Broadly Neutralizing Bovine Antibodies: Highly Effective New Tools against Evasive Pathogens?

Abstract

Potent antibody-mediated neutralization is critical for an organism to combat the vast array of pathogens it will face during its lifetime. Due to the potential genetic diversity of some viruses, such as HIV-1 and influenza, standard neutralizing antibodies are often ineffective or easily evaded as their targets are masked or rapidly mutated. This has thwarted efforts to both prevent and treat HIV-1 infections and means that entirely new formulations are required to vaccinate against influenza each year. However, some rare antibodies isolated from infected individuals confer broad and potent neutralization. A subset of these broadly neutralizing antibodies possesses a long complementarity-determining 3 region of the immunoglobulin heavy chain (CDR H3). This feature generates unique antigen binding site configurations that can engage conserved but otherwise inaccessible epitope targets thus neutralizing many viral variants. Remarkably, ultralong CDR H3s are a common feature of the cow antibody repertoire and are encoded by a single variable, diversity, joining (VDJ) recombination that is extensively diversified prior to antigen exposure. Recently, it was shown that cows rapidly generate a broadly neutralizing response upon exposure to HIV-1 and this is primarily mediated by these novel ultralong antibody types. This review summarises the current knowledge of these unusual CDR H3 structures and discusses their known and potential future uses.

Transchromosomic bovines‐derived broadly neutralizing antibodies as potent biotherapeutics to counter important emerging viral pathogens with a special focus on SARS‐CoV‐2, MERS‐CoV, Ebola, Zika, HIV‐1, and influenza A virus

“…BrNAbs with long CDR H3 are promising candidates for prophylaxis and antibody‐based immunotherapy 122,123 . Other viruses, such as influenza or SARS‐CoV‐2, 124 may benefit from a similar approach, eliminating the need for expensive annual vaccinations or offering a therapeutic response to prevent pandemic outbreaks 125 . The TcB platform for producing hIgs is still relatively new, and products are only now making their way into clinical trials.…”

“…122,123 Other viruses, such as influenza or SARS-CoV-2, 124 may benefit from a similar approach, eliminating the need for expensive annual vaccinations or offering a therapeutic response to prevent pandemic outbreaks. 125 The TcB platform for producing hIgs is still relatively…”

An Ultralong Bovine CDRH3 that Targets a Conserved, Cryptic Epitope on SARS-CoV and SARS-CoV-2

“…The structure of bovine ultralong antibodies makes them exceptionally well suited to achieve broad and potent neutralisation [24][25][26]. This subset of Abs possesses a long CDRH3 of 40-71 amino acids (aa) which forms an extended β-strand stalk supporting a disulphide-bonded 'knob' domain [25,27,28].…”

Reshaping the murine immunoglobulin heavy chain repertoire with bovine DH genes

“…Furthermore, early experiments showed that ultralong CDRH3 antibodies against bovine viral diarrhoea virus (BVDV) completely lost their ability to bind BVDV once the knob domain was removed. In this regard, we may infer that ultralong CDRH3s could bind to or recognize antigen epitopes independently and therefore have great potential applications [36][37][38]. Very recently, special knob domain antibodies with an approximately 4.2 kDa of molecular weight, even smaller than nanobodies, have been reported to be derived from ultralong bovine CDRH3 [39].…”