JP6948685B2 - 抗癌作用増強剤及び癌治療支援方法 - Google Patents
抗癌作用増強剤及び癌治療支援方法 Download PDFInfo
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Description
(1)インターフェロンλ4をコードするポリヌクレオチド;インターフェロンλ4;又はインターフェロンλ4をリガンドとする受容体に対するアゴニストを有効成分として含有する抗癌剤の抗癌作用増強剤。
(2)上記インターフェロンλ4は配列番号2に示すアミノ酸配列又は当該アミノ酸配列に対して90%以上の同一性を有するアミノ酸配列からなることを特徴とする(1)記載の抗癌作用増強剤。
(3)上記抗癌剤は、5−フルオロウラシル又はシスプラチンであることを特徴とする(1)記載の抗癌作用増強剤。
(4)インターフェロンλ4遺伝子の発現量に基づいて用量を増減することを特徴とする(1)記載の抗癌作用増強剤。
(5)インターフェロンλ3をコードするIL-28B遺伝子におけるss469415590で規定される多型がメジャーアレルかマイナーアレルかに基づいて用量を増減することを特徴とする(1)記載の抗癌作用増強剤。
(6)投与対象患者を、インターフェロンλ4遺伝子の発現量が低い癌患者とすることを特徴とする(1)記載の抗癌作用増強剤。
(7)投与対象患者を、インターフェロンλ3をコードするIL-28B遺伝子におけるss469415590で規定される多型がメジャーアレルである癌患者とすることを特徴とする(1)記載の抗癌作用増強剤。
(8)インターフェロンλ4遺伝子の発現を特異的に検出可能な手段を用いて、被験体におけるインターフェロンλ4遺伝子の発現を測定する工程と、被験体におけるインターフェロンλ4遺伝子の発現量に基づいて、抗癌剤と(1)〜(7)いずれか記載の抗癌作用増強剤との併用効果を判定する、癌治療支援方法。
(9)上記手段は、インターフェロンλ4遺伝子の転写産物を特異的に増幅する一対のプライマーと、当該一対のプライマーにて増幅された核酸に対して特異的にハイブリダイズするプローブとを有することを特徴とする(8)記載の癌治療支援方法。
(10)上記(1)〜(7)いずれか記載の抗癌作用増強剤と、抗癌剤とを組み合わせてなる医薬組成物。
(11)上記抗癌剤は、5−フルオロウラシル又はシスプラチンであることを特徴とする(10)記載の医薬組成物。
(12)上記(1)〜(7)いずれか記載の抗癌作用増強剤を含む、抗癌剤と併用される医薬組成物。
(13)上記抗癌剤は、5−フルオロウラシル又はシスプラチンであることを特徴とする(12)記載の医薬組成物。
インターフェロンλ4(IFNλ4或いはIFNL4)とは、Ludmila Prokunina-Olsson et al., Nat Genet. 2013 Feb; 45(2):164-71に開示されるように、インターフェロンλ3遺伝子(IFNL3遺伝子、IL28B遺伝子)の上流に位置する多型であって、ssID番号(Submitted SNP ID number):ss469415590で規定される多型によって作られる遺伝子にコードされる。ss469415590で規定される多型は、一塩基挿入/欠失型(Indel型)の多型であり、メジャーアレルがTTであり、マイナーアレルがΔG(メジャーアレルにおける5’側のTが欠失する多型(rs67272382又はrs11322783)と、メジャーアレルにおける3’側のTがGとなる多型(rs74597329)との組み合わせ)となる。このss469415590で規定される多型がマイナーアレル(ΔG)である場合、フレームシフトが生じることとなり179個のアミノ酸配列からなるインターフェロンλ4が生成される。
本発明に係る抗癌作用増強剤は、上述したインターフェロンλ4をコードするポリヌクレオチドをベクターに組み入れ、当該ベクターを用いて目的とする組織(例えば肝臓)において発現させることができるように調製できる。ベクターとしては、特に限定されず、ヒトに使用することができる各種ベクターを用いることができる。ベクターとしては、ウイルスベクター及び非ウイルスベクターのいずれを用いてもよい。
また、本発明に係る抗癌作用増強剤は、有効成分が上述したインターフェロンλ4(タンパク質)である場合、定法に従って調整することができる。すなわち、配列番号2のアミノ酸配列に基づいて、上記タンパク質を得ることができる。かかるタンパク質は、そのアミノ酸配列をコードするポリヌクレオチドの発現によって、原核生物又は真核生物の宿主細胞内に生成することができる。あるいは、かかるタンパク質は化学的方法で合成することができる。
一方、上述したように、インターフェロンλ4は、リガンドとして受容体であるIL-10Rα及びIL-28Rβを介してシグナル伝達に関与する。詳細を後述の実施例で示したように、インターフェロンλ4の発現を強化することで、抗癌剤による癌細胞の増殖抑制効果を増強することができ、癌の進行を抑制することができ、又は癌を改善することができることから、インターフェロンλ4の受容体と相互作用するアゴニストもまた、抗癌剤による癌細胞の増殖抑制効果を増強することができ、癌の進行を抑制することができ、又は癌を改善することができる。
本発明に係る抗癌作用増強剤は、抗癌剤による癌細胞の増殖抑制効果を増強するものである。
ここで、抗癌剤としては、特に限定されないが、化学療法剤、ホルモン療法剤、免疫療法剤及び分子標的薬等を挙げることができる。すなわち、本発明に係る抗癌作用増強剤は、これらから選ばれる1種以上の薬剤(以下、併用薬剤と略記することがある)と組み合わせて使用することができる。これらの活性成分(薬剤)は、低分子化合物であってもよく、また高分子の蛋白、ポリペプチド、抗体であるか、あるいはワクチン等であってもよい。また、活性成分(薬剤)は、2種以上を適宜の割合で混合して用いてもよい。
