Tailored Linker Chemistries for the Efficient and Selective Activation of ADCs with KSPi Payloads.,Bioconjugate Chemistry

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Tailored Linker Chemistries for the Efficient and Selective Activation of ADCs with KSPi Payloads.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-07-15 , DOI: 10.1021/acs.bioconjchem.0c00357
Hans-Georg Lerchen ₁ , Beatrix Stelte-Ludwig ₁ , Anette Sommer ₂ , Sandra Berndt ₂ , Anne-Sophie Rebstock ₃ , Sarah Johannes ₁ , Christoph Mahlert ₁ , Simone Greven ₁ , Lisa Dietz ₁ , Hannah Jörißen ₁

Affiliation

Several antibody–drug conjugates (ADCs) have failed to achieve a sufficiently large therapeutic window in patients due to toxicity induced by unspecific payload release in the circulation or ADC uptake into healthy organs. Herein, we describe the successful engineering of ADCs consisting of novel linkers, which are efficiently and selectively cleaved by the tumor-associated protease legumain. ADCs generated via this approach demonstrate high potency and a preferential activation in tumors compared to healthy tissue, thus providing an additional level of safety. A remarkable tolerance of legumain for different linker peptides, including those with just a single asparagine residue, together with a modifier of the physicochemical metabolite profile, proves the broad applicability of this approach for a tailored design of ADCs.

中文翻译：

量身定制的链接器化学试剂，可有效和选择性地激活带有KSPi有效负载的ADC。

由于循环中非特异性有效负载释放或健康器官中ADC的吸收所引起的毒性，几种抗体-药物偶联物（ADC）无法在患者中获得足够大的治疗窗口。在本文中，我们描述了由新型接头组成的ADC的成功工程改造，这些接头被肿瘤相关蛋白酶legumain有效和选择性地裂解。与健康组织相比，通过这种方法生成的ADC在肿瘤中显示出高效力和优先激活，从而提供了更高的安全性。豆蔻因对不同的接头肽（包括仅具有一个天冬酰胺残基的那些）以及理化代谢产物谱的修饰剂具有显着的耐受性，证明了这种方法在ADC定制设计中的广泛适用性。

更新日期：2020-08-19

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