The History of Antibodies

Overview

The earliest reference to antibodies came from Emil von Behring and Shibasabura Kitasato in 1890¹. In a landmark publication they showed that the transfer of therapeutic serum from animals immunized against diphtheria to animals suffering from it could cure the infected animals^1,2. The potential for treatment in humans was immediately apparent and Behring was later awarded the Nobel Prize for this work in 1901³.

In 1900 Paul Ehrlich, proposed the side-chain theory, where he hypothesized that side chain receptors on cells bind to a given pathogen. He was the first to propose a model for an antibody molecule in which the antibody was branched and consisted of multiple sites for binding to foreign material, known as antigen, and for the activation of the complement pathway. This model agreed with the ‘lock and key’ hypothesis for enzymes proposed by Emil Fischer^4,5.

Astrid Fagraeus in 1948 described that plasma B cells are specifically involved in antibody generation and by 1957 Frank Burnet and David Talmage had developed the clonal selection theory⁶. This stated that a lymphocyte makes a single specific antibody molecule that is determined before it encounters an antigen, which was in contrast to the instructive theory developed by Linus Pauling in 1940 where the antigen acted as a template for the antibody⁷.

By 1959 Gerald Edelman and Rodney Porter independently published the molecular structure of antibodies^8,9, for which they were later jointly awarded the Nobel Prize in 1972¹⁰. The first atomic resolution structure of an antibody fragment was published in 1973¹¹ and this was quickly followed by the invention of monoclonal antibodies¹² in 1975 by Georges Köhler and César Milstein signaling the start of the modern era of antibody research and discovery.

Figure 1: Antibody research has come a long way from its earliest reference by Emil Von Behring in 1890.

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References

1. Behring, E. a. K., S. Ueber das Zustandekommen der Diphtherie-Immunitat und der Tetanus-Immunitat bei thieren. Deutsche medizinsche Wochenschrift 16, 1113-1114 (1890).
2. Behring, E. Untersuchungen ueber das Zustandekommen der Diphtherie-Immunitat bei Thieren. Dt. Med. Wochenschr 16, 1145-1148 (1890).
3. Nobelprize.org. The Nobel Prize in Physiology or Medicine 1908
4. Fischer, E. Einfluss der Configuration auf die Wirkung der Enzyme. Berichte Der Deutschen Chemischen Gesellschaft 27, 2985-2993 (1894).
5. Lemieux, R. U., and Spohr, U. . How Emil Fischer was led to the lock and key concept for enzyme specificity. Adv Carbohydr Chem Biochem 50, 1-20 (1994).
6. Burnet, F. M. A modification of Jerne's theory of antibody production using the concept of clonal selection. CA Cancer J Clin 26, 119-121 (1976).
7. Pauling, L. A Theory of the Structure and Process of Formation of Antibodies. J. Am. Chem. Soc. 62, 2643-2657 (1940).
8. Porter, R. R. The hydrolysis of rabbit y-globulin and antibodies with crystalline papain. Biochem J 73, 119-126 (1959).
9. Edelman, G. M., Benacerraf, B., Ovary, Z., Poulik, M.D. Structural differences among antibodies of different specificities. Proc Natl Acad Sci USA 47, 1751-1758 (1961).
10. Nobelprize.org. The Nobel Prize in Physiology or Medicine 1972
11. Inbar, D., Hochman, J., and Givol, D. . Localization of antibody-combining sites within the variable portions of heavy and light chains. Proc. Natl. Acad. Sci. USA 69, 2659-2662 (1972).
12. Kohler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495-497 (1975).