JP2020510432A - Nectin−4への特異性を有する抗体及びその使用 - Google Patents
Nectin−4への特異性を有する抗体及びその使用 Download PDFInfo
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Landscapes
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Abstract
Description
本発明は、ネクチン−4への特異性を有する抗体及びその使用に関する。
ネクチン−4は、タンパク質のネクチンファミリーに属する表面分子であり、4つのメンバーを含む。ネクチンは、発生及び成人期の間での上皮細胞、内皮細胞、免疫細胞、及び神経細胞についての種々の生物学的プロセス、例えば極性、増殖、分化、移動などにおいて重要な役割を果たす細胞接着分子である。それらはヒトにおけるいくつかの病理学的プロセスに含まれる。それらは、ポリオウイルス、単純ヘルペスウイルス、及び麻疹ウイルスについての主な受容体である。ネクチン−1(PVRL1)又はネクチン−4(PVRL4)をコードする遺伝子中での変異は、他の異常に関連付けられる外胚葉異形成症候群を起こす。ネクチン−4は胎児発生中に発現する。成人組織では、その発現はファミリーの他のメンバーの発現よりも制限されている。ネクチン−4は、乳癌、卵巣癌、及び肺癌のそれぞれ30%、49%、86%における腫瘍関連抗原であり、大半が予後不良の腫瘍である。その発現は対応する正常組織中では検出されない。乳房腫瘍では、ネクチン−4は主に三重陰性癌で発現している。これらの癌を伴う患者の血清では、可溶形態のネクチン−4の検出は予後不良と関連付けられる。血清ネクチン−4のレベルが転移進行の間に増加し、処置後に減少する。これらの結果は、ネクチン−4が癌の処置のための信頼できる標的でありうることを示唆する。したがって、いくつかの抗ネクチン−4抗体が先行技術において記載されている。特に、エンフォルツマブ・ベドチン(ASG−22ME)は、ネクチン−4を標的とする抗体−薬物複合物(ADC)であり、現在、固形腫瘍に苦しむ患者の処置のために臨床的に研究されている。
本発明は、ネクチン−4への特異性を有する抗体及びその使用に関する。特に、本発明は特許請求の範囲により定義する。
本発明は、ネクチン−4への特異性を有する抗体(特にモノクローナル抗体)及びその使用に関する。特に、本発明は、14A5.2抗体(14A5.2 mabとも呼ばれる)から由来する抗体を提供する。実際に、本発明者らは、その固有の抗転移特性のためにこの抗体を選択した。また、本発明者らは、14A5.2が、類似の親和性を伴い、Ha22−2抗体(アステラス社からのASG−22MEとしても公知である)により認識されるエピトープとは異なるエピトープを認識することを示した。14A5.2は、転移性疾患の防止及び/又は局在型の原発性もしくは転移性癌の処置のために適応できうる。さらに、14A5.2は、ASG−22MEに耐性である癌の処置のために適応できうる。
配列番号1:14A5.2 mabのVH領域FR1−CDR1−FR2−CDR2−FR3−CDR3−FR4
配列番号2:14A5.2 mab抗体のVL領域FR1−CDR1−FR2−CDR2−FR3−CDR3−FR4
− i)14A5.2 mabのH−CDR1と少なくとも90%の同一性を有するH−CDR1、ii)14A5.2 mabのH−CDR2と少なくとも90%の同一性を有するH−CDR2、及びiii)14A5.2 mabのH−CDR3と少なくとも90%の同一性を有するH−CDR3を含む重鎖、ならびに
− i)14A5.2 mabのL−CDR1と少なくとも90%の同一性を有するL−CDR1、ii)14A5.2 mabのL−CDR2と少なくとも90%の同一性を有するL−CDR2、及びiii)14A5.2 mabのL−CDR3と少なくとも90%の同一性を有するL−CDR3を含む軽鎖。
それにおいて
