We worked exclusively with the recombinant immunotoxins (RIT), which are molecules made partly of tumor-specific antibody and partly of a potent protein toxin. Our collaborator, Dr. Ira Pastan, and his group are making and testing these molecules as a new class of potent and specific anti-cancer protein drugs. We have published the initial mathematical model of the RIT delivery process (Chen et al., Annals of Biomedical Engineering, 36: 486-512, 2008). The model considers a tumor as a collection of N identical representative units (RUs), which is a spherical unit of approximately 100 micrometer diameter centered around a spherical blood vessel, which serves as the source of the RIT. The advantage of this model is that it can handle tumors of any size while handling only one RU of a reasonable, constant size. The model consists of two main sets of differential equations. One set describes the kinetic steps that the RIT molecules go through within each RU, which include extravasation from the blood vessel into the tumor ECS, diffusion in ECS, binding to the surface antigen, internalization by endocytosis, travel through endosomal compartments, translocation into the cytosol, and finally intoxication of the cell. The other set of differential equations describe the growth, death, and movement of tumor cells within each RU and their flow in and out of the RUs. Cells move because the number of cells increases when the tumor grows and because intoxicated cells die and are cleared, creating an empty space into which neighboring cells move in. This model reproduces the experimental volume change with time of human tumors growing in mice in response to the administration of different doses of RIT and demonstrates the well-known binding site barrier effect. It also identified some two dozen factors that are involved in the delivery process, some of which affect the efficacy of the RIT much more than others. We have now improved upon this model by re-writing the entire set of differential equations to make the model quantitatively more precise and by including the effect of antigen shedding, which was not included in the original model. The new model has, so far, been applied on only one RIT called SS1P, which selectively binds to mesothelin expressed on several solid tumors including mesothelioma, ovarian cancer, pancreatic cancer and lung cancer. SS1P is currently under clinical testing in mesothelioma patients. The new model gives accurate accounting of all the RITs that enter the tumor tissue at all times. (Manuscript in preparation.) In accordance with the experimental data (Zhang et al., Clin Cancer Res, 12:4695, 2006), the model indicates that only about 0.5% of the injected dose enters the tumor tissue of approximately 100 cc size growing in mice. Most of the RITs that enter the tumor tissue are degraded in the endosomal compartment within the tumor cells, again as expected from many earlier studies. A major, unexpected finding with the new model is the fact that antigen shedding greatly enhances, not retards, the efficacy of the RITs. The model shows that there are two mechanisms by which antigen shedding helps the effectiveness. One mechanism is that the shed antigen binds RITs, which then diffuses with shed antigen without binding, and thereby being consumed by, the cells. In effect, the shed antigen acts as a protective reservoir, which releases the bound antigen at later times and at places far away from the blood vessel. The idea that there was a reservoir of RITs in the system had been suggested by experimental data (Zhang et al., Cancer Res, 70:1082, 2010), although concrete nature of the reservoir had not been identified. The second mechanism is that the antigen shedding helps reduce binding of RITs to already intoxicated cells much more than un-intoxicated cells. This is because the number of antigens on the surface of intoxicated cells constantly decreases since the protein synthesis has been stopped in these cells while shedding still goes on. In contrast, the number on the surface of un-intoxicated cells is maintained at a constant steady state value through shedding, endocytosis, recycling and de novo synthesis. This finding suggests that the efficacy of RITs can be improved by simultaneous administration of agents that will increase the amount of the shed antigen. In fact, future research effort will be directed to modeling the effect of various combination therapies. Possible auxiliary agents for such therapies include un-loaded, competing antibodies and taxol and other anti-cancer agents, as well agents that might increase the amount of shed antigen.
|Pak, Youngshang; Zhang, Yujian; Pastan, Ira et al. (2012) Antigen shedding may improve efficiencies for delivery of antibody-based anticancer agents in solid tumors. Cancer Res 72:3143-52|
|Yomtovian, Inbal; Teerakulkittipong, Nuttinee; Lee, Byungkook et al. (2010) Composition bias and the origin of ORFan genes. Bioinformatics 26:996-9|