TY - JOUR
AU - MD, Richard J Farrell,
AB - As basic science research unravels the pathogenesis of inflammatory bowel disease (IBD) and other chronic inflammatory conditions, novel therapeutics are being engineered to help neutralize novel targets in various inflammatory pathways. The development of biologic therapies has been one of the major biomedical advances in recent times. Biologic therapies come in the form of naturally occurring or modified biologic compounds (vaccines, hormones, and blood products), recombinant proteins (granulocyte macrophage stimulating factor), monoclonal antibodies (infliximab), fusion proteins (etanercept), and antisense oligonucleotides.1 Because these agents are targeted at specific disease mechanisms, they have the potential to be more efficacious. However, modulation of the immune system by these agents may be associated with adverse events, potentially limiting their long-term safety. The drug-specific factors and mechanisms that influence the way the immune system responds to these exogenous biologic therapies is poorly understood. The induction of antidrug antibodies is the direct marker of an agent's immunogenicity. Antibodies can be neutralizing or nonneutralizing. Neutralizing antibodies can inhibit the therapeutic effect of the biologic agent. Nonneutralizing antibodies may have no clinical significance or may prolong bioavailability by creating a slow release effect. Additionally, biologic therapies can also indirectly induce immunologic events through the induction or blockage of other pathways or proteins (hypersensitivity, allergic, and serum sickness reactions) or through the generation or stimulation of other auto-antibodies (antinuclear antibodies, anti-double-stranded DNA antibodies), the clinical significance of which is uncertain.2 The success of infliximab, a chimeric monoclonal antibody against tumor necrosis factor α (TNFα), has become a major therapeutic milestone and has opened the door for future biologic therapeutics in IBD. While initially approved in the late 1990s as a single infusion [luminal Crohn's disease (CD)] or a triple induction regimen (fistulizing CD), it was subsequently realized that many patients would relapse or lose their initial response if not retreated. With maintenance therapy now approved and common practice, many patients have received repeat infusions, and the formation of antidrug antibodies, antibodies to infliximab (ATIs; formerly known as human antichimeric antibody), has come into question as the potential Achilles heel in maintaining the safety and long-term efficacy of this important therapy in CD. Numerous reports have postulated that infusion reactions, delayed reactions, serum sickness-like reactions, neurologic and hematologic syndromes, infections, and loss of response to infliximab may be a consequence of a immunologic phenomenon after an infliximab infusion. Recent work has focused on studying the significance of immunogenicity and the formation of ATI on maintaining the long-term safety and efficacy of infliximab therapy. This paper will review the current knowledge of the influence of immunogenicity on the safety and efficacy of infliximab and will also discuss some of the novel biologic agents that are under study for IBD and the current strategies employed to circumvent the development of immunogenicity. Factor Associated with Immunogenicity and Antibody Formation After the realization that the majority of patents treated with infliximab would relapse if not retreated, the ACCENT 1 trial3 showed that patients with luminal CD who received a triple induction regimen (0, 2, and 6 wk) followed by maintenance infusions every 8 weeks exhibited a longer-lasting response to therapy and greater rate of mucosal healing4 than those who received a single dose followed by placebo or episodic treatment. In the study, 573 patients with active CD received 5 mg/kg infliximab at week 0 and then were randomly assigned to placebo infusions at weeks 2 and 6 and every 8 weeks until week 46 (group 1), 5 mg/kg infliximab at weeks 2 and 6 and every 8 weeks until week 46 (group 2), or 5 mg/kg infliximab at weeks 2 and 6, followed by 10 mg/kg infliximab every 8 weeks until week 46 (group 3). At week 14 or later, patients losing response could cross over to episodic infliximab treatment increased by 5 mg/kg. The study identified that the incidence of ATI was significantly lower for patients who received the triple induction regimen followed by maintenance infusions (9% in the 5 mg/kg maintenance group and 6% in the 10 mg/kg maintenance group) compared with 28% in those who received a single dose of infliximab followed by placebo. Of note, antibody titers were similar across all treatment groups, and only 3 patients had a titer greater than 1:80. In the original ACCENT 1 study, the