Anti-Human von Willebrand factor (vWF) (Caplacizumab) (V30-GRP)

von Willebrand factor (vWF) is a plasma glycoprotein involved in clot formation via the adhesion of platelets to subendothelial collagen1,2. A severe deficiency of the vWF-cleaving metalloproteinase ADAMTS13 leads to acquired thrombotic thrombocytopenic purpura (aTTP), a rare autoimmune blood clotting disorder caused by anti-ADAMTS13 autoantibodies2. Reduced ADAMTS13 activity leads to the accumulation of ultra-large vWF multimers in the blood. These bind to platelets, leading to the formation of platelet-rich microthrombi in the microvasculature. These microvascular occlusions ultimately lead to thrombocytopenia, hemolytic anemia, tissue ischemia, and organ dysfunction. ADAMTS13 activity can be normalized via a combination of plasma exchange, immunosuppression, and immunotherapy. ALX-0081 (Caplacizumab) was developed as a treatment for thrombosis in high-risk patients with acute coronary syndrome, including treatment of aTTP2. Caplacizumab was generated as a single-domain antibody fragment and consists of two identical, humanized building blocks linked by a 3-alanine linker2,3. The precursor of Caplacizumab was isolated from a llama immunized with the recombinant A1 domain of vWF, humanized, and used to form a monovalent vWF-binding Nanobody (PMP12A2h1)3. The bivalent form was subsequently produced in Escherichia coli using a secretory system. Caplacizumab inhibits the interaction between vWF and the platelet glycoprotein Ib-IX-V receptor, preventing platelet adhesion at high shear rates like those observed in stenosed arteries2,3. Administration of caplacizumab in patients leads to rapid suppression of ristocetin cofactor, a biomarker for vWF activity, as well as reductions in VWF antigen and factor VIII.