Abstract
The ability to label antigens and antibodies with simple chemicals and even with whole proteins fostered new approaches to basic studies of the immune system as well as new methods of immunodiagnosis and immunotherapy. This was especially true following the introduction of monoclonal antibodies, which enhanced the specificity of many of these applications. The uses to which these labeled immunoreagents were put were legion, and those who employed them might come from any field of biology or medicine. Many of these technical elaborations were critical to progress in immunology and in many other biomedical sciences. They illustrate also the often complex interplay between technology and theory.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ehrlich, P. The Collected Papers of Paul Ehrlich Vol. 3, 59 (Pergamon, London, 1960).
Keating, P. & Cambrosio, A. J. Hist. Biol. 27, 449–479 (1994).
Obermeyer, F. & Pick, E.P. Wien. klin. Wochenschr 19, 327–334 (1906); Pick, E.P. Biochimie der Antigene in Handbuch der pathogenen Mikroorganismen 2nd edn. Part I 685–868 (Fischer, Jena, 1912).
Further testimony to the rapid expansion of interest in these techniques is provided by Immunocytochemistry: Practical Applications in Pathology and Biology (eds. Polak, J.M. & Van Noorden, S.) (J. Wright, Bristol, 1983). In just 3 years between the first and second editions (1983–1986), the size increased from 396 to 703 pages.
Landsteiner, K. & Lampl, H.Z. Immunitätsforsch 26, 258–276; 293–304 (1917); also Landsteiner's magnum opus The Specificity of Serological Reactions (Dover, New York, 1962). This is a reprint of the second edition (Harvard University Press, Cambridge, 1945).
D. W. Talmage discussed degeneracy in the context of Burnet's clonal selection theory in Science 129, 1643–1648 (1959).
Landsteiner, K. & van der Scheer, J. J. Exp. Med 67, 709–723 (1938); Kabat, E.A. J. Immunol. 77, 377–385 (1956) and 97, 1–11 (1966).
Pressman, D.P. Adv. Biol. Med. Physics 3, 100–152 (1953); Karush, F. Adv. Immunol. 2, 1–40 (1962).
Kabat, E.A. Structural Concepts in Immunology and Immunochemistry (Rinehart & Winston, New York, 1968); Pressman, D.P. & Grossberg, A. The Structural Basis of Antibody Specificity (Benjamin, New York, 1968).
Eisen, H.N. & Karush, F. J. Am. Chem. Soc. 71, 363–364 (1949).
Sabin, F. J. Exp. Med. 70, 67–82 (1939).
Nairn, R.C. in Fluorescent Protein Tracing 3rd edn. 95–110 (Williams & Wilkins, Baltimore, 1964).
The first use of radiolabeled antigen was that of Libby, R.L. & Madison, C.R. J. Immunol 55, 15–26 (1947); they studied the distribution of radiophosphorus-labeled tobacco mosaic virus.
Pressman, D., Yagi, Y. & Hiramoto, R. Int. Arch. Allergy 12, 127–136 (1958).
Dixon, F.J., Talmage, D.E. & Maurer, P.E. J. Immunol 68, 693–700 (1952); Waldmann, T.A. & Strober, W. Progr. Allergy 13, 1–110 (1969).
Campbell, D.H. & Garvey, J.S. Adv. Immunol. 3, 261–313 (1963). Dan Campbell had been a student of Pauling's, as had David Pressman.
Heidelberger, M., Kendall, F.E. & Soo Hoo, C. J. Exp. Med. 58, 137–152 (1933).
Farr, R.S. J. Infect. Dis 103, 239–262 (1958). Polyethylene glycol was also used as the precipitating agent by Debuquois, B. & Auerbach, G.D. J. Clin. Endocrinol. Metab. 33, 732–738 (1971).
Yalow, R.S. & Berson, S.A. J. Clin. Invest 39, 1157–1175 (1960). Yalow shared the Nobel Prize in physiology or medicine for 1977 for this discovery.
