JP7126956B2 - 全細胞蓄積を高めるコンジュゲート - Google Patents
全細胞蓄積を高めるコンジュゲート Download PDFInfo
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- JP7126956B2 JP7126956B2 JP2018568469A JP2018568469A JP7126956B2 JP 7126956 B2 JP7126956 B2 JP 7126956B2 JP 2018568469 A JP2018568469 A JP 2018568469A JP 2018568469 A JP2018568469 A JP 2018568469A JP 7126956 B2 JP7126956 B2 JP 7126956B2
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Description
[0001] 本願は、その全体が本明細書に援用される、2016年3月15日出願の米国仮特許出願第63/308,457号の利益を請求する。
[0002] 本発明は、全細胞内蓄積を高めるコンジュゲート化合物に関する。
[0012] 別の態様では、抗体は、モノクローナル又はポリクローナル抗体である。
[0014] ある態様では、抗体はヒト化抗体である。
[0016] さらなる態様では、核局在化配列は、SV40ラージT抗原に由来する。[0017] 別の態様では、細胞膜非透過性ペプチドは、少なくとも1つのスペーサー残基を含む。
[0019] さらなる態様では、細胞膜非透過性ペプチドは配列番号1に規定される。
[0021] さらなる態様では、目的の化合物へコンジュゲートされるChAcNLSペプチドの比は、化合物あたり1~21個のペプチドである。
[0023] ある態様では、放射性核種は、47Sc、51Cr、52mMn、55Co、58Co、52Fe、56Ni、57Ni、61Cu、62Cu、64Cu、67Cu、66Ga、68Ga、67Ga、72As、77As、89Zr、90Y、94mTc、99mTc、97Ru、105Rh、109Pd、111Ag、110In、111In、113mIn、114mIn、117mSn、121Sn、127Te、142Pr、143Pr、149Pm、151Pm、149Tb、153Sm、157Gd、161Tb、166Ho、165Dy、169Er、169Yb、175Yb、172Tm、177Lu、186Re、188Re、191Pt、197Hg、198Au、199Au、201Tl、203Pb、211At、212Bi、213Bi、11C、75Br、76Br、77Br、82Br、18F、120I、123I、124I、125I、131I、89Sr、及び225Acの少なくとも1つである。
[0025] 別の態様では、本明細書に記載されるコンジュゲート化合物は、それに結合した低分子毒素をさらに含む。
[0027] 別の態様では、低分子毒素は、微小管破壊剤又はDNAアルキル化剤である。
[0028] さらなる態様では、低分子毒素は、ビンブラスチン、エムタンシン、モノメチルアウリスタチンE、又は4,4-ジフルオロ-8-(4-カルボキシフェニル)-1,3,5,7-テトラメチル-4-ボラ-3a,4a-ジアザ-s-インダセン(BODIPY)である。
[0036] 以下、添付の図面について言及する。
[0060] 別の態様では、抗体は、マウス抗体、ヤギ抗体、ヒト抗体、又はウサギ抗体、又はヒト化抗体である。
[0062] 細胞膜非透過性であって、SV-40ラージT抗原由来の典型的なNLS(下線部)のセグメントを有する13マーのペプチド(CGYGPKKKRKVGG;配列番号1)は、以前、抗CD123(IL-3Rα)抗体(7G3)とそのキメラバージョン(CSL360)にコンジュゲートされたことがある(Leyton et al., 2011, J Nucl Med, 52: 1465-1473)。コンジュゲートされた111Inを輸送するNLS-7G3及びNLS-CSL360を使用して、核移行能が評価された。NLS配列が存在しても、核へ送達される放射活性の比率はきわめて低く、その一方で、大多数の放射活性は細胞表面又は細胞質に留まった(Zerashkian et al., 2014, Nucl Med Biol, 41: 377-383)。したがって、111In-NLSCSL360は、エンドソーム内に捕捉されたままであった。
