Neutralizing antibodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are among the most promising approaches against COVID-191,2. A bispecific IgG1-like molecule (CoV-X2) has been developed on the basis of C121 and C135, two antibodies derived from donors who had recovered from COVID-193. Here we show that CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable spike binding to the cellular receptor of the virus, angiotensin-converting enzyme 2 (ACE2). Furthermore, CoV-X2 neutralizes wild-type SARS-CoV-2 and its variants of concern, as well as escape mutants generated by the parental monoclonal antibodies. We also found that in a mouse model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, the simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, and combines the advantages of antibody cocktails with those of single-molecule approaches.

• MeSH
• angiotensin-konvertující enzym 2 antagonisté a inhibitory   genetika   metabolismus   MeSH
• COVID-19 imunologie   prevence a kontrola   virologie   MeSH
• Dependovirus genetika   MeSH
• epitopy B-lymfocytární chemie   imunologie   MeSH
• farmakoterapie COVID-19 MeSH
• glykoprotein S, koronavirus antagonisté a inhibitory   chemie   imunologie   MeSH
• imunitní únik genetika   MeSH
• imunoglobulin G imunologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• monoklonální protilátky imunologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neutralizující protilátky imunologie   terapeutické užití   MeSH
• protilátky bispecifické imunologie   terapeutické užití   MeSH
• SARS-CoV-2 genetika   imunologie   MeSH
• tělesná hmotnost MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Peptides presented on major histocompatibility (MHC) class I molecules form an essential part of the immune system's capacity to detect virus-infected or transformed cells. Earlier works have shown that pioneer translation peptides (PTPs) for the MHC class I pathway are as efficiently produced from introns as from exons, or from mRNAs targeted for the nonsense-mediated decay pathway. The production of PTPs is a target for viral immune evasion but the underlying molecular mechanisms that govern this non-canonical translation are unknown. Here, we have used different approaches to show how events taking place on the nascent transcript control the synthesis of PTPs and full-length proteins. By controlling the subcellular interaction between the G-quadruplex structure (G4) of a gly-ala encoding mRNA and nucleolin (NCL) and by interfering with mRNA maturation using multiple approaches, we demonstrate that antigenic peptides derive from a nuclear non-canonical translation event that is independently regulated from the synthesis of full-length proteins. Moreover, we show that G4 are exploited to control mRNA localization and translation by distinguishable mechanisms that are targets for viral immune evasion.

• MeSH
• antigeny genetika   imunologie   MeSH
• buněčné jádro genetika   imunologie   MeSH
• G-kvadruplexy MeSH
• imunitní únik genetika   imunologie   MeSH
• lidé MeSH
• messenger RNA genetika   imunologie   MeSH
• MHC antigeny I. třídy genetika   imunologie   MeSH
• nonsense mediated mRNA decay genetika   imunologie   MeSH
• peptidy genetika   imunologie   MeSH
• proteosyntéza genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH