Researchers release new method of synthesizing antibody drug coupling

Antibody drug conjugates (ADCs) is a class of drugs that have emerged in recent years. By covalently attaching a small molecule to a specific antibody and using recombinant human proteins, people can target the drug to the target region, thereby increasing the effective concentration of the drug in that region while avoiding the potential side effects of systemic administration.

However, ADC application also has its limitations. One of the biggest challenges is how to use a linker that can both stably attach drug molecules to the antibody and can completely release the drug molecules in the target area in certain circumstances in order to exercise its killing effect. In this process, we may encounter two problems: First, the hydrophilicity of drugs or joint molecules may lead to aggregation of ADC, which greatly affects its stability; the second is whether the effective combination of drug molecules and antibodies stand up.

Recently, scientists from Genentech and WuXi PharmaTech have designed a new linker that contains the p-aminophenyl quaternary ammonium salt (PABQ) component, which can be efficiently conjugated with tertiary amine or heterocyclic nitrogen of the drug molecule Antibody, and it can be released in time to play a pharmacological effects, while because the ammonium salt itself overcomes the hydrophobicity of the charge to overcome the problem. The results are published in the recent issue of the journal Nature. The PABQ linker can be released by proteolytic cleavage or disulfide bond cleavage to release drug molecules to suit different vectors or cell environments.

In the case of the release of drug molecules by proteolytic hydrolysis, the investigators chose a commercially available linker molecule as a starter with a maleimide group that reacts with the thiol group on the antibody molecule linked to the antibody; the ValCit dipeptide contains in the target cells can be protease degraded so that the drug molecules can be released. The bianhydroxyl group in the starting molecule becomes an ideal leaving group after reaction with thionyl chloride and covalently linked to it by reaction with a tertiary amine or heterocyclic nitrogen in the drug molecule. This synthesis method needs no protective groups, thus simplifying the steps, and with thionyl chloride generated by the reaction of intermediates to facilitate separation and purification to facilitate the next step with the drug molecules. The generated ADC thus can be degraded by lysosomes in the target cell, thereby releasing the drug intact.

In the case of disulfide bond cleavage using drug molecules, the pyridine thiol group in the linker molecule is replaced with an antibody molecule that also contains a thiol group, forming an ADC molecule assembled by a disulfide bond. When the ADC enters into the cell, it can react with the widespread existence of intracellular reductant glutathione reaction to break the disulfide bonds, which led to cyclization and 1,6-elimination reaction, finally releasing drug molecules.

The researchers found that the ADC prepared by the above method showed a remarkable killing effect on the human lymphoma and intracellular MRSA in mice, thus showing the potential of drug molecules that are difficult to be applied by ADC technology before.

The new connector technology, developed by GeneTek scientist Dr. Thomas H. Pillow, has greatly expanded the scope of ADC applications and provided valuable new insights into targeted therapy for cancer, bacterial or viral infections. Flarebio offers recombinant proteins of good quality such as recombinant Dpp4 at competitive prices.