JP6845177B2 - 長寿命ポリペプチド結合分子 - Google Patents
長寿命ポリペプチド結合分子 Download PDFInfo
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
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Description
本願は、2012年3月1日に出願された「Long life polypeptide binding molecules」を表題とする米国仮出願61/605,681および2012年3月2日に出願された「Long life polypeptide binding molecules」を表題とする米国仮出願61/606,268に関連する。これらの関連出願は、その全体が参照により組み入れられる。
本発明は、第1の結合ドメインが標的細胞上の細胞表面分子に結合することができる結合ドメインであり、第2の結合ドメインがT細胞CD3受容体複合体に結合することができる結合ドメインであり、第3のドメインが血清アルブミンに結合することができる結合ドメインであり、該第3のドメインが第2のドメインのC末端に位置する、少なくとも1つのポリペプチド鎖中に含まれる少なくとも3つのドメインを含む結合分子に関する。さらに、本発明は、該結合分子をコードする核酸配列、該核酸配列を含むベクターおよび該ベクターで形質転換またはトランスフェクトされた宿主細胞を提供する。さらに、本発明は、本発明の結合分子の産生のための方法、該結合分子の医学的使用、および該結合分子を含むキットを提供する。
半減期の延長は、一般に、免疫グロブリン、特に抗体、その中でも特に小サイズの抗体フラグメントのインビボ適用において有用である。そのようなフラグメント(Fv、ジスルフィド結合型Fv、Fab、scFv、dAb)は、体内からの迅速なクリアランスが問題となることが多く;それゆえ、それらは体内のほとんどの部分に迅速に到達することができ、かつ素早く産生され取り扱いが容易であるにもかかわらず、それらのインビボ適用はインビボでのそれらの持久力の弱さによって制限され得る。
(a)第1の結合ドメインが、標的細胞上の細胞表面分子に結合することができるドメインであり、
(b)第2の結合ドメインが、T細胞CD3受容体複合体に結合することができるドメインであり、かつ
(c)第3の結合ドメインが、血清アルブミンに結合することができるドメインであり、第3のドメインが第2のドメインのC末端に位置する、
結合分子、を提供する。
・第1の結合ドメイン、
・第2の結合ドメイン、および
・第3の結合ドメイン、
の順で、1つのポリペプチド上に存在する。
(a)第1の結合ドメインが、ヒトおよび非ヒト霊長類の細胞上の細胞表面分子に結合することができ、
(b)第2の結合ドメインが、ヒトおよび非ヒト霊長類の細胞上のT細胞CD3受容体複合体に結合することができ、かつ
(c)第3の結合ドメインが、ヒトおよび非ヒト霊長類の血清アルブミンに結合することができる、
結合分子である。
(a)第1の結合ドメインが、抗体由来のVLおよびVH鎖を含み、かつ/または
(b)第2の結合ドメインが、抗体由来のVLおよびVH鎖を含む、
点で特徴づけられる。
[本発明1001]
少なくとも1つのポリペプチド鎖中に含まれる少なくとも3つの結合ドメインを含む結合分子であって、
(a)第1のドメインが、標的細胞上の細胞表面分子に結合することができる結合ドメインであり、
(b)第2のドメインが、T細胞CD3受容体複合体に結合することができる結合ドメインであり、かつ
(c)第3のドメインが、血清アルブミンに結合することができる結合ドメインであり、該第3のドメインが、第2のドメインのC末端に位置する、
結合分子。
[本発明1002]
前記3つのドメインが、N末端からC末端に向かって、
・第1の結合ドメイン、
・第2の結合ドメイン、および
・第3の結合ドメイン、
の順で、1つのポリペプチド上に存在する、本発明1001の結合分子。
[本発明1003]
前記結合分子の第3の結合が、scFvまたは単一ドメイン抗体である、本発明1001または1002の結合分子。
[本発明1004]
(a)第1の結合ドメインが、ヒトおよび非ヒト霊長類の細胞上の細胞表面分子に結合することができ、
(b)第2の結合ドメインが、ヒトおよび非ヒト霊長類の細胞上のT細胞CD3受容体複合体に結合することができ、かつ
