MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans

Abstract

A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. 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.

The contact pathway and sepsis

“…While these data suggest that the CAS contributes to the pathology of sepsis in humans, further study is needed before any major conclusions are drawn to determine if targeting this pathway could offer a meaningful benefit to septic patients. As multiple novel contact pathway inhibitors enter clinical testing, additional clinical investigations may begin to address this question …”

“…Finally, while contact pathway inhibition in general holds promise, it remains to be clarified which specific component(s) of this pathway should be targeted to optimize clinical outcomes. Phase 1 clinical trial data have now been published on 4 different monoclonal antibodies targeting FXI, all with unique mechanisms . Our group has worked extensively with 14E11/3G3, a monoclonal antibody inhibiting FXIIa‐mediated activation of FXI.…”

Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia

“…[23][24][25][26][27] Thus, the search for safer anticoagulant drugs with little-to-none bleeding risk continues. Towards this goal, several FXI(a)-targeting agents are in development including small molecules (BMS-986177 and EP-7041), [35][36][37][38][39][40][41] monoclonal antibodies (AB023, MAA868, and Osocimab), [42][43][44][45] aptamers (FELIAP), [48,49] and sulfated glycosaminoglycan mimetics (SPGG and SCI). [54][55][56] Osocimab and BMS-986177, in particular, are currently in advanced clinical trials.…”

The Safety and Efficacy of Novel Agents Targeting Factors XI and XII in Early Phase Human Trials

“…MAA868 is a fully humanized monoclonal immunoglobulin G (IgG)1 antibody that binds the catalytic domain of both FXI and FXIa with high affinity, 11 preventing further activation of the coagulation pathway. Specifically, the Fab segments of MAA868 bind to the FXI enzymatic active site region in multiple locations, inducing a conformational change in the active site structure in both the FXI zymogen and FXIa, essentially locking FXI/FXIa in a zymogen-like state and preventing further procoagulant catalytic action.…”