JPWO2020113141A5 - - Google Patents
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- JPWO2020113141A5 JPWO2020113141A5 JP2021530877A JP2021530877A JPWO2020113141A5 JP WO2020113141 A5 JPWO2020113141 A5 JP WO2020113141A5 JP 2021530877 A JP2021530877 A JP 2021530877A JP 2021530877 A JP2021530877 A JP 2021530877A JP WO2020113141 A5 JPWO2020113141 A5 JP WO2020113141A5
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Description
いくつかの態様では、疾患または病態は、炎症性または自己免疫性の疾患または病態である。いくつかの態様では、疾患または病態は、抗好中球細胞質抗体（ANCA）関連血管炎、血管炎、自己免疫性皮膚疾患、移植（transplantation）、リウマチ性疾患、炎症性消化器疾患、炎症性眼疾患、炎症性神経疾患、炎症性肺疾患、炎症性内分泌疾患、または自己免疫性血液疾患である。いくつかの態様では、疾患または病態は、炎症性腸疾患、移植片（transplant）、クローン病、潰瘍性大腸炎、多発性硬化症、喘息、関節リウマチ、または乾癬から選択される。
[本発明1001]
細胞外ドメインまたはIgVドメインまたはその特異的結合断片を含む、バリアントCD86ポリペプチドであって、SEQ ID NO：29に示される位置を基準として13、18、25、28、33、38、39、40、43、45、52、53、60、68、71、77、79、80、82、86、88、89、90、92、93、97、102、104、113、114、123、128、129、132、133、137、141、143、144、148、153、154、158、170、172、175、178、180、181、183、185、192、193、196、197、198、205、206、207、212、215、216、222、223、または224の中から選択される位置に対応する、非改変CD86ポリペプチドまたはその特異的結合断片における1つまたは複数のアミノ酸改変を含む、バリアントCD86ポリペプチド。
[本発明1002]
前記アミノ酸改変が、アミノ酸置換、欠失、または挿入を含む、本発明1001のバリアントCD86ポリペプチド。
[本発明1003]
前記非改変CD86ポリペプチドが、哺乳動物のCD86ポリペプチドまたはその特異的結合断片である、本発明1001または本発明1002のバリアントCD86ポリペプチド。
[本発明1004]
前記非改変CD86ポリペプチドが、ヒトCD86ポリペプチドまたはその特異的結合断片である、本発明1003のバリアントCD86ポリペプチド。
[本発明1005]
前記バリアントCD86ポリペプチドがヒトCD86の細胞外ドメインを含み、前記1つまたは複数のアミノ酸改変が、非改変CD86ポリペプチドの細胞外ドメインの1つまたは複数の残基にある、本発明1001～1004のいずれかのバリアントCD86ポリペプチド。
[本発明1006]
前記非改変CD86ポリペプチドが、
（i）SEQ ID NO：29に示されるアミノ酸配列、（ii）SEQ ID NO：29に対して少なくとも95％の配列同一性を有するアミノ酸配列；または（iii）その一部分であって、IgVドメインもしくはIgVドメインの特異的結合断片を含む、部分
を含む、本発明1001～1005のいずれかのバリアントCD86ポリペプチド。
[本発明1007]
前記非改変CD86が、SEQ ID NO：29に示されるアミノ酸配列を含む、本発明1001～1006のいずれかのバリアントCD86ポリペプチド。
[本発明1008]
前記部分が、IgVドメインまたはIgVドメインの特異的結合断片の33～131番目または24～134番目のアミノ酸残基を含む、本発明1006のバリアントCD86ポリペプチド。
[本発明1009]
前記非改変CD86ポリペプチドが、
（i）SEQ ID NO：123に示されるアミノ酸配列、（ii）SEQ ID NO：123に対して少なくとも95％の配列同一性を有するアミノ酸配列；または（iii）その一部分であって、IgVドメインもしくはIgVドメインの特異的結合断片を含む、部分
を含む、本発明1001～1006および本発明1008のいずれかのバリアントCD86ポリペプチド。
[本発明1010]
前記非改変CD86が、SEQ ID NO：123に示されるアミノ酸配列を含む、本発明1001～1006のいずれかのバリアントCD86ポリペプチド。
[本発明1011]
前記非改変CD86ポリペプチドが、
（i）SEQ ID NO：122に示されるアミノ酸配列、（ii）SEQ ID NO：122に対して少なくとも95％の配列同一性を有するアミノ酸配列；または（iii）その特異的結合断片
を含む、本発明1001～1006、1008および1009のいずれかのバリアントCD86ポリペプチド。
[本発明1012]
前記非改変CD86が、SEQ ID NO：122に示されるアミノ酸配列を含む、本発明1001～1006、1008、1009および1011のいずれかのバリアントCD86ポリペプチド。
[本発明1013]
前記特異的結合断片が、少なくとも50、60、70、80、90、95アミノ酸、もしくはそれより多いアミノ酸の長さを有するか；または
前記特異的結合断片が、SEQ ID NO：2の33～131番目の残基として示されるIgVドメインの長さの少なくとも80％の長さを含む、
本発明1001～1012のいずれかのバリアントCD86ポリペプチド。
[本発明1014]
最大で1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、または20個のアミノ酸改変、任意でアミノ酸置換、挿入、および/または欠失を含む、本発明1001～1013のいずれかのバリアントCD86ポリペプチド。
[本発明1015]
前記1つまたは複数のアミノ酸改変が、
[本発明1016]
[本発明1017]
前記1つまたは複数のアミノ酸改変が、25位および/または90位にある、本発明1001～1014のいずれかのバリアントCD86ポリペプチド。
[本発明1018]
前記1つまたは複数のアミノ酸改変が、Q25L、H90Y、またはH90Lを含む、本発明1001～1014および1017のいずれかのバリアントCD86ポリペプチド。
[本発明1019]
前記1つまたは複数のアミノ酸改変が、25位および90位に改変を含む、本発明1001～1014および1017のいずれかのバリアントCD86ポリペプチド。
[本発明1020]
前記1つまたは複数のアミノ酸改変が、Q25L/H90YまたはQ25L/H90Lから選択される、本発明1019のバリアントCD86ポリペプチド。
[本発明1021]
[本発明1022]
1つまたは複数のアミノ酸改変A13V/Q25L/H90Lを含む、本発明1001～1021のいずれかのバリアントCD86ポリペプチド。
[本発明1023]
1つまたは複数のアミノ酸改変A13V/Q25L/H90L/S181P/L197M/S206Tを含む、本発明1001～1022のいずれかのバリアントCD86ポリペプチド。
[本発明1024]
1つまたは複数のアミノ酸改変Q25L/H90L/K93T/M97Lを含む、本発明1001～1021のいずれかのバリアントCD86ポリペプチド。
[本発明1025]
1つまたは複数のアミノ酸改変Q25L/H90L/K93T/M97L/T133A/S181P/D215Vを含む、本発明1001～1021および1024のいずれかのバリアントCD86ポリペプチド。
[本発明1026]
1つまたは複数のアミノ酸改変Q25L/Q86R/H90Lを含む、本発明1001～1021および1024のいずれかのバリアントCD86ポリペプチド。
[本発明1027]
1つまたは複数のアミノ酸改変Q25L/Q86R/H90L/N104Sを含む、本発明1001～1021および1026のいずれかのバリアントCD86ポリペプチド。
[本発明1028]
1つまたは複数のアミノ酸改変I89V/H90Lを含む、本発明1001～1021のいずれかのバリアントCD86ポリペプチド。
[本発明1029]
1つまたは複数のアミノ酸改変I89V/H90L/I193Vを含む、本発明1001～1021および1028のいずれかのバリアントCD86ポリペプチド。
[本発明1030]
1つまたは複数のアミノ酸改変M60K/H90Lを含む、本発明1001～1021のいずれかのバリアントCD86ポリペプチド。
[本発明1031]
1つまたは複数のアミノ酸改変Q25L/F33I/H90Lを含む、本発明1001～1021のいずれかのバリアントCD86ポリペプチド。
[本発明1032]
1つまたは複数のアミノ酸改変Q25L/H90L/P185Sを含む、本発明1001～1021のいずれかのバリアントCD86ポリペプチド。
[本発明1033]
SEQ ID NO：29に対して少なくとも85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、もしくは99％の配列同一性を示すアミノ酸配列またはその特異的結合断片を含む、本発明1001～1032のいずれかのバリアントCD86ポリペプチド。
[本発明1034]
CD28のエクトドメインに、同じエクトドメインに対する前記非改変CD86の結合性と比較して向上した親和性で特異的に結合する、本発明1001～1033のいずれかのバリアントCD86ポリペプチド。
[本発明1035]
前記結合親和性が、少なくとも1.5倍もしくは少なくとも約1.5倍、少なくとも2.0倍もしくは少なくとも約2.0倍、少なくとも5.0倍もしくは少なくとも約5.0倍、少なくとも10倍もしくは少なくとも約10倍、少なくとも20倍もしくは少なくとも約20倍、少なくとも30倍もしくは少なくとも約30倍、少なくとも40倍もしくは少なくとも約40倍、少なくとも50倍もしくは少なくとも約50倍、少なくとも60倍もしくは少なくとも約60倍、少なくとも70倍もしくは少なくとも約70倍、少なくとも80倍もしくは少なくとも約80倍、少なくとも90倍もしくは少なくとも約90倍、少なくとも100倍もしくは少なくとも約100倍、または少なくとも125倍もしくは少なくとも約125倍向上している、本発明1034のバリアントCD86ポリペプチド。
[本発明1036]
CTLA-4のエクトドメインに、同じエクトドメインに対する前記非改変CD86の結合性と比較して低下した親和性で特異的に結合する、本発明1001～1035のいずれかのバリアントCD86ポリペプチド。
[本発明1037]
前記低下した結合親和性が、少なくとも1.2倍もしくは少なくとも約1.2倍、少なくとも1.4倍もしくは少なくとも約1.4倍、少なくとも1.5倍もしくは少なくとも約1.5倍、少なくとも1.75倍もしくは少なくとも約1.75倍、少なくとも2.0倍もしくは少なくとも約2.0倍、少なくとも2.5倍もしくは少なくとも約2.5倍、少なくとも3.0倍もしくは少なくとも約3.0倍、少なくとも4.0倍もしくは少なくとも約4.0倍、または少なくとも5.0倍もしくは少なくとも約5.0倍低下している、本発明1036のバリアントCD86ポリペプチド。
[本発明1038]
前記バリアントCD86ポリペプチドが、CTLA-4のエクトドメインに、同じエクトドメインに対する前記非改変CD86の結合性と同じまたは同等の結合親和性で特異的に結合し、任意で、該同じまたは同等の結合親和性が、該非改変CD86の結合親和性の90％～120％または約90％～約120％である、本発明1001～1037のいずれかのバリアントCD86ポリペプチド。
[本発明1039]
細胞外ドメイン全体を含む、本発明1001～1038のいずれかのバリアントCD86ポリペプチド。
[本発明1040]
SEQ ID NO：85～121のいずれかに示されるアミノ酸配列またはその特異的結合断片、SEQ ID NO：85～121のいずれかに対して少なくとも95％の配列同一性を示しかつSEQ ID NO：85～121のいずれかに示されるそれぞれの配列番号のアミノ酸改変のうちの1つまたは複数を含有するアミノ酸配列またはその特異的結合断片を含む、本発明1001～1039のいずれかのバリアントCD86ポリペプチド。
[本発明1041]
SEQ ID NO：141～177のいずれかに示されるアミノ酸配列またはその特異的結合断片、SEQ ID NO：141～177のいずれかに対して少なくとも95％の配列同一性を示しかつSEQ ID NO：141～177のいずれかに示されるそれぞれの配列番号のアミノ酸改変のうちの1つまたは複数を含有するアミノ酸配列またはその特異的結合断片を含む、本発明1001～1040のいずれかのバリアントCD86ポリペプチド。
[本発明1042]
前記CD28がヒトCD28である、本発明1034～1041のいずれかのバリアントCD86ポリペプチド。
[本発明1043]
前記CTLA-4がヒトCTLA-4である、本発明1034～1042のいずれかのバリアントCD86ポリペプチド。
[本発明1044]
可溶性タンパク質である、本発明1001～1043のいずれかのバリアントCD86ポリペプチド。
[本発明1045]
CD86膜貫通ドメインおよび細胞内シグナル伝達ドメインを欠いており；かつ/または
細胞の表面上に発現することができない、
本発明1001～1044のいずれかのバリアントCD86ポリペプチド。
[本発明1046]
多量体化ドメインに連結されている、本発明1001～1045のいずれかのバリアントCD86ポリペプチド。
[本発明1047]
前記多量体化ドメインが、Fcドメインであるか、またはエフェクター機能が低下しているそのバリアントである、本発明1046のバリアントCD86ポリペプチド。
[本発明1048]
Fcドメインに連結されているか、またはエフェクター機能が低下しているそのバリアントに連結されている、本発明1001～1047のいずれかのバリアントCD86ポリペプチド。
[本発明1049]
前記Fcドメインが、ヒトIgG1であるか、またはエフェクター機能が低下しているそのバリアントである、本発明1047または本発明1048のバリアントCD86ポリペプチド。
[本発明1050]
前記Fcドメインが、SEQ ID NO：229に示されるアミノ酸配列を含むか、またはSEQ ID NO：229に対して少なくとも85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、もしくは99％の配列同一性を示すアミノ酸配列を含む、本発明1047～1049のいずれかのバリアントCD86ポリペプチド。
[本発明1051]
前記Fcドメインが、SEQ ID NO：229に示されるアミノ酸配列であるかまたはそれを含む、本発明1047～1050のいずれかのバリアントCD86ポリペプチド。
[本発明1052]
前記Fcドメインが、それぞれEUナンバリングによるE233P、L234A、L234V、L235A、L235E、G236del、G237A、S267K、N297G、V302C、およびK447delの中から選択される1つまたは複数のアミノ酸改変を含むバリアントIgG1 Fcドメインである、本発明1047～1050のいずれかのバリアントCD86ポリペプチド。
[本発明1053]
前記Fcドメインが、アミノ酸改変L234A/L235E/G237Aを含む、本発明1047～1050および1052のいずれかのバリアントCD86ポリペプチド。
[本発明1054]
前記Fcドメインが、EUナンバリングによるアミノ酸改変C220Sを含む、本発明1047～1050、1052および1053のいずれかのバリアントCD86ポリペプチド。
[本発明1055]
前記Fcドメインが、EUナンバリングによるアミノ酸改変K447delを含む、本発明1047～1050および1052～1054のいずれかのバリアントCD86ポリペプチド。
[本発明1056]
前記Fcドメインが、SEQ ID NO：230に示されるアミノ酸配列を含むか、またはSEQ ID NO：230に対して少なくとも85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、もしくは99％の配列同一性を示しかつヒトIgG1と比較したSEQ ID NO：230に示される各アミノ酸改変のうちの1つもしくは複数を含むアミノ酸配列を含む、本発明1047～1050および1052～1055のいずれかのバリアントCD86ポリペプチド。
[本発明1057]
前記Fcドメインが、SEQ ID NO：230に示されるアミノ酸配列であるかまたはそれを含む、本発明1047～1050および1052～1056のいずれかのバリアントCD86ポリペプチド。
[本発明1058]
前記多量体化ドメインまたはFcに、リンカー、任意でG4Sリンカーを介して間接的に連結されている、本発明1047～1057のいずれかのバリアントCD86ポリペプチド。
[本発明1059]
前記バリアントCD86ポリペプチドが、膜貫通ドメインをさらに含む膜貫通型免疫調節タンパク質であり、任意で、該膜貫通ドメインが、前記バリアントCD86ポリペプチドの前記細胞外ドメイン（ECD）またはその特異的結合断片に直接的または間接的に連結されている、本発明1001～1043のいずれかのバリアントCD86ポリペプチド。
[本発明1060]
前記膜貫通ドメインが、SEQ ID NO：2の248～268番目の残基として示されるアミノ酸配列を含むか、またはSEQ ID NO：2の248～268番目の残基に対して少なくとも85％の配列同一性を示すその機能的バリアントを含む、本発明1059のバリアントCD86ポリペプチド。
[本発明1061]
前記バリアントCD86ポリペプチドが細胞質ドメインをさらに含み、任意で、該細胞質ドメインが、前記膜貫通ドメインに直接的または間接的に連結されている、本発明1059または本発明1060のバリアントCD86ポリペプチド。
[本発明1062]
前記細胞質ドメインが、天然型CD86細胞質ドメインであるかまたはそれを含む、本発明1061のバリアントCD86ポリペプチド。
[本発明1063]
前記細胞質ドメインが、SEQ ID NO：2の269～329番目の残基として示されるアミノ酸配列を含むか、またはSEQ ID NO：2の269～329番目の残基に対して少なくとも85％の配列同一性を示すその機能的バリアントを含む、本発明1061または本発明1062のバリアントCD86ポリペプチド。
[本発明1064]
前記細胞質ドメインが、ITAMシグナル伝達モチーフを含み、かつ/または、CD3ζの細胞内シグナル伝達ドメインであるかもしくはそれを含む、本発明1061のバリアントCD86ポリペプチド。
[本発明1065]
細胞質シグナル伝達ドメインを含まず、かつ/または細胞上で発現したときに細胞内シグナルを媒介することも調節することもできない、本発明1059または本発明1060のバリアントCD86ポリペプチド。
[本発明1066]
本発明1001～1058のいずれかの第1のバリアントCD86ポリペプチドと、本発明1001～1058のいずれかの第2のバリアントCD86ポリペプチドとを含む、免疫調節タンパク質。
[本発明1067]
前記第1および第2のバリアントCD86ポリペプチドが、リンカーを介して間接的に連結されている、本発明1066の免疫調節タンパク質。
[本発明1068]
前記第1および第2のバリアントCD86ポリペプチドが、各々、多量体化ドメインに連結されており、前記免疫調節タンパク質が、該第1および第2のバリアントCD86ポリペプチドを含む多量体である、本発明1066または本発明1067の免疫調節タンパク質。
[本発明1069]
前記多量体が、二量体、任意でホモ二量体である、本発明1068の免疫調節タンパク質。
[本発明1070]
前記第1のバリアントCD86ポリペプチドおよび前記第2のバリアントCD86ポリペプチドが同じである、本発明1066～1069のいずれかの免疫調節タンパク質。
[本発明1071]
IgSFファミリーメンバーの免疫グロブリンスーパーファミリー（IgSF）ドメインを含む第2のポリペプチドに直接的に、またはリンカーを介して間接的に連結された本発明1001～1058のいずれかのバリアントCD86ポリペプチドを含む、免疫調節タンパク質。
[本発明1072]
前記IgSFドメインが親和性改変IgSFドメインであり、該親和性改変IgSFドメインが、IgSFファミリーメンバーの非改変または野生型IgSFドメインと比較して1つまたは複数のアミノ酸改変を含む、本発明1071の免疫調節タンパク質。
[本発明1073]
前記IgSFドメインが親和性改変IgSFドメインであり、該親和性改変IgSFドメインが、その同族結合パートナーのうちの1つまたは複数に対して、同じ1つまたは複数の同族結合パートナーに対する前記IgSFファミリーメンバーの非改変または野生型IgSFドメインの結合性と比較して、変化した結合性を示す、本発明1072の免疫調節タンパク質。
[本発明1074]
前記IgSFドメインが、その同族結合パートナーのうちの1つまたは複数に対して、同じ1つまたは複数の同族結合パートナーに対する前記IgSFファミリーメンバーの非改変または野生型IgSFドメインの結合性と比較して、向上した結合性を示す、本発明1073の免疫調節タンパク質。
[本発明1075]
前記第2のポリペプチドのIgSFドメインが、腫瘍上に発現しているリガンドに結合するもしくは腫瘍上に発現しているリガンドに結合する腫瘍局在化部分であるか、または炎症環境に関連する細胞もしくは組織に結合する炎症局在化部分である、本発明1071～1074のいずれかの免疫調節タンパク質。
[本発明1076]
前記リガンドがB7H6である、本発明1075の免疫調節ポリペプチド。
[本発明1077]
前記IgSFドメインが、NKp30由来である、本発明1075または本発明1076の免疫調節ポリペプチド。
[本発明1078]
前記バリアントCD86ポリペプチドまたは前記第2のポリペプチドの少なくとも1つに連結された多量体化ドメインをさらに含む、本発明1071～1077のいずれかの免疫調節タンパク質。
[本発明1079]
前記免疫調節タンパク質が、IgSFファミリーメンバーのIgSFドメインまたはその親和性改変IgSFドメインを含む第3のポリペプチドをさらに含み、該親和性改変IgSFドメインが、IgSFファミリーメンバーの非改変または野生型IgSFドメインと比較して1つまたは複数のアミノ酸改変を含む、本発明1071～1078のいずれかの免疫調節タンパク質。
[本発明1080]
前記第3のポリペプチドが、前記第1および/もしくは第2のポリペプチドと同じであるか；または
前記第3のポリペプチドが、前記第1および/もしくは第2のポリペプチドと異なる、
本発明1079の免疫調節タンパク質。
[本発明1081]
前記バリアントCD86ポリペプチド、前記第2のポリペプチド、および/または前記第3のポリペプチドの少なくとも1つに連結された多量体化ドメインをさらに含む、本発明1079または本発明1080の免疫調節タンパク質。
[本発明1082]
前記多量体化ドメインが免疫グロブリンのFcドメインであり、任意で、該免疫グロブリンタンパク質がヒトのものであり、かつ/または該Fcドメインがヒトのものである、本発明1068～1070、1078および1081のいずれかの免疫調節タンパク質。
[本発明1083]
前記Fcドメインが、IgG1、IgG2、もしくはIgG4であるか、またはエフェクター機能が低下しているそのバリアントである、本発明1082の免疫調節タンパク質。
