JP7442555B2 - 免疫チェックポイントモジュレーターおよび共生微生物叢による発酵産物の併用がん療法 - Google Patents
免疫チェックポイントモジュレーターおよび共生微生物叢による発酵産物の併用がん療法 Download PDFInfo
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Description
本出願は35 U.S.C.§119に基づいて2016年3月30日に出願された米国仮出願第62/315259号の利益を主張するものであり、その内容全体が参照により本明細書に組み込まれる。
本明細書に記載される併用がん療法は、免疫チェックポイントモジュレーターおよび活性剤としての発酵ダイズ組成物などの発酵組成物の使用を含む。
免疫チェックポイントタンパク質とは、自己寛容を維持するために、ならびに付随する組織損傷を最小化するために末梢組織における生理学的免疫応答の持続時間および大きさを調節するために、免疫系を調節する(例えば、免疫系のシグナルを上げるかまたは下げるかのいずれか)多くの調節経路に関与する分子を指す。典型的には、免疫チェックポイントタンパク質はがん細胞(例えば、腫瘍)によって調節不全にされる。いかなる特定の理論にも束縛されることを望まないが、免疫チェックポイントタンパク質は、例えば、Pardollら、Nature Reviews Cancer、12:252-264、2012によって記載されているように、抗がん療法としてモジュレーター(活性化剤または阻害剤)で標的化され得る。
いくつかの実施形態において、本明細書に記載される併用抗がん療法に使用するための免疫チェックポイントモジュレーターは、免疫チェックポイント分子に特異的に結合し、例えば、同族リガンドへのその結合を妨げることによって、その生物活性を阻害する抗体である。本明細書に使用される場合、「抗体」という用語は、限定されないが、ポリクローナル、モノクローナル、ヒト化、キメラ、Fab断片、Fv断片、F(ab’)断片、およびF(ab’)2断片、ならびに一本鎖抗体(scFv)、融合タンパク質および抗体の抗原結合部位を含む他の合成タンパク質が挙げられる。
いくつかの実施形態において、チェックポイントモジュレーターは、低分子干渉RNA(siRNA)ショートヘアピンRNA(shRNA)などの干渉RNAである。いくつかの実施形態において、チェックポイントモジュレーターはチェックポイントタンパク質のmRNAに結合し、その翻訳をブロックするか、またはRNA干渉を介してmRNAを分解する低分子干渉RNA(siRNA)である。例示的な低分子干渉RNAは、Hannonら、Nature、418(6894):244-51(2002);Brummelkampら、Science 21(2002);およびSuiら、Proc.Natl Acad.Sci.USA 99、5515-5520(2002)に記載されている。RNA干渉(RNAi)は、サイレンシングされた遺伝子と配列が相同な二本鎖(dsRNA)によって開始される動物における配列特異的な転写後遺伝子サイレンシングのプロセスである。siRNAは一般にRNA二重鎖であり、それぞれの鎖の長さは20~25(例えば19~21)塩基対である。いくつかの実施形態において、チェックポイントモジュレーターは、チェックポイントタンパク質またはその断片の核酸(例えば、mRNA)に相補的であるショートヘアピンRNA(shRNA)である。shRNAは、典型的には19~29塩基対のステム、少なくとも4ヌクレオチド(nt)のループ、および任意選択で3’末端にジヌクレオチドオーバーハングを含む。対象におけるshRNAの発現は、shRNAをコードするベクター(例えば、プラスミドまたはウイルスもしくは細菌ベクター)の送達によって得ることができる。siRNAおよびshRNAは、当該技術分野において公知のまたは商業的に利用可能な任意の方法を使用して設計することができる(例えば、DharmaconおよびLife Technologiesから入手可能な製品を参照のこと)。siRNAはまた、標的mRNAに対するその安定性および結合親和性を少なくとも改善するために塩基修飾および/または結合修飾などの1つ以上の化学修飾を含んでもよい。
