EP1261745A2 - Acides nucleiques, proteines et anticorps - Google Patents

Acides nucleiques, proteines et anticorps

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Publication number
EP1261745A2
EP1261745A2 EP01924085A EP01924085A EP1261745A2 EP 1261745 A2 EP1261745 A2 EP 1261745A2 EP 01924085 A EP01924085 A EP 01924085A EP 01924085 A EP01924085 A EP 01924085A EP 1261745 A2 EP1261745 A2 EP 1261745A2
Authority
EP
European Patent Office
Prior art keywords
polypeptide
seq
sequence
polypeptides
polynucleotides
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01924085A
Other languages
German (de)
English (en)
Inventor
Craig A. Rosen
Steven C. Barash
Steven M. Ruben
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Human Genome Sciences Inc
Original Assignee
Human Genome Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Human Genome Sciences Inc filed Critical Human Genome Sciences Inc
Priority claimed from PCT/US2001/001334 external-priority patent/WO2001059063A2/fr
Publication of EP1261745A2 publication Critical patent/EP1261745A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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

  • Sequence Listing is provided as an electronic file (PC010PCT_seqList.txt, 23,109,132 bytes in size, created on January 12, 2001) on four identical compact discs (CD-R), labeled "COPY 1," "COPY 2,” “COPY 3,” and "CRF.”
  • the Sequence Listing complies with Annex C of the Administrative Instructions, and maybe viewed, for example, on an IBM-PC machine running the MS-Windows operating system by using the V viewer software, version 2000 (see World Wide Web URL: http://www.fileviewer.com).
  • the present invention relates to novel nervous system related polynucleotides, the polypeptides encoded by these polynucleotides herein collectively referred to as "nervous system antigens," and antibodies that immunospecifically bind these polypeptides, and the use of such nervous system polynucleotides, antigens, and antibodies for detecting, treating, preventing and/or prognosing disorders of the nervous system, including, but not limited to, the presence of cancers of the nervous system and metastases of nervous system cancers. More specifically, isolated nervous system nucleic acid molecules are provided encoding novel nervous system polypeptides. Novel nervous system polypeptides and antibodies that bind to these polypeptides are provided.
  • vectors, host cells, and recombinant and synthetic methods for producing human nervous system polynucleotides, polypeptides, and/or antibodies are also provided.
  • the invention further relates to diagnostic ai d therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to the nervous system, including cancers of the nervous 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 brain is the control center of the body, encoding such functions as the ability to move, touch, taste, smell, hear, and see, for example. It reviews all stimuli, whether from internal organs or the surface of the body, and generates a reaction, such as movement of the limbs, adjustment of the rate at which internal organs function, and/or alteration of mood. Stimuli and reactions are transmitted to and from the brain via the spinal cord, a collection of nerves encased within bony vertebrae. Both the brain and spinal cord are wrapped in three layers of tissue, collectively called the meninges, which provide cushioning and protection. Together, these components make up the central nervous system (CNS).
  • CNS central nervous system
  • the human brain is subdivided into three major segments: the brain stem, midbrain, and forebrain.
  • the brain stem is considered to be the seat of the "primitive brain". It comprises such structures as the medulla and cerebellum, which control basic functions like breathing, heart rate, and digestion and the coordination of the senses and muscle movement, respectively. Many of these features are homologous across species.
  • the midbrain controls many sensory and motor functions, including eye movement, and links the brain stem to such structures as the thalamus (for information relay) and hypothalamus (which is instrumental in regulating autonomic functions, like maintaining body temperature, regulating water balance, and controlling sleep).
  • the forebrain is associated with the "high-level" functions of complex organisms.
  • This area includes specialized regions for the control of skilled motor behaviors (e.g., speech, mood, thought, and planning for the future), interpretation of sensory input from the rest of the body, control of voluntary body movements, interpretation of vision, retrieval of long-term memories, recognition of familiar objects, and initiation of communication or action.
  • skilled motor behaviors e.g., speech, mood, thought, and planning for the future
  • Common injuries resulting from head trauma include herniation, edema, hematomas ( subdural and epidural) , amnesia, coma, stupor, delirium, persistent or chronic vegetative state, concussion and post-concussion syndrome, cerebral contusions, damage to specific brain areas (e.g., the aphasias, apraxia, agnosia, and amnesia), and posttraumatic epilepsy.
  • Bacteria and other infectious organisms can reach the CNS in through the blood stream or by penetration through an injury or surgery wound, leading to several serious diseases, such as bacterial meningitis, Waterhouse-Friderichsen syndrome, chronic meningitis, viral meningitis (e.g., lyphocytic choriomeningitis), bacterial meningitis (e.g., Haemophilus, Listeria, Meningococcal, pneumococcal, or meningeal tuberculosis), encephalitis, encephalomyelitis, Hallervorden-Spatz syndrome, aseptic meningitis, parainfectious encephalitis, subacute sclerosing panencephalitis, brain abscesses, AIDS dementia complex, Japanese encephalitis, St.
  • diseases such as bacterial meningitis, Waterhouse-Friderichsen syndrome, chronic meningitis, viral meningitis (e.g., lyphocytic chorio
  • brain diseases include hydrocephalus (e.g., Dandy-Walker syndrome or normal pressure hydroencephalitis), Rhett syndrome, Reye's syndrome, pseudotumor cerebri, intracranial tuberculoma, Zellweger syndrome, narcolepsy, cataplexy, and cerebellar diseases.
  • the spinal cord is equally susceptible to injury and disease, which can result in cervical spondylosis, cysts, acute transverse myelitis, spinal hematoma, nerve root disorders (e.g., sciatica, spinal stenosis, and shingles), ruptured disk, and spinal cord compression. Together, this illustrates the relative frailty of the CNS.
