hemoglobin modified with maleimide - activated polyethylene glycol

We have recently described human hemoglobin surfacemodified with polyethylene glycol (MP4, registered trademark Hemospan) that does not possess the vasoconstrictive properties which have hampered development of some hemoglobin-based oxygen carriers. Based on in vitro studies, we postulated that this lack of vasoconstriction is due to decreased diffusive oxygen transfer in the plasma space as a result of increased molecular size and oxygen affinity. Animal data have supported this hypothesis and have suggested that MP4 may be of clinical benefit in augmenting oxygen delivery to hypoxic or ischemic tissue. Although phase I clinical trials with earlier polyethylene glycol (PEG)-modified hemoglobins have been performed, the results have not been reported in the literature, and their safety and clinical potential remain undocumented. Therefore we have initiated clinical trials with MP4 in humans. MP4 is prepared from stroma-free human hemoglobin (SFH), chemically modified with monofunctional PEG activated with a terminal maleimide group. The physical properties of MP4 are presented in Table 1. The product is formulated in physiological lactated Ringer’s solution, and is stable for long periods at –20°C. The effectiveness of MP4 in maintaining tissue perfusion and oxygenation is postulated to occur by a combination of properties which avoid engaging autoregulatory vasoconstriction. These properties include large molecular excluded volume, relatively high viscosity, high oncotic pressure and oxygen affinity, properties associated with maintained functional capillary density and acid-base balance, which correlate directly with survival after Karolinska Hospital and Institute, Stockholm, Sweden (MB, BF); University of Wisconsin, Madison, Wisconsin (RP); Sangart, Inc., San Diego, California, USA; Sangart, Inc., San Diego, California, USA (NW, MY, RMW); Department of Bioengineering, University of California, San Diego, CA, USA (RMW).