JP2021500854A - Strep−タグ特異的結合タンパク質およびその使用 - Google Patents
Strep−タグ特異的結合タンパク質およびその使用 Download PDFInfo
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Abstract
Description
本出願は、本明細書に完全に明記されたものとしてあらゆる目的のために参照により本明細書に組み込まれる2017年9月6日に出願した米国特許出願第62/555,017号の優先権の利益を主張する。
本願に関連する配列表は、紙コピーの代わりにテキスト形式で提供され、これによって参照により本明細書に組み込まれる。配列表を含むテキストファイルの名称は、360056_451WO_SEQUENCE_LISTING.txtである。このテキストファイルは28.9KBであり、2018年9月3日に作成されたものであり、EFS−Web経由で電子的に提出されている。
組換えタンパク質およびそれを発現する細胞は、通常、組換えタンパク質に融合する合成タグペプチドを使用して、検出、ソート、および精製される。例えば、合成Strep(登録商標)−Tag IIペプチドは、目的のタンパク質に容易に融合することができ、操作されたストレプトアビジン誘導体であるStrep−Tactin(登録商標)に高い親和性で結合する。Strep−Tag(登録商標)システムは、典型的には、磁気ナノビーズまたは樹脂であるStrep−Tactin(登録商標)含有基質への結合を介して、Strep−タグ標識タンパク質および細胞の単離およびアフィニティー精製を可能にする。
本開示は、Strep(登録商標)−Tag II(WSHPQFEK、配列番号19)を含むかまたは発現する組換えタンパク質および宿主細胞を識別、ソート、追跡、および選択的にモジュレートするための組成物および方法を提供する。ある特定の態様では、例えば、養子細胞治療のために、タグ付き免疫細胞をモジュレートするのに有用な免疫グロブリン結合タンパク質、融合タンパク質、およびこれらを発現する宿主細胞が提供される。
ある特定の態様では、本開示は、strep−タグペプチドに特異的に結合する結合ドメインを含む免疫グロブリン結合タンパク質を提供する。本明細書で使用される場合、用語「strep−タグペプチド」は(本明細書において、「strep−タグ」、「strepタグ」、「ST」、および「タグペプチド」(文脈がそれ自体を明確に示し、目的のタンパク質(例えば、Myc、His、またはFlag)をタグ付けするために使用される異なるタイプのペプチドを示さない場合)とも呼ばれる)、ストレプトアビジン(Streptomyces avidiniiから精製される四量体タンパク質であり、ビオチンに対するその高い親和性により分子生物学のプロトコールにおいて広く使用される)またはストレプトアビジンの操作された変異タンパク質であるStreptactin(登録商標)に特異的に結合することが可能なペプチドを意味する。本開示の例示的なstrep−タグペプチドは、ストレプトアビジンまたはその変異タンパク質もしくはバリアント(例えば、Streptactin(登録商標))への結合に関してビオチンと競合し、例えば、Strep(登録商標)タグ(WRHPQFGG、配列番号48);Strep(登録商標)Tag II(本明細書において、「STII」とも呼ばれ、アミノ酸配列WSHPQFEK(配列番号19)からなる);ならびに、例えば、Schmidt and Skerra, Nature Protocols, 2:1528-1535 (2007)、米国特許第7,981,632号;およびPCT特許出願公開第WO2015/067768号(これらのstrep−タグペプチド、step−タグ−ペプチド含有ポリペプチド、およびその配列は、参照により本明細書に組み込まれる)に開示されているものを含むそれらのバリアントを含む。
(i)配列番号2に示されるアミノ酸配列を含むかまたはそれからなるVLドメイン、および配列番号3に示されるアミノ酸配列を含むかまたはそれからなるVHドメイン;(ii)配列番号10に示されるアミノ酸配列を含むかまたはそれからなるVLドメイン、および配列番号8に示されるアミノ酸配列を含むかまたはそれからなるVHドメイン;または配列番号16に示されるアミノ酸配列を含むかまたはそれからなるVLドメイン、および配列番号14に示されるアミノ酸配列を含むかまたはそれからなるVHドメインを含む。
ある特定の態様では、本明細書に記載の免疫グロブリン結合タンパク質または融合タンパク質のうちのいずれか1つまたは複数をコードする核酸分子が提供される。ある特定の実施形態では、本開示のポリヌクレオチドは、(a)配列番号1、7、および13のうちのいずれか1つに示されるヌクレオチド配列と少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、または100%の同一性を有するポリヌクレオチドならびに(b)配列番号4、9、および15のうちのいずれか1つに示されるヌクレオチド配列と少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、または100%の同一性を有するポリヌクレオチドのうちの1つまたは両方を含む。
