JP5291671B2 - 融合タンパク質の免疫原性の低減 - Google Patents
融合タンパク質の免疫原性の低減 Download PDFInfo
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Landscapes
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- Peptides Or Proteins (AREA)
Description
本願は、2001年3月30日に出願された米国仮出願特許出願シリアル番号60/280,625号(その全開示内容は言及によって本願に組込まれる)に基づく優先権およびその利益を主張する。
本発明は概括的に言えば、治療剤として免疫原性が低減されているか免疫原性のない修飾された融合タンパク質を製造および使用するための方法および組成物に関する。より具体的には、本発明は、T−細胞エピトープ候補を識別し、そうしたエピトープを除去するようにアミノ酸配列を修正することにより免疫原性を低減した融合タンパク質に関する。
多くの治療用タンパク質は正常なヒトタンパク質である。例えば、インターロイキン−2、エリスロポエチンおよび成長ホルモンは、すべて、通常これらのタンパク質を既に内成的なレベルで産生しているヒトに与えるヒトタンパク質である。一般に、これらのタンパク質を治療用に用いる場合、完全に正常なヒトタンパク質に対する免疫反応は稀にしか起こらない。
本発明は、治療目的で使用される免疫原性の低減された融合タンパク質を産生するのに有用な方法および組成物を特色とする。例えば、本発明はイムノサイトカイン、イムノフュージン(immunofusins;免疫融合体)、イムノリガンド(immunoligands;免疫リガンド)、他の抗体およびFc融合タンパク質、サイトカイン−サイトカイン融合タンパク質および免疫原性の低減されたアルブミン融合タンパク質を特色とする。
治療用途での使用のために患者に投与される、抗体を含むタンパク質はすべて、レシピエントホストにおいて免疫反応を引き起こす可能性を有する。この免疫反応は、Tリンパ球(T細胞)によって仲介されるが、これは、次いで、Bリンパ細胞(B細胞)を起動して抗体を産生させる。治療剤に対する抗体産生は、治療剤のより多くの迅速な除去に結びつき、アレルギー反応を引き起こすおそれがあるため不利益である。
QKTIDRLAGKPTH(配列番号:8)をQKTADRTAGKPTH(配列番号:9)に変更。
KKLVAASQAALGL(配列番号:13)をKKLVAASQAATTA(配列番号:14)に変更。
HuKS−IL2は、ヒト化されたVHおよびVL領域をヒトのHおよびL鎖定常領域と組み合わせてなる。H鎖は、前に述べたようにそのカルボキシル末端をヒトIL−2の成熟配列に融合した。このH鎖はγ1アイソタイプであり、Fcレセプターに高い親和性がある。この高い親和性のためHuKS−IL2は血液循環からすばやく取り除かれた。特定の理論に拘束されるものではないが、HuKS−IL2の除去は肝臓(クッパー(Kupffer)細胞)および脾臓(抗原提示細胞)中のFcR担持細胞を介して生じると推測される。
(1)Hu14.18−IL2、完全に異なるヒト化されたV領域を備えているが正確に同じC領域およびIL−2との融合接合部を有する分子;
(2)VH1、ヒト残基に張り合わせされた(veneered)、表面露出マウスB細胞エピトープを備えたマウスV領域に由来する、VHおよびVLの領域中にT−細胞エピトープを含まないhuKS−IL2の脱−免疫形;
(3)VH2、ヒト残基に張り合わせされた(veneered)、表面露出マウスB細胞エピトープを備えたマウスV領域に由来する、CDR3中に1個の残存T−細胞エピトープを含むhuKS−IL2の脱−免疫形で、このVHは1個のT−細胞エピトープを含む;
(4)KOLまたはEU Cγ1領域(KSではなく)のいずれかで構築された425−IL2(アロタイプの活性と比較するため);
(5)huKS−mIL2−、マウスC領域およびマウスIL−2に融合したhuKS V領域を備えた分子;
(6)ヒトFc−IL2;
(7)ヒトFcのみ;
(8)ヒトIL−2のみ。
ペプチドスレッディング分析により、強いMHC可能性を有する2個の重複するペプチドセグメントが、イムノサイトカインのFcとIL2部分の間の接合部に識別された。潜在的なT−細胞エピトープのペプチドスレッディングおよび識別は、Carr(WO00/34317)に開示されるように実行した。アミノ酸の変更は、既存の潜在的なMHCクラスII結合エピトープを除去するが、新たな潜在的なMHCクラスIIエピトープを導入しないように行われた。
接合部配列LSLSPGK−AP(配列番号:17)のLNLSPGA−AP(配列番号:19)への修飾(「LSLSからLNLSへ」)(ここで、ハイフンはイムノサイトカインhuKS−IL2接合部である)によっても、接合部由来ペプチド配列はある種のヒトのMHCクラスIIには結合可能である。しかし、KS−IL2タンパク質が哺乳類細胞中で発現され分泌される場合、タンパク質は、NXS/T配列であるため接合部近傍でN−グリコシル化される。
反応性エピトープの修飾による免疫原性の低減を、LSLSをATATに変化させることにより以下のように直接試験する。この配列を模倣する合成ペプチドは、樹状細胞(DC)などの古典的抗原提示細胞の免疫反応を変更する。以下の合成ペプチド:
ヒト血清アルブミン(HSA)は、その著しい半減期の長さのため、生体内で広く分配されるとともに酵素的または免疫学的機能が欠如していることから、治療用のペプチド/タンパク質用の担体として用いられてきた。遺伝子的に操作されたHSA−CD4ハイブリッドは、生体外で可溶性CD4に似た抗ウイルス性を示すとともにCD4+細胞中へのヒト免疫不全ウイルスの侵入を阻むことが示されている(Yehら、PNAS 89:1904−190S、1992年)。したがって、HSAに生体に影響するペプチドを遺伝的に融合することは、分泌される治療用HSA誘導体を設計および回復に有用である。しかし、すべての融合タンパク質と同様に、HSA−CD4は新規な接合部を有し、これは免疫原になり得るとともに、MHCクラスII分子上で提示され得るT−細胞エピトープを含む。実施例1、2、3および4の方法を使用したHSAとCD4との間の接合部の分析はペプチドを、MHCと結合する可能性を識別する。潜在的に免疫原性の配列は、潜在的なTおよびB細胞エピトープを減少または除去させて免疫原性を低減するために修飾される。同様に、免疫原性を低減するために新規なグリコシル化部位を接合領域に導入することができる。
いくつかの例では、X−Fcの向きの融合タンパク質を創出するのが有利である。これらの構成体により、標的タンパク質はN−末端融合タンパク質であり、Fc断片が続く。例えば、グルカゴン様ペプチド(GLP−1)は、その活性のために遊離N−末端が必要であり、したがって、GLP−1−Fc融合体が有用である。
ENBRELまたはエタネルセプト(FDAによって承認されたX−Fc融合タンパク質)は、慢性関節リウマチを治療するために使用される腫瘍壊死因子(TNF)阻害剤である。ENBRELは、ヒトIgG1のFcタンパク質に結合されたTNFレセプターの細胞外のリガンド結合ドメインからなる二量体の融合タンパク質である。TNFR−Fcは、TNFのそのレセプターへの結合を競争的に阻害し、結合したTNFを生物学的に不活性にし、炎症性の活性を顕著に低減させる。GLP−1−Fcについて上述したように、TNFR−Fcは潜在的なT−細胞エピトープを含む新規な接合部を有する。
Fc−IL12−IL2などのFc−X−Yの配置の融合タンパク質は、潜在的に免疫原性である多数の新規な融合接合部を有する。例えば、Fc−IL12は、他のFc−X融合タンパク質またはイムノサイトカイン(実施例1)に類似した融合接合部を有するが、サイトカインIL12の使用のために新規である。融合接合部は免疫原性の結合サイトについて分析され、従って修飾される。第2に、融合タンパク質を構成する2個の異なるサイトカインとともに、実施例5に記載されたそれに匹敵するX−Y融合接合部がある。ペプチドスレッディング分析が融合接合部の各々について使用される。
