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WO2001005425A2 - Combined preparations comprising daunorubicin derivatives and her2 antibodies - Google Patents

Combined preparations comprising daunorubicin derivatives and her2 antibodies Download PDF

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Publication number
WO2001005425A2
WO2001005425A2 PCT/EP2000/006540 EP0006540W WO0105425A2 WO 2001005425 A2 WO2001005425 A2 WO 2001005425A2 EP 0006540 W EP0006540 W EP 0006540W WO 0105425 A2 WO0105425 A2 WO 0105425A2
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Prior art keywords
recombmant
humanized
antι
her2
antibody
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Ceased
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PCT/EP2000/006540
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French (fr)
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WO2001005425A3 (en
Inventor
Cristina Geroni
Marina Ripamonti
Michele Caruso
Antonino Suarato
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Pfizer Italia SRL
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Pharmacia and Upjohn SpA
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Priority to JP2001510479A priority Critical patent/JP2003504413A/en
Priority to AU59839/00A priority patent/AU5983900A/en
Priority to EP00945903A priority patent/EP1200098A2/en
Publication of WO2001005425A2 publication Critical patent/WO2001005425A2/en
Publication of WO2001005425A3 publication Critical patent/WO2001005425A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07K16/32—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
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention pertains to the field of neoplastic disease therapy.
  • this invention provides an antitumor composition comprising an alkylating anthracycline and a recombmant humanized ant ⁇ -HER2 antibody, for example the recombmant humanized monoclonal antibody (rhuMab) anti-
  • trastuzumab (HerceptmTM) , having a synergistic or additive antmeoplastic effect.
  • the present invention provides, in a first aspect, a pharmaceutical composition for use antmeoplastic therapy m mammals, including humans, comprising
  • a recombmant humanized ant ⁇ -HER2 antibody and a pharmaceutically acceptable carrier or excipient .
  • the recombmant humanized ant ⁇ -HER2 antibody is preferably, the recombmant humanized monoclonal antibody ant ⁇ -HER2 trastuzumab .
  • alkylating anthracyclmes of formula la and lb are 4-demethoxy-3' -deam ⁇ no-3' -az ⁇ r ⁇ dmyl- ' - methansulfonyl daunorubicin (la) and 4-demethoxy-N, N-bis (2- chloroethyl ) -4 ' -methansulfonyl daunorubicin (lb).
  • These alkylating anthracyclmes were described in Anticancer Drug Design (1995), vol. 10, 641-653, and claimed respectively in US-A-5, 532, 218 and US-A-5, 496, 800.
  • the recombmant humanized monoclonal antibody ant ⁇ -HER2 trastuzumab (HerceptinTM) is described in various scientific publications, for example Cancer Res., 1998, 58:2825-2831.
  • the present invention also provides a product comprising an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized ant ⁇ -HER2 antibody, preferably the recombmant humanized monoclonal antibody ant ⁇ -HER2 trastuzumab, as combined preparation for simultaneous, separate or seguential use m antitumor therapy.
  • a further aspect of the present invention is to provide a method of treating a mammal, including a human, suffering from a neoplastic disease comprising administering to said mammal an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized ant ⁇ -HER2 antibody, preferably the recombmant humanized monoclonal antibody anti- HER2 trastuzumab, in amounts effective to produce a synergistic antmeoplastic effect.
  • a still further aspect of the present invention is to provide a method for lowering the side effects caused by antmeoplastic therapy with an antmeoplastic agent a mammal, including a human, in need thereof, the method comprising administering to said mammal a combined preparation comprising an alkylating anthracycline of formula la or lb as defined above, and a recombmant humanized ant ⁇ -HER2 antibody, preferably the the recombmant humanized monoclonal antibody ant ⁇ -HER2 trastuzumab, in amounts effective to produce a synerqistic antmeoplastic effect.
  • a synergistic antmeoplastic effect as used herein is meant the inhibition of the growth tumor, preferably the complete regression of the tumor, administering an effective amount of the combination of an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized ant ⁇ -HER2 antibody to mammals, including humans.
  • parenteral is meant intravenous, subcutaneous and intramuscular administration.
  • Oral administration includes administering the costituents of the combined preparation m a suitable oral form such as, e.g., tablets, capsules, suspensions, solutions, emulsions, powders, syrups and the like.
  • Parenteral administration includes administering the costituents of the combined preparation by subcutaneous, intravenous or intramuscular injections.
  • the actual preferred method and order of administration of the combined preparations of the invention may vary according to, inter alia, the particular pharmaceutical formulation of the alkylating anthracycline of formula la or lb as defined above being utilized, the particular pharmaceutical formulation of the recombmant humanized ant ⁇ -HER2 antibody being utilized, the particular cancer being treated, and the particular patient being treated.
  • the dosage ranges for the administration of the combined preparation may vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill m the art.
  • the dosage regimen must therefore be tailored to the particular of the patient's conditions, response and associate treatments m a manner which is conventional for any therapv, and may need to be adjusted in response to changes in conditions and/or in light of other clinical conditions.
  • the alkylating anthracycline may be administered simultaneously with the recombmant humanized ant ⁇ -HER2 antibody, or the compounds may be administered sequentially, in either order.
  • the course of therapy generally employed is from about
  • the course therapy employed is from about 1 to about 50 mg/m 2 of body surface area.
  • the course of therapy generally employed is from about 1 to about 1000 mg/m 2 of body surface area. More preferably, the course therapy employed is from about 50 to about 500 mg/m 2 of body surface area.
  • the antmeoplastic therapy of the present invention is, in particular, suitable for treating breast, ovary, lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors m mammals, including humans.
  • an alkylating anthracycline according to the invention and a recombmant humanized ant ⁇ -HER2 antibody for example the recombmant humanized monoclonal antibody anti- HER2 trastuzumab, can be suitable for the treatment of patients with cancers over-expressing the HER2 protein, for example, for patient with metastatic breast cancer over- expressing the HER2 protein.
  • the antmeoplastic therapy according to this invention also comprises the prevention and/or treatment of tumor metastasis.
  • a still further aspect of the present invention is the use of an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized ant ⁇ -HER2 antibody, preferably the recombmant humanized monoclonal antibody anti- HER2 trastuzumab, for the treatment of tumors by angiogenesis inhibition .
  • the effectiveness of an alkylating anthracycline of formula la or lb and a recombmant humanized ant ⁇ -HER2 antibody is significantly increased without a parallel increased toxicity.
  • the combined therapy of the present invention enhances the antitumoral effects of the alkylating anthracycline of formula la or lb as defined above and of a recombmant humanized ant ⁇ -HER2 antibody and thus yields the most effective and least toxic treatment for tumors.
  • the synergistic action displayed by the combined preparations according to the present invention can be shown, for instance, by testing the activity of the combination m mice bearing human tumor xenografts overexpressmg HER2 protein, following, for example, the method described in Cancer Research, 1998, 58:2825-2831.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biophysics (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

There are provided the combined use of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methansulfonyl daunorubicin or 4-demethoxy-N,N-bis(2-chloroethyl)-4'-methansulfonyl daunorubicin and a recombinant humanized anti-HER2 antibody, preferably trastuzumab, in the treatment of tumors and the use of said combination in the treatment and/or prevention of tumor metastasis.

Description

Title: "Combined preparations comprising antitumor agents'
The present invention pertains to the field of neoplastic disease therapy. Particularly, this invention provides an antitumor composition comprising an alkylating anthracycline and a recombmant humanized antι-HER2 antibody, for example the recombmant humanized monoclonal antibody (rhuMab) anti-
HER2, trastuzumab (Herceptm™) , having a synergistic or additive antmeoplastic effect.
The present invention provides, in a first aspect, a pharmaceutical composition for use antmeoplastic therapy m mammals, including humans, comprising
- an alkylating anthracycline of formula la or lb
Figure imgf000002_0001
a recombmant humanized antι-HER2 antibody and a pharmaceutically acceptable carrier or excipient . The recombmant humanized antι-HER2 antibody is preferably, the recombmant humanized monoclonal antibody antι-HER2 trastuzumab .
The chemical names of the alkylating anthracyclmes of formula la and lb are 4-demethoxy-3' -deamιno-3' -azιrιdmyl- ' - methansulfonyl daunorubicin (la) and 4-demethoxy-N, N-bis (2- chloroethyl ) -4 ' -methansulfonyl daunorubicin (lb). These alkylating anthracyclmes were described in Anticancer Drug Design (1995), vol. 10, 641-653, and claimed respectively in US-A-5, 532, 218 and US-A-5, 496, 800. Both compounds intercalate into DNA via the chromophore and alkylate guanine at N7 position n DNA minor groove via their reactive moiety on position 3' of the ammo sugar. Compounds la and lb are able to circumvent the resistance to all major classes of cytotoxics, indicating that the compounds represent a new class of cytotoxic antitumor drugs.
The recombmant humanized monoclonal antibody antι-HER2 trastuzumab (Herceptin™) is described in various scientific publications, for example Cancer Res., 1998, 58:2825-2831. The present invention also provides a product comprising an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized antι-HER2 antibody, preferably the recombmant humanized monoclonal antibody antι-HER2 trastuzumab, as combined preparation for simultaneous, separate or seguential use m antitumor therapy.
A further aspect of the present invention is to provide a method of treating a mammal, including a human, suffering from a neoplastic disease comprising administering to said mammal an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized antι-HER2 antibody, preferably the recombmant humanized monoclonal antibody anti- HER2 trastuzumab, in amounts effective to produce a synergistic antmeoplastic effect. A still further aspect of the present invention is to provide a method for lowering the side effects caused by antmeoplastic therapy with an antmeoplastic agent a mammal, including a human, in need thereof, the method comprising administering to said mammal a combined preparation comprising an alkylating anthracycline of formula la or lb as defined above, and a recombmant humanized antι-HER2 antibody, preferably the the recombmant humanized monoclonal antibody antι-HER2 trastuzumab, in amounts effective to produce a synerqistic antmeoplastic effect. By the term "a synergistic antmeoplastic effect" as used herein is meant the inhibition of the growth tumor, preferably the complete regression of the tumor, administering an effective amount of the combination of an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized antι-HER2 antibody to mammals, including humans.
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 and intramuscular administration. Oral administration includes administering the costituents of the combined preparation m a suitable oral form such as, e.g., tablets, capsules, suspensions, solutions, emulsions, powders, syrups and the like. Parenteral administration includes administering the costituents of the combined preparation by subcutaneous, intravenous or intramuscular injections. The actual preferred method and order of administration of the combined preparations of the invention may vary according to, inter alia, the particular pharmaceutical formulation of the alkylating anthracycline of formula la or lb as defined above being utilized, the particular pharmaceutical formulation of the recombmant humanized antι-HER2 antibody being utilized, the particular cancer being treated, and the particular patient being treated. The dosage ranges for the administration of the combined preparation may vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill m the art. The dosage regimen must therefore be tailored to the particular of the patient's conditions, response and associate treatments m a manner which is conventional for any therapv, and may need to be adjusted in response to changes in conditions and/or in light of other clinical conditions. In the method of the subject invention, the alkylating anthracycline may be administered simultaneously with the recombmant humanized antι-HER2 antibody, or the compounds may be administered sequentially, in either order.
In the method of the subject invention, for the administration of the alkylating anthracycline of formula la or lb as defined above, the course of therapy generally employed is from about
0.1 to about 200 mg/m of body surface area. More preferably, the course therapy employed is from about 1 to about 50 mg/m2 of body surface area.
In the method of the subject invention, for the administration of the recombmant humanized antι-HER2 antibody, for example for the administration of the recombmant humanized monoclonal antibody antι-HER2 trastuzumab, the course of therapy generally employed is from about 1 to about 1000 mg/m2 of body surface area. More preferably, the course therapy employed is from about 50 to about 500 mg/m2 of body surface area.
The antmeoplastic therapy of the present invention is, in particular, suitable for treating breast, ovary, lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors m mammals, including humans. More in particular, the combined use of an alkylating anthracycline according to the invention and a recombmant humanized antι-HER2 antibody, for example the recombmant humanized monoclonal antibody anti- HER2 trastuzumab, can be suitable for the treatment of patients with cancers over-expressing the HER2 protein, for example, for patient with metastatic breast cancer over- expressing the HER2 protein.
The antmeoplastic therapy according to this invention also comprises the prevention and/or treatment of tumor metastasis. A still further aspect of the present invention is the use of an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized antι-HER2 antibody, preferably the recombmant humanized monoclonal antibody anti- HER2 trastuzumab, for the treatment of tumors by angiogenesis inhibition . As stated above, the effectiveness of an alkylating anthracycline of formula la or lb and a recombmant humanized antι-HER2 antibody is significantly increased without a parallel increased toxicity. In other words, the combined therapy of the present invention enhances the antitumoral effects of the alkylating anthracycline of formula la or lb as defined above and of a recombmant humanized antι-HER2 antibody and thus yields the most effective and least toxic treatment for tumors. The synergistic action displayed by the combined preparations according to the present invention can be shown, for instance, by testing the activity of the combination m mice bearing human tumor xenografts overexpressmg HER2 protein, following, for example, the method described in Cancer Research, 1998, 58:2825-2831.
Suitable modifications and adaptations of a variety of conditions and parameters normally encountered in clinical therapy which are obvious to those skilled m the art are within the scope of this invention.

Claims

1. Products containing an alkylating anthracycline of formula la or lb:
Figure imgf000007_0001
and a recombmant humanized antι-HER2 antibody as a combined preparation for simultaneous, separate or sequential use in antitumor therapy.
2. Products according to claim 1, wherein the recombmant humanized antι-HER2 antibody is the recombmant humanized monoclonal antibody antι-HER2 trastuzumab.
3. Products according to claim 1 or 2, wherein the alkylating anthracycline is 4-demethoxy-3' -deammo-3' -azιrιdιnyl-4 ' - methansulfon 1 daunorubicin.
4. Products according to any one of claims 1 to 3, wherein the antitumor therapy is for treating cancers over-expressing HER2 protein.
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and, as active ingredient, an alkylating anthracycline of formula la or lb as defined m claim 1 and a recombmant humanized antι-HER2 antibody.
6. A pharmaceutical composition according to claim 5 wherein the recombmant humanized antι-HER2 antibody is the recombmant humanized monoclonal antibody antι-HER2 trastuzumab .
7. Use of an alkylating anthracycline of formula la or lb as defined in claim 1 and a recombmant humanized antι-HER2 antibody in the preparation of a medicament for use in the treatment of tumors, wherein the alkylating anthracycline and the recombmant humanized antι-HER2 antibody are administered simultaneously, separately or sequentially.
8. Use according to claim 7 wherein the recombmant humanized antι-HER2 antibody is the recombmant humanized monoclonal antibody antι-HER2 trastuzumab.
9. Use of an alkylating anthracycline of formula la or lb as defined m claim 1 and a recombmant humanized antι-HER2 antibody m the preparation of a medicament for use in the prevention and/or treatment of tumor metastasis, wherein the alkylating anthracycline and the recombmant humanized anti- HER2 antibody are administered simultaneously, separately or sequentially.
10. Use according to claim 9 wherein the recombmant humanized antι-HER2 antibody is the recombmant humanized monoclonal antibody antι-HER2 trastuzumab.
11. A method of treating a mammal, including a human, suffering from a neoplastic disease comprising administering to said mammal an alkylating anthracycline of formula la or lb as defined above and a recombmant humanized antι-HER2 antibody, in amounts effective to produce a synergistic antmeoplastic effect.
12. A method according to claim 11, wherein the recombinant humanized antι-HER2 antibody is the recombinant humanized monoclonal antibody anti-HER2 trastuzumab.
13. A method for lowering the side effects caused by antmeoplastic therapy with an antineoplastic agent in a mammal, including a human, in need thereof, the method comprising administering to said mammal a combined preparation comprising an alkylating anthracycline of formula la or lb as defined above, and a recombinant humanized anti-HER2 antibody, in amounts effective to produce a synergistic antineoplastic effect .
14. A method according to claim 13, wherein the recombinant humanized anti-HER2 antibody is the recombinant humanized monoclonal antibody anti-HER2 trastuzumab.
PCT/EP2000/006540 1999-07-20 2000-07-10 Combined preparations comprising daunorubicin derivatives and her2 antibodies Ceased WO2001005425A2 (en)

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JP2001510479A JP2003504413A (en) 1999-07-20 2000-07-10 Combination preparation containing an antitumor substance
AU59839/00A AU5983900A (en) 1999-07-20 2000-07-10 Combined preparations comprising antitumor agents
EP00945903A EP1200098A2 (en) 1999-07-20 2000-07-10 Combined preparations comprising daunorubicin derivatives and anti her2 antibodies

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GBGB9917012.8A GB9917012D0 (en) 1999-07-20 1999-07-20 Combined preparations comprising antitumor agents

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WO2002102817A1 (en) * 2001-06-15 2002-12-27 Pharmacia Italia S.P.A. Anti-tumour anthracycline glycoside 14-sulfonic acid derivatives
US7485302B2 (en) 1999-06-25 2009-02-03 Genentech, Inc. Treatment with anti-ErbB2 antibodies and chemotherapeutic agents
WO2010108127A1 (en) 2009-03-20 2010-09-23 Genentech, Inc. Bispecific anti-her antibodies
WO2010136569A1 (en) 2009-05-29 2010-12-02 F. Hoffmann-La Roche Ag Modulators for her2 signaling in her2 expressing patients with gastric cancer
US7981418B2 (en) 2007-03-02 2011-07-19 Genentech, Inc. Predicting response to a HER inhibitor
US7993834B2 (en) 2000-05-19 2011-08-09 Genentech, Inc. Detection of ErbB2 gene amplification to increase the likelihood of the effectiveness of ErbB2 antibody breast cancer therapy
WO2011103242A1 (en) 2010-02-18 2011-08-25 Genentech, Inc. Neuregulin antagonists and use thereof in treating cancer
WO2011146568A1 (en) 2010-05-19 2011-11-24 Genentech, Inc. Predicting response to a her inhibitor
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WO2012069466A1 (en) 2010-11-24 2012-05-31 Novartis Ag Multispecific molecules
WO2012085111A1 (en) 2010-12-23 2012-06-28 F. Hoffmann-La Roche Ag Polypeptide-polynucleotide-complex and its use in targeted effector moiety delivery
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EP2592156A2 (en) 2007-06-08 2013-05-15 Genentech, Inc. Gene expression markers of tumor resistance to HER2 inhibitor treatment
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WO2014083178A1 (en) 2012-11-30 2014-06-05 F. Hoffmann-La Roche Ag Identification of patients in need of pd-l1 inhibitor cotherapy
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US10167342B2 (en) 2016-08-29 2019-01-01 Fazel Shokri Production of hersintuzumab: a new humanized antibody against HER2 for cancer treatment
WO2019147152A1 (en) 2018-01-26 2019-08-01 Universidade Nova De Lisboa L2a5 antibody or functional fragment thereof against tumour antigens
US10689457B2 (en) 2008-06-16 2020-06-23 Genentech, Inc. Treatment of metastatic breast cancer
EP3698807A1 (en) 2005-01-21 2020-08-26 Genentech, Inc. Fixed dosing of her antibodies
WO2022074206A1 (en) 2020-10-08 2022-04-14 Affimed Gmbh Trispecific binders
WO2023007023A1 (en) 2021-07-30 2023-02-02 Affimed Gmbh Duplexbodies
WO2023078968A1 (en) 2021-11-03 2023-05-11 Affimed Gmbh Bispecific cd16a binders
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US7485302B2 (en) 1999-06-25 2009-02-03 Genentech, Inc. Treatment with anti-ErbB2 antibodies and chemotherapeutic agents
US7537931B2 (en) 1999-06-25 2009-05-26 Genentech, Inc. Humanized anti-ERBB2 antibodies and treatment with anti-ERBB2 antibodies
US7993834B2 (en) 2000-05-19 2011-08-09 Genentech, Inc. Detection of ErbB2 gene amplification to increase the likelihood of the effectiveness of ErbB2 antibody breast cancer therapy
US8076066B2 (en) 2000-05-19 2011-12-13 Genentech, Inc. Gene detection assay for improving the likelihood of an effective response to a HER2 antibody cancer therapy
WO2002102817A1 (en) * 2001-06-15 2002-12-27 Pharmacia Italia S.P.A. Anti-tumour anthracycline glycoside 14-sulfonic acid derivatives
EP3698807A1 (en) 2005-01-21 2020-08-26 Genentech, Inc. Fixed dosing of her antibodies
US8691232B2 (en) 2005-02-23 2014-04-08 Genentech, Inc. Extending time to disease progression or survival in cancer patients
EP2399605A1 (en) 2005-02-23 2011-12-28 Genentech, Inc. Extending time to disease progression or survival in cancer patients
US8940302B2 (en) 2007-03-02 2015-01-27 Genentech, Inc. Predicting response to a HER inhibitor
EP2899541A1 (en) 2007-03-02 2015-07-29 Genentech, Inc. Predicting response to a HER dimerisation inhbitor based on low HER3 expression
US7981418B2 (en) 2007-03-02 2011-07-19 Genentech, Inc. Predicting response to a HER inhibitor
EP2592156A2 (en) 2007-06-08 2013-05-15 Genentech, Inc. Gene expression markers of tumor resistance to HER2 inhibitor treatment
US10385405B2 (en) 2007-06-08 2019-08-20 Genentech, Inc. Gene expression markers of tumor resistance to HER2 inhibitor treatment
US9551033B2 (en) 2007-06-08 2017-01-24 Genentech, Inc. Gene expression markers of tumor resistance to HER2 inhibitor treatment
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