Identification of novel KRASG12D neoantigen specific TCRs and a strategy to eliminate off-target recognition

Identification of novel KRASG12D neoantigen specific TCRs and a strategy to eliminate off-target recognition | 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 Identification of novel KRASG12D neoantigen specific TCRs and a strategy to eliminate off-target recognition Xiaojian Han, xiaxia Han, Yanan Hao, Bozhi Wang, Luo Li, Siyin Chen, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5223285/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Jan, 2025 Read the published version in Journal of Translational Medicine → Version 1 posted 5 You are reading this latest preprint version Abstract Background: T cell receptor (TCR)–engineered T cells targeting neoantigens originated from mutations in KRAS gene have demonstrated promising outcomes in clinical trials against solid tumors. However, the challenge lies in developing tumor-specific TCRs that avoid cross-reactivity with self-antigens to minimize the possibility of severe clinical toxicities. Current research efforts have been put towards strategies to eliminate TCR off-target recognition. Methods: Naive T cell repertoire was used for screening KRASG12D-reactive TCRs. Specific TCRs were subsequently identified and their functionality was assessed using TCR Jurkat cells and TCR T cells. Peptide specificity was evaluated using the X-scan assay. To enhance TCR specificity for KRASG12D and reduce their reactivity to self-peptide SMC1A29-38, mammalian TCR display libraries were employed for the design of modification in the complementarity-determining region (CDR). Results: HLA-A*11:01-restricted TCRs targeting the KRASG12D epitope were isolated, and TCR1 was characterized with superior functional avidity and specificity. Alongside a robust recognition of endogenous KRASG12D epitope, this TCR displayed cross-reactivity with the SMC1A29-38 epitope. With an approach utilizing structural-guided mutations in the CDR-1A region of TCR1, we obtained an engineered TCR variant (TCR1a7). Functional characterization of TCR1a7 showed that this TCR not only exhibited enhanced specificity towards KRASG12D, but also demonstrated successful elimination of the off-target recognition of SMC1A29-38. Conclusions: TCRs targeting the KRASG12D peptide could be isolated from naive T cell repertoires. Integrating the TCR-pHLA structure with a mammalian TCR library system could serve as a functional strategy to reduce potential cross-reactivity with self-antigens, such as SMC1A29-38. Our findings evidenced an operable method to enhance TCR peptide specificity, while maintaining advanced functional avidity and potent anti-tumor activity. KRAS mutation T cell receptor cross-reactivity off-target Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Supplementary Files AishunJinsupplementarymaterials.pdf Cite Share Download PDF Status: Published Journal Publication published 17 Jan, 2025 Read the published version in Journal of Translational Medicine → Version 1 posted Editorial decision: Minor revision 18 Dec, 2024 Reviewers agreed at journal 06 Nov, 2024 Reviewers invited by journal 06 Nov, 2024 Editor assigned by journal 23 Oct, 2024 First submitted to journal 08 Oct, 2024 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5223285","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":375000668,"identity":"d9e1b31d-0441-4146-9a10-95be9e590577","order_by":0,"name":"Xiaojian Han","email":"","orcid":"","institution":"Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaojian","middleName":"","lastName":"Han","suffix":""},{"id":375000669,"identity":"70fd05c3-040f-4518-b2b9-b44992ab9455","order_by":1,"name":"xiaxia Han","email":"","orcid":"","institution":"Chongqing Medical 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University","correspondingAuthor":false,"prefix":"","firstName":"Jingjing","middleName":"","lastName":"Huang","suffix":""},{"id":375000676,"identity":"68217604-a709-4cdf-a9f1-ca0ea1f2e940","order_by":8,"name":"Tong Chen","email":"","orcid":"","institution":"Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tong","middleName":"","lastName":"Chen","suffix":""},{"id":375000677,"identity":"2ee290d6-0b83-436e-a400-260ffbd11629","order_by":9,"name":"Wang