  • the peripheral nervous system includes all nerves outside the CNS: the cranial nerves that connect the head and face directly to the brain, the nerves that connect the eyes and nose to the brain, and all the nerves that connect the spinal cord to the rest of the body.
  • the brain communicates with much of the body through the thirty-one pairs of spinal nerves that emerge from the spinal cord. Each pair includes one nerve at the front of the spinal cord, which carries information from the brain to the muscles, and one nerve located at the back of the spinal cord, which carries sensory information to the brain.
  • Peripheral nerves are actually bundles of nerve fibers - some of which are very small (less than 1/64 of and inch in diameter) and others are quite large. Large fibers convey the messages that activate muscles (motor nerves) and the sensations of touch and position (sensory nerves), whereas small fibers convey sensations of pain and temperature and control the automatic functions of the body, such as heart rate and blood pressure (autonomic nerves).
  • plexus disorders e.g., acute brachial neuritis
  • thoracic outlet syndromes mononeuropathy (e.g., carpal tunnel syndrome, leprosy, ulnar nerve palsy, radial nerve palsy, and peroneal nerve palsy), multiple mononeuropathy, polyneuropathy (e.g., chronic polyneuropathy and diabetic neuropathy), Guillain-Barre syndrome, and heredtiary neuropathies (e.g., Charcot-Marie-Tooth disease and Dejerine-Sottas disease).
  • plexus disorders e.g., acute brachial neuritis
  • thoracic outlet syndromes e.g., thoracic outlet syndromes
  • mononeuropathy e.g., carpal tunnel syndrome, leprosy, ulnar nerve palsy, radial nerve palsy, and peroneal nerve palsy
  • multiple mononeuropathy e.g., polyneuropathy (e.g.,
  • Nerve cells are the fundamental elements of both the CNS and PNS. In total, there are an estimated 100 billion neurons in a human body. While neurons are similar to other cells of the body in their general organization, they also posses highly specialized and unique features which are critical to the function of the nervous system. Each neuron is comprised of four distinct regions: the cell body, a single axon, dendrites, and axon terminals. The cell body contains the nucleus and other organelles necessary for the life and functioning of the neuron. The dendrites are processes that extend outward from the cell body and receive signals from sensory organs or from other neurons. In the dendrites, incoming signals are converted to electrical impulses and transmitted to the cell body for processing.
  • a single axon extends from the cell body, which conducts information from the cell body to organs, muscles, or other neurons.
  • At the end of the axon is an array of axon termini. These termini are the transmitting elements of a neuron. By means of these termini, an axon is able to transmit information to the receptive surfaces (typically the dendrites or the cell body) of other neurons or muscle cells.
  • cytoskeletal fibers including microtubules and neurofilaments, which run the length of the axon and function in transporting proteins, vesicles, and other macromolecules to the axon terminal.
  • some axons are surrounded by a myelin sheath made up of membranes from either oligodendrocyte cells (CNS) or Schwann cells (PNS).
  • CNS oligodendrocyte cells
  • PNS Schwann cells
  • Damage to the myelin sheath has been associated with several known disease states, including multiple sclerosis, acute disseminated encephalomyelitis, Canavan disease, diffuse cerebral sclerosis, encephalitis periaxialis, global cell leukodystrophy, metachromatic leukodystrophy, allergic encephalomyelitis, necrotizing hemorrhagic encephalomyelitis, progressive multifocal leukoencephalopathy, central pontine myelinolysis, transverse myelinolysis, neuromyelitis optica, scrapie, swayback, adrenoleukodystrophy, adrenomyeloneuropathy, Leber's hereditary optic atrophy, and HTLV-associated myelopathy.
  • synapse contact between neurons occurs at a specialized site called a synapse.
  • the axon terminal from one neuron (the presynaptic cell) sends a signal to another neuron (the postsynaptic cell).
  • Synapses may be connected either electrically or chemically.
  • An electrical synapse consists of gap junctions that directly connect two neurons. This allows electrical signals to pass unabated from the presynaptic to postsynaptic neuron.
  • the electrical signals are produced by temporary changes in the current flow into and out of the cell.
  • Ion channels embedded in the membrane regulate current flow by selectively regulating the passage of a specific ion or ions across the membrane.
  • Gated channels in contrast, exist in two stable conformations - open and closed. Most gated channels are closed when the membrane is at its resting potential, and open when stimulated by external factors such as a change in membrane potential, ligand binding, or membrane stretch.
  • Agonists, antagonists, and antibodies that bind to or block ion channels are extremely useful tools for studying brain function, which could lead to significant advances in understanding disease and the development of therapies.
  • tertrodotoxin (TTX) isolated from the poison sacks of the puffer fish, selectively blocks the voltage-gated sodium channels necessary for producing an excitatory electrical potential. This provides the researcher with a powerful tool for studying the effects of activity blockade on such processes as neural network development, learning and memory.
  • the axon termini of the presynaptic cell contain vesicles filled with a particular molecule (neurotransmitter).
  • An electrical signal from the cell body travels down the axon to the axon termini, where it triggers the release of neurotransmitter from the vesicle by exocytosis.
  • the neurotransmitter rapidly diffuses across the synaptic cleft separating the presynaptic from the postsynaptic neuron.
  • the neurotransmitter then binds to receptors located on the dendrites of the postsynaptic neuron, which open ion channels and provokes a qhange in the cell's electric potential. This change in electrical potential prompts further transmission of the signal.
  • axon termini reside adjacent to muscle cells within depressions formed in the motor end-plate.
  • An electrical signal prompts the release of neurotransmitter from axon termini, which diffuses across the synaptic cleft and binds to receptors located on the surface of the muscle cell. Binding of neurotransmitter provokes an electrical response that stimulates contraction of the muscle. Dysfunction of the neuromuscular junction plays a role in several neurological disorders. For example, in myasthenia gravis the immune system produces antibodies that attack the neurotransmitter receptors located on the muscle, preventing neurotransmitter binding and muscle contraction.
  • these antibodies can also be transferred from mother to child through the placenta, resulting in a variation of the disease called neonatal myasthenia, whose symptoms typically disappear shortly after birth.
  • Other known neuromuscular junction disorders include Eaton-Lambert syndrome and botulism.
  • Neurotransmitters comprise a diverse group of small molecules, such as L- glutamine and acetylcholine, or peptides like enkephalin (McCance and Huenther, Pathophysiology, the Biological Basis for Disease in Adults and Humans,2 nd edition, pp.403-404 (1994)). Neurotransmitters are synthesized within the cell body of the presynaptic neuron and transported to the axon termini in vesicles, where they reside until exocytosed. The effects of neurotransmitters can be excitatory (e.g initiation of neuron stimulation) or inhibitory (e.g., to hyperpolarize the plasma membrane and inhibit signal transmission). Many neurotransmitters are capable of eliciting either an excitatory or inhibitory response, dependent on the number and type of receptors located on the postsynaptic neuron.
  • L- glutamine and acetylcholine or peptides like enkephalin
  • the aberrant activity of neurotransmitters and their receptors has been linked to a number of neurological disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, and myasthenia gravis (Planells-Cases et al., PNAS 90: 5057-5061 (1993)), identifying an important need for the discovery of novel polypeptides, agonists, antagonists, and corresponding to neurotransmitters.
  • each neuron is connected to approximately ten thousand other neurons (Tessier-Lavigne et al., Science 274: 1123-1133 (1996)). While the overall program for determining which neurons should be connected together is under genetic control, it is external stimuli from sensory neurons that are crucially important in determining what network connections are actually made. To clarify, precise neural wiring is not fully developed at birth, but only roughly approximates the final network required to be fully functional. During embryonic development, neural connections are initiated via the programmed extension of axons, tipped at the leading end with a growth cone that is guided by molecular cues.
  • the present invention relates to novel nervous system related polynucleotides, the polypeptides encoded by these polynucleotides herein collectively referred to as "nervous system antigens," and antibodies that immunospecifically bind these polypeptides, and the use of such nervous system polynucleotides, antigens, and antibodies for detecting, treating, preventing and/or prognosing disorders of the nervous system, including, but not limited to, the presence of cancers of the nervous system and metastases of cancers of the nervous system. More specifically, isolated nervous system nucleic acid molecules are provided encoding novel nervous system polypeptides. Novel nervous system polypeptides and antibodies that bind to these polypeptides are provided.
  • vectors, host cells, and recombinant and synthetic methods for producing human nervous 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 nervous system, including cancers of the nervous 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 (SEQ ID NO:X)) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby.
  • the first column provides a unique clone identifier, "Clone ID NO:Z”, for a cDNA plasmid related to each nervous 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 1A.
  • the third column provides the sequence identifier, "SEQ ID NO:X”, for each of the 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 of SEQ ED NO:X that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table 1A as SEQ J_D NO:Y (column 5).
  • Column 6 lists residues comprising predicted epitopes contained in the polypeptides encoded by each of the preferred ORFs (SEQ DD NO:Y).
  • nervous 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 1 A.
  • 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 represents the tissue/cell source identifier code corresponding to the code and description provided in Table 4. Expression of these polynucleotides was not observed in the other tissues and/or cell libraries tested.
  • the second number in column 7 represents the number of times a sequence corresponding to the reference polynucleotide sequence (e.g., SEQ JD NO:X) 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 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. The value presented after "[array code]:" represents the mean of the duplicate values, following background subtraction and probe normalization.
  • PSL Phosphor Stimulating Luminescence
  • OMEVI identification number is provided in Table 1A, column 9 labeled "OMEvI Disease Reference(s)".
  • a key to the OMJJVI reference identification numbers is provided in Table 5.
  • Table IB 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 ED:” for each contig sequence.
  • the fourth column provides a BAG 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 1 A.
  • 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 ED 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 nervous system associated contig sequences disclosed in Table 1A.
  • the second column provides the sequence identifier, "SEQ ED NO:X”, for contig polynucleotide sequences disclosed in Table 1A.
  • the third column provides the unique contig identifier, "Contig ED”, for contigs disclosed in Table 1A.
  • the fourth column provides a unique integer 'a' where 'a' is any integer between 1 and the final nucleotide minus 15 of SEQ ED 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 ED NO:X, represented as "Range of b", where both a and b correspond to the positions of nucleotide residues shown ir SEQ ID NO'.X, and where b is greater than or equal to a + 14.
  • polynucleotides shown as SEQ ED 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 Table 1A, column 7.
  • Column 1 provides the key to the tissue/cell source identifier code disclosed in Table 1 A, Column 7.
  • Columns 2-5 provide a description of the tissue or cell source. Codes corresponding to diseased tissues are indicated in column 6 with the word "disease". The use of the word "disease" in column 6 is non-limiting.
  • the 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).
  • 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.
  • the tissue/cell source is a library
  • column 7 identifies the vector used to generate the library.
  • Table 5 provides a key to the OMfMTM reference identification numbers disclosed in Table 1A, column 9.
  • OMEVI reference identification numbers (Column 1) were derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMfMTM. Mc usick-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 JD 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 ED 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 JD 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 ED NO:B as defined in column 6 of Table IB or a fragment or variant thereof; or a nucleotide coding sequence in SEQ ED NO:B as defined in column 6 of Table IB 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 "nervous system antigen” refers collectively to any polynucleotide disclosed herein (e.g., a nucleic acid sequence contained in SEQ JD NO:X or the complement therof, or cDNA sequence contained in Clone ED NO:Z, or a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ED NO:B as defined in column 6 of Table IB, or a nucleotide coding sequence in SEQ ED NO:B as defined in column 6 of Table IB 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 ED NO:Y, an amino acid sequence encoded by SEQ ED NO:X, or the complement thereof, an amino acid sequence encoded by the cDNA sequence contained in Clone ED NO:Z, an amino acid sequence encoded by SEQ ED NO:B, or the complement
  • SEQ ED 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 ED 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 ED (identifier generally referred to herein as Clone ED NO:Z).
  • Clone ED 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 ED 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 ED NO:X.
  • 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).
  • 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 JD 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 JD 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 IB 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 0.1 x 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 Tables 1A or 2, while “SEQ ED NO:Y” refers to a polypeptide sequence described in column 5 of Table 1A. SEQ ED NO:X is identified by an integer specified in column 3 of Table 1 A. The polypeptide sequence SEQ ED NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ED NO:X. "Clone ED 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 1 A summarizes some of the polynucleotides encompassed by the invention (including contig sequences (SEQ JD NO:X) and clones (Clone ED NO:Z) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby.
  • the first column in Table 1A 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 nervous 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 1A, 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.
  • 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.
  • Table IB 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 NR database which comprises the NBRF PIR database, the NCBI GenPept database, and the SIB SwissProt and TrEMBL databases, 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 e.g., SEQ ID NO:X or the 'Query' sequence
  • 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.
  • the PFam database PFam version 5.2, (Sonnhammer et al., Nucl. Acids Res., 26:320-322, (1998)) consists of a series of multiple sequence alignments; one alignment for each protein family. Each multiple sequence alignment is converted into a probability model called a Hidden Markov Model, or HMM, that represents the position-specific variation among the sequences that make up the multiple sequence alignment (see, e.g., R. Durbin et al., Biological sequence analysis: probabilistic models of proteins and nucleic acids, Cambridge University Press, 1998 for the theory of HMMs).
  • HMM Hidden Markov Model
  • 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 ID 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).
  • 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 SKJJ (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.
  • 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 IB which correspond to the same Clone ID NO:Z (see Table IB, 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 IB which correspond to the same Clone JD NO:Z (see Table IB, 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 IB which correspond to the same Clone JD NO:Z (see Table IB, column 1) and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table IB, column 4).
  • the above- described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table IB which correspond to the same Clone JD NQ:Z (see Table IB, column 1) and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table IB, 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.
  • 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 IB 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.
  • polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table IB, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table IB, 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 IB, and the polynucleotide sequence of SEQ JD NO:X (e.g., as defined in Table IB, 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 IB which correspond to the same Clone ID NO:Z (see Table IB, column 1), and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1A or IB) or fragments or variants thereof.
  • the delineated sequence(s) and polynucleotide sequence of SEQ ID NO:X correspond to the same Clone ID 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 a polynucleotide sequence in which the 3' 10 polynucleotides of one of the sequences delineated in column 6 of Table IB and the 5' 10 polynucleotides of the sequence of SEQ ID 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.
  • 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 IB and the 5' 10 polynucleotides of a fragment or variant of the sequence of SEQ ID 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 a fragment or variant of the sequence of SEQ ID NO:X and the 5' 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table IB 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.
  • 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 IB 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.
  • 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 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).

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  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux polynucléotides liés au système nerveux et les polypeptides codés par ces polynucléotides qu'on appelle collectivement 'antigènes du système nerveux'' et l'utilisation de ces mêmes antigènes du système nerveux pour détecter des troubles du système nerveux, particulièrement la présence de cancers du système nerveux et les métastases cancéreuses du système nerveux. De manière plus spécifique, on décrit des molécules d'acide nucléique isolées associées au système nerveux qui codent de nouveaux polypeptides associés au système nerveux ; de nouveaux polypeptides du système nerveux et des anticorps qui se lient à ces polypeptides ainsi que des vecteurs, des cellules hôtes et des procédés de recombinaison et de synthèse utiles pour produire les polynucléotides et/ou les polypeptides associés au système nerveux. La présente invention concerne également des procédés de diagnostic et de thérapie utiles pour diagnostiquer, traiter, prévenir et/ou pronostiquer des troubles liés au système nerveux, y compris les cancers du système nerveux et des procédés de thérapie utilisés pour traiter ces troubles; un procédé de criblage qui permet d'identifier des agonistes et des antagonistes des polynucléotides et des polypeptides selon l'invention; et des procédés et/ou des compositions permettant d'inhiber la production et le fonctionnement des peptides selon la présente invention.
EP01924085A 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps Withdrawn EP1261745A2 (fr)

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PCT/US2001/001334 WO2001059063A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps

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EP01912664A Withdrawn EP1255778A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910337A Withdrawn EP1255776A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01916068A Withdrawn EP1255817A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912651A Withdrawn EP1252303A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01924085A Withdrawn EP1261745A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910334A Withdrawn EP1259642A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910332A Withdrawn EP1255864A1 (fr) 2000-01-31 2001-01-17 Acides nucl iques, proteines et anticorps
EP01910326A Withdrawn EP1252289A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01920102A Withdrawn EP1254152A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines, et anticorps
EP01910328A Withdrawn EP1261634A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912649A Withdrawn EP1261380A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912654A Withdrawn EP1254172A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912653A Withdrawn EP1252185A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912656A Withdrawn EP1252176A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910331A Withdrawn EP1259540A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01924081A Withdrawn EP1254153A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910325A Withdrawn EP1254219A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912662A Withdrawn EP1255767A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01920103A Withdrawn EP1261637A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01926335A Withdrawn EP1263944A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912657A Withdrawn EP1261618A2 (fr) 2000-01-31 2001-01-17 Acides ncleiques, proteines et anticorps
EP01912650A Withdrawn EP1255777A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01914331A Withdrawn EP1254173A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912655A Withdrawn EP1261703A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et antigenes
EP01924086A Withdrawn EP1259531A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01922230A Withdrawn EP1259526A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912658A Withdrawn EP1254248A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910330A Withdrawn EP1255768A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines, et anticorps
EP01914330A Withdrawn EP1252297A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01908617A Withdrawn EP1252290A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01924084A Withdrawn EP1265910A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910329A Withdrawn EP1255766A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910335A Withdrawn EP1254218A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910336A Withdrawn EP1252302A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01928288A Withdrawn EP1254147A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01918156A Withdrawn EP1254151A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines, et anticorps
EP01908611A Withdrawn EP1261633A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912652A Withdrawn EP1254171A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps

Family Applications Before (4)

Application Number Title Priority Date Filing Date
EP01912664A Withdrawn EP1255778A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910337A Withdrawn EP1255776A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01916068A Withdrawn EP1255817A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912651A Withdrawn EP1252303A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps

Family Applications After (33)

Application Number Title Priority Date Filing Date
EP01910334A Withdrawn EP1259642A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910332A Withdrawn EP1255864A1 (fr) 2000-01-31 2001-01-17 Acides nucl iques, proteines et anticorps
EP01910326A Withdrawn EP1252289A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01920102A Withdrawn EP1254152A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines, et anticorps
EP01910328A Withdrawn EP1261634A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912649A Withdrawn EP1261380A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912654A Withdrawn EP1254172A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912653A Withdrawn EP1252185A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912656A Withdrawn EP1252176A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910331A Withdrawn EP1259540A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01924081A Withdrawn EP1254153A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910325A Withdrawn EP1254219A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912662A Withdrawn EP1255767A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01920103A Withdrawn EP1261637A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01926335A Withdrawn EP1263944A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912657A Withdrawn EP1261618A2 (fr) 2000-01-31 2001-01-17 Acides ncleiques, proteines et anticorps
EP01912650A Withdrawn EP1255777A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01914331A Withdrawn EP1254173A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912655A Withdrawn EP1261703A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et antigenes
EP01924086A Withdrawn EP1259531A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01922230A Withdrawn EP1259526A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912658A Withdrawn EP1254248A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910330A Withdrawn EP1255768A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines, et anticorps
EP01914330A Withdrawn EP1252297A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01908617A Withdrawn EP1252290A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01924084A Withdrawn EP1265910A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910329A Withdrawn EP1255766A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910335A Withdrawn EP1254218A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01910336A Withdrawn EP1252302A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01928288A Withdrawn EP1254147A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01918156A Withdrawn EP1254151A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines, et anticorps
EP01908611A Withdrawn EP1261633A2 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps
EP01912652A Withdrawn EP1254171A1 (fr) 2000-01-31 2001-01-17 Acides nucleiques, proteines et anticorps

Country Status (1)

Country Link
EP (38) EP1255778A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013174404A1 (fr) 2012-05-23 2013-11-28 Ganymed Pharmaceuticals Ag Polythérapie impliquant des anticorps dirigés contre la claudine 18,2 pour le traitement du cancer
JP6499079B2 (ja) 2012-11-13 2019-04-10 バイオエヌテック アーゲーＢｉｏＮＴｅｃｈ ＡＧ クローディンを発現するガン疾患を処置するための剤
WO2014127785A1 (fr) 2013-02-20 2014-08-28 Ganymed Pharmaceuticals Ag Polythérapie impliquant des anticorps dirigés contre la claudine 18,2 pour le traitement du cancer
WO2014146672A1 (fr) 2013-03-18 2014-09-25 Ganymed Pharmaceuticals Ag Thérapie comprenant des anticorps dirigés contre cldn 18.2 pour le traitement du cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0159063A2 *

Also Published As

Publication number Publication date
EP1252290A1 (fr) 2002-10-30
EP1254218A2 (fr) 2002-11-06
EP1261634A1 (fr) 2002-12-04
EP1265910A2 (fr) 2002-12-18
EP1259531A2 (fr) 2002-11-27
EP1255778A2 (fr) 2002-11-13
EP1255766A2 (fr) 2002-11-13
EP1261618A2 (fr) 2002-12-04
EP1254219A2 (fr) 2002-11-06
EP1254173A1 (fr) 2002-11-06
EP1254172A1 (fr) 2002-11-06
EP1255768A2 (fr) 2002-11-13
EP1261633A2 (fr) 2002-12-04
EP1255776A1 (fr) 2002-11-13
EP1254152A2 (fr) 2002-11-06
EP1252297A1 (fr) 2002-10-30
EP1255864A1 (fr) 2002-11-13
EP1263944A2 (fr) 2002-12-11
EP1259540A1 (fr) 2002-11-27
EP1254147A2 (fr) 2002-11-06
EP1252176A2 (fr) 2002-10-30
EP1255767A2 (fr) 2002-11-13
EP1252289A2 (fr) 2002-10-30
EP1252303A2 (fr) 2002-10-30
EP1252185A1 (fr) 2002-10-30
EP1259526A2 (fr) 2002-11-27
EP1255817A1 (fr) 2002-11-13
EP1261637A1 (fr) 2002-12-04
EP1254171A1 (fr) 2002-11-06
EP1261703A1 (fr) 2002-12-04
EP1252302A2 (fr) 2002-10-30
EP1261380A1 (fr) 2002-12-04
EP1254248A2 (fr) 2002-11-06
EP1259642A1 (fr) 2002-11-27
EP1254153A2 (fr) 2002-11-06
EP1255777A1 (fr) 2002-11-13
EP1254151A1 (fr) 2002-11-06

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