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Vipivotide tetraxetan Ligand-Linker Conjugate (PSMA-617 Ligand-Linker Conjugate) is a complex composed of pharmacophore group Glutamate-urea-Lysine peptide coupling linker, which can be used to synthesize Vipivotide tetraxetan (PSMA-617). Glutamate-urea-Lysine selectively binds to prostate-specific membrane antigen (PSMA)

Vipivotide tetraxetan Ligand-Linker Conjugate (PSMA-617 Ligand-Linker Conjugate) 是药效基团 Glutamate-urea-Lysine 肽偶联连接子组成的复合物，可用于合成 Vipivotide tetraxetan (PSMA-617)。Glutamate-urea-Lysine 可以与前列腺特异性膜抗原 (PSMA) 选择性结合。

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/

前列腺特异性膜抗原（prostate-specificmembraneantigen，PSMA）是存在于前列腺细胞膜的一种多功能的Ⅱ型跨膜蛋白，由750个氨基酸残基组成。PSMA具有较高的前列腺组织特异性，在区分前列腺癌和其他类型恶性肿瘤的敏感度和特异性分别是65.9%和94.5%，因此PSMA仍然是前列腺癌细胞上一个相当敏感的、高度特异性的抗原物质。PSMA在前列腺组织良、恶性鉴别中优于PSA，且临床分期越晚，其表达越强，与肿瘤恶性程度成正相关。因此PSMA是较PSA更具特异性的前列腺癌瘤标志物，可作为前列腺癌预后评估的重要指标。