Wang","email":"","orcid":"","institution":"Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wang","middleName":"","lastName":"Wang","suffix":""},{"id":375000678,"identity":"28f838ad-4e77-451a-a335-f48f77b3fe0c","order_by":10,"name":"Shengchun Liu","email":"","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shengchun","middleName":"","lastName":"Liu","suffix":""},{"id":375000679,"identity":"56601203-3289-4722-bc41-b393fbc6aaac","order_by":11,"name":"Meiying Shen","email":"","orcid":"","institution":"The First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Meiying","middleName":"","lastName":"Shen","suffix":""},{"id":375000680,"identity":"c0997718-53fd-4841-9dc2-a73dc9a03cba","order_by":12,"name":"Aishun Jin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYDACZgY2IMnGw8DeABU5QLQWHphSgloYwFqAQCKBSC387ezPHvPu4JMxl3z88NbNNgY5vhsJjJ8L8GiROMxjbsx7ho3HcnaasXVuG4Ox5I0EZukZ+Kw5zMMmzdvGxmNwO4dNGqglccONBDZmHjw65A+zP4NouXkGrKWeoBaDwwxmEC03eMBaEgwIaTE8zGMmORek5QzQLznnJAxnnnnYLI1Pi9z5488k3rYdszc4fvjh7ZwyG3m+48kHP+PTAgXHwKQEGDEwNhDWwMBQA9MyCkbBKBgFowATAABhEUHKLoxUJAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-9746-4220","institution":"Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Aishun","middleName":"","lastName":"Jin","suffix":""}],"badges":[],"createdAt":"2024-10-08 08:21:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5223285/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5223285/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12967-025-06094-1","type":"published","date":"2025-01-17T15:58:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70583778,"identity":"d77c5018-a98d-4ca2-a083-859f36df0a04","added_by":"auto","created_at":"2024-12-04 15:30:18","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":692817,"visible":true,"origin":"","legend":"\u003cp\u003eDiscovery and functional characterization of HLA-A*11:01-restricted KRASG12D specific TCR clones. (A) KRASG12D -specific T cells were assessed using KRASG12D tetramer, showing live+ CD3+ CD8+ T cells. (B) TCR Jurkat cells were evaluated for TCR expression and KRASG12D tetramer binding. (C, D) TCR Jurkat cells were co-cultured with HLA-A11:01+ K562 cells loaded with KRASG12D peptide and functional avidity (EC50) determined by CD69 expression. Peptide specificity of TCR1 (E) and TCR2 (F) was assessed by X-scan assay. Normalized data are displayed as heatmaps. (G) TCR1 expression on CD8+ T cells was measured; TCR1 T cells were co-cultured with HLA-A11:01+ K562 cells and analyzed for CD137 (H) and IFN-γ release (I). (J) TCR1 T cells were co-cultured with HLA-A*11:01+ SW480 cells expressing KRASWT or KRASG12D and the cytotoxicity were assessed after 24 hours. Data are presented as mean ± SD and all panels represent data from two independent experiments. HD, healthy donor. N.T., non-transduced.\u003c/p\u003e","description":"","filename":"AishunJinFigures1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5223285/v1/c619808bb2802ba42291120e.jpg"},{"id":70582160,"identity":"66d91fe4-34bf-4c7d-bf15-67adc9eac278","added_by":"auto","created_at":"2024-12-04 15:22:19","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":314041,"visible":true,"origin":"","legend":"\u003cp\u003ePeptide specificity profiling of TCR1 T cells for identifying potential off-target peptides. (A) TCR1 peptide specificity was assessed by X-scan assay and shown as a heatmap. (B) TCR T cells were co-cultured with HLA-A11:01+ K562 cells with Minigene-cluster constructs; CD137 expression was analyzed after 24 hours. E7 TCR and P64 TCR served as negative and positive controls, respectively. (C) Peptides from Minigene-cluster 1 were loaded onto HLA-A11:01+ K562 cells and co-cultured with TCR1 T cells; CD137 expression was measured. (D) TCR1 T cells were co-cultured with HLA-A11:01+ K562 cells loaded with SMC1A29-38 peptide. CD137 expression was analyzed. (E) TCR1 T cells were co-cultured with HLA-A11:01+ COS-7 cells expressing full-length SMC1A; CD137 expression was measured. Data are presented as mean ± SD and all panels represent data from two independent experiments. N.T., non-transduced T cells. P.C., positive control. N.C., negtive control N.P., Non-peptide.\u003c/p\u003e","description":"","filename":"AishunJinFigures2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5223285/v1/c9cc9a93db03da7c3e036a3b.jpg"},{"id":70582162,"identity":"b2d43e88-72b7-4264-992a-2be5449fe0a0","added_by":"auto","created_at":"2024-12-04 15:22:19","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":394084,"visible":true,"origin":"","legend":"\u003cp\u003eDiminishing TCR1 recognition ability of SMC1A29-38 peptide through Q112.1 residue mutation in the CDR-3B region. (A) Analysis of the TCR and peptide interaction region of the JDI/pHLA complex. The AA sequences of KRASG12D and SMC1A29-38 are shown. (B) Q112.1 residue was mutated into 19 other AAs. These mutant TCR clones were stained with KRASG12D Tetramer and SMC1A29-38 Tetramer. Functional avidity of TCR1Q112.1A clone and TCR1Q112.1E clone towards KRASG12D peptide (C) and SMC1A29-38 peptide (D) were assessed. All panels represent data from two independent experiments. AA, amino acid.\u003c/p\u003e","description":"","filename":"AishunJinFigures3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5223285/v1/debb27908758a04b6124b9d5.jpg"},{"id":70583779,"identity":"c6217af3-8526-410e-b7cd-49d090bf089a","added_by":"auto","created_at":"2024-12-04 15:30:19","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1232731,"visible":true,"origin":"","legend":"\u003cp\u003eFunctional evaluation and peptide specificity profiling of TCR clones derived from TCR1 libraries. (A) Functional avidity (EC50) of 24 TCR clones was assessed by co-culturing with HLA- A11:01+ K562 cells loaded with KRASG12D peptide, measuring CD69 expression after 6 hours. Dashed line represents TCR1 EC50. (B) TCR clones were stained with SMC1A29-38 and KRASG12D tetramers. (C) TCR clones were co-cultured with HLA-A11:01+ K562 cells loaded with 0.1µM and 1µM SMC1A29-38 peptides, and CD69 expression was analyzed. (D) TCR activation was assessed with K562 cells under three conditions: unmodified, HLA-A11:01+ without peptide, and HLA-A11:01+ with KRASG12D peptide. (E) Peptide specificity of TCR clones was profiled using X- scan assay and results are shown as heatmaps. Data are presented as mean ± SD and all panels represent data from two independent experiments. AA, amino acid.\u003c/p\u003e","description":"","filename":"AishunJinFigures4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5223285/v1/1d0a635f75f2641567ae5d52.jpg"},{"id":70582158,"identity":"7cdedd56-804c-43be-b4e2-546fbdf96783","added_by":"auto","created_at":"2024-12-04 15:22:18","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":774198,"visible":true,"origin":"","legend":"\u003cp\u003eFunctional characterization and specificity profiling of engineered TCR1a7 T cells. hTCR- KO TCRs T cells were co-cultured with HLA-A11:01+ K562 cells loaded with KRASG12D peptide. After 24 hours, CD137 expression (A) and IFN-γ release (B) were analyzed. (C) hTCR-KO TCR T cells were co-cultured with HLA-A11:01+ K562 cells loaded with SMC1A29-38 peptide and CD137 expression was measured. (D-F) TCR1a7 T cells were co-cultured with HLA-A11:01+ AGS, AsPC- 1, or KRASG12D SW480 cells, and cytotoxicity was assessed. (G) CD137 expression on TCR1a7 T cells co-cultured with HLA-A11:01+ cancer cell lines was analyzed. (H, I) Peptide specificity profiling of TCR1a7 was performed by X-scan assay. (J) TCR1a7 T cells were co-cultured with HLA-A*11:01+ K562 cells expressing Minigene-cluster constructs, and CD137 expression was analyzed. E7 TCR served as N.C. and P64 TCR as P.C. HLA+ K562 cells without constructs were N.T., and those with antigen peptide were P.C. Data are presented as mean ± SD and all panels represent data from two independent experiments. N.T., non-transduced. N.C., negative control. P.C., positive control.\u003c/p\u003e","description":"","filename":"AishunJinFigures5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5223285/v1/7f5eb0f19a27694eb3aa0f19.jpg"},{"id":74284701,"identity":"61a8313b-59e8-4151-a648-125fb4d9beb6","added_by":"auto","created_at":"2025-01-20 16:11:10","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3982115,"visible":true,"origin":"","legend":"","description":"","filename":"AishunJinmannuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5223285/v1_covered_88cf21d7-f314-48e2-892e-80e8a9f2544a.pdf"},{"id":70582164,"identity":"b021d3b3-9293-4064-a2da-99cc1d51b1e5","added_by":"auto","created_at":"2024-12-04 