Prevention of Herpes Simplex Virus Induced Stromal Keratitis by a Glycoprotein B-Specific Monoclonal Antibody

Abstract

The increasing incidence of acyclovir (ACV) and multidrug-resistant strains in patients with corneal HSV-1 infections leading to Herpetic Stromal Keratitis (HSK) is a major health problem in industrialized countries and often results in blindness. To overcome this obstacle, we have previously developed an HSV-gB-specific monoclonal antibody (mAb 2c) that proved to be highly protective in immunodeficient NOD/SCID-mice towards genital infections. In the present study, we examined the effectivity of mAb 2c in preventing the immunopathological disease HSK in the HSK BALB/c mouse model. Therefore, mice were inoculated with HSV-1 strain KOS on the scarified cornea to induce HSK and subsequently either systemically or topically treated with mAb 2c. Systemic treatment was performed by intravenous administration of mAb 2c 24 h prior to infection (pre-exposure prophylaxis) or 24, 40, and 56 hours after infection (post-exposure immunotherapy). Topical treatment was performed by periodical inoculations (5 times per day) of antibody-containing eye drops as control, starting at 24 h post infection. Systemic antibody treatment markedly reduced viral loads at the site of infection and completely protected mice from developing HSK. The administration of the antiviral antibody prior or post infection was equally effective. Topical treatment had no improving effect on the severity of HSK. In conclusion, our data demonstrate that mAb 2c proved to be an excellent drug for the treatment of corneal HSV-infections and for prevention of HSK and blindness. Moreover, the humanized counterpart (mAb hu2c) was equally effective in protecting mice from HSV-induced HSK when compared to the parental mouse antibody. These results warrant the future development of this antibody as a novel approach for the treatment of corneal HSV-infections in humans.

Lymphangiogenesis: a new player in herpes simplex virus 1‐triggered T‐cell response

“…A number of approaches have been explored to counteract HSV‐1 infection. Notably, monoclonal antibodies have recently been developed to neutralize both circulating virions and viral transmission, 9 and an alternative strategy to block HSV‐1‐induced LG has been achieved using anti‐VEGF‐A monoclonal antibody in mice 4 . On the basis of additional new information provided by this study, 1 lymphatic‐based therapy should offer a promising new strategy to treat HSV‐1 infections.…”

Immunotherapeutic strategies for sexually transmitted viral infections: HIV, HSV and HPV

“…Humanized monoclonal antibody mAb hu2c were administered in mice and resulted in inhibition of cell-to-cell viral transmission a key mechanism by which HSV-1/2 escapes humoral immune surveillance. mAb hu2c was found to neutralize HSV fully independent of complement or/and recruit immune effector cell in a highly efficient manner [167,168]. These features guarantee the clinical development of mAb hu2c for treatment of HSV infections in drug-resistant and immunocompromised patients.…”

A Therapeutic Antiviral Antibody Inhibits the Anterograde Directed Neuron-to-Cell Spread of Herpes Simplex Virus and Protects against Ocular Disease

“…Topical treatment was carried out by periodical inoculations (five times a day) of the ipsilateral and contralateral eye with 5 μl (20 μg) of mAb 2c solution (in PBS; eye drops) started at 24 h post-infection until day 12. The antibody dose of 300 μg/injection was adjusted according to our prior studies where we demonstrated the efficacy of these antibodies in the NOD/SCID mouse model for immune deficiency ( Krawczyk et al, 2013 ) and BALB/c model for HSK ( Krawczyk et al, 2015 ). Moreover, 15 mg/kg body weight (equal to 300 μg/mouse) represents the dosage for palivizumab, the only humanized antiviral antibody (IgG1, like mAb hu2c) that was approved by the Food and Drug Administration for the reduction of serious lower respiratory tract infections caused by the respiratory syncytial virus ( Brady et al, 2014 ).…”

“…Furthermore, they successfully block the cell-to-cell transmission of HSV between infected and non-infected Vero cells ( Krawczyk et al, 2011 , 2013 ). Moreover, these antibodies effectively prevented mice from the development of a lethal infection in the NOD/SCID mouse model for immunosuppression ( Krawczyk et al, 2013 ) and from HSK in the corresponding mouse model ( Krawczyk et al, 2015 ). Besides generalized infections that may lead to lethal encephalitis and infections of the cornea resulting in HSK, infections of the cornea with HSV are a severe disease that urgently needs an improved therapy.…”