LAUSR

Acute lymphoblastic leukemia (ALL) arises from the uncontrolled proliferation of precursor B or T cells (B- or T-ALL). Novel immunotherapies are urgently needed to reduce polychemotherapy-related toxicities and to target relapsed/refractory disease. The Interleukin 7 receptor (IL7R) plays a pivotal role in the development of ALL through mutations leading to constitutive activation of the oncogenic IL7R pathway or through overexpression of the receptor. The IL7Rα chain (CD127)-targeting antibody OSE-127 is a full antagonist of the IL7R pathway with an excellent safety profile (NCT03980080), currently evaluated in phase 2 trials in inflammatory and autoimmune diseases (NCT04882007, NCT04605978). We previously reported in vivo efficacy of OSE-127 in CD127+ ALL patient-derived xenografts (PDXs) and synergy with standard of care polychemotherapy, but we had not evaluated CD127 protein expression in ALL patient cells. Moreover, the mechanism of action underlying OSE-127’s anti-leukemic activity remained to be fully elucidated. Here we show that CD127 is expressed by >84% ALL patients and that OSE-127 efficiently targets CD127 not only via its IL7R antagonist activity but also through macrophage-mediated antibody dependent phagocytosis (ADCP). First, CD127 surface expression was prospectively measured by flow cytometry in 372 diagnostic ALL patient samples. We detected CD127-positivity (defined as ≥10% CD127+ blasts) in 84.4% (314/372) cases, of which 39.5% (147/372) were CD127hi (≥ 50% CD127+ blasts). CD127 expression was higher in T- than in B-ALL. Among B-ALL, highest expression was detected in E2A-PBX1+ and BCR-ABL-like ALLs. Mechanistically, OSE-127 blocked STAT5 phosphorylation in IL7-responsive ALL-PDX cells, leading to decreased cell survival and proliferation. Surprisingly, we detected high in vivo efficacy of OSE-127 therapy in IL7-unresponsive PDXs (e.g., unable to induce phosphorylation of STAT5 upon ex vivo IL7 stimulation or with IL7R mutation-induced constitutive phosphorylation of STAT5). We uncovered that OSE-127 induced macrophage-mediated ADCP of CD127+ ALL cells in vitro. Accordingly, treatment of IL7-unresponsive, but OSE-127-sensitive models with an OSE-127-LALAPG variant (conserving IL7R-antagonistic properties but lacking ADCP activity due to Fc-inactivating mutations) did not impact leukemia development, thereby substantiating that ADCP contributes to the anti-leukemic efficacy of OSE-127. In fact, ADCP levels induced by OSE-127 treatment in vitro correlated with its capacity to reduce ALL blasts in the blood of PDX mice in vivo. Altogether, through its dual mode of action, OSE-127 may represent a powerful novel immunotherapy option for ALL patients, including cases with dysregulated IL7R signaling, particularly in combination with standard of care polychemotherapy. Citation Format: Irene Baccelli, Lennart Lenk, Anna Laqua, Dorothee Winterberg, Anna Dietterle, Frederique Corallo, Julien Taurelle, Emma Narbeburu, Beat Bornhauser, Jean-Pierre Bourquin, Fotini Vogiatzi, Simon Raffel, Martin Schrappe, Gunnar Cario, Monika Brüggemann, Denis M Schewe, Nicolas Poirier. CD127 is expressed by acute lymphoblastic leukemias and is efficiently targeted by the IL7R-antagonist OSE-127 through macrophage-mediated antibody dependent phagocytosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2957.