JP2018507168A - 四級アミン化合物及びその抗体−薬物コンジュゲート - Google Patents
四級アミン化合物及びその抗体−薬物コンジュゲート Download PDFInfo
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- 239000011593 sulfur Substances 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical compound S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000035782 susceptibility to 1 Hirschsprung disease Diseases 0.000 description 1
- 229960005566 swainsonine Drugs 0.000 description 1
- FXUAIOOAOAVCGD-WCTZXXKLSA-N swainsonine Chemical compound C1CC[C@@H](O)[C@@H]2[C@H](O)[C@H](O)CN21 FXUAIOOAOAVCGD-WCTZXXKLSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229950005687 tamolarizine Drugs 0.000 description 1
- 229950005890 tariquidar Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940120811 technetium tc 99m tilmanocept Drugs 0.000 description 1
- 229950001847 teludipine Drugs 0.000 description 1
- MODVSQKJJIBWPZ-VLLPJHQWSA-N tesetaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3CC[C@@]2(C)[C@H]2[C@@H](C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C(=CC=CN=4)F)C[C@]1(O)C3(C)C)O[C@H](O2)CN(C)C)C(=O)C1=CC=CC=C1 MODVSQKJJIBWPZ-VLLPJHQWSA-N 0.000 description 1
- 229950009016 tesetaxel Drugs 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 108010037277 thymic shared antigen-1 Proteins 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- UURAUHCOJAIIRQ-QGLSALSOSA-N tiamulin Chemical compound CCN(CC)CCSCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 UURAUHCOJAIIRQ-QGLSALSOSA-N 0.000 description 1
- 229960004885 tiamulin Drugs 0.000 description 1
- HUNGUWOZPQBXGX-UHFFFAOYSA-N tirbanibulin Chemical compound C=1C=CC=CC=1CNC(=O)CC(N=C1)=CC=C1C(C=C1)=CC=C1OCCN1CCOCC1 HUNGUWOZPQBXGX-UHFFFAOYSA-N 0.000 description 1
- 230000025366 tissue development Effects 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ZHAKYGFJVGCOAE-UHFFFAOYSA-N topixantrone Chemical compound OCCNCCN1N=C2C3=CN=CC=C3C(=O)C3=C2C1=CC=C3NCCN(C)C ZHAKYGFJVGCOAE-UHFFFAOYSA-N 0.000 description 1
- 229950007204 topixantrone Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960002190 topotecan hydrochloride Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229950000185 tozasertib Drugs 0.000 description 1
- KXSIHXHEHABEJX-UHFFFAOYSA-N trans-4-(7-carbamoyl-1h-benzimidazol-2-yl)-1-propylpiperidinium Chemical compound C1CN(CCC)CCC1C1=NC2=CC=CC(C(N)=O)=C2N1 KXSIHXHEHABEJX-UHFFFAOYSA-N 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 1
- 229960001183 venetoclax Drugs 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- BOELCLFVOBIXIF-MAKKXPIGSA-N vinfosiltine Chemical compound C([C@@H](C[C@@](O)(CC)C1)C[C@@]2(C3=C(OC)C=C4N(C)[C@H]5[C@@]([C@@H]([C@]6(CC)C=CCN7CC[C@]5([C@H]67)C4=C3)O)(O)C(=O)N[C@@H](P(=O)(OCC)OCC)C(C)C)C(=O)OC)N1CCC1=C2NC2=CC=CC=C12 BOELCLFVOBIXIF-MAKKXPIGSA-N 0.000 description 1
- 229950001739 vinfosiltine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229950003294 voruciclib Drugs 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 229950005752 zosuquidar Drugs 0.000 description 1
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- A61K31/47—Quinolines; Isoquinolines
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Abstract
Description
米国特許法施行規則1.53(b)によって出願されたこの非仮出願は、米国特許法119(e)の元で、その全体が出典明示によって本明細書に援用されている2014年12月3日に出願された米国特許仮出願第62/087127号の利益を主張するものである。
Ab−(L−D)p
{式中、
Abは、抗体であり、
pは、1−8であり、
L−Dは、下記の式
−Str−(Pep)−Sp−D
[式中、
Strは、Abに共有結合的に結合しているストレッチャー単位であり、
Pepは、リンカーであり、
Dは、下記の式
(式中、
R20及びR30は、それぞれ独立して、C1−C6アルキルであり、
R10は、非水素置換基である、又は
R30は、C1−C6アルキルであり、R10及びR20は、Nと一緒になって、置換C3−C7ヘテロシクロアルキル環を形成する、又は
R30は存在せず、R10及びR20は、Nと一緒になって、置換ヘテロアリール環を形成する)
によって表される抗腫瘍剤であり、
Sp−Dは、式
のスペーサー部分である]
によって表される化学部分である}
によって表される抗体−薬物コンジュゲートに関する。
(式中、
Wは、−NH−ヘテロシクロアルキル−又はヘテロシクロアルキルであり、
Yは、ヘテロアリール、アリール、−C(O)C1−C6アルキレン、C2−C6アルケニル、C1−C6アルキレニル又は−C1−C6アルキレン−NH−であり、
各R1は、独立して、C1−C10アルキル、C2−C10アルケニル、(C1−C10アルキル)NHC(NH)NH2又は(C1−C10アルキル)NHC(O)NH2であり、
R3及びR2は、それぞれ独立して、H、C1−C10アルキル、C2−C10アルケニル、アリールアルキル若しくはヘテロアリールアルキルであり、又はR3及びR2は、一緒になって、C3−C7シクロアルキルを形成し得、
R4及びR5は、それぞれ独立して、C1−C10アルキル、C2−C10アルケニル、アリールアルキル、ヘテロアリールアルキル、(C1−C10アルキル)OCH2−であり、又はR4及びR5は、C3−C7シクロアルキル環を形成し得、
pは、1−8の整数である)
からなる群から選択される非ペプチド化学部分である。
Ab−(L−D)p
[式中、Abは、抗体であり、L−Dは、下記の式
(式中、
R1は、C1−C6アルキル、C2−C6アルケニル、(C1−C6アルキル)NHC(NH)NH2又は(C1−C6アルキル)NHC(O)NH2であり、
R3及びR2は、それぞれ独立して、H、C1−C10アルキルである)
によって表される化学部分である]
によって表される式(I)の抗体−コンジュゲートに関する。
Ab−(L−D)p
[式中、Abは、抗体であり、L−Dは、下記の式
(式中、
R1は、C1−C6アルキル、(C1−C6アルキル)NHC(NH)NH2又は(C1−C6アルキル)NHC(O)NH2であり、
R4及びR5は、一緒になって、C3−C7シクロアルキル環を形成する)
の化学部分である]
によって表される式(I)の抗体−コンジュゲートに関する。
Ab−(L−D)p
[式中、
Abは、抗体であり、
L−Dは、下記の式
(式中、R1は、C1−C6アルキル、(C1−C6アルキル)NHC(NH)NH2又は(C1−C6アルキル)NHC(O)NH2である)
によって表される化学部分である]
によって表される式(I)の抗体−コンジュゲートに関する。
[式中、
Strは、下記の式
(式中、
R6は、C1−C10アルキレン及びC1−C10アルキレン−C(O)N(Ra)−C2−C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオアリール、C3−C8シクロアルキル、C4−C7ヘテロシクロアルキル、ヘテロアリールアルキル及びヘテロアリールからなる群から選択される1−5個の置換基で置換されていてもよく、
各Raは、独立して、H又はC1−C6アルキルである)
によって表される化学部分であり、
pは、1、2、3又は4である]
によって表される式(I)の抗体−コンジュゲートに関する。
[式中、
Strは、下記の式
(式中、
R6は、C1−C10アルキレン及びC1−C10アルキレン−C(O)N(Ra)−C2−C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオアリール、C3−C8シクロアルキル、C4−C7ヘテロシクロアルキル、ヘテロアリールアルキル及びヘテロアリールからなる群から選択される1−5個の置換基で置換されていてもよく、
各Raは、独立して、H又はC1−C6アルキルである)
によって表される化学部分であり、
pは、1、2、3又は4である]
によって表される式(I)の抗体−コンジュゲートに関する。
[式中、
Strは、下記の式
(式中、
R6は、C1−C10アルキレン及びC1−C10アルキレン−C(O)N(Ra)−C2−C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオアリール、C3−C8シクロアルキル、C4−C7ヘテロシクロアルキル、ヘテロアリールアルキル及びヘテロアリールからなる群から選択される1−5個の置換基で置換されていてもよく、
各Raは、独立して、H又はC1−C6アルキルである)
によって表される化学部分であり、
pは、1、2、3又は4である]
によって表される式(I)の抗体−コンジュゲートに関する。
(式中、
R1は、C1−C6アルキル−NH2、(C1−C6アルキル)NHC(NH)NH2又は(C1−C6アルキル)NHC(O)NH2であり、
pは、1、2、3又は4である)
によって表される式(I)(A1)の抗体−コンジュゲートに関する。
(式中、
pは、1、2、3又は4であり、
R1は、C1−C6アルキル−NH2、(C1−C6アルキル)NHC(NH)NH2又は(C1−C6アルキル)NHC(O)NH2であり、
R4及びR5は、それぞれ独立して、C1−C6アルキルであり、前記アルキルは、置換されていないか、又はR4及びR5は、C3−C7シクロアルキル環を形成し得る)
によって表される式(I)(B1)の抗体−コンジュゲートに関する。
(式中、
R1は、C1−C6アルキル−NH2、(C1−C6アルキル)NHC(NH)NH2又は(C1−C6アルキル)NHC(O)NH2であり、
pは、1、2、3又は4である)
によって表される式(I)(C1)の抗体−コンジュゲートに関する。
(式中、
R6は、C1−C10アルキレン、C2−C10アルケニル、C3−C8シクロアルキル、(C1−C8アルキレン)O−及びC1−C10アルキレン−C(O)N(Ra)−C2−C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオアリール、C3−C8シクロアルキル、C4−C7ヘテロシクロアルキル、ヘテロアリールアルキル及びヘテロアリールからなる群から選択される1−5個の置換基で置換されていてもよく、
各Raは、独立して、H又はC1−C6アルキルである)
によって表される化学部分である、上記の抗体−コンジュゲートの任意の1つに関する。
(式中、
R7は、C1−C10アルキレン、C2−C10アルケニル、(C1−C10アルキレン)O−、N(Rc)−(C2−C6アルキレン)−N(Rc)及びN(Rc)−(C2−C6アルキレン)から選択され、
各Rcは、独立して、H又はC1−C6アルキルである)
を有する、上記の抗体−コンジュゲートの任意の1つに関する。
本発明はまた、下記の式
−Str−(Pep)−Sp−D
[式中、
Strは、Abに共有結合的に結合しているストレッチャー単位であり、
Pepは、リンカーであり、
Dは、下記の式
(式中、
R20及びR30は、それぞれ独立して、C1−C6アルキルであり、
R10は、非水素置換基である、又は
R30は、C1−C6アルキルであり、R10及びR20は、Nと一緒になって、置換C3−C7ヘテロシクロアルキル環を形成する、又は
R30は、存在せず、R10及びR20は、Nと一緒になって、置換ヘテロアリール環を形成する)
によって表される抗腫瘍抗生物質剤であり、
Sp−Dは、式
の化学部分である]
によって表される式L−Dの化合物に関する。
(式中、
Strは、抗体に共有結合的に結合し得るストレッチャー単位であり、
Yは、ヘテロアリール、アリール、−C(O)C2−C6アルケニル、C2−C6アルケニル又は−C2−C6アルケニル−NH−であり、
R1は、C1−C10アルキル、(C1−C10アルキル)NHC(NH)NH2又は(C1−C10アルキル)NHC(O)NH2であり、
R3及びR2は、それぞれ独立して、H、C1−C10アルキル、アリールアルキル若しくはヘテロアリールアルキルであり、又はR3及びR2は、一緒になって、C3−C7シクロアルキルを形成し得、
Dは、薬物である)
の非ペプチド化合物に関する。
(式中、
Strは、抗体に共有結合的に結合し得るストレッチャー単位であり、
R1は、C1−C10アルキル、(C1−C10アルキル)NHC(NH)NH2又は(C1−C10アルキル)NHC(O)NH2であり、
R4及びR5は、それぞれ独立して、C1−C10アルキル、アリールアルキル、ヘテロアリールアルキル、(C1−C10アルキル)OCH2−であり、又はR4及びR5は、C3−C7シクロアルキル環を形成し得る)
の非ペプチド化合物に関する。
(式中、
R6は、C1−C10アルキレン、C3−C8シクロアルキル、O−(C1−C8アルキレン)及びC1−C10アルキレン−C(O)N(Ra)−C2−C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオアリール、C3−C8シクロアルキル、C4−C7ヘテロシクロアルキル及びヘテロアリールからなる群から選択される1−5個の置換基で置換されていてもよく、
各Raは、独立して、H又はC1−C6アルキルである)
を有し、
Spが、−Ar−Rb−(式中、Arは、アリール又はヘテロアリールであり、Rbは、(C1−C10アルキレン)O−である)である、
