SC134-deruxtecan a fucosyl-GM1 targeting ADC for small cell lung cancer therapy

SC134-deruxtecan a fucosyl-GM1 targeting ADC for small cell lung cancer therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article SC134-deruxtecan a fucosyl-GM1 targeting ADC for small cell lung cancer therapy Bryony Heath, Bubacarr G. Kaira, Dhruma Thakker, Omar J. Mohammed, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6888650/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Aug, 2025 Read the published version in Journal of Translational Medicine → Version 1 posted 5 You are reading this latest preprint version Abstract Background Small cell lung cancer (SCLC) remains a difficult disease to treat with poor long-term survival rates. New therapies offer modest overall survival benefit beyond that of chemotherapy alone, necessitating the development of improved therapies. Fucosyl-GM1 (FucGM1) is a glycolipid highly expressed on SCLC cells, but virtually absent in normal tissues, suggesting strong potential for targeted therapy. We have developed SC134-deruxtecan, an antibody drug conjugate (ADC) targeting FucGM1 in SCLC, and characterized its preclinical activity. Methods SC134 binding specificity and affinity were tested through enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), flow cytometry against several SCLC cell lines, and immunohistochemistry (IHC) of clinical samples and animal tissues. In silico modelling supplemented the FucGM1 binding specificity. Internalization kinetics and colocalization of SC134 with the lysosomes were investigated through imaging flow cytometry. Direct cytotoxicity as well as bystander killing and antibody dependent cell cytotoxicity (ADCC) by SC134-deruxtecan were determined using in vitro cell cytotoxicity assays. SC134-deruxtecan’s efficacy was evaluated in vivo using a DMS79 xenograft model. Results SC134 specifically targets FucGM1, without GM1 cross-reactivity, with nanomolar affinity. In silico modelling of the SC134 FucGM1 binding site revealed a relatively narrow binding pocket, occupied by the terminal three glycans with multiple Fucose-engaging interactions. Robust FucGM1 expression in frozen SCLC patient tissues was evident, whilst tissue cross-reactivity analysis indicated non-human primates as well as mice as suitable toxicology models. FucGM1 binding by SC134 led to effective internalization, with a 6.9-hour half-life, lysosomal colocalization, culminating in sub-nanomolar efficiency drug delivery, across a range of payloads. Covalent deruxtecan conjugation of SC134 with a DAR8 and a cleavable linker showed effective (nanomolar) in vitro killing of SCLC cell lines such as DMS79 and DMS153, with concentration-dependent bystander killing of FucGM1-negative AGS cells. SCLC cell killing was further augmented through ADCC. Potent in vivo DMS79 xenograft killing was seen at 3mg/kg SC134-deruxtecan, which was well tolerated. Conclusions The tumour-specific nature of FucGM1, combined with the potent SCLC killing by SC134-deruxtecan underscore the development potential of SC134-deruxtecan for use as an ADC therapy against SCLC. fucosyl-GM1 glycolipid internalization ADC small cell lung cancer Full Text Supplementary Files SC134ADCPaperSupplementalv130625.pptx SupplTable1humantissueinformation.docx SupplementalTable2animaltissues.docx Cite Share Download PDF Status: Published Journal Publication published 19 Aug, 2025 Read the published version in Journal of Translational Medicine → Version 1 posted Editorial decision: Minor revision 10 Jul, 2025 Reviewers agreed at journal 18 Jun, 2025 Reviewers invited by journal 16 Jun, 2025 Editor assigned by journal 14 Jun, 2025 First submitted to journal 13 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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therapy","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-translational-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jtrm","sideBox":"Learn more about [Journal of Translational Medicine](http://translational-medicine.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/jtrm/default.aspx","title":"Journal of Translational Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"fucosyl-GM1, glycolipid, internalization, ADC, small cell lung cancer","lastPublishedDoi":"10.21203/rs.3.rs-6888650/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6888650/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground Small cell lung cancer (SCLC) remains a difficult disease to treat with poor long-term survival rates. New therapies offer modest overall survival benefit beyond that of chemotherapy alone, necessitating the development of improved therapies. Fucosyl-GM1 (FucGM1) is a glycolipid highly expressed on SCLC cells, but virtually absent in normal tissues, suggesting strong potential for targeted therapy. We have developed SC134-deruxtecan, an antibody drug conjugate (ADC) targeting FucGM1 in SCLC, and characterized its preclinical activity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods SC134 binding specificity and affinity were tested through enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), flow cytometry against several SCLC cell lines, and immunohistochemistry (IHC) of clinical samples and animal tissues. In silico modelling supplemented the FucGM1 binding specificity. Internalization kinetics and colocalization of SC134 with the lysosomes were investigated through imaging flow cytometry. Direct cytotoxicity as well as bystander killing and antibody dependent cell cytotoxicity (ADCC) by SC134-deruxtecan were determined using in vitro cell cytotoxicity assays. SC134-deruxtecan’s efficacy was evaluated in vivo using a DMS79 xenograft model.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults SC134 specifically targets FucGM1, without GM1 cross-reactivity, with nanomolar affinity. In silico modelling of the SC134 FucGM1 binding site revealed a relatively narrow binding pocket, occupied by the terminal three glycans with multiple Fucose-engaging interactions. Robust FucGM1 expression in frozen SCLC patient tissues was evident, whilst tissue cross-reactivity analysis indicated non-human primates as well as mice as suitable toxicology\u0026nbsp;models. FucGM1 binding by SC134 led to effective internalization, with a 6.9-hour half-life, lysosomal colocalization, culminating in sub-nanomolar efficiency drug delivery, across a range of payloads. Covalent deruxtecan conjugation of SC134 with a DAR8 and a cleavable linker showed effective (nanomolar) in vitro killing of SCLC cell lines such as DMS79 and DMS153, with concentration-dependent bystander killing of FucGM1-negative AGS cells. SCLC cell killing was further augmented through ADCC. Potent in vivo DMS79 xenograft killing was seen at 3mg/kg SC134-deruxtecan, which was well tolerated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusions The tumour-specific nature of FucGM1, combined with the potent SCLC killing by SC134-deruxtecan underscore the development potential of SC134-deruxtecan for use as an ADC therapy against SCLC.\u003c/p\u003e","manuscriptTitle":"SC134-deruxtecan a fucosyl-GM1 targeting ADC for small cell lung cancer therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-18 13:35:38","doi":"10.21203/rs.3.rs-6888650/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2025-07-10T06:06:22+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-06-18T16:31:52+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-16T05:51:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-14T15:43:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Translational Medicine","date":"2025-06-13T09:29:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-translational-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jtrm","sideBox":"Learn more about [Journal of Translational Medicine](http://translational-medicine.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/jtrm/default.aspx","title":"Journal of Translational Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"255d1c4f-6e3f-41a2-92d6-b3f25a983a59","owner":[],"postedDate":"June 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-25T16:33:59+00:00","versionOfRecord":{"articleIdentity":"rs-6888650","link":"https://doi.org/10.1186/s12967-025-06940-2","journal":{"identity":"journal-of-translational-medicine","isVorOnly":false,"title":"Journal of Translational Medicine"},"publishedOn":"2025-08-19 16:29:17","publishedOnDateReadable":"August 19th, 2025"},"versionCreatedAt":"2025-06-18 13:35:38","video":"","vorDoi":"10.1186/s12967-025-06940-2","vorDoiUrl":"https://doi.org/10.1186/s12967-025-06940-2","workflowStages":[]},"version":"v1","identity":"rs-6888650","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6888650","identity":"rs-6888650","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}