Recent advances in therapeutic applications of neutralizing antibodies for virus infections: an overview

Abstract

Antibodies are considered as an excellent foundation to neutralize pathogens and as highly specific therapeutic agents. Antibodies are generated in response to a vaccine but little use as immunotherapy to combat virus infections. A new generation of broadly cross-reactive and highly potent antibodies has led to a unique chance for them to be used as a medical intervention. Neutralizing antibodies (monoclonal and polyclonal antibodies) are desirable for pharmaceutical products because of their ability to target specific epitopes with their variable domains by precise neutralization mechanisms. The isolation of neutralizing antiviral antibodies has been achieved by Phage displayed antibody libraries, transgenic mice, B cell approaches, and hybridoma technology. Antibody engineering technologies have led to efficacy improvements, to further boost antibody in vivo activities. "Although neutralizing antiviral antibodies have some limitations that hinder their full development as therapeutic agents, the potential for prevention and treatment of infections, including a range of viruses (HIV, Ebola, MERS-COV, CHIKV, SARS-CoV, and SARS-CoV2), are being actively pursued in human clinical trials."

Keywords: Epitope; Glycoprotein; Humoral immune response; Monoclonal; Neutralizing antibodies; Phage display; Polyclonal.

Fig. 1

Techniques for isolation of antiviral antibodies. (a) Phage display library: isolation of antibody from B cells followed by PCR amplification of heavy and light chain genes of antibody. Phagemid is constructed, replicated, translated, and assembled into infective phages. They are then screened to select the desired antibody to clone for more antibodies production and washed undesired antibody. (b) Transgenic mice: A human gene locus knocked-in into an immunized transgenic mouse. B cell is harvested from mice and fused with a myeloma cell line to produce the humanized antibodies. (c) Single B cell technique: isolated B cell from infected patients transformed with Epstein-Barr virus (EBV) and polyclonal memory B cell–activating elements (irradiated mononuclear cells and CpG oligonucleotides), then screened to select the desired antibodies. (d) Humanization: complementarity determining regions (CDRs) graft with the appropriate framework region of the variable domains, then transferred into acceptor human antibody frameworks to produce the desired antibody

Fig. 2

Modes of viral neutralization. Antibodies neutralize viruses by several mechanisms, either inhibition of virus entry into host cells as (a) Antibodies bind to an epitope in the viral glycoprotein envelope, lead to inhibit attachment to host cells. (b) Antibodies through the fab region can bind to host cell receptors or coreceptors (have Fcγr)) lead to inhibit viral entry. Or post binding inhibition of antibody-virus complex as (c) antibodies can bind to a non-binding region in the virus envelope lead to inhibit the conformational change to allow membrane fusion. (d) for certain viruses that need low endosomal PH for conformational change, antibodies bind to viral inside the endosome lead to inhibit the change in PH to achieve the membrane fusion, and antibodies can inhibit the release of the viral virion

Fig. 3

The antiviral mechanism through antibody FC fragment.The Fc fragments of antibodies bind to the immune cells to perform neutralization activities. (a) Binding of complement to antibody activates complement-mediated virolysis and activation of phagocytosis. (b) Binding of antibodies to a phagocyte (Fcγr) via antibody-dependent cellular phagocytosis (ADCP) opsonizes the infected cell. (c) Antibodies bind to natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC) to lyse the infected cells