JP4580340B2 - 最適化Fc変異体およびそれらの生成方法 - Google Patents
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- JP4580340B2 JP4580340B2 JP2005501987A JP2005501987A JP4580340B2 JP 4580340 B2 JP4580340 B2 JP 4580340B2 JP 2005501987 A JP2005501987 A JP 2005501987A JP 2005501987 A JP2005501987 A JP 2005501987A JP 4580340 B2 JP4580340 B2 JP 4580340B2
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Description
本発明は、新規最適化Fc変異体、それらの生成のための工学処理方法、および特に治療目的へのそれらの適用に関する。
抗体は、特定の抗原に結合する免疫タンパク質である。ヒトやマウスを含む殆どの哺乳動物において、抗体は、対になった重鎖と軽鎖のポリペプチド鎖から構築される。各々の鎖は、個々の免疫グロブリン(Ig)ドメインからできており、従って一般用語の免疫グロブリンは、このようなタンパク質に対して使用される。各鎖は、2個の別個の領域からなり、これらは可変および定常領域と呼ばれる。軽鎖と重鎖の可変領域は、抗体間でかなりの配列多様性を示し、標的抗原の結合を担う。定常領域は、乏しい配列多様性を示し、重要な生化学的事象を誘起する数々の天然タンパク質の結合を担う。ヒトでは、5種の異なるクラスの抗体があり、IgA(サブクラスIgA1およびIgA2を含む)、IgD、IgE、IgG(サブクラスIgG1、IgG2、IgG3およびIgG4を含む)、およびIgMが含まれる。これらの抗体クラス間を区別する顕著な特徴は、それらの定常領域であり、一方V領域には微妙な違いが存在することがある。図1は、本明細書で免疫グロブリンの一般的構造特徴を説明する例として用いられるIgG1抗体を示す。IgG抗体は、2本の重鎖および2本の軽鎖から構成される四量体タンパク質である。IgG重鎖は、N末端からC末端へVH−Cγ1−Cγ2−Cγ3(各々、重鎖可変ドメイン、定常ガンマ1ドメイン、定常ガンマ2ドメインおよび定常ガンマ3ドメインを表す)の順に連結された4個の免疫グロブリンドメインから構成される。IgG軽鎖は、N末端からC末端へVL−CL(各々、軽鎖可変ドメインおよび軽鎖定常ドメインを表す)の順に連結された2個の免疫グロブリンドメインから構成される。
本発明は、数々の治療関連特性について最適化されたFc変異体を提供する。
図1。抗体の構造および機能。示されているのは、pdb受託コード1CE1(James et al., 1999, J Mol Biol 289:293-301)由来のヒト化Fab構造、およびpdb受託コード1DN2(DeLano et al., 2000, Science 287:1279-1283)由来のヒトIgG1Fc構造を使用してモデル化された、完全長ヒトIgG1抗体のモデルである。FabとFc領域を連結する可撓性ヒンジは示していない。IgG1は、ヘテロ二量体のホモ二量体であり、2本の軽鎖および2本の重鎖からなる。抗体を構成するIgドメインを表示しており、それには軽鎖のVLおよびCL、重鎖のVH、Cガンマ1(Cγ1)、Cガンマ2(Cγ2)およびCガンマ3(Cγ3)が含まれる。Fc領域を表示している。関連タンパク質の結合部位を表示しており、それには可変領域の抗原結合部位、並びにFc領域のFcγR類、FcRn、C1qおよびプロテインAおよびGの結合部位が含まれる。
本発明がより詳細に理解されるように、数個の定義を以下に記載する。かかる定義は、文法的に均等なものを包含することを意図している。
