JP2019506843A - 抗原特異的cd8+t細胞の産生におけるインターロイキン−10及びその使用方法 - Google Patents
抗原特異的cd8+t細胞の産生におけるインターロイキン−10及びその使用方法 Download PDFInfo
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Abstract
Description
本願は、2016年1月11日に出願された米国仮出願第62/277,442号の優先権を主張し、前記出願はその全体を参照によって本明細書に援用する。
本発明は、抗原特異的CD8+T細胞を誘発するためのIL−10剤の使用方法に関する。
サイトカインのインターロイキン−10(IL−10)は、T細胞、B細胞、マクロファージ、及び抗原提示細胞(APC)に対する作用を介して複数の免疫応答を調節する多面発現性サイトカインである。IL−10は、活性化単球及び活性化マクロファージにおけるIL−1α、IL−1β、IL−6、IL−8、TNF−α、GM−CSF及びG−CSFの発現を阻害することによって免疫応答を抑制することができ、NK細胞によるIFN−γ産生も抑制する。IL−10は主にマクロファージで発現するが、発現は活性化T細胞、B細胞、肥満細胞及び単球においても検出されている。IL−10は、免疫応答を抑制することに加えて、IL−2及びIL−4処理した胸腺細胞の増殖を刺激し、B細胞の生存率を高め、MHCクラスIIの発現を刺激することを含む免疫刺激特性を示す。
本開示は、疾患抗原特異的T細胞受容体を発現する単離されたCD8+T細胞、ならびにそのような疾患抗原特異的T細胞のT細胞受容体(TCR)のVα及びVβポリペプチド対をコードする核酸に関連する方法及び組成物を提供する。そのような疾患抗原特異的CD8+T細胞は、IL−10剤による治療を受け入れ可能な疾患を有する被験体の末梢(例えば、血液)から得ることができる。本開示はまた、単離された疾患抗原特異的CD8+T細胞の被験体への投与に関連する治療方法及び組成物、ならびに疾患抗原特異的TCR及び/またはキメラ抗原受容体を発現するように遺伝子改変したCD8+T細胞に関連する治療方法及び組成物を企図する。
本開示をさらに説明する前に、本開示は本明細書に記載の特定の実施形態に限定されるものでないことは理解されたく、また、本明細書中で使用する用語は、単に特定の実施形態を説明するためのものに過ぎず、これに限定することを意図するものでないことも理解されたい。
CAR−T T細胞療法などの遺伝子改変CD8+T細胞による治療は、例えばがん関連(例えばB細胞及びT細胞リンパ腫)ならびに免疫関連悪性腫瘍の治療のための治療的アプローチである。CAR−T T細胞には、一般的に、例えば関心対象の腫瘍上に存在する既知の抗原に特異的な組換えT細胞受容体を発現するように遺伝子改変した患者由来記憶CD8+T細胞が含まれる。本開示は、がんの治療のためにCAR−T細胞療法を用いることに関連して一般的に記載しているが、そのような療法はまた、他の適応症、例えばウイルス感染(例えば、HBV、HCV、HIV、CMV)の治療にも利用できることを理解されたい。
他に特段の指示がない限り、以下の用語は以下に示す意味を有することを意図するものとする。他の用語は、本明細書中の別の箇所において定義される。
G グリシン Gly P プロリン Pro
A アラニン Ala V バリン Val
L ロイシン Leu I イソロイシン Ile
M メチオニン Met C システイン Cys
F フェニルアラニ Phe Y チロシン Tyr
ン
W トリプトファン Trp H ヒスチジン His
K リジン Lys R アルギニン Arg
Q グルタミン Gln N アスパラギン Asn
E グルタミン酸 Glu D アスパラギン酸 Asp
S セリン Ser T スレオニン Thr
本開示は、一実施形態では、IL−10剤療法で治療可能な疾患を有する患者の末梢における疾患抗原特異的CD8+T細胞の増殖の誘導方法を提供し、本方法は、そのような疾患抗原特異的CD8+T細胞の誘導を誘発するのに有効な量のIL−10剤を患者に投与し、患者から疾患抗原特異的CD8+T細胞を採取する(例えば、末梢血試料などの患者の組織試料中のCD8+T細胞)。したがって、本開示は、IL−10剤、IL−10剤の製造方法、疾患抗原特異的CD8+T細胞の産生及びIL−10剤療法のための投薬レジメン、疾患抗原特異的CD8+T細胞の産生方法、そのようなT細胞のTCRの分析、TCRα及びβ配列及び核酸のライブラリーの作製、そのようなT細胞のTCRの抗原特異性の分析、そのようなT細胞の疾患抗原特異的TCRのTCRα及びβ配列を有する組換えTCRを発現する遺伝子改変T細胞(例えば、CAR−T)の産生、遺伝子改変T細胞組成物、ならびにそれらの製造方法及び治療における使用法、ならびに医薬組成物及びキットを提供する。いくつかの実施形態では、抗原特異的CD8+T細胞は、PD1+でもある末梢CD8+T細胞である。これらの本開示の特徴を以下に説明する。
