Human ADCC-Mediating Monoclonal Antibodies for Treatment and Prevention of HSV

About This Grant

New approaches such as monoclonal antibodies (mAbs) are needed to treat genital and neonatal herpes simplex virus (HSV) infections and reduce the frequency and magnitude of viral reactivation. Technological advances that reduce manufacturing costs, extend monoclonal antibody half-life and augment cytolytic activity highlight the potential for mAbs to alter the natural history of lifelong infections such as HSV. The few mAbs in preclinical or clinical development were designed to provide neutralizing activity but none has demonstrated therapeutic efficacy or been approved for clinical use. We propose a fundamentally different strategy and will prioritize the identification, characterization, and development of human mAbs whose primary protective mechanism is antibody-dependent cellular cytotoxicity (ADCC). The rationale for this paradigm shift builds from preclinical mouse data with candidate vaccines and clinical studies demonstrating that ADCC plays a critical role in immune protection and may surpass the efficacy of neutralizing antibodies. We found that ∆gD-2, a candidate vaccine strain deleted in glycoprotein D, provided significantly greater active and passive protection compared to the adjuvanted glycoprotein D protein vaccine (gD/AS04) against clinical isolates of HSV-1 and HSV-2 following vaginal, skin, or neonatal challenge in female and male mice. Results recapitulated clinical trial outcomes with gD/AS04. The passive transfer studies demonstrated that protection was mediated by antibodies with ADCC, but not neutralizing, activity. We isolated and evaluated mAbs from the ΔgD-2-vaccinated mice and identified several that provided significant protection when administered before or after viral challenge. Cryo-EM studies localized the epitope of the most potent ADCC-mediating mAb isolated to domain IV of HSV glycoprotein B. We hypothesize that combinations of mAbs that target different viral proteins, different epitopes on the same protein, and/or act via different mechanisms will provide the best protection against HSV. We will use the ∆gD-2 vaccine mouse model as a tool to identify candidate targets and isolate human mAbs from a biorepository of human peripheral blood mononuclear cells isolated from donors with chronic HSV infection. The antibodies will be evaluated in vitro for antiviral activity including ADCC, antibody-dependent cellular phagocytosis, and neutralization (complement independent and complement enhanced), as well as breadth of activity against clinical isolates. We will identify the antigenic targets and map epitopes of the most potent mAbs. We will then test the mAbs alone and in combination in optimized mouse models of primary, recurrent, and neonatal disease. The ADCC-mediating mAbs will be configured as mouse IgG2c for studies in wild-type mice and as human IgG1 for studies in mice expressing human Fcγ receptors. Results obtained will enable us to select the best mAbs and combinations to advance for clinical development.