A new highly active antibody targeting HIV identified by: Henning Gül, Philipp Schommers and Florian Klein (left to right). © Uniklinik Köln/Thies Schöning
Currently, antiretroviral drugs are used for the treatment of HIV infection. They effectively inhibit the multiplication of the HIV virus, but require lifelong and daily administration, which can be accompanied by side effects. Due to the high mutability of HIV, a combination of several drugs is also necessary to prevent the development of drug resistance and therapy failure.
Broadly neutralizing antibodies targeting HIV
A possible new option for the treatment and prevention of HIV infection are broadly neutralizing antibodies representing a promising approach to prevent and treat HIV-1 infection. These differ fundamentally from antiretroviral drugs in their mode of action, as they attack the virus directly by binding specifically to its surface.
In animal models bNAbs targeting the HIV-1 envelope protein (Env) can prevent infection and broadly neutralizing antibodies have been demonstrated to suppress viraemia and delay viral rebound after interruption of antiretroviral therapy (ART) in HIV-1-infected individuals. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications.
In several clinical studies with the participation of Cologne researchers the potential of broadly neutralizing antibodies by reducing the viral load was demonstrated. However, comparable to antiretroviral drugs, the effect of individual antibodies was limited in time due to the development of viral resistance.
Identification of a highly potent antibody 1-18
In the current study, published in the renowned scientific journal Cell, the researchers describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 μg/mL). The antibody showed a great effect even at low concentrations and was active against 97 percent of the HIV variants tested. Of importance is, that 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape.
"1-18 is thus one of the best antibodies described so far that can neutralize HIV," explains Dr. Philipp Schommers, resident physician at the Department I for Internal Medicine and first author of the study.
In cooperation with colleagues from the California Institute of Technology (Pasadena, USA), the researchers were also able to elucidate the mode of action of antibody 1-18 in detail. The antibody binds and inactivates a particularly relevant surface structure of HIV on which the virus depends for infection and reproduction.
The Cologne virologists investigated the therapeutic effect of the newly discovered antibody 1-18 using a mouse model that enables HIV infection comparable to that of humans. In this model, other broadly neutralizing antibodies showed only short-term effects on the viral load in the blood, as rapid resistance development occurred. In contrast, treatment with 1-18 led to a reduction in the amount of virus in the blood, which persisted for the entire duration of therapy.
"These results make it clear that the development of resistance to the new antibody 1-18 is significantly more difficult compared to other antibodies," Henning Grüll, resident physician at the Institute of Virology and also first author of the current study.
"The broad activity of the new antibody 1-18 also makes it conceivable that it can be used in the form of a passive vaccination for the prevention of HIV infection," adds Florian Klein, head and senior author of the study. In clinical trials the newly discovered antibody 1-18 in clinical trials will be further investigated.
Original publication:
Philipp Schommers, Henning Gruell, Morgan Abernathy, My-Kim Tran, Adam Dingens, Harry Gristick, Christopher Barnes, Till Schoofs, Maike Schlotz, Kanika Vanshylla, Christoph Kreer, Daniela Weiland, Udo Holtick, Christof Scheid, Marks Valter, Marit van Gils, Rogier Sanders, Jörg Vehreschild, Oliver Cornely, Clara Lehmann, Gerd Fätkenheuer, Michael Seaman, Jesse Bloom, Pamela Bjorkman, Florian Klein:
Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody. Cell 30. Januar 2020, DOI: https://doi.org/10.1016/j.cell.2020.01.010
Press releases by:
University Hospital Cologne: https://www.uk-koeln.de/uniklinik-koeln/presse-mediathek/presse/details/hochwirksamer-hiv-antikoerper-unterdrueckt-resistenzentwicklung/
German Centre for Infection Research (DZIF): https://www.dzif.de/en/highly-active-hiv-antibody-restricts-development-viral-resistance
Scientific contact:
Univ.-Prof. Dr. Florian Klein
Director - Institute for Virology and associated with the Center for Molecular Medicine Cologne (CMMC)
University Hospital Cologne and Medical Faculty - University of Cologne
florian.klein[at]uk-koeln.de
https://klein-lab.de/
https://www.cmmc-uni-koeln.de/research/research-areas-projects/research-area-b/florian-klein-assoc-rg
CMMC news release:
Debora Grosskopf-Kroiher
Center for Molecular Medicine Cologne
debora.grosskopf-kroiher[at]uni-koeln.de
Copyright ©
Prof. Dr. med. Thomas Benzing
Chair of the CMMC
