Characterization of drug-neutralizing antibodies in patients with Fabry disease during infusion Malte Lenders, PhD, Boris Schmitz, PhD, Stefan-Martin.

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Presentation transcript:

Characterization of drug-neutralizing antibodies in patients with Fabry disease during infusion Malte Lenders, PhD, Boris Schmitz, PhD, Stefan-Martin Brand, MD, PhD, Dirk Foell, MD, Eva Brand, MD, PhD Journal of Allergy and Clinical Immunology Volume 141, Issue 6, Pages 2289-2292.e7 (June 2018) DOI: 10.1016/j.jaci.2017.12.1001 Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Acute effect of ERT on antibody titers during infusion. Patients' inhibition profiles per microgram purified total IgG before (pre) and directly after (post) infusion. A, Patient 1 (53d infusion with agalsidase-α [14 mg]; body weight [BW]: 72 kg, infusion length: 60 minutes). B, Patient 4 (98th infusion with agalsidase-α [14 mg]; BW: 82 kg, infusion length: 60 minutes). C, Patient 10 (8th infusion with agalsidase-β [55 mg]; BW: 58 kg, infusion length: 240 minutes). D, Patient 16 (12th infusion with agalsidase-β [70 mg]; BW: 60.0 kg, infusion length: 240 minutes). E, Patient 17 (7th infusion with agalsidase-β [35 mg]; BW: 91 kg, infusion length: 240 minutes). F, Patient 19 (308th infusion with agalsidase-α [17.5 mg]; BW: 87.5 kg, infusion length: 60 minutes). G, Patient 23 (354th infusion with agalsidase-β [70 mg]; BW: 70 kg, infusion length: 240 minutes). H, Patient 24 (267th infusion with agalsidase-β [105 mg]; BW: 102 kg, infusion length: 150 minutes). I, Increasing amounts of infused ERT are associated with decreasing ERT inhibition per microgram total IgG after infusion. Green: Patient changed to inhibition-negative after infusion. Red: Patient remained inhibition-positive after infusion. Journal of Allergy and Clinical Immunology 2018 141, 2289-2292.e7DOI: (10.1016/j.jaci.2017.12.1001) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Impact of infused ERT amounts on antibody titers during infusion. A, Fifteenth infusion with agalsidase-β (35 mg). B, Sixteenth infusion with agalsidase-β (70 mg). p, Premedication (para-acetylaminophenol, 500 mg; ranitidine, 25 mg; clemastine, 1 mg; prednisolone, 25 mg). Circles indicate infused ERT amounts. Squares indicate ERT inhibition. Values are given as mean ± SEM. Journal of Allergy and Clinical Immunology 2018 141, 2289-2292.e7DOI: (10.1016/j.jaci.2017.12.1001) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Ex vivo ERT inhibition is IgG antibody-dependent. A, Serum-mediated inhibition measurements in ERT-naive patients (n = 12) result in high background signals. The dotted line represents the cutoff value of 50% ERT inhibition. B, Increasing amounts of purified total IgGs from ERT-naive patients (n = 12) do not result in significant ERT inhibition. Dotted lines represent the 95% CI. C, Representative measurements of an inhibition-positive and an inhibition-negative patient before and after ERT start. Samples from both patients before ERT start (P1/P2 naive, blue and black lines) show no significant ERT inhibition. Samples after ERT initiation demonstrates decrease rescued GLA activity with increasing amounts of total IgGs in the inhibition-positive (P1, red line) but not in the inhibition-negative patient (P2, green line). D, Patient classification using the AIA. ERT inhibition-negative patients do not show a significant reduction of GLA activity (n = 10, green). ERT inhibition-positive patients demonstrate a significant and IgG dose-dependent GLA activity inhibition (n = 14, red). E, ERT inhibition per microgram of total IgG. ERT inhibition-positive patients demonstrate different inhibitory capacities of total IgGs. F, Longitudinal measurements reveal first ERT inhibition 3 months after ERT initiation. Red: inhibition-positive patients; green: inhibition-negative patients. Patient 10 was switched from agalsidase-α to -β after the third infusion. ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2018 141, 2289-2292.e7DOI: (10.1016/j.jaci.2017.12.1001) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Isolation of human total IgG antibodies from patients with FD. A, Representative Coomassie blue staining from pure serum (s) samples and purified IgG (MG) fractions (each 5 μg) show typical pattern of heavy (H) and light (L) Fc chains in purified IgG samples. B, Purified IgG fractions from ERT-naive patients (n = 8, pooled; patients 1 to 8) demonstrate presence of major IgG isotypes (1 to 4), as well as a moderate IgA presence, but no measurable signals for IgEs. Journal of Allergy and Clinical Immunology 2018 141, 2289-2292.e7DOI: (10.1016/j.jaci.2017.12.1001) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Anti-GLA IgG isotype identification in patients with FD. A, Change of IgG isotype titers in patients after ERT initiation in inhibition-negative (n = 4, white bars) and -positive (n = 4, black bars) patients. B, GEAR assay demonstrates the inhibitory property of anti-GLA IgG4 antibodies. Immobilized anti-human IgG4 antibody was used to capture IgG4 from patients' total IgG. Recombinant GLA is inhibited only in anti-GLA IgG4-positive patients. Subsequent GLA activity measurements demonstrate rescued GLA activity only in IgG4-negative patients. White bars: ERT-naive, black bars: under ERT. *P < .05, **P < .01, ***P < .001. Journal of Allergy and Clinical Immunology 2018 141, 2289-2292.e7DOI: (10.1016/j.jaci.2017.12.1001) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 IgG4 anti-GLA antibodies are responsible for ERT binding. One hundred nanograms of either agalsidase-α or -β were blotted onto a polyvinylidene difluoride membrane. Purified total IgGs were used as primary antibodies (end concentration in PBS/BSA 2%: 5.5 μg/mL). Discrimination between IgG1 and IgG4 isotypes was performed by using either mouse α-human IgG isotype 1 (ab99774) or mouse α-human IgG isotype 4 (ab99823) as secondary antibodies in a dilution according to manufacturer's (Abcam) instructions. Anti-human IgG-HRP (sc-2907, Santa Cruz Biotechnology; final concentration: 0.04 μg/mL) served as positive control. Values in seconds are exposure times. Journal of Allergy and Clinical Immunology 2018 141, 2289-2292.e7DOI: (10.1016/j.jaci.2017.12.1001) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions