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A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib.
Simoni-Nieves, Arturo; Lindzen, Moshit; Giri, Suvendu; Gupta, Nitin; Chatterjee, Rishita; Selvadurai, Boobash-Raj; Van Daele, Marieke; Love, Danielle; Haga, Yuya; Romaniello, Donatella; Salame, Tomer-Meir; Zerbib, Mirie; Oren, Roni; Tsutsumi, Yasuo; Lauriola, Mattia; Marrocco, Ilaria; Yarden, Yosef.
Afiliación
  • Simoni-Nieves A; Departments of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Lindzen M; Departments of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Giri S; Departments of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Gupta N; Departments of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Chatterjee R; Departments of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Selvadurai BR; Departments of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Van Daele M; Departments of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Love D; Departments of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Haga Y; Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
  • Romaniello D; Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy.
  • Salame TM; Flow Cytometry Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Zerbib M; Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Oren R; Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Tsutsumi Y; Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan; Global Center for Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan; Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan.
  • Lauriola M; Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy.
  • Marrocco I; Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy. Electronic address: ilaria.marrocco@unicatt.it.
  • Yarden Y; Departments of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: yosef.yarden@weizmann.ac.il.
Cell Rep Med ; 5(9): 101703, 2024 Sep 17.
Article en En | MEDLINE | ID: mdl-39216477
ABSTRACT
Activating EGFR (epidermal growth factor receptor) mutations can be inhibited by specific tyrosine kinase inhibitors (TKIs), which have changed the landscape of lung cancer therapy. However, due to secondary mutations and bypass receptors, such as AXL (AXL receptor tyrosine kinase), drug resistance eventually emerges in most patients treated with the first-, second-, or third-generation TKIs (e.g., osimertinib). To inhibit AXL and resistance to osimertinib, we compare two anti-AXL drugs, an antibody (mAb654) and a TKI (bemcentinib). While no pair of osimertinib and an anti-AXL drug is able to prevent relapses, triplets combining osimertinib, cetuximab (an anti-EGFR antibody), and either anti-AXL drug are initially effective. However, longer monitoring uncovers superiority of the mAb654-containing triplet, possibly due to induction of receptor endocytosis, activation of immune mechanisms, or disabling intrinsic mutators. Hence, we constructed a bispecific antibody that engages both AXL and EGFR. When combined with osimertinib, the bispecific antibody consistently inhibits tumor relapses, which warrants clinical trials.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Acrilamidas / Proteínas Proto-Oncogénicas / Proteínas Tirosina Quinasas Receptoras / Anticuerpos Biespecíficos / Resistencia a Antineoplásicos / Receptores ErbB / Tirosina Quinasa del Receptor Axl / Compuestos de Anilina Límite: Animals / Female / Humans Idioma: En Revista: Cell Rep Med Año: 2024 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Acrilamidas / Proteínas Proto-Oncogénicas / Proteínas Tirosina Quinasas Receptoras / Anticuerpos Biespecíficos / Resistencia a Antineoplásicos / Receptores ErbB / Tirosina Quinasa del Receptor Axl / Compuestos de Anilina Límite: Animals / Female / Humans Idioma: En Revista: Cell Rep Med Año: 2024 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos