WO2006132907A2 - Procedes de traitement, de diagnostic ou de detection du cancer - Google Patents

Procedes de traitement, de diagnostic ou de detection du cancer Download PDF

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Publication number
WO2006132907A2
WO2006132907A2 PCT/US2006/021246 US2006021246W WO2006132907A2 WO 2006132907 A2 WO2006132907 A2 WO 2006132907A2 US 2006021246 W US2006021246 W US 2006021246W WO 2006132907 A2 WO2006132907 A2 WO 2006132907A2
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WIPO (PCT)
Prior art keywords
ephb3
mer
modulator
cancer
patient
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PCT/US2006/021246
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English (en)
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WO2006132907A3 (fr
Inventor
Deborah Lee Zimmerman
Mary Jo Janatpour
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Novartis Vaccines And Diagnostics Inc.
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Priority to EP06771814A priority Critical patent/EP1888648A2/fr
Priority to CA002610685A priority patent/CA2610685A1/fr
Priority to AU2006255536A priority patent/AU2006255536A1/en
Priority to JP2008514843A priority patent/JP2008545750A/ja
Publication of WO2006132907A2 publication Critical patent/WO2006132907A2/fr
Publication of WO2006132907A3 publication Critical patent/WO2006132907A3/fr

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    • 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
    • C07K16/2866—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 cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • the cancer cells are taken from established cell lines that are publicly available, hi some embodiments, cancer cells are isolated from pre-existing patient samples or from libraries comprising cancer cells. In some embodiments, cancer cells are isolated and then implanted in a different host, e.g., in a xenograft. In some embodiments cancer cells are transplanted and used in a SCID mouse model, hi some embodiments, the cancer is ovarian, colon or esophageal cancer. In some preferred embodiments the cancer is ovarian or esophageal cancer.
  • antibody refers to monoclonal and polyclonal antibodies, single chain antibodies, chimeric antibodies, bifunctional/bispecific antibodies, humanized antibodies, human antibodies, and complementary determining region (CDR)- grafted antibodies, that are specific for the target protein or fragments thereof.
  • the term “antibody” further includes in vivo therapeutic antibody gene transfer.
  • Antibody fragments including Fab, Fab', F(ab')2, scFv, and Fv are also provided by the invention.
  • Antibodies may, in some preferred embodiments, be monoclonal, humanized, primatized, single chain, or chimeric antibodies.
  • oligonucleotide refers to a series of linked nucleotide residues.
  • the term "decoy receptor” refers to an EphB3 receptor comprising at least a portion of a polypeptide, mimetic, or other macromolecule capable of binding an
  • the term "therapeutically effective amount” is meant to refer to an amount of a medicament which produces a medicinal effect observed as reduction or reverse in one or more clinical endpoints, growth and/or survival of cancer cell, or metastasis of cancer cells in an individual when a therapeutically effective amount of the medicament is administered to the individual.
  • Therapeutically effective amounts are typically determined by the effect they have compared to the effect observed when a composition which includes no active ingredient is administered to a similarly situated individual. The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition, and the therapeutics or combination of therapeutics selected for administration.
  • the term "susceptible" refers to patients for whom EphB3 therapy is an acceptable method of treatment, i.e., patients who are likely to respond positively.
  • Cancer patients susceptible to EphB3 therapy express high levels of EphB3 relative to those patients not susceptible to EphB3 therapy.
  • Cancer patients who are not good candidates for EphB3 therapy include cancer patients with tumor samples that lack or have lower levels of EphB3 in or on their cancer cells.
  • Percent homology or identity can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison WI), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482-489). In some preferred embodiments, homology between the probe and target is between about 50% to about 60%.
  • polypeptides are about 60%, about 70%, about 80%, about 85%, about 90%, about 92%, about 94%, about 95%, about 97%, about 98%, about 99% and about 100% homologous to SEQ ID NO:2 or a portion thereof.
  • mixing refers to the process of combining- one or more compounds, cells, molecules, and the like together in the same area. This may be performed, for example, in a test tube, petri dish, or any container that allows the one or more compounds, cells, or molecules, to be mixed.
  • isolated refers to a polynucleotide, a polypeptide, an antibody, or a host cell that is in an environment different from that in which the polynucleotide, the polypeptide, or the antibody naturally occurs. Methods of isolating cells are well known to those skilled in the art. A polynucleotide, a polypeptide, or an antibody which is isolated is generally substantially purified.
  • substantially purified refers to a compound (e.g., either a polynucleotide or a polypeptide or an antibody) that is removed from its natural environment and is at least 60% free, at least 75% free, and at least 90% free from other components with which it is naturally associated.
  • binding means the physical or chemical interaction between two or more biomolecules or compounds. Binding includes ionic, non-ionic, hydrogen bonds, Van der Waals, hydrophobic interactions, etc. Binding can be either direct or indirect, indirect being through or due to the effects of another biomolecule or compound. Direct binding refers to interactions that do not take place through or due to the effect of another molecule or compound but instead are without other substantial chemical intermediates.
  • contacting means bringing together, either directly or indirectly, one molecule into physical proximity to a second molecule.
  • the molecule can be in any number of buffers, salts, solutions, etc.
  • Contacting includes, for example, placing a polynucleotide into a beaker, microtiter plate, cell culture flask, or a microarray, or the like, which contains a nucleic acid molecule.
  • Contacting also includes, for example, placing an antibody into a beaker, microtiter plate, cell culture flask, or microarray, or the like, which contains a polypeptide. Contacting may take place in vivo, ex vivo, or in vitro.
  • stringent hybridization conditions refers to conditions under which a probe, primer, or oligonucleotide will hybridize to its target sequence, but to a minimal number of other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences will hybridize with specificity to their proper complements at higher temperatures. Generally, stringent conditions are selected to be about 5 0 C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% of the probes complementary to the target sequence hybridize to the target sequence at equilibrium.
  • Tm thermal melting point
  • stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30 0 C for short probes, primers or oligonucleotides (e.g., 10 to 50 nucleotides) and at least about 60°C for longer probes, primers or oligonucleotides.
  • Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide.
  • Moderate stringency conditions refers to conditions under which a probe, primer, or oligonucleotide will hybridize to its target sequence, but to a limited number of other sequences. Moderate conditions are sequence-dependent and will be different in different circumstances. Moderate conditions are well-known to the art skilled and are described in, inter alia, Manitatis et al. (Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory; 2nd Edition (December 1989)).
  • the nucleic acid compositions described herein can be used, for example, to produce polypeptides, as probes for the detection of mRNA in biological samples (e.g., extracts of human cells) or cDNA produced from such samples, to generate additional copies of the polynucleotides, to generate ribozymes or oligonucleotides (single and double stranded), and as single stranded DNA probes or as triple-strand forming oligonucleotides.
  • the probes described herein can be used to, for example, determine the presence or absence of the polynucleotides provided herein in a sample.
  • the polypeptides can be used to generate antibodies specific for a polypeptide associated with cancer, which antibodies are in turn useful in diagnostic methods, prognostic methods, and the like as discussed in more detail herein. Polypeptides are also useful as targets for therapeutic intervention, as discussed in more detail herein. Antibodies of the present invention may also be used, for example, to purify, detect, and target the polypeptides of the present invention, including both in vitro and in vivo diagnostic and therapeutic methods. For example, the antibodies are useful in immunoassays for qualitatively and quantitatively measuring levels of the polypeptides of the present invention in biological samples. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988). These and other uses are described in more detail below.
  • imaging agent refers to a composition linked to an antibody, small molecule, or probe of the invention that can be detected using techniques known to the art-skilled.
  • vidence of gene expression refers to any measurable indicia that a gene is expressed.
  • pharmaceutically acceptable carrier refers to a carrier for administration of a therapeutic agent, such as antibodies or a polypeptide, genes, and other therapeutic agents.
  • a therapeutic agent such as antibodies or a polypeptide, genes, and other therapeutic agents.
  • the term refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without undue toxicity.
  • Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, lipid aggregates and inactive virus particles. Such carriers are well known to those of ordinary skill in the art.
  • Pharmaceutically acceptable carriers in therapeutic compositions can include liquids such as water, saline, glycerol and ethanol. Auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, can also be present in such vehicles.
  • EphB3 When bound to an EphB3 ligand, EphB3 becomes phosphorylated and then subsequently degraded. Accordingly, the present invention is based, in part, on the discovery that EphB3 modulators can inhibit cancer cell proliferation and invasiveness by reducing the levels of EphB3 expression in cancer cells and/or by inducing ligand-like EphB3 signaling, EphB3 phosphorylation, and/or EphB3 degradation. Cancer cell growth and/or migration is therefore decreased.
  • the present invention is also applicable to any tumor cell-type where EphB3 plays a role in cell adhesion, migration or repulsion.
  • the cancer is ovarian, esophageal, colon, prostate, breast, skin cancer, lung, stomach or pancreatic cancer.
  • the cancers amenable to treatment and/or diagnosis according to the present invention are characterized by overexpression of E ⁇ hB3.
  • such cancers exhibit overexpression of EpliB3 by at least about 25%, at least about 50%, at least about
  • the present invention provides methods and compositions that provide for the treatment, inhibition, prevention and management of diseases and disorders associated with
  • EphB3 overexpression as well as the treatment, inhibition, prevention and management of symptoms of such diseases and disorders.
  • Some embodiments of the invention relate to methods and compositions comprising compositions that inhibit cancer cell proliferation and invasion.
