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of October 9, 2015. This information is current as Taught Us? Standard of Care: What Lessons Has It Anti-TNF Therapy, from Rationale to Marc Feldmann and Ravinder N. Maini http://www.jimmunol.org/content/185/2/791 doi: 10.4049/jimmunol.1090051 2010; 185:791-794; ; J Immunol References http://www.jimmunol.org/content/185/2/791.full#ref-list-1 , 10 of which you can access for free at: cites 38 articles This article Subscriptions http://jimmunol.org/subscriptions is online at: The Journal of Immunology Information about subscribing to Permissions http://www.aai.org/ji/copyright.html Submit copyright permission requests at: Email Alerts http://jimmunol.org/cgi/alerts/etoc Receive free email-alerts when new articles cite this article. Sign up at: Print ISSN: 0022-1767 Online ISSN: 1550-6606. Immunologists, Inc. All rights reserved. Copyright © 2010 by The American Association of 9650 Rockville Pike, Bethesda, MD 20814-3994. The American Association of Immunologists, Inc., is published twice each month by The Journal of Immunology at Indian Veterinary Research Institute on October 9, 2015 http://www.jimmunol.org/ Downloaded from at Indian Veterinary Research Institute on October 9, 2015 http://www.jimmunol.org/ Downloaded from

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of October 9, 2015.This information is current as

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

Marc Feldmann and Ravinder N. Maini

http://www.jimmunol.org/content/185/2/791doi: 10.4049/jimmunol.1090051

2010; 185:791-794; ;J Immunol 

Referenceshttp://www.jimmunol.org/content/185/2/791.full#ref-list-1

, 10 of which you can access for free at: cites 38 articlesThis article

Subscriptionshttp://jimmunol.org/subscriptions

is online at: The Journal of ImmunologyInformation about subscribing to

Permissionshttp://www.aai.org/ji/copyright.htmlSubmit copyright permission requests at:

Email Alertshttp://jimmunol.org/cgi/alerts/etocReceive free email-alerts when new articles cite this article. Sign up at:

Print ISSN: 0022-1767 Online ISSN: 1550-6606. Immunologists, Inc. All rights reserved.Copyright © 2010 by The American Association of9650 Rockville Pike, Bethesda, MD 20814-3994.The American Association of Immunologists, Inc.,

is published twice each month byThe Journal of Immunology

at Indian Veterinary R

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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, newmolecular tools enabled the biol-ogy of cytokine expression and regulation to be studied.Ourgroupuncovered aTNF-dependent cascade in activerheumatoid synovium, suggesting that TNF might be atherapeutic target; this concept was supported in an ani-mal model of the disease. The proof of concept was a ser-ies of clinical trials, which have led to marked changes inthe therapy of human rheumatoid arthritis and subse-quently of other diseases. The work with TNF clearlydemonstrated the importance of cytokines in medicineas well as the capacity of mAbs (or receptor fusion pro-teins) to be used long-term in large populations, thuschanging the therapeutic landscape. The Journal ofImmunology, 2010, 185: 791–794.

In the early 1980s, rheumatoid arthritis (RA), a diseaseaffecting ∼1% of the population worldwide, was a majorclinical problem. Twenty-five years later, RA is far from

curable, but it is much more manageable, less crippling, andless lethal. Research in immunology has had time to bear fruitand yield clinical benefit, resulting in reduced disease activityand progression.RA is an autoimmune disease with chronic inflammation

leading to joint destruction. The classical autoantibodies, orrheumatoid factors, have long been known; more recentlydiscovered are IgG Abs to deiminated citrullinated proteins.The HLA association is well documented (1), with the sharedepitope of HLA DR4/DR1 (2) suggesting the importance ofCD41 T cells in disease pathogenesis, as described byMcDevitt and collegues (3) and others.The role of cytokines in disease was investigated following

the realization that cytokines augment HLA expression and Agpresentation to T cells in local autoimmune disease sites likesynovial joints. A hypothesis linking these processes waspublished in 1983 (4). Cytokine research was propelled by thesuccessful biochemical purification and cloning of cytokinecDNAs. Molecular biology techniques also helped providekey therapeutics, such as engineered mAbs and receptor fusionproteins. The availability of specific Abs, many generouslydonated by the biotech industry, with Dr. Michael Shepardfrom Genentech (South San Francisco, CA) being a majordonor, allowed us to identify which cytokines were present inrheumatoid disease tissue.

Our studies on cytokine mRNA expression in joints werecontemporaneous with those of others, including J.M. Dayer,G.W. Duff, and G.S. Firestein (5–9). The results were morecomplex than anticipated, as essentially all cytokines assessedwere present, including many proinflammatory cytokines.Thus, merely studying cytokine expression in joints was notsufficient to define the elusive therapeutic target. However, byusing a tissue culture system to analyze the complex regulationof cytokines in the rheumatoid synovium, TNF-a wasidentified as a therapeutic target. First, culturing synovialtissue cells revealed abnormally prolonged cytokine produc-tion, a finding in keeping with a chronic disease. Second, theuse of neutralizing anti-TNF Abs demonstrated the existenceof a TNF-dependent proinflammatory cytokine cascade.These experiments, performed in the late 1980s by ResearchFellows in our laboratory, Glenn Buchan and FionulaBrennan, have been fully described in review articles (10,11). Important confirmation of the importance of TNF camefrom the collagen-induced arthritis model. Although widelyaccepted now as the best (in reality, least bad) mouse model ofRA, it has limitations in predicting the success of clinicaltrials. Nevertheless, using hamster anti-mouse anti-TNFmAb generously donated by Robert Schreiber (WashingtonUniversity, St. Louis, MO), Richard Williams and colleagues(12) showed that disease activity was ameliorated when anti-TNF Ab was administered post disease onset.We believe that having two research leaders with similar

interests and overlapping expertise and many talented ResearchFellows, support staff, and well-equipped laboratories withlong-term funding, was very important in the efficient progressof this research project toward the clinic. We were not aware atthe time that our efforts would lead to the first effective use ofmolecular biological techniques to define an inflammatorytherapeutic target and the first use of modern biological ther-apeutics (mAbs and receptor fusion proteins) for long-termtreatment of a large number of patients.Having defined TNF as a therapeutic target in preclinical

experiments, we were very keen to test our novel, but for manya heretical, idea that a single cytokine could drive a multi-cytokine, multicellular chronic disease. Arising from the workof Anthony Cerami, Bruce Beutler, and Kevin Tracey (13, 14),many companies had produced anti-TNF inhibitors, bothmAbs and TNFR fusion proteins, for the treatment of sepsis,but without success when applied in clinical trials. We were

Kennedy Institute of Rheumatology, Imperial College, London, United Kingdom

Address correspondence and reprint requests to Dr. Marc Feldmann, Kennedy Instituteof Rheumatology, Imperial College, 65 Aspenlea Road, London, W6 8LH, U.K. E-mailaddress: [email protected]

Abbreviations used in this paper: MTX, methotrexate; RA, rheumatoid arthritis.

Copyright� 2010 by TheAmerican Association of Immunologists, Inc. 0022-1767/10/$16.00

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fortunately able to interest an ex-colleague, James N. Woody,Chief Scientist at Centocor (Malvern, PA), a company spe-cializing in mAbs, to work with us in RA clinical trials. JohnGhrayeb at Centocor had chimerized (made three-fourthshuman by using molecular biology techniques to graft humanFc and part of Fab onto a mouse Ab) a mouse anti-TNFmonoclonal generated by Jan Vilcek (15). This therapeutic,cA2, was later known as infliximab (Remicade, Centocor).Our first clinical trial of infliximab in RA was in April 1992,

at Charing Cross Hospital (London, U.K.). This was an open-label trial due to concerns about safety of a blinded clinical trial.Infliximab was well tolerated with no short-term safety signalsand impressive efficacy, but as the Ab metabolized, all patientsrelapsed by 12–18 wk. In further extension studies, we wereable to retreat some patients for several more courses and dem-onstrate clinical benefit lasting over a year (16, 17). Next, weperformed a formal double-blind placebo-controlled random-ized trial with three European collaborators, Ferdinand Breed-veld, Joachim Kalden, and Josef Smolen, in 1993. A singleinfusion, with either a previously used effective dose (10 mg/kg) or a tenth of that, was used; both were accompanied bydramatic dose-related efficacy over 4wk comparedwith placebo(18). From this trial, we were able to perform a series of studieson the mechanism of action of the anti-TNF Ab.By the time the extensive, longer trials designed for drug

registration were being planned (1994), the work of MichaelWeinblatt and others had led to low-dose methotrexate (MTX)being widely used for the treatment of RA as the gold standard(19). But most patients could not remain on MTX long-term,and an emerging unmet need was treatment of MTX-resistantpatients. Thus long-term randomized controlled and registra-tion trials were performed in patients with persistent inflam-matory activity and an incomplete response to ongoingtreatment with low-dose MTX. Initially, a 3-mo treatmentwith a 3-mo follow-up protocol compared MTX plus anti-TNF, with anti-TNF at three doses or MTX alone. The MTXplus anti-TNF was far superior and at low anti-TNF doses(1 mg/kg) was clearly synergistic, with augmented benefitclear at 3 mg/kg and discernable at 10 mg/kg (20). Thereafter,phase III registration trials were performed in combinationwith MTX, and consequently, the label (permitted use) ofinfliximab in RA is with MTX (21).One of the key clinical findings was that the combination

treatment, MTX plus anti-TNF, but not MTX alone, protectsjoints from progressive damage to cartilage and bone destruc-tion, as evaluated by serial radiographs. This occurred at allconcentrations of anti-TNF/MTX tested. Efficacy correlatedwith blood concentration of the Ab. Subsequent secondary lossof efficacy at the 1 mg/kg dose administered as monotherapyclearly reflected the induction of an anti-chimeric Ab response,with MTX reducing immunogenicity in the cotherapy arm(20). It was striking that results with the TNFR fusion proteinetanercept (Enbrel, Amgen, Chesterbrook, PA and Wyeth,Madison, NJ) (22) and the fully human monoclonal adali-mumab (Humira, Abbott, Abbott Park, IL) also demonstra-ted marked joint protection and the marked effect of addedMTX (23) in the absence of Abs to the therapeutic agent.With the very marked differences between treated and

control groups and the high specificity of the treatment, it waspossible to perform a detailed analysis of biomarkers andmechanism of action following TNF blockade. Our own

studies, and those of other investigators, are continuingto illuminate the role of TNF in immune-mediated diseases(18, 24–26). Of particular note are the following studies:

1) Within hours of anti-TNF administration, the elevated levelsof IL-6 in serum plummet virtually to baseline, thus confirm-

ing the existence of a TNF-dependent cytokine network in RApatients in vivo, a hypothesis supported by other studies (24).

2) Retention of 111In-radiolabeled neutrophils in joints is

reduced, as is expression of adhesion molecules and chemo-kines, supporting a role for TNF in cell recruitment (27).

3) The production of vascular endothelial growth factor, a cyto-

kine implicated in angiogenesis, is reduced and partly depend-ent on TNF (28).

4) Rapid normalization of low hemoglobin, high platelet counts,and fibrinogen concentration and restoration of abnormal reg-

ulatory T cell function demonstrate a role for TNF in the lossof homeostasis of the immune and hemopoietic systemsobserved in disease (29).

5) Destructive enzymes (e.g., matrix metalloproteinase 3) arereduced, and osteoprotegerin levels are restored, pointing tothe TNF dependence of pathways of matrix destruction in

cartilage and bone (30, 31).6) Although there is a falloff of response to anti-TNF with time,

some patients have remained responsive to anti-TNF for over

5 y (32). This indicates that cytokine networks in RA evolveslowly, if at all, and if TNF is blocked, its pivotal role inorchestrating the inflammatory response is not displaced byanother proinflammatory cytokine.

Demonstrating that a new therapeutic in clinical trials iseffective completes the translation of science into medicine.But there remains a need for the knowledge to be disseminatedand, most importantly, for the new therapeutic to be usedeffectively and with minimal harm. These are significanthurdles. First, not all clinical trials provide the data clinicianswant and need for application in practice. Secondly, newtherapeutics can be prohibitively priced. Our clinical trials inMTX poor responders did provide much of the informationclinicians needed, but not all. The cost of anti-TNF therapeu-tics has restricted their use, but the degree of clinical benefit,including joint protection and the lack of alternatives at thetime (1998/1999 onwards) has meant that it has becomethe standard of care for moderate to severe RA. Cost-benefitanalyses, such as provided by the United Kingdom’s NationalInstitute for Clinical Excellence, have documented the benefitof these therapeutics, even at their high cost ($15,000–20,000/y) (33). By now, ∼2 million patients have been trea-ted with the various anti-TNF therapeutics.It is of significant interest that in clinical trials of all five anti-

TNF biologics that have been licensed by the U.S. Food andDrug Administration, only a proportion of patients respond totreatment. The percentage of primary nonresponders varies butis ∼30%. Why some patients never respond is intriguing, andefforts have been made using biomarker studies to identifyresponse to therapy, but none have been validated. A studybased on a genome-wide association scan suggests a complexmultigenetic basis for response or resistance to therapy (34–36). Secondary nonresponsiveness after a successful initialresponse does appear, in part, to be related to the immuno-genicity of the therapeutic Ab (37).The obvious impact of the discovery of anti-TNF therapy is

on RA patients and their care. But the success of anti-TNF

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in RA prompted its use in other related diseases, for which ithas also been successful. Anti-TNF therapy is now an approvedtreatment for immune-inflammatory diseases, such as juvenileRA, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease,ulcerative colitis, and psoriasis. In all of these, the effect onpatients has been dramatic (e.g., the healing of fistulas inCrohn’s disease) and has greatly improved quality of life(38, 39).The successful long-term use of anti-TNF in a chronic dis-

ease has challenged a prejudice of the pharmaceutical industrythat patients do not tolerate repeated injections and preferorally available drugs. The good efficacy/safety ratio of biolog-icals (mAbs and receptor fusion proteins), patient compliance,and high profitability in the market, not only of anti-TNF,but subsequently anti-CD20, anti-vascular endothelial growthfactor, and anti-HER2, have highlighted the increasing impor-tance of biological therapeutics. The invention of anti-TNFtherapy has contributed to this change in the therapeutic land-scape and the practice of medicine well beyond its impact onpatients directly treated.

AcknowledgmentsWe thank numerous colleagues and collaborators, mostly named in the text or

references, and long-term funders, especially Arthritis Research UK, for invalu-

able support.

DisclosuresM.F. and R.N.M. are named on patents for anti-TNF therapy. M.F. owns

shares of Johnson & Johnson, Inc., and Centocor (a subsidiary of Johnson &

Johnson, Inc.) is a manufacturer of anti-TNF Abs.

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