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

Acute lymphoblastic leukemia (ALL) arises from the uncontrolled proliferation of B-cell precursors (BCP-ALL) or T cells (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/refract...

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Main Authors: Lenk, Lennart (Author) , Baccelli, Irène (Author) , Laqua, Anna (Author) , Heymann, Julia (Author) , Reimer, Claas (Author) , Dietterle, Anna (Author) , Winterberg, Dorothee (Author) , Mary, Caroline (Author) , Corallo, Frédérique (Author) , Taurelle, Julien (Author) , Narbeburu, Emma (Author) , Neyton, Stéphanie (Author) , Déramé, Mylène (Author) , Pengam, Sabrina (Author) , Vogiatzi, Fotini (Author) , Bornhauser, Beat (Author) , Bourquin, Jean-Pierre (Author) , Raffel, Simon (Author) , Dovhan, Vladyslava (Author) , Schüler, Thomas (Author) , Escherich, Gabriele (Author) , Boer, Monique L. den (Author) , Boer, Judith M. (Author) , Wessels, Wiebke (Author) , Peipp, Matthias (Author) , Alten, Julia (Author) , Antić, Željko (Author) , Bergmann, Anke Katharina (Author) , Schrappe, Martin (Author) , Cario, Gunnar (Author) , Brüggemann, Monika (Author) , Poirier, Nicolas (Author) , Schewe, Denis Martin (Author)
Format: Article (Journal)
Language:English
Published: June 27 2024
In: Blood
Year: 2024, Volume: 143, Issue: 26, Pages: 2735-2748
ISSN:1528-0020
DOI:10.1182/blood.2023021088
Online Access:Resolving-System: https://dx.doi.org/10.1182/blood.2023021088
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Author Notes: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 Déramé, Sabrina Pengam, Fotini Vogiatzi, Beat Bornhauser, 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, and Denis M. Schewe

MARC

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520 |a Acute lymphoblastic leukemia (ALL) arises from the uncontrolled proliferation of B-cell precursors (BCP-ALL) or T cells (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 (HR) leukemias and T-ALL, in which immunotherapy approaches remain scarce. Although 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 (LUSV; 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 LUSV 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 HR leukemias. Importantly, LUSV 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, LUSV 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). LUSV-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, LUSV may represent a novel immunotherapy option for any CD127+ ALL, particularly in combination with standard-of-care polychemotherapy. 
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