  • the present invention further provides methods and compositions for the treatment, inhibition, prevention or management of cancer or cancer metastases. Further compositions and methods of the invention include other active ingredients in combination with the EphB3 modulators of the present invention. In some embodiments, the methods further comprise administering one or more traditional cancer therapeutics to the patient. In some embodiments the methods of the present invention further comprise treating the patient with one or more of chemotherapy, radiation therapy or surgery.
  • the invention also provides diagnostic and/or imaging methods using the EphB3 modulators of the invention, particularly EphB3 antibodies, to diagnose cancer and/or predict cancer progression.
  • the methods of the invention provide methods of imaging and localizing tumors and/or metastases and methods of diagnosis and prognosis.
  • the methods of the invention provide methods to evaluate the appropriateness of EphB3 -related therapy.
  • the present invention provides EphB3 modulators for, inter alia, the treatment, diagnosis, detection or imaging of cancer.
  • the EphB3 modulator is an oligonucleotide, a small molecule, a mimetic, a soluble receptor, a decoy, or an antibody. In some embodiments, the
  • EphB3 modulator induces EphB3 phosphorylation. In some embodiments, the EphB3 modulator induces EphB3 oligomerization. In some embodiments, the EphB3 modulator induces EphB3 degradation. In some embodiments, the EphB3 modulator induces EphB3 oligomerization and induces EphB3 degradation. In some embodiments the EphB3 modulator stimulates EphB3 binding to intracellular adaptor proteins.
  • the EphB3 modulator inhibits and/or inactivates FAK, the Erk/MAPK pathway, the Cdc42/Rac pathway, activates RasGAP, inhibits and/or inactivates Abl/Arg, Fyn, Src, LMW- PTP, Mersectin, the Cdc42 pathway, Kalirin or the Rac pathway.
  • the EphB3 modulator causes phosphorylation of R-Ras.
  • the EphB3 modulator inactivates R-Ras or activates Syndecan.
  • intracellular adaptor proteins refers to a protein that connects different segments of a signaling complex.
  • the adaptor protein may or may not have enzymatic activity.
  • the adaptor protein is Grb2, an adaptor protein not having intrinsic enzymatic activity.
  • the adaptor protein is RasGAP, an adaptor protein having enzymatic activity.
  • the EphB3 modulator increases EphB3 phosphorylation by 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 97%, 98%, 99% or 100%, as compared to a control.
  • Methods are known in the art to determine the level of receptor phosphorylation, activity, or expression and can be used to assay candidate EphB3 modulators in order to determine their properties. Examples of such methods are set forth, for example, in Cancer Research 62:2840 (2002); and Cancer Research 63: 7907 (2003).
  • the EphB3 modulator increases EphB3 oligomerization/degradation/internalization by 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 97%, 98%, 99% or 100%, as compared to a control.
  • Methods of determining levels of receptor oligomerization/degradation/internalization are known to those of skill in the art. (See, for example, Methods 27 (4): 340, 2002; Cancer Res. 64: 781, 2004; Cancer Res. 63: 7907, 2003).
  • the EphB3 modulator increases EphB3 phosphorylation by 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 97%, 98%, 99% or 100%, as compared to a control.
  • Methods of determining levels of receptor phosphorylation are known to those of skill in the art. (See, for example, Cancer Res. 62: 2840, 2002; Cancer Res. 63: 7907, 2003).
  • the EphB3 modulator inhibits EphB3 expression. In some embodiments, EphB3 expression is inhibited by 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 97%, 98%, 99% or 100%, as compared to a control. Methods of determining levels of EphB3 expression are known to those of skill in the art. [000109] Antibodies
  • the EphB3 modulator is an antibody.
  • the EphB3 modulator is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a humanized antibody, a single-chain antibody, or a Fab fragment.
  • the antibody may be labeled with, for example, an enzyme, radioisotope, or fluorophore.
  • the antibody has a binding affinity less than about IxIO 5 Ka for a polypeptide other than EphB3.
  • the EphB3 modulator is a monoclonal antibody which binds to EphB3 with an affinity of at least IxIO 8 Ka. In some embodiments, the monoclonal antibody does not bind to the ligand binding domain of EphB3.
  • the monoclonal antibody induces E ⁇ hB3 phosphorylation.
  • the EphB3 modulator induces EphB3 oligomerization.
  • the EphB3 modulator induces EphB3 degradation.
  • the EphB3 modulator induces EphB3 oligomerization and induces EphB3 degradation.
  • the invention also provides antibodies that competitively inhibit binding of an antibody to an epitope of the invention as determined by any method known in the art for determining competitive binding using, for example, immunoassays.
  • the antibody competitively inhibits binding to the epitope by at least 95%, at least 90%, at least 85 %, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50%.
  • the antibody is selected from the group consisting of a monoclonal antibody, a humanized antibody, a chimeric antibody, a primatized antibody, a phage-displayed antibody, a single chain antibody, or a fragment of any of the preceding.
  • the antibody is a humanized antibody.
