Targeted delivery of interleukin-10 to chronic cardiac allograft rejection using a human antibody specific to the extra domain A of fibronectin

Detection of Soluble ED-A+Fibronectin and Evaluation as Novel Serum Biomarker for Cardiac Tissue Remodeling

“…Anyhow, a very interesting finding of the current study is that there seem to be differences between the disease-associated tissue deposition of ED-A + Fn and its liberation into the circulation. Our group could recently show that the molecule is deposited in diseased cardiac tissue in spatial association with vascular structures and with interstitial fibrosis in a variety of diseases, for example, DCM, ICM, and valvular heart disease, or in an animal model of cardiac rejection, respectively [26–32]. Surprisingly, only in ICM an association with disease severity could be shown for serum ED-A + Fn in this study.…”

“…As already mentioned above, not in serum but in diseased tissue, a distinct reexpression of ED-A + Fn could be demonstrated in several neoplastic, inflammatory, or cardiovascular disorders qualifying the molecule as an excellent target structure for an antibody based delivery of bioactive payloads or diagnostic agents using the human antibody F8 [15, 32, 63, 64]. In this context one could imagine that the individual level of soluble in particular serum ED-A + Fn might be of importance since the systemically administered antibody based agent could possibly bind to circulating molecules hindering the antibody to accumulate in the target tissue, where ED-A + Fn is abundantly expressed and deposited.…”

“…When investigating the reoccurrence of fetal splicing variants of fibronectin in cardiovascular diseases, one could learn that especially the extra domain A of fibronectin (ED-A + Fn) can be frequently detected in diseased cardiac tissue from patients with ischemic cardiomyopathy, valvular heart disease, and dilated cardiomyopathy and also in a rat model of chronic cardiac rejection by our group [25–30]. Against that background and due to its stable tissue deposition, the molecule could be shown to be a robust target for antibody based delivery of diagnostic agents or bioactive payloads using the human ED-A domain specific antibody F8 as a vehicle [31, 32]. In addition, it could recently be shown that fibronectin in general may serve as a serum biomarker in several diseases like viral hepatitis, pulmonary tuberculosis, Duchenne muscular dystrophy, and melanoma [33, 34].…”

Lung tissue remodelling in MCT-induced pulmonary hypertension: a proposal for a novel scoring system and changes in extracellular matrix and fibrosis associated gene expression

“…To elucidate this, further pre-clinical studies using the MCT induced PH rat model should be performed in the near future. The principle of an F8 based targeted delivery of cytokines or contrast agents has been proven for cardiovascular disease by our group using a heterotopic rat heart transplantation model [21, 22]. Against the background of these findings and data from the literature [10], a central role for ED-A + Fn and also fetal Tn-C variants has been postulated for the chronic cardiac rejection process with vasculopathy and fibrosis [14].…”

“…cytokines; or classical drugs) directly to the site of pathologic remodelling where the antigen is abundantly expressed while sparing normal tissue where the antigen is virtually absent. Such agents, in particular immunocytokines or antibody-drug conjugates, have been successfully administered in a variety of animal models of neoplastic and also non-neoplastic chronic-inflammatory disease [21, 22]. At least in part, such immunocytokines have already reached the stage of clinical testing [23–26].…”