I started my PhD at the LMB with Brian Hartley in 1973, working on the sequencing of the enzyme tyrosyl tRNA synthetase (TyrTS), followed by a postdoc with George Brownlee on the sequencing of influenza virus genes. In 1981, in collaboration with Alan Fersht (then at Imperial College London), I used oligonucleotide-directed mutagenesis of the TyrTS gene to dissect out the contributions of amino acid residues at the active site of the enzyme to catalysis. Subsequently my work focussed on antibodies.
In the 1980s, we developed a method for humanising mouse antibodies. The technology was widely licensed by the MRC to biotechnology and pharmaceutical companies, and led to the commercial development of many therapeutic antibodies, including Keytruda, which became the world’s top-selling pharmaceutical drug.
By the late 1980s, we had developed a method for making human antibodies from libraries of antibody genes. The genes were expressed as small antigen-binding fragments fused to the coat protein of a filamentous bacteriophage, and phage directed against specific antigens captured on solid phase. The corresponding antibody genes were then rebuilt into complete antibodies for expression in large-scale mammalian cell culture. This method led to the development of Humira, until recently the world’s top selling pharmaceutical drug, and to a share of the 2018 Nobel Prize in chemistry. The phage antibody technology was developed commercially through two start-up companies I founded: Cambridge Antibody Technology in 1989 which floated on the London Stock Exchange in 1997 and was bought by AstraZeneca in 2006, and Domantis in 2000, which was bought by GSK in 2007.
More recently, we used the same evolutionary method to develop bicyclic peptides as tiny antibody mimics, and exploited this through Bicycle Therapeutics in 2009, which floated on NASDAQ in 2019. Several ‘bicycles’ are currently in clinical trials.
During my career at the LMB, I served as Head of the PNAC Division (1994-2008), as Deputy Director of the MRC Centre for Protein Engineering (1990-2010) and Deputy Director of the LMB (2006-2011). Now retired, my current interests involve helping in the development of antibody and peptide medicines through advice to venture capital investors, and by serving on the boards of relevant companies.