Evaluation of the biological activities of the IL-15 superagonist complex, ALT-803, following intravenous versus subcutaneous administration in murine models

Bai Liu, Monica Jones, Lin Kong, Terra Noel, Emily K. Jeng, Sixiang Shi, Christopher G. England, Sarah Alter, Jeffrey S. Miller, Weibo Cai, Peter R. Rhode, Hing C. Wong

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

ALT-803 is a fusion protein complex consisting of an interleukin (IL)-15 superagonist and a dimeric IL-15 receptor alpha sushi domain IgG1 Fc fusion protein. When administered to mice, ALT-803 is capable of inducing natural killer (NK) and CD8 + T cell proliferation and activation, and effectively promoting potent anti-tumor responses. Currently, ALT-803 is in clinical trials for treatment of various solid tumors and hematological malignancies. In the initial phase of these clinical studies, intravenous (iv) injection was used according to the route used in pre-clinical efficacy studies. In order to evaluate the possible advantage of subcutaneous (sc) injection versus iv injection, this study compared the biological activity of the two treatment regimens of ALT-803 in pre-clinical in vivo models. The pharmacokinetics, immune stimulation, and anti-tumor efficacy of iv and sc injection routes of ALT-803 in C57BL/6 mice were compared. The half-life of ALT-803 was 7.5 h for iv versus 7.7 h for sc with the maximal detected serum concentration of ALT-803 to be 3926 ng/ml at 0.5 h time-point following iv injection versus 495 ng/ml at 16 h post sc injection. Biodistribution studies indicated that sc ALT-803, similarly to iv ALT-803 as previously reported, has a greater tissue distribution and longer residence time in lymphoid tissues compared to recombinant IL-15. Notably, ALT-803 when administered either iv or sc induced comparable proliferation and activation of CD8 + T and NK cells and resulted in similar reductions of tumor burden. A toxicity study of mice receiving multiple injections of ALT-803 for 4 weeks by iv or sc routes revealed equivalent immune-related changes. The gradual absorbance into the blood stream and lower maximal blood levels of ALT-803 in sc-injected mice, along with similar anti-tumor efficacy support the administration of ALT-803 by sc injection in patients with various malignancies and infectious diseases.

Original languageEnglish (US)
Pages (from-to)105-112
Number of pages8
JournalCytokine
Volume107
DOIs
StatePublished - Jul 2018

Bibliographical note

Funding Information:
This work was supported, in part, by the University of Wisconsin - Madison, the National Institutes of Health [NIBIB/NCI 1R01CA169365 and P30CA014520]; and the American Cancer Society [125246-RSG-13-099-01-CCE].

Keywords

  • ALT-803
  • CD8 T cells
  • Immunotherapy
  • Interleukin-15
  • Interleukin-15Rα
  • NK cells

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