title: Palmitate-derivatized human IL-2: a potential anticancer immunotherapeutic of low systemic toxicity.
abstract: OBJECTIVE
  Recombinant human IL-2 (rhIL-2) is a potent cytokine and FDA-approved anticancer drug. However, its clinical use has been limited by severe toxicity, associated primarily with systemic administration with excess protein distributing freely throughout the body. We hypothesized that rhIL-2 in alternate forms permitting more restricted localization may exert stronger antitumor efficacy and less toxicity. Here, we have tested the utility of palmitate-derivatized rhIL-2. rhIL-2 was reacted with N-hydroxysuccinimide palmitate ester. The resultant lipidated rhIL-2 (pIL-2), when mixed with cells, could spontaneously transfer from solution to cell surfaces. Next, anticancer efficacy of pIL-2 was assessed in two modalities. For adoptive T cell therapy, antitumor cytotoxic T cells (CTLs) were protein transferred ("painted") with pIL-2 and injected into mice bearing lymphoma. For in situ therapy, pIL-2 was injected intratumorally into mice bearing melanoma. Tumor growth and IL-2-associated toxicity were determined.
  
  
  RESULTS
  In the lymphoma model, painting of the antitumor CTLs with pIL-2 markedly increased their viability and titer. In the melanoma model, intratumoral injection of pIL-2, but not rhIL-2, increased the number of activated CD8(+) T cells (IFN-γ(+)) in the spleen, reduced lung metastasis and prolonged the survival of treated mice. Moreover, while repeated intratumoral injection of rhIL-2 at an excessively high dose (10 injections of 10,000 IU/mouse) caused marked vascular leakage syndrome, the same regimen using pIL-2 caused no detectable toxicity.
  
  
  CONCLUSIONS
  Transferring spontaneously from solution to cell surfaces, pIL-2 may bypass the current limitations of rhIL-2 and, thus, serve as a more effective and tolerable anticancer drug.
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, 1601 Parkview Avenue, Rockford, IL 61107, USA.
authors.forename: Sharon H
authors.initials: SH
authors.lastname: Chou
authors.forename: Aditya V
authors.initials: AV
authors.lastname: Shetty
authors.forename: Yajun
authors.initials: Y
authors.lastname: Geng
authors.forename: Lipeng
authors.initials: L
authors.lastname: Xu
authors.forename: Gnanasekar
authors.initials: G
authors.lastname: Munirathinam
authors.forename: Anne
authors.initials: A
authors.lastname: Pipathsouk
authors.forename: Isaiah
authors.initials: I
authors.lastname: Tan
authors.forename: Timothy
authors.initials: T
authors.lastname: Morris
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Aoshuang
authors.initials: A
authors.lastname: Chen
authors.forename: Guoxing
authors.initials: G
authors.lastname: Zheng
mesh_terms: D000818:Animals; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics; D008223:Lymphoma / Q000628:therapy*; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D019308:Palmitic Acid; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D013388:Succinimides; D013602:T-Lymphocytes, Cytotoxic / Q000637:transplantation
chemical_list: D007376:Interleukin-2; D011994:Recombinant Proteins; D013388:Succinimides; D019308:Palmitic Acid; C001426:N-hydroxysuccinimide