JP2021529799A - 架橋ピロロベンゾジアゼピン二量体(pbd)誘導体及びその共役体 - Google Patents
架橋ピロロベンゾジアゼピン二量体(pbd)誘導体及びその共役体 Download PDFInfo
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Abstract
Description
を表す;式中、2つの原子の中央にある化学結合は、隣接する2つの原子のいずれかと連結できることを意味する。
、X、X’、Y、Y’、Z、Z’、l、l’、m、m’、n、q、q’、R1、R1’、R2、R2’、R3、R3’、R4、R4’、V、V’、U、U’、L1、L2、G、Q、E1、及びE2は、式(I)と同じ定義である。
を表す;式中、2つの原子の中央にある化学結合は、隣接する2つの原子のいずれかと連結できることを意味する。
−(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t−、−(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t−、−(Aa)r−(CR5R6)m(CR7R8)n(OCH2CH2)t−、−(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t−、−(CR5R6)m−(CR7=R8)(CR9R10)n(Aa)t(OCH2CH2)r−、−(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(OCO)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(CO)(Aa)t−(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(OCO)(Aa)t(CR9R10)n−(OCH2CH2)r−、−(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m−フェニル−(CO)(Aa)t(CR7R8)n−、−(CR5R6)m−フリル−(CO)(Aa)t(CR7R8)n−、−(CR5R6)m−オキサゾリル−(CO)(Aa)t(CR7R8)n−、−(CR5R6)m−チアゾリル−(CO)(Aa)t(CCR7R8)n−、−(CR5R6)t−チエニル−(CO)(CR7R8)n−、−(CR5R6)t−イミダゾリル−(CO)(CR7R8)n−、−(CR5R6)t−モルホリノ−(CO)(Aa)t(CR7R8)n−、−(CR5R6)t−ピペラジノ−(CO)(Aa)t(CR7R8)n−、−(CR5R6)t−N−メチルピペラジン−(CO)(Aa)t(CR7R8)n−、−(CR5R)m−(Aa)tフェニル−、−(CR5R6)m−(Aa)tフリル−、−(CR5R6)m−オキサゾリル(Aa)t−、−(CR5R6)m−チアゾリル(Aa)t−、−(CR5R6)m−チエニル(Aa)t−、−(CR5R6)m−イミダゾリル(Aa)t−、−(CR5R6)m−モルホリノ−(Aa)t−、−(CR5R6)m−ピペラジノ−(Aa)t−、−(CR5R6)m−N−メチルピペラジノ−(Aa)t−、−K(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t−、−K(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t−、−K(Aa)r(CR5R6)m(CR7R8)n(OCH2CH2)t−、−K(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t−、−K(CR5R6)m(CR7=R8)(CR9R10)n(Aa)t(OCH2CH2)r−、−K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(OCO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(OCO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m−フェニル−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)m−フリル−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)m−オキサゾリル−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)m−チアゾリル−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)t−チエニル−(CO)(CR7R8)n−、−K(CR5R6)t−イミダゾリル−(CO)(CR7R8)n−、−K(CR5R6)t−モルホリノ−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)t−ピペラジノ−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)t−N−メチルピペラジン−(CO)(Aa)t(CR7R8)n−、−K(CR5R)m−(Aa)tフェニル−、−K(CR5R6)m−(Aa)tフリル−、−K(CR5R6)m−オキサゾリル(Aa)t−、−K(CR5R6)m−チアゾリル(Aa)t−、−K(CR5R6)m−チエニル(Aa)t−、−K(CR5R6)m−イミダゾリル(Aa)t−、−K(CR5R6)m−モルホリノ−(Aa)t−、−K(CR5R6)m−ピペラジノ−(Aa)tG−、−K(CR5R6)m−N−メチルピペラジノ−(Aa)t;式中、m、Aa、m、及びnは上記の通りである;t及びrは独立して0〜100である;R3、R4、R5、R6、R7、及びR8は独立して、H;ハロゲン化物;C1〜C8アルキル;C2〜C8アリール、アルケニル、アルキニル、エーテル、エステル、アミン、又はアミドから選択され、これらは任意に、1又は複数のハロゲン化物、CN、NR1R2、CF3、OR1、アリール、複素環、S(O)R1、SO2R1、−
CO2H、−SO3H、−OR1、−CO2R1、−CONR1、−PO2R1R2、−PO3H、又はP(O)R1R2R3で置換されてもよい;KはNR1、−SS−、−C(=O)−、−C(=O)NH−、−C(=O)O−、−C=NH−O−、−C=N−NH−、−C(=O)NH−NH−、O、S、Se、B、Het(C3−C8を有する複素環式又はヘテロ芳香族環)、又は1〜20アミノ酸を含むペプチドである;
は連結部位である;X2、X3、X4、X5、又はX6は独立して、NH、NHNH;N(R3);N(R3)N(R3’);O;S;C1−C6アルキル;C2−C6ヘテロアルキル、アルキルシクロアルキル、又はヘテロシクロアルキル;C3−C8アリール、Ar−アルキル、複素環式、炭素環式、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、又はヘテロアリール;1〜8個の同一の又は異なるアミノ酸から選択される;ここで、R3及びR3’は独立して、H;C1−C8アルキル;C2−C8ヘテロアルキル、アルキルシクロアルキル、又はヘテロシクロアルキル;C3−C8アリール、Ar−アルキル、複素環式、炭素環式、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、又はヘテロアリール;又はC2−C8エステル、エーテル、又はアミド;又は式(OCH2CH2)p若しくは(OCH2CH(CH3))pを有するポリエチレンオキシ単位であり、pは、0から約5000までの整数、あるいは上記の組み合わせである。
、X、X’、Y、Y’、Z、Z’、l、l’、m、m’、n、q、q’、R1、R1’、R2、R2’、R3、R3’、R4、R4’、V、V’、U、U’、L1、L2、E1、E2、及びQは式(I)と同じである。
、X、X’、Y、Y’、Z、Z’、l、l’、m、m’、n、q、q’、R1、R1’、R2、R2’、R3、R3’、R4、R4’、V、V’、U、U’、L1、L2、G、Q、E1、及びE2は、式(I)で定義された通りである。
、X、X’、Y、Y’、Z、Z’、l、l’、m、m’、n、q、q’、R1、R1’、R2、R2’、R3、R3’、R4、R4’、V、V’、U、U’、L1、L2、E1、及びE2は、式(I)で定義された通りである。
菌抗体)、ウステキヌマブ(Ustekinumab)(別名:Stelara、抗IL−12、IL−23抗体)、バパリキシマブ(Vapaliximab)(抗AOC3(VAP−1)抗体)、ベドリズマブ(Vedolizumab)、(抗インテグリンα4β7抗体)、ベルツズマブ(抗CD20抗体)、ベパリモマブ(Vepalimomab)(抗AOC3(VAP−1))抗体)、ビシリズマブ(別名:Nuvion、抗CD3抗体)、ビタキシン(抗血管新生インテグリンavb3抗体)、ボロシキシマブ(Volociximab)(抗インテグリンα5β1)、ボツムマブ(Votumumab)(別名:HumaSPECT、抗腫瘍抗原CTAA16.88抗体)、ザルツムマブ(別名:HuMax-EGFr、(抗EGFR抗体)、ザノリムマブ(別名:HuMax-CD4、抗CD4抗体)、ジラリムマブ(Ziralimumab)(抗CD147(基本免疫グロブリン)抗体)、ゾリモマブ(zolimomab)(抗CD5抗体)、エタネルセプト(登録商標「Enbrel」)、アレファセプト(Alefacept)(登録商標「Amevive」)、アバタセプト(登録商標「Orencia」)、リロナセプト(Rilonacept)(Arcalyst)、14F7[抗IRP−2(鉄調節タンパク質2)抗体]、14G2a(Nat.Cancer Inst.から黒色腫及び固形腫瘍のための抗ガングリオシドGD2抗体)、J591(Weill Cornell Medical Schoolから前立腺癌を治療するための抗PSMA抗体、)、225.28S[黒色腫のための抗HMW−MAA(高分子量黒色腫関連抗原)抗体、Sorin Radiofarmaci S.R.L.(ミラノ、イタリア)]、COL−1(Nat. Cancer Inst.から大腸癌及び胃癌のための抗CEACAM3抗体、CGM1)、CYT−356(登録商標「Oncoltad」、前立腺癌)、HNK20(Ora Vax Inc.からRSウイルスのための)、ImmuRAIT(IMMUNOMEDICSから非ホジキンリンパ腫のための)、Lym−1(抗HLA−DR10抗体、Peregrine Pharmから腫瘍のため)、MAK−195F[Abbott/Knollから敗血症、毒素ショックのための抗TNF(腫瘍壊死因子;TNFA、TNF−α;TNFSF2)抗体]、MEDI−500[別名:T10B9、MedImmune Incから移植片対宿主病のための抗CD3抗体、TRαβ(T細胞受容体α/β)、]、RING SCAN[Neoprobe Corp.から乳癌、結腸癌及び結腸直腸癌のための抗TAG72(腫瘍関連糖タンパク質72)抗体)]、Avicidin(抗EPCAM(上皮細胞接着分子)抗体)、抗TACSTD1(腫瘍関連カルシウムシグナルトランスデューサー1)抗体、抗GA733−2(胃腸腫瘍関連タンパク質2)抗体、抗EGP−2(上皮糖タンパク質2)抗体;抗KSA抗体;KS1/4抗原;M4S;腫瘍抗原17−1A;NeoRx Corp.から結腸癌、卵巣癌、前立腺癌、及び非ホジキンリンパ腫のためのCD326;LYMPHOCIDE、スマートID10、Oncolym、Allomune、抗VEGF抗体(ジェネンテック、CA);CEAcide、IMC−1C11、並びにセツキシマブ。
は、本特許の側鎖連結体を連結する部位である;X4及びY1は独立して、O、NH、NHNH、NR1、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R1)、CH2、C(O)NHNHC(O)、及びC(O)NR1である;X1はH、CH2、OH、O、C(O)、C(O)NH、C(O)N(R1)、R1、NHR1、NR1、C(O)R1、又はC(O)Oである;X5はH、CH3、F、又はClである;M1及びM2は独立して、H、Na、K、Ca、Mg、NH4、N(R1R2R3R4)である;R1、R2、R3、及びR4は式(I)に定義されている。