− 14A5.2 mabのH−CDR1は、配列番号1中の位置31のアミノ酸残基から位置35のアミノ酸残基まで及ぶ配列により定義する;
− 14A5.2 mabのH−CDR2は、配列番号1中の位置50のアミノ酸残基から位置66のアミノ酸残基まで及ぶ配列により定義する;
− 14A5.2 mabのH−CDR3は、配列番号1中の位置99のアミノ酸残基から位置104のアミノ酸残基まで及ぶ配列により定義する;
− 14A5.2 mabのL−CDR1は、配列番号2中の位置24のアミノ酸残基から位置38のアミノ酸残基まで及ぶ配列により定義する;
− 14A5.2 mabのL−CDR2は、配列番号2中の位置54のアミノ酸残基から位置60のアミノ酸残基まで及ぶ配列により定義する;及び
− 14A5.2 mabのL−CDR3は、配列番号2中の位置93のアミノ酸残基から位置101のアミノ酸残基まで及ぶ配列により定義する。
したがって、本発明のさらなる目的は、本発明に従った抗体をコードする核酸分子に関する。特に、核酸分子は、本発明の抗体の重鎖又は軽鎖をコードする。
本発明はこのように、14A5.2 mabのVL領域、VH領域の機能的変異体を含む抗体を提供する。本発明のモノクローナル抗体の文脈において使用されるVL又はVHの機能的変異体は、抗体が、親抗体(即ち、14A5.2 mab)の親和性/結合力及び/又は特異性/選択性の少なくとも実質的な割合(少なくとも約50%、60%、70%、80%、90%、95%又はそれ以上)を保持することを依然として可能にし、及び、一部の場合において、本発明のそのようなモノクローナル抗体は、親Abよりも高い親和性、選択性、及び/又は特異性と関連付けられうる。そのような変異体は、CDRの変異(Yang et al., J. Mol. Biol., 254, 392-403, 1995)、鎖シャッフリング(Marks et al., Bio/Technology, 10, 779-783, 1992)、大腸菌のミューテーター株の使用(Low et al., J. Mol. Biol., 250, 359-368, 1996)、DNAシャフリング(Patten et al., Curr. Opin. Biotechnol., 8, 724-733, 1997)、ファージディスプレイ(Thompson et al., J. Mol. Biol., 256, 77-88, 1996)、及びセクシャルPCR(Crameri et al., Nature, 391, 288-291, 1998)を含む多数の親和性成熟プロトコルにより得ることができる。Vaughan et al.(上記)は親和性成熟のこれらの方法を考察する。そのような機能的変異体は、典型的には、親Abとの有意な配列同一性を保持する。CDR変異体の配列は、大半の保存的置換を通じて、親抗体配列のCDRの配列と異なりうる;例えば、変異体における少なくとも約35%、約50%又はそれ以上、約60%又はそれ以上、約70%又はそれ以上、約75%又はそれ以上、約80%又はそれ以上、約85%又はそれ以上、約90%又はそれ以上(例、約65〜95%、例えば約92%、93%、又は94%など)の置換は保存的アミノ酸残基の置換である。CDR変異体の配列は、大半の保存的置換を通じて、親抗体配列のCDRの配列と異なりうる;例えば、変異体における少なくとも10、例えば少なくとも9、8、7、6、5、4、3、2、又は1などの置換は保存的アミノ酸残基置換である。本発明の文脈において、保存的置換は、以下のように反映されるアミノ酸のクラス内の置換により定義してもよい:
脂肪族残基I、L、V、及びM
シクロアルケニル関連残基F、H、W、及びY
疎水性残基A、C、F、G、H、I、L、M、R、T、V、W、及びY
負荷電残基D及びE
極性残基C、D、E、H、K、N、Q、R、S、及びT
正荷電残基H、K、及びR
小さな残基A、C、D、G、N、P、S、T、及びV
非常に小さな残基A、G、及びS
ターンA、C、D、E、G、H、K、N、Q、R、S、P、及びフォーメーションTに含まれる残基
柔軟な残基Q、T、K、S、G、P、D、E、及びR
別の態様では、本発明は、ネクチン−4への結合について本発明の抗体と競合する抗体を提供する。
本発明の操作抗体は、例えば、抗体の特性を改善するために、VH及び/又はVL内のフレームワーク残基に改変が作製されたものを含む。典型的には、そのようなフレームワークの改変は、抗体の免疫原性を減少させるために作製する。例えば、1つのアプローチは、1つ又は複数のフレームワーク残基を対応する生殖系列配列に「逆変異」させることである。より具体的には、体細胞変異を受けた抗体は、抗体が由来する生殖系列配列とは異なるフレームワーク残基を含みうる。そのような残基は、抗体のフレームワーク配列を、抗体が由来する生殖系列配列と比較することにより同定することができる。フレームワーク領域配列をそれらの生殖系列配置に戻すために、体細胞変異は、例えば、部位特異的変異誘発又はPCR媒介性変異誘発により生殖系列配列に「復帰変異」することができる。そのような「復帰変異」抗体も本発明により包含されることが意図される。別の型のフレームワーク改変は、フレームワーク領域内、あるいは1つ又は複数のCDR領域内の1つ又は複数の残基を変異させてT細胞エピトープを除去し、それにより抗体の潜在的な免疫原性を低下させることを含む。このアプローチは「脱免疫化」としても言及され、Carr et al.による米国特許公開第20030153043号においてさらに詳細に記載されている。
一部の実施形態では、開示される重鎖及び軽鎖、可変領域ドメイン、ならびにCDRを使用し、ネクチン−4に特異的に結合することができる抗原結合領域を含むポリペプチドを調製することができる。例えば、14A5.2 mabのCDRを共有結合的に又は非共有結合的に分子(例、ポリペプチド)中に組み入れて、免疫接着を作製することができる。免疫接着は、より大きなポリペプチド鎖の一部としてCDRを組み入れうる、CDRを別のポリペプチド鎖に共有結合的に連結させうる、又はCDRを非共有結合的に組み入れうる。CDRは、免疫接着が目的の特定の抗原(例、ネクチン−4又はそのエピトープ)に特異的に結合することを可能にする。
本発明はまた、本発明の抗体の抗原結合ドメインを含むキメラ抗原受容体(CAR)を提供する。典型的には、前記キメラ抗原受容体は、本発明の抗体の少なくとも1つのVH及び/又はVL配列を含む。本発明のキメラ抗原受容体はまた、細胞外ヒンジドメイン、膜貫通ドメイン、及び細胞内T細胞シグナル伝達ドメインを含む。
一部の実施形態では、本発明は、本明細書で上に記載する本発明の分子の抗体からの第1の抗原結合部位及び少なくとも1つの第2の抗原結合部位を含む多特異性抗体を提供する。
本発明の抗体を検出可能な標識と結合させて、抗ネクチン−4免疫複合体を形成することができる。適切な検出可能な標識は、例えば、放射性同位体、蛍光標識、化学発光標識、酵素標識、生物発光標識、又はコロイド金を含む。そのような検出可能に標識された免疫複合体を作製及び検出する方法は、当業者に周知であり、以下により詳細に記載されている。検出可能な標識は、オートラジオグラフィーにより検出される放射性同位元素でありうる。本発明の目的のために特に有用な同位体は、3H、125I、131I、35S、及び14Cである。
本発明のさらなる態様は、癌、特にネクチン−4が過剰発現している癌を診断及び/又はモニター及び/又は病期分類するための本発明の抗ネクチン−4抗体に関する。
典型的には、本発明の抗体は、医薬的に許容可能な担体を含む医薬組成物の形態で対象に投与する。これらの組成物中で使用されうる医薬的に可能な担体は、イオン交換体、アルミナ、ステアリン酸アルミニウム、レシチン、血清タンパク質(例えばヒト血清アルブミンなど)、緩衝物質(例えばリン酸塩など)、グリシン、ソルビン酸、ソルビン酸カリウム、飽和植物性脂肪酸の部分グリセリド混合物、水、塩、又は電解質(例えば硫酸プロタミン、リン酸水素二ナトリウム、リン酸水素カリウム、塩化ナトリウム、亜鉛塩など)、コロイドシリカ、三ケイ酸マグネシウム、ポリビニルピロリドン、セルロースベースの物質、ポリエチレングリコール、カルボキシメチルセルロースナトリウム、ポリアクリレート、ワックス、ポリエチレン−ポリオキシプロピレンブロックポリマー、ポリエチレングリコール、及び羊毛脂肪を含むが、これらに限定しない。患者への投与における使用のために、組成物は患者への投与用に製剤化する。本発明の組成物は、経口、非経口、吸入噴霧、局所、直腸、経鼻、頬側、経膣、又は埋め込み貯蔵部により投与してもよい。本明細書で使用するのは、皮下、静脈内、筋肉内、関節内、滑液内、胸骨内、くも膜下腔内、肝内、病巣内及び頭蓋内注射又は注入技術を含む。本発明の滅菌注射剤型の組成物は、水性又は油性懸濁剤でよい。これらの懸濁剤は、適当な分散剤又は湿潤剤及び懸濁剤を使用して、当技術分野において公知の技術に従って製剤化してもよい。滅菌注射用製剤はまた、毒性のない非経口の許容可能な希釈剤又は溶媒、例えば、1,3−ブタネジオール中の溶液としての滅菌注射用溶液又は懸濁剤でもよい。用いてもよい許容可能な媒体及び溶媒のなかには、水、リンガー溶液、及び等張の塩化ナトリウム溶液がある。また、滅菌固定油は従来、溶媒又は懸濁媒体として用いられる。この目的のために、任意の無菌性の固定油を用いてもよく、合成モノ又はジグリセリドを含む。脂肪酸(例えばオレイン酸及びそのグリセリド誘導体など)は、注入剤の調製において有用であり、天然の医薬的に許容可能な油(例えばオリーブ油又はヒマシ油、特にそれらのポリオキシエチル化型など)と同様である。これらの油剤又は懸濁剤はまた、長鎖アルコール希釈剤もしくは分散剤(例えばカルボキシメチルセルロースなど)又は医薬的に許容可能な剤形(乳剤及び懸濁剤を含む)の製剤化において一般に使用される同様の分散剤を含みうる。他の一般に使用される界面活性剤(例えばTweens、Spans、及び他の乳化剤など)、又は医薬的に許容可能な固形、液体、又は他の剤形の製造において一般に使用される生物学的利用率の賦活薬は、製剤化の目的でも使用してもよい。本発明の組成物は、経口で許容可能な任意の剤形(カプセル、錠剤、水性懸濁液、又は溶液などを含むが、これらに限定しない)で経口投与できる。経口使用のための錠剤の場合において、一般に使用される担体はラクトース及びコーンスターチを含む。潤滑剤(例えばステアリン酸マグネシウムなど)も典型的に加えられる。カプセル形状での経口投与のために、有用な希釈剤は、例えばラクトースを含む。水性懸濁剤が経口使用のために要求される場合、活性成分を乳化剤及び懸濁剤と組み合わせる。望ましい場合、特定の甘味剤、香味剤、又は着色剤も加えてもよい。あるいは、本発明の組成物は、直腸投与のために坐剤の形状で投与してもよい。これらは、室温では固体であるが、しかし、直腸温で液体であり、従って、直腸において溶けて薬物を放出する適切な非刺激性賦形剤と薬剤とを混合させることにより調製することができる。そのような材料は、カカオ脂、蜜蝋、及びポリエチレングリコールを含む。本発明の組成物はまた、特に処置の標的に、眼、皮膚、又は下部腸管の疾患を含む、局所適用により容易に接近可能な領域又は器官が含まれる場合、局所投与してもよい。適当な局所製剤は、これらの領域又は器官の各々について容易に調製される。局所適用のために、組成物を、1又は複数の担体中に懸濁又は溶解させた活性成分を含む適切な軟膏剤中に製剤化してもよい。本発明の化合物の局所投与のための担体は、鉱物油、液体ワセリン、白色ワセリン、プロピレングリコール、ポリオキシエチレン、ポリオキシプロピレン化合物、乳化ワックス、及び水を含むが、これらに限定しない。あるいは、組成物を、1又は複数の医薬的に許容可能な担体中に懸濁又は溶解させた活性成分を含む適切なローション又はクリーム中に製剤化することができる。適切な担体は、鉱物油、モノステアリン酸ソルビタン、ポリソルベート60、セチルエステルワックス、セテアリルアルコール、2−オクチルドデカノール、ベンジルアルコール、及び水を含むが、これらに限定しない。下部腸管のための局所適用は、直腸坐剤製剤(上を参照のこと)中又は適切な浣腸製剤中でもたらすことができる。貼付剤を使用してもよい。本発明の組成物はまた、鼻エアロゾル又は吸入により投与してもよい。そのような組成物は、医薬製剤化の技術分野において周知の技術に従って調製され、ベンジルアルコール又は他の適切な保存剤、生物学的利用率を増強させるための吸収促進剤、フルオロカーボン、及び/又は他の従来の可溶化剤もしくは分散剤を用いて、生理食塩水中の溶液として調製してもよい。例えば、本発明の医薬組成物中に存在する抗体は、100mg(10mL)又は500mg(50mL)の使い捨てバイアルのいずれかにおいて10mg/mLの濃度で供給することができる。この産物は、静脈内投与用に9.0mg/mL塩化ナトリウム、7.35mg/mLクエン酸ナトリウム二水和物、0.7mg/mLポリソルベート80、及び注射用滅菌水を用いて製剤化する。pHは6.5に調整する。本発明の医薬組成物中の抗体についての例示的な適切な投与量の範囲は、約1mg/m2から500mg/m2の間でありうる。しかし、これらのスケジュールは例示であり、臨床試験において決定しなければならない医薬組成物中の特定の抗体の親和性及び忍容性を考慮して最適なスケジュール及びレジメンを適応することができることが理解されるであろう。注射用(例、筋肉内、静脈内)の本発明の医薬組成物は、滅菌緩衝水(例、筋肉内では1ml)、及び約1ng〜約100mgの間(例、約50ng〜約30mg、又はより好ましくは約5mg〜約25mg)の本発明の抗ミオシン18A抗体を含むように調製することができうる。
材料&方法
ウエスタンブロット
ネクチン−4の発現は、100mmディッシュ中のMDA−MB−231 wt又はネクチン4トランスフェクト細胞において分析し、氷冷PBSで3回洗浄し、50mM Hepes(pH 7.5)、150mM NaCl、1.5mM MgCl2、1mM EGTA、1%Triton X−100、及び10%グリセロールを含む750μlの氷冷溶解緩衝液中で30分間にわたり再懸濁した。プロテアーゼインヒビター混合物を推奨の通りに加えた(Roche Diagnostics)。溶解物をSDSサンプル緩衝液(60mM Tris−HCl、pH 6.7、3% SDS、2%(v/v)2−メルカプトエタノール、及び5%グリセロール)中で加熱し、8%SDS−PAGEにより分離し、ポリフッ化ビニリデン膜(Immobilon-P、Millipore、米国マサチューセッツ州ボストン)に半乾燥で移し、1μg/ml 14A5.2モノクローナル抗体を用いてプローブした。可視化をECL(Pierce)で行った。
Mab競合アッセイをELISAにより実施した。96ウェルトレイを、示すように、+4℃で一晩ネクチン4VCC−Fcを用いてコーティングした。ペルオキシダーゼ結合14A5.2−HRP mabの結合を、変動濃度の4つの異なる抗ネクチン−4 mab(mab1、mab2、mab3、及びHa22−2 mab)の存在において測定した。
ヒト化抗体の効果を分析するために、SUM190細胞を、0.65nMタンパク質−G−DM1の存在において、示した濃度の抗体とインキュベートした。細胞成長を、製造者(Biosource、米国カリフォルニア州)により推奨されるalamarBlue染色手順を使用して測定した。テストには、蛍光酸化−還元指示薬が組み入れられている。蛍光強度は細胞の代謝低下に比例している。実験を、96ウェルプレート中で0日目に3000個細胞/ウェルをインキュベートすることにより行った。alamarBlueを5日目に、37℃で2時間にわたり1/10容量のalamarBlue溶液をインキュベートすることにより測定し、595nmで読み取った(FLUOstar Optima、BMG Labtech)。
ADCはConcortis(米国カリフォルニア州サンディエゴ)により産生された。複合体は、精製されたch14A5.2モノクローナル抗体から産生した。使用したリンカーは、モノメチルアウリスタチン−E(MMAE)に共有結合的に結合されたMC−Val−Cit−PAB−PNP(マレイミドカプロイル−L−バリン−L−シトルリン−p−アミノベンジルアルコールp−ニトロフェニルカーボネート)であった。この切断可能なリンカーを選択した。なぜなら、強力なバイスタンダー死滅を誘導したためである。薬物と抗体の比率は約4であった。ADCの効果を分析するために、SUM190細胞を、示した濃度のADCとインキュベートした。細胞成長を、製造者(Biosource、米国カリフォルニア州)により推奨されるalamarBlue染色手順を使用して測定した。テストには、蛍光酸化−還元指示薬が組み入れられている。蛍光強度は細胞の代謝低下に比例している。実験を、96ウェルプレート中で0日目に3000個細胞/ウェルをインキュベートすることにより行った。alamarBlueを5日目に、37℃で2時間にわたり1/10容量のalamarBlue溶液をインキュベートすることにより測定し、595nmで読み取った(FLUOstar Optima、BMG Labtech)。
全ての実験は、動物の取り扱いに関するフランスのガイドラインと一致して実施し、地元の倫理委員会により承認された(Agreement n°01152−01)。NOD/SCID/γcnullマウス(NSG)は、C.Rivers博士(英国マーゲイト)から得た。マウスを滅菌条件下で飼育し、滅菌食品及び水を自由に提供し、12時間の明サイクル及び12時間の暗サイクルで維持した。SUM190細胞を、50%フェノールレッド不含Matrigel(Becton Dickinson Bioscience)中に懸濁した(0.5×106)を用いて乳房脂肪パッド中に接種した。
SUM190標的細胞(10E5細胞)を96ウェルの白色マイクロプレートに一晩播種した。NK細胞を、製造者により推奨されるようにEasySep(商標)キットを使用して健常ドナーから精製した。10E6細胞(比率E:T=10)を、示した濃度の抗体と4時間にわたりインキュベートした。カスパーゼ−3/−7活性化は、PromegaからのCaspase-Glo発光キットを使用して測定した。発光を、30分間のインキュベーション後に測定した(FLUOstar Optima、BMG Labtech)。
本明細書で提示する14A5.2モノクローナル抗体は、特異性、エピトープマッピング、及び抗腫瘍活性などの厳しい基準に従って一連の抗ネクチン−4モノクローナル抗体の選択からもたらされる。これは、クリニックにおける使用、即ち、最小限の有害作用を伴い抗腫瘍活性を最適化することに関して最も重要である。
一連の抗ネクチン−4モノクローナル抗体のうち、14A5.2によって、ヌルベクターでトランスフェクトされた細胞ではなく、トランスフェク細胞でユニークな72kDaバンドが検出される(図1)。このm.w.は、以前に記載するように、ネクチン−4単量体に対応する(Reymond et al. JBC, 2001)。MDAMB231 wt細胞はネクチン−1、ネクチン−2、及びネクチン−3を発現した。これは、14A5.2がネクチン−4について高度に特異的であり、他のネクチンメンバー又は他の無関係なタンパク質を検出しないことを示す。同様の結果がFACS分析により得られた。
一連の抗ネクチン−4モノクローナル抗体のうち、本発明者らは、Ha22−2とは異なるエピトープに結合する抗体についてスクリーニングした。14A5.2エピトープは、ネクチン−4のIgV遠位ドメイン中のHa22−2について異なる。図2に見られるように、Ha22−2は14A5.2結合について競合しなかった。Mab1は抗ネクチン4陽性対照である(14A5.2結合について競合する)。Mab2は抗ネクチン4陰性対照である(14A5.2結合について競合しなかった)。
この結果(図3)は、プロテインG−DM1の存在において、ch14A5.2(IC50=6ng/ml)及びHa22.2(IC50=5ng/ml)の同様の細胞傷害特性を示す。同じ条件において、本発明者らは、トラスツズマブについてのIC50が100ng/mlであることを記述している。
