JP6911105B2 - 抗体重鎖不変部位ヘテロ二量体(heterodimeric Fc)に融合したIL−21(heterodimeric Fc−fused IL−21)及びこれを含む薬剤学的組成物 - Google Patents
抗体重鎖不変部位ヘテロ二量体(heterodimeric Fc)に融合したIL−21(heterodimeric Fc−fused IL−21)及びこれを含む薬剤学的組成物 Download PDFInfo
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Description
(2)第1Fc領域のCH3ドメインのK409位置でのアミノ酸残基の置換、及び第2Fc領域のCH3ドメインのF405及び/又はD399位置でのアミノ酸残基の置換。
前記第1Fc領域のCH3ドメインのK409位置でのアミノ酸残基の置換はK409Wであり、前記第2Fc領域のCH3ドメインのF405位置でのアミノ酸残基の置換はF405Tであり、D399位置でのアミノ酸の置換はD399Vであることを特徴とすることができる。
(2)第2Fc領域のCH3ドメインのQ347位置でのQ347Rのアミノ酸残基の置換、
(3)第1Fc領域のCH3ドメインのK409位置でのK409Wのアミノ酸残基の置換、及び
(4)第2Fc領域のCH3ドメインのF405位置でのF405Tアミノ酸残基の置換及びD399位置でのD399Vのアミノ酸残基の置換。
1)試験管内でIL−21によって誘導されるナチュラルキラー細胞の増殖能を保存、
2)生体内でナチュラルキラー細胞との併用投与時、IL−21単独処理群に比べて卓越した坑癌活性増大の誘導、又は
3)IL−21及び他のγ鎖サイトカイン(例えば、IL−2、IL−7、IL−15など)の短い半減期のために要求される頻繁な生体投与の代替を特徴とすることができる。
以下、実施例に基づいて本発明をより詳細に説明する。これらの実施例はただ本発明をより具体的に説明するためのもので、本発明の要旨によって本発明の範囲がこれらの実施例に制限されないというのは当該分野で通常の知識を有する者に明らかであろう。
ヘテロ二量体の形成が好まれるCH3ドメイン突然変異が導入されたヒト抗体重鎖不変部位ヘテロ二量体の断片を作るために、まず二量体の形成のための相互作用に主に作用するCH3ドメインのヒト抗体アイソフォーム別間のアミノ酸配列の類似程度を分析した。ここで、異種のCH3A:CH3B(本発明において、CH3A及びCH3Bはそれぞれ第1Fc領域のCH3領域及び第2Fc領域のCH3領域を意味する)に誘導される突然変異対(EW/RVT)は既存の文献又は特許に公開された重鎖不変部位ヘテロ二量体の形成を増進させるための戦略でCH3A:CH3Bが高収率で形成されるようにする(Choi et al、2013;韓国特許登録第10−1522954号)。図4は各ヒト抗体兔疫グロブリンG(IgG)アイソフォーム別CH3ドメインの配列(IgG1:配列番号4;IgG2:配列番号5;IgG3:配列番号6;IgG4:配列番号7)を羅列して比較したものである。
ヘテロ二量体の形成能が既存に報告されたIgG1基盤EW/RVT重鎖不変部位ヘテロ二量体変異体と類似した程度に維持されると予想される図5のアイソフォーム別変異体のうちIgG4に基づく変異体(IgG4−EW/RVT、配列番号1、2)を用いてヒトIL−21(Interleukin 21、配列番号3)融合タンパク質を構築した。自然界に存在するIL−21は単量体として作動するサイトカインであり、一つのIL−21が一つのIL−21受容体(IL21R)及び一つのγc−chainと結合することによって活性を有する。したがって、前記IgG4−EW/RVTヘテロ二量体変異体を用い、一つのIL−21を互いに異なるヘテロ二量体Fc変異体(CH3A又はCH3B)の一つにだけ連結して自然界に存在するIL−21の単量体の形態を維持しようとした。
図3のFc−IL21単量体融合タンパク質はヒトIL−21が融合したIgG4 CH3A(EW)及びIgG4 CH3B(RVT)の発現ベクターを1:1の比率にし、ポリエチレンイミン(Polyethylenimine、PEI)(Polyscineces社製)の混合物をHEK293−F(Invitrogen社製)細胞に過渡トランスフェクション(transient transfection)し、無血清FreeStyle 293発現培地(Invitrogen社製)が入っている振盪フラスコで培養することによって作られる。詳細な方法は次のようである。
