Magic Bullets to Blockbusters Marian Turner Delves Into a History of the Rapid Rise of Monoclonal Antibodies

BOOKS & ARTS COMMENT

IMMUNOLOGY Magic bullets to blockbusters Marian Turner delves into a history of the rapid rise of monoclonal antibodies.

n 2003, freshly graduated from ‘Humanized’ also describes what Marks university, I made a monoclonal anti- has done for the antibody story. The Lock and body. After weeks of waiting for the mice Key of Medicine presents rich details of who Ithat I had immunized with Acanthamoeba at which institute collaborated with whom parasites to mount a robust immune on which scientific advance or commerciali- response, I fused some of their spleen cells zation process, and when. The meticulous to cells derived from a mouse myeloma can- accounts sometimes blur, but they convey cer. The aim: to generate immortal hybri- a deep sense of the cumulative thought and doma cells, from which I could purify an effort embodied in today’s antibody technol- LTD/SPL HOLMES/CELLTECH JAMES endless stream of specific antibodies that ogies, and remind us that interdisciplinary bound to the parasites. and international collaborations are not new. The protocol I used was a barely refined Readers in the field will appreciate the atten- version of one described by biologists César tion paid to defining episodes, such as the Milstein and Gorges Köhler in the United HLDA workshops starting in 1982, which Kingdom almost three decades before. resulted in classification and verification sys- Hybridoma technology spawned the broad- tems that brought coherence to the expand- reaching field of monoclonal antibodies, ing catalogue of monoclonal antibodies. which is celebrated by historian of medicine In the closing chapters, Marks describes Lara Marks in The Lock and Key of Medicine. some of the monoclonals that have become Essential reagents in any cell-biology labo- blockbuster drugs: rituximab, infliximab and ratory, monoclonal antibodies are now also trastuzumab. The stories of these antibodies common in medicine, from pregnancy testing reflect how serendipitous clinical outcomes, to blood typing and disease diagnostics. such as cancer drugs successfully treating Marks begins by summarizing scien- The fundamental protocol for making monoclonal arthritis, have led to deeper understanding tists’ early attempts to understand protec- antibodies has changed little in 40 years. of the biology of both classes of disease. tive immunity and vaccination. The term There are some surprising gaps. There is magic bullets, coined by German physician by focused commercialization, leading to no mention of the catastrophic 2006 phase I Paul Ehrlich (who died 100 years ago next an exponential rise in patents and several clinical trial of the monoclonal antibody month) in his 1897 description of antibodies, intellectual-property battles. Although some TGN1412, manufactured by TeGenero is held up as an early beacon of researchers’ scientists have found this unpalatable, anti- to treat cancer and autoimmune diseases. hopes for antibodies in medicine. As Marks body-related royalties have been ploughed The drug induced multiple organ failure in shows, the hypotheses of pioneering scien- back into medical research — by 2012, the six healthy volunteers, caused by an unan- tists, amazingly, have often only just missed UK Medical Research Council’s patents alone ticipated extreme immune reaction called a the mark. Ehrlich’s description of a cell pro- had earned £486 million (US$770 million). cytokine storm. The episode led to a revision ducing ‘side chains’ that break off as anti- The possible ways of modifying antibod- of European guidelines for first-in-human bodies in response to encountering foreign ies have surged in the 40 years since Milstein trials. Also missing is a discussion of mono- substances is remarkably close to our current and Köhler published their hybridoma pro- clonal antibodies that block the immune knowledge of surface immunoglobulins and tocol. Marks discusses the generation of anti- regulatory proteins PD-1 or CTLA-4, which secreted antibodies. The book’s early chapters body fragments, chimaeric antibodies and are arguably the hottest up-and-coming also chronicle how physicians of the 1920s ‘humanized’ antibodies — products from agents in cancer therapy today, or of the use and 1930s developed serum-based therapies non-human cells that of HIV-specific monoclonal antibodies for decades before anyone understood the basic have been modified treatment and vaccine design. mechanisms of antibody action. to reduce unwanted But it is a fast-paced field. The history of There were high hopes for the revenue immune responses. monoclonal antibodies ricochets between potential of monoclonal antibodies, but The unfolding anti- basic science, the clinic and the commercial not everyone was convinced at first. Marks body story paralleled world, and The Lock and Key of Medicine describes how the National Research and advances in recombi- documents how lessons from one sphere Development Corporation in the United nant-DNA technol- have repeatedly led to advances in another. Kingdom initially failed to see the practical ogy and transgenic Marks concludes by pointing out that mono- applications. As a result, the original hybri- animal models, which clonal antibodies have received less fanfare doma technology was not patented. In 1979 made such alterations The Lock and than their biotechnological peers, genetic and 1980, US scientists won patents for essen- possible. Yet it is mind- Key of Medicine: engineering and stem cells. Her thorough Monoclonal tially equivalent technology using myeloma boggling that the first Antibodies and the telling of this rich history goes some way cells provided by Milstein — a development humanized antibodies Transformation of towards restoring the balance. ■ that left many in Britain chagrined, including were made before the Healthcare then-prime minister Margaret Thatcher. advent of DNA-ampli- LARA V. MARKS Marian Turner is a senior News & Views Such early hiccups were soon replaced fication technology. Yale Univ. Press: 2015. editor for Nature.