Chimeric camel-human heavy chain antibodies protect mice from MERS-CoV infection
V. Stalin Raj1,2*, Nisreen M.A. Okba1, Javier Gutierrez-Alvarez3, Dubravka Drabek4, Brenda van Dieren5, W. Widagdo1, Mart M. Lamers1, Ivy Widjaja5, Raul Fernandez-Delgado2, Isabel Sola2, Albert Bensaid6, Marion P. Koopmans1, Joaquim Segalés7, Albert D.M.E. Osterhaus 8, Berend Jan Bosch5, Luis Enjuanes3, Bart L. Haagmans1* 1Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands; 2School of Biology, Indian Institute of Science Education and Research, Thiruvananthapuram, Kerala, India; 3Department of Molecular and Cell Biology, CNB-CSIC, Madrid, Spain; 4Department of Cell Biology, Erasmus Medical Center, Rotterdam, the Netherlands; 5Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands; 6Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus de la UAB, 08193 Bellaterra, Spain; 7UAB, CReSA (IRTA-UAB), Campus de la UAB, 08193 Bellaterra, Spain; 8Center for Infection Medicine and Zoonoses Research, University of Veterinary Medicine, Hannover, Germany
Middle East respiratory syndrome coronavirus (MERS-CoV) continues to cause outbreaks in humans as a result of spillover events from dromedaries. In contrast to humans, MERS-CoV exposed dromedaries develop only very mild infections and exceptionally potent virus neutralizing antibody responses. These strong antibody responses may be caused by affinity maturation as a result of repeated exposure to the virus or by the fact that dromedaries - apart from conventional antibodies - possess relatively unique, heavy-chain-only antibodies (HCAbs). These HCAbs are devoid of light chains and have long complementarity determining regions with unique epitope binding properties, allowing them to recognize and bind with high affinity to epitopes not recognized by conventional antibodies. Through direct cloning and expression of the variable heavy chains (VHHs) of HCAbs from the bone marrow of MERS-CoV infected dromedaries, we identified several MERS-CoV specific VHHs or nanobodies. In vitro, these VHHs efficiently blocked virus entry at picomolar concentrations. The selected VHHs bind with exceptionally high affinity to the receptor binding domain of the viral spike protein. Furthermore, camel/human chimeric HCAbs - composed of the camel VHH linked to a human Fc domain lacking the CH1 exon - had an extended half-life in the serum and protected mice against a lethal MERS-CoV challenge. HCAbs represent a promising alternative strategy to develop novel interventions not only for MERS-CoV but for other emerging pathogens as well.
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