[本発明1084]
前記Fcドメインが、IgG1 Fcドメイン、任意でヒトIgG1であるか、またはエフェクター機能が低下しているそのバリアントである、本発明1083の免疫調節タンパク質。
[本発明1085]
前記Fcドメインが、SEQ ID NO：229に示されるアミノ酸配列を含むか、またはSEQ ID NO：229に対して少なくとも85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、もしくは99％の配列同一性を示すアミノ酸配列を含む、本発明1082～1084のいずれかの免疫調節タンパク質。
[本発明1086]
前記Fcドメインが、SEQ ID NO：229に示されるアミノ酸配列であるかまたはそれを含む、本発明1082～1085のいずれかの免疫調節タンパク質。
[本発明1087]
前記Fcドメインが、1つまたは複数のアミノ酸置換を含むバリアントIgG1であり、該1つまたは複数のアミノ酸置換が、E233P、L234A、L234V、L235A、L235E、G236del、G237A、S267K、またはN297Gから選択され、これらは各々、KabatによるEUインデックスに従ってナンバリングされている、本発明1084または本発明1085の免疫調節タンパク質。
[本発明1088]
前記Fcドメインが、アミノ酸置換N297G、アミノ酸置換R292C/N297G/V302C、またはアミノ酸置換L234A/L235E/G237Aを含み、これらは各々、KabatのEUインデックスに従ってナンバリングされている、本発明1087の免疫調節タンパク質。
[本発明1089]
前記バリアントFcドメインがアミノ酸置換C220Sをさらに含み、該残基はKabatのEUインデックスに従ってナンバリングされている、本発明1087または本発明1088の免疫調節タンパク質。
[本発明1090]
前記FcドメインがK447delを含み、該残基はKabatのEUインデックスに従ってナンバリングされている、本発明1087～1089のいずれかの免疫調節タンパク質。
[本発明1091]
前記Fcドメインが、SEQ ID NO：230に示されるアミノ酸配列を含むか、またはSEQ ID NO：230に対して少なくとも85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、もしくは99％の配列同一性を示しかつヒトIgG1と比較したSEQ ID NO：230に示される各アミノ酸改変のうちの1つもしくは複数を含むアミノ酸配列を含む、本発明1084、1085および1087～1090のいずれかの免疫調節タンパク質。
[本発明1092]
前記Fcドメインが、SEQ ID NO：230に示されるアミノ酸配列であるかまたはそれを含む、本発明1084、1085および1087～1091のいずれかの免疫調節タンパク質。
[本発明1093]
第1のポリペプチドおよび第2のポリペプチドを含む免疫調節タンパク質であって、
該第1のポリペプチドが、リンカーを介して第1のFcドメインに連結されている少なくとも1つのIgSFドメインを含み、該少なくとも1つのIgSFドメインが、以下の一方または両方を含む：本発明1001～1046のいずれかのバリアントCD86ポリペプチド、またはPD1ポリペプチドもしくはそのバリアントのIgSFドメインであり；かつ
該第2のポリペプチドが、リンカーを介して第2のFcドメインに連結されている少なくとも1つのIgSFを含み、該少なくとも1つのIgSFドメインが、以下の一方または両方を含む：本発明1001～1046のいずれかのバリアントCD86ポリペプチド、またはPD1ポリペプチドもしくはそのバリアントのIgSFドメインであり、
該免疫調節タンパク質が、CD86の少なくとも1つのIgSFドメインおよびPD-1の少なくとも1つのIgSFドメインまたはそのバリアントを含む、
免疫調節タンパク質。
[本発明1094]
前記第1のポリペプチドの少なくとも1つのIgSFドメインが、本発明1001～1046のいずれかのバリアントCD86ポリペプチドを含む、本発明1093の免疫調節タンパク質。
[本発明1095]
前記第2のポリペプチドの少なくとも1つのIgSFドメインが、バリアントPD1ポリペプチドを含む、本発明1093または本発明1094の免疫調節タンパク質。
[本発明1096]
前記第1のポリペプチドの少なくとも1つのIgSFドメインが第1のIgSFドメインであり、該第1のIgSFドメインが、本発明1001～1046のいずれかのバリアントCD86ポリペプチドであり、該第1のポリペプチドが、リンカーを介して前記第1のFcドメインに連結されている第2のIgSFドメインを含む、本発明1093～1095のいずれかの免疫調節タンパク質。
[本発明1097]
前記第1のポリペプチドの第2のIgSFドメインが、バリアントPD1ポリペプチドを含む、本発明1096の免疫調節タンパク質。
[本発明1098]
前記第2のポリペプチドの少なくとも1つのIgSFドメインが第1のIgSFドメインであり、該第1のIgSFドメインが、本発明1001～1046のいずれかのバリアントCD86ポリペプチドであり、該第2のポリペプチドが、リンカーを介して前記第2のFcドメインに連結されている第2のIgSFドメインを含む、本発明1093～1097のいずれかの免疫調節タンパク質。
[本発明1099]
前記第2のポリペプチドの第2のIgSFドメインが、バリアントPD1ポリペプチドを含む、本発明1098の免疫調節タンパク質。
[本発明1100]
前記第1のポリペプチドの少なくとも1つのIgSFドメインが、リンカーを介して前記第1のFcドメインのN末端またはC末端に連結されており；かつ
前記第2のポリペプチドの少なくとも1つのIgSFドメインが、リンカーを介して前記第2のFcドメインのN末端またはC末端に連結されている、
本発明1093～1099のいずれかの免疫調節タンパク質。
[本発明1101]
前記第1のポリペプチドの第2のIgSFドメインが、前記第1のFcドメインの、前記第1のIgSFドメインに連結されている末端とは反対側の末端に連結されている、本発明1096～1097のいずれかの免疫調節タンパク質。
[本発明1102]
前記第2のポリペプチドの第2のIgSFドメインが、前記第2のFcドメインの、前記第1のIgSFドメインに連結されている末端とは反対側の末端に連結されている、本発明1098～1101のいずれかの免疫調節タンパク質。
[本発明1103]
前記リンカーが独立に、SEQ ID NO：222または224の配列を含み、任意で、該リンカーが、SEQ ID NO：222または224の配列の1～4つの反復配列を含む、本発明1093～1102のいずれかの免疫調節タンパク質。
[本発明1104]
前記第1のFcドメインおよび前記第2のFcドメインが同一であり、任意で、該第1のFcドメインおよび該第2のFcドメインが、SEQ ID NO：230の配列を含む、本発明1093～1103のいずれかの免疫調節タンパク質。
[本発明1105]
前記第1のポリペプチドおよび前記第2のポリペプチドが、前記第1および前記第2のFcドメインを通じて二量体化して、ホモ二量体を形成する、本発明1093～1104のいずれかの免疫調節タンパク質。
[本発明1106]
ホモ二量体の前記第1および第2のポリペプチドが、左から右に、バリアントPD1ポリペプチド－リンカー－Fc－リンカー－バリアントCD86ポリペプチドを含む、本発明1093～1104および1105のいずれかの免疫調節タンパク質。
[本発明1107]
前記バリアントPD1ポリペプチドが、SEQ ID NO：315の配列を含む、本発明1093～1104および1105～1106のいずれかの免疫調節タンパク質。
[本発明1108]
前記バリアントCD86ポリペプチドが、SEQ ID NO：94または150の配列を含む、本発明1093～1104および1105～1107のいずれかの免疫調節タンパク質。
[本発明1109]
ホモ二量体の前記第1および第2のポリペプチドが、各々、SEQ ID NO：348または349の配列を含む、本発明1093～1104および1105～1108のいずれかの免疫調節タンパク質。
[本発明1110]
前記第1のFcドメインおよび前記第2のFcドメインが異なり、任意で、該第1および第2のFcドメインが、ノブ－イントゥ－ホール（knob-into-hole）変異を含み、任意で、該第1のFcドメインまたは該第2のFcドメインが、SEQ ID NO：346の配列を含み、該第1のFcドメインまたは該第2のFcドメインのもう一方が、SEQ ID NO：347の配列を含む、本発明1093～1103のいずれかの免疫調節タンパク質。
[本発明1111]
前記第1のポリペプチドおよび前記第2のポリペプチドが、前記第1および第2のFcドメインを通じて二量体化して、ヘテロ二量体を形成する、本発明1093～1103および1110のいずれかの免疫調節タンパク質。
[本発明1112]
ヘテロ二量体の前記第1のポリペプチドが、左から右に、バリアントPD1ポリペプチド－リンカー－Fcを含み、かつヘテロ二量体の前記第2のポリペプチドが、左から右に、バリアントCD86ポリペプチド－リンカー－Fc、Fc－リンカー－バリアントCD86ポリペプチド、またはバリアントPD1－リンカー－Fc－リンカー－バリアントCD86を含む、本発明1093～1103、1110、および1111のいずれかの免疫調節タンパク質。
[本発明1113]
前記バリアントPD1ポリペプチドが、SEQ ID NO：315の配列を含む、本発明1093～1103、1110、および1111～1112のいずれかの免疫調節タンパク質。
[本発明1114]
前記バリアントCD86ポリペプチドが、SEQ ID NO：94または150の配列を含む、本発明1093～1103、1110、および1111～1113のいずれかの免疫調節タンパク質。
[本発明1115]
ヘテロ二量体の前記第1のポリペプチドが、SEQ ID NO：350の配列を含み；かつ
ヘテロ二量体の前記第2のポリペプチドが、SEQ ID NO：351、352、または353の配列を含む、
本発明1093～1103、1110、および1111～1114のいずれかの免疫調節タンパク質。
[本発明1116]
細胞の表面上の分子に特異的に結合するターゲティング部分に連結された本発明1001～1065のいずれかのバリアントCD86ポリペプチドを含む、コンジュゲート。
[本発明1117]
前記細胞が、免疫細胞または腫瘍細胞である、本発明1116のコンジュゲート。
[本発明1118]
前記部分が、タンパク質、ペプチド、核酸、低分子またはナノ粒子である、本発明1116または本発明1117のコンジュゲート。
[本発明1119]
前記部分が、抗体または抗原結合断片である、本発明1116～1118のいずれかのコンジュゲート。
[本発明1120]
前記バリアントCD86ポリペプチドが、抗体のV
H
またはV
L
のN末端またはC末端に連結されている、本発明1119のコンジュゲート。
[本発明1121]
前記抗体が、抗HER2抗体または抗EGFR抗体である、本発明1119のコンジュゲート。
[本発明1122]
前記抗HER2抗体が、ペルツズマブである、本発明1121のコンジュゲート。
[本発明1123]
前記バリアントCD86ポリペプチドが、ペルツズマブのV
H
のN末端、ペルツズマブのV
H
のC末端、ペルツズマブのV
L
のN末端、またはペルツズマブのV
L
のC末端に連結されており、任意で、それぞれSEQ ID NO：342、344、343、または345の配列を含む、本発明1122のコンジュゲート。
[本発明1124]
前記抗EGFR抗体が、パニツムマブである、本発明1121のコンジュゲート。
[本発明1125]
前記バリアントCD86ポリペプチドが、パニツムマブのV
H
のN末端、パニツムマブのV
H
のC末端、パニツムマブのV
L
のN末端、またはパニツムマブのV
L
