title: HemaMax™, a recombinant human interleukin-12, is a potent mitigator of acute radiation injury in mice and non-human primates.
abstract: HemaMax, a recombinant human interleukin-12 (IL-12), is under development to address an unmet medical need for effective treatments against acute radiation syndrome due to radiological terrorism or accident when administered at least 24 hours after radiation exposure. This study investigated pharmacokinetics, pharmacodynamics, and efficacy of m-HemaMax (recombinant murine IL-12), and HemaMax to increase survival after total body irradiation (TBI) in mice and rhesus monkeys, respectively, with no supportive care. In mice, m-HemaMax at an optimal 20 ng/mouse dose significantly increased percent survival and survival time when administered 24 hours after TBI between 8-9 Gy (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by increases in plasma interferon-γ (IFN-γ) and erythropoietin levels, recovery of femoral bone hematopoiesis characterized with the presence of IL-12 receptor β2 subunit-expressing myeloid progenitors, megakaryocytes, and osteoblasts. Mitigation of jejunal radiation damage was also examined. At allometrically equivalent doses, HemaMax showed similar pharmacokinetics in rhesus monkeys compared to m-HemaMax in mice, but more robustly increased plasma IFN-γ levels. HemaMax also increased plasma erythropoietin, IL-15, IL-18, and neopterin levels. At non-human primate doses pharmacologically equivalent to murine doses, HemaMax (100 ng/Kg and 250 ng/Kg) administered at 24 hours after TBI (6.7 Gy/LD(50/30)) significantly increased percent survival of HemaMax groups compared to vehicle (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by a significantly higher leukocyte (neutrophils and lymphocytes), thrombocyte, and reticulocyte counts during nadir (days 12-14) and significantly less weight loss at day 12 compared to vehicle. These findings indicate successful interspecies dose conversion and provide proof of concept that HemaMax increases survival in irradiated rhesus monkeys by promoting hematopoiesis and recovery of immune functions and possibly gastrointestinal functions, likely through a network of interactions involving dendritic cells, osteoblasts, and soluble factors such as IL-12, IFN-γ, and cytoprotectant erythropoietin.
authors.affiliation: Neumedicines, Inc, Pasadena, California, United States of America. basile@neumedicines.com
authors.forename: Lena A
authors.initials: LA
authors.lastname: Basile
authors.forename: Dolph
authors.initials: D
authors.lastname: Ellefson
authors.forename: Zoya
authors.initials: Z
authors.lastname: Gluzman-Poltorak
authors.forename: Katiana
authors.initials: K
authors.lastname: Junes-Gill
authors.forename: Vernon
authors.initials: V
authors.lastname: Mar
authors.forename: Sarita
authors.initials: S
authors.lastname: Mendonca
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Miller
authors.forename: Jamie
authors.initials: J
authors.lastname: Tom
authors.forename: Alice
authors.initials: A
authors.lastname: Trinh
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Gallaher
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000737:chemistry* / Q000627:therapeutic use; D007421:Intestine, Small / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008253:Macaca mulatta; D008297:Male; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*; D053707:Receptors, Interleukin-12 / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C508443:Il12rb2 protein, mouse; D018950:Lipopolysaccharide Receptors; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma