JP2022043372A - Dual inhibition therapy of vegf-a/vegfr2 pathway and pharmaceutical composition used therefor - Google Patents

Dual inhibition therapy of vegf-a/vegfr2 pathway and pharmaceutical composition used therefor Download PDF

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JP2022043372A
JP2022043372A JP2018247198A JP2018247198A JP2022043372A JP 2022043372 A JP2022043372 A JP 2022043372A JP 2018247198 A JP2018247198 A JP 2018247198A JP 2018247198 A JP2018247198 A JP 2018247198A JP 2022043372 A JP2022043372 A JP 2022043372A
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哲夫 馬島
Tetsuo Majima
尊 若槻
Takeru WAKATSUKI
啓之 清宮
Hiroyuki Kiyomiya
研成 山口
Kensei YAMAGUCHI
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Abstract

To provide a drug to be used in combination with an anti-VEGFR2 antibody drug, and a therapeutic method.SOLUTION: Administering an anti-VEGF antibody drug together with an anti-VEGFR2 antibody drug as a combination drug is effective even for tumors to which the anti-VEGFR2 antibody alone is not effective.SELECTED DRAWING: None

Description

本発明は抗ＶＥＧＦＲ２（ｖａｓｃｕｌａｒ ｅｎｄｏｔｈｅｌｉａｌ ｇｒｏｗｔｈ ｆａｃｔｏｒ ｒｅｃｅｐｔｏｒ ２、血管内皮増殖因子受容体２）抗体と、抗ＶＥＧＦ－Ａ（ｖａｓｃｕｌａｒ ｅｎｄｏｔｈｅｌｉａｌ ｇｒｏｗｔｈ ｆａｃｔｏｒ－Ａ、血管内皮増殖因子）中和抗体を併用する新しい治療方法に関する。 The present invention is a novel method using anti-VEGFR2 (vascular endothelial growth factor 2, vascular endothelial growth factor receptor 2) antibody and anti-VEGF-A (vascular endothelial growth factor-A, vascular endothelial growth factor) neutralizing antibody in combination. Regarding.

がんが増殖、転移する際には、増殖能を維持するための栄養補給経路として血管新生と言われる栄養血管の新生が起こる。血管新生は間質および腫瘍細胞より産生される血管内皮細胞増殖因子（ＶＥＧＦ）とその受容体（ＶＥＧＦＲ）が主要な役割を果たしており、血管新生を制御する目的でこれらの分子を標的とする薬剤の開発が広く行われてきた。 When cancer grows and metastasizes, vasa vasorum, which is called angiogenesis, occurs as a feeding route to maintain the ability to grow. Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFR), which are produced by stromal and tumor cells, play a major role in angiogenesis, and drugs that target these molecules for the purpose of controlling angiogenesis. Has been widely developed.

ＶＥＧＦの受容体であるＶＥＧＦＲは、受容体型チロシンキナーゼの一種でありＶＥＧＦＲ１からＶＥＧＦＲ３の３種のタンパク質が存在する。特に、ＶＥＧＦＲ２はＶＥＧＦＲ１と比較してリガンドに対する結合能は弱いものの、チロシンキナーゼ活性は強く、総合的に見て細胞内シグナル伝達に対する寄与が大きく、血管新生の過程に大きく関与していると考えられている。ＶＥＧＦＲ２はＶＥＧＦ－Ａ、Ｃ、ＤおよびＥとの結合能を有しており、３種のＶＥＧＦＲのうち、ＶＥＧＦによって誘発される腫瘍血管新生と最も密接に関連しているといわれる受容体である。 VEGFR, which is a receptor for VEGF, is a kind of receptor tyrosine kinase, and there are three kinds of proteins, VEGFR1 to VEGFR3. In particular, VEGFR2 has a weaker binding ability to a ligand than VEGFR1, but has a strong tyrosine kinase activity, and has a large contribution to intracellular signal transduction as a whole, and is considered to be greatly involved in the process of angiogenesis. ing. VEGFR2 has the ability to bind to VEGF-A, C, D and E, and is the receptor that is said to be most closely associated with VEGF-induced tumor angiogenesis among the three VEGFRs. ..

がんの増殖、及び転移に関わる血管新生において重要な作用をするＶＥＧＦＲ２に対する抗体医薬品が開発されつつあり、その代表的な抗体医薬品であるラムシルマブ（Ｒａｍｕｃｉｒｕｍａｂ、商品名「サイラムザ」、イーライ・リリー社製）は、ＶＥＧＦＲ２に対する遺伝子組換えヒト免疫グロブリンＧ１（ＩｇＧ１ｂ）のヒト型モノクローナル抗体である。 An antibody drug against VEGFR2, which plays an important role in angiogenesis related to cancer growth and metastasis, is being developed, and its representative antibody drug, Ramucirumab (trade name "Siramza", manufactured by Eli Lilly and Company) is being developed. ) Is a humanized monoclonal antibody of recombinant human immunoglobulin G1 (IgG1 b ) against VEGFR2.

ラムシルマブはＶＥＧＦＲ２に特異的に結合することによって、リガンドであるＶＥＧＦ－Ａ、ＶＥＧＦ－Ｃ、ＶＥＧＦ－Ｄとの結合を阻害し、ＶＥＧＦＲ２とその下流のシグナル伝達系の活性化を阻害する。その結果、血管内皮細胞の増殖、遊走を阻害し、腫瘍血管の新生を阻害して抗腫瘍効果を発揮する。 By specifically binding to VEGFR2, ramucirumab inhibits binding to the ligands VEGF-A, VEGF-C, VEGF-D and inhibits activation of VEGFR2 and its downstream signaling system. As a result, it inhibits the proliferation and migration of vascular endothelial cells, inhibits the formation of tumor blood vessels, and exerts an antitumor effect.

近年、胃がんにおいても血管新生阻害剤の有用性が示され、ラムシルマブは進行胃がんの２次治療に用いられている。根治切除不能な進行胃がん症例に対しては全身化学療法が施行されているが、その予後は平均１年前後と満足できるものではない。ラムシルマブは、進行胃がんの２次治療において全生存期間の有意な延長を認め、２０１５年６月に本邦で胃がんにおける承認が得られ、以降、大腸がん、肺がんにおいても広く用いられている。 In recent years, the usefulness of angiogenesis inhibitors has been shown in gastric cancer, and ramucirumab has been used as a second-line treatment for advanced gastric cancer. Systemic chemotherapy is given to patients with unresectable advanced gastric cancer, but the prognosis is unsatisfactory with an average of around one year. Ramucirumab was found to have a significant prolongation of overall survival in the second-line treatment of advanced gastric cancer, and was approved for gastric cancer in Japan in June 2015, and has been widely used in colorectal cancer and lung cancer since then.

