JP2003504413A - Combination preparation containing an antitumor substance - Google Patents
Combination preparation containing an antitumor substanceInfo
- Publication number
- JP2003504413A JP2003504413A JP2001510479A JP2001510479A JP2003504413A JP 2003504413 A JP2003504413 A JP 2003504413A JP 2001510479 A JP2001510479 A JP 2001510479A JP 2001510479 A JP2001510479 A JP 2001510479A JP 2003504413 A JP2003504413 A JP 2003504413A
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- JP
- Japan
- Prior art keywords
- recombinant humanized
- her2
- antibody
- alkylated
- anthracycline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- 238000002360 preparation method Methods 0.000 title claims description 8
- 230000000259 anti-tumor effect Effects 0.000 title claims description 6
- 239000000126 substance Substances 0.000 title description 3
- 229960000575 trastuzumab Drugs 0.000 claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 206010027476 Metastases Diseases 0.000 claims abstract description 3
- 230000002265 prevention Effects 0.000 claims abstract description 3
- 230000009401 metastasis Effects 0.000 claims abstract 2
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 24
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 11
- 238000002560 therapeutic procedure Methods 0.000 claims description 8
- 230000002195 synergetic effect Effects 0.000 claims description 7
- 241000282412 Homo Species 0.000 claims description 6
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 5
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 229940034982 antineoplastic agent Drugs 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 230000001613 neoplastic effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 229940022353 herceptin Drugs 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940043239 cytotoxic antineoplastic drug Drugs 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000003712 glycosamine group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Microbiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
(57)【要約】 本発明は、４−デメトキシ−３’−デアミノ−３’−アジリジニル−４’−メタンスルホニルダウノルビシンまたは４−デメトキシ−Ｎ，Ｎ−ビス（２−クロロエチル）−４’−メタンスルホニルダウノルビシンと組換えヒト型化抗ＨＥＲ２抗体、好ましくはトラスツズマブとの組み合わせ使用、腫瘍の治療での使用および腫瘍転移の治療および／または予防における前記組み合わせの使用を提供する。 (57) [Summary] The present invention relates to the use of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methanesulfonyldaunorubicin or 4-demethoxy-N, N-bis (2-chloroethyl) -4'-methanesulfonyldaunorubicin as a recombinant human There is provided use in combination with a typed anti-HER2 antibody, preferably trastuzumab, use in the treatment of tumors and use of said combination in the treatment and / or prevention of tumor metastasis.
Description
【０００１】
本発明は新生物疾患治療の分野に関する。特に、本発明は、アルキル化アント
ラサイクリンおよび組換えヒト型化抗ＨＥＲ２抗体、例えば組換えヒト型化モノ
クローナル抗体（ｒｈｕＭａｂ）抗ＨＥＲ２、トラスツズマブ（商標ハーセプチ
ン）を含む抗腫瘍組成物であって、相乗的または相加的な抗新生物効果を有する
組成物を提供する。The present invention relates to the field of treatment of neoplastic diseases. In particular, the present invention provides an anti-tumor composition comprising an alkylated anthracycline and a recombinant humanized anti-HER2 antibody, such as a recombinant humanized monoclonal antibody (rhuMab) anti-HER2, trastuzumab (Herceptin), which is synergistic. Provided is a composition having a positive or additive anti-neoplastic effect.
【０００２】
本発明は、第１の態様において、ヒトを含む哺乳動物における抗新生物治療に
用いるための医薬品組成物であって、
下記の式ＩａまたはＩｂのアルキル化アントラサイクリンとThe invention in a first aspect is a pharmaceutical composition for use in antineoplastic therapy in mammals, including humans, which comprises an alkylated anthracycline of formula Ia or Ib:
【０００３】[0003]
【化２】
組換えヒト型化抗ＨＥＲ２抗体と、医薬品として許容される担体または賦形剤
とを含む組成物を提供する。[Chemical 2] A composition comprising a recombinant humanized anti-HER2 antibody and a pharmaceutically acceptable carrier or excipient is provided.
【０００４】
組換えヒト型化抗ＨＥＲ２抗体は組換えヒト型化モノクローナル抗体である抗
ＨＥＲ２トラスツズマブであることが好ましい。The recombinant humanized anti-HER2 antibody is preferably anti-HER2 trastuzumab, which is a recombinant humanized monoclonal antibody.
【０００５】
式ＩａおよびＩｂのアルキル化アントラサイクリンの化学名は４−デメトキシ
−３’−デアミノ−３’−アジリジニル−４’−メタンスルホニルダウノルビシ
ン（Ｉａ）および４−デメトキシ−Ｎ，Ｎ−ビス（２−クロロエチル）−４’−
メタンスルホニルダウノルビシン（Ｉｂ）である。これらのアルキル化アントラ
サイクリンはＡｎｔｉｃａｎｃｅｒ Ｄｒｕｇ Ｄｅｓｉｇｎ（１９９５），ｖ
ｏｌ．１０，６４１−６５３に記載されており、それぞれＵＳ−Ａ−５５３２２
１８およびＵＳ−Ａ−５４９６８００として特許されている。いずれの化合物も
発色団を介してＤＮＡ中に挿入され、アミノ糖の３’位の反応性部分を介してＤ
ＮＡの小さい溝におけるＮ７位のグアニンをアルキル化する。化合物Ｉａおよび
Ｉｂはすべての主要な細胞毒群に対する耐性を回避することができ、細胞毒性抗
腫瘍薬物の新しいクラスであることが示される。The chemical names for alkylated anthracyclines of formula Ia and Ib are 4-demethoxy-3′-deamino-3′-aziridinyl-4′-methanesulfonyldaunorubicin (Ia) and 4-demethoxy-N, N-bis ( 2-chloroethyl) -4'-
Methanesulfonyldaunorubicin (Ib). These alkylated anthracyclines are described in Anticancer Drug Design (1995), v.
ol. 10, 641-653, and US-A-55322, respectively.
18 and US-A-54996800. Both compounds were inserted into DNA via a chromophore, and D was inserted via the reactive moiety at the 3'position of the amino sugar.
The guanine at the N 7 position in the groove with a small NA is alkylated. Compounds Ia and Ib are able to evade resistance to all major cytotoxic groups, indicating a new class of cytotoxic antitumor drugs.
【０００６】
組換えヒト型化モノクローナル抗体抗ＨＥＲ２トラスツズマブ（商標ハーセプ
チン）は様々な科学出版物、例えばＣａｎｃｅｒ Ｒｅｓ．，１９９８，５８：
２８２５−２８３１に記載されている。Recombinant humanized monoclonal antibody anti-HER2 trastuzumab (Trademark Herceptin) has been reported in various scientific publications, such as Cancer Res. , 1998, 58:
2825-2831.
【０００７】
本発明はまた、前述の式ＩａまたはＩｂのアルキル化アントラサイクリンおよ
び組換えヒト型化抗ＨＥＲ２抗体、好ましくは組換えヒト型化モノクローナル抗
体抗ＨＥＲ２トラスツズマブを、抗腫瘍治療において同時に、別々に、または順
次用いるための組み合わせ調製物として含む製品も提供する。The present invention also provides that the alkylated anthracycline of formula Ia or Ib and a recombinant humanized anti-HER2 antibody, preferably a recombinant humanized monoclonal antibody anti-HER2 trastuzumab, as described above, are separately administered simultaneously in an antitumor treatment. Also provided are products that are included in or as a combined preparation for sequential use.
【０００８】
本発明の他の態様は、新生物疾患を患う、ヒトを含む哺乳動物を治療する方法
であって、前記哺乳動物に前述の式ＩａまたはＩｂのアルキル化アントラサイク
リンおよび組換えヒト型化抗ＨＥＲ２抗体、好ましくは組換えヒト型化モノクロ
ーナル抗体抗ＨＥＲ２トラスツズマブを、相乗的抗新生物効果を生じるのに有効
な量で投与することを含む方法を提供することである。Another aspect of the invention is a method of treating a mammal, including a human, suffering from a neoplastic disease, wherein the mammal comprises an alkylated anthracycline of formula Ia or Ib as described above and a recombinant human form. Anti-HER2 antibody, preferably recombinant humanized monoclonal antibody anti-HER2 trastuzumab, is provided in an amount effective to produce a synergistic anti-neoplastic effect.
