Novel drug combinations for improving survival from acute radiation syndrome when administered 48 hours post- irradiation

Abstract. Bone marrow is one of the most radiation-sensitive tissues, and patients acutely exposed to total body irradiation (TBI) doses > 2 Gy develop severe neutropenia, thrombocytopenia, anemia, and lymphopenia within days to weeks of exposure, often dying from infections (due to a lack of neutrophils) and uncontrolled bleeding (insufficient platelets) (referred to as the hematopoietic acute radiation syndrome, or H-ARS). The few drugs that have received FDA approval to treat H-ARS increase survival when administered within 24h of radiation exposure, but do not increase survival when administered at later times such as 48h post-irradiation in animal H-ARS models. In a radiological/nuclear emergency, hundreds of thousands of people potentially will be exposed to > 2 Gy radiation and it is extremely unlikely that they all can be treated within the first 24 hours of radiation exposure. Thus, there is a critical unmet medical need for drugs capable of increasing survival from H-ARS when administered 48h or later post-irradiation. We demonstrated that a novel drug (PEG IL-11) and 3 drug combination including PEG IL-11 significantly improve 30d and 180d survival of LD70/30 irradiated mice when administered once 48h post-TBI. This is the only drug/drug combination we are aware of capable of increasing survival when dosing is delayed until 48h post-TBI in mice. When dosed once 24h or 48h post-TBI, the 3 proteins interact positively with each other to increase survival more than the individual proteins, most evident at high TBI doses. The 3 protein combination and PEG IL-11 show sex-specific survival effects, up to 100% survival at LD95/30 TBI doses, when combined with a 4th radiation mitigator, an angiotensin converting enzyme inhibitor (ACEI), an unprecedented survival rate. Most H-ARS studies to date have used inbred young adult mice. Since mouse strains and different age mice show different radiation sensitivities, the Phase 2 grant will evaluate whether these exciting findings extend to pediatric mice and outbred mice to determine whether the survival efficacy and sex-specific effects of the proteins (+/- ACEI) are universal or mouse strain / age specific. We will evaluate whether (1) PEG IL-11 and the 3 protein combination (+/- the ACEI) increase survival of pediatric and outbred mice exposed to LD70/30 radiation doses when the proteins are administered 24 and 48h post-TBI; (2) whether increased 30d survival correlates with accelerated peripheral blood cell recovery (neutrophils, platelets) and more rapid increases in hematopoietic stem and progenitor cell numbers early after irradiation; and (3) whether drug treatment and increased survival correlate with specific plasma biomarker changes. We will evaluate safety of different doses of PEG IL-1 in a mouse GLP toxicology study to identify safe doses of the drug for use in humans, and manufacture a GMP lot of the protein, both of which are required for filing an IND to begin testing the protein in humans. PEG IL-11 and TC are potential life-saving treatment options for a heretofore untreatable H-ARS population – patients who cannot be treated until 48h or later post-TBI.