好ましい実施態様では、本発明の抗体は、ヒト化されている。現在のモノクローナル抗体技法を使用して、事実上同定可能ないかなる標的抗原に対しても、ヒト化抗体を産生することができる[Stein, Trends Biotechnol. 15:88-90 (1997)]。非ヒト(例えば、マウス)抗体のヒト化形態は、非ヒト免疫グロブリンから誘導された最小配列を含有する、免疫グロブリン、免疫グロブリン鎖またはそれらのフラグメント(Fv、Fc、Fab、Fab'、F(ab')2または他の抗体の抗原結合下位配列など)のキメラ分子である。ヒト化抗体には、レシピエント(recipient)の相補性決定領域(CDR)を形成する残基が、所望の特異性、親和性および能力を有するマウス、ラットまたはウサギなどの非ヒト種(ドナー抗体)のCDR由来の残基により置き換えられているヒト免疫グロブリン(レシピエント抗体)が含まれる。ある例では、ヒト免疫グロブリンのFvフレームワーク残基が、対応する非ヒト残基により置き換えられる。ヒト化抗体はまた、レシピエント抗体にも移入されたCDRまたはフレームワーク配列にも見出されない残基を含んでもよい。一般に、ヒト化抗体は、CDR領域の全部または実質的に全部が非ヒト免疫グロブリンのものに対応し、全部または実質的に全部のFR領域がヒト免疫グロブリン共通配列のものである、少なくとも1個、そして典型的に2個の可変ドメインの実質的に全部を含む。ヒト化抗体はまた、最適には、典型的にヒト免疫グロブリンのものである免疫グロブリン定常領域(Fc)の少なくとも一部も含む[Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992)]。非ヒト抗体をヒト化する方法は当分野で周知である。一般的に、ヒト化抗体は、非ヒトである供給源からそれに導入された1個またはそれ以上のアミノ酸残基を有する。これらの非ヒトアミノ酸残基は、しばしば移入残基(import residue)と呼ばれ、それは典型的に移入可変ドメインから取られたものである。ヒト化は、本質的に、Winter および共同研究者の方法[Jones et al., supra; Riechmann et al., supra; and Verhoeyen et al., Science, 239:1534-1536 (1988)]に従って、齧歯類CDRまたはCDR配列を対応するヒト抗体の配列の代わりに置換することにより実施できる。例えば、ヒトタンパク質C[O'Connor et al., Protein Eng. 11:321-8 (1998)]、インターロイキン2受容体[Queen et al., Proc. Natl. Acad. Sci., U.S.A. 86:10029-33 (1989)]、およびヒト上皮成長因子受容体2[Carter et al., Proc. Natl. Acad. Sci. U.S.A. 89:4285-9 (1992)]に結合する抗体など、さらなるヒト化マウスモノクローナル抗体の例も当分野で知られている。従って、かかるヒト化抗体はキメラ抗体であり(米国特許第4,816,567号)、そこでは無傷のヒト可変ドメインより実質的に少ないものが、対応する非ヒト種由来配列により置換されている。実際には、ヒト化抗体は、典型的に、いくつかのCDR残基およびおそらくいくつかのFR残基が齧歯類抗体の類似部位由来残基により置換されているヒト抗体である。
本発明は、Fc変異体を生成させるのに使用し得る工学処理方法を提供する。過去のFc工学処理の試みを妨げてきた主な障害は、部分的には、不十分な工学処理戦略および方法のために、そして抗体産生およびスクリーニングが低処理量である性質のために、修飾におけるランダムな試みしか可能ではなかったことである。本発明は、これらの短所を克服する工学処理方法に関する。様々な設計戦略、コンピューター処理スクリーニング方法、ライブラリー生成方法並びに実験的産生およびスクリーニング方法が企図されている。これらの戦略、アプローチ、技法および方法は、個別に、または様々な組合せで、最適化Fc変異体を工学処理するのに適用し得る。
