JP5596559B2 - 安定化アンジオポエチン2抗体とその用途 - Google Patents
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Description
患者における抗癌効果の生産に使用する医薬品の製造におけるアンジオポエチン-2、および/またはTie2の生物学的活性のアンタゴニスト、ならびに化学治療薬の使用を含むものである。かかる組合わせはまた、アンジオポエチン-2および/またはTie-2の活性に関連する他の疾患の治療にも有用である。
タンパク質におけるジスルフィド結合形成は複雑なプロセスであり、環境の酸化還元ポテンシャルおよび特殊なチオール-ジスルフィド交換酵素により決定される(Creighton, Methods Enzymol. 107, 305-329, 1984;Houee-Levin, Methods Enzymol. 353, 35-44, 2002)。一般的に、タンパク質(例えば、Ang-2に特異的な抗体)中のシステイン残基は、システイン-システインジスルフィド結合に関わるかまたは、フォールディングしたタンパク質領域の一部である場合、立体的にジスルフィド結合形成から保護されている。システイン残基がタンパク質構造中に対を持たず、かつフォールディングにより立体的に保護されてない場合、そのシステイン残基は、ジスルフィドシャッフリングとして知られるプロセスで、溶液からの未結合システインとジスルフィド結合を形成しうる。ジスルフィドスクランブルとして知られる他のプロセスでは、未結合のシステインはまた、天然のジスルフィド結合(例えば、抗体構造に存在するもの)と干渉し、結合の低下、生物学的活性の低下および/または安定性の低下をもたらしうる。
可変域のグリコシル化は、おそらく立体障害に因って、抗体結合親和性に悪い影響を与えうることが示されている(Co, M. S., et al., Mol. Immunol. (1993) 30:1361-1367)。グリコシル化プロセスの不均一性はまた、改変された結合特性を持ついくつもの抗体種をもたらしうる。このようなわけで、干渉するグリコシル化部位を除去または改変して、一致した抗原結合プロファイルを保証することが所望される。可能性のあるまたは観察されるグリコシル化部位を除去する1つの方法は、部位特異的突然変異誘発を行い、少なくとも1つの可能性のあるグリコシル化部位(例えばアスパラギン、トレオニンまたはセリンアミノ酸)を、グリコシル化部位を果たすことができない他のアミノ酸で置換することである。従って、一実施形態において、本発明の抗体はグリコシル化部位を果たさない置換されたアミノ酸を含む。一実施形態において、改変すべきグリコシル化部位は可変域に存在する。他の実施形態において、改変すべきグリコシル化部位は抗体の相補性決定域(CDR)に存在する。他の実施形態において、改変すべきグリコシル化部位は第2軽鎖CDRである。他の実施形態においては、グリコシル化部位周りの配列が改変される。他の実施形態において、改変すべきグリコシル化部位は定常域に存在する。他の実施形態において、本発明の抗体は少なくとも1つ、少なくとも2つ、少なくとも3つ、少なくとも4つまたはそれ以上の改変されたグリコシル化部位を含む。
本発明はまた、改変されたFc域(本明細書では「変異Fc域」とも呼ぶ)をもつ抗体を提供する。従って、本発明の一実施形態において、本発明の抗体は変異Fc域(すなわち、以下に考察するように改変されているFc域)を含む。変異Fc域を含む本発明の抗体は、本明細書において「Fc変異タンパク質」とも呼ぶ。
最近の研究は、シアル酸をIgG分子上のオリゴ糖へ付加すると、その抗炎症性活性を増進しその細胞障害性を変えることを示唆している(Keneko et al., Science 313, 670-673(2006);Scallon et al., Mol. Immuno. 2007 Mar;44(7):1524-34)。従って、抗体治療薬の効力は、意図する応用に最も好適な糖型の選択により最適化することができる。抗体の2つのCH2ドメインの間に挿入される2つのオリゴ糖鎖はFc域とその受容体との結合に関わる。上記の研究は、シアリル化の増加したIgG分子は抗炎症特性を有するが、シアリル化の低下したIgG分子は高い免疫刺激特性を有することを示す。それ故に、抗体治療薬を適当なシアリル化プロファイルによって特定の応用に対して「仕立てる」ことができる。抗体のシアリル化状態をモジュレートする方法は、WO2007/005786:件名「増大した治療活性をもつ方法と組成物(Methods And Compositions With Enhanced Therapeutic Activity)」、およびWO2007/117505:件名「増大した抗炎症性と減少した細胞傷害性特性をもつポリペプチドと関係する方法(Polypeptides With Enhanced Anti-Inflammatory And Decreased Cytotoxic Properties And Related Methods)」に開示されており、それぞれ、本明細書に参照によりその全てが全ての目的のために組み入れられる。
抗体親和性
本発明の一実施形態においては、アンジオポエチン-1と結合しかつアンジオポエチン-1とTie2の結合を阻止する抗体を提供する。本発明のなお他の実施形態は、アンジオポエチン-1および/またはアンジオポエチン-2と結合しかつアンジオポエチン-1および/またはアンジオポエチン-2誘導性Tie2リン酸化を阻害するモノクローナル抗体である。一実施形態において、本抗体はアンジオポエチン-1および/またはアンジオポエチン-2と1ナノモル(nM)未満のKdで結合する。他の実施形態において、本抗体は500ピコモル(pM)未満のKdで結合する。他の実施形態において、本抗体は100ピコモル(pM)未満のKdで結合する。なお他の実施形態において、本抗体は30ピコモル(pM)未満のKdで結合する。さらなる実施形態において、本抗体は20ピコモル(pM)未満のKdで結合する。なおさらなる実施形態において、本抗体は10または5ピコモル(pM)未満のKdで結合する。
本発明の抗体をコードする核酸
本発明はまた、本発明の抗体をコードする単離された核酸分子を包含する。他の実施形態において、本抗体は完全ヒトモノクローナル抗体3.19.3から誘導される。一実施形態においては、完全ヒトモノクローナル抗体3.19.3と同じ1以上のエピトープと結合する抗体が提供される。
本発明の抗体の組換え発現は、本発明の抗体をコードするポリヌクレオチドを含有する発現ベクターの構築を必要とする。いったん本発明の抗体をコードするポリヌクレオチドが得られると、抗体を生産するベクターは当技術分野で周知の技法を用いて組換えDNA技法により生産することができる(本明細書に参照によりその全てが組み入れられる米国特許番号6,331,415)。従って、コードするヌクレオチド配列を含有するポリヌクレオチドを発現するタンパク質を調製する方法を本明細書に記載する。本発明の抗体は多くの異なる発現系で生産することができる。一実施形態において、本発明の抗体は哺乳動物細胞により生産されかつ分泌される。他の実施形態において、本発明の抗体はヒト細胞で生産されかつ分泌される。特定の実施形態において、本発明の抗体は293F、CHO、またはNS0細胞株の細胞で生産される。
大量生産するために、本発明の抗体をスケーラブルプロセス(scalable process)(生産可能な規模のプロセスを意味し、本明細書では以後「本発明のスケーラブルプロセス」と呼ぶ)により生産することができる。いくつかの実施形態においては、抗体を本発明のスケーラブルプロセスにより研究室で生産して、本発明の抗体を分析規模バイオリアクター(例えば、限定されるものでないが、5L、10L、15L、30L、または50Lバイオリアクター)で生産することができる。他の実施形態においては、本抗体を本発明のスケーラブルプロセスにより研究室で生産して、本発明の抗体を生産規模バイオリアクター(例えば、限定されるものでないが、75L、100L、150L、300L、または500Lバイオリアクター)で生産することができる。いくつかの実施形態において、本発明のスケーラブルプロセスは、研究室で行う生産プロセスと比較して、少ししかまたは全く生産効率の低下をもたらさない。他の実施形態において、本発明のスケーラブルプロセスは約10mg/L、約20m/L、約30mg/L、約50mg/L、約75mg/L、約100mg/L、約125mg/L、約150mg/L、約175mg/L、約200mg/L、約250mg/L、または約300mg/Lまたはそれ以上の生産効率で抗体を生産する。
組換え技法を用いる場合、本発明の抗体を細胞内で生産し、周辺質に、または直接培地中に分泌することができる。もし細胞内で生産すれば、第1ステップとして、宿主細胞または溶解断片のいずれかである微粒子デブリスを、例えば遠心分離または限外濾過により除去する。Carter et al., Bio/Technology, 10:163-167 (1992)は、大腸菌の周辺質空間中に分泌された抗体を単離する手順を記載している。簡単に説明すると、細胞ペーストを酢酸ナトリウム(pH3.5)、EDTA、およびフェニルメチルスルホニルフルオリド(PMSF)の存在のもとで約30分間にわたって解凍する。細胞デブリスは遠心分離により除去することができる。抗体が培地中に分泌される場合、かかる発現系からの上清を一般的には、最初に市販タンパク質濃縮フィルター、例えばAmiconまたはMillipore Pellicon限外濾過ユニットを用いて濃縮する。PMSFなどのプロテアーゼインヒビターを先行するステップのいずれかで含ませてタンパク質分解を阻害してもよいし、また抗生物質を含ませて外来汚染物の増殖を防止してもよい。
タンパク質製剤の安定性を評価するために利用できる様々な方法があり、それらはタンパク質の物理的および化学的構造ならびに生物学的活性に基づく。例えば、タンパク質の変性を研究するためには、電荷移動吸収、熱分析、蛍光分光測定、円二色性、NMR、rCGE(還元キャピラリーゲル電気泳動)およびHPSEC(高性能サイズ排除クロマトグラフィ)などの方法を利用することができる(例えば、Wang et al., 1988, J. of Parenteral Science & Technology 42(Suppl):S4-S26を参照)。
さらに、本発明の実施形態は、疾患を治療するためにこれらの抗体を使用する方法を含む。抗Ang-2抗体は、Ang-2介在性Tie2シグナル伝達を防止し、それにより血管新生を阻害するために有用である。
I Tie-2受容体;
II アンジオポエチン-1および/またはアンジオポエチン-2;
III Tie-2受容体-アンジオポエチン-1複合体;または
IV Tie-2受容体-アンジオポエチン-2複合体、
V またはこれらの任意の組合わせ
と結合することができる前記アンタゴニストが提供される。
I. アンタゴニストのアンジオポエチン-1との結合およびアンジオポエチン-1のその受容体Tie-2との結合の阻害、および/または
II. アンタゴニストのアンジオポエチン-2との結合およびアンジオポエチン-2のその受容体Tie-2との結合の阻害、および/または
III. アンジオポエチン-1および/またはアンジオポエチン-2のクリアランスの増強、それによりTie2と結合するために利用可能なアンジオポエチン-1および/またはアンジオポエチン-2の有効濃度の低下、
IV. または、アンジオポエチン-1およびアンジオポエチン-2の生物学的活性にアンタゴニスト作用を果たすために十分な、これらの項の任意の組合わせ
を含みうる。
本明細書に定義した抗血管新生治療は、単独療法として応用してもよいしまたは本発明の化合物に加えて、慣用の外科または放射線療法または化学療法を含んでもよい。かかる化学療法は、次のカテゴリーの1以上の抗腫瘍薬を含んでもよい:
(i)細胞分裂停止薬、例えば、抗エストロゲン(例えば、タモキシフェン、トレミフェン、ラロキシフェン、ドロロキシフェンおよびヨードキシフェン)、エストロゲン受容体ダウンレギュレーター(例えば、フルベストラント)、抗アンドロゲン(例えばビカルタミド、フルタミド、ニルタミドおよびシプロテロン酢酸塩)、LHRHアンタゴニストまたはLHRHアゴニスト(例えば、ゴセレリン、リュープロレリンおよびブセレリン)、プロゲストーゲン(例えば酢酸メゲストロール)、アロマターゼインヒビター(例えば、アナストロゾール、レトロゾール、ボラゾールおよびエグゼメスタン)およびフィナステリドなどの5'レダクターゼのインヒビター;
(ii)癌細胞浸潤を阻害する薬剤(例えば、マリマスタットの様なメタロプロテイナーゼインヒビターおよびウロキナーゼプラスミノーゲンアクチベーター受容体機能のインヒビター);
(iii)成長因子機能のインヒビター、例えば、かかるインヒビターには成長因子抗体、成長因子受容体抗体(例えば、抗ErbB2抗体トラスツズマブ[Herceptin(登録商標)]および抗ErbB1抗体セツキシマブ[C225])、ファルネシルトランスフェラーゼインヒビター、チロシンキナーゼインヒビターおよびセリン/トレオニンキナーゼインヒビター、例えば上皮成長因子ファミリーのインヒビター(例えば、EGFRファミリーチロシンキナーゼインヒビター、例えば、N(3-クロロ4-フルオロフェニル)7-メトキシ6(3-モルホリノプロポキシ)キナゾリン4-アミン(ゲフィチニブ、AZD1839)、N(3-エチニルフェニル)6,7ビス(2-メトキシエトキシ)キナゾリン4-アミン(エルロチニブ、OSI774)および6-アクリルアミドN(3-クロロ4-フルオロフェニル)7(3-モルホリノプロポキシ)キナゾリン4-アミン(CI1033))、例えば血小板由来の成長因子ファミリーのインヒビターおよび例えば肝細胞成長因子ファミリーのインヒビターが含まれる。
(v)血管障害薬、例えば、コンブレタスタチンA4および国際公開番号WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434 および WO 02/08213に開示されている化合物;
(vi)アンチセンス療法、例えば上に掲げた標的に関するもの、例えばISIS 2503、抗rasアンチセンス;
(vii)遺伝子治療手法:例えば、異常な遺伝子、例えば、異常なp53または異常なBRCA1またはBRCA2を置換える手法、GDEPT(遺伝子に依存する酵素プロ薬物療法)手法、例えばシトシンデアミナーゼ、チミジンキナーゼまたは細菌のニトロレダクターゼ酵素を用いるもの、および化学療法または放射線療法に対する患者耐性を増加する手法、例えば、多剤耐性遺伝子治療;ならびに
(viii)免疫療法手法(例えば、患者腫瘍細胞の免疫原性を増加するためのex vivoおよびin vivo手法を含む)、例えばサイトカイン、例えば、インターロイキン-2、インターロイキン-4または顆粒球マクロファージコロニー刺激因子によるトランスフェクション、T細胞アネルギーを減少する手法、トランスフェクトした免疫細胞、例えばサイトカイントランスフェクトした樹状細胞を用いる手法、サイトカイントランスフェクトした腫瘍細胞株を用いる手法、および抗イディオタイプの抗体を用いる手法。
本発明者らは、アンジオポエチン-2の生物学的活性のアンタゴニスト(限定されるものでないが、モノクローナル抗体3.19.3を含む)と化学治療薬のある特定の組合わせは、アンジオポエチン-2の生物学的活性のアンタゴニストまたは化学治療薬の単独使用と比較して、腫瘍に対して有意に優れた効果をもたらすことを見出した。
本発明はまた、アンジオポエチン-2および/またはTie-2の生物学的活性のアンタゴニストとCSF1Rおよび/またはCSF1の生物学的活性のアンタゴニストとを含む医薬品組合わせ、ならびにかかる組合わせの使用を提供する。
2-クロロ-N-ピリジン-3-イル-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
2-クロロ-N-(5-フルオロピリジン-3-イル)-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
2-クロロ-N-(5-フルオロピリジン-3-イル)-5-{[3-フルオロ-5-(トリフルオロメチル)ベンゾイル]アミノ}-ベンズアミド;
2-メチル-N-ピリジン-3-イル-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
5-{[3-フルオロ-5-(トリフルオロメチル)ベンゾイル]アミノ}-2-メチル-N-ピリジン-3-イルベンズアミド;
2-クロロ-5-[(3-シクロプロピルベンゾイル)アミノ]-N-ピリジン-3-イルベンズアミド;
2-クロロ-5-[(3-クロロベンゾイル)アミノ]-N-ピリジン-3-イルベンズアミド;
5-[(3-クロロ-5-フルオロベンゾイル)アミノ]-2-メチル-N-ピリジン-3-イルベンズアミド;
5-[(3-シクロプロピル-5-フルオロベンゾイル)アミノ]-2-メチル-N-ピリジン-3-イルベンズアミド;
5-[(3-クロロベンゾイル)アミノ]-2-メチル-N-ピリジン-3-イルベンズアミド;
5-{[3-(1-シアノ-1-メチルエチル)ベンゾイル]アミノ}-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2-クロロ-N-1,3-チアゾール-5-イル-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
2-クロロ-5-[(3-クロロベンゾイル)アミノ]-N-1,3-チアゾール-5-イルベンズアミド;
2-クロロ-5-[(3,5-ジメチルベンゾイル)アミノ]-N-1,3-チアゾール-5-イルベンズアミド;
5-{[3-(1-シアノ-1-メチルエチル)ベンゾイル]アミノ}-2-メチル-N-1,3-チアゾール-5-イルベンズアミド;
2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
2-クロロ-5-[(3-クロロベンゾイル)アミノ]-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2-クロロ-5-[(3,5-ジメチルベンゾイル)アミノ]-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2-クロロ-N-(2-メチル-1,3-チアゾール-5-イル)-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
2-クロロ-5-{[3-フルオロ-5-(トリフルオロメチル)ベンゾイル]アミノ}-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(5-{[3-(1-シアノ-1-メチルエチル)ベンゾイル]アミノ}-2-メチルベンゾイル)アミノ]-N-メチル-1,3-チアゾール-2-カルボキサミド;
5-{[3-フルオロ-5-(トリフルオロメチル)ベンゾイル]アミノ}-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(3-クロロ-5-フルオロベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(3-シクロプロピル-5-フルオロベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(3-クロロベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[3,4-ジクロロベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(3-シクロプロピルベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(3,5-ジメチルベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2-メチル-5-[(3-メチルベンゾイル)アミノ]-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2,6-ジクロロ-N-(4-メチル-3-{[(2-メチル-1,3-チアゾール-5-イル)アミノ]カルボニル}フェニル)イソニコチンアミド
2-メチル-5-{[(3-メチルシクロヘキシル)カルボニル]アミノ}-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)-5-(ペンタノイルアミノ)ベンズアミド;
