Cancer and blood coagulation

Abstract

We know that both intrinsic and extrinsic blood coagulation factors are involved in tumor vascular permeability as well as tumor-induced fibrin clot formation in the extra-vascular space. Inflow of fibroblasts and inflammatory cells into the tumor tissue occurs accompanying blood coagulation. Consequently, cancer induced blood coagulation generates insoluble fibrin rich tumor stroma. The stroma becomes a barrier preventing macromolecular DDS drugs from directly attacking cancer cells within the cancer tissue. To tackle this problem, we successfully developed a new strategy that uses a monoclonal antibody (mAb), generated in this laboratory that reacts only with human insoluble fibrin, and not with human fibrinogen or fibrin degradation product (FDP). Another advantage of this mAb is that it cross-reacts with mouse insoluble fibrin, but not with mouse fibrinogen or FDP. As a result of the unique properties of the mAb, it is not neutralized by soluble fibrinogen or soluble fibrin products in the body. Our anti-fibrin clot mAb recognizes an unexplored pocket that is only uncovered when a fibrin clot forms. The epitope in the pocket is a hydrophobic region on the Bβ-chain that interacts closely with a counterpart region on the ?-chain in a soluble state. Using the new mAb, we succeeded in constructing an antibody drug conjugate (ADC) that binds to polymerized fibrin and slowly releases a cytotoxic drug that, on account of its small molecular size, can diffuse through the dense stroma to kill cancer cells. Cancer and blood clotting research may lead to new therapeutic strategies as well as to the biological understanding of cancer.