JP7458318B2 - 癌治療のためのslamf6スプライスバリアントの調節 - Google Patents
癌治療のためのslamf6スプライスバリアントの調節 Download PDFInfo
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- JP7458318B2 JP7458318B2 JP2020542989A JP2020542989A JP7458318B2 JP 7458318 B2 JP7458318 B2 JP 7458318B2 JP 2020542989 A JP2020542989 A JP 2020542989A JP 2020542989 A JP2020542989 A JP 2020542989A JP 7458318 B2 JP7458318 B2 JP 7458318B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
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- C—CHEMISTRY; METALLURGY
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- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
Description
a)対象から、または対象と組織適合性のあるドナーからT細胞を得ることと、
b)細胞をエクスビボで調節して、SLAMF6var3を優先的に発現させることと、
c)得られたT細胞を前記対象に養子移入し、それによって前記対象の癌を治療することと、を含む。
a)T細胞、腫瘍細胞およびDCからなる群から選択される細胞集団を得ることと、
b)細胞をエクスビボで調節して、SLAMF6var3を優先的に発現させることと、を含む、方法が提供される。
a)対象から、または対象と組織適合性のあるドナーからT細胞を得ることと、
b)細胞をエクスビボで調節して、SLAMF6var3を優先的に発現させることと、
c)得られたT細胞を前記対象に養子移入し、それによって前記対象の癌を治療することと、を含む。
a)T細胞、腫瘍細胞およびDCからなる群から選択される細胞集団を得ることと、
b)細胞をエクスビボで調節して、SLAMF6var3を優先的に発現させることと、を含む、方法が提供される。
一般に、SLAMF6は、N’からC’の順序で次のドメインから構成される。
I.N末端シグナルペプチド、
II.2つの保存された免疫グロブリン(Ig)様モチーフを含む細胞外部分(エクトドメイン):N’Ig様V型ドメイン(IgV、2層のβシート構造を有し、主に中性であるが極性の前面を有する)、およびC’Ig様C2型ドメイン(IgC2、全体的なβ鎖トポロジーといくつかのジスルフィド結合を特徴とする)、
III.らせん膜貫通ドメイン、ならびに
IV.SLAM関連タンパク質(SAP)のSH2ドメインと、関連するユーイング肉腫関連転写産物とのドッキング部位である免疫受容体チロシンベースのスイッチモチーフ(ITSM)を含む、トポロジカル(細胞質)ドメイン。ITSMモチーフは、活性化および阻害結合パートナーに対する重複した特異性を有するコンセンサス配列TxYxxV/I/Lを担持する。
MLWLFQSLLFVFCFGPGNVVSQSSLTPLMVNGILGESVTLPLEFPAGEKVNFITWLFNETSLAFIVPHETKSPEIHVTNPKQGKRLNFTQSYSLQLSNLKMEDTGSYRAQISTKTSAKLSSYTLRILRQLRNIQVTNHSQLFQNMTCELHLTCSVEDADDNVSFRWEALGNTLSSQPNLTVSWDPRISSEQDYTCIAENAVSNLSFSVSAQKLCEDVKIQYTDTKMILFMVSGICIVFGFIILLLLVLRKRRDSLSLSTQRTQGPAESARNLEYVSVSPTNNTVYASVTHSNRETEIWTPRENDTITIYSTINHSKESKPTFSRATALDNVV(配列番号1)。
MLWLFQSLLFVFCFGPVPHETKSPEIHVTNPKQGKRLNFTQSYSLQLSNLKMEDTGSYRAQISTKTSAKLSSYTLRILRQLRNIQVTNHSQLFQNMTCELHLTCSVEDADDNVSFRWEALGNTLSSQPNLTVSWDPRISSEQDYTCIAENAVSNLSFSVSAQKLCEDVKIQYTDTKMILFMVSGICIVFGFIILLLLVLRKRRDSLSLSTQRTQGPESARNLEYVSVSPTNNTVYASVTHSNRETEIWTPRENDTITIYSTINHSKESKPTFSRATALDNV(配列番号:16)、
KSPEIHVTNPKQGKRLNFTQSYSLQLSNLKMEDTGSYRAQISTKTSAKLSSYTLRILRQLRNIQVTNHSQLFQNMTCELHLTCSVEDADDNVSFRWEALGNTLSSQPNLTVSWDPRISSEQDYTCIAENAVSNLSFSVSAQKLCEDVKIQYTDTKM(配列番号18)。
VPHETKSPEIHVTNPKQGKRLNFTQSYSLQLSNLKMEDTGSYRAQISTKTSAKLSSYTLRILRQLRNIQVTNHSQLFQNMTCELHLTCSVEDADDNVSFRWEALGNTLSSQPNLTVSWDPRISSEQDYTCIAENAVSNLSFSVSAQKLCEDVKIQYTDTKM(配列番号14)。
特定の実施形態によれば、本発明は、細胞工学、ならびにSLAMF6アイソフォームの発現を差次的に変化させるように選択された細胞集団が修飾されるまたはマニピュレートされる組成物および方法に関する。特に、本発明の実施形態は、SLAMF6var3を優先的に発現するように操作された細胞を用いる。ある特定の実施形態において、細胞集団は、T細胞、腫瘍細胞および樹状細胞(DC)からなる群から選択される。このような細胞は、いくつかの実施形態において、本明細書に詳述されるように、遺伝子工学または他の形態のエクスビボ調節を使用して作製される。
a)対象から、または対象と組織適合性のあるドナーからT細胞を得ることと、
b)細胞をエクスビボで調節して、SLAMF6var1発現を選択的に下方制御することと、
c)得られたT細胞を前記対象に養子移入し、それによって前記対象の癌を治療することと、を含む。
別の態様では、養子移入を必要とするレシピエント対象への養子移入に適した、本明細書に記載されるように調製されたT細胞組成物が提供される。本明細書で使用される場合、また別段の規定のない限り、用語「養子移入」は、以前に感作された免疫性物質(例えば、細胞または血清)がレシピエントに移入される受動免疫療法の形態を指す。「養子移入免疫療法」、「養子細胞療法」および「養子細胞免疫療法」という語句は、本明細書において互換的に使用され、癌または感染症疾患の発生または症状を緩和または改善するために、本発明のT細胞組成物等のエフェクター免疫担当細胞がそれを必要とする対象に投与(養子移入)される、治療または予防レジメンまたはモダリティを表す。
いくつかの実施形態によれば、本発明は、改善された腫瘍細胞ワクチンの生成および使用に関する。ワクチンおよび免疫原性組成物の調製において使用するための腫瘍細胞株は、周知の方法を使用して入手および調製され得る。確立された腫瘍細胞株、例えば、その全体が本明細書に組み入れられるWO2012/156969に開示されているものが使用されてもよいか、または腫瘍生検から得られてもよい。例えば、細胞は、生検を化学的(酵素的)または物理的方法(破壊または濾過)によって破壊することによって得ることができる。細胞は、細胞懸濁液(新鮮細胞または凍結保存細胞)から得ることもできる。
他の実施形態において、本発明の方法で使用されるSLAMF6var3エクトドメインおよびそのアゴニストは、任意選択的に薬学的に許容される担体、賦形剤または希釈剤をさらに含む、医薬組成物の形態で提供される。
別の態様では、SLAMF6var3を差次的に発現するように操作されたT細胞を対象に投与することを含む、癌の治療を必要とするヒト対象の癌を治療するための方法が提供される。一実施形態において、T細胞は、SLAMF6var3発現を選択的に上方制御するように操作されている。別の実施形態において、T細胞は、SLAMF6var1発現を選択的に下方制御するように操作されている。さらに別の実施形態において、T細胞は、SLAMF6var3発現を選択的に上方制御し、SLAMF6var1発現を選択的に下方制御するように設計されている。別の実施形態において、前記T細胞は自家性である。別の実施形態において、前記T細胞は、前記対象と組織適合性の同種T細胞である。
a)対象から、または対象と組織適合性のあるドナーからT細胞を得ることと、
b)細胞をエクスビボで調節して、SLAMF6var3を差次的に発現させることと、
c)得られたT細胞を前記対象に養子移入し、それによって前記対象の癌を治療することと、を含む。
a)T細胞、腫瘍細胞およびDCからなる群から選択される細胞集団を得ることと、
b)前記細胞をエクスビボで調節して、SLAMF6var3を差次的に発現させることと、を含む、方法が提供される。
スプライスバリアントmRNAの検出
mRNAは、ヒト末梢血単核細胞(PBMC)、JurkatT細胞、CD8+腫瘍浸潤リンパ球(TIL)、およびSLAMF6トランスフェクトメラノーマ細胞から抽出した。逆転写ポリメラーゼ連鎖反応(RT-PCR)は、以下のように、異なるSLAMF6バリアントに対して異なるサイズのPCR産物を生成するように設計されたプライマーを用いて行った。
フォワードプライマー-GCGGAAAGCATGTTGTGGCTG(エクソン1、配列番号2);
リバースプライマー-GGAGACAGTGAGGTTTGGCTG(エクソン3、配列番号3)。
SLAMF6var1+SLAMF6var2フォワード:CTGTTCCAATCGCTCCTGTT(配列番号:4);
SLAMF6var1+SLAMF6var2リバース:GGGGTTAAGCTGCTTTGTGA(配列番号:5);
SLAMF6var4フォワード:CTGTTCCAATCGCTCCTGTT(配列番号6)。
SLAMF6var4リバース:CAGATGGAGCTCACAGGTCA(配列番号:7);
SLAMF6var3フォワード:CTGTTCCAATCGCTCCTGTT(配列番号:8);
SLAMF6var3リバース:CAGGGAGTAGGACTGGGTGA(配列番号9)。
SLAMF6特異的CRISPR-Cas9ゲノム編集用の核酸構築物を生成するために、下の表1に指定される配列を、本質的には記載されているように(Wu et al.2016、同所)、ベクターpSpCas9(BB)-2A-GFP(Addgene、Cambridge,MA)にクローニングした。構築物1はエクソン2を標的としているため、SLAMF6var1のみに影響を与えるが、構築物2はシグナルペプチド領域を標的としているため、3つのバリアント全てに影響を与える。表1は、転写されたシングルガイドRNA(sgRNA)配列の配列を指定する。
Jurkat細胞をRPMI-/-で2回洗浄し、10x106細胞/mlのRPMIに再懸濁した。ECM 630 Electro Cell Manipulator(BTX Harvard)を260V、975μF、1575Ωで使用して、5×106Jurkat細胞をSLAMF6-CRISPRプラスミド5μgとともにBiorad 0.4cmキュベット中でエレクトロポレーションした。エレクトロポレーション後、完全RPMI培地に細胞を直ちに播種した。トランスフェクションの48時間後、GFPを発現する細胞をソーティング(ARIA-III Sorter)により選択した。NT-7抗体(Biolegend、バリアント1および2を特異的に認識する)を使用した単一細胞選別によりヒトSLAMF6を欠く細胞を選択し、コロニーの確立のために培養した。
異なるSLAMF6バリアントをコードするPCDNA3.1+/C-(K)DYKプラスミドをGenScriptから購入した(クローンID:SLAMF6var1、SLAMF6var3、およびSLAMF6var4のためのOHu04772、OHu04774、OHu04776、それぞれ、アクセション番号NM_001184714.1、NM_001184715.1およびNM_001184716.1)。リポフェクタミンを使用してヒトメラノーマ細胞をトランスフェクトした。G-418耐性メラノーマ細胞をサブクローニングし、安定にトランスフェクトされた細胞を実験に使用した。SLAMF6var1の場合、細胞を抗NTB-A抗体(NT-7、Biolegend)で染色し、ソートした(ARIA-III)。陽性細胞を培養して実験に使用した。
腫瘍浸潤リンパ球(TIL、1x105)を、指示された標的メラノーマ細胞と1:1の比で一晩共培養した。別のタイプの実験では、健康なドナーから末梢血単核細胞を入手し、seSLAMF6-var3またはIL-2の存在下で3日間インキュベートした。インキュベーション終了時に、細胞を洗浄し、抗CD3を結合させた1ug/mlプレートで一晩活性化した。両方の実験で、馴化培地を回収し、製造業者のプロトコルに従ってELISA(R&D)によりIFN-γ分泌を検出した。
TIL(1x105)を、指示された標的メラノーマ細胞と1:1の比で、37℃で6時間共培養した。2時間後、ブレフェルジンA(eBioscience、1μg/ml)を4時間かけて加えた。インキュベーション後、細胞をPBSで2回洗浄し、抗CD8抗体(Biolegend)で染色した。固定および透過処理(eBioscienceプロトコル)に続いて、細胞内IFN-γおよび腫瘍壊死因子α(TNF-α)を室温で30分間、抗IFN-γおよび抗TNF-α(Biolegend)で標識した。細胞を透過処理緩衝液で洗浄し、FACS緩衝液に再懸濁し、フローサイトメトリーに供した。
野生型(WT)Jurkat細胞または単一細胞KO Jurkat細胞(1x105)を、ホルボール12-ミリスタート13-アセタート(PMA、200ng/ml)およびイオノマイシン(300ng/mlを使用して、37℃で48時間活性化した。馴化培地を回収し、ELISA(R&D)を使用してIL-2分泌を検出した。
MaxiSorbプレートを、SLAMF6var1のFc融合エクトドメイン(seSLAMF6_Fc、Creative Biomart、1μg/mlおよび4℃)で一晩プレコートした。翌日、プレートを洗浄し、PBSX1中に1%BSAを含むブロッキング緩衝液を使用してブロックした。次に、SLAMF6var1(Prospec、seSLAMF6)もしくはSLAMF6var3(Novoprotein/Bonopus、seSLAMF6-V3)から、またはSLAMF1、SLAMF7もしくはSLAMF8(それぞれ、seSLAMF1、seSLAMF7およびseSLAMF8)からの異なる濃度の単離されたエクトドメイン(6-ヒスチジンタグを含む)で、プレートを2時間インキュベートした。受容体結合エクトドメインポリペプチドの量は、ヒスチジンタグ(抗HIS抗体)を標的とする、西洋ワサビペルオキシダーゼ(HRP)結合抗体を使用して検出し、ELISAリーダーを使用して定量化した。
Pmelマウス 脾細胞を、1μg/mlのgp100(25-33)ペプチドおよび30U/mlのIL-2を使用して7日間活性化した。増殖後、脾細胞を洗浄し、カウントし、1x105細胞をIL-2もしくはseSLAMF6var3のいずれかを添加した培地で培養するか、または未処理のままにした(「未処理」)。さらに4日後、細胞を採取し、洗浄し、アネキシンVアポトーシス検出キットで標識した。生存細胞(アネキシンVおよびヨウ化プロピジウムの両方に陰性、アネキシンV-/PI-)をフローサイトメトリーにより分析した。
SLAMF6相互作用をトランスで(隣接する細胞間で)評価するために、またSLAMF6は、典型的には造血細胞でのみ発現されるため、SLAMF6を異常に発現するメラノーマ標的細胞を生成した。このために、SLAMF6バリアントを、上記のようにpcDNA3.1+/C-(K)DYKプラスミド(Genscript)を使用して、メラノーマ株526melにおいて安定に発現させた。トランスフェクトされたメラノーマ細胞における異なるバリアントのmRNA発現を図1に示す。
リンパ球におけるSLAMF6バリアントの役割をさらに探求するために、異なるバリアントの発現を休止および活性化T細胞においてRT-PCRによりアッセイした。図4Aに見られるように、試験した全てのバリアントのmRNAは、Jurkat(CD4+)T細胞、抗メラノーマTIL(CD8+)、およびPBMCを含む様々なT細胞集団において検出され、var1 mRNAのレベルは全てのセルで最高であった。図4A(中央パネル、Jurkat細胞)および図4Bにさらに示されるように、全てのバリアントの発現レベルがT細胞の活性化後に増加した。
以下の配列を発現プラスミド(Novoprotein/BonOpus)にクローニングし、哺乳動物細胞株に組換え発現した。
核酸配列:ATGTTGTGGCTGTTCCAATCGCTCCTGTTTGTCTTCTGCTTTGGCCCAGGGAATGTAGTTTCAGTACCCCATGAAACCAAAAGTCCAGAAATCCACGTGACTAATCCGAAACAGGGAAAGCGACTGAACTTCACCCAGTCCTACTCCCTGCAACTCAGCAACCTGAAGATGGAAGACACAGGCTCTTACAGAGCCCAGATATCCACAAAGACCTCTGCAAAGCTGTCCAGTTACACTCTGAGGATATTAAGACAACTGAGGAACATACAAGTTACCAATCACAGTCAGCTATTTCAGAATATGACCTGTGAGCTCCATCTGACTTGCTCTGTGGAGGATGCAGATGACAATGTCTCATTCAGATGGGAGGCCTTGGGAAACACACTTTCAAGTCAGCCAAACCTCACTGTCTCCTGGGACCCCAGGATTTCCAGTGAACAGGACTACACCTGCATAGCAGAGAATGCTGTCAGTAATTTATCCTTCTCTGTCTCTGCCCAGAAGCTTTGCGAAGATGTTAAAATTCAATATACAGATACCAAAATGGGATCTCACCACCACCACCACCACTGA(配列番号19)。
アミノ酸配列:
MLWLFQSLLFVFCFGPGNVVSVPHETKSPEIHVTNPKQGKRLNFTQSYSLQLSNLKMEDTGSYRAQISTKTSAKLSSYTLRILRQLRNIQVTNHSQLFQNMTCELHLTCSVEDADDNVSFRWEALGNTLSSQPNLTVSWDPRISSEQDYTCIAENAVSNLSFSVSAQKLCEDVKIQYTDTKMGSHHHHHH(配列番号15)。
次いで、単離されたseSLAMF6var3ポリペプチドの機能特性を決定した。この目的のために、実施例3に記載されるエクトドメインポリペプチド(実施例および図全体を通してseSLAMF6var3またはseSLAMF6-V3として示されている)を、長期T細胞活性化および二次アポトーシス(活性化誘導細胞死、AICD)を測定するように設計された系においてマウス脾細胞とインビトロでインキュベートした。図9Aおよび図9Bに見られるように、seSLAMF6var3はAICDを有意に減少させ、1週間の激しい活性化後のT細胞生存を改善した。ヒトPBMCを使用して行った実験で、ヒトT細胞について同様の結果が得られた。図9A~図9Bにさらに見られるように、マウス脾細胞におけるAICDの防止にseSLAMF6var3が与える効果は、IL-2の効果と比較して著しく顕著であった。
Claims (26)
