Anti-antibody enhancement of tumor imaging

  • Robert M. Sharkey
  • Rosalyn D. Blumenthal
  • David M. Goldenberg
Part of the Cancer Treatment and Research book series (CTAR, volume 51)


Although there are many factors that influence the ability of a radiolabeled antibody to image tumors by external scintigraphy, perhaps the most problematic has been the ability to distinguish specific radioantibody uptake in tumor from the background radioactivity in uninvolved tissues, particularly that due to excessive blood-pool activity. This problem was recognized even as the technology was first developing in the mid-1950s [1], but it was thought that the development of more highly specific anti-tumor antibodies would be a solution. However, even as specificity of the antibodies was improved, tumor imaging was difficult. For example, in animals bearing human tumor xenografts in peripheral sites, such as the cheek pouch in hamsters or subcutaneously in nude mice, tumors were not clearly imaged until 4–7 days after the radioantibody was injected [2–4], because it took several days for the blood-pool radioactivity to clear. Otherwise, the majority of the counts in the images was derived from radioactivity residing in the blood and uninvolved tissues. Excessive background radioactivity also interfered with the detection of tumors in humans [5], but this problem was overcome initially by Golden-berg et al. [6]. They developed a dual-isotope subtraction procedure that used 99mTc-pertechnetate and labeled albumin to estimate the contribution of interstitial and blood-pool radioactivity in the images produced.


Second Antibody Nude Mouse Antibody Fragment Tumor Imaging Cheek Pouch 
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.
    Bale, W.F., and Spar, I.L. (1957) Studies directed toward the use of antibodies as carriers of radioactivity for therapy. Adv. Biol. Med. Phys. 5:285–356.PubMedGoogle Scholar
  2. 2.
    Primus, F.J., Wang, R.H., Goldenberg, D.M., and Hansen, H.J. (1973) Localization of human GW-39 tumors in hamsters by radiolabeled heterospecific antibody to carcino-embryonic antigen. Cancer Res. 33:2977–2982.PubMedGoogle Scholar
  3. 3.
    Goldenberg, D.M., Preston, D.F., Primus, F.J., and Hansen, H.J. (1974) Photoscan localization of GW-39 tumors in hamsters using radiolabeled anticarcinoembryonic antigen immunoglobulin G. Cancer Res. 34:1–9.PubMedGoogle Scholar
  4. 4.
    Mach, J.P., Carrel, S., Merenda, C., Sordat, B., and Cerottini, J.C. (1974) In vivo localization of radiolabeled antibodies to carcinoembryonic antigen in human colon carcinoma grafted into nude mice. Nature 248:704–706.PubMedCrossRefGoogle Scholar
  5. 5.
    Reif, A.E., Curtis, L.E., Duffield, R., and Shauffer, I.A. (1974) Trial of radiolabeled antibody localization in metastases of a patient with a tumor containing carcinoembryonic antigen (CEA). J. Surg. Oncol. 6:133–150.PubMedCrossRefGoogle Scholar
  6. 6.
    Goldenberg, D.M., Deland, F., Kim, E., Bennett, S., Primus, F.J., van Nagell, J.R., Jr., Estes, N., DeSimone, P., and Rayburn, P. (1978) Use of radiolabeled antibodies to carcino-embryonic antigen for detection and localization of diverse cancers by external photo-scanning. N. Engl. J. Med. 298:1384–1388.PubMedCrossRefGoogle Scholar
  7. 7.
    Goldenberg, D.M., Kim, E.E., Bennett, S.J., Nelson, M.O., and Deland, F.H. (1983) Carcinoembryonic antigen radioimmunodetection in the evaluation of colorectal cancer and in the detection of occult neoplasms. Gastroenterology 84:524–552.PubMedGoogle Scholar
  8. 8.
    Mach, J.P., Carrel, S., Forni, M., Ritschard, J., Donath, A., and Alberto, P. (1980) Tumor localization of radiolabeled antibodies against carcinoembryonic antigen in patients with carcinoma. N. Engl. J. Med. 303:5–10.PubMedCrossRefGoogle Scholar
  9. 9.
    Smedley, H.M., Finan, P., Lennox, E.S., Ritson, A., Takei, F., Wraight, P., and Sikora, K. (1983) Localization of metastatic carcinoma by radiolabeled monoclonal antibody. Br. J. Cancer 47:253–259.PubMedCrossRefGoogle Scholar
  10. 10.
    Sullivan, D.C., Silva, J.S., Cox, C.E., Haagensen, D.E., Jr., Harris, C.C., Briner, W.H., and Wells, S.A., Jr. (1982) Localization of 131I-labeled goat and primate anti-carcinoembryonic antigen (CEA) antibodies in patients with cancer. Invest. Radiol. 17:350–355.PubMedCrossRefGoogle Scholar
  11. 11.
    Green, A.J., Begent, R.H.J., Keep, P.A., and Bagshawe, K.D. (1984) Analysis of radioimmunodetection of tumors by the subtraction technique. J. Nucl. Med. 25:96–100.PubMedGoogle Scholar
  12. 12.
    Ott, R.J., Grey, L.J.L., Zivaovic, M.A., Flower, M.A., Trott, N.G., Moshaki, V., Combes, R.C., Neville, A.M., Ormerod, M.G., Westwood, J.H., and McCready, V.R. (1983) The limitations of the dual-radionuclide subtraction technique for external detection of tumors by radioiodine labeled antibodies. Br. J. Radiol. 56:101–108.PubMedCrossRefGoogle Scholar
  13. 13.
    Perkins, A.C., Whalley, D.R., and Hardy, J.G. (1984) Physical approach for the reduction of dual radionucleotide image subtraction artifacts in immunoscintigraphy. Nucl. Med. Commun. 5:501–512.PubMedCrossRefGoogle Scholar
  14. 14.
    Siegel, J.A., Greenspan, B., Madsen, M.T., Sharkey, R.M., Brennen, K., Lee, R.E., and Goldenberg, D.M. (1987) Improvement of subtraction imaging in radioimmunodetection. Radiology 165:133.Google Scholar
  15. 15.
    Wahl, R.L., Parker, C.W., and Philpott, G.W. (1983) Improved radioimaging and tumor localization with monoclonal F(ab′)2. J. Nucl. Med. 24:317–325.Google Scholar
