JP6359028B2 - テロメラーゼ阻害剤を用いて細胞増殖性障害を処置するための診断マーカー - Google Patents
テロメラーゼ阻害剤を用いて細胞増殖性障害を処置するための診断マーカー Download PDFInfo
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Description
この出願は、2012年11月30日に出願された米国仮特許出願第61/732,263号、2013年3月13日に出願された米国仮特許出願第61/780,851号、2013年3月13日に出願された米国特許出願第13/802,035号、2013年3月15日に出願された米国仮特許出願第61/798,478号、および2013年4月5日に出願された米国仮特許出願第61/809,228号への優先権(これらの開示は、その全体が参考として本明細書に援用される)を主張する。
本発明は、テロメラーゼ阻害化合物による処置から利益を得ると思われる、がんを有する、またはがんを有する疑いのある個体を同定する方法およびこれらの個体を処置する方法に関する。
がんは、世界的な死亡の主因である。化学療法の分野における顕著な進歩にもかかわらず、がんの最も高頻度な型の多くは、依然として化学療法的介入に抵抗したままである。
本明細書を通して、さまざまな特許、特許出願および他のタイプの刊行物(例えば雑誌論文)が参照される。本明細書に引用されたすべての特許、特許出願および刊行物の開示は、すべての目的のために、それら全体が参照により本明細書に組み込まれる。
I.一般技術
II.定義
III.テロメラーゼ阻害化合物
A.低分子化合物
B.オリゴヌクレオチド系テロメラーゼ阻害剤:配列および組成物
C.脂質−オリゴヌクレオチド接合体
D.医薬組成物
IV.発明の方法
A.細胞増殖性障害
B.テロメラーゼ阻害剤処置から利益を得ると思われる個体を選択する方法
1.生体試料の獲得
2.生体試料におけるテロメア長の測定
a.ホルマリン固定・パラフィン包埋(FFPE)試料におけるqPCR
b.テロメア蛍光インサイツハイブリダイゼーション(telo−FISH)
1.376×log2(強度)−6.215×√(面積)[方程式1]
の方程式を使用して計算され、式中、「強度」は、テロメアの強度として定義され、「面積」は、その周りにひかれた線により画定されたテロメアの面積として定義される。
3.テロメラーゼ阻害剤による処置から利益を得ると思われる、がんを有すると診断された、またはがんを有する疑いのある個体の選択
C.テロメラーゼ阻害剤を使用して、細胞増殖性障害を処置する方法
D.テロメラーゼ阻害剤の投与
オリゴヌクレオチドN3’→P5’ホスホルアミデート(NP)またはN3’→P5’チオホスホルアミデート(NPS)の調製および脂質接合体
本実施例は、脂質接合オリゴヌクレオチドN3’→P5’ホスホルアミデート(NP)またはN3’→P5’チオホスホルアミデート(NPS)の合成方法を示す。
材料および方法
出発化合物
脂質の結合
FlashPlate(商標)アッセイ
(実施例2)
イメテルスタットのNSC第II相(CP14B−012)試験由来のホルマリン固定・パラフィン包埋試料におけるqPCR
材料および方法
臨床試験のデザイン
ホルマリン固定およびパラフィン包埋
DNAの抽出
定量的PCR(qPCR)
結果
(実施例3)
NSC第II相(CP14B)試験由来のホルマリン固定・パラフィン包埋試料におけるTelo−FISH
材料および方法
1.376×log2(強度)−6.215×√(面積)[方程式1]
に従って、生体試料に由来する細胞に関する平均テロメア長を決定した。
初期結果
後期結果
(実施例4)
イメテルスタットのNSC第II相(CP14B−012)試験由来のホルマリン固定・パラフィン包埋試料におけるqPCR
定量的PCR(qPCR)
結果
例えば、本発明は以下の項目を提供する。
(項目1)
テロメラーゼ阻害剤による処置から利益を得ると思われる、がんを有すると診断された、またはがんを有する疑いのある個体を選択する方法であって、
a.該個体由来の生体試料中に存在するがん細胞におけるテロメア核酸の相対的長さを分析することによって、相対的テロメア長を決定するステップ;および
b.該個体由来の生体試料中に存在する該がん細胞における平均相対的テロメア長が、1以上の公知の標準から決定された相対的テロメア長範囲の50パーセンタイル以下である事が決定される場合、テロメラーゼ阻害剤による処置から利益を得ると思われる個体を選択するステップ、
を含む方法。
(項目2)
がんを有すると診断された、またはがんを有する疑いのある個体を処置する方法であって、
a.該個体由来の生体試料中に存在するがん細胞におけるテロメア核酸の相対的長さを分析することによって相対的テロメア長を決定するステップ;
b.該個体由来の生体試料中に存在する該がん細胞における平均相対的テロメア長が、1以上の公知の標準から決定された相対的テロメア長範囲の50パーセンタイル以下である事が決定される場合、テロメラーゼ阻害剤による処置から利益を得ると思われる個体を選択するステップ;ならびに
c.治療有効量の該テロメラーゼ阻害剤を該個体に投与するステップ、を含む方法。
(項目3)
がんを有すると診断された、またはがんを有する疑いのある個体を処置する方法であって、該個体由来の生体試料中に存在するがん細胞における平均相対的テロメア長が、1以上の公知の標準から決定された相対テロメア長範囲の50パーセンタイル以下であることが決定されている場合、治療有効量のテロメラーゼ阻害剤を該個体に投与するステップ、を含む方法。
(項目4)
前記テロメラーゼ阻害剤がオリゴヌクレオチドを含む、項目2に記載の方法。
(項目5)
前記オリゴヌクレオチドが、テロメラーゼのRNA成分に相補的である、項目4に記載の方法。
(項目6)
前記オリゴヌクレオチドが10−20塩基対の長さであり、少なくとも1つのN3’→P5’チオホスホルアミデートヌクレオシド間結合を含む、項目5に記載の方法。
(項目7)
前記テロメラーゼ阻害剤が、イメテルスタット(Imetelstat)である、項目5に記載の方法。
(項目8)
前記がんが固形腫瘍である、項目1に記載の方法。
(項目9)
前記がんが、非小細胞肺がん、小細胞肺がん、膀胱がん、上部胃腸がん、胃がん、胆嚢がん、卵巣がん、神経膠芽腫、肉腫または血液がんである、項目1に記載の方法。
(項目10)
前記テロメラーゼ阻害剤が、薬学的に許容され得る賦形剤と一緒に投与される、項目2に記載の方法。
(項目11)
治療有効量の1以上の追加のがん治療作用物質を、前記個体に投与するステップをさらに含む、項目1に記載の方法。
(項目12)
平均テロメア長が、qPCR、telo−FISHまたはサザンブロットにより決定される、項目1に記載の方法。
(項目13)
前記個体がヒトである、項目1に記載の方法。
(項目14)
前記1以上の公知の標準が、特徴付けられた細胞系である、項目1に記載の方法。
(項目15)
前記細胞系が、M14細胞、A549細胞、SK−5細胞およびOvcar5細胞からなる群から選択される、項目14に記載の方法。
(項目16)
前記特徴付けられた細胞系が、項目1に記載の生体試料のタイプを代表する細胞系から選択される、項目14に記載の方法。
(項目17)
前記特徴付けられた細胞系が、非小細胞肺がん細胞系、肝細胞細胞系または卵巣細胞系である、項目16に記載の方法。
(項目18)
前記1以上の公知の標準が、複数の個体由来の複数の天然腫瘍から確立されたテロメア長範囲である、項目1に記載の方法。
(項目19)
