Potent antitumor activity of a tumor-specific soluble TCR/IL-2 fusion protein.
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.
Belmont
Heather J
HJ
Altor BioScience Corporation, 2810 N Commerce Parkway, Miramar, FL 33025, USA.
Price-Schiavi
Shari
S
Liu
Bai
B
Card
Kimberlyn F
KF
Lee
Hyung-Il
HI
Han
Kai-Ping
KP
Wen
Jinghai
J
Tang
Shamay
S
Zhu
Xiaoyung
X
Merrill
Jane
J
Chavillaz
Pierre-Andre
PA
Wong
Jeffrey L
JL
Rhode
Peter R
PR
Wong
Hing C
HC
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
D000970:Antineoplastic Agents; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53