5 Available Linkers for Antibody Drug Conjugates

Consisting of a fulfilling monoclonal antibody, an active cytotoxic drug and a suitable linker, antibody-drug conjugates (ADCs) are regarded as an efficient and innovative therapy for targeted treatment of cancers and tumors. Owing to its unique benefits and brilliant performance, ADCs are also considered to be a ‘Magic Bullet’, the concept that German Nobel Laureate Paul Ehrlich came up with in the early 1900s to describe an ideal therapy for diseases. More detailedly, it refers to a drug that accurately targets to an invader and carries a destructive payload straight to the disease.

During the development of effective and safe antibody-drug conjugates, the generation of appropriate chemical linkers between the monoclonal antibody and the cytotoxic drug turns out to be a major difficulty for scientists due to a complex synthesis of linker chemistry. On the other hand, the design of adc linker is highly dependent on the target cells biology, the antibody characteristics and the molecule structure. With the development of ADCs introduced to clinical trials or approved by the FDA, a series of typical linkers have been exploited.

pH-sensitive linkers

pH-sensitive linkers are a class of chemically cleavable linkers that were firstly used in early ADC developments. For instance, hydrazonesand cis-Aconityl is one of the most widely used PH sensitive linker. A cis-aconityl linkage is often used to conjugate payloads such as doxorubicin (DOX) or daunomycin to the carbohydrate moiety of an antibody. Recently, pH-sensitive hydrazone linkers that covalently conjugate the payloads to antibody amino acid residues (e.g. Lys or Cys) have been developed and used in ADC preparation.

Disulfide linkers

Disulfide linkers (sometimes referred to as glutathione-sensitive linkers) are a family of chemically cleavable linkers that non-selectively release the payload drug when exposed to an altered chemical environment. In this case, the reduction potential in the tumor cells is higher than that of the circulating plasma. Disulfides are thermodynamically stable at physiological pH and are designed to release the conjugated payload drug when it is internalized into the tumor cells.

Peptide linkers

As one of protease-sensitivity linkers, peptide linkers have gained increasing attention in ADC development as a result of their excellent plasma stability and controlled payload release mechanism. A peptide linker generally consists of either a di-peptide or tetra-peptide, which is recognized and cleaved by lysosomal enzymes to ensure the intracelluar drug release once the ADC is internalized and trafficked to the lysozome. Meanwhile, additional components are added to the short peptide to facilitate antibody conjugation or drug release in its most "native" form, another feature that makes peptide linkers appealing choices for ADC applications.

?-Glucuronide Linker

The?-glucuronide linker has been used for antibody?drug conjugates (ADCs) to deliver amine-containing cytotoxic agents. By structure,?-glucuronide linkers incorporate a hydrophilic sugar group (?-glucuronic acid) into the linker moiety.

By design, the?-glucuronic acid-based linkers are developed as a novel class of linkers or as an extension of the peptide-based linker strategies to provide ADCs with high solubility and plasma stability. The linker is stable in circulation, hydrophilic and provides ADCs that are highly active in vitro and in vivo.

Non-cleavable Linker

Non-cleavable linkers are a novel class of new generation linkers with improved plasma stability compared to many cleavable linkers, which require mAb degradation within the lysosome after ADC internalization to release active drug. With this mechanism, differences between parent drug and potential ADC metabolites must be taken into consideration. Despite the limited "bystander" effect, the resistance to cleavage outside of target cells may actually increase the specificity of drug release.

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