Title: Anti-PEG IgE in anaphylaxis associated with polyethylene glycol

Abstract

Polyethylene glycol (PEG) with its unique properties, including solubility in water and non-polar solvents, has been used in many medical and pharmaceutical products including LNP/mRNA COVID vaccines as an active ingredient or excipient. Despite the success of these products, acute drug allergic reactions associated with PEG have been observed in both clinical trials and practice, with many cases occurring without a known prior PEG exposure. Many cases of PEG associated anaphylaxis may not be recognized, especially for products where PEG is not identified as an active ingredient. Although skin testing suggested a potential IgE-mediated type 1 hypersensitivity reaction in some cases, a reliable lab assay to sensitively detect specific anti-PEG IgE was not available to evaluate these events. Studies with ELISA-based anti-PEG assays have reported high background and lack of specificity and thus, could only detect higher levels of IgG and IgM. To fill this important gap in assessing the increasing risks associated with the use of PEG and PEGylated drugs, we developed a dual cytometric beads assay (DCBA, with built-in specificity control) for the detection of anti-PEG antibodies, with a 100-fold greater sensitivity than conventional assays. This increased assay sensitivity allows for reliable detection of anti-PEG IgE. This assay was used to test samples from patients who had developed clinical anaphylaxis upon PEG exposure (cases) and those who did not (controls). The DCBA method and results enabled us to first confirm the long-considered hypothesis that PEG-associated acute allergy can be due to IgE-mediated type 1 hypersensitivity. We also demonstrated pre-existing antibodies to PEG in normal sera that can explain allergic responses on apparently initial exposures.

Biography

Zhaohua (Joe) Zhou, Ph.D., is a Research/Reviewer Scientist at the Office of Biotechnology Products, CDER, US Food & Drug Administration. Dr. Zhou’s research interest is in the development of lab models to pinpoint and predict drug-induced acute allergic reactions. These methods are based upon and covering current understanding to the mechanisms of a clinical anaphylaxis, including: 1) Drug-specific IgE screening and in vitro Type 1 sensitization model (drug-binding antibodies and mast cell degranulation); 2) Drug-specific IgG/IgM screening followed by complement- activation through classical and non-classical pathway-generated anaphylatoxins assay (C3a, C4a and C5a); 3) mast cell directly degranulation; 4) cytokine storm assay (activated T cells and macrophages using PBMC or whole blood culture); and 5) contact system (kinin/kallikrein) activation assay. These models, when using comprehensively, can quickly rule in and rule out drug quality related causes as well as predict patient sensitivity to particular therapeutics.