How do antibodies kill neuroblastoma cells?


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03-10-09 05:26 AM
How do antibodies kill neuroblastoma cells?

Antibody therapy is believed to rely on three different methods to kill neuroblastoma cells.  These are called antibody dependent cell-mediated cytotoxicity (ADCC), complement mediated cytotoxicity (CMC), and passive immunotherapy using the anti-idiotypic network.  The names sound much scarier that it really is ? unless you are a neuroblastoma cell.

ADCC is where a cell of the immune system actively lyses (cuts open) a neuroblastoma cell that has been bound by an antibody.   This happens because the antibody alerts the immune system which then sends effector cells (such as natural killer (NK) cells, monocytes and eosinophils) to kill the tumor cells.

We have discussed the antigen-binding site portion of the antibody previously.  This is the part of the antibody that connects to the tumor cell.  On the other side of the antibody is what is called the Fc portion.  This is the part that signals the immune system to recruit cells to come attack the cancer cell.  A natural killer cell?s Fc receptor recognizes the Fc portion of an antibody, such as IgG.  Once bound to the Fc receptor of IgG, the natural killer cell releases cytokines and cytotoxic granules that enter the neuroblastoma cell and promote cell death.

CMC or complement mediated cytotoxicity works a bit differently to kill neuroblastoma cells.  The complement system consists of some 30 proteins circulating in the blood.  Complement proteins circulate in the blood in an inactive form.  The so-called "complement cascade" is set off when the first complement molecule, C1, encounters an antibody (such as ch14.18) bound to antigen (such as GD2) in an antigen-antibody complex.  Each of the complement proteins performs its specialized job, acting, in turn, on the molecule next in line.   The end product is a cylinder that punctures the cell membrane and, by allowing fluids and molecules to flow in and out, dooms the neuroblastoma cell.  You can think of this system as the domino effect.  The antibody is the first domino and by attaching to the tumor cell it sets off a chain reaction of protein signals which eventually ends in the death of the neuroblastoma cell.

Finally, reports also suggest that there could also be a third mechanism by which antibodies could help to kill neuroblastoma cells.  This method of killing utilizes the anti-idiotypic network.   Specifically, the immune (humoral) response of the child against the monoclonal antibody (called Ab1, such as 3f8 or 14.18) leads to the generation of an anti-idiotype-antibody (called Ab2, such as the HAMA response).  In a subsequent immune response to Ab2 the immune system may generate an anti-anti-idiotypic antibody (called Ab3, a third antibody in response to the HAMA), which is also capable of specifically recognizing the nominal antigen (GD2) expressed by the tumor cell.   It should be noted that this anti-idiotypic network was first discovered  with the use of 3F8.  The role of the anti-idiotypic network in the activity of ch14.18 is still unknown as it has not been studied.