McArdel et al. showed that red blood cell progenitors transduced in vitro to express immunomodulators, and then cultured through expansion, differentiation, and maturation phases, gave rise to a candidate drug delivery system: Red Cell Therapeutic (RCT). In vitro results showed that one such RTC (RTX-240), expressing both 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP) on the surface, augmented anti-CD3-dependent activation of human CD8+ T cells and provided direct stimulation to both memory CD8+ T cells and NK cells. In two mouse models, 4-1BBL and IL-15(TX) on RBCs inhibited tumors without toxicity or unwanted off-tissue effects.
Contributed by Margot O’Toole
ABSTRACT: Recombinant agonists that activate co-stimulatory and cytokine receptors have shown limited clinical anticancer utility, potentially due to narrow therapeutic windows, the need for coordinated activation of co-stimulatory and cytokine pathways and the failure of agonistic antibodies to recapitulate signaling by endogenous ligands. RTX-240 is a genetically engineered red blood cell expressing 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP). RTX-240 is designed to potently and simultaneously stimulate the 4-1BB and IL-15 pathways, thereby activating and expanding T cells and NK cells, while potentially offering an improved safety profile through restricted biodistribution. We assessed the ability of RTX-240 to expand and activate T cells and NK cells and evaluated the in vivo efficacy, pharmacodynamics and tolerability using murine models. Treatment of PBMCs with RTX-240 induced T cell and NK cell activation and proliferation. In vivo studies using mRBC-240, a mouse surrogate for RTX-240, revealed biodistribution predominantly to the red pulp of the spleen, leading to CD8 + T cell and NK cell expansion. mRBC-240 was efficacious in a B16-F10 melanoma model and led to increased NK cell infiltration into the lungs. mRBC-240 significantly inhibited CT26 tumor growth, in association with an increase in tumor-infiltrating proliferating and cytotoxic CD8 + T cells. mRBC-240 was tolerated and showed no evidence of hepatic injury at the highest feasible dose, compared with a 4-1BB agonistic antibody. RTX-240 promotes T cell and NK cell activity in preclinical models and shows efficacy and an improved safety profile. Based on these data, RTX-240 is now being evaluated in a clinical trial.
Author Info: (1) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (2) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (3) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (4) Rubius Therapeutics¨ In
Author Info: (1) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (2) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (3) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (4) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (5) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (6) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (7) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (8) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (9) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (10) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (11) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (12) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (13) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (14) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (15) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. (16) Rubius Therapeutics¨ Inc., Cambridge, MA, USA. sivan.elloul@rubiustx.com.