  16. 16.
    Buchegger, F., Haskell, C.M., Schreyer, M., Scazziaga, B.R., Randin, S., Carrel, S., and Mach, J.P. (1983) Radiolabeled fragments of monoclonal antibodies against carcinoembryonic antigen for localization of human colon carcinoma grafted into nude mice. J. Exp. Med. 158:413–427.PubMedCrossRefGoogle Scholar
  17. 17.
    Delaloye, B., Bischof-Delaloye, A., Buchegger, F., von Fliedner, V., Grob, J.P., Volant, J.C., Pettavel, J., and Mach, J.P. (1986) Detection of colorectal carcinoma by emission-computerized tomography after injection of I-123-labeled Fab or F(ab′)2 fragments from monoclonal anti-carcinoembryonic antigen antibodies. J. Clin. Invest. 77:301–311.PubMedCrossRefGoogle Scholar
  18. 18.
    Khaw, B.A., Strauss, H.W., Cahill, S.L., Soule, H.R., Edgington, T., and Cooney, J. (1984) Sequential imaging of indium-111-labeled monoclonal antibody in human mammary tumors hosted in nude mice. J. Nucl. Med. 25:592–603.PubMedGoogle Scholar
  19. 19.
    Gaffar, S.A., Bennett, S.S., DeLand, F.H., Primus, F.J., and Goldenberg, D.M. (1982) Carcinoembryonic antigen (CEA) radioactive antibody fragments for cancer localization in vivo. Proc. Am. Assoc. Cancer Res. 23:249.Google Scholar
  20. 20.
    Pant, K.D., Dahlman, H.L., and Goldenberg, D.M. (1977) A putatively new antigen (CSAp) associated with gastrointestinal and ovarian neoplasia. Immunol. Commun. 6: 411–421.PubMedGoogle Scholar
  21. 21.
    Sharkey, R.M., Primus, F.J., and Goldenberg, D.M. (1984) Second antibody clearance of radiolabeled antibody in cancer detection. Proc. Natl. Acad. Sci. USA 8:2843–2847.CrossRefGoogle Scholar
  22. 22.
    Goldenberg, D.M., Sharkey, R.M., and Ford, E. (1987) Anti-antibody enhancement of iodine-131 anti-CEA radioimmunodetection in experimental and clinical studies. J. Nucl. Med. 28:1604–1610.PubMedGoogle Scholar
  23. 23.
    Spar, I.L., Goodland, R.L., and Desiderio, M.A. (1964) Immunological removal of circulating I-131-labeled rabbit antibody to rat fibrinogen in normal and tumor-bearing rats. J. Nucl. Med. 5:428–443.PubMedGoogle Scholar
  24. 24.
    McCardle, R.J., Harper, P.V., Spar, I.L., Bale, W.F., Andros, G., and Jiminez, F. (1966) Studies with iodine-131-labeled antibody to human fibrinogen for diagnosis and therapy of tumors. J. Nucl. Med. 7:837–847.PubMedGoogle Scholar
  25. 25.
    Barrett, G.M., Ryman, B.E., Boden, J.A., Keeps, P.A., Searle, F., Begent, R.H., and Bagshawe, K.D. (1981) Liposomal clearance of antibodies to tumour products: Possible improvement of tumour detection. Biochem. Soc. Trans. 9:564–565.Google Scholar
  26. 26.
    Barratt, G.M., Ryman, B.E., Begent, R.H.J., Keep, P.A., Searle, F., Boden, J.A., and Bagshawe, K.D. (1983) Improved radioimmunodetection of tumours using liposome-entrapped antibody. Biochem. Biophys. Acta 762:154–164.PubMedCrossRefGoogle Scholar
  27. 27.
    Begent, R.H.J., Green, A.J., Bagshawe, K.D., Jones, B.E., Keep, P.A., Searle, F., Jewkes, R.F., Barratt, G.M., and Ryman, B.E. (1982) Liposomally entrapped second antibody improves tumor imaging with radiolabeled (first) antitumor antibody. Lancet 2: 739–742.PubMedCrossRefGoogle Scholar
  28. 28.
    Ryman, B.E., and Baratt, G.M. (1982) Possible improvement of radioimmunodetection of tumors by liposomal clearance of antibodies to tumor products. In: Akoyunoglou, G., Evangelopopulos, A.E., Georgatsos, J., Palaiologos, G., Trakatelli, A., and Tsiganos, C.P. (eds.), Progress in Clinical and Biological Research, Vol 102A. New York: Alan Liss, pp. 299–308.Google Scholar
  29. 29.
    Bradwell, A.R., Vaughan, A., Fairweather, D.S., and Kykes, P.W. (1983) Improved radioimmunodetection of tumors using a second antibody. Lancet 1:247.PubMedCrossRefGoogle Scholar
  30. 30.
