Rubic-Schneider, Tina, Kuwana, Masataka, Christen, Brigitte, Aßenmacher, Manuela, Hainzl, O., Zimmermann, F., Fischer, Robert, Koppenburg, Vera, Chibout, Salah-Dine, Wright, Timothy M., Seidl, Andreas and Kammueller, Michael (2017) T-cell assays confirm immunogenicity of tungsten-induced erythropoietin aggregates associated with pure red cell aplasia. Blood Advances, 1 (6). pp. 367-379. ISSN 2473-9537

Abstract

Immunogenicity of biotherapeutics and the elicitation of anti-drug antibodies (ADA) are a key concern for their efficacy, pharmacokinetics and safety. Prediction of clinical immunogenicity on the basis of quality attributes of biopharmaceuticals or by utilizing preclinical in vitro and in vivo screening remains challenging. Even fully human biotherapeutics have the potential for immunogenicity, and one important factor that might enhance potential immunogenicity is protein aggregation. A particularly severe consequence of immunogenicity of a biotherapeutic is the rare development of antibody-mediated pure red cell aplasia (PRCA) in anemic patients treated with aggregated forms of recombinant human erythropoietin (rhEPO). Here, we investigated in vitro T cell responses to (i) heat-induced rhEPO aggregates, (ii) tungsten-induced rhEPO aggregates in clinical lots associated with rhEPO-neutralizing antibodies and PRCA, and (iii) ex vivo T cell recall responses of patients treated with rhEPO without PRCA, and of a patient who developed PRCA after treatment with a clinical batch with elevated levels of tungsten and aggregates. To our knowledge, this is the first time that T cell assays confirm the root cause of increased rhEPO immunogenicity associated with PRCA.

Item Type:	Article
Date Deposited:	18 Feb 2017 00:45
Last Modified:	09 Aug 2018 00:45
URI:	https://oak.novartis.com/id/eprint/29970