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Structure-guided residence time optimization of a dabigatran reversal agent
Felix Schiele1, Joanne van Ryn, Tobias Litzenburger
1a New Biological Entities Discovery; Boehringer Ingelheim GmbH & Co. KG ; Biberach , Germany.
Mabs
|June 6, 2015
Summary
A novel antibody fragment, aDabi-Fab2, shows potential as a backup reversal agent for dabigatran (Pradaxa®). Protein engineering improved its efficacy and duration of action, enhancing its potential clinical utility.
Area of Science:
- Pharmacology
- Biochemistry
- Protein Engineering
Background:
- Novel oral anticoagulants offer alternatives to vitamin-K antagonists but increase bleeding risk.
- Reversal agents are crucial for managing bleeding during anticoagulation therapy.
- Idarucizumab is a reversal agent for dabigatran, currently in Phase 3 studies.
Purpose of the Study:
- To evaluate aDabi-Fab2, a potential backup reversal agent for dabigatran.
- To improve the efficacy and duration of action of aDabi-Fab2 through protein engineering.
Main Methods:
- In vivo rat model to assess dabigatran reversal by aDabi-Fab2.
- X-ray crystallography to determine the structure of aDabi-Fab2.
- Rational protein engineering to create mutant Y103W.
- Binding affinity and kinetic assays to characterize dabigatran-aDabi-Fab2 interactions.
Main Results:
- aDabi-Fab2 reversed dabigatran effects in vivo but had a shorter duration of action than idarucizumab.
- Mutant Y103W exhibited enhanced binding affinity for dabigatran due to a slower off-rate.
- The engineered mutant demonstrated a prolonged duration of action in vivo.
Conclusions:
- Rational protein engineering can significantly enhance the efficacy of antibody fragments.
- Mutant Y103W shows promise as a backup reversal agent for dabigatran, with improved pharmacokinetic properties.
- Engineered aDabi-Fab2 represents a viable candidate for further development as a dabigatran reversal agent.
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