JP2019202936A - Combination drug of anti-Epiregulin antibody and anti-EGFR antibody - Google Patents

Combination drug of anti-Epiregulin antibody and anti-EGFR antibody Download PDF

Info

Publication number
JP2019202936A
JP2019202936A JP2016159983A JP2016159983A JP2019202936A JP 2019202936 A JP2019202936 A JP 2019202936A JP 2016159983 A JP2016159983 A JP 2016159983A JP 2016159983 A JP2016159983 A JP 2016159983A JP 2019202936 A JP2019202936 A JP 2019202936A
Authority
JP
Japan
Prior art keywords
antibody
epiregulin
cancer
seq
egfr
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.)
Pending
Application number
JP2016159983A
Other languages
Japanese (ja)
Inventor
暢也 石井
Akiya Ishii
暢也 石井
芽衣 小野
Mei Ono
芽衣 小野
祥規 渡邉
Yoshinori Watanabe
祥規 渡邉
順子 岩▲崎▼
Junko Iwasaki
順子 岩▲崎▼
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chugai Pharmaceutical Co Ltd
Original Assignee
Chugai Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Chugai Pharmaceutical Co Ltd filed Critical Chugai Pharmaceutical Co Ltd
Priority to JP2016159983A priority Critical patent/JP2019202936A/en
Priority to PCT/JP2017/029425 priority patent/WO2018034301A1/en
Publication of JP2019202936A publication Critical patent/JP2019202936A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

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

Abstract

To provide a cancer treatment method that is more effective than and replaces the conventional antibody therapy in order to treat cancer or prevent cancer relapse or metastasis.SOLUTION: The present invention provides a method that exhibits a synergistic effect in cancer treatment by combination use of an anti-epiregulin antibody with an anti-EGFR antibody, as compared to the conventional treatment with the anti-EGFR antibody alone. There is also provided a method for treating cancer or preventing cancer relapse or metastasis.SELECTED DRAWING: Figure 1

Description

本発明は、癌を治療する、または癌の再発もしくは転移を抑制するための医薬組成物、癌の治療または癌の再発もしくは転移の抑制の効果を増幅させる方法、ならびに癌を治療するための製剤を含む製品に関する。   The present invention relates to a pharmaceutical composition for treating cancer or suppressing the recurrence or metastasis of cancer, a method for amplifying the effect of treating cancer or suppressing the recurrence or metastasis of cancer, and a preparation for treating cancer Related to products.

癌は、先進国において、死亡率の主要原因である。癌治療の目的で、多くの化学療法剤が過去50年間に開発された。化学療法剤の大半は、アルキル化剤、代謝措抗剤、アンスラサイクリン（anthracycline）、植物アルカ口イドトポイソメラーゼ阻害剤、及び抗腫蕩剤に分類することができる。これらの薬剤すべてが細胞分裂またはDNAの合成に影響し、何らかの形で機能するメカニズムを通して治療効果をもたらす。
特定の化学療法剤の有効性は、癌の間で、患者の間で、あるいは個々の患者における時間経過により異なる。化学療法剤に曝露された癌細胞は、こうした化学療法剤に対する耐性を生じ、他の複数の抗癌剤に対しても同様に交差耐性を生じることも多い。さらに、上記の化学療法剤のメカニズムによってこれらの化学療法剤が正常細胞に与える細胞傷害の結果もたらされる副作用を制御するため、化学療法剤の用量または用法は多くの場合制約される。 Cancer is a leading cause of mortality in developed countries. Many chemotherapeutic agents have been developed in the last 50 years for the purpose of cancer treatment. Most chemotherapeutic agents can be categorized as alkylating agents, antimetabolic agents, anthracyclines, plant alkaloid topoisomerase inhibitors, and antitumor agents. All of these drugs affect cell division or DNA synthesis and provide therapeutic effects through mechanisms that function in some way.
The effectiveness of a particular chemotherapeutic agent varies between cancers, between patients, or over time in individual patients. Cancer cells exposed to chemotherapeutic agents develop resistance to such chemotherapeutic agents, and often develop cross-resistance to multiple other anticancer agents as well. In addition, the dose or use of chemotherapeutic agents is often constrained because the chemotherapeutic agent mechanisms described above control the side effects that these chemotherapeutic agents cause as a result of cytotoxicity on normal cells.

従来の化学療法剤に代わり近年癌細胞に特異的に発現する分子を標的とする分子標的薬の開発が進められている。こうした分子標的薬の登場によって従来の化学療法剤に固有の副作用が回避され癌患者のQOLに寄与する癌治療が可能となっている。こうした分子標的薬には低分子（small molecule）の薬剤のほか抗体等の高分子の薬剤も含まれる。
抗体の薬剤としては、さまざまな悪性腫瘍で過剰発現がみられるEpidermal growth factor receptor (以下、「EGFR」)を標的とした抗体による癌の治療剤が開発されている。例えば、セツキシマブ（cetuximab：商品名Erbitux（登録商標））やパニツムマブ（panitumumab：商品名Vectibix（登録商標））はEGFR依存的な腫瘍を治療するための医薬として開発され上市されている。また、EGFRのリガンドであるEpidermal growth factor (以下、「EGF」) familyの一つであり、大腸癌、肺腺癌、膵癌、胃癌、腎癌で高発現しているEpiregulinを標的とした抗体が開示されている（特許文献1、特許文献２）。 In recent years, instead of conventional chemotherapeutic agents, development of molecular targeted drugs that target molecules specifically expressed in cancer cells has been underway. With the advent of these molecularly targeted drugs, the side effects inherent in conventional chemotherapeutic agents are avoided, and cancer treatment that contributes to the quality of life of cancer patients is possible. Such molecular target drugs include small molecule drugs as well as high molecular drugs such as antibodies.
As antibody drugs, cancer therapeutic agents using antibodies targeting the epidermal growth factor receptor (hereinafter "EGFR"), which is overexpressed in various malignant tumors, have been developed. For example, cetuximab (trade name Erbitux (registered trademark)) and panitumumab (trade name Vectibix (registered trademark)) have been developed and marketed as drugs for treating EGFR-dependent tumors. In addition, an antibody targeting Epiregulin, a member of the epidermal growth factor (EGF) family of EGFR ligands, which is highly expressed in colorectal cancer, lung adenocarcinoma, pancreatic cancer, gastric cancer, and renal cancer. (Patent Document 1 and Patent Document 2).

セツキシマブに代表される抗EGFR抗体による治療と、治療対象におけるEpiregulinの発現との関係については、多くの報告がなされている。例えば、Takahashiらは、抗Epiregulin抗体による治療を受けた転移性大腸癌患者から採取した血清中のhepatocyte growth factor及びEpiregulinの発現量を分析した結果、比較的発現量の低い患者群において比較的発現量の高い患者群よりも有意な治療効果が見られることから、hepatocyte growth factor及びEpiregulinの発現が抗EGFR抗体による治療の予後不良に関連することを示唆している（非特許文献１）。また、Oliveras-Ferraros Cらは、Epiregulin と、同じくEGF familyであるAmphiregulinの高発現がセツキシマブによる治療の耐性となり得ることを示唆している（非特許文献２）。これらの結果は、抗EGFR抗体による治療に対する応答性の指標としてEpiregulinの発現量が関連していることを示唆している。
一方、これらの開示情報とは異なり、Epiregulinの発現が抗EGFR抗体による治療に肯定的に作用することが複数の文献で示されている。例えばB Jacobsらは、EpiregulinやAmphiregulinの高発現が、セツキシマブ等の抗EGFR抗体による大腸癌治療の有意な応答性の予測となることを述べている（非特許文献３）。その他、Epiregulinの発現による肯定的な作用については、複数の論文が報告されている（非特許文献４-７）。
しかし、上記のいずれの報告においても、抗Epiregulin抗体と抗EGFR抗体との併用効果についてのデータは示されていない。 Many reports have been made on the relationship between treatment with anti-EGFR antibodies typified by cetuximab and the expression of Epiregulin in treatment subjects. For example, Takahashi et al. Analyzed the expression levels of hepatocyte growth factor and Epiregulin in serum collected from patients with metastatic colorectal cancer treated with anti-Epiregulin antibodies. Since a significant therapeutic effect is seen as compared with a high-dose patient group, it is suggested that expression of hepatocyte growth factor and Epiregulin is associated with poor prognosis of treatment with anti-EGFR antibody (Non-patent Document 1). Moreover, Oliveras-Ferraros C et al. Suggest that high expression of Epiregulin and Amphiregulin, which is also the EGF family, can be resistant to treatment with cetuximab (Non-patent Document 2). These results suggest that the expression level of Epiregulin is related as an index of responsiveness to treatment with anti-EGFR antibody.
On the other hand, unlike these disclosed information, it has been shown in several documents that the expression of Epiregulin acts positively on treatment with anti-EGFR antibodies. For example, B Jacobs et al. Describe that high expression of Epiregulin and Amphiregulin predicts significant responsiveness of colorectal cancer treatment with anti-EGFR antibodies such as cetuximab (Non-patent Document 3). In addition, several papers have been reported on the positive action by the expression of Epiregulin (Non-patent Documents 4-7).
However, none of the above reports show data on the combined effect of anti-Epiregulin antibody and anti-EGFR antibody.

