β-Galactosidase Cleavable Linkers

β-Galactosidase Cleavable Linkers

β-Galactosidase is overexpressed in certain tumors and hydrolyze β-galactosidase cleavable linker in the lysosome. BOC Sciences provides an integrated biological platform with antibody-drug conjugate (ADC) linkers development and manufacturing capabilities to support from preclinical to commercial stages. We can support and guide you in developing the testable candidate matrix, thus discovering ideal ADCs for your patients.

Introduction

Glycosidase-cleavable linkers are another commonly used enzyme category exploited in ADC development. These hydrolytic enzymes are typically confined to lysosomal compartments, but like cathepsin B, they can be secreted by tumor cells in necrotic areas. β-Glucuronidase and β-galactosidase cleavable linkers are the most used type of glycosidase-cleavable chemistry currently in use. Similar to β-glucuronidase, β-galactosidase is overexpressed in certain tumor types. Mechanistically, β-galactosidase is analogous to β-glucuronidase in its hydrolytic activity but instead hydrolyses β-galactoside. Researchers found that this type of linker, when used with trastuzumab and MMAE, was more potent than the Val-Cit-PABC analog. Furthermore, this linker-payload combination was more efficient than the previously approved drug trastuzumab emtansine (T-DM1) for treating HER2+ mammary tumors in mice.

The mechanism by which an ADC containing β-glycosidic  is released Fig. 1. The mechanism by which an ADC containing β-glycosidic is released (Pharmaceutics 2022, 14, 396).

Recently, the use of β-galactosidase cleavable linkers for ADCs was reported incorporating a PEG10 spacer. In terms, the spacer was substituted by a nitro group in order to increase the rate of self-immolation. By the analogy of β-glucuronidase linkers, the cleavage mechanism involves the hydrolysis of the β-galactosidase moiety, which confers hydrophilicity to the chemical precursor. Another advantage is that the β-galactosidase enzyme is present only in the lysosome, whereas β-glucuronidase is expressed in lysosomes and also in the microenvironment of solid tumors.

Research Applications

β-Galactosidase Cleavable Linkers

β-Galactosidase is another class of hydrolytic lysosomal enzymes, which degrades the β-glycosidic linkage formed between galactose and its organic moiety. Kolodych and coworkers recently described the in vitro and in vivo activities of β-galactosidase cleavable ADCs, and this study revealed that galactosidase-based drug conjugates have greater therapeutic efficacy in isolated mouse plasma than the approved trastuzumab emtansine used to treat breast cancer.

Our Services

  • β-Galactosidase Cleavable Linker Design For Payload

BOC Sciences has recruited small molecule drug development experts committed to developing β-galactosidase cleavable linkers for various payloads, from Auristatin, Calicheamicins, Daunorubicins/Doxorubicins to Duocarmycins and more. We provide optimized linker design schemes to balance ADC stability and payload release kinetics so that the payload release within tumor cells reaches its highest therapeutic threshold.

  • β-Galactosidase Cleavable Linker Design For Antibody

BOC Sciences has designed and developed a series of novel methods for the design, synthesis, purification, and analysis of ADC linkers for human antibodies. We are confident in becoming your essential research assistant in the field of β-galactosidase cleavable linkers. Furthermore, our one-stop service platform supports a wide range of antibody modification and conjugation services to meet your research needs.

  • β-Galactosidase Cleavable Linker Design For Target

With expertise in bioconjugation, we offer tailor-made β-galactosidase cleavable linker design and synthesis to our institutional and industrial customers. We are committed to linker development for specific targets, such as CD33, CD30, CD22, HER2 and TROP-2, etc. Our strong expertise in process development, characterization, optimization, and scale-up can support successful GMP manufacturing and productive long-term cooperative relationships with pharmaceutical companies, institutions, and universities.

What Can We Do For You?

BOC Sciences provides comprehensive solutions involving conjugation site selection and linker modification to enhance ADC stability, such as adjusting conjugation sites point, linker length, and linker steric hindrance. We provide optimized linker design schemes to balance ADC stability and payload release kinetics to release the payload 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. Zhang, G. et al. Linkers having a crucial role in antibody-drug conjugates. Int. J. Mol. Sci. 2016, 17: 561.
  4. Albericio, F. et al. Linkers: an assurance for controlled delivery of antibody-drug conjugate. Pharmaceutics. 2022, 14: 396.
* Only for research. Not suitable for any diagnostic or therapeutic use.

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