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Posted on 24 February 2022 by Hanna Kurlanda-Witek

The Chemistry of Antibodies

Antibodies attacking a virus cell. Photo/Credit: Christoph Burgstedt/iStockphoto.

It was fifty years ago that Gerald M. Edelman and Rodney R. Porter were awarded the Nobel Prize in Physiology or Medicine “for their discoveries concerning the chemical structure of antibodies”. Antibodies are proteins produced by a type of white blood cell known as B lymphocytes. When an antibody comes across an antigen, or a foreign substance, it binds specifically with the antigen like a key matches a lock. The antigen is then neutralised by T lymphocytes, while the B lymphocytes make significant amounts of clones of large plasma cells, which produce more of the particular antibody – monoclonal antibodies.

Both Edelman and Porter had begun working on deciphering the structure of antibodies independently in the late 1950s. Up until that point, it wasn’t understood how our immune systems produce antibodies for each antigen and how specifically an immune response is triggered.

Molecular Giants

Working out the structure of complex organic molecules was a hot topic in those days. Francis Crick, James Watson and Maurice Wilkins were famously awarded the Nobel Prize in Physiology or Medicine in 1962 for solving the mystery of the molecular structure of nucleic acids. In that same year, Max Perutz and John Kendrew shared the Nobel Prize in Chemistry for studying large globular proteins, haemoglobin and myoglobin. Four years earlier, Frederick Sanger won his first Nobel Prize in Chemistry, on the structure of proteins, particularly insulin. Molecular biologists and chemists expected that bringing the structures to light would point the way to new discoveries, and rightly so. But identifying these molecular compounds took years. There was a limited number of laboratory methods that could be applied to this type of work, namely, electrophoresis, chromatography and X-ray crystallography. Also, the compounds are large in size (as an example, haemoglobin consists of 10,000 atoms), so it was very difficult to figure out how the molecular chains were assembled in relation to one another.

Building a Molecule

y-shaped antibodies
Y-shaped antibodies attacking SARS-CoV-2 virus. Photo/Credit: ktsimage/iStockphoto

Antibodies are very large proteins, so both Edelman and Porter devised ways of breaking them up. Porter used the protein-degrading enzyme papain to cut up the antibody, known as immunoglobulin G (or IgG), into fragments.

Edelman’s technique of using solvents to break up sulfur bonds, which linked particular polypeptide chains of the molecule like bridges, was equally successful. It was found that antibodies are composed of four polypeptide chains – two light ones and two heavy ones. Together, they form the characteristic Y shape, the “stem” of the Y being the constant element, and the two arms forming the antigen-binding sites.

Custom-made monoclonal antibodies

“Indeed, many immunologists believe that (…) immunology will have a great impact on other branches of biology and medicine”, stated Edelman in the introduction to his Nobel lecture in 1972. Only three years later, Georges Köhler and César Milstein devised a means of making large amounts of specific monoclonal antibodies by connecting antibody-producing B lymphocytes with tumour cells. This method allows the B lymphocytes to keep dividing just like a tumour cell, and the antibodies can be grown under laboratory conditions. Köhler and Milstein were awarded the Nobel Prize in Physiology or Medicine in 1984, along with Niels Jerne. Since that time, monoclonal antibodies have transformed immunology and medicine. They are used in analytic tests to diagnose a number of disorders and diseases, as well as in the treatment of autoimmune diseases, HIV, many types of cancer and recently, COVID-19. The beauty of the therapy is that these engineered antibodies help the immune system in attacking a particular targeted antigen. The number of patients cured with monoclonal antibody therapies keeps growing.

Hanna Kurlanda-Witek

Hanna Kurlanda-Witek is a science writer and environmental consultant, based in Warsaw, Poland. She has a PhD in geosciences from the University of Edinburgh, where she spent a lot of time in the lab. As someone familiar with both worlds of research and industry, she enjoys simplifying science communication across the divide.