免疫チェックポイントモジュレーター、例えば、抗体、コード核酸または核酸セット、このようなものを含むベクター、siRNA、アンチセンスRNA、およびこのようなものを保有するベクター、ならびに小分子モジュレーターのいずれかは、標的疾患(例えば、がん)を治療する際に使用するための医薬組成物を形成するために薬学的に許容される担体(賦形剤)と混合され得る。「許容される」は、担体が組成物の活性成分と適合性でなければならず(好ましくは、活性成分を安定化することができ)、治療される対象に有害ではないことを意味する。緩衝液を含む薬学的に許容される賦形剤(担体)は、当該技術分野において周知である。例えば、Remington:The Science and Practice of Pharmacy 20th Ed.(2000)Lippincott Williams and Wilkins、Ed.K.E.Hooverを参照のこと。
発酵は、酵母および細菌などの微生物が、嫌気性条件下で炭水化物を酸(例えば、乳酸などの有機酸)、アルコール(例えば、エタノール)および/または他の代謝産物に変換する代謝過程である。本明細書に記載される併用抗がん療法において使用するための発酵組成物は、1種以上の適切な微生物、例えば共生微生物叢の集団による1種以上のマメ科植物の発酵産物である。このような発酵成分は、例えば従来の発酵プロセスにより、1種以上の適切な微生物によって、適切な出発物質、例えば、マメ科植物、その部分(例えば、葉、果実、種子など)、またはそれらの抽出物を発酵させることから誘導される多数の代謝産物を含んでもよい。適切な微生物としては、限定されないが、酵母および乳酸菌が挙げられる。例えば、米国特許出願公開第20060251748号(それらの関連する開示は、本明細書において参照される目的または主題について本明細書に参照として組み込まれる)を参照されたい。いくつかの実施形態において、本明細書に記載される発酵組成物は、乳酸、酢酸、および3-アミノイソ酪酸などの代謝産物の1つまたは複数を含んでもよい。例えば、発酵組成物は、約5~20重量%(例えば、5~10重量%、10~20重量%、5~15重量%、または15~20重量%)の乳酸を含んでもよい。あるいは、またはさらに、発酵組成物は、5重量%未満の酢酸、3-アミノイソ酪酸、またはその両方(例えば、1~5重量%、0.5~5重量%、1~3重量%、0.5~3重量%、または3~5重量%)を含んでもよい。
本開示はまた、本明細書に記載される免疫チェックポイントモジュレーターのいずれか、およびまた、本明細書に記載される発酵組成物(例えば、発酵ダイズ組成物)のいずれかを用いてがんを治療する際に使用するためのキットを提供する。このようなキットは、免疫チェックポイントモジュレーターおよび発酵組成物を含む1つ以上の容器を含んでもよい。例えば、キットは、抗PD1抗体またはそのコード核酸、および発酵ダイズ組成物を含んでもよい。
本明細書に記載される免疫チェックポイントモジュレーターおよび発酵組成物の組み合わせを使用する併用がん療法が本明細書に提供される。本明細書において使用される場合、併用療法という用語は、逐次様式でのこれらの薬剤(例えば、免疫チェックポイントモジュレーターおよび発酵組成物)の投与を包含し、すなわち、各治療剤は異なる時間に投与され、ならびにこれらの治療剤、または少なくとも2つの治療剤の投与は実質的に同時にされる。各薬剤の連続的または実質的に同時の投与は、限定されないが、経口経路、静脈内経路、筋肉内経路、皮下経路、および粘膜組織を介した直接吸収を含む、任意の適切な経路によって影響を受け得る。薬剤は同じ経路または異なる経路によって投与されてもよい。例えば、第1の薬剤(例えば、発酵組成物)を経口投与することができ、第2の薬剤(例えば、抗PD1抗体などの抗チェックポイント抗体)を静脈内投与することができる。さらに、選択された組み合わせの薬剤は静脈内注射によって投与されてもよく、一方、組み合わせの他の薬剤は経口的に投与されてもよい。あるいは、例えば、薬剤の2つ以上が静脈内注射または皮下注射によって投与されてもよい。
本発明の実施は、他に示さない限り、分子生物学(組換え技術を含む)、微生物学、細胞生物学、生化学および免疫学の従来の技術を利用し、これらは、当該技術分野の範囲内である。このような技術は、Molecular Cloning:A Laboratory Manual、第2版(Sambrookら、1989)Cold Spring Harbor Press;Oligonucleotide Synthesis(M.J.Gait、ed.、1984);Methods in Molecular Biology、Humana Press;Cell Biology:A Laboratory Notebook(J.E.Cellis、ed.、1998)Academic Press;Animal Cell Culture(R.I.Freshney、ed.、1987);Introduction to Cell and Tissue Culture(J.P.MatherおよびP.E.Roberts、1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle、J.B.Griffiths、およびD.G.Newell、eds.、1993-8)J.WileyおよびSons;Methods in Enzymology(Academic Press,Inc.);Handbook of Experimental Immunology(D.M.WeirおよびC.C.Blackwell、eds.);Gene Transfer Vectors for Mammalian Cells(J.M.MillerおよびM.P.Calos、eds.、1987);Current Protocols in Molecular Biology(F.M.Ausubelら、eds.、1987);PCR:The Polymerase Chain Reaction、(Mullisら、eds.、1994);Current Protocols in Immunology(J.E.Coliganら、eds.、1991);Short Protocols in Molecular Biology(WileyおよびSons、1999);Immunobiology(C.A.JanewayおよびP.Travers、1997);Antibodies(P.Finch、1997);Antibodies:a practical approach(D.Catty.、ed.、IRL Press、1988-1989);Monoclonal antibodies:a practical approach(P.ShepherdおよびC.Dean、eds.、Oxford University Press、2000);Using antibodies:a laboratory manual(E.HarlowおよびD.Lane(Cold Spring Harbor Laboratory Press、1999);The Antibodies(M.ZanettiおよびJ.D.Capra、eds.、Harwood Academic Publishers、1995)などの文献に十分に説明されている。
組成物Xは、以下のように調製した発酵ダイズ組成物である。ダイズの水性抽出物を従来の方法によって調製した。乳酸菌および酵母の混合物を、微生物によるダイズ抽出物の発酵を可能にする条件下で、水性ダイズ抽出物を含有する培地中で培養した。発酵液を回収し、濾過して固形物を除去し、滅菌した。こうして調製した液体溶液を濃縮して、組成物X(液体形態)を生成した。組成物Xの1ミリグラムは、約2.7gのダイズの発酵ブロスを含有する。
組成物Xを、上記の実施例1に記載したように調製した。組成物Xおよび抗PD1抗体の肺がんに対する併用療法の有効性を、肺がんマウスモデルにおいて以下のように調べた。
組成物Xを、上記実施例1に記載される方法に従って調製した。静脈内投与した組成物Xおよび抗PD1抗体の結腸がんに対する併用療法の有効性を、以下のように結腸がんマウスモデルにおいて調べた。
