Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn's disease.

BACKGROUND & AIMS: Adalimumab is an efficacious therapy for active Crohn's disease, but long-term data are scarce. We conducted an observational study to assess the long-term clinical benefit of adalimumab in patients who failed to respond to infliximab, specifically focusing on the influence of trough serum concentration and antibodies against adalimumab on clinical outcome. METHODS: A total of 168 patients with Crohn's disease treated with adalimumab in a tertiary center were included in a prospective follow-up program. Trough serum concentration and antibodies against adalimumab were measured at predefined time points using enzyme-linked immunosorbent assays. RESULTS: A total of 71% and 67% of patients responded by weeks 4 and 12, respectively; among them, 61.5% demonstrated sustained clinical benefit until the end of follow-up (median [interquartile range], 20.4 [11.7-30.0] months). Of the 156 patients receiving maintenance therapy, 102 (65.4%) had to step up to 40 mg weekly and 60 (38.5%) eventually stopped adalimumab therapy mainly due to loss of response. Significantly lower adalimumab trough serum concentrations were measured throughout the follow-up period in patients who discontinued therapy as compared with patients who stayed on adalimumab. Antibodies against adalimumab were present in 9.2% of the patients and affected trough serum concentration. Serious adverse events occurred in 12% of the patients. CONCLUSIONS: Introduction of adalimumab after failure of infliximab therapy resulted in a sustained clinical benefit in two thirds of patients during a median follow-up period of almost 2 years. Discontinuation was directly related to low adalimumab trough serum concentration, which was observed more frequently in patients who developed antibodies against adalimumab.

Trough infliximab concentrations predict efficacy and sustained control of disease activity in rheumatoid arthritis.

Infliximab is a chimeric monoclonal antibody that binds to human tumor necrosis factor alpha and is approved for refractory rheumatoid arthritis. We studied the association between infliximab concentration and long-term control of disease activity in patients with rheumatoid arthritis treated on a routine basis both in cross-sectional analysis and over the long term. Trough serum infliximab concentrations were measured in patients with rheumatoid arthritis receiving infliximab infusions during the period August to October 2006. Disease activity was assessed by the Disease Activity Score for 28 Joints (DAS28) and usual biologic markers. During a 42-week follow-up period, patients were classified into two groups: those continuing with the same or lower doses of infliximab (Group A = treatment success) and those who switched to another biopharmaceutical or required an increase in infliximab dose (Group B = treatment failure). Treatment maintenance for Group A was analyzed by categories of infliximab concentration at baseline and compared by the log rank test. In 28 patients, C-reactive protein and infliximab concentrations were inversely related. Infliximab concentration in patients with low disease activity (DAS28 3.2 or less) was higher than in those with persistent active disease (DAS28 greater than 3.2); median values were 3.26 and 0.16 mg/L, respectively (P < 0.01). Analysis after 42 weeks showed that patients in Group A had higher infliximab concentrations at baseline than those with treatment failure (P < 0.01). In rheumatoid arthritis, infliximab concentration is predictive of sustained efficacy with the same infliximab regimen and should be considered on a routine basis.

Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial.

BACKGROUND & AIMS: The benefit to risk ratio of concomitant immunosuppressives with scheduled infliximab (IFX) maintenance therapy for Crohn's disease is an issue of debate. We aimed to study the influence of immunosuppressives discontinuation in patients in remission with combination therapy in an open-label, randomized, controlled trial. METHODS: Patients with controlled disease > or = 6 months after the start of IFX (5 mg/kg intravenously) combined with immunosuppressives were randomized to continue (Con) or to interrupt (Dis) immunosuppressives, while all patients received scheduled IFX maintenance therapy for 104 weeks. Primary end point was the proportion of patients who required a decrease in IFX dosing interval or stopped IFX therapy. Secondary end points included IFX trough levels, safety, and mucosal healing. RESULTS: A similar proportion (24/40, 60% Con) and (22/40, 55% Dis) of patients needed a change in IFX dosing interval or stopped IFX therapy (11/40 Con, 9/40 Dis). C-reactive protein (CRP) was higher and IFX trough levels were lower in the Dis group (Dis: CRP, 2.8 mg/L; interquartile range [IQR], 1.0-8.0; Con: CRP, 1.6 mg/L; IQR, 1.0-5.6, P < .005; trough IFX: Dis: 1.65 microg/mL; IQR, 0.54-3.68; Con: 2.87 microg/mL; IQR, 1.35-4.72, P < .0001). Low IFX trough levels correlated with increased CRP and clinical score. Mucosal ulcers were absent at week 104 in 64% (Con) and 61% (Dis) of evaluated patients with ongoing response to IFX. CONCLUSIONS: Continuation of immunosuppressives beyond 6 months offers no clear benefit over scheduled IFX monotherapy but is associated with higher median IFX trough and decreased CRP levels. The impact of these observations on long-term outcomes needs to be explored further.

[Neonatal Fc receptor, key control of immunoglobulins biodistribution]. / FcRn, un récepteur d'IgG aux multiples facettes.

In 1969, Brambell, while studying the long serum half-life of IgG and their ability to cross the materno-foetal barrier, attributed these two properties to the existence of a specific Fc receptor, which was later denominated FcRn for neonatal Fc receptor. The resolution of its structure revealed that it is a MHC class-I-like molecule. FcRn is able to load IgG and albumin in a pH-dependent manner. It acts as an intracellular transport protein and as such is controling the serum half-life of these proteins (apical recycling of IgG and albumin in endothelial cells), IgG biodistribution (apical to basolateral and basolateral to apical transport of IgG in epithelial and endothelial cells) and it may also contribute to phagocytosis. FcRn is thus a key partner in the pharmacokinetics of therapeutic antibodies, opening interesting prospects for optimisation of their use.

Structure-function relationships of the variable domains of monoclonal antibodies approved for cancer treatment.

Due to their exquisite specificity for a given epitope on the target antigen, recombinant monoclonal antibodies (rmAb) can deliver "targeted therapy" in oncology. This review focuses on the structural bases of "antigen specificity" to aid clinical researchers and pharmacologists in managing these new drugs. The fine structure of the Fv (Fragment variable) module (combination of VH and VL domains) from the five unconjugated antibodies currently approved for cancer treatment, namely rituximab, cetuximab, alemtuzumab, trastuzumab and bevacizumab, is presented and analysed. Co-crystal and functional studies are reviewed to define rmAb residues contributing to antigen binding site (paratope)-epitope interfaces. The genetic origin of these recombinant monoclonal antibodies, determined through the IMGT/3Dstructure-DB database and IMGT/V-QUEST (http://imgt.cines.fr), is presented, allowing the evaluation of homologies between antibodies and their closest germline human counterparts and hence their possible immunogenicity. Overall, the IMGT standards appear as a first and crucial step in the evaluation of recombinant antibodies.

Therapeutic antibodies in ophthalmology: old is new again.

More than a century after the first successful use of serotherapy, antibody-based therapy has been renewed by the availability of recombinant monoclonal antibodies. As in the past, current clinical experience has prompted new pharmacological questions and induced much debate among practitioners, notably in the field of ophthalmology. An examination of the history of antibodies as treatments for ocular disorders reveals interesting parallels to the modern era. The fact that a treatment administered by a systemic route could be efficacious in a local disease was not widely accepted and the "chemical" nature of antibodies was not clearly understood in the late 19(th) century. Clinical studies by Henry Coppez, a Belgian ophthalmologist, established in 1894 that antidiphtheric antitoxins could be used to treat conjunctival diphtheria. Nearly 20 years later, Coppez and Danis described age-related macular degeneration, a disorder which today benefits from ranibizumab therapy. The product, a locally-administered recombinant monoclonal Fab fragment, is directed against vascular endothelial growth factor A. Interestingly, its full-size counterpart, bevacizumab, which is approved for the treatment of solid tumors, has also demonstrated efficacy in age-related macular degeneration when administered either intravenously or locally, which raises new questions about antibody pharmacology and biodistribution.In order to shed some light on this debate, we recount the early history of serotherapy applied to ophthalmology, review the exact molecular differences between ranibizumab and bevacizumab, and discuss what is known about IgG and the blood-retina barrier and the possible role of FcRn, an IgG transporter.

Infliximab concentration monitoring improves the control of disease activity in rheumatoid arthritis.

INTRODUCTION: Adjustment of infliximab dosage for individuals may be useful in improving therapeutic response in rheumatoid arthritis (RA). Herein, we aimed to determine whether measurement of infliximab serum concentration modifies the therapeutic decision and improves the control of disease activity. METHODS: RA patients routinely treated with infliximab were included in an observational open-label study. On visit 1 (V1), according to the disease activity, a preliminary therapeutic decision was selected among four therapeutic options and a blood sample was collected to measure trough serum infliximab concentration. The final therapeutic decision, based on both disease activity and serum infliximab concentration assessed at V1, was applied at the following infusion (V2). Clinical and biological evaluations were performed at V3 and V4 and compared with those at V1. RESULTS: We included 24 patients. The final therapeutic decision differed from the preliminary decision for 12 patients (50%). For patients with increased infliximab dosage at V2, mean disease activity score for 28 joints (DAS28) decreased by about 20% at V3 or V4 as compared with V1 (P < 0.05). Decreased DAS28 was correlated with increased serum infliximab concentration (P < 0.02). CONCLUSIONS: The measurement of infliximab trough concentration modifies the therapeutic decision for RA patients and helps improve control of disease activity. Therapeutic drug monitoring of infliximab in RA may be useful for individual dosage adjustment.

