Cancer immunology, immunotherapy : CII · 2003
Effect of albumin fusion on the biodistribution of interleukin-2.
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Yao Zhengsheng, Dai Weili, Perry James, Brechbiel Martin W, Sung Cynthia
Аннотация
PURPOSE: We investigated and compared the biodistribution of Albuleukin, a human serum albumin (HSA)-interleukin-2 (IL-2) fusion protein, with those of IL-2 and HSA. The objective was to determine whether Albuleukin distributes differently to normal organs and lymphoid tissues than IL-2 by virtue of its genetic fusion with HSA.
METHODS: The chelating agent 2-( p-isothiocyanato-benzyl)-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-A(II) was selected for radiolabeling with (111)In, and conjugation with CHX-A(II) did not alter bioactivities of IL-2 and Albuleukin on proliferation of CTLL-2 cells. The radiolabeled proteins were injected intravenously into mice, uptake in organs was measured, and whole-body autoradiography was performed.
RESULTS: Striking differences in the biodistribution of IL-2 and Albuleukin were noted. (111)In-IL-2 cleared from blood rapidly, with less than 1% ID/g (percentage of injected dose per gram of tissue) at 20 min after injection. At this time, the kidneys showed more than 120% ID/g uptake, and these high levels persisted through 6 h. (111)In-Albuleukin, by contrast, showed significantly longer circulation (14% ID/g at 6 h), lower kidney uptake (<6% ID/g), and higher localization in liver, spleen, and lymph nodes (maximal uptake approximately 22% ID/g for all three organs). Uptake in liver, spleen, and lymph nodes appears to be mediated in part by the IL-2 component of Albuleukin because (111)In-HSA showed significantly lower accumulation in those tissues despite more prolonged circulation in blood.
CONCLUSION: These data support the hypothesis that Albuleukin targets tissues where lymphocytes reside to a much greater extent than does IL-2, and suggest that Albuleukin may exhibit improved efficacy and reduced toxicity in the treatment of solid tumors. Clinical trials underway will determine whether the improved targeting in the mice translates into a better therapeutic index in humans.
METHODS: The chelating agent 2-( p-isothiocyanato-benzyl)-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-A(II) was selected for radiolabeling with (111)In, and conjugation with CHX-A(II) did not alter bioactivities of IL-2 and Albuleukin on proliferation of CTLL-2 cells. The radiolabeled proteins were injected intravenously into mice, uptake in organs was measured, and whole-body autoradiography was performed.
RESULTS: Striking differences in the biodistribution of IL-2 and Albuleukin were noted. (111)In-IL-2 cleared from blood rapidly, with less than 1% ID/g (percentage of injected dose per gram of tissue) at 20 min after injection. At this time, the kidneys showed more than 120% ID/g uptake, and these high levels persisted through 6 h. (111)In-Albuleukin, by contrast, showed significantly longer circulation (14% ID/g at 6 h), lower kidney uptake (<6% ID/g), and higher localization in liver, spleen, and lymph nodes (maximal uptake approximately 22% ID/g for all three organs). Uptake in liver, spleen, and lymph nodes appears to be mediated in part by the IL-2 component of Albuleukin because (111)In-HSA showed significantly lower accumulation in those tissues despite more prolonged circulation in blood.
CONCLUSION: These data support the hypothesis that Albuleukin targets tissues where lymphocytes reside to a much greater extent than does IL-2, and suggest that Albuleukin may exhibit improved efficacy and reduced toxicity in the treatment of solid tumors. Clinical trials underway will determine whether the improved targeting in the mice translates into a better therapeutic index in humans.