JP6420331B2 - タンパク質−高分子−薬剤コンジュゲート - Google Patents
タンパク質−高分子−薬剤コンジュゲート Download PDFInfo
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Description
本出願は、35 USC §119(e)に基づき、2013年10月11日に出願された米国特許出願第61/890,046号;2014年4月4日に出願された同第61/975,455号;2014年5月2日に出願された同第61/988,011号;及び2014年6月11日に出願された同第62/010,972号の優先権を主張する。これらの出願の内容は、参照によりその全体を本明細書中に援用する。
足場は、約2kDa〜約40kDaの範囲の分子量を有する、ポリ(1−ヒドロキシメチルエチレンヒドロキシメチル−ホルマール)(PHF)を含み;
Dの各存在は、独立して≦5kDaの分子量を有する治療薬であり、そして、Dとカルボニル基の間の
XはCH2、O、又はNHであり、
mは1〜約300の整数であり、
m1は1〜約140の整数であり、
m7は1〜約40の整数であり、
m3は1〜約18の整数であり、
m、m1、m3、及びm7の合計は約15〜約300の範囲である)
の高分子足場に関する。
Xa及びXbの一方がHであり、もう片方がマレイミドブロッキング部分であるか、又はXa及びXbは、それらが結合している炭素原子と一緒に、炭素−炭素二重結合を形成し;
m3aは0〜約17の整数であり、
m3bは1〜約8の整数であり、ここで、m3aとm3bの合計はm3であり、
m、m1、m7、m3a、及びm3bの合計は約15〜約300の範囲であり、そして、
m5は1〜約10の整数である)
のコンジュゲートである。
足場は、約2kDa〜約40kDaの範囲の分子量を有する、ポリ(1−ヒドロキシメチルエチレンヒドロキシメチル−ホルマール)(PHF)を含み;
XはCH2、O、又はNHであり;
mは1〜約300の整数であり、
m1は1〜約140の整数であり、
m2は1〜約40の整数であり、
m3は1〜約18の整数であり、
m、m1、m2、及びm3の合計は約15〜約300の範囲である)
の高分子足場に関する。
PHFは、約5kDa〜約10kDaの範囲の分子量を有し;
mは1〜約75の整数であり、
m1は約5〜約35の整数であり、
m2は約3〜約10の整数であり、
m3は1〜約5の整数であり、
m、m1、m2、及びm3の合計は40〜約75の範囲である)
の足場である。
Xa及びXbの一方がHであり、もう片方がマレイミドブロッキング部分であるか、又はXa及びXbは、それらが結合している炭素原子と一緒に、炭素−炭素二重結合を形成し;
m3aは0〜約17の整数であり、
m3bは1〜約8の整数であり、ここで、m3aとm3bの合計はm3(例えば、1〜約18の整数)であり、
m、m1、m2、m3a、及びm3bの合計は約15〜約300の範囲であり、そして、
m5は1〜約10の整数である)
の足場である。
R90はNHR91、OH、COOR93、CH(NHR91)COOR93又は置換されたフェニル基であり;
R93は水素又はC1-4アルキルであり;
R91は水素、CH3又はCH3COであり、そして、
dは1〜3の整数である)
のチオール含有化合物とマレイミド基の反応によって2つのオレフィン炭素原子のうちの1つと共有結合され得る部分である。
R93は水素又はCH3であり;
R91は水素又はCH3COであり;そして、
dは1又は2である。
PHFは、5kDa〜10kDaの範囲の分子量を有し;
mは1〜75の整数であり、
m1は約5〜約35の整数であり、
m2は約3〜約10の整数であり、
m3aは0〜約4の整数であり、
m3bは1〜約5の整数であり、
m、m1、m2、m3a、及びm3bの合計は約40〜約75の範囲であり、そして、
m5は2〜約4の整数である)
の足場である。
足場は、約2kDa〜約40kDaの範囲の分子量を有するPHFを含み;
XはCH2、O、又はNHであり;
mは1〜約300の整数であり、
m6は2〜約180の整数であり、
m3は1〜約18の整数であり、
m、m6、及びm3の合計は約15〜約300の範囲である)
の高分子足場も提供する。
PHFは、約5kDa〜約10kDaの範囲の分子量を有し;
mは1〜約75の整数であり、
m6は約8〜約45の整数であり、
m3は1〜約5の整数であり、そして、
m、m6、及びm3の合計は約40〜約75の範囲である)
の足場である。
(a)ヒト癌胎児タンパク質5T4標的とする免疫グロブリン又はその機能的な断片をを含むリガンド(LG)、該リガンド(例えば、いくつかの実施形態において、約40kDa以上の分子量を有する)(b)の高分子足場のm5に結合し;ここで、m5は1〜約10であり;そして、
(b)約2kDa〜約40kDaの範囲の分子量を有するポリ(1−ヒドロキシメチルエチレンヒドロキシメチル−ホルマール)(PHF)を含む高分子足場;ここで、該高分子足場は、ランダムに配列された、以下に規定したモノマーユニットm、m1、m2、m3a、及びm3bを含む:
(i)m3a:
(ii)m3b:
(iii)m:
(iv)m1:
(v)m2:
ここで、それぞれモノマーユニットm、m1、m2、m3a、及びm3bでは、XがCH2、O又はNHであり、m、m1、m2、m3a、及びm3bの合計が約15〜約300の範囲であり、そしてここで、Dの各存在は独立して、≦5kDaの分子量を有する治療薬であり、且つDとカルボニル基の間の
PHFは、5kDa〜10kDaの範囲の分子量を有し;
mは1〜75であり、m1は約5〜約35であり、m2は約3〜約10であり、m3aは0〜約4であり、m3bは1〜約5であり、m、m1、m2、m3a、及びm3bの合計は約40〜約75であり、そして、m5は2〜約4である)
を有する。
m5は1〜10であり;mは1〜約300の整数であり;m1は1〜約140の整数であり;m2は1〜約40の整数であり;m3aは0〜約17の整数であり;m3bは1〜約8の整数であり;ここで、m3aとm3bの合計は1〜約18の整数であり;且つm、m1、m2、及びm3の合計は約15〜約300の範囲であり;XはNHであり;Xa又はXbの一方がHであり、もう片方がマレイミドブロッキング部分であり;そして、Dの各存在が独立して、≦5kDaの分子量を有する治療薬である場合、Dとカルボニル基の間の
のコンジュゲートである。例えば、抗−5T4の分子量は、少なくとも約40kDaである。
抗−5T4は、配列番号Aとして示されたアミノ配列を含む一本鎖抗体構築物であり;PHFは、約2kDa〜約40kDaの範囲の分子量を有し;高分子足場対抗−5T4抗体の比の平均は約2:1〜約3:1又は約3:1〜4:1であり、且つAF HPA対抗−5T4抗体の比は約12:1〜約18:1である)
を含むポリ(1−ヒドロキシメチルエチレンヒドロキシメチル−ホルマール)(PHF)高分子足場を含む、抗腫瘍治療法に有効な治療薬及びターゲッティングコンジュゲートが提供される。
本発明は、新規なタンパク質−高分子−薬剤コンジュゲート、そのコンジュゲートを作製するための高分子足場、そのコンジュゲート又は高分子足場を作製するための合成方法、それらを含んでなる医薬組成物、及びそのコンジュゲートの様々な用途を供する。
本発明のある種の化合物、及び特定の官能基の定義はまた、本明細書中で更に詳細に記述されている。本発明の目的のために、その化学元素は、the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics,75th Ed.(内表紙)で同定されており、また、特定の官能基は、一般に、本明細書中で記述のように、定義されている。更に、有機化学の一般的な原理だけでなく、特定の官能部分及び反応性は、“Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999で記述されており、その全内容は、本明細書中で参考として援用されている。更に、本明細書中で記述した合成方法は、種々の保護基を利用することが当業者に理解できる。
ある例示的な実施形態では、本発明のコンジュゲートは、生物医学的適用、例えば、薬剤送達及び体内組織エンジニアリングにおける用途を見出し、担体は生体適合性であり生分解性である。ある実施形態では、担体は、可溶性高分子、ナノ粒子、ゲル、リポソーム、ミセル、縫合糸、移植片などである。ある実施形態では、語句「可溶性高分子」は、ポリアルポリアル(例えば、親水性ポリアセタール又はポリケタール)のような生分解性、生体適合性高分子を包含する。ある他の実施形態では、担体は完全な合成、半合成又は天然起源の高分子である。ある他の実施形態では、担体は親水性である。
R7及びR8は独立に、水素、ヒドロキシル、ヒドロキシアルキル(例えば-CH2OH)、-CH(OH)-CH2OH)、-CHO、-CH(OH)-CHO、又は−カルボニルであり;
oは、20〜2000の整数である)
によって表されるポリアセタール部分0.1%から100%を含む活性化された親水性の生分解性で生体適合性の高分子を含む。
ある実施形態において、治療薬は、好ましくは≦約5kDa、より好ましくは≦約4kDa、より好ましくは≦約3kDa、最も好ましくは≦約1.5kDa又は≦約1kDaの分子量を有する小分子である。
R14は、水素、-C(O)-C1-3アルキル又は-C(O)-クロロ置換されたC1-3アルキルであり;
R15は、水素、-CH3又は-CHOであり;
R17及びR18は、独立してあるとき、R18は水素であり、且つR16又はR17のどちらかがエチルであり、そして、もう片方がヒドロキシルであり;
R17及びR18は、それらが結合されている炭素と一緒にあるとき、オキシラン環を形成し、R16はエチルであり;
R19は、水素、OH、アミノ基、アルキルアミノ又は-[C(R20R21)]-R22であり;
各R20及びR21は独立して、水素、C1-6アルキル、C6-10アリール、ヒドロキシル化C6-10アリール、ポリヒドロキシル化C6-10アリール、5〜12員複素環化合物、C3-8シクロアルキル、ヒドロキシル化C3-8シクロアルキル、ポリヒドロキシル化C3-8シクロアルキル又は天然若しくは非天然のアミノ酸側鎖であり;
R22は、-OH、-NH2、-COOH、-R82-C(O)(CH2)c-C(H)(R23)-N(H)(R23)、-R82-C(O)(CH2)d-(OCH2-CH2)f-N(H)(R23)又は-R82-(C(O)-CH(X2)-NH)d-R77であり;
各R23は独立して、水素、C1-6アルキル、C6-10アリール、C3-8シクロアルキル、-COOH、又は-COO-C1-6アルキルであり;
X2は、天然又は非天然のアミノ酸側鎖であり;
R77は、水素であるか、又はX2とNR77は、窒素含有複素環部分を形成し;
R82は、-NH又は酸素であり;
aは、1〜6の整数であり;
cは、0〜3の整数であり;
dは、1〜3の整数であり;そして
fは、1〜12の整数である)。
R40は、水素、-OH、-NH2、又は次の構造:
aは、1〜6の整数であり;そして
cは、0〜3の整数である)
のいずれである)
の化合物である。
R24は、-H、-Cl、-F、-OH又はアルキルであるか;又はR24及びR25は一緒に、5又は6員環を形成してもよく;
R25は、-H、-F、-OH、-CH3CH=N-O-t-ブチル、-CH2CH2Si(CH3)3、Si((CH3)2)-t-ブチル、-O-C(O)-R29であり;
R29は、-NH2、-R28-C1-6アルキル-R22、5〜12員ヘテロシクロアルキル、R28-C5-12ヘテロシクロアルキル-C1-6アルキル-R22又は-R28-C1-6アルキル-C6-12アリール-C1-6アルキル-R22であり;
R26は、-H、-CH2-N(CH3)2、NH2、又はNO2であり;
R27は、エチル、N-メチルピペリジン、シクロアルキル、-CH2CH2NHCH(CH3)2、又は-N-4-メチルシクロヘキシルアミンであり;
R79は、-H又は-C(O)-R28-[C(R20R21]a-R22であり;
各R20及びR21は独立して、水素、C1-6アルキル、C6-10アリール、ヒドロキシル化C6-10アリール、ポリヒドロキシル化C6-10アリール、5〜12員複素環化合物、C3-8シクロアルキル、ヒドロキシル化C3-8シクロアルキル、ポリヒドロキシル化C3-8シクロアルキル又は天然若しくは非天然のアミノ酸側鎖であり;
R22は、-OH、-NH2、-COOH、-R82-C(O)(CH2)c-C(H)(R23)-N(H)(R23)、-R82-C(O)(CH2)d-(OCH2-CH2)f-N(H)(R23)、又は-R82-(C(O)-CH(X2)-NH)d-R77であり;
各R23は独立して、水素、C1-6アルキル、C6-10アリール、C3-8シクロアルキル、-COOH、又は-COO-C1-6アルキルであり;
X2は、天然又は非天然のアミノ酸側鎖であり;
R77は、水素であるか、又はX2とNR77は、窒素含有環化合物を形成し;
R82は、-NH又は酸素であり;或いは
R26及びR27は、それらが結合された2つの炭素原子と一緒にあり、且つ3番目の炭素原子がその2つの炭素原子と結合しているとき、任意に置換される6員環を形成し;
R28は、存在しない、NH又は酸素であり;
aは、1〜6の整数であり;
cは、0〜3の整数であり;
dは、1〜3の整数であり;
fは、1〜12の整数であり;
uは、0又は1の整数であり;
wは、0又は1の整数であり;そして
但し、式(VII)の化合物は、R29及びR79のうちの少なくとも1つを含まなければならない)。
R30は、-NH2、-R28-C1-6アルキル-R22、5〜12員ヘテロシクロアルキル、R28-C5-12ヘテロシクロアルキル-C1-6アルキル-R22又は-R28-C1-6アルキル-C6-12アリール-C1-6アルキル-R22であり;
R28は、存在しない、NH又は酸素であり;
各R20及びR21は独立して、水素、C1-6アルキル、C6-10アリール、ヒドロキシル化C6-10アリール、ポリヒドロキシル化C6-10アリール、5〜12員複素環化合物、C3-8シクロアルキル、ヒドロキシル化C3-8シクロアルキル、ポリヒドロキシル化C3-8シクロアルキル又は天然若しくは非天然のアミノ酸側鎖であり;
R22は、-OH、-NH2、-COOH、-R82-C(O)(CH2)c-C(H)(R23)-N(H)(R23)、-R82-C(O)(CH2)d-(OCH2-CH2)f-N(H)(R23)又は-R82-(C(O)-CH(X2)-NH)d-R77であり;
各R23は独立して、水素、C1-6アルキル、C6-10アリール、C3-8シクロアルキル、-COOH、又は-COO-C1-6アルキルであり;
X2は、天然又は非天然のアミノ酸側鎖であり;
R77は、水素であるか、又はX2とNR77は、窒素含有環化合物を形成し;
R82は、-NH又は酸素であり;
cは、0〜3の整数であり;
dは、1〜3の整数であり;そして
fは、1〜12の整数である)。
R47は、アミノ基、-R9-[C(R20R21)]a-R10、-R9-C5-12ヘテロシクロアルキル-C1-6アルキル-R10、又は5〜12員ヘテロシクロアルキルであり;
各R20及びR21は独立して、水素、C1-6アルキル、C6-10アリール、ヒドロキシル化C6-10アリール、ポリヒドロキシル化C6-10アリール、5〜12員複素環化合物、C3-8シクロアルキル、ヒドロキシル化C3-8シクロアルキル、ポリヒドロキシル化C3-8シクロアルキル又は天然若しくは非天然のアミノ酸側鎖であり;
R10は、-OH、-NHR83、-N-(R83)R11、-COOH、-R82-C(O)(CH2)c-C(H)(R23)-N(H)(R23)、-R82-C(O)(CH2)d-(OCH2-CH2)f-N(H)(R23)、-R82-(C(O)-CH(X2)-NH)d-R77又は-R82-C(O)-[C(R20R21]-R82-R83であり;
各R23は独立して、水素、C1-6アルキル、C6-10アリール、C3-8シクロアルキル、-COOH、又は-COO-C1-6アルキルであり;
X2は、天然若しくは非天然のアミノ酸側鎖であり;
R77は、水素であるか、又はX2とNR77は、窒素含有環化合物を形成し;
R82は、-NH又は酸素であり;
R9は、存在しない、N-(R83)又は酸素であり;
R83は、水素又はCH3であり;
R11は、
各R12は、独立して、水素、クロリド、-CH3又は-OCH3であり;
R13は、水素又は-C(O)-(CH2)d-(O-CH2-CH2)f-NH2であり;
R82は−NH又は酸素であり;
X4は、リジン、アルギニン、シトルリン、アラニン又はグリシンの側鎖であり;
X5は、フェニルアラニン、バリン、ロイシン、イソロイシン又はトリプトファンの側鎖であり;
各X6及びX7は独立して、グリシン、アラニン、セリン、バリン又はプロリンの側鎖であり;
aは、1〜6の整数であり;
cは、0〜3の整数であり;
dは、1〜3の整数であり;
fは、1〜12の整数であり;
各uは独立して、0又は1の整数であるか;或いは
R11は、-Yu-Wq-R88であり、
ここで、Yは、以下の構造:
Yの末端のNR83は、R88に対して近位であり;
R83は、水素又はCH3であり;
各Wは、アミノ酸単位であり;
各R12'は、独立して、ハロゲン、-C1-8アルキル、-O-C1-8アルキル、ニトロ又はシアノであり;
R88は、水素又は-C(O)-(CH2)ff-(NH-C(O))aa-Ej-(CH2)bb-R85であり;
R85は、NH2又はOHであり;
Eは、-CH2- 又は -CH2CH2O-であり;
uは、0又は1の整数であり;
qは、0〜12の整数であり;
aaは、0又は1の整数であり;
bbは、0又は2の整数であり;
ffは、0〜10の整数であり;
hは、0〜4の整数であり;
jは、0〜12の整数であり;そして
Eが-CH2-であり、bbが0であり、そしてjが0〜10の整数であるとき;そしてEが-CH2CH2-O-であり、bbが2であり、そしてjが1〜12の整数であるときである)
のいずれか1つであり;
或いは、R11は、以下の式:
R83は、水素又はCH3であり;
R84は、C1-6アルキル又はC6-10アリールであり;
各R12'は、独立して、ハロゲン、-C1-8アルキル、-O-C1-8アルキル、ニトロ又はシアノであり;
hは、0〜4の整数であり;そして
uは、0又は1の整数である)
である)。
R83は、水素又はCH3であり;
R84は、C1-6アルキル又はC6-10アリールであり;
各R12'は、独立して、クロリド、-CH3又は-OCH3であり;
R88は、水素又はC(O)-(CH2)ff-(CH2-CH2O)j-CH2-CH2-NH2であり;
