Antibody-drug conjugates – selective and precise weapons against cancer
For many types of cancer classic chemotherapy is frequently still the only form of treatment available. It functions on the basis of a cytotoxic effect: a cell toxin kills cancer cells, thus halting tumor growth. However, since such drugs also damage healthy cells, patients suffer severe side effects.
Modern cancer therapies now target the cancer more precisely. They include the recently developed approach of antibody-drug conjugates (ADC). Bayer currently has several projects using this approach in its research pipeline.
Chemotherapy damages the cancer – but also healthy cells
Chemotherapeutic agents primarily damage and destroy cells with a high level of cell-division activity. Because cancer cells – degenerated cells whose control mechanisms are deactivated – divide faster than normal cells and spread uncontrollably, they are hit particularly hard by chemotherapy.
Even so, healthy tissue is not spared the effect of the cytotoxins. In particular, mucosal cells in the gastrointestinal tract, and hair, germ and immune cells are attacked because they, too, divide and re-form more rapidly than other cells. If they are damaged, one observes the typical side effects of chemotherapy: nausea and vomiting, hair loss, and a weakening of the immune system. Because of these severe side effects, patients can often only be given low doses of the substances, and this may, in turn, be insufficient to fight the tumor.
Precise attack: Trojan horse against the tumor
By contrast, new approaches like antibody-drug conjugates attack the cancer in a much more targeted way, so that healthy cells are less severely affected.
Antibodies are an important, naturally occurring part of the immune system, large molecules that can specifically bind to the cell surface of an 'intruder' (e.g. a virus) and in this way eliminate the other cell. The researchers make use of this natural mechanism of the body in the development of tumor therapies using antibody-drug conjugates (or 'immunoconjugates'). The cancer drug, e.g. a cell toxin, is coupled to an antibody that specifically targets a certain tumor marker, i.e. a protein that, ideally, is only to be found in or on tumor cells.
The antibodies track these proteins down in the body and attach themselves to the surface of cancer cells. The biochemical reaction between the antibody and the target protein (antigen) triggers a signal in the tumor cell which then absorbs the antibody together with the active ingredient.
Like a Trojan horse, the toxin enters the cancer cell unnoticed in this way. At this point, the toxin is still firmly connected with the antibody. This connection must be broken before the active substance can begin its deadly work within the tumor.
The tumor cell itself releases the poison
The development of the connecting point between the antibody and the cytotoxin – called the linker – poses a special challenge for the researchers. For, while the conjugate is still circulating in the patient's blood searching for cancer cells – a process that can take several weeks – the active substance must not detach itself from the carrier molecule, since it will otherwise do harm. It is therefore essential to find a linker that does not release the toxic substance until it is inside the tumor cell. The solution: the researchers design it in such a way that it can only be split by cancer-cell-specific enzymes. In this way, the tumor cell itself releases the toxic substances that cause its cell death.
The researchers hope that antibody-drug conjugates represent a whole new concept for a pinpointed cancer therapy which, although highly effective, causes much fewer side effects than traditional chemotherapy.