15:22:19","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":1653474,"visible":true,"origin":"","legend":"","description":"","filename":"AishunJinsupplementarymaterials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5223285/v1/d1f05c345a38530396e9d3c4.pdf"}],"financialInterests":"","formattedTitle":"Identification of novel KRASG12D neoantigen specific TCRs and a strategy to eliminate off-target recognition","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":false,"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":"KRAS mutation, T cell receptor, cross-reactivity, off-target","lastPublishedDoi":"10.21203/rs.3.rs-5223285/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5223285/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: T cell receptor (TCR)–engineered T cells targeting neoantigens originated from mutations in KRAS gene have demonstrated promising outcomes in clinical trials against solid tumors. However, the challenge lies in developing tumor-specific TCRs that avoid cross-reactivity with self-antigens to minimize the possibility of severe clinical toxicities. Current research efforts have been put towards strategies to eliminate TCR off-target recognition.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: Naive T cell repertoire was used for screening KRASG12D-reactive TCRs. Specific TCRs were subsequently identified and their functionality was assessed using TCR Jurkat cells and TCR T cells. Peptide specificity was evaluated using the X-scan assay. To enhance TCR specificity for KRASG12D and reduce their reactivity to self-peptide SMC1A29-38, mammalian TCR display libraries were employed for the design of modification in the complementarity-determining region (CDR).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: HLA-A*11:01-restricted TCRs targeting the KRASG12D epitope were isolated, and TCR1 was characterized with superior functional avidity and specificity. Alongside a robust recognition of endogenous KRASG12D epitope, this TCR displayed cross-reactivity with the SMC1A29-38 epitope. With an approach utilizing structural-guided mutations in the CDR-1A region of TCR1, we obtained an engineered TCR variant (TCR1a7). Functional characterization of TCR1a7 showed that this TCR not only exhibited enhanced specificity towards KRASG12D, but also demonstrated successful elimination of the off-target recognition of SMC1A29-38.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusions: TCRs targeting the KRASG12D peptide could be isolated from naive T cell repertoires. Integrating the TCR-pHLA structure with a mammalian TCR library system could serve as a functional strategy to reduce potential cross-reactivity with self-antigens, such as SMC1A29-38. Our findings evidenced an operable method to enhance TCR peptide specificity, while maintaining advanced functional avidity and potent anti-tumor activity.\u003c/p\u003e","manuscriptTitle":"Identification of novel KRASG12D neoantigen specific TCRs and a strategy to eliminate off-target recognition","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-04 15:22:14","doi":"10.21203/rs.3.rs-5223285/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2024-12-18T17:03:44+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-11-06T21:33:43+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-06T19:37:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-23T15:04:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Translational Medicine","date":"2024-10-08T04:19:30+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":"7d80144d-ac49-4383-bb3f-9af4944475f6","owner":[],"postedDate":"December 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-20T16:04:30+00:00","versionOfRecord":{"articleIdentity":"rs-5223285","link":"https://doi.org/10.1186/s12967-025-06094-1","journal":{"identity":"journal-of-translational-medicine","isVorOnly":false,"title":"Journal of Translational Medicine"},"publishedOn":"2025-01-17 15:58:00","publishedOnDateReadable":"January 17th, 2025"},"versionCreatedAt":"2024-12-04 15:22:14","video":"","vorDoi":"10.1186/s12967-025-06094-1","vorDoiUrl":"https://doi.org/10.1186/s12967-025-06094-1","workflowStages":[]},"version":"v1","identity":"rs-5223285","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5223285","identity":"rs-5223285","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}