AU5630901A - Aromatase inhibitors and monoclonal anti-her2 antibodies as antitumors agents - Google Patents
Aromatase inhibitors and monoclonal anti-her2 antibodies as antitumors agents Download PDFInfo
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- AU5630901A AU5630901A AU56309/01A AU5630901A AU5630901A AU 5630901 A AU5630901 A AU 5630901A AU 56309/01 A AU56309/01 A AU 56309/01A AU 5630901 A AU5630901 A AU 5630901A AU 5630901 A AU5630901 A AU 5630901A
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- aromatase inhibitor
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Classifications
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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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- 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
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Microbiology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
WO 01/87334 PCT/EPO1/04468 1 aromatase inhibitors and monoclonal anti-her2 antibodies as antitumors agents 5 The present invention concerns the treatment of hormone dependent disorders characterized by the overexpression of HER2. More specifically, the invention concerns the treatment of a human being susceptible to or diagnosed 10 with a disorder characterized by the overexpression of HER2 with a combination of an anti-HER2 antibody and an aromatase inhibitor. Proto-oncogens that encode growth factors and growth factors receptors have been identified to play important 15 roles in the pathogenesis of various malignancies, including breast cancer. In particular numerous studies have demonstrated the prognostic relevance of p185(HER2), which is overexpressed in 10% to 40% of human breast tumors. Moreover a recombinant humanized anti-HER2 20 monoclonal antibody (a humanized version of the murine anti-HER-2 antibody 4D5, referred to as Herceptin*) has been found clinically active in patients with HER2 overexpressing breast cancer (J. Clin. Oncol. 14:737-744, 1996) . Also the utility of aromatase inhibitors is well 25 acknowledged in anticancer therapy. However, it is also well known in the art that administration to a patient of therapeutically effective amounts of aromatase inhibitors can cause considerable side effects. The major toxicities are for instance lethargy, hot flashes, rash, transient 30 leukopenia, dizzines, nausea, constipation and vomiting. On the other hand, also administration to a patient of therapeutically effective amounts of an antibody against HER2 can similarly cause considerable side effects, e.g. hypersensitivity, alterations of renal function, 35 myocardial lesions and cardiotoxicity in general. 0I IOOTITI ITC LCUCT IOI II )a% WO 01/87334 PCT/EPO1/04468 2 The inventors of the present invention have found that a combination therapy of an hormone dependent disorder characterized by the overexpression of HER2, comprising a therapeutically effective amount of an aromatase inhibitor 5 and a therapeutically effective amount of an antibody against HER2, can produce a therapeutic effect which is greater than that obtainable by single administration of a therapeutically effective amount of either a sole aromatase inhibitor or a sole antibody against HER2. 10 Similarly they have found that a combination therapy of an hormone dependent disorder characterized by the overexpression of HER2, comprising a therapeutically sub effective amount of an aromatase inhibitor and a therapeutically sub-effective amount of an antibody 15 against HER2, can produce substantially the same therapeutic effect, which is obtainable by single administration of a therapeutically effective amount of either an aromatase inhibitor or an antibody against HER2. The most important, they have found that such newly 20 obtained therapeutic effect is not paralleled by the toxic effects, otherwise caused by single administrations of either therapeutically effective amounts of an aromatase inhibitor or therapeutically effective amounts of an anti HER2 antibody. 25 In view of the above, the effectiveness of an aromatase inhibitor and an antibody against HER2 is significantly increased without a parallel increased toxicity. In other words, the combined therapy of the present invention enhances the therapeutic effects of the aromatase 30 inhibitor and the antibody against HER2 and thus yields more effective and less toxic treatment for hormone dependent disorders. Accordingly, the present invention provides a new and 35 valuable tool in the therapy of hormone dependent 0I IOTITI ITC OUCCT 1DI 11 C O)\ WO 01/87334 PCT/EPO1/04468 3 disorders characterized by the overexpression of HER2. The advantages provided by the present invention can be appreciated by their preferred features, described herebelow. 5 Examples of such disorders are cancers, e.g. breast, cervical, ovarian and endometrial cancers, and endometriosis. However such disorder is preferably breast cancer in a human being, in particular a female. 10 Accordingly, the present invention provides, as a first object, a pharmaceutical composition comprising an aromatase inhibitor and an antibody against HER2, having a synergistic or superadditive therapeutic activity against an hormone-dependent disorder characterized by the 15 overexpression of HER2. The present invention also provides the use of an aromatase inhibitor in the manufacture of a pharmaceutical composition for treatment of an hormone-dependent disorder 20 characterized by the overexpression of HER2, the treatment additionally comprising the administration of a composition comprising an antibody against HER2, in amounts effective to produce a superadditive effect. 25 Examples of aromatase inhibitors according to the invention are exemestane, aminoglutethimide, roglethimide, pyridoglutethimide, anastrazole, trilostane, testolactone, formestane, atamestane, 1-methyl-1,4-androstadiene-3,17 dione (MAD), ketokonazole, fadrozole, letrozole, vorozole 30 and anastrozole. Preferred examples of aromatase inhibitors according to the invention are exemestane, anastrozole and letrozole, in particular exemestane. 0I IOOTITI IT OUCCT IOI II )a% WO 01/87334 PCT/EPO1/04468 4 The aromatase inhibitors cited herein are well known products, which are cited for instance in Cancer-Treat Res.: 94, 231-254, 1998 and WO 99/30708. Unless otherwise indicated, the terms "HER2" and ErbB2" 5 when used herein refer to the human protein and are used interchangeably. An antibody against HER2, according to the invention, can be either and "intact" antibody or a fragment thereof. The term "antibody" is used in the broadest sense and 10 specifically covers intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity. "Antibody fragments" 15 comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single chain antbody molecules; and multispecific antibodies 20 formed from antibody fragments. A preferred example of an antibody against HER2 is trastuzumab. The recombinant humanized monoclonal antibody anti-HER2 trastuzumab (Herceptin*) is described in various 25 scientific publications, for example Cancer Res., 1998, 58: 2825-2831. The present invention also provides a product comprising an aromatase inhibitor and an antibody against HER2, as 30 combined preparation for simultaneous, separate or sequential administration, in amounts to produce a synergistic or superadditive therapeutic activity against an hormone-dependent disorder characterized by the overexpression of HER2. 35 0I IOTITI ITC OUCCT 1DI 11 C Oa\ WO 01/87334 PCT/EPO1/04468 5 In a further aspect, the present invention provides a kit comprising, in a suitable container means, a pharmaceutical composition containing an aromatase inhibitor, as an active agent, and an antibody against 5 HER2, as a further active agent, in amounts to produce a synergistic or superadditive therapeutic activity against hormone-dependent disorder characterized by the overexpression of HER2. 10 A further aspect of the present invention is to provide a method of treating a human being, particularly a female, suffering from an hormone-dependent disorder characterized by the overexpression of HER2 comprising administering to said human being an aromatase inhibitor and an antibody 15 against HER2, in amounts effective to produce a superadditive or synergistic therapeutic effect. A still further aspect of the present invention is to provide a method for lowering the side effects (adverse 20 reactions) caused by antitumor therapy with an aromatase inhibitor in a human being, particularly a female, suffering from an hormone-dependent tumor overexpressing HER2, the method comprising administering to said human being a combined preparation comprising an aromatase 25 inhibitor and an antibody against HER2, in amounts effective to produce a superadditive or synergistic antitumor effect. A still further aspect of the present invention is to 30 provide a method for lowering the side effects (adverse reactions) caused by antitumor therapy with an antibody against HER2 in a human being, particularly a female, suffering from an hormone-dependent tumor overexpressing HER2, the method comprising administering to said human 35 being a combined preparation comprising an antibody 0I IOTITI ITC OLUCCT 1DI 11 C Oa\ WO 01/87334 PCT/EPO1/04468 6 against HER2 and an aromatase inhibitor, in amounts effective to produce a superadditive or synergistic antitumor effect. 5 By the term "a superadditive or synergistic antitumor effect" as used herein is meant the inhibition of the growth tumor, preferably the complete regression of the tumor, by administering a combination of an aromatase inhibitor, as defined above, and an antibody against a 10 HER2, to a human being, particularly a human female. Said preparation having therefore a potentiated antitumor (superadditive) activity with respect to products containing either an aromatase inhibitor or an antibody against HER2. 15 By the term "administered" or "administering" as used herein is meant any acceptable manner of -administering a drug to a patient which is medically acceptable including parenteral and oral administration. By "parenteral" is meant intravenous, subcutaneous, 20 intradermal or intramuscular administration. Oral administration includes administering the costituents of the combined preparation in a suitable oral form such as, e.g., tablets, capsules, suspensions, solutions, emulsions, powders, syrups and the like. 25 Parenteral administration includes administering the constituents of the combined preparation by subcutaneous, subcutaneous, intravenous or intramuscular injections. The actual preferred method and order of administration of 30 the combined preparations of the invention may vary according to, inter alia, the particular pharmaceutical formulation of the aromatase inhibitor being utilized, the particular pharmaceutical formulation of the antibody against the growth factor receptor being utilized, the 35 particular cancer being treated and the particular patient 0I IOTITI ITC OUCCT 1DI 11 C Oa\ WO 01/87334 PCT/EPO1/04468 7 being treated. The dosage ranges for the administration of the combined preparation may vary with the age, condition and extent of the disease in the patient and can be determined by one of 5 skill in the art. The dosage regimen must therefore be tailored to the particular of the patient's conditions, response and associate treatments in a manner which is conventional for any therapy, and may need to be adjusted in response to 10 changes in conditions and/or in light of other clinical conditions. In the combined method of treatment according to the subject invention, the aromatase inhibitor may be administered simultaneously with the antibody against HER2 15 or the compounds may be administered sequentially, in either order. An effective amount of an aromatase inhibitor antitumor agent may vary from about 0.5 to about 500 mg pro dose 1-2 times a day. Exemestane, for example, may be administered 20 orally in a dosage range varying from about 5 to about 200 mg, and particularly, from about 10 to about 25 mg, or parenterally from about 50 to about 500 mg, in particular from about 100 to about 250 mg. Fadrozole, for example, may be administered orally in a 25 dosage range varying from about 0.5 to about 10 mg, and particularly, from about 1 to about 2 mg. Letrozole, for example, may be administered orally in a dosage range varying from about 0.5 to about 10 mg, and particularly, from about 1 to about 2.5 mg. 30 Formestane, for example, may be administered parenterally in a dosage range varying from about 250 to about 500 mg, and particularly, from about 250 to about 300 mg. Anastrozole, for example, may be administered orally in a dosage range varying from about 0.5 to about 10 mg, and 35 particularly, from about 1 to about 2 mg. 0I IOTITI ITC OUCCT 1DI 11 C O)\ WO 01/87334 PCT/EPO1/04468 8 In the method of the subject invention, for example for the administration of the recombinant humanized monoclonal antibody anti-HER2 trastuzumab, the course of therapy generally employed is from about 1 to about 1000 mg/m 2 of 5 body surface area. More preferably, the course therapy employed is from about 50 to about 500 mg/m 2 of body surface area. The therapy method according to the present invention is, in particular, suitable for treating a human being 10 suffering from hormone dependent disorders, characterized by the overexpression of HER2. Typical examples of such disorders are endometriosis and tumors, like ovarian, cervical and endometrial cancers in a human female or breast cancer in a human being, in particular a female. 15 More in particular, the combined use of an aromatase inhibitor, according to the invention, preferably exemestane, and a recombinant humanized anti-HER2 antibody, for example the recombinant humanized monoclonal antibody anti-HER2 trastuzumab, can be suitable for the 20 treatment of patients with cancers over-expressing the HER2 protein, for example, for patient with breast cancer, in particular with metastatic breast cancer, over expressing the HER2 protein. Suitable modifications and adaptations of a variety of 25 conditions and parameters normally encountered in clinical therapy which are obvious to those skilled in the art are within the scope of this invention. A pharmaceutically composition containing an aromatase inhibitor and/or an antibody against HER2 can be prepared 30 according to well known techniques to those skilled in the art. For instance a pharmaceutical composition containing exemestane can be prepared according to US 4,808,616. 0I IOTITI ITC OUCCT 1DI 11 C O)\
Claims (16)
1. Use of an aromatase inhibitor in the manufacture of a pharmaceutical composition for treatment of an 5 hormone-dependent disorder characterized by the overexpression of HER2, the treatment additionally comprising the administration of a composition comprising an antibody against HER2, in amounts effective to produce a superadditive effect. 10
2. Use, according to claim 1, wherein the disorder- is breast, cervical, ovarian and endometrial cancers, and endometriosis. 15
3. Use, according to claim 2, wherein the disorder is breast cancer.
4. Use, according to claim 1, wherein the aromatase inhibitor is selected from exemestane, 20 aminoglutethimide, roglethimide, pyridoglutethimide, anastrazole, trilostane, testolactone, formestane, atamestane, 1-methyl-1,4-androstadiene-3,17-dione (MAD) , ketokonazole, fadrozole, letrozole, vorozole and anastrozole. 25
5. Use, according to claim 1, wherein the aromatase inhibitor is exemestane.
6. Use, according to claim 1, wherein the antibody 30 against HER2 is trastuzumab.
7. Use, according to claim 3, wherein the aromatase inhibitor is exemestane and the antibody against HER2 is trastuzumab. 35 0I IOOTITI IT OUCCT IOI II ')C\ WO 01/87334 PCT/EPO1/04468 10
8. A method of treating a human being suffering from an hormone-dependent disorder characterized by the overexpression of HER2 comprising administering to said human being an aromatase inhibitor and an 5 antibody against HER2, in amounts effective to produce a superadditive or synergistic therapeutic effect.
9. A method for lowering the side effects caused by antitumor therapy with an aromatase inhibitor in a 10 human being suffering from an hormone-dependent tumor overexpressing HER2, the method comprising administering to said human being a combined preparation comprising an aromatase inhibitor and an antibody against HER2, in amounts effective to produce 15 a superadditive or synergistic antitumor effect.
10. A method for lowering the side effects caused by antitumor therapy with an antibody against HER2 in a human being suffering from an hormone-dependent tumor 20 overexpressing HER2, the method comprising administering to said human being a combined preparation comprising an antibody against HER2 and an aromatase inhibitor, in amounts effective to produce a superadditive or synergistic antitumor effect. 25
11. A method according to claim 8, wherein the disorder is breast, cervical, ovarian and endometrial cancers, and endometriosis. 30
12. A method according to claim 8, wherein the disorder is breast cancer.
13. A method according to claim 8, wherein the aromatase inhibitor is selected from exemestane, 35 aminoglutethimide, roglethimide, pyridoglutethimide, 0I IOTITI ITC OUCCT 1DI 11 C Oa\ WO 01/87334 PCT/EPO1/04468 11 anastrazole, trilostane, testolactone, formestane, atamestane, 1-methyl-1,4-androstadiene-3,17-dione (MAD) , ketokonazole, fadrozole, letrozole, vorozole and anastrozole. 5
14. A method according to claim 8, wherein the aromatase inhibitor is exemestane.
15. A method according to claim 8, wherein the antibody 10 against HER2 is trastuzumab.
16. A method according to claim 8, wherein the aromatase inhibitor is exemestane and the antibody against HER2 is trastuzumab. 0I IOOTITI ITC OLICT IOI II C ')a\
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| PCT/EP2001/004468 WO2001087334A1 (en) | 2000-05-15 | 2001-04-19 | Aromatase inhibitors and monoclonal anti-her2 antibodies as antitumors agents |
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| ZA9811162B (en) | 1997-12-12 | 2000-06-07 | Genentech Inc | Treatment with anti-ERBB2 antibodies. |
| AUPQ105799A0 (en) | 1999-06-18 | 1999-07-08 | Victor Chang Cardiac Research Institute, The | Cell growth inhibition |
| EP1282443B1 (en) | 2000-05-19 | 2009-09-02 | Genentech, Inc. | Gene detection assay for improving the likelihood of an effective response to an erbb antagonist cancer therapy |
| ES2269682T3 (en) * | 2001-01-26 | 2007-04-01 | Pfizer Italia S.R.L. | EXEMESTANE TO TREAT DISORDERS THAT DEPEND ON HORMONES. |
| GB2375958B (en) | 2001-04-09 | 2005-03-02 | George Margetts | The use of steroids to lower the levels of cortisol |
| AU2003218600C1 (en) | 2002-03-26 | 2009-12-17 | Zensun (Shanghai) Science & Technology Co., Ltd. | ERBB3 based methods and compositions for treating neoplasms |
| CN1678348A (en) * | 2002-07-01 | 2005-10-05 | 萨文特医药公司 | Compositions and methods for therapeutic treatment |
| FR2844455B1 (en) * | 2002-09-13 | 2007-12-14 | Lab Francais Du Fractionnement | TREATMENT OF PATHOLOGIES EXCLUDING IMMUNE RESPONSE BY OPTIMIZED ANTIBODIES |
| CN101014365B (en) * | 2004-07-16 | 2011-04-13 | 辉瑞产品公司 | Combination treatment for non-hematologic malignancies using an anti-igf-1r antibody |
| UA94899C2 (en) | 2005-01-21 | 2011-06-25 | Дженентек, Инк. | Fixed dosing of her antibodies |
| EP1850874B1 (en) | 2005-02-23 | 2013-10-16 | Genentech, Inc. | Extending time to disease progression or survival in ovarian cancer patients using pertuzumab |
| EP1945224B1 (en) | 2005-10-19 | 2012-05-02 | Chavah Pty Ltd | Reduction of side effects from aromatase inhibitors used for treating breast cancer |
| EP2132573B1 (en) | 2007-03-02 | 2014-04-23 | Genentech, Inc. | Predicting response to a her dimerisation inhbitor based on low her3 expression |
| DK2171090T3 (en) | 2007-06-08 | 2013-06-10 | Genentech Inc | Gene expression markers for tumor resistance to HER2 inhibitor therapy |
| US9551033B2 (en) | 2007-06-08 | 2017-01-24 | Genentech, Inc. | Gene expression markers of tumor resistance to HER2 inhibitor treatment |
| BRPI0812682A2 (en) | 2008-06-16 | 2010-06-22 | Genentech Inc | metastatic breast cancer treatment |
| ES2572728T3 (en) | 2009-03-20 | 2016-06-02 | F. Hoffmann-La Roche Ag | Bispecific anti-HER antibodies |
| CA2761280A1 (en) | 2009-05-29 | 2010-12-02 | F. Hoffmann-La Roche Ag | Modulators for her2 signaling in her2 expressing patients with gastric cancer |
| CN102892779B (en) | 2010-02-18 | 2016-12-21 | 基因泰克公司 | Neuregulin antagonist and the purposes in treatment cancer thereof |
| WO2011146568A1 (en) | 2010-05-19 | 2011-11-24 | Genentech, Inc. | Predicting response to a her inhibitor |
| WO2012069466A1 (en) | 2010-11-24 | 2012-05-31 | Novartis Ag | Multispecific molecules |
| JP5766296B2 (en) | 2010-12-23 | 2015-08-19 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Polypeptide-polynucleotide complexes and their use in targeted delivery of effector components |
| CN102068429B (en) * | 2010-12-28 | 2011-12-14 | 西南大学 | Application of fadrozole in inducing transformation of differentiated ovary of tilapia mossambica into functional testis and induction method thereof |
| MX2014001766A (en) | 2011-08-17 | 2014-05-01 | Genentech Inc | Neuregulin antibodies and uses thereof. |
| 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 |
| CN106987620A (en) | 2011-11-30 | 2017-07-28 | 霍夫曼-拉罗奇有限公司 | Erbb3 mutation in cancer |
| WO2013083810A1 (en) | 2011-12-09 | 2013-06-13 | F. Hoffmann-La Roche Ag | Identification of non-responders to her2 inhibitors |
| JP2015514710A (en) | 2012-03-27 | 2015-05-21 | ジェネンテック， インコーポレイテッド | Diagnosis and treatment of HER3 inhibitors |
| US20160038490A1 (en) * | 2012-07-18 | 2016-02-11 | Angion Biomedica Corp. | Compositions and methods for treating dysproliferative diseases |
| WO2014083178A1 (en) | 2012-11-30 | 2014-06-05 | F. Hoffmann-La Roche Ag | Identification of patients in need of pd-l1 inhibitor cotherapy |
| US10064874B2 (en) | 2014-10-22 | 2018-09-04 | Havah Therapeutics Pty Ltd. | Methods of reducing mammographic breast density and/or breast cancer risk |
| AU2016343297A1 (en) | 2015-10-22 | 2018-05-10 | Havah Therapeutics Pty Ltd | Methods of reducing mammographic breast density and/or breast cancer risk |
| US20190151346A1 (en) | 2016-05-10 | 2019-05-23 | INSERM (Institute National de la Santé et de la Recherche Médicale) | Combinations therapies for the treatment of cancer |
| CN107417791B (en) * | 2017-08-17 | 2020-09-22 | 合肥瀚科迈博生物技术有限公司 | Anti-human ErbB2 bispecific antibody, preparation method and application thereof |
| CN119970752A (en) | 2019-06-03 | 2025-05-13 | 哈瓦赫治疗有限公司 | Pharmaceutical formulations for delivery of androgens and aromatase inhibitors |
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| EA005931B1 (en) | 2005-08-25 |
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| CA2409652A1 (en) | 2001-11-22 |
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