Antiviral Monoclonal Antibodies: Can They Be More Than Simple Neutralizing Agents?

Abstract

Monoclonal antibodies (mAbs) are increasingly being considered as agents to fight severe viral diseases. So far, they have essentially been selected and used on the basis of their virus-neutralizing activity and/or cell-killing activity to blunt viral propagation via direct mechanisms. There is, however, accumulating evidence that they can also induce long-lasting protective antiviral immunity by recruiting the endogenous immune system of infected individuals during the period of immunotherapy. Exploiting this property may revolutionize antiviral mAb-based immunotherapies, with benefits for both patients and healthcare systems.

Keywords: Fc receptors; antiviral therapy; immune complexes; immunotherapy; monoclonal antibodies; vaccine-like effects.

Figure 1

Fc Fragment(Fc)-Mediated Activities of Antiviral Monoclonal Antibodies (mAbs). (A) Upon administration, an antiviral mAb can opsononize virus, as well as infected cells if the viral antigen is also expressed on their surface. This can lead to virus elimination by complement activation and/or phagocytosis mediated by cells of the innate immune system. Infected cells can also be eliminated by complement-dependent cytotoxicity (CDC) as well as by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or antibody-dependent cellular phagocytosis (ADCP) mediated by FcγR-bearing effector cells. (B) Immune complexes (IC), constituted by mAb-coated virions or infected cells, can be recognized by FcγRs expressed on antigen-presenting cells such as dendritic cells (DC). Such IC recognition leads to enhanced antigen uptake and presentation, allowing induction of stronger humoral and cellular antiviral immune responses. Abbreviation: NK cells, natural killer cells.

Figure 2

Key Figure: Induction of Life-Long Protective Immunity Against FrCasE by Neutralizing Antiviral Monoclonal Antibodies (mAbs) The administration, to FrCasE-infected mice, of a neutralizing antiviral IgG2a mAb directed to the viral Env glycoprotein limits viral propagation through neutralization of virus (a) and elimination of infected cells (b). At the same time, the immune complexes (ICs) formed with the virus, and probably more importantly with infected cells expressing Env at their surface, prevent the expansion of regulatory T cells (Treg cells) (c), which is necessary for the development of protective humoral (d) and cellular (e, f) responses by the host. In particular, the ICs formed between the therapeutic mAbs and infected cells activate dendritic cells (DCs), leading to an enhanced virus-specific CD8 T-cell response (f). Once the therapeutic antibody has been eliminated from treated mice, both arms of the adaptive immune system contribute to viral propagation control, as the endogenous antiviral antibodies, induced by the immunotherapy, control viral propagation (g, h) and contribute to the maintenance of a T-cell memory response. This requires the formation of ICs engaging residual infected cells and activation of DCs (i). Abbreviation: ADCC, antibody-dependent cell-mediated cytotoxicity.

Figure 3

Possible Improvements in Monoclonal Antibody(mAb)-Based Antiviral Immunotherapies. The identification of the molecular and cellular mechanisms responsible for the induction of vaccine-like effects by antiviral mAbs will be paramount to the improvement of future antiviral passive immunotherapies. They are currently the object of intense research. Furthermore, several possibilities pertaining to the conditions of mAb administration, the mAbs themselves, and their targets, can already be considered. These include combined therapies affecting viral propagation and/or enhancing immune responses; engineering mAbs to improve their effector functions, i.e., increasing their binding to Fcγ receptors (FcγRs) by affecting their glycosylation or their amino acid sequence; pertinent selection of their isotype; taking into account FcγR polymorphisms in patients to be treated; and selecting the most appropriate viral antigens.