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、アルデヒド(例えば、グルタルアルデヒド)、ビスアジド化合物(例えば、ビス(p−アジドベンゾイル)ヘキサンジアミン)、ビス−ジアゾニウム誘導体(例えば、ビス−(p−ジアゾニウムベンゾイル)−エチレンジアミン)、ジイソシアネート(例えば、トルエン−2,6−ジイソシアネート)、 ビス−活性化フッ素系化合物(例えば、1,5−ジフルオロ−2,4−ジニトロベンゼン) 、γ−マレイミド酪酸N−スクシンイミドエステル(GMBS)、E−マレイミドカプロン酸N−ヒドロキシスクシンイミドエステル(EMCS)、5−マレイミド吉草酸NHS、HBVS、N−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−(6−アミノカプロン酸エステル)(SMCCの長鎖類縁物質(LC−SMCC))、m−マレイミドベンゾイル−N−ヒドロキシスクシンイミドエステル(MBS)、4−(4−N−マレイミドフェニル)−酪酸ヒドラジド又は塩酸塩(MPBH)、N−スクシンイミジル−3−(ブロモアセトアミド)プロピオン酸エステル(SBAP)、N−スクシンイミジル−ヨード酢酸エステル(SIA)、κ−マレイミドウンデカン酸スクシンイミドエステル(KMUA)、N−スクシンイミジル−4−(p−マレイミドフェニル)酪酸エステル(SMPB)、スクシンイミジル−6−(β−マレイミドプロピオニルアミド)−ヘキサン酸エステル(SMPH)、スクシンイミジル−(4−ビニルスルホニル)安息香酸エステル(SVSB)、ジチオビス−マレイミドエタン(DTME)、1,4−ビス−マレイミドブタン(BMB)、1,4−ビスマレイミジル−2,3−ジヒドロキシブタン(BMDB)、ビス−マレイミドヘキサン(BMH)、ビス−マレイミドエタン(BMOE)、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−カルボン酸エステル(sulfo−SMCC)、スルホスクシンイミジル(4−ヨードアセチル)アミノ安息香酸エステル(sulfo−SIAB)、m−マレイミドベンゾイル−N−ヒドロキシスルホスクシンイミドエステル(sulfo−MBS)、N−(γ−マレイミドブチルオキシ)スルホスクシンイミドエステル(sulfo−GMBS)、N−(ε−マレイミドカプロイルオキシ)スルホスクシンイミドエステル(sulfo−EMCS)、N−(κ−マレイミドウンデカノイルオキシ)スルホスクシンイミドエステル(sulfo−KMUS)、及びスルホスクシンイミジル−4−(p−マレイミドフェニル)酪酸エステル(sulfo−SMPB);又は商業的に入手可能な連結体 (例えば、Thermo Scientific’s Pierceから購入できるイミドエステル結合物:DMA(アジプイミド酸ジメチル二塩酸塩)、DMP(ピメルイミド酸ジメチル二塩酸塩)、DMS(スベルイミド酸ジメチル二塩酸塩)、DTBP(3,3−ジチオビスプロピオンイミド酸ジメチル二塩酸塩);NHS−エステル架橋アミン:BS(PEG)5(ビス(スクシンイミジル)ペンタ(エチレングリコール)、BS(PEG)9(ビス(スクシンイミジル)ノナ(エチレングリコール)、BS3(ビス[スルホスクシンイミジル]スベリン酸塩)、BSOCOES(ビス[2−(スクシンイミドオキシカルボニルオキシ)エチル]スルホン酸塩)、DSG(グルタル酸ジスクシンイミジル)、DSP(ジチオビス[スクシンイミジル]プロピオン酸エステル)、DSS(スベリン酸ジスクシンイミジル)、DST(酒石酸ジスクシンイミジル)、DTSSP(3,3’−ジチオビス[スルホスクシンイミジルプロピオン酸エステル])、EGS(エチレングリコールビス[コハク酸スクシンイミジル])、Sulfo−EGS(エチレングリコールビス(コハク酸スルホスクシンイミジル))、TSAT(トリス−スクシンイミジルアミノトリ酢酸エステル)、DFDNB(1,5−ジフルオロ−2,4−ジニトロベンゼン);アミン−スルフヒドリル架橋剤:Sulfo−SIAB(スルホスクシンイミジル(4−ヨードアセチル)アミノ安息香酸エステル)、SIAB(スクシンイミジル(4−ヨウ化アセチル)アミノ安息香酸エステル)、SBAP(スクシンイミジル−3−(ブロモアセトアミド)プロピオン酸エステル)、SIA(スクシンイミジルN−ヨウ化酢酸エステル)、Sulfo−SMCC(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−カルボン酸エステル)、SM(PEG)n(NHS−PEG−マレイミド架橋剤:スクシンイミジル−([N−マレイミドプロピオンアミド)−#エチレングリコール)エステル、#=1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、18、20、22、24)、LC−SMCC(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−(6−アミドカプロン酸エステル))、Sulfo−EMCS(N−ε−マレイミドカプロイルオキシスルホスクシンイミドエステル)、EMCS(N−ε−マレイミドカプロイルオキシスクシンイミドエステル)、Sulfo−GMBS(N−γ−マレイミドブチルオキシスルホスクシンイミドエステル)、GMBS(N−γ−マレイミドブチルオキシスクシンイミドエステル)、Sulfo−KMUS(N−κ−マレイミドウンデカノイルオキシスルホスクシンイミドエステル)、Sulfo−MBS(m−マレイミドベンゾイル−N−ヒドロキシスルホスクシンイミドエステル)、MBS(m−マレイミドベンゾイル−N−ヒドロキシスクシンイミドエステル)、Sulfo−SMPB((スルホスクシンイミジル−4−(p−マレイミドフェニル)酪酸エステル)、SMPB((スクシンイミジル−4−(p−マレイミジルフェニル)酪酸エステル)、AMAS(N−(α−マレイミドアセトキシ)スクシンイミドエステル)、BMPS(N−β−マレイミジルプロピルオキシスクシンイミドエステル)、SMPH(スクシンイミジル−6−[(β−マレイミドプロピオンアミド)ヘキサン酸エステル)、PEG12−SPDP(2−ピリジルジチオール−テトラオキサオクタトリアコンタン−N−ヒドロキシスクシンイミドエステル)、PEG4−SPDP(2−ピリジルジチオール−テトラオキサテトラデカン−N−ヒドロキシスクシンイミドエステル)、Sulfo−LC−SPDP(スルホスクシンイミジル−6−[3’−(2−ピリジルジチオ)プロピオンアミド]ヘキサン酸エステル)、LC−SPDP(スクシンイミジル−6−[3−(2−ピリジルジチオ)プロピオンアミド]ヘキサン酸エステル)、SMPT(4−スクシンイミジルオキシカルボニル−α−メチル−α(2−ピリジルジチオ)トルエン);カルボニル−アミン架橋剤:DCC(ジシクロヘキシルカルボジイミド)、EDC(1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド);光活性化架橋剤:ANB−NOS(N−5−アジド−2−ニトロベンゾイルオキシスクシンイミドエステル);NHS−ジアジリン(SDA)架橋剤:SDA(NHS−ジアジリン)(スクシンイミジル−4,4’−アジペンタノエート)、LC−SDA(NHS−LC−ジアジリン)(スクシンイミジル−6−(4,4’−アジペンタンアミド)ヘキサン酸エステル)、SDAD(NHS−SS−ジアジリン)(スクシンイミジル−2−([4,4’−アジペンタンアミド]エチル)−1,3’−ジチオプロピオン酸エステル)、Sulfo−SDA(Sulfo−NHS−ジアジリン)(スルホスクシンイミジル−4,4’−アジペンタノエート)、Sulfo−LC−SDA(Sulfo−NHS−LC−ジアジリン)(スルホスクシンイミジル−6−(4,4’−アジペンタンアミド)へキサン酸エステル)、Sulfo−SDAD(Sulfo−NHS−SS−ジアジリン)(スルホスクシンイミジル−2−([4,4’−アジペンタンアミド]エチル)−1,3’−ジチオプロピオン酸エステル)、Sulfo−SANPAH(スルホスクシンイミジル−6−(4’−アジド−2’−ニトロフェニルアミノ)−ヘキサン酸エステル)、SPB(スクシンイミジル−[4−(ソラレン−8−イルオキシ)]−酪酸エステル);スルフィドリル−炭化水素架橋剤:BMPH(N−β−マレイミジルプロピオン酸ヒドラジド−TFA)、EMCH(N−ε−マレイミジドカプロン酸ヒドラジド−TFA)、KMUH(N−κ−マレイミドウンデカン酸ヒドラジド−TFA)、MPBH(4−(4−N−マレイミドフェニル)酪酸ヒドラジド塩酸塩)、PDPH(3−(2−ピリジルジチオ)プロピオニルヒドラジド);スルフィドリル−ヒドロキシ架橋剤:PMPI(p−マレイミドフェニルイソシアネート);スルフヒドリル−スルフヒドリル架橋剤:BM(PEG)2(1,8−ビスマレイミド−ジエチレングリコール)、BM(PEG)3(1,11−ビスマレイミド−トリエチレングリコール)、BMB(1,4−ビスマレイミドブタン)、BMDB(1,4−ビスマレイミド−2,3−ジヒドロキシブタン)、BMH(ビスマレイミドヘキサン)、BMOE(ビスマレイミドエタン)、DTME(ジチオビスマレイミドエタン)、TMEA(トリス(2−マレイミドエチル)アミン)、及びSVSB(スクシンイミジル−(4−ビニルスルフォン)安息香酸エステル)が含まれる。
1614666467490_1
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Claims (20)
- 架橋PBD二量体誘導体及び式(I)の構造を有する細胞結合分子との共役体又はそれらの薬学的に許容される塩、水和物、若しくは水和塩、又はこれらの化合物若しくはそれらの光学異性体、ラセミ体、ジアステレオマー、若しくはエナンチオマーの多形結晶構造:
式中:
は任意に、単結合を表すか、又は存在しなくてもよく;
は任意に、単結合又は二重結合を表す;
V及びV’は同一の又は異なる、H、OH、−NHOH;OR5(エーテル); OCOR5(エステル); OCOOR5(炭酸塩); NR5R5’、NR5COR5’、又はNR5NR5’NR5’’(アミン);OCONR5R5’(カーバメート);NR5(C=NH)NR5’R5’’(グアニジウム); NR5CONR5’R5’’(尿素);OCSNHR5(チオカルバメート); −SH(チオール);−SR5(硫化物);SOR5スルホキシド(スルホキシド);SOOR5(スルホン); SO3、HSO3、HSO2、又はHSO3−、SO3 2−、若しくは−HSO2 −の塩(亜硫酸塩);OSO3(重亜硫酸塩);NR5SOOR5’(スルホンアミド);H2S2O5又はS2O5 2−の塩(メタ重亜硫酸塩);PO3SH3、PO2S2H2、POS3H2、PS4H2、又はPO3S3−、PO2S2 3−、POS3 3−、PS4 3−の塩(モノ−、ジ−、トリ−、及びテトラ−チオホスフェート);(R5O)2POSR5’(チオリン酸エステル);HS2O3又はS2O3 2−の塩(チオ硫酸塩);HS2O4又はS2O4 2−の塩(亜ジチオン酸);P(=S)(OR5)(S)(OH)(ホスホロジチオエート)又は陽イオンと形成されるその塩;−NR5OR5’(ヒドロキシルアミン誘導体);R5C(=O)NOH(ヒドロキサム酸)又は陽イオンと形成された塩;HOCH2SO2 −又はその塩(ホルムアルデヒドスルホキシレート);NR5COR5’(アミド);O−グリコシド;N3(アジド);CN(シアノ);X(ハロ:F、Cl、Br、又はI);C(R5)(R5’)(R5’’)(トリアルキル)、OP(O)(OR5)(NHR5’)又はOP(O)(NHR5)(NHR5’)(ホスホルアミデート(ホスホルアミド酸)、又はP(R5)(R5’)(R5’’)トリアリールホスホニウム;Aa(アミノ酸)又はNR5CO(Aa)t(ペプチド)からなる群から独立して選択され、式中、Aaはアミノ酸又はt=1〜100アミノ酸単位を含むポリペプチド;アミノ酸由来の基:α−、β−、γ−、若しくはω−アミノ酸、又は非天然アミノ酸である;式中、R5、R5’、及びR5’’は、下記に示す通りである;
l、m、q、l’、m’、及びq’は独立して、0、1、2、3、4、又は5である;
nは1〜30である;
X、X’、Y、及びY’は独立して、同一の又は異なる、N、O、S、又はCH2若しくはCHR5等のアルキル、=CH−又は=CR5−等のアルケン、又は−C(OR5)H等のエーテルを表す;
Z及びZ’は独立して、同一の又は異なるN、CH、CR5、COH、CNH2、CNHR5、又はCOR5を表すか、あるいはZ及びZ’は連結して−COR5OC−を形成し、式中、R5は、C1〜C8アルキル及びアリールから独立して選択される;
