Fc-Dependent Immunomodulation Induced by Antiviral Therapeutic Antibodies: New Perspectives for Eliciting Protective Immune Responses

Abstract

The multiple mechanisms of action of antiviral monoclonal antibodies (mAbs) have made these molecules a potential therapeutic alternative for treating severe viral infections. In addition to their direct effect on viral propagation, several studies have shown that mAbs are able to enhance the host's adaptive immune response and generate long-lasting protective immunity. Such immunomodulatory effects occur in an Fc-dependent manner and rely on Fc-FcγR interactions. It is noteworthy that several FcγR-expressing cells have been shown to play a key role in enhancing humoral and cellular immune responses (so-called "vaccinal effects") in different experimental settings. This review recalls recent findings concerning the vaccinal effects induced by antiviral mAbs, both in several preclinical animal models and in patients treated with mAbs. It summarizes the main cellular and molecular mechanisms involved in these immunomodulatory properties of antiviral mAbs identified in different pathological contexts. It also describes potential therapeutic interventions to enhance host immune responses that could guide the design of improved mAb-based immunotherapies.

Keywords: FcγR; antiviral immunity; antiviral monoclonal antibodies; immunomodulation; immunotherapy; vaccinal effect.

Figure 1

Fc-FcγR interactions constitute a very versatile system to modulate immune responses. The different properties of antibodies (affinity, specificity, isotype, Fc-glyco-engineering, etc.) in addition to the complexity of FcγRs biology (multiple FcγRs, different antibody expression patterns and affinities, multiple FcγR-expressing cells with specific functions, etc.) allow a myriad of immune functions capable of controlling viral spread and modulating immune responses.

Figure 2

Mechanisms involved in the induction of vaccinal effects. Short treatment of retrovirus-infected mice with a therapeutic monoclonal antibody (mAb) induces a long-term protective response. This is due to (A) the establishment of a humoral antiviral response, (B) the induction of a cellular antiviral response, and (C) the inhibition of immunosuppressive responses (i.e., lack of development of the regulatory T cell response). The mechanisms underlying the induction of protective immunity have been described in this mouse model of a retroviral infection. It has been shown that neutrophils acquire B cell helper functions and are required for the induction of the humoral response (A). Neutrophils also cooperate with monocytes and NK cells to enhance protective immunity. It has also been described that FcγRIV play a key role in the immunomodulatory function of neutrophils and monocytes. Dendritic cells are activated by immune complexes (ICs) formed between the virus and the mAb via their interaction with FcγRs. This results in the enhancement of the antiviral cellular response (B). NK cells are involved in the induction of humoral and cellular responses (A and B), but also, through their ability to control viral spread, they play a role in preventing the development of immunosuppressive immune responses (C) (i.e., the expression of molecules involved in immunosuppressive pathways, such as CD39, PD1, and PD1-L, which are associated with immune cell exhaustion). Thus, several immune cells are involved and may cooperate in establishing a long-term protective immune response.