IL4−Fc−GMCSFなどのX−Fc−Y配置の融合タンパク質は、潜在的なT−細胞エピトープを含む多数の新規な融合接合部を有する。IL4−Fcは、他のX−Fc融合タンパク質(実施例6および7)と類似している接合であるが、サイトカインIL4の使用のために新規である。例えば、ヒンジ領域を使用するFc、CH2およびヒトγ1からのCH3領域を用いる形態が使用される。前述のように、pdCshuFcγl中のγ1ヒンジ配列は、IgG1中の軽鎖とのジスルフィド結合を形成するCys残基を除去するCysのSerへの変異(下線)を含んでもよいし(Loら(1998)Protein Engineering 11:495−500)、これにより、分析のための第3の潜在的に免疫原の融合接合部を生成してもよい。融合接合部は潜在的なT−細胞エピトープについて分析し、実施例1〜4の方法によって修飾した。
抗体またはハイブリッドアイソタイプとの抗体に基づく融合タンパク質を構築し、その結果、異なるアイソタイプの有用な特徴を単一の分子中に組み合わせることは多くの場合有用である。ハイブリッドアイソタイプとの融合タンパク質は免疫原性を低減するために本発明によって修飾してもよい。
Fcエリスロポエチン融合タンパク質を生成するために、次の発現プラスミドを標準的分子生物学技術を使用して構築した。アミノ酸置換His32Gly、Cys33Pro、Trp88CysおよびPro90Alaをもたらす変異を備えた配列をコードするヒトエリスロポエチンの形態を含むXmaI−XhoI DNA断片を、WO01/36489に示されるように、使用した。対応するタンパク質配列は配列番号:56
本発明によれば、融合タンパク質の接合領域のエピトープは、その免疫系との相互作用を調整するためにタンパク質中に変異体を導入する方法を使用して修飾することができる。本発明によれば、本発明によって適用することができる当業者には知られた方法は、先行技術(WO92/10755およびWO96/40792(Novo Nordisk)、EP 0519 596(Merck & Co.)、EP 0699 755(Centro de Immunologia Moelcular)、WO98/52976およびWO98/59244(Biovation Ltd.)に記載されたもの、さらに関連する方法を含む。
(1)予め定義した長さのペプチドセグメントの1次配列を走査し、存在する疎水性脂肪族と芳香族側鎖をすべて識別する。(2)疎水性脂肪族側鎖には芳香族側鎖用のそれより大きな値、好ましくは芳香族側鎖に割り当てる値の約2倍を割り当てる(例えば、疎水性脂肪族側鎖に対しては値2を、芳香族側鎖に対しては値1を割り当てる)。(3)ペプチド内の予め定義した一定の長さの各重複するアミノ酸残基セグメント(ウィンドウ)について存在が決定された値を合計し、特定のセグメント(ウィンドウ)に対する値の合計を、セグメント(ウィンドウ)の中間位置で単一のアミノ酸残基、好ましくは、サンプリングされたセグメント(ウィンドウ)の中間点付近の残基に割り当てる。この手続きを、サンプリングされた各重複するアミノ酸残基セグメント(ウィンドウ)について繰り返す。したがって、ペプチドの各アミノ酸残基は、特定のセグメント(ウィンドウ)内に存在するT細胞エピトープの可能性に関係のある値を割り当てられる。(4)上記ステップ3に記載するように計算し割り当てた値は、評価するアミノ酸残基配列全体のアミノ酸座標に対してプロットすることができる。(5)予め定義した値(例えば値1)のスコアを有する配列のすべての部分は、T細胞エピトープを含むと認められ、必要であれば、修飾することができる。
(ΔGbind)=(ΔGo)+(ΔGhbxNhb)+(ΔGionicxNionic)+(ΔGlipoxNlipo)+(ΔGrot+Nrot)+(EvdW)
式中、Nは特定の項の相互作用を特徴付ける数であり、1つの実施形態では、ΔGo、ΔGhb、ΔGionic、ΔGlipoおよびΔGrotは、それぞれ5.4、−4.7、−4.7、−0.17および1.4の値を与えられる定数である。
Nhb=Σh-bondsf(ΔR,Δα)×f(Nneighb)×fpcs
によって計算される。
f(ΔR,Δ−α)=f1(ΔR)×f2(Δα)
ここで、f1(ΔR)=1(ΔR<=TOLの場合)、
または =1−(ΔR−TOL)/0.4(ΔR<=0.4+TOLの場合)、
または =0(ΔR>0.4+TOLの場合)。
さらに、f2(Δα)=1(Δα<30°の場合)
または =1−(Δα−30)/50(Δα<=80°の場合)
または =0(Δα>80°の場合)。
ΔRはH−O/N水素結合長さの理想的な値(=1.9Å)からの偏差、
Δαは水素結合角度∠N/O-H,O/Nの理想的な値(=180°)からの偏差、
f(Nneighb)は、タンパク質表面の凹面と凸面の部分を識別し、したがってタンパク質表面で見られるものではなくポケットで見られる極性相互作用に大きな重みを割り当てる。この関数は下記方程式4:
f(Nneighb)=(Nneighb/Nneighb,0)α(ここで、α=0.5)
によって計算される。
Nneighb,0=定数25である。
fpcs=β(Apolar/NHB<10Å2の場合)、
またはfpcs=1(Apolar/NHB>10Å2の場合)
Apolarはタンパク質リガンド接触表面の大きさであり、
NHBは水素結合の数であり、
βは定数=1.2である。
Nlipo=ΣILf(rIL)
f(rIL)はすべての脂肪親和性リガンド原子について、1また、すべての脂肪親和性タンパク質原子についてLであり、以下の基準により計算される:
f(rIL)=1(rIL<=R1f(rIL)=(rIL−R1)/(R2−R1)でR2<rIL>R1の場合、
f(rIL)=0(rIL>=R2の場合)。
R2=R1+3.0であり、
r1vdwは、原子1のファンデアワールスの半径であり、
rL vdwは、原子Lのファンデアワールスの半径である。
Evdw=ε1ε2((r1 vdw+r2 vdw)12/r12−(r1 vdw+r2 vdw)6/r6)。
r1 vdw+r2 vdwはファンデアワールスの原子半径であり、
rは1対の原子間の距離である。
本発明は他の具体的なかたちでその精神または基本的な特徴から離れることなく具体化することができる。さらなる具体例として、ここに記載されている発明に限定するというよりは実例として全ての面において、従って考えうる。本発明の範囲内で、従って、先述の明細書によってというよりはさらなる特許請求の範囲によって意図される。さらに、本特許請求の範囲の同等の意味および範囲内に起こる全ての変化は、その中に包括されることを意図している。
ここで上記に意図する、全ての特許、特許明細書および化学文献は、すべてこの明細書の中に組み込まれる。
Claims (5)
- 第1のタンパク質が重鎖C−末端にMHEALHNHYTQKSLSLSPGK(配列番号:60)を含むIg分子であり、該C−末端側のアミノ酸であるリジンを介して、第2のタンパク質であるサイトカインのN−末端側のアミノ酸と連結する、該第1のタンパク質と該第2のタンパク質とを含む融合タンパク質の、非自己T細胞エピトープを除去することにより免疫原性を低減する方法であって、前記融合タンパク質の該Ig分子の重鎖C末端のアミノ酸配列LSLSをATATに変更し、MHEALHNHYTQKSATATPGK(配列番号:61)の重鎖C−末端を形成することを含む方法。
- 血中半減期を増大するために、前記Ig重鎖のC−末端のリジンをアラニンまたはロイシンに変更することを特徴とする、請求項1に記載の方法。
- 前記サイトカインがIL−2またはIL−12であることを特徴とする、請求項1に記載の方法。
- 前記Ig分子が抗体部分であることを特徴とする、請求項1に記載の方法。
- 前記Ig分子が抗体のFc領域であることを特徴とする、請求項1に記載の方法。
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