Monoclonal Antibodies in the Treatment of Cancer

Paul Ehrlich was the first proponent of using antibodies or “magic bullets” to target tumor cells (1) and in recent years, monoclonal antibodies found their way into cancer treatment regimens.(2) Why can’t the body’s own immune cells go  after the malignant cells?  Cancer is clever.  The transformed cancer cells evade the immune system through biochemical camouflage.(3) Immunotherapy (monoclonal antibodies and cancer vaccines) can make cancer cells visible to the natural immune system by taking advantage of molecular markers selectively present on cancer cells only.(4)

Monoclonal antibodies, engineered in the laboratory and produced either in mice or through advanced hybridoma technology in humanized or chimeric forms, mimic the natural antibodies of the body.(5) In addition to re-targeting cancer cells to the immune system, monoclonal antibodies can also function by attenuating hyperactive growth signals (inhibiting cancer cell multiplication), and through antiangiogenesis (inhibiting new blood vessel formation, in turn starving cancer cells of nutrition and oxygen supply).(6) Hence, monoclonal antibodies are either used alone (‘Unconjugated’) or in combination with other cellular targets (‘Chimeric’ or ‘Conjugated’). For example, a monoclonal antibody can be conjugated to a radioactive particle.  This method promotes transport of the particle to the cancerous cells and only the cancerous cells.  The radiation can thus be targeted at a microscopic level.  This precise targeting is what Paul Ehrlich had in mind a century ago and maximizes the chances of positive outcome and while minimizing non-specific damaging exposure to radiation.

 

Major differences between monoclonal antibodies and small-molecule drugs

The primary difference lies in their mechanisms of action.  Small-molecule drugs are usually cell membrane permeable, diffusing into the cells to find their organelle targets.(4,5) In comparison, monoclonal antibodies target unique cell-specific markers on the external surface of the cell (peptide antigens) and do not permeate through the cell. Small molecule drugs have a direct impact on their targets, whereas all that monoclonal antibodies do is re-direct targets to the immune system for resolution. Small molecule drugs are given in oral or intravenous administration while monoclonal antibodies are always administered intravenously (they would be destroyed in the digestive system before making their way to the cancerous cells.)

More on clinical use of monoclonal antibodies.

Common Challenges of Monoclonal Antibody Usage
I. Low immunogenicity of xenogeneic antibodies
II. Unscrupulous antigen shedding into circulation causing bystander effects
III. Inordinate vasculature in the tumor making targeting through intravenous injection to site of tumor challenging.
IV. Elevated hydrostatic pressure at the tumor site. Limited number of effector immune cells in the tumor microenvironment; hence even after recognition by the natural immune system the cells might still not be completely destroyed.

Dosing for monoclonal antibodies

Although doctors’ first instincts are to vary the dose of monoclonal antibodies with patient body size, mathematical simulation of pharmacokinetics suggest this variation may not provide better efficacy.  This is in contrast to many drugs – and indeed most chemotherapy drugs – where bigger patients get higher doses.  But mAbs are target-specific with a relatively large therapeutic window.  The dangers of overdosing are lower than they are for conventional chemotherapy drugs.  Some scientists therefore recommend a fixed dose (i,e, everyone gets the same dose) when these drugs are first used in humans, at least until data from real patients indicates a more nuanced approach is preferable.

 

Some monoclonal antibody agents used to treat cancer

 

Alemtuzumab (Campath) is used for the treatment of B-cell chronic lymphocytic leukemia (CLL).  

Bevacizumab (2005, Avastin) is used for the treatment of breast cancer, colon cancer and lung cancer.  It targets VEGF.

Cetuximab (2006, Erbitux) is used for the treatment of colon cancer, Squamous Cell Carcinoma, and head and neck cancers.  It targets EGFR.

Gemtuzumab (Mylotarg) was used for the treatment of acute myelogenous leukemia. However, this drug has been withdrawn from the market.

Ibritumomab (Zevalin) is used for the treatment of non-Hodgkin’s lymphoma. Although this drug is currently on the market, in some patients it is known to cause serious side effects.

Panitumumab (Vectibix) is used for the treatment of colon cancer.  Panitumumab (2007, targets EGFR)

Rituximab (Rituxan) is used for the treatment of hematological cancers.

Tositumomab (Bexxar) was used for the treatment of non-Hodgkin’s lymphoma, but it has been withdrawn from the market.

Trastuzumab (1998, Herceptin) is used for the treatment of breast cancer.  It targets HER-2.

 

 

References

1. Ehrlich P. Collected studies on immunity. (New York: J. Wiley & Sons, 1906).

2. Old LJ. Immunotherapy for cancer. Sci Am. 1996; 275:136-143.

3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 144:646-674, 2011.

4. Cersosimo RJ. Monoclonal antibodies in the treatment of cancer, Part 1 Am J Health Syst Pharm 60:1531-1548, 2003.

5. Cersosimo RJ. Monoclonal antibodies in the treatment of cancer, Part 2 Am J Health Syst Pharm 60:1631-1641, 2003.