Optimisation and Scale Up of EXACTYMER

Lead Research Organisation: Imperial College London
Department Name: Department of Chemical Engineering

Abstract

Nature uses biopolymers with defined sequences to transmit vital information, through DNA and RNA, which in turn fabricates unique 3-D structures in the form of peptides and proteins. If practical synthesis of similarly defined monomer sequence synthetic polymers that can mimic nature's accuracy, size and complexity, a whole wide range of opportunities and possibilities would be revealed. From the delivery of medicines (Hartmann & Börner, 2009) to the fabrication of complex materials (Lutz, et al., 2016) to molecular information storage (Lutz, 2015), a new paradigm shift will occur if this synthetic pathway is established.
The production of synthetic polymers with precisely defined monomer sequences have been attempted through various process, such as ionic polymerisation, controlled radical polymerisations such as atom radical transfer process (ARTP), and ring-opening metathesis (Srichan, et al., 2014). But as quoted, "owing to the statistical nature or chain growth co-polymerisation, chain to chain sequence inhomogeneity is still present in these polymers". Overall, to achieve complete control over monomer sequences with low error rates, a two-step procedure is required. Firstly, a building block is added to the growing chain terminus, to which, secondly, a new reactive chain terminus is generated, by removing a temporary protecting group or transforming passive functionality into reactive functional ends. It is imperative that each step is 100% selective and complete, no side reactions and no sequence deletion errors. This is, in total, referred to as iterative synthesis. Currently accurate purification and eventual scale-up are barriers to the wide-scale uptake of this technology.
To date, a great majority of sequence-defined polymers have been developed through solid phase platforms, with the principal advantage of this technology, allowing for simple removal of reaction debris and excess monomer through washing with solvent. However, many limitations, from the support capping the concentration of the growing oligomer, to slow reaction rates due to reagent diffusion into the solid support, as well chemical and thermal instability of the support for many of the novel chemistries required for synthetic sequence-defined polymers, leaves a more robust process to be desired. Liquid phase systems, on the contrary, do not suffer from these drawbacks, but has not been widely used due to the lack of a general separation methodology.
The ambition of the EXACTYMER project looks to utilised liquid phase systems to create new super-stable, ultra-selective nanomembranes with high permeances, that ultimately will allow for rapid, repeated purifications in exactymer fabrication and integration into other ISPPPS technologies. With automation and in-line analysis, a breakthrough platform will be creating providing access to a new range of exact monomer sequences (exactymers) which will have transformative impacts on molecular healthcare, nanotechnology and information storage. Building off the established HOMOSTAR nanofiltration platform developed within the Livingston group and other OSN technologies (Székely, et al., 2014), the success of this project will place Europe in a world leading position in this emerging field.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509486/1 01/10/2016 31/03/2022
1966280 Studentship EP/N509486/1 01/10/2017 31/03/2021 Jack Henry Cordrey
 
Description Nature uses bio-polymers with defined sequences to transmit vital information, through DNA and RNA, which in turn fabricates unique 3-D structures in the form of peptides and proteins. If practical synthesis of similarly sequence defined synthetic polymers that can mimic nature's accuracy, size and complexity, a whole wide range of opportunities and possibilities would be revealed. Directly related to this work has been the development of the nanostar sieving technology (NST) platform which utilises membrane nanofiltration systems in-situ to liquid phase chemistry to synthesis oligonucleotide drugs. These are a novel class of drug with the potential to treat various diseases from cancer to cardiovascular and metabolic conditions to neurological disorders. Currently the industry standard method of manufacture is solid phase synthesis, which is limited in scale and general efficiency. To date, this work has spearheaded the design, development and optimisation of the NST platform and has shown that it is possible to achieve the same quality output as solid phase synthesis but with the advantages of greater scale and potentially better environmental and economic impacts, thus leading to the availability of these drugs at a more affordable cost to pharmaceutical companies and therefore the patients that require these specialist drugs.
Exploitation Route The continued growth of Exactmer Ltd will be a quantitative measure of the success of this work, as well as continued investment from research funding groups as well as industrial collaboration. Overall, if the nanostar sieving technology can become a staple of industry and become a standard manufacturing technology, then the success of this work would be complete.
Sectors Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL https://exactmer.com
 
Description The objectives of this PhD research were to design, develop and optimise the nanostar sieving technology platform. To date, the underlying chemistry has been tuned from previously reported procedures and subsequent improvements in terms of material usage and analytical characterisation have significantly improved. This has then been further developed into a more scalable manufacturing technology platform which is being used by Exactmer Ltd to complete work under NDA contracts for various pharmaceutical companies looking to explore nanostar sieving as an alternative to the current industry standard of solid phase synthesis. The largest selling point directly related to my work has been the ability to monitor the reactions in almost real time to ensure all reactions are completed perfectly using UHPLC-MS and current efforts are looking at options for in-line IR, UV-Vis and potential flow 31-P NMR. Further developments have included the development of a novel trap for the deprotection strategies, tuning the membranes for more enhanced purification, scaling this technology to membrane modules that have shown theoretically and practically to synthesis at the 100g scale, economic analysis of the technology platform vs. solid phase synthesis and computational modelling of the membrane system to better understand the impacts of mass transfer kinetics on this process.
First Year Of Impact 2017
Sector Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Title DEFINED MONOMER SEQUENCE POLYMERS 
Description Processes of preparing defined monomer sequence polymers are disclosed, in which a backbone portion of the polymer is first prepared by performing one or more sequential monomeric coupling reactions with intervening membrane diafiltration purification/isolation steps, followed by a step of decorating the backbone portion with one or more side chains at predetermined positions along its length. The process represents an improvement on prior art techniques, which impose limitations on the size of the side chains that may be present. Defined monomer sequence polymers that are obtainable by the processes are also disclosed. 
IP Reference US2018244845 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact The patent technology has been expanded and commercialised into the Exactmer business.
 
Company Name EXACTMER LIMITED 
Description Exactmer owns the Nanostar Sieving technology platform. This employs iterative liquid phase chemistry coupled to membrane purification to create polymers of outstanding purity. Exactmer currently supplies unimolecular polyethylene glycols (PEGS) up to 5kDa, and is exploring the production of oligonucleotides and peptides. 
Year Established 2017 
Impact A number of NDA contracts to explore the nanostar sieving technology for oligonucleotide synthesis.