(c)第3の結合ドメインが、ヒトおよび非ヒト霊長類の血清アルブミンに結合することができる、
本発明1001〜1003のいずれかの結合分子。
[本発明1005]
血清アルブミンに結合することができる第3の結合ドメインが、コンビナトリアルライブラリまたは抗体結合ドメインに由来する、本発明1001〜1004のいずれかの結合分子。
[本発明1006]
第3の結合ドメインが、10〜25アミノ酸残基を含む、本発明1001〜1005のいずれかの結合分子。
[本発明1007]
血清アルブミンに結合することができる第3の結合ドメインが、アミノ酸配列Asp-Xaa-Cys-Leu-Pro-Xaa-Trp-Gly-Cys-Leu-Trpを含み、Xaaが任意のアミノ酸である、本発明1001〜1006のいずれかの結合分子。
[本発明1008]
血清アルブミンに結合することができる第3の結合ドメインが、単一ドメイン抗体のCDRに由来する、本発明1001〜1006のいずれかの結合分子。
[本発明1009]
第3の結合ドメインが、≦500nMの親和性(KD)で血清アルブミンに結合する、本発明1001〜1008のいずれかの結合分子。
[本発明1010]
10%ヒト血清アルブミン存在下でのエフェクター細胞による標的細胞の溶解を測定するインビトロアッセイにおいて細胞毒性活性を示す、本発明1001〜1009のいずれかの結合分子。
[本発明1011]
単一ポリペプチド鎖からなる、本発明1001〜1010のいずれかの結合分子。
[本発明1012]
(a)第1の結合ドメインが、抗体由来のVLおよびVH鎖を含み、かつ/または
(b)第2の結合ドメインが、抗体由来のVLおよびVH鎖を含む、
本発明1001〜1011のいずれかの結合分子。
[本発明1013]
1つまたは複数のさらなる異種ポリペプチドを含む、本発明1001〜1012のいずれかの結合分子。
[本発明1014]
細胞表面分子に結合することができる第1の結合ドメインが、腫瘍抗原に結合する、本発明1001〜1013のいずれかの結合分子。
[本発明1015]
T細胞CD3受容体複合体に結合することができる第2の結合ドメインが、ヒトおよびコモンマーモセット(Callithrix jacchus)、ワタボウシタマリン(Saguinus oedipus)またはコモンリスザル(Saimiri sciureus)のCD3ε鎖のエピトープに結合することができ、該エピトープが、SEQ ID NO:2、4、6または8からなる群に含まれるアミノ酸配列の一部でありかつ少なくともアミノ酸配列Gln-Asp-Gly-Asn-Gluを含む、本発明1001〜1014のいずれかの結合分子。
[本発明1016]
SEQ ID NO:51、52、54、55、57、58、60、61、75、76、81、82、85、86、90、91、85、96、100または101に示されるアミノ酸配列によって特徴づけられる、本発明1001〜1007のいずれかの結合分子。
[本発明1017]
本発明1001〜1016のいずれかにおいて定義される結合分子をコードする、核酸配列。
[本発明1018]
本発明1017において定義される核酸配列を含む、ベクター。
[本発明1019]
本発明1017において定義される核酸配列または本発明1018において定義されるベクターで形質転換またはトランスフェクトされた、宿主細胞。
[本発明1020]
本発明1001〜1016のいずれかの結合分子の産生方法であって、本発明1001〜1016のいずれかにおいて定義された結合分子の発現を可能にする条件下で本発明1019において定義された宿主細胞を培養する工程、および、産生された結合分子を培養物から回収する工程を含む、方法。
[本発明1021]
本発明1001〜1016のいずれかの結合分子または本発明1020の方法にしたがい産生された結合分子を含む、薬学的組成物。
[本発明1022]
増殖性疾患、炎症性疾患、感染症、および自己免疫疾患からなる群より選択される疾患の予防、処置または改善に使用するための、本発明1001〜1016のいずれかの結合分子または本発明1020の方法にしたがい産生された結合分子。
[本発明1023]
増殖性疾患、炎症性疾患、感染症、および自己免疫疾患からなる群より選択される疾患の処置または改善のための方法であって、それを必要とする対象に、本発明1001〜1016のいずれかの結合分子または本発明1020の方法にしたがい産生された結合分子を投与する工程を含む、方法。
