JP5913980B2 - 免疫グロブリン変異体及びその用途 - Google Patents
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- JP5913980B2 JP5913980B2 JP2011531249A JP2011531249A JP5913980B2 JP 5913980 B2 JP5913980 B2 JP 5913980B2 JP 2011531249 A JP2011531249 A JP 2011531249A JP 2011531249 A JP2011531249 A JP 2011531249A JP 5913980 B2 JP5913980 B2 JP 5913980B2
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Description
この出願は、内容を出典明示によりここに援用する2008年10月14日出願の仮出願第61/105086号、2009年2月12日出願の仮出願第61/152131号、2009年4月22日出願の仮出願第61/171768号、2009年6月25日出願の仮出願第61/220514号に対して米国特許法第119条第(e)項の下の優先権を主張する米国特許法施行規則1.53(b)(1)条の下に出願した非仮出願である。
本発明は一般的に分子生物学の分野に関する。より詳細には、本発明は、改変された生物学的性質を有するIgG免疫グロブリン変異体と、同変異体を使用する方法に関する。
本発明の方法はまた癌又は腫瘍の再発について患者をモニタリングすることを含みうる。
この明細書を解釈する目的には、次の定義が適用され、適切な場合には、単数で使用される用語は複数をまた含み、その逆もある。ここで使用される用語法は特定の実施態様を説明する目的だけのものであって、限定することを意図するものではない。以下に記載される何れかの定義が、出典明示によりここに援用される何れかの文献と矛盾している場合には、以下に記載の定義が優先するものである。
---- ----- --- ------- -------
L1 L24-L34 L24-L34 L26-L32 L30-L36
L2 L50-L56 L50-L56 L50-L52 L46-L55
L3 L89-L97 L89-L97 L91-L96 L89-L96
H1 H31-H35B H26-H35B H26-H32 H30-H35B
(Kabat番号付け)
H1 H31-H35 H26-H35 H26-H32 H30-H35
(Chothia番号付け)
H2 H50-H65 H50-H58 H53-H55 H47-H58
H3 H95-H102 H95-H102 H96-H101 H93-H101
分率X/Yの100倍
ここで、Xは配列アラインメントプログラムALIGN-2のA及びBのプログラムアラインメントによって同一であると一致したスコアのアミノ酸残基の数であり、YはBの全アミノ酸残基数である。アミノ酸配列Aの長さがアミノ酸配列Bの長さと等しくない場合、AのBに対する%アミノ酸配列同一性は、BのAに対する%アミノ酸配列同一性とは異なることが理解されるであろう。特に断らない限りは、ここで使用される全ての%アミノ酸配列同一性値は、ALIGN-2コンピュータプログラムを用いて直ぐ上の段落に記載されるようにして得られる。
抗体は特定の抗原に結合特異性を示すタンパク質である。天然抗体は、通常、2つの同一の軽(L)鎖及び2つの同一の重(H)鎖からなる約150000ダルトンのヘテロ四量体糖タンパク質である。各軽鎖は一つの共有ジスルフィド結合により重鎖に結合しており、ジスルフィド結合の数は、異なった免疫グロブリンアイソタイプの重鎖の中で変化する。また各重鎖と軽鎖は、規則的に離間した鎖間ジスルフィド結合を有している。各重鎖は、多くの定常ドメインが続く可変ドメイン(VH)を一端に有する。各軽鎖は、一端に可変ドメイン(VL)を、他端に定常ドメインを有する;軽鎖の定常ドメインは重鎖の第一定常ドメインと整列し、軽鎖の可変ドメインは重鎖の可変ドメインと整列している。特定のアミノ酸残基が、軽鎖及び重鎖可変ドメイン間の界面を形成すると考えられている。
本発明は抗体断片を包含する。特に興味深いものは、Fc領域を含む抗体、Fc融合体及び重鎖の定常領域である。ある実施態様では、抗体断片は、Fc領域を含む変異体免疫グロブリン(IgGs)の断片である。抗体断片は伝統的な手段、例えば酵素的消化、又は組換え技術によって産生されうる。
本発明は、ヒト化抗体を含む。ある実施態様では、ヒト化抗体は野生型IgGに対してFc領域中に一又は複数のアミノ酸修飾を含むヒト化変異体IgGである。非ヒト抗体をヒト化するための様々な方法が当該分野で知られている。例えば、ヒト化抗体は、非ヒトのソースからそれに導入された一又は複数のアミノ酸残基を有することができる。これらの非ヒトアミノ酸残基は、しばしば「移入」残基と呼ばれ、これは典型的には「移入」可変ドメインに由来する。ヒト化は、本質的にヒト抗体の該当する配列を高頻度可変領域配列で置換することにより、Winter及び共同研究者(Jones等(1986)Nature 321:522-525;Riechmann等(1988)Nature, 332:323-327;Verhoeyen等(1988)Science 239:1534-1536)の方法に従って実施される。従って、このような「ヒト化」抗体は、インタクトなヒト可変ドメインより実質的に少ない分が非ヒト種由来の対応する配列で置換されたキメラ抗体(米国特許第4816567号)である。実際には、ヒト化抗体は典型的には幾つかの高頻度可変領域残基が、及び場合によっては幾つかのFR残基が齧歯類抗体の類似する部位由来の残基によって置換されたヒト抗体である。
ある実施態様では、本発明のヒト抗体は、野生型IgGに対してFc領域に一又は複数のアミノ酸修飾を含むヒト変異体IgGである。ヒト抗体は、上記のように、ヒト由来のファージディスプレイライブラリーから選択したFvクローン可変ドメイン配列を既知のヒト定常ドメイン配列と組合わせることによって構築することができる。あるいは、ヒトモノクローナル抗体は、ハイブリドーマ法によって作製することができる。ヒトモノクローナル抗体の産生のためのヒトミエローマ及びマウス-ヒトヘテロミエローマ細胞株は、例えば、Kozbor, J. Immunol. 133, 3001(1984);Brodeur等, Monoclonal Antibody Production Techniques and Applications, pp.51-63(Marcel Dekker, Inc., New York, 1987);及びBoerner 等, J. Immunol., 147: 86 (1991)に記載されている。
二重特異性抗体は、少なくとも2つの異なるエピトープに対して結合特異性を有するモノクローナル抗体である。ある実施態様では、二重特異性抗体は、野生型抗体に対してFc領域に一又は複数のアミノ酸修飾を持つ二重特異性抗体である。ある実施態様では、二重特異性抗体はヒト抗体又はヒト化抗体である。ある実施態様では、結合特異性の一つはVEGFに対するものであり、他方は任意の他の抗原に対するものである。ある実施態様では、二重特異性抗体は、VEGFの2つの異なるエピトープに結合しうる。二重特異性抗体はVEGFを発現する細胞に細胞傷害剤を局在化するためにも使用されうる。これらの抗体はVEGF結合アーム及び細胞傷害剤、例えば、サポリン、抗インターフェロン-α、ビンカアルカロイド、リシンA鎖、メトトレキセート又は放射性同位体ハプテンと結合するアームを有する。二重特異性抗体は完全長抗体又はFc領域を含む抗体断片として調製することができる。
多価抗体は、抗体が結合する抗原を発現する細胞により、二価抗体よりも早く内部移行(及び/又は異化)されうる。本発明の抗体は、3又はそれ以上の結合部位を有する多価抗体(IgMクラス以外のもの)であり得(例えば四価抗体)、抗体のポリペプチド鎖をコードする核酸の組換え発現により容易に産生せしめることができる。多価抗体は二量体化ドメインと3又はそれ以上の抗原結合部位を有しうる。ある実施態様では、二量体化ドメインはFc領域又はヒンジ領域を有する(又はそれらからなる)。このシナリオにおいて、抗体はFc領域と、Fc領域のアミノ末端に3又はそれ以上の抗原結合部位を有しているであろう。ある実施態様では、多価抗体は3ないし約8の抗原結合部位を有する(又はそれらからなる)。そのような一実施態様では、多価抗体は4つの抗原結合部位を含む(又はそれらからなる)。多価抗体は少なくとも一つのポリペプチド鎖(例えば2つのポリペプチド鎖)を有し、ポリペプチド鎖は2又はそれ以上の可変ドメインを含む。例えば、ポリペプチド鎖は、VD1-(X1)n-VD2-(X2)n-Fcを有し得、ここでVD1は第1の可変ドメインであり、VD2は第2の可変ドメインであり、FcはFc領域の一つのポリペプチド鎖であり、X1及びX2はアミノ酸又はポリペプチドを表し、nは0又は1である。例えば、ポリペプチド鎖は、VH-CH1-柔軟なリンカー-VH-CH1-Fc領域鎖;又はVH-CH1-VH-CH1-Fc領域鎖を含みうる。ここでの多価抗体は、少なくとも2つ(例えば4つ)の軽鎖可変ドメインポリペプチドを更に有しうる。ここでの多価抗体は、例えば約2から約8の軽鎖可変ドメインポリペプチドを有しうる。ここで考察される軽鎖可変ドメインポリペプチドは軽鎖可変ドメインを有し、場合によってはCLドメインを更に有する。
ある実施態様では、本発明の抗体はFc領域を含む単一ドメイン抗体である。ある実施態様では、単一ドメイン抗体は野生型IgGに対してFc領域に一又は複数のアミノ酸修飾を有する。単一ドメイン抗体は、抗体の重鎖可変ドメインの全て又は一部又は軽鎖可変ドメインの全て又は一部を含む単一ポリペプチド鎖である。
ある実施態様では、ここに記載された免疫グロブリンのアミノ酸配列修飾が考慮される。ある実施態様では、修飾は本発明の変異体IgGに対して一又は複数のアミノ酸修飾を含む。ある実施態様では、本発明の変異体IgGの結合親和性、インビボ半減期及び/又は他の生物学的特性を改変させることができれば望ましい場合がある。ある実施態様では、アミノ酸修飾は、ここでは記載されていないFc領域一又は複数のアミノ酸修飾を含む。変異体IgGの修飾されたアミノ酸配列は、抗体をコードする核酸中に適切な変化を導入して、又はペプチド合成により、調製されうる。そのような修飾は、抗体のアミノ酸配列内の残基の、例えば、欠失、及び/又は挿入及び/又は置換を含む。最終コンストラクトが所望される特徴を有しているならば、最終コンストラクトに達するために、欠失、挿入及び置換をどのように組合せることもできる。アミノ酸変化は、配列が作製されるときに主題の抗体アミノ酸配列中に導入されうる。
(1)非極性:Ala(A)、Val(V)、Leu(L)、Ile(I)、Pro(P)、Phe(F)、Trp(W)、Met(M)
(2)無荷電極性:Gly(G)、Ser(S)、Thr(T)、Cys(C)、Tyr(Y)、Asn(N)、Gln(Q)
(3)酸性:Asp(D)、Glu(E)
(4)塩基性:Lys(K)、Arg(R)、His(H)
