Abstract Number: PB0578
Meeting: ISTH 2022 Congress
Background: Factor XI (FXI) is a promising target for novel anticoagulants considering that it is strongly involved in thromboembolic diseases, while fulfilling a mostly supportive role in haemostasis. Anticoagulants targeting FXI could therefore reduce the risk for thrombosis, without increasing the chance of bleeding side effects.
Aims: The generation and characterisation of nanobodies that can interfere with FXIa-mediated activation of FIX.
Methods: After production of a library of FXI-binding nanobodies, nanobodies were selected with a binding epitope located on the apple 3 domain, where the interaction between FXIa and FIX occurs. A system with purified proteins was used to test whether these nanobodies exhibited an inhibitory effect on FIX activation by FXIa. The effect of the nanobodies on coagulation was examined in plasma-based coagulation assays. Additionally, the binding epitope of selected nanobodies was further elucidated by hydrogen deuterium exchange mass spectrometry.
Results: We identified five nanobodies that inhibit FIX activation by FXI. These nanobodies share a binding epitope with FIX on the apple 3 domain, and thereby prevent binding of FIX to FXIa. A sixth nanobody interferes with the FXI-HK interaction by targeting a different region in the apple 3 domain.
Conclusion(s): We have produced six nanobodies against the apple 3 domain of FXI that could serve as candidates for anticoagulation therapy. Five of these inhibit coagulation by interfering with the FXIa-FIX interaction. Interestingly, we have also produced a nanobody targeting the FXI apple 3 domain that hinders the FXI-HK interaction, further elucidating the binding orientation of HK on FXI.
To cite this abstract in AMA style:Bar Barroeta A, Marquart J, Bakhtiari K, Urbanus R, Meijers J. Generation and characterization of novel nanobodies inhibiting factor XI function [abstract]. https://abstracts.isth.org/abstract/generation-and-characterization-of-novel-nanobodies-inhibiting-factor-xi-function/. Accessed September 29, 2023.
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