The development of antibody–drug conjugates (ADC), a promising class of anticancer agents, has traditionally relied on the use of antibodies capable of selective internalization in tumor cells. We have recently shown that also noninternalizing antibodies, coupled to cytotoxic drugs by means of disulfide linkers that can be cleaved in the tumor extracellular environment, can display a potent
Site-specific chemical modification of antibody fragments using traceless cleavable linkers. Gonçalo J L Bernardes 1,2,3, Martina Steiner 1, Isabelle Hartmann 1, Dario Neri 1 & Delivery and Release of Small-Molecule Probes in Here, we describe cleavable linkers designed for the traceless release of chemical cargo from MPPs following mitochondrial transit. The cleavage kinetics of a number of disulfides were investigated using a fluorescent reporter system in order to optimize linker stability for mitochondrial release. The stability of mono- and disubstituted Cleavable vs. Non-Cleavable Linkers in Antibody-Drug
Figure: Enzymatically cleavable linkers and the mechanisms of drug release (AAPS J, 2015) As one of the new generation linkers, enzymatically cleavable linkers provide ADCs with improved plasma stability characteristics comparable to that of non-cleavable linkers while boasting a more defined method of drug release.
Current designs for small molecule theranostics, which serve both a diagnostic and therapeutic role, often involve dyes linked to therapeutic agents through a cleavable, traceless linker. In order to facilitate the separation of the dye from the therapeutic in response to a biological or chemical stimulus, linkers must incorporate elements of molecular logic, increasing their complexity and
Principle of a traceless linker. When designing a traceless linker, one has to start from a heteroatom-carbon bond, which is labile toward protogenolytic, hydrogenolytic, or hydridolytic cleavage. Since most heteroatom-carbon single bonds are less stable than a carboncarbon bond, traceless linkers can be synthesized based on nearly all heteroatoms.
Cleavable linkers are generally preferred to non-cleavable linkers in ADC research for a number of reasons. 5 First, traceless drug release allows the unmodified payload to perform its intracellular function without an unwanted linker appendage, thereby maximising cytotoxicity. Belyntic's Peptide Easy Clean (PEC) technology breaks barriers in peptide manufacturing. We designed a catch-and-release methodology based on novel traceless cleavable linker molecules (PEC-Linkers) and activated filter materials for the purification and modification of chemically synthesized peptides. Jun 28, 2018 · However, non-cleavable ADC 4, which lacks a cathepsin-cleavable sequence within the linker scaffold, showed 1.8–4.2-fold higher EC 50 values than those of cleavable ADC 3a (Fig. 3c, d The use of self-immolative linkers has permitted temporary drug conjugation to polymers and antibodies. In the case of antibody–drug conjugates, these linkers can be engineered to act as ‘traceless’ bond from which cleavage results in the native antibody and unmodified drug . Self-immolative linkers containing disulfides have hypothesized Jul 19, 2017 · However, upon cleavage, residual atoms from the linker remain attached to the protein, potentially complicating downstream processes such as activity assays or proteomic analysis. Thus, traceless cleavage13, 17, 18 in which the unmodified parent protein is released is a key requirement for new biotinylation reagents. The most popular linker is the protease cleavable linker that contains a valine-citrulline-para-aminobenzyl-carbamate moiety (vc-PABC). 10 This is a traceless linker that allows the release of amine containing cytotoxins.