JP2022506781A - メソテリンを標的とする免疫療法 - Google Patents
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Abstract
Description
本出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ており、これにより参照により本明細書に組み込まれる。配列表を含有するテキストファイルの名称は、360056_475WO_SEQUENCE_LISTING.txtである。テキストファイルは115KBであり、2019年11月8日に作成され、EFS-Webを介して電子的に提出されている。
自己/腫瘍反応性TCRを発現するT細胞は中枢性および末梢性寛容に晒されるため、このような高親和性自己/腫瘍反応性T細胞はまれであり(Stone and Kranz, Frontiers Immunol. 4:244, 2013を参照)、相対的なTCR親和性はドナー間で広範に変化する。それゆえに、多くの一致したドナーをスクリーニングして、TCRα/β遺伝子治療構築物を生成できる十分に高い親和性の腫瘍特異的なT細胞クローンを同定しなければならない。例えば、単一のHLA-対立遺伝子に対する高い機能的なアビディティを有する天然に誘発されたウィルムス腫瘍抗原1(WT1)特異的TCRの単離は、75人より多くの正常なドナーの末梢レパートリーからの数千もの個々のT細胞クローンを表す数百ものWT特異的T細胞株のスクリーニングを必要とした(Chapuis et al., 2013;Schmitt et al., Hum. Gene Ther. 20:1240, 2009;およびHo et al., J. Immunol. Methods 310:40, 2006を参照)。これは極めて多大な時間と労力を要するプロセスである。
本明細書で開示の実施形態は、添付の図面と併せて、以下の説明および添付の特許請求の範囲を参照すると、より完全に明らかになる。
メソテリン特異的結合タンパク質
ポリヌクレオチド、ベクター、および宿主細胞
使用
PD-1阻害剤は、ニボルマブ(OPDIVO(登録商標));ペムブロリズマブ(KEYTRUDA(登録商標));イピリムマブ+ニボルマブ(YERVOY(登録商標)+OPDIVO(登録商標));セミプリマブ;IBI-308;ニボルマブ+リラトリマブ;BCD-100;カムレリズマブ;JS-001;スパルタリズマブ;チスレリズマブ;AGEN-2034;BGBA-333+チスレリズマブ;CBT-501;ドスタルリマブ;デュルバルマブ+MEDI-0680;JNJ-3283;パゾパニブ塩酸塩+ペムブロリズマブ;ピジリズマブ;REGN-1979+セミプリマブ;ABBV-181;ADUS-100+スパルタリズマブ;AK-104;AK-105;AMP-224;BAT-1306;BI-754091;CC-90006;セミプリマブ+REGN-3767;CS-1003;GLS-010;LZM-009;MEDI-5752;MGD-013;PF-06801591;Sym-021;チスレリズマブ+パミパリブ;XmAb-20717;AK-112;ALPN-202;AM-0001;アルツハイマー病に関してPD-1をアンタゴナイズする抗体;BH-2922;BH-2941;BH-2950;BH-2954;固形腫瘍に関してCTLA-4およびPD-1をアンタゴナイズする生物製剤;腫瘍学に関してPD-1およびLAG-3を標的とする二重特異性モノクローナル抗体;BLSM-101;CB-201;CB-213;CBT-103;CBT-107;細胞性免疫療法+PD-1阻害剤;CX-188;HAB-21;HEISCOIII-003;IKT-202;JTX-4014;MCLA-134;MD-402;mDX-400;MGD-019;腫瘍学に関してPDCD1をアンタゴナイズするモノクローナル抗体;腫瘍学に関してPD-1をアンタゴナイズするモノクローナル抗体;腫瘍学に関してPD-1を阻害する腫瘍溶解性ウイルス;OT-2;PD-1アンタゴニスト+ロペグインターフェロンアルファ-2b;PEGMP-7;PRS-332;RXI-762;STIA-1110;TSR-075;腫瘍学に関してHER2およびPD-1を標的とするワクチン;腫瘍学および自己免疫障害に関してPD-1を標的とするワクチン;XmAb-23104;腫瘍学に関してPD-1を阻害するアンチセンスオリゴヌクレオチド;AT-16201;腫瘍学に関してPD-1を阻害する二重特異性モノクローナル抗体;IMM-1802;固形腫瘍および血液腫瘍に関してPD-1およびCTLA-4をアンタゴナイズするモノクローナル抗体;ニボルマブバイオシミラー;腫瘍学に関してCD278およびCD28をアゴナイズし、PD-1をアンタゴナイズする組換えタンパク質;自己免疫障害および炎症性障害に関してPD-1をアゴナイズする組換えタンパク質;SNA-01