Discovery of an uncovered region in fibrin clots and its clinical significance

Abstract

Despite the pathological importance of fibrin clot formation, little is known about the structure of these clots because X-ray and nuclear magnetic resonance (NMR) analyses are not applicable to insoluble proteins. In contrast to previously reported anti-fibrin monoclonal antibodies (mAbs), our anti-fibrin clot mAb (clone 102–10) recognises an uncovered region that is exposed only when a fibrin clot forms. The epitope of the 102–10 mAb was mapped to a hydrophobic region on the Bβ chain that interacted closely with a counterpart region on the γ chain in a soluble state. New anti-Bβ and anti-γ mAbs specific to peptides lining the discovered region appeared to bind exclusively to fibrin clots. Furthermore, the radiolabelled 102–10 mAb selectively accumulated in mouse spontaneous tumours, and immunohistochemistry using this mAb revealed greater fibrin deposition in World Health Organization (WHO) grade 4 glioma than in lower-grade gliomas. Because erosive tumours are apt to cause micro-haemorrhages, even early asymptomatic tumours detected with a radiolabelled 102-10 mAb may be aggressively malignant.

Coagulation and fibrinolysis in gastric cancer

“…The accumulation of such particles in tumor vessels can lead to additional local clotting, thereby producing new binding sites for more particles, thus amplifying the targeting. The clotting‐based amplification of particles might greatly enhance the antitumor effect of the drug, and the addition of a drug carrier to the particles is underway …”

“…Cross‐linked fibrin and FBG‐related proteins are deposited extravascularly from the local hypermeable blood vessels within tumor stroma, and they play important roles in the pathogenesis of tumor growth and spread . The tumor stroma and the local ECM is a versatile environment where coagulation‐related events (i.e., platelet activation, fibrin clot deposition, fibrinolysis) are activated by cancer, and their biochemical composition is dramatically affected by tumor cell growth and its further metastasis, accompanied by tumor‐driven production and release of specific factors (e.g., proinflammatory, prothrombotic, and proangiogenic) …”

Preparation and characterization of anti‐tissue factor single‐chain variable fragment antibody for cancer diagnosis

“…We also found high expression levels of mTF especially in the invasion site of cancer clusters, which are well‐differentiated squamous cell carcinoma (SCC). In addition, this spontaneous tumor is very slow in tumor growth and lastly metastasized to other organs to kill host mice in almost a year that are also more similar to general clinical human cancer as compared to the xenografts …”

The evolution of fibrin-specific targeting strategies

“…This was the case with NIB 5F3 which was eventually determined to specifically bind the E-Fragment of fibrin, 48 and the MH-1 antibody 49 that was eventually determined to bind DD-Dimer. 50 Additionally, it is possible to identify an antibody through this method that specifically targets fibrin but is also capable of targeting a fibrin degradation product. This is the case with NIH 1H10 48 which possesses an affinity for fibrin of K D = 3.9 nM, though it also possess a strong affinity for the E-Fragment ( K D = 8.04 nM).…”

“…with their mAb that targets residues 149–234 of the fibrin Bβ chain, and that does not bind to any fibrin or fibrinogen degradation products. 50 In its debut study, this mAb showed promise for diagnostic imaging of gliomas in rats.…”