Intratumoral injection of adenoviral vectors encoding tumor-targeted immunoconjugates for cancer immunotherapy.
The efficacy and safety of a new immunotherapy protocol for cancer were tested in a severe combined immunodeficient mouse model of human skin and metastatic lung melanoma. The protocol involves intratumoral injections of replication-incompetent adenoviral vectors encoding immunoconjugates composed of the Fc region of an IgG1 immunoglobulin conjugated to a tumor-targeting domain. One targeting domain is factor VII that binds to tissue factor expressed on endothelial cells lining the tumor neovasculature and on tumor cells; the active site of factor VII was mutated to inhibit the initiation of blood coagulation. Another targeting domain is a single-chain Fv antibody that binds to a cognate antigen expressed on human melanoma cells. The adenoviral vectors infect mainly the cells of the injected tumor, which synthesize and secrete the immunoconjugates. The bloodborne immunoconjugates induce a cytolytic immune response against the targeted neovasculature endothelial cells and tumor cells. The mouse model experiments showed that intratumoral delivery of the factor VII immunoconjugate, either alone or together with the single-chain Fv immunoconjugate, resulted in growth inhibition and regression of the injected tumor, and also of distant metastatic tumors, without evidence of damage to normal organs. There was extensive destruction of the tumor neovasculature, presumably mediated by the factor VII immunoconjugate bound to tissue factor on neovasculature endothelial cells. Because tissue factor is generally expressed on neovascular endothelial cells and tumor cells, a factor VII immunoconjugate could be used for immunotherapy against a broad range of human solid tumors.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
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D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000628:therapy*; D014407:Tumor Cells, Cultured
D018796:Immunoconjugates