JP2012503203A - 基底乳癌腫の診断および処置のためのcspg4に対するモノクローナル抗体 - Google Patents
基底乳癌腫の診断および処置のためのcspg4に対するモノクローナル抗体 Download PDFInfo
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4722—Proteoglycans, e.g. aggreccan
Abstract
Description
本願は、2008年9月19日に出願された米国仮特許出願第61/098,548号の利益を主張し、この米国仮特許出願の全体の内容は、本明細書中に参考として援用される。
本発明は、国立癌研究所により授与された助成金CA16056およCA105500の下、政府支援により成された。合衆国政府は、本発明に一定の権利を有する。
本出願は、乳癌分野、具体的には、基底乳癌腫の検出および処置方法に関する。
乳癌は、米国人女性の間で最も一般的な上皮癌型である。毎年180,000人を超える女性が乳癌と診断されている。米国人女性8人のうち約1人(およそ12.8パーセント)が存命中に乳癌を発症するであろう。現時点では、その元の部位から転移した乳癌に利用可能な治癒的治療は存在しない。さらに、乳癌の検出および病期分類で用いる診断マーカーが必要である。
コンドロイチン(condroitin)硫酸プロテオグリカン4(CSPG4)(高分子量黒色腫関連抗原としても公知)がトリプルネガティブ乳癌細胞(TNBC)としても公知の型の基底乳癌腫細胞(BBC)上で過剰発現することを本明細書中に開示する。
本明細書中に記載の作業において、トリプルネガティブ乳癌(TNBC)のDNAマイクロアレイプロファイルおよびその後のヒト乳癌組織の異なるサブタイプの免疫組織化学(IHC)を分析して、免疫療法の標的を同定した。この分析により、膜結合コンドロイチン硫酸プロテオグリカン4(CSPG4)(高分子量黒色腫関連抗原(Campoli,M.R.,et al.,Crit Rev Immunol 24,267−296,2004)としても公知)がTNBC細胞上で優先的に発現することが示された。本明細書中に開示の研究で使用した細胞株を、DNAマイクロアレイによって基底様と定義した(Neve,RM,et al.(2006),Cancer Cell 10:515−527(本明細書中で参考として援用される))。
他で断りのない限り、技術用語を、従来の用法に従って使用する。分子生物学における一般用語の定義を、Benjamin Lewin,Genes V,published by Oxford University Press,1994(ISBN 0−19−854287−9);Kendrew et al.(eds.),The Encyclopedia of Molecular Biology,published by Blackwell Science Ltd.,1994(ISBN 0−632−02182−9);およびRobert A.Meyers(ed.),Molecular Biology and Biotechnology:a Comprehensive Desk Reference,published by VCH Publishers,Inc.,1995(ISBN1−56081−569−8)中に見出すことができる。
CSPG4に特異的に結合する抗体(モノクローナル抗体が含まれる)を産生した。一例を挙げれば、CSPG4は以下のアミノ酸配列を有する。
(1)Fab(抗体分子の1価の抗原結合フラグメントを含み、酵素パパインを使用した全抗体の消化によってインタクトな軽鎖および1つの重鎖の一部を産生することができるフラグメント);
(2)Fab’、(全抗体をペプシンで処置し、その後に還元してインタクトな軽鎖および重鎖の一部を生成することによって抗体分子のフラグメントを得ることができる。抗体1分子あたり2個のFab’フラグメントが得られる);
(3)(Fab’)2(全抗体を酵素ペプシンで処置し、その後に還元しないことによって得ることができる抗体のフラグメント。F(ab’)2は2つのジスルフィド結合によって共に保持された2個のFab’フラグメントの二量体である);
(4)Fv(2つの鎖として発現された軽鎖の可変領域および重鎖の可変領域を含む遺伝子操作されたフラグメント);および
(5)単鎖抗体(scFvなど)(遺伝子融合された単鎖分子として適切なポリペプチドリンカーによって連結された軽鎖の可変領域、重鎖の可変領域を含む遺伝子操作された分子として定義される)。CSPG4に特異的に結合する例示的なscFVはscFv−FcC21であり、scFvフラグメントを、本明細書中に開示の任意の方法で使用することができる。
上記で開示するように、CSPG4に特異的に結合する抗体を含む組成物を、基底乳癌腫(BBC)の処置のために使用することができる。一例を挙げれば、エストロゲン、プロゲステロン、またはHer2を発現しないトリプルネガティブ基底乳癌(TNBC)の処置方法を本明細書中に開示する。したがって、BBC(TNBCなど)の処置で用いる治療有効量のCSPG4に特異的に結合する抗体を含む組成物を本明細書中に提供する。一例を挙げれば、BBC(TNBCなど)は転移性を示す。さらなる実施形態では、結腸癌、卵巣癌、乳癌、前立腺、肺癌、または膵臓癌の処置方法を提供する。
CSPG4はヒト乳癌で差次的に発現されることを本明細書中に開示する。具体的には、CSPG4は、しばしば化学療法抵抗性および放射線抵抗性を示すBBC(具体的にはTNBC)中に発現する。CSPG4は、癌幹細胞(CSC)中に発現する。したがって、CSPG4ポリペプチドの発現を使用してBBC(TNBC)を診断することができるか、これを使用して乳癌を病期分類することができるか、これを使用して乳癌(BBC(例えば、TNBC)など)を有する被験体の予後を決定することができる。したがって、BBC(TNBCなど)の診断のためのCSPG4に特異的に結合する抗体の使用を本明細書中に開示する。いくつかの実施形態では、本方法は、被験体が別の乳癌形態と比較してBBC(TNBCなど)を有するかどうかを決定する。診断方法を使用して、転移(脳転移など)がBBC(TNBCなど)であるかどうかを決定することができる。
1つの実施形態では、CSPG4ポリペプチドに対して免疫応答を生成する方法を提供する。本方法は、例えば、被験体における癌の成長の軽減または癌の徴候または症状の軽減などによる癌の処置に有用である。癌は、乳癌(BBC(例えば、TNBC)など)であり得る。本方法は、治療有効量のポリペプチド(CSPG4ポリペプチドが含まれる)またはそのフラグメントを被験体に投与する工程を含む。本方法は、このポリペプチドをコードする核酸を被験体に投与する工程も含むことができる。
患者、胸水、および細胞調製物。乳癌患者由来の胸水を、承認された細胞および組織獲得プロトコール下で得た。簡潔に述べれば、PleurXカテーテルを用いて滲出液を排出させてこの液体をボトルに回収した。腫瘍細胞を、流動物のフィコールでの分離(典型的には、500ML−2L)によって単離してデブリおよび赤血球交雑物を除去し、低温保存した。典型的な細胞収量は2×108〜3×1011細胞/リットル流動物であった。
CSPG4:患者から得た腫瘍のホルマリン固定パラフィン包埋(FFPE)切片を脱パラフィンし、水和した。1mM EDTA(pH8.0)中で15分間ボイルすることによって抗原回復を行った。スライドを、3%水素ペルオキシダーゼおよび1%ウシ血清アルブミン/5%正常ウマ血清を含むトリス緩衝化生理食塩水によってツウィーン20(Sigma−Aldrich Inc.,St.Louis,MO)と共にブロッキングして、CSPG4特異的mAbであるD2.8.5−C4B8(3μg/ml)と加湿した密室中にて4℃で一晩インキュベートした。EnVision+System−HRP(DakoCytomation Inc)を使用してシグナルを増幅し、ジアミノベンジジン(DAB,DakoCytomation Inc.)によって発色させた。サンプルをヘマトキシリンを用いて対比染色し、脱水し、カナダバルサム(Sigma−Aldrich Inc.)中にマウントした。
公的に利用可能な臨床的な注釈つきの乳癌データセット(GSE5460)を使用したER−/Her2−、ER−/Her2+、ER+/Her2−、およびER+/Her2+乳癌細胞におけるCSPG4 mRNAレベルの比較により、CSPG4遺伝子発現レベルがER−/Her2−亜群で他の亜群よりも有意に(マン・ホイットニー、p=0.01〜0.06)高いことが示された。これは、基底乳癌表現型(ER−/Her2−)と最良に相関するようである(図1a)。