;SSI-361;YBL-006;AK-103;JY-034;AUR-012;BGB-108;固形腫瘍に関してPD-1、Gal-9、およびTIM-3を阻害する薬物;ENUM-244C8;ENUM-388D4;MEDI-0680;転移性黒色腫および転移性肺がんに関してPD-1をアンタゴナイズするモノクローナル抗体;腫瘍学に関してPD-1を阻害するモノクローナル抗体;腫瘍学に関してCTLA-4およびPD-1を標的とするモノクローナル抗体;NSCLCに関してPD-1をアンタゴナイズするモノクローナル抗体;腫瘍学に関してPD-1およびTIM-3を阻害するモノクローナル抗体;腫瘍学に関してPD-1を阻害するモノクローナル抗体;血液悪性腫瘍および固形腫瘍に関してPD-1およびVEGF-Aを阻害する組換えタンパク質;腫瘍学に関してPD-1をアンタゴナイズする小分子;Sym-016;イネビリズマブ+MEDI-0680;転移性黒色腫に関してPDL-1およびIDOを標的とするワクチン;膠芽腫に関する抗PD-1モノクローナル抗体+細胞性免疫療法;腫瘍学に関してPD-1をアンタゴナイズする抗体;血液悪性腫瘍および細菌感染症に関してPD-1/PD-L1を阻害するモノクローナル抗体;HIVに関してPD-1を阻害するモノクローナル抗体;および/または固形腫瘍に関してPD-1を阻害する小分子を含んでいてもよい。
Msln20またはMsln530に特異的なTCRの同定および選択。
例示的なMsln20またはMsln530に特異的なTCRクローンは、それぞれ図1Aおよび1Bに示され、本明細書で示されたTCR単離のための次世代シーケンシング(NGS)ベースの方法における各TCRクローン型の富化スコアがT細胞頻度と比較される。y軸における富化スコアは、ペプチド:HLA四量体への結合の大きさと相関する。全てのTCRを合成し、レポーターT細胞株および一次CD8+PBMCで発現されたときの機能に関して試験した。最大の機能的なアビディティを有するTCRは、レシピエントのCD8+T細胞に移行したときに、取り囲まれる(encircled)。これらのデータは、最大の機能的な活性を有すると同定されたTCRが、最大規模の四量体結合を有さず、ペプチド拡大T細胞集団でまれであったことを示す。理論に縛られることはないが、これは、これらのアビディティが高い(highly avid)クローン型によるTCR表面発現の減少に部分的に起因し得る。100種より多くのTCR構築物を合成し、評価した(Msln20=60種のTCRを合成した;Msln530=42種のTCRを合成した)。メソテリン特異的なT細胞株を18人のドナーから生成した。細胞を滴定した濃度の四量体で染色し、ソートし、単一細胞TCRシーケンシングによって分析した(合計で約8回のソーティング実験)。
(実施例2)
Msln530TCRによる四量体結合
(実施例3)
抗原特異的T細胞応答の評価
(実施例4)
Msln530特異的TCRの機能的な評価
(実施例5)
選択されたTCRの機能的な評価
(実施例6)
TCRを形質導入したCD8+T細胞による腫瘍細胞殺滅
(実施例7)
Msln20およびMsln530ペプチドのアラニンスキャニングによるエピトープ分析
(実施例8)
ヒトプロテオームにおけるMsln530に相同なエピトープのための分析
(実施例9)
ヒトプロテオームにおけるMsln530に潜在的な相同性を有する合成されたペプチドの分析
(実施例10)
多様なドナー由来のLCLを標的化することによるアロ反応性の分析
上記の詳細な説明に照らして、こうしたおよび他の変化を実施形態になすことができる。一般に、以下の特許請求の範囲では、使用される用語は、特許請求の範囲を、明細書および特許請求の範囲に開示されている特定の実施形態に限定するものとは解釈されるべきではなく、そのような特許請求の範囲の権利内にある均等物の完全な範囲と共にすべての考え得る実施形態を含むと解釈されるべきである。したがって、特許請求の範囲は本開示により限定されない。
Claims (97)
- T細胞受容体(TCR)α鎖可変ドメイン(Vα)およびTCRβ鎖可変ドメイン(Vβ)を含む結合タンパク質であって、
(a)前記Vαは、配列番号39または37に示されているCDR3アミノ酸配列を含み、前記Vβは、必要に応じて、配列番号101または99に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含み、
(b)前記Vβは、配列番号40または配列番号38に示されているCDR3アミノ酸配列を含み、前記Vαは、必要に応じて、配列番号102または100に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含み、および/あるいは
(c)前記Vαは、配列番号39または37に示されているCDR3アミノ酸配列を含み、前記Vβは、配列番号40または38に示されているCDR3アミノ酸配列を含み、