2-メチル-5-[(4-メチルヘキサノイル)アミノ]-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-エトキシ-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(2,3-ジクロロフェニル)アミノ]-7-エトキシ-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-5-メチルフェニル)アミノ]-6-(4-イソプロピルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(3-クロロ-2-フルオロフェニル)アミノ]-7-エトキシ-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-5-メチルフェニル)アミノ]-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-(2-メトキシエトキシ)-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-7-(2-メトキシエトキシ)-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(2-フルオロ-5-メチルフェニル)アミノ]-7-(2-メトキシエトキシ)-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(4-イソプロピルピペラジン-1-イル)-7-(2-メトキシエトキシ)キノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(1-メチルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-エトキシ-6-(1-メチルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-エトキシ-6-(1-イソプロピルピペリジン-4-イル)キノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(1-イソプロピルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-7-メトキシ-6-(1-メチルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(3-クロロ-2-フルオロフェニル)アミノ]-7-メトキシ-6-(1-メチルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-メトキシ-6-(1-メチルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(1-イソプロピルピペリジン-4-イル)-7-メトキシキノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-6-(1-イソプロピルピペリジン-4-イル)-7-メトキシキノリン-3-カルボキサミド;および
4-[(3-クロロ-2-フルオロフェニル)アミノ]-6-(1-イソプロピルピペリジン-4-イル)-7-メトキシキノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-4-メチル-フェニル)アミノ]-6-(4-メチルピペラジン-1-イル)シンノリン-3-カルボキサミド;
4-(2-フルオロ-4-メチルフェニルアミノ)-7-メトキシ-6-(4-メチルピペラジン-1-イル)シンノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-メトキシ-6-(4-メチルピペラジン-1-イル)シンノリン-3-カルボキサミド;
6-[(3R,5S)-3,5-ジメチルピペラジン-1-イル]-4-[(2-フルオロ-4-メチルフェニル)アミノ]-7-メトキシシンノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-[4-(2-ヒドロキシエチル)ピペラジン-1-イル]-7-メトキシシンノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-[4-(2-ヒドロキシエチル)ピペラジン-1-イル]シンノリン-3-カルボキサミド;
4-[(3-クロロ-2-フルオロフェニル)アミノ]-6-[(3R,5S)-3,5-ジメチルピペラジン-1-イル]-7-メトキシシンノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(1-イソプロピルピペリジン-4-イル)-7-メトキシシンノリン-3-カルボキサミド塩酸塩;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]-7-メトキシシンノリン-3-カルボキサミド;および
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-{4-[(2R)-2-ヒドロキシプロパノイル]ピペラジン-1-イル}-7-メトキシシンノリン-3-カルボキサミド
またはその製薬上許容される塩。
ロイコトリエン生合成インヒビター、5-リポキシゲナーゼ(5-LO)インヒビターまたは5-リポキシゲナーゼ活性化タンパク質(FLAP)アンタゴニスト、例えばジロイトン;ABT-761;フェンレウトン;テポキサリン;Abbott-79175;Abbott-85761;N-(5-置換)-チオフェン-2-アルキルスルホンアミド;2,6-ジ-tert-ブチルフェノールヒドラゾン;メトキシテトラヒドロピラン、例えばZeneca ZD-2138;化合物SB-210661;ピリジニル置換2-シアノナフタレン化合物、例えばL-739,010;2-シアノキノリン化合物、例えばL-746,530;インドールおよび/またはキノリン化合物、例えばMK-591、MK-886および/またはBAY x 1005;ロイコトリエン(LT)B4、LTC4、LTD4、およびLTE4の受容体アンタゴニストであって、フェノチアジン-3-1類、例えばL-651,392;アミジノ化合物、例えばCGS-25019c;ベンゾキサラミン、例えばオンタゾラスト;ベンゼンカルボキシミドアミド、例えばBIIL 284/260;および化合物、例えばザフィルルカスト、アブルカスト、モンテルカスト、プランルカスト、ベルルカスト(MK-679)、RG-12525、Ro-245913、イラルカスト(CGP 45715A)およびBAY x 7195からなる群から選択されるもの;
ホスホジエステラーゼ(PDE)インヒビター、例えばメチルキサンタニン、例えばテオフィリンおよび/またはアミノフィリン;および/または選択的PDEアイソザイム阻害剤、例えばPDE4インヒビターおよび/またはアイソタイプPDE4Dのインヒビターおよび/またはPDE5のインヒビター;ヒスタミン1型受容体アンタゴニスト、例えばセチリジン、ロラタジン、デスロラタジン、フェキソフェナジン、アクリバスチン、テルフェナジン、アステミゾール、アゼラスチン、レボカバスチン、クロルフェニラミン、プロメタジン、シクリジン、および/またはミゾラスチン(一般的に経口、局所または非経口で投与される);プロトンポンプインヒビター(例えばオメプラゾール)または胃保護性ヒスタミン2型受容体アンタゴニスト;ヒスタミン4型受容体のアンタゴニスト;α-1/α-2アドレナリン受容体アゴニスト血管収縮性交感神経模倣薬、例えばプロピルヘキセドリン、フェニレフリン、フェニルプロパノールアミン、エフェドリン、シュードエフェドリン、塩酸ナファゾリン、塩酸オキシメタゾリン、塩酸テトラヒドロゾリン、塩酸キシロメタゾリン、塩酸トラマゾリンおよび塩酸エチルノルエピネフリン;抗コリン作動薬、例えばムスカリン受容体(M1、M2、およびM3)アンタゴニスト、例えばアトロピン、ヒヨスチン、グリコピロレート、イプラトロピウムブロミド、チオトロピウムブロミド、ピレンゼピンおよびテレンゼピン;β-アドレナリン受容体アゴニスト(β受容体サブタイプ1-4を含む)、例えばイソプレナリン、サルブタモール、フォルモテロール、サルメテロール、テルブタリン、オルシプレナリン、ビトルテロールメシレートおよび/またはピルブテロール、例えばそのキラルエナンチオマー;クロモン、例えばクロモグリク酸ナトリウムおよび/またはネドクロミルナトリウム;糖質コルチコイド、例えばフルニソリド、トリアムシノロンアセトニド、ジプロピオン酸ベクロメタゾン、ブデソニド、プロピオン酸フルチカゾン、シクレソニド、および/またはフランカルボン酸モメタゾン;核ホルモン受容体、例えばPPARをモジュレートする物質;免疫グロブリン(Ig)またはIg調製物またはIg機能をモジュレートするアンタゴニストもしくは抗体、例えば抗IgE(例えばオマリズマブ);他の全身または局所適用の抗炎症剤、例えばサリドマイドまたはその誘導体、レチノイド、ジトラノールおよび/またはカルシポトリオール;アミノサリチル酸およびスルファピリジンの組み合わせ、例えばスルファサラジン、メサラジン、バルサラジド、およびオルサラジン;および免疫調節剤、例えばチオプリン;およびコルチコステロイド、例えばブデソニド;抗菌剤、例えばペニシリン誘導体、テトラサイクリン、マクロライド、β-ラクタム、フルオロキノロン、メトロニダゾールおよび/または吸入アミノグリコシド;および/または抗ウイルス剤、例えばアシクロビル、ファムシクロビル、バラシクロビル、ガンシクロビル、シドフォビル;アマンタジン、リマンタジン;リバビリン;ザナマビルおよび/またはオセルタマビル;プロテアーゼインヒビター、例えばインジナビル、ネルフィナビル、リトナビルおよび/またはサキナビル;ヌクレオシド逆転写酵素インヒビター、例えばジダノシン、ラミブジン、スタブジン、ザルシタビン、ジドブジン;非ヌクレオシド逆転写酵素インヒビター、例えばネビラピン、エファビレンツ;心血管作動薬、例えばカルシウムチャネルブロッカー、β-アドレナリン受容体ブロッカー、アンジオテンシン変換酵素(ACE)インヒビター、アンジオテンシン-2受容体アンタゴニスト;脂質低下剤、例えばスタチンおよび/またはフィブラート;血球形態のモジュレーター、例えばペントキシフィリン;血栓溶解剤および/または抗凝血剤、例えば血小板凝集インヒビター;中枢神経系作用薬、例えば抗うつ剤(例えばセルトラリン)、抗パーキンソン薬(例えばデプレニル、L-ドーパ、ロピニロール、プラミペキソール;MAOBインヒビター、例えばセレギンおよびラサギリン;comPインヒビター、例えばタスマル;A-2インヒビター、ドーパミン再摂取インヒビター、NMDAアンタゴニスト、ニコチンアゴニスト、ドーパミンアゴニストおよび/またはニューロン一酸化窒素シンターゼのインヒビター)および抗アルツハイマー薬、例えばドネペジル、リバスティグミン、タクリン、COX-2インヒビター、プロペントフィリンまたはメトリホナート;急性および慢性痛を治療するための薬剤、例えば中枢または末梢作用鎮痛剤、例えばオピオイド類似体または誘導体、カルバマゼピン、フェニトイン、バルプロ酸ナトリウム、アミトリプチリンまたは他の抗うつ剤、パラセタモール、または非ステロイド性抗炎症剤;非経口または局所適用(吸入を含む)局所麻酔剤、例えばリグノカインまたはその類似体;抗骨粗鬆症薬、例えばホルモン剤、例えばラロキシフェン、またはビホスホナート、例えばアレンドロナート;次の(i)〜(xxvi)の作用薬:(i)トリプターゼインヒビター;(ii)血小板活性化因子(PAF)アンタゴニスト(iii)インターロイキン変換酵素(ICE)インヒビター;(iv)IMPDHインヒビター;(v)接着分子インヒビター、例えばVLA-4アンタゴニスト;(vi)カテプシン;(vii)キナーゼインヒビター、例えばチロシンキナーゼ(例えばBtk、Itk、Jak3 MAP、インヒビターの例にはゲフィチニブ、メシル酸イマチニブが含まれる)、セリン/スレオニンキナーゼ(例えばMAPキナーゼ、例えばp38、JNK、プロテインキナーゼA、BおよびCおよびIKKのインヒビター)、または細胞周期調節に関与するキナーゼ(例えばサイクリン依存性キナーゼ)のインヒビター;(viii)グルコース-6リン酸デヒドロゲナーゼインヒビター;(ix)キニン-B.sub1.