Abstract
The impact of monoclonal antibodies (mAbs) is all around us. They transformed our discipline. The book under review is a history of how mAbs were developed, and their subsequent medical exploitation.
The focus of the book, inevitably, is human medicine. But some diseases of animals, such as foot-and-mouth disease and commercial mAbs to treat personnel exposed to anthrax spores, receive fleeting mention. I expected the narrative to be largely a paean to César Milstein, an émigré immunologist/enzyme chemist and joint recipient of the 1984 Nobel Prize for Physiology or Medicine. Indeed, Milstein looms large early in the story, and as gray eminence later on, when he advocated for transitioning commercial mAbs from murine products to chimeric, humanized, and “fully human” mAbs. Equally important, and in some ways more interesting, is the centrality of various reagent companies, most of them startups, that took the initiative of promoting mAbs as laboratory reagents. At the time, serology and immunohistochemistry relied on hard-to-standardize polyclonal antibodies. The advent of mAbs meant that serologic and immunohistochemical (IHC) assays, among others, could be greatly improved in specificity and sensitivity.
The book’s author, Dr. Lara Marks, is a medical historian. Her specialty is understanding the nexus of scientific innovation, alliances between pharmaceutical and biotechnology companies, and government regulation. Part of her theme is how small companies (Sera-Lab in the United Kingdom; Hybritech and Centocor in the United States), leveraged access to mAbs from government and university laboratories to become established businesses supplying high-quality immunologic reagents. The researcher-company relationship was particularly interesting in the case of mAbs, given that the Medical Research Council (MRC) did not patent hybridoma technology. The book covers the contrast between the United Kingdom and the United States in the 1970s and 1980s, particularly differences in patent law and national cultures of academic entrepreneurship.
Milstein, the son of Jewish immigrants, received his early training as an enzyme biochemist in Argentina. He left Argentina for good when a military coup in 1962 resulted in the firing of the director of his institute, along with several colleagues. Milstein accepted a job with the MRC in Cambridge in the United Kingdom. His research focus in the 1970s switched from enzymes to understanding the variable region of antibodies and the underlying genetics. To that end, his laboratory needed antibodies of defined specificity. His group’s initial insight was to immortalize lymphocytes by combining them with myeloma cell lines. It was a surprise to find that Milstein and coinventors took a little time to grasp the wide-ranging implications of immortalized monospecific antibodies. He was not alone. The original hybridoma paper, although published in Nature (1975;256:495–497), was not accorded full paper status. Milstein, a naturally modest man, was often asked the question of who really “discovered” monoclonal technology. His answer was that the 1975 paper resulted from close collaboration between him, postdoctoral fellow Georges Köhler, and Shirley Howe, a skilled technician.
As the impact of mAbs dawned on people, Milstein and others wrote several editorial pieces explaining how they might be exploited. He collaborated with others outside his field, such as neurophysiologists, essentially as demonstration projects for how mAbs might be used as basic and applied reagents. As late as 1978, when the first mAb to detect a human leukocyte differentiation antigen was developed, editors of the Journal of Experimental Medicine rejected the resultant manuscript as having “little scientific interest.” The paper was eventually published in the European Journal of Immunology (1979;9:205-210). It became a citation classic.
Milstein and Köhler were later criticized for not patenting hybridomas, a decision made by the UK’s National Research Development Corporation and not them. When queried about whether he was unhappy at the “failure” to patent such a basic medical advance, Milstein wryly remarked “I was not unhappy. Margaret Thatcher was.”
I am skeptical of Marks’s claim that the impact of mAbs is comparable to that of genetic engineering, particularly when she addresses their rise as therapeutic agents. The marketing of mAb drugs such as rituximab occupy much of the latter part of the book, as companies moved from the small beer of laboratory reagents to the more profitable poitín of humanized mAbs used to treat cancer and immune-mediated diseases. The book might have benefitted by dilating more on the many interesting personalities involved, commercial and academic, but that’s Wyoming nitpicking. This is a well-researched, finely written book. It is scrupulously referenced (55 pages). At $40 it is not cheap, even as a hardback. It provides valuable insights into the translation of research from benchtop to commercial laboratory reagent.