前記結合タンパク質が、メソテリン(Msln)ペプチド:HLA複合体に特異的に結合することが可能である、結合タンパク質。 - (i)(a)、(b)、および/または(c)の前記Vαは、配列番号102または100に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むが、ただし前記CDRの少なくとも3つまたは4つは配列に変化がなく、配列変化を有する前記CDRは、最大でわずか2つのアミノ酸置換、最大で連続する5つのアミノ酸欠失、またはそれらの組合せを有し、および/あるいは
(ii)(a)、(b)、および/または(c)の前記Vβは、配列番号101または99に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むが、ただし前記CDRの少なくとも3つまたは4つは配列に変化がなく、配列変化を有する前記CDRは、最大でわずか2つのアミノ酸置換、最大で連続する5つのアミノ酸欠失、またはそれらの組合せを有する、請求項1に記載の結合タンパク質。 - (a)配列番号93に示されているCDR1αアミノ酸配列、
(b)配列番号94に示されているCDR2αアミノ酸配列、
(c)配列番号39に示されているCDR3αアミノ酸配列、
(d)配列番号83に示されているCDR1βアミノ酸配列、必要に応じて配列番号84に示されている、さらに必要に応じて配列番号91に示されているCDR1βアミノ酸配列、
(e)配列番号92に示されているCDR2βアミノ酸配列、および
(f)配列番号40に示されているCDR3βアミノ酸配列
を含む、請求項1または2に記載の結合タンパク質。 - (a)TRBJ2-3*01、
(b)TRAV21*01もしくはTRAV21*02、
(c)TRBV5-4*01、
(d)TRAJ57*01、および/または
(e)TRBD1*01もしくはTRBD2*02
によりコードされるアミノ酸配列と少なくとも85%同一性を有するアミノ酸配列を含む、請求項1~3のいずれか一項に記載の結合タンパク質。 - 前記Vαは、配列番号102に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含み、前記Vβは、配列番号101に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含む、請求項1~4のいずれか一項に記載の結合タンパク質。
- 前記Vαは、配列番号102に示されているアミノ酸配列を含むかまたはそれからなり、前記Vβは、配列番号101に示されているアミノ酸配列を含むかまたはそれからなる、請求項5に記載の結合タンパク質。
- TCRα鎖(TCRα)およびTCRβ鎖(TCRβ)を含み、前記TCRαは、配列番号110または29に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むかまたはそれからなり、および/または前記TCRβは、配列番号109または28に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むかまたはそれからなる、請求項1~6のいずれか一項に記載の結合タンパク質。
- 前記TCRαは、配列番号110または29に示されているアミノ酸配列を含むかまたはそれからなり、前記TCRβは、配列番号109または28に示されているアミノ酸配列を含むかまたはそれからなる、請求項7に記載の結合タンパク質。
- (a)配列番号89に示されているCDR1αのアミノ酸配列、
(b)配列番号90に示されているCDR2αのアミノ酸配列、
(c)配列番号37に示されているCDR3αのアミノ酸配列、
(d)配列番号83に示されているCDR1βのアミノ酸配列、必要に応じて配列番号87に示されているCDR1βのアミノ酸配列、
(e)配列番号88に示されているCDR2βのアミノ酸配列、および
(f)配列番号38に示されているCDR3βのアミノ酸配列
を含む、請求項1または2に記載の結合タンパク質。 - (a)TRBJ1-1*01もしくはTRBJ2-3*01、
(b)TRAV4-1*01、
(c)TRAJ18*01、および/または
(d)TRBD1*01もしくはTRBD2*02
によりコードされるアミノ酸配列と少なくとも85%同一性を有するアミノ酸配列を含む、請求項1、2、または9のいずれか一項に記載の結合タンパク質。 - 前記Vαは、配列番号100に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含み、前記Vβは、配列番号99に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含む、請求項1、2、9、または10のいずれか一項に記載の結合タンパク質。
- 前記Vαは、配列番号100に示されているアミノ酸配列を含むかまたはそれからなり、前記Vβは、配列番号99に示されているアミノ酸配列を含むかまたはそれからなる、請求項11に記載の結合タンパク質。
- TCRα鎖(TCRα)およびTCRβ鎖(TCRβ)を含み、前記TCRαは、配列番号108または23に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むかまたはそれからなり、および/または前記TCRβは、配列番号107または22に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むかまたはそれからなる、請求項1、2、または9~12のいずれか一項に記載の結合タンパク質。
- 前記TCRαは、配列番号108または23に示されているアミノ酸配列を含むかまたはそれからなり、前記TCRβは、配列番号107または22に示されているアミノ酸配列を含むかまたはそれからなる、請求項13に記載の結合タンパク質。
- 配列番号32:ヒト白血球抗原(HLA)複合体に特異的に結合することが可能である、請求項1~14のいずれか一項に記載の結合タンパク質。
- HLAは、HLA-A*201を含む、請求項1~15のいずれか一項に記載の結合タンパク質。
- 配列番号32の残基3、5、6、または9のいずれか1つまたは複数のアラニン変異誘発は、前記結合タンパク質による前記Mslnペプチド:HLA複合体への結合を阻止しないか、または実質的に損なわない、請求項15または16に記載の結合タンパク質。
- 前記結合タンパク質は、ペプチド:HLA複合体に結合することが可能であり、前記ペプチドは、配列番号61に示されているコンセンサスアミノ酸配列を含むかまたはそれからなる、請求項15~17のいずれか一項に記載の結合タンパク質。
- 配列番号32の残基1、5、または9のいずれか1つまたは複数のアラニン変異誘発は、前記結合タンパク質による前記Mslnペプチド:HLA複合体への結合を阻止しないか、または実質的に損なわない、請求項15~18のいずれか一項に記載の結合タンパク質。
- 前記結合タンパク質は、ペプチド:HLA複合体に結合することが可能であり、前記ペプチドは、配列番号62に示されているコンセンサスアミノ酸配列を含むかまたはそれからなる、請求項15~19のいずれか一項に記載の結合タンパク質。
- 前記結合タンパク質は、ペプチド:HLA複合体に結合しないかまたは特異的に結合せず、前記ペプチドは、配列番号63~77のいずれか1つまたは複数に示されているアミノ酸配列を含むかまたはそれからなり、前記HLAは、必要に応じてHLA-A:02*01である、請求項1~20のいずれか一項に記載の結合タンパク質。
- T細胞受容体(TCR)α鎖可変ドメイン(Vα)およびTCRβ鎖可変ドメイン(Vβ)を含む結合タンパク質であって、
(a)前記Vαは、配列番号33または35に示されているCDR3アミノ酸配列を含み、前記Vβは、必要に応じて、配列番号95または97に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含み、
(b)前記Vβは、配列番号34または36に示されているCDR3アミノ酸配列を含み、前記Vαは、必要に応じて、配列番号96または98に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含み、および/あるいは
(c)前記Vαは、配列番号33または35に示されるCDR3アミノ酸配列を含み、前記Vβは、配列番号40または38に示されるCDR3アミノ酸配列を含み、
前記結合タンパク質が、メソテリン(Msln)ペプチド:HLA複合体に特異的に結合することが可能である、結合タンパク質。 - (i)(a)、(b)、および/または(c)の前記Vαが、配列番号96または98に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むが、ただし前記CDRの少なくとも3つまたは4つは、配列に変化がなく、配列変化を有する前記CDRは、最大でわずか2つのアミノ酸置換、最大で連続する5つのアミノ酸欠失、またはそれらの組合せを有し、および/あるいは
(ii)(a)、(b)、および/または(c)の前記Vβは、配列番号95または97に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むが、ただし前記CDRの少なくとも3つまたは4つは、配列に変化がなく、配列変化を有する前記CDRは、最大でわずか2つのアミノ酸置換、最大で連続する5つのアミノ酸欠失、またはそれらの組合せを有する、請求項22に記載の結合タンパク質。 - (a)配列番号80に示されているCDR1αアミノ酸配列、
(b)配列番号81または118に示されているCDR2αアミノ酸配列、
(c)配列番号33に示されているCDR3αアミノ酸配列、
(d)配列番号83に示されているCDR1βのアミノ酸配列、必要に応じて配列番号84に示されている、さらに必要に応じて配列番号78に示されているCDR1βのアミノ酸配列、
(e)配列番号79に示されているCDR2βアミノ酸配列、および
(f)配列番号34に示されているCDR3βアミノ酸配列
を含む、請求項22または23に記載の結合タンパク質。 - (a)TRBJ2-7*01もしくはTRBJ2-3*01、
(b)TRAV1-1*01、
(c)TRBV12-4*01、
(d)TRAJ3*01、および/または
(e)TRBD1*01もしくはTRBD2*02
によりコードされるアミノ酸配列と少なくとも85%同一性を有するアミノ酸配列を含む、請求項22~24のいずれか一項に記載の結合タンパク質。 - 前記Vαは、配列番号96に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含み、前記Vβは、配列番号95に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含む、請求項22~25のいずれか一項に記載の結合タンパク質。
- 前記Vαは、配列番号96に示されているアミノ酸配列を含むかまたはそれからなり、前記Vβは、配列番号95に示されているアミノ酸配列を含むかまたはそれからなる、請求項26に記載の結合タンパク質。
- TCRα鎖(TCRα)およびTCRβ鎖(TCRβ)を含み、前記TCRαは、配列番号104または7に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むかまたはそれからなり、および/または前記TCRβは、配列番号103または6に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むかまたはそれからなる、請求項22~27のいずれか一項に記載の結合タンパク質。
- 前記TCRαは、配列番号104または7に示されているアミノ酸配列を含むかまたはそれからなり、前記TCRβは、配列番号103または106に示されているアミノ酸配列を含むかまたはそれからなる、請求項28に記載の結合タンパク質。
- (a)配列番号85に示されているCDR1αアミノ酸配列、
(b)配列番号86または119に示されているCDR2αアミノ酸配列、
(c)配列番号35に示されているCDR3αアミノ酸配列、
(d)配列番号83に示されているCDR1βアミノ酸配列、必要に応じて配列番号84に示されている、さらに必要に応じて配列番号82に示されているCDR1βアミノ酸配列、
(e)配列番号79に示されているCDR2βアミノ酸配列、および
(f)配列番号36に示されているCDR3βアミノ酸配列
を含む、請求項22または23に記載の結合タンパク質。 - (a)TRBJ2-3*01、
(b)TRAV12-3*01、
(c)TRBV12-3*01、
(d)TRAJ29*01、および/または
(e)TRBD1*01もしくはTRBD2*02
によりコードされるアミノ酸配列と少なくとも85%同一性を有するアミノ酸配列を含む、請求項22、23、または30のいずれか一項に記載の結合タンパク質。 - 前記Vαは、配列番号98に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含み、前記Vβは、配列番号97に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含む、請求項22、23、30、または31のいずれか一項に記載の結合タンパク質。
- 前記Vαは、配列番号98に示されているアミノ酸配列を含むかまたはそれからなり、前記Vβは、配列番号97に示されているアミノ酸配列を含むかまたはそれからなる、請求項32に記載の結合タンパク質。
- TCRα鎖(TCRα)およびTCRβ鎖(TCRβ)を含み、前記TCRαは、配列番号106または15に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むかまたはそれからなり、および/または前記TCRβは、配列番号105または14に示されているアミノ酸配列と少なくとも約85%同一性を有するアミノ酸配列を含むかまたはそれからなる、請求項22、23、または30~33のいずれか一項に記載の結合タンパク質。
- 前記TCRαは、配列番号106または15に示されているアミノ酸配列を含むかまたはそれからなり、前記TCRβは、配列番号105または14に示されているアミノ酸配列を含むかまたはそれからなる、請求項34に記載の結合タンパク質。
- 配列番号31:ヒト白血球抗原(HLA)複合体に特異的に結合することが可能である、請求項22~35のいずれか一項に記載の結合タンパク質。
- 前記HLAは、HLA-A*201を含む、請求項22~35のいずれか一項に記載の結合タンパク質。
- 前記結合タンパク質は、TCRであるかまたはそれを含み、前記TCRは、必要に応じて、可溶性、TCRの抗原結合断片、scTCR、またはCARである、請求項1~35のいずれか一項に記載の結合タンパク質。
- ヒトであるか、ヒト化されているか、またはキメラである、請求項1~38のいずれか一項に記載の結合タンパク質。
- CD8の非存在下で、またはCD8とは独立して、前記メソテリン:HLA複合体に結合することが可能である、請求項1~38のいずれか一項に記載の結合タンパク質。
- 約9μM、約8μM、約7μM、約6μM、約5μM、約4μM、約3μM、約2μM、約1μM、約0.9μM、約0.8μM、約0.7μM、約0.6μM、約0.5μM、約0.4μM、約0.3μM、約0.2μM、またはそれ未満のMslnペプチドのEC50を有する、請求項1~40のいずれか一項に記載の結合タンパク質。
- 請求項1~41のいずれか一項に記載の結合タンパク質および薬学的に許容される担体、希釈剤、または賦形剤を含む組成物。
- 請求項1~41のいずれか一項に記載の結合タンパク質をコードするポリヌクレオチド。
- 前記ポリヌクレオチドは、宿主細胞における発現のためにコドン最適化されており、前記宿主細胞は、必要に応じて、ヒト免疫系細胞であり、好ましくはT細胞である、請求項43に記載のポリヌクレオチド。
- 配列番号1~4、9~12、17~20、25、および26のいずれか1つに示されているポリヌクレオチド配列と少なくとも約50%同一性を有するポリヌクレオチドを含む、請求項43または44に記載のポリヌクレオチド。
- (i)それぞれ配列番号1および3、
(ii)それぞれ配列番号2および4、
(iii)それぞれ配列番号9および11、
(iv)それぞれ配列番号10および12、
(v)それぞれ配列番号17および19、
(vi)それぞれ配列番号18および20、または
(vii)それぞれ配列番号25および26
に示されているポリヌクレオチド配列と少なくとも約50%同一性を有する、TCRα鎖をコードするポリヌクレオチドおよびTCRβ鎖をコードするポリヌクレオチドを含む、請求項43~45のいずれか一項に記載のポリヌクレオチド。 - TCRβ鎖をコードするポリヌクレオチドと、TCRα鎖をコードするポリヌクレオチドとの間に配置された自己切断性ペプチドをコードするポリヌクレオチドを含む、請求項43~46のいずれか一項に記載のポリヌクレオチド。
- コードされるポリペプチドは、配列番号8、16、24、および30のいずれか1つに示されているアミノ酸配列を含む、請求項47に記載のポリヌクレオチド。
- 前記結合タンパク質をコードする前記ポリヌクレオチドは、配列番号5、13、21、27、および120のいずれか1つに示されているポリヌクレオチド配列と少なくとも約50%同一性を有する、請求項47または48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43~49のいずれか一項に記載のポリヌクレオチドを含む発現ベクター。
- 前記ポリヌクレオチドを宿主細胞に送達することが可能である、請求項50に記載の発現ベクター。
- 前記宿主細胞は、造血前駆細胞またはヒト免疫系細胞である、請求項51に記載の発現ベクター。
- 前記免疫系細胞は、CD4+T細胞、CD8+T細胞、CD4-CD8-二重陰性T細胞、γδT細胞、ナチュラルキラー細胞、ナチュラルキラーT細胞、マクロファージ、樹状細胞、またはそれらの任意の組合せである、請求項52に記載の発現ベクター。
- 前記T細胞は、ナイーブT細胞、セントラルメモリーT細胞、幹細胞メモリーT細胞、エフェクターメモリーT細胞、またはそれらの任意の組合せである、請求項53に記載の発現ベクター。
- ウイルスベクターである、請求項50~54のいずれか一項に記載の発現ベクター。
- 前記ウイルスベクターは、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である、請求項55に記載の発現ベクター。
- 請求項43~49のいずれか一項に記載の異種性ポリヌクレオチドおよび/または請求項50~56のいずれか一項に記載の発現ベクターを含む組換え宿主細胞であって、その細胞表面上で、コードされる前記結合タンパク質を発現することが可能である組換え宿主細胞。
- 前記組換え宿主細胞は、造血前駆細胞またはヒト免疫系細胞である、請求項57に記載の組換え宿主細胞。
- 前記免疫系細胞は、CD4+T細胞、CD8+T細胞、CD4-CD8-二重陰性T細胞、γδT細胞、ナチュラルキラー細胞、ナチュラルキラーT細胞、マクロファージ、樹状細胞、またはそれらの任意の組合せである、請求項58に記載の組換え宿主細胞。
- 前記免疫系細胞は、T細胞である、請求項58または59に記載の組換え宿主細胞。
- 前記T細胞が、ナイーブT細胞、セントラルメモリーT細胞、幹細胞メモリーT細胞、エフェクターメモリーT細胞、またはそれらの任意の組合せである、請求項60に記載の組換え宿主細胞。