式(I)(A1)(LD)、(I)(A2)(LD)、(I)(A3)(LD)、(I)(B1)(LD)、(I)(B2)(LD)、(I)(B3)(LD)、(II)(A1)(LD)又は(III)(A1)(LD)の上記の化合物のいずれかに関する。
Spが、−Ar−Rb−(式中、Arは、アリールであり、Rbは、C1−C6アルキレンである)である、
式(I)(A1)(LD)、(I)(A2)(LD)、(I)(A3)(LD)、(I)(B1)(LD)、(I)(B2)(LD)、(I)(B3)(LD)、(II)(A1)(LD)、(II)(A2)(LD)、(II)(A3)(LD)及び(IV)(A1)(LD)の化合物に関する。
(式中、
R6は、C1−C10アルキレン、C2−C10アルケニル、C3−C8シクロアルキル、(C1−C8アルキレン)O−及びC1−C10アルキレン−C(O)N(Ra)−C2−C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオアリール、C3−C8シクロアルキル、C4−C7ヘテロシクロアルキル、ヘテロアリールアルキル及びヘテロアリールからなる群から選択される1−5個の置換基で置換されていてもよく、
各Raは、独立して、H又はC1−C6アルキルである)
によって表される化学部分である、式(I)(A1)(LD)、(I)(A2)(LD)、(I)(A3)(LD)、(I)(B1)(LD)、(I)(B2)(LD)、(I)(B3)(LD)、(II)(A1)(LD)、(II)(A2)(LD)、(II)(A3)(LD)及び(IV)(A1)(LD)の化合物に関する。
(式中、
R7は、C1−C10アルキレン、C2−C10アルケニル、(C1−C10アルキレン)O−、N(Rc)−(C2−C6アルキレン)−N(Rc)及びN(Rc)−(C2−C6アルキレン)から選択され、
各Rcは、独立して、H又はC1−C6アルキルである)
を有する、式(I)(A1)(LD)、(I)(A2)(LD)、(I)(A3)(LD)、(I)(B1)(LD)、(I)(B2)(LD)、(I)(B3)(LD)、(II)(A1)(LD)、(II)(A2)(LD)、(II)(A3)(LD)及び(IV)(A1)(LD)の化合物に関する。
CLL1;
BMPR1B;
E16;
STEAP1;
0772P;
MPF;
NaPi2b;
Sema 5b;
PSCA hlg;
ETBR;
MSG783;
STEAP2;
TrpM4;
CRIPTO;
CD21;
CD79b;
FcRH2;
HER2;
NCA;
MDP;
IL20Rα;
ブレビカン;
EphB2R;
ASLG659;
PSCA;
GEDA;
BAFF−R;
CD22;
CD79a;
CXCR5;
HLA−DOB;
P2X5;
CD72;
LY64;
FcRH1;
IRTA2;
TENB2;
PMEL17;
TMEFF1;
GDNF−Ra1;
Ly6E;
TMEM46;
Ly6G6D;
LGR5;
RET;
LY6K;
GPR19;
GPR54;
ASPHD1;
チロシナーゼ;
TMEM118;
GPR172A;
MUC16及び
CD33
からなる群から選択されるポリペプチドのうち1つ又は複数に結合する、上記の抗体−薬物コンジュゲートの任意の1つに関する。
CLL1;
STEAP1;
NaPi2b;
STEAP2;
TrpM4;
CRIPTO;
CD21;
CD79b;
FcRH2;
HER2;
CD22;
CD79a;
CD72;
LY64;
Ly6E;
MUC16;及び
CD33
からなる群から選択されるポリペプチドの1つ又は複数に結合する、抗体−薬物コンジュゲートに関する。
特に断りのない限り、下記の用語及び語句は、本明細書において使用する場合、下記の意味を有することを意図する。商品名が本明細書において使用されるとき、出願人等は、商品名製品の製剤、ジェネリック薬物、及び商品名製品の医薬品有効成分(一又は複数)を独立して含むことを意図する。
本発明の治療用抗体−薬物コンジュゲート(ADC)の薬学的製剤は典型的には、薬学的に許容される非経口ビヒクルを有する非経口投与、すなわち、ボーラス、静脈内、腫瘍内注射のために、及び単位投薬注射可能形態で調製される。所望の程度の純度を有する抗体−薬物コンジュゲート(ADC)を、凍結乾燥製剤又は水溶液の形態で、薬学的に許容される希釈剤、担体、賦形剤又は安定剤と任意選択的に混合する(Remington's Pharmaceutical Sciences (1980)、第16版、Osol, A.編)。
本発明の化合物は、システイン操作抗体を含む抗体−薬物コンジュゲートを含み、野性型又は親抗体の1つ又は複数のアミノ酸は、システインアミノ酸で置き換えられている。任意の形態の抗体を、このように操作、すなわち、変異導入し得る。例えば、親Fab抗体断片を操作して、本明細書において「ThioFab」と称されるシステイン操作Fabを形成し得る。同様に、親モノクローナル抗体を操作して、「ThioMab」を形成し得る。単点突然変異は、ThioFabにおいて単一の操作されたシステイン残基を生じさせ、一方、単点突然変異は、IgG抗体のダイマーの性質によって、ThioMabにおいて2つの操作されたシステイン残基を生じさせることに留意すべきである。置き換えられた(「操作された」)システイン(Cys)残基を有する変異体は、新たに導入された操作されたシステインチオール基の反応性について評価される。チオール反応性値は、相対的な0−1.0の範囲の数値的用語であり、任意のシステイン操作抗体について測定することができる。本発明のシステイン操作抗体のチオール反応性値は、0.6−1.0;0.7−1.0;又は0.8−1.0の範囲である。
これらに限定されないが、システイン操作抗体を含めた、がんの治療において本発明の抗体−薬物コンジュゲート中で有用であり得る抗体には、これらに限定されないが、細胞表面受容体及び腫瘍関連抗原(TAA)に対する抗体が含まれる。特定の腫瘍関連抗原は当該技術分野で公知であり、当該技術分野で周知である方法及び情報を使用して抗体を生じさせることにおいて使用するために調製することができる。がんの診断及び治療法のための有効な細胞の標的を発見する試みにおいて、研究者は、1つ又は複数の正常な非癌性細胞(一又は複数)上と比較して1つ又は複数の特定のタイプ(一又は複数)のがん細胞の表面上に特異的に発現している膜貫通又は他の腫瘍関連ポリペプチドを同定することを探求してきた。しばしば、このような腫瘍関連ポリペプチドは、非癌性細胞の表面上と比較して、がん細胞の表面上でより豊富に発現している。このような腫瘍関連細胞表面抗原ポリペプチドの同定は、さらに具体的には抗体をベースとする治療法による破壊のためのがん細胞を標的とする能力を生じさせた。腫瘍関連抗原TAAの例は、これらに限定されないが、下記に列挙したものが含まれる。便宜上、これらの抗原に関する情報は、これらの全てが当該技術分野で公知であるが、下記で列挙し、名称、代替名称、Genbank寄託番号及び主要な出典(一又は複数)、下記の国立バイオテクノロジー情報センター(NCBI)の核酸及びタンパク質配列同定規定を含む。下記で列挙したTAAに対応する核酸及びタンパク質配列は、公共データベース、例えば、GenBankにおいて利用可能である。抗体によって標的とされる腫瘍関連抗原は、引用した参考文献において同定される配列に対して少なくとも約70%、80%、85%、90%、若しくは95%の配列同一性を有し、及び/又は引用した参考文献において見出される配列を有するTAAと実質的に同じ生物学的特性若しくは特性を示す全てのアミノ酸配列変異体及びアイソフォームを含む。例えば、変異体配列を有するTAAは一般に、列挙した対応する配列を有するTAAに特異的に結合する抗体に特異的に結合することができる。本明細書において特に記載した出典における配列及び開示は、出典明示によって明白に援用されている。
ten Dijke,P.ら、Science、264 (5155):101−104 (1994)、Oncogene、14 (11):1377−1382 (1997));国際公開第2004063362号(請求項2);国際公開第2003042661号(請求項12);米国特許出願第2003134790−A1号(p38−39);国際公開第2002102235号(請求項13;p296);国際公開第2003055443号(p91−92);国際公開第200299122号(実施例2;p528−530);国際公開第2003029421号(請求項6);国際公開第2003024392号(請求項2;図112);国際公開第200298358号(請求項1;p183);国際公開第200254940号(p100−101);国際公開第200259377号(p349−350);国際公開第200230268号(請求項27;p376);国際公開第200148204号(実施例;図4)
NP_001194骨形成タンパク質受容体、タイプIB/pid=NP_001194.1−
クロスリファレンス:MIM:603248;NP_001194.1;AY065994
(2)E16(LAT1、SLC7A5、Genbank寄託番号NM_003486)
Biochem. Biophys. Res. Commun. 255 (2)、283−288 (1999)、Nature 395 (6699):288−291 (1998)、Gaugitsch、H.W.ら(1992) J. Biol. Chem. 267 (16):11267−11273);国際公開第2004048938号(実施例2);国際公開第2004032842号(実施例IV);国際公開第2003042661号(請求項12);国際公開第2003016475号(請求項1);国際公開第200278524号(実施例2);国際公開第200299074号(請求項19;p127−129);国際公開第200286443号(請求項27;p222、393);国際公開第2003003906号(請求項10;p293);国際公開第200264798号(請求項33;p93−95);国際公開第200014228号(請求項5;p133−136);米国特許出願第2003224454号(図3);国際公開第2003025138号(請求項12;p150);
NP_003477溶質担体ファミリー7(カチオン性アミノ酸輸送体、y+系)、メンバー5/pid=NP_003477.3−ホモサピエンス(Homo sapiens)
クロスリファレンス:MIM:600182;NP_003477.3;NM_015923;NM_003486_1
(3)STEAP1(前立腺の6回膜貫通上皮抗原、Genbank寄託番号NM_012449)
Cancer Res. 61 (15)、5857−5860 (2001)、Hubert, R.S.ら(1999) Proc. Natl. Acad. Sci. U.S.A. 96 (25):14523−14528);国際公開第2004065577号(請求項6);国際公開第2004027049号(図1L);欧州特許第1394274号(実施例11);国際公開第2004016225号(請求項2);国際公開第2003042661号(請求項12);米国特許出願第2003157089号(実施例5);米国特許出願第2003185830号(実施例5);米国特許出願第2003064397号(図2);国際公開第200289747号(実施例5;p618−619);国際公開第2003022995号(実施例9;図13A、実施例53;p173、実施例2;図2A);
NP_036581前立腺の6回膜貫通上皮抗原
クロスリファレンス:MIM:604415;NP_036581.1;NM_012449_1
(4)0772P(CA125、MUC16、Genbank寄託番号AF361486)
J. Biol. Chem. 276 (29):27371−27375 (2001);国際公開第2004045553号(請求項14);国際公開第200292836号(請求項6;図12);国際公開第200283866号(請求項15;p116−121);米国特許出願第2003124140号(実施例16);
クロスリファレンス:GI:34501467;AAK74120.3;AF361486_1
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン、Genbank寄託番号NM_005823)Yamaguchi, N.ら、Biol. Chem. 269 (2)、805−808 (1994)、Proc. Natl. Acad. Sci. U.S.A. 96 (20):11531−11536 (1999)、Proc. Natl. Acad. Sci. U.S.A. 93 (1):136−140 (1996)、J. Biol. Chem. 270 (37):21984−21990 (1995);国際公開第2003101283号(請求項14);(国際公開第2002102235号(請求項13;p287−288);国際公開第2002101075号(請求項4;p308−309);国際公開第200271928号(p320−321);国際公開第9410312号(p52−57);クロスリファレンス:MIM:601051;NP_005814.2;NM_005823_1
(6)NaPi2b(NAPI−3B、NPTIIb、SLC34A2、溶質担体ファミリー34(リン酸ナトリウム)、メンバー2、タイプIIナトリウム依存性リン酸輸送体3b、Genbank寄託番号NM_006424)
J. Biol. Chem. 277 (22):19665−19672 (2002)、Genomics 62 (2):281−284 (1999)、Feild, J.A.ら、(1999) Biochem. Biophys. Res. Commun. 258 (3):578−582);国際公開第2004022778号(請求項2);欧州特許第1394274号(実施例11);国際公開第2002102235号(請求項13;p326);欧州特許第875569号(請求項1;p17−19);国際公開第200157188号(請求項20;p329);国際公開第2004032842号(実施例IV);国際公開第200175177号(請求項24;p139−140);
クロスリファレンス:MIM:604217;NP_006415.1;NM_006424_1
(7)Sema5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、semaドメイン、7回トロンボスポンジンリピート(タイプ1及びタイプ1−様)、膜貫通ドメイン(TM)及び短い細胞質ドメイン、(セマフォリン)5B、Genbank寄託番号AB040878)
Nagase T.ら(2000) DNA Res. 7 (2):143−150);国際公開第2004000997号(請求項1);国際公開第2003003984号(請求項1);国際公開第200206339号(請求項1;p50);国際公開第200188133号(請求項1;p41−43、48−58);国際公開第2003054152号(請求項20);国際公開第2003101400号(請求項11);
アクセッション:Q9P283;EMBL;AB040878;BAA95969.1.Genew;HGNC:10737;
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA2700050C12、RIKEN cDNA2700050C12遺伝子、Genbank寄託番号AY358628);Rossら(2002) Cancer Res. 62:2546−2553;米国特許出願第2003129192号(請求項2);米国特許出願第2004044180号(請求項12);米国特許出願第2004044179号(請求項11);米国特許出願第2003096961号(請求項11);米国特許出願第2003232056号(実施例5);国際公開第2003105758号(請求項12);米国特許出願第2003206918号(実施例5);欧州特許第1347046号(請求項1);国際公開第2003025148号(請求項20);
クロスリファレンス:GI:37182378;AAQ88991.1;AY358628_1
(9)ETBR(エンドセリンタイプB受容体、Genbank寄託番号AY275463);
