Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
1995-05-01
2002-06-25
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S190100, C424S192100, C424S193100, C424S197110, C424S236100, C530S300000, C530S324000, C530S403000
Reexamination Certificate
active
06410022
ABSTRACT:
GENERAL FIELD OF THE INVENTION
This invention is generally in the field of peptide-based vaccines to control atherogenic activity in the circulatory system of humans and other animals. In particular, this invention provides compositions and methods for providing endogenous means to inhibit the activity of endogenous cholesteryl ester transfer protein (CETP) and to effectively modulate the relative levels of lipoproteins to produce a condition correlated with a reduced risk of cardiovascular disease, such as atherosclerosis.
BACKGROUND OF THE INVENTION
Cholesterol circulates through the body predominantly as components of lipoprotein particles (lipoproteins), which are composed of a protein portion, called apolipoproteins (Apo) and various lipids, including phospholipids, triglycerides, cholesterol and cholesteryl esters. There are ten major classes of 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. For example, 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 (TG) than do HDL or LDL and are particularly important in delivering endogenously synthesized triglycerides from liver to adipose and other tissues. The features and functions of various lipoproteins have been reviewed (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., et al., “Introduction: Structure and metabolism of plasma lipoproteins”, In
The Metabolic Basis of Inherited Disease
, 6th ed., pp. 1129-1138 (Scriver, C. R., et al., eds.) (McGraw-Hill, Inc., New York, 1989); Zannis, V. I., et al., “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, is generally correlated with increased absolute levels of circulating HDL and also increased levels of HDL relative to circulating levels of lower density lipoproteins such as VLDL and LDL (see, e.g., 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 transport protein (CETP) mediates the transfer of cholesteryl esters from HDL to TG-rich lipoproteins such as VLDL and LDL, and also the reciprocal exchange of TG 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 TG 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, e.g., 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.
CETP isolated from human plasma is a hydrophobic glycoprotein having 476 amino acids and a molecular weight of approximately 66,000 to 74,000 daltons on sodium dodecyl sulfate (SDS)-polyacrylamide gels (Albers, J. J., et al.,
Arteriosclerosis
, 4: 49-58 (1984); Hesler, C. B., et al.,
J. Biol. Chem
., 262: 2275-2282 (1987); Jarnagin, S. S., et al.,
Proc. Natl. Acad. Sci. USA
, 84: 1854-1857 (1987)). A cDNA encoding human CETP has been cloned and sequenced (Drayna, D., et al.,
Nature
, 327: 632-634 (1987)). CETP has been shown to bind CE, TG, phospholipids (Barter, P. J. et al.,
J. Lipid Res
., 21:238-249 (1980)), and lipoproteins (see, e.g., Swenson, T. L., et al.,
J. Biol. Chem
., 264: 14318-14326 (1989)). More recently, the region of CETP defined by the carboxyl terminal 26 amino acids, and in particular amino acids 470 to 475, has been shown to be especially important for neutral lipid binding involved in neutral lipid transfer (Hesler, C. B., et al.,
J. Biol. Chem
., 263: 5020-5023 (1988)), but not phospholipid binding (see, Wang, S., et al.,
J. Biol. Chem
., 267: 17487-17490 (1992); Wang, S., et al.,
J. Biol. Chem
., 270: 612-618 (1995)).
A monoclonal antibody (Mab), TP2 (formerly designated 5C7 in the literature), has been produced which inhibits completely the cholesteryl ester and TG transfer activity of CETP, and to a lesser extent the phospholipid transfer activity (Hesler, C. B., et al.,
J. Biol. Chem
., 263: 5020-5023 (1988)). The epitope of TP2 was localized to the carboxyl terminal 26 amino acids, i.e., the amino acids from arginine-451 to serine-476, of the 74,000 dalton human CETP molecule (see, Hesler, C. B., et al., (1988)). TP2 was reported to inhibit CETP activity in human plasma in vitro (Yen, F. T., et al.,
J. Clin. Invest
., 83: 2018-2024 (1989)). Further analysis of the region of CETP bound by TP2 revealed that amino acids between phenylalanine-463 and leucine-475 are necessary for TP2 binding and for neutral lipid (e.g., cholesteryl ester) transfer activity (see, Wang, S., et al., 1992).
A number of in vivo studies utilizing animal models or humans have indicated that CETP activity can affect the level of circulating cholesterol-containing HDL. Increased CETP cholesteryl ester transfer activity can produce a decrease in HDL-C levels relative to LDL-C and/or VLDL-C (where HDL-C, LDL-C, and VLDL-C refer generally to cholesteryl ester and/or unesterified cholesterol associated with HDL, LDL, and VLDL, respectively) levels which in turn is correlated with an increased susceptibility to atherosclerosis. Injection of partially purified human CETP into rats (which normally lack CETP activity), resulted in a shift of cholesteryl ester from HDL to VLDL, consistent with CETP-promoted transfer of cholesteryl ester from HDL to VLDL (Ha, Y. C., et al.,
Biochim. Biophys. Acta
, 833: 203-211 (1985); Ha, Y. C., et al.,
Comp. Biochem. Physiol
., 83B: 463-466 (1986); Gavish, D., et al.,
J. Lipid Res
., 28: 257-267 (1987)). Transgenic mice expressing human CETP were reported to exhibit a significant decrease in the level of cholesterol associated with HDL (see, e.g., Hayek, T., et al.,
J. Clin. Invest
., 90: 505-510 (1992); Breslow, J. L., et al.,
Proc. Natl. Acad. Sci. USA
, 90: 8314-8318 (1993)).
Avant Immunotherapeutics, Inc.
Berka Thomas R.
Saunders David
Yankwich Leon R.
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