JP2017532310A - 免疫原性/治療用糖コンジュゲート組成物およびその使用 - Google Patents
免疫原性/治療用糖コンジュゲート組成物およびその使用 Download PDFInfo
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Abstract
Description
本発明者らは、複数のGlobo H部分と連結したKLHの二量体、三量体ならびに他の多量体で主に構成される、有効性が驚くほど増大した組成物を開発した。
を有する単離された治療用コンジュゲートを包含する。ある特定の実施形態では、単量体KLH部分は、約1〜約160個のGlobo H部分を含み得る。構造はイミニウム塩酸塩として例示されているが、イミン形態としても存在または共存し得ることが当業者には理解されよう。したがって、本発明は、イミンならびに例えばイミニウム塩酸塩を含めたその塩の両方を包含する。ある特定の実施形態では、単量体KLH部分は、約個〜約125個のGlobo H部分を含み得る。ある特定の実施形態では、単量体KLH部分は、約1〜約100個のGlobo H部分を含み得る。ある特定の実施形態では、単量体KLH部分は、1〜約75個のGlobo H部分を含み得る。ある特定の実施形態では、単量体KLH部分は、約1〜約50個のGlobo H部分を含み得る。ある特定の実施形態では、単量体KLH部分は、約1〜約25個のGlobo H部分を含み得る。ある特定の実施形態では、単量体KLH部分は、約1〜約10個のGlobo H部分を含み得る。
Fobs=Fmax[P]/(KD,surf+[P])
(式中、Fmaxは、表面上の活性な炭水化物の量の尺度である最大蛍光強度であり、[P]は、総抗体濃度であり、KD,surfは、表面炭水化物および抗体についての平衡解離定数である)。Wangらに記載の通り。一部の実施形態では、Globo H類似体の好ましい(KD,surf)は、Wangらに記載の通り、VK−9、Mbr1、および抗SSEA−3抗体に関して、少なくとも、約、または正確に0.4、0.5.、0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5または1.6nMである。
治療用コンジュゲートに対する抗体
生物学的アッセイ
組合せ
R1はβ−D−アピオースまたはβ−D−キシロースであり、
R2およびR3は、独立に、H、アルキル、
である)
を含む。
式中、
(i)R1がβ−D−アピオースであり、R2が上記の1989化合物の脂肪アシル部分であり、R3がHである(1989化合物V1A);
(ii)R1がβ−D−アピオースであり、R2がHであり、R3が上記の1989化合物の脂肪アシル部分である(1989化合物V1B);
(iii)R1がβ−D−キシロースであり、R2が上記の1989化合物の脂肪アシル部分であり、R3がHである(1989化合物V2A);または
(iv)R1がβ−D−キシロースであり、R2がHであり、R3が上記の1989化合物の脂肪アシル部分である(1989化合物V2B)
化合物を含んでもよい。集合的に、1989化合物V1A、1989化合物V1B、1989化合物V2Aおよび1989化合物V2Bは「1989化合物混合物」と称する。
式中、
(i)R1がβ−D−アピオースであり、R2が上記の1857化合物の脂肪アシル部分であり、R3がHである(1857化合物V1A);
(ii)R1がβ−D−アピオースであり、R2がHであり、R3が上記の1857化合物の脂肪アシル部分である(1857化合物V1B);
(iii)R1がβ−D−キシロースであり、R2が上記の1857化合物の脂肪アシル部分であり、R3がHである(1857化合物V2A);または
(iv)R1がβ−D−キシロースであり、R2がHであり、R3が上記の1857化合物の脂肪アシル部分である(1857化合物V2B)
化合物を含んでよい。集合的に、1857化合物V1A、1857化合物V1B、1857化合物V2Aおよび1857化合物V2Bを「1857化合物混合物」と称する。
(i)1857化合物V1A;
(ii)1857化合物V1B;
(iii)1857化合物V2A;
(iv)1857化合物V2B;
(v)1989化合物V1A;
(vi)1989化合物V1B;
(vii)1989化合物V2A;または
(viii)1989化合物V2B
のうちの1つまたは複数を含む。
(i)OBI−821の約1モル%〜約15モル%が1857化合物混合物で構成され;
(ii)OBI−821の約85モル%〜約99モル%が1989化合物混合物で構成される。
R1はβ−D−アピオースまたはβ−D−キシロースであり、
R2およびR3は、独立に、H、アルキル、または
および、薬学的に許容される担体を含む。
本発明の製剤
剤形
キット
本発明の組成物の合成方法
本発明の糖コンジュゲート(Globo H−KLH)の調製
糖コンジュゲート中のGlobo HとKLHとの重量比の分析
糖コンジュゲート中のGlobo HとKLHとのエピトープ比の分析
ワクチン組成物の調製およびラットにおける免疫
ラットにおける体液性および細胞性免疫応答の誘導に関するアッセイ
マウスにおける免疫およびELISAによる抗体検査
マウスにおける、異なるアジュバントを伴うGlobo H−KLHの免疫原性試験
KLH上のGlobo−Hコンジュゲーション部位(リシン)のLC−MS/MS分析
K=リシン;LC−MS/MS=液体クロマトグラフィー−タンデム質量分析;DTT=ジチオトレイトール(Dithiolthreitol);IAM=ヨードアセトアミド;ACN=アセトニトリル;FA=ギ酸;Glu−C=エンドプロテイナーゼGlu−C;ABC=炭酸水素アンモニウム;RT=室温;MW=分子量。
酵素:消化方法に応じて、トリプシン、Glu−C、キモトリプシンおよびサーモリシン;固定修飾:カルバミドメチル(C);
MMCCH誘導体(MMCCH単独)に対する変動修飾:脱アミド(NQ)、酸化(M)、dK_MMCCH−1(K)、dK_MMCCH−2(K);
Globo H誘導体(Globo H+MMCCH)に対する変動修飾:脱アミド(NQ)、酸化(M)、Globo_H_MMCCH(K)、dK_MMCCH_NL997(K)、dK_MMCCH_NL835(K)、dK_MMCCH_NL673(K)、dK_MMCCH_NL511(K)、dK_MMCCH_NL308(K);
Peptide Mass Tolerance:±10ppm;Fragment Mass Tolerance:±0.05Da;Max Missed Cleavages:5;計器の型:ESI−TRAP;Ion cut−off score:13。
KLH上のGlobo−Hコンジュゲーション部位(ヒスチジン、アスパラギン、プロリン、グルタミンおよびアルギニン)のLC−MS/MS分析
K=リシン;H=ヒスチジン;N=アスパラギン;P=プロリン;Q=グルタミン;R=アルギニン;LC−MS/MS=液体クロマトグラフィー−タンデム質量分析;MW=分子量。
酵素:消化方法に応じてトリプシン、Glu−C、キモトリプシンおよびサーモリシン;
固定修飾:カルバミドメチル(C);
変動修飾:酸化(M)、脱アミド(NQ);
1.OBI822_GMd(HKNPQR)、GMd_NL997(HKNPQR);
2.OBI822_Md(HKNPQR)、Md_脱アミド(HKNPQR);
Peptide Mass Tolerance:±10ppm;Fragment Mass Tolerance:±0.05Da;Max Missed Cleavages:5;計器の型:ESI−TRAP;Ion cut−off score:13。
例えば、本発明は以下の項目を提供する。
(項目1)
1〜20個(n=1〜20)のキーホールリンペットヘモシアニン(KLH)部分と共有結合により連結した複数のGlobo H部分を含む組成物であって、前記Globo H部分が、前記KLH部分と1個または複数のアミノ酸残基において共有結合により結合している、組成物。
(項目2)
前記アミノ酸残基が、塩基性、中性、疎水性アミノ酸残基および/またはそれらの組合せである、項目1に記載の組成物。
(項目3)
前記アミノ酸残基が、リシン、アルギニン、ヒスチジン、アスパラギン、プロリン、グルタミンおよび/またはそれらの組合せである、項目1に記載の組成物。
(項目4)
前記KLH部分が、単量体(n=1)である、項目1に記載の組成物。
(項目5)
前記KLH部分が、二量体(n=2)である、項目1に記載の組成物。
(項目6)
前記KLH部分が、三量体(n=3)である、項目1に記載の組成物。
(項目7)
前記KLH部分が、四量体(n=4)である、項目1に記載の組成物。
(項目8)
前記KLH部分が、五量体(n=5)である、項目1に記載の組成物。
(項目9)
前記KLH部分が、六量体(n=6)である、項目1に記載の組成物。
(項目10)
前記KLH部分が、七量体(n=7)である、項目1に記載の組成物。
(項目11)
前記KLH部分が、八量体(n=8)である、項目1に記載の組成物。
(項目12)
前記KLH部分が、九量体(n=9)である、項目1に記載の組成物。
(項目13)
前記KLH部分が、十量体(n=10)である、項目1に記載の組成物。
(項目14)
前記KLH部分が、十一量体(n=11)である、項目1に記載の組成物。
(項目15)
前記KLH部分が、十二量体(n=12)である、項目1に記載の組成物。
(項目16)
前記KLH部分が、十三量体(n=13)である、項目1に記載の組成物。
(項目17)
前記KLH部分が、十四量体(n=14)である、項目1に記載の組成物。
(項目18)
前記KLH部分が、十五量体(n=15)である、項目1に記載の組成物。
(項目19)
前記KLH部分が、十六量体(n=16)である、項目1に記載の組成物。
(項目20)
前記KLH部分が、十七量体(n=17)である、項目1に記載の組成物。
(項目21)
前記KLH部分が、十八量体(n=18)である、項目1に記載の組成物。
(項目22)
前記KLH部分が、十九量体(n=19)である、項目1に記載の組成物。
(項目23)
前記KLH部分が、二十量体(n=20)である、項目1に記載の組成物。
(項目24)
前記KLH部分が互いに同じである、項目1に記載の組成物。
(項目25)
前記KLH部分が互いに異なる、項目1に記載の組成物。
(項目26)
各KLH部分が、同じ数のGlobo H部分を有する、項目1に記載の組成物。
(項目27)
各KLH部分が、異なる数のGlobo H部分を有する、項目1に記載の組成物。
(項目28)
前記Globo H部分が、(Fucα1→2Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glc)を含む、項目1に記載の組成物。
(項目29)
前記KLH部分サブユニットが、配列番号1のものである、項目1に記載の組成物。
(項目30)
前記KLH部分サブユニットが、対応する配列番号1のKLH部分と少なくとも95%同一である、項目1に記載の組成物。
(項目31)
前記KLH部分サブユニットが、対応する配列番号1のKLH部分と少なくとも90%同一である、項目1に記載の組成物。
(項目32)
前記KLH部分サブユニットが、対応する配列番号1のKLH部分と少なくとも80%同一である、項目1に記載の組成物。
(項目33)
前記KLH部分サブユニットが、配列番号2のものである、項目1に記載の組成物。
(項目34)
前記KLH部分サブユニットが、対応する配列番号2のKLH部分と少なくとも95%同一である、項目1に記載の組成物。
(項目35)
前記KLH部分サブユニットが、対応する配列番号2のKLH部分と少なくとも90%同一である、項目1に記載の組成物。
(項目36)
前記KLH部分サブユニットが、対応する配列番号2のKLH部分と少なくとも80%同一である、項目1に記載の組成物。
(項目37)
キーホールリンペットヘモシアニン(KLH)部分サブユニットと共有結合により連結したGlobo H部分が、4−(4−N−マレイミドメチル)シクロヘキサン−1−カルボキシルヒドラジド(MMCCH)連結によって連結している、項目1に記載の組成物。
(項目38)
少なくとも150:1のエピトープ比を有する、項目1に記載の単離された治療用コンジュゲート。
(項目39)
少なくとも125:1のエピトープ比を有する、項目1に記載の組成物。
(項目40)
少なくともまたは約100:1のエピトープ比を有する、項目1に記載の単離された治療用コンジュゲート。
(項目41)
少なくとも75:1のエピトープ比を有する、項目1に記載の組成物。
(項目42)
少なくとも50:1のエピトープ比を有する、項目1に記載の組成物。
(項目43)