[本発明1024]
本発明1001〜1016のいずれかにおいて定義された結合分子、本発明1017において定義された核酸分子、本発明1018において定義されたベクター、または本発明1020において定義された宿主細胞を含む、キット。
標的細胞上の細胞表面分子、例えば腫瘍抗原、およびT細胞CD3受容体複合体の両方に結合する結合分子の作用様式は、公知となっている。T細胞を標的細胞の近くに運ぶ、すなわちT細胞を誘引すると、その状況下で、標的細胞はT細胞によって殺傷される。このプロセスは、増殖性疾患、炎症性疾患、感染症、および自己免疫疾患に対する取り組みの中で利用することができる。したがって、CD3結合ドメイン、すなわち結合分子の「エフェクタードメイン」、または標的結合ドメインに、何か、例えば追加のアミノ酸配列を融合すると、結合分子の特性が影響を受け、もはや適切にT細胞を誘引するおよび/またはその標的に結合するその機能を発揮しなくなる可能性がある。事実、T細胞は、パーフォリンと呼ばれる孔形成タンパク質およびグランザイムと呼ばれる細胞死誘導プロテアーゼという死の組み合わせを含む顆粒を備えている。これらのタンパク質は、死滅させようとする標的細胞の近くにT細胞が存在する場合にのみ形成され得る細胞溶解シナプスを通じて標的細胞に送達される。通常、T細胞と標的細胞の最大の接近は、T細胞がそれに対応するT細胞受容体を用いてMHCクラスI/ペプチド複合体に結合することによって達成される。しかし、T細胞受容体/MHCの相互作用の非存在下でもT細胞をそのように標的細胞の近くに運ぶことが、本発明の結合分子の機能である。したがって、本発明の結合分子の第1および/または第2の結合ドメインのいずれかまたは両方に、何か、例えば追加のアミノ酸配列を融合することによって、その機能、すなわち標的細胞を殺傷するために標的細胞とT細胞を引き合わせることが負の影響を受ける可能性があると想像され得る。
・第1の結合ドメイン、
・第2の結合ドメイン、および
・第3の結合ドメイン、
の順で、1つのポリペプチド上に存在する。
(a)第1の結合ドメインが、ヒトおよび非ヒト霊長類の細胞上の細胞表面分子に結合することができるドメインであり、
(b)第2の結合ドメインが、ヒトおよび非ヒト霊長類の細胞上のT細胞CD3受容体複合体に結合することができるドメインであり、かつ
(c)第3の結合ドメインが、ヒトおよび非ヒト霊長類の血清アルブミンに結合することができるドメインである、
3つの結合ドメインを含む。
(a)第1の結合ドメインが、抗体由来のVLおよびVH鎖を含み、かつ/または
(b)第2の結合ドメインが、抗体由来のVLおよびVH鎖を含む、
結合分子に関連する。
(a)WO 2008/119567のSEQ ID NO: 27に示されるCDR-L1、WO 2008/119567のSEQ ID NO: 28に示されるCDR-L2およびWO 2008/119567のSEQ ID NO: 29に示されるCDR-L3;
(b)WO 2008/119567のSEQ ID NO: 117に示されるCDR-L1、WO 2008/119567のSEQ ID NO: 118に示されるCDR-L2およびWO 2008/119567のSEQ ID NO: 119に示されるCDR-L3;ならびに
(c)WO 2008/119567のSEQ ID NO: 153に示されるCDR-L1、WO 2008/119567のSEQ ID NO: 154に示されるCDR-L2およびWO 2008/119567のSEQ ID NO: 155に示されるCDR-L3
から選択されるCDR-L1、CDR-L2およびCDR-L3を含むVL領域を含む本発明の結合分子が、特に好ましい。
(a)WO 2008/119567のSEQ ID NO: 12に示されるCDR-H1、WO 2008/119567のSEQ ID NO: 13に示されるCDR-H2およびWO 2008/119567のSEQ ID NO: 14に示されるCDR-H3;
(b)WO 2008/119567のSEQ ID NO: 30に示されるCDR-H1、WO 2008/119567のSEQ ID NO: 31に示されるCDR-H2およびWO 2008/119567のSEQ ID NO: 32に示されるCDR-H3;
