Ensovibep, a novel trispecific DARPin candidate that protects against SARS-CoV-2 variants

Ensovibep, a novel trispecific DARPin candidate that protects against SARS-CoV-2 variants | 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 Article Ensovibep, a novel trispecific DARPin candidate that protects against SARS-CoV-2 variants Michael Stumpp This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1170399/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Jul, 2022 Read the published version in Nature Biotechnology → Version 1 posted You are reading this latest preprint version Abstract SARS-CoV-2 has infected millions of people globally and continues to undergo evolution. Emerging variants can be partially resistant to vaccine induced and therapeutic antibodies, emphasizing the urgent need for accessible, broad-spectrum therapeutics. Here, we report a comprehensive study of ensovibep, the first trispecific clinical DARPin candidate, that can simultaneously engage all three units of the spike protein trimer to potently inhibit ACE2 interaction, as revealed by structural analyses. The cooperative binding of the individual modules enables ensovibep to retain inhibitory potency against all frequent SARS-CoV-2 variants, including Omicron, as of December 2021. Moreover, viral passaging experiments show that ensovibep, when used as a single agent, can prevent development of escape mutations comparably to a cocktail of monoclonal antibodies (mAb). Finally, we demonstrate that the very high in vitro antiviral potency also translates into significant therapeutic protection and reduction of pathogenesis in Roborovski dwarf hamsters infected with either the SARS-CoV-2 wild-type or the Alpha variant. In this model, ensovibep prevents fatality and provides substantial protection equivalent to the standard of care mAb cocktail. These results support further clinical evaluation and indicate that ensovibep could be a valuable alternative to mAb cocktails and other treatments for COVID-19. SARS-CoV-2 COVID-19 coronavirus mutations emerging variants antiviral therapy ensovibep MP0420 DARPin drug ankyrin repeat protein DARPin multispecific K417N K417T L452R E484K N501Y B.1.1.7 B.1.1.529 B.1.351 P.1 B.1.429 B.1.526 B.1.617 B.1.618 B.1.621 AY.1 alpha beta gamma delta mu omicron Roborovski dwarf hamster Full Text Additional Declarations Yes there is potential Competing Interest. Authors from Molecular Partners own performance share units and/or stock of the company. H.K.B. owns stock of the company. I.D. is an employee of Thermo Fisher Scientific. C.G.K.; K.K.B. and K.R. are employees of Novartis. Cite Share Download PDF Status: Published Journal Publication published 21 Jul, 2022 Read the published version in Nature Biotechnology → Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-1170399","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":70283369,"identity":"b0fdaed0-962d-42fd-9dce-0ff563cd7340","order_by":0,"name":"Michael Stumpp","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-7356-2061","institution":"Molecular Partners AG","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Stumpp","suffix":""}],"badges":[],"createdAt":"2021-12-14 13:25:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1170399/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1170399/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41587-022-01382-3","type":"published","date":"2022-07-21T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":26523442,"identity":"b3227956-945f-495b-99fd-3870d0452441","added_by":"auto","created_at":"2022-09-15 20:18:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4836490,"visible":true,"origin":"","legend":"","description":"","filename":"Rothenberger2021Ensovibep.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1170399/v1_covered.pdf"},{"id":16627449,"identity":"c10b2161-7bc6-49e6-bf45-bdc8ff05267a","added_by":"auto","created_at":"2021-12-20 19:00:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4831708,"visible":true,"origin":"","legend":"","description":"","filename":"Rothenberger2021Ensovibep.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1170399/v1_covered.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nAuthors from Molecular Partners own performance share units and/or stock of the company. H.K.B. owns stock of the company. I.D. is an employee of Thermo Fisher Scientific. C.G.K.; K.K.B. and K.R. are employees of Novartis.","formattedTitle":"Ensovibep, a novel trispecific DARPin candidate that protects against SARS-CoV-2 variants","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-1170399/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"SARS-CoV-2, COVID-19, coronavirus, mutations, emerging variants, antiviral therapy, ensovibep, MP0420, DARPin drug, ankyrin repeat protein, DARPin, multispecific, K417N, K417T, L452R E484K, N501Y, B.1.1.7, B.1.1.529, B.1.351, P.1, B.1.429, B.1.526, B.1.617, B.1.618, B.1.621, AY.1, alpha, beta, gamma, delta, mu, omicron, Roborovski dwarf hamster","lastPublishedDoi":"10.21203/rs.3.rs-1170399/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1170399/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"SARS-CoV-2 has infected millions of people globally and continues to undergo evolution. Emerging variants can be partially resistant to vaccine induced and therapeutic antibodies, emphasizing the urgent need for accessible, broad-spectrum therapeutics. Here, we report a comprehensive study of ensovibep, the first trispecific clinical DARPin candidate, that can simultaneously engage all three units of the spike protein trimer to potently inhibit ACE2 interaction, as revealed by structural analyses. The cooperative binding of the individual modules enables ensovibep to retain inhibitory potency against all frequent SARS-CoV-2 variants, including Omicron, as of December 2021. Moreover, viral passaging experiments show that ensovibep, when used as a single agent, can prevent development of escape mutations comparably to a cocktail of monoclonal antibodies (mAb). Finally, we demonstrate that the very high in vitro antiviral potency also translates into significant therapeutic protection and reduction of pathogenesis in Roborovski dwarf hamsters infected with either the SARS-CoV-2 wild-type or the Alpha variant. In this model, ensovibep prevents fatality and provides substantial protection equivalent to the standard of care mAb cocktail. These results support further clinical evaluation and indicate that ensovibep could be a valuable alternative to mAb cocktails and other treatments for COVID-19.","manuscriptTitle":"Ensovibep, a novel trispecific DARPin candidate that protects against SARS-CoV-2 variants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-12-20 19:00:27","doi":"10.21203/rs.3.rs-1170399/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-biotechnology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nbt","sideBox":"Learn more about [Nature Biotechnology](http://www.nature.com/nbt/)","snPcode":"","submissionUrl":"","title":"Nature Biotechnology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"855bb239-b8a3-4024-b282-6d68be595633","owner":[],"postedDate":"December 20th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2022-09-15T20:18:06+00:00","versionOfRecord":{"articleIdentity":"rs-1170399","link":"https://doi.org/10.1038/s41587-022-01382-3","journal":{"identity":"nature-biotechnology","isVorOnly":false,"title":"Nature Biotechnology"},"publishedOn":"2022-07-21 04:00:00","publishedOnDateReadable":"July 21st, 2022"},"versionCreatedAt":"2021-12-20 19:00:27","video":"","vorDoi":"10.1038/s41587-022-01382-3","vorDoiUrl":"https://doi.org/10.1038/s41587-022-01382-3","workflowStages":[]},"version":"v1","identity":"rs-1170399","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1170399","identity":"rs-1170399","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}