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WO2001055320A2 - Acides nucleiques, proteines et anticorps - Google Patents

Acides nucleiques, proteines et anticorps Download PDF

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Publication number
WO2001055320A2
WO2001055320A2 PCT/US2001/001339 US0101339W WO0155320A2 WO 2001055320 A2 WO2001055320 A2 WO 2001055320A2 US 0101339 W US0101339 W US 0101339W WO 0155320 A2 WO0155320 A2 WO 0155320A2
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Prior art keywords
polypeptide
seq
sequence
polypeptides
polynucleotides
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PCT/US2001/001339
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WO2001055320A3 (fr
WO2001055320A8 (fr
Inventor
Craig A. Rosen
Steven C. Barash
Steven M. Ruben
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Human Genome Sciences Inc
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Human Genome Sciences Inc
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Priority to AU2001243134A priority Critical patent/AU2001243134A1/en
Priority to US09/908,711 priority patent/US20020045230A1/en
Publication of WO2001055320A2 publication Critical patent/WO2001055320A2/fr
Publication of WO2001055320A8 publication Critical patent/WO2001055320A8/fr
Publication of WO2001055320A3 publication Critical patent/WO2001055320A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6489—Metalloendopeptidases (3.4.24)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to novel reproductive system related polynucleotides, the polypeptides encoded by these polynucleotides herein collectively referred to as "reproductive system antigens," and antibodies that immunospecifically bind these polypeptides, and the use of such reproductive system polynucleotides, antigens, and antibodies for detecting, treating, preventing and/or prognosing disorders of the reproductive system, including, but not limited to, the presence of cancer and cancer metastases. More specifically, isolated reproductive system nucleic acid molecules are provided encoding novel reproductive system polypeptides. Novel reproductive system polypeptides and antibodies that bind to these polypeptides are provided.
  • vectors, host cells, and recombinant and synthetic methods for producing human reproductive system polynucleotides, polypeptides, and/or antibodies are also provided.
  • the invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to the reproductive system, including cancers of the reproductive system, and therapeutic methods for treating such disorders.
  • the invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention.
  • the invention further relates to methods and/or compositions for inhibiting or promoting the production and/or function of the polypeptides of the invention.
  • the human reproductive system enables continuation of the species. Human beings - reproduce sexually, require the involvement of both a male and a female. Reproduction involves the coalition of sex cells. A new human being begins its development after a sex cell (sperm), created by the male unites with a sex cell (ovum) created by the female. Both the male and female reproductive systems function through the complex interaction of several organs. Diseases or malfunctions of these organs can impair reproduction or cause infertility.
  • Male reproductive functions can be divided into three major subdivisions; spermatogenesis (the formation and maturation of sperm), performance of the male sexual act (arousal, erection, and ejaculation), and regulation of male sexual functions by the various hormones (mainly testosterone). Associated with these reproductive functions are the effects of the male sex hormones on the accessory sexual organs, cellular metabolism, growth, and on several other bodily functions. The onset of sexual maturation and these reproductive functions in males occurs at puberty, which, in humans, typically begins around age thirteen.
  • the male reproductive system is composed of the testes, a pair of organs contained in the scrotum which include the seminiferous tubules and epididymus; secretory glands, such as the prostate gland, seminal vesicles, bulbourethral glands, and urethral glands; tubular passageways, such as the vas deferens and urethra; and the penis, which functions in performance of the sexual act and sperm transmission.
  • Common disorders of the male reproductive system include infections, cancers, and inflammations of the above listed components, which are described in greater detail below.
  • testes The two primary functions of the testes are 1) production of testosterone and 2) production of sperm.
  • Testosterone produced in the testes is released into the blood stream, where it travels to and acts on a wide range of tissues and organs within the male body.
  • Disorders resulting from testosterone deficiency are manifested in the male reproductive system typically by symptoms of hypogonadism, which is the failure to go through puberty. Specifically, erectile function is impaired, and libido and sperm production are decreased or absent.
  • Known dysfunctions of sperm production include aspermia (the failure to produce an ejaculate), asthenospermia (the production of an ejaculate in which less than 50% of spermatozoa are motile), azoospermia (the production of an ejaculate devoid of spermatozoa), oligospermia (production of an ejaculate containing less than 20x100 spermatozoa per milliliter of semen), and teratospermia (the production of an ejaculate in which more than 50% of the spermatozoa are of abnormal shape), all of which result in impaired fertility.
  • aspermia the failure to produce an ejaculate
  • asthenospermia the production of an ejaculate in which less than 50% of spermatozoa are motile
  • azoospermia the production of an ejaculate devoid of spermatozoa
  • oligospermia production of an e
  • Improper sperm formation may result from a variety of factors, including congenital defects, genetic abnormalities, injury, and infection. For example, contraction of the mumps virus early in male adolescence can infect the testicles, leading to permanent complications in sperm production.
  • Sperm formation may also be impaired by disorders of the epididymus, the labyrinthine tube system located in each testis where sperm mature. Common disorders include infections (e.g., Neisseria gonorrhoea, Pseudomonas, Enterobacteriaceae, and Chlamydia trachomatis), cyst formation or other obstructions, and enlargement of the spermatoceles (liquid filled cavities in the epididymus).
  • infections e.g., Neisseria gonorrhoea, Pseudomonas, Enterobacteriaceae, and Chlamydia trachomatis
  • cyst formation or other obstructions e.g., cyst formation or other obstructions
  • enlargement of the spermatoceles liquid filled cavities in the epididymus.
  • testes During fetal development, the testes mature within the abdominal cavity and descend through the inguinal canal into the scrotum prior to birth. It is well known that the testicles reside in the scrotum because it is cooler than other places within the body cavity, and even minor temperature differences can have a dramatic influence on the ability of the testicle to make sperm.
  • An undescended testicle sometimes called a cryptorchid testicle, is a fairly common problem in male babies. Typically, testicles undescended at birth will move into the scrotum within the first year of life, however in a small percentage of cases this migration does not occur.
  • testicles Early correction of this problem is crucial in preserving the fertility of the male, as the testicles begin to loose the ability to make sperm very early in life in they are not properly stored in the scrotum. Additionally, undescended testicles have a much higher rate of developing testicular cancer than testicles that descended spontaneously. Testicular cancer is the most common solid tumor in males aged 18 to 35. It typically is extremely aggressive and spreads early. A tumor of the testicle often shows itself by a fast enlargement of the testicle. Bringing the testes into the scrotum will allow for easier and more accurate examination of the testes, hopefully resulting in earlier detection of tumors. Further, undescended testicles are also associated with a greater risk of hernia.
  • disorders of the scrotal pouch commonly involve the small amount of fluid lining the pouch that allows for small movements and cushioning of the testicles.
  • Several causes such as testicular torsion, trauma, or tumors, may lead to an increase in the amount of liquid, causing the scrotal pouch to bulge. While this condition is harmless, it may cause irritation and discomfort if the bulge becomes too large.
  • the sperm become mixed with a viscous, alkaline fluid from the seminal vesicles that constitutes 60% of semen.
  • This fluid contains the components for generating sperm motility and the enzymes necessary for fertilization of the egg within the female reproductive system.
  • Disorders of the vas deferens and seminal vesicles are unusual, however a congenital defect where the vas deferens is absent is known to be associated with mutations in the CFTR gene, and a defect in seminal vesicle function is associated with the hydatid disease of the urogenital system.
  • disorders of the prostate gland are typically manifested by enlargement of the gland, leading to such symptoms as impaired urinary flow, infertility, and pain.
  • benign prostatic hyperplasia is the non-cancerous growth of the prostate gland, a condition that is fairly common in men over sixty.
  • Prostate cancer too, is extremely prevalent and is now the second most common type of cancer in males.
  • men of any age can develop prostate cancer, it is found most frequently in men over age 50.
  • Types of prostate cancers include, but not limited to, adenocarcinomas, transitional cell carcinomas, ductal carcinomas, and squamous cell carcinomas.
  • the prostate is subject to infections or inflammation, which may also result in enlargement of the prostate, such as acute bacterial prostatitis, chronic bacterial prostatitis, and nonbacterial prostatitis.
