PEG Linkers in Antibody Drug Conjugates and PROTACs

Polyethylene glycol (PEG), also known as polyethylene oxide (PEO) or polyoxyethylene (POE), refers to an oligomer or polymer of ethylene oxide. Depending on molecular weight, polyethylene glycol can be a liquid or a low-melting solid. Due to the influence of chain length, polyethylene glycols with different molecular weights often have different physical properties and applications, but the chemical properties of most polyethylene glycols are similar. Those with a relative molecular mass between 700 and 900 are semi-solid, and those with a relative molecular mass of 1000 and above are light white waxy solids or flake-like paraffin or fluid powder.

What are PEG Linkers?

PEG linkers are PEG molecules that are used to connect two or more molecules together. PEG linkers are commonly used in drug development, protein engineering, and other biotechnology applications to improve the solubility, stability, and bioavailability of molecules. They are also used as spacers to prevent steric hindrance between molecules and to reduce immunogenicity. PEG linkers can be tailored to vary in length, flexibility, and hydrophilicity to suit specific applications.

Fig. 1. Structure of PEG and mPEG (Progress in Polymer Science. 2013, 38: 421-444).

Typically, PEG linkers are classified as monodisperse and polydisperse. Monodisperse PEG linkers are PEG molecules that have uniform molecular weights, meaning that all of the PEG molecules in the sample have the same length. This makes it ideal for use in applications where consistency is important, such as in drug delivery or protein engineering. Polydisperse PEG linkers are PEG molecules that has a range of molecular weights, meaning that the PEG molecules in the sample have different lengths. This can be problematic in applications where consistency is important, as it can lead to variability in the properties of the final product. However, polydisperse PEG linkers can be useful in some applications where a range of PEG lengths is desired, such as in the development of new materials or in certain types of chemical reactions.

PEG Linkers in PROTACs

PROTAC (Proteolysis Targeting Chimera) is a new technology for inducing targeted protein degradation through the ubiquitin-proteasome system. It consists of three parts: target protein ligand, linker and E3 ligase ligand. PROTAC can be divided into alkyl chains and PEG chains according to the composition of the linker. There are also literatures that use more rigid alkynyl bispiperidine rings, spiro rings or bridge rings containing nitrogen atoms as linkers to limit the flexibility and freedom of PROTAC molecules.

Fig. 2. Protein degradation mechanism of PROTAC (Molecular Therapy - Oncolytics. 2022, 27: 204-223).

At present, existing literature reports indicate that the type, length and connection site of linker will affect the structural rigidity, hydrophobicity and solubility of PROTAC, thereby affecting the complex formation and final activity. PEG plays a common role in PROTAC development. The introduction of PEG can increase the water solubility of PROTAC molecules and affect the cell permeability. In addition, by using PEGs with different chain lengths, the linker length can be systematically changed, affecting the degradation efficiency of PROTAC molecules. Moreover, by using various bifunctional PEG linkers, molecules with different linking groups can be assembled simply and quickly, and the screening can be accelerated to obtain effective degradation structures.

PEG Linkers in ADCs

Antibody-drug conjugate (ADC) consists of monoclonal antibody, linker and active drug. The simple mechanism is to deliver cytotoxic drugs to tumor lesions through the binding of monoclonal antibodies to specific antigens on the surface of tumor cells. Compared with traditional chemical drugs and biological drugs, ADC has significantly improved safety and efficacy.

Fig. 3. The general components of ADC (Molecules. 2017, 22: 1281).

Polyethylene glycol is one of the most widely used linkers in targeted therapy. Appropriate linkers help maintain the stability between the antibody and the drug and help the antibody selectively deliver the drug to tumor cells and release the drug accurately. The PEG linker has the characteristics of high usage rate, strong targeting, and pH adjustment. Through the selection of a variety of functional groups, PEG linkers can be combined with different antibodies and drugs to form different linkers, such as pH-sensitive linkers, disulfide bond linkers, β-glucuronide linkers, etc. The role of PEG linker in ADC:

• To increase water solubility, drug molecules generally have poor water solubility. Adding PEG to the linker structure can increase the water solubility of the entire molecule.
• Appropriately increasing the DAR value (DAR value is drug-to-antibody ratio, drug-to-antibody ratio) can improve the efficacy of ADC drugs on the basis of low toxicity.
• Increases ADC cycle half-life.

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BOC Sciences offers a comprehensive range of PEG products with different molecular weights, functional groups, and end-capping options to meet the specific needs of customers. Our PEG products are manufactured to the highest quality standards and undergo rigorous quality control testing to ensure their purity and consistency. The company's experienced scientists and engineers can also provide customized PEG solutions tailored to the specific requirements of customers.

References

1. Li, W. et al. Current drug research on PEGylation with small molecular agents. Progress in Polymer Science. 2013, 38: 421-444.
2. Xiao, Z. et al. PROTACs in gastrointestinal cancers. Molecular Therapy - Oncolytics. 2022, 27: 204-223.
3. Wei, L. et al. Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy. Molecules. 2017, 22: 1281.