WO2005074633A2 - Compositions and methods for characterizing, regulating, diagnosing, and treating cancer - Google Patents

Compositions and methods for characterizing, regulating, diagnosing, and treating cancer Download PDF

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WO2005074633A2
WO2005074633A2 PCT/US2005/003419 US2005003419W WO2005074633A2 WO 2005074633 A2 WO2005074633 A2 WO 2005074633A2 US 2005003419 W US2005003419 W US 2005003419W WO 2005074633 A2 WO2005074633 A2 WO 2005074633A2
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cells
cell
tumorigenic
subject
notch
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French (fr)
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WO2005074633A3 (en
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Michael F. Clarke
Muhammad Al-Hajj
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University of Michigan System
University of Michigan Ann Arbor
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University of Michigan System
University of Michigan Ann Arbor
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Priority to EP05722705A priority Critical patent/EP1718767B1/en
Priority to AU2005209909A priority patent/AU2005209909B8/en
Priority to AT05722705T priority patent/ATE552851T1/de
Priority to ES05722705T priority patent/ES2383306T3/es
Priority to JP2006552240A priority patent/JP2007526455A/ja
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Priority to CA002554779A priority patent/CA2554779A1/en
Publication of WO2005074633A2 publication Critical patent/WO2005074633A2/en
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Priority to IL177346A priority patent/IL177346A0/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
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    • 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
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3015—Breast
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    • 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
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57415—Specifically defined cancers of breast
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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    • C12Q2600/00—Oligonucleotides characterized by their use
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/136—Screening for pharmacological compounds

Definitions

  • the present invention relates to compositions and methods for characterizing, regulating, diagnosing, and treating cancer.
  • the present invention provides compositions and methods for inhibiting tumorigenesis of certain classes of cancer cells, including breast cancer cells and preventing metastasis.
  • the present invention also provides systems and methods for identifying compounds that regulate tumorigenesis.
  • BACKGROUND Cancer is one of the leading causes of death and metastatic cancer is often incurable 6 .
  • current therapies can produce tumor regression, they rarely cure common tumors such as metastatic breast cancer 6 .
  • Solid tumors consist of heterogeneous populations of cancer cells.
  • AML acute myeloid leukemia
  • a small, distinct population of cancer cells are enriched for the ability to form tumors in immunodeficient mice 1 .
  • the CD44 + CD24 " low Lineage " population had the ability to form tumors when injected into immunodeficient mice.
  • tumororigenic As few as 200 of these cells, termed "tumorigenic" cells, consistently formed tumors in mice.
  • the majority of the cancer cells in a tumor consisted of "non-tumorigenic” cells with alternative phenotypes. These cells failed to form tumor in NOD/SCED mice even when as many as 10 4 cells were injected 1 . In some tumors further enrichment of the tumorigenic cells was possible by isolating the ESA + CD44 + CD24 " Iow Lineage " population of cancer cells. The ability to prospectively isolate the tumorigenic cancer cells permits investigation of critical biological pathways that represent therapeutic targets in these cells. The art is in need of additional systems and methods for characterizing, regulating, diagnosing, and treating cancer.
  • FIGURES Figure 1 shows Notch signaling in breast cancer cells.
  • Figure 1 A shows that soluble Delta promotes colony formation.
  • ESA + CD44 + CD24 "/low Lineage" TI tumorigenic breast cancer cells were sorted and plated on collagen-coated plates in tissue culture medium alone (control), medium supplemented with the Fc control fragment 11 (Fc), or medium supplemented with Delta-Fc (Delta). Culture of cells with soluble Delta-Fc resulted in 5 fold more colonies than either the control cells or cells treated with just the control Fc fragment 1 ' .
  • Figure IB shows inhibition of Notch signaling by a dominant-negative adenovirus vector.
  • MCF-7 cells were stably transfected with a luciferase minigene under the regulation of the Notch-responsive HES-1 promoter 38 . Luciferase activity was then measured in control MCF-7 cells cultured in medium containing Delta-Fc with no virus (Control) or 48 hours after infection with a GFP only adenovirus (Ad-GFP) or the dominant negative adenoviral vector dnMAMLl (Ad-GFP-dnMAMLl). The Ad-GFP-dnMAMLl adenovirus, but not the Ad-GFP adenovirus, significantly decreased luciferase activity.
  • Figure IC shows that effect of Notch receptor transcriptional down-regulation on primary tumor cells.
  • ESA + CD44 + CD24 " l0W Lineage " cancer cells 1 (TI) or Lineage " cancer cells from different patients 1 (T2-T5) were sorted in 12-well, collagen coated tissue culture plates. Cells were infected with the dominant negative adenoviral construct or the control GFP virus as indicated. Trypan blue exclusion was used to count viable cells 48 hours after infection. dnMAMLl significantly decreases the number of viable cells in TI, T2 T4and T5 while having a lesser effect on T3 cells.
  • Figure 2 shows Notch4 signaling in tumorigenic breast cancer cells.
  • Figure 2A shows results of a Notch pathway reporter gene assay.
  • FIG. 4 shows the isolation of tumorigenic and.nontumorigenic cancer cells. Flow cytometry was used to isolate subpopulations of Tumor 1 (a,b,c) or Tumor 4 (d,e,f) that had previously been tested for tumorigenicity in NOD/SCEO mice 1 .
  • ESA CD24 staining patterns of live human Lineage" cancer cells The re-analyses of the sorted tumorigenic (c,f) and non-tumorigenic (b,e) populations of cells are shown. The tumorigenic cells were isolated based on detectable expression of CD44 (gates not shown). The ESA " CD24 " low CD44 + Lineage " population of T4 cells had reduced, but present, tumorigenic potential 1 .
  • Figure 5 shows adenovirus inhibition of Notch signaling, showing depiction of the Ad-GFP-dnMAMLl viral construct. The coding region of amino acids 1-302 of the Human MAMLl was cloned into the MSCVneoEB vector upstream of the IRES-GFP gene.
  • FIG. 6 shows a graph demonstrating the effect of ⁇ -secretase inhibitor on MCF-7 cell viability and the Notch receptor activation.
  • Cell viability was assayed by plating triplicate 20,000 MCF-7 cells that are shown to express Notch in 6-well plates. 48 hours later, varying amounts of ⁇ -secretase inhibitor were added to the cells. Total and Trypan Blue negative (viable) cells were counted 24 hours later and % cell viability was determined.
  • Stably transfected MCF-7 cells with the reporter luciferase gene under the control of the HES-1 promoter were co-cultivated in 6-well plates with varying concentrations of the ⁇ -secretase inhibitor as above.
  • the trans-activation or suppression of the HES1 promoter was monitored with a standard luciferase assay.
  • the ⁇ -secretase inhibitor clearly suppresses the expression of the notch receptor and significantly decreases the cell's viability.
  • the terms "anticancer agent,” “conventional anticancer agent,” or “cancer therapeutic drug” refer to any therapeutic agents (e.g., chemotherapeutic compounds and/or molecular therapeutic compounds), radiation therapies, or surgical interventions, used in the treatment of cancer (e.g., in mammals).
  • the terms “drug” and “chemotherapeutic agent” refer to pharmacologically active molecules that are used to diagnose, treat, or prevent diseases or pathological conditions in a physiological system (e.g., a subject, or in vivo, in vitro, or ex vivo cells, tissues, and organs).
  • prodrugs include acid derivatives such as esters prepared by reaction of parent acids with a suitable alcohol (e.g., a lower alkanol), amides prepared by reaction of the parent acid compound with an amine (e.g., as described above), or basic groups reacted to form an acylated base derivative (e.g., a lower alkylamide).
  • An "effective amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations.
  • Coadministration refers to administration of more than one chemical agent or therapeutic treatment (e.g., radiation therapy) to a physiological system (e.g. , a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs). “Coadministration” of the respective chemical agents and therapeutic treatments (e.g., radiation therapy) may be concurrent, or in any temporal order or physical combination.
  • a chemical agent or therapeutic treatment e.g., radiation therapy
  • bioavailability refers to any measure of the ability of an agent to be absorbed into a biological target fluid (e.g., blood, cytoplasm, CNS fluid, and the like), tissue, organelle or intercellular space after administration to a physiological system (e.g., a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs).
  • a biological target fluid e.g., blood, cytoplasm, CNS fluid, and the like
  • tissue, organelle or intercellular space after administration to a physiological system e.g., a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs.
  • hyperproliferative disease refers to any condition in which a localized population of proliferating cells in an animal is not governed by the usual limitations of normal growth. Examples of hyperproliferative disorders include tumors, neoplasms, lymphomas and the like. A neoplasm is said to be benign if it does not undergo invasion or metastasis and malignant if it does either of these. A "metastatic" cell or tissue means that the cell can invade and destroy neighboring body structures. Hyperplasia is a form of cell proliferation involving an increase in cell number in a tissue or organ without significant alteration in structure or function.
  • Metaplasia is a form of controlled cell growth in which one type of fully differentiated cell substitutes for another type of differentiated cell. Metaplasia can occur in epithelial or connective tissue cells. A typical metaplasia involves a somewhat disorderly metaplastic epithelium.
  • neoplastic disease refers to any abnormal growth of cells or tissues being either benign (non-cancerous) or malignant (cancerous).
  • anti-ne ⁇ plastic agent refers to any compound that retards the proliferation, growth, or spread of a targeted (e.g., malignant) neoplasm.
  • the prevention may also be partial, such that the occurrence of hyperproliferative or neoplastic cells in a subject is less than that which would have occurred without the present invention.
  • in vitro' ' ' refers to an artificial environment and to processes or reactions that occur within an artificial environment. In vitro environments can consist of, but are not limited to, test tubes and cell cultures.
  • in vivo refers to the natural environment (e.g., an animal or a cell) and to processes or reactions that occur within a natural environment.
  • the term “cell culture” refers to any in vitro culture of cells.
  • the term “competes for binding” is used in reference to a first molecule with an activity that binds to the same target as does a second molecule.
  • the efficiency (e.g., kinetics or thermodynamics) of binding by the first molecule may be the same as, or greater than, or less than, the efficiency of the target binding by the second molecule.