ヒト抗ＶＥＧＦＲ２抗体であるラムシルマブは、胃がん２次治療症例を対象としたＧｌｏｂａｌ第三相試験であるＲＡＩＮＢＯＷ試験において、パクリタキセルとの併用において全生存期間の有意な延長が示され、本邦においても標準治療となっている（ｍＯＳ（ｍｅｄｉａｎ ｏｖｅｒａｌｌ ｓｕｒｖｉｖａｌ、全生存期間中央値）：９．６カ月ｖｓ７．４カ月、ＨＲ（Ｈａｚａｒｄ Ｒａｔｉｏ、ハザード比）０．８１ ９５％ＣＩ０．６８－０．９６、ｐ＝０．０１７）（非特許文献１）。しかしながらその治療効果は十分ではなく、先のＲＡＩＮＢＯＷ試験の日本人におけるサブセット解析では、２次治療におけるラムシルマブ／パクリタキセル併用療法の奏効率は約４０％、生存期間中央値は１１．４カ月前後であった（非特許文献２）。 Ramucirumab, a human anti-VEGFR2 antibody, showed a significant increase in overall survival when used in combination with paclitaxel in the RAINBOW study, which is a global phase III study in patients with second-line gastric cancer. (MOS (median overall survival): 9.6 months vs 7.4 months, HR (Hazard Ratio) 0.81 95% CI 0.68-0.96, p = 0.017) (Non-Patent Document 1). However, the therapeutic effect was not sufficient, and in the subset analysis of the previous RAINBOW study in Japanese, the response rate of ramucirumab / paclitaxel combination therapy in the second-line treatment was about 40%, and the median survival time was about 11.4 months. (Non-Patent Document 2).

ラムシルマブは、副作用も少なく胃がんで効果が認められる患者が多い一方で、さほど治療効果が得られない患者もいる。こうした治療上のベネフィットが少ない患者に対しては、ラムシルマブの治療開始前、あるいは治療開始早期に治療効果予測を行うことができれば、治療効果が期待できない患者に対して無駄な治療を行うことなく、代替の治療を行うことができる。また、医薬品の適正使用の観点からもこれを可能とする適切な治療効果予測のバイオマーカーを開発すればメリットが大きい。さらに、ラムシルマブに対する耐性機序が分かれば、新たな治療戦略の開発につながる。そこで、本発明者らはラムシルマブ治療効果と相関のあるバイオマーカーの解析を行った。 While ramucirumab has few side effects and is effective for gastric cancer in many patients, there are also patients who do not have much therapeutic effect. For patients with little therapeutic benefit, if the therapeutic effect can be predicted before the start of treatment with ramucirumab or at the early stage of the start of treatment, it is possible to prevent unnecessary treatment for patients who cannot expect the therapeutic effect. Alternative treatments can be given. In addition, there is a great merit if a biomarker for predicting the appropriate therapeutic effect that enables this from the viewpoint of proper use of pharmaceuticals is developed. Furthermore, understanding the mechanism of resistance to ramucirumab will lead to the development of new therapeutic strategies. Therefore, the present inventors analyzed biomarkers that correlate with the therapeutic effect of ramucirumab.

その結果、ラムシルマブが投与された胃がん症例において、血漿中のＶＥＧＦ－Ａが以下のような挙動を示し、予後と相関することを明らかにした。図１は、２例はラムシルマブ単独投与、他はパクリタキセルとの併用投与を行った患者において、ラムシルマブ投与開始８日後の患者血漿中のＶＥＧＦ－Ａ値を測定し、ＰＦＳ（Ｐｒｏｇｒｅｓｓｉｏｎ Ｆｒｅｅ Ｓｕｒｖｉｖａｌ、無増悪生存期間）、ＯＳとの相関を解析した結果である。血漿中のＶＥＧＦ－Ａ濃度とＰＦＳ、ＯＳはどちらも負の相関が見られた（図１（Ａ））。また、血漿中のＶＥＧＦ－Ａ濃度を至適カットオフ値（４２４ｐｇ／ｍｌ）により高値群、低値群の２群に分けてＰＦＳ、ＯＳを解析したところ、ＶＥＧＦ-Ａ高値群では有意に予後が不良であった（図１（Ｂ））。血漿中のＶＥＧＦ－Ａ濃度とＰＦＳ、ＯＳとの負の相関は、パクリタキセル投与においては観察されないことから、ラムシルマブ投与に特徴的な現象と考えられる。ラムシルマブ投与によって、以下の現象が認められる。（１）投与後早期に血漿ＶＥＧＦ－Ａは著明に上昇し、このＶＥＧＦ－Ａ値と生存期間には負の相関が認められる。（２）至適カットオフにより２群に分け高値群と低値群で比較したところ高値群の予後が有意に不良であった。（３）投与後早期のＶＥＧＦ－Ａの上昇は一過性ではなく、増悪時まで高値が維持される（特許文献１、非特許文献３）。 As a result, it was clarified that VEGF-A in plasma showed the following behavior and correlated with prognosis in gastric cancer cases treated with ramucirumab. In FIG. 1, the VEGF-A level in the patient's plasma 8 days after the start of ramucirumab administration was measured in patients who received ramucirumab alone in 2 cases and in combination with paclitaxel, and PFS (Progression Free Survival, no exacerbation). Survival period), the result of analysis of the correlation with OS. A negative correlation was observed between the plasma VEGF-A concentration and PFS and OS (FIG. 1 (A)). In addition, when the VEGF-A concentration in plasma was divided into two groups, a high value group and a low value group, according to the optimal cutoff value (424 pg / ml) and PFS and OS were analyzed, the prognosis was significantly significant in the VEGF-A high value group. Was defective (FIG. 1 (B)). Since a negative correlation between plasma VEGF-A concentration and PFS and OS is not observed in paclitaxel administration, it is considered to be a characteristic phenomenon of ramucirumab administration. The following phenomena are observed by administration of ramucirumab. (1) Plasma VEGF-A increased markedly early after administration, and a negative correlation was observed between this VEGF-A value and survival time. (2) When divided into two groups according to the optimal cutoff and compared between the high-value group and the low-value group, the prognosis of the high-value group was significantly poor. (3) The increase in VEGF-A at an early stage after administration is not transient, and the high value is maintained until the exacerbation (Patent Document 1, Non-Patent Document 3).

上記結果によれば、ラムシルマブ投与によって、血中ＶＥＧＦ－Ａ濃度が上昇する患者群で、ラムシルマブの効果が得られないことから、ＶＥＧＦの上昇を抑制することによって、奏効が得られる可能性がある。しかしながら、すでに報告されているＶＥＧＦ、ＶＥＧＦＲ双方を抑制する治療法からは望ましい結果が得られていない（非特許文献４～７）。これらの治療法は、具体的にはキナーゼ阻害剤ソラフェニブ（Ｓｏｒａｆｅｎｉｂ）とＶＥＧＦに対するモノクローナル抗体であるベバシズマブ（ｂｅｖａｃｉｚｕｍａｂ）によって、ＶＥＧＦＲ、ＶＥＧＦ双方を抑制しようという治療法である。しかし、上記報告によれば、ソラフェニブ、ベバシズマブの併用療法はさほど効果を示さない、あるいは、副作用が強く、治療を継続できず、確立した治療法となるには至っていない。 According to the above results, since the effect of ramucirumab cannot be obtained in the group of patients whose blood VEGF-A concentration is increased by the administration of ramucirumab, it is possible that the effect can be obtained by suppressing the increase in VEGF. .. However, desirable results have not been obtained from the previously reported treatments that suppress both VEGF and VEGFR (Non-Patent Documents 4 to 7). Specifically, these treatment methods are treatment methods in which both VEGFR and VEGF are suppressed by the kinase inhibitor sorafenib and bevacizumab, which is a monoclonal antibody against VEGF. However, according to the above report, the combination therapy of sorafenib and bevacizumab is not so effective, or the side effects are so strong that the treatment cannot be continued and the treatment has not been established.

