{"doi":"10.1101/2023.11.14.566994","title":"PI3Kδ activation, IL6 over-expression, and CD37 loss cause resistance to the targeting of CD37-positive lymphomas with the antibody-drug conjugate naratuximab emtansine","abstract":"Purpose The transmembrane protein CD37 is expressed almost exclusively in lymphoid tissues, with the highest abundance in mature B cells. CD37-directed antibody- and, more recently, cellular-based approaches have shown preclinical and promising early clinical activity. Naratuximab emtansine (Debio 1562, IMGN529) is an antibodydrug conjugate (ADC) that incorporates an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload. Naratuximab emtansine has shown activity as a single agent and in combination with the anti-CD20 monoclonal antibody rituximab in B cell lymphoma patients. Experimental Design We assessed the activity of naratuximab emtansine using in vitro models of lymphomas, correlated its activity with CD37 expression levels, characterized two resistance mechanisms to the ADC, and identified combination partners providing synergy. Results The anti-tumor activity of naratuximab emtansine was tested in 54 lymphoma cell lines alongside its free payload. The median IC 50 of naratuximab emtansine was 780 pM, and the activity, primarily cytotoxic, was more potent in B than in T cell lymphoma cell lines. In the subgroup of cell lines derived from B cell lymphoma, there was some correlation between sensitivity to DM1 and sensitivity to naratuximab emtansine (r=0.28, P = 0.06). After prolonged exposure to the ADC, one diffuse large B cell lymphoma (DLBCL) cell line developed resistance to the ADC due to the biallelic loss of the CD37 gene. After CD37 loss, we also observed upregulation of IL6 (IL-6) and other transcripts from MYD88/IL6-signaling. Recombinant IL6 led to resistance to naratuximab emtansine, while the anti-IL6 antibody tocilizumab improved the cytotoxic activity of the ADC in CD37-positive cells. In a second model, resistance was sustained by an activating mutation in the PIK3CD gene, associated with increased sensitivity to PI3K δ inhibition and a switch from functional dependence on the anti-apoptotic protein MCL1 to reliance on BCL2. The addition of idelalisib or venetoclax to naratuximab emtansine overcame resistance to the ADC in the resistant derivative while also improving the cytotoxic activity of the ADC in the parental cells. Conclusions Targeting B cell lymphoma with the CD37 targeting ADC naratuximab emtansine showed vigorous anti-tumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as MYC translocations and TP53 inactivation or resistance to R-CHOP. Resistance DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL6, PI3K δ , and BCL2. Despite notable progress in recent decades, we still face challenges in achieving a cure for a substantial number of lymphoma patients (1,2). A pertinent example is diffuse large B cell lymphoma (DLBCL), the most prevalent type of lymphoma (3). More than half of DLBCL patients can achieve remission, but around 40% of them experience refractory disease or relapse following an initial positive response (3). Regrettably, the prognosis for many of these cases remains unsatisfactory despite introducing the most recent antibody-based or cellular therapies (3,4), underscoring the importance of innovating new therapeutic strategies and gaining insights into the mechanisms of therapy resistance. CD37 is a transmembrane glycoprotein belonging to the tetraspanin family, primarily expressed on the surface of immune cells, principally in mature B cells but also, at lower levels, in T cells, macrophages/monocytes, granulocytes and dendritic cells (5) (6-8). CD37 plays a crucial role in various immune functions, including B cell activation, proliferation, and signaling, although its precise role still needs to be fully elucidated. CD37 interacts with multiple molecules, including SYK, LYN, CD19, CD22, PI3K δ , PI3K γ , and different integrins, among others (6-8). In mice, the lack of CD37 is paired with reduced T cell-dependent antibody-secreting cells ","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":393837,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9583,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1072122,"name":"Eugenio Gaudio","orcid":"0009-0006-6956-6135","position":1,"is_corresponding":false},{"id":887378,"name":"Sara Napoli","orcid":"0000-0002-9699-7540","position":2,"is_corresponding":false},{"id":774718,"name":"Charles Herbaux","orcid":"0000-0003-4910-476X","position":3,"is_corresponding":false},{"id":513252,"name":"Chiara Tarantelli","orcid":"0000-0002-4394-7742","position":4,"is_corresponding":false},{"id":1168330,"name":"Roberta Bordone","orcid":null,"position":5,"is_corresponding":false},{"id":513257,"name":"Luciano Cascione","orcid":"0000-0002-4606-0637","position":6,"is_corresponding":false},{"id":1168331,"name":"Nicolas Munz","orcid":null,"position":7,"is_corresponding":false},{"id":1129225,"name":"Luca Aresu","orcid":"0000-0002-7893-1740","position":8,"is_corresponding":false},{"id":653693,"name":"Jacopo Sgrignani","orcid":"0000-0002-8633-1032","position":9,"is_corresponding":false},{"id":564816,"name":"Andrea Rinaldi","orcid":"0000-0003-3234-0563","position":10,"is_corresponding":false},{"id":1167929,"name":"Ivo Kwee","orcid":"0000-0002-2751-4218","position":11,"is_corresponding":false},{"id":814398,"name":"Davide Rossi","orcid":"0000-0002-2837-1597","position":12,"is_corresponding":false},{"id":653694,"name":"Andrea Cavalli","orcid":"0000-0003-4063-4502","position":13,"is_corresponding":false},{"id":838692,"name":"Emanuele Zucca","orcid":"0000-0002-5522-6109","position":14,"is_corresponding":false},{"id":887383,"name":"Georg Stüssi","orcid":"0000-0002-1667-0637","position":15,"is_corresponding":false},{"id":887382,"name":"Anastasios Stathis","orcid":"0000-0002-2859-7529","position":16,"is_corresponding":false},{"id":1168332,"name":"Callum M. Sloss","orcid":null,"position":17,"is_corresponding":false},{"id":233541,"name":"Matthew S. Davids","orcid":"0000-0003-4529-2003","position":18,"is_corresponding":false},{"id":327227,"name":"Francesco Bertoni","orcid":"0000-0001-5637-8983","position":19,"is_corresponding":false},{"id":887377,"name":"Alberto J. Arribas","orcid":"0000-0003-3123-6203","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:05.913428Z","pmid":"38014209","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}