  • balanitis xerotica obliterans a hardening of the tip of the penis which ultimately blocks urine and semen flow
  • phimosis the shrinking or tightening of the foreskin
  • paraphimosis theinability of the retracted foreskin to be pulled back over the head of the penis
  • Erythroplasia of Queyrat an infection causing a clearly defined reddish, velvety area on the skin of the penis. If left untreated, many of these infections may become cancerous.
  • Priapism is a painful, persistant erection unaccompanied by sexual desire or excitement. In most cases, priapism is believed to stem from habitual drug use, but is had also been associated with blood disorders (e.g., blood clots, leukemia, or sickle cell disease), tumors in the pelvis or spine, and infection of the genitals.
  • blood disorders e.g., blood clots, leukemia, or sickle cell disease
  • tumors in the pelvis or spine e.g., tumors in the pelvis or spine
  • infection of the genitals e.g., blood clots, leukemia, or sickle cell disease
  • Peyronie's disease is manifested as a fibrous thickening of tissue that causes the penis to develop contractures so that the shape of an erection is distorted. The curvature of the erect penis can make sexual penetration difficult or impossible and may make erections extremely painful.
  • Current therapies include cortico
  • Impotence, or erectile dysfunction is the consistent or recurrent inability to attain and maintain a penile erection rigid enough for satisfactory sexual intercourse.
  • Erectile dysfunction relates only to the erectile capability of the penis, excluding problems of libido, ejaculation, and orgasm. It is now accepted that the majority of cases have a physical and not a psychogenic root. Physical causes include anatomic deformations (e.g., malformed genitalia or penile injury), diabetes mellitus, coronary disease, hypertension, atherosclerosis, high cholesterol levels, multiple sclerosis, stroke, lower spine diseases, and rectal or prostate surgery.
  • anatomic deformations e.g., malformed genitalia or penile injury
  • diabetes mellitus e.g., coronary disease, hypertension, atherosclerosis, high cholesterol levels, multiple sclerosis, stroke, lower spine diseases, and rectal or prostate surgery.
  • the female reproductive system is comprised of both external and internal organs.
  • the external organs function in permitting sperm to enter the body and protecting the internal genital organs from infection and injury.
  • the internal organs form a pathway (the genital tract) for reproduction, beginning at the ovaries, through the fallopian tubes (oviducts) and uterus, to the birth canal (vagina).
  • the sexual and reproductive functions in the female can be divided into two major phases: first, preparation of the body for conception, and second, the gestation and parturition. Gestation and parturition only occur if an ovum becomes fertilized. If fertilization does not occur, the reproductive system undergoes a cycle to ensure frequent readiness for conception and fertilization.
  • disorders of the uterus include absent bleeding (amenorrhea) and abnormal bleeding.
  • Amenorrhea is normal only before puberty, during pregnancy, while breastfeeding, and after menopause.
  • the absence of menses at other times is considered aberrant and may be indicative of problems in the brain, pituitary gland, thyroid gland, adrenal glands, ovaries, or virtually any other part of the reproductive tract.
  • the hypothalamus signals the pituitary gland to release hormones that cause the ovaries to release eggs. Inappropriately low levels of hypothalamic hormones prevent egg release, halting the menstrual cycle. The same is true for the thyroid and adrenal glands.
  • Premature menopause is also a condition resulting in amenorrhea. Menopause is considered abnormal when it occurs in women under the age of forty. Causes of premature menopause include genetic (usually chromosomal) abnormalities and autoimmune disorders in which antibodies damage the ovaries. Estrogen replacement therapy can prevent or reverse the symptoms of menopause, however the chance of conceiving a child remains less than ten percent.
  • Uterine bleeding is considered abnormal when it is atypically heavy, light, frequent, or irregular. Moreover, bleeding before puberty or after menopause is almost always abnormal. Uterine polyps, fibroids (noncancerous growths of muscle and fibrous tissues), and cancers are common causes of abnormal uterine bleeding and usually can be surgically removed. Cancers of the uterus include adenocarcinomas (cancers arising from the endometrial lining), leiomyosarcomas (cancers of the uterine smooth muscle), and sarcomas (cancers arising from the stroma).
  • Endometriosis is a disorder of the uterus in which patches of endometrial tissue, which normally is found only in the uterine lining, grow outside the uterus. Because the misplaced tissue responds to the same hormone that the uterus responds to, it may bleed during the menstrual period, causing cramps, pain, irritation, and the formation of scar tissue. As the disease progresses, adhesions may form and block the functioning of organs.
  • disorders of uterine contraction include, for example, dysmenorrhea and pre- term labor.
  • the uterus undergoes mild contractions in order to aid in blood flow.
  • Dysmenorrhea results when the contractions become inappropriately strong, inhibiting blood flow to the uterus. This deprives uterine muscle of oxygen, causing severe abdominal pain, as well as nausea, vomiting, diarrhea, headaches, weakness, and/or fainting. Sever cases of dysmenorrhea can significantly disrupt a womans life, leading to heavy work/school absenteeism and cases of pain killer addiction.
  • Anovulation the absence of egg release by the ovaries is a serious condition leading to infertility.
  • Current treatments include clomiphene injections or hormonal therapy, although both can lead to serious side effects such as ovarian cancer and ovarian hyperstimulation syndrome.
  • Anovulation is also associated with polycyctic ovary syndrome (also known as
  • Stein-Leventhal syndrome This syndrome is and endocrine disorder characterized by an elevated level of male hormones (androgens). Other than anovulation, symptoms include growth of male-patterned body hair (hirsutism), excessive acne, irregular or absent menses, excessive bleeding, and obesity. Usually, the ovaries appear enlarged and may contain many follicular cysts.
  • Ovarian cancer develops most often in women between the ages of 50 and 70.
  • Ovaries include a variety of cell types, each of which may give rise to a distinct type of cancer, including, but not limited to, ovarian epithelial cancer, ovarian germ cell tumors, ovarian papillary serous adenocarcinoma, ovarian mucinous adenocarcinoma, ovarian Krukenberg tumor, malignant mixed Mullerian tumors, and ovarian low malignant tumors.
  • disorders of the ovaries also include, but are not limited to, inflammatory disorders, such as oophoritis (e.g., caused by viral or bacterial infection), ovarian cysts, and autoimmune disorders (e.g., premature ovarian failure and autoimmune oophoritis).
  • inflammatory disorders such as oophoritis (e.g., caused by viral or bacterial infection), ovarian cysts, and autoimmune disorders (e.g., premature ovarian failure and autoimmune oophoritis).
  • vagina and vulva are self-cleaning. Secretions and discharges flow downward through the vagina and vulva, flushing out dead cells and other substances. Despite this cleaning mechanism, infections and inflammation are a common problem.
  • the most common vaginal infections are bacterial vaginitis, Candida vaginitis (e.g., yeast infections), trichomonas vaginitis, and vulvitis. Vaginal or vulvar itching, irritation, and abnormal discharge characterize all.
  • Cancer of the vagina is extremely rare, accounting for only two percent of all gynecological cancers, and occurs primarily in women over the age of 50. The severity of the disease depends on the type of cancer and its exact location. Varieties include, for example, squamous cell carcinoma and clear cell adenocarcinoma. Once cancer appears in the vagina, it easily spreads to surrounding tissues. Vulvar cancer is equally unusual as vaginal, and is predominantly manifested as a form of skin cancer, e.g. squamous cell carcinomas and basal cell carcinomas. Other vulvar cancers include Paget's disease, cancer of Bartholin's gland, and melanomas. Unlike cancer of the vagina, vulvar cancers typically grow slowly and infrequently metastasize.
  • disorders of the breast typically involve the formation of lesions within breast tissue. While many of these lesions are benign in nature, they may lead to cancer if left untreated.
  • Benign breast lesions include, for example, cysts, which are non-cancerous, fluid-filled sacs that forma mass within breast tissue.
  • the cause of breast cysts is unknown, though injury may be involved, and their main symptom is pain. While considered harmless, a professional should drain cysts and the fluid examined because cancer of the cyst wall, although quite rare, is possible.
