Payload Cassette Technology

  • Payload Cassette Technology

    Our Payload Cassettes enable the rapid release of both multiple and mixed payloads and can drive higher concentrations of the payload inside the cell. We have two basic payload cassette designs, which we refer to as ‘palm’ and ‘comb’ formats. Payload cassettes can incorporate multiple copies of highly potent toxins (the same kind of toxins typically used in ADCs) or pairs of chemotherapeutic agents in an optimal ratio that work together synergistically to kill cancer cells. This could potentially allow us to improve the Therapeutic Index of widely used chemotherapeutic combination therapies.

  • Our preference is to incorporate Conditionally Active Payloads (CAPs) into our payload cassettes. These payloads (e.g. MMAF, SN-38, TSIs) have properties that align with the acid-sensitive properties of our SiLinkers. At physiological pH they are charged and cannot freely permeate into normal cells, lowering their toxicity to these normal cells. However, once internalized into a tumor cell as part of a TDC and released in the acidic environment of the endosome or lysosome, they can freely permeate out of these compartments to access the cytoplasm where the neutral pH once again leads to a charged species which is trapped inside the cell. This leads to accumulation of the payload inside the cell. CAPs can also be advantageous in the acidic tumor microenvironment, where the payload released due to cleavage of the SiLinker is uncharged and can enter the cells much more readily further enhancing the bystander effect and anti-tumor activity. Notwithstanding our internal focus on CAPs, we have demonstrated the ability to incorporate multiple non-CAP payloads such as Auristatin F and Vinblastine. To date, in all cases (CAP and non-CAP), the silanol adduct of the payload released after SiLinker cleavage retains or improves the potency of the parent payload.