末梢血液単核球と放射線照射されたJurkat細胞とEBV−LCL細胞を実施例3のヒトIL−21融合タンパク質の存在の下で培養しながらNK細胞の増殖及び機能向上の誘導を確認した。
生体内でも実施例3のヒトIL−21融合タンパク質のNK細胞増殖効果が同様に現れるかを確認した。
一態様において、本発明は以下を提供する。
[項目1]
抗体(immunoglobulin)重鎖不変部位(Fc)対の第1Fc領域及び第2Fc領域を含み、前記第1Fc領域及び/又は第2Fc領域のN末端及びC末端の一つ以上の末端にIL−21が結合されているヘテロ二量体融合タンパク質(heterodimeric Fc−fused protein)であって、
前記第1Fc領域及び第2Fc領域はヘテロ二量体(heterodimeric Fc)の形成を促進するようにCH3ドメインが変異されたものであることを特徴とする、ヘテロ二量体融合タンパク質(heterodimeric Fc−fused protein)。
[項目2]
前記第1Fc領域又は第2Fc領域のN末端のいずれか一末端にだけIL−21が結合されている、項目1に記載のヘテロ二量体融合タンパク質。
[項目3]
前記第1Fc領域及び第2Fc領域は、それぞれヒトのIgG1、IgG2、IgG3、IgG4、IgM、IgA、IgD及びIgEからなる群から選択されたFc領域由来のものであることを特徴とする、項目1に記載のヘテロ二量体融合タンパク質。
[項目4]
前記第1Fc領域及び第2Fc領域はヒトのIgG1、IgG2、IgG3、IgG4、IgM、IgA、IgD及びIgEからなる全抗体(whole antibody)の形態で含まれていることを特徴とする、項目1に記載のヘテロ二量体融合タンパク質。
[項目5]
前記第1Fc領域又は第2Fc領域のCH3ドメインの変異は次の群から選択された一つ以上の変異を含むことを特徴とする、項目1に記載のヘテロ二量体融合タンパク質(ただし、変異位置はEU indexに従う)。
(1)第1Fc領域のCH3ドメインのK360位置でのK360Eのアミノ酸残基の置換、
(2)第2Fc領域のCH3ドメインのQ347位置でのQ347Rのアミノ酸残基の置換、
(3)第1Fc領域のCH3ドメインのK409位置でのK409Wのアミノ酸残基の置換、及び
(4)第2Fc領域のCH3ドメインのF405位置でのF405Tアミノ酸残基の置換、及びD399位置でのD399Vのアミノ酸残基の置換。
[項目6]
項目1〜5のいずれか一項に記載のヘテロ二量体融合タンパク質を含む、薬剤学的組成物。
[項目7]
癌治療のための、項目6に記載の薬剤学的組成物。
[項目8]
前記癌は、大膓癌、黒色腫、乳房癌、膵膓癌、腎臓癌、前立腺癌、卵巣癌、小腸癌、食道癌、子宮頸部癌、肺癌、リンパ腫及び血液癌からなる群から選択されることを特徴とする、項目7に記載の薬剤学的組成物。
[項目9]
他の抗癌剤との併用治療のための、項目7に記載の薬剤学的組成物。
[項目10]
NK細胞及び項目1に記載のヘテロ二量体融合タンパク質を含む、免疫抗癌組成物。
[項目11]
IL−2をさらに含むことを特徴とする項目10に記載の免疫抗癌組成物。
[項目12]
前記癌は、大膓癌、黒色腫、乳房癌、膵膓癌、腎臓癌、前立腺癌、卵巣癌、小腸癌、食道癌、子宮頸部癌、肺癌、リンパ腫及び血液癌からなる群から選択されることを特徴とする、項目10に記載の免疫抗癌組成物。
Claims (10)
- 抗体(immunoglobulin)重鎖不変部位(Fc)対の第1Fc領域及び第2Fc領域を含み、前記第1Fc領域及び/又は第2Fc領域のN末端及びC末端のいずれか一つのみの末端にIL−21が結合されているヘテロ二量体融合タンパク質(heterodimeric Fc−fused protein)であって、