のC末端に連結されており、任意で、それぞれSEQ ID NO：348、350、349、または351の配列を含む、本発明1124のコンジュゲート。あるいは抗EGFR抗体。
[本発明1126]
融合タンパク質である、本発明1116～1125のいずれかのコンジュゲート。
[本発明1127]
本発明1001～1065のいずれかのバリアントCD86ポリペプチド、本発明1066～1115のいずれかの免疫調節タンパク質、または本発明1116～1126のいずれかの融合タンパク質であるコンジュゲートをコードする、核酸分子。
[本発明1128]
本発明1127の核酸分子を含む、ベクター。
[本発明1129]
本発明1128のベクターを含む、細胞。
[本発明1130]
バリアントCD86ポリペプチドを含むタンパク質を生産する方法であって、本発明1127の核酸分子または本発明1128のベクターを、宿主細胞において該タンパク質が発現する条件下で宿主細胞に導入する工程を含む、方法。
[本発明1131]
前記細胞から前記タンパク質を単離または精製する工程をさらに含む、本発明1130の方法。
[本発明1132]
バリアントCD86ポリペプチドを発現する細胞を改変する方法であって、本発明1001～1065のいずれかのバリアントCD86ポリペプチド、本発明1066～1115のいずれかの免疫調節タンパク質、または本発明1116～1126のいずれかの融合タンパク質であるコンジュゲートをコードする核酸分子を、宿主細胞において該ポリペプチドが発現する条件下で宿主細胞に導入する工程を含む、方法。
[本発明1133]
本発明1001～1065のいずれかのバリアントCD86ポリペプチド、本発明1066～1115のいずれかの免疫調節タンパク質、または本発明1116～1126のいずれかの融合タンパク質であるコンジュゲート、本発明1127の核酸分子、または本発明1128のベクターを含む、改変された細胞。
[本発明1134]
前記バリアントCD86ポリペプチドが、膜貫通ドメインを含むか、もしくは本発明1059～1065のいずれかの膜貫通型免疫調節タンパク質であり；かつ/または
前記バリアントCD86ポリペプチドを含むタンパク質が、前記細胞の表面上に発現する、
本発明1133の改変された細胞。
[本発明1135]
前記バリアントCD86ポリペプチドが、膜貫通ドメインを含まず、かつ/もしくは、前記細胞の表面上に発現せず；かつ/または
前記バリアントCD86ポリペプチドが、前記改変された細胞から分泌されることができる、
本発明1133の改変された細胞。
[本発明1136]
免疫細胞である、本発明1133～1135のいずれかの改変された細胞。
[本発明1137]
前記免疫細胞がリンパ球であり、任意で該リンパ球がT細胞である、本発明1136の改変された細胞。
[本発明1138]
初代細胞である、本発明1133～1137のいずれかの改変された細胞。
[本発明1139]
キメラ抗原受容体（CAR）をさらに含む、本発明1133～1138のいずれかの改変された細胞。
[本発明1140]
改変されたT細胞受容体（TCR）をさらに含む、本発明1133～1139のいずれかの改変された細胞。
[本発明1141]
本発明1001～1065のいずれかのバリアントCD86ポリペプチド、本発明1066～1115のいずれかの免疫調節タンパク質、または本発明1116～1126のいずれかの融合タンパク質であるコンジュゲート、本発明1127の核酸分子、または本発明1128のベクターを含む、感染性物質。
[本発明1142]
細菌またはウイルスである、本発明1141の感染性物質。
[本発明1143]
前記感染性物質がウイルスであり、該ウイルスが腫瘍溶解性ウイルスである、本発明1142の感染性物質。
[本発明1144]
本発明1001～1065のいずれかのバリアントCD86ポリペプチド、本発明1066～1115のいずれかの免疫調節タンパク質、または本発明1116～1126のいずれかの融合タンパク質であるコンジュゲート、本発明1133～1140のいずれかの改変された細胞、または本発明1141～1143のいずれかの感染性物質を含む、薬学的組成物。
[本発明1145]
薬学的に許容される賦形剤を含む、本発明1144の薬学的組成物。
[本発明1146]
バイアルまたは容器中に本発明1144～1145のいずれかの薬学的組成物を含む、製造物品。
[本発明1147]
本発明1144～1145のいずれかの薬学的組成物または本発明1146の製造物品と、使用説明書とを含む、キット。
[本発明1148]
対象における免疫応答を調節する方法であって、本発明1001～1065のいずれかのバリアントCD86ポリペプチド、本発明1066～1115のいずれかの免疫調節タンパク質、または本発明1116～1126のいずれかの融合タンパク質であるコンジュゲート、本発明1133～1140のいずれかの改変された細胞、本発明1141～1143のいずれかの感染性物質、または本発明1144～1145のいずれかの薬学的組成物を投与する工程を含む、方法。
[本発明1149]
対象における免疫応答を調節する方法であって、本発明1133～1140のいずれかの改変された細胞を投与する工程を含む、方法。
[本発明1150]
前記改変された細胞が、前記対象にとって自家である、本発明1149の方法。
[本発明1151]
前記改変された細胞が、前記対象にとって同種である、本発明1149の方法。
[本発明1152]
前記免疫応答を調節することが、前記対象における疾患または病態を治療する、本発明1148～1151のいずれかの方法。
[本発明1153]
その必要のある対象における疾患または病態を治療する方法であって、本発明1001～1065のいずれかのバリアントCD86ポリペプチド、本発明1066～1115のいずれかの免疫調節タンパク質、または本発明1116～1126のいずれかの融合タンパク質であるコンジュゲート、本発明1133～1140のいずれかの改変された細胞、本発明1141～1143のいずれかの感染性物質、または本発明1144～1145のいずれかの薬学的組成物を投与する工程を含む、方法。
[本発明1154]
その必要のある対象における疾患または病態を治療する方法であって、本発明1133～1140のいずれかの改変された細胞を投与する工程を含む、方法。
[本発明1155]
前記改変された細胞が、前記対象にとって自家である、本発明1154の方法。
[本発明1156]
前記改変された細胞が、前記対象にとって同種である、本発明1154の方法。
[本発明1157]
前記対象において免疫応答が増強される、本発明1148～1156のいずれかの方法。
[本発明1158]
腫瘍局在化部分に連結されたバリアントCD86ポリペプチドを含む免疫調節タンパク質またはコンジュゲートが前記対象に投与される、本発明1148、1152、1153および1157のいずれかの方法。
[本発明1159]
前記腫瘍局在化部分が、腫瘍抗原を認識する結合分子であるか、またはそれを含む、本発明1158の方法。
[本発明1160]
前記結合分子が、抗体もしくはその抗原結合断片または野生型IgSFドメインもしくはそのバリアントを含み、任意で、抗HER2抗体もしくは抗原結合断片または抗EGFR抗体もしくは抗原結合断片を含む；あるいは
前記結合分子が、腫瘍抗原に結合するIgSFメンバーのIgSFドメインまたはその特異的結合断片を含み、任意で、該IgSFドメインが、PD-1またはNkp30のIgSFドメインである、
本発明1159の方法。
[本発明1161]
本発明1071～1115のいずれかの免疫調節タンパク質または本発明1116～1126のいずれかのコンジュゲートを含む薬学的組成物が前記対象に投与される、本発明1148および1152～1160のいずれかの方法。
[本発明1162]
膜貫通型免疫調節タンパク質であるバリアントCD86ポリペプチドを含む改変された細胞が前記対象に投与され、任意で、該改変された細胞が、本発明1133、1134および1136～1140のものである、本発明1148～1160のいずれかの方法。
[本発明1163]
前記疾患または病態が、腫瘍またはがんである、本発明1152～1162のいずれかの方法。
[本発明1164]
前記疾患または病態が、黒色腫、肺がん、膀胱がん、血液悪性腫瘍、肝臓がん、脳がん、腎臓がん、乳がん、膵臓がん、大腸がん、脾臓がん、前立腺がん、精巣がん、卵巣がん、子宮がん、胃がん、筋骨格がん、頭頚部がん、消化器がん、生殖細胞がん、または内分泌および神経内分泌がんから選択される、本発明1152～1163のいずれかの方法。
[本発明1165]
免疫応答が低減される、本発明1148～1156のいずれかの方法。
[本発明1166]
可溶性であるバリアントCD86ポリペプチドまたは免疫調節タンパク質が前記対象に投与される、本発明1148、1152、1153および1165のいずれかの方法。
[本発明1167]
前記可溶性のポリペプチドまたは免疫調節タンパク質が、Fc融合タンパク質である、本発明1166の方法。
[本発明1168]
本発明1001～1058のいずれかのバリアントCD86ポリペプチド、または本発明1066～1074および1078～1115のいずれかの免疫調節タンパク質を含む薬学的組成物が前記対象に投与される、本発明1148、1152、1153および1165～1167のいずれかの方法。
[本発明1169]
分泌可能なバリアントCD86ポリペプチドを含む改変された細胞が対象に投与され、任意で、該改変された細胞が、本発明1133および1135～1140のいずれかのものである、本発明1148、1152、1153および1165のいずれかの方法。
[本発明1170]
前記疾患または病態が、炎症性または自己免疫性の疾患または病態である、本発明1148、1152、1153および1165～1169のいずれかの方法。
[本発明1171]
前記疾患または病態が、抗好中球細胞質抗体（ANCA）関連血管炎、血管炎、自己免疫性皮膚疾患、移植（transplantation）、リウマチ性疾患、炎症性消化器疾患、炎症性眼疾患、炎症性神経疾患、炎症性肺疾患、炎症性内分泌疾患、または自己免疫性血液疾患である、本発明1148、1152、1153および1165～1169のいずれかの方法。
[本発明1172]
前記疾患または病態が、炎症性腸疾患、移植（transplant）、クローン病、潰瘍性大腸炎、多発性硬化症、喘息、関節リウマチ、または乾癬から選択される、本発明1170または本発明1171の方法。
In some aspects, the disease or condition is an inflammatory or autoimmune disease or condition. In some embodiments, the disease or condition is antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, vasculitis, autoimmune skin disease, transplantation, rheumatic disease, inflammatory gastrointestinal disease, inflammatory eye disease, inflammatory neurological disease, inflammatory lung disease, inflammatory endocrine disease, or autoimmune hematologic disease. In some embodiments, the disease or condition is selected from inflammatory bowel disease, transplant, Crohn's disease, ulcerative colitis, multiple sclerosis, asthma, rheumatoid arthritis, or psoriasis.
