1. Directional coupling technology
The ADC drugs currently in the forefront of the development all use traditional conjugation technology (no-specific conjugation). The biggest disadvantage is that the product obtained is a mixture of different numbers of drug molecules per antibody); Combined drugs, more importantly, it is difficult to obtain uniform data (eg, PK) for clinical evaluation. In view of these shortcomings, directional coupling technology has become a hot spot pursued by major companies. Using directional conjugation technology, each antibody can carry the same number of drug molecules to obtain a homogeneous ADC drug. Facilitate the study and evaluation of pharmacodynamics. And more stable and effective effect can be obtained in clinical practice. Among them, the UnaturalAminoacid (pAcPhe) technology of Ambrx is more promising for application and promotion.
2. Multivalent conjugated ADC drugs
The development process of antibody drugs and vaccines is from monovalent drugs to multivalent drugs. ADC should also follow this development process, that is, linking several synergistic small molecules in the same antibody to improve the efficacy of the drug. This requires a more complete even-chain technology, or even the integrated use of two or more technologies. But now, in Site-specific technology, the coupling of a specific number of molecules at a specific site is excessively pursued, ignoring the diversity of coupling.
The use of traditional technology for multivalent drug conjugation requires simultaneous conjugation of multiple drugs on one antibody. At this time, the singleness of the modified linking group of the antibody itself will result in mixed products, and it is impossible to ensure that each antibody can carry different drugs at the same time.
This problem can be solved by site-specific technology. When performing site-specific modification, a variety of different coupling groups can be designed, which can use one group to target the linker with the corresponding group for drug coupling link. Finally, through the diversification of linker, the linking of multiple drugs is carried out to realize multivalent conjugated ADC drugs.
Monoclonal antibodies and their conjugates are macromolecular substances. It is difficult for bulky drug molecules to penetrate the capillary endothelial layer and through the tumor extracellular space to reach the deep part of solid tumors. The use of antibody fragments, such as Fab and Fab’, to prepare conjugates with smaller molecular weights may improve the penetration into the extracellular space and increase the amount of drugs reaching deep tumor cells. “Miniaturization or modest miniaturization is an important way to develop ADC drugs.”
