JP2021500875A - キメラ抗原受容体 - Google Patents
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- JP2021500875A JP2021500875A JP2020519675A JP2020519675A JP2021500875A JP 2021500875 A JP2021500875 A JP 2021500875A JP 2020519675 A JP2020519675 A JP 2020519675A JP 2020519675 A JP2020519675 A JP 2020519675A JP 2021500875 A JP2021500875 A JP 2021500875A
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Abstract
Description
本出願は2017年10月6日に出願された米国仮出願第62/568,837号、および2017年11月8日に出願された米国仮出願第62/583,058号の優先権および利益を主張し、それらの全体が参照により本明細書に組み込まれる。
免疫療法のための組成物および方法が、本明細書において提供される。特に、キメラ抗原受容体、キメラ抗原受容体を発現する細胞、および免疫療法(例えば、ガン免疫療法)におけるそのような細胞の使用が、本明細書において提供される。
T細胞の力を結びつけ、そして腫瘍に対してT細胞を再指向させる免疫療法は、過去5年間に、非常に成功するものであることが判明しており、そしてかなりの関心を引き付けている。それは、選択された抗原受容体を用いるエフェクター細胞(主にT細胞およびナチュラルキラー細胞)の再指向を含む。現在までに、以下の2つの主な再指向剤が開発されている:抗体由来の抗原結合ドメインに基づくキメラ抗原受容体(CAR);および、T細胞受容体(TCR)。抗体は、可溶性タンパク質であり、(i)抗原結合ドメインを内在するタンパク質膜貫通(TM)ドメインに融合させ、そして(ii)既知のTCRシグナル伝達タンパク質のシグナル伝達ドメイン、主にシグナルIおよびIIに関与するパートナーのリン酸化部位を付加することによって、細胞受容体に改変される(Letourneur, F. & Klausner, T-cell and basophil activation through the cytoplasmic tail of T-cell-receptor zeta family proteins. Proc. Nat’l Acad. Sci. 88, 8905-8909 (1991);Romeo, C. & Seed, B. Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides. Cell 64, 1037-1046 (1991);Irving, B. A. & Weiss, A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 64, 891-901 (1991))。抗体の単鎖可変部分(scFv)に連結されたドメインの組成および組み合わせは多様であり、そして最も強力な普遍的設計の明確なロードマップはこれまで描かれていない。これらのCARは、免疫シナプスを生成し、そしてエフェクター細胞機能、サイトカイン放出および標的死滅を誘発する能力を有する。血液悪性腫瘍の処置のために抗CD19 CARを使用した様々なチームによって生み出された驚くべき結果の後(Jensen, M. C. & Riddell, S. R. Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev 257, 127-144, doi:10.1111/imr.12139 (2014);Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5, (2013);Kochenderfer, J. N. & Rosenberg, S. A. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol 10, 267-276, (2013);Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3, 95ra73, (2011))、これらの構築物の使用が華々しく上昇した。新たな標的が現在評価されているが、成果は、特に固形腫瘍を扱う場合、一般的なB細胞マーカーであるCD19について観察されるほどの成功ではなかった(Park, J. R. et al. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther 15, 825-833, (2007);Lamers, C. H. et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther 21, 904-912, (2013);Katz, S. C. et al. Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor-Modified T-cell Therapy for CEA+ Liver Metastases. Clin Cancer Res 21, 3149-3159, (2015))。
免疫療法のための組成物および方法が、本明細書において提供される。特に、キメラ抗原受容体、キメラ抗原受容体を発現する細胞、および免疫療法(例えば、ガン免疫療法)におけるそのような細胞の使用が、本明細書において提供される。
図1。TCR−CAR構築物の設計。(a)TCR−CAR遺伝子設計。TCRαおよびβ鎖を、それらの膜貫通領域(TM)またはドメインのレベルで短縮化し、システインをそれらの定常ドメインに付加し、そして2つの鎖を2Aペプチド配列によって連結した。(b)sTCRは、可溶性タンパク質として産生され、これはおそらく、小胞分泌経路に従って、細胞媒質中に放出された(左)。適正な折り畳みは、ペプチド−MHC(pMHC)複合体への特異的結合およびCD28−CD3シグナル伝達テイルを介したシグナル伝達を確実にするはずである(右)。
本明細書において使用する場合、用語「腫瘍反応性TCR」は、腫瘍またはガン細胞に対する特異的親和性を有し、そして非ガン細胞に対する低い親和性を有するかまたは非ガン細胞に対する親和性を有しない任意のTCRを指す。いくつかの実施形態において、腫瘍反応性TCR由来の抗原結合ドメインは、「ペプチドを提示するHLA複合体に対する特異的親和性」を有する。
免疫療法のための組成物および方法が、本明細書において提供される。特に、キメラ抗原受容体、キメラ抗原受容体を発現する細胞、および免疫療法(例えば、ガン免疫療法)におけるそのような細胞の使用が、本明細書において提供される。
膜貫通ドメインを介してCARシグナル伝達テイルに融合された可溶性TCR構築物を含む構築物が本明細書において提供される。TCRは、MHC/HLA分子の文脈で、ペプチドを認識するヘテロ二量体膜貫通タンパク質(例えば、TCRα/β)である。本開示は、TCR鎖の1つ(例えば、TCRβ)の細胞質およびTMドメインをキメラシグナル伝達ドメインで置換することによって膜貫通(TM)ドメインが変化させられている、天然TCRの改変型の発現を記載する。
いくつかの実施形態において、本発明は、本明細書に記載のCARを含む細胞を提供する。本発明は、特定の細胞型に限定されない。例としては、限定するものではないが、T細胞、ナチュラルキラー細胞、NK−92細胞などが挙げられる。細胞は、初代(例えば、自己もしくは異種ドナー由来)または不死化細胞株であり得る。
本明細書に記載のCARは、種々の治療適用における使用を見出す。いくつかの実施形態において、本明細書に記載のTCR−CARを発現する細胞は、抗ガン養子細胞移入(ACT)において使用される。いくつかの実施形態において、細胞は、標的化されるエピトープ(ペプチド)およびHLAアレルについてその腫瘍が陽性である患者に注射される。いくつかの実施形態において、これは、NK細胞(および任意の非T細胞)のような死滅能力を有するエフェクター細胞を、T細胞標的に対して、そしてまた制御機能(例えば、サイトカイン放出または抗原提示)を有する他の型の免疫エフェクター細胞(マクロファージ)に対して再指向させる。
実施例1
方法
細胞株、培地、化学物質およびペプチド。T細胞を、血液バンク(Ulleval hospital, Oslo, Norway)からの健常血液ドナー由来のバフィーコートから得た。J7631(M.Heemskerk, Leiden University Medical Center, The Nederlandsから入手)を、10%HyClone FCS(HyClone, Logan, UT, USA)およびゲンタマイシン(50μg/mL)を補充したRPMI(PAA, Paschung, Austria)中で維持した。K562(ATCC, CCL-243)、Granta−519(DSMZ, ACC 342)およびT2細胞を、同じ培地中で維持した。パッケージング細胞は、改変ヒト胎児腎細胞293、Hek−Phoenix(Hek−P)であり、そしてそれらを10%FCSを含むDMEM(PAA)中で増殖させた。T細胞を、5%熱不活性化ヒト血清(Trina Bioreactives AG, Nanikon、Switzerland)、1.25mg/mL N−アセチルシステイン(Mucomyst 200mg/mL, AstraZeneca AS, London, UK)、0.01M HEPES(Life Technologies, Norway)、ゲンタマイシン0.05mg/mL(Garamycin, Schering-Plough Europe, Belgium)を補充したCellGro DC培地(CellGenix, Freiburg, Germany)中で増殖させた。NK−92細胞を、5%熱不活化HSおよび500IU/mL IL−2を補充したX−Vivo10培地中で培養および維持した。TGFbR2フレームシフトペプチド131−139、RLSSCVPVAは、Norsk Hydro ASA(Porsgrunn, Norway)によって提供された。MART−1ペプチド26−35 EAAGIGILTVは、ProImmune Ltd(Oxford, UK)によって製造され、そしてMART−1デキストラマーは、Immudex(Copenhagen, Denmark)から入手した。DNA構築物。CAR25ドメイン由来の膜貫通および細胞質ドメインを、以下のプライマーを使用することによるオーバーラップPCRによって、以前に記載された可溶性TCR24に付加した:CARテンプレート(5’−3’)フォワードggtagagcagactgtggtaaattttgggtgctggtggtgg(配列番号27)(1)、リバースctcgagttagcgaggaggcagggcctgcatgtgaag(配列番号28)(2)、sTCRテンプレートフォワード(Radium1)caccatgaagaggatat(配列番号29)(3)、(DMF5)caccatgatgaaatcct(配列番号30)(4)、リバースccaccaccagcacccaaaatttaccacagtctgctctaccc(配列番号31)(5)。続いて、Radium−1については以下のプライマー対(3)および(2)を、そしてDMF5については(4)および3(2)を使用して、2つのPCR産物をTCR−CARに組み合わせた。最終的なPCR産物をpENTR(Themofisher、Waltham, MA, USA)中にクローニングした。配列を確認した構築物を、記載されるように、Gateway改変pMP71(レトロウイルスベクター)またはpCIpA102(mRNA合成構築物)に組換えた(Walchli, S. et al. A practical approach to T-cell receptor cloning and expression. PLoS One 6, e27930 (2011))。ここで使用したTCR発現構築物は、それぞれDMF5およびRadium−1について記載されている(Inderberg, E. M. et al. T cell therapy targeting a public neoantigen in microsatellite instable colon cancer reduces in vivo tumor growth. Oncoimmunology 6, (2017);Walchli, S. et al. A practical approach to T-cell receptor cloning and expression. PLoS One 6, e27930 (2011))。HLA−A2構築物は、以前に記載されている(Walchli, S. et al. Invariant chain as a vehicle to load antigenic peptides on human MHC class I for cytotoxic T-cell activation. Euro. J Immunol. 44, 774-784, (2014))、Addgene(Plasmid #85162)。インビトロmRNA転写。インビトロmRNA合成を、本質的に以前に記載されるように行った(Aggen, D. H. et al. Identification and engineering of human variable regions that allow expression of stable single-chain T cell receptors. Protein Eng Des Sel 24, 361-372 (2010))。Anti−Reverse Cap Analog(Trilink Biotechnologies Inc., San Diego, CA, USA)を、RNAをキャッピングするために使用した。mRNAの質を、アガロースゲル電気泳動およびNanodrop(Thermo Fisher Scientific)によって評価した。
TCR−CARの設計。ヒト胎児腎(Hek)細胞および誘導体(例えば、Hek−Phoenix)において可溶性TCR(sTCR)を効率的に発現させることができることが以前に示された(Walseng, E. et al. Soluble T-cell receptors produced in human cells for targeted delivery. PLoS One 10, (2015))。2Aベースの発現システムを利用することによって、高収量(4mg/L)の活性材料を得た(Kim, J. H. et al. High cleavage efficiency of a 2A peptide derived from porcine teschovirus-1 in human cell lines, zebrafish and mice. PLoS One 6, e18556, (2011))。これらの結果はそれ自体予測不可能であった。なぜなら、2つの分離された可溶性鎖の遊離は安定な分子の形成を機械的にはもたらさず、起こりそうな結果は、ERにおけるそれらの分解か、または形質膜に送られることはないことであり得たからである。sTCR生成の合成および輸送が可能であったので、TCRβ鎖を、CARのために使用されるものと同様の人工シグナル伝達ドメインに融合させた関連する構築物を設計した(図1a):すなわち、CD28膜貫通コード配列およびそれに続く2つのシグナル伝達モジュール(CD28およびCD3ζ)。さらに、TCR二量体安定性を増加させるために、定常ドメイン(C−ドメイン)上でシステイン置換を行った(Cohen, C. J. et al. Enhanced antitumor activity of T cells engineered to express T-cell receptors with a second disulfide bond. Cancer Res 67, 3898-3903 (2007);Walseng et al.、前出)。このTCR−CARカセットを、先に公開されたストラテジーを使用して、2つの異なる発現システム、すなわちMP71レトロウイルスベクターおよびmRNA合成ベクター中にサブクローニングした(Walchli et al、前出)。
Claims (39)
- 以下を含むキメラ抗原受容体(CAR):
a)ペプチドを提示するHLA複合体に特異的に結合する細胞外抗原結合ドメインであって、前記細胞外抗原結合ドメインは2つのポリペプチドを含み、前記ポリペプチドの各々は可変ドメインおよび定常ドメインを含む、細胞外抗原結合ドメイン;
b)前記細胞外抗原結合ドメインに作動可能に連結された単一の膜貫通ドメインおよび
c)前記膜貫通ドメインに作動可能に連結された細胞内シグナル伝達ドメイン。 - 前記2つのポリペプチドが、少なくとも2つのジスルフィド架橋によって連結され、各々の架橋が前記ポリペプチドの定常ドメインにおける2つのシステイン残基によって形成される、請求項1に記載の受容体。
- 前記膜貫通ドメインが以下を含む、請求項1または2に記載の受容体:
a)配列番号5もしくは配列番号5と少なくとも90%同一の配列;
b)配列番号12もしくは配列番号12と少なくとも90%同一の配列;または
c)配列番号14もしくは配列番号14と少なくとも90%同一の配列。 - 前記細胞内シグナル伝達ドメインが以下を含む、請求項1〜3のいずれか1項に記載の受容体:
a)配列番号6もしくは配列番号6と少なくとも90%同一の配列;
b)配列番号13もしくは配列番号13と少なくとも90%同一の配列;または
c)配列番号15もしくは配列番号15と少なくとも90%同一の配列。 - 前記細胞内シグナル伝達ドメインが、配列番号6および配列番号7を含む、請求項1〜4のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号1および配列番号2、またはその機能的フラグメントを含む、請求項1〜5のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、腫瘍反応性T細胞受容体に由来する、請求項1〜6のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号1および配列番号2、または配列番号1および2に対する少なくとも95%の同一性を有する配列を含む、請求項1〜7のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号1および配列番号2、または配列番号1および2に対する少なくとも95%の同一性を有する配列を含み、ただし、配列番号1は3つのCDRであるDSVNN、IPSGTおよびAVNAGNMLTFを含み、そして配列番号2または16は3つのCDRであるMDHEN、SYDVKMおよびASSSGVTGELFFを含む、請求項1〜8のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号8および配列番号9、または配列番号8および9に対する少なくとも95%の同一性を有する配列を含む、請求項1〜7のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号8および配列番号9もしくは17、または配列番号8および9に対する少なくとも95%の同一性を有する配列を含み、ただし、配列番号8は3つのCDRであるDRGSQS、IYSNGDおよびAVNFGGGKLIFを含み、そして配列番号9は3つのCDRであるMRHNA、SNTAGTおよびASSLSFGTEAFFを含む、請求項1〜7のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号3または配列番号3に対する少なくとも98%の同一性を有する配列によって表される1つの定常ドメインを含み、ただし、48位および91位におけるアミノ酸残基の両方はシステイン残基であり;そして前記抗原結合ドメインが、配列番号4または配列番号4に対する98%より高い同一性を有する配列によって表される1つの定常ドメインを含み、ただし、57位および131位におけるアミノ酸残基の両方はシステイン残基である、請求項1〜11のいずれか1項に記載の受容体。
- α鎖由来の定常ドメインおよびβ鎖由来の定常ドメインを含み;前記α鎖由来の定常ドメイン中の48位におけるスレオニン残基がシステイン残基で置換され、そして前記β鎖由来の定常ドメイン中の57位におけるセリン残基がシステイン残基で置換されている、請求項2に記載の受容体。
- 以下を含むキメラ抗原受容体(CAR):
a)ペプチドを提示するHLA複合体に特異的に結合する細胞外抗原結合ドメインであって、前記細胞外抗原結合ドメインは2つのポリペプチドを含み、前記ポリペプチドの各々は可変ドメインおよび定常ドメインを含み、前記2つのポリペプチドは少なくとも2つのジスルフィド架橋によって連結され、各々の架橋は前記ポリペプチドの定常ドメインにおける2つのシステイン残基によって形成される、細胞外抗原結合ドメイン;
b)前記細胞外抗原結合ドメインに作動可能に連結された単一の膜貫通ドメイン;および
c)前記膜貫通ドメインに作動可能に連結された細胞内シグナル伝達ドメイン。 - 前記膜貫通ドメインが以下を含む、請求項14に記載の受容体:
d)配列番号5もしくは配列番号5と少なくとも90%同一の配列;
e)配列番号12もしくは配列番号12と少なくとも90%同一の配列;または
f)配列番号14もしくは配列番号14と少なくとも90%同一の配列。 - 前記細胞内シグナル伝達ドメインが以下を含む、請求項14または15に記載の受容体:
d)配列番号6もしくは配列番号6と少なくとも90%同一の配列;
e)配列番号13もしくは配列番号13と少なくとも90%同一の配列;または
f)配列番号15もしくは配列番号15と少なくとも90%同一の配列。 - 前記細胞内シグナル伝達ドメインが、配列番号6および配列番号7を含む、請求項14〜16のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、腫瘍反応性T細胞受容体に由来する、請求項14〜17のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号1および配列番号2、またはその機能的フラグメントを含む、請求項14〜18のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号1および配列番号2、または配列番号1および2に対する少なくとも95%の同一性を有する配列を含む、請求項14〜18のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号1および配列番号2、または配列番号1および2に対する少なくとも95%の同一性を有する配列を含み、ただし、配列番号1は3つのCDRであるDSVNN、IPSGTおよびAVNAGNMLTFを含み、そして配列番号2は3つのCDRであるMDHEN、SYDVKMおよびASSSGVTGELFFを含む、請求項14〜18のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号8および配列番号9、または配列番号8および9に対する少なくとも95%の同一性を有する配列を含む、請求項14〜18のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号8および配列番号9、または配列番号8および9もしくは17に対する少なくとも95%の同一性を有する配列を含み、ただし、配列番号8は3つのCDRであるDRGSQS、IYSNGDおよびAVNFGGGKLIFを含み、そして配列番号9は3つのCDRであるMRHNA、SNTAGTおよびASSLSFGTEAFFを含む、請求項14〜18のいずれか1項に記載の受容体。
- 前記抗原結合ドメインが、配列番号3または配列番号3に対する少なくとも98%の同一性を有する配列によって表される1つの定常ドメインを含み、ただし、48位および91位におけるアミノ酸残基の両方はシステイン残基であり;そして前記抗原結合ドメインが、配列番号4または配列番号4に対する98%より高い同一性を有する配列によって表される1つの定常ドメインを含み、ただし、57位および131位におけるアミノ酸残基の両方はシステイン残基である、請求項14〜23のいずれか1項に記載の受容体。
- α鎖由来の定常ドメインおよびβ鎖由来の定常ドメインを含み、前記α鎖由来の定常ドメイン中の48位におけるスレオニン残基がシステイン残基で置換され、そして前記β鎖由来の定常ドメイン中の57位におけるセリン残基がシステイン残基で置換されている、請求項14に記載の受容体。
- 前記受容体が、配列番号22、23、24、25および26からなる群より選択されるアミノ酸配列をコードする核酸から発現される、請求項1〜25のいずれか1項に記載の受容体。
- 請求項1〜26のいずれか1項に記載の受容体をコードする核酸。
- 可変ドメインおよび定常ドメインを含む2つの配列が、2Aリボソームスキッピング配列によって分離される、請求項27に記載の核酸。
- 請求項27または28に記載の核酸を含むベクター。
- 自細胞膜において請求項1〜26のいずれか1項に記載の受容体を発現する細胞。
- 前記細胞が、T細胞、ナチュラルキラー細胞およびNK−92細胞からなる群より選択される、請求項30に記載の細胞。
- 自細胞膜において、抗体由来の抗原結合ドメインを介して表面エピトープを標的化する従来のCARをさらに発現する、請求項30または31に記載の細胞。
- 前記細胞が不死化細胞株である、請求項30〜32のいずれか1項に記載の細胞。
- 対象において標的細胞集団または組織に対するリンパ球媒介性免疫応答を刺激する方法であって、請求項30〜33のいずれか1項に記載の細胞の有効量を対象に投与する工程を含む、方法。
- 前記標的細胞集団または組織が、ガン細胞または腫瘍である、請求項34に記載の方法。
- 対象においてガンを処置する方法であって、請求項30〜33のいずれか1項に記載の細胞の有効量を哺乳動物に投与する工程を含む、方法。
- 前記リンパ球が、自己T細胞、ナチュラルキラー細胞、不死化細胞株、およびNK−92細胞からなる群より選択される、請求項34〜36のいずれか1項に記載の方法。
- 対象におけるガンの処置または標的細胞集団もしくは組織に対するリンパ球媒介性免疫応答の刺激における使用のための、請求項30〜33のいずれか1項に記載の細胞。
- 治療における使用のための、請求項30〜33のいずれか1項に記載の細胞を含む、医薬組成物。
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US11929064B2 (en) | 2018-07-13 | 2024-03-12 | Google Llc | End-to-end streaming keyword spotting |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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KR20220122831A (ko) * | 2021-02-26 | 2022-09-05 | 주식회사 이뮤노로지컬디자이닝랩 | HLA class II에 특이적으로 결합하는 키메릭 항원 수용체 및 이의 용도 |
WO2022203226A1 (ko) * | 2021-03-22 | 2022-09-29 | 주식회사 이뮤노로지컬디자이닝랩 | 키메릭 항원 수용체(car)를 포함하는 형질전환된 항원 특이적 전문적 항원표출세포 및 이의 용도 |
Family Cites Families (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR901228A (fr) | 1943-01-16 | 1945-07-20 | Deutsche Edelstahlwerke Ag | Système d'aimant à entrefer annulaire |
US6352694B1 (en) | 1994-06-03 | 2002-03-05 | Genetics Institute, Inc. | Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells |
US6534055B1 (en) | 1988-11-23 | 2003-03-18 | Genetics Institute, Inc. | Methods for selectively stimulating proliferation of T cells |
US5858358A (en) | 1992-04-07 | 1999-01-12 | The United States Of America As Represented By The Secretary Of The Navy | Methods for selectively stimulating proliferation of T cells |
US6905680B2 (en) | 1988-11-23 | 2005-06-14 | Genetics Institute, Inc. | Methods of treating HIV infected subjects |
US5585362A (en) | 1989-08-22 | 1996-12-17 | The Regents Of The University Of Michigan | Adenovirus vectors for gene therapy |
US5199942A (en) | 1991-06-07 | 1993-04-06 | Immunex Corporation | Method for improving autologous transplantation |
GB9125768D0 (en) | 1991-12-04 | 1992-02-05 | Hale Geoffrey | Therapeutic method |
US5350674A (en) | 1992-09-04 | 1994-09-27 | Becton, Dickinson And Company | Intrinsic factor - horse peroxidase conjugates and a method for increasing the stability thereof |
US7175843B2 (en) | 1994-06-03 | 2007-02-13 | Genetics Institute, Llc | Methods for selectively stimulating proliferation of T cells |