および/またはB.sub2.受容体アンタゴニスト;(x)抗痛風剤、例えばコルヒチン;(xi)キサンチンオキシダーゼインヒビター、例えばアロプリノール;(xii)尿酸排泄剤、例えばプロベネシド、スルフィンピラゾン、および/またはベンズブロマロン;(xiii)成長ホルモン分泌促進剤;(xiv)トランスフォーミング成長因子(TGFβ);(xv)血小板由来成長因子(PDGF);(xvi)線維芽細胞成長因子、例えば塩基性線維芽細胞成長因子(bFGF);(xvii)顆粒球マクロファージコロニー刺激因子(GM-CSF);(xviii)カプサイシンクリーム;(xix)タキキニンNK.sub1.および/またはNK.sub3.受容体アンタゴニスト、例えばNKP-608C、SB-233412(タルネタント)および/またはD-4418;(xx)エラスターゼインヒビター、例えばUT-77および/またはZD-0892;(xxi)TNF-α変換酵素インヒビター(TACE);(xxii)誘導性一酸化窒素シンターゼ(iNOS)インヒビターまたは(xxiii)TH2細胞上で発現される化学誘引物質受容体相同分子(例えばCRTH2アンタゴニスト);(xxiv)P38のインヒビター(xxv)Toll様受容体(TLR)の機能をモジュレートする物質および(xxvi)プリン受容体の活性をモジュレートする物質、例えばP2X7;(xxvii)転写因子、例えばNFkB、APIおよび/またはSTATS活性化のインヒビター;局所適用または全身適用に関わらず、非選択的シクロオキシゲナーゼ(COX)-1/COX-2インヒビターを含む非ステロイド性抗炎症剤(以後、NSAIDと呼ぶ)(例えばピロキシカム、ジクロフェナク、プロピオン酸、例えばナプロキセン、フルルビプロフェン、フェノプロフェン、ケトプロフェンおよびイブプロフェン、フェナマート、例えばメフェナム酸、インドメタシン、スリンダク、アザプロパゾン、ピラゾロン、例えばフェニルブタゾン、サリチラート、例えばアスピリン);選択的COX-2インヒビター(例えばメロキシカム、セレコキシブ、ロフェコキシブ、バルデコキシブ、ルマロコキシブ、パレコキシブおよびエトリコキシブ);シクロオキシゲナーゼ阻害性一酸化窒素ドナー(CINOD);グルココルチコステロイド(局所、経口、筋肉内、静脈内または関節内経路による投与のいずれでもよい);メトトレキセート、レフルノミド;ヒドロキシクロロキン、d-ペニシラミン、オーラノフィンまたは他の非経口もしくは経口金製剤;鎮痛剤;ジアセレイン;関節内治療薬、例えばヒアルロン酸誘導体;および栄養補助食品、例えばグルコサミン。
他の態様において本発明は、組成物、例えば、限定されるものでないが、製薬上許容される担体と一緒に製剤化した1以上の本発明の抗体を含有する医薬組成物を提供する。
本発明の抗体を含む医薬品または無菌組成物を調製するためには、抗体を製薬上許容される担体または賦形剤と混合する。治療薬および診断薬の製剤は、生理学的に許容される担体、賦形剤、または安定剤と、例えば、凍結乾燥粉末、スラリー、水溶液、ローション、または懸濁液の剤形で混合することにより調製することができる(例えば、Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.;Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.;Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY;Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY;Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY;Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, N.Y.を参照)。
特許、特許出願、論文、教科書などを含む本明細書で引用された全ての参考文献、およびそれに引用された参考文献は、それらが既に引用されていない限り、本明細書に参照によりその全てが組み入れられる。さらに、次の米国予備特許出願番号61/023,958(2008年1月28日出願)、61/100,063(2008年9月25日出願)、および 61/142,778(2009年1月6日出願)は本明細書に参照によりその全てが全ての目的のために組み入れられる。
前述の書面での明細書は、当業者が本発明を実施できるようにするのに十分であると考えられる。前述の説明および実施例は、本発明のある特定の好ましい実施形態を詳述し、本発明者らが考えた最良の様式を記載している。しかし、前述内容が本文中にいかに詳細に記載されていても、本発明は多数の方法で実行可能であり、かつ本発明は添付の特許請求の範囲およびそれらの任意の均等物に従って解釈されるべきであることは理解されるであろう。
1. Ang-2と結合する単離された抗体であって、前記抗体が可変軽鎖を含み、前記軽鎖が配列番号3(MEDI1);配列番号4(MEDI2);配列番号5(MEDI3);配列番号6(MEDI4);および配列番号8(MEDI6)からなる群より選択される配列を含む前記抗体。
2-クロロ-N-ピリジン-3-イル-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
2-クロロ-N-(5-フルオロピリジン-3-イル)-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
2-クロロ-N-(5-フルオロピリジン-3-イル)-5-{[3-フルオロ-5-(トリフルオロメチル)ベンゾイル]アミノ}-ベンズアミド;
2-メチル-N-ピリジン-3-イル-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
5-{[3-フルオロ-5-(トリフルオロメチル)ベンゾイル]アミノ}-2-メチル-N-ピリジン-3-イルベンズアミド;
2-クロロ-5-[(3-シクロプロピルベンゾイル)アミノ]-N-ピリジン-3-イルベンズアミド;
2-クロロ-5-[(3-クロロベンゾイル)アミノ]-N-ピリジン-3-イルベンズアミド;
5-[(3-クロロ-5-フルオロベンゾイル)アミノ]-2-メチル-N-ピリジン-3-イルベンズアミド;
5-[(3-シクロプロピル-5-フルオロベンゾイル)アミノ]-2-メチル-N-ピリジン-3-イルベンズアミド;
5-[(3-クロロベンゾイル)アミノ]-2-メチル-N-ピリジン-3-イルベンズアミド;
5-{[3-(1-シアノ-1-メチルエチル)ベンゾイル]アミノ}-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2-クロロ-N-1,3-チアゾール-5-イル-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
2-クロロ-5-[(3-クロロベンゾイル)アミノ]-N-1,3-チアゾール-5-イルベンズアミド;
2-クロロ-5-[(3,5-ジメチルベンゾイル)アミノ]-N-1,3-チアゾール-5-イルベンズアミド;
5-{[3-(1-シアノ-1-メチルエチル)ベンゾイル]アミノ}-2-メチル-N-1,3-チアゾール-5-イルベンズアミド;
2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
2-クロロ-5-[(3-クロロベンゾイル)アミノ]-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2-クロロ-5-[(3,5-ジメチルベンゾイル)アミノ]-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2-クロロ-N-(2-メチル-1,3-チアゾール-5-イル)-5-{[3-(トリフルオロメチル)ベンゾイル]アミノ}ベンズアミド;
2-クロロ-5-{[3-フルオロ-5-(トリフルオロメチル)ベンゾイル]アミノ}-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(5-{[3-(1-シアノ-1-メチルエチル)ベンゾイル]アミノ}-2-メチルベンゾイル)アミノ]-N-メチル-1,3-チアゾール-2-カルボキサミド;
5-{[3-フルオロ-5-(トリフルオロメチル)ベンゾイル]アミノ}-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(3-クロロ-5-フルオロベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(3-シクロプロピル-5-フルオロベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(3-クロロベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[3,4-ジクロロベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(3-シクロプロピルベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
5-[(3,5-ジメチルベンゾイル)アミノ]-2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2-メチル-5-[(3-メチルベンゾイル)アミノ]-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2,6-ジクロロ-N-(4-メチル-3-{[(2-メチル-1,3-チアゾール-5-イル)アミノ]カルボニル}フェニル)イソニコチンアミド
2-メチル-5-{[(3-メチルシクロヘキシル)カルボニル]アミノ}-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
2-メチル-N-(2-メチル-1,3-チアゾール-5-イル)-5-(ペンタノイルアミノ)ベンズアミド;
2-メチル-5-[(4-メチルヘキサノイル)アミノ]-N-(2-メチル-1,3-チアゾール-5-イル)ベンズアミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-エトキシ-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(2,3-ジクロロフェニル)アミノ]-7-エトキシ-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-5-メチルフェニル)アミノ]-6-(4-イソプロピルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(3-クロロ-2-フルオロフェニル)アミノ]-7-エトキシ-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-5-メチルフェニル)アミノ]-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-(2-メトキシエトキシ)-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-7-(2-メトキシエトキシ)-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(2-フルオロ-5-メチルフェニル)アミノ]-7-(2-メトキシエトキシ)-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(4-イソプロピルピペラジン-1-イル)-7-(2-メトキシエトキシ)キノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(1-メチルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-エトキシ-6-(1-メチルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-エトキシ-6-(1-イソプロピルピペリジン-4-イル)キノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(1-イソプロピルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-7-メトキシ-6-(1-メチルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(3-クロロ-2-フルオロフェニル)アミノ]-7-メトキシ-6-(1-メチルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-メトキシ-6-(1-メチルピペリジン-4-イル)キノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(1-イソプロピルピペリジン-4-イル)-7-メトキシキノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-6-(1-イソプロピルピペリジン-4-イル)-7-メトキシキノリン-3-カルボキサミド;および
4-[(3-クロロ-2-フルオロフェニル)アミノ]-6-(1-イソプロピルピペリジン-4-イル)-7-メトキシキノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-4-メチル-フェニル)アミノ]-6-(4-メチルピペラジン-1-イル)シンノリン-3-カルボキサミド;
4-(2-フルオロ-4-メチルフェニルアミノ)-7-メトキシ-6-(4-メチルピペラジン-1-イル)シンノリン-3-カルボキサミド;
4-[(2,4-ジフルオロフェニル)アミノ]-7-メトキシ-6-(4-メチルピペラジン-1-イル)シンノリン-3-カルボキサミド;
6-[(3R,5S)-3,5-ジメチルピペラジン-1-イル]-4-[(2-フルオロ-4-メチルフェニル)アミノ]-7-メトキシシンノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-[4-(2-ヒドロキシエチル)ピペラジン-1-イル]-7-メトキシシンノリン-3-カルボキサミド;
7-エトキシ-4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-[4-(2-ヒドロキシエチル)ピペラジン-1-イル]シンノリン-3-カルボキサミド;
4-[(3-クロロ-2-フルオロフェニル)アミノ]-6-[(3R,5S)-3,5-ジメチルピペラジン-1-イル]-7-メトキシシンノリン-3-カルボキサミド;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-(1-イソプロピルピペリジン-4-イル)-7-メトキシシンノリン-3-カルボキサミド塩酸塩;
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]-7-メトキシシンノリン-3-カルボキサミド;および
4-[(2-フルオロ-4-メチルフェニル)アミノ]-6-{4-[(2R)-2-ヒドロキシプロパノイル]ピペラジン-1-イル}-7-メトキシシンノリン-3-カルボキサミド、またはその製薬上許容される塩のいずれか1つから選択される、実施形態69に記載の組成物。
3.19.3 軽鎖配列番号:1
本配列中の箱に入った残基は、任意の他のアミノ酸へ変えることができる不対システイン(C49)を表す。かかる変更の例を以下の軽鎖配列において箱に入れて強調した。
本実施例においては、Ang-2抗体3.19.3の軽鎖と重鎖を含むAng-2特異的抗体を改変して、軽鎖の位置49においてシステインのアミノ酸置換を導入した。得られる抗体の効力をAng-2:Tie-2効力アッセイで測定した。結果を以下の表1に示した。
Ang-2:Tie-2効力アッセイにおいて、位置49の様々な改変は抗体において類似の効力をもたらした。例示の抗体は、限定されるものでないが、C49A、C49T、C49N、およびC49Dを含む。嵩ばった、疎水性置換を含む改変のいくつか、例えば、C49WはIC50値の増加により示される効力の低下をもたらした。様々な荷電残基を含む他の改変、例えば、C49KおよびC49HもIC50値の増加により示される効力の低下をもたらした。
本実施例においては、Ang-2抗体3.19.3の軽鎖と重鎖を含むAng-2特異的抗体を改変して、軽鎖の位置49においてシステインのアミノ酸置換を導入した。得られる抗体の相対的発現を測定した。さらに、いくつかの抗体の重鎖の位置37も改変してVal残基(MEDI5)を導入した。
3.19.3の重鎖と軽鎖(それぞれ配列番号2および1)、ならびにそれぞれ配列番号7および3と記述された重鎖と軽鎖(IgG1およびIgG2フォーマットの両方で)をコードするベクターを293F細胞にて、次のプロトコルによって発現させた:すなわち、生存細胞(>95%)をFreestyle293(登録商標)培地(Invitrogen)中で1.0 x 106細胞/minの細胞密度にて希釈した。様々なDNA調製物を293Fectin(登録商標)(Invitrogen)に溶解し、細胞に、製造業者の指示書に従って加えた。形質転換の第6日に、培養上清を回収することにより発現した抗体を収穫した。抗体レベルをプロテインA結合により測定した後に精製した。
“MEDI1/5 IgG1”(配列番号7および3として記述した重鎖と軽鎖をIgGフォーマットで有する)、および“MEDI1/5 IgG2”(配列番号7および3として記述した重鎖と軽鎖をIgGフォーマットで有する)抗体の生産効率は3.19.3抗体の生産効率と比較して増加した。その結果を表2に総括した。
システイン置換が行われたAng-2抗体の安定性増加を評価するために、安定性研究を実施した。IgG1およびIgG2フォーマットのWT3.19.3抗体ならびにMEDI1/5を、10mMヒスチジンpH 6.0中で10mg/mlに濃縮した。上記製剤のサンプルを25℃または40℃の両方で2週間インキュベートした。安定性の尺度として、凝集速度(%凝集/月)を2週間時点後に計算した。結果を表3に示した。
システイン置換が行われたAng-2抗体の安定性の増加を評価するために、WT(3.19.3)およびMEDI1/5 IgG1およびIgG2抗体の示差走査熱量測定(DSC)分析を実施した。この実施例においては、WT、MEDI1/5 IgG1およびMEDI1/5 IgG2抗体の製剤を、10mMヒスチジン、pH6.0中の抗体1g/Lにて調製し、DSC分析で処理した。結果を図1に示す。提示したように、WT抗体は約61℃の融点を示した。MEDI1/5 IgG1抗体はより高い約76℃の融点を示した。MEDI1/5 IgG2もより高い約76℃の融点を示したが、この場合、その後、2つの独立した試験で観察される食い違いを生じた(試験1と2)。
本実施例においては、Ang-2抗体の3.19.3、およびC49T(MEDI1/5)置換を含む改変された3.19.3抗体を、競合ELISAフォーマットアッセイにおけるAng-2結合について分析した。
競合Tie-2 Fc/Ang2 ELISA:Maxisorp ELISAプレート(Nunc、Rochester、NY)を、100μlの4μg/ml Tie-2 Fc(R & D Systems、Minneapolis、MN)を含む0.1M炭酸塩バッファーpH 9.4(Pierce、Rockford、IL)でコートし、一晩4℃でインキュベートした。翌日、プレートを1時間室温で0.5%ウシ血清アルブミン(BSA)(Sigma, St. Louis, MO)および0.1% Tween-20(Sigma, St. Louis、MO)を含有するリン酸緩衝化生理食塩水(PBS)(Invitrogen、Carlsbad、CA)の200μlを用いてブロックした。プレートを洗浄バッファー(0.05% Tween-20を含有するPBS)を用いて3回洗浄した。3.19.3または改変された抗Ang2抗体の11点連続三次希釈液(30μg/ml高濃度)50μlを、ネガティブ対照のPBSと共にプレーティングした。抗体捕獲については、200ng/mlビオチンAng2(R & D Systems, Minneapolis, MN)50μlを加え、プレートを2時間室温にてインキュベートした。プレートを3回洗浄バッファーによって洗浄した。洗浄後、1:5000ストレプトアビジンHRP(Pierce, Rockford, IL)の洗浄バッファー中の希釈液100μlを加え、1時間室温にてインキュベートした。プレートを3回洗浄バッファーによって洗浄した。プレートを、100 μlのTMBペルオキシダーゼ基質(KPL, Gaithersburg, MD)を加えることにより5分間現像した。反応を、100μl/wellの1Mリン酸を加えることにより停止した。光学密度を450nmにてマイクロプレートリーダー(Molecular Devices, Sunnyvale, CA)を用いて測定した。
