Biomedical Engineering Reference
In-Depth Information
IIIB MULTIFUNCTIONAL ANTIBODIES
35
RESURGENCE OF BISPECIFIC ANTIBODIES
P ATRICK A. B AEUERLE AND T OBIAS R AUM
Amgen Research (Munich) GmbH, Munich, Germany
35.1 A brief history of bispecific antibodies
35.2 Asymmetric IgG-like bispecific antibodies
35.3 Symmetric IgG-like bispecific antibodies
35.4 IgG-like bispecific antibodies with fused antibody fragments
35.5 Bispecific constructs based on the Fc g fragment
35.6 Bispecific constructs based on Fab fragments
35.7 Bispecific constructs based on diabodies or single-chain
antibodies
35.8 Bifunctional fusions of antibodies or fragments with other
proteins
35.9 Bispecific antibodies for various functions: how to select the
right format?
References
by fusing hydridoma lines of rat and mouse origin. Secreted
antibodies no longer had mixed heavy and light chains but
formed one defined rat IgG2b/mouse IgG2a bispecific anti-
body species because of a preferential species-restricted
heavy/light chain pairing [2]. Catumaxomab (Removab 1 )
is a bispecific antibody using this technology which, in
2009, was the first bispecific antibody to obtain market
approval [3].
In parallel to the quadroma technology, Brennan et al. [4]
succeeded in 1985 in chemically cross-linking antibody
fragments in high yield and free of monovalent species.
Recently, chemical cross-linking of antibody fragments still
is a viable technology for making bispecific antibodies. For
instance, it was the basis for generating MDX-210, a
HER2/CD64 (Fc g RI)-bispecific F(ab) 2 antibody, which
has been broadly explored in clinical trials [5].
Staerz et al. [6] were first to demonstrate redirected lysis
of cancer cells by T cells with the help of a bispecific
antibody cross-linking the two different cell types. Corvalan
and Smith [7] produced an antibody bispecific for carci-
noembryonic antigen (CEA) and vinca alkaloids, which can
be considered an early prototype of today's popular antibody
drug conjugate (ADC) format. Since then, we have seen a
spade of different bispecific antibodies, which have been
described in numerous review articles (for example, [8-10]).
Frequently, new bispecific antibodies are constructed for
the purpose of redirected cancer cell lysis [10]. However,
one should not forget that regular human IgG1 or IgG3
antibodies can function as nature's bispecific antibodies by
tethering immune and target cells. Their bifunctionality
resides in binding arms that attach to the target antigen,
and in the CH2 domain of the Fc g fragment, which can bind
to Fc g receptors on cytotoxic immune cells. Another appar-
ently natural form of bispecific antibody results from Fab-
arm exchange among antibodies of the human IgG4 class
35.1 A BRIEF HISTORY OF BISPECIFIC
ANTIBODIES
Bispecific antibodies have a history of at least 25 years. With
the simultaneous availability in the 1980s of monoclonal
antibody (mAb), hybrid-hybridoma (or quadroma), and
recombinant DNA technologies, it became possible to gener-
ate antibodies containing two different sets of variable
domains. In a brief time period between 1983 and 1987, the
most essential technologies and biomedical applications were
already elaborated, which have been influential until today.
A first example of a bispecific mAb, which for a diag-
nostic purpose is binding to somatostatin and horse radish
peroxidase, was described by Milstein and Cuello [1]. They
fused two hydridoma lines into one hybrid-hybridoma line
secreting various combinations of the heavy and light
chains of the two mAbs, including the desired bispecific
variant. In themid-1990s, Lindhofer refined this technology
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