Nakamuta M.ら、Biochem. Biophys. Res. Commun. 177、34−39、1991;Ogawa Y.ら、Biochem. Biophys. Res. Commun. 178、248−255、1991;Arai H.ら、Jpn. Circ. J. 56、1303−1307、1992;Arai H.ら、J. Biol. Chem. 268、3463−3470、1993;Sakamoto A.、Yanagisawa M.ら、Biochem. Biophys. Res. Commun. 178、656−663、1991;Elshourbagy N.A.ら、J. Biol. Chem. 268、3873−3879、1993;Haendler B.ら、J. Cardiovasc. Pharmacol. 20、s1−S4、1992;Tsutsumi M.ら、Gene 228、43−49、1999;Strausberg R.L.ら、Proc. Natl. Acad. Sci. U.S.A. 99、16899−16903、2002;Bourgeois C.ら、J. Clin. Endocrinol. Metab. 82、3116−3123、1997;Okamoto Y.ら、Biol. Chem. 272、21589−21596、1997;Verheij J.B.ら、Am. J. Med. Genet. 108、223−225、2002;Hofstra R.M.W.ら、Eur. J. Hum. Genet. 5、180−185、1997;Puffenberger E.G.ら、Cell 79、1257−1266、1994;Attie T.ら、Hum. Mol. Genet. 4、2407−2409、1995;Auricchio A.ら、Hum. Mol. Genet.5:351−354、1996;Amiel J.ら、Hum. Mol. Genet. 5、355−357、1996;Hofstra R.M.W.ら、Nat. Genet. 12、445−447、1996;Svensson P.J.ら、Hum. Genet. 103、145−148、1998;Fuchs S.ら、Mol. Med. 7、115−124、2001;Pingault V.ら、(2002) Hum. Genet. 111、198−206;国際公開第2004045516号(請求項1);国際公開第2004048938号(実施例2);国際公開第2004040000号(請求項151);国際公開第2003087768号(請求項1);国際公開第2003016475号(請求項1);国際公開第2003016475号(請求項1);国際公開第200261087号(図1);国際公開第2003016494号(図6);国際公開第2003025138号(請求項12;p144);国際公開第200198351号(請求項1;p124−125);欧州特許第522868号(請求項8;図2);国際公開第200177172号(請求項1;p297−299);米国特許出願第2003109676号;米国特許第6518404号(図3);米国特許第5773223号(請求項1a;31−34欄);国際公開第2004001004号;
(10)MSG783(RNF124、仮定上のタンパク質FLJ20315、Genbank寄託番号NM_017763);
国際公開第2003104275号(請求項1);国際公開第2004046342号(実施例2);国際公開第2003042661号(請求項12);国際公開第2003083074号(請求項14;p61);国際公開第2003018621号(請求項1);国際公開第2003024392号(請求項2;図93);国際公開第200166689号(実施例6);
クロスリファレンス:ローカスID:54894;NP_060233.2;NM_017763_1
(11)STEAP2(HGNC_8639、IPCA−1、PCANAP1、STAMP1、STEAP2、STMP、前立腺がんと関連する遺伝子1、前立腺がんと関連するタンパク質1、前立腺2の6回膜貫通上皮抗原、6回膜貫通前立腺タンパク質、Genbank寄託番号AF455138)
Lab. Invest. 82 (11):1573−1582 (2002);国際公開第2003087306号;米国特許出願第2003064397号(請求項1;図1);国際公開第200272596号(請求項13;p54−55);国際公開第200172962号(請求項1;図4B);国際公開第2003104270号(請求項11);国際公開第2003104270号(請求項16);米国特許出願第2004005598号(請求項22);国際公開第2003042661号(請求項12);米国特許出願第2003060612号(請求項12;図10);国際公開第200226822号(請求項23;図2);国際公開第200216429号(請求項12;図10);
クロスリファレンス:GI:22655488;AAN04080.1;AF455138_1
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容体電位カチオンチャネル、サブファミリーM、メンバー4、Genbank寄託番号NM_017636)
Xu, X.Z.ら、Proc. Natl. Acad. Sci. U.S.A. 98 (19):10692−10697 (2001)、Cell 109 (3):397−407 (2002)、J. Biol. Chem. 278 (33):30813−30820 (2003);米国特許出願第2003143557号(請求項4);国際公開第200040614号(請求項14;p100−103);国際公開第200210382号(請求項1;図9A);国際公開第2003042661号(請求項12);国際公開第200230268号(請求項27;p391);米国特許出願第2003219806号(請求項4);国際公開第200162794号(請求項14;図1A−D);
クロスリファレンス:MIM:606936;NP_060106.2;NM_017636_1
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形がん由来増殖因子、Genbank寄託番号NP_003203又はNM_003212)
Ciccodicola, A.ら、EMBO J. 8 (7):1987−1991 (1989)、Am. J. Hum. Genet. 49 (3):555−565 (1991);米国特許出願第2003224411号(請求項1);国際公開第2003083041号(実施例1);国際公開第2003034984号(請求項12);国際公開第200288170号(請求項2;p52−53);国際公開第2003024392号(請求項2;図58);国際公開第200216413号(請求項1;p94−95、105);国際公開第200222808号(請求項2;図1);米国特許第5854399号(実施例2;17−18欄);米国特許第5792616号(図2);
クロスリファレンス:MIM:187395;NP_003203.1;NM_003212_1
(14)CD21(CR2(補体受容体2)又はC3DR(C3d/エプスタインバーウイルス受容体)又はHs.73792Genbank寄託番号M26004)
Fujisakuら(1989) J. Biol. Chem. 264 (4):2118−2125;Weis J.J.ら、J. Exp. Med. 167、1047−1066、1988;Moore M.ら、Proc. Natl. Acad. Sci. U.S.A. 84、9194−9198、1987;Barel M.ら、Mol. Immunol. 35、1025−1031、1998;Weis J.J.ら、Proc. Natl. Acad. Sci. U.S.A. 83、5639−5643、1986;Sinha S.K.ら(1993) J. Immunol. 150、5311−5320;国際公開第2004045520号(実施例4);米国特許出願第2004005538号(実施例1);国際公開第2003062401号(請求項9);国際公開第2004045520号(実施例4);国際公開第9102536号(図9.1−9.9);国際公開第2004020595号(請求項1);
アクセッション:P20023;Q13866;Q14212;EMBL;M26004;AAA35786.1。
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン−関連ベータ)、B29、Genbank寄託番号NM_000626又は11038674)
Proc. Natl. Acad. Sci. U.S.A. (2003) 100 (7):4126−4131、Blood (2002) 100 (9):3068−3076、Mullerら(1992) Eur. J. Immunol. 22 (6):1621−1625;国際公開第2004016225号(請求項2、図140);国際公開第2003087768号、米国特許出願第2004101874号(請求項1、p102);国際公開第2003062401号(請求項9);国際公開第200278524号(実施例2);米国特許出願第2002150573号(請求項5、p15);米国特許第5644033号;国際公開第2003048202号(請求項1、p306及び309);国際公開第99/558658号、米国特許第6534482号(請求項13、図17A/B);国際公開第200055351号(請求項11、p1145−1146);
クロスリファレンス:MIM:147245;NP_000617.1;NM_000626_1
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C、Genbank寄託番号NM_030764、AY358130)
Genome Res. 13 (10):2265−2270 (2003)、Immunogenetics 54 (2):87−95 (2002)、Blood 99 (8):2662−2669 (2002)、Proc. Natl. Acad. Sci. U.S.A. 98 (17):9772−9777 (2001)、Xu, M.J.ら(2001) Biochem. Biophys. Res. Commun. 280 (3):768−775;国際公開第2004016225号(請求項2);国際公開第2003077836号;国際公開第200138490号(請求項5;図18D−1−18D−2);国際公開第2003097803号(請求項12);国際公開第2003089624号(請求項25);
クロスリファレンス:MIM:606509;NP_110391.2;NM_030764_1
(17)HER2(ErbB2、Genbank寄託番号M11730)
Coussens L.ら、Science (1985) 230(4730):1132−1139);Yamamoto T.ら、Nature 319、230−234、1986;Semba K.ら、Proc. Natl. Acad. Sci. U.S.A. 82、6497−6501、1985;Swiercz J.M.ら、J. Cell Biol. 165、869−880、2004;Kuhns J.J.ら、J. Biol. Chem. 274、36422−36427、1999;Cho H.−S.ら、Nature 421、756−760、2003;Ehsani A.ら(1993) Genomics 15、426−429;国際公開第2004048938号(実施例2);国際公開第2004027049号(図1I);国際公開第2004009622号;国際公開第2003081210号;国際公開第2003089904号(請求項9);国際公開第2003016475号(請求項1);米国特許出願第2003118592号;国際公開第2003008537号(請求項1);国際公開第2003055439号(請求項29;図1A−B);国際公開第2003025228号(請求項37;図5C);国際公開第200222636号(実施例13;p95−107);国際公開第200212341号(請求項68;図7);国際公開第200213847号(p71−74);国際公開第200214503号(p114−117);国際公開第200153463号(請求項2;p41−46);国際公開第200141787号(p15);国際公開第200044899号(請求項52;図7);国際公開第200020579号(請求項3;図2);米国特許第5869445号(請求項3;31−38欄);国際公開第9630514号(請求項2;p56−61);欧州特許第1439393号(請求項7);国際公開第2004043361号(請求項7);国際公開第2004022709号;国際公開第200100244号(実施例3;図4);
アクセッション:P04626;EMBL;M11767;AAA35808.1.EMBL;M11761;AAA35808.1。
(18)NCA(CEACAM6、Genbank寄託番号M18728);
Barnett T.ら、Genomics 3、59−66、1988;Tawaragi Y.ら、Biochem. Biophys. Res. Commun. 150、89−96、1988;Strausberg R.L.ら、Proc. Natl. Acad. Sci. U.S.A. 99:16899−16903、2002;国際公開第2004063709号;欧州特許第1439393号(請求項7);国際公開第2004044178号(実施例4);国際公開第2004031238号;国際公開第2003042661号(請求項12);国際公開第200278524号(実施例2);国際公開第200286443号(請求項27;p427);国際公開第200260317号(請求項2);
アクセッション:P40199;Q14920;EMBL;M29541;AAA59915.1.EMBL;M18728;
(19)MDP(DPEP1、Genbank寄託番号BC017023)
Proc. Natl. Acad. Sci. U.S.A. 99 (26):16899−16903 (2002);国際公開第2003016475号(請求項1);国際公開第200264798号(請求項33;p85−87);JP05003790(図6−8);国際公開第9946284号(図9);
クロスリファレンス:MIM:179780;AAH17023.1;BC017023_1
(20)IL20Rα(IL20Ra、ZCYTOR7、Genbank寄託番号AF184971);
Clark H.F.ら、Genome Res. 13、2265−2270、2003;Mungall A.J.ら、Nature 425、805−811、2003;Blumberg H.ら、Cell 104、9−19、2001;Dumoutier L.ら、J. Immunol. 167、3545−3549、2001;Parrish−Novak J.ら、J. Biol. Chem. 277、47517−47523、2002;Pletnev S.ら(2003) Biochemistry 42:12617−12624;Sheikh F.ら(2004) J. Immunol. 172、2006−2010;欧州特許第1394274号(実施例11);米国特許出願第2004005320号(実施例5);国際公開第2003029262号(p74−75);国際公開第2003002717号(請求項2;p63);国際公開第200222153号(p45−47);米国特許出願第2002042366号(p20−21);国際公開第200146261号(p57−59);国際公開第200146232号(p63−65);国際公開第9837193号(請求項1;p55−59);
アクセッション:Q9UHF4;Q6UWA9;Q96SH8;EMBL;AF184971;AAF01320.1。
(21)ブレビカン(BCAN、BEHAB、Genbank寄託番号AF229053)
Gary S.C.ら、Gene 256、139−147、2000;Clark H.F.ら、Genome Res. 13、2265−2270、2003;Strausberg R.L.ら、Proc. Natl. Acad. Sci. U.S.A. 99、16899−16903、2002;米国特許出願第2003186372号(請求項11);米国特許出願第2003186373号(請求項11);米国特許出願第2003119131号(請求項1;図52);米国特許出願第2003119122号(請求項1;図52);米国特許出願第2003119126号(請求項1);米国特許出願第2003119121号(請求項1;図52);米国特許出願第2003119129号(請求項1);米国特許出願第2003119130号(請求項1);米国特許出願第2003119128号(請求項1;図52);米国特許出願第2003119125号(請求項1);国際公開第2003016475号(請求項1);国際公開第200202634号(請求項1);
(22)EphB2R(DRT、ERK、Hek5、EPHT3、Tyro5、Genbank寄託番号NM_004442)
Chan,J.及びWatt, V.M.、Oncogene 6 (6)、1057−1061 (1991)、Oncogene 10 (5):897−905 (1995)、Annu. Rev. Neurosci. 21:309−345 (1998)、Int. Rev. Cytol. 196:177−244 (2000);国際公開第2003042661号(請求項12);国際公開第200053216号(請求項1;p41);国際公開第2004065576号(請求項1);国際公開第2004020583号(請求項9);国際公開第2003004529号(p128−132);国際公開第200053216号(請求項1;p42);
クロスリファレンス:MIM:600997;NP_004433.2;NM_004442_1
(23)ASLG659(B7h、Genbank寄託番号AX092328)