さらなる態様では、配列番号19に示されるアミノ酸配列を有する(すなわち、それを含むかまたはそれからなる)タグペプチドを発現する細胞または細胞の集団を識別するために、本開示の免疫グロブリン結合タンパク質または融合タンパク質を使用するための方法が提供される。そのような方法は、例えば、養子細胞治療において使用されるタグ付き細胞がそれを必要とする対象に移入されるのに成功したかどうか、またはタグ付き細胞が養子細胞治療を施される対象において増殖したか、または存続したか、または目的の部位に局在したかどうかを決定するために有用であり得る。ある特定の実施形態では、方法は、(i)1つまたは複数のタグ付き細胞を含む対象由来の試料を、本開示の免疫グロブリン結合タンパク質または融合タンパク質と接触させることと、(ii)免疫グロブリン結合タンパク質または融合タンパク質の1つまたは複数のタグ付き細胞への特異的結合を検出し、それによって、タグペプチドを発現する1つまたは複数の細胞を識別することとを含む。
抗STIIモノクローナル抗体の開発および特徴付け
Strep(登録商標)−tag II(「STII」)−特異的mAbは、従来の免疫化およびハイブリドーマ方法を使用して開発された。手短に述べると、10〜12週例のメスのマウス(BALB/cもしくはCD1またはSwiss WebsterまたはB57BL/6)を、単一のSTIIペプチドで、またはKLHキャリアタンパク質にマレイミドカップリングしたSTIIペプチド配列(Ac−C(dPEG4)NWSHPQFEK−アミド(配列番号50)、H2N−CGNWSHPQFEK−アミド(配列番号51)、H2N−CGNWSHPQFEKGC−OH(配列番号52))の組合せで免疫処置することによって、抗STIIモノクローナル抗体ハイブリドーマのクローン4E2、5G2、および3E8を作成した。完全フロインドアジュバント/不完全フロインドアジュバントまたはAdjuplexアジュバントを用いる12週の追加免疫プロトコール後に、高力価マウスから脾臓細胞を単離し、FoxNY骨髄腫(BTX、Harvard Apparatus)に電気融合させた。ハイブリドーマが分泌するペプチド特異的抗体を識別し、ClonePix2(Molecular Devices)コロニーピッカーを使用して単離した。ピックアップしたクローン由来の抗体を、BSAキャリアタンパク質にマレイミドカップリングした、STIIペプチドを運ぶサイトメトリックビーズアレイを使用して、フローサイトメトリーによって、ペプチド結合について検証した。ClonePix2ピッカーを使用して、選択したハイブリドーマクローンをサブクローニングして、ペプチド結合について繰り返し検証した。IgGをコードするDNA配列を、各クローン(4E2、5G2、および3E8)に由来する複数のサブクローンから識別した。次いで、ハイブリドーマからアフィニティー精製したIgGを、in vitroおよびin vivoでさらに特徴付けた。
STIIタグ付きCAR T細胞のin vivoでの標的化
STII特異的抗体は、STIIタグ付きCAR T細胞を用いる治療を改善するのに有用である場合がある。CAR T活性に関連する望ましくない副作用が、STII特異的抗体によって低減または逆転し得るかどうかを検査するために、in vivo B細胞枯渇アッセイを設計し(図2A)、ここで、CD45.2+ C57/BL6マウスは、B細胞無形成症を誘導するために、亜致死線量照射(6Gy TBI)および5×106 CD45.1+ STII−タグ付き(1STIIまたは3STII)抗CD19−CD28ζ_EGFRt CAR T細胞の注入を受容した。+37日目と+42日目に、マウスを、抗STII 5G2 mAbまたはセツキシマブ(STII−CAR形質導入マーカーEGFRtを標的とする)をマウス1頭当たり1mg、i.p.で処置した。図2Bに示すように、レシピエントマウスへの形質導入細胞の注入前に、マウスT細胞におけるEGFRtおよびSTII−CARの発現を、フローサイトメトリーを使用して形質導入の7日後に測定した。これらのデータは、1STII−CAR構築物と3STII−CAR構築物の両方が、T細胞によって発現されることを示す。
STIIタグ付きCAR T細胞の機能的刺激
抗STII mAbは、例えば、免疫治療としてのタグ付きCAR T細胞の患者への注入前に、タグ付きCAR T細胞を刺激するのに有用である場合もある。CD19−1STII CAR T細胞(CD28zまたは4−1BBz)を、抗原を発現するRaji細胞、抗体をコーティングしたマイクロビーズ(0.1μg、0.3μg、もしくは0.5μgの抗STII、または抗STIIと抗CD28をいずれも0.3μg)を使用して刺激した。対照は、抗原なしの培地のみ(Medium)におけるCD19−1STII CAR T細胞であった。カルボキシフルオレセインスクシンイミジルエステル(CFSE)を使用して細胞を標識した。FACSによって増殖を測定した。図3Aに示すように、抗STIIでコーティングしたマイクロビーズによって増殖が刺激され、最も低いレベルの抗STII mAbが、培地のみと比較して、最も高い効果を有した。刺激されたCAR T細胞によるサイトカイン産生を測定した。図3Bに示すように、CAR T細胞によるIL−2およびIFN−γ産生は、抗STII mAbの存在量と共に増加した。最も高いレベルのサイトカイン産生は、抗STII/抗CD28でコーティングしたマイクロビーズを使用して刺激した細胞によるものであった。
STIIタグ付きCAR T細胞の拡大
タグ付き免疫治療用細胞をプライミングするための抗STII mAbの有用性をさらに調査するために、抗STII mAbのみまたは抗CD28抗体との組み合わせでコーティングしたマイクロビーズを使用して、CD8+およびCD4+STII含有CAR T細胞を3回刺激した。
刺激したSTIIタグ付きCAR T細胞の特徴付け
CAR T細胞(刺激前、または1回目、2回目、もしくは3回目の刺激後;実施例4を参照されたい)を、STIIおよびT細胞の成熟、活性化、または抑制(CD45RO、CD62L、CD28、CTLA4、およびPD1)のいくつかのマーカーの発現について調査した。各マーカーについて、抗体を使用して細胞を染色し、フローサイトメトリーを実施した。データを図4Bに示す。
Claims (110)
- 配列番号19のアミノ酸配列を含むかまたはそれからなるタグペプチドに特異的に結合する結合ドメインを含む免疫グロブリン結合タンパク質であって、前記結合ドメインが、
(a)
i.配列番号31に示されるCDR1アミノ酸配列、もしくはそのバリアント、配列番号32に示されるCDR2アミノ酸配列、もしくはそのバリアント、および配列番号33に示されるCDR3アミノ酸配列、もしくはそのバリアント;
ii.配列番号25に示されるCDR1アミノ酸配列、もしくはそのバリアント、配列番号26に示されるCDR2アミノ酸配列、もしくはそのバリアント、および配列番号27に示されるCDR3アミノ酸配列、もしくはそのバリアント;または
iii.配列番号37に示されるCDR1アミノ酸配列、もしくはそのバリアント、配列番号38に示されるCDR2アミノ酸配列、もしくはそのバリアント、および配列番号39に示されるCDR3アミノ酸配列、もしくはそのバリアント
を含むVLドメイン、ならびにVHドメイン;あるいは
(b)
i.配列番号28に示されるCDR1アミノ酸配列、もしくはそのバリアント、配列番号29に示されるCDR2アミノ酸配列、もしくはそのバリアント、および配列番号30に示されるCDR3アミノ酸配列、もしくはそのバリアント;
ii.配列番号22に示されるCDR1アミノ酸配列、もしくはそのバリアント、配列番号23に示されるCDR2アミノ酸配列、もしくはそのバリアント、および配列番号24に示されるCDR3アミノ酸配列、もしくはそのバリアント;または
iii.配列番号34に示されるCDR1アミノ酸配列、もしくはそのバリアント、配列番号35に示されるCDR2アミノ酸配列、もしくはそのバリアント、および配列番号36に示されるCDR3アミノ酸配列、もしくはそのバリアントを含むVHドメイン、ならびにVLドメイン;あるいは
(c)(a)の前記VLドメインおよび(b)の前記VHドメイン
を含む、免疫グロブリン結合タンパク質。 - 前記VLドメインが、配列番号3、10、および16のうちのいずれか1つに示されるアミノ酸配列と少なくとも80%同一であるアミノ酸配列を含み、前記VHドメインが、配列番号2、8、および14のうちのいずれか1つに示されるアミノ酸配列と少なくとも80%同一であるアミノ酸配列を含む、請求項1に記載の免疫グロブリン結合タンパク質。
- 前記VLが、配列番号10、3、および16のうちのいずれか1つに示されるアミノ酸配列を含むかまたはそれからなり、前記VHが、配列番号8、2、および14のうちのいずれか1つに示されるアミノ酸配列を含むかまたはそれからなる、請求項1または2に記載の免疫グロブリン結合タンパク質。
- 前記VLが、配列番号10に示される前記アミノ酸配列を含むかまたはそれからなり、前記VHが、配列番号8に示される前記アミノ酸配列を含むかまたはそれからなる、請求項3に記載の免疫グロブリン結合タンパク質。
- 前記VLが、配列番号3に示される前記アミノ酸配列を含むかまたはそれからなり、前記VHが、配列番号2に示される前記アミノ酸配列を含むかまたはそれからなる、請求項3に記載の免疫グロブリン結合タンパク質。
- 前記VLが、配列番号16に示される前記アミノ酸配列を含むかまたはそれからなり、前記VHが、配列番号14に示される前記アミノ酸配列を含むかまたはそれからなる、請求項3に記載の免疫グロブリン結合タンパク質。
- 抗体またはその抗原結合部分を含む、請求項1〜6のいずれか一項に記載の免疫グロブリン結合タンパク質。
- 前記抗体またはその抗原結合部分が、モノクローナル抗体5G2を含む、請求項7に記載の免疫グロブリン結合タンパク質。
- 前記抗体またはその抗原結合部分が、モノクローナル抗体3E8を含む、請求項7に記載の免疫グロブリン結合タンパク質。
- 前記抗体またはその抗原結合部分が、モノクローナル抗体4E2を含む、請求項7に記載の免疫グロブリン結合タンパク質。
