Antibodies or immunoglobulins are proteins made by the B-cells of the bodies immune system in response to infection. These antibodies occur in different forms known as isotypes within an individual and they show variations within the population as a result of differences in allotype. Using recombinant DNA techniques it is possible to express antibodies in culture and to make very precise changes to their sequences and hence structure. We have been investigating the functions of antibody isotypes and allotypes using sets of recombinant antibodies matched for identical specificities. Studies have concentrated on the functions of antibodies in association with human effector mechanisms, where possible keeping everything autologous. We have revealed striking variation between antibodies which differ by both isotype and allotype and in several cases we have identified sequences within the molecule which are critical for such functional differences. These basic findings are being put into practice in the design of better recombinant antibodies for potential clinical use in human therapy. Some of this work was conducted in collaboration with Prof. Waldmann's group. Various monoclonal antibodies including CAMPATH-1H see below have been humanised and some are in clinical trials, work continues on the humanisation and production of other therapeutic antibodies.
The name CAMPATH derives from this Department ie CAMbridge PATHology Department. When I joined the Department of Pathology in 1982 it was to work with Dr. Herman Waldmann (now Professor Waldmann at the Sir William Dunn School Of Pathology in Oxford) on an MRC funded programme to develop antibodies for the prevention of organ graft rejection. Over the years I worked on key aspects of a number of research projects involving different antibodies which emerged from this initial MRC funded research programme. Many of these were later developed for therapeutic applications including in particular various CD3 antibodies, CD4 antibodies, CD45 antibodies and what has become known as the CAMPATH-1 series or CD52 antibodies.
Bispecific antibodies are novel antibodies constructed in vitro which have two different antigen specificities. By fusing two different hybridomas together a bispecific antibody with specificities for the human T-cell antigen CD3 and the human B-cell antigen CD19 was constructed. Methods were established to purify the bispecific antibody away from the other mixed molecular immunoglobulin species produced by the hybridoma. In-vitro studies demonstrated that the antibody could activate T-cells and induce them to kill B-lymphoma cells. Therapeutic batches of the antibody have been prepared in collaboration with the Therapeutic Antibody Centre (Directed by Prof. H. Waldmann and Dr. G. Hale now at the University of Oxford) and many of the in-vitro experiments and the clinical trials are being conducted in collaboration with the University Hospital of Utrecht. In this respect, particular mention should be made of the major contributions to this work from Dr. J. Phillips of the Therapeutic Antibody Centre, Cambridge and Drs. I-A Haagen, A. Geerars and Prof. B. de Gast, University Hospital of Utrecht, The Netherlands. The early results for the treatment of several patients have been encouraging with no serious adverse effects and signs of T- cell activation and lymphokine release being documented. Further studies are in progress and the antibody treatment is being combined with the T-cell growth factor Interleukin-2.
I also continued this research and participated in a European consortium for research into bispecific antibody therapy, headed by Prof. Bast.
This is a collaborative project with Prof Sirpa Jalkanen of the University of Turku in Finland, and also with a Finnish biotech company, BioTie. The aim of the project is to inhibit inflammation by use of engineered antibodies which block leukocyte adhesion and migration out of the circulation.
A separate listing of commercial applications arising from Mike Clark's research interests is available.