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Molecular Targets for Therapy

Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts

Leukemia volume 28, pages 278–288 (2014)Cite this article

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Abstract

T-acute lymphoblastic leukemia (T-ALL) is characterized by several genetic alterations and poor prognosis in about 20–25% of patients. Notably, about 60% of T-ALL shows increased Notch1 activity, due to activating NOTCH1 mutations or alterations in the FBW7 gene, which confer to the cell a strong growth advantage. Therapeutic targeting of Notch signaling could be clinically relevant, especially for chemotherapy refractory patients. This study investigated the therapeutic efficacy of a novel anti-Notch1 monoclonal antibody by taking advantage of a collection of pediatric T-ALL engrafted systemically in NOD/SCID mice and genetically characterized with respect to NOTCH1/FBW7 mutations. Anti-Notch1 treatment greatly delayed engraftment of T-ALL cells bearing Notch1 mutations, including samples derived from poor responders or relapsed patients. Notably, the therapeutic efficacy of anti-Notch1 therapy was significantly enhanced in combination with dexamethasone. Anti-Notch1 treatment increased T-ALL cell apoptosis, decreased proliferation and caused strong inhibitory effects on Notch-target genes expression along with complex modulations of gene expression profiles involving cell metabolism. Serial transplantation experiments suggested that anti-Notch1 therapy could compromise leukemia-initiating cell functions. These results show therapeutic efficacy of Notch1 blockade for T-ALL, highlight the potential of combination with dexamethasone and identify surrogate biomarkers of the therapeutic response.

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Acknowledgements

We thank E Giarin (University of Padova) for immunophenotyping the T-ALL samples used in this study, E Rossi (University of Padova) for performing microarray hybridization and V Tosello and A Ferrando (Columbia University) for genetic analysis of NOTCH1/FBW7 and critical reading of the manuscript. We also thank many people at OncoMed Pharmaceuticals who contributed to the generation and characterization of OMP-52M51, including Aaron Sato, Sasha Lazetic, Kellie Pickell and Timothy Velilla.

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Author notes

  1. V Agnusdei and S Minuzzo: These authors contributed equally to this work.

Authors and Affiliations

  1. UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto—IRCCS, Padova, Italy

    V Agnusdei, A Grassi, A Amadori & S Indraccolo

  2. Dipartimento Scienze Chirurgiche, Oncologiche e Gastroenterologiche -Sez. Oncologia e Immunologia, Università di Padova, Padova, Italy

    S Minuzzo & A Amadori

  3. Department of Woman and Child Health, Oncohematology Laboratory, Università di Padova, Padova, Italy

    C Frasson, E Seganfreddo & G Basso

  4. OncoMed Pharmaceuticals Inc., Redwood City, CA, USA

    F Axelrod, S Satyal, A Gurney & T Hoey

  5. Nuclear Medicine Department, San Raffaele Scientific Institute; IBFM-CNR, Milan, Italy

    S Valtorta & R M Moresco

  6. Fondazione Tecnomed, University of Milan Bicocca, Milan, Italy

    S Valtorta & R M Moresco

  7. IBFM-CNR, Milan, Italy

    S Valtorta & R M Moresco

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  1. V Agnusdei
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Correspondence to S Indraccolo.

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Competing interests

FA, SS, AG and TH are employees, or former employees, and stockholders of OncoMed Pharmaceuticals. The other authors declare no conflict of interest.

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Agnusdei, V., Minuzzo, S., Frasson, C. et al. Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts. Leukemia 28, 278–288 (2014). https://doi.org/10.1038/leu.2013.183

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