R82は、-NH又は酸素であり;
X4は、リジン、アルギニン、シトルリン、アラニン又はグリシンの側鎖であり;
X5は、フェニルアラニン、バリン、ロイシン、イソロイシン又はトリプトファンの側鎖であり;
各X6及びX7は独立して、グリシン、アラニン、セリン、バリン又はプロリンの側鎖であり;
ffは、1〜3の整数であり;
jは、1〜12の整数であり;
hは、0〜4の整数であり;そして
各uは独立して、0又は1の整数である)
である。
各R31及びR32は独立して、水素又はC1-8アルキルであり、且つ最大でR31及びR32の1つが水素であり;
R33は、水素、C1-8アルキル、C3-8炭素環、C6-10アリール、C1-8ル-C6-10アリール、X1-(C3-8炭素環)、C3-8複素環化合物又はX1-(C3-8複素環化合物)であり;
R34は、水素、C1-8アルキル、C3-8炭素環、C6-10アリール、X1-C6-10アリール、X1-(C3-8炭素環)、C3-8複素環化合物又はX1-(C3-8複素環化合物)であり;
R35は、水素又はメチルであり;又は
R34及びR35は、それらが結合されている炭素原子と一緒に、式-(CR55R41)b-(式中、各R55及びR41は独立して、水素又はC1-8アルキルであり、且つbは、3〜7の整数である)を有する炭素環式環を形成し;
R36は、水素又はC1-8アルキルであり;
R37は、水素、C1-8アルキル、C3-8炭素環、C6-10アリール、-X1-C6-10アリール、-X1-(C3-8炭素環)、C3-8複素環化合物又は-X1-(C3-8複素環化合物)であり;
各R38は独立して、水素、OH、C1-8アルキル、C3-8炭素環又はO-(C1-8アルキル)であり;
R53は、
R39は、H、C1-8アルキル、C6-10アリール、-X1-C6-10-アリール、C3-8炭素環、C3-8複素環化合物、-X1-C3-8複素環化合物、-C1-8アルキレン-NH2、又は(CH2)2SCH3であり;
各X1は独立して、C1-10アルキレン又はC3-10シクロアルキレンであり;
R44は、水素又はC1-8アルキルであり;
R45は、X3-R42又はNH-R19であり;
X3は、O又はSであり;
R19は、水素、OH、アミノ基、アルキルアミノ又は-[C(R20R21)]a-R22であり;
R42は、アミノ基、C1-6アルキルアミノ又は-[C(R20R21)]a-R22であり;
各R20及びR21は独立して、水素、C1-6アルキル、C6-10アリール、ヒドロキシル化C6-10アリール、ポリヒドロキシル化C6-10アリール、5〜12員複素環化合物、C3-8シクロアルキル、ヒドロキシル化C3-8シクロアルキル、ポリヒドロキシル化C3-8シクロアルキル又は天然若しくは非天然のアミノ酸側鎖であり;
R22は、-OH、-NHR23、-COOH、-R82-C(O)(CH2)c-C(H)(R23)-N(H)(R23)、-R82-C(O)(CH2)d-(OCH2-CH2)f-N(H)(R23)又は-R82-(C(O)-CH(X2)-NH)d-R77であり;
各R23は独立して、水素、C1-6アルキル、C6-10アリール、C3-8シクロアルキル、-COOH、又は-COO-C1-6アルキルであり;
X2は、天然若しくは非天然のアミノ酸側鎖であり;
R77は、水素であるか、又はX2とNR77は、窒素含有環化合物を形成し;
R82は、-NH又は酸素であり;
R54は、-C(R56)2-C(R56)2-C6-10アリール、-C(R56)2-C(R56)2-C3-8複素環化合物又は-C(R56)2-C(R56)2-C3-8炭素環であり;
R56は、H、OH、C1-8アルキル、C3-8炭素環、-O-C1-8アルキル、-O-C(O)-R29、及び-O-R23-O-C1-6アルキル-NH2から独立して選択され;
R29は、アミノ基、5〜12員ヘテロシクロアルキル、-R28-C1-6アルキル-R22、R28-C5-12ヘテロシクロル-C1-6アルキル-R22、-[C(R20R21)]a-R22、又は-R28-C1-6アルキル-C6-12アリール-C1-6アルキル-R22であり;
R28は、存在しない、NH又は酸素であり;
aは、1〜6の整数であり;
cは、0〜3の整数であり;
dは、1〜3の整数であり;そして
fは、1〜12の整数である)。
R33からR38まで、及びR44は本明細書中に定義されるとおりのものであり、
R31及びR32のうちの一方が水素又はC1-8アルキルであり、もう片方が以下とおりである:
R83は、水素又はCH3であり;
R84は、C1-6アルキル又はC6-10アリールであり;
各R12’は独立して、ハロゲン、−C1-8アルキル、−O−C1-8アルキル、ニトロ又はシアノであり;
hは、0〜4の整数であり;そして
uは、0又は1の整数であり;
R53は、
R39は、H、C1-8アルキル、C6-10アリール、-X1-C6-10-アリール、C3-8炭素環、C3-8複素環化合物、-X1-C3-8複素環化合物、-C1-8アルキレン-NH2、又は(CH2)2SCH3であり;
各X1は独立して、C1-10アルキレン又はC3-10シクロアルキレンであり;
R45は、X3-R42又はNH-R19であり;
X3は、O又はSであり;
R19は、水素、OH、アミノ基、アルキルアミノ又は-[C(R20R21)]a-R22であり;
R42は、アミノ基、C1-6アルキルアミノ又は-[C(R20R21)]a-R22であり;
各R20及びR21は独立して、水素、C1-6アルキル、C6-10アリール、ヒドロキシル化C6-10アリール、ポリヒドロキシル化C6-10アリール、5〜12員複素環化合物、C3-8シクロアルキル、ヒドロキシル化C3-8シクロアルキル、ポリヒドロキシル化C3-8シクロアルキル又は天然若しくは非天然のアミノ酸側鎖であり;
R22は、-OH、-NHR23、-COOH、-R82-C(O)(CH2)c-C(H)(R23)-N(H)(R23)、-R82-C(O)(CH2)d-(OCH2-CH2)f-N(H)(R23)又は-R82-(C(O)-CH(X2)-NH)d-R77であり;
各R23は独立して、水素、C1-6アルキル、C6-10アリール、C3-8シクロアルキル、-COOH、又は-COO-C1-6アルキルであり;
X2は、天然若しくは非天然のアミノ酸側鎖であり;
R77は、水素であるか、又はX2とNR77は、窒素含有環化合物を形成し;
R82は、-NH又は酸素であり;
R54は、-C(R56)2-C(R56)2-C6-10アリール、-C(R56)2-C(R56)2-C3-8複素環化合物又は-C(R56)2-C(R56)2-C3-8炭素環であり;
R56は、H、OH、C1-8アルキル、C3-8炭素環、-O-C1-8アルキル、-O-C(O)-R29、及び-O-R23-O-C1-6アルキル-NH2から独立して選択され;
R29は、アミノ基、5〜12員ヘテロシクロアルキル、-R28-C1-6アルキル-R22、R28-C5-12ヘテロシクロル-C1-6アルキル-R22、-[C(R20R21)]a-R22、又は-R28-C1-6アルキル-C6-12アリール-C1-6アルキル-R22であるか、又はR29は、本明細書中に定義されるようにR47であり;
R28は、存在しない、NH又は酸素であり;
aは、1〜6の整数であり;
cは、0〜3の整数であり;
dは、1〜3の整数であり;そして
fは、1〜12の整数である)。
ここで、式(XI)の化合物は:
aは、1〜6の整数であり;
cは、0〜3の整数である;そして
gは、2〜6の整数である))
であり;
ここで、式(XII)の化合物は:
aは、1〜6の整数であり;
gは、2〜6の整数であり;そして
cは、0〜3の整数である))
であり;
ここで、式(XIII)の化合物は:
R29は、アミノ基、5〜12員ヘテロシクロアルキル、-R28-C1-6アルキル-R22、R28-C5-12ヘテロシクロル-C1-6アルキル-R22、-R28[C(R20R21)]a-R22、又は-R28-C1-6アルキル-C6-12アリール-C1-6アルキル-R22であるか、又はR29は、本明細書中に定義されるようにR47であり;
各R20及びR21は独立して、水素、C1-6アルキル、C6-10アリール、ヒドロキシル化C6-10アリール、ポリヒドロキシル化C6-10アリール、5〜12員複素環化合物、C3-8シクロアルキル、ヒドロキシル化C3-8シクロアルキル、ポリヒドロキシル化C3-8シクロアルキル又は天然若しくは非天然のアミノ酸側鎖であり;
R22は、-OH、-NHR23、-COOH、-R82-C(O)(CH2)c-C(H)(R23)-N(H)(R23)、-R82-C(O)(CH2)d-(OCH2-CH2)f-N(H)(R23)又は-R82-(C(O)-CH(X2)-NH)d-R77であり;
各R23は独立して、水素、C1-6アルキル、C6-10アリール、C3-8シクロアルキル、-COOH、又は-COO-C1-6アルキルであり;
X2は、天然若しくは非天然のアミノ酸側鎖であり;
R77は、水素であるか又はX2とNR77は、窒素含有環化合物を形成し;
R82は、-NH又は酸素であり;
R28は、存在しない、NH又は酸素であり;
aは、1〜6の整数であり;
cは、0〜3の整数であり;
dは、1〜3の整数であり;そして
fは、1〜12の整数である)
である。
R29は、-NH2、5員ヘテロシクロアルキル、-R28-C1-6アルキル-R22、R28-C5-12ヘテロシクロル-C1-6アルキル-R22又は-R28-C1-6アルキル-C6-12アリールC1-6アルキル-R22であるか、又はR29は、本明細書中に定義されるようにR47であり;
R28は、存在しない、NH又は酸素であり;
R22は、-OH、-NHR23、-COOH、-R82-C(O)(CH2)c-C(H)(R23)-N(H)(R23)、-R82-C(O)(CH2)d-(OCH2-CH2)f-N(H)(R23)又は-R82-(C(O)-CH(X2)-NH)d-R77であり;
各R23は独立して、水素、C1-6アルキル、C6-10アリール、C3-8シクロアルキル、-COOH、又は-COO-C1-6アルキルであり;
X2は、天然若しくは非天然のアミノ酸側鎖であり;
R77は、水素であるか、又はX2とNR77は、窒素含有環化合物を形成し;
R82は、-NH又は酸素であり;
cは、0〜3の整数であり;
dは、1〜3の整数であり;そして
fは、1〜12の整数である。
R43は、H又は-R46-R47であり;
各R20及びR21は独立して、水素、C1-6アルキル、C6-10アリール、ヒドロキシル化C6-10アリール、ポリヒドロキシル化C6-10アリール、5〜12員複素環化合物、C3-8シクロアルキル、ヒドロキシル化C3-8シクロアルキル、ポリヒドロキシル化C3-8シクロアルキル又は天然若しくは非天然のアミノ酸側鎖であり;
R22は、-OH、-NH2、-COOH、-R82-C(O)(CH2)c-C(H)(R23)-N(H)(R23)、-R82-C(O)(CH2)d-(OCH2-CH2)f-N(H)(R23)又は-R82-(C(O)-CH(X2)-NH)d-R77であり;
各R23は独立して、水素、C1-6アルキル、C6-10アリール、C3-8シクロアルキル、-COOH、又は-COO-C1-6アルキルであり;
X2は、天然若しくは非天然のアミノ酸側鎖であり;
R77は、水素であるか、又はX2とNR77は、窒素含有環化合物を形成し;
R82は、-NH又は酸素であり;
R46は、-C(O)-、C(O)-O-、-C(O)-NH又は存在せず;
R47は、本明細書中に定義されるものであり;
aは、1〜6の整数であり;
cは、0〜3の整数であり;
dは、1〜3の整数であり;そして
fは、1〜12の整数である)。
R43は、-C(O)-(CH2)a-NH2、又は-C(O)C(H)(CH3)-(CH2)c-NH2であり;式中、aは、1〜6の整数であり;且つcは、0〜3の整数である。
R47は、本明細書中に定義されるものであり;
R48は、水素、-COO-C1-6アルキル、-COOH、-NH2又は-CH3であり;
R49は、Cl、Br又は-OHであり;
R50は、水素、-OCH3、
環AAは、フェニル又はピロリル環のうちのいずれかである。
R49は、Cl、Br又は-OHであり;そして
R47は、本明細書中に定義されるとおりのものである)。
R42は、C1-6アルキルアミノ又は-[C(R20R21)]a-R22であり;
各R20及びR21は独立して、水素、C1-6アルキル、C6-10アリール、ヒドロキシル化C6-10アリール、ポリヒドロキシル化C6-10アリール、5〜12員複素環化合物、C3-8シクロアルキル、ヒドロキシル化C3-8シクロアルキル、ポリヒドロキシル化C3-8シクロアルキル又は天然若しくは非天然のアミノ酸側鎖であり;
R22は、-OH、-NH2、-COOH、-R82-C(O)(CH2)c-C(H)(R23)-N(H)(R23)、-R82-C(O)(CH2)d-(OCH2-CH2)f-N(H)(R23)、又は-R82-(C(O)-CH(X2)-NH)d-R77であり;
各R23は独立して、水素、C1-6アルキル、C6-10アリール、C3-8シクロアルキル、-COOH、又は-COO-C1-6アルキルであり;
X2は、天然若しくは非天然のアミノ酸側鎖であり;
R77は、水素であるか、又はX2とNR77は、窒素含有環化合物を形成し;
R82は、-NH又は酸素であり;
aは、1〜6の整数であり;
cは、0〜3の整数であり;
dは、1〜3の整数であり;そして
fは、1〜12の整数である)。
タンパク質ベースの認識分子は、細胞内の特定の組織、細胞、又は位置に薬剤−高分子−担体コンジュゲートを向かわせる。タンパク質ベースの認識分子は、標的である培養物に、又は生体全体に、又はそれら両方に修飾した高分子を向かわせることができる。いずれの場合も、タンパク質ベースの認識分子は、標的とされた細胞(複数可)の細胞表面に存在するリガンドを有し、それに、有効な特異性、親和性及び結合活性で結合する。一部の実施形態では、タンパク質ベースの認識分子は、標的である肝臓以外の組織に修飾した高分子を向かわせる。他の実施形態では、タンパク質ベースの認識分子は、標的である肝臓、腎臓、肺又は膵臓などの特異的な組織に修飾した高分子を向かわせる。タンパク質ベースの認識分子は、標的である癌細胞など標的細胞、癌細胞などの細胞で発現される受容体、マトリックス組織又は腫瘍抗原などの癌に関連するタンパク質などに修飾した高分子を差し向けることができる。別法では、腫瘍血管系を含む細胞を標的とすることができる。クッパー細胞とは対照的に肝臓中の肝細胞への特異的ターゲティングなど、タンパク質ベースの認識分子は特異的な種類の細胞に高分子を向かわせることができる。他の場合には、タンパク質ベースの認識分子は高分子を、網様内皮若しくはリンパ系の細胞に、又はマクロファージ若しくは好酸球などの専門の食細胞に向かわせることができる。(そのような場合、高分子自体もまた、特異的ターゲティングを必要としない有効な送達系であることがある)。
EVQLQQSGPDLVKPGASVKISCKASGYSFTGYYMHWVKQSPGKGLEWIGRINPNNGVTLYNQKFKDKATLTVDKSSTTAYMELRSLTSEDSAVYYCARSTMITNYVMDYWGQGTSVTVSSGGGGSGGGGSGGGGSSIVMTQTPTSLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPKLLISYTSSRYAGVPDRFTGSGSGTDFTLTISSVQAEDAAVYFCQQDYNSPPTFGGGTKLEIK
EVQLVESGGGLVQPGGSLRLSCKASGYSFTGYYMHWVRQAPGKGLEWVSRINPNNGVTLYNQKFKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSTMITNYVMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYTSSRYAGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQDYNSPPTFGGGTKLEIK
EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
EVQLQQSGPDLVKPGASVKISCKASGYSFTGYYMHWVKQSPGKGLEWIGRINPNNGVTLYNQKFKDKATLTVDKSSTTAYMELRSLTSEDSAVYYCARSTMITNYVMDYWGQGTSVTVSSGGGGSGGGGSGGGGSSIVMTQTPTSLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPKLLISYTSSRYAGVPDRFTGSGSGTDFTLTISSVQAEDAAVYFCQQDYNSPPTFGGGTKLEIKASTCEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
EVQLVESGGGLVQPGGSLRLSCKASGYSFTGYYMHWVRQAPGKGLEWVSRINPNNGVTLYNQKFKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSTMITNYVMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYTSSRYAGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQDYNSPPTFGGGTKLEIKASTCEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
EVQLVESGGGLVQPGGSLRLSCKASGYSFTGYYMHWVRQAPGKGLEWVSRINPNNGVTLYNQKFKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSTMITNYVMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYTSSRYAGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQDYNSPPTFGGGTKLEIKASTXEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
本発明のコンジュゲートは、1又は2以上のDの存在を含んでなり、ここで、Dは、治療薬、例えば、薬剤であり、式中、1又は2以上のDの存在は、同じであっても、異なっていてもよい。
