Abstract
Bone marrow failure and hematopoietic damage is one of the major consequences of irradiation-induced lethality. There is an immediate need to develop medical countermeasures (MCMs) to combat irradiation-induced lethality. We tested the efficacy of CDX-301, developed by Celldex Therapeutics Inc., in mice exposed to Co-60 gamma total body irradiation (TBI). The drug demonstrated its efficacy both as a prophylactic countermeasure and a mitigator in CD2F1 mice exposed to TBI. A single dose of CDX-301 administered 24 h prior to 24 h post–exposure conferred significant survival. Accelerated recovery from irradiation-induced peripheral blood cytopenia, bone marrow damage as well as apoptosis in sternum was observed in mice pre-treated with CDX-301. Analysis of splenocytes revealed alterations in T cell profiles that were dependent on the time of drug administration. Prophylactic treatment of CDX-301 resulted in increased splenic CD3+ T cells, specifically CD4+T helper cells, compared to splenocytes from non-irradiated mice. These results indicate that CDX-301 is a promising radiation countermeasure and demonstrate its capability to protect cells within hematopoietic organs. These data support potential use of CDX-301, both pre- and post-radiation, against hematopoietic acute radiation syndrome with a broad window for medical management in a radiological or nuclear event.
Highlights
Bone marrow failure and hematopoietic damage is one of the major consequences of irradiationinduced lethality
Preclinical studies have demonstrated that human CD34+ Flt3+ HSC are capable of reconstituting myelopoiesis and, in particular, lymphopoiesis in vivo in NOD/SCID mice[8], indicating the potential of Fms-related tyrosine kinase 3 ligand (Flt3L) to overcome long lasting lymphoid deficiencies associated with radiation exposure
Mice were free of Sendai, pneumonia virus of mice (PVM), reovirus-3 (Reo 3), mouse adenovirus (MAD-1, MAD-2), mouse cytomegalovirus (MCMV), Ectromelia, K virus, lymphocytic choriomeningitis virus (LCM), epidemic diarrhea of infant mice (EDIM), Hantaan virus, rotavirus, mouse parvovirus (MPV), polyoma virus, mouse minute virus (MMV), mouse thymic virus (MTV), Theiler’s mouse encephalomyelitis virus (TMEV/GDVII), Encephalitozoon cuniculi, CAR bacillus, Mycoplasma pulmonis and Clostridium piliforme
Summary
Bone marrow failure and hematopoietic damage is one of the major consequences of irradiationinduced lethality. Prophylactic treatment of CDX301 resulted in increased splenic CD3+ T cells, CD4+T helper cells, compared to splenocytes from non-irradiated mice These results indicate that CDX-301 is a promising radiation countermeasure and demonstrate its capability to protect cells within hematopoietic organs. Preclinical studies have demonstrated that human CD34+ Flt3+ HSC are capable of reconstituting myelopoiesis and, in particular, lymphopoiesis in vivo in NOD/SCID mice[8], indicating the potential of Flt3L to overcome long lasting lymphoid deficiencies associated with radiation exposure. Flt[3] signaling is involved early on in the generation of lymphoid lineage precursors from multipotent hematopoietic progenitors (MPP) in bone marrow[17], indicating the potential of Flt3L to overcome long lasting T cell deficiencies. The recovery of lymphoid cells within tissue from irradiated mice vary depending on the time of drug administration
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