ヒトサイトカイン合成阻害因子(CSIF)としても知られる抗炎症性サイトカインIL−10は、IL−19、IL−20、IL−22、IL−24(Mda−7)、及びIL−26、インターフェロン(IFN−α、−β、−γ、−δ、−ε、−κ、−Ω、及び−τ)ならびにインターフェロン様分子(リミチン、IL−28A、IL−28B、及びIL−29)を含むサイトカインのセットであるタイプ(クラス)−2サイトカインに分類される。
本開示のポリペプチドは、非組換え法(例えば、化学合成法)及び組換え法を含む任意の適切な方法によって産生することができる。
ポリペプチドを化学的に合成する場合、液相または固相を介して合成を進行させることができる。固相ペプチド合成(SPPS)により、非天然アミノ酸の取り込み及び/またはペプチド/タンパク質主鎖修飾が可能になる。本開示のポリペプチドを合成するために、9−フルオレニルメトキシカルボニル(Fmoc)及びt−ブチルオキシカルボニル(Boc)などの様々な形態のSPPSが利用可能である。化学合成の詳細は当技術分野で公知である(例えば、Ganesan A.(2006)Mini Rev.Med.Chem.6:3−10;及びCamarero J.A.et al.,(2005)Protein Pept Lett.12:723−8)。
ヒト及びマウスIL−10の調製を記載する方法は、例えば、組換え技術及び他の合成技術を含む、IL−10活性を有するタンパク質の製造方法を示す米国特許第5,231,012号に見出すことができる。IL−10はウイルス起源であり得、エプスタイン−バーウイルス(BCRF1タンパク質)からのウイルスIL−10のクローニング及び発現は、Moore et al.,(1990)Science 248:1230に開示されている。IL−10は、本明細書に記載するような当該技術分野で公知の標準技術を使用して、多くの方法で得ることができる。組換えヒトIL−10はまた、例えば、PeproTech,Inc.、Rocky Hill、N.Jから市販されている。
いくつかの場合には、IL−10は、ペプチド結合以外の1つ以上の結合を含み、例えば、少なくとも2つの隣接するアミノ酸が、アミド結合以外の結合を介して結合する。例えば、望ましくないタンパク質分解または他の分解手段を低減または排除するため、及び/または血清安定性を増加させるため、及び/または立体構造の自由度を制限または高めるために、IL−10の骨格内の1つ以上のアミド結合を置換することができる。
IL−10ポリペプチド中に1つ以上のアミノ酸置換を作製することができる。以下は非限定的な例である:
システイン残基またはシステインアナログをIL−10ポリペプチドに導入して、ジスルフィド結合を介して別のペプチドへの結合を提供するか、またはIL−10ポリペプチドの環化を提供することができる。システインまたはシステイン類似体の導入方法は、当該分野で公知であり;例えば、米国特許第8,067,532号を参照されたい。
本明細書中に開示する治療様式(例えば、IL−10)の1つ以上の物理的特性及び/またはそれらを投与する様式を改善することは、多くの場合に有益であり、時には不可欠である。物理的特性の改善には、例えば、免疫原性の調節;水溶性、バイオアベイラビリティー、血清半減期、及び/または治療半減期を高める方法;及び/または生物活性の調節が含まれる。特定の修飾はまた、例えば、検出アッセイ(例えば、エピトープタグ)に用いるための抗体の産生及びタンパク質精製を容易にするために有用であり得る。そのような改善は、通常、治療様式の生物活性に悪影響を及ぼさず、及び/またはその免疫原性を増加させることなく加えなければならない。
末梢PD1+,CD8+,疾患抗原特異的T細胞を誘発するために、IL−10剤(例えば、PEG−IL−10)を治療有効量で被験体に投与する。治療有効量は、治療する疾患、治療によって達成する目標、被験体に投与する他の治療剤、ならびに被験体の年齢、体重、性別、健康状態及び身体状態、投与するIL−10製剤ならびに投与経路などの一般的に評価される被験体の様々な特性などの要因を考慮して、熟練した医師によって容易に決定され得る。IL−10剤の治療有効量は、例えば、安全性及び用量漸増試験、in vivo試験(例えば、動物モデル)、及び当業者に公知の他の方法から容易に決定することができる。
本開示は、任意の適切な様式でのIL−10剤(例えば、PEG−IL−10)、及びその組成物の投与を企図する。投与の最適な経路として、非経口(例えば、筋肉内、静脈内、皮下(例えば、注射またはインプラント)、腹腔内、大槽内、関節内、腹腔内、脳内(実質内)及び脳室内)、経口、経鼻、経膣、舌下、眼内、経直腸、局所(例えば、経皮)、舌下及び吸入が挙げられる。一般的に、皮下または筋肉内に投与するデポー注射もまた、本明細書に開示するIL−10剤を規定の期間にわたって放出するために利用することができる。
