Biologics as countermeasures for acute radiation syndrome: where are we now?

Figures & data

Figure 1. 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. Additional countermeasure candidates, at various developmental stages, are presented.

Table 1. Biologics with US FDA IND/procured for SNS/close to FDA approval.

Countermeasures	Mode of action	Efficacy in animal model of radiation injury	Clinical remarks	Remarks	Ref.
Entolimod/CBLB502/truncated flagellin	NF-κB activator, stimulates G-CSF and IL-6, immunomodulator, free radical scavenger	Radioprotective and radiomitigative efficacy in murine and NHP models	Safe	IND, Cleveland BioLabs, Inc. preparing pre-EAU application	[6-8]
HemaMax/NMIL12-1/rhuIL-12	T-cell-activating factor, promotes Th1 maturation, possibly NF-κB activator	Effective in mice and NHPs, promotes hematopoietic and GI recovery as a protector and mitigator	Safe, well tolerated	IND, appears promising	[9,10]
Neupogen/filgrastim/G-CSF	Stimulates proliferation, differentiation, maturation and function of neutrophils	Effective in murine, canines, swine (minipigs) and NHP models as a mitigator	Approved for other indications, used off-label for radiation-accident victims	IND, available in SNS, procured under PAHPRA	[4,5,20]
Leukine/sargramostim/GM-CSF	Promotes differentiation, maturation and activation of granulocytes, monocytes and macrophages	Effective in murine, canines and NHP models of radiation injury as a mitigator	Approved for other indications, used off-label for radiation-accident victims	Available in SNS, procured under PAHPRA	[4,5]
Neulasta/PEGylated filgrastim/PEGylated G-CSF	Stimulates proliferation, differentiation, maturation and function of neutrophils	Effective in murine and NHP models, better mitigating efficacy than filgrastim in NHP survival study	Safe, longer half-life than filgrastim, used off-label for radiation-accident victims	Slow-acting, needs fewer injections, NHP efficacy study data submitted to study sponsor for FDA approval	[4,5,19]

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.

Table 2. Promising biologics under development as radiation countermeasures for ARS.

Countermeasures	Mode of action	Efficacy in animal model of radiation injury	Clinical remarks	Remarks	Ref.
Myeloid progenitors	Bridging therapy, stimulates myeloid, erythroid and dendritic cell development	Effective against supralethal doses and efficacious when administered as late as 7 days post-irradiation in mice	CLT-008 (cells of human origin), appears to be safe	CLT-008 under Phase I trial in patients undergoing transplant for hematological malignancies	[11,12]
Anti-ceramide antibody	Reduces apoptosis, increases crypt survival and GI recovery	Efficacious in GIS of murine model	Not used in clinical study	Effective against supralethal doses of radiation causing GIS	[13]
FGF-2/FGF-P	Reduces apoptosis, increases cell proliferation and crypt survival	Effective as radioprotector and radiomitigator in murine model	FGF-2 has been reported as safe	Also holds promise for thermal burns, ischemic wound healing, tissue engineering, and stem-cell regeneration	[14]
IGF-1	Decreases apoptosis and promotes hematopoietic progenitor cell survival	Accelerates hematopoietic recovery in mice	Safe	Mitigates radiation-induced H-ARS through protecting hematopoietic stem and progenitor cells	[15]
Cytokines	Tissue protective, anti-apoptotic, anti-inflammatory	Most of the cytokines have been investigated in murine and NHP models, also used as 4F and SFT3 cytokine cocktails	Overall safe with some side effects	Majority of these cytokines have been used off-label for treating radiological accident victims	[16-18]

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.

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.

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