Avrameas, S.P., Druet, P., Masseyeff, R. & Feldmann, G. Immunoenzymatic Techniques (Elsevier, Amsterdam, 1983).
Carroll, M.C. Annu. Rev. Immunol. 16, 545–568 (1998).
Villiers, M.B. J. Immunol 162, 3647–3652 (1999); Rest, S.T. Infect. Immun. 69, 3031–3040 (2001).
Reiner, L. Science 72, 483–484 (1930).
Breinl, F. & Haurowitz, F. Z. Physiol. Chem. 192, 45–57 (1930).
Breinl, F. & Haurowitz, F.Z. Immunitätsforsch. 77, 176–186 (1932).
Marrack, J.R. Nature 133, 292–293 (1934).
Coons, A.H. J. Immunol. 87, 499–503 (1961).
Coons, A.H., Creech, H.J. & Jones, R.N. Proc. Soc. Exp. Biol. Med. 47, 200–202 (1941).
Coons, A.H., Creech, H.J., Jones, R.N. & Berliner, E. J. Immunol. 45, 159–170 (1942). Coupling via the isothiocyanate in place of the more difficult isocyanate derivative was introduced by Riggs, J.L. et al. Am. J. Pathol. 34, 1081–1097 (1958).
Hijmans, W. & Schaeffer, M. (eds.). Fifth International Conference on Immunofluorescence and Related Staining Techniques. Ann. NY Acad. Sci. 254, (1975); Nairn, R.C. Fluorescent Protein Tracing 4th edn. (Churchill Livingstone, Edinburgh, 1976); Knapp, W., Holubar, K. & Wick, G. Immunofluorescence and Related Staining Techniques (Elsevier, New York, 1978); Larsson, L.-I. Immunocytochemistry: Theory and Practice (CRC Press, Boca Raton, Florida, 1988).
Coons, A.H., Leduc, E.H. & Connolly, J.M. J. Exp. Med. 102, 49–60 (1955). Another 'sandwich' method involves the conjugation of a hapten to the antibody, with development of color using fluorescein-labeled anti-hapten, Lamm, M.E. et al. Proc. Natl. Acad. Sci. USA 69, 3732–3736 (1972); Wofsy, L. et al. J. Exp. Med. 140, 523–537 (1974).
Silverstein, A.M. J. Histochem. Cytochem. 5, 94–95 (1957); Hiramoto, R., Engel, K. & Pressman, D.P. Proc. Soc. Exp. Biol. Med. 97, 611–614 (1958).
Coons, A.H., Leduc, E.H. & Connally, J.M. J. Exp. Med. 102, 49–60 (1955); this conclusion had earlier been reached by Astrid Fagreaus in Antibody production in relation to the development of plasma cells. Acta Med. Scand. 204 (Suppl.) (1948).
Ortega, L.G. & Mellors, R.C. J. Exp. Med. 106, 627–640 (1957).
Chu, A.C. Immunocytochemistry in dermatology. in Immunocytochemistry 2nd edn. (eds. Polak, J.M. & Van Noorden, S.) 618–637 (Wright, Bristol, 1986); Unanue, E.R. & Dixon, F.J. Adv. Immunol. 6, 1–90 (1967); Elias, J.M. Immunohistopathology: A Practical Approach to Diagnosis (ASCP Press, Chicago, 1990).
Nakane, P.K. & Pierce, G.B. J. Histochem. Cytochem. 14, 929–931 (1966); Avrameas, S. & Lespinats, G. C.R. Acad. Sci. Paris 265, 1149–1153 (1967); Avrameas, S. Immunochemistry 6, 43–52 (1969).
The many uses of this approach are detailed in chapters 3–7 of Cuello, A.C. (ed.). Immunohistochemistry (New York, John Wiley, 1983). The technique has largely been superseded by an immunoenzyme sandwich method in which the enzyme binds to an antibody-combining site rather than being attached chemically (Sternberger, L.A. & Cuculis, J.J. J. Histochem. Cytochem. 17, 190 (1969); Sternberger, L.A. Immunocytochemistry 4th edn. (John Wiley, New York, 1989)).
Mason, D.Y. & Sammons, R.E. J. Clin. Pathol. 31, 454–462 (1978). For applications of this technique using monoclonal antibodies, Boorsma, D.M. Histochemistry 80, 103–106 (1984).
Edwards, J.C. & Moon, C.R. in Immunodiagnosis of Cancer 2nd edn. (eds. Herberman, R.B. & Mercer, D.W.) 95–106 (Decker, New York, 1990).
For example, Hunt, S.P., Allanson, J. & Mantyh, P.W. Radioimmunocytochemistry. in Immunocytochemistry 2nd edn. (eds. Polak, J.M. & Van Noorden, S.) 99–114 (Wright, Bristol, 1986).
Coggi, G., Dell'Orto, P. & Viale, G. in Immunocytochemistry 2nd edn. (eds. Polak, J.M. & Van Noorden, S.) 54–70 (Wright, Bristol, 1986).
Towbin, H., Staehelin, T. & Gordon, J. Proc. Natl Acad. Sci. USA 76, 4350–4354 (1979).
Galfré, G. & Milstein, C. Methods Enzymol. 73, 3–46 (1981); Cuello, A.C., Milstein, C. & Galfré, G. in Immunohistochemistry (ed. Cuello, A.C.) 215–256 (John Wiley, New York, 1983).
Polak, J.M. & Varndell, I.M. (eds). Immunolabeling for Electron Microscopy (Elsevier, Amsterdam, 1984).
Mason, D.Y. et al. in Monoclonal Antibodies in Clinical Medicine (eds. McMichael, A.J. & Fabre, J.) 585–635 (Academic Press, London, 1982).
Singer, S.J. Nature 183, 1523–1524 (1959).
Uranium: Sternberger, L.A. et al. Exp. Mol. Pathol. 4, 112–125 (1965); iron: Yamamoto, N., Acta Histochem. Cytochem. 10, 246–262 (1977); mercury: Kendall, P.A., Biochim. Biophys. Acta 97, 174–176 (1965).
Faulk, W.P. & Taylor, G. Immunochemistry, 8, 1081–1083 (1971); De May, J.R. in Immunohistochemistry (ed. Cuello, A.C.) 347–372 (John Wiley, New York, 1983).
Roth, J. J. Histochem. Cytochem. 31, 987–999 (1983).
Romano, E.L. & Romano, M. Immunochem. 14, 711–715 (1977).
Varndell, I.M. & Polak, J.M. in Immunolabeling for Electron Microscopy (eds. Polak, J.M. & Varndell, I.M.) 155–177 (Elsevier, Amsterdam, 1984).
McCluskey, R.T., Benacerraf, B. & McCluskey, J.W. J. Immunol 90, 466–477 (1963); Feldman, J.D. & Najarian, J.S. J. Immunol. 91, 306–312 (1963); Prendergast, R.A. J. Exp. Med. 119, 377–388 (1964).
Bain, B. & Lowenstein, L. Science 145, 1315–1316 (1964); Dupont, B. & Hansen, J.A. Adv. Immunol. 23, 107–202 (1976).
Möller, G. J. Exp. Med. 114, 415–434 (1961); Cerottini, J.-C. & Brunner, K.T. Immunology 13, 395–403 (1967).
Raff, M.C., Sternberg, M. & Taylor, R.B. Nature 225, 553–554 (1970).
Loken, M.R. & Herzenberg, L.A. Ann. NY Acad. Sci. 254, 163–171 (1975); Herzenberg, L.A. & De Rosa, S.C. Immunol. Today 21, 383–390 (2000).
Cambrosio, A. & Keating, P. Med. Anthropol. Quarterly 6, 362–384 (1992). Also Cambrosio and Keating's Biomedical Platforms (MIT Press, Cambridge, Massachusetts, 2003).
Nomenclature for clusters of differentiation (CD) of antigens defined on human leukocyte populations. Bull. World Health Org. 62, 809–811 (1984); Shaw, S. Immunol. Today 8, 1–3 (1987). For the application of FACS to cell surface markers, Herzenberg, L.A. (ed.). Weir's Handbook of Experimental Immunology 5th edn. Vol. II Cell Surface and Messenger Molecules of the Immune System (Blackwell Scientific, Cambridge, Massachusetts, 1996).
Chess, L. & Schlossman, S.F. Adv. Immunol. 25, 213–241 (1977).
A useful general review of the broad field of cancer immunotherapy is by Vitetta, E.S. et al. in Fundamental Immunology 5th edn. (ed. Paul, W.E.) 1621–1659 (Lippincott Williams & Wilkins, New York, 2003).
Héricourt, J. & Richet, C. C.R. Acad. Sci 120, 948–950; 121, 567–569 (1895); Salvati, V. & de Gaetano, L. Riforma Med. 11, 495–507 (1895).
Sell. S. (ed.). Serological Cancer Markers (Humana Press, Totowa, New Jersey, 1992); Garrett, C.T. & Sell, S. (eds.). Cellular Cancer Markers (Humana Press, Totowa, New Jersey, 1995).
Vogel, C.-W. Immunoconjugates: Antibody Conjugates in Radioimaging and Therapy of Cancer (Oxford University Press, New York, 1987); Antibody Immunoconj. Radiopharmaceut. 2 (1989, special issue); Chatal, J.-F. (ed.). Monoclonal Antibodies in Immunoscintigraphy (CRC Press, Boca Raton, Florida, 1989); Goldenberg, D.M. (ed.). Cancer Imaging with Radiolabeled Antibodies (Kluwer, Boston, 1990); Perkins, A.C. & Pimm, M.V. Immunoscintigraphy: Practical Aspects and Clinical Applications (Wiley-Liss, New York, 1991).
Pressman, D.P. & Keighly, G. J. Immunol. 59, 141–146 (1948); this approach was then used by Pressman, D.P. & Korngold, L. Cancer 6, 619–623 (1953) and by Pressman, D.P. & Day, E.D. Cancer Res. 17, 845–850 (1957).
The history of early attempts at the immunodetection of tumors is reviewed by Goldenberg, D.M. in Cancer Imaging with Radiolabeled Antibodies (ed. Goldenberg, D.M.) 3–9 (Kluwer, Boston, 1990).
Köhler, G. & Milstein, C. Nature 256, 495–497 (1975). The history of monoclonal antibody technology and its influence on various basic and clinical fields can be found in Cambrosio, A. & Keating, P. Exquisite Specificity: The Monoclonal Antibody Revolution (Oxford University Press, New York, 1995).
Saccavini, J.C., Bohy, J. & Bruneau, J. in Monoclonal Antibodies in Immunoscintigraphy (ed. Chatal, J.-F.) 61–73 (CRC Press, Boca Raton, Florida,1989).
Gansow, O.A. et al. in Cancer Imaging with Radiolabeled Antibodies (ed. Goldenberg, D.M.) 153–171 (Kluwer, Boston, 1990).
Gohr-Rosenthal, S. et al. Invest. Radiol. 28, 789–795 (1993).
Remsen, L.G. et al. Am. J. Neuroradiol. 17, 411–418 (1996).
Bashford, E.F., Murray, J.A. & Haaland, M. Sci. Rep. Imper. Cancer Res. Fund 3, 396 (1908).
Hauschka, T.S. Cancer Res. 12, 615–633 (1953).
Bagshawe, K.D. Drug Dev. Res. 34, 220–230 (1995); Senter, P.D. & Springer, C.J. Adv. Drug Del. Rev. 53, 247–264 (2001).
Pressman, D.P. J. Allergy 22, 387–396 (1951). He pointed out that 1 milligram of antibody could carry as much as 100 millicuries of 131I.
