IMMUNOLOGY
`
`The iquest }or a magic bullet
`Widely used in science and medicine today, monoclonal
`antibodies got off to a rocky start
`
`The Lock and Key of Medicine
`Monoclonal Antibodies and the
`Transformation of Healthcare
`Lara V. Marks
`Yale University Press, 2015.
`344pp.
`
`By Sudhakaran Prabakaran
`
`I n a cold January evening in 1975,
`
`postdoctoral fellow Georges Kohler
`brought his wife to the lab to keep
`him company as he checked on his
`latest experiment. Far from the un(cid:173)
`eventful evening he anticipated, what
`he observed that night would transform the
`world of drug development and disease treat(cid:173)
`ment. "I looked down at the first two plates.
`I saw these halos .... It was the best result I
`could think of;' he recalls. The halos were
`evidence that the cells in the pet1i
`dish were secreting highly specific
`antibodies. Dubbed "monoclonal
`antibodies;' or Mabs, they would
`have a radical influence on both
`science and medicine in the years
`that followed.
`In her book, The Lock and Key
`of Medicine, Lara Marks presents
`a compelling, well-researched ac(cid:173)
`count of the discovery of Mabs
`and the development of Mab(cid:173)
`based treatments and therapies.
`The book also narrates the chal(cid:173)
`lenges faced by Cesar Milstein
`(Kohler's postdoctoral adviser)
`and his collaborators, from pat(cid:173)
`enting their findings to raising;
`money for further testing and
`scaling up production. It is an ex(cid:173)
`cellent account of all the impedi-
`ments the researchers faced in bringing
`Mabs from the bench to the market. Per(cid:173)
`sonal stories of the major players involved
`are skillfully interwoven with the narrative,
`bringing a human face to the drug discov(cid:173)
`ery process.
`In the early 1970s, Kohler and Milstein
`were studyin:!1; the variable regions of anti(cid:173)
`bodies-the proteins that recognize foreign
`molecules and tag them for destruction(cid:173)
`with the hope of understanding how diverse
`populations of antibodies are generated
`by the mammalian immune system. In the
`course of their studies, they developed a
`technique that enabled the mass production
`of antibodies designed to recognize a spe(cid:173)
`cific antigen. The technique involved fusing
`a myeloma cell with an antibody-producing
`
`The reviewer is at Science Signaling, AAAS, Washington, DC
`20005, USA. E-mail: sprabaka@aaas.org
`
`SCIENCE sciencemag.org
`
`Gesar Milstein (left), Georges Kohler (right), and Niels Jerne (not pictured) were
`awarded the Nobel Prize in 1984 for their work on monoclonal antibodies.
`
`B cell taken from the spleen of an immu(cid:173)
`nized mouse. The B cell provided the immu(cid:173)
`nological specificity, whereas the myeloma
`lent immortality to the construct.
`These hybrid cells, or hybridomas as they
`were later called, became a vehicle for thou(cid:173)
`sands of other biomedical inventions. How(cid:173)
`ever, the initial reception to this breakthrough
`was lukewarm. When they tried to publish
`their results, the editors at Nature reportedly
`requested that the article be shortened and
`did not feature it prominently in the journal,
`and their patent application was rejected.
`
`Milstein sent samples and protocols of his
`newly created antibody-secreting cell lines to
`other research institutions and even trained
`scientists to generate their own hybridomas.
`One such scientist who benefited from this
`goodwill was Hilary Koprowski, director
`of the Wistar Institute in Philadelphia. The
`first patents for monoclonal antibodies were
`granted to Koprowski and his colleagues in
`October 1979 (for Mabs targeting influenza
`antigens) and April 1980 (for Mabs target(cid:173)
`ing tumor antigens). The ''Wistar patents"
`proved controversial in the scientific com(cid:173)
`munity, because the antibodies had been cre(cid:173)
`ated using the cell lines originally supplied
`by Milstein.
`In the years that followed, there was an
`explosion in Mab research. Some were gener(cid:173)
`ated to identify different types of white blood
`cells, and several proved to be important in
`investigating HIV/AIDS. The first medical
`
`application of this technology used Mabs to
`purify interferons, signaling proteins that are
`released by cells in response to the presence
`of pathogens.
`Mabs were soon being used to identify
`blood group types, an application that radi(cid:173)
`cally improved the accuracy and cost of
`blood typing. This now-routine test has since
`saved millions of lives.
`After these initial success stories, many
`clinicians and founders ofbiotech companies
`began to believe that Mabs were "magic bul(cid:173)
`lets" for diagnosing and curing diseases. In
`1979, Koprowski cofounded Cento(cid:173)
`cor, one of the original companies
`that exploited Mabs to diagnose
`cancer, cardiovascular disorders,
`and liver problems. The fortunes
`of Centocor ebbed and flowed dur(cid:173)
`ing the 1980s and 1990s. It was
`acquired by Johnson & Johnson in
`1999 and is known today as Jans(cid:173)
`sen Biotech. It is one of the few
`original companies still in exis(cid:173)
`tence today.
`In 1995, edrecolomab (Panorex)(cid:173)
`a Mab developed in mice-was
`licensed by German authorities
`as an adjuvant therapy for post(cid:173)
`operative colorectal cancer.
`It
`was the first Mab-based cancer
`therapeutic to proceed to mar(cid:173)
`ket. In 1997, rituximab (Rituxan),
`a chimeric (part human and part
`mouse) Mab, was authorized by the FDA to
`treat B cell lymphoma. It was later found to
`be beneficial in the treatment of rheumatoid
`arthritis as well.
`By 2012, there were more than 30 Mab
`drugs on the market, generating more than
`$50 billion in revenue (IO of which gener(cid:173)
`ated profits exceeding $1 billion each). The
`number of Mab-based therapies (and their
`market share) will likely increase with time.
`Marks has done great justice to the
`topic, although the book would have been
`strengthened by the inclusion of additional
`illustrations and a broader discussion of the
`impact of Mabs on basic science. This book
`is in many ways a tribute to Kohler and Mil(cid:173)
`stein, which makes the timing of its publi(cid:173)
`cation (just over 40 years since tha:t fateful
`January evening) all the more appropriate.
`
`10.1126/science.aac5603
`
`24 JULY 2015 • VOL 349 ISSUE 6246 389
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`1 of 1
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`Celltrion, Inc., Exhibit 1023
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