Project Grant R44AI142909

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.