JP5185813B2 - 癌免疫治療のための組成物および方法 - Google Patents
癌免疫治療のための組成物および方法 Download PDFInfo
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- JP5185813B2 JP5185813B2 JP2008509049A JP2008509049A JP5185813B2 JP 5185813 B2 JP5185813 B2 JP 5185813B2 JP 2008509049 A JP2008509049 A JP 2008509049A JP 2008509049 A JP2008509049 A JP 2008509049A JP 5185813 B2 JP5185813 B2 JP 5185813B2
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Description
本発明は、癌免疫治療のための組成物および方法を提供する。
癌免疫治療は、癌性細胞、または癌に罹患しやすくする感染に対する個体自身の免疫系を誘発および増強するための組成物の使用および方法を含む。癌ワクチンは、免疫系の引き金を引いて、抗原(例えば、典型的に、タンパク質、ペプチド、または炭水化物)に対する反応を惹起させることにより、機能する。この抗原は、非発癌性形態で体内に導入され、そして体に免疫を付与するかまたは長期間維持される「記憶」免疫反応を獲得させる。例えば、非特許文献1;非特許文献2を参照のこと。いったん、上記免疫系反応が確立されると、(例えば、癌性腫瘍の形態の)この抗原に対する免疫系の曝露は、迅速な、かつ、強い免疫反応をもたらす。
Kast,Peptide−Based Cancer Vaccines,Landes Bioscience,2000年 Sternら,Cancer Vaccines and Immunotherapy,Cambridge University Press,2000年 Waldnerら,J.Clin.Invest,2004年、113,p.990−997
本発明は、(i)1つ以上の癌抗原、癌関連ウイルス由来の1つ以上の抗原;1つ以上の抗癌抗体;および抗癌抗体に対する抗イディオタイプ抗体であり得る、少なくとも1つの免疫治療剤;ならびに、(ii)式(I)、(II)、(III)、(IV)、および(V)の1つ以上の化合物ならびに/またはその薬学的に受容可能な塩、水和物、溶媒化合物、立体異性体、アモルファス固体、もしくはその任意の組み合わせを有する、組成物に関する。
本発明は、(i)1つ以上の癌抗原、癌関連ウイルス由来の1つ以上の抗原、1つ以上の抗癌抗体、および抗癌抗体に対する抗イディオタイプ抗体から選択される、少なくとも1つの免疫治療剤、ならびに、(ii)式(I)、(II)、(III)、(IV)、および(V)から選択される1つ以上の化合物、ならびに/またはその薬学的に受容可能な塩、水和物、溶媒化合物、立体異性体、アモルファス固体、もしくはその任意の組み合わせを含む、組成物を提供する。これらの化合物は、下に詳細に説明されている。上記組成物は、治療用であり得、すなわち、上記化合物は、存在する癌を処置するため、または癌の再発を防ぐために投与され、あるいは、上記組成物は、予防用であり得、すなわち、上記化合物は、癌の発症を予防するため、または癌の発症を遅らせるために投与される。上記組成物は、治療上用いられる場合、癌患者に投与され、そして、存在する癌の増殖を防ぐことまたは遅らせることによって腫瘍を安定化させるため、腫瘍の広がりまたは転移を防ぐため、その腫瘍サイズを縮小するため、処置された癌の再発を防ぐため、または早期の処置によって殺傷されていない癌細胞を除去するために、免疫反応を誘発するように設計される。予防上の処置として用いられる組成物は、癌を有しない個体に投与され、そして、潜在的な癌細胞を標的とするためまたは癌関連ウイルスに由来する抗原を標的とするために免疫反応を誘発するように設計される。
上記薬学的組成物の1つの免疫治療剤は、1つ以上の癌抗原であり得る。癌抗原は、(a)悪性細胞上に見出され得る細胞表面抗原、(b)悪性細胞内に見出され得る抗原または(c)腫瘍細胞増殖のメディエーターである。
上記薬学的組成物の1つの免疫治療剤は、癌関連ウイルス由来の1つ以上の抗原であり得る。特定のウイルス(例えば、ヒトパピローマウイルス(HPV)、肝炎ウイルス感染、エプスタイン−バーウイルス(EBV)、ヒトヘルペスウイルス8(HHV−8)、ヒトT細胞白血病ウイルス−1(HTLV−I)およびヒトT細胞白血病ウイルス−2(HTLV−2))の感染は、種々の型の癌の発症を引き起こすことが公知である。
上記薬学的組成物の1つの免疫治療剤は、1つ以上の抗癌抗体、すなわち、1つ以上の癌抗原に対して生成された抗体であり得る。典型的な抗癌抗体としては、以下が挙げられる:
HER−2/neu陽性乳癌または転移性乳癌を処置するために用いられるトラスツズマブ(GenentechによるHERCEPTIN(登録商標));
結腸直腸癌、転移性結腸直腸癌、乳癌、転移性乳癌、非小細胞肺癌、または腎細胞癌を処置するために用いられるベバシズマブ(bevacizumab)(GenentechによるAVASTIN(登録商標));
非ホジキンリンパ腫または慢性リンパ球性白血病を処置するために用いられる、リツキシマブ(GenentechによるRITUXAN(登録商標));
乳癌、前立腺癌、非小細胞肺癌、または卵巣癌を処置するために用いられるペルツズマブ(pertuzumab)(GenentechによるOMNITARG(登録商標));
結腸直腸癌、転移性結腸直腸癌、肺癌、頭部および頸部の癌、結腸癌、乳癌、前立腺癌、胃癌、卵巣癌、脳の癌、膵臓癌、食道癌、腎細胞癌、前立腺癌、子宮頸癌、または膀胱癌を処置するために用いられ得る、セツキシマブ(cetuximab)(ImClone Systems IncorporatedによるERBITUX(登録商標));
結腸直腸癌、頭部および頸部の癌、ならびに他の潜在的な癌標的を処置するために用いられるIMC−1C11(ImClone Systems Incorporated);
非ホジキンリンパ腫(この非ホジキンリンパ腫は、形質転換を有しても有さなくてもよい、CD20陽性、濾胞性の非ホジキンリンパ腫であり得、リツキシマブ抵抗性であり、化学療法後に再発した非ホジキンリンパ腫である)を処置するために用いられるトシツモマブ(tositumomab)ならびにトシツモマブおよびヨウ素I131(Corixa CorporationによるBEXXAR(登録商標));
リンパ腫または非ホジキンリンパ腫(再発した濾胞性リンパ腫;再発もしくは治療抵抗性の低い等級の非ホジキンリンパ腫または再発もしくは治療抵抗性の濾胞性非ホジキンリンパ腫;または形質転換したB細胞非ホジキンリンパ腫が挙げられ得る)を処置するために用いられるIn111ibirtumomab tiuxetan;Y90 ibirtumomab tiuxetan;In111ibirtumomab tiuxetanおよびY90 ibirtumomab tiuxetan(Biogen IdecによるZEVALIN(登録商標));
癌(小細胞肺癌または子宮頸癌)を処置するために用いられるEMD 7200(EMD Pharmaceuticals);
SGN−30(Seattle Geneticsにより遺伝子操作された、CD30抗原に対して標的化されたモノクローナル抗体)(ホジキンリンパ腫または非ホジキンリンパ腫);SGN−15(Seattle Geneticsにより遺伝子操作された、ドキソルビシンと結合体化された、Lewisγ関連抗原に対して標的化されたモノクローナル抗体)(非小細胞肺癌);SGN−40(Seattle Geneticsによる、CD40抗原に対して標的化されたヒト化モノクローナル抗体)(多発性骨髄腫または非ホジキンリンパ腫);SGN−35(Seattle Geneticsにより遺伝子操作された、Auristatin Eと結合体化された、CD30抗原に対して標的化されたモノクローナル抗体)(非ホジキンリンパ腫);SGN−17/19(Seattle Geneticsによる、メルファランプロドラッグと結合体化された抗体および酵素を含む融合タンパク質)(メラノーマまたは転移性メラノーマ)。
抗原に対する抗体は、その抗原結合部位において血清学的に特有の構造(イディオタイプと呼ばれる)を有する。抗体は、その原型抗体に対して産生され得、抗イディオタイプ抗体の産生をもたらし得る。上記原型抗体は、Ab1と呼ばれ、上記抗イディオタイプ抗体は、Ab2と呼ばれる。上記Ab2抗体は、Ab1の抗原結合部位を認識し、従って、その元の抗原と、モチーフまたは構造類似性を共有する。Ab2における結合部位に対して惹起された抗体は、従って、その元の抗原と反応し得る。上記元の抗原が癌抗原である場合、上記抗Ab2抗体は、治療効果を有し得る。
上記薬学的組成物の投与は、送達に適切であるいくつかの経路により達成され得る。典型的な送達様式としては、非経口投与(例えば、皮下注射、経皮投与(transcutaneous)、静脈内投与、腫瘍内投与、腫瘍周囲投与、鼻内投与、眼の投与、筋肉内投与、皮内投与、腹腔内投与、肺の投与)、および非経口でない投与(例えば、経粘膜投与、経皮投与(transdermal)、吸入、膣内投与、直腸投与または経口投与)が挙げられる。
上記薬学的組成物は、被験個体における免疫反応を刺激するか誘発するかまたは増大させるための方法を提供する。本発明は、動物種(哺乳動物または鳥類種が挙げられる)に対し獣医学の用途で適用され得るが、上記被験個体は、好ましくは、ヒトである。
上記免疫治療の方法の一実施形態において、上記免疫反応はさらに、免疫刺激化合物として作用し得る化合物の投与により増大される。典型的な免疫刺激化合物としては、toll様レセプター(TLR)アゴニスト(例えば、TLR4、TLR7、TLR9)、N−アセチルムラミル−L−アラニン−D−イソグルタミン(MDP)、リポ多糖(LPS)、遺伝子改変されたLPSおよび/または分解されたLPS、ミョウバン、グルカン、コロニー刺激因子(例えば、EPO、GM−CSF、G−CSF、M−CSF、ペグ化G−CSF、SCF、IL−3、IL6、PIXY 321)、インターフェロン(例えば、γ−インターフェロン、α−インターフェロン)、インターロイキン(例えば、IL−2、IL−7、IL−12、IL−15、IL−18)、MHC クラスII結合ペプチド、サポニン(例えば、QS21)、メチル化されていないCpG配列、1−メチルトリプトファン、アルギナーゼインヒビター、シクロホスファミド、または免疫抑制機能を遮断する抗体(例えば、抗−CTLA4抗体)、ならびにその2つ以上の混合物挙げられる。典型的なTLR4アゴニストとしては、リポ多糖(LPS);E.coli LPS;およびP.gingivalis LPSが挙げられる。典型的なTLR7アゴニストとしては、イキダゾキノリン化合物(例えば、イミキモド(imiquimod)、レシキモド(resiquimod)など);およびロキソリビン(loxoribine)挙げられる。
上記薬学的組成物は、その意図された投与経路に適合するように処方され、そして、典型的に、薬学的に受容可能なキャリアを含む。本明細書中に用いられているように、用語「薬学的に受容可能なキャリア」は、薬学的投与に適合する溶媒、分散媒質、コーティング、抗菌剤および抗真菌剤、等張剤および吸収遅延剤などを含む。補助活性化合物もまた、上記組成物に組み込まれ得る。上記薬学的組成物は、従来の薬学的実施に従って、処方され得る(例えば、Remington:The Science and Practice of Pharmacy(第20版),A.R.Gennaro編集,Lippincott Williams & Wilkins, 2000 ならびに Encyclopedia of Pharmaceutical Technology,(J.Swarbrick および J.C.Boylan編集),1988−1999,Marcel Dekker,New Yorkを参照のこと)。
一実施形態において、1つ以上の免疫治療剤ならびに式(I)、(II)、(III)、(IV)、および(V)から選択される化合物は、式(I)、(II)、(III)、(IV)、および(V)から選択される化合物のアルキル部分、アミノ部分、カルボニル部分、エーテル部分、ヒドロキシル部分、ホスフェート部分、ホスホニル部分、スルホニル部分、スルフェート部分、チオエーテル部分、またはチオール部分を通じて、一緒に共有結合で結合され得る。例えば、1つ以上の免疫治療剤は、式(I)、(II)、(III)、(IV)、および(V)から選択される化合物におけるR1置換基、X1置換基および/またはY1置換基に、共有結合され得る。例えば、上記免疫治療剤は、本発明の1つ以上の化合物における−C(O)−基のカルボニル部分(例えば、C1カルボニル)またはR1置換基の−C(O)−C1−14アルキル−C(O)−基に、共有結合され得る。別の例として、上記免疫治療剤は、式(I)、(II)、(III)、(IV)、および(V)から選択される化合物のX1置換基および/またはY1置換基における窒素原子を通じて、共有結合され得る。当業者は、記載されている方法(例えば、Hoffmanら,Biol.Chem.Hoppe−Sayler,370:575−582(1989);Wiesmullerら,Vaccine,7:29−33(1989);Wiesmullerら,Int.J.Peptide Protein Res.,40:255−260(1992);Defourtら,Proc.Natl.Acad.Sci.,89:3879−3883(1992);Tohokuniら,J.Am.Chem.Soc,116:395−396(1994);Reichel,Chem.Comrnun.,2087−2088(1997);Kamitakahara,Agnew.Chem.Int.Ed.37:1524−1528(1998);Dullenkopfら,Chem.Eur.J.,5:2432−2438(1999);その開示は、参考により本明細書中に全体が援用されている)に従って、1つ以上の免疫治療剤を、式(I)、(II)、(III)、(IV)、および(V)から選択される化合物と結合することが可能である。
上記薬学的組成物は、上記免疫治療剤ならびに式(I)、(II)、(III)、(IV)、および(V)から選択される化合物ならびに/またはその薬学的に受容可能な塩、水和物、溶媒化合物、立体異性体、アモルファス固体またはその任意の組み合わせを含む。式(I)、(II)、(III)、(IV)、および(V)の化合物は、アジュバントとしておよび/または免疫刺激化合物として、これらが用いられる用途に依存して、作用し得る。
R1は、以下:(a)−C(O)−;
(b)−C(O)−C1−14アルキル−C(O)−または−C(O)−C1−14アルケニル−C(O)−;
(ここで、この−C1−14アルキル−または−C1−14アルケニル−は、ヒドロキシ、C1−6アルキル、C1−6アルコキシ、C1−6アルキルジオキシ、C1−5アルキルアミノ、カルボキシ、C1−6アルコキシカルボニル、C1−6カルバモイル、C1−6アシルアミノ、および/または(アリール)C1−6アルキルから選択される1つ以上の置換基で、必要に応じて置換され;そしてここで、この(アリール)C1−6アルキルのアリール部分は、C1−6アルキル、C1−6アルコキシ、C1−6アルキルアミノ、C1−6アルコキシアミノ、C1−6アルキルアミノ−C1−6アルコキシ、−O−C1−6アルキルアミノ−C1−6アルコキシ、−O−C1−6アルキルアミノ−C(O)−C1−6アルキル−C(O)OH、−O−C1−6アルキルアミノ−C(O)−C1−6アルキル−C(O)−C1−6アルキル、−O−C1−6アルキル−NH−C1−6アルキル−O−C1−6アルキル、−O−C1−6アルキル−NH−C(O)−C1−6アルキル−C(O)OH、および/または−O−C1−6アルキル−NH−C(O)−C1−6アルキル−C(O)−C1−6アルキルから選択される1つ以上の置換基で、必要に応じて置換される);