少なくとも25:1のエピトープ比を有する、項目1に記載の組成物。
(項目44)
少なくとも10:1のエピトープ比を有する、項目1に記載の組成物。
(項目45)
少なくとも1:1のエピトープ比を有する、項目1に記載の組成物。
(項目46)
それを必要とする患者においてがんを処置する方法であって、前記患者に治療有効量の項目1に記載の組成物を投与するステップを含む方法。
(項目47)
前記がんが、乳がん、肺がん、胃がん(gastric cancer)、結腸がん、膵がん、前立腺がん、卵巣がん、上皮がんまたは子宮体がんである、項目46に記載の方法。
(項目48)
前記がんが、Globo H発現がんである、項目46に記載の方法。
(項目49)
治療または診断に使用するためのモノクローナル抗体を創出するために対象において抗体を誘導する方法であって、前記対象に有効量の項目1に記載の組成物を投与するステップを含む方法。
(項目50)
前記対象が、動物またはヒトである、項目49に記載の方法。
(項目51)
(a)1個または複数のKLH部分サブユニットと共有結合により連結した複数のGlobo H部分と、
(b)α−ガラクトシル−セラミド(α−GalCer)アジュバントと
を含む医薬組成物。
(項目52)
前記α−GalCerアジュバントが以下の構造:
(項目53)
前記KLH部分が、単量体、二量体、三量体、四量体、五量体、六量体、六量体、七量体、八量体、九量体、十量体、十一量体、十二量体、十三量体、十四量体、十五量体、十六量体、十七量体、十八量体、十九量体または二十量体を形成し得る、項目51に記載の組成物。
(項目54)
治療または診断に使用するためのモノクローナル抗体を創出するために、対象において抗体を誘導する方法であって、前記対象に有効量の項目51に記載の組成物を投与するステップを含む方法。
(項目55)
前記対象が、動物またはヒトである、項目54に記載の方法。
Claims (55)
- 1〜20個(n=1〜20)のキーホールリンペットヘモシアニン(KLH)部分と共有結合により連結した複数のGlobo H部分を含む組成物であって、前記Globo H部分が、前記KLH部分と1個または複数のアミノ酸残基において共有結合により結合している、組成物。
- 前記アミノ酸残基が、塩基性、中性、疎水性アミノ酸残基および/またはそれらの組合せである、請求項1に記載の組成物。
- 前記アミノ酸残基が、リシン、アルギニン、ヒスチジン、アスパラギン、プロリン、グルタミンおよび/またはそれらの組合せである、請求項1に記載の組成物。
- 前記KLH部分が、単量体(n=1)である、請求項1に記載の組成物。
- 前記KLH部分が、二量体(n=2)である、請求項1に記載の組成物。
- 前記KLH部分が、三量体(n=3)である、請求項1に記載の組成物。
- 前記KLH部分が、四量体(n=4)である、請求項1に記載の組成物。
- 前記KLH部分が、五量体(n=5)である、請求項1に記載の組成物。
- 前記KLH部分が、六量体(n=6)である、請求項1に記載の組成物。
- 前記KLH部分が、七量体(n=7)である、請求項1に記載の組成物。
- 前記KLH部分が、八量体(n=8)である、請求項1に記載の組成物。
- 前記KLH部分が、九量体(n=9)である、請求項1に記載の組成物。
- 前記KLH部分が、十量体(n=10)である、請求項1に記載の組成物。
- 前記KLH部分が、十一量体(n=11)である、請求項1に記載の組成物。
- 前記KLH部分が、十二量体(n=12)である、請求項1に記載の組成物。
- 前記KLH部分が、十三量体(n=13)である、請求項1に記載の組成物。
- 前記KLH部分が、十四量体(n=14)である、請求項1に記載の組成物。
- 前記KLH部分が、十五量体(n=15)である、請求項1に記載の組成物。
- 前記KLH部分が、十六量体(n=16)である、請求項1に記載の組成物。
- 前記KLH部分が、十七量体(n=17)である、請求項1に記載の組成物。
- 前記KLH部分が、十八量体(n=18)である、請求項1に記載の組成物。
- 前記KLH部分が、十九量体(n=19)である、請求項1に記載の組成物。
- 前記KLH部分が、二十量体(n=20)である、請求項1に記載の組成物。
