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Disulfide Linkers

Scientists from Creative Biolabs are committed to researching ADC development utilizing different kinds of linkers, among which, disulfide linkers are potential ones. Taking advantages of cellular reducing environment, disulfide linkers are extensively exploited as a kind of chemically labile linkages. With profound expertise and advanced techniques and platforms, Creative Biolabs provides custom-designed disulfide linkers with best quality in a highly productive and cost-effective way to meet the custom demands. You can count on us all through your project. 

 Disulfide linkers
Figure: Structure of an ADC with a disulfide linker (Nat Biotechnol. 2005)

Besides acid-labile linkers such as hydrazonesand cis-Aconityl, disulfides are another kind of chemically labile linkers which are extensively exploited in the development of ADCs. Disulfides are thermodynamically (in the absence of free sulfhydryls) stable at physiological pH and are designed to release the drug upon internalization inside cells. The release of disulfide-linked drugs requires cytoplasmic thiol cofactors, such as glutathione (GSH). So disulfides maintain stable at physiological pH and only when ADCs are internalized inside cells, the cytosol provides reducing environment including intracellular enzyme protein disulfide isomerase, or similar enzymes, drugs can be released. Actually, lysosomal processing is necessary for drug activation which means the majority of disulfide-linked drugs are first liberated intact by proteolytic degradation of the antibody and only then released as active metabolites through disulfide exchange or by reducing agents such as glutathione. Up to now, the examples for the use of disulfide linkers in ADCs include calicheamicin, taxoids and maytansinoid conjugates, among which maytansinoid conjugates are the most important. Maytansinoids and thiol-containing maytansine analogues represent a class of highly potent antimitotic drugs inhibiting tubulin polymerization. Maytansinoids containing sulfhydryl groups can be linked to antibodies via disulfide bonds or thioether linkage in a chemically cleavable or noncleavable manner respectively. The ADCs SAR3419, BT-062, BAY 94-9343 and SAR-566658 that are in clinical trials are maytansine-based conjugates using disulfide linkers.

Disulfide linkers belong to chemically cleavable linkers. ADCs with cleavable linkers may be active against targets even when they are poorly internalized (passive diffusion) or effect killing of bystander antigen-negative cells present in the vicinity of the antigen-positive tumor cells (bystander effect). Compared with earlier acid-labile linkers such as hydrazones with low serum stability, more recent disulfide linkers show higher stability in circulation resulting in lower nonspecific cell killing and reduced off-target toxicity. Creative Biolabs provides disulfide linkers to conjugate various payloads. Although great advances have been made in the development of the linker technology for ADCs, there is no general guideline for linker selection. Creative Biolabs conducts customized-design services for disulfide linkers depending on the antibody, drug and tumor target. We will design and select the most suited linker evaluated based on efficacy and toxicity of an individual ADC construct.

We are offering different strategies of linkers in ADC development:

References:
Jan Anderl, et al. Linker Technologies for Antibody–Drug Conjugates. Antibody-Drug Conjugates, 2013:77-80.
Jessica R, et al. Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry. AAPS J. 2015 Mar; 17(2):339-51. 
Wu AM and Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005 Sep; 23(9):1137-46.

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