複数の天然腫瘍由来の前記がん細胞が、前記個体由来の前記生体試料中に存在する前記がん細胞と同じタイプである、項目18に記載の方法。
(項目20)
前記生体試料中に存在する前記がん細胞における前記テロメア長が、前記テロメア長範囲の40パーセンタイル、35パーセンタイル、30パーセンタイル、25パーセンタイル、20パーセンタイル、15パーセンタイル、10パーセンタイル、5パーセンタイルの範囲であること、または該テロメア長範囲より短いことが決定される、項目1に記載の方法。
Claims (31)
- がんを有すると診断された、またはがんを有する疑いのある個体の平均相対的テロメア長を、テロメラーゼ阻害剤による処置から利益を得ると思われる個体を選択するための指標として用いる方法であって、該がんが固形腫瘍であり、該方法は、
該個体由来の生体試料中に存在するがん細胞におけるテロメア核酸の相対的長さを分析することによって、相対的テロメア長を決定するステップを含み、
ここで、該個体由来の生体試料中に存在する該がん細胞における平均相対的テロメア長であって、1以上の公知の標準から決定された相対的テロメア長範囲の50パーセンタイル以下である事が決定される平均相対的テロメア長が、テロメラーゼ阻害剤による処置から利益を得ると思われる個体を選択する指標であり、
該1以上の公知の標準が、複数の個体由来の複数の天然腫瘍由来のがん細胞から確立されたテロメア長範囲であり、該複数の天然腫瘍由来の該がん細胞が、該個体由来の該生体試料中に存在する該がん細胞と同じタイプであるか、または
該1以上の公知の標準が、特徴付けられた細胞系である、方法。 - がんを有すると診断された、またはがんを有する疑いのある個体を処置するための、治療有効量のテロメラーゼ阻害剤を含む組成物であって、該がんが固形腫瘍であり、該組成物は以下:
a.該個体由来の生体試料中に存在するがん細胞におけるテロメア核酸の相対的長さを分析することによって相対的テロメア長を決定するステップ;ならびに
b.該個体由来の生体試料中に存在する該がん細胞における平均相対的テロメア長が、1以上の公知の標準から決定された相対的テロメア長範囲の50パーセンタイル以下である事が決定される場合、該個体をテロメラーゼ阻害剤による処置から利益を得ると思われる個体として選択するステップ
を含む方法によって選択された個体に投与されることを特徴とし、
該1以上の公知の標準が、複数の個体由来の複数の天然腫瘍由来のがん細胞から確立されたテロメア長範囲であり、該複数の天然腫瘍由来の該がん細胞が、該個体由来の該生体試料中に存在する該がん細胞と同じタイプであるか、または
該1以上の公知の標準が、特徴付けられた細胞系である、組成物。 - がんを有すると診断された、またはがんを有する疑いのある個体を処置するための、治療有効量のテロメラーゼ阻害剤を含む組成物であって、該がんが固形腫瘍であり、該組成物が、該個体に投与され、該個体が、該個体由来の生体試料中に存在するがん細胞における平均相対的テロメア長が、1以上の公知の標準から決定された相対的テロメア長範囲の50パーセンタイル以下であることが決定されている場合に選択されることを特徴とし、
該1以上の公知の標準が、複数の個体由来の複数の天然腫瘍由来のがん細胞から確立されたテロメア長範囲であり、該複数の天然腫瘍由来の該がん細胞が、該個体由来の該生体試料中に存在する該がん細胞と同じタイプであるか、または
該1以上の公知の標準が、特徴付けられた細胞系である、組成物。 - 前記テロメラーゼ阻害剤がオリゴヌクレオチドを含む、請求項2または3に記載の組成物。
- 前記オリゴヌクレオチドが、テロメラーゼのRNA成分に相補的である、請求項4に記載の組成物。
- 前記オリゴヌクレオチドが10−20塩基対の長さであり、少なくとも1つのN3’→P5’チオホスホルアミデートヌクレオシド間結合を含む、請求項5に記載の組成物。
- 前記テロメラーゼ阻害剤が、イメテルスタット(Imetelstat)である、請求項6に記載の組成物。
- 前記がんが、肺がん、乳がん、肝臓がん、卵巣がん、胃がん、胃腸がん、胆嚢がん、膀胱がん、神経膠芽腫、肉腫、黒色腫、結腸直腸がんおよび膵臓がんから選択される、請求項2または3に記載の組成物。
- 前記がんが、非小細胞肺がんである、請求項2または3に記載の組成物。
- 薬学的に許容され得る賦形剤をさらに含む、請求項2または3に記載の組成物。
- 治療有効量の1以上の追加のがん治療作用物質をさらに含む、請求項2または3に記載の組成物。
- 相対的テロメア長が、qPCR、telo−FISHまたはサザンブロットにより決定される、請求項2または3に記載の組成物。
- 前記個体がヒトである、請求項2または3に記載の組成物。
- 前記1以上の公知の標準が、特徴付けられた細胞系である、請求項2または3に記載の組成物。
- 前記特徴付けられた細胞系が、M14細胞、A549細胞、SK−5細胞およびOvcar5細胞からなる群から選択される、請求項14に記載の組成物。
- 前記特徴付けられた細胞系が、前記個体由来の生体試料のタイプを代表する細胞系から選択される、請求項14に記載の組成物。
- 前記特徴付けられた細胞系が、非小細胞肺がん細胞系、肝細胞細胞系または卵巣細胞系である、請求項16に記載の組成物。
- 前記生体試料中に存在する前記がん細胞における前記平均相対的テロメア長が、前記1以上の公知の標準から決定された前記相対的テロメア長範囲の40パーセンタイル、35パーセンタイル、30パーセンタイル、25パーセンタイル、20パーセンタイル、15パーセンタイル、10パーセンタイル、もしくは5パーセンタイル、またはそれ未満の範囲であることが決定される、請求項2または3に記載の組成物。
- 前記テロメラーゼ阻害剤がオリゴヌクレオチドを含む、請求項1に記載の方法。
- 前記オリゴヌクレオチドが、テロメラーゼのRNA成分に相補的である、請求項19に記載の方法。
- 前記オリゴヌクレオチドが10−20塩基対の長さであり、少なくとも1つのN3’→P5’チオホスホルアミデートヌクレオシド間結合を含む、請求項20に記載の方法。
- 前記テロメラーゼ阻害剤が、イメテルスタット(Imetelstat)である、請求項21に記載の方法。
- 前記がんが、肺がん、乳がん、肝臓がん、卵巣がん、胃がん、胃腸がん、胆嚢がん、膀胱がん、神経膠芽腫、肉腫、黒色腫、結腸直腸がんおよび膵臓がんから選択される、請求項1に記載の方法。
- 前記がんが、非小細胞肺がんである、請求項1に記載の方法。
- 相対テロメア長が、qPCR、telo−FISHまたはサザンブロットにより決定される、請求項1に記載の方法。
- 前記個体がヒトである、請求項1に記載の方法。
- 前記1以上の公知の標準が、特徴付けられた細胞系である、請求項1に記載の方法。
- 前記特徴付けられた細胞系が、M14細胞、A549細胞、SK−5細胞およびOvcar5細胞からなる群から選択される、請求項27に記載の方法。
- 前記特徴付けられた細胞系が、前記個体由来の生体試料のタイプを代表する細胞系から選択される、請求項27に記載の方法。
- 前記特徴付けられた細胞系が、非小細胞肺がん細胞系、肝細胞細胞系または卵巣細胞系である、請求項29に記載の方法。
- 前記生体試料中に存在する前記がん細胞における前記平均相対的テロメア長が、前記1以上の公知の標準から決定された前記相対的テロメア長範囲の40パーセンタイル、35パーセンタイル、30パーセンタイル、25パーセンタイル、20パーセンタイル、15パーセンタイル、10パーセンタイル、もしくは5パーセンタイル、またはそれ未満の範囲であることが決定される、請求項1に記載の方法。
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