JP2020533305A - 免疫調節剤としてのホスファプラチン化合物およびその治療的使用 - Google Patents
免疫調節剤としてのホスファプラチン化合物およびその治療的使用 Download PDFInfo
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Abstract
Description
本出願は、米国特許法第35条、§119(e)の下で、2017年9月8日に出願された米国仮出願第62/555,676号の利益を主張し、参照によりその全体が本明細書に組み込まれる。
本発明は癌の治療のための治療剤としてのホスファプラチン化合物の使用およびその方法に関し、特に、組み合わせ相乗効果をもたらし得るそれらの免疫調節作用メカニズムに関する。
本発明はホスファプラチン複合体が腫瘍微小環境に対する免疫原性細胞死およびそれに続く免疫T細胞動員を強力に誘導するという驚くべき発見に基づいており、これは、単独または腫瘍学および血液学内の他の薬剤と組み合わせたそれらの使用に影響を及ぼす他のPt含有化合物とは異なるメカニズム的特性である。
PT−112は免疫原性細胞死(ICD)を誘導する
アポトーシスはしばしば寛容原性または非免疫原性であるが、ある種の薬剤はICDと呼ばれる癌細胞におけるアポトーシスの形態を誘導することができる。癌細胞がICD誘導剤への暴露によって死滅すると、損傷関連分子パターン(DAMP)を放出する。これらの分子は、樹状細胞、続いて細胞傷害性T細胞の活性化を介して、癌細胞の存在に免疫システムをアラートするのに役立つ。包括的なレビューとしては、Kroemer 他、2013 AnnuRev.Immunol.31:51−72を参照されたい。
マウス同種移植実験におけるPT−112免疫調節の試験、およびPD−1 CPIとの併用による相乗効果
マウス同種移植実験では、免疫適格マウスにCT26マウス結腸癌細胞(図5)を移植し、続いてマウスを群(n=7)に無作為化し、1日目に90mg/kgのPT−112 IVを週1回、合計6用量投与、2日目に10mg/kgの抗PD−1抗体を週2回、合計6用量投与、またはその2つの組合せで処置を開始した。さらに、対照動物にビヒクルを投与した。治療中および治療後に腫瘍体積をモニタリングした。
さらなるマウス同種移植実験におけるPT−112免疫調節の試験、およびPD−L1 CPIとの併用による相乗効果
MC38マウス癌モデルにおいて、PT−112と抗PD−L1抗体との組み合わせを用いた陽性の有効性結果が観察され、実施例2に記載されたものと同様であった(データは示さず)。T細胞集団に対する異なる処置の効果をよりよく理解するために、追加の免疫適格マウスにMC38細胞を移植し、その後、対照、PT−112、抗PD−L1抗体、または併用処置群(n=5)にランダム化した。処置の2週間後(90mg/kg QWでPT−112、10mg/kg BIWでPD−L1)、腫瘍組織を取り出し、FACSを介して白血球集団の差について分析した。抗PD−L1抗体による処理は測定された細胞集団のいずれにおいても大きな変化をもたらさなかったが、PT−112による処理は細胞傷害性T細胞(CD8+)およびヘルパーT細胞(CD4+)を含む様々な細胞集団において大きな変化を引き起こした(図8)。これらの変化は併用群でさらに顕著であった。データは、100%と定義される、未処理マウスから収集されたサンプルに対して正規化されることに留意されたい。
免疫適格多発性骨髄腫マウスモデルにおけるPT−112の効力およびCPIとの相乗作用の試験
異なる実験において、PT−112の使用を、ボルテゾミブ耐性多発性骨髄腫癌モデルvk12598を移植されたマウスにおいて試験したことが、Chesi等、2012に記載されている。偽抗体(ラットIgG)対照群(n=5)、PT−112+偽抗体群(n=8)、またはPT−112+抗PD−1抗体群(n=8)におけるマウスのMスパイクレベルを、疾病の進行をモニターするための手段として測定した(図10)。
Claims (21)
- 癌を有する対象を治療するための方法であって、治療有効量の式IまたはIIの構造を有するホスファプラチン化合物、
またはその薬学的に許容される塩を、免疫原性細胞死(ICD)を誘発するために対象に投与することを含み、式中、R1およびR2は、それぞれ独立して、NH3、置換または非置換脂肪族アミン、および置換または非置換芳香族アミンから選択され、R3は置換または非置換脂肪族ジアミン、および置換または非置換芳香族ジアミンから選択される、方法。 - R1およびR2は、それぞれ独立して、NH3、メチルアミン、エチルアミン、プロピルアミン、イソプロピルアミン、ブチルアミン、シクロヘキサンアミン、アニリン、ピリジンおよび置換ピリジンから選択され、R3は1,2−エチレンジアミンおよびシクロヘキサン−1,2−ジアミンから選択される、請求項1に記載の方法。
- 前記ホスファプラチン化合物が、
薬学的に許容される塩、およびそれらの混合物からなる群から選択される、請求項1に記載の方法。 - 前記ホスファプラチン化合物が、
R,R−ピロダック−2である、請求項1に記載の方法。 - 癌を有する対象を治療するための方法であって、治療有効量の式IIIまたはIVの構造を有するホスファプラチン化合物、
またはその薬学的に許容される塩を、対象における免疫原性細胞死(ICD)を誘発するために対象に投与することを含み、式中、R1およびR2は、それぞれ独立して、NH3、置換または非置換脂肪族アミン、および置換または非置換芳香族アミンから選択され、R3は置換または非置換脂肪族ジアミン、および置換または非置換芳香族ジアミンから選択される、方法。 - R1およびR2は、それぞれ独立して、NH3、メチルアミン、エチルアミン、プロピルアミン、イソプロピルアミン、ブチルアミン、シクロヘキシルアミン、アニリン、ピリジンおよび置換ピリジンから選択され、R3は1,2−エチレンジアミン、およびシクロヘキサン−1,2−ジアミンから選択される、請求項5に記載の方法。
- 単量体白金(IV)ピロリン酸錯体が、式(IV)を有し、式中、R3は1,2−エチレン−ジアミンまたはシクロヘキサン−1,2−ジアミンである、請求項5に記載の方法。
- 前記投与が静脈内注射または腹腔内注射を含む、請求項1〜7のいずれか1項に記載の方法。
- ピロリン酸白金錯体の用量が、対象の体重に基づいて約1mg〜約200mg/Kgの範囲である、請求項1〜8のいずれか1項に記載の方法。
- 前記癌が、結腸癌、膵臓癌、胃癌、肝臓癌、乳癌、前立腺癌、肺癌、およびメラノーマ、骨肉腫、軟骨肉腫,ユーイング腫瘍、悪性線維性組織球腫(MFH)、線維肉腫(mibrosarcoma)、巨細胞腫瘍、脊索腫、紡錘細胞肉腫、多発性骨髄腫、非ホジキンリンパ腫、ホジキンリンパ腫、白血病、小児急性骨髄性白血病(AML)、慢性骨髄単球性白血病(CMML)、有毛細胞白血病、若年性骨髄単球性白血病(JMML)、骨髄異形成症候群、骨髄線維症,骨髄増殖性腫瘍、真性赤血球増加症、血小板血症骨肉腫、軟骨肉腫、ユーイング腫瘍、悪性線維性組織球腫(MFH)、線維肉腫(mibrosarcoma)、巨細胞腫、脊索腫、紡錘細胞肉腫、多発性骨髄腫、非ホジキンリンパ腫、ホジキンリンパ腫および白血病からなる群から選択される、請求項1〜9のいずれか1項に記載の方法。
- 前記対象に第2の抗癌剤を対象に投与することを併用する、請求項1〜10のいずれか1項に記載の方法。
- 前記第2の抗癌剤が、アルキル化剤、グルココルチコイド、免疫調節薬(IMiD)およびプロテアソーム阻害剤、シクロクレアチン、RNAi剤、核酸、ベクター、5−フルオロウラシル、オキサリプラチン、イリノテカン、カペシタビン、ゲムシタビン、セツキシマブ、タキソール、アバスチン、フォリン酸(ロイコボリン)、レゴラフェニブ、ザルトラップ、トポイソメラーゼI阻害剤、NKTR−102、チバンチニブ、PX−866、ソラフェニブ、リニファニブ、キナーゼ阻害剤、テラチニブ、XL281(BMS)、ロバツムマブ、およびIGF1−R阻害剤からなる群から選択される、請求項11に記載の方法。
- 治療有効量の免疫チェックポイントタンパク質阻害剤を対象に投与することをさらに併用する、請求項1〜12のいずれか1項に記載の方法。
- 前記ホスファプラチン化合物が、前記免疫チェックポイントタンパク質阻害剤の投与前に対象に投与される、請求項13に記載の方法。
- 前記ホスファプラチン化合物が、前記免疫チェックポイントタンパク質阻害剤の投与と実質的に同時に対象に投与される、請求項13に記載の方法。
- 前記対象が、免疫チェックポイントタンパク質阻害剤単独での処置に対して低い応答を有するかまたは応答を有さない癌を有する患者である、請求項13〜15のいずれか1項に記載の方法。
- 前記免疫チェックポイントタンパク質阻害剤が、PD−1阻害剤、PD−L1阻害剤、B7−1/B7−2阻害剤、CTLA−4阻害剤、およびこれらの組み合わせからなる群から選択される、請求項13〜16のいずれか1項に記載の方法。
- 前記免疫チェックポイントタンパク質阻害剤が、ペンブロリズマブ(キートルダ)、ニボルマブ(オプジーボ)、ピジリズマブ(CT−011)、アテゾリズマブ(テセントリク)、アベルマブ(バベンシオ)、デュルバルマブ(イムフィンジ)、イピリムマブ(エルボイ)、およびこれらの組み合わせからなる群より選択される抗体である、請求項13〜17のいずれか1項に記載の方法。
- 前記癌が、結腸癌、膵臓癌、胃癌、肝臓癌、乳癌、前立腺癌、肺癌、膀胱癌、尿路上皮癌、胸腺上皮癌、頭頸部癌、基底細胞癌およびメラノーマなどの皮膚癌、骨肉腫、軟骨肉腫、ユーイング腫瘍、悪性線維性組織球腫(MFH)、線維肉腫(mibrosarcoma)、巨細胞腫、脊索腫、紡錘細胞肉腫、多発性骨髄腫、非ホジキンリンパ腫、ホジキンリンパ腫、白血病、小児急性骨髄性白血病(AML),慢性骨髄単球性白血病(CMML)、有毛細胞白血病、若年性骨髄単球性白血病(JMML)、骨髄異形成症候群、骨髄線維症、骨髄増殖性腫瘍、真性赤血球増加症、血小板血症骨肉腫、軟骨肉腫、ユーイング腫瘍、悪性線維性組織球腫(MFH)、線維肉腫(mibrosarcoma)、巨細胞腫、脊索腫、紡錘細胞肉腫、多発性骨髄腫、非ホジキンリンパ腫、ホジキンリンパ腫および白血病からなる群より選択される、請求項13〜18のいずれか1項に記載の方法。
- 前記癌が、低レベルの腫瘍浸潤リンパ球(TIL)で特徴付けられる、請求項13〜19のいずれか一項に記載の方法。
- 前記ホスファプラチン化合物による免疫原性細胞死の誘導が、前記ホスファプラチン化合物で処置された対象の細胞からの損傷関連分子パターン(DAMP)、高移動度群ボックス1(HMGB1)、カルレチクリン(CRT)、およびDAMPアデノシン三リン酸(ATP)の放出を特徴とする、請求項1〜20のいずれか1項に記載の方法。
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