上記のように、本開示は、一実施形態において、治療有効量のIL−10剤を患者に投与することによる、IL−10剤療法で治療可能な疾患を有する被験体の末梢における疾患抗原特異的CD8+T細胞の増殖の誘導方法を提供する。さらに、疾患抗原特異的CD8+T細胞は、治療有効量のIL−10剤を被験体に投与した後に被験体から組織試料を得ることによって単離され得る。一実施形態では、抗原特異的CD8+T細胞は、PD1+(例えば、PD1mid−high)であり、被験体から末梢血試料を採取することによって、治療有効量のIL−10剤で治療した被験体からCD8+T細胞を得ることができる。
配列決定さらなる態様において、本開示の方法は、抗原特異的(例えば、PD1+及び/またはLAG3+)CD8+T細胞を含む試料由来のT細胞受容体(TCR)のα及びβ鎖をコードするヌクレオチド配列を含む核酸の配列決定を含む。配列決定は、CD8+T細胞、例えば単離されたCD8+T細胞を含有する試料中に発現する機能的な抗原特異的TCRを構成するα及びβ鎖の可変領域中の少なくとも相補性決定領域(CDR)のアミノ酸配列を決定可能な任意の適切な方法を用いて行ってもよい。適切な方法は、例えば、US20140322716、US20130273647、US20150031043に記載されている(例えば、Howie et al.“High−throughput pairing of T cell receptor α and β sequences.”Science translational medicine 7.301(2015):301ra131−301ra131も参照)。
本開示は、組換え疾患抗原特異的TCRを発現する遺伝子改変T細胞の新規生成、同定、増大、産生及び使用、ならびに治療における使用方法を意図する。
本開示は、遺伝子改変T細胞を提供し、前記T細胞は、組換えT細胞受容体(TCR)を発現するように改変され、前記TCRは、可変α(Vα)T細胞受容体(TCR)ポリペプチドの1つ、2つ、及び/または3つの相補性決定領域(CDR)及びVα/VβTCRペアの可変β(Vβ)TCRポリペプチドの1つ、2つ、及び/または3つのCDRを含み、前記Vα/VβTCRペアは、IL−10剤の投与に応答して哺乳類において誘導されるPD1+,CD8+末梢T細胞の疾患抗原特異的TCR由来である。一実施形態では、遺伝子改変T細胞上に発現するTCRは、IL−10剤の投与に応答して哺乳類に誘導されるCD8+末梢T細胞の疾患抗原特異的TCRに由来するVα/VβTCRペアの完全長Vα及びVβポリペプチドを含み得る。
記載する遺伝子改変T細胞(例えば、CAR−T T細胞)は、単独で、または他の治療剤との組合せで、CD8+細胞療法を受け入れ可能な疾患の治療に有用である。一般的に、遺伝子改変T細胞(複数可)(例えば、CAR−T T細胞)は、治療対象の疾患に従って選択する。
本開示はまた、遺伝子改変T細胞単独療法ならびに併用療法の両方を企図する。例えば、本発明の遺伝子改変T細胞を、単独で、または遺伝子改変T細胞を用いた併用療法に使用してもよい1つ以上の活性剤(例えば、化学療法剤)または他の予防的もしくは治療的非薬理学的様式(例えば、局在化放射線療法または放射線全身照射療法)と併用して哺乳類被験体に投与してもよい。一例として、本開示は、本明細書に記載するように、放射フェイズが1つ以上のさらなる療法(例えば、CAR−T T細胞療法、及び場合により、IL−10剤の投与)または治療剤による治療に先行するか、または後に続く、治療レジメンを企図する。いくつかの実施形態では、本開示は、CAR−T T細胞療法及びIL−10剤(例えば、PEG−IL−10)を、骨髄移植、末梢血幹細胞移植、または他の種類の移植療法と併用して使用することをさらに意図する。
遺伝子改変T細胞(例えば、CAR−T T細胞)またはIL−10剤などの治療剤を被験体に投与する場合、本開示は、被験体への投与に適した任意の形態の組成物の使用を意図する。通常、そのような組成物は、治療剤(例えば、遺伝子改変T細胞(例えば、CAR−T T細胞)またはIL−10)及び1つ以上の薬学的に許容可能な、または生理学的に許容可能な希釈剤、担体または賦形剤を含む「医薬組成物」である。医薬組成物は、本開示の方法において使用することができ;したがって、例えば、本明細書に記載する治療方法及び予防方法及び使用を実施するために、医薬組成物をex vivoまたはin vivoで被験体に投与することができる。
