title: Control of fibrotic changes through the synergistic effects of anti-fibronectin antibody and an RGDS-tagged form of the same antibody.
abstract: TGF-β and myofibroblasts play a key role in fibrosis, characterized by aberrant synthesis and deposition of extracellular matrix (ECM) proteins, such as fibronectin (Fn) and collagen type I. There are two major roles played by integrins in the fibrotic pathology: (i) Fn-integrin interaction, coupled with cytokines like TGF-β, facilitates the self-polymerization of Fn and regulates cell-matrix fibrillar adhesions, thereby promoting fibrillogenesis; (ii) Integrin interaction with an RGD (arginine-glycine-aspartic) consensus sequence in the latent TGF-β, resulting in its activation. This study describes an anti-fibrotic strategy using a combination of two antibodies: Fn52 (targeted against the N-terminal 30 kDa region of fibronectin, a major site for Fn self-association), and its engineered form, Fn52RGDS (which binds to integrins). Interestingly, a synergistic effect of the cocktail in causing a decline in fibrotic features was confirmed in the context of fibrotic posterior capsular opacification (PCO), mediated by the lens epithelial cells (left behind after cataract surgery). Inclusion of Fn52RGDS to Fn52 aids in better diffusion of the antibodies; such combination therapies could be useful in the context of pathologies involving extensive remodeling of the fibronectin matrix, where the thick ECM offers a major challenge for efficient drug delivery.
authors.affiliation: Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
authors.forename: Anil
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: UGC Centre of Excellence in Applications of Nanomaterials, Nano particles and Nanocomposites, Panjab University Chandigarh, 160014, India.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Ophthalmology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
authors.forename: Jagat
authors.initials: J
authors.lastname: Ram
authors.affiliation: Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
authors.forename: Maryada
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
authors.forename: Manni
authors.initials: M
authors.lastname: Luthra-Guptasarma
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000276:immunology; D004357:Drug Synergism; D005353:Fibronectins; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010857:Pigment Epithelium of Eye / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D057127:Single-Chain Antibodies / Q000494:pharmacology*
chemical_list: D016207:Cytokines; C067625:FN1 protein, human; D005353:Fibronectins; D016023:Integrins; D009842:Oligopeptides; D057127:Single-Chain Antibodies; C046617:arginyl-glycyl-aspartyl-serine