Ocular distribution, spectrum of activity, and in vivo viral neutralization of a fully humanized anti-herpes simplex virus IgG Fab fragment following topical application.
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 μg/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.
INSERM, UMR S 872, Les Cordeliers, Paris, France. francine.behar@gmail.com
Marianne
M
Berdugo
Inna V
IV
Larsen
Claire
C
Abadie
Catherine
C
Deloche
Laura
L
Kowalczuk
Elodie
E
Touchard
Richard
R
Dubielzig
Curtis R
CR
Brandt
Francine
F
Behar-Cohen
Jean-Marc
JM
Combette
D000287:Administration, Topical; D000595:Amino Acid Sequence; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D000914:Antibodies, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D024882:Drug Resistance, Viral; D019573:Epithelium, Corneal / Q000378:metabolism; D005123:Eye / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D016849:Keratitis, Herpetic / Q000188:drug therapy / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009457:Neuroglia / Q000378:metabolism; D051381:Rats; D012160:Retina / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D014018:Tissue Distribution; D014271:Trifluridine / Q000008:administration & dosage
D061067:Antibodies, Monoclonal, Humanized; D000914:Antibodies, Viral; D000998:Antiviral Agents; D007140:Immunoglobulin Fab Fragments; D014271:Trifluridine