Advertisement

Antibody-Toxin Conjugates as Potential Therapeutic Agents

  • D. Caird Edwards
  • Philip E. Thorpe
  • Anthony J. S. Davies
Part of the NATO Advanced Study Institutes Series book series (NSSA, volume 47)

Abstract

In his book ‘Selective Toxicity’, Adrian Albert1 gave three main principles upon which he averred drug selectivity to depend. Defining the living matter to be injured as the “uneconomic species”, the principles were (1) accumulation by, (2) injury to a chemical system important for, and (3) exclusive reaction with cytological features of, the uneconomic species. Commonly, more than one of these principles was to be seen in the action of any selective agent. These rules provide a set of guidelines to be followed in the design and testing of new agents, the functional partition being particularly useful in the present discussion of antibodies, toxins and their conjugates. The role of antibody is to be accumulated, hopefully in an exclusive fashion, by antigenic cytological features presented by the target cells. This interaction itself need not be harmful but fulfils two of Albert’s three principles. For their part the toxins, such as diphtheria toxin, abrin or ricin, are extremely powerful cytotoxic agents but they lack the exquisite tissue binding specificities which antibodies can be prepared to have. By producing chemical conjugates of antibodies and toxins the hope is to combine the desirable qualities of specificity of binding and effectiveness in killing in order to generate a new series of chemotherapeutic agents accumulated by and highly injurious to the uneconomic species.

