Modern Antibody Applications: Standing on the Shoulders of Giants

Contributed by Jane Naberhuis, Ph.D.

Applications for antibodies in research and medicine have evolved tremendously since antibodies were first described in the late 1800s. The very first Nobel Prize in Physiology or Medicine was awarded in 1901 for work related to antibodies. Since then, the prize has been awarded an additional six times for antibody-related discoveries.

1901, Emil von Behring - “for his work on serum therapy, especially its application against diphtheria…1 Von Behring discovered that injecting small doses of weakened diphtheria bacteria into an animal led to a release of “antitoxins” within the blood. Furthermore, transferring antitoxin-containing serum into animals infected with diphtheria cured the animal’s symptoms.2 This observation sparked great interest in expanding the use of passive serum therapy.

1908, Ilyich Mechnikov and Paul Ehrlich - "in recognition of their work on immunity."3 Mechnikov and Ehrlich had different theories on how the immune system is primed to respond to an infection. Mechnikov posited that a host uses special cells to engulf and destroy bacteria. He termed these cells “phagocytes,” and the process “phagocytosis.”4 Ehrlich, on the other hand, theorized that, like the lock-and-key specificity of enzymatic reactions, cells within the body produced specific antibody side chains to recognize and defend against pathogens.5

1972, Gerald M. Edelman and Rodney R. Porter - "for their discoveries concerning the chemical structure of antibodies."6 Edelman and Porter both tackled the question of antibody structure by breaking antibodies into smaller, more easily studied pieces. Edelman accomplished this through chemical means, while Porter used protein-cleaving enzymes. The results of these differing methods were later combined to provide a more complete picture of antibody structure, the Y-shaped molecule we know today.7

1977, Rosalyn Yalow - "for the development of radioimmunoassays of peptide hormones."8 Yalow developed the radioimmunological assay (RIA). Using this sensitive new technique, she elucidated the physiology of insulin, growth hormone, and adrenocorticotropic hormone, which had previously been impossible given the low concentration of these hormones in blood.9

1984, Niels Jerne, Georges Köhler, and César Milstein - “for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies.10 Jerne theorized that the body has an arsenal of antibodies available, and selects the one necessary to fend off an invader. This was contrary to popular opinion of the time that the immune system produced custom antibodies after detecting an invader. Jern also described immune system control, built on the idea that antibodies can act as antigens themselves, leading to a self-regulating network.11 Kohler and Milsteain fused a tumor cell with a normal antibody-producing cell, forming an immortal hybrid capable of producing a specific antibody.11 Thus, monoclonal antibody production was born.

1987, Susumu Tonegawa - “for his discovery of the genetic principle for generation of antibody diversity.12 The body generates millions of antibody proteins, each capable of defending against a specific pathogen. It was Tonegawa who explained how this degree of antibody diversity was possible given that the body only possesses tens of thousands of genes. Genetic information for antibody protein production is contained in multiple gene segments along a chromosome. Tonegawa discovered that during development of antibody-producing B-lymphocytes, these gene segments are assembled by recombination.13 Thus, an enormous number of possible combinations can be generated from a comparatively small number of genes.

2018, James Allison and Tasuku Honjo - “for their discovery of cancer therapy by inhibition of negative immune regulation.”14 Allison developed an antibody that could bind cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and Honjo discovered programmed cell death protein 1 (PD-1). Through different mechanisms, these two proteins act as brakes on the immune system.15,16 Targeting CTLA-4 and PD-1 with antibodies, deemed immune checkpoint therapy, has significantly transformed modern cancer treatment and improved prognosis for certain patients with cancer.

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References

1. Nobel Media. Nobel Prize in Physiology or Medicine 1901.  http://www.nobelprize.org/nobel_prizes/medicine/laureates/1901/. February 10, 2019.

2. Nobel Media. The Nobel Prize in Physiology or Medicine 1901 - Speed Read. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1901/speedread.html. February 10, 2019. 

3. Nobel Media. The Nobel Prize in Physiology or Medicine 1908. https://www.nobelprize.org/prizes/medicine/1908/summary/. February 10, 2019.

4. Brown H. 1995. Ilya Mechnikov and his studies on comparative inflammation. Proc Soc Exp Biol Med. Jun;209(2):99-101.

5. Piro A, Tagarelli A, Tagarelli G, et al. 2008. Paul Ehrlich: the Nobel Prize in physiology or medicine 1908. Int Rev Immunol. Jan-Apr;27(1-2):1-17.

6. Nobel Media. The Nobel Prize in Physiology or Medicine 1972. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1972/. February 10, 2019.

7. Raju T. 1999. The Nobel Chronicles. Lancet. Sep;354(9183):1040.

8. Nobel Media. The Nobel Prize in Physiology or Medicine 1977. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1977/. February 10, 2019.

9. Glick S. 2011. Rosalyn Sussman Yalow (1921-2011). Nature. Jun;474(7353):580.

10. Nobel Media. The Nobel Prize in Physiology or Medicine 1984. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1984/. February 10, 2019.

11. Raju T. 2000. The Nobel Chronicles. Lancet. Jan;355(9197):75. 

12. Nobel Media. The Nobel Prize in Physiology or Medicine 1987.  http://www.nobelprize.org/nobel_prizes/medicine/laureates/1987/. February 10, 2019.

13. Tonegawa S. 1983. Somatic Generation of Antibody Diversity. Nature. Apr;302:575-81.

14. Nobel Media. The Nobel Prize in Physiology or Medicine 2018. https://www.nobelprize.org/prizes/medicine/2018/summary. February 10, 2019.

15. Ishida Y, Agata Y, Shibahara K, et al. 1992. Induced expression of PD-1, a novel member of

the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. Nov;11(11):3887-95.

16. Freeman GJ, Long AJ, Iwai Y, et al. 2000. Engagement of the PD-1 immunoinhibitory receptor by a

novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. Oct;192(7):1027-34.