JP2015500796A - ポリペプチド構築物およびその使用 - Google Patents
ポリペプチド構築物およびその使用 Download PDFInfo
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- JP2015500796A JP2015500796A JP2014537430A JP2014537430A JP2015500796A JP 2015500796 A JP2015500796 A JP 2015500796A JP 2014537430 A JP2014537430 A JP 2014537430A JP 2014537430 A JP2014537430 A JP 2014537430A JP 2015500796 A JP2015500796 A JP 2015500796A
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor
Abstract
Description
本出願は、その内容全体が参照により本明細書中に組み込まれている、2011年10月28日に出願された、表題「ポリペプチド構築物およびその使用」の豪州特許出願第2011904502号の優先権を主張する。
癌、稀な癌および関連障害、腎細胞癌、網膜芽細胞腫、横紋筋肉腫、ロスムンド-トムソン症候群、唾液腺癌、肉腫、シュワン腫、セザリー症候群、皮膚癌、小細胞肺癌(SCLC)、小腸癌、軟組織肉腫、脊髄腫瘍、扁平細胞癌(皮膚)、胃癌、滑膜肉腫、精巣癌、胸腺癌、甲状腺癌、移行細胞癌(膀胱)、移行細胞癌(腎盂/輸尿管)、絨毛細胞癌、尿道癌、泌尿器系癌、ウロプラキン、子宮肉腫、子宮癌、膣癌、外陰部癌、ワルデンストレーム-マクログロブリン血症ならびにウィルムス腫瘍が含まれる。一実施形態では、腫瘍は多発性骨髄腫または非ホジキンリンパ腫の群から選択される。
Piehler, Jacob、Roisman, Laila C、Schreiber, Gideon (2000). New structural and functional aspects of the Type I interferon-receptor interaction revealed by comprehensive mutational analysis of the binding interface. J. Biol. Chem.、275:40425〜40433頁。
Jaitin, Diego A.、Roisman, Laila C.、Jaks, Eva、Gavutis, Martynas、Piehler, Jacob、Van der Heyden, Jose、Uze, Gilles、Schreiber, Gideon (2006). Inquiring into the differential action of interferons (IFNs): an IFN-α2 mutant with enhanced affinity to IFNAR1 is functionally similar to IFN-β. Mol. Cell. Biol.、26:1888〜1897頁。
Slutzki, Michal、Jaitin, Diego A.、Yehezkel, Tuval Ben、Schreiber, Gideon (2006). Variations in the unstructured C-terminal tail of interferons contribute to differential receptor binding and biological activity. J. Mol. Biol.、360:1019〜1030頁。
Kalie, Eyal、Jaitin, Diego A.、Abramovich, Renne、Schreiber, Gideon (2007). An interferon α2 mutant optimized by phage display for IFNAR1 binding confers specifically enhanced antitubor activities. J. Biol. Chem.、282:11602〜11611頁。
Pan, Manjing、Kalie, Eyal、Scaglione, Brian J.、Raveche, Elizabeth S.、Schreiber, Gideon、Langer, Jerome A. (2008). Mutation of te IFNAR-1 receptor binding site of human IFN-α2 generates Tyep I IFN competitive antagonists. Biochemistry、47:12018〜12027頁。