  • Humanized antibodies may be achieved by a variety of methods including, for example: (1) grafting the non-human complementarity determining regions (CDRs) onto a human framework and constant region (a process referred to in the art as “humanizing”), or, alternatively, (2) transplanting the entire non-human variable domains, but “cloaking" them with a human-like surface by replacement of surface residues (a process referred to in the art as “veneering”).
  • humanized antibodies will include both “humanized” and “veneered” antibodies.
  • human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated.
  • Antibodies of the present invention may function through different mechanisms.
  • antibodies trigger antibody-dependent cellular cytotoxicity (ADCC), a lytic attack on antibody-targeted cells.
  • ADCC antibody-dependent cellular cytotoxicity
  • antibodies have multiple therapeutic functions, including, for example, antigen-binding, induction of apoptosis, and complement-dependent cellular cytotoxicity (CDC).
  • antibodies of the present invention may act as agonists of the polypeptides of the present invention.
  • the present invention provides antibodies which disrupt the receptor/ligand interactions with the polypeptides of the invention either partially or fully.
  • antibodies of the present invention bind an epitope disclosed herein, or a portion thereof.
  • binding of the antibody to the receptor induces receptor degradation.
  • binding of the antibody to the receptor induces receptor oligomerization.
  • binding of the antibody to the receptor induces receptor phosphorylation.
  • binding of the antibody to the receptor induces receptor activation.
  • Receptor activation i.e., signaling
  • receptor activation can be determined by detecting the phosphorylation (e.g., tyrosine or serine/threonine) of the receptor or its substrate by immunoprecipitation followed by Western blot analysis.
  • antibodies are provided that modulate ligand activity or receptor activity by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50% of the activity in absence of the antibody.
  • the EphB3 antibodies stimulate EphB3 binding to intracellular adaptor proteins.
  • the EphB3 antibodies block and/or interfere with the interaction of the cytoplasmic domain of EphB3 with one or more intracellular adaptor proteins.
  • EphB3 antibodies inhibit and/or inactivate FAK, the Erk/MAPK pathway., the Cdc42/Rac pathway, activates RasGAP, inhibits and/or inactivates Abl/Arg, Fyn, Src, LMW-PTP, Intersectin, the Cdc42 pathway, Kalirin or the Rac pathway.
  • the EphB3 antibodies inactivate R-ras or activate Syndecan.
  • the E ⁇ hB3 antibodies lead to the phosphorylation of R-Ras.
  • intracellular adaptor proteins refers to a protein that connects different segments of a signaling complex.
  • the adaptor may or may not have enzymatic activity.
  • adaptor proteins are known to those of skill in the art.
  • Grb2 is an adaptor protein that does not have intrinsic enzymatic activity
  • RasGAP is an adaptor protein that has enzymatic activity.
  • the present invention provides activating antibodies.
  • the activating antibodies act as receptor agonists, i.e., modulating either all or a subset of the biological activities of the ligand-mediated receptor activation, for example, by inducing oligomerization of the receptor.
  • the antibodies may be specified as agonists for biological activities comprising the specific biological activities of the peptides of the invention disclosed herein.
  • Antibody agonists can be made using methods known in the art. See, e.g., PCT publication WO 96/40281; U.S. Patent No. 5,811,097; Deng et al., Blood 92(6): 1981-1988 (1998); Chen et al., Cancer Res.
  • the antibodies of the present invention may be used either alone or in combination with other compositions.
  • the antibodies may further be recombinantly fused to a heterologous polypeptide at the N- or C-terminus or chemically conjugated (including covalently and non- covalently conjugations) to polypeptides or other compositions.
  • antibodies of the present invention may be recombinantly fused or conjugated to molecules useful as labels in detection assays and effector molecules such as heterologous polypeptides, drugs, radionuclides, or toxins. See, e.g., PCT publications WO 92/08495; WO 91/14438; WO 89/12624; U.S. Patent No. 5,314,995; and EP 396,387.
  • radioactive material examples include I, 131 I, or "Tc.
  • cytotoxins or cytocidals include one or more of paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1- dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof.
  • Antibody conjugates of the present invention can be used for modifying a given biological response.
  • the drug moiety may be a protein or polypeptide, or fragments thereof, possessing a desired biological activity.
  • proteins include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, ⁇ -interferon, ⁇ -interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, e.g., TNF- alpha, TNF-beta, AIM I (See, International Publication No.
  • a thrombotic agent or an anti- angiogenic agent e.g., angiostatin or endostatin
  • biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-I”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.
  • IL-I interleukin-1
  • IL-2 interleukin-2
  • IL-6 interleukin-6
  • GM-CSF granulocyte macrophage colony stimulating factor
  • G-CSF granulocyte colony stimulating factor
  • Antibodies of the present invention may also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen.
  • solid supports include without limitation, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.
