Human antibodies to SARS-CoV-2 with a recurring YYDRxG motif retain binding and neutralization to variants of concern including Omicron

Liu, Hejun; Kaku, Chengzi I.; Ge, Song; Yuan, Meng; Andrabi, Raiees; Burton, Dennis R.; Walker, Laura M.; Wilson, Ian A.

doi:10.1038/s42003-022-03700-6

Cited by 12 publications

(17 citation statements)

References 76 publications

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“…In addition to mAbs targeting the RBS, COVA309-38 was found to target a more conserved cryptic site at the base and lateral face of the RBD. mAbs directed at this RBD region are generally broadly reactive but weakly neutralizing, although few exceptions exist like COVA1-16 6,49 and ADI-62113 51 . COVA1-16 exhibits a special angle of approach and is able to directly compete with the receptor binding through steric hindrance, thereby neutralizing SARS-CoV-2 much more potently.…”

Section: Discussionmentioning

confidence: 99%

Broad SARS-CoV-2 Neutralization by Monoclonal and Bispecific Antibodies Derived from a Gamma-infected Individual

Guerra

Beaumont

Radić

et al. 2022

Preprint

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The worldwide pandemic caused by SARS-CoV-2 has remained a human medical threat due to the continued evolution of multiple variants that acquire resistance to vaccines and prior infection. Therefore, it is imperative to discover monoclonal antibodies (mAbs) that neutralize a broad range of SARS-CoV-2 variants for therapeutic and prophylactic use. A stabilized autologous SARS-CoV-2 spike glycoprotein was used to enrich antigen-specific B cells from an individual with a primary Gamma variant infection. Five mAbs selected from those B cells showed considerable neutralizing potency against multiple variants of concern, with COVA309-35 being the most potent against the autologous virus, as well as against Omicron BA.1 and BA.2. When combining the COVA309 mAbs as cocktails or bispecific antibody formats, the breadth and potency was significantly improved against all tested variants. In addition, the mechanism of cross-neutralization of the COVA309 mAbs was elucidated by structural analysis. Altogether these data indicate that a Gamma-infected individual can develop broadly neutralizing antibodies.

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Section: Discussionmentioning

confidence: 99%

Broad SARS-CoV-2 Neutralization by Monoclonal and Bispecific Antibodies Derived from a Gamma-infected Individual

Guerra

Beaumont

Radić

et al. 2022

Preprint

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“…These three nanobodies bind the conserved epitope site previously described for CR3022 and COVA1-16 ( 41 , 42 ). Coincidently, these nanobodies bind SARS-CoV-2 RBD in a highly similar way as YYDRxG antibodies, e.g., COVA1-16 ( Bottom ) and ADI-62113 ( 43 ). ( F ) Nb-C4-225, Nb-C4-240, and Nb-C4-255 share similar CDRH3 motifs as COVA1-16.…”

Section: Resultsmentioning

confidence: 94%

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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“…Utilizing these sequences in the pursuit of a pancoronavirus vaccine could prove useful. A very recent study showed a conserved YYDRxG motif in the CDRH-3 region of antibodies predicts broad neutralizing activity (126). Neutralizing antibodies with a YYDrxG motif bind to a conserved epitope on the RBD of the spike protein (126).…”

Section: Discussionmentioning

confidence: 99%

“…A very recent study showed a conserved YYDRxG motif in the CDRH-3 region of antibodies predicts broad neutralizing activity (126). Neutralizing antibodies with a YYDrxG motif bind to a conserved epitope on the RBD of the spike protein (126). These results suggest that an epitope-targeted strategy to identify and isolate broadly neutralizing antibodies could also be fruitful.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 epitopes inform future vaccination strategies

et al. 2022

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All currently approved COVID-19 vaccines utilize the spike protein as their immunogen. SARS-CoV-2 variants of concern (VOCs) contain mutations in the spike protein, enabling them to escape infection- and vaccination-induced immune responses to cause reinfection. New vaccines are hence being researched intensively. Studying SARS-CoV-2 epitopes is essential for vaccine design, as identifying targets of broadly neutralizing antibody responses and immunodominant T-cell epitopes reveal candidates for inclusion in next-generation COVID-19 vaccines. We summarize the major studies which have reported on SARS-CoV-2 antibody and T-cell epitopes thus far. These results suggest that a future of pan-coronavirus vaccines, which not only protect against SARS-CoV-2 but numerous other coronaviruses, may be possible. The T-cell epitopes of SARS-CoV-2 have gotten less attention than neutralizing antibody epitopes but may provide new strategies to control SARS-CoV-2 infection. T-cells target many SARS-CoV-2 antigens other than spike, recognizing numerous epitopes within these antigens, thereby limiting the chance of immune escape by VOCs that mainly possess spike protein mutations. Therefore, augmenting vaccination-induced T-cell responses against SARS-CoV-2 may provide adequate protection despite broad antibody escape by VOCs.

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Human antibodies to SARS-CoV-2 with a recurring YYDRxG motif retain binding and neutralization to variants of concern including Omicron

Cited by 12 publications

References 76 publications

Broad SARS-CoV-2 Neutralization by Monoclonal and Bispecific Antibodies Derived from a Gamma-infected Individual

Broad SARS-CoV-2 Neutralization by Monoclonal and Bispecific Antibodies Derived from a Gamma-infected Individual

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

SARS-CoV-2 epitopes inform future vaccination strategies

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