Tumor targeting of the IL-15 superagonist RLI by an anti-GD2 antibody strongly enhances its antitumor potency

Abstract

Immunocytokines (ICKs) targeting cytokines to the tumor environment using antibodies directed against a tumor-associated antigen often have a higher therapeutic index than the corresponding unconjugated cytokines. Various ICKs displaying significant antitumoral effects in several murine tumor models have already been developed, and some of them, in particular interleukin (IL)-2-based ICKs, are in Phase II clinical trials. Although sharing common biological activities with IL-2 in vitro, IL-15 is now considered as having a better potential in antitumor immunotherapeutical strategies and has been shown to be less toxic than IL-2 in preclinical studies. We previously developed the fusion protein RLI, linking a soluble form of human IL-15Rα-sushi+ domain to human IL-15. RLI showed better biological activities than IL-15 in vitro as well as higher antitumoral effects in vivo in murine and human cancer models. Here, we investigated, in the context of an ICK, the effect of associating RLI with an antibody targeting the GD2 ganglioside, a validated tumoral target expressed on many neurectodermal tumors. Anti-GD2-RLI fully retained the cytokine potential of RLI and the antibody effector functions (antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity). It displayed strong antitumor activities in two syngeneic cancer models in immunocompetent mice (subcutaneous EL4 and metastatic NXS2). Its therapeutic potency was higher than those of RLI and anti-GD2 alone or in combination. We suggest that this is related to its bifunctional (cytokine and antibody) nature. What's new? Many antibody-cytokine fusion proteins known as immunocytokines (ICKs) have been developed to deliver cytokines with antitumoral potencies to the tumor microenvironment using antibodies directed against a tumor-associated antigen. Several ICKs using notably interleukin 2 (IL2) present encouraging results in phase-II clinical trials. IL15, which belongs to the IL2 family, and the superagonist RLI, which the authors previously developed, present many advantages over IL2 as immunological adjuvant, such as chemotherapy potentiation and toxicity reduction. Here they show that a RLI-based ICK targeting the GD2 tumor antigen has a higher therapeutic potency in vivo than RLI and antiGD2 alone or in combination. Copyright © 2013 UICC.