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Fmoc-PEG3-Val-Cit是含有Fmoc保护的胺和可酶切的Val-Cit基团的PEG连接体。亲水性PEG间隔物增加了在水性介质中的溶解度。Fmoc基团可以在碱性条件下脱保护以获得可用于进一步偶联的游离胺。Val-Cit被溶酶体蛋白水解酶有效切割，同时在人类血浆中高度稳定，这使其成为ADC接头设计中的一个潜在缺陷。

Fmoc-PEG3-Val-Cit is a PEG linker containing an Fmoc-protected amine and enzymatically cleavable Val-Cit group. The hydrophilic PEG spacer increases solubility in aqueous media. The Fmoc group can be deprotected under basic condition to obtain the free amine which can be used for further conjugations. The Val-Cit is effectively cleaved by lysosomal proteolytic enzymes while being highly stable in human plasma, making this a potentent stragy in ADC linker design

ADC linkers的介绍

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.

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

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.

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

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.

Journal Reference:

Halford, "A new generation of antibody-drug conjugates for cancer patients", Chemical and Engineering News, vol 98, 14, (2020) https://cen.acs.org/biological-chemistry/cancer/new-generation-antibody-drug-conjugates/98/i14

Staudacher, Brown, "Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required?", Br J Cancer 117, (2017): 1736–1742, https://www.nature.com/articles/bjc2017367#citeas

Joubert, et al., "Antibody-Drug Conjugates: The Last Decade", Pharmaceuticals (Basel, Switzerland) vol 13,9, (2020): 245-276, https://pubmed.ncbi.nlm.nih.gov/32937862/