PMID- 38518105
OWN - NLM
STAT- Publisher
LR  - 20240322
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
DP  - 2024 Mar 22
TI  - The IL-7R antagonist Lusvertikimab reduces leukemic burden in xenograft-ALL via 
      antibody-dependent cellular phagocytosis.
LID - blood.2023021088 [pii]
LID - 10.1182/blood.2023021088 [doi]
AB  - 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-7Ralpha 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.
CI  - Copyright (c) 2024 American Society of Hematology.
FAU - Lenk, Lennart
AU  - Lenk L
AUID- ORCID: 0000-0002-3916-7604
AD  - Christian-Albrechts University Kiel and University Medical Center 
      Schleswig-Holstein, Kiel, Germany, Kiel, Germany.
FAU - Baccelli, Irene
AU  - Baccelli I
AD  - OSE Immunotherapeutics, France.
FAU - Laqua, Anna
AU  - Laqua A
AD  - Christian-Albrechts University Kiel and University Medical Center 
      Schleswig-Holstein, Kiel, Germany, Germany.
FAU - Heymann, Julia
AU  - Heymann J
AD  - Christian-Albrechts University Kiel and University Medical Center 
      Schleswig-Holstein, Kiel, Germany, Germany.
FAU - Reimer, Claas
AU  - Reimer C
AD  - Christian-Albrechts University Kiel and University Medical Center 
      Schleswig-Holstein, Kiel, Germany, Kiel, Germany.
FAU - Dietterle, Anna
AU  - Dietterle A
AD  - Christian-Albrechts University Kiel and University Medical Center 
      Schleswig-Holstein, Kiel, Germany, Kiel, Germany.
FAU - Winterberg, Dorothee
AU  - Winterberg D
AD  - Universitatsklinikum Schleswig-Holstein, Kiel, Germany.
FAU - Mary, Caroline
AU  - Mary C
AD  - OSE Immunotherapeutics, Nantes, France.
FAU - Corallo, Frederique
AU  - Corallo F
AD  - OSE Immunotherapeutics, Nantes, France.
FAU - Taurelle, Julien
AU  - Taurelle J
AD  - OSE Immunotherapeutics, Nantes, France.
FAU - Narbeburu, Emma
AU  - Narbeburu E
AD  - OSE Immunotherapeutics, Nantes, France.
FAU - Neyton, Stephanie Lara
AU  - Neyton SL
AD  - OSE Immunotherapeutics, LYON, France.
FAU - Derame, Mylene
AU  - Derame M
AD  - OSE Immunotherapeutics, Nantes, France.
FAU - Pengam, Sabrina
AU  - Pengam S
AD  - OSE Immunotherapeutics, Nantes, France.
FAU - Vogiatzi, Fotini
AU  - Vogiatzi F
AD  - Christian-Albrechts University Kiel and University Medical Center 
      Schleswig-Holstein, Kiel, Germany, Kiel, Germany.
FAU - Bornhauser, Beat
AU  - Bornhauser B
AD  - University Childrens Hospital, Zurich, Switzerland.
FAU - Bourquin, Jean-Pierre
AU  - Bourquin JP
AD  - Universitaets-Kinderklinik Zurich, Zurich, Switzerland.
FAU - Raffel, Simon
AU  - Raffel S
AD  - Heidelberg University Hospital, Heidelberg, Germany.
FAU - Dovhan, Vladyslava
AU  - Dovhan V
AD  - Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
FAU - Schuler, Thomas
AU  - Schuler T
AUID- ORCID: 0000-0002-0567-4827
AD  - Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
FAU - Escherich, Gabriele
AU  - Escherich G
AD  - University hospital Hamburg Eppendorf, Hamburg, Germany.
FAU - den Boer, Monique L
AU  - den Boer ML
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands.
FAU - Boer, Judith M
AU  - Boer JM
AUID- ORCID: 0000-0003-4848-7789
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands.
FAU - Wessels, Wiebke
AU  - Wessels W
AD  - Christian-Albrechts University Kiel and University Medical Center 
      Schleswig-Holstein, Kiel, Germany, Germany.
FAU - Peipp, Matthias
AU  - Peipp M
AD  - Christian-Albrechts University Kiel and University Medical Center 
      Schleswig-Holstein, Kiel, Germany, Germany.
FAU - Alten, Julia
AU  - Alten J
AD  - Christian-Albrechts University Kiel and University Medical Center 
      Schleswig-Holstein, Kiel, Germany, Germany.
FAU - Antic, Zeljko
AU  - Antic Z
AD  - Institute of Human Genetics, Medical School Hannover, Hannover, Germany.
FAU - Bergmann, Anke Katharina
AU  - Bergmann AK
AD  - Hannover Medical School, Hannover, Germany.
FAU - Schrappe, Martin
AU  - Schrappe M
AUID- ORCID: 0000-0003-0034-5845
AD  - Christian-Albrechts University Kiel and University Medical Center 
      Schleswig-Holstein, Kiel, Germany, Germany.
FAU - Cario, Gunnar
AU  - Cario G
AD  - Christian-Albrechts University Kiel and University Medical Center 
      Schleswig-Holstein, Kiel, Germany, Germany.
FAU - Bruggemann, Monika
AU  - Bruggemann M
AD  - University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
FAU - Poirier, Nicolas
AU  - Poirier N
AD  - OSE Immunotherapeutics, Nantes, France.
FAU - Schewe, Denis M
AU  - Schewe DM
AD  - Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
LA  - eng
PT  - Journal Article
DEP - 20240322
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
SB  - IM
EDAT- 2024/03/22 18:44
MHDA- 2024/03/22 18:44
CRDT- 2024/03/22 15:13
PHST- 2024/03/09 00:00 [accepted]
PHST- 2023/05/08 00:00 [received]
PHST- 2024/03/08 00:00 [revised]
PHST- 2024/03/22 18:44 [medline]
PHST- 2024/03/22 18:44 [pubmed]
PHST- 2024/03/22 15:13 [entrez]
AID - 515436 [pii]
AID - 10.1182/blood.2023021088 [doi]
PST - aheadofprint
SO  - Blood. 2024 Mar 22:blood.2023021088. doi: 10.1182/blood.2023021088.