MT1 ProgramME

Bicycle Therapeutics’ lead programme is a Bicycle Drug Conjugate® (BDC) targeting Membrane Type 1 Matrix Metalloproteinase (MT1-MMP), also known as MMP-14. MT1 is highly expressed in many solid tumours, especially at the leading edge of tumours including connective and soft tissues sarcomas, breast, lung, ovarian and colon cancer. MT1 expression has been linked to poor cancer prognoses aligned with MT1’s role in cell invasion and migration and MT1 has a particular role in tumour cell metastasis. Increased MT1 mRNA levels correlate well with the increased efficacy observed with BT1718 in pre-clinical models. The functional role of MT1 in normal adult tissue is believed to be minor, except possibly during wound healing and chronic inflammatory conditions.

 
Schematic representation of BT1718 and MT1-MMP expression in breast carcinoma.

Schematic representation of BT1718 and MT1-MMP expression in breast carcinoma.

 

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. Bicycle’s 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 to the designated tumour antigen target is independent of the toxin-linker combination. Because of its low molecular weight and favourable volume of distribution, BT1718 penetrates tumours rapidly. This contrasts with antibodies, which are mainly restricted to the vasculature, with more limited tumour penetration. Additionally, because of its peptidic nature BT1718 is rapidly cleared through the kidney which minimises toxicity relating to payload mediated gastrointestinal and liver toxicity.

BT1718 couples an MT1-binding Bicycle to the maytansinoid toxin used in the approved ADC therapeutic (Kadcyla™), and has shown superior efficacy to standard of care controls in multiple pre-clinical patient and cell derived mouse xenograft models.

 
Efficacy of BT1718 in high, but not low MT1-MMP-expressing NSCLC patient-derived xenograft model

Efficacy of BT1718 in high, but not low MT1-MMP-expressing NSCLC patient-derived xenograft model

 

BT1718 is tumour eradicating without tumour re-growth, even in large xenograft tumours, and is well tolerated in pre-clinical GLP toxicology studies at the predicted efficacious dose.

 
Efficacy of BT1718 in EBC-1 (NSCLC) derived large mouse Xenograft

Efficacy of BT1718 in EBC-1 (NSCLC) derived large mouse Xenograft

 

The next step for BT1718 is to begin clinical testing in 2017. Cancer Research UK, the largest cancer charitable organization in the UK, will sponsor and fund the Phase 1 study which will be co-managed by Bicycle and Cancer Research, UK. Through this collaboration, Bicycle accesses Cancer Research UK’s strong network of collaborators and existing infrastructure and expertise to deliver the most robust dataset for BT1718. Bicycle retains the right to further advance the BT1718 programme, at which point an undisclosed payment split between cash and equity, success based milestones and royalty payments would be due to Cancer Research UK.