Single-dose anti-PD-L1/IL-15 fusion protein KD033 generates synergistic anti-tumor immunity with robust tumor-immune gene signatures and memory responses

Abstract

Immunocytokines hold great potential as anti-cancer agents as they utilize a specific anti-tumor antibody to deliver an immune activating cytokine directly to the immunosuppressive tumor-microenvironment (TME). We have developed a novel immunocytokine (KD033) comprised of a fully human, high affinity anti-programmed death-ligand 1 (PD-L1) linked to the sushi domain of the human IL-15/IL-15 receptor alpha (IL-15/IL-15Rα) complex. A murine PD-L1 cross-reactive KD033 surrogate (srKD033) and a non-targeting antibody (ntKD033) were also developed to investigate mechanism of action in murine tumor models. Efficacy analyses showed a robust anti-tumor effect of single-dose srKD033 in several diverse syngeneic murine tumor models. In a CT26 murine colon tumor model, single dose srKD033 produced durable anti-tumor immunity as evidenced by resistance to subsequent tumor re-challenges. Mice responding to srKD033 treatment showed increased retention of PD-L1/IL-15 in the TME which likely facilitated prolonged IL-15-induced expansion of cytotoxic cells. Importantly, target-based PD-L1/IL-15 delivery via srKD033 was well-tolerated and induced significant anti-tumor activity in murine carcinoma models that are non- or minimally responsive to IL-15 or anti-PD-L1/PD-1 monotherapy.