JP2020531535A - Cd33標的剤と共に使用するためのcd33エクソン2欠損型ドナー幹細胞 - Google Patents
Cd33標的剤と共に使用するためのcd33エクソン2欠損型ドナー幹細胞 Download PDFInfo
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Abstract
Description
本出願は、2017年8月28日出願の米国特許仮出願第62/551,075号(その全体が本明細書中で参考として援用される)の優先権を主張する。
ASCIIテキストファイル「01001_006139_WO0_ST25.txt」(ファイルサイズ73,728キロバイト)として提出された配列表は、その全体が本明細書中で参考として援用される。
数十年にわたる努力にも関わらず、抗体またはT細胞(T細胞受容体を介する)のいずれかによる抗原認識能力を基本原理とする治効ある免疫学的がん治療は、その達成が非常に困難である(Cousin−Frankel,Science(2013)342:1432)。抗体に基づいた免疫療法は、標的抗原(例えば、Her−2増幅乳癌におけるHer−2)が腫瘍細胞中で正常細胞と比較して上方制御される症例、または腫瘍細胞が抗体または抗体−毒素抱合体(例えば、CD20に対するリツキシマブ)によって認識され得る抗原を発現する症例(Baselga et al.,Annals Oncology(2001)12:S35)における癌に対して広く使用されている。抗体に基づいた免疫療法を使用した臨床試験では、限られた数のがん型で患者の生存が改善されている(通常は標準的な化学療法と併用した場合)が、これらの効果は、しばしば、重大な安全性および有効性の懸念を伴う(Cousin−Frankel Cancer,Science(2013)342:1432)。
本開示は、造血器悪性疾患を処置する方法であって、前述の処置を必要とする被験体に以下の:(i)CD33を標的にする薬剤の有効量であって、前述の薬剤がCD33を結合する抗原結合断片を含む、薬剤の有効量;および(ii)変異型または欠損型のエクソン2を有するCD33の成熟転写物を含む造血細胞集団、を投与する工程を含む、方法を提供する。
(a)ヒンジドメイン、
(b)膜貫通ドメイン、
(c)少なくとも1つの共刺激ドメイン、
(d)細胞質シグナル伝達ドメイン、または
(e)これらの組み合わせ
をさらに含み得る。
(i)系譜特異的細胞表面抗原を標的にする薬剤の有効量であって、前述の薬剤が、CD33である系譜特異的細胞表面抗原を結合する抗原結合断片を含む、薬剤の有効量;および
(ii)変異型または欠損型のエクソン2を有するCD33の成熟転写物を含む造血細胞集団
を投与する工程を含む、方法を含む。
(i)系譜特異的細胞表面抗原を標的にする薬剤の有効量であって、前述の薬剤が、CD33である系譜特異的細胞表面抗原を結合する抗原結合断片を含む、薬剤の有効量および
(ii)変異型または欠損型のエクソン2を有するCD33の成熟転写物を含むように遺伝子操作されている造血細胞集団
を投与する工程を含む、方法を提供する。
包袋は、カラーで作成された少なくとも1つの図面を含む。カラー図面を含む本特許または特許出願公開の複写物は、請求および必要な料金の支払いによって、特許庁より提供されるであろう。
癌細胞表面上に存在する抗原を標的にするがん免疫療法は、標的抗原が被験体の発生および/または生存に必要とされるか非常に関与する正常な非癌細胞の表面上にも存在する場合に、特に困難である。これらの抗原を標的にすることは、癌細胞に加えてかかる細胞に対しても免疫療法の細胞傷害効果が及ぶので、被験体に悪影響をもたらし得る。
用語「被験体」、「個体」、および「患者」は、互換的に使用され、脊椎動物、好ましくは、ヒトなどの哺乳動物を指す。哺乳動物は、ヒト霊長類、非ヒト霊長類、またはマウス、ウシ、ウマ、イヌ、もしくはネコの種を含むが、これらに限定されない。本開示の文脈では、用語「被験体」はまた、in vitroまたはex vivoで培養できるか、in vivoで操作できる組織および細胞を含む。用語「被験体」を、用語「生物」と互換的に使用できる。
本開示の態様は、例えば、標的癌細胞上の系譜特異的細胞表面抗原を標的にする薬剤を提供する。かかる薬剤は、系譜特異的細胞表面抗原を結合し標的にする抗原結合断片を含み得る。いくつかの例では、抗原結合断片は、系譜特異的抗原に特異的に結合する単鎖抗体(scFv)であり得る。
本明細書中で使用される場合、用語「系譜特異的細胞表面抗原」および「細胞表面系譜特異的抗原」は、互換的に使用でき、細胞表面上に十分に存在し、かつ細胞系譜(複数可)の1つまたは複数の集団に関連する任意の抗原を指す。例えば、抗原は、細胞系譜(複数可)の1つまたは複数の集団上に存在してよく、かつ他の細胞集団の細胞表面上で不在であり得る(または低レベルで存在し得る)。
任意の抗体またはその抗原結合断片を、本明細書中に記載の系譜特異的細胞表面抗原を標的にする薬剤の構築のために使用できる。かかる抗体または抗原結合断片を、従来の方法、例えば、ハイブリドーマテクノロジーまたは組換えテクノロジーによって調製できる。
いくつかの実施形態では、本明細書中に記載の系譜特異的細胞表面抗原を標的にする薬剤は、系譜特異的抗原(例えば、CD33またはCD19)に結合できる抗原結合断片(例えば、単鎖抗体)を含むキメラ受容体を発現する免疫細胞である。キメラ受容体の抗原結合断片によってその細胞表面上に系譜特異的抗原を有する標的細胞(例えば、癌細胞)が認識されると、キメラ受容体のシグナル伝達ドメイン(複数可)(例えば、共刺激シグナル伝達ドメインおよび/または細胞質シグナル伝達ドメイン)に活性化シグナルが伝達され、それはキメラ受容体を発現する免疫細胞におけるエフェクター機能を活性化できる。
本開示はまた、系譜特異的細胞表面抗原を欠損するように遺伝子改変されているHSCなどの造血細胞を提供する。いくつかの実施形態では、造血細胞は造血幹細胞である。造血幹細胞(HSC)は、骨髄系前駆細胞およびリンパ球系前駆細胞の両方を生成でき、これらの前駆細胞は、骨髄性細胞(例えば、単球、マクロファージ、好中球、好塩基球、樹状細胞、赤血球、血小板など)およびリンパ球系細胞(例えば、T細胞、B細胞、NK細胞など)をそれぞれさらに生成できる。HSCは細胞表面マーカーCD34(例えば、CD34+)の発現(これをHSCの同定および/または単離に使用できる)およびある細胞系譜への拘束に関連する細胞表面マーカーが存在しないことを特徴とする。
(i)系譜特異的細胞表面抗原を標的にする薬剤の有効量であって、前述の薬剤が、CD33である系譜特異的細胞表面抗原を結合する抗原結合断片を含む、薬剤の有効量;および
(ii)変異型または欠損型のエクソン2を有するCD33の成熟転写物を含む造血細胞集団
を投与する工程を含む、方法を含む。
(i)系譜特異的細胞表面抗原を標的にする薬剤の有効量であって、前述の薬剤が、CD33である系譜特異的細胞表面抗原を結合する抗原結合断片を含む、薬剤の有効量および
(ii)変異型または欠損型のエクソン2を有するCD33の成熟転写物を含むように遺伝子操作されている造血細胞集団
を投与する工程を含む、方法を提供する。
ウイルスベクターを、患者に直接投与でき(in vivo)、または細胞を操作するためにin vitroまたはex vivoで使用し、改変された細胞を患者に投与できる。1つの実施形態では、本開示は、遺伝子移入のためにウイルスベースのシステム(レトロウイルスベクター、レンチウイルスベクター、アデノウイルスベクター、アデノ随伴ウイルスベクター、および単純ヘルペスウイルスベクターを含むが、これらに限定されない)を利用する。さらに、本開示は、レトロウイルスまたはレンチウイルスなどの、宿主ゲノム中の組み込みができるベクターを提供する。好ましくは、本開示のCRISPR−Casシステムの発現のために使用されるベクターは、レンチウイルスベクターである。
本明細書中に記載のように、細胞表面系譜特異的抗原に結合する抗原結合断片を含む薬剤を、細胞表面系譜特異的抗原を欠損している造血細胞と組み合わせて被験体に投与できる。本明細書中で使用される場合、「被験体」、「個体」、および「患者」は、互換的に使用され、脊椎動物、好ましくは、ヒトなどの哺乳動物を指す。哺乳動物は、ヒト霊長類、非ヒト霊長類、またはマウス、ウシ、ウマ、イヌ、もしくはネコの種を含むが、これらに限定されない。いくつかの実施形態では、被験体は、造血器悪性疾患を有するヒト患者である。
細胞表面系譜特異的抗原を欠損している造血細胞集団と組み合わせた細胞表面系譜特異的抗原を標的にする薬剤を使用するためのキットも本開示の範囲内にある。かかるキットは、細胞表面系譜特異的抗原を結合する抗原結合断片を含む任意の薬剤(例えば、本明細書中に記載のキメラ受容体を発現する免疫細胞)および薬学的に許容され得る担体を含む第1の医薬組成物、ならびに細胞表面系譜特異的抗原を欠損している造血細胞集団(例えば、造血幹細胞)および薬学的に許容され得る担体を含む第2の医薬組成物を含む1つまたは複数の容器を含み得る。
本開示の実施は、別段の指示がない限り、当該分野の技術の範囲内の分子生物学(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技術を用いるであろう。かかる技術は、Molecular Cloning:A Laboratory Manual,second edition(Sambrook,et al.,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.,1989)Academic Press;Animal Cell Culture(R.I.Freshney,ed.1987);Introuction to Cell and Tissue Culture(J.P.Mather and P.E.Roberts,1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle,J.B.Griffiths,and