本開示はまた、標的疾患の抗原に特異的なTCRを有する遺伝子改変T細胞(例えば、CAR−T T細胞)、所望によりIL−10剤(例えば、PEG−IL−10)を含み、及びその医薬組成物を含むキットも企図する。キットは、一般的に、以下に記載するように、様々な構成要素を収容する物理的構造の形態であり、例えば上記方法の実施において利用することができる。
単離されたマウスCD8+T細胞機能に対するIL−10の効果をin vitroで評価した。マウスCD8+T細胞を単離し、上記のように組換えマウスIL−10(rMuIL−1)の存在下で、または対照としてrMuIL−10の非存在下で処置した。細胞毒性マーカーであるグランザイムA、グランザイムB、パーフォリン及びサイトカインIFNγの遺伝子発現のqPCR分析によって、T細胞活性化を評価した。上記のように、SIINFEKL(配列番号35)の存在下でパルスしたPDV6細胞を溶解するためのIL−10処置したSIINFEKL初回刺激CD8+T細胞の能力によって、T細胞の細胞傷害性を評価した。
培養で増殖させたメラノーマ腫瘍の患者生検から、ヒトCD8+T細胞を採取し、加熱溶解した腫瘍細胞抗原で再刺激し、次いで上記のように、IL−10の非存在下で、または記載の濃度の組換えヒトIL−10(rHuIL−10)の存在下で培養した。細胞毒性マーカーであるグランザイムA、グランザイムB、パーフォリン及びサイトカインIFNγの遺伝子発現のqPCR分析によって、T細胞活性化を評価した。同種のメラノーマ腫瘍細胞、A375細胞(ヒト無色素性メラノーマ細胞株)、またはK562細胞(ヒト骨髄性白血病細胞株)を溶解する能力によってT細胞の細胞傷害性を評価した。
CT26腫瘍を有するマウスを、1mg/kgのPEG−rMuIL−10、または対照としてビヒクルで、毎日、6、10または15日間処置し、CD8+腫瘍内T細胞を単離した。PBMCまたは機械的に破壊し、酵素消化したCT26(ATCC)腫瘍から1,000個のCD8+T細胞を磁気(Miltenyi)ビーズで単離することによりELISPOT(R&D Systems)を作製した。CD8+T細胞を、二次刺激なし(w/o)、1μg/mLの可溶性抗CD3(eBiosciences)、100CT26細胞(ATCC、マウス扁平上皮腫瘍)または4T1細胞(ATCC、マウス乳房腫瘍)(陰性対照として)に24時間曝露した。スポットをImmunoSpot Softwareで定量した。
PD1及びIFNγ発現レベルに対する、実施例3に記載のPEG−rMuIL−10による15日間の処置の効果を評価した。PD1は、CD8+T細胞活性化のマーカーである(Agata,et al.,Int Immunol,1996.8(5):p.765−72)。PD1の発現はまた、活性化誘導細胞死(Fang et al.,Mol Vis,2015.21:p.901−10)及びT細胞の疲弊(Jiang et al.,Cell Death Dis,2015.6:p.e1792)に関連する。
健常ドナー由来のPD1+CD8+末梢T細胞をさらに分析して、それらの表現型を評価した。活性化誘導細胞死のモデルを使用してこれらのT細胞の評価を行い、そこにおいては、末梢CD8+T細胞を複数回の抗CD3/抗CD28再刺激に曝露し、活性化した細胞を休止期にPEG−rHuIL−10(AM0010)またはビヒクル(対照)に曝露した。次いで、細胞を、記憶T細胞のマーカーであるPD1及びCD45ROの両方の表面発現について分析した。図4に示すように、このようにしてIL−10でCD8+T細胞を処置すると、PD1+記憶CD8+T細胞が蓄積する。
患者の末梢PD1+CD8+T細胞に対するIL−10処置の効果を評価した(図5)。メラノーマ(Mel)、腎細胞癌(RCC)、または結腸直腸癌(CRC)を有し、上記のPEG−IL−10(AM0010)単剤療法、または抗PD1モノクローナル抗体と併用したPEG−IL−10(AM0010)治療を受けたがん患者からPBMCを採取した。PEG−IL−10療法の開始前に採取した末梢血試料を対照試料として用いた。図5の括弧内に示す日に試料を患者から採取し;投与したPEG−IL−10(AM0010)の用量を図5のX軸上に示す。患者を、進行性疾患(PD)、安定疾患(SD)、または少なくとも部分奏効(PR)として分類した。試験試料及び参照試料中の少なくともVβTCRポリペプチドをコードする核酸を配列決定し、試験試料中の少なくともVβTCRポリペプチド配列をコードする核酸の出現頻度を、参照試料中の同じVβTCRをコードする核酸の出現頻度と比較した。参照試料に対して試験試料中で出現頻度が増加した場合、その配列を「増大した」T細胞クローンによって発現されたものと分類した。参照試料に対して試験試料中で出現頻度が減少した場合、その配列を「収縮した」T細胞クローンによって発現されたものと分類した。「増大した」クローンは、疾患抗原特異的T細胞を表す。結果を図5に示す。
