Application of Monoclonal Antibodies to Issues of Plasma Lipoprotein Structure and Function

  • Linda K. Curtiss


An understanding of the role of plasma lipoproteins in biology and in diverse pathophysiologic states is expanding rapidly. The ability of these supramolecular complexes to transport smaller hydrophobic molecules, including cholesteryl esters, triglycerides, fat-soluble vitamins, and hormones, places them in the limelight as important mediators of molecular traffic in vivo. However, much remains obscure regarding the organization of these protein-lipid complexes as well as the structure and the function of the individual molecular constituents that make up the lipoproteins. Immunochemical approaches to studies of apoprotein structure and analyses of lipoproteins per se have been utilized for many years. These studies have facilitated both identification and quantitation of the protein constituents of the plasma lipoproteins. However, not until monoclonal antibodies of defined specificity were available in significant numbers did immunochemical approaches gain the popularity they hold today. The striking degree of specificity inherent in a monoclonal antibody has been successfully applied to relevant issues of lipoprotein biology, including the identification of receptor binding domains, genetic polymorphisms, and putative atherogenic lipoproteins. These advances will be discussed in detail following a brief description of the important participants in these studies, the antibodies and the lipoproteins.


Plasma Lipoprotein Density Class Chylomicron Remnant Human Apolipoprotein Human Plasma Lipoprotein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Alaupovic, P., Lee D. M., and McConathy, W. J., 1972, Studies on the composition and structure of plasma lipoproteins (distribution of lipoprotein families in major density classes of normal human plasma lipoproteins), Biochim. Biophys. Acta 260:689–707.PubMedGoogle Scholar
  2. 2.
    Fielding, C. J., and Fielding, P. E., 1977, in: Cholesterol Metabolism and Lipolytic Enzymes (J. Bionovski, ed.), Massen, New York, pp. 165–172.Google Scholar
  3. 3.
    Sparrow, J. T., and Gotto, Jr., A. M., 1981, Apolipoprotein/lipid interactions: Studies with synthetic peptides, CRC Crit. Rev. Biochem. 13:87–107.CrossRefGoogle Scholar
  4. 4.
    Mao, S. J. T., Kazmar, R. E., Silverfield, J. C., Alley, M. C., Kluge, K., and Fathman, C. G., 1982, Immunochemical properties of human low density lipoproteins as explored by monoclonal antibodies. Binding characteristics distinct from those of conventional serum antibodies, Biochim. Biophys. Acta 713:365–374.PubMedGoogle Scholar
  5. 5.
    Patton, J. G., Alley, M. C., and Mao, S. J. T., 1982, Evaluation of monoclonal antibodies to human plasma low density lipoproteins. A requirement for lipids to maintain antigenic structures, J. Immunol. Meth. 55:193–203.CrossRefGoogle Scholar
  6. 6.
    Tikkanen, M. J., Dargar, R., Pfleger, B., Gonen, B., Davie, J. M., and Schonfeld, G., 1982, Antigenic mapping of human low density lipoprotein with monoclonal antibodies, J. Lipid Res. 23:1032–1038.PubMedGoogle Scholar
  7. 7.
    Marcel, Y. L., Hogue, M., Theolis, J. R., and Milne, R. W., 1982, Mapping of antigenic determinants of human apolipoprotein B using monoclonal antibodies against low density lipoproteins, J. Biol. Chem. 257:13165–13168.PubMedGoogle Scholar
  8. 8.
    Watt, T. S., and Watt, R. M., 1983, Detection of unique antigenic determinants on human plasma low density lipoprotein and on delipidated apolipoprotein B, Proc. Natl. Acad. Sci. USA 80:124–128.PubMedCrossRefGoogle Scholar
  9. 9.
    Curtiss, L. K., and Edgington, T. S., 1982, Immunochemical heterogeneity of human plasma apolipoprotein B. I. Apolipoprotein B binding of mouse hybridoma antibodies, J. Biol. Chem. 257:15213–15221.PubMedGoogle Scholar
  10. 10.
    Hui, D. Y., Innerarity, T. L., and Mahley, R. W., 1984, Defective hepatic lipoprotein receptor binding of β-very low density lipoproteins from Type III hyperlipoproteinemic patients. Importance of apolipoprotein E, J. Biol. Chem. 259:860–869.PubMedGoogle Scholar
  11. 11.