WO2013100120 A1WO2013100120 A1 WO2014208482 A1WO2014208482 A1

British Journal of Cancer 2014 May 27;110(11):2716-27British Journal of Cancer 2014 May 27; 110 (11): 2716-27 Invest New Drugs 2012 Apr;30(2):846-52Invest New Drugs 2012 Apr; 30 (2): 846-52 J Clin Oncol. 2009 Oct 20;27(30):5068-74J Clin Oncol. 2009 Oct 20; 27 (30): 5068-74 J Clin Oncol. 2010 Mar 1; 28(7):1181-9J Clin Oncol. 2010 Mar 1; 28 (7): 1181-9 British Journal of Cancer 2011 Feb 1;104(3):488-95British Journal of Cancer 2011 Feb 1; 104 (3): 488-95 Cancer discovery 2015 June;5(6):598-609Cancer discovery 2015 June; 5 (6): 598-609 Mol Cancer Ther. 2015 Jul;14(7):1625-36Mol Cancer Ther. 2015 Jul; 14 (7): 1625-36

本発明は、従来の抗体治療に代わる、より有効な癌治療法を提供することを課題とする。   It is an object of the present invention to provide a more effective cancer therapy that replaces conventional antibody therapy.

上記目的を達成するために鋭意研究した結果、本発明者らは、抗Epiregulin抗体を抗EGFR抗体と併用することによって、抗EGFR抗体単独による処置と比べて、癌の治療において相乗的な効果を得られることを見いだし、本発明を完成した。   As a result of earnest research to achieve the above-mentioned object, the present inventors have used the anti-Epiregulin antibody in combination with the anti-EGFR antibody, thereby producing a synergistic effect in the treatment of cancer compared with the treatment with the anti-EGFR antibody alone. The present invention has been completed by finding out that it can be obtained.

すなわち、本発明は以下のものを提供する。
〔１〕抗Epiregulin抗体を有効成分として含む、抗EGFR抗体と併用して癌を治療する、または癌の再発もしくは転移を抑制するための医薬組成物。
〔２〕前記抗Epiregulin抗体が、前記抗EGFR抗体と同時に投与される、〔１〕の医薬組成物。
〔３〕前記抗Epiregulin抗体が、前記抗EGFR抗体の投与前又は投与後に投与される、〔１〕の医薬組成物。
〔４〕抗Epiregulin抗体と抗EGFR抗体とを有効成分として含む、癌を治療する、または癌の再発もしくは転移を抑制するための医薬組成物。
〔５〕抗Epiregulin抗体と抗EGFR抗体との配合剤である、〔４〕の医薬組成物。
〔６〕前記抗Epiregulin抗体が、配列番号：２に記載のCDR1、配列番号：３に記載のCDR2、配列番号：４に記載のCDR3を有する重鎖可変領域、および配列番号：７に記載のCDR1、配列番号：８に記載のCDR2、配列番号：９に記載のCDR3を有する軽鎖可変領域を含む抗体である、〔１〕〜〔５〕のいずれかの医薬組成物。
〔７〕前記抗Epiregulin抗体が、配列番号：１に記載の重鎖可変領域、配列番号：６に記載の軽鎖可変領域、配列番号：５に記載の重鎖定常領域、および配列番号：１０に記載の軽鎖定常領域を含む抗体である、〔１〕〜〔５〕の医薬組成物。
〔８〕前記抗EGFR抗体がセツキシマブまたはパニツムマブである、〔７〕の医薬組成物。
〔９〕癌が大腸癌である、〔１〕〜〔５〕のいずれかの医薬組成物。
〔１０〕対象に有効量の抗Epiregulin抗体を投与する工程を含む、抗EGFR抗体による癌の治療または癌の再発もしくは転移の抑制の効果を増幅させる方法。
〔１１〕前記抗Epiregulin抗体を、前記抗EGFR抗体と同時に投与する、〔１０〕の方法。
〔１２〕前記抗Epiregulin抗体を、前記抗EGFR抗体の投与前又は投与後に投与する、〔１０〕の方法。
〔１３〕対象におけるEpiregulinの発現を測定する工程と、当該測定結果にもとづき対象に前記抗Epiregulin抗体を投与する工程とを含む、〔１０〕の方法。
〔１４〕（１）抗Epiregulin抗体を含有する製剤、（２）容器、および（３）癌を治療し、または癌の再発もしくは転移を抑制するために前記抗Epiregulin抗体と少なくとも一種の抗EGFR抗体とを組み合わせて対象に投与することを示す指示書又はラベル、を含む製品。
〔１５〕前記抗Epiregulin抗体が、配列番号：２に記載のCDR1、配列番号：３に記載のCDR2、配列番号：４に記載のCDR3を有する重鎖可変領域、および配列番号：７に記載のCDR1、配列番号：８に記載のCDR2、配列番号：９に記載のCDR3を有する軽鎖可変領域を含む抗体である、〔１４〕の製品。
〔１６〕抗EGFR抗体を有効成分として含む、抗Epiregulin抗体と併用して癌を治療する、または癌の再発もしくは転移を抑制するための医薬組成物。
〔１７〕前記抗EGFR抗体が、前記抗Epiregulin抗体と同時に投与される、〔１６〕の医薬組成物。
〔１８〕前記抗EGFR抗体が、前記抗Epiregulin抗体の投与前又は投与後に投与される、〔１６〕の医薬組成物。
〔１９〕対象に有効量の抗EGFR抗体を投与する工程を含む、抗Epiregulin抗体による癌の治療または癌の再発もしくは転移の抑制の効果を増幅させる方法。
〔２０〕前記抗EGFR抗体を、前記抗Epiregulin抗体と同時に投与する、〔１９〕の方法。
〔２１〕前記抗EGFR抗体を、前記抗Epiregulin抗体の投与前又は投与後に投与する、〔１９〕の方法。
〔２２〕対象におけるEGFRの発現を測定する工程と、当該測定結果にもとづき対象に前記抗EGFR抗体を投与する工程とを含む、〔１９〕の方法。
〔２３〕（１）抗EGFR抗体を含有する製剤、（２）容器、および（３）癌を治療し、または癌の再発もしくは転移を抑制するために前記抗EGFR抗体と少なくとも一種の抗Epiregulin抗体とを組み合わせて対象に投与することを示す指示書又はラベル、を含む製品。
〔２４〕前記抗Epiregulin抗体が、配列番号：２に記載のCDR1、配列番号：３に記載のCDR2、配列番号：４に記載のCDR3を有する重鎖可変領域、および配列番号：７に記載のCDR1、配列番号：８に記載のCDR2、配列番号：９に記載のCDR3を有する軽鎖可変領域を含む抗体である、〔２３〕の製品。 That is, the present invention provides the following.
[1] A pharmaceutical composition for treating cancer or inhibiting cancer recurrence or metastasis in combination with an anti-EGFR antibody, comprising an anti-Epiregulin antibody as an active ingredient.
[2] The pharmaceutical composition of [1], wherein the anti-Epiregulin antibody is administered simultaneously with the anti-EGFR antibody.
[3] The pharmaceutical composition of [1], wherein the anti-Epiregulin antibody is administered before or after administration of the anti-EGFR antibody.
[4] A pharmaceutical composition for treating cancer or inhibiting cancer recurrence or metastasis, comprising an anti-Epiregulin antibody and an anti-EGFR antibody as active ingredients.
[5] The pharmaceutical composition of [4], which is a combination drug of an anti-Epiregulin antibody and an anti-EGFR antibody.
[6] The anti-Epiregulin antibody comprises a heavy chain variable region having CDR1 of SEQ ID NO: 2, CDR2 of SEQ ID NO: 3, CDR3 of SEQ ID NO: 4, and SEQ ID NO: 7. The pharmaceutical composition according to any one of [1] to [5], which is an antibody comprising a light chain variable region having CDR1, CDR2 set forth in SEQ ID NO: 8 and CDR3 set forth in SEQ ID NO: 9.
[7] The anti-Epiregulin antibody comprises a heavy chain variable region set forth in SEQ ID NO: 1, a light chain variable region set forth in SEQ ID NO: 6, a heavy chain constant region set forth in SEQ ID NO: 5, and SEQ ID NO: 10 The pharmaceutical composition of [1] to [5], which is an antibody comprising the light chain constant region described in 1.
[8] The pharmaceutical composition according to [7], wherein the anti-EGFR antibody is cetuximab or panitumumab.
[9] The pharmaceutical composition according to any one of [1] to [5], wherein the cancer is colorectal cancer.
[10] A method for amplifying the effect of cancer treatment or suppression of cancer recurrence or metastasis with an anti-EGFR antibody, comprising a step of administering an effective amount of an anti-Epiregulin antibody to a subject.
[11] The method of [10], wherein the anti-Epiregulin antibody is administered simultaneously with the anti-EGFR antibody.
[12] The method of [10], wherein the anti-Epiregulin antibody is administered before or after administration of the anti-EGFR antibody.
[13] The method according to [10], comprising a step of measuring the expression of Epiregulin in the subject, and a step of administering the anti-Epiregulin antibody to the subject based on the measurement result.
[14] (1) a preparation containing an anti-Epiregulin antibody, (2) a container, and (3) the anti-Epiregulin antibody and at least one anti-EGFR antibody for treating cancer or suppressing recurrence or metastasis of cancer A product containing instructions or a label indicating that the combination is administered to a subject.
[15] The anti-Epiregulin antibody comprises a heavy chain variable region having CDR1 of SEQ ID NO: 2, CDR2 of SEQ ID NO: 3, CDR3 of SEQ ID NO: 4, and SEQ ID NO: 7. The product according to [14], which is an antibody comprising a light chain variable region having CDR1, CDR2 set forth in SEQ ID NO: 8, and CDR3 set forth in SEQ ID NO: 9.
[16] A pharmaceutical composition for treating cancer or inhibiting cancer recurrence or metastasis in combination with an anti-Epiregulin antibody, comprising an anti-EGFR antibody as an active ingredient.
[17] The pharmaceutical composition of [16], wherein the anti-EGFR antibody is administered simultaneously with the anti-Epiregulin antibody.
[18] The pharmaceutical composition according to [16], wherein the anti-EGFR antibody is administered before or after administration of the anti-Epiregulin antibody.
[19] A method for amplifying the effect of cancer treatment or suppression of cancer recurrence or metastasis with an anti-Epiregulin antibody, comprising a step of administering an effective amount of an anti-EGFR antibody to a subject.
[20] The method of [19], wherein the anti-EGFR antibody is administered simultaneously with the anti-Epiregulin antibody.
[21] The method of [19], wherein the anti-EGFR antibody is administered before or after administration of the anti-Epiregulin antibody.
[22] The method according to [19], comprising a step of measuring the expression of EGFR in the subject, and a step of administering the anti-EGFR antibody to the subject based on the measurement result.
[23] (1) a preparation containing an anti-EGFR antibody, (2) a container, and (3) the anti-EGFR antibody and at least one anti-Epiregulin antibody for treating cancer or suppressing cancer recurrence or metastasis A product containing instructions or a label indicating that the combination is administered to a subject.
[24] The anti-Epiregulin antibody comprises a heavy chain variable region having CDR1 of SEQ ID NO: 2, CDR2 of SEQ ID NO: 3, CDR3 of SEQ ID NO: 4, and SEQ ID NO: 7. The product according to [23], which is an antibody comprising a light chain variable region having CDR1, CDR2 set forth in SEQ ID NO: 8, and CDR3 set forth in SEQ ID NO: 9.

また、本発明は以下のものも提供する。
〔２５〕対象に有効量の抗Epiregulin抗体を投与する工程を含む、抗EGFR抗体と併用して癌を治療するまたは癌の再発もしくは転移を抑制する方法。
〔２６〕対象に有効量の抗EGFR抗体を投与する工程を含む、抗Epiregulin抗体と併用して癌を治療するまたは癌の再発もしくは転移を抑制する方法。
〔２７〕抗EGFR抗体との併用による癌の治療または癌の再発もしくは転移の抑制において用いるための、抗Epiregulin抗体。
〔２８〕抗Epiregulin抗体との併用による癌の治療または癌の再発もしくは転移の抑制において用いるための、抗EGFR抗体。
〔２９〕抗EGFR抗体と併用される癌の治療剤または癌の再発もしくは転移の抑制剤の製造における、抗Epiregulin抗体の使用。
〔３０〕抗Epiregulin抗体と併用される癌の治療剤または癌の再発もしくは転移の抑制剤の製造における、抗EGFR抗体の使用。
〔３１〕対象に有効量の抗Epiregulin抗体および抗EGFR抗体の組み合わせを投与する工程を含む、癌を治療するまたは癌の再発もしくは転移を抑制する方法。
〔３２〕癌の治療または癌の再発もしくは転移の抑制において用いるための、抗Epiregulin抗体および抗EGFR抗体の組み合わせ。
〔３３〕癌の治療剤または癌の再発もしくは転移の抑制剤の製造における、抗Epiregulin抗体および抗EGFR抗体の組み合わせの使用。
〔３４〕抗Epiregulin抗体を有効成分として含む、抗EGFR抗体の抗腫瘍効果増強剤（抗EGFR抗体による癌の治療または癌の再発もしくは転移の抑制の効果を増幅させるための医薬組成物）。
〔３５〕抗EGFR抗体を有効成分として含む、抗Epiregulin抗体の抗腫瘍効果増強剤（抗Epiregulin抗体による癌の治療または癌の再発もしくは転移の抑制の効果を増幅させるための医薬組成物）。
〔３６〕抗EGFR抗体の抗腫瘍効果の増強（抗EGFR抗体による癌の治療または癌の再発もしくは転移の抑制の効果の増幅）において用いるための、抗Epiregulin抗体。
〔３７〕抗Epiregulin抗体の抗腫瘍効果の増強（抗Epiregulin抗体による癌の治療または癌の再発もしくは転移の抑制の効果の増幅）において用いるための、抗EGFR抗体。
〔３５〕抗EGFR抗体の抗腫瘍効果増強剤（抗EGFR抗体による癌の治療または癌の再発もしくは転移の抑制の効果を増幅させるための医薬組成物）の製造における抗Epiregulin抗体の使用。
〔３８〕抗Epiregulin抗体の抗腫瘍効果増強剤（抗Epiregulin抗体による癌の治療または癌の再発もしくは転移の抑制の効果を増幅させるための医薬組成物）の製造における抗EGFR抗体の使用。 The present invention also provides the following.
[25] A method of treating cancer or suppressing cancer recurrence or metastasis in combination with an anti-EGFR antibody, comprising a step of administering an effective amount of an anti-Epiregulin antibody to a subject.
[26] A method of treating cancer or suppressing cancer recurrence or metastasis in combination with an anti-Epiregulin antibody, comprising a step of administering an effective amount of an anti-EGFR antibody to a subject.
[27] An anti-Epiregulin antibody for use in the treatment of cancer by combined use with an anti-EGFR antibody or suppression of cancer recurrence or metastasis.
[28] An anti-EGFR antibody for use in the treatment of cancer by combined use with an anti-Epiregulin antibody or suppression of cancer recurrence or metastasis.
[29] Use of an anti-Epiregulin antibody in the manufacture of a therapeutic agent for cancer or an inhibitor of cancer recurrence or metastasis used in combination with an anti-EGFR antibody.
[30] Use of an anti-EGFR antibody in the manufacture of a cancer therapeutic agent or a cancer recurrence or metastasis inhibitor used in combination with an anti-Epiregulin antibody.
[31] A method for treating cancer or suppressing cancer recurrence or metastasis, comprising a step of administering an effective amount of a combination of an anti-Epiregulin antibody and an anti-EGFR antibody to a subject.
[32] A combination of an anti-Epiregulin antibody and an anti-EGFR antibody for use in the treatment of cancer or the suppression of cancer recurrence or metastasis.
[33] Use of a combination of an anti-Epiregulin antibody and an anti-EGFR antibody in the manufacture of a therapeutic agent for cancer or an inhibitor of cancer recurrence or metastasis.
[34] An anti-tumor effect enhancer of an anti-EGFR antibody comprising an anti-Epiregulin antibody as an active ingredient (a pharmaceutical composition for amplifying the effect of treatment of cancer or suppression of cancer recurrence or metastasis by an anti-EGFR antibody).
[35] An anti-tumor effect enhancer of an anti-Epiregulin antibody comprising an anti-EGFR antibody as an active ingredient (a pharmaceutical composition for amplifying the effect of treating cancer or suppressing cancer recurrence or metastasis with an anti-Epiregulin antibody).
[36] An anti-Epiregulin antibody for use in enhancing the anti-tumor effect of an anti-EGFR antibody (amplifying the effect of suppressing cancer recurrence or metastasis by treating cancer with an anti-EGFR antibody).
[37] An anti-EGFR antibody for use in enhancing the anti-tumor effect of an anti-Epiregulin antibody (amplifying the effect of treating cancer or suppressing the recurrence or metastasis of cancer with an anti-Epiregulin antibody).
[35] Use of an anti-Epiregulin antibody in the production of an anti-tumor effect potentiator of an anti-EGFR antibody (pharmaceutical composition for amplifying the effect of treatment of cancer with anti-EGFR antibody or suppression of cancer recurrence or metastasis).
[38] Use of an anti-EGFR antibody in the manufacture of an anti-tumor effect potentiator of an anti-Epiregulin antibody (a pharmaceutical composition for amplifying the effect of treatment of cancer with anti-Epiregulin antibody or suppression of cancer recurrence or metastasis).

本発明者らは、抗Epiregulin抗体と抗EGFR抗体を有効成分とする本発明の併用医薬が、抗Epiregulin抗体単独または抗EGFR抗体単独による処置と比べて、癌の治療または予防において相乗的な効果を示すことを初めて実証することに成功した。   The inventors of the present invention have a synergistic effect in the treatment or prevention of cancer compared to the treatment with the anti-Epiregulin antibody alone or the anti-EGFR antibody alone, in which the combined medicament of the present invention comprising an anti-Epiregulin antibody and an anti-EGFR antibody as active ingredients. Successfully demonstrated for the first time.

抗Epiregulin抗体単剤もしくはセツキシマブ単剤、または抗Epiregulin抗体とセツキシマブの組み合わせの存在下で、各濃度のヒトリコンビナントEpiregulinで刺激したLIM1215ヒト大腸癌細胞の細胞培養密度を経時的に示すグラフである。グラフ中のエラーバーは、n＝3のS.D.値を示している。It is a graph which shows the cell culture density of the LIM1215 human colorectal cancer cell stimulated with human recombinant Epiregulin of each concentration in the presence of anti-Epiregulin antibody alone or cetuximab alone, or a combination of anti-Epiregulin antibody and cetuximab over time. Error bars in the graph indicate S.D. values for n = 3. 抗Epiregulin抗体単剤もしくはパニツムマブ単剤、または抗Epiregulin抗体とパニツムマブの組み合わせの存在下で、各濃度のヒトリコンビナントEpiregulinで刺激したLIM1215ヒト大腸癌細胞の細胞培養密度を経時的に示すグラフである。グラフ中のエラーバーは、n＝3のS.D.値を示している。It is a graph which shows the cell culture density of the LIM1215 human colorectal cancer cell stimulated with human recombinant Epiregulin of each concentration in the presence of anti-Epiregulin antibody alone or panitumumab alone, or a combination of anti-Epiregulin antibody and panitumumab over time. Error bars in the graph indicate S.D. values for n = 3. 抗Epiregulin抗体単剤、セツキシマブ単剤、もしくはパニツムマブ単剤、または抗Epiregulin抗体と抗EGFR抗体の組み合わせの存在下で、各濃度のヒトリコンビナントEpiregulinで72時間刺激したLIM1215ヒト大腸癌細胞の細胞培養密度を示すグラフである。グラフ中のエラーバーは、n＝3のS.D.値を示している。Cell culture density of LIM1215 human colon cancer cells stimulated with human recombinant Epiregulin for 72 hours in the presence of anti-Epiregulin antibody alone, cetuximab alone, or panitumumab alone, or a combination of anti-Epiregulin and anti-EGFR antibodies It is a graph which shows. Error bars in the graph indicate S.D. values for n = 3. 抗Epiregulin抗体単剤もしくはセツキシマブ単剤、または抗Epiregulin抗体とセツキシマブの組み合わせの存在下で、各濃度のヒトリコンビナントEpiregulinと共に6日間培養したCCK-81ヒト大腸癌細胞の生細胞数を、発色試薬を加えて吸光度を測定することにより測定したグラフである。グラフ中のエラーバーは、n＝3のS.D.値を示している。In the presence of anti-Epiregulin antibody alone or cetuximab alone, or a combination of anti-Epiregulin antibody and cetuximab, the number of living CCK-81 human colon cancer cells cultured with human recombinant Epiregulin at various concentrations for 6 days In addition, it is a graph measured by measuring absorbance. Error bars in the graph indicate S.D. values for n = 3. 抗Epiregulin抗体、セツキシマブ、もしくはパニツムマブ、またはそれらの組み合わせの存在下で、ヒトリコンビナントEpiregulinで10分間刺激したLIM1215ヒト大腸癌細胞におけるHERファミリー受容体とその下流シグナルタンパク質のリン酸化をウエスタンブロッティング法で検出した写真である。Western blotting detects phosphorylation of HER family receptors and their downstream signal proteins in LIM1215 human colon cancer cells stimulated with human recombinant Epiregulin for 10 minutes in the presence of anti-Epiregulin antibody, cetuximab, or panitumumab, or a combination thereof It is a photograph. CXF 2172およびCXF 2067ヒト大腸癌患者由来腫瘍モデルにおける、腫瘍体積の経時的な変化を示すグラフである。グラフ中のエラーバーは、n＝10のS.D.値を示している。当該モデルには、実施例３に記載されたスケジュールで抗Epiregulin抗体および/またはセツキシマブが投与された。It is a graph which shows the time-dependent change of the tumor volume in the CXF 2172 and the CXF 2067 human colon cancer patient derived tumor model. Error bars in the graph indicate S.D. values for n = 10. The model was administered anti-Epiregulin antibody and / or cetuximab according to the schedule described in Example 3. CXF 2172およびCXF 2067ヒト大腸癌患者由来腫瘍モデルにおける、抗Epiregulin抗体および/またはセツキシマブの投与開始時の腫瘍体積を100%としたときのCXF 2172モデルにおける102日後と、CXF 2067モデルにおける45日後の各個体の相対腫瘍体積変化率を示すグラフである。In CXF 2172 and CXF 2067 human colorectal cancer patient-derived tumor models, 102 days after CXF 2172 model and 45 days after CXF 2067 model when the tumor volume at the start of administration of anti-Epiregulin antibody and / or cetuximab was taken as 100% It is a graph which shows the relative tumor volume change rate of each individual | organism | solid. CXF 2172およびCXF 2067ヒト大腸癌患者由来腫瘍モデルにおける、抗Epiregulin抗体および/またはセツキシマブの投与開始時の腫瘍体積に対して2倍の腫瘍体積になった日を腫瘍増日と定義した場合のKaplan-Meierプロットを示すグラフである。Kaplan when the tumor volume is defined as the day when the tumor volume was doubled relative to the tumor volume at the start of administration of anti-Epiregulin antibody and / or cetuximab in tumor models derived from CXF 2172 and CXF 2067 human colon cancer patients -A graph showing a Meier plot.

本発明は、抗Epiregulin抗体を有効成分として含む、抗EGFR抗体と併用して癌を治療する、または癌の再発もしくは転移を抑制するための医薬組成物に関する。また本発明は、抗EGFR抗体を有効成分として含む、抗Epiregulin抗体と併用して癌を治療する、または癌の再発もしくは転移を抑制するための医薬組成物に関する。   The present invention relates to a pharmaceutical composition comprising an anti-Epiregulin antibody as an active ingredient, for treating cancer in combination with an anti-EGFR antibody, or suppressing cancer recurrence or metastasis. The present invention also relates to a pharmaceutical composition comprising an anti-EGFR antibody as an active ingredient, for treating cancer in combination with an anti-Epiregulin antibody, or suppressing cancer recurrence or metastasis.

本発明において、「抗体」は、最も広い意味で使用され、所望の抗原結合活性を示す限りは、これらに限定されるものではないが、モノクローナル抗体、ポリクローナル抗体、多重特異性抗体（例えば、二重特異性抗体）および抗体断片を含む、種々の抗体構造を包含する。   In the present invention, “antibody” is used in the broadest sense, and is not limited to these as long as it exhibits a desired antigen-binding activity. Various antibody structures are included, including bispecific antibodies) and antibody fragments.

本発明において、「抗Epiregulin抗体」または「Epiregulinに結合する抗体」は、充分なアフィニティでEpiregulinと結合することのできる抗体であって、その結果その抗体がEpiregulinを標的化したときに診断剤および／または治療剤として有用であるような抗体のことをいい、上述の特許文献１および２に記載される抗体の他、例えば開発コード；LY3016859（Eli Lilly）に示される抗体が含まれる。   In the present invention, an “anti-Epiregulin antibody” or “an antibody that binds to Epiregulin” is an antibody that can bind to Epiregulin with sufficient affinity, so that when the antibody targets Epiregulin, the diagnostic agent and It refers to an antibody that is useful as a therapeutic agent, and includes, for example, the antibody shown in the development code; LY3016859 (Eli Lilly) in addition to the antibodies described in Patent Documents 1 and 2 described above.

また本発明において、「抗EGFR抗体」または「EGFRに結合する抗体」は、充分なアフィニティでEGFRと結合することのできる抗体であって、その結果その抗体がEGFRを標的化したときに診断剤および／または治療剤として有用であるような抗体のことをいい、例えばセツキシマブ、パニツムマブ、ニモツズマブ（Nimotuzumab）、ネシツムマブ（Necitumumab）、フツキシマブ（Futuximab）の他、開発コード；GT-MAB 5.2-GEX（Glycotope）、MM-151（Merrimack Pharmaceuticals）、ABT-806（Abbott）、SCT-200（Sinocelltech）、GC-1118A（Green Cross）に示される抗体等が含まれる。   In the present invention, the “anti-EGFR antibody” or “antibody that binds to EGFR” is an antibody that can bind to EGFR with sufficient affinity, and as a result, when the antibody targets EGFR, the diagnostic agent And / or an antibody that is useful as a therapeutic agent, for example cetuximab, panitumumab, Nimotuzumab, Necitumumab, Futuximab, development code; GT-MAB 5.2-GEX (Glycotope ), MM-151 (Merrimack Pharmaceuticals), ABT-806 (Abbott), SCT-200 (Sinocelltech), GC-1118A (Green Cross) and the like.

本発明において、抗Epiregulin抗体と抗EGFR抗体との「併用」とは、抗Epiregulin抗体を含有する製剤と抗EGFR抗体を含有する製剤とが別々に提供され、これらの製剤が、同時に、別々に、または順次に投与されることを意味する。順次に投与されるとは、一方の抗体を含む製剤が、他方を含む製剤の投与前または投与後に投与されることを意味する。この場合には、対象における一方の抗体の残留濃度を測定することにより、その後に投与する他方の抗体の投与時期が最適化され得る。当該濃度は、対象から採取された試料を各種のクロマトグラフィー等の分離装置を用いた当業者において公知の分析方法に基づいて決定され得る。投与量としては、例えば、一回の投与につき体重1 kgあたり0.0001 mgから1000 mgの範囲で投与量が選択できる。あるいは、例えば、患者あたり0.001から100000 mg/bodyの範囲で投与量が選択できる。しかしながら、本発明の医薬組成物はこれらの投与量に制限されるものではない。   In the present invention, “combination” of an anti-Epiregulin antibody and an anti-EGFR antibody means that a preparation containing an anti-Epiregulin antibody and a preparation containing an anti-EGFR antibody are separately provided, and these preparations are simultaneously and separately provided. Or are administered sequentially. Sequentially administered means that the formulation comprising one antibody is administered before or after administration of the formulation comprising the other. In this case, by measuring the residual concentration of one antibody in the subject, the administration timing of the other antibody to be administered thereafter can be optimized. The said density | concentration can be determined based on the analysis method well-known by those skilled in the art using various apparatuses, such as chromatography, about the sample extract | collected from the object. As the dosage, for example, the dosage can be selected in the range of 0.0001 mg to 1000 mg per kg body weight per administration. Alternatively, for example, the dose can be selected within the range of 0.001 to 100,000 mg / body per patient. However, the pharmaceutical composition of the present invention is not limited to these doses.

また抗Epiregulin抗体を含有する製剤と抗EGFR抗体を含有する製剤の剤型は、同じ剤型であっても異なる剤型であってもよい。例えば、双方が経口剤、非経口製剤、注射剤、点滴剤、静脈内点滴剤のうちの一つであって互いに異なる剤型であってもよく、双方が経口剤、非経口製剤、注射剤、点滴剤、静脈内点滴剤のうちの一つであって同種の剤型であってもよい。また、上記の医薬組成物には、さらに異なる一種以上の製剤を組み合わせてもよい。
本発明による併用医薬は、他の化学療法、例えばFOLFIRIやFOLFOXとともに用いることができる。この場合、化学療法剤は、抗Epiregulin抗体又は抗EGFR抗体と同時に、あるいは投与前または投与後に投与されることが出来る。 The dosage form of the preparation containing the anti-Epiregulin antibody and the preparation containing the anti-EGFR antibody may be the same dosage form or different dosage forms. For example, both are oral preparations, parenteral preparations, injections, infusions, intravenous infusions and may be in different dosage forms, both of which are oral preparations, parenteral preparations, injections , One of a drop and an intravenous drop and the same type of dosage form. Moreover, you may combine 1 or more types of different formulation with said pharmaceutical composition.
The combination medicament according to the present invention can be used together with other chemotherapy such as FOLFIRI and FOLFOX. In this case, the chemotherapeutic agent can be administered simultaneously with the anti-Epiregulin antibody or the anti-EGFR antibody, or before or after the administration.

本発明において、「癌」には、例えば、大腸癌、肺腺癌、膵癌、胃癌、腎癌が含まれ、大腸癌には低分化大腸癌、中分化大腸癌、高分化大腸癌が含まれる。   In the present invention, “cancer” includes, for example, colorectal cancer, lung adenocarcinoma, pancreatic cancer, gastric cancer, and renal cancer. Colorectal cancer includes poorly differentiated colorectal cancer, moderately differentiated colorectal cancer, and well differentiated colorectal cancer. .

別の観点においては、本発明は、抗Epiregulin抗体と抗EGFR抗体とを有効成分として含む、癌を治療または癌の再発もしくは転移を抑制するための医薬組成物に関する。本発明の医薬組成物は、抗Epiregulin抗体および抗EGFR抗体が同一医薬組成物中に共に含有される形、すなわち抗Epiregulin抗体と抗EGFR抗体との配合剤の形で提供することができる。   In another aspect, the present invention relates to a pharmaceutical composition for treating cancer or suppressing cancer recurrence or metastasis, comprising an anti-Epiregulin antibody and an anti-EGFR antibody as active ingredients. The pharmaceutical composition of the present invention can be provided in a form in which the anti-Epiregulin antibody and the anti-EGFR antibody are both contained in the same pharmaceutical composition, that is, in the form of a combination of an anti-Epiregulin antibody and an anti-EGFR antibody.

別の観点においては、本発明は、対象に有効量の抗Epiregulin抗体を投与する工程を含む、抗EGFR抗体による癌の治療または癌の再発もしくは転移の抑制の効果（あるいは抗EGFR抗体の抗腫瘍効果または細胞増殖阻害効果）を増幅させる（増強する）方法に関する。また別の観点においては、本発明は、対象に有効量の抗EGFR抗体を投与する工程を含む、抗Epiregulin抗体による癌の治療または癌の再発もしくは転移の抑制の効果（あるいは抗Epiregulin抗体の抗腫瘍効果または細胞増殖阻害効果）を増幅させる（増強する）方法に関する。
抗EGFR抗体（抗Epiregulin抗体）による癌の治療ならびに癌の再発および転移の抑制の効果、ならびに当該抗体の抗腫瘍効果および細胞増殖阻害効果は、当業者に公知の様々な方法による評価することができ、例えば本明細書の実施例１や３に記載された方法によって評価することができる。 In another aspect, the present invention includes the step of administering an effective amount of an anti-Epiregulin antibody to a subject, the effect of treating cancer or suppressing cancer recurrence or metastasis with an anti-EGFR antibody (or anti-EGFR antibody antitumor) The present invention relates to a method for amplifying (enhancing) an effect or a cell growth inhibitory effect. In another aspect, the present invention includes a step of administering an effective amount of an anti-EGFR antibody to a subject, the effect of treating cancer or suppressing cancer recurrence or metastasis with an anti-Epiregulin antibody (or anti-Epiregulin antibody anti-Epiregulin antibody). The present invention relates to a method for amplifying (enhancing tumor effect or cell growth inhibitory effect).
Treatment of cancer with an anti-EGFR antibody (anti-Epiregulin antibody) and the effect of suppressing cancer recurrence and metastasis, and the antitumor effect and cell growth inhibitory effect of the antibody can be evaluated by various methods known to those skilled in the art. For example, it can be evaluated by the method described in Examples 1 and 3 of this specification.

ある剤（例えば、薬学的製剤）の「有効量」は、所望の治療的または予防的結果を達成するために有効である、必要な用量におけるおよび必要な期間にわたっての、量のことをいう。   An “effective amount” of an agent (eg, a pharmaceutical formulation) refers to that amount at the required dose and over the required period of time that is effective to achieve the desired therapeutic or prophylactic result.

好ましくは、本発明を用いた癌の治療、または癌の再発もしくは転移の抑制は、Epiregulinを高発現している対象に対して行うことができる。Epiregulinを高発現しているとは、対象におけるEpiregulinの発現量が、他の対象群の平均よりも高いことを意味する。したがって、この観点では、本発明は、抗Epiregulin抗体を有効成分として含む、抗EGFR抗体と併用して、Epiregulinを高発現している対象の癌を治療する、または癌の再発もしくは転移を抑制するための医薬組成物に関する。また、本発明は、抗Epiregulin抗体と抗EGFR抗体とを有効成分として含む、Epiregulinを高発現している対象の癌を治療または癌の再発もしくは転移を抑制するための医薬組成物に関する。また、本発明は、Epiregulinを高発現している対象に有効量の抗Epiregulin抗体を投与する工程を含む、抗EGFR抗体による癌の治療または癌の再発もしくは転移の抑制の効果（あるいは抗EGFR抗体の抗腫瘍効果または細胞増殖阻害効果）を増幅させる（増強する）方法に関する。また、本発明は、対象におけるEpiregulinの発現を測定する工程と、当該測定結果にもとづきEpiregulinを高発現している対象を選定する工程と、選定された対象に前記抗Epiregulin抗体を投与する工程とを含む、抗EGFR抗体による癌の治療または癌の再発もしくは転移の抑制の効果（あるいは抗EGFR抗体の抗腫瘍効果または細胞増殖阻害効果）を増幅させる（増強する）方法に関する。   Preferably, cancer treatment or suppression of cancer recurrence or metastasis using the present invention can be performed on a subject that highly expresses Epiregulin. High expression of Epiregulin means that the expression level of Epiregulin in a subject is higher than the average of other subject groups. Therefore, in this aspect, the present invention treats cancer of a subject highly expressing Epiregulin, or suppresses recurrence or metastasis of cancer, in combination with an anti-EGFR antibody, which contains an anti-Epiregulin antibody as an active ingredient. The present invention relates to a pharmaceutical composition. The present invention also relates to a pharmaceutical composition for treating cancer of a subject that highly expresses Epiregulin or suppressing recurrence or metastasis of cancer, comprising an anti-Epiregulin antibody and an anti-EGFR antibody as active ingredients. The present invention also includes a step of administering an effective amount of an anti-Epiregulin antibody to a subject that highly expresses Epiregulin, or an effect of treating cancer with anti-EGFR antibody or suppressing cancer recurrence or metastasis (or anti-EGFR antibody). The method of amplifying (enhancing) the antitumor effect or cell growth inhibitory effect of The present invention also includes a step of measuring the expression of Epiregulin in a subject, a step of selecting a subject highly expressing Epiregulin based on the measurement result, and a step of administering the anti-Epiregulin antibody to the selected subject. And a method of amplifying (enhancing) an effect of suppressing cancer recurrence or metastasis (or antitumor effect or cell growth inhibitory effect of anti-EGFR antibody) with anti-EGFR antibody.

また別の観点においては、本発明は、（１）抗Epiregulin抗体を含有する製剤、（２）容器、および（３）癌を治療または癌の再発もしくは転移を抑制するために前記抗Epiregulin抗体と少なくとも一種の抗EGFR抗体とを組み合わせて対象に投与することを示す指示書又はラベル、を含む製品に関する。「指示書」は、医薬品の使用に関する適応症、使用法、用量、投与、禁忌および／または警告についての情報を含み得る、医薬品の市販の箱の中に通常入っている指示書を指し、添付文書が含まれる。また「製品」にはキットが含まれる。   In another aspect, the present invention relates to (1) a preparation containing an anti-Epiregulin antibody, (2) a container, and (3) the anti-Epiregulin antibody to treat cancer or suppress recurrence or metastasis of cancer. The present invention relates to a product comprising an instruction or label indicating that it is administered to a subject in combination with at least one anti-EGFR antibody. “Instructions” refers to instructions usually contained in a commercial box of pharmaceuticals, which may include information on indications, usage, dosage, administration, contraindications and / or warnings regarding the use of the pharmaceutical Document is included. The “product” includes a kit.

（実施例1）抗Epiregulin抗体および抗EGFR抗体による細胞増殖抑制
ヒト大腸癌KRAS野生型培養細胞株であるLIM1215（DSファーマ）を用いて、Epiregulinによる増殖、また抗Epiregulin抗体（重鎖は、可変領域全長：配列番号1、CDR1：配列番号2、CDR2：配列番号3、CDR3：配列番号4、定常領域：配列番号5；軽鎖は、可変領域全長：配列番号6、CDR1：配列番号7、CDR2：配列番号8、CDR3：配列番号9、定常領域：配列番号10）や抗EGFR抗体(セツキシマブまたはパニツムマブ)による細胞増殖抑制活性を検討した。
LIM1215細胞は、10%FBS、0.6 μg/mLインスリン、1 μg/mLコルチゾール、10 μM 1-チオグリセロールを含むRPMI1640培地（以下、継代用培地という。）中で継代維持した。LIM1215細胞を96ウェルプレートに播種し、各抗体 (抗Epiregulin抗体、抗EGFR抗体：セツキシマブまたはパニツムマブ)を66 nMとなるように単剤、あるいは抗Epiregulin抗体と抗EGFR抗体との両剤を組み合わせて処理し、ヒトリコンビナントEpiregulin (R&D systems社, Cat. NO. 1195-EP-025/CF) を、0、1、100 ng/mLの濃度で用いて処理した。その後IncuCyte Zoom SystemTMにて、4時間毎の各wellの細胞の培養密度をモニターする事により、継時的増殖活性を検討した。図1、図2に示すとおり、LIM1215細胞増殖は、Epiregulin濃度が0の場合は抗EGFR抗体単剤による細胞増殖抑制活性が認められた。一方、高濃度ヒトリコンビナントEpiregulin (100 ng/mL)存在下では、図1、図2に示すとおり、セツキシマブまたはパニツムマブのような抗EGFR抗体単剤による細胞増殖抑制活性は、Epiregulin濃度が0の場合と比べて減弱された。抗Epiregulin抗体と抗EGFR抗体を組み合わせて処理した場合は、ヒトリコンビナントEpiregulinの濃度に関わらず細胞増殖阻害を維持していた。実際、72時間後の細胞培養密度を比較すると、高濃度ヒトリコンビナントEpiregulin (100 ng/mL)条件においても、抗Epiregulin抗体を併用することでセツキシマブやパニツムマブの細胞増殖抑制活性を維持していた（図３）。 (Example 1) Inhibition of cell growth by anti-Epiregulin antibody and anti-EGFR antibody Using human colon cancer KRAS wild-type cell line LIM1215 (DS Pharma), growth by Epiregulin, anti-Epiregulin antibody (heavy chain is variable) Region full length: SEQ ID NO: 1, CDR1: SEQ ID NO: 2, CDR2: SEQ ID NO: 3, CDR3: SEQ ID NO: 4, constant region: SEQ ID NO: 5; light chain is variable region full length: SEQ ID NO: 6, CDR1: SEQ ID NO: 7, CDR2: SEQ ID NO: 8, CDR3: SEQ ID NO: 9, constant region: SEQ ID NO: 10) and cell growth inhibitory activity by anti-EGFR antibody (cetuximab or panitumumab) were examined.
LIM1215 cells were maintained in passage in RPMI1640 medium (hereinafter referred to as passage medium) containing 10% FBS, 0.6 μg / mL insulin, 1 μg / mL cortisol, 10 μM 1-thioglycerol. LIM1215 cells are seeded in a 96-well plate, and each antibody (anti-Epiregulin antibody, anti-EGFR antibody: cetuximab or panitumumab) is treated to 66 nM as a single agent or a combination of both anti-Epiregulin antibody and anti-EGFR antibody. Then, human recombinant Epiregulin (R & D systems, Cat. NO. 1195-EP-025 / CF) was used at concentrations of 0, 1, and 100 ng / mL. Subsequently, the growth activity over time was examined by monitoring the culture density of cells in each well every 4 hours using IncuCyte Zoom System ™ . As shown in FIG. 1 and FIG. 2, LIM1215 cell proliferation was observed to have cell growth inhibitory activity with a single anti-EGFR antibody when the Epiregulin concentration was 0. On the other hand, in the presence of high concentration human recombinant Epiregulin (100 ng / mL), as shown in Fig. 1 and Fig. 2, the cell growth inhibitory activity of anti-EGFR antibody alone, such as cetuximab or panitumumab, is shown when Epiregulin concentration is 0. It was attenuated compared to When combined with anti-Epiregulin antibody and anti-EGFR antibody, cell growth inhibition was maintained regardless of the concentration of human recombinant Epiregulin. In fact, when cell culture density after 72 hours was compared, cell growth inhibitory activity of cetuximab and panitumumab was maintained by using an anti-Epiregulin antibody in combination with high concentration human recombinant Epiregulin (100 ng / mL) ( FIG. 3).

一方、ヒト大腸癌KRAS野生型培養細胞株であるCCK-81細胞（JCRB）を用いて、ヒトリコンビナントEpiregulinによる増殖、また抗Epiregulin抗体や抗EGFR抗体による細胞増殖阻害活性を検討した。
CCK-81細胞は、10% FBSを含むEMEM培地（以下、継代用培地という。）中で継代維持した。CCK-81細胞を96ウェルプレートに播種し、各抗体 (LIM1215細胞を処置したのと同じ抗Epiregulin抗体、抗EGFR抗体：セツキシマブまたはパニツムマブ)を66 nMとなるように単剤、あるいは抗Epiregulin抗体と抗EGFR抗体との両剤を組み合わせて処理し、ヒトリコンビナントEpiregulin (R&D systems社, Cat. NO. 1195-EP-025/CF) を0、1、100 ng/mLの濃度で用いて処理した。細胞は37℃、5% CO２インキュベータにて1% FBSを含むEMEM培地中で6日間培養された。培養後Cell Counting（同仁化学）の測定試薬を添加し、1時間発色を行い、マイクロプレートリーダーにより460 nmでの反応液の吸光度を測定することで細胞数を測定した。
図４に示した通り、ヒトリコンビナントEpiregulin 100 ng/mL処理時のCCK-81細胞において、抗Epiregulin抗体やセツキシマブ単剤に比べ、両剤を組み合わせて処理した場合に強い細胞増殖の阻害活性が認められた。 On the other hand, using CCK-81 cells (JCRB), a human colon cancer KRAS wild-type cultured cell line, proliferation by human recombinant Epiregulin and cell growth inhibitory activity by anti-Epiregulin antibody or anti-EGFR antibody were examined.
CCK-81 cells were passaged and maintained in EMEM medium (hereinafter referred to as passage medium) containing 10% FBS. CCK-81 cells are seeded in a 96-well plate, and each antibody (same anti-Epiregulin antibody treated with LIM1215 cells, anti-EGFR antibody: cetuximab or panitumumab) is 66 nM alone or with anti-Epiregulin antibody The anti-EGFR antibody and both agents were treated in combination and treated with human recombinant Epiregulin (R & D systems, Cat. NO. 1195-EP-025 / CF) at concentrations of 0, 1, and 100 ng / mL. The cells were cultured for 6 days in EMEM medium containing 1% FBS in a 37 ° C., 5% CO 2 incubator. After incubation, a Cell Counting (Dojin Chemical) measurement reagent was added, color was developed for 1 hour, and the number of cells was measured by measuring the absorbance of the reaction solution at 460 nm with a microplate reader.
As shown in FIG. 4, in CCK-81 cells treated with human recombinant Epiregulin 100 ng / mL, compared to anti-Epiregulin antibody and cetuximab alone, a strong cell growth inhibitory activity was observed when both were combined. It was.

（実施例2）抗Epiregulin抗体および抗EGFR抗体によるHERファミリー受容体のリン酸化と下流シグナル因子のリン酸化抑制
ヒト大腸癌KRAS野生型培養細胞株であるLIM1215を用いて、抗Epiregulin抗体や抗EGFR抗体(セツキシマブまたはパニツムマブ)による、HERファミリー受容体のリン酸化と下流シグナル因子のリン酸化阻害活性を検討した。
LIM1215細胞を6ウェルプレートに播種し、各抗体 (実施例１と同じ抗Epiregulin抗体、抗EGFR抗体：セツキシマブ、パニツムマブ)を66 nMとなるように単剤、あるいは抗Epiregulin抗体と抗EGFR抗体との両剤を組み合わせて処理し、ヒトリコンビナントEpiregulin (R&D systems社, Cat. NO. 1195-EP-025/CF) を100 ng/mLの濃度で処理した。10分後に細胞を溶解し、ウエスタンブロッティング法を用いて、EGFR、HER2、HER3、ERK、AKTのリン酸化を評価した。ウエスタンブロッティングでは、NuPAGE 4-12% Bis-Tris Gel（サーモサイエンティフィック）を用いて泳動を行い、Trans-Turboトランスファーシステム(バイオラッド)を用いてニトロセルロース膜に転写した。転写されたニトロセルロース膜は、抗リン酸化EGFR抗体（CST: #2234）、抗EGFR抗体（サンタクルズ: sc-03）、抗リン酸化HER2抗体（CST: #6942）、抗HER2抗体（サンタクルズ: sc-284）、抗リン酸化HER3抗体（CST: 4791）、抗HER3抗体（サンタクルズ: sc-285）、抗リン酸化ERK抗体（CST: #4370）、抗ERK抗体（CST: #9102）、抗リン酸化AKT抗体（CST: #9271）、抗AKT抗体（CST: #9272）、抗GAPDH抗体（CST: #5174）と反応させた。ニトロセルロース上のバンドは、HRP標識した抗体（CST）を添加し洗浄した後、ECL（GEヘルスケア）またはECL Prime（GEヘルスケア）で発光後、ImageQuant LAS 4000（GEヘルスケア）を用いて検出した。
図５で示された通り、ヒトリコンビナントEpiregulinによって刺激されたリン酸化HERファミリー受容体EGFR、HER2、HER3とその下流シグナルにあるリン酸化ERKとAKTは、抗EGFR抗体単剤の処理では、リン酸化状態が観察できていたのに対し、抗Epiregulin抗体を併用することで、これらのリン酸化が阻害されることを確認した。 (Example 2) Phosphorylation of HER family receptor and inhibition of phosphorylation of downstream signal factor by anti-Epiregulin antibody and anti-EGFR antibody Using human colon cancer KRAS wild-type cell line LIM1215, anti-Epiregulin antibody and anti-EGFR We examined the phosphorylation of HER family receptors and phosphorylation of downstream signaling factors by antibodies (cetuximab or panitumumab).
LIM1215 cells are seeded in a 6-well plate, and each antibody (the same anti-Epiregulin antibody, anti-EGFR antibody: cetuximab, panitumumab as in Example 1) is adjusted to 66 nM, or a single agent or anti-Epiregulin antibody and anti-EGFR antibody. Both drugs were treated in combination, and human recombinant Epiregulin (R & D systems, Cat. NO. 1195-EP-025 / CF) was treated at a concentration of 100 ng / mL. Cells were lysed 10 minutes later, and phosphorylation of EGFR, HER2, HER3, ERK, and AKT was evaluated using Western blotting. In Western blotting, electrophoresis was performed using NuPAGE 4-12% Bis-Tris Gel (Thermo Scientific), and transferred to a nitrocellulose membrane using a Trans-Turbo transfer system (BioRad). The transferred nitrocellulose membrane is composed of anti-phosphorylated EGFR antibody (CST: # 2234), anti-EGFR antibody (Santa Cruz: sc-03), anti-phosphorylated HER2 antibody (CST: # 6942), anti-HER2 antibody (Santa Cruz: sc -284), anti-phosphorylated HER3 antibody (CST: 4791), anti-HER3 antibody (Santa Cruz: sc-285), anti-phosphorylated ERK antibody (CST: # 4370), anti-ERK antibody (CST: # 9102), anti-phosphorus This was reacted with oxidized AKT antibody (CST: # 9271), anti-AKT antibody (CST: # 9272), and anti-GAPDH antibody (CST: # 5174). The band on the nitrocellulose is washed with the addition of HRP-labeled antibody (CST), then luminescence with ECL (GE Healthcare) or ECL Prime (GE Healthcare), and then using ImageQuant LAS 4000 (GE Healthcare) Detected.
As shown in FIG. 5, phosphorylated HER family receptors EGFR, HER2, and HER3 stimulated by human recombinant Epiregulin and phosphorylated ERK and AKT in the downstream signal are phosphorylated by treatment with anti-EGFR antibody alone. While the condition could be observed, it was confirmed that these phosphorylations were inhibited by using an anti-Epiregulin antibody together.

（実施例3）in vivoモデルを用いた抗Epiregulin抗体と抗EGFR抗体の併用による薬効試験
ヒト患者由来腫瘍がオスのヌードマウスの皮下に移植された腫瘍モデルを用いて、in vivoでの抗腫瘍活性を評価した。評価されたCXF 2172およびCXF 2067ヒト大腸癌患者由来腫瘍モデルにおいて、実施例1と同じ抗Epiregulin抗体25 mg/kg、抗EGFR抗体セツキシマブを30 mg/kgでそれぞれ単剤または組み合わせて処理し、腫瘍体積を測定することで抗腫瘍活性を測定した。CXF 2172ヒト大腸癌患者由来腫瘍モデルには、無作為割付した翌日からセツキシマブを2週間に1回腹腔内に投与し、抗Epiregulin抗体を1週間に1回尾静脈に投与した。CXF 2067ヒト大腸癌由来腫瘍モデルには、セツキシマブと抗Epiregulin抗体を無作為割付した翌日に1度だけ投与した。腫瘍体積は週に2回ノギスを用いて腫瘍の長径と短径を測定し、腫瘍体積を以下の式のとおり算出した。
[腫瘍体積 (mm3) = 長径 (mm) x 短径 (mm)x 短径 (mm) x 0.5]

図６に示したとおり、セツキシマブと抗Epiregulin抗体の組み合わせによる投与は、2つのヒト大腸癌患者由来腫瘍モデルにおいて、それぞれの単剤に比べて腫瘍増殖を抑制している。その効果は、図７で示されるように、投与開始時の腫瘍体積を100%としたときの各個体の相対腫瘍体積変化率は、セツキシマブ投与群において、腫瘍が増大する傾向があるのに対して、セツキシマブと抗Epiregulin抗体の組み合わせ投与群は、過半数の個体で腫瘍消失が認められるほどの強い活性を示した。また、投与開始時の腫瘍体積に対して2倍の腫瘍体積になった日を腫瘍増日と定義し、Kaplan-Meierプロットで示した（図８）。その結果、2つのヒト大腸癌患者由来腫瘍モデルにおいて、セツキシマブ単剤に比べて、セツキシマブと抗Epiregulin抗体を組み合わせにより投与することで、腫瘍が増悪するまでの日数が大幅に延長した。 (Example 3) Drug efficacy test using anti-Epiregulin antibody and anti-EGFR antibody in combination using in vivo model In vivo antitumor using a tumor model in which a tumor derived from a human patient was implanted subcutaneously in a male nude mouse Activity was evaluated. In the tumor models derived from CXF 2172 and CXF 2067 human colorectal cancer patients evaluated, the same anti-Epiregulin antibody 25 mg / kg and anti-EGFR antibody cetuximab as in Example 1 were each treated with a single agent or a combination at 30 mg / kg, and the tumor Antitumor activity was measured by measuring the volume. In the CXF 2172 human colorectal cancer patient-derived tumor model, cetuximab was intraperitoneally administered once every two weeks and the anti-Epiregulin antibody was administered once a week into the tail vein from the next day after random allocation. CXF 2067 human colon cancer-derived tumor model was administered cetuximab and anti-Epiregulin antibody only once the day after random allocation. The tumor volume was determined by measuring the major axis and minor axis of the tumor with a caliper twice a week, and calculating the tumor volume as follows.
[Tumor volume (mm 3 ) = major axis (mm) x minor axis (mm) x minor axis (mm) x 0.5]

As shown in FIG. 6, administration with a combination of cetuximab and anti-Epiregulin antibody suppressed tumor growth in two human colorectal cancer patient-derived tumor models compared to each single agent. As shown in FIG. 7, the effect of the relative tumor volume change rate of each individual when the tumor volume at the start of administration is taken as 100% is that the tumor tends to increase in the cetuximab administration group. The combination administration group of cetuximab and anti-Epiregulin antibody showed such a strong activity that tumor disappearance was observed in the majority of individuals. Moreover, the day when the tumor volume was doubled relative to the tumor volume at the start of administration was defined as the tumor increase day, and was shown in the Kaplan-Meier plot (FIG. 8). As a result, in the two human colorectal cancer patient-derived tumor models, the combination of cetuximab and anti-Epiregulin antibody combined with cetuximab alone increased the number of days until tumor progression.

抗Epiregulin抗体と抗EGFR抗体を有効成分とする本発明の併用医薬は、抗Epiregulin抗体または抗EGFR抗体を有効成分とする従来の医薬と比べて、癌の治療または予防において相乗的な効果を有する。   The combined medicament of the present invention comprising an anti-Epiregulin antibody and an anti-EGFR antibody as active ingredients has a synergistic effect in the treatment or prevention of cancer compared with conventional medicines comprising an anti-Epiregulin antibody or an anti-EGFR antibody as active ingredients .

