The SARS-CoV-2 Variant B.1.1.5291 evolved rapidly in late November 2021 from the existing mutants sparking fear worldwide owing to its infamous immune escape from a varied class of neutralising antibodies. To assess the structural behaviour of Omicron-Receptor Binding Domain (RBD) upon interacting with cross-reactive CR3022 antibody, we investigated the computational approach of structural engagement in B.1.1529 RBD and wild-type RBD with CR3022 antibody. The current study investigates the interacting interface between the RBDs and CR3022 to decipher the key residues accompanying the potential mutational landscape of SARS-CoV-2 variants. We conducted in-silico docking followed by molecular dynamics simulation analysis to examine the dynamic behaviour of protein-protein interactions. Furthermore, the study unleashed possible interactions post energy decomposition analysis via MM-GBSA. Conclusively, the mutational landscape of RBD eases in designing and discovering the effective neutralisation accompanied by development of a universal vaccine.Communicated by Ramaswamy H. Sarma.

01 Feb 2024·Structure

Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain

Article

Author: Donofrio, Gina C ; Modjarrad, Kayvon ; Laing, Eric D ; Krebs, Shelly J ; Bai, Hongjun ; Zemil, Michelle ; de Val, Natalia ; Broder, Christopher C ; Dussupt, Vincent ; King, Jocelyn ; Wieczorek, Lindsay ; Loo, Yueh Ming ; Rajan, Saravanan ; Joyce, M Gordon ; Paquin-Proulx, Dominic ; Sankhala, Rajeshwer S ; Choe, Misook ; Yan, Lianying ; Gromowski, Gregory D ; Lal, Kerri G ; McTamney, Patrick M ; Michael, Nelson L ; Corbitt, Courtney ; Mendez-Rivera, Letzibeth ; Chang, William C ; Green, Ethan C ; Rolland, Morgane ; Rees, Phyllis A ; Esser, Mark T ; van Dyk, Dewald ; Soman, Sandrine ; Swafford, Isabella ; Currier, Jeffrey R ; Townsley, Samantha M ; Peterson, Caroline E ; Sterling, Spencer L ; Britton, Zachary ; Martinez, Elizabeth J ; Smith, Clayton ; Tran, Ursula ; Hajduczki, Agnes ; Jensen, Jaime L ; Kuklis, Caitlin ; Chen, Wei-Hung ; Polonis, Victoria R

Given the continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs), immunotherapeutics that target conserved epitopes on the spike (S) glycoprotein have therapeutic advantages. Here, we report the crystal structure of the SARS-CoV-2 S receptor-binding domain (RBD) at 1.95 Å and describe flexibility and distinct conformations of the angiotensin-converting enzyme 2 (ACE2)-binding site. We identify a set of SARS-CoV-2-reactive monoclonal antibodies (mAbs) with broad RBD cross-reactivity including SARS-CoV-2 Omicron subvariants, SARS-CoV-1, and other sarbecoviruses and determine the crystal structures of mAb-RBD complexes with Ab246 and CR3022 mAbs targeting the class IV site, WRAIR-2134, which binds the recently designated class V epitope, and WRAIR-2123, the class I ACE2-binding site. The broad reactivity of class IV and V mAbs to conserved regions of SARS-CoV-2 VoCs and other sarbecovirus provides a framework for long-term immunotherapeutic development strategies.

01 Jan 2024·Frontiers in immunology

Impact of mAb-FcRn affinity on IgG transcytosis across human well-differentiated airway epithelium.

Article

Author: Okuda, Kenichi ; Lai, Samuel K ; Wolf, Whitney ; Schaefer, Alison ; Card, Madison ; Zeitlin, Larry ; Whaley, Kevin ; Togami, Kohei ; Olson, Lucas C ; Pauly, Michael ; Pickles, Raymond J ; Shen, Limei

Effective treatment and immunoprophylaxis of viral respiratory infections with neutralizing monoclonal antibodies (mAbs) require maintaining inhibitory concentrations of mAbs at the airway surface. While engineered mAbs with increased affinity to the neonatal Fc receptor (FcRn) are increasingly employed, little is known how increased affinity of Fc to FcRn influences basal-to-apical transepithelial transport (transcytosis) of mAbs across the airway epithelium. To investigate this, we utilized a model of well-differentiated human airway epithelium (WD-HAE) that exhibited robust FcRn expression, and measured the transepithelial transport of a mAb against SARS-CoV-2 Spike protein (CR3022) with either wildtype IgG₁-Fc or Fc modified with YTE or LS mutations known to increase affinity for FcRn. Despite the marked differences in the affinity of these CR3022 variants for FcRn, we did not find substantial differences in basal-to-apical transport reflective of systemic dosing, or apical-to-basal transport reflective of inhaled dosing, compared to the transport of wildtype IgG₁-Fc. These results suggest increasing FcRn affinity may only have limited influence over transcytosis rates of systemically dosed mAbs across the human airway epithelium over short time scales. Over longer time scales, the elevated circulating levels of mAbs with greater FcRn affinity, due to more effective FcRn-mediated recycling, may better resupply mAb into the respiratory tract, leading to more effective extended immunoprophylaxis.

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Indication	Highest Phase	Country/Location	Organization	Date
COVID-19	Preclinical	US	The Ragon Institute of MGH MIT & Harvard	11 Jan 2021

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