The Significance of Hydrophilic Linkers in the Development of ADC
With the development of ADCs, hydrophilicity must be considered. Low hydrophilicity of the linker shows the following disadvantages[1-4]:
(1) low conjugate efficiency and DAR
(2) polymerization and sedimentation in human plasma
(3) off-target toxicity by nonspecific uptake
(4) undesirable pharmacokinetics by rapid elimination from plasma
Simmons et al. [5-8] studied MMAE-based ADCs with linkers containing 0, 4, 8, or 12 PEG units to investigate the relationship between off-target toxicity and hydrophilicity. In their tolerance experiments, all mice in the PEG0 ADC group died by the 5th day at a 20 mg/kg dose, while the PEG8 and PEG12 groups had a 100% survival rate after 28 days. Immunohistochemical (IHC) staining of mouse livers showed that PEG0-containing ADCs had nonspecific uptake and released a large quantity of MMAE after 2 hours at 10 mg/kg. It was therefore proven that the low dose tolerance of ADCs with low hydrophilicity was caused by nonspecific liver absorption. ADCs with PEG12 had slower plasma clearance (7.3 mL·kg/day) and longer plasma exposure than PEG0 ADCs (>46.3 mL·kg/day). Thus, ADCs with higher hydrophilicity improve pharmacokinetic parameters and reduce nonspecific uptake and off-target toxicity.
Incorporating PEG, sulfonate, phosphate, and other hydrophilic groups into linkers is a popular way to enhance ADC’s hydrophilicity. Currently, incorporating PEG into ADC linkers is very common practice. For instance, marketed drugs like Trodelvy® and Zynlonta® incorporate PEG.
ChemExpress Advantages
• As one of the earliest CDMO companies engaged in ADC payload & linker, ChemExpress has an ADC R&D team of over 230 professional scientists. We have supported ADC projects for over 800 clients and successfully assisted in more than 40 CMC projects.
• We offer a vast inventory of products, including 80+ payloads, 400+ linkers, and have experience in synthesizing over 1000+ linkers. Additionally, we provide a variety of hydrophilic linkers
• With R&D site and HPAPIs manufacturing plants meeting GLP/GMP requirement, we offer stable inventory of payloads and linkers to accelerate clients’ ADC projects from early-stage research to commercial production.
• Passed 1 US FDA inspection with zero 483 observations
• Passed 2 EU QP audits
If you have any requirements regarding ADC, in addition to the ADC payloads & linkers in stock, we can also support you with customized services to meet your needs for ADC projects. Feel free to contact us for further inquiries [email protected]
Reference
[1] Acta Pharmaceutica Sinica B, 2021, 12, 3889-3907
[2] Drug Metab Dispos, 2021, 42, 1914–1920
[3] Nat Biotechnol, 2015, 33, 733–735
[4] Bioconjug Chem, 2017, 28, 1371–1381
[5] Pharmacol Ther, 2018, 181, 126-142
[6] Blood, 2018, 10, 1094-1105
[7] Hebei Medicine, 2019, 37, 18-22
[8] Toxicol Appl Pharmacol, 2020, 392, 114932