さらに、ラムシルマブ投与後の過剰なＶＥＧＦ－Ａはその後の治療経過に悪影響を与える可能性がある。その理由として過剰なＶＥＧＦ－ＡがＶＥＧＦＲ１を介した経路で血管新生・腫瘍増殖をきたすからである。また近年、ＶＥＧＦ－Ａは制御性Ｔ細胞の増殖・浸潤などを介して腫瘍免疫への抑制効果も報告されており（非特許文献８）、免疫抑制を介した機序により悪影響を及ぼす可能性がある。 In addition, excess VEGF-A after ramucirumab administration can adversely affect the subsequent course of treatment. The reason is that excess VEGF-A causes angiogenesis and tumor growth via the VEGFR1-mediated pathway. In recent years, VEGF-A has also been reported to have an inhibitory effect on tumor immunity through proliferation and infiltration of regulatory T cells (Non-Patent Document 8), and may have adverse effects due to the mechanism mediated by immunosuppression. There is.

国際公開第２０１８／１２４１５３号International Publication No. 2018/124153

Wilke, H. et al.,2014, Lancet Oncol., Vol.15, p.1224-1235.Wilke, H. et al., 2014, Lancet Oncol., Vol.15, p.1224-1235. Shitara, K. et al., 2016, Gastric Cancer,Vol.19(3), pp.927-938, doi: 10.1007/s10120-015-0559-z.Shitara, K. et al., 2016, Gastric Cancer, Vol.19 (3), pp.927-938, doi: 10.1007 / s10120-015-0559-z. https://meetinglibrary.asco.org/record/156166/abstracthttps://meetinglibrary.asco.org/record/156166/abstract CastellanoD. et al., 2013, Eur. J. Cancer. Vol.49(18), pp.3780-3787.CastellanoD. Et al., 2013, Eur. J. Cancer. Vol.49 (18), pp.3780-3787. Galanis, E. et al., 2013, Clin. CancerRes., Vol.19(17), pp.4816-4823.Galanis, E. et al., 2013, Clin. CancerRes., Vol.19 (17), pp.4816-4823. Lee, J.M., et al., 2010, Br. J. Cancer,Vol.102(3), pp.495-459.Lee, J.M., et al., 2010, Br. J. Cancer, Vol.102 (3), pp.495-459. Azad, N.S. et al., 2008, J. Clin.Oncol., Vol.26(22), pp.3709-3714.Azad, N.S. et al., 2008, J. Clin.Oncol., Vol.26 (22), pp.3709-3714. Kahn, K.A. and Kerbel, R.S.,2018, Nat. Rev. Clin. Oncol.,Vol.15(5), pp. 310-324.Kahn, K.A. and Kerbel, R.S., 2018, Nat. Rev. Clin. Oncol., Vol.15 (5), pp. 310-324.

すでに本発明者らが示しているように、ラムシルマブで代表される抗ＶＥＧＦＲ２抗体投与による有効性は治療開始早期に血中のＶＥＧＦ－Ａ濃度によって見極めることができる。しかし、ラムシルマブ投与による治療の効果が認められない患者群に対し、ラムシルマブ治療を行わないという選択肢はあるものの、効果のある代替の治療法があるわけではない。本発明は、ラムシルマブ投与により有効性が認められない患者群に対し、効果を奏する治療薬、及び治療法を提供することを課題とする。また、抗ＶＥＧＦＲ２抗体投与により産生される過剰のＶＥＧＦ－Ａによる治療に対する悪影響を排除する治療薬、及び治療法を提供することを課題とする。 As have already been shown by the present inventors, the efficacy of anti-VEGFR2 antibody administration represented by ramucirumab can be determined by the blood VEGF-A concentration at an early stage of the start of treatment. However, although there is an option not to treat ramucirumab for a group of patients who do not respond to treatment with ramucirumab, there is no effective alternative treatment. An object of the present invention is to provide a therapeutic agent and a therapeutic method that are effective for a group of patients whose efficacy is not recognized by administration of ramucirumab. Another object of the present invention is to provide a therapeutic agent and a therapeutic method for eliminating an adverse effect on the treatment with excess VEGF-A produced by administration of an anti-VEGFR2 antibody.

本発明は、ラムシルマブをはじめとする抗ＶＥＧＦＲ抗体投与によって、治療効果が得られない患者に対して治療効果を改善する新規治療法、治療薬に関する。
（１）血管新生が増悪の原因となる疾患において、抗ＶＥＧＦＲ２抗体医薬品と併用する医薬品であって、抗ＶＥＧＦ抗体を有効成分とすることを特徴とする併用薬。
（２）前記抗ＶＥＧＦ抗体が、抗ＶＥＧＦ－Ａ抗体であることを特徴とする（１）記載の併用薬。
（３）前記疾患が腫瘍であることを特徴とする（１）、又は（２）記載の併用薬。
（４）前記腫瘍が胃がん、大腸がん、又は小細胞肺がんであることを特徴とする（３）記載の併用薬。
（５）前記抗ＶＥＧＦＲ２抗体医薬品と、同時に、又は個別に用いられることを特徴とする（１）～（４）いずれか１つ記載の併用薬。
（６）前記抗ＶＥＧＦＲ２抗体医薬品がラムシルマブであって、前記抗ＶＥＧＦ抗体を有効成分とする併用薬がベバシズマブであることを特徴とする（１）～（５）いずれか１つ記載の併用薬。
（７）抗ＶＥＧＦＲ２抗体医薬品と抗ＶＥＧＦ抗体医薬品を併用することにより奏効する患者を検査する方法であって、患者より採取された抗ＶＥＧＦＲ２抗体医薬品による治療開始前、及び治療開始後早期の試料中のＶＥＧＦ－Ａ濃度を測定し、比較することを特徴とする検査方法。
（８）（７）に記載の検査方法であって、前記試料が血液、血漿、又は血清であることを特徴とする検査方法。
（９）抗ＶＥＧＦＲ２抗体医薬品と抗ＶＥＧＦ抗体医薬品を併用することにより奏効する患者を検査するキットであって、患者試料中のＶＥＧＦ－Ａ濃度を測定するための試薬を含むことを特徴とする検査キット。
（１０）血管新生が増悪の原因となる疾患に対し、抗ＶＥＧＦＲ２抗体医薬品と抗ＶＥＧＦ抗体医薬品を併用投与する治療方法。
（１１）（１０）に記載の治療方法であって、抗ＶＥＧＦＲ２抗体医薬品と抗ＶＥＧＦ抗体医薬品は、同時に、又は個別のタイミングで併用投与する治療方法。
（１２）抗ＶＥＧＦＲ２抗体医薬品投与前、及び投与後早期に血中ＶＥＧＦ濃度を測定し、抗ＶＥＧＦＲ２抗体医薬品投与後、血中ＶＥＧＦ濃度の有意な増加が認められた場合には、抗ＶＥＧＦＲ２抗体医薬品と抗ＶＥＧＦ抗体医薬品を併用投与する（１０）、又は（１１）に記載の治療方法。 The present invention relates to a novel therapeutic method and a therapeutic agent for improving a therapeutic effect on a patient who cannot obtain a therapeutic effect by administration of an anti-VEGFR antibody such as ramucirumab.
(1) A drug that is used in combination with an anti-VEGFR2 antibody drug in a disease in which angiogenesis causes exacerbation, and is characterized by containing an anti-VEGF antibody as an active ingredient.
(2) The combination drug according to (1), wherein the anti-VEGF antibody is an anti-VEGF-A antibody.
(3) The combination drug according to (1) or (2), wherein the disease is a tumor.
(4) The combination drug according to (3), wherein the tumor is gastric cancer, colon cancer, or small cell lung cancer.
(5) The combination drug according to any one of (1) to (4), which is used simultaneously with or individually with the anti-VEGFR2 antibody drug.
(6) The concomitant drug according to any one of (1) to (5), wherein the anti-VEGFR2 antibody drug is ramucirumab, and the concomitant drug containing the anti-VEGF antibody as an active ingredient is bevacizumab.
(7) A method for inspecting a patient who responds by using an anti-VEGFR2 antibody drug and an anti-VEGF antibody drug in combination, and in a sample before the start of treatment with the anti-VEGFR2 antibody drug collected from the patient and in the early stage after the start of treatment. A test method comprising measuring and comparing VEGF-A concentrations of.
(8) The test method according to (7), wherein the sample is blood, plasma, or serum.
(9) A kit for testing a patient who responds by using an anti-VEGFR2 antibody drug and an anti-VEGF antibody drug in combination, and comprising a reagent for measuring the VEGF-A concentration in a patient sample. kit.
(10) A therapeutic method in which an anti-VEGFR2 antibody drug and an anti-VEGF antibody drug are co-administered for a disease in which angiogenesis causes exacerbation.
(11) The therapeutic method according to (10), wherein the anti-VEGFR2 antibody drug and the anti-VEGF antibody drug are administered simultaneously or in combination at individual timings.
(12) The blood VEGF concentration was measured before and early after the administration of the anti-VEGFR2 antibody drug, and if a significant increase in the blood VEGF concentration was observed after the administration of the anti-VEGFR2 antibody drug, the anti-VEGFR2 antibody drug was observed. The treatment method according to (10) or (11), wherein the anti-VEGF antibody drug is co-administered with the drug.

