Cancer stromal targeting therapy to overcome the pitfall of EPR effect.

Many animal experiments performed worldwide have proven EPR effects However, it is hard to say that the EPR effect works in clinical practice. In the case of hematological malignancies, the administered anticancer agents (ACA) can physically interact with the malignant cells, making it easier to reflect in vitro data. In solid tumors, however, the extravasated ACAs must diffuse evenly within the whole tumor mass. Therefore, the cancer stroma and the tumor mass itself can be obstacles to drug delivery systems (DDS) including antibody therapeutics. We have demonstrated that hypercoagulability caused by cancer forms cancer stroma. We further showed that the more aggressive the cancer, the greater the deposition of insoluble fibrin (IF) in cancer tissue. In this background, we decided to create monoclonal antibody (mAb) that specifically binds to IF. After a long effort, a new and unique IF-specific mAb was developed. Subsequently, anti-IF mAb conjugated with an ACA using a V-L-K linker which can be cut by plasmin. Because plasmin is activated only during IF formation, the ACA is released from the ADC only when the conjugate is bound to the IF. The released ACA may readily get to cancer cells through the stromal obstacle because of its small size. The ACA also damages the capillary that nourish cancer cells. We have named this strategy cancer (CA) stroma (S) targeting (T) therapy, or CAST therapy.