Claims (15)

抗Epiregulin抗体を有効成分として含む、抗EGFR抗体と併用して癌を治療する、または癌の再発もしくは転移を抑制するための医薬組成物。   A pharmaceutical composition comprising an anti-Epiregulin antibody as an active ingredient for treating cancer in combination with an anti-EGFR antibody, or suppressing cancer recurrence or metastasis. 前記抗Epiregulin抗体が、前記抗EGFR抗体と同時に投与される、請求項１に記載の医薬組成物。   The pharmaceutical composition according to claim 1, wherein the anti-Epiregulin antibody is administered simultaneously with the anti-EGFR antibody. 前記抗Epiregulin抗体が、前記抗EGFR抗体の投与前又は投与後に投与される、請求項１に記載の医薬組成物。   The pharmaceutical composition according to claim 1, wherein the anti-Epiregulin antibody is administered before or after administration of the anti-EGFR antibody. 抗Epiregulin抗体と抗EGFR抗体とを有効成分として含む、癌を治療する、または癌の再発もしくは転移を抑制するための医薬組成物。   A pharmaceutical composition for treating cancer or inhibiting cancer recurrence or metastasis, comprising an anti-Epiregulin antibody and an anti-EGFR antibody as active ingredients. 抗Epiregulin抗体と抗EGFR抗体との配合剤である、請求項４に記載の医薬組成物。   The pharmaceutical composition according to claim 4, which is a combination agent of an anti-Epiregulin antibody and an anti-EGFR antibody. 前記抗Epiregulin抗体が、配列番号：２に記載のCDR1、配列番号：３に記載のCDR2、配列番号：４に記載のCDR3を有する重鎖可変領域、および配列番号：７に記載のCDR1、配列番号：８に記載のCDR2、配列番号：９に記載のCDR3を有する軽鎖可変領域を含む抗体である、請求項１〜５のいずれかに記載の医薬組成物。   The anti-Epiregulin antibody comprises a heavy chain variable region having CDR1 as shown in SEQ ID NO: 2, CDR2 as shown in SEQ ID NO: 3, CDR3 as shown in SEQ ID NO: 4, and CDR1 as shown in SEQ ID NO: 7. The pharmaceutical composition according to any one of claims 1 to 5, which is an antibody comprising a light chain variable region having CDR2 of No. 8 and CDR3 of SEQ ID NO: 9. 前記抗Epiregulin抗体が、配列番号：１に記載の重鎖可変領域、配列番号：６に記載の軽鎖可変領域、配列番号：５に記載の重鎖定常領域、および配列番号：１０に記載の軽鎖定常領域を含む抗体である、請求項１〜５に記載の医薬組成物。   The anti-Epiregulin antibody comprises a heavy chain variable region set forth in SEQ ID NO: 1, a light chain variable region set forth in SEQ ID NO: 6, a heavy chain constant region set forth in SEQ ID NO: 5, and a sequence set forth in SEQ ID NO: 10. The pharmaceutical composition according to claim 1, which is an antibody comprising a light chain constant region. 前記抗EGFR抗体がセツキシマブまたはパニツムマブである、請求項７に記載の医薬組成物。   The pharmaceutical composition according to claim 7, wherein the anti-EGFR antibody is cetuximab or panitumumab. 癌が大腸癌である、請求項１〜８のいずれかに記載の医薬組成物。   The pharmaceutical composition according to any one of claims 1 to 8, wherein the cancer is colorectal cancer. 対象に有効量の抗Epiregulin抗体を投与する工程を含む、抗EGFR抗体による癌の治療または癌の再発もしくは転移の抑制の効果を増幅させる方法。   A method of amplifying the effect of cancer treatment or suppression of cancer recurrence or metastasis with an anti-EGFR antibody, comprising a step of administering an effective amount of an anti-Epiregulin antibody to a subject. 前記抗Epiregulin抗体を、前記抗EGFR抗体と同時に投与する、請求項１０に記載の方法。   The method according to claim 10, wherein the anti-Epiregulin antibody is administered simultaneously with the anti-EGFR antibody. 前記抗Epiregulin抗体を、前記抗EGFR抗体の投与前又は投与後に投与する、請求項１０に記載の方法。   The method according to claim 10, wherein the anti-Epiregulin antibody is administered before or after administration of the anti-EGFR antibody. 対象におけるEpiregulinの発現を測定する工程と、当該測定結果にもとづき対象に前記抗Epiregulin抗体を投与する工程とを含む、請求項１０に記載の方法。   The method according to claim 10, comprising a step of measuring the expression of Epiregulin in a subject, and a step of administering the anti-Epiregulin antibody to the subject based on the measurement result. （１）抗Epiregulin抗体を含有する製剤、（２）容器、および（３）癌を治療し、または癌の再発もしくは転移を抑制するために前記抗Epiregulin抗体と少なくとも一種の抗EGFR抗体とを組み合わせて対象に投与することを示す指示書又はラベル、を含む製品。   (1) a preparation containing an anti-Epiregulin antibody, (2) a container, and (3) a combination of the anti-Epiregulin antibody and at least one anti-EGFR antibody in order to treat cancer or suppress recurrence or metastasis of cancer Product containing instructions or labels indicating that it is administered to the subject. 前記抗Epiregulin抗体が、配列番号：２に記載のCDR1、配列番号：３に記載のCDR2、配列番号：４に記載のCDR3を有する重鎖可変領域、および配列番号：７に記載のCDR1、配列番号：８に記載のCDR2、配列番号：９に記載のCDR3を有する軽鎖可変領域を含む抗体である、請求項１４に記載の製品。   The anti-Epiregulin antibody comprises a heavy chain variable region having CDR1 as shown in SEQ ID NO: 2, CDR2 as shown in SEQ ID NO: 3, CDR3 as shown in SEQ ID NO: 4, and CDR1 as shown in SEQ ID NO: 7. The product according to claim 14, which is an antibody comprising a light chain variable region having CDR2 of SEQ ID NO: 8 and CDR3 of SEQ ID NO: 9.
JP2016159983A 2016-08-17 2016-08-17 Combination drug of anti-Epiregulin antibody and anti-EGFR antibody Pending JP2019202936A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2016159983A JP2019202936A (en) 2016-08-17 2016-08-17 Combination drug of anti-Epiregulin antibody and anti-EGFR antibody
PCT/JP2017/029425 WO2018034301A1 (en) 2016-08-17 2017-08-16 Combination drug of anti-epiregulin antibody and anti-egfr antibody

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2016159983A JP2019202936A (en) 2016-08-17 2016-08-17 Combination drug of anti-Epiregulin antibody and anti-EGFR antibody

Publications (1)

Publication Number Publication Date
JP2019202936A true JP2019202936A (en) 2019-11-28

Family

ID=61196824

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2016159983A Pending JP2019202936A (en) 2016-08-17 2016-08-17 Combination drug of anti-Epiregulin antibody and anti-EGFR antibody

Country Status (2)

Country Link
JP (1) JP2019202936A (en)
WO (1) WO2018034301A1 (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2436397B1 (en) * 2009-05-29 2017-05-10 Chugai Seiyaku Kabushiki Kaisha Pharmaceutical composition containing antagonist of egf family ligand as component
TWI593705B (en) * 2011-12-28 2017-08-01 Chugai Pharmaceutical Co Ltd Humanized anti-epiregulin antibody and cancer therapeutic agent containing the antibody as an active ingredient
SG11201507739TA (en) * 2013-03-19 2015-10-29 Toppan Printing Co Ltd Method for predicting sensitivity to egfr inhibitor
CA2931176A1 (en) * 2013-11-26 2015-06-04 Integragen A method for predicting responsiveness to a treatment with an egfr inhibitor

Also Published As

Publication number Publication date
WO2018034301A1 (en) 2018-02-22

Similar Documents

Publication Publication Date Title
Li et al. HER2-mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers
Huang et al. The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells
CN102858335B (en) Use of ERBB3 inhibitors in the treatment of triple negative and basal-like breast cancers
ES2611337T3 (en) Use of anti-VEGF antibody in combination with chemotherapy to treat breast cancer
KR20230023810A (en) Combination of a pd-1 antagonist and a vegfr inhibitor for treating cancer
EP3191523B1 (en) Compositions and methods for treating cancer resistant to a tyrosine kinase inhibitor (tki)
US9822170B2 (en) Co-use of a clusterin inhibitor with an EGFR inhibitor to treat cancer
Gandullo‐Sánchez et al. HER3 targeting with an antibody‐drug conjugate bypasses resistance to anti‐HER2 therapies
Gvozdenovic et al. A bispecific antibody targeting IGF-IR and EGFR has tumor and metastasis suppressive activity in an orthotopic xenograft osteosarcoma mouse model
EP2710038B1 (en) COMBINATIONS OF ANTI ErbB ANTIBODIES FOR THE TREATMENT OF CANCER
RU2576027C2 (en) Anti-angiogenesis therapy for treating previously treated breast cancer
US20220195059A1 (en) Rank Pathway Inhibitors in Combination with CDK Inhibitors
EP3176183A1 (en) Compositions and methods for treating cancer not resistant to a tyrosine kinase inhibitor (tki)
WO2018034301A1 (en) Combination drug of anti-epiregulin antibody and anti-egfr antibody
US20140056910A1 (en) Therapeutic agent for cancer having reduced sensitivity to molecular target drug and pharmaceutical composition for enhancing sensitivity to molecular target drug
Kotowski et al. Emerging therapies in pancreas cancer
Cao et al. A ligand-based and enediyne-energized bispecific fusion protein targeting epidermal growth factor receptor and insulin-like growth factor-1 receptor shows potent antitumor efficacy against esophageal cancer
CA3097750A1 (en) Treating solid tumors with bromodomain inhibitors
WO2022270523A1 (en) Medicament for treatment and/or prevention of cancer
US20180208674A1 (en) Combinations of epidermal growth factor receptor targeting antibodies for treating cancer
KR102662228B1 (en) Combination of PD-1 antagonists and VEGFR/FGFR/RET tyrosine kinase inhibitors to treat cancer
WO2012172555A1 (en) Combination therapy to prevent dcis formation and progression to breast cancer