  • the equilibrium binding constant (Kd) for binding to the target may be different for the two molecules.
  • antisense is used in reference to nucleic acid sequences (e.g.
  • test compound refers to any chemical entity, pharmaceutical, drug, and the like, that can be used to treat or prevent a disease, illness, sickness, or disorder of bodily function, or otherwise alter the physiological or cellular status of a sample.
  • Test compounds comprise both known and potential therapeutic compounds.
  • a test compound can be determined to be therapeutic by using the screening methods of the present invention.
  • test compounds are anticancer agents.
  • test compounds are anticancer agents that induce apoptosis in cells.
  • purified or “to purify” refers to the removal of undesired components from a sample.
  • substantially purified refers to molecules (e.g., polynucleotides, polypeptides, chemical compounds) that are removed from their natural environment, isolated or separated, and are at least 60% free, preferably at least 75% free, and most preferably at least 90% free from other components with which they are naturally associated.
  • an "isolated polynucleotide” is therefore a substantially purified polynucleotide.
  • Nucleic acid sequence and “nucleotide sequence” as used herein refer to an oligonucleotide or polynucleotide, and fragments or portions thereof, and to DNA or RNA of genomic or synthetic origin which may be single- or double-stranded, and represent the sense or antisense strand.
  • nucleic acid molecule encoding refers to the order or sequence of deoxyribonucleotides or ribonucleotides along a strand of deoxyribonucleic acid or ribonucleic acid.
  • the order of these deoxyribonucleotides or ribonucleotides determines the order of amino acids along the polypeptide (protein) chain translated from the mRNA.
  • the DNA or RNA sequence thus codes for the amino acid sequence.
  • the term "gene” refers to a nucleic acid (e.g., DNA or RNA) sequence that comprises coding sequences necessary for the production of a polypeptide or precursor (e.g., proinsulin).
  • the polypeptide can be encoded by a full length coding sequence or by any portion of the coding sequence so long as the desired activity or functional properties (e.g., enzymatic activity, ligand binding, signal transduction, etc.) of the full-length or fragment are retained.
  • the term also encompasses the coding region of a structural gene and includes sequences located adjacent to the coding region on both the 5' and 3' ends for a distance of about 1 kb or more on either end such that the gene corresponds to the length of the full-length mRNA.
  • the sequences that are located 5' of the coding region and which are present on the mRNA are referred to as 5' untranslated sequences.
  • the sequences that are located 3' or downstream of the coding region and which are present on the mRNA are referred to as 3' untranslated sequences.
  • gene encompasses both cDNA and genomic forms of a gene.
  • RNA expression refers to the process of converting genetic information encoded in a gene into RNA (e.g., mRNA, rRNA, tRNA, or snRNA) through “transcription” of the gene (i.e., via the enzymatic action of an RNA polymerase), and for protein encoding genes, into protein through “translation” of mRNA.
  • Gene expression can be regulated at many stages in the process.
  • Up- regulation” or “activation” refers to regulation that increases the production of gene expression products (i.e., RNA or protein), while “down-regulation” or “repression” refers to regulation that decreases production.
  • Molecules e.g., transcription factors that are involved in up-regulation or down-regulation are often called “activators” and “repressors,” respectively.
  • antigen binding protein refers to proteins which bind to a specific antigen.
  • Antigen binding proteins include, but are not limited to, immunoglobulins, including polyclonal, monoclonal, chimeric, single chain, and humanized antibodies, Fab fragments, F(ab')2 fragments, and Fab expression libraries. Various procedures known in the art are used for the production of polyclonal antibodies.
  • various host animals can be immunized by injection with the peptide corresponding to the desired epitope including, but not limited to, rabbits, mice, rats, sheep, goats, etc.
  • the peptide is conjugated to an immunogenic carrier (e.g., diphtheria toxoid, bovine serum albumin (BSA), or keyhole limpet hemocyanin (KLH)).
  • an immunogenic carrier e.g., diphtheria toxoid, bovine serum albumin (BSA), or keyhole limpet hemocyanin (KLH).
  • adjuvants are used to increase the immunological response, depending on the host species, including, but not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (Bacille Calmette-Guerin) and Corynebacterium parvum.
  • BCG Bacille Calmette-Guerin
  • Corynebacterium parvum any technique that provides for the production of antibody molecules by continuous cell lines in culture may be used (See e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY).
  • 4,946,778 herein incorporated by reference
  • An additional embodiment of the invention utilizes the techniques known in the art for the construction of Fab expression libraries (Huse et al, Science, 246:1275-1281 (1989)) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity.
  • Antibody fragments that contain the idiotype (antigen binding region) of the antibody molecule can be generated by known techniques.
  • such fragments include, but are not limited to: the F(ab')2 fragment that can be produced by pepsin digestion of an antibody molecule; the Fab' fragments that can be generated by reducing the disulfide bridges of an F(ab')2 fragment, and the Fab fragments that can be generated by treating an antibody molecule with papain and a reducing agent.
  • Genes encoding antigen-binding proteins can be isolated by methods known in the art.
  • screening for the desired antibody can be accomplished by techniques known in the art (e.g., radioimmunoassay, ELISA (enzyme- linked immunosorbant assay), "sandwich” immunoassays, immunoradiometric assays, gel diffusion precipitin reactions, immunodifflision assays, in situ immunoassays (using colloidal gold, enzyme or radioisotope labels, for example), Western Blots, precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays, etc.), complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis assays, etc.) etc.
  • the term "modulate” refers to the activity of a compound to affect
  • an aspect of the cellular function including, but not limited to, cell growth, proliferation, invasion, angiogenesis, apoptosis, and the like.
  • the identification of the tumorigenic cell is used in selecting a treatment course of action for a subject.
  • the treatment course of action comprises administration of a Notch4 pathway inhibitor to the subject.
  • the treatment course of action comprises administration of a drug that initiates mitochondrial apoptosis (e.g., regulators of Bak and Bax, regulators of Bcl-2 and Bcl XL , regulators of electron transfer — see e.g., U.S. Pat. Appln. No. 20030119029, herein incorporated by reference in its entirety, etc.).
  • a drug that initiates mitochondrial apoptosis e.g., regulators of Bak and Bax, regulators of Bcl-2 and Bcl XL , regulators of electron transfer — see e.g., U.S. Pat. Appln. No. 20030119029, herein incorporated by reference in its entirety, etc.
  • Manic Fringe inhibitors include, but are not limited to, anti-Manic Fringe antibodies, siRNA molecules targeted at Manic Fringe expression, small molecules that inhibit Manic Fringe and the like.
  • the present invention also provides methods for selecting or characterizing compounds (e.g., for basic research, drug screening, drug trials, monitoring therapy, etc.), comprising the steps of: a) providing a sample comprising a tumorigenic cell (e.g., breast cell); b) exposing the sample to a test compound; and c) detecting a change in the cell in response to the test compound.
  • the test compound comprises an antibody (e.g., an antibody that regulates a Notch signaling pathway), i some embodiments, the compound comprises an anti-neoplastic compound, i some embodiments a second or additional compound is co-administered (e.g., a known antineoplastic therapeutic compound).
  • the detecting step comprises detecting cell death of said tumorigenic cell (e.g., detection of apoptosis markers such as caspace, etc.).
  • the present invention also provides methods for identifying subjects having tumorigenic cells and treating the subject with an appropriate treatment course of action based on the nature of the identified tumorigenic cell.
  • the present invention provides a method for treating a subject having tumorigenic cells (e.g., breast cells), comprising the steps of: a) identifying the presence of a tumorigenic breast cell in the subject; b) identifying one or more markers or properties characteristic of the tumorigenic cell to identify the nature of the tumorigenic cell; and c) selecting a therapeutic course of action based on the nature of the tumorigenic cell.
  • the course of action comprises administration of a Notch 4 pathway inhibitor or other appropriate therapeutic to the subject when the tumorigenic cell is characterized as expressing Notch4, or for example, where the tumorigenic cell does not express Notch4, but where neighboring, non-tumorigenic cells express Notch 4.
  • the course of action comprises surgical removal of a tumor from the subject and administration of a Notch4 pathway inhibitor or other appropriate therapeutic compound to the subject (e.g., to prevent tumorigenesis or metastasis caused by remaining tumorigenic cells, i some embodiments, the course of action comprises co-administration of a Notch4 pathway inhibitor or other appropriate therapeutic compound and a second anti-neoplastic agent to the subject.
  • the present invention further provides methods of preventing or reducing metastasis, for example, comprising the step of administering a Notch pathway inhibitor or other appropriate therapeutic compound to a subject suspected of having metastasis (e.g., suspected of undergoing metastasis or a risk of metastasis).
  • the Notch pathway inhibitor comprises an anti-Notch4 antibody.
  • the compound comprises a drug that initiates mitochondrial apoptosis.
  • the compound is a ⁇ -secretase inhibitor.
  • the administration is conducted in conjunction with removal of a solid tumor (e.g., abreast tumor) from the subject.
  • the present invention also provides a method of reducing or eliminating tumorigenic cells in a subject having cancer (e.g., breast cancer), comprising: administering a ⁇ -secretase inhibitor to the subject (e.g., under conditions such that tumorigenic cells are killed or inhibited from proliferating or causing metastasis).
  • the present invention identifies classes of cells within cancers that are tumorigenic and provides detectable characteristics of such cells, such that their presence can be determined, for example, in choosing whether to submit a subject to a medical intervention, selecting an appropriate treatment course of action, monitoing the success or progress of a therapeutic course of action (e.g., in a drug trial or in selecting individualized, ongoing therapy), or screening for new therapeutic compounds or therapeutic targets.
  • the present invention also provides therapeutic compositions and methods.
  • the present invention identifies biological targets and regulators of those biological targets that modulate tumorigenesis and metastasis.
  • Such therapeutic methods can be used, for example, either alone, or in combination with other therapeutic courses of action (e.g., coadministration of other anti-neoplastic agents) or with diagnostic procedures (e.g., patients that are amenable to the therapeutic methods of the present invention are identified by the diagnostic methods of the present invention.