上記に示したように、IL−10剤による治療を受け入れ可能な疾患を有し、IL−10剤療法を受けた患者の組織試料(例えば、末梢血由来)は、抗原特異的CD8+T細胞の供給源を提供する。図7は、そのような抗原特異的CD8+T細胞のTCRの配列を得るためのこの供給源の使用可能な方法の例示的な概略を提供する。
PEG−rhIL10(AM0010)処置患者における免疫応答を評価し、客観的腫瘍縮小効果との免疫相関を同定するために、20μg/kgのAM0010を毎日、28日間処置した30人のヒト被験体において、83の免疫関連サイトカイン、ケモカイン及び血清タンパク質を繰り返し測定した。
患者におけるLag−3+PD−1+CD8+T細胞の増殖の増加及び増大は、別個の抗原チャレンジしたクローンT細胞集団の増大及び/または末梢T細胞の既存のサブセットの機能的成熟を示す。各集団の寄与を評価するために、末梢血由来のTCRディープシークエンシングにより、AM0010処置患者のT細胞レパートリーの組成を分析した。DNeasyキット(Qiagen)を用いてEDTA血液試料からDNAを単離し、TCRディープシークエンシングを行った。増大及び収縮クローンを、前処置及び処置中の試料の間に10倍超の変化を有するT細胞クローンとして定義した。
Claims (95)
- 疾患抗原特異的T細胞のTCRの可変α(Vα)T細胞受容体(TCR)ポリペプチド及び/または可変β(Vβ)TCRポリペプチドの同定方法であって、
IL−10剤療法を受け入れ可能な疾患を有する被験体にIL−10剤を投与すること;
前記被験体から採取した1つ以上のCD8+T細胞を含有する試料由来の核酸配列を配列決定すること;及び
前記VαTCRポリペプチドをコードする前記核酸及び/または前記VβTCRポリペプチドをコードする前記核酸の存在量を、IL−10剤療法に先立って、またはIL10剤療法中のより早い時点で、IL−10剤療法を受け入れ可能な前記疾患を有する1人以上の患者から採取した参照試料中の前記VαTCRポリペプチドをコードする前記核酸及び/またはVβTCRポリペプチドをコードする核酸の存在量と比較すること
を含み;
前記配列決定が、核酸可変α(Vα)TCRポリペプチドをコードする核酸及び/または可変β(Vβ)TCRポリペプチドをコードする核酸を配列決定することを含み
前記参照試料中よりも多量に前記試料中に存在する前記Vα及び/またはVβTCRポリペプチドが、疾患抗原特異的CD8+T細胞に特異的なVα/VβTCRポリペプチド対を表す、同定方法。 - 前記被験体が、IL−10剤治療に対して、少なくとも安定または少なくとも部分奏効を示す、請求項1に記載の方法。
- 前記被験体が、IL−10剤療法に対する少なくとも部分奏効を示す、請求項2に記載の方法。
- 前記試料を、PD1+,CD8+T細胞について富化する、請求項1〜3のいずれか一項に記載の方法。
- 前記PD1+,CD8+T細胞が、少なくともPD1+midのレベルで細胞表面PD1を発現する、請求項4に記載の方法。
- 前記PD1+,CD8+T細胞が、少なくともPD1+highのレベルで細胞表面PD1を発現する、請求項4に記載の方法。
- 前記試料を、CD45RO+,CD8+T細胞について富化する、請求項1〜6のいずれか一項に記載の方法。
- 前記試料を、IFNγ+CD8+T細胞について富化する、請求項1〜7のいずれか一項に記載の方法。
- 前記CD8+T細胞をCD3アゴニストと接触させてIFNγ発現を刺激することを含む、請求項8に記載の方法。
- 前記CD3アゴニストが抗CD3抗体である、請求項9に記載の方法。
- 前記試料を、PD1+、IFNγ+、CD45RO+、グランザイムB+、及び/またはパーフォリン+であるCD8+T細胞について富化する、請求項1〜3のいずれか一項に記載の方法。
- 前記1人以上の患者に前記被験体が含まれる、請求項1〜11のいずれか一項に記載の方法。
- 前記被験体が腫瘍を有し、
前記CD8+T細胞が腫瘍抗原に特異的である、請求項1〜12のいずれか一項に記載の方法。 - 前記被験体が腫瘍を有し、
前記CD8+T細胞が腫瘍浸潤性リンパ球である、請求項1〜12のいずれか一項に記載の方法。 - 前記腫瘍が固形腫瘍である、請求項13または14に記載の方法。
- 前記腫瘍が、子宮、子宮頸部、乳房、前立腺、精巣、胃腸管、腎臓、腎細胞、膀胱、骨、骨髄、皮膚、頭頸部、肝臓、胆嚢、心臓、肺、膵臓、唾液腺、副腎、甲状腺、脳、神経節、中枢神経系(CNS)及び末梢神経系(PNS)の癌、または造血系、脾臓、もしくは胸腺の癌から選択されるがんの腫瘍である、請求項13または14に記載の方法。
- 前記腫瘍が、食道、咽頭、胃、小腸、大腸、結腸、または直腸の癌の腫瘍である、請求項13または14に記載の方法。
- 前記腫瘍が、メラノーマ、結腸直腸癌、または腎臓癌である、請求項13または14に記載の方法。
- 前記被験体が、ウイルス感染を有し、
前記CD8+T細胞が感染ウイルスの抗原に特異的である、請求項1〜12のいずれか一項に記載の方法。 - 前記ウイルスが、ヘパドナウイルス、フラビウイルス、レトロウイルス、ヘルペスウイルスである、請求項19に記載の方法。
- 前記ウイルスが、B型肝炎ウイルス、C型肝炎ウイルス、サイトメガロウイルス(CMV)またはヒト免疫不全ウイルス(HIV)である、請求項20に記載の方法。
- 前記IL−10剤がヒトIL−10である、請求項1〜21のいずれか一項に記載の方法。
- 前記IL−10剤がペグ化IL−10(PEG−IL−10)である、請求項1〜22のいずれか一項に記載の方法。
- 前記PEG−IL−10が、IL−10の少なくとも1つのモノマーのN末端アミノ酸残基に共有結合した少なくとも1つのPEG分子を含む、請求項23に記載の方法。
- 前記PEG−IL−10が、モノペグ化IL−10及びジペグ化IL−10の混合物を含む、請求項23に記載の方法。
- 前記PEG−IL−10の前記PEG成分が、5kDa〜30kDaの分子量を有する、請求項23〜25のいずれかに記載の方法。
- 前記IL−10剤を、被験体に皮下投与する、請求項1〜26のいずれか一項に記載の方法。
- 前記被験体がヒト被験体である、請求項1〜27のいずれか一項に記載の方法。
- 前記VαTCRポリペプチドをコードする核酸及び/または前記VβTCRポリペプチドをコードする核酸を配列決定すること;及び
前記VαTCRポリペプチド及び/または前記VβTCRポリペプチドの少なくとも前記相補性決定領域(CDR)の前記アミノ酸配列を決定すること;
前記VαTCRポリペプチドのアミノ酸配列及び/または前記VβTCRポリペプチドのアミノ酸配列の存在量を、IL−10剤療法に先立って、またはIL10剤療法中のより早い時点で、IL−10剤療法を受け入れ可能な前記疾患を有する1人以上の患者から採取した参照試料中の前記VαTCRポリペプチドのアミノ酸配列及び/または前記VβTCRポリペプチドのアミノ酸配列と比較すること
を含む、請求項1〜28のいずれか一項に記載の方法。 - 請求項1〜29のいずれか一項に記載の方法に従って単離したCD8+T細胞上に発現するTCRの抗原特異性を、前記Vα及び/またはVβTCRポリペプチドのアミノ酸配列を前記参照試料中のVα及び /またはVβTCRポリペプチドのアミノ酸配列と比較することによって評価することを含む、請求項1〜29のいずれか一項に記載の方法。
- 疾患抗原特異的T細胞のTCRの可変α(Vα)T細胞受容体(TCR)ポリペプチド及び可変β(Vβ)TCRポリペプチドをコードするベクターの生成方法であって、
IL−10剤療法を受け入れ可能な疾患に対してIL−10剤療法を投与した被験体から採取した1つ以上のCD8+T細胞を含む試料由来の核酸を配列決定すること;及び
疾患抗原特異的CD8+T細胞のTCRのVα及びVβTCRポリペプチド対をコードする核酸を1つ以上の構築物にクローニングして、疾患抗原特異的TCRのVα及びVβTCRポリペプチドの一方または両方をコードするベクターを作製すること
を含み、
前記CD8+T細胞が、可変α(Vα)TCRポリペプチド及び可変β(Vβ)TCRポリペプチドをコードする核酸を有する疾患抗原特異的T細胞受容体(TCR)を発現し、
IL−10剤に先立って、またはIL10剤治療中のより早い時点で、前記IL−10剤療法を受け入れ可能な疾患を有する1人以上の患者から採取した参照試料よりも豊富に存在するVα及び/またはVβTCRポリペプチドが、疾患抗原特異的CD8+T細胞の前記Vα/VβTCRポリペプチド対を表す、方法。 - 前記ベクターが、前記Vα及びVβTCRポリペプチド対の促進された発現の、CD8+T細胞への安定な形質移入に適している、請求項31に記載の方法。
- 前記被験体が、IL−10剤治療に対して、少なくとも安定または少なくとも部分奏効を示す、請求項31または32に記載の方法。
- 前記被験体が、IL−10薬剤療法に対して少なくとも部分奏効を示す、請求項33に記載の方法。
- 前記試料を、PD1+,CD8+T細胞について富化する、請求項31〜34のいずれか一項に記載の方法。
- 前記PD1+,CD8+T細胞が、少なくともPD1+midのレベルで細胞表面PD1を発現する、請求項35に記載の方法。
- 前記PD1+,CD8+T細胞が、少なくともPD1+highのレベルで細胞表面PD1を発現する、請求項35に記載の方法。
- 前記試料を、CD45RO+,CD8+T細胞について富化する、請求項31〜37のいずれか一項に記載の方法。
- 前記試料を、IFNγ+CD8+T細胞について富化する、請求項31〜38のいずれか一項に記載の方法。
- 前記CD8+T細胞をCD3アゴニストと接触させてIFNγ発現を刺激することを含む、請求項39に記載の方法。
- 前記CD3アゴニストが抗CD3抗体である、請求項40に記載の方法。
- 前記試料を、PD1+、IFNγ+、CD45RO+、グランザイムB+、及び/またはパーフォリン+であるCD8+T細胞について富化する、請求項31〜34のいずれか一項に記載の方法。
- 前記一人以上の患者に、前記被験体が含まれる、請求項31〜42のいずれか一項に記載の方法。
- 前記被験体が腫瘍を有し、
前記CD8+T細胞が腫瘍抗原に特異的である、請求項31〜43のいずれか一項に記載の方法。 - 前記被験体が腫瘍を有し、
前記CD8+T細胞が腫瘍浸潤性リンパ球である、請求項31〜43のいずれか一項に記載の方法。 - 前記腫瘍が固形腫瘍である、請求項44または45に記載の方法。
- 前記腫瘍が、子宮、子宮頸部、乳房、前立腺、精巣、胃腸管、腎臓、腎細胞、膀胱、骨、骨髄、皮膚、頭頸部、肝臓、胆嚢、心臓、肺、膵臓、唾液腺、副腎、甲状腺、脳、神経節、中枢神経系(CNS)及び末梢神経系(PNS)、または造血系、脾臓、もしくは胸腺の癌から選択されるがんの腫瘍である、請求項44または45に記載の方法。
- 前記腫瘍が、食道、咽頭、胃、小腸、大腸、結腸、または直腸の癌の腫瘍である、請求項44または45に記載の方法。
- 前記腫瘍が、メラノーマ、結腸直腸癌、または腎臓癌である、請求項44または45に記載の方法。
- 前記被験体がウイルス感染を有し、
前記PD1+,CD8+T細胞が、前記感染性ウイルスの抗原に特異的である、請求項31〜43のいずれか一項に記載の方法。 - 前記ウイルスが、ヘパドナウイルス、フラビウイルス、レトロウイルス、ヘルペスウイルスである、請求項50に記載の方法。
- 前記ウイルスが、B型肝炎ウイルス、C型肝炎ウイルス、サイトメガロウイルス(CMV)またはヒト免疫不全ウイルス(HIV)である、請求項51に記載の方法。
- 前記IL−10剤がヒトIL−10である、請求項31〜52のいずれか一項に記載の方法。
- 前記IL−10剤がペグ化IL−10である、請求項31〜52のいずれか一項に記載の方法。
- 前記PEG−IL−10が、IL−10の少なくとも1つのモノマーのN末端アミノ酸残基に共有結合した少なくとも1つのPEG分子を含む、請求項54に記載の方法。
- 前記PEG−IL−10が、モノペグ化IL−10及びジペグ化IL−10の混合物を含む、請求項54に記載の方法。
- 前記PEG−IL−10の前記PEG成分が、5kDa〜30kDaの分子量を有する、請求項54〜56のいずれか一項に記載の方法。
- 前記IL−10剤を、前記被験体に皮下投与する、請求項31〜57のいずれか一項に記載の方法。
- 前記被験体がヒト被験体である、請求項31〜58のいずれか一項に記載の方法。
- 前記CD8+T細胞のTCRの複数のVα/VβTCRペアの前記Vα及びVβTCRポリペプチドをコードする複数の核酸を複数のベクターにクローニングし、前記CD8+T細胞の前記疾患抗原特異的TCRのVα及びVβTCRポリペプチド対をコードする構築物のライブラリーを作製する、請求項31〜59のいずれか一項に記載の方法。
- 前記VαTCRポリペプチド及び前記VβTCRポリペプチドを、同一ベクター中にクローニングする、請求項31〜59のいずれか一項に記載の方法。
- 前記VαTCRポリペプチド及び前記VβTCRポリペプチドをベクターにクローニングし、それによって全長αTCRポリペプチドをコードする核酸及び全長βTCRポリペプチドをコードする核酸を提供する、請求項61に記載の方法。
- 前記VαTCRポリペプチド及び前記VβTCRポリペプチドをベクターにクローニングし、それによって一本鎖T細胞受容体(scTv)をコードする核酸を提供する、請求項61に記載の方法。
- 前記scTvが、N末端からC末端方向に、前記VβTCRポリペプチド、リンカー、及び前記VαTCRポリペプチドを含む、請求項63に記載の方法。
- 前記ベクターが発現ベクターである、請求項31〜64のいずれか一項に記載の方法。
- 請求項60に記載の方法によって作製する核酸ベクターのライブラリー。
- 遺伝子改変T細胞の生成方法であって、
請求項31〜59のいずれか一項に記載の方法によって得られた構築物をCD8+T細胞内に導入して、疾患抗原特異的TCRの前記Vα及びVβTCRポリペプチド対を発現する遺伝子改変T細胞を産生することを含む、生成方法。 - 前記VαTCRポリペプチド及び前記VβTCRポリペプチドが、同一または異なる発現構築物上の別個の発現カセットにコードされる、請求項67に記載の方法。
- 前記構築物によりコードされる前記VαTCRポリペプチドが、そのC末端で、定常αTCRポリペプチドに作動可能に連結する、請求項67または68に記載の方法。
- 前記構築物によりコードされる前記VβTCRポリペプチドが、そのC末端で、β定常TCRポリペプチドに作動可能に連結する、請求項67または68に記載の方法。
