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A fully human anti-IL-7Ra antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia

  1. Author:
    Akkapeddi, Padma
    Fragoso, Rita
    Hixon, Julie
    Ramalho, Ana Sofia
    Oliveira, Mariana L
    Carvalho, Tânia
    Gloger, Andreas
    Matasci, Mattia
    Corzana, Francisco
    Durum, Scott
    Neri, Dario
    Bernardes, Gonçalo J L
    Barata, João T

  2. Author Address

    Instituto de Medicina Molecular Jo 227;o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal., Cytokines and Immunity Section, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA., Departamento de Qu 237;mica, Universidad de La Rioja, Centro de Investigaci 243;n en S 237;ntesis Qu 237;mica, 26006, Logro 241;o, Spain., Philochem AG, Libernstrasse 3, Otelfingen, Switzerland., Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Z 252;rich), Vladimir-Prelog-Weg 4, Z 252;rich, Switzerland., Instituto de Medicina Molecular Jo 227;o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal. gbernardes@medicina.ulisboa.pt., Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK. gbernardes@medicina.ulisboa.pt., Instituto de Medicina Molecular Jo 227;o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal. joao_barata@medicina.ulisboa.pt.,
    1. Year: 2019
    2. Date: SEP
    3. Epub Date: 2019 03 08
  2. Journal: Leukemia
    1. 33
    2. 9
    3. Pages: 2155-2168
  4. Type of Article: Article
  5. ISSN: 0887-6924
  1. Abstract:

    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer for which treatment options often result in incomplete therapeutic efficacy and long-term side-effects. Interleukin 7 (IL-7) and its receptor IL-7Ra promote T-ALL development and mutational activation of IL-7Ra associates with very high risk in relapsed disease. Using combinatorial phage-display libraries and antibody reformatting, we generated a fully human IgG1 monoclonal antibody (named B12) against both wild-type and mutant human IL-7Ra, predicted to form a stable complex with IL-7Ra at a different site from IL-7. B12 impairs IL-7/IL-7R-mediated signaling, sensitizes T-ALL cells to treatment with dexamethasone and can induce cell death per se. The antibody also promotes antibody-dependent natural killer-mediated leukemia cytotoxicity in vitro and delays T-cell leukemia development in vivo, reducing tumor burden and promoting mouse survival. B12 is rapidly internalized and traffics to the lysosome, rendering it an attractive vehicle for targeted intracellular delivery of cytotoxic cargo. Consequently, we engineered a B12-MMAE antibody-drug conjugate and provide proof-of-concept evidence that it has increased leukemia cell killing abilities as compared with the naked antibody. Our studies serve as a stepping stone for the development of novel targeted therapies in T-ALL and other diseases where IL-7Ra has a pathological role.

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External Sources

  1. View Full Text
  2. DOI: 10.1038/s41375-019-0434-8
  3. PMID: 30850736
  4. View record in Web of Science®
  5. WOS: 000484399300003
  6. PII : 10.1038/s41375-019-0434-8

Library Notes

  1. Fiscal Year: FY2018-2019
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