Keywords

Diphtheria Toxin Selective Toxicity Mumps Virus Human Lymphoblastoid Cell Radiolabelled Antibody 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    A. Albert, “Selective Toxicity,” Chapman and Hall, London (1979).Google Scholar
  2. 2.
    G. Köhler, and C. Milstein, Derivation of specific antibody-producing tissue culture and tumour lines by cell fusion, Eur.J.Immunol. 6: 511 (1976).Google Scholar
  3. 3.
    T-M. Chang, A. Dazord, and D.M. Neville, Jr., Artificial hybrid protein containing a toxic protein fragment and a cell membrane receptor-binding moiety in a disulphide conjugate, J.Biol.Chem. 252: 1515 (1977).Google Scholar
  4. 4.
    T.N. Oeltmann, and C. Heath, A hybrid protein containing the toxic subunit of ricin and the cell specific subunit of human chorionic gonadotropin, J.Biol.Chem. 254: 1028 (1979).Google Scholar
  5. 5.
    R.J. Youle, G.J. Murray, and D.M. Neville, Jr., Ricin linked to monophosphopentamannose binds to fibroblast lysosomal hydrolase receptors, resulting in a cell-type-specific toxin, Proc.Natl.Acad.Sci.USA 76: 5559 (1979).Google Scholar
  6. 6.
    D.B. Cawley, H.R. Herschman, D.G. Gilliland, and R.J. Collier, Epidermal growth factor - toxin A chain conjugates, Cell 22: 563 (1980).PubMedCrossRefGoogle Scholar
  7. 7.
    W.K. Miskimins, and N. Shimizer, Synthesis of a cytotoxic insulin cross-linked to diphtheria toxin fragment A capable of recognizing insulin receptors, Biochem.Biophys. Res.Commun. 91:143 (1978).Google Scholar
  8. 8.
    H.B. Hewitt, E.R. Blake,and A.S.Wadler, A critique of the evidence for active host defence against cancer, Br.J. Cancer 33: 241 (1976).PubMedCrossRefGoogle Scholar
  9. 9.
    J.H. Coggin, Jr., and N.G. Anderson, Cancer, differentiation and embryonic antigens: some central problems, Adv.Cancer Res. 19: 105 (1974).Google Scholar
  10. 10.
    L. Korngold, and D. Pressman, The localization of antilymphosarcoma antibodies in the Murphy lymphosarcoma of the rat, Cancer Res. 14: 96 (1954).Google Scholar
  11. 11.
    E.D. Day, J.A. Planinsek, and D. Pressman, Localization in vivo of radioiodinated anti-rat-fibrin antibodies and radioiodinated rat fibrinogen in the Murphy rat lymphosarcoma and in other transplantable rat tumours, J.Natl. Cancer Inst. 22:413 (1959).Google Scholar
  12. 12.
    E.D. Day, J.A. Planinsek, and D. Pressman, Localization of radioiodinated antibodies in rats bearing tumours induced by N-2-fluorenyl-acetamide, J.Natl.Caneer Inst. 25: 787 (1960).Google Scholar
  13. 13.
    A.E. Rief, Studies on the localization of radiolabelled antibodies to a mouse myeloma protein, Cancer 27: 1433 (1971).Google Scholar
  14. 14.
    D. Pressman, E.D. Day, and M.Blau, The use of paired labeling in the determination of tumor-localizing antibodies, Cancer Res. 17: 845 (1957).Google Scholar
  15. 15.
    D. Pressman, and B.Sherman, The zone of localization of antibodies. XII Immunological specificities and cross reactions in the vascular beds of liver, kidney and lung. J.Immunol. 67: 21 (1951).PubMedGoogle Scholar
  16. 16.
    F.J. Primus, R. MacDonald, D.M. Goldenberg, and H.J. Hansen, Localisation of GW-39 human tumours in hamsters by affinity-purified antibody.to carcinoembryonic antigen, Cancer Res. 37: 1544 (1977).Google Scholar
  17. 17.
    J-P. Mach, S. Carrel, M. Forni, J. Ritschard, A. Donath, and P. Alberto, Tumor localization of radiolabelled antibodies against carcinoembryonic antigen in patients with carcinoma, New Eng.J.Med. 303: 5 (1980).Google Scholar
  18. 18.
    V. Moshakis, M.J. Bailey, M.G. Ormerod, J.H. Westwood, and A.M. Neville, Localization of human breast-carcinoma xenografts using antibodies to carcinoembryonic antigen, Br.J.Cancer 43: 575 (1981).Google Scholar
  19. 19.
    L.L. Houston, R.C. Nowinski, and D. Bernstein, Specific in vivo localization of monoclonal antibodies directed against the thy 1.1 antigen, J.Immunol. 125: 837 (1980).Google Scholar
  20. 20.
    T. Chose, and A.H. Blair, Antibody-linked cytotoxic agents in the treatment of cancer: current status and future progress, J.Natl.Cancer Inst. 61: 657 (1978).Google Scholar
  21. 21.
    G.J. O’Neill, The use of antibodies as drug carriers, in: “Drug Carriers in Biology and Medicine,” G. Gregoriadis, ed., Academic Press, London (1979).Google Scholar
  22. 22.
    R.J. Collier, Diphtheria toxin: mode of action and structure, Bact.Rev. 39: 54 (1975).Google Scholar
  23. 23.
    S. Olsnes, and A. Pihl, Abrin, ricin and their associated agglutinins, in: “The Specificity and Action of Animal, Bacterial and Plant Toxins,” P. Cuatrecasus, ed., Chapman and Hall, London (1977).Google Scholar
  24. 24.
    P.E. Thorpe, W.C.J. Ross, A.J. Cumber, C.A. Hinson, D.C. Edwards, and A.J.S. Davies, Toxicity of diphtheria toxin for lymphoblastoid cells is increased by conjugation to antilymphocytic globulin, Nature 272: 752 (1978).Google Scholar
  25. 25.
