{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T06:08:05Z","timestamp":1784268485500,"version":"3.55.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":41,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019533","name":"Moderna, Inc.","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019533","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The mRNA technology represents a paradigm shift for the biopharmaceutical industry because in vivo delivery of antibody-based therapeutics can expand their clinical applications. Moreover, the mRNA delivery shifts the burden of assuring CMC (chemistry, manufacturing, and control) to the mRNA molecule. However, in vivo developability issues such as intracellular expression, proper protein folding, secretion into extracellular milieu, degradation in physiological conditions, poly-specificity, immunogenicity, safety, efficacy, and pharmacology can still pose significant barriers to the success of these products. Here, we have leveraged insights from the sequence\u2014structural properties of the variable regions (Fvs) from the marketed biotherapeutics to build a medicine-likeness profile for the mRNA-delivered biotherapeutics. Our dataset consists of 122 unique Fvs from 117 marketed biotherapeutics (as of February 2024) and was systematically evaluated using 9 nonredundant sequence and structural parameters to capture a holistic view of developability attributes relevant to in vivo performance of mRNA-delivered antibody therapeutics. To ensure robustness, 25 antibodies that failed to reach approval due to developability issues, as well as those withdrawn from the market post approval, were included as controls. Our findings highlight a complementary relationship between sequence- and structure-based characteristics, leading us to develop a combined scoring system. This integrated \u201cmedicine-likeness\u201d profile enables early-stage in silico assessments of mRNA-delivered therapeutic antibody candidates, offering a valuable tool for researchers to predict and optimize their in vivo developability.<\/jats:p>","DOI":"10.1093\/bib\/bbag284","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T12:05:44Z","timestamp":1778760344000},"source":"Crossref","is-referenced-by-count":0,"title":["An intrinsic sequence-structural profile for mRNA-delivered therapeutic antibodies"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4647-598X","authenticated-orcid":false,"given":"Farbod","family":"Mahmoudinobar","sequence":"first","affiliation":[{"name":"Molecular Design and Modeling Group, Computational Sciences, Moderna, Inc ., 325 Binney Street, Cambridge, MA 02142 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3425-1986","authenticated-orcid":false,"given":"Grace","family":"Meng","sequence":"additional","affiliation":[{"name":"Molecular Design and Modeling Group, Computational Sciences, Moderna, Inc ., 325 Binney Street, Cambridge, MA 02142 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1111-6848","authenticated-orcid":false,"given":"J Wade","family":"Davis","sequence":"additional","affiliation":[{"name":"Molecular Design and Modeling Group, Computational Sciences, Moderna, Inc ., 325 Binney Street, Cambridge, MA 02142 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2840-6398","authenticated-orcid":false,"given":"Sandeep","family":"Kumar","sequence":"additional","affiliation":[{"name":"Molecular Design and Modeling Group, Computational Sciences, Moderna, Inc ., 325 Binney Street, Cambridge, MA 02142 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"2026071701414764800_ref1","doi-asserted-by":"publisher","first-page":"55","DOI":"10.3390\/antib8040055","article-title":"Antibody structure and function: the basis for engineering therapeutics","volume":"8","author":"Chiu","year":"2019","journal-title":"Antibodies"},{"key":"2026071701414764800_ref2","doi-asserted-by":"publisher","first-page":"871","DOI":"10.2165\/00003495-198937060-00004","article-title":"Muromonab CD3","volume":"37","author":"Todd","year":"1989","journal-title":"Drugs"},{"key":"2026071701414764800_ref3","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.msard.2015.11.007","article-title":"Reducing clinical trial risk in multiple sclerosis","volume":"5","author":"Gasperis-Brigante","year":"2016","journal-title":"Mult Scler Relat Disord"},{"key":"2026071701414764800_ref4","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1186\/s43141-021-00264-6","article-title":"Hybridoma technology; advancements, clinical significance, and future aspects","volume":"19","author":"Mitra","year":"2021","journal-title":"J Genet Eng Biotechnol"},{"key":"2026071701414764800_ref5","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1016\/j.it.2021.10.008","article-title":"Single B cell technologies for monoclonal antibody discovery","volume":"42","author":"Pedrioli","year":"2021","journal-title":"Trends Immunol"},{"key":"2026071701414764800_ref6","doi-asserted-by":"publisher","first-page":"2213793","DOI":"10.1080\/19420862.2023.2213793","article-title":"Evolution of phage display libraries for therapeutic antibody