Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer
Louise A. Koopman, … , Esther C.W. Breij, Henrik J. Ditzel
Louise A. Koopman, … , Esther C.W. Breij, Henrik J. Ditzel
Published November 1, 2019; First published October 10, 2019
Citation Information: JCI Insight. 2019;4(21):e128199. https://doi.org/10.1172/jci.insight.128199.
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Research Article Oncology Therapeutics

Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer

Abstract

Targeted therapies and immunotherapy have shown promise in patients with non-small cell lung cancer (NSCLC). However, the majority of patients fail or become resistant to treatment, emphasizing the need for novel treatments. In this study, we confirm the prognostic value of levels of AXL, a member of the TAM receptor tyrosine kinase family, in NSCLC and demonstrate potent antitumor activity of the AXL-targeting antibody-drug conjugate enapotamab vedotin across different NSCLC subtypes in a mouse clinical trial of human NSCLC. Tumor regression or stasis was observed in 17/61 (28%) of the patient-derived xenograft (PDX) models and was associated with AXL mRNA expression levels. Significant single-agent activity of enapotamab vedotin was validated in vivo in 9 of 10 AXL-expressing NSCLC xenograft models. In a panel of EGFR-mutant NSCLC cell lines rendered resistant to EGFR inhibitors in vitro, we observed de novo or increased AXL protein expression concomitant with enapotamab vedotin–mediated cytotoxicity. Enapotamab vedotin also showed antitumor activity in vivo in 3 EGFR-mutant, EGFR inhibitor–resistant PDX models, including an osimertinib-resistant NSCLC PDX model. In summary, enapotamab vedotin has promising therapeutic potential in NSCLC. The safety and preliminary efficacy of enapotamab vedotin are currently being evaluated in the clinic across multiple solid tumor types, including NSCLC.

Authors

Louise A. Koopman, Mikkel G. Terp, Gijs G. Zom, Maarten L. Janmaat, Kirstine Jacobsen, Elke Gresnigt-van den Heuvel, Marcel Brandhorst, Ulf Forssmann, Freddy de Bree, Nora Pencheva, Andreas Lingnau, Maria A. Zipeto, Paul W.H.I Parren, Esther C.W. Breij, Henrik J. Ditzel

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Figure 7

Increased AXL expression and sensitivity to EnaV in a panel of EGFR-mutant NSCLC cell lines upon acquired resistance to EGFR inhibitors in vitro.

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Increased AXL expression and sensitivity to EnaV in a panel of EGFR-muta...
(A) Cell viability of the NSCLC parental and erlotinib-resistant (ER20) HCC827 cell line after exposure to erlotinib, gefitinib, or afatinib. (B) Detection of AXL protein on parental and erlotinib-resistant HCC827 NSCLC cells as determined by Western blot. A full, uncut, and unedited version of the blot is provided in Supplemental Figure 3. (C) Histogram representing AXL protein expression on parental and erlotinib-resistant HCC827 NSCLC cells as determined by flow cytometry. (D) Cell viability (in vitro cytotoxicity) of parental and erlotinib-resistant HCC827 NSCLC cells after exposure to EnaV or isotype-ADC at the indicated concentrations. (E) Cell viability of NSCLC cell lines PC9, H1975, H1650, and HCC4006 and resistant derivatives (ER/OR) upon exposure to 0.1 μM erlotinib (left half of graph) or osimertinib (right half of graph). Percentage of cell viability was calculated relative to the percentage of cells alive after exposure to isotype-ADC at the same concentration. (F) Expression of AXL on NSCLC cell lines and resistant derivatives as determined by flow cytometry. The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range. (G) Cell viability of parental NSCLC cell lines H1975 and osimertinib-resistant derivative H1975-OR2 (considered osimertinib resistant at 2 μM osimertinib concentration) upon exposure to indicated concentrations of EnaV or isotype-ADC. Viability was calculated as follows: % viability = (luminescence sample of interest – luminescence STAU) / (average luminescence of control vehicle treated – luminescence STAU), with STAU representing 1 μM staurosporin for 100% cell killing.