Dataset Information

Rapid prototyping of microbial production strains for the biomanufacture of potential materials monomers.

ABSTRACT: Bio-based production of industrial chemicals using synthetic biology can provide alternative green routes from renewable resources, allowing for cleaner production processes. To efficiently produce chemicals on-demand through microbial strain engineering, biomanufacturing foundries have developed automated pipelines that are largely compound agnostic in their time to delivery. Here we benchmark the capabilities of a biomanufacturing pipeline to enable rapid prototyping of microbial cell factories for the production of chemically diverse industrially relevant material building blocks. Over 85 days the pipeline was able to produce 17 potential material monomers and key intermediates by combining 160 genetic parts into 115 unique biosynthetic pathways. To explore the scale-up potential of our prototype production strains, we optimized the enantioselective production of mandelic acid and hydroxymandelic acid, achieving gram-scale production in fed-batch fermenters. The high success rate in the rapid design and prototyping of microbially-produced material building blocks reveals the potential role of biofoundries in leading the transition to sustainable materials production.

SUBMITTER: Robinson CJ

PROVIDER: S-EPMC7225752 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Rapid prototyping of microbial production strains for the biomanufacture of potential materials monomers.

Robinson Christopher J CJ Carbonell Pablo P Jervis Adrian J AJ Yan Cunyu C Hollywood Katherine A KA Dunstan Mark S MS Currin Andrew A Swainston Neil N Spiess Reynard R Taylor Sandra S Mulherin Paul P Parker Steven S Rowe William W Matthews Nicholas E NE Malone Kirk J KJ Le Feuvre Rosalind R Shapira Philip P Barran Perdita P Turner Nicholas J NJ Micklefield Jason J Breitling Rainer R Takano Eriko E Scrutton Nigel S NS

Metabolic engineering 20200423

Bio-based production of industrial chemicals using synthetic biology can provide alternative green routes from renewable resources, allowing for cleaner production processes. To efficiently produce chemicals on-demand through microbial strain engineering, biomanufacturing foundries have developed automated pipelines that are largely compound agnostic in their time to delivery. Here we benchmark the capabilities of a biomanufacturing pipeline to enable rapid prototyping of microbial cell factorie ...[more]

PMID: 32335188

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Project description:Multispecific antibody-like molecules have the potential to advance the standard-of-care in many human diseases. The design of therapeutic molecules in this class, however, has proven to be difficult and, despite significant successes in preclinical research, only one trivalent antibody, catumaxomab, has demonstrated clinical utility. The challenge originates from the complexity of the design space where multiple parameters such as affinity, avidity, effector functions, and pharmaceutical properties need to be engineered in concurrent fashion to achieve the desired therapeutic efficacy. Here, we present a rapid prototyping approach that allows us to successfully optimize these parameters within one campaign cycle that includes modular design, yeast display of structure focused antibody libraries and high throughput biophysical profiling. We delineate this approach by presenting a design case study of MM-141, a tetravalent bispecific antibody targeting two compensatory signaling growth factor receptors: insulin-like growth factor 1 receptor (IGF-1R) and v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ErbB3). A MM-141 proof-of-concept (POC) parent molecule did not meet initial design criteria due to modest bioactivity and poor stability properties. Using a combination of yeast display, structured-guided antibody design and library-scale thermal challenge assay, we discovered a diverse set of stable and active anti-IGF-1R and anti-ErbB3 single-chain variable fragments (scFvs). These optimized modules were reformatted to create a diverse set of full-length tetravalent bispecific antibodies. These re-engineered molecules achieved complete blockade of growth factor induced pro-survival signaling, were stable in serum, and had adequate activity and pharmaceutical properties for clinical development. We believe this approach can be readily applied to the optimization of other classes of bispecific or even multispecific antibody-like molecules.

Dataset Information

Rapid prototyping of microbial production strains for the biomanufacture of potential materials monomers.

Publications

Rapid prototyping of microbial production strains for the biomanufacture of potential materials monomers.

Similar Datasets

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