JP2021535215A - 疾患治療のためのparp阻害と組み合わせたcd47遮断 - Google Patents
疾患治療のためのparp阻害と組み合わせたcd47遮断 Download PDFInfo
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Abstract
Description
本出願は、2018年9月4日出願の米国特許仮出願第62/726,497号の利益を主張するものであり、この開示内容全体が参照により本明細書に組み込まれる。
本発明は、CD47/SIRPα相互作用を遮断する薬物の使用方法に関する。より具体的には、本発明は、組み合わせた場合に、癌療法に有用な方法および手段に関する。
EELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGA[配列番号1]
EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPS[配列番号5]
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK*[配列番号2]
ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK[配列番号6]
ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK[配列番号7]
EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK*[配列番号3]
EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK[配列番号8]
EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK[配列番号9]
1)配列番号8または配列番号9を有するSIRPαFcおよびニラパリブとして知られるPARP阻害薬。特定の実施形態では、組み合わせは、配列番号8を有するSIRPαFcおよびPARPiニラパリブを含む。別の特定の実施形態では、組み合わせは、配列番号9を有するSIRPαFcおよびPARPiニラパリブを含む。
2)配列番号8または配列番号9を有するSIRPαFcおよびPARP阻害薬ベリパリブ。特定の実施形態では、組み合わせは、配列番号8を有するSIRPαFcおよびPARPiベリパリブを含む。別の特定の実施形態では、組み合わせは、配列番号9を有するSIRPαFcおよびPARPiベリパリブを含む。
3)配列番号8または配列番号9または配列番号7を有するSIRPαFcおよびルカパリブとして知られるPARP阻害薬。特定の実施形態では、組み合わせは、配列番号8を有するSIRPαFcおよびPARPiルカパリブを含む。別の特定の実施形態では、組み合わせは、配列番号9を有するSIRPαFcおよびPARPiルカパリブを含む。
4)配列番号8または配列番号9または配列番号7を有するSIRPαFcおよびPARPiオラパリブ。特定の実施形態では、組み合わせは、配列番号8を有するSIRPαFcおよびオラパリブを含む。別の特定の実施形態では、組み合わせは、配列番号9を有するSIRPαFcおよびオラパリブを含む。組み合わせて含まれる各薬物は、組み合わせて使用するために別々に製剤化できる。
RT、PARP阻害薬およびCD47遮断薬SIRPαFcの組み合わせを、異種移植片腫瘍モデルで試験した。
材料および方法
SIRPαFc、RTおよびニラパリブ(PARP阻害薬)のインビボ効力を、BRCAコンピテントおよびノックダウンルシフェラーゼ発現卵巣癌細胞の腹腔内腫瘍異種移植片をNOD/SCIDマウス中で、単独で、または組み合わせて評価した。SIRPαFc(10mg/kg)を、RTの1時間前に、週3回で3週間、腹腔内に投与した。ニラパリブ(50mg/kg)を、RTの1時間前に、週5回で1週間投与した。マウスを全腹部放射線治療(体外照射療法)により2Gyの線量の2分割量で、画像誘導小動物照射器(225kVp、13mA)を用いて治療した。治療は、腫瘍接種後7日目に開始した。治療効力は、生物発光イメージング(BLI)および動物生存により評価した。全身毒性を臨床パラメーター採点により評価した。
SIRPαFc単剤療法は、BRCAコンピテント異種移植片モデルで腫瘍増殖を抑制したが、SIRPαFcおよびRTの組み合わせは、RT単独に比べて生存を有意に改善し、生存期間中央値が34日から47日に延長された(p=0.0085)。
Claims (40)
- CD47+疾患細胞を示す対象を治療する方法であって、PARP阻害薬およびCD47遮断薬を前記対象に投与することを含む、方法。
- 前記PARP阻害薬が、PARP−1阻害薬である、請求項1に記載の方法。
- 前記PARP阻害薬が、タラゾパリブである、請求項1に記載の方法。
