Neutralizing Antibodies: Role in Immune Response and Viral Vector Based Gene Therapy

Abstract

Neutralizing antibodies (nAbs) are an important component of the immune system, which plays a dual role in modern medicine. On the one hand, they significantly limit the effectiveness of gene therapy based on viral vectors, reducing the effectiveness of treatment of diseases such as spinal muscular atrophy, which is especially evident with repeated administration of therapeutic vectors. On the other hand, nAbs is a promising tool for combating viral infections. This review systematizes current data on the mechanisms of nAbs formation against AAV vectors, analyzes the factors influencing their production, and discusses strategies to overcome this limitation, including modification of vectors and the development of methods to suppress the immune response. Special attention is paid to the prospects of using nAbs as therapeutic agents against viral infections. The key problems and possible directions of research development in this area are considered, which is important for improving approaches to the treatment of both rare genetic and infectious diseases.

Keywords: antibodies; gene therapy; humoral immunity; immune response; immunogenicity of vectors; neutralizing antibodies; overcoming the immune response; tolerance to gene therapy; viral vectors.

Figure 1

nAbs’ mechanisms of action. (A) Successful viral transduction and attachment in the absence of nAbs. (B–E) Four primary mechanisms of action of nAbs. (B) Steric obstruction after viral attachment. Fusion of the viral and host cell membranes is blocked when a bulky antibody molecule interacts with the relevant viral site. The steric blockade can be enhanced by binding of the complex to the FcyR receptor on immune cells. (C) Aggregation of virions by nAbs prevents their attachment to host cell receptors. It can be enhanced by cross-binding of antibodies to the FcR receptor on the cell membrane. (D) Disruption or conformational modifications of viral spikes. Neutralization occurs when an antibody occupies a substantial number of accessible epitopes on the virion surface, leading to the inhibition of viral adhesion and impairing its entry. (E) Endosomal neutralization is carried out through the interaction of nAbs with the FcyRIIB receptor. nAbs can neutralize viruses within endosomes by preventing the release of viral genetic material, which obstructs its integration and replication within host cells. Intracellular antibody activity also includes interactions with receptors such as TRIM21.