[Invention 1001]
13, 18, 25, 28, 33, 38, 39, 40 relative to the positions shown in SEQ ID NO: 29, comprising a variant CD86 polypeptide comprising an extracellular domain or an IgV domain or specific binding fragment thereof , 43, 45, 52, 53, 60, 68, 71, 77, 79, 80, 82, 86, 88, 89, 90, 92, 93, 97, 102, 104, 113, 114, 123, 128, 129 , 132, 133, 137, 141, 143, 144, 148, 153, 154, 158, 170, 172, 175, 178, 180, 181, 183, 185, 192, 193, 196, 197, 198, 205, 206 , 207, 212, 215, 216, 222, 223, or 224. Polypeptide.
[Invention 1002]
A variant CD86 polypeptide of the invention 1001, wherein said amino acid alterations comprise amino acid substitutions, deletions or insertions.
[Invention 1003]
The variant CD86 polypeptide of invention 1001 or invention 1002, wherein said unmodified CD86 polypeptide is a mammalian CD86 polypeptide or a specific binding fragment thereof.
[Invention 1004]
The variant CD86 polypeptide of the invention 1003, wherein said unmodified CD86 polypeptide is a human CD86 polypeptide or a specific binding fragment thereof.
[Invention 1005]
1001-1004 of the invention, wherein said variant CD86 polypeptide comprises the extracellular domain of human CD86, and said one or more amino acid modifications are at one or more residues of the extracellular domain of the unmodified CD86 polypeptide A variant CD86 polypeptide of any of
[Invention 1006]
wherein said unmodified CD86 polypeptide is
(i) the amino acid sequence shown in SEQ ID NO:29, (ii) an amino acid sequence having at least 95% sequence identity to SEQ ID NO:29; or (iii) a portion thereof comprising an IgV domain or A portion containing a specific binding fragment of an IgV domain
A variant CD86 polypeptide of any of the inventions 1001-1005, comprising:
[Invention 1007]
The variant CD86 polypeptide of any of the inventions 1001-1006, wherein said unmodified CD86 comprises the amino acid sequence shown in SEQ ID NO:29.
[Invention 1008]
The variant CD86 polypeptide of the invention 1006, wherein said portion comprises amino acid residues 33-131 or 24-134 of an IgV domain or a specific binding fragment of an IgV domain.
[Invention 1009]
wherein said unmodified CD86 polypeptide is
(i) the amino acid sequence shown in SEQ ID NO:123, (ii) an amino acid sequence having at least 95% sequence identity to SEQ ID NO:123; or (iii) a portion thereof, wherein the IgV domain or A portion containing a specific binding fragment of an IgV domain
A variant CD86 polypeptide of any of inventions 1001-1006 and invention 1008, comprising:
[Invention 1010]
The variant CD86 polypeptide of any of the inventions 1001-1006, wherein said unmodified CD86 comprises the amino acid sequence shown in SEQ ID NO:123.
[Invention 1011]
wherein said unmodified CD86 polypeptide is
(i) the amino acid sequence set forth in SEQ ID NO:122, (ii) an amino acid sequence having at least 95% sequence identity to SEQ ID NO:122; or (iii) a specific binding fragment thereof
A variant CD86 polypeptide of any of the inventions 1001-1006, 1008 and 1009, comprising:
[Invention 1012]
The variant CD86 polypeptide of any of the invention 1001-1006, 1008, 1009 and 1011, wherein said unmodified CD86 comprises the amino acid sequence shown in SEQ ID NO:122.
[Invention 1013]
said specific binding fragment has a length of at least 50, 60, 70, 80, 90, 95 amino acids, or more; or
said specific binding fragment comprises a length of at least 80% of the length of the IgV domain shown as residues 33-131 of SEQ ID NO:2;
A variant CD86 polypeptide of any of the inventions 1001-1012.
[Invention 1014]
up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid modifications, optionally amino acids A variant CD86 polypeptide of any of the inventions 1001-1013 containing substitutions, insertions and/or deletions.
[Invention 1015]
The one or more amino acid modifications are
[Invention 1016]
[Invention 1017]
The variant CD86 polypeptide of any of invention 1001-1014, wherein said one or more amino acid alterations are at positions 25 and/or 90.
[Invention 1018]
The variant CD86 polypeptide of any of inventions 1001-1014 and 1017, wherein said one or more amino acid alterations comprises Q25L, H90Y, or H90L.
[Invention 1019]
The variant CD86 polypeptide of any of invention 1001-1014 and 1017, wherein said one or more amino acid alterations comprise alterations at positions 25 and 90.
[Invention 1020]
The variant CD86 polypeptide of the invention 1019, wherein said one or more amino acid alterations are selected from Q25L/H90Y or Q25L/H90L.
[Invention 1021]
[Invention 1022]
A variant CD86 polypeptide of any of the inventions 1001-1021 comprising one or more amino acid alterations A13V/Q25L/H90L.
[Invention 1023]
A variant CD86 polypeptide of any of the inventions 1001-1022 comprising one or more amino acid alterations A13V/Q25L/H90L/S181P/L197M/S206T.
[Invention 1024]
A variant CD86 polypeptide of any of the inventions 1001-1021 comprising one or more amino acid alterations Q25L/H90L/K93T/M97L.
[Invention 1025]
A variant CD86 polypeptide of any of the inventions 1001-1021 and 1024 comprising one or more amino acid alterations Q25L/H90L/K93T/M97L/T133A/S181P/D215V.
[Invention 1026]
A variant CD86 polypeptide of any of the inventions 1001-1021 and 1024 comprising one or more amino acid alterations Q25L/Q86R/H90L.
[Invention 1027]
A variant CD86 polypeptide of any of the inventions 1001-1021 and 1026 comprising one or more amino acid alterations Q25L/Q86R/H90L/N104S.
[Invention 1028]
A variant CD86 polypeptide of any of the inventions 1001-1021 comprising one or more amino acid alterations I89V/H90L.
[Invention 1029]
A variant CD86 polypeptide of any of the inventions 1001-1021 and 1028 comprising one or more amino acid alterations I89V/H90L/I193V.
[Invention 1030]
A variant CD86 polypeptide of any of the inventions 1001-1021 comprising one or more amino acid alterations M60K/H90L.
[Invention 1031]
A variant CD86 polypeptide of any of the inventions 1001-1021 comprising one or more amino acid alterations Q25L/F33I/H90L.
[Invention 1032]
A variant CD86 polypeptide of any of the inventions 1001-1021 comprising one or more amino acid alterations Q25L/H90L/P185S.
[Invention 1033]
At least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% against SEQ ID NO:29 , or a variant CD86 polypeptide of any of the inventions 1001-1032 comprising an amino acid sequence exhibiting 99% sequence identity or a specific binding fragment thereof.
[Invention 1034]
The variant CD86 polypeptide of any of the inventions 1001-1033, which specifically binds the ectodomain of CD28 with enhanced affinity compared to the binding of said unmodified CD86 to the same ectodomain.
[Invention 1035]
said binding affinity is at least 1.5-fold or at least about 1.5-fold, at least 2.0-fold or at least about 2.0-fold, at least 5.0-fold or at least about 5.0-fold, at least 10-fold or at least about 10-fold, at least 20-fold or at least about 20-fold at least 30 times or at least about 30 times, at least 40 times or at least about 40 times, at least 50 times or at least about 50 times, at least 60 times or at least about 60 times, at least 70 times or at least about 70 times, at least 80 times A variant CD86 polypeptide of the invention 1034 that is at least about 80-fold, at least 90-fold or at least about 90-fold, at least 100-fold or at least about 100-fold, or at least 125-fold or at least about 125-fold improved.
[Invention 1036]
The variant CD86 polypeptide of any of the inventions 1001-1035, which specifically binds the ectodomain of CTLA-4 with reduced affinity compared to the binding of said unmodified CD86 to the same ectodomain.
[Invention 1037]
said decreased binding affinity is at least 1.2-fold or at least about 1.2-fold, at least 1.4-fold or at least about 1.4-fold, at least 1.5-fold or at least about 1.5-fold, at least 1.75-fold or at least about 1.75-fold, at least 2.0-fold or at least about Variant CD86 of invention 1036 that is 2.0-fold, at least 2.5-fold or at least about 2.5-fold, at least 3.0-fold or at least about 3.0-fold, at least 4.0-fold or at least about 4.0-fold, or at least 5.0-fold or at least about 5.0-fold Polypeptide.
[Invention 1038]
Said variant CD86 polypeptide specifically binds to the ectodomain of CTLA-4 with a binding affinity that is the same or equivalent to the binding of said unmodified CD86 to the same ectodomain; The variant CD86 polypeptide of any of invention 1001-1037, wherein the affinity is 90% to 120% or about 90% to about 120% of the binding affinity of said unmodified CD86.
[Invention 1039]
A variant CD86 polypeptide of any of the inventions 1001-1038 comprising the entire extracellular domain.
[Invention 1040]
an amino acid sequence set forth in any of SEQ ID NO:85-121 or a specific binding fragment thereof, exhibiting at least 95% sequence identity to any of SEQ ID NO:85-121 and SEQ ID NO:85 A variant CD86 polypeptide of any of the inventions 1001-1039, comprising an amino acid sequence containing one or more of the amino acid modifications of each of the SEQ ID NOs set forth in any of -121, or a specific binding fragment thereof.
[Invention 1041]
an amino acid sequence set forth in any of SEQ ID NO: 141-177 or a specific binding fragment thereof, exhibiting at least 95% sequence identity to any of SEQ ID NO: 141-177 and SEQ ID NO: 141 A variant CD86 polypeptide of any of the inventions 1001-1040, comprising an amino acid sequence containing one or more of the amino acid modifications of each of the SEQ ID NOs set forth in any of 177, or a specific binding fragment thereof.
[Invention 1042]
The variant CD86 polypeptide of any of inventions 1034-1041, wherein said CD28 is human CD28.
[Invention 1043]
The variant CD86 polypeptide of any of inventions 1034-1042, wherein said CTLA-4 is human CTLA-4.
[Invention 1044]
A variant CD86 polypeptide of any of the inventions 1001-1043 that is a soluble protein.
[Invention 1045]
lacks the CD86 transmembrane and intracellular signaling domains; and/or
unable to be expressed on the surface of the cell,
A variant CD86 polypeptide of any of the inventions 1001-1044.
[Invention 1046]
A variant CD86 polypeptide of any of the inventions 1001-1045, linked to a multimerization domain.
[Invention 1047]
A variant CD86 polypeptide of the invention 1046, wherein said multimerization domain is an Fc domain or a variant thereof with reduced effector function.
[Invention 1048]
A variant CD86 polypeptide of any of the inventions 1001-1047 linked to an Fc domain or linked to variants thereof with reduced effector function.
[Invention 1049]
A variant CD86 polypeptide of the invention 1047 or invention 1048, wherein said Fc domain is human IgG1 or a variant thereof with reduced effector function.
[Invention 1050]
said Fc domain comprises the amino acid sequence set forth in SEQ ID NO:229, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91% relative to SEQ ID NO:229; A variant CD86 polypeptide of any of Inventions 1047-1049, comprising an amino acid sequence exhibiting 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity.
