6The transfer of a laboratory based hypothesis to a clinically useful therapy: the development of anti-TNF therapy of rheumatoid arthritis
Section snippets
Immune
The association with HLA-DR4, the infiltration of synovium with abundant T lymphocytes (especially CD4+ cells) and the upregulation of local MHC class I and II2., 3. (Figure 1) led to the concept in the ‘mid-late’ 1980s that CD4+ T cells were dominant drivers of RA4, leading to clinical trials of anti-CD4 antibody, with minimal success.5 While these failures may have been technical, due to inappropriate antibodies, dosing regimens, etc. schools of thought have cast doubt on the relevance of CD4+
Therapeutic agents which block TNF
The work of Bruce Beutler, Tony Cerami and their colleagues37., 38. in the 1980s showed that TNF had a major role in the pathogenesis of the sepsis syndrome in response to Gram-negative bacteria. This was convincingly shown in a variety of species, and models, and led to a number of clinical trials to evaluate this hypothesis in human sepsis. A variety of therapeutic agents were prepared by various companies in order to generate ‘blockbuster’ drugs for this seemingly lucrative indication with a
Clinical trials
The chimeric antibody to TNF developed by Centocor from a murine hybridoma, A2, generated in Jan Vilcek's laboratory by J. Lee, was termed cA2 (chimeric A2). It was chimerized by David Knight and John Ghrayeb39 by grafting the murine Fv segments to a human IgG1,K backbone, and produced in large quantities sufficient for clinical trials; phase I studies had already been performed before rheumatoid studies were initiated.
A feature of the therapy of murine collagen-induced arthritis with Bob
Formal proof of principle
While the first open trial of 20 patients was performed solely at Charing Cross Hospital40, the formal proof of principle, a double-blind randomized placebo-controlled trial was performed in four European centres, with the assistance of the teams of Ferry Breedveld in Leiden, Joachim Kalden in Erlangen and Joseph Smolen in Vienna. This was a simple trial design in which two doses of cA2 (1 and 10 mg/kg) were compared against a placebo. So that its appearance was the same, of a protein solution,
Does TNF blockade have long-term efficacy? Longer-term clinical trials
While the 4-week randomized double-blind placebo-controlled trials constitute the formal proof of principle, in terms of the lifespan of a patient with RA it is a benefit of little consequence because all patients showed a relapse of their disease. The key issue was whether patients could be re-treated, whether cA2 would be too immunogenic, and whether, in the absence of TNF, another pro-inflammatory cytokine would step in to drive the disease activity.
The first clue that long-term benefit
Competition and early disclosure is good for patients
A principle of science is early disclosure of important information, and this was the case here. The results of the open trials were disclosed within a few months of the trial beginning (in May, 1992), at a meeting in Arad, Israel, in October 1992. With representatives of other companies possessing anti-TNF therapeutics present at Arad, the stage was set for having other groups verify the hypothesis that TNF blockade was therapeutic in RA. The first confirmatory report came from Celltech56,
Mechanism of action studies
The clinical studies with infliximab (Remicade®), the anti-TNF now sold by Centocor/J&J/Schering-Plough, showed marked clinical benefit.40., 41., 44. This provided a relatively unique opportunity to study the mechanism of benefit of a drug with a relatively defined biochemical mode of action. This would provide information about the pathogenesis of the disease process, as revealed by the concomitant changes during benefit and relapses.
The studies performed during the analysis of TNF blockade
Lessons yet to learn
Some of the unexpected adverse events observed with the use of anti-TNF agents have yet to be explained. While the increased susceptibility to infections was anticipated the induction of dsDNA antibodies in about 15% was expected on the basis of animal models67, and rare cases of lupus need to be explored further.51 Similarly, the rare cases of demyelinating syndrome that occur is another as yet unexplained clinical finding.68 That both syndromes largely resolve when therapy is discontinued
What have we learnt about ‘translational medicine’, the transition of concepts from laboratory to clinic?
In summary, it is a complex and uncertain process, involving industry in a multi-million dollar gamble, or risk.
- 1.
A well founded rationale is essential, but insufficient. This is obvious for many reasons, but most importantly what seems a strong rationale to academic experts may not be to industry. There may be no experts in the company, so they need to get consultants whose knowledge may or may not be commensurate with the task. For industry the best founded rationale is an existing proof of
Summary
The application of laboratory knowledge and its conversion into practical therapeutics is a fraught, long and expensive process, with a horrendous failure rate and monumental costs. We describe here some of the steps in translation of laboratory knowledge into clinical therapeutics, and review some of the things that we have learnt.
Acknowledgements
The work described here was mostly supported by the arthritis rheumatism campaign (arc) with grants from the Nuffield Foundation, Wellcome Trust and Centocor, Inc. The clinical trials were supported by Centocor, Inc. This work also involved many colleagues at the Kennedy Institute, for example, Ewa Paleolog, Peter Taylor and many at Centocor, especially Harlan Weissman, John Ghrayeb and Tom Schaible.
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