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2)中性の親水性:Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)塩基性:His、Lys、Arg;
(5)鎖配向に影響する残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe。
ある実施態様では、本発明の変異体IgGは当該分野において知られ直ぐに利用できる更なる非タンパク質性部分を含むように更に修飾することができる。ある実施態様では、変異体IgGは細胞傷害剤とコンジュゲートされうる。ある実施態様では、細胞傷害剤が結合した変異体IgGは細胞によって内部移行せしめられ、それが結合する癌細胞の死滅化におけるコンジュゲートの治療的効能を増加させる。一実施態様では、細胞傷害剤は癌細胞中の核酸を標的とし又はそれを妨害する。
変異体IgGは当該分野で知られている任意の方法によって作成されうる。ある実施態様では、変異体IgG配列を使用して、メンバー配列をコードし、また宿主細胞にクローニングされ、発現され、所望されるならばアッセイされる核酸を作製する。これらの操作は、よく知られた手順を使用して実施され、使用されうる様々な方法が、双方ともその全体を出典明示により援用するMolecular Cloning--A Laboratory Manual, 3版(Maniatis, Cold Spring Harbor Laboratory Press, New York, 2001)及びCurrent Protocols in Molecular Biology (John Wiley & Sons)に記載されている。変異体IgGをコードする核酸は、タンパク質を発現せしめるために発現ベクター中に導入されうる。発現ベクターは典型的にはコントロール又は調節配列と作用可能に連結された、つまり機能的関係に置かれたタンパク質、選択可能マーカー、任意の融合パートナー、及び/又は更なるエレメントを含む。変異体IgGは、変異体IgGをコードする核酸を含む核酸、好ましくは発現ベクターで形質転換された宿主細胞を、タンパク質の発現を誘発又は引き起こす適切な条件下で培養することによって、産生されうる。限定するものではないが、哺乳動物細胞、細菌、昆虫細胞、及び酵母を含む広範囲の適切な宿主細胞を使用することができる。例えば、使用が見出されうる様々な細胞株は、その全体が出典明示によりここに援用されるアメリカン・タイプ・カルチャー・コレクションから入手できるATCC細胞株カタログに記載されている。宿主細胞中に外因性核酸を導入する方法は当該分野でよく知られており、使用される宿主細胞と共に変化する。
本発明の変異体IgGは、限定しないが、インビトロアッセイ、インビボ及び細胞ベースアッセイ、及び選択技術に使用するものを含む様々な方法を使用してスクリーニングされうる。自動化及びハイスループットスクリーニング技術がスクリーニング手順において利用されうる。スクリーニングは、融合パートナー又は標識、例えば免疫標識、同位体標識、又は蛍光もしくは熱量測定染料のような小分子標識の使用を利用する場合がある。
変異体IgGは広い範囲の製品における使用が見出されうる。ある実施態様では、IgG変異体は治療、診断、又は研究試薬である。変異体IgGは、モノクローナル又はポリクローナルである抗体組成物における使用が見出されうる。ある実施態様では、変異体IgGは、VEGFのような標的抗原をブロックし、アンタゴナイズし又はアゴナイズするために使用される。ある実施態様では、変異体IgGは、VEGF活性をブロックし又は中和するために使用される。一実施態様では、VEGF活性は血管新生である。
癌段階付けシステムは、癌が解剖学的に如何に遠くに拡がるかを記述しており、同じステージの集団において類似の予後及び治療に患者を置くことを試みるものである。生検及び所定の画像法、例えば胸部X線、マンモグラム、骨スキャン、CTスキャン、及びMRIスキャンを含む幾つかの試験を癌の段階付けの補助として実施されうる。また、血液検査及び臨床評価を使用して、患者の全体的な健康状態を評価し、癌が所定の器官まで拡がったかどうか検出する。
限局(Localized)は、発生した臓器に限局しており、拡散の所見が見られない癌である。
局所(Regional)は、近くのリンパ節又は器官及び組織に起源の(原発性)部位を越えて蔓延した癌である。
遠位(Distant)は、原発性部位から遠位器官又は遠位リンパ節まで蔓延した癌である。
未知(Unknown)は、段階を表すために十分な情報がない症例を表すために用いる。
ある実施態様では、変異体IgGは、良性、前癌性又は早い段階の癌の治療のために、又は、腫瘍再発の治療又は防止のために使われうる。ある実施態様では、変異体IgGは抗VEGF抗体である。一実施態様では、変異体IgGはベバシズマブの変異体である。一実施態様では、変異体IgGは、ベバシズマブの相補性決定領域を含む。他の実施態様では、変異体IgGは重鎖可変ドメイン(配列番号:1)及び軽鎖可変ドメイン(配列番号:2)を含む。更に他の実施態様では、変異体IgGは重鎖可変ドメイン(配列番号:7)及び軽鎖可変ドメイン(配列番号:8)を含む。
本発明は、被検体、例えばヒト患者の手術可能な癌の外科的除去の前のネオアジュバント療法であって、患者(例えば、ここで患者は、腫瘍及び/又は癌と診断されている)に変異体IgGの有効量を投与することを含む方法を提供する。ある実施態様では、変異体IgGは抗VEGF抗体である。一実施態様では、変異体IgGはベバシズマブの変異体である。一実施態様では、変異体IgGは、ベバシズマブの相補性決定領域を含む。他の実施態様では、変異体IgGは重鎖可変ドメイン(配列番号:1)及び軽鎖可変ドメイン(配列番号:2)を含む。更に他の実施態様では、変異体IgGは重鎖可変ドメイン(配列番号:7)及び軽鎖可変ドメイン(配列番号:8)を含む。
本発明は、根治手術の後に、変異体IgGを非転移性の癌を有する被検体に投与することを含むアジュバント療法の方法を提供する。ある実施態様では、変異体IgGは抗VEGF抗体である。一実施態様では、変異体IgGはベバシズマブの変異体である。一実施態様では、変異体IgGは、ベバシズマブの相補性決定領域を含む。他の実施態様では、変異体IgGは重鎖可変ドメイン(配列番号:1)及び軽鎖可変ドメイン(配列番号:2)を含む。更に他の実施態様では、変異体IgGは重鎖可変ドメイン(配列番号:7)及び軽鎖可変ドメイン(配列番号:8)を含む。
変異体IgG組成物は、良好な医療実務に一致した形で製剤化され、用量決定され、投与される。この文脈で考慮する要因は、治療される特定の疾患、治療される特定の哺乳動物、個々の患者の臨床状態、疾患の原因、薬剤のデリバリー部位、投与の方法、投与のスケジューリング、及び医師が知る他の因子を含む。疾患の予防又は治療では、(単独で又は一又は複数の他の更なる治療剤と組み合わせて使用される場合)本発明の変異体IgG、例えば抗体の適切な投薬量は、治療される疾患のタイプ、抗体のタイプ、疾患の重篤度及び過程、抗体が予防目的か又は治療目的で投与されるかどうか、過去の療法、患者の臨床履歴及び抗体に対する応答、及び主治医の裁量に依存する。変異体IgGは一度に又は一連の治療にわたって患者に適切に投与される。
変異体IgGの効果は、限定しないが、「定義」の下にここに記載された方法を含む様々な方法で測定されうる。例えば、腫瘍の治療における効果は、腫瘍の増殖又は転移を阻害又は低減させる変異体IgGの能力を検出することによって測定することができる。ある実施態様では、変異体IgGは、変異体IgGが野生型IgGを使用しての治療で達成される腫瘍増殖と比較して腫瘍増殖の速度を減少させることができるならば、より高い効果を有している。ある実施態様では、変異体IgGは、変異体IgGが腫瘍増殖の同じ最大阻害を達成するのに野生型IgGに必要な用量よりも低いIgG用量でっしゅようぞうしょくの最大阻害を達成することができるならば、より高い効果を有している。ある実施態様では、変異体IgGは、変異体IgGが野生型IgGに必要な用量よりも低いIgG用量で癌細胞の増殖又は転移を阻害又は低減させる能力を有しているならば、野生型IgGと比較して高い効果を有している。ある実施態様では、本発明の変異体IgGは野生型IgGと比較して等価な又はより高い効果を有している。ある実施態様では、本発明の変異体IgGは野生型IgGと比較して低い効果は有していない。
ここに記載された治療剤は、他の治療剤と共に同時に投与されうる。つまり、ここに記載された治療剤は、例えば小分子、他の生物剤、放射線療法、外科手術等を含む他の治療法又は治療剤と同時に投与されうる。
本発明の他の態様では、上記の疾患の治療、予防及び/又は診断に有用な物質を含む製造品が提供される。該製造品は容器と該容器の又は該容器に付随するラベル又はパッケージ挿入物を具備する。好適な容器には、例えば、ビン、バイアル、シリンジ等々が含まれる。容器は、様々な材料、例えばガラス又はプラスチックから形成されうる。容器は、それのみによって又は他の組成物と組み合わせて症状を治療、予防及び/又は診断するのに有効な組成物を収容し、滅菌アクセスポートを有しうる(例えば、容器は皮下注射針が貫通可能なストッパーを有するバイアル又は静脈内投与溶液バッグでありうる)。ラベル又はパッケージ挿入物は、組成物が選択した症状の治療に使用されることを示す。ある実施態様では、製造品は、(a)組成物を中に収容し、その組成物が本発明の抗体を含む第一の容器と;(b)組成物を中に収容し、その組成物が更なる細胞傷害性薬物を含む第二の容器とを含みうる。該製造品は、組成物を特定の症状の治療に使用することができることを示しているパッケージ挿入物を更に含みうる。あるいは、もしくは付加的に、製造品は、薬学的に許容されるバッファー、例えば注射用の静菌水(BWFI)、リン酸緩衝生理食塩水、リンガー液及びデキストロース溶液を含む第二の(又は第三の)容器を更に具備してもよい。更に、他のバッファー、希釈剤、フィルター、針、シリンジを含む、商業上及び使用者の見地から望ましい他の材料を含んでもよい。
野生型抗VEGF(ベバシツマブ)IgG1重鎖及び軽鎖のFv領域を、ヒトIgG1定常ドメインを含む2つのpRKベースの一過性形質移入プラスミド中に別個にクローニングした。ついで、Kunkelベースの部位特異的突然変異誘発を使用して、CH2及びCH3ドメイン中の残基が変異せしめられた全ての抗VEGF IgG1変異体を産生させた。この研究で産生された抗VEGF変異体を以下の表2にまとめる。各変異体はCH2及びCH3ドメインに単一、二重及び三重の変異を何れか含んでいる。変異体はKabatにおけるようなEUインデックスに従って番号付けする。
