 45

Leu Phe Gly Val Arg Arg Met Leu Pro Leu He Trp Ser Lys Glu Pro 50 55 60

Gly Val Arg Glu 65

(2) INFORMATION FOR SEQ ID NO: 29:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 97 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 29:

Ala Arg Ala Gin Ala Leu Phe Gly Val Arg Arg Met Leu Pro Leu He

1 5 10

15

Trp Ser Lys Glu Pro Gly Val Arg Glu Ala Val Leu Asn Ala Tyr Arg

20 25 30

Gin Leu Tyr Leu Asn Pro Lys Gly Asp Ser Ala Arg Ala Lys Ala Gin

35 40 45

Ala Leu He Gin Asn Leu Ser Leu Leu Leu Val Asp Ala Ser Val Gly

50 55 60

Thr He Gin Cys Leu Glu Glu He Leu Cys Glu Phe Val Gin Lys Asp

65 70 75

80

Glu Leu Lys Pro Ala Val Thr Gin Leu Leu Trp Glu Pro Ala Thr Glu

85 90

95

Lys

(2) INFORMATION FOR SEQ ID NO: 30:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 116 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear ( i ) SEQUENCE DESCRIPTION : SEQ ID NO : 30 :

Ala Arg Ala Thr Thr Ala Phe Gly Cys Arg He Trp Asn Pro Cys Ala

1 5 10

15

Ala Leu Thr Met Lys Gin Ser Ser Asn Val Pro Ala Phe Leu Ser Lys

20 25 30

Leu Trp Thr Leu Val Glu Glu Thr His Thr Asn Glu Phe He Thr Trp

35 40 45

Ser Gin Asn Gly Gin Ser Phe Leu Val Leu Asp Glu Gin Arg Phe Ala

50 55 60

Lys Glu He Leu Pro Lys Tyr Phe Lys His Asn Asn Met Ala Ser Phe

65 70 75

80

Val Arg Gin Leu Asn Met Tyr Gly Phe Arg Lys Val He His He Asp

85 90

95

Ser Gly He Val Lys Gin Glu Arg Asp Gly Pro Val Glu Phe Gin His

100 105 110

Pro Tyr Phe Gin 115

(2) INFORMATION FOR SEQ ID NO: 31:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 124 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31:

Ala Arg Gly Ala Thr Cys Glu Arg Cys Lys Gly Gly Phe Ala Pro Ala

1 5 10

15

Glu Lys He Val Asn Ser Asn Gly Glu Leu Tyr His Glu Gin Cys Phe 20 25 30

Val Cys Ala Gin Cys Phe Gin Gin Phe Pro Glu Gly Leu Phe Tyr Glu

35 40 45

Phe Glu Gly Arg Lys Tyr Cys Glu His Asp Phe Gin Met Leu Phe Ala

50 55 60

Pro Cys Cys His Gin Cys Gly Glu Phe He He Gly Arg Val He Lys

65 70 75

80

Ala Met Asn Asn Ser Trp His Pro Glu Cys Phe Arg Cys Asp Leu Cys

85 90

95

Gin Glu Val Leu Ala Asp He Gly Phe Val Lys Asn Ala Gly Arg His

100 105 110

Leu Cys Arg Pro Cys His Asn Arg Glu Lys Ala Arg 115 120

(2) INFORMATION FOR SEQ ID NO:32:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 768 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32:

TACGAGGAGG AGGAGGAGGA GGCCCCGGAG GAGGAGGCGT TGGAGGTCGA

TGCGGAGGCG 60

GAGGATGAGG AGGCCGAGGC GCCGGAGGAG GCCGAGGCGC CGGAGCAGGA

GGAGGCCGGC 120

CGGAGGCGGC ATGAGACGAG CGTGGCGGCC GCGGCTGCTC GGGGCCGCGC

TGGTTGCCCA 180

TTGACAGCGG CGTCTGCAGC TCGCTTCAAG ATGGCCGCTT GGCTCGCATT

CATTTTCTGC 240

TGAACGACTT TTAACTTTCA TTGTCTTTTC CGCCCGCTTC GATCGCCTCG

CGCCGGCTGC 300

TCTTTCCGGG ATTTTTTATC AAGCAGAAAT GCATCGAACA ACGAGAATCA

AGATCACTGA 360

GCTAAATCCC CACCTGATGT GTGTGCTTTG TGGAGGGTAC TTCATTGATG

CCACAACCAT 420 AATAGAATGT CTACATTCCT TCTGTAAAAC GTGTATTGTT CGTTACCTGG

AGACCAGCAA 480

GTATTGTCCT ATTTGTGATG TCCAAGTTCA CAAGACCAGA CCACTACTGA

ATATAAGGTC 540

AGATAAAACT CTCCAAGATA TTGTATACAA ATTAGTTCCA GGGCTTTTCA

AAAATGAAAT 600

GAAGAGAAGA AGGGATTTTT ATGCAGCTCA TCCTTCTGCT GATGCTGCCA

ATGGCTCTAA 660

TGAAGATNGA GGAGAGGTTG CAGATGAAGA TAAGAGAATT ATAACTGATG

ATGAGATAAT 720

AAGCTTATCC ATTGAATTCT TTGACCAGAA CAGATTGGAT CGGAAAGT

768

(2) INFORMATION FOR SEQ ID NO: 33:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 642 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33:

TTTAAATAAA CCAGCAGGTT GCTAAAAGAA GGCATTTTAT CTAAAGTTAT

TTTAATAGGT 60

GGTATAGCAG TAATTTTAAA TTTAAGAGTT GCTTTTACAG TTAACAATGG

AATATGCCTT 120

CTCTGCTATG TCTGAAAATA GAAGNTATTT ATTATGAGCT TNTACAGGTA

TTTTTAAATA 180

GAGCAAGCAT GTTGAATTTA AAATATGAAT AACCCCACCC AACAATTTTC

AGTTTATTTT 240

TTGCTTTGGT CGAACTTGGT GTGTGTTCAT CACCCATCAG TTATTTGTGA

GGGTGTTTAT 300

TCTATATGAA TATTGTTTCA TGTTTGTATG GGAAAATTGT AGCTAAACAT

TTCATTGTCC 360

CCAGTCTGCA AAAGAAGCAC AATTCTATTG CTTTGTCTTG CTTATAGTCA

TTAAATCATT 420

ACTTTTACAT ATATTGCTGT TACTTCTGCT TTCTTTAAAA ATATAGTAAA

GGATGTTTTA 480

TGAAGTCACA AGATACATAT ATTTTTATTT TGACCTAAAT TTGTACAGTC

CCATTGTAAG 540

TGTTGTTTCT AATTATAGAT GTAAAATGAA ATTTCATTTG TAATTGGAAA

AAATCCAATA 600

AAAAGGATAT TCATTTAAAA AAAAAAAAAA AAAAAAAAAA AA

642 (2) INFORMATION FOR SEQ ID NO: 34:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 236 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34:

CGGCACGAGC TGCCAGAGCC AAGGCCCAGG CTTTGATTCA GAATCTCTCT

CTGCTGCTAG 60

TGGATGCCTC GGTTGGGACC ATTCAGTGTC TTGAGGAAAT TCTCTGTGAG

TTTGTGCAGA 120

AGGATGAGTT GAAACCAGCA GTGACCCANC TGCTGTGGGA GCGGGCCACC

GAGAAAGTCG 180

CCTGCTGTCC TCTGGAACGC TGTTCCTCTG TCATGCTTCT TGGCATGATG GCACGA

236

(2) INFORMATION FOR SEQ ID NO: 35:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 333 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35:

CCGGGCGTAT TGGCGTGCGC CTGTAATCCC AGCTAACTCA AGAGGCTGAG

GCAGGAGAAT 60

CGCCTGAACC CAGAGGCGGA GGTTGTAGTG AGCCGAAATC ACACCATTGC

ACTCCAGCTT 120

GGGCAACAAT AGCGAACCTC CATCTCAAAT TAAAAAAAAA AATGCCTACA

CGCTCTTTAA 180

AATGCAAGGC TTTCTCTTAA ATTAGCCTAA CTGAACTGCG TTGAGCTGCT

TCAACTTTGG 240

AATATATGTT TGCCAATCTC CTTGTTTTCT AATGAATAAA TGTTTTTATA

TACTTTTAGA 300

AAAAAAAAAA AAAAAAAAAA AAAAAAACTC GAG

333

(2) INFORMATION FOR SEQ ID NO: 36: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1272 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36:

GCAAGATGGT GTTGGAAAGC ACTATGGTGT GTGTGGACAA CAGTGAGTAT

ATGCGGAATG 60

GAGACTTCTT ACCCACCAGG CTGCAGGCCC AGCAGGATGC TGTCAACATA

GTTTGTCATT 120

CAAAGACCCG CAGCAACCCT GAGAACAACG TGGGCCTTAT CACACTGGCT

AATGACTGTG 180

AAGTGCTGAC CACACTCACC CCAGACACTG GCCGTATCCT GTCCAAGCTA

CATACTGTCC 240

AACCCAAGGG CAAGATCACC TTCTGCACGG GCATCCGCGT GGCCCATCTG

GCTCTGAAGC 300

ACCGACAAGG CAAGAATCAC AAGATGCGCA TCATTGCCTT TGTGGGAAGC

CCAGTGGAGG 360

ACAATGAGAA GGATCTGGTG AAACTGGCTA AACGCCTCAA GAAGGAGAAA

GTAAATGTTG 420

ACATTATCAA TTTTGGGGAA GAGGAGGTGA ACACAGAAAA GCTGACAGCC

TTTGTAAACA 480

CGTTGAATGG CAAAGATGGA ACCGGTTCTC ATCTGGTGAC AGTGCCTCCT

GGGCCCAGTT 540

TGGCTGATGC TCTCATCAGT TCTCCGATTT TGGCTGGTGA AGGTGGTGCC

ATGCTGGGTC 600

TTGGTGCCAG TGACTTTGAA TTTGGAGTAG ATCCCAGTGC TGATCCTGAG

CTGGCCTTGG 660

CCCTTCGTGT ATCTATGGAA GAGCAGCGGC AGCGGCAGGA GGAGGAGGCC

CGGCGGGCAG 720

CTGCAGCTTC TGCTGCTGAG GCCGGGATTG CTACGACTGG GACTGAAGAC

TCAGACGATG 780

CCCTGCTGAA GATGACCATC AGCCAGCAAG AGTTTGGCCG CACTGGGCTT

CCTGACCTAA 840

GCAGTATGAC TGAGGAAGAG CAGATTGCTT ATGCCATGCA GATGTCCCTG

CAGGGAGCAG 900

AGTTTGGCCA GGCGGAATCA GCAGACATTG ATGCCAGCTC AGCTATGGAC

ACATCTGAGC 960

CAGCCAAGGA GGAGGATGAT TACGACGTGA TGCAGGACCC CGAGTTCCTT

CAGAGTGTCC 1020

TAGAGAACCT CCCAGGTGTG GATCCCAACA ATGAAGCCAT TCGAAATGCT

ATGGGCTCCC 1080

TGCCTCCCAG GCCACCAAGG ACGGCAAGAA GGACAAGAAG GAGGAAGACA AGAAGTGAGA 1140

CTGGAGGGAA AGGGTAGCTG AGTCTGCTTA GGGGACTGCA TGGGAAGCAC

GGAATATAGG 1200

GTTAGATGTG TGTTATCTGT AACCATTACA GCCTAAATAA AGCTTGGCAA

CTTTTAAAAA 1260

AAAAAAAAAA AA

1272

(2) INFORMATION FOR SEQ ID NO: 37:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 206 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37:

CGGCACGAGA TGCCTACAGC TTCTCCCGGA AGATTACAGA GGCCATTGGC

ATCATCAGCA 60

AGATGATGTA TGAAAACACA ACTACAGTGG TGCAGGAGGT GATTGAATTC

TTTGTGATGG 120

TCTTCCAATT TGGGGTACCC CAGGCCCTGT TTGGGGTGCG CCGTATGCTG

CCTCTCATCT 180

GGTCTAAGGA GCCTGGTGTC CGGGAA

206

(2) INFORMATION FOR SEQ ID NO: 38:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 341 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38:

TACTAAAAAT AAAAAATTAG CCGGGCGTAT TGGCGTGCGC CTGTAATCCC

AGCTACTCAA 60

GAGGCTGAGG CAGGAGAATC GCCTGAACCC AGAGGCGGAG GTTGTAGTGA

GCCGAAATCA 120

CACCATTGCA CTCCAGCTTG GGCAACAATA GCGAACCTCC ATCTCAAATT

AAAAAAAAAA 180

TGCCTACACG CTCTTTAAAA TGCAAGGCTT TCTCTTAAAT TAGCCTAACT

GAACTGCGTT 240 GAGCTGCTTC AACTTTGGAA TATATGTTTG CCAATCTCCT TGTTTTCTAA

TGAATAAATG 300

TTTTTATATA CTTTTAANGA GAGAAAAAAA ANAAACTCGA G

341

(2) INFORMATION FOR SEQ ID NO: 39:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 293 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39:

CGGCACGAGC CCAGGCCCTG TTTGGGGTGC GCCGTATGCT GCCTCTCATC

TGGTCTAAGG 60

AGCCTGGTGT CCGGGAAGCC GTGCTTAATG CCTACCGCCA ACTCTACCTC

AACCCCAAAG 120

GGGACTCTGC CAGAGCCAAG GCCCAGGCTT TGATTCAGAA TCTCTCTCTG

CTGCTAGTGG 180

ATGCCTCGGT TGGGACCATT CAGTGTCTTG AGGAAATTCT CTGTGAGTTT

GTGCAGAAGG 240

ATGAGTTGAA ACCAGCAGTG ACCCAGCTGC TGTGGGAACC GGCCACCGAG AAA

293

(2) INFORMATION FOR SEQ ID NO: 40:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 350 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 40:

CGGCACGAGC TACCACCGCG TTCGGGTGTA GAATTTGGAA TCCCTGCGCC

GCGTTAACAA 60

TGAAGCAGAG TTCGAACGTG CCGGCTTTCC TCAGCAAGCT GTGGACGCTT

GTGGAGGAAA 120

CCCACACTAA CGAGTTCATC ACCTGGAGCC AGAATGGCCA AAGTTTTCTG

GTCTTGGATG 180

AGCAACGATT TGCAAAAGAA ATTCTTCCCA AATATTTCAA GCACAATAAT

ATGGCAAGCT 240

TTGTGAGGCA ACTGAATATG TATGGTTTCC GTAAAGTAAT ACATATCGAC TCTGGAATTG 300

TTAAGCAAGA AAGAGATGGT CCTGTAGAAT TTCAGCATCC TTACTTCCAA

350

(2) INFORMATION FOR SEQ ID NO: 41:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 377 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41:

TCCTAAAGCT TTCTCTGCTC CAGTTATTTT TATTAAATAT TTTTCACTTG

GCTTATTTTT 60

AAAACTGGGA ACATAAAGTG CCTGTATCTT GTAAAACTTC ATTTGTTTCT

TTTGGTTCAG 120

AGAAGTTCAT TTATGTTCAA AGACGTTTAT TCATGTTCAA CAGGAAAGAC

AAAGTGTACG 180

TGAATGCTCG CTGTCTGATA GGGTTCCAGC TCCATATATA TAGAAAGATC

GGGGGTGGGA 240

TGGGATGGAG TGAGCCCCAT CCAGTTAGTT GGACTAGTTT TAAATAAAGG

TTTTCCGGTT 300

TGTGTTTTTT TGAACCATAC TGTTTAGTAA AATAAATACA ATGAATGTTG

NAAAAAAAAA 360

AAAAAAAAAA ACTCGAG

377

(2) INFORMATION FOR SEQ ID NO: 42:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 374 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42:

CGGCACGAGG CGCCACTTGC GAGCGCTGCA AGGGCGGCTT TGCGCCCGCT

GAGAAGATCG 60

TGAACAGTAA TGGGGAGCTG TACCATGAGC AGTGTTTCGT GTGCGCTCAG

TGCTTCCAGC 120

AGTTCCCAGA AGGACTCTTC TATGAGTTTG AAGGAAGAAA GTACTGTGAA

CATGACTTTC 180 AGATGCTCTT TGCCCCTTGC TGTCATCAGT GTGGTGAATT CATCATTGGC

CGAGTTATCA 240

AAGCCATGAA TAACAGCTGG CATCCGGAGT GCTTCCGCTG TGACCTCTGC

CAGGAAGTTC 300

TGGCAGATAT CGGGTTTGTC AAGAATGCTG GGAGACACCT GTGTCGCCCC

TGTCATAATC 360

GTGAGAAAGC CAGA

374

(2) INFORMATION FOR SEQ ID NO: 43:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 492 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43:

CTTTGCATTT TACAGTAAGA ATCAAAGTCC CTTCAGTGTG CCTTTGTCAG

CTAATATGTG 60

ACCAGCAATG ACAACCTTGG GAGTATTTAT TAAATATTAT GCTATGAATA

TAGGCAACAC 120

AGAACAGGGT TTGCAGTATA GCGTCTTGAT GCTAAATTCT CATATACCTC

TACACGAGAA 180

ATATGGAGGA GAAAAACAAG CATTTACATA TATTCTTCGT CACTTTGAAG

ATGCATGACC 240

TGAACTCGAC TGCTTGTGTT TGTTTACATA TCAGGCATAC CCAGGCATCT

CCTGCAGCCA 300

GAGGTTCCAT TGCTGTCTTT GCTCAGTCCT CTTTTAAAAT ATGAATTAGT

GGACAGGCAC 360

GGTGCCTCAC ACCTGTAATC CCAGCACTTT GGGAGGTCGA GGCAGGTGGA

TCACGAGGTC 420

AGGAGATCAA GACCATCCTG GCTACCACTG AAACCCCATC TCTACTACAA

AAAAAAAAAA 480

AAAAAACTCG AG

492

(2) INFORMATION FOR SEQ ID NO: 44:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 44 :

Ser Gin He Cys Glu Leu Val Ala His Glu Thr He Ser Phe Leu

1 5 10

15

(2) INFORMATION FOR SEQ ID NO: 45:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45:

Xaa Xaa Xaa Xaa Xaa Ser He Leu Asp Glu Val He Arg Gly Thr

1 5 10

15

(2) INFORMATION FOR SEQ ID NO: 46:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46:

Val Val Lys Thr Tyr Leu He Ser Ser He Pro Gin Gly Ala Phe Asn

1 5 10

15

Tyr Lys Tyr Thr Ala 20

(2) INFORMATION FOR SEQ ID NO: 47:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47:

Val Val Lys Thr Tyr Leu He Ser Ser He Pro Leu Gin Ala Phe Asn

1 5 10

15

Tyr Lys Tyr Thr Ala 20

(2) INFORMATION FOR SEQ ID NO: 48:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48:

Xaa Ala Lys Lys Phe Leu Asp Ala Glu His Lys Leu Asn Phe Ala

1 5 10

15

(2) INFORMATION FOR SEQ ID NO: 49:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 49 :

Xaa Xaa Xaa Lys He Lys Lys Phe He Gin Glu Asn He Phe Gly

1 5 10

15

(2) INFORMATION FOR SEQ ID NO: 50:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50:

Xaa Lys Val Lys Val Gly Val Asn Gly Phe Gly Arg He Gly Arg Leu

1 5 10

15

Val Thr

(2) INFORMATION FOR SEQ ID NO: 51:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51:

Xaa Tyr Gin Tyr Pro Ala Leu Thr Xaa Glu Gin Lys Lys Glu Leu

1 5 10

15

(2) INFORMATION FOR SEQ ID NO:52:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 14 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52:

Xaa Pro Ala Val Tyr Phe Lys Xaa Xaa Phe Leu Asp Xaa Asp 1 5 10

(2) INFORMATION FOR SEQ ID NO:53: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 53:

Xaa Pro Ala Val Tyr Phe Lys Glu Gin Phe Leu Asp Gly Asp Gly

1 5 10

15

(2) INFORMATION FOR SEQ ID NO: 54:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 18 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 54:

Xaa Xaa Val Ala Val Leu Xaa Ala Ser Xaa Xaa He Gly Gin Pro Leu

1 5 10

15

Ser Leu

(2) INFORMATION FOR SEQ ID NO: 55:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 55 :

Val Val Lys Thr Tyr Leu He Ser Xaa He Pro Leu Gin Gly Ala

1 5 10

15

(2) INFORMATION FOR SEQ ID NO: 56: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56:

Xaa Xaa Lys Thr Tyr Leu He Ser Ser He Pro Leu Gin Gly Ala

1 5 10

15

(2) INFORMATION FOR SEQ ID NO: 57:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57:

Met Asp He Pro Gin Thr Lys Gin Asp Leu Glu Leu Pro Lys Leu

1 5 10

15

(2) INFORMATION FOR SEQ ID NO: 58:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1497 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(vi) ORIGINAL SOURCE:

(A) ORGANISM: Homo sapiens

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58:

GGAGGGCAGA GATATCCAGT AGACAGAAGA TCTTGGACCC CAGGAAGTAT ATTGGAAGAG 60

GTGCCTGGAG AAATGGATGC TAGAAGAAAA CACTGGAAGG AGAATATGTT

TACTCCTTTT 120

TTTAGTGCAC AAGATGTTCT AGAAGAGACT TCTGAGCCTG AATCTTCTTC

TGAACAAACG 180

ACTGCAGATA GCAGCAAGGG AATGGAAGAA ATTTATAATT TGTCCAGTAG

AAAGTTTCAG 240

GAAGAAAGTA AATTTAAGAG GAAAAAATAT ATTTTCCAAC TAAATGAAAT

AGAACAAGAA 300

CAAAATTTAA GAGAGAACAA GAGAAACATT TCAAAGAATG AAACAGACAC

AAATTCTGCA 360

TCCTATGAAT CATCTAATGT GGATGTTACA ACAGAAGAAA GCTTTAACAG

CACAGAAGAT 420

AACTCTACCT GCAGTACAGA TAACTTACCA GCTCTACTAA GACAAGACAT

AAGAAAGAAA 480

TTTATGGAAA GAATGTCTCC AAAACTTTGC CTGAATCTTT TGAATGAAGA

ACTGGAAGAA 540

CTTAATATGA AATACAGAAA AATAGAAGAG GAATTTGAAA ATGCTGAAAA

AGAACTTTTG 600

CACTACAAAA AAGAAATATT CACAAAACCC CTAAATTTTC AAGAAACAGA

GACGGATGCT 660

TCAAAAAGTG ACTATGAACT TCAAGCTTTA AGAAATGACC TGTCTGAAAA

AGCAACAAAT 720

GTAAAAAACT TAAGTGAACA GCTCCAGCAA GCCAAAGAAG TCATCCACAA

ATTGAACCTA 780

GAGAACAGAA ATTTAAAAGA AGCTGTTAGG AAGTTAAAGC ATCAAACCGA

GGTTGGAAAT 840

GTGCTCCTAA AAGAAGAAAT GAAATCATAT TATGAATTAG AAATGGCAAA

GATCCGCGGA 900

GAGCTCAGTG TCATCAAGAA TGAACTGAGA ACTGAGAAGA CCCTACAAGC

AAGAAATAAC 960

AGAGCCTTGG AGTTGCTTAG AAAATACTAT GCTTCTTCAA TGGTAACATC

ATCAAGTATC 1020

CTTGACCACT TTACTGGGGA TTTTTTTTAA AACTTAAAAA AATCCTTCCA

GTAGGCAAGT 1080

CATTGAGCCA AATCAGTGTT TATTGTATTT TCTTTGCGTA TTACTTAAAA

TATATGTAAT 1140

AGGATGTTAT TTTCATTTTC AGTAAATCAC AGTATCTATA AAACATATAC

ATGTTTCCAA 1200

GCTTCTGCTT TCTCTTTCTG ATGAAGTTAT TGCAGGAATA CAAATGGAAA

CGAAGCTTTG 1260

GAAATCTCAT ATCAGAGTGT GTGTGTGTGT GTGTGTGTGT GTGTGTACAC

ACACACATAT 1320

ATTCACTCAA AAACACATAA TGATTCACCA AATCATTTAT GAATACAAAT

CAGCAATTTT 1380 GTGATCTCGT AAGCAAATAT GTCTTTGGCA CGTGAATATT TTTCCATCTG

TGTTCATTGA 1440

TGTTAACAAT AAAAATCTTG TTTATGTGTA TAAGCCTAAA AAAAAAAAAA AAAAAAA

1497

(2) INFORMATION FOR SEQ ID NO: 59:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1050 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(vi) ORIGINAL SOURCE:

