Biomedical Engineering Reference
In-Depth Information
5.7 CONCLUSIONS
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The ability to analyze and prospectively predict the immu-
nogenicity of a potential protein therapeutic has tremendous
benefits at every stage of the drug development process.
Fusion-protein-based biotherapeutics can pose an immuno-
genicity risk due to their structural differences from con-
ventional fully human monoclonal or recombinant protein
therapeutics. Reliable in silico immunogenicity screening
makes it possible to rank lead candidates at the preclinical
stage of development and/or reengineer proteins to make
them less immunogenic. Moving forward in the preclinical
development process, in vitro methods and in vivo animal
models are important for validating the in silico findings.
The in vitro methods can also address any non-sequence
post-translational and manufacturing-associated changes
such as aggregation or contaminants. Owing to limitations
of the in silico and in vitro approaches, these assessments
cannot substitute for clinical studies during drug develop-
ment. Further downstream, the measurement of immunoge-
nicity in patients enrolled in Phase I/II clinical trials of
protein therapeutics should reflect the considerations taken
in the preclinical process and provide additional opportuni-
ties to refine a lead candidate should anti-drug immunity
arise. Finally, rigorous data collection in clinical trials may
confer the ability to identify prospectively individuals at a
higher risk of developing an antidrug response, such as by
HLA typing, where alternative therapies would be indicated.
ACKNOWLEDGMENT
The contributions of Ryan Tassone and Frances Terry, of
EpiVax, to the process of illustrating and curating this
manuscript, are gratefully acknowledged.
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