Biological Activities of IL-15 superagonist - IL-15 Mutein:IL-15RaFc complex following Intravenous or Subcutaneous Administration

Abstract

Abstract ALT-803 is a fusion protein complex consisting of IL-15N72D superagonist and a dimeric IL-15 receptor alpha (IL-15Rα) sushi domain IgG1 Fc fusion protein. When administered to mice, ALT-803 is capable of inducing NK and CD8+ T cell proliferation and activation, as well as potent antitumor responses. ALT-803 is currently in clinical studies using an intravenous (iv) route of administration. We were interested in exploring treatment regimens using subcutaneous (sc) administration of ALT-803 as an alternative to iv administration in order to lessen the adverse side effects that were observed. In this study, we compared the pharmacokinetics, immunostimulation, and anti-tumor efficacy of iv and sc administration of ALT-803 in C57BL/6 mice. We found the half-life of ALT-803 to be 7.5 hrs for iv administration vs. 7.7 hrs for sc. The maximal detected serum concentration of ALT-803 was 495 ng/ml at 16 hr time point following sc administration or 3926 ng/ml at 0.5 hr time point following iv administration. Similar bio-distribution of radio-labeled ALT-803 in mice was observed using quantitative PET-scan studies. We also demonstrated that ALT-803 administered iv or sc induced comparable proliferation of CD8+ T cells and NK cells and similarly activated immune cells which resulted in the reduction of tumor burden. A toxicity study of mice receiving multiple injections of ALT-803 for 4 weeks by iv or sc administration revealed that comparable immune system-related changes were observed and ALT-803 was well tolerated. The gradual absorbance into blood stream and lower maximal blood level of ALT-803 in sc injected mice, along with similar antitumor efficacy supports the use of ALT-803 by sc administration in patients with metastatic malignancies.