Potential Clinical Implication of the Vascular Targeting Approach

Molecules containing the CNGRC motif are expected to target murine as well as human angiogenic vessels (36,51). Thus, human NGR-TNF might be expected to have better antitumor properties than human TNF in patients, based on what we observed with mouse NGR-TNF in animal models. Findings from murine models suggest that doses required for antitumor effectiveness in humans are at least one order of magnitude higher than the maximum tolerated dose. Thus, it is possible that targeted delivery of TNF to aminopeptidase N could contribute to overcoming this problem. Moreover, NGR-TNF cDNA could be used for gene therapy in place of the TNF gene (64), and biotinylated NGR-TNF could be used, in principle, in tumor pretargeting with biotinylated antibodies and avidin to further increase its therapeutic index. Because tumor debulking with targeted TNF is associated with induction of protective immunity in our models, one appealing possibility is that this approach could be useful to reduce the tumor burden prior to other therapeutic intervention aimed at treating the minimal residual disease (e.g., immunotherapy, antiangiogenic therapy, conventional chemotherapy, and so forth), particularly those relying on a functional immune system.

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