[R21] Targeting Evasion Factors: Discovery of novel antibodies for durable suppression of HSV reactivation

Ente: National Institute of Allergy and Infectious Diseases

Scadenza: 2028-03-31

Importo max: 215.758 EUR

Paese: US

Descrizione

ABSTRACT Chronically-reactivating HSV is an underserved disease. Beyond lesions suffered by affected individuals, reactivation results in risk of transmission to others, especially as subclinical reactivation occurs with high frequency. Further, the isolation of ACV resistant strains, the inability of long-term ACV treatment to fully control reactivation, and the emerging evidence for HSV infection as a risk factor for neurodegeneration provide strong rationale for development of novel therapies to reduce rates of reactivation. Promisingly, epidemiological and preclinical evidence supports the ability of antibodies to modify rates of reactivation. However, because reactivation takes place in individuals with endogenous antibodies, there is reason to believe that monoclonal antibodies (mAbs) with attributes distinct from those commonly induced by natural infection will be needed to provide optimal benefit in this challenging clinical setting. To this end, diverse viral glycoproteins function to evade host defenses, and targeting these activities could both interfere with viral pathogenesis and drive immune-mediated clearance. Glycoproteins E and I form a complex (gE/gI) thought to function by binding to the IgG Fc domain and sweeping virus-specific Ab off the surface of virions and infected cells for degradation. Glycoprotein C (gC) inhibits complement activation by binding C3b. Both glycoproteins facilitate cell-to-cell spread. Blocking these host evasion and viral spreading mechanisms through binding of mAb Fab domains at the same time as driving innate immune clearance mechanisms through the effector functions of the Fc domain has the potential to turn these evasion mechanisms from assets into vulnerabilities. We hypothesize that mAbs targeting viral evasion factors gE/gI and gC will exhibit both direct and indirect antiviral effects. They will inhibit the functions of these evasion factors and contribute to viral and infected cell clearance through Fc-domain dependent effector functions. These activities can be further enhanced by Fc engineering, synergistically increasing the contribution of multiple mechanisms of action to the antiviral effects of mAbs in vivo. Our objective is to initially isolate and then systematically optimize mAbs with antiviral activity in vivo in reducing reactivation in mouse and guinea pig models. The rationale for this project is supported by the clinically apparent need to improve Ab potency to achieve robust reduction of reactivation, and preliminary data that Fc engineering can substantially improve mAb antiviral activity in vivo. Istituzione: DARTMOUTH COLLEGE PI: Margaret E Ackerman, David A Leib Progetto: 1R21AI195395-01

Settori: National Institute of Allergy and Infectious Diseases

Vai al bando originale

Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.