JP2009531325A - カンプトテシン結合部分 - Google Patents
カンプトテシン結合部分 Download PDFInfo
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- JP2009531325A JP2009531325A JP2009501636A JP2009501636A JP2009531325A JP 2009531325 A JP2009531325 A JP 2009531325A JP 2009501636 A JP2009501636 A JP 2009501636A JP 2009501636 A JP2009501636 A JP 2009501636A JP 2009531325 A JP2009531325 A JP 2009531325A
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Abstract
【選択図】なし
Description
(a)標的部分と、
(b)カンプトテシン(CPT)またはその誘導体もしくは類似体である治療薬部分と、
(c)標的部分に結合する官能基を介して該標的部分に結合し、細胞内で開裂可能な部分を介して該CPT部分に結合するリンカーと、を含む複合体に関する。
(a)標的部分と、
(b)カンプトテシン(CPT)またはその誘導体もしくは類似体である治療薬部分と、
(c)標的部分に結合する官能基を介して該標的部分に結合し、細胞内で開裂可能な部分に付着するアミノ酸のC末端を介して該CPTまたはその誘導体に結合するリンカーと、を含む複合体に関する。
例示的な好適な実施形態は、カンプトテシン薬物誘導体および一般式2の抗体の複合体に関する。
MAb−[L]−AA−CPT
(2)
ここで、MAbは、疾患標的抗体であり、CPTは、カンプトテシン(camptothecin:CPT)またはその類似体であり、Lは、X−Y−Z型のリンカー系であって、Xは抗体結合部分であり、Yはリソソーム性に開裂可能なポリペプチドであり、ZはCPT薬物に連結される4−アミノベンジルオキシ部分である。XおよびYは、直鎖または環状炭化水素である、またはポリエチレングリコール(polyethyleneglycol:PEG)などの水溶性化部分である介在スペーサーでアミド結合を介して連結されてもよい。AAは、CPTの20−ヒドロキシル間でエステルを形成し、その(AAの)N末端を介してリンカーLのZ構成要素にさらに付着されるアミノ酸またはポリペプチド部分である。
別の例示的な実施形態は、カンプトテシン薬物誘導体および一般式6の抗体の複合体に関する。
MAb−[L]−CPT
(6)
ここで、MAbは、疾患標的抗体であり、CPTは、カンプトテシン(camptothecin:CPT)またはその類似体であり、Lは、X−Y−Z型のリンカー系であって、Xは抗体結合部分であり、Yはリソソーム性に開裂可能なポリペプチドであり、ZはCPT薬物に直接または間接的に連結される4−アミノベンジルオキシ部分であり、最後に、XおよびYは、XおよびYは、直鎖または環状炭化水素である、またはポリエチレングリコール(PEG)などの水溶性化部分である介在スペーサーでアミド結合を介して連結される。方法2の実施形態において、X−Y−Zから成るリンカーLは、CPTの20−O−カルボニル部分に直接または間接的に付着される。
さらに別の例示的な実施形態は、カンプトテシン薬物誘導体および一般式11の抗体の複合体に関する。
MAb−[架橋剤]−AA−CPT
(11)
ここで、アミノ酸またはポリペプチド部分AAのC末端で形成されたCPTの20−O−AAエステルは、抗体結合基Xに直接的に結合され、それによって、スキーム1&2のリンカーLのY−Z構成要素を取り除く。方法1&2の、XおよびY間の結合に関連するスペーサーの様態とともに、Xのすべての実施形態、およびCPT定義は、方法3においてXおよびY間のスペーサーがXとエステルのアミン末端との間のスペーサーで置換されることを除いては、全体として本明細書において適用する。
モノクローナル抗体の生成方法は、当技術分野において既知であり、任意のかかる既知の方法は、主張される方法および組成物において使用される抗体を生成するために使用されてもよい。主張される方法および/または組成物の一部の実施形態は、抗体フラグメントに関してもよい。かかる抗体フラグメントは、従来の方法で抗体全体のペプシンまたはパパイン消化によって得られてもよい。例えば、抗体フラグメントは、F(ab’)2という5Sフラグメントを得るために、ペプシンで抗体を酵素的開裂することによって生成されてもよい。このフラグメントは、3.5S Fab’1価のフラグメントを得るため、チオール還元剤および、随意に、ジスルフィド連結の開裂により生じるスルフヒドリル基に対する保護基を使用してさらに開裂されてもよい。あるいは、ペプシンを使用する酵素的開裂は、2つの1価のFabフラグメントおよびFcフラグメントを生成する。抗体フラグメントを生成するための例示的な方法は、米国特許第4,036,945号、米国特許第4,331,647号、Nisonoff et al,1960,Arch.Biochem.Biophys.,89:230;Porter,1959,Biochem.J.,73: 119;Edelman et al.,1967,METHODS IN ENZYMOLOGY,page 422 (Academic Press),およびColigan et al.(eds.), 1991,CURRENT PROTOCOLS IN IMMUNOLOGY,(John Wiley & Sons)に開示されている。