血漿中のＶＥＧＦ－Ａ濃度と予後の相関を解析した図。（Ａ）ラムシルマブ投与後８日目の患者血漿中のＶＥＧＦ－Ａ濃度とＰＦＳ（左）、ＯＳ（右）の関係を示す図。（Ｂ）ラムシルマブ投与８日目の血漿中ＶＥＧＦ－Ａ高値群、低値群のＰＦＳ（左）、ＯＳ（右）を示す図。The figure which analyzed the correlation between the VEGF-A concentration in plasma and the prognosis. (A) The figure which shows the relationship between the VEGF-A concentration in the patient plasma on the 8th day after the administration of ramucirumab, and PFS (left) and OS (right). (B) The figure which shows PFS (left) and OS (right) of the plasma VEGF-A high value group and the low value group on the 8th day of ramucirumab administration. ヒト胃がん細胞におけるＶＥＧＦ－Ａ産生量を示す図。The figure which shows the VEGF-A production amount in the human gastric cancer cells. マウス移植腫瘍モデルにおける解析結果を示す図。（Ａ）ラムシルマブのマウス・サロゲート抗体であるＤＣ１０１抗体投与スケジュールを示す図。（Ｂ）ＤＣ１０１抗体投与後の血漿中のマウスＶＥＧＦ－Ａの変化。（Ｃ）ＤＣ１０１抗体投与後の血漿中のヒトＶＥＧＦ－Ａの変化。The figure which shows the analysis result in the mouse transplantation tumor model. (A) The figure which shows the administration schedule of DC101 antibody which is a mouse surrogate antibody of ramucirumab. (B) Changes in mouse VEGF-A in plasma after administration of DC101 antibody. (C) Changes in human VEGF-A in plasma after administration of DC101 antibody. マウス移植腫瘍モデルにおける解析結果を示す図。（Ａ）ＤＣ１０１抗体投与後の血漿中のヒト、あるいはマウスＰｌＧＦ（Ｐｌａｃｅｎｔａｌ Ｇｒｏｗｔｈ ｆａｃｔｏｒ、胎盤増殖因子）の変化、（Ｂ）ＤＣ１０１抗体投与後の血漿中のヒト、あるいはマウスＶＥＧＦ－Ｃの変化、（Ｃ）ＤＣ１０１抗体投与後の血漿中のヒト、あるいはマウスＶＥＧＦ－Ｄの変化。The figure which shows the analysis result in the mouse transplantation tumor model. (A) Changes in human or mouse PlGF (Placental Growth factor) after administration of DC101 antibody, (B) Changes in human or mouse VEGF-C after administration of DC101 antibody, (B) C) Changes in human or mouse VEGF-D in plasma after administration of DC101 antibody. マウス移植腫瘍モデルにおける抗ＶＥＧＦＲ２抗体（ＤＣ１０１）、抗ＶＥＧＦ－Ａ抗体（ｍＶＥＧＦ）併用投与の効果を示す図。（Ａ）抗体投与スケジュールを示す図。（Ｂ）各抗体投与による腫瘍容積の変化を示す図。（Ｃ）各抗体投与におけるマウスに移植した腫瘍の抗体投与開始後１４日目の様子を示す写真。The figure which shows the effect of the combined administration of anti-VEGFR2 antibody (DC101) and anti-VEGF-A antibody (mVEGF) in a mouse transplant tumor model. (A) The figure which shows the antibody administration schedule. (B) The figure which shows the change of the tumor volume by administration of each antibody. (C) A photograph showing the state on the 14th day after the start of antibody administration of the tumor transplanted into the mouse in each antibody administration.

図１に示すように、ラムシルマブ投与後、血漿ＶＥＧＦ－Ａの上昇がさほど見られない患者群では、ラマシルマブの治療効果が得られることから、上昇したＶＥＧＦ－Ａを中和することによって、奏効が得られる可能性が高いと考えた。前述のように、ＶＥＧＦＲを標的とする小分子医薬を用いた治療はその特有の副作用発症のため治療が妨げられるが、より副作用の少ない抗体医薬を用いて、ＶＥＧＦ、ＶＥＧＦＲ双方を抑制することによって効果が得られる可能性があると考えられた。そこで、以下の解析を行った。 As shown in FIG. 1, in the patient group in which the increase in plasma VEGF-A is not so much observed after the administration of ramucirumab, the therapeutic effect of lamasylumab can be obtained. Therefore, the effect is achieved by neutralizing the increased VEGF-A. I thought it was likely to be obtained. As mentioned above, treatment with small molecule drugs targeting VEGFR is hindered due to the onset of its unique side effects, but by suppressing both VEGF and VEGFR using antibody drugs with fewer side effects. It was thought that the effect could be obtained. Therefore, the following analysis was performed.