本発明に係る抗癌作用増強剤は、上述のように、ポリヌクレオチド、タンパク質又はその部分断片、若しくはアゴニストを有効成分として含有するが、これら有効成分に加え、任意の担体、例えば医薬上許容される担体を含むことができる。
以上のように、本発明に係る抗癌作用増強剤は、上述した抗癌剤による癌細胞の増殖抑制効果を増強させるが、インターフェロンλ4遺伝子が発現していないか、当該遺伝子の発現量が低い患者に対する抗癌作用増強効果をより期待することができる。したがって、インターフェロンλ4遺伝子の発現に基づいて、本発明に係る抗癌作用増強剤と抗癌剤との併用効果を判定する癌治療支援方法を実現することができる。
本実施例では、Child-Pugh分類A或いはB、かつ肝外病変のない109例の肝細胞癌症例を対象として、CDDP+5FU+IFNαのレジメで肝動注化学療法を施行したときの奏功率をIL28B遺伝子多型メジャー型(rs8099917のメジャーアレル(TT))とマイナー型(rs8099917のマイナーアレル(TG又はGG))について比較した。
IFNA1 Forward primer 5’-ATGGCCTCGCCCTTTGC-3’(配列番号6)
IFNA1 Reverse primer 5’-TCACTTGTCATCGTCATCCTTGTAGTCTTCCTTCCTCCTTAATC-3’(配列番号7)
IL28B Forward primer 5’-ATGACCGGGGACTGCATG-3’(配列番号8)
IL28B Reverse primer 5’-TCACTTGTCATCGTCATCCTTGTAGTCGACACACAGGTCCCCG-3’(配列番号9)
IFNL4 Forward primer 5’-ATGCGGCCGAGTGTCTG-3’(配列番号10)
IFNL4 Reverse primer 5’-TCACTTGTCATCGTCATCCTTGTAGTCGAGGCAAGGCCCAGAG-3’(配列番号11)
本実施例では、IFNλ4と抗癌剤とを併用したときの抗腫瘍効果を検証した。
先ず、Huh7.5細胞 (12 well plate、1×105個) に、実施例1で作製したIFNA1-FLAG発現プラスミド500ng又はIFNL4-FLAG発現プラスミド500ngをFuGENE6 Transfection regent (Promega) を用いて導入した。24時間後、5FUを10ig/ml処置した。この時間をDay0 (D0) とした。その後、D0、D1、D2、D3及びD4においてCell Counting Kit-8 (DOJINDO) を用いて細胞増殖能を評価した。
本実施例では、IFNλ4を特異的に検出するための測定系を確立した。すなわち、図11に示すIFNλ4をコードするコーディング領域の塩基配列、p107、p124、p131、p143及びp170に関する同塩基配列に基づいて、IFNλ4を特異的に検出可能なリアルタイムPCR用のプライマー、プローブセットを設計した。図11にプライマーセット(フォワードプライマー及びリバースプライマー)の位置及びプローブの位置を示した。
Forward primer 5’-CTCCGCGGCCATCGT-3(配列番号12)
Reverse primer 5’-AGACCACGCTGGCTTTGC-3(配列番号13)
Probe 5’-TGCCTTGAGCTGGCA-3’ (FAM)(配列番号14)
本実施例では、上述のようにATF2-cJUN経路を介したアポトーシス誘導活性を有するIFNλ4を組み換えタンパク質として精製する系を確立した。
Claims (10)
- インターフェロンλ4をコードするポリヌクレオチド;又は
インターフェロンλ4を有効成分として含有する5−フルオロウラシル又はシスプラチンの抗癌作用増強剤。 - 上記インターフェロンλ4は配列番号2に示すアミノ酸配列又は当該アミノ酸配列に対して90%以上の同一性を有するアミノ酸配列からなることを特徴とする請求項1記載の抗癌作用増強剤。
- インターフェロンλ4遺伝子の発現量に基づいて用量を増減することを特徴とする請求項1記載の抗癌作用増強剤。
- インターフェロンλ3をコードするIL-28B遺伝子におけるss469415590で規定される多型がメジャーアレルかマイナーアレルかに基づいて用量を増減することを特徴とする請求項1記載の抗癌作用増強剤。
- 投与対象患者を、インターフェロンλ4遺伝子の発現量が低い癌患者とすることを特徴とする請求項1記載の抗癌作用増強剤。
- 投与対象患者を、インターフェロンλ3をコードするIL-28B遺伝子におけるss469415590で規定される多型がメジャーアレルである癌患者とすることを特徴とする請求項1記載の抗癌作用増強剤。
- 5−フルオロウラシル又はシスプラチンと請求項1〜6いずれか一項記載の抗癌作用増強剤との併用効果を判定するためのデータの取得方法であって、
インターフェロンλ4遺伝子の発現を特異的に検出可能な手段を用いて、採取した生体サンプルにおけるインターフェロンλ4遺伝子の発現を測定する工程を含み、
上記データは、当該生体サンプルにおけるインターフェロンλ4遺伝子の発現量が低い場合に前記併用効果が高いことを示す、上記データの取得方法。 - 上記手段は、インターフェロンλ4遺伝子の転写産物を特異的に増幅する一対のプライマーと、当該一対のプライマーにて増幅された核酸に対して特異的にハイブリダイズするプローブとを有することを特徴とする請求項7記載の方法。
- 請求項1〜6いずれか一項記載の抗癌作用増強剤と、5−フルオロウラシル又はシスプラチンとを組み合わせてなる癌治療用医薬組成物。
- 請求項1〜6いずれか一項記載の抗癌作用増強剤を含む、5−フルオロウラシル又はシスプラチンと併用される癌治療用医薬組成物。
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