Bicycle Therapeutics’ lead program is a Bicycle Drug Conjugate® (BDC) targeting Membrane Type 1 Matrix Metalloproteinase (MT1-MMP). MT1 is highly expressed in many solid tumours including connective and soft tissues carcinoma, breast, lung, ovarian and colon cancer. Evaluating MT1 expression in non-small cell lung cancer biopsies compared to normal tissue shows differential expression comparable to HER2 for normal breast versus cancerous breast tissue. MT1 expression is also linked to poor outcomes aligned with MT1’s role in cell invasion and migration. The functional role of MT1 in normal adult tissue is believed to be minor, except possibly during wound healing and chronic inflammatory conditions.
Bicycle Therapeutics is using MT1 as a targeting antigen for the delivery of a cytotoxic payload using a BDC. The Bicycle® component of this molecule does not inhibit the catalytic activity of MT1 but rather binds to its hemopexin domain, using the high constitutive rate of internalization of MT1 as a mechanism to internalize cell-killing toxins. Our lead candidate exhibits high-affinity cross-species binding to MT1 and has excellent selectivity versus other matrix metalloproteinases.
The Bicycle® component has been evaluated in combination with a matrix of different linkers and toxins and its affinity is independent of the toxin linker combination. As expected from its small molecule nature, the final BDC shows high extravasation and rapid uptake into the tumour with short systemic exposure. This contrasts with an antibody, which classically distributes mainly to the vasculature and the liver, with delayed tumour uptake.
Bicycle Therapeutics’ lead BDC program has shown efficacy in multiple mouse xenograft models at a variety of dose intervals, including well-tolerated doses that ablate large tumours in less than 10 days with no sign of tumour re-growth. The toxin load achievable using a BDC is significantly higher than that historically shown for an antibody drug conjugate which is probably due to renal clearance, sparing known gastrointestinal and liver toxicity. The next step for the program is to begin clinical testing in 2017.