FF-10850, a Novel Liposomal Topotecan Achieves Superior Anti-tumor Activity via Macrophage- and Ammonia-mediated Payload Release in the Tumor Microenvironment

Topotecan, an approved treatment for refractory or recurrent ovarian Cancer, has clinical limitations such as rapid clearance and hematological toxicity. To overcome these limitations and maximize clinical benefit, we designed FF-10850, a dihydrosphingomyelin-based liposomal topotecan. FF-10850 demonstrated superior anti-tumor activity to topotecan in ovarian Cancer cell line-based xenograft models, as well as in a clinically relevant DF181 platinum-refractory ovarian Cancer patient-derived xenograft model. The safety profile was also improved with mitigation of hematological toxicity. The improved anti-tumor activity and safety profile are achieved via its preferential accumulation and payload release triggered in the tumor microenvironment. Our data indicate that tumor-associated macrophages internalize FF-10850, resulting in complete payload release. The release mechanism also appears to be mediated by high ammonia concentration resulting from glutaminolysis, which is activated by tumor metabolic reprogramming. In ammonia-rich conditions, FF-10850 released payload more rapidly and to a greater extent than liposomal doxorubicin, a currently approved treatment for ovarian Cancer. FF-10850 significantly enhanced anti-tumor activity in combination with carboplatin or PARP Inhibitor without detrimental effects on body weight in murine xenograft models, and demonstrated synergistic anti-tumor activity combined with anti-PD-1 antibody with the development of tumor antigen-specific immunity. These results support phase Ⅰ investigation of FF-10850 for the treatment of solid tumors including ovarian Cancer (NCT04047251), and further evaluation in combination settings.