Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody

Abstract

Despite the availability of antiviral chemotherapy, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections remain a severe global health problem. Of particular concern is the growing incidence of drug resistance in immunocompromised patients, which stresses the urgency to develop new effective treatment alternatives. We have developed a humanized monoclonal antibody (mAb hu2c) that completely abrogates viral cell-to-cell spread, a key mechanism by which HSV-1/2 escapes humoral immune surveillance. Moreover, mAb hu2c neutralized HSV fully independent of complement and/or immune effector cell recruitment in a highly efficient manner. Prophylactic and therapeutic administration of mAb hu2c completely prevented infection-related mortality of severely immunodeficient mice being challenged with a lethal dose of HSV-1. The high neutralization capacity of mAb hu2c was fully maintained toward clinical HSV isolates being multiresistant to standard antiviral drugs, and infection was fully resolved in 7/8 nonobese diabetic/SCID mice being infected with a multidrug resistant HSV-1 patient isolate. Immunohistochemical studies revealed no significant cross-reactivity of the antibody toward human tissues. These features warrant further clinical development of mAb hu2c as an immunotherapeutic compound for the management of severe and particularly drugresistant HSV infections.acyclovir resistance | immunocompromised mice | stem cell transplantation

Broad anti-herpesviral activity of α-hydroxytropolones

“…For example, clinical trials assessing the efficacy of oral and ophthalmologic anti-FHV-1 therapy in cats with FHV-1 revealed improved clinical signs with limited adverse effects (Fontenelle et al, 2008; Gould, 2011; Thomasy et al, 2011; Thomasy et al, 2016). In people, most anti-herpesviral therapeutics target the viral DNA polymerase, in which acquired mutations and subsequent viral resistance are a major limitation, especially in patients undergoing prolonged therapy (Collins and Darby, 1991; Gable et al, 2014; Krawczyk et al, 2013). Thus, a great need exists for novel anti-herpesviral compounds in both medical and veterinary medicine.…”

A Multiplexed Hybrid LC–MS/MS Pharmacokinetic Assay to Measure Two Co-Administered Monoclonal Antibodies in A Clinical Study

“…The strong binding affinity of mAbs allows them to bind specifically to target cells or proteins, which enhances efficacy, reduces systemic toxicity and, therefore, potentially increases the therapeutic index. In addition, mAbs have been increasingly explored in the therapy of infectious diseases, such as in various types of viral infections including herpes simplex virus (HSV) [3], hepatitis C virus (HCV) [4], or human immunodeficiency virus (HIV) [5]. Particularly, in the situations where drug resistance is developed in patients undergoing conventional antiviral treatments, mAbs offer novel and effective treatment alternatives as they demonstrate no significant cross-reactivity to human tissues.…”

The current state of vaccine development for ocular HSV-1 infection

“…Clinical trials for the Herpevac vaccine introduced a paradigm shift for the field by showing that antibody titer against gD but not cell mediated immunity is the correlate of protection against genital HSV-1 infection [64]. Antibody responses specific for gB have been shown to successfully prevent cell-to-cell spread of HSV-1, a mechanism classically associated with evasion of humoral immune responses [95,96]. Additionally, antibody titers generated from vaccination with various live-attenuated HSV-2 strains in mice and guinea pigs correlates with protection against challenge infection in mucosal sites including the eye [97].…”