(A) ORGANISM: Homo sapiens

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 59:

ACCAGCTCTA CTAAGACAAG ACATAAGAAA GAAATTTATG GAAAGAATGT

CTCCAAAACT 60

TTGCCTGAAT CTTTTGAATG AAGAACTGGA AGAACTTAAT ATGAAATACA

GAAAAATAGA 120

AGAGGAATTT GAAAATGCTG AAAAAGAACT TTTGCACTAC AAAAAAGAAA

TATTCACAAA 180

ACCCCTAAAT TTTCAAGAAA CAGAGACGGA TGCTTCAAAA AGTGACTATG

AACTTCAAGC 240

TTTAAGAAAT GACCTGTCTG AAAAAGCAAC AAATGTAAAA AACTTAAGTG

AACAGCTCCA 300

GCAAGCCAAA GAAGTCATCC ACAAATTGAA CCTAGAGAAC AGAAATTTAA

AAGAAGCTGT 360

TAGGAAGTTA AAGCATCAAA CCGAGGTTGG AAATGTGCTC CTAAAAGAAG

AAATGAAATC 420

ATATTATGAA TTAGAAATGG CAAAGATCCG CGGAGAGCTC AGTGTCATCA

AGAATGAACT 480

GAGAACTGAG AAGACCCTAC AAGCAAGAAA TAACAGAGCC TTGGAGTTGC

TTAGAAAATA 540

CTATGCTTCT TCAATGGTAA CATCATCAAG TATCCTTGAC CACTTTACTG

GGGATTTTTT 600

TTAAAACTTA AAAAAATCCT TCCAGTAGGC AAGTCATTGA GCCAAATCAG

TGTTTATTGT 660

ATTTTCTTTG CGTATTACTT AAAATATATG TAATAGGATG TTATTTTCAT

TTTCAGTAAA 720

TCACAGTATC TATAAAACAT ATACATGTTT CCAAGCTTCT GCTTTCTCTT TCTGATGAAG 780

TTATTGCAGG AATACAAATG GAAACGAAGC TTTGGAAATC TCATATCAGA

GTGTGTGTGT 840

GTGTGTGTGT GTGTGTGTGT ACACACACAC ATATATTCAC TCAAAAACAC

ATAATGATTC 900

ACCAAATCAT TTATGAATAC AAATCAGCAA TTTTGTGATC TCGTAAGCAA

ATATGTCTTT 960

GGCACGTGAA TATTTTTCCA TCTGTGTTCA TTGATGTTAA CAATAAAAAT

CTTGTTTATG 1020

TGTATAAGCC TAAAAAAAAA AAAAAAAAAA

1050

(2) INFORMATION FOR SEQ ID NO: 60:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 325 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:

Met Asp Ala Arg Arg Lys His Trp Lys Glu Asn Met Phe Thr Pro Phe

1 5 10 15

Phe Ser Ala Gin Asp Val Leu Glu Glu Thr Ser Glu Pro Glu Ser Ser

20 25 30

Ser Glu Gin Thr Thr Ala Asp Ser Ser Lys Gly Met Glu Glu lie Tyr

35 40 45

Asn Leu Ser Ser Arg Lys Phe Gin Glu Glu Ser Lys Phe Lys Arg Lys

50 55 60

Lys Tyr lie Phe Gin Leu Asn Glu lie Glu Gin Glu Gin Asn Leu Arg 65 70 75 80

Glu Asn Lys Arg Asn lie Ser Lys Asn Glu Thr Asp Thr Asn Ser Ala

85 90 95

Ser Tyr Glu Ser Ser Asn Val Asp Val Thr Thr Glu Glu Ser Phe Asn

100 105 110

Ser Thr Glu Asp Asn Ser Thr Cys Ser Thr Asp Asn Leu Pro Ala Leu

115 120 125

Leu Arg Gin Asp lie Arg Lys Lys Phe Met Glu Arg Met Ser Pro Lys

130 135 140

Leu Cys Leu Asn Leu Leu Asn Glu Glu Leu Glu Glu Leu Asn Met Lys 145 150 155 160

Tyr Arg Lys lie Glu Glu Glu Phe Glu Asn Ala Glu Lys Glu Leu Leu

165 170 175

His Tyr Lys Lys Glu lie Phe Thr Lys Pro Leu Asn Phe Gin Glu Thr

180 185 190

Glu Thr Asp Ala Ser Lys Ser Asp Tyr Glu Leu Gin Ala Leu Arg Asn

195 200 205

Asp Leu Ser Glu Lys Ala Thr Asn Val Lys Asn Leu Ser Glu Gin Leu 210 215 220 Gin Gin Ala Lys Glu Val lie His Lys Leu Asn Leu Glu Asn Arg Asn 225 230 235 240

Leu Lys Glu Ala Val Arg Lys Leu Lys His Gin Thr Glu Val Gly Asn

245 250 255

Val Leu Leu Lys Glu Glu Met Lys Ser Tyr Tyr Glu Leu Glu Met Ala

260 265 270

Lys lie Arg Gly Glu Leu Ser Val lie Lys Asn Glu Leu Arg Thr Glu

275 280 285

Lys Thr Leu Gin Ala Arg Asn Asn Arg Ala Leu Glu Leu Leu Arg Lys

290 295 300

Tyr Tyr Ala Ser Ser Met Val Thr Ser Ser Ser lie Leu Asp His Phe 305 310 315 320

Thr Gly Asp Phe Phe 325

(2) INFORMATION FOR SEQ ID NO: 61:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 702 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61:

ANAANTGTAC TCGCGCGCCT GCANGTCGAC ACTAGTGGGA TCCAAAGAAT TCGGCACGAG 60

CTGANGTGAA GCTCCCCAGN GCTCCTGANG TCAAGCTTCC AAAAGTGCCC GANGCAGCCC 120

TTCCAGATGT TCGACTCCCA GAGGTGGAGC TCCCCAAGGT GTCAGAGATG AAACTCCCAA 180

AGGTGCCAGA NATGGCTGTG CCGGANGTGC GGCTTCCAGA NGTAGACTGC CCANAGTGTC 240

AGAGATGAAA CTCCCAAAGG TGCCAGAAAT GCTGTGCCGG AAGTNCCGCT TCCAGAAGTA 300

CAGCTGCTGA AAGTGTCGGA GATNAAACTC CCAAAGGTGC CANAGATGGC TGTGCCGGAN 360

GTGCGGCTTC CAGANGTACA GCTGCCGAAT GTGTCAAGAA TGAAACTCCC ANAAGTGTCA 420

NANGTGGCTG TGCCANAAGT GCGGCTTCCA GANGTGCAGC TGCCGAATGT GCCAGAANAT 480

NAAAGTCCCT GANATGAAGC TTCCAANGGT GCCTGAAATG AAACTTCCTG AAGATGAAAC 540

TCCCTGAAAT TGCNNCTCCC GAAAGGTGCC CAAAATGGCC GTGCCCGATN TGCCCTCCCA 600

GAANTTCNNC TTCCNAAANT CCAGAAATAA NCNCCCTGAA ATGAAACCCC CGAGGTGAAC 660

NCCCNAAGGT GCCCAAAATN GCTGTNCCCC AATTTNCCCC NC 702

(2) INFORMATION FOR SEQ ID NO: 62:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 688 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: CDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 62:

GTTCTGATTG GGTACATTAC TGGTACCCAC CGGGTGGAAA TCNATGGGCC GCGGTCGCTC 60 TANAAGTACT CTCGANTTTT TTTNTNTTNT NNNNTTTTTT NNNTNNNNNT TTTCATNNTN 120 NTTTTTTTNN CNCNTNTNNN TACTTCCAAA TTATTTTATT CACATGGCTT GGTGGGGTAC 180 AGGCACTCCT GCCAAAAANA CAGGAACAGG CCTCCCTGCC ANCCCTGNTC ATTCACCACC 240

TCCCGGCCCT CTTAGGGTTN GTGCTANTTA NTCACACACA CACAGCGAAG GGGTAAAAAA 300

ATGAATGCAA AAAGGGATCC CCATCTNACT AGGGGCTTCA AACAGCCGCA GCCTGAGCCC 360

CCTCCATCCT GGNCGGGCCT GAAACCCTGT CTCNAAAAAC CCACGCTGGG CACCGNACCG 420

CAATCCACCT CTTCCTGNTC CCACTCCCAC TCCGGGCCTN GGGGCTTAGG GACCCCTGGG 480

GGAANCNGAA CTTGGGTGAC TTCTCTCTAA CNGGGGACTT GGGGGCTTCA TCCCCCTCCT 540

GCCCCCAAAA GCTTTAAAAG GGGCCCTCAN NCCTACCTTT GNCAANCCGG AACCNGAACC 600

GGCCCCGGNA CCCAAGCCCC TTCCCAATGC CTTTACTCCT CNCCTCTTCT NTNTNGGGGC 660

TGGGGGGACC TTNCCCAGTT AACCATCC 688

(2) INFORMATION FOR SEQ ID NO: 63:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 814 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63:

CGGCGGATCT GGACACCCAG CGGTCTGACA TCGCGACGCT GCTCAAAACC TCGCTCCGGA 60

AAGGGGACAC CTGGTACCTA GTCGATAGTC GCTGGTTCAA ACAGTGGAAA AAATATGTTG 120

GCTTTGACAG TTGGGACAAA TACCAGATGG GAGATCAAAA TGTGTATCCT GGACCCATTG 180

ATAACTCTGG ACTTCTCAAA NATGGTGATG CCCAGTCACT TAAGGAACAC CTTATTGATG 240

AATTGGATTA CATACTGTTG CCAACTGAAG GTTGGAATAA ACTTGTCAGC TGGTACACAT 300

TGATGGAAGG TCAAGAGCCA ATAGCACGAA AGGTGGTTGA ACAGGGTATG TTTGTAAAGC 360

ACTGCAAAGT ANAAGTATAT CTCACAGAAT TGAAGCTATG TGAAAATGGA AACATGAATA 420

ATGTTGT AC TCGAARAATT TAGCAAAGCT GACACAATAG ATACGATTGA AAAAGGAAAT 480

AAGAAAAATC TTCAGTTATT CCAGATGAAA AGGAGACCAG ATTGTGGAAC AAATACATGA 540

GTAACACATT TGAACCACTG AATAAACCAG ACAGCACCAT TCAGGATGCT GGTTTATACC 600

AAGGACAGGT ATTAGTGATA GAACAGAAAA ATGAANATGG AACATGGCCA AGGGGTCCTT 660

CTACTCCTAA GTCCCCAGGT GCATCCAATT TTTCAACTTT ACCAAAGATC TCTCCTTCAT 720

CTCTATCAAA TTNATTATTA CAACATGAAC AACAGAAATG TGAAAAACTC AAATTACTGT 780

CTTCCATCAT ATACCGCTTA TAAGAACTAT GATT 814

(2) INFORMATION FOR SEQ ID NO: 64:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 966 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64: _{ττττττττττ TTTTTTTTTA AA ττΑAAAG} GGATTTATTT GTGATTTCCT ATATATATTT 60

AGCTTGTAAA TACAAGACTG TAAATGTATT AANANACAAT TTCTGTTAAA GTTTTCATTG 120

TGTTTCACTT CAAGTACTGC ACAAGTTAAA ATCTGATAAA GGATTTACAT TCGGTTATCT 180

GAAACTCCCC ATCTCANACT TTTGTTTTAA TGTGGTGGGT AACTTCATCA TTTCCATAGA 240

TACCACCAGC AGGAAAGTGT CTCTTTTATG GCTTCTAGGA CTTTCATTAG TTAGTGTGCA 300

TACAGTTTTC ATTTTCTATA TCATTGTCAT TATCATTGCT ATCTTCATCA CTTTCTAATG 360 GGATGCCAGT GGCAGCTGAA GCACCTTTAG TTTCTCGGTC AAGAGGAAAA AAGCCAGTTC 420