- キメラ、ヒト化、もしくはヒト抗体またはその抗原結合部分である、請求項1〜10のいずれか一項に記載の免疫グロブリン結合タンパク質。
- 前記結合ドメインが、scFv、タンデムscFv、scFv−Fc、タンデムscFv−Fc、scFv二量体、scFv−ジッパー、ダイアボディ、ダイアボディ−Fc、ダイアボディ−CH3、scダイアボディ、scダイアボディ−Fc、scダイアボディ−CH3、ナノボディ、ミニボディ、ミニ抗体、トリアボディ、テトラボディ、Fab、F(ab)’2、scFab、Fab−scFv、Fab−scFv−Fc、scFv−CH−CL−scFv、F(ab’)2−scFv2、二重特異的T細胞エンゲージャー(BiTE)分子、DART、ノブ・イントゥ・ホール(KIH)アセンブリ、scFv−CH3−KIHアセンブリ、KIH Common Light−Chain抗体、TandAb、Triple Body、TriBiミニボディ、Fab−scFv、scFv−CH−CL−scFv、F(ab’)2−scFv2、四価のHCab、イントラボディ、CrossMab、Dual Action Fab(DAF)(トゥーインワンまたはフォーインワン)、DutaMab、DT−IgG、Charge Pair、Fab−アームExchange、SEEDbody、Triomab、LUZ−Y、Fcab、κλ−ボディ、直交Fab、DVD−IgG、IgG(H)−scFv、scFv−(H)IgG、IgG(L)−scFv、scFv−(L)IgG、IgG(L,H)−Fv、IgG(H)−V、V(H)−IgG、IgG(L)−V、V(L)−IgG、KIH IgG−scFab、2scFv−IgG、IgG−2scFv、scFv4−Ig、Zybody、またはDVI−IgG(フォーインワン)を含む、請求項1〜11のいずれか一項に記載の免疫グロブリン結合タンパク質。
- 前記結合ドメインが、scFvを含み、前記scFvが、モノクローナル抗体3E8のVLおよびVHを含む、請求項12に記載の免疫グロブリン結合タンパク質。
- 前記scFvが、配列番号5または6のアミノ酸配列を含むかまたはそれからなる、請求項13に記載の免疫グロブリン結合タンパク質。
- 前記結合ドメインが、scFvを含み、前記scFvが、モノクローナル抗体5G2のVLおよびVHを含む、請求項12に記載の免疫グロブリン結合タンパク質。
- 前記scFvが、配列番号11または12のアミノ酸配列を含むかまたはそれからなる、請求項15に記載の免疫グロブリン結合タンパク質。
- 前記結合ドメインが、scFvを含み、前記scFvが、モノクローナル抗体4E2のVLおよびVHを含む、請求項12に記載の免疫グロブリン結合タンパク質。
- 前記scFvが、配列番号17または18のアミノ酸配列を含むかまたはそれからなる、請求項17に記載の免疫グロブリン結合タンパク質。
- 多重特異的結合タンパク質を含み、前記多重特異的結合タンパク質が、前記タグペプチドに特異的に結合する結合ドメインおよび前記タグペプチドではない少なくとも1つの標的に特異的に結合する結合ドメインを含む、請求項1〜18のいずれか一項に記載の免疫グロブリン結合タンパク質。
- 前記多重特異的結合タンパク質が、二重特異的結合タンパク質を含む、請求項19に記載の免疫グロブリン結合タンパク質。
- 前記タグペプチドではない前記少なくとも1つの標的が、免疫細胞マーカーである、請求項19または20に記載の免疫グロブリン結合タンパク質。
- 前記免疫細胞マーカーが、CD3またはCD16である、請求項21に記載の免疫グロブリン結合タンパク質。
- 前記結合ドメインが、二重特異的scFvを含む、請求項19〜22のいずれか一項に記載の免疫グロブリン結合タンパク質。
- 多価である、請求項1〜23のいずれか一項に記載の免疫グロブリン結合タンパク質。
- 二価である、請求項24に記載の免疫グロブリン結合タンパク質。
- 請求項1〜25のいずれか一項に記載の結合ドメインを含む細胞外成分、およびエフェクタードメインを含む細胞内成分を含み、前記細胞外成分と細胞内成分が、膜貫通ドメインによって接続されている、融合タンパク質。
- 前記結合ドメインが、scFvを含み、前記細胞外成分が、ヒンジを含むコネクター領域をさらに含む、請求項26に記載の融合タンパク質。
- キメラ抗原受容体を含む、請求項26または27に記載の融合タンパク質。
- 細胞傷害剤、放射性同位体、放射性金属、または検出可能な作用剤をさらに含む、請求項1〜25のいずれか一項に記載の免疫グロブリン結合タンパク質、または請求項26〜28のいずれか一項に記載の融合タンパク質。
- (a)請求項1〜25および29のいずれか一項に記載の免疫グロブリン結合タンパク質、または(b)請求項26〜29のいずれか一項に記載の融合タンパク質、および薬学的に許容される担体もしくは賦形剤を含む組成物。
- (a)請求項1〜25および29のいずれか一項に記載の免疫グロブリン結合タンパク質または(b)請求項26〜29のいずれか一項に記載の融合タンパク質をコードする単離されたポリヌクレオチド。
- (a)配列番号1、7、および13のうちのいずれか1つに示されるヌクレオチド配列と少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、もしくは100%の同一性を有するポリヌクレオチド;ならびに/または
(b)配列番号4、9、および15のうちのいずれか1つに示されるヌクレオチド配列と少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、または100%の同一性を有するポリヌクレオチドを含む、請求項31に記載のポリヌクレオチド。 - 前記ポリヌクレオチドを含有する宿主細胞に対してコドン最適化されている、請求項31または32に記載のポリヌクレオチド。
- 発現制御配列に作動可能に連結した請求項31〜33のいずれか一項に記載のポリヌクレオチドを含む発現構築物。
- 請求項34の発現構築物を含むベクター。
- プラスミドベクターまたはウイルスベクターである、請求項35に記載のベクター。
- ウイルスベクターであり、前記ウイルスベクターが、レンチウイルスベクターまたはγ−レトロウイルスベクターから選択される、請求項36に記載のベクター。
- 前記ポリヌクレオチドまたは前記発現構築物が、前記免疫グロブリン結合タンパク質または前記融合タンパク質をコードし、前記宿主細胞が、コードされた前記免疫グロブリン結合タンパク質またはコードされた前記融合タンパク質を発現する、請求項31〜33のいずれか一項に記載のポリヌクレオチドまたは請求項34に記載の発現構築物を含む宿主細胞。
- 配列番号19に示されるアミノ酸配列を含むかまたはそれからなるタグペプチドを細胞表面に発現するタグ付き細胞またはタグ付き細胞の集団を識別するための方法であって、
(i)1つまたは複数のタグ付き細胞を含む対象由来の試料を、請求項1〜25および29のいずれか一項に記載の免疫グロブリン結合タンパク質、または請求項26〜29のいずれか一項に記載の融合タンパク質と接触させることと;
(ii)前記免疫グロブリン結合タンパク質または前記融合タンパク質の前記1つまたは複数のタグ付き細胞との特異的結合を検出することとを含み、
それによって、前記タグペプチドを発現する1つまたは複数の細胞を識別する、方法。 - 対象由来のタグ付き細胞またはタグ付き細胞の集団を濃縮または単離するための方法であって、
(i)配列番号19に示されるアミノ酸配列を含むかまたはそれからなるタグペプチドを細胞表面に発現する1つまたは複数の細胞を含む前記対象由来の試料を、請求項1〜25および29のいずれか一項に記載の免疫グロブリン結合タンパク質または請求項26〜29のいずれか一項に記載の融合タンパク質と接触させることと、
(ii)前記免疫グロブリン結合タンパク質または前記融合タンパク質が特異的に結合したタグ付き細胞を選択またはソートすることとを含み、
それによって、前記タグペプチドを発現する1つまたは複数の細胞を濃縮または単離する、方法。 - 前記細胞表面のタグペプチドが、細胞表面タンパク質に含有される、請求項39または40に記載の方法。
- 前記細胞表面タンパク質が、キメラ抗原受容体(CAR)、T細胞受容体(TCR)、マーカー、またはそれらの組合せを含む、請求項41に記載の方法。
- 前記細胞表面タンパク質が、マーカーを含む、請求項41または42に記載の方法。
- 前記マーカーが、EGFRt、CD19t、CD34t、またはNGFRtを含む、請求項43に記載の方法。
- 前記免疫グロブリン結合タンパク質または融合タンパク質が、検出可能な部分を含む、請求項39〜44のいずれか一項に記載の方法。
- 前記検出可能な部分が、1つまたは複数の酵素、色素、蛍光標識、またはペプチドタグを含み、ただし、前記ペプチドタグは、配列番号19に示されるアミノ酸配列を含まないかまたはそれからならない、請求項45に記載の方法。
- 前記検出可能な部分が、前記酵素を含み、前記酵素が、発色レポーター酵素を含む、請求項46に記載の方法。
- 前記発色レポーター酵素が、セイヨウワサビペルオキシダーゼまたはアルカリホスファターゼを含む、請求項47に記載の方法。
- 前記検出可能な部分が、前記色素を含む、請求項46に記載の方法。
- 前記検出可能な部分が、前記蛍光標識を含む、請求項46に記載の方法。
- 前記蛍光標識が、シアニン色素、クマリン、ローダミン、キサンテン、フルオレセインもしくはそのスルホン化誘導体、蛍光タンパク質、またはそれらの任意の組合せを含む、請求項50に記載の方法。
- 前記検出可能な部分が、前記ペプチドタグを含み、前記ペプチドタグが、His−タグまたはMyc−タグを含む、請求項46に記載の方法。
- 前記検出可能な部分が、蛍光部分を含む、請求項46に記載の方法。
- 前記蛍光部分が、PE、Pacific blue、Alexa fluor、APCまたはFITCである、請求項53に記載の方法。
- 前記タグ付き細胞またはタグ付き細胞の集団が、フローサイトメトリーを使用して識別、検出またはソートされる、請求項39〜54のいずれか一項に記載の方法。
- 前記免疫グロブリン結合タンパク質または前記融合タンパク質が特異的に結合した前記タグ付き細胞または前記タグ付き細胞の集団が、磁気カラムクロマトグラフィーによって、試料の他の構成成分から濃縮されるかまたは単離される、請求項39〜55のいずれか一項に記載の方法。
- 前記試料が、血液である、請求項39〜56のいずれか一項に記載の方法。
- 前記試料が、組織である、請求項39〜56のいずれか一項に記載の方法。
- 前記対象が、ヒトである、請求項39〜58のいずれか一項に記載の方法。
- 配列番号19に示されるアミノ酸配列を含むかまたはそれからなるタグペプチドをその細胞表面に発現するように改変された免疫細胞を活性化するための方法であって、前記改変された免疫細胞を、請求項1〜25および29のいずれか一項に記載の免疫グロブリン結合タンパク質、または請求項26〜29のいずれか一項に記載の融合タンパク質と、前記改変された免疫細胞の活性化を誘導するのに十分な条件下および時間で、接触させることを含む、方法。
- 前記改変された免疫細胞の前記活性化が、in vitroまたはex vivoで実施される、請求項60に記載の方法。
- 濃縮または単離の前に、前記試料中の活性化した免疫細胞の集団を拡大させるステップをさらに含む、請求項60または61に記載の方法。
- 前記タグペプチドが、前記改変された免疫細胞によって発現された細胞表面タンパク質に含有される、請求項60〜62のいずれか一項に記載の方法。
- 前記タグ付き細胞表面タンパク質が、CAR、TCR、マーカー、またはそれらの組合せを含み、必要に応じて、前記マーカーが、EGFRt、CD19t、CD34t、またはNGFRtから選択される、請求項63に記載の方法。
- 前記タグペプチドを発現する前記細胞が、ヒトT細胞、NK細胞、またはNK−T細胞を含む、請求項60〜64のいずれか一項に記載の方法。
- 前記免疫グロブリン結合タンパク質または融合タンパク質が、固体表面に結合している、請求項39〜65のいずれか一項に記載の方法。
- 前記免疫グロブリン結合タンパク質または融合タンパク質が、平坦な表面、アガロース、樹脂、3Dファブリックマトリックス、またはビーズに結合している、請求項39〜66のいずれか一項に記載の方法。
- 前記免疫グロブリン結合タンパク質または融合タンパク質が、マイクロビーズまたはナノビーズに結合している、請求項67に記載の方法。
- 改変された免疫細胞の局所活性化のためのin vivo方法であって、
(i)
(a)請求項1〜25、および29のいずれか一項に記載の免疫グロブリン結合タンパク質、または請求項26〜29のいずれか一項に記載の融合タンパク質、および
(b)共刺激分子に特異的な結合ポリペプチド
を含むマトリックス組成物またはデバイス;ならびに
(ii)配列番号19に示されるアミノ酸配列を含むかまたはそれからなるタグペプチドをその細胞表面に発現する改変された免疫細胞であって、前記タグペプチドが、CAR、TCR、マーカー、またはそれらの組合せに含有され、
必要に応じて、前記マーカーが、EGFRt、CD19t、CD34t、またはNGFRtから選択される、改変された免疫細胞
を対象に投与することを含み、
サブパート(i)の前記マトリックス組成物の(a)と、前記細胞表面タグペプチドとの会合により、前記改変された免疫細胞が活性化される、方法。 - 前記マトリックス組成物が、アルギネート、基底膜マトリックス、またはバイオポリマーを含む、請求項69に記載の方法。
- 前記改変された細胞が、T細胞、NK細胞、またはNK−T細胞である、請求項69または70に記載の方法。
- 細胞増殖を促進するための方法であって、配列番号19に示されるアミノ酸配列を含むかまたはそれからなるタグペプチドを発現する細胞を
(a)請求項1〜29のいずれか一項に記載の免疫グロブリン結合タンパク質または融合タンパク質、および
(b)増殖因子サイトカインと、
前記タグ付き細胞の増殖を可能にするのに十分な条件下および時間で、接触させることを含む、方法。 - 前記免疫グロブリン結合タンパク質または融合タンパク質が、固体表面に結合している、請求項72に記載の方法。
- 前記免疫グロブリン結合タンパク質または融合タンパク質が、平坦な表面、アガロース、樹脂、3Dファブリックマトリックス、またはビーズに結合している、請求項72または73に記載の方法。
- 前記免疫グロブリン結合タンパク質または融合タンパク質が、マイクロビーズまたはナノビーズに結合している、請求項72〜74のいずれか一項に記載の方法。
- 前記増殖因子であるサイトカインが、IL−12、IL−15、またはその両方を含む、請求項72〜75のいずれか一項に記載の方法。
- 前記細胞を、抗CD27結合タンパク質、抗CD28結合タンパク質、抗CD137結合タンパク質、抗OX40結合タンパク質、またはそれらの任意の組合せとインキュベートすることをさらに含み、前記結合タンパク質のうちの1つまたは複数が、固体表面に結合している、請求項75〜76のいずれか一項に記載の方法。
- 前記抗CD27結合タンパク質、抗CD28結合タンパク質、抗CD137結合タンパク質、抗OX40結合タンパク質、またはそれらの任意の組合せが、平坦な表面、アガロース、樹脂、3Dファブリックマトリックス、またはビーズに結合している、請求項77に記載の方法。
- 前記増殖が、in vivoまたはex vivoで誘導される、請求項72〜78のいずれか一項に記載の方法。
- 前記細胞が、T細胞、NK細胞、またはNK−T細胞である、請求項72〜79のいずれか一項に記載の方法。
- 前記細胞が、機能的な改変されたT細胞である、請求項80に記載の方法。
- 前記機能的に改変されたT細胞が、ウイルス特異的細胞、腫瘍抗原特異的細胞傷害性T細胞、メモリーT幹細胞、セントラルメモリーT細胞、エフェクターT細胞、またはCD4+CD25+調節T細胞である、請求項81に記載の方法。
- 前記タグペプチドが、前記細胞によって発現される細胞表面タンパク質内に含有される、請求項72〜76のいずれか一項に記載の方法。
- 前記細胞表面タンパク質が、CAR、TCR、マーカー、またはそれらの組合せを含み、必要に応じて、前記マーカーが、EGFRt、CD19t、CD34t、またはNGFRtから選択される、請求項83に記載の方法。
- 前記増殖が、in vitroまたはex vivoで誘導される、請求項72〜84のいずれか一項に記載の方法。
- in vivoイメージング方法であって、
(a)
(i)請求項1〜25または29のいずれか一項に記載の免疫グロブリン結合タンパク質、または
(ii)請求項26〜29のいずれか一項に記載の融合タンパク質
のうちの1つまたは複数を、配列番号19に示されるアミノ酸配列を含むかまたはそれからなるタグペプチドを発現する改変された細胞を受容した対象に投与することであって、前記免疫グロブリン結合タンパク質または融合タンパク質が、in vivoイメージングに好適な検出可能な部分をさらに含む、投与することと;
(b)前記対象のイメージングを実施すること
とを含む、方法。 - 前記検出可能な部分が、放射活性トレーサーを含む、請求項86に記載の方法。
- 前記放射活性トレーサーが、68Ga、64Cu、86Y、89Zr、124I、99mTc、123I、111In、177Lu、131I、76Br、78Zr、18F、または124Tである、請求項87に記載の方法。
- 前記イメージングが、ポジトロン断層法(PET)を含む、請求項86〜88のいずれか一項に記載の方法。
- 前記結合ドメインが、抗体の抗原結合断片を含み、前記抗原結合断片が、scFv、タンデムscFv、scFv−Fc、scFv二量体、scFvジッパー、ダイアボディ、ミニボディ、トリアボディ、テトラボディ、Fab、F(ab’)2、scFab、ミニ抗体、ナノボディ、ナノボディ−HSA、二重特異的T細胞エンゲージャー(BiTE)、DART、scダイアボディ、scダイアボディ−CH3、またはscFv−CH3ノブ・イントゥ・ホール(KIH)アセンブリである、請求項86〜89のいずれか一項に記載の方法。
- タグ付き免疫治療用細胞の標的アブレーションのための方法であって、
(a)請求項1〜25または29のいずれか一項に記載の免疫グロブリン結合タンパク質;
(b)請求項26〜29のいずれか一項に記載の融合タンパク質;または
(c)請求項30に記載の組成物を、
前記タグ付き免疫治療用細胞のアブレーションを引き起こすのに十分な条件下および時間で、対象に投与することを含み、
前記対象に、タグペプチドを含む細胞表面タンパク質を発現するタグ付き免疫治療用細胞が以前に投与されており、前記タグペプチドが、配列番号19のアミノ酸配列を含むかまたはそれからなり、
前記免疫グロブリン結合タンパク質、融合タンパク質、または組成物が、前記タグペプチドに結合すると、直接的または間接的に、細胞死を誘導することが可能である、方法。 - 前記免疫グロブリン結合タンパク質、融合タンパク質、または組成物が、細胞傷害剤を含む、請求項91に記載の方法。
- 前記免疫グロブリン結合タンパク質が、前記タグペプチドに結合すると、前記タグ付き免疫治療用細胞に対して、
(a)オプソニン化;
(b)貪食;
(c)抗体指向性細胞介在性細胞傷害(ADCC);および
(d)補体指向性細胞傷害(CDC)
のうちの1つまたは複数を誘引することが可能である抗体を含む、請求項91または92に記載の方法。 - 前記免疫グロブリン結合タンパク質が、二重特異的であり、前記タグペプチドに結合するのと同時に、(a)T細胞マーカーまたは(b)NK細胞マーカーに結合することが可能である、請求項93に記載の方法。
- 前記T細胞マーカーが、CD3であり、前記NK細胞マーカーが、CD16である、請求項94に記載の方法。
- 前記免疫グロブリン結合タンパク質が、二重特異的scFv、二重特異的T細胞エンゲージャー(BiTE)分子、ナノボディ、ダイアボディ、DART、TandAb、scダイアボディ、scダイアボディ−CH3、ダイアボディ−CH3、Triple Body、ミニ抗体、ミニボディ、TriBiミニボディ、scFv−CH3 KIH、Fab−scFv、scFv−CH−CL−scFv、F(ab’)2、F(ab’)2−scFv2、scFv−KIH、Fab−scFv−Fc、四価のHCab、scダイアボディ−Fc、ダイアボディ−Fc、タンデムscFv−Fc、イントラボディ、Dock and Lock融合タンパク質、ImmTAC、HSAbody、scダイアボディ−HSA、タンデムscFv、crossMab、DAF(トゥーインワンまたはフォーインワン)、DutaMab、DT−IgG、ノブ・イントゥ・ホール(KIH)アセンブリ、KIH