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 6 months.

Bicycle is also exploring the potential of bicyclic peptides as targeted, titratable and rapidly penetrant immunomodulators, overcoming the challenges seen for other agents with long exposure, irreversible effects and attendant toxicities.