Non-Allergic Urticarial Skin Reactions Associated With MOv18 IgE, a First-In-Class IgE Antibody Recognising Folate Receptor Alpha.

Debra H Josephs, Katie E Lacy, Clive E H Grattan, Kristina V Semkova, Zena Willsmore, Nabeel Naban, Thomas J Tull, Rebecca Adams, Alexandra J McCraw, Katie Stoker, Roman Laddach, Ashley Di Meo, Amy Pope, Sheila M McSweeney, Sophia N Karagiannis, Sophia Tsoka, Heather J Bax, Sarah Pinder, Cheryl Gillett, Jitesh Chauhan, Chara Stavraka, Stephen J Till, Christopher J Corrigan, Rebecca Kristeleit, James Spicer, John McGrath, Silvia Crescioli, Eleftherios P Diamandis, Ioannis Prassas

Journal: Allergy 2025;80(8):2225-2239

PMID: 40045925

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Abstract

BACKGROUND

IgE antibodies directed against cancer antigens have demonstrated potent anti-tumour effects in pre-clinical studies. MOv18 IgE, the first-in-class IgE recognising the cancer antigen folate receptor alpha (FRα), showed preliminary signs of efficacy in a Phase I trial. Treatment was well tolerated, with the most common adverse event being transient urticarial skin reactions. We investigated immunological and allergic response parameters associated with urticarial skin reactions in MOv18 IgE-treated patients.

METHODS

Expression of target antigen, FRα, and MOv18 IgE reactivity with FRα or any component in human skin was studied by immunohistochemistry, immunofluorescence and immuno-mass spectrometry. We conducted transcriptomic analyses in paired lesional and non-lesional skin biopsies from a patient who developed an urticarial skin reaction. Systemic immunological markers including cytokines, β-tryptase and basophil activation states were interrogated throughout the trial and contemporaneously with the skin reaction.

RESULTS

Of the 24 IgE-treated patients, 62.5% developed transient urticarial skin reactions, with onset during the first infusion, diminishing with consecutive infusions and no β-tryptase elevation nor clinical features indicating allergic aetiology. No FRα expression or MOv18 IgE binding to human skin was identified. Lesional skin biopsies from a patient given the highest antibody dose revealed scattered eosinophils, neutrophils and mast cell degranulation, but no increased immune cell infiltration. Transcriptomic analysis indicated pro-inflammatory, but not allergic, pathway activation. No systemic allergic or hypersensitivity mediators or basophil activation were detected.

CONCLUSIONS

Urticarial skin reactions following MOv18 IgE treatment were unlikely to result from allergic mechanisms or skin antigen recognition. The clinical presentation is consistent with infusion-related reactions commonly observed with monoclonal antibody treatments.

TRIAL REGISTRATION

EudraCT number: 2014-000070-19; ClinicalTrials.gov identifier: NCT02546921, registered 11/Sept/2015.

Address: St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London, UK.; School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, UK.; St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London, UK.; King's Health Partners Cancer Biobank, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, UK.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Division of Clinical Biochemistry, Laboratory Medicine Program, Toronto General Hospital, Toronto, Canada.; Mount Sinai Hospital, Toronto, Canada.; Laboratory Medicine Program, University Health Network, Toronto, Canada.; St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London, UK.; Department of Informatics, Faculty of Natural, Mathematical and Engineering Sciences, King's College London, London, UK.; St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London, UK.; St. John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.; Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK.; St. John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.; King's Centre for Lung Health, School of Immunology and Microbial Sciences, King's College London, London, UK.; School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, UK.; Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK.; Department of Informatics, Faculty of Natural, Mathematical and Engineering Sciences, King's College London, London, UK.; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada.; St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London, UK.; Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK.; St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London, UK.; Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, UK.

DOI: 10.1111/all.16514

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MeSH Terms: Adult, Aged, Female, Humans, Male, Middle Aged, Folate Receptor 1, Immunoglobulin E, Skin, Urticaria