以下の実施例で示すように、ＶＥＧＦ、あるいはＶＥＧＦＲに対する抗体を併用して使用することにより、抗ＶＥＧＦＲ抗体単独では効果を奏さない患者群に対しても治療効果を得ることができる。現在、臨床で用いられている抗ＶＥＧＦ－Ａ抗体としては、ベバシズマブ、抗ＶＥＧＦＲ２抗体としてはラムシルマブがあるが、これに限らず今後開発される抗ＶＥＧＦＲ抗体医薬や抗ＶＥＧＦ抗体医薬を用いることができる。また、ＶＥＧＦ－Ａに対するＦａｂ断片であるラニビズマブのような抗体断片を有効成分とする医薬を用いることができる。さらに、ＶＥＧＦＲ２、及びＶＥＧＦ－Ａの両方を標的とする二重特異性抗体を有効成分とする医薬を用いてもよい。 As shown in the following examples, by using an antibody against VEGF or VEGFR in combination, a therapeutic effect can be obtained even for a group of patients who are not effective with the anti-VEGFR antibody alone. Currently, the anti-VEGF-A antibody currently used clinically includes vevasizumab, and the anti-VEGFR2 antibody includes ramsylmab, but the present invention is not limited to this, and anti-VEGFR antibody drugs and anti-VEGF antibody drugs developed in the future can be used. .. In addition, a drug containing an antibody fragment such as ranibizumab, which is a Fab fragment for VEGF-A, as an active ingredient can be used. Furthermore, drugs containing bispecific antibodies targeting both VEGFR2 and VEGF-A as active ingredients may be used.

本実施例で示す治療薬、治療方法の対象となる疾患は、血管新生が疾患の発症、増悪に関与する疾患である。このような疾患としては腫瘍があるが、特にラムシルマブ投与によって効果があることが認められている胃がん、大腸がん、非小細胞肺がんは代表的な疾患として挙げられる。特にラムシルマブの適応症として承認されている治癒切除不能な進行・再発胃がん、治癒切除不能な進行・再発結腸・直腸がん、治癒切除不能な進行・再発非小細胞肺がんが対象となる疾患として挙げられる。また、上記に限らず、抗ＶＥＧＦＲ抗体医薬の効果が認められる疾患であれば、併用薬として抗ＶＥＧＦ抗体医薬を使用することにより、より高い治療効果が得られる可能性がある。 The target diseases of the therapeutic agents and treatment methods shown in this example are diseases in which angiogenesis is involved in the onset and exacerbation of the disease. Tumors are examples of such diseases, but gastric cancer, colorectal cancer, and non-small cell lung cancer, which have been found to be effective by administration of ramucirumab, are typical diseases. In particular, unresectable advanced / recurrent gastric cancer, unresectable advanced / recurrent colorectal cancer, and unresectable advanced / recurrent non-small cell lung cancer, which are approved as indications for ramucirumab, are listed as target diseases. Will be. Further, not limited to the above, if the disease has an effect of the anti-VEGFR antibody drug, a higher therapeutic effect may be obtained by using the anti-VEGF antibody drug as a combination drug.

治療薬投与のタイミングは、同時でも良いし、各治療薬の半減期等を考慮して別々のスケジュールで個別に投与することも可能である。 The timing of administration of the therapeutic drug may be simultaneous, or it may be administered individually according to different schedules in consideration of the half-life of each therapeutic drug.

ラムシルマブはパクリタキセルとの併用投与が標準治療であるが、他の抗体医薬と併用して投与することはない。抗体医薬として、抗ＶＥＧＦＲ抗体医薬のみを投与した場合には効果を示さないが、抗ＶＥＧＦ抗体医薬を併用することによって効果を奏する患者群は、抗ＶＥＧＦＲ抗体投与後、早期に血中ＶＥＧＦ－Ａの上昇が見られる患者群である。したがって、現在標準治療となっているラムシルマブとパクリタキセルとの併用投与に加えて、ベバシズマブの併用投与を行えば良い。 Ramucirumab is standard treatment with paclitaxel, but not with other antibody drugs. When only the anti-VEGFR antibody drug is administered as an antibody drug, no effect is shown, but the group of patients who are effective by using the anti-VEGF antibody drug in combination can see the blood VEGF-A at an early stage after the administration of the anti-VEGFR antibody. This is a group of patients with an increase in. Therefore, in addition to the combination administration of ramucirumab and paclitaxel, which is currently the standard of care, the combination administration of bevacizumab may be performed.

あるいは、標準治療であるパクリタキセルと抗ＶＥＧＦＲ抗体医薬治療後、早期に血中ＶＥＧＦ－Ａ濃度を測定し、高値であれば抗ＶＥＧＦ抗体医薬を併用薬として用い、低値であれば抗体医薬としては抗ＶＥＧＦＲ抗体医薬単独投与による治療を行えば良い。 Alternatively, the blood VEGF-A concentration is measured early after the standard treatment of paclitaxel and anti-VEGFR antibody drug treatment, and if the value is high, the anti-VEGF antibody drug is used as a concomitant drug, and if the value is low, the antibody drug is used. Treatment with anti-VEGFR antibody drug alone may be performed.

血中のＶＥＧＦ－Ａ濃度は、ここでは８日目に測定しているが、抗ＶＥＧＦＲ２抗体投与開始後、早期であれば良く、概ね４日目から１０日目の試料を測定すればよい。また、試料としては、血漿、血液、血清を使用することができる。血液、血漿、血清であれば、切除不能な進行・再発がんであっても患者から試料を得て検査を行うことができるだけではなく、患者の身体的負担も少なくてすむ。 The VEGF-A concentration in the blood is measured here on the 8th day, but it may be as early as after the start of the anti-VEGFR2 antibody administration, and the sample may be measured on the 4th to 10th days. Moreover, plasma, blood, and serum can be used as the sample. With blood, plasma, and serum, not only can samples be obtained from patients for unresectable advanced / relapsed cancer, but the physical burden on patients can be reduced.

また、以下の実施例で示すように、抗ＶＥＧＦＲ抗体投与に対して効果が少ない場合であっても、抗ＶＥＧＦ－Ａ抗体を併用して投与することにより顕著な効果が得られることが明らかとなった。２つの抗体の作用機序を考えると、抗ＶＥＧＦ－Ａ抗体投与に対して効果が得られない患者に対して、抗ＶＥＧＦＲ抗体を併用して投与することによって効果が得られる可能性がある。 Further, as shown in the following examples, it is clear that even when the effect is small with respect to the administration of the anti-VEGFR antibody, a remarkable effect can be obtained by administering the anti-VEGF-A antibody in combination. became. Considering the mechanism of action of the two antibodies, it is possible that the effect can be obtained by administering the anti-VEGFR antibody in combination to the patients who are not effective against the anti-VEGF-A antibody administration.

［実施例］
本発明者らは、ラムシルマブ投与後に上昇した過剰なＶＥＧＦ－Ａがその後の生存期間に悪影響を及ぼし、この過剰なＶＥＧＦ－Ａを中和する事で治療効果の改善が得られるのではないかと考えた。しかしながら、上述のように、キナーゼ阻害剤であるソラフェニブによってＶＥＧＦＲの活性化を抑制し、ベバシズマブによってＶＥＧＦのＶＥＧＦＲへの結合を阻害する治療法は、リガンド、受容体の双方を抑制する治療法であり、ある程度の効果は得られているものの、毒性が強くなり併用療法は断念されている。さらに、リガンド、及びレセプターを同時に抗体医薬によって抑制することによって治療を行った例はない。 [Example]
The present inventors consider that the excess VEGF-A increased after the administration of ramucirumab adversely affects the subsequent survival time, and that the therapeutic effect can be improved by neutralizing this excess VEGF-A. rice field. However, as described above, the therapeutic method of suppressing the activation of VEGFR by the kinase inhibitor sorafenib and inhibiting the binding of VEGF to VEGFR by bevacizumab is a therapeutic method of suppressing both the ligand and the receptor. Although some effects have been obtained, the combination therapy has been abandoned due to the increased toxicity. Furthermore, there is no example of treatment by simultaneously suppressing a ligand and a receptor with an antibody drug.

