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Monomethyl auristatin E

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Catalog No.
A3631
抗有丝分裂剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 4,250.00
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1mg
¥ 850.00
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5mg
¥ 2,000.00
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10mg
¥ 3,200.00
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50mg
¥ 9,800.00
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Background

IC50: less than 1 nM for various cancer cell lines

Monomethyl auristatin E(MMAE) is a potent antimitotic agent by blocking the polymerisation of tubulin.

Microtubules play essential role in the function of the cell. Microtubules are also reported to be involved in migration, transport and reorganization and have numerous dynamic roles including movement through motor proteins such as dynein and kinesin and the separation and segregation ofchromosomes during cell division.

In vitro: The cytotoxic effects of the MMAE conjugates on H3396 cells were determined using both pulsed and long-term drug exposure assays. It was found that under both exposure conditions, high degrees of immunological specificity were obtained with the Val-Cit conjugates. cBR96-Val-Cit-MMAE was highly active at <1/100th of the concentration required for antigen saturation [1].

In vivo: In vivo therapy tests were undertaken in athymic mice with subcutaneous L2987 human lung adenocarcinoma xenografts. MMAE conjugates were administered at 3 mg mAb component/kg/dose. All of the tested MMAE conjugates were highly efficacious, leading to long-term regressions of established tumors, whereas the nonbinding control conjugates had no effect on tumor growth. In addition, there were no apparent toxicities associated with conjugate treatment [1].

Clinical trial: In a ongoing Phase I study with platinum-resistant ovarian cancer patients, nonlinear PK of MMAE conjugate had been observed in the dose range of 0.3 to 3.2 mg/kg. Circulating CA125 results suggested no impact on the PK at 2.4 mg/kg, which was the potential clinically relevant dose. Systemic free MMAE concentration was low and consistent with other MMAE containing ADCs [2].

References:
[1] Doronina SO,Toki BE,Torgov MY,Mendelsohn BA,Cerveny CG,Chace DF,DeBlanc RL,Gearing RP,Bovee TD,Siegall CB,Francisco JA,Wahl AF,Meyer DL,Senter PD.  Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol.2003 Jul;21(7):778-84.
[2] Jian Xu*, Priya Agarwal, Ola Saad, et al.  Clinical Pharmacokinetics (PK) of Anti-MUC16 Antibody-Drug Conjugates (ADCs), DMUC5754A, in Patients with Platinum-Resistant Ovarian Cancer: Results from Phase I study. This poster was presented at World ADC Summit 2014.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt717.98
Cas No.474645-27-7
FormulaC39H67N5O7
SynonymsVedotin; MMAE
Solubility≥35.9 mg/mL in DMSO, ≥48.5 mg/mL in EtOH with ultrasonic and warming, <2.34 mg/mL in H2O
Chemical Name(2S)-N-[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]-3-methyl-2-(methylamino)butanamide
SDFDownload SDF
Canonical SMILESCCC(C)C(C(CC(=O)N1CCCC1C(C(C)C(=O)NC(C)C(C2=CC=CC=C2)O)OC)OC)N(C)C(=O)C(C(C)C)NC(=O)C(C(C)C)NC
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验 [1]:

细胞系

Karpas 299, H3396 以及 RCA细胞系

溶解方法

在DMSO中的溶解度> 35.9 mg/mL。为了获得更高浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃一下储存几个月。

反应条件

0~10000 ng/ml孵育92小时

应用

在RCA结肠直肠癌细胞上对mAb-Val-Cit-MMAE偶联物96小时细胞毒性活性进行了考察。 结果表明,cBR96-Val-Cit-MMAE处理的细胞中细胞存活率降低了104倍。同时,在系列肿瘤细胞系上对mAb-Val-Cit-MMAE活性进行了考察,结果发现在所有情况下,MMAE偶联物都是有效的,并且其作用是由于特异性药物递送引起的,因为未偶联的非偶联mAb几乎都没有细胞毒性活性。

动物实验 [1]:

动物模型

Karpas 299 以及 L2987实体瘤CB17 SCID小鼠模型

剂量

L2987人肺腺癌肿瘤:3 mg单抗成分/公斤/单次注射,静脉给药;Karpas 299人ALCL肿瘤:1 mg单抗成分/公斤/单次注射,静脉给药

应用

在皮下接种Karpas 299ALCL肿瘤(cBR96 Ag–, cAC10Ag+)的SCID小鼠中进行了药效学实验,其中cAC10-Val-Cit-MMAE是结合偶联物,而cBR96-Val-Cit-MMAE是非结合对照。 结果显示cAC10-Val-Cit-MMAE的治疗效果明显,在1 mg mAb组分/ kg /注射剂量下对相对大的肿瘤(> 200mm 3)具有疗效,对应于MTD的1/30,而等效剂量的非结合对照耦合物cBR96-Val-Cit-MMAE显示无效。 用1mg mAb组分/ kg /注射和0.5mg / kg /注射的cAC10-Val-Cit-MMAE治疗可以分别产生100%和80%的肿瘤治愈。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1] Doronina SO,Toki BE,Torgov MY,μMendelsohn BA,Cerveny CG,Chace DF,DeBlanc RL,Gearing RP,Bovee TD,Siegall CB,Francisco JA,Wahl AF,μMeyer DL,Senter PD. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol.2003 Jul;21(7):778-84.

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