Abstract 3949: Characterization of MP1115; a new natural killer cell activator

Abstract

Abstract MP1115 is in development as a new immuno-oncology therapeutic lead comprised of bioactive phospholipid containing nanoparticles with activities unique to phospholipid active pharmaceutical ingredients. MP1115 demonstrated potent activation of NK cells in vitro and in vivo and had a secondary anti-tumor cell proliferation mechanism of action. Methods: MP1115 was formulated as ~100 nM diameter nanoparticles formulated in buffered sucrose and stably stored frozen. MP1115 nanoparticles were also loaded with a CDK8 inhibitor test compound at a 30 percent loading efficiency. MP1115 was tested for anti-tumor cell proliferation in 2D and 3D in vitro assays, NK cell activation in ex vivo splenocyte and NK cell activation assays, and anti-tumor efficacy and NK cell activation in vivo in immunocompetent and immunodeficient mice. MP1115-CDK8 inhibitor loaded nanoparticles were tested in vitro for increased anti-tumor cell proliferation compared to non-loaded MP1115 nanoparticles and non-loaded CDK8 inhibitor controls. Results: MP1115 demonstrated increased NK cell activation compared to a CDK8 test compound as measured by IFN-γ release in an ex vivo mouse splenocytes-Yac-1 mouse lymphoma assay (p<0.0001). This activity was maintained with splenocytes from immunocompetent BALB/c mice, immunodeficient BALB/c scid mice, and with purified NK cells from each strain background. MP1115 demonstrated increased NK cell activation of mouse splenocytes in vivo in immunocompetent BALB/c mice compared to controls (p<0.0001), as seen by increased CD69 and CD107a signal, as well as the significant killing of target Yac-1 cells ex vivo (p<0.001). The levels of activation and killing observed were similar to that achieved by a CDK8 inhibitor test compound (p>0.9999). MP1115 also successfully demonstrated the ability to deliver a CDK8 test compound payload to human non-Hodgkin’s lymphoma cells in vitro with increased anti-tumor cell proliferation compared to controls (p<0.0001). MP1115 achieved increased anti-tumor cell proliferation efficacy in acute myeloid leukemia, multiple myeloma, non-Hodgkin’s lymphoma, non-small cell lung cancer, KRAS mutant colorectal cancer models in vitro, and in pancreatic cancer tumor models in vivo. MP1115 demonstrated high tolerability in rodent models when dosed at over 200 mg/kg daily for multiple doses. MP1115 is currently being validated in additional in vivo models including human immune system mice with human xenografts. Conclusions: MP1115 is being advanced to IND-enabling studies based on demonstrated low toxicity, high systemic delivery, potent NK cell activation, and anti-tumor cell proliferation activities. Citation Format: Pitchaimani Kandasamy, Jason E. Duex, Greg Miknis, Julie Lang, Ana Chauca-Diaz, Chris Johnson, Colleen Hudson, Jakub Staszak-Jirkovsky, Neal C. Goodwin. Characterization of MP1115; a new natural killer cell activator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3949.