Recent Status of Development of Hb-based Blood Substitute With Pharmacologic Properties of ATP, Adenosine and Reduced Glutathione

ABSTRACT

Background: SARS-CoV-2 pandemic brought new attention to blood substitutes as a potential remedy for treatment of COVID-19 associated hypoxemia and more importantly to provide relief for sagging blood banks. In fact the American Red Cross declared a national blood crisis, the worst in decades. Although commercialization attempts of 1st generation blood substitutes have been unsuccessful due to toxicity and/or poor efficacy problems, the artificial oxygen carriers' field is rapidly expanding again creating more innovative products. To attenuate the adverse effects of blood substitutes caused by intrinsic toxicity of Hb we implemented a novel concept of 'pharmacologic cross-linking' and formulated a safe and effective blood substitute - HemoTech. Methods: HemoTech consists of pure bovine Hb cross-linked intramolecularly with o-ATP and intermolecularly with oadenosine and conjugated with reduced glutathione (GSH). HemoTech cGMP manufacturing includes a novel, validated orthogonal technology platform for effective clearance of endotoxin, prions and non-enveloped and enveloped viruses. Regulatory mandated requirements have been met including CMC and GLP non-clinical pharmacology, toxicology, genotoxicity and efficacy studies. HemoTech's clinical 'proof-of-concept' was performed in children with sickle cell anemia. Results: HemoTech is formulated as a 6.5 g/dL modified Hb solution in oxy- or carbon monoxy-form, enriched with electrolytes and mannitol. The 'pharmacologic cross-linking' does not interfere with Hb respiratory function, but eradicates Hb's intrinsic toxicity and provides Hb molecules with new medicinal properties of ATP, adenosine and GSH. The results of preclinical and clinical studies indicate that HemoTech is non-toxic and works as a physiological oxygen carrier with prolonged intravascular persistence, is vasodilatory and can reduce vasoconstriction that follows hemorrhage, has antioxidant and anti-inflammatory activities, and erythropoietic properties. Conclusion: HemoTech promises to be an effective blood substitute for various clinical indications.