US6692964B1 (en) | 1995-05-04 | 2004-02-17 | The United States Of America As Represented By The Secretary Of The Navy | Methods for transfecting T cells |
US7067318B2 (en) | 1995-06-07 | 2006-06-27 | The Regents Of The University Of Michigan | Methods for transfecting T cells |
EP1235842A4 (en) | 1999-10-15 | 2003-04-23 | Univ Massachusetts | GENESIS OF THE RNA INTERFERENCE PATH AS AID OF TARGETED GENTIAN INTERFERENCE |
US6326193B1 (en) | 1999-11-05 | 2001-12-04 | Cambria Biosciences, Llc | Insect control agent |
US6770749B2 (en) | 2000-02-22 | 2004-08-03 | City Of Hope | P53-specific T cell receptor for adoptive immunotherapy |
US6867041B2 (en) | 2000-02-24 | 2005-03-15 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
US6797514B2 (en) | 2000-02-24 | 2004-09-28 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
JP2004500095A (ja) | 2000-02-24 | 2004-01-08 | エクサイト セラピーズ, インコーポレイテッド | 細胞の同時の刺激および濃縮 |
US7572631B2 (en) | 2000-02-24 | 2009-08-11 | Invitrogen Corporation | Activation and expansion of T cells |
AU2001275474A1 (en) | 2000-06-12 | 2001-12-24 | Akkadix Corporation | Materials and methods for the control of nematodes |
US7723111B2 (en) | 2001-03-09 | 2010-05-25 | The United States Of America As Represented By The Department Of Health And Human Services | Activated dual specificity lymphocytes and their methods of use |
DK1546188T3 (da) | 2001-06-05 | 2008-10-27 | Altor Bioscience Corp | P53-bindende T-cellereceptormolekyler og anvendelser deraf |
DE10156482A1 (de) | 2001-11-12 | 2003-05-28 | Gundram Jung | Bispezifisches Antikörper-Molekül |
GB0304068D0 (en) | 2003-02-22 | 2003-03-26 | Avidex Ltd | Substances |
WO2005000889A1 (en) | 2003-06-05 | 2005-01-06 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Immunogenic peptides for the treatment of prostate and breast cancer |
GB0328363D0 (en) | 2003-12-06 | 2004-01-14 | Imp College Innovations Ltd | Therapeutically useful molecules |
NZ550810A (en) | 2004-05-19 | 2009-05-31 | Immunocore Ltd | High affinity NY-ESO T cell receptor |
ATE430164T1 (de) | 2004-05-26 | 2009-05-15 | Immunocore Ltd | Hochaffine telomerase-t-zellen-rezeptoren |
JP5563194B2 (ja) | 2004-06-29 | 2014-07-30 | イムノコア リミテッド | 改変t細胞レセプターを発現する細胞 |
US7915036B2 (en) | 2004-09-13 | 2011-03-29 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Compositions comprising T cell receptors and methods of use thereof |
GB0524477D0 (en) | 2005-11-30 | 2006-01-11 | Avidex Ltd | Isolated T cell receptors which specifically bind to vygfvracl-hla-24 |
GB0511124D0 (en) | 2005-06-01 | 2005-07-06 | Avidex Ltd | High affinity melan-a t cell receptors |