  • the present invention also provides systems and methods for identifying the genes and proteins expressed by tumorigenic cells to identify proteins whose function is necessary for tumorigenesis, providing novel drug targets.
  • the expression of Notch proteins and or regulators of the Notch signaling pathways is used to identify tumorigenic cells. Regulators of Notch proteins and/or Notch signaling pathways also find use in research, drug screening, and therapeutic methods.
  • neoplastic conditions benefit from the teachings of the present invention, including, but not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma,
  • tumorigenic and non-tumorigenic cancer cells differed in their expression of Notches, Notch ligands, and members of the Fringe family of Notch modifiers.
  • Notch4 expression was detected in the non-tumorigenic but not the tumorigenic cancer cells.
  • Notch activation promotes the growth of clonogenic cells
  • the expression of Notch ligands by cells in a particular tissue may contribute to the spread of a tumor to that particular site.
  • Activation of the Notch receptor has previously been implicated in breast cancer and Notch signaling plays a role in transformation of cells transfected with an activated Ras oncogene, but its role in de novo human breast cancers is not known 17"20 .
  • TI cancer cells were cultured in the presence of a polyclonal antibody against Notch4 that inhibited Notch signaling (Fig. 2a).
  • a polyclonal antibody against Notch4 that inhibited Notch signaling
  • Fig. 2a When TI cancer cells, which expressed Notch4 (Table 1, Fig. 2b), were exposed to this antibody in vitro, colony formation was markedly inhibited (Fig. 2c,d). This inhibition was nearly completely eliminated by pre-incubation of the antibody with the Notch4 peptide against which the antibody was generated, confirming the specificity of the anti-Notch4 antibody (Fig. 2c,d). On the other hand, colony formation by the T4 cancer cells was not affected by the anti-Notch 4 antibody (Fig. 2c).
  • TI tumorigenic cancer cells are able to consistently form tumors inNOD/SCID mice 1 . Therefore, 200 TI tumorigenic cancer cells were incubated with either control buffer or the anti-Notch4 antibody and then injected into mice. 7 of 9 injections of untreated cells and 0 of 9 injections of treated cells formed tumors (Fig. 2e). Tumor formation by larger numbers of antibody-treated cells was delayed relative to control cells. Further experiments studied the mechanism by which anti-Notch4 antibody inhibited proliferation of the cancer cells in this tumor as well as in tumor cells isolated from additional patients. Notch stimulation has been shown to promote cell proliferation in some circumstances, inhibit proliferation in other circumstances, and to promote cell survival in other cases 13 ' 25,26 .
  • a pharmaceutical composition containing a regulator of tumorigenesis according the present invention can be administered by any effective method.
  • a Notch ligand, an anti-Notch antibody, or other therapeutic agent that acts as an agonist or antagonist of proteins in the Notch signal transduction response pathway can be administered by any effective method.
  • a physiologically appropriate solution containing an effective concentration of anti-Notch therapeutic agent can be administered topically, intraocularly, parenterally, orally, intranasally, intravenously, intramuscularly, subcutaneously or by any other effective means.
  • the anti-Notch therapeutic agent may be directly injected into a target cancer or tumor tissue by a needle in amounts effective to treat the tumor cells of the target tissue.
  • a cancer or tumor present in a body cavity such as in the eye, gastrointestinal tract, genitourinary tract (e.g., the urinary bladder), pulmonary and bronchial system and the like can receive a physiologically appropriate composition (e.g., a solution such as a saline or phosphate buffer, a suspension, or an emulsion, which is sterile) containing an effective concentration of anti-Notch therapeutic agent via direct injection with a needle or via a catheter or other delivery tube placed into the cancer or tumor afflicted hollow organ.
  • a physiologically appropriate composition e.g., a solution such as a saline or phosphate buffer, a suspension, or an emulsion, which is sterile
  • Any effective imaging device such as X-ray, sonogram, or fiber-optic visualization system may be used to locate the target tissue and guide the needle or catheter tube.
  • a physiologically appropriate solution containing an effective concentration of anti-Notch therapeutic agent can be administered systemically into the blood circulation to treat a cancer or tumor that cannot be directly reached or anatomically isolated. All such manipulations have in common the goal of placing the anti-Notch therapeutic agent in sufficient contact with the target tumor to permit the anti-Notch therapeutic agent to contact, transduce or transfect the tumor cells (depending on the nature of the agent).
  • solid tumors present in the epithelial linings of hollow organs may be treated by infusing the vector suspension into a hollow fluid filled organ, or by spraying or misting into a hollow air filled organ.
  • the tumor cells may be present in or among the epithelial tissue in the lining of pulmonary bronchial tree, the lining of the gastrointestinal tract, the lining of the female reproductive tract, genitourinary tract, bladder, the gall bladder and any other organ tissue accessible to contact with the anti-Notch therapeutic agent.
  • the solid tumor may be located in or on the lining of the central nervous system, such as, for example, the spinal cord, spinal roots or brain, so that anti- Notch therapeutic agent infused in the cerebrospinal fluid contacts and transduces the cells of the solid tumor in that space.
  • the anti-Notch therapeutic agent can be modified to cross the blood brain barrier using method known in the art).
  • the anti-Notch therapeutic agent can be administered to the solid tumor by direct injection of the vector suspension into the tumor so that anti-Notch therapeutic agent contacts and affects the tumor cells inside the tumor.
  • the tumorigenic cells identified by the present invention can also be used to raise anti-cancer cell antibodies.
  • the method involves obtaining an enriched population of tumorigenic cells or isolated tumorigenic cells; treating the population to prevent cell replication (for example, by irradiation); and administering the treated cell to a human or animal subject in an amount effective for inducing an immune response to solid tumor stem cells.
  • an effective dose of cells to be injected or orally administered see, U.S. Pat. Nos.
  • the method involves obtaining an enriched population of solid tumor stem cells or isolated solid tumor stem cells; mixing the tumor stem cells in an in vitro culture with immune effector cells (according to immunological methods known in the art) from a human subject or host animal in which the antibody is to be raised; removing the immune effector cells from the culture; and transplanting the immune effector cells into a host animal in a dose that is effective to stimulate an immune response in the animal.
  • the therapeutic agent is an antibody (e.g., an anti-Notch4 antibody).
  • Monoclonal antibodies to may be prepared using any technique which provides for the production of antibody molecules by continuous cell lines in culture.
  • hybridoma technique examples include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EBV-hybridoma technique (see, e.g., Kozbor, D. et al., J. Immunol. Methods 81:31-42 (1985); Cote R J et al. Proc. Natl. Acad. Sci. 80:2026- 2030 (1983); and Cole S P et al. Mol. Cell Biol. 62:109-120 (1984)).
  • the antibody can also be a humanized antibody.
  • humanized antibody refers to antibody molecules in which the amino acid sequence in the non-antigen binding regions has been altered so that the antibody more closely resembles a human antibody, and still retains its original binding ability.
  • Antibodies are humanized so that they are less immunogenic and therefore persist longer when administered therapeutically to a patient.
  • Human antibodies can be generated using the XENOMOUSE technology from Abgenix (Fremont, Calif, USA), which enables the generation and selection of high affinity, fully human antibody product candidates to essentially any disease target appropriate for antibody therapy. See, U.S. Pat. Nos.
  • Antibodies with fully human protein sequences are generated using genetically engineered strains of mice in which mouse antibody gene expression is suppressed and functionally replaced with human antibody gene expression, while leaving intact the rest of the mouse immune system. Moreover, the generation of antibodies directed against markers present in or on the tumorigenic cells of the invention can be used as a method of identifying targets for drug development.
  • Some embodiments of the present invention provide methods (therapeutic methods, research methods, drug screening methods) for administering a therapeutic compound of the present invention and at least one additional therapeutic agent (e.g., including, but not limited to, chemotherapeutic antineoplastics, antimicrobials, antivirals, antifungals, and anti-inflammatory agents) and/or therapeutic technique (e.g., surgical intervention, radiotherapies).
  • additional therapeutic agent e.g., including, but not limited to, chemotherapeutic antineoplastics, antimicrobials, antivirals, antifungals, and anti-inflammatory agents
  • therapeutic technique e.g., surgical intervention, radiotherapies.
  • antineoplastic agents e.g., anticancer agents are contemplated for use in certain embodiments of the present invention.
  • Anticancer agents suitable for use with the present invention include, but are not limited to, agents that induce apoptosis, agents that inhibit adenosine deaminase function, inhibit pyrimidine biosynthesis, inhibit purine ring biosynthesis, inhibit nucleotide interconversions, inhibit ribonucleotide reductase, inhibit thymidine monophosphate (TMP) synthesis, inhibit dihydrofolate reduction, inhibit DNA synthesis, form adducts with DNA, damage DNA, inhibit DNA repair, intercalate with DNA, deaminate asparagines, inhibit RNA synthesis, inhibit protein synthesis or stability, inhibit microtubule synthesis or function, and the like.
  • agents that induce apoptosis agents that induce apoptosis, agents that inhibit adenosine deaminase function, inhibit pyrimidine biosynthesis, inhibit purine ring biosynthesis, inhibit nucleotide interconversions, inhibit ribonucleotide reductase,
  • biological response modifiers e.g. , interferons (e.g. , IFN- , etc.) and interleukins (e.g., IL-2, etc.), etc.); 10) adoptive immunotherapy; 11) hematopoietic growth factors; 12) agents that induce tumor cell differentiation (e.g., all- trans-retinoic acid, etc.); 13) gene therapy techniques; 14) antisense therapy techniques; 15) tumor vaccines; 16) therapies directed against tumor metastases (e.g., batimastat, etc.); 17) angiogenesis inhibitors; 18) proteosome inhibitors (e.g., VELCADE); 19) inhibitors of acetylation and/or methylation (e.g., HDAC inhibitors); 20) modulators of NF kappa B; 21) inhibitors of cell cycle regulation (e.g., CDK inhibitors); 22) modulators of p53 protein function; and 23) radiation.
  • interferons e.g. , I
  • any oncolytic agent that is routinely used in a cancer therapy context finds use in the compositions and methods of the present invention.