キメラ抗体は、例えば、マウス抗体の相補性決定領域(complementarity−determining region:CDR)を含むマウス抗体の可変ドメインにより、ヒト抗体の可変ドメインが置換された組み換えタンパク質である。キメラ抗体は、被験者に投与された場合、免疫原性の減少および安定性の増加を呈示する。キメラ抗体を構成する方法は当技術分野において既知である(例えば、Leungら、1994,Hybridoma 13:469)。
組み合わせのアプローチまたはヒト免疫グロブリン遺伝子座で形質転換された方法遺伝子導入動物のいずれか一方を使用して、完全なヒト抗体を生成する方法は、当技術分野において既知である(例えば、Manciniら、2004, New Microbiol.27:315−28、Conrad and Scheller,2005,Comb.Chem.High Throughput Screen.8:117−26、Brekke and Loset,2003,Curr.Opin.Phamacol.3:544−50であり、それぞれ参照することにより本願明細書に組み込まれる)。かかる完全なヒト抗体は、キメラまたはヒト化抗体よりもさらに少ない副作用を呈示し、本質的に内在性ヒト抗体として体内で機能することが予想される。特定の実施形態において、主張される方法および手順は、かかる技術によって生成されたヒト抗体を活用してもよい。
特定の実施形態において、本明細書に記述される前駆物質、モノマーおよび/または錯体は、1つ以上のアビマー配列を含んでもよい。アビマーは、種々の標的分子に対するそれらの親和性および特異性において、抗体とある程度同様である結合タンパク質のクラスである。それらは、体外エキソンシャッフリングおよびファージディスプレイによってヒト細胞外受容体ドメインから開発された。(Silverman ら、2005,Nat.Biotechnol.23:1493−94;Silvermanら、2006,Nat.Biotechnol.24:220)。結果と生じるマルチドメインタンパク質は、単一エピトープ結合タンパク質と比べて向上された親和性(一部の例ではnM以下)および特異性を呈示し得る多数の非依存的結合ドメインを含んでもよい。(同文献)種々の実施形態において、アビマーは、例えば、主張される方法および組成物において使用されるDDD配列に付着されてもよい。アビマーの構成および使用方法に関するさらなる詳細は、例えば、米国特許出願広報第20040175756号、第20050048512号、第20050053973号、第20050089932号および第20050221384号に開示され、それぞれの実施例部分は、参照することにより本願明細書に組み込まれる。
主張される組成物および/または方法の特定の実施形態は、結合ペプチドおよび/または種々の標的分子、細胞または組織のペプチド模倣薬に関してもよい。結合ペプチドは、ファージディスプレイ技術を含むがそれに限定されない、当技術分野において既知の任意の方法により同定することができる。ファージディスプレイの種々の方法およびペプチドの多様な集団を生成するための技術は、当技術分野において既知である。例えば、米国特許第5,223,409号、第5,622,699号および第6,068,829号は、ファージライブラリーを調製する方法を開示し、それぞれは参照することにより本願明細書に組み込まれる。ファージディスプレイ技術は、小ペプチドがそれらの表面上に発現できるように、バクテリオファージを遺伝子操作することを含む(Smith and Scott,1985,Science 228:1315−1317;Smith and Scott,1993,Meth.Enzymo 1.21:228−257)。
特定の実施形態において、有益な標的部分はアプタマーであってもよい。アプタマーの結合特性を構成および決定する方法は、当技術分野において既知である。例えば、かかる技術は、米国特許第5,582,981号、第5,595,877号および第5,637,459号に記述され、それぞれ参照することにより本願明細書に組み込まれる。特定の関心標的に結合するアプタマーの調製および選別方法は、例えば、米国特許第5,475,096号および米国特許第5,270,163号において既知であり、それぞれ参照することにより本願明細書に組み込まれる。
好適な結合手順は、中性または酸性pHで容易なチオール−マレイミド、チオール−ビニルスルホン、チオール−ブロモアセトアミド、またはチオール−ヨードアセトアミド反応に基づく。これは、活性エステルを使用する場合に必要とされるような結合に対するより高いpH条件の必要性を取り除く。
10−ヒドロキシ−CPT(0.2307g)を、下記の実施例2の与えられる条件下において、ジ−tert−ブチル二炭酸およびピリジンと反応させ、10−BOC−O−CPT誘導体を得た。後者(24.7mg)を無水ジクロロメタン中の4−ジメチルアミノピリジン(20.7mg)およびトリホスゲン(5.9mg)で処置し、そのように形成されたクロロギ酸を、短時間、通常5分間、等モル量のMC−Phe−Lys(MMT)−PABOHと反応させた。メタノール−ジクロロメタン勾配を使用したシリカゲル(230〜400メッシュ)上のクロマトグラフィーにより、いくらかの未反応出発物質との厳密な溶離混合物としての表題生成物の単離がもたらされた。質量スペクトルは、生成物の形成を明確に示した(m/e1376でのM+Na)。反応時間1−7/4分間の薄層クロマトグラフィーによる経時的解析と、最適化された条件で得られた生成物のペクトルデータ(m/e982での強MH+)とによって示されるように、単に2から5分間のTFA媒介の開裂は必要なBOC除去生成物を与えた。30分間の延長TFA脱保護は、20−炭酸塩結合の開裂ももたらし、10−OH−CPTを形成した。故に、20−炭存在下、短時間TFA反応による10−BOCの選択的な開裂を達成した。
の調製
SN−38(0.5114g、1.305ミリモル)を無水ピリジン(8mL)中のジ−tert−ブチル二炭酸(0.307g)と18時間外気温で反応させた。溶媒を蒸発させ、メタノール−ジクロロメタン勾配を使用して、シリカゲル(230−400メッシュ)上のフラッシュクロマトグラフィーで粗材料を精製し、0.55gの淡黄色固形生成物としてBOC−SN−38であるSN−38の10−t−ブチルオキシルカルボニル誘導体を得た。この材料(0.0358g)を無水ジクロロメタン(1.5mL)に溶解し、4−N,N−ジメチルアミノピリジン(DMAP、26.6mg)およびトリホスゲン(0.0095mg)で7分間処置し、BOC−SN−38−20−クロロギ酸である産生されたクロロギ酸をMC−Phe−Lys(MMT)−PABOHと原位置で短時間、通常5分間反応させた。次いで、メタノール−ジクロロメタン勾配を使用して、反応混合物をシリカゲル(230−400メッシュ)上のフラッシュクロマトグラフィーで精製した。収率:42.4mg。この生成物の一部(21.9mg)を、数分間、通常5分未満、トリフルオロ酢酸(「TFA」、1mL)、ジクロロメタン(0.25mL)、およびアニソール(0.14mL)の混合物で処置し、生成物をジエチルエーテルで沈殿させることにより単離させた。随意に、TFA処置をそれぞれ5分未満の短時間でさらに2または3回繰り返した。逆相HPLCによる解析(C18カラム、勾配溶離で使用した溶液Aは、3mL/分で10分で溶液Bに変わり、その後5分間100%のBを維持した。Aは、pH4.43の0.3%含水酢酸アンモニウムであり、Bは、pH4.43の9:1CH3CN/0.3%含水酢酸アンモニウムである)は、表題化合物のためにピーク10.796分(360nmでの吸光度)を示し、これは、通常76%〜83%で、残部の殆どはSN−38であった。さらなる精製は、残部がSN−38である、約90%の純度を有する生成物をもたらした。これらのレベルの純度を有する最終的な生成物を抗体への結合に使用する。エレクトロスプレー質量スペクトルは、表題化合物に対し、陰イオンモード(M−H)においてm/e1009で質量ピークを示し、陽イオンモードにおいてm/e1011で強いピークを示した。
市販のヘテロ2官能性の架橋剤、マレイミド−PEG12−NHSエステル(0040、式3を参照)を使用して、DMF中の中間体Phe−Lys(MMT)−PABOHおよびジイソプロピルエチルアミンを反応させることによって、マレイミド−PEG12部分を、実施例2のマレイミドカプロイルに置換し、架橋剤マレイミド−PEG12−Phe−Lys(MMT)−PABOHを産生した。ここで、PEG12は、12モノマー単位を含有する定義されたPEG基質であり、MAb結合条件下において薬物−リンカー中間体の溶解度を増強させるために使用した。架橋剤であるマレイミド−PEG12−Phe−Lys(MMT)−PABOHを、実施例2のBOC−SN−38 20−クロロギ酸と反応させた。実験条件および精製は、実施例2で詳述したものと類似した。生成物をTFA媒介の脱保護にさらし、表題生成物を得た。エレクトロスプレー質量スペクトルは、表題化合物に対し、陰イオンモードにおいてm/e1602(M+Cl)および1681(M+TFA)でピークを示し、陽イオンモードにおいてm/e1568(M+H)で強いピークを示した。
(CL−AA−S−38)の調製
生成物の一般式を式13に示す。BOC−グリシン、MMT−グリシン、BOC−サルコシン、またはBOC−アラニンを使用し、実施例2のBOC−SN−38を20−ヒドロキシル位置でエステル化した。基本手順は、触媒量の4−ジメチルアミノピリジンが存在下で、BOC−SN−38を、約20%のモル過剰のそれぞれのアミンで保護されたアミノ酸(amine−protected amino acid:AA)および無水ジクロロメタン中のジシクロヘキシルカルボジイミドと外気温で一晩反応させることを含んだ。フラッシュクロマトグラフィーで精製したエステル化生成物をジクロロ酢酸(dichloro acetic acid:DCA)で処置し、単にMMT基を除去、またはTFAで処置し、エステルのアミン末端およびSN−38上のBOC基上の両方の保護基を除去した。