  • Fibrous breast lumps are small, solid lumps of glandular tissue. These lumps usually appear in young women, often in teenagers, and are easy to remove.
  • Intraductal papilloma are small lumps located within a milk duct, often causing inappropriate discharge from the nipple.
  • Breast abscesses are collections of pus in breast tissue that develop from breast infections that go untreated.
  • Breast cancer is the most common cancer among women, other than skin cancer and is the second leading cause of cancer death in women, after lung cancer.
  • the American Cancer Society predicts that there will be about 182,800 new cases of invasive breast cancer in the year 2000 among women in this country and about 40,800 deaths from the disease.
  • Breast cancer also occurs among men, although much less often. It is generally believed that this malignancy arises from a multi step process involving mutations in a relatively small number of genes, perhaps 10 or less. These mutations result in significant changes in the growth and differentiation of breast tissue that allow it to grow independent of normal cellular controls, to metastasize, and to escape immune surveillance.
  • the genetic heterogeneity of most breast cancers suggests that they arise by a variety of initiating events and that the characteristics of individual cancers are due to the collective pattern of genetic changes that accumulate.
  • the present invention relates to novel reproductive system related polynucleotides, the polypeptides encoded by these polynucleotides herein collectively referred to as "reproductive system antigens," and antibodies that immunospecifically bind these polypeptides, and the use of such reproductive system polynucleotides, antigens, and antibodies for detecting, treating, preventing and or prognosing disorders of the reproductive system, including, but not limited to, the presence of cancer and cancer metastases. More specifically, isolated reproductive system nucleic acid molecules are provided encoding novel reproductive system polypeptides. Novel reproductive system polypeptides and antibodies that bind to these polypeptides are provided.
  • vectors, host cells, and recombinant and synthetic methods for producing human reproductive system polynucleotides, polypeptides, and/or antibodies are also provided.
  • the invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to the reproductive system, including cancers of the reproductive system, and therapeutic methods for treating such disorders.
  • the invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention.
  • the invention further relates to methods and/or compositions for inhibiting or promoting the production and/or function of the polypeptides of the invention.
  • Table 1A summarizes some of the polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO:Z), contig sequences (contig identifier (Contig ID:) and contig nucleotide sequence identifier
  • the first column provides a unique clone identifier, "Clone ID NO:Z", for a cDNA plasmid related to each reproductive system associated contig sequence disclosed in Table 1A.
  • the second column provides a unique contig identifier, "Contig ID:” for each of the contig sequences disclosed in Table 1 A.
  • the third column provides the sequence identifier,
  • ORFs SEQ ID NO:Y. Identification of potential immunogenic regions was performed according to the method of Jameson and Wolf (CABIOS, 4:181-186
  • reproductive system associated polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the predicted epitopes described in Table 1A. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly.
  • Column 7, “Tissue Distribution” shows the expression profile of tissue, cells, and/or cell line libraries which express the polynucleotides of the invention. The first number in column 7 (preceding the colon), represents the tissue/cell source identifier code corresponding to the code and description provided in Table 4.
  • tissue/cell source identifier codes in which the first two letters are "AR” designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array.
  • cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of 33 P dCTP, using oligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array. A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations.
  • PSL Phosphor Stimulating Luminescence
  • an OMLM identification number is provided in Table 1A, column 9 labeled "OMEVI Disease Reference(s)".
  • OMJVI reference identification numbers A key to the OMJVI reference identification numbers is provided in Table 5.
  • Table 1B summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO:Z), contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ ID NO:B).
  • the first column provides a unique clone identifier, "Clone ID NO:Z”, for a cDNA clone related to each contig sequence.
  • the second column provides the sequence identifier, "SEQ ID NO:X”, for each contig sequence.
  • the third column provides a unique contig identifier, "Contig ID:” for each contig sequence.
  • the fourth column provides a BAC identifier "BAC ID NO:A” for the BAC clone referenced in the corresponding row of the table.
  • the fifth column provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of the BAC clone identified in column four of the corresponding row of the table.
  • the sixth column provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof).
  • Table 2 summarizes homology and features of some of the polypeptides of the invention.
  • the first column provides a unique clone identifier, "Clone ID NO:Z”, corresponding to a cDNA disclosed in Table 1A.
  • the second column provides the unique contig identifier, "Contig ID:” corresponding to contigs in Table 1A and allowing for correlation with the information in Table 1A.
  • the third column provides the sequence identifier, "SEQ ID NO:X”, for the contig polynucleotide sequences.
  • the fourth column provides the analysis method by which the homology/identity disclosed in the row was determined.
  • NR non-redundant protein database
  • PFAM protein families
  • polypeptides of the invention comprise, or alternatively consist of, an amino acid sequence encoded by the polynucleotides in SEQ ID NO:X as delineated in columns 8 and 9, or fragments or variants thereof.
  • Table 3 provides polynucleotide sequences that may be disclaimed according to certain embodiments of the invention.
  • the first column provides a unique clone identifier, "Clone ID NO:Z”, for a cDNA clone related to reproductive system associated contig sequences disclosed in Table 1A.
  • the second column provides the sequence identifier, "SEQ ID NO:X”, for contig polynucleotide sequences disclosed in Table 1 A.
  • the third column provides the unique contig identifier, "Contig ID”, for contigs disclosed in Table 1 A.
  • the fourth column provides a unique integer 'a' where 'a' is any integer between 1 and the final nucleotide minus 15 of SEQ ID NO:X, represented as "Range of a”, and the fifth column provides a unique integer 'b' where 'b' is any integer between 15 and the final nucleotide of SEQ ID NO:X, represented as "Range of b", where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and where b is greater than or equal to a + 14.
  • polynucleotides shown as SEQ ID NO:X the uniquely defined integers can be substituted into the general formula of a-b, and used to describe polynucleotides which may be preferably excluded from the invention.
  • preferably excluded from the polynucleotides of the invention are at least one, two, three, four, five, ten, or more of the polynucleotide sequence(s) having the accession number(s) disclosed in the sixth column of this Table (including for example, published sequence in connection with a particular BAC clone).
  • preferably excluded from the invention are the specific polynucleotide sequence(s) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including for example, the actual sequence contained in an identified BAC clone).
  • Table 4 provides a key to the tissue/cell source identifier code disclosed in
  • tissue or cell source may be specific (e.g. a neoplasm), or may be disease-associated (e.g., a tissue sample from a normal portion of a diseased organ). Furthermore, tissues and/or cells lacking the "disease" designation may still be derived from sources directly or indirectly involved in a disease state or disorder, and therefore may have a further utility in that disease state or disorder.
  • tissue/cell source is a library
  • column 7 identifies the vector used to generate the library.
  • Table 5 provides a key to the OMEVITM reference identification numbers disclosed in Table 1 A, column 9.
  • OMEVI reference identification numbers (Column 1) were derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMEVITM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine, (Bethesda, MD) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/).
  • Column 2 provides diseases associated with the cytologic band disclosed in Table 1A, column 8, as determined from the Morbid Map database.
  • Table 6 summarizes ATCC Deposits, Deposit dates, and ATCC designation numbers of deposits made with the ATCC in connection with the present application.
  • Table 7 shows the cDNA libraries sequenced, tissue source description, vector information and ATCC designation numbers relating to these cDNA libraries.
  • Table 8 provides a physical characterization of clones encompassed by the invention.
  • the first column provides the unique clone identifier, "Clone ID NO:Z", for certain cDNA clones of the invention, as described in Table 1A.
  • the second column provides the size of the cDNA insert contained in the corresponding cDNA clone.
  • isolated refers to material removed from its original environment (e.g., the natural environment if it is naturally occurring), and thus is altered “by the hand of man” from its natural state.
  • an isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be “isolated” because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide.
  • isolated does not refer to genomic or cDNA libraries, whole cell total or mRNA preparations, genomic DNA preparations (including those separated by electrophoresis and transferred onto blots), sheared whole cell genomic DNA preparations or other compositions where the art demonstrates no distinguishing features of the polynucleotide sequences of the present invention.
