Chemistry: molecular biology and microbiology – Vector – per se
Reexamination Certificate
1998-10-02
2001-09-04
Nguyen, Dave T. (Department: 1633)
Chemistry: molecular biology and microbiology
Vector, per se
C435S069100, C435S455000, C536S023100, C536S023400, C536S023500, C514S04400A
Reexamination Certificate
active
06284533
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of immunobiology and specifically to a plasmid DNA vaccine for controlling the activity or effect of cholesteryl ester transfer protein, or CETP, in the body.
BACKGROUND OF THE INVENTION
Cholesterol circulates through the body predominantly as components of lipoprotein particles (lipoproteins), which are composed of a protein portion consisting of one or more apolipoproteins (Apo) and various lipids, including phospholipids, triacylglycerols (triglycerides), cholesterol and cholesteryl esters. There are ten major classes of is apolipoproteins: Apo A-I, Apo A-II, Apo-IV, Apo B-48, Apo B-100, Apo C-I, Apo C-II, Apo C-III, Apo D, and Apo E.
Lipoproteins are classified by density and composition. High density lipoproteins (HDL), one function of which is to mediate transport of cholesterol from peripheral tissues to the liver, have a density usually in the range of approximately 1.063-1.21 g/ml. HDL contain various amounts of Apo A-I, Apo A-II, Apo C-I, Apo C-II, Apo C-III, Apo D, Apo E, as well as various amounts of lipids, such as cholesterol, cholesteryl esters, phospholipids, and triglycerides.
In contrast to HDL, low density lipoproteins (LDL), which generally have a density of approximately 1.019-1.063 g/ml, contain Apo B-100 in association with various lipids. In particular, the amounts of the lipids, cholesterol, and cholesteryl esters are considerably higher in LDL than in HDL, when measured as a percentage of dry mass. LDL are particularly important in delivering cholesterol to peripheral tissues.
Very low density lipoproteins (VLDL) have a density of approximately 0.95-1.006 g/ml and also differ in composition from other classes of lipoproteins, both in their protein and lipid content. VLDL generally have a much higher amount of triglycerides than do HDL or LDL and are particularly important in delivering endogenously synthesized triglycerides from liver to adipose and other tissues.
Even less dense than LDL, chylomicrons (density usually less than 0.95 g/ml) contain Apo A-I, Apo A-II, Apo B, Apo C-I, Apo C-II, and Apo C-III and mediate transport of dietary triglycerides and cholesteryl esters from the intestine to adipose tissue and the liver.
The features and functions of the various lipoproteins have been extensively studied. (See, for example, Mathews, C. K. and van Holde, K. E.,
Biochemistry,
pp. 574-576, 626-630 (The Benjamin/Cummings Publishing Co., Redwood City, Calif., 1990); Havel, R. J., et al., “Introduction: Structure and metabolism of plasma lipoproteins”, in
The Metabolic Basis of Inherited Disease,
6
th ed.,
pp. 1129-1138 (Scriver, C. R., et al., eds.) (McGraw-Hill, Inc., New York, 1989); Zannis, V. I., et a., “Genetic mutations affecting human lipoproteins, their receptors, and their enzymes”, in
Advances in Human Genetics. Vol.
21, pp. 145-319 (Plenum Press, New York, 1993)).
Decreased susceptibility to cardiovascular disease, such as atherosclerosis, has been generally correlated with increased absolute levels of circulating HDL and also with increased levels of HDL relative to circulating levels of lower density lipoproteins such as VLDL and LDL (see, for example, Gordon, D. J., et al.,
N. Engl. J Med.,
321: 1311-1316 (1989); Castelli, W. P., et al.,
J. Am. Med. Assoc.,
256: 2835-2838 (1986); Miller, N. E., et al.,
Am. Heart J.,
113: 589-597 (1987); Tall, A. R.,
J. Clin. Invest.,
89: 379-384 (1990); Tall, A. R.,
J. Internal Med.,
237: 5-12 (1995)).
Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins such as VLDL and LDL, and also the reciprocal exchange of triglycerides from VLDL to HDL (Tall, A. R.,
J. Internal Med.,
237: 5-12 (1995); Tall, A. R.,
J. Lipid Res.,
34: 1255-1274 (1993); Hesler, C. B., et al.,
J. Biol. Chem.,
262: 2275-2282 (1987); Quig, D. W. et al.,
Ann. Rev. Nutr.,
10: 169-193 (1990)). CETP may play a role in modulating the levels of cholesteryl esters and triglycerides associated with various classes of lipoproteins. A high CETP cholesteryl ester transfer activity has been correlated with increased levels of LDL-associated cholesterol and VLDL-associated cholesterol, which in turn are correlated with increased risk of cardiovascular disease (see, for example, Tato, F., et al.,
Arterioscler. Thromb. Vascular Biol.,
15: 112-120 (1995)).
Hereinafter, LDL-C will be used to refer to total cholesterol, including cholesteryl esters and/or unesterified cholesterol, associated with low density lipoprotein. VLDL-C will be used to refer to total cholesterol, including cholesteryl esters and/or unesterified cholesterol, associated with very low density lipoprotein. HDL-C will be used to refer to total cholesterol, including cholesteryl esters and/or unesterified cholesterol, associated with high density lipoprotein.
All lipoproteins contain apolipoproteins that serve to maintain the structural integrity of lipoproteins and mediate the transport and metabolism of lipids by acting as ligands for specific receptors or co-factors of certain enzymes. In addition to CETP, other proteins, including hepatic lipase, lipoprotein lipase, lecithin:cholesterol acyltransferase (LCAT), LDL receptor, HDL-receptor (SR-B1) and chylomicron remnant receptor, are important in lipid transport and metabolism. Disruption in the function of these components may lead to dyslipidemia, the abnormal metabolism of plasma lipids, which in turn may contribute to the development of atherosclerosis.
The proteins, apolipoproteins, and lipoproteins described above participate in three pathways of lipid transport and metabolism: (1) the chylomicron pathway, (2) the VLDL-LDL pathway, and, (3) the reverse cholesterol pathway. Chylomicrons and chylomicron remnants transport dietary lipids from intestine to peripheral tissues, such as adipose tissue, and the liver. The VLDL-LDL pathway transports lipids from the intestine to peripheral tissues. In the reverse cholesterol pathway excess cholesterol, which cannot be degraded by most tissue, is esterified and delivered either directly in HDL or indirectly after exchange into other lipoprotein fractions to the liver for excretion from peripheral tissues. Specifically, nascent HDL, which is produced by the liver and intestine, enlarges and is transformed into HDL3 and then to HDL2 as cholesterol is acquired and esterified to cholesteryl ester. Cholesteryl esters (CE) can remain with HDL2 for transport and uptake by the liver or can be transferred to lower density lipoproteins, such as VLDL and LDL, by CETP in exchange for triglycerides. In the liver, HDL2 is depleted of triglycerides by hepatic lipase which converts HDL2 back to HDL3 for re-use. During this process CE may also be transferred to hepatocytes. In addition, some HDL may be directly taken up by hepatocytes (see, for example, Havel, R. J., et al.,
The Metabolic Basis of Inherited Disease,
6th ed., pages 1129-1138 (Scriver, C. R., et al., eds.) (McGraw-Hill, Inc., New York, 1989); Fielding, C. J., et al.,
J. Lipid Res.,
36: 211-228 (1995)).
Thus, the transfer of CE follows one of two pathways. First, lipoproteins may deliver cholesteryl esters to the liver for excretion, thus participating in the reverse cholesterol transport pathway. Second, cholesteryl esters may be recycled back to peripheral tissues.
When all components of these pathways are operating properly, dietary lipids are rapidly absorbed, transported, and stored or utilized. In the fasting state, lipids are efficiently transported to tissue, and cholesterol is recycled or excreted. Naturally occurring dyslipidemias, perhaps as a result of mutations of apolipoproteins, are often due to dysfunction of one or several of the components in the pathways described above (see, for example, Farmer, J. A. et al.,
Heart Disease, A Textbook of Cardiovascular Medicine,
4
th ed
., pp. 1125-1160 (Braunwald, E., ed.) (W.B. Saunders Co., Philadelphia, 1992); Havel, R. J., et al, 1992; Zannis, V. I., et al, 1993). Chronic dietary excess of cholesterol may overwh
AVANT Immunotherapeutics, Inc.
Berka Thomas R.
Nguyen Dave T.
Yankwich Leon R.
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