β-Glucuronide Linkers

Taking advantage of enzymes in lysosome, enzymatically cleavable linkers including peptide linkers and β-glucuronide linkers are developed. With enriched experience in ADC development and linker technologies, Creative Biolabs has successfully generated numerous ADC constructs using β-Glucuronide linkers with best quality in a highly productive and cost-effective way. 

β-Glucuronide linkers
Figure: Drug release from ADC containing β-glucuronide linkers (Antibody-Drug Conjugates, 2013)

Besides peptide linkers, b-glucuronide linkers are another kind of enzymatically cleavable linkers. The β-glucuronic acid-based linker is developed in an extension of the peptide-based linker strategies to provide high ADC stability. Facile release of the active drug can be achieved through cleavage of the b-glucuronide glycosidic bond by the lysosomal enzyme b-glucuronidase (GUSB). GUSB is an important lysosomal enzyme involved in the degradation of glucuronate-containing glycosaminoglycan. GUSB is abundant in lysosomes and is overexpressed in some tumor types but has low activity outside cells. These features facilitate ADCs with β-Glucuronide linkers remain high stability in systemic circulation and selectively release intracellular active drugs through hydrolysis by β-glucuronidase. Furthermore, β-glucuronide is highly hydrophilic and it can circumvent the tendency of some ADCs, particularly those incorporating highly hydrophobic drugs, to undergo aggregation. β-Glucuronide linkers can be developed as complements to other cleavable linkers. And they have been employed to prepare ADCs composed of several drug classes, such as auristatins, camptothecin and doxorubicin analogues, CBI minor-groove binders, and psymberin. It is reported that glucuronide-linked conjugates show minimal aggregation and great efficacy, which indicates that β-glucuronide linkers are potent in ADC development. ADCs with β-Glucuronide linkage have been found to be highly stable in plasma, well tolerated at high doses, and efficacious both in vitro and in vivo.
With continued and intense researches, Creative Biolabs has ability to develop b-glucuronide linker system which can be a complementary alternative to peptide linkers. In concert with the numerous methods for bioconjugation to antibodies, the linker is an integral aspect for ADCs development. The selection of linker should depend on the application and conditions a given antibody is likely to encounter. Creative Biolabs provides customized-design services for b-glucuronide 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:

Jan Anderl, et al. Linker Technologies for Antibody–Drug Conjugates. Antibody-Drug Conjugates, 2013:85-86.
Jessica R, et al. Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry. AAPS J. 2015 Mar; 17(2):339-51. 
Scott Jeffrey. Beta-glucuronide-linker drug conjugates. Patent EP1912671 A2. 

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