[Invention 1051]
The variant CD86 polypeptide of any of the inventions 1047-1050, wherein said Fc domain is or comprises the amino acid sequence shown in SEQ ID NO:229.
[Invention 1052]
a variant IgG1 Fc domain, wherein said Fc domain comprises one or more amino acid alterations selected among E233P, L234A, L234V, L235A, L235E, G236del, G237A, S267K, N297G, V302C, and K447del, each according to EU numbering A variant CD86 polypeptide of any of the inventions 1047-1050 which is
[Invention 1053]
The variant CD86 polypeptide of any of invention 1047-1050 and 1052, wherein said Fc domain comprises amino acid alteration L234A/L235E/G237A.
[Invention 1054]
The variant CD86 polypeptide of any of the invention 1047-1050, 1052 and 1053, wherein said Fc domain comprises an amino acid modification C220S according to EU numbering.
[Invention 1055]
The variant CD86 polypeptide of any of the invention 1047-1050 and 1052-1054, wherein said Fc domain comprises the amino acid modification K447del according to EU numbering.
[Invention 1056]
said Fc domain comprises the amino acid sequence set forth in SEQ ID NO:230 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91% relative to SEQ ID NO:230, of each amino acid modification shown in SEQ ID NO: 230 showing 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity and compared to human IgG1 A variant CD86 polypeptide of any of the invention 1047-1050 and 1052-1055, comprising an amino acid sequence comprising one or more.
[Invention 1057]
The variant CD86 polypeptide of any of the invention 1047-1050 and 1052-1056, wherein said Fc domain is or comprises the amino acid sequence shown in SEQ ID NO:230.
[Invention 1058]
The variant CD86 polypeptide of any of inventions 1047-1057, which is indirectly linked to said multimerization domain or Fc via a linker, optionally a G4S linker.
[Invention 1059]
Said variant CD86 polypeptide is a transmembrane immunomodulatory protein further comprising a transmembrane domain, optionally wherein said transmembrane domain is said extracellular domain (ECD) of said variant CD86 polypeptide or a specific binding fragment thereof A variant CD86 polypeptide of any of the inventions 1001-1043, which is linked directly or indirectly to a
[Invention 1060]
said transmembrane domain comprises the amino acid sequence shown as residues 248-268 of SEQ ID NO:2, or is at least 85% of the sequence of residues 248-268 of SEQ ID NO:2 A variant CD86 polypeptide of the invention 1059, including functional variants thereof exhibiting identity.
[Invention 1061]
A variant CD86 polypeptide of invention 1059 or invention 1060, wherein said variant CD86 polypeptide further comprises a cytoplasmic domain, and optionally said cytoplasmic domain is directly or indirectly linked to said transmembrane domain.
[Invention 1062]
A variant CD86 polypeptide of the invention 1061, wherein said cytoplasmic domain is or comprises a native CD86 cytoplasmic domain.
[Invention 1063]
said cytoplasmic domain comprises the amino acid sequence shown as residues 269-329 of SEQ ID NO:2 or has at least 85% sequence identity to residues 269-329 of SEQ ID NO:2 A variant CD86 polypeptide of the invention 1061 or invention 1062, including functional variants thereof that exhibit sex.
[Invention 1064]
The variant CD86 polypeptide of the invention 1061, wherein said cytoplasmic domain comprises an ITAM signaling motif and/or is or comprises the intracellular signaling domain of CD3zeta.
[Invention 1065]
A variant CD86 polypeptide of the invention 1059 or invention 1060 that does not contain a cytoplasmic signaling domain and/or is incapable of mediating or regulating an intracellular signal when expressed on a cell.
[Invention 1066]
An immunomodulatory protein comprising a first variant CD86 polypeptide of any of inventions 1001-1058 and a second variant CD86 polypeptide of any of inventions 1001-1058.
[Invention 1067]
The immunomodulatory protein of invention 1066, wherein said first and second variant CD86 polypeptides are indirectly linked via a linker.
[Invention 1068]
The first and second variant CD86 polypeptides are each linked to a multimerization domain, and the immunomodulatory protein is a multimer comprising the first and second variant CD86 polypeptides. An immunomodulatory protein of invention 1066 or invention 1067.
[Invention 1069]
The immunomodulatory protein of the invention 1068, wherein said multimers are dimers, optionally homodimers.
[Invention 1070]
The immunomodulatory protein of any of inventions 1066-1069, wherein said first variant CD86 polypeptide and said second variant CD86 polypeptide are the same.
[Invention 1071]
A variant CD86 polypeptide of any of the inventions 1001-1058 linked directly or indirectly through a linker to a second polypeptide comprising an immunoglobulin superfamily (IgSF) domain of an IgSF family member , immunomodulatory proteins.
[Invention 1072]
The immunological of invention 1071, wherein said IgSF domain is an affinity-modified IgSF domain, said affinity-modified IgSF domain comprising one or more amino acid modifications compared to an unmodified or wild-type IgSF domain of an IgSF family member regulatory protein.
[Invention 1073]
said IgSF domain is an affinity-modified IgSF domain, wherein said affinity-modified IgSF domain binds to one or more of its cognate binding partners of said IgSF family member to the same one or more cognate binding partners; An immunomodulatory protein of the invention 1072 that exhibits altered binding compared to that of an unmodified or wild-type IgSF domain.
[Invention 1074]
said IgSF domain to one or more of its cognate binding partners compared to the binding of an unmodified or wild-type IgSF domain of said IgSF family member to the same one or more cognate binding partners, An immunomodulatory protein of the invention 1073 that exhibits improved binding.
[Invention 1075]
wherein the IgSF domain of said second polypeptide binds to a ligand expressed on a tumor or is a tumor localizing moiety that binds to a ligand expressed on a tumor or cells associated with an inflammatory environment or an immunomodulatory protein of any of the inventions 1071-1074, which is an inflammatory localizing moiety that binds tissue.
[Invention 1076]
The immunomodulatory polypeptide of the invention 1075, wherein said ligand is B7H6.
[Invention 1077]
The immunomodulatory polypeptide of invention 1075 or invention 1076, wherein said IgSF domain is derived from NKp30.
[Invention 1078]
The immunomodulatory protein of any of inventions 1071-1077, further comprising a multimerization domain linked to at least one of said variant CD86 polypeptide or said second polypeptide.
[Invention 1079]
said immunomodulatory protein further comprising a third polypeptide comprising an IgSF domain of an IgSF family member or an affinity-modified IgSF domain thereof, wherein said affinity-modified IgSF domain is an unmodified or wild-type IgSF domain of an IgSF family member; The immunomodulatory protein of any of the inventions 1071-1078, comprising one or more amino acid modifications in comparison.
[Invention 1080]
said third polypeptide is the same as said first and/or second polypeptide; or
said third polypeptide is different from said first and/or second polypeptide,
An immunomodulatory protein of the invention 1079.
[Invention 1081]
The immunomodulatory protein of invention 1079 or invention 1080 further comprising a multimerization domain linked to at least one of said variant CD86 polypeptide, said second polypeptide, and/or said third polypeptide.
[Invention 1082]
1068-1070, 1078 and 1081 of the invention, wherein said multimerization domain is an immunoglobulin Fc domain, optionally said immunoglobulin protein is human and/or said Fc domain is human any immunomodulatory protein of
[Invention 1083]
The immunomodulatory protein of invention 1082, wherein said Fc domain is IgG1, IgG2, or IgG4, or a variant thereof with reduced effector function.
[Invention 1084]
The immunomodulatory protein of the invention 1083, wherein said Fc domain is an IgG1 Fc domain, optionally human IgG1, or a variant thereof with reduced effector function.
[Invention 1085]
said Fc domain comprises the amino acid sequence set forth in SEQ ID NO:229, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91% relative to SEQ ID NO:229; The immunomodulatory protein of any of inventions 1082-1084, comprising an amino acid sequence exhibiting 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity.
[Invention 1086]
The immunomodulatory protein of any of the inventions 1082-1085, wherein said Fc domain is or comprises the amino acid sequence shown in SEQ ID NO:229.
[Invention 1087]
said Fc domain is a variant IgG1 comprising one or more amino acid substitutions, wherein said one or more amino acid substitutions are selected from E233P, L234A, L234V, L235A, L235E, G236del, G237A, S267K, or N297G , immunomodulatory proteins of the invention 1084 or invention 1085, each numbered according to the EU index according to Kabat.
[Invention 1088]
1087. The immunomodulatory protein of the invention 1087, wherein said Fc domain comprises the amino acid substitution N297G, the amino acid substitution R292C/N297G/V302C, or the amino acid substitution L234A/L235E/G237A, each numbered according to the Kabat EU index.
[Invention 1089]
The immunomodulatory protein of invention 1087 or invention 1088, wherein said variant Fc domain further comprises the amino acid substitution C220S, wherein said residues are numbered according to the EU index of Kabat.
[Invention 1090]
1089. The immunomodulatory protein of any of the invention 1087-1089, wherein said Fc domain comprises K447del, wherein said residues are numbered according to Kabat's EU index.
[Invention 1091]
said Fc domain comprises the amino acid sequence set forth in SEQ ID NO:230 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91% relative to SEQ ID NO:230, of each amino acid modification shown in SEQ ID NO: 230 showing 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity and compared to human IgG1 The immunomodulatory protein of any of the inventions 1084, 1085 and 1087-1090, comprising an amino acid sequence comprising one or more.
[Invention 1092]
The immunomodulatory protein of any of the invention 1084, 1085 and 1087-1091, wherein said Fc domain is or comprises the amino acid sequence shown in SEQ ID NO:230.
[Invention 1093]
An immunomodulatory protein comprising a first polypeptide and a second polypeptide,
The first polypeptide comprises at least one IgSF domain linked to the first Fc domain via a linker, wherein the at least one IgSF domain comprises one or both of: Invention 1001- A variant CD86 polypeptide of any of 1046, or an IgSF domain of a PD1 polypeptide or variant thereof; and
Said second polypeptide comprises at least one IgSF linked via a linker to a second Fc domain, said at least one IgSF domain comprising one or both of: Invention 1001-1046 or an IgSF domain of a PD1 polypeptide or variant thereof,
said immunomodulatory protein comprises at least one IgSF domain of CD86 and at least one IgSF domain of PD-1 or variants thereof;
immunomodulatory protein.
[Invention 1094]
The immunomodulatory protein of invention 1093, wherein at least one IgSF domain of said first polypeptide comprises a variant CD86 polypeptide of any of inventions 1001-1046.
[Invention 1095]
The immunomodulatory protein of invention 1093 or invention 1094, wherein at least one IgSF domain of said second polypeptide comprises a variant PD1 polypeptide.
[Invention 1096]
at least one IgSF domain of said first polypeptide is a first IgSF domain, said first IgSF domain is a variant CD86 polypeptide of any of inventions 1001-1046, said first polypeptide The immunomodulatory protein of any of inventions 1093-1095, wherein the peptide comprises a second IgSF domain linked via a linker to said first Fc domain.
[Invention 1097]
The immunomodulatory protein of invention 1096, wherein the second IgSF domain of said first polypeptide comprises a variant PD1 polypeptide.
[Invention 1098]
at least one IgSF domain of said second polypeptide is a first IgSF domain, said first IgSF domain is a variant CD86 polypeptide of any of inventions 1001-1046, said second polypeptide The immunomodulatory protein of any of inventions 1093-1097, wherein the peptide comprises a second IgSF domain linked via a linker to said second Fc domain.
[Invention 1099]
1098. The immunomodulatory protein of invention 1098, wherein the second IgSF domain of said second polypeptide comprises a variant PD1 polypeptide.
[Invention 1100]
at least one IgSF domain of said first polypeptide is linked via a linker to the N-terminus or C-terminus of said first Fc domain; and
at least one IgSF domain of said second polypeptide is linked via a linker to the N-terminus or C-terminus of said second Fc domain;
An immunomodulatory protein of any of the inventions 1093-1099.
[Invention 1101]
the invention 1096-, wherein the second IgSF domain of said first polypeptide is linked to the end of said first Fc domain opposite to the end linked to said first IgSF domain 1097 any immunomodulatory protein.
[Invention 1102]
the invention 1098-, wherein the second IgSF domain of said second polypeptide is linked to the end of said second Fc domain opposite to the end linked to said first IgSF domain 1101 any immunomodulatory protein.
[Invention 1103]
of the invention 1093-1102, wherein said linker independently comprises the sequence of SEQ ID NO: 222 or 224, optionally said linker comprises 1-4 repeats of the sequence of SEQ ID NO: 222 or 224 Any immunomodulatory protein.
[Invention 1104]
1093- of the invention, wherein said first Fc domain and said second Fc domain are identical, optionally said first Fc domain and said second Fc domain comprise the sequence of SEQ ID NO:230 1103 any immunomodulatory protein.
[Invention 1105]
The immunization of any of inventions 1093-1104, wherein said first polypeptide and said second polypeptide dimerize through said first and said second Fc domains to form homodimers regulatory protein.
[Invention 1106]
Any of invention 1093-1104 and 1105, wherein said homodimeric first and second polypeptides comprise, from left to right, variant PD1 polypeptide-linker-Fc-linker-variant CD86 polypeptide immunomodulatory protein.
[Invention 1107]
The immunomodulatory protein of any of the invention 1093-1104 and 1105-1106, wherein said variant PD1 polypeptide comprises the sequence of SEQ ID NO:315.
[Invention 1108]
The immunomodulatory protein of any of the invention 1093-1104 and 1105-1107, wherein said variant CD86 polypeptide comprises the sequence of SEQ ID NO:94 or 150.
[Invention 1109]
The immunomodulatory protein of any of the invention 1093-1104 and 1105-1108, wherein said homodimeric first and second polypeptides comprise the sequence of SEQ ID NO: 348 or 349, respectively.
[Invention 1110]
said first Fc domain and said second Fc domain are different, optionally said first and second Fc domains comprise a knob-into-hole mutation, optionally said wherein the first Fc domain or said second Fc domain comprises the sequence of SEQ ID NO:346 and the other of said first Fc domain or said second Fc domain comprises the sequence of SEQ ID NO:347 The immunomodulatory protein of any of the inventions 1093-1103, comprising:
[Invention 1111]
any of the inventions 1093-1103 and 1110, wherein said first polypeptide and said second polypeptide dimerize through said first and second Fc domains to form a heterodimer immunomodulatory protein.
[Invention 1112]
said heterodimeric first polypeptide comprises, from left to right, variant PD1 polypeptide-linker-Fc, and said heterodimeric second polypeptide, from left to right, comprises variant CD86 The immunomodulatory protein of any of inventions 1093-1103, 1110, and 1111, comprising a polypeptide-linker-Fc, Fc-linker-variant CD86 polypeptide, or variant PD1-linker-Fc-linker-variant CD86.
[Invention 1113]
The immunomodulatory protein of any of the invention 1093-1103, 1110, and 1111-1112, wherein said variant PD1 polypeptide comprises the sequence of SEQ ID NO:315.
[Invention 1114]
The immunomodulatory protein of any of the invention 1093-1103, 1110, and 1111-1113, wherein said variant CD86 polypeptide comprises the sequence of SEQ ID NO:94 or 150.
[Invention 1115]
said heterodimeric first polypeptide comprises the sequence of SEQ ID NO: 350; and
said heterodimeric second polypeptide comprises the sequence of SEQ ID NO: 351, 352, or 353;
The immunomodulatory protein of any of the inventions 1093-1103, 1110, and 1111-1114.
[Invention 1116]
A conjugate comprising a variant CD86 polypeptide of any of the inventions 1001-1065 linked to a targeting moiety that specifically binds to a molecule on the surface of a cell.
[Invention 1117]
The conjugate of invention 1116, wherein said cells are immune cells or tumor cells.
[Invention 1118]
The conjugate of invention 1116 or invention 1117, wherein said moiety is a protein, peptide, nucleic acid, small molecule or nanoparticle.
[Invention 1119]
The conjugate of any of Inventions 1116-1118, wherein said portion is an antibody or antigen-binding fragment.
[Invention 1120]
The conjugate of invention 1119 , wherein said variant CD86 polypeptide is linked to the N-terminus or C-terminus of the VH or VL of the antibody.
[Invention 1121]
The conjugate of the invention 1119, wherein said antibody is an anti-HER2 antibody or an anti-EGFR antibody.
[Invention 1122]
The conjugate of Invention 1121, wherein said anti-HER2 antibody is pertuzumab.
[Invention 1123]
Said variant CD86 polypeptide is linked to the N-terminus of the pertuzumab V H , the C-terminus of the pertuzumab V H , the N-terminus of the pertuzumab V L , or the C-terminus of the pertuzumab V L , and optionally SEQ ID NO: A conjugate of invention 1122 comprising the sequence of ID NO: 342, 344, 343, or 345.
[Invention 1124]
The conjugate of invention 1121, wherein said anti-EGFR antibody is panitumumab.
[Invention 1125]
The variant CD86 polypeptide is linked to the N-terminus of the panitumumab V H , the C-terminus of the panitumumab V H , the N-terminus of the panitumumab V L , or the C-terminus of the panitumumab V L , and optionally each comprising a SEQ A conjugate of the invention 1124 comprising the sequence of ID NO: 348, 350, 349, or 351. Or an anti-EGFR antibody.
[Invention 1126]
The conjugate of any of inventions 1116-1125 that is a fusion protein.
[Invention 1127]
A nucleic acid molecule that encodes a conjugate that is a variant CD86 polypeptide of any of inventions 1001-1065, an immunomodulatory protein of any of inventions 1066-1115, or a fusion protein of any of inventions 1116-1126.
[Invention 1128]
A vector comprising a nucleic acid molecule of the invention 1127.
[Invention 1129]
A cell containing the vector of the 1128 of the present invention.
[Invention 1130]
A method of producing a protein comprising a variant CD86 polypeptide, the method comprising introducing a nucleic acid molecule of invention 1127 or a vector of invention 1128 into a host cell under conditions for expression of the protein in the host cell. .
[Invention 1131]
The method of invention 1130, further comprising isolating or purifying said protein from said cell.
[Invention 1132]
A method of modifying a cell that expresses a variant CD86 polypeptide comprising the variant CD86 polypeptide of any of inventions 1001-1065, the immunomodulatory protein of any of inventions 1066-1115, or the immunomodulatory protein of any of inventions 1116-1126. A method comprising introducing a nucleic acid molecule encoding any fusion protein conjugate into a host cell under conditions in which the polypeptide is expressed in the host cell.
[Invention 1133]
A conjugate that is a variant CD86 polypeptide of any of inventions 1001-1065, an immunomodulatory protein of any of inventions 1066-1115, or a fusion protein of any of inventions 1116-1126, a nucleic acid molecule of invention 1127 , or a modified cell containing the vector of the invention 1128.
[Invention 1134]
said variant CD86 polypeptide comprises a transmembrane domain or is a transmembrane immunomodulatory protein of any of the inventions 1059-1065; and/or
a protein comprising said variant CD86 polypeptide is expressed on the surface of said cell;
Modified cells of the invention 1133.
[Invention 1135]
said variant CD86 polypeptide does not contain a transmembrane domain and/or is not expressed on the surface of said cell; and/or
said variant CD86 polypeptide is capable of being secreted from said modified cell;
Modified cells of the invention 1133.
[Invention 1136]
The modified cell of any of inventions 1133-1135 that is an immune cell.
[Invention 1137]
The modified cell of invention 1136, wherein said immune cells are lymphocytes, optionally said lymphocytes are T cells.
[Invention 1138]
A modified cell of any of the inventions 1133-1137 that is a primary cell.
[Invention 1139]
The modified cell of any of inventions 1133-1138, further comprising a chimeric antigen receptor (CAR).
[Invention 1140]
The modified cell of any of inventions 1133-1139, further comprising a modified T cell receptor (TCR).
[Invention 1141]
A conjugate that is a variant CD86 polypeptide of any of inventions 1001-1065, an immunomodulatory protein of any of inventions 1066-1115, or a fusion protein of any of inventions 1116-1126, a nucleic acid molecule of invention 1127 , or an infectious agent comprising the vector of the invention 1128.
[Invention 1142]
Infectious agents of the invention 1141, which are bacteria or viruses.
[Invention 1143]
The infectious agent of Invention 1142, wherein said infectious agent is a virus, and said virus is an oncolytic virus.
[Invention 1144]
a conjugate that is a variant CD86 polypeptide of any of inventions 1001-1065, an immunomodulatory protein of any of inventions 1066-1115, or a fusion protein of any of inventions 1116-1126, of inventions 1133-1140 A pharmaceutical composition comprising any of the modified cells or infectious agents of any of the inventions 1141-1143.
[Invention 1145]
A pharmaceutical composition of the invention 1144 comprising a pharmaceutically acceptable excipient.
[Invention 1146]
An article of manufacture comprising a pharmaceutical composition of any of the inventions 1144-1145 in a vial or container.
[Invention 1147]
A kit comprising a pharmaceutical composition of any of the inventions 1144-1145 or an article of manufacture of the invention 1146 and instructions for use.
[Invention 1148]
A method of modulating an immune response in a subject, comprising a variant CD86 polypeptide of any of inventions 1001-1065, an immunomodulatory protein of any of inventions 1066-1115, or a fusion of any of inventions 1116-1126 administering a conjugate that is a protein, a modified cell of any of inventions 1133-1140, an infectious agent of any of inventions 1141-1143, or a pharmaceutical composition of any of inventions 1144-1145 A method comprising steps.
[Invention 1149]
A method of modulating an immune response in a subject comprising administering a modified cell of any of the inventions 1133-1140.
[Invention 1150]
1149. The method of invention 1149, wherein said modified cell is autologous to said subject.
[Invention 1151]
1149. The method of the invention 1149, wherein said modified cell is allogeneic to said subject.
[Invention 1152]
The method of any of inventions 1148-1151, wherein modulating said immune response treats a disease or condition in said subject.
