Characterisation of novel antibodies which are completely silenced with respect to Fc binding function

For forty years, I’ve been researching therapeutic antibodies with a particular interest in effector functions of the Fc region. With Herman Waldmann and Greg Winter, I took several of the early engineered antibodies into the clinic. We realised that activation of immune effector systems is not always desirable, but found that mutations designed to reduce binding to Fc receptors (e.g. ‘LALA’, aglycosyl) were not completely effective. At mAbsolve we have screened hundreds of new variants and identified some which are completely devoid of binding to Fc receptors.
Receptor binding is one thing, but cellular activity is more important. The modest binding levels of previous variants translated to quite substantial cellular activity, but our new variants remained completely negative. The risk of unwanted immunogenicity is always a concern when proteins are modified, but the variants gave no increased risk signals either in silico or in vitro.
The optimised Fc variant is comparable with wild type IgG for binding to FcRn, stability and manufacturability and is available for licensing.