Pharmacology

The unconjugated MoAb is a structurally complex macromolecule comprising an immunoglobulin with a constant region (Fc) and a variable region (Fab) that is engineered to target a specific cell surface marker. Ideally, cell surface markers would be found solely on malignant clones; unfortunately, a cell surface marker of this type has not yet been discovered. Thus, these cell surface proteins are found not only on malignant cells, but on healthy lymphoid or myeloid cell lines as well. These agents bind to the targeted cell surface protein and form an antigen-MoAb complex, which then allows the exposed Fc fragment of the drug to activate host effector mechanisms.5 Cellular destruction can occur via two pathways: (1) complement-mediated cytotoxicity (CMC), which involves activation of complement C1q on the Fc region, leading to the formation of a membrane-attack complex that lyses the target cell and (2) antibody-dependent cellular cytotoxicity (ADCC), which occurs through binding of Fc region receptors to natural killer cells, monocytes, and macrophages, leading to opsonization of the target. Because host effector mechanisms require activation by Fc region receptors located on cell surfaces, these molecules cannot be internalized, but must remain on the cell surface in order to function.15 The immunoglobulin isotypes vary in their ability to activate these cellular functions. The IgG1 subclass is thought to be the most effective in stimulating ADCC and CMC functions in humans.6

0 0

Post a comment