NH2-PEG3-Val-Cit-PAB-OH是一种可裂解的ADC连接体，具有伯胺、亲水性PEG间隔区、Val-Cit二肽和PAB基团。
编号：436830
CAS号：2055024-62-7
单字母：H2N-PEG3-CH2CH2CO-VCit-PAB-OH
| 编号: | 436830 |
| 中文名称: | H2N-PEG3-Val-Cit-PAB-OH |
| 英文名: | H2N-PEG3-Val-Cit-PAB-OH |
| CAS号: | 2055024-62-7 |
| 单字母: | H2N-PEG3-CH2CH2CO-VCit-PAB-OH |
| 三字母: | H2N 暂无说明 -PEG暂无说明 -PEG暂无说明 -PEG暂无说明 -CH2CH2COPEG丙酸形式 -Val缬氨酸 -Cit瓜氨酸 -PAB暂无说明 -OHC端羧基 |
| 氨基酸个数: | 5 |
| 分子式: | C27H46N6O8 |
| 平均分子量: | 582.69 |
| 精确分子量: | 582.34 |
| 标签: | 氨基酸衍生物肽 Peptide linkers (ADC Linkers) |
NH2-PEG3-Val-Cit-PAB-OH是一种可裂解的ADC连接体，具有伯胺、亲水性PEG间隔区、Val-Cit二肽和PAB基团。PAB上的苄醇可用于连接反应性基团，如PNP，以与药物有效载荷结合。伯胺可以自由地进行多种反应，例如与羧酸偶联、与酮或醛还原胺化，或其他更专业的用途，例如在SNAr反应或杂环化学中。Val-Cit二肽被细胞内的细胞蛋白酶切割，以允许通过PAB结构内的消除机制进行有效的有效载荷递送。
NH2-PEG3-Val-Cit-PAB-OH is a cleavable ADC linker featuring a primary amine, a hydrophilic PEG spacer, a Val-Cit dipeptide, and a PAB group. The benzylic alcohol on the PAB can be used to attach with reactive groups such as PNP for conjugation with drug payloads. The primary amine is free to perform a wide variety of reactions such as coupling with carboxylic acids, reductive aminations with ketones or aldehydes, or other more specialized uses such as in SNAr reactions or heterocyclic chemistry. The Val-Cit dipeptide is cleaved by cellular proteases within the cell to allow for efficient payload delivery via an elimination mechanism within the PAB structure.
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.
| Linker | Strategy | Mechanism | Advantages |
| Cleavable Linker | Peptides | Selectively cleaved by hydrolytic enzymes | Stability during circulation Hydrophilicity Traceless release of payload |
| Hydrazone | Acid-sensitive environments endosomal (pH = 5-6) lysosomal (pH = 4.8) | Intracellular release of payload | |
| Disulfide | Intracellular reducing molecules, such as glutathione | Intracellular release of payload | |
| Non-cleavable Linker | Stable linker without cleavage mechanism | Unknown mechanism of lysosomal cleavage | Stability 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
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/
