What are ADC Linkers?

What are ADC Linkers?

Published by BroadPharm on July 21, 2021

ADC linkers are one of the three main components of the antibody drug conjugates (ADC) that connect an antibody with a potent drug (payload) through a chemical bond.

Role of ADC Linkers

ADC linkers play key roles in determining the overall success of the Antibody Drug Conjugates. One of the main challenges in developing a safe and effective ADC drug (Figure 1) is the assembly of a desirable chemical linker between cytotoxic payload and mAb. A well-designed ADC linker can help the antibody to selectively deliver and accurately release the cytotoxic drug at tumor sites. It also plays critical roles in an ADCs' stability during preparation, storage, and systemic circulation. A stable ADC drug ensures that less cytotoxic payloads fall off before reaching tumor cells, increasing safety, and limiting dose.

There are two main categories of ADC linkers in current ADC drugs, cleavable linkers and non-cleavable linkers.

diagram of antibody drug conjugate linker
Figure 1. There are three major components of an ADC drug; the antibody used, the linker, and the payload to be delivered.

Cleavable linkers are designed to be stable in the bloodstream and then release the payload once in the cell. Cleavable linker types include enzymatically-cleavable peptide linkers, acid sensitive hydrazone linkers, and glutathione-sensitive disulfide linkers.

Example of Cleavable Linkers in ADC

diagram of adcetris
Figure 2. Adcetris with enzymatically cleavable val-cit linkage.

The non-cleavable linkers, such as SMCC, rely on lysosomal degradation within the cell to release the drug payload.

A summary of linker types is provided in Table 1.

Table 1. Linker type, mechanism and advantages of cleavable and non-cleavable linkers.
LinkerStrategyMechanismAdvantages
Cleavable LinkerPeptidesSelectively cleaved by hydrolytic enzymesStability during circulation Hydrophilicity Traceless release of payload
HydrazoneAcid-sensitive environments endosomal (pH = 5-6) lysosomal (pH = 4.8)Intracellular release of payload
DisulfideIntracellular reducing molecules, such as glutathioneIntracellular release of payload
Non-cleavable LinkerStable linker without cleavage mechanismUnknown mechanism of lysosomal cleavageStability during circulation

An interesting part of the ongoing discussion about linker stability is whether the payload can or should be released into the area outside of the tumor cell. This effect, referred to as the ‘bystander effect’, is seen by some as a beneficial attribute for an ADC to display. However, recent studies indicate that, depending on the linker and payload combination, this mechanism may not be essential, and ADCs can be cleaved extracellularly or via other mechanisms.

PEG Increases the Solubility of ADC Linkers

The solubility of the linker is another parameter that has been explored using Monodispered PEG chains. Two of the latest ADCs to be approved, Trodelvy and Zynlonta, were developed with PEG moiety as part of their linker technology to improve solubility and stability in vivo. 

Example of ADC Linkers with PEG Chain

diagram of antibody drug conjugate linker as well as a description
Figure 3. Zynlonta, shown above, has several unique features including a maleimide group for attachment to the mAbs, a PEG8 linker for solubility, and a cleavable Val-Ala section bound to the drug SG3199.

BroadPharm, a leading supplier of ADC Linkers

BroadPharm offers a wide array of different ADC Linkers, PEG Linkers to empower our customer’s advanced research worldwide. These compounds feature great aqueous solubility, smart choice of PEG length, and a broad selection of functional groups to choose from.