この結果(図4)は、ch14A5.2−MMAE及びHa22.2−MMAEの同様の細胞傷害特性を示す。IC50は5ng/mlである。
本発明者らのADCの活性を、SUM190細胞株を異種移植した免疫不全NSGマウスでテストした。マウスを、静脈内用量のchN41−vc−MMAE、ch14A5.2−vc−MMAE、及びHa22.2−vc−MMAE抗体を用いて2回連続で処理した(図5)。CD30−vc−MMAEを無関係な対照として使用した。これらの用量はマウスについて毒性はなかった。両方のADCは、chN41(本発明者の別の抗ネクチン−4抗体)と比較し、迅速(4日間)で顕著な腫瘍退縮を示し、ch14A5.2の優れた効果を伴った(期間は最大20日間続いた)。
マウスに、ネクチン−4を発現するルシフェラーゼ陽性MDA−MB−231細胞を同所異種移植する。原発腫瘍の容量を35日後に測定する。マウスを、毎週10mg/kgのネイキッド14A5.2 mabを用いて静脈内処置する。殺したマウスの肺及び肝臓を生物発光により分析する。定量化は、肺について及び肝臓について示す。MMAEに結合された2つの連続した静脈内用量の14A5.2 mabを用いて同所異種移植の処置によって、35日間にわたる発光分析により観察される、全ての転移病変の迅速な低下及び消失が誘導される(データは示さず)。
14A5.2抗体を含む異なる抗体のADCC活性を実施した。14A5.2のADCC活性はN41抗体と同様であったが、しかし、IC50に関してHa22より4倍良好であった(図6A)。14A5.2及びN41抗体の溶解効率は、Ha22より2倍良好であった(図6B)。トラスツズマブ/ハーセプチン及びリツキシマブは、それぞれ陽性対照及び陰性対照として使用した。
実現した異なるテストによって、抗体14A5.2はADCにおいてN41よりも良好であり、ADCCにおいてHa22よりも良好であることが示された。14A5.2抗体は、このように、テストした最良の抗体である(表1)。
本願を通して、種々の参考文献によって、本発明が関係する最新技術が記載されている。これらの参考文献の開示を、参照により本開示中に組み入れる。
Claims (15)
- i)14A5.2 mabのH−CDR1、ii)14A5.2 mabのH−CDR2、及びiii)14A5.2 mabのH−CDR3を含む重鎖ならびにi)14A5.2 mabのL−CDR1、ii)14A5.2 mabのL−CDR2、及びiii)14A5.2 mabのL−CDR3を含む軽鎖を有する抗体であって、
それにおいて
− 14A5.2 mabのH−CDR1は、配列番号1中の位置31のアミノ酸残基から位置35のアミノ酸残基まで及ぶ配列により定義する;
− 14A5.2 mabのH−CDR2は、配列番号1中の位置50のアミノ酸残基から位置66のアミノ酸残基まで及ぶ配列により定義する;
− 14A5.2 mabのH−CDR3は、配列番号1中の位置99のアミノ酸残基から位置104のアミノ酸残基まで及ぶ配列により定義する;
− 14A5.2 mabのL−CDR1は、配列番号2中の位置24のアミノ酸残基から位置38のアミノ酸残基まで及ぶ配列により定義する;
− 14A5.2 mabのL−CDR2は、配列番号2中の位置54のアミノ酸残基から位置60のアミノ酸残基まで及ぶ配列により定義する;及び
− 14A5.2 mabのL−CDR3は、配列番号2中の位置93のアミノ酸残基から位置101のアミノ酸残基まで及ぶ配列により定義する。 - 配列番号1と少なくとも70%の同一性を有する重鎖及び配列番号2と少なくとも70%の同一性を有する軽鎖を有する、請求項1記載の抗体。
- 配列番号1と同一の重鎖及び配列番号2と同一の軽鎖を有する、請求項2記載の抗体。
- キメラ抗体である請求項1記載の抗体。
- 14A5.2 mab抗体のCDRを含むヒト化抗体である、請求項1記載の抗体。
- 請求項1記載の抗体をコードする核酸分子。
- 細胞傷害性部分に結合されている請求項1記載の抗体。