Common Light−Chain抗体、Charge Pair、Fab−アームExchange、SEEDbody、Triomab、LUZ−Y、Fcab、κλ−ボディ、直交Fab、DVD−IgG、IgG(H)−scFv、scFv−(H)IgG、IgG(L)−scFv、scFv−(L)IgG、IgG(L,H)−Fv、IgG(H)−V、V(H)−IgG、IgG(L)−V、V(L)−IgG、KIH IgG−scFab、2scFv−IgG、IgG−2scFv、scFv4−Ig、Zybody、またはDVI−IgG(フォーインワン)を含む、請求項94または95に記載の方法。
- 前記細胞表面タンパク質が、CAR、TCR、マーカー、またはそれらの組合せを含む、請求項91〜96のいずれか一項に記載の方法。
- 前記細胞表面タンパク質が、マーカータンパク質を含む、請求項91〜97のいずれか一項に記載の方法。
- 前記マーカータンパク質が、EGFRt、CD19t、CD34t、またはNGFRtである、請求項98に記載の方法。
- 前記免疫グロブリン結合タンパク質、融合タンパク質、または組成物が、前記タグ付き免疫治療用細胞の存在に関連する少なくとも1つの有害事象を有する前記対象に投与される、請求項91〜99のいずれか一項に記載の方法。
- 前記アブレーション後に、
(i)請求項86〜90のいずれか一項に記載の対象のin vivoイメージングを実施すること;
(ii)前記対象から得られる試料において、請求項39〜59のいずれか一項に記載の検出方法を実施すること;
(iii)前記対象において1つまたは複数のサイトカインのレベルをモニタリングすること;
(iv)前記対象または前記対象から得られた試料において、前記タグ付き免疫治療用細胞によって標的化された標的細胞または組織の存在および/または量を検出すること;
(v)前記タグ付き免疫治療用細胞のin vivo追跡を実施すること;または
(vi)それらの任意の組合せ
をさらに含む、請求項91〜100のいずれか一項に記載の方法。 - 前記in vivo追跡が、磁気粒子;超常磁性酸化鉄(SPIO);フルオロデオキシグルコース(18F);蛍光化合物;またはそれらの任意の組合せにコンジュゲートした前記免疫グロブリン結合タンパク質または前記融合タンパク質の使用を含む、請求項101に記載の方法。
- 前記in vivo追跡が、MRI、PET、または近赤外イメージングの使用を含む、請求項101または102に記載の方法。
- 前記タグ付き免疫治療用細胞が、T細胞、NK細胞、NK−T細胞、造血幹細胞、組織細胞、間葉細胞、またはそれらの任意の組合せを含む、請求項91〜103のいずれか一項に記載の方法。
- 前記対象が、1つまたは複数のタグ付き免疫治療用細胞を含む移植後に、移植片対宿主病(GvHD)、宿主対移植片病(HvGD)、またはサイトカイン放出症候群(CRS)を有するかまたは有することが疑われる、請求項91〜104のいずれか一項に記載の方法。
- (a)配列番号19に示されるアミノ酸配列を含むかまたはそれからなるタグペプチドをコードする発現ベクターまたはポリヌクレオチド、および前記ベクターまたはポリヌクレオチドを宿主細胞に形質導入するための必要に応じた試薬;ならびに
(b)(i)請求項1〜25および29のいずれか一項に記載の免疫グロブリン結合タンパク質、
(ii)請求項23〜29のいずれか一項に記載の融合タンパク質、
(iii)請求項30に記載の組成物、
(iv)請求項31〜33のいずれか一項に記載の単離されたポリヌクレオチドまたは請求項34〜37のいずれか一項に記載の発現ベクター、および前記ポリヌクレオチドまたは発現ベクターを宿主細胞に形質導入するための必要に応じた試薬、および/または
(v)請求項38に記載の宿主細胞
を含む、キット。 - (i)請求項1〜25および29のいずれか一項に記載の免疫グロブリン結合タンパク質、または請求項26〜29のいずれか一項に記載の融合タンパク質を含むマトリックス組成物;および
(ii)免疫共刺激分子に特異的に結合する結合ポリペプチドであって、前記結合によって前記免疫共刺激分子の活性レベルが増加する、結合ポリペプチド
を含むマトリックス組成物。 - アルギネート、基底膜マトリックス、もしくはバイオポリマー、またはそれらの任意の組合せをさらに含む、請求項107に記載のマトリックス組成物。
- (i)請求項1〜25および29のいずれか一項に記載の免疫グロブリン結合タンパク質、または請求項26〜29のいずれか一項に記載の融合タンパク質、ならびに
(ii)免疫共刺激分子に特異的に結合する結合ポリペプチドであって、前記結合によって前記免疫共刺激分子の活性レベルが増加する、結合ポリペプチド
を含むデバイス。 - (i)および(ii)のうちの一方または両方が、固体表面、アガロースビーズ、樹脂、3Dファブリックマトリックス、またはビーズに配置されている、請求項109に記載のデバイス。
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