title: Down selection of polymerized bovine hemoglobins for use as oxygen releasing therapeutics in a guinea pig model.
abstract: Hemoglobin (Hb)-based oxygen carriers (HBOCs) are being developed as resuscitative fluids for use in multiple medical applications and in lieu of blood transfusion. However, cardiovascular, central nervous system, and renal adverse events have largely impeded progress. This has prompted a need to evaluate novel down selection approaches for HBOCs prior to in-depth preclinical and clinical safety testing. In the present study, polymerized bovine Hbs (PolybHbs) were prepared with increasing ratios of glutaraldehyde to bovine Hb (10:1, 20:1, 30:1, and 40:1). The optimal PolybHb candidate selection was based on a priori determined in vivo response to include a long circulating PolybHb with no measurable renal exposure, minimal cardiovascular response, limited oxidation to metHb in vitro, or in circulation and absence of acute end organ toxicity. Guinea pigs were dosed via a 50% blood for PolybHb exchange transfusion. Data suggested that the 30:1 preparation exhibited maximum circulatory exposure (AUC(0)(-∞)) with the lowest level of oxidation (plasma metHb formation) and minimal (< 10%) blood pressure elevation. Additionally, the 30:1 preparation was absent renal iron deposition as well as abnormal glomerular/tubular histopathology or serum creatinine elevation. Clearance pathways predominantly followed those consistent with endogenous Hb clearance based pathways. Therefore, data confirmed the ability to select a single PolybHb from a small library of HBOCs based on a priori determined characteristics. Moreover, the approach to down selection described could be applied to enhance the early predictability of human safety for this class of biological therapeutics to optimize for specific indications.
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, Maryland 20892, USA.
authors.forename: Jin Hyen
authors.initials: JH
authors.lastname: Baek
authors.forename: Yipin
authors.initials: Y
authors.lastname: Zhou
authors.forename: David R
authors.initials: DR
authors.lastname: Harris
authors.forename: Dominik J
authors.initials: DJ
authors.lastname: Schaer
authors.forename: Andre F
authors.initials: AF
authors.lastname: Palmer
authors.forename: Paul W
authors.initials: PW
authors.lastname: Buehler
mesh_terms: D000818:Animals; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D001802:Blood Substitutes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001803:Blood Transfusion; D002417:Cattle; D003404:Creatinine / Q000097:blood; D003432:Cross-Linking Reagents / Q000737:chemistry; D005976:Glutaral / Q000737:chemistry; D006168:Guinea Pigs; D006454:Hemoglobins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008706:Methemoglobin / Q000378:metabolism; D023421:Models, Animal; D008970:Molecular Weight; D010084:Oxidation-Reduction; D010100:Oxygen / Q000097:blood*; D058105:Polymerization; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D018570:Risk Assessment; D013154:Spleen / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001802:Blood Substitutes; D003432:Cross-Linking Reagents; D006454:Hemoglobins; D011108:Polymers; C080663:polymerized bovine hemoglobin; D008706:Methemoglobin; D003404:Creatinine; D010100:Oxygen; D005976:Glutaral