The IL-7R antagonist lusvertikimab reduces leukemic burden in xenograft ALL via antibody-dependent cellular phagocytosis

白细胞介素-7受体 微小残留病 免疫疗法 体内 白血病 抗体 免疫学 癌症研究 医学 生物 肿瘤科 T细胞 免疫系统 白细胞介素2受体 生物技术
作者
Lennart Lenk,Irène Baccelli,Anna Laqua,Julia Heymann,Claas Reimer,Anna Dietterle,Dorothee Winterberg,Caroline Mary,Frédérique Corallo,Julien Taurelle,Emma Narbeburu,Stéphanie Neyton,Mylène Deramé,Sabrina Pengam,Fotini Vogiatzi,Beat Bornhäuser,Jean‐Pierre Bourquin,Simon Raffel,Vladyslava Dovhan,Thomas Schüler,Gabriele Escherich,Monique L. den Boer,Judith M. Boer,Wiebke Weßels,Matthias Peipp,Julia Alten,Željko Antić,Anke K. Bergmann,Martin Schrappe,Gunnar Cario,Monika Brüggemann,Nicolas Poirier,Denis M. Schewe
出处
期刊:Blood [Elsevier BV]
卷期号:143 (26): 2735-2748 被引量:3
标识
DOI:10.1182/blood.2023021088
摘要

Acute lymphoblastic leukemia (ALL) arises from the uncontrolled proliferation of precursor B or T cells (BCP- or T-ALL). Current treatment protocols obtain high cure rates in children but are based on toxic polychemotherapy. Novel therapies are urgently needed, especially in relapsed/refractory (r/r) disease, high-risk leukemias and T-ALL, where immunotherapy approaches remain scarce. While the Interleukin-7 receptor (IL-7R) plays a pivotal role in ALL development, no IL-7R-targeting immunotherapy has yet reached clinical application in ALL. The IL-7Rα chain (CD127)-targeting IgG4 antibody Lusvertikimab (formerly OSE-127) is a full antagonist of the IL-7R pathway showing a good safety profile in healthy volunteers. Here, we show that ~85% of ALL cases express surface CD127. We demonstrate significant in vivo efficacy of Lusvertikimab immunotherapy in a heterogeneous cohort of BCP- and T-ALL patient-derived xenografts (PDX) in minimal residual disease (MRD) and overt leukemia models, including r/r and high-risk leukemias. Importantly, Lusvertikimab was particularly effective when combined with polychemotherapy in a phase 2-like PDX study with CD127high samples leading to MRD-negativity in >50% of mice treated with combination therapy. Mechanistically, Lusvertikimab targeted ALL cells via a dual mode of action comprising direct IL-7R antagonistic activity and induction of macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Lusvertikimab-mediated in vitro ADCP levels significantly correlated with CD127 expression levels and the reduction of leukemia burden upon treatment of PDX animals in vivo. Altogether, through its dual mode of action and good safety profile, Lusvertikimab may represent a novel immunotherapy option for any CD127-positive ALL, particularly in combination with standard-of-care polychemotherapy.
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