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Review
. 2015 Jul 13;6:315.
doi: 10.3389/fimmu.2015.00315. eCollection 2015.

Antibody-Based Strategies to Prevent and Treat Influenza

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Free PMC article
Review

Antibody-Based Strategies to Prevent and Treat Influenza

Zachary Shriver et al. Front Immunol. .
Free PMC article

Abstract

Passive immunization using antibodies is a promising alternative to other antiviral treatment options. The potential for seasonal protection arising from a single injection of antibodies is appealing and has been pursued for a number of infectious agents. However, until recently, antibody-based strategies to combat infectious agents have been hampered due to the fact that most antibodies have been found to be strain specific, with the virus evolving resistance in many cases. The discovery of broadly neutralizing antibodies (bNAbs) in influenza, dengue virus, and HIV, which bind to multiple, structurally diverse strains, has provided renewed interest in this area. This review will focus on new technologies that enable the discovery of bNAbs, the challenges and opportunities of immunotherapies as an important addition to existing antiviral therapy, and the role of antibody discovery in informing rational vaccine discovery - with agents targeting influenza specifically addressed. Multiple candidates have entered the clinic and raise the possibility that a single antibody or small combination of antibodies can effectively neutralize a wide variety of strains. However, challenges remain - including combating escape variants, pharmacodynamics of antibody distribution, and development of efficacy biomarkers beyond virologic endpoints.

Keywords: hemagglutinins; influenza A virus; monoclonal antibodies; mutations; therapeutics; viral.

Figures

Figure 1
Figure 1
(A) Network-view of bNAb epitopes. HA trimer is represented in a solvent accessible surface format and colored based on normalized residue network scores. Coloring varies from white to red where white indicates poorly networked residues and red indicates highly networked residues. The three bNAb epitopes are highlighted by dotted borderlines (green: antibody targeting trimeric interface; blue: CR6261; pink: CR8020). The 2D network map of the epitope is also shown. A network is made up of nodes and edges. Nodes colored in red indicate functional epitope residues whereas nodes colored in blue indicate residues that are in the network environment of the epitope residues. (B) Different bispecific formats that have demonstrated activity against infectious disease targets. (a) A dual-variable domain immunoglobulin format containing two distinct Vh-Vl pairings (one in red and one in green) has demonstrated activity against hepatitis B. (b) A bispecific format where a single chain variable region against Psl (red) targets the antibody to the cell surface of Pseudomonas enables engagement of a traditional Vh-Vl paratope with the rarer PcrV target. (c) Crosslinking of binding domains of variable and constant regions (VH-CH1/VL-CL; Fabs), either homotypic (left) or heterotypic (right) with a defined DNA-based spacer enables more potent neutralization of HIV virus.

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