次いで、TFAまたはDCA塩として存在するアミン末端を有する、および保護されたまたは遊離10−ヒドロキシルを有するC−20エステルを含有するSN−38誘導体を、10%モル過剰のMC−Phe−Lys(MMT)−PABOCOO−PNP(記述は、実施例の一般項目を参照)およびDMF中のDIEAと反応させた。フラッシュクロマトグラフィーでの精製は、それぞれの場合において最後から2番目の中間体を提供し、TFAと反応させて表題材料を得た。表題化合物:C−20でグリシン酸塩を有する(構造中R1=R2=H):質量スペクトル、m/e1065でのM−H、C−20でサルコシネートを有する(構造中R1=メチル、R2=H):質量スペクトル、m/e1081でのM+H(陽イオンモード)およびm/e1079でのM−H(陰イオンモード);C−20でアラネートを有する(構造中R1=H、R2=メチル):質量スペクトル、陽および陰イオンモードそれぞれにおいてm/e1662でのM+Na、m/e1638でのM−H。
(CLS−SN−38)の調製
ジイソプロピルエチルアミン(diisopropylethyamine:DIEA)の2.5等価物を含有する無水ジクロロメタン中のMMTクロライドのモル等価物と後者を反応させることによって、ステップ2においてチオプロピオン酸からサクシニミジルS−メトキシトリチルチオプロピオン酸を調製したが、MMTとはモノメトキシトリチルの略称である。薄層クロマトグラフィーで監視された、反応の終了後、反応混合物を酢酸エチルで希釈し、水および飽和塩化ナトリウムで洗浄した。フラッシュクロマトグラフィーで精製された生成物を、等モル量のN−ヒドロキシサクシニミドおよびDMF中のジシクロヘキシルカルボジイミドを有するそのサクシニミジル エステルに変換した。沈殿したDCC−ウレアをろ過し、濾液を、等モル量の反応物およびDIEAを使用してDMF中の中間体Phe−Lys(MMT)−PABOH(実施例の一般項目を参照)との反応に使用した。必要な生成物をフラッシュクロマトグラフィーで単離した。生成物MMT−S−(CH2)2−CO−Phe−Lys(MMT)−PABOHを、84.7%の収率で得た。そのエレクトロスプレー質量スペクトルは、その構造に対して予測されたように、陽イオンモードにおいて、m/e1032でのM+Hおよびm/e1054での強いM+Na、ならびに陰イオンモードにおいて、m/e1030でのM−Hピークを示した。この材料をBOC−SN−38−(20)−クロロギ酸と反応させ、生成物を実施例2に記述したものと同様の方法で精製し、生成物MMT−S−(CH2)2−CO−Phe−Lys−PABOCO−(20)−SN−38−(l0)−BOCを得た。その質量スペクトルは構造と一致した(m/e1572でのM+Na、m/e1548でのM−H、m/e1663でのM+TFA)。最後に、実施例2に記述したようなTFAとの短時間処置は、副生成物として約5%のSN−38を有するHPLCによって>87%の純度の表題生成物を提供した。その質量スペクトルは、陽および陰イオンモードそれぞれにおいて、m/e906でのM+Hおよびm/e904でのM−Hを示した。
の鎖間領域への付着
抗CD22ヒト化MAb、hLL2、抗CD74ヒト化MAb、hLL1、抗EGP−1ヒト化MAb、hRS7、および抗IGFR1キメラMAb、cR1をこれらの研究に使用した。5.4mM EDTAを含有するpH7.4の40mM PBS中のジチオスレイトール(DTT)(50から70倍モル過剰で使用) で、各抗体を45分間37℃(浴槽)で還元した。還元された生成物を、遠心分離したサイズ排除カラムで精製し、75mM酢酸ナトリウム−1mM EDTAで緩衝液交換を行った。チオール含有量をエルマンのアッセイで決定し、6.5から8.5SH/IgGの範囲であった。還元したMAbを実施例2の12.5から22.5倍モル過剰のCL−SN−38または実施例3のPEG−CL−SN−38、あるいは、実施例4のCL−AA−SN−38と、5〜10%v/vのDMFを共溶媒として使用して反応させ、外気温で20分間インキュベートした。複合体を遠心分離したSEC、疎水性カラムの通過、および最後に限外ろ過ダイアフィルトレーションで精製した。生成物を、SN−38に対して366nmの吸収度で分析し、基準値と相関させ、一方、タンパク質濃度は、この波長でSN−38吸光度の溢流に対して採取された280nmの吸光度から推定した。この方法により、SN−38/MAb置換率を決定した。精製した複合体を、ガラス製薬瓶内に凍結乾燥製剤として保管し、真空下でふたをして、−20℃のフリーザー内に保管した。SN−38モル置換率(molar substitution ratio:MSR)をこれらの一部の複合体に対して取得し、これは表2に示すように、結合モードを考慮して一般的に5〜8の範囲である。
のリジン側鎖への付着
抗CD22ヒト化MAb、hLL2および抗EGP−1ヒト化MAb、hRS7を、これらの研究において検討した。pH7.4のPBS中の7から10倍モル過剰のスルホ−SMCCによって、40分間4℃で、各抗体を誘導体化した。遠心分離したSECおよび5mg/mLに希釈したpH6.5の75mM 酢酸ナトリウム−1mM EDTAによる緩衝液交換で、各例における複合体を精製し、酢酸でpHをpH5に調節した。次いで、マレイミド付加の抗体を、約10%v/vで共溶媒として使用したDMFで、実施例5のCLS−SN−38の僅かなモル過剰(抗体上の各マレイミド基に対して約1.15等価)と反応させた。外気温で15分後、複合体を精製し、SN−38モル置換を実施例6の複合体に関して記述したように決定した。薬物がMAbのリジンアミノ基に付着されるこれらの複合体の一部に対して得られたSN−38置換を表2(イタリック体のもの全体)に示す。代替調剤は一般的に実施例6の複合体のものよりも少ない。