  • the antibodies of the present invention can be conjugated to a second antibody to form an antibody heteroconjugate (see, for example U.S. Patent No. 4,676,980).
  • the present invention provides therapeutic antibodies, with or without a therapeutic moiety conjugated thereto, administered alone or in combination with other agents, including, for example, cytotoxic factor(s) and/or cytoldne(s).
  • the antibody disrupts or prevents cell-cell interactions.
  • the antibody inhibits cell migration or chemotactic properties of a cell expressing EphB3.
  • Fully human antibodies can be derived from transgenic mice having human immunoglobulin genes (see, e.g., U.S. Patent Nos. 6,075,181, 6,091,001, and 6,114,598, all of which are incorporated herein by reference), or from phage display libraries of human immunoglobulin genes (see, e.g. McCafferty et al., Nature, 348:552-554 (1990). Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. MoI. Biol., 222:581-597 (1991)).
  • Monoclonal antibodies can be prepared using the method of Kohler et al. (1975) Nature 256:495-496, or a modification thereof.
  • a mouse is immunized with a solution containing an antigen. Immunization can be performed by mixing or emulsifying the antigen-containing solution in saline, preferably in an adjuvant such as Freund's complete adjuvant, and injecting the mixture or emulsion parenterally. Any method of immunization known in the art may be used to obtain the monoclonal antibodies of the invention.
  • the spleen and optionally, several large lymph nodes
  • the spleen cells may be screened by applying a cell suspension to a plate or well coated with the antigen of interest.
  • the B cells expressing membrane bound immunoglobulin specific for the antigen bind to the plate and are not rinsed away.
  • Resulting B cells, or all dissociated spleen cells are then induced to fuse with myeloma cells to form hybridomas, and are cultured in a selective medium.
  • the resulting cells are plated by serial or limiting dilution and are assayed for the production of antibodies that specifically bind the antigen of interest (and that do not bind to unrelated antigens).
  • the selected monoclonal antibody (mAb)-secreting hybridomas are then cultured either in vitro (e.g., in tissue culture bottles or hollow fiber reactors), or in vivo (as ascites in mice).
  • mAb monoclonal antibody
  • hybridomas for expression, antibodies can be produced in a cell line such as a CHO or myeloma cell lines, as disclosed in U.S. Patent Nos. 5,545,403; 5,545,405; and 5,998,144; incorporated herein by reference. Briefly the cell line is transfected with vectors capable of expressing a light chain and a heavy chain, respectively. By transfecting the two proteins on separate vectors, chimeric antibodies can be produced. Immunol.
  • Antibodies of the present invention may also be administered to a subject via in vivo therapeutic antibody gene transfer as discussed by Fang et al. (2005), Nat. Biotechnol. 23, 584-590.
  • recombinant vectors can be generated to deliver a multicistronic expression cassette comprising a peptide that mediates enzyme independent, cotranslational self cleavage of polypeptides placed between MAb heavy and light chain encoding sequences. Expression leads to stochiometric amounts of both MAb chains.
  • a preferred example of the peptide that mediates enzyme independent, cotranslational self cleavage is the foot-and- mouth-disease derived 2A peptide.
  • Anti-EphB3 antibodies or antibody fragments thereof may be conjugated prior to use in the methods of the present invention.
  • Methods for producing conjugated antibodies are known in the art.
  • the anti-EphB3 antibody may be labeled using an indirect labeling or indirect labeling approach.
  • indirect labeling or “indirect labeling approach” is intended that a chelating agent is covalently attached to an antibody and at least one radionuclide is inserted into the chelating agent. See, for example, the chelating agents and radionuclides described in Srivagtava and Mease (1991) Nucl. Med. Bio. 18:589-603, herein incorporated by reference.
  • Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6- mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorabicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and antliramycin (AMC)), and anti-mitotic agents (e
  • the monoclonal antibody binds to an epitope of EphB3, wherein the epitope is selected from the group consisting of SEQ ID NOS: 14-424. In some embodiments, the monoclonal antibody binds to an epitope of EphB3, wherein the epitope is in the domain selected from the group consisting of the ligand binding domain, the TNFR domain, the 1st fibronectin domain, and the 2nd fibronectin domain. In some embodiments, the monoclonal antibody binds to an epitope of the ligand binding domain of EphB3, wherein the epitope is selected from the group consisting of SEQ ID NOS: 14- 148.
  • the monoclonal antibody binds to an epitope of the TNFR domain of EphB3, wherein the epitope is selected from the group consisting of SEQ ID NOS: 164-262. In some embodiments, the monoclonal antibody binds to an epitope of the 1st fibronectin domain of EphB3, wherein the epitope is selected from the group consisting of SEQ ID-NOS:263-304. In some embodiments, the monoclonal antibody binds to an epitope of the 2nd fibronectin domain of EphB3, wherein the epitope is selected from the group consisting of SEQ ID NOS-.383-424.
