They are tiny magic bullets that are quietly shaping the lives of millions of patients around the world. Produced in the lab, invisible to the naked eye, relatively few people are aware of these molecules' existence or where they came from. Yet monoclonal antibodies are contained in six out of ten of the world’s bestselling drugs, helping to treat everything from cancer to heart disease to asthma.
Known as Mabs for short, these molecules are derived from the millions of antibodies the immune system continually makes to fight foreign invaders such as bacteria and viruses. The technique for producing them was first published 40 years ago. It was developed by César Milstein, an Argentinian émigré, and Georges Köhler, a German post-doctoral researcher. They were based at the UK Medical Research Council’s Laboratory of Molecular Biology in Cambridge.
Harnessing the power of the immune system
Milstein and Köhler wanted to investigate how the immune system can produce so many different types of antibodies, each capable of specifically targeting one of a near-infinite number of foreign substances that invade the body. This had puzzled scientists ever since the late 19th century, but an answer had proved elusive. Isolating and purifying single antibodies with known targets, out of the billions made by the body, was a challenge.
The two scientists finally solved this problem by immunising a mouse against a particular foreign substance and then fusing antibodies taken from its spleen with a cell associated with myeloma, a cancer that develops in the bone marrow. Their method created a hybrid cell that secreted Mabs. Such cells could be grown indefinitely, in the abdominal cavity of mice or in tissue culture, producing endless quantities of identical antibodies specific to a chosen target. Mabs can be tailored to combat a wide range of conditions.
When Milstein and Köhler first publicised their technique, relatively few people understood its significance. Editors of Nature missed its importance, asking the two scientists to cut short their article outlining the new technique; as did staff at the British National Research Development Corporation, who declined to patent the work after Milstein submitted it for consideration. Within a short period, however, the technique was being adopted by scientists around the world, and less than ten years later Milstein and Köhler were Nobel laureates.
A transformation in therapeutic medicine
In the years that have passed since 1975, Mab drugs have radically reshaped medicine and spawned a whole new industry. It is predicted that 70 Mab products will have reached the worldwide market by 2020, with combined sales of nearly $125bn (£81bn).
Key to the success of Mab drugs are the dramatic changes they have brought to the treatment of cancer, helping in many cases to shift it away from being a terminal disease. Mabs can very specifically target cancer cells while avoiding healthy cells, and can also be used to harness the body’s own immune system to fight cancer. Overall, Mab drugs cause fewer debilitating side-effects than more conventional chemotherapy or radiotherapy. Mabs have also radically altered the treatment of inflammatory and autoimmune disorders like rheumatoid arthritis and multiple sclerosis, moving away from merely relieving symptoms to targeting and disrupting their cause.
Aside from cancer and autoimmune disorders, Mabs are being used to treat over 50 other major diseases. Applications include treatment for heart disease, allergic conditions such as asthma, and prevention of organ rejection after transplants. Mabs are also under investigation for the treatment of central nervous disorders such as Alzheimer’s disease, metabolic diseases like diabetes, and the prevention of migraines. More recently they were explored as a means to combat Ebola, the virus disease that ravaged West Africa in 2014.
Fast and accurate diagnosis
Mabs have enabled faster and more accurate clinical diagnostic testing, opening up the means to detect numerous diseases that were previously impossible to identify until their advanced stages. They have paved the way in personalised medicine, where patients are matched with the most suitable drug. Mabs are intrinsic components in over-the-counter pregnancy tests, are key to spotting a heart attack, and help to screen blood for infectious diseases like hepatitis B and AIDS. They are also used on a routine basis in hospitals to type blood and tissue, a process vital to ensuring safe blood transfusion and organ transplants.
Mabs are also invaluable to many other aspects of everyday life. For example they are vital to agriculture, helping to identify viruses in animal livestock or plants, and to the food industry in the prevention of the spread of salmonella. In addition they are instrumental in the efforts to curb environmental pollution.
Yet Mabs remain hidden from public view. This is partly because the history of the technology has often been overshadowed by the groundbreaking and controversial American development of genetic engineering in 1973, which revolutionised the manufacturing and production of natural products such as insulin, and inspired the foundation of Genentech, one of the world’s first biotechnology companies.
Looking back, the oversight is not surprising. Mabs did not transform medicine overnight or with any major fanfare, and the scientists who made the discovery did not seek fame. Instead, Mabs quietly slipped unobserved into everyday healthcare practice.
An Argentinian and a German came together in a British Laboratory and changed the face of medicine forever; their story deserves to be told.
Lara Marks has received funding from the UK Medical Research Council. She has research affiliations with Cambridge University and King's College London. She is author of 'The Lock and Key of Medicine: Monoclonal antibodies and the transformation of healthcare' (Yale University Press, 2015).
Authors: The Conversation