[Invention 1153]
A method of treating a disease or condition in a subject in need thereof comprising: a variant CD86 polypeptide of any of inventions 1001-1065; an immunomodulatory protein of any of inventions 1066-1115; or an immunomodulatory protein of any of inventions 1116-1126 modified cells of any of inventions 1133-1140; infectious agents of any of inventions 1141-1143; or pharmaceutical agents of any of inventions 1144-1145. A method comprising administering a composition.
[Invention 1154]
A method of treating a disease or condition in a subject in need thereof comprising administering a modified cell of any of the inventions 1133-1140.
[Invention 1155]
1154. The method of invention 1154, wherein said modified cell is autologous to said subject.
[Invention 1156]
The method of invention 1154, wherein said modified cell is allogeneic to said subject.
[Invention 1157]
The method of any of inventions 1148-1156, wherein an immune response is enhanced in said subject.
[Invention 1158]
The method of any of inventions 1148, 1152, 1153 and 1157, wherein an immunomodulatory protein or conjugate comprising a variant CD86 polypeptide linked to a tumor-localizing moiety is administered to said subject.
[Invention 1159]
1158. The method of invention 1158, wherein said tumor localizing moiety is or comprises a binding molecule that recognizes a tumor antigen.
[Invention 1160]
said binding molecule comprises an antibody or antigen-binding fragment thereof or a wild-type IgSF domain or variant thereof, optionally comprising an anti-HER2 antibody or antigen-binding fragment or an anti-EGFR antibody or antigen-binding fragment; or
said binding molecule comprises an IgSF domain of an IgSF member that binds to a tumor antigen or a specific binding fragment thereof, optionally said IgSF domain is the IgSF domain of PD-1 or Nkp30;
The method of the invention 1159.
[Invention 1161]
The method of any of inventions 1148 and 1152-1160, wherein a pharmaceutical composition comprising an immunomodulatory protein of any of inventions 1071-1115 or a conjugate of any of inventions 1116-1126 is administered to said subject. .
[Invention 1162]
modified cells comprising a variant CD86 polypeptide that is a transmembrane immunomodulatory protein are administered to said subject, optionally said modified cells are those of inventions 1133, 1134 and 1136-1140. The method of any of Inventions 1148-1160.
[Invention 1163]
The method of any of Inventions 1152-1162, wherein said disease or condition is a tumor or cancer.
[Invention 1164]
The disease or condition is melanoma, lung cancer, bladder cancer, hematological malignancy, liver cancer, brain cancer, kidney cancer, breast cancer, pancreatic cancer, colon cancer, spleen cancer, prostate cancer, testis Invention 1152-1163 selected from cancer, ovarian cancer, uterine cancer, gastric cancer, musculoskeletal cancer, head and neck cancer, gastrointestinal cancer, germ cell cancer, or endocrine and neuroendocrine cancer Either method.
[Invention 1165]
The method of any of inventions 1148-1156, wherein the immune response is reduced.
[Invention 1166]
The method of any of inventions 1148, 1152, 1153 and 1165, wherein a variant CD86 polypeptide or immunomodulatory protein that is soluble is administered to said subject.
[Invention 1167]
1166. The method of invention 1166, wherein said soluble polypeptide or immunomodulatory protein is an Fc fusion protein.
[Invention 1168]
inventions 1148, 1152, wherein a pharmaceutical composition comprising a variant CD86 polypeptide of any of inventions 1001-1058 or an immunomodulatory protein of any of inventions 1066-1074 and 1078-1115 is administered to said subject , 1153 and 1165-1167.
[Invention 1169]
the invention 1148, 1152, wherein modified cells comprising a secretable variant CD86 polypeptide are administered to the subject, optionally wherein the modified cells are of any of the inventions 1133 and 1135-1140; Either 1153 and 1165 methods.
[Invention 1170]
The method of any of the inventions 1148, 1152, 1153 and 1165-1169, wherein said disease or condition is an inflammatory or autoimmune disease or condition.
[Invention 1171]
said disease or condition is antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, vasculitis, autoimmune skin disease, transplantation, rheumatic disease, inflammatory gastrointestinal disease, inflammatory eye disease, inflammatory The method of any of inventions 1148, 1152, 1153 and 1165-1169, which is a neurological disease, an inflammatory lung disease, an inflammatory endocrine disease, or an autoimmune hematologic disease.
[Invention 1172]
The method of Invention 1170 or Invention 1171, wherein said disease or condition is selected from inflammatory bowel disease, transplant, Crohn's disease, ulcerative colitis, multiple sclerosis, asthma, rheumatoid arthritis, or psoriasis. .
Claims (43)
（i）SEQ ID NO：29に示されるアミノ酸配列、（ii）SEQ ID NO：29に対して少なくとも95％の配列同一性を有するアミノ酸配列；または（iii）前記（i）または（ii）の配列の一部分であって、IgVドメインもしくはIgVドメインの特異的結合断片を含む、部分
を含む、請求項1記載のバリアントCD86ポリペプチド。 wherein said unmodified CD86 polypeptide is
(i) the amino acid sequence set forth in SEQ ID NO:29, (ii) an amino acid sequence having at least 95% sequence identity to SEQ ID NO:29; or (iii) of (i) or (ii) above. 2. The variant CD86 polypeptide of claim 1, comprising a portion of the sequence , the portion comprising an IgV domain or a specific binding fragment of an IgV domain.
SEQ ID NO：29に対して少なくとも85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、もしくは99％の配列同一性を示すアミノ酸配列を含むバリアントCD86ポリペプチドまたはその特異的結合断片を含むバリアントCD86ポリペプチドである、
請求項1～3のいずれか一項記載のバリアントCD86ポリペプチド。 up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 of said variant CD86 polypeptides a variant CD86 polypeptide containing amino acid alterations, optionally amino acid substitutions, insertions, and/or deletions; or
At least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% against SEQ ID NO:29 or a variant CD86 polypeptide comprising an amino acid sequence exhibiting 99% sequence identity or a variant CD86 polypeptide comprising a specific binding fragment thereof;
A variant CD86 polypeptide according to any one of claims 1-3 .
A13V, Q18K, Q25L, S28G, F33I, E38V, N39D, L40M, L40S, N43K, V45I, F52L, D53G, M60K, D68N, T71A, L77P, I79N, K80E, K80M, K80R, K82T, Q86K, Q86R, I88F, I88T, I89V, H90 L, H90Y, K92I, K93T, M97L, Q102H, N104S,F113S, S114G, N123D, V128A, Y129N, L132M, T133A, I137T, P141A, P143H, K144E, V148D, K153E, K153R, N154D, E158G, V170D, E172G, D175E, I178T, L180S, S181P, S183P, P185S, T192N, I193V, I196V, L197M, E198D, L205S, S206T, S207P, E212V, D215V, P216H, H222T もしくは I223F
から選択される1つもしくは複数のアミノ酸置換、またはその保存的アミノ酸置換である、請求項1～4のいずれか一項記載のバリアントCD86ポリペプチド。 The one or more amino acid modifications are
A13V, Q18K, Q25L, S28G, F33I, E38V, N39D, L40M, L40S, N43K, V45I, F52L, D53G, M60K, D68N, T71A, L77P, I79N, K80E, K80M, K80R, K82T, Q86K, Q86R, I88F, I88T, I89V, H90 L, H90Y, K92I, K93T, M97L, Q102H, N104S, F113S, S114G, N123D, V128A, Y129N, L132M, T133A, I137T, P141A, P143H, K144E, V148D, K154R, E154R, K153E, K153E , V170D, E172G, D175E, I178T, L180S, S181P, S183P, P185S, T192N, I193V, I196V, L197M, E198D, L205S, S206T, S207P, E212V, D215V, P216H, H222T or I223
5. The variant CD86 polypeptide of any one of claims 1-4 , wherein one or more amino acid substitutions are selected from, or conservative amino acid substitutions thereof.
の中から選択される1つまたは複数のアミノ酸改変を含む、請求項1～5のいずれか一項記載のバリアントCD86ポリペプチド。 Q25L/T71A/H90Y, Q25L/D53G/E212V, Q25L/H90L, Q25L/H90Y, N43K/I79N/H90L/I178T/E198D, A13V/Q25L/H90L/S181P/L197M/S206T, Q25L/Q86R/H93T/L/K L132M/V148D/S181P/P216H, Q25L/F33I/H90Y/V128A/P141A/E158G/S181P, Q25L/N39D/K80R/Q86R/I88F/H90L/K93T/N123D/N154D, Q25L/H90L/K93L/T17T/M93T S181P/D215V, Q25L/Q86R/H90L/N104S, Q25L/L40M/H90L/L180S/S183P, Q18K/Q25L/F33I/L40S/H90L, Q25L/Q86K/H90L/I137T/S181P, Q25L/L77P/H90Y/ V170D/S181P, Q25L/S28G/F33I/F52L/H90L/Q102H/I178T, Q25L/F33I/H90L/K144E/ L180S, Q25L/F33I/H90L/K153E/E172G/T192N, Q25L/F33I/Q86R/H790 I196V/E198D, Q25L/V45I/D68N/H90L/S183P/L205S, E38V/S114G/P143H, H90Y/L180S, H90Y/Y129N, I89V/H90L/I193V, K80E/H90Y/H222T/I223F/P223F/P224L, K80M/I8T, I8T K92I/F113S, M60K/H90L, Q25L/F33I/H90L, Q25L/F33I/Q86R/H90L/K93T, Q25L/H90L, Q25L/H90L/P185S, Q25L/H90L/P185S/P224L, Q25L/H90L/S15L/R, Q2 H90Y/S181P/I193V, Q25L/K82T/H90L/T152S/S207P, Q25L/Q86R/H90L/K93T , A13V/Q25L/H90L, Q25L/H90L/K93T/M97L, Q25L/Q86R/H90L, I89V/H90G/L or S28 H90Y
6. The variant CD86 polypeptide of any one of claims 1-5 , comprising one or more amino acid alterations selected from:
CD86膜貫通ドメインおよび細胞内シグナル伝達ドメインを欠いており；かつ/または
細胞の表面上に発現することができない、
請求項1～10のいずれか一項記載のバリアントCD86ポリペプチド。 is a soluble protein;
lacks the CD86 transmembrane domain and intracellular signaling domain; and/or is unable to be expressed on the surface of the cell,
A variant CD86 polypeptide according to any one of claims 1-10 .
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- 2019-11-27 KR KR1020217020465A patent/KR20210135987A/en unknown
- 2019-11-27 AU AU2019389151A patent/AU2019389151A1/en active Pending
- 2019-11-27 US US17/298,506 patent/US20220372106A1/en active Pending
- 2019-11-27 CA CA3120868A patent/CA3120868A1/en active Pending
- 2019-11-27 JP JP2021530877A patent/JP2022510276A/en active Pending
- 2019-11-27 CN CN201980090516.0A patent/CN113727998A/en active Pending
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