Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Oct 1;100(7):1804–1812. doi: 10.1172/JCI119708

Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor.

D Wu 1, J Yang 1, W M Pardridge 1
PMCID: PMC508366  PMID: 9312181

Abstract

Peptide radiopharmaceuticals are potential imaging agents for brain disorders, should these agents be enabled to undergo transport through the blood-brain barrier (BBB) in vivo. Radiolabeled Abeta1-40 images brain amyloid in tissue sections of Alzheimer's disease autopsy brain, but this peptide radiopharmaceutical cannot be used to image brain amyloid in vivo owing to negligible transport through the BBB. In these studies, 125I-Abeta1-40 was monobiotinylated (bio) and conjugated to a BBB drug delivery and brain targeting system comprised of a complex of the 83-14 monoclonal antibody (mAb) to the human insulin receptor, which is tagged with streptavidin (SA). A marked increase in rhesus monkey brain uptake of the 125I-bio-Abeta1-40 was observed after conjugation to the 8314-SA delivery system at 3 h after intravenous injection. In contrast, no measurable brain uptake of 125I-bio-Abeta1-40 was observed in the absence of a BBB drug delivery system. The peptide radiopharmaceutical was degraded in brain with export of the iodide radioactivity, and by 48 h after intravenous injection, 90% of the radioactivity was cleared from the brain. In conclusion, these studies describe a methodology for BBB drug delivery and brain targeting of peptide radiopharmaceuticals that could be used for imaging amyloid or other brain disorders.

