Caplacizumab binds VWF

Caplacizumab (CABLIVI®, also known as ALX-0081) is a bivalent humanized antibody fragment consisting of a single variable domain (also called nanobody) that targets von Willebrand factor (VWF) (Ulrichts H et al., 2011; van Loon JE et al., 2011). Caplacizumab binds the A1 domain of VWF with high affinity (Ulrichts H et al., 2011; Lee HT et al., 2021). This interaction inhibits binding between VWF and the platelet glycoprotein Ib (GPIb) receptor complex preventing VWF-mediated tethering of platelets to the damaged vessel wall. Structural insights into the mechanism of action suggest that caplacizumab acts by stabilizing an inactive conformation of VWF, which does not interact with platelets, rather than competing with GPIb (Lee HT et al., 2021). Caplacizumab is the Food and Drug Administration (FDA) approved drug to treat thrombotic thrombocytopenic purpura (TTP), a clinical condition associated with immune-mediated deficiency of VWF–cleaving protease ADAMTS13 (Lämmle B 2016; Scully M et al., 2019; Hollifield AL et al., 2020; Peyvandi F et al., 2021).

卡普拉齐单抗（CABLIVI®，亦称ALX-0081）是一种由单一可变区段（亦称纳米抗体）组成的人源化双价抗体片段，该片段特异性靶向血管性血友病因子（VWF）（Ulrichts H 等，2011；van Loon JE 等，2011）。卡普拉齐单抗与VWF的A1结构域以高亲和力结合（Ulrichts H 等，2011；Lee HT 等，2021）。此相互作用抑制了VWF与血小板糖蛋白Ib（GPIb）受体复合物的结合，从而阻止了VWF介导的血小板与受损血管壁的附着。对作用机制的构效关系分析表明，卡普拉齐单抗通过稳定VWF的非活性构象，该构象不与血小板相互作用，而非与GPIb竞争（Lee HT 等，2021）。卡普拉齐单抗是美国食品药品监督管理局（FDA）批准用于治疗血栓性血小板减少性紫癜（TTP）的药物，这是一种与免疫介导的VWF裂解蛋白酶ADAMTS13缺乏相关的临床疾病（Lämmle B 2016；Scully M 等，2019；Hollifield AL 等，2020；Peyvandi F 等，2021）。