D.G.Newell,eds.1993−8)J.Wiley and Sons;Methods in Enzymology(Academic Press,Inc.);Handbook of Experimental Immunology(D.M.Weir and C.C.Blackwell,eds.):Gene Transfer Vectors for Mammalian Cells(J.M.Miller and M.P.Calos,eds.,1987);Current Protocols in Molecular Biology(F.M.Ausubel,et al.eds.1987);PCR:The Polymerase Chain Reaction,(Mullis,et al.,eds.1994);Current Protocols in Immunology(J.E.Coligan et al.,eds.,1991);Short Protocols in Molecular Biology(Wiley and Sons,1999);Immunobiology(C.A.Janeway and P.Travers,1997);Antibodies(P.Finch,1997);Antibodies:a practice approach(D.Catty.,ed.,IRL Press,1988−1989);Monoclonal antibodies:a practical approach(P.Shepherd and C.Dean,eds.,Oxford University Press,2000);Using antibodies:a laboratory manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press,1999);The Antibodies(M.Zanetti and J.D.Capra,eds.Harwood Academic Publishers,1995);DNA Cloning:A practical Approach,Volumes I and II(D.N.Glover ed.1985);Nucleic Acid Hybridization(B.D.Hames & S.J.Higgins eds.(1985>>;Transcription and Translation(B.D.Hames & S.J.Higgins,eds.(1984>>;Animal Cell Culture(R.I.Freshney,ed.(1986>>;Immobilized Cells and Enzymes(lRL Press,(1986>>;およびB.Perbal,A practical Guide To Molecular Cloning(1984);F.M.Ausubel et al.(eds.)などの文献で十分に説明されている。
CRSPR−Cas9システムがin vitroでCD33を標的にする能力を試験するために、ヒト白血病細胞K−562を、Neon(商標)(Thermo Fisher Scientific)を使用して、Cas9−GFP(PX458、S.pyogenes)およびNGG PAM配列を含むガイドRNA(図4)(ガイドRNAを、hCD33ゲノム配列を標的にするようにデザインした)で同時トランスフェクトした。トランスフェクションから48時間後に、Cas9を発現する細胞を同定し、GFPについて選別するFACSを使用して単離した。細胞を次いで、96時間インキュベートし、フローサイトメトリーによりCD33発現について試験した(図5)。抗CD33抗体を使用するフローサイトメトリープロットは、Cas9ベクターおよびガイドRNAの送達前(上のプロット)および後(下のプロット)のK−562細胞によるCD33発現を示す。図5に示すように、98%の細胞がトランスフェクション後にCD33発現を欠いていた。
in vitroでCD45RAを標的にするためにCRISPR−Cas9システムを使用した。簡潔に述べれば、TIB−67細網肉腫マウスマクロファージ様細胞を、Neon(商標)試薬(Thermo Fisher Scientific)を使用して、Cas9−GFP(PX458、S.pyogenes)およびhCD45RAゲノム配列を標的にするCRISPR gRNA(「NGG」PAM配列を含む)で同時トランスフェクトした。トランスフェクションから48時間後に、CRISPR−Cas9システムを発現する細胞を同定し、GFPについて選別するFACSを使用して単離した。細胞を次いで、96時間インキュベートし、CD45RA発現について試験した(図6)。CD45RA抗体を使用するフローサイトメトリープロットは、Cas9ベクターおよびガイドRNAの送達前(上のプロット)および後(下のプロット)のCD45RA発現を示す。
本実施例は、AMLにおけるCD33抗原の標的化を含む。本実施例の特定の工程を、表9に概説する。
A.抗CD33CAR構築物の生成
本明細書中に記載のCD33を標的にするキメラ抗原受容体は、5’から3’への順序で以下の成分からなり得る:pHIV−Zsgreenレンチウイルスバックボーン(www.addgene.org/18121/)、ペプチドシグナル、CD33scFv、ヒンジ、CD28分子の膜貫通領域、CD28の細胞内ドメイン、およびTCR−ζ分子のシグナル伝達ドメイン。
パート1:軽鎖−リンカー−重鎖(配列番号16):Kozak開始部位を太字で示す。ペプチドシグナルL1を斜体で示す。リンカーで分離された抗CD33の軽鎖および重鎖を太字の斜体で示す。
パート2:ヒンジ−CD28/ICOS−CD3ζNotI制限酵素認識部位を、大文字で示す。翻訳停止部位を太字で示す。BamHI制限切断部位を、下線で示す。
例示的なキメラ受容体の略図を、図7のパネルA〜Dに示す。キメラ受容体を、CD33抗原を認識する細胞外ヒト化scFv(細胞外CD8ヒンジ領域によって連結される)、膜貫通ドメインおよび細胞質シグナル伝達ドメイン、ならびにCD3ζ−シグナル伝達鎖を使用して生成するであろう(図7、パネルB)。抗CD33キメラ受容体をコードするDNAを、ヒト化scFv使用して生成するであろう(Essand et al.,J Intern Med.(2013)273(2):166)。代替法は、CD28もしくはCD28/OX1またはCD28/4−1−B−Bハイブリッドの代わりにOX−1または41−BBを含むCAR T細胞を含む(図7、パネルCおよびD)。
次に、抗CD33scFvを、細胞外CD8ヒンジ領域、膜貫通ドメインおよび細胞質CD28シグナル伝達ドメイン、およびCD3ζ−シグナル伝達鎖に連結するであろう。簡潔に述べれば、抗CD33scFv配列に特異的なプライマーを使用して、上記のscFvを増幅するであろう。完全なヒトCD8コード配列を保有するプラスミド(pUN1−CD8)(www.invivogen.com/puno−cd8a)を使用して、CD8ヒンジおよび膜貫通ドメイン(アミノ酸135〜205)を増幅するであろう。CD3ζフラグメントを、完全なヒトCD3ζコード配列を保有するInvivogenプラスミド pORF9−hCD247a(http://www.invivogen.com/PDF/pORF9−hCD247a_10E26v06.pdf)から増幅するであろう。最後に、CD28(アミノ酸153〜220、CD28のTMドメインおよびシグナル伝達ドメインに対応する)を、Trizol法によって活性化T細胞から回収したRNAを使用して生成したcDNAから増幅するであろう。抗CD33−scFv−CD8−ヒンジ+TM−CD28−CD3ζを含むフラグメントを、スプライス重複伸長(SOE)PCRを使用してアセンブリするであろう。次いで、得られたPCRフラグメントを、pELPSレンチウイルスベクターにクローン化するであろう。pELPSは、第3世代レンチウイルスベクターpRRL−SIN−CMV−eGFP−WPREの誘導体であり、それはCMVプロモーターがEF−1αプロモーターに置換され、HIVのセントラルポリプリン配列がプロモーターの5’側に挿入されている(Milone et al.,Mol Ther.(2009)(8):1453,Porter et al.,NEJM(2011)(8):725)。全構築物を、配列決定によって検証するであろう。
初代ヒトCD8+T細胞を、免疫磁気分離法(Miltenyi Biotec)によって患者の末梢血から単離するであろう。T細胞を、以前に記載のように(Levine et al.,J.Immunol.(1997)159(12):5921)、完全培地(10%熱失活FBS、100U/mLペニシリン、100μg/mL硫酸ストレプトマイシン、10mM HEPESを補足したRPMI1640)中で培養し、抗CD3および抗CD28mAbをコーティングしたビーズ(Invitrogen)で刺激するであろう。
患者への抗CD33CAR T細胞のi.v.注入前に、細胞をリン酸緩衝生理食塩水で洗浄し、濃縮するであろう。無菌の閉鎖系を提供するHaemonetics CellSaver(Haemonetics Corporation,Braintree,MA)などのセルプロセッサーを、製剤化前の洗浄および濃縮工程で使用するであろう。抗CD33キメラ受容体を発現する終末T細胞を、ヒト血清アルブミンを補足した100mlの滅菌規定食塩液に処方するであろう。最後に、患者に、1〜10×107個T細胞/kgを1〜3日間にわたって注入するであろう(Maude et al.,NEJM(2014)371(16):1507)。注入される抗CD33キメラ受容体を発現するT細胞の数は、癌患者の状態、患者の年齢、以前の処置など多数の要因に依存するであろう。
患者からの幹細胞の単離、移植前処置移植前処置、および患者への幹細胞の注入に関するプロトコールは、患者の年齢、状態、治療歴、および処置が行われる施設に依るところが非常に大きいと理解される。したがって、下記のプロトコールは単なる例示であり、当業者によって日常的に最適化される。
AML患者を、10mg/kg/日の顆粒球コロニー刺激因子(G−CSF)のi.v.投与によって刺激するであろう。CD34+細胞のポジティブ選択を、免疫磁性ビーズおよび免疫磁性富化デバイスを使用して行うであろう。最少で2×106個CD34+細胞/kg体重が、FenwallCS3000+セルセパレーターを用いて収集されると予想される(Park et al.,Bone Marrow Transplantation(2003)32:889)。
自家末梢血幹細胞移植片(PBSCT)の移植前処置を、エトポシド(VP−16)+シクロホスファミド(CY)+全身照射(TBI)を使用して行うであろう。簡潔に述べれば、このレジメンは、単回用量としての26時間にわたる1.8g/m2のエトポシド(VP−16)のi.v.持続注入(c.i.v.)、その後の2時間にわたる3日間の60mg/kg/日i.v.でのシクロホスファミド(CY)、その後の3日間の300cGy/日の全身照射(TBI)からなるであろう。
インサートCas9およびピューロマイシン耐性遺伝子を含むlentiCRISPR v2を、Addgene(プラスミド番号52961)から入手するであろう(Sanjana et al.,Nat Methods(2014)(8):783)。単鎖ガイドRNA(sgRNA)CD33ガイド配列をクローン化するために、lentiCRISPR v2を切断し、FastDigest BsmBIおよびFastAP(Fermentas)を用いて37℃で2時間脱リン酸化するであろう。CD33を標的にするgRNAを、crispr.mit.edu.でのオンライン最適化デザインツールを使用してデザインするであろう。あるいは、gRNAは、図12に示す配列を有するであろう(配列番号11)。CD33gRNAオリゴヌクレオチドを、Integrated DNA Technologies(IDT)から入手し、ポリヌクレオチドキナーゼ(Fermentas)を使用して37℃で30分間リン酸化し、95℃への5分間の加熱および25℃への1.5℃/分の冷却によってアニーリングするであろう。T7リガーゼを使用して、オリゴをアニーリングし、その後にアニーリングしたオリゴをゲル精製したベクター(Qiagen)に25℃で5分間ライゲートするであろう。次いで、得られたプラスミドを、無内毒素−midi−prepキット(Qiagen)を使用して増幅できる(Sanjana et al.,Nat Methods(2014)(8):783)。
新たに単離した末梢血由来CD34+細胞(工程4由来)を、1×106細胞/mlで、細胞培養グレードの幹細胞因子(SCF)300ng/ml、FLT3−L 300ng/ml、トロンボポエチン(TPO)100ng/ml、およびIL−3 60ng/mlの存在下で無血清CellGro SCGM培地に播種するであろう。24時間の事前刺激後に、CD34+HSCを、AmaxaヒトCD34細胞Nucleofectorキット(U−008)(#VPA−1003)を使用して、Cas9およびCD33gRNAを含むLentiCRISPRv2でトランスフェクトするであろう(Mandal et al.,Cell Stem Cell(2014)15(5):643)。トランスフェクションから24〜48時間後に、CD34+CD33−細胞を1.2μg/mlピューロマイシンで選択する。ピューロマイシン選択後に、CD34+CD33−細胞を、無ピューロマイシン培地中で2日間維持するであろう。
ex vivoにてCRISPR−Cas9−CD33でトランスフェクトしたCD34+細胞(CD34+CD33−細胞)を、フィルターを使用しない標準的な血液投与セットを使用して、直ちにヒックマンカテーテルによって再注入する(Hacein−Bey Abina et al.JAMA(2015)313(15):1550)。
A.CD33免疫毒素ゲムツズマブオゾガマイシン(GO)による患者の処置
患者を、2週間間隔で2回の用量における2時間の静脈内注入として、9mg/m2の抗CD33抗体ゲムツズマブオゾガマイシン(GO)で処置するであろう(Larson et al.,Cancer(2005),104(7):1442−52)。GOは、細胞増殖抑制薬カリチアマイシンと抱合されたCD33に対するヒト化モノクローナル抗体から構成される(図8)。
CD33へのキメラ受容体の結合
CD33を結合するキメラ受容体(例えば、CART1、CART2、CART3)を、従来の組換えDNAテクノロジーを使用して生成し、pHIV−Zsgreenベクター(Addgene;Cambridge、MA)に挿入した。キメラ受容体を含むベクターを使用してレンチウイルス粒子を生成し、これを使用して、異なる細胞型、例えば、T細胞株(例えば、293T細胞)およびNK細胞株(例えば、NK92細胞)に形質導入した。キメラ受容体の発現を、ウェスタンブロッティング(図9、パネルA)およびフローサイトメトリー(図9、パネルB)によって検出した。
キメラ受容体を発現するNK−92細胞を、細胞表面上にCD33を提示する標的細胞(例えば、K562は、CD33+であるヒト慢性骨髄性白血病(新)細胞株である)の細胞傷害性を誘導する能力について機能的に特徴づけた。細胞傷害性アッセイを行うために、エフェクター細胞(NK−92細胞などの免疫細胞)を、キメラ受容体をコードするレンチウイルス粒子で感染させ、拡大した。感染から7日後に、キメラ受容体を発現する細胞を、キメラ受容体コードベクターによってもコードされる蛍光マーカー(例えば、GFP+またはRed+)について選択することによるFACS分析によって選択した。キメラ受容体を発現する選択された細胞を、1週間拡大した。感染から14日後に、標的細胞(標的細胞表面系譜特異的抗原CD33を発現する細胞)のカルボキシフルオレセインスクシンイミジルエステル(carboyxfluorescein succinimidyl ester)(CFSE)での染色ならびに標的細胞およびキメラ受容体を発現する細胞の計数を含む細胞傷害性アッセイを行った。標的細胞およびキメラ受容体を発現する細胞を、異なる比で丸底96ウェルプレート中にて4.5時間同時インキュベートし、その後に7−アミノアクチノマイシンD(7−AAD)を添加して生育不能細胞を染色した。フローサイトメトリーを行って、生存標的細胞集団および生育不能標的細胞集団を計数した。図11のパネルAおよびBに示すように、キメラ受容体CART1、CART2、またはCART3を発現するNK92細胞は、評価した各細胞比で相当量の標的K562細胞の細胞死を誘導した。
初代T細胞集団を、FACSによるCD4+細胞、CD8+細胞、またはCD4+/CD8+細胞の陽性選択によってドナーから得たPMBCから単離し、それにより、高純度の集団を得た(図13、パネルAおよびB)。各初代T細胞集団(CD4+細胞、CD8+細胞、またはCD4+/CD8+細胞)を、キメラ受容体(例えば、CART1およびCART8)を含むレンチウイルスベクターで形質導入し、それによって得られたキメラ受容体を発現する初代T細胞を使用して、上記のように細胞傷害性アッセイを行った。キメラ受容体を発現するCD4+T細胞集団のK562(1000個の標的K562細胞)との同時インキュベーションは、K562細胞の細胞傷害性を生じなかった(図14、パネルA)。対照的に、キメラ受容体を発現するCD8+細胞またはCD4+/CD8+細胞のいずれかおよび1000個の標的K562細胞を使用する細胞傷害性アッセイでは、CD8+細胞またはCD4+/CD8+細胞は、低細胞比でK562細胞の細胞死を誘導できた(図14、パネルB)。
いくつかのgRNAを、CD33のIgCドメインとハイブリッド形成するようにデザインした(例えば、表4、配列番号11または28〜31を参照のこと)。各gRNAを、K562細胞中でCas9エンドヌクレアーゼ(endonculease)と共に発現させた。CD33の発現を、フローサイトメトリーによって評価した(図15)。Crispr3(配列番号28)およびCrispr5(配列番号29)について示すように、CD33を標的にするCRISPR/Casシステムを発現する細胞において、CD33を発現する対照細胞と比較して、CD33が顕著に減少した。
ある実施形態では、本発明は、CD33遺伝子のエクソン2中に一塩基多型を示すドナーHSCの利用に関する。ある実施形態では、SNPは:CD33遺伝子のエクソン2中の(SNP)rs12459419(C>T;Ala14Val)(図19を参照のこと)である。このSNPは、SRSF2のエクソン内スプライシングエンハンサー(ESE)結合部位に干渉し、その結果、成熟転写物からエクソン2が喪失する。エクソン2によってコードされる領域は、CD33を標的にするほとんどのモノクローナル抗体の結合部位である。したがって、このSNP(またはエクソン2を喪失させる類似のSNP)と共にHSCを利用することは、系譜特異的細胞表面抗原を欠損している造血細胞集団を提供し、それ故に抗原特異的処置後に正常な造血細胞を回復できる標的化方法である。
(i)系譜特異的細胞表面抗原を標的にする薬剤の有効量であって、前述の薬剤が、CD33である系譜特異的細胞表面抗原を結合する抗原結合断片を含む、薬剤の有効量;および
(ii)CD33遺伝子のエクソン2が変異しているか欠損している造血細胞集団
を投与する工程を含む、方法を提供する。
(i)系譜特異的細胞表面抗原を標的にする薬剤の有効量であって、前述の薬剤が、CD33である系譜特異的細胞表面抗原を結合する抗原結合断片を含む、薬剤の有効量および
(ii)CD33遺伝子のエクソン2が変異するか欠損するように遺伝子操作された造血細胞集団
を投与する工程を含む、方法を提供する。
Lamba JK1,et al.,J.Clin.Oncol.2017 Aug 10;35(23):2674−2682.doi:10.1200/JCO.2016.71.2513.Epub 2017 Jun 23. CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia:Report From Randomized Phase III Children’s Oncology Group Trial AAML0531.
