Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform.
Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform.
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DOI：
10.3390/ph14030247
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发表时间：
2021-03-09
期刊：
影响因子：
--
通讯作者：
Viricel W
中科院分区：
文献类型：
--
作者：
Conilh L;Fournet G;Fourmaux E;Murcia A;Matera EL;Joseph B;Dumontet C;Viricel W
我们在此报告了基于拓扑异构酶I抑制剂有效载荷依沙替康的新型HER 2靶向抗体-药物偶联物（ADC）的开发和评价，使用我们的亲水性单分散聚肌氨酸（PSAR）药物-接头平台（PSARlink）。在乳腺癌和胃癌模型中进行了体外和体内实验，以表征这种原始ADC并了解药物-接头结构-活性关系。包含PSAR疏水性掩蔽实体有效地降低了缀合物的总体疏水性，并产生了与未缀合的抗体共享相同的药代动力学特征的ADC，尽管喜树碱衍生的有效载荷的药物载量高（药物-抗体比为8）。Tra-Exa-PSAR 10在NCI-N87异种移植模型中以lmg/kg表现出强的抗肿瘤活性，优于FDA批准的ADC DS-8201 a（Enhertu），同时在小鼠中以100 mg/kg的剂量耐受良好。体外实验表明，这种基于艾西替康的ADC表现出比DS-8201 a更高的旁观者杀伤效应，并在临床前HER 2+乳腺和食管模型中克服了对T-DM 1（Kadcyla）的耐药性，表明在异质性和耐药肿瘤中具有潜在活性。总之，基于聚肌氨酸的疏水性掩蔽方法允许产生具有优异的物理化学性质、改善的药代动力学特征和有效的体内抗肿瘤活性的高度缀合的基于依西替康的ADC。
We herein report the development and evaluation of a novel HER2-targeting antibody–drug conjugate (ADC) based on the topoisomerase I inhibitor payload exatecan, using our hydrophilic monodisperse polysarcosine (PSAR) drug-linker platform (PSARlink). In vitro and in vivo experiments were conducted in breast and gastric cancer models to characterize this original ADC and gain insight about the drug-linker structure–activity relationship. The inclusion of the PSAR hydrophobicity masking entity efficiently reduced the overall hydrophobicity of the conjugate and yielded an ADC sharing the same pharmacokinetic profile as the unconjugated antibody despite the high drug-load of the camptothecin-derived payload (drug–antibody ratio of 8). Tra-Exa-PSAR10 demonstrated strong anti-tumor activity at 1 mg/kg in an NCI-N87 xenograft model, outperforming the FDA-approved ADC DS-8201a (Enhertu), while being well tolerated in mice at a dose of 100 mg/kg. In vitro experiments showed that this exatecan-based ADC demonstrated higher bystander killing effect than DS-8201a and overcame resistance to T-DM1 (Kadcyla) in preclinical HER2+ breast and esophageal models, suggesting potential activity in heterogeneous and resistant tumors. In summary, the polysarcosine-based hydrophobicity masking approach allowsfor the generation of highly conjugated exatecan-based ADCs having excellent physicochemical properties, an improved pharmacokinetic profile, and potent in vivo anti-tumor activity.
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DOI：
10.3390/ph13090245
发表时间：
2020-09-14
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Joubert N;Beck A;Dumontet C;Denevault-Sabourin C
通讯作者：
Denevault-Sabourin C
影响因子：
7.3
作者：
Lambert, John M.;Chari, Ravi V. J.
通讯作者：
Chari, Ravi V. J.
影响因子：
--
作者：
Goldenberg DM;Cardillo TM;Govindan SV;Rossi EA;Sharkey RM
通讯作者：
Sharkey RM
影响因子：
11.5
作者：
Keam, Susan J.
通讯作者：
Keam, Susan J.
影响因子：
4.6
作者：
Fischer, Holger;Kansy, Manfred;Senner, Frank
通讯作者：
Senner, Frank