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In-Depth Information
Chapter 6
Immunoinformatics Applied to Modifying
and Improving Biological Therapeutics
Anne S. De Groot,
1,2
Paul M. Knopf, Daniel Rivera,
2
and William Martin
2
1
Brown University, Department of Medicine, Providence, RI 02912, USA
2
EpiVax, Inc., 146, Clifford Street, Providence, RI 02903, USA, AnnieD@EpiVax.com
1,2
Abstract.
Protein therapeutics have recently emerged as a viable means of treating chronic
diseases and are beginning to rival small-molecule drugs in market share. Although their
promise of targeted therapy is a major medical advance, repeated administrations in many
cases lead to development of antitherapeutic antibodies that compromise treatment. Multiple
sources of immunogenicity are considered in this chapter with a focus on the T-cell-dependent
immune response. Development of high-affinity antibodies depends on activation of T
helper cells by antigen presentation. Disruption of antigen presentation in an antigen-
specific manner would be a rational solution to this problem. Here we present the powerful
combination of recombinant protein expression and immunoinformatic and molecular
modeling tools as a means of reducing immunogenicity by modification of T-cell epi-
topes. This approach promises to bring to the clinic safer protein therapeutics both as
first- and second-generation products.
6.1 Introduction
6.1.1 Deimmunization Defined
The number of therapeutic protein products available for use in clinical settings has
dramatically increased in recent years. This category of biomedical products, also
known as biological therapeutics, includes neuromuscular antagonists such as
botulinum toxin, cytokines such as alpha interferon, growth factors, hormones, and
monoclonal antibodies. Biological therapeutics are generally considered to be safe
and non-toxic. The production and purification of therapeutic proteins has now be-
come extremely efficient, and a number of such products are commonly used in
today's standard medical practice.
Unfortunately, the use of these products in clinical practice is often associated
with the development of antibodies directed against the therapeutic proteins. These
anti-therapeutic protein antibodies may neutralize or otherwise compromise the
clinical effect of the biologics and can also be associated with serious adverse events