Ada, G.L. & Byrt, P. Nature 222, 1291–1292 (1969); Humphrey, J.H. & Keller, H.U. in Developmental Aspects of Antibody Formation and Structure Vol. 2 (eds. J. Ŝterzl & I. R̂iha) 485–502 (Academic Press, New York, 1970); Ada, G.L. in Developmental Aspects of Antibody Formation and Structure Vol. 2 (eds. J. Ŝterzl & I. R̂iha) 503–519 (Academic Press, New York, 1970).
Burnet, F.M. The Clonal Selection Theory of Acquired Immunity (Cambridge University Press, London, 1959).
Volkman, D.J. et al. J. Exp. Med. 156, 634–639 (1982); Vitetta, E.S. et al. Science 219, 644–650 (1983).
Goldenberg, D.M. (ed.). Cancer Therapy with Radiolabeled Antibodies (CRC Press, Boca Raton, Florida, 1995); Wahl, R.L. in Diagnostic Nuclear Medicine 4th edn. (eds. Sandler, M.P. et al.) 969–985 (Lippincott Williams & Wilkins, New York, 2003).
Mishima, Y. (ed.). Cancer Neutron Capture Therapy (Kluwer, Boston, 1996).
Bale, W.F. Proc. Nat. Cancer Conf. 2, 967–976 (1952).
Hall, W.A. (ed.). Immunotoxin Methods and Protocols (Humana Press, Totowa, New Jersey, 2000).
Moolten, F.L. & Cooperband, S.R. Science 169, 68–70 (1970); also Thorpe, P.E. et al. Nature 271, 752–755 (1978).
Houston, L.L. & Ramakrishnan, S. in Immunoconjugates: Antibody Conjugates in Radioimaging and Therapy of Cancer (ed. Vogel, C.-W.) 71–96 (Oxford University Press, New York, 1987). A list of the various immunotoxins and their applications is given by Thrush, G.R. et al. Annu. Rev. Immunol 14, 49–71 (1996).
Kahan, B.D., Rajagopalan, P.R. & Hall, M.L. Transplantation 67, 276–284 (1999); Vincent, F. et al. N. Engl. J. Med. 338, 161–165 (1998).
Vallera, D.A. in Immunotoxins (ed. Frankel, A.E.) 515–535 (Kluwer, Boston, 1988); Bachier, C.R. & LeMaistre, C.F. in Monoclonal Antibody-Based Therapy of Cancer (ed. Grossbard, M.L.) 211–227 (Marcel Dekker, New York, 1998).
Mathé, G., Loc, T.B. & Bernard, J. C.R. Acad. Sci. 246, 1626–1628 (1958). Ghose et al. later used a chlorambucil conjugate, Brit. Med. J. 3, 495–499 (1972).
These include aminopterin, methotrexate, idarubicin, doxorubicin, vindesine, cisplatin, mitomycin C, adriamycin, daunamycin and cytosine arabinoside; Blair, A.H. & Ghose, T.I. J. Immunol. Methods 59, 129–143, 1983; Sela, M. & Hurwitz, E. in Immunoconjugates: Antibody Conjugates in Radioimaging and Therapy of Cancer (ed. Vogel, C.-W.) 189–216 (Oxford University Press, New York, 1987); Pietersz, G.A. et al. Antibody Immunoconj. Radiopharmaceut. 3, 27–35 (1990).
Vogel, C-W. in Immunoconjugates: Antibody Conjugates in Radioimaging and Therapy of Cancer (ed. Vogel, C.-W.) 170–188 (Oxford University Press, New York, 1987).
Sievers, E.L. et al. J. Clin. Oncol. 19, 3244–3254 (2001).
Bagshawe, K.D. Brit. J. Cancer 56, 531–532 (1987); Senter, P.D. et al. Proc. Natl. Acad. Sci. USA 85, 4842–4846 (1988); Melton, R.G. & Knox, R.J. Enzyme-Prodrug Strategies for Cancer Therapy (Kluwer, New York, 1999).
Mew, D. et al. J. Immunol 130, 1473–1477 (1983); Yarmush, M.L. et al. Crit. Rev. Ther. Drug Carrier Syst. 10, 197–252 (1993).
