Single-domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors

ABSTRACT: Novel therapies for hemophilia, including non-factor replacement and in vivo gene therapy are showing promising results in the clinic, including for those patients having a history of inhibitor development. Here, we propose a novel therapeutic approach for hemophilia based on llama-derived single domain antibody fragments (sdAbs) able to restore hemostasis by inhibiting the antithrombin (AT) anticoagulant pathway. We demonstrated that sdAbs engineered in multivalent conformations were able to block efficiently AT activity in vitro, restoring the thrombin generation potential in FVIII deficient plasma. When delivered as a protein to hemophilia A mice, a selected bi-paratopic sdAb significantly reduced the blood loss in a model of acute bleeding injury. We then packaged this sdAb in a hepato

SUBMITTER: Dr. Elena Barbon 

PROVIDER: S-SCDT-EMM-2019-11298 | biostudies-other |

REPOSITORIES: biostudies-other