フローサイトメトリーによってCD44+CD24−/lo細胞と同定されたCSCの頻度は、管腔乳癌細胞株よりもTMBCで遥かに高かった。これらは、細胞株SK−BR−3では検出不可能であり、細胞株T−47DおよびMCF−7でそれぞれ1.5%および34.6%の頻度であった。対照的に、これらはTNBC細胞株HS578T、MDA−MB−231、MDA−MB−435、およびSUM−149において92.5〜99.0%の頻度であった12(図1c)。興味深いことに、CSPG4は、基底乳癌細胞株および管腔乳癌細胞株に存在するCD44+CD24−/lo細胞上に差次的に発現する。これは、4つのTNBC細胞株において高い比率(66.7〜96.1%)でCSC上で高発現するが、3つの管腔乳癌細胞株において低比率(1.5〜13.0%)のCSC上で低発現するか、発現がほとんど検出されない(図1c)。
Al−Hajj et al.の方法(Proc Natl Acad Sci U S A 100:3983−3988)を使用して、14人の乳癌患者の胸水から単離した細胞中の0.71〜92.7%の乳房CSCが系統陰性(CD2、3、10、16、18、31、45、64、140b)、CD45−、CD44+、CD24−/loと同定された(表2)。この表面表現型を有する細胞は、腫瘍形成性の高い亜集団について富化されることが示されている。系統陰性胸水細胞中のCSCの比率は、9人の患者で低く(10%未満)、4人の患者で中程度であり(18.6〜35.0%)、1人の患者で高かった(92.7%)。CSC表現型と一致して、全滲出細胞中のCSCの比率は0.01%〜0.89%の範囲であった(表2)。富化の範囲は、染色のために使用したCSPG4特異的mAbに応じて異なり、結果は、細胞株上に認められた対応する決定基の発現の異種性と一致した(表3)。
RT−PCRによってMDA−MB−435細胞中でCSPG4 mRNAが検出され、そのほとんど(99%)がCSC表現型(CD44+CD24−/lo)を発現した(図6a)。mAb763.74を用いたMDA−MB−435細胞溶解物のウェスタンブロット分析により、CSPG4の2つの成分が検出された(図6b)。
以前の研究により、CSPG4が前駆体および腫瘍細胞の運動性、接着、および成長を促進し、それによって黒色腫細胞および神経膠腫細胞が成長および転移することが示されている。CSPG特異的モノクローナル抗体を、in vitroで腫瘍細胞の運動性および成長を遮断する能力について試験した。図2に示すように、CSPG4特異的mAbである225.28はin vitroでCSPG4+TNBC細胞の成長、接着、および遊走を阻害した。図2に示すように、表示の投薬量のmAb225.28の存在下でTNBC細胞は、三次元マトリックス設定(これはin vivo腫瘍成長条件に密接に類似する)において細胞成長を70%阻害し(図2a,b)これらの細胞のフィブロネクチン(figronectin)への接着も45%阻害し(図2c)、Boydenチャンバーアッセイにおいてフィブロネクチンへのこれらの細胞の運動性を56%阻害した(図2d)。
CSPG4特異的mAb225.28は、高い比率でCD44+/CD24−/lo細胞を有し、中レベルから高レベルでCSPG4を発現するMDA−MB−231細胞の実験的転移を阻害した(図4A)。腫瘍細胞の静脈内(i.v.)注射の3日後、マウスを2群に無作為に分けた。一方の群にmAb225.28(100μg/注射)を週2回注射し、他方の群にコントロールmAb(100μg/注射)を週2回注射した。腫瘍細胞接種したマウスの79日後の評価により、CSPG4特異的mAbがコントロールmAbと比較して99%を超えるMDA−MB−231転移を阻害することが証明された。同様に、CSPG4を高発現し、且つMDA−MB−231細胞に類似のCD44+/CD24−/lo表現型を有するMDA−MB−435細胞の転移は、コントロールmAbと比較してmAb225.28またはmAb763.74のいずれかで95%を超えて阻害された(図4b)。
