Long-lived antibodies increase the effectiveness of anti-cancer drugs
Monoclonal antibodies: they lived long and effectivelyElena Novoselova, STRF
One of the problems of using monoclonal antibodies (MAT) in therapy is their short life span in mammalian cells.
The strategy of many laboratories of biotech companies is aimed at developing a new type of MAT with an extended life span, and some of them have achieved success and licensed the results of their research.
Antibodies usually have two variable Fab sites (fragment antigen binding, antigen-binding fragment) and one stable Fc fragment (fragment crystallizable, fragment capable of crystallization). Fab sites selectively bind to the antigen, and Fc fragments bind to effector cells of the immune system.
An example of successful work in the direction of prolonging the "life" of the MAT can be the research of the biotechnology company Xencor Inc., in which it was proved that a certain mutation in the Fc fragment region contributes to an increase in the stability in vivo of tumor-oriented mats obtained in mammalian cells.
The relatively short period of the "life" of the MAT introduced into the cell is the result of internalization (like endocytosis) and degradation of circulating antibodies by vascular endothelial cells. This process occurs naturally and is part of the body's biological response to the appearance of unnecessary protein in the serum.
The antagonist of the internalization process is the Fc receptor (or rather, the Fc fragment of the IgG immunoglobulin, FcRn). The binding of IgG to FcRn receptors protects it from cellular metabolism. The Xencor team has created a mutant form of the Fc domain with a high affinity for FcRn receptors.
The MAT with modified Fc domains was integrated into anticancer drugs based on Erbitux monoclonal antibodies (for the treatment of colon cancer, manufactured by Merck KGaA, Eli Lilly, Bristol-Myers Squibb) and Avastin (created by Genentech and Roche for the treatment of rectal, lung, breast and kidney cancer).
Monkeys who took a modified form of drugs had a longer presence of the active substance compared to the basic MAT. In experiments on xenograft mice (experimental oncological models using human tumors vaccinated in mice), it was proved that the longer monoclonal antibodies were present in the body, the more noticeably the tumor volume decreased.
The results of the work are published in Nature Biotechnology: Jonathan Zalevsky et al., Enhanced antibody half-life improves in vivo activityPortal "Eternal youth" http://vechnayamolodost.ru