Raji B−リンパ腫細胞をAmerican Type Culture Collection(ATCC、Rockville、MD)から得た。SN−38複合体をジスルフィド還元の抗CD74MAb、hLL1、または、陰性対照MAb抗EGP−1 MAb、hRS7(対照として使用)から調製し、以下の組成を有した。hLL1(またはhRS7)−[サクシニミドカプロイル(SCと略す)]−CL−SN−38およびhLL1(またはhRS7)−[サクシニミド−PEG12(S−PEG12と略す)J−CL−SN−38、ここで、CLは、p−アミノベンジル由来のPABを有するPhe−Lys−PABOCO部分である。凍結乾燥された複合体を生理食塩水で5mg/mLに再構成した。他の対照は未修飾hLL1およびSN−38(DMSO溶液)を含んだ。細胞を収集し、96ウェルプレート(25,000細胞/ウェル)内に蒔いた。20μLの連続的に希釈した複合体溶液または対照 を、SN−38と等価の最終濃度0−7μMの最終濃度になるまで各ウェルに加え、37℃でインキュベートした。培地を4時間または48時間で廃棄し、培地を洗浄し、その後新鮮な培地を追加した。インキュベーションの合計時間は48時間であった。MTS色素還元アッセイを使用して用量反応曲線を決定し、PrismPad(登録商標)Software(Advanced Graphics Software、Encinitas、CA)を使用して効果的なEC50濃度を決定した。下記の表3は、hLL1複合体による特異的細胞傷害性を示す。
評価した複合体は、抗CD74MAb、hLL1に由来し、hLL1−[サクシニミドカプロイル(SCと略す)]−CL−SN−38およびhLL1−[サクシニミド−PEG12(S−PEG12と略す)]−CL−SN−38の構造を有し、CLは、Phe−Lys−PABOCO部分であって、 PABはp−アミノベンジルに由来し、PheおよびLyはそれぞれ、アミノ酸フェニルアラニンおよびリジンである。8週齢のメスSCIDマウスに2.5x106Raji細胞を静脈内注射によって接種した。翌日、500μgの検査薬または未修飾hLL1抗体を5つのマウスの群に静脈内注射した。後肢麻痺および/または20%を超える体重減少が兆候である疾患進行について、動物を毎日観察した。未修飾抗体で処理したものの56日の生存期間中央値と比べて、どちらかの複合体で処理したマウスは125日の生存期間中央値を超えて生存している。さらに、hLL1−[SC−CL]−SN−38(「hLL1−CL−SN−38」)は、抗体単独の対照よりも有意に良好だった(P<0.0064)。これらのデータは、治療的効果がこれらの複合体で得られたことを示した。
Daudi全身性リンパ腫の体内療法
8週齢メスSCIDマウスに1.5x107Daudi細胞を静脈内注射により接種した。翌日、100、200、または500μgのhLL2−SN−38を注射し、その後、3週間の間週2回および第4週目に1回注射した。対照は、未処置マウスおよび未修飾hLL2の等用量を受け取るものから成った。1群当り8匹の動物を使用した。疾患進行の兆候である動物の後肢麻痺および/または20%を超える体重減少について毎日観察した。500μg用量、200μg用量、および100μg用量群の生存期間中央値、および括弧内に示される各相当する裸hLL2用量群生存期間中央値は、それぞれ98日(49.5日)、92.5日(54.5日)、74.5日(42日)であった。未処置の動物は、27日目に死んだ。最も高い用量グループでは、8匹のマウス中7匹が生存し、生存期間中央値は98日目にまだ到達していなかった。これらのデータは、抗CD22hLL2−SN−38複合体の治療効果を示した。
P4/D10などのHIV外被タンパク質gpl20、抗gp120抗体に標的化されたMAbを、実施例5に記述した条件を使用して還元し、還元したMAbを実施例1に対して記述したような20倍モル過剰の薬物−リンカーCL−SN−38と反応させる。抗体当り約8薬物分子の置換を有する抗gp120−SN−38複合体を得る。非感染Jurkat T細胞および完全にHIB感染したJurkat T細胞の種々の混合物を使用し(99.8:2から95:5の比率で)、複合体、非特異的hRS7−CL−SN38複合体対照、裸抗体、およびHIV陰性血清の100から0.00001μg/mLまでの連続希釈法で処置し、該複合体での体外HIV抑制検査を行う。そのように処置した細胞を、RPMI1640培地内で7日間37℃でインキュベートし、次いで、関連するELISAテストによってHIV抑制を検査する。この実験は、特異的薬物複合体によるHIVの細胞間伝播の強い特異的な抑制を示す。特異的および非特異的SN−38複合体とともに同種HIV感染の細胞を用いて、マウスに投与することで体内有効性をテストする。このため、免疫抱合体投与と同時に、HIV−1/MuLV偽型ウイルスに感染した一次マウスの脾細胞をマウスの群に腹腔内移動させる。腹膜細胞を10日後に収集する。対照マウスにおいて感染性HIVの存在が示される一方、100μg未満の抗gp120−SN−38複合体で処置したマウスにおいて感染性HIVは検出されない。対照複合体処置したマウスに保護は見られない。