    Goodwin, D., Meares, C., Diamanti, C., McCall, M., Lai, C., Torti, F., McTigue, M., and Martin, B. (1984) Use of specific antibody for rapid clearance of circulating blood pool background from radiolabeled tumor imaging proteins. Eur. J. Nucl. Med. 9:209–215.PubMedCrossRefGoogle Scholar
  31. 31.
    Goldenberg, D.M., and Hansen, H.J. (1972) Carcinoembryonic antigen present in human colonic neoplasis serially propagated in hamsters. Science 175:1117–1118.PubMedCrossRefGoogle Scholar
  32. 32.
    Sharkey, R.M., Mabus, J., and Goldenberg, D.M. (1900) Factors influencing anti-antibody enhancement of tumor targeting. Cancer Res., in press.Google Scholar
  33. 33.
    Silver, S., ed. (1968) In: Radioactive Nuclides in Medicine and Biology. Philadelphia: Lea and Febiger.Google Scholar
  34. 34.
    Scheinberg, D.A., Strand, M., and Gansow, O.A. (1983) Tumor imaging with radioactive chelates conjugated to monoclonal antibodies. Science 215:1511–1513.CrossRefGoogle Scholar
  35. 35.
    Perkins, A.C., and Pimm, M.V. (1985) Differences in tumor and normal tissue concentrations of iodine- and indium-labeled monoclonal antibody. Eur. J. Nucl. Med. 11:295–299.PubMedCrossRefGoogle Scholar
  36. 36.
    Sharkey, R.M., Filion, D., Primus, F.J., and Goldenberg, D.M. (1986) A human colon cancer metastasis model for radioimmunodetection. Cancer Res. 46:3677–3683.PubMedGoogle Scholar
  37. 37.
    Primus, F.J., Newell, K.S., Blue, A., and Goldenberg, D.M. (1983) Immunological heterogeneity of carcinoembryonic antigen: Antigenic determinants on CE A distinguished by monoclonal antibodies. Cancer Res. 43:686–692.PubMedGoogle Scholar
  38. 38.
    Primus, F.J., Sharkey, R.M., Ballance, C., Kelly, E., Varga, D., and Goldenberg, D.M. (1986) Radiolocalizing monoclonal antibodies against concealed epitopes on carcinoembryonic antigen (CEA). J. Nucl. Med. 27:1016.Google Scholar
  39. 39.
    Sharkey, R.M., Primus, F.J., Shochat, D., and Goldenberg, D.M. (1988) Comparison of tumor targeting of mouse monoclonal and goat polyclonal antibodies to carcinoembryonic antigen in the GW-39 human tumor host model. Cancer Res. 48:1823–1828.PubMedGoogle Scholar
  40. 40.
    Goodwin, D.A., Meares, C.F., McCall, M.J., Haseman, M.K., McTigue, M., Diamanti, C.I., and Chaovapong, W. (1985) Chelate conjugates of monoclonal antibodies for imaging lymphoid structures in the mouse. J. Nucl. Med. 26:493–502.PubMedGoogle Scholar
  41. 41.
    Hnatowich, D., Virzi, F., and Rusckowski, M. (1987) Investigations of avridin and biotin for imaging applications. J. Nucl. Med. 28:1294–1302.PubMedGoogle Scholar
  42. 42.
    Goodwin, D.A., Meares, C.F., McCall, M.J., McTigue, M., Chaovapoong, W., Levy, R., and Starnes, C (1987) Pre-targeted immunoscintography with chimeric antibodies. J. Nucl. Med. 28(Supplement):561.Google Scholar
  43. 43.
    Blumenthal, R., Sharkey, R.M., Snyder, D., and Goldenberg, D.M. (1989) Reduction by anti-antibody administration of the radiotoxicity associated with I-131-labeled antibody to carcinoembryonic antigen in cancer radioimmunotherapy. J. Natl. Cancer Inst. 81:194–199.PubMedCrossRefGoogle Scholar
  44. 44.
    Schroff, R.W., Foon, K.A., Beatty, S.M., Oldham, R.K., and Morgan, A.C., Jr. (1985) Human anti-murine immunoglobulin responses in patients receiving monoclonal antibody therapy. Cancer Res: 45:879–885.PubMedGoogle Scholar
  45. 45.
    Pimm, M.V., Perkins, A.C., Armitage, N.C., and Baldwin, R.W. (1985) The characteristics of blood-borne radiolabels and the effect of anti-mouse IgG antibodies on localization of radiolabeled monoclonal antibody in cancer patients. J. Nucl. Med. 26:1011–1023.PubMedGoogle Scholar
  46. 46.
    Pollack, W., Gorman, J.G., and Freda, V.J. (1969) Prevention of Rh hemolytic disease. Prog. Hematol. 6:121–147.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1990

Authors and Affiliations

  • Robert M. Sharkey
  • Rosalyn D. Blumenthal
  • David M. Goldenberg

There are no affiliations available

Personalised recommendations