- 前記構築物が、VβTCRポリペプチド及びVαTCRポリペプチドを含む一本鎖TCR(scTv)をコードする核酸を含む、請求項67に記載の方法。
- 前記scTvが、N末端からC末端方向に、前記VβTCRポリペプチド、リンカー、及び前記VαTCRポリペプチドを含む、請求項71に記載の方法。
- 請求項67〜72のいずれか一項に記載の方法によって産生する遺伝子改変CD8+T細胞の集団。
- CD8+T細胞療法を受け入れ可能な疾患を有する被験体の治療方法であって、
遺伝子改変CD8+T細胞を前記被験体に投与すること
を含み、
前記T細胞が、前記被験体の前記疾患の抗原に特異的である疾患抗原特異的TCRのVα/VβペアのVαTCRポリペプチド及びVβTCRポリペプチドを含む組換えTCRを発現するように遺伝子改変されており;
前記投与が、前記被験体の前記疾患を治療するのに有効である、治療方法。 - 前記VαTCRポリペプチドの前記CDR及び前記VβTCRポリペプチドの前記CDRの前記アミノ酸配列を、請求項1〜26のいずれか一項に記載の方法に従って同定する、請求項74に記載の方法。
- 前記VαTCRポリペプチド及び前記VβTCRポリペプチドの前記アミノ酸配列を、請求項25の方法に従って同定する、請求項74に記載の方法。
- 前記遺伝子改変T細胞の前記VαTCRポリペプチド及び前記VβTCRポリペプチドが、同一または異なる発現構築物の別々の発現カセットにコードされる、請求項74〜76のいずれか一項に記載の方法。
- 前記遺伝子改変T細胞の前記VαTCRポリペプチドが、前記構築物にコードされ、そのC末端で定常αTCRポリペプチドに作動可能に連結する、請求項74〜77のいずれか一項に記載の方法。
- 前記遺伝子改変T細胞の前記VβTCRポリペプチドが、前記構築物にコードされ、そのC末端でβ定常TCRポリペプチドに作動可能に連結する、請求項74〜78のいずれか一項に記載の方法。
- 前記遺伝子改変T細胞の前記VβTCRポリペプチド及び前記VαTCRポリペプチドが、前記VβTCRポリペプチド及び前記VαTCRポリペプチドを含む一本鎖TCR(scTv)をコードする核酸を含む構築物にコードされる、請求項74〜76のいずれか一項に記載の方法。
- 前記scTvが、N−末端からC−末端方向に、前記VβTCRポリペプチド、リンカー、及び前記VαTCRポリペプチドを含む、請求項80に記載の方法。
- 前記CD8+T細胞療法を受け入れ可能な疾患ががんであり、
前記遺伝子改変CD8+T細胞の前記疾患抗原特異的TCRががんの抗原に特異的である、請求項74〜81のいずれか一項に記載の方法。 - 前記がんが固形腫瘍である、請求項82に記載の方法。
- 前記腫瘍が、子宮、子宮頸部、乳房、前立腺、精巣、胃腸管、腎臓、腎細胞、膀胱、骨、骨髄、皮膚、頭頸部、肝臓、胆嚢、心臓、肺、膵臓、唾液腺、副腎、甲状腺、脳、神経節、中枢神経系(CNS)及び末梢神経系(PNS)、または造血系、脾臓、もしくは胸腺の癌から選択されるがんの腫瘍である、請求項82または83に記載の方法。
- 前記がんが、食道、咽頭、胃、小腸、大腸、結腸、または直腸の癌である、請求項82または83に記載の方法。
- 前記がんが、メラノーマ、結腸直腸癌、または腎臓癌である、請求項82または83に記載の方法。
- 前記CD8+T細胞療法を受け入れ可能な疾患がウイルス感染であり、
前記遺伝子改変CD8+T細胞の前記疾患抗原特異的TCRが前記ウイルスの抗原に特異的である、請求項74〜81のいずれか一項に記載の方法。 - 前記ウイルスが、ヘパドナウイルス、フラビウイルス、レトロウイルス、ヘルペスウイルスである、請求項87に記載の方法。
- 前記ウイルスが、B型肝炎ウイルス、C型肝炎ウイルス、サイトメガロウイルス(CMV)またはヒト免疫不全ウイルス(HIV)である、請求項87に記載の方法。
- さらなる治療剤を投与することを含む、請求項74〜89のいずれか一項に記載の方法。
- 前記治療剤がIL−10剤である、請求項90に記載の方法。
- 前記CD8+T細胞療法を受け入れ可能な疾患ががんであり、
前記治療剤が化学療法剤である、請求項90または91に記載の方法。 - 前記CD8+T細胞療法を受け入れ可能な疾患がウイルス感染であり、
前記治療剤が抗ウイルス剤である、請求項90または91に記載の方法。 - 前記投与が、複数の遺伝子改変CD8+T細胞を投与することを含み、
前記複数の前記遺伝子改変CD8+T細胞が、異なる疾患抗原特異的TCRを有する遺伝子改変CD8+T細胞を含む、請求項74〜93のいずれか一項に記載の方法。 - 前記遺伝子改変CD8+T細胞が、前記被験体に対して自己由来である、請求項74〜94のいずれか一項に記載の方法。
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