Claims (65)
- カンプトテシン薬物、および式TM−[L]−CPTの標的部分(targeting moiety:TM)の複合体であって、TMは、疾患標的部分であり、CPTは、カンプトテシンまたはその類似体であり、Lは、X−Y−Z型のリンカー系であって、Xは疾患標的部分結合部分であり、Yはリソソーム性に開裂可能なポリペプチドであり、ZはCPT薬物に連結される4−アミノベンジルオキシ部分である、複合体。
- 前記疾患標的部分は、モノクローナル抗体(MAb)である、請求項1に記載の複合体。
- 前記抗体は、キメラ抗体である、請求項2に記載の複合体。
- 前記抗体は、ヒト化抗体である、請求項2に記載の複合体。
- 前記抗体は、ヒト抗体である、請求項2に記載の複合体。
- 前記標的部分は、2重特異性または多特異性抗体である、請求項1に記載の複合体。
- 前記標的部分は、3価の2重特異性抗体複合体である、請求項6に記載の複合体。
- 前記CPTは、CPT、10−ヒドロキシカンプトテシン、SN−38、トポテカン、ルルトテカン、9−アミノカンプトテシン、9−ニトロカンプトテシン、およびその誘導体から成る群から選択される、請求項1に記載の複合体。
- 前記CPTはSN−38である、請求項1に記載の複合体。
- 前記開裂可能なポリペプチドは、フェニルアラニン−リジン、バリン−シトルリン、アラニン−ロイシン、ロイシン−アラニン−ロイシン、およびアラニン−ロイシン−アラニン−ロイシンから成る群から選択される、請求項1に記載の複合体。
- Zは、CPTの20−ヒドロキシ基とアミノ酸またはポリペプチドとのエステル結合のアミン末端に連結される、請求項1に記載の複合体。
- 前記エステル結合は、グリシン、アラニン、およびサルコシンを含む群から選択されるアミノ酸に由来する、請求項11に記載の複合体。
- 前記リンカー系Lは、ポリエチレングリコール(PEG)により置換され、抗体複合基において終結する、請求項11に記載の複合体。
- Zは、前記CPTの20−ヒドロキシ基へ炭酸塩結合を介して連結する、請求項1に記載の複合体。
- 前記抗体連結基Xは、チオール反応性であり、マレイミド、ビニルスルホン、ブロモアセトアミド、およびヨードアセトアミドから成る群から選択される、請求項2に記載の複合体。
- 前記抗体連結基Xは、前記抗体上のチオール反応性残基と反応するチオール基であり、前記チオール反応性残基は、マレイミド、ビニルスルホン、ブロモアセトアミド、およびヨードアセトアミドから成る群から選択される、請求項2に記載の複合体。
- 前記リンカーは、Xの構成要素として水溶性化ポリエチレングリコール(PEG)をさらに備え、XおよびY間の結合を構成する、請求項1に記載の複合体。
- 前記PEGは、大きさが最大5KDであり、好ましくは1〜30モノマー単位を有する定義されたPEGを含有し、より好ましくは1〜12モノマー単位を有する定義されたPEGを含有する、請求項13に記載の複合体。
- 前記PEGは、大きさが最大5KDであり、好ましくは1〜30モノマー単位を有する定義されたPEGを含有し、より好ましくは1〜12モノマー単位を有する定義されたPEGを含有する、請求項17に記載の複合体。
- 請求項1に記載の複合体を生成する工程であって、前記リンカーは、前記CPT薬物に最初に結合され、それによってCTP薬物−リンカー複合体を生成し、その後、前記CTP薬物−リンカー複合体は疾患標的部分に結合される、工程。
- CTP薬物−リンカー調製は、10−ヒドロキシル基を含有するCPT類似体の10−ヒドロキシル保護基の選択的脱保護を含み、 CPTの20−ヒドロキシル基を介する前記リンカーへのCPTの結合を本質的に影響されない状態に維持する、請求項20に記載の工程。
- 前記10−ヒドロキシル保護基は、tert−ブチルオキシカルボニルである、請求項21に記載の工程。
- 前記CPTはSN−38である、請求項21に記載の工程。
- 前記CTP薬物−リンカーは、モノクローナル抗体またはフラグメントへの結合前に精製されない、請求項21に記載の工程。
- 前記疾患標的部分は、モノクローナル抗体である、請求項20に記載の工程。
- 前記抗体は、1から12CPT部分の間に付着される、請求項2に記載の複合体。
- 前記MAbは、マウス、キメラ、霊長類化、ヒト化、またはヒトモノクローナル抗体であり、前記抗体は、無傷、フラグメント(Fab、Fab’、F(ab)2、F(ab’)2)、またはサブ−フラグメント(単鎖コンストラクト)の形態である、請求項2に記載の複合体。
- 前記MAbは、キメラ抗体である、請求項27に記載の複合体。
- 前記MAbは、ヒト化抗体である、請求項27に記載の複合体。
- 前記MAbは、ヒト抗体である、請求項27に記載の複合体。
- 前記MAbは、多特異性であり、標的細胞または病原体上に含有される少なくとも2つの異なる抗原またはエピトープを標的とする多数の結合アームを有し、1つ以上の特異的標的アームは、CPTに結合される、請求項2に記載の複合体。
- 前記多特異性MAbは、LLl、LL2、hA20、1F5、L243、RS7、PAM−4、MN−14、MN−15、Mu−9、L19、G250、J591、CC49およびImmu31から成る群から選択される1つ以上の抗体を含む2重特異性および/または2価抗体構成である、請求項31に記載の複合体。
- 前記CPTはSN−38である、請求項31に記載の複合体。
- 前記MAbは、癌または悪性細胞、感染性の生物、自己免疫疾患、循環器疾患、または神経系疾患と関連する抗原または抗原のエピトープと反応する、請求項2に記載の複合体。
- 前記癌細胞は、造血器腫瘍、癌腫、肉腫、黒色腫または神経膠腫からの細胞である、請求項34に記載の複合体。
- 前記MAbは、B細胞系列抗原、T細胞抗原、骨髄細胞系列抗原またはHLA−DR抗原に結合する、請求項34に記載の複合体。
- 癌抗原またはエピトープに対して標的化された前記MAbは、CD20抗原に対するA20である、請求項34に記載の複合体。
- 前記MAbは、内在化抗体である、請求項34に記載の複合体。
- 前記MAbは、CD22抗原に対するLL2である、請求項38に記載の複合体。
- 前記MAbは、EGP−1抗原に対するRS7である、請求項38に記載の複合体。
- 前記MAbは、CD74抗原に対するLLlである、請求項38に記載の複合体。
- 前記感染性の生物は、細菌、ウイルス、真菌、微生物または寄生虫である、請求項34に記載の複合体。
- 前記感染性の生物は、AIDSの原因となるヒト免疫不全ウイルス(HIV)、結核菌、ストレプトコッカスアガラクチア、メチシリン耐性黄色ブドウ球菌、在郷軍人病菌、化膿性連鎖球菌、大腸菌、淋菌、髄膜炎菌、肺炎球菌菌種、インフルエンザ菌B、梅毒トレポネーマ、ライム病スピロヘータ、ウエストナイルウイルス、緑膿菌、らい菌、ウシ流産菌、狂犬病ウイルス、インフルエンザウイルス、サイトメガロウイルス、単純ヘルペスウイルスI、単純ヘルペスウイルスII、ヒト血清パルボ様ウイルス、RSウイルス、水痘帯状疱疹ウイルス、B型肝炎ウイルス、麻疹ウイルス、アデノウイルス、ヒトT細胞白血病ウイルス、エプスタインバーウイルス、マウス白血病ウイルス、ムンプスウイルス、水疱性口内炎ウイルス、シンドビスウイルス、リンパ球性脈絡髄膜炎ウイルス、疣ウイルス、ブルータングウイルス、センダイウイルス、ネコ白血病ウイルス、レオウイルス、ポリオウイルス、シミアンウイルス40、マウス乳癌ウイルス、デングウイルス、風疹ウイルス、熱帯熱マラリア原虫、三日熱マラリア原虫、トキソプラズマ原虫、ランゲルトリパノソーマ、クルーズトリパノソーマ、ローデシアトリパノソーマ、ブルセイトリパノソーマ、マンソン住血吸虫、日本住血吸虫、ウシバベシア、アイメリアテネラ、回旋糸状虫、熱帯リーシュマニア、旋毛虫、タイレリアパルバ、胞状条虫、羊条虫、無鉤条虫、単包条虫、有線条虫属、マイコプラズマ アルスリチジス、マイコプラズマ ハイオリニス、マイコプラズマ オラーレ、マイコプラズマ アルギニニ、アコレプラズマ レイドロウイ、マイコプラズマ サリバリウム、および肺炎マイコプラズマから成る群から選択される、請求項34に記載の複合体。
- 前記自己免疫疾患は、免疫性の血小板減、皮膚筋炎、シェーグレン症候群、多発性硬化症、シデナム舞踏病、重症筋無力症、全身性エリテマトーデス、ループス腎炎、リウマチ熱、関節リウマチ、多腺性症候群、類天疱瘡、糖尿病、ヘノッホシェーンライン紫斑病、連鎖球菌感染後腎炎、結節性紅斑、高安動脈炎、アジソン病、関節リウマチ、サルコイドーシス、潰瘍性大腸炎、多形性紅斑、IgA腎症、結節性多発動脈炎、強直性脊椎炎、グッドパスチャー症候群、閉塞性血栓血管炎、原発性胆汁性肝硬変、橋本甲状腺炎、甲状腺中毒症、強皮症、慢性活動性肝炎、多発性筋炎/皮膚筋炎、多発性軟骨炎、尋常性天疱瘡、ウェゲナー肉芽腫症、膜性腎症、筋萎縮性側索硬化症、脊髄癆、巨細胞性動脈炎/多発性筋痛、悪性貧血、急速進行性糸球体腎炎線維化肺胞炎、および若年性糖尿病から成る群から選択される、請求項34に記載の複合体。
- 前記循環器疾患は、心筋梗塞、虚血性心疾患、動脈硬化巣、フィブリン塊、塞栓、またはそれらの組み合わせを含む、請求項34に記載の複合体。
- 前記抗体は、神経系疾患と関連する抗原を特異的に結合し、前記抗原は、アミロイドまたはβアミロイドを含む、請求項34に記載の複合体。
- 前記MAbは、CD74、CD22、上皮糖タンパク質−1、癌胎児抗原(CEAまたはCD66e)、結腸特異的原−p、αフェトプロテイン、CC49、前立腺特異的膜抗原、カルボニックアンヒドラーゼIX、HER−2/neu、上皮成長因子受容体(ErbBl)、ErbB2、ErbB3、ILGF、BrE3、CD19、CD20、CD21、CD23、CD33、CD45、CD74、CD80、VEGF、ED−Bフィブロネクチン、PlGF、他の腫瘍血管新生抗原、MUCl、MUC2、MUC3、MUC4、ガングリオシド、HCG、EGP−2、CD37、HLA−DR、CD30、Ia、A3、A33、Ep−CAM、KS−I、Le(y)、SlOO、PSA、テネイシン、葉酸受容体、トーマス−フリードライヒ抗原、腫瘍壊死抗原、Ga733、IL−2、IL−6、TlOl、MAGE、遊走阻止因子(migration inhibition factor:MIF)、L243により結合される抗原、PAM4により結合される抗原、CD66a(BGP)、CD66b(CGM6)、66CDc(NCA)、66CDd(CGMl)、TACおよびそれらの組み合わせから成る群から選択される抗原に結合する、請求項2に記載の複合体。
- 前記MAbは、LLl、LL2、RFB4、hA20、1F5、L243、RS7、PAM−4、MN−14、MN−15、Mu−9、AFP−31、L19、G250、J591、CC49、L243、PAM4およびImmu31から成る群から選択される、請求項2に記載の複合体。
- 前記複合体は、非経口投与に適した形態である、請求項2に記載の複合体。
- 前記モノクローナル抗体は、複合多特異性抗体の一部である、請求項2に記載の複合体。
- 前記複合抗体は、CD74、CD22、上皮糖タンパク質−1、癌胎児抗原(CEAまたはCD66e)、結腸特異的抗原−p、αフェトプロテイン、CC49、前立腺特異的膜抗原、カルボニックアンヒドラーゼIX、HER−2/neu、BrE3、CD19、CD20、CD21、CD23、CD33、CD45、CD74、CD80、VEGF、EGF受容体(ErbBl)、ErbB2、ErbB3、PlGF、VEGF、ED−Bフィブロネクチン、MUCl、MUC2、MUC3、MUC4、ILGF、ガングリオシド、HCG、EGP−2、CD37、HLA−DR、CD30、Ia、A3、A33、Ep−CAM、KS−I、Le(y)、SlOO、PSA、テネイシン、葉酸受容体、トーマス−フリードライヒ抗原、腫瘍壊死抗原、腫瘍血管新生抗原、MIF、Ga733、IL−2、IL−6、T101、MAGE、L243により結合される抗原、PAM4により結合される抗原、CD66a(BGP)、CD66b(CGM6)、66CDc(NCA)、66CDd(CGMl)およびTACから成る群から選択される2つ以上の抗原に結合する、請求項50に記載の複合体。
- 前記複合抗体は、CD20およびCD22に結合する、請求項50に記載の複合体。
- 前記複合抗体は、EGP−1のための少なくとも1つの結合部位を含有する、請求項50に記載の複合体。
- 前記複合抗体は、CD74のための少なくとも1つの結合部位を含有する、請求項50に記載の複合体。
- 前記標的部分は、融合タンパク質である、請求項1に記載の複合体。
- 前記融合タンパク質は、抗体または抗体フラグメントを含む、請求項55に記載の複合体。
- 第2の融合タンパク質、抗体または抗体フラグメントをさらに含む、請求項56に記載の複合体。
- 第3の融合タンパク質、抗体または抗体フラグメントをさらに含む、請求項57に記載の複合体。
- 前記第2の融合タンパク質、抗体または抗体フラグメントはまた、1つ以上のCPT部分に連結される、請求項57に記載の複合体。
- 前記第3の融合タンパク質、抗体または抗体フラグメントはまた、1つ以上のCPT部分に連結される、請求項58に記載の複合体。
- 前記融合タンパク質は、マウス、キメラ、霊長類化、ヒト化、またはヒトモノクローナル抗体を含み、前記抗体は、無傷、フラグメント(Fab、Fab’、F(ab)2、F(ab’)2)、またはサブ−フラグメント(単鎖コンストラクト)の形態である、請求項56に記載の複合体。
- 前記2つの融合タンパク質は、同一のエピトープ、同一の抗原上の異なるエピトープ、または異なる抗原に結合する、請求項57に記載の複合体。
- 請求項1に記載の複合体を被験者に投与するステップを含む、疾患を治療する方法。
- 前記複合体は、非結合抗体、放射性標識抗体、薬物結合抗体、毒素結合抗体、遺伝子治療、化学療法、治療用ペプチド、オリゴヌクレオチド、限局性放射線治療、手術および干渉RNA療法から成る群から選択される1つ以上の他の治療法と組み合わせて投与される、請求項63に記載の方法。
- 前記疾患は、癌、病原生物感染、自己免疫疾患、循環器疾患、または神経系疾患である、請求項63に記載の方法。
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EP3263598B1 (en) | 2020-09-09 |
US8877901B2 (en) | 2014-11-04 |
CA2647130A1 (en) | 2007-10-04 |
CA2860175C (en) | 2017-02-14 |
EP3263598A1 (en) | 2018-01-03 |
WO2007112193A3 (en) | 2008-11-20 |
EP1994057A2 (en) | 2008-11-26 |
EP1994057A4 (en) | 2013-02-27 |
AU2007230822A8 (en) | 2008-10-02 |
AU2007230822B2 (en) | 2013-06-13 |
JP5314590B2 (ja) | 2013-10-16 |
AU2007230822A1 (en) | 2007-10-04 |
CA2860175A1 (en) | 2007-10-04 |
CA2647130C (en) | 2014-12-09 |
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