title: Tumor necrosis therapy antibody interleukin-2 fusion protein elicits prolonged and targeted antitumor effects in vivo.
abstract: Interleukin-2 (IL-2) is one of the most successful cytokines applied in tumor immunotherapy because of its ability to stimulate potent cellular immune response. The life-threatening toxicity of vascular leak syndrome (VLS) associated with the high-dose IL-2 treatment regimen has limited its use in tumor immunotherapy. To reverse this situation, a tumor-targeted fusion protein, recombinant human TNT-IL2 (rhTNT-IL2), was generated with both the cytokine activity of IL-2 and the tumor-targeting ability of TNT antibody. TNT is a human tumor necrosis therapy monoclonal antibody capable of binding intracellular antigens which are accessible and abundant in necrotic regions of tumors. The immunotherapeutic potential of this fusion protein was tested in murine melanoma and lung cancer models, and tumor-bearing mice showed satisfied tumor regressions after rhTNT-IL2 immunotherapy. Immunohistochemical study showed a distinct penetration of IL-2 in tumors in mice treated with rhTNT-IL2, indicating its evident tumor-targeting activity. Moreover, the rhTNT-IL2 was well tolerated in cynomolgus monkeys in a 12-week long-term repeated toxicity study. These studies indicate that the targeting of IL-2 to necrotic areas of tumors might be a new approach for the immunotherapy of solid tumors.
authors.affiliation: Department of Biosynthesis & Key Lab of Smart Drug Delivery MOE, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai, 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ye
authors.forename: Jiajun
authors.initials: J
authors.lastname: Fan
authors.forename: Xunlong
authors.initials: X
authors.lastname: Shi
authors.forename: Qun
authors.initials: Q
authors.lastname: Tao
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.forename: Zongshu
authors.initials: Z
authors.lastname: Xian
authors.forename: Xian
authors.initials: X
authors.lastname: Zeng
authors.forename: Yubin
authors.initials: Y
authors.lastname: Li
authors.forename: Meiqing
authors.initials: M
authors.lastname: Feng
authors.forename: Dianwen
authors.initials: D
authors.lastname: Ju
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000235:genetics; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001688:Biological Products / Q000008:administration & dosage*; D004195:Disease Models, Animal; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy*; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001688:Biological Products; C508594:IL2 protein, human; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha