Frontiers in immunology · 2026
Discovering novel therapeutic VHHs for emerging viruses: perspectives from VEEV selection strategies.
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LaPointe Autumn T, Ferrara Fortunato, Zupancic Jennifer M, Montoya Alba L, Schmidt Jurgen, Hung Li-Wei, Kell Alison M, Velappan Nileena
Аннотация
INTRODUCTION: Evolution or emergence of a new viral variant is a significant public health concern. Alphaviruses, such as Venezuelan equine encephalitis virus (VEEV), are mosquito-borne viruses which are becoming more prevalent due to expansion of vector habitats. Despite this, there are currently no antiviral therapies or FDA-approved vaccines available to treat or prevent VEEV infection. The increased prevalence of such viruses provides opportunities for novel variants to evolve. Key therapeutic molecules that could be developed against viral pathogens are recombinant antibodies or antibody fragments, such as the variable heavy domain of heavy chain antibodies (VHHs).
METHODS: In vitro selections offer a promising pathway for identification of therapeutic antibodies, here we explored isolation of VHHs using phage and yeast display methodology with three antigen formats 1) recombinant E2, 2) linear peptides of E2, selected based on molecular dynamics analysis, and 3) UV inactivated virus.
RESULTS: Here we report four novel "human" VHHs which bind to the VEEV E2 protein selected using different strategies that include both computational and biochemical design of suitable antigens and whole virus selections. These VHHs have distinct complementarity-determining regions (CDRs). Multiple VHHs bind to the VEEV viral particles in ELISAs, and we report the peptide epitope recognized by these VHHs.
DISCUSSION: Though non-neutralizing, these VHHs bind to and sequester VEEV viral particles preventing infection, demonstrating the potential of these VHHs to perform viral "sponging" which represents a novel therapeutic approach. The selection strategies we report may have applications to further antibody developments against other viruses.
METHODS: In vitro selections offer a promising pathway for identification of therapeutic antibodies, here we explored isolation of VHHs using phage and yeast display methodology with three antigen formats 1) recombinant E2, 2) linear peptides of E2, selected based on molecular dynamics analysis, and 3) UV inactivated virus.
RESULTS: Here we report four novel "human" VHHs which bind to the VEEV E2 protein selected using different strategies that include both computational and biochemical design of suitable antigens and whole virus selections. These VHHs have distinct complementarity-determining regions (CDRs). Multiple VHHs bind to the VEEV viral particles in ELISAs, and we report the peptide epitope recognized by these VHHs.
DISCUSSION: Though non-neutralizing, these VHHs bind to and sequester VEEV viral particles preventing infection, demonstrating the potential of these VHHs to perform viral "sponging" which represents a novel therapeutic approach. The selection strategies we report may have applications to further antibody developments against other viruses.