Wat, C.-K. et al. Progr. Clin. Biol. Res. 170, 351–359 (1984); Oseroff, A.R. et al. Proc. Natl. Acad. Sci. USA 83, 8744–8748 (1986).
Torchilin, V.P. Immunomethods 4, 244–258. The entire issue is devoted to liposome technology and applications.
Ghetie, M.A. et al. Blood 80, 2315–2320 (1992); Flavell, D.J. et al. Int. J. Cancer 62, 1–8 (1995).
Smallshaw, J.E. Nat. Biotechnol. 21, 387–391 (2003); Kreitman, R.J. Nat. Biotechnol. 21, 372–374 (2003).
Bjorn, M.J. & Villemez, C.L. in Immunotoxins (ed. Frankel, A.E.) 255–277 (Kluwer, Boston, 1988); Fidias, P. in Monoclonal Antibody-Based Therapy of Cancer (ed. Grossbard, M.L.) 281–307 (Marcel Dekker, New York, 1998).
Morrison, S.L. et al. Proc. Natl. Acad. Sci. USA 81, 6851–6855 (1984); Boulianne, G.L., Hozumi, N. & Shulman, M.J. Nature 312, 643–646 (1984); Reichmann, L. et al. Nature 332, 323–327 (1988); Winter, G. & Harris, W.J. Immunol. Today 14, 243–246 (1993).
A recombinant IT, by fusing two antibody variable domains to pseudomonas toxin, was described by Chaudhary, V.K. et al. Nature 339, 394–397 (1989); Brinkmann, U. et al. Proc. Natl. Acad. Sci. USA 90, 7538–7542 (1993); Pastan, I. & Kreitman, R.J. Investigational Drugs 3, 1089–1091 (2002).
Green, L.L. et al. Nat. Genet. 7, 13–21 (1994); Little, M., Kipriyanov, S.M., Le Gall, F. & Moldenhauer, G. Immunol. Today 21, 364–370 (2000).
For Fvs, Owens, R.J. & Young, R.J. J. Immunol. Methods 168, 149–165 (1994); for T cell receptors, Shusta, E.V. Nat. Biotechnol. 7, 754–759 (2000).
Boder, E.T. & Wittrup, K.D. Nat. Biotechnol. 15, 553–557 (1997); Feldhaus, M.J. et al. Nat. Biotechnol. 21, 163–170 (2003).
Boder, E.T., Midelfort, K.S. & Wittrup, K.D. Proc. Natl. Acad. Sci. USA 97, 10701–10705 (2000); Holler, P.D. et al. Proc. Natl. Acad. Sci. USA 97, 5387–5392 (2000); van den Beuken, T. et al. FEBS Lett. 546, 288–294 (2003).
Foote, J. & Eisen, H.E. Proc. Natl. Acad. Sci. USA 97, 10697–10681 (2000).
The technological revolution that would accompany monoclonal antibodies was not immediately apparent at the time, even to its authors. Thus, the editors of Nature might be forgiven for having rejected the Köhler-Milstein manuscript as not worthy to appear as a scientific report. They consigned it to the middle of a very long list of letters.
Rheinberger, H.-J. Stud. Hist. Philos. Sci. 23, 305–331 (1992).
Adrian, E.D. The Mechanism of Nervous Action. Electrical Studies of the Neurone 4 (University of Pennsylvania Press, Philadelphia, 1932).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Silverstein, A. Labeled antigens and antibodies: the evolution of magic markers and magic bullets. Nat Immunol 5, 1211–1217 (2004). https://doi.org/10.1038/ni1140
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni1140
This article is cited by
-
Single-cell screening of multiple biophysical properties in leukemia diagnosis from peripheral blood by pure light scattering
Scientific Reports (2017)
-
Fluorescently-tagged anti-ganglioside antibody selectively identifies peripheral nerve in living animals
Scientific Reports (2015)
-
A new immunosensing method by galactose oxidase-mediated electrocatalysis using a virtual beaker array
Biotechnology Letters (2006)