Non TargetMediated Elimination Mechanisms

Both intracellular and extracellular proteolytic processes contribute to nonspecific elimination of protein and peptide therapeutics. These processes could potentially be affected by genetic polymorphisms or disease-related alterations in gene expression, as has been described for the SOCS-targeted proteolytic degradation of specific receptors (see sect. "Target-Mediated Elimination Pathways"). No Pgx studies have been published on these protein clearance mechanisms.

Antibody-bound protein therapeutics may form immune complexes that are rapidly cleared by the reticuloendothelial systems (phagocytic cells in the skin, liver, and spleen). Genetic variability may influence this elimination pathway, both by favoring formation of anti-drug antibodies (see sect. "Immunogenicity Predictions") and through the FcR-mediated events that initiate clearance of immune complexes (see sect. "Effects of Upstream and Downstream Processes").

Clearance of proteins modified with specific carbohydrate residues may be mediated by the mannose receptor on macrophages or asialoglycoprotein receptor (ASGP-R) on parenchymal hepatocytes. The ASGP-R has been investigated as a nonviral carrier for gene therapy transduction and as a potential method of improving tumor targeting of protein therapeutics and imaging agents (74,75). If a glycosylated protein drug is subject to ASGP-R binding, rapid distribution phase elimination may limit exposures. Recombinant tissue plas-minogen activator, and the experimental drugs lenercept and recombinant neutrophil inhibitory factor are subject to this mechanism (76-78). Although the number of glycoproteins in therapeutic development has increased with construction of soluble receptor fusion proteins, Pgx investigations of ASGP-R variants have not yet been published.

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