JP2017531028A - 免疫学的試薬 - Google Patents
免疫学的試薬 Download PDFInfo
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- JP2017531028A JP2017531028A JP2017526774A JP2017526774A JP2017531028A JP 2017531028 A JP2017531028 A JP 2017531028A JP 2017526774 A JP2017526774 A JP 2017526774A JP 2017526774 A JP2017526774 A JP 2017526774A JP 2017531028 A JP2017531028 A JP 2017531028A
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Abstract
Description
122F10(配列番号1、24、47、70、93および116);
139D6(配列番号2、25、48、71、94および117);
135D1(配列番号3、26、49、72、95および118);
134D2(配列番号4、27、50、73、96および119);
121G1(配列番号5、28、51、74、97および120);
136B5(配列番号6、29、52、75、98および121);
127C2(配列番号7、30、53、76、99および122);
137F2(配列番号8、31、54、77、100および123);
138H5(配列番号9、32、55、78、101および124);
140A1(配列番号10、33、56、79、102および125);
135H12(配列番号11、34、57、80、103および126);
131D11(配列番号12、35、58、81、104および127);
132F7(配列番号13、36、59、82、105および128);
126E4(配列番号14、37、60、83、106および129);
135G1(配列番号15、38、61、84、107および130);
136E10(配列番号16、39、62、85、108および131);
135C12(配列番号17、40、63、86、109および132);
136F4(配列番号18、41、64、87、110および133);
136B4(配列番号19、42、65、88、111および134);
135E10(配列番号20、43、66、89、112および135);
140G5(配列番号21、44、67、90、113および136);
122H2(配列番号22、45、68、91、114および137);または
139F11(配列番号23、46、69、92、115および138)
当業者が確認できるように、その他の組合せも有用となり得る。
PD−1結合剤の生成および特性解析
4種のマウス系統(マウス計16匹)を、2種のPD−1タンパク質、すなわちヒトPD−1 Fc融合タンパク質およびヒトPD−1モノマータンパク質で免疫した。活性化ヒトTリンパ球上に発現されたPD−1に対して血清反応性を示すマウスを、抗PD−1ハイブリドーマ細胞株を作成するために選択した。組換えPD−1タンパク質に結合する抗体を作成するために、計240のPD−1ハイブリドーマ細胞株を選択した。第1ラウンドの抗体選択のための一次基準は:i)フローサイトメトリーによる活性化ヒトTリンパ球上のPD−1の染色;ii)既存の抗PD−1抗体と比較したCDR VHおよびVL配列の多様性;および(iii)PD−1共役LuminexビーズとPD−1上の様々なエピトープに結合する2種の市販の抗PD−1抗体との競合結合試験によって実施されるエピトープマッピングであった。第2ラウンドの選択は、次に:iv)親和性結合アッセイ(抗PD−1抗体の刺激能力とは相関しないので一次基準ではない);v)PD−1に結合し、かつLuminex生化学的アッセイにおいてPD−L1の結合と競合的、部分競合的または非競合的のいずれかである抗PD−1抗体の評価;およびvi)アゴニスト(T細胞を機能的疲弊から回復させられない)またはアンタゴニスト(T細胞を機能的疲弊から回復させられる)としての抗体の機能的特性解析;によって実施した。これらの試験では、抗体がHIV特異的疲弊CD8 T細胞における増殖を救済する能力に基づき、抗体を試験および識別した。
抗体の組合せ
様々なPD−1エピトープに結合する抗体の組合せが、機能的疲弊回復アッセイにおいて、HIVペプチド特異的CD8 T細胞増殖の回復を増強することが見いだされた(図8)。抗体タイプ間の相乗作用も観察された。例えば、クラス1(図8におけるMK−3475)およびクラス2(図8における139D6)の抗体が同時にPD−1に結合できることが特定された。MK−3475について観察された最高の刺激は、HIVペプチドに対して一貫して約200%であるが、5μg/mlでのMK−3475および139D6モノクローナル抗体の組合せは、HIVペプチドコントロール単独に対してHIV特異的CD8 T細胞増殖の288%の増加、またはMK−3475もしくは139D6添加単独に対して144%の増殖増加をもたらし、相乗作用を示した(図8)。増殖におけるこの相乗的増加は、数回の実験による試験において0.007の統計的有意なp値をもって観察された。比較として、MK−3475または139D6いずれか単独の10μg/mlの添加は、EFRAにおける増殖増加を生じさせなかった。そこで、PD−1とPD−L1との相互作用を遮断する第1結合剤およびPD−1とPD−L1との相互作用を遮断しない第2結合剤のような、結合剤の組合せは、T細胞を疲弊から救済するために相乗的に作用すると決定された。
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Claims (54)
- 配列番号1〜138からなる群より選択される少なくとも1つのアミノ酸配列、および/または表1Aおよび/または1Bに示される少なくとも1つのアミノ酸配列を含む、プログラム細胞死1(PD1)に結合する結合剤。
- 単離モノクローナル抗体である、請求項1記載の結合剤。
- 配列番号1〜23からなる群より選択される少なくとも1つの重鎖CDR1アミノ酸配列を含む、請求項1または2記載の結合剤。
- 配列番号24〜46からなる群より選択される少なくとも1つの重鎖CDR2アミノ酸配列を含む、請求項1〜3いずれか1項記載の結合剤。
- 配列番号47〜69からなる群より選択される少なくとも1つの重鎖CDR3アミノ酸配列を含む、請求項1〜4いずれか1項記載の結合剤。
- 配列番号70〜92からなる群より選択される少なくとも1つの軽鎖CDR1アミノ酸配列を含む、請求項1〜5いずれか1項記載の結合剤。
- 配列番号93〜115からなる群より選択される少なくとも1つの軽鎖CDR2アミノ酸配列を含む、請求項1〜6いずれか1項記載の結合剤。
- 配列番号116〜138からなる群より選択される少なくとも1つの軽鎖CDR3アミノ酸配列を含む、請求項1〜7いずれか1項記載の結合剤。
-
- 配列番号1、24、47、70、93および116;
配列番号2、25、48、71、94および117;
配列番号3、26、49、72、95および118;
配列番号4、27、50、73、96および119;
配列番号5、28、51、74、97および120;
配列番号6、29、52、75、98および121;
配列番号7、30、53、76、99および122;
配列番号8、31、54、77、100および123;
配列番号9、32、55、78、101および124;
配列番号10、33、56、79、102および125;
配列番号11、34、57、80、103および126;
配列番号12、35、58、81、104および127;
配列番号13、36、59、82、105および128;
配列番号14、37、60、83、106および129;
配列番号15、38、61、84、107および130;
配列番号16、39、62、85、108および131;
配列番号17、40、63、86、109および132;
配列番号18、41、64、87、110および133;
配列番号19、42、65、88、111および134;
配列番号20、43、66、89、112および135;
配列番号21、44、67、90、113および136;
配列番号22、45、68、91、114および137;および
配列番号23、46、69、92、115および138
からなる群より選択されるアミノ酸配列の組合せを含む、請求項9記載の結合剤。 - ヒト抗体、ヒトIgG、ヒトIgG1、ヒトIgG2、ヒトIgG2a、ヒトIgG2b、ヒトIgG3、ヒトIgG4、ヒトIgM、ヒトIgA、ヒトIgA1、ヒトIgA2、ヒトIgD、ヒトIgE、イヌ抗体、イヌIgGA、イヌIgGB、イヌIgGC、イヌIgGD、ニワトリ抗体、ニワトリIgA、ニワトリIgD、ニワトリIgE、ニワトリIgG、ニワトリIgM、ニワトリIgY、ヤギ抗体、ヤギIgG、マウス抗体、マウスIgG、ブタ抗体またはラット抗体に由来する、請求項1〜10いずれか1項記載の結合剤。
- 請求項1〜11いずれか1項記載の結合剤の誘導体。
- Fab、Fab2、Fab’一本鎖抗体、Fv,一本鎖、単一特異性抗体、二重特異性抗体、三量体抗体、多重特異性抗体、多価抗体、キメラ抗体、イヌ−ヒトキメラ抗体、イヌ−マウスキメラ抗体、イヌFcを含む抗体、ヒト化抗体、ヒト抗体、イヌ化抗体、CDRグラフト化抗体、サメ抗体、ナノボディおよびラクダ抗体からなる群より選択される、請求項12記載の誘導体。
- 少なくとも第1および第2の特異性を有し、前記第1の特異性はPD−1に対するものであり、および前記第2の特異性は異なる抗原に対するものである、請求項1〜13いずれか1項記載の結合剤もしくは誘導体または請求項38〜40いずれか1項記載の組合せ。
- 前記第2の特異性は、感染性因子の抗原または腫瘍抗原に対するものである、請求項14記載の結合剤または誘導体。
- 前記感染性因子はヒト免疫不全ウイルス(HIV)である、請求項15記載の結合剤または誘導体。
- 前記抗原はHIV envである、請求項16記載の結合剤または誘導体。
- 固定的に付着した検出可能な標識を含む、請求項1〜17いずれか1項記載の結合剤またはその誘導体。
- 前記検出可能な標識は、フルオロセイン、DyLight、Cy3、Cy5、FITC、HiLyte Fluor 555、HiLyte Fluor 647、5−カルボキシ−2,7−ジクロロフルオレセイン、5−カルボキシフルオレセイン、5−FAM、ヒドロキシトリプタミン、5−ヒドロキシトリプタミン(5−HAT)、6−カルボキシフルオレセイン(6−FAM)、FITC、6−カルボキシ−1,4−ジクロロ−2’,7’−ジクロロフルオレセイン(TET)、6−カルボキシ−1,4−ジクロロ−2’,4’、5’,7’−テトラクロロフルオレセイン(HEX)、6−カルボキシ−4’,5’−ジクロロ−2’,7’−ジメトキシフルオレセイン(6−JOE)、Alexa fluor、Alexa fluor 350、Alexa fluor 405、Alexa fluor 430、Alexa fluor 488、Alexa fluor 500、Alexa fluor 514、Alexa fluor 532、Alexa fluor 546、Alexa fluor 555、Alexa fluor 568、Alexa fluor 594、Alexa fluor 610、Alexa fluor 633、Alexa fluor 635、Alexa fluor 647、Alexa fluor 660、Alexa fluor 680、Alexa fluor 700、Alexa fluor 750、BODIPY蛍光体、BODIPY 492/515、BODIPY 493/503、BODIPY 500/510、BODIPY 505/515、BODIPY 530/550、BODIPY 542/563、BODIPY 558/568、BODIPY 564/570、BODIPY 576/589、BODIPY 581/591、BODIPY 630/650−X、BODIPY 650/665−X、BODIPY 665/676、FL、FL ATP、FI−セラミド、R6G SE、TMR、TMR−X複合体、TMR−X、SE、TR、TR ATP、TR−X SE、ローダミン、ローダミン110、ローダミン123、ローダミンB、ローダミンB 200、ローダミンBB、ローダミンBG、ローダミンB extra、5−カルボキシテトラメチルローダミン(5−TAMRA)、5 GLD、6−カルボキシローダミン6G、リサミン、リサミンローダミンB、ファリシジン、ファロイジン、ローダミンレッド、Rhod−2、6−カルボキシ−X−ローダミン(ROX)、カルボキシ−X−ローダミン(5−ROX)、スルホローダミンB can C、スルホローダミンG Extra、6−カルボキシテトラメチルローダミン(TAMRA)、テトラメチルローダミン(TRITC)、ローダミンWT、テキサスレッドおよびテキサスレッド−Xからなる群より選択される、請求項18記載の結合剤。
- 固定的に付着したエフェクター部分を含む、請求項1〜19いずれか1項記載の結合剤またはその誘導体。
- 前記エフェクター部分は、細胞傷害性薬、毒素、ジフテリアA鎖、外毒素A鎖、リシンA鎖、アブリンA鎖、クルシン、クロチン、フェノマイシン、エノマイシンおよび放射化学薬品からなる群より選択される、請求項20記載の結合剤または誘導体。
- 請求項1〜17いずれか1項記載の結合剤をコードする単離ポリヌクレオチド。
- 請求項22記載の1つ以上のポリヌクレオチドを含む発現ベクター。
- 請求項22記載の単離ポリヌクレオチドおよび/または請求項23記載の発現ベクターを含む、宿主細胞。
- 請求項1〜21いずれか1項記載の少なくとも1つの結合剤もしくは誘導体;請求項22記載の少なくとも1つの単離ポリヌクレオチド;請求項23記載の少なくとも1つの発現ベクター;および/または請求項24記載の少なくとも1つの宿主細胞;またはそれらの組合せ;および/または請求項39〜43いずれか1項記載の組合せ;ならびに医薬上許容される担体を含む、組成物。
- 細胞上のPD−1を検出する方法において、
試験生物学的サンプルを、請求項1〜21いずれか1項記載の結合剤もしくは誘導体および/または請求項39〜43いずれか1項記載の組合せと接触させる工程、および
前記生物学的サンプルもしくはその成分に結合した前記結合剤を検出する工程、を含む、方法。 - 前記試験生物学的サンプルもしくはその成分に結合する量を、コントロール生物学的サンプルもしくはその成分に結合する量と比較する工程をさらに含み、前記コントロール生物学的サンプルもしくはその成分に結合する量と比較して、増加した試験生物学的サンプルもしくはその成分に結合する量は、試験生物学的サンプルにおけるPD−1を発現する細胞の存在を示す、請求項26記載の方法。
- 前記試験生物学的サンプルは哺乳動物血液である、請求項26または27記載の方法。
- 前記方法はin vivo法である、請求項26〜28いずれか1項記載の方法。
- 前記方法はin vitro法である、請求項26〜28いずれか1項記載の方法。
- 哺乳動物における感染性疾患、癌および/または自己免疫状態を治療、予防および/または改善する方法において、前記哺乳動物に、請求項1〜21いずれか1項記載の結合剤もしくはその誘導体、および/または請求項39〜43いずれか1項記載の組合せを含む、少なくとも1つの有効量の医薬組成物を投与する工程を含む、方法。
- 前記感染性疾患はヒト免疫不全ウイルス(HIV)である、請求項31記載の方法。
- 感染性疾患、HIVおよび/または癌を治療するために使用される前記結合剤および/またはその誘導体は、PD−1アンタゴニストである、請求項31または32記載の方法。
- 自己免疫状態を治療するために使用される前記結合剤および/またはその誘導体は、PD−1アゴニストである、請求項31記載の方法。
- 前記動物に複数回投与される、請求項31〜34いずれか1項記載の方法。
- 前記結合剤は、約1〜50mg/kgの投与量で投与される、請求項31〜35いずれか1項記載の方法。
- 細胞内または細胞上でのPD−1の発現を検出するためのキットにおいて、請求項1〜21いずれか1項記載の結合剤もしくはその誘導体または組合せ、ならびに使用説明書を含む、キット。
- 前記結合剤、抗体または誘導体は、凍結乾燥形態にある、請求項37記載のキット。
- PD−1とPD−L1との相互作用を遮断する第1結合剤、およびPD−1とPD−L1との相互作用を遮断しない第2結合剤を含む、結合剤の組合せ。
- 前記第2結合剤はPD−1に結合する、請求項39記載の組合せ。
- 前記第1および/または第2結合剤は抗体である、請求項39記載の組合せ。
- 前記結合剤はモノクローナル抗体である、請求項40記載の組合せ。
- 前記第2結合剤は、配列番号2、25、48、71、94および117のアミノ酸配列、または配列番号17、40、63、86、109および132のアミノ酸配列を含む、請求項39記載の組合せ。
- PD−1とPD−L1との相互作用を遮断する第1結合剤、およびPD−1とPD−L1との相互作用を遮断しない第2結合剤を組み合わせる工程を含む、請求項39〜43いずれか1項記載の組合せを製造する方法。
- 前記第2結合剤はPD−1に結合する、請求項44記載の方法。
- 前記第1および/または第2結合剤は抗体である、請求項44記載の方法。
- 前記結合剤はモノクローナル抗体である、請求項44記載の方法。
- 前記第2結合剤は、配列番号2、25、48、71、94および117のアミノ酸配列、または配列番号17、40、63、86、109および132のアミノ酸配列を含む、請求項44記載の方法。
- 医薬上許容される賦形剤の添加をさらに含む、請求項44〜48いずれか1項記載の方法。
- 免疫細胞を請求項39〜43いずれか1項記載の組合せと接触させることにより、抗原の存在下で免疫細胞の増殖を誘導する方法。
- PD−1抗体結合剤を同定する方法において、
a)疲弊機能回復アッセイ(EFRA)により候補PD−1結合剤をアッセイする工程;
b)PD−1に対する前記候補結合剤の親和性を決定する工程;および
c)前記候補結合剤の相補性決定領域(CDR)のヌクレオチド配列を決定する工程;を含む、方法。 - 請求項1〜11いずれか1項記載の結合剤を製造する方法において、
細胞において前記結合剤を発現させる工程;および
前記細胞または前記細胞の培養上清から前記結合剤を単離する工程;を含む、方法。 - 請求項1〜11いずれか1項記載の結合剤をコードする核酸を宿主細胞において発現させる工程をさらに含む、請求項52記載の方法。
- 単離後、前記結合剤を医薬上許容される賦形剤と組み合わせる工程をさらに含む、請求項52または53記載の方法。
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SG11201700672YA (en) | 2017-02-27 |
WO2016020856A2 (en) | 2016-02-11 |
US9982053B2 (en) | 2018-05-29 |
KR102357893B1 (ko) | 2022-02-04 |
PL3177644T3 (pl) | 2021-06-14 |
CN107074947A (zh) | 2017-08-18 |
CN107074947B (zh) | 2021-04-09 |
CA2957258A1 (en) | 2016-02-11 |
DK3177644T3 (da) | 2021-01-11 |
KR20170069996A (ko) | 2017-06-21 |
EP3177644B1 (en) | 2020-10-07 |
JP6629321B2 (ja) | 2020-01-15 |
US11130807B2 (en) | 2021-09-28 |
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