Interaction with complement factor C1q can contribute to and improve monoclonal antibody-mediated protection against lethal HSV-1 challenge

Abstract

Herpes simplex virus (HSV) has extensive strategies to evade host defense, including mechanisms that limit clearance by the complement cascade. Using Fc engineering, we incorporated a complement-enhancing (E430G, EG) or a complement-abrogating mutation (K322A, KA) to a panel of glycoprotein D- and glycoprotein B-specific monoclonal antibodies (mAbs) to assess the role of complement-driven antiviral activity in a neonatal mouse HSV-1 infection model. In vitro characterization confirmed that Fc modifications preserved antigen recognition while selectively amplifying or reducing complement activity. In vivo, complement modulation altered the protective capacity of select mAbs to protect against lethal HSV-1 challenge, demonstrating that complement contributes to antibody-mediated control of HSV-1 infection in an antibody- and antigen-dependent manner. The differential effects observed across the mAb panel indicate that complement activity does not function as a uniform determinant of antibody efficacy, but instead operates in concert with antibody-specific properties to shape antiviral protection. Collectively, these findings establish complement-mediated activity as an important component of antibody function in HSV-1 infection, and highlight Fc engineering as a strategy to optimize antibody-mediated protection. More broadly, these findings underscore the multifaceted nature of antibody-mediated protection and provide a mechanistic framework for considering complement-dependent functions in the development of antibody-based therapeutics.