CACTGAGAAG TGTCTTGTCT CTGGTAAAAN ARTACATATG CTGCTTGTGG ACACAATTTG 480

GTCTTCANAT GCAGTGGAGA CNCTACTGTC ATCAAAATAG TACCATTTNC CATCATCTTT 540

ATTTTTTGCA AAAGCAGTAT AGTGTCCTCC TCCCATCCCT CCATAGTGGT TGGAAACAGC 600

AATCANATTA TAGCGGCAAG GACCTGCATT TGGATTAATT AANAATTCCG ACATATCCAA 660

GTCATTGATA GGAAAATCAA CTAAGGTATC CAACTTGTCT CTCATGTATC GACTGTAANA 720

AAATCGCTTG AGATGTACTA CAAGTACTGG AGGCAGGGAC CATAAATCCA ATTTCTTTGT 780

GGCTTGCTGA TGTTCTTTAC AATTCGGACA ATACCAGGGA TCTTCAGCAC CTAGCTTTTC 840

TTTTGTTGTA AAAAGTTCAA TGCAATCTTT TAATTTCACA AAGGGTTTTT TAGGAGGTTT 900

ATACTCCACA CTTTCATGTT TTTCAAAGTC CTCAGCAGCA TTTTCATCAA AAATATCTTT 960

TTTTCA 966

(2) INFORMATION FOR SEQ ID NO: 65

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1020 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65:

TGGGAGCTCG CGCGCCTGCA GGTCGACACT AGTGGATCCA AAGAATTCGG CACGAGCTGA 60

GCACCACTGC CTGGCCGAGG AGGAGCTCAT CAAAGCCCAG AAGGTGTTTG AGGAGATGAA 120

TGTGGATCTG CAGGAGGAGC TGCCGTCCCT GTGGAACAGC CGCGTAGGTT TCTACGTCAA 180

CACGTTCCAG AGCATCGCGG GCCTGGAGGA AAACTTCCAC AAGGAGATGA GCAAGCTCAA 240

CCAGAACCTC AATGATGTGC TGGTCGGCCT GGAGAAGCAA CACGGGAGCA ACACCTTCAC 300

GGTCAAGGCC CAGCCCAGTG ACAACGCGCC TGCAAAAGGG AACAAGAGCC CTTCGCCTCC 360

AGATGGCTCC CCTGCCGCCA CCCCCGAGAT CAGAGTCAAC CACGAGCCAG AGCCGGCCGG 420

CGGGGCCACG CCCGGGGCCA CCCTCCCCAA GTCCCCATCT CAGCTCCGGA AAGGCCACCA 480

GTCCCTCCGC CTCCCAAACA CACCCCGTCC AAGGAAGTCA AGCAGGAACA GATCCTCAGC 540

CTGTTTGAAG GACACGTTTG TTCCCTTGAA AATCAGCGTN GACCACCCCC TCCCANCCCA 600

GCAAAAAGCC TCCGAAAGTT TGGCGGGGTT GGGGAACCCA AACCTTGGCG GGNTTGGGAA 660

ACCCCAGGAA AACCNAGGGG GGAAAAANCG GGGGGGCCNA AATTNTAAAA NCAAANCCCN 720

TCCCAAAGCT TCTTCTTTTC CCCTGGCTTG TTTTCNTTTN GGGNTTGGGN AAAAAAACCT 780

TTTCCCCCCA AGCCAAAAAN TTGGTTNNAA AATTTGGGGC CNCCCCCNNT TGGAAAAAGG 840

GGGGGNGGGC CNAATTTTGG GGGGCCCNGG GCCCCCTTTG GGAAACCTNG CCCCCCCAAG 900

GTTTTCCATN NTTTCAANGG GTTAAAGGGC CNACANAAAA AAACCCGGGC CCTTGAACCC 960

AAAAAAAACT GCNCCTCAAG GGGGGGGGAA ATTTGNGCCG GGGTANTCCC TTCCAAAACC 1020

(2) INFORMATION FOR SEQ ID NO: 66:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 928 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:

ATCTGGGTAC ATTACCTNGG TACCCCACCC GGGTGGAAAA TCGATGGGCC CGCGGCCGCT 60 CTANAAGTAC TCTCGAGTTT _{ττττττττττ} TTTTTGAGAG TTTTTATCAT TTTTTTTTTG 120

TTTCATTTTG TTTTGAACAC TAANATTTAT TTTCAAACAG CACACAGACC GTCTGCGGGG 180

CAGAGCCAGG CTAGGCTGGT GTCTGGGCCC CACCCACAGC AGCTGCCAGG AAAAGAGGAC 240

CCTTGCCCGG GTGGCGCGGC CGAAGCTTCA GGCAAGCATG GTGGCTCGGC AGCCCCCAGC 300

CCCGCCCTGC GGCCAGGCAC ACATGCGGGC ACAGGCAGGG GCGCCAGAAA CTCAACTAGA 360

GGACACAGCA GCTTCAGGAA CACTGGTGAA TTCCGCCGGA CTTGCCGGGA CGCGGCTCTT 420

TGGAAAACGA CCTAATCTTT GGGAGAACGC CCCTCTGCCT GGGGGTCTCC TCTTGATTTC 480

CCTTTGCTCT TCAAAAGATG AAAAACGAAA ACCNAACNAA AAAAAGAACC NCACATTTTT 540

CGGGAGGAAG TGTTCTTCAC ACGCCCGGAG GCTGCCTGGG CCCGCCGTCA TGGGACCTCT 600

CAGTGAATTC TCGGGGAAAA ACCACGGNAC TTCTCCAGCT CCTTGTGCTG GTTCCAGTCG 660

CNCTCCTTCN CGCCCATGAA CCANCCTTCA TCCTGCTCTT TCANGGTTCT GGAAAGGGGG 720

ATNACCAACA NCCACATTCN CCAAGCCCTT GAACCTGCAA CTTCCNTCTG NTNTTCAGTT 780

GGCCCGTNTT NATNCCTTGC TTGGGGCCTT NTTCCCTTTN AAAAATNAAA AACCTTGGGG 840

GGGGGGGGTT CCAAANCGCC CCGGGGCCCC ACTTGGCCCG CCCTNCCCAC GGGNTGCCNN 900

TTCCNCNANT TTCTTTGGGG NAAAGGTC 928

Claims

1. A polypeptide comprising an immunogenic portion of a prostate protein having a partial sequence selected from the group consisting of SEQ ID NOS: 2, 4, 5, 6, 7 and 8, or a variant of said protein that differs only in conservative substitutions and/or modifications.