図3に掲げたように、ELISA結果は、ELISAフォーマットでTie2に対する競合により測定すると、IgG1またはIgG2フォーマットのMEDI1/5抗体は3.19.3抗体と比較して、非常に類似したAng-2との結合プロファイルを表すことを示した。
小分子CSF1Rチロシンキナーゼインヒビターと組合わせた3.19.3のin vivo効力を評価した。
抗アンジオポエチン-2モノクローナル抗体3.19.3の、小分子CSF1RチロシンキナーゼインヒビターAZD6495(4-[(2,4-ジフルオロフェニル)アミノ]-7-エトキシ-6-(4-メチルピペラジン-1-イル)キノリン-3-カルボキサミド)と組合わせた抗腫瘍活性を、ヒト乳癌の異種移植モデルでMCF7細胞株を用いて評価した(図4a)。
乳癌MCF7細胞を日常の方法でフラスコ内で培養して細胞をサブコンフルエンスに到達させた。免疫不全の7〜10週齢雄NCr-ヌードマウスに、マトリゲル中に1:1で懸濁した8x106 MCF7細胞を右横腹に皮下移植した。17-B-エストラジオールのペレット(0.72mg/ペレット)も、標準の手順で移植し、このERポジティブ(エストロゲン要求性)細胞株の成長を支援した。
3.19.3(10mg/kg 2 x wk)=62%阻害;(p<0.04)
AZD6495(30mg/kg bid)=32%阻害;(p<0.42)
3.19.3+AZD6495の組合わせ=81%阻害(p<0.01)。
抗アンジオポエチン-2モノクローナル抗体3.19.3の、小分子CSF1RチロシンキナーゼインヒビターAZD6495と組合わせた抗腫瘍活性を、ヒト乳癌の異種移植モデルでMDA-MB-231細胞株を用いて評価した。
3.19.3(10mg/kg 2 x wk)=17%阻害;(p<0.20)
AZD6495(30mg/kg bid)=25%阻害;(p<0.04)
3.19.3+AZD6495の組合わせ=52%阻害(p<0.09)。
モノクローナル抗体3.19.3の活性を、化学治療薬との組合わせ研究で評価し、ヒト腫瘍異種移植モデルにおけるin vivo効力と耐性を決定した。
3.19.3の、5-フルオウラシル(5FU)と組合わせた抗腫瘍活性を、結腸直腸癌のLoVo異種移植モデルで評価した。LoVo細胞を日常の方法でフラスコ内で培養して細胞をサブコンフルエンスに到達させた。雌Swissヌードマウスの横腹に、およそ3 x10E6細胞を含有する細胞懸濁液を皮下注射した。腫瘍体積が200mm3に達すると、マウスを8〜10マウスの治療グループに無作為化し、治療を開始した。3.19.3(10mg/kg)を含む生理食塩水を毎週2回、2週間、腹腔内に注射し、5-フルオウラシル(100mg/kg)を週スケジュールに従って腹腔内投与した。各腫瘍の次元と体重を、毎週少なくとも2回測定した。腫瘍の体積は、体積=長さx(幅)2x0.5(cm3)として計算した。図6aに図解した通り、3.19.3と5FUは単剤としてLoVo腫瘍の成長を遅延した。しかし、3.19.3と5FUの組合わせは、図6aに図解した通り、単剤だけより大きい効果を有した。達成された%腫瘍成長阻害は次の通りである:
3.19.3(10mg/kg 2 x wk)=59%阻害;(p<0.09)
5FU(100mg/kg/week)=62%阻害;(p<0.02)
3.19.3+5FUの組合わせ=85%阻害(p<0.007)
体重変化により測定して、単剤治療だけと比較して、組合わせによるさらなる毒性は観察されなかった(図6b)。これらの結果は、抗Ang2抗体3.19.3と5-フルオウラシルによる組合わせ治療が結腸癌の前臨床モデルにおいてさらなる毒性なしに効力の改善をもたらすことを実証し、この組合わせのさらなる臨床研究のための根拠を提供する。
3.19.3の、イリノテカンと組合わせた抗腫瘍活性を、結腸直腸癌のHT-29異種移植モデルで評価した。HT-29細胞を日常の方法でフラスコ内で培養して細胞をサブコンフルエンスに到達させた。雌Swissヌードマウスの横腹に、およそ3 x10E6細胞を含有する細胞懸濁液を皮下注射した。腫瘍体積が200mm3に達すると、マウスを8〜10マウスの治療グループに無作為化し、治療を開始した。3.19.3(10mg/kg)を含む生理食塩水を毎週2回、2週間、腹腔内に注射した。イリノテカン(35mg/kg)を週スケジュールに従って静脈内投与した。各腫瘍の次元と体重を、少なくとも毎週2回測定した。腫瘍の体積は、体積=長さx(幅)2x0.5(cm3)として計算した。図7aに図解した通り、3.19.3とイリノテカンは単剤としてHT29腫瘍の成長を遅延した。しかし、3.19.3とイリノテカンの組合わせは、図7aに図解した通り、単剤だけより大きい効果を有した。達成された%腫瘍成長阻害は次の通りである:
3.19.3(10mg/kg 2 x wk)=44% 阻害; (p<0.005)
イリノテカン(35mg/kg/week)=56%阻害;(p<0.006)
3.19.3+イリノテカンの組合わせ=71%阻害(p<0.0001)
体重変化により測定して、単剤治療だけと比較して、組合わせによるさらなる毒性は観察されなかった(図7b)。これらの結果は、抗Ang2抗体3.19.3とイリノテカンによる組合わせ治療が結腸癌の前臨床モデルにおいてさらなる毒性なしに効力の改善をもたらすことを実証し、この組合わせのさらなる臨床研究のための根拠を提供する。
3.19.3の、ゲムシタビンと組合わせた抗腫瘍活性を、結腸直腸癌のColo205異種移植モデルで評価した。Colo205細胞を日常の方法でフラスコ内で培養して細胞をサブコンフルエンスに到達させた。雌Swissヌードマウスの横腹に、およそ3 x 10E6細胞を含有する細胞懸濁液を皮下注射した。腫瘍体積が200mm3に達すると、マウスを8〜10マウスの治療グループに無作為化し、治療を開始した。3.19.3(10mg/kg)を含む生理食塩水を毎週2回、2週間、腹腔内に注射した。ゲムシタビン(50mg/kg)を毎3日1回のスケジュールに従って静脈内投与した。各腫瘍の次元と体重を、少なくとも毎週2回測定した。腫瘍の体積は、体積=長さx(幅)2x0.5(cm3)として計算した。図8aに図解した通り、3.19.3は単剤としてColo205腫瘍の成長を遅延したが、Colo205腫瘍はゲムシタビン治療に対してかなり耐性がありおだやかな8%腫瘍成長遅延をもたらした。しかし、3.19.3とゲムシタビンの組合わせは、図8aに図解した通り、単剤だけより大きい効果を有した。達成された%腫瘍成長阻害は次の通りである:
3.19.3(10mg/kg 2 x wk)=74%阻害;(p<0.001)
ゲムシタビン(50mg/kg q3d x 2)=8%阻害;(p<0.2)
3.19.3+ゲムシタビンの組合わせ=88%阻害(p<0.0003)。
3.19.3の、ドセタキセルと組合わせた抗腫瘍活性を、肺癌のCalu6異種移植モデルで評価した。Calu6細胞を日常の方法でフラスコ内で培養して細胞をサブコンフルエンスに到達させた。雌Swissヌードマウスの横腹に、およそ3 x 10E6細胞を含有する細胞懸濁液を皮下注射した。腫瘍体積が200mm3に達すると、マウスを8〜10マウスの治療グループに無作為化し、治療を開始した。3.19.3(10mg/kg)を含む生理食塩水を毎週2回、2週間、腹腔内に注射した。ドセタキセル(15mg/kg)を週スケジュールに従って静脈内投与した。各腫瘍の次元と体重を、少なくとも毎週2回測定した。各腫瘍の体積は、体積=長さx(幅)2x0.5(cm3)として計算した。図9aに図解した通り、3.19.3とドセタキセルは単剤としてCalu6腫瘍の成長を遅延した。しかし、3.19.3とドセタキセルの組合わせは、図9aに図解した通り、単剤だけより大きい効果を有した。
3.19.3(10mg/kg 2xwk)=20%阻害;(p<0.12)
ドセタキセル(15mg/kg/week)=43%阻害;(p<0.0007)
3.19.3+ドセタキセルの組合わせ=71%阻害(p<0.0001)。
3.19.3の、オキサリプラチンと組合わせた抗腫瘍活性を、肺癌のH460異種移植モデルで評価した。H460細胞を日常の方法でフラスコ内で培養して細胞をサブコンフルエンスに到達させた。雌Swissヌードマウスの横腹に、およそ3 x 10E6細胞を含有する細胞懸濁液を皮下注射した。腫瘍体積が200mm3に達すると、マウスを8〜10マウスの治療グループに無作為化し、治療を開始した。3.19.3(10mg/kg)を含む生理食塩水を毎週2回、2週間、腹腔内に注射した。オキサリプラチン(5mg/kg)を週スケジュールに従って腹腔内投与した。各腫瘍の次元と体重を、少なくとも毎週2回測定した。各腫瘍の体積は、体積=長さx(幅)2x0.5(cm3)として計算した。図10aに図解した通り、3.19.3とオキサリプラチンは単剤としてH460腫瘍の成長を遅延した。しかし、3.19.3とオキサリプラチンの組合わせは、図10aに図解した通り、単剤だけより大きい効果を有した。達成された%腫瘍成長阻害は次の通りである:
3.19.3(10mg/kg 2 x wk)=67%阻害;(p<0.001)
オキサリプラチン(5mg/kg/week)=35%阻害;(p<0.01)
3.19.3+オキサリプラチンの組合わせ=75%阻害(p<0.0001)。
3.19.3の、AZD4877と組合わせた抗腫瘍活性を、肺癌のH460異種移植モデルで評価した。H460細胞を日常の方法でフラスコ内で培養して細胞をサブコンフルエンスに到達させた。雄NCr nu/nuマウスの右横腹に、およそ3 x 10E6細胞を含有する細胞懸濁液を皮下注射した。腫瘍体積が200mm3に達すると、マウスを8〜10マウスの治療グループに無作為化し、治療を開始した。3.19.3(10mg/kg)を含む生理食塩水を毎週2回、2週間、腹腔内に注射した。AZD4877(10mg/kg)を毎4日のスケジュールに従って腹腔内投与した。各腫瘍の次元と体重を、少なくとも毎週2回測定した。各腫瘍の体積は、体積=長さx(幅)2x0.5(cm3)として計算した。図11aに図解した通り、3.19.3とAZD4877は単剤としてH460腫瘍の成長を遅延した。しかし、3.19.3とAZD4877の組合わせは、図11aに図解した通り、単剤だけより大きい効果を有した。達成された%腫瘍成長阻害は次の通りである:
3.19.3(10mg/kg 2 x wk)=64%阻害;(p<0.001)
AZD4877(10mg/kg q4d x2)=50%阻害;(p<0.001)
3.19.3+AZD4877の組合わせ=78%阻害(p<0.0001)
体重変化により測定して、単剤治療だけと比較して、組合わせによるさらなる毒性は観察されなかった(図11b)。これらの結果は、抗Ang2抗体3.19.3とAZD4877による組合わせ治療が肺癌の前臨床モデルにおいてさらなる毒性なしに効力の改善をもたらすことを実証し、この組合わせのさらなる臨床研究のための根拠を提供する。
ラットコラーゲンII型乳濁液の調製: ウシコラーゲンII型(MD Biosciences, Cat # IMBII; Lot 090205)は4℃にて暗所で使用まで貯蔵した。動物を免疫感作する前に、ウシコラーゲンはストック溶液2mg/mLにて0.01M酢酸に溶解し、一晩暗所にて貯蔵した。免疫感作の当日、コラーゲンを等体積のフロイント完全アジュバント(FCA [Difco、Cat # 231131; Lot 850262/R1])によって乳濁化し、1mg/mLの溶液を得た。
第0日に、雄DBA/1マウス(6〜8週齢、Harlan Sprague Dawley、UK)を3.5%イソフランを用いて軽く麻酔をかけ、そして尾根の直ぐ上の皮膚内に、FCA中に乳濁化したラットコラーゲンII型の100μg(1mg/mL;0.1mL/マウス)を用いて免疫感作した。ブドウ球菌エンテロトキシンB(SEB)ブースター: 第21日、全てのマウスを前記の通り麻酔し、30μg SEB(注射用水[Toxin Technology, Cat # BT202; Lot 70903]中の600μg/mlを等体積のフロイント不完全アジュバント[Sigma, Cat # F5506; Lot 112K8930]中に乳濁化して最終濃度300μg/mlとしたもの)のブースター注射を行った。50μl x 2(30μg SEBと等価)を免疫感作部位に隣接した皮膚内に注射した。
動物の健康状態の臨床観察を投薬時点から毎日行った。疾患の臨床徴候についての観察を、免疫感作後の第20日に行い、その際、動物をそのミクロ環境から取り出し、以下に概説したスコアリング系を用いてスコアを付けた。
動物を下記の通り、無作為に治療グループに割当てた。
動物を疾患発症後14日に高濃度の二酸化炭素に曝露して終結した。マウス足を死後切除し、10%緩衝化ホルマリンで固定し、脱灰した。脱灰した足を日常の方法で処理し、次いでパラフィンブロックに包埋した。連続切片(10μm)を切断し、ヘマトキシリンおよびエオシンで染色して組織学分析を行った。
臨床疾患進行に対する曲線下面積(AUC)を、疾患発症後の各動物について計算した。
10mg/kgの用量での3.19.3(ビヒクル対照とのDunnettのpost-hoc比較を用いる一方向ANOVA)によって、疾患進行(関節炎のスコア)の臨床徴候と滑膜炎および関節破壊の組織学的評価の両方において、有意な低下が観察された。
結果は、3.19.3の投与後の抗関節炎効果の明解な確証を示し、これは形態学的には滑膜の過形成および線維症について最も明らかであった。本研究においては、非定形細胞型は存在しなかったし、骨の非定形徴候も存在しなかった。本研究において、臨床スコアと組織学的測定の間には良い相関がある。
PBSビヒクルで治療した動物の大部分において著しい関節症が認められた。その病理症状は広汎な(本質的に単核細胞)滑膜炎であって、脛骨-距骨空間に侵入しかつおよび踵骨の表面の小面に広がる。両方の接触滑膜炎からおよびパンヌス拡大から骨髄空洞および間質空洞中への骨(特に距骨および舟状骨)の広汎な溶解破壊が存在した。滑膜の線維症が共通し、時折、類線維素堆積、様々な程度の滑膜過形成を伴った。
3.19.3治療グループは、全ての関節症病変の発生率および重症度において組織学的に有意な低下を示したが、最も顕著であったのは、滑膜の過形成および線維症の低下と共に関節空間および骨髄限局性パンヌスの両方の重症度の低下であった。
組織学的に、このグループとPBSビヒクルグループとの間に有意差はなかった。
本研究は、アンジオポエチン-2の中和は、雄dba/1マウスにおけるコラーゲン誘導関節炎を改善するのに有効であり(図12a)、疾患発症からの期間を通して各治療グループ間で平均体重の有意な変化が観察されず、3.19.3療法が十分に耐えられる(図12b)ことを示す。本研究は10mg/kgの用量における3.19.3の効力を評価し、かつ疾患進行の臨床徴候(関節炎のスコア)と滑膜炎および関節破壊の組織学的評価の両方の低下を実証した。
抗Ang-2抗体、MEDI1/5抗体の網膜血管発生に対する効果を、治療マウスと対照治療マウスを対比した網膜サンプルを比較することにより研究した。
CD1子マウスを無治療のまま置くかまたは腹腔内にMEDI1/5(1mg/kgまたは10mg/kg)を第1日、第3日および第5日(第1日は誕生日)に投薬した。第10日に、子マウスをイソフルランを用いて麻酔し、次いで12.5mg/ml FITC-デキストラン(Vector Labs)を潅流した。角膜に小さいスリットを作り、全眼を眼杯から取り出した後、10%中和緩衝化ホルマリン中に置いた。ホルマリンに1時間固定した後、眼を簡単にPBSでリンス洗浄し、次いでPBSの皿に移して解剖した。網膜を注意深く解剖し、クローバ葉型に切断し、その後、Vectashield(Vector Labs)を用いてガラススライド上に載せた。平滑なスライドの画像を検査し、蛍光顕微鏡(Nikon)を用いて付属デジタルカメラシステムにより撮影した。
無治療の子マウス(図13a)と0.3mg/kgのMEDI1/5で治療した子マウス(図13b)の網膜脈管構造は、白い矢で示した網膜の外端へ伸びている。MEDI1/5の用量を増加した治療をすると、本発明者らは、進行する網膜血管の阻害のレベルに用量応答があることを認めた(図13cおよび13d)。網膜の外縁の境界は点線で示され、両方の用量において硝子体血管(白い矢)は網膜の外縁に達するが、1mg/kg MEDI1/5(図13c)の網膜血管(白い矢頭)は10mg/kg MEDI1/5(図13d)治療グループと比較して網膜の外周により近い位置にある。これらの結果は、MEDI1/5抗Ang-2抗体の治療による網膜血管新生の用量依存性の阻害を示す。
抗Ang-2抗体MEDI1/5を、FGF2(塩基性FGF)誘導Matrigel(登録商標)プラグアッセイで抗血管新生効果について評価した。組換えマウスFGF2(rmFGF塩基性;R&D Systems)をMatrigel(登録商標)(成長因子含量が低く、フェノールレッドを含まないもの;Trevigen)と1μg/mlで予め混合した。それぞれ5〜6週齢の雌胸腺欠損マウスに500μlのFGF2/Matrigel(登録商標)混合物を皮下移植した。抗体MEDI1/5を投与して、10分間後に、FGF2/Matrigel(登録商標)移植をし、続いて3日毎に腹腔内に1、10、および20mg/kgにて合計3用量を投与した。血管新生の程度を10日後にデキストラン機能性血管を測定することにより評価した。マウスに、FITC-デキストラン(250,000MW;Sigma)25mg/mlを含む生理食塩水100μlを静脈注射した。FITC-デキストラン注射後20分に、マウスを人為的に安楽死させ、プラグを分析した。プラグを次いで、1mlのPBSを含有する溶解マトリックスチューブA(MP Biomedicals)中に置き、そしてFastPrepマシーン(MP Biomedicals)で60秒間、6.0M/Sにてホモジナイズした。サンプルを次いで10,000rpmにて5分間遠心分離し、上清を採集した。各サンプル(二重の)の200μlを次いで白色、透明底の96ウエルプレート中に置き、FITC出力をEnVision計器(Perkin Elmer)で読取った。
およそ0.78μgのFITC-デキストランを1μg/mlのFGF2により誘導したプラグ中に検出することができた(図14a)。他方、これらのFGF2処理したプラグを、1、10、および20mg/kgの範囲の3用量のMEDI1/5に曝すと、収穫したプラグ中に存在するFITC-デキストランの量は0.05〜3μgであった。MEDI1/5治療した動物におけるFITC-デキストランのこの有意な低下は、MEDI1/5がMatrigel(登録商標)プラグ中のFGF2誘導性血管新生を阻害することを示唆する。プラグをヘマトキシリンおよびエオシンで染色すると(図14b)、FGF2+MEDI1/5プラグはFGF2プラグ単独と比較して血管が少ないことを示し、従って、抗Ang-2抗体MEDI1/5はFGF-介在性血管新生を阻害するという確証をさらに提供した。
本実施例においては、抗Ang-2抗体3.19.3をコラーゲン誘導関節炎(CIA)マウスモデルに用いて治療効力を実証することを試みた。
コラーゲン誘導関節炎(CIA)疾患モデルにおける臨床疾患進行に対する治療の効果を研究するために、 コラーゲン誘導関節炎を雄DBA/1マウスに誘導し、動物に治療として試験治療薬を投薬した。
ウシコラーゲンII型(MD Biosciences)の調製物を使用まで4℃にて暗所に貯蔵した。動物の免疫感作に先立って、ウシコラーゲンを0.01M酢酸中に2mg/mLのストック溶液にて溶解し、一晩暗所で4℃にて貯蔵した。免疫感作の第1日、コラーゲンを等体積のフロイント完全アジュバント(FCA(Difco))を用いて乳濁化し、1mg/mLの溶液を得た。
第0日に、雄DBA/1マウス(6〜8週齢、Harlan Sprague Dawley、UK)を3.5%イソフランを用いて軽く麻酔をかけ、そして尾根の直ぐ上の皮膚内に、FCA中に乳濁化したラットコラーゲンII型の100μg(1mg/mL;0.1mL/マウス)を用いて免疫感作した。
第21日、全てのマウスを前記の通り麻酔し、30μg SEB(注射用水(Toxin Technology)中の600μg/mlを等体積のフロイント不完全アジュバント(Sigma)中に乳濁化して最終濃度300μg/mlとしたもの)のブースター注射を行った。50μl x 2(30μgSEBと等価)を免疫感作部位に隣接した皮膚内に注射した。
動物の健康状態の臨床観察を投薬時点から毎日行った。疾患の臨床徴候についての観察を、免疫感作後の第20日に行い、その際、動物をそのミクロ環境から取り出し、以下に概説したスコアリング系を用いてスコアを付けた。
動物を下記の表11に記載の通り、無作為に治療グループに割当てた。
動物を疾患発症後14日に高濃度の二酸化炭素に曝露して終結した。マウス足を死後切除し、10%緩衝化ホルマリンで固定し、脱灰した。脱灰した足を日常の方法で治療し、次いでパラフィンブロックで包埋した。連続切片(10μm)を切断し、ヘマトキシリンおよびエオシンで染色して組織学分析を行い、ならびにCD31染色して滑膜におけるミクロ血管密度を定量した。
図15Aは疾患発症からの日数(すなわち治療日数)に対する関節炎のスコア平均(平均の+/-標準誤差)を示す(白四角=PBS、白三角=アイソタイプ対照、黒四角=0.1mg/kg 3.19.3、黒三角=1mg/kg 3.19.3、黒丸=10mg/kg 3.19.3および白円=プレドニソロン)。疾患進行の臨床徴候(関節炎スコア)における用量依存性の低下が観察された。1および10mg/kg用量において有意な低下が存在した。臨床疾患進行に対する曲線下面積(AUC)を、各動物について疾患発症から計算した(図15Bおよび表12)。特に断らない限り、統計的分析はビヒクル対照に対するDunnettのpost-hoc比較を用いる一方向ANOVAによった。
結果は、評価した全てのパラメーターについて3.19.3の投与後の用量依存性の抗関節炎効果の確証を示し、前記パラメーターには、滑膜の過形成(図15C)、滑膜炎(図15D)、パンヌス(図15E)、滑膜の線維症(図15F)、および骨膜炎(図15G)が含まれる。組織学的に、アイソタイプ対照治療グループとPBSビヒクルグループとの間に有意差はなかった(図15C〜G)。
結果は、用量1および10mg/kgにおいてならびにプレドニソロンを用いると滑膜におけるミクロ血管密度の有意な低下を示した。0.1mg/kgにおける3.19.3による治療は無効であった(図15H)。
本研究は、アンジオポエチン-2の中和が雄DBA/1マウスにおけるコラーゲン誘導関節炎を改善するのに有効であることを実証する。本研究は0.1、1、および10mg/kgの用量における3.19.3の効力を評価し、疾患進行(関節炎のスコア)の臨床徴候と、滑膜炎および関節破壊ならびに滑膜のミクロ血管密度の組織学的評価との両方において、用量依存性の低下を実証した。プレドニソロン治療グループは、全ての尺度の出現率および重症度において顕著な低下を示した。
本実施例では、単剤または抗TNFα薬ENBREL(登録商標)との組合わせとしての抗Ang-2抗体MEDI1/5を、関節炎の予防モデルにおいて研究した。さらに具体的には、MEDI1/5抗体+/-ENBREL(登録商標)の、グルコース6リン酸イソメラーゼ(G6PI)関節炎疾患モデルにおける臨床疾患進行に対する効果を研究した。
G6PI乳濁液の調製:
免疫感作の日に、結核菌(M. tuberculosis(Difco))をIFA(Chondrex)中に粉砕することによりFCA(フロイント完全アジュバント)を調製して、1mg/mLストックを作った。ヒトG6PIをリン酸緩衝化生理食塩水(Gibco)中の3mg/mLの濃度に設定した。G6PIを超音波処理により等体積のFCAと共に乳濁化し、1.5mg/mLの乳濁液を得た。
第0日に、雄DBA/1Jマウス(9〜10週齢、Jackson Laboratories)に、0.2mL(300μgG6PI)を尾の基部の2つの部位にわたって皮下注射により投与した。
疾患の臨床徴候についての観察を、免疫感作後第0日から毎日行い、その際、動物をそのミクロ環境から取り出し、下表13に概説したスコアリング系を用いてスコアを付けた。
動物を免疫感作後16日に高濃度の二酸化炭素に曝露して終結した。マウス足を死後切除し、10%緩衝化ホルマリンで固定し、骨無機質密度を評価し、次いで脱灰した。脱灰した足を日常の方法で処理し、次いでパラフィンブロックで包埋した。連続切片を切断し、ヘマトキシリンおよびエオシンで染色して組織学分析を行った。組織学分析は次のスケジュールによりスコアを付けた:
・合計関節スコア
・後膝と足首関節の両方を次に対してスコアを付けた:
>炎症
>骨損傷
>パンヌス形成
>軟骨損傷
・0〜5のスコア
>0=正常
>1=最小
>2=軽度
>3=中度
>4=顕著
>5=重症
骨無機質密度
骨無機質密度は後肢の後膝関節においてDEXA法イメージング(GE Piximus)を用いて評価した。採集後、後肢を10%中和緩衝化生理食塩水中に4日間入れた。イメージングの直前、肢を70%エタノール中に入れ、次いで乾燥させた。
疾患進行(関節炎のスコア)の臨床徴候の低下がエタネルセプトまたはMEDI1/5治療によって観察された[図16A(黒丸=アイソタイプ対照、黒菱形=10mg/kg MEDI1/5、白菱形=1mg/kg エタネルセプト、灰菱形=10mg/kg MEDI1/5と1mg/kg エタネルセプトの組合わせ、白四角=4mg/kg エンブレル、灰四角=10mg/kg MEDI1/5と4mg/kg エタネルセプトの組合わせ)および16B]。MEDI1/5を低い用量のエタネルセプトを組合わせて投与すると、さらなる臨床スコアの低下が存在した(一方向ANOVA、アイソタイプ対照に対するDunnettのpost-hoc比較)。アイソタイプ対照抗体で治療した動物の全関節は疾患の確証を示したが、MEDI1/5または1mg/kgエタネルセプト治療は31%または22%の関節においてそれぞれ疾患の徴候を示さなかった。10mg/kg MEDI1/5と1mg/kgエタネルセプトを組合わせ投与した場合、このグループの動物の関節の50%は、疾患が無く、高用量(4mg/kg)のエンブレル(53%)により与えられた保護のレベルと比較し得た(表15)。滑膜炎および関節破壊の組織学的評価(図16C)は、骨無機質密度の損失から保護することを示した臨床スコア結果(図16D)を支持した。
本研究は、アンジオポエチン-2の中和が、雄DBA/1JマウスにおけるG6PI誘導関節炎の発生を阻害する上で有効であり、抗TNF比較薬であるエタネルセプトと比較しうることを実証する。本研究はまた、MEDI1/5とエタネルセプトの組合わせ効力を評価し、疾患の発症に先立って投与すると、低い用量のエンブレルとの組合わせ治療は、疾患進行の臨床徴候(関節炎スコア)と滑膜炎および関節破壊の組織学評価、ならびに骨無機質密度の喪失との両方において、さらなる効力を提供することを実証した。
MEDI1/5によるエタネルセプトを伴わないまたは伴う場合の治療効果を、グルコース6リン酸イソメラーゼ(G6PI)関節炎疾患モデルにおける臨床疾患の発症後に評価した。
本研究のマウスは実施例12に記載したのと同様に調製した。
本研究はローリング投与研究であった:いったん動物が3.5〜5.0の臨床スコアに達すると、無作為に治療グループに割り当て(下記の通り)そして投薬を始めた。最初の投薬の日がこの動物に対する研究日0になった。治療グループは実施例12に記載したのと同様であった。
研究は治療開始後12日に終結した。これらの動物についてさらなる終点を評価しなかった。
臨床疾患の発症後に治療手法として投与した場合、疾患進行の臨床徴候(関節炎スコア)の軽度の低下が、MEDI1/5治療によって観察される一方、試験した両方の用量のエタネルセプトは疾患進行に効果がなかった。MEDI1/5(10mg/kg)を高用量のエタネルセプト(4mg/kg)と組合わせて投与した場合、さらに劇的な疾患進行の阻害が認められた(図17A(黒丸=アイソタイプ対照、黒菱形=MEDI1/5、白菱形=1mg/kgエタネルセプト、灰菱形=MEDI1/5と1mg/kgエタネルセプトの組合わせ、白四角=4mg/kgエタネルセプト、灰四角=MEDI1/5と4mg/kgエタネルセプトの組合わせ)。
本研究は、疾患の臨床徴候の発症後に投与した場合、アンジオポエチン-2の中和が、雄DBA/1JマウスにおけるG6PI誘導性関節炎の発生を改善する上で有効であり、抗TNF比較薬であるエタネルセプトと比較しうることを実証する。本研究はまた、MEDI1/5とエタネルセプトの組合わせた効力を評価し、組合わせ治療がいずれかの薬剤単独を超える高い効力を提供することを実証した。
Claims (7)
- アンジオポエチン-2(Ang-2)と結合する単離された抗体であって、前記抗体が、配列番号3(MEDI1)を含む軽鎖可変領域と配列番号7(MEDI5)を含む重鎖可変領域を含む、上記抗体。
- 前記抗体が配列番号1および配列番号2を含むAng-2抗体(3.19.3)の融点よりも高い融点を示す、請求項1記載の抗体。
- 配列番号3(MEDI1)および配列番号7(MEDI5)を含む軽鎖可変域および重鎖可変域を含む、Ang-2と結合する少なくとも1つの単離された抗体をコードしている、単離された核酸。
- a)Ang-2と結合する単離された抗体であって、配列番号3(MEDI1)を含む軽鎖可変域と配列番号7(MEDI5)を含む重鎖可変域を含む、上記抗体;および
b)賦形剤、を含む医薬組成物。 - それを必要とする動物における癌腫瘍の血管新生を阻害するために使用する組成物であって、
a)Ang-2と結合する単離された抗体であって、配列番号3(MEDI1)を含む軽鎖可変域と配列番号7(MEDI5)を含む重鎖可変域を含む、上記抗体;および
b)賦形剤、を含む上記組成物。 - 1以上の他の癌治療薬をさらに含む、請求項5記載の組成物。
- 前記癌が黒色腫、結腸癌、結腸直腸、肺癌、小細胞肺癌、非小細胞肺癌、乳癌、直腸癌、胃癌、神経膠腫、前立腺癌、卵巣癌、精巣癌、甲状腺癌、腎臓癌、肝臓癌、肝細胞癌、膵臓癌、脳癌、頚部癌、神経膠芽細胞腫、子宮内膜癌、および中枢神経系癌からなる群より選択される、請求項5記載の組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
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JP2015038067A (ja) * | 2008-01-28 | 2015-02-26 | メディミューン リミテッド | 安定化アンジオポエチン2抗体とその用途 |
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AU2009209251A1 (en) | 2009-08-06 |
US8507656B2 (en) | 2013-08-13 |
RU2509085C2 (ru) | 2014-03-10 |
EP2247305A4 (en) | 2012-11-14 |
MX2010008099A (es) | 2010-08-04 |
JP2011510632A (ja) | 2011-04-07 |
US20110044998A1 (en) | 2011-02-24 |
AU2009209251A8 (en) | 2015-03-26 |
JP6335249B2 (ja) | 2018-05-30 |
EP2247305A1 (en) | 2010-11-10 |
JP2014128271A (ja) | 2014-07-10 |
JP2017075153A (ja) | 2017-04-20 |
AU2009209251B8 (en) | 2015-03-26 |
RU2010135624A (ru) | 2012-07-10 |
WO2009097325A1 (en) | 2009-08-06 |
AU2009209251B2 (en) | 2015-03-12 |
CA2712000A1 (en) | 2009-08-06 |
JP2015038067A (ja) | 2015-02-26 |
US20130280251A1 (en) | 2013-10-24 |
US10329345B2 (en) | 2019-06-25 |
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