ヒトFcRnは、α鎖とβ2−ミクログロブリンサブユニットのヘテロ二量体である。これれらの二つのサブユニットを二つのpRKベースの一過性形質移入プラスミド中に別個にクローニングした。α鎖とβ2-ミクログロブリンの双方を含むプラスミドを、製造プロトコルに従って、FUGENE(登録商標)(Roche, Basel, Switzerland)を使用して293細胞中に同時形質移入した。形質移入複合体と共に24時間インキュベートした後、形質移入細胞を、ついで、10mg/Lのインスリン及び微量元素を補填した無血清培地PSO4に5日間切替えた。集めた上清を濾過し、1Mの塩酸及び5MのNaClで条件化し、最終pH6.0及び濃度の50mMのNaClを得た。条件化された上清をIgG−セファロースクロマトグラフィーを使用して精製した。結合したFcRnを、30mMのTRIS及び150nMのNaClを含むpH8.0のバッファーを使用してカラムから溶離させた。溶離されたFcRnをSuperdex−75サイズ排除クロマトグラフィーカラムを使用して更に精製して、あらゆる凝集物を除去した。FcRn濃度を、280nMでの吸光度の読み取り値を使用して計算し、1.9の吸光度が1mg/mlのFcRnに対応した。カニクイザルFcRnは、cynoα鎖及びcynoβ2−ミクログロブリンを含むプラスミドが形質移入に使用されたことを除いて、ヒトFcRnと同様にして生産され、精製される。
ヒトFcRnに対する抗VEGF変異体の結合性を、BIAcore3000機器(GE healthcare, Piscataway, NJ)を使用して表面プラズモン共鳴によって研究した。ヒトFcRnを、アミンカップリングキットを使用してセンサーチップにカップリングさせた。すなわち、CM5センサーチップを、5μl/分で7分間、EDC/NHSで活性化させた。100μg/mlのヒトFcRnを活性化されたチップに対して10μl/分の流量で30秒から2分の間注入して、50から200の最大結合応答単位(RU)を得た。コンジュゲーション後、FcRn結合チップを、5μl/分での35μlの1Mエタノールアミン塩酸塩の注入によりブロックした。
BIAcore3000機器(GE healthcare, Piscataway, NJ)を使用する結合形式では、抗VEGF野生型(ベバシズマブ)及び抗VEGF変異体を、アミンカップリングキットを使用してセンサーチップの異なったフローセルにコンジュゲートした。すなわち、CM5センサーチップを5μl/分で7分間、EDC/NHSで活性化させた。10から50μg/mlの抗体を、活性化されたチップに対して10μl/分の流量で30秒から2分注入して、50から200の最大結合応答単位(RU)を生じた。コンジュゲーション後、FcRn結合チップを、5μl/分で35μlの1Mのエタノールアミン塩酸塩の注射によってブロックした。
様々なpHでの解離速度を測定するために、200nMから2μMのヒト又はcyno FcRnを、定常状態を達成するために5分間、PBS(pH6.0)/0.01%のP20/0.02%のNaN3中で30μl/分で抗体コンジュゲートフローセルに最初に注入した。ついで、6から7.4の範囲のpHのPBSバッファーを、8分間、フローセルに30μl/分で注入して、複合体が解離するようにした。FcRnをまたバックグラウンドのサブトラクションのために未コンジュゲート表面に注入した。解離速度定数は、BIAevaluationソフトウェア(GE healthcare, Piscataway, NJ)を使用してセンサーグラムの解離相をフィットさせて決定した。図7の結果は、ヒトFcRn(図7A)及びcyno FcRn(図7B)の双方に対する変異体のkoffがpHの増加と共に増加し、各変異体に対してkoff増加の速度が同様であったことを示している。
VEGF-A109の組換え型を、アミンカップリングキットを使用してCM5チップにコンジュゲートさせた。すなわち、CM5センサーチップを5μl/分で7分間、EDC/NHSで活性化させた。1から2μg/mlのVEGF-A109 を10μl/分の流量で30秒間、活性化チップに注入して、100から400の最大結合応答単位(RU)を得た。コンジュゲーション後、FcRn結合チップを、5μl/分での35μlの1Mエタノールアミン塩酸塩の注入によりブロックした。100nMから6nMの抗体の2倍希釈物を、37℃で PBS/0.05% Tween/0.02% NaN3 中、4分間、VEGFコンジュゲートチップに注入した。複合体を18分間解離させた。チップを20mMの塩酸の30秒パルスで再生させた。抗体をまたバックグラウンドのサブトラクションのために未コンジュゲート表面に注入した。図9の結果は、Fc変異がVEGF結合を改変せず、変異体の全ては野生型と同じ結合応答を有していることを示している。
様々な濃度の抗VEGF野生型(ベバシズマブ)及び抗VEGF変異体を室温で1時間、組換えヒトVEGFと共にプレインキュベートした。抗VEGF野生型(ベバシズマブ)及び抗VEGF変異体の濃度は33nMから0.05nMの範囲であった。組換えヒトVEGFの濃度は0.26nMであった。ついで、複合体を、37℃及び5%CO2で培養中のヒト臍血管内皮細胞(HUVEC)に提示した。培養の4日後にHUVECの生存率を、37℃及び5%CO2で6時間、細胞を20%のアラマーブルー染料(Trek Diagnostic Systems, Cleveland, OH)と共に細胞をインキュベートすることによって評価した。ついで、アラマーブルーの蛍光をMolecular Devices(Sunnyvale, CA)マイクロプレートリーダーで検出した。図10に示されるように、変異体の全てが野生型及びアバスチン(登録商標)と同じ増殖阻害レベルを有しており、Fc変異が変異体のVEGFを中和する能力に影響しないことが再び確認される。
