Fc receptors and their influence on efficacy of therapeutic antibodies for treatment of viral diseases

Abstract

The lack of vaccines against several important viral diseases necessitates the development of therapeutics to save lives and control epidemics. In recent years, therapeutic antibodies have received considerable attention due to their good safety profiles and clinical success when used against viruses such as respiratory syncytial virus, Ebola virus and Hendra virus. The binding affinity of these antibodies can directly impact their therapeutic efficacy. However, we and others have also demonstrated that the subtype of Fc-gamma receptors (FcγRs) engaged influences the stoichiometric requirement for virus neutralization. Hence, the development of therapeutic antibodies against infectious diseases should consider the FcγRs engaged and Fc-effector functions involved. This review highlights the current state of knowledge about FcγRs and FcγR effector functions involved in virus neutralization, with emphasis on factors that can affect FcγR engagement. A better understanding of Fc-FcγR interactions during virus neutralization will allow development of therapeutic antibodies that are efficacious and can be administered with minimal side effects.

Keywords:

• antibody
• Fc-effector functions
• Fc-receptors
• neutralization
• therapeutics

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• The lack of effective vaccines against multiple infectious diseases necessitates the development of new therapeutics.

• Therapeutic antibodies are increasingly used for the treatment of infectious diseases as they are well-established and well-tolerated by humans.

• Therapeutic antibodies targeted against similar antigenic targets may differ in clinical profile, depending on the type of FcγRs that are engaged.

• Interaction between antibody Fc region and activating FcγRs can trigger Fc-mediated effector functions that are essential for virus neutralization.

• For viruses that can infect FcγR-bearing cells, therapeutic antibodies should be able neutralize viruses intracellularly to minimize the risk of ADE.

• Cytokine production from activating FcγR signaling is essential for enhanced antigen presentation and antiviral responses.

• Antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity mediated by therapeutic antibodies can directly kill virus infected cells.

• A better understanding of how therapeutic antibodies neutralize virus infections can allow development of modified therapeutic antibodies with improved therapeutic efficacy and reduced side effects.

Notes