A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib

• Published in: Cell reports. Medicine Vol. 5; no. 9; p. 101703
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.09.2024; Elsevier
• Subjects: Acrylamides - pharmacology; adaptive mutability; Advanced Basic Science; Aniline Compounds - pharmacology; Aniline Compounds - therapeutic use; Animals; Antibodies, Bispecific - pharmacology; AXL; Axl Receptor Tyrosine Kinase; bispecific antibody; Cell Line, Tumor; Cetuximab - pharmacology; Cetuximab - therapeutic use; drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; EGFR; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Humans; Indoles; kinase inhibitors; lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; monoclonal antibody; mutators; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Pyrimidines; receptor dimerization; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - immunology; Xenograft Model Antitumor Assays; lung cancer; receptor dimerization; kinase inhibitors; AXL; bispecific antibody; mutators; drug resistance; adaptive mutability; monoclonal antibody; EGFR
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101703

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. [Display omitted] •Kinase inhibitors (KIs) can block EGFR-positive NSCLC but relapses limit drug efficacy•Blocking AXL better delays relapses if anti-AXL antibodies, not KIs, are used•Combining a KI and a bispecific antibody engaging AXL and EGFR delays relapses in mice Simoni-Nieves et al. combine an EGFR kinase inhibitor (osimertinib) and a bispecific antibody co-inhibiting AXL and EGFR to block relapses of EGFR-mutated lung cancer models. This combination exceeds the efficacy achieved by other drug combinations, including osimertinib plus an AXL-specific kinase inhibitor.