BICYCLE DRUG CONJUGATES®

Bicycle Therapeutics’ initial therapeutic focus is in oncology, where it is developing Bicycle Drug Conjugates (BDCs) for a range of tumour types of high unmet medical need. Conventional cytotoxics rely on indiscriminate mechanisms to kill cells and as such are unable to discriminate tumour from healthy tissue resulting in a narrow therapeutic index and severe toxicities.  In contrast, BDCs link a toxin payload to a specific high-affinity Bicycle® designed to bind a tumour antigen and take advantage of Bicycles®’ inherent properties of high target specificity, rapid penetration into the tumour and low systemic exposure, combined with liver-sparing rapid clearance. Other drug conjugate approaches such as Antibody Drug Conjugates (ADCs) and nanoparticles rely on long half-lives to extend exposure and deliver sufficient toxin over time, with an increased risk of damage to normal tissue.

 
Cartoon comparing the distribution and elimination of Bicycles and ADCs (extrapolated from murine studies)

Cartoon comparing the distribution and elimination of Bicycles and ADCs (extrapolated from murine studies)

 

This property of ADCs limits their mechanism of action to internalizing targets which transport the toxin-conjugate into the cell where cleavage and toxin release occur within the lysosome. To prevent premature cleavage in the systemic circulation, these therapies rely on non-cleavable linkers between the pharmacological delivery vehicle and the toxin, prolonging exposure to the circulating toxin. BDCs also deliver part of their efficacy via tumour-specific antigen mediated cell uptake. However, in addition, due to their short systemic half-life, BDCs can be designed with more labile linker systems permitting tumour-specific release of the toxin but external to the cells to which the Bicycle targeting agent binds. This so called “bystander effect” has huge advantages in that it increases efficacy, allows poorly-internalizing targets to be drugged, and most importantly allows killing of cells within the heterogeneous tumour that do not necessarily maintain expression of the tumour specific antigen to which the Bicycle is targeted.
 

 
Proposed mechanism of action of BDCs

Proposed mechanism of action of BDCs

 

In pre-clinical models this BDC approach has shown considerable promise and has allowed us to deliver 10-fold higher levels of toxins, whilst exposing the body for 30-fold less time and yet maintaining efficacy over toxin alone or ADC. The BDC approach to toxin targeting has the potential to change the treatment paradigm in both solid tumours and haematological cancers. Bicycle Therapeutics has created a pipeline of preclinical BDCs with plans to move the first of these (MT1 programme) into the clinic within the next 9 months.

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.