(c)1つ以上のヒドロキシ基および/またはアルコキシ基で必要に応じて置換されるC2〜C15の直鎖アルキル基または分岐鎖アルキル基;または
(d)−C(O)−C6−12アリール−C(O)−(ここで、このアリールは、1つ以上のヒドロキシ基、ハロ基(例えば、フルオロ基)、ニトロ基、アミノ基、C1−6アルキル基および/またはC1−6アルコキシ基で、必要に応じて置換される)であり;
aおよびbは、各々独立的に、0、1、2、3または4であり;(好ましくは2);
a’およびb’は、独立的に、2、3、4、5、6、7または8であり;(好ましくは2);
dおよびeは、各々独立的に、1、2、3、4、5または6であり;
d’およびe’は、各々独立的に、0、1、2、3または4であり;(好ましくは0、1または2);
d’’およびe’’は、各々独立的に、0、1、2、3または4であり;(好ましくは1、2、3または4);
Tは、酸素または硫黄であり;
X1、X2、Y1およびY2は、各々独立的に、無、酸素、NH、−N(C(O)C1−4アルキル)−、または−N(C1−4アルキル)−であり;
W1およびW2は、各々独立的に、カルボニル、メチレン、スルホンまたはスルホキシドであり;
R2、R3、R4、R5、R6およびR7は、各々独立的に、以下:
(a)1つ以上のオキソ基、ハロ基(好ましくはフルオロ基)、ヒドロキシ基および/またはアルコキシ基で、必要に応じて置換されるC2〜C20の直鎖アルキルまたは分岐鎖アルキル;
(b)1つ以上のオキソ基、ハロ基(好ましくはフルオロ基)、ヒドロキシ基および/またはアルコキシ基で、必要に応じて置換されるC2〜C20の直鎖アルケニルまたは分岐鎖アルケニル;
(c)1つ以上のオキソ基、ハロ基(例えば、フルオロ基)、ヒドロキシ基および/またはアルコキシ基で、必要に応じて置換されるC2〜C20の直鎖アルコキシまたは分岐鎖アルコキシ;
(d)−NH−C2−20直鎖アルキルまたは−NH−C2−20分岐鎖アルキル(ここで、このアルキル基は、1つ以上のオキソ基、ハロ基(例えば、フルオロ基)、ヒドロキシ基および/またはアルコキシ基で、必要に応じて置換される);
(e)−C(O)−C2−20直鎖アルキルもしくはアルケニルまたは−C(O)−C2−20分岐鎖アルキルもしくはアルケニル(ここで、このアルキルもしくはアルケニルは、1つ以上のオキソ基、ハロ基(例えば、フルオロ基)、ヒドロキシ基および/またはアルコキシ基で、必要に応じて置換される);
(f)
(g)
R9およびR10は、独立的に、
(i)C1〜C20の直鎖アルキルまたは分岐鎖アルキル(ここで、このアルキルは、1つ以上のハロ、オキソ、ヒドロキシおよび/またはアルコキシで、必要に応じて置換される);そして
(ii)C2〜C20の直鎖アルケニルもしくはアルキニルまたはC2〜C20の分岐鎖アルケニルもしくアルキニル(ここで、このアルケニルもしくはアルキニルは、1つ以上のハロ、オキソ、ヒドロキシおよび/またはアルコキシで、必要に応じて置換される)からなる群から選択される)であり;
G1、G2、G3、G4およびG5は、各々独立的に、酸素、メチレン、−NH−、チオール、−N(C1−4アルキル)−、−N[C(O)−C1−4アルキル]−、−NH−C(O)−、−NH−SO2−、−C(O)−O−、−C(O)−NH−、−O−C(O)−、−O−C(O)−NH−、−O−C(O)−O−、−NH−C(O)−NH−、−C(O)NH−、−C(O)N(C1−4アルキル)、アリール、および−S(O)n−であり、ここで、nは、0、1、または2であり;
あるいはG1R2、G2R4、G3R5および/またはG4R7は、共に水素原子またはヒドロキシルであり得;
Z1およびZ2は、各々独立的に、−OP(O)(OH)2、−P(O)(OH)2、−OP(O)(OR8)(OH){ここで、R8はC1−4アルキルである}、−OS(O)2OH、−S(O)2OH−、−CO2H、−OB(OH)2、−OH、−CH3、−NH2、および−N(R9)2{ここで、R9はC1−4アルキルである}から選択され;
R12は、HまたはC1−4の直鎖アルキルもしくは分岐鎖アルキルであり;そして
Mは、独立的に、水素原子および薬学的に受容可能な陽イオン{一価の陽イオンは、1つのM変数の位置を占め得、二価の陽イオンは、2つのM変数の位置を占め得る}から選択される。
ER 803022;下に示されているその薬学的に受容可能な塩(ナトリウム塩を除く)であり;および/または下に示されている1つ以上のナトリウム陽イオンは、水素原子で置換され得る:
TLRアゴニストの腹腔内投与は、ワクチンの治療効果を高める
癌ワクチン(例えば、顆粒球マクロファージコロニー刺激因子(GM−CSF)分泌腫瘍細胞)と共に腹腔内に投与する場合に、E6020の効果を決定するために、メラノーマ細胞を用いたマウスモデルを、用いた。E6020は、TLR−4(Toll様レセプター−4)アゴニストである。B6マウス(C57BL/6マウス)に、1×106個の同系B16F10マウスメラノーマ細胞を、皮下移植した。腫瘍細胞接種の3日後、これらのマウスに、(1)マウスGM−CSFを安定的に発現および分泌するように遺伝子改変されたB16F10腫瘍細胞(B16−GM−CSF細胞)1×106個を、皮下的に(s.c.)ワクチン接種したか;(2)腹腔内に(i.p.)、E6020をワクチン接種したか;または(3)s.c.のGM−CSF細胞ワクチン接種とi.p.のE6020の組み合わせで処置した(上記GM−CSF細胞ワクチン接種およびE6020ワクチン接種を、マウスの別々の部位に投与した)。これらの実験において、上記GM−CSF細胞を、接種前にγ線照射により不活性化した。これらの動物の生存を、モニタリングした。
TLRアゴニストの局所的投与は、癌ワクチンの治療効果を高める
1×106個の同系B16F10マウスメラノーマ細胞を皮下移植したB6マウスの処置におけるE6020の効果を、調べた。腫瘍が触診可能であった場合、上記マウスに、GM−CSF細胞単独、またはE6020(約3〜10μg)との組み合わせを、腫瘍内に注射した。これらの動物の生存を、モニタリングした。
MUC−1/E6020ワクチンの治療効果
炎症性腸疾患(EBD)および結果的な結腸腺癌の発症を処置するための、E6020アジュバントと一緒のMUC−Iワクチンの効果を試験するために、IL−10遺伝子を欠き、トランスジェニックヒトMUC1を発現する、遺伝子操作されたマウス系を、用いた。このようなマウスは、IBDに似た腸炎症およびその後の結腸腺癌を、自発的に発症する。これらのデータは、Beattyら、AACR Annual Meeting 2006、Washington D.C.、2006年4月4日において示され、そして刊行された。
アジュバントを伴ったEGFRvIIIの治療的効果
アジュバントが腫瘍学抗原(oncology antigen)(すなわち、動物にワクチン接種するために用いられ得る、癌に対する抗原)の効果を高め得るかどうかを決定するために、C57/BL6Jマウスを、皮下的に、E6020またはマウスGM−CSF(免疫反応をブーストさせるための癌ワクチン試験において用いられるサイトカイン)と一緒にまたはそれなしで、タンパク質キャリアキーホールリンペットヘモシアニン(KLH)に結合体化した腫瘍関連ペプチド、LEEKKGNYVVTDHC(配列番号2)(EGFRの変異体形態に由来する、EGFRvIII)で免疫した。E6020を3μg/用量で、GM−CSFを5μg/用量で、そして上記ペプチド−KLH結合体を25μg/用量で投与した。マウスを、3週間間隔で3回、免疫した。各免疫の2週間後、血清をマウスから調製し、そして、ウシ血清アルブミンに結合体化したEGFRvIIIペプチドでコーティングしたプレートにおけるELISAを用いて、EGFRvIIIペプチド−特異的抗体について試験した。表2における結果は、個々の動物からの力価として提示されている。上記力価は、0.25 OD単位でバックグラウンドを超えて観察されたシグナルにおける、最終の血清希釈率として定義されている。
Claims (13)
- 1つ以上の抗癌抗体;ならびに、
式(I)、(II)、(III)、(IV)、および(V)から選択される1つ以上の化合物ならびに/またはその薬学的に受容可能な塩、水和物、溶媒化合物、立体異性体、アモルファス固体、もしくはその任意の組み合わせを含み、
該1つ以上の抗癌抗体は、トラスツズマブであり、
該1つ以上の化合物は、ER804057および/もしくはその薬学的に受容可能な塩、水和物、溶媒化合物、立体異性体、アモルファス固体、またはそれらの任意の組み合わせである、
組成物。 - 請求項1に記載の組成物であって、さらに、1つ以上の癌抗原;癌関連ウイルス由来の1つ以上の抗原;および抗癌抗体に対する1つ以上の抗イディオタイプ抗体から選択される免疫治療剤を含む、組成物。
- 被験個体における免疫反応を刺激するための組成物であって、
該組成物は、式(I)、(II)、(III)、(IV)、および(V)から選択される1つ以上の化合物ならびに/またはその薬学的に受容可能な塩、水和物、溶媒化合物、立体異性体、アモルファス固体、もしくはその任意の組み合わせを含み、
該1つ以上の抗癌抗体は、トラスツズマブであり、
該1つ以上の化合物は、ER804057および/もしくはその薬学的に受容可能な塩、水和物、溶媒化合物、立体異性体、アモルファス固体、またはそれらの任意の組み合わせであり、
該組成物は、1つ以上の抗癌抗体と組み合わせて投与されることを特徴とする、組成物。 - 請求項3に記載の組成物であって、ここで、前記1つ以上の抗癌抗体ならびに式(I)、(II)、(III)、(IV)、および(V)から選択される前記化合物は、ほぼ同時に投与されることを特徴とする、組成物。
- 請求項3に記載の組成物であって、ここで、前記1つ以上の抗癌抗体ならびに式(I)、(II)、(III)、(IV)、および(V)から選択される前記化合物は、別々に投与されることを特徴とする、組成物。
- 請求項3に記載の組成物であって、ここで、前記1つ以上の抗癌抗体ならびに式(I)、(II)、(III)、(IV)、および(V)から選択される前記化合物は、癌を発症する危険に瀕している被験個体、癌と診断された被験個体、癌のための処置を受けている被験個体、または治療後の癌からの回復中の被験個体に投与されることを特徴とする、組成物。
- 請求項6に記載の組成物であって、ここで、前記1つ以上の抗癌抗体ならびに式(I)、(II)、(III)、(IV)、および(V)から選択される前記化合物は、癌腫瘍を除去するかまたは癌腫瘍サイズを縮小するための外科的処置、放射線治療、化学療法、および/または切除療法と組み合わせて、治療上投与されることを特徴とする、組成物。
- 請求項6に記載の組成物であって、ここで、前記1つ以上の抗癌抗体ならびに式(I)、(II)、(III)、(IV)、および(V)から選択される前記化合物は、存在する癌の増殖を防ぐことまたは遅らせることによって腫瘍を安定化するため、腫瘍の広がりまたは転移を防ぐため、腫瘍サイズを縮小するため、処置された癌の再発を防ぐため、または早期の処置によって殺されていない癌細胞を除去するために、治療上投与されることを特徴とする、組成物。
- 請求項3に記載の組成物であって、ここで、前記1つ以上の抗癌抗体ならびに式(I)、(II)、(III)、(IV)、および(V)から選択される前記化合物は、癌治療と組み合わせて投与されることを特徴とする、組成物。
- 請求項9に記載の組成物であって、ここで、前記癌治療は、樹状細胞療法、ケモカイン、サイトカイン、腫瘍壊死因子、TNF−α、化学療法剤、アデノシンアナログ、クラドリビン、ペントスタチン、スルホン酸アルキル、ブスルファン、抗腫瘍抗生物質、ブレオマイシン、ダクチノマイシン、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、ミトキサントロン、マイトマイシン、アジリジン、チオテパ、カンプトテシンアナログ、イリノテカン、トポテカン、クリプトフィシン、クリプトフィシン 52、クリプトフィシン 1、ドラスタチン、ドラスタチン 10、ドラスタチン 