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aplastic anemia were associated with exposure to just one formulation of rEPO,
suggesting that factors extrinsic to the protein itself were associated with the
adverse outcome (Haselbeck 2003). Currently, evidence suggests that this
adverse effect was associated with the development of aggregates due to the
reformulation of the therapeutic product (Prabhakar and Muhlfelder 1997;
Rosenberg 2003).
6.2.1.2 Neutralizing Antibodies
Antibodies that interfere with the function of a therapeutic product may not have as
severe consequences for the patient as cross-reactive antibodies, but they can have a
dramatic effect on the efficacy of the therapy. Neutralizing antibodies have been
observed to common biological therapeutics such as insulin, factor VIII, and beta
interferon. In some cases, where different forms of the product are available (e.g.,
insulin, factor VIII), changing treatment to an alternative has allowed for continued
use of the therapy. In addition, as is the case with clotting factors, modifying the
dose of the therapy regimen has been shown to induce tolerance. However, this ap-
proach is clinically intensive and success is not assured.
6.2.1.3 Nonneutralizing Antibodies
Nonneutralizing antibodies, which do not interfere with the function of the
biologic, also known as binding antibodies, are the most common form of anti-
therapeutic protein antibody. In some cases, nonneutralizing antibodies to thera-
peutic compounds have been noted in patients who have never been exposed to
the compounds, suggesting that some anti-human protein antibodies are naturally
occurring.
6.2.2 Factors Contributing to the Development of Antibodies
6.2.2.1 Extrinsic Factors Contributing to Antibody Formation
Route, dose, and formulation are among a set of extrinsic factors that can influ-
ence the immunogenicity of therapeutic proteins (Table 1) (Rosenberg 2003).
Contamination of the product with proinflammatory or nonspecific mitogenic
compounds such as LPS and the development of product aggregates can provide
the critical “second signal” (Signal 2) to the T-cell that is required for induction
of T-cell help. In addition, proteins that are denatured during formulation may be
more immunogenic than their native counterparts (Braun, Kwee, Labow, and
Alsenz 1997), as these products may present new T- and B-cell epitopes that
were not present in the parent molecule, leading to the stimulation of an immune
response (Josic, Buchacher, Kannicht, Lim, Loster, Pock, Robinson, Schwinn,
and Stadler 1999). In contrast, glycosylation and pegylation reduce the immu-
nogenicity of therapeutic proteins. Modification of extrinsic factors such as route,
dose, purity, formation of aggregates, and formulation has been used to reduce
immunogenicity.
