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1. WO2021099480 - METHOD OF DESIGNING CARBOHYDRATES

Publication Number WO/2021/099480
Publication Date 27.05.2021
International Application No. PCT/EP2020/082713
International Filing Date 19.11.2020
IPC
C12P 21/00 2006.1
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
PFERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
21Preparation of peptides or proteins
C12P 21/02 2006.1
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
PFERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
21Preparation of peptides or proteins
02having a known sequence of two or more amino acids, e.g. glutathione
C07K 14/46 2006.1
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
KPEPTIDES
14Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
435from animals; from humans
46from vertebrates
CPC
C12N 9/1048
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
9Enzymes; Proenzymes; Compositions thereof
10Transferases (2.)
1048Glycosyltransferases (2.4)
C12N 9/2402
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
9Enzymes; Proenzymes; Compositions thereof
14Hydrolases (3)
24acting on glycosyl compounds (3.2)
2402hydrolysing O- and S- glycosyl compounds (3.2.1)
C12P 21/005
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
PFERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
21Preparation of peptides or proteins
005Glycopeptides, glycoproteins
C12P 21/02
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
PFERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
21Preparation of peptides or proteins
02having a known sequence of two or more amino acids, e.g. glutathione
Applicants
  • THE REGENTS OF THE UNIVERSITY OF CALIFORNIA [US]/[US]
Inventors
  • LEWIS, Nathan, E.
  • CHIANG, Wan-Tien
  • LIANG, Chenguang
Agents
  • INSPICOS P/S
Priority Data
62/937,93220.11.2019US
Publication Language English (en)
Filing Language English (EN)
Designated States
Title
(EN) METHOD OF DESIGNING CARBOHYDRATES
(FR) PROCÉDÉ DE CONCEPTION DE CARBOHYDRATES
Abstract
(EN) Glycosylated biopharmaceuticals are important in the global pharmaceutical market. Despite the importance of their glycan structures, our limited knowledge of the glycosylation machinery still hinders controllability of this critical quality attribute. To facilitate discovery of glycosyltransferase specificity and predict glycoengineering efforts, here we extend an approach to model therapeutic protein glycosylation as a Markov process. Our model leverages putative glycosyltransferase (GT) specificity to define the biosynthetic pathways for all measured glycans, and the Markov chain modelling is used to learn glycosyltransferase isoform activities and predict glycosylation following glycosyltransferase knock-in/knockout. We apply our methodology to four different glycoengineered therapeutics (i.e., Rituximab, erythropoietin, Enbrel, and alpha-1 antitrypsin) produced in CHO cells, along with o-glycosylation and lipid profiles. Our models accurately predict N-linked glycosylation following glycoengineering and further quantified the impact of glycosyltransferase mutations on reactions catalyzed by other glycosyltransferases. By applying these learned GT-GT interaction rules identified from single glycosyltransferase mutants, our model further predicts the outcome of multi-gene glycosyltransferase mutations on the diverse biotherapeutics. We further apply this to study differential O-glycosylation and lipidomics. Thus, this modeling approach enables rational glycoengineering and the elucidation of relationships between glycosyltransferases and other enzyme classes, thereby facilitating biopharmaceutical research and aiding the broader study of glycosylation to elucidate the genetic basis of complex changes in glycosylation and the lipidome.
(FR) Les produits biopharmaceutiques glycosylés sont importants sur le marché pharmaceutique mondial. Malgré l'importance de leurs structures de glycane, les connaissances limitées de la machinerie de glycosylation empêchent encore la contrôlabilité de cet attribut de qualité critique. Pour faciliter la découverte de la spécificité de la glycosyltransférase et prédire des efforts de glyco-modification, l'invention concerne une approche permettant de modéliser la glycosylation de protéines thérapeutiques en tant que processus de Markov. Le modèle selon l'invention tire partie de la spécificité de la glycosyltransférase (GT) putative pour définir les voies de biosynthèse de tous les glycanes mesurés, et la modélisation de la chaîne de Markov sert à apprendre les activités des isoformes de la glycosyltransférase et à prédire la glycosylation qui suit une validation/invalidation de la glycosyltransférase. La méthodologie selon l'invention est appliquée à quatre agents thérapeutiques glyco-modifiés différents (c'est-à-dire le Rituximab, l'érythropoïétine, l'Enbrel et l'alpha-1 antitrypsine) produits dans des cellules de CHO, conjointement avec des profils d'o-glycosylation et de lipide. Les modèles selon l'invention prédisent avec précision la glyco-modification qui suit la glycosylation à liaison N et quantifient en outre l'impact de mutations de la glycosyltransférase sur des réactions catalysées par d'autres glycosyltransférases. En appliquant ces règles d'interaction GT-GT apprises identifiées à partir de mutants de glycosyltransférase unique, le modèle de l'invention prédit en outre le résultat de mutations de glycosyltransférase multigène sur les diverses biothérapies. L'invention concerne en outre l'étude de la O-glycosylation différentielle et des aspects lipidomiques. La présente approche de modélisation permet donc une glyco-modification rationnelle et l'élucidation de relations entre les glycosyltransférases et d'autres classes d'enzymes, ce qui facilite la recherche biopharmaceutique et favorise l'étude plus large de la glycosylation pour élucider la base génétique de changements complexes dans la glycosylation et le lipidome.
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