IgG1 heavy chain-coding gene polymorphism (G1m allotypes) and development of antibodies-to-infliximab.

OBJECTIVE: The chimeric anti-tumor necrosis factor-alpha antibody infliximab is known to induce antibodies-to-infliximab (ATI) in some treated patients. Immunogenicity in murine variable domains is expected; however, constant domains of its human heavy gamma1 chain may also be implicated as it expresses G1m1 and G1m17 allotypes. This allelic form may be immunogenic in patients that are homozygous for the G1m3 allotype commonly expressed in Caucasoid populations. METHODS: As G1m allotypic divergence may explain the presence of ATI or may influence their concentration, a genotyping method was developed and validated to determine antithetical (i.e. mutually exclusive) G1m3 and G1m17 allotypes (amino acid 120 of CH1 according to the international ImMunoGeneTics information system unique numbering) at the IGHG1 gene level (CH1 359g/a nucleotide polymorphism). Two hundred forty-five blood donors and 118 previously described patients suffering from Crohn's disease, treated with infliximab, and having developed ATI in 73 of them, were genotyped. RESULTS: The IGHG1 CH1 359g/a polymorphism does not depart from the Hardy-Weinberg equilibrium in the control population, and allele frequencies were similar in controls and patients. No association was found between the patient G1m allotypes and the presence of ATI or their concentration. It remains possible that anti-Gm1 antibodies are not well detected by the enzyme-linked immunosorbent assays used for ATI detection and/or that the G1m allotypes are minor antigens on IgG1. CONCLUSION: The IGHG1 polymorphism does not seem to play a major role in the induction of ATI. Further analyses will be required to determine whether it is also the case for humanized or fully human antibodies bearing the same G1m allotypes.

Infliximab pharmacokinetics in inflammatory bowel disease patients.

Infliximab, a chimeric monoclonal antibody, has profoundly modified the treatment of several inflammatory diseases, but no satisfactory description of its pharmacokinetics is available. The objective of this study is to describe the pharmacokinetics of infliximab and to explore the sources of its interindividual variability. Thirty-three chronic inflammatory bowel disease patients were studied. Infliximab serum concentrations, obtained during therapeutic drug monitoring, were analyzed using a population approach. Influence of sex, weight, age, concomitant immunosuppressive treatment, and development of antibodies toward infliximab (ATI) on pharmacokinetic parameters was investigated. A two-compartment model with first-order distribution and elimination constants allowed a satisfactory description of infliximab serum concentrations. Mean population distribution and elimination half-lives were 4.3 and 18.5 days, respectively. Weight and sex were found to significantly influence volume of distribution of the central compartment, which increased with weight and was higher in men. Clearance was 2.7 times higher, and elimination half-life was 34% lower in the presence of ATI. In two patients, an increase in infliximab dose or a decrease in dosing interval lead to a decrease in infliximab clearance toward its value in patients without ATI. Infliximab pharmacokinetics are similar to those of other monoclonal antibodies, notably with an elimination half-life of approximately 3 weeks. Both body weight and sex were found to influence infliximab pharmacokinetics, and its clearance increased thrice in the presence of ATI.

The homozygous FcgammaRIIIa-158V genotype is a risk factor for heparin-induced thrombocytopenia in patients with antibodies to heparin-platelet factor 4 complexes.

We hypothesized that Fcgamma receptor IIIa (FcgammaRIIIa), a polymorphic receptor for the Fc portion of immunoglobulin G (IgG) other than FcgammaRIIa, was involved in heparin-induced thrombocytopenia (HIT). FcgammaRIIa-131 and FcgammaRIIIa-158 genotypes were determined in 102 patients with definite HIT and in 2 control groups of patients treated by heparin (86 subjects without detectable antibodies [Abs] to heparin-platelet factor 4 [H/PF4], Ab(-) group; 84 patients with Abs to H/PF4 without HIT, Ab(+) group). There were no significant differences in genotype distribution or allele frequencies between the 3 groups for FcgammaRIIa-131H/R polymorphism. In contrast, FcgammaRIIIa-158V homozygotes were more frequent in the HIT group than in the Ab(+) group (P = .02), a difference that was more pronounced in patients with high levels of anti-H/PF4 Abs (P = .01). Since anti-H/PF4 Abs are mainly IgG1 and IgG3, clearance of sensitized platelets may be increased in patients homozygous for the FcgammaRIIIa-158V allotype, thus contributing to the development of thrombocytopenia.