  • a "polynucleotide” refers to a molecule having a nucleic acid sequence encoding SEQ ID NO:Y or a fragment or variant thereof, a nucleic acid sequence contained in SEQ ID NO:X (as described in column 3 of Table 1 A) or the complement thereof, a cDNA sequence contained in Clone ID NO:Z (as described in column 1 of Table 1A and contained within a library deposited with the ATCC); a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B or a fragment or variant thereof; or a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table 1B or the complement thereof.
  • the polynucleotide can contain the nucleotide sequence of the full length cDNA sequence, including the 5' and 3' untranslated sequences, the coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence.
  • a "polypeptide” refers to a molecule having an amino acid sequence encoded by a polynucleotide of the invention as broadly defined (obviously excluding poly-Phenylalanine or poly-Lysine peptide sequences which result from translation of a polyA tail of a sequence corresponding to a cDNA).
  • a "reproductive system antigen” refers collectively to any polynucleotide disclosed herein (e.g., a nucleic acid sequence contained in SEQ ID NO:X or the complement therof, or cDNA sequence contained in Clone ID NO:Z, or a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B, or a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table 1B or the complement thereof and fragments or variants thereof as described herein) or any polypeptide disclosed herein (e.g., an amino acid sequence contained in SEQ ID NO:Y, an amino acid sequence encoded by SEQ ID NO:X, or the complement thereof, an amino acid sequence encoded by the cDNA sequence contained in Clone ID NO:Z, an amino acid sequence encoded by SEQ ID NO:B, or the complement thereof, and fragments or variants
  • SEQ ID NO:X was often generated by overlapping sequences contained in multiple clones (contig analysis).
  • a representative clone containing all or most of the sequence for SEQ ID NO:X is deposited at Human Genome Sciences, Inc. (HGS) in a catalogued and archived library.
  • HGS Human Genome Sciences, Inc.
  • each clone is identified by a cDNA Clone ID (identifier generally referred to herein as Clone ID NO:Z).
  • Clone ID NO:Z identifier generally referred to herein as Clone ID NO:Z.
  • Each Clone ID is unique to an individual clone and the Clone ED is all the information needed to retrieve a given clone from the HGS library.
  • ATCC American Type Culture Collection
  • Library names contain four characters, for example, "HTWE.”
  • the name of a cDNA clone (Clone ID NO:Z) isolated from that library begins with the same four characters, for example "HTWEP07".
  • Table 1A correlates the Clone ID NO:Z names with SEQ ID NO:X.
  • SEQ ID NO:X the Clone ID NO:Z names with SEQ ID NO:X.
  • Tables 1A, 6 and 7 to determine the corresponding Clone ID NO:Z, which library it came from and which ATCC deposit the library is contained in.
  • it is possible to retrieve a given cDNA clone from the source library by techniques known in the art and described elsewhere herein.
  • the ATCC is located at 10801 University Boulevard, Manassas, Virginia 20110-2209, USA.
  • the ATCC deposits were made pursuant to the terms of the Budapest Treaty on' the international recognition of the deposit of microorganisms for the purposes of patent procedure.
  • the polynucleotides of the invention are at least 15, at least 30, at least 50, at least 100, at least 125, at least 500, or at least 1000 continuous nucleotides but are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb, 2.0 kb, or 1 kb, in length.
  • polynucleotides of the invention comprise a portion of the coding sequences, as disclosed herein, but do not comprise all or a portion of any intron.
  • the polynucleotides comprising coding sequences do not contain coding sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest in the genome). In other embodiments, the polynucleotides of the invention do not contain the coding sequence of more than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic flanking gene(s).
  • a "polynucleotide” of the present invention also includes those polynucleotides capable of hybridizing, under stringent hybridization conditions, to sequences contained in SEQ ID NO:X, or the complement thereof (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments described herein), the polynucleotide sequence delineated in columns 8 and 9 of Table 2 or the complement thereof, and/or cDNA sequences contained in Clone ID NO:Z (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments, or the cDNA clone within the pool of cDNA clones deposited with the ATCC, described herein) and/or the polynucleotide sequence delineated in column 6 of Table 1B or the complement thereof.
  • “Stringent hybridization conditions” refers to an overnight incubation at 42 degree C in a solution comprising 50% formamide, 5x SSC (750 mM NaCl, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt's solution, 10% dextran sulfate, and 20 ⁇ g/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.lx SSC at about 65 degree C.
  • nucleic acid molecules that hybridize to the polynucleotides of the present invention at lower stringency hybridization conditions. Changes in the stringency of hybridization and signal detection are primarily accomplished through the manipulation of formamide concentration (lower percentages of formamide result in lowered stringency), salt conditions, or temperature.
  • washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5X SSC).
  • blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations.
  • the inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility.
  • polynucleotide which hybridizes only to polyA+ sequences (such as any 3' terminal polyA+ tract of a cDNA shown in the sequence listing), or to a complementary stretch of T (or U) residues, would not be included in the definition of "polynucleotide,” since such a polynucleotide would hybridize to any nucleic acid molecule containing a poly (A) stretch or the complement thereof (e.g., practically any double-stranded cDNA clone generated using oligo dT as a primer).
  • the polynucleotide of the present invention can be composed of any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA.
  • polynucleotides can be composed of single- and double-stranded DNA, DNA that is a mixture of single- and double- stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions.
  • polynucleotide can be composed of triple- stranded regions comprising RNA or DNA or both RNA and DNA.
  • a polynucleotide may also contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons.
  • Modified bases include, for example, tritylated bases and unusual bases such as inosine.
  • a variety of modifications can be made to DNA and RNA; thus, "polynucleotide” embraces chemically, enzymatically, or metabolically modified forms.
  • the polypeptide of the present invention can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids.
  • the polypeptides may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini.
  • polypeptides may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods.
  • Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.
  • SEQ ID NO:X refers to a polynucleotide sequence described, for example, in
  • SEQ ID NO:Y refers to a polypeptide sequence described in column 5 of Table 1A.
  • SEQ ID NO:X is identified by an integer specified in column 3 of Table 1A.
  • the polypeptide sequence SEQ ID NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ED NO:X.
  • Clone DD NO:Z refers to a cDNA clone described in column 1 of Table 1A.
  • a polypeptide having biological activity refers to a polypeptide exhibiting activity similar to, but not necessarily identical to, an activity of a polypeptide of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar 'to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 25-fold less and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention).
  • Table 1A summarizes some of the reproductive system associated polynucleotides encompassed by the invention (including contig sequences (SEQ DD NO:X) and clones (Clone DD NO:Z) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby.
  • the first column in Table 1 A provides a unique "Clone ID NO:Z" for a cDNA clone related to each contig sequence disclosed in Table 1A.
  • This clone ID references the cDNA clone which contains at least the 5' most sequence of the assembled contig and at least a portion of SEQ ID NO:X was determined by directly sequencing the referenced clone.
  • the reference clone may have more sequence than described in the sequence listing or the clone may have less. In the vast majority of cases, however, the clone is believed to encode a full-length polypeptide. In the case where a clone is not full-length, a full-length cDNA can be obtained by methods known in the art and/or as described elsewhere herein.
  • the second column in Table 1A provides a unique "Contig ID” identification for each contig sequence.
  • the third column provides the "SEQ ID NO:X” identifier for each of the reproductive system associated contig polynucleotide sequences disclosed in Table 1A.
  • the fourth column, "ORF (From-To)" provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence "SEQ ID NO:X” that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table 1 A, column 5, as SEQ ID NO:Y. Where the nucleotide position number "To" is lower than the nucleotide position number "From”, the preferred ORF is the reverse complement of the referenced polynucleotide sequence.
  • the fifth column in Table 1A provides the corresponding SEQ ID NO:Y for the polypeptide sequence encoded by the preferred ORF delineated in column 4.
  • the invention provides an amino acid sequence comprising, or alternatively consisting of, a polypeptide encoded by the portion of SEQ ID NO:X delineated by "ORF (From-To)". Also provided are polynucleotides encoding such amino acid sequences and the complementary strand thereto.
  • polypeptides of the invention comprise, or alternatively consist of, at least one, two, three, four, five or more of the predicted epitopes as described in Table 1A.
  • Column 7 in Table 1A provides an expression profile and library code: count for each of the contig sequences (SEQ ID NO:X) disclosed in Table 1 A, which can routinely be combined with the information provided in Table 4 and used to determine the normal or diseased tissues, cells, and/or cell line libraries which predominantly express the polynucleotides of the invention.
  • the first number in column 7 represents the tissue/cell source identifier code corresponding to the code and description provided in Table 4.
  • the second number in column 7 represents the number of times a sequence corresponding to the reference polynucleotide sequence was identified in the tissue/cell source.
  • tissue/cell source identifier codes in which the first two letters are "AR” designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of P dCTP, using oligo(dT) to prime reverse transcription.
  • Column 8 in Table 1A provides a chromosomal map location for certain polynucleotides of the invention. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Each sequence in the UniGene database is assigned to a "cluster"; all of the ESTs, cDNAs, and STSs in a cluster are believed to be derived from a single gene. Chromosomal mapping data is often available for one or more sequence(s) in a UniGene cluster; this data (if consistent) is then applied to the cluster as a whole. Thus, it is possible to infer the chromosomal location of a new polynucleotide sequence by determining its identity with a mapped UniGene cluster.
  • HODEZ11 429 952166 AL049780 6303 1-79 1741-2345 2372-4365 4520-4951 4965-5086 8909-9080 9623-9884 11171-11276 11444-11552 12317-12505 12525-12605 13051-13119 13647-13742 14956-15395 15412-15622 16059-16168 17969-18042 18135-18576 18752-19394 20745-21012 21580-21955 26195-26275 27457-27874 28194-28464 28567-28646 30337-30467 30873-31422 32480-32632 33300-33564 33909-33994 34103-34189 34258-35147
  • HODEZ11 429 952166 AC006530 6304 1-79 1741-2345 2372-4365 4520-4951 4965-5086 HODFY16 459 958329 AL138499 6357 1-74
  • HODJZ90 502 965049 AC068659 6453 1-168 775-979 1331-1594 2315-2847 3900-4316 4491-5027 5100-7427 7603-8027 8209-8523 9220-9673 9808-9950 10065-10377
  • HUVHB59 1652 963129 AC011448 8319 1-406 7558-7707 8256-8999 9619-10069 10534-11483 12567-13076 13206-13306 14715-15081 15383-16006 17113-17421 20025-20379 20494-21037 21820-22049 25986-26138 26738-27046 30607-30829 31608-32051 32666-33121 33412-33853 33981-34267 34795-34926 36372-36867 37528-38224 38263-38433 39877-40078 40299-40555 40657-40936 43330-43632 44090-44737 46930-47485 47555-51146 53945-54090 54624-55209 55358-55711 55751-57192 57277-57864 57977-58467 58604-58920 59772-59859 59916-60034 61018-61515 61960-62306 63123-6
  • Table 1B summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO:Z), contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ ID NO:B).
  • the first column provides a unique clone identifier, "Clone ID NO:Z”, for a cDNA clone related to each contig sequence.
  • the second column provides the sequence identifier, "SEQ ID NO:X”, for each contig sequence.
  • the third column provides a unique contig identifier, "Contig ID:” for each contig sequence.
  • the fourth column provides a BAC identifier "BAC ID NO: A” for the BAC clone referenced in the corresponding row of the table.
  • the fifth column provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of the BAC clone identified in column four of the corresponding row of the table.
  • the sixth column provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof).
  • Table 2 further characterizes certain encoded polypeptides of the invention, by providing the results of comparisons to protein and protein family databases.
  • the first column provides a unique clone identifier, "Clone ID NO:”, corresponding to a cDNA clone disclosed in Table 1A.
  • the second column provides the unique contig indentifier, "Contig ID:” which allows correlation with the information in Table 1A.
  • the third column provides the sequence identifier, "SEQ ID NO:X”, for the contig polynucleotide sequences.
  • the fourth column provides the analysis method by which the homology/identity disclosed in the row was determined.
  • the fifth column provides a description of PFam/NR hits having significant matches identified by each analysis.
  • the NR database which comprises the NBRF PER. database, the NCBI
  • GenPept database was made non- redundant using the computer program nrdb2 (Warren Gish, Washington University in Saint Louis).
  • nrdb2 Warren Gish, Washington University in Saint Louis.
  • Each of the polynucleotides shown in Table 1A, column 3 was used to search against the NR database.
  • the computer program BLASTX was used to compare a 6-frame translation of the Query sequence to the NR database (for information about the BLASTX algorithm please see Altshul et al, J. Mol. Biol. 215:403-410 (1990), and Gish et al., Nat. Genet. 3:266-272 (1993)).
  • a description of the sequence that is most similar to the Query sequence (the highest scoring 'Subject') is shown in column five of Table 2 and the database accession number for that sequence is provided in column six.
  • the highest scoring 'Subject' is reported in Table 2 if (a) the estimated probability that the match occurred by chance alone is less than 1.0e-07, and (b) the match was not to a known repetitive element.
  • BLASTX returns alignments of short polypeptide segments of the Query and Subject sequences which share a high degree of similarity; these segments are known as High-Scoring Segment Pairs or HSPs.
  • Table 2 reports the degree of similarity between the Query and the Subject for each HSP as a percent identity in Column 7.
  • the percent identity is determined by dividing the number of exact matches between the two aligned sequences in the HSP, dividing by the number of Query amino acids in the HSP and multiplying by 100.
  • the polynucleotides of SEQ ID NO:X which encode the polypeptide sequence that generates an HSP are delineated by columns, 8 and 9 of Table 2.
  • HMM Hidden Markov Model
  • a HMM derived from PFam version 5.2 was said to be a significant match to a polypeptide of the invention if the score returned by HMMER 1.8 was greater than 0.8 times the HMMER 1.8 score obtained with the most distantly related known member of that protein family.
  • the description of the PFam family which shares a significant match with a polypeptide of the invention is listed in column 5 of Table 2, and the database accession number of the PFam hit is provided in column 6.
  • Column 7 provides the score returned by HMMER version 1.8 for the alignment.
  • Columns 8 and 9 delineate the polynucleotides of SEQ ID NO:X which encode the polypeptide sequence which shows a significant match to a PFam protein family.
  • the invention provides a protein comprising, or alternatively consisting of, a polypeptide encoded by the polynucleotides of SEQ ID NO:X delineated in columns 8 and 9 of Table 2. Also provided are polynucleotides encoding such proteins, and the complementary strand thereto.
  • nucleotide sequence SEQ ID NO:X and the translated SEQ ID NO:Y are sufficiently accurate and otherwise suitable for a variety of uses well known in the art and described further below.
  • the nucleotide sequences of SEQ ID NO:X are useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ ID NO:X or the cDNA contained in Clone ID NO:Z. These probes will also hybridize to nucleic acid molecules in biological samples, thereby enabling immediate applications in chromosome mapping, linkage analysis, tissue identification and/or typing, and a variety of forensic and diagnostic methods of the invention.
  • polypeptides identified from SEQ ID NO:Y may be used to generate antibodies which bind specifically to these polypeptides, or fragments thereof, and/or to the polypeptides encoded by the cDNA clones identified in, for example, Table 1A.
  • DNA sequences generated by sequencing reactions can contain sequencing errors.
  • the errors exist as misidentified nucleotides, or as insertions or deletions of nucleotides in the generated DNA sequence.
  • the erroneously inserted or deleted nucleotides cause frame shifts in the reading frames of the predicted amino acid sequence.
  • the predicted amino acid sequence diverges from the actual amino acid sequence, even though the generated DNA sequence may be greater than 99.9% identical to the actual DNA sequence (for example, one base insertion or deletion in an open reading frame of over 1000 bases).
  • the present invention provides not only the generated nucleotide sequence identified as SEQ ID NO:X, and a predicted translated amino acid sequence identified as SEQ ID NO:Y, but also a sample of plasmid DNA containing cDNA Clone TD NO:Z (deposited with the ATCC on October 5, 2000, and receiving ATCC designation numbers PTA 2574 and PTA 2575; deposited with the ATCC on January 5, 2001, having the depositor reference numbers TS-1, TS-2, AC-1, and AC-2; and/or as set forth, for example, in Table 1A, 6 and 7).
  • nucleotide sequence of each deposited clone can readily be determined by sequencing the deposited clone in accordance with known methods. Further, techniques known in the art can be used to verify the nucleotide sequences of SEQ ID NO:X. [082] The predicted amino acid sequence can then be verified from such deposits.
  • amino acid sequence of the protein encoded by a particular clone can also be directly determined by peptide sequencing or by expressing the protein in a suitable host cell containing the deposited human cDNA, collecting the protein, and determining its sequence.
  • Partial cDNA clones can be made full-length by utilizing the rapid amplification of cDNA ends (RACE) procedure described in Frohman, M.A., et al, Proc. Nat'l. Acad. Sci. USA, 85:8998-9002 (1988).
  • RACE rapid amplification of cDNA ends
  • RNA Poly A+ or total RNA is reverse transcribed with Superscript II (Gibco/BRL) and an antisense or complementary primer specific to the cDNA sequence.
  • the primer is removed from the reaction with a Microcon Concentrator (Amicon).
  • the first-strand cDNA is then tailed with dATP and terminal deoxynucleotide transferase (Gibco/BRL).
  • the second strand is synthesized from the dA-tail in PCR buffer, Taq DNA polymerase (Perkin-Elmer Cetus), an oligo-dT primer containing three adjacent restriction sites (Xhol, Sail and Clal) at the 5' end and a primer containing just these restriction sites.
  • This double-stranded cDNA is PCR amplified for 40 cycles with the same primers as well as a nested cDNA-specific antisense primer.
  • the PCR products are size-separated on an ethidium bromide- agarose gel and the region of gel containing cDNA products the predicted size of missing protein-coding DNA is removed.
  • cDNA is purified from the agarose with the Magic PCR Prep kit (Promega), restriction digested with Xhol or Sail, and ligated to a plasmid such as pBluescript SJ JJ (Stratagene) at Xhol and EcoRV sites.
  • This DNA is transformed into bacteria and the plasmid clones sequenced to identify the correct protein-coding inserts. Correct 5' ends are confirmed by comparing this sequence with the putatively identified homologue and overlap with the partial cDNA clone. Similar methods known in the art and/or commercial kits are used to amplify and recover 3' ends.
  • kit form Similar reagents and methods to those above are supplied in kit form from Gibco/BRL for both 5' and 3' RACE for recovery of full length genes.
  • a second kit is available from Clontech which is a modification of a related technique, SLIC (single-stranded ligation to single-stranded cDNA), developed by Dumas et al., Nucleic Acids Res., 19:5227-32 (1991).
  • SLIC single-stranded ligation to single-stranded cDNA
  • the major differences in procedure are that the RNA is alkaline hydrolyzed after reverse transcription and RNA ligase is used to join a restriction site- containing anchor primer to the first-strand cDNA. This obviates the necessity for the dA-tailing reaction which results in a polyT stretch that is difficult to sequence past.
  • An alternative to generating 5' or 3' cDNA from RNA is to use cDNA library double-stranded DNA.
  • An asymmetric PCR-amplified antisense cDNA strand is synthesized with an antisense cDNA-specific primer and a plasmid-anchored primer. These primers are removed and a symmetric PCR reaction is performed with a nested cDNA-specific antisense primer and the plasmid-anchored primer.
  • RNA oligonucleotide is ligated to the 5' ends of a population of RNA presumably containing full-length gene RNA transcript.
  • a primer set containing a primer specific to the ligated RNA oligonucleotide and a primer specific to a known sequence of the gene of interest is used to PCR amplify the 5' portion of the desired full length gene which may then be sequenced and used to generate the full length gene.
  • This method starts with total RNA isolated from the desired source, poly A RNA may be used but is not a prerequisite for this procedure.
  • RNA preparation may then be treated with phosphatase if necessary to eliminate 5' phosphate groups on degraded or damaged RNA which may interfere with the later RNA ligase step.
  • the phosphatase if used, is then inactivated and the RNA is treated with tobacco acid pyrophosphatase in order to remove the cap structure present at the 5' ends of messenger RNAs.
  • This reaction leaves a 5' phosphate group at the 5' end of the cap cleaved RNA which can then be ligated to an RNA oligonucleotide using T4 RNA ligase.
  • This modified RNA preparation can then be used as a template for first strand cDNA synthesis using a gene specific oligonucleotide.
  • the first strand synthesis reaction can then be used as a template for PCR amplification of the desired 5' end using a primer specific to the ligated RNA oligonucleotide and a primer specific to the known sequence of the reproductive system antigen of interest.
  • the resultant product is then sequenced and analyzed to confirm that the 5' end sequence belongs to the relevant reproductive system antigen.
  • the present invention also relates to vectors or plasmids, which include such
  • the material deposited with the ATCC (deposited with the ATCC on October 5, 2000, and receiving ATCC designation numbers PTA 2574 and PTA 2575; deposited with the ATCC on January 5, 2001, having the depositor reference numbers TS-1, TS-2, AC-1, and AC-2; and/or as set forth, for example, in Table 1 A, 6 and 7) is a mixture of cDNA clones derived from a variety of human tissue and cloned in either a plasmid vector or a phage vector, as shown, for example, in Table 7. These deposits are referred to as "the deposits" herein.
  • the tissues from which some of the clones were derived are listed in Table 7, and the vector in which the corresponding cDNA is contained is also indicated in Table 7.
  • the deposited material includes cDNA clones corresponding to SEQ ID NO:X described, for example, in Table 1A (Clone ID NO:Z).
  • a clone which is isolatable from the ATCC Deposits by use of a sequence listed as SEQ ID NO:X may include the entire coding region of a human gene or in other cases such clone may include a substantial portion of the coding region of a human gene.
  • sequence listing may in some instances list only a portion of the DNA sequence in a clone included in the ATCC Deposits, it is well within the ability of one skilled in the art to sequence the DNA included in a clone contained in the ATCC Deposits by use of a sequence (or portion thereof) described in, for example Tables 1A or 2 by procedures hereinafter further described, and others apparent to those skilled in the art.
  • Table 7 Also provided in Table 7 is the name of the vector which contains the cDNA clone. Each vector is routinely used in the art. The following additional information is provided for convenience.
  • Phagemid pBS contains an ampiciUin resistance gene and pBK contains a neomycin resistance gene.
  • Phagemid pBS may be excised from the Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express vector. Both phagemids may be transformed into E. coli strain XL-1 Blue, also available from Stratagene.
  • Vectors pSportl, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0 were obtained from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All Sport vectors contain an ampiciUin resistance gene and may be transformed into E. coli strain DH10B, also available from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59- (1993). Vector lafrnid BA (Bento Soares, Columbia University, New York, NY) contains an ampiciUin resistance gene and can be transformed into E. coli strain XL-1 Blue.
  • Vector pCR ® 2.1 which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an ampiciUin resistance gene and may be transformed into E. coli strain DH10B, available from Life Technologies. See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology 9: (1991). [091] The present invention also relates to the genes corresponding to SEQ ED NO:X,
  • SEQ ID NO:Y SEQ ID NO:Y
  • the deposited clone Clone ID NO:Z
  • the corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic material.
  • allelic variants, orthologs, and/or species homologs are also provided in the present invention. Procedures known in the art can be used to obtain full-length genes, allelic variants, splice variants, full-length coding portions, orthologs, and/or species homologs of reproductive system associated genes corresponding to SEQ ED NO:X or the complement thereof, polypeptides encoded by SEQ ED NO:X or the complement thereof, and/or the cDNA contained in Clone ED NO:Z, using information from the sequences disclosed herein or the clones deposited with the ATCC.
  • allelic variants and/or species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source for allelic variants and/or the desired homologue.
  • polypeptides of the invention can be prepared in any suitable manner.
  • polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art.
  • polypeptides may be in the form of the secreted protein, including the mature form, or may be a part of a larger protein, such as a fusion protein (see below). It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification, such as multiple histidine residues, or an additional sequence for stability during recombinant production.
  • polypeptides of the present invention are preferably provided in an isolated form, and preferably are substantially purified.
  • a recombinantly produced version of a polypeptide, including the secreted polypeptide can be substantially purified using techniques described herein or otherwise known in the art, such as, for example, by the one-step method described in Smith and Johnson, Gene 67:31-40 (1988).
  • Polypeptides of the invention also can be purified from natural, synthetic or recombinant sources using techniques described herein or otherwise known in the art, such as, for example, antibodies of the invention raised against the reproductive system polypeptides of the present invention in methods which are well known in the art.
  • the present invention provides a polynucleotide comprising, or alternatively consisting of, the nucleic acid sequence of SEQ ED NO:X, and/or the cDNA sequence contained in Clone ED NO:Z.
  • the present invention also provides a polypeptide comprising, or alternatively, consisting of, the polypeptide sequence of SEQ ED NO: Y, a polypeptide encoded by SEQ ED NO:X or a complement thereof, a polypeptide encoded by the cDNA contained in Clone ED NO:Z, and/or the polypeptide sequence encoded by a nucleotide sequence in SEQ ED NO:B as defined in column 6 of Table 1B.
  • Polynucleotides encoding a polypeptide comprising, or alternatively consisting of the polypeptide sequence of SEQ ED NO:Y, a polypeptide encoded by SEQ ED NO:X, a polypeptide encoded by the cDNA contained in Clone ED NO:Z and/or a polypeptide sequence encoded by a nucleotide sequence in SEQ ED NO:B as defined in column 6 of Table 1B are also encompassed by the invention.
  • the present invention further encompasses a polynucleotide comprising, or alternatively consisting of, the complement of the nucleic acid sequence of SEQ ED NO:X, a nucleic acid sequence encoding a polypeptide encoded by the complement of the nucleic acid sequence of SEQ ED NO:X, and/or the cDNA contained in Clone ED NO:Z.
  • representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in Table 1B column 6, or any combination thereof.
  • Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in Table 1B column 6, or any combination thereof.
  • the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ED NO:B (see Table 1B, column 5).
  • the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ED NO:A (see Table 1B, column 4).
  • the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ED NO:A (see Table 1B, column 4).
  • Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.
  • representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ED NO:Z (see Table 1B, column 1), or any combination thereof.
  • Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ED NO:Z (see Table 1B, column 1), or any combination thereof.
  • the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same Clone ED NO:Z (see Table 1B, column 1) and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ED NO:B (see Table 1B, column 5).
  • polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same Clone ED NO:Z (see Table 1B, column 1) and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ED NO:A (see Table 1B, column 4).
  • the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same Clone ED NO:Z (see Table 1B, column 1) and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ED NO: A (see Table 1B, column 4).
  • Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above- described polynucleotides and polypeptides are also encompassed by the invention.
  • polynucleotides of the invention comprise, or altematively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ED NO:X (see Table 1B, column 2), or any combination thereof.
  • polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ED NO:X (see Table 1B, column 2), or any combination thereof.
  • the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ED NO:X (see Table 1B, column 2) and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ED NO:B (see Table 1B, column 5).
  • polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ED NO:X (see Table 1B, column 2) and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ED NO:A (see Table 1B, column 4).
  • the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ED NO:X (see Table 1B, column 2) and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ED NO:A (See Table 1B, column 4).
  • Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.
  • representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in the same row of Table 1B column 6, or any combination thereof.
  • Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in the same row of Table 1B column 6, or any combination thereof.
  • the polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strand(s) of the sequences delineated in the same row of Table 1B column 6, wherein sequentially delineated sequences in the table (i.e. corresponding to those exons located closest to each other) are directly contiguous in a 5' to 3' orientation.
  • above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ED NO:B (see Table 1B, column 5).
  • the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ED NO:A (see Table 1B, column 4).
  • polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ED NO: A (see Table 1B, column 4).
  • Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.
  • polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B, and the polynucleotide sequence of SEQ ED NO:X (e.g., as defined in Table 1B, column 2) or fragments or variants thereof.
  • Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.
  • polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ED NO:Z (see Table 1B, column 1), and the polynucleotide sequence of SEQ ED NO:X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof.
  • the delineated sequence(s) and polynucleotide sequence of SEQ ED NO:X correspond to the same Clone ED NO:Z.
  • Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.
  • polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in the same row of column 6 of Table 1B, and the polynucleotide sequence of SEQ ED NO:X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof.
  • the delineated sequence(s) and polynucleotide sequence of SEQ ED NO:X correspond to the same row of column 6 of Table 1B.
  • Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.
  • polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3' 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5' 10 polynucleotides of the sequence of SEQ ED NO:X are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention.
  • Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above- described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
  • polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5' 10 polynucleotides of a fragment or variant of the sequence of SEQ ED NO:X are directly contiguous Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention.
  • Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
  • polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides of the sequence of SEQ ED NO:X and the 5' 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1B are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention.
  • Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above- described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
  • polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides of a fragment or variant of the sequence of SEQ ED NO:X and the 5' 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1B are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention.
  • Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides, are also encompassed by the invention.
  • polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5' 10 polynucleotides of another sequence in column 6 are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention.
  • Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above- described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
  • polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5' 10 polynucleotides of another sequence in column 6 corresponding to the same Clone ED NO:Z (see Table 1B, column 1) are directly contiguous. Nucleic acids which hybridize to the complement of these 20 lower stringency conditions, are also encompassed by the invention.
  • Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
  • polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides of one sequence in column 6 corresponding to the same contig sequence identifer SEQ ED NO:X (see Table 1B, column 2) are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention.
  • Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
  • polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3' T0 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5' 10 polynucleotides of another sequence in column 6 corresponding to the same row are directly contiguous.
  • the 3' 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B is directly contiguous with the 5' 10 polynucleotides of the next sequential exon delineated in Table 1B, column 6.
  • Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions are also encompassed by the invention.
  • Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above- described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
  • polynucleotide sequences such as EST sequences, are publicly available and accessible through sequence databases and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention.
  • each contig sequence (SEQ ED NO:X) listed in the third column of Table 1A, preferably excluded are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 and the final nucleotide minus 15 of SEQ ED NO:X, b is an integer of 15 to the final nucleotide of SEQ ED NO:X, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and where b is greater than or equal to a + 14.
  • polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a and b are integers as defined in columns 4 and 5, respectively, of Table 3.
  • the polynucleotides of the invention do not consist of at least one, two, three, four, five, ten, or more of the specific polynucleotide sequences referenced by the Genbank Accession No. as disclosed in column 6 of Table 3 (including for example, published sequence in connection with a particular BAC clone).
  • preferably excluded from the invention are the specific polynucleotide sequence(s) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including for example, the actual sequence contained in an identified BAC clone). In no way is this listing meant to encompass all of the sequences which may be excluded by the general formula, it is just a representative example. All references available through these accessions are hereby incorporated by reference in their entirety.

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Abstract

L'invention concerne de nouveaux polynucléotides associés au cancer de l'appareil génital et les polypeptides codés par ces polynucléotides désignés ici sous le nom collectif de « antigènes du cancer de l'appareil génital », ainsi que l'utilisation de ces antigènes du cancer de l'appareil génital pour détecter des troubles de l'appareil génital, notamment la présence du cancer de l'appareil génital et de métastases du cancer de l'appareil génital. D'une manière plus spécifique, l'invention concerne des molécules isolées d'acide nucléique associées au cancer de l'appareil génital codant pour de nouveaux polypeptides associés au cancer de l'appareil génital; de nouveaux polypeptides et anticorps associés au cancer de l'appareil génital qui se lient à ces polypeptides; des vecteurs, des cellules hôtes et des méthodes de recombinaison et de synthèse permettant de produire ces polynucléotides et/ou ces polypeptides associés au cancer de l'appareil génital humain; des méthodes diagnostiques et thérapeutiques qui conviennent pour le diagnostic, le traitement, la prévention et/ou le pronostic de troubles associés à l'appareil génital, notamment le cancer de l'appareil génital, ainsi que des méthodes thérapeutiques permettant de traiter ces troubles; des méthodes de criblage permettant d'identifier des agonistes et des antagonistes des polynucléotides et des polypeptides selon l'invention; des méthodes et/ou des compositions permettant d'inhiber la production et la fonction des polypeptides selon l'invention.