そこで抗体製剤によるＶＥＧＦ－Ａ／ＶＥＧＦＲ２双方を抑制することによって治療効果が得られるか解析を行った。最初に、ヌードマウスにヒト胃がん細胞株を接種し、抗ＶＥＧＦＲ抗体に対してヒト胃がん患者と同様の反応を示すモデルマウスの構築を行った。 Therefore, it was analyzed whether the therapeutic effect can be obtained by suppressing both VEGF-A / VEGFR2 with the antibody preparation. First, nude mice were inoculated with a human gastric cancer cell line, and a model mouse showing the same response to anti-VEGFR antibody as that of a human gastric cancer patient was constructed.

（１）マウスモデルの確立
疾患モデルとして、抗ＶＥＧＦＲ抗体投与後に、ＶＥＧＦ－Ａの上昇が観察されるモデルを作製する必要がある。マウスにヒト腫瘍細胞を移植してモデルを構築するにあたり、移植する腫瘍細胞に十分なＶＥＧＦ－Ａ分泌能があることが望ましい。まず、移植する腫瘍細胞を決定するために、ヒト胃がん細胞株のＶＥＧＦ－Ａ量をＥＬＩＳＡにより測定した（図２）。 (1) Establishment of mouse model As a disease model, it is necessary to prepare a model in which an increase in VEGF-A is observed after administration of anti-VEGFR antibody. When transplanting human tumor cells into mice to construct a model, it is desirable that the tumor cells to be transplanted have sufficient VEGF-A secretory capacity. First, in order to determine the tumor cells to be transplanted, the amount of VEGF-A of a human gastric cancer cell line was measured by ELISA (FIG. 2).

ヒト胃がん細胞Ｓｔ４、ＭＫＮ１、ＭＫＮ７、ＭＫＮ２８、ＭＫＮ４５、ＭＫＮ７４（Ｓｔ４は医用細胞資源センター・細胞バンク、他の細胞は、ＪＣＲＢ細胞バンクより入手。）を用いて解析を行った。 Analysis was performed using human gastric cancer cells St4, MKN1, MKN7, MKN28, MKN45, and MKN74 (St4 is obtained from the Medical Cell Resource Center / Cell Bank, and other cells are obtained from the JCRB Cell Bank).

各細胞をサブコンフルエントな条件でシャーレに播種し、３日後にＶＥＧＦ－Ａ量をヒトＶＥＧＦ－Ａ測定キット（Ｒ＆Ｄ社）により測定した。培養上清中の細胞１０，０００個あたりのＶＥＧＦ－Ａ分泌量を算出した。図２に示すように、解析した細胞の中では、ＭＫＮ４５細胞から分泌されるＶＥＧＦ－Ａが最も多かったことから、ＭＫＮ４５細胞を用いてマウスモデルを構築することとした。 Each cell was seeded in a petri dish under subconfluent conditions, and 3 days later, the amount of VEGF-A was measured with a human VEGF-A measurement kit (R & D). The amount of VEGF-A secreted per 10,000 cells in the culture supernatant was calculated. As shown in FIG. 2, among the analyzed cells, VEGF-A secreted from MKN45 cells was the largest, so it was decided to construct a mouse model using MKN45 cells.

ヌードマウス、ＣＡｎＮ．Ｃｇ－Ｆｏｘｎ１ｎｕ／ＣｒｌＣｒｌｊ（６週齢、メス、日本チャールズリバー株式会社より入手。）に、２，０００，０００個のヒト胃がん細胞株ＭＫＮ４５を皮下移植し、移植１４日後に腫瘍サイズを測定しランダムに群分けした。なお、群分け時の腫瘍容積は８０～１５０ｍｍ３であった。ラムシルマブのマウス・サロゲート抗体ＤＣ１０１（Ｂｉｏ Ｘ Ｃｅｌｌ社）を投与して、ＶＥＧＦ－Ａ分泌量の測定を行った。なお、ＭＫＮ４５細胞は、ＤＣ１０１抗体によって、腫瘍退縮効果がすでに検討された細胞であることが、サイラムザ添付文書に開示されている。 Nude mouse, CANN. 2,000,000 human gastric cancer cell lines MKN45 were subcutaneously transplanted into Cg-Foxn1nu / CrlCrlj (6 weeks old, female, obtained from Charles River Laboratories, Japan), and the tumor size was measured 14 days after the transplantation and randomly. It was divided into groups. The tumor volume at the time of grouping was 80 to 150 mm 3 . The mouse surrogate antibody DC101 (Bio X Cell) of ramucirumab was administered, and the amount of VEGF-A secreted was measured. It is disclosed in the package insert of Cyramza that MKN45 cells are cells for which the tumor regression effect has already been examined by the DC101 antibody.

ＤＣ１０１抗体を５、１０、２０ｍｇ/ｋｇで週２回、２週間腹腔内投与を行った（図３（Ａ））。投与１４日目で採血を行い、血漿中のヒト及びマウスＶＥＧＦ－Ａを測定した。測定は、ヒトＶＥＧＦ－Ａ測定キット、マウスＶＥＧＦ－Ａ測定キット（いずれもＲ＆Ｄ社製）を用いた。なお、ヒトＶＥＧＦ－Ａ測定キットは、ヒトのＶＥＧＦ－Ａのみ、マウスＶＥＧＦ－Ａ測定キットはマウスＶＥＧＦ－Ａのみを検出することを事前に確認している。その結果、投与量１０、２０ｍｇ/ｋｇでＤＣ１０１抗体を投与した場合には、マウスＶＥＧＦ－Ａの誘導が確認された（図３（Ｂ））。一方、ヒトＶＥＧＦ－Ａの上昇は見られなかった（図３（Ｃ））。 The DC101 antibody was intraperitoneally administered at 5, 10, 20 mg / kg twice a week for 2 weeks (FIG. 3 (A)). Blood was collected on the 14th day of administration, and human and mouse VEGF-A in plasma was measured. For the measurement, a human VEGF-A measurement kit and a mouse VEGF-A measurement kit (both manufactured by R & D) were used. It has been confirmed in advance that the human VEGF-A measurement kit detects only human VEGF-A, and the mouse VEGF-A measurement kit detects only mouse VEGF-A. As a result, the induction of mouse VEGF-A was confirmed when the DC101 antibody was administered at a dose of 10 or 20 mg / kg (FIG. 3 (B)). On the other hand, no increase in human VEGF-A was observed (FIG. 3 (C)).

なお、図３において、ｔｕｍｏｒ（＋）の表記は、胃がん細胞株であるＭＫＮ４５、またはＭＫＮ７４を移植したマウスを示す。また、ｔｕｍｏｒ（－）の表記は、コントロールとしてがん細胞株を移植していないマウスにおけるＤＣ１０１抗体の効果を解析した結果を示している。 In FIG. 3, the notation of tumor (+) indicates a mouse transplanted with MKN45 or MKN74, which is a gastric cancer cell line. In addition, the notation of tumor (-) indicates the result of analysis of the effect of DC101 antibody in mice not transplanted with a cancer cell line as a control.

次に、血管新生に関係する他の因子ＰｌＧＦ、ＶＥＧＦ－Ｃ、ＶＥＧＦ－Ｄについてもその変動を解析した。ＶＥＧＦ－Ａと同様に、ＤＣ１０１抗体投与開始１４日目の血漿中のヒト、マウスのＰｌＧＦ、ＶＥＧＦ－Ｃ、ＶＥＧＦ－Ｄ量をＥＬＩＳＡにより測定を行った（図４）。 Next, changes in other factors involved in angiogenesis, PlGF, VEGF-C, and VEGF-D, were also analyzed. Similar to VEGF-A, the amounts of human and mouse PlGF, VEGF-C, and VEGF-D in plasma 14 days after the start of DC101 antibody administration were measured by ELISA (FIG. 4).

その結果、ＰｌＧＦがＤＣ１０１投与により顕著に増加し、ＶＥＧＦ－Ｃ、ＶＥＧＦ－Ｄについては弱い誘導が見られた。この結果は、ラムシルマブ投与患者血漿の結果と同様であった（特許文献１、非特許文献３）。また、いずれのサイトカインについても、誘導はマウス由来であり、ヒト由来のものは誘導されなかった。 As a result, PlGF was significantly increased by administration of DC101, and weak induction was observed for VEGF-C and VEGF-D. This result was similar to the result of plasma of ramucirumab-administered patients (Patent Document 1, Non-Patent Document 3). In addition, the induction of all cytokines was derived from mice, and those derived from humans were not.

上記示したように、ヌードマウスの皮下にＭＫＮ４５細胞を移植して構築したマウスにおいて、ＤＣ１０１抗体投与後に産生する血管増殖因子の挙動は、患者にラムシルマブを投与した場合の挙動と非常に似ており、良いモデルであると考えられる。 As shown above, in mice constructed by transplanting MKN45 cells subcutaneously into nude mice, the behavior of vascular growth factors produced after administration of DC101 antibody is very similar to the behavior when ramucirumab is administered to patients. , Considered to be a good model.

（２）抗ＶＥＧＦＲ２抗体と抗ＶＥＧＦ－Ａ抗体との併用による効果
胃がん細胞株ＭＫＮ４５を移植したマウスモデルにおいて、ＤＣ１０１抗体投与後に宿主であるマウス由来のＶＥＧＦ－Ａが上昇することが明らかになった。そこで、同マウスモデルにおいて、ＤＣ１０１抗体、抗マウスＶＥＧＦ－Ａ抗体を併用投与することによる腫瘍抑制効果の解析を行った。 (2) Effect of combined use of anti-VEGFR2 antibody and anti-VEGF-A antibody In a mouse model transplanted with the gastric cancer cell line MKN45, it was clarified that VEGF-A derived from the host mouse increased after administration of DC101 antibody. .. Therefore, in the same mouse model, the tumor suppressive effect of the combined administration of DC101 antibody and anti-mouse VEGF-A antibody was analyzed.

上記と同様にして、ヌードマウスにＭＫＮ４５細胞を皮下移植し、１４日後に腫瘍サイズを測定し、８０～１５０ｍｍ３のものを群分けした。ＤＣ１０１抗体単独投与（ｎ＝３、１０ｍｇ／ｋｇ）、マウスＶＥＧＦ－Ａ中和抗体である２Ｇ１１－２Ａ０５抗体単独投与（ｎ＝２、５ｍｇ／ｋｇ）、ＤＣ１０１抗体（１０ｍｇ／ｋｇ）及び２Ｇ１１－２Ａ０５抗体（５ｍｇ／ｋｇ）併用投与（ｎ＝３）を、週２回、２週間の腹腔内投与を行い、腫瘍サイズ、マウス体重を経時的に測定した（図５（Ａ））。また、コントロールとしては、溶媒のみを投与した（ｎ＝３）。 In the same manner as above, MKN45 cells were subcutaneously transplanted into nude mice, the tumor size was measured 14 days later, and those of 80 to 150 mm 3 were grouped. DC101 antibody alone (n = 3, 10 mg / kg), mouse VEGF-A neutralizing antibody 2G11-2A05 antibody alone (n = 2, 5 mg / kg), DC101 antibody (10 mg / kg) and 2G11-2A05 The antibody (5 mg / kg) combined administration (n = 3) was intraperitoneally administered twice a week for 2 weeks, and the tumor size and mouse body weight were measured over time (FIG. 5 (A)). Moreover, as a control, only the solvent was administered (n = 3).

ＤＣ１０１抗体（１０ｍｇ／ｋｇ）単独投与群、及びマウスＶＥＧＦ－Ａ中和抗体２Ｇ１１－２Ａ０５（５ｍｇ／ｋｇ）単独投与群において、弱い腫瘍増殖抑制効果が見られた。一方、ＤＣ１０１抗体（１０ｍｇ／ｋｇ）と２Ｇ１１－２Ａ０５抗体（５ｍｇ／ｋｇ）併用群では統計的に有意な腫瘍抑制効果が認められた（図５（Ｂ））。また、肉眼観察による腫瘍の様子においても、併用群では明らかな腫瘍の退縮が観察された（図５（Ｃ））。 A weak tumor growth inhibitory effect was observed in the DC101 antibody (10 mg / kg) alone administration group and the mouse VEGF-A neutralizing antibody 2G11-2A05 (5 mg / kg) alone administration group. On the other hand, a statistically significant tumor suppressive effect was observed in the DC101 antibody (10 mg / kg) and 2G11-2A05 antibody (5 mg / kg) combination group (FIG. 5 (B)). In addition, in the appearance of the tumor by macroscopic observation, clear tumor regression was observed in the combination group (FIG. 5 (C)).

ベバシズマブは、重篤な副作用が起きることが比較的少ないことから、併用することによっても毒性が軽微であると考えられる。実際に、マウスモデルのおいても重篤な副作用は観察されなかった。 Since bevacizumab causes relatively few serious side effects, it is considered that the toxicity is slight even when used in combination. In fact, no serious side effects were observed in the mouse model.

以上、マウスモデルを用いた前臨床試験において、抗マウスＶＥＧＦ－Ａ中和抗体と抗マウスＶＥＧＦＲ２抗体であるＤＣ１０１の併用療法は、それぞれ単剤療法と比べ有意な腫瘍縮小効果が認められた。 As described above, in the preclinical study using the mouse model, the combination therapy of the anti-mouse VEGF-A neutralizing antibody and the anti-mouse VEGFR2 antibody DC101 was found to have a significant tumor shrinkage effect as compared with the monotherapy.

上記の結果から、実臨床で治療に用いる場合には、ラムシルマブに限らず、作用機序が同様であると考えられるＶＥＧＦＲ２を標的とする抗体医薬品を広く適用することができると考えられる。また、抗ＶＥＧＦ抗体についても、既存の抗体であるベバシズマブだけではなく、同様の作用機序を示す抗体であればどのような抗体医薬品を用いてもよい。 From the above results, it is considered that not only ramucirumab but also antibody drugs targeting VEGFR2, which are considered to have the same mechanism of action, can be widely applied when used for treatment in clinical practice. As for the anti-VEGF antibody, not only bevacizumab, which is an existing antibody, but also any antibody drug may be used as long as it is an antibody showing a similar mechanism of action.

