The Effect of Chemical Deglycosylation of Ricin A-Chain on the Therapeutic Potential of Ricin A-Chain Immunotoxins

  • D. C. Blakeyl
  • G. J. Watson
  • P. P. Knowles
  • P. E. Thorpe
Conference paper

Abstract

Novel antitumour agents have been synthesised in several laboratories by linking the A-chain of the plant toxin, ricin, to monoclonal antibodies directed against tumour-associated antigens. These immunotoxins bind to antigens on the tumour cell surface via the antibody moiety and the A-chain enters the cell, killing it by inactivating its ribosomes. Although such immunotoxins often show good specificity and high potency in vitro they have generally produced less impressive antitumour effects in vivo (Reviewed in Thorpe, 1985; Vitetta and Uhr, 1985; Blakey et al 1987a). The poor therapeutic activity of ricin A-chain immunotoxins in vivo can be partly explained by their rapid clearance from the bloodstream. This rapid clearance of ricin A-chain immunotoxins is mainly due to recognition of mannose and fucose residues on the A-chain component by receptors present on liver parenchymal and non-parenchymal cells (Kupffer and sinusoidal endothelial cells). The evidence for this comes from several reports that ricin A-chain (Skilleter and Foxwell, 1986; Blakey and Thorpe, 1986) and ricin A-chain immunotoxins (Blakey et al 1987b; Bourrie et al 1986; Worrell et al 1986; Blakey et al 1987c) are taken up by liver cells in vitro and in vivo through a route that can be antagonised by mannose and fucose — terminating glycoproteins and saccharides.

Keywords

Sugar Toxicity Carbohydrate Lymphoma Aldehyde 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Blakey D C, Thorpe P E (1986) Effect of chemical deglycosylation on the in vivo fate of ricin A-chain. Cancer Drug Delivery 3. 189–196.PubMedCrossRefGoogle Scholar
  2. Blakey D C, Wawrzynczak E J, Wallace P M, Thorpe P E (1987a) Antibody toxin conjugates: a perspective.in: Waldmann H (ed) Progress in Allergy. S Karger A G Basel, in press.Google Scholar
  3. Blakey D C, Watson G J, Knowles P P, Thorpe P E (1987b) Effect of chemical deglycosylation of ricin A-chain on the in vivo fate and cytotoxic activity of an immunotoxin composed of ricin A-chain and anti-Thyl.1 antibody. Cancer Res 47: 947–952.PubMedGoogle Scholar
  4. Blakey D C, Skilleter D N, Price R J, Thorpe P E (1987c) Uptake of native and deglycosylated ricin A-chain immunotoxins by mouse liver parenchymal and non-parenchymal cells in vitro and in vivo. Biochim. Biophys. Acta, in press.Google Scholar
  5. Bourrie B J P, Casellas P, Blythman H E, Jansen F K (1986) Study of the plasma clearance of antibody-ricin A-chain immunotoxins. Evidence for specific recognition sites on the A-chain that mediate rapid clearance of the immunotoxins. Eur J Biochem 155: 1–10.Google Scholar
  6. Foxwell B M J, Donovan T A, Thorpe P E, Wilson G (1985) The removal of carbohydrates from ricin with endoglycosidases H, F and D and amannosidase. Biochim. Biophys. Acta 840: 193–203.Google Scholar
  7. Jennrich R I, Sampson P F (1968) Application of stepwise regression to non-linear least squares estimation. Technometrics 10: 63–72.CrossRefGoogle Scholar
  8. Skilleter D N, Foxwell B M J (1986) Selective uptake of ricin A-chain by hepatic non-parenchymal cells in vitro. Importance of mannose oligosaccharides in the toxin. FEBS Lett 196: 344–348.PubMedCrossRefGoogle Scholar
  9. Thorpe P E (1985) Antibody carriers of cytotoxic agents in cancer therapy.in: Pinchera A, Doria G, Dammacco F, Bargellesi A (eds). Monoclonal Antibodies ’84: Biological and Clinical Applications. Edritice Kurtis s.r.l. Milan, pp 475–512.Google Scholar
  10. Thorpe P E, Detre S I, Foxwell B M J, Brown A N F, Skilleter D N, Wilson G, Forrester J A, Stirpe F (1985) Modification of the carbohydrate in ricin with metaperiodate-cyanoborohydride mixtures. Effects on toxicity and in vivo distribution. Eur J Biochem 147: 187–206.CrossRefGoogle Scholar
  11. Vitetta E S, Uhr J W (1985) Immunotoxins. Ann Rev Immunol 3: 197–212.CrossRefGoogle Scholar
  12. Worrell N R, Skilleter D N, Cumber A J, Price R J (1986)Mannose receptor dependent uptake of a ricin A-chain-antibody conjugate by rat liver non-parenchymal cells.Biochem Biophys Res Comm 137: 892–896.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1988

Authors and Affiliations

  • D. C. Blakeyl
    • 1
  • G. J. Watson
    • 1
  • P. P. Knowles
    • 1
  • P. E. Thorpe
    • 1
  1. 1.Drug Targeting LaboratoryImperial Cancer Research FundLondonEngland

Personalised recommendations