title: Targeted delivery of interleukin-10 to chronic cardiac allograft rejection using a human antibody specific to the extra domain A of fibronectin.
abstract: OBJECTIVE
  Management of chronic rejection is challenging since there are not sufficient preventive or therapeutic strategies. The rejection process leads to overexpression of ED-A(+) fibronectin (ED-A(+) Fn). The human antibody F8, specific to ED-A(+) Fn, may serve as a vehicle for targeted delivery of bioactive payloads, e.g. interleukin 10 (IL-10). The aim of this study was to investigate the therapeutic effects of the fusion protein F8-interleukin-10 (F8-IL10) in the process of chronic rejection development.
  
  
  METHODS
  A heterotopic rat heart transplantation model was used to induce chronic rejection. For therapeutic interventions, the immunocytokines F8-humanIL10 (DEKAVIL), F8-ratIL10 as well as KSF-humanIL10 (irrelevant antigen-specificity) were used. Treatment was performed weekly for 10 weeks starting at day 7 after transplantation (1mg/animal).
  
  
  RESULTS
  In the cardiac allografts, treatment with F8-huIL10 or F8-ratIL10 was associated with increased heart weights, a higher grade of chronic rejection, increased CIF, higher protein expression levels of alpha-smooth muscle actin (α-SMA), an augmented infiltration with inflammatory cells (CD4+, CD8+ and CD68+ cells) and higher serum levels of brain natriuretic peptide (BNP) compared to the control groups.
  
  
  CONCLUSIONS
  All observed treatment effects are transplantation-specific since the F8 antibody is specific to ED-A(+) Fn that is not expressed in healthy hearts. A clear targeting effect of F8-huIL10 as well as F8-ratIL10 could be proven. Against that background, a further study is needed to address the question, if F8-IL10 treatment is capable to reduce CAV and CIF starting at a time point when chronic rejection has fully developed (therapeutic approach).
authors.affiliation: Department of Internal Medicine I, Jena University Hospital, Jena, Germany. Electronic address: Marcus.Franz@med.uni-jena.de.
authors.forename: Marcus
authors.initials: M
authors.lastname: Franz
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland.
authors.forename: Fabia
authors.initials: F
authors.lastname: Doll
authors.affiliation: Department of Internal Medicine I, Jena University Hospital, Jena, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Grün
authors.affiliation: Institute of Pathology, Jena University Hospital, Jena, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Richter
authors.affiliation: Institute of Pathology, Jena University Hospital, Jena, Germany.
authors.forename: Nilay
authors.initials: N
authors.lastname: Köse
authors.affiliation: Department of Internal Medicine I, Jena University Hospital, Jena, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ziffels
authors.affiliation: Institute of Laboratory Animal Science and Welfare, Jena University Hospital, Jena, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Schubert
authors.affiliation: Department of Internal Medicine I, Jena University Hospital, Jena, Germany.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Figulla
authors.affiliation: Department of Internal Medicine I, Jena University Hospital, Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Jung
authors.affiliation: Clinic for Thoracic and Cardiovascular Surgery, Heart Center North Rhine-Westphalia, Ruhr-University of Bochum, Bad Oeynhausen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Gummert
authors.affiliation: Clinic for Thoracic and Cardiovascular Surgery, Heart Center North Rhine-Westphalia, Ruhr-University of Bochum, Bad Oeynhausen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Renner
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland.
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
authors.affiliation: Institute of Pathology, Jena University Hospital, Jena, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Berndt
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D002908:Chronic Disease; D004195:Disease Models, Animal; D016903:Drug Monitoring / Q000379:methods; D005353:Fibronectins / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology*; D008955:Models, Cardiovascular; D058990:Molecular Targeted Therapy; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C528643:F8 monoclonal antibody; D005353:Fibronectins; C508609:IL10 protein, human; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10
keywords: Antibody; Cardiac allograft rejection; Cardiac allograft vasculopathy; Cardiac remodelling; ED-A domain containing fibronectin; Interleukin-10; Interstitial fibrosis; Targeted therapy