    D.C. Edwards, A. Smith, W.C.J. Ross, A.J. Cumber, P.E. Thorpe, A.N.F. Brown and A.J.S. Davies, In vitro and in vivo effects of anti-mouse lymphocyte globulin abrin and their conjugates, Clin.exp.Immunol. submitted for publication.Google Scholar
  26. 26.
    J. Carlsson, H. Drevin, and R. Axén, Protein thiolation and reversible protein-protein conjugation, Biochem.J. 173: 723 (1978).Google Scholar
  27. 27.
    S. Olsnes, and A. Pihl, Chimaeric toxin, in: “Pharmacology of Bacterial Toxins,” J. Drews and F. Dorner, eds., Pergamon Press, London (1981).Google Scholar
  28. 28.
    F.L. Moolten, and S.R. Cooperband, Selective destruction of target cells by diphtheria toxin conjugated to antibody directed against antigens on the cells, Science 169: 68 (1970).Google Scholar
  29. 29.
    F.L. Moolten, N.J. Capparell, and S.R. Cooperband, Antitumor effects of antibody-diphtheria toxin conjugates: use of hapten-coated tumor cells as an antigenic target, J.Natl. Cancer Inst. 49: 1057 (1972).Google Scholar
  30. 30.
    F.L. Moolten, N.J. Capparell, S.H. Zajdel, and S.R. Cooperband, Antitumor effects of antibody-diphtheria toxin conjugates. II Immunotherapy with conjugates directed against tumor antigens induced by Simian virus 40, J.Natl. Cancer Inst. 55:473 (1975).Google Scholar
  31. 31.
    G.W. Philpott, R.J. Bower, and C.W. Parker, Improved selective cytotoxicity with an antibody-diphtheria toxin conjugate, Surgery 73: 728 (1973).Google Scholar
  32. 32.
    W.C.J. Ross, P.E. Thorpe, A.J. Cumber, D.C. Edwards, C.A. Hinson, and A.J.S. Davies, Increased toxicity of diphtheria toxin for human lymphoblastoid cells following covalent linkage to anti-(human lymphocyte) globulin or its F(ab’)2 fragment, Eur.J.Biochem. 104: 381 (1980).Google Scholar
  33. 33.
    A.M. Denman, and E.P. Frenkel, Mode of action of anti-lymphocyte globulin, Immunology 14: 107 (1968).Google Scholar
  34. 34.
    D.C. Edwards, A. Smith, W.C.J. Ross, A.J. Cumber, P.E. Thorpe, and A.J.S. Davies, The effect of abrin, antilymphocytic globulin and their conjugates on the immune response of mice to sheep red blood cells, Experientia 37: 256 (1981).Google Scholar
  35. 35.
    K. Refsnes, and A.C. Munthe-Kass, Introduction of B-chain inactivated ricin into mouse macrophages and rat Kupffer cells via their membrane Fc receptors, J.Exp.Med. 143: 1464 (1976).Google Scholar
  36. 36.
    V. Raso, and T. Griffin, Delivery of ricin to immunoglobulin (Ig) bearing cells by hybrid antibodies, Proc.Amer.Assoc. Cancer Res. 20:207 (1979).Google Scholar
  37. 37.
    R.J. Youle, and D.M. Neville, Jr., Anti-thy 1.2 monoclonal antibody linked to ricin is a potent cell-type-specific toxin, Proc.Natl.Acad.Sci.USA 77: 5483 (1980).Google Scholar
  38. 38.
    P.E. Thorpe, A.J. Cumber, N. Williams, D.C. Edwards, W.C.J. Ross, and A.J.S. Davies, Abrogation of the non-specific toxicity of abrin conjugated to anti-lymphocyte globulin, Clin.Exp.Immunol. 43: 195 (1981).Google Scholar
  39. 39.
    K.A. Krolick, C. Villemey, P. Isakson, J.W. Uhr, and E.S. Vitetta, Selective killing of normal or neoplastic B cells by antibodies coupled to the A chain of ricin, Proc.Natl. Acad.Sci.USA 77: 5419 (1980).CrossRefGoogle Scholar
  40. 40.
    D.G. Gilliland, Z. Steplewski, R.J. Collier, K.F. Mitchell, T.H. Chang, and H.Koprowski, Antibody-directed cytotoxic agents: use of monoclonal antibody to direct the action of toxin A chains to colorectal carcinoma cells, Proc.Natl.Acad.Sci.USA 77: 4539 (1980).Google Scholar
  41. 41.
    F.K. Jansen, H.E. Blythman, D. Carriere, P. Casellas, J. Diaz, P. Gros, J.R. Hennequin, E. Paolucci, B. Pau, P. Poncelet, G. Richer, S.L. Salhi, H. Vidal and G.A. Voisin, High specific cytotoxicity of antibody-toxin hybrid molecules (immunotoxins) for target cells, Immunol.Lett. 2: 97 (1980).Google Scholar
  42. 42.
    P.E. Thorpe, A.N.F. Brown, W.C.J. Ross, A.J. Cumber, S.I. Detre, D.C. Edwards, A.J.S. Davies, and F. Stirpe, Cytotoxicity acquired by conjugation of an anti-thy 1.1 monoclonal antibody and the ribosome-inactivating protein, gelonin, Eur.J.Biochem. 116: 447 (1981).Google Scholar
  43. 43.
    F. Stirpe, S. Olsnes, and A. Pihl, Gelonin, a new inhibitor of protein synthesis, non toxic to intact cells, J.Biol. Chem. 255: 6947 (1980).Google Scholar
  44. 44.
    W.S. Sly, Saccharide traffic signals in receptor-mediated endocytosis and transport of acid hydrolases, in: “Structure and Function of the Gangliosides,” L. Svennerholm, P. Mandel, H. Dreyfus, and P-F. Urban, eds., Plenum Publishing Corporation, New York (1980).Google Scholar
  45. 45.
    L.S. Simeral, W. Kapmeyer, W.P. MacConnell, and N.O. Kaplan, On the role of the covalent carbohydrate in the action of ricin, J.Biol.Chem. 255: 11098 (1980).Google Scholar

Copyright information

© Plenum Press, New York 1982

Authors and Affiliations

  • D. Caird Edwards
    • 1
  • Philip E. Thorpe
    • 1
  • Anthony J. S. Davies
    • 1
  1. 1.Institute of Cancer Research: Royal Cancer HospitalChester Beatty Research InstituteLondonEngland

Personalised recommendations