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such as autoimmunity. Examples of anti-biologic therapeutic antibodies include
antibodies to botulinum toxin and antibodies to erythropoietin (Vuong and Jankovic
2005; Haselbeck 2003).
Deimmunization, the subject of this chapter, is the process of modifying biologi-
cal therapeutics so as to diminish the development of anti-biological therapeutic
antibodies. Until recently, reduced immunogenicity could only be achieved by care-
ful formulation of the biologic therapeutic, and in some cases, pegylation of the
protein (see below). One of the more recent means of deimmunizing proteins is to
apply immunoinformatics tools to identify T-cell epitopes, and then to use related
tools to select and modify amino acids contained in those T-cell epitopes. These
modifications, achieved using immunoinformatics tools followed by
in vitro
and
in
vivo
confirmation, may lead to improved biological therapeutics characterized by
significantly diminished immunogenicity profiles.
6.1.1.1 Sources of Biologic Therapeutic Immunogenicity
Several mechanisms for the induction of antibodies against therapeutic proteins have
been described. These have included (1) inadvertent formulation of the biologic with
proinflammatory contaminants or adjuvants (Haselbeck 2003); (2) formation of
immunogenic aggregates; and (3) T-cell-dependent antibody formation. Drug manu-
facturers have developed methods for addressing the first two mechanisms, including
improvements in the purity and formulation of recombinant protein products. The
third mechanism for anti-therapeutic antibody formulation involves the adaptive arm
of the cellular immune system and the presentation of epitopes derived from the
therapeutic proteins to T cells in the context of human leukocyte antigen (HLA)
molecules.
HLA class II molecules are genetically encoded on chromosome 6 and expressed
as cell-surface proteins on antigen-presenting cells (APC). Class II HLA molecules
are involved with the presentation of peptide epitopes derived from therapeutic
proteins to T cells, engendering a T-cell-dependent immune response. For more
information on HLA-epitope binding see Finkelman, Lees, and Morris (1992).
6.1.1.2 Epitope-Directed Deimmunization
This chapter will discuss a new immunoinformatics-driven strategy for reducing
the immunogenicity of biological therapeutics, which is to eliminate HLA class II
peptide epitopes by minimal amino acid replacement. This application of immu-
noinformatics to the modification of protein therapeutics is termed “epitope-
directed deimmunization”.
Without such epitopes, helper T-cell (T
H
) stimulation is avoided; induction of
both humoral and cell-mediated adaptive immunity is significantly diminished, along
with the potential for adverse clinical events. T
H
-mediated induction of immunologi-
cal memory is also compromised, reducing affinity maturation of antibodies and
encouraging apoptosis (death) of the antigen-specific T and B lymphocytes.
Immunoinformatics is but one of the tools that must be applied in the process of
epitope-directed deimmunization. Each step in this new approach to therapeutics is
