A fully human anti-IL-7Rα antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia
| Autor: | Rita Fragoso, Mattia Matasci, Julie A. Hixon, Gonçalo J. L. Bernardes, Scott K. Durum, Padma Akkapeddi, João T. Barata, Francisco Corzana, Mariana L. Oliveira, Dario Neri, Ana Sofia Ramalho, Tânia Carvalho, Andreas Gloger |
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| Přispěvatelé: | Lopes Bernardes, Goncalo [0000-0001-6594-8917], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class T-Lymphocytes T cell Antineoplastic Agents Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Monoclonal antibody Article Cell Line Mice 03 medical and health sciences Targeted therapies 0302 clinical medicine Animals Humans Cytotoxic T cell Medicine Receptors Interleukin-7 Acute lymphocytic leukaemia biology business.industry Interleukin-7 Antibodies Monoclonal Interleukin Cancer Hematology medicine.disease 3. Good health Leukemia 030104 developmental biology Cell killing medicine.anatomical_structure Oncology Immunoglobulin G 030220 oncology & carcinogenesis biology.protein Cancer research Antibody business Signal Transduction |
| Zdroj: | RIUR. Repositorio Institucional de la Universidad de La Rioja instname Leukemia Leukemia, 33 (9) |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/s41375-019-0434-8 |
| Popis: | 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-7Rα promote T-ALL development and mutational activation of IL-7Rα 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-7Rα, predicted to form a stable complex with IL-7Rα 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-7Rα has a pathological role. ISSN:1476-5551 ISSN:0887-6924 |
| Databáze: | OpenAIRE |
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