【０００９】
本発明のさらに他の態様は、抗新生物療法を必要としている、ヒトを含む哺乳
動物において、抗新生物物質を用いた抗新生物療法により引き起こされる副作用
を低下させるための方法であって、前記哺乳動物に前述の式ＩａまたはＩｂのア
ルキル化アントラサイクリンおよび組換えヒト型化抗ＨＥＲ２抗体、好ましくは
組換えヒト型化モノクローナル抗体抗ＨＥＲ２トラスツズマブを、相乗的抗新生
物効果を生じるのに有効な量で投与することを含む方法を提供することである。Yet another aspect of the invention is a method for reducing the side effects caused by antineoplastic therapy with antineoplastic agents in mammals, including humans, in need of antineoplastic therapy. Wherein said mammal is provided with said alkylated anthracycline of formula Ia or Ib and a recombinant humanized anti-HER2 antibody, preferably a recombinant humanized monoclonal antibody anti-HER2 trastuzumab, which produces a synergistic anti-neoplastic effect To provide a method comprising administering an effective amount of the agent.
【００１０】
本明細書において用いられる場合、「相乗的抗新生物効果」なる用語は、ヒト
を含む哺乳動物に前述の式ＩａまたはＩｂのアルキル化アントラサイクリンおよ
び組換えヒト型化抗ＨＥＲ２抗体の組み合わせの有効な量で投与することによる
、腫瘍の増殖阻害、好ましくは腫瘍の完全な退行を意味する。As used herein, the term “synergistic anti-neoplastic effect” refers to mammals, including humans, of alkylated anthracyclines of formula Ia or Ib as described above and recombinant humanized anti-HER2 antibodies. By administration of an effective amount of the combination is meant tumor growth inhibition, preferably complete regression of the tumor.
【００１１】
本明細書において用いられる場合、「投与した」または「投与する」なる用語
は、非経口および経口投与を含む、医学的に許容される薬物を患者に投与する、
任意の許容される様式を意味する。「非経口」とは静脈内、皮下および筋肉内投
与を意味する。経口投与は、組み合わせ調製物の成分を、例えば錠剤、カプセル
剤、懸濁剤、液剤、乳剤、散剤、シロップ剤などの適当な経口型で投与すること
を含む。非経口投与は、組み合わせ調製物の成分を、皮下、静脈内、または筋肉
内注射によって投与することを含む。As used herein, the terms “administered” or “administering” administer a pharmaceutically acceptable drug to a patient, including parenteral and oral administration,
Means any acceptable format. "Parenteral" means intravenous, subcutaneous and intramuscular administration. Oral administration includes administering the components of the combination preparation in a suitable oral form such as tablets, capsules, suspensions, solutions, emulsions, powders, syrups and the like. Parenteral administration includes administering the components of the combination preparations by subcutaneous, intravenous, or intramuscular injection.
【００１２】
本発明の組み合わせ調製物を投与するための実際の好ましい方法および順序は
、とりわけ、用いる前述の式ＩａまたはＩｂのアルキル化アントラサイクリンの
特定の医薬品調合物、用いる組換えヒト型化抗ＨＥＲ２抗体の特定の医薬品調合
物、治療する特定のがんおよび治療する特定の患者に応じて変動しうる。The actual preferred method and sequence for administering the combination preparations of the present invention is, inter alia, the particular pharmaceutical formulation of the aforementioned alkylated anthracycline of formula Ia or Ib used, the recombinant humanized anti-body used. It may vary depending on the particular pharmaceutical formulation of the HER2 antibody, the particular cancer being treated and the particular patient being treated.
【００１３】
組み合わせ調製物を投与するための用量範囲は、患者の年齢、状態、性別およ
び疾患の程度によって変動することがあり、当業者であれば決定することができ
る。The dosage range for administering the combination preparations can vary according to the age, condition, sex and extent of the disease of the patient and can be determined by the person skilled in the art.
【００１４】
したがって、投与法はいかなる治療にとっても通常の様式で、患者の状態、反
応および併用治療の詳細に合わせて調整しなければならず、状態の変化に対応し
て、および／または他の臨床状態を考慮して調節する必要があろう。Accordingly, the dosage regimen must be adjusted to the patient's condition, response, and details of combination therapy in the usual manner for any treatment, in response to changes in the condition, and / or by other means. Adjustment may be necessary considering the clinical condition.
【００１５】
本発明の方法において、アルキル化アントラサイクリンは組換えヒト型化抗Ｈ
ＥＲ２抗体と同時に投与してもよく、または化合物をいずれかの順序で順次投与
してもよい。In the method of the present invention, the alkylated anthracycline is a recombinant humanized anti-H
The ER2 antibody may be administered at the same time or the compounds may be administered sequentially in either order.
【００１６】
本発明の方法において、前述の式ＩａまたはＩｂのアルキル化アントラサイク
リンを投与するために、一般に用いられる治療クールは体表面積１ｍ２あたり約
０．１から約２００ｍｇである。用いられる治療クールは体表面積１ｍ２あたり
約１から約５０ｍｇであることがより好ましい。In the method of the present invention, the therapeutic course commonly used to administer the alkylated anthracycline of formula Ia or Ib described above is from about 0.1 to about 200 mg / m 2 of body surface area. More preferably, the therapeutic course used is from about 1 to about 50 mg / m 2 of body surface area.
【００１７】
本発明の方法において、組換えヒト型化抗ＨＥＲ２抗体を投与するため、例え
ば組換えヒト型化モノクローナル抗体抗ＨＥＲ２トラスツズマブを投与するため
に、一般に用いられる治療クールは体表面積１ｍ２あたり約１から約１０００ｍ
ｇである。用いられる治療クールは体表面積１ｍ２あたり約５０から約５００ｍ
ｇであることがより好ましい。In the method of the present invention, a therapeutic course generally used to administer a recombinant humanized anti-HER2 antibody, eg, to administer a recombinant humanized monoclonal antibody anti-HER2 trastuzumab, is per m 2 body surface area. About 1 to about 1000m
It is g. The therapeutic cool used is about 50 to about 500 m per 1 m 2 of body surface area
More preferably, it is g.
【００１８】
本発明の抗新生物療法は、特に、ヒトを含む哺乳動物の乳房、卵巣、肺、大腸
、腎臓、胃、膵臓、肝臓の腫瘍、黒色腫、白血病および脳腫瘍を治療するのに適
している。特に、本発明によるアルキル化アントラサイクリンおよび組換えヒト
型化抗ＨＥＲ２抗体、例えば組換えヒト型化モノクローナル抗体抗ＨＥＲ２トラ
スツズマブを組み合わせての使用は、ＨＥＲ２蛋白質を過剰発現する癌の患者、
例えばＨＥＲ２蛋白質を過剰発現する転移性乳癌の患者を治療するのに適当であ
りうる。The anti-neoplastic therapy of the present invention is particularly suitable for treating breast, ovary, lung, colon, kidney, stomach, pancreas, liver tumors, melanoma, leukemia and brain tumors of mammals including humans. ing. In particular, the use of a combination of an alkylated anthracycline according to the invention and a recombinant humanized anti-HER2 antibody, such as a recombinant humanized monoclonal antibody anti-HER2 trastuzumab, in patients with cancers that overexpress the HER2 protein,
For example, it may be suitable for treating patients with metastatic breast cancer that overexpress the HER2 protein.
【００１９】 本発明による抗新生物療法は、腫瘍転移の予防および／または治療も含む。[0019] Anti-neoplastic therapy according to the invention also comprises the prevention and / or treatment of tumor metastases.
【００２０】
本発明のさらに他の態様は、脈管形成阻害によって腫瘍を治療するための、前
述の式ＩａまたはＩｂのアルキル化アントラサイクリンおよび組換えヒト型化抗
ＨＥＲ２抗体、好ましくは組換えヒト型化モノクローナル抗体抗ＨＥＲ２トラス
ツズマブの使用である。Yet another aspect of the invention is the use of an alkylated anthracycline of formula Ia or Ib as described above and a recombinant humanized anti-HER2 antibody, preferably recombinant human, for treating a tumor by inhibiting angiogenesis. Use of the typed monoclonal antibody anti-HER2 trastuzumab.
【００２１】
前述のとおり、式ＩａおよびＩｂのアルキル化アントラサイクリンおよび組換
えヒト型化抗ＨＥＲ２抗体の有効性は、毒性が平行して増大することなく著しく
高められる。すなわち、本発明の組み合わせ療法は前述の式ＩａまたはＩｂのア
ルキル化アントラサイクリンおよび組換えヒト型化抗ＨＥＲ２抗体の抗腫瘍効果
を増強し、したがって腫瘍に対する最も有効で最も毒性が低い治療を提供する。As mentioned above, the efficacy of the alkylated anthracyclines of formula Ia and Ib and the recombinant humanized anti-HER2 antibody is significantly enhanced without a parallel increase in toxicity. Thus, the combination therapies of the present invention enhance the anti-tumor effect of the alkylated anthracyclines of formula Ia or Ib and recombinant humanized anti-HER2 antibody described above, thus providing the most effective and least toxic treatment for tumors. .
【００２２】
本発明による組み合わせ調製物が示す相乗作用は、例えば、ＨＥＲ２蛋白質を
過剰発現するヒト腫瘍異種移植片を移植したマウスにおいて、例えばＣａｎｃｅ
ｒ Ｒｅｓｅａｒｃｈ，１９９８，５８：２８２５−２８３１に記載の方法に従
って組み合わせの活性を試験することにより明らかにすることができる。The synergistic effect of the combination preparation according to the invention is shown, for example, in mice transplanted with human tumor xenografts overexpressing the HER2 protein, for example Cancer.
r Research, 1998, 58: 2825-2831, which can be demonstrated by testing the activity of the combination.
【００２３】
当業者には明白な、臨床治療において通常行われる様々な条件およびパラメー
ターの適当な変更および順応は本発明の範囲内である。Appropriate modifications and adaptations of the variety of conditions and parameters normally practiced in clinical therapy that are obvious to those skilled in the art are within the scope of the invention.
───────────────────────────────────────────────────── フロントページの続き (81)指定国 ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＣＹ， ＤＥ，ＤＫ，ＥＳ，ＦＩ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，Ｉ Ｔ，ＬＵ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＯＡ(ＢＦ，ＢＪ ，ＣＦ，ＣＧ，ＣＩ，ＣＭ，ＧＡ，ＧＮ，ＧＷ，ＭＬ， ＭＲ，ＮＥ，ＳＮ，ＴＤ，ＴＧ)，ＡＰ(ＧＨ，ＧＭ，Ｋ Ｅ，ＬＳ，ＭＷ，ＭＺ，ＳＤ，ＳＬ，ＳＺ，ＴＺ，ＵＧ ，ＺＷ)，ＥＡ(ＡＭ，ＡＺ，ＢＹ，ＫＧ，ＫＺ，ＭＤ， ＲＵ，ＴＪ，ＴＭ)，ＡＥ，ＡＧ，ＡＬ，ＡＭ，ＡＴ， ＡＵ，ＡＺ，ＢＡ，ＢＢ，ＢＧ，ＢＲ，ＢＹ，ＢＺ，Ｃ Ａ，ＣＨ，ＣＮ，ＣＲ，ＣＵ，ＣＺ，ＤＥ，ＤＫ，ＤＭ ，ＤＺ，ＥＥ，ＥＳ，ＦＩ，ＧＢ，ＧＤ，ＧＥ，ＧＨ， ＧＭ，ＨＲ，ＨＵ，ＩＤ，ＩＬ，ＩＮ，ＩＳ，ＪＰ，Ｋ Ｅ，ＫＧ，ＫＰ，ＫＲ，ＫＺ，ＬＣ，ＬＫ，ＬＲ，ＬＳ ，ＬＴ，ＬＵ，ＬＶ，ＭＡ，ＭＤ，ＭＧ，ＭＫ，ＭＮ， ＭＷ，ＭＸ，ＭＺ，ＮＯ，ＮＺ，ＰＬ，ＰＴ，ＲＯ，Ｒ Ｕ，ＳＤ，ＳＥ，ＳＧ，ＳＩ，ＳＫ，ＳＬ，ＴＪ，ＴＭ ，ＴＲ，ＴＴ，ＴＺ，ＵＡ，ＵＧ，ＵＳ，ＵＺ，ＶＮ， ＹＵ，ＺＡ，ＺＷ (72)発明者 カルーソ，ミケーレ イタリー国、イ−20131・ミラン、ビア・ デシデリオ、３ (72)発明者 スアラート，アントニーノ イタリー国、イ−20100・ミラノ、ビア・ デツリ・インブリアーニ、39 Ｆターム(参考） 4C085 AA13 AA14 DD62 4C086 AA01 AA02 EA10 MA02 MA04 NA05 ZB26 ─────────────────────────────────────────────────── ─── Continued front page (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, C A, CH, CN, CR, CU, CZ, DE, DK, DM , DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, K E, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, R U, SD, SE, SG, SI, SK, SL, TJ, TM , TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Caruso, Michele Italy, Lee-20131, Milan, Via Desiglio, 3 (72) Inventor Suertal, Antonino Italy, E-20100, Milan, Via Desuli Imbriani, 39 F-term (reference) 4C085 AA13 AA14 DD62 4C086 AA01 AA02 EA10 MA02 MA04 NA05 ZB26
Claims (14)
たは順次用いるための組み合わせ調製物として含む製品。1. An alkylated anthracycline of formula Ia or Ib and A product comprising a recombinant humanized anti-HER2 antibody as a combined preparation for simultaneous, separate or sequential use in anti-tumor therapy.
ナル抗体抗ＨＥＲ２トラスツズマブである請求項１に記載の製品。2. The product of claim 1, wherein the recombinant humanized anti-HER2 antibody is the recombinant humanized monoclonal antibody anti-HER2 trastuzumab.
アミノ−３’−アジリジニル−４’−メタンスルホニルダウノルビシンである請
求項１または２に記載の製品。3. A product according to claim 1 or 2 wherein the alkylated anthracycline is 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methanesulfonyldaunorubicin.
めである請求項１から３のいずれか一項に記載の製品。4. The product according to any one of claims 1 to 3, wherein the anti-tumor treatment is for treating a cancer that overexpresses the HER2 protein.
て請求項１に記載の式ＩａまたはＩｂのアルキル化アントラサイクリンおよび組
換えヒト型化抗ＨＥＲ２抗体とを含む医薬品組成物。5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and an alkylated anthracycline of formula Ia or Ib according to claim 1 and a recombinant humanized anti-HER2 antibody as active ingredients. .
ナル抗体抗ＨＥＲ２トラスツズマブである請求項５に記載の医薬品組成物。6. The pharmaceutical composition according to claim 5, wherein the recombinant humanized anti-HER2 antibody is a recombinant humanized monoclonal antibody anti-HER2 trastuzumab.
Ｒ２抗体が同時に、別々に、または順次投与される、腫瘍の治療において用いる
ための医薬品調製物における請求項１に記載の式ＩａまたはＩｂのアルキル化ア
ントラサイクリンおよび組換えヒト型化抗ＨＥＲ２抗体の使用。7. Alkylated anthracycline and recombinant humanized anti-HE
Of an alkylated anthracycline of formula Ia or Ib and a recombinant humanized anti-HER2 antibody according to claim 1 in a pharmaceutical preparation for use in the treatment of tumors, wherein the R2 antibody is administered simultaneously, separately or sequentially. use.
ナル抗体抗ＨＥＲ２トラスツズマブである請求項７に記載の使用。8. The use according to claim 7, wherein the recombinant humanized anti-HER2 antibody is the recombinant humanized monoclonal antibody anti-HER2 trastuzumab.
Ｒ２抗体が同時に、別々に、または順次投与される、腫瘍転移の予防および／ま
たは治療において用いるための医薬品調製物における請求項１に記載の式Ｉａま
たはＩｂのアルキル化アントラサイクリンおよび組換えヒト型化抗ＨＥＲ２抗体
の使用。9. Alkylated anthracycline and recombinant humanized anti-HE
The alkylated anthracycline of formula Ia or Ib and recombinant human form of claim 1 in a pharmaceutical preparation for use in the prevention and / or treatment of tumor metastasis, wherein R2 antibody is administered simultaneously, separately or sequentially. Use of a modified anti-HER2 antibody.
クローナル抗体抗ＨＥＲ２トラスツズマブである請求項９に記載の使用。10. The use according to claim 9, wherein the recombinant humanized anti-HER2 antibody is a recombinant humanized monoclonal antibody anti-HER2 trastuzumab.
トラサイクリンおよび組換えヒト型化抗ＨＥＲ２抗体を、相乗的抗新生物効果を
生じるのに有効な量で投与することを含む、新生物疾患を患う、ヒトを含む哺乳
動物を治療する方法。11. A method comprising administering to said mammal said alkylated anthracycline of formula Ia or Ib and a recombinant humanized anti-HER2 antibody in an amount effective to produce a synergistic anti-neoplastic effect. , A method of treating mammals, including humans, suffering from neoplastic diseases.
ーナル抗体抗ＨＥＲ２トラスツズマブである請求項１１に記載の方法。12. The method according to claim 11, wherein the recombinant humanized anti-HER2 antibody is a recombinant humanized monoclonal antibody anti-HER2 trastuzumab.
トラサイクリンおよび組換えヒト型化抗ＨＥＲ２抗体を、相乗的抗新生物効果を
生じるのに有効な量で投与することを含む、抗新生物療法を必要としている、ヒ
トを含む哺乳動物において、抗新生物物質を用いた抗新生物療法により引き起こ
される副作用を低下させるための方法。13. A method comprising administering to said mammal said alkylated anthracycline of formula Ia or Ib and a recombinant humanized anti-HER2 antibody in an amount effective to produce a synergistic anti-neoplastic effect. , A method for reducing the side effects caused by antineoplastic therapy with antineoplastic agents in mammals, including humans, in need of antineoplastic therapy.
ーナル抗体抗ＨＥＲ２トラスツズマブである請求項１３に記載の方法。14. The method according to claim 13, wherein the recombinant humanized anti-HER2 antibody is a recombinant humanized monoclonal antibody anti-HER2 trastuzumab.
Applications Claiming Priority (3)
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| PCT/EP2000/006540 WO2001005425A2 (en) | 1999-07-20 | 2000-07-10 | Combined preparations comprising daunorubicin derivatives and her2 antibodies |
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| JP (1) | JP2003504413A (en) |
| AU (1) | AU5983900A (en) |
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| WO (1) | WO2001005425A2 (en) |
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| KR20130056201A (en) | 2000-05-19 | 2013-05-29 | 제넨테크, 인크. | Gene detection assay for improving the likelihood of an effective response to an erbb antagonist cancer therapy |
| GB0114654D0 (en) * | 2001-06-15 | 2001-08-08 | Pharmacia & Upjohn Spa | Anti-tumor compound |
| KR20200058588A (en) | 2005-01-21 | 2020-05-27 | 제넨테크, 인크. | Fixed dosing of her antibodies |
| RS53128B (en) | 2005-02-23 | 2014-06-30 | Genentech Inc. | Extending time to disease progression or survival in ovarian cancer patients using pertuzumab |
| CN103432580A (en) | 2007-03-02 | 2013-12-11 | 健泰科生物技术公司 | Predicting response to a HER dimerisation inhibitor based on low HER3 expression |
| US9551033B2 (en) | 2007-06-08 | 2017-01-24 | Genentech, Inc. | Gene expression markers of tumor resistance to HER2 inhibitor treatment |
| CA2917355C (en) | 2007-06-08 | 2018-07-17 | 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 |
