Immunogenicity Predictions Development of Antidrug Antibody Responses

Protein drugs are known to elicit immune responses in patients. Immunoge-nicity was first detected a century ago with therapeutic proteins of animal origin, such as bovine and porcine insulin for the treatment of diabetes (118). Although recombinant technologies now produce proteins using fully human sequences, some patients still develop antibodies. Therapeutic proteins are often engineered with regions of "nonnatural" sequence. Novel sequences, or the novel presentation of endogenous sequences, can trigger the development of specific binding or neutralizing anti-drug antibodies. Almost all therapeutic proteins have been shown to be immunogenic; however, the incidence of antidrug antibody responses varies greatly among products.

The risks associated with drug immunogenicity depend on many factors, including the nature of the drug and the strength and duration of the antibody response. If a drug supplements an autologous protein, anti-drug antibody responses could potentially neutralize the endogenous protein as well, so the risk depends on the redundancy of the pathway targeted. If the drug is a nonautologous protein or peptide, diminished efficacy may result if the antibody response prevents target binding or significantly reduces exposure by accelerating clearance. Strong antibody responses could cause hypersensitivity reactions, which range from mild to life-threatening ones. Several excellent reviews on immunogenicity risk management strategies and bioanalytical approaches to monitoring anti-drug antibody responses have been published recently (119-121).

Development of an antibody response requires the presentation of peptide epitopes to T cells in the context of an activating costimulatory signal. In general, this transaction is mediated by professional antigen-presenting cells (APC). Besides the primary protein sequence, which will govern binding to MHC and the T-cell receptor (TCR), other factors intrinsic to a drug product may affect its immunogenicity: propensity toward self-aggregation into structures that might activate pattern recognition receptors on APC, tendency to transition into non-native forms, and the presence of other factors such as drug product contaminants (122).

Recognition of antigenic peptides by T lymphocytes can be split into two essential steps. First, a peptide bound to MHC is presented by an APC; second, the peptide-MHC complex is recognized by TCR to initiate T-cell activation. This double mechanism for recognition restricts the range of peptide sequences recognized by the system; thus, only a limited fraction of a protein sequence can elicit an immune response.

Peptides derived from therapeutic proteins are presented by MHC class II molecules, which bind peptides resulting from the cleavage of soluble proteins. The MHC class II proteins are composed of two chains encoded by several similar highly polymorphic genes, each of which binds a different range of peptide sequences (123). Degenerate binding sites on MHC proteins allow a relatively small number of different MHC molecules present in a person to recognize many different peptide sequences. This characteristic gives an individual the ability to respond to a wide range of pathogens. The surface of the TCR that interacts with the peptide-MHC class II complex is extremely variable, since the TCR repertoire is produced in part by somatic recombination. Therefore, a particular peptide-MHC complex will be recognized specifically by a particular TCR.

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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