PI3Kδ activation, IL-6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas
Abstract: CD37-directed antibody and cellular-based approaches have shown preclinical and promising early clinical activity. Naratuximab emtansine (Debio 1562; IMGN529) is an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload, w...
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Elsevier
2024-12-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952924006013 |
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| author | Alberto J. Arribas Sara Napoli Eugenio Gaudio Charles Herbaux Eleonora Cannas Chiara Tarantelli Roberta Bordone-Pittau Luciano Cascione Nicolas Munz Luca Aresu Jacopo Sgrignani Andrea Rinaldi Ivo Kwee Davide Rossi Andrea Cavalli Emanuele Zucca Georg Stussi Anastasios Stathis Callum Sloss Matthew S. Davids Francesco Bertoni |
| author_facet | Alberto J. Arribas Sara Napoli Eugenio Gaudio Charles Herbaux Eleonora Cannas Chiara Tarantelli Roberta Bordone-Pittau Luciano Cascione Nicolas Munz Luca Aresu Jacopo Sgrignani Andrea Rinaldi Ivo Kwee Davide Rossi Andrea Cavalli Emanuele Zucca Georg Stussi Anastasios Stathis Callum Sloss Matthew S. Davids Francesco Bertoni |
| author_sort | Alberto J. Arribas |
| collection | DOAJ |
| description | Abstract: CD37-directed antibody and cellular-based approaches have shown preclinical and promising early clinical activity. Naratuximab emtansine (Debio 1562; IMGN529) is an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload, with activity as a single agent and in combination with rituximab in patients with lymphoma. We studied naratuximab emtansine and its free payload in 54 lymphoma models, correlated its activity with CD37 expression, characterized two resistance mechanisms, and identified combination partners providing synergy. The activity, primarily cytotoxic, was more potent in B- than T-cell lymphoma cell lines. After prolonged exposure to the ADC, one diffuse large B-cell lymphoma (DLBCL) cell line developed resistance to the ADC due to the CD37 gene biallelic loss. After CD37 loss, we also observed upregulation of interleukin-6 (IL-6) and related transcripts. Recombinant IL-6 led to resistance. Anti-IL-6 antibody tocilizumab improved the ADC’s cytotoxic activity in CD37+ cells. In a second model, resistance was sustained by a PIK3CD activating mutation, with increased sensitivity to PI3Kδ inhibition and a functional dependence switch from MCL1 to BCL2. Adding idelalisib or venetoclax overcame resistance in the resistant derivative and improved cytotoxic activity in the parental cells. In conclusion, targeting B-cell lymphoma with the naratuximab emtansine showed vigorous antitumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as Myc Proto-Oncogene (MYC) translocations and TP53 inactivation or R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone) resistance. Resistant DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL-6, PI3Kδ, and BCL2. |
| format | Article |
| id | doaj-art-f13d1f95148f4ba0b57e2b41397d19d2 |
| institution | Kabale University |
| issn | 2473-9529 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-f13d1f95148f4ba0b57e2b41397d19d22024-12-13T11:00:38ZengElsevierBlood Advances2473-95292024-12-0182462686281PI3Kδ activation, IL-6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomasAlberto J. Arribas0Sara Napoli1Eugenio Gaudio2Charles Herbaux3Eleonora Cannas4Chiara Tarantelli5Roberta Bordone-Pittau6Luciano Cascione7Nicolas Munz8Luca Aresu9Jacopo Sgrignani10Andrea Rinaldi11Ivo Kwee12Davide Rossi13Andrea Cavalli14Emanuele Zucca15Georg Stussi16Anastasios Stathis17Callum Sloss18Matthew S. Davids19Francesco Bertoni20Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland; Swiss Institute of Bioinformatics, Lausanne, SwitzerlandInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, SwitzerlandInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, SwitzerlandDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MAInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, SwitzerlandInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, SwitzerlandOncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, SwitzerlandInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland; Swiss Institute of Bioinformatics, Lausanne, SwitzerlandInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, SwitzerlandInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland; Department of Veterinary Science, University of Turin, Turin, ItalyInstitute of Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, SwitzerlandInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, SwitzerlandInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland; Swiss Institute of Bioinformatics, Lausanne, SwitzerlandInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, SwitzerlandSwiss Institute of Bioinformatics, Lausanne, Switzerland; Institute of Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, SwitzerlandInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, SwitzerlandOncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, SwitzerlandOncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, SwitzerlandTranslational Sciences, Immunogen Inc, Waltham, MADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MAInstitute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland; Correspondence: Francesco Bertoni, Institute of Oncology Research, via Francesco Chiesa 5, 6500 Bellinzona, Switzerland;Abstract: CD37-directed antibody and cellular-based approaches have shown preclinical and promising early clinical activity. Naratuximab emtansine (Debio 1562; IMGN529) is an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload, with activity as a single agent and in combination with rituximab in patients with lymphoma. We studied naratuximab emtansine and its free payload in 54 lymphoma models, correlated its activity with CD37 expression, characterized two resistance mechanisms, and identified combination partners providing synergy. The activity, primarily cytotoxic, was more potent in B- than T-cell lymphoma cell lines. After prolonged exposure to the ADC, one diffuse large B-cell lymphoma (DLBCL) cell line developed resistance to the ADC due to the CD37 gene biallelic loss. After CD37 loss, we also observed upregulation of interleukin-6 (IL-6) and related transcripts. Recombinant IL-6 led to resistance. Anti-IL-6 antibody tocilizumab improved the ADC’s cytotoxic activity in CD37+ cells. In a second model, resistance was sustained by a PIK3CD activating mutation, with increased sensitivity to PI3Kδ inhibition and a functional dependence switch from MCL1 to BCL2. Adding idelalisib or venetoclax overcame resistance in the resistant derivative and improved cytotoxic activity in the parental cells. In conclusion, targeting B-cell lymphoma with the naratuximab emtansine showed vigorous antitumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as Myc Proto-Oncogene (MYC) translocations and TP53 inactivation or R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone) resistance. Resistant DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL-6, PI3Kδ, and BCL2.http://www.sciencedirect.com/science/article/pii/S2473952924006013 |
| spellingShingle | Alberto J. Arribas Sara Napoli Eugenio Gaudio Charles Herbaux Eleonora Cannas Chiara Tarantelli Roberta Bordone-Pittau Luciano Cascione Nicolas Munz Luca Aresu Jacopo Sgrignani Andrea Rinaldi Ivo Kwee Davide Rossi Andrea Cavalli Emanuele Zucca Georg Stussi Anastasios Stathis Callum Sloss Matthew S. Davids Francesco Bertoni PI3Kδ activation, IL-6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas Blood Advances |
| title | PI3Kδ activation, IL-6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas |
| title_full | PI3Kδ activation, IL-6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas |
| title_fullStr | PI3Kδ activation, IL-6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas |
| title_full_unstemmed | PI3Kδ activation, IL-6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas |
| title_short | PI3Kδ activation, IL-6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas |
| title_sort | pi3kδ activation il 6 overexpression and cd37 loss cause resistance to naratuximab emtansine in lymphomas |
| url | http://www.sciencedirect.com/science/article/pii/S2473952924006013 |
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