    Young, S., Witztum, J. L., and Curtiss, L. K., 1985, Evidence for evolutionary conservation of the LDL receptor recognition domain on apolipoprotein B using monoclonal antibodies, Clin. Res. 33:68A.Google Scholar
  12. 12.
    Hopp, T. P., and Woods, K. R., 1981, Prediction of protein antigenic determinants from amino acid sequences, Proc. Natl. Acad. Sci. USA 78:3824–3828.PubMedCrossRefGoogle Scholar
  13. 13.
    Hopp, T. P., and Woods, K. R., 1983, A complete program for predicting protein antigenic determinants, Mol. Immunol. 20:483–489.PubMedCrossRefGoogle Scholar
  14. 14.
    Milne, R. W., Douste-Blazy, P. H., Marcel, Y. L., and Retequi, L., 1981, Characterization of monoclonal antibodies against human apolipoprotein E, J. Clin. Invest. 68:111–117.PubMedCrossRefGoogle Scholar
  15. 15.
    Voyta, J. C., Via, D. P., and Sparrow, J. T., 1982, Monoclonal antibodies to human apolipoprotein E, Fed. Proc. 41:931.Google Scholar
  16. 16.
    Pepe, M. G., and Curtiss, L. K., 1985, A sensitive radioimmunoassay for monitoring cellular synthesis and secretion of apolipoprotein E. In press.Google Scholar
  17. 17.
    Weisgraber, K. H., Innerarity, T.L., Harder, K. J., Mahley, R. W., Milne, R. W., Marcel, Y. L., and Sparrow, J. T., 1983, The receptor-binding domain of human apolipoprotein E. Monoclonal antibody inhibition of binding, J. Biol Chem. 258:12348–12354.PubMedGoogle Scholar
  18. 18.
    Fielding, P. E., Fielding, C. J., Havel, R. J., Kane, J. P., and Tun, P., 1983, Cholesterol net transport, esterification and transfer in human hyperlipidemic plasma, J. Clin. Invest. 71:449–460.PubMedCrossRefGoogle Scholar
  19. 19.
    Fager, C., Wiklund, O., and Olofsson, S., 1980, Serum apolipoprotein levels in relation to acute myocardial infarction and its risk factors, apolipoprotein A-I levels in male survivors of myocardial infarction, Atherosclerosis 36:67–74.PubMedCrossRefGoogle Scholar
  20. 20.
    Curtiss, L. K., and Edgington, T. S., 1985, Heterogeneity of human plasma high density lipoproteins. I. Identification with apolipoprotein AI- and All-specific monoclonal antibodies, J. Biol. Chem. 260:2982–2993.PubMedGoogle Scholar
  21. 21.
    Stein, E. A., and Pesce, A. J., 1983, Enzyme linked immunoassays for apolipoproteins: Advantages, problems and prototype assay, in: Proceedings Workshop on Apolipoprotein Quantification, NIH Pub. No. 83–1266, pp. 319–328.Google Scholar
  22. 22.
    Marhaug, C., Gaudernack, C., Bogen, B., and Husby, G., 1982, Monoclonal hybridoma antibodies to human amyloid related protein SAA, Clin. Exp. Immunol. 50:390–396.PubMedGoogle Scholar
  23. 23.
    Curtiss, L. K., and Plow, E. F., 1984, Interaction of plasma lipoproteins with human platelets, Blood 64:365–374.PubMedGoogle Scholar
  24. 24.
    Whayne, T. F., Alaupovic, P., Curry, M. D., Lee, E. T., Anderson, P. S., and Schecter, E., 1981, Plasma apolipoprotein B and VLDL-, LDL-, and HDL-cholesterol as risk factors in the development of coronary artery disease in male patients examined by angiography, Atherosclerosis 39:411–424.PubMedCrossRefGoogle Scholar
  25. 25.
    Sniderman, A., Shapiro, S., Marpole, D., Skinner, B., Teng, B., and Kwiterovich, P. O., Jr., 1980, Association of coronary atherosclerosis with hyperapobetaalipoproteinemia [increased protein but normal cholesterol levels in human plasma low density lipoproteins], Proc. Natl Acad. Sci. USA 77:604–608.PubMedCrossRefGoogle Scholar
  26. 26.
    Gordon, T., Castelli, W. P., and Hjortland, M. C., 1977, High density lipoprotein as a protective factor against coronary heart disease, The Framingham Study, Am. J. Med. 62:707–714.PubMedCrossRefGoogle Scholar
  27. 27.
    Mao, S. J. T., Patton, J. G., Badimon, J., Kottke, B. A., Alley, M. C., and Cardin, A. D., 1983, Monoclonal antibodies to human plasma low density lipoproteins. I. Enhanced binding of 125I-labeled low density lipoproteins by combined use of two monoclonal antibodies, Clin. Chem. 29:1890–1897.PubMedGoogle Scholar
  28. 28.
    Tsao, B. P., Curtiss, L. K., and Edgington, T. S., 1982, Immunochemical heterogeneity of human plasma apolipoprotein B. II. Expression of apolipoprotein B epitopes on native lipoproteins. J. Biol. Chem. 257:15222–15228.PubMedGoogle Scholar
  29. 29.
    Tikkanen, M. J., Cole, T. G., and Schonfeld, G., 1983, Differential reactivity of human low density lipoproteins with monoclonal antibodies, J. Lipid Res. 24:1494–1499.PubMedGoogle Scholar
  30. 30.
    Patton, J. G., Badimon, J., and Mao, S. J. T., 1983, Monoclonal antibodies to human plasma low density lipoproteins. II. Evaluation for use in radioimmunoassay for apolipoprotein B in patients with coronary artery disease, Clin. Chem. 29:1898–1903.PubMedGoogle Scholar
  31. 31.
    Smith, R., Dawson, J. R., and Tanford, C., 1972, The size and number of polypeptide chains in human serum low density lipoprotein, J. Biol. Chem. 247:3376–3381.PubMedGoogle Scholar
  32. 32.
    Socorro, L., Lopez, F., Lopez, A., and Camejo, G., 1982, Apo LDL: Evidence for an aggregating system of heterogeneous subunits, J. Lipid Res. 23:1283–1291.PubMedGoogle Scholar
  33. 33.
    Olofsson, S. O., Bostrom, K., Svanberg, U., and Bondjers, G., 1980, Isolation and partial characterization of a polypeptide belonging to Apolipoprotein B from low density lipoproteins of human plasma, Biochemistry 19:1059–1064.PubMedCrossRefGoogle Scholar
  34. 34.
    Bradley, W. A., Rohde, M. F., Gotto, Jr., A. M., and Jackson, R. L., 1978, The cyanogen bromide peptides of the apoprotein of low density lipoprotein (ApoB): Its molecular weight from a chemical view, Biochem. Biophys. Res. Commun. 81:928–935.PubMedCrossRefGoogle Scholar
  35. 35.
    Hahm, K., Tikkanen, M. J., Dargar, R., Cole, T. G., Davie, J. M., and Schonfeld, G., 1983, Limited proteolysis selectively destroys epitopes on apolipoprotein B in low density lipoproteins, J. Lipid Res. 24:877–885.PubMedGoogle Scholar
  36. 36.
    Watt, T. S., and Watt, R. M., 1984, Probing the antigenic structure of human serum low density lipoproteins (LDL) with monoclonal antibodies. Fed. Proc. 43:1642.Google Scholar
  37. 37.
    Milne, R. W., and Marcel, Y. L., 1982, Monoclonal antibodies against human low density lipoprotein. Stoichiometric binding studies using Fab fragments, FEBS Lett. 146:97–100.PubMedCrossRefGoogle Scholar
  38. 38.
    Wiklund, O., Dyer, C. A., Tsao, B. P., and Curtiss, L. K., 1985, Studies of the stoichiometric binding of apolipoprotein B-specific monoclonal antibodies to low density lipoproteins, J. Biol. Chem. In press.Google Scholar
  39. 39.
    Munson, P. J., and Rodbard, D., 1980, LIGAND: A versatile computerized approach for characterization of ligand-binding systems, Anal. Biochem. 107:220–239.PubMedCrossRefGoogle Scholar
  40. 40.
    Schumaker, V. N., Robinson, M. T., Curtiss, L. K., Butler, R., and Sparks, R. S., 1984, Antiapoprotein B monoclonal antibodies detect human low density lipoprotein polymorphism, J. Biol. Chem. 259:6423–6430.PubMedGoogle Scholar
  41. 41.
    Balla, M. A., Schumaker, V. N., and Curtiss, L. K., 1985, Demonstration of apolipoprotein B genetic polymorphism using the Western blot technique, J. Lipid, Res. In press.Google Scholar
  42. 42.
    Schumaker, V. N., Balla, M. A., Robinsen, M., Spence, A., Sparks, R., and Curtiss, L. K., 1985, The use of monoclonal antibodies to detect genetic polymorphism: Application to apolipoprotein B, in: Genetic Disorders Medical Genetics: Past, Present and Future, Alan Liss, New York.Google Scholar
  43. 43.
    Brown, M. S., and Goldstein, J. L., 1983, Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic, J. Clin. Invest. 72:743–747.PubMedCrossRefGoogle Scholar
  44. 44.
    Brown, M. S., Kovanen, P. T., and Goldstein, J. L., 1981, Regulation of plasma cholesterol by lipoprotein receptors, Science 212:628–635.PubMedCrossRefGoogle Scholar
  45. 45.
    Kane, J. P., Hardman, P. A., and Paulus, H. E., 1980, Heterogeneity of apolipoprotein B: Isolation of a new species from human chylomicrons, Proc. Natl. Acad. Sci. USA 77:2365–2369.Google Scholar
  46. 46.
    Malloy, M. J., Kane, J. P., Hardman, D. A., Hamilton, R. L., and Dalai, K. B., 1981, Normotriglyceridemic abetalipoproteinemia: Absence of the B-100 apolipoproteins, J. Clin. Invest. 67:1441–1450.PubMedCrossRefGoogle Scholar
  47. 47.
    Tikkanen, M. J., Cole, T. G., Hahm, K., Krul, E. S., and Schonfeld, G., 1984, Expression of apolipoprotein B epitopes in very low density lipoprotein subfractions. Studies with monoclonal antibodies, Arteriosclerosis 4:138–146.PubMedCrossRefGoogle Scholar
  48. 48.
    Milne, R. W., Weech, P. K., Blanchette, L., Davignon, J., Alaupovic, P., and Marcel, Y. L., 1984, Isolation and characterization of apolipoprotein B-48 and B-100 very low density lipoproteins from Type III hyperlipoproteinemic subjects, J. Clin. Invest. 73:816–823.PubMedCrossRefGoogle Scholar
  49. 49.
    Milne, R. W., Theolis, J. R., Verdery, R. B., and Marcel, Y. L., 1983, Characterization of monoclonal antibodies against human low density lipoprotein, Arterioclerosis 3:23–30.CrossRefGoogle Scholar
  50. 50.
    Weisgraber, K. H., Innerarity, T. L., and Mahley, R. W., 1978, Role of the lysine residues of plasma lipoproteins in high affinity binding to cell surface receptors on human fibroblasts, J. Biol. Chem. 253:9053–9062.PubMedGoogle Scholar
  51. 51.
    Marcel, Y. L., Hogue, M., Weech, P. K., and Milne, R. W., 1984, Characterization of antigenic determinants on human solubilized apolipoprotein B. Conformational requirements for lipids, J. Biol. Chem. 259:6952–6957.PubMedGoogle Scholar
  52. 52.
    Nelson, C. A., Tasch, M. A., Tikkanen, M., Dargar, R., and Schonfeld, G., 1984, Evolution of low density lipoprotein structure probed with monoclonal antibodies, J. Lipid Res, 25:821–830.PubMedGoogle Scholar
  53. 53.
    Innerarity, T. L., Friedlander, E. J., Rail, Jr., S. C., Weisgraber, K. H., and Mahley, R. W., 1983, The receptor-binding domain of human apolipoprotein E. Binding of apolipoprotein E fragments, J. Biol. Chem. 258:12341–12347.PubMedGoogle Scholar
  54. 54.
    Russell, D. W., Schneider, W. J., Yamamoto, T., Luskey, K. L., Brown, M. S., and Goldstein, J. L., 1984, Domain map of the LDL receptor: Sequence homology with the epidermal growth factor precursor, Cell 37:577–585.PubMedCrossRefGoogle Scholar
  55. 55.
    Bernini, F., Tanenbaum, S. R., Sherrill, B. C., Gotto, A. M., Jr., and Smith, L. C., 1985, Enhancement of Fab fragment uptake in the rat liver by lactosamination, In press.Google Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • Linda K. Curtiss
    • 1
  1. 1.Department of ImmunologyResearch Institute of Scripps ClinicLa JollaUSA

Personalised recommendations