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described in this chapter, including methods for identifying the amino acids that need
to be changed using immunoinformatics; measurement of binding of the modified
peptide to HLA and measurement of T-cell response by ELISpot. Changes to amino
acid sequences, however minimal, can have serious consequences on protein func-
tion. This chapter will also describe the need for careful structural modeling and
confirmation of activity and decreased immunogenicity
in vitro
and
in vivo
. Epitope-
directed deimmunization will also be contrasted with other existing techniques such
as pegylation.
6.1.2 Dimensions of the Problem
A number of therapeutic proteins have been shown to induce T-cell-dependent IgG
antibody responses when used as biologics (Koren, Zuckerman, and Mire-Suis 2002;
Stein 2002; Ryff and Schellekens 2002). The prevalence of antidrug antibodies
ranges from less than 1% for drugs such as tissue plasminogen activator (Nilsson,
Nilsson, Jansson, Boman, Soderberg, and Naslund 2002) to over 70% for drugs such
as OKT3, a murine monoclonal antibody (Jensen, Birkeland, Rohrp, Elbirk, and
Jorgensen 1996; Chatenoud 1993). The clinical impact of these antibodies can range
from no effect (nonneutralizing or binding antibodies) or some loss of efficacy (neu-
tralizing antibodies) to severe reactions such as anaphylaxis.
Antitherapeutic antibodies can also develop to recombinant human protein or a
humanized monoclonal antibody, products that should not, in theory, breach toler-
ance (Diamond 2003; Wadhwa, Mellstedt, Small, and Thorpe 2003). The basis for
the development of T-cell responses to autologous proteins is not well understood.
However, it is well known that autologous proteins, including many proteins used in
therapy, are not devoid of immunogenic potential. T-cell responses to a number of
autologous proteins have been associated with autoimmunity, as is clearly the case
with diabetes (Fowell and Mason 1993; Reijonen, Novak, Kochik, Heninger, Liu,
Kwok, and Nepom 2002) and multiple sclerosis (MS) (Forsthuber, Shive, Wienhold,
de Graaf, Spack, Sublett, Melms, Kort, Racke, and Weissert 2001; Keech, Farris,
Beroukas, Gordon, and McCluskey 2001).
6.2 Components of the Immune Response to Biologicals
6.2.1 Types of Antibodies to Biological Therapeutics
6.2.1.1 Cross-Reactive Antibodies
One of the most significant safety concerns related to the clinical use of thera-
peutic proteins is the formation of neutralizing antibodies that cross-react with or
neutralize autologous counterparts. For example, cross-reactive antibodies have
been associated with the development of aplastic anemia following treatment
with recombinant erythropoietin (rEPO). This severe form of anemia was shown
to be due to the development of antibodies cross-reactive with endogenous
erythropoietin (Casadevall, Nataf, Viron, Kolta, Kiladjian, Martin-Dupont,
Michaud, Papo, Ugo, Teyssandier, Varet, and Mayeux 2002). These cases of