- 前記宿主細胞は、内因性TCRをコードするT細胞またはNK-T細胞であり、前記結合タンパク質が、前記内因性TCRと比較して、CD3タンパク質とより効率的に会合することが可能である、請求項57~61のいずれか一項に記載の組換え宿主細胞。
- 前記宿主細胞が、約10-2μMのペプチド、約10-1μMのペプチド、約1μMのペプチド、または約101μMのペプチドの濃度の、前記結合タンパク質が結合する前記Mslnペプチドの存在下にある場合、前記宿主細胞におけるNur77発現が増加し、前記ペプチドは、必要に応じて、抗原提示細胞によって前記宿主細胞に提示される、請求項57~62のいずれか一項に記載の組換え宿主細胞。
- 前記組換え宿主細胞が、コードされる前記結合タンパク質が結合する前記メソテリンペプチドが存在しないという条件で、
(i)HLA-C6:02:01
(ii)HLA-B13:02:01ではなくHLA-B13:01:01;
(iii)HLA-A3;
(iv)HLA-A29;
(v)HLA-B40;
(vi)HLA-B44;
(vii)HLA-C3;
(viii)HLA-C16;
(ix)HLA-A1;
(x)HLA-24;
(xi)HLA-B7;
(xii)HLA-B57;
(xiii)HLA-C7;
(xiv)HLA-A11;
(xv)HLA-B15;
(xvi)HLA-C4;
(xvii)HLA-C12;
(xviii)HLA-B8;
(xix)HLA-B49;
(xx)HLA-B51;
(xxi)HLA-C15;
(xxii)HLA-A30;
(xxiii)HLA-A68;
(xxiv)HLA-C2;
(xxv)HLA-A32;
(xxvi)HLA-A33;
(xxvii)HLA-B55;
(xxviii)HLA-C1;
(xxvix)HLA-C5;
(xxix)HLA-B8;
(xxx)HLA-B35または
(xxxi)(i)~(xxx)の任意の組合せ
を発現する細胞と接触させた場合、IFN-γを産生しないか、ならびに/または活性化および/もしくは細胞傷害活性を示さない、請求項57~63のいずれか一項に記載の組換え宿主細胞。 - 前記宿主細胞は、内因性TCRをコードするT細胞またはNK-T細胞であり、前記異種性ポリヌクレオチドによりコードされる前記結合タンパク質は、前記内因性TCRと比較してより高い細胞表面発現を有する、請求項57~64のいずれか一項に記載の組換え宿主細胞。
- 請求項57~65のいずれか一項に記載の組換え宿主細胞、および薬学的に許容される担体、賦形剤、または希釈剤を含む細胞組成物。
- 請求項57~65のいずれか一項に記載の組換え宿主細胞または請求項66に記載の組成物を含む単位用量。
- 対象におけるメソテリンの発現および/または活性に関連する疾患または障害を処置する方法であって、有効量の請求項1~41のいずれか一項に記載の結合タンパク質、請求項57~65のいずれか一項に記載の組換え宿主細胞、請求項66に記載の組成物、または請求項67に記載の単位用量を前記対象に投与することを含む、方法。
- メソテリンの発現および/または活性に関連する疾患または障害は、過剰増殖性疾患または増殖性疾患である、請求項68に記載の方法。
- メソテリンの発現および/または活性に関連する前記疾患または障害は、がんである、請求項68または69に記載の方法。
- 前記がんは、固形がんまたは血液学的悪性腫瘍である、請求項70に記載の方法。
- 前記がんは、胆嚢がん、膀胱がん、骨および軟部組織の癌、脳腫瘍、乳がん、子宮頸がん、結腸がん、結腸直腸腺癌、結腸直腸がん、類腱腫、胎児性がん、子宮内膜がん、食道がん、胃がん、胃腺癌、多形性膠芽腫、婦人科腫瘍、頭頸部扁平上皮癌、肝がん、肺がん、中皮腫、悪性黒色腫、骨肉腫、卵巣がん、膵臓がん、膵管腺癌、原発性星状細胞腫瘍、原発性甲状腺がん、前立腺がん、腎臓がん、腎細胞癌、横紋筋肉腫、皮膚がん、軟部組織肉腫、精巣胚細胞腫瘍、尿路上皮がん、子宮肉腫、または子宮がんを含む、請求項70または71に記載の方法。
- 前記がんは、膵臓がん、卵巣がん、乳がん、胃がん、結腸直腸がん、中皮腫、または肺がんを含む、請求項70または71に記載の方法。
- 前記結合タンパク質、宿主細胞、組成物、または単位用量は、非経口的に、または静脈内に投与される、請求項68~73のいずれか一項に記載の方法。
- 複数の用量の前記結合タンパク質、宿主細胞、組成物、または単位用量を前記対象に投与することを含む、請求項68~74のいずれか一項に記載の方法。
- 前記複数の用量が、約2~約4週間の投与間隔で投与される、請求項75に記載の方法。
- サイトカインを前記対象に投与することをさらに含む、請求項68~76のいずれか一項に記載の方法。
- 前記サイトカインが、IL-2、IL-15、IL-21、またはそれらの任意の組合せを含む、請求項77に記載の方法。
- 前記対象が、免疫チェックポイント阻害剤、刺激性免疫チェックポイント作用物質のアゴニスト、放射線療法、抗体、抗体-薬物コンジュゲート、Fc融合タンパク質、アンチセンスヌクレオチド療法、遺伝子治療、ワクチン、外科手術、化学療法、またはそれらの任意の組合せをさらに受けているか、または受けたことがある、請求項78に記載の方法。
- メソテリンの発現および/または活性によって特徴付けられる疾患または障害の処置における使用のための、請求項1~41のいずれか一項に記載の結合タンパク質、請求項42に記載の組成物、請求項43~49のいずれか一項に記載のポリヌクレオチド、請求項50~56のいずれか一項に記載の発現ベクター、請求項57~65のいずれか一項に記載の組換え宿主細胞、請求項66に記載の細胞組成物、または請求項67に記載の単位用量。
- メソテリンの発現および/または活性によって特徴付けられる疾患または障害の養子免疫療法における使用のための、請求項1~41のいずれか一項に記載の結合タンパク質、請求項42に記載の組成物、請求項43~49のいずれか一項に記載のポリヌクレオチド、請求項50~56のいずれか一項に記載の発現ベクター、請求項57~65のいずれか一項に記載の組換え宿主細胞、請求項66に記載の細胞組成物、または請求項67に記載の単位用量。
- メソテリンの発現および/または活性によって特徴付けられる疾患または障害を処置するための医薬品の製造における使用のための、請求項1~41のいずれか一項に記載の結合タンパク質、請求項42に記載の組成物、請求項43~49のいずれか一項に記載のポリヌクレオチド、請求項50~56のいずれか一項に記載の発現ベクター、請求項57~65のいずれか一項に記載の組換え宿主細胞、請求項66に記載の細胞組成物、または請求項67に記載の単位用量。
- メソテリンの発現および/または活性によって特徴付けられる前記疾患または障害は、中皮腫、膵臓がん、卵巣がん、肺がん、Msln20-28ペプチドを、がんの腫瘍細胞上で発現するそのがん、またはMsln530-538ペプチドを、がんの腫瘍細胞上で発現するそのがんである、請求項80~82のいずれか一項に記載の使用のための前記結合タンパク質、組成物、ポリヌクレオチド、発現ベクター、組換え宿主細胞、細胞組成物、または単位用量。
- メソテリンの発現および/または活性によって特徴付けられる前記疾患または障害が、膵臓がん、卵巣がん、乳がん、胃がん、結腸直腸がん、中皮腫、または肺がんである、請求項80~83のいずれか一項に記載の使用のための前記結合タンパク質、組成物、ポリヌクレオチド、発現ベクター、組換え宿主細胞、細胞組成物、または単位用量。
- 配列番号32:HLA-A:02*01複合体に特異的に結合することが可能である結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であって、配列番号120に示されているポリヌクレオチド配列を含むかまたはそれからなる、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85に記載のポリヌクレオチドを含む発現ベクター。
- 宿主細胞に前記ポリヌクレオチドを送達することが可能である、請求項86に記載の発現ベクター。
- 前記宿主細胞は、造血前駆細胞またはヒト免疫系細胞である、請求項87に記載の発現ベクター。
- 前記免疫系細胞が、CD4+T細胞、CD8+T細胞、CD4-CD8-二重陰性T細胞、γδT細胞、ナチュラルキラー細胞、ナチュラルキラーT細胞、マクロファージ、樹状細胞、またはそれらの任意の組合せである、請求項88に記載の発現ベクター。
- 前記T細胞が、ナイーブT細胞、セントラルメモリーT細胞、幹細胞メモリーT細胞、エフェクターメモリーT細胞、またはそれらの任意の組合せである、請求項89に記載の発現ベクター。
- ウイルスベクターである、請求項86~90のいずれか一項に記載の発現ベクター。
- 前記ウイルスベクターは、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である、請求項91に記載の発現ベクター。
- 請求項85に記載のポリヌクレオチドおよび/または請求項86~92のいずれか一項に記載の発現ベクターを含む組換え宿主細胞であって、その細胞表面上で、コードされる前記結合タンパク質を発現することが可能である組換え宿主細胞。
- 造血前駆細胞またはヒト免疫系細胞である、請求項83に記載の組換え宿主細胞。
- 前記免疫系細胞が、CD4+T細胞、CD8+T細胞、CD4-CD8-二重陰性T細胞、γδT細胞、ナチュラルキラー細胞、ナチュラルキラーT細胞、マクロファージ、樹状細胞、またはそれらの任意の組合せである、請求項94に記載の組換え宿主細胞。
- 前記免疫系細胞が、T細胞である、請求項94または95に記載の組換え宿主細胞。
- 前記T細胞が、ナイーブT細胞、セントラルメモリーT細胞、幹細胞メモリーT細胞、エフェクターメモリーT細胞、またはそれらの任意の組合せである、請求項96に記載の組換え宿主細胞。
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