Dr Gerry Gallacher and Dr Elizabeth Ostler
Introduction
Catalytic antibodies are antibodies that also have the properties of enzymes - they can catalyse or accelerate chemical reactions. Under normal circumstances antibodies simply recognise and bind to molecules. Enzymes, on the other hand recognise molecules and catalyse reactions of those molecules. Enzymes do this because they bind to high energy intermediates (transition states) in the reaction rather than the starting molecules. By immunising with analogues of high energy intermediates (transition states) antibodies are generated that bind these high energy intermediates and so behave like enzymes. They catalyse the reactions of the starting molecules.
The importance of this is that we can design and generate catalytic antibodies that will accelerate reactions for which there are no known enzymes. One can imagine this being used in medical treatments and in industrial and biotechnological applications.
Discoveries
Catalytic antibodies were produced for the first time in 1986 by two groups in the U.S. They produced monoclonal antibodies that catalysed the hydrolysis of esters and carbonates. Our group, in collaboration with Professor Keith Brocklehurst's group in London, produced the first ever polyclonal catalytic antibodies in 1991. We used a phosphate immunogen to generate antibodies that catalyse the hydrolysis of carbonates, esters and certain amides. This opens up the possibility of generating a patients own catalytic antibodies by immunising with a suitable immunogen.
Current and Future Research
Our research is directed towards medical applications of catalytic antibodies and two areas in particular:
(i) Synthesising transition state analogues and developing antibodies that will catalyse the hydrolysis and destruction of toxic molecules, for example cocaine.
(ii) Synthesising transition state analogues and developing antibodies that will catalyse the activation of prodrugs for cancer treatment.
Recent Publications
Evidence that the mechanism of antibody-catalysed hydrolysis of arylcarbamates can be determined by the structure of the immunogen used to elicit the catalytic antibody. G. Boucher, B. Said, E. L. Ostler, M. Resmini, K. Brocklehurst, and G. Gallacher, Biochemical Journal, (2007), 401, 721-726.
Polyclonal antibody catalysed hydrolysis of a b-lactam. E.L.Ostler, M.Resmini, G.Boucher, N.Romanov, K.Brocklehurst, and G.Gallacher. Chemical Communications (2002), 226-227.
Synthesis of a transition state analogue for the hydrolysis of cocaine: assistance to phosphonylation of a 3b-hydroxytropane by a neighbouring amide group. E.P. Hagi-Pavli, C.S.Simms, E.L.Ostler, K.Brocklehurst, and G.Gallacher. Bioorganic and Medicinal Chemistry Letters, (1999), 9, 1881-1884.
Catalytic antibody activity elicited by active immunisation. G.Gallacher, C.S.Jackson, M.Searcey, R.Goel, G.W.Mellor, and K.Brocklehurst, Eur. J. Biochem., (1993), 214, 197-207.
A polyclonal antibody preparation with Michaelian catalytic properties: G.Gallacher, C.S.Jackson, M.Searcey, G.T.Badman, R.Goel, C.M.Topham, G.Mellor, and K.Brocklehurst, Biochemical Journal, (1991), 279, 871-881.
