Immune Effector Function
Antibody Mechanisms of Action
The preferred type of unconjugated antibody for target cell-killing applications, e.g., for elimination of cancer cells, is an IgG1-type monoclonal antibody, where at least the constant region is of human origin. Unconjugated IgG1 antibodies exert their therapeutic effects via three different mechanisms:
- Direct binding of the antibody to the target molecules can trigger cell death-inducing mechanisms, such as apoptosis, or can block the action of cell survival factors, such as growth factors.
- The Fc region of target-cell bound antibodies can bind to soluble proteins of the “complement” system found in blood and trigger “complement mediated lysis” of target cells.
- The Fc region of target-cell bound antibodies can bind to Fc gamma receptors (“FcgRs”) on the surface of immune effector cells, such as natural killer cells, and trigger “FcgR-mediated killing” of the target cells by immune effectors.
Clinical Relevance of Fc-Fc Receptor Binding
Recent studies have highlighted the importance of FcgR-mediated killing of target cells for the outcome of antibody therapies.
First, commercially successful anti-cancer antibodies require intact Fc-FcgR interactions to be effective in murine models of human cancer (see Clynes et al, Sampson et al).
Second, clinical pharmacogenomic studies have demonstrated the importance of increasing the binding affinity of the FcgRIIIa-Fc interaction. Approximately 10-15% of the population carry two copies of a gene encoding a variant of FcgRIIIa that binds with higher affinity to the Fc region of antibodies. Patients belonging to this population respond significantly better to certain antibody therapies (see Cartron et al, Wang et al).
GlycoMAb enhances Fc-FcgRIIIa affinity to much higher levels than those found in nature and this improvement applies to the whole population.
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