Monoclonal Antibodies

Traditional chemotherapy (ex. fludarabine) lowers the lymphocyte count and all the other blood cells. There is no distinction among the good cells and the bad. Campath (and rituxan) attack only the cells that are carrying their respective CD (52 or 20), so that the vast majority of cells that are killed are the malignant ones.

Traditional chemo can not be used as aggressively as these monoclonal antibodies can because the damage that is done to the bone marrow is too great. Traditional chemo has to be stopped when the counts for plts, rbc and grans get too low. The monoclonals do not have this problem so they are the perfect choice to use against malignant cells in a person whose marrow needs some protection or relief.

From: Carolyn Pendleton <JoeCPendle@AOL.COM> >Subject: CD 20 and CD 52 > >Maybe Susan can explain what's happening. After >completing my Rituxan/Campath TX, the bone marrow >procedure indicates that the CD 20 is gone, but the >CD 52 is still above 90%. The lymphs in the bone >marrow went down only slightly from 92% to 75%. >CD5/19 (Dr. Keating says these are the CLL cells) is >still 70%. What does this mean? It looks to me as >if I responded to the Rituxan but not the Campath. >He said I will need more Campath and that the bone >marrow is harder to clear than the blood. Lymph >nodes are smaller but not gone. Bottom line: Did I >have a poor response to Campath? Will it work if >given longer. On this protocol you get Rituxan once >a week and Campath twice a week which is less than >the regular Campath tx I think. Any opinions or info >will be appreciated.
Since this type of treatment is pretty recent, we don't have a whole lot of explanations on this stuff but ... It does seem as if the cells in the nodes are more difficult to get rid of. Two possible explanations are 1) they are somehow more resistant to immune therapy or 2) If , in order to work, you need to have a sufficient concentration of antibody attaching itself onto the antigen, then maybe there is a difficulty in getting the antibody concentration to a high enough level inside the nodes. The good news is that additional treatments do seem to be effective so I would agree with Dr. Keating ( a real easy thing to do and make me look really smart!). Give the process a little more time.
Are you having a good response? Let me ask you - if you wanted to lose weight really quickly and you lost 20% of your total goal in one week, would you think that a good response to a diet? Perhaps a poor analogy but I want you to think about the complexity of the situation here. It has probably taken years for you to get the tumor number up to what it is now so, while I know you want this to go away now, it will probably take more than 1 cycle of medication to see a dramatic change. A 20% drop is a good response by any standard other than the personal and valid emotion of "I want it gone now".
 

Monoclonal antibodies are not the magic bullets that people hoped they would be.

Just because an antibody reacts with a target doesn't mean that it will kill it. There are 3 ways that antibodies kill target cells. 1. They can set the apoptosis pathway going. This doesn't usually happen, but it may be synergistic with other apoptosis activators like chemotherapy. 2. It might activate complement. Complement is a cascade of proteins that are used for killing bacteria. Most human cancer cells have a defence against complement killing. 3. It might induce killer cells, especially macrophages and natural killer cells to kill the target cells. It is believed that rituximab mostly acts in this way.

Cancer cells have lots of defences against antibodies. one of the chief is antigenic modulation. By this the target antigen is taken inside the cell where it hides till the danger is past. If the antigen is secreted by the cell it acts as a barrier stopping the antibody reaching the cell.

There are very few antigens that are only present on CLL cells. CD23 is a good candidate. But it turns out that anti-CD23 is not terribly good at killing CLL cells. Many anti-CD20s that have been tested are not as good as rituximab. We have tested a whole range of antibodies, including several anti-CD20s, anti-CD19, anti-CD21, anti-CD37 and anti-CD38. None are as good as rituximab or Campath. I have been trying to find a good antibody to treat CLL with since 1974. It's not easy.