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Use of cell lines to produce active therapeutic proteinsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Whole Live Micro-organism, Cell, Or Virus Containing, Genetically Modified Micro-organism, Cell, Or Virus (e.g., Transformed, Fused, Hybrid, Etc.), Eukaryotic CellUse of cell lines to produce active therapeutic proteins description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070104696, Use of cell lines to produce active therapeutic proteins. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application claims the benefit of U.S. provisional application Ser. No. 60/510,509, filed on Oct. 10, 2003, which is hereby incorporated in its entirety by reference. FIELD OF THE INVENTION [0003] This invention relates to the use of cell lines, particularly virally-immortalized normal human cell lines, to produce proteins, especially therapeutic proteins, including therapeutic plasma proteins (TPP), that are capable of being expressed in active form by hepatocytes and to the use of proteins, therapeutic proteins, and especially plasma proteins, produced by hepatocytes for the treatment of diseases and conditions affecting the liver and other organs. BACKGROUND OF THE INVENTION [0004] The safe and efficient production of novel therapeutic proteins represents an expanding market of the biopharmaceutical industry that is fueled by the recent completion of the Human Genome Project and by rapid technological advances in the field of proteomics. Paulaus, A., The reengineering of drug development in the genomics and proteomics era. Am Clinical lab, 2001. 5: p. 55-57. [0005] Although many of these therapeutic proteins are mass-produced by recombinant technology in Chinese Hamster Ovary (CHO) cells and other non human cell types, there are occasions where the commercialization of complex heterologous proteins is better accomplished by using the native form of the therapeutically effective protein. This is particularly true when such proteins are the products of multiple genes and the resulting proteins are highly processed post-translationally. It follows that this may be accomplished by isolating the native form of the protein or a recombinant form of the protein that is expressed and processed in the human producer cell. [0006] In addition, the production of therapeutic plasma proteins (TPP) by cell-based systems would avoid the hazards of blood-derived products, the most notable of which is viral contamination. Although, when processed correctly, blood-derived products are virtually free of transmitting viral infections, a perceived risk exists for the manufacturer, user, and patient. Indeed, the recent discovery of new strains of human immunodeficiency virus and the agents responsible for the transmissible spongiform encephalopathies, such as mad cow disease, exemplify the everlasting concern for blood-derived products. Collinge, J., et al., Molecular analysis of prion strain variation and the aetiology of `new variant` CJD. Nature, 1996. 383(6602): p. 685-90. Limitations of Recombinant Proteins as Therapeutic Drugs. [0007] Currently, many proteins that have been approved for clinical and therapeutic use, with the exception of monoclonal antibodies, are mass-produced by recombinant protein technology. Although these products have been proven safe and effective, not all behave identically to their native counterparts. For example, recombinant factors blood clotting factors (rF) VIII and IX are more rapidly cleared following infusion than their plasma derived counterparts. Shapiro, A., E. Berntorp, and M. Morfini, Incremental recovery assessment and effects of weight and age in previously untreated patients treated with recombinant factor IX. Blood, 2000. 96 (suppl 1): p. 265a [0008] Recent findings suggest that this is the result of incomplete or inappropriate post-translational modification. The rapid clearance of the .beta.-domain deleted form of Factor VIII, which is used in the United States, is due to differences in phospholipid binding. In contrast, differences in sulfation at tyrosine 155 and phosphorylation of serine 158 of Factor IX result in more rapid clearance of the clotting factor. White, C. G. I., A. Beebe, and B. Nielsen, Recombinant factor IX. Thromb Haemost, 1997. 