Discovery and Characterization of a Bicyclic Peptide (Bicycle) Binder to Thymic Stromal Lymphopoietin

Thymic
stromal lymphopoietin (TSLP) is an epithelial-derived
pro-inflammatory
cytokine involved in the development of asthma and other atopic diseases.
We used Bicycle Therapeutics’ proprietary phage display platform
to identify bicyclic peptides (Bicycles) with high affinity for TSLP,
a target that is difficult to drug with conventional small molecules
due to the extended protein–protein interactions it forms with
both receptors. The hit series was shown to bind to TSLP in a hotspot,
that is also used by IL-7Rα. Guided by the first X-ray crystal
structure of a small peptide binding to TSLP and the identification
of key metabolites, we were able to improve the proteolytic stability
of this series in lung S9 fractions without sacrificing binding affinity.
This resulted in the potent Bicycle 46 with nanomolar
affinity to TSLP (KD = 13 nM), low plasma
clearance of 6.4 mL/min/kg, and an effective half-life of 46 min after
intravenous dosing to rats.