  • the U.S. Food and Drug Administration maintains a formulary of oncolytic agents approved for use in the United States. International counte ⁇ art agencies to the U.S.F.D.A. maintain similar formularies.
  • Table X provides a list of exemplary antineoplastic agents approved for use in the U.S. Those skilled in the art will appreciate that the "product labels" required on all U.S. approved chemotherapeutics describe approved indications, dosing information, toxicity data, and the like, for the exemplary agents.
  • Antimicrobial therapeutic agents may also be used as therapeutic agents in the present invention. Any agent that can kill, inhibit, or otherwise attenuate the function of microbial organisms may be used, as well as any agent contemplated to have such activities. Antimicrobial agents include, but are not limited to, natural and synthetic antibiotics, antibodies, inhibitory proteins (e.g. , defensins), antisense nucleic acids, membrane disruptive agents and the like, used alone or in combination. Indeed, any type of antibiotic maybe used including, but not limited to, antibacterial agents, antiviral agents, antifungal agents, and the like. In still further embodiments, the present invention provides compounds of the present invention (and any other chemotherapeutic agents) associated with targeting agents that are able to specifically target particular cell types (e.g.
  • the therapeutic compound that is associated with a targeting agent targets neoplastic cells through interaction of the targeting agent with a cell surface moiety that is taken into the cell through receptor mediated endocytosis.
  • a cell surface moiety that is taken into the cell through receptor mediated endocytosis.
  • Any moiety known to be located on the surface of target cells finds use with the present invention.
  • an antibody directed against such a moiety targets the compositions of the present invention to cell surfaces containing the moiety.
  • the targeting moiety may be a ligand directed to a receptor present on the cell surface or vice versa.
  • vitamins also may be used to target the therapeutics of the present invention to a particular cell.
  • targeting molecules refers to chemical moieties, and portions thereof useful for targeting therapeutic compounds to cells, tissues, and organs of interest.
  • Various types of targeting molecules are contemplated for use with the present invention including, but not limited to, signal peptides, antibodies, nucleic acids, toxins and the like.
  • Targeting moieties may additionally promote the binding of the associated chemical compounds (e.g., small molecules) or the entry of the compounds into the targeted cells, tissues, and organs.
  • targeting moieties are selected according to their specificity, affinity, and efficacy in selectively delivering attached compounds to targeted sites within a subject, tissue, or a cell, including specific subcellular locations and organelles.
  • cytotoxic drugs e.g., anticancer drugs
  • One issue of particular importance is ensuring that the administered agents affect only targeted cells (e.g., cancer cells), tissues, or organs.
  • the nonspecific or unintended delivery of highly cytotoxic agents to nontargeted cells can cause serious toxicity issues.
  • Numerous attempts have been made to devise drug-targeting schemes to address the problems associated with nonspecific drug delivery. (See e.g. , K.N. Syrigos and A.A. Epenetos Anticancer Res., 19:606-614 (1999); YJ. Park et al, J. Controlled Release, 78:67-79 (2002); R.V.J.
  • the pharmacokinetics of agents are considered when testing and developing potential therapeutics.
  • the rate of agent clearance in a subject is typically manageable. For instance, attaching (e.g., binding) the agent to a macromolecular carrier normally prolongs circulation and retention times.
  • some embodiments of the present invention provide small molecules conjugated to polyethylene glycol (PEG), or similar biopolymers, to decrease (prevent) the molecules' degradation and to improve its retention in the subject's bloodstream. (See e.g., R.B. Greenwald et al, Critical Rev.
  • the ability of PEG to discourage protein-protein interactions can reduce the immunogenicity of many drugs.
  • Another issue affecting the administration of some therapeutic agents, and especially hydrophilic and macromolecular drugs such as peptides and nucleic acids, is that these agents have difficulty crossing into targeted cellular membranes. Small (typically less than 1,000 Daltons) hydrophobic molecules are less susceptible to having difficulties entering target cell membranes.
  • low molecular weight cytotoxic drugs often localize more efficiently in normal tissues rather than in target tissues such as tumors (K.
  • nanocarriers such as water-soluble polymers (e.g., enhanced permeation and retention "EPR", See e.g., H. Maeda et al, J. Controlled Release, 65:271-284 (2000); H. Maeda et al, supra; and L.W. Seymour, Grit. Rev. Therapeu. Drug Carrier Systems, 9:135-187 (1992)); bacterial toxins (See e.g., T.I. Prior et al, Biochemistry, 31:3555-3559 (1992); and H. Stenmark et al, J. Cell Biol.,
  • TAP tumor-activated prodrug
  • the compounds and anticancer agents may be administered in any sterile, biocompatible pharmaceutical carrier, including, but not limited to, saline, buffered saline, dextrose, and water.
  • the pharmaceutical compositions of the present invention may contain one agent (e.g., an antibody).
  • the pharmaceutical compositions contain a mixture of at least two agents (e.g., an antibody and one or more conventional anticancer agents), hi still further embodiments, the pharmaceutical compositions of the present invention contain at least two agents that are administered to a patient under one or more of the following conditions: at different periodicities, at different durations, at different concentrations, by different administration routes, etc.
  • the therapeutic compound is administered prior to the anticancer agent, e.g., 0.5, 1, 2 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, 1, 2, 3, or 4 weeks prior to the administration of the anticancer agent.
  • the therapeutic compound is administered after the anticancer agent, e.g., 0.5, 1, 2 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, 1, 2, 3, or 4 weeks after the administration of the anticancer agent.
  • the therapeutic compound and the anticancer agent are administered concurrently but on different schedules, e.g., the therapeutic compound is administered daily while the anticancer agent is administered once a week, once every two weeks, once every three weeks, or once every four weeks.
  • the therapeutic compound is administered once a week while the anticancer agent is administered daily, once a week, once every two weeks, once every three weeks, or once every four weeks.
  • Suitable embodiments of the present pharmaceutical compositions are formulated and administered systemically or locally.
  • Techniques for formulation and administration can be found in the latest edition of "Remington's Pharmaceutical Sciences” (Mack Publishing Co, Easton Pa.). Suitable routes may, for example, include oral or transmucosal administration as well as parenteral delivery (e.g, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration).
  • parenteral delivery e.g, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration.
  • the present invention contemplates administering therapeutic compounds and, in some embodiments, one or more conventional anticancer agents, in accordance with acceptable pharmaceutical delivery methods and preparation techniques.
  • therapeutic compounds and suitable anticancer agents can be administered to a subject intravenously in a pharmaceutically acceptable carrier such as physiological saline.
  • a pharmaceutically acceptable carrier such as physiological saline.
  • Standard methods for intracellular delivery of pharmaceutical agents are contemplated (e.g., delivery via liposome). Such methods are well known to those of ordinary skill in the art.
  • the formulations of the present invention are useful for parenteral administration (e.g., intravenous, subcutaneous, intramuscular, intramedullary, and intraperitoneal).
  • Therapeutic co-administration of some contemplated anticancer agents can also be accomplished using gene therapy reagents and techniques.
  • therapeutic compounds are administered to a subject alone, or in combination with one or more conventional anticancer agents (e.g., nucleotide sequences, drugs, hormones, etc.) or in pharmaceutical compositions where the components are optionally mixed with excipient(s) or other pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers are biologically inert.
  • the pharmaceutical compositions of the present invention are formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, capsules, dragees, liquids, gels, syrups, slurries, solutions, suspensions and the like, for respective oral or nasal ingestion by a subject.
  • compositions for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, and processing the mixture into granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are carbohydrate or protein fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, etc.; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; gums including arabic and tragacanth; and proteins such as gelatin and collagen.
  • disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate.
  • the pharmaceutical compositions of the invention maybe formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline.
  • penetrants appropriate to the particular barrier to be permeated are used. Such penetrants are known to those skilled in the art.
  • Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended pu ⁇ ose.
  • compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into pharmaceutically useful forms.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into pharmaceutically useful forms.
  • the pharmaceutical compositions of the present invention may be manufactured using any acceptable techniques for preparing pharmaceutical compositions including, but not limited to, by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes, and the like.
  • frigestible formulations of the present compositions may further include any material approved by the United States Department of Agriculture for inclusion in foodstuffs and substances that are generally recognized as safe (GRAS), such as food additives, flavorings, colorings, vitamins, minerals, and phytonutrients.
  • GRAS United States Department of Agriculture
  • phytonutrients refers to organic compounds isolated from plants that have a biological effect, and includes, but is not limited to, compounds of the following classes: isoflavonoids, oligomeric proanthcyanidins, indol-3-carbinol, sulforaphone, fibrous ligands, plant phytosterols, ferulic acid, anthocyanocides, trite ⁇ enes, omega 3/6 fatty acids, polyacetylene, quinones, te ⁇ enes, cathechins, gallates, and quercitin.
  • Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound, (i.e., dosage).
  • Pharmaceutical preparations contemplated for oral administration include push-fit capsules made of gelatin, as well as soft sealed capsules of gelatin and a coating such as glycerol or sorbitol.
  • push-fit capsules can contain the active ingredients mixed with fillers or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active compounds are dissolved or suspended in a suitable liquid or solvent, such as fatty oils, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.
  • suitable liquid or solvent such as fatty oils, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds.
  • Aqueous injection suspensions optionally contain substances that increase the viscosity of the suspension such as sodium carboxymethyl cellulose, sorbitol, or dextran. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
  • suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • suspensions contain suitable stabilizers or agents that increase the solubility of the compounds thus allowing for the preparation of highly concentrated solutions.
  • dosing and administration regimes are tailored by the clinician, or others skilled in the pharmacological arts, based upon well known pharmacological and therapeutic considerations including, but not limited to, the desired level of therapeutic effect, and the practical level of therapeutic effect obtainable.
  • chemotherapeutic agents e.g., it is generally advisable to not change dosages by more than 50% at time and no more than every 3-4 agent half-lives.
  • doses in excess of the average required dose are not uncommon. This approach to dosing is commonly referred to as the "maximal dose” strategy.
  • Additional dosing considerations relate to calculating proper target levels for the agent being administered, the agent's accumulation and potential toxicity, stimulation of resistance, lack of efficacy, and describing the range of the agent's therapeutic index.
