Phosphatase cleavable linkers have emerged as an effective antibody-drug conjugate (ADC) linker type due to their high stability in blood and high reactivity in the lysosomal environment. BOC Sciences aims to provide our global clients with phosphatase cleavable linker design services and support related research. As a pioneering service provider in ADC drug discovery and research, BOC Sciences is competent and devoted to one-stop linker development services.
Phosphatase-cleavable linkers belong to another vital class of enzyme-cleavable linkers expressed to target enzymes in the lysosomal compartment exclusively. This linker targets pyrophosphatase and acid phosphatase enzymes then hydrolyze pyrophosphates and terminal monophosphates into the respective alcohols. Kern et al. reported the usefulness of a phosphate-bridged cathepsin B-sensitive linker in delivering glucocorticoids to tumor cells. Since then, the phosphatase-cleavable linkers system has increased its use as ADC payloads by exploiting the attachment via the aliphatic alcohol. Moreover, in vitro study of ADCs containing this linker revealed high blood stability, rapid lysosomal cleavage, and aqueous solubility.
Fig. 1. The mechanism of ADC containing pyrophosphate is released (Pharmaceutics 2022, 14, 396).
Like cathepsins, pyrophosphatases and phosphatases are hydrolases exhibiting selective expression in the lysosome. Phosphatases are of interest in pharmaceutical research because of their importance in cellular signaling and activity regulation. The pyrophosphate linker is highly soluble in water, which facilitates the aqueous bioconjugation to antibodies and reduces the aggregation possibility of ADC. While these properties support the applicability of this linker in bioconjugation and ADCs containing lipophilic payloads, there is no in vivo validation.
In 2016, researchers designed phosphate and pyrophosphate-containing linkers coupled with the well-established, cathepsin B sensitive, Val-Cit-PABA moiety aiming to deliver glucocorticoids. The phosphate/pyrophosphate moiety is incorporated between the self-immolative spacer PABA and the payload. After internalization, the payload may be released via an original sequence involving cathepsin B, self-immolation, and phosphatase. Furthermore, researchers also developed a unique pyrophosphatase-based linker applied in anti-CD70 ADCs releasing hydroxyl-containing payloads dexamethasone and fluticasone propionate. Both ADCs exhibit good in vitro mouse and human plasma stability over seven days and strong activity against CD70 cell lines.
For ADCs conjugated to phosphatase cleavable linkers, the hydroxyl-containing attachment point's nature is crucial for efficient release. Based on this, BOC Sciences is capable of designing phosphatase cleavable linkers for specific payload or attachment points to accelerate clients' new drug development programs. Our ADC development process involves target validation, process characterization, preclinical efficacy, and safety evaluation.
Choice of linkers is also one of the biggest challenges in ADC drug development. BOC Sciences provides customized phosphatase cleavable linker design services for specific antibodies. Furthermore, our one-stop service platform supports a wide range of antibody modifications and conjugation services to meet your research needs.
As a leading ADC service and product supplier, BOC Sciences is committed to linker development for specific targets, such as CD33, CD30, CD22, HER2, TROP-2, etc. We possessed the most advanced equipment and unique R&D expertise to provide personalized linker development services promptly. Moreover, we monitored our products according to strict quality control standards during development and optimization processes to ensure first-class services and products.
BOC Sciences is committed to the development of cutting-edge ADC technology. We have established the most comprehensive ADC linker development service, including integrated linker design for dose scheme design and ADC efficacy. BOC Sciences is capable of helping our customers to identify the most suitable dosage that achieves the highest curative effect and minimal toxicity. Furthermore, we also provide optimized linker design schemes to balance ADC stability and payload release kinetics, so that payload release within tumor cells reaches its highest therapeutic threshold.