Developing the next generation of cancer therapies
Avacta’s proprietary pre|CISIONTM technology incorporates a substrate that is sensitive to cleavage by fibroblast activation protein (FAPα) which is highly upregulated in the tumour microenvironment of most solid tumours compared with healthy tissues. The pre|CISIONTM substrate can be utilised in a drug conjugate linker or to generate chemotherapy pro-drugs that are only activated in the tumour.
When added to a chemotoxin, the pre|CISIONTM substrate prevents the chemotoxin from entering cells and therefore renders it inert until the substrate is cleaved in the tumour microenvironment. Using this pro-drug approach, the systemic exposure to the chemotoxin is dramatically reduced, and the safety and therapeutic window of these powerful anti-cancer treatments is improved.
Avacta’s long term focus is on achieving a more durable response for patients through synergy of the innate immune response to pre|CISIONTM chemotherapies with the adaptive immune response to Affimer immunotherapies in the form of co-administered combinations and in novel tumour-microenvironment activated drug conjugates
Avacta’s proprietary pre|CISIONTM technology has a number of essential advantages.
Fibroblast activation protein alpha (FAPα) is a protease expressed at 10-100-fold above background in many solid tumours, including breast, pancreatic, liver, lung and ovarian tumours. The pre|CISIONTM substrate is specifically cleaved by FAPα and not by any other enzyme, providing a targeting mechanism that ensures localised release of chemotherapeutic agents in the tumour.
When conjugated to a chemotoxin the pre|CISIONTM substrate prevents the chemotoxin from entering cells, rendering it inactive. Thus, the pre|CISIONTM platform can be used to generate pro-drug forms of many chemotherapies, that are inactive in circulation and activated by FAPα in the tumour microenvironment. As a result of this targeting, systemic exposure to the active drug is limited, creating the potential for increased and longer-duration dosing.
Tumour microenvironment activated drug conjugates (TMAC®)
Incorporating pre|CISIONTM technology in the linker of Affimer-drug conjugates ensures localised, extracellular release of a chemotoxin payload in the tumour microenvironment. This mechanism overcomes the need to target an internalising cancer marker as with conventional drug conjugates allowing the Affimer® to be selected to target an immune checkpoint. Thus, the innate immune response to the chemotoxin is supported by the Affimer® immune checkpoint blockade in this novel class of checkpoint targeting tumour microenvironment activated drug conjugates – TMAC®.