Dの各存在は、独立して≦5kDaの分子量を有する治療薬であり、そして、Dとカルボニル基の間の
m1は1〜約140の整数であり、
m7は1〜約40の整数であり、ここで、m1とm7の合計がm6(すなわち、2〜約180)である)
のコンジュゲートである。
Xa及びXbの一方がHであり、もう片方がマレイミドブロッキング部分であるか、又はXa及びXbは、それらが結合している炭素原子と一緒に、炭素−炭素二重結合を形成し;
m3aは0〜約17の整数であり、
m3bは1〜約8の整数であり、ここで、m3aとm3bの合計はm3であり、
m、m1、m7、m3a、及びm3bの合計は約15〜約300の範囲であり、そして、
m5は1〜約10の整数である)
のコンジュゲートである。
Xa及びXbの一方がHであり、もう片方がマレイミドブロッキング部分であるか、又はXa及びXbは、それらが結合している炭素原子と一緒に、炭素−炭素二重結合を形成し;
m3aは0〜約17の整数であり、
m3bは1〜約8の整数であり、ここで、m3aとm3bの合計はm3であり、
m、m1、m2、m3a、及びm3bの合計は約15〜約300の範囲であり、そして、
m5は1〜約10の整数である)
のものである。
R90はNHR91、OH、COOR93、CH(NHR91)COOR93又は置換されたフェニル基であり;
R93は水素又はC1-4アルキルであり;
R91は水素、CH3又はCH3COであり、そして、
dは1〜3の整数である)
のチオール含有化合物とマレイミド基の反応によって2つのオレフィン炭素原子のうちの1つと共有結合され得る部分である。
R93は水素又はCH3であり;
R91は水素又はCH3COであり;そして、
dは1又は2である。
足場は、約2kDa〜約40kDaの範囲の分子量を有する、ポリ(1−ヒドロキシメチルエチレンヒドロキシメチル−ホルマール)(PHF)を含み;
XはCH2、O、又はNHであり;
mは1〜約300の整数であり、
m1は1〜約140の整数であり、
m2は1〜約40の整数であり、
m3は1〜約18の整数であり、
m、m1、m2、及びm3の合計は約15〜約300の範囲である)
の高分子担体を含む。
Xは、CH2、O、又はNHであり;
mは1〜約300の整数であり、
m6は2〜約180の整数であり、
m3は1〜約18の整数であり、そして
m、m6、及びm3の合計は約15〜約300の範囲である)
の高分子足場も提供する。
(i)m3a:
(ii)m3b:
(iii)m:
(iv)m1:
(v)m2:
ここで、それぞれモノマーユニットm、m1、m2、m3a、及びm3bでは、XがCH2、O又はNHであり、m、m1、m2、m3a、及びm3bの合計が約15〜約300の範囲であり、そしてここで、Dの各存在は独立して、≦5kDaの分子量を有する治療薬であり、且つDとカルボニル基の間の
PHFは、約5kDa〜約10kDaの範囲の分子量を有し;
mは1〜75であり、m1は約5〜約35であり、m2は約3〜約10であり、m3aは0〜約4であり、m3bは1〜約5であり、m、m1、m2、m3a、及びm3bの合計は約40〜約75であり、そして、m5は2〜約4である)
に例示した構造を特徴とする。
、構造中、m5は1〜10であり;mは1〜約300の整数であり;m1は1〜約140の整数であり;m2は1〜約40の整数であり;m3aは0〜約17の整数であり;m3bは1〜約8の整数であり;ここで、m3aとm3bの合計は1〜約18の整数であり;且つm、m1、m2、及びm3の合計は約15〜約300の範囲であり;XはNHであり;Xa又はXbの一方がHであり、もう片方がマレイミドブロッキング部分であり;そして、Dの各存在が独立して、≦5kDaの分子量を有する治療薬である場合、Dとカルボニル基の間の
のコンジュゲートである。例えば、抗−5T4の分子量は、少なくとも約40kDaである。一実施形態において、Dは、ヒドロキシプロピルアミド−L−アラニン部分を介してm2のカルボニル部分に結合されたアウリスタチン又はその類似体である。一実施形態において、薬剤対抗−5T4の比は、約5:1〜約30:1、又は約12:1〜約18:1である。別の実施形態において、PHF薬剤コンジュゲート対抗−5T4抗体の平均の比は、約2:1〜約4:1である。
抗−5T4(ANTI-5T4)は、配列番号Aのアミノ配列を含む一本鎖抗体構築物であり;PHFは、約2kDa〜約40kDaの範囲の分子量を有し;高分子足場対抗−5T4抗体の比の平均は約2:1〜約3:1又は約3:1〜4:1であり、且つAF HPA対抗−5T4抗体の比は約12:1〜約18:1である)
を含むPHF高分子足場とを含む、抗腫瘍治療法に有効な治療薬及びターゲッティングコンジュゲートが提供される。
合成方法
担体
ある実施形態において、薬剤は、高分子担体への結合前に修飾されてもよい。スキーム1及び2は、ビンカアルカロイドを修飾する方法の実例である。スキーム3は、非天然カンプトテシン誘導体を修飾する方法を示している。スキーム4は、アウリスタチンFを修飾する方法を示している。より多くの修飾方法が、US2010/0305149に記載されており、この文献を参照により本明細書中に援用する。
以下のスキーム5は、本発明の高分子薬剤足場を作り出す合成スキームを示す。一実施形態において、コンジュゲートは、以下の数ステップで形成される:(1)COOH部分を含むように、高分子PHFを改変し(例えば、−C(O)−X−(CH2)2−COOH);(2)次に、高分子がPBRMの官能基と反応できるマレイミド部分(例えば、EG2−MI)を含むように、高分子をさらに改変し;(3)異なった2つの官能基を含んでいる修飾高分子を薬剤又はその誘導体(例えば、AF−HPA−Ala)の官能基と反応させて、高分子−薬剤コンジュゲートを形成し;(4)PBRMのジスルフィド結合を還元し;(5)次に、還元したPBRMを高分子−薬剤コンジュゲートと反応させて、タンパク質−高分子−薬剤コンジュゲートを形成し;そして(6)適宜、残っているマレイミド部分を、マレイミドブロッキング化合物(例えば、システイン)と反応させる。
安定剤、緩衝剤などの許容される担体中に本明細書に開示されているとおりの1又は2以上のタンパク質−高分子−薬剤コンジュゲートを含む医薬組成物もまた包含される。コンジュゲートは、標準的な手段によって、医薬組成物を形成するための安定剤、緩衝剤などを用いて、又は用いずに、対象に投与及び導入することができる。投与は、局所投与(眼ならびに膣及び直腸送達を包含する粘膜への投与を包含する)、例えばネブライザーによる投与を包含する散剤又はエアロゾルの吸入又は注入による肺投与;気管内、鼻腔内、表皮及び経皮、経口投与、又は静脈内、動脈内、皮下、腹腔内若しくは筋肉内注射若しくは点滴若しくは頭蓋内、例えばクモ膜下若しくは脳室内投与を包含する非経口投与であってよい。コンジュゲートは、注射投与のための無菌液剤及び/又は懸濁剤;注射/点滴の前に再構成するための凍結乾燥散剤;局所組成物として;経口投与のための錠剤、カプセル剤又はエリキシル剤;又は直腸投与のための坐剤ならびに当分野で公知の他の組成物として製剤化し、使用することができる。
越えるのにカ月、カ月を含んでいる
約2時間毎、約6時間毎、約8時間毎、約12時間毎、約24時間毎、約36時間毎、約48時間毎、約72時間毎、約1週間毎、約2週間毎、約3週間毎、約1カ月毎、及び約2カ月毎を含めた様々な期間にわたり投与されてもよい。治療が完了するまでの期間に応じた投薬回数と頻度が、健康管理の医療関係者の判断に従って決定される。本明細書中に記載した治療上有効な量は、所定の期間にわたって投与された総量を指す;すなわち、本明細書中に記載した2以上の別々のコンジュゲートを投与するなら、治療上有効な量は投与された総量に相当する。特定の対象に関する具体的な用量水準が、特定のコンジュゲートの活性、年齢、体重、健康全般、性別、食事、投与時期、投与経路、及び排出速度、他の活性物質との組み合わせ、及び治療を受ける特定の疾患の重症度を含めたさまざまな因子に依存することが理解される。
処置方法
本発明のある好ましい実施形態では、本発明のタンパク質−高分子−薬剤コンジュゲートコンジュゲートは、動物(好ましくは哺乳類、最も好ましくは男性、女性、幼児、子供、及び成人を含めたヒト)を処置する方法において使用される。一実施形態では、本発明のコンジュゲートは、本発明の生分解性、生体適合性コンジュゲートを動物に投与することを含む、動物を処置する方法において使用されてもよい。例えば、本発明によるコンジュゲートは、可溶性直鎖重合体、共重合体、コンジュゲート、コロイド、粒子、ゲル、固形状物、繊維、フィルムなどの形で投与することができる。本発明の生分解性、生体適合性コンジュゲートは、薬剤キャリア、薬剤キャリア成分、管理された薬剤放出、低侵入式外科用処置用の製剤などとして、使用することができる。医薬品製剤は、注射可能であり、移植可能である。
下記の略語を、下記の反応スキーム及び合成例において使用する。このリストは、本出願で使用される略語の包括的なリストであることを意図したものではなく、したがって有機合成の分野の当業者には容易に理解される追加の標準的な略語もまた、合成スキーム及び実施例において使用され得る。
ACN アセトニトリル
AF−HPA アウリスタチンF−ヒドロキシプロピルアミド
Ala アラニン
BA β−アラニン
BOC tert-ブチロキシカルボニル
DCC N,N’−ジシクロヘキシルカルボジイミド