- 前記KLH部分が互いに同じである、請求項1に記載の組成物。
- 前記KLH部分が互いに異なる、請求項1に記載の組成物。
- 各KLH部分が、同じ数のGlobo H部分を有する、請求項1に記載の組成物。
- 各KLH部分が、異なる数のGlobo H部分を有する、請求項1に記載の組成物。
- 前記Globo H部分が、(Fucα1→2Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glc)を含む、請求項1に記載の組成物。
- 前記KLH部分サブユニットが、配列番号1のものである、請求項1に記載の組成物。
- 前記KLH部分サブユニットが、対応する配列番号1のKLH部分と少なくとも95%同一である、請求項1に記載の組成物。
- 前記KLH部分サブユニットが、対応する配列番号1のKLH部分と少なくとも90%同一である、請求項1に記載の組成物。
- 前記KLH部分サブユニットが、対応する配列番号1のKLH部分と少なくとも80%同一である、請求項1に記載の組成物。
- 前記KLH部分サブユニットが、配列番号2のものである、請求項1に記載の組成物。
- 前記KLH部分サブユニットが、対応する配列番号2のKLH部分と少なくとも95%同一である、請求項1に記載の組成物。
- 前記KLH部分サブユニットが、対応する配列番号2のKLH部分と少なくとも90%同一である、請求項1に記載の組成物。
- 前記KLH部分サブユニットが、対応する配列番号2のKLH部分と少なくとも80%同一である、請求項1に記載の組成物。
- キーホールリンペットヘモシアニン(KLH)部分サブユニットと共有結合により連結したGlobo H部分が、4−(4−N−マレイミドメチル)シクロヘキサン−1−カルボキシルヒドラジド(MMCCH)連結によって連結している、請求項1に記載の組成物。
- 少なくとも150:1のエピトープ比を有する、請求項1に記載の単離された治療用コンジュゲート。
- 少なくとも125:1のエピトープ比を有する、請求項1に記載の組成物。
- 少なくともまたは約100:1のエピトープ比を有する、請求項1に記載の単離された治療用コンジュゲート。
- 少なくとも75:1のエピトープ比を有する、請求項1に記載の組成物。
- 少なくとも50:1のエピトープ比を有する、請求項1に記載の組成物。
- 少なくとも25:1のエピトープ比を有する、請求項1に記載の組成物。
- 少なくとも10:1のエピトープ比を有する、請求項1に記載の組成物。
- 少なくとも1:1のエピトープ比を有する、請求項1に記載の組成物。
- それを必要とする患者においてがんを処置する方法であって、前記患者に治療有効量の請求項1に記載の組成物を投与するステップを含む方法。
- 前記がんが、乳がん、肺がん、胃がん(gastric cancer)、結腸がん、膵がん、前立腺がん、卵巣がん、上皮がんまたは子宮体がんである、請求項46に記載の方法。
- 前記がんが、Globo H発現がんである、請求項46に記載の方法。
- 治療または診断に使用するためのモノクローナル抗体を創出するために対象において抗体を誘導する方法であって、前記対象に有効量の請求項1に記載の組成物を投与するステップを含む方法。
- 前記対象が、動物またはヒトである、請求項49に記載の方法。
- (a)1個または複数のKLH部分サブユニットと共有結合により連結した複数のGlobo H部分と、
(b)α−ガラクトシル−セラミド(α−GalCer)アジュバントと
を含む医薬組成物。 - 前記α−GalCerアジュバントが以下の構造:
- 前記KLH部分が、単量体、二量体、三量体、四量体、五量体、六量体、六量体、七量体、八量体、九量体、十量体、十一量体、十二量体、十三量体、十四量体、十五量体、十六量体、十七量体、十八量体、十九量体または二十量体を形成し得る、請求項51に記載の組成物。
- 治療または診断に使用するためのモノクローナル抗体を創出するために、対象において抗体を誘導する方法であって、前記対象に有効量の請求項51に記載の組成物を投与するステップを含む方法。
- 前記対象が、動物またはヒトである、請求項54に記載の方法。
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