Biomedical Engineering Reference
In-Depth Information
the case for many recombinant ligand-based molecules such
as erythropoietin, immunogenicity to therapeutic antibodies
is rarely directly life threatening. However, reduced drug
exposure due to development of antidrug antibodies can
reduce efficacy and have a significant impact on the approv-
ability and utility of such therapeutics. Unfortunately, no
tool has yet been able to clearly predict immunogenicity in
humans. As the key amino acid interactions that drive
preferential heterodimerization in SEED reside largely at
the interface of the IgG and IgA heavy chain residues within
the CH3 domain core, the opportunity exists to alter the
surface exposed residues to those most typical of an IgG in a
surface veneering approach.
2. Licastro F, Chiappelli M, Ianni M, Porcellini E. (2009) Tumor
necrosis factor-alpha antagonists: differential clinical effects
by different biotechnological molecules. Int. J. Immunopathol.
Pharmacol. 22, 567-572.
3. Strohl WR. (2009) Optimization of Fc-mediated effector
functions of monoclonal antibodies. Curr. Opin. Biotechnol.
20, 685-691.
4. Teicher BA. (2009) Antibody-drug conjugate targets. Curr.
Cancer Drug Targets. 9, 982-1004.
5. Presta LG. (2008) Molecular engineering and design of thera-
peutic antibodies. Curr. Opin. Immunol. 20, 460-470.
6. Lu D, Zhang H, Ludwig D, Persaud A, Jimenez X, Burtrum D,
Balderes P, Liu M, Bohlen P, Witte L, Zhu Z. (2004) Simulta-
neous blockade of both the epidermal growth factor receptor
and the insulin-like growth factor receptor signaling pathways
in cancer cells with a fully human recombinant bispecific
antibody. J. Biol. Chem. 279, 2856-2865.
7. Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponu-
goti AH, Wiedemeyer R, Stegh AH, Bradner JE, Ligon KL,
Brennan C, Chin L, DePinho RA. (2007) Coactivation of
receptor tyrosine kinases affects the response of tumor cells
to targeted therapies. Science 318, 287-290.
8. Baeuerle PA, Reinhardt C. (2009) Bispecific T-cell engaging
antibodies for cancer therapy. Cancer Res. 69, 4941-4944.
9. Kohler G, Milstein C. (1975) Continuous cultures of fused cells
secreting antibody of predefined specificity. Nature 256, 495-
497.
10. Milstein C, Cuello AC. (1983) Hybrid hybridomas and their
use in immunohistochemistry. Nature 305, 537-540.
11. Milstein C, Cuello AC. (1984) Hybrid hybridomas and the
production of bi-specific monoclonal antibodies. Immunol.
Today 5, 299-304.
12. Carter P. (2001) Bispecific human IgG by design. J. Immunol.
Methods 248, 7-15.
13. Brennan M, Davison PF, Paulus H. (1985) Preparation of
bispecific antibodies by chemical recombination of monoclo-
nal immunoglobulin G1 fragments. Science 229, 81-83.
14. Glennie MJ, McBride HM, Worth AT, Stevenson GT. (1987)
Preparation and performance of bispecific F(ab
0
gamma)2
antibody containing thioether-linked Fab
0
gamma fragments.
J. Immunol. 139, 2367-2375.
15. Atwell JL, Pearce LA, Lah M, Gruen LC, Kortt AA, Hudson
PJ. (1996) Design and expression of a stable bispecific scFv
dimer with affinity for both glycophorin and N9 neuramini-
dase. Mol. Immunol. 33, 1301-1312.
16. George AJT, Huston JS. (1997) Bispecific antibody engineer-
ing. In: Zanetti M, Capra J. D. (Eds), The Antibodies, Vol. 4,
Harwood Academic Publishers.
17. Seimetz D, Lindhofer H, Bokemeyer C. (2010) Development
and approval of the trifunctional antibody catumaxomab (anti-
EpCAM x anti-CD3) as a targeted cancer immunotherapy.
Cancer Treat. Rev. 36, 458-467.
18. Ridgway JB, Presta LG, Carter P. (1996) Knobs-into-holes
engineering of antibody CH3 domains for heavy chain hetero-
dimerization. Protein Eng. 9, 617-621.
37.5 CONCLUSIONS
There are a growing number of engineered antibody plat-
forms, ranging greatly in complexity that offer new opportu-
nities to create biotherapeutic candidates to meet specific
purposes. Within the catalog of options, the SEED platform
offers certain advantages that enable significant flexibility. In
particular, the heavy chain interface design strongly drives
selective heterodimerization in a platform that can be highly
expressed in conventional mammalian cell systems. More-
over, final products retain the critical drug-like properties of
conventional antibodies, including expression, effector func-
tion, biophysical characteristics, and in vivo behavior. By
addition of biologically active building blocks, whether they
are binding arms, active ligands, or receptor components, a
wide variety of mono or multifunctional therapeutic candi-
dates can be constructed that can be designed to address many
diverse clinical opportunities (Figure 37.6 ). The true potential
of this platform awaits final validation in the clinic.
ACKNOWLEDGMENTS
We gratefully acknowledge the contributions, support, and
expert advice from many scientists at EMD Serono, and in
particular Chaomei He, Emmi Kurosawa, Rene Schweick-
hardt,MelanieDugas,Maria Soloviev, AnnaBernhardt, David
Fischer, John S. Wesolowski, Berend Neuteboom, Xuliang
Jiang, Paul Towler, Kris Josephson, AroopSircar, TerryBrush,
Nina Crowley, Angela Lim, Sue McKenzie, and Scott Lauder.
In addition we thank Georg Feger, Steve Arkinstall, and
Robert Campbell for their encouragement and support.
REFERENCES
1. Via MC. (2009) Monoclonal Antibodies: Pipeline Analysis and
Competitive Assessment. Cambridge Healthtech Institute,
Needham, MA, USA.
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