Since the dawn of antibody engineering in the 1980s, we've been working to improve the safety and effectiveness of therapeutic antibodies. After screening hundreds of mutants we discovered a new Fc variant, which for the first time has truly silenced binding to Fc gamma receptors.
Antibodies - Nature's pro-drugs
... but sometimes things go wrong
That's fine for fighting infections, or treating cancer, but when therapeutic antibodies are needed for other applications, release of immune mediators may be the last thing you want. A tragic example occurred in 2006, when six healthy volunteers were treated with the CD28 antibody TGN1412 causing a devastating cytokine storm with long-lasting effects.
TGN1412 was an IgG4 antibody, once thought to be unable to bind to human Fc receptors. But that was not the case. Today developers seek to limit unwanted inflammatory effects by using antibodies with Fc domains that have been mutated to reduce binding to Fc receptors. Mutations like LALA (L234A/L235A) or aglycosyl (N287A)) are commonly used. Many others have been described. But none are truly silent.
Our new variant completely eliminates binding to Fc receptors
Unlike other variants, it shows no binding to Fc gamma receptors. The graph shows the binding to FcgRI (CD64) of various Fc variants used in therapeutic antibodies, compared with wild-type IgG1. All showed significant binding (and corresponding cellular activity). In comparison, the binding and activity of our new variant is completely eliminated. Similar results are obtained with the other receptors FcgRII (CD32) and FcgRIII (CD16) and also with binding to complement component C1q.
The mutations can be used with all isotypes and are compatible with other commonly used Fc variants (e.g. half-life extension).
Extensive testing shows that they do not compromise binding to FcRn nor the manufacturability, stability or immunogenicity of antibodies