Ocular Distribution, Spectrum of Activity, and In Vivo Viral Neutralization of a Fully Humanized Anti-Herpes Simplex Virus IgG Fab Fragment following Topical Application

Abstract

Herpes simplex ocular infection is a major cause of corneal blindness. Local antiviral treatments exist but are associated with corneal toxicity, and resistance has become an issue. We evaluated the biodistribution and efficacy of a humanized anti-herpes simplex virus (anti-HSV) IgG FAb fragment (AC-8; 53 kDa) following repeated topical administration. AC-8 was found in the corneal epithelium, anterior stroma, subepithelial stromal cells, and retinal glial cells, with preferential entry through the ocular limbus. AC-8 was active against 13 different strains of HSV-1, with 50% and 90% mean effective concentrations (MEC 50 and MEC 90 , respectively) ranging from 0.03 to 0.13 g/ml, indicating broad-spectrum activity. The in vivo efficacy of AC-8 was evaluated in a mouse model of herpes-induced ocular disease. Treatment with low-dose AC-8 (1 mg/ml) slightly reduced the ocular disease scores. A greater reduction of the disease scores was observed in the 10-mg/ml AC-8-treated group, but not as much as with trifluridine (TFT). AC-8 treatment reduced viral titers but less than trifluridine. AC-8 did not display any toxicity to the cornea or other structures in the eye. In summary, topical instillation of an anti-HSV FAb can be used on both intact and ulcerated corneas. It is well tolerated and does not alter reepithelialization. Further studies to improve the antiviral effect are needed for AC-8 to be considered for therapeutic use.

In Vivo Anti-Herpes Simplex Virus Activity of a Sulfated Derivative of Agaricus brasiliensis Mycelial Polysaccharide

“…Previously, we characterized the antiviral activity of MI-S against one HSV-1 and one HSV-2 strain. To determine if MI-S had broad-spectrum activity against herpes simplex virus, we assessed the activity against four ocular HSV-1 isolates (CJ 360, CJ311, CJ394, and OD4 [19,20]) as well as HSV-1 KOS and HSV-2 333 in a yield reduction assay, adding the MI-S either simultaneously with the virus or 1 h after the adsorption period. The resulting EC 50 s are shown in Table 1.…”

“…The antiviral spectrum of activity of MI-S against HSV-1 strains CJ311, CJ360, CJ394, OD4 (19,20), and KOS as well as HSV-2 strain 333 was evaluated by yield reduction assay. Briefly, Vero cells (2.5 ϫ 10 5 cells/ml) were seeded into 24-well plates and incubated for 24 h at 37°C in a CO 2 incubator.…”

Targeted localized use of therapeutic antibodies: a review of non-systemic, topical and oral applications

“…Consequently, the ability of topically applied antibody to penetrate the surface of the eye has been extensively studied in recent years. Low-MW antibody fragments in the form of eye drops have been shown to give good ocular penetration with the potential to reach therapeutic levels within the anterior and even posterior chambers (Figure 2) in human and animal models (Berdugo et al, 2012;Brereton et al, 2005;Ferrari et al, 2013;Furrer et al, 2009;Lichtlen et al, 2010;Ottiger et al, 2009;Stevenson et al, 2012;Thiel et al, 2002;Thiel et al, 2013;Williams et al, 2013). Preliminary clinical studies with topical VEGF inhibitor monoclonal antibodies indicated that the low-MW (48 kDa) Fab (Ranibizumab) is modestly superior to the larger MW (149 kDa) IgG (Bevacizumab) at inhibiting corneal neovascularization via this route (Stevenson et al, 2012).…”

“…Infection of the surface or cornea of the eye may be caused by a range of infectious agents, such as the Herpes simplex virus or bacteria including Pseudomonas aeruginosa and Corynebacterium diphtheriae, and can result in blindness if left untreated (Berdugo et al, 2012;Roy et al, 2008;Zaidi et al, 2012). The current treatment for ocular herpes is the locally applied antiviral drug trifluridine.…”

“…Limitations of this treatment are the corneal toxicity associated with its use and the inability to treat resistant strains of the Herpes simplex virus. Consequently, work is currently underway to develop a virus-neutralizing topical antibody therapy (Berdugo et al, 2012;Klager et al, 1993). Bacterial infections of the eye normally respond well to an appropriate antibiotic treatment.…”