Kalie, Eyal、Jaitin, Diego A.、Podoplelova, Yulia、Piehler, Jacob、Schreiber, Gideon (2008). The Stability of the ternary interferon-receptor complex rather than the affinity to the individual subunits dictates differential biological activities. J. Biol. Chem.、283:32925〜32936頁。
* * * *
1 MSYNLLGFLQ RSSNFQCQKL LWQLNGRLEY CLKDRMNFDI PEEIKQLQQF 50
* * *
51 QKEDAALTIY EMLQNIFAIF RQDSSSTGWN ETIVENLLAN VYHQINHLKT 100
* ** * *
101 VLEEKLEKED FTRGKLMSSL HLKRYYGRIL HYLKAKEYSH CAWTIVRVEI 150
*
151 LRNFYFINRL TGYLRN 166
(1)Runkel, L.、Pfeffer, L.、Lewerenz, M.、Mogensen, K. (1998). Differences in Activity between α and β Type I Interferons Explored by Mutational Analysis. J. Biol. Chem.、273:8003〜8008頁
(2)Stewart, A. G.、Adair, J. R.、Catlin, G.、Hynes, C、Hall, J.、Davies, J.、Dawson, K.およびPorter, A. G. (1987). Chemical mutagenesis of human interferon-beta: construction, expression in E. coli, and biological activity of sodium bisulfite-induced mutations. DNA、6:119〜128頁。
(3)インハウスの結果
(抗体-IFNα融合タンパク質構築物の産生)
(発現ベクター:)
リツキシマブ(Andersonら、米国特許第5,843,439号、1998年12月1日)およびパリビズマブ(Johnson、米国特許第5,824,307号、1998年10月20日)可変領域をコードするDNAを、公開されたアミノ酸配列に従って設計された18(重鎖)および16(軽鎖)のDNAオリゴヌクレオチドから、PCRベースの遺伝子アセンブリによって作製した。G005抗CD38およびnBT062抗CD138モノクローナル抗体の可変領域をコードするDNAを、DeWeersら(米国特許第7829673号)およびDaelkenら(WO2009/080832)による刊行物からそれぞれ引き出し、稀なコドンおよび好ましくない制限部位を排除する配列修飾の後、Integrated DNA Technology,Inc.(Coralville、IA)による合成に供した。
(IgGおよびIgGインターフェロン融合タンパク質構築物の産生:)
[mabの名称]-[重鎖(「HC」)または軽鎖(「LC」)への連結]-[リンカー名称]-[リガンド名称][(突然変異)][アイソタイプ]。
L0:リンカーなし(サイトカインのN末端による抗体鎖のC末端の直接融合)
L6:SGGGGS(配列番号132)
L16:SGGGGSGGGGSGGGGS(配列番号133)
(抗体-IFNα融合タンパク質構築物の抗原-標的化活性の測定のための方法)
(抗体-IFNα融合タンパク質構築物の非抗原-標的化活性を測定するための方法)
(結果:抗体-IFNα融合タンパク質構築物の抗原特異性)
(新規なCD38抗体の開発)
(発現のためのCD38構築物のフォーマット)
(抗体発現のためのベクターの構築)
(HEK293-6E細胞における構築物の一過性発現)
(抗体の発現および精製)
(組織培養上清からのヒスチジンタグ化タンパク質の精製)
(ファージディスプレイのための抗原のビオチン化)
(ファージディスプレイによる抗CD38抗体の産生)
(CD38結合のためのFAbの、ELISAベースのスクリーニング)
(ヒトCD38ポジティブ細胞系RPMI-8226に対するIgGの結合の評価)
(遺伝子免疫による抗CD38抗体の産生)
(ヒトおよびカニクイザルCD-38交差反応性についてのハイブリドーマ上清のスクリーニング)
(ラット抗体のヒトCD38ポジティブ細胞系RPMI-8226へのフローサイトメトリー結合)
(ラット抗体の分子性質決定)
(標的化、弱毒化IFNαの抗ウイルス活性)
(方法:)
(結果:)
(標的化、弱毒化IFNβ)
(方法:)
(結果:)
(インターロイキン-6(IL-6))
(方法:)
(抗体-標的化弱毒化IFNαのin vivo研究)
(方法:)
(結果:)
(方法:)
(結果:)
(方法:)
(結果:)
(方法:)
(結果:)
(方法:)
(結果:)
(方法:)
(結果:)
(方法:)
(結果:)
(方法:)
(結果:)
(方法:)
(結果:)
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(結果:)
(方法:)
(結果:)
(配列表)
Claims (32)
- 細胞表面関連抗原と結合する抗体またはその抗原結合部分と連結したペプチドまたはポリペプチドシグナル伝達リガンドを含むポリペプチド構築物であって、リガンドが、前記抗原の発現を欠く細胞に対するその効力を低下させる少なくとも1つのアミノ酸置換または欠失を含む、ポリペプチド構築物。
- ペプチドまたはポリペプチドシグナル伝達リガンドが、ペプチド結合を介して抗体またはその抗原結合部分と連結している、請求項1に記載のポリペプチド構築物。
- ペプチドまたはポリペプチドシグナル伝達リガンドが、直接または1〜20個のアミノ酸の長さのリンカーを介して抗体またはその抗原結合部分と連結している、請求項1または請求項2に記載のポリペプチド構築物。
- ペプチドまたはポリペプチドシグナル伝達リガンドが、抗体またはその抗原結合部分の軽鎖または重鎖定常領域のC末端と連結している、請求項1から3のいずれか一項に記載のポリペプチド構築物。
- ペプチドまたはポリペプチドシグナル伝達リガンドがIFN、IL-4およびIL-6からなる群から選択される、請求項1から4のいずれか一項に記載のポリペプチド構築物。
- ペプチドまたはポリペプチドシグナル伝達リガンドがIFNα、IFNβ、およびIFNγからなる群から選択される、請求項1から5のいずれか一項に記載のポリペプチド構築物。
- IFNαのアミノ酸配列が配列番号1〜3、80〜90、434および435から選択され、IFNαが、前記抗原の発現を欠く細胞に対するその効力を低下させる少なくとも1つのアミノ酸置換または欠失を含む、請求項6に記載のポリペプチド構築物。
- 少なくとも1つのアミノ酸置換を含むIFNαのアミノ酸配列が、R144A(配列番号30)、R144S(配列番号40)、R144T(配列番号41)、R144Y(配列番号43)、R144I(配列番号35)、R144L(配列番号37)、A145D(配列番号44)、A145H(配列番号47)、A145Y(配列番号58)、A145K(配列番号49)、R33A+YNS(配列番号65)、R33A(配列番号16)およびR144A+YNS(配列番号68)からなる群から選択される、請求項7に記載のポリペプチド構築物。
- 抗体またはその抗原結合部分が、その細胞外ドメインが240kD未満の分子量を有する抗原と結合する、請求項1から8のいずれか一項に記載のポリペプチド構築物。
- 抗体またはその抗原結合部分が抗原と結合し、抗原が、12,600コピー/細胞を超えるまたは15,000コピー/細胞を超える密度で細胞上に存在する、請求項1から9のいずれか一項に記載のポリペプチド構築物。
- 抗体またはその抗原結合部分が、50nMから、25nMから、10nMから、または5nMから1pMまでの親和性で細胞表面関連抗原と結合する、請求項1から10のいずれか一項に記載のポリペプチド構築物。
- 細胞表面関連抗原が、CD38、HM1.24、CD56、CS1、CD20、CD74、IL-6R、Blys(BAFF)、BCMA、HLA-SR、キニノーゲン、ベータ2ミクログロブリン、FGFR3、ICAM-1、マトリプターゼ、CD52、EGFR、GM2、アルファ4-インテグリン、IFG-1R、KIR、CD3、CD4、CD8、CD24、CD44、CD69、CD71、CD83、CD86、CD96、HLA-DR、PD-1、ICOS、CD33、CD115、CD11c、CD14、CD52、CD14、FSP1、FAP、PDGFRアルファ、PDGFRベータ、ASGR1、ASGR2、FSP1、RTI140/Ti-アルファ、HTI56、VEGF受容体、RCHE遺伝子の産物CD241、CD117(c-kit)、CD71(トランスフェリン受容体)、CD36(トロンボスポンジン受容体)、CD34、CD45RO、CD45RA、CD115、CD168、CD235、CD236、CD237、CD238、CD239およびCD240からなる群から選択される、請求項1から11のいずれか一項に記載のポリペプチド構築物。
- 抗体またはその抗原結合部分が抗体またはFab断片である、請求項1から12のいずれか一項に記載のポリペプチド構築物。
- 50を超える抗原特異性指数を有する、請求項1から13のいずれか一項に記載のポリペプチド構築物。
- 100を超える抗原特異性指数を有する、請求項14に記載のポリペプチド構築物。
- 1000を超える抗原特異性指数を有する、請求項15に記載のポリペプチド構築物。
- ペプチドまたはポリペプチドシグナル伝達リガンドがIFNβであり、アミノ酸置換がR35Aである、請求項6に記載のポリペプチド構築物。
- 請求項1から16のいずれか一項に記載のポリペプチド構築物と薬学的に許容される担体または希釈剤とを含む組成物。
- 請求項1から16のいずれか一項に記載のポリペプチド構築物または請求項17に記載の組成物を対象に投与するステップを含む、対象において腫瘍を処置する方法。
- 腫瘍が多発性骨髄腫または非ホジキンリンパ腫から選択される、請求項18に記載の対象において腫瘍を処置する方法。
- 癌の処置における請求項1から16のいずれか一項に記載のポリペプチド構築物の使用。
- 多発性骨髄腫または非ホジキンリンパ腫である癌の処置における請求項1から16のいずれか一項に記載のポリペプチド構築物の使用。
- リガンド受容体を保有する抗原陰性細胞に対するペプチドまたはポリペプチドシグナル伝達リガンドの効力を、抗原陰性細胞と比較した場合にリガンド受容体をより高い程度で保有する抗原陽性細胞に対するリガンドの効力を維持したままで低下させる方法であって、抗原陰性細胞に対するその効力を低下させる少なくとも1つのアミノ酸置換または欠失をリガンドが含むように、リガンドを改変させるステップと、改変されたリガンドを抗体またはその抗原結合部分と連結させるステップとを含み、抗体またはその抗原結合部分が、抗原陽性細胞上の細胞表面関連抗原に特異的であるが抗原陰性細胞上のものには特異的でない方法。
- ペプチドまたはポリペプチドシグナル伝達リガンドが、ペプチド結合を介して抗体またはその抗原結合部分と連結している、請求項23に記載の方法。
- ペプチドまたはポリペプチドシグナル伝達リガンドが、直接または1〜20個のアミノ酸の長さのリンカーを介して抗体またはその抗原結合部分と連結している、請求項23または請求項24に記載の方法。
- ペプチドまたはポリペプチドシグナル伝達リガンドがIFN、IL-4およびIL-6からなる群から選択される、請求項23から25のいずれか一項に記載の方法。
- ペプチドまたはポリペプチドシグナル伝達リガンドがIFNα、IFNβ、およびIFNγからなる群から選択される、請求項23から26のいずれか一項に記載の方法。
- 改変前のIFNαのアミノ酸配列が配列番号1〜3、80〜90、434および435から選択される、請求項27に記載の方法。
- 改変が、R144A(配列番号30)、R144S(配列番号40)、R144T(配列番号41)、R144Y(配列番号43)、R144I(配列番号35)、R144L(配列番号37)、A145D(配列番号44)、A145H(配列番号47)、A145Y(配列番号58)、A145K(配列番号49)、R33A+YNS(配列番号65)、R33A(配列番号16)およびR144A+YNS(配列番号68)からなる群から選択される少なくとも1つのアミノ酸置換を含む、請求項28に記載の方法。
- 抗体またはその抗原結合部分が、50nMから、25nMから、10nMから、または5nMから1pMまでの親和性で細胞表面関連抗原と結合する、請求項23から29のいずれか一項に記載の方法。
- 細胞表面関連抗原が、CD38、HM1.24、CD56、CS1、CD20、CD74、IL-6R、Blys(BAFF)、BCMA、HLA-SR、キニノーゲン、ベータ2ミクログロブリン、FGFR3、ICAM-1、マトリプターゼ、CD52、EGFR、GM2、アルファ4-インテグリン、IFG-1R、KIR、CD3、CD4、CD8、CD24、CD44、CD69、CD71、CD83、CD86、CD96、HLA-DR、PD-1、ICOS、CD33、CD115、CD11c、CD14、CD52、CD14、FSP1、FAP、PDGFRアルファ、PDGFRベータ、ASGR1、ASGR2、FSP1、RTI140/Ti-アルファ、HTI56、VEGF受容体、RCHE遺伝子の産物CD241、CD117(c-kit)、CD71(トランスフェリン受容体)、CD36(トロンボスポンジン受容体)、CD34、CD45RO、CD45RA、CD115、CD168、CD235、CD236、CD237、CD238、CD239およびCD240からなる群から選択される、請求項23から30のいずれか一項に記載の方法。
- 抗体またはその抗原結合部分が抗体またはFab断片である、請求項23から31のいずれか一項に記載の方法。
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