A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib

Arturo Simoni-Nieves; Moshit Lindzen; Suvendu Giri; Nitin Gupta; Rishita Chatterjee; Boobash Raj Selvadurai; Marieke Van Daele; Danielle Love; Yuya Haga; Donatella Romaniello; Tomer Meir Salame; Mirie Zerbib; Roni Oren; Yasuo Tsutsumi; Mattia Lauriola; Ilaria Marrocco; Yosef Yarden

doi:10.1016/j.xcrm.2024.101703

A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib

Arturo Simoni-Nieves
, Moshit Lindzen
, Suvendu Giri
, Nitin Gupta
, Rishita Chatterjee
, Boobash Raj Selvadurai
, Marieke Van Daele
, Danielle Love
, Yuya Haga
, Donatella Romaniello
, Tomer Meir Salame
, Mirie Zerbib
, Roni Oren
, Yasuo Tsutsumi
, Mattia Lauriola
, Ilaria Marrocco^*
, Yosef Yarden^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

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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.

Original language	English
Article number	101703
Journal	Cell Reports Medicine
Volume	5
Issue number	9
Early online date	30 Aug 2024
DOIs	https://doi.org/10.1016/j.xcrm.2024.101703
Publication status	Published - 17 Sept 2024

Funding

We thank all members of our laboratories for their kind help and insightful comments. This work was performed in the Marvin Tanner Laboratory for Research on Cancer. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our studies were supported by Merck KGaA , the Israel Science Foundation , the European Research Council (ERC), the Israel Cancer Research Fund (ICRF), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation .

All Science Journal Classification (ASJC) codes

General Medicine
General Biochemistry,Genetics and Molecular Biology

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10.1016/j.xcrm.2024.101703

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Simoni-Nieves, A., Lindzen, M., Giri, S., Gupta, N., Chatterjee, R., Selvadurai, B. R., Van Daele, M., Love, D., Haga, Y., Romaniello, D., Salame, T. M., Zerbib, M., Oren, R., Tsutsumi, Y., Lauriola, M., Marrocco, I., & Yarden, Y. (2024). A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib. Cell Reports Medicine, 5(9), Article 101703. https://doi.org/10.1016/j.xcrm.2024.101703

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title = "A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib",

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.",

author = "Arturo Simoni-Nieves and Moshit Lindzen and Suvendu Giri and Nitin Gupta and Rishita Chatterjee and Selvadurai, \{Boobash Raj\} and \{Van Daele\}, Marieke and Danielle Love and Yuya Haga and Donatella Romaniello and Salame, \{Tomer Meir\} and Mirie Zerbib and Roni Oren and Yasuo Tsutsumi and Mattia Lauriola and Ilaria Marrocco and Yosef Yarden",

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year = "2024",

month = sep,

day = "17",

doi = "10.1016/j.xcrm.2024.101703",

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Simoni-Nieves, A, Lindzen, M , Giri, S , Gupta, N, Chatterjee, R, Selvadurai, BR, Van Daele, M, Love, D, Haga, Y, Romaniello, D, Salame, TM, Zerbib, M, Oren, R, Tsutsumi, Y, Lauriola, M, Marrocco, I & Yarden, Y 2024, 'A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib', Cell Reports Medicine, vol. 5, no. 9, 101703. https://doi.org/10.1016/j.xcrm.2024.101703

TY - JOUR

T1 - A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib

AU - Simoni-Nieves, Arturo

AU - Lindzen, Moshit

AU - Giri, Suvendu

AU - Gupta, Nitin

AU - Chatterjee, Rishita

AU - Selvadurai, Boobash Raj

AU - Van Daele, Marieke

AU - Love, Danielle

AU - Haga, Yuya

AU - Romaniello, Donatella

AU - Salame, Tomer Meir

AU - Zerbib, Mirie

AU - Oren, Roni

AU - Tsutsumi, Yasuo

AU - Lauriola, Mattia

AU - Marrocco, Ilaria

AU - Yarden, Yosef

PY - 2024/9/17

Y1 - 2024/9/17

N2 - 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.

AB - 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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DO - 10.1016/j.xcrm.2024.101703

M3 - Article

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AN - SCOPUS:85204510705

SN - 2666-3791

VL - 5

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 9

M1 - 101703

ER -

A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib

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