75811 20200217133052.0 doi 10.1038/s41598-018-32986-y sideral 108519 ART-2018-108519 eng Clavero-Alvarez, A. Humanization of Antibodies using a Statistical Inference Approach 2018 Access copy available to the general public Unrestricted Antibody humanization is a key step in the preclinical phase of the development of therapeutic antibodies, originally developed and tested in non-human models (most typically, in mouse). The standard technique of Complementarity-Determining Regions (CDR) grafting into human Framework Regions of germline sequences has some important drawbacks, in that the resulting sequences often need further back-mutations to ensure functionality and/or stability. Here we propose a new method to characterize the statistical distribution of the sequences of the variable regions of human antibodies, that takes into account phenotypical correlations between pairs of residues, both within and between chains. We define a "humanness score" of a sequence, comparing its performance in distinguishing human from murine sequences, with that of some alternative scores in the literature. We also compare the score with the experimental immunogenicity of clinically used antibodies. Finally, we use the humanness score as an optimization function and perform a search in the sequence space, starting from different murine sequences and keeping the CDR regions unchanged. Our results show that our humanness score outperforms other methods in sequence classification, and the optimization protocol is able to generate humanized sequences that are recognized as human by standard homology modelling tools. info:eu-repo/grantAgreement/ES/DGA/E24-3 info:eu-repo/grantAgreement/ES/MINECO/FIS2014-55867-P info:eu-repo/grantAgreement/ES/MINECO/FIS2015-65078-C2-2-P info:eu-repo/grantAgreement/ES/MINECO/FIS2017-87519-P info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 4.011 2018 MULTIDISCIPLINARY SCIENCES 14 / 69 = 0.203 2018 Q1 T1 1.414 2018 Multidisciplinary 2018 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Di Mambro, T. (orcid)0000-0001-8425-7345 Perez-Gaviro, S. Universidad de Zaragoza Magnani, M. (orcid)0000-0002-5833-8798 Bruscolini, P. Universidad de Zaragoza 2004 405 Universidad de Zaragoza Dpto. Física Teórica Área Física Teórica 8 (2018), 14820 [11 pp] Sci. rep. SCIENTIFIC REPORTS 2045-2322 1516520 http://zaguan.unizar.es/record/75811/files/texto_completo.pdf Versión publicada 117091 http://zaguan.unizar.es/record/75811/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:75811 articulos driver 2020-02-17-12:43:33 ARTICLE