- タキソール;サイトカラシンB;グラミシジンD;エチジウムブロマイド;エメチン;マイトマイシン;エトポシド;テノポシド;ビンクリスチン;ビンブラスチン;コルヒチン;ドキソルビシン;ダウノルビシン;ジヒドロキシアントラシンジオン;チューブリンインヒビター、例えばメイタンシン又はそれらの類似体もしくは誘導体;抗有糸分裂剤、例えばモノメチルオーリスタチンE又はF又はそれらの類似体もしくは誘導体;ドラスタチン10もしくは15又はそれらの類似体;イリノテカン又はその類似体;ミトキサントロン;ミトラマイシン;アクチノマイシンD;1−デヒドロテストステロン;グルココルチコイド;プロカイン;テトラカイン;リドカイン;プロプラノロール;ピューロマイシン;カリケアマイシン又はその類似体もしくは誘導体;代謝拮抗剤、例えばメトトレキサート、6メルカプトプリン、6チオグアニン、シタラビン、フルダラビン、5フルオロウラシル、デカルバジン、ヒドロキシウレア、アスパラギナーゼ、ゲムシタビン、又はクラドリビン;アルキル化剤、例えばメクロレタミン、チオエパ、クロラムブシル、メルファラン、カルムスチン(BSNU)、ロムスチン(CCNU)、シクロホスファミド、ブスルファン、ジブロモマンニトール、ストレプトゾトシン、ダカルバジン(DTIC)、プロカルバジン、マイトマイシンC;白金誘導体、例えばシスプラチン又はカルボプラチン;デュオカルマイシンA、デュオカルマイシンSA、ラケルマイシン(CC−1065)、又はそれらの類似体もしくは誘導体;抗生物質、例えばダクチノマイシン、ブレオマイシン、ダウノルビシン、ドキソルビシン、イダルビシン、ミトラマイシン、マイトマイシン、ミトキサントロン、プリカマイシン、アントラマイシン(AMC);ピロロ[2、l−c][1,4]−ベンゾジアゼピン(PDB);ジフテリア毒素及び関連分子、例えばジフテリアA鎖及びその活性フラグメント及びハイブリッド分子、リシン毒素、例えばリシンA又は脱グリコシル化リシンA鎖毒素、コレラ毒素、志賀様毒素、例えばSLT I、SLT II、SLT IIV、LT毒素、C3毒素、志賀毒素、百日咳毒素、破傷風毒素、大豆Bowman−Birkプロテアーゼインヒビター、シュードモナス外毒素、アロリン、サポリン、モデシン、ゲラニン、アブリンA鎖、モデシンA鎖、アルファサルシン、アレウリテス・フォルディタンパク質、ジアンチンタンパク質、フィトラッカ・アメリカナタンパク質、例えばPAPI、PAPII、及びPAP−S、モモルディカ・チャランチアインヒビター、クルシン、クロチン、サパオナリア・オフィシナリスインヒビター、ゲロニン、マイトゲリン、レストリクトシン、フェノマイシン、及びエノマイシン毒素;リボヌクレアーゼ(RNase);DNase I、ブドウ球菌エンテロトキシンA;ヨウシュヤマゴボウ抗ウイルスタンパク質;ジフテリン毒素;及びシュードモナス内毒素からなる群より選択される細胞傷害性部分に結合されている請求項7記載の抗体。
- 医薬としての使用のための請求項1記載の抗体。
- 請求項1記載の抗体の治療的有効量を対象に投与することを含む、それを必要とする対象において癌を処置する方法。
- 癌が、乳癌、卵巣癌、又は肺癌である、請求項11記載の方法。
- 癌が、転移性癌である、請求項11記載の方法。
- 請求項1記載の抗体を含む、医薬組成物。
- 請求項1記載の抗体の少なくとも1つのVH及び/又はVL配列を含む、キメラ抗原受容体。
- ネクチン−4への結合について請求項1記載の抗体と競合する抗体。
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WO2018158398A1 (en) | 2018-09-07 |
US11274160B2 (en) | 2022-03-15 |
CN110392697A (zh) | 2019-10-29 |
US20210324104A1 (en) | 2021-10-21 |
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