Abelacimab Clinical Naked monospecific

A commercially available phage display library (HuCAL PLATINUM library)20 was used to conduct liquid phase phage panning with full-length biotinylated FXIa and FXI and with the biotinylated catalytic/protease domain (CD) of FXIa. Variable domain fragments of heavy (VH) and light chains of specific binders were used to generate full-length immunoglobulin G1 (IgG1). Six light chain framework mutations were introduced to make the MAA868 amino acid sequence as similar as possible to the human germline Vλ1_1c sequence (“germlining”). The VH framework (VH3-23) did not require any changes. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process, revealing a particularly attractive anticoagulant profile of the antibody. MAA868 exhibited favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a ferric chloride-induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by activated partial thromboplastin time without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects and showed that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose- and time-dependent robust and sustained prolongation of activated partial thromboplastin time and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as a potential once-monthly subcutaneous anticoagulant therapy. (Koch et al, Blood. 2019 Mar 28;133(13):1507-1516. doi: 10.1182/blood-2018-10-880849)