Targeting tumor vasculature endothelial cells and tumor cells for immunotherapy of human melanoma in a mouse xenograft model.
An immunotherapy treatment for cancer that targets both the tumor vasculature and tumor cells has shown promising results in a severe combined immunodeficient mouse xenograft model of human melanoma. The treatment involves systemic delivery of an immunoconjugate molecule composed of a tumor-targeting domain conjugated to the Fc effector domain of human IgG1. The effector domain induces a cytolytic immune response against the targeted cells by natural killer cells and complement. Two types of targeting domains were used. One targeting domain is a human single-chain Fv molecule that binds to a chondroitin sulfate proteoglycan expressed on the surface of most human melanoma cells. Another targeting domain is factor VII (fVII), a zymogen that binds with high specificity and affinity to the transmembrane receptor tissue factor (TF) to initiate the blood coagulation cascade. TF is expressed by endothelial cells lining the tumor vasculature but not the normal vasculature, and also by many types of tumor cells including melanoma. Because the binding of a fVII immunoconjugate to TF might cause disseminated intravascular coagulation, the active site of fVII was mutated to inhibit coagulation without affecting the affinity for TF. The immunoconjugates were encoded as secreted molecules in a replication-defective adenovirus vector, which was injected into the tail vein of severe combined immunodeficient mice. The results demonstrate that a mutated fVII immunoconjugate, administered separately or together with a single-chain Fv immunoconjugate that binds to the tumor cells, can inhibit the growth or cause regression of an established human tumor xenograft. This procedure could be effective in treating a broad spectrum of human solid tumors that express TF on vascular endothelial cells and tumor cells.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
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Hu
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Sun
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Garen
D000256:Adenoviridae; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D005167:Factor VII / Q000276:immunology* / Q000502:physiology; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000235:genetics / Q000627:therapeutic use; D007167:Immunotherapy; D008545:Melanoma / Q000098:blood supply* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000627:therapeutic use; D013925:Thromboplastin / Q000276:immunology* / Q000502:physiology; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D005167:Factor VII; D013925:Thromboplastin