臨床的に関連する研究を行うために、CSPG4特異的mAbがSCIDマウスにおけるヒト乳房MDA−MB−435乳腺腫瘍の再発および自発的転移を阻害する能力を、原発性腫瘍の外科的除去(ヒト疾患と臨床的に類似する背景)後に試験した。mAb225.28および763.74で処置したマウスは、コントロールmAbを投与したマウスよりも自発的肺転移が有意に低かった(図5a)。さらに、mAb763.74および225.28でそれぞれ処置したそれぞれ5匹のマウスからなる2群では、たった1つの小さいサイズの局所腫瘍再発のみの検出および検出なしであった。対照的に、コントロールmAbで処置した5匹のマウスにおいて3つの巨大な腫瘍再発が見出された(図5B)。結果は、2つの独立した実験の代表である。結果は、CSPG4のターゲティングが原発性腫瘍の外科的除去後の腫瘍の転移および再発の両方を阻害するのに臨床的に有用であり得ることを示す。
Claims (27)
- 被験体における基底乳癌腫の検出方法であって、
該被験体から得たサンプルをCSPG4に特異的に結合する抗体と、免疫複合体の形成に十分な期間接触させる工程、
該免疫複合体の存在を検出する工程であって、免疫複合体の存在が該被験体における基底乳癌腫の存在を証明する、工程
を含む、方法。 - 前記サンプルが生検サンプル、血液サンプル、血清サンプル、または尿サンプルである、請求項1に記載の方法。
- 前記サンプルが非乳房由来の生検サンプルである、請求項1に記載の方法。
- 前記サンプルが乳房生検である、請求項1に記載の方法。
- 前記サンプルをCSPG4に特異的に結合する抗体のパネルと接触させる工程を含む、請求項1に記載の方法。
- 前記抗体がモノクローナル抗体225.28、その機能的フラグメント、そのキメラ形態、またはそのヒト化形態である、請求項1に記載の方法。
- 前記抗体が標識されている、請求項1に記載の方法。
- 前記基底乳癌がエストロゲン受容体、プロゲステロン受容体、Her2のいずれも発現しない、請求項1に記載の方法。
- 前記被験体が乳癌と診断されている、請求項1に記載の方法。
- 基底乳癌細胞の成長を阻害する方法であって、
該基底乳癌細胞を有効量の抗体と接触させ、それにより、該癌細胞の成長を阻害する工程であって、該抗体は、CSPG4に特異的に結合する、工程
を含む、方法。 - 前記抗体がエフェクター分子に共有結合する、請求項10に記載の方法。
- 前記抗体がモノクローナル抗体である、請求項10に記載の方法。
- 前記モノクローナル抗体が、225.28、その機能的フラグメント、そのキメラ形態、またはそのヒト化形態である、請求項12に記載の方法。
- 前記エフェクター分子が化学療法薬である、請求項11に記載の方法。
- 前記エフェクター分子が有毒部分を含む、請求項11に記載の方法。
- 前記有毒部分が、リシンA、アブリン、ジフテリア毒素またはそのサブユニット、シュードモナス外毒素またはその一部、およびボツリヌス毒素A〜Fからなる群から選択される、請求項15に記載の方法。
- 前記シュードモナス外毒素がPE35、PE37、PE38、およびPE40からなる群から選択される、請求項16に記載の方法。
- 前記基底乳癌細胞がin vivoにおけるものである、請求項12に記載の方法。
- 前記基底乳癌細胞がトリプルネガティブ乳癌細胞である、請求項12に記載の方法。
- 前記基底乳癌細胞の成長を阻害する工程が、前記基底乳癌細胞の転移をin vivoで減少させる工程を含む、請求項18に記載の方法。
- 被験体において基底乳癌腫に対する免疫応答をもたらす方法であって、
基底乳癌腫を有する被験体を選択する工程、および
該被験体に治療有効量のCSPG4ポリペプチドを投与し、それにより、該被験体において該基底乳癌腫に対する免疫応答をもたらす、工程
を含む、方法。 - 前記免疫応答がB細胞応答である、請求項21に記載の方法。
- 前記免疫応答がT細胞応答である、請求項21に記載の方法。
- 前記免疫応答によって前記被験体における前記基底乳癌の徴候または症状が軽減される、請求項21に記載の方法。
- 前記免疫応答によって転移数が減少される、請求項21に記載の方法。
- アジュバントを投与する工程をさらに含む、請求項21に記載の方法。
- 前記基底乳癌腫がトリプルネガティブ乳癌癌腫である、請求項20に記載の方法。
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WO2010033866A2 (en) | 2010-03-25 |
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