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Structural similarity to tear-lipocalin is thought to limit immunogenicity risk; however, a range of treatment-emergent hypersensitivity-like adverse events were observed in a clinical study. This study aimed to (i) explore the activation of drug-exposed human T-cells with AZD1402- and tear lipocalin-derived peptides, (ii) characterise any T-cell epitopes contained within AZD1402 and (iii) define the nature of any response. Peripheral blood mononuclear cells (PBMC) from AZD1402-exposed study participants, alongside AZD1402-na\u00efve donors, were cultured with AZD1402 and AZD1402-derived overlapping 18mer peptides. Proliferation and cytokine secretion were measured. T-cell clones were generated to characterise the diversity of T-cell epitopes and reactivity against equivalent tear-lipocalin peptides. AZD1402 contained multiple epitopes located in engineered \u201chotspot\u201d regions of the molecule that activated PBMC and MHC class II-restricted CD4\u2009+\u2009T-cell clones from both study participants and AZD1402-na\u00efve donors. T-cell stimulatory peptides contained amino acid substitutions generated through mutagenesis to create AZD1402 target binding properties; similar T-cell epitopes were not found in tear-lipocalin. Detection of T-cell clones responsive towards AZD1402 and AZD1402-derived peptides provides evidence that immunogenic epitopes are formed naturally through processing of the AZD1402. These data describe a recall immunogenicity risk associated with AZD1402 and provide a framework by which to explore the immunogenic potential of modified sequences within anticalin or other large molecule therapeutics.<\/jats:p>","DOI":"10.1007\/s00204-026-04403-1","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T19:25:27Z","timestamp":1777404327000},"page":"3535-3552","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The immunogenic potential of AZD1402 (Elarekibep) T-cell epitopes in healthy volunteers and drug-exposed clinical trial participants"],"prefix":"10.1007","volume":"100","author":[{"given":"Liam","family":"Farrell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie M","family":"Bates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monday","family":"Ogese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian","family":"Piper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katy","family":"Saide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorrit","family":"Hornberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Close","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Wallace","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine J","family":"Betts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean J","family":"Naisbitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"4403_CR1","doi-asserted-by":"publisher","first-page":"100054","DOI":"10.1016\/j.yjsbx.2021.100054","volume":"6","author":"S Achatz","year":"2022","unstructured":"Achatz S, Jarasch A, Skerra A (2022) Structural plasticity in the loop region of engineered lipocalins with novel ligand specificities, so-called Anticalins. 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