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Table 1. Factors associated with induction of immunogenicity.
Extrinsic factors
Intrinsic factors
Route (oral/subcutaneous/IM/IV)
Autologous vs. foreign
Dose (small/large)
T H epitope content**
Formulation (adjuvant effect)
Aggregates (crosslinking Ab)
Contaminants (adjuvant effect)
Glycosylation/pegylation*
*Decreases immunogenicity;
**Theoretical - See section 6.2.
6.2.2.2 Intrinsic Factors Contributing to Antibody Formation
Factors that are intrinsic to the therapeutic protein itself can also potentially contrib-
ute to immune response. For example, therapeutic proteins that tend to look more
like “self,” or with few mutations compared to wild type, are considerably less im-
munogenic than proteins that look very unique to the immune system; for example,
mutated or fused proteins that may contain novel antigenic epitopes and/or therapeu-
tic proteins that are derived from pathogens such as streptokinase (Miller, Korn,
Stevens, Janik, Gause, Kopp, Holmlund, Curti, Sznol, Smith, Urba, Donegan,
Watson, and Longo 1999; Kontsek, Liptakova, and Kontsekova 1999).
Modification of the therapeutic protein sequence from foreign (a murine mono-
clonal) to a less foreign (a humanized monoclonal) has resulted in reduced immuno-
genicity. For example, this approach reduced the immunogenicity of the Campath
therapeutic (a monoclonal anti-CD52 antibody used to treat cancer patients). Figure 1
illustrates the concept of “humanizing” monoclonal antibodies.
6.2.3 T-Independent and T-Dependent Immune Response
The pathways that lead to B-cell activation, and the resultant production of anti-
bodies, can be divided into T-cell-independent (Ti) and T-cell-dependent (Td)
categories (Table 2). Ti activation of B cells occurs when structural features of
certain molecules, such as polymeric repeats, induce the “signals” required to
stimulate activation of a B-cell subset. Ti activation of B cells results in a weaker
immune response than Td activation due to a lack of affinity maturation or of de-
velopment of B-cell memory. Conversely, Td activation of B cells results in a
robust and long-lived antibody response. Most high-affinity IgG responses to
therapeutic antibodies are T-dependent.
 
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