(c)WO 2008/119567のSEQ ID NO: 48に示されるCDR-H1、WO 2008/119567のSEQ ID NO: 49に示されるCDR-H2およびWO 2008/119567のSEQ ID NO: 50に示されるCDR-H3;
(d)WO 2008/119567のSEQ ID NO: 66に示されるCDR-H1、WO 2008/119567のSEQ ID NO: 67に示されるCDR-H2およびWO 2008/119567のSEQ ID NO: 68に示されるCDR-H3;
(e)WO 2008/119567のSEQ ID NO: 84に示されるCDR-H1、WO 2008/119567のSEQ ID NO: 85に示されるCDR-H2およびWO 2008/119567のSEQ ID NO: 86に示されるCDR-H3;
(f)WO 2008/119567のSEQ ID NO: 102に示されるCDR-H1、WO 2008/119567のSEQ ID NO: 103に示されるCDR-H2およびWO 2008/119567のSEQ ID NO: 104に示されるCDR-H3;
(g)WO 2008/119567のSEQ ID NO: 120に示されるCDR-H1、WO 2008/119567のSEQ ID NO: 121に示されるCDR-H2およびWO 2008/119567のSEQ ID NO: 122に示されるCDR-H3;
(h)WO 2008/119567のSEQ ID NO: 138に示されるCDR-H1、WO 2008/119567のSEQ ID NO: 139に示されるCDR-H2およびWO 2008/119567のSEQ ID NO: 140に示されるCDR-H3;
(i)WO 2008/119567のSEQ ID NO: 156に示されるCDR-H1、WO 2008/119567のSEQ ID NO: 157に示されるCDR-H2およびWO 2008/119567のSEQ ID NO: 158に示されるCDR-H3;ならびに
(j)WO 2008/119567のSEQ ID NO: 174に示されるCDR-H1、WO 2008/119567のSEQ ID NO: 175に示されるCDR-H2およびWO 2008/119567のSEQ ID NO: 176に示されるCDR-H3
から選択されるCDR-H1、CDR-H2およびCDR-H3を含むVH領域を含む。
(a)WO 2008/119567のSEQ ID NO: 17または21に示されるVL領域およびWO 2008/119567のSEQ ID NO: 15または19に示されるVH領域;
(b)WO 2008/119567のSEQ ID NO: 35または39に示されるVL領域およびWO 2008/119567のSEQ ID NO: 33または37に示されるVH領域;
(c)WO 2008/119567のSEQ ID NO: 53または57に示されるVL領域およびWO 2008/119567のSEQ ID NO: 51または55に示されるVH領域;
(d)WO 2008/119567のSEQ ID NO: 71または75に示されるVL領域およびWO 2008/119567のSEQ ID NO: 69または73に示されるVH領域;
(e)WO 2008/119567のSEQ ID NO: 89または93に示されるVL領域およびWO 2008/119567のSEQ ID NO: 87または91に示されるVH領域;
(f)WO 2008/119567のSEQ ID NO: 107または111に示されるVL領域およびWO 2008/119567のSEQ ID NO: 105または109に示されるVH領域;
(g)WO 2008/119567のSEQ ID NO: 125または129に示されるVL領域およびWO 2008/119567のSEQ ID NO: 123または127に示されるVH領域;
(h)WO 2008/119567のSEQ ID NO: 143または147に示されるVL領域およびWO 2008/119567のSEQ ID NO: 141または145に示されるVH領域;
(i)WO 2008/119567のSEQ ID NO: 161または165に示されるVL領域およびWO 2008/119567のSEQ ID NO: 159または163に示されるVH領域;ならびに
(j)WO 2008/119567のSEQ ID NO: 179または183に示されるVL領域およびWO 2008/119567のSEQ ID NO: 177または181に示されるVH領域;
からなる群より選択されるVL領域およびVH領域を含むT細胞CD3受容体複合体に結合できる第2の結合ドメインによって特徴づけられる。
刺激されたヒトT細胞を用いたクロム放出アッセイ
CD8+T細胞について濃縮された刺激されたT細胞を、以下のようにして得た。
ヒト血清アルブミンおよびその他の種の血清アルブミンに対するタグ付加PSMA BiTE分子の結合を確認するため、以下の血清アルブミン調製物を提供した:ヒト血清アルブミン(HSA)、Sigma A9511;アカゲザル血清アルブミン(RSA)、bioWorld 22070099;マウス血清アルブミン(MSA)、Sigma A3139;ウシ血清アルブミン(BSA)、Sigma A7906。
HSA = ヒト血清アルブミン、RSA = アカゲザル血清アルブミン、MSA = マウス血清アルブミン、BSA = ウシ血清アルブミン、「陽性」は、BiaEvalソフトウェアによって正確に決定することができなかった検出可能な結合を意味する;「陰性」は、選択された実験条件下で有意な結合がなかったことを意味する。
BiTE抗体配列をコードするpEF DHFRベクターで安定的にトランスフェクトされたチャイニーズハムスター卵巣CHO細胞を、60%の残存生存度に達するまでローラーボトル中で培養した。細胞培養上清を0.2μm濾過により清浄化し、そして固定化金属親和性クロマトグラフィー(IMAC)捕捉のために亜鉛保持キレートゲルFractogel EMD Chelate(Merck, Darmstadt)を満たしたカラムに適用した。
親のヒトEpCAM BiTE分子の例は、WO 2005/040220に記載されている。
エフェクター(ヒトPBMC、2 x 106/ウェル)および標的細胞(MDA-MB-453、1 x 105/ウェル)を、異なるEpCAM BITE濃度(250 ng/mL〜4.2 pg/mL)の存在下、20:1のエフェクター対標的比で共培養する。16〜20時間後、ToxiLight試薬を添加し、発光を測定する(詳細な説明についてはSOP-BIA-110-012を参照のこと)。
相対効力 = EC50サンプル/ EC50標準
HIV-1 HXB2株(Uniprot KB, Acc. No. P04578)のHIV gp160(gp140)の細胞外ドメインを、EpCAMの膜貫通および細胞内ドメインに融合させた。この融合タンパク質のオープンリーディングフレームを、標準的な手順にしたがいpEF DHFRベクターにクローニングし(細胞表面分子を用いてCHO細胞をトランスフェクトし適当な標的細胞を作製する一般的手順は、WO 2008/119567から導かれる)、その後にこれを示された二重特異性コンストラクトの分析のために使用した。
以下に記載される二重特異性コンストラクトのHIV標的結合ドメインは、ヒトCD4起源のものである。CD4(1+2)と命名されたコンストラクトは、ヒトCD4の最初の2つのドメインを含む。コンストラクトCD4 D1.1またはCD4 D1.2は、1つの点変異を含むヒトCD4ドメイン1起源のものであり、これはChen, W., et al. (2011, J Virol 85(18):9395-9405)に記載されている。本明細書に記載される2つのコンストラクトはBiTEに関連するそれらの適用性が証明されているが、それはこれらの2つのCD4ドメイン1コンストラクトに限定されるものではない、すなわち、記載されている二重特異性形式は、すべての記載されているそれらの変種に適用され得る、特に公開されている変種CD4 D1.3〜CD4 D1.19に関して適用され得るものである。概ね、細胞膜上でアクセス可能となっているHIVタンパク質に対する固有の結合部分を有する分子は、二重特異性の状況で適用可能であり、例えば、そのコアペプチド配列等のヒトCD4の一部のみを含むコンストラクト、ヒトCD4タンパク質のアプタマーまたは例えばJames H. M. Simon(1993, J. Exp. Med, Volume 177, April 1993, 949-954)によって解説されているgp120結合に関与するヒトCD4挿入物を含むラットCD4のキメラが、BiTEの状況で使用され得る。ヒトCD4起源の結合ドメインとは別に、抗HIVヒトモノクローナル抗体の抗体特異性、例えばVH-VLまたはVL-VHの並びのscFv形式のB12、VRC01または4E10もまた、BiTEの状況で適用可能であり、それらの二重特異性結合および細胞毒性活性に関連して特徴づけられている。記載されているHIV gp120結合ドメインを、異種間特異的(cross-specific)ヒトCD3結合体に融合させた。標準的な手順にしたがいこれらの親HIV特異的コンストラクトの長寿命版を設計およびクローニングし、それを以下で特徴づける。