本明細書中に開示の全ての特徴を、任意の組み合わせで組み合わせることができる。本明細書中に開示の各特徴を、同一、等価、または類似の目的を果たす別の特徴に置き換えることができる。したがって、特に明記しない限り、開示の各特徴は、一般的な一連の等価または類似の特徴の一例にすぎない。
本明細書中にいくつかの本発明の実施形態を記載および例示しているが、当業者は、本明細書中に記載の機能を発揮し、そして/または結果および/または1つまたは複数の利点を得るための種々の他の手段および/または構造を容易に想定し、かかる変形および修正の各々が本明細書中に記載の本発明の実施形態の範囲内にあると見なされる。より一般的には、当業者は、本明細書中に記載の全てのパラメーター、寸法、材料、および構成が例示であることを意味すること、ならびに、実際のパラメーター、寸法、材料、および構成が本発明の教示が使用される特定の適用に依存することを容易に理解するであろう。当業者は、日常的な実験のみを使用して、本明細書中に記載の本発明の特定の実施形態の多数の均等物を認識するか、確認できるであろう。したがって、前述の実施形態がほんの一例として示されおり、添付の特許請求の範囲およびその均等物の範囲内で、本発明の実施形態を、具体的に説明および主張された方法以外の方法で実施できると理解すべきである。本開示の本発明の実施形態は、本明細書中に記載の個別の特徴、システム、製品、材料、キット、および/または方法に関する。さらに、かかる特徴、システム、製品、材料、キット、および/または方法が相互に矛盾しない場合、2つまたはそれを超えるかかる特徴、システム、製品、材料、キット、および/または方法の任意の組み合わせが、本開示の本発明の範囲内に含まれる。
Claims (28)
- 造血器悪性疾患を処置する方法であって、前記処置を必要とする被験体に:
(i)CD33を標的にする薬剤の有効量であって、前記薬剤が、CD33を結合する抗原結合断片を含む、薬剤の有効量;および
(ii)変異型または欠損型のエクソン2を有するCD33の成熟転写物を含む造血細胞集団
を投与することを含む、方法。 - 前記薬剤が、前記抗原結合断片を含むキメラ受容体を発現する免疫細胞である、請求項1に記載の方法。
- 前記造血細胞が、同種または自家である、請求項2に記載の方法。
- 前記造血細胞が、造血幹細胞である、請求項1に記載の方法。
- 前記造血細胞が、遺伝子操作される、請求項1に記載の方法。
- 前記造血細胞が、CD33遺伝子のエクソン2中に一塩基多型(SNP)rs12459419を含む、請求項1に記載の方法。
- 前記造血細胞が、エクソン2を欠くCD33の成熟転写物を含む、請求項1に記載の方法。
- 前記造血細胞が、変異型エクソン2を有するCD33の成熟転写物を含む、請求項1に記載の方法。
- 前記造血細胞が、IgVドメインを欠損しているCD33を含む、請求項1に記載の方法。
- 前記造血細胞が、IgVドメインを欠くCD33を含む、請求項1に記載の方法。
- 前記造血細胞が、変異型IgVドメインを有するCD33を含む、請求項1に記載の方法。
- 前記免疫細胞が、T細胞である、請求項2に記載の方法。
- 前記キメラ受容体が、
(e)ヒンジドメイン、
(f)膜貫通ドメイン、
(g)少なくとも1つの共刺激ドメイン、
(h)細胞質シグナル伝達ドメイン、または
(e)これらの組み合わせ
をさらに含む、請求項2に記載の方法。 - 前記キメラ受容体が、4−1BB、CD28、およびICOSからなる群から選択される共刺激受容体に由来する、少なくとも1つの共刺激シグナル伝達ドメインを含む、請求項13に記載の方法。
- 前記造血幹細胞が、CD34+/CD33−である、請求項4に記載の方法。
- 前記造血幹細胞が、骨髄細胞または末梢血単核球(PBMC)に由来する、請求項4に記載の方法。
- 造血器悪性疾患を処置する方法であって、前記処置を必要とする被験体に:
(i)CD33を標的にする薬剤の有効量であって、前記薬剤が、CD33を結合する抗原結合断片を含む、薬剤の有効量および
(ii)変異型または欠損型のエクソン2を有するCD33の成熟転写物を含むように遺伝子操作される造血細胞集団
を投与することを含む、方法。 - 前記造血細胞が、CRISPR−Cas9によって操作される、請求項17に記載の方法。
- 前記遺伝子操作された造血細胞が、CD33の成熟転写物からのエクソン2の喪失をもたらすようにCD33をコードする内因性遺伝子を編集することによって調製される、請求項17に記載の方法。
- 前記CRISPR−Cas9操作が、SRSF2のエクソン内スプライシングエンハンサー(ESE)結合部位に干渉しかつCD33の成熟転写物からのエクソン2の喪失をもたらす変異を作出する、請求項18に記載の方法。
- 前記造血細胞が、エクソン2を欠くCD33の成熟転写物を含む、請求項17に記載の方法。
- 前記造血細胞が、変異型エクソン2を有するCD33の成熟転写物を含む、請求項17に記載の方法。
- 前記造血細胞が、IgVドメインを欠損しているCD33を含む、請求項17に記載の方法。
- 前記造血細胞が、IgVドメインを欠くCD33を含む、請求項17に記載の方法。
- 前記造血細胞が、変異型IgVドメインを有するCD33を含む、請求項17に記載の方法。
- 前記造血細胞が、CD33を標的にする薬剤によって認識されないCD33を含む、請求項1または請求項17に記載の方法。
- 前記被験体が、ホジキンリンパ腫、非ホジキンリンパ腫、白血病、および/または多発性骨髄腫を有する、請求項1または請求項17に記載の方法。