| TWI461211B (en) | 2009-03-20 | 2014-11-21 | Genentech Inc | Anti-her antibodies |
| EP2435071A1 (en) | 2009-05-29 | 2012-04-04 | F. Hoffmann-La Roche AG | Modulators for her2 signaling in her2 expressing patients with gastric cancer |
| 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 |
| US20130245233A1 (en) | 2010-11-24 | 2013-09-19 | Ming Lei | Multispecific Molecules |
| EP2655413B1 (en) | 2010-12-23 | 2019-01-16 | F.Hoffmann-La Roche Ag | Polypeptide-polynucleotide-complex and its use in targeted effector moiety delivery |
| EP2744824A1 (en) | 2011-08-17 | 2014-06-25 | F.Hoffmann-La Roche Ag | 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 |
| JP2015500638A (en) | 2011-11-30 | 2015-01-08 | ジェネンテック， インコーポレイテッド | ERBB3 mutations in cancer |
| US9376715B2 (en) | 2011-12-09 | 2016-06-28 | Roche Molecular Systems, Inc | Methods for detecting mutations in the catalytic subunit of the phosphoinositol-3 kinase (PIK3CA) gene |
| BR112014024017A8 (en) | 2012-03-27 | 2017-07-25 | Genentech Inc | METHODS FOR TREATMENT OF A TYPE OF CANCER, FOR TREATMENT OF CARCINOMA, FOR SELECTING A THERAPY AND FOR QUANTIFICATION AND HER3 INHIBITORS |
| KR102291355B1 (en) | 2012-11-30 | 2021-08-19 | 에프. 호프만-라 로슈 아게 | Identification of patients in need of pd-l1 inhibitor cotherapy |
| 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 |
| US10167342B2 (en) | 2016-08-29 | 2019-01-01 | Fazel Shokri | Production of hersintuzumab: a new humanized antibody against HER2 for cancer treatment |
| PT110526B (en) | 2018-01-26 | 2021-02-04 | Univ Nova De Lisboa | ANTIBODY, FUNCTIONAL FRAGMENT OR PROBE OF THE SAME AGAINST TUMORAL ANTIGENS |
| AU2021357841A1 (en) | 2020-10-08 | 2023-06-15 | Affimed Gmbh | Trispecific binders |
| AU2022320948A1 (en) | 2021-07-30 | 2024-01-18 | Affimed Gmbh | Duplexbodies |
| KR20240099382A (en) | 2021-11-03 | 2024-06-28 | 아피메트 게엠베하 | Bispecific CD16A binding agent |
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| WO1989006692A1 (en) * | 1988-01-12 | 1989-07-27 | Genentech, Inc. | Method of treating tumor cells by inhibiting growth factor receptor function |
| FI102355B (en) * | 1988-02-11 | 1998-11-30 | Squibb Bristol Myers Co | A method for preparing anthracycline immunoconjugates having a linking spacer |
| US5705157A (en) * | 1989-07-27 | 1998-01-06 | The Trustees Of The University Of Pennsylvania | Methods of treating cancerous cells with anti-receptor antibodies |
| ZA9811162B (en) * | 1997-12-12 | 2000-06-07 | Genentech Inc | Treatment with anti-ERBB2 antibodies. |
| CA2357525A1 (en) * | 1999-01-27 | 2000-08-03 | Cornell Research Foundation, Inc. | Treating cancers associated with overexpression of her-2/neu |
| US6333348B1 (en) * | 1999-04-09 | 2001-12-25 | Aventis Pharma S.A. | Use of docetaxel for treating cancers |
| ES2320311T3 (en) * | 1999-05-14 | 2009-05-21 | Genentech, Inc. | TREATMENT WITH ANTI-ERBB2 ANTIBODIES. |
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- 2000-07-10 AU AU59839/00A patent/AU5983900A/en not_active Abandoned
- 2000-07-10 JP JP2001510479A patent/JP2003504413A/en not_active Withdrawn
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| AU5983900A (en) | 2001-02-05 |
| WO2001005425A2 (en) | 2001-01-25 |
| GB9917012D0 (en) | 1999-09-22 |
| WO2001005425A3 (en) | 2001-05-17 |
| EP1200098A2 (en) | 2002-05-02 |
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