78: p. 261-265. [0009] Clinically, more rapid clearance of these clotting factors means potentially more frequent and higher dosages depending upon the patient population. Although one strategy to circumvent these shortcomings is to use plasma-derived proteins, there are also perceived risks, as mentioned above, associated with this approach. Significant Unmet Need for Therapeutic Proteins [0010] Hemophilia A (Factor VIII deficiency) and hemophilia B (Factor IX deficiency) are bleeding disorders that are inherited as X-linked recessive traits. Thus, both affect males almost exclusively. Both hemophilia A and hemophilia B are heterogeneous conditions with variable degrees of clinical expression. Hemophilia A is far more common, occurring in 1 in 5000 to 10,000 males in the United States. Soucie, J. M., B. Evatt, and D. Jackson, Hemophilia Occurrence in the United States. American Journal of Hematology, 1998. 59: p. 288-294. [0011] In contrast, the incidence of hemophilia B is 0.25 in 10,000 males. Currently, plasma-derived and recombinant Factor VIII and IX concentrates are used for the lifetime treatment of hemophilia. It is estimated that three-quarters of the worldwide hemophilia population receive little or no treatment due to a shortage of this TPP. Thus, there is a clear need for fully functional, naturally-processed blood-clotting factors to overcome the shortcomings of traditional recombinant methodologies and/or the limited availability of blood-derived TPPs. [0012] .alpha.-1-antitrypsin (AAT) is a human blood protein whose prime physiological target is neutrophil elastase. Severe AAT deficiency (hereditary emphysema) is thought to affect around 150,000-200,000 individuals in Europe and US. Donohue, T. M., et al., Synthesis and secretion of plasma proteins by the liver, in Hepatology: A Textbook of Liver Disease, D. Zakim and T. D. Boyer, Editors. 1990, W.B. Sounders Company: Philadelphia p. 124-137. Many respiratory diseases including AAT congenital deficiency, cystic fibrosis, and chronic obstructive pulmonary disease are characterized by an imbalance of AAT and elastase in the lung. Elastase is a serine protease that hydrolyzes the extracellular matrix protein molecule elastin, among other proteins. An abundance of elastase is thought to contribute to damage of the pulmonary epithelium. [0013] Administration of supplemental AAT is therefore expected to alleviate the deleterious effects of elastase in the lung in these diseases. [0014] Approximately one in 2000 children is born with the CF genetic defect in the Western Hemisphere. Currently, there is only one plasma-derived AAT licensed in the United States, which has been in very limited supply. Many of the diagnosed patients have therefore not had access to AAT treatment. Despite the large body of evidence of the clinical efficacy of AAT to treat general inflammatory conditions, its use has been restricted due to the limited availability of the product. Thus, there is a clear need for fully functional, naturally-processed AAT to overcome the shortcomings of recombinant or blood-derived TPPs. [0015] Sepsis is a disease characterized by an overwhelming systemic response to infection, which can rapidly lead to organ dysfunction and ultimately death. Sepsis can strike anyone and can be triggered by events such as pneumonia, trauma, surgery and burns, or by conditions such as cancer or AIDS. Once triggered, an uncontrolled cascade of coagulation, impaired fibrinolysis (clot breakdown), and inflammation fuels the progression of sepsis. In the United States, sepsis is the leading cause of death in the noncardiac intensive care unit and the 11.sup.th leading cause of death overall. [0016] Each year, over 700,000 new cases of sepsis are diagnosed and every day 1400 people worldwide die from severe sepsis. Currently, treatment for sepsis is limited to attempts to manage the underlying infection and supportive therapy if the infection leads to organ dysfunction. Despite intensive medical care, up to 50% of patients still die from this illness. Rangel-Frausto, M. S., et al., The natural history of the systemic inflammatory response syndrome (SIRS): a prospective study. JAMA, 1995. 