The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region

Abstract

BackgroundIn 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.ObjectivesTo study which proportion of antibodies to human(ised) anti-TNF (adalimumab, golimumab, certolizumab) as well as chimeric anti-TNF (infliximab) is neutralising.MethodsNeutralising 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.ResultsIn 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).ConclusionsOur 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.

Functional Analysis of the Anti-adalimumab Response Using Patient-derived Monoclonal Antibodies

“…In the case of adalimumab, a fully human anti-TNF agent, recent data indicate that essentially all ADA are anti-idiotypic antibodies, directed against the TNF binding region of adalimumab and resulting in neutralization of the drug (8). This is confirmed by inhibition experiments showing that TNF completely prevents binding of ADA in patient sera (9). These observations suggest that the immune response against adalimumab is restricted, but it leaves unanswered the question of whether the immune system targets just a single epitope or multiple determinants that are spatially confined to the TNF-binding site on adalimumab.…”

Cross-reactive and pre-existing antibodies to therapeutic antibodies—Effects on treatment and immunogenicity

“…[25][26][27] Notably, for both monoclonal and polyclonal anti-adalimumab antibodies, no cross-reactivity was observed to infliximab. 26,27 A study on the actual binding sites of anti-adalimumab antibodies revealed that the antibody response against adalimumab is highly restricted.…”

“…Strikingly, >90% of the antibody response to the chimeric infliximab could be inhibited by TNF. 25 Several cases were identified with a small but definite fraction of non-neutralizing antibodies (i.e., <10%) that were not cross-reactive to polyclonal mouse IgG, suggesting that infliximab-specific idiotopes outside of the antigen binding site were recognized.…”

“…27 Furthermore, more than 97% of the anti-idiotype antibody response to adalimumab, golimumab, and certolizumab, all 3 of which are either human or humanized anti-TNF antibodies, could be inhibited by TNF. 25 All-in-all, the vast majority of antibodies formed to these TNF blockers appear to be neutralizing, anti-idiotype antibodies. Strikingly, >90% of the antibody response to the chimeric infliximab could be inhibited by TNF.…”

Biological treatments

“…Zaten bu nedenle, araflt›rma amaçl› d›-fl›nda, anti-TNF alan hastalarda rutin anti-ilaç antikorlar›n›n bak›lmas› önerilmemektedir. [4,21,[33][34][35] • Otoimmün yan etkiler: Yaklafl›k %40 olguda antinükleer antikor pozitifli¤i geliflir ve süre uzad›kça bu s›kl›k artar. Temel mekanizma normalde TNF'nin inhibe etti¤i IL-10 ve IFN-α düzeylerindeki art›flt›r.…”