- 前記被験体が、急性骨髄球性白血病(新)、慢性骨髄性白血病(新)、急性リンパ芽球性白血病、または慢性リンパ芽球性白血病である、白血病を有する、請求項1または請求項17に記載の方法。
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CN108290939B (zh) | 2015-10-16 | 2023-01-13 | 纽约市哥伦比亚大学理事会 | 用于抑制谱系特异性抗原的组合物和方法 |
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KR20220036908A (ko) | 2018-08-28 | 2022-03-23 | 보르 바이오파마 인크. | 유전자 조작된 조혈 줄기 세포 및 그의 용도 |
US11866494B2 (en) * | 2018-08-31 | 2024-01-09 | Innovative Cellular Therapeutics Holdings, Ltd. | CAR T therapy through uses of co-stimulation |
JP2022534813A (ja) * | 2019-05-23 | 2022-08-03 | ブイオーアール バイオファーマ インコーポレーテッド | Cd33改変のための組成物および方法 |
KR20220047380A (ko) | 2019-08-28 | 2022-04-15 | 보르 바이오파마 인크. | Cll1 변형을 위한 조성물 및 방법 |
US20220333116A1 (en) * | 2019-08-28 | 2022-10-20 | Vor Biopharma Inc. | Compositions and methods for cd123 modification |
CN114729368A (zh) * | 2019-09-09 | 2022-07-08 | 斯克里贝治疗公司 | 用于免疫疗法的组合物和方法 |
EP4048790A4 (en) * | 2019-10-22 | 2024-03-27 | Fred Hutchinson Cancer Center | REDUCTION OF CD33 EXPRESSION MEDIATED BY BASE EDITORS TO SELECTIVELY PROTECT THERAPEUTIC CELLS |
CA3180738A1 (en) * | 2020-06-03 | 2021-12-09 | Siddhartha MUKHERJEE | Compositions and methods for inhibition of lineage specific antigens using crispr-based base editor systems |
EP4204565A1 (en) | 2020-08-28 | 2023-07-05 | Vor Biopharma Inc. | Compositions and methods for cll1 modification |
EP4204564A1 (en) | 2020-08-28 | 2023-07-05 | Vor Biopharma Inc. | Compositions and methods for cd123 modification |
JP2023541458A (ja) | 2020-09-14 | 2023-10-02 | ブイオーアール バイオファーマ インコーポレーテッド | Cd5修飾のための化合物および方法 |
WO2022056489A1 (en) | 2020-09-14 | 2022-03-17 | Vor Biopharma, Inc. | Compositions and methods for cd38 modification |
WO2022061115A1 (en) | 2020-09-18 | 2022-03-24 | Vor Biopharma Inc. | Compositions and methods for cd7 modification |
WO2022067240A1 (en) | 2020-09-28 | 2022-03-31 | Vor Biopharma, Inc. | Compositions and methods for cd6 modification |
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WO2022094245A1 (en) | 2020-10-30 | 2022-05-05 | Vor Biopharma, Inc. | Compositions and methods for bcma modification |
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WO2022232411A2 (en) * | 2021-04-28 | 2022-11-03 | Eisai R&D Mangement Co., Ltd. | Antisense oligonucleotides and their use for treatment of neurodegenerative disorders |
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