Val-Cit-PAB-OH是一种肽可裂解的ADC Linker，用于合成抗体-药物偶联物（ADC）。Val-Cit将被组织蛋白酶B专门切割。
编号：407719
CAS号：159857-79-1
单字母：H2N-V-Cit-PABOH-OH
| 编号: | 407719 |
| 中文名称: | Peptide Linkers（ADC Linkers）：Val-Cit-PAB-OH |
| 英文名: | Val-Cit-PAB-OH |
| CAS号: | 159857-79-1 |
| 单字母: | H2N-V-Cit-PABOH-OH |
| 三字母: | H2N N端氨基 -Val缬氨酸 -Cit瓜氨酸 -Pro脯氨酸 -Ala丙氨酸 -Bip联苯丙氨酸Bip -Orn鸟氨酸 -His组氨酸 -OHC端羧基 |
| 氨基酸个数: | 7 |
| 分子式: | C45H64N12O9 |
| 平均分子量: | 917.06 |
| 精确分子量: | 916.49 |
| 等电点(PI): | - |
| pH=7.0时的净电荷数: | 1.21 |
| 平均亲水性: | -0.83333333333333 |
| 疏水性值: | 0.3 |
| 外观与性状: | 粉末状固体 |
| 消光系数: | - |
| 来源: | 人工化学合成，仅限科学研究使用，不得用于人体。 |
| 储存条件: | 负80℃至负20℃ |
| 标签: | 氨基酸衍生物肽 Peptide linkers (ADC Linkers) 二肽(Dipeptide) |
Val-Cit-PAB-OH是一种肽可裂解的ADC Linker，用于合成抗体-药物偶联物（ADC）。Val-Cit将被组织蛋白酶B专门切割。
Val-Cit-PAB-OH is a peptide cleavable ADC linker used in the synthesis of antibody-drug conjugates (ADCs). The Val-Cit will specifically be cleaved by Cathepsin B.
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/
