Radiopharmaceutical Treatment of Cancer: Strategy of Tumor-Pretargeting
Relating to current cancer mortality statistics the development of alternative and more efficient therapy options in combination with fewer side effects is more essential than ever. Standard therapies are surgical intervention, application of chemotherapeutics and external irradiation. All these options also result in damage of healthy tissue due to its very invasive procedure (surgery), low selectivity of targeting tumor tissue (chemotherapy) or the lack of precise application of irradiation dose. Disadvantageously, chemotherapeutic agents are also destroying fast-growing, healthy cells resulting in strong side effects (nausea and vomiting, infections, pain, etc.).
Anti-tumor antibodies realize the specific targeting of tumor cells due to their high affinity against specific antigens on tumor cell surfaces. To destroy targeted tumor tissue we are focused on the application of β--emitting radionuclides. The internal usage of radionuclides benefits from several advantages: First of all, with the help of the energy of the emitting particles the mean penetration range can be limited in relation to tumor sizes resulting in maximum protection of surrounded, healthy tissue. Secondly, the cytotoxic effect against tumor cells of emitted β--particles is caused by effective damage of cell membrane, DNA fragmentation or formation of toxic radicals, for example. Relating to the extraordinary high efficiency, such an endoradionuclide therapy will be performed by administrating extremely low amounts of radiolabeled substances (10-11-10-9 mol) distinguishing from other (internal) therapeutics.
The combination of tumor-specific antibodies and radiation-induced cytotoxicity offers an alternative approach for the treatment of tumor diseases. Such agents for endoradionuclide therapy provide satisfying accumulation rates in tumor tissues and consequently efficacious local radiation doses. However, due to their size antibodies exhibit restrained passage of biological barriers, which implicates very slow blood clearances. Together with the uptake of antibodies by the reticular endothelial system an unpredictable radiation exposure for healthy tissue would occur when using such radiolabeled antibodies. So far, only for non-Hodgkin-Lymphoma therapeutics based on radiolabeled antibodies are approved (Bexxar® and Zevalin®).
Therefore, the challenge we are facing is to combine the tumor-specificity of tumor-antigen related antibodies, the therapeutically effect of special radionuclides, and minimal irradiation exposure to healthy tissue. A very promising approach to fulfill these conditions is Tumor-Pretargeting. This strategy consists of a two-step process (see Figure 1). In the first step a modified tumor-antigen specific antibody is administrated followed by a sufficient waiting period to ensure a high tumor accumulation and the elimination of unbound antibodies from the blood. In the second step a radiolabeled compound with a high specific binding-affinity against the pretargeting antibody localized on tumor cell surfaceis administrated. Such radiolabeled compounds should exhibit ideal pharmacokinetics with rapid distribution, very low accumulation rates in healthy tissues, and fast renal blood clearance.
To realize the specific recognition and the very fast and stable binding of the radiolabeled component to the antibody a complementary system (see Figure 1, illustrated as the two puzzle parts) is necessary. Therefore, the antibody has to be modified in terms of grafting one part of this complementary system and the counterpart has to be radiolabeled.
Figure 1: Concept of Tumor-Pretargeting