米国特許出願第20040101899号(請求項2);国際公開第2003104399号(請求項11);国際公開第2004000221号(図3);米国特許出願第2003165504号(請求項1);米国特許出願第2003124140号(実施例2);米国特許出願第2003065143号(図60);国際公開第2002102235号(請求項13;p299);米国特許出願第2003091580号(実施例2);国際公開第200210187号(請求項6;図10);国際公開第200194641号(請求項12;図7b);国際公開第200202624号(請求項13;図1A−1B);米国特許出願第2002034749号(請求項54;p45−46);国際公開第200206317号(実施例2;p320−321、請求項34;p321−322);国際公開第200271928号(p468−469);国際公開第200202587号(実施例1;図1);国際公開第200140269号(実施例3;p190−192);国際公開第200036107号(実施例2;p205−207);国際公開第2004053079号(請求項12);国際公開第2003004989号(請求項1);国際公開第200271928号(p233−234、452−453);国際公開第0116318号;
(24)PSCA(前立腺幹細胞抗原前駆体、Genbank寄託番号AJ297436)
Reiter R.E.ら、Proc. Natl. Acad. Sci. U.S.A. 95、1735−1740、1998;Gu Z.ら、Oncogene 19、1288−1296、2000;Biochem. Biophys. Res. Commun. (2000) 275(3):783−788;国際公開第2004022709号;欧州特許第1394274号(実施例11);米国特許出願第2004018553号(請求項17);国際公開第2003008537号(請求項1);国際公開第200281646号(請求項1;p164);国際公開第2003003906号(請求項10;p288);国際公開第200140309号(実施例1;図17);米国特許出願第2001055751号(実施例1;図1b);国際公開第200032752号(請求項18;図1);国際公開第9851805号(請求項17;p97);国際公開第9851824号(請求項10;p94);国際公開第9840403号(請求項2;図1B);
アクセッション:O43653;EMBL;AF043498;AAC39607.1。
(25)GEDA(Genbank寄託番号AY260763);
AAP14954脂肪腫HMGIC融合−パートナー−様タンパク質/pid=AAP14954.1−ホモサピエンス
種:ホモサピエンス(ヒト)
国際公開第2003054152号(請求項20);国際公開第2003000842号(請求項1);国際公開第2003023013号(実施例3、請求項20);米国特許出願第2003194704号(請求項45);
クロスリファレンス:GI:30102449;AAP14954.1;AY260763_1
(26)BAFF−R(B細胞−活性化因子受容体、BLyS受容体3、BR3、Genbank寄託番号AF116456);BAFF受容体/pid=NP_443177.1−ホモサピエンス
Thompson, J.S.ら、Science 293 (5537)、2108−2111 (2001);国際公開第2004058309号;国際公開第2004011611号;国際公開第2003045422号(実施例;p32−33);国際公開第2003014294号(請求項35;図6B);国際公開第2003035846号(請求項70;p615−616);国際公開第200294852号(136−137欄);国際公開第200238766号(請求項3;p133);国際公開第200224909号(実施例3;図3);
クロスリファレンス:MIM:606269;NP_443177.1;NM_052945_1;AF132600
(27)CD22(B細胞受容体CD22−Bアイソフォーム、BL−CAM、Lyb−8、Lyb8、SIGLEC−2、FLJ22814、Genbank寄託番号AK026467);
Wilsonら(1991) J. Exp. Med. 173:137−146;国際公開第2003072036号(請求項1;図1);
クロスリファレンス:MIM:107266;NP_001762.1;NM_001771_1
(28)CD79a(CD79A、CD79α、免疫グロブリン−関連アルファ、Igベータ(CD79B)と共有結合的に相互作用し、その表面上でIgM分子と複合体を形成し、B−細胞分化に関与するシグナルを伝達するB細胞特異的タンパク質)、pI:4.84、MW:25028TM:2[P]遺伝子染色体:19q13.2、Genbank寄託番号NP_001774.10)
国際公開第2003088808号、米国特許出願第20030228319号;国際公開第2003062401号(請求項9);米国特許出願第2002150573号(請求項4、p13−14);国際公開第9958658号(請求項13、図16);国際公開第9207574号(図1);米国特許第5644033号;Haら(1992) J. Immunol. 148(5):1526−1531;Muellerら(1992) Eur. J. Biochem. 22:1621−1625;Hashimotoら(1994) Immunogenetics 40(4):287−295;Preud’hommeら(1992) Clin. Exp. Immunol. 90(1):141−146;Yuら(1992) J. Immunol. 148(2) 633−637;Sakaguchiら(1988) EMBO J. 7(11):3457−3464;
(29)CXCR5(バーキットリンパ腫受容体1、CXCL13ケモカインによって活性化され、リンパ球移動及び液性防御において機能し、HIV−2感染並びに恐らくAIDS、リンパ腫、骨髄腫、及び白血病の発生において役割を果たしているGタンパク質共役受容体);372aa、pI:8.54MW:41959TM:7[P]遺伝子染色体:11q23.3、Genbank寄託番号NP_001707.1)
国際公開第2004040000号;国際公開第2004015426号;米国特許出願第2003105292号(実施例2);米国特許第6555339号(実施例2);国際公開第200261087号(図1);国際公開第200157188号(請求項20、p269);国際公開第200172830号(p12−13);国際公開第200022129号(実施例1、p152−153、実施例2、p254−256);国際公開第9928468号(請求項1、p38);米国特許第5440021号(実施例2、49−52欄);国際公開第9428931(p56−58);国際公開第9217497号(請求項7、図5);Dobnerら(1992) Eur. J. Immunol. 22:2795−2799;Barellaら(1995) Biochem. J. 309:773−779;
(30)HLA−DOB(ペプチドに結合し、これらをCD4+Tリンパ球に提示するMHCクラスII分子(Ia抗原)のベータサブユニット);273aa、pI:6.56MW:30820TM:1[P]遺伝子染色体:6p21.3、Genbank寄託番号NP_002111.1)
Tonnelleら(1985) EMBO J. 4(11):2839−2847;Jonssonら(1989) Immunogenetics 29(6):411−413;Beckら(1992) J. Mol. Biol. 228:433−441;Strausbergら(2002) Proc. Natl. Acad. Sci USA99:16899−16903;Serveniusら(1987) J. Biol. Chem. 262:8759−8766;Beckら(1996) J. Mol. Biol. 255:1−13;Naruseら(2002) Tissue Antigens 59:512−519;国際公開第9958658号(請求項13、図15);米国特許第6153408号(35−38欄);米国特許第5976551号(168−170欄);米国特許第6011146号(145−146欄);Kasaharaら(1989) Immunogenetics 30(1):66−68;Larhammarら(1985) J. Biol. Chem. 260(26):14111−14119;
(31)P2X5(プリン受容体P2Xリガンド開口型イオンチャネル5、細胞外ATPによって開閉され、シナプス伝達及び神経発生に関与し得、その欠失が特発性排尿筋不安定の病態生理に関与し得る);422aaイオンチャネル)、pI:7.63、MW:47206TM:1[P]遺伝子染色体:17p13.3、Genbank寄託番号NP_002552.2)
Leら(1997) FEBS Lett. 418(1−2):195−199;国際公開第2004047749号;国際公開第2003072035号(請求項10);Touchmanら(2000) Genome Res. 10:165−173;国際公開第200222660号(請求項20);国際公開第2003093444号(請求項1);国際公開第2003087768号(請求項1);国際公開第2003029277号(p82);
(32)CD72(B−細胞分化抗原CD72、Lyb−2)タンパク質配列Full maeaity...tafrfpd(1..359;359aa)、pI:8.66、MW:40225TM:1[P]遺伝子染色体:9p13.3、Genbank寄託番号NP_001773.1)
国際公開第2004042346号(請求項65);国際公開第2003026493号(p51−52、57−58);国際公開第200075655号(p105−106);Von Hoegenら(1990) J. Immunol. 144(12):4870−4877;Strausbergら(2002) Proc. Natl. Acad. Sci USA 99:16899−16903;
(33)ロイシンリッチリピート(LRR)ファミリーのLY64(リンパ球抗原64(RP105)、タイプI膜タンパク質は、B細胞活性化及びアポトーシスをレギュレートし、機能喪失は、全身性狼瘡を有する患者における疾患活性の増加と関連する);661aa、pI:6.20、MW:74147TM:1[P]遺伝子染色体:5q12、Genbank寄託番号NP_005573.1)
米国特許出願第2002193567号;国際公開第9707198号(請求項11、p39−42);Miuraら(1996) Genomics 38(3):299−304;Miuraら(1998) Blood 92:2815−2822;国際公開第2003083047号;国際公開第9744452号(請求項8、p57−61);国際公開第200012130号(p24−26);
(34)FcRH1(Fc受容体−様タンパク質1、C2タイプIg−様及びITAMドメインを含有する免疫グロブリンFcドメインについての推定上の受容体は、B−リンパ球分化において役割を有し得る);429aa、pI:5.28、MW:46925TM:1[P]遺伝子染色体:1q21−1q22、Genbank寄託番号NP_443170.1)
国際公開第2003077836号;国際公開第200138490号(請求項6、図18E−1−18−E−2);Davisら(2001) Proc. Natl. Acad. Sci USA 98(17):9772−9777;国際公開第2003089624号(請求項8);欧州特許第1347046号(請求項1);国際公開第2003089624号(請求項7);
(35)IRTA2(免疫グロブリンスーパーファミリー受容体トランスロケーション関連2、B細胞発生及びリンパ腫形成において可能性のある役割を有する推定上の免疫受容体;いくつかのB細胞悪性腫瘍において起こるトランスロケーションによる遺伝子のディレギュレーション);977aa、pI:6.88MW:106468TM:1[P]遺伝子染色体:1q21、Genbank寄託番号ヒト:AF343662、AF343663、AF343664、AF343665、AF369794、AF397453、AK090423、AK090475、AL834187、AY358085;マウス:AK089756、AY158090、AY506558;NP_112571.1
国際公開第2003024392号(請求項2、図97);Nakayamaら(2000) Biochem. Biophys. Res. Commun. 277(1):124−127;国際公開第2003077836号;国際公開第200138490号(請求項3、図18B−1−18B−2);
(36)TENB2(TMEFF2、tomoregulin、TPEF、HPP1、TR、推定上の膜貫通プロテオグリカン、増殖因子及びフォリスタチンのEGF/ヘレグリンファミリーに関連する);374aa、NCBIアクセッション:AAD55776、AAF91397、AAG49451、NCBI RefSeq:NP_057276;NCBI遺伝子:23671;OMIM:605734;SwissProt Q9UIK5;Genbank寄託番号AF179274;AY358907、CAF85723、CQ782436
国際公開第2004074320号(配列番号810);JP2004113151(配列番号2、4、8);国際公開第2003042661号(配列番号580);国際公開第2003009814号(配列番号411);欧州特許第1295944号(p69−70);国際公開第200230268号(p329);国際公開第200190304号(配列番号2706);米国特許出願第2004249130号;米国特許出願第2004022727号;国際公開第2004063355号;米国特許出願第2004197325号;米国特許出願第2003232350号;米国特許出願第2004005563号;米国特許出願第2003124579号;Horieら(2000) Genomics 67:146−152;Uchidaら(1999) Biochem. Biophys. Res. Commun. 266:593−602;Liangら(2000) Cancer Res. 60:4907−12;Glynne−Jonesら(2001) Int J Cancer. Oct 15;94(2):178−84;
(37)PMEL17(銀ホモログ;SILV;D12S53E;PMEL17;(SI);(SIL);ME20;gp100)BC001414;BT007202;M32295;M77348;NM_006928;McGlinchey,R.P.ら(2009) Proc. Natl. Acad. Sci. U.S.A. 106 (33)、13731−13736;Kummer, M.P.ら(2009) J. Biol. Chem. 284 (4)、2296−2306;
(38)TMEFF1(EGF−様及び2つのフォリスタチン−様ドメイン1を有する膜貫通タンパク質;Tomoregulin−1;H7365;C9orf2;C9ORF2;U19878;X83961)NM_080655;NM_003692;Harms, P.W. (2003) Genes Dev. 17 (21)、2624−2629;Gery, S.ら(2003) Oncogene 22 (18):2723−2727;
(39)GDNF−Ra1(GDNFファミリー受容体アルファ1;GFRA1;GDNFR;GDNFRA;RETL1;TRNR1;RET1L;GDNFR−アルファ1;GFR−ALPHA−1;U95847;BC014962;NM_145793)NM_005264;Kim, M.H.ら(2009) Mol. Cell. Biol. 29 (8)、2264−2277;Treanor, J.J.ら(1996) Nature 382 (6586):80−83;
(40)Ly6E(リンパ球抗原6複合体、ローカスE;Ly67、RIG−E、SCA−2、TSA−1)NP_002337.1;NM_002346.2;de Nooij−van Dalen,A.G.ら(2003) Int. J. Cancer 103 (6)、768−774;Zammit, D.J.ら(2002) Mol. Cell. Biol. 22 (3):946−952;
(41)TMEM46(shisaホモログ2(アフリカツメガエル(Xenopus laevis));SHISA2)NP_001007539.1;NM_001007538.1;Furushima, K.ら(2007) Dev. Biol. 306 (2)、480−492;Clark, H.F.ら(2003) Genome Res. 13 (10):2265−2270;
(42)Ly6G6D(リンパ球抗原6複合体、ローカスG6D;Ly6−D、MEGT1)NP_067079.2;NM_021246.2;Mallya, M.ら(2002) Genomics 80 (1):113−123;Ribas, G.ら(1999) J. Immunol. 163 (1):278−287;
(43)LGR5(Gタンパク質共役受容体5を含有するロイシンリッチリピート;GPR49、GPR67)NP_003658.1;NM_003667.2;Salanti, G.ら(2009) Am. J. Epidemiol. 170 (5):537−545;Yamamoto, Y.ら(2003) Hepatology 37 (3):528−533;
(44)RET(retがん原遺伝子;MEN2A;HSCR1;MEN2B;MTC1;(PTC);CDHF12;Hs.168114;RET51;RET−ELE1)NP_066124.1;NM_020975.4;Tsukamoto, H.ら(2009) Cancer Sci. 100 (10):1895−1901;Narita, N.ら(2009) Oncogene 28 (34):3058−3068;
(45)LY6K(リンパ球抗原6複合体、ローカスK;LY6K;HSJ001348;FLJ35226)NP_059997.3;NM_017527.3;Ishikawa, N.ら(2007) Cancer Res. 67 (24):11601−11611;de Nooij−van Dalen, A.G.ら(2003) Int. J. Cancer 103 (6):768−774;
(46)GPR19(Gタンパク質共役受容体19;Mm.4787)NP_006134.1;NM_006143.2;Montpetit,A.及びSinnett,D.(1999)Hum.Genet.105(1−2):162−164;O’Dowd, B.F.ら(1996) FEBS Lett. 394 (3):325−329;
(47)GPR54(KISS1受容体;KISS1R;GPR54;HOT7T175;AXOR12)NP_115940.2;NM_032551.4;Navenot, J.M.ら(2009) Mol. Pharmacol. 75 (6):1300−1306;Hata, K.ら(2009) Anticancer Res. 29 (2):617−623;
(48)ASPHD1(アスパルテートベータ−ヒドロキシラーゼドメイン含有1;LOC253982)NP_859069.2;NM_181718.3;Gerhard, D.S.ら(2004) Genome Res. 14 (10B):2121−2127;
(49)チロシナーゼ(TYR;OCAIA;OCA1A;チロシナーゼ;SHEP3)NP_000363.1;NM_000372.4;Bishop, D.T.ら(2009) Nat. Genet. 41 (8):920−925;Nan, H.ら(2009) Int. J. Cancer 125 (4):909−917;
(50)TMEM118(ringフィンガータンパク質、膜貫通2;RNFT2;FLJ14627)NP_001103373.1;NM_001109903.1;Clark, H.F.ら(2003) Genome Res. 13 (10):2265−2270;Scherer, S.E.ら(2006) Nature 440 (7082):346−351
(51)GPR172A(Gタンパク質共役受容体172A;GPCR41;FLJ11856;D15Ertd747e)NP_078807.1;NM_024531.3;Ericsson, T.A.ら(2003) Proc. Natl. Acad. Sci. U.S.A. 100 (11):6759−6764;Takeda, S.ら(2002) FEBS Lett. 520 (1−3):97−101。
薬物添加量は、抗体当たりの薬物部分の平均数である。薬物添加量は、抗体(Ab)当たり1−8つの薬物(D)の範囲でよく、すなわち、1つ、2つ、3つ、4つ、5つ、6つ、7つ、及び8つの薬物部分は、抗体に共有結合的に結合している。ADCの組成物は、1−8の一連の薬物とコンジュゲートした抗体のコレクションを含む。コンジュゲーション反応からのADCの調製物中の抗体当たりの薬物の平均数は、通常の手段、例えば、質量分析、ELISAアッセイ、電気泳動、及びHPLCによって特徴を明らかにし得る。pに関するADCの定量的分布をまた決定し得る。ELISAによって、ADCの特定の調製物中のpの平均値を決定し得る(Hamblettら(2004) Clin. Cancer Res. 10:7063-7070;Sandersonら(2005) Clin. Cancer Res. 11:843-852)。しかし、p(薬物)値の分布は、抗体−抗原結合、及びELISAの検出限界によって識別可能でない。また、抗体−薬物コンジュゲートの検出のためのELISAアッセイは、薬物部分が抗体、例えば、重鎖若しくは軽鎖断片、又は特定のアミノ酸残基のどこに結合しているかを決定しない。場合によって、均一ADC(pは、他の薬物添加量を有するADCからの特定の値である)の分離、精製、及び特徴づけは、手段、例えば、逆相HPLC又は電気泳動によって達成し得る。
三級アミン又はピリジン官能基を含有する薬物の例は、これらに限定されないが、トポテカン、LB−100、IB−01212、Mcl−1阻害剤、68Ga−BNOTA−PRGD2、ベネトクラクス、テクネチウムTc 99mチルマノセプト(tilmanocept)、E−7016、HM−30181AK、パクリタキセル、AS−1896596、EM−015、ガドテリドール、BGJ−398、EC−1456、ドビチニブ(Dovitinib)、ピロルチニブ(pyrroltinib)マレイン酸塩、GSK−923295、イリノテカン、BGP−15、90Y−エドトレオチド(edotreotide)、ミベフラジル、レスミノスタット(resminostat)、イタルナフロキシン(itarnafloxin)、NMS−P153、NMS−P937、イリノテカンスクロソフェート(sucrosofate)、アビラテロン、A−366、SB−743921、ギルテリチニブ(Gilteritinib)、アベマシクリブ(Abemaciclib)、IPP−204106、ビンフルニン、CX−5461、ドキシサイクリン、TP−0903、TLK−58747、イリノテカン、ヌモナフィド(numonafide)、ON−123300、ビンタフォリド、KX2391、ガドペンテト酸ジメグルミン、ゲダトリシブ(gedatolisib)、タシドチン(tasidotin)HCl、Genzyme/Ergomed、TTL−1177、ナルトレキソン、CFI−400945フマル酸塩、ピクチリシブ(Pictilisib)、フェロタキセル(Felotaxel)、OTX−008、バノキサントロン(Banoxantrone)、G−773、トラベクテジン、NO−サキナビル、ENMD−2076、ガドブトロール、BGB−102、Ga68標識されたスクテラリン(scutellarin)コンジュゲート、THZ−1、TSR−011、ONC−201、ASP−3026、ガラクトシルセラミド増強されたビノレルビン、PMX−20005、111In−RP−782、DSR−6434、ビンクリスチン硫酸塩、J−21475、アピトリシブ(Apitolisib)、MDX−1203、ガリウム−68−SH−7139、CNX−1351、CT−1578、TG−02、イマチニブ、ルミネスピブ(luminespib)、ビンデシン−CB−3717コンジュゲート、AMG511、AZD1152hQPAアキュリン(Accurin)、メパクリン、CGM−097、TR−100、BGB−324、CEP−37440、OTSSP−167、APR−246、インドテカン(Indotecan)、ガドテル酸メグルミン、ルカントン、ナビトクラックス(navitoclax)、サマリウム(153Sm)レキシドロナム、DMDAPatA、OCT−1002、イリノテカン塩酸塩、BAY−87−2243、SIMM−559、CEP−33779、XL−388、SHR−1258、ボルシクリブ(Voruciclib)、UNBS−5162、ノスカピン、アルテミシニン、PHA−665752、ピロロベンゾジアゼピン、葉酸塩−ビンデシンヒドラジドコンジュゲート、BRN−103、NSC−134754、AMP−53、PKI−402、タリキダル(Tariquidar)、CG−200745、VO−100、PRLX−93936、セニセルチブ(Cenisertib)、SSR−125329、CRD−401、SN−24771、バラマピモド(Balamapimod)、BIBX−1382、105509、KW−2152、リダマイシン(Lidamycin)、CT−17、SN−23490、L−000021649、U−74389G、JNJ−17029259、PAK−200、PFP−6、XR−842、RP−697、NCO−700、B−220、パゼリプチン(Pazelliptine)、R−116010、NL−2001、RC−3940−II、BIM−46068、MDL−73811、CHIR−200131、ハリツリン(Halitulin)、フレゼラスチン(Flezelastine)、シンコニン、BN−52207、ABT−546、NSC−639366、ダテリプチウム(datelliptium)塩化物、WR−63320、LY−329146、ドラフェニン(dolaphenine)アンドロスタンSR−25989、XR−9051、RSU−1069、N−1379、エペルマイシン(epelmycin)A、PNU−144113、FCE−27726、NSC−357704、PD−171851、DZ−3358、B−9309−068、Goe−7874、Ro−44−5912、MDL−103323、モファロテン(Mofarotene)、Ro−46−7864、RU−45144、Win−63320、NC−190、NSC−646958、VA−033、GI−149893、BBR−2378、NSC−639365、ビンホシルチン(Vinfosiltine)、SDZ−62−434、BCH−2051、RB−90745、TI−356、ER−37328、SR−26050、CL−329753、LY−326315、AN−1006、CP−117227、R−テルジピン(teludipine)、RB−90740、SYUIQ−05、SR−16388、SN−28049、SN−30000、トポテカン塩酸塩、ビノレルビン、WBZ−7、S−44563、GSK−1070916、RPR−203360、デスメチル、デスアミノパテアミンA、EU−517、AT−9283、スピロゲルマニウム塩酸塩、E−7974、アゾアクリドン、ビノレルビン、GTx−134、アステミゾール、レテリプチン(retelliptine)、ミトナフィド(mitonafide)、リムカゾール、PBT−1、アチプリモド、トピキサントロン(Topixantrone)、A−620223、トリドルゴシル(tridolgosir)、テセタキセル(tesetaxel)EMD−94283、A−923573、E−7107、NRC−2694、アルベスピマイシン(alvespimycin)塩酸塩、SMT−14400、PHA−793887、HB−19、S−12363、ソブリドチン、CEP−28122、TKS−040、ABT−306552、ATI−1025、A−928605、PF−3758309、99mTc−RP−527、MLN−576、K−454、W−198、Debio−0931、ゾスキダル(Zosuquidar)、PF−337210、ABT−737、葉酸塩ツブリシン(folatetubulysin)コンジュゲート、エラクリダール(elacridar)、CP−31398、AV−412、エロモテカン(Elomotecan)、GSK−1838705A、ABT−839、AEW−541、ビンクリスチン、ゲフィチニブ、ドキソルビシン、YHO−13351、ペリチニブ(Pelitinib)、セマドチン、A−947864、トザセルチブ(Tozasertib)、PD−115934、ドラスタチン−10、SU−11274、オマセタキシン・メペサクシネート、EHT−1864、ドフェキダール(Dofequidar)、DX−52−1、RTA−502、カネルチニブ、メトクロプラミド、BMS−753493、PD−166285、アウリスタチンPYE、アルケミクス(Alchemix)、C−1305、ANG−1009、プロカイン塩酸塩、シラメシン(siramesine)、Hoe−33342、マンザミン(Manzamine)、OSI−632、STX−1801、BIBF−1000、ラルトテカン(lurtotecan)、ZK−191703、チアムリン(Tiamulin)、VX−322、ドセタキセル、Ro−28−2653、ベカテカリン(Becatecarin)、GS−164、JNK−401、タモラリジン(Tamolarizine)、ピブロゼレシン(Pibrozelesin)、S−16020−2、NK−611、ラジルビシン(Ladirubicin)、TOP−008、デクロプラミド(Declopramide)、ラルトテカン、TAS−103、デクスニグルジピン(Dexniguldipine)、BAM−1120、コノフィリン(Conophylline)、ICRF−193、アンヒドロビンブラスチン、ツブリシン、エクチナサイジン及びL−745631を含む。
本発明の抗体−薬物コンジュゲート(ADC)を使用して、例えば、腫瘍抗原の過剰発現によって特徴が明らかにされる様々な疾患又は障害を治療し得ることが意図されている。例示的状態又は過剰増殖性疾患は、良性又は悪性の固形腫瘍及び血液学的障害、例えば、白血病及びリンパ性悪性腫瘍を含む。その他のものは、ニューロン、グリア、アストロサイト、視床下部、腺、マクロファージ、上皮、間質、胞胚腔、炎症、血管新生、及び自己免疫を含めた免疫の障害を含む。
[4−[[(2S)−2−[[1−[5−(2,5−ジオキソピロール−1−イル)ペンチルカルバモイル]シクロブタンカルボニル]アミノ]−5−ウレイド−ペンタノイル]アミノ]フェニル]メチル−[(1S)−1−[[(1S)−1−[[(1S,2R)−2−メトキシ−4−[(2S)−2−[(1R,2R)−1−メトキシ−2−メチル−3−オキソ−3−[[(1S)−2−フェニル−1−チアゾール−2−イル−エチル]アミノ]プロピル]ピロリジン−1−イル]−1−[(1S)−1−メチルプロピル]−4−オキソ−ブチル]−メチル−カルバモイル]−2−メチル−プロピル]カルバモイル]−2−メチル−プロピル]−ジメチル−アンモニウム
小型のバイアル中に、N1’−[(1S)−1−[[4−(クロロメチル)フェニル]カルバモイル]−4−ウレイド−ブチル]−N1−[5−(2,5−ジオキソピロール−1−イル)ペンチル]シクロブタン−1,1−ジカルボキサミド(100質量%、1当量、0.04713mmol、1.000、27.76mg)、ドラスタチン10(100質量%、37mg、0.04713mmol、1.000、37mg)及びテトラブチルアンモニウムヨージド(65.65質量%、0.3当量、0.01414mmol、0.3000、7.956mg)を混合し、N,N−ジメチルホルムアミド(100質量%、50μL、0.646mmol、13.7、47.3mg、0.05mL)に溶解した。混合物を室温で3時間撹拌したところ、反応は観察されなかった。この反応混合物に、N,N−ジイソプロピルエチルアミン(100質量%、1.5当量、0.07069mmol、1.500、9.136mg、0.0123mL)を加えた。反応混合物を一晩室温で撹拌した。反応混合物のLC/MSは、16%生成物を示した。追加当量の塩基を加え、これにより、生成物形成を改善し、より明瞭なLC/MSピークを得た。
1H NMR (400 MHz, DMSO-d6) δ 10.47 (d, J = 2.5 Hz, 1H), 8.92 (q, J = 9.0 Hz, 1H), 8.31 (s, 4H), 8.05 - 7.91 (m, 0H), 7.91 - 7.75 (m, 4H), 7.67 (s, 0H), 7.63 (d, J = 3.2 Hz, 0H), 7.62 - 7.54 (m, 0H), 7.54 (s, 0H), 7.58 - 7.45 (m, 2H), 7.33 - 7.11 (m, 5H), 7.08 - 6.95 (m, 2H), 6.13 (t, J = 5.6 Hz, 1H), 5.75 (s, 1H), 5.57 - 5.37 (m, 3H), 4.76 - 4.55 (m, 3H), 4.41 (dt, J = 15.5, 6.0 Hz, 1H), 3.98 (q, J = 6.3 Hz, 2H), 3.61 - 3.28 (m, 4H), 3.28 - 3.07 (m, 9H), 3.07 - 2.87 (m, 10H), 2.84 - 2.68 (m, 1H), 2.49 - 2.31 (m, 6H), 2.31 - 1.90 (m, 0H), 1.88 - 1.54 (m, 7H), 1.41 (ddt, J = 28.5, 22.6, 10.5 Hz, 10H), 1.18 (tdd, J = 19.3, 7.8, 4.5 Hz, 3H), 1.12 - 1.02 (m, 5H), 1.02 - 0.91 (m, 5H), 0.91 - 0.82 (m, 6H), 0.79 (td, J = 7.4, 3.0 Hz, 4H).
(2R)−2−((2S,3S)−1−(((1R,3R)−1−アセトキシ−1−(4−((2R,4S)−4−カルボキシ−1−フェニルペンタン−2−イルカルバモイル)チアゾール−2−イル)−4−メチルペンタン−3−イル)(メチル)アミノ)−3−メチル−1−オキソペンタン−2−イルカルバモイル)−1−(4−((S)−2−(1−(5−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)ペンチルカルバモイル)シクロブタンカルボキサミド)−5−ウレイドペンタンアミド)ベンジル)−1−メチルピペリジニウム
小型のバイアル中に、N1’−[(1S)−1−[[4−(クロロメチル)フェニル]カルバモイル]−4−ウレイド−ブチル]−N1−[5−(2,5−ジオキソピロール−1−イル)ペンチル]シクロブタン−1,1−ジカルボキサミド(100質量%、17mg、0.02886mmol、1.000、17mg)、(2S,4R)−4−[[2−[(1R,3R)−1−アセトキシ−4−メチル−3−[メチル−[(2S,3S)−3−メチル−2−[[(2R)−1−メチルピペリジン−2−カルボニル]アミノ]ペンタノイル]アミノ]ペンチル]チアゾール−4−カルボニル]アミノ]−2−メチル−5−フェニル−ペンタン酸(100質量%、1当量、0.02886mmol、1.000、21.01mg)及びテトラブチルアンモニウムヨージド(65.65質量%、0.3当量、0.008657mmol、0.3000、4.872mg)を、N,N−ジメチルホルムアミド(100質量%、75μL、0.970mmol、33.6、70.9mg、0.075mL)に取った。得られた反応混合物を1時間室温で撹拌したところ、所望の生成物は観察されなかった。この反応混合物に、N,N−ジイソプロピルエチルアミン(100質量%、1.1当量、0.03174mmol、1.100、4.103mg、0.00554mL)を加えたところ、僅かな量の生成物が形成された。次いで反応混合物を一晩室温で撹拌し、その後、1追加当量の塩基を加え、その日の残り時間中、混合物を撹拌した。すると所望の生成物が観察され、これを希釈し、HPLCにおいて精製して、生成物のいかなる損失も回避した。
1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 2H), 9.50 (s, 2H), 8.48 (s, 6H), 8.36 (s, 3H), 8.12 (s, 2H), 8.05 (s, 1H), 7.75 (s, 3H), 7.33 - 7.26 (m, 4H), 7.26 - 7.18 (m, 5H), 7.13 (d, J = 7.6 Hz, 5H), 6.99 (d, J = 5.7 Hz, 2H), 6.42 (s, 2H), 5.73 (s, 2H), 5.56 (s, 3H), 4.64 (s, 4H), 4.57 (t, J = 7.8 Hz, 2H), 4.38 (dq, J = 15.0, 5.4 Hz, 2H), 4.13 (dd, J = 13.0, 7.6 Hz, 2H), 3.05 (q, J = 6.9, 6.2 Hz, 12H), 3.00 - 2.87 (m, 10H), 2.84 - 2.70 (m, 3H), 2.50 (s, 2H), 2.40 (ヘプタ, J = 13.1, 10.5 Hz, 9H), 2.25 (d, J = 11.2 Hz, 1H), 2.18 - 1.94 (m, 0H), 1.91 - 1.64 (m, 0H), 1.58 (s, 0H), 1.42 (ddt, J = 23.8, 16.7, 8.4 Hz, 15H), 1.32 - 1.23 (m, 12H), 1.17 (p, J = 8.3, 7.4 Hz, 6H), 1.11 - 0.99 (m, 6H), 0.94 - 0.85 (m, 12H), 0.80 (q, J = 7.6 Hz, 10H).
(2S,4R)−4−[[2−[(1R,3R)−1−アセトキシ−4−メチル−3−[メチル−[(2S,3S)−3−メチル−2−[[(2R)−1−メチル−1−[[4−[[(2R)−2−[(6−ニトロ−3−ピリジル)ジスルファニル]プロポキシ]カルボニルアミノ]フェニル]メチル]ピペリジン−1−イウム−2−カルボニル]アミノ]ペンタノイル]アミノ]ペンチル]チアゾール−4−カルボニル]アミノ]−2−メチル−5−フェニル−ペンタン酸
工程1:
モノメチル−ニトロ−PDS−PAB−Cl
モノメチル(R)−2−((6−ニトロピリジン−3−イル)ジスルファニル)プロピル4−(クロロメチル)フェニルカルバメート
小型のバイアル中に、モノメチル(R)−2−((6−ニトロピリジン−3−イル)ジスルファニル)プロピル4−(ヒドロキシメチル)フェニルカルバメート(−ニトロ−PDS−PAB−OH)(100質量%、50mg、0.1265mmol、1.000、50mg)を、N,N−ジメチルホルムアミド(100質量%、0.2mL、3mmol、20、200mg、0.2mL)に溶解した。得られた反応混合物を氷浴中で冷却し、塩化チオニル(100質量%、1.2当量、0.1517mmol、1.200、18.05mg、0.01106mL)のジクロロメタン(100質量%、50μL、0.7800mmol、6.168、66.25mg、0.05mL)中溶液を滴加した。氷浴からこの反応混合物を除去し、室温における30分間の撹拌後に、LCMSは、所望の生成物を示した。DCM中溶液としての一(1)追加当量の塩化チオニルを、反応混合物に滴加して、一晩室温で撹拌した。新たなLCMSピークが、質量が438の生成物ピークの近くに形成された。反応混合物を酢酸エチルで希釈し、水でクエンチし、有機層を水で2回洗浄し、MgSO4で脱水し、シリカにおいて濃縮し、30%EtOAc/ヘプタンにより溶出するフラッシュクロマトグラフィーによって精製した。白色固体を単離した。LC/MSは、材料が、不純物としてアルコール前駆体を有することを示した。モノメチル(R)−2−((6−ニトロピリジン−3−イル)ジスルファニル)プロピル4−(クロロメチル)フェニルカルバメート(−ニトロ−PDS−PAB−Cl)(100質量%、B、38mg、0.09181mmol、0.7260、38mg)。(72.6%収率)M/Z=414.00。
小型のバイアル中で、[(2R)−2−[(6−ニトロ−3−ピリジル)ジスルファニル]プロピル]N−[4−(クロロメチル)フェニル]カルバミン酸塩(100質量%)及び(2S,4R)−4−[[2−[(1R,3R)−1−アセトキシ−4−メチル−3−[メチル−[(2S,3S)−3−メチル−2−[[(2R)−1−メチルピペリジン−2−カルボニル]アミノ]ペンタノイル]アミノ]ペンチル]チアゾール−4−カルボニル]アミノ]−2−メチル−5−フェニル−ペンタン酸(100質量%、9.6mg、0.013mmol、1.0、9.6mg)を、N,N−ジメチルホルムアミド(100質量%)に取った。この反応混合物に、テトラブチルアンモニウムヨージド(65.65質量%、0.2当量、0.0026mmol、0.20、1.5mg)と、続いてN,N−ジイソプロピルエチルアミン(100質量%、1当量、0.013mmol、1.0、1.7mg、0.0023mL)を加えた。反応混合物を38℃まで20分間温め、次いで室温で2時間撹拌した。LC/MSは、所望の生成物を示した。反応をほぼ半分の過程で停止して分解を回避し、DMFで希釈し、酸性条件下でHPLCにおいて直接精製した。(2S,4R)−4−[[2−[(1R,3R)−1−アセトキシ−4−メチル−3−[メチル−[(2S,3S)−3−メチル−2−[[(2R)−1−メチル−1−[[4−[[(2R)−2−[(6−ニトロ−3−ピリジル)ジスルファニル]プロポキシ]カルボニルアミノ]フェニル]メチル]ピペリジン−1−イウム−2−カルボニル]アミノ]ペンタノイル]アミノ]ペンチル]チアゾール−4−カルボニル]アミノ]−2−メチル−5−フェニル−ペンタン酸を単離した。(100質量%、4.6mg、0.0041576mmol、0.32、4.6mg)(32%収率)、M/Z=1106.4。
2−[[2−[(1S)−1−(クロロメチル)−5−ヒドロキシ−1,2−ジヒドロベンゾ[e]インドール−3−カルボニル]−1H−インドール−5−イル]オキシ]エチル−[[4−[[(2S)−2−[[1−[5−(2,5−ジオキソピロール−1−イル)ペンチルカルバモイル]シクロブタンカルボニル]アミノ]−5−ウレイド−ペンタノイル]アミノ]フェニル]メチル]−ジメチル−アンモニウムの調製
工程1:(S)−N−(5−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)ペンチル)−N−(1−(4−(ヒドロキシメチル)フェニルアミノ)−1−オキソ−5−ウレイドペンタン−2−イル)シクロブタン−1,1−ジカルボキサミド
化合物1(150g、1.53mol)を、化合物2(201g、1.53mol)のHOAc(1000mL)中の撹拌された溶液に加えた。混合物を室温で2時間撹拌した後、これを8時間加熱還流した。有機溶媒を減圧下に除去し、残留物をEtOAc(500mL×3)で抽出し、H2Oで洗浄した。混合した有機層をNa2SO4で脱水し、濃縮して、生成物を得た。このように得られた生成物を石油エーテルで洗浄して、化合物3を白色固体として得た(250g、77.4%)。
1H NMR(400MHz, DMSO-d6): δ 8.02(s, 2H), 6.99(s, 2H), 3.37-3.34(m, 2H), 2.71-2.64(m, 2H), 1.56-1.43(m, 4H), 1.23-1.20(m, 2H).
