PEG Linkers for Antibody Drug Conjugates

Antibody-drug conjugate (ADC) is one of the fastest growing fields in tumor therapy, which consists of monoclonal antibody (Antibody), linker (Linker) and active drug (Payload). So far, there are only 15 drugs on the market in the world. However, with the development of some perfect antibody modification techniques, advanced site-specific coupling techniques and powerful small-molecule toxins, ADC drug research has mushroomed and a large number of ADC drugs are in clinical trials.

Choosing the most suitable linker is crucial to the ADC development process. The idea of antibody-drug conjugates comes from the "magic bullet" theory proposed by Paul Ehrlich in 1908. The real ADC was not approved for marketing by the US FDA until 2000, that is, Wyeth's gemtuzumab, in which the antibody is a recombinant humanized CD33 monoclonal antibody conjugated with the cytotoxin calicheamicin for the treatment of acute myeloid leukemia. However, through a large number of clinical studies, it was found that it could not improve the survival rate of patients, and had extremely serious side effects, so it was withdrawn from the market in 2010. The first-generation ADC drugs are not strong in targeting tumors, and their localization rate is low. One of the reasons for the failure of Gemtuzumab was that the linker used at that time was chemically unstable, and it was easily hydrolyzed when it did not reach the target, so that the drug was more toxic. As the first generation of ADC, it is also a major breakthrough of ADC. The lessons of its success and failure will affect the development of ADC later, especially for the selection of linker.

A suitable linker helps maintain the stability between the antibody and the drug and helps the antibody selectively deliver the drug to tumor cells and release the drug accurately. PEG is one of the most widely used linkers in targeted therapy. PEG linker has the characteristics of high usage rate, strong targeting, and pH adjustment. On the one hand, drug molecules generally have poor water solubility, adding PEG to the linker structure can increase the water solubility of the entire molecule. On the other hand, an important indicator DAR needs to be considered, that is, the number of drug molecules that can be carried on a unit amount of antibody. PEG can appropriately increase the DAR value, so that the ADC drug can improve the drug efficacy on the basis of low toxicity. In addition, it can also increase the circulating half-life of ADC.

In May 2021, China's CFDA approved goxatuzumab (Trodelvy®, sacituzumab govitecan-hziy) for the treatment of unresectable metastatic disease who have previously received at least 2 systemic therapies or at least 1 of them. Adult patients with locally advanced or metastatic triple-negative breast cancer (mTNBC). The drug was conjugated to the cytotoxic drug SN-38, an active metabolite of irinotecan, via a cleavable maleimide linker with a short PEGylated unit.

Biochempeg is dedicated to provide a chemical synthesis and high-quality PEG linkers. We are committed to promoting the progress of your ADC discovery and development projects. Some featured PEG linkers for ADC from Biopharma PEG as below.

NH2-PEG24-COOH, CAS No.: 196936-04-6

2-((Azido-PEG8-carbamoyl)methoxy)acetic acid, CAS No.: 846549-37-9

Mal-NH-PEG8-COOH, CAS No.: 1334177-86-4

N3-PEG3-SPA, CAS NO.: 1245718-89-1

mPEG36-NH2, CAS NO.: 32130-27-1

OH-PEG8-OH, CAS NO.: 5117-19-1

OH-PEG9-OH, CAS NO.: 3386-18-3

Fmoc-NH-PEG12-COOH, CAS NO.: 1952360-91-6


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