前記第1Fc領域及び第2Fc領域はヘテロ二量体(heterodimeric Fc)の形成を促進するようにCH3ドメインが変異されたものであることを特徴とする、ヘテロ二量体融合タンパク質(heterodimeric Fc−fused protein)であって、前記ヘテロ二量体融合タンパク質は次の(1)〜(4)変異の中で、(1)及び(3)の変異を含むこと、または(2)及び(4)の変異を含むことを特徴とする、ヘテロ二量体融合タンパク質(ただし、変異位置はEU indexに従う):
(1)第1Fc領域のCH3ドメインのK360位置でのK360Eのアミノ酸残基の置換、
(2)第2Fc領域のCH3ドメインのQ347位置でのQ347Rのアミノ酸残基の置換、
(3)第1Fc領域のCH3ドメインのK409位置でのK409Wのアミノ酸残基の置換、及び
(4)第2Fc領域のCH3ドメインのF405位置でのF405Tアミノ酸残基の置換、及びD399位置でのD399Vのアミノ酸残基の置換。 - 前記第1Fc領域又は第2Fc領域のN末端のいずれか一末端にだけIL−21が結合されている、請求項1に記載のヘテロ二量体融合タンパク質。
- 前記第1Fc領域及び第2Fc領域は、それぞれヒトのIgG1、IgG2、IgG3、IgG4、IgM、IgA、IgD及びIgEからなる群から選択されたFc領域由来のものであることを特徴とする、請求項1に記載のヘテロ二量体融合タンパク質。
- 請求項1〜3のいずれか一項に記載のヘテロ二量体融合タンパク質を含む、薬剤学的組成物。
- 癌治療のための、請求項4に記載の薬剤学的組成物。
- 前記癌は、大膓癌、黒色腫、乳房癌、膵膓癌、腎臓癌、前立腺癌、卵巣癌、小腸癌、食道癌、子宮頸部癌、肺癌、リンパ腫及び血液癌からなる群から選択されることを特徴とする、請求項5に記載の薬剤学的組成物。
- 他の抗癌剤との併用治療のための、請求項5に記載の薬剤学的組成物。
- NK細胞及び請求項1に記載のヘテロ二量体融合タンパク質を含む、免疫抗癌組成物。
- IL−2をさらに含むことを特徴とする請求項8に記載の免疫抗癌組成物。
- 前記癌は、大膓癌、黒色腫、乳房癌、膵膓癌、腎臓癌、前立腺癌、卵巣癌、小腸癌、食道癌、子宮頸部癌、肺癌、リンパ腫及び血液癌からなる群から選択されることを特徴とする、請求項8に記載の免疫抗癌組成物。
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US9580486B2 (en) * | 2013-03-14 | 2017-02-28 | Amgen Inc. | Interleukin-2 muteins for the expansion of T-regulatory cells |
EP3041865A2 (en) | 2013-09-03 | 2016-07-13 | NovImmune S.A. | Readily isolated bispecific binding molecules with native format having mutated constant regions |
WO2018030806A1 (ko) * | 2016-08-10 | 2018-02-15 | 아주대학교산학협력단 | 항체 중쇄불변부위 이종이중체에 융합된 사이토카인 및 이를 포함하는 약제학적 조성물 |
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KR101928981B1 (ko) | 2018-12-13 |
EP3508495B1 (en) | 2021-11-24 |
US11459367B2 (en) | 2022-10-04 |
US20190218267A1 (en) | 2019-07-18 |
US10800825B2 (en) | 2020-10-13 |
EP3508495A1 (en) | 2019-07-10 |
KR20180026279A (ko) | 2018-03-12 |
CN110088124A (zh) | 2019-08-02 |
WO2018044105A1 (ko) | 2018-03-08 |
JP2019530657A (ja) | 2019-10-24 |
EP3508495A4 (en) | 2020-01-22 |
US20200399336A1 (en) | 2020-12-24 |
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