Robert Frederick Smith School of Chemical and Biomolecular Engineering , Cornell University , 113 Ho Plaza , Ithaca , New York 14850 , United States.
Catalent Biologics , 5703 Hollis Street , Emeryville , California 94608 , United States.
Bioconjug Chem. 2019 Nov 20;30(11):2982-2988. doi: 10.1021/acs.bioconjchem.9b00713. Epub 2019 Nov 12.
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.
抗体药物偶联物 (ADCs) 是一种将化疗药物靶向递送至特定组织的成熟方法。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 ADC 方面仍然存在挑战。在之前的研究中，有效载荷结构、独特的刺激响应化学和聚乙二醇化交联剂已被用于降低 ADC 的疏水性。在这项工作中，我们研究了一个新参数，即交联剂序列的影响。开发了一种无支撑的聚乙二醇化、序列定义的交联剂的合成方法，并将其应用于含有聚乙二醇侧链和单甲基奥瑞他汀 E 有效载荷的三种结构异构体 ADC 的合成中。发现将 PEG 侧链置于有效载荷的远端可以得到具有改变的亲水性、抗原结合和体外效力的 ADC。这项工作建立了一种合成多功能交联剂的通用方法，并确定了交联剂序列作为调节 ADC 性能的新方法。
