human acute radiation syndrome ( ars ) follows intense , acute whole - body or significant partial - body radiation , of doses > 1 gy , delivered at relatively high rates . clinical components of ars include the hematopoietic sub - syndrome ( h - ars , 2  6 gy ) , gastrointestinal sub - syndrome ( gis ; 6  8 gy ) and the cerebrovascular ( > 8 gy ) sub - syndrome . dividing ars into these  sub - syndromes oversimplifies the clinical reality of ars as it often involves complex , concurrent and multi - organ dysfunctions . cerebrovascular sub - syndrome is considered incurable , whereas h - ars alone or in combination with gis , are more likely to be amenable to countermeasures ; therefore , the later two sub - syndromes are specific targets for the development of novel medical countermeasures ( mcm ) . there are several biologics at different developmental stages to be considered as mcm for ars ( figure 1 , tables 1 and 2 ) . a brief description and current status of promising biologics are provided in this article . schematic representation of the biological agents as radiation countermeasures under development . currently , there are three agents with fda ind status : entolimod , hemamax and neupogen . neupogen and leukine have been procured for sns availability and are expected to obtain fda eua in the near future . pegylated g - csf is not currently stocked in the sns but may also obtain fda eua approval once filgrastim is approved . ars : acute radiation syndrome ; eua : emergency use authorization ; fgf : fibroblast growth factor ; ind : investigational new drug ; sns : strategic national stockpile . ars : acute radiation syndrome ; eua : emergency use authorization ; fgf : fibroblast growth factor ; ind : investigational new drug ; sns : strategic national stockpile . biologics with us fda ind / procured for sns / close to fda approval . gi : gastrointestinal ; ind : investigational new drug ; nhp : nonhuman primate ; pahpra : pandemic and all hazards preparedness reauthorization act ; rhuil-12 : recombinant human il-12 ; sns : strategic national stockpile . we are unable to cite all relevant references because of limitation of total number of references for this article . ars : acute radiation syndrome ; fgf : fibroblast growth factor ; fgf - p : fibroblast growth factor - derived peptide ; gi : gastrointestinal ; gis : gastrointestinal sub - syndrome ; nhp : nonhuman primate . biologics are evaluated for marketing by the fda through the filing of a biologic license application ( bla ) , the equivalent to new drug application for other agents . the agents discussed here qualify for consideration by the fda under bla for approval . since conventional human clinical efficacy trials for ars mcm are not possible due to ethical reasons , these trials are substituted with animal efficacy rule , a very stringent and possibly more difficult fda approval pathway . the criteria required to move through this approval process include : well - characterized animal model(s ) that is predictive of human response , a good understanding of the mechanism of action of radiation injury and that of the mcm , study end point focused on prevention of mortality or major morbidity , as well as the good understanding of pharmacodynamics so that the effective human mcm doses can be determined . this pathway relies heavily on a large animal model for preclinical safety and efficacy studies . the majority of agents at advanced stages of development have received fda  fast track and  orphan drug statuses . the fda fast track approval process is designed to facilitate development and expedite the review and approval processes for new treatments of serious or life - threatening conditions . radiation mcm for ars are considered emergency need drugs . the us emergency use authorization ( eua ) program , established by project bioshield , is a critical tool for the medical and public health communities . it permits the fda to approve the emergency , off - label use of products approved for other indications or the use of drugs , devices and medical products that currently have no prior approval , clearance or licensing by fda . it is applicable to both civilian and military use , and it fills the need for timely medical treatment in emergency situations . the strategic national stockpile ( sns ) program ensures that such agents are appropriately pre - positioned so that they are readily available and easily accessible for state and local public health agency distribution in the event of a national emergency . as stated above , there are several biologics under development as radiation mcm for ars ( tables 1 and 2 , figure 1 ) . neupogen and two others , entolimod and hemamax , have considerable efficacy and safety profiles and have received fda investigational new drug status for clinical investigation . mechanistic studies have suggested that the various countermeasures for ars have different modes of action ( figure 2 ) . simplified representation of systemic biological effects due to radiation exposure , with promising biologics intervening at various steps . radiation induces free radical formation , dna damage and apoptosis , which can then lead to ars or death . various biologics are able to minimize the damaging effects of irradiation through different mechanisms of action . ars : acute radiation syndrome ; fgf - p : fibroblast growth factor - derived peptide ; mpc : myeloid progenitor cells . ars : acute radiation syndrome ; fgf - p : fibroblast growth factor - derived peptide ; mpc : myeloid progenitor cells . csf have high potential and well - documented therapeutic efficacy in countering myelosuppression and may receive full licensing approval from the fda in the future . filgrastim , sargramostim and pegylated filgrastim have already been used off - label for treating radiation accident victims . currently , there are four recombinant leukocyte growth factors with bla for related indications : bla 103353 ( neupogen ) , bla 125031 ( neulasta ) , bla 103362 ( leukine ) and bla 125294 ( tbo - filgrastim ) . g - csf / filgrastim has completed a good laboratory practice compliant study in a nonhuman primate ( nhp ) model . the use of growth factors to treat radiation - exposed victims has been rationalized based on three facts : i ) a large clinical database documenting consistent efficacy in mitigating chemotherapy - induced myelosuppression and that associated with stem - cell transplant conditioning regimens as well as consistent safety profile ; ii ) enhanced recovery from radiation - induced myelosuppression in four animal species and improved survival in sublethal and lethally irradiated animal models ; and iii ) demonstration of effective granulopoietic activity in a number of radiation - accident victims . additionally , the american society of clinical oncology extended their recommendation for use of recombinant human g - csf ( rhu g - csf ) and pegylated rhu g - csf to treat patients exposed to therapeutic doses of total - body radiation . radiation - accident reports show that csfs have been used to treat the victims of 16 radiological and nuclear accidents with observed benefits . in three accidents csfs were used within 48 h of accidents ( tokai - mura , soreq and nesvizh ) , but in others csf administration was initiated weeks after the incidence . the limited and anecdotal clinical data available regarding these growth factors validate their biological response ; however , the variable and delayed manner in which these agents were administered makes the csf s role in recovery difficult to determine concisely . during a recently conducted fda meeting , members overwhelmingly voted ( 17:1 ) to support that filgrastim will produce clinical benefits to humans who have been exposed to radiation with doses capable of inducing myelosuppression . the one committee member , who voted  no , concluded that those who survive a radiological or nuclear incident will most likely not have received a radiation dose high enough to produce myelosuppressive effects and therefore would not benefit g - csf administration . its pharmacological action is based on its binding to toll - like receptor 5 and the activation of nf-b signaling . studies conducted with entolimod using rodent and nhp ( good laboratory practice ) models suggest that it will be a highly promising treatment for lethally irradiated humans , due to its ability to efficiently ameliorate h - ars and gis , as well as having an extended therapeutic time window after radiation exposure [ 6 - 8 ] . entolimod is currently in clinical development ; a human safety study indicated that it was well tolerated and the biomarker results correspond to data from animal models . ( buffalo , ny , usa ) is preparing a pre - eua application for entolimod . hemamax is recombinant human il-12 ( rhuil-12 ) cytokine and has been shown to increase mice survival when a single dose was administered , either 24 h before or within 1 h after total - body irradiation . allometrically equivalent doses of mouse and human hemamax had similar pharmacokinetics and significantly increased mouse and nhp survival , when administered 24 h post - irradiation , even when no antibiotics , fluids or blood products were administered . to demonstrate the safety of hemamax , neumedicines conducted a phase ib study where healthy volunteers were administered a single dose of hemamax that is predicted to be the effective dose for treating h - ars , based on nhp data ; this trial suggests rhuil-12 to be safe and well tolerated . phase ii equivalent data ( randomized , double - blinded , good laboratory practice ) showed that single administration of rhuil-12 to nhps significantly increased survival and reduced radiation - induced hematopoietic toxicity when administered 24 h post - irradiation . administration of rhuil-12 promotes multilineage hematopoietic recovery , immune functions and possibly , gi functions . neumedicines is developing rhuil-12 for the treatment of h - ars for bla submission to the fda under the animal efficacy rule . several additional biologics have been identified as potential countermeasures and have shown promise in murine and nhp models of ars . some of these agents have already been used off - label in radiological accident victims . hopefully , in the future , they will be fully developed agents to combat radiation injury . some of these potential agents are myeloid progenitors , anti - ceramide antibody , fibroblast growth factor-2 ( fgf-2 ) , its derived peptide ( fgf - p ) , igf-1   and various cytokines ( table 2 ) [ 16 - 18 ] . csf have high potential and well - documented therapeutic efficacy in countering myelosuppression and may receive full licensing approval from the fda in the future . filgrastim , sargramostim and pegylated filgrastim have already been used off - label for treating radiation accident victims . currently , there are four recombinant leukocyte growth factors with bla for related indications : bla 103353 ( neupogen ) , bla 125031 ( neulasta ) , bla 103362 ( leukine ) and bla 125294 ( tbo - filgrastim ) . g - csf / filgrastim has completed a good laboratory practice compliant study in a nonhuman primate ( nhp ) model . the use of growth factors to treat radiation - exposed victims has been rationalized based on three facts : i ) a large clinical database documenting consistent efficacy in mitigating chemotherapy - induced myelosuppression and that associated with stem - cell transplant conditioning regimens as well as consistent safety profile ; ii ) enhanced recovery from radiation - induced myelosuppression in four animal species and improved survival in sublethal and lethally irradiated animal models ; and iii ) demonstration of effective granulopoietic activity in a number of radiation - accident victims . additionally , the american society of clinical oncology extended their recommendation for use of recombinant human g - csf ( rhu g - csf ) and pegylated rhu g - csf to treat patients exposed to therapeutic doses of total - body radiation . radiation - accident reports show that csfs have been used to treat the victims of 16 radiological and nuclear accidents with observed benefits . in three accidents csfs were used within 48 h of accidents ( tokai - mura , soreq and nesvizh ) , but in others csf administration was initiated weeks after the incidence . the limited and anecdotal clinical data available regarding these growth factors validate their biological response ; however , the variable and delayed manner in which these agents were administered makes the csf s role in recovery difficult to determine concisely . during a recently conducted fda meeting , members overwhelmingly voted ( 17:1 ) to support that filgrastim will produce clinical benefits to humans who have been exposed to radiation with doses capable of inducing myelosuppression . the one committee member , who voted  no , concluded that those who survive a radiological or nuclear incident will most likely not have received a radiation dose high enough to produce myelosuppressive effects and therefore would not benefit g - csf administration . its pharmacological action is based on its binding to toll - like receptor 5 and the activation of nf-b signaling . studies conducted with entolimod using rodent and nhp ( good laboratory practice ) models suggest that it will be a highly promising treatment for lethally irradiated humans , due to its ability to efficiently ameliorate h - ars and gis , as well as having an extended therapeutic time window after radiation exposure [ 6 - 8 ] . entolimod is currently in clinical development ; a human safety study indicated that it was well tolerated and the biomarker results correspond to data from animal models . ( buffalo , ny , usa ) is preparing a pre - eua application for entolimod . hemamax is recombinant human il-12 ( rhuil-12 ) cytokine and has been shown to increase mice survival when a single dose was administered , either 24 h before or within 1 h after total - body irradiation . allometrically equivalent doses of mouse and human hemamax had similar pharmacokinetics and significantly increased mouse and nhp survival , when administered 24 h post - irradiation , even when no antibiotics , fluids or blood products were administered . to demonstrate the safety of hemamax , neumedicines conducted a phase ib study where healthy volunteers were administered a single dose of hemamax that is predicted to be the effective dose for treating h - ars , based on nhp data ; this trial suggests rhuil-12 to be safe and well tolerated . phase ii equivalent data ( randomized , double - blinded , good laboratory practice ) showed that single administration of rhuil-12 to nhps significantly increased survival and reduced radiation - induced hematopoietic toxicity when administered 24 h post - irradiation . administration of rhuil-12 promotes multilineage hematopoietic recovery , immune functions and possibly , gi functions . additionally , there is a report of successful interspecies dose conversion . neumedicines is developing rhuil-12 for the treatment of h - ars for bla submission to the fda under the animal efficacy rule . several additional biologics have been identified as potential countermeasures and have shown promise in murine and nhp models of ars . some of these agents have already been used off - label in radiological accident victims . hopefully , in the future , they will be fully developed agents to combat radiation injury . some of these potential agents are myeloid progenitors , anti - ceramide antibody , fibroblast growth factor-2 ( fgf-2 ) , its derived peptide ( fgf - p ) , igf-1   and various cytokines ( table 2 ) [ 16 - 18 ] . since no fda - approved ars mcm exits , there is an urgent need to develop such agents . based on studies with large numbers of nhps , entolimod appears to be a promising radiation countermeasure for h - ars as well as for gis . entolimod s existing efficacy , safety data and animal - to - human dose conversion are enough to proceed with a pre - eua application to reduce the risk of death following radiation exposure . independent of the fda s approval and licensing process , the us federal government has procured filgrastim and sargramostim to be stockpiled in the sns under the pandemic and all - hazards preparedness reauthorization act . filgrastim and pegylated filgrastim have demonstrated efficacy in recently conducted nhp studies , and these data have been submitted to the study sponsor for submission to the fda for approval . in a recent study , g - csf failed to demonstrate efficacy in the nhp model ; however , this discrepancy may be due to the lack of supportive care . the center for disease control currently holds both investigational new drug and eua applications with the fda for the use of neupogen / g - csf in the event of a nuclear or radiological incident . however , the stability , the implementation plans in the radiological nuclear incident scenario and potential side effects are not fully understood and are of concern . a single injection of hemamax , without supportive care , significantly improved survival and promoted multilineage hematopoietic recovery in an nhp model of h - ars . each drugs sponsor have made clinical progress ; these drugs are moving forward to fill the need for mcm that has increased over the past decade due to increased terrorist threats . in our opinion , the above biologics hold the most promise in the future due to their limited side effects and would be safe and effective agents when approved .