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

All 3 patients were female; 602-004 was treated at a site in Poland and the other 2 patients were treated in Germany. For additional information regarding these patients, see this article’s REG1-CLIN211a section in the Online Repository at www.jacionline. org. Note: As substantially more information is available on these 3 subjects than for other trial participants, inferences regarding the possible role of sex, geography, or allergic history are cautioned against. D, Dermal; GI, gastrointestinal; H, hypotension; H1, H1 blocker; H2, H2 blocker; I, intubation; Inh, inhalers; IVV, intravenous vasopressors; IVF, intravenous fluid resuscitation; P, pulmonary; S, steroids. To the Editor: Nucleic acid aptamers are a novel class of drugs that can be selected to inhibit targets of interest, including protein-protein interactions. Pegnivacogin is a 29-fluoropyrimidine–modified RNA aptamer that inhibits coagulation factor IXa, coupled to an approximately 40-kDa branched molecule of methoxypolyethylene glycol (mPEG), to increase its concentration and half-life in plasma. During the RADAR phase 2b clinical trial in patients with acute coronary syndrome, allergic reactions occurred within minutes of a first dose of pegnivacogin in 3 of 640 patients (Table I). Two met criteria for anaphylaxis, and 1 was an isolated dermal reaction; each event was deemed serious, and 1 life-threatening, and together they led to early termination of the trial. In a broad investigation into a cause for these 3 events (detailed in Methods in this article’s Online Repository at www. jacionline.org), a clinical database review found no other serious allergic reactions (SARs) to pegnivacogin; a quality analysis found no aggregation, degradation, or other deviations of the study product from specifications; and a primate pharmacology study found no evidence that pegnivacogin caused an inflammatory response, histamine release, or complement activation. However, blinded testing of more than half of all RADAR patients identified an association between high levels of antibody to polyethylene glycol (PEG) and the first-exposure allergic reactions. In addition to the immediate relevance, our findings are the first to document the potential clinical significance of pre-existing antibody to PEG, a component of numerous consumer and medicinal products. Initially, coded samples from31RADARpatientswere tested for anti-PEG antibody (see Analytical methods and Fig E1 in this article’s Online Repository at www.jacionline.org) in 2 ELISAs to detect IgGbinding to pegloticase, a PEGylated urate oxidase (a protein not expressed in humans), and to the 40-kDamPEGcomponent of pegnivacogin. Unblinding of the data revealed that samples giving the highest signals in both ELISAs were from the 3 patients with SARs (predose from patients 418-008 and 406-003; 88-day postinfusion from patient 602-004 from whom no predose sample was available). Direct (Fig 1, A) and competition ELISAs (Fig 1, B) showed that antibody from each patient could bind to linear and branched PEGs of 5 to 40 kDa, presented as free mPEG or PEG-diol (lacking methoxy termini), or when conjugated via different linkages to 2 proteins and pegnivacogin; importantly,