Biomedical Engineering Reference
In-Depth Information
IMMUNOGENICITY OF THERAPEUTIC FUSION
PROTEINS: CONTRIBUTORY FACTORS AND
CLINICAL EXPERIENCE
V
IBHA
J
AWA
,
1
L
ESLIE
C
OUSENS
,
2
AND
A
NNE
S. D
E
G
ROOT
2,3
1
Medical Sciences, Amgen Inc., Thousand Oaks, CA, USA
2
EpiVax Inc., Providence, RI, USA
3
Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA
5.1 Introduction
5.2 Basis of therapeutic protein immunogenicity
5.3 Tools for immunogenicity screening
5.4 Approaches for risk assessment and minimization
5.5 Case study and clinical experience
5.6 Preclinical and clinical immunogenicity assessment strategy
5.7 Conclusions
Acknowledgment
References
to developing new drugs as compared to small molecules,
drug developers and regulatory agencies are turning their
attention to factors that reduce protein immunogenicity as a
means of improving clinical success. Fortunately, years of
thorough study of the parameters influencing vaccine effi-
cacy allow parallels to be drawn for protein therapeutics.
Factors including delivery route, delivery vehicle, dose
regimen, aggregation, innate immune system activation,
and the ability of the protein to interface with the humoral
(B cell) and cellular (T cell) components of the immune
system all impact the intended immunogenicity of vaccine
immunogens when delivered to humans. The influence of
these factors on the unintended immunogenicity of thera-
peutic proteins is discussed here, with a particular focus on
Fc-fusion proteins, together with the use of state-of-the-art
technology in predicting and mitigating this risk. Notwith-
standing the recent advances discussed here, the current state
of science is such that clinical studies are required to
evaluate immunogenicity of protein therapeutics.
5.1
INTRODUCTION
The past two decades have been remarkable for advances in
the field of protein engineering. The impact of these advan-
ces on human health is now becoming evident. A wide
variety of biologically engineered products are already in
clinical use or under preclinical development by the bio-
technology industry. Developers are engineering novel ther-
apeutic proteins, monoclonal antibodies (mAbs), fusion
proteins, and antibody-like protein scaffolds, intent on
expanding the number of clinical applications for these
products. The caveat is that virtually all therapeutic proteins
elicit some level of immune response that can lead to loss of
efficacy or other adverse events, some of them serious; these
effects have led to costly failures in clinical trials. Thus,
while there is a greater emphasis on biologics as a pathway
5.2 BASIS OF THERAPEUTIC PROTEIN
IMMUNOGENICITY
Therapeutic protein products encompass diverse proteins
such as human cytokines, cellular growth factors, hormones,
clotting factors, enzymes, fusion proteins, and mAbs. Ther-
apeutic proteins are attractive drug products, as they are
generally considered safe, specific, and nontoxic. However,
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