Geoff Hale: 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.
Geoff trained as a biochemist at Cambridge. In 1980 he joined Herman Waldmann to research therapeutic antibodies. From this came the first humanised antibody, Campath, a powerful immunosuppressant and treatment for CLL and multiple sclerosis. In 1995, Herman and Geoff moved to Oxford and set up a centre to manufacture monoclonal antibodies. The Therapeutic Antibody Centre supplied more than 25 new antibodies for clinical trials in over 5000 patients worldwide and went on to produce the Oxford coronavirus vaccine. In 2002 Geoff founded BioAnaLab, a service laboratory specialising in the analysis of biologics. In 2009 the company was acquired by Millipore and Geoff went on to found two other successful companies, Native Antigen Company and Absolute Antibody. Now he works as a scientist, consultant and company director, with interests in the development of a next generation oncolytic virus. His latest enterprise, mAbsolve, is devoted to the improvement of safety and efficacy of therapeutic antibodies by identifying mutations in the Fc domain which optimise their function.