The effect of PEG on proteins is mainly reflected in two aspects: reducing renal clearance and enhancing protection against protein degradation, both of which reduce the total clearance of the drug. Therefore, the main advantage of PEGylated protein drugs is to prolong the half-life.
1. Improve pharmacodynamic properties and reduce known toxicity
PEG minimizes exposure of epitopes and reduces or prevents the production of neutralizing antibodies. Reduce antigenicity and immunogenicity and maximize biological activity.
For drugs whose toxicity is associated with peak plasma, a flatter pharmacokinetic profile can be obtained by subcutaneous injection of PEGylated protein. Immune-related adverse reactions caused by certain protein drugs can also be reduced by PEGylation.
2. Improve drug stability
In aqueous solution, PEG forms a thick hydration film with water molecules through hydrogen bonds. This hydration film and the flexible chain of PEG are connected in series to resist the adsorption of proteins to the underlying surface and prevent protein aggregation and precipitation. Modifying the linkage between PEG and lipid derivatives (acyl, ether, disulfide, etc.) can also increase the stability of liposomes. The flexible chain of PEG can produce a steric hindrance effect, protect the modification from protease attack, and increase the stability of the modification. PEGylation can also improve the thermal and mechanical stability of the molecule.
3. Improve the distribution of drugs in the body and improve the pharmacokinetic properties
After PEG modification, the molecular weight of the drug increases, which greatly reduces its glomerular filtration effect when it is administered systemically, and reduces the renal clearance rate, thereby reducing urinary excretion. At the same time, it escapes the clearance mechanism of RES, thereby significantly prolonging the plasma half-life in vivo and increasing the release of drugs in the body. In addition, PEGylated drugs improve the stability of the systemic circulation and prolong the residence time, which is beneficial to improve the distribution of drugs in the body, especially the accumulation of macromolecular drugs in tumors and inflammatory sites. PEGylation can improve bioavailability by reducing loss at the subcutaneous injection site. PEGylation modifies the in vivo circulation time of the drug and protects it from proteolytic or metabolic bioinactivation, thus also reducing the dose and improving patient compliance by reducing the number of injections.
4. Improve solubility
PEG has been found to be soluble in water and many organic solvents such as toluene, dichloromethane, ethanol and acetone. One application of this technology is the phase separation of target molecules or cells using PEG-modified antibodies.
Additionally, PEGylated antibody fragments can be concentrated to > 200 mg/mL, providing more options for formulation and administration, such as subcutaneous administration of high-dose proteins. This contrasts with the intravenous administration of many other therapeutic antibodies.