IL7R Targeting Using OSE-127 Shows Robust Anti-Leukemic Activity in B-Cell Precursor Acute Lymphoblastic Leukemia Xenografts
Authors: Lenk Lennart , Baccelli Irène , Winterberg Dorothee , Corallo Frédérique , Vogiatzi Fotini , Spory Lea , Schrappe Martin , Cario Gunnar , Laqua Anna , Brüggemann Monika , Poirier Nicolas , Schewe Denis Martin 
Published: November 2021

Abstract
Despite the favorable prognosis of B cell precursor acute lymphoblastic leukemia (BCP-ALL), relapse remains a clinical challenge. Antibody-based immunotherapies like Blinatumomab have improved BCP-ALL outcome, yet these can quickly turn ineffective due to CD19 antigen escape. Therefore, novel targeted immunotherapy options are urgently needed.
We previously showed that high IL7R expression associates with adverse outcome in BCP-ALL patients and that IL7R targeting using laboratory-grade blocking antibodies significantly reduced leukemic burden in E2A-PBX1 and BCR-ABL patient derived xenografts (PDX) (Alsadeq et al., Blood, 2017; Abdelrasoul et al., Nat. Commun., 2020). Here we used the humanized monoclonal antibody OSE-127, a full IL7R antagonist which is not internalized by target cells and prevents IL7R heterodimerization and subsequent downstream signaling (Belarif et al., Nat. Commun. 2018, Belarif et al. JCI, 2019). Importantly, OSE-127 has recently been positively evaluated in a phase 1 study conducted in 63 healthy volunteers receiving either a single dose or two doses two weeks apart (EUDRACT 2018-001832-22). OSE-127 demonstrated an excellent safety and tolerability profile showing no signs of lymphopenia, cytokine release syndrome or T-cell compartment alterations. Based on these preclinical and clinical results, we investigated the anti-leukemic efficacy of OSE-127 immunotherapy in PDX models of BCP-ALL.
First, to identify patients that may benefit from IL7R-immunotherapy, we measured IL7R surface expression in diagnostic BCP-ALL patient samples of different cytogenetic subgroups via flow cytometry.
We detected IL7R-positivity (defined as ≥10% IL7R + BCP-ALL cells) in 52% (49/94) of patient samples including BCR-ABL + (25%; 5/20), TEL-AML1 + (41%; 7/17) and B-other (40%, 8/20) samples. Particularly high numbers of IL7R + patients were found in the E2A-PBX1 + and MLL-rearranged (MLLr) BCP-ALL subgroups (79%; 19/24 and 85%; 11/13 IL7R + patient samples, respectively).
Next, we tested the efficacy of OSE-127 in NSG mice injected with PDX cells from two different E2A-PBX1 + patients (63.0% and 89.6% IL7R-positive blasts, respectively) modelling an MRD-situation by starting treatment one day after injection of PDX cells. While 100% of control animals developed overt leukemia, 0% of the OSE-127-treated animals developed the disease, with 10/10 and 7/10 mice per PDX-group being MRD-negative by the time of sacrifice. Of note, OSE-127-therapy was also effective in corresponding PDX models when therapy was initiated upon detection of 1% BCP-ALL cells in the peripheral blood, modelling an overt leukemia situation (P&lt;0.0001 in both cases).
To investigate the efficacy of OSE-127 in a variety of BCP-ALL samples, we conducted a preclinical phase II-like study using PDX from different cytogenetic patient subgroups (8E2A-PBX1 +, including 1 matched diagnostic/relapse sample, 1 BCR-ABL, 1 MLLr and 1 ETV6-NTRK3). Two mice per PDX were injected, randomly assigned to control or OSE-127 treatment groups and therapy was initiated when &gt;1% blasts were detected in the peripheral blood. Response to OSE-127 was detected in 9/11 (82%) PDX samples in vivo, including BCR-ABL +, MLLr and E2A-PBX1 +-relapse samples. Accordingly, OSE-127 immunotherapy led to a significant increase in median overall survival (85 days versus 55 days; P=0.0122). Of note, OSE-127 therapy response associated with IL7R expression levels on BCP-ALL cells and no significant downregulation of the IL7R antigen was observed upon OSE-127 treatment.
Taken together, our data demonstrate that IL7R-targeting using OSE-127, which has already demonstrated a good safety profile in healthy volunteers, is an efficient approach for BCP-ALL immunotherapy and may be particularly beneficial for patients with high IL7R-expression and/or relapsed/refractory disease after CD19-directed therapy.

Disclosures
Lenk: OSE Immunotherapeutics: Research Funding. Baccelli: OSE Immunotherapeutics: Current Employment, Other: Author of patents related to anti-IL7R antibodies. Corallo: OSE Immunotherapeutics: Current Employment. Schrappe: SHIRE: Other: research support; JazzPharma: Honoraria, Other: research support; Servier: Honoraria, Other: research support; Novartis: Honoraria, Other: research support; SigmaTau: Other: research support; Amgen: Other: research support; Servier: Honoraria; Novartis: Honoraria; JazzPharma: Honoraria. Cario: Novartis: Other: Lecture Fee. Brüggemann: Incyte: Other: Advisory Board; Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Poirier: OSE Immunotherapeutics: Current Employment, Other: Author of patents related to anti-IL7R antibodies. Schewe: OSE Immunotherapeutics: Research Funding; Bayer: Other: Advisory Board; SOBI: Other: Advisory Board; Jazz Pharmaceuticals: Other: Advisory Board.