Targeted delivery of TNF potentiates the antibody-dependent cell-mediated cytotoxicity of an anti-melanoma immunoglobulin

IgG therapeutics directed against solid tumor antigens can be effective in preventing disseminated cancer spread in mouse models, but are typically ineffective in eradicating established solid tumor masses. Here, we have studied the anti-tumor activity of the recombinant murine IgG2a antibody TA99, directed against a melanoma antigen. As previously reported, IgG2a(TA99) was extremely efficacious in preventing the growth of B16 lung metastases. However, the same antibody only mediated a minimal tumor growth retardation, when used to treat established neoplastic masses. The therapeutic activity of IgG2a(TA99) could be substantially enhanced by co-administration with an antibody-cytokine fusion (TA99-mTNF), consisting of the TA99 antibody in scFv format fused to murine TNF. This fusion protein efficiently killed endothelial cells in vitro, while displaying only minimal activity against B16 melanoma cells. In vivo, TA99-mTNF boosted the influx of NK cells into B16 melanoma lesions. Therapy studies with two different administration schedules revealed that the combination of TA99-mTNF and IgG2a(TA99) was superior to the individual products used as single agents. The combination treatment converted most of the tumor mass into a necrotic lesion, but a vital tumor rim eventually regrew. The treatment modality described in this article may be applicable for the treatment of melanoma patients, given the specificity of the gp75 antigen and its conservation across species. Addition of a third combination partner may be required, in order to eradicate the last tumor cells, which survive treatment.