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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Lennart Lenk - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Irène Baccelli - , OSE Immunotherapeutics SA (Autor:in)
  • Anna Laqua - , Universitätsklinikum Schleswig-Holstein Campus Kiel (Autor:in)
  • Julia Heymann - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Claas Reimer - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Anna Dietterle - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Dorothee Winterberg - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Caroline Mary - , OSE Immunotherapeutics SA (Autor:in)
  • Frédérique Corallo - , OSE Immunotherapeutics SA (Autor:in)
  • Julien Taurelle - , OSE Immunotherapeutics SA (Autor:in)
  • Emma Narbeburu - , OSE Immunotherapeutics SA (Autor:in)
  • Stéphanie Neyton - , OSE Immunotherapeutics SA (Autor:in)
  • Mylène Déramé - , OSE Immunotherapeutics SA (Autor:in)
  • Sabrina Pengam - , OSE Immunotherapeutics SA (Autor:in)
  • Fotini Vogiatzi - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Beat Bornhauser - , Universität Zürich (Autor:in)
  • Jean Pierre Bourquin - , Universität Zürich (Autor:in)
  • Simon Raffel - , Universität Heidelberg (Autor:in)
  • Vladyslava Dovhan - , Otto-von-Guericke-Universität Magdeburg (Autor:in)
  • Thomas Schüler - , Otto-von-Guericke-Universität Magdeburg (Autor:in)
  • Gabriele Escherich - , Universität Hamburg (Autor:in)
  • Monique L. den Boer - , Princess Máxima Center for Pediatric Oncology (Autor:in)
  • Judith M. Boer - , Princess Máxima Center for Pediatric Oncology (Autor:in)
  • Wiebke Wessels - , Universitätsklinikum Schleswig-Holstein Campus Kiel (Autor:in)
  • Matthias Peipp - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Julia Alten - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Željko Antić - , Medizinische Hochschule Hannover (MHH) (Autor:in)
  • Anke K. Bergmann - , Medizinische Hochschule Hannover (MHH) (Autor:in)
  • Martin Schrappe - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Gunnar Cario - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Monika Brüggemann - , Universitätsklinikum Schleswig-Holstein Campus Kiel (Autor:in)
  • Nicolas Poirier - , OSE Immunotherapeutics SA (Autor:in)
  • Denis M. Schewe - , Otto-von-Guericke-Universität Magdeburg (Autor:in)

Abstract

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.

Details

OriginalspracheEnglisch
Seiten (von - bis)2735-2748
Seitenumfang14
FachzeitschriftBlood
Jahrgang143
Ausgabenummer26
PublikationsstatusVeröffentlicht - 27 Juni 2024
Peer-Review-StatusJa
Extern publiziertJa

Externe IDs

PubMed 38518105

Schlagworte