published ATI rates were based on sera drawn no later than week 56 (i.e., 8 wk after the last infusion at week 46).4 This may have underestimated the prevalence of ATI in the maintenance groups, because 46% of patients had indeterminate tests because of the presence of circulating infliximab in the serum, which interferes with the ATI assay. Consequently, as part of a follow-on study, the ACCENT I cohort was reevaluated at 72 weeks, 26 weeks following the last study infusion, for the development of ATIs. The number of patients with inconclusive results decreased from 46% at 54 weeks to 27% at 72 weeks. ATIs were present in 30% in those treated with infliximab 5 mg/kg at week 0 followed by placebo infusions at weeks 2 and 6 and every 8 weeks thereafter until week 46 (group 1) compared with 10% of patients who received the triple induction regimen followed by 5 mg/kg maintenance infusions (group 2) and 7% of pa-tients who received the triple induction regimen followed by 10 mg/kg maintenance infusions (group 3; P < 0.001).5 Not only did the patients in the episodic treatment group (group 1) have a higher incidence of antibodies, but they also exhibited significantly higher antibody titers, leading the authors to conclude that the 3-dose induction regimen followed by regular maintenance infusions is less immunogenic in inducing ATI than the single dose induction followed by episodic retreatment. Given that no group received a triple induction regimen followed by placebo maintenance, the relative importance of triple induction regimen versus maintenance therapy in reducing ATI formation remains unclear. Concurrent use of immunomodulators (6-mercaptopurine, azathioprine, or methotrexate) was associated with a significant reduction in the formation of ATI (10% versus 18%, P = 0.2) and lower ATI titers. The effects of concurrent corticosteroids in reducing the incidence of ATI was difficult to evaluate in ACCENT 1 because their use was tapered after week 6 in patients responding to infliximab therapy. The authors suggested that a maintenance infusion schedule and immunomodulator therapies work independently to reduce the incidence of ATI formation. During the study, it was noted that many patients that had previously developed ATI became “immunotolerant” and became seronegative while continuing to receive infliximab, indicating that ATIs are not a permanent feature of infliximab maintenance therapy. In a cohort study, Baert et al6 studied 125 patients with CD in the pre-ACCENT 1 era who received a single 5 mg/kg infliximab infusion for luminal disease and patients with fistulous disease with a series of infusions (0, 2, and 6 weeks). Retreatment with infliximab for all patients was episodic or on-demand rather than per schedule (i.e., it was dictated by clinical relapse). Overall, they found a 61% incidence of ATI, the majority forming after the first infusion. Similar to the findings of the ACCENT 1 cohort, patients taking concurrent immunomodulators had a lower incidence of ATI (43% versus 75%, P < 0.01) as well as lower titers compared with those not taking immunomodulators. In a similar cohort study, Farrell et al7 observed that 36% of 53 patients with luminal and fistulous CD receiving episodic 5 mg/kg infliximab therapy developed ATIs, including 7 patients who had serious infusion reactions. Administration of a second infusion within 8 weeks of the first (odds ratio, 0.13; 95% confidence interval, 0.03-0.5; P = 0.0007) or concurrent immunomodulators, including concurrent prednisone ≥20 mg/d (odds ratio, 0.19; 95% confidence interval, 0.04-1.03; P = 0.007) significantly reduced ATI formation. While inferences can be drawn between the 3 studies, it is difficult to compare them directly because the studies employed different study designs, treatment strategies, different infliximab dosages (up to 15 mg/kg in the ACCENT 1 cohort), and used different assays to measure ATIs. However, taken together, the studies provide compelling evidence that use of an induction regimen, concurrent immunomodulators, and a maintenance rather than an episodic retreatment strategy decreases immunogenicity of infliximab therapy in CD. These findings are also supported by those of the ATTRACT rheumatoid arthritis study, in which 428 patients were randomly assigned to receive methotrexate plus placebo or infliximab 3 or 10 mg/kg every 4 or every 8 weeks for up to 102 weeks. Similar to the incidence observed for patients receiving maintenance therapy in ACCENT 1, ATIs were observed in 8% of infliximab plus methotrexate-treated patients in the ATTRACT study.8 Does Immunogenicity Influence Efficacy? While the ACCENT 1 studies showed that scheduled maintenance infliximab infusions are more efficacious and less often induce ATIs than an episodic strategy, overall neither the presence of ATI nor the titer of antibodies in this cohort correlated with the rate of clinical response or clinical remission. In fact, the 2 patients with the highest titers (1:2560) were both in remission at 54 weeks. Patients in the maintenance groups had similar remission rates, regardless of ATIs. For patients in the episodic treatment groups who received a single infusion of infliximab followed by placebo and subsequently “crossed over” and received active drug, the presence of ATI did not seem to influence patients' response rates (86% with ATI versus 85% without ATI).4 Baert et al6 identified that it was not the presence of ATIs that was associated with alterations in efficacy but rather a threshold titer of detectable antibodies (8 μg/mL) that was clinically significant. For patients with antibody titers above the threshold (37% of cohort), the duration of response after an infliximab infusion was one-half as long (35 versus 71 d; P < 0.001). They also observed that after an infusion reaction, there was prompt disappearance of infliximab from the serum, and the duration of response after a subsequent infusion was decreased from 65 to 38 days. Immunomodulators were strongly associated with lower antibody titers, higher infliximab concentrations, and therefore, positively linked associated with a longer duration of response. Farrell et al7 observed that 73% (11/15) of patients who subsequently lost their response to infliximab after having had an initial response were ATI positive compared with 0% (0/21) of those who continued to maintain a good response to repeated infliximab infusions. Patients with positive ATIs also had a shorter median duration of response that was reduced from 61 to 28 days when ATIs were present. As noted above, while the studies cannot be directly compared because of different methodologies, they do indicate that, whereas the presence of antibodies may not influence the rate of response or rate of remission, the presence or titer of antibodies to infliximab may contribute to a decrease in the duration of response to subsequent infusions. Does Immunogenicity Influence Safety? Infusion Reactions Infusion reactions including fevers, chills, rash headache, and shortness of breath or chest tightness have been described during infusions and within the 2-hour postinfusion window. Mild infusion reactions occur in 5% to 13% of patients. Fortunately, serious infusion reactions leading to termination of an infusion occur only in a minority (≤1%) of infusions.5,9 The majority of infusion reactions likely represent anaphylactoid-type reactions to the mouse component of the chimeric protein and is similar to those seen with the infusion of other high-protein load solutions such as immunoglobulins, chemotherapeutics, and other monoclonal antibodies. The majority of infusion reactions respond to a slowing of the rate of infusion. The alleviation of symptoms with a slowing of the infusion rate is evidence against the reactions being a true type 1 IgE-mediated allergic reaction. Additionally, markers of mast cell degranulation that are elevated in true allergic reactions have not been found to be elevated in patients with acute reactions during infliximab infusions.9 Several clinical trials suggest an association between infusion reactions and ATIs. Follow-up data from the ACCENT 1 cohort revealed that, whereas mild infusion reactions occurred more commonly in patients with an ATI (odds ratio, 1.8), ATIs provided a positive predictive value of only 36%. There was no correlation between incidence or severity of an infusion reaction with the level of antibody titer. Immunomodulator use was associated with a reduction in ATI and a 50% reduction (6%-3%, P = 0.001) in the incidence of infusion reactions. The reduction of infusion reactions was particularly apparent for those receiving infliximab on an episodic basis because of the higher incidence of ATIs within that group. While the authors do not advocate immunomodulators for every patient, they do point out that it could be a strategy to increase the long-term safety of episodic infliximab use. Baert et al6 identified that the majority of ATIs develop after the first infusion. When patients with an ATI titer above a defined threshold level (8 μg/mL) were treated with a subsequent infusion, there was a 2.4-fold increase in the risk of an infusion reaction. Once an infusion reaction occurred, there was prompt disappearance of infliximab from the serum and a reduced duration of response. The authors concluded that infusion reactions represent important immunologic events induced by substantial concentrations of ATIs. Based on this, Baert et al advocate starting immunomodulators before starting infliximab to prevent the immunogenic cascade resulting in a reduction in therapeutic efficacy. Farrell et al7 found that patients with ATIs were 8 times as likely to have an infusion reaction compared with those without ATI (40% versus 5%, P = 0.0001). All 7 patients (4.5% of the cohort) who developed a serious infusion reaction had elevated ATI titers (median ATI level, 19.6 μg/mL; range, 2.9-31 μg/mL), with all but 1 of the 7 patients having ATI levels greater than 16.0 μg/mL. Patients having an ATI level >8 μg/mL before an infusion had a 4-fold increase in the risk of developing a serious infusion reaction. While the 3 studies similarly found infusion reactions occurred more frequently in those with ATIs, the ACCENT 1 study found ATIs to be a poor predictor of infusion reactions, whereas Baert et al6 and Farrell et al7 found high ATI titers to be a stronger predictor of infusion reaction. The ACCENT 1 data and the study by Baert et al6 showed that immunomodulators decrease the rate of adverse events, which indicates that there are probably immunologic factors in addition to ATIs that are involved in infusion reactions. Delayed Reactions Delayed type reactions consist of flu-like symptoms, fevers, myalgias, arthralgias, rash, edema, and headache that occur 24 hours or more after an infusion. The clinical presentation is similar to that of a type 3 serum sickness reaction resulting from immune system activation by circulating antibody-antigen complexes. Although similar in symptoms, there is a distinct difference given the absence of hypocomplementemia in individuals with infliximab who develop these delayed reactions. A long lapse between infliximab infusions is thought to be a risk factor for the development of a delayed reaction on reinfusion. Hanauer et al10 observed that 25% (10 of 41) of patients with CD developed a delayed infusion reaction when retreated with infliximab after a 2- to 4-year hiatus. All delayed reactions occurred 3 to 12 days after reinfusion and were considered serious in 6 of the 10 patients. Of the 41 patients enrolled, delayed adverse reactions occurred in 9 of 23 (39%) of patients who had received liquid formulation, which is no longer in use, and 1 of 17 (6%) who received the lyophilized formulation, which is currently used in practice. All 10 patients were found to have elevated ATI titers, and based on this observation, it was initially thought that delayed infusion reactions were related to ATI formation. However, none of the 10 patients who experienced delayed reactions had experienced infusion-related reactions associated with their initial infliximab therapy, and follow-up data from the ACCENT I cohort5 do not support an association between ATIs and delayed reactions. In fact, none of the 13 patients in the ACCENT 1 cohort with a delayed serum sickness like reaction tested positive for ATIs. Similarly, Baert et al6 did not find an association between ATI and serum sickness type symptoms. Farrell et al7 prospectively assessed the clinical outcome in a subgroup of 44 patients who received a total of 68 infliximab infusions after follow-up sera was drawn to determine their ATIs status. Whereas response to subsequent infliximab therapy, duration of response, and infusion reactions were significantly higher among 16 ATI-positive patients compared with 28 ATI-negative patients, there was no difference in the incidence of delayed reactions. Antinuclear Antibody and Anti-Double-Stranded DNA Antibodies The development of antinuclear antibodies (ANAs) after infliximab infusion has been reported by numerous studies.3,11,12 While the mechanism remains to be elicited, it has been postulated that the down-regulation of C-reactive protein after an infliximab infusion results in decreased clearance of nuclear material from lysed cells and prolonged stimulation of the immune system. Vermeire et al11 studied the occurrence of ANAs and the relationship with symptoms of autoimmunity in 125 patients with CD treated with infliximab. At baseline, 7.2% of patients had positive ANAs, comparable with the incidence in the general population. The incidence of ANAs was 57% (71 of 125) at 24 months, with nearly one-half of the patients developing ANAs after the first infusion. While there was no temporal association between the formation of ANAs and ATIs, there was a near significant relationship for patients to either develop both positive ANAs and ATIs or remain seronegative for both antibodies. Loss of ANAs was observed in only 20% of patients, with antibodies remaining detectable for a median of 12 months. For patients who had ANA subtyping, 33% had dsDNA, 40% had single-stranded DNA, 21% had antihistone antibodies, and 0% had antibodies to extractable nuclear antigens. Two patients who were both antihistone and dsDNA positive developed symptoms consistent with drug-induced lupus without major organ damage, and 1 patient developed an autoimmune hemolytic anemia. In