US8003770B2 (en) | 2005-09-13 | 2011-08-23 | Mie University | T-cell receptor and nucleic acid encoding the receptor |
US7820174B2 (en) | 2006-02-24 | 2010-10-26 | The United States Of America As Represented By The Department Of Health And Human Services | T cell receptors and related materials and methods of use |
ATE550356T1 (de) * | 2006-05-03 | 2012-04-15 | Us Gov Health & Human Serv | Chimäre t-zellen-rezeptoren sowie entsprechende materialien und verwendungsverfahren |
EP1870418A1 (en) | 2006-06-20 | 2007-12-26 | GSF-Forschungszentrum für Umwelt und Gesundheit GmbH | Allorestricted peptide-specific T cells |
EP1878744A1 (en) | 2006-07-13 | 2008-01-16 | Max-Delbrück-Centrum für Molekulare Medizin (MDC) | Epitope-tag for surface-expressed T-cell receptor proteins, uses thereof and method of selecting host cells expressing them |
WO2008039818A2 (en) | 2006-09-26 | 2008-04-03 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Modified t cell receptors and related materials and methods |
US8216565B2 (en) | 2007-01-12 | 2012-07-10 | The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services | GP100-specific T cell receptors and related materials and methods of use |
US20100297093A1 (en) * | 2007-09-25 | 2010-11-25 | The United States Of America, As Represented By The Secretary, Department Of Health And Human | Modified t cell receptors and related materials and methods |
AU2009317161B2 (en) | 2008-11-24 | 2014-09-11 | Helmholtz Zentrum Munchen Deutsches Forschungszentrum Fur Gesundheit Und Umwelt Gmbh | High affinity T cell receptor and use thereof |
WO2010088160A1 (en) | 2009-01-28 | 2010-08-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | T cell receptors and related materials and methods of use |
GB0911566D0 (en) | 2009-07-03 | 2009-08-12 | Immunocore Ltd | T cell receptors |
WO2011059836A2 (en) | 2009-10-29 | 2011-05-19 | Trustees Of Dartmouth College | T cell receptor-deficient t cell compositions |
CA2805320A1 (en) | 2010-07-28 | 2012-02-02 | Immunocore Ltd | T cell receptors |
EP2601521B1 (en) | 2010-08-06 | 2018-05-02 | Ludwig-Maximilians-Universität München | Identification of t cell target antigens |
ES2734889T3 (es) | 2010-09-21 | 2019-12-12 | Us Health | Receptores de células T anti-SSX-2 y materiales relacionados y métodos de uso |
AU2014262282B2 (en) * | 2011-02-11 | 2016-10-27 | Memorial Sloan-Kettering Cancer Center | HLA-restricted, peptide-specific antigen binding proteins |
WO2013147606A1 (en) | 2012-03-28 | 2013-10-03 | Umc Utrecht Holding B.V. | Combinatorial gamma 9 delta 2 t cell receptor chain exchange |
PT2852613T (pt) | 2012-05-22 | 2019-05-20 | Us Health | Recetores de célula t anti-ny-eso-1 murinos |
HUE048312T2 (hu) * | 2013-05-03 | 2020-07-28 | Ohio State Innovation Foundation | CS-1 specifikus kiméra antigén receptor módosított immuneffektor sejtek |
US9717758B2 (en) | 2013-05-17 | 2017-08-01 | University Of Massachusetts | High-affinity DMF5 T cell receptor (TCR) variants |
EP3572423B1 (en) | 2013-07-15 | 2023-12-06 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Anti-human papillomavirus 16 e6 t cell receptors |
EP3593812A3 (en) * | 2014-03-15 | 2020-05-27 | Novartis AG | Treatment of cancer using chimeric antigen receptor |
CN108884167A (zh) * | 2016-03-15 | 2018-11-23 | 癌症研究技术有限公司 | 嵌合抗原受体 |
MX2018012268A (es) | 2016-04-08 | 2019-02-07 | Adaptimmune Ltd | Receptores de celulas t. |
PL3440106T3 (pl) | 2016-04-08 | 2022-01-31 | Adaptimmune Limited | Receptory występujące na limfocytach t |
CA3020530A1 (en) | 2016-04-08 | 2017-10-12 | Adaptimmune Limited | T cell receptors |
WO2017189254A1 (en) | 2016-04-26 | 2017-11-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anti-kk-lc-1 t cell receptors |
US20170319638A1 (en) | 2016-05-06 | 2017-11-09 | Virttu Biologics Limited | Treatment of cancer |
GB201608052D0 (en) * | 2016-05-09 | 2016-06-22 | Univ Oslo Hf | T-cell receptors which recognise frameshift mutants of TGF-beta RII |
GB201608060D0 (en) | 2016-05-09 | 2016-06-22 | Univ Birmingham | Method of culturing T cells |
US11261223B2 (en) | 2016-05-11 | 2022-03-01 | The University Of Chicago | Methods of treating cancers with CT45 targeted therapies |
WO2017197347A1 (en) | 2016-05-12 | 2017-11-16 | Adicet Bio, Inc. | METHODS FOR SELECTIVE EXPANSION OF γδ T-CELL POPULATIONS AND COMPOSITIONS THEREOF |
WO2017203370A2 (en) | 2016-05-23 | 2017-11-30 | The Council Of The Queensland Institute Of Medical Research | Cmv epitopes |
-
2018
- 2018-03-05 KR KR1020207012876A patent/KR20200063215A/ko not_active Application Discontinuation
- 2018-03-05 JP JP2020519675A patent/JP2021500875A/ja active Pending
- 2018-03-05 EP EP18722717.8A patent/EP3692058A1/en active Pending
- 2018-03-05 WO PCT/IB2018/000303 patent/WO2019069125A1/en unknown
- 2018-03-05 US US16/753,948 patent/US20200308279A1/en active Pending
- 2018-03-05 AU AU2018346719A patent/AU2018346719A1/en active Pending
- 2018-03-05 CA CA3078472A patent/CA3078472A1/en active Pending
Non-Patent Citations (2)
Title |
---|
CANCER RES., vol. 67, no. 8, JPN6021051363, 2007, pages 3898 - 3903, ISSN: 0004676624 * |
SCIENTIFIC REPORTS, vol. 7, no. 10713, JPN6021051362, 2017, pages 1 - 10, ISSN: 0004676623 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11929064B2 (en) | 2018-07-13 | 2024-03-12 | Google Llc | End-to-end streaming keyword spotting |
US11967310B2 (en) | 2018-07-13 | 2024-04-23 | Google Llc | End-to-end streaming keyword spotting |
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