Releasable PEGylation of proteins with customized linkers.

Releasable PEGylation employs customized linkers that reversibly tether a therapeutic moiety with polyethylene glycol polymers. The choice of releasable PEG linkers may have numerous applications that are insufficiently addressed by stable polymer attachment. Releasable PEGylation provides regeneration of authentic and fully active drug and allows tailored design of critical pharmacological parameters such as the maximal drug concentration and total drug exposure. This provides a prodrug format that combines beneficial attributes of PEGylation with controlled release. The linker release mechanisms are shown to be kinetically controlled by the design of a hydrolytically labile center and side chains for the steric modulation of the intramolecular elimination reactions and linker self-immolation. Recent reports have described both aromatic and aliphatic based customized linkers that release the unaltered original drug under physiological conditions and at therapeutically useful release rates. These studies have examined bioconjugates of cytokines, peptide hormones, immunotoxins, enzymes, and reporter proteins.