the ACCENT 1 cohort, a greater proportion of the patients in the maintenance group developed ANAs and antibodies to dsDNA (56% and 34%, respectively) than in the episodic treatment group (35% and 11%). These findings are dissimilar from those of Vermeire et al,11 where there was ANA and ATI congruence. However, similarly, only 1 patient with positive ANAs and anti-dsDNA (who was part of the 10 mg/kg scheduled treatment group) developed an acquired lupus-like syndrome. In the recent ACCENT II trial12 (a CD clinical trial evaluating infliximab in a new long-term treatment regimen in patients with fistulizing CD), compared with patients assigned placebo maintenance, patients assigned to infliximab maintenance therapy were more than twice as likely to have ANA antibodies (45.9% versus 18.2%, P < 0.001) and nearly 4 times as likely to have dsDNA antibodies (23.3% versus 6.3%, P < 0.001). A lupus-like syndrome developed in 1 patient; however, this patient was both ANA and dsDNA negative. The clinical significance of ANA and dsDNA positivity in infliximab-treated populations is unclear. While the incidence of overt lupus-like syndrome is reportedly low in patients receiving infliximab and in the postmarketing surveillance TREAT survey, the development of ANAs and dsDNA are of potential concern because autoantibodies may be present for several years in patients with systemic lupus erythematosus before the disease becomes clinically apparent.13 Given that ANA and dsDNA formation occurs in a large proportion of patients receiving prolonged treatment regimens and that long-term maintenance infliximab therapy in CD is advocated by the ACCENT I and II studies, long-term surveillance of infliximab-treated patients is imperative in fully assessing the true significance of autoantibody formation.14 In current clinical practice, we do not routinely check ANA serology unless a patient develops symptoms suggestive of a lupus-like syndrome. Similarly, in the absence of lupus-type symptoms, we do not avoid infliximab retreatment if ANAs are present at baseline or are later found to be present. Other Potentially Immune-Mediated Reactions There have been numerous reports of multiple sclerosis, demyelinating disorders, central nervous system vascularities, neutropenia, leukopenia, thrombocytopenia, and pancytopenia, some with fatal outcomes.15,–17 Although a causal relationship has not been determined, an immune-mediated mechanism has been theorized. The current recommendations are for close monitoring in patients with a history of, or ongoing, hematologic abnormalities. Discontinuation of infliximab therapy should be considered in patients who develop significant hematologic abnormalities. We are not using infliximab in patients with a history of multiple sclerosis or demyelinating disorders. Strategies for Reducing Infliximab-Mediated Immunogenicity It is clear from all the studies mentioned above that administration of a single induction dose of infliximab 5 mg/kg without concomitant immunosuppressive therapy is an immunogenic regimen that frequently leads to the formation of ATIs and that the presence of high concentrations of ATIs leads to adverse patient outcomes in the form of shortened duration of benefit or complete loss of response and infusion reactions.18 The high incidence and significance of infliximab-mediated immunogenicity is now better appreciated than it was 5 years ago and has led to a number of strategies designed to minimize antibody formation. These include a triple-induction regimen for all patients with CD (luminal and fistulous) and an attempt to have patients on concurrent immunosuppressants for a clinically relevant period (3 mo for azathioprine/6-mercaptopurine; 6-8 wk for methotrexate) before they initiate infliximab therapy. While a scheduled maintenance rather than an episodic retreatment strategy is also associated with reduced immunogenicity of infliximab therapy in CD, it remains unclear whether a triple-induction regimen and/or concurrent immunosuppressant therapy is more important in reducing immunogenicity than a subsequent scheduled maintenance regimen and whether retreatment should be administered at longer (or shorter) intervals than the 8-week schedule advocated as a result of the ACCENT I and II trials. It is also unknown whether a dual-induction regimen may obtain the same clinical efficacy and reduced immunogenicity of triple-induction regimens. Specific premedication strategies have recently been studied. In a randomized controlled trial of 80 patients with CD who received 5 mg/kg infliximab therapy (at weeks 0, 2, 6, and then after relapse), Farrell et al7 reported that premedication with high doses of intravenous hydrocortisone (200 mg/kg) immediately before infliximab reduced the incidence of ATI from 42% among hydrocortisone-treated patients to 26% among placebo patients. Although these findings were not statistically significant (P = 0.06) and steroid pretreatment did not significantly reduce infusion reaction rates (P = 0.3) or clinical outcome (P = 0.5), hydrocortisone premedication was significantly associated with a reduction in mean ATI levels. Mean ATI concentrations at weeks 8 and 16 were 2.9 and 1.6 μg/mL in hydrocortisone-treated patients compared with 11.2 and 3.4 μg/mL in placebo patients (P = 0.002 at week 8 and P = 0.02 at week 16). Although the optimal premedication strategy is currently unknown, and further controlled studies are warranted to evaluate dose, administration, and timing variables, this study suggests that intravenous hydrocortisone premedication should be considered in patients who have only recently commenced immunosuppressant therapy at the time that infliximab therapy is being initiated and in those patients intolerant to all immunosuppressants. Emerging Biologics Therapies The way in which a biopharmaceutical influences the immune system varies with patient factors such as disease state, genetics of the individual, state of the immune system, and the size, structure, dose, and route of administration.2 Although it is generally believed, although not proven, that the murine components of infliximab has the strongest influence on immunogenicity because it is the most foreign to the human immune system, formation of antidrug antibodies is not a problem unique to infliximab nor is it necessarily a function of infliximab being a chimeric molecule. Unfortunately, it is well known that the administration of any protein, including those that are fully human, may be associated with the development of antibodies. For example, a large proportion of patients develop antibodies to recombinant human insulin and recombinant human factor VIII. It is particularly notable that up to 12% of patients develop antibodies against the recently developed, fully human antitumor necrosis factor monoclonal antibody adalimumab during scheduled maintenance therapy with this drug.19 Antibodies also develop in up to 7% of patients receiving a different type of therapeutic molecule, the recombinant humanized antibody against α4 integrin, natalizumab.20 The mechanisms underlying a protein's immunogenicity are complex and poorly understood and go far beyond the species from which a therapeutic protein is derived. It is likely that immunogenicity will be an issue for most, if not all, therapeutic proteins. Currently, monoclonal antibodies, cytokines, growth hormones, and antisense nucleotides and other structures are being engineered for potential therapeutic use in IBD. The following section highlights some of the biologic therapeutics that are currently under study for use in IBD. Adalimunab (Humira) is a subcutaneously administered fully human anti-TNF-α monoclonal antibody (IgG1) that contains no nonhuman components or artificially fused human peptide sequences. In a recent short-term dose finding study of adalimumab in patients with CD,19 adalimumab achieved a 40% to 60% rate of response and a 24% to 36% rate of remission compared with a 36% response and 12% remission rate for placebo. Sandborn et al,21 presented the results of an open-label study of adalimumab of which 20 of 24 patients had prior treatment limiting infusion reactions or delayed reactions to infliximab. All patients tolerated adalimumab with efficacy at 12 weeks that was similar to those reported in the randomized trial.19 Because of its fully human design, adalimumab should theoretically be indistinguishable from naturally occurring human immunoglobulins.21 However, in the trials leading to Food and Drug Administration approval for maintenance therapy in rheumatoid arthritis, there was a 5% overall incidence of antidrug antibodies: 12% when used as monotherapy and 1% when used in conjunction with methotrexate.22 While the immunogenicity data for rheumatoid arthritis can not be compared directly to that of patients with CD in the ACCENT 1 cohort,3 it must be kept in mind if only for perspective that the incidence of ATIs in the maintenance group was 8%. While the early results of adalimumab in CD look promising, especially in patients with prior treatment limiting adverse reactions to infliximab, only longer-term studies will determine if immunogenicity plays a key role in the long-term safety and efficacy in CD. Other TNF blocking agents such as CDP-571, a humanized monoclonal antibody; etanercept, a soluble TNF receptor fusion protein; and onercept, a recombinant TNF receptor antibody, have had at best, modest efficacy in CD. CDP870, a fully human pegylated antibody fragment to TNF, is currently under study for patients with CD with elevated serum C-reactive protein levels. Selective blockade of leukocyte adhesion and migration has been targeted as a novel and promising strategy in CD. The results of 2 phase 3 studies of the intravenous α-4 integrin antagonist natalizumab (Antegren) were recently presented. While the ENACT-1 (evaluation of natalizumab in active CD) trial failed to meet the primary endpoint, a significant number of patients met secondary endpoints for clinical response and remission at other time-points.23,24 In the follow-up study, ENACT-2,25 responders that received monthly maintenance infusions had a significantly higher remission rate over those who received placebo. While natalizumab seems safe and well tolerated, antidrug antibodies were found in 7% of patients in earlier studies.23 The significance of the antidrug antibodies on the long-term clinical safety and efficacy remains unknown in the absence of any published long-term clinical trials. Multiple other biologics are currently being studied as potential targets for the development of new therapies for CD. Biologic therapies that inhibit the proinflammatory cytokines such as IL-6 and IL-12 or those that induce anti-inflammatory cytokines, IL-10 and IL-11, may hold promise. Other biologic therapies such as anti-interferon-γ (fontolizumab) and granulocyte-macrophage stimulating factors (GM-CSF; Sargramostim) are currently under study for CD. The enthusiasm and the success of biologics in CD has also expanded the number of trials for the treatment of ulcerative colitis (UC). While the early open-label studies with infliximab in UC have provided some promise,26 the results from of the randomized controlled phase 3 trials in UC have not yet been released. MLN-02, a humanized monoclonal antibody to α-4,β-7 integrin showed efficacy in early stage trials.27 Two humanized monoclonal antibodies that inhibit IL-2 (basiliximab and daclizumab) are in the early stages of study for use in UC.28,29 Topically applied ISIS-2303, an antisense oligonucleotide to intracellular adhesion molecule-1, has shown efficacy in phase 2 trials in active UC and refractory pouchitis and is currently in stage 3 studies.30 Medications that can be delivered by the oral route for obvious reasons represent an attractive delivery system. Anti-TNF agents OPC-6535 and RDP58 are both currently under study for UC.31,32 Conclusions The success of infliximab in clinical practice after Food and Drug Administration approval in 1998 has revolutionized the management of patients with moderate-to-severe CD and has heralded the era of biologic agents for IBD therapy. However, along with the beneficial effects of this chimeric therapeutic agent is the risk of developing immunologic phenomena such as early and delayed allergic-type reactions, formation of antidrug antibodies, which may limit the long-term use of the agent, autoantibody formation, and development of autoimmune syndromes. Mounting evidence from large clinical trials and cohort studies with infliximab is that a triple induction regimen, use of concurrent immunosuppressants, and possibly scheduled rather than episodic maintenance therapy are associated with reduced antibody to infliximab formation, improved safety, and improved efficacy. However, whereas the above studies indicate that patients who develop ATIs may have a shorter duration of response and are more likely to experience a infusion reaction after a subsequent infusion, there are likely other immunologic factors in addition to ATIs that are involved. The optimal induction, scheduled, and premedication strategies in addition to the possible yet to be defined immunologic factors need to be determined, and the long-term significance of ANA and dsDNA positivity needs to be followed closely. The issue of immunogenicity will not be eliminated with the development of newer, more humanized, or completely humanized biologic agents and optimal induction regimens; regularly scheduled maintenance therapy with the avoidance of long drug holidays is likely the preferred treatment strategy for all protein biologics that must be given on a repeated basis. References 1. Sandborn WJ, Faubion WA. Biologics in inflammatory bowel disease: how much progress have we made? Gut.  2004; 53: 1366- 1373. Google Scholar CrossRef Search ADS PubMed  2. Ryff JC, Schellekens H. Immunogenicity of rDNA-derived pharmaceuticals. Trends Pharmacol Sci.  2002; 23: 254- 256. Google Scholar CrossRef Search ADS PubMed  3. Hanauer SB, Feagan BG, Lichtenstein GR, et al. 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TI - Immunogenicity of Biological Agents in Inflammatory Bowel Disease
JO - Inflammatory Bowel Diseases
DO - 10.1097/01.MIB.0000161536.97412.41
DA - 2005-05-01
UR - https://www.deepdyve.com/lp/oxford-university-press/immunogenicity-of-biological-agents-in-inflammatory-bowel-disease-MH6yW2CAxF
SP - 497
EP - 503
VL - 11
IS - 5
DP - DeepDyve
ER -