2−5kgの体重の試験前の理学的検査時に2から7歳であった36匹の雄及び36匹の雌のナイーブなカニクイザルを、それぞれが6匹の雄と6匹の雌からなる6つの処置群に割り当てた。処置群に対して体重のバランスを達成するように設計されたコンピュータ化ブロッキング手順を使用して動物を処置群に割り当てた。健康であるように見え、明らかな異常がなかった動物のみを研究に使用した。全ての動物には、伏在静脈を介して単一の静脈内ボーラス用量と、ついで0.9%の生理食塩水流を1日目に投与した。全ての群に対する用量レベルは5mg/kgであった。大腿静脈からの血液試料(およそ1.0mL)を投薬前及び投薬後の0.5、2、4、8時間、1、2、4、7、10、14、21、28、35、42、49、56及び70日に採血した。全ての群に対する血清中濃度−時間曲線を、一群当たりn=11から12匹の動物の平均血清中濃度を使用して構築した。この実験で採血した血清試料を、実施例9に記載されたELISAプロトコルを使用して分析した。
Maxisorp ELISAプレート(Thermo Fisher Scientific, Rochester, NY)を、50mMの炭酸塩バッファー(pH9.6)中の0.5μg/mlの組換えヒトVEGFで4℃で一晩、被覆した。プレートを、PBS、0.5%のBSA、10ppmのProclin,pH7.2を用いて室温で1時間ブロックし、ついで、洗浄バッファー(PBS/0.05%のTween20/pH7.2)で洗浄した。0.5%のウシ血清アルブミン、0.05%のTween20、5mMのEDTA(pH8.0)、0.25%のCHAPS、0.2%のウシγグロブリン、10ppmのProclin及び0.35MのNaClを含むPBSバッファー中で2倍に連続希釈した標準物質(抗VEGF IgG1野生型(ベバシズマブ))並びに3倍に連続希釈したcyno血清試料(1:10で出発)を、ブロックしたプレートに加え、振とうしながら室温で2時間インキュベートした。プレートを6回洗浄し、結合した薬剤を、振とうしながら室温で1時間、アッセイバッファー(PBS、pH7.4,0.5%のBSA、0.05%のTween20、10ppmのProclin)中で1:10Kで希釈したヒツジ抗ヒトIgG(Fc特異的)−HRP(Jackson ImmunoResearch, West Grove, PA)で検出した。ついで、プレートを再び6回洗浄した後、発色のためにテトラメチルベンジジン基質(Moss, Pasadena, MD)を加えた。1Mのリン酸(H3PO4)の添加によっって20分後に反応を停止させた。プレートを、450−620nmの波長にてMolecular Devicesマイクロプレートリーダーで読み取った。5mg/kgの単一IV用量の後のカニクイザル中の野生型及び5種の抗VEGF変異体の血清プロファイルを図11に示す。5種全ての変異体は野生型と比較して減少したクリアランスと延長した半減期を示した。
PKパラメータを、WinNonLin−Enterprise,バージョン5.1.1(Pharsight Corporation;Mountain View, CA)を使用して推定した。IV−ボーラス投与量、一次排除、及びマイクロ速度定数を持つ2コンパートメントモデル(モデル7)を使用して観察データを記述した。濃度は、繰り返しの再秤量(n=−1乗と予想)及びLevenberg及びHartley修正を伴うガウス・ニュートン最小化アルゴリズムを使用して計量した。次のPKパラメータが、WinNonLinモデル7を使用して報告された:AUC∞=無限大まで外挿された濃度−時間曲線下の面積として定義される全薬剤暴露;t1/2,α=α相の半減期(α半減期);t1/2,β=β相の半減期(β半減期);Cmax=最大の観察された濃度;CL=クリアランス;V1=中央コンパートメントの体積;Vss=定常状態での分布体積。
この研究に使用されるマウスの系統はMu.VEGFhuX.KI.R1.B6.129である。MuVEGFhuMUTX(+/+)ノックイン、RAG2(−/−)ノックアウトマウスは、VEGFのヒト化型の二つの対立遺伝子を含み、これが野生型抗VEGF抗体(ベバシズマブ)によって中和されうる。RAG2(−/−)マウスは免疫不全性であり、機能的T及びB細胞を産生しない。ヒト腫瘍は、腫瘍細胞に対する明白な免疫応答の不存在下でVEGFのヒト化型を発現するこれらのマウスにおいて増殖させることができる。よって、ヒト腫瘍及びマウス間質細胞VEGFから由来するVEGFは、マウスVEGFを中和しない野生型抗VEGF抗体(ベバシズマブ)によって中和されるであろう。抗VEGF野生型及び抗VEGF変異体T307Q/N434AのPKを、これらの腫瘍を持たないトランスジェニックマウスにおいて評価した。
ヒトHT−55、Colo−205(結腸直腸癌)及びCalu−6(肺癌)細胞をアメリカン・タイプ・カルチャー・コレクション(Manassas, VA)から得た。ヒト結腸直腸癌HM−7細胞株は、LS174Tの誘導体である。Calu−6及びHM−7をハムのF12、低グルコースDMEM1:1で増殖させた。Colo−205及びHT−55をRPMI1640培地で増殖させた。双方の培地に10%v/vのFBS、1%v/vのペニシリン/ストレプトマイシン(Invitrogen, Carlsbad, CA)、2mMのL−グルタミン(Invitrogen, Carlsbad, CA)及び1mg/mlのFUNGIZONE(登録商標)(Invitrogen, Carlsbad, CA)を補填した。集密になるまで細胞を5%CO2中で37℃で増殖させ、収集し、1ml当たり50×106細胞で滅菌メトリゲル中に再懸濁させた。異種移植片は6週から8週齢のRAG2 KO;hum−X VEGF KI二重ホモ接合マウス(Genentech, South San Francisco, CA)中において1マウス当たり5×106細胞の背側腹部皮下注射によって樹立し、増殖させた。毎週2回の5、0.5及び0.05mg/kgの用量での抗体の腹腔内治療を、腫瘍細胞接種後24時間で開始した。移植した腫瘍を、記載されたように長軸及び直交軸に沿って毎週2回測定した。腫瘍を測定したそれぞれの日に、各マウスノ腫瘍体積を計算し、コントロール抗体群(抗ブタクサ)及び各抗VEGF群からの平均腫瘍体積をP<0.05のレベルでスチューデント検定によって比較した。腫瘍体積が2000mm3に達したときにマウスを殺した。