- 前記PARP阻害薬が、ベリパリブである、請求項1に記載の方法。
- 前記PARP阻害薬が、ニラパリブである、請求項1に記載の方法。
- 前記PARP阻害薬が、オラパリブである、請求項1に記載の方法。
- 前記PARP阻害薬が、ルカパリブである、請求項1に記載の方法。
- 前記PARP阻害薬が、イニパリブである、請求項1に記載の方法。
- 前記CD47遮断薬が、CD47結合SIRPαポリペプチドである、請求項1〜8のいずれか1項に記載の方法。
- 前記SIRPαポリペプチドが、ヒトSIRPαポリペプチドである、請求項9に記載の方法。
- 前記ヒトSIRPαFcポリペプチドが、ヒトSIRPαのCD47結合領域を含むFc融合タンパク質である、請求項10に記載の方法。
- 前記Fc融合タンパク質が、配列番号8の可溶性SIRPαを含む、請求項11に記載の方法。
- 前記Fc融合タンパク質が、配列番号9の可溶性SIRPαを含む、請求項11に記載の方法。
- 前記SIRPαFcポリペプチドが、L4V/I、V6I/L、A21V、V27I/L、I31T/S/F、E47V/L、K53R、E54Q、H56P/R、S66T/G、K68R、V92I、F94V/L、V63I、およびF103Vから選択される1個または複数の活性増強アミノ酸置換を有する可溶性SIRPαを含む、請求項9に記載の方法。
- SIRPαFcおよびPARP−1阻害薬、および請求項1〜14のいずれか1項に記載の治療方法でのそれらの使用を教示する説明書を含む抗癌剤の医薬組合せ。
- 疾患細胞の治療のための放射線療法と組み合わせた、請求項15で定められる医薬組合せの使用。
- 前記放射線療法が、体外照射療法である、請求項16に記載の使用。
- 前記CD47+疾患細胞を示す対象の治療のための、請求項1〜17のいずれか1項に記載の組み合わせの使用。
- 前記CD47+疾患細胞が、CD47+癌細胞である、請求項17に記載の使用。
- 前記CD47+癌細胞が、血液癌または固形腫瘍である、請求項17に記載の使用。
- 前記癌細胞が、急性リンパ性白血病(ALL)、急性骨髄性白血病(AML)、慢性リンパ性白血病(CLL)、慢性骨髄性白血病(CML)、骨髄増殖性疾患/腫瘍(MPDS)、および骨髄異形成症候群から選択される癌型の細胞である、請求項17に記載の使用。
- 前記癌が、ホジキンリンパ腫、無痛性および侵襲性両方の非ホジキンリンパ腫、T細胞リンパ腫、CD20+リンパ腫、バーキットリンパ腫、ならびに小細胞濾胞性リンパ腫および大細胞濾胞性リンパ腫から選択されるリンパ腫である、請求項17に記載の使用。
- 前記癌が、多発性骨髄腫(MM)、巨細胞骨髄腫、重鎖骨髄腫、および軽鎖またはベンス・ジョーンズ骨髄腫から選択される骨髄腫である、請求項17に記載の使用。
- 前記癌が黒色腫である、請求項17に記載の使用。
- 前記癌が卵巣癌である、請求項17に記載の使用。
- 前記癌がCTCLである、請求項17に記載の使用。
- 前記癌が菌状息肉腫である、請求項17に記載の使用。
- 前記癌が乳癌である、請求項17に記載の使用。
- 前記癌が神経膠芽腫である、請求項17に記載の使用。
- PARP阻害薬およびCD47遮断薬の少なくとも1種、および請求項1〜14の方法に記載のそれらの使用のための説明書を含むキット。
- 放射線療法と組み合わせた、請求項30に記載のキットの使用。
- CD47+疾患細胞を示す対象を治療するための、PARP阻害薬およびCD47遮断薬の使用。
- 前記PARP阻害薬が、PARP−1阻害薬である、請求項32に記載の方法。
- 前記PARP阻害薬が、タラゾパリブ、ベリパリブ、ニラパリブ、オラパリブ、ルカパリブおよびイニパリブからなる群より選択される、請求項32に記載の使用。
- 前記CD47遮断薬が、CD47結合SIRPαポリペプチドである、請求項32〜34のいずれか1項に記載の使用。
- 前記SIRPαポリペプチドが、ヒトSIRPαポリペプチドである、請求項35に記載の使用。
- 前記ヒトSIRPαFcポリペプチドが、ヒトSIRPαのCD47結合領域を含むFc融合タンパク質である、請求項36に記載の使用。
- 前記Fc融合タンパク質が、配列番号8の可溶性SIRPαを含む、請求項37に記載の使用。
- 前記Fc融合タンパク質が、配列番号9の可溶性SIRPαを含む、請求項37に記載の使用。
- 前記SIRPαFcポリペプチドが、L4V/I、V6I/L、A21V、V27I/L、I31T/S/F、E47V/L、K53R、E54Q、H56P/R、S66T/G、K68R、V92I、F94V/L、V63I、およびF103Vから選択される1個または複数の活性増強アミノ酸置換を有する可溶性SIRPαを含む、請求項35に記載の使用。
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