DCM ジクロロメタン
DIEA N,N-ジイソプロピルエチルアミン
DMA ジメチルアセトアミド
DMAP N,N−ジメチルピリジン-4−アミン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
EDAC N1−((エチルイミノ)メチレン)−N3,N3−ジメチルプロパン-1,3−ジアミンヒドロクロリド
EDC.HCl 1-エチル-3-[3-ジメチルアミノプロピル]カルボジイミドヒドロクロリド
GA グルタル酸
HPLC−HIC 疎水性相互作用高圧液体クロマトグラフィー
HOAt 1−ヒドロキシ-7−アザベンゾトリアゾール
HOBt 1−ヒドロキシベンゾトリアゾール水和物
HPLC 高圧液体クロマトグラフィー
HPSEC 高性能サイズ排除クロマトグラフィー
HPV ヒドロキシプロピルビンデシン
2HPV 2-ヒドロキシプロピルビンデシン
MWCO 分子量排除
NHS 1−ヒドロキシピロリジン−2,5−ジオン(すなわち、N−ヒドロキシ−スクシンイミド)
NMP N-メチル−2-ピロリドン
PBS リン酸緩衝生理食塩水、0.9%のNaCl
EG エチレングリコール
EG2 ジエチレングリコール
MI マレイミド(Maleimide又はmaleimide)
HPA−Ala ヒドロキシプロピルアミド−L−アラニン
PHF ポリ(1-ヒドロキシメチルエチレンヒドロキシルメチルホルマル)又はFLEXIMER(登録商標)
RP−HPLC 逆相高速液体クロマトグラフィー
SEC サイズ排除クロマトグラフィー
TBSCl tert−ブチルジメチルシリルエーテルクロリド
TCEP Tris[2-カルボキシエチル]ホスフィン
TEA トリエチルアミン
TEAA トリエチルアンモニウムアセテート
TFA トリフルオロ酢酸
WCX 弱陽イオン交換クロマトグラフィー
マレイミド−EG2−NHSエステルをBiomatrik, Chinaから購入した。
一般的な手法A.リンカー又は薬剤と高分子との結合
通常、例えば、EG2−マレイミドなどのアミン含有リンカー又は例えば、AF−HPA−Ala、HPV−Alaなどのアミン含有リンカー薬剤を用いた高分子(PHF−BA又はPHF−GA)の結合は、例えば、EDC.HClなどの活性化剤の存在下で水性溶媒又は10〜90%の有機/水性溶媒混合物中でおこなわれる。典型的な有機溶媒としては、これだけに限定されるものではないが、例えば、DMSO、DMF、DMA、NMP及びACNなどの水混合性溶媒が挙げられる。カップリングを促進するために、例えば、NHSなどの補助活性化因子を加える。高分子を最初に、アミノ含有化合物と混合し、続いて補助活性化因子(NHS)を添加し、次に、活性化因子(EDC.HCl)を添加する。反応を、0〜10℃、pH4.5〜7.5、周囲温度にて1時間〜24時間おこなう。得られた高分子結合生成物を透析濾過又はSECによって精製する。その生成物を2〜50mg/mLまで濃縮し、そして、pHを4.5〜6.5に調整して、薬剤−高分子リンカーの安定性を確保し、そして、該コンジュゲートを更なる使用まで−20〜−80℃にて冷凍して保存する。
高分子−薬剤コンジュゲートとの結合前の関連PBRM内の鎖間ジスルフィド基又は不対ジスルフィドの部分的な選択的還元を、例えば、TCEP、DTT又はβ−メルカプトエタノールなどの還元剤を使用することによって達成する。還元が過剰量の還元剤を用いておこなわれるとき、還元剤は結合前にSECによって取り除かれる。PBRMジスルフィド基の反応性スルフヒドリル基への反応率は、PBRMの化学量論、還元剤、pH、温度、及び/又は反応の持続性による。PBRMのジスルフィド基のすべてではなく一部が還元されるとき、還元PBRMは部分的還元PBRMである。
高分子−薬剤コンジュゲートへの部分的に還元したPBRMの結合を、1〜10mg/mLのPBRM濃度及び0.5〜10mg/mLの高分子−薬剤コンジュゲート濃度にて中性又は弱塩基性条件下(pH6.5〜8.5)で実施する。高分子−薬剤コンジュゲートは一般的に、所望のタンパク質−高分子−薬剤コンジュゲートの化学量論に対して1〜5.0倍過剰量で使用する。PBRMを高分子−薬剤コンジュゲートのマレイミド基に結合するとき、結合は適宜、例えば、N−アセチルシステイン、システインメチルエステル、N−メチルシステイン、2−メルカプトエタノール、3−メルカプトプロパン酸、2−メルカプト酢酸、メルカプトメタノール(すなわち、HOCH2SH)、ベンジルチオールなどの水溶性マレイミドブロッキング化合物の添加によって停止させる。
コンジュゲートA:10K PHF−BA(30%)−AF−HPA−Ala(9.5%)を、10K PHF−BA(30%)(100mg)から先に記載した手法を使用して調製した。
1H−NMRによって測定されるEG2−MIリンカー荷重は、高分子構造ユニットの〜2%molであった。表題化合物の分子量は約20kDaであった。1個の高分子鎖あたり平均で6個のAF−HPA分子が存在した。
1H−NMRによって測定される結合する生成物の薬剤負荷(すなわち、薬剤を含む高分子ユニットの含有量)は、高分子構造ユニットの7.5%mol(又は、1個の高分子鎖あたり平均で約5.7個のt−ブチルグリシンAF−HPA分子)であった。
PBRM−高分子−薬剤コンジュゲートを、インビトロの腫瘍細胞株におけるその抗細胞増殖特性について、Cell Titer-Glo(Promega Corp)を使用して評価した。細胞を、黒色の壁面で囲まれた96ウェルプレート内で平板培養し、5%のCO2の湿気のある環境内で37℃にて一晩定着させた。SKBR3、BT474、NCI-N87細胞(HER2発現細胞)、MCF7細胞(HER2低発現レベル細胞)及びJIMT1細胞(HER2中程度発現レベル細胞)を、1ウェルあたり5,000細胞の密度で平板培養した。次の日に、培地を50μLの新鮮な培地に交換し、そして、50μLの2x PBRM−高分子−薬剤コンジュゲートの原液、薬剤−高分子コンジュゲート又は薬剤を、適当なウェルに加え、混合し、そして、72時間インキュベートした。Cell Titer-Glo試薬を、室温にてウェルに加え、そして、発光シグナルをSpectraMax M5プレートリーダー(Molecular Devices)を使用して10分後に評価した。用量反応曲線を、SoftMax Proソフトウェアを使用して作成した。IC50値を4つのパラメーター曲線の当てはめから決定した。
固定した受容体へのPBRM−高分子−薬剤コンジュゲートの動的結合を、BIAcore SPRによって測定する。PBRM−高分子−薬剤コンジュゲート及びPBRM単独内のPBRMの結合定数を、標準的なBIAcore手順を用いて測定できる。
PBRM−高分子−薬剤コンジュゲートのトラスツズマブ−((EG2−MI(3%))−(10kDa PHF−BA(30%)−(AF−HPA−Ala(8%))(AF−HPA:トラスツズマブ 約12:1〜約17:1)(実施例4)の細胞表面結合を、様々なヒト癌細胞株においてMACSQuant(登録商標)Analyzer 10デジタルベンチトップフローサイトメーターを使用して評価した。100,000個の細胞を、氷上、6%のヤギ血清中でインキュベートした。PBRM−高分子−薬剤コンジュゲート又は非結合PBRMを細胞に加え、氷上で3時間インキュベートし、次に、細胞を、氷冷PBSで洗浄し、氷中で二次蛍光ラベル抗体と一緒に1時間インキュベートした。完了時に、細胞を、PBSで洗浄し、1%のパラホルムによって固定し、フローサイトメータによって分析した。PBRM−高分子−薬剤コンジュゲートの細胞表面結合を滴定によって測定し、そして、非結合PBRMのものと比較した。
実施例49.BIAcore Surface Plasmon Resonance(SPR)によるリガンド結合試験
雌CB-17SCIDマウスに、BT474腫瘍(各群n=4)を皮下に接種した。ビヒクル又はPBRM−高分子−薬剤コンジュゲート:トラスツズマブ−((EG2−MI(3%))−(10kDa PHF−BA(30%)−(AF−HPA−Ala(8%))、(AF−HPA:トラスツズマブ 約12:1〜約17:1)、実施例4、5mg/kg;及びトラスツズマブ−((EG2−MI(1%))−(10kDa PHF−GA(29%)−(AF−HPA−Ala(6%))、(AF−HPA:トラスツズマブ 約18:1〜約23:1)、実施例13、5mg/kg、を1日目に単回投与としてIV投与した。
実施例52.PBRM−高分子−薬剤コンジュゲートの投与に対する腫瘍増殖応答
雌CD-1マウスは、最初の投薬前の少なくとも4日間、順応させた。すべてのマウスには、通常の食餌及び水が自由摂取で与えられ、化合物投与前にも断食しなかった。試験化合物又はビヒクルを、1日目の単回投与としてIV投与した。
実施例54.PBRM−高分子−薬剤コンジュゲートの投与の後のマウス血漿PK
PBRM−高分子医薬コンジュゲートの耐容性を、CD-1雌マウスで推定した。PBRM−高分子−薬剤コンジュゲート(実施例4)を、単回IV用量として20mg/kg、40mg/kg、60mg/kg(各群n=6)の用量にて投与した。ビヒクル対照群には生理的塩類溶液を与えた。動物は21日間にわたり臨床徴候に関して観察した。すべての試験動物の個別の体重を、ゼロ日目(ベースライン)、最初の5日間は毎日、そして、それ以降はほぼ1日おきに記録した。結果を表Xにまとめる。
