Background
Bicycle therapeutics is a transatlantic company based in the life science cluster of Cambridge, UK, with key oncology functions located in the biotech hub of Boston, US Emerging from Nobel prize winning work in the laboratory of Sir Greg Winter, Bicycles are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry.
Bicycles represent a unique therapeutic class, combining the pharmacological properties normally associated with a biological agent with the manufacturing and pharmacokinetic advantages of a small molecule. The small size and precision tumour targeting of Bicycles delivers rapid tumour penetration and retention, while clearance rates and routes minimize bystander toxicities. Bicycle therapeutics approached the Node to help translate their most advanced programme for a novel compound, BT1718, that targets matrix metalloproteinase MT1 (MMP14) into an early phase clinical trial. The molecule BT1718 is comprised of an MT1-MMP targeting Bicycle, a hindered disulphide cleavable linker and a cytotoxic DM1 payload.
Funding
A tripartite contract was developed between the Node, CRUK and Bicycle that has funded the project (£47,892).
Purpose
To develop a validated clinical grade immunohistochemical assay for MT1-MMP that could be used to inform recruitment into a phase 1/ 2 clinical trial of BT1718 to tumours that are high expressers of MT1-MMP.
Main achievements / outcomes
- A clinical grade immunohistochemistry assay was developed using the Millipore antibody MAB3328 on the Ventana platform employing Optiview chemistry.
- Cell line controls crucial to validation of the assay were developed with a local SME (Histiocyte) who are now Node partners in other projects.
- Node pathologists led by Bacon used the assay on a large cohort of tumours in TMAs and developed a reliable H-scoring system for evaluation.
- The results indicated that squamous lung, squamous oesophagus and all comers with high MT1-MMP expression were suitable for expansion cohorts in the trial.
Future direction
The Node hopes to be selected for the next Bicycle in the pipeline, EphA2 (BT5528), which is still in the preclinical phase of development. The success of the project has positioned the Node well to undertake similar translational studies with other companies.
Bicycles are created by taking linear peptides and circularising these on a scaffold. For the clinical trial with the Node the MTI-MMP specific Bicycle is linked to an anti-tubulin cytotoxic drug.