- 癌または感染症疾患を治療するための細胞組成物であって、ヒトSLAMF6のアミノ酸17~65の選択的欠失を特徴とするSLAMF6スプライスバリアント(SLAMF6var3)を他のヒトSLAMF6スプライスバリアントよりも優先的に発現するように操作された細胞集団を含み、
前記細胞集団はT細胞集団、腫瘍細胞集団、または樹状細胞(DC)集団である、
細胞組成物。 - 養子移入T細胞組成物、腫瘍細胞ワクチンおよびDCワクチンからなる群から選択される、請求項1に記載の組成物。
- 前記細胞集団はヒトT細胞集団であり、前記組成物は養子移入T細胞組成物である、請求項1に記載の組成物。
- 前記細胞集団はヒト腫瘍細胞集団であり、前記組成物は腫瘍細胞ワクチンである、請求項1に記載の組成物。
- 前記腫瘍細胞集団はメラノーマ細胞集団である、請求項4に記載の組成物。
- 前記細胞集団はヒトDC集団であり、前記組成物はDCワクチンである、請求項1に記載の組成物。
- 前記細胞集団は、SLAMF6var1発現を選択的に下方制御するように操作されている、請求項2~6のいずれか一項に記載の組成物。
- 前記細胞集団は、SLAMF6var3発現を選択的に上方制御するように操作されている、請求項2~7のいずれか一項に記載の組成物。
- 前記細胞集団は、SLAMF6var3を外因的に発現するように操作されている、請求項2~7のいずれか一項に記載の組成物。
- 癌の治療を必要とするヒト対象の癌の治療における使用のための請求項2~9のいずれか一項に記載の組成物。
- 前記細胞集団はヒトT細胞集団であり、前記組成物は養子移入T細胞組成物であり、前記T細胞は、自家性であるか、または前記対象と組織適合性の同種T細胞である、請求項10に記載の組成物。
- 前記T細胞は、前記対象のエクスビボT細胞、または前記対象と組織適合性のあるドナーのエクスビボT細胞を調節して、SLAMF6var3を他のヒトSLAMF6スプライスバリアントよりも優先的に発現させることと、得られたT細胞を癌治療のための養子移入組成物として配合することと、を含む方法によって生成されている、請求項11に記載の組成物。
- 前記T細胞は、単離されたSLAMF6var3エクトドメインとのインキュベーションによってさらに増殖および/または活性化されている、請求項11または12に記載の組成物。
- 前記細胞集団はヒト腫瘍細胞集団であり、前記組成物は腫瘍細胞ワクチンである、請求項10に記載の組成物。
- 前記腫瘍細胞集団はメラノーマ細胞集団である、請求項14に記載の組成物。
- 前記細胞集団はDC集団であり、前記組成物はDCワクチンである、請求項10に記載の組成物。
- 癌または感染症疾患を治療するための細胞組成物を生成する方法であって、
a)T細胞、腫瘍細胞およびDCからなる群から選択される細胞集団を得ることと、
b)前記細胞をエクスビボで調節して、ヒトSLAMF6のアミノ酸17~65の選択的欠失を特徴とするSLAMF6スプライスバリアント(SLAMF6var3)を他のヒトSLAMF6スプライスバリアントよりも優先的に発現させることと、
を含む、方法。 - 癌の治療を必要とするヒト対象の癌の治療における使用のための医薬組成物であって、単離された、ヒトSLAMF6のアミノ酸17~65の選択的欠失を特徴とするSLAMF6スプライスバリアント(SLAMF6var3)のエクトドメインを含む、医薬組成物。
- 前記使用は、前記対象の癌を治療するのに有効な量での前記対象への投与を含む、請求項18に記載の組成物。
- 前記使用は、前記対象のT細胞を、前記T細胞を増殖および/または活性化するのに有効な量の前記単離されたヒトSLAMF6var3エクトドメインとエクスビボで接触させることと、得られたT細胞を前記対象に養子移入し、それによって前記対象の癌を治療することと、を含む、請求項18に記載の組成物。
- そのN末端でヒトSLAMF6var1のシグナルペプチドに融合されている、単離された、ヒトSLAMF6のアミノ酸17~65の選択的欠失を特徴とするSLAMF6スプライスバリアント(SLAMF6var3)のエクトドメインを含む、キメラポリペプチド前駆体であって、
前記シグナルペプチドは、配列番号1のアミノ酸の1~21に対応する、
キメラポリペプチド前駆体。 - 配列番号15に示されるアミノ酸配列を有する、請求項21に記載のポリペプチド前駆体。
- 配列番号19に示されるポリヌクレオチドによってコードされる、請求項21に記載のポリペプチド前駆体。
- 請求項21に記載のポリペプチド前駆体をコードする、ポリヌクレオチド。
- 請求項21に記載のポリペプチド前駆体を哺乳動物発現系で発現させることと、得られたエクトドメインポリペプチドを単離することと、を含むプロセスによって作製される、単離されたヒトSLAMF6var3エクトドメイン。
- 癌の治療を必要とするヒト対象の癌の治療における使用のための医薬組成物であって、請求項25に記載の単離されたヒトSLAMF6var3エクトドメインを含む、医薬組成物。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090017014A1 (en) | 2001-08-29 | 2009-01-15 | Valdez Patricia A | Compositions and methods for the treatment of immune related diseases |
JP2017503810A (ja) | 2014-01-09 | 2017-02-02 | ハダシット メディカル リサーチ サービシーズ アンド ディベロップメント リミテッド | 癌治療のための改善された細胞組成物および方法 |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4376110A (en) | 1980-08-04 | 1983-03-08 | Hybritech, Incorporated | Immunometric assays using monoclonal antibodies |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
GB8422238D0 (en) | 1984-09-03 | 1984-10-10 | Neuberger M S | Chimeric proteins |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
US7479269B2 (en) | 1988-11-23 | 2009-01-20 | Genetics Institute, Llc | Methods for selectively enriching TH1 and TH2 cells |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
IL162181A (en) | 1988-12-28 | 2006-04-10 | Pdl Biopharma Inc | A method of producing humanized immunoglubulin, and polynucleotides encoding the same |
US5719867A (en) | 1995-06-30 | 1998-02-17 | Scientific-Atlanta, Inc. | Plural telephony channel baseband signal demodulator for a broadband communications system |
WO2003008449A1 (en) | 2001-07-19 | 2003-01-30 | Innate Pharma | Ntb-a, a surface molecule involved in natural killer cells activity |
JP2005206478A (ja) | 2004-01-20 | 2005-08-04 | Kirin Brewery Co Ltd | 樹状細胞膜分子−IgFc融合ポリペプチドまたはそれに対する抗体を含む医薬組成物 |
US7592313B2 (en) | 2004-05-17 | 2009-09-22 | Board Of Trustees Of The University Of Illinois | Method of stimulating proliferation of regulatory T cells in a diabetic mammal |
DE602004019215D1 (de) | 2004-10-02 | 2009-03-12 | Immatics Biotechnologies Gmbh | Immunogene T-Helfer Epitope von menschlichen Tumorantigenen und deren Verwendung in immunotherapeutischen Methoden |
US20090220495A1 (en) | 2005-04-07 | 2009-09-03 | Abdallah Fanidi | Cancer Related Genes (PRLR) |
CN101243187B (zh) | 2005-08-17 | 2012-07-11 | 宝生物工程株式会社 | 淋巴细胞的制备方法 |
EP1777523A1 (en) | 2005-10-19 | 2007-04-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | An in vitro method for the prognosis of progression of a cancer and of the outcome in a patient and means for performing said method |
WO2008027739A2 (en) | 2006-08-28 | 2008-03-06 | Nuvelo, Inc. | Antibodies to ntb-a |
US20120244133A1 (en) | 2011-03-22 | 2012-09-27 | The United States of America, as represented by the Secretary, Department of Health and | Methods of growing tumor infiltrating lymphocytes in gas-permeable containers |
CN105431449B (zh) | 2013-04-05 | 2021-08-24 | 港大科桥有限公司 | 新的pd1同种型及其用于加强免疫应答的用途 |
US10287354B2 (en) | 2013-12-20 | 2019-05-14 | Novartis Ag | Regulatable chimeric antigen receptor |
ES2878188T3 (es) | 2015-07-29 | 2021-11-18 | Novartis Ag | Terapias de combinación que comprenden moléculas de anticuerpos contra LAG-3 |
WO2017075478A2 (en) | 2015-10-28 | 2017-05-04 | The Broad Institute Inc. | Compositions and methods for evaluating and modulating immune responses by use of immune cell gene signatures |
NL2017267B1 (en) | 2016-07-29 | 2018-02-01 | Aduro Biotech Holdings Europe B V | Anti-pd-1 antibodies |
US20190262399A1 (en) | 2016-09-07 | 2019-08-29 | The Broad Institute, Inc. | Compositions and methods for evaluating and modulating immune responses |
IL267614A (en) | 2019-06-24 | 2019-09-26 | Lotem Michal | Nucleic acids to modulate SLAMF6 isoforms |
-
2019
- 2019-02-11 WO PCT/IL2019/050163 patent/WO2019155474A1/en unknown
- 2019-02-11 JP JP2020542989A patent/JP7458318B2/ja active Active
- 2019-02-11 US US16/968,967 patent/US11834487B2/en active Active
- 2019-02-11 EP EP19751265.0A patent/EP3752252A4/en active Pending
-
2020
- 2020-07-16 IL IL276117A patent/IL276117A/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090017014A1 (en) | 2001-08-29 | 2009-01-15 | Valdez Patricia A | Compositions and methods for the treatment of immune related diseases |
JP2017503810A (ja) | 2014-01-09 | 2017-02-02 | ハダシット メディカル リサーチ サービシーズ アンド ディベロップメント リミテッド | 癌治療のための改善された細胞組成物および方法 |
Non-Patent Citations (2)
Title |
---|
Accession No. AK303990.1, Homo sapiens cDNA FLJ52047 complete cds, highly similar to SLAM family member 6 precursor,Database GenBank [online],2008年07月24日,[Retrieved on 2023.06.09], Retrieved from the Internet, URL:<https://www.ncbi.nlm.nih.gov/nuccore/194384267> |
Cancer Immunology Research,2018年02月01日,Vol. 6, No. 2,pp. 127-138 |
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