{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T12:49:21Z","timestamp":1772887761038,"version":"3.50.1"},"reference-count":28,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rothschild Foundation"},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1638\/19"],"award-info":[{"award-number":["1638\/19"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2505\/24"],"award-info":[{"award-number":["2505\/24"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2704\/19"],"award-info":[{"award-number":["2704\/19"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lewis Family Trust"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Transcriptomic analyses of public datasets (TCGA and GTEx) revealed that both CD74 and Cathepsin L (CTSL) are significantly overexpressed in diffuse large B-cell lymphoma (DLBCL) compared to normal tissues, and that their expression levels are highly correlated to each other (Spearman R = 0.64, p = 3 \u00d7 10\u221246). Kaplan\u2013Meier analysis showed that elevated expression of both genes is associated with reduced overall survival (OS), defining a high-risk CD74+\/CTSL+ DLBCL subgroup. This is the first study demonstrating coordinated overexpression of CD74 and CTSL and proposing their dual targeting via antibody\u2013drug conjugates (ADCs) to improve outcomes in relapsed or refractory DLBCL. Cysteine cathepsins, a family of proteases, are upregulated in many cancers, facilitating tumor invasion and metastasis. Cathepsins are overexpressed and play key roles in DLBCL progression. GB111-NH2, a potent broad-spectrum cathepsin inhibitor, significantly reduced cathepsin activity in lymphoma cell lines and patient samples. GB111-NH2 treatment increased apoptosis and caspase-3 activation in DLBCL patient cells and chronic lymphocytic leukemia (CLL) mononuclear cells. Here, we developed a modified cathepsin inhibitor, M-GB, containing a maleimide linker for site-specific antibody conjugation. While M-GB alone has poor cell permeability, when conjugated to an antibody, it forms an ADC (M-GB\u2013ADC) that selectively induces lymphoma cell death. One M-GB\u2013ADC demonstrated high specificity for CD74-expressing lymphoma cells while exhibiting minimal toxicity to non-target cells in vitro. Our findings highlight the potential of another M-GB\u2013ADC as a targeted therapy for overcoming rituximab resistance and treatment failure in DLBCL. This strategy enhances therapeutic efficacy and represents a preclinical proof-of-concept treatment option by directing a cathepsin-inhibitor payload specifically to malignant B cells.<\/jats:p>","DOI":"10.3390\/cells15030291","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T09:02:01Z","timestamp":1770195721000},"page":"291","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CD74-Targeted Cathepsin-Inhibitor Antibody\u2013Drug Conjugate Triggers Apoptosis in DLBCL"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2012-2024","authenticated-orcid":false,"given":"Ihab","family":"Abd-Elrahman","sequence":"first","affiliation":[{"name":"Department of Hematology, Hadassah Medical Center, Jerusalem 9112001, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noha","family":"Khairi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hadassah Medical Center, Jerusalem 9112001, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reut","family":"Sinai-Turyansky","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Zlotber","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riki","family":"Perlman","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hadassah Medical Center, Jerusalem 9112001, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuelle","family":"Merquiol","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Galia","family":"Blum","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dina","family":"Ben Yehuda","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hadassah Medical Center, Jerusalem 9112001, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1002\/ajh.26151","article-title":"2021 Update on Diffuse large B cell lymphoma: A review of current data and potential applications on risk stratification and management","volume":"96","author":"Barta","year":"2021","journal-title":"Am. 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