Hydrophilic Sequence-Defined Cross-Linkers for Antibody-Drug Conjugates.,Bioconjugate Chemistry

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Hydrophilic Sequence-Defined Cross-Linkers for Antibody-Drug Conjugates.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2019-11-12 , DOI: 10.1021/acs.bioconjchem.9b00713
Joshua A Walker ₁ , Michelle R Sorkin ₁ , Francis Ledesma ₁ , Sneha R Kabaria ₁ , Robyn M Barfield ₂ , David Rabuka ₂ , Christopher A Alabi ₁

Affiliation

Antibody-drug conjugates (ADCs) are an established modality for the tissue-specific delivery of chemotherapeutics. However, due to the hydrophobic nature of many cytotoxic payloads, challenges remain in developing chemically stable ADCs with high drug loading. In previous studies, payload structure, unique stimuli-responsive chemistries, and PEGylated cross-linkers have been used to decrease ADC hydrophobicity. In this work, we investigate the effect of a new parameter, cross-linker sequence. A support-free synthesis of PEGylated, sequence-defined cross-linkers was developed and applied to the synthesis of three constitutionally isomeric ADCs containing PEG side chains and a monomethyl auristatin E payload. Placement of PEG side chains distally from the payload was found to yield an ADC with altered hydrophilicity, antigen binding, and in vitro potency. This work establishes a versatile method for synthesizing multifunctional cross-linkers and identifies cross-linker sequence as a new handle for modulating the performance of ADCs.

中文翻译：

抗体-药物偶联物的亲水序列定义的交联剂。

抗体-药物偶联物（ADC）是用于化学疗法的组织特异性递送的已建立模式。然而，由于许多细胞毒性有效载荷的疏水性，在开发具有高载药量的化学稳定的ADC方面仍然存在挑战。在以前的研究中，有效载荷结构，独特的刺激反应性化学物质和PEG化交联剂已被用于降低ADC疏水性。在这项工作中，我们研究了新参数交联剂序列的作用。开发了无支撑的聚乙二醇化，序列定义的交联剂，并将其应用于包含PEG侧链和单甲基澳瑞他汀E有效载荷的三个结构异构ADC的合成。发现将PEG侧链从有效负载向远端放置会产生具有改变的亲水性，抗原结合，和体外效力。这项工作为合成多功能交联剂建立了一种通用方法，并将交联剂序列确定为调节ADC性能的新方法。

更新日期：2019-11-13

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