Polymers are long molecules comprising repeated chemical units known as monomers. Some biopolymers, such as oligonucleotides (oligos) comprising a sequence of nucleotides, are used as therapeutic agents. Oligo medicines work by modulating the expression of proteins and the functioning of genes. There are now 10 approved oligo drugs on the market and many more in development, and there is a growing need for an efficient manufacturing technology to make these high value molecules. The exact order of the nucleotides in an oligo is absolutely crucial its function. Oligos are made industrially by sequential addition of monomers to growing oligos, taking care to remove residual, unreacted monomer before the next cycle, so that there are no errors in the sequence. This requires excellent separation at the end of each coupling cycle. A very effective way of doing this is to attach the growing oligo to a solid support, which is washed with clean solvents to remove residuals, before the next nucleotide is added - this is known as Solid Phase Synthesis (SPS). When oligo growth is complete, it is cleaved from the solid support. All other side chain protecting groups are then removed, and we proceed to test the purity of the final oligo - have all the required nucleotides been added? Often there are "missing" monomers because the reactions on the solid support did not go to completion, and it is typical to find 60-80% of the desired n-mer oligo, together with a "ladder" of n-1, n-2, n-3 mer shorter oligos which are missing 1, 2, 3 or more nucleotides. The ladder must be removed, and this requires extensive, and expensive, chromatography. Exactmer Limited, a UK Life Sciences business is commercialising a new technology platform, Nanostar Sieving, for large scale oligo synthesis. The key innovation is to use organic solvent nanofiltration (OSN) membranes to separate a growing oligo from unreacted monomers. This is carried out in the liquid phase and analysis is relatively straightforward. By connecting three growing oligos to a central hub molecule, a large nanostar complex is created, enhancing membrane retention and promoting efficient separation. Exactmer use Nanostar Sieving to produce oligos with unprecedented control over purity, and have recently entered into licensing and development agreements with several large pharma companies including Novartis and AstraZeneca. Exactmer has OSN membranes that work satisfactorily. They are crosslinked to make them stable in the organic solvent environment required for oligo synthesis, and are very robust. However, they have a wide distribution of pore sizes, and this means that the separation lacks efficiency, resulting in the need for multiple membrane stages to maintain a high yield, and a high volume of solvent to achieve the desired purity. In water treatment, molecular separation membranes have been designed that have an isoporous (single pore size) structure, through using micro-phase separations of block co-polymers. These membranes cannot yet be used in organic solvent systems, as there is no way currently to crosslink them. In this project the Future Leadership Fellow, Dr Zhiwei Jiang, intends to develop isoporous membranes for organic solvent use, and to apply these in oligo synthesis. To achieve this, he will work with two approaches, one based on creating new polymers which can be used to form membranes that can undergo etching and crosslinking; and a second approach in which a thin film separating layer is made on a support matrix by crosslinking, and then etched. This powerful combination of a dynamic growing high-tech business, a highly talented research engineer/scientist, unique membrane making facilities, and a crucial manufacturing need, offers a unique team well equipped to make a fundamental breakthrough in OSN membranes that will offer paradigm changing options to oligo synthesis and beyond.

Polymers are long molecules comprising repeated chemical units known as monomers. Some polymers, such as polyethylene glycol (PEG), comprising ethylene glycol (Eg) monomers, are very useful parts of sophisticated nanomedicines, because they regulate the way that a medicine is transported around and retained in the body. Other polymers, including oligonucleotides (oligos) are used as therapeutic agents. It is extremely difficult to make polymers such as PEG and oligos accurately, because chemical techniques often add a few more or a few less monomers to the chain. For example, in making Eg112, a PEG polymer with 112 repeated units and a molecular weight close to 5kDa, current processes also make Eg111, Eg113, Eg110, Eg114, and so on, so that the material is known as polydisperse. This is a problem for use as part of a medicine, because the different chain lengths can act in different ways in the body, and analysis of multiple species is harder to do accurately. EXACTMER is a start-up company which has licensed a breakthrough new technology invented at Imperial College London- Nanostar Sieving. A hub molecule with three or more arms is used to form a macromolecular Nanostar. Monomers are added to each of the arms, one by one, to form polymers with an exactly controlled sequence of monomers. After the addition of each monomer, all the debris are removed by molecular sieving through a specially designed membrane. The process is repeated over and over until the desired number of monomers has been added, and then the polymers are cut off the hub and recovered, with all polymer molecules having the same, exact number and sequence of monomers. During 2019 we have sold small quantities (1g) of PEGs, and have carried out paid trials to show that Nanostar Sieving can produce purer oligos than conventional technology. We generated £235K in revenue, indicative of strong interest from a range of customers. Now we must quickly capitalise on this by innovating to make our process more efficient, and using it to make 10-20g batches. Success in this innovation project will provide the technical basis for EXACTMER to invest in 1kg scale manufacturing in 2022, rising to 10kg scale in 2023/24\. It will establish Nanostar Sieving as a competitor to the current state-of-the-art, expensive solid phase synthesis. Exactmer will strive to become the dominant global producer of exact, high value polymers, based in the UK.

Millions of molecules are made of repeating units of individual building blocks (monomers). DNA and RNA are important natural polymers made of repeating nucleotides as building blocks. The manufacture of short strands of chemically modified RNA (oligonucleotides) has shown great promise for the development of novel therapies. It is currently achieved using solid-phase synthesis in which the growing oligo is bound to an insoluble substrate and monomers are added one at a time. Solid-phase synthesis is difficult to scale and the resulting purity is low, leading to high prices. The UK start-up Exactmer has developed patented technology enabling polymer synthesis entirely in the liquid phase to overcome these obstacles. The EU-funded NANOLIGO project will bring this technology to market with the potential to significantly speed the development of novel complex polymeric pharmaceuticals and slash manufacturing costs.

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"Polymers are long molecules comprising repeated chemical units known as monomers. Some polymers, such as polyethylene glycol (PEG), which comprises ethylene glycol (EG) monomers, are very useful as therapeutic agents and as parts of sophisticated nanomedicines, because they regulate the way that a medicine is transported around and retained in the body. Other polymers mimic naturally produced polymers including peptides and oligonucleotides (oligos). However it is extremely difficult to make polymers such as PEG and oligos accurately, because chemical techniques often add a few more or a few less monomers to the chain. For example, in making EG112, a PEG polymer with 112 repeated EG units and a molecular weight close to 5,000 Da, current processes also make EG111, EG113, EG110, EG114, and so on, so that the material is known as polydisperse. This is a problem when it comes to use as part of a medicine, because the different chain lengths can act in different ways in the body, and analysis of multiple species is harder to do accurately. EXACTMER is a start-up company that has licensed a new technology invented at Imperial College London, Nanostar Sieving. A hub molecule with three or more arms is used to form a macromolecular Nanostar. Monomers are added to each of the arms, one by one, to form polymers with an exactly controlled sequence of monomers. After the addition of each monomer, all the debris are removed by molecular sieving through a specially designed membrane. The process is repeated over and over until the desired number of monomers has been added, and then the polymers are cut off the hub and recovered, with all molecules having the same, exact number of monomers. This feasibility project aims to show that this completely new approach can scaled up to produce pure PEGs and oligonucleotides at scales of at least 10 g product per batch, and with rapid cycle times. If we are successful, this will be a breakthrough for PEG fabrication and will enable EXACTMER to launch a range of PEG products of high molecular weight and unprecedented purity. It will enable us to introduce Nanostar Sieving as an alternative to the widely used and expensive solid phase synthesis for peptides and oligonucleotides. We will develop Nanostar Sieving for the assembly of further, more sophisticated nanomedicines, and strive to become the UK based dominant global producer of exact, high value polymers."