TopDDRiveTM
Despite initial efficacy, majority of patients develop resistance to topoisomerase 1 inhibitor (Topo1i) ADCs, and further lines of treatment are limited. The DNA damage repair pathway is a key driver of resistance to Topo1i ADCs, and blocking DNA damage response sensitizes cells to Topo1i. TopDDRiveTM is our dual-payload ADC approach for targeted delivery of Topo1i and DNA damage response inhibitors (DDRi).
Synergism of Topo1i + DDRi payload ADCs
Topo1i resistance can potentially be overcome by a combination approach blocking both Topo1 and DNA damage response. Topo1i kill tumor cells via DNA damage and replicative stress. When DNA damage response is activated, tumor cells kickstart the DNA damage repair process, a key driver of resistance to Topo1i ADCs. Blocking DNA damage response promotes accumulation of DNA damage. In the absence of effective repair, the DNA damage pushes cells to apoptosis.
