The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region
The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region
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DOI：
10.1136/annrheumdis-2014-206237
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发表时间：
2015-01-01
影响因子：
27.4
通讯作者：
Rispens, T.
中科院分区：
文献类型：
--
作者：
van Schie, K. A.;Hart, M. H.;Rispens, T.
背景在一部分患者中，抗肿瘤坏死因子（TNF）治疗性抗体具有免疫原性，导致抗药抗体（ADA）的形成。中和ADA与TNF竞争其结合位点并降低有效血清浓度，导致临床无应答。然而，ADA的中和程度尚不清楚。（阿达木单抗、戈利木单抗、赛妥珠单抗）以及嵌合抗TNF方法在用阿达木单抗（n=21），戈利木单抗（n=4），结果在34份抗阿达木单抗、戈利木单抗或赛妥珠单抗ADA阳性血清中，中和抗体阳性率>97%。在34份具有抗英夫利西单抗ADA的血清中，>90%的抗体被中和。对英夫利西单抗的更广泛抗体反应的进一步表征显示，英夫利西单抗的非中和抗体不靶向鼠域，但可能结合不参与TNF结合的英夫利西单抗独特域（位于互补位外）。这种高度限制的ADA应答表明抗TNF治疗剂的互补位具有免疫显性作用。
Background In a subset of patients, anti tumour necrosis factor (TNF) therapeutic antibodies are immunogenic, resulting in the formation of antidrug antibodies (ADAs). Neutralising ADAs compete with TNF for its binding site and reduces the effective serum concentration, causing clinical non-response. It is however unknown to which extent ADAs are neutralising.Objectives To study which proportion of antibodies to human(ised) anti-TNF (adalimumab, golimumab, certolizumab) as well as chimeric anti-TNF (infliximab) is neutralising.Methods Neutralising capacity of ADAs was assessed using a TNF competition assay in ADA-positive sera of patients treated with adalimumab (n=21), golimumab (n=4), certolizumab (n=9) or infliximab (n=34) sent in to our diagnostic department.Results In 34 sera with ADAs to adalimumab, golimumab or certolizumab, >97% of the antibodies were neutralising. In 34 sera with ADAs to infliximab >90% of the antibodies were neutralising. Further characterisation of the broader antibody response to infliximab revealed that non-neutralising antibodies to infliximab do not target murine domains, but may bind infliximab-unique domains not involved in TNF binding (located outside the paratope).Conclusions Our study shows that ADAs to human (ised) as well as chimeric anti-TNF therapeutic antibodies are largely neutralising. This highly restricted ADA response suggests an immunodominant role for the paratope of anti-TNF therapeutics.