15、エネジン抗癌剤、エスペラミシン、カリケアミシン、ダイネミシン、ネオカルチノスタチン、ネオカルチノスタチンクロモフォア、ケダルシジン、ケダルシジンクロモフォア、C−1027クロモフォアなど、エピポドフィロトキシン、エトポシド、テニポシド、フォレートアナログ、メトトレキサート、マイタンシノイド、マイタンシノールおよびマイタンシノールアナログ、微小管薬剤、ドセタキセル、パクリタキセル、ビンブラスチン、ビンクリスチン、ビノレルビン、ナイトロジェンマスタード、クロラムブシル、シクロホスファミド、エストラムスチン、イホスファミド、メクロレタミン、メルファラン、ニトロソ尿素類、カルムスチン、ラムスチン、ストレプトキサシン、非古典的なアルキル化剤、アルトレタミン、ダカルバジン、プロカルバジン、テモゾラミド、白金錯体、カルボプラチン、シスプラチン、プリンアナログ、フルダラビン、メルカプトプリン、チオグアニン、ピリミジンアナログ、カペシタビン、シタラビン、デポサイト(depocyt)、フロクスウリジン、フルオロウラシル、ゲムシタビン、置換された尿素、ヒドロキシ尿素、抗血管新生剤、カンスタチン、トロポニン I、生物学的製剤、ZD 1839、ビルリジン、インターフェロン、抗体およびそのフラグメント、抗EGFR、抗HER−2/neu、抗KDR、IMC−C225、制吐薬、ロラゼパム、メトロクロプラミド、ドンペリドン、上皮増殖因子インヒビター、トランスホーミング増殖因子β1、抗粘膜炎薬剤、ジクロニン、リグノカイン、アゼラスチン、グルタミン、コルチコイドステロイド、アロプリノール、抗破骨薬剤、ビホスホネート、エチドロネート、パミドロネート、イバンドロネート、オステオプロテジェリン、ホルモン調節剤、抗アンドロゲン、LHRHアゴニスト、アナストロゾール、タモキシフェン、造血増殖因子、抗毒性剤、アミホスチンならびにその2つ以上の混合物である、組成物。
- 請求項3に記載の組成物であって、ここで、前記1つ以上の抗癌抗体ならびに式(I)、(II)、(III)、(IV)、および(V)から選択される前記化合物は、癌の発症を予防するためまたは癌の発症を遅らせるために、予防上、前記被験個体に投与されることを特徴とする、組成物。
- 請求項3に記載の組成物であって、さらに免疫刺激化合物と組み合わせて投与されることを特徴とする、組成物。
- 請求項12に記載の組成物であって、前記免疫刺激化合物は、toll様レセプター(TLR)アゴニスト、TLR4、TLR7、TLR9、N−アセチルムラミル−L−アラニン−D−イソグルタミン(MDP)、リポ多糖(LPS)、遺伝子改変されたLPSおよび/または分解されたLPS、ミョウバン、グルカン、コロニー刺激因子、EPO、GM−CSF、G−CSF、M−CSF、ペグ化G−CSF、SCF、IL−3、IL6、PIXY 321、インターフェロン、γ−インターフェロン、α−インターフェロン、インターロイキン、IL−2、IL−7、IL−12、IL−15、IL−18、MHC クラスII結合ペプチド、サポニン、QS21、メチル化されていないCpG配列、1−メチルトリプトファン、アルギナーゼインヒビター、シクロホスファミド、または免疫抑制機能を遮断する抗体、抗−CTLA4抗体、あるいはその2つ以上の混合物である、組成物。
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JP5539460B2 (ja) | 2014-07-02 |
CA2605749A1 (en) | 2006-11-02 |
EP1874342B1 (en) | 2018-06-06 |
US20070020232A1 (en) | 2007-01-25 |
US20140065100A1 (en) | 2014-03-06 |
JP2008539249A (ja) | 2008-11-13 |
WO2006116423A3 (en) | 2008-10-09 |
CN101355928B (zh) | 2013-05-22 |
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