title: Potent antitumor activity of a tumor-specific soluble TCR/IL-2 fusion protein.
abstract: We previously have generated a single-chain T cell receptor-cytokine fusion protein (264scTCR/IL-2) comprising interleukin-2 genetically linked to a soluble HLA-A2.1-restricted TCR recognizing a peptide of human p53 protein. In this report, we show that 264scTCR/IL-2 inhibits the growth of primary tumors derived from the A375 (p53+/HLA-A2.1+) human melanoma and exhibits significantly better antitumor activity than recombinant human IL-2 alone. Moreover, treatment with 264scTCR/IL-2 results in tumor growth retardation in mice bearing large A375 tumors and other p53+/HLA-A2.1+ human tumors but does not affect tumor outgrowth of HLA-A2.1-negative tumors. This suggests that antigen targeting plays a substantial role in the efficacy of 264scTCR/IL-2 against p53+/HLA-A2+ tumors. Further, the antitumor activity of 264scTCR/IL-2 was found to be likely mediated by NK cell activation and tumor infiltration. A biologically active chimeric version of the molecule (c264scTCR/IL-2) also exhibits favorable pharmacokinetic properties required of a clinical candidate for this novel class of potent antitumor activities and targeted anticancer immunotherapeutics.
authors.affiliation: Altor BioScience Corporation, 2810 N Commerce Parkway, Miramar, FL 33025, USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Belmont
authors.forename: Shari
authors.initials: S
authors.lastname: Price-Schiavi
authors.forename: Bai
authors.initials: B
authors.lastname: Liu
authors.forename: Kimberlyn F
authors.initials: KF
authors.lastname: Card
authors.forename: Hyung-Il
authors.initials: HI
authors.lastname: Lee
authors.forename: Kai-Ping
authors.initials: KP
authors.lastname: Han
authors.forename: Jinghai
authors.initials: J
authors.lastname: Wen
authors.forename: Shamay
authors.initials: S
authors.lastname: Tang
authors.forename: Xiaoyung
authors.initials: X
authors.lastname: Zhu
authors.forename: Jane
authors.initials: J
authors.lastname: Merrill
authors.forename: Pierre-Andre
authors.initials: PA
authors.lastname: Chavillaz
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wong
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rhode
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D012995:Solubility; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53