  • the present invention contemplates using routine methods of titrating the agent's administration.
  • One common strategy for the administration is to set a reasonable target level for the agent in the subject, i some preferred embodiments, agent levels are measured in the subject's plasma. Proper dose levels and frequencies are then designed to achieve the desired steady-state target level for the agent. Actual, or average, levels of the agent in the subject are monitored (e.g., hourly, daily, weekly, etc.) such that the dosing levels or frequencies can be adjusted to maintain target levels.
  • the pharmacokinetics and pharmacodynamics e.g.
  • the present invention provides intermittent dosing methods, since marked fluctuations in agent concentration between doses are generally undesirable. In situations where the abso ⁇ tion and distribution of the agent are balanced and spontaneous, concentration fluctuations are dictated by the agent's elimination half- life.
  • the minimal steady- state concentration of administered agents are determined using equations, optionally corrected for the bioavailability of the agents, which are well known to those skilled in the pharmacological arts.
  • the estimation of the maximal steady-state concentration involves manipulation of several exponential constants concerning agent distribution and abso ⁇ tion.
  • the present invention also provides methods for administering loading doses of an agent, or agents, to a subject.
  • a "loading dose” is one or a series of doses that when given at the onset of a treatment quickly provide the target concentration of the therapeutic agent.
  • the clinician designs an individualized dosing regimen based on knowledge of various pharmacological and pharmacokinetic properties of the agent, including, but not limited to, F (fractional bioavailability of the dose), Cp (concentration in the plasma), CL (clearance/clearance rate), Vss (volume of drug distribution at steady state) Css (concentration at steady state), and tl/2 (drug half-life), as well as information about the agent's rate of abso ⁇ tion and distribution.
  • F fractional bioavailability of the dose
  • Cp concentration in the plasma
  • CL clearance/clearance rate
  • Vss volume of drug distribution at steady state
  • Css concentration at steady state
  • tl/2 drug half-life
  • Css data is used is to further refine the estimates of CL/F and to subsequently adjust the individual's maintenance dosing to achieve desired agent target levels using known pharmacological principles and equations.
  • Therapeutic drug monitoring can be conducted at practically any time during the dosing schedule.
  • monitoring is carried out at multiple time points during dosing and especially when administering intermittent doses.
  • drug monitoring can be conducted concomitantly, within fractions of a second, seconds, minutes, hours, days, weeks, months, etc., of administration of the agent regardless of the dosing methodology employed (e.g., intermittent dosing, loading doses, maintenance dosing, random dosing, or any other dosing method).
  • dosing methodology e.g., intermittent dosing, loading doses, maintenance dosing, random dosing, or any other dosing method.
  • changes in agent effects and dynamics may not be readily observable because changes in plasma concentration of the agent may be delayed (e.g., due to a slow rate of distribution or other pharmacodynamic factors). Accordingly, subject samples obtained shortly after agent administration may have limited or decreased value.
  • the methods of the present invention further contemplate that when a constant maintenance dosage is administered, steady state is reached only after expiration of four agent half-lives. Samples collected too soon after dosing begins do not accurately reflect agent clearance. However, for potentially highly toxic agents, significant toxicity and damage may already have ensued before expiration of the agent's fourth half-life. Thus, in some instances when it is important to maintain control over agent concentrations, a first sample is taken after two half-lives, assuming a loading dose has not been administered. If agent concentration already exceeds 90% of the eventual expected mean steady-state concentration, the dosage rate is halved, and another sample obtained following an additional two half-lives. The dosage is halved again if this sample once more exceeds the target level.
  • Biological samples taken from a subject can be analyzed for chemical or biochemical changes (e.g., changes in gene expression) or other effects resultant from administration of the therapeutic agent. Further biological sample and sampling consideration are described below.
  • the biological and pharmacological effects of the therapeutic compositions are determined using routine laboratory procedures on the collected samples including, but not limited to, microscopy (e.g., light, fluorescence (confocal fluorescence, immunofluorescence), phase-contrast, differential interference- contrast, dark field, or electron (transmission, scanning, cryo-), NMR, autoradiography), cell sorting techniques (e.g., fluorescence-activated), chromatography techniques (e.g., gel-filtration, ion exchange, hydrophobic, affinity, HPLC), electrophoretic techniques (e.g., SDS-PAGE, 2D-, 3D-, isoelectric focusing), ultracentrifugation, immunocytochemical and immunohistochemical technologies (e.g.
  • ELIS A Western blotting
  • Immuno blotting nucleic acid, including recombinant, technologies (e.g., PCR (inverse, reverse, nested), Northern blotting, Southern blotting, Southwestern blotting, in situ hybridization, FISH, nick-translation, DNAse footprinting, DNAse hypersensitivity site mapping, Maxam-Gilbert sequencing, Sanger sequencing, gel-shift (mobility shift) analysis, SI nuclease analysis, RNAse protection assay, CAT assays, transgenic techniques, knock-out techniques, and reporter gene systems), amino acid analysis (e.g., Edman degradation), mo ⁇ hological, pathological, or phenotypical observations, and other observations with or without aid of instrumentation.
  • technologies e.g., PCR (inverse, reverse, nested)
  • Northern blotting e.g., Southern blotting
  • Southwestern blotting in situ hybridization
  • FISH nick-translation
  • DNAse footprinting DNAse hypersensitivity site
  • agents that are primarily removed by the kidneys and excreted unchanged into the urinary system tend to show less inte ⁇ atient variability in subjects with similar renal function than agents that are metabolically inactivated.
  • Agents that are extensively metabolized, and agents that have high metabolic clearance and large first-pass elimination rates show large differences in inte ⁇ atient bioavailability.
  • Agents with slower rates of biotransformation typically have the largest variation in elimination rates among individual subjects. Differences in subject genotypes also plays an important part in determining different metabolic rates.
  • Pathological and physiological variations in individual subjects' organ functions e.g., renal or hepatic diseases
  • Kidney or liver diseases often impair drug disposition and thus increase inte ⁇ atient drug variability.
  • invasive patient samples e.g., blood, serum, plasma, tissues, etc.
  • design of the collection procedures should be undertaken after considering various criteria including, but not limited to: 1) whether a relationship exists between the concentration of the agent and any desired therapeutic effects or avoidable toxic effects; 2) whether these is substantial inte ⁇ atient variability, but small intrapatient variation in agent disposition; 3) whether it is otherwise difficult or impractical to monitor the effects of the agent; and 4) whether the therapeutic concentration of the agent is close to the toxic concentration.
  • concentration measurements are supplemented with additional measurements of pharmacokinetic, pharmacodynamic, or pharmacological effects.
  • considerable inte ⁇ atient response variations exist after the concentration of agent has been adjusted to the target level.
  • this pharmacodynamic variability accounts for much of the total variation in subject response.
  • the relationship among the concentration of an agent and the magnitude of the observed response may be complex, even when responses are measured in simplified systems in vitro, although typically a sigmoidal concentration-effect curve is seen. Often there is no single characteristic relationship between agent concentration (e.g., in the subject's plasma) and measured effect.
  • the concentration-effect curve may be concave upward. In other embodiments, the curve is concave downward.
  • potency is often expressed as the dose of an agent required to produce the desired effect, it is more appropriately expressed as relating to the concentration of the agent in the subject (e.g, in plasma) that most closely approximates the desired situation in an in vitro system to avoid complicating pharmacokinetic variables.
  • concentration of the agent in the subject e.g, in plasma
  • potency affects agent dosing, knowledge of an agent's potency alone is relatively unimportant in clinical use so long as a dose sufficient to obtain the target level can be conveniently administered to the subject. It is generally accepted that more potent agents are not necessarily therapeutically superior to less potent agents.
  • One exception to this principle is in the field of transdermal agents. The maximum effect that an agent can induce in a subject is called its maximal or clinical efficacy.
  • An agent's maximal efficacy is typically determined by the properties of the agent and its receptor-effector system and is reflected in the plateau of the concentration-effect curve. In clinical use, however, an agent's dosage may be limited by undesirable effects (e.g., toxicity), and the true maximal efficacy of the agent may not be practically achievable without harming the subject.
  • the slope and shape of the concentration-effect curve reflects the agent's mechanism of action, including the shape of the curve that, at least in part, describes binding to the agent's receptor. The rise of the concentration-effect curve indicates the clinically useful dosage range of the agent.
  • concentration-effect curves are either based on an average response, or are tailored to reflect an actual response in a particular individual at a particular time.
  • concentration of an agent that produces a specified effect in a particular subject is called the individual effective concentration.
  • Individual effective concentrations usually show a lognormal distribution, resulting in a normal variation curve from plotting the logarithms of the concentration against the frequency of achieving the desired effect.
  • concentration-percent curve A cumulative frequency distribution of individuals achieving the desired effect as a function of agent concentration is called the concentration-percent curve or quantal concentration-effect curve.
  • the shape of this curve is typically sigmoidal.
  • the slope of the concentration-percent curve is an expression of the pharmacodynamic variability in the population rather than an expression of the concentration range from a threshold to a maximal effect in the individual patient.
  • ED 50 median effective dose
  • MTD dose
  • the dose, or preferably the concentration, of an agent sufficient to produce toxic effects is compared to the concentration required for the therapeutic effects in the population to provide a clinical therapeutic index.
  • concentration or dose of an agent required to produce the therapeutic effect in most subjects occasionally overlaps the concentration that produces toxicity in some subjects despite the agent having a large therapeutic index.
  • optimal treatment regimens for particular subjects are designed after considering a variety of biological and pharmacological factors including, but not limited to, potential sources of variation in subject response to the administered agent(s), diagnosis specifics (e.g., severity and stage of disease, presence of concurrent diseases, etc.), other prescription and non prescription medications being taken, predefined efficacy goals, acceptable toxicity limits, cost- benefit analyses of treatment versus non treatment or treatment with other various available agents, likelihood of subject compliance, possible medication errors, rate and extent of agent abso ⁇ tion, the subject's body size and compositions, the agent's distribution, the agent's pharmacokinetic profile (e.g., physiological variables, pathological variables, genetic factors and predispositions, drug interactions, potential drug resistances, predicted rate of clearance), potential drug-receptor interactions, functional state, and placebo effects.
  • diagnosis specifics e.g., severity and stage of disease, presence of concurrent diseases, etc.
  • other prescription and non prescription medications being taken, predefined efficacy goals, acceptable toxicity limits, cost- benefit analyses of treatment
  • the clinician selects an appropriate marker for measuring the ultimate effectiveness of the administered agent(s) in the subject.
  • appropriate markers of an agent's effectiveness include a decrease (or increase) in some measurable biological state, condition, or chemical level (e.g., toxin load, viral titer, antigen load, temperature, inflammation, blood cell counts, antibodies, tumor mo ⁇ hology, and the like).
  • a large number of diagnostic procedures and tests are available for gathering information on various markers including, but not limited to, cell culture assays (e.g., invasion assays in soft-agar and the like), radiographic examination (e.g, chest X-ray), computed tomography, computerized tomography, or computerized axial tomography (CAT) scans, positron emission tomography (PET) scans, magnetic resonance imaging (MRI or NMRI), mammography, ultrasonography (transvaginal, transcolorectal), scintimammography (e.g., technetium 99m sestamibi, technetium-99m tetrofosmin), aspiration (e.g., endometrial), palpation, PAP tests (e.g., smears), sigmoidoscopy (e.g., flexible fiberoptic), fecal occult blood testing (e.g., Guaiac-based FOBT), digital rectal examination, colonoscopy, virtual colono
  • the toxicity and therapeutic efficacy of agents is determined using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the MTD and the ED 50 .
  • Agents that exhibit large therapeutic indices are preferred.
  • the data obtained from cell culture assays or animal models can be used to formulate dosing ranges in, for example, mammals (e.g, humans, Equus cabalhis, Felis catus, and Canisfamiliaris, etc.).
  • Preferable dosing concentrations are near the calculated or observed ED 50 value for an agent. More preferable dosing concentrations are near an agent's ED 50 value and cause little or no toxicity.
  • Any given dosage may vary within, exceed, or be less than, the therapeutic index for any particular agent, depending upon the formulation, sensitivity of the patient, and the route of administration.
  • EXAMPLES The following examples are provided in order to demonstrate and further illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof.
  • Antibodies were directly conjugated to various fluorochromes depending on the experiment. In all experiments, mouse cells were eliminated by discarding H2K (class I MHC) cells during flow cytometry. Dead cells were eliminated using the viability dye 7-AAD. Flow cytometry was performed on a FACSVantage (Becton Dickinson, San Jose, CA).
  • Ad-GFP-dnMAMLl The E3-deleted adenoviral vector designated Ad-GFP-dnMAMLl was constructed as follows: The coding region of amino acids 1-302 of the Human MAMLl was generated from normal breast cells by PCR with a forward primer with an EcoRI site and an ATG start codon, and the reverse primer with an Hpal site. The resulting DNA fragment was cloned in the MSCVneoEB vector upstream of the IRES-GFP gene. The dnMAMLl -IRES-GFP was then cloned into the adenovirus shuttle vector pACCMV2 at the EcoRI and BamHI sites. The recombinant adenovirus was then generated at the University of Michigan viral core.
  • Tumor 4 For Primary Tumors 1 Tumor 4 (designated TI and T4), samples of 2000 cells from the tumorigenic ESA + CD44 + CD24 "/,0W Lineage population (designated T), or 2000 cells from the non-tumorigenic population (designated NT) from each of the tumors were sorted as described previously 1 ; For Primary tumors 2, 3 and 5 (designated T2, T3 and T5), 2000 H2K " cells from each tumor were sorted as previously described. This represents a mixed population of tumorigenic and non-tumorigenic cancer cells. Each gene was analyzed using 3 independently sorted samples of cells. (+) indicates that expression of a gene was detected. (-) indicates that gene expression was not detected. (ND) indicates the assay was not done. Analysis of each of the 4 Notch receptors is indicated, as well as the Notch ligands of the Delta and Jagged families. The Fringes (Lunatic, Manic and Radical) were also analyzed.
  • y-Secretase Inhibitor Cell viability was assayed by plating triplicate 20,000 MCF-7 cells that are shown to express Notch in 6-well plates. 48 hours later, 1.19 ⁇ g/ml of ⁇ - secretase inhibitor was added to the cells. Total and Trypan Blue negative (viable) cells were counted 12, 24 and 48 hours later and % of viable cells compared to the control wells was determined.

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008091641A3 (en) * 2007-01-24 2008-12-04 Oncomed Pharm Inc Compositions and methods for diagnosing and treating cancer
WO2008122794A3 (en) * 2007-04-05 2009-04-02 Imp Innovations Ltd Breast cancer methods, medicaments and agents
US7919092B2 (en) 2006-06-13 2011-04-05 Oncomed Pharmaceuticals, Inc. Antibodies to notch receptors
US8226943B2 (en) 2008-07-08 2012-07-24 Oncomed Pharmaceuticals, Inc. Antibodies to notch receptors
US8501472B2 (en) 2007-01-24 2013-08-06 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing pancreatic cancer
US8834875B2 (en) 2010-01-13 2014-09-16 Oncomed Pharmaceuticals, Inc. Notch1 binding agents and methods of use thereof
US8940301B2 (en) 2008-11-11 2015-01-27 The Regents Of The University Of Michigan Breast tumor treatment with anti-CXCR1 compositions
US9089556B2 (en) 2000-08-03 2015-07-28 The Regents Of The University Of Michigan Method for treating cancer using an antibody that inhibits notch4 signaling
US9132189B2 (en) 2008-07-08 2015-09-15 Oncomed Pharmaceuticals, Inc. Notch1 binding agents and methods of use thereof
US9527921B2 (en) 2015-04-16 2016-12-27 Eisai R&D Management Co., Ltd. Anti human Notch4 antibody
WO2022120187A3 (en) * 2020-12-03 2022-08-18 Shattuck Labs, Inc. Method of determining resistance to checkpoint inhibitor therapies

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8044259B2 (en) 2000-08-03 2011-10-25 The Regents Of The University Of Michigan Determining the capability of a test compound to affect solid tumor stem cells
CA2516259A1 (en) * 2003-02-18 2004-09-02 Roskamp Research, Llc Anti-angiogenic and anti-tumoral properties of beta and gamma secretase inhibitors
NZ555216A (en) * 2004-11-10 2010-05-28 Hubrecht Lab Treatment of an intestinal adenoma and/or adenocarcinoma by inhibition of notch pathway activation
US10538742B2 (en) * 2004-11-12 2020-01-21 Cambridge Enterprise Limited Methods and means related to cancer stem cells
WO2007053648A2 (en) 2005-10-31 2007-05-10 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing cancer
US20070220621A1 (en) * 2005-10-31 2007-09-20 Clarke Michael F Genetic characterization and prognostic significance of cancer stem cells in cancer
US20070243192A1 (en) * 2006-02-21 2007-10-18 Regents Of The University Of Michigan Growth hormone receptor antagonist cancer treatment
CA2644136A1 (en) * 2006-02-27 2007-09-07 The Johns Hopkins University Cancer treatment with gamma-secretase inhibitors
US20080187938A1 (en) 2006-09-22 2008-08-07 The Regents Of The University Of Michigan ALDH1 As A Cancer Stem Cell Marker
JP5386364B2 (ja) 2006-12-18 2014-01-15 ジェネンテック， インコーポレイテッド 抗Ｎｏｔｃｈ３アンタゴニスト抗体とＮｏｔｃｈ３関連疾患の予防及び治療におけるその使用
JP5547964B2 (ja) * 2007-06-29 2014-07-16 株式会社ステリック再生医科学研究所 生理活性物質を定着および発現させる方法
EP3424529A1 (en) 2007-07-02 2019-01-09 Oncomed Pharmaceuticals, Inc. Compositions and methods for treating and diagnosing cancer
US8119366B2 (en) * 2007-10-05 2012-02-21 Trojan Technologies, Ltd. Antennapedia-dominant negative mastermind-like construct
AR073717A1 (es) * 2008-10-01 2010-11-24 Genentech Inc Anticuerpos anti-notch2 de murino y humano, y metodos de uso
US8945569B2 (en) 2009-11-19 2015-02-03 Oncomed Pharmaceuticals, Inc. Jagged-binding agents and uses thereof
EP2715359A4 (en) * 2011-05-30 2015-01-21 String Therapeutics Inc METHODS AND COMPOSITIONS FOR THE MONITORING AND DOSED ADMINISTRATION OF A THERAPEUTIC MEDICINE BY PHARMACO-KINETIC PROFILING ON PLACES OF CARE
WO2012166579A1 (en) * 2011-05-31 2012-12-06 Fox Chase Cancer Center Synergistic inhibition of erbb2/erbb3 signal pathways in the treatment of cancer
CN106167526A (zh) 2011-07-15 2016-11-30 昂考梅德药品有限公司 Rspo结合剂和其应用
DK3485903T5 (da) 2011-09-23 2024-09-02 Mereo Biopharma 5 Inc Vegf/dll4-bindende midler og anvendelser deraf
WO2013063229A1 (en) 2011-10-25 2013-05-02 The Regents Of The University Of Michigan Her2 targeting agent treatment in non-her2-amplified cancers having her2 expressing cancer stem cells
KR20150036603A (ko) 2012-07-13 2015-04-07 온코메드 파마슈티칼스, 인크. Rspo3 결합제 및 그의 용도
KR102450486B1 (ko) 2012-10-05 2022-10-04 다이앤 몰드 수학적 모형 함수로서 환자-특이적 투여법을 제공하는 시스템 및 방법
MX366911B (es) * 2012-11-28 2019-07-30 Nektar Therapeutics Método para evaluar y predecir la eficacia del tratamiento del cáncer de mama con un inhibidor de topoisomerasa i de acción prolongada.
EP2970468B1 (en) 2013-03-13 2021-07-07 Novartis AG Notch2 binding molecules for treating respiratory diseases
TW201628648A (zh) 2014-09-16 2016-08-16 安可美德藥物股份有限公司 纖維變性疾病之治療
CA2988724C (en) 2015-04-09 2023-10-10 Diane R. Mould Systems and methods for patient-specific dosing
ES2968074T3 (es) 2015-09-23 2024-05-07 Mereo Biopharma 5 Inc Anticuerpo bi-específico anti-VEGF/DLL4 para su uso en el tratamiento del cáncer de ovario resistente al platino
JOP20190259A1 (ar) * 2017-05-31 2019-10-31 Amgen Inc بروتينات ربط مولد ضد مضادة لـ jagged1
JP2021519338A (ja) * 2018-03-26 2021-08-10 クリア クリーク バイオ， インコーポレイテッド 測定された代謝産物レベルに基づいて治療剤の投与を決定する方法
US10889548B2 (en) 2018-03-26 2021-01-12 Clear Creek Bio, Inc. Compositions and methods for inhibiting dihydroorotate dehydrogenase
US20200321096A1 (en) * 2019-03-08 2020-10-08 Diane R. MOULD Systems and methods for drug-agnostic patient-specific dosing regimens
US20210315880A1 (en) 2020-03-20 2021-10-14 Clear Creek Bio, Inc. Methods of treating viral infections using inhibitors of nucleotide synthesis pathways

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018544A2 (en) 2000-08-31 2002-03-07 Loyola University Chicago Method and reagents for treatment of skin disorders by modulating the notch pathway
WO2003050502A2 (en) 2001-12-07 2003-06-19 Regents Of The University Of Michigan Prospective identification and characterization of breast cancer stem cells

Family Cites Families (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687808A (en) * 1969-08-14 1972-08-29 Univ Leland Stanford Junior Synthetic polynucleotides
US4109496A (en) * 1977-12-20 1978-08-29 Norris Industries Trapped key mechanism
US4323546A (en) * 1978-05-22 1982-04-06 Nuc Med Inc. Method and composition for cancer detection in humans
US4411990A (en) * 1979-06-13 1983-10-25 University Patents, Inc. Primary bioassay of human tumor stem cells
US4873191A (en) * 1981-06-12 1989-10-10 Ohio University Genetic transformation of zygotes
US4612282A (en) * 1981-12-15 1986-09-16 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Monoclonal antibodies reactive with human breast cancer
US4670393A (en) * 1982-03-22 1987-06-02 Genentech, Inc. DNA vectors encoding a novel human growth hormone-variant protein
US5019497A (en) * 1984-11-09 1991-05-28 Lennart Olsson Human squamous lung carcinoma cell specific antigens and antibodies
US5034506A (en) * 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5225539A (en) * 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US5080891A (en) * 1987-08-03 1992-01-14 Ddi Pharmaceuticals, Inc. Conjugates of superoxide dismutase coupled to high molecular weight polyalkylene glycols
US5087570A (en) * 1988-05-10 1992-02-11 Weissman Irving L Homogeneous mammalian hematopoietic stem cell composition
US4981785A (en) * 1988-06-06 1991-01-01 Ventrex Laboratories, Inc. Apparatus and method for performing immunoassays
US4968103A (en) * 1988-07-22 1990-11-06 Photofinish Cosmetics Inc. Method of making a brush
US5223409A (en) * 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
US5994617A (en) * 1988-09-19 1999-11-30 Hsc Research Development Corporation Engraftment of immune-deficient mice with human cells
US5534617A (en) * 1988-10-28 1996-07-09 Genentech, Inc. Human growth hormone variants having greater affinity for human growth hormone receptor at site 1
US5688666A (en) * 1988-10-28 1997-11-18 Genentech, Inc. Growth hormone variants with altered binding properties
US5530101A (en) * 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5061620A (en) * 1990-03-30 1991-10-29 Systemix, Inc. Human hematopoietic stem cell
US5614396A (en) * 1990-06-14 1997-03-25 Baylor College Of Medicine Methods for the genetic modification of endogenous genes in animal cells by homologous recombination
US5602240A (en) * 1990-07-27 1997-02-11 Ciba Geigy Ag. Backbone modified oligonucleotide analogs
US5489677A (en) * 1990-07-27 1996-02-06 Isis Pharmaceuticals, Inc. Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms
CA2095633C (en) * 1990-12-03 2003-02-04 Lisa J. Garrard Enrichment method for variant proteins with altered binding properties
US5856441A (en) * 1991-05-03 1999-01-05 Yale University Serrate fragments and derivatives
IL101728A (en) * 1991-05-03 2007-08-19 Univ Yale Human Abandonment and Delta, Restrictive Areas of Effect in Tophoric Proteins, and Methods Based on Them
IE20030749A1 (en) * 1991-05-03 2003-11-12 Indiana University Foundation Human notch and delta binding domains in torporythmic proteins, and methods based thereon
US5539082A (en) * 1993-04-26 1996-07-23 Nielsen; Peter E. Peptide nucleic acids
US5719262A (en) * 1993-11-22 1998-02-17 Buchardt, Deceased; Ole Peptide nucleic acids having amino acid side chains
US5714331A (en) * 1991-05-24 1998-02-03 Buchardt, Deceased; Ole Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility
US5750376A (en) * 1991-07-08 1998-05-12 Neurospheres Holdings Ltd. In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny
US5851832A (en) * 1991-07-08 1998-12-22 Neurospheres, Ltd. In vitro growth and proliferation of multipotent neural stem cells and their progeny
US5565332A (en) * 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
US5753229A (en) * 1991-09-25 1998-05-19 Mordoh; Jose Monoclonal antibodies reactive with tumor proliferating cells
US6353150B1 (en) * 1991-11-22 2002-03-05 Hsc Research And Development Limited Partnership Chimeric mammals with human hematopoietic cells
US6004924A (en) * 1991-12-11 1999-12-21 Imperial Cancer Research Technology, Ltd. Protein sequences of serrate gene products
US5869282A (en) * 1991-12-11 1999-02-09 Imperial Cancer Research Technology, Ltd. Nucleotide and protein sequences of the serrate gene and methods based thereon
DE69326967T2 (de) * 1992-01-17 2000-06-15 Lakowicz, Joseph R. Phasenmodulationsenergieübertragungsfluoroimmunassay
US5376313A (en) * 1992-03-27 1994-12-27 Abbott Laboratories Injection molding a plastic assay cuvette having low birefringence
US5786158A (en) * 1992-04-30 1998-07-28 Yale University Therapeutic and diagnostic methods and compositions based on notch proteins and nucleic acids
US5693482A (en) * 1992-07-27 1997-12-02 California Institute Of Technology Neural chest stem cell assay
US5654183A (en) * 1992-07-27 1997-08-05 California Institute Of Technology Genetically engineered mammalian neural crest stem cells
US5849553A (en) * 1992-07-27 1998-12-15 California Institute Of Technology Mammalian multipotent neural stem cells
NZ256154A (en) * 1992-07-27 1997-02-24 California Inst Of Techn Production of mammalian multipotent neural stem cells, antibodies
US5589376A (en) * 1992-07-27 1996-12-31 California Institute Of Technology Mammalian neural crest stem cells
GB9223084D0 (en) * 1992-11-04 1992-12-16 Imp Cancer Res Tech Compounds to target cells
CA2156288C (en) * 1993-02-19 2005-10-18 Junichi Yano Glycerol derivative, device and pharmaceutical composition
US5643765A (en) * 1993-04-06 1997-07-01 University Of Rochester Method for quantitative measurement of gene expression using multiplex competitive reverse transcriptase-polymerase chain reaction
US5876978A (en) * 1993-04-06 1999-03-02 Medical College Of Ohio Method for quantitative measurement of gene expression using multiplex competitive reverse transcriptase-polymerase chain reaction
US5639606A (en) * 1993-04-06 1997-06-17 The University Of Rochester Method for quantitative measurement of gene expression using multiplex competitive reverse transcriptase-polymerase chain reaction
US5538848A (en) * 1994-11-16 1996-07-23 Applied Biosystems Division, Perkin-Elmer Corp. Method for detecting nucleic acid amplification using self-quenching fluorescence probe
US5599677A (en) * 1993-12-29 1997-02-04 Abbott Laboratories Immunoassays for prostate specific antigen
EP0784690B1 (en) * 1994-06-10 2006-08-16 Genvec, Inc. Complementary adenoviral vector systems and cell lines
ATE200190T1 (de) * 1994-08-04 2001-04-15 Stefcom Spa Schuhwerk mit einem abnehmbaren, dekorativen element
US5650317A (en) * 1994-09-16 1997-07-22 Michigan State University Human breast epithelial cell type with stem cell and luminal epithelial cell characteristics
US5736396A (en) * 1995-01-24 1998-04-07 Case Western Reserve University Lineage-directed induction of human mesenchymal stem cell differentiation
US5872154A (en) * 1995-02-24 1999-02-16 The Trustees Of The University Of Pennsylvania Method of reducing an immune response to a recombinant adenovirus
US5707618A (en) * 1995-03-24 1998-01-13 Genzyme Corporation Adenovirus vectors for gene therapy
US5633161A (en) * 1995-03-29 1997-05-27 Millennium Pharmaceuticals, Inc. Murine gene fomy030 coding for tumor progression inhibitor
US5821108A (en) * 1995-04-07 1998-10-13 The Board Of Trustees Of The Leland Stanford Junior University Enrichment for a thymocyte subset having progenitor cell activity using c-kit as a selection marker
KR100470180B1 (ko) * 1995-06-15 2005-02-04 크루셀 홀란드 비.브이. 유전자 요법에 사용할 수 있는 인간의 재조합아데노바이러스 패키징 시스템