discovery","volume":"15","author":"Zhang","year":"2023","journal-title":"mAbs"},{"key":"2026071701414764800_ref7","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.jim.2004.04.009","article-title":"Yeast display of antibody fragments: a discovery and characterization platform","volume":"290","author":"Feldhaus","year":"2004","journal-title":"J Immunol Methods"},{"key":"2026071701414764800_ref8","doi-asserted-by":"publisher","first-page":"2502","DOI":"10.4049\/jimmunol.1800708","article-title":"Observed antibody space: a resource for data mining next-generation sequencing of antibody repertoires","volume":"201","author":"Kovaltsuk","year":"2018","journal-title":"J Immunol"},{"key":"2026071701414764800_ref9","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1002\/pro.4205","article-title":"Observed antibody space: a diverse database of cleaned, annotated, and translated unpaired and paired antibody sequences","volume":"31","author":"Olsen","year":"2022","journal-title":"Protein Sci"},{"key":"2026071701414764800_ref10","doi-asserted-by":"publisher","first-page":"2206","DOI":"10.3389\/fimmu.2018.02206","article-title":"AIRR community standardized representations for annotated immune repertoires","volume":"9","author":"Heiden","year":"2018","journal-title":"Front Immunol"},{"key":"2026071701414764800_ref11","doi-asserted-by":"publisher","first-page":"1221626","DOI":"10.3389\/fmolb.2023.1221626","article-title":"How can we discover developable antibody-based biotherapeutics","volume":"10","author":"Bauer","year":"2023","journal-title":"Front Mol Biosci"},{"key":"2026071701414764800_ref12","doi-asserted-by":"publisher","first-page":"bbaf023","DOI":"10.1093\/bib\/bbaf023","article-title":"Deep learning-based design and experimental validation of a medicine-like human antibody library","volume":"2025","author":"Rajagopal","year":"2025","journal-title":"Brief Bioinform"},{"key":"2026071701414764800_ref13","doi-asserted-by":"publisher","first-page":"bbae403","DOI":"10.1093\/bib\/bbae403","article-title":"AntiFormer: graph enhanced large language model for binding affinity prediction","volume":"25","author":"Wang","year":"2024","journal-title":"Brief Bioinform"},{"key":"2026071701414764800_ref14","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s12967-019-1804-8","article-title":"How mRNA therapeutics are entering the monoclonal antibody field","volume":"17","author":"Hoecke","year":"2019","journal-title":"J Transl Med"},{"key":"2026071701414764800_ref15","doi-asserted-by":"publisher","first-page":"108","DOI":"10.3390\/vaccines9020108","article-title":"Advancements in mRNA encoded antibodies for passive immunotherapy","volume":"9","author":"Deal","year":"2021","journal-title":"Vaccines"},{"key":"2026071701414764800_ref16","doi-asserted-by":"crossref","first-page":"137","DOI":"10.4161\/mabs.2.2.11271","article-title":"Certolizumab pegol","volume":"2","author":"Goel","year":"2010","journal-title":"mAbs"},{"key":"2026071701414764800_ref17","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1056\/nejmoa067594","article-title":"Certolizumab Pegol for the treatment of Crohn\u2019s disease","volume":"357","author":"Sandborn","year":"2007","journal-title":"N Engl J Med"},{"key":"2026071701414764800_ref18","doi-asserted-by":"publisher","first-page":"2412","DOI":"10.1161\/circulationaha.115.019628","article-title":"Idarucizumab","volume":"132","author":"Eikelboom","year":"2015","journal-title":"Circulation"},{"key":"2026071701414764800_ref19","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1056\/nejmoa1502000","article-title":"Idarucizumab for dabigatran reversal","volume":"373","author":"Pollack","year":"2015","journal-title":"N Engl J Med"},{"key":"2026071701414764800_ref20","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.pharmthera.2012.07.013","article-title":"Blinatumomab: a historical perspective","volume":"136","author":"Nagorsen","year":"2012","journal-title":"Pharmacol Ther"},{"key":"2026071701414764800_ref21","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1177\/1078155215618770","article-title":"A review of blinatumomab, a novel immunotherapy","volume":"22","author":"Newman","year":"2016","journal-title":"J Oncol Pharm Pract"},{"key":"2026071701414764800_ref22","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1002\/phar.2409","article-title":"Systematic review of crizanlizumab: a new parenteral option to reduce vaso-occlusive pain crises in patients with sickle cell disease","volume":"40","author":"Han","year":"2020","journal-title":"Pharmacotherapy"},{"key":"2026071701414764800_ref23","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1056\/nejmoa1611770","article-title":"Crizanlizumab for the prevention of pain crises in sickle cell disease","volume":"376","author":"Ataga","year":"2017","journal-title":"N Engl J Med"},{"key":"2026071701414764800_ref24","doi-asserted-by":"publisher","first-page":"e2020577118","DOI":"10.1073\/pnas.2020577118","article-title":"Intrinsic physicochemical profile of marketed antibody-based biotherapeutics","volume":"118","author":"Ahmed","year":"2021","journal-title":"Proc Natl Acad Sci"},{"key":"2026071701414764800_ref25","doi-asserted-by":"publisher","first-page":"D1006","DOI":"10.1093\/nar\/gkn838","article-title":"IMGT, the international ImMunoGeneTics information system","volume":"37","author":"Lefranc","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"2026071701414764800_ref26","doi-asserted-by":"publisher","DOI":"10.1201\/b19023","article-title":"Developability of biotherapeutics","author":"Kumar","year":"2019","journal-title":"Computational Approaches"},{"key":"2026071701414764800_ref27","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1021\/acs.molpharmaceut.2c00838","article-title":"Embedding dynamics in intrinsic physicochemical profiles of market-stage antibody-based biotherapeutics","volume":"20","author":"Licari","year":"2022","journal-title":"Mol Pharm"},{"key":"2026071701414764800_ref28","volume-title":"Molecular Operating Environment (MOE), 2022.02. Chemical Computing Group ULC, 910-1010 Sherbrooke St. W., Montreal, QC H3A 2R7","author":"CCG","year":"2022"},{"key":"2026071701414764800_ref29","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btae576","article-title":"ABodyBuilder3: improved and scalable antibody structure predictions","volume":"40","author":"Kenlay","journal-title":"Bioinformatics"},{"key":"2026071701414764800_ref30","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1111\/j.0011-7315.2004.00025.x","article-title":"Correlation coefficient rule of thumb","volume":"2","author":"Krehbiel","year":"2004","journal-title":"Decis Sci J Innov Educ"},{"key":"2026071701414764800_ref31","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.sbi.2006.01.011","article-title":"Protein aggregation and amyloidosis: confusion of the kinds?","volume":"16","author":"Rousseau","year":"2006","journal-title":"Curr Opin Struct Biol"},{"key":"2026071701414764800_ref32","doi-asserted-by":"publisher","first-page":"eadj6367","DOI":"10.1126\/sciadv.adj6367","article-title":"Accurate prediction of HLA class II antigen presentation across all loci using tailored data acquisition and refined machine learning","volume":"9","author":"Nilsson","year":"2023","journal-title":"Sci Adv"},{"key":"2026071701414764800_ref33","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41551-023-01074-6","article-title":"Optimization of therapeutic antibodies for reduced self-association and non-specific binding via interpretable machine learning. Nature","volume":"8","author":"Makowski","year":"2024","journal-title":"Biomed Eng"},{"key":"2026071701414764800_ref34","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1080\/19420862.2016.1256723","article-title":"Developability of biotherapeutics: computational approaches. Edited by Sandeep Kumar and Satish K. Singh","volume":"9","author":"Deane","year":"2017","journal-title":"mAbs"},{"key":"2026071701414764800_ref35","doi-asserted-by":"publisher","first-page":"2403156","DOI":"10.1080\/19420862.2024.2403156","article-title":"A comparative study of the developability of full-length antibodies, fragments, and bispecific formats reveals higher stability risks for engineered constructs","volume":"16","author":"Condado-Morales","year":"2024","journal-title":"mAbs"},{"key":"2026071701414764800_ref36","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1002\/jps.22758","article-title":"Developability index: a rapid in silico tool for the screening of antibody aggregation propensity","volume":"101","author":"Lauer","year":"2012","journal-title":"J Pharm Sci"},{"key":"2026071701414764800_ref37","doi-asserted-by":"publisher","first-page":"18601","DOI":"10.1073\/pnas.1421779112","article-title":"In silico selection of therapeutic antibodies for development: viscosity, clearance, and chemical stability","volume":"111","author":"Sharma","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026071701414764800_ref38","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1007\/978-1-0716-1450-1_5","article-title":"Therapeutic antibodies, methods and protocols","volume":"2313","author":"Raybould","year":"2021","journal-title":"Methods Mol Biol"},{"key":"2026071701414764800_ref39","article-title":"Proteins: structures and molecular properties (second edition)","author":"Creighton"},{"key":"2026071701414764800_ref40","doi-asserted-by":"publisher","first-page":"W34","DOI":"10.1093\/nar\/gkt382","article-title":"IgBLAST: an immunoglobulin variable domain sequence analysis tool","volume":"41","author":"Ye","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2026071701414764800_ref41","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1038\/nbt1012","article-title":"Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins","volume":"22","author":"Fernandez-Escamilla","year":"2004","journal-title":"Nat Biotechnol"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/27\/3\/bbag284\/68514530\/bbag284.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/27\/3\/bbag284\/68514530\/bbag284.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:42:00Z","timestamp":1784266920000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbag284\/8706541"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":41,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,5,4]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbag284","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,5]]},"published":{"date-parts":[[2026,5]]},"article-number":"bbag284"}}