Antibody-
cytokine fusion
proteins ("immunocytokines") represent a promising class of armed antibody products, which allow the selective delivery of potent pro-inflammatory payloads at the
tumor site. The antibody-based selective delivery of
interleukin-2 (
IL2) is particularly attractive for the treatment of metastatic
melanoma, an indication for which this
cytokine received marketing approval from the US Food and drug administration. We used the K1735M2 immunocompetent syngeneic model of murine
melanoma to study the therapeutic activity of F8-IL2, an immunocytokine based on the
F8 antibody in diabody format, fused to human
IL2. F8-IL2 was shown to selectively localize at the
tumor site in vivo, following
intravenous administration, and to mediate
tumor growth retardation, which was potentiated by the combination with
paclitaxel or
dacarbazine. Combination treatment led to a substantially more effective
tumor growth inhibition, compared to the cytotoxic drugs used as single agents, without additional toxicity. Analysis of the immune infiltrate revealed a significant accumulation of CD4(+) T cells 24 h after the administration of the combination. The fusion
proteins F8-IL2 and L19-IL2, specific to the alternatively spliced extra domain A and extra domain B of
fibronectin respectively, were also studied in combination with
tumor necrosis factor (TNF)-based immunocytokines. The combination treatment was superior to the action of the individual immunocytokines and was able to eradicate neoplastic lesions after a single intratumoral injection, a procedure that is being clinically used for the treatment of Stage IIIC
melanoma. Collectively, these data reinforce the rationale for the use of IL2-based immunocytokines in combination with
cytotoxic agents or TNF-based
immunotherapy for the treatment of
melanoma patients.