Full Text

The Full Text of this article is available as a PDF (353.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bickel U., Yoshikawa T., Landaw E. M., Faull K. F., Pardridge W. M. Pharmacologic effects in vivo in brain by vector-mediated peptide drug delivery. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2618–2622. doi: 10.1073/pnas.90.7.2618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Biere A. L., Ostaszewski B., Stimson E. R., Hyman B. T., Maggio J. E., Selkoe D. J. Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma. J Biol Chem. 1996 Dec 20;271(51):32916–32922. doi: 10.1074/jbc.271.51.32916. [DOI] [PubMed] [Google Scholar]
  3. Cummings B. J., Cotman C. W. Image analysis of beta-amyloid load in Alzheimer's disease and relation to dementia severity. Lancet. 1995 Dec 9;346(8989):1524–1528. doi: 10.1016/s0140-6736(95)92053-6. [DOI] [PubMed] [Google Scholar]
  4. Fischman A. J., Babich J. W., Strauss H. W. A ticket to ride: peptide radiopharmaceuticals. J Nucl Med. 1993 Dec;34(12):2253–2263. [PubMed] [Google Scholar]
  5. Gearing M., Rebeck G. W., Hyman B. T., Tigges J., Mirra S. S. Neuropathology and apolipoprotein E profile of aged chimpanzees: implications for Alzheimer disease. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9382–9386. doi: 10.1073/pnas.91.20.9382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ghersi-Egea J. F., Gorevic P. D., Ghiso J., Frangione B., Patlak C. S., Fenstermacher J. D. Fate of cerebrospinal fluid-borne amyloid beta-peptide: rapid clearance into blood and appreciable accumulation by cerebral arteries. J Neurochem. 1996 Aug;67(2):880–883. doi: 10.1046/j.1471-4159.1996.67020880.x. [DOI] [PubMed] [Google Scholar]
  7. Ghilardi J. R., Catton M., Stimson E. R., Rogers S., Walker L. C., Maggio J. E., Mantyh P. W. Intra-arterial infusion of [125I]A beta 1-40 labels amyloid deposits in the aged primate brain in vivo. Neuroreport. 1996 Nov 4;7(15-17):2607–2611. doi: 10.1097/00001756-199611040-00040. [DOI] [PubMed] [Google Scholar]
  8. Glenner G. G., Wong C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984 May 16;120(3):885–890. doi: 10.1016/s0006-291x(84)80190-4. [DOI] [PubMed] [Google Scholar]
  9. Haldemann A. R., Rösler H., Barth A., Waser B., Geiger L., Godoy N., Markwalder R. V., Seiler R. W., Sulzer M., Reubi J. C. Somatostatin receptor scintigraphy in central nervous system tumors: role of blood-brain barrier permeability. J Nucl Med. 1995 Mar;36(3):403–410. [PubMed] [Google Scholar]
  10. Jarrett J. T., Lansbury P. T., Jr Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell. 1993 Jun 18;73(6):1055–1058. doi: 10.1016/0092-8674(93)90635-4. [DOI] [PubMed] [Google Scholar]
  11. Jefferies W. A., Brandon M. R., Hunt S. V., Williams A. F., Gatter K. C., Mason D. Y. Transferrin receptor on endothelium of brain capillaries. Nature. 1984 Nov 8;312(5990):162–163. doi: 10.1038/312162a0. [DOI] [PubMed] [Google Scholar]
  12. Kang J., Lemaire H. G., Unterbeck A., Salbaum J. M., Masters C. L., Grzeschik K. H., Multhaup G., Beyreuther K., Müller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19;325(6106):733–736. doi: 10.1038/325733a0. [DOI] [PubMed] [Google Scholar]
  13. Krenning E. P., Kwekkeboom D. J., Reubi J. C., Van Hagen P. M., van Eijck C. H., Oei H. Y., Lamberts S. W. 111In-octreotide scintigraphy in oncology. Metabolism. 1992 Sep;41(9 Suppl 2):83–86. doi: 10.1016/0026-0495(92)90038-c. [DOI] [PubMed] [Google Scholar]
  14. Kuo Y. M., Emmerling M. R., Vigo-Pelfrey C., Kasunic T. C., Kirkpatrick J. B., Murdoch G. H., Ball M. J., Roher A. E. Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains. J Biol Chem. 1996 Feb 23;271(8):4077–4081. doi: 10.1074/jbc.271.8.4077. [DOI] [PubMed] [Google Scholar]
  15. Maggio J. E., Stimson E. R., Ghilardi J. R., Allen C. J., Dahl C. E., Whitcomb D. C., Vigna S. R., Vinters H. V., Labenski M. E., Mantyh P. W. Reversible in vitro growth of Alzheimer disease beta-amyloid plaques by deposition of labeled amyloid peptide. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5462–5466. doi: 10.1073/pnas.89.12.5462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Marsh J. W. Antibody-mediated routing of diphtheria toxin in murine cells results in a highly efficacious immunotoxin. J Biol Chem. 1988 Nov 5;263(31):15993–15999. [PubMed] [Google Scholar]
  17. Martin L. J., Sisodia S. S., Koo E. H., Cork L. C., Dellovade T. L., Weidemann A., Beyreuther K., Masters C., Price D. L. Amyloid precursor protein in aged nonhuman primates. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1461–1465. doi: 10.1073/pnas.88.4.1461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Masters C. L., Simms G., Weinman N. A., Multhaup G., McDonald B. L., Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4245–4249. doi: 10.1073/pnas.82.12.4245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nordstedt C., Näslund J., Tjernberg L. O., Karlström A. R., Thyberg J., Terenius L. The Alzheimer A beta peptide develops protease resistance in association with its polymerization into fibrils. J Biol Chem. 1994 Dec 9;269(49):30773–30776. [PubMed] [Google Scholar]
  20. Pardridge W. M., Boado R. J., Kang Y. S. Vector-mediated delivery of a polyamide ("peptide") nucleic acid analogue through the blood-brain barrier in vivo. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5592–5596. doi: 10.1073/pnas.92.12.5592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pardridge W. M., Eisenberg J., Yang J. Human blood-brain barrier insulin receptor. J Neurochem. 1985 Jun;44(6):1771–1778. doi: 10.1111/j.1471-4159.1985.tb07167.x. [DOI] [PubMed] [Google Scholar]
  22. Pardridge W. M., Kang Y. S., Buciak J. L., Yang J. Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood-brain barrier in vivo in the primate. Pharm Res. 1995 Jun;12(6):807–816. doi: 10.1023/a:1016244500596. [DOI] [PubMed] [Google Scholar]
  23. Pardridge W. M., Triguero D., Yang J., Cancilla P. A. Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier. J Pharmacol Exp Ther. 1990 May;253(2):884–891. [PubMed] [Google Scholar]
  24. Pardridge W. M., Vinters H. V., Yang J., Eisenberg J., Choi T. B., Tourtellotte W. W., Huebner V., Shively J. E. Amyloid angiopathy of Alzheimer's disease: amino acid composition and partial sequence of a 4,200-dalton peptide isolated from cortical microvessels. J Neurochem. 1987 Nov;49(5):1394–1401. doi: 10.1111/j.1471-4159.1987.tb01005.x. [DOI] [PubMed] [Google Scholar]
  25. Prigent S. A., Stanley K. K., Siddle K. Identification of epitopes on the human insulin receptor reacting with rabbit polyclonal antisera and mouse monoclonal antibodies. J Biol Chem. 1990 Jun 15;265(17):9970–9977. [PubMed] [Google Scholar]
  26. Prior R., D'Urso D., Frank R., Prikulis I., Cleven S., Ihl R., Pavlakovic G. Selective binding of soluble Abeta1-40 and Abeta1-42 to a subset of senile plaques. Am J Pathol. 1996 Jun;148(6):1749–1756. [PMC free article] [PubMed] [Google Scholar]
  27. Reubi J. C., Kvols L., Krenning E., Lamberts S. W. Distribution of somatostatin receptors in normal and tumor tissue. Metabolism. 1990 Sep;39(9 Suppl 2):78–81. doi: 10.1016/0026-0495(90)90217-z. [DOI] [PubMed] [Google Scholar]
  28. Riddles P. W., Blakeley R. L., Zerner B. Ellman's reagent: 5,5'-dithiobis(2-nitrobenzoic acid)--a reexamination. Anal Biochem. 1979 Apr 1;94(1):75–81. doi: 10.1016/0003-2697(79)90792-9. [DOI] [PubMed] [Google Scholar]
  29. Roher A. E., Lowenson J. D., Clarke S., Woods A. S., Cotter R. J., Gowing E., Ball M. J. beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10836–10840. doi: 10.1073/pnas.90.22.10836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rubin R. H., Fischman A. J., Callahan R. J., Khaw B. A., Keech F., Ahmad M., Wilkinson R., Strauss H. W. 111In-labeled nonspecific immunoglobulin scanning in the detection of focal infection. N Engl J Med. 1989 Oct 5;321(14):935–940. doi: 10.1056/NEJM198910053211404. [DOI] [PubMed] [Google Scholar]
  31. Saito Y., Buciak J., Yang J., Pardridge W. M. Vector-mediated delivery of 125I-labeled beta-amyloid peptide A beta 1-40 through the blood-brain barrier and binding to Alzheimer disease amyloid of the A beta 1-40/vector complex. Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10227–10231. doi: 10.1073/pnas.92.22.10227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Samuel A., Paganelli G., Chiesa R., Sudati F., Calvitto M., Melissano G., Grossi A., Fazio F. Detection of prosthetic vascular graft infection using avidin/indium-111-biotin scintigraphy. J Nucl Med. 1996 Jan;37(1):55–61. [PubMed] [Google Scholar]
  33. Schlageter N. L., Carson R. E., Rapoport S. I. Examination of blood-brain barrier permeability in dementia of the Alzheimer type with [68Ga]EDTA and positron emission tomography. J Cereb Blood Flow Metab. 1987 Feb;7(1):1–8. doi: 10.1038/jcbfm.1987.1. [DOI] [PubMed] [Google Scholar]
  34. Selkoe D. J., Abraham C. R., Podlisny M. B., Duffy L. K. Isolation of low-molecular-weight proteins from amyloid plaque fibers in Alzheimer's disease. J Neurochem. 1986 Jun;46(6):1820–1834. doi: 10.1111/j.1471-4159.1986.tb08501.x. [DOI] [PubMed] [Google Scholar]
  35. Shin S. U., Wu D., Ramanathan R., Pardridge W. M., Morrison S. L. Functional and pharmacokinetic properties of antibody-avidin fusion proteins. J Immunol. 1997 May 15;158(10):4797–4804. [PubMed] [Google Scholar]
  36. Stern R. A., Otvos L., Jr, Trojanowski J. Q., Lee V. M. Monoclonal antibodies to a synthetic peptide homologous with the first 28 amino acids of Alzheimer's disease beta-protein recognize amyloid and diverse glial and neuronal cell types in the central nervous system. Am J Pathol. 1989 May;134(5):973–978. [PMC free article] [PubMed] [Google Scholar]
  37. Tomlinson B. E., Blessed G., Roth M. Observations on the brains of demented old people. J Neurol Sci. 1970 Sep;11(3):205–242. doi: 10.1016/0022-510x(70)90063-8. [DOI] [PubMed] [Google Scholar]
  38. Walker L. C., Masters C., Beyreuther K., Price D. L. Amyloid in the brains of aged squirrel monkeys. Acta Neuropathol. 1990;80(4):381–387. doi: 10.1007/BF00307691. [DOI] [PubMed] [Google Scholar]
  39. Walker L. C., Price D. L., Voytko M. L., Schenk D. B. Labeling of cerebral amyloid in vivo with a monoclonal antibody. J Neuropathol Exp Neurol. 1994 Jul;53(4):377–383. doi: 10.1097/00005072-199407000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Walus L. R., Pardridge W. M., Starzyk R. M., Friden P. M. Enhanced uptake of rsCD4 across the rodent and primate blood-brain barrier after conjugation to anti-transferrin receptor antibodies. J Pharmacol Exp Ther. 1996 May;277(2):1067–1075. [PubMed] [Google Scholar]
  41. Weiner H. L. Oral tolerance. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10762–10765. doi: 10.1073/pnas.91.23.10762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Winter G., Milstein C. Man-made antibodies. Nature. 1991 Jan 24;349(6307):293–299. doi: 10.1038/349293a0. [DOI] [PubMed] [Google Scholar]
  43. Yoshikawa T., Pardridge W. M. Biotin delivery to brain with a covalent conjugate of avidin and a monoclonal antibody to the transferrin receptor. J Pharmacol Exp Ther. 1992 Nov;263(2):897–903. [PubMed] [Google Scholar]
  44. Zlokovic B. V., Ghiso J., Mackic J. B., McComb J. G., Weiss M. H., Frangione B. Blood-brain barrier transport of circulating Alzheimer's amyloid beta. Biochem Biophys Res Commun. 1993 Dec 30;197(3):1034–1040. doi: 10.1006/bbrc.1993.2582. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES