WO1999060023A1 - Traitement de tumeurs humaines a l'aide d'un rayonnement et d'inhibiteurs de tyrosine kinases de recepteurs du facteur de croissance - Google Patents

Traitement de tumeurs humaines a l'aide d'un rayonnement et d'inhibiteurs de tyrosine kinases de recepteurs du facteur de croissance Download PDF

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WO1999060023A1
WO1999060023A1 PCT/US1999/010741 US9910741W WO9960023A1 WO 1999060023 A1 WO1999060023 A1 WO 1999060023A1 US 9910741 W US9910741 W US 9910741W WO 9960023 A1 WO9960023 A1 WO 9960023A1
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Prior art keywords
egfr
family
radiation
antibodies
receptor tyrosine
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PCT/US1999/010741
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English (en)
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Harlan W. Waksal
Mansoor N. Saleh
Francisco Robert
Donald Jay Buchsbaum
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Imclone Systems Incorporated
Uab Research Foundation
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Application filed by Imclone Systems Incorporated, Uab Research Foundation filed Critical Imclone Systems Incorporated
Priority to BR9910511-0A priority Critical patent/BR9910511A/pt
Priority to AU40799/99A priority patent/AU4079999A/en
Priority to SK1728-2000A priority patent/SK17282000A3/sk
Priority to MXPA00011248A priority patent/MXPA00011248A/es
Priority to KR1020007012832A priority patent/KR20010071271A/ko
Priority to IL13970799A priority patent/IL139707A0/xx
Priority to EP99924253A priority patent/EP1080113A4/fr
Priority to CA002332331A priority patent/CA2332331A1/fr
Priority to JP2000549641A priority patent/JP2002515511A/ja
Publication of WO1999060023A1 publication Critical patent/WO1999060023A1/fr
Priority to HK02102068.1A priority patent/HK1040720A1/zh

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    • 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
    • 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
    • C07K16/2863—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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Normal cells proliferate by the highly controlled activation of growth factor receptors by their respective ligands.
  • An example of such receptors are the growth factor receptor tyrosine kinases.
  • Cancer cells also proliferate by the activation of growth factor receptors, but lose the careful control of normal proliferation.
  • the loss of control may be caused by numerous factors, such as the autocrine secretion of growth factors, increased expression of receptors, and autonomous activation of biochemical pathways regulated by growth factors.
  • EGFR epidermal growth factor
  • PDGFR platelet-derived growth factor
  • IGFR insulinlike growth factor
  • NGFR nerve growth factor
  • FGF fibroblast growth factor
  • EGF epidermal growth factor
  • EGFR EGF receptor
  • HER1 human EGF receptor-1
  • EGF and transforming growth factor alpha are two known ligands of EGFR.
  • tumors that express EGF receptors include glioblastomas, as well as cancers of the lung, breast, head and neck, and bladder.
  • the amplification and/or overexpression of the EGF receptors on the membranes of tumor cells is associated with a poor prognosis.
  • the programmed death of cells is known as apoptosis.
  • Treatments of cancer traditionally include chemotherapy or radiation therapy.
  • chemotherapeutic agents include doxorubicin, cis-platin, and taxol.
  • the radiation can be either from an external beam or from a source placed inside a patient, i.e., brachytherapy.
  • Another type of treatment includes inhibitors of growth factors or growth factor receptors involved in the proliferation of cells. Such inhibitors neutralize the activity of the growth factor or receptor, and inhibit the growth of tumors that express the receptor.
  • U.S. Patent No. 4,943,533 describes a murine monoclonal antibody called 225 that binds to the EGF receptor.
  • the patent is assigned to the University of California and licensed exclusively to ImClone Systems Incorporated.
  • the 225 antibody is able to inhibit the growth of cultured EGFR-expressing tumor lines as well as the growth of these tumors in vivo when grown as xenografts in nude mice. See Masui et al., Cancer Res. 44, 5592-5598 (1986).
  • Prewett et al. reported the inhibition of tumor progression of well- established prostate tumor xenografts in mice with a chimeric form of the anti-EGFR 225 monoclonal antibody discussed above.
  • the chimeric form is called c225. Journal of Immunotherapy 19, 419-427 (1997).
  • a disadvantage of using murine monoclonal antibodies in human therapy is the possibility of a human anti-mouse antibody (HAMA) response due to the presence of mouse Ig sequences.
  • HAMA human anti-mouse antibody
  • This disadvantage can be minimized by replacing the entire constant region of a murine (or other non-human mammalian) antibody with that of a human constant region. Replacement of the constant regions of a murine antibody with human sequences is usually referred to as chimerization.
  • the chimerization process can be made even more effective by also replacing the framework variable regions of a murine antibody with the corresponding human sequences.
  • the framework variable regions are the variable regions of an antibody other than the hypervariable regions.
  • the hypervariable regions are also known as the complementarity-determining regions (CDRs).
  • the replacement of the constant regions and framework variable regions with human sequences is usually referred to as humanization.
  • the humanized antibody is less immunogenic (i.e. elicits less of a HAMA response) as more murine sequences are replaced by human sequences.
  • both the cost and effort increase as more regions of a murine antibodies are replaced by human sequences.
  • Another approach to reducing the immunogenicity of antibodies is the use of antibody fragments.
  • an article by Aboud-Pirak et al, Journal of the National Cancer Institute 8.0, 1605-1611 (1988) compares the anti-tumor effect of an anti-EGF receptor antibody called 108.4 with fragments of the antibody.
  • the tumor model was based on KB cells as xenografts in nude mice. KB cells are derived from human oral epidermoid carcinomas, and express elevated levels of EGF receptors.
  • Balaban et al. reported the ability of anti-EGFR monoclonal antibodies to sensitize human squamous carcinoma xenografts in mice to radiation when the radiation treatment was preceded by administration of an anti-EGFR antibody called LA22. See Biochimica et Biophysica Acta 1314. 147-156 (1996).
  • Saleh et al. also reported better tumor control in vitro and in mice when radiation therapy was augmented with anti-EGFR monoclonal antibodies. Saleh et al. concluded that: "Further studies... may lead to a novel combined modality RT/Mab therapy.” See abstract 4197 in the proceedings of the American Association for Cancer Research 21, 612 (1996).
  • the objective of the present invention is to provide an improved method for treating certain cancers in humans.
  • the method comprises treating the human patients with an effective amount of a combination of radiation and a non-radiolabeled protein receptor tyrosine kinase inhibitor, the overexpression of which can lead to tumorigenesis.
  • the present invention provides an improved method for treating tumors, particularly malignant tumors, in human patients who have cancer, or are at risk of developing cancer.
  • the types of tumors that can be treated in accordance with the invention are tumors that overexpress one or more growth factor receptor tyrosine kinases.
  • Some examples of growth factor receptor tyrosine kinases that can lead to tumorigenesis if overexpressed include the EGFR family of receptors, PDGFR family of receptors, IGFR family of receptors, NGFR family of receptors, TGF family of receptors, and FGFR family of receptors.
  • the EGFR family of receptors includes EGFR, which is also referred to in the literature as HER1 ; HER2, which is also referred to in the literature as Neu, c-erbB-2, and pi 85erbB-2; erbB-3 and erbB-4.
  • EGFR refers to the EGFR family of receptors.
  • the specific member of the EGFR family of receptors that is also called EGFR will be referred to as EGFR/HER1.
  • the PDGFR family of receptors includes PDGFR ⁇ and PDGFR ⁇ .
  • the IGF family of receptors includes IGFR- 1.
  • Members of the FGFR family include FGFR- 1 , FGFR-2, FGFR-3, and FGFR-4.
  • the TGFR family of receptors includes TGFR ⁇ and TGFR ⁇ .
  • Any type of tumor that overexpresses at least one growth factor receptor tyrosine kinase, the overexpression of which can lead to tumorigenesis, can be treated in accordance with the method of the invention.
  • These types of tumor include carcinomas, gliomas, sarcomas, adenocarcinomas, adenosarcomas and adenomas.
  • tumors occur in virtually all parts of the human body, including every organ.
  • the tumors may, for example, be present in the breast, lung, colon, kidney, bladder, head and neck, ovary, prostate, brain, pancreas, skin, bone, bone marrow, blood, thymus, uterus, testicles, cervix, and liver.
  • tumors that overexpress the EGF receptor include breast, lung, colon, kidney, bladder, head and neck, especially squamous cell carcinoma of the head and neck, ovary, prostate, and brain.
  • the tumors are treated with a combination of radiation therapy and a non- radiolabeled growth factor receptor tyrosine kinase inhibitor.
  • the inhibition of a growth factor receptor tyrosine kinase means that the growth of cells overexpressing such receptors is inhibited.
  • phosphorylation assays are useful in predicting the inhibitors useful in the present invention.
  • synergy when tumors in human patients are treated with a combination of an inhibitor of a growth factor receptor tyrosine kinase and radiation, as described herein.
  • the inhibition of tumor growth from the combined treatment with an inhibitor and radiation is better than would be expected from treatment with either the inhibitor or radiation alone.
  • Synergy may be shown, for example, by greater inhibition of tumor growth with the combined treatment than would be expected from treatment with either inhibitor or radiation alone.
  • synergy is demonstrated by remission of the cancer with the combined treatment with inhibitor and radiation where remission is not expected from treatment with either inhibitor or radiation alone.
  • the source of radiation can be either external or internal to the patient being treated.
  • the therapy is known as external beam radiation therapy (EBRT).
  • EBRT external beam radiation therapy
  • BT brachytherapy
  • the radiation is administered in accordance with well known standard techniques with standard equipment manufactured for this purpose, such as AECL Theratron and Varian Clinac.
  • the dose of radiation depends on numerous factors as is well known in the art. Such factors include the organ being treated, the healthy organs in the path of the radiation that might inadvertently be adversely affected, the tolerance of the patient for radiation therapy, and the area of the body in need of treatment.
  • the dose will typically be between 1 and 100 Gy, and more particularly between 2 and 80 Gy. Some doses that have been reported include 35 Gy to the spinal cord, 15 Gy to the kidneys, 20 Gy to the liver, and 65-80 Gy to the prostate. It should be emphasized, however, that the invention is not limited to any particular dose.
  • the dose will be determined by the treating physician in accordance with the particular factors in a given situation, including the factors mentioned above.
  • the distance between the source of the external radiation and the point of entry into the patient may be any distance that represents an acceptable balance between killing target cells and minimizing side effects.
  • the source of the external radiation is between 70 and 100 cm from the point of entry into the patient.
  • Brachytherapy is generally carried out by placing the source of radiation in the patient. Typically, the source of radiation is placed approximately 0-3 cm from the tissue being treated.
  • Known techniques include interstitial, intercavitary, and surface brachytherapy.
  • the radioactive seeds can be implanted permanently or temporarily. Some typical radioactive atoms that have been used in permanent implants include iodine- 125 and radon. Some typical radioactive atoms that have been used in temporary implants include radium, cesium-137, and iridium-192. Some additional radioactive atoms that have been used in brachytherapy include americium-241 and gold-198.
  • the dose of radiation for brachytherapy can be the same as that mentioned above for external beam radiation therapy.
  • the nature of the radioactive atom used is also taken into account in determining the dose of brachytherapy.
  • the growth factor receptor tyrosine kinase inhibitor is administered before, during, or after commencing the radiation therapy, as well as any combination thereof, i.e. before and during, before and after, during and after, or before, during, and after commencing the radiation therapy.
  • the antibody is typically administered between 1 and 30 days, preferably between 3 and 20 days, more preferably between 5 and 12 days before commencing radiation therapy and/or termination of external beam radiation therapy.
  • any non-radiolabeled inhibitor of a growth factor receptor tyrosine kinase, the overexpression of which can be tumorigenic, is useful in the method of the invention.
  • the types of tumors that overexpress such receptors have been discussed above.
  • the inhibitors may be biological molecules or small molecules.
  • Biological inhibitors include proteins or nucleic acid molecules that inhibit the growth of cells that overexpress a growth factor receptor tyrosine kinase. Most typically, biological molecules are antibodies, or functional equivalents of antibodies.
  • Functional equivalents of antibodies have binding characteristics comparable to those of antibodies, and inhibit the growth of cells that overexpress growth factor receptor tyrosine kinase receptors.
  • Such functional equivalents include, for example, chimerized, humanized and single chain antibodies as well as fragments thereof.
  • Functional equivalents of antibodies include polypeptides with amino acid sequences substantially the same as the amino acid sequence of the variable or hypervariable regions of the antibodies of the invention. "Substantially the same" amino acid sequence is defined herein as a sequence with at least 70%, preferably at least about 80%, and more preferably at least about 90% homology to another amino acid sequence, as determined by the FASTA search method in accordance with
  • DNA molecules that encode functional equivalents of antibodies typically bind under stringent conditions to the DNA of the antibodies.
  • the functional equivalent of an antibody is preferably a chimerized or humanized antibody.
  • a chimerized antibody comprises the variable region of a non- human antibody and the constant region of a human antibody.
  • a humanized antibody comprises the hypervariable region (CDRs) of a non-human antibody.
  • the variable region other than the hypervariable region, e.g. the framework variable region, and the constant region of a humanized antibody are those of a human antibody.
  • suitable variable and hypervariable regions of non-human antibodies may be derived from antibodies produced by any non-human mammal in which monoclonal antibodies are made. Suitable examples of mammals other than humans include, for example, rabbits, rats, mice, horses, goats, or primates. Mice are preferred. Functional equivalents further include fragments of antibodies that have binding characteristics that are the same as, or are comparable to, those of the whole antibody. Suitable fragments of the antibody include any fragment that comprises a sufficient portion of the hypervariable (i.e. complementarity determining) region to bind specifically, and with sufficient affinity, to a growth factor receptor tyrosine kinase to inhibit growth of cells that overexpress such receptors.
  • the hypervariable i.e. complementarity determining
  • Such fragments may, for example, contain one or both Fab fragments or the F(ab') 2 fragment.
  • the antibody fragments may contain all six complementarity determining regions of the whole antibody, although functional fragments containing fewer than all of such regions, such as three, four or five CDRs, are also included.
  • the preferred fragments are single chain antibodies, or Fv fragments.
  • Single chain antibodies are polypeptides that comprise at least the variable region of the heavy chain of the antibody linked to the variable region of the light chain, with or without an interconnecting linker.
  • Fv fragment comprises the entire antibody combining site.
  • These chains may be produced in bacteria or in eucaryotic cells.
  • the antibodies and functional equivalents may be members of any class of immunoglobulins, such as: IgG, IgM, IgA, IgD, or IgE, and the subclasses thereof.
  • the preferred antibodies are members of the IgGl subclass.
  • the functional equivalents may also be equivalents of combinations of any of the above classes and subclasses.
  • Antibodies may be made from the desired receptor by methods that are well known in the art.
  • the receptors are either commercially available, or can be isolated by well known methods.
  • methods for isolating and purifying EGFR are found in Spada, U.S. Patent 5,646,153 starting at column 41, line 55.
  • Methods for isolating and purifying FGFR are found in Williams et al., U.S. Patent 5,707,632 in examples 3 and 4.
  • the methods for isolating and purifying EGFR and FGFR described in the Spada and Williams et al. patents are incorporated herein by reference.
  • Methods for making monoclonal antibodies include the immunological method described by Kohler and Milstein in Nature 256. 495-497 (1975) and by
  • a host mammal inoculated with a receptor or a fragment of a receptor, as described above, and then, optionally, boosted.
  • the receptor fragment must contain sufficient amino acid residues to define the epitope of the molecule being detected. If the fragment is too short to be immunogenic, it may be conjugated to a carrier molecule.
  • suitable carrier molecules include keyhold limpet hemocyanin and bovine serum albumen. Conjugation may be carried out by methods known in the art. One such method is to combine a cysteine residue of the fragment with a cysteine residue on the carrier molecule.
  • Spleens are collected from the inoculated mammals a few days after the final boost. Cell suspensions from the spleens are fused with a tumor cell. The resulting hybridoma cells that express the antibodies are isolated, grown, and maintained in culture.
  • Suitable monoclonal antibodies as well as growth factor receptor tyrosine kinases for making them are also available from commercial sources, for example, from Upstate Biotechnology, Santa Cruz Biotechnology of Santa Cruz, California, Transduction Laboratories of Lexington, Kentucky, R&D Systems Inc of
  • chimeric and humanized antibodies are also known in the art.
  • methods for making chimeric antibodies include those described in U.S. patents by Boss (Celltech) and by Cabilly (Genentech). See U.S. Patent Nos. 4,816,397 and 4,816,567, respectively.
  • Methods for making humanized antibodies are described, for example, in Winter, U.S. Patent No. 5,225,539.
  • CDR-grafting The preferred method for the humanization of antibodies is called CDR-grafting.
  • CDR-grafting the regions of the mouse antibody that are directly involved in binding to antigen, the complementarity determining region or CDRs, are grafted into human variable regions to create "reshaped human" variable regions.
  • the human variable regions into which the CDRs will be grafted should be carefully selected, and it is usually necessary to make a few amino acid changes at critical positions within the framework regions (FRs) of the human variable regions.
  • the reshaped human variable regions may include up to ten amino acid changes in the FRs of the selected human light chain variable region, and as many as twelve amino acid changes in the FRs of the selected human heavy chain variable region.
  • the DNA sequences coding for these reshaped human heavy and light chain variable region genes are joined to DNA sequences coding for the human heavy and light chain constant region genes, preferably ⁇ l and K, respectively.
  • the reshaped humanized antibody is then expressed in mammalian cells and its affinity for its target compared with that of the corresponding murine antibody and chimeric antibody.
  • Preferred antibodies are those that inhibit the EGF receptor.
  • Preferred EGFR antibodies are the chimerized, humanized, and single chain antibodies derived from a murine antibody called 225, which is described in U.S. Patent No. 4,943,533. The patent is assigned to the University of California and licensed exclusively to ImClone
  • the 225 antibody is able to inhibit the growth of cultured EGFR/HER1- expressing tumor cells in vitro as well as in vivo when grown as xenografts in nude mice. See Masui et /., Cancer Res. 44, 5592-5598 (1986). More recently, a treatment regimen combining 225 plus doxorubicin or cis-platin exhibited therapeutic synergy against several well established human xenograft models in mice. Basalga et al, J. Natl. Cancer Inst. 85_, 1327-1333 (1-? 3).
  • the chimerized, humanized, and single chain antibodies derived from murine antibody 225 can be made from the 225 antibody, which is available from the ATCC. Alternatively, the various fragments needed to prepare the chimerized, humanized, and single chain 225 antibodies can be synthesized from the sequence provided in Wels et al. in Int. J. Cancer 60, 137-144 (1995). Chimerized 225 antibody (c225) can be made in accordance with the methods described above. Humanized 225 antibody can be prepared in accordance with the method described in example IV of PCT application WO 96/40210, which is incorporated herein by reference. Single chain 225 antibodies (Fv225) can be made in accordance with methods described by Wels et al. in Int. J. Cancer 60, 137-144 (1995) and in European patent application 502 812.
  • the sequences of the hypervariable (CDR) regions of the light and heavy chain are reproduced below.
  • the amino acid sequence is indicated below the nucleotide sequence.
  • the inhibitors useful in the present invention may also be small molecules.
  • small molecules include any organic or inorganic molecule, other than a biological molecule, that inhibits the growth of cells that overexpress at least one growth factor receptor tyrosine kinase.
  • the small molecules typically have molecular weights less than 500, more typically less than 450.
  • Most of the small molecules are organic molecules that usually comprise carbon, hydrogen and, optionally, oxygen, nitrogen, and/or sulfur atoms.
  • U.S. Patent 5,656,655 discloses styryl substituted heteroaryl compounds that inhibit EGFR.
  • the heteroaryl group is a monocyclic ring with one or two heteroatoms, or a bicyclic ring with 1 to about 4 heteroatoms, the compound being optionally substituted or polysubstituted.
  • the compounds disclosed in U.S. Patent 5,656,655 are incorporated herein by reference.
  • U.S. Patent 5,646,153 discloses bis mono and or bicyclic aryl heteroaryl carbocyclic and heterocarbocyclic compounds that inhibit EGFR and/or PDGFR.
  • the compounds disclosed in U.S. Patent 5,646,153 are incorporated herein by reference.
  • U.S. Patent 5,616,582 discloses quinazoline derivatives that have receptor tyrosine kinase inhibitory activity. The compounds disclosed in U.S. Patent 5,616,582 are incorporated herein by reference.
  • Fry et al. Science 265. 1093-1095 (1994) discloses a compound having a structure that inhibits EGFR. The structure is shown in Figure 1. The compound shown in Figure 1 of the Fry et al. article is incorporated herein by reference.
  • Osherov et al. disclose tyrphostins that inhibit EGFR/HER1 and HER2.
  • PD 161570 is identified as t-butyl-3-(6-(2,6-dichlorophenyl)-2-(4-diethylamino-butylamino)- pyrido(2,3-d)pyrimidin-7-yl)urea having the structure shown in Figure 1 on page 146.
  • the compound described in Figure 1 on page 146 of the Batley et al. article in Life is identified as t-butyl-3-(6-(2,6-dichlorophenyl)-2-(4-diethylamino-butylamino)- pyrido(2,3-d)pyrimidin-7-yl)urea having the structure shown in Figure 1 on page 146.
  • Panek, et al., Journal of Pharmacology and Experimental Therapeutics 283. 1433-1444 disclose a compound identified as PD166285 that inhibits the EGFR, PDGFR, and FGFR families of receptors.
  • PD 166285 is identified as 6-(2,6- dichlorophenyl)-2-(4-(2-diethylaminoethoxy)phenylamino)-8-methyl-8H-pyrido(2,3- d)pyrimidin-7-one having the structure shown in Figure 1 on page 1436.
  • the compound described in Figure 1 on page 1436 of the Panek et al. article is incorporated herein by reference.
  • Parrizas, et al., Endocrinology 138. 1427-1433 disclose tyrphostins that inhibit the IGF-1 receptor.
  • the compounds disclosed in the Parrizas et al. article, in particular those in Table 1 on page 1428, are incorporated herein by reference.
  • the biological molecules preferably antibodies and functional equivalents of antibodies, significantly inhibit the growth of tumor cells when administered to a human patient in an effective amount in combination with radiation, as described above.
  • the optimal dose of the antibodies and functional equivalents of antibodies can be determined by physicians based on a number of parameters including, for example, age, sex, weight, severity of the condition being treated, the antibody being administered, and the route of administration.
  • a serum concentration of polypeptides and antibodies that permits saturation of the target receptor is desirable.
  • a concentration in excess of approximately 0.1 nM is normally sufficient.
  • a dose of 100 mg/m 2 of C225 provides a serum concentration of approximately 20 nM for approximately eight days.
  • doses of antibodies may be given weekly in amounts of 10-300 mg/m 2 .
  • Equivalent doses of antibody fragments should be used at more frequent intervals in order to maintain a serum level in excess of the concentration that permits saturation of the receptors.
  • Some suitable routes of administration include intravenous, subcutaneous, and intramuscle administration. Intravenous administration is preferred.
  • the peptides and antibodies of the invention may be administered along with additional pharmaceutically acceptable ingredients.
  • additional pharmaceutically acceptable ingredients include, for example, adjuvants, such as BCG, immune system stimulators and chemotherapeutic agents, such as those mentioned above.

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Abstract

L'invention concerne un procédé servant à inhiber la croissance de tumeurs chez des patients humains, qui comporte l'étape consistant à traiter les patients humains à l'aide d'une quantité efficace de rayonnement combiné à un inhibiteur de tyrosine kinase de récepteurs protéinique non radiomarqué, la surexpression de celle-ci pouvant entraîner la formation de tumeurs.
PCT/US1999/010741 1998-05-15 1999-05-14 Traitement de tumeurs humaines a l'aide d'un rayonnement et d'inhibiteurs de tyrosine kinases de recepteurs du facteur de croissance WO1999060023A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
BR9910511-0A BR9910511A (pt) 1998-05-15 1999-05-14 Tratamento de tumores humanos com radiação einibidores de tirosina cinases receptoras de fatorde crescimento
AU40799/99A AU4079999A (en) 1998-05-15 1999-05-14 Treatment of human tumors with radiation and inhibitors of growth factor receptor tyrosine kinases
SK1728-2000A SK17282000A3 (sk) 1998-05-15 1999-05-14 Nerádioaktívne označený inhibítor proteínového tyrozínkynázového receptora
MXPA00011248A MXPA00011248A (es) 1998-05-15 1999-05-14 Tratamientos de tumores humanos con radiacion e inhibidores de tirosina cinasas de recptor de factor de crecimiento.
KR1020007012832A KR20010071271A (ko) 1998-05-15 1999-05-14 방사선 및 성장 인자 수용체 티로신 키나아제 억제제에의한 사람 종양의 치료법
IL13970799A IL139707A0 (en) 1998-05-15 1999-05-14 Treatment of human tumors with radiation and inhibitors of growth factor receptor tyrosine kinases
EP99924253A EP1080113A4 (fr) 1998-05-15 1999-05-14 Traitement de tumeurs humaines a l'aide d'un rayonnement et d'inhibiteurs de tyrosine kinases de recepteurs du facteur de croissance
CA002332331A CA2332331A1 (fr) 1998-05-15 1999-05-14 Traitement de tumeurs humaines a l'aide d'un rayonnement et d'inhibiteurs de tyrosine kinases de recepteurs du facteur de croissance
JP2000549641A JP2002515511A (ja) 1998-05-15 1999-05-14 放射線及び成長因子レセプター・チロシン・キナーゼのインヒビターを使用するヒト腫瘍の治療
HK02102068.1A HK1040720A1 (zh) 1998-05-15 2002-03-18 用輻射和生長因子受體酪氨酸激酶抑制劑治療人腫瘤

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US8561398P 1998-05-15 1998-05-15
US7961298A 1998-05-15 1998-05-15
US60/085,613 1998-05-15
US09/079,612 1998-05-15
US20613898A 1998-12-07 1998-12-07
US09/206,138 1998-12-07

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CA2332331A1 (fr) 1999-11-25
EP1080113A1 (fr) 2001-03-07
JP2002515511A (ja) 2002-05-28
BR9910511A (pt) 2001-11-20
CN1314917A (zh) 2001-09-26
EP1080113A4 (fr) 2002-04-17
CZ20004224A3 (cs) 2002-02-13
KR20010071271A (ko) 2001-07-28
AU4079999A (en) 1999-12-06
MXPA00011248A (es) 2004-09-06
HK1040720A1 (zh) 2002-06-21
PL348634A1 (en) 2002-06-03
IL139707A0 (en) 2002-02-10
SK17282000A3 (sk) 2002-04-04

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