Cavaco Marco, Frutos Silvia, Oliete Paula, Valle Javier, Andreu David, Castanho Miguel A R B, Vila-Perelló Miquel, Neves Vera
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof Egas Moniz, 1649-028 Lisboa, Portugal.
Proteomics and Protein Chemistry Unit, Department of Experimental and Health Sciences, Pompeu Fabra University, Dr. Aiguader 88, Barcelona Biomedical Research Park, 08003 Barcelona, Spain.
ACS Med Chem Lett. 2021 Sep 2;12(11):1663-1668. doi: 10.1021/acsmedchemlett.1c00225. eCollection 2021 Nov 11.
The frequency of brain disease has increased significantly in the past years. After diagnosis, therapeutic options are usually limited, which demands the development of innovative therapeutic strategies. The use of antibody-drug conjugates (ADCs) is promising but highly limited by the existence of the blood-brain barrier (BBB). To overcome the impermeability of this barrier, antibody fragments can be engineered and conjugated to BBB peptide shuttles (BBBpS), which are capable of brain penetration. Herein, we linked the highly efficient BBBpS, PepH3, to the IgG fragment crystallizable (Fc) domain using the streamlined expressed protein ligation (SEPL) method. With this strategy, we obtained an Fc-PepH3 scaffold that can carry different payloads. Fc-PepH3 was shown to be nontoxic, capable of crossing an in vitro cellular BBB model, and able to bind to the neonatal Fc receptor (FcRn), which is responsible for antibody long half-life ( ). Overall, we demonstrated the potential of Fc-PepH3 as a versatile platform readily adaptable to diverse drugs of therapeutic value to treat different brain conditions.
在过去几年中，脑部疾病的发病率显著上升。诊断后，治疗选择通常有限，这就需要开发创新的治疗策略。抗体药物偶联物（ADC）的应用前景广阔，但由于血脑屏障（BBB）的存在而受到极大限制。为了克服这一屏障的不透性，可以对抗体片段进行工程改造，并与能够穿透大脑的血脑屏障肽穿梭体（BBBpS）偶联。在此，我们使用简化的表达蛋白连接（SEPL）方法，将高效的BBBpS PepH3与免疫球蛋白G（IgG）的可结晶片段（Fc）结构域相连。通过这种策略，我们获得了一种可以携带不同载荷的Fc-PepH3支架。研究表明，Fc-PepH3无毒，能够穿过体外细胞血脑屏障模型，并且能够与负责抗体长半衰期的新生儿Fc受体（FcRn）结合。总体而言，我们证明了Fc-PepH3作为一个通用平台的潜力，它可以很容易地适配各种具有治疗价值的药物，以治疗不同的脑部疾病。
