(2008). HBOC-201, hemoglobin glutamer-250 (bovine), Hemopure® (Biopure Corporation) Expert Opinion on Biological Therapy: Vol. 8, No. 9, pp. 1425-1433. doi: 10.1517/14712598.8.9.1425

To discuss the development and current status of blood substitutes, including hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbons. Research in this field offers an important view into the future of transfusion medicine in the operating room, as well as in trauma and combat arenas. A pivotal multinational phase III trial of the Biopure product HBOC-201 (Hemopure) has been completed in orthopedic surgery patients. HBOC-201 consists of polymerized bovine hemoglobin and has already been well tolerated in patients undergoing cardiopulmonary bypass and abdominal aortic reconstruction. Polyheme is a polymerized human hemoglobin in early phase III clinical trials with trauma patients, having infused up to 10,000 ml, with efficacy apparently demonstrated in phase II. The Sangart product, Hemospan, is currently undergoing phase II trials. Polymerized hemoglobin preparations have proven most successful in clinical trials due to their improved side-effect profile. The goal is to evaluate blood substitutes with enhanced intravascular retention, reduced osmotic activity, and attenuated hemodynamic derangements such as vasoconstriction. Although not without substantial morbidity and mortality, the current safety of allogeneic blood transfusion demands that comparative studies show minimal adverse effects, as well as efficacy and potential for novel applications.

Blood substitutes, especially hemoglobin based oxygen carriers (HBOC) have been widely studied and reviewed over the past 30 years. The development of HBOCs was highlighted by crosslinking to minimize adverse effects. However, even early attempts at single crosslinking using alpha-alpha crosslinks or diaspirin crosslinking failed clinical trials due to renal morbidity and increased mortality. In fact, preclinical trials may have predicted failure of this first generation product, DCLHb (diaspirin-crosslinked Hb) (HemAssist ®, Baxter). In the 1980's, three small biopharmaceutical companies developed "second generation" HBOCs, the first being Hemosol with their raffinose crosslinked HBOC, hemoglobin- raffimer. The other two development programs modified the HBOC using glutaraldehyde polymerization, in an attempt to further alleviate the toxicities of the "first" generation HBOCs. This paper will review the definitive clinical trials of the two polymerized HBOCs, Biopure's hemoglobin glutamer-250 (bovine) and Northfield's polymerized human Hb, pegylated HBOC and Sangart's peg-conjugated HBOC, with an introductory brief review of Hemosol's hemoglobinraffimer. The paper will then introduce the newest polymerized hemoglobin, zero-linked hemoglobin polymer, which has not yet undergone clinical trials but has undergone some preclinical work that will be discussed in a section on this product. As a new generation HBOC, zero-linked hemoglobin polymer may begin to address the issues presented by the first two generations of HBOCs, and may hold promise as a universally applicable HBOC.

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