Disulfide Linkers

Disulfide Linkers

Disulfide linkers are reducible bonds susceptible to the variation of reduction potential between intracellular compartments and circulation. BOC Sciences provides comprehensive customized antibody-drug conjugate (ADC) linker development services by using a range of cytotoxins as payloads for targeted immunotherapy. With state-of-art equipment and advanced techniques, scientists from BOC Sciences are dedicated to helping you develop payload-linker complexes using readily available or customized linkers for antibody conjugation in a timely and cost-effective manner.

Introduction

Reducible or glutathione-sensitive disulfide linker is an alternative to acid-labile hydrazone linker in ADC design. Disulfide linker-based ADC strategies rely on higher concentrations of reducing molecules such as glutathione in the cytoplasm (1-10 mmol/L) compared to the extracellular environment (~5 µmol/L in blood). Mechanistically, disulfide bonds resist reductive cleavage in circulation by being embedded in the linker. After internalization, disulfide bonds are reductively cleaved by abundant intracellular glutathione to release free payload molecules. Additionally, methyl is usually introduced next to the disulfide bond to further improve the circulation stability. Currently, this class of linker has been employed in Mylotarg® and several maytansine-based candidates in clinical trials.

Disulfide LinkersFig. 1. Structure of an ADC with a disulfide linker (Pharmaceutics 2022, 14: 396).

In short, disulfide bond linkers keep conjugates intact during systemic circulation, and are selectively cleaved by the high intracellular concentration of glutathione, releasing the active drugs at the tumor sites from the non-toxic prodrugs. Studies have shown that reduced glutathione presented in tumor cells' cytoplasma is up to 1000-fold higher than that present in normal cells' cytoplasma, and the tumor cells also contain enzymes of the protein disulfide isomerase family, which may contribute to reduction of the disulfide bond in cellular compartments. Furthermore, the reactivity of the disulfide bond can be modulated by steric hindrance. For example, the linker structure of SAR-3419 was fine-tuned for optimal antitumoral activity selecting SPDB-DM4, which displays a gem-dimethyl substitution on the payload side.

Research Applications

Disulfide Linkers1

Representative disulfide linker-based conjugates contain the cytotoxic maytansinoids conjugated to the different monoclonal antibodies. In particular, huC242-SPDB-DM4 (IMGN242) is a novel ADC comprised of huC242 antibody conjugated to the potent maytansinoid via the cleavable disulfide-linker, which allows targeted delivery to pancreatic tumor cells and releases the potent maytansinoid in tumor cells. Compared with uncleavable huC242-SMCC-DM1 containing a thioether linker, huC242-SPDB-DM4 with an average of three to four maytansinoid molecules showed the approximate activities in vitro. However, huC242-SPDB-DM4 exhibited significantly higher activity in multiple xenograft tumor models in vivo. The conjugate, which was linked via a disulfide bond exert an excellent effect and clearance rate for the conjugate, was about four times faster than that for the antibody component.

Our Services

  • Disulfide Linker Design For Payload

ADCs cytotoxin with linker compounds are often patented by pharmaceutical companies as core elements. In addition to providing high-quality design and synthesis services of disulfide linkers, BOC Sciences also offers customized conjugation services for drug-disulfide complexes to facilitate the development of next-generation ADCs with enahnced plasma stability.

  • Disulfide Linker Design For Antibody

With years of experience in antibody conjugation, scientists at BOC Sciences are experinced with disulfide linkers complex preparation. To fulfill customers' specific demands, we are dedicated in providing customized design services using disulfide linkers for ADC developments. We will design or select the most suitable linker to achieve targeted drug delivery according to the antibody conjugation requirements.

  • Disulfide Linker Design For Target

BOC Sciences offers high-quality services in the ADCs discovery and development against mutiple cancer targets. We have established an advanced organic synthesis platform to promote the design and preparation of various drug-linker complexes containing disulfide linkers for antibody drug conjugates (ADCs) development.

What Can We Do For You?

Based on the elaborate chemical synthesis platform and experienced chemical experts, BOC Sciences is dedicated to designing and synthesizing linkers with suitable release mechanisms. In addition to constructing antibody-linker conjugates, our one-stop service platform provides structural modification of antibodies and characterization of novel linker-payload conjugates. Our customarily tailored services and high-quality products will contribute greatly to the success of your projects.

Our Linker Development Workflow

Linker Development Workflow

References

  1. Kotschy, A. et al. The Chemistry Behind ADCs. Pharmaceuticals (Basel). 2021, 14(5): 422.
  2. Zhang, G. et al. Linkers Having a Crucial Role in Antibody-Drug Conjugate. Int. J. Mol. Sci. 2016, 17: 561.
  3. Tsuchikama, K. et al. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell. 2018, 9: 33-46.
* Only for research. Not suitable for any diagnostic or therapeutic use.

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