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Multivalent nanobodies block SARS-CoV-2 infection

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An international group of scientists including CSSB Research Hotel’s Martin Hällberg (Karolinska Institutet) have identified a combination of nanobodies that not only block SARS-CoV-2 infection but also suppress the escape of viral mutations. These multivalent nanobodies could be used to develop additional therapeutic modalities against COVID-19. The findings were published in the renowned journal Science.


Nanobodies are simplified antibodies derived from the immunization of lamas or alpacas. Hällberg and his collaborators identified four neutralizing nanobodies that directly target the receptor binding domains (RBD) of the SARS-CoV-2 spike protein.  Using both X-ray crystallography and cryo-electron microscopy the scientist analyzed how each of the four nanobodies bonded to the RBDs. “The cryo-EM structures provided us a detailed molecular picture of how and where nanobodies bind to the spike protein’s RBDs,” explains Hällberg.

“The best nanobodies in this set lock all the spike’s RBDs into an upward conformation and this conformation appears to destabilise the spike”, explains Hällberg “furthermore, all these nanobodies prevent viral binding to the host cell receptor thus halting the spread of the infection”. Based upon the structural information, the scientists were able to develop a set of multivalent nanobodies, where two nanobodies are covalently coupled, that binds to two different parts of the SARS-CoV-2 spike protein. These combinations result in neutralization activities that are more than 100 times stronger than that of a single nanobody. Furthermore, the study also showed that these multivalent nanobodies prevent mutational escape of the virus.

Nanobodies are significantly easier and more cost effective to produce that antibody treatments making this multivalent nanobody combination a particularly attractive treatment option for those infected with SARS-CoV-2. DiosCURE Therapeutics, a spin-off of the University of Bonn, will test the nanobodies in clinical studies and hope to reach phase 4 trails in late 2021. “Even if we have several effective vaccines there will always be individuals who for medical reasons cannot be effectively vaccinated,” notes Hällberg “We need to develop more effective treatment for these individuals as well as for those who, vaccinated or not, still become infected and are in need of intensive care.”


Koenig PA, Das H, Liu H, Kümmerer BM, Gohr FN, Jenster LM, Schiffelers LDJ, Tesfamariam YM, Uchima M, Wuerth JD, Gatterdam K, Ruetalo N, Christensen MH, Fandrey CI, Normann S, Tödtmann JMP, Pritzl S, Hanke L, Boos J, Yuan M, Zhu X, Schmid-Burgk JL, Kato H, Schindler M, Wilson IA, Geyer M, Ludwig KU, Hällberg BM, Wu NC, Schmidt FI. (2021) Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape. 12:eabe6230. doi: 10.1126/science.abe6230. Epub ahead of print. PMID: 33436526.