What Lessons Has It Anti-TNF Therapy, from Rationale To

Anti-TNF Therapy, from Rationale to Standard of Care: What Lessons Has It Taught Us?

This information is current as Marc Feldmann and Ravinder N. Maini of September 27, 2021. J Immunol 2010; 185:791-794; ; doi: 10.4049/jimmunol.1090051 http://www.jimmunol.org/content/185/2/791 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Anti-TNF Therapy, from Rationale to Standard of Care: What Lessons Has It Taught Us? Marc Feldmann and Ravinder N. Maini In the mid-1980s, new molecular tools enabled the biol- Our studies on cytokine mRNA expression in joints were ogy of cytokine expression and regulation to be studied. contemporaneous with those of others, including J.M. Dayer, Our group uncovered a TNF-dependent cascade in active G.W. Duff, and G.S. Firestein (5–9). The results were more rheumatoid synovium, suggesting that TNF might be a complex than anticipated, as essentially all cytokines assessed therapeutic target; this concept was supported in an ani- were present, including many proinflammatory cytokines. mal model of the disease. The proof of concept was a ser- Thus, merely studying cytokine expression in joints was not ies of clinical trials, which have led to marked changes in sufficient to define the elusive therapeutic target. However, by the therapy of human rheumatoid arthritis and subse- using a tissue culture system to analyze the complex regulation Downloaded from quently of other diseases. The work with TNF clearly of cytokines in the rheumatoid synovium, TNF-a was demonstrated the importance of cytokines in medicine identified as a therapeutic target. First, culturing synovial as well as the capacity of mAbs (or receptor fusion pro- tissue cells revealed abnormally prolonged cytokine produc- teins) to be used long-term in large populations, thus tion, a finding in keeping with a chronic disease. Second, the changing the therapeutic landscape. The Journal of use of neutralizing anti-TNF Abs demonstrated the existence Immunology, 2010, 185: 791–794. of a TNF-dependent proinflammatory cytokine cascade. http://www.jimmunol.org/ These experiments, performed in the late 1980s by Research Fellows in our laboratory, Glenn Buchan and Fionula Brennan, have been fully described in review articles (10, n the early 1980s, rheumatoid arthritis (RA), a disease 11). Important confirmation of the importance of TNF came affecting ∼1% of the population worldwide, was a major clinical problem. Twenty-five years later, RA is far from from the collagen-induced arthritis model. Although widely I accepted now as the best (in reality, least bad) mouse model of curable, but it is much more manageable, less crippling, and less lethal. Research in immunology has had time to bear fruit RA, it has limitations in predicting the success of clinical and yield clinical benefit, resulting in reduced disease activity trials. Nevertheless, using hamster anti-mouse anti-TNF by guest on September 27, 2021 and progression. mAb generously donated by Robert Schreiber (Washington RA is an autoimmune disease with chronic inflammation University, St. Louis, MO), Richard Williams and colleagues leading to joint destruction. The classical autoantibodies, or (12) showed that disease activity was ameliorated when anti- rheumatoid factors, have long been known; more recently TNF Ab was administered post disease onset. discovered are IgG Abs to deiminated citrullinated proteins. We believe that having two research leaders with similar The HLA association is well documented (1), with the shared interests and overlapping expertise and many talented Research epitope of HLA DR4/DR1 (2) suggesting the importance of Fellows, support staff, and well-equipped laboratories with 1 CD4 T cells in disease pathogenesis, as described by long-term funding, was very important in the efficient progress McDevitt and collegues (3) and others. of this research project toward the clinic. We were not aware at The role of cytokines in disease was investigated following the time that our efforts would lead to the first effective use of the realization that cytokines augment HLA expression and Ag molecular biological techniques to define an inflammatory presentation to T cells in local autoimmune disease sites like therapeutic target and the first use of modern biological ther- synovial joints. A hypothesis linking these processes was apeutics (mAbs and receptor fusion proteins) for long-term published in 1983 (4). Cytokine research was propelled by the treatment of a large number of patients. successful biochemical purification and cloning of cytokine Having defined TNF as a therapeutic target in preclinical cDNAs. Molecular biology techniques also helped provide experiments, we were very keen to test our novel, but for many key therapeutics, such as engineered mAbs and receptor fusion a heretical, idea that a single cytokine could drive a multi- proteins. The availability of specific Abs, many generously cytokine, multicellular chronic disease. Arising from the work donated by the biotech industry, with Dr. Michael Shepard of Anthony Cerami, Bruce Beutler, and Kevin Tracey (13, 14), from Genentech (South San Francisco, CA) being a major many companies had produced anti-TNF inhibitors, both donor, allowed us to identify which cytokines were present in mAbs and TNFR fusion proteins, for the treatment of sepsis, rheumatoid disease tissue. but without success when applied in clinical trials. We were

Kennedy Institute of Rheumatology, Imperial College, London, United Kingdom Abbreviations used in this paper: MTX, methotrexate; RA, rheumatoid arthritis.

Address correspondence and reprint requests to Dr. Marc Feldmann, Kennedy Institute Ó of Rheumatology, Imperial College, 65 Aspenlea Road, London, W6 8LH, U.K. E-mail Copyright 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1090051 792 TRANSLATING IMMUNOLOGY: ANTI-TNF THERAPY, FROM RATIONALE TO STANDARD OF CARE fortunately able to interest an ex-colleague, James N. Woody, studies, and those of other investigators, are continuing Chief Scientist at Centocor (Malvern, PA), a company spe- to illuminate the role of TNF in immune-mediated diseases cializing in mAbs, to work with us in RA clinical trials. John (18, 24–26). Of particular note are the following studies: Ghrayeb at Centocor had chimerized (made three-fourths 1) Within hours of anti-TNF administration, the elevated levels human by using molecular biology techniques to graft human of IL-6 in serum plummet virtually to baseline, thus confirm- Fc and part of Fab onto a mouse Ab) a mouse anti-TNF ing the existence of a TNF-dependent cytokine network in RA monoclonal generated by Jan Vilcek (15). This therapeutic, patients in vivo, a hypothesis supported by other studies (24). cA2, was later known as infliximab (Remicade, Centocor). 2) Retention of 111In-radiolabeled neutrophils in joints is Our first clinical trial of infliximab in RA was in April 1992, reduced, as is expression of adhesion molecules and chemo- at Charing Cross Hospital (London, U.K.). This was an open- kines, supporting a role for TNF in cell recruitment (27). label trial due to concerns about safety of a blinded clinical trial. 3) The production of vascular endothelial growth factor, a cyto- Infliximab was well tolerated with no short-term safety signals kine implicated in angiogenesis, is reduced and partly depend- and impressive efficacy, but as the Ab metabolized, all patients ent on TNF (28). relapsed by 12–18 wk. In further extension studies, we were 4) Rapid normalization of low hemoglobin, high platelet counts, able to retreat some patients for several more courses and dem- and fibrinogen concentration and restoration of abnormal reg- onstrate clinical benefit lasting over a year (16, 17). Next, we ulatory T cell function demonstrate a role for TNF in the loss performed a formal double-blind placebo-controlled random- of homeostasis of the immune and hemopoietic systems ized trial with three European collaborators, Ferdinand Breed- observed in disease (29). Downloaded from veld, Joachim Kalden, and Josef Smolen, in 1993. A single 5) Destructive enzymes (e.g., matrix metalloproteinase 3) are infusion, with either a previously used effective dose (10 mg/ reduced, and osteoprotegerin levels are restored, pointing to kg) or a tenth of that, was used; both were accompanied by the TNF dependence of pathways of matrix destruction in dramatic dose-related efficacy over 4 wk compared with placebo cartilage and bone (30, 31). (18). From this trial, we were able to perform a series of studies 6) Although there is a falloff of response to anti-TNF with time, some patients have remained responsive to anti-TNF for over on the mechanism of action of the anti-TNF Ab. http://www.jimmunol.org/ By the time the extensive, longer trials designed for drug 5 y (32). This indicates that cytokine networks in RA evolve slowly, if at all, and if TNF is blocked, its pivotal role in registration were being planned (1994), the work of Michael orchestrating the inflammatory response is not displaced by Weinblatt and others had led to low-dose methotrexate (MTX) another proinflammatory cytokine. being widely used for the treatment of RA as the gold standard (19). But most patients could not remain on MTX long-term, Demonstrating that a new therapeutic in clinical trials is and an emerging unmet need was treatment of MTX-resistant effective completes the translation of science into medicine. patients. Thus long-term randomized controlled and registra- But there remains a need for the knowledge to be disseminated

tion trials were performed in patients with persistent inflam- and, most importantly, for the new therapeutic to be used by guest on September 27, 2021 matory activity and an incomplete response to ongoing effectively and with minimal harm. These are significant treatment with low-dose MTX. Initially, a 3-mo treatment hurdles. First, not all clinical trials provide the data clinicians with a 3-mo follow-up protocol compared MTX plus anti- want and need for application in practice. Secondly, new TNF, with anti-TNF at three doses or MTX alone. The MTX therapeutics can be prohibitively priced. Our clinical trials in plus anti-TNF was far superior and at low anti-TNF doses MTX poor responders did provide much of the information (1 mg/kg) was clearly synergistic, with augmented benefit clinicians needed, but not all. The cost of anti-TNF therapeu- clear at 3 mg/kg and discernable at 10 mg/kg (20). Thereafter, tics has restricted their use, but the degree of clinical benefit, phase III registration trials were performed in combination including joint protection and the lack of alternatives at the with MTX, and consequently, the label (permitted use) of time (1998/1999 onwards) has meant that it has become infliximab in RA is with MTX (21). the standard of care for moderate to severe RA. Cost-benefit One of the key clinical findings was that the combination analyses, such as provided by the United Kingdom’s National treatment, MTX plus anti-TNF, but not MTX alone, protects Institute for Clinical Excellence, have documented the benefit joints from progressive damage to cartilage and bone destruc- of these therapeutics, even at their high cost ($15,000– tion, as evaluated by serial radiographs. This occurred at all 20,000/y) (33). By now, ∼2 million patients have been trea- concentrations of anti-TNF/MTX tested. Efficacy correlated ted with the various anti-TNF therapeutics. with blood concentration of the Ab. Subsequent secondary loss It is of significant interest that in clinical trials of all five anti- of efficacy at the 1 mg/kg dose administered as monotherapy TNF biologics that have been licensed by the U.S. Food and clearly reflected the induction of an anti-chimeric Ab response, Drug Administration, only a proportion of patients respond to with MTX reducing immunogenicity in the cotherapy arm treatment. The percentage of primary nonresponders varies but (20). It was striking that results with the TNFR fusion protein is ∼30%. Why some patients never respond is intriguing, and etanercept (Enbrel, Amgen, Chesterbrook, PA and Wyeth, efforts have been made using biomarker studies to identify Madison, NJ) (22) and the fully human monoclonal adali- response to therapy, but none have been validated. A study mumab (Humira, Abbott, Abbott Park, IL) also demonstra- based on a genome-wide association scan suggests a complex ted marked joint protection and the marked effect of added multigenetic basis for response or resistance to therapy (34– MTX (23) in the absence of Abs to the therapeutic agent. 36). Secondary nonresponsiveness after a successful initial With the very marked differences between treated and response does appear, in part, to be related to the immuno- control groups and the high specificity of the treatment, it was genicity of the therapeutic Ab (37). possible to perform a detailed analysis of biomarkers and The obvious impact of the discovery of anti-TNF therapy is mechanism of action following TNF blockade. Our own on RA patients and their care. But the success of anti-TNF The Journal of Immunology 793 in RA prompted its use in other related diseases, for which it 14. Beutler, B., I. W. Milsark, and A. C. Cerami. 1985. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science has also been successful. Anti-TNF therapy is now an approved 229: 869–871. treatment for immune-inflammatory diseases, such as juvenile 15. Knight, D. M., H. Trinh, J. Le, S. Siegel, D. Shealy, M. McDonough, B. Scallon, M. A. Moore, J. Vilcek, P. Daddona, and J. Ghrayeb. 1993. Construction and RA, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease, initial characterization of a mouse-human chimeric anti-TNF antibody. Mol. Immu- ulcerative colitis, and psoriasis. In all of these, the effect on nol. 30: 1443–1453. patients has been dramatic (e.g., the healing of fistulas in 16.Elliott,M.J.,R.N.Maini,M.Feldmann,A.Long-Fox,P.Charles,H.Bijl,and J. N. Woody. 1994. Repeated therapy with monoclonal antibody to tumour Crohn’s disease) and has greatly improved quality of life necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet 344: (38, 39). 1125–1127. 17. Elliott, M. J., R. N. Maini, M. Feldmann, A. Long-Fox, P. Charles, P. Katsikis, The successful long-term use of anti-TNF in a chronic dis- F.M.Brennan,J.Walker,H.Bijl,J.Ghrayeb,etal.1993.Treatmentofrheu- ease has challenged a prejudice of the pharmaceutical industry matoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 36: 1681–1690. that patients do not tolerate repeated injections and prefer 18. Elliott, M. J., R. N. Maini, M. Feldmann, J. R. Kalden, C. Antoni, J. S. Smolen, B. orally available drugs. The good efficacy/safety ratio of biolog- Leeb, F. C. Breedveld, J. D. Macfarlane, H. Bijl, and J. N. Woody. 1994. Randomised icals (mAbs and receptor fusion proteins), patient compliance, double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344: 1105–1110. and high profitability in the market, not only of anti-TNF, 19. Weinblatt, M. E., H. Kaplan, B. F. Germain, S. Block, S. D. Solomon, R. C. but subsequently anti-CD20, anti-vascular endothelial growth Merriman, F. Wolfe, B. Wall, L. Anderson, E. Gall, et al. 1994. Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study. Arthritis Rheum. 37: factor, and anti-HER2, have highlighted the increasing impor- 1492–1498. tance of biological therapeutics. The invention of anti-TNF 20. Maini, R. N., F. C. Breedveld, J. R. Kalden, J. S. Smolen, D. Davis, J. D. Macfarlane, C. Antoni, B. Leeb, M. J. Elliott, J. N. Woody, et al. 1998. Therapeutic therapy has contributed to this change in the therapeutic land- Downloaded from efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha mono- scape and the practice of medicine well beyond its impact on clonal antibody combined with low-dose weekly methotrexate in rheumatoid arthri- patients directly treated. tis. [see comments] Arthritis Rheum. 41: 1552–1563. 21. Lipsky, P. E., D. M. F. M. van der Heijde, E. W. St Clair, D. E. Furst, F. C. Breedveld, J. R. Kalden, J. S. Smolen, M. Weisman, P. Emery, M. Feldmann, et al; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Acknowledgments Therapy Study Group. 2000. Infliximab and methotrexate in the treatment of We thank numerous colleagues and collaborators, mostly named in the text or rheumatoid arthritis. N. Engl. J. Med. 343: 1594–1602. 22. Klareskog, L., D. van der Heijde, J. P. de Jager, A. Gough, J. Kalden, M. 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