[0066] また、本発明に含まれるのは、限定されるものではないが、47Sc、51Cr、52mMn、55Co、58Co、52Fe、56Ni、57Ni、61Cu、62Cu、64Cu、67Cu、66Ga、68Ga、67Ga、72As、77As、89Zr、90Y、94mTc、99mTc、97Ru、105Rh、109Pd、111Ag、110In、111In、113mIn、114mIn、117mSn、121Sn、127Te、142Pr、143Pr、149Pm、151Pm、149Tb、153Sm、157Gd、161Tb、166Ho、165Dy、169Er、169Yb、175Yb、172Tm、177Lu、186Re、188Re、191Pt、197Hg、198Au、199Au、201Tl、203Pb、211At、212Bi、213Bi、11C、75Br、76Br、77Br、82Br、18F、120I、123I、124I、125I、131I、89Sr、及び225Acより選択される放射性核種へコンジュゲートされる、本明細書に記載される化合物である。加えて、例えばビンブラスチンのような化学療法剤へコンジュゲートされる、本明細書に記載される化合物も包含される。
[0088] 13日齢のニワトリ胚において、非特異的な急性・胚毒性についてex ovoで評価した。1匹のニワトリあたり10μgのChAcNLS-SM(PEG)2-T-DM1及び10μgのChAcNLS-MCC-T-DM1(20μgのChAcNLS/抗体をロード)を静脈内に1回注射して、72時間での生存を評価した。等量のT-DM1も注射して、比較用に評価した。結果を表2に表示する。
[0090] 本明細書に記載されるようなコンジュゲートは、抗体の送達を高める手段を提供するだけでなく、ChAcNLSは、抗体のみならず結合した分子ペイロードの送達を高めることができる。ChAcNLSは、増加量の分子ペイロードを核へ送達することができる。
ChAcNLS-7G3の構築
[0094] GYGスペーサー残基及びGGスペーサー残基をそれぞれN末端及びC末端に有するSV-40ラージT抗原由来の核局在化配列を用いて、ChAcNLSを設計した。N末端は、ChAc及び7G3へのコンジュゲーションのためにシステインでキャップした。ChAcNLSのN末端システインとマレイミド誘導体化7G3との反応によって、ChAcNLSとNLSを7G3 mAb又はmIgG2a mAbへコンジュゲートした。マレイミド基は、PBS(pH7.6)中10mg/mLの7G3を、10、25、又は50倍モル過剰のスルホスクシンイミジル-4-(N-マレイミドメチル)-シクロヘキサン-1-カルボキシレート(スルホ-SMCC;VWR、ケベック州、カナダ)と室温で1時間反応させるによって7G3へ導入した。マレイミド誘導体化7G3は、セファデックスG-50(シグマ・アルドリッチ)カラムにて、PBS(pH7.0)で溶出させて精製した。マレイミド-7G3を含有する画分をセントリコンYM-100限外濾過装置(EMD ミリポア、オンタリオ州、カナダ)へ移し、10mg/mLに濃縮してから、これを100倍モル過剰のChAcNLSと4℃にて18時間反応させた。過剰のChAcNLSからChAcNLS-7G3を精製し、PBS(pH7.4)中にて、セントリコンYM-100による限外濾過によって濃縮した。
[0095] 細胞のmAbコンジュゲートへの曝露
TF-1a白血病細胞及びRajiバーキットリンパ腫細胞を、アメリカン・タイプ・ティシュー・コレクション(バージニア州マナッサス)より入手した。TF-1a細胞は、フローサイトメトリーによれば、IL-3Rα陽性であり(7G3の111In標識キメラバージョンでは、7.8×103個の受容体/細胞に相当する)、Raji細胞は、IL-3Rα陰性である。1%ペニシリン/ストレプトマイシン、1%非必須アミノ酸、1%ピルビン酸ナトリウム、10%非働化FBS、及び0.2%アンホテリシンBを添加したRPMI 1640培地(Wisent、ケベック州、カナダ)において細胞を培養した。
ChAcNLS-7G3内在化とIL-3Rαリサイクリング
[00101] TF-1a細胞の細胞表面での7G3及びIL-3Rαの運命をモニターするために、24×106個の細胞を含有する試料を7G3コンジュゲートへ1時間曝露した。次いで、この細胞を洗浄して非結合リガンドを除去し、早期(5分、15分、30分、1時間)又は後期(1時間、2時間、3時間、及び4時間)の時点でのポストインキュベーションを実施した。各時点で、4×106個の細胞アリコートを固定して洗浄したが、透過性にはしなかった。この細胞を、氷上で1時間、AF647を含有するPBSで染色し、細胞表面の7G3レベルについてモニターするか、又は抗IL-3Rα-PE-Cy7 mAb(クローン6H6;BD Biosciences)によって、IL-3Rαの表面発現についてモニターした。6H6は7G3に干渉しない。TF-1a細胞は、5、10、30、60、及び120分間の7G3コンジュゲートへの曝露に先立って、フィリピン(5μg/mL)にも30分間曝露した。PI陰性細胞集団は、非透過性細胞のみが分析されることを確認するためにのみ評価した。
化学療法剤エムタンシンにコンジュゲートしたmAbトラスツズマブ
[00102] ChAcNLS-T-DM1を構築するために、初めに、本明細書の上記と同じ架橋剤を使用して、トラスツズマブの表面リジンへACCUMを架橋結合させた。
Claims (17)
- コール酸(ChAc)又はその変異体を含むコンジュゲート化合物であって、ChAcは、抗体にコンジュゲートされた核局在化配列(NLS)を含む細胞膜非透過性ペプチドにコンジュゲートされており、核局在化配列はSV40ラージT抗原に由来し、細胞膜非透過性ペプチドは配列番号1に規定される、前記コンジュゲート化合物。
- 抗体が、モノクローナル又はポリクローナル抗体である、請求項1のコンジュゲート化合物。
- 抗体が、マウス抗体、ヤギ抗体、ヒト抗体、又はウサギ抗体である、請求項1又は2のコンジュゲート化合物。
- 抗体がヒト化抗体である、請求項1~3のいずれか1項のコンジュゲート化合物。
- 抗体が、Fv、F(ab’)、及びF(ab’)2から成る群より選択されるエピトープ結合断片を含む、請求項1~4のいずれか1項のコンジュゲート化合物。
- 細胞膜非透過性ペプチドが、少なくとも1つのスペーサー残基を含む、請求項1~5のいずれか1項のコンジュゲート化合物。
- 細胞膜非透過性ペプチドが、ChAcと抗体へ結合するための少なくとも1つのシステインを含む、請求項1~6のいずれか1項のコンジュゲート化合物。
- 抗体が、7G3抗体又は6G7抗体である、請求項1~7のいずれか1項のコンジュゲート化合物。
- コンジュゲート化合物に結合した放射性核種をさらに含む、請求項1~8のいずれか1項のコンジュゲート化合物。
- 放射性核種が、47Sc、51Cr、52mMn、55Co、58Co、52Fe、56Ni、57Ni、61Cu、62Cu、64Cu、67Cu、66Ga、68Ga、67Ga、72As、77As、89Zr、90Y、94mTc、99mTc、97Ru、105Rh、109Pd、111Ag、110In、111In、113mIn、114mIn、117mSn、121Sn、127Te、142Pr、143Pr、149Pm、151Pm、149Tb、153Sm、157Gd、161Tb、166Ho、165Dy、169Er、169Yb、175Yb、172Tm、177Lu、186Re、188Re、191Pt、197Hg、198Au、199Au、201Tl、203Pb、211At、212Bi、213Bi、11C、75Br、76Br、77Br、82Br、18F、120I、123I、124I、125I、131I、89Sr、及び225Acのうち少なくとも1つである、請求項9のコンジュゲート化合物。
- 放射性核種が64Cuである、請求項10のコンジュゲート化合物。
- コンジュゲート化合物に結合した低分子毒素をさらに含む、請求項1~8のいずれか1項のコンジュゲート化合物。
- 低分子毒素が化学療法剤である、請求項12のコンジュゲート化合物。
- 低分子毒素が、微小管破壊剤又はDNAアルキル化剤である、請求項12又は13のコンジュゲート化合物。
- 低分子毒素が、ビンブラスチン、エムタンシン、モノメチルアウリスタチンE、又は4,4-ジフルオロ-8-(4-カルボキシフェニル)-1,3,5,7-テトラメチル-4-ボラ-3a,4a-ジアザ-s-インダセン(BODIPY)である、請求項12~14のいずれか1項のコンジュゲート化合物。
- 前立腺癌、乳癌、肝臓癌、胃癌、結腸癌、膵臓癌、卵巣癌、肺癌、腎臓癌、脳腫瘍、精巣癌、膠芽腫、肉腫、骨癌、頭頚部癌、皮膚癌、リンパ腫、白血病、結直腸癌、ホジキンリンパ腫、非ホジキンリンパ腫、又はランゲルハンス細胞組織球症を検出するための、請求項1~11のいずれか1項のコンジュゲート化合物。
- 前立腺癌、乳癌、肝臓癌、胃癌、結腸癌、膵臓癌、卵巣癌、肺癌、腎臓癌、脳腫瘍、精巣癌、膠芽腫、肉腫、骨癌、頭頚部癌、皮膚癌、リンパ腫、白血病、結直腸癌、ホジキンリンパ腫、非ホジキンリンパ腫、又はランゲルハンス細胞組織球症を治療するための、請求項1~8及び12~15のいずれか1項のコンジュゲート化合物。
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