Abstract

Membrane type 1-matrix metalloproteinase (MT1-MMP) is naturally expressed in some tissues during structural remodelling but is heavily overexpressed in tumour tissue (both tumour and stromal cells) of multiple tumour types. In addition, high MT1-MMP expression is indicative of poor prognosis in NSCLC. MT1-MMP therefore presents a focus for targeted delivery of a cytotoxic agent as a therapeutic agent.
A proprietary phage display and cyclic peptide technology (Bicycle® technology) was utilized to identify high affinity binding peptides to MT1-MMP/MMP14. Initial binders were affinity matured by directed screens and stabilisation by chemical optimisation, resulting in the Bicycle binder N241. Conjugation of this Bicycle with the maytansinoid DM1, through a cleavable linker, resulted in the Bicycle Toxin Conjugate BT1718.
BT1718 showed efficacy in several MT1-MMP expressing xenograft models (CDX and PDX) with doses as low as 3 mg/kg twice weekly affording a rapid and complete regression. Similar efficacy is seen in small (200 mm3) or large tumours (upto 1000mm3).
Bicycle Therapeutics, in collaboration with CRUK, has progressed BT1718 into a Phase 1 clinical trail in adult patients with advanced solid tumours, including Triple Negative Breast Cancer, Non-Small Cell Lung Cancer or Sarcoma.