Chemically Cleavable Linkers

Based on the differential properties between the plasma and some cytoplasmic compartments, chemically labile linkers are designed and widely used in ADC development. With state-of-art equipments, advanced techniques and platforms, scientists and technicians from Creative Biolabs can perform dedicated custom-designed chemically cleavable linkers including acid-labile linkers and disulfide linkers to meet every client’s requirements in a highly productive and cost-effective way. 

Chemically cleavable linkers
Figure: Structure of ADCs using chemically cleavable linkers (Nat Biotechnol. 2005)

Chemically cleavable linkers are popular in the ADC clinical pipeline with acid-labile linkers, such as hydrazones, and disulfide linkers. Cleavable linkers take advantage of the antibody-drug conjugate targeting mechanism which involves sequential binding of the antibody-drug conjugate to its cognate antigen on the surface of the target cancer cells, and internalization of the ADC-antigen complexes through the endosomal-lysosomal pathway. For acid-labile linkers, such as hydrazone, intracellular release of the cytotoxic anticancer drug relies on the fact that endosomes/lysosomes are acidic compartments that will facilitate cleavage of chemical linkages and drug release, while in the blood’s neutral pH environment, the linkers can retain intact and stable. In addition, if a lysosomal-specific protease cleavage site is engineered into the linker, the cytotoxins will be liberated in proximity to their intracellular targets. Alternatively, the release of disulfide-linked drugs is controlled by the cytoplasmic thiol cofactors and intracellular enzyme protein disulfide isomerase, which are located only in intracellular environment. In this case, cytotoxic payloads can be liberated intracellularly as they are selectively cleaved in the reducing environment of the cell, but not in the oxygen-rich environment in the bloodstream. Although chemically labile linkers are often suffering from limited plasma stability which blocks ADC function, steric hindrance using substituents can be introduced near the linkage to improve the stability of chemically cleavable linkers.

Chemically cleavable linkers are developed in the early of ADC development and still used widely. Creative Biolabs provides different kinds of linkers to conjugate various payloads. While earlier cleavable linkers (hydrazones) have been associated with low serum stability, more recent cleavable linkers (hindered disulfides, peptide linkers) show higher stability in circulation resulting in lower nonspecific cell killing and reduced off-target toxicity. ADCs possessing cleavable linkers may be active against targets even when they are poorly internalized (passive diffusion) or effect killing of bystander antigen-negative cells present in the vicinity of the antigen-positive tumor cells (bystander effect). Therefore, although great advances have been made in the development of the linker technology for ADCs, there is no general guideline for linker selection. Creative Biolabs provides customized-design services for cleavable 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. Methods for Conjugating Antibodies to Nanocarriers. Antibody-Drug Conjugates, 2013:249-266.
Wu AM and Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005 Sep; 23(9):1137-46.

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