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Acute lymphoblastic leukemia

New anti-IL-7Rα monoclonal antibodies show efficacy against T cell acute lymphoblastic leukemia in pre-clinical models

Leukemia volume 34, pages 35–49 (2020)Cite this article

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Abstract

Pediatric T cell acute lymphoblastic leukemia (T-ALL) cells frequently contain mutations in the interleukin-7 (IL-7) receptor pathway or respond to IL-7 itself. To target the IL-7 receptor on T-ALL cells, murine monoclonal antibodies (MAbs) were developed against the human IL-7Rα chain and chimerized with human IgG1 constant regions. Crystal structures demonstrate that the two MAbs bound different IL-7Rα epitopes. The MAbs mediated antibody-dependent cell-mediated cytotoxicity (ADCC) against patient-derived xenograft (PDX) T-ALL cells, which was improved by combining two MAbs. In vivo, the MAbs showed therapeutic efficacy via ADCC-dependent and independent mechanisms in minimal residual and established disease. PDX T-ALL cells that relapsed following a course of chemotherapy displayed elevated IL-7Rα, and MAb treatment is effective against relapsing disease, suggesting the use of anti-IL7Rα MAbs in relapsed T-ALL patients or patients that do not respond to chemotherapy.

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Acknowledgements

We thank Dr. Curt Civin for T-ALL#5, Roberta Matthai for flow cytometry, and Kelli Czarra for expert animal technical work. X-ray data were collected using the National Institutes of Health GM/CA 23ID beamline at the Advanced Photon Source at Argonne National Laboratory, which is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. STRW thank Drs. Craig Ogata and Michael Becker of the GM/CA staff for their assistance. This research was supported by extramual support from the National Institute of Allergy and Infectious Diseases and National Cancer Institute of the NIH (STRW) and the Children’s Cancer Foundation (SKD) and intramural support from the NCI-NIH (JPS, STRW, and SKD).

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Authors and Affiliations

  1. Cytokines and Immunity Section, Cancer and Inflammation Program (CIP), National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick, MD, USA

    Julie A. Hixon, Caroline Andrews, Emilee Senkevitch, Kelli Czarra, Wenqing Li & Scott K. Durum

  2. Comparative Biomedical Scientist Training Program, NIH, Bethesda, MD, USA

    Caroline Andrews

  3. Michigan State University, East Lansing, MI, USA

    Caroline Andrews

  4. Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD, USA

    Lila Kashi, Casey L. Kohnhorst & Scott T. R. Walsh

  5. Cancer Biology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

    Joao T. Barata

  6. Chemical Biology Laboratory, NCI, NIH, Frederick, MD, USA

    Joel P. Schneider & Scott T. R. Walsh

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Contributions

JAH and CA designed and performed experiments and wrote the paper. LK, CLK, ES, and KC performed experiments. JTB and JPS provided helpful discussions. WL supervised, designed, and performed the experiments. STRW supervised, designed and performed the experiments, and wrote the paper. SKD supervised the project and wrote the paper.

Corresponding authors

Correspondence to Scott T. R. Walsh or Scott K. Durum.

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Conflict of interest

Several of the co-authors (JAH, LK, WL, STRW, and SKD) are listed as co-inventors on the patent application “IL-7R-alpha specific antibodies for treating acute lymphoblastic leukemia” filed by the NIH (DHHS). U.S. Patent Application No. 62/238,612. The remaining authors declare that they have no conflict of interest.

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Hixon, J.A., Andrews, C., Kashi, L. et al. New anti-IL-7Rα monoclonal antibodies show efficacy against T cell acute lymphoblastic leukemia in pre-clinical models. Leukemia 34, 35–49 (2020). https://doi.org/10.1038/s41375-019-0531-8

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