Extended blood half-life of monomethoxypolyethylene glycol-conjugated hen lysozyme is a key parameter controlling immunological tolerogenicity

Abstract

The blood half-life of a protein is prolonged by conjugating a protein with a linear amphiphilic polymer, monomethoxypolyethylene glycol (mPEG). The conjugation gives a protein immunotolerogenicity; hence, it is likely that the long half-life is crucial for the tolerogenicity. We prepared a tolerogenic mPEG conjugate of hen egg lysozyme (mPEG1.5-HEL), which is conjugated 1.5-fold the molecular weight of mPEG against that of HEL, and evaluated the relationship between in vivo stability and the tolerogenicity. mPEG1.5-HEL retained immunogenicity to prime HEL-specific T cell and antibody responses and had a long blood half-life, more than 27 times that of native HEL. The tolerant state was maintained as long as mPEG1.5-HEL was detected in sera. With a decrease in the blood mPEG1.5-HEL level, the tolerant state returned gradually to the responsive state; however, reinjection of mPEG1.5-HEL again restored the tolerance. Thus, the extended blood half-life of HEL by mPEG conjugation is probably vital for establishing and maintaining the tolerant states.

PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile

“…In many cases, repeat administration of a PEGylated compound can induce immune tolerance to the native compound. 33,34 In other instances, antibodies against PEGylated antigens have been detected. 35 Both of these scenarios could have deleterious effects in patient populations in the context of inducing tolerance to natural adenoviral infection or prevention of successful readministration of the PEGylated virus over time, making additional studies to characterize the immunological properties of PEGylated HD-Ad vectors warranted.…”

CNS drug delivery: Opioid peptides and the blood-brain barrier

“…Polymer conjugations are used to increase peptide stability, reduce elimination, and reduce immunogenicity. [168][169][170][171][172] Chemical modifi cation E83 of peptides with macromolecular polymers, such as poly(ethylene glycol) (PEG), 170 , 172 and poly(styrene maleic acid), 173 , 174 shows signifi cant promise.…”

A method to induce hen egg lysozyme-specific humoral immune tolerance in mice by pre-exposition with the protein's oligomers

“…with 100 μg of HEL-oligomers on day −7 and were immunized with HEL in CFA on day 0, as described above. On day 1 and 15, spleen cells were harvested from mice and the residual amount of HEL-oligomers in spleen cells was measured by competitive ELISA according to a previously described method [22]. The same experiments were carried out in triplicate, i.e.…”