抗PD1抗体および組成物Xを、図1Aに示す手順に従って、結腸がんCT26細胞を移植したBalb/cマウスに与えた。処置後、処置マウスの近接結腸組織を17日目に切除し、マウスを屠殺し、次世代シークエンス技術による微生物叢解析に供した。結果は、結腸がんを有するマウスを抗PD1/組成物Xの組み合わせで処理した場合、いかなる処置も行わない結腸がんを有するマウスと比較して、細菌種のいくつかが変化したことを示した。例示的な細菌種を表5に列挙した。
本明細書に開示される特徴の全ては、任意の組み合わせで組み合わせることができる。本明細書に開示される各特徴は、同じ、等価な、または類似の目的を果たす代替の特徴によって置き換えられてもよい。したがって、特に明記しない限り、開示される各特徴は、等価または類似の特徴の一般的なシリーズの例に過ぎない。
いくつかの本発明の実施形態を本明細書に説明および例示してきたが、当業者は本明細書に説明される機能を実施し、ならびに/または結果および/もしくは1つもしくは複数の利点を得るための様々な他の手段および/または構造を容易に想定し、そのような変形および/または修飾の各々は本明細書に説明される本発明の実施形態の範囲内にあるとみなされる。より一般的には当業者であれば、本明細書に記載された全てのパラメーター、寸法、材料、および構成は例示的であることを意図し、実際のパラメーター、寸法、材料、および/または構成は具体的な適用、または発明の教示が使用される適用に依存することは容易に認識するであろう。当業者であれば、慣用的な実験のみを使用して、本明細書に記載された具体的な本発明の実施形態に対する多くの等価物を認識し、またはそれを確認することができる。従って、これまでの実施形態は例のみによって提示され、添付の特許請求の範囲およびその等価物の範囲内で、発明的実施形態は、具体的に記載され、および特許請求されるものとは異なる方法で実施することができると理解されるべきである。本開示の発明的実施形態は、本明細書に記載された各個々の特徴、系、物品、材料、キットおよび/または方法を対象とする。加えて、2つ以上のそのような特徴、系、物品、材料、キット、および/または方法のいずれの組み合わせも、そのような特徴、系、物品、材料、キット、および/または方法が相互に矛盾しないならば、本開示の発明的範囲内に含まれる。
Claims (24)
- がんを治療するための医薬またはキットを製造するための免疫チェックポイントモジュレーターおよび発酵組成物の組み合わせの使用であって、前記組み合わせが、前記免疫チェックポイントモジュレーター単独と比較してより増強された、前記免疫チェックポイントモジュレーターの抗がん作用を提供し、
前記免疫チェックポイントモジュレーターが、PD-1に特異的な抗体であり、
前記発酵組成物が、酵母及び乳酸菌を含む複数の微生物によるダイズ又はその水性抽出物の発酵によって生成される複数の代謝産物を含む、使用。 - 前記発酵組成物が、経口投与または静脈内投与によって投与するためのものである、請求項1に記載の使用。
- 前記発酵組成物が液体形態である、請求項1又は2に記載の使用。
- 前記複数の代謝産物が、乳酸、酢酸、および/または3-アミノイソ酪酸の組み合わせを含む、請求項1~3のいずれか一項に記載の使用。
- 前記発酵組成物が、5~20重量%の乳酸、5重量%未満の酢酸、および5重量%未満の3-アミノイソ酪酸を含む、請求項4に記載の使用。
- 前記発酵組成物が、
(i)前記ダイズ又はその水性抽出物の発酵を可能にする条件下で、前記ダイズ又はその水性抽出物を含む培地中で酵母及び乳酸菌を増殖させる工程と、
(ii)工程(i)から得られた発酵組成物を収集する工程と
を含むプロセスによって調製される、請求項1~5のいずれか一項に記載の使用。 - 調製するプロセスが、工程(ii)から得られた発酵組成物を濾過する工程、前記発酵組成物を滅菌する工程、および/または前記発酵組成物を濃縮する工程をさらに含む、請求項6に記載の使用。
- 前記発酵組成物が、前記免疫チェックポイントモジュレーターの投与前、その投与後、またはその投与と同時に投与するためのものである、請求項1~7のいずれか一項に記載の使用。
- 前記抗体が、ヒト抗体、ヒト化抗体、またはキメラ抗体である、請求項1~8のいずれか一項に記載の使用。
- 前記がんが、結腸がん、肺がん、乳がん、膵臓がん、皮膚がん、脳がん、卵巣がん、腎臓がん、胃がん、頭頸部がん、食道がん、膀胱がん、直腸がん、骨がん、子宮がん、前立腺がん、および血液悪性腫瘍からなる群から選択される、請求項1~9のいずれか一項に記載の使用。
- 必要とする対象におけるがんを治療するための医薬またはキットを製造するための発酵組成物の使用であって、前記発酵組成物が、酵母及び乳酸菌を含む複数の微生物によるダイズ又はその水性抽出物の発酵によって生成される複数の代謝産物を含み、前記対象が、免疫チェックポイントモジュレーターを含む抗がん療法を受けていたか、または受けており、
前記免疫チェックポイントモジュレーターが、PD-1に特異的な抗体であり、
前記発酵組成物が、前記免疫チェックポイントモジュレーターと組み合わせて、前記免疫チェックポイントモジュレーター単独と比較してより増強された、前記免疫チェックポイントモジュレーターの抗がん作用を提供する、使用。 - 前記発酵組成物が、経口投与または静脈内投与によって投与するためのものである、請求項11に記載の使用。
- 前記発酵組成物が液体形態である、請求項11又は12に記載の使用。
- 前記複数の代謝産物が、乳酸、酢酸、および/または3-アミノイソ酪酸の組み合わせを含む、請求項11~13のいずれか一項に記載の使用。
- 前記発酵組成物が、5~20重量%の乳酸、5重量%未満の酢酸、および5重量%未満の3-アミノイソ酪酸を含む、請求項14に記載の使用。
- 前記発酵組成物が、
(i)前記ダイズ又はその水性抽出物の発酵を可能にする条件下で、前記ダイズ又はその水性抽出物を含む培地中で、酵母及び乳酸菌を増殖させる工程と、
(ii)工程(i)から得られた前記発酵組成物を収集する工程と
を含むプロセスによって調製される、請求項11~15のいずれか一項に記載の使用。 - 調製するプロセスが、工程(ii)から得られた前記発酵組成物を濾過する工程、前記発酵組成物を滅菌する工程、および/または前記発酵組成物を濃縮する工程をさらに含む、請求項16に記載の使用。
- 前記抗体が、ヒト抗体、ヒト化抗体、またはキメラ抗体である、請求項11~17のいずれか一項に記載の使用。
- 前記がんが、結腸がん、肺がん、乳がん、膵臓がん、皮膚がん、脳がん、卵巣がん、腎臓がん、胃がん、頭頸部がん、食道がん、膀胱がん、直腸がん、骨がん、子宮がん、前立腺がん、および血液悪性腫瘍からなる群から選択される、請求項11~18のいずれか一項に記載の使用。
- (i)PD-1に特異的な抗体である免疫チェックポイントモジュレーターと、
(ii)発酵組成物と
を含むキットまたは医薬組成物であって、
前記発酵組成物が、酵母及び乳酸菌を含む複数の微生物によるダイズ又はその水性抽出物の発酵によって生成される複数の代謝産物を含み、
前記複数の代謝産物が、乳酸、酢酸、および/または3-アミノイソ酪酸の組み合わせを含む、キットまたは医薬組成物。 - 前記発酵組成物が液体形態である、請求項20に記載のキットまたは医薬組成物。
- 前記発酵組成物が、
(i)前記ダイズ又はその水性抽出物の発酵を可能にする条件下で、前記ダイズ又はその水性抽出物を含む培地中で酵母及び乳酸菌を増殖させる工程と、
(ii)工程(i)から得られた発酵組成物を収集する工程と
を含むプロセスによって調製される、請求項20~21のいずれか一項に記載のキットまたは医薬組成物。 - 前記調製するプロセスが、工程(ii)から得られた発酵組成物を濾過する工程、前記発酵組成物を滅菌する工程、および/または前記発酵組成物を濃縮する工程をさらに含む、請求項22に記載のキットまたは医薬組成物。
- 前記発酵組成物が、5~20重量%の乳酸、5重量%未満の酢酸、および5重量%未満の3-アミノイソ酪酸を含む、請求項20~23のいずれか一項に記載のキットまたは医薬組成物。
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