New concept of cytotoxic immunoconjugate therapy targeting cancer-induced fibrin clots.

Fibrin clots in non-malignant conditions form only at the onset or during the active stage of disease and disappear within a few weeks as a result of plasmin digestion or replacement with collagen. In contrast, fibrin clot formation and subsequent replacement with collagen in cancer persist for as long as the cancer cells survive in the body. We developed an anti-fibrin chimeric antibody that reacts with fibrin only, and not fibrinogen (the precursor of fibrin), and then attached an anticancer agent (ACA) to the antibody. Thus, the immunoconjugate did not create an immune complex in the blood stream and was selectively accumulated to fibrin clots in the tumor stroma to create a scaffold, from which effective sustained release of the ACA occurred. In a mouse model, the ACA diffused throughout the tumor tissue to damage both tumor cells and vessels, resulting in potent antitumor activity in stroma-rich spontaneous tumors. This new cancer stroma-targeting therapy may result in an increased duration of drug exposure and be a highly effective new therapy, particularly for refractory, stroma-rich cancers.