アウリスタチンF−ヒドロキシプロピルアミド(AF−HPA)の耐容性を、CD-1雌マウスで推定した。AF−HPA(US13/493,899、本明細書中では米国特許第8,685,383号、実施例48に記載のものと類似した様式で調製する)を、単回IV用量として1.6mg/kg、3.2mg/kg、4.7mg/kg(各群n=6)の用量にて投与した。ビヒクル対照群には生理的塩類溶液を与えた。動物は21日間にわたり臨床徴候に関して観察した。すべての試験動物の個別の体重を、ゼロ日目(ベースライン)、最初の5日間は毎日、そして、それ以降はほぼ1日おきに記録した。結果を表XIにまとめる。
5T4抗原に対する、実施例10に記載のものと類似した様式で調製した抗−5T4 scFvFc高分子医薬コンジュゲートの結合の親和性及び動態学的パラメーターを、GE Healthcare製のBIAcore T200装置を使用した表面プラズモン共鳴法によって計測した。5T4−ECD−Fc抗原(ヒトIgG1サブタイプのFcドメインに融合したヒト5T4細胞外ドメイン)を、キット(GE Healthcare)として提供された試薬を使用したアミンカップリング法によってBIAcore CM5センサーチップ上に共有結合で固定した。結合研究では、抗−5T4 scFvFc高分子医薬コンジュゲート又は対照タンパク質を、BIAcore泳動バッファーHBS EP+(EDTA及びP20を補ったHEPES緩衝化生理食塩水)で濃度系列に連続希釈し、結合させるための一定期間にわたり固定した抗原上に流し、それに続いて、抗原を解離するために泳動バッファーのみを流し、そして最後に、低pH溶液(10mMのグリシン−HCl、pH2)を使用して表面を再生した。すべてのBIAcore試薬をGE Healthcareから調達した。得られたデータ曲線をセンサーグラムと呼び、未加工の結合データを構成する。データを、BIAevaluationソフトウェア(GE Healthcare)を使用して1:1ラングミュア結合モデルに当てはめ、そして、結合速度、解離速度、及び親和性などの親和性/動態学的パラメーターを推定した。親和性推定値は複数の計測の平均である。
抗−5T4 scFvFc高分子医薬コンジュゲート(抗−5T4 scADC)(実施例10)の細胞表面結合を、様々なヒト癌細胞株においてFACS Calibreフローサイトメーター(Beckton Dickinson)を使用して計測した。抗−5T4 scFvFc高分子医薬コンジュゲートの細胞表面結合を、滴定によって測定し、そして、非結合抗−5T4 scFvFc抗体について計測した細胞表面結合と比較した。
材料:BD 1mLシリンジ(271/2 Gauge)、無菌培養培地、無菌リン酸緩衝生理食塩水、Matrigel−BD Biosciences(カタログNo.354248)、無菌綿栓、無菌Eppendrofチューブ(1.5mL及び2mL)、ピペット、濾紙、70% アルコール/イソプロピルアルコール、Vernier Caliper(Mitutoyo)。使用したその他の不可欠なアイテムはすべて分析用のものであった。
A431の皮下異種移植での抗腫瘍活性:
A431細胞株[「Characterization of the A431 tumor xenograft as an in vivo model for testing epidermal growth factor-receptor antagonists」, S. Robinson et al., Int. J. Oncol. 1992, 1(3):293-8]の異種移植実験では、実施例10に記載のものに類似した様式で調製した抗−5T4 scADCを、以下の用量にて癌を担持するマウスにIV投与した:10mg/kg、単回投与;1mg/kg、Q4D×4;3mg/kg、Q4D×4;6mg/kg、Q4D×4。「Q4D×4」とは、合計4回の用量に関して、4日おきの投与を意味する。別々の群の癌を担持するマウスに、非結合抗−5T4 scFvFc(10mg/kgのIV、Q4D×4)を投与した。この試験では、抗−5T4 scADC治療法が、上記の投与量レベルにて単回投与又は繰返し投与として投与した場合に、A431癌移植片に対して強い抗腫瘍活性を実証した(図12)。単回投与(10mg/kgのIV)にて抗−5T4 scADCを用いた処置は、24日目に−4%の最適T/C値をもたらした。10mg/kgのIV単回投与群の腫瘍増殖阻害(TGI)率(%)が104%(24日目、p<0.001)であることがわかった。反復投与群(1mg/kg、3mg/kg、及び6mg/kgのIV、Q4D×4)における最適T/C値は、24日目にそれぞれ−2%、−4%、及び−3%であったことがわかった。さらに、反復投与群(1mg/kg、3mg/kg、及び6mg/kgのIV、Q4D×4)の腫瘍増殖阻害(TGI)率(%)が、それぞれ102%(24日目、p<0.001)、104%(24日目、p<0.001)及び103%(24日目、p<0.001)であったことがわかった。単回投与と反復投与の抗−5T4 scADC処置群の間には、有意差がなかった。10mg/kgのIV、Q4D×4の用量での非結合抗−5T4 scFvFcの投与は、A431異種移植の腫瘍体積の有意な低減をまったく引き起こさなかった。24日目の%T/Cが87%であることがわかった。ビヒクル投与群と抗−5T4 ScFvFc投与群の間の腫瘍サイズにおける相違は統計的に有意でなかった、そして、この用量における腫瘍増殖阻害(TGI)率(%)が13%(24日目)であることがわかった。治療計画後、抗−5T4 scADC試験群の動物を90日目まで観察し、その時点で試験を終了させた。6mpk、i.v、Q4D×4にて処置した抗−5T4 scADC反復投与群では、24日目までに処置関連の激しい体重減少と死亡(7/10匹の動物)があった;この用量群における生き残り動物を90日目まで観察した。完全な腫瘍増殖退縮を抗−5T4 scADC投与群のすべてで観察し、腫瘍再増殖の徴候は研究期間の終了までなかった(6mpk、i.v、Q4D×4用量群の3/10匹を含む)。
MDA−MB231-5T4 OEの異種移植による実験では、実施例10に記載のものに類似した様式で調製した抗−5T4 scADCを、以下の用量にて癌を担持するマウスに投与した:10mg/kgのIV、単回投与;1mg/kgのIV、Q4D×4;3mg/kgのIV、Q4D×4;及び6mg/kgのIV、Q4D×4。別々の群に、非結合抗−5T4 scFvFc(10mg/kgのIV、Q4D×4)を投与した。この試験では、抗−5T4 scADC治療法が、上記の投与量レベルにて単回投与又は繰返し投与として投与した場合に、MDA−MB−231−5T4 OE異種移植に対して強い抗腫瘍活性を実証した(図13)。単回投与(10mg/kgのIV)にて抗−5T4 scADCを用いた処置は、18日目に−25%の最適T/C値をもたらした。10mg/kgのIV単回投与群の腫瘍増殖阻害(TGI)率(%)が125%(18日目、p<0.001)であることがわかった。反復投与群(1mg/kg、3mg/kg、及び6mg/kgのIV、Q4D×4)における最適T/C値は、18日目にそれぞれ−26%、−32%及び−38%であることがわかった。さらに、反復投与群(1mg/kg、3mg/kg、及び6mg/kgのIV、Q4D×4)の腫瘍増殖阻害(TGI)率(%)が、それぞれ126%(18日目、p<0.001)、132%(18日目、p<0.001)及び138%(18日目、p<0.001)であったことがわかった。単回投与と反復投与の抗−5T4 scADC処置群の間には、有意差がなかった。10mg/kgのIV、Q4D×4の用量における非結合抗−5T4 scFvFc治療法が、MDA−MB−231 5T4 OE異種移植に対して抗腫瘍活性を抑えることを示した。18日目の%T/Cが45%であることがわかったので、この用量での腫瘍増殖阻害(TGI)は55%(18日目、p<0.001)であった。さらに、Vehicle対照群の66日目の平均腫瘍体積は1763mm3であることがわかった。抗−5T4 scADC反復投与群(i.v;1mpk、3mpk、Q4D×4)及び単回投与群(10mpk、i.v)では、45日目から90日目まで完全な腫瘍増殖退縮があった。その時点で試験を終了させた。上記の抗−5T4 scADC投与群において、腫瘍再増殖の徴候は研究期間の終了までなかった。しかしながら、6mpk、i.v、Q4D×4にて処置した抗−5T4 scADC反復投与群では、21日目に処置関連の激しい体重減少と死亡(10/10)があった。72日目の非結合抗−5T4 scFvFc抗体投与群の平均腫瘍体積は1502mm3であることがわかった。この抗体投与群に関する66日目の%T/Cが60%であることがわかったので、この用量での腫瘍増殖阻害(TGI)は40%(66日目、p<0.001)であった。
H1975肺癌細胞株を用いて同じようにおこなった異種移植実験では、実施例10に記載のものに類似した様式で調製した抗−5T4 scADCを、以下の用量にて癌を担持するマウス(各群n=5匹のマウス、最初の腫瘍体積〜150mm3)にIV投与した:0.3mg/kg、Q4D×4;1mg/kg、Q4D×4;及び3mg/kg、Q4D×4。別々の群に、3mg/kg、IV、Q4D×4にて非結合抗−5T4 scFvFc抗体を投与した。上記の投薬量レベルにて繰返し投与として投与した場合に、抗−5T4 scADC(0.3及び1mg/kg、i.v、Q4D×4)を用いた処置が、H1975腫瘍異種移植の部分寛解(39日目)をもたらした。3mg/kg、i.v、Q4D×4にて抗−5T4 scADCを用いた処置が、H1975腫瘍異種移植の完全寛解をもたらした(39日目)。0.3、1及び3mpk、i.v;Q4D×4にて抗−5T4 scADCを用いた処置が、39日目にそれぞれ−0.7%、−4%及び−5%の最適T/C値をもたらし、そして、腫瘍増殖阻害(TGI)率(%)は101%、104%及び完全寛解(CR)であることがわかった(39日目、p<0.001)。
非結合抗−5T4 scFvFc抗体を用いた処置が、%TGIが12%である39日目に88%の%T/Cを有する乏しい抗腫瘍活性をもたらした。治療計画後、試験群の動物を81日目まで観察し、その時点で試験を終了させた。60日目に、抗−5T4 scADC治療法(i.v;0.3mg/kg、Q4D×4)は、H1975異種移植を担持するヌードマウスにおいて完全寛解を実証したが、腫瘍再増殖が39日目以降60日目まで2匹の動物で観察され、この時点でこの群の動物を屠殺した(3/5)。しかしながら、81日目には、抗−5T4 scADC(i.v;1及び3mg/kg、Q4D×4)を用いた治療法は、H1975異種移植片を担持しているヌードマウスにいて完全寛解(5/5;81日目)をもたらした。
上記腫瘍異種移植試験に類似した様式で、異種移植実験をNCI−N87(胃癌)細胞株を用いておこなった。実施例10に記載のものに類似した様式で調製した抗−5T4 scADCを、以下の用量にて癌を担持するSCIDマウス(各群n=10匹のマウスに、最初の腫瘍体積〜135mm3)にIV投与した:3mg/kg、単回投与;及び3mg/kg、Q4D×3。別々の群に、3mg/kg、IV、Q4D×3にて非結合抗−5T4 scFvFc抗体を投与した。1匹の処置に関連しない死亡を、抗−5T4 scADC、3mg/kg、単回投与群において評価し、この動物のデータを分析から除外した。19日目には、抗−5T4 scADC処置群は3mg/kg、単回投与;及び3mg/kg、Q4D×3にて、それぞれ92%及び87%の腫瘍増殖阻害を示した。両方の抗−5T4 scADC処置群で100%の完全退縮があり、そしてそれらは、75日目の試験の終了まで続いた。非結合抗−5T4 scFvFc抗体を用いた処置は、19日目の14%の腫瘍増殖阻害値を有する乏しい抗腫瘍活性をもたらした;この処置群のすべての動物が56日目までに800mm3の腫瘍体積エンドポイントに達した。
Claims (22)
- タンパク質ベースの認識分子(PBRM)と結合するために有効である式(Id)の高分子足場:
該足場は、2kDa〜40kDaの範囲の分子量を有する、ポリ(1−ヒドロキシメチルエチレンヒドロキシメチル−ホルマール)(PHF)を含み;
Dの各存在は、独立して5kDa以下の分子量を有する治療薬であり、そして、Dとカルボニル基の間の
XはCH2、O、又はNHであり;
mは1〜300の整数であり、
m1は1〜140の整数であり、
m7は1〜40の整数であり、
m3は1〜18の整数であり、そして
m、m1、m3、及びm7の合計は15〜300の範囲である)。 - 前記PHFが2kDa〜20kDaの範囲の分子量を有し、m7は1〜20の整数であり、m3は1〜10の整数であり、m1は1〜70の整数であり、そして、m、m1、m3、及びm7の合計は15〜150の範囲である、請求項1に記載の足場。
- 前記PHFが3kDa〜15kDaの範囲の分子量を有し、m7は2〜15の整数であり、m3は1〜8の整数であり、m1 は2〜50の整数であり、そして、m、m1、m3、及びm7の合計は20〜110の範囲である、請求項1に記載の足場。
- 前記PHFが5kDa〜10kDaの範囲の分子量を有し、m7 は3〜10の整数であり、m3は1〜5の整数であり、m1 は5〜35の整数であり、そして、m、m1、m3、及びm7の合計は40〜75の範囲である、請求項1に記載の足場。
- Dの各存在が、独立して、アウリスタチン化合物、トポイソメラーゼ阻害剤、カリケアマイシン化合物、ビンカ化合物、チューブリシン化合物、デュオカルマイシン化合物、ピロロベンゾジアゼピン化合物、キナーゼ阻害剤、KSP阻害剤、マイタンシノイド、DNA結合剤、DNAアルキル化剤又はDNAインターカレーター、RNAポリメラーゼ阻害剤、タンパク質合成阻害剤;並びにその類似体から選択される、請求項1〜4のいずれか1項に記載の足場。
- 前記PHFが2kDa〜20kDaの範囲の分子量を有し、m2は1〜20の整数であり、m3は1〜10の整数であり、m1は1〜70の整数であり、そして、m、m1、m2、及びm3の合計は15〜150の範囲である、請求項6に記載の足場。
- 前記PHFが3kDa〜15kDaの範囲の分子量を有し、m2は2〜15の整数であり、m3は1〜8の整数であり、m1 は2〜50の整数であり、そして、m、m1、m2、及びm3の合計は20〜110の範囲である、請求項6に記載の足場。
- 前記PHFが5kDa〜10kDaの範囲の分子量を有し、m2 は3〜10の整数であり、m3は1〜5の整数であり、m1 は5〜35の整数であり、そして、m、m1、m2、及びm3の合計は40〜75の範囲である、請求項6に記載の足場。
- マレイミド基を介してPHFに結合されるPBRMをさらに含む、請求項1〜10のいずれか1項に記載の足場。
- 前記PHFが2kDa〜20kDaの範囲の分子量を有し、m、m1、m2、m3a、及びm3bの合計は15〜150の範囲であり、そして、m1は1〜70の整数であり、m2は1〜20の整数であり、m3aは0〜9の整数であり、m3bは1〜8の整数であり、そして、m5は2〜8の整数である、請求項13に記載の足場。
- 前記PHFが3kDa〜15kDaの範囲の分子量を有し、m、m1、m2、m3a、及びm3bの合計は20〜110の範囲であり、そして、m1は2〜50の整数であり、m2は2〜15の整数であり、m3aは0〜7の整数であり、m3bは1〜8の整数であり、そして、m5は2〜4の整数である、請求項13に記載の足場。
- 前記PHFが5kDa〜10kDaの範囲の分子量を有し、m、m1、m2、m3a、及びm3bの合計は40〜75の範囲であり、そして、m1 は5〜35の整数であり、m2 は3〜10の整数であり、m3aは0〜4の整数であり、m3bは1〜5の整数であり、そして、m5は2〜4の整数である、請求項13に記載の足場。
- 前記PBRMが40kDa超の分子量を有する、請求項1〜17のいずれか1項に記載の足場。
- 請求項11〜18のいずれか1項に記載の足場及び医薬的に許容される担体を含んでなる、医薬組成物。
- 治療法における使用のための、請求項1〜19のいずれか1項に記載の足場又は請求項20に記載の医薬組成物。
- 癌の処置用であり、前記癌は好ましくは、肛門癌、星状細胞腫、白血病、リンパ腫、頭頚部癌、肝臓癌、精巣癌、子宮頚癌、肉腫、血管腫、食道癌、眼癌、喉頭癌、口腔癌(mouth cancer)、中皮腫、皮膚癌、骨髄腫、口腔癌(oral cancer)、直腸癌、咽喉癌、膀胱癌、乳癌、子宮癌、卵巣癌、前立腺癌、肺癌、結腸癌、膵臓癌、腎臓癌、及び胃癌から成る群から選択される、請求項11〜18のいずれか1項に記載の足場又は請求項20に記載の医薬組成物。
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EP3054991B1 (en) | 2019-04-03 |
IL244816B (en) | 2020-05-31 |
EA032231B1 (ru) | 2019-04-30 |
EA201690744A1 (ru) | 2016-09-30 |
CA2926586A1 (en) | 2015-04-16 |
AU2014331714A1 (en) | 2016-04-21 |
BR112016007736A2 (ja) | 2017-08-01 |
IL244816A0 (en) | 2016-05-31 |
EP3054991A1 (en) | 2016-08-17 |
WO2015054659A1 (en) | 2015-04-16 |
MX2016004596A (es) | 2016-11-11 |
US9849191B2 (en) | 2017-12-26 |
JP2016535728A (ja) | 2016-11-17 |
CN105979970A (zh) | 2016-09-28 |
KR102087850B1 (ko) | 2020-03-12 |
CA2926586C (en) | 2020-04-07 |
US20150104407A1 (en) | 2015-04-16 |
ES2726850T3 (es) | 2019-10-09 |
US20180140716A1 (en) | 2018-05-24 |
KR20160067181A (ko) | 2016-06-13 |
CN105979970B (zh) | 2019-09-10 |
MX367851B (es) | 2019-09-09 |
BR112016007736B1 (pt) | 2022-09-27 |
AU2014331714B2 (en) | 2019-05-02 |
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