2. A polypeptide comprising an immunogenic portion of a prostate protein or a variant of said protein that differs only in conservative substitutions and/or modifications wherein said protein comprises an amino acid sequence encoded by a DNA sequence selected from the group consisting of sequences recited in SEQ ID NOS: 11, 13-19, 58, 59 and 61-64, the complements of said sequences, and DNA sequences that hybridize to a sequence recited in SEQ ID NOS: 11, 13-19, 58, 59 and 61-64, or a complement thereof under moderately stringent conditions.

3. A DNA molecule comprising a nucleotide sequence encoding the polypeptide of claims 1 or 2.

4. An expression vector comprising the DNA molecule of claim 3.

5. A host cell transformed with the expression vector of claim 4.

6. The host cell of claim 5 wherein the host cell is selected from the group consisting of E. coli, yeast and mammalian cell lines.

7. A pharmaceutical composition comprising the polypeptide of claims 1 or 2 and a physiologically acceptable carrier.

8. A vaccine comprising the polypeptide of claims 1 or 2 and a nonspecific immune response enhancer.

9. The vaccine of claim 8 wherein the non-specific immune response enhancer is an adjuvant.

10. A vaccine comprising a DNA molecule and a non-specific immune response enhancer, the DNA molecule comprising a nucleotide sequence encoding the polypeptide of claims 1 or 2.

11. The vaccine of claim 10 wherein the non-specific immune response enhancer is an adjuvant.

12. A pharmaceutical composition for the treatment of prostate cancer comprising a polypeptide and a physiologically acceptable carrier, the polypeptide comprising an immunogenic portion of a prostate protein having a partial sequence selected from the group consisting of SEQ ID NOS: 1, 3, 20, 21, 25-31 and 44-57.

13. A vaccine for the treatment of prostate cancer comprising a polypeptide and a non-specific immune response enhancer, the polypeptide comprising an immunogenic portion of a prostate protein having a partial sequence selected from the group consisting of SEQ ID NOS: 1, 3, 20, 21, 25-31 and 44-57.

14. The vaccine of claim 13 wherein the non-specific immune response enhancer is an adjuvant.

15. A method for inhibiting the development of prostate cancer in a patient, comprising administering to the patient an effective amount of the pharmaceutical composition of claims 7 or 12.

16 A method for inhibiting the development of prostate cancer in a patient, comprising administering to the patient an effective amount of the vaccine of claims 8, 10 or 12

17 A method for detecting prostate cancer in a patient, comprising

(a) contacting a biological sample obtained from a patient with a binding agent which is capable of binding to the polypeptide of claims 1 or 2, and

(b) detecting in the sample a protein or polypeptide that binds to the binding agent, thereby detecting prostate cancer in the patient

18 The method of claim 17 wherein the binding agent is a monoclonal antibody

19 The method of claim 17 wherein the binding agent is a polyclonal antibody

20 A method for monitoring the progression of prostate cancer in a patient, comprising

(a) contacting a biological sample obtained from a patient with a binding agent that is capable of binding to the polypeptide of claims 1 or 2,

(b) determining in the sample an amount of a protein or polypeptide that binds to the binding agent,

(c) repeating steps (a) and (b), and

(d) comparing the amount of polypeptide detected in steps (b) and (c) to monitor the progression of prostate cancer in the patient.

21 A method for detecting prostate cancer in a patient, comprising

(a) contacting a biological sample obtained from a patient with a binding agent which is capable of binding to a polypeptide, the polypeptide comprising an immunogenic portion of a prostate protein having a partial sequence selected from the group consisting of SEQ ID NOS: 1, 3, 20, 21, 25-31 and 44-57; and

(b) detecting in the sample a protein or polypeptide that binds to the binding agent, thereby detecting prostate cancer in the patient.

22. The method of claim 21 wherein the binding agent is a monoclonal antibody.

23. The method of claim 21 wherein the binding agent is a polyclonal antibody.

24. A method for monitoring the progression of prostate cancer in a patient, comprising:

(a) contacting a biological sample obtained from a patient with a binding agent that is capable of binding to a polypeptide, the polypeptide comprising an immunogenic portion of a prostate protein having a partial sequence selected from the group consisting of: SEQ ID NOS: 1, 3, 20, 21, 25-31 and 44-57;

(b) determining in the sample an amount of a protein or polypeptide that binds to the binding agent;

(c) repeating steps (a) and (b); and

(d) comparing the amount of polypeptide detected in steps (b) and (c) to monitor the progression of prostate cancer in the patient.

25. A monoclonal antibody that binds to the polypeptide of claims 1 or 2.

26. A monoclonal antibody according to claim 25, for use in the manufacture of a medicament for inhibiting the development of prostate cancer.

27. The monoclonal antibody of claim 26 wherein the monoclonal antibody is conjugated to a therapeutic agent.

28. A method for detecting prostate cancer in a patient, comprising:

(a) contacting a biological sample from a patient with at least two oligonucleotide primers in a polymerase chain reaction, wherein at least one of the oligonucleotide primers is specific for a DNA molecule selected from the group consisting of SEQ ID NOS: 9-19, 22-24, 32-43, 58, 59 and 61-64; and

(b) detecting in the sample a DNA sequence that amplifies in the presence of the oligonucleotide primer, thereby detecting prostate cancer.

29. The method of claim 28, wherein at least one of the oligonucleotide primers comprises at least about 10 contiguous nucleotides of a DNA molecule selected from the group consisting of SEQ ID NOS: 9-19, 22-24, 32-43, 58, 59 and 61-64.

30. A method for detecting prostate cancer in a patient, comprising:

(a) contacting a biological sample from the patient with at least one oligonucleotide probe specific for a DNA molecule selected from the group consisting of SEQ ID NOS: 9-19, 22-24, 32-43, 58, 59 and 61-64; and

(b) detecting in the sample a DNA sequence that hybridizes to the oligonucleotide probe, thereby detecting prostate cancer.

31. The method of claim 30 wherein the probe comprises at least about 15 contiguous nucleotides of a DNA molecule selected from the group consisting of SEQ ID NOS: 9-19, 22-24, 32-43, 58, 59 and 61-64.