Engineering SARS-CoV-2 neutralizing antibodies for increased potency and reduced viral escape pathways

Zhao, Fangzhu; Keating, Celina; Ozorowski, Gabriel; Shaabani, Namir; Francino-Urdániz, Irene M.; Barman, Shawn; Limbo, Oliver; Burns, Alison; Zhou, Panpan; Ricciardi, Michael J.; Woehl, Jordan L.; Tran, Quoc; Turner, Hannah L.; Peng, Linghang; Huang, Deli; Nemazee, David; Andrabi, Raiees; Sok, Devin; Teijaro, John R.; Whitehead, Timothy A.; Ward, Andrew B.; Burton, Dennis R.; Jardine, Joseph G.

doi:10.1016/j.isci.2022.104914

Cited by 7 publications

(3 citation statements)

References 72 publications

(94 reference statements)

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“…The engineering of already discovered antibodies can be used to improve their performance, including their neutralizing potency and breadth. One approach is to construct libraries containing a large number of different V h /V l sequences by phage or yeast display methods to yield antibodies with better performance 89 – 92 . Another approach is to try different formats of antibodies, such as nanobodies.…”

Section: Discussionmentioning

confidence: 99%

Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogenic human coronavirus that belongs to the sarbecovirus lineage of the genus Betacoronavirus. The ancestor strain has evolved into a number of variants of concern, with the Omicron variant of concern now having many distinct sublineages. The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use. Many are in preclinical and clinical development, and a few have been approved for emergency use. Here we summarize neutralizing antibodies that target four key regions within the SARS-CoV-2 spike (S) protein, namely the N-terminal domain and the receptor-binding domain in the S1 subunit, and the stem helix region and the fusion peptide region in the S2 subunit. Understanding the characteristics of these broadly neutralizing antibodies will accelerate the development of new antibody therapeutics and provide guidance for the rational design of next-generation vaccines.

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Section: Discussionmentioning

confidence: 99%

Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

et al. 2022

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“…( A ) Neutralization of SARS-CoV-2 PSVs by LM18-based bsNb 4 -Igs, LM18-Nb 4 -Ig, and Nb-C2/Nb-C4 bsNb 4 -Igs. IC 50 values of clinical antibody candidates (LY-CoV16, REGN10933, and REGN-10987), CC12.1, and CC6.30 from our previous study ( 35 ) were added for reference. ( B ) Neutralization of omicron PSV by LM18- or Nb-C2-136-based bsNb 4 Igs.…”

Section: Resultsmentioning

confidence: 99%

Fully synthetic platform to rapidly generate tetravalent bispecific nanobody–based immunoglobulins

Misson Mindrebo,

Liu,

Ozorowski

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Nanobodies bind a target antigen with a kinetic profile similar to a conventional antibody, but exist as a single heavy chain domain that can be readily multimerized to engage antigen via multiple interactions. Presently, most nanobodies are produced by immunizing camelids; however, platforms for animal-free production are growing in popularity. Here, we describe the development of a fully synthetic nanobody library based on an engineered human V H 3-23 variable gene and a multispecific antibody-like format designed for biparatopic target engagement. To validate our library, we selected nanobodies against the SARS-CoV-2 receptor–binding domain and employed an on-yeast epitope binning strategy to rapidly map the specificities of the selected nanobodies. We then generated antibody-like molecules by replacing the V H and V L domains of a conventional antibody with two different nanobodies, designed as a molecular clamp to engage the receptor-binding domain biparatopically. The resulting bispecific tetra-nanobody immunoglobulins neutralized diverse SARS-CoV-2 variants with potencies similar to antibodies isolated from convalescent donors. Subsequent biochemical analyses confirmed the accuracy of the on-yeast epitope binning and structures of both individual nanobodies, and a tetra-nanobody immunoglobulin revealed that the intended mode of interaction had been achieved. This overall workflow is applicable to nearly any protein target and provides a blueprint for a modular workflow for the development of multispecific molecules.

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“…Based on this post-relaxation structure, two parallel 500 ns MD simulations were performed for each of the three complexes of the WT (TMEM106B–WT) and variants (TMEM106B–BA.2.86/EG.5.1) to obtain equilibrium trajectories for subsequent energy and confirmation analysis. The molecular mechanics/generalized Born surface area (MM/GBSA) method was employed to assess the binding affinity and the individual energy terms of the three complexes, , while the alanine scanning (AS) mutagenesis method was utilized to identify the effect of mutations on the affinity contribution of binding interface residues. , In addition, we further dissected the structure–dynamics characterization of WT/BA.2.86/EG.5.1 RBDs with TMEM106B through umbrella sampling (US), and we provide a reliable reference for antibody design by analyzing the residues at the binding interface for six representative antibodies. − We aspire that this study will provide a novel perspective for the prevention and treatment of this new viral invasion pathway.…”

mentioning

confidence: 99%

Novel Omicron Variants Enhance Anchored Recognition of TMEM106B: A New Pathway for SARS-CoV-2 Cellular Invasion

Zhao,

Gao

2024

J. Phys. Chem. Lett.

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The recent discovery that TMEM106B serves as a receptor mediating ACE2independent SARS-CoV-2 entry into cells deserves attention, especially in the background of the frequent emergence of mutant strains. Here, the structure−dynamic features of this novel pathway are dissected deeply. Our investigation revealed that the large loop (RBD@ 471−491) could anchor TMEM106B, which was then firmly locked by another loop (RBD@444−451). The novel and widely disseminated Omicron variants (BA.2.86/EG.5.1) affect the anchoring recognition of proteins, with BA.2.86 being more likely to impact cells with limited or undetectable ACE2 expression. The large loop of the EG.5.1 variant captures TMEM106B poorly due to impaired electrostatic complementarity. Furthermore, we emphasize that antibody design against these two loops could enhance the protection of ACE2 low-expressing cells according to the alanine scanning mutagenesis of multiple antibodies. We hope this study will provide a novel perspective for the prevention and treatment against this new viral invasion pathway.

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Engineering SARS-CoV-2 neutralizing antibodies for increased potency and reduced viral escape pathways

Cited by 7 publications

References 72 publications

Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

Fully synthetic platform to rapidly generate tetravalent bispecific nanobody–based immunoglobulins

Novel Omicron Variants Enhance Anchored Recognition of TMEM106B: A New Pathway for SARS-CoV-2 Cellular Invasion

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