Immunotherapy for amyloidosis

For 30 years the MRC has supported my work on a rare disease known as amyloidosis. We have discovered much of what is known about this condition and about a normal protein in the blood, known as serum amyloid P component (SAP), which contributes to the disease. Our MRC funded research on SAP led us to invent a new diagnostic test which has delivered significant improvements in treatment and survival of amyloidosis patients. We went on to establish the UK NHS National Amyloidosis Centre, the world?s leading centre for diagnosis and management of amyloidosis. The survival of our patients is not bettered anywhere else. However amyloidosis, which is responsible for the death of one per thousand of the population, is still an almost universally fatal disease. Alzheimer?s disease and maturity onset diabetes, both of which are associated with amyloid, inflict prolonged suffering on patients and carers, at great cost to society. We have now invented new medicines that specifically target SAP and amyloid, and produce clinical benefit in animal models which closely resemble human disease. Our most advanced drug, that removes SAP from the blood, helpfully slows disease progression in amyloidosis patients but this is not sufficient. We have now developed another novel treatment, using antibodies to SAP, which completely removes the amyloid deposits that cause disease. Our achievements have so impressed GlaxoSmithKline, the second largest pharmaceutical company in the world, that it has agreed to collaborate with us to develop these medications. They have insisted that our university research team shares the early risk in the long, difficult and extremely costly process of drug development. They are therefore deliberately not funding our component of the programme. The present proposal seeks the funding necessary for our contribution, while GSK conduct their own in house development work. This represents extraordinarily good value for the MRC and for the patients who will ultimately benefit from potentially life saving new treatments. Enabled by the laboratory research proposed here, the GSK collaboration will bring our key inventions into clinical trials as soon as possible and, within the 3 year period of the grant, the basic laboratory work, for which we now seek MRC support, will translate towards benefits for sick people.

Systemic amyloidosis is a fatal disease caused by extracellular deposition of autologous proteins as insoluble fibrils coated with the normal plasma protein, serum amyloid P component (SAP). Treatments are urgently needed to promote regression of amyloid deposits. We have demonstrated in mice that depletion of circulating SAP by CPHPC, our novel small molecule drug, followed by injection of anti-SAP antibodies to target residual amyloid-bound SAP, rapidly and safely clears visceral amyloid via an antibody, complement and macrophage dependent mechanism. We have produced efficacious mouse monoclonal anti-SAP antibodies suitable for humanisation, but clinical development and testing will be challenging and costly. In a highly innovative step for big pharma, GlaxoSmithKline have recognised the exceptional opportunity provided by our research and are developing our unprecedented, small molecule plus antibody, combination therapy in a shared risk collaboration. GSK will humanise the anti-SAP antibodies, develop CPHPC for regulatory approval, manufacture GMP products and conduct formulation, pre-clinical pharmacology, toxicology and clinical testing. Their work is absolutely dependent on the research proposed here which, under the shared risk agreement, is not funded by GSK. We will characterise the mouse monoclonals comprehensively in vitro and investigate them in vivo in amyloidotic mice, enabling selection of the optimal humanisation candidate. We will characterise the humanised derivatives and validate efficacy of the eventual anti-SAP product in murine amyloidosis, defining pharmacokinetics, optimal dosing and time course of amyloid clearance. Our results will illuminate the mechanisms of this novel immunotherapy and inform design of the initial clinical studies, scheduled for 2012. We shall also use our extensive panel of amyloid fibrils and GSK?s Domantis domain antibody technology, to produce anti-fibril antibodies for treating amyloid without needing CPHPC. Antibodies cross-reactive with several but not all amyloid fibril types are described but, in a new approach, we will target the universal fibril ligand for SAP to generate genuinely pan anti-fibril antibodies suitable for use in all forms of amyloidosis. We will evaluate the anti-fibril antibodies in parallel with the anti-SAP reagents, validating them as potential candidates for clinical development. There is no a priori reason why anti-SAP should not be as effective in man as it is in mice; the anti-fibril strategy is also very promising. We are extremely fortunate that GSK?s development resources and industry expertise are available. Renewed MRC support for our research will now enable final translation of our MRC-funded discoveries into treatments addressing grave unmet medical need.