INFLAMMATORY DISORDERS Anti-VEGF monoclonal antibody-induced regression of corneal neovascularization and inflammation in a rabbit model of herpetic stromal keratitis Mario Saravia & Gustavo Zapata & Paula Ferraiolo & Lourdes Racca & Alejandro Berra Received: 11 August 2008 / Revised: 6 April 2009 / Accepted: 18 April 2009 / Published online: 5 August 2009 # Springer-Verlag 2009 Abstract Background To determine the efficacy of bevacizumab (Avastin), an anti-VEGF monoclonal antibody, administrat- ed via subconjunctival injection as a corneal anti- angiogenic treatment. Methods Right corneas of rabbits were infected with herpes simplex virus type 1, KOS strain. On day 13 post-infection (p.i.), animals were treated subconjunctivally (sc) with a single 10-μl dose (25 μg/μl) of bevacizumab (group A) or with the same volume of an isotype monoclonal antibody, as negative control (group B). All animals were observed clinically on days 2, 5, 7, 14, 21, and 28 p.i., and two corneas each day were obtained for histological assessment and viral titration. Results Viral replication was observed no longer than 5 days after infection. By day 7 a dense neutrophil invasion of the cornea was detected, which significantly increased while herpetic stromal keratitis progressed in severity. Positive outcomes observed following the treatment with bevacizumab, compared to control, included: (1) Total involution of neovascularization, (2) reduction in disease severity, (3) improved corneal translucency, (4) absence of scarring, (5) preservation of corneal thickness, (6) no neutrophil infiltration of the cornea. Conclusions Subconjunctival administration of bevacizu- mab induced involution of new vessels, abolished inflam- matory response, and resulted in return of corneal function. Furthermore, bevacizumab is a novel approach for the treatment of herpetic stromal keratitis. Keywords Herpes . Keratitis . VEGF . Bevacizumab Background Herpes simplex virus type 1 (HSV-1) induces an ocular disease in humans named (HSK), a significant cause of ocular morbidity. This results from recurrent episodes of quiescent virus that reactivate in the cornea from the innervating ganglion [1]. A chronic immunoinflammatory syndrome is established that can lead to vision impairment and blindness [2]. Multiple early events occur that set the stage for the subsequent pathology, which include viral replication, the production of specific cytokines, and corneal neovascularization, which facilitates the inflamma- tory response [3]. Corneal angiogenesis contributes to persistent corneal damage [4, 5]. Continuous arrival of inflammatory cells into the stroma after viral replication takes place. CD4+ T cells, macrophages, and neutrophils are the main mediators in the pathogenesis of HSK [6, 7]. There are multiple molecules responsible for HSK- induced angiogenesis [8–10]. The VEGF family has a critical role in this process [11]. Recently, several angiogenesis inhibitors have been approved by the US Food and Drug Administration (FDA). Bevacizumab (Avastin; Genentech, South San Francisco, CA) has been approved for colorectal cancer and non-small-cell lung cancer treatment [12]. Graefes Arch Clin Exp Ophthalmol (2009) 247:1409–1416 DOI 10.1007/s00417-009-1101-y We have full control of all primary data and agree to allow Graefe’ s Archive for Clinical and Experimental Ophthalmology to review our data if requested. M. Saravia (*) : G. Zapata : P. Ferraiolo : L. Racca : A. Berra Laboratory of Investigation in Ophthalmology, Department of Pathology, School of Medicine, University of Buenos Aires, J.E. Uriburu 950, E.P, 1114 Buenos Aires, Argentina e-mail: mario.saravia@gmail.com