CD25 targeting with the afucosylated human IgG1 antibody RG6292 eliminates regulatory T cells and CD25+ blasts in acute myeloid leukemia

Frontiers in Oncology

Oncology

Bruno C. Medeiros¹  Vera Griesser²  Marco Berrera²  Nadine Kumpesa²  Jan Eckmann³  Koorosh Korfi⁴  Vaios Karanikas⁴  Laurène Pousse⁴  Idil Karakoc Hutter⁴  Maria Amann⁴  Christian Klein⁴ 

[1] Genentech, Inc. Hematology Department, South San Francisco, CA, United States;Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel (RICB), Basel, Switzerland;Roche Pharma Research and Early Development (pRED), Roche Innovation Center Münich (RICM), Penzberg, Germany;Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich (RICZ), Schlieren, Switzerland;

关键词: acute myeloid leukemia (AML);    leukemic stem cells (LSC);    regulatory T cell (Treg);    CD25;    antibody dependent cellular cytotoxicity (ADCC);   

DOI  :  10.3389/fonc.2023.1150149

 received in 2023-01-23, accepted in 2023-04-11,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundAcute Myeloid leukemia is a heterogeneous disease that requires novel targeted treatment options tailored to the patients’ specific microenvironment and blast phenotype.MethodsWe characterized bone marrow and/or blood samples of 37 AML patients and healthy donors by high dimensional flow cytometry and RNA sequencing using computational analysis. In addition, we performed ex vivo ADCC assays using allogeneic NK cells isolated from healthy donors and AML patient material to test the cytotoxic potential of CD25 Mab (also referred to as RG6292 and RO7296682) or isotype control antibody on regulatory T cells and CD25+ AML cells.ResultsBone marrow composition, in particular the abundance of regulatory T cells and CD25 expressing AML cells, correlated strongly with that of the blood in patients with time-matched samples. In addition, we observed a strong enrichment in the prevalence of CD25 expressing AML cells in patients bearing a FLT3-ITD mutation or treated with a hypomethylating agent in combination with venetoclax. We adopted a patient-centric approach to study AML clusters with CD25 expression and found it most highly expressed on immature phenotypes. Ex vivo treatment of primary AML patient samples with CD25 Mab, a human CD25 specific glycoengineered IgG1 antibody led to the specific killing of two different cell types, CD25+ AML cells and regulatory T cells, by allogeneic Natural Killer cells.ConclusionThe in-depth characterization of patient samples by proteomic and genomic analyses supported the identification of a patient population that may benefit most by harnessing CD25 Mab’s dual mode of action. In this pre-selected patient population, CD25 Mab could lead to the specific depletion of regulatory T cells, in addition to leukemic stem cells and progenitor-like AML cells that are responsible for disease progression or relapse.

【 授权许可】

Unknown   
Copyright © 2023 Pousse, Korfi, Medeiros, Berrera, Kumpesa, Eckmann, Hutter, Griesser, Karanikas, Klein and Amann