Gは、−CH2−、O、−N(R5)−、S,−P(O)(OR5)−、−P(O)(NR5R5’)−、
であり、式中、Z及びZ’は上記で定義の通りである;
U及びU’は独立して、C(O)、C(O)O、C(O)NH、C(O)N(R5)、C(=NH)、C(=NH)O、C(=NH)、NH、C(=NH)N(R5)、−C=N−、C(=S)、C(O)S、C(S)NH、C(S)N(R5)、S(O)、S(O)O、S(O)NH、S(O)(OR5)、S(O)(N(R5))、S(O2)、S(O2)O、P(O)(OR5)、P(O)(OR5)O、P(O)(NH2)、P(O)(NR5R5’)、P(O)(OR5)NH−、P(O)(OR5)NR5’−、P(O)(N(R5R5’)(N(R5)、P(S)(OR5)、P(S)(OR5)O、P(S)(NH2)、P(S)(NR5R5’)、P(S)(OR5)NH−、P(S)(OR5)NR5’−、P(S)(N(R5R5’)N(R5)、R5、R5Oである;
E1及びE2は独立して、S、R5S、C(O)S、C(O)NH、C(O)O、C(O)R5S、C(=NH)NH、C(=NH)N(R5)、C(=NH)S、−C=N−、C(=S)S、C(O)S、C(=S)NH、C(=S)N(R5)、Ar−S、NC(O)CH2S、ArC(O)CH2S、S−S、
を表す;式中、2つの原子の中央にある化学結合は、隣接する2つの原子のいずれかと連結できることを意味する;波線は接続部位を表す;
L1及びL2は独立して、放出可能連結体、又は細胞結合剤(CBA)との反応が可能である官能基を有する連結体である。L1及びL2は独立して、−Ww−(Aa)r−Tt−、−Ww−(Aa)r−Tt−Q、又はQ−Ww−(Aa)r−Ttを有し、式中、−W−は拡張ユニットである;wは0又は1である;−Aa−は独立したアミノ酸単位である;rは独立して0〜100の間の整数である;−T−はスペーサー単位であり、直鎖アルキル若しくは分岐アルキル、又はポリエチレングリコールスペーサーとすることができる;並びにtは0若しくは1〜100である;前記拡張ユニットWは独立して、自壊性スペーサー、ペプチド単位、ヒドラゾン結合、ジスルフィド結合、エステル結合、又はチオエーテル結合を含んでいてもよい;wは1、2、又は3である;前記拡張ユニット(−W−)は、存在する場合、標的結合分子単位(CBA)をアミノ酸単位と結合してもよく、あるいは、Aaが存在しない場合はTと結合する。前記拡張ユニットWは独立して、自壊性スペーサー、ペプチド単位、ヒドラゾン結合、ジスルフィド結合、エステル結合、又はチオエーテル結合を含んでいてもよい。この点について、細胞結合分子(CBA)は、拡張ユニットの官能基と結合を形成できる官能基を有する。自然に又は化学的操作を介して結合分子上に存在することができる官能基には、スルフヒドリル(−SH)、アミノ、ヒドロキシ、カルボニル、オキシアミノ、アルキニル、ヘテロ芳香族、炭水化物のアノマーヒドロキシ基、及びカルボキシルが含まれる。
更に、L1及びL2は独立して、O、NH、N、S、P、NNH、NHNH、N(R3)、N(R3)N(R3’)、CH、CO、C(O)NH、C(O)O、NHC(O)NH、NHC(O)O、式(OCH2CH2)pOR3、(OCH2CH(CH3))pOR3、NH(CH2CH2O)pR3、NH(CH2CH(CH3)O)pR3、N[(CH2CH2O)pR3][(CH2CH2O)p’R3’]、(OCH2CH2)pCOOR3、又はCH2CH2(OCH2CH2)pCOOR3のポリエチレンオキシ単位で、式中、p及びp’は独立して0から約1000、あるいはそれらの組み合わせ;C1−C8アルキル、アミド、アミン、イミン、ヒドラジン、ヒドラゾン;C2−C8ヘテロアルキル、アルキルシクロアルキル、エーテル、エステル、ヒドラゾン、尿素、セミカルバジド、カルバジド、アルコキシアミン、アルコキシルアミン、ウレタン、アミノ酸、ペプチド、アシルオキシルアミン、ヒドロキサム酸、又はヘテロシクロアルキル;C3−C8アリール、Ar−アルキル、複素環式、炭素環式、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、又はヘテロアリール;式(OCH2CH2)pOR3、又は(OCH2CH(CH3))pOR3、又はNH(CH2CH2O)pR3、NH(CH2CH(CH3)O)pR3、N[(CH2CH2O)pR3][(CH2CH2O)p’R3’]、(OCH2CH2)pCOOR3、又はCH2CH2(OCH2CH2)pCOOR3のポリエチレンオキシ単位で、式中、p及びp’は独立して、0から約5000から選択される整数、またはそれらの組み合わせである;式中、R3及びR3’は独立してH;C1−C8アルキル;C2−C8ヘテロアルキル、アルキルシクロアルキル、又はヘテロシクロアルキル;C3−C8アリール、Ar−アルキル、複素環式、炭素環式、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、又はヘテロアリール;又はC2−C8エステル、エーテル、又はアミド;又は1〜8アミノ酸;又は式(OCH2CH2)p又は(OCH2CH(CH3))pを有するポリエチレンオキシ、式中、pは0から約5000までの整数、あるいはそれらの上記の組み合わせ;又は(Aa)r、r=1−12(1〜12アミノ酸単位)で、天然又は非天然アミノ酸で構成される、又は同じ又は異なるジペプチド、トリペプチド、テトラペプチド、ペンタペプチド、ヘキサペプチド、ヘプタペプチド、オクタペプチド、ノナペプチド、デカペプチド、ウンデカペプチド、又はドデカペプチド単位;から独立して選択される;放出可能連結体という用語は、生理学的条件下で切断され得る少なくとも1つの結合:pH不安定、酸不安定、塩基不安定、酸化的に不安定、代謝的に不安定、生化学的に不安定、又は酵素に不安定な結合を含む連結体を指す;
R1、R2、R3、R4、R1’、R2’、R3’、及びR4’は独立して、同一の又は異なる、−H、置換された直鎖、分岐若しくは環状アルキル、アルケニル、又は1〜10個の炭素原子を有するアルキニル−(OCH2CH2)tR5(ポリエチレングリコール単位)、ハロゲン、NH(C=NH)NH2(グアニジニウム)、−OR5、−NR5R5’、−NO2、−NCO、−NR5COR5’、−SR5、-SOR5(スルホキシド)、−SO2R5(スルホン)、−SO3 −M+又は−SO3H(スルホン酸塩)、−OSO3 −M+又はOSO3H(硫酸塩)、−SO2NR5R5’(スルホンアミド)、CN(シアノ)、N3(アジド)、−COR5、−OCOR5、−OCONR5R5’、CF3、OR5、アリール、複素環、又はP(O)R5R5’R5’’から選択される;
R5、R5’、及びR5’’は独立して、H、C1〜C8のアルキル、アルケニル、アルキル、ヘテロアルキル、アリール、アリールアルキル、カルボニル、又は薬用塩から選択される;
更に、R1とR2又はR1’とR2’が互いに結合し、=O(ケトン)、=S、=NR、−C(=O)R、又は=CR5R5’基を含む二重結合を形成する;並びにR1とR2、R1’とR2’、R3とR4、又はR3’とR4’が結合し、C3−C12芳香族、複素環式、炭素環式、又はヘテロアリール環を形成する;
Qは細胞結合分子(CBA)、又は細胞結合剤との反応を可能にする官能基、又は細胞結合剤に付着した連結体と反応することができる官能基である。前記官能基は、チオール、アミン、ヒドラジン、アルコキシルアミノ、ジスルフィド置換基、マレイミド、ハロアセチル基、N−ヒドロキシスクシンイミドエステル、ケトン、エステル、アルデヒド、アルキニル、アルケニル、又は保護されたチオール若しくはジスルフィド基、SAc、SSR1又はSSArから選択され、式中、Arは芳香族基又はヘテロ芳香族基である。前記細胞結合剤/分子は、抗体、一本鎖抗体、標的細胞に結合する抗体フラグメント、モノクローナル抗体、一本鎖モノクローナル抗体に結合するモノクローナル抗体フラグメント、標的細胞、キメラ抗体、標的細胞に結合するキメラ抗体フラグメント、ドメイン抗体、標的細胞に結合するドメイン抗体フラグメント、抗体を模倣するアドネクチン、DARPins、リンホカイン、ホルモン、ビタミン、成長因子、コロニー刺激因子、栄養素輸送分子(トランスフェリン)、およびアルブミン、ポリマー、樹状突起、リポソーム、ナノ粒子、小胞に付着した結合ペプチド、タンパク質、又は小分子、又は(ウイルス)キャプシドから選択される;
更に、U、U’、L1、L2、L’、E1、又はE2は独立して、以下に示す成分の1以上で構成されていてもよい;
式中、原子の中央にある接続結合は、隣接する炭素原子結合のいずれかと接続できることを意味する;波線は、別の結合と接続できる部位である;
あるいは、U、U’、E1、又はE2は独立して存在しなくてもよい。 - 式(Ia)、(Ib)、(Ic)、及び(Ie)である、請求項1に記載の架橋PBD二量体誘導体及びその共役体、又はこれらの化合物の薬学的に許容される塩、水和物、水和塩、若しくは多形結晶構造、又は光学異性体、ラセミ体、ジアステレオマー若しくはエナンチオマー:
Z1はOH、NH2、OR1、NHR1、NR1R2、SR1、NHR1COX1R1、OR1COX1R1、又はN(R2)R1COX1R1であり;
X、X’、Y、Y’、Z、Z’、l、l’、m、m’、n、q、q’、R1、R1’、R2、R2’、R3、R3’、R4、R4’、V、V’、U、U’、L1、L2、E1、E2、およびQは請求項1と同じ定義である。 - 架橋されたPBD二量体誘導体並びに以下に示す式(V)(VI)、(VII)、及び(VIII)の構造を有する細胞結合分子との共役体:
式中、
式中、E3及びE’3は独立して、以下から選択される:
X1’及びX3’は独立してF、Cl、Br、I、又はLv3である;X2’はO、NH、N(R1)、又はCH2である;R3及びR5は独立して、H、R1、芳香族、ヘテロ芳香族、又は1若しくは複数のH原子が独立して、−R1、−ハロゲン、−OR1、−SR1、−NR1R2、−NO2、−S(O)R1、若しくは−COOR1に置き換えられる芳香族基であり;Lv3はメタンスルホニル(メシル)、トルエンスルホニル(トシル)、トリフルオロメチルスルホニル(トリフラート)、トリフルオロメチルスルホネート、ニトロフェノキシル、フェニルチオ、ピリジニルチオ、N−スクシンイミジルオキシル(NHS)、フェノキシルから選択される脱離基である;ジニトロフェノキシル; ペンタフルオロフェノキシル、テトラフルオロフェノキシル、トリフルオロフェノキシル、ジフルオロフェノキシル、モノフルオロフェノキシル、ペンタクロロフェノキシル、1H−イミダゾール−1−イル、クロロフェノキシル、ジクロロフェノキシル、トリクロロフェノキシル、テトラクロロフェノキシル、N−(ベンゾトリアゾール-イル)オキシル、2−エチル−5−フェニルイソキサゾリウム−イル 、フェニルオキサジアゾール−イル(ODA)、オキサジアゾール−イル、又はミツノブ反応用の縮合試薬で生成された中間分子であり、ここで、R1及びR2の定義は上記の通りである;
追加的に、E3及びE’3は独立して、−SH、−S−SCH3、−S−SAc、−SS−ピリジン、−SS−Ar(−NO2)、−S−細胞結合剤、又は以下のいずれの式から選択される:
式中、R5及びR5’は、C1〜C6アルキル、アリール、環状、シクロヘテロ、H、又はMから独立して選択され、Mは、Na、K、Ca、アンモニウム、又は他の薬学的に許容される塩である。 - 請求項1、2、4、又は6のL1及びL2は独立して、以下から構成される:
(A):6−マレイミドカプロイル(「MC」)、マレイミドプロパノイル(「MP」)、バリン−シトルリン(「val−cit」又は「vc」)、アラニン−フェニルアラニン(「ala−phe」又は「af」)、p−アミノベンジルオキシカルボニル(「PAB」)、4−チオペンタノエート(「SPP」)、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(「MCC」)、(4−アセチル)アミノ−ベンゾエート(「SIAB」)、1又は複数の繰り返し単位としてのエチレンオキシ(−CH2CH2O−)(「EO」又は「PEO」)、4−チオ−ブチレート(SPDB)、4−チオ−2−ヒドロキシスルホニル−ブチレート(2−Sulfo−SPDB)、又は1〜12個の天然若しくは非天然アミノ酸単位の同一若しくは異なる配列を有する天然若しくは非天然ペプチドである1以上の成分;
(B):自壊性成分、ペプチド単位、ヒドラゾン結合、ジスルフィド、エステル、オキシム、アミド、又はチオエーテル結合のうちの1又は複数であり、前記自壊性ユニットは、パラアミノベンジルカルバモイル(PAB)基、2−アミノイミダゾール−5−メタノール誘導体、複素環PAB類縁体、β−グルクロニド、及びo−又はp−アミノベンジルアセタールに電子的に類似した芳香族化合物を含み;又は以下の構造の1つである:
(C):以下の構造の1つを含む1又は複数の非自壊性連結体成分:
(D):少なくとも1つの結合が、生理的条件:pH不安定性、酸不安定性、アルカリ不安定性、酸化不安定性、代謝不安定性、生物化学的不安定性、又は酵素不安定性で崩壊することができる、以下の構造のいずれかを有する1又は複数の放出可能連結体:−(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t−、−(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t−、−(Aa)r−(CR5R6)m(CR7R8)n(OCH2CH2)t−、−(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t−、−(CR5R6)m−(CR7=R8)(CR9R10)n(Aa)t(OCH2CH2)r−、−(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(OCO)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(CO)(Aa)t−(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(OCO)(Aa)t(CR9R10)n−(OCH2CH2)r−、−(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−(CR5R6)m−フェニル−(CO)(Aa)t(CR7R8)n−、−(CR5R6)m−フリル−(CO)(Aa)t(CR7R8)n−、−(CR5R6)m−オキサゾリル−(CO)(Aa)t(CR7R8)n−、−(CR5R6)m−チアゾリル−(CO)(Aa)t(CCR7R8)n−、−(CR5R6)t−チエニル−(CO)(CR7R8)n−、−(CR5R6)t−イミダゾリル−(CO)(CR7R8)n−、−(CR5R6)t−モルホリノ−(CO)(Aa)t(CR7R8)n−、−(CR5R6)t−ピペラジノ−(CO)(Aa)t(CR7R8)n−、−(CR5R6)t−N−メチルピペラジン−(CO)(Aa)t(CR7R8)n−、−(CR5R)m−(Aa)tフェニル−、−(CR5R6)m−(Aa)tフリル−、−(CR5R6)m−オキサゾリル(Aa)t−、−(CR5R6)m−チアゾリル(Aa)t−、−(CR5R6)m−チエニル(Aa)t−、−(CR5R6)m−イミダゾリル(Aa)t−、−(CR5R6)m−モルホリノ−(Aa)t−、−(CR5R6)m−ピペラジノ−(Aa)t−、−(CR5R6)m−N−メチルピペラジノ−(Aa)t−、−K(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t−、−K(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t−、−K(Aa)r(CR5R6)m(CR7R8)n(OCH2CH2)t−、−K(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t−、−K(CR5R6)m(CR7=R8)(CR9R10)n(Aa)t(OCH2CH2)r−、−K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(OCO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(OCO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r−、−K(CR5R6)m−フェニル−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)m−フリル−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)m−オキサゾリル−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)m−チアゾリル−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)t−チエニル−(CO)(CR7R8)n−、−K(CR5R6)t−イミダゾリル−(CO)(CR7R8)n−、−K(CR5R6)t−モルホリノ−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)t−ピペラジノ−(CO)(Aa)t(CR7R8)n−、−K(CR5R6)t−N−メチルピペラジン−(CO)(Aa)t(CR7R8)n−、−K(CR5R)m−(Aa)tフェニル−、−K(CR5R6)m−(Aa)tフリル−、−K(CR5R6)m−オキサゾリル(Aa)t−、−K(CR5R6)m−チアゾリル(Aa)t−、−K(CR5R6)m−チエニル(Aa)t−、−K(CR5R6)m−イミダゾリル(Aa)t−、−K(CR5R6)m−モルホリノ−(Aa)t−、−K(CR5R6)m−ピペラジノ−(Aa)tG−、−K(CR5R6)m−N−メチルピペラジノ−(Aa)t;式中、m、Aa、m、及びnは上記の通りである;t及びrは独立して0〜100である;R3、R4、R5、R6、R7、及びR8は独立して、H;ハロゲン化物;C1〜C8アルキル;C2〜C8アリール、アルケニル、アルキニル、エーテル、エステル、
アミン、又はアミドから選択され、これらは任意に、1又は複数のハロゲン化物、CN、NR1R2、CF3、OR1、アリール、複素環、S(O)R1、SO2R1、−CO2H、−SO3H、−OR1、−CO2R1、−CONR1、−PO2R1R2、−PO3H、又はP(O)R1R2R3で置換されてもよい;KはNR1、−SS−、−C(=O)−、−C(=O)NH−、−C(=O)O−、−C=NH−O−、−C=N−NH−、−C(=O)NH−NH−、O、S、Se、B、Het(C3−C8を有する複素環式又はヘテロ芳香族環)、又は1〜20アミノ酸を含むペプチドである;
(E):1又は複数の以下の親水性構造:
式中、
(F)式(I)、(Ia)、(Ib)、(Ic)、(Ie):(III)、(II)、(III)、又は(IV)のE1及び/又はE2と結合する1又は複数の以下の成分;あるいは、Qが式(I)、(Ia)、(Ib)、(Ic)、(Ie):(III)、(II)、(III)、又は(IV)のL1及び/又はL2に直接結合している場合、式中、V1及び/又はV2は独立して存在しない。
R7、R8、及びR9は、−C1〜C8アルキレン−、−C1〜C7炭素環−、−O−(C1〜C8アルキル)−、−アリーレン−、−C1〜C8アルキレン−アリーレン−、−アリレン、−C1〜C8アルキレン−、−C1〜C8アルキレン−(C1〜C8炭素環)−、−(C3〜C7炭素環)−C1〜C8アルキレン−、−C3〜C8ヘテロシクロ−、−C1〜C8アルキレン −(C3〜C8ヘテロシクロ)−、−(C3〜C8ヘテロシクロ)−C1〜C9アルキレン−、−(CH2CH2O)k−、−(CH(CH3)CH2O)k−、及び−(CH2CH2O)k−CH2−;kは1〜30の範囲の整数である;X’’’、Y’’’、及びZ’’’は独立して、NH、O、又はSから選択される。Q、R1、及びR2は上記のとおりである。 - 請求項1、2、3、4、5、6、又は8に記載の細胞結合剤/分子は、以下から選択される:
(A);抗体、タンパク質、プロボディ、ナノボディ、ビタミン(葉酸類を含む。)、ペプチド、ポリマーミセル、リポソーム、リポタンパク系薬物担体、ナノ粒子薬物担体、デンドリマー、及び細胞結合リガンドと結合又は細胞結合リガンドで被覆された上記の分子若しくは粒子、又は上記の組み合わせからなる群;
(B);抗体様タンパク質、完全長抗体(ポリクローナル抗体、モノクローナル抗体、抗体二量体、抗体多量体)、多特異的抗体(二重特異的抗体、三重特異性抗体、又は四重特異性抗体から選択される。);単鎖抗体、標的細胞と結合する抗体断片、モノクローナル抗体、単鎖モノクローナル抗体、標的細胞と結合するモノクローナル抗体断片、キメラ抗体、標的細胞と結合するキメラ抗体断片、ドメイン抗体、標的細胞と結合するドメイン抗体断片、表面再構成型抗体、単鎖表面再構成型抗体、標的細胞と結合する表面再構成型抗体、ヒト化抗体、表面再構成型ヒト化抗体、単鎖ヒト化抗体、標的細胞と結合するヒト化抗体断片、抗イディオタイプ(抗Id)抗体、CDR’s、二特異性抗体、三特異性抗体、四特異性抗体、ミニ抗体、プロボディ、プロボディ断片、小免疫タンパク質(SIP)、リンホカイン、ホルモン、ビタミン、成長因子、コロニー刺激因子、栄養輸送因子、大分子量タンパク質、融合タンパク質、キナーゼ阻害剤、遺伝子標的化剤、ナノ粒子、又は抗体若しくは大分子量タンパク質で修飾されたポリマー;
(C)以下から選択される細胞結合リガンド又は受容体アゴニスト:葉酸誘導体;グルタミン酸尿素誘導体;ソマトスタチン及びその類縁体(オクトレオチド(サンドスタチン)及びランレオチド(ソマトリン)からなる群から選択される。);芳香族スルホンアミド;下垂体アデニル酸シクラーゼ活性化ペプチド(PACAP)(PAC1);血管作動性腸管ペプチド(VIP/PACAP)(VPAC1、VPAC2);メラニン細胞刺激ホルモン(α−MSH);コレシストキニン(CCK)/ガストリン受容体アゴニスト;ボンベシン(Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2からなる群から選択される)/ガストリン放出ペプチド(GRP)からなる群から選択される。);ニューロテンシン受容体リガンド(NTR1、NTR2、NTR3);サブスタンスP(NK1受容体)リガンド;ニューロペプチドY(Y1−Y6);RGD(Arg-Gly-Asp)、NGR(Asn-Gly-Arg)、二量体及び多量体環状RGDペプチド(cRGDfVcから選択される。)、TAASGVRSMH及びLTLRWVGLMS(コンドロイチン硫酸プロテオグリカンNG2受容体リガンド)及びF3ペプチドを含むホーミングペプチド;細胞透過性ペプチド(CPPs);黄体形成ホルモン放出ホルモン(LHRH)アゴニスト及びアンタゴニスト、並びに性腺刺激ホルモン放出ホルモン(GnRH)アゴニストからなる群から選択される、テストステロン産生と同様に、卵胞刺激ホルモン(FSH)及び黄体形成ホルモン(LH)を標的とすることによって作用する、ブセレリン(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt)、ゴナドレリン(Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2)、ゴセレリン(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzGly-NH2)、ヒストレリン(Pyr-His-Trp-Ser-Tyr-D-His(N-ベンジル)-Leu-Arg-Pro-NHEt)、ロイプロリド(Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt)、ナフレリン(Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2)、トリプトレリン(Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2)、ナファレリン、デスロレリン、アバレリックス(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-ピリジル)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-イソプロピル-Pro-DAla-NH2)、セトロレリックス (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-ピリジル)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2)、デガレリックス (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-ピリジル)Ala-Ser-4-amioPhe(L-ヒドロオロチル)-D-4-amioPhe(カルバモイル)-Leu-イソプロピルLys-Pro-D-Ala-NH2)、及びガニレリックス(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-ピリジル)Ala-Ser-Tyr-D-(N9, N10-ジエチル)-ホモArg-Leu-(N9, N10-ジエチル)-ホモArg-Pro-D-Ala-NH2)からなる群から選択されるペプチドホルモン;Toll様受容体(TLR)リガンド、C型レクチン、及びNod様受容体(NLRs)リガンドからなる群から選択されるパターン認識受容体(PRRs);カルシトニン受容体アゴニスト;インテグリン受容体及びそれらの受容体サブタイプ(αVβ1、αVβ3、αVβ5、αVβ6、α6β4、α7β1、αLβ2、αIIbβ3からなる群から選択される。)アゴニスト(GRGDSPK、シクロ(RGDfV)(L1)及びその誘導体[シクロ(−N(Me)R−GDfV)、シクロ(R−Sar−DfV), シクロ(RG−N(Me)D−fV)、シクロ(RGD−N(Me)f−V)、シクロ(RGDf−N(Me)V−)(繊毛虫)];ナノボディ(VHH(ラクダIg)の誘導体);ドメイン抗体(dAb、VH又はVLドメインの誘導体)、二重特異的T細胞誘導(Bite、二重特異性抗体);二重親和性リターゲティング(DART、二重特異性抗体);四価のタンデム抗体(TandAb、二量化二重特異性抗体);アンチカリン(リポカリンの誘導体);アドネクチン(第10番目のFN3(フィブロネクチン));設計されたアンキリン反復タンパク質(DARPins);アビマー(avimer);EGF受容体及びVEGF受容体アゴニスト;
