Antibodies of the highest quality
Australian scientists from the Garvan Institute of Medical Research, working under the leadership of Dr. Daniel Christ, have overcome one of the most serious problems currently troubling the minds of specialists in the pharmaceutical industry. They have developed a method for producing large quantities of antibodies that meet strict requirements, ensuring the possibility of administration to patients and long-term storage. The secret of the method lies in specific mutations that increase the stability of antibody molecules.
To date, 30-50% of drugs developed by the pharmaceutical industry based on monoclonal antibodies are rejected by regulatory authorities as not meeting the requirements for quality control results. Until now, one of the main difficulties – the instability of antibody preparations – was solved in its own way in each specific case, which did not allow to eliminate the problem as a whole.
Antibodies are produced by immune cells to B-lymphocytes in response to the penetration of various infectious agents into the body, so their diversity is almost infinite.
Antibody molecules consist of light and heavy chains that contain constant (C) and variable (V) domains. The latter determine the specificity of the antibody, i.e. its ability to selectively bind to a specific antigen – a protein or a fragment of the pathogen protein. The shape of the variable domain of the antibody exactly corresponds to the shape of the antigen, which ensures their binding to each other according to the so-called "key-lock" principle.
Simultaneously with infinite variability, the structure of antibodies provides a very unstable level of stability. It happens quite often that very effective specific antibodies are simultaneously characterized by exceptionally low stability.
The antibodies included in the drugs experience additional stress due to conditions to which they were not adapted in the process of evolution. As a rule, the antibody preparation recovered from lyophilizate is a thick concentrated liquid intended for intravenous administration. In such conditions, antibody molecules can become entangled with each other or stick to the inner surface of the walls of the syringe or dropper tubes.
Researchers have developed a universal set of mutations affecting both light and heavy chains of antibody molecules. These mutations are manifested by replacing a number of surface amino acids of the antibody molecule with a glutamic or aspartic amino acid. Along with preserving the ability of variable domains to bind to antigens, these mutations provide an improvement in many indicators by which the stability of antibodies is assessed. Modified antibodies do not tangle and do not aggregate even with a significant increase in temperature.
The developed method is suitable for modifying the type of human antibodies traditionally used for the production of therapeutic drugs. Therefore, researchers believe that it will significantly improve the quality of future pharmaceutical developments. They are currently planning a collaboration with colleagues from the pharmaceutical industry dedicated to the development of monoclonal antibody drugs for the treatment of cancer and inflammatory diseases.
Article by Kip Dudgeon et al. The general strategy for the generation of human antibody variable domains with increased aggregation resistance is published in the journal Proceedings of the Academy of Science.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the Garvan Institute of Medical Research: Making biologically active yet stable antibodies.
29.06.2012