  • binding affinities include those with a Kd less than 5 x 1(T 2 M, 10 '2 M, 5 x 10 "3 M, 10- 3 M, 5 x 10 "4 M, 10 "4 M, 5 x 10 '5 M, 10 '5 M, 5 x 10 "6 M, 10 “6 M, 5 x 10 "7 M, 10 "7 M, 5 x 1(T 8 M, 10 “8 M, 5 x 10 "9 M, 1(T 9 M, 5 x 1(T 10 M, 10 "10 M, 5 x 10 " ⁇ M, 10 " ⁇ M, 5 x 1(T 12 M, 10 "12 M, 5 x 10 "13 M 5 1(T 13 M, 5 x 1(T 14 M, 10 "14 M, 5 x 10 "15 M, or 10 "15 M, or less.
  • Suitable antibodies according to the present invention can recognize linear or conformational epitopes, or combinations thereof.
  • the antibody is specific for an epitope of the ligand binding domain (SEQ ID NO:3), TNFR domain (SEQ ID NO:4), 1st fibronectin domain (SEQ ID NO:5), or 2nd fibronectin domain of EphB3 (SEQ ID NO:6).
  • SEQ ID NO:3 the ligand binding domain
  • SEQ ID NO:4 1st fibronectin domain
  • SEQ ID NO:6 2nd fibronectin domain of EphB3
  • these peptides do not necessarily precisely map one epitope, but may also contain E ⁇ hB3 sequence that is not immunogenic.
  • the following sequences are given by amino acid number (i.e., "AAn") where n is the amino acid number of the amino acid sequence set forth in SEQ ID NO:2.
  • an epitope is defined from about amino acid 80 of SEQ ID NO:2 to about amino acid 90 of SEQ ID NO:2.
  • the term “about” refers to +/- one or two amino acid residues:
  • variable regions of the antibodies of the invention recognize and bind target polypeptides exclusively by virtue of measurable differences in properties including binding affinity, despite the possible existence of localized sequence identity, homology, or similarity between the target protein and other polypeptides).
  • specific antibodies may also interact with other proteins (for example, S. aureus protein A or other antibodies in ELISA techniques) through interactions with sequences outside the variable region of the antibodies, and, in particular, in the constant region of the molecule.
  • Screening assays to determine binding specificity of an antibody of the invention are well known and routinely practiced in the art, as discussed in Harlow et al. (Eds.), Antibodies: A Laboratory Manual; Cold Spring Harbor Laboratory; Cold Spring Harbor, NY (1988), Chapter 6.
  • the antibodies of the present invention do not bind to known related polypeptide molecules, for example, if they bind EphB3 polypeptide but not known related polypeptides using a standard Western blot analysis (Ausubel et al.).
  • known related polypeptides include, without limitation, other members of the Ephrin receptor protein family such as EphA5 (Ephrin receptor EphA5), EphB2 (Ephrin receptor EphB2), EphB4 (Ephrin receptor EphB4), and the like.
  • EphA5 Ephrin receptor EphA5
  • EphB2 Ephrin receptor EphB2
  • EphB4 Ephrin receptor EphB4
  • antibodies may be screened against known related polypeptides to isolate an antibody population that specifically binds to EphB3 polypeptides.
  • EphB3 receptor polypeptides For example, antibodies specific to human EphB3 receptor polypeptides will flow through a column comprising Ephrin receptor family polypeptides (with the exception of EphB3) adhered to insoluble matrix under appropriate buffer conditions.
  • EphB3 Ephrin receptor family polypeptides
  • Screening and isolation of specific antibodies is well known in the art (see, Fundamental Immunology, Paul (eds.), Raven Press, 1993; Getzoff et al., Adv.
  • the antibodies of the present invention have at least about 1000 fold, and at least about 10,000 fold greater affinity for EphB3 than for known related family members.
  • the binding affinity of an antibody of the present invention is less than about 1 x 10 5 Ka, less than about 1 x 10 4 Ka, and preferably less than 1 x 10 3 Ka, for a related polypeptide other than EphB3.
  • the E ⁇ hB3 modulator is an oligonucleotide.
  • the oligonucleotide is an antisense or RNAi oligonucleotide.
  • the oligonucleotide is complementary to a region, domain, portion, or segment of EphB3.
  • the oligonucleotide comprises from about 5 to about 100 nucleotides, from about 10 to about 50 nucleotides, from about 12 to about 35, and from about 18 to about 25 nucleotides.
  • the oligonucleotide is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% homologous to a region, portion, domain, or segment of the EphB3 gene. In some embodiments there is substantial sequence homology over at least 15, 20, 25, 30, 35, 40, 50, or 100 consecutive nucleotides of the E ⁇ hB3 gene. In some embodiments there is substantial sequence homology over the entire length of the EphB3 gene. In some embodiments, the oligonucleotide binds under moderate or stringent hybridization conditions to a nucleic acid molecule having a nucleotide sequence of SEQ ID NO:1.
  • the EphB3 modulator is an oligonucleotide having a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11 5 SEQ ID NO:12, SEQ ID NO:13 and SEQ ID NO: 425.
  • the EphB3 modulator is a double stranded RNA (dsRNA) molecule and works via RNAi (RNA interference).
  • one strand of the dsRNA is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% homologous to a region, portion, domain, or segment of the EphB3 gene.
  • oligonucleotides are used in a polymerase chain reaction (PCR). This sequence may be based on (or designed from) a genomic sequence or cDNA sequence and is used to amplify, confirm, or detect the presence of an identical, similar, or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides may also be used to modulate the expression of a gene. Oligonucleotides comprise portions of a DNA sequence and have at least about 10 nucleotides and as many as about 500 nucleotides.
  • oligonucleotides comprise from about 10 nucleotides to about 50 nucleotides, from about 15 nucleotides to about 30 nucleotides, and from about 20 nucleotides to about 25 nucleotides. Oligonucleotides may be chemically synthesized and can also be used as probes. In some embodiments oligonucleotides are single stranded. In some embodiments oligonucleotides comprise at least one portion which is double stranded. In some embodiments the oligonucleotides are antisense oligonucleotides (ASO). In some embodiments the oligonucleotides are RNA interference oligonucleotides (RNAi oligonucleotides). [000151] Small molecules
  • the present invention also provides pharmaceutical compositions comprising one or more of the EphB3 modulators described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared. Liposomes are included within the definition of a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable salts can also be present in the pharmaceutical composition, e.g., mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like
  • the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • the present invention also provides methods for determining susceptibility of a patient to EphB3 therapy.
  • the methods comprise detecting the presence or absence of evidence of EphB3 expression in a patient or patient sample.
  • the presence of evidence of EphB3 expression in the patient or sample is indicative of a patient who is susceptible to EphB3 therapy.
  • the absence of evidence of EphB3 expression in the patient or patient sample is indicative of a patient who is not a candidate for EphB3 therapy.
  • the therapeutic methods comprise first identifying patients susceptible to EphB3 therapy comprising administering to the patient in need thereof a composition comprising an EphB3 antibody, probe, primer, or oligonucleotide linked to an imaging agent and detecting the presence or absence of evidence of the gene or gene product in the patient.
  • the presence of evidence of EphB3 expression, especially EphB3 overexpression, in the patient is indicative of a patient who is a candidate for EphB3 therapy and the absence of evidence of EphB3 expression in the patient is indicative of a patient who is not a candidate for EphB3 therapy.
  • the therapeutic methods further comprise administering one or more EphB3 modulators to the patient if the patient is a candidate for EphB3 therapy and treating the patient with conventional cancer treatment if the patient is not a candidate for EphB3 therapy.
  • the present invention also provides methods of screening for anti-cancer agents.
  • the methods comprise contacting a cell expressing EphB3 with a candidate compound and determining whether an EphB3-related biological activity is modulated.
  • induction of one or more of tyrosine kinase activity, receptor phosphorylation, receptor oligomerization, or receptor degradation is indicative of a cancer inhibitor.
  • inhibition of EpliB3 expression is indicative of a cancer inhibitor.
  • the present invention further provides methods of identifying a cancer inhibitor.
  • the methods comprise contacting a cell expressing EphB3 with a candidate compound and an EpliB3 ligand, and determining whether an EphB3-related biological activity is modulated.
  • induction of one or more of tyrosine kinase activity, receptor phosphorylation, receptor oligomerization, or receptor degradation is indicative of a cancer inhibitor.
  • inhibition of EphB3 expression is indicative of a cancer inhibitor.
  • the invention provides methods of screening for anti-cancer agents, particularly anti-metastatic cancer agents, by, for example,- screening putative modulators for an ability to increase receptor phosphorylation and/or induce receptor degradation.
  • kits for imaging and/or detecting a gene or gene product correlated with EphB3 overexpression comprise detectable antibodies, small molecules, oligonucleotides, soluble receptors, decoy receptors, mimetics or probes as well as instructions for performing the methods of the invention.
  • kits may also contain one or more of the following: controls (positive and/or negative), containers for controls, photographs or depictions of representative examples of positive and/or negative results.
  • Example 2 Clustered Ligand-Induced Phosphorylation of EphB3
  • An anti-human IgG antibody was used to induce clustering of the ephrinB2-Fc ligand for 10 minutes, before adding clustered ligands to cells.
  • Clustered ligand was added to cells at a concentration of 6.25 ⁇ g/mL, and cells were incubated in starvation media for various times to observe results at several timepoints. After incubation, starvation media was removed and the cells were washed once with PBS. Cells were then lysed with a denaturing lysis buffer including protease and phosphatase inhibitors.
  • oligonucleotides were further diluted in OptiMEMTM (Gibco/BRL), in a microfuge tube, to 2 ⁇ M, or approximately 20 ⁇ g oligo/ml of OptiMEMTM.
  • the carrier molecule typically in the amount of about 1.5-2 rrmol carrier/ ⁇ g antisense oligonucleotide was diluted into the same volume of OptiMEMTM used to dilute the oligonucleotide.
  • the diluted antisense oligonucleotide is immediately added to the diluted carrier and mixed by pipetting up and down. Oligonucleotide was added to the cells to a final concentration of 300 nM (antisense oligonucleotides). siRNAs were added to the cells to a final concentration of about 67nM.
  • a buffer/enzyme mixture prepared by mixing (in the order listed) 2.5 ⁇ l H 2 O, 2.0 ⁇ l 1OX reaction buffer, 10 ⁇ l oligo dT (20 pmol), 1.0 ⁇ l dNTP mix (10 mM each), 0.5 ⁇ l RNAsin® (2Ou) (Ambion, Inc., Hialeah, FL), and 0.5 ⁇ l MMLV reverse transcriptase (5Ou) (Ambion, Inc.). The contents were mixed by pipetting up and down, and the reaction mixture was incubated at 42°C for 1 hour. The contents of each tube were centrifuged prior to amplification.
  • An amplification mixture was prepared using ABI sybr master mix, plus 0.175 pmol of each oligonucleotide.
  • SYBR® Green (Molecular Probes, Eugene, OR) is a dye which fluoresces when bound to double-stranded DNA. As double stranded PCR product is produced during amplification, the fluorescence from SYBR® Green increases.
  • the oligonucleotide-OptiMEMTM was then added to a delivery vehicle, selected so as to be optimized for the particular cell type to be used in the assay.
  • the oligo/delivery vehicle mixture was then further diluted into medium with serum on the cells.
  • the final concentration of antisense oligonucleotides was about 300 nM and the final concentration of siRNA oligonucleotides was 67-100 nM.
  • antisense or siRNA that resulted in inhibition of proliferation of MDA231 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous breast cells.
  • Linear epitopes of EphB3 for antibody recognition and preparation can be identified by any of numerous methods known in the art. Some example methods include probing antibody-binding ability of peptides derived from the amino acid sequence of the antigen. Binding can be assessed by using BLACORE or ELISA methods. Other techniques include exposing peptide libraries on planar solid support ("chip") to antibodies and detecting binding through any of multiple methods used in solid-phase screening. Additionally, phage display can be used to screen a library of peptides with selection of epitopes after several rounds of biopanning.

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Abstract

La présente invention a trait, entre autres, à des procédés pour le traitement du cancer, à des compositions pour le traitement du cancer, et à des procédés et des compositions pour le diagnostic et/ou la détection du cancer. En particulier, la présente invention a trait à des compositions et des procédés pour le traitement, le diagnostic et la détection des cancers associés à la surexpression de EphB3.
PCT/US2006/021246 2005-06-03 2006-06-02 Procedes de traitement, de diagnostic ou de detection du cancer WO2006132907A2 (fr)

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AU2006255536A AU2006255536A1 (en) 2005-06-03 2006-06-02 Methods of treating, diagnosing or detecting cancer using an EphB3 modulator
JP2008514843A JP2008545750A (ja) 2005-06-03 2006-06-02 Ｅｐｈｂ３モジュレーターを使用する、癌を処置、診断または検出するための方法

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WO2008019326A2 (fr) * 2006-08-04 2008-02-14 Novartis Ag Anticorps spécifique de ephb3 et ses utilisations
WO2008070780A1 (fr) * 2006-12-07 2008-06-12 Novartis Ag Anticorps antagonistes contre ephb3

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* Cited by examiner, † Cited by third party
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WO2008019326A2 (fr) * 2006-08-04 2008-02-14 Novartis Ag Anticorps spécifique de ephb3 et ses utilisations
WO2008019326A3 (fr) * 2006-08-04 2008-05-02 Novartis Ag Anticorps spécifique de ephb3 et ses utilisations
EP2420252A1 (fr) * 2006-08-04 2012-02-22 Novartis AG Anticorps spécifique EPHB3 et ses utilisations
US9006398B2 (en) 2006-08-04 2015-04-14 Novartis Ag EPHB3-specific antibody and uses thereof
WO2008070780A1 (fr) * 2006-12-07 2008-06-12 Novartis Ag Anticorps antagonistes contre ephb3
US8377439B2 (en) 2006-12-07 2013-02-19 Novartis Ag Antagonist antibodies against EPHB3
US8961969B2 (en) 2006-12-07 2015-02-24 Novartis Ag Antagonist antibodies against EphB3
US9541004B2 (en) 2006-12-07 2017-01-10 Novartis Ag Antagonist antibodies against EphB3

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