所望の特性について最適化されたFc変異体を生成させるための最も効率的なアプローチは、その目標に対して工学処理の努力を向けることである。従って、本発明は、最適化Fc変異体を工学処理するのに使用し得る設計戦略を教示する。設計戦略の使用は、Fc工学処理を先導することを意味するが、Fc変異体を工学処理に使用した設計戦略に基づく特定の最適化特性に制限することを意味しない。一見するとこれは直感に反すると思われるかもしれない;しかしながら、その妥当性は、タンパク質およびタンパク質−タンパク質複合体の構造、安定性、溶解性および機能を決定する微妙な相互作用の膨大な複雑さから演繹される。どのタンパク質の位置、残基、相互作用などが設計目標のために重要であるかを予想する努力をすることはできるが、しばしば決定的なものは予想できない。タンパク質の構造、安定性、溶解性および機能に対する効果は、好都合であろうと不都合であろうと、しばしば予見できない。そのうえ、タンパク質に不利益または有害な無数のアミノ酸修飾がある。従って、しばしば、工学処理への最良のアプローチは、概して設計目標に対して焦点を向けているが不利益な結果を引き起こさないタンパク質の生成によりもたらされる。このように、設計戦略の主な目的は、品質の多様性の生成であり得る。極度に単純化されたレベルでは、これは勝ち目の積み重ねとみなすことができる。例として、下記のようなFcの炭水化物または特定のドメイン−ドメイン角の動揺は、どのように炭水化物およびドメイン−ドメイン角がFcの特性を決定しているかは、よくわかっていないにも関わらず、最適化Fc変異体を生成させるための妥当な設計戦略である。スクリーニングされる不利益なアミノ酸修飾の数を減らすことにより、即ち、品質多様性をスクリーニングすることにより、これらの設計戦略は実用的になる。従って、本発明で考えられている設計戦略の真の価値は、工学処理の努力を価値あるFc変異体の生成に向かわせる能力である。任意の得られる変異体の特異的価値は、実験後に決定される。
価値あるFc変異体を得るための主な障害は、膨大な数の可能性から、どのアミノ酸修飾が所望の目標を達成するかを予期することの難しさである。実際に、過去のFc工学処理の試みが有意な臨床的価値のあるFc変異体を産生するのに失敗してきた主な理由の一つは、Fc工学処理へのアプローチが今までは行き当たりばったりのアプローチを含んだことである。本発明は、定量的かつ系統的なFc変異体の工学処理を可能にするコンピューター処理スクリーニング方法を提供する。これらの方法は、典型的に、原子レベルのスコアリング(scoring)関数、側鎖回転異性体サンプリング(sampling)、およびタンパク質の配列、構造および機能の間の関係を正確に捉える進歩した最適化方法を使用する。コンピューター処理スクリーニングは、生じる膨大な多様性のフィルタリング(filtering)により、標的位置での可能性のある配列空間全体の探査を可能にする。コンピューター処理によりスクリーニングされる変異体ライブラリーは、安定な、正しく折り畳まれた、機能的な配列を効果的に増やされており、所望の目標のための有効なFcの最適化を可能にする。タンパク質の構造、安定性、溶解性および機能に対する重複配列の制限のために、ライブラリー中の多数の候補は、「無駄な」配列空間を占める。例えば、配列空間の大部分が、折り畳まれない、誤って折り畳まれた、不完全に折り畳まれた、部分的に折り畳まれた、または凝集したタンパク質をコードする。これは、Fc工学処理に特に該当する。なぜなら、Igドメインは小さいベータシート構造であり、その工学処理は、極度に要求が厳しいと証明されたからである(Quinn et al., 1994, Proc Natl Acad Sci U S A 91:8747-8751;Richardson et al., 2002, Proc Natl Acad Sci U S A 99:2754-2759)。ベータシートの表面上の無害に見える置換でさえ、激しいパッキング(packing)の矛盾をもたらすことができ、折り畳みの平衡を劇的に動揺させる(Smith et al., 1995, Science 270:980-982);ちなみに、アラニンは最悪のベータシート形成物の一つである (Minor et al., 1994, Nature 371:264-267)。