(D):細胞結合分子/リガンドの小分子又は以下から選択される細胞受容体アゴニスト:以下の構造で示されるLB01(葉酸)、LB02(PMSAリガンド)、LB03(PMSAリガンド)、LB04(PMSAリガンド)、LB05(ソマトスタチン)、LB06(ソマトスタチン)、LB07(オクトレオチド、ソマトスタチン類似体)、LB08(ラマレオチド、ソマトスタチン類似体)、LB09(バプレオチド(サンバー)、ソマトスタチン類似体)、LB10(CAIXリガンド)、LB11(CAIXリガンド)、LB12(ガストリン放出ペプチド受容体(GRPr)、MBA)、LB13(黄体形成ホルモン放出ホルモン(LH−RH)リガンド及びGnRH)、LB14(黄体形成ホルモン放出ホルモン(LH−RH)及びGnRHリガンド)、LB15(GnRHアンタゴニスト、アバレリックス)、LB16(コバラミン、ビタミンB12類縁体)、LB17(コバラミン、ビタミンB12類縁体)、LB18(αvβ3インテグリン受容体のための、環状RGDペンタペプチド)、LB19(VEGF受容体のためのヘテロ二価ペプチドリガンド)、LB20(ニューロメジンB)、LB21(Gタンパク質共役受容体のためのボンベシン)、LB22(トール様受容体のためのTLR2)、LB23(アンドロゲン受容体のための)、LB24(αvインテグリン受容体のためのシレンギチド(Cilengitide)/シクロ(−RGDfV−)、LB23(フルドロコルチゾン)、LB25(リファブチン類縁体)、LB26(リファブチン類縁体)、LB27(リファブチン類縁体)、LB28(フルドロコルチゾン)、LB29(デキサメタゾン)、LB30(プロピオン酸フルチカゾン)、LB31(ジプロピオン酸ベクロメタゾン)、LB32(トリアムシノロンアセトニド)、LB33(プレドニゾン)、LB34(プレドニゾロン)、LB35(メチルプレドニゾロン)、LB36(ベタメタゾン)、LB37(イリノテカン類縁体)、LB38(クリゾチニブ類縁体)、LB39(ボルテゾミブ類縁体)カーフィルゾミブ類似体)、LB40(カーフィルゾミブ類縁体)、LB41(カーフィルゾミブ類縁体)、LB42(リュープロリド類縁体)、LB43(トリプトレリン類縁体)、LB44(クリンダマイシン)、LB45(リラグルチド類縁体)、LB46(セマグルチド類縁体)、LB47(レタパムリン類縁体)、LB48(インジブリン類縁体)、LB49(ビンブラスチン類縁体)、LB50(リキシセナチド類縁体)、LB51(オシメルチニブ類縁体)、LB52(ヌクレオシド類縁体)、LB53(エルロチニブ類縁体)、又はLB54(ラパチニブ類縁体);
- 請求項1、2、3、4、5、6、8、又は10に記載の前記細胞結合剤/分子は、腫瘍細胞、ウイルス感染細胞、微生物感染細胞、寄生虫感染細胞、自己免疫疾患細胞、活性化腫瘍細胞、骨髄細胞、活性化T細胞、影響されているB細胞、メラニン細胞、又は以下の抗原若しくは受容体のいずれか1つを発現する任意の細胞を標的とすることができる:CD1、CD1a、CD1b、CD1c、CD1d、CD1e、CD2、CD3、CD3d、CD3e、CD3g、CD4、CD5、CD6、CD7、CD8、CD8a、CD8b、CD9、CD10、CD11a、CD11b、CD11c、CD11d、CD12w、CD14、CD15、CD16、CD16a、CD16b、CDw17、CD18、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD26、CD27、CD28、CD29、CD30、CD31、CD32、CD32a、CD32b、CD33、CD34、CD35、CD36、CD37、CD38、CD39、CD40、CD41、CD42、CD42a、CD42b、CD42c、CD42d、CD43、CD44、CD45、CD46、CD47、CD48、CD49b、CD49c、CD49c、CD49d、CD49f、CD50、CD51、CD52、CD53、CD54、CD55、CD56、CD57、CD58、CD59、CD60、CD60a、CD60b、CD60c、CD61、CD62E、CD62L、CD62P、CD63、CD64、CD65、CD65s、CD66、CD66a、CD66b、CD66c、CD66d、CD66e、CD66f、CD67、CD68、CD69、CD70、CD71、CD72、CD73、CD74、CD75、CD75s、CD76、CD77、CD78、CD79、CD79a、CD79b、CD80、CD81、CD82、CD83、CD84、CD85、CD85a、CD85b、CD85c、CD85d、CD85e、CD85f、CD85g、CD85g、CD85i、CD85j、CD85k、CD85m、CD86、CD87、CD88、CD89、CD90、CD91、CD92、CD93、CD94、CD95、CD96、CD97、CD98、CD99、CD100、CD101、CD102、CD103、CD104、CD105、CD106、CD107、CD107a、CD107b、CD108、CD109、CD110、CD111、CD112、CD113、CD114、CD115、CD116、CD117、CD118、CD119、CD120、CD120a、CD120b、CD121、CD121a、CD121b、CD122、CD123、CD123a、CD124、CD125、CD126、CD127、CD128、CD129、CD130、CD131、CD132、CD133、CD134、CD135、CD136、CD137、CD138、CD139、CD140、CD140a、CD140b、CD141、CD142、CD143、CD144、CD145、CDw145、CD146、CD147、CD148、CD149、CD150、CD151、CD152、CD153、CD154、CD155、CD156、CD156a、CD156b、CD156c、CD156d、CD157、CD158、CD158a、CD158b1、CD158b2、CD158c、CD158d、CD158e1、CD158e2、CD158f2、CD158g、CD158h、CD158i、CD158j、CD158k、CD159、CD159a、CD159b、CD159c、CD160、CD161、CD162、CD163、CD164、CD165、CD166、CD167、CD167a、CD167b、CD168、CD169、CD170、CD171、CD172、CD172a、CD172b、CD172g、CD173、CD174、CD175、CD175s、CD176、CD177、CD178、CD179、CD179a、CD179b、CD180、CD181、CD182、CD183、CD184、CD185、CD186、CDw186、CD187、CD188、CD189、CD190、CD191、CD192、CD193、CD194、CD195、CD196、CD197、CD198、CD199、CDw198、CDw199、CD200、CD201、CD202、CD202(a,b)、CD203、CD203c、CD204、CD205、CD206、CD207、CD208、CD209、CD210、CDw210a、CDw210b、CD211、CD212、CD213、CD213a1、CD213a2、CD214、CD215、CD216、CD217、CD218、CD218a、CD218、CD21b9、CD220、CD221、CD222、CD223、CD224、CD225、CD226、CD227、CD228、CD229、CD230、CD231、CD232、CD233、CD234、CD235、CD235a、CD235b、CD236、CD237、CD238、CD239、CD240、CD240ce、CD240d、CD241、CD242、CD243、CD244、CD245、CD246、CD247、CD248、CD249、CD250、CD251、CD252、CD253、CD254、CD255、CD256、CD257、CD258、CD259、CD260、CD261、CD262、CD263、CD264、CD265、CD266、CD267、CD268、CD269、CD270、CD271、CD272、CD273、CD274、CD275、CD276、CD277、CD278、CD279、CD281、CD282、CD283、CD284、CD285、CD286、CD287、CD288、CD289、CD290、CD291、CD292、CD293、CD294、CD295、CD296、CD297、CD298、CD299、CD300、CD300a、CD300b、CD300c、CD301、CD302、CD303、CD304、CD305、CD306、CD307、CD307a、CD307b、CD307c、CD307d、CD307e、CD307f、CD308、CD309、CD310、CD311、CD312、CD313、CD314、CD315、CD316、CD317、CD318、CD319、CD320、CD321、CD322、CD323、CD324、CD325、CD326、CD327、CD328、CD329、CD330、CD331、CD332、CD333、CD334、CD335、CD336、CD337、CD338、CD339、CD340、CD341、CD342、CD343、CD344、CD345、CD346、CD347、CD348、CD349、CD350、CD351、CD352、CD353、CD354、CD355、CD356、CD357、CD358、CD359、CD360、CD361、CD362、CD363、CD364、CD365、CD366、CD367、CD368、CD369、CD370、CD371、CD372、CD373、CD374、CD375、CD376、CD377、CD378、CD379、CD381、CD382、CD383、CD384、CD385、CD386、CD387、CD388、CD389、CRIPTO、CRIPTO、CR、CR1、CRGF、CRIPTO、CXCR5、LY64、TDGF1、4−1BB、APO2、ASLG659、BMPR1B、4−1BB、5AC、5T4(絨毛性糖タンパク質、TPBG、5T4、Wnt活性化阻害因子1又はWAIF1)、腺癌抗原、AGS−5、AGS−22M6、アクチビン受容体様キナーゼ1、AFP、AKAP−4、ALK、αインテグリン、αvβ6、アミノペプチダーゼN、アミロイドβ、アンドロゲン受容体、アンジオポイエチン2、アンジオポイエチン3、アネキシンA1、炭疽菌トキシン防御抗原、抗トランスフェリン受容体、AOC3(VAP−1)、B7−H3、炭疽菌、BAFF(B−細胞活性化因子)、BCMA、B−リンパ腫細胞、bcr−abl、ボンベシン、BORIS、C5、C242抗原、CA125(炭水化物抗原125、MUC16)、CA−IX(又はCAIX、炭酸脱水酵素9)、CALLA、CanAg、イヌIL31、炭酸脱水酵素IX、心筋ミオシン、CCL11(C−Cモチーフケモカイン11)、CCR4(CCケモカイン受容体4型)、CCR