Epitopes recognized by neutralizing therapy‐induced human anti‐interferon‐α antibodies are localized within the N‐terminal functional domain of recombinant interferon‐α2

Nolte, Klaus-Ulrich; Günther, Gritt; Wussow, Peter von

doi:10.1002/eji.1830260929

Cited by 19 publications

(8 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The highresolution structure models we described in this report clearly showed the molecular details of the interaction between the antibody and antigen, and giving clear picture of antibody binding epitope, both Pro26-Gln40 region in loop AB and Glu147-Arg150 region in helix E of IFNα1b contribute to the antibody binding, and four residues of above two regions (Leu30, Asp32, Asp35, and Arg150) are critical for the formation of antigen-antibody complexes. The results is also consistent with a previous reported epitope residues 22-31 recognized by another IFNα targeted human neutralizing antibody [34].…”

Section: Discussionsupporting

confidence: 82%

Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus

Ouyang

Gong

Li³

et al. 2012

J Mol Med

View full text Add to dashboard Cite

Increasing evidences suggest that the type I interferon α (IFN α) plays a critical role in the etiopathogenesis of systemic lupus erythematosus (SLE), which makes it a promising therapeutic target for the treatment of the disease. By screening a large size non-immune human antibody library, we have developed a human single-chain antibody (ScFv) AIFN α 1bScFv01 and corresponding whole antibody AIFN α 1bIgG01 to human interferon α 1b (IFN α 1b) with high specificity and high affinity. The IgG antibody could down-regulate the expression of ISG15 and IFIT-1 induced by either recombinant IFN α 1b or naïve IFN α from SLE patients' sera, and reduced total serum IgG and IgM antibodies level in a pristane-primed lupus-like mouse model. The crystal structure of AIFN α 1bScFv01-IFN α 1b complex solved to 2.8 Å resolution revealed that both Pro26-Gln40 region in loop AB and Glu147-Arg150 region in helix E of IFN α 1b contribute to binding with AIFN α 1bScFv01. Four residues of above two regions (Leu30, Asp32, Asp35 and Arg150) are critical for the formation of antigen-antibody complexes. AIFN α 1bScFv01 shares partial epitopes of IFN α 1b with its receptor IFNAR2 but with much higher binding affinity to IFN α 1b than IFNAR2. Thus, AIFN α 1bIgG01 exhibits its neutralizing activity through competition with IFNAR2 to bind with IFN α and prevents the activation of IFN α-mediated signaling pathway. Our results highlight the potential use of the human antibody for modulating the activity of IFN α in SLE.

show abstract

Section: Discussionsupporting

confidence: 82%

Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus

Ouyang

Gong

Li³

et al. 2012

J Mol Med

View full text Add to dashboard Cite

show abstract

“…Neutralisation of IFN-α evidently can occur in vivo during therapy with IFN-α2; some patients clearly become resistant because they make antibodies against it—usually with much lower titres/cross-reactivity than in APS1 [ 43 , 44 ]. Possibly, however, neutralising antibodies might be less effective in vivo if IFNs secreted in tissues can bind to their receptors before the antibodies neutralise their activity, e.g., because IFN-producing cells are so ubiquitous and mobile or the IFNs they release act at short range.…”

Section: Discussionmentioning

confidence: 99%

Anti-Interferon Autoantibodies in Autoimmune Polyendocrinopathy Syndrome Type 1

et al. 2006

View full text Add to dashboard Cite

BackgroundThe autoimmune regulator (AIRE) gene influences thymic self-tolerance induction. In autoimmune polyendocrinopathy syndrome type 1 (APS1; OMIM 240300), recessive AIRE mutations lead to autoimmunity targetting endocrine and other epithelial tissues, although chronic candidiasis usually appears first. Autoimmunity and chronic candidiasis can associate with thymomas as well. Patients with these tumours frequently also have high titre immunoglobulin G autoantibodies neutralising type I interferon (IFN)–α and IFN-ω, which are secreted signalling proteins of the cytokine superfamily involved in both innate and adaptive immunity.Methods and FindingsWe tested for serum autoantibodies to type I IFNs and other immunoregulatory cytokines using specific binding and neutralisation assays. Unexpectedly, in 60/60 Finnish and 16/16 Norwegian APS1 patients with both AIRE alleles mutated, we found high titre neutralising immunoglobulin G autoantibodies to most IFN-α subtypes and especially IFN-ω (60% homologous to IFN-α)—mostly in the earliest samples. We found lower titres against IFN-β (30% homologous to IFN-α) in 23% of patients; two-thirds of these (from Finland only) also had low titres against the distantly related “type III IFN” (IFN-λ1; alias interleukin-29). However, autoantibodies to the unrelated type II IFN, IFN-γ, and other immunoregulatory cytokines, such as interleukin-10 and interleukin-12, were much rarer and did not neutralise.Neutralising titres against type I IFNs averaged even higher in patients with APS1 than in patients with thymomas. Anti–type I IFN autoantibodies preceded overt candidiasis (and several of the autoimmune disorders) in the informative patients, and persisted for decades thereafter. They were undetectable in unaffected heterozygous relatives of APS1 probands (except for low titres against IFN-λ1), in APS2 patients, and in isolated cases of the endocrine diseases most typical of APS1, so they appear to be APS1-specific.Looking for potentially autoimmunising cell types, we found numerous IFN-α+ antigen-presenting cells—plus strong evidence of local IFN secretion—in the normal thymic medulla (where AIRE expression is strongest), and also in normal germinal centres, where it could perpetuate these autoantibody responses once initiated. IFN-α2 and IFN-α8 transcripts were also more abundant in antigen-presenting cells cultured from an APS1 patient's blood than from age-matched healthy controls.ConclusionsThese apparently spontaneous autoantibody responses to IFNs, particularly IFN-α and IFN-ω, segregate like a recessive trait; their high “penetrance” is especially remarkable for such a variable condition. Their apparent restriction to APS1 patients implies practical value in the clinic, e.g., in diagnosing unusual or prodromal AIRE-mutant patients with only single components of APS1, and possibly in prognosis if they prove to predict its onset. These autoantibody responses also raise numerous questions, e.g., about the rarity of other infections in APS1. Moreover, there must also be clues ...

show abstract

“…Indeed, IFN-a-induced antibodies have been found previously to be highly subtype specific, thus restricting their cross-reactivity with natural IFN-a. (30) We conclude that IFN-a antibodies develop in .70% of AMD patients on IFN-a2a and that such antibodies may profoundly influence the outcome of therapy. Larger studies are required to confirm this observation.…”

Section: Discussionmentioning

confidence: 98%

IFN-α Antibodies in Patients with Age-Related Macular Degeneration Treated with Recombinant Human IFN-α2a

Roß

Engler

Sander

et al. 2002

Journal of Interferon & Cytokine Research

View full text Add to dashboard Cite

We tested for development of binding and neutralizing antibodies to interferon-alpha (IFN-alpha) during IFN-alpha2a therapy of patients with age-related macular degeneration (AMD) of the eyes. Antibodies were investigated retrospectively in sera of 34 patients treated with 3 x 10(6) IU IFN-alpha2a (Roceron-A), Hoffmann La-Roche, Basel, Switzerland) three times weekly for periods of 8-16 weeks with or without a drug-free 4-12-week intermission. Additionally, 10 patients were investigated prospectively; 7 received 1.5-6 x 10(6) IU IFN-alpha2a three times weekly for 12 months, and 3 received placebo. Binding antibodies were tested by molecular size and protein G affinity chromatography using 125I-IFN-alpha2a. Neutralizing activities were tested by antiviral neutralization bioassay. IgG antibodies were detected in 24 of 34 IFN-alpha2a-treated patients (71%). Significantly higher anti-IFN-alpha levels were observed in patients who after discontinuation were readministered IFN-alpha2a (p < 0.02). Three of the IFN-alpha2a-treated patients in the prospective study had high and 1 had low antibody titers. Neutralizing antibody titers were high against IFN-alpha2a and IFN-alpha2c and low against lymphoblastoid and leukocyte IFN-alpha. Impaired clinical responses were observed in antibody-positive patients (p < 0.01). The development of neutralizing anti-IFN-alpha antibodies in patients with AMD during recombinant human IFN-alpha therapy may explain the often poor clinical effect of IFN-alpha treatment.

show abstract

Epitopes recognized by neutralizing therapy‐induced human anti‐interferon‐α antibodies are localized within the N‐terminal functional domain of recombinant interferon‐α2

Cited by 19 publications

References 30 publications

Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus

Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus

Anti-Interferon Autoantibodies in Autoimmune Polyendocrinopathy Syndrome Type 1

IFN-α Antibodies in Patients with Age-Related Macular Degeneration Treated with Recombinant Human IFN-α2a

Contact Info

Product

Resources

About