Sulfatase Cleavable Linkers

Sulfatase Cleavable Linkers

Sulfatase cleavable linkers are used in antibody-drug conjugate (ADC) drug development to release payloads by lysosomal sulfatase enzymes after cleavage. BOC Sciences provides high-quality custom synthesis services of sulfatase cleavable linkers targeting different payloads, antibodies, and tumors, thereby supporting our clients in better developing new drug projects. Our efficient and reliable services are guaranteed to accelerate your research.

Introduction

Sulfatases are enzymes involved in the cleavage of sulfate ester bonds in biological systems; they play an essential role in monitoring the function of many physiological molecules. Sulfatases are concerned with many biological processes, such as bacterial pathogenesis, cell signaling development, and hormone regulation. Moreover, sulfatases are overexpressed in several types of cancers cells that give additional selectivity for cancer targeting ADCs. Further, the sulfatase cleavable linker exhibits high stability in human and mouse plasma but is only reactive within lysosomes that offer an additional opportunity for arylsulfate-containing ADCs toward a tumor for selective release payloads.

Chemical structure of sulfatase-cleaved linker and corresponding release  mechanism Fig. 1. Chemical structure of sulfatase-cleaved linker and corresponding release mechanism (Pharmaceuticals (Basel). 2021, 14(5): 422).

In 2020, Bargh et al. used a sulfatase-based cleavable linker to develop a new class of ADCs. The sulfatase cleavable linker was highly soluble in water and showed high stability in human and mouse plasma. Moreover, this linker exhibited high reactivity within the lysosomes. In 2021, Bargh et al. used a new dual-enzyme cleavable linker susceptible to arylsulfatase A and β-galactosidase for developing ADCs. Within their studies, they employed a 3-O-sulfo-β-galactose linker to develop ADCs; this linker was sequentially cleaved by two different enzymes-arylsulfatase A and β-galactosidase to deliver the potent payload in targeted cells. These two functional groups, anionic sulfate and pyranose displayed high hydrophilicity that reduced the possibility of aggregation of ADC. Further, the 3-O-sulfo-galactose linked ADC showed excessive cytotoxicity for HER2-positive SKBR3 cells, which is comparable to arylsulfate ADC analog.

Research Applications

Sulfatase Cleavable Linkers

As glycosidases and (pyro) phosphatase-based linkers, sulfatase cleavable linkers display good hydrophilicity due to the nature of the substrate (permanently-charged sulfate) while being mainly expressed in the lysosome. Researchers have rationally designed linkers to assess cleavage rates in vitro before using MMAE as payload and anti-Her2 antibody. Compared to classical cleavable Val-Cit and Val-Ala linkers, sulfatase linkers show similar cellular potencies against Her2+ cell lines. In parallel to the academic comparison with standard linkers, sulfatase linkers have also recently attracted industrial attention for potential development.

Our Services

  • Sulfatase Cleavable Linker Design For Payload

The linkage between the linker and payload is an important part of maintaining the stability of ADC circulation in vivo. BOC Sciences is capable of developing complete service processes for customer-designed linker-toxin combinations. All our synthetic products will undergo multiple inspection processes to ensure that all provided products are of high purity and quality.

  • Sulfatase Cleavable Linker Design For Antibody

The attachment sites on antibodies are important when considering the design and assessment of ADCs, which could be attributed in larger impact to the chemical groups on linkers. In BOC Sciences, we provide custom-design services for ADC linkers. Our sulfatase cleavable linkers are designed with a wide range of chemical groups that can meet the needs of various antibody attachment sites. Furthermore, our one-stop service platform supports a wide range of antibody modification and conjugation services that fulfills your research needs.

  • Sulfatase Cleavable Linker Design For Target

When designing an ADC, the choice of target tumor-specific antigen is important. BOC Sciences' scientists can provide high-level linker design services based on customers' research targets. In addition to sulfatase cleavable linker, our enzymatically cleavable linker design services include cathepsin B cleavable linkers/peptide linkers, phosphatase cleavable linkers, β-glucuronidases cleavable linkers, and β-galactosidase cleavable linkers.

What Can We Do For You?

BOC Sciences provides high-quality custom synthesis of ADC linkers to our customers applying optimal synthetic routes and experimental conditions. We have established the most comprehensive ADC linker development service, including integrated linker design for dose scheme design and ADC efficacy. In addition, we also provide optimized linker design schemes to balance ADC stability and payload release kinetics to release payloads within tumor cells for optimal ADC efficacy.

Our Linker Development Workflow

Linker Development Workflow

References

  1. Owen, S.C. Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry. The AAPS Journal. 2015, 17(2): 339-351.
  2. Kotschy, A. et al. The chemistry behind ADCs. Pharmaceuticals (Basel). 2021, 14(5): 422.
  3. Spring, D.R. et al. Sulfatase-cleavable linkers for antibody-drug conjugates. Chem. Sci. 2020, 11: 2375-2380.
* Only for research. Not suitable for any diagnostic or therapeutic use.

Send Inquiry

Verification code
Inquiry Basket