US6117985A (en) * 1995-06-16 2000-09-12 Stemcell Technologies Inc. Antibody compositions for preparing enriched cell preparations
DK0851925T3 (da) * 1995-09-21 2005-11-28 Genentech Inc Humane Væksthormonvarianter
US5780300A (en) * 1995-09-29 1998-07-14 Yale University Manipulation of non-terminally differentiated cells using the notch pathway
US5986170A (en) * 1995-11-13 1999-11-16 Corixa Corporation Murine model for human carcinoma
US5753506A (en) * 1996-05-23 1998-05-19 Cns Stem Cell Technology, Inc. Isolation propagation and directed differentiation of stem cells from embryonic and adult central nervous system of mammals
EP0921818A4 (en) * 1996-05-31 2002-09-25 Nat American Red Cross THERAPEUTIC AND DIAGNOSTIC METHODS AND COMPOSITIONS BASED ON JAGGED / NOTCH PROTEINS AND AMINO ACIDS
US5885529A (en) * 1996-06-28 1999-03-23 Dpc Cirrus, Inc. Automated immunoassay analyzer
CA2263883C (en) * 1996-08-29 2003-07-08 The Regents Of The University Of California Kuz, a novel family of metalloproteases
US5859535A (en) * 1997-02-12 1999-01-12 The United States Of America As Represented By The Secretary Of The Navy System for determining size and location of defects in material by use of microwave radiation
US5830730A (en) * 1997-05-08 1998-11-03 The Regents Of The University Of California Enhanced adenovirus-assisted transfection composition and method
US6379925B1 (en) * 1997-06-18 2002-04-30 The Trustees Of Columbia University In The City Of New York Angiogenic modulation by notch signal transduction
US6136952A (en) * 1997-06-25 2000-10-24 University Of Washington Human jagged polypeptide, encoding nucleic acids and methods of use
US6004528A (en) * 1997-09-18 1999-12-21 Bergstein; Ivan Methods of cancer diagnosis and therapy targeted against the cancer stemline
US6197523B1 (en) * 1997-11-24 2001-03-06 Robert A. Levine Method for the detection, identification, enumeration and confirmation of circulating cancer and/or hematologic progenitor cells in whole blood
US5981225A (en) * 1998-04-16 1999-11-09 Baylor College Of Medicine Gene transfer vector, recombinant adenovirus particles containing the same, method for producing the same and method of use of the same
JP2002520007A (ja) * 1998-07-13 2002-07-09 イエール ユニバーシティー Ｄｅｌｔａ切断産物およびそれに基づく方法
AU768269B2 (en) * 1998-10-02 2003-12-04 Government of The United States of America, as represented by The Secretary Department of Health & Human Services, The National Institutes of Health, The Apoptosis inducing agents and methods
US6316462B1 (en) * 1999-04-09 2001-11-13 Schering Corporation Methods of inducing cancer cell death and tumor regression
US20030119029A1 (en) * 1999-04-30 2003-06-26 Regents Of The University Of Michigan Compositions and methods relating to novel benzodiazepine compounds and targets thereof
US6380362B1 (en) * 1999-12-23 2002-04-30 Genesis Research & Development Corporation Ltd. Polynucleotides, polypeptides expressed by the polynucleotides and methods for their use
WO2001053255A1 (en) * 2000-01-24 2001-07-26 Merck Sharp & Dohme Limited Gamma-secretase inhibitors
GB0005251D0 (en) * 2000-03-03 2000-04-26 Merck Sharp & Dohme Therapeutic compounds
GB0008710D0 (en) * 2000-04-07 2000-05-31 Merck Sharp & Dohme Therapeutic compounds
GB0016681D0 (en) * 2000-07-06 2000-08-23 Merck Sharp & Dohme Therapeutic compounds
US6984522B2 (en) * 2000-08-03 2006-01-10 Regents Of The University Of Michigan Isolation and use of solid tumor stem cells
US6689744B2 (en) * 2000-09-22 2004-02-10 Genentech, Inc. Notch receptor agonists and uses
IL149701A0 (en) * 2001-05-23 2002-11-10 Pfizer Prod Inc Use of anti-ctla-4 antibodies
ES2292772T3 (es) * 2001-06-22 2008-03-16 Stemcells, Inc. Celulas de injerto de higado, analisis, y sus usos.
WO2003013527A1 (en) * 2001-08-03 2003-02-20 Schering Corporation Sulfonamide derivatives as gamma secretase inhibitors
ATE515495T1 (de) * 2001-08-03 2011-07-15 Schering Corp Gamma sekretase inhibitoren
JP2003177126A (ja) * 2001-12-13 2003-06-27 Kenichi Katsube Ｃｃｎファミリー蛋白質活性制御剤のスクリーニング方法
PL2032166T3 (pl) * 2006-06-13 2013-09-30 Oncomed Pharm Inc Kompozycje i sposoby diagnozowania i leczenia nowotworów

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018544A2 (en) 2000-08-31 2002-03-07 Loyola University Chicago Method and reagents for treatment of skin disorders by modulating the notch pathway
WO2003050502A2 (en) 2001-12-07 2003-06-19 Regents Of The University Of Michigan Prospective identification and characterization of breast cancer stem cells

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1718767A4

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9089556B2 (en) 2000-08-03 2015-07-28 The Regents Of The University Of Michigan Method for treating cancer using an antibody that inhibits notch4 signaling
US8404237B2 (en) 2006-06-13 2013-03-26 OncoMed Pharamaceuticals, Inc. Antibodies to the NOTCH1 receptor
US7919092B2 (en) 2006-06-13 2011-04-05 Oncomed Pharmaceuticals, Inc. Antibodies to notch receptors
US8784811B2 (en) 2006-06-13 2014-07-22 Oncomed Pharmaceuticals, Inc. Method of treating cancer using antibodies to a non-ligand binding region of NOTCH1
US8206713B2 (en) 2006-06-13 2012-06-26 Oncomed Pharmaceuticals, Inc. Method of treating cancer using antibodies to a non-ligand binding region of NOTCH2
US9676865B2 (en) 2006-06-13 2017-06-13 Oncomed Pharmaceuticals, Inc. Antibodies to a non-ligand binding region of at least two NOTCH receptors
US8088617B2 (en) 2007-01-24 2012-01-03 Oncomed Pharmaceuticals, Inc. Antibodies that bind the glutamate ligand binding region of Notch1
US9617340B2 (en) 2007-01-24 2017-04-11 Oncomed Pharmaceuticals, Inc. Compositions and methods for diagnosing and treating cancer
WO2008091641A3 (en) * 2007-01-24 2008-12-04 Oncomed Pharm Inc Compositions and methods for diagnosing and treating cancer
US8460661B2 (en) 2007-01-24 2013-06-11 Oncomed Pharmaceuticals, Inc. Methods of using antibodies that bind the glutamate ligand binding region of Notch1
US8501472B2 (en) 2007-01-24 2013-08-06 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing pancreatic cancer
US8921106B2 (en) 2007-01-24 2014-12-30 Oncomed Pharmaceuticals, Inc. Antibodies that bind the glutamate ligand binding region of NOTCH3
WO2008122794A3 (en) * 2007-04-05 2009-04-02 Imp Innovations Ltd Breast cancer methods, medicaments and agents
US9499613B2 (en) 2008-07-08 2016-11-22 Oncomed Pharmaceuticals, Inc. Notch1 receptor binding agents and methods of use thereof
US9505832B2 (en) 2008-07-08 2016-11-29 Oncomed Pharmaceuticals, Inc. Method of treating cancer by administering a monoclonal antibody that binds human NOTCH2 and NOTCH3
US8945873B2 (en) 2008-07-08 2015-02-03 Oncomed Pharmaceuticals, Inc. Polynucleotides encoding Notch receptor antibodies
US8945874B2 (en) 2008-07-08 2015-02-03 Oncomed Pharmaceuticals, Inc. Polynucleotides encoding NOTCH1 receptor antibodies
US8945547B2 (en) 2008-07-08 2015-02-03 Oncomed Pharmaceuticals, Inc. Notch1 receptor antibodies and methods of treatment
US8980260B2 (en) 2008-07-08 2015-03-17 Oncomed Pharmaceuticals, Inc. Monoclonal antibody that binds human notch2 and notch3
US8226943B2 (en) 2008-07-08 2012-07-24 Oncomed Pharmaceuticals, Inc. Antibodies to notch receptors
US9132189B2 (en) 2008-07-08 2015-09-15 Oncomed Pharmaceuticals, Inc. Notch1 binding agents and methods of use thereof
US8435513B2 (en) 2008-07-08 2013-05-07 Oncomed Pharmaceuticals, Inc. NOTCH1 receptor antibodies and methods of treatment
US8425903B2 (en) 2008-07-08 2013-04-23 Oncomed Pharmaceuticals, Inc. Methods of treatment by administering antibodies to notch receptors
US9606124B2 (en) 2008-11-11 2017-03-28 The Regents Of The University Of Michigan Methods of detecting and treating stem-cell containing solid tumors
US8940301B2 (en) 2008-11-11 2015-01-27 The Regents Of The University Of Michigan Breast tumor treatment with anti-CXCR1 compositions
EP3153862A1 (en) 2008-11-11 2017-04-12 The Regents of the University of Michigan Anti-cxcr1 compositions and methods
US10557850B2 (en) 2008-11-11 2020-02-11 The Regents Of University Of Michigan Anti-CXCR1 compositions and methods
US8834875B2 (en) 2010-01-13 2014-09-16 Oncomed Pharmaceuticals, Inc. Notch1 binding agents and methods of use thereof
US9527921B2 (en) 2015-04-16 2016-12-27 Eisai R&D Management Co., Ltd. Anti human Notch4 antibody
US9969812B2 (en) 2015-04-16 2018-05-15 Eisai R&D Management Co., Ltd. Anti human Notch4 antibody
WO2022120187A3 (en) * 2020-12-03 2022-08-18 Shattuck Labs, Inc. Method of determining resistance to checkpoint inhibitor therapies

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AU2009200959A1 (en) 2009-04-09
JP2007526455A (ja) 2007-09-13
IL177346A0 (en) 2006-12-10
US20170119880A1 (en) 2017-05-04
AU2005209909B8 (en) 2009-01-15
AU2005209909A1 (en) 2005-08-18
EP1718767A4 (en) 2008-11-05
EP1718767A2 (en) 2006-11-08
US20050232927A1 (en) 2005-10-20
AU2005209909B2 (en) 2008-12-18
US20150132294A1 (en) 2015-05-14
EP1718767B1 (en) 2012-04-11
US20080260734A1 (en) 2008-10-23

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