Monodisperse PEGs for therapeutics

In the world of therapeutics, several challenges have hindered development and overall success of drugs and vaccines. One pressing issue is the short half-life of therapeutics, with drugs rapidly breaking down and being eliminated from the body. This leads to poor drug efficacy and consequently having to introduce frequent dosing, and potential issues with patient compliance. Additionally, some drugs face problems with solubility, making it difficult for poorly soluble compounds to be effectively absorbed. Maintaining drug stability during storage and administration is also crucial as many compounds, in particular biologics tend to degrade or undergo chemical changes. Addressing these problems is essential for optimal therapeutic outcomes and clinical approval (1). One strategy for increasing the stability of drugs before and after administration, as well as increasing water solubility, is to chemically incorporate inert polyethylene glycol (PEG) into the drugs. This process has been critical in new drug discovery as well as in generating new therapeutics from previously known drugs.

 

PEGylation is a bioconjugation technique, which involves attaching PEG chains to therapeutic agents, such as drugs or vaccines. This process enhances the pharmacokinetic and pharmacodynamic properties of the molecules, leading to prolonged circulation time in the body, better solubility, and improved stability. PEGylation has been a successful strategy for new drug development in many instances but until now it has been performed with commercially available off-the-shelf chemicals that are composed of polymers with non-uniform chain length, known as polydisperse PEGs (2).

 

European Union’s Horizon 2020 Research and Innovation Programme through the Marie Skłodowska-Curie Actions PAVE project (MSCA Grant #861190)

 

R&D project

The success of the SARS-CoV-2 mRNA vaccine has showcased the substantial contribution that PEGs can make in advancing vaccine development. The PAVE project (MSCA Grant #861190) seeks to establish immunotherapy-driven strategies for the treatment of pancreatic cancer. Polypure’s responsibility in the PAVE network is to develop PEG products that can be used for vaccine technologies such as lipid nanoparticles (LNPs) and peptide-based vaccines. 

 

PEG-peptides

Peptide-based cancer vaccines are made up of sequences of amino acids derived from tumor antigens (Figure 1). These peptide sequences are typically lengthy and comprise blocks of hydrophobic amino acids, making the synthesis difficult and requiring rigorous purification to obtain a high-quality product. The contribution of Polypure is to assist in PEGylating peptides to improve solubility and simplify downstream processing of vaccines. We have shown that incorporation of PEG chains in peptide sequences reduces synthesis, purification, and solubility problems frequently encountered with hydrophobic peptides (3).



PEG lipids

Another area of research that Polypure has been exploring is the development of synthesis methods for acquiring monodisperse PEG lipids utilized in LNPs. Incorporating PEG lipids in vaccine LNPs, extends circulation time and thereby improves vaccine efficacy (Figure 2). Commonly polydisperse DMG-PEG-2000 has been used in the rapid development of new vaccines. We intend to provide similar structures but with defined chain lengths for reliable reproducibility and better outcomes. 

 

The technology of producing uniform PEGs utilized at Polypure has been previously employed on a commercial scale to provide multi-kilogram quantities. This will be particularly important when incorporating monodisperse PEG in LNPs manufacturing (4,5).



  1. Harris, J. M., & Chess, R. B. (2003). Effect of pegylation on pharmaceuticals. Nature reviews Drug discovery, 2(3), 214-221.

 

  1. Székely, G., Schaepertoens, M., Gaffney, P. R., & Livingston, A. G. (2014). Beyond PEG2000: synthesis and functionalisation of monodisperse PEGylated homostars and clickable bivalent polyethyleneglycols. Chemistry–A European Journal, 20(32), 10038-10051.

 

  1. Harris, J. M., & Chess, R. B. (2003). Effect of pegylation on pharmaceuticals. Nature reviews Drug discovery, 2(3), 214-221.

 

  1. Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021). Lipid nanoparticles for mRNA delivery. Nature Reviews Materials, 6(12), 1078-1094.

 

  1. Tenchov, R., Bird, R., Curtze, A. E., & Zhou, Q. (2021). Lipid nanoparticles – from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS nano, 15(11), 16982-17015.