LCMS(ESI):m/z503.0[M+1]。
LCMS(ESI):m/z435.0[M+1]。
LCMS(ESI):m/z406.9[M+1]。
1H NMR(400MHz, メタノール-d4) δ 8.86(d, J=8.4Hz, 2H), 8.51(d, J=8.4Hz, 2H), 5.88-5.85(m, 1H), 5.78(s, 2H), 4.54-4.49(m, 3H), 4.38-4.32(m, 1H), 3.86 - 3.75(m, 1H), 3.84-3.80(m, 2H), 3.28-3.21(m, 1H), 3.30-3.24(m, 1H), 3.00-2.80(m, 1H), 2.37-2.28(m, 2H).
1H NMR(400MHz, DMSO-d6): δ 10.00(s, 1H), 7.82-7.77(m, 2H), 7.53(d, J=8.4Hz, 2H), 7.19(d, J=8.4Hz, 2H), 6.96(s, 2H), 5.95(t, J=6.4Hz, 1H), 5.39(s, 2H), 5.08(t, J=5.6Hz, 1H), 4.40-4.35(m, 3H), 4.09(d, J=4.8Hz, 1H), 3.01(d, J=3.2Hz, 2H), 3.05-2.72(m, 4H), 2.68-2.58(m, 3H), 2.40-2.36(m, 4H), 1.72-1.70(m, 3H), 1.44-1.42(m, 1H), 1.40-1.23(m, 6H), 1.21-1.16(m, 4H).
化合物14(2.0g、3.5mmol)のNMP(50mL)中溶液に、SOCl2(1.25g、10.5mmol)を0℃で滴加した。反応混合物を20℃で30分間撹拌した後に、これを水(50mL)で希釈し、EtOAc(50mL×3)で抽出した。有機層を乾燥し、濃縮し、フラッシュカラム(DCM:MeOH=20:1)によって精製して、生成物15(1.0g、48.4%)を灰色固体として得た。LCMS:(5−95、AB、1.5分)、0.696分、m/z=589.0[M+1]+。
N1’−[(1S)−1−[[4−(クロロメチル)フェニル]カルバモイル]−4−ウレイド−ブチル]−N1−[5−(2,5−ジオキソピロール−1−イル)ペンチル]シクロブタン−1,1−ジカルボキサミド15(100質量%、1当量、0.04310mmol、1.000、25.39mg)及び[(1S)−1−(クロロメチル)−5−ヒドロキシ−1,2−ジヒドロベンゾ[e]インドール−3−イル]−[5−(2−ジメチルアミノエチルオキシ)−1H−インドール−2−イル]メタノン(100質量%、20mg、0.04310mmol、1.000、20mg)を、N,N−ジメチルホルムアミド(100質量%)において混合し、得られた混合物を数日間撹拌した。次に、テトラブチルアンモニウムヨージド(65.65質量%、0.3当量、0.01293mmol、0.3000、7.276mg)を加え、混合物を一晩撹拌した。塩化物によるヨウ化物の交換は観察されなかった。次いで、N,N−ジイソプロピルエチルアミン(100質量%、1.2当量、0.05172mmol、1.200、6.685mg、0.00902mL)を加え、混合物を4時間撹拌した。反応混合物は、所望の生成物質量に対応する、LCMSにおける主ピークを含有した。次いで、反応混合物をDMFで希釈し、酸性条件下でHPLCにおいて直接精製し、純粋画分を単離した。室温における画分の濃縮は、一部の材料を分解した。結果として、材料を再度精製した。2−[[2−[(1S)−1−(クロロメチル)−5−ヒドロキシ−1,2−ジヒドロベンゾ[e]インドール−3−カルボニル]−1H−インドール−5−イル]オキシ]エチル−[[4−[[(2S)−2−[[1−[5−(2,5−ジオキソピロール−1−イル)ペンチルカルバモイル]シクロブタンカルボニル]アミノ]−5−ウレイド−ペンタノイル]アミノ]フェニル]メチル]−ジメチル−アンモニウム(100質量%、11.8mg、0.0116mmol、0.269、11.8mg)。26.9%収率。M/Z=1017.35
(5S,7S,9S)−9−((3aR,3a1R,4R,5S,5aR,10bR)−4−アセトキシ−3a−エチル−5−ヒドロキシ−8−メトキシ−5−(メトキシカルボニル)−6−メチル−3a,3a1,4,5,5a,6,11,12−オクタヒドロ−1H−インドリジノ[8,1−cd]カルバゾール−9−イル)−3−(4−((S)−2−(1−((5−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)ペンチル)カルバモイル)シクロブタンカルボキサミド)−5−ウレイドペンタンアミド)ベンジル)−5−エチル−5−ヒドロキシ−9−(メトキシカルボニル)−1,2,3,4,5,6,7,8,9,10−デカヒドロ−3,7−メタノ[1]アザシクロウンデシノ[5,4−b]インドール−3−イウム
小型のバイアル中で、N,N−ジメチルホルムアミド(100質量%、100μL、1.29mmol、29.4、94.5mg、0.1mL)においてN1’−[(1S)−1−[[4−(クロロメチル)フェニル]カルバモイル]−4−ウレイド−ブチル]−N1−[5−(2,5−ジオキソピロール−1−イル)ペンチル]シクロブタン−1,1−ジカルボキサミド(100質量%、1当量、0.04400mmol、1.000、25.92mg)及びビンブラスチン(89.21質量%、B、40mg、0.04400mmol、1.000、40mg)を加えた。この混合物に、テトラブチルアンモニウムヨージド(65.65質量%、0.3当量、0.01320mmol、0.3000、7.428mg)及びN,N−ジイソプロピルエチルアミン(100質量%、1当量、0.04400mmol、1.000、5.687mg、0.00767mL)を加え、混合物を数日間撹拌した。一(1)追加当量の塩基を加えて、反応をさらに押し進めた。
1H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.84 (s, 1H), 8.78 (s, 1H), 8.43 (s, 2H), 8.11 (d, J = 7.9 Hz, 1H), 7.91 (t, J = 5.6 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.14 - 6.99 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.57 (s, 1H), 6.41 (s, 1H), 6.31 (t, J = 6.6 Hz, 1H), 5.80 (dd, J = 10.5, 4.9 Hz, 1H), 5.54 (s, 2H), 5.28 (d, J = 10.1 Hz, 1H), 5.13 (s, 2H), 4.60 (d, J = 12.4 Hz, 2H), 4.40 (dt, J = 17.3, 6.1 Hz, 2H), 4.18 - 4.07 (m, 2H), 3.78 (s, 3H), 3.62 (t, J = 14.1 Hz, 6H), 3.36 (t, J = 7.0 Hz, 2H), 3.20 (dq, J = 29.0, 8.5, 6.3 Hz, 2H), 3.07 (q, J = 6.6 Hz, 2H), 2.98 (q, J = 6.4 Hz, 2H), 2.93 - 2.86 (m, 1H), 2.83 - 2.71 (m, 2H), 2.67 (s, 3H), 2.48 - 2.33 (m, 5H), 2.30 (d, J = 14.8 Hz, 1H), 2.12 - 2.04 (m, 1H), 1.97 (s, 3H), 1.70 (ddtd, J = 44.3, 19.2, 9.5, 8.5, 4.4 Hz, 4H), 1.56 - 1.31 (m, 14H), 1.26 - 1.14 (m, 3H), 0.81 (t, J = 7.4 Hz, 4H), 0.60 (t, J = 7.3 Hz, 3H).
実施例6 −− MC−Sq−Cit−PAB−morph連結したゲフィチニブ
(S)−4−(3−(4−(3−クロロ−4−フルオロフェニルアミノ)−7−メトキシキナゾリン−6−イルオキシ)プロピル)−4−(4−(2−(1−(5−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)ペンチルカルバモイル)シクロブタンカルボキサミド)−5−ウレイドペンタンアミド)ベンジル)モルホリン−4−イウム
(S)−4−(3−クロロ−4−フルオロフェニルアミノ)−1−(4−(2−(1−(5−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)ペンチルカルバモイル)シクロブタンカルボキサミド)−5−ウレイドペンタンアミド)ベンジル)−7−メトキシ−6−(3−モルホリノプロポキシ)キナゾリン−1−イウム
LCMS(5−95AB/1.5分):RT=0.673分、[M+H]+931.3。
3の1HNMR: (DMSO, 400MHz) δ: 10.59(s, 1H), 10.05(s, 1H), 8.50(s, 2H), 8.46(s, 1H), 8.18-8.16(d, J=8.0Hz, 1H), 8.00(s,1H), 7.88-7.71(m, 7H), 7.514-7.24 (m, 8H), 6.29(s, 1H), 5.54 (s, 2H), 4.69 (s, 2H), 4.30-4.14 (m, 6H), 3.97-3.95 (m, 8H), 3.57-3.51 (m, 6H), 2.98-2.97(d, J=5.6Hz, 2H), 1.68-1.60 (m, 2H), 1.47-1.40 (m, 2H);
LCMS(5−95AB/1.5分):RT=0.662分、[M+H]+931.3。
化合物3(50.0mg、0.050mmol)のDMF(1.5mL)中溶液に、ピペリジン(9.13mg、0.110mmol)を加え、混合物を23℃で3.0時間撹拌した。LCMSは、50.6%の生成物を示した。混合物を濃縮し、残留物をMTBE(6.0mL)で2回洗浄して、化合物4(31mg、0.044mmol、81.4%)を白色固体として得、これを直接使用した。LCMS(5−95AB/1.5分):RT=0.553分、[M+H]+709.2。
化合物4(31.0mg、0.040mmol)のDMF(3.0mL)中溶液に、化合物5(41.4mg、0.090mmol)及びDIEA(11.3mg、0.090mmol)を加えた。混合物を23℃で18.0時間撹拌した後に、LCMSは、52%の生成物を示した。残留物をprep−HPLC(FA、アセトニトリル20%−50%)によって精製して、(S)−4−(3−(4−(3−クロロ−4−フルオロフェニルアミノ)−7−メトキシキナゾリン−6−イルオキシ)プロピル)−4−(4−(2−(1−(5−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)ペンチルカルバモイル)シクロブタンカルボキサミド)−5−ウレイドペンタンアミド)ベンジル)モルホリン−4−イウム、実施例6(10.4mg、23.6%収率)を白色固体として得た。LCMS(5−95AB/1.5分):RT=0.736分、[M+H]+1001.1
化合物3A(110.0mg、0.120mmol)のDMF(2.5mL)中溶液に、ピペリジン(20.1mg、0.240mmol)を加えた。混合物を23℃で3.0時間撹拌した。LCMSは、50.7%の生成物を示した。混合物を濃縮してDMFを除去し、MTBE(10.0mL)で2回洗浄して、粗製の化合物4A(85mg、100%収率)を黄色固体として得、これを次の工程に直接使用した。
化合物4A(40mg、0.060mmol)のDMF(3mL)中溶液に、化合物5(53.4mg、0.110mmol)及びDIEA(14.6mg、0.113mmol)を加えた。混合物を23℃で18.0時間撹拌した。得られた残留物を分取HPLC(FA、アセトニトリル20%−50%)によって精製して、(S)−4−(3−クロロ−4−フルオロフェニルアミノ)−1−(4−(2−(1−(5−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)ペンチルカルバモイル)シクロブタンカルボキサミド)−5−ウレイドペンタンアミド)ベンジル)−7−メトキシ−6−(3−モルホリノプロポキシ)キナゾリン−1−イウム、実施例7(10.3mg、17.9%収率)を黄色固体として得た。LCMS(5−95AB/1.5分):RT=0.740分、[M]+1001.6。
化合物6(1000mg、1.99mmol)を充填したフラスコに、HBr/HOAcの溶液(4.0mL)を0℃で滴加した。これを25℃で3.0時間撹拌した。LCMS(5−95AB/1.5分)は、90.2%の生成物を示した。混合物を濃縮し、EtOAc(300mL)を加え、濃縮して少量の酸を除去し、次いで残留物を氷水(50.0mL)に注ぎ、固体を濾過によって収集して、化合物2(726mg、41.3%収率)を灰色固体として得た。LCMS(5−95AB/1.5分):RT=0.772分、[M+H]+567.0。
化合物7(200mg、0.65mmol)のDCM(12mL)中溶液に、化合物7(179mg、0.97mmol)及びDIC(123mg、0.97mmol)を加え、混合物を23℃で1.5時間撹拌した。LCMSは、70.9%の生成物を示した。混合物を濃縮し、THF(2.0mL)で2回洗浄して、化合物5(120mg、0.263mmol、40.5%収率)を無色の油状物として得、これを次の工程に直接使用した。
還元及び再酸化によるコンジュゲーションのためのシステイン操作抗体の調製
特定の条件下で、システイン操作抗体は、本発明のリンカー−薬物中間体とのコンジュゲーションのために、還元剤、例えば、DTT(クレランド試薬、ジチオスレイトール)又はTCEP(トリス(2−カルボキシエチル)ホスフィン塩酸塩による処理によって反応性とし得る;Getzら(1999) Anal. Biochem.、第273巻:73−80;Soltec Ventures、Beverly、MA)。CHO細胞上で発現している完全長システイン操作モノクローナル抗体(ThioMab)(Gomezら(2010) Biotechnology and Bioeng. 105(4):748-760;Gomezら(2010) Biotechnol. Prog. 26:1438-1445)を、例えば、約50倍過剰なDTTで室温にて一晩還元し、新たに導入したシステイン残基及び培養培地中に存在するシステインの間に形成し得るジスルフィド結合を還元した。
操作抗体システインを、CHO細胞において発現しているようにグルタチオン及び/又はシステインを伴う混合ジスルフィドとしてブロックした。これらのシステインは、コンジュゲーションの前に「非ブロック化」されなくてはならない。
上記の例の還元及び再酸化手順後、抗体を、PBS(リン酸緩衝生理食塩水)バッファーに溶解し、氷上で冷却する。チオール−反応性官能基、例えば、マレイミド又はブロモ−アセトアミドを有する過剰な約1.5モルから20当量のリンカー−薬物中間体を、DMSOに溶解し、アセトニトリル及び水に希釈し、PBS中の冷却し、還元し、再酸化した抗体に加える。約1時間後、過剰なマレイミドを加え、反応物をクエンチし、未反応の抗体チオール基をキャップする。コンジュゲーション混合物を添加し、HiTrap SP FFカラムを通して溶出させて、過剰な薬物−リンカー中間体及び他の不純物を除去し得る。反応混合物を遠心限外濾過によって濃縮し、システイン操作抗体薬物コンジュゲートを精製し、PBS中のG25樹脂を通す溶出によって脱塩し、滅菌条件下で0.2μmフィルターを通して濾過し、貯蔵のために冷凍する。
次いで、選択したリンカーを試験し、インビトロ及びインビボでのアッセイにおいて活性であることが見出された。切断データを、下記の表において示す。
ペプチドリンカーと同様に、ADCのための非ペプチドリンカーは、適正な薬物放出のためにリソソーム中で切断可能であると予想される。細胞の消化オルガネラとして、リソソームは、酸性pHにて最適な加水分解活性を示すいくらかのプロテアーゼが濃縮されている。カテプシンBは代表的なリソソームのプロテアーゼであり、ADCペプチドリンカーの活性化の一因となることが示されてきた。最初のスクリーニングとして、抗体とのコンジュゲーションに適した切断可能なリンカー−薬物コンストラクトを同定するために精製したカテプシンBを使用したアッセイを開発した。ノルフロキサシンを使用して、リンカー−薬物の薬物成分を表した。コントロールペプチド(例えば、Val−Cit)に対する切断の百分率並びに切断反応の動力学的パラメーター(Km及びVmax)を、所与の時点において測定した。アッセイの詳細な記載を下で示す。このアッセイから、種々のタンパク質分解性活性及び構造的に多様なリンカーを同定し、後でADCの作製において使用し得る。
ADCの有効性を、下記のプロトコール(CELLTITER GLO(商標)発光細胞生存能力アッセイ、Promega Corpを用いた細胞増殖アッセイによって測定した。Technical Bulletin TB288;Mendozaら(2002) Cancer Res. 62:5485−5488):
1.培地中の約104個の細胞(SKBR−3、BT474、MCF7又はMDA−MB−468)を含有する100μlのアリコートの細胞培養物を、96ウェル不透明壁プレートの各ウェルに入れた。
2.培地を含有し、細胞を含有しないコントロールウェルを調製した。
3.ADCを実験ウェルに加え、3−5日間インキュベートした。
4.プレートを、概ね30分間室温に平衡化させた。
5.各ウェル中に存在する細胞培地の容量と等しい容量のCELLTITER GLO(商標)試薬を加えた。
6.内容物をオービタルシェーカー上で2分間混合し、細胞溶解を誘導した。
7.プレートを室温にて10分間インキュベートし、発光シグナルを安定化した。
8.発光を記録し、RLU=相対発光ユニットとしてグラフにおいて報告した。
培地:SK−BR−3は、50/50/10%FBS/グルタミン/250μg/mL中で増殖する。G−418OVCAR−3は、RPMI/20%FBS/グルタミン中で増殖する。
1.抗Napi2B抗体−薬物コンジュゲート(ADC)の有効性を、Igrov−1のマウス異種移植モデル(ヒト卵巣がん)において調査した。
NaPi2bヒト化抗体:
一実施態様において、本発明のADCのNapi2b抗体は、3つの軽鎖超可変領域及び3つの重鎖超可変領域(配列番号1−6)を含み、これらの配列を下記に示す。
一実施態様において、本発明のADCの抗CD33抗体は、3つの軽鎖超可変領域及び3つの重鎖超可変領域を含み、これらの配列(配列番号11−16)を下記に示す。
一実施態様において、本発明のADCの抗CD22抗体は、3つの軽鎖超可変領域及び3つの重鎖超可変領域(配列番号41−46)を含み、これらの配列を下記に示す。
下記のADCを、上記のインビボアッセイにおいて試験したが、活性であることが見出された。前記ADCの活性を、図1及び下の記述において例示する。
Claims (26)
- 式(I)
{式中、
Abは、抗体であり、
pは、1−8であり、
L−Dは、下記の式
[式中、
Strは、Abに共有結合的に結合しているストレッチャー単位であり、
Pepは、
(式中、
Wは、−NH−ヘテロシクロアルキル−又はヘテロシクロアルキルであり、
Yは、ヘテロアリール、アリール、−C(O)C1−C6アルキレン、C2−C6アルケニル、C1−C6アルキレン又は−C1−C6アルキレン−NH−であり、
各R1は、独立して、C1−C10アルキル、C2−C10アルケニル、(C1−C10アルキル)NHC(NH)NH2又は(C1−C10アルキル)NHC(O)NH2であり、
R3及びR2は、それぞれ独立して、H、C1−C10アルキル、C2−C10アルケニル、アリールアルキル、ヘテロアリールアルキルであり、又はR3及びR2は、一緒になって、C3−C7シクロアルキルを形成し得、
R4及びR5は、それぞれ独立して、C1−C10アルキル、C2−C10アルケニル、アリールアルキル、ヘテロアリールアルキル、(C1−C10アルキル)OCH2−であり、又はR4及びR5は、一緒になって、C3−C7シクロアルキル環を形成し得る)
からなる群から選択される非ペプチド化学部分であり、
Dは、下記の式
(式中、
(a)R20及びR30は、それぞれ独立して、C1−C6アルキルであり、R10は、非水素置換基である、
(b)R30は、C1−C6アルキルであり、R10及びR20は、Nと一緒になって、置換C3−C7ヘテロシクロアルキル環を形成する、又は
(c)R30は、存在せず、R10及びR20は、Nと一緒になって、置換ヘテロアリール環を形成する)
によって表される抗腫瘍剤であり、
Sp−Dは、式
のスペーサー−薬物部分である]
によって表される化学部分である}
の抗体−薬物コンジュゲート。 - Strが、式
(式中、R6は、C1−C10アルキレン、C2−C10アルケニル、C3−C8シクロアルキル、(C1−C8アルキレン)O−及びC1−C10アルキレン−C(O)N(Ra)−C2−C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオアリール、C3−C8シクロアルキル、C4−C7ヘテロシクロアルキル、ヘテロアリールアルキル及びヘテロアリールからなる群から選択される1−5個の置換基で置換されていてもよく、各Raは、独立して、H又はC1−C6アルキルである)
によって表される化学部分である、請求項1に記載の抗体−薬物コンジュゲート。 - R6が、C1−C6アルキレンである、請求項3に記載の抗体−薬物コンジュゲート。
- L−Dが、
(式中、R1は、C1−C6アルキル、(C1−C6アルキル)NHC(NH)NH2又は(C1−C6アルキル)NHC(O)NH2である)、
(式中、R1は、C1−C6アルキル、C2−C6アルケニル、(C1−C6アルキル)NHC(NH)NH2又は(C1−C6アルキル)NHC(O)NH2であり、R3及びR2は、それぞれ独立して、H、C1−C10アルキルである)
及び
(式中、R1は、C1−C6アルキル、(C1−C6アルキル)NHC(NH)NH2又は(C1−C6アルキル)NHC(O)NH2であり、R4及びR5は、一緒になって、C3−C7シクロアルキル環を形成する)
から選択される式によって表される、請求項1に記載の抗体−薬物コンジュゲート。 - R4及びR5が、シクロブチル環を形成する、請求項8に記載の抗体−薬物コンジュゲート。
- pが、2である、請求項1に記載の抗体−薬物コンジュゲート。
- 抗体が、システイン操作抗体である、請求項1に記載の抗体−薬物コンジュゲート。
- 抗体が、BMPR1B;E16;STEAP1;0772P(Muc16);MPF;NaPi2b(NaPi3b);Sema 5b;PSCA hlg;ETBR;MSG783;STEAP2;TrpM4;CRIPTO;CD21;CD79b;FcRH2;HER2;NCA;MDP;IL20Rα;Brevican;EphB2R;ASLG659;PSCA;GEDA;BAFF−R;CD22;CD79a;CXCR5;HLA−DOB;P2X5;CD72;LY64;FcRH1;IRTA2;TENB2;PMEL17;TMEFF1;GDNF−Ra1;Ly6E;TMEM46;Ly6G6D;LGR5;RET;LY6K;GPR19;GPR54;ASPHD1;Tyrosinase;TMEM118;GPR172A;CD33;及びCLL1からなる群から選択されるポリペプチドの1つ又は複数に結合する、請求項1に記載の抗体−薬物コンジュゲート。
- 抗体が、NaPi2bに結合する、請求項12に記載の抗体−薬物コンジュゲート。
- NaPi2b抗体が、配列番号1のアミノ酸配列を含むHVR−L1、配列番号2のアミノ酸配列を含むHVR−L2、配列番号3のアミノ酸配列を含むHVR−L3、配列番号4のアミノ酸配列を含むHVR−H1、配列番号5のアミノ酸配列を含むHVR−H2、及び配列番号6のアミノ酸配列を含むHVR−H3を含む、請求項13に記載の抗体−薬物コンジュゲート。
- 前記NaPi2b抗体が、配列番号7のアミノ酸配列を含むVLドメイン、及び配列番号8のアミノ酸配列を含むVHドメインを含む、請求項14に記載の抗体−薬物コンジュゲート。
- 前記NaPi2b抗体が、配列番号9のアミノ酸配列及び配列番号10のアミノ酸配列を含む、請求項14に記載の抗体−薬物コンジュゲート。
- 前記NaPi2b抗体が、配列番号9のアミノ酸配列と少なくとも95%配列同一性を有するアミノ酸配列、及び配列番号10のアミノ酸配列と少なくとも95%配列同一性を有するアミノ酸配列を含む、請求項14に記載の抗体−薬物コンジュゲート。
- 抗体が、CD22に結合する、請求項12に記載の抗体−薬物コンジュゲート。
- CD22抗体が、配列番号41のアミノ酸配列を含むHVR−L1、配列番号42のアミノ酸配列を含むHVR−L2、配列番号43のアミノ酸配列を含むHVR−L3、配列番号44のアミノ酸配列を含むHVR−H1、配列番号45のアミノ酸配列を含むHVR−H2、及び配列番号46のアミノ酸配列を含むHVR−H3を含む、請求項18に記載の抗体−薬物コンジュゲート。
- 前記CD22抗体が、配列番号47のアミノ酸配列を含むVLドメイン、及び配列番号48のアミノ酸配列を含むVHドメインを含む、請求項18に記載の抗体−薬物コンジュゲート。
- 前記CD22抗体が、配列番号49のアミノ酸配列及び配列番号50のアミノ酸配列を含む、請求項18に記載の抗体−薬物コンジュゲート。
- 前記CD22抗体が、配列番号49のアミノ酸配列と少なくとも95%配列同一性を有するアミノ酸配列、及び配列番号50のアミノ酸配列と少なくとも95%配列同一性を有するアミノ酸配列を含む、請求項18に記載の抗体−薬物コンジュゲート。
- 請求項1に記載の抗体−薬物コンジュゲート及びその薬学的に許容される担体を含む薬学的組成物。
- それを必要とするヒトにおいて疾患を治療する方法であって、請求項23に記載の薬学的組成物の有効量を前記ヒトに投与することを含む、方法。
- 請求項1に記載の抗体−薬物コンジュゲートを調製する方法であって、請求項25に記載のリンカー−薬物中間体と抗体をコンジュゲートすることを含む、方法。
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CN107206101B (zh) | 2021-06-25 |
IL252622B (en) | 2020-11-30 |
EP3226909A1 (en) | 2017-10-11 |
WO2016090050A1 (en) | 2016-06-09 |
CA2969689A1 (en) | 2016-06-09 |
CN107206101A (zh) | 2017-09-26 |
IL252622A0 (en) | 2017-08-31 |
JP6752204B2 (ja) | 2020-09-09 |
US20200087297A1 (en) | 2020-03-19 |
AU2015358532B2 (en) | 2020-05-07 |
US20170232113A1 (en) | 2017-08-17 |
AU2015358532C1 (en) | 2020-10-29 |
US10556895B2 (en) | 2020-02-11 |
US11104673B2 (en) | 2021-08-31 |
MX2017007169A (es) | 2018-05-02 |
KR20170086121A (ko) | 2017-07-25 |
AU2015358532A1 (en) | 2017-06-29 |
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