Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1998-06-22
2001-04-17
Gambel, Phillip (Department: 1644)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S385000, C530S386000, C530S350000, C514S002600, C424S192100, C424S193100
Reexamination Certificate
active
06218513
ABSTRACT:
FIELD OF THE INVENTION
This invention generally relates to modified hemoglobins, and more particularly to globins containing non-naturally occurring binding domains.
BACKGROUND OF THE INVENTION
The oxygen carrying portion of red blood cells is the protein hemoglobin. Hemoglobin is a tetrameric molecule composed of two identical alpha globin subunits (alpha
1
, alpha
2
), two identical beta globin subunits (beta
1
, beta
2
) and four heme molecules, with one heme incorporated per globin. Heme is a large macrocyclic organic molecule containing an iron atom; each heme can combine reversibly with one ligand molecule such as oxygen. In a hemoglobin tetramer, each alpha subunit is associated with a beta subunit to form a stable alpha/beta dimer, two of which in turn associate to form the tetramer. The subunits are noncovalently associated through Van der Waals forces, hydrogen bonds and salt bridges.
Severe blood loss often requires replacement of the volume of lost blood as well as the oxygen carrying capacity of that blood. This replacement is typically accomplished by transfusing red blood cells (RBC's), either as packed RBC's or as units of whole blood. However, it is not always possible, practical or desirable to transfuse a patient with donated blood. Human blood transfusions are associated with many risks such as, for example, transmission of diseases and disease causing agents such as human immunodeficiency virus (HIV), non-A and non-B hepatitis, hepatitis B,
Yersinia enterocolitica
, cytomegalovirus, and human Tell leukemia virus. In addition, blood transfusions can be associated with immunologic reactions such as hemolytic transfusion reactions, imnmunosuppression, and graft versus host reactions. Moreover, blood must be typed and cross-matched prior to administration, and may not be available due to limited supplies.
When human blood is not available or the risk of transfusion is too great, plasma expanders can be administered. However, plasma expanders, such as colloid and crystalloid solutions, replace only blood volume, and not oxygen carrying capacity. In situations where blood is not available for transfusion, a red blood cell substitute that can transport oxygen in addition to providing volume replacement is desirable. Solutions of cell-free hemoglobin can increase and/or maintain plasma volume and decrease blood viscosity in the same manner as conventional plasma expanders, but, in addition, a hemoglobin-based red blood cell substitute can support adequate transport of oxygen from the lungs to peripheral tissues. Moreover, an oxygen-transporting hemoglobin-based solution can be used in most situations where red blood cells are currently utilized. For example, oxygen-transporting hemoglobin-based solutions can be used to temporarily augment oxygen delivery during or after pre-Aonation of autologous blood prior to the return of the autologous blood to the patient.
To address this need, a number of red blood cell substitutes have been developed (Winslow, R. M. (1992)
Hemoglobin-based Red Cell Substitutes
, The Johns Hopkins University Press, Baltimore 242 pp). These substitutes include synthetic perfluorocarbon solutions, (Long, D. M. European Patent 0307087), stroma-free hemoglobin solutions derived from a variety of mammalian red blood cells which may or may not be chemically crosslinked (Rausch, C. and Feola, M., U.S. Pat. Nos. 5,084,558 and 5,296,465; Sehgal, L. R., U.S. Pat. Nos. 4,826,811 and 5,194,590; Vlahakes, G. J. et al., (1990)
J. Thorac. Cardiovas. Surg.
100: 379-388) and hemoglobins expressed in and purified from genetically engineered organisms (for example, non-erythrocyte cells such as bacteria and yeast, Hoffman et al., WO 90/13645; bacteria, Fronticelli, C. et al., U.S. Pat. No. 5,239,061; yeast, De Angelo et al., WO 93/08831 and WO 91/16349; and transgenic mammals, Logan et al., WO 92/22646; Townes, T. M and McCune, S. L., WO 92/11283). These red blood cell substitutes have been designed to replace or augment the volume and the oxygen carrying capability of red blood cells.
However, red blood cell replacement solutions that have been administered to animals and humans have exhibited certain adverse events upon administration. These adverse reactions have included hypertension, renal failure, neurotoxicity, and liver toxicity (Winslow, R. M., (1992)
Hemoglobin-based Red Cell Substitutes
, The Johns Hopkins University Press, Baltimore 242 pp.; Biro, G. P. et al., (1992)
Biomat., Art. Cells & Immob. Biotech.
20: 1013-1020). In the case of perfluorocarbons, hypertension, activation of the reticulo-endothelial system, and complement activation have been observed (Reichelt, H. et al., (1992) in
Blood Substitutes and Oxygen Carriers
, T. M. Chang (ed.), pg. 769-772; Bentley, P. K. supra, pp. 778-781). For hemoglobin based oxygen carriers, renal failure and renal toxicity is the result of the formation of hemoglobin alpha/beta dimers. The formation of dimers can be prevented by chemically crosslinking (Sehgal, et al., U.S. Pat. Nos. 4,826,811 and 5,194,590; Walder, J. A. U.S. Reissue Pat. No. RE34271) or genetically linking (Hoffman, et al., WO 90/13645) the hemoglobin dimers so that the tetramer is prevented from dissociating.
Prevention of dimer formation has not alleviated all of the adverse events associated with hemoglobin administration. Blood pressure changes and gastrointestinal effects upon administration of hemoglobin solutions have been attributed to vasoconstriction resulting from the binding of endothelium derived relaxing factor (EDRF) by hemoglobin (Spahn, D. R. et al., (1994)
Anesth. Analg.
78: 1000-1021; Biro, G. P., (1992)
Biomat., Art. Cells & Immob. Biotech.,
20: 1013-1020; Vandegriff, K. D. (1992)
Biotechnology and Genetic Engineering Reviews
, Volume 10: 4044493 M. P. Tombs, Editor, Intercept Ltd., Andover, England). Endothelium derived relaxing factor has been identified as nitric oxide (NO) (Moncada, S. et al., (1991)
Pharmacol. Rev.
43: 109-142 for review); both inducible and constitutive NO are primarily produced in the endothelium of the vasculature and act as local modulators of vascular tone.
Some inflammatory responses are also mediated by nitric oxide (Vandegriff, (1992)
Biotechnology and Genetic Engineering Reviews
, Volume 10: 404 453 M. P. Tombs, Editor, Intercept Ltd., Andover, England; Moncada, S., et al., supra.). For example, nitric oxide produced by the endothelium inhibits platelet aggregation and as nitric oxide is bound by cell-free hemoglobin -solutions, platelet aggregation may be increased. As platelets aggregate, they release potent vasoconstrictor compounds such as thromboxane A
2
and serotonin (Shuman, M. (1992) in
Cecil Textbook of Medicine
, J.B. Wyngaarden, L. H. Smith and J. C. Bennett, ed., W. B. Saunders Co, Philadelphia, pages 987-992). These may act synergistically with the reduced nitric oxide levels due to binding by hemoglobin to result in an exaggerated vasoconstriction.
In addition to modulating platelet aggregation, nitric oxide inhibits neutrophil attachment to cell walls. Increased adhesion of neutrophils to cell walls may lead to cell wall damage. Endothelial cell wall damage in rabbits has been observed upon infusion of some hemoglobin solutions; this kind of damage is consistent with uptake of endogenous nitric oxide by hemoglobin (White, et al., (1986)
J. Lab. Clin. Med.
108: 121-131; Vandogriff (1992)
Biotechnology and Genetic Engineering Reviews
, Volume 10: 404453 M. P. Tombs, Editor, Intercept Ltd., Andover, England). In all these cases, a hemoglobin molecule with reduced scavenging of nitric oxide and with a physiologically acceptable oxygen affinity might ameliorate some of these possible effects while still functioning as an effective oxygen carrier.
When hemoglobin is contained in red blood cells, it cannot move beyond the boundaries of blood vessels. Therefore, nitric oxide must diffuse to the hemoglobin in an RBC before it is bound. When hemoglobin is not contained within an RBC, such as is the case with hemoglobin based blood substitutes, it may p
Anthony-Cahill Spencer J.
Epp Janet K.
Kerwin Bruce A.
Mathews Antony J.
Olins Peter O.
Baxter Biotech Technology Sarl
DiBrino Marianne
Gambel Phillip
Senniger Powers Leavitt & Roedel
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