Development of Monoclonal Antibodies: The Dawn of mAb Rule
Dig Dis Sci
Development of Monoclonal Antibodies: The Dawn of mAb Rule
Jonathan D. Kaunitz 0 1 2
0 UCLA School of Medicine Los Angeles , Los Angeles, CA 90073 , USA
1 West Los Angeles VA Medical Center , Bldg. 114/217E, 11301 Wilshire Boulevard, Los Angeles, CA 90073 , USA
2 & Jonathan D. Kaunitz
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Underlying most major therapeutic advances are
fundamental discoveries that shake scientific discourse to its
core, usually generating Nobel prizes and entirely new
fields of study. In this eighth installment of the series
entitled ‘‘Paradigm Shifts in Perspective,’’ Drs. Sofia and
Rubin highlight the considerable impact that therapeutic
monoclonal antibodies (mAbs) have made on
gastrointestinal practice.
The history of antibody development can be traced back
to the eighteenth century, with the discovery that fluid
obtained from a smallpox pustule when injected into a
recipient provided immunity from acquiring the disease.
Edward Jenner, who famously used fluid from cowpox
pustules to immunize against smallpox, advanced these
studies. The discovery of antibodies can be traced to von
Behring and Kitasato, who in 1890 published the landmark
finding that transfer of serum from animals that had been
immunized to diphtheria to animals infected with
diphtheria altered the course of the disease. Going forward to
the twentieth century, the pioneering work of Paul Ehrlich
and Emil Fischer regarding antibody configuration was
remarkably predictive of the current understanding of
antibody structure. The Nobel Prize was awarded in 1972
to Gerald Edelman and Rodney Porter for their
contributions to the understanding of the chemical structure of
antibodies.
The background to the concept of monoclonal
antibodies dates from the 1930s, when McMaster and Hudack
isolated agglutinins from lymph nodes [1]. Further work by
Harris et al. [2] identified lymphocytes as the source of
antibody production. In 1942, Bjørneboe and Gormsen,
correlated plasma cell proliferation with antibody
production, concluding that plasma cells were the primary source
of antibody production [3]. In the same year, Moore,
Kabat, and Gutman published a groundbreaking study on
the characteristics of Bence-Jones proteins characteristic of
myeloma [4]. Many studies of the 1940s–1960s focused on
physical descriptions of these proteins with suggestions of
their monoclonal origin [5, 6], with the first confirmation of
their origin from a single plasma cell clone published by
Awdeh et al. [7] from the National Institute for Medical
Research in London (NIMR).
Antibodies were traditionally made by immunizing
experimental animals with an antigen with subsequent
purification of the serum in order to isolate the antibody
fraction. In 1970, Brigitte Askonas et al. [8] from the
NIMR described a technique wherein they isolated a single
plasma cell clone that generated a homogeneous antibody,
propagated by repeated passage of spleen cells into
irradiated syngeneic mice, apparently the first description of
laboratory monoclonal antibody production. In 1975,
Ko¨ hler and Milstein published a revolutionary paper in
which they fused an antibody-producing plasma cell with a
myeloma cell, the latter, which, due to its transformed
nature, could be propagated indefinitely in culture. The
advantage of this technique is that it enabled the production
of limitless amounts of antibodies in vitro [9]. Thus, the
‘‘hybridoma’’ was born with its promise to produce
unlimited quantities of monospecific antibodies, an
innovation that changed the field of immunology forever,
recognized by the awarding of the Nobel Prize in 1984 to
Ko¨ hler and Milstein. Since 1975, refinements of the
technique have enabled the production of engineered, fully
humanized antibodies suitable for the therapy of humans
[10]. Monoclonal antibodies have been in clinical
development, with the anti-rejection monoclonal antibody
muromonab-CD3 the first monoclonal antibody to be approved
by the US Food and Drug Administration (FDA) for
clinical use in 1985 [11]. Since then, many have followed, with
the first monoclonal antibody approved for the therapy of
inflammatory bowel disease (IBD), infliximab, approved in
1988 [12].
In the accompanying article, Drs. Sofia and Rubin
provide an in-depth overview of monoclonal antibody-based
therapeutics for IBD and other digestive diseases,
treatments that have revolutionized the therapy of complex and
difficult-to-treat diseases.
1. McMaster PD , Hudack SS . The formation of agglutinins within lymph nodes . J Exp Med . 1935 ; 61 : 783 - 805 .
2. Harris TN , Grimm E , Mertens E , Ehrich WE . The role of the lymphocyte in antibody formation . J Exp Med . 1945 ; 81 : 73 - 83 .
3. Bjørneboe M , Gormsen H. Experimental studies on the role of plasma cells as antibody producers . 1942 . APMIS. 2007 ; 115 : 440 - 483 .
4. Moore DH , Kabat EA , Gutman AB. Bence-Jones proteinemia in multiple myeloma . J Clin Invest . 1943 ; 22 : 67 - 75 .
5. Osserman EF , Lawlor DP . Abnormal serum and (...truncated)