Biomedical Engineering Reference
In-Depth Information
34
BREAKING NEW THERAPEUTIC GROUNDS:
FUSION PROTEINS OF DARPINS AND OTHER
NONANTIBODY BINDING PROTEINS
H
ANS
K
ASPAR
B
INZ
Molecular Partners AG, Schlieren, Switzerland
34.1 Introduction
34.2 Novel scaffolds—alternatives to antibodies
34.3 New therapeutic concepts with nonantibody binding proteins
34.4 Scaffold-fusion proteins beyond antibody possibilities
Acknowledgments
References
in a vast field of novel therapeutic innovations. This accel-
eration of research will lead to a more rapid identification
of relevant novel therapeutic approaches and interesting
new drugs, ultimately to the benefit of patients lacking
appropriate treatment possibilities.
34.2 NOVEL SCAFFOLDS—ALTERNATIVES
TO ANTIBODIES
34.2.1 Success and Limitations of Antibodies
34.1
INTRODUCTION
The successful use of monoclonal antibodies for therapeutic
applications has revolutionized modern medicine. Drugs
with predefined target molecule-binding properties can be
designed at will and due to a high degree of therapeutic
validation; there is little toxicology risk on the molecule's
side, minimizing side effects to mostly mechanism-related
toxicology. Consequently, all major pharmaceutical compa-
nies run therapeutic antibody platforms for drug develop-
ment. Currently, two main therapeutic approaches are used
in the monoclonal antibody field: One antibody application
is to target soluble cytokines removing them from the blood.
Another successful application is to use antibodies specifi-
cally binding targets on tumor cells and recruiting effector
functions to the site of binding. The success of both
approaches is exemplified by several blockbuster antibody
drugs. Recently, it became evident that the commercial
success of monoclonal antibodies is only partly reflected
in therapeutic efficacy. For example, bevacizumab currently
struggles to deliver clinical benefit in all of its approved
indications [1]. A next generation drug thus should build on
Monospecific antagonistic monoclonal antibodies and ago-
nistic biologics are among the commercially most successful
drugs. This success is in contrast to increasing evidence that
several of these proteins exhibit limited therapeutic efficacy.
Redundant signaling pathways and other escape mecha-
nisms may lead to such limits. One way to achieve efficacy
beyond the one of currently approved drugs is to combine
these simple mechanisms of action at will, bringing together
a multitude of functionalities in one drug. While fusion
proteins are an ideal platform for such a task, antibody-based
fusion approaches show clear technical limitations due to the
molecular properties of the immunoglobulin fold and pro-
duction issues. DARPins (designed ankyrin repeat proteins)
are highly stable and more favorably behaved alternatives to
antibodies, which can bind target molecules with high
affinity and specificity. DARPins are currently in clinical
development for various therapeutic applications. DARPins
and other alternatives to antibodies clearly overcome the
technical limitations of antibodies and enable fast research
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