TY - JOUR
T1 - Insights into the Mechanism of Action of Highly Diluted Biologics
AU - Tarasov, Sergey A.
AU - Gorbunov, Evgeniy A.
AU - Don, Elena S.
AU - Emelyanova, Alexandra G.
AU - Kovalchuk, Alexander L.
AU - Yanamala, Naveena
AU - Schleker, A. Sylvia S.
AU - Klein-Seetharaman, Judith
AU - Groenestein, Reno
AU - Tafani, Jean Pierre
AU - Van Der Meide, Peter
AU - Epstein, Oleg I.
N1 - Funding Information:
This work was supported by OOO “NPF “Materia Medica Holding,” Moscow, Russian Federation.
Publisher Copyright:
Copyright © 2020 by The American Association of Immunologists, Inc.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - The therapeutic use of Abs in cancer, autoimmunity, transplantation, and other fields is among the major biopharmaceutical advances of the 20th century. Broader use of Ab-based drugs is constrained because of their high production costs and frequent side effects. One promising approach to overcome these limitations is the use of highly diluted Abs, which are produced by gradual reduction of an Ab concentration to an extremely low level. This technology was used to create a group of drugs for the treatment of various diseases, depending on the specificity of the used Abs. Highly diluted Abs to IFN-g (HD-anti-IFN-g) have been demonstrated to be efficacious against influenza and other respiratory infections in a variety of preclinical and clinical studies. In the current study, we provide evidence for a possible mechanism of action of HD-anti-IFN-g. Using high-resolution solution nuclear magnetic resonance spectroscopy, we show that the drug induced conformational changes in the IFN-g molecule. Chemical shift changes occurred in the amino acids located primarily at the dimer interface and at the C-terminal region of IFN-g. These molecular changes could be crucial for the function of the protein, as evidenced by an observed HD-anti-IFN-g-induced increase in the specific binding of IFN-g to its receptor in U937 cells, enhanced induced production of IFN-g in human PBMC culture, and increased survival of influenza A-infected mice.
AB - The therapeutic use of Abs in cancer, autoimmunity, transplantation, and other fields is among the major biopharmaceutical advances of the 20th century. Broader use of Ab-based drugs is constrained because of their high production costs and frequent side effects. One promising approach to overcome these limitations is the use of highly diluted Abs, which are produced by gradual reduction of an Ab concentration to an extremely low level. This technology was used to create a group of drugs for the treatment of various diseases, depending on the specificity of the used Abs. Highly diluted Abs to IFN-g (HD-anti-IFN-g) have been demonstrated to be efficacious against influenza and other respiratory infections in a variety of preclinical and clinical studies. In the current study, we provide evidence for a possible mechanism of action of HD-anti-IFN-g. Using high-resolution solution nuclear magnetic resonance spectroscopy, we show that the drug induced conformational changes in the IFN-g molecule. Chemical shift changes occurred in the amino acids located primarily at the dimer interface and at the C-terminal region of IFN-g. These molecular changes could be crucial for the function of the protein, as evidenced by an observed HD-anti-IFN-g-induced increase in the specific binding of IFN-g to its receptor in U937 cells, enhanced induced production of IFN-g in human PBMC culture, and increased survival of influenza A-infected mice.
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U2 - 10.4049/jimmunol.2000098
DO - 10.4049/jimmunol.2000098
M3 - Article
C2 - 32727888
AN - SCOPUS:85090074884
SN - 0022-1767
VL - 205
SP - 1345
EP - 1354
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -