Systemic delivery of liposome-anchored anti-CD137 and IL2-Fc prevents lethal toxicity and elicits potent antitumor immunity

Many immunostimulatory drugs, such as agonistic antibodies to CD137 and interleukin (IL)-2, generate effective antitumor immune responses in preclinical studies, but demonstrate serious toxicity profiles after systemic administration, which hampers their clinical application. We recently discovered that a combination of antiCD137 with an extended half-life IL-2-Fc fusion protein (lacking Fc receptor binding) had pronounced antitumor activity, but also induced toxic levels of systemic inflammatory cytokines. In order to reduce their in vivo toxicity and enhance the therapeutic window, antiCD137 and IL2-Fc were anchored to the surface of PEGylated liposomes (Lipo-aCD137/IL2-Fc), which served as a scaffold to deliver sufficient quantities of immunostimulatory cytokines to primary and metastatic tumors following systemic administration, while minimizing systemic toxicity. In the aggressive, poorly immunogenic B16F10 melanoma model, soluble mixtures of anti-CD137 and IL2-Fc (aCD137/IL2-Fc) dramatically retarded tumor growth, but also elicited lethal toxicity in 100% of animals following 2 injections; reduced doses of this combination therapy exhibited less toxicity but also lost therapeutic efficacy. In striking contrast, mice treated with Lipo-aCD137/IL2-Fc showed