Biomedical Engineering Reference
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designed to neutralize the proinflammatory cytokines IL-12
and IL-18, or IL-1 a and IL-1 b . A trispecific antibody has
been mentioned, which binds the two tyrosine kinase recep-
tors EphA2 and EphA4 as well as one of their ligands,
Ephrin 2 [41].
All companies fusing extra domains to mAbs make a
substantial effort to investigate and demonstrate the equiv-
alency of their bispecific antibody constructs to regular
mAbs with respect to productivity in Chinese hamster ovary
(CHO) cells, stability, pharmacokinetics, aggregation
behavior, and unencumbered binding affinity and specificity.
It is expected that the performance of particular bispecific
antibodies will mostly depend on the stability and properties
of the fused scFv or V H /V L elements rather than on the
bispecific format. It is obvious that all formats in Figure 35.3
exceed the size of a conventional mAb of 145-160 kDa by
increments of 25 kDa. This may impact their capability to
well penetrate into target tissue.
IgG's Fc g part as the core element for attachment of either
single-chain antibodies or diabodies. Academic laboratories
have published on bispecific antibodies attaching several
different scFvs to the N- and C-termini of Fc g part
(Figure 35.4A) [42,43]. The company Trubion (now Emer-
gent BioSolutions) is featuring a bispecific antibody format
called “SCORPION” with a total of four scFvs attached to N-
and C-termini of the Fc g part (Figure 35.4B). A SCORPION
construct with specificity for CD79B and HR (MHC II) has
been presented [44]. Asimilar construct has been described by
researchers from ZymoGenetics. They constructed an
empowered anti-angiogenic antibody with dual specificity
for VEGF-A and receptor tyrosine kinase PDGFR b for
treatment of age-related macular degeneration [45] and a
further construct targeting CD19 and CD37.
MacroGenics is using an Fc g part for attaching disulfide
bond-stabilized diabodies they call DART for “dual affinity
retargeting technology” (Figure 35.4C) [46]. Similar to
SCORPION antibody constructs, Fc-DARTs can bivalently
bind their target antigen, which will lead to high avidity
binding. Another DART format is replacing V H /V L domains
in IgG with stabilized diabodies.
The Chinese Government's National Engineering
Research Center of Antibody Medicine has presented a bis-
pecific antibody format consisting of two tandem single-chain
antibodies (scFv) 2 N-terminally fused to a Fc g
35.5 BISPECIFIC CONSTRUCTS BASED ON THE
Fcg FRAGMENT
While all bispecific antibody formats shown in Figures 35.1-
35.3 still contain CH1/kappa or lambda domains, Figure 35.4
features bispecific antibodies that have been reduced to an
domain
FIGURE 35.4 Bispecific constructs based on the Fc g part of IgG. Red and green colors highlight
variable antibody domains of distinct specificity. The Fc g part is shown in grey. Disclosed binding
specificities and particular structural features are labeled. Single-chain antibodies (scFvs) show a
peptide linker between variable domains.
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