Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028, Barcelona, Spain.
Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050, Brussels, Belgium.
Angew Chem Int Ed Engl. 2018 Oct 15;57(42):13843-13847. doi: 10.1002/anie.201807736. Epub 2018 Sep 21.
One of the hallmarks of cancer is the overproduction of growth factors such as EGF. Despite the clinical success achieved by EGFR-targeted therapies, their long-term efficacy is compromised by the onset of drug-resistant mutations. To address this issue, a family of camelid-derived single-domain antibodies (Nbs) were generated, obtaining the first direct EGF inhibitors that prevent EGFR phosphorylation and pathway activation through this new mechanism of action. The two best Nbs were subjected to a detailed investigation of their interaction mechanism that revealed important differences in their binding kinetics and equilibrium thermodynamics. These distinct behaviors at the biophysical level translate into an equally efficient inhibition of the cellular EGFR phosphorylation, thus proving the efficacy of these Nbs to turn off the initiation of this key oncogenic pathway in cancer cells.
癌症的一个特征是生长因子的过度产生，例如 EGF。尽管 EGFR 靶向治疗取得了临床成功，但由于耐药性突变的出现，其长期疗效受到影响。为了解决这个问题，生成了一系列骆驼科来源的单域抗体 (Nbs)，获得了首个直接的 EGF 抑制剂，通过这种新的作用机制来阻止 EGFR 磷酸化和信号通路激活。对其中两个最好的 Nbs 进行了详细的相互作用机制研究，揭示了它们在结合动力学和平衡热力学方面的重要差异。这些在生物物理水平上的不同行为转化为对细胞 EGFR 磷酸化的同样有效的抑制，从而证明了这些 Nbs 能够有效地关闭癌细胞中这条关键致癌通路的启动。
