Pre-existing anti–polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer Nancy J. Ganson,

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Presentation transcript:

Pre-existing anti–polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer Nancy J. Ganson, PhD, Thomas J. Povsic, MD, Bruce A. Sullenger, PhD, John H. Alexander, MD, Steven L. Zelenkofske, DO, Jeffrey M. Sailstad, PhD, Christopher P. Rusconi, PhD, Michael S. Hershfield, MD Journal of Allergy and Clinical Immunology Volume 137, Issue 5, Pages 1610-1613.e7 (May 2016) DOI: 10.1016/j.jaci.2015.10.034 Copyright © 2015 The Authors Terms and Conditions

Fig 1 Characterization of anti-PEG antibodies in RADAR patient samples. A, ELISAs to assess binding to the antigens indicated in the figure (for description and source of these materials, see this article's Online Repository at www.jacionline.org). B, Competition ELISA. Duplicate aliquots of samples, one spiked with 20 μg of the indicated competing antigen, were tested in the antipegloticase ELISA. IDs 406-003, 602-004, and 418-008 are the 3 patients who experienced SARs to pegnivacogin; ID 304-017 had no reaction to pegnivacogin, but was positive for anti-PEG antibody. C, Automated competition ELISA. The 90 samples tested had an A405 value of more than 0.2 in the antipegloticase ELISA (see text for details). Blue and red bars are, respectively, the A405 obtained in the absence and presence of competing antigen (10 kDa PEG-diol). The darker blue and red bars with sample IDs indicate the 3 patients who experienced SARs to pegnivacogin. Journal of Allergy and Clinical Immunology 2016 137, 1610-1613.e7DOI: (10.1016/j.jaci.2015.10.034) Copyright © 2015 The Authors Terms and Conditions

Fig E1 Ability of anti-PEG antibody-positive QC to recognize molecular species relevant to the RADAR trial. A, ELISAs. Plates were coated with 3 μg per well of the indicated antigens, washed, and then incubated with duplicate aliquots of human plasma samples previously characterized as negative (designated control plasma and –QC) or positive for anti-PEG antibody (designated 213-10, + QC, and + standard). B, Competition ELISAs. Duplicate aliquots of the positive QC were incubated with 0 to 20 μg of the competing antigens indicated in the figure legend, then carried through the antipegloticase ELISA. Antigens tested are defined in the Methods section; uricase is the un-PEGylated recombinant porcine urate oxidase used in pegloticase. Journal of Allergy and Clinical Immunology 2016 137, 1610-1613.e7DOI: (10.1016/j.jaci.2015.10.034) Copyright © 2015 The Authors Terms and Conditions

Fig E2 Determination of anti-PEG antibody isotype and IgG subclass. The samples tested are from the 3 patients who experienced first-exposure serious allergic-like reactions to pegnivacogin (IDs shown in figure legend). Journal of Allergy and Clinical Immunology 2016 137, 1610-1613.e7DOI: (10.1016/j.jaci.2015.10.034) Copyright © 2015 The Authors Terms and Conditions

Fig E3 Physiologic response of cynomolgus monkeys to pegnivacogin treatment. A, Body temperature. B, Heart rate. C, Mean arterial pressure. Spikes in readouts bracketing the 5-minute and 6-hour time period are sample collection times. N = 6 for all measures. Journal of Allergy and Clinical Immunology 2016 137, 1610-1613.e7DOI: (10.1016/j.jaci.2015.10.034) Copyright © 2015 The Authors Terms and Conditions

Fig E4 Cytokine and histamine response of cynomolgus monkeys to pegnivacogin treatment. A, TNF-α. B, IFN-γ. C, MCP-1. D, MIP-1α. E, IL-6. F, Histamine. Data presented as mean ± SD. N = 6 for all measures. Journal of Allergy and Clinical Immunology 2016 137, 1610-1613.e7DOI: (10.1016/j.jaci.2015.10.034) Copyright © 2015 The Authors Terms and Conditions

Fig E5 Complement response of cynomolgus monkeys to pegnivacogin treatment. A, C3a. B, C4a. C, Bb fragment. D, CH50 activity. Data presented as mean ± SD. N = 6 for all measures. Journal of Allergy and Clinical Immunology 2016 137, 1610-1613.e7DOI: (10.1016/j.jaci.2015.10.034) Copyright © 2015 The Authors Terms and Conditions