Once ADCs release their cytotoxic payload into targeted cells, the drug is often able to cross cell membranes, entering and potentially killing neighboring cells whether those cells are cancerous or not. This effect is called bystander-killing, which is advantageous when bystander cells are cancerous but toxic if the cytotoxic drug is able to enter adjacent healthy cells.
The DolaLock payload controls the bystander effect by locking the cytotoxic drug inside cells after allowing a short period of diffusion throughout the tumor. As the drug diffuses through neighboring tissue, the DolaLock payload is metabolized to a form that is still highly potent but no longer able to cross the cell membrane. DolaLock effectively locks the drug inside cells, controlling the bystander effect for a safer and more effective cancer therapy.
Our DolaLock payload is a proprietary auristatin cytotoxic drug and is a highly potent anti-tubulin agent selectively toxic to rapidly dividing cells.
A common mechanism of resistance in cancer is the up-regulation of multi-drug resistance (MDR) pumps, such as PgPs, which actively pump drugs out of cancer cells to help them survive. Our DolaLock payload cannot be pumped out by PgPs, thereby avoiding this resistance mechanism. In addition, our proprietary auristatin payload has also been shown in preclinical tests to cause immunogenic cell death and to stimulate the immune system through dendritic cell activation. Because of this, synergy with immuno-oncology agents such as PD-1 inhibitors has been observed in preclinical models. Our DolaLock payload with controlled bystander effect allows us to create ADCs that produce a highly potent, well-tolerated, and specifically-targeted cancer therapy.