CD127-Directed Immunotherapy with Lusvertikimab Outperforms Imatinib in Preclinical ABL-Class-Fusion-Positive BCP-ALL
Authors: Dietterle Anna , Heymann Julia , Laqua Anna , Reimer Claas , Mahachi Denny Takudzwa , Gehlert Carina Lynn , Winterberg Dorothee , Kowol Maja , Wurm Alexander Arthur , Fanter Philipp , Pinkle Denis , Das Gupta Dennis , Vokuhl Christian , Schmid Jan Philipp , Peipp Matthias , Schrappe Martin , Baccelli Irène , Poirier Nicolas , Brüggemann Monika , Cario Gunnar , Schewe Denis Martin , Lenk Lennart 
Published: December 2024

Current therapy strategies for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are mainly based on polychemotherapy. ABL-class-fusion-positive (+) BCP-ALL is associated with poor outcomes and is additionally treated with tyrosine kinase inhibitors such as Imatinib. Yet, Imatinib combined with chemotherapy can cause excessive toxicity and is ineffective in a substantial proportion of cases. Therefore, new treatment strategies are needed. Immunotherapy targeting IL-7Rα (CD127) employing research-grade antibodies has shown promising results in preclinical models of BCP-ALL, including BCR::ABL1+ patient-derived xenograft (PDX) models (Abdelrasoul et al., 2020). Moreover, we recently showed anti-leukemic efficacy of the CD127-targeting IgG4 clinical-grade antibody Lusvertikimab (LUSV) in a wide range of BCP-ALL samples, which was mainly driven by antibody-dependent phagocytosis (ADCP) and highly dependent on CD127 surface expression. Importantly, LUSV showed a good safety profile in healthy volunteers (Poirier et al., 2022) and has recently demonstrated a favorable safety and tolerability profile accompanied by positive efficacy results in a phase-2 trial of ulcerative colitis (NCT04882007). Therefore, we aimed to evaluate LUSV for treating ABL-class-fusion+ BCP-ALL in preclinical models.
First, to determine the number of pediatric ABL-class-fusion+ patients that may potentially benefit from CD127-immunotherapy, CD127 surface expression was prospectively measured via flow cytometry in diagnostic BCP-ALL samples in accordance with EuroFlow and iBFM Flow guidelines. CD127-positivity (defined as ≥10% CD127+ ALL cells) was detected in 16/24 (66.6%) of cases, of which 6 (25%) were CD127high (≥ 50% CD127+ blasts), indicating that a substantial number of ABL-class-fusion+ patients could be eligible for LUSV therapy.
Next, we tested the in vivo efficacy of LUSV in a preclinical phase2-like PDX study employing 7 ABL-class-fusion+ PDX samples (3x pediatric or adult BCR::ABL1+, 1x EBF::PDGFRB+, and 2x ETV6::ABL1+ PDX, including one bearing a CRISPR-Cas9-mediated CD19 knockout). Two mice per patient were transplanted with PDX cells and randomly assigned into treatment groups. LUSV therapy was initiated when mice showed 1% blasts in the peripheral blood (PB). When one of the two mice (control or LUSV therapy) developed clinical signs of leukemia, the peripheral blood of both PDX mice was analyzed for BCP-ALL cells. A blast reduction was observed in 7/7 (100%) of LUSV-treated PDX animals. This translated into a survival prolongation of LUSV-treated animals as compared to the control group (p=0.082).
We next investigated the effect of Imatinib on CD127 expression in ABL-class-fusion+ cell lines and PDX cells in vitro. Pretreatment with sublethal doses of Imatinib (1µM) enhanced CD127 expression in ABL-class-fusion+ cell lines and PDX cells. This effect was more pronounced in CD127low than in CD127high BCP-ALL PDX samples. Importantly, both Imatinib and LUSV enhanced macrophage-mediated phagocytosis in ABL-class fusion+ cell lines and PDX cells as monotherapies. The strongest in vitro ADCP induction was observed when Imatinib and LUSV were combined.
To verify this effect in vivo, we conducted a phase2-like PDX study employing 7 ABL-class-fusion+ PDX samples, testing the efficacy of LUSV, Imatinib, or the combination of both in an overt leukemia setting. Imatinib induced a reduction in median PB blast counts in treated mice compared to control animals (72.6% in the control group vs 58.1% in Imatinib-treated animals, not significant). LUSV treatment significantly reduced PB blasts as compared to control (17.15% PB blasts, p&lt;0.0001). This effect was even more pronounced when comparing the control group with the Imatinib/LUSV combination (11.4% PB blasts, p&lt;0.0001). Imatinib slightly prolonged the median survival of PDX-mice as compared to control (77 days vs. 70 days, not significant). LUSV and LUSV/Imatinib both led to a survival prolongation as compared to the controls (93 days in the LUSV- and 93 days in the LUSV/Imatinib group, p=0.0805 and p=0.0389, respectively). Animals treated with the combination showed no signs of enhanced toxicity as compared to the monotherapy groups. Overall, our data suggest LUSV as a potential immunotherapeutic agent for the treatment of ABL-class fusion+ BCP-ALL, warranting clinical investigation in pediatric and adult patients.