上記実施例で示した、抗ＶＥＧＦＲ抗体、抗ＶＥＧＦ-Ａ中和抗体を併用する治療法、すなわちＶＥＧＦ－Ａ／ＶＥＧＦＲ２経路のｄｕａｌ ｉｎｈｉｂｉｔｉｏｎ療法は、抗ＶＥＧＦＲ抗体投与後早期に血液中のＶＥＧＦ－Ａが著明に上昇する患者群、あるいはＶＥＧＦ－Ａ値が至適カットオフにより２群に分けた場合の高値群に対して奏効を示す。しかし、ＶＥＧＦ－Ａ／ＶＥＧＦＲ２経路のｄｕａｌ ｉｎｈｉｂｉｔｉｏｎ療法は、重篤な副作用を示さないと考えられることから、抗ＶＥＧＦＲ抗体投与による患者のＶＥＧＦ-Ａ値の上昇を検討せずに最初から併用投与を行ってもよい。 The treatment method in which the anti-VEGFR antibody and the anti-VEGF-A neutralizing antibody shown in the above examples are used in combination, that is, the dual inhibition therapy of the VEGF-A / VEGFR2 pathway, is the VEGF-A in the blood at an early stage after the administration of the anti-VEGFR antibody. The response is shown to the patient group in which the amount is markedly increased, or the high value group when the VEGF-A value is divided into two groups by the optimal cutoff. However, since dual indication therapy of the VEGF-A / VEGFR2 pathway is not considered to show serious side effects, the combination administration was started from the beginning without considering the increase in VEGF-A level in patients due to anti-VEGFR antibody administration. You may go.

本発明により抗ＶＥＧＦＲ２抗体医薬品、具体的にはラムシルマブ投与に奏効を示さなかった患者に対しても、有効な治療法を提供することができることから、治癒切除不能・再発胃がんに対して有効な治療法を提供することができる。 Since the present invention can provide an effective treatment method even for a patient who has not responded to an anti-VEGFR2 antibody drug, specifically, ramucirumab administration, an effective treatment for unresectable / recurrent gastric cancer. The law can be provided.

また、本実施例で示したように、リガンド、レセプターを同時に抗体医薬によって、抑制し治療効果を得るｌｉｇａｎｄ－ｒｅｃｅｐｔｏｒ ｄｕａｌ ｂｌｏｃｋａｄｅ療法は、今まで試みられた治療法ではなく、全く新しい発想の治療法である。 In addition, as shown in this example, the ligand-receptor dual blockade therapy, in which the ligand and the receptor are simultaneously suppressed by an antibody drug to obtain a therapeutic effect, is not a therapeutic method that has been tried so far, but a therapeutic method with a completely new concept. Is.

Claims (12)

血管新生が増悪の原因となる疾患において、
抗ＶＥＧＦＲ２抗体医薬品と併用する医薬品であって、
抗ＶＥＧＦ抗体を有効成分とすることを特徴とする併用薬。 In diseases where angiogenesis causes exacerbations
A drug to be used in combination with an anti-VEGFR2 antibody drug.
A combination drug characterized by containing an anti-VEGF antibody as an active ingredient. 前記抗ＶＥＧＦ抗体が、
抗ＶＥＧＦ－Ａ抗体であることを特徴とする請求項１記載の併用薬。 The anti-VEGF antibody
The combination drug according to claim 1, which is an anti-VEGF-A antibody. 前記疾患が腫瘍であることを特徴とする請求項１、又は２記載の併用薬。 The combination drug according to claim 1 or 2, wherein the disease is a tumor. 前記腫瘍が胃がん、大腸がん、又は小細胞肺がんであることを特徴とする請求項３記載の併用薬。 The combination drug according to claim 3, wherein the tumor is gastric cancer, colorectal cancer, or small cell lung cancer. 前記抗ＶＥＧＦＲ２抗体医薬品と、
同時に、又は個別に用いられることを特徴とする請求項１～４いずれか１項記載の併用薬。 With the anti-VEGFR2 antibody drug
The combination drug according to any one of claims 1 to 4, which is used simultaneously or individually. 前記抗ＶＥＧＦＲ２抗体医薬品がラムシルマブであって、
前記抗ＶＥＧＦ抗体を有効成分とする併用薬がベバシズマブであることを特徴とする請求項１～５いずれか１項記載の併用薬。 The anti-VEGFR2 antibody drug is ramucirumab,
The concomitant drug according to any one of claims 1 to 5, wherein the concomitant drug containing the anti-VEGF antibody as an active ingredient is bevacizumab. 抗ＶＥＧＦＲ２抗体医薬品と抗ＶＥＧＦ抗体医薬品を併用することにより奏効する患者を検査する方法であって、
患者より採取された抗ＶＥＧＦＲ２抗体医薬品による治療開始前、及び治療開始後早期の試料中のＶＥＧＦ－Ａ濃度を測定し、
比較することを特徴とする検査方法。 It is a method for examining patients who respond by using an anti-VEGFR2 antibody drug and an anti-VEGF antibody drug in combination.
The VEGF-A concentration in the sample before the start of treatment with the anti-VEGFR2 antibody drug collected from the patient and early after the start of treatment was measured.
An inspection method characterized by comparison. 請求項７に記載の検査方法であって、
前記試料が血液、血漿、又は血清であることを特徴とする検査方法。 The inspection method according to claim 7.
A test method comprising the sample being blood, plasma, or serum. 抗ＶＥＧＦＲ２抗体医薬品と抗ＶＥＧＦ抗体医薬品を併用することにより奏効する患者を検査するキットであって、
患者試料中のＶＥＧＦ－Ａ濃度を測定するための試薬を含むことを特徴とする検査キット。 A kit for testing patients who respond by using an anti-VEGFR2 antibody drug and an anti-VEGF antibody drug in combination.
A test kit comprising a reagent for measuring VEGF-A concentration in a patient sample. 血管新生が増悪の原因となる疾患に対し、
抗ＶＥＧＦＲ２抗体医薬品と抗ＶＥＧＦ抗体医薬品を併用投与する治療方法。 For diseases in which angiogenesis causes exacerbations
A therapeutic method in which an anti-VEGFR2 antibody drug and an anti-VEGF antibody drug are administered in combination. 請求項１０に記載の治療方法であって、
抗ＶＥＧＦＲ２抗体医薬品と抗ＶＥＧＦ抗体医薬品は、同時に、又は個別のタイミングで併用投与する治療方法。 The treatment method according to claim 10.
A therapeutic method in which an anti-VEGFR2 antibody drug and an anti-VEGF antibody drug are administered simultaneously or in combination at individual timings. 抗ＶＥＧＦＲ２抗体医薬品投与前、及び投与後早期に血中ＶＥＧＦ濃度を測定し、
抗ＶＥＧＦＲ２抗体医薬品投与後、血中ＶＥＧＦ濃度の有意な増加が認められた場合には、
抗ＶＥＧＦＲ２抗体医薬品と抗ＶＥＧＦ抗体医薬品を併用投与する請求項１０、又は１１に記載の治療方法。 Anti-VEGFR2 antibody Blood VEGF concentration was measured before and early after administration of the drug.
If a significant increase in blood VEGF concentration is observed after administration of the anti-VEGFR2 antibody drug,
The treatment method according to claim 10 or 11, wherein the anti-VEGFR2 antibody drug and the anti-VEGF antibody drug are administered in combination.
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JP2010538972A (en) * 2007-08-20 2010-12-16 ブリストル−マイヤーズ スクイブ カンパニー Use of a VEGFR-2 inhibitor for the treatment of metastatic cancer
WO2018124153A1 (en) * 2016-12-28 2018-07-05 公益財団法人がん研究会 Biomarker for predicting therapeutic effect of anti-vegfr-2 antibody drug, screening method, and screening kit

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