JP6961625B2 - 抗tnfrsf25抗体 - Google Patents
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- JP6961625B2 JP6961625B2 JP2018563618A JP2018563618A JP6961625B2 JP 6961625 B2 JP6961625 B2 JP 6961625B2 JP 2018563618 A JP2018563618 A JP 2018563618A JP 2018563618 A JP2018563618 A JP 2018563618A JP 6961625 B2 JP6961625 B2 JP 6961625B2
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Description
本出願は2016年6月9日に出願された米国仮特許出願第62/348009号の優先権の利益を主張するものである。
本文書は、抗TNFRSF25抗体、ならびに研究、療法および診断目的でのその使用に関する。
EVQLVESGGGLSQPGNSLQLSCEASGFTFSNHDLNWVRQAPGKGLEWVAYISSASGLISYADAVRGRFTISRDNAKNSLFLQMNNLKSEDTAMYYCARDPPYSGLYALDFWGQGTQVTVSS(配列番号5)、
QPVLTQSPSASASLSGSVKLTCTLSSELSSYTIVWYQQRPDKAPKYVMYLKSDGSHSKGDGIPDRFSGSSSGAHRYLSISNVQSEDDATYFCGAGYTLAGQYGWVFGSGTKVTVL(配列番号6)。
実施例1−エピトープマッピング
いくつかのTNFRSF25発現構築物を調製した。これらは、位置25(Q25)のGlnから位置201(F201)のPheに及ぶ細胞外ドメイン(ECD)全体、またはQ25から位置181(T181)のThrに及ぶ可溶性スプライスバリアントのいずれかを含んでいた。構築物はまた、6His、hFc−6HisおよびmFc−Hisを含む、様々なタグを含んでいた。6つの構築物(表1)を293F細胞にトランスフェクトし、その発現レベルを図2に示すように測定した。
W3153−P8R32−H6抗体の親和性最適化:ハイブリダイゼーション変異誘発法(Kunkel、Proc Natl Acad Sci USA 82(2):488−492、1985)を使用して、親クローンの3つのCDRの各アミノ酸を、全20個のアミノ酸に個々に変異した。20個のアミノ酸をコードするNNSコドンを含有するDNAプライマーを使用して、各標的化されたCDR位置に変異を導入した。個々の縮重プライマーを、ハイブリダイゼーション変異誘発反応に使用した。簡単に言えば、各縮重プライマーをリン酸化し、次いでウリジニル化したssDNAと10:1の比で使用した。混合物を85℃に5分間加熱し、次いで55℃まで1時間かけて冷却した。その後、T4リガーゼおよびT4DNAポリメラーゼを添加し、混合物を37℃で1.5時間インキュベートした。VHおよびVLのCDRの合成生成物を各々プールした。典型的には、BL21細菌叢上でのプラーク形成のため、またはscFvフラグメントの生成のために、プールしたライブラリーDNA 200ngをBL21に電気穿孔した。
重鎖可変領域:EVQLVESGGGLSQPGNSLQLSCEASGFTFSNHDLNWVRQAPGKGLEWVAYISSASGLISYADAVRGRFTISRDNAKNSLFLQMNNLKSEDTAMYYCARDPPYSGLYALDFWGQGTQVTVSS(配列番号5)
FW1:EVQLVESGGGLSQPGNSLQLSCEAS(配列番号11)
CDR1:GFTFSNHDLN(配列番号12)
FW2:WVRQAPGKGLEWVA(配列番号13)
CDR2:YISSASGLISYADAVRG(配列番号14)
FW3:RFTISRDNAKNSLFLQMNNLKSEDTAMYYCAR(配列番号15)
CDR3:DPPYSGLYALDF(配列番号16)
FW4:WGQGTQVTVSS(配列番号17)
軽鎖可変領域:QPVLTQSPSASASLSGSVKLTCTLSSELSSYTIVWYQQRPDKAPKYVMYLKSDGSHSKGDGIPDRFSGSSSGAHRYLSISNVQSEDDATYFCGAGYTLAGQYGWVFGSGTKVTVL(配列番号6)
FW1:QPVLTQSPSASASLSGSVKLTC(配列番号18)
CDR1:TLSSELSSYTIV(配列番号19)
FW2:WYQQRPDKAPKYVMY(配列番号20)
CDR2:LKSDGSHSKGD(配列番号21)
FW3:GIPDRFSGSSSGAHRYLSISNVQSEDDATYF(配列番号22)
CDR3:CGAGYTLAGQYGWV(配列番号23)
FW4:FGSGTKVTVL(配列番号24)
一次スクリーニングでは、野生型よりも少なくとも2倍高い捕獲ELISAシグナルを示す、7つのCDR位置で11個の変異体が産生された(表4)。軽鎖CDR1の位置42での複数の変異は、TNFRSF25−Fcタンパク質への改善された結合を一貫して示した。この位置でのSerのTrpへの置換の結果、ELISAシグナルが10倍超増加した。2つの他の変異、重鎖CDR3の位置27でのAlaのThrへの変異、および軽鎖CDR1の位置43でのTyrのPheへの変異も顕著な結合の改善を示した。これらの変異体を、IgG1に変換し、カスパーゼ−3アッセイを用いて活性について試験した(表5)。位置42の変異体のみが、カスパーゼ−3放出アッセイにおいて改善された有効性を示した。軽鎖CDR1でのSerからTrpへの変異を含有する1つの特定のIgGクローンであるW3072−z4C12−R1−42G2−uIgG1Lは、カスパーゼ−3アゴニスト活性の最大の増加を示した。
1F10→W3072−z4C12−m1(本明細書においてM1とも称される)
5A6→W3072−z4C12−m2(本明細書においてM2とも称される)
9A5→W3072−z4C12−m3(本明細書においてM3とも称される)
9G2→W3072−z4C12−m4(本明細書においてM4とも称される)
42G2→W3072−z4C12−m5(本明細書においてM5とも称される)
本発明を、その詳細な説明と共に記載してきたが、前述の説明は、例示を意図するものであり、添付の特許請求の範囲により定義される本発明の範囲を限定するものではないことが理解される。他の態様、利点および変形は、以下の特許請求の範囲内にある。
Claims (16)
- (i)重鎖CDR1、CDR2およびCDR3配列および配列番号5と95%同一性を有するアミノ酸を含み、前記重鎖CDR1配列がGFTFSNHDLN(配列番号12)であり、前記重鎖CDR2配列がYISSASGLISYADAVRG(配列番号14)であり、前記重鎖CDR3配列がDPAYTGLYALDF(配列番号26)またはDPPYSGLYALDF(配列番号16)である、重鎖可変領域、ならびに
(ii)軽鎖CDR1、CDR2およびCDR3配列および配列番号6と95%同一性を有するアミノ酸を含み、前記軽鎖CDR1配列がTLSSELSWYTIV(配列番号25)であり、前記軽鎖CDR2配列がLKSDGSHSKGD(配列番号21)であり、前記軽鎖CDR3配列がCGAGYTLAGQYGWV(配列番号23)である、軽鎖可変領域
を含む、抗腫瘍壊死因子受容体スーパーファミリーメンバー25抗体。 - ヒト重鎖および軽鎖定常領域を更に含む、請求項1に記載の抗体。
- 前記定常領域が、ヒトIgG1、IgG2、IgG3およびIgG4からなる群から選択される、請求項2に記載の抗体。
- 前記定常領域がIgG1である、請求項3に記載の抗体。
- 前記定常領域がIgG4である、請求項3に記載の抗体。
- 薬学的に許容される担体、および請求項1〜5のいずれか一項に記載の抗体を含む医薬組成物。
- 癌を治療するための請求項6に記載の医薬組成物および少なくとも1つの追加の薬剤を含む製造品。
- 前記少なくとも1つの追加の薬剤が、CTLA−4、PD−1、PD−L1、LAG−3、Tim−3、TNFRSF4、TNFRSF9、TNFRSF18、CD27、CD39、CD47、CD73もしくはCD278を標的とする薬剤であるか、またはA2A受容体アンタゴニストもしくはTGF−βアンタゴニストである、請求項7に記載の製造品。
- 前記少なくとも1つの追加の薬剤が、B7ファミリー共刺激分子、TNF受容体スーパーファミリー共刺激分子、ワクチン組成物または化学療法剤である、請求項7に記載の製造品。
- 前記少なくとも1つの追加の薬剤が、インビトロまたは対象における養子T細胞療法での使用のためのキメラ抗原受容体トランスフェクトT細胞または増殖腫瘍浸潤リンパ球を含む、請求項7に記載の製造品。
- 前記少なくとも1つの追加の薬剤が、自己T細胞療法のインビトロ製造方法において用いられる、請求項7に記載の製造品。
- 対象の癌を治療する方法において使用するための組成物であって、前記方法は、前記対象の癌においてTNFRSF25発現腫瘍細胞のアポトーシスを誘導するのに有効な量の前記組成物を前記対象に投与することを含む、請求項6に記載の組成物。
- 対象の癌を治療する方法において使用するための組成物であって、前記組成物は、前記対象のCD8+T細胞の増殖を刺激し、前記方法は、治療有効量の前記組成物を前記対象に投与することを含む、請求項6に記載の組成物。
- CD8+T細胞の増殖が、抗原特異的CD8+T細胞のフローサイトメトリー分析により測定されるように、投与前の増殖のベースラインレベルと比較して少なくとも20%増加する、請求項13に記載の組成物。
- 対象の癌を治療する方法において使用するための組成物であって、治療有効量の前記組成物を前記対象に投与することにより、前記対象の免疫応答を誘導する、請求項6に記載の組成物。
- 対象の癌を治療する方法において使用するための組成物であって、治療有効量の前記組成物を前記対象に投与することにより、前記対象のCD4+FoxP3+制御性T細胞の増殖を刺激する、請求項6に記載の組成物。
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KR102423942B1 (ko) | 2022-07-22 |
EP3468998B1 (en) | 2021-12-01 |
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IL263406B2 (en) | 2023-09-01 |
CN109219620A (zh) | 2019-01-15 |
RU2018143977A (ru) | 2020-07-09 |
AU2017278192A1 (en) | 2018-12-13 |
SG11201810853UA (en) | 2019-01-30 |
EP3468998A1 (en) | 2019-04-17 |
IL263406A (en) | 2018-12-31 |
ZA201808317B (en) | 2019-08-28 |
US20170355773A1 (en) | 2017-12-14 |
CA3026652A1 (en) | 2017-12-14 |
JP2019526528A (ja) | 2019-09-19 |
US10683359B2 (en) | 2020-06-16 |
RU2018143977A3 (ja) | 2020-10-05 |
CN109219620B (zh) | 2023-01-31 |
DK3468998T3 (en) | 2022-03-07 |
KR20190015716A (ko) | 2019-02-14 |
WO2017214547A1 (en) | 2017-12-14 |
US10005843B2 (en) | 2018-06-26 |
US20180312599A1 (en) | 2018-11-01 |
RU2746314C2 (ru) | 2021-04-12 |
IL263406B1 (en) | 2023-05-01 |
BR112018075222A2 (pt) | 2019-03-19 |
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