刺激されたヒトT細胞を用いたFACSベースの細胞毒性アッセイ
CD8+T細胞について濃縮された刺激されたT細胞を、以下に記載されるようにして得た。
ペトリ皿(直径145mm、Greiner bio-one GmbH, Kremsmunster)を、最終濃度1μg/mlの市販の抗CD3特異的抗体(OKT3、Orthoclone)および抗CD28(Art.No. 340975、BD)を用いて、37℃で1時間コーティングした。未結合のタンパク質を、PBSを用いた1回の洗浄工程により除去した。安定化型グルタミン/10% FCS/IL-2 20 U/ml(Proleukin(登録商標)、Chiron)を含む100mlのRPMI 1640中3〜5 x 107個のヒトPBMCを、プレコートしたペトリ皿に添加し、3日間刺激した。3日目に、細胞を回収し、RPMI 1640で1回洗浄した。IL-2を最終濃度20 U/mlとなるよう添加し、そして細胞を再度、上記の細胞培養培地中で1日培養した。
係数*:係数は、その親のABPタグ非含有二重特異性分子に対する示された二重特異性分子のEC50値の差を表している。
係数*:係数は、その親のABPタグ非含有二重特異性分子に対する示された二重特異性分子のEC50値の差を表している。
ヒト血清アルブミンおよびその他の種の血清アルブミンに対するタグ付加HIV特異的BiTE分子の結合を確認するため、以下の血清アルブミン調製物を提供した:ヒト血清アルブミン(HSA)、Sigma A9511;マウス血清アルブミン(MSA)、Sigma A3139。
ヒトCD3に対するC末端ABPタグ付加HIV BiTE分子の結合を確認するため、標準的な手順にしたがいCD3エピトープを含むヒトCD3ペプチドをヒトFcに融合させ、これを親和性の測定に使用した。
係数*:親のABPタグ非含有BiTE分子との比較で減少したCD3親和性
HIV gp120に対するN末端ABPタグ付加HIV BiTE分子の結合を確認するため、以下のHIV gp120を提供した:組み換えHIV-1 IIIBエンベロープ糖タンパク質gp120(バキュロウイルス)、製品# 1001、Immunodiagnostics, Incorporation。
係数*:親のABPタグ非含有BiTE分子との比較で減少したHIV gp120親和性
ヒト胎児由来腎臓(HEK 293−F、Invitrogen)細胞を、293フェクチン(製造元のマニュアルにしたがう、Invitorogen)を用いてBiTE抗体配列をコードする200μgのpEF DHFRベクターで一過的にトランスフェクトした。トランスフェクト細胞を、エルレンマイヤー細胞培養フラスコ中、37℃、135rpm、5% CO2の下で72時間培養した。あるいは、同BiTE抗体配列をコードするpEF DHFRベクターで安定的にトランスフェクトされたチャイニーズハムスター卵巣CHO細胞を、60%の残存生存度に達するまでローラーボトル中で培養した。細胞培養上清を、4'000rpmで10分間遠心分離することによって清浄化し、その後にろ過(0.2μm)し、そして固定化金属親和性クロマトグラフィー(IMAC)捕捉のために亜鉛保持キレートゲルFractogel FMD Chelate(Merck, Darmstadt)を満たしたカラムに適用した。
Claims (18)
- 少なくとも1つのポリペプチド鎖中に含まれる少なくとも3つの結合ドメインを含む二重特異性抗体であって、
(a)第1の結合ドメインが、抗体由来のVL鎖およびVH鎖を含み、かつPSMAに結合し、
(b)第2の結合ドメインが、T細胞CD3受容体複合体に結合することができる結合ドメインであり、かつ抗体由来のVL鎖およびVH鎖を含み、ヒトおよびコモンマーモセット(Callithrix jacchus)、ワタボウシタマリン(Saguinus oedipus)またはコモンリスザル(Saimiri sciureus)のCD3ε鎖のエピトープに結合し、該エピトープが、SEQ ID NO:2、4、6または8からなる群に含まれるアミノ酸配列の一部でありかつ少なくともアミノ酸配列Gln-Asp-Gly-Asn-Glu(SEQ ID NO:103)を含む、結合ドメインであり、
(c)第3の結合ドメインが、血清アルブミンに結合することができる結合ドメインであり、該第3の結合ドメインが、第2の結合ドメインのC末端に位置し、
該3つの結合ドメインが、N末端からC末端に向かって、
・第1の結合ドメイン、
・第2の結合ドメイン、および
・第3の結合ドメイン、
の順で、1つのポリペプチド上に存在する、
単一ポリペプチド鎖からなる、二重特異性抗体。 - 前記二重特異性抗体の第3の結合ドメインが、scFvまたは単一ドメイン抗体である、請求項1記載の二重特異性抗体。
- (a)第1の結合ドメインが、ヒトおよび非ヒト霊長類の細胞上のPSMAに結合することができ、
(b)第2の結合ドメインが、ヒトおよび非ヒト霊長類の細胞上のT細胞CD3受容体複合体に結合することができ、かつ
(c)第3の結合ドメインが、ヒトおよび非ヒト霊長類の血清アルブミンに結合することができる、
請求項1または2記載の二重特異性抗体。 - 血清アルブミンに結合することができる第3の結合ドメインが、コンビナトリアルライブラリまたは抗体結合ドメインに由来する、請求項1〜3のいずれか一項記載の二重特異性抗体。
- 第3の結合ドメインが、10〜25アミノ酸残基を含む、請求項1〜4のいずれか一項記載の二重特異性抗体。
- 血清アルブミンに結合することができる第3の結合ドメインが、アミノ酸配列Asp-Xaa-Cys-Leu-Pro-Xaa-Trp-Gly-Cys-Leu-Trp(SEQ ID NO:102)を含み、Xaaが任意のアミノ酸である、請求項1〜5のいずれか一項記載の二重特異性抗体。
- 血清アルブミンに結合することができる第3の結合ドメインが、単一ドメイン抗体のCDRに由来する、請求項1〜5のいずれか一項記載の二重特異性抗体。
- 第3の結合ドメインが、≦500nMの親和性(KD)で血清アルブミンに結合する、請求項1〜7のいずれか一項記載の二重特異性抗体。
- 10%ヒト血清アルブミン存在下でのエフェクター細胞による標的細胞の溶解を測定するインビトロアッセイにおいて細胞毒性活性を示す、請求項1〜8のいずれか一項記載の二重特異性抗体。
- 1つまたは複数のさらなる異種ポリペプチドを含む、請求項1〜9のいずれか一項記載の二重特異性抗体。
- SEQ ID NO:51、52、54、55、57、58、60、61、75、76、81、82、85、86、90、91、95、96、100または101に示されるアミノ酸配列を含む、請求項1〜6のいずれか一項記載の二重特異性抗体。
- 請求項1〜11のいずれか一項において定義される二重特異性抗体をコードする、核酸分子。
- 請求項12において定義される核酸分子を含む、ベクター。
- 請求項12において定義される核酸分子または請求項13において定義されるベクターで形質転換またはトランスフェクトされた、宿主細胞。
- 請求項1〜11のいずれか一項記載の二重特異性抗体の産生方法であって、請求項1〜11のいずれか一項において定義された二重特異性抗体の発現を可能にする条件下で請求項14において定義された宿主細胞を培養する工程、および、産生された二重特異性抗体を培養物から回収する工程を含む、方法。
- 請求項1〜11のいずれか一項記載の二重特異性抗体または請求項15記載の方法にしたがい産生された二重特異性抗体を含む、薬学的組成物。
- 増殖性疾患、炎症性疾患、感染症、および自己免疫疾患からなる群より選択される疾患の予防、処置または改善に使用するための、請求項1〜11のいずれか一項記載の二重特異性抗体または請求項15記載の方法にしたがい産生された二重特異性抗体。
- 請求項1〜11のいずれか一項において定義された二重特異性抗体、請求項12において定義された核酸分子、請求項13において定義されたベクター、または請求項14において定義された宿主細胞を含む、キット。
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