プレートに被覆した2種の異なった抗体捕捉試薬(VEGF又は抗ヒトIgG1Fc)の何れかを伴う二つの異なったELISAアッセイ形式を使用して、トランスジェニックマウス中の抗体濃度を検出した。Maxisorp ELISAプレート(Thermo Fisher Scientific, Rochester, NY)に、4℃で一晩、50mMの炭酸塩バッファー中の0.5μmg/mlの組換えヒトVEGF又は0.25μg/ml(Fab’2)ウサギ抗ヒトIgG1 Fc(Jackson ImmunoResearch, West Grove, PA)の何れかを被覆した。プレートをPBS、0.5%のBSA、10ppmのProclin(pH7.2)で室温にて1時間ブロックし、ついで、洗浄バッファー(PBS/0.05%のTween20/pH7.2)で洗浄した。0.5%のウシ血清アルブミン、0.05%のTween20、5mMのEDTA(pH8.0)、0.25%のCHAPS、0.2%のウシγグロブリン、10ppmのProclin及び0.35MのNaClを含むPBSバッファー中の12.5ng/mlまで2倍の連続希釈した標準物質(VEGF形式ではベバシズマブ又はFc形式ではヒトIgG1)並びに3倍の連続希釈したcyno血清試料(1:10で出発)をブロックしたプレートに加え、振とうしながら室温で2時間インキュベートした。プレートを6回洗浄し、結合した薬剤を、振とうしながら室温で1時間、アッセイバッファー(PBS、pH7.4、0.5%のBSA、0.05%のTween20、10ppmのProclin)で1:20Kから1:60Kに希釈されたヤギ(Fab’2)抗ヒトIgG(Fc特異的)−HRPコンジュゲート(Jackson)で検出した。ついで、プレートを6回再び洗浄した後、発色のためにテトラメチルベンジジン基質(Moss, Pasadena, MD)を加えた。反応を、1Mのリン酸(H3PO4)の添加によって20分後に停止させた。プレートを450−620nmの波長にてMolecular Devicesマイクロプレートリーダーで読み取った。
図24に示されたFc変異の更なる組合せを、ヒト抗HER2(トラツズマブ)に導入してIgG変異体を構築した。IgG1変異体を、実施例1に記載された方法を使用して発現させた。野生型抗HER2 IgG1及び抗HER2 IgG1変異体の解離定数を図4に記載されたようにして測定し、結果を図24に示す。結果は、異なった変異を組み合わせることにより、我々は一桁のナノモル親和性をもってヒトFcRnに結合でき、野生型IgG1に対して約450倍の改善を示すM252Y/V308P/N434YのようなIgG変異体を構築できることを示している。
5百万の細胞/何れかHM−7、HT−55、Calu−6又はRaji(B細胞リンパ腫)株の各々を、1%のNonidet P−40、0.5%のデオキシコール酸ナトリウム、0.1%のSDS、2mMのEDTA、150mMのNaCl及び1×のプロテアーゼインヒビター(Pierce, Rockland, IL)を含む25mMのリン酸バッファーpH6.0中で4℃で1時間、インキュベートすることによって可溶化した。可溶化した細胞を4℃で12000gで30分、遠心分離し、ついで、50nMのトラスツズマブFc変異体M252Y/V308P/N434Y(Yeung等, 提出済み)を上清に加えてFcRnを捕捉した。4℃での一晩のインキュベーション後、プロテイン−L(Pierce)樹脂を加え、4℃で4時間複合体に結合させた。ついで、樹脂を溶解バッファーで5回洗浄し、結合したタンパク質を2×の負荷バッファー(Invitrogen, Carlsbad, CA)で溶離させた。タンパク質を4−12%のBIS−TRISゲル(Invitrogen)で分離し、ニトロセルロース膜(Invitrogen)上にブロットした。膜をPBS中の3%脱脂乳ブロックし、1ng/mlのウサギ抗ヒトFcRn抗体(Santa Cruz, Santa Cruz, CA)で室温で1時間、ついで1:104希釈(Pierce)のヤギ抗ウサギIgG−ペルオキシダーゼコンジュゲートで室温で1時間、プローブした。膜は、ブロッキング工程と抗体インキュベーション工程の間において、PBS/0.05%のTweenで洗浄した。FcRnタンパク質をECL検出キット(GE Healthcare, Piscataway, NJ)によって可視化した。図25を参照。
異なった抗VEGF変異体を用いた二つの別個の結合実験を各pH、pH6.0及びpH7.4で実施した。pH6.0及びpH7.4に対する濃度の関数として定常状態結合応答単位(RU)を、それぞれ図1及び図2にプロットした。pH6.0での解離定数(KD)を図1から推定し、図2にまとめた。二つの異なった実験から計算した同じ変異体の解離定数は僅かに異なっていた。例えば、変異体N434Aは最初の実験では550nMのKDを有していたが、第二の実験からのそのKDは250nMであった。該差は、FcRn結合チップ上に二価抗体を流すことを含むアッセイ形式でのアビディティー効果によるものであった。入り定数へのアビディティー寄与のレベルはチップ上に結合したFcRnのレベルに依存しており、より高いレベルのFcRn結合がより高いアビディティーを生じた。これは、第一の実験よりも約2倍高いRUであった第二の実験で観察されたより高い親和性を説明するかも知れない。アッセイの設定においてアビディティー効果があったが、この形式は細胞内の自然の結合プロセスに最も類似しており、そこでは、飲作用した二価抗体の膜結合FcRnへの結合が許容される。絶対KDは実験毎に異なっているかもしれないが、これらの変異体の親和性ランキングは、結合したFcRnの異なったレベルとさえ一致していた。図1及び図2は双方ともV308P/N434Aが試験した変異体間で最も高い親和性を一貫して有しており、試験した変異体の全てがpH6.0においてFcRnに対しての結合性を改善したことを示している。
Claims (19)
- カバットのEUインデックスに従った番号付けで、アミノ酸残基251、252、307、308、378、380、428、430、434、及び436の二以上において野生型ヒトIgG1 Fc領域に対して二以上のアミノ酸置換を含むヒトIgG1 Fc領域を含む変異体IgGであって、野生型ヒトIgG Fc領域を有するIgGの半減期と比較して増加した半減期を有し、
前記Fc領域は、
アミノ酸307におけるグルタミンでのアミノ酸置換及びアミノ酸434におけるアラニンでのアミノ酸置換、
アミノ酸307におけるグルタミンでのアミノ酸置換及びアミノ酸378におけるバリンでのアミノ酸置換、
アミノ酸307におけるグルタミンでのアミノ酸置換及びアミノ酸436におけるイソロイシンでのアミノ酸置換、
アミノ酸308におけるプロリンでのアミノ酸置換及びアミノ酸434におけるアラニンでのアミノ酸置換、
アミノ酸308におけるプロリンでのアミノ酸置換及びアミノ酸434におけるチロシンでのアミノ酸置換、
アミノ酸378におけるバリンでのアミノ酸置換及びアミノ酸434におけるアラニンでのアミノ酸置換、
アミノ酸434におけるアラニンでのアミノ酸置換及びアミノ酸436におけるイソロイシンでのアミノ酸置換、
アミノ酸252におけるチロシンでのアミノ酸置換、アミノ酸308におけるプロリンでのアミノ酸置換、及びアミノ酸434におけるチロシンでのアミノ酸置換、
アミノ酸307におけるグルタミンでのアミノ酸置換、アミノ酸380におけるアラニンでのアミノ酸置換、及びアミノ酸434におけるセリンでのアミノ酸置換、
アミノ酸307におけるグルタミンでのアミノ酸置換、アミノ酸380におけるアラニンでのアミノ酸置換、及びアミノ酸434におけるアラニンでのアミノ酸置換、
アミノ酸307におけるグルタミンでのアミノ酸置換、アミノ酸378におけるバリンでのアミノ酸置換、及びアミノ酸436におけるイソロイシンでのアミノ酸置換、又は、
アミノ酸251におけるアスパラギン酸でのアミノ酸置換、アミノ酸307におけるグルタミンでのアミノ酸置換、アミノ酸428におけるロイシンでのアミノ酸置換、アミノ酸434におけるヒスチジンでのアミノ酸置換、及びアミノ酸436におけるイソロイシンでのアミノ酸置換、を含む、変異体IgG。 - アミノ酸308におけるプロリンでのアミノ酸置換とアミノ酸434におけるアラニンでのアミノ酸置換を含む請求項1に記載の変異体IgG。
- 野生型ヒトIgG1 Fc領域を有するIgGより高いFcRnへの結合親和性を有する請求項1又は2に記載の変異体IgG。
- pH7.4においてよりもpH6.0においてFcRnへの高い結合親和性を有する請求項1〜3のいずれか一項に記載の変異体IgG。
- 野生型ヒトIgG1 Fc領域を有するIgGに等しいか又は高い効果を有する請求項1〜4のいずれか一項に記載の変異体IgG。
- 野生型ヒトIgG1 Fc領域を有するIgGよりも高い効果を有する請求項5に記載の変異体IgG。
- ヒト又はヒト化IgGである請求項1〜6のいずれか一項に記載の変異体IgG。
- 変異体IgGが抗VEGF抗体である請求項1〜7のいずれか一項に記載の変異体IgG。
- 変異体IgGがベバシズマブの変異体である請求項1〜8のいずれか一項に記載の変異体IgG。
- 配列番号:1を含む重鎖可変ドメインと配列番号:2を含む軽鎖可変ドメインを含む請求項1〜9のいずれか一項に記載の変異体IgG。
- 請求項1〜10のいずれか一項に記載の変異体IgGと薬学的に許容可能な担体を含有する薬学的組成物。
- 請求項1〜10のいずれか一項に記載の変異体IgGを容器中に、また使用のための指示書を含むキット。
- カバットのEUインデックスに従った番号付けで、アミノ酸残基308及び434において野生型ヒトIgG1 Fc領域に対してアミノ酸置換を含むヒトIgG1 Fc領域を含む変異体IgG1であって、野生型ヒトIgG1 Fc領域を有するIgG1の半減期と比較して増加した半減期を有し、アミノ酸残基308におけるアミノ酸置換がプロリンでの置換であり、アミノ酸残基434におけるアミノ酸置換がアラニンでの置換である変異体IgG1。
- 請求項1〜10のいずれか一項に記載の変異体IgGの有効量を含む、対象における腫瘍を治療するための医薬。
- 請求項1〜10のいずれか一項に記載の変異体IgGの有効量を含む、対象におけるVEGF活性を阻害するための医薬。
- VEGF活性が血管新生である請求項15に記載の医薬。
- 請求項1〜10のいずれか一項に記載の変異体IgGの有効量を含む、対象における血管透過性を調節するための医薬。
- 請求項1〜10のいずれか一項に記載の変異体IgGの有効量を含む、対象における癌細胞の増殖を阻害し又は防止するための医薬。
- 変異体IgGが対象に4週間毎又はそれより長い間隔で投与される請求項14、15、16、17又は18に記載の医薬。
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