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the impact of glycosylation on processing and presentation of peptides derived from
the therapeutic protein in the context of MHC to T cells.
6.2.3.5 Deimmunization by T-Cell Epitope Modification
While deimmunization by T-cell epitope modification is a relatively recent concept
in the field of therapeutics, extensive evidence for the attenuating effect of epitope
sequence modification on T-cell response exists in the context of infectious disease,
particularly with reference to immune escape from Class I and Class II restricted
immune response in viral infections (Vossen, Westerhout, Soderberg-Naucler, and
Wiertz 2002). Thus, the idea that therapeutic proteins can be modified so that they
may also “escape” immune response, thereby reducing their immunogenicity, has
been emerging in recent years, particularly since new tools for mapping T-cell epi-
topes have become widely available. A number of research teams are actively modi-
fying therapeutic proteins by mutating their amino sequences so as to eliminate the
formation of MHC Class II epitopes during intracellular processing. Ideally, these
modifications would have little effect on the therapeutic activity of the protein but
would ablate MHC Class II presentation of both “self” and “nonself” epitopes.
In the remaining sections of this chapter, we provide a rationale for the deimmu-
nization of therapeutic biologics by T-cell epitope modification. One retrospective
example supporting the concept is provided, and examples of possible applications
of the deimmunization approach to the design or redesign of therapeutic proteins are
discussed.
6.3 A New Concept: Deimmunization by T-Cell Epitope
Modification
T helper (T
H
) epitope content may explain differences in observed antibody re-
sponses to slightly different versions of the same recombinant human protein. For
example, “humanizing” chimeric antibodies so that they contain fewer T
H
epitopes,
as described above, is carried out by swapping “foreign” regions of the antibody for
regions that are more like self and has been shown to reduce immunogenicity. The
postive effect of humanization may be due at least in part to a reduction in the total
Th epitope content of the modified sequence. “Epitope content” may also influence
the propensity of any given protein to induce an immune response.
We observed, as illustrated in Fig. 2, that the immunogenicity scores of abundant
serum proteins (those contributing almost 90% of serum protein content) were lower
than expected. Antigenic proteins from pathogens such as influenza, tetanus and,
allergens, in contrast, generally scored much higher. Based on this analysis, it would
appear that some common human proteins contain significantly fewer T-cell epi-
topes, when compared to random proteins and common antigens. This preliminary
discovery, which needs to be substantiated using
in vitro
assays, may change existing
ideas about the nature of tolerance.
