Scientists at the U.S. Food and Drug Administration (FDA) have compiled the first comprehensive molecular and chemical comparison of all hemoglobin (Hb)-based oxygen carriers (HBOCs) that have been tested in humans.

The FDA scientists performed identical biochemical studies of these HBOCs, all of which had failed in clinical studies due to their toxicity, in order to create individual profiles of their biochemical actions; for example, their ability to bind and release oxygen under various conditions and their individual interactions with cells.

The results of the study are important because they could help to explain the individual safety and efficacy characteristics of each type of HBOC. In turn, this would enable scientists to pick and choose among various biochemical characteristics to support the design of safe and effective products.

HBOCs are a type of artificial blood substitute made from molecules of hemoglobin (Hb)—the oxygen-carrying protein in red blood cells—that are either removed from cells and chemically modified during processing into a product, or developed through genetic engineering. They have been studied as treatments for patients who have suffered serious loss of blood due to injuries. However, since the Hb molecules comprising these products are not inside cells, but rather circulate in the body as free molecules, they can accumulate to toxic levels.

The key to the HBOC toxicity is that, unlike Hb inside red blood cells, these free molecules undergo a disruptive chemical reaction that cannot be reversed. This reaction, called oxidation, occurs after the HBOCs release their oxygen molecules and leaves the protein unable to bind to additional oxygen molecules. In addition, the reaction makes the HBOC highly chemically reactive, causing potentially life-threatening high blood pressure, heart attack, and stroke. These complications have prevented full development of HBOC products despite attempts to modify various Hb products to eliminate their toxic effects.

In addition, HBOC products are usually complex combinations of Hb molecules that have a variety of possible chemical modifications, making it difficult to predict how well they will perform as oxygen carriers and what type of toxicity they might have. To date, FDA has not approved any HBOCs for use in humans.

The FDA side-by-side comparison of the various types of HBOCs provides scientists a better understanding of how the structures and chemical activities of these proteins are related to both their ability to carry oxygen in the body and their potential toxicity in humans.

TITLE

Comprehensive Biochemical and Biophysical Characterization of Hemoglobin-Based Oxygen Carrier Therapeutics: All HBOCs Are Not Created Equally.

Bioconjug Chem. 2018 Apr 2. doi: 10.1021/acs.bioconjchem.8b00093.

AUTHORS

Meng F¹, Kassa T¹, Jana S¹, Wood F¹, Zhang X¹, Jia Y¹, D'Agnillo F¹, Alayash AI¹.

Laboratory of Biochemistry and Vascular Biology, Division of Blood Components and Devices, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993, United States

*E-mail: [email protected].