5、CD3E(イプシロン)、CEA(癌胎児性抗原)、CEACAM3、CEACAM5(癌胎児性抗原)、CFD(因子D)、Ch4D5、コレシストキニン2(CCK2R)、CLDN18(クラウディン−18)、クランピング因子A、cMet、CRIPTO、FCSF1R(コロニー刺激因子1受容体)、CSF2(コロニー刺激因子2、顆粒球マクロファージコロニー刺激因子(GM−CSF))、CSP4、CTLA4(細胞傷害性Tリンパ球関連タンパク質4)、CTAA16.88腫瘍抗原、CXCR4、CXCケモカイン受容体4型、cADPリボースヒドロラーゼ、サイクリンB1、CYP1B1、サイトメガロウイルス、サイトメガロウイルス糖タンパク質B、ダビガトラン、DLL4(デルタ様リガンド4)、DPP4(ジペプチジルペプチダーゼ4)、DR5(デスレセプター5)、大腸菌志賀毒素1型、大腸菌志賀毒素2型、ED−B、EGFL7(EGF様ドメイン含有タンパク質7)、EGFR、EGFRII、EGFRvIII、エンドグリン、エンドセリンB受容体、エンドトキシン、EpCAM(上皮細胞接着分子)、EphA2、エピシアリン、ERBB2(上皮成長因子受容体2)、ERBB3、ERG(TMPRSS2ETS融合遺伝子)、大腸菌、ETV6−AML、FAP(線維芽細胞活性化タンパク質α)、FCGR1、α−フェトプロテイン、フィブリンII、β鎖、フィブロネクチン外部ドメインB、FOLR(葉酸受容体)、葉酸受容体α、葉酸ヒドロラーゼ、Fos関連抗原1F、RSウイルスのFタンパク質、Frizzled受容体、フコシルGM1、GD2ガングリオシド、G−28(細胞表面糖脂質抗原)、GD3イディオタイプ、GloboH、グリピカン3、N−グリコリルノイラミン酸、GM3、GMCSF受容体α鎖、成長分化因子8、GP100、GPNMB(膜貫通タンパク質NMB)、GUCY2C(グアニル酸シクラーゼ2C、グアニル酸シクラーゼC(GC−C)、腸グアニル酸シクラーゼ、グアニル酸シクラーゼ−C受容体、熱安定性エンテロトキシン受容体(hSTAR))、熱ショックタンパク質、血球凝集素、B型肝炎表面抗原、B型肝炎ウイルス、HER1(ヒト上皮成長因子受容体1)、HER2、HER2/neu、HER3(ERBB−3)、IgG4、HGF/SF(幹細胞増殖因子/細胞分散因子)、HHGFR、HIV−1、ヒストン複合体、HLA−DA(ヒト白血球抗原)、HLA−DR10、HLA−DRB、HMWMAA、ヒト絨毛性ゴナドトロピン、HNGF、ヒト細胞散乱因子受容体キナーゼ、HPV E6/E7、Hsp90、hTERT、ICAM−1(細胞間接着分子1)、イディオタイプ、IGF1R(IGF−1、インスリン様増殖因子1受容体)、IGHE、IFN−γ、インフルエンザ赤血球凝集素、IgE、IgE Fc領域、IGHE、インターロイキン(IL−1、IL−2、IL−3、IL−4、IL−5、IL−6、IL−6R、IL−7、IL−8、IL−9、IL−10、IL−11、IL−12、IL−13、IL−15、IL−17、IL−17A、IL−18、IL−19、IL−20、IL−21、IL−22、IL−23、IL−27、又はIL−28)、IL−31RA、ILGF2(インスリン様増殖因子2)、インテグリン(α4、αIIIbβ3、αvβ3、α4β7、α5β1、α6β4、α7β7、αIIβ3、α5β5、αvβ5)、インターフェロンγ誘導タンパク質、ITAGA2、ITGB2、KIR2D、LCK、Le、
レグマイン、ルイス−Y抗原、LFA−1(リンパ球機能関連抗原1、CD11a)、LHRH、LINGO−1、リポタイコ酸、LIV1A、LMP2、LTA、MAD−CT−1、MAD−CT−2、MAGE−1、MAGE−2、MAGE−3、MAGEA1、MAGEA3、MAGE4、MART1、MCP−1、MIF(マクロファージ遊走阻止因子又はグリコシル化阻害因子(GIF))、MS4A1(膜貫通4ドメインサブファミリーAメンバー1)、MSLN(メソテリン)、MUC1(ムチン1、細胞表面関連(MUC1)又は多型性上皮ムチン(PEM))、MUC1−KLH、MUC16(CA125)、MCP1(単球走化性タンパク質1)、MelanA/MART1、ML−IAP、MPG、MS4A1(膜貫通型4ドメインサブファミリーA)、MYCN、ミエリン関連糖タンパク質、ミオスタチン、NA17、NARP−1、NCA−90(顆粒球抗原)、ネクチン−4(ASG−22ME)、NGF、神経アポトーシス制御プロテイナーゼ1、NOGO−A、Notch受容体、ヌクレオリン、Neu癌遺伝子産物、NY−BR−1、NY−ESO−1、OX−40、OxLDL(酸化低密度リポタンパク質)、OY−TES1、P21、p53非変異体、P97、Page4、PAP、抗(N−グリコリルノイラミン酸)のパラトープ、PAX3、PAX5、PCSK9、PDCD1(PD−1、プログラムされた細胞死タンパク質1)、PDGF−Rα、(血小板由来成長因子受容体α)、PDGFR−β、PDL−1、PLAC1、PLAP様精巣アルカリホスファターゼ、血小板由来成長因子受容体β、リン酸ナトリウム共輸送体、PMEL17、ポリシアル酸、プロテイナーゼ3(PR1)、前立腺癌、PS(ホスファチジルセリン)、前立腺癌細胞、緑膿菌、PSMA、PSA、PSCA、狂犬病ウイルス糖タンパク質、RHD(Rhポリペプチド1(RhPI))、アカゲザル因子(Rhesus factor)、RANKL、PhoC、Ras変異体、RG55、ROBO4、RSウイルス、RON、肉腫転移ブレイクポイント、SART3、スクレロスチン、SLAMF7(SLAMファミリーメンバー7)、セレクチンP、SDC1(シンデカン1)、sLe(a)、ソマトメジンC、SIP(スフィンゴシン−1−ホスフェート)、ソマトスタチン、精子タンパク質17、SSX2、STEAP1(前立腺1の6回膜貫通上皮抗原)、STEAP2、STn、TAG−22(腫瘍関連糖タンパク質72)、サバイビン、T細胞受容体、T細胞膜貫通タンパク質、TEM1(腫瘍上皮マーカー1)、TENB2、テナスシンC(TN−C)、TGF−α、TGF−β(トランスフォーミング増殖因子β)、TGF−β1、TGF−β2(トランスフォーミング増殖因子β2)、Tie(CD202b)、Tie2、TIM−1(CDX−014)、TN、TNF、TNF−α、TNFRSF8、TNFRSF10B(腫瘍壊死因子受容体スーパーファミリーメンバー10B)、TNFRSF13B(腫瘍壊死因子受容体スーパーファミリーメンバー13B)、TPBG(栄養膜糖タンパク質)、TRAIL−R1(腫瘍壊死アポトーシス誘導リガンド受容体1)、TRAILR2(細胞死受容体5(DR5))、主要関連カルシウムシグナルトランスデューサー2、MUC1の腫瘍特異的グリコシル化、TWEAK受容体、TYRP1(糖タンパク質75)、TRP−2、チロシナーゼ、VCAM−1、VEGF、VEGF−A、VEGF−2、VEGFR−1、VEGFR2、又はビメンチン、WT1、XAGE1、又は任意のインスリン成長因子受容体を発現する細胞、又は任意の上皮増殖因子受容体。 - 請求項12に記載の腫瘍細胞は、リンパ腫細胞、骨髄腫細胞、腎細胞、乳癌細胞、前立腺癌細胞、卵巣癌細胞、結腸直腸癌細胞、胃癌細胞、扁平上皮癌細胞、小細胞から選択される。肺がん細胞、小細胞肺がん細胞、精巣がん細胞、悪性細胞、又は無秩序で速いペースで成長及び分裂してがんを引き起こす任意の細胞からなる群から選択される。
- 治療有効量の請求項1、2、3、4、5、又は8のいずれか1項に記載の共役体及び薬学的に許容される塩、担体、希釈剤若しくは賦形剤、又は前記共役体の組み合わせを含む、がん、自己免疫疾患、又は感染症の治療又は予防のための医薬組成物。
- 請求項1、2、3、4、5、又は8のいずれか1項に記載の1以上の共役体を0.01%〜99重量%;
1又は複数のポリオールを0.0%〜20.0%;
1又は複数の界面活性剤を0.0%〜2.0%;
1又は複数の保存剤を0.0%〜5.0%;
1又は複数のアミノ酸を0.0%〜30%;
1又は複数の抗酸化剤を0.0%〜5.0%;
1又は複数の金属キレート剤を0.0%〜0.3%;
製剤のpHをpH4.5〜8.5に調整するための1又は複数の緩衝塩を0.0%〜30.0%;及び
患者への投与のために再構成された場合に、浸透圧を約250〜350mOsmに調整するための1又は複数の等張化剤を0.0%〜30.0%;
を含み、
前記ポリオールは、フルクトース、マンノース、マルトース、ラクトース、アラビノース、キシロース、リボース、ラムノース、ガラクトース、グルコース、スクロース、トレハロース、ソルボース、メレジトース、ラフィノース、マンニトール、キシリトール、エリスリトール、マルチトール、ラクチトール、エリスリトール、スレイトール、ソルビトール、グリセロール、又はL−グルコン酸塩及びその金属塩から選択される;
前記界面活性剤は、ポリソルベート20、ポリソルベート40、ポリソルベート65、ポリソルベート80、ポリソルベート81、又はポリソルベート85、ポロキサマー、ポリ(エチレンオキシド)−ポリ(プロピレンオキシド)、ポリエチレン−ポリプロピレン、トリトン、ドデシル硫酸ナトリウム(SDS)、ラウレル硫酸ナトリウム;オクチルグリコシドナトリウム;ラウリル−、ミリスチル−、リノレイル−、又はステアリル−スルホベタイン;ラウリル−、ミリスチル−、リノレイル−、又はステアリル−サルコシン;リノレイル−、ミリスチル−、又はセチル−ベタイン;ラウロアミドプロピル−、コカミドプロピル−、リノールアミドプロピル−、ミリスタミドプロピル−、パルミドプロピル−、又はイソステアラミドプロピル−ベタイン(ラウロアミドプロピル);ミリスタミドプロピル−、パルミドプロピル−、又はイソステアラミドプロピル−ジメチルアミン;ナトリウムメチルココイル−又は二ナトリウムメチルオレイル−タウレート;ドデシルベタイン、ドデシルジメチルアミンオキシド、コカミドプロピルベタイン、及びココアンフォグリシネート;又はイソステアリルエチルイミドニウムエトサルフェート;ポリエチルグリコール、ポリプロピレングリコール、及びエチレンとプロピレングリコールとの共重合体から選択される;
前記保存剤は、ベンジルアルコール、オクタデシルジメチルベンジルアンモニウムクロリド、ヘキサメトニウムクロリド、ベンザルコニウムクロリド、ベンゼトニウムクロリド、フェノール、ブチルおよびベンジルアルコール、アルキルパラベン、メチルまたはプロピルパラベン、カテコール、レゾルシノール、シクロヘキサノール、3−ペンタノール、又はm−クレゾールから選択される;
前記アミノ酸は、アルギニン、シスチン、グリシン、リジン、ヒスチジン、オルニチン、イソロイシン、ロイシン、アラニン、グリシングルタミン酸、又はアスパラギン酸から選択される;
前記抗酸化剤は、アスコルビン酸、グルタチオン、シスチン、又はメチオニンから選択される;
前記キレート剤は、EDTA又はEGTAから選択される;
前記緩衝塩は、クエン酸、アスコルビン酸、グルコン酸、炭酸、酒石酸、コハク酸、酢酸、又はフタル酸のナトリウム、カリウム、アンモニウム、又はトリヒドロキシエチルアミノ塩;トリス又はトロメタミンの塩酸塩、リン酸塩又は硫酸塩;アルギニン、グリシン、グリシルグリシン、又はヒスチジンとアニオン性の酢酸塩、塩化物、リン酸塩、硫酸塩、又はコハク酸塩から選択される;
前記等張化剤は、マンニトール、ソルビトール、酢酸ナトリウム、塩化カリウム、リン酸ナトリウム、リン酸カリウム、クエン酸三ナトリウム、または塩化ナトリウムから選択される、請求項14に記載の液体処方物又は処方された凍結乾燥固体のいずれかの医薬組成物。 - 液体または凍結乾燥粉末/固体の形態で、バイアル、ボトル、プレフィルドシリンジ、またはプレフィルドオートインジェクターシリンジに充填される、請求項14または15に記載の医薬組成物。
- インビトロ、インビボまたはエクスビボで細胞殺傷活性を有する,請求項1、2、3、4、5、若しくは8のコンジュゲート、または請求項14若しくは15の医薬組成物の形態。
- 化学療法剤、放射線療法、免疫療法剤、自己免疫障害剤、抗感染剤、または癌、自己免疫疾患、若しくは感染症の相乗的治療・予防するための他の共役体と同時に投与される、請求項14または15に記載される医薬組成物、
- 請求項18に記載される化学療法剤は以下から選択される。
(1)a)アルキル化剤:ナイトロジェンマスタード:クロラムブシル、クロルナファジン、シクロホスファミド、ダカルバジン、エストラムスチン、イホスファミド、メクロレタミン、塩酸メクロレタミン、マンノムスチン、ミトブロニトール、メルファラン、ミトラクトール、ピポブロマン、ノベンビチン、フェネステリン、プレドニムスチン;CC−1065及びアドゼレシン、カルゼレシン、ビゼレシン又はそれらの合成類似体;デュオカルマイシン及びその合成類似体、KW−2189、CBI−TMI、又はCBI二量体。ベンゾジアゼピン二量体又はピロロベンゾジアゼピン(PBD)二量体、トマイマイシン二量体、インドリノベンゾジアゼピン二量体、イミダゾベンゾチアジアゼピン二量体、またはオキサゾリジノベンゾジアゼピン二量体;ニトロソウレア:カルムスチン、ロムスチン、クロロゾトシン、フォテムスチン、ニムスチン、ラニムスチン;アルキルスルホン酸塩:ブスルファン、トレオサルファン、インプロスルファンおよびピポスルファン;トリアゼンまたはダカルバジン;Pt含有化合物:カルボプラチン、シスプラチン、及びオキサリプラチン;アジリジン、ベンゾドーパ、カルボクオン、メチュレドーパ、又はウレドパ;アルトレタミン、トリエチレンメラミン、トリエチレンホスホルアミド、トリエチレンチオホスホルアミド及びトリメチルオロメラミン;エチレンイミン及びメチルアメラミンから選択される;
b)植物アルカロイド:ビンカアルカロイド:ビンクリスチン、ビンブラスチン、ビンデシン、ビノレルビン、及びナベルビンを含む。タキソイド:パクリタキセル、ドセタキソール及びそれらの類似体、DM1、DM2、DM3、DM4、DM5、DM6、DM7、メイタンシン、アンサミトシン及びそれらの類似体、クリプトフィシン(クリプトフィシン1及びクリプトフィシン8の群を含む)、メイタンシノイド、エポチロン、エレウテロビン、ディスコデルモライド、ブリオスタチン、ドロスタチン、オーリスタチン、ツブリシン、セファロスタチン; パンクラチスタチン; サルコディクチン; スポンジスタチンから選択される;
c)DNAトポイソメラーゼ阻害剤:エピポドフィリン:9−アミノカンプトテシン、カンプトテシン、クリスナトール、ダウノマイシン、エトポシド、リン酸エトポシド、イリノテカン、ミトキサントロン、ノバントロン、レチノイン酸(又はレチノール)、テニポシド、トポテカン、9−ニトロ2000;及びマイトマイシン及びそれらの類似体から選択される;
d)代謝拮抗剤:{[葉酸拮抗薬:(DHFR阻害剤:メトトレキサート、トリメトレキサート、デノプテリン、プテロプテリン、アミノプテリン(4−アミノプテロン酸)または葉酸類似体); IMPデヒドロゲナーゼ阻害剤:(ミコフェノール酸、チアゾフリン、リバビリン、EICARを含む);リボヌクレオチドレダクターゼ阻害剤:(ヒドロキシ尿素、デフェロキサミンを含む)];[ピリミジン類似体:ウラシル類似体:(アンシタビン、アザシチジン、6−アザウリジン、カペシタビン、カルモフル、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、5−フルオロウラシル、フロクスウリジン、ラチトレックスを含む); シトシン類似体:(シタラビン、シトシンアラビノシド、フルダラビンを含む); プリン類似体:(アザチオプリン、フルダラビン、メルカプトプリン、チアミプリン、チオグアニンを含む)];葉酸補充剤、フロリン酸}から選択される;
e)ホルモン療法:受容体拮抗薬:[抗エストロゲン:(メゲストロール、ラロキシフェン、タモキシフェンを含む); LHRHアゴニスト:(ゴスクリン、酢酸リュープロリドを含む); 抗アンドロゲン:(ビカルタミド、フルタミド、カルステロン、プロピオン酸ドロモスタノロン、エピチオスタノール、ゴセレリン、リュープロリド、メピチオスタン、ニルタミド、テストラクトン、トリロスタン及び他のアンドロゲン阻害剤を含む)]; レチノイド/三角筋:[ビタミンD3類似体:( CB1093、EB1089 KH1060、コレカルシフェロール、エルゴカルシフェロールを含む); 光線力学療法:(ベルテポルフィン、フタロシアニン、光増感剤Pc4、デメトキシヒポクレリンAを含む); サイトカイン:(インターフェロン−アルファ、インターフェロン−ガンマ、腫瘍壊死因子(TNF)、TNFドメインを含むヒトタンパク質を含む))]から選択される;
f)キナーゼ阻害剤:BIBW 2992(抗EGFR/Erb2)、イマチニブ、ゲフィチニブ、ペガプタニブ、ソラフェニブ、ダサチニブ、スニチニブ、エルロチニブ、ニロチニブ、ラパチニブ、アキシチニブ、パゾパニブ、、バンデタニブ、E7080(抗VEGFR2)、ムブリチニブ、ポナチニブ、バフェチニブ、ボスチニブ、カボザンチニブ、ビスモデギブ、イニパリブ、ルキソリチニブ、CYT387、アキシチニブ、チボザニブ、ソラフェニブ、ベバシズマブ、セツキシマブ、トラスツズマブから選択される;
g). ポリ(ADPリボース)ポリメラーゼ(PARP)阻害剤:オラパリブ、ニラパリブ、イニパリブ、タラゾパリブ、ベリパリブ、CEP9722(セファロン)、E7016(エーザイ)、BGB−290(ベイジーン)、又は3−アミノベンズアミド;
h)エンジイン抗生物質(カリケアマイシン、カリケアマイシンγ1、Δ1、α1、又はβ1の群から選択;ダイネミシンA及びデオキシダイネマイシンを含むダイネミシン;エスペラミシン、ケダルシジン、C−1027、マズロペプチン、又はネオカルジノスタチン発色団)からなる群から選択される抗生物質及び関連するクロモプロテインエンジイン抗生物質クロモモフォア)、アクラシノマイシン、アクチノマイシン、オートラマイシン、アザセリン、ブレオマイシン、カクチノマイシン、カラビシン、カルミノマイシン、カルジノフィリン;クロモマイシン、ダクチノマイシン、ダウノルビシン、デトルビシン、6−ジアゾ−5−オキソ−L−ノルロイシン、ドキソルビシン、モルホリノ−ドキソルビシン、シアノモルホリノ-ドキソルビシン、2−ピロリノ-ドキソルビシン及びデオキシドキソルビシン、エピルビシン、エリブリン、エソルビシンミコフェノール酸、ノガラマイシン、オリボマイシン、ペプロマイシン、ポトフィロマイシン、プロマイシン、ケラマイシン、ロドルビシン、ストレプトニグリン、ストレプトゾシン、ツベルシジン、ウベニメックス、ジノスタチン、ゾルビシンから選択される;
i)ポリケチド(アセトゲニン)、ブラタシンおよびブラタシノン;ゲムシタビン、エポキシミシンおよびカルフィルゾミブ、ボルテゾミブ、サリドマイド、レナリドマイド、ポマリドマイド、トセドスタット、ザイブレスタット、PLX4032、STA−9090、スティムバックス、アロベクチン−7、ゼゲバ、プロベンジ、ヤーボイ、イソプレニル化阻害剤及びロバスタチン、ドパミン、細胞サイクル阻害剤(スタウロスポリンを含む)、アクチノマイシン(アクチノマイシンD、ダクチノマイシンを含む)、アマニチン、ブレオマイシン(ブレオマイシンA2、ブレオマイシンB2、ペプロマイシンを含む)、アントラサイクリン(ダウノルビシン、ドキソルビシン(アドリアマイシン)、イダルビシン、エピルビシンを含む)ミトキサントロン、MDR阻害剤又はベラパミル、Ca2+ ATPase阻害剤又はタプシガルギン、ヒストンデアセチラーゼ阻害剤((ボリノスタット、ロミデプシン、パノビノスタット、バルプロ酸、モセチノスタット(MGCD0103)、ベリノスタット、PCI−24781、エンチノスタット、SB939、レスミノスタット、ギビノスタット、AR−42を含む)、CUDC−101、スルホラファン、トリコスタチンA);タプシガルギン、セレコキシブ、グリタゾン、エピガロカテキンガレート、ジスルフィラム、サリノスポラミドA;アミノグルテチミド、ミトタン、トリロスタンのグループから選択された抗副腎;アセグラトン;アルドホスファミド配糖体;アミノレブリン酸;アムサクリン;アラビノシド、ベストラブシル;ビサントレン;edatraxate;デフォファミン;デメコルシン;ジアジクオン;エフロルニチン(DFMO)、エルフォミチン;酢酸エリプチニウム、エトグルシッド;硝酸ガリウム;ガシトシン、ヒドロキシ尿素;イバンドロネート、レンチナン;ロニダミン;ミトグアゾン;ミトキサントロン;モピダモール;ニトラクリン;ペントスタチン;フェナメット;ピラルビシン;ポドフィリン酸;2−エチルヒドラジド;プロカルバジン;PSK(登録商標);ラゾキサン;リゾキシン;シゾフィラン;スピロゲルマニウム;テヌアゾン酸;トリアジクオン; 2、2’、2’’トリクロロトリエチルアミン;トリコテセン(T−2トキシン、ベルカリンA、ロリジンA、アンギジンの群を含む);ウレタン、siRNA、アンチセンス薬;
(2)抗自己免疫疾患薬:シクロスポリン、シクロスポリンA、アミノカプロン酸、アザチオプリン、ブロモクリプチン、クロランブシル、クロロキン、シクロホスファミド、コルチコステロイド(アムシノニド、ベタメタゾン、ブデソニド、ヒドロコルチゾン、フルニソリッド、プロピオン酸フルチカゾンからなる群を含む)トリアムシノロンアセトニド、ジプロピオン酸ベタメタゾン)、DHEA、エナネルセプト、ヒドロキシクロロキン、インフリキシマブ、メロキシカム、メトトレキサート、モフェチル、マイコフェニレート、プレドニゾン、シロリムス、タクロリムス;
(3)抗感染症剤:
a)アミノグリコシド:アミカシン、アストロミシン、ゲンタマイシン(ネチルマイシン、シソマイシン、イセパマイシン)、ハイグロマイシンB、カナマイシン(アミカシン、アルベカシン、ベカナマイシン、ジベカシン、トブラマイシン)、ネオマイシン(フラミセチン、パロモマイシン、リボスタマイシン)、ネオマイシン(フラミセチン、パロモマイシン、リボスタマイシン)、ネチルマイシン;
b)アムフェニコール:アジダムフェニコール、クロラムフェニコール、フロルフェニコール、チアンフェニコール;
c)アンサマイシン:ゲルダナマイシン、ハービマイシン;
d)カルバペネム:ビアペネム、ドリペネム、エルタペネム、イミペネム、シラスタチン、メロペネム、パニペネム;
e) セフェム:カルバセフェム(ロラカルベフ)、セファセトリル、セファクロル、セフラジン、セファドロキシル、セファロニウム、セファロリジン、セファロチンまたはセファロチン、セファレキシン、セファログリシン、セファマンドール、セフォキシチン、セファピリン、セファトリジン、セファザフル、セファザフル、セファゼドン、セファゼドン、セフプロジル、セフロキサジン、セフテゾール、セフロキシム、セフィキシム、セフジニル、セフジトレン、セフェピム、セフェタメット、セフメノキシム、セフォジジム、セフォニシド、セフォペラゾン、セフォラニド、セフォタキシム、セフォチアム、セフォゾプラン、セファレキシン、セフォタキシム、セフォチアム、セフォゾプラン、セファレキシン、セフタジジム、セフテラム、セフチブテン、セフチオレン、セフチゾキシム、セフトビプロール、セフトリアキソン、セフロキシム、セフゾナム、セファマイシン(セフォキシチン、セフォテタン、セフメタゾールを含む)、オキサセフェム(フロモキセフ、ラタモキセフ);
f)糖ペプチド:ブレオマイシン、バンコマイシン(オリタバンシン、テラバンシンを含む)、テイコプラニン(ダルババンシン)、ラモプラニン;
g)グリシルサイクリン:チゲサイクリン;
h)β-ラクタマーゼ阻害剤:ペナム(スルバクタム、タゾバクタム)、クラバム(クラブラン酸);
i)リンコサミド:クリンダマイシン、リンコマイシン;
j)リポペプチド:ダプトマイシン、A54145、カルシウム依存性抗生物質(CDA);
k) マクロライド系抗生物質:アジスロマイシン、セスロマイシン、クラリスロマイシン、ジリスロマイシン、エリスロマイシン、フルリスロマイシン、ジョサマイシン、ケトリド(テリスロマイシン、セスロマイシン)、ミデカマイシン、ミオカマイシン、オレアンドマイシン、リファマイシン(リファンピシン、リファンピン、リファブチン、リファブチン、リファブチンFK506)、トロレアンドマイシン、テリスロマイシン;
l)モノバクタム:アズトレオナム、チゲモナム;
m)オキサゾリジノン:リネゾリド;
n)ペニシリン:アモキシシリン、アンピシリン、ピバンピシリン、ヘタシリン、バカンピシリン、メタンピシリン、タランピシリン、アジド、アズロシリン、ベンジルペニシリン、ベンザチンベンジルペニシリン、ベンザチンフェノキシメチル、クロメトシリン、プロカインベンジルペニシリン、カルベニシリン(カリンダシリン)、クロキサシリン、ジクロキサシリン、エピシリン、フルクロキサシリン、メシリナム(ピブメシリナム)、メズロシリン、メチシリン、ナフシリン、オキサシリン、ペナメシリン、ペニシリン、フェネチシリン、フェノキシメチルペニシリン、ピペラシリン、プロピシリン、スルベニシリン、テモシリン、チカルシリン;
o)ポリペプチド:バシトラシン、コリスチン、ポリミキシンB;
p)キノロン:アラトロフロキサシン、バロフロキサシン、シプロフロキサシン、クリナフロキサシン、ダノフロキサシン、ジフロキサシン、エノキサシン、エンロフロキサシン、フロキシン、ガレノキサシン、ガチフロキサシン、ゲミフロキサシン、グレパフロキサシン、オフロキサシン、オフロキサシン、オフロキサシン、、グレパフロキサシン、シタフロキサシン、スパルフロキサシン、テマフロキサシン、トスフロキサシン、トロバフロキサシン;
q)ストレプトグラミン:プリスチナマイシン、キヌプリスチン/ダルホプリスチン;
r)スルホンアミド:マフェニド、プロントジル、スルファセタミド、スルファメチゾール、スルファニルイミド、スルファサラジン、スルフィソキサゾール、トリメトプリム、トリメトプリム-スルファメトキサゾール(コトリモキサゾール);
s)ステロイド抗菌剤:フシジン酸から選択される;
t)テトラサイクリン:ドキシサイクリン、クロルテトラサイクリン、クロモサイクリン、デメクロサイクリン、リメサイクリン、メクロサイクリン、メタサイクリン、ミノサイクリン、オキシテトラサイクリン、ペニメピサイクリン、ロリテトラサイクリン、テトラサイクリン、グリシルサイクリン(チゲサイクリンを含む);
u)その他の抗生物質:アノナシン、アルスフェナミン、バクトプレノール阻害剤(バシトラシン)、DADAL/AR阻害剤(サイクロセリン)、ディクチオスタチン、ディスコーダーモリド、ロイテロビン、エポチロン、エタンブトール、エトポシド、ファロペネム、フシド酸、フラゾリドン、イソニアジドからなる群から選択メトロニダゾール、ムピロシン、マイコラクトン、NAM合成阻害剤(フォスフォマイシン)、ニトロフラントイン、パクリタキセル、プラテンシマイシン、ピラジンアミド、キヌプリスチン/ダルホプリスチン、リファンピシン(リファンピン)、タゾバクタムチニダゾール、ウバリシン;
(4)抗ウイルス薬:
a)侵入阻害剤/融合阻害剤:アプラビロック、マラビロク、ビクリビロク、gp41(エンフビルタイド)、PRO 140、CD4(イバリズマブ);
b)インテグラーゼ阻害剤:ラルテグラビル、エルビテグラビル、グロボイドナンA;
c)成熟阻害剤:ベビリマット、ビベコン;
d)ノイラミニダーゼ阻害剤:オセルタミビル、ザナミビル、ペラミビル;
e)ヌクレオシドとヌクレオチド:アバカビル、アシクロビル、アデホビル、アムドキソビル、アプリシタビン、ブリブジン、シドフォビル、クレブジン、デクセルブシタビン、ジダノシン(ddI)、エルブシタビン、エムトリシタビン(FTC)、エンテカビル、ファムシクロビル、フルオロウラシル(5−FU)、3’−フルオロ置換2’,3’−ジデオキシヌクレオシド類似体(3’−フルオロ−2’,3’−ジデオキシチミジン(FLT)及び3’−フルオロ−2’,3’−ジデオキシグアノシン(FLG)、フォミビルセン、ガンシクロビル、イドクスウリジン、ラミブジン(3TC)、l−ヌクレオシド(β−1−チミジン及びβ−1−デオキシシチジンからなる群を含む。)、ペンシクロビル、ラシビル、リバビリン、スタンピジン、スタブジン(d4T)、タリバビリン(ビラミジン)、テルビブジン、テノホビル、トリフルリジンバラシクロビル、バルガンシクロビル、ザルシタビン(dd)ジドブジン(AZT);
f)非ヌクレオシド:アマンタジン、アテビリジン、カプラビリン、ジアリールピリミジン(エトラビリン、リルピビリン)、デラビルジン、ドコサノール、エミビリン、エファビレンツ、ホスカルネット(ホスホノホルミン酸)、イミキモド、インターフェロンアルファ、ロビリド、ロデノシン、メチサゾン、ネビラピン、ポドフィロトキシン、リファンピシン、リマンタジン、レシキモド(R−848)、トロマンタジン;
g)プロテアーゼ阻害剤:アンプレナビル、アタザナビル、ボセプレビル、ダルナビル、フォサンプレナビル、インジナビル、ロピナビル、ネルフィナビル、プレコナリル、リトナビル、サキナビル、テラプレビル(VX-950)、チプラナビル;
h)他の種類の抗ウイルス薬:アブザイム、アルビドール、カラノリドa、セラゲニン、シアノビリン−n、ジアリールピリミジン、エピガロカテキンガレート(EGCG)、ホスカルネット、グリフィスシン、タリバビリン(ビラミジン)、ヒドロキシ尿素、KP−1461、ミルテフォシン、プレコナリル、ポートマントー阻害剤、リバビリン、セリシクリブ;
(5)薬学的に許容される塩、酸、誘導体、水和物または水和塩;、結晶構造、あるいは上記の薬物のいずれかの光学異性体、ラセミ体、ジアステレオマー又はエナンチオマー。 - 請求項20に記載の相乗剤は、以下の薬物のうちの1つまたはいくつかから選択される:アバタセプト、アベマシクリブ、酢酸アビラテロン、アブラキサン、アセトアミノフェン/ヒドロコドン、アカラブルチニブ、アダカヌマブ、アダリムマブ、ADXS31−142、ADXS−HER2、ジマレイン酸アファチニブ、アルデスロイキン、アレクチニブ、アレムツズマブ、アリトレチノイン、アドレチノイン、アントラサイクリン、アリピプラゾール、アタザナビル、アテゾリズマブ、アトルバスタチン、アベルマブ、アクシカブタジーンシロロイセル、アキシチニブ、ベリノスタット、BCGライブ、ベバシズマブ、ベキサロテン、カブゾニブ、ブリナツモマブ、ボルテゾミブ、ボスチニブ、ブレンツキシマブカプマチニブ、カペシタビン、カルフィルゾミブ、キメラ抗原受容体操作T(CAR−T)細胞、セレコキシブ、セリチニブ、セツキシマブ、チダミド、シクロスポリン、シナカルセット、クリゾチニブ、コビメチニブ、コセンティクス、クリゾチニブ、CTL019、ダビガトラン、ダブラフェナクダカルブ、ダプトマイシン、ダラツムマブ、ダルベポエチンアルファ、ダルナビル、ダサチニブ、デニロイキンジフチトックス、デノスマブ、デパコート、デックスランソプラゾール、デクスメチルフェニデート、デキサメタゾン、DigniCap冷却システム、ジヌツキシマブ、ドキシサイクリン、デュロキセチン、デュベリシブ、デュルバルマブ、エロツズマブ、エムトリシビン/リルピビリン/テノエルタミエエノフォビル、フマル酸ジソプロキシル、エムトリシトビン/テノフィロエゾピクロン、エタネルセプト、エベロリムス、エキセメスタン、エベロリムス、エクセナチドER、エゼチミベ、エゼチミベ/シンバスタチン、フェノフィブレート、フィルグラスチム、フィンゴリモド、プロピオン酸フルチカゾン、フルチカゾン/サルメテロール、フルベストラント、ガジバ、ゲフィチニブイブルチニブ、イデラリシブ、イフォスファミド、インフリキシマブ、イミキモド、ImmuCyst、免疫BCG、イニパリブ、インスリンアスパート、インスリンデテミール、インスリングラルギン、インスリンリスプロ、インターフェロンアルファ、インターフェロンアルファ−1b、インターフェロンアルファ−2a、インターフェロンアルファ−2b、インターフェロンベータ、インターフェロンベータ1a、インターフェロンベータ1b、インターフェロンガンマ−1a、ラパチニブ、イピリムマブ、臭化イプラトロピウム/サルブタモール、イキサゾミブ、カヌマ(Kanuma)、酢酸ランレオチド、レナリドマイド、レナリオミド、メシル酸レンバチニブ、レトロゾール、レボチロキシン、レボチロキシン、リドカイン、リネゾリド、リラグルチド、リスデキサムフェタミン、LN−144、ロラチニブ、メマンチン、メチルフェニデート、メトプロロール、メキニスト、メマンチン、メチルフェニデート、メトプロロール、メキニストC、ネシツムマブ、ネラチニブ、ニロチニブ、ニラパリブ、ニボルマブ、オファツムマブ、オビヌツズマブ、オラパリブ、オルメサルタン、オルメサルタン/ヒドロクロロチアジド、オマリズマブ、オメガ-3脂肪酸エチルエステル、オンコリン、オセルタミビル、オシメルチニブ、オキシコドマブ、オシメルチニブ、オキシコドンパゾパニブ、ペンブロリズマブ、PD−1抗体、PD−L1抗体、ペメトレキセド、ペルツズマブ、肺炎球菌抱合ワクチン、ポマリドマイド、プレガバリン、プロスカバックス、プロプラノロール、ケチアピン、ラベプラゾール、ラジウム223塩化物、ラロキシフェン、ラルテグラビル、ラシリツキシマブ、リバロキサバン、ロミデプシン、ロスバスタチン、リン酸ルキソリチニブ、サルブタモール、サボリチニブ、セマグルチド、セベラマー、シルデナフィル、シルツキシマブ、シプルーセル-T、シタグリプチン、シタグリプチン/メトホルミン、ソリフェナシン、ソラネズマブ、ソニデギブ、ソラフェニブ、スニチニブ、タクロリムス、タクリムス、タダラフィル、タモキシフェン、タフィンラー、タリモジーンラヘルパレプベック、、フマル酸テノフォビルジソプロキシル、テストステロンゲル、サリドマイド、TICE BCG、臭化チオトロピウム、チサゲンレクロイセル、トレミフェン、トラメチニブ、トラスツズマブ、トラベクテジン(エクテイナシジン743)、トラベクテジン(エクテイナシジン743)、トラメチニブ、トレメリムマブ、トリフルリジン/チピラバンデタニブ、ベムラフェニブ、ベネトクラクス、ボリノスタット、ジブアフリベルセプト、ゾスタバックス、およびそれらの類似体、誘導体、薬学的に許容される塩、担体、希釈剤、またはそれらの賦形剤、あるいはそれらの組み合わせ。
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WO2018156180A1 (en) | 2017-02-24 | 2018-08-30 | Kindred Biosciences, Inc. | Anti-il31 antibodies for veterinary use |
AU2018316532B2 (en) | 2017-08-18 | 2022-11-24 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
GB201803342D0 (en) | 2018-03-01 | 2018-04-18 | Medimmune Ltd | Methods |
GB201806022D0 (en) | 2018-04-12 | 2018-05-30 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
KR20210076056A (ko) * | 2018-10-12 | 2021-06-23 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | 2,3-다이아미노석신일기를 함유하는 접합 링커 |
CR20210435A (es) | 2019-02-18 | 2021-09-20 | Lilly Co Eli | Formulación de anticuerpos terapéuticos |
CN111205251B (zh) * | 2020-02-28 | 2022-04-15 | 苏州楚凯药业有限公司 | 手性配体(3s,4s)-2,5-二氧四氢呋喃-3,4-双氨基甲酸苄基酯的制备方法 |
WO2021202429A1 (en) * | 2020-03-28 | 2021-10-07 | Esrail Medical Corp. | Methods and compositions for treatment of covid-19 |
US11045546B1 (en) | 2020-03-30 | 2021-06-29 | Cytodyn Inc. | Methods of treating coronavirus infection |
CN111635524B (zh) * | 2020-06-10 | 2023-07-07 | 陕西安得科技实业有限公司 | 一种环保型荧光示踪阻垢剂及其制备方法 |
GB202011993D0 (en) | 2020-07-31 | 2020-09-16 | Adc Therapeutics Sa | ANTI-IL 13Ra2 antibodies |
GB202105186D0 (en) * | 2021-04-12 | 2021-05-26 | Medimmune Ltd | Pyrrolobenzodiazepine conjugates |
CN115677666A (zh) * | 2021-07-30 | 2023-02-03 | 上海艾力斯医药科技股份有限公司 | 一种吲哚联嘧啶类化合物、其中间体、制备方法及其应用 |
AU2022353890A1 (en) | 2021-09-30 | 2024-04-04 | Jiangsu Hengrui Pharmaceuticals Co., Ltd. | Pyrrolo benzodiazepine derivative, and conjugate, preparation method and use thereof |
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