ベータシートの安定性および特異性の決定要因は、極度に多数の微妙な相互作用間の繊細なバランスである。コンピューター処理スクリーニングは、主として生産的な配列空間からなるライブラリーの生成を可能にし、結果的に所望の目標のために最適化されたタンパク質を同定する機会を増加させる。事実上、コンピューター処理スクリーニングは、当たりの割合を高め、それにより実験的にスクリーニングしなければならない変異体の数を減らす。Fc工学処理へのさらなる障害は、相関または共役する変異を有効に設計する必要性である。例えば、今までに観察された最大のFc/FcγR親和性増強は、アラニンスキャンで別々に得られた3つの良好な結合物を組合せて得られたS298A/E333A/K334Aである(Shields et al., 2001, J Biol Chem 276:6591-6604)。コンピューター処理スクリーニングは、このような3倍の変異体を、3回の別々の実験ではなく1回の実験で生成させる能力があり、さらにそれらの位置で、アラニンだけではなく20個全部のアミノ酸の官能基を試験することができる。コンピューター処理スクリーニングは、組合せの問題を実験的に扱いやすいサイズに縮小することにより、このような複雑さに対処する。
本発明は、最適化Fc変異体を選抜するために後に実験的にスクリーニングし得るライブラリーの生成方法を提供する。「ライブラリー」は、本明細書で使用されるとき、1またはそれ以上のFc変異体のセットを意味する。ライブラリーは、いかなる形態の変異体のセットを表してもよい。ある実施態様では、ライブラリーは、核酸またはアミノ酸配列のリスト、可変位置での核酸またはアミノ酸置換のリストである。例えば、下記で本発明を例示説明するために使用される実施例は、可変位置でのアミノ酸置換としてライブラリーを提供する。ある実施態様では、ライブラリーは、所望の特性について最適化されたFc変異体である少なくとも1つの配列のリストである。例えば、Filikov et al., 2002, Protein Sci 11:1452-1461 および Luo et al., 2002, Protein Sci 11:1218-1226 参照。別の実施態様では、ライブラリーは、組合せのリストとして定義され得る。これは、各可変位置についてアミノ酸置換のリストを生成させることを意味し、各置換は他の全可変位置で他の全ての設計された置換と組み合わされるものであることを暗示する。この場合、全可変位置での全可能性の組合せの拡大は、大きい明確に定義されたライブラリーをもたらす。ライブラリーは、Fc領域またはFc領域のいくつかのドメインまたはフラグメントを含むポリペプチドの物理的組成物を表してもよい。従って、ライブラリーは、精製または未精製形態のどちらでも、抗体またはFc融合体の物理的組成物を表し得る。ライブラリーは、ライブラリー配列をコードする核酸の物理的組成物を表し得る。当該核酸は、ライブラリーのメンバーをコードする遺伝子、ライブラリーのメンバーを任意の機能し得るように連結された核酸と共にコードする遺伝子、またはライブラリーのメンバーを機能し得るように連結された調節配列、選択マーカー、融合体コンストラクトおよび/または他のエレメントと共にコードする発現ベクターであってもよい。例えば、ライブラリーは、Fcライブラリーのメンバーをコードする哺乳動物発現ベクター、後に実験的に発現、精製およびスクリーニングされ得るそのタンパク質産物のセットであり得る。他の例として、ライブラリーは、ディスプレイライブラリーであり得る。そのようなライブラリーは、例えば、ファージディスプレイ、リボソームディスプレイ、酵母ディスプレイ、細菌表面ディスプレイなどを可能にするいくつかの融合体パートナーに機能し得るように連結されたライブラリーのメンバーをコードする発現ベクターのセットを含み得る。
本発明は、Fc変異体ライブラリーの産生およびスクリーニングの方法を提供する。記載した方法は、本発明をいかなる特定の適用または操作理論にも制限することを意味しない。むしろ、提供される方法は、1またはそれ以上のFc変異体または1またはそれ以上のFc変異体ライブラリーを実験的に産生およびスクリーニングし、最適化Fc変異体を入手し得ることを一般的に例示説明する意味である。Fc変異体は、本明細書で厳密に定義した通りのFc領域、そのドメインまたはフラグメント、または抗体またはFc融合体などのFcを含む大きいポリペプチドとしてなど、いかなる文脈で産生およびスクリーニングしてもよい。抗体の分子生物学、発現、生成およびスクリーニングのための一般方法は、Antibody Engineering, edited by Duebel & Kontermann, Springer-Verlag, Heidelberg, 2001;および Hayhurst & Georgiou, 2001, Curr Opin Chem Biol 5:683-689;Maynard & Georgiou, 2000, Annu Rev Biomed Eng 2:339-76 に記載されている。
本発明を例示説明するために、下記の実施例を提供する。これらの実施例は、本発明をいかなる特定の適用または操作理論に制限することも意味しない。
最適化Fc変異体を設計するために、コンピューター処理スクリーニング計算を実行した。数回のコンピューター処理/実験のサイクルにわたり、Fc変異体をコンピューター処理的にスクリーニングし、構築し、そして実験的に調べた。各々の連続サイクルについて、実験データは次セットのコンピューター処理スクリーニング計算およびライブラリー設計にフィードバックを与えた。全コンピューター処理スクリーニング計算およびライブラリー設計を実施例1に提示する。各セットの計算につき、結果を提示し関連情報およびパラメーターを提供する表を提供する。
Fc変異体の実験法の大部分は、抗癌抗体アレムツズマブ(Campath(登録商標)、Ilex Pharmaceuticals LPの登録商標)に関して実行した。アレムツズマブは、その標的抗原であるCD52中の短い線状のエピトープに結合する(Hale et al., 1990, Tissue Antigens 35:118-127; Hale, 1995, Immunotechnology 1:175-187)。アレムツズマブは、その効力が一部にはそのエフェクター細胞を募らせる能力によるので(Dyer et al., 1989, Blood 73:1431-1439; Friend et al., 1991, Transplant Proc 23:2253-2254; Hale et al., 1998, Blood 92:4581-4590; Glennie et al., 2000, Immunol Today 21:403-410)、そして結合アッセイにおけるその抗原の産生と使用が比較的簡単であるので、主たる工学処理の鋳型として選択された。他の抗体に関して本発明の最適化Fc変異体を評価するために、選択されたFc変異体を抗CD20抗体リツキシマブ(Rituxan(登録商標)、IDEC Pharmaceuticals Corporation の登録商標)および抗Her2抗体トラスツズマブ(Herceptin(登録商標)、Genentechの登録商標)で評価した。スクリーニング目的でのアレムツズマブ、リツキシマブおよびトラスツズマブの使用は、本発明をいかなる特定の抗体にも制限することを意味しない。
FcγRIIIaおよびFcγRIIbのスクリーニングから、最適化特性を有する数々の有望なFc変異体を得た。表61は、FcγRIIIaにより緊密に結合し、従って抗体およびFc融合体のエフェクター機能改良のための候補であるFc変異体を提供する。これらには、239、264、330および332で置換を含む数々の変異体が含まれる。図13は、これらのFc変異体のいくつかについて、AlphaScreen(商標)結合データを示す。これらのFc変異体の大部分は、S298A/E333A/K334Aよりも実質的に大きいFcγRIIIa結合増強を提供する。