PCT/US2001/001339 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps Ceased WO2001055320A2 (fr)

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AU2001243134A AU2001243134A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
US09/908,711 US20020045230A1 (en) 2000-08-14 2001-07-20 Nucleic acids, proteins, and antibodies

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Family Applications (48)

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PCT/US2001/001339 Ceased WO2001055320A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001326 Ceased WO2001055315A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines, et anticorps
PCT/US2001/001350 Ceased WO2001055350A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001314 Ceased WO2001055310A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001317 Ceased WO2001055201A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001354 Ceased WO2001057182A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001301 Ceased WO2001055303A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001336 Ceased WO2001055204A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001355 Ceased WO2001055207A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001357 Ceased WO2001055208A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001312 Ceased WO2001054733A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001325 Ceased WO2001055202A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001344 Ceased WO2001055324A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001343 Ceased WO2001055323A2 (fr) 2000-01-31 2001-01-17 Acides ncleiques, proteines et anticorps
PCT/US2001/001316 Ceased WO2001054473A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001352 Ceased WO2001055327A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001328 Ceased WO2001055316A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001358 Ceased WO2001055163A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines, et anticorps
PCT/US2001/001348 Ceased WO2001055368A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001340 Ceased WO2001055321A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001353 Ceased WO2001055206A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001332 Ceased WO2001055318A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001315 Ceased WO2001055311A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001240 Ceased WO2001055302A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001330 Ceased WO2001055447A1 (fr) 2000-01-31 2001-01-17 Acides nucléiques, proteines et anticorps
PCT/US2001/001239 Ceased WO2001055301A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001327 Ceased WO2001055203A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001337 Ceased WO2001055205A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001356 Ceased WO2001055173A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001311 Ceased WO2001055309A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001345 Ceased WO2001055325A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001359 Ceased WO2001055328A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001324 Ceased WO2001055314A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001310 Ceased WO2001055387A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001313 Ceased WO2001055200A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001333 Ceased WO2001055448A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001338 Ceased WO2001055367A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et antigenes
PCT/US2001/001302 Ceased WO2001055304A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001349 Ceased WO2001054474A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001322 Ceased WO2001055343A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001306 Ceased WO2001055307A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001341 Ceased WO2001055322A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001321 Ceased WO2001055312A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001342 Ceased WO2001059064A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001309 Ceased WO2001055308A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001308 Ceased WO2001055364A2 (fr) 2000-01-31 2001-01-17 Acides nucléiques, protéines et anticorps
PCT/US2001/001351 Ceased WO2001055355A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001335 Ceased WO2001055319A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps

Family Applications After (47)

Application Number Title Priority Date Filing Date
PCT/US2001/001326 Ceased WO2001055315A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines, et anticorps
PCT/US2001/001350 Ceased WO2001055350A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001314 Ceased WO2001055310A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001317 Ceased WO2001055201A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001354 Ceased WO2001057182A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001301 Ceased WO2001055303A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001336 Ceased WO2001055204A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001355 Ceased WO2001055207A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001357 Ceased WO2001055208A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001312 Ceased WO2001054733A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001325 Ceased WO2001055202A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001344 Ceased WO2001055324A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001343 Ceased WO2001055323A2 (fr) 2000-01-31 2001-01-17 Acides ncleiques, proteines et anticorps
PCT/US2001/001316 Ceased WO2001054473A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001352 Ceased WO2001055327A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001328 Ceased WO2001055316A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001358 Ceased WO2001055163A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines, et anticorps
PCT/US2001/001348 Ceased WO2001055368A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001340 Ceased WO2001055321A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001353 Ceased WO2001055206A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001332 Ceased WO2001055318A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001315 Ceased WO2001055311A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001240 Ceased WO2001055302A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001330 Ceased WO2001055447A1 (fr) 2000-01-31 2001-01-17 Acides nucléiques, proteines et anticorps
PCT/US2001/001239 Ceased WO2001055301A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001327 Ceased WO2001055203A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001337 Ceased WO2001055205A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001356 Ceased WO2001055173A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001311 Ceased WO2001055309A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001345 Ceased WO2001055325A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001359 Ceased WO2001055328A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001324 Ceased WO2001055314A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001310 Ceased WO2001055387A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001313 Ceased WO2001055200A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001333 Ceased WO2001055448A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001338 Ceased WO2001055367A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et antigenes
PCT/US2001/001302 Ceased WO2001055304A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001349 Ceased WO2001054474A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001322 Ceased WO2001055343A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001306 Ceased WO2001055307A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001341 Ceased WO2001055322A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001321 Ceased WO2001055312A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001342 Ceased WO2001059064A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001309 Ceased WO2001055308A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001308 Ceased WO2001055364A2 (fr) 2000-01-31 2001-01-17 Acides nucléiques, protéines et anticorps
PCT/US2001/001351 Ceased WO2001055355A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
PCT/US2001/001335 Ceased WO2001055319A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps

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EP4294933A4 (fr) * 2021-02-19 2025-10-15 Nuclear Rna Networks Inc Compositions et procédés pour moduler des réseaux de transcription de gènes en fonction de séquences rémanentes d'éléments transposables à haute identité partagées et de transcrits de promoteur non processif et de transcrits proximaux de promoteur

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WO2001055303A8 (fr) 2001-09-07
WO2001055323A2 (fr) 2001-08-02
WO2001055364A8 (fr) 2001-09-07
AU2001241416A1 (en) 2001-08-07
WO2001055200A8 (fr) 2001-09-07
AU2001241405A1 (en) 2001-08-07
WO2001055322A8 (fr) 2001-09-07
WO2001055315A2 (fr) 2001-08-02
WO2001055350A8 (fr) 2001-09-07
WO2001055322A2 (fr) 2001-08-02
AU2001241415A1 (en) 2001-08-07
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WO2001055320A3 (fr) 2002-04-11
WO2001055316A2 (fr) 2001-08-02
WO2001055308A3 (fr) 2002-07-04
WO2001055324A8 (fr) 2001-09-07
WO2001055387A1 (fr) 2001-08-02
WO2001055307A8 (fr) 2001-09-07
WO2001055367A8 (fr) 2001-12-20
WO2001055324A3 (fr) 2002-01-24
WO2001059064A2 (fr) 2001-08-16
AU2001241410A1 (en) 2001-08-07
WO2001055208A8 (fr) 2001-09-07
WO2001054473A8 (fr) 2001-09-07
AU4141101A (en) 2001-08-20
CA2393002A1 (fr) 2001-08-02
CA2393652A1 (fr) 2001-08-02
WO2001055301A3 (fr) 2009-06-04
CA2395787A1 (fr) 2001-08-02
WO2001054474A8 (fr) 2001-12-20
WO2001055163A8 (fr) 2001-09-07
CA2398877A1 (fr) 2001-08-09
WO2001055312A2 (fr) 2001-08-02
WO2001055207A8 (fr) 2001-09-07
WO2001055321A8 (fr) 2001-09-07
AU2001241412A1 (en) 2001-08-07
WO2001055303A3 (fr) 2001-12-20
CA2395827A1 (fr) 2001-08-02
WO2001055318A8 (fr) 2001-09-07
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WO2001055364A2 (fr) 2001-08-02
WO2001055206A8 (fr) 2001-12-13
WO2001055367A1 (fr) 2001-08-02
WO2001055316A8 (fr) 2001-09-07
WO2001055355A1 (fr) 2001-08-02
WO2001055319A2 (fr) 2001-08-02
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WO2001055368A8 (fr) 2001-09-07
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