JP2018524981A - 患者由来異種移植片を用いた非hlaマッチヒト化nsgマウスモデル - Google Patents
患者由来異種移植片を用いた非hlaマッチヒト化nsgマウスモデル Download PDFInfo
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Abstract
【選択図】図1
Description
本出願は、米国特許法第119条(e)の下に、本明細書にその全内容が援用される、2015年6月23日に出願された米国仮特許出願第62/183,386号に、出願日の優先権を請求する。
本発明の1つの側面は、ヒト化免疫不全非肥満糖尿病(NOD)マウスであって:(1)scid突然変異に関してホモ接合性であり;(2)IL−2受容体ガンマ鎖不全を有し;(3)CD34+ヒト造血幹細胞(HSC)を生着(engrafted)させており;(4)ヒト患者由来異種移植片を接種されており;HSCおよびPDXが非HLAマッチである(例えば部分的にしかマッチしないか、またはマッチしない)、前記マウスを提供する。
特定の態様において、IL−2受容体ガンマ鎖不全は、遺伝子ヌル突然変異、例えばIl2rgtm1Wjlである。他の態様において、IL−2受容体ガンマ鎖不全は、IL−2Rガンマ鎖における一部切除(truncation)突然変異(例えば細胞外または細胞内ドメインのラッチング)である。
特定の態様において、マウスは、ヒト胸腺および肝臓断片をさらに外科的に移植されている、雌NSGマウス、例えばhu−BLT NSGTMマウス(BLTマウスまたはBLTヒト化マウス)である。
特定の態様において、マウスは、ヒトインターロイキン−3(IL−3)、ヒト顆粒球/マクロファージ刺激因子(GM−CSF)、および/またはヒトSteel因子(SF)を構成的に発現する導入遺伝子をさらに含む。
特定の態様において、CD34+ヒトHSCは、約2〜4週齢、例えば約2週齢、3週齢、または4週齢のマウスに生着される。
特定の態様において、約0.5〜10x106細胞(例えば約1〜9x106細胞、約2〜8x106細胞、約3〜7x106細胞、約4〜6x106細胞、または約5x106細胞)のヒトPDXを接種する。
特定の態様において、マウスには、抗癌化合物が投与される。例えば、抗癌化合物は、5−FU、アバスチン、シスプラチン、カルボプラチン、キートルーダ、ドセタキセル、またはその組み合わせである。特定の態様において、抗癌化合物は化学療法試薬である。特定の態様において、抗癌化合物は前臨床薬剤である。特定の態様において、抗癌化合物は、免疫調節剤、例えば、PD−1またはそのリガンド/受容体の調節剤、あるいはCTLA−4またはそのリガンド/受容体の調節剤である。特定の態様において、抗癌化合物は、抗PD−1および/または抗PD−L1剤、例えば抗PD−1抗体および/または抗PD−L1抗体である。
特定の態様において、抗癌剤は、養子移入(adaptive transfer)前に腫瘍特異的抗原によってプライミングされている養子移入された樹状細胞である。
特定の態様において、マウスは、IL−2受容体ガンマ鎖不全に関してホモ接合性または半接合性である。
癌治療に対する伝統的なアプローチは、迅速に分裂する細胞、例えば腫瘍/癌細胞に対して毒性である、広域作用化学剤を利用する。この化学療法アプローチは成功することもありうるが、広い範囲のオフ・ターゲット毒性によって複雑なものになる可能性もあり、そして薬剤耐性を誘導するリスクを有する。哺乳動物免疫系は、病原体に感染した細胞および癌性になった細胞を含む、ターゲット細胞を排除するための多くの効率的で非常に特異的な機構を発展させてきている。これに反応して、腫瘍細胞は、免疫検出を回避するためのそれ自体の機構セットを発展させてきている。したがって、免疫エフェクター細胞および腫瘍の間の相互作用のよりよい理解を得ることで、臨床使用のための、永続性がある免疫仲介性の腫瘍退行を刺激する治療戦略の新規でそして有望な手段への道が開く。このクラスの新規免疫腫瘍学治療戦略は、非常に有望であるが、この分野におけるさらなる研究は、ヒト免疫および腫瘍細胞相互作用のより優れた生物学的理解に関する洞察を可能にし、そして臨床適用に移行する際に、成功するより高い確率を有する新規療法の前臨床試験を可能にする、対象のヒト化小動物モデルに基づく(例えばマウスに基づく)in vivo試験プラットホームから利益を受けうる。
本発明のヒト化マウスは、いくつかのみを挙げると、癌生物学、免疫腫瘍学、再生医学、ヒト造血、感染性疾患、移植、前臨床薬剤有効性試験研究、ならびに免疫および自己免疫を含む、広い範囲の生物学的、医学的、および臨床研究において使用可能である。
対象のヒト化マウスモデルはまた、前臨床予測研究においても使用可能であり、したがって、生着させたヒト造血系の存在下で、対象のマウスモデルにおいて、患者特異的異種移植片(例えば癌由来のPDX)を研究することも可能である。対象のマウスモデルに対する1またはそれより多い投与計画の下に、こうした試験化合物または薬剤を投与することによって、任意の試験化合物または薬剤の効果、安全性(例えば免疫系に対する何らかの関連副作用)、および有効性を研究することも可能である。これは特に、免疫腫瘍学または免疫調節剤の研究、あるいは疾患組織(例えば癌、自己免疫疾患)および免疫系の間の相互作用を伴う任意の研究において強力である。
2.定義
別に示さない限り、本明細書で用いる科学的および技術的用語は、一般の当業者に一般的に理解される意味を有すると意図される。こうした用語は、例えば、J. SambrookおよびD. W. Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press;第3版, 2001; F. M. Ausubel監修, Short Protocols in Molecular Biology, Current Protocols;第5版, 2002; B. Albertsら, Molecular Biology of the Cell, 第4版, Garland, 2002; D. L. NelsonおよびM. M. Cox, Lehninger Principles of Biochemistry, 第4版, W.H. Freeman & Company, 2004; Herdewijn, P.(監修), Oligonucleotide Synthesis: Methods and Applications, Methods in Molecular Biology, Humana Press, 2004; A. Nagy, M. Gertsenstein, K. Vintersten, R. Behringer(監修) 2002, Manipulating the Mouse Embryo: A Laboratory Manual, 第3版, Cold Spring Harbor Laboratory Press, ISBN−10: 0879695919;およびK. Turksen(監修), “Embryonic Stem Cells: Methods And Protocols in Methods,” Mol. Biol., 185:499, 2002, Humana Press; Current Protocols in Stem Cell Biology, ISBN: 9780470151808を含む、多様な標準的参考文献の背景で定義され、そして用いられていることが見出される。
用語「発現する」、「発現」、「発現している」、および「発現する」は、遺伝子に関するか、または対応するmRNAを産生するための遺伝子の転写、そして/または機能的な対応するコードタンパク質を産生するためのmRNAの翻訳を指す。
SCIDの一般的な型には:IL2RG遺伝子におけるガンマ鎖遺伝子突然変異およびリンパ球表現型T(−)B(+)NK(−)によって特徴付けられるX連鎖SCID;ならびにJak3遺伝子突然変異およびリンパ球表現型T(−)B(+)NK(−)、ADA遺伝子突然変異およびリンパ球表現型T(−)B(−)NK(−)、IL−7Rアルファ鎖突然変異およびリンパ球表現型T(−)B(+)NK(+)、CD3デルタまたはイプシロン突然変異およびリンパ球表現型T(−)B(+)NK(+)、RAG1/RAG2突然変異およびリンパ球表現型T(−)B(−)NK(+)、アルテミス遺伝子突然変異およびリンパ球表現型T(−)B(−)NK(+)、CD45遺伝子突然変異およびリンパ球表現型T(−)B(+)NK(+)によって特徴付けられる常染色体劣性SCIDが含まれる。
場合によって、本発明の遺伝子修飾免疫不全非ヒト動物(例えばマウス)は、選択的育種によって産生される。第一の望ましい遺伝子型を有する非ヒト動物の第一の親系統を、第二の望ましい遺伝子型を有する非ヒト動物の第二の親系統と交配して、第一および第二の望ましい遺伝子型を有する、遺伝子修飾非ヒト動物である子孫を生じることも可能である。
本発明の側面にしたがって提供される、scid突然変異と組み合わせて、IL2受容体ガンマ鎖不全を有する、遺伝子修飾された免疫不全マウスは、NSGマウス、NSGSマウス、ヒトCD34+ HSC生着NSG/NSGSマウス、またはヒトCD34+生着BLTマウスであることも可能である。
用語「造血幹細胞」は、本明細書において、免疫系を生じさせる機能を有する、多能性幹細胞を指す。マウス由来の造血幹細胞は、c−Kit受容体を発現する。c−Kit受容体は、当該技術分野に周知であり、例えば、Vandenbarkら, “Cloning and structural analysis of the human c−kit gene,” Oncogene, 7(7): 1259−1266, 1992;およびEdling & Hallberg, “c−Kit−−a hematopoietic cell essential receptor tyrosine kinase,” Int. J. Biochem. Cell Biol., 39(11):1995−1998, 2007に記載される通りである。ヒト造血幹細胞はCD34を発現する。CD34は、例えばSimmonsら, “Molecular cloning of a cDNA encoding CD34, a sialomucin of human hematopoietic stem cells,” J. Immunol., 148(1):267−271, 1992に記載されるような、周知のタンパク質である。
特定の態様において、HSCは、細胞マーカー、例えばCD34に関する選択によって精製される。
場合によって、免疫系の特定の細胞集団、例えば樹状細胞、形質細胞様樹状細胞、骨髄樹状細胞、マスト細胞、単球/マクロファージ、ナチュラルキラー細胞、好中球、好塩基球および好酸球、Tリンパ球(CD3+CD4+またはCD3+CD8+ T細胞)、Bリンパ球(例えばCD19+ B細胞)をアッセイする。
Jackson Laboratory NSGマウス(NOD.Cg−Prkdcscid Il2rgtm1Wjl/SzJ、ストック番号005557)はまた、一般的に、NOD scidガンマ;NSG;NOD−scid IL2Rガンマヌル;およびNOD−scid IL2Rgヌルとしても知られる。これらは、NOD/ShiLtJバックグラウンド(Jackson Laboratoryストック番号001976)、重症複合免疫不全突然変異(scid)およびIL2受容体ガンマ鎖不全の特徴を合わせ持つ。その結果、NSGマウスは、成熟T細胞、B細胞(そしてしたがってマウス抗体を産生しない)、および機能するNK細胞を欠き、補体系を持たず、そしてサイトカインシグナル伝達が欠損しており、他の公表されているマウス系統いずれよりも、ヒト造血幹細胞(HSC)および末梢血単核細胞(PBMC)のより優れた生着を導く。NSGマウスはまた、欠陥マクロファージおよび樹状細胞も有する。最近の刊行物によって、膵島移植、造血幹細胞および癌幹細胞の研究における、この系統の驚くべき有用性が立証されてきている。
単純化のため、特定の態様において、多様なNSGまたはNSG由来マウス系統を集合的に、NSGマウスと称することも可能である。
本明細書に記載する発明の非ヒト動物(例えばマウス)、組成物、および方法は、特定の例示的態様、代表的態様の現在の代表であり、そしてそうでなければ本発明の範囲に対する限定とは意図されない。その改変および他の使用が、当業者に思い浮かぶであろう。こうした改変および他の使用は、請求項に示すような本発明の範囲から逸脱することなく、実行可能である。
NOD.Cg−PrkdcscidIl2rgtml Wjl/SzJ(NOD−scid IL2rγヌル、NSG)マウスをJackson Laboratory(メイン州バーハーバー)で開発され、そして維持されているコロニーから得た。すべての動物を、特定病原体除去施設で、マイクロアイソレーターケージ中で飼育し、そしてオートクレーブされたフードを与え、そして1週おきにスルファメトキサゾール−トリメトプリム添加水(Goldline Laboratories、フロリダ州フォート・ローダーデール)および酸性化オートクレーブ水で維持した。
Pearsonら(Curr. Protoc. Immunol. 81:15.21.1−15.21.21, 2008)に記載されるように、24〜72時間齢(新生)NSGマウスの群に、100cGyで照射する。Brehmら(Clinic. Immunol. 135(1):84−98, 2010)に記載されるように、照射したマウスに、25〜50μL体積中、3×104 CD34+造血幹細胞(HSC)を含有するCD3 T細胞枯渇ヒト臍帯血(UCB)を、心内注射を通じて注射する。12週後、HSCレシピエントの血液のフローサイトメトリー分析によって、ヒト免疫系の生着を定量化する。実験研究には、>20%の末梢ヒトCD45+細胞および>5%のヒトCD3+ T細胞を有するマウスのみを用いる。
実質的に実施例2に上述するように、NSGマウスのヒト化を行った。簡潔には、標準的技術を用い、側方尾静脈注射を通じて、約0.2〜1x106 CD34+HSCを注射する前に、約3週齢NSGマウスの群を全身照射(約200cGy)に供した。3つの異なる癌試料(乳癌細胞BR0620、肺癌細胞LG1208、および膀胱癌細胞BL0440)を用いたPDX異種移植片を、対象のヒト化NSGマウスモデル、すなわち、HLAミスマッチHSCドナーから得た、樹立され、そして機能的に成熟したヒト免疫細胞を含む、hu−CD34 NSGマウス内に皮下移植し、そしてPDX生着の増殖を、PDX生着後最長約55日まで監視した。3つの腫瘍はすべて、ロバストな増殖を示し、そして拒絶の明らかな徴候はなかった(図1)。
実施例4 Hu−CD34 NSGTMマウスにおける腫瘍増殖に対するPDX生着の時間的評価
非HLAマッチヒト化hCD34+ NSGマウスにおけるPDX異種移植片腫瘍増殖に対するいかなる時間的影響も評価するため、約5x106ヒトSKOV3卵巣癌細胞を、実質的に上記の実施例2および3に記載するような方法にしたがって、非HLAマッチヒトCD34+細胞注射の2または12週後のいずれかに、NSGマウスに接種した。体重および腫瘍体積を週2回監視しながら、異種移植片を約7週間さらに増殖させた。ヒトCD45+ドナー細胞生着の度合いを分析するため、マウスから末梢血を研究終了時に収集した。各7匹のマウス2群(2週対12週)からの平均結果を図2に示した。
これらの上記実験で取り組まれていない重要な問題は、ヒト免疫細胞の存在が、正常非ヒト化NSGマウスにおける増殖率に比較して、腫瘍増殖率に影響を及ぼすかどうかであった。
上に示すように、ヒト化NSGマウスが非HLAマッチヒト腫瘍の増殖を支持可能であることは、この前臨床試験プラットホームの開発において、重要な知見であった。
プログラム細胞死タンパク質1(PD−1およびCD279としても知られる)は、ヒトにおいて、PDCD1遺伝子によってコードされるタンパク質である。PD−1は、免疫グロブリン(Ig)スーパーファミリーのCD28ファミリーに属し、そしてT細胞、プロB細胞、単球、ナチュラルキラー細胞、および多くの腫瘍浸潤リンパ球(TIL)上に発現される、免疫阻害細胞表面受容体である。該タンパク質は、重要な免疫「チェックポイント」受容体であり、T細胞反応を阻害し、そしてT細胞機能の調節において重要な役割を果たす。
非HLAマッチPD−L1陽性乳癌細胞株MDA−MB−231細胞を非HLAマッチPD−L1陽性乳癌細胞株BR1126細胞、三重陰性乳癌細胞(TNBC)細胞株で置き換えた本実施例では、実施例7と実質的に同じ結果を得た。三重陰性乳癌は、治療オプションが限定されている、悪性度が高い乳癌のサブセットである。PD−L1発現はTNBC患者で報告されている。PD−L1発現をTILにおいて評価する際、これはより高い悪性度およびより大きい腫瘍と相関する。腫瘍PD−L1発現はまた、TNBCにおけるT制御細胞の浸潤とも相関し、この知見は、TNBCにおける免疫反応の制御における、PD−L1発現腫瘍およびPD−1/PD−L1発現TILの役割を示唆する。
hu−CD34 NSGマウスにおける腫瘍の組み合わせ治療が、いずれかの単剤療法よりも、より高い有効性を示すかどうかを決定するため、実験を行った。
Claims (23)
- ヒト化免疫不全非肥満糖尿病マウスであって:
(1)scid突然変異に関してホモ接合性であり;
(2)IL−2受容体ガンマ鎖不全を有し;
(3)CD34+ヒト造血幹細胞(HSC)を生着させており;
(4)ヒト患者由来異種移植片(PDX)を接種されており;
前記HSCおよび前記PDXは非HLAマッチである、前記マウス。 - ヒト胸腺および肝臓断片をさらに外科的に移植されている、雌NSGマウスである、請求項1のマウス。
- ヒトインターロイキン−3(IL−3)、ヒト顆粒球/マクロファージ刺激因子(GM−CSF)、および/またはヒトSteel因子(SF)を構成的に発現する導入遺伝子をさらに含む、請求項1のマウス。
- 前記scid突然変異がCg−Prkdcscidである、請求項1のマウス。
- 前記IL−2受容体ガンマ鎖不全がIl2rgtm1Wjlである、請求項1のマウス。
- NOD.Cg−Prkdcscid Il2rgtm1Wjl/SzJ(すなわち、NOD scidガンマ(NSG))である、請求項1のマウス。
- 前記CD34+ヒトHSCが尾静脈注射を通じて生着される(好ましくはマウスは雌である)、請求項1のマウス。
- 前記CD34+ヒトHSCが約3週齢のマウスに生着される、請求項1のマウス。
- 前記CD34+ヒトHSCがマウスの全身放射線照射(例えば約700〜1300cGyの線量)後に生着される、請求項1のマウス。
- マウスに前記CD34+ヒトHSCを生着させた約2週間後に、前記ヒトPDXが前記マウスに接種される、請求項1のマウス。
- マウスに前記CD34+ヒトHSCを生着させた約12週間後に、前記ヒトPDXが前記マウスに接種される、請求項1のマウス。
- 前記ヒトPDXが初代患者試料由来である、請求項1のマウス。
- 前記ヒトPDXが、少なくとも1世代、異種移植片として継代されている、アーカイブされた腫瘍試料由来である、請求項1のマウス。
- 前記ヒトPDXが、卵巣癌、非小細胞肺癌(NSCLC)のような肺癌、膀胱癌、リンパ腫(例えばAML、CML、ALL、CLL、DLBCL(びまん性大細胞型B細胞リンパ腫))、三種陰性乳癌(TNBC)のような乳癌、脳癌、膵臓癌、前立腺癌、結腸癌、結腸直腸癌、子宮内膜癌、胃/GIST癌、肝細胞癌、腎臓癌/腎癌、皮膚癌(例えば黒色腫)、柔組織癌、肉腫、または癌細胞株由来の異種移植片である、請求項1のマウス。
- 約5x106細胞の前記ヒトPDXを接種される、請求項1のマウス。
- マウス末梢血中のヒトCD45+細胞の割合が、PDX接種後50日(またはHSC生着後約9週)で約20〜30%に到達する、請求項1のマウス。
- 抗癌化合物が投与される、請求項1のマウス。
- 抗癌化合物が、5−FU、アバスチン、シスプラチン、カルボプラチン、キートルーダ、ドセタキセル、またはその組み合わせである、請求項17のマウス。
- マウスがIL−2受容体ガンマ鎖不全に関してホモ接合性または半接合性である、請求項1のマウス。
- 患者由来異種移植片を用いてヒト化免疫不全非肥満糖尿病マウスを作製する方法であって:
(1)免疫不全非肥満糖尿病マウスに、CD34+ヒト造血幹細胞(HSC)を導入すること、ここでマウスは:
(a)scid突然変異に関してホモ接合性であり;そして
(b)IL−2受容体ガンマ鎖不全を有する;
(2)前記マウスに、ヒト患者由来異種移植片(PDX)を接種すること、ここで前記HSCおよび前記PDXは非HLAマッチである、
を含む、前記方法。 - 腫瘍を治療するための複数の抗腫瘍剤に関して、有効性順位序列を予測する方法であって:
(1)前記の複数の抗腫瘍剤の各1つを、単剤として、請求項1のマウスに投与し、そして有効性を決定すること、ここで前記PDXは前記腫瘍に相当する;
(2)前記の複数の抗腫瘍剤の各1つに関して、有効性を比較しそして/または順位付けし、それによって前記腫瘍を治療するための前記の複数の抗腫瘍剤に関して、有効性順位序列を予測すること、
を含む、前記方法。 - 2またはそれより多い候補剤を用いた、腫瘍を治療するための組み合わせ療法を試験する方法であって:
(1)前記の2またはそれより多い候補剤を、単剤としてまたは組み合わせとしてのいずれかで、請求項1のマウスに投与し、そして有効性を決定すること、ここで前記PDXは前記腫瘍に相当する;
(2)組み合わせの有効性および単剤の有効性を比較すること、ここで単剤の相加的有効性に比較して組み合わせの有効性がより高ければ、組み合わせが優れていることの指標となる、
を含む、前記方法。 - 剤を用いて腫瘍を治療するための投与計画の有効性および/または安全性を決定する方法であって:
(1)請求項1のマウスに前記剤を投与すること、ここで前記PDXは前記腫瘍に相当し、そして前記剤は前記投与計画にしたがって投与される;
(2)有効性および/または安全性を決定すること、
を含む、前記方法。
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