We reaffirm that antibodies preferentially develop in the severe vintage Fabry phenotype, which can mislead into interpreting that antibodies are associated with much severe clinical events. Keywords: Fabry disease, Antibodies, Inhibition, Phenotype Dear Editors We go through with interest the letter from Lenders et al. disease individuals, a prospective analysis from your French multicenter cohort FFABRY [1, 2]. In the letter, our main message seems to have been eluded: the development of anti-drug antibodies (ADAs) depends on the medical phenotype (ADA-positivity in AZ 10417808 classic individuals 58.6% vs 6.7% in non-classic individuals, p?p?=?0.7). There was also no difference in the mean infused dose received by individuals during their whole exposure to ERT (ADA-positive vs ADA-negative individuals 0.43?mg/kg vs 0.64?mg/kg, p?=?ns). We agree with Lenders and colleagues that purifying IgG subclasses could bring essential information concerning immunogenicity as AZ 10417808 a first approach. Also, it appears that this has not been performed in the referenced paper [3] where authors used purified total IgGs. We also agree with the authors that ADAs do not possess a required neutralizing activity. This is the Rabbit polyclonal to ZNF33A reason why we believe that inhibition assays should only become performed after a first step using an immune-based assay such as an ELISA. Our goal was to study all ADAs, neutralizing and non-neutralizing. We may have to clarify that we did perform inhibition assay in all the males, contrary to what is pointed out in the letter. As expected, any of the antibody-negative serum was associated with enzymatic inhibition (Fig. 4a). It should also become reminded to readers that there is no consensus for inhibition assay and that the percentage of enzyme inhibition depends on the concentrations of ERT used in the protocol of the inhibition assay. Consequently, there is a need to standardize the protocol and the threshold retained to define inhibition. In summary, we cannot conclude that antibodies (not only neutralizing) are associated with medical events in our cohort with this time-point study. Funding Not relevant. Availability of data and materials The datasets generated and/or analysed during the current study are not publicly available due to the individual individuals data that are involved but are available from the related author on sensible request. Abbreviations ADAAnti-drug antibodiesERTEnzyme alternative therapy Authors contributions WM, OL and OB designed the study, performed the experiments, interpreted the data, drafted the manuscript and authorized this final version. Notes Ethics authorization and consent to participate Legal authorizations were from the Comit consultatif sur le traitement de linformation en matire de recherche dans le domaine de la sant (n14.324bis) and the Comit de Safety des personnes Paris VI, according to the relevant People from france legislation. All individuals authorized written consent after specific oral and written info, for this study and its publication. Consent for publication All individuals authorized written consent after specific oral and written info, for this study and its publication. Competing interests Inserm U974 study team received monetary support from Shire, AFM-Tlthon, SNFMI (Socit Nationale Fran?aise de Mdecine Interne) and VML (Vaincre les Maladies Lysosomales) for this study. Wladimir Mauhin: Travel charges and accommodations: Shire, Orphan Europe, Amicus, Sanofi-Genzyme, AZ 10417808 honorarium: Shire. Olivier Lidove: Travel charges, accommodations and honorarium: Shire, Sanofi-Genzyme; honorarium: Amicus. Olivier Benveniste: Travel charges Shire, LFB, CSL Behring; honorarium: Novartis, Neovacs, LFB. Publishers Note Springer Nature remains neutral.