Immunogenicity of anti-tumor necrosis factor antibodies—toward improved methods of anti-antibody measurement

Aarden, Lucien A.; Ruuls, Sigrid R.; Wolbink, Gertjan

doi:10.1016/j.coi.2008.06.011

Cited by 162 publications

(115 citation statements)

References 30 publications

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“…The most relevant consequence of antibody formation is either an increased clearance of immune complexes or neutralization of the antigen-binding site, both resulting in decreased pharmacological availability (Lobo et al, 2004). Therefore, the serum levels of functional therapeutic antibody and its rate of decay can be seen as the best indication of how much clinically relevant ADA is formed (Aarden et al, 2008). Based on the absence of increased infliximab clearance in the minipig in this study, it is plausible to conclude that the level of anti-infliximab antibodies is low in these animals, or at least that the amount of clinically relevant antibodies against infliximab in the minipig is low.…”

Section: Discussionmentioning

confidence: 99%

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

Mierlo

Cnubben

Wouters

et al. 2013

Journal of Immunotoxicology

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Immunogenicity is a major issue of concern for monoclonal antibodies used in human diseases and is by default mainly determined in non-human primates (NHP), as target molecules are considered most similar in NHP compared to human. In this manuscript the predictive value of immunogenicity testing in minipigs for human safety is evaluated, as the immune system of the pig is functionally similar to that in other mammalian species. Adalimumab and infliximab (both monoclonal antibodies blocking TNFa) were used as model substances. Female Gö ttingen minipigs (4/group) were treated every other week with low (0.1 mg/kg), mid (1.0 mg/kg), or high dose (5 mg/kg) adalimumab or 5 mg/kg infliximab subcutaneous (SC) over a period of 8 weeks. After first and last dosing, pharmacokinetic analysis was performed. Anti-drug antibodies (ADAs) were measured on several time points. Furthermore, hematology, clinical chemistry, body weight, clinical signs, and histopathology of several organs were evaluated. No signs of toxicity of the treatments were observed in the limited organs and tissues collected. Eleven out of 12 minipigs treated with adalimumab elicited a detectable ADA response. Induction of ADA was correlated with decreased plasma levels of adalimumab. Infliximab clearance was comparable after first and last dose. Therefore, the presence of ADA directed to infliximab was considered highly unlikely. It was concluded that the minipig and NHP showed comparable suitability for immunogenicity prediction in humans. More studies with other biopharmaceutical products are needed to strengthen the status of the minipig as an alternative model for immunotoxicity testing including immunogenicity.

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Section: Discussionmentioning

confidence: 99%

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

Mierlo

Cnubben

Wouters

et al. 2013

Journal of Immunotoxicology

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“…The formation of anti-infliximab antibodies has, however, become one of the foremost reasons for drug discontinuation (16). Blocking infliximab binding to its target or accelerating its clearance from serum lead to a loss in efficacy (17,18), while anti-infliximab antibodies also increase the risk of infusion reactions (10). The data in this study agree with these concepts.…”

Section: Discussionmentioning

confidence: 99%

“…In turn, several studies have shown that higher doses of infliximab correlate with lower incidence of anti-infliximab-antibody formation and improved infliximab effectiveness both in adults and children (2,20). The monitoring of serum infliximab levels and formation of anti-infliximab antibodies can therefore explain the loss of therapeutic response to infliximab in a number of patients and can help with decisions for future treatments, either by increasing the dose or switching to a different TNF-blocking biologic (17,21).…”

Section: Discussionmentioning

confidence: 99%

Exploring the Binding Sites of Anti-Infliximab Antibodies in Pediatric Patients With Rheumatic Diseases Treated With Infliximab

et al. 2011

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Over the past decade, the treatment of a variety of immune-mediated diseases has improved greatly due to the introduction of biologics for therapies in cases that are nonresponsive to traditional treatments. However, a side effect not encountered in traditional treatments is the immunogenicity of the biologics themselves. Our aim was to investigate the anti-infliximab-antibody response in pediatric patients receiving infliximab for juvenile idiopathic arthritis and other pediatric rheumatic diseases, with a focus on an analysis of the binding sites of these antibodies. We show that anti-infliximab antibodies developed in 43% of patients receiving infliximab therapy. Neutralization studies showed that in all these patients, the antibodies were directed toward the variable domains of infliximab, as they inhibited binding of infliximab to TNF. A more precise determination of the antibody epitopes using synthetic peptides was not achieved, indicating that all the antibody binding sites were composed of discontinuous segments of infliximab. (Pediatr Res 69: 243-248, 2011) J uvenile idiopathic arthritis (JIA) is the umbrella term for a heterogeneous group of inflammatory arthropathies that can affect children and young adults. As the name suggests, the cause and pathogenesis of JIA are still largely unknown but are thought to include both genetic and environmental factors. Although none of the drugs available for treatment of JIA provides a cure, disease prognosis has improved greatly in recent years due to improved disease management and with the introduction of biologics that can provide an efficient alternative for patients who are nonresponsive to other treatments (1). Infliximab is one such biological agent, which acts by blocking the activity of TNF in the inflammatory response. Although infliximab is not formally approved for use in JIA, it is commonly used and its efficacy has been documented in several studies (2-5).Infliximab is a chimeric MAb composed of variable domains of murine origin and constant domains of human origin (6,7). Although it is usually well tolerated and safe for JIA therapy (8), an important aspect for consideration is its immunogenicity. It has become clear in recent years that all biologics have some degree of immunogenicity, even fully humanized ones. This can lead to the development of so-called antidrug antibodies (9), which can lead to loss of efficacy of treatment and higher incidence of adverse events (10).The generation and specificity of anti-infliximab antibodies has not been well studied in pediatric patients. Therefore, in this study, we analyzed the levels of infliximab and antiinfliximab antibodies in patients with JIA and other pediatric rheumatic diseases, from two European pediatric centers. We also looked for possible epitopes of these antibodies, using overlapping synthetic peptides that covered the amino acid sequences of both of the infliximab variable domains. METHODSPatients and sera. Twenty-one pediatric patients receiving infliximab for treatment of rhe...

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“…In the chimeric antibody construct, the murine Fc was replaced by its human counterpart, which resulted in approximately 75% humanization of mouse antibody molecule (Morrison et al, 1984), and could therefore induce a significantly decreased HAMA response in human recipients. However, the remaining 25% mouse component in this chimera is still immunogenic, and human anti-chimeric antibody response (HACA) have been observed (Aarden et al, 2008). However, considering the particular nature of STEC infection in humans, where only a few times of antibody administration can effectively eliminate the toxin from the body, the severe side effect associated with cancer patients due to long term and large dosage use, would not happen in this situation.…”

Section: Discussionmentioning

confidence: 99%

Engineering and evaluation of a mouse/human chimeric antibody against Shiga toxin 2

Li¹,

Lin²,

Zeng³

et al. 2013

Afr. J. Microbiol. Res.

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Hemolytic-uremic syndrome (HUS), mainly caused by Shiga toxin (Stx) producing Escherichia coli(STEC) such as E. coli O157:H7 and STEC/EAggEC, is a serious complication predominantly leading to renal failure and even death. We have previously reported that a monoclonal antibody effectively neutralizes Stx2 in vitro and in vivo toxicity models. As a therapeutic agent against HUS, the mouse origin of this antibody can trigger human anti-murine antibody (HAMA) reactions thereby restricting its clinical application. In order to reduce its immunogenicity for use in humans, in this study, a mouse/human chimeric antibody designated rS2C4-IgG1 was developed in baculovirus/insect cell expression system. Analysis of antigen-binding and competitive binding revealed that rS2C4-IgG1 possessed specificity and affinity similar to that of S2C4. Results from cytotoxicity assays and mouse toxicity model analysis showed that rS2C4-IgG1offers neutralizing activity comparable to its parent MAb in vitro and in vivo. Therefore, the chimeric rS2C4-IgG1 had great potential for use in the treatment of STEC infection.

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Immunogenicity of anti-tumor necrosis factor antibodies—toward improved methods of anti-antibody measurement

Cited by 162 publications

References 30 publications

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

Exploring the Binding Sites of Anti-Infliximab Antibodies in Pediatric Patients With Rheumatic Diseases Treated With Infliximab

Engineering and evaluation of a mouse/human chimeric antibody against Shiga toxin 2

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