Targeted Payload Therapies Using Radioimmunotherapy Hit the Right Marks
For patients with acute myeloid leukemia (AML), there is both good news and bad news. The good news is that standard induction therapy, using cytarabine and an anthracycline, produces complete responses in half to almost three-quarters of cases. The bad news is that long-term survival is at 20-40 percent; when a patient relapses, salvage chemotherapy results in remission only one in five, possibly one in four times. For those over 65, the results are even more depressing, with a 5 percent survival rate over five years. Among the therapies under investigation to improve these results are those involving the use of alpha-particle radiation using monoclonal antibodies as the delivery mechanism.
The fight against cancer has relied on a variety of treatments that fall broadly into three categories: surgery, chemotherapy and radiation. Other forms of treatment, like hormonal therapy, phototherapy, cryotherapy, etc., are less frequently administered. In early-stage cancers, where the disease is localized, surgery to remove the tumor or focused radiation to kill it can prove effective. Any cancer that has metastasized or is not localized (as in blood-borne cancers like AML) tends to require chemotherapy to address the disease systemically. Broadly speaking, chemotherapies are either cytotoxic or targeted.
Monoclonal antibodies (mAb) form the basis of one of the more commonly studied targeted therapy approaches. These molecules are engineered to attach to the specific markers on the cancer cells, essentially mimicking the antibodies that the immune system should produce to fight the disease.
MAbs are useful because they can make the cancer cells more visible to the patient’s immune system. As the Mayo Clinic experts state, “The monoclonal antibody drug rituximab (Rituxan) attaches to a specific protein (CD20) found only on B cells, one type of white blood cell. Certain types of lymphomas arise from these same B cells. When rituximab attaches to this protein on the B cells, it makes the cells more visible to the immune system, which can then attack.” (http://www.mayoclinic.org/diseases-conditions/cancer/in-depth/monoclonal-antibody/art-20047808
They can also block growth signals and thus impede the growth of new cancerous cells. For instance, Cetuximab (Erbitux), a MAb approved to treat colon cancer and head and neck cancers, attaches to receptors for epidermal growth factor on cancer cells, thereby slowing or even stopping the cancer from growing.
In addition, MAbs can stop new blood vessels from forming, choking off the blood supply to any tumor. Bevacizumab (Avastin) is a mAb that targets vascular endothelial growth factor (VEGF) used by cancer cells to stimulate growth of new blood vessels. This mAb prevents the cancer from growing by slowing down growth of new blood vessels.
Because they attach themselves to the cancer cells, mAbs also make good delivery devices for chemotherapy and radiation therapy. The cancer-fighting agent is delivered right to the spot where it is needed – the mAb is sort of a guided missile, and the agent is the warhead.
In the case of AML, a promising type of targeted treatment is known as radioimmunotherapy (RIT). It uses a mAb to deliver radiation to the cancer cell. This is far safer and more efficient than using an external radiation beam that causes significant damage to the healthy tissues it passes through in order to reach cancer cells.
Currently available radioimmunotherapies rely on beta-particle emitting isotopes like iodine-131 or yttrium-90. These are good at eliminating large tumor burdens, but they are efficient mostly in lymphomas that are very sensitive to radiation. Researchers believe that alpha-particle emitters, such as bismuth- 213 or actinium-225, currently being investigated by Actinium Pharmaceuticals, may be more effective and efficient at killing cancerous cells not currently treated with radiation while simultaneously decreasing nonspecific cytotoxic effects.
The physics of alpha particles versus beta particles is the secret to their differing radiobiological effects. Beta particles are highly charged electrons with a range of 800-10,000 micrometers, and their linear energy transfer (LET) level is around 0.2-0.6 mega electron volts per millimeter. Alpha particles are composed of two neutrons and two protons (essentially a helium nucleus). Their range is just 50-80 micrometers, but their LET is around 100 mega electron volts per millimeter. In short, while their range is limited to only the targeted cells and those right next to them, they pack a much bigger punch. It can take just one or two alpha particles to kill a target cell. As a result, non-specific cytoxicity should be lessened when using alpha-emitters compared to beta-emitters.
One promising alpha-emitter is of bismuth-213 (213Bi). 213Bi was attached to the mAb called lintuzumab. The feasibility of manufacturing and dosing, safety and antileukemic effects of 213Bi have been shown in Phase 1 and 2 studies, where it produced remissions in some patients with AML after partial cytoreduction with cytarabine. This suggests the utility of targeted alpha-particle therapy for small-volume disease.
Another alpha-emitter with a much longer half-life (and therefore, more medically useful) is actinium-225 (225Ac). A Phase 1 trial demonstrated that it is safe and has antileukemic activity at doses as low as 0.5 to 3 microcuries per kilogram or less.
Studies on the efficacy of alpha-emitters delivered by mAb continue, and the early results are promising.
Dragan Cicic, M.D., is the chief operating officer and chief medical officer at Actinium Pharmaceuticals Inc., having joined the company in 2005 and previously serving as medical director at Actinium. Cicic joined the company after holding the position of project director at QED Technologies, prior to which he was an investment banker at SG Cowen Securities. For more information on Actinium and its investigation of radioimmunotherapies, please visit www.actiniumpharma.com.