A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib
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.
Authors
- Roni Oren (ORCID: https://orcid.org/0000-0003-1228-412X)
- Yasuo M Tsutsumi (ORCID: https://orcid.org/0000-0002-1997-082X)
- Moshit Lindzen (ORCID: https://orcid.org/0000-0002-4485-1355)
- Donatella Romaniello (ORCID: https://orcid.org/0000-0001-8278-1637)
- Yuya Haga (ORCID: https://orcid.org/0000-0003-4148-2256)
- Nitin Gupta (ORCID: https://orcid.org/0000-0001-9075-5156)
- Ilaria Marrocco (ORCID: https://orcid.org/0000-0002-8225-2177)
- Arturo Simoni‐Nieves (ORCID: https://orcid.org/0000-0002-1353-260X)
- Suvendu Giri (ORCID: https://orcid.org/0000-0002-7595-1359)
- Mirie Zerbib (ORCID: https://orcid.org/0009-0008-4074-1344)
- Yosef Yarden (ORCID: https://orcid.org/0000-0003-4168-7884)
- Rishita Chatterjee (ORCID: https://orcid.org/0000-0001-8484-3897)
- Mattia Lauriola (ORCID: https://orcid.org/0000-0002-7966-0065)
- Boobash-Raj Selvadurai
- Marieke Van Daele
- Danielle Love
- Tomer-Meir Salame
Institutions
- Università Cattolica del Sacro Cuore (IT)
- Weizmann Institute of Science (IL)
- Osaka University of Pharmaceutical Sciences (JP)
- University of Bologna (IT)
- The University of Osaka (JP)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101703
- Citations
- 11
- Primary Topic
- Lung Cancer Treatments and Mutations
- Type
- article
- Field-Weighted Citation Impact
- 4.61
Funders
- Israel Cancer Research Fund
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Merck KGaA