273: p. 117-123. [0017] Given the intensive and prolonged care necessary to treat patients with sepsis, the economic burden is profound. For decades, physicians treating patients with severe septic illness have searched for an effective addition to their available therapeutic arsenal (mainly antibiotics) that could reduce the high mortality rate associated with this disease. Many of the attempted therapeutic interventions in human sepsis have been based upon the premise that circulating endotoxin is responsible for the critical clinical manifestations and morbidity of sepsis. Indeed, some investigators have concluded that any adjunctive therapy is destined to fail because once the clinical signs of severe sepsis are present, irreversible organ injury has already occurred. Recently, a promising new class of therapeutic agents based on natural plasma proteins with anti-coagulative activities has appeared on the clinical horizon. In severe sepsis, the coagulation system is activated; an event evidenced by the presence of intravascular thrombi in vessels and tissue and the occurrence of disseminated intravascular coagulation. Large multicenter phase III studies of activated protein C (APC) and antithrombin III (AT-III) in sepsis were completed in early 2001. In late 2001, Eli Lilly began marketing, Xigris, a genetically engineered version of the human activated protein C molecule; however, this drug only reduces the absolute risk of death by six percent. There is a clear need for more effective treatments of this severe sepsis. [0018] Inter-.alpha.-inhibitor proteins (I.alpha.Ip), natural serine protease inhibitors found in relatively high concentration in plasma have been shown to play roles in inflammation, wound healing and cancer metastasis reviewed by Bost et al. Bost, F., M. Diarra-Mehrpour, and J. P. Martin, Inter-alpha-trypsin inhibitor proteoglycan family--a group of proteins binding and stabilizing the extracellular matrix. Eur J Biochem, 1998. 252: p. 339-346. The major forms of I.alpha.Ip are inter-.alpha.-inhibitor (I.alpha.I, containing one light chain peptide called bikunin and two heavy chains) and pre-.alpha.-inhibitor P.alpha.I, containing one light chain and one heavy chain). In I.alpha.I, the two heavy chains are designated H1 and H2. [0019] These are cleaved from precursors designated H1P and H2P. These precursors are encoded by genes designated ITH1 and ITH2. The bikunin subunit is a double-headed, Kunitz-type, protease inhibitor. It is produced by cleavage from a .alpha.1m/bikunin precursor known as AMBP and encoded by a gene designated AMBP. The properties of the AMBP fusion protein precursor and the cleavage process are discussed further below. In P.alpha.I, the light chain is bikunin, and the heavy chain is H3, cleaved from a precursor designated H3P, encoded by a gene designated ITIH3. Both I.alpha.I and P.alpha.I are designated I.alpha.Ip protein complexes, and that term is used herein to refer generally to either of I.alpha.I and P.alpha.I, or to both I.alpha.I and P.alpha.I. [0020] Recently, a monoclonal antibody that recognizes the light chain of human I.alpha.Ip (MAb 69.31) was developed by scientists at Prothera Biologics (Providence, R.I.). Using MAb 69.31 in a competitive ELISA, these investigators demonstrated that plasma I.alpha.Ip levels were significantly decreased in severe septic patients compared to healthy controls. This decrease correlated with mortality suggesting that I.alpha.Ip might have predictive value in septic patients. Lim, Y. P., et al., Inter-trypsin inhibitor: decreased plasma levels in septic patients and its beneficial effects in an experimental sepsis model. Shock, 2000. 13 (Suppl.): p. 161. In-vivo animal studies using a polymicrobial sepsis rat model of cecal ligation and puncture showed that administration of I.alpha.Ip produced dramatic improvements in survival rates compared to saline controls. Yang S, et al., Administration of human inter-alpha-inhibitors maintains hemodynamic stability and improves survival during sepsis. Crit Care Med. March 2002; 30(3):617-22. Taken together, the results strongly support the therapeutic potential of I.alpha.Ip in the management of severe sepsis. Although I.alpha.Ip can be purified from human serum or plasma, if proven effective there will remain a worldwide shortage of this protein to treat sepsis. There is presently no means to produce or express highly functional, naturally-processed forms of this I.alpha.Ip (e.g. naturally occurring or recombinant produced). Further the complexity of this protein increases the difficulty of both expressing it in an active, processed form and isolating it in an active state. Continue reading about Use of cell lines to produce active therapeutic proteins... Full patent description for Use of cell lines to produce active therapeutic proteins Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Use of cell lines to produce active therapeutic proteins patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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