論じたように、より高いエフェクター機能への要望があるが、いくつかの抗体治療には、低減または排除されたエフェクター機能が望ましいことがある。表61中のいくつかのFc変異体は、実質的にFcγR結合を低減または除去し、従ってエフェクター機能が望ましくない抗体およびFc融合体において用途を見出し得る。そのような変異体のいくつかの例について、AlphaScreen(商標)結合データを図19aおよび19bに示す。これらのFc変異体並びにそれらの組み合わせた使用は、望ましい場合に、例えばその作用メカニズムが阻害または拮抗作用を含むが標的抗原を有する細胞の殺傷を含まない抗体およびFc融合体において、エフェクター機能を除去するのに用途を見出し得る。
論じたように、本実験の1つの目標は、最適化非グリコシル化Fc変異体を得ることであった。いくつかのFc変異体は、この目標に対して有意な進歩を提供する。グリコシレーション部位であるので、N297での置換は、非グリコシル化Fcをもたらす。N297での置換を有する他の全てのFc変異体は完全にFcγR結合を除去するが、一方N297D/I332Eは、表61に示し、図20に図解するように、有意なFcγRIIIaへの結合親和性を有する。この結果の正確な理由はこの変異体の高解像度の構造がないので不確かであるが、コンピューター処理スクリーニング予想は、これは新しい好都合なFc/FcγR相互作用と好都合な静電気的特性の組合せによる可能性があることを示唆する。実際に、他の静電気的置換が、さらなる非グリコシル化Fcの最適化のために構想されている。表61は、S239D/N297D/I332EおよびN297D/A330Y/I332Eなどの他の非グリコシル化Fc変異体が、FcγRIIIaに対する親和性をグリコシル化WTアレムツズマブの各々0.28−および0.43倍にする結合の増強をもたらすことを示す。これらの変異体の他のFcγR結合を増強するFc変異体との組合せが企図されており、グリコシル化親Fcとほぼ同等かまたはより良好な親和性を有する1またはそれ以上のFcγR類に結合する非グリコシル化Fc変異体を得ることを目標としている。さらなる有望なFc変異体のセットは、炭水化物の非存在下で安定性と溶解性の増強をもたらす。FγR結合を媒介しないが炭水化物とFcとの間の接点を決定する位置である位置241、243、262および264で置換を含むFc変異体は、恐らくそれらが炭水化物の立体構造を乱すので、FγR結合を除去する。しかしながら、脱グリコシル化形態では、Fc変異体F241E/F243R/V262E/V264R、F241E/F243Q/V262T/V264E、F241R/F243Q/V262T/V264RおよびF241E/F243Y/V262T/V264Rは、図21のAlphaScreen(商標)データで示すように、グリコシル化形態よりも強いFcγRIIIaへの結合を示す。この結果は、これらが非グリコシル化Fcの構造、安定性、溶解性および機能の最適化の鍵となる位置であることを示す。これらの結果は共に、タンパク質工学処理を使用して、炭水化物の非存在下で、抗体およびFc融合体の好都合な機能および溶解特性を回復でき、これらおよび他のFc位置で置換を含む好都合な溶解特性および十分な機能性を有する非グリコシル化抗体およびFc融合体への道を開くことができることを示唆する。
上記で論じた通り、Fc−媒介エフェクター機能の重要なパラメーターは、FcγRIIIaのV158とF158の両多型に対するFcの親和性である。選択された変異体の2つの受容体アロタイプへの結合を比較するAlphaScreen(商標)データを、図22a(V158 FcγRIIIa)および図22b(F158 FcγRIIIa)に示す。見られるように、全変異体は、両FcγRIIIaアロタイプへの結合を改善する。これらのデータは、エフェクター機能が増強された本発明のこれらのFc変異体が全患者群に広く適用可能であり、臨床効力への増強は、それを最も必要とする低応答患者群に対して潜在的に最大であることを示す。
エフェクター機能に対する効果を測定するために、選択されたFc変異体の細胞をベースとするADCCアッセイを実施した。精製ヒト末梢血単球(PBMC)をエフェクター細胞として用いるDELFIA(登録商標)EuTDAベースの細胞傷害作用アッセイ(Perkin Elmer, MA)を使用して、ADCCを測定した。標的細胞にBATDAを1x106細胞/mlで載せ、4回洗浄し、96ウェルプレートに10,000細胞/ウェルで播いた。次いで、明記した最終濃度でFc変異体またはWTの抗体を使用して、標的細胞をオプソニン化した。ヒトPBMCを指示された過剰倍率の標的細胞で添加し、プレートを37℃で4時間インキュベートした。一緒に培養した細胞を500xgで遠心分離し、上清を別のプレートに移し、Eu溶液とインキュベートし、Packard Fusion(商標) リーダー(Packard Biosciences, IL)を使用して相対的蛍光ユニットを測定した。サンプルを3重(triplicate)とし、誤差評価を得た(n=3、+/−S.D.)。PCRを使用して、PBMCをV158またはF158 FcγRIIIaアロタイプについてアロタイプ分析した。
補体タンパク質C1qは、Fc上のFcγR結合部位に近接する部位に結合し、従って、Fc変異体が補体を募り活性化するそれらの能力を維持するか否かを判定することが賢明であった。AlphaScreen(商標)アッセイを使用して、選択されたFc変異体の補体タンパク質C1qへの結合を測定した。実施例2に記載のようにストレプトアビジンドナービーズに付着したビオチン化WTアレムツズマブ抗体を用いて、そしてアクセプタービーズに直接結合させたC1qを使用して、アッセイを実行した。図27aに示す選択されたFc変異体の結合データは、C1q結合が損なわれていないことを示す。選択されたFc変異体の細胞をベースとするCDCアッセイも実施し、Fc変異体が補体を活性化する能力を維持するか否かを調べた。Amar Blue を使用して、Fc変異体およびWTのリツキシマブでオプソニン化されたWIL2−Sリンパ腫細胞のヒト血清補体(Quidel, San Diego, CA)による溶解をモニタリングした。図27bに示す選択されたFc変異体についての結果は、CDCが損なわれていないことを示す。
論じたように、細菌のプロテインAは、Cγ2とCγ3のドメインの間のFc領域に結合し、抗体の精製に頻繁に用いられる。AlphaScreen(商標)アッセイを使用して、実施例2に記載のようにストレプトアビジンドナービーズに付着したビオチン化WTアレムツズマブ抗体を使用して、そしてアクセプタービーズに直接結合させたプロテインAを使用して、選択されたFc変異体のプロテインAへの結合を測定した。図28に示す選択されたFc変異体についての結合データは、Fc変異体のプロテインAに結合する能力が損なわれていないことを示す。これらの結果は、新生児Fc受容体FcRnやタンパク質Gなどの、プロテインAと同じFcの部位に結合する他のFcリガンドに対するFc変異体の親和性も影響されないことを示唆する。
非ヒトFcγR類のFc最適化は、動物モデルでFc変異体を実験的に試験するのに有用であり得る。例えば、マウス(例えば、ヌードマウス、SCIDマウス、異種移植マウスおよび/または遺伝子組換えマウス)で試験する場合、1またはそれ以上のマウスFcγRについて最適化されたFc変異体を含む抗体およびFc融合体は、効力、作用メカニズムなどに関して価値ある情報を提供し得る。本発明のFc変異体がそのような実験に有用であり得るか否かを評価するために、選択されたFc変異体のマウスFcγRIIIに対する親和性を、AlphaScreen(商標)アッセイを使用して測定した。実施例2に記載のようにストレプトアビジンドナービーズに付着したビオチン化WTアレムツズマブ、および実施例2に記載の通り発現および精製した、グルタチオンキレートアクセプタービーズに結合したGSTタグ付きマウスFcγRIIIを使用して、AlphaScreen(商標) アッセイを実行した。これらの結合データを図29に示す。結果は、ヒトFcγRIIIaへの結合を増強するいくつかのFc変異体は、マウスFcγRIIIへの結合も増強することを示す。この結果は、本発明のFc変異体または非ヒトFcγR類について最適化された他のFc変異体が、動物モデルを使用する実験において用途を見出し得ることを示す。
本発明のFc変異体をスクリーニングの目的で293T細胞に発現させたが、大スケールでの抗体の産生は、典型的にチャイニーズハムスター卵巣(CHO)細胞株での発現により実行される。CHOで発現されたFc変異体の特性を評価するために、選択されたFc変異体およびWTのアレムツズマブを、実施例2に記載の通りにCHO細胞で発現させ、精製した。図30は、CHOおよび293Tで発現させたFc変異体およびWTのアレムツズマブのヒトV158 FcγRIIIaへの結合を比較するAlphaScreen(商標)データを示す。結果は、293TまたはCHOのどちらで発現されても、本発明のFc変異体が同等のFcγR結合の増強を示すことを示す。
本発明について記載された数々のFc変異体は、抗癌抗体の治療効力の改善に有意な潜在能力を有する。例示説明のために、数々の本発明のFc変異体を抗体リツキシマブの配列に組み込んだ。US5,736,137に記載されたWTリツキシマブの軽鎖および重鎖を図31aおよび32bに提供する。改善された抗CD20抗体の配列を図31cに提供する。改善された抗CD20抗体の配列は、X1、X2、X3、X4、X5およびX6からなる群から選択される非WTアミノ酸を少なくとも含む。これらの改善された抗CD20抗体の配列は、置換Z1も含み得る。ここでのリツキシマブの使用は、単なる例示であり、Fc変異体の適用をこの抗体または何らかの他の特定の抗体またはFc融合体に制限することを意味しない。
Claims (12)
- 親FcポリペプチドのFc領域に少なくとも1つのアミノ酸修飾を含むFc変異体部分を含む抗体またはイムノアドヘシンであって、当該Fc変異体部分は239Dおよび239Eから選択される置換を含み、当該Fc変異体がFcγRへの結合を親Fcポリペプチドと比較して増加するものであり、番号付けはEUインデックスに従う、抗体またはイムノアドヘシン。
- 当該FcγRがFcγRIIIaである、請求項1に記載の抗体またはイムノアドヘシン。
- 当該FcγRIIIaが、FcγRIIIaのV158またはF158アロタイプである、請求項2に記載の抗体またはイムノアドヘシン。
- 当該Fc変異体を含むFc融合体を含む、請求項1に記載の抗体またはイムノアドヘシン。
- 当該抗体が工学処理された糖形態をさらに含む、請求項1または請求項4に記載の抗体またはイムノアドヘシン。
- 当該工学処理された糖形態がエフェクター機能を改善するものである、請求項5に記載の抗体またはイムノアドヘシン。
- 請求項1に記載の抗体またはイムノアドヘシンおよび医薬的に許容し得る担体を含む、抗体関連障害を処置するための医薬組成物。
- 請求項1に記載の抗体またはイムノアドヘシンであって、当該抗体またはイムノアドヘシンがCD19、CD20、CD22、CD33、CD52、Her2/neu、EGFR、EpCAM、MUC1、GD3、CEA、CA125、HLA−DR、TNFアルファおよびVEGFからなる群から選択される標的抗原に特異性を有する、抗体またはイムノアドヘシン。
- 処置を必要としている哺乳動物を処置するための医薬を製造するための、請求項1に記載の抗体またはイムノアドヘシンの使用。
- 請求項1から8のいずれか1項に記載の抗体またはイムノアドヘシンをコードする核酸。
- 請求項10に記載の核酸を含むベクター。
- 請求項11に記載の核酸を含む宿主細胞。
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US11053308B2 (en) | 2016-08-05 | 2021-07-06 | Chugai Seiyaku Kabushiki Kaisha | Method for treating IL-8-related diseases |
US11780912B2 (en) | 2016-08-05 | 2023-10-10 | Chugai Seiyaku Kabushiki Kaisha | Composition for prophylaxis or treatment of IL-8 related diseases |
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