Enhancement of tumor necrosis factor antitumor immunotherapeutic
properties by targeted delivery to aminopeptidase N (CD13)
Flavio Curnis, Angelina Sacchi, Laura Borgna, Fulvio Magni, Anna Gasparri
& Angelo Corti
Department of Biological and Technological Research,
San Raffaele H Scientific Institute, via Olgettina 58,
20132 Milan, Italy.
Correspondence should be addressed to Angelo Corti corti.angelo@hsr.ittumor necrosis factortumor targetingimmunotherapyaminopeptidase N/CD13angiogenesisvascular targeting
The clinical use of tumor necrosis factor (TNF) as an anticancer
drug is limited to local treatments because of its dose-limiting systemic
toxicity. We show here that murine TNF fused with CNGRC peptide (NGR-TNF),
an aminopeptidase N (CD13) ligand that targets activated blood vessels in
tumors, is 12−15 times more efficient than murine TNF in decreasing
the tumor burden in lymphoma and melanoma animal models, whereas its toxicity
is similar. Similarly, human NGR-TNF induced stronger antitumor effects than
human TNF, even with 30 times lower doses. Coadministration of murine NGR-TNF
with a CNGRC peptide or an anti-CD13 antibody markedly decreased its antitumor
effects. Tumor regression, induced by doses of murine NGR-TNF lower than the
LD50, was accompanied by protective immunity. In contrast, no cure
was induced by TNF at any dose. These results suggest that targeted delivery
of TNF to CD13 may enhance its immunotherapeutic properties. Moreover, these
findings reveal the potential of tumor homing peptides to generate a new class
of recombinant cytokines that compared to immunocytokines have a simpler structure,
could be easier to produce and are potentially less immunogenic.
antitumor immunotherapeutic
properties by targeted delivery to aminopeptidase N (CD13)
(TNF) as an anticancer
drug is limited to local treatments because of its dose-limiting systemic
toxicity. We show here that murine TNF fused with CNGRC peptide (NGR-TNF),
an aminopeptidase N (CD13) ligand that targets activated blood vessels in
tumors, is 12−15 times more efficient than murine TNF in decreasing
the tumor burden in lymphoma and melanoma animal models, whereas its toxicity
is similar. Similarly, human NGR-TNF induced stronger antitumor effects than
human TNF, even with 30 times lower doses. Coadministration of murine NGR-TNF
with a CNGRC peptide or an anti-CD13 antibody markedly decreased its antitumor
effects. Tumor regression, induced by doses of murine NGR-TNF lower than the
LD50, was accompanied by protective immunity. In contrast, no cure
was induced by TNF at any dose. These results suggest that targeted delivery
of TNF to CD13 may enhance its immunotherapeutic properties. Moreover, these
findings reveal the potential of tumor homing peptides to generate a new class
of recombinant cytokines that compared to immunocytokines have a simpler structure,
could be easier to produce and are potentially less immunogenic.
