INTRODUCTION & BACKGROUND
In 1986 we began a collaboration with Sandoz in Basle, Switzerland to produce monoclonal antibodies to endotoxin. The agreed primary objective was to produce MAbs which were cross-reactive across all Escherichia coli LPS, the most common Gram-negative clinical isolate in sepsis.
This collaboration grew out of discussions between Brian McClelland, Director of the Edinburgh Regional Transfusion Centre of the Scottish National Blood Transfusion Service (SNBTS), and Max Schreier of the Preclinical Research department of Sandoz Pharma, Basle.
In the Edinburgh Blood Transfusion Service (BTS) Boyd Scott and I worked on ELISA development for screening and characterization, building on our experience with human anti-endotoxin antibodies and EndoCAb. Ian Poxton, in the Edinburgh University Medical School (Department of Medical Microbiology) with Frances McLoughlin (later with David Nelson) produced bacteria and various LPS preparations for immunizations and assays, conducted LPS characterizations including electrophoresis and Western blotting (immunoblotting), and conducted immunizations. Loraine McMillan (also Nitin Mehta, for a short time), working under the late Lisel Micklem in Keith Kames' laboratories in the Department of Surgery (Edinburgh University Medical School) collaborated on immunizations and conducted the fusions, hybridoma production and cloning and all cell culture and preservation. Clinical oversight was provided by Graham Ramsay and the shock team at Glasgow University Department of Surgery in the unit established by Professor Ian Ledingham: there John Reidy and Steven Boom conducted studies of effects of LPS on cardiac output in rats and its mitigation by anti-LPS MAbs. Inhibition by MAbs of the pyrogenic response to endotoxin in rabbits was performed at the SNBTS West of Scotland facilities. The Edinburgh group was chaired initially by Chris Prowse, latterly by me.
In Basle, the work with Sandoz was channelled through Franco Di Padova, who set up a parallel MAb production study and immunoassay facilities with his staff and colleagues. Aussi Kocher performed bulk culture and purification of selected MAbs, and Hermann Gram conducted the molecular biology for humanisation of selected mouse MAbs. At Sandoz Forschungsinstitut in Vienna, Ekke Liehl conducted mouse protection studies, and in the early stages Frank Unger supplied various complex sugars and oligosaccharides for immunizations. We were delighted to collaborate later with Ernst Rietschel and Helmut Brade at Borstel, Germany on the characterization of epitope specificity, pyrogenicity inhibition, supply of various bacterial strains and their enthusiastic support and discussion. Franco enlisted collaborative studies, especially with MAb WN1 222-5, with many of the endotoxin research community. The group of Baumgartner and Glauser at Lausanne were involved in critical discussion, especially of clinical objectives, and in particular Didier Heumann who conducted a number of laboratory studies with selected MAbs. Others have contributed indirectly through exchange of reagents and bacterial strains and through supportive critical discussion. Amongst these we should thank especially Alan Cross of the Walter Reid Institute in Washington and Nils Carlsson of the Karolinska